RESUMO

BACKGROUND: Melanoma, the most lethal form of skin cancer, has undergone a transformative treatment shift with the advent of checkpoint blockade immunotherapy (CBI). Understanding the intricate network of immune cells infiltrating the tumor and orchestrating the control of melanoma cells and the response to CBI is currently of utmost importance. There is evidence underscoring the significance of tissue-resident memory (TRM) CD8 T cells and classic dendritic cell type 1 (cDC1) in cancer protection. Transcriptomic studies also support the existence of a TCF7+ (encoding TCF1) T cell as the most important for immunotherapy response, although uncertainty exists about whether there is a TCF1+TRM T cell due to evidence indicating TCF1 downregulation for tissue residency activation. METHODS: We used multiplexed immunofluorescence and spectral flow cytometry to evaluate TRM CD8 T cells and cDC1 in two melanoma patient cohorts: one immunotherapy-naive and the other receiving immunotherapy. The first cohort was divided between patients free of disease or with metastasis 2 years postdiagnosis while the second between CBI responders and non-responders. RESULTS: Our study identifies two CD8+TRM subsets, TCF1+ and TCF1-, correlating with melanoma protection. TCF1+TRM cells show heightened expression of IFN-γ and Ki67 while TCF1- TRM cells exhibit increased expression of cytotoxic molecules. In metastatic patients, TRM subsets undergo a shift in marker expression, with the TCF1- subset displaying increased expression of exhaustion markers. We observed a close spatial correlation between cDC1s and TRMs, with TCF1+TRM/cDC1 pairs enriched in the stroma and TCF1- TRM/cDC1 pairs in tumor areas. Notably, these TCF1- TRMs express cytotoxic molecules and are associated with apoptotic melanoma cells. Both TCF1+ and TCF1- TRM subsets, alongside cDC1, prove relevant to CBI response. CONCLUSIONS: Our study supports the importance of TRM CD8 T cells and cDC1 in melanoma protection while also highlighting the existence of functionally distinctive TCF1+ and TCF1- TRM subsets, both crucial for melanoma control and CBI response.

Assuntos

Linfócitos T CD8-Positivos , Fator 1-alfa Nuclear de Hepatócito , Imunoterapia , Melanoma , Humanos , Melanoma/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Imunoterapia/métodos , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Feminino , Masculino , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Idoso

RESUMO

OBJECTIVES: • Gather a panel of Latin American experts in testing and treating BRAF-melanoma. • Describe the current landscape of BRAF-mutated melanoma in Latin America. • Outline the current gaps in testing and recommend improvements for testing and treating BRAF-mutated melanoma in the region. INTRODUCTION: Melanoma prevalence in Latin America is lower than in high- and middle-income countries. However, recent data indicate that the region's incidence and mortality are rising, with more stage IV patients being diagnosed. According to international clinical practice guidelines, conducting BRAF-mutation testing in patients with stage III or stage IV melanoma and high-risk resected disease is imperative. Still, BRAF-mutation testing and targeted therapies are inconsistently available in the region. METHODS: Americas Health Foundation convened a meeting of Latin American experts on BRAF-mutated melanoma to develop guidelines and recommendations for diagnosis through treatment. RESULTS AND CONCLUSIONS: Some recommendations for improving diagnostics through improving access and reducing the cost of BRAF-mutation testing, enhancing efficiency in pathology laboratories, and creating country-specific local guidelines. The panel also gave treatment recommendations for neo-adjuvant therapy, adjuvant therapy, and therapy for patients with metastatic disease in Latin America.

Assuntos

Melanoma , Mutação , Proteínas Proto-Oncogênicas B-raf , Humanos , Melanoma/genética , Melanoma/terapia , Melanoma/diagnóstico , Proteínas Proto-Oncogênicas B-raf/genética , América Latina/epidemiologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/diagnóstico , Guias de Prática Clínica como Assunto

RESUMO

Cancer vaccines are gaining ground as immunotherapy options. We have previously demonstrated in cutaneous melanoma (CM) patients that adjuvant treatment with VACCIMEL, a mixture of four irradiated CM cell lines co-adjuvanted with BCG and GM-CSF, increases the cellular immune response to melanocyte differentiation antigens, cancer-testis antigens and neoantigens, with respect to basal levels. On the other hand, it is also known that treatment with anti-PD-1 monoclonal antibodies (MAbs), acting on pre-existing tumor-reactive lymphocytes, induces clinical responses in CM patients, albeit in a fraction of treated patients. A combination of both treatments would appear therefore desirable. In this paper, we describe CM patients who, having progressed even years after vaccination, were treated with anti-PD-1 MAbs. In 5/5 of such progressor patients, complete responses were obtained which lasted between 3 and 65+ months. Three of the patients remain disease-free and two recurred. One of the patients passed away after a recurrence of brain metastases. We suggest that clonally expanded reactive lymphocytes induced by VACCIMEL partially remain as memory cells, which may be recalled after tumor recurrence and may foster ulterior activity of anti-PD-1 MAbs.

Assuntos

Anticorpos Monoclonais , Vacinas Anticâncer , Melanoma Maligno Cutâneo , Receptor de Morte Celular Programada 1 , Neoplasias Cutâneas , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adjuvantes Imunológicos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma Maligno Cutâneo/imunologia , Melanoma Maligno Cutâneo/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapia , Resultado do Tratamento

RESUMO

BACKGROUND: Mycosis fungoides is the most frequent form of cutaneous T-cell lymphoma. It is characterized by a chronic, slow, and progressive course, and is associated with mortality rates that depend on several factors, such as clinical staging. A median survival time of up to 13 months is found in patients with advanced stages that require more aggressive treatments, with greater toxicity and higher costs. In Latin America, few prognostic studies of the disease are available. OBJECTIVE: To determine the rate of progression from early stages (IA, IB, IIA) to more advanced stages (> IIB) in patients older than 18 years with mycosis fungoides treated at two medical centers in Colombia between January 1, 2010, and December 31, 2019. METHODS: Retrospective cohort study with a longitudinal design. RESULTS: 112 patients diagnosed with early mycosis fungoides were included. 56.2% were male (n = 63), with a median age of 53 years (IQR 43‒67). The most frequent clinical variant was classic (67.9%; n = 76), followed by folliculotropic (16%; n = 18), and hypopigmented (10.7%; n = 12). The most common first-line treatment was NB-UVB phototherapy (27.7%; n = 31), followed by PUVA phototherapy (25.8%; n = 29%), and topical corticosteroids (25%; n = 28). The global rate of disease progression was 8% (n = 9), with an overall mortality of 12.5% (n = 14). STUDY LIMITATIONS: Its retrospective design and the lack of molecular studies for case characterization. CONCLUSIONS: Early mycosis fungoides is a disease with a good prognosis in most patients, with a progression rate of 8% (n = 9).

Assuntos

Progressão da Doença , Micose Fungoide , Estadiamento de Neoplasias , Neoplasias Cutâneas , Humanos , Micose Fungoide/patologia , Micose Fungoide/terapia , Micose Fungoide/mortalidade , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/terapia , Adulto , Idoso , Colômbia/epidemiologia , Estudos Longitudinais , Fatores de Risco , Prognóstico , Terapia PUVA , Fatores de Tempo , Terapia Ultravioleta

RESUMO

Background: 5-Fluorouracil (5-FU) is a first-line drug to treat cutaneous field cancerization (CFC). There are few clinical trials with topical colchicine (COL). Objective: To evaluate the effectiveness of 0.5% COL cream versus 5% 5-FU cream in the treatment of CFC. Method: This was a randomized, open, self-controlled clinical trial. Forty-five patients (90 forearms), with three to ten actinic keratoses (AK) on each forearm, used 0.5% COL cream 2×/day for seven days on one forearm, and 5% 5-FU cream 2× /day, for 21 days, on the other forearm. The dosages were defined based on previous clinical trials for each drug. Adverse effects were evaluated after 14 days and outcomes after 90 days of inclusion. The primary outcome was complete AK clearance and the secondary outcomes were: partial clearance (≥50%), reduction in AK count, assessment of the Forearm Photoaging Scale (FPS), AK Severity Score (AKSS), and adverse effects. Results: After 90 days, there was complete clearance of AK in 37% (95% CI 24%­49%) and partial clearance in 85% (95% CI 76%­93%) of the forearms treated with 5-FU,versus 17% (95% CI 7%­27%) and 78% (95% CI 66%­88%) for COL (p > 0.07). There was a percentage reduction of 75% in the AK count of the forearms treated with 5-FU (95% CI 66%­83%) and 64% in those treated with COL (95% CI 55%­72%). Regarding FPS and AKSS, there was improvement in both groups, with no difference regarding FPS (p = 0.654), and 5-FU superiority for AKSS (p = 0.012). Study limitations: Single-center study.

Assuntos

Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Neoplasias Cutâneas/terapia , Colchicina/administração & dosagem , Ceratose Actínica/terapia , Fluoruracila/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Resultado do Tratamento , Creme para a Pele/uso terapêutico

RESUMO

PURPOSE: Palpebral congenital melanocytic nevi (PCMN) is a rare congenital skin lesion affecting the eyelids that can lead to cosmetic and psychological concerns and potential health risks such as malignancy. Several authors have analyzed therapeutical strategies to treat PCMN. However, there was no consensus in the literature. This systematic review aimed to evaluate the effectiveness, safety, and success of treatments of PCMN. METHODS: We conducted a systematic review following PRISMA guidelines from October 2022 to April 2023. We included all types of study designs that described or compared PCMN treatments and interventions, as well as histology, recurrence, adverse events, patient satisfaction, and malignant transformation. The search strategy was based on specific search words through the following databases: PubMed, Embase, Latin American and Caribbean Health Sciences Literature (Lilacs), Web of Science, and Scopus. Ongoing studies and gray literature studies were included. RESULTS: We analyzed 25 case reports with 148 participants. The effectiveness, success, and satisfaction with various treatments for PCMN depend on the specific treatment method and the individual patient's case. CONCLUSIONS: Most of the studies showed that surgical procedures (exeresis) are able to treat PCMN in the eyelid. The variability in outcomes emphasizes the importance of further research to better understand the most effective and safe approaches for treating congenital melanocytic nevi.

Assuntos

Nevo Pigmentado , Neoplasias Cutâneas , Humanos , Nevo Pigmentado/cirurgia , Nevo Pigmentado/congênito , Pálpebras/patologia , Pele/patologia , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/patologia

RESUMO

Merkel cell carcinoma (MCC) is an aggressive and rare cutaneous neuroendocrine carcinoma that predominantly affects the sun-damaged skin of the head and neck region, extremities, and trunk of older white individuals. Microscopically, MCC is characterized by nests or sheets of uniform small round blue cells with scant cytoplasm, granular nuclei with a salt-and-pepper chromatin pattern, high proliferative activity, and occasional necrosis. They are usually positive for epithelial and neuroendocrine markers, particularly for cytokeratin 20 and AE1/AE3 in a paranuclear dot-like staining. We herein contribute by reporting a case of MCC affecting the auricular pavilion of a 66-year-old female patient from Campinas, Brazil. Additionally, a review of the current literature is also included to analyze all the cases that have been reported in the English-language literature, totalizing 27 cases of MCC on the external ear. The 5-year overall survival rate for individuals with localized MCC is 50% and the most common treatment choice is the combination of surgery with adjuvant radiotherapy and sentinel lymph node biopsy.

Assuntos

Carcinoma de Célula de Merkel , Neoplasias Cutâneas , Feminino , Humanos , Idoso , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma de Célula de Merkel/terapia , Carcinoma de Célula de Merkel/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/patologia , Biópsia de Linfonodo Sentinela , Radioterapia Adjuvante , Pescoço/patologia

RESUMO

Introduction: Tissue biomarkers that aid in identifying cutaneous melanoma (CM) patients who will benefit from adjuvant immunotherapy are of crucial interest. Metastatic tumor-draining lymph nodes (mTDLN) are the first encounter site between the metastatic CM cells and an organized immune structure. Therefore, their study may reveal mechanisms that could influence patients´ outcomes. Methods: Twenty-nine stage-III CM patients enrolled in clinical trials to study the vaccine VACCIMEL were included in this retrospective study. After radical mTDLN dissection, patients were treated with VACCIMEL (n=22) or IFNα-2b (n=6), unless rapid progression (n=1). Distant Metastasis-Free Survival (DMFS) was selected as an end-point. Two cohorts of patients were selected: one with a good outcome (GO) (n=17; median DMFS 130.0 months), and another with a bad outcome (BO) (n=12; median DMFS 8.5 months). We analyzed by immunohistochemistry and immunofluorescence the expression of relevant biomarkers to tumor-cell biology and immune cells and structures in mTDLN, both in the tumor and peritumoral areas. Results: In BO patients, highly replicating Ki-67+ tumor cells, low tumor HLA-I expression and abundant FoxP3+ lymphocytes were found (p=0.037; p=0.056 and p=0.021). In GO patients, the most favorable biomarkers for prolonged DMFS were the abundance of peri- and intra-tumoral CD11c+ cells (p=0.0002 and p=0.001), peri-tumoral DC-LAMP+ dendritic cells (DCs) (p=0.001), and PNAd+ High Endothelial Venules (HEVs) (p=0.004). Most strikingly, we describe in GO patients a peculiar, heterogeneous structure that we named FAPS (Favoring Antigen-Presenting Structure), a triad composed of DC, HEV and CD62L+ naïve lymphocytes, whose postulated role would be to favor tumor antigen (Ag) priming of incoming naïve lymphocytes. We also found in GO patients a preferential tumor infiltration of CD8+ and CD20+ lymphocytes (p=0.004 and p=0.027), as well as peritumoral CD20+ aggregates, with no CD21+ follicular dendritic cells detected (p=0.023). Heterogeneous infiltration with CD64+CD68-CD163-, CD64+CD68+CD163- and CD64+CD68+CD163+ macrophages were observed in both cohorts. Discussion: The analysis of mTDLN in GO and BO patients revealed marked differences. This work highlights the importance of analyzing resected mTDLN from CM patients and suggests a correlation between tumor and immune characteristics that may be associated with a spontaneous or vaccine-induced long DMFS. These results should be confirmed in prospective studies.

Assuntos

Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/terapia , Neoplasias Cutâneas/terapia , Vênulas , Estudos Prospectivos , Estudos Retrospectivos , Adjuvantes Imunológicos , Adjuvantes Farmacêuticos , Linfonodos , Imunoterapia , Células Dendríticas , Melanoma Maligno Cutâneo

Assuntos

Humanos , Neoplasias Cutâneas/terapia , Dermoscopia/métodos , Melanoma/terapia , Eficácia , Análise Custo-Benefício

RESUMO

INTRODUÇÃO: O carcinoma basocelular (CB) compreende de 80% a 90% dos casos de câncer de pele não melanoma e o mais frequente entre todas as neoplasias malignas diagnosticadas. A primeira linha de tratamento do carcinoma basocelular é a excisão cirúrgica. Para pacientes inoperáveis ou com tumores de baixo risco, a terapia fotodinâmica é um tratamento em duas etapas que consiste na aplicação de um fotossensibilizador seguida por um período de incubação por irradiação. Entre os fotossensibilizadores utilizados na terapia estão o ácido 5-aminolevulínico (ALA) e seu éster, o aminolevulinato de metila (metil-ALA). Apenas o metil-ALA possui registro sanitário válido no Brasil. PERGUNTA: A terapia fotodinâmica com metil-ALA é eficaz, segura e custo-efetiva para o tratamento de carcinoma basocelular quando comparada à excisão cirúrgica? EVIDÊNCIAS CLÍNICAS: Foi realizada um overview de revisões sistemáticas para identificar uma revisão que contemplasse a pergunta de pesquisa e atendesse aos critérios de elegibilidade. Para eleger a de melhor qualidade metodológica foi realizada a avali

Assuntos

Humanos , Fotoquimioterapia/métodos , Neoplasias Cutâneas/terapia , Síndrome do Nevo Basocelular/terapia , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economia