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1.
Magy Onkol ; 63(3): 239-245, 2019 09 18.
Artigo em Húngaro | MEDLINE | ID: mdl-31538441

RESUMO

Skin cancers represent the most common type of malignancy. The incidence rate of melanoma and non-melanoma skin cancer depicts a continuous rise worldwide, which is attributed mainly (but not exclusively) to the growing incidence of non-melanoma skin cancer in the elderly population. Most skin cancer types are sensitive to immunotherapy. Melanoma, Merkel cell carcinoma, cutaneous squamous cell carcinoma showed response rates of at least 40% for PD-1 inhibitor therapy as reported in recent articles. In this article we review the current and future immunotherapy agents and procedures for skin cancers.


Assuntos
Imunoterapia/mortalidade , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Carcinoma de Célula de Merkel/imunologia , Carcinoma de Célula de Merkel/patologia , Carcinoma de Célula de Merkel/terapia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Intervalo Livre de Doença , Feminino , Humanos , Hungria , Masculino , Melanoma/imunologia , Melanoma/patologia , Melanoma/terapia , Terapia de Alvo Molecular/métodos , Prognóstico , Medição de Risco , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Análise de Sobrevida , Resultado do Tratamento
2.
Anticancer Res ; 39(9): 4995-5001, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519606

RESUMO

BACKGROUND/AIM: Adoptive transfer of tumor-infiltrating lymphocytes (TILs) combined with non-myeloablative chemotherapy (NMA) has been shown to prolong survival in patients with metastatic disease. MATERIALS AND METHODS: Tissue harvesting was performed form a variety of sites. TILs were isolated, expanded and infused with bolus high-dose IL-2. RESULTS: Between 2008 and 2018, 242 lesions were resected for TILs harvesting from a range of sites form 196 patients without mortality and with minimal morbidity. Of those harvested, 75 were unable to complete therapy because of clinical deterioration during the wait period. Of 121 evaluable treated patients, there was no effect of metastatic site biopsied on the mean fold TIL expansion. Those receiving prior ipilimumab had a higher TIL fold expansion but a lower TIL fold expansion than those exposed to anti-PD1 therapy. CONCLUSION: Harvesting may be safely performed with successful TIL expansion from most sites. Prior check point inhibitory immunotherapy may potentially influence TIL fold expansion.


Assuntos
Imunoterapia Adotiva , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Melanoma/terapia , Adolescente , Adulto , Idoso , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Feminino , Humanos , Imunoterapia Adotiva/métodos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto Jovem
3.
Pol J Pathol ; 70(1): 26-32, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556548

RESUMO

The distinction between atypical Spitz lesions, conventional melanocytic nevi including Spitz nevi, and malignant melanomas may be difficult in some cases or may even be impossible. The histological assessment of these lesions is necessary to ensure correct diagnosis and treatment. Nevertheless, pathologists may be subject to suboptimal concordance in the diagnosis of some atypical lesions. In literature, certain atypical lesions have been defined differently: the terms atypical and metastasising Spitz tumour, malignant Spitz nevus, borderline and intermediate melanocytic tumour, melanocytic tumour of uncertain malignant potential MELTUMP, and low-grade malignant melanoma have been introduced to designate this heterogeneous group of pathological entities and variants. This review focuses on some issues concerning the historical background, diagnostic state-of-the-art, evolution, and classification of these complicated lesions.


Assuntos
Melanoma/diagnóstico , Nevo de Células Epitelioides e Fusiformes/diagnóstico , Neoplasias Cutâneas/diagnóstico , Diagnóstico Diferencial , Humanos , Melanoma/patologia , Nevo de Células Epitelioides e Fusiformes/patologia , Neoplasias Cutâneas/patologia
4.
Medicina (B Aires) ; 79(4): 265-270, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31487245

RESUMO

Malignant melanoma (MM) is the more aggressive form of skin cancer with a mortality rate in Argentina 1997-2001 = 1.1/100 000 in men and 0.6 in women. BRAF proto-oncogene is focus of intense research; its mutation is one of the main tumor promoters and occurs in approximately 50% of MM. Several drugs with clinical activity on BRAF mutations have been approved. The aim of the study is to evaluate the mutational status of BRAF (exon 15) in cutaneous MM biopsies and its relationship with histopathological characteristics. We carried out an observational, retrospective study of samples fixed in formaldehyde and paraffin embedded; reviewing age, sex, diagnosis, histopathological data, tumor size and percentage, viability for molecular analysis and melanin presence. We evaluated BRAF mutations with PCR/Sanger sequencing. For statistics we used Student's t test, Chi square, Wilcoxon and Fisher's exact test. We were able to purify and sequence 76% (38/49) samples, 13/38 (34%) from women and 25/38 (66%) from men, the median age being 70 years. Most frequent location: thorax 14/35 (40%). Histological type: Superficial spreading 18/38 (47%). Clark's levels, 11/38 (29%): I-II and 27/38 (71%): III, IV and V. Breslow's median: 1.6 mm. Radial growth phase 11/38 (29%) and 27/38 (71%) vertical. Presented mutations 16/38 (42%). As reported by other authors, no association was found between the mutational state of exon 15 and clinical or histopathological parameters.


Assuntos
Melanoma/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Neoplasias Cutâneas/patologia
5.
Mol Biol (Mosk) ; 53(4): 648-653, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31397438

RESUMO

Acral melanoma is one of the most aggressive and fast-growing forms of cutaneous melanoma and is characterized by a predominant location on the palms and feet. Primary tumors, metastases, and normal tissue samples from five acral melanoma patients were examined by massive parallel sequencing, focusing on the coding regions of 4100 genes involved in the origin and progression of hereditary and oncology diseases. Somatic mutations were found in genes related to cell division, proliferation, and apoptosis (BRAF, NRAS, VAV1, GATA1, and GCM2); cell adhesion (CTNND2 and ITGB4); angiogenesis (VEGFA); and the regulation of energy metabolism (BCS1L). Comparisons of target DNA sequences between morphologically normal and primary tumor tissues and between normal and metastatic tissues identified the candidate genes responsible for rapid metastasis in acral melanoma.


Assuntos
Melanoma/genética , Melanoma/patologia , Mutação , Metástase Neoplásica/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Humanos , Análise de Sequência de DNA
6.
Pan Afr Med J ; 33: 78, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31448040

RESUMO

Nearly 75% of patients with metastatic melanoma develop brain metastases. We here report the case of an 83 year-old woman hospitalized for secondarily generalized clonic seizures of the left leg with partial convulsive seizures in the Resuscitation Department. Melanoma resection of the left ankle had been performed 6 months before her admission. Neurological examination showed left ataxic crural monoparesis. Electro-encephalogram showed central and right frontal focus with left-sided dissemination. Gadolinium-enhanced magnetic resonance imaging (MRI) of the brain showed multiple supratentorial and subtentorial encephalic lesions with varying size and shape, with T1 hypersignal (A and A'), haemorrhage on T2*-weighted sequences (B and B'), gadolinium-enhancing T1 with perilesional edema on Flair sequences. Positron emission tomography (PET) showed multiple lymph node and bone metastases. Lymph node biopsy was negative for VE1 antibody with no BRAFV600E mutation by immunohistochemistry. An increase in the number of metastatic lesions was observed during control brain CT scan despite 10 brain radiotherapy sessions motivating palliative care. Epileptic seizures were controlled with levetiracetam. In patient with multiple hemorrhagic and spontaneous brain lesions, it is essential to obtain informations on patient's history of melanoma and to perform a thorough dermatologic examination in order to investigate its cause and to establish adequate therapeutic treatment.


Assuntos
Neoplasias Ósseas/diagnóstico , Neoplasias Encefálicas/diagnóstico , Melanoma/diagnóstico , Neoplasias Cutâneas/diagnóstico , Idoso de 80 Anos ou mais , Anticonvulsivantes/administração & dosagem , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/secundário , Feminino , Humanos , Levetiracetam/administração & dosagem , Metástase Linfática , Imagem por Ressonância Magnética , Melanoma/patologia , Tomografia por Emissão de Pósitrons , Convulsões/tratamento farmacológico , Convulsões/etiologia , Neoplasias Cutâneas/patologia
7.
Anticancer Res ; 39(8): 4085-4093, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366492

RESUMO

BACKGROUND/AIM: The identification of novel prognostic biomarkers for melanoma metastasis is essential to improve patient outcomes. To this aim, we characterized miRNA expression profiles in relation to metastasis in melanoma and correlated miRNAs expression with clinical-pathological factors. MATERIALS AND METHODS: MiR-145-5p, miR-150-5p, miR-182-5p, miR-203-3p, miR-205-5p and miR-211-5p expression levels were analyzed in primary cutaneous melanomas, including thin and thick melanomas, and in melanoma metastases by quantitative Real-Time PCR. RESULTS: A significantly lower miR-205-5p expression was found in metastases compared to primary melanomas. Furthermore, a progressive down-regulation of miR-205-5p expression was observed from loco-regional to distant metastasis. Significantly lower miR-145-5p and miR-203-3p expression levels were found in cases with Breslow thickness >1 mm, high Clark level, ulceration and mitotic rate ≥1/mm2 Conclusion: Our findings point to miR-205-5p as potential biomarker of distant metastases and to miR-145-5p and miR-203-3p as markers of aggressiveness in melanoma.


Assuntos
Melanoma/genética , MicroRNAs/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Neoplasias Cutâneas/patologia
8.
Chem Biol Interact ; 311: 108789, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31401089

RESUMO

The cytotoxicity of a dinuclear imine-copper (II) complex 2, and its analogous mononuclear complex 1, toward different melanoma cells, particularly human SKMEL-05 and SKMEL-147, was investigated. Complex 2, a tyrosinase mimic, showed much higher activity in comparison to complex 1, and its reactivity was verified to be remarkably activated by UVB-light, while the mononuclear compound showed a small or negligible effect. Further, a significant dependence on the melanin content in the tumor cells, both from intrinsic pigmentation or stimulated by irradiation, was observed in the case of complex 2. Similar tests with keratinocytes and melanocytes indicated a much lower sensitivity to both copper (II) complexes, even after exposition to UV light. Clonogenic assays attested that the fractions of melanoma cells survival were much lower under treatment with complex 2 compared to complex 1, both with or without previous irradiation of the cells. The process also involves generation of reactive oxygen species (ROS), as verified by EPR spectroscopy, and by using fluorescence indicators. Autophagic assays indicated a remarkable formation of cytoplasmic vacuoles in melanomas treated with complex 2, while this effect was not observed in similar treatment with complex 1. Monitoring of specific protein LC3 corroborated the simultaneous occurrence of autophagy. A balance interplay between different modes of cell death, apoptosis and autophagy, occurs when melanomas were treated with the dinuclear complex 2, in contrast to the mononuclear complex 1. These results pointed out to different mechanisms of action of such complexes, depending on its nuclearity.


Assuntos
Complexos de Coordenação/química , Cobre/química , Iminas/química , Monofenol Mono-Oxigenase/metabolismo , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Espectroscopia de Ressonância de Spin Eletrônica , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos da radiação , Humanos , Melaninas/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tubulina (Proteína)/metabolismo , Raios Ultravioleta
9.
Zhonghua Zhong Liu Za Zhi ; 41(7): 481-485, 2019 Jul 23.
Artigo em Chinês | MEDLINE | ID: mdl-31357833

RESUMO

Melanoma is a malignant tumor derived from the skin and mucous membrane, the epidemiological data showed that the incidence of melanoma elevated rapidly in the last decade. Early lymph node metastasis is a distinguishing characteristic of melanoma. The assessment of regional lymph nodes is a vital factor for melanoma staging and comprehensive therapeutic strategies. The sentinel lymph node biopsy (SLNB) plays an important role in this comprehensive diagnosis and treatment system. Completion lymph node dissection (CLND) with positive sentinel lymph node was accepted by traditional theories. But it has recently been questioned via the latest global clinical trial. CLND limited the benefit for melanoma specific survival. However, SLNB is the reliable procedure for staging and prognostic evaluation of melanoma patients with positive sentinel lymph node, and CLND can significantly improve the local control and decrease the regional recurrence according to the evidence-based medicine. The authors summary the recently correlational research of SLNB and CLND in melanoma in this review.


Assuntos
Excisão de Linfonodo/métodos , Melanoma/patologia , Melanoma/cirurgia , Biópsia de Linfonodo Sentinela/métodos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Humanos , Metástase Linfática , Recidiva Local de Neoplasia , Biópsia de Linfonodo Sentinela/tendências
10.
Hautarzt ; 70(10): 804-810, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31267179

RESUMO

BACKGROUND: Treatment of patients with malignant melanoma includes informing the patients about their rights regarding social/disability benefits. In particular, every patient has the right to rehabilitation treatment according to SGB V and IX (SGB: Sozialgesetzbuch; Social Security Code) and to an examination regarding the classification of the disability. OBJECTIVES: The present study examines the extent to which patients with invasive malignant melanoma are informed after initial diagnosis about their social rights to medical rehabilitation measures and the classification of disability. MATERIALS AND METHODS: In the course of a survey in 2014, n = 1800 German dermatological practices were contacted and provided a standardized questionnaire on several care-relevant questions, including the aforementioned ones. RESULTS: Evaluable questionnaires were submitted by n = 424 practices. In all, 52% of dermatologists stated that they regularly provided information on the right to rehabilitation, 15% sometimes, 41% rarely or never. Furthermore, 44% of dermatologists regularly, 17% sometimes and 38% rarely or never informed their patients about the classification of disability. Relevant differences were found in regional comparisons. CONCLUSIONS: Practicing dermatologists seem to transfer the information requirement to the clinics involved in the treatment. It would be beneficial if the information were also provided again by the dermatologists in private practice. In view of the known limited capacity to receive new information from patients with newly diagnosed melanoma, repeated counselling appears to be more patient-friendly.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Melanoma/terapia , Educação de Pacientes como Assunto/métodos , Direitos do Paciente , Reabilitação/legislação & jurisprudência , Neoplasias Cutâneas/terapia , Assistência ao Convalescente/normas , Avaliação da Deficiência , Humanos , Melanoma/patologia , Neoplasias Cutâneas/patologia , Inquéritos e Questionários
11.
Medicine (Baltimore) ; 98(29): e16417, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335691

RESUMO

We aimed to assess serial F-FDG PET/CT imaging according to morphological (RECIST1.1, iRECIST) and functional (PERCIST, PECRIT) criteria to predict clinical response to therapy in patients with advanced melanoma receiving immune checkpoint blocking agents.Retrospective data collection and analysis was done for 37 patients with unresectable metastatic cutaneous melanoma eligible for immunotherapy (cycles: 4 for ipilimumab and pembrolizumab/ 6 for nivolumab).F-FDG PET/CT imaging was performed prior to (F-FDG PET/CT 0) and 14 weeks after ICI onset (F-FDG PET/CT 1). Some cases during the follow-up required imaging (F-FDG PET/CT 2). Assessment of patient response to treatment was done according to RECIST1.1, iRECIST, PERCIST and PECRIT criteria.Among 37 assessed patients, 27 had 1 line of ICI, 8 had 2 lines of ICI and 2 patients had 3 lines of ICI: total of 49 PET/CTs. Mean time between initiation of ICI and F-FDG PET/CT (1 or 2) were respectively 13.82 ±â€Š4.32 and 24.73 ±â€Š9.53 weeks. Time between F-FDG PET/CT 1 and F-FDG PET/CT 2 was at mean +/- SD: 11.19w ±â€Š5.59. Median PFS was 29.62 months (range 22.52-36.71) (P = .001: RECIST 1.1), (P < .0001: iRECIST), (P = .000: PERCIST), (P = .072: PECRIT). Median OS was 36.62 months (30.46-42.78) (P = .005: RECIST 1.1), (P < .0001: iRECIST), (P = .001: PERCIST), (P = .082 PECRIT).F-FDG PET/CT could detect eventual ICI-response in patients with metastatic melanoma undergoing ICI using iRECIST and PERCIST criteria.


Assuntos
Anticorpos Monoclonais Humanizados , Ipilimumab , Melanoma , Nivolumabe , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Neoplasias Cutâneas , Tomografia Computadorizada por Raios X/métodos , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos Antineoplásicos , Feminino , Fluordesoxiglucose F18/farmacologia , Humanos , Ipilimumab/administração & dosagem , Ipilimumab/efeitos adversos , Masculino , Melanoma/diagnóstico , Melanoma/tratamento farmacológico , Melanoma/patologia , Estadiamento de Neoplasias , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Valor Preditivo dos Testes , Prognóstico , Compostos Radiofarmacêuticos/farmacologia , Reprodutibilidade dos Testes , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia
12.
Medicine (Baltimore) ; 98(30): e16366, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348237

RESUMO

RATIONALE: Primary melanomas of the female genital tract are rare and usually occur in the vulva and vagina. Involvement of the cervix, uterus, and ovary are extremely rare. Surgery and adjuvant therapy remain the mainstay of treatment. The majority of patients experience poor long-term survival. This report aimed at highlighting an extremely rare case of primary melanoma of the female genitalia, synchronously involving the vulva and uterine cervix. PATIENT CONCERNS: A 58-year-old multiparous female presented with postmenopausal bleeding for 10 days. DIAGNOSES: Speculum examination and histologic analysis of the surgical specimens revealed synchronous involvement of the vulva and uterine cervix by malignant melanoma. According to the American Joint Committee on Cancer stage grouping for melanoma, this tumor was at stage V. INTERVENTIONS: The patient subsequently underwent radical surgery and postoperative chemotherapy. OUTCOMES: She has been on regular follow-up, and is now free of disease for 50 months after the operation. LESSONS: Primary melanomas of the female genital tract have biologically aggressive characteristics. Optimal management consists of individualized surgery and adjuvant therapy. However, early recognition and prompt intervention offer maximal benefit from treatment.


Assuntos
Neoplasias dos Genitais Femininos/patologia , Melanoma/patologia , Colo do Útero/patologia , Feminino , Neoplasias dos Genitais Femininos/terapia , Humanos , Melanoma/terapia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Vulva/patologia
13.
Medicine (Baltimore) ; 98(30): e16542, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348273

RESUMO

Pembrolizumab has been approved in the United States for treating advanced melanoma for >4 years. We examined real-world pembrolizumab use and associated outcomes in US oncology clinical practices, including patients who would not be eligible for clinical trials.Flatiron Health longitudinal database was used to identify adult patients with advanced melanoma initiating ≥1 dose of pembrolizumab from September 4, 2014, through December 31, 2016, with follow-up through December 31, 2017. Patients in any clinical trial during the study period were excluded. Overall survival (OS) and time on treatment from pembrolizumab initiation were analyzed using the Kaplan-Meier (KM) method. Subgroup analyses were conducted to examine OS for several patient characteristics including Eastern Cooperative Oncology Group (ECOG) performance status >1, brain metastases, and corticosteroids before pembrolizumab initiation.Pembrolizumab was administered to 315 (59%), 152 (29%), and 65 (12%) patients as first-, second-, and third-line/later therapy. Median age at pembrolizumab initiation was 68 years (range, 18-84); most patients were male (66%) and white (94%). Of those with available data, 38% had BRAF-mutant melanoma, 21% had elevated lactate dehydrogenase (LDH) level, and 23% had ECOG >1. Overall, 18% had brain metastases, and 23% were prescribed corticosteroids <3 months before initiating pembrolizumab. Median study follow-up was 12.9 months (range, 0.03-39.6). Median OS was 21.8 months (95% confidence interval [CI] 16.8-29.1); KM 1-year and 2-year survival rates were 61% and 48%, respectively; and median time on pembrolizumab treatment was 4.9 months (95% CI 3.7-5.5). Median OS for first-line pembrolizumab was not reached, and for second-line and third-line/later was 13.9 and 12.5 months, respectively (log-rank P = .0095). Significantly better OS (all P ≤.0014, log-rank test) was evident for patients with ECOG performance status (PS) of 0 to 1 (vs >1), normal (vs elevated) LDH level, and no (vs yes) corticosteroid prescription <3 months before. No difference was recorded in OS by brain metastases (log-rank P = .22) or BRAF mutation status (log-rank P = .90).These findings support effectiveness of pembrolizumab in the real-world clinical setting and provide important insights into patient characteristics and outcomes associated with pembrolizumab therapy for a heterogeneous patient population with advanced melanoma, including patients who would not be eligible for clinical trials.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Melanoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Estudos Longitudinais , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
14.
J Cancer Res Clin Oncol ; 145(9): 2241-2250, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31342168

RESUMO

PURPOSE: The tripartite motif (TRIM)16 acts as a tumour suppressor in both squamous cell carcinoma (SCC) and melanoma. TRIM16 is known to be secreted by keratinocytes, but no studies have been reported yet to assess the relationship between TRIM16 keratinocyte expression and melanoma development. METHODS: To study the role of TRIM16 in skin cancer development, we developed a keratinocyte TRIM16-specific knockout mouse model, and used the classical two-stage skin carcinogenesis challenge method, to assess the loss of keratinocyte TRIM16 on both papilloma, SCC and melanoma development in the skin after topical carcinogen treatment. RESULTS: Heterozygous, but not homozygous, TRIM16 knockout mice exhibited an accelerated development of skin papillomas and melanomas, larger melanoma lesions and an increased potential for lymph node metastasis. CONCLUSION: This study provides the first evidence that keratinocyte loss of the putative melanoma tumour suppressor protein, TRIM16, enhances melanomagenesis. Our data also suggest that TRIM16 expression in keratinocytes is involved in cross talk between keratinocytes and melanocytes, and has a role in melanoma tumorigenesis.


Assuntos
Proteínas de Transporte/genética , Queratinócitos/metabolismo , Perda de Heterozigosidade/fisiologia , Linfonodos/metabolismo , Melanócitos/metabolismo , Melanoma/genética , Neoplasias Cutâneas/genética , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proteínas de Transporte/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células Cultivadas , Regulação Neoplásica da Expressão Gênica , Queratinócitos/patologia , Linfonodos/patologia , Metástase Linfática , Melanócitos/patologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Knockout , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
15.
Gene ; 716: 144010, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31352009

RESUMO

Alternative splicing can generate multiple protein messages from a single gene and has emerged as an important mechanism to regulate cancer pathways. The human SAT1 gene produces two transcript variants: one translates spermidine/spermine N-1 acetyltransferase (SSAT1), the rate-limiting enzyme in the catabolism of polyamines, and the other generates SSATX, which has largely unknown biological functions. Here, we used experimental data and analyses of several melanoma transcriptome datasets to reveal that SSATX is weakly expressed in melanoma cells. SSATX knockdown promoted the proliferation, migration, and invasion of human melanoma cells via the activation of the Wnt signaling pathway in a manner that was independent of SSAT1 expression. Based on our data, we propose that SSATX functions as a long non-coding RNA prior to its degradation in melanoma cells. Overall, our findings indicate that SSATX acts as a tumor suppressor, which may aid the future diagnosis and treatment of melanoma.


Assuntos
Melanoma/genética , RNA Longo não Codificante/fisiologia , Acetiltransferases/genética , Processamento Alternativo , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Regulação para Baixo , Técnicas de Silenciamento de Genes , Humanos , Melanoma/metabolismo , Melanoma/patologia , Invasividade Neoplásica , RNA Longo não Codificante/genética , Via de Sinalização Wnt
16.
Lancet ; 394(10197): 471-477, 2019 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-31280965

RESUMO

BACKGROUND: The optimal surgical excision margins are uncertain for patients with thick (>2 mm) localised cutaneous melanomas. In our previous report of this multicentre, randomised controlled trial, with a median follow-up of 6·7 years, we showed that a narrow excision margin (2 cm vs 4 cm) did not affect melanoma-specific nor overall survival. Here, we present extended follow-up of this cohort. METHODS: In this open-label, multicentre randomised controlled trial, we recruited patients from 53 hospitals in Sweden, Denmark, Estonia, and Norway. We enrolled clinically staged patients aged 75 years or younger diagnosed with localised cutaneous melanoma thicker than 2 mm, and with primary site on the trunk or upper or lower extremities. Patients were randomly allocated (1:1) to treatment either with a 2-cm or a 4-cm excision margin. A physician enrolled the patients after histological confirmation of a cutaneous melanoma thicker than 2 mm. Some patients were enrolled by a physician acting as responsible for clinical care and as a trial investigator (follow-up, data collection, and manuscript writing). In other cases physicians not involved in running the trial enrolled patients. Randomisation was done by telephone call to a randomisation office, by sealed envelope, or by computer generated lists using permuted blocks. Patients were stratified according to geographical region. No part of the trial was masked. The primary outcome in this extended follow-up study was overall survival and the co-primary outcome was melanoma-specific survival. All analyses were done on an intention-to-treat basis. The study is registered with ClinicalTrials.gov, number NCT03638492. FINDINGS: Between Jan 22, 1992, and May 19, 2004, 936 clinically staged patients were recruited and randomly assigned to a 4-cm excision margin (n=465) or a 2-cm excision margin (n=471). At a median overall follow-up of 19·6 years (235 months, IQR 200-260), 621 deaths were reported-304 (49%) in the 2-cm group and 317 (51%) in the 4-cm group (unadjusted HR 0·98, 95% CI 0·83-1·14; p=0·75). 397 deaths were attributed to cutaneous melanoma-192 (48%) in the 2-cm excision margin group and 205 (52%) in the 4-cm excision margin group (unadjusted HR 0·95, 95% CI 0·78-1·16, p=0·61). INTERPRETATION: A 2-cm excision margin was safe for patients with thick (>2 mm) localised cutaneous melanoma at a follow-up of median 19·6 years. These findings support the use of 2-cm excision margins in current clinical practice. FUNDING: The Swedish Cancer Society, Stockholm Cancer Society, the Swedish Society for Medical Research, Radiumhemmet Research funds, Stockholm County Council, Wallström funds.


Assuntos
Extremidade Inferior/patologia , Melanoma/mortalidade , Melanoma/cirurgia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/cirurgia , Tronco/patologia , Extremidade Superior/patologia , Idoso , Dinamarca , Estônia , Feminino , Humanos , Análise de Intenção de Tratamento , Extremidade Inferior/cirurgia , Masculino , Margens de Excisão , Melanoma/patologia , Pessoa de Meia-Idade , Mortalidade , Noruega , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Suécia , Tronco/cirurgia , Resultado do Tratamento , Extremidade Superior/cirurgia
17.
Int J Nanomedicine ; 14: 4319-4331, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354263

RESUMO

Objective: The study aimed to synthesize superparamagnetic NaYF4:Yb,Er@PE3@Fe3O4 upconversion nanoprobes and to study their photothermal effects for the treatment of malignant melanoma. Methods: Morphological characteristics of the synthesized nanoprobes were examined by scanning electron microscopy. Their biocompatibility and biodistribution profiles were assessed through blood routine/biochemistry tests and the inductively coupled plasma/optical emission spectrometry-based analysis of tissue metal elements. Their photothermal conversion efficiency and their potential as contrast agents for upconversion luminescence (UCL)/magnetic resonance imaging (MRI) dual-modal imaging were tested. Efficacy in photothermal therapy, which was achieved by combining nanoprobes with near-infrared (NIR) irradiation, was evaluated in both A375 cell line and BALB/c mice models. The underlying mechanisms were interrogated by molecular approaches including the MTT assay, flow cytometry, semiquantitative PCR, western blot, and immunohistochemistry. Results: 1) Our synthesized NaYF4:Yb,Er@PE3@Fe3O4 nanoprobes exhibited a uniform cubic morphology with a diameter of ~50 nm. Subcutaneous administration led to no severe, long-lasting adverse effects in mice, possibly due to complete removal of these nanomaterials within one month. 2) Our nanoprobes possessed superior photothermal conversion efficiency and strong contrasting effects during UCL/MRI dual-modal imaging, corroborating their applications in imaging-guided photothermal therapy. 3) Combinatorial treatment of these nanoprobes with NIR irradiation induced profound apoptosis/necrosis in A375 cells. Similarly, the same treatment modality led to strong therapeutic effects in BALB/c mice implanted with A375 tumor xenografts. Mechanistic studies suggested an involvement of heat shock protein 70 in mediating the observed antitumor effects of our nanoprobes. Conclusion: Our study describes a convenient method to synthesize a new type of superparamagnetic upconversion nanoprobes, which possess high biocompatibility and can be used in imaging-guided photothermal therapy for the treatment of malignant melanoma. Importantly, our findings will promote clinical applications of NaYF4:Yb,Er@PE3@Fe3O4 as novel theranostic agents in treating melanoma and many other tumors.


Assuntos
Érbio/química , Fluoretos/química , Hipertermia Induzida , Nanopartículas de Magnetita/uso terapêutico , Melanoma/terapia , Fototerapia , Ítrio/química , Animais , Linhagem Celular Tumoral , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Raios Infravermelhos , Imagem por Ressonância Magnética/métodos , Nanopartículas de Magnetita/ultraestrutura , Melanoma/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Distribuição Tecidual , Carga Tumoral
18.
Medicine (Baltimore) ; 98(28): e16328, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305421

RESUMO

Recently, the effectiveness of novel immune checkpoint inhibitors and BRAF-directed therapies has been demonstrated in advanced melanoma trial populations. Limited research, however, has evaluated the impact of these therapies in a real-world setting. The aim of this study was to evaluate treatment patterns and clinical outcomes among advanced melanoma patients treated with modern therapies within community oncology clinics. Adult patients with advanced melanoma who initiated treatment within the US Oncology Network between 1/1/14 and 12/31/16 were included. Data were sourced from electronic healthcare records. Patients were followed through 12/31/17. Descriptive analyses were performed to assess patient and treatment characteristics and Kaplan-Meier methods were used for time-to-event outcomes. In total, 484 patients met eligibility criteria (32.0% with brain metastasis, 12.6% with Eastern Cooperative Oncology Group performance status ≥2). In the first-line (1L) setting during the study period, 37.0% received anti-PD1 monotherapies, 26.4% ipilimumab monotherapy, 19.8% BRAF/MEK combination therapy, 6.4% BRAF or MEK monotherapy, 4.1% ipilimumab/nivolumab combination therapy and 6.2% other regimens. Differences in baseline demographic and clinical characteristics were observed across treatment groups. For the overall study population, the median (95% confidence interval) estimates for overall survival, time to next treatment and progression-free survival were 20.7 (16.0, 26.8), 5.8 (5.3, 6.5), and 4.9 (4.2, 5.7) months, respectively. The results of this study provide real-world insight into advanced melanoma treatment trends and clinical outcomes, including high utilization of immunotherapies and BRAF/MEK combination therapy. Future research can explore underlying differences in patient subpopulations and the sequence of therapies across lines of therapy.


Assuntos
Melanoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Feminino , Seguimentos , Humanos , Masculino , Melanoma/epidemiologia , Melanoma/patologia , Pessoa de Meia-Idade , Padrões de Prática Médica , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
19.
Medicine (Baltimore) ; 98(28): e16395, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305447

RESUMO

RATIONALE: The main cause of death in melanoma patients is widespread metastases as it can metastasize to almost every organ. However, melanoma skeletal muscle metastases (MSMM) are exceptional, and only a few cases of MSMM to the rectus abdominis muscles have been previously described. And our case maybe the first reported case in Asia region. PATIENT CONCERNS: A 45-year-old man with history of right scalp melanoma, pT3aN0M0, stage IIA status post wide excision with 2 cm safe margin and right neck lymph node dissection at 5 years before. He had an almost 5 years disease-free period but presented to our clinic due to intermittent abdominal sharp pain for 1 to 2 months, with a palpable soft tissue mass over his right abdomen. Metastatic melanoma to rectus abdominis muscles was highly suspected. INTERVENTIONS: The patient subsequently underwent radical en-block extraperitoneal 15 cm segmental resection of the right rectus abdominis muscle including tumor mass. The resected tumor was a black-gray colored solid mass, and the final histologic study showed a metastasis of melanoma. OUTCOMES: Postoperative course of the patient was uneventful, and the right abdominal pain was improved. The patient was referred for further target therapy, but passed away half a year later due to multiple metastasis. LESSONS: Scalp melanoma with isolated rectus muscle metastasis is extremely rare especially for a young aged patient who had an almost 5-year disease-free period. Surgery is a potentially curative therapy for patients with isolated metastatic melanoma. The goal is negative resection margins, in order to avoid local recurrences. Radical compartmental surgery should be considered for selected stage IV melanoma patients with sole rectus abdominis MSMM, whose disease could be amenable to complete resection, in preliminary procedure to prolong disease-free survival time. For oligometastatic disease, surgical resection is sometimes useful in carefully selected patients after systemic therapy; also, it could be performed as symptomatic treatment.


Assuntos
Neoplasias Abdominais/secundário , Neoplasias de Cabeça e Pescoço/patologia , Melanoma/patologia , Neoplasias Musculares/secundário , Neoplasias Cutâneas/patologia , Neoplasias Abdominais/diagnóstico , Neoplasias Abdominais/cirurgia , Evolução Fatal , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Masculino , Melanoma/diagnóstico , Melanoma/cirurgia , Pessoa de Meia-Idade , Neoplasias Musculares/diagnóstico , Neoplasias Musculares/cirurgia , Reto do Abdome , Couro Cabeludo , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/cirurgia
20.
Nat Commun ; 10(1): 2782, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31239444

RESUMO

Melanoma is one of the most deadly and therapy-resistant cancers. Here we show that N6-methyladenosine (m6A) mRNA demethylation by fat mass and obesity-associated protein (FTO) increases melanoma growth and decreases response to anti-PD-1 blockade immunotherapy. FTO level is increased in human melanoma and enhances melanoma tumorigenesis in mice. FTO is induced by metabolic starvation stress through the autophagy and NF-κB pathway. Knockdown of FTO increases m6A methylation in the critical protumorigenic melanoma cell-intrinsic genes including PD-1 (PDCD1), CXCR4, and SOX10, leading to increased RNA decay through the m6A reader YTHDF2. Knockdown of FTO sensitizes melanoma cells to interferon gamma (IFNγ) and sensitizes melanoma to anti-PD-1 treatment in mice, depending on adaptive immunity. Our findings demonstrate a crucial role of FTO as an m6A demethylase in promoting melanoma tumorigenesis and anti-PD-1 resistance, and suggest that the combination of FTO inhibition with anti-PD-1 blockade may reduce the resistance to immunotherapy in melanoma.


Assuntos
Adenosina/análogos & derivados , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Anticorpos Monoclonais/administração & dosagem , Melanoma/enzimologia , Melanoma/terapia , Adenosina/genética , Adenosina/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Animais , Carcinogênese , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Desmetilação , Feminino , Humanos , Imunoterapia , Melanoma/genética , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
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