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1.
N Engl J Med ; 385(13): 1196-1206, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34551229

RESUMO

BACKGROUND: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells. METHODS: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival. RESULTS: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported. CONCLUSIONS: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).


Assuntos
Antineoplásicos/uso terapêutico , Melanoma/secundário , Neoplasias Uveais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/efeitos adversos , Síndrome da Liberação de Citocina/induzido quimicamente , Dacarbazina/uso terapêutico , Exantema/induzido quimicamente , Feminino , Humanos , Ipilimumab/uso terapêutico , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Pessoa de Meia-Idade , Análise de Sobrevida , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/mortalidade
2.
Int J Mol Sci ; 22(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34502169

RESUMO

Cutaneous melanoma (CM) is the deadliest skin cancer, whose molecular pathways underlying its malignancy remain unclear. Therefore, new information to guide evidence-based clinical decisions is required. Adenosine diphosphate (ADP)-ribosylation factor-like (ARL) proteins are membrane trafficking regulators whose biological relevance in CM is undetermined. Here, we investigated ARL expression and its impact on CM prognosis and immune microenvironment through integrated bioinformatics analysis. Our study found that all 22 ARLs are differentially expressed in CM. Specifically, ARL1 and ARL11 are upregulated and ARL15 is downregulated regardless of mutational frequency or copy number variations. According to TCGA data, ARL1 and ARL15 represent independent prognostic factors in CM as well as ARL11 based on GEPIA and OncoLnc. To investigate the mechanisms by which ARL1 and ARL11 increase patient survival while ARL15 reduces it, we evaluated their correlation with the immune microenvironment. CD4+ T cells and neutrophil infiltrates are significantly increased by ARL1 expression. Furthermore, ARL11 expression was correlated with 17 out of 21 immune infiltrates, including CD8+ T cells and M2 macrophages, described as having anti-tumoral activity. Likewise, ARL11 is interconnected with ZAP70, ADAM17, and P2RX7, which are implicated in immune cell activation. Collectively, this study provides the first evidence that ARL1, ARL11, and ARL15 may influence CM progression, prognosis, and immune microenvironment remodeling.


Assuntos
Fatores de Ribosilação do ADP/genética , Fatores de Ribosilação do ADP/metabolismo , Biologia Computacional , Suscetibilidade a Doenças , Melanoma/etiologia , Melanoma/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/metabolismo , Animais , Biomarcadores Tumorais , Comunicação Celular , Biologia Computacional/métodos , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Melanoma/diagnóstico , Melanoma/mortalidade , Metástase Neoplásica , Estadiamento de Neoplasias , Regiões Promotoras Genéticas , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/mortalidade , Vesículas Transportadoras , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Fluxo de Trabalho
3.
BMC Cancer ; 21(1): 1068, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34587931

RESUMO

BACKGROUND: Uveal melanoma (UVM) is the leading cause of eye-related mortality worldwide. This study aimed to explore the expression and prognostic value of matrix metalloproteinases (MMPs) in UVM. METHODS: Gene expression levels were obtained from the Gene Expression Omnibus (GEO) and Oncomine databases. Functional and pathway enrichment analyses were performed using the Metascape database. GeneMANIA was then applied to construct a protein-protein interaction network and identify the hub genes. Moreover, overall survival (OS) and disease-free survival (DFS) analysis for the hub genes was performed using the UALCAN and Gene Expression Profiling Interactive Analysis (GEPIA) online tool. Furthermore, TRRUST was used to predict the targets of the MMPs. RESULTS: Our results revealed that the transcriptional levels of MMP1, MMP9, MMP10, MMP11, MMP13, MMP14, and MMP17 were upregulated in UVM tissues compared to normal tissues. A protein-protein interaction (PPI) network was constructed and the top 50 hub genes were identified. The functions of MMPs and their neighboring proteins are mainly associated with ECM-receptor interaction, proteoglycans in cancer, the IL-17 signaling pathway, and microRNAs in cancer. Among the MMPs, MMP1/2/9/11/14/15/16/17/24 played significant roles in the progression of UVM from stage 3 to stage 4. We also found that the expression of MMP1, MMP2, MMP9, and MMP16 positively correlated with OS and DFS in patients with UVM. Additionally, 18 transcription factors associated with nine MMPs were identified. CONCLUSIONS: The results of this study may provide potential biomarkers and targets for UVM. However, further studies are required to confirm these results.


Assuntos
Biomarcadores Tumorais/metabolismo , Colagenases/metabolismo , Melanoma/enzimologia , Mapas de Interação de Proteínas/genética , Neoplasias Uveais/enzimologia , Biomarcadores Tumorais/genética , Colagenases/genética , Bases de Dados Genéticas , Progressão da Doença , Intervalo Livre de Doença , Perfilação da Expressão Gênica/métodos , Humanos , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Melanoma/genética , Melanoma/mortalidade , Melanoma/patologia , Prognóstico , Fatores de Transcrição/metabolismo , Regulação para Cima , Úvea/enzimologia , Neoplasias Uveais/genética , Neoplasias Uveais/mortalidade , Neoplasias Uveais/patologia
4.
Medicine (Baltimore) ; 100(38): e27223, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34559114

RESUMO

BACKGROUND: The aim of this study was to systematically evaluate the prognostic role of platelet lymphocyte ratio (PLR) in patients with melanoma through performing a meta-analysis. METHODS: PubMed, EMBASE, Web of Science, and China National Knowledge Infrastructure were searched for potential studies. The basic characteristics and relevant data were extracted. Hazard ratios with 95% confidence intervals (CIs) were pooled to evaluate the prognostic role of PLR in patients with melanoma. RESULTS: Ten studies enrolling 2422 patients were included. The pooled hazard ratios of higher PLR for overall survival and progression-free survival in melanoma were 1.70 (95% CI, 1.22-2.37) and 1.65 (95% CI, 1.10-2.47), respectively. Sensitivity analysis and subgroup analyses were also performed. No significant publication bias was observed. CONCLUSION: Our results showed that higher PLR was associated with poorer overall survival and progression-free survival in patients with melanoma. These findings may help to determine the prognosis and explore future novel therapies based on modulating inflammation and immune responses in melanoma.


Assuntos
Plaquetas , Linfócitos , Melanoma/sangue , Valor Preditivo dos Testes , Humanos , Melanoma/complicações , Melanoma/mortalidade , Modelos de Riscos Proporcionais
5.
Cancer Sci ; 112(11): 4526-4542, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34533860

RESUMO

Melanoma is a fatal skin malignant tumor with a poor prognosis. We found that long noncoding RNA BASP1-AS1 is essential for the development and prognosis of melanoma. The methylation, RNA sequencing, copy number variation, mutation data, and sample follow-up information of melanoma from The Cancer Genome Atlas (TCGA) were analyzed using weighted gene co-expression network analysis and 366 samples common to the three omics were selected for multigroup clustering analysis. A four-gene prognostic model (BASP1-AS1, LOC100506098, ARHGAP27P1, and LINC01532) was constructed in the TCGA cohort and validated using the GSE65904 series. The expression of BASP1-AS1 was upregulated in melanoma tissues and various melanoma cell lines. Functionally, the ectopic expression of BASP1-AS1 promoted cell proliferation, migration, and invasion in both A375 and SK-MEL-2 cells. Mechanically, BASP1-AS1 interacted with YBX1 and recruited it to the promoter of NOTCH3, initiating its transcription process. The activation of the Notch signaling then resulted in the transcription of multiple oncogenes, including c-MYC, PCNA, and CDK4, which contributed to melanoma progression. Thus, BASP1-AS1 could act as a potential biomarker for cutaneous malignant melanoma.


Assuntos
Melanoma/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , RNA Longo não Codificante/metabolismo , Receptor Notch3/metabolismo , Proteínas Repressoras/metabolismo , Neoplasias Cutâneas/metabolismo , Proteína 1 de Ligação a Y-Box/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteínas Ativadoras de GTPase/metabolismo , Inativação Gênica , Humanos , Masculino , Melanoma/mortalidade , Melanoma/patologia , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Vírus da Pneumonia Murina , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias , Células-Tronco Neoplásicas , Proteínas do Tecido Nervoso/genética , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Distribuição Aleatória , Proteínas Repressoras/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Transcrição Genética , Regulação para Cima
6.
PLoS One ; 16(9): e0257949, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34591891

RESUMO

BACKGROUND: Integrating additional factors into the TNM staging system is needed for more accurate risk classification and survival prediction for patients with cutaneous melanoma. In the present study, we introduce machine learning as a novel tool that incorporates additional prognostic factors to improve the current TNM staging system. METHODS AND FINDINGS: Cancer-specific survival data for cutaneous melanoma with at least a 5 years follow-up were extracted from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute and split into the training set (40,781 cases) and validation set (5,390 cases). Five factors were studied: the primary tumor (T), regional lymph nodes (N), distant metastasis (M), age (A), and sex (S). The Ensemble Algorithm for Clustering Cancer Data (EACCD) was applied to the training set to generate prognostic groups. Utilizing only T, N, and M, a basic prognostic system was built where patients were stratified into 10 prognostic groups with well-separated survival curves, similar to 10 AJCC stages. These 10 groups had a significantly higher accuracy in survival prediction than 10 stages (C-index = 0.7682 vs 0.7643; increase in C-index = 0.0039, 95% CI = (0.0032, 0.0047); p-value = 7.2×10-23). Nevertheless, a positive association remained between the EACCD grouping and the AJCC staging (Spearman's rank correlation coefficient = 0.8316; p-value = 4.5×10-13). With additional information from A and S, a more advanced prognostic system was established using the training data that stratified patients into 10 groups and further improved the prediction accuracy (C-index = 0.7865 vs 0.7643; increase in C-index = 0.0222, 95% CI = (0.0191, 0.0254); p-value = 8.8×10-43). Both internal validation using the training set and temporal validation using the validation set showed good stratification and a high predictive accuracy of the prognostic systems. CONCLUSIONS: The EACCD allows additional factors to be integrated into the TNM to create a prognostic system that improves patient stratification and survival prediction for cutaneous melanoma. This integration separates favorable from unfavorable clinical outcomes for patients and improves both cohort selection for clinical trials and treatment management.


Assuntos
Melanoma/mortalidade , Melanoma/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Algoritmos , Estudos de Coortes , Feminino , Humanos , Aprendizado de Máquina , Masculino , Estadiamento de Neoplasias , Prognóstico , Programa de SEER , Sensibilidade e Especificidade , Análise de Sobrevida
7.
Cancer Sci ; 112(10): 4355-4364, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34375487

RESUMO

Mitosis is a prognostic factor for cutaneous melanoma (CM), but accurate mitosis detection in CM tissues is difficult. Therefore, the 8th Edition of the American Joint Committee on Cancer staging system has removed the mitotic rate as a category criterion of the tumor T-category, based on the evidence that the mitotic rate was not an independent prognostic factor for melanoma survival. As single-nucleotide polymorphisms (SNPs) have been shown to be potential predictors for cutaneous melanoma-specific survival (CMSS), we investigated the potential prognostic value of SNPs in mitosis-related pathway genes in CMSS by analyzing their associations with outcomes of 850 CM patients from The University of Texas MD Anderson Cancer Center in a discovery dataset and validated the findings in another dataset of 409 CM patients from the Harvard University Nurses' Health Study and Health Professionals Follow-up Study. In both datasets, we identified two SNPs (SDCCAG8 rs10803138 G>A and MAGI2 rs3807694 C>T) as independent prognostic factors for CMSS, with adjusted allelic hazards ratios of 1.49 (95% confidence interval = 1.17-1.90, P = .001) and 1.45 (1.13-1.86, P = .003), respectively. Furthermore, their combined unfavorable alleles also predicted a poor survival in both discovery and validation datasets in a dose-response manner (Ptrend  = .0006 and .0001, respectively). Additional functional analysis revealed that both SDCCAG8 rs10803138 A and MAGI2 rs3807694 T alleles were associated with elevated mRNA expression levels in normal tissues. Therefore, these findings suggest that SDCCAG8 rs10803138 G>A and MAGI2 rs3807694 C>T are independent prognostic biomarkers for CMSS, possibly by regulating the mRNA expression of the corresponding genes involved in mitosis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Autoantígenos/genética , Variação Genética , Guanilato Quinases/genética , Melanoma/mortalidade , Mitose/genética , Proteínas de Neoplasias/genética , Neoplasias Cutâneas/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Intervalos de Confiança , Feminino , Humanos , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Curva ROC , Neoplasias Cutâneas/genética , Adulto Jovem
8.
Bull Cancer ; 108(10): 915-930, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34340842

RESUMO

OBJECTIVE: To preliminarily explore death risk factors in primary melanoma patients. METHOD: Competing risk model analysis was used using a large sample public cohort and Cox proportional hazard model was compared. RESULT: In the competing risk model analysis, age, gender, ethnicity, stage, site, TMN stage and metastases were the independent risk factors of single primary melanoma (SPM) death. T stage had a particularly important impact on SPM death. T2 stage had a 3.212 times greater risk of interest event than T1 stage [hazard ratio (HR)=3.212, 95%CI: 2.994-3.446], T3 stage was 5.747 times greater than that T1 stage (HR=5.747, 95%CI: 5.337-6.187) and T4 stage had a 7.086 times than T1 stage (HR=7.086, 95%CI: 6.514-7.708). Gender, ethnicity, stage, site, T stage and brain and liver metastases were the independent risk factors of multiple primary melanoma (MPM) death. When some groups had a very high death rate or the reference group had a very low death rate in competing events, the results of Cox proportional hazard model may not be as accurate as the results obtained by fine-Gray regression model. CONCLUSION: Early diagnosis and therapy, and prevention of tumor progression and metastases of primary melanoma patients are important measures to improve its prognosis and survival.


Assuntos
Melanoma/mortalidade , Adulto , Fatores Etários , Idoso , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Estudos de Coortes , Intervalos de Confiança , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Masculino , Melanoma/etnologia , Melanoma/patologia , Melanoma/secundário , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Análise de Regressão , Fatores de Risco , Fatores Sexuais
9.
Eur J Cancer ; 156: 83-92, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34425407

RESUMO

PURPOSE: The combination of vascular endothelial growth factor receptor (VEGFR) inhibitor and programmed cell death-1 (PD-1) blockade provides promising therapeutic opportunities for advanced mucosal melanoma in early phase trials. The aim of this retrospective study was to evaluate the efficacy and safety of the combination regimen for advanced mucosal melanoma in the real world. METHODS: Patients with advanced mucosal melanoma received an anti-PD-1 antibody plus the VEGFR inhibitor axitinib until confirmed disease progression or unacceptable toxicity. In addition, those with liver metastasis were allowed to take hepatic transcatheter arterial chemoembolisation (TACE). The primary endpoint was overall response rate (ORR). Secondary endpoints included disease control rate (DCR), time to treatment failure (TTF), duration of response (DOR), overall survival (OS) and treatment-related adverse events (TRAEs). RESULTS: Eighty-one and sixty-six patients received axitinib plus immunotherapy as first-line and salvage therapy, respectively. Overall, ORR was 24.5% (95% CI, 17.3-31.6), DCR was 72.7% (95% CI, 65.3-80.1). Median TTF, DOR and OS were 5.2 months (95% CI, 3.7-6.6), 9.2 months (95% CI, 7.2-11.2) and 11.1 months (95% CI, 7.2-15.0). ORR was 30.0% (95% CI, 19.7-40.3) and 17.5% (95% CI, 7.8-27.1) as first-line and salvage therapy, respectively. No statistical difference among the primary sites was noted for ORR. The ORR of patients with liver metastasis with or without hepatic TACE was 26.1% (95% CI, 6.7-45.5) and 15.0% (95% CI, 2.1-32.1), respectively (P = 0.467). Elevated LDH and poor ECOG status are negative predictive factors. CONCLUSION: This is the largest analysis of anti-PD-1 plus VEGFR inhibitor therapy for mucosal melanoma to date. Immunotherapy plus anti-angiogenesis is applicable for advanced mucosal melanoma, especially as front-line. Hepatic TACE might act synergistically with systemic immunotherapy and anti-angiogenesis.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Axitinibe/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/tratamento farmacológico , Membrana Mucosa/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Axitinibe/efeitos adversos , Sinergismo Farmacológico , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Membrana Mucosa/imunologia , Membrana Mucosa/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
10.
Front Immunol ; 12: 685370, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220837

RESUMO

The tumor immune microenvironment (TIME) is likely an important determinant of sensitivity to immune checkpoint inhibitor (ICI) treatment. However, a comprehensive analysis covering the complexity and diversity of the TIME and its influence on ICI therapeutic efficacy is still lacking. Data from 782 samples from 10 ICI clinical trials were collected. To infer the infiltration of 22 subsets of immune cells, CIBERSORTx was applied to the bulk tumor transcriptomes. The associations between each cell fraction and the response to ICI treatment, progression-free survival (PFS) and overall survival (OS) were evaluated, modeling cellular proportions as quartiles. Activity of the interferon-γ pathway, the cytolytic activity score and the MHC score were associated with good prognosis in melanoma. Of the immune cells investigated, M1 macrophages, activated memory CD4+ T cells, T follicular helper (Tfh) cells and CD8+ T cells correlated with response and prolonged PFS and OS, while resting memory CD4+ T cells was associated with unfavorable prognosis in melanoma and urothelial cancer. Consensus clustering revealed four immune subgroups with distinct responses to ICI therapy and survival patterns. The cluster with high proportions of infiltrated CD8+ T cells, activated memory CD4+ T cells, and Tfh cells and low levels of resting memory CD4+ T cells exhibited a higher tumor mutation burden and neoantigen load in melanoma and conferred a higher probability of response and improved survival. Local systemic immune cellular differences were associated with outcomes after ICI therapy. Further investigations of the tumor-infiltrating cellular immune response will lay the foundation for achieving durable efficacy.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Melanoma/tratamento farmacológico , Melanoma/imunologia , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Biologia Computacional/métodos , Humanos , Melanoma/mortalidade , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Microambiente Tumoral
11.
Front Immunol ; 12: 691032, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34290710

RESUMO

Background: Anti-PD-1 monotherapy is the standard therapy for advanced melanoma patients, including those with NRAS mutations. The influence of NRAS mutation on immunotherapy, especially in noncutaneous melanoma, is largely uncharacterized. Materials and Methods: We analyzed clinical data of four clinical trials for advanced melanoma patients treated with anti-PD-1 monotherapy between 2016 and 2019. The impact of NRAS mutation on efficacy and outcome of immunotherapy were analyzed in cutaneous and noncutaneous groups separately. Results: A total of 206 patients were assessed, including 92 cutaneous melanoma patients with 12 NRAS mutations and 114 noncutaneous melanoma patients with 21 NRAS mutations. In cutaneous melanoma, the response rates of NRAS mutant patients were lower than patients without NRAS mutations (9.5% vs. 23.9%), the median progression-free survival (PFS) and median overall survival (OS) were shorter for patients with NRAS mutations, although without significant difference for OS (P=0.081). In noncutaneous melanoma, the response rates were 0 and 13.7% for NRAS mutant and wild-type patients, the median PFS were 3.6 months (95% CI: 0.9-6.3) and 4.3 months (95%CI: 2.9-5.7) (P=0.015), and the median OS were 10.8 months (95% CI: 1.5-20.1) and 15.3 months (95% CI: 13.2-17.4) (P=0.025), respectively. In multivariate analysis, NRAS mutation, along with ECOG performance score and LDH level, was negatively associated with both PFS (HR 1.912, P=0.044) and OS (HR 2.210, P=0.025) in noncutaneous melanoma. Conclusion: In advanced Asian melanoma treated with anti-PD-1 monotherapy, NRAS mutant patients had lower response rates and poorer prognoses compared to wild-type patients, especially in noncutaneous subtypes.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , GTP Fosfo-Hidrolases/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/tratamento farmacológico , Proteínas de Membrana/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Humanos , Imunoterapia , Estimativa de Kaplan-Meier , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/mortalidade , Mutação , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Resultado do Tratamento
12.
Eur J Cancer ; 154: 57-65, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34243078

RESUMO

BACKGROUND: BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM). In a large phase IIIb, single-arm, open-label, multicenter French study, we assessed safety, response to treatment, progression-free survival (PFS) and factors associated with progression, and stratified the population into risk groups. METHODS: Patients with unresectable, advanced, BRAF V600-mutant melanoma were included, including those with the presence of BM, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2, elevated lactate dehydrogenase (LDH) or previous melanoma treatments. Responses were determined locally, without central review. PFS was estimated using the Kaplan-Meier analysis and modelled with multivariate Cox model. Risk subgroups were identified using a regression tree analysis. RESULTS: Between March 2015 and November 2016, 856 patients received at least one D + T dose. Overall, 92% had stage IV melanoma, 38% ECOG PS ≥1, 32% BM and 37.5% elevated LDH. Median PFS was 8.02 months (95% confidence interval [CI] 7.33-8.77). Significant factors associated with lower PFS were ECOG PS ≥1, elevated LDH, ≥3 metastatic sites and presence of BM. Patients with <3 metastatic sites, ECOG = 0 and no BM had the highest probability of PFS at 6 months (83%, 95% CI 76-87) and 12 months (56%, 95% CI 47-64), respectively. CONCLUSIONS: This is the largest prospective study in advanced BRAF V600-mutant melanoma patients treated with D + T, conducted in conditions close to 'real-world practice'. We confirm previous findings that LDH, ECOG PS and ≥3 metastatic sites are associated with shorter PFS, but the real-world setting introduces BM as a major prognostic factor.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Masculino , Melanoma/genética , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Oximas/administração & dosagem , Oximas/efeitos adversos , Estudos Prospectivos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos
13.
Eur J Cancer ; 154: 111-119, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34256280

RESUMO

OBJECTIVE: To examine stage-specific trends in the incidence and survival of cutaneous melanoma in the Netherlands between 2003 and 2018, as well as the uptake of the sentinel lymph node biopsy (SLNB) and novel drugs during that period. METHODS: Data were obtained from the nationwide population-based Netherlands Cancer Registry for all patients diagnosed with invasive primary cutaneous melanoma (n = 60,267). We presented age-standardized incidence rates, the proportion of patients with an SLNB, the proportion of patients who received a novel drug (for their primary diagnosis) and one- and five-year relative survival rates. RESULTS: Between 2003 and 2018, the incidence rate increased from 10.9 to 23.9 for men and from 15.6 to 27.3 for women. This increase reflected the increasing incidence rate of patients with stage I and III. The proportion of patients with an SLNB increased from 23% to 64%. A reasonable increase was observed in the proportion of patients with a positive outcome (from 2% to 11%). For patients with stage IV, there was a shift from chemotherapy towards novel drugs as from 2013. The five-year relative survival rate increased from 81% to 92% for men and from 88% to 96% for women. This increase reflected the increasing five-year relative survival rate of patients with stage II, III, and IV. CONCLUSION: We observed an increase in incidence for patients with stage I and III and an improvement in survival for patients with stage II, III and IV. These trends can be partly explained by the introduction of the SLNB and the novel drugs.


Assuntos
Melanoma/epidemiologia , Neoplasias Cutâneas/epidemiologia , Adulto , Idoso , Feminino , Humanos , Incidência , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Países Baixos/epidemiologia , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Fatores de Tempo
14.
J Clin Oncol ; 39(26): 2914-2925, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34255535

RESUMO

PURPOSE: Therapies that produce deep and durable responses in patients with metastatic melanoma are needed. This phase II cohort from the international, single-arm PIVOT-02 study evaluated the CD122-preferential interleukin-2 pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in first-line metastatic melanoma. METHODS: A total of 41 previously untreated patients with stage III/IV melanoma received BEMPEG 0.006 mg/kg plus NIVO 360 mg once every 3 weeks for ≤ 2 years; 38 were efficacy-evaluable (≥ 1 postbaseline scan). Primary end points were safety and objective response rate (blinded independent central review); other end points included progression-free survival, overall survival (OS), and exploratory biomarkers. RESULTS: At 29.0 months' median follow-up, the objective response rate was 52.6% (20 of 38 patients), and the complete response rate was 34.2% (13 of 38 patients). Median change in size of target lesions from baseline was -78.5% (response-evaluable population); 47.4% (18 of 38 patients) experienced complete clearance of target lesions. Median progression-free survival was 30.9 months (95% CI, 5.3 to not estimable). Median OS was not reached; the 24-month OS rate was 77.0% (95% CI, 60.4 to 87.3). Grade 3 and 4 treatment-related and immune-mediated adverse events occurred in 17.1% (7 of 41) and 4.9% (2 of 41) of patients, respectively. Increased polyfunctional responses in CD8+ and CD4+ T cells were seen in blood after treatment, driven by cytokines with effector functions. Early on-treatment blood biomarkers (CD8+ polyfunctional strength difference and eosinophils) correlated with treatment response. CONCLUSION: BEMPEG in combination with NIVO was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging antitumor activity in first-line metastatic melanoma, including an extended median progression-free survival. Exploratory analyses associated noninvasive, on-treatment biomarkers with response, before radiologic evidence was observed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Interleucina-2/análogos & derivados , Melanoma/tratamento farmacológico , Nivolumabe/uso terapêutico , Polietilenoglicóis/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Europa (Continente) , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Interleucina-2/efeitos adversos , Interleucina-2/uso terapêutico , Masculino , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nivolumabe/efeitos adversos , Polietilenoglicóis/efeitos adversos , Intervalo Livre de Progressão , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Fatores de Tempo , Estados Unidos
15.
Gac Med Mex ; 157(2): 207-211, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34270542

RESUMO

Background: Melanoma epidemiological and prognostic studies are based on Caucasian populations, in whom the predominant subtype is superficially-spreading melanoma and in whom thin melanomas (Breslow < 3 mm) predominate. Mexican patients show a predominance of thick melanomas (Breslow ≥ 3 mm), and the acral subtype is the most common. There are no publications on prognostic factors in thick melanomas. We hypothesize that we will identify factors that determine the prognosis in this group of patients. Objective: To identify clinical-pathological factors associated with the prognosis of patients with thick melanomas in the Mexican population. Material and methods: Data on melanomas with Breslow > 3 mm were collected from 2010 to 2015. The prognostic influence of various clinical-pathological factors was analyzed. Results: The most common subtypes were acral melanoma in 271 patients (74.9 %) and nodular melanoma in 49 (13.5 %). Median Breslow thickness was 7 mm. 56.6 % of the patients had lymph node metastases (clinical stage [CS] III), 269 (74.3 %) had ulceration, and surgical margins were positive in 15 (4.1 %). Elevated neutrophil: lymphocyte ratio (≥ 2) was found in 188 (51.9 %). The variables associated with lower overall survival were CS (p < 0.001), Breslow thickness (p = 0.044), ulceration (p = 0.004), mitotic activity (p < 0.001), < 2-cm margin (p < 0.001) and an increased neutrophil: lymphocyte ratio (p = 0.037). In the multivariate analysis, the factors associated with overall survival were CS, mitotic activity, and surgical margin. Conclusions: In patients with thick melanomas, overall survival is influenced by mitotic activity, a positive margin, and clinical stage.


Assuntos
Melanoma/mortalidade , Melanoma/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Carga Tumoral , Adulto , Idoso , Feminino , Humanos , Metástase Linfática , Masculino , Margens de Excisão , Melanoma/classificação , México , Pessoa de Meia-Idade , Mitose , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/classificação , Úlcera/patologia , Adulto Jovem
16.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201614

RESUMO

The use of MEK inhibitors in the therapy of uveal melanoma (UM) has been investigated widely but has failed to show benefits in clinical trials due to fast acquisition of resistance. In this study, we investigated a variety of therapeutic compounds in primary-derived uveal melanoma cell lines and found monosomy of chromosome 3 (M3) and mutations in BAP1 to be associated with higher resistance to MEK inhibition. However, reconstitution of BAP1 in a BAP1-deficient UM cell line was unable to restore sensitivity to MEK inhibition. We then compared UM tumors from The Cancer Genome Atlas (TCGA) with mutations in BAP1 with tumors with wild-type BAP1. Principal component analysis (PCA) clearly differentiated both groups of tumors, which displayed disparate overall and progression-free survival data. Further analysis provided insight into differential expression of genes involved in signaling pathways, suggesting that the downregulation of the eukaryotic translation initiation factor 2A (EIF2A) observed in UM tumors with BAP1 mutations and M3 UM cell lines might lead to a decrease in ribosome biogenesis while inducing an adaptive response to stress. Taken together, our study links loss of chromosome 3 with decreased sensitivity to MEK inhibition and gives insight into possible related mechanisms, whose understanding is fundamental to overcome resistance in this aggressive tumor.


Assuntos
Cromossomos Humanos Par 3/genética , Resistencia a Medicamentos Antineoplásicos/genética , Melanoma/genética , Monossomia , Inibidores de Proteínas Quinases/farmacologia , Neoplasias Uveais/genética , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Piridonas/farmacologia , Pirimidinonas/farmacologia , Sulfonamidas/farmacologia , Análise de Sobrevida , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/mortalidade
17.
Front Immunol ; 12: 672521, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177913

RESUMO

A significant number of patients (pts) with metastatic melanoma do not respond to anti-programmed cell death 1 (PD1) therapies. Identifying predictive biomarkers therefore remains an urgent need. We retrospectively analyzed plasma DNA of pts with advanced melanoma treated with PD-1 antibodies, nivolumab or pembrolizumab, for five PD-1 genotype single nucleotide polymorphisms (SNPs): PD1.1 (rs36084323, G>A), PD1.3 (rs11568821, G>A), PD1.5 (rs2227981, C>T) PD1.6 (rs10204225, G>A) and PD1.9 (rs2227982, C>T). Clinico-pathological and treatment parameters were collected, and presence of SNPs correlated with response, progression free survival (PFS) and overall survival (OS). 115 patients were identified with a median follow up of 18.7 months (range 0.26 - 52.0 months). All were Caucasian; 27% BRAF V600 mutation positive. At PD-1 antibody commencement, 36% were treatment-naïve and 52% had prior ipilimumab. The overall response rate was 43%, 19% achieving a complete response. Overall median PFS was 11.0 months (95% CI 5.4 - 17.3) and median OS was 31.1 months (95% CI 23.2 - NA). Patients with the G/G genotype had more complete responses than with A/G genotype (16.5% vs. 2.6% respectively) and the G allele of PD1.3 rs11568821 was significantly associated with a longer median PFS than the AG allele, 14.1 vs. 7.0 months compared to the A allele (p=0.04; 95% CI 0.14 - 0.94). No significant association between the remaining SNPs and responses, PFS or OS were observed. Despite limitations in sample size, this is the first study to demonstrate an association of a germline PD-1 polymorphism and PFS in response to anti-PD-1 therapy in pts with metastatic melanoma. Extrinsic factors like host germline polymorphisms should be considered with tumor intrinsic factors as predictive biomarkers for immune checkpoint regulators.


Assuntos
Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/genética , Receptor de Morte Celular Programada 1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Intervalo Livre de Progressão , Estudos Retrospectivos
18.
J Surg Oncol ; 124(4): 655-664, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34085291

RESUMO

BACKGROUND AND OBJECTIVES: Clinicopathologic characteristics have prognostic value in clinical stage IB-II patients with melanoma. Little is known about the prognostic value of obesity that has been associated with an increased risk for several cancer types and worsened prognosis after diagnosis. This study aims to examine effects of obesity on outcome in patients with clinical stage IB-II melanoma. METHODS: Prospectively recorded data of patients with clinical stage IB-II melanoma who underwent sentinel lymph node biopsy (SLNB) between 1995 and 2018 at the University Medical Center of Groningen were collected from medical files and retrospectively analyzed. Cox-regression analyses were used to determine associations between obesity (body mass index> 30), tumor (location, histology, Breslow-thickness, ulceration, mitotic rate, SLN-status) and patient-related variables (gender, age, and social-economic-status [SES]) and disease-free interval (DFI), melanoma-specific survival (MSS), and overall survival (OS). RESULTS: Of the 715 patients, 355 (49.7%) were women, median age was 55 (range 18.6-89) years, 149 (20.8%) were obese. Obesity did not significantly affect DFI (adjusted hazard ratio [HR] = 1.40; 95% confidence interval [CI] = 0.98-2.00; p = 0.06), MSS (adjusted HR = 1.48;95%CI = 0.97-2.25; p = 0.07), and OS (adjusted HR = 1.25; 95% CI = 0.85-1.85; p = 0.25). Increased age, arm location, increased Breslow-thickness, ulceration, increased mitotic rate, and positive SLN-status were significantly associated with decreased DFI, MSS, and OS. Histology, sex, and SES were not associated. CONCLUSION: Obesity was not associated with DFI, MSS, or OS in patients with clinical stage IB-II melanoma who underwent SLNB.


Assuntos
Índice de Massa Corporal , Melanoma/mortalidade , Obesidade/complicações , Biópsia de Linfonodo Sentinela/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Melanoma/etiologia , Melanoma/patologia , Melanoma/cirurgia , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
19.
Medicine (Baltimore) ; 100(22): e26219, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087900

RESUMO

BACKGROUND: Autophagy is closely related to skin cutaneous melanoma (SKCM), but the mechanism involved is unclear. Therefore, exploration of the role of autophagy-related genes (ARGs) in SKCM is necessary. MATERIALS AND METHODS: Differential expression autophagy-related genes (DEARGs) were first analysed. Univariate and multivariate Cox regression analyses were used to evaluate the expression of DEARGs and prognosis of SKCM. Further, the expression levels of prognosis-related DEARGs were verified by immunohistochemical (IHC) staining. Finally, gene set enrichment analysis (GSEA) was used to explore the underlying molecular mechanisms of SKCM. RESULTS: Five ARGs (APOL1, BIRC5, EGFR, TP63, and SPNS1) were positively correlated with the prognosis of SKCM. IHC verified the results of the differential expression of these 5 ARGs in the bioinformatics analysis. According to the receiver operating characteristic curve, the signature had a good performance at predicting overall survival in SKCM. The signature could classify SKCM patients into high-risk or low-risk groups according to distinct overall survival. The nomogram confirmed that the risk score has a particularly large impact on the prognosis of SKCM. Calibration plot displayed excellent agreement between nomogram predictions and actual observations. Principal component analysis indicated that patients in the high-risk group could be distinguished from those in low-risk group. Results of GSEA indicated that the low-risk group is enriched with aggressiveness-related pathways such as phosphatidylinositol-3-kinase/protein kinase B and mitogen-activated protein kinase signalling pathways. CONCLUSION: Our study identified a 5-gene signature. It revealed the mechanisms of autophagy that lead to the progression of SKCM and established a prognostic nomogram that can predict overall survival of patients with SKCM. The findings of this study provide novel insights into the relationship between ARGs and prognosis of SKCM.


Assuntos
Autofagia/genética , Biologia Computacional/métodos , Melanoma/genética , Neoplasias Cutâneas/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Apolipoproteína L1/genética , Receptores ErbB/genética , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/mortalidade , Proteínas de Membrana/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Nomogramas , Fosfatidilinositol 3-Quinase/metabolismo , Prognóstico , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Curva ROC , Fatores de Risco , Survivina/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética
20.
Nat Commun ; 12(1): 3530, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112755

RESUMO

Targeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observe MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibit decreased TAM immunosuppressive functions corresponding with enhanced antitumor immunity. MAOI treatment induces TAM reprogramming and suppresses tumor growth in preclinical mouse syngeneic and human xenograft tumor models. Combining MAOI and anti-PD-1 treatments results in synergistic tumor suppression. Clinical data correlation studies associate high intratumoral MAOA expression with poor patient survival in a broad range of cancers. We further demonstrate that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.


Assuntos
Imunoterapia/métodos , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Neoplasias/tratamento farmacológico , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Linfoma/genética , Linfoma/metabolismo , Linfoma/mortalidade , Melanoma/genética , Melanoma/metabolismo , Melanoma/mortalidade , Camundongos , Camundongos Endogâmicos C57BL , Monoaminoxidase/deficiência , Monoaminoxidase/genética , Inibidores da Monoaminoxidase/uso terapêutico , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/mortalidade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , RNA-Seq , Espécies Reativas de Oxigênio/metabolismo , Análise de Célula Única , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
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