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1.
Int J Cancer ; 142(3): 641-648, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28960289

RESUMO

The clinical value of sentinel lymph node (SLN) biopsy in thick melanoma patients (Breslow >4 mm) has not been sufficiently studied. The aim of the study is to evaluate whether SLN biopsy increases survival in patients with thick cutaneous melanoma, and, as a secondary objective, to investigate correlations between survival and lymph node status. We included 1,211 consecutive patients with thick melanomas (>4 mm) registered in the participating hospitals' melanoma databases between 1997 and 2015. Median follow-up was 40 months. Of these patients, 752 were matched into pairs by propensity scores based on sex, age, tumor location, histologic features of melanoma, year of diagnosis, hospital and adjuvant interferon therapy. The SLN biopsy vs. observation was associated with better DFS [adjusted hazard ratio (AHR), 0.74; 95% confidence interval (CI) 0.61-0.90); p = 0.002] and OS (AHR, 0.75; 95% CI, 0.60-0.94; p = 0.013) but not MSS (AHR, 0.84; 95% CI, 0.65-1.08; p = 0.165). SLN-negative patients had better 5- and 10-year MSS compared with SLN-positive patients (65.4 vs. 51.9% and 48.3 vs. 38.8%; p = 0.01, respectively). As a conclusion, SLN biopsy was associated with better DFS but not MSS in thick melanoma patients after adjustment for classic prognostic factors. SLN biopsy is useful for stratifying these patients into different prognostic groups.


Assuntos
Linfonodos/patologia , Melanoma/patologia , Neoplasias Cutâneas/patologia , Idoso , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Estudos Retrospectivos , Biópsia de Linfonodo Sentinela , Análise de Sobrevida
2.
Gastroenterology ; 151(5): 961-972, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27521480

RESUMO

BACKGROUND & AIMS: There are few validated biomarkers that can be used to predict outcomes for patients with colorectal cancer. Part of the challenge is the genetic and molecular heterogeneity of colorectal tumors not only among patients, but also within tumors. We have explored intratumor heterogeneity at the epigenetic level, due to its dynamic nature. We analyzed DNA methylation profiles of the digestive tract surface and the central bulk and invasive front regions of colorectal tumors. METHODS: We determined the DNA methylation profiles of >450,000 CpG sites in 3 macrodissected regions of 79 colorectal tumors and 23 associated liver metastases, obtained from 2 hospitals in Spain. We also analyzed samples for KRAS and BRAF mutations, 499,170 single nucleotide polymorphisms, and performed immunohistochemical analyses. RESULTS: We observed differences in DNA methylation among the 3 tumor sections; regions of tumor-host interface differed the most from the other tumor sections. Interestingly, tumor samples collected from areas closer to the gastrointestinal transit most frequently shared methylation events with metastases. When we calculated individual coefficients to quantify heterogeneity, we found that epigenetic homogeneity was significantly associated with short time of relapse-free survival (log-rank P = .037) and short time of overall survival (log-rank P = .026) in patients with locoregional colorectal cancer. CONCLUSIONS: In an analysis of 79 colorectal tumors, we found significant heterogeneity in patterns of DNA methylation within each tumor; the level of heterogeneity correlates with times of relapse-free and overall survival.


Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais/genética , Metilação de DNA , Epigênese Genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Estudos Retrospectivos , Análise de Sobrevida
3.
Melanoma Res ; 33(5): 388-397, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36988401

RESUMO

BRAF and MEK inhibitor, dabrafenib plus trametinib, adjuvant therapy is effective for high-risk resected melanoma patients with BRAF - V600 mutations. However, real-world evidence is limited. We aimed to determine the feasibility of this therapy in routine clinical practice. DESCRIBE-AD, a retrospective observational study, collected real-world data from 25 hospitals in Spain. Histologically confirmed and resected BRAF -mutated melanoma patients aged ≥18 years who were previously treated with dabrafenib plus trametinib adjuvant therapy, were included. The primary objectives were treatment discontinuation rate and time to discontinuation. The secondary objectives included safety and efficacy. From October 2020 to March 2021, 65 patients were included. Dabrafenib and trametinib discontinuation rate due to treatment-related adverse events (TRAEs) of any grade was 9%. Other reasons for discontinuation included patients' decisions (6%), physician decisions (6%), unrelated adverse events (3%), disease progression (5%), and others (5%). The median time to treatment discontinuation was 9 months [95% confidence interval (CI), 5-11]. G3-4 TRAEs occurred in 21.5% of patients, the most common being pyrexia (3%), asthenia (3%), and diarrhoea (3%). Unscheduled hospitalisations and clinical tests occurred in 6 and 22% of patients, respectively. After 20-month median follow-up (95% CI, 18-22), 9% of patients had exitus due to disease progression, with a 12-month relapse-free survival and overall survival rates of 95.3% and 100%, respectively. Dabrafenib and trametinib adjuvant therapy proved effective for melanoma patients in a real-world setting, with a manageable toxicity profile. Toxicity frequencies were low leading to low incidence of unscheduled medical visits, tests, and treatment discontinuations.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Adolescente , Adulto , Melanoma/patologia , Neoplasias Cutâneas/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Oximas , Piridonas , Progressão da Doença , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Mutação
4.
Oncologist ; 17(3): 339-45, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22363067

RESUMO

UNLABELLED: Single-agent cetuximab is safe and active in elderly patients with advanced colorectal cancer (CRC). A cetuximab-capecitabine combination has not previously been tested in elderly patients with advanced CRC. MATERIAL AND METHODS: Sixty-six patients with advanced CRC were treated with cetuximab as a 400 mg/m2 i.v. infusion followed by 250 mg/m2 i.v. weekly plus capecitabine at a dose of 1,250 mg/m2 every 12 hours. After the inclusion of 27 patients, the protocol was amended for safety reasons, reducing the dose of capecitabine to 1,000 mg/m2 every 12 hours. Thirty-nine additional patients were treated with the reduced dose of capecitabine. RESULTS: The overall response rate was 31.8%. KRAS status was determined in 58 patients (88%). Fourteen of 29 patients with wild-type KRAS tumors responded (48.3%; 95% confidence interval [CI], 29.4%-67.5%), compared with six of 29 patients with mutant KRAS tumors (20.7%; 95% CI, 8.0%-39.7%). The median progression-free survival (PFS) interval was 7.1 months. The median PFS interval for patients whose tumors were wild-type KRAS was significantly longer than for those with mutant KRAS tumors (8.4 months versus 6.0 months; p = .024). The high incidence of severe paronychia (29.6%) declined (7.7%) after capecitabine dose adjustment. CONCLUSIONS: Cetuximab plus capecitabine at a dose of 1,000 mg/m2 every 12 hours may be an alternative to more aggressive regimens in elderly patients with advanced wild-type KRAS CRC.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina , Cetuximab , Neoplasias Colorretais/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Masculino , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Resultado do Tratamento , Proteínas ras/genética
5.
Melanoma Res ; 28(3): 195-203, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29481492

RESUMO

Serial analysis of BRAF mutations in circulating-free DNA (cfDNA) could be of prognostic value in melanoma patients. We collected blood samples from 63 advanced BRAFV600E/K melanoma patients and determined BRAFV600E/K status in cfDNA using a quantitative 5'-nuclease PCR-based assay. Levels of BRAF mutation in pre-cfDNAs were associated significantly with tumour burden, progression-free survival and overall survival. Changes in BRAF status in cfDNA after initiation of treatment (early-cfDNA) had a significant correlation with outcome. In patients with persistent BRAF mutations (n=12), progression-free survival and overall survival were 3.5 months [95% confidence interval (CI): 1.6-4.6] and 5.3 months (95% CI: 3.4-8.1) compared with 16.6 months (95% CI: 8.2-22.3) and 21.9 months (95% CI: 10.2-NR) in patients with BRAF negativization (n=16), and 15.1 months (95% CI: 2.3-NR) and NR (95% CI: 5.1-NR) in patients who maintained their initial negative status (n=12) (P<0.0001). The median duration of response in patients with radiological response, but persistence of BRAFV600 in early-cfDNA (n=5) was 4 months. Our study indicates that serial BRAF testing in the blood of advanced melanoma identifies patients refractory to therapy.


Assuntos
Melanoma/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Melanoma/enzimologia , Melanoma/patologia , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Prospectivos , Proteínas Proto-Oncogênicas B-raf/sangue , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
6.
Melanoma Res ; 25(6): 486-95, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26366702

RESUMO

BRAFV600E is a unique molecular marker for metastatic melanoma, being the most frequent somatic point mutation in this malignancy. Detection of BRAFV600E in blood could have prognostic and predictive value and could be useful for monitoring response to BRAF-targeted therapy. We developed a rapid, sensitive method for the detection and quantification of BRAFV600E in circulating free DNA (cfDNA) isolated from plasma and serum on the basis of a quantitative 5'-nuclease PCR (Taqman) in the presence of a peptide-nucleic acid. We validated the assay in 92 lung, colon, and melanoma archival serum and plasma samples with paired tumor tissue (40 wild-type and 52 BRAFV600E). The correlation of cfDNA BRAFV600E with clinical parameters was further explored in 22 metastatic melanoma patients treated with BRAF inhibitors. Our assay could detect and quantify BRAFV600E in mixed samples with as little as 0.005% mutant DNA (copy number ratio 1 : 20 000), with a specificity of 100% and a sensitivity of 57.7% in archival serum and plasma samples. In 22 melanoma patients treated with BRAF inhibitors, the median progression-free survival was 3.6 months for those showing BRAFV600E in pretreatment cfDNA compared with 13.4 months for those in whom the mutation was not detected (P=0.021). Moreover, the median overall survival for positive versus negative BRAFV600E tests in pretreatment cfDNA differed significantly (7 vs. 21.8 months, P=0.017). This finding indicates that the sensitive detection and accurate quantification of low-abundance BRAFV600E alleles in cfDNA using our assay can be useful for predicting treatment outcome.


Assuntos
Análise Mutacional de DNA/métodos , DNA de Neoplasias/sangue , Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Pessoa de Meia-Idade , Mutação , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real/métodos , Resultado do Tratamento
7.
Nat Med ; 21(7): 741-50, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26030178

RESUMO

Metastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade. This short isoform of TBC1D16 exacerbates melanoma growth and metastasis both in vitro and in vivo. By combining immunoprecipitation and mass spectrometry, we identified RAB5C as a new TBC1D16 target and showed that it regulates EGFR in melanoma cells. We also found that epigenetic reactivation of TBC1D16-47KD is associated with poor clinical outcome in melanoma, while conferring greater sensitivity to BRAF and MEK inhibitors.


Assuntos
Progressão da Doença , Epigênese Genética , Receptores ErbB/metabolismo , Proteínas Ativadoras de GTPase/genética , Melanoma/genética , Melanoma/patologia , Animais , Linhagem Celular Tumoral , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Epigênese Genética/efeitos dos fármacos , Proteínas Ativadoras de GTPase/metabolismo , Imunoprecipitação , Camundongos Nus , Peso Molecular , Metástase Neoplásica , Prognóstico , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/genética , Resultado do Tratamento , Proteínas rab de Ligação ao GTP/metabolismo
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