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1.
Mol Oncol ; 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33236532

RESUMO

MET inhibitors have shown activity in non-small cell lung cancer patients (NSCLC) with MET amplification and exon 14 skipping (METΔex14). However, patient stratification is imperfect and thus response rates have varied widely. Here, we studied MET alterations in 474 advanced NSCLC patients by nCounter, an RNA-based technique, together with Next Generation Sequencing (NGS), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and reverse transcriptase polymerase chain reaction (RT-PCR), exploring correlation with clinical benefit. Of the 474 samples analyzed, 422 (89%) yielded valid results by nCounter, which identified 13 patients (3%) with METΔex14 and 15 patients (3.5%) with very-high MET mRNA expression. These two subgroups were mutually exclusive, displayed distinct phenotypes and did not generally co-exist with other drivers. For METΔex14, 3/8 (37.5%) samples positive by nCounter tested negative by NGS. Regarding patients with very-high MET mRNA, 92% had MET amplification by FISH and/or NGS. However, FISH failed to identify three patients (30%) with very high MET RNA expression, among which one received MET tyrosine kinase inhibitor treatment deriving clinical benefit. Our results indicate that quantitative mRNA-based techniques can improve the selection of patients for MET-targeted therapies.

2.
Cancers (Basel) ; 12(6)2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32516941

RESUMO

Treatment of advanced (metastatic) non-small-cell lung cancer (NSCLC) is currently mainly based on immunotherapy with antibodies against PD-1 or PD-L1, alone, or in combination with chemotherapy. In locally advanced NSCLC and in early resected stages, immunotherapy is also employed. Tumor PD-L1 expression by immunohistochemistry is considered the standard practice. Response rate is low, with median progression free survival very short in the vast majority of studies reported. Herein, numerous biological facets of NSCLC are described involving driver genetic lesions, mutations ad fusions, PD-L1 glycosylation, ferroptosis and metabolic rewiring in NSCLC and lung adenocarcinoma (LUAD). Novel concepts, such as immune-transmitters and the effect of neurotransmitters in immune evasion and tumor growth, the nascent relevance of necroptosis and pyroptosis, possible new biomarkers, such as gasdermin D and gasdermin E, the conundrum of K-Ras mutations in LUADs, with the growing recognition of liver kinase B1 (LKB1) and metabolic pathways, including others, are also commented. The review serves to charter diverse treatment solutions, depending on the main altered signaling pathways, in order to have effectual immunotherapy. Tumor PDCD1 gene (encoding PD-1) has been recently described, in equilibrium with tumor PD-L1 (encoded by PDCD1LG1). Such description explains tumor hyper-progression, which has been reported in several studies, and poises the fundamental criterion that IHC PD-L1 expression as a biomarker should be revisited.

3.
J Clin Epidemiol ; 126: 1-8, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32540384

RESUMO

OBJECTIVES: The objectives of this study are to evaluate the relationship between authorship networking, socioeconomic factors, and scientific productivity across Latin America. METHODS: In a bibliometric analysis of cancer-related Latin-American publications, the relationship between authorship network indicators, sociodemographic factors, and number of peer-reviewed indexed publications per country was explored. A systematic review of the literature for cancer publications between 2000 and 2018 using the Scopus database limited to Latin-American authors was used for the construction of coauthorship and publication networks and their respective metrics. Sociodemographic variables including percentage of invested gross domestic product in research, population, and cancer incidence were also estimated. Multiple linear regression models were constructed to determine the relationship between productivity and the aforementioned variables. RESULTS: A total of 8,528 articles across nine countries were included. Brazil was the most productive nation with 41.8% of identified references followed by Mexico (16.6%) and Argentina (12.9%). Latin America experienced a 9% growth in number of publications across the studied time frame. After analyzing networking and sociodemographic variables, number of authors in a collaboration network and percentage of invested gross domestic product were associated with high productivity yielding a multiple regression model with an R2 value of 0.983. CONCLUSIONS: This study indicates that extensive authorship networking and a high investment in research strongly predict cancer-related productivity.

4.
Expert Rev Respir Med ; 13(10): 1019-1028, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31411906

RESUMO

Introduction: The therapy of patients with lung adenocarcinoma has significantly changed after the discovery of epidermal growth factor receptor (EGFR) mutations. EGFR mutations occur in 10-15% of Caucasian lung cancer patients and are associated with favorable outcome to orally administered EGFR tyrosine kinase inhibitors (TKIs), like erlotinib. However, as soon as the tumor cells are under the pressure of the specific inhibitor, compensatory signaling pathways are activated and resistance emerges. Areas covered: In this review we will focus on the mechanisms of resistance to the first-generation EGFR TKI, erlotinib, and will mainly summarize the findings throughout the last 10 years in the field of EGFR-mutant lung cancer. Expert opinion: Widespread research has been performed and several mechanisms of resistance to EGFR TKIs, especially first- and second-generation, have been identified. Still, no adequate combinatory therapies have received regulatory approval for the treatment of EGFR-mutant patients at the time of resistance. The third-generation EGFR TKI, osimertinib has been approved for patients whose tumor has become resistant through the secondary T790M resistant EGFR mutation. The identification of the mechanisms of resistance and the application of the adequate therapy to each patient is still an unmet need.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Apoptose , Carcinoma Pulmonar de Células não Pequenas/genética , Reparo do DNA , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Mutação
5.
Front Oncol ; 9: 288, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31058088

RESUMO

Objective: Synchronous multiple ground-glass nodules (SM-GGNs) are a distinct entity of lung cancer which has been emerging increasingly in recent years in China. The oncogenesis molecular mechanisms of SM-GGNs remain elusive. Methods: We investigated single nucleotide variations (SNV), insertions and deletions (INDEL), somatic copy number variations (CNV), and germline mutations of 69 SM-GGN samples collected from 31 patients, using target sequencing (TRS) and whole exome sequencing (WES). Results: In the entire cohort, many known driver mutations were found, including EGFR (21.7%), BRAF (14.5%), and KRAS (6%). However, only one out of the 31 patients had the same somatic missense or truncated events within SM-GGNs, indicating the independent origins for almost all of these SM-GGNs. Many germline mutations with a low frequency in the Chinese population, and genes harboring both germline and somatic variations, were discovered in these pre-stage GGNs. These GGNs also bore large segments of copy number gains and/or losses. The CNV segment number tended to be positively correlated with the germline mutations (r = 0.57). The CNV sizes were correlated with the somatic mutations (r = 0.55). A moderate correlation (r = 0.54) was also shown between the somatic and germline mutations. Conclusion: Our data suggests that the precancerous unstable CNVs with potentially predisposing genetic backgrounds may foster the onset of driver mutations and the development of independent SM-GGNs during the local stimulation of mutagens.

6.
Nat Commun ; 10(1): 1812, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-31000705

RESUMO

Non-small cell lung cancer (NSCLC) tumors harboring mutations in EGFR ultimately relapse to therapy with EGFR tyrosine kinase inhibitors (EGFR TKIs). Here, we show that resistant cells without the p.T790M or other acquired mutations are sensitive to the Aurora B (AURKB) inhibitors barasertib and S49076. Phospho-histone H3 (pH3), a major product of AURKB, is increased in most resistant cells and treatment with AURKB inhibitors reduces the levels of pH3, triggering G1/S arrest and polyploidy. Senescence is subsequently induced in cells with acquired mutations while, in their absence, polyploidy is followed by cell death. Finally, in NSCLC patients, pH3 levels are increased after progression on EGFR TKIs and high pH3 baseline correlates with shorter survival. Our results reveal that AURKB activation is associated with acquired resistance to EGFR TKIs, and that AURKB constitutes a potential target in NSCLC progressing to anti-EGFR therapy and not carrying resistance mutations.


Assuntos
Antineoplásicos/farmacologia , Aurora Quinase B/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/uso terapêutico , Aurora Quinase B/antagonistas & inibidores , Aurora Quinase B/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Histonas/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Organofosfatos/farmacologia , Organofosfatos/uso terapêutico , Fosforilação/efeitos dos fármacos , Poliploidia , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , RNA Interferente Pequeno/metabolismo , Análise de Sobrevida , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Clin Lung Cancer ; 20(3): 167-177, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30885551

RESUMO

INTRODUCTION: Epidermal growth factor receptor (EGFR) pathway deregulation promotes the acquisition of stemlike properties in non-small-cell lung cancer. EGFR inhibition through NOTCH enriches lung cancer stem cells (CSCs). Src through Yes-associated protein 1 (YAP1) activates NOTCH. Signal transduction and activator of transcription 3 (STAT3) activation occurs upon EGFR blockade and regulates the generation of CSCs. PATIENTS AND METHODS: Using the Aldefluor assay kit, we investigated the enrichment of aldehyde dehydrogenase (ALDH)-positive cells in EGFR-mutation-positive cells treated with gefitinib, afatinib, and osimertinib. Western blot analysis was performed to evaluate changes in CSC marker expression upon EGFR blockade. We performed gene expression analysis in a cohort of EGFR-mutation-positive non-small-cell lung cancer patients. We evaluated the association of gene expression with treatment outcomes. RESULTS: The cell subpopulation surviving EGFR inhibition had high ALDH activity and elevated CSC marker expression. Concurrent inhibition of EGFR, STAT3, and Src diminished the CSC subpopulation in an EGFR-mutation-positive cellular model. In a cohort of 64 EGFR-mutation-positive patients, 2 ALDH1 isoforms and the NOTCH target hairy and enhancer of split 1 (HES1), when highly expressed, were predictive of worse outcome to EGFR blockade. The gene expression of B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) that maintains the self-renewal of stem cells was also related to treatment outcome. CONCLUSION: Single EGFR inhibitors increase the population of CSCs. Combinatory therapy targeting STAT3 and Src may be of potential benefit. ALDH1, HES1, and Bmi-1 are essential biomarkers in the initial assessment of EGFR-mutation-positive patients.


Assuntos
/metabolismo , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Mutação/genética , Células-Tronco Neoplásicas/metabolismo , Fatores de Transcrição HES-1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Quimioterapia Combinada , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Complexo Repressor Polycomb 1/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Quinases da Família src/antagonistas & inibidores
8.
EBioMedicine ; 39: 207-214, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30473379

RESUMO

BACKGROUND: The activation of multiple signaling pathways jeopardizes the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutation positive non-small cell lung cancer (NSCLC). Integrin-linked kinase (ILK) regulates the interactions between tumor cells and extracellular environment to activate signaling pathways and promote cell proliferation, migration, and epithelial-mesenchymal transition. Src homology 2 domain-containing phosphatase 2 (SHP2) is essential for receptor tyrosine kinase signaling and mitogen-activated protein kinase (MAPK) pathway activation. METHODS: We analyzed tumor ILK, ß-receptor subunit glycoprotein 130 (gp130), SHP2, and stromal hepatocyte growth factor (HGF) and interleukin-6 (IL-6) mRNA expression in baseline tumor specimens of advanced EGFR-mutation positive NSCLC patients treated with EGFR TKIs. RESULTS: ILK, when highly expressed, was an independent poor prognostic factor for the progression-free survival of the patients, both in the univariate (hazard ratio [HR for disease progression, 2.49; 95% CI, 1.37-4.52; P = .0020]) and in the multivariate (HR 3.74; 95% CI, 1.33-10.56; P = .0126) Cox regression model. Patients with high SHP2 expression had an almost 13-month shorter progression-free survival (P = .0094) and an 18-month shorter overall survival (P = .0182) in comparison to those with low SHP2 mRNA expression. INTERPRETATION: The levels of ILK and SHP2 could be predictive for upfront combinatory therapy of EGFR TKIs plus SHP2 or ILK inhibitors. FUND: A grant from La Caixa Foundation, an Instituto de Salud Carlos III grant (RESPONSE, PIE16/00011), an Instituto de Salud Carlos III grant (PI14/01678), a Marie Sklodowska-Curie Innovative Training Networks European Grant (ELBA No 765492) and a Spanish Association Against Cancer (AECC) grant (PROYE18012ROSE).


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Serina-Treonina Quinases/genética , Regulação para Cima , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento de Hepatócito/genética , Humanos , Interleucina-6/genética , Sistema de Sinalização das MAP Quinases , Masculino , Mutação , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Análise de Regressão
9.
Acta neurol. colomb ; 34(4): 239-244, oct.-dic. 2018. tab, graf
Artigo em Espanhol | LILACS | ID: biblio-973530

RESUMO

RESUMEN Se expone el caso de una mujer de 19 años a quien se le realizó el diagnóstico de un xantoastrocitoma pleomórfico anaplásico parietooccipital izquierdo, neoplasia poco frecuente que suele presentarse en la población pediátrica y en los adultos jóvenes. Dicho tumor debuta generalmente con crisis convulsivas y sus características histológicas patognomónicas son el pleomorfismo celular, la vacuolización lipídica de su citoplasma y la reactividad a la proteína ácida fibrilar glial (PAFG) y S100. El estudio de nuevos marcadores que puedan brindar otras oportunidades terapéuticas ha permitido encontrar mutaciones en el oncogén BRAF. Este tumor presenta una variante anaplásica más agresiva que se trata con cirugía y quimiorradiación. En nuestro caso, después de varias progresiones a otras intervenciones, se utilizó bevacizumab y carmustine como tratamiento de segunda línea con respuesta completa.


SUMMARY The case of a young woman of 19-years-old is presented; whom the diagnosis was made of a left parietal-occipital xanthoastrocytoma pleomorphic anaplastic; this neoplasia is rare and usually affects the pediatric and young adult population. This generally debuts with seizures and their pathognomonic histologic characteristics are the pleomorphic cells with cytoplasmatic lipid vacuolation and the reactivity of glial fibrillary acidic protein (GFAP) and S100. The study of new markers that may provide other therapeutic opportunities has allowed finding mutations in the BRAF oncogene. This tumor has a more aggressive anaplastic variant that is treated with surgery and chemoradation. In our case after several progressions to other interventions, we used bevacizumab and carmustine as second-line treatment obtaining complete response.


Assuntos
Radioterapia , Carmustina , Bevacizumab , Glioma , Antineoplásicos
10.
EBioMedicine ; 29: 112-127, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29433983

RESUMO

Epidermal growth factor receptor (EGFR)-mutation-positive non-smallcell lung cancer (NSCLC) is incurable, despite high rates of response to EGFR tyrosine kinase inhibitors (TKIs). We investigated receptor tyrosine kinases (RTKs), Src family kinases and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR-mutation-positive NSCLC. We performed gene expression analysis in two cohorts (Cohort 1 and Cohort 2) of EGFR-mutation-positive NSCLC patients treated with EGFR TKI. We evaluated the efficacy of gefitinib or osimertinib with the Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005 in vitro and in vivo. In Cohort 1, CUB domain-containing protein-1 (CDCP1) was an independent negative prognostic factor for progression-free survival (hazard ratio of 1.79, p=0.0407) and overall survival (hazard ratio of 2.23, p=0.0192). A two-gene model based on AXL and CDCP1 expression was strongly associated with the clinical outcome to EGFR TKIs, in both cohorts of patients. Our preclinical experiments revealed that several RTKs and non-RTKs, were up-regulated at baseline or after treatment with gefitinib or osimertinib. TPX-0005 plus EGFR TKI suppressed expression and activation of RTKs and downstream signaling intermediates. Co-expression of CDCP1 and AXL is often observed in EGFR-mutation-positive tumors, limiting the efficacy of EGFR TKIs. Co-treatment with EGFR TKI and TPX-0005 warrants testing.


Assuntos
Antígenos CD/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Moléculas de Adesão Celular/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Mutação , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos de Neoplasias , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Moléculas de Adesão Celular/agonistas , Sobrevivência Celular , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Ativação Enzimática , Receptores ErbB/antagonistas & inibidores , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Proteínas de Neoplasias/agonistas , Proteômica/métodos , Proteínas Proto-Oncogênicas/agonistas , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores Proteína Tirosina Quinases/agonistas , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Lung Cancer ; 113: 30-36, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29110845

RESUMO

BACKGROUND: A proportion of patients with NSCLC is diagnosed at 40 years or younger. These patients tend to be never-smokers, usually present with stage IV adenocarcinoma, and have somatic genomic alterations. Few studies have documented and analyzed epidemiological characteristics of this population. MATERIALS AND METHODS: We performed an international epidemiological analysis of 389 young patients with NSCLC. Data was collected from centers participating in the Latin American Consortium for Lung Cancer Research (AduJov-CLICaP). Patients were identified and data was retrospectively collected from different Latin American countries and Canada (Argentina=6, Canada=19, Colombia=29, Costa Rica=9, Mexico=219, Nicaragua=2, Panama=19, Perú=76 and Venezuela=10). The period of study was from 2012 to 2017. Inclusion criteria were: age 40 years or less and a histologically confirmed NSCLC. Clinical data was obtained, and EGFR mutation status and EML4-ALK translocation were collected. RESULTS: NSCLC patients aged 40 years or less accounted for approximately 4% of the total NSCLC population. Female patients accounted for 54.5%, while median age was of 37 years. Adenocarcinoma accounted for 86.1% (n=335/389), 72.5% (n=282/389; unknown=5) of patients were non-smokers, and 90.3% (n=351/389) had stage IV disease. Site of metastasis was obtained from 260/351 (unknown=91) stage IV patients (lung metastasis=40.0%, CNS metastasis=35.7%, and bone metastasis=31.5%). OS for the total population was 17.3 months (95%CI=13.9-20.7). OS for EGFRm(+)=31.4months (95%CI=11.6-51.3), EGFRm(-)=14.5months (95%CI=11.0-17.9) (p=0.005). OS for alk(+)=9.8months (95%CI=3.1-16.5) and alk(-)=5.6months (95%CI=3.9-7.3) (p=0.315). CONCLUSIONS: Patients aged 40 years or less account for a small but important proportion of NSCLC cases. Younger patients may have different characteristics compared to the older population. EGFRm and EML4-alk translocation frequency is higher than that of the general population.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutação , Proteínas de Fusão Oncogênica/genética , Adolescente , Adulto , Fatores Etários , Canadá/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Feminino , Genótipo , Humanos , América Latina/epidemiologia , Neoplasias Pulmonares/epidemiologia , Masculino , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
12.
J Natl Cancer Inst ; 109(9)2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28376152

RESUMO

Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response. Methods: We used MTT and clonogenic assays, immunoblotting, and quantitative polymerase chain reaction to evaluate the efficacy of EGFR TKI alone and in combination with STAT3 and Src inhibition in three EGFR-mutant NSCLC cell lines. The Chou-Talalay method was used for the quantitative determination of drug interaction. We examined tumor growth inhibition in one EGFR-mutant NSCLC xenograft model (n = 4 mice per group). STAT3 and YAP1 expression was evaluated in tumors from 119 EGFR-mutant NSCLC patients (64 in an initial cohort and 55 in a validation cohort) by quantitative polymerase chain reaction. Kaplan-Meier and Cox regression analyses were used to assess the correlation between survival and gene expression. All statistical tests were two-sided. Results: We discovered that lung cancer cells survive initial EGFR inhibitor treatment through activation of not only STAT3 but also Src-YAP1 signaling. Cotargeting EGFR, STAT3, and Src was synergistic in two EGFR-mutant NSCLC cell lines with a combination index of 0.59 (95% confidence interval [CI] = 0.54 to 0.63) for the PC-9 and 0.59 (95% CI = 0.54 to 0.63) for the H1975 cell line. High expression of STAT3 or YAP1 predicted worse progression-free survival (hazard ratio [HR] = 3.02, 95% CI = 1.54 to 5.93, P = .001, and HR = 2.57, 95% CI = 1.30 to 5.09, P = .007, respectively) in an initial cohort of 64 EGFR-mutant NSCLC patients treated with firstline EGFR TKIs. Similar results were observed in a validation cohort. Conclusions: Our study uncovers a coordinated signaling network centered on both STAT3 and Src-YAP signaling that limits targeted therapy response in lung cancer and identifies an unforeseen rational upfront polytherapy strategy to minimize residual disease and enhance clinical outcomes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Fosfoproteínas/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/biossíntese , Fosfoproteínas/genética , Inibidores de Proteínas Quinases/administração & dosagem , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Estudos Retrospectivos , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/biossíntese , Fator de Transcrição STAT3/genética , Transdução de Sinais , Fatores de Transcrição
13.
Neurooncol Pract ; 4(1): 15-23, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31385992

RESUMO

Background: The use of bevacizumab for recurrent glioblastoma is controversial. Here we show data on patients who responded to bevacizumab, then stopped bevacizumab for any reason other than progression and were rechallenged with bevacizumab at the time of subsequent progression. Methods: This retrospective study included 28 patients, classified in 2 cohorts: those for whom the first exposure to bevacizumab (BEV-1) was first-line treatment for newly diagnosed glioblastoma (Bev-F; N = 12) and those for whom BEV-1 was second- or third-line treatment for recurrent disease after standard treatment (Bev-S; N = 16). Results: All patients received standard radiotherapy plus temozolomide. Bev-F patients also received concomitant bevacizumab. All 28 patients received a total of 57 treatment lines with bevacizumab (12 first-line and 45 second- or further-line). Twenty-nine lines were rechallenges (BEV-2 [N = 26] or BEV-3 [N = 3]). Objective response to rechallenge was 58.6% and clinical benefit was 89.6%. Overall survival (OS) was 55 months for RPA class IV and 26.7 months for RPA class V patients (P = .01). OS was 26.7 months for Bev-F patients and 52.1 months for Bev-S patients (P = .004). Post-progression survival was 20 months for Bev-F patients and 39.6 months for Bev-S patients (HR = 0.26; P = .007). Conclusion: This is the largest study to examine the impact of a bevacizumab rechallenge in glioblastoma patients who had responded to previous bevacizumab treatment but who stopped before progression. Our findings indicate that these patients can attain a second response or clinical benefit from re-introduction of bevacizumab. The potential benefit from intermittent versus continuous treatment warrants comparison in clinical trials.

14.
Am J Clin Oncol ; 40(6): 631-638, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26270443

RESUMO

OBJECTIVE: To assess anaplastic lymphoma kinase (ALK) rearrangement detection with immunohistochemistry (IHC) and real-time polymerase chain reaction (RT-qPCR) in comparison with fluorescence in situ hybridization (FISH). METHODS: Tumor tissue samples from 230 patients with advanced non-small cell lung cancer (NSCLC) were analyzed by FISH to detect ALK rearrangements. Additional IHC tests using 5A4 clone and RT-qPCR (variants 1 to 5) were performed in 63 and 48 patients, respectively. RESULTS: Thirteen percent of FISH tests were not evaluable. From the remaining tests (n=200), 18 (9.0%) were ALK positive (ALK). ALK patients were significantly younger at the time of diagnosis (below 55 y, 14.3% vs. 5.5%, P=0.035), were light smokers (tobacco index <10, 12.6% vs. 4.1%, P=0.049), and presented adenocarcinoma with a mucinous component (30.8 vs. 8.0%, P=0.007). When comparing FISH with IHC using a cutoff of 1+ or 2+, and only 2+ staining intensity, the sensitivity, specificity, negative predictive value, and positive predictive value were as follows: 83.3%, 100.0%, 93.75%, and 100.0%; and 55.6%, 100.0%, 84.9%, and 100.0%, respectively. For RT-qPCR, these results were 55.6, 100, 90.7, and 100.0%, respectively. CONCLUSIONS: Our results suggest that RT-qPCR is an inadequate initial test for detecting ALK-positive lung cancer. IHC is highly useful as an initial screening test for ALK rearrangement detection in NSCLC. These results contribute to the medical literature on the establishment of IHC as a standard diagnostic test for ALK rearrangements in NSCLC.


Assuntos
Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Proteínas de Fusão Oncogênica/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Estadiamento de Neoplasias , Proteínas de Fusão Oncogênica/metabolismo , Valor Preditivo dos Testes , Reação em Cadeia da Polimerase em Tempo Real
15.
PLoS One ; 11(5): e0154293, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27191954

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of pemetrexed, carboplatin and bevacizumab (PCB) followed by maintenance therapy with pemetrexed and bevacizumab (PB) in chemotherapy-naïve patients with stage IV non-squamous non-small cell lung cancer (NSCLC) through the influence of thymidylate synthase (TS) protein and mRNA expression on several outcomes. The primary endpoints were the overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). METHODS: A cohort of 144 patients were administered pemetrexed (500 mg/m2), carboplatin (AUC, 5.0 mg/ml/min) and bevacizumab (7.5 mg/kg) intravenously every three weeks for up to four cycles. Maintenance PB was administered until disease progression or unacceptable toxicity. RESULTS: One hundred forty-four Colombian patients with a median follow-up of 13.8 months and a median number of 6 maintenance cycles (range, 1-32) were assessed. The ORR among the patients was 66% (95% CI, 47% to 79%). The median PFS and (OS) rates were 7.9 months (95% CI, 5.9-10.0 months) and 21.4 months (95% CI, 18.3 to 24.4 months), respectively. We documented grade 3/4 hematologic toxicities, including anemia (14%), neutropenia (8%), and thrombocytopenia (16%). The identified grade 3/4 non-hematologic toxicities were proteinuria (2%), venous thrombosis (4%), fatigue (11%), infection (6%), nephrotoxicity (2%), and sensory neuropathy (4%). No grade >3 hemorrhagic events or hypertension cases were reported. OS was significantly higher in patients with the lowest TS mRNA levels [median, 29.6 months (95% CI, 26.2-32.9)] compared with those in patients with higher levels [median, 9.3 months (95% CI, 6.6-12.0); p = 0.0001]. TS expression (mRNA levels or protein expression) did not influence the treatment response. CONCLUSION: Overall, PCB followed by maintenance pemetrexed and bevacizumab was effective and tolerable in Hispanic patients with non-squamous NSCLC. This regimen was associated with acceptable toxicity and prolonged OS, particularly in patients with low TS expression. We found a role for Ki67 and TS expression as prognostic factors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Expressão Gênica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Timidilato Sintase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Biópsia , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Terapia Combinada , Feminino , Humanos , Quimioterapia de Indução , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Pemetrexede/administração & dosagem , Prognóstico , Fatores de Risco , Resultado do Tratamento
16.
Neurooncol Pract ; 3(3): 164-172, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31386063

RESUMO

Background: Low-grade gliomas (LGGs) are classified by the World Health Organization as astrocytoma (DA), oligodendroglioma (OD), and mixed oligoastrocytoma (OA). TP53 mutation and 1p19q codeletion are the most-commonly documented molecular abnormalities. Isocitrate dehydrogenase (IDH) 1/2 mutations are frequent in LGGs; however, IDH-negative gliomas can also occur. Recent research suggests that ATRX plays a significant role in gliomagenesis. Methods: We investigated p53 and Olig2 protein expression, and MGMT promoter methylation, 1p19q codeletion, IDH, and ATRX status in 63 Colombian patients with LGG. The overall survival (OS) rate was estimated and compared according to genotype. Results: The most common histology was DA, followed by OD and OA. IDH1/2 mutations were found in 57.1% and MGMT+ (positive status of MGMT promoter methylation methyl-guanyl-methyl-transferase gene) in 65.1% of patients, while overexpression of p53 and Olig2 was present in 30.2% and 44.4%, respectively, and 1p19q codeletion in 34.9% of the patients. Overexpression of ATRX was analyzed in 25 patients, 16% tested positive and were also mutations in isocitrate dehydrogenase and negative 1p19q-codelition. The median follow-up was 15.8 months (95% CI, 7.6-42.0) and OS was 39.2 months (95% CI, 1.3-114). OS was positively and significantly affected by MGMT+, 1p19q codeletion, surgical intervention extent, and number of lobes involved. Multivariate analysis confirmed that MGMT methylation status and 1p19q codeletion affected OS. Conclusions: This is the first study evaluating the molecular profile of Hispanic LGG patients. Findings confirmed the prognostic relevance of MGMT methylation and 1p19q codeletion, but do not support IDH1/2 mutation as a relevant marker. The latter may be explained by sample size and selection bias. ATRX alterations were limited to patients with DA and were mutations in isocitrate dehydrogenase and negative 1p19q-codelition.

17.
Cochrane Database Syst Rev ; (5): CD004783, 2015 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-26002823

RESUMO

BACKGROUND: This is an update of the original review published in 2005. Acute laryngitis is a common illness worldwide. Diagnosis is often made by case history alone and treatment often targets symptoms. OBJECTIVES: To assess the effectiveness and safety of different antibiotic therapies in adults with acute laryngitis. A secondary objective was to report the rates of adverse events associated with these treatments. SEARCH METHODS: We searched CENTRAL (2014, Issue 11), MEDLINE (January 1966 to November week 3, 2014), EMBASE (1974 to December 2014), LILACS (1982 to December 2014) and BIOSIS (1980 to December 2014). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing any antibiotic therapy with placebo for acute laryngitis. The main outcome was objective voice scores. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and synthesised data. MAIN RESULTS: We included three RCTs (351 participants) that had moderate to high risk of bias. The quality of the evidence was very low for all outcomes. We downgraded the studies because of limitations in study design or execution (risk of bias), imprecision and inconsistency of results. We included a new trial presented only as a conference abstract in this update.In one study of acute laryngitis in adults, 100 participants were randomised to receive penicillin V (800 mg twice daily for five days) or an identical placebo. A recording of each patient reading a standardised text was made at the first visit, during re-examination after one and two weeks, and at follow-up after two to six months. No significant differences were found between the groups. The trial also measured symptoms reported by participants and found no significant differences.One study investigated erythromycin for acute laryngitis in 106 adults. The mean objective voice scores measured at the first visit, at re-examination after one and two weeks, and at follow-up after two to six months did not significantly differ between the groups. At one week there were significant beneficial differences in the severity of reported vocal symptoms (slight, moderate and severe) as judged by participants (P value = 0.042). However, the rates of participants having improved voice disturbance (subjective symptoms) at one and two weeks were not significantly different among groups. Comparing erythromycin and placebo groups on the rate of persistence of cough at two weeks, the risk ratio (RR) was 0.38 (95% confidence interval (CI) 0.15 to 0.97, P value = 0.04) and the number needed to treat for an additional beneficial outcome (NNTB) was 5.87 (95% CI 3.09 to 65.55). We calculated a RR of 0.64 (95% CI 0.46 to 0.90, P value = 0.034) and a NNTB of 3.76 (95% CI 2.27 to 13.52; P value = 0.01) for the subjective voice scores at one week.A third trial from Russia included 145 patients with acute laryngitis symptoms. Participants were randomised to three treatment groups: Group 1: seven-day course of fusafungine (six times a day by inhalation); Group 2: seven-day course of fusafungine (six times a day by inhalation) plus clarithromycin (250 mg twice daily for seven days); Group 3: no treatment. Clinical cure rates were measured at days 5 ± 1, 8 ± 1 and 28 ± 2. The authors reported significant differences in the rates of clinical cure at day 5 ± 1 favouring fusafungine (one trial; 93 participants; RR 1.50, 95% CI 1.02 to 2.20; P value = 0.04) and fusafungine plus clarithromycin (one trial 97 participants; RR 1.47, 95% CI 1.00 to 2.16; P value = 0.05) when compared to no treatment. However, no significant differences were found at days 8 ± 1 and 28 ± 2. Also, no significant differences were found when comparing fusafungine to fusafungine plus clarithromycin at days 5 ± 1, 8 ± 1 and 28 ± 2. AUTHORS' CONCLUSIONS: Antibiotics do not appear to be effective in treating acute laryngitis when assessing objective outcomes. They appear to be beneficial for some subjective outcomes. Erythromycin could reduce voice disturbance at one week and cough at two weeks when measured subjectively. Fusafungine could increase the cure rate at day five. The included RCTs had important methodological problems and these modest benefits from antibiotics may not outweigh their cost, adverse effects or negative consequences for antibiotic resistance patterns.


Assuntos
Antibacterianos/uso terapêutico , Laringite/tratamento farmacológico , Doença Aguda , Adulto , Claritromicina/uso terapêutico , Depsipeptídeos , Eritromicina/uso terapêutico , Fusarium , Humanos , Penicilina V/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
19.
Lung Cancer ; 87(2): 169-75, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25558790

RESUMO

OBJECTIVES: In non-small cell lung cancer (NSCLC), the association between common EGFR mutations (Del EX19/L858R) with EGFR tyrosine kinase inhibitors (EGFR-TKIs) has been well established. However, this has not been investigated for rare EGFR mutations or their impact on treatment response and outcome to EGFR TKIs (primary objective) and chemotherapy (secondary objective). MATERIALS AND METHODS: In an observational prospective cohort, we analyzed 188 NSCLC patients from Mexico, Colombia and Costa Rica with EGFR mutations. As a first line of treatment, 66.5% received platinum-based chemotherapy. All patients received TKIs in first-line treatment or after progression to chemotherapy. The clinical-pathological characteristics as well as the f of common and rare EGFR mutations associated with treatment response were analyzed. RESULTS: Of all patients, 79.5% had common and 20.5% had rare EGFR mutations. Lepidic and acinar adenocarcinomas were associated with common EGFR mutations (p=0.010). Patients with common EGFR mutations had higher response rates to EGFR-TKIs than those who had rare EGFR mutations (63.8 vs 32.4%, p<0.001). Women had increased progression-free survival (PFS) to EGFR-TKIs than men (16.4 vs 9.5 months, p=0.02). The median PFS and overall survival (OS) were better in patients with common EGFR mutations (15.5 vs 3.9 months, p<0.001; and 37.3 vs 17.4 months, p<0.001) respectively. CONCLUSION: Our findings suggested that only patients with rare EGFR mutations could receive platinum-based chemotherapy as a first-line treatment, due to their low response rates and short PFS in response to EGFR-TKIs. Consequently, EGFR-TKIs could be reserved as a second- or third-line treatment. In patients with EGFR mutations, women have better PFS to EGFR-TKIs than men, and rare EGFR mutations are more frequent in high grade adenocarcinomas than in low grade tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Análise Mutacional de DNA , Éxons , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Platina/administração & dosagem , Estudos Prospectivos , Inibidores de Proteínas Quinases/administração & dosagem , Fatores de Risco , Resultado do Tratamento
20.
Cochrane Database Syst Rev ; (10): CD010340, 2014 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-25356860

RESUMO

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, not malignant, disease of the hematopoietic stem cells, associated with significant morbidity and mortality. It is a rare disease with an estimated incidence of 1.3 new cases per one million individuals per year. The treatment of PNH has been largely empirical and symptomatic, with blood transfusions, anticoagulation, and supplementation with folic acid or iron. Eculizumab, a biological agent that inhibits complement cascade, was developed for preventing hemolytic anemia and severe thrombotic episodes. OBJECTIVES: To assess the clinical benefits and harms of eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria (PNH). SEARCH METHODS: We conducted a comprehensive search strategy. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2014, Issue 5), Ovid MEDLINE (from 1946 to 15 May 2014), EMBASE (from 1980 to 25 June 2014), and LILACS (from 1982 to 25 June 2014). We did not apply any language restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) irrespective of their publication status or language. No limits were applied with respect to period of follow-up. We excluded quasi-RCTs. We included trials comparing eculizumab with placebo or best available therapy. We included any patient with a confirmed diagnosis of PNH. Primary outcome was overall survival. DATA COLLECTION AND ANALYSIS: We independently performed a duplicate selection of eligible trials, risk of bias assessment, and data extraction. We estimated risk ratios (RRs) and 95% confidence interval (CIs) for dichotomous outcomes, and mean differences (MDs) and 95% CIs for continuous outcomes. We used a random-effects model for analysis. MAIN RESULTS: We identified one multicenter (34 sites) phase III RCT involving 87 participants. The trial compared eculizumab versus placebo, and was conducted in the US, Canada, Europe, and Australia with 26 weeks of follow-up. This small trial had high risk of bias in many domains (attrition and selective reporting). It was sponsored by a pharmaceutical company. No patients died during the study. By using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (scores can range from 0 to 100, with higher scores on the global health status and functioning scales indicating improvement), the trial showed improvement in health-related quality of life in patients treated with eculizumab (mean difference (MD) 19.4, 95% CI 8.25 to 30.55; P = 0.0007; low quality of evidence). By using the Functional Assessment of Chronic Illness Therapy Fatigue instrument (scores can range from 0 to 52, with higher scores indicating improvement in fatigue), the trial showed a reduction in fatigue (MD 10.4, 95% CI 9.97 to 10.83; P = 0.00001; moderate quality of evidence) in the eculizumab group compared with placebo. Eculizumab compared with placebo showed a greater proportion of patients with transfusion independence: 51% (22/43) versus 0% (0/44); risk ratio (RR) 46.02, 95% CI 2.88 to 735.53; P = 0.007; moderate quality of evidence; and withdrawal for any reason: 4.7% (2/43) versus 22.72% (10/44); RR 0.20, 95% CI 0.05 to 0.88; P = 0.03; moderate quality of evidence. Due to the low rate of events observed, the included trial did not show any difference between eculizumab and placebo in terms of serious adverse events: 9.3% (4/43) versus 20.4% (9/44); RR 0.15, 95% CI 0.15 to 1.37; P = 0.16; low quality of evidence. We did not observe any difference between intervention and placebo for the most frequent adverse events. One participant receiving placebo showed an episode of thrombosis. The trial did not assess overall survival, transformation to myelodysplastic syndrome and acute myelogenous leukemia, or development or recurrence of aplastic anemia on treatment. AUTHORS' CONCLUSIONS: This review has detected an absence of evidence for eculizumab compared with placebo for treating paroxysmal nocturnal hemoglobinuria (PNH), in terms of overall survival, nonfatal thrombotic events, transformation to myelodysplastic syndrome and acute myelogenous leukemia, and development and recurrence of aplastic anemia on treatment. Current evidence indicates that compared with placebo, eculizumab increases health-related quality of life and increases transfusion independence. During the execution of the included trial, no patients died. Furthermore, the intervention seems to reduce fatigue and withdrawals for any reason. The safety profile of eculizumab is unclear. These conclusions are based on one small trial with risk of attrition and selective reporting bias.Therefore, prescription of eculizumab for treating patients with PNH can neither be supported nor rejected, unless new evidence from a large high quality trial alters this conclusion. Therefore, we urge the reader to interpret the trial results with much caution. Future trials on this issue should be conducted according to the SPIRIT statement and reported according to the CONSORT statement by independent investigators, and using the Foundation of Patient-Centered Outcomes Research recommendations.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Hemoglobinúria Paroxística/tratamento farmacológico , Ensaios Clínicos Fase III como Assunto , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto
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