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1.
Blood ; 137(5): 637-645, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32870269

RESUMO

Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, showed promising activity in relapsed or refractory (R/R) follicular lymphoma (FL) in a phase 1 study. We conducted a phase 2 trial to further evaluate its efficacy and safety in patients with R/R FL and to explore biomarkers of response. Patients with R/R FL and at least 2 prior lines of therapy, each containing a CD20 antibody or an alkylating agent, were treated with nivolumab 3 mg/kg every 2 weeks. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Biomarker analyses included gene expression profiling and multiplex immunofluorescence studies of pretreatment tumor samples. A total of 92 patients were treated. After a minimum follow-up of 12 months, ORR was 4% (4 of 92 patients). Median progression-free survival (PFS) was 2.2 months (95% confidence interval [CI], 1.9-3.6 months). Median duration of response was 11 months (95% CI, 8-14 months). Exploratory analyses suggested that responders had significantly higher proportion of CD3+ T cells in the tumor microenvironment than nonresponders, but no significant differences in PD-1 or programmed death-ligand 1 expression were observed. High expression of a set of tumor-associated macrophage genes was associated with reduced PFS (hazard ratio, 3.28; 95% CI, 1.76-6.11; P = .001). The safety profile was consistent with previous reports of nivolumab. In conclusion, nivolumab monotherapy was associated with very limited activity in patients with R/R FL. Better understanding of the immune biology of this disease may facilitate the development of effective checkpoint-based strategies. This trial was registered at www.clinicaltrials.gov as #NCT02038946.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Nivolumabe/uso terapêutico , Terapia de Salvação , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Linfoma Folicular/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Recidiva , Rituximab/administração & dosagem , Microambiente Tumoral
2.
Oncology ; 97(2): 102-111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31230047

RESUMO

BACKGROUND: Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the United States for the treatment of various B-cell malignancies. Preclinical data suggest synergistic antitumor activity of ibrutinib with programmed death-ligand 1 (PD-L1) inhibitors in solid tumors. This study evaluated ibrutinib plus durvalumab, a PD-L1-targeting antibody, in patients with relapsed/refractory solid tumors. METHODS: This open-label, multicenter, phase 1b/2 study enrolled previously treated patients with stage III/IV pancreatic adenocarcinoma, breast cancer, or non-small cell lung cancer (NSCLC). Phase 1b determined the recommended phase 2 dose (RP2D). In phase 2, patients were treated at the RP2D to evaluate the safety and antitumor activity of ibrutinib plus durvalumab. RESULTS: The RP2D was identified as ibrutinib 560 mg p.o. daily and durvalumab 10 mg/kg i.v. every 2 weeks, with 122 patients treated at the RP2D. Median age was 61 years, and the majority of patients (94%) had stage IV disease. Overall response rates (complete or partial responses) were 2% for pancreatic cancer, 3% for breast cancer, and 0% for NSCLC. Median progression-free survival was 1.7, 1.7, and 2.0 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. Median overall survival was 4.2, 4.2, and 7.9 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. The safety profiles observed across tumor types were consistent with the known safety profiles for ibrutinib and durvalumab. Grade ≥3 adverse events in ≥5% of all patients were hyponatremia (10%), dyspnea (7%), maculopapular rash (7%), pneumonia (7%), anemia (6%), and diarrhea (6%). CONCLUSIONS: The combination of ibrutinib 560 mg daily and durvalumab 10 mg/kg every 2 weeks had an acceptable safety profile. The antitumor activity of the ibrutinib-durvalumab combination was limited in our study population.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas , Estudos Prospectivos , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética
3.
Nat Biotechnol ; 24(1): 89-94, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16378095

RESUMO

The application of RNA interference (RNAi) to stem cell-based therapies will require highly specific and lineage-restricted gene silencing. Here we show the feasibility and therapeutic potential of coregulating transgene expression and RNAi in hematopoietic stem cells. We encoded promoterless small-hairpin RNA (shRNA) within the intron of a recombinant gamma-globin gene. Expression of both gamma-globin and the lariat-embedded small interfering RNA (siRNA) was induced upon erythroid differentiation, specifically downregulating the targeted gene in tissue- and differentiation stage-specific fashion. The position of the shRNA within the intron was critical to concurrently achieve high-level transgene expression, effective siRNA generation and minimal interferon induction. Lentiviral transduction of CD34(+) cells from patients with sickle cell anemia led to erythroid-specific expression of the gamma-globin transgene and concomitant reduction of endogenous beta(S) transcripts, thus providing proof of principle for therapeutic strategies that require synergistic gene addition and gene silencing in stem cell progeny.


Assuntos
Anemia Falciforme/genética , Anemia Falciforme/metabolismo , Terapia Genética/métodos , Globinas/genética , Globinas/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Interferência de RNA , Anemia Falciforme/patologia , Anemia Falciforme/terapia , Células Cultivadas , Regulação da Expressão Gênica/genética , Inativação Gênica , Marcação de Genes/métodos , Globinas/uso terapêutico , Humanos , Resultado do Tratamento
4.
J Clin Oncol ; 37(6): 481-489, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30620669

RESUMO

PURPOSE: Treatment options are limited for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Tumor cells can exploit the programmed death-1 checkpoint pathway to evade immune surveillance. In the current study, we evaluated the efficacy and safety of programmed death-1 blockade by nivolumab in patients with relapsed/refractory DLBCL. METHODS: In this phase II, open-label study, patients with relapsed/refractory DLBCL who were ineligible for autologous hematopoietic cell transplantation (auto-HCT) or who had experienced failure with auto-HCT received nivolumab 3 mg/kg every 2 weeks. We assessed the efficacy and safety of nivolumab as well as genetic alterations of 9p24.1. RESULTS: Among 121 treated patients, patients in the auto-HCT-failed cohort (n = 87) received a median of four nivolumab doses and a median of three doses were administered to those in the auto-HCT-ineligible cohort (n = 34). At a median follow-up of 9 months in the auto-HCT-failed cohort and 6 months in the auto-HCT-ineligible cohort, independently assessed objective response rates were 10% and 3%, and median durations of response were 11 and 8 months, respectively. Median progression-free survival and overall survival were 1.9 and 12.2 months in the auto-HCT-failed cohort and 1.4 and 5.8 months in the auto-HCT-ineligible cohort respectively. All three patients with complete remission-3% of the auto-HCT-failed cohort-had durable response (11 or more, 14 or more, and 17 months). Treatment-related grade 3 and 4 adverse events were reported in 24% of patients. The most common were neutropenia (4%), thrombocytopenia (3%), and increased lipase (3%). Of all evaluable samples for 9p24.1 analysis, 16% exhibited low-level copy gain and 3% had amplification. CONCLUSION: Nivolumab monotherapy is associated with a favorable safety profile but a low overall response rate among patients with DLBCL who are ineligible for auto-HCT or who experienced failure with auto-HCT. Genetic alterations of 9p24.1 are infrequent in DLBCL.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Cromossomos Humanos Par 9 , Progressão da Doença , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/cirurgia , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Indução de Remissão , Fatores de Tempo , Transplante Autólogo/efeitos adversos , Falha de Tratamento , Adulto Jovem
5.
Ann N Y Acad Sci ; 1054: 78-91, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16339654

RESUMO

The beta-thalassemias are congenital anemias that are caused by mutations that reduce or abolish expression of the beta-globin gene. They can be cured by allogeneic hematopoietic stem cell (HSC) transplantation, but this therapeutic option is not available to most patients. The transfer of a regulated beta-globin gene in autologous HSCs is a highly attractive alternative treatment. This strategy, which is simple in principle, raises major challenges in terms of controlling expression of the globin transgene, which ideally should be erythroid specific, differentiation- and stage-restricted, elevated, position independent, and sustained over time. Using lentiviral vectors, May et al. demonstrated in 2000 that an optimized combination of proximal and distal transcriptional control elements permits lineage-specific and elevated beta-globin expression, resulting in therapeutic hemoglobin production and correction of anemia in beta-thalassemic mice. Several groups have by now replicated and extended these findings to various mouse models of severe hemoglobinopathies, thus fueling enthusiasm for a potential treatment of beta-thalassemia based on globin gene transfer. Current investigation focuses on safety issues and the need for improved vector production methodologies. The safe implementation of stem cell-based gene therapy requires the prevention of the formation of replication-competent viral genomes and minimization of the risk of insertional oncogenesis. Importantly, globin vectors, in which transcriptional activity is highly restricted, have a lesser risk of activating oncogenes in hematopoietic progenitors than non-tissue-specific vectors, by virtue of their late-stage erythroid specificity. As such, they provide a general paradigm for improving vector safety in stem cell-based gene therapy.


Assuntos
Terapia Genética , Globinas/genética , Talassemia beta/terapia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Regulação Viral da Expressão Gênica , Inativação Gênica , Técnicas de Transferência de Genes , Terapia Genética/efeitos adversos , Vetores Genéticos/efeitos adversos , Vetores Genéticos/uso terapêutico , Globinas/biossíntese , HIV-1/genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Proteínas com Domínio LIM , Lentivirus/genética , Leucemia Linfoide/etiologia , Região de Controle de Locus Gênico/genética , Metaloproteínas/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Mutagênese Insercional , Oncogenes , Proteínas Proto-Oncogênicas , Retroviridae/genética , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia , Sequências Repetidas Terminais , Transgenes
6.
Best Pract Res Clin Haematol ; 17(3): 517-34, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15498721

RESUMO

The beta-thalassemias and sickle cell disease are severe congenital anemias that are caused by mutations that alter the production of the beta chain of hemoglobin. Allogeneic hematopoietic stem cell (HSC) transplantation is curative, but this therapeutic option is not available to the majority of patients. The transfer of a functional globin gene in autologous HCSs thus represents a highly attractive alternative treatment. This strategy, simple in principle, raises major challenges in terms of controlling the expression of the globin transgene, which ideally should be erythroid specific, differentiation-stage restricted, elevated, position independent, and sustained over time. Using lentiviral vectors, we have demonstrated that an optimised combination of proximal and distal transcriptional control elements permits lineage-specific, elevated expression of the beta-globin gene, resulting in therapeutic hemoglobin production and correction of anemia in beta-thalassemic mice. Several groups have now confirmed and extended these findings in various mouse models of severe hemoglobinopathies, thus generating enthusiasm for a genetic treatment based on globin gene transfer. Furthermore, globin vectors represent a general paradigm for the regulation of transgene function and the improvement of vector safety by restricting transgene expression to the differentiated progeny within a single lineage, thereby reducing the risk of activating oncogenes in hematopoietic progenitors. Here we review the principles underlying the genesis of regulated vectors for stem cell therapy.


Assuntos
Terapia Genética/métodos , Globinas/uso terapêutico , Hemoglobinopatias/terapia , Anemia Falciforme/terapia , Animais , Modelos Animais de Doenças , Globinas/genética , Humanos , Camundongos , Talassemia beta/terapia
7.
Cancer Genomics Proteomics ; 9(2): 77-92, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22399498

RESUMO

BACKGROUND: Although the addition of epidermal growth factor receptor (EGFR) antibodies to various platinum-based chemotherapy regimens for non-small cell lung cancer (NSCLC) is being actively pursued in the clinic, rationale for the prioritization of specific regimens is lacking. MATERIALS AND METHODS: We evaluated the antitumor effects of necitumumab, a recombinant human IgG1 antibody targeting EGFR, in combination with cisplatin plus gemcitabine, pemetrexed, or paclitaxel in a panel of 9 subcutaneous tumor models of NSCLC established in nu/nu athymic mice. RESULTS: Necitumumab in combination with cisplatin/gemcitabine was particularly effective, although interestingly, the mechanisms underlying these benefits were model dependent. For example, increased tumor cell apoptosis contributed towards combination efficacy in the A549 model, in association with increased expression of hsa-miR-29b and reduced expression of antiapoptotic genes including DNA methyltransferase DNMT3B, commonly up-regulated in patients with NSCLC. Such inverse effects of combination therapy on DNMT3B and hsa-miR-29b expression were found in multiple models. Importantly, in the A549 model, hsa-miR-29b down-regulation of DMNT3b reduced promoter methylation of tumor suppressor genes such as Cell adhesion molecule 1 (CADM1), Ras associated (RalGDS/AF-6) domain family member 1 (RASSF1), and Fragile histidine triad gene (FHIT), increasing their expression. CONCLUSION: These results offer a preclinical rationale for combining an EGFR antibody with cisplatin/gemcitabine for patients with NSCLC, and provide potential molecular biomarkers for tailoring therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Sequência de Bases , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Análise por Conglomerados , Metilação de DNA/efeitos dos fármacos , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Avaliação Pré-Clínica de Medicamentos , Receptores ErbB/imunologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Camundongos , Camundongos Nus , MicroRNAs/genética , Regiões Promotoras Genéticas , RNA Mensageiro/genética , Transdução de Sinais , Proteínas Supressoras de Tumor/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
8.
Anticancer Res ; 31(6): 2149-60, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21737635

RESUMO

BACKGROUND: Clinically relevant targets for developmental drug efficacy in animal models of cancer are critical yet understudied parameters. MATERIALS AND METHODS: Cetuximab, a chimeric antibody to epidermal growth factor receptor (EGFR), was administered to athymic mice bearing subcutaneous tumors established with 13 human colorectal cancer cell lines of varying biomarker status, defined by DNA sequencing and RT-PCR. RESULTS: If tumor growth inhibition is taken as a target, as is commonly done, then in contrast to the clinical situation where KRAS mutation strongly predicts for a lack of clinically meaningful benefit in colorectal cancer patients, cetuximab alone and in combination with irinotecan-based chemotherapy were efficacious in a similar proportion of KRAS wild-type and mutant models. It was only when tumor regression was utilized to define relevant efficacy that cetuximab monotherapy was efficacious in KRAS wild-type, but not mutant models. Adding cytotoxic therapy to cetuximab treatment increased tumor regression frequency in both genotypes to the point that once again the response was similar for KRAS wild-type and mutant models. CONCLUSION: Our data support shifting the threshold for claiming clinically relevant targeted therapy efficacy in subcutaneous xenograft models towards tumor regression, rather than tumor growth inhibition, focusing on the evaluation of tumor cells that are addicted to the pathways being targeted.


Assuntos
Anticorpos Monoclonais/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Genes ras , Mutação , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/metabolismo , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Cetuximab , Neoplasias Colorretais/metabolismo , Dosagem de Genes , Genes erbB-1 , Humanos , Irinotecano , Camundongos , Camundongos Nus , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Proteínas Proto-Oncogênicas B-raf/genética , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Neoplasia ; 13(1): 49-59, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21245940

RESUMO

The benefits of inhibiting vascular endothelial growth factor (VEGF) signaling in cancer patients are predominantly attributed to effects on tumor endothelial cells. Targeting non-endothelial stromal cells to further impact tumor cell growth and survival is being pursued through the inhibition of additional growth factor pathways important for the survival and/or proliferation of these cells. However, recent data suggest that VEGF receptor (VEGFR)-specific inhibitors may target lymphatic vessels and pericytes in addition to blood vessels. Here, in fact, we demonstrate that DC101 (40 mg/kg, thrice a week), an antibody specific to murine VEGFR2, significantly reduces all three of these stromal components in subcutaneous (SKRC-29) and orthotopic (786-O-LP) models of renal cell carcinoma (RCC) established in nu/nu athymic mice. Sunitinib (40 mg/kg, once daily), a receptor tyrosine kinase inhibitor of VEGFR2 and other growth factor receptors, also caused significant loss of tumor blood vessels in RCC models but had weaker effects than DC101 on pericytes and lymphatic vessels. In combination, sunitinib did not significantly add to the effects of DC101 on tumor blood vessels, lymphatic vessels, or pericytes. Nevertheless, sunitinib increased the effect of DC101 on tumor burden in the SKRC-29 model, perhaps related to its broader specificity. Our data have important implications for combination therapy design, supporting the conclusion that targeting VEGFR2 alone in RCC has the potential to have pleiotropic effects on tumor stroma.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Indóis/farmacologia , Neoplasias Renais/tratamento farmacológico , Pirróis/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/irrigação sanguínea , Carcinoma de Células Renais/patologia , Modelos Animais de Doenças , Interações Medicamentosas , Feminino , Humanos , Fator 1 Induzível por Hipóxia/biossíntese , Indóis/uso terapêutico , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/patologia , Vasos Linfáticos/efeitos dos fármacos , Vasos Linfáticos/patologia , Camundongos , Camundongos Nus , Mutação , Transplante de Neoplasias , Neovascularização Patológica , Pericitos/efeitos dos fármacos , Pericitos/patologia , Pirróis/uso terapêutico , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Sunitinibe , Carga Tumoral , Células Tumorais Cultivadas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Proteína Supressora de Tumor Von Hippel-Lindau/genética
10.
Mol Ther ; 6(6): 793-803, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12498775

RESUMO

Erythropoiesis has been considered as a potential treatment for beta-thalassemia. Although Epo secretion from genetically engineered muscles allowed long-term correction of the disease in the mouse, repeated injections of rHuEpo were disappointing in human patients. Whether different mechanisms operate in humans and mice or whether Epo exhibits different biological activity depending on the administration route is currently unknown. We provide evidence that mechanisms recruited over a 36-week follow-up in beta-thalassemic mice were similar to those acting during stress-induced erythropoiesis in humans. beta-Thalassemic mice were rendered steadily normocythemic by the intramuscular injection of a tetracycline-inducible AAV vector encoding mouse Epo. Doxycycline dosage was adapted to hematocrit. Circulating red blood cells essentially synthesized beta-minor globin, the mouse equivalent to human gamma-globin. Quantification of erythroid progenitors indicated a steady-state expansion of erythroid burst-forming units programmed for beta-minor globin synthesis and a hastening of their maturation to hemoglobin-synthesizing cells. We discuss hypotheses that could account for the failure to recruit this mechanism over the long term in beta-thalassemic patients and raise the possibility of Epo gene therapy trials to treat beta-thalassemia.


Assuntos
Doxiciclina/farmacologia , Eritropoetina/uso terapêutico , Terapia Genética/métodos , Músculos/efeitos dos fármacos , Músculos/metabolismo , Talassemia beta/genética , Talassemia beta/terapia , Animais , Células da Medula Óssea/citologia , Divisão Celular , Dependovirus/genética , Células Precursoras Eritroides/citologia , Eritropoetina/genética , Eritropoetina/metabolismo , Vetores Genéticos , Globinas/genética , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Baço/citologia , Fatores de Tempo
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