RESUMO
BACKGROUND: Anti-angiogenic regulators may have therapeutic implications for onset and progression of atherosclerosis. OBJECTIVES: To demonstrate histological changes secondary to the use of bevacizumab in the aorta of pigs after interruption of flow in the vasa vasorum. METHODS: Twelve pigs were divided into two groups. The intercostal arteries of the descending aorta were dissected and ligated and wrapped with a polyvinyl chloride membrane. The treatment group received an intravenous dose of bevacizumab. After 15 days, the animals were euthanized and the aorta removed. Histological slides were prepared for control and treatment groups and for non-manipulated areas and analyzed for degree of angiogenesis, injury, inflammation, and intimal thickening. Data were expressed as mean (SD) of scores and groups were compared using the Mann-Whitney test. The Poisson distribution was used to calculate 95% confidence intervals for mean scores, in order to determine effect statistics. RESULTS: Bevacizumab had adverse effects on all treated pigs. The analysis using a Scale of Magnitudes for Effect Statistics showed a trend toward a decrease in angiogenesis [0.58 (1.79/-0.63)] and injury [0.55 (1.76/-0.66)] and an increase in inflammation [0.67 (1.89/-0.55)] with threshold moderate effects. There was no difference in intimal thickening [0 (1.19/-1.19)]. CONCLUSIONS: The medication exhibited a trend toward reduced angiogenesis and injury, but no reduction in the inflammatory process or intimal thickening of the aortic wall. These findings are in disagreement with studies that correlate neovascularization with increased migration of inflammatory cells. Bevacizumab exhibited toxicity in the porcine model.
CONTEXTO: Agentes antiangiogênicos podem ter implicações terapêuticas na progressão e manifestação da aterosclerose. OBJETIVOS: Demonstrar a alteração histológica secundária ao uso de bevacizumabe na aorta descendente de suínos submetida à interrupção dos vasa vasorum. MÉTODOS: Em doze suínos, divididos em dois grupos, foi realizada dissecção da aorta torácica, além de ligadura das artérias intercostais e proteção com polivinil. O grupo tratamento recebeu dose endovenosa de bevacizumabe. Após 15 dias, os animais foram sacrificados para retirada da artéria e preparo das lâminas histológicas dos grupos tratamento, controle e áreas não manipuladas para análise quanto aos graus de angiogênese, injúria, inflamação e espessamento intimal. A análise estatística foi conduzida através da média e do desvio padrão dos escores. As comparações entre os grupos foram realizadas pelo teste de Mann-Whitney. A distribuição de Poisson calculou os intervalos de confiança de 95% para as médias, a fim de determinar o efeito estatístico. RESULTADOS: O bevacizumabe causou efeitos adversos em todos os suínos tratados. As variáveis analisadas através da Escala de Magnitude para Efeito Estatístico demonstraram tendência de redução da angiogênese [0,58 (1,79/-0,63)] e da injúria [0,55 (1,76/-0,66)] e aumento da inflamação [0,67 (1,89/-0,55)] no limite do moderado. Não ocorreu diferença no espessamento intimal [0 (1,19/-1,19)]. CONCLUSÕES: A medicação utilizada mostrou tendência de redução da angiogênese e da injúria, mas não reduziu o processo inflamatório ou o espessamento intimal da parede arterial. Esses achados contrariam estudos que correlacionam a neovascularização com o aumento da migração de células inflamatórias. O bevacizumabe mostrou toxicidade no modelo suíno.
RESUMO
Background Anti-angiogenic regulators may have therapeutic implications for onset and progression of atherosclerosis. Objectives To demonstrate histological changes secondary to the use of bevacizumab in the aorta of pigs after interruption of flow in the vasa vasorum. Methods Twelve pigs were divided into two groups. The intercostal arteries of the descending aorta were dissected and ligated and wrapped with a polyvinyl chloride membrane. The treatment group received an intravenous dose of bevacizumab. After 15 days, the animals were euthanized and the aorta removed. Histological slides were prepared for control and treatment groups and for non-manipulated areas and analyzed for degree of angiogenesis, injury, inflammation, and intimal thickening. Data were expressed as mean (SD) of scores and groups were compared using the Mann-Whitney test. The Poisson distribution was used to calculate 95% confidence intervals for mean scores, in order to determine effect statistics. Results Bevacizumab had adverse effects on all treated pigs. The analysis using a Scale of Magnitudes for Effect Statistics showed a trend toward a decrease in angiogenesis [0.58 (1.79/-0.63)] and injury [0.55 (1.76/-0.66)] and an increase in inflammation [0.67 (1.89/-0.55)] with threshold moderate effects. There was no difference in intimal thickening [0 (1.19/-1.19)]. Conclusions The medication exhibited a trend toward reduced angiogenesis and injury, but no reduction in the inflammatory process or intimal thickening of the aortic wall. These findings are in disagreement with studies that correlate neovascularization with increased migration of inflammatory cells. Bevacizumab exhibited toxicity in the porcine model
Agentes antiangiogênicos podem ter implicações terapêuticas na progressão e manifestação da aterosclerose. Objetivos Demonstrar a alteração histológica secundária ao uso de bevacizumabe na aorta descendente de suínos submetida à interrupção dos vasa vasorum. Métodos Em doze suínos, divididos em dois grupos, foi realizada dissecção da aorta torácica, além de ligadura das artérias intercostais e proteção com polivinil. O grupo tratamento recebeu dose endovenosa de bevacizumabe. Após 15 dias, os animais foram sacrificados para retirada da artéria e preparo das lâminas histológicas dos grupos tratamento, controle e áreas não manipuladas para análise quanto aos graus de angiogênese, injúria, inflamação e espessamento intimal. A análise estatística foi conduzida através da média e do desvio padrão dos escores. As comparações entre os grupos foram realizadas pelo teste de Mann-Whitney. A distribuição de Poisson calculou os intervalos de confiança de 95% para as médias, a fim de determinar o efeito estatístico. Resultados O bevacizumabe causou efeitos adversos em todos os suínos tratados. As variáveis analisadas através da Escala de Magnitude para Efeito Estatístico demonstraram tendência de redução da angiogênese [0,58 (1,79/-0,63)] e da injúria [0,55 (1,76/-0,66)] e aumento da inflamação [0,67 (1,89/-0,55)] no limite do moderado. Não ocorreu diferença no espessamento intimal [0 (1,19/-1,19)]. Conclusões A medicação utilizada mostrou tendência de redução da angiogênese e da injúria, mas não reduziu o processo inflamatório ou o espessamento intimal da parede arterial. Esses achados contrariam estudos que correlacionam a neovascularização com o aumento da migração de células inflamatórias. O bevacizumabe mostrou toxicidade no modelo suíno
Assuntos
Animais , Aorta Torácica , Suínos , Vasa Vasorum , Inibidores da Angiogênese/uso terapêutico , Modelos Animais , Aterosclerose , Placa Aterosclerótica , Bevacizumab/efeitos dos fármacos , InflamaçãoRESUMO
OBJETIVO: evaluar el efecto de la fotocoagulación panretinal e inyección intravítrea de bevacizumab sobre las áreas de neovascularización en pacientes con retinopatía diabética proliferativa activa. MÉTODOs: estudio experimental en 80 ojos de 62 pacientes con retinopatía diabética proliferativa con características de alto riesgo, a quienes se les asignó aleatoriamente fotocoagulación panretinal (Grupo L) o fotocoagulación panretinal con bevacizumab intravítreo (Grupo L + B). Variables: edad, sexo, color de la piel, tipo de diabetes mellitus, tiempo de evolución, tipo de tratamiento, área de difusión de fluoresceína y regresión de neovascularización retinal y/o del disco óptico. Se realizó un seguimiento de 9 meses. RESULTADOS: en la evaluación inicial el área media de difusión fue de 8,95 mm2 en el grupo L y de 10,08 mm2 en el grupo L + B (p = 0,347), que se modificó a 6,40 mm2 y 3,91 mm2 (p = 0,012) al mes; 3,15 mm2 y 1,02 mm2(p = 0,002) a los tres meses; 2,45 mm2 y 0,58 mm2 (p = 0,001) a los seis meses; 2,18 mm2 y 0,46 mm2 (p = 0,001) a los nueve meses, respectivamente. El análisis de las diferencias absolutas de los promedios mostró una reducción significativa de las áreas de difusión a favor del tratamiento combinado en comparación con el momento inicial. CONCLUSIONES: en pacientes con retinopatía diabética proliferativa activa el bevacizumab intravítreo combinado con fotocoagulación panretinal produjo regresión dramática de la neovascularización, permaneciendo estable desde el tercer mes al noveno.
OBJECTIVE: to evaluate the effect of panretinal photocoagulation and intravitreal injection of bevacizumab on neovascularization areas of patients with active proliferative diabetic retinopathy. METHODS: experimental study conducted in 80 eyes from 62 patients with proliferative diabetic retinopathy with high risk characteristics. These patients were randomly assigned to panretinal photocoagulation group (group L) or to the panretinal photocoagulation plus intravitreal bevacizumab group (group L + B). The studied variables were age, sex, race, type of diabetes mellitus, illness duration, type of treatment, fluorescein distribution area and retinal/optical disc neovascularization regression area. They were followed-up for 9 months. RESULTS: in the initial evaluation, the average diffusion area was 8,95 mm2 in group L and 10,08 mm2 in group L + B (p = 0,347), which changed to 6,40 mm2 and 3,91 mm2 (p = 0,012) respectively, after one month; 3,15 mm2 and 1,02 mm2 (p = 0,002) three months later, 2,45 mm2 and 0,58 mm2 (p = 0,001) after six months and 2,18 mm2 and 0,46 mm2 (p = 0,001) after nine months, respectively. The analysis of absolute differences of averages showed a significant reduction in the distribution areas of fluorescein that favored the combined therapy. CONCLUSIONS: in patients with active proliferative diabetic retinopathy, intravitreal bevacizumab combined with panretinal photocoagulation bring about dramatic regression of neovascularization, which remained stable from the third to the ninth month.
Assuntos
Humanos , Pessoa de Meia-Idade , Idoso , Neovascularização Retiniana/patologia , Neovascularização Retiniana/terapia , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Retinopatia Diabética/complicações , Retinopatia Diabética/terapia , Fotocoagulação , Ensaio ClínicoRESUMO
Introducción: Los tumores cerebrales continúan siendo una patología de mal pronóstico, lo que se refleja en la baja expectativa de vida de quienes los padecen. La angiogénesis es un proceso cardinal en el crecimiento tumoral y en la producción de metástasis. No obstante el conocimiento de los mecanismos subyacentes a la oncogénesis, las terapias continúan obteniendo resultados modestos. Está demostrado que el parénquima tumoral secreta factores que estimulan la cascada angiogénica. Sin embargo, no existen trabajos que evalúen el efecto angiogénico del líquido cefalorraquídeo (LCR). La hipótesis propuesta en este trabajo es que el LCR de los pacientes con tumores primarios del sistema nervioso central (SNC), posee en sí mismo propiedades angiogénicas. Material y Método: Estudio experimental preclínico. Se utilizó, en ciento ochenta huevos de gallina White Leghorn, el modelo de membrana alantocoriónica (MAC) de pollo. Estos huevos fueron incubados y sobre la membrana se implantaron filtros de metilcelulosa con líquidos cefalorraquídeos de pacientes con diferentes tumores cerebrales. Al grupo control se le adicionó suero fisiológico. Tras diez días de incubación se realizaron cortes histológicos de las muestras y se procedió al conteo de vasos sanguíneos en un microscopio con rejilla graduada. Resultados: Se demostró con significancia estadística (p<0,05) que existe efecto angiogénico en el LCR de pacientes con tumores primarios del SNC. Discusión: A partir de los resultados obtenidos, podemos proyectar futuros trabajos hacia nuevas terapias enfocadas en la angiogénesis diferencial. Los factores angiogénicos presentes en el LCR podrían constituir un nuevo blanco terapéutico contra los tumores cerebrales.
Introduction: Nowadays, brain tumors remains being a poor-prognosis pathology, which is reflected in the low life expectancy of the patients. The angiogenesis, is a fundamental process in the tumoral growing and the metastatic feasibility. In spite of knowing of the underlying mechanism of the oncogenesis, therapies still get poor results. It is demonstrated that tumoralparenchyma secretes factors that enhance the angiogenic cascade. However, any work has ever evaluated the angiogenic effect in the cerebrospinal fluid (CSF) itself. We hypothesize that CSF belonging of patients with primary central nervous system (CNS) brain tumors, presents angiogenic properties on their own. Material and Method: Preclinical experimental trial. In 180 eggs of White Legorn chicken it was used the chorioallantoic membrane (CAMA) assay. This eggs were incubated for tendays and over the membrane were implanted methylcellulose filters containing cerebrospinal fluid coming from patients affected by different brain tumors. The control group was instilledwith saline solution. It was performed different histological sections of the samples and then proceeded to the counting of the vessels in a microscope with a squared grille inside it. Results:We demonstrated with statistical significance (p<0.05) that CSF from primary brain tumors affected patients presents angiogenic effect. Discussion: Owing the presented results, we can plan future investigations targeting new therapies focused on the differential angiogenesis. The angiogenic factors in the CSF could represent a new therapeutic target against brain tumors.
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Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Indutores da Angiogênese/líquido cefalorraquidiano , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/líquido cefalorraquidiano , Neovascularização Patológica/líquido cefalorraquidiano , Embrião de Galinha , Membrana CorioalantoideRESUMO
OBJECTIVE: To demonstrate the role of angiogenesis in the progression of cutaneous squamous cell carcinoma. INTRODUCTION: Angiogenesis is a pivotal phenomenon in carcinogenesis. Its time course in cutaneous squamous cell carcinoma has not yet been fully established. METHODS: We studied the vascular bed in 29 solar keratoses, 30 superficially invasive squamous cell carcinomas and 30 invasive squamous cell carcinomas. The Chalkley method was used to quantify the microvascular area by comparing panendothelial (CD34) with neoangiogenesis (CD105) immunohistochemical markers. The vascular bed from non-neoplastic adjacent skin was evaluated in 8 solar keratoses, 10 superficially invasive squamous cell carcinomas and 10 invasive squamous cell carcinomas. RESULTS: The microvascular area in CD105-stained specimens significantly increased in parallel with cutaneous squamous cell carcinoma progression. However, no differences between groups were found in CD34 sections. Solar keratosis, superficially invasive squamous cell carcinoma and invasive squamous cell carcinoma samples showed significant increases in microvascular area for both CD34- and CD105-stained specimens compared with the respective adjacent skin. DISCUSSION: The angiogenic switch occurs early in the development of cutaneous squamous cell carcinoma, and the rate of neovascularization is parallel to tumor progression. In contrast to panendothelial markers, CD105 use allows a dynamic evaluation of tumor angiogenesis. CONCLUSION: This study demonstrated the dependence of skin carcinogenesis on angiogenesis.