RESUMEN
PURPOSE: To compare the effectiveness of octreotide/everolimus vs. sunitinib for the systemic treatment of recurrent aggressive meningiomas. METHODS: 31 patients with recurrent or refractory WHO II or WHO III meningiomas were examined in two reference centers in Colombia. Patients who had systemic treatment (sunitinib, everolimus/octreotide) and a complete follow-up were included. Overall survival (OS), progression-free survival (PFS) and toxicities were evaluated. Additionally, tissue samples were examined for PDGFRß and VEGFR2, their expression was correlated with outcomes. RESULTS: Twenty-two patients (72%) were female with a median age of 55 years (SD±15.3). The most prevalent histology was anaplastic meningioma in 20 patients (65%) with 48% of patients suffering from three previous relapses before the start of systemic treatment. A total of 14 patients received combination therapy with octreotide/everolimus, 11 received sunitinib and the remaining 6 received other second-line agents. Median OS was 37.3 months (95%CI 28.5-42.1) and the PFS during the treatment with everolimus/octreotide (EO) and sunitinib (Su) was 12.1 months (95%CI 9.2-21.1) and 9.1 months (95%CI 6.8-16.8); p = 0.43), respectively. The OS of the group treated with the EOâSuâBev sequence (1st/2nd/3rd line) was 6.5 months longer than the SuâEOâBev sequence (36.0 vs. 29.5 months) (p = 0.0001). When analyzing molecular markers, the positive PDGFRß and negative VEGFR2 expression were associated with longer survival both in OS and PFS. CONCLUSION: Sunitinib and octreotide/everolimus have similar efficacy and safety in the systemic management of refractory meningioma. VEGFR2 and PDGFRß expression are associated with better outcomes.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores de Tumor/sangre , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Meníngeas , Meningioma , Proteínas de Neoplasias/sangre , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Everolimus/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Neoplasias Meníngeas/sangre , Neoplasias Meníngeas/tratamiento farmacológico , Neoplasias Meníngeas/mortalidad , Meningioma/sangre , Meningioma/tratamiento farmacológico , Meningioma/mortalidad , Persona de Mediana Edad , Octreótido/administración & dosificación , Estudios Retrospectivos , Sunitinib/administración & dosificación , Tasa de SupervivenciaRESUMEN
BACKGROUND: The effects of chronic exposure to exercise training on vascular biomarkers have been poorly explored. OBJECTIVE: Our study aimed to compare the amounts of endothelial progenitor cells (EPCs), and endothelial (EMP) and platelet (PMP) microparticles between professional runners and healthy controls. METHODS: Twenty-five half-marathon runners and 24 age- and gender-matched healthy controls were included in the study. EPCs (CD34+/KDR+, CD133+/KDR+, and CD34+/CD133+), EMP (CD51+) and PMP (CD42+/CD31+) were quantified by flow-cytometry. All blood samples were obtained after 12 h of fasting and the athletes were encouraged to perform their routine exercises on the day before. RESULTS: As compared with controls, the CD34+/KDR+ EPCs (p=0.038) and CD133+/KDR+ EPCs (p=0.018) were increased, whereas CD34+/CD133+ EPCs were not different (p=0.51) in athletes. In addition, there was no difference in MPs levels between the groups. CONCLUSION: Chronic exposure to exercise in professional runners was associated with higher percentage of EPCs. Taking into account the similar number of MPs in athletes and controls, the study suggests a favorable effect of exercise on these vascular biomarkers.
Asunto(s)
Atletas , Plaquetas/fisiología , Micropartículas Derivadas de Células/fisiología , Células Progenitoras Endoteliales/fisiología , Carrera/fisiología , Antígeno AC133/sangre , Antígenos CD34/sangre , Biomarcadores/sangre , Prueba de Esfuerzo , Femenino , Citometría de Flujo , Humanos , Masculino , Valores de Referencia , Espirometría , Estadísticas no Paramétricas , Factores de Tiempo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangreRESUMEN
Abstract Background: The effects of chronic exposure to exercise training on vascular biomarkers have been poorly explored. Objective: Our study aimed to compare the amounts of endothelial progenitor cells (EPCs), and endothelial (EMP) and platelet (PMP) microparticles between professional runners and healthy controls. Methods: Twenty-five half-marathon runners and 24 age- and gender-matched healthy controls were included in the study. EPCs (CD34+/KDR+, CD133+/KDR+, and CD34+/CD133+), EMP (CD51+) and PMP (CD42+/CD31+) were quantified by flow-cytometry. All blood samples were obtained after 12 h of fasting and the athletes were encouraged to perform their routine exercises on the day before. Results: As compared with controls, the CD34+/KDR+ EPCs (p=0.038) and CD133+/KDR+ EPCs (p=0.018) were increased, whereas CD34+/CD133+ EPCs were not different (p=0.51) in athletes. In addition, there was no difference in MPs levels between the groups. Conclusion: Chronic exposure to exercise in professional runners was associated with higher percentage of EPCs. Taking into account the similar number of MPs in athletes and controls, the study suggests a favorable effect of exercise on these vascular biomarkers.
Resumo Fundamento: Os efeitos da exposição crônica ao exercício sobre biomarcadores vasculares foram pouco estudados. Objetivo: Nosso estudo teve como objetivo comparar as quantidades de células progenitoras endoteliais (CPEs), e de micropartículas endoteliais (MPEs) e plequetárias (MPPs) de corredores profissionais com controles sadios. Métodos: Vinte e cinco corredores de meia maratona e 24 controles pareados quanto à idade e ao sexo foram incluídos no estudo. CPEs (CD34+/KDR+, CD133+/KDR+ e CD34+/CD133+), MPE (CD51+) e MPPs (CD42+/CD31+) foram quantificadas por citometria de fluxo. Todas as amostras de sangue foram obtidas após 12 horas de jejum, e os atletas foram incentivados a realizar seus exercícios de rotina no dia anterior à coleta. Resultados: Em comparação aos controles, CPEs CD34+/KDR+ (p=0,038) e CD133+/KDR+ (p=0,018) estavam aumentados, e CPEs CD34+/CD133+ não foram diferentes (p=0,51) nos atletas. As concentrações de MP não diferiram entre os grupos. Conclusão: A exposição crônica ao exercício em corredores profissionais associou-se a uma maior porcentagem de CPEs. Considerando o número similar de MPs entre atletas e controles, o estudo sugere um efeito favorável do exercício sobre esses biomarcadores vasculares.
Asunto(s)
Humanos , Masculino , Femenino , Carrera/fisiología , Plaquetas/fisiología , Micropartículas Derivadas de Células/fisiología , Atletas , Células Progenitoras Endoteliales/fisiología , Valores de Referencia , Espirometría , Factores de Tiempo , Biomarcadores/sangre , Estadísticas no Paramétricas , Antígenos CD34/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , Prueba de Esfuerzo , Citometría de Flujo , Antígeno AC133/sangreRESUMEN
INTRODUCTION: Vascular endothelial growth factor (VEGF) is a central mediator of angiogenesis in breast cancer. Research in antiangiogenic cancer treatment has been marked by the development of the monoclonal antibody bevacizumab, which targets VEGF in many solid tumors. As patients do not equally benefit from bevacizumab, it has become necessary to define the profile of patients who will benefit from the drug. MATERIALS AND METHODS: We have conducted a prospective phase II study in 39 patients using bevacizumab in breast cancer in the neoadjuvant setting, and found improved pathologic complete response (pCR) when bevacizumab was added to chemotherapy in patients with hormone receptor negative and invasive ductal carcinoma. Blood samples were collected at baseline and serially while patients were on treatment. Circulating angiogenesis-related proteins angiopoietin (ANG)1, ANG2, basic fibroblast growth factor, IL-1a, matrix metalloproteinase 9, platelet derived growth factor - BB, platelet endothelial cell adhesion molecule -1, Tie2, VEGF, and vascular endothelial growth factor receptor 2 were measured at baseline and during treatment. This correlative study was conducted to identify specific serum angiogenic factor profiles that might be associated with pCR in the neoadjuvant setting in breast cancer patients receiving bevacizumab and chemotherapy. RESULTS: Elevated baseline serum Tie2 and basic fibroblast growth factor were associated with pCR in response to this combination. Changes in serum levels of these proteins were seen during treatment but were not significantly different between the pCR and non-pCR groups. CONCLUSIONS: Baseline-circulating Tie2 levels may help distinguish patients who will have pCR from those who will not and may form the basis for future development of antiangiogenic therapy in breast cancer. Larger studies are needed to validate these findings. ClinicalTrials.gov Identifier: NCT00203502.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Receptor TIE-2/sangre , Angiopoyetina 1/sangre , Angiopoyetina 2/sangre , Becaplermina , Bevacizumab/administración & dosificación , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/química , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/cirugía , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Docetaxel , Doxorrubicina/administración & dosificación , Femenino , Factor 2 de Crecimiento de Fibroblastos/sangre , Humanos , Interleucina-1alfa/sangre , Metaloproteinasa 9 de la Matriz/sangre , Terapia Neoadyuvante , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/sangre , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Estudios Prospectivos , Proteínas Proto-Oncogénicas c-sis/sangre , Receptor ErbB-2/análisis , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Taxoides/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangreRESUMEN
Bleeding complications in dengue may occur irrespective of the presence of plasma leakage. We compared plasma levels of modulators of the endothelial barrier among three dengue groups: bleedings without plasma leakage, dengue hemorrhagic fever, and non-complicated dengue. The aim was to evaluate whether the presence of subtle alterations in microvascular permeability could be detected in bleeding patients. Plasma levels of VEGF-A and its soluble receptors were not associated with the occurrence of bleeding in patients without plasma leakage. These results provide additional rationale for considering bleeding as a complication independent of endothelial barrier breakdown, as proposed by the 2009 WHO classification.
Asunto(s)
Dengue/fisiopatología , Dengue Grave/fisiopatología , Adulto , Brasil , Permeabilidad Capilar , Dengue/sangre , Dengue/complicaciones , Países en Desarrollo , Endotelio Vascular/fisiopatología , Femenino , Hemorragia/sangre , Hemorragia/etiología , Hemorragia/fisiopatología , Humanos , Masculino , Dengue Grave/sangre , Dengue Grave/complicaciones , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangreRESUMEN
BACKGROUND: Endothelial cell dysfunction is believed to play an important role in the pathogenesis of plasma leakage in patients with acute dengue virus (DENV) infection. Several factors, produced by activated endothelial cells, have been associated with plasma leakage or severe disease in patients with infectious diseases. OBJECTIVES: The aim of this study was to investigate which of these markers could serve as a surrogate marker for the occurrence of plasma leakage in patients with acute DENV infection. STUDY DESIGN: A case-control study was performed in patients with acute DENV infection in Santos, Brazil. Plasma leakage was detected with X-ray and/or ultrasound examination at admission. Serum levels of soluble endoglin, endothelin-1, angiopoietin-2, VEGF, soluble VEGFR-2, MMP-2, MMP-9, TIMP-1 and TIMP-2 were determined using commercially available ELISAs. RESULTS: Increased levels of angiopoietin-2, endothelin-1 and MMP-2 and decreased levels of soluble VEGFR-2 were significantly associated with the occurrence of plasma leakage. An unsupervised cluster analysis confirmed that angiopoietin-2 and soluble VEGFR-2 were strongly associated with clinical apparent vascular leakage. CONCLUSION: Angiopoietin-2 and soluble VEGFR-2 can serve as surrogate markers for the occurrence of plasma leakage in patients with acute DENV infection.
Asunto(s)
Angiopoyetina 2/sangre , Permeabilidad Capilar/fisiología , Dengue Grave/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , Adolescente , Adulto , Anticuerpos Antivirales/inmunología , Afinidad de Anticuerpos/inmunología , Biomarcadores/sangre , Brasil , Estudios de Casos y Controles , Niño , Virus del Dengue/patogenicidad , Células Endoteliales/patología , Células Endoteliales/virología , Endotelina-1/sangre , Femenino , Humanos , Inmunoglobulina G/inmunología , Masculino , Metaloproteinasa 2 de la Matriz/sangre , Persona de Mediana Edad , Radiografía , Dengue Grave/diagnóstico por imagen , Dengue Grave/virología , Adulto JovenRESUMEN
PURPOSE: To assess the efficacy and safety of the anti-VEGF receptor-2 (VEGFR-2) antibody ramucirumab as first-line therapy in patients with advanced hepatocellular carcinoma and explore potential circulating biomarkers. EXPERIMENTAL DESIGN: Adults with advanced hepatocellular carcinoma and no prior systemic treatment received ramucirumab 8 mg/kg every two weeks until disease progression or limiting toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR) and overall survival (OS). Circulating biomarkers were evaluated before and after ramucirumab treatment in a subset of patients. RESULTS: Forty-two patients received ramucirumab. Median PFS was 4.0 months [95% confidence interval (CI), 2.6-5.7], ORR was 9.5% (95% CI, 2.7-22.6; 4/42 patients had a partial response), and median OS was 12.0 months (95% CI, 6.1-19.7). For patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease, median OS was 4.4 months (95% CI, 0.5-9.0) for patients with Child-Pugh B cirrhosis versus 18.0 months (95% CI, 6.1-23.5) for patients with Child-Pugh A cirrhosis. Treatment-related grade ≥ 3 toxicities included hypertension (14%), gastrointestinal hemorrhage and infusion-related reactions (7% each), and fatigue (5%). There was one treatment-related death (gastrointestinal hemorrhage). After treatment with ramucirumab, there was an increase in serum VEGF and placental growth factor (PlGF) and a transient decrease in soluble VEGFR-2. CONCLUSION: Ramucirumab monotherapy may confer anticancer activity in advanced hepatocellular carcinoma with an acceptable safety profile. Exploratory biomarker studies showed changes in circulating VEGF, PlGF, and sVEGFR-2 that are consistent with those seen with other anti-VEGF agents.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Antineoplásicos/farmacología , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Factor de Crecimiento Placentario , Proteínas Gestacionales/sangre , Modelos de Riesgos Proporcionales , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , RamucirumabRESUMEN
BACKGROUND: Endothelial dysfunction has been previously described in metabolic syndrome patients. The levels of circulating endothelial progenitor cells (EPCs) inversely correlates with the incidence of cardiovascular disease. The aim of this study was to investigate the association between NAFLD, metabolic syndrome and EPC levels. MATERIAL AND METHODS: A cross-sectional pilot study was performed at a university hospital in Mexico. Two groups of patients without previously known chronic diseases were studied and classified according to the presence of NAFLD. Anthropometric, dietary, and biochemical variables, and circulating EPC number were measured and compared between the groups. RESULTS: Forty subjects were included and classified into two groups: patients with NAFLD (n = 20) and a control group (n = 20). The overall prevalence of insulin resistance and metabolic syndrome was 25% and 17.5%, respectively. EPC levels were found to be higher in the NAFLD group (p < 0.05) as in the patients with insulin resistance (p < 0.01) and metabolic syndrome (p < 0.01). These levels showed correlation with the severity of steatosis. CONCLUSIONS: Patients with NAFLD have increased levels of EPC, such levels are associated with the severity of NAFLD. These findings may suggest that these cells may play a role in the early natural history of NAFLD. EPC might be increased in an attempt to repair the endothelial damage resulting from metabolic alterations accompanying NAFLD. Further studies are needed to establish the dynamics of these cells in NAFLD.
Asunto(s)
Células Endoteliales/patología , Hígado Graso/patología , Síndrome Metabólico/patología , Células Madre/patología , Antígeno AC133 , Antígenos CD/sangre , Antígenos CD34/sangre , Biomarcadores/sangre , Estudios de Casos y Controles , Estudios Transversales , Células Endoteliales/metabolismo , Hígado Graso/sangre , Glicoproteínas/sangre , Hospitales Universitarios , Humanos , Resistencia a la Insulina , Antígenos Comunes de Leucocito/sangre , Síndrome Metabólico/sangre , México , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico , Péptidos/sangre , Proyectos Piloto , Índice de Severidad de la Enfermedad , Células Madre/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangreRESUMEN
BACKGROUND: Metronomic chemotherapy (MCT) with cyclophosphamide (Cy) and celecoxib (Cel) has therapeutic efficacy and low toxicity profile in advanced breast cancer patients (ABCP), but no reliable biomarkers of response have been found yet that allow patient selection for treatment. AIM: To investigate the potential role as biomarkers of pro- and antiangiogenic parameters and evaluate their response in ABCP receiving metronomic Cy 50 mg p.o./day + Cel 400 mg p.o./day. MATERIALS AND METHODS: Serum levels of vascular endothelial growth factor-C (VEGF-C), soluble VEGF receptors 2 and 3 (sVEGFR-2, sVEGFR-3), were measured at different time points in 13/15 patients included in a phase II trial of MCT with Cy+Cel. RESULTS: Serum levels of sVEGFR-2 and sVEGFR-3 increased significantly during treatment (P = 0.0392; P = 0.0066, respectively). VEGF-C showed no significant modifications. Previous determinations of VEGF and TSP-1 in the same patients were utilized. VEGF/sVEGFR-2, VEGF/TSP-1, and VEGF-C/sVEGFR-3 ratios decreased significantly along the treatment (P = 0.0092; P = 0.0072; P = 0.0141, respectively). Nonsignificant variations were observed for VEGF-C/sVEGFR-2 ratio. Baseline values of VEGF/sVEGFR-2 and VEGF/TSP-1 ratios were associated with time to progression (TTP) (P = 0.0407; P = 0.0394, respectively) meanwhile baseline VEGF was marginally significant (P = 0.0716). Patients with values lower than the 50th percentile for both ratios showed longer TTP. CONCLUSIONS: We have identified the baseline VEGF/sVEGFR-2 and VEGF/TSP-1 ratios as potential biomarkers of response in ABCP treated metronomically with Cy+Cel. This finding warrants its confirmation in a higher number of patients.