RESUMEN
High-frequency volumetric Power Doppler ultrasound (HF-VPDU) captures flow-dependent signals in blood vessels and can be used to assess antiangiogenic therapy effects in rodent tumors. However, the sensitivity is limited to vessels larger than capillaries. Contrast-enhanced HF-VPDU reveals all perfused vessels by assessing stimulated acoustic emissions from disintegrating microbubbles. Thus, we investigated whether flow-sensitive and contrast-enhanced HF-VPDU can depict different vessel fractions and assess their early response to antiangiogenic therapy. Mice with A431 tumors were scanned before and after administration of polybutylcyanoacrylate microbubbles by HF-VPDU. Animals received either antiangiogenic treatment (SU11248) or a control substance and were imaged repeatedly over 9 days. At each time point, tumors were removed for immunohistochemical analysis. During growth of untreated tumors, vascularization decreased correspondingly on flow-sensitive and contrast-enhanced scans. Treated tumors showed a significantly (P < 0.05) stronger decline in vascularization than controls, which was more pronounced in contrast-enhanced scans. Surprisingly, whereas vascularization remained low in contrast-enhanced scans, flow-sensitive ultrasound indicated a reincrease after day 6 with a higher vascularization than the controls at day 9. Histologic evaluation indicated that immature vessels degraded markedly on therapy, whereas large mature vessels on the tumor periphery were more therapy resistant and drew closer due to tumor shrinkage. In conclusion, contrast-enhanced HF-VPDU and flow-sensitive HF-VPDU are both capable of assessing the effects of antiangiogenic therapy. Because contrast-sensitive ultrasound is more sensitive for small immature vessels and flow-sensitive ultrasound mostly captures large vessels at the tumor periphery, the combination of both methods can provide evidence of vascular maturity in tumors.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Neoplasias Experimentales/irrigación sanguínea , Ultrasonografía Doppler/métodos , Animales , Femenino , Inmunohistoquímica , Ratones , Ratones DesnudosRESUMEN
OBJECTIVES: To assess the pharmacodynamic behavior of cyanoacrylate, streptavidin-coated microbubbles (MBs) and to investigate their suitability for molecular ultrasound imaging. MATERIALS AND METHODS: Biodistribution of MBs was analyzed in tumor-bearing mice using gamma-counting, immunohistochemistry, flow cytometry, and ultrasound. Further, vascular endothelial growth factor receptor 2-antibody coupled MBs were used to image tumor neovasculature. RESULTS: After 1 minute >90% of MBs were cleared from the blood and pooled in the lungs, liver, and spleen. Subsequently, within 1 hour a decent reincrease of MB-concentration was observed in the blood. The remaining MBs were removed by liver and spleen macrophages. About 30% of the phagocytosed MBs were intact after 48 hours. Shell fragments were found in the kidneys only. No relevant MB-accumulation was observed in tumors. In contrast, vascular endothelial growth factor receptor 2-specific MBs accumulated significantly within the tumor vasculature (P < 0.05). CONCLUSIONS: The pharmacokinetic behavior of streptavidin-coated cyanoacrylate MBs has been studied. In this context, the low amount of MBs in tumors after >5 minutes is beneficial for specific targeting of angiogenesis.
Asunto(s)
Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/metabolismo , Medios de Contraste/farmacocinética , Cianoacrilatos/química , Microburbujas , Estreptavidina/farmacocinética , Animales , Materiales Biocompatibles Revestidos/química , Tasa de Depuración Metabólica , Ratones , Ratones Desnudos , Especificidad de Órganos , Estreptavidina/química , Distribución Tisular , UltrasonografíaRESUMEN
The objective of this study was to evaluate inflammatory response and recanalization after embolization with a new spherical embolic agent based on a core and shell design with a hydrogel core of polymethylmethacrylate (PMMA) and a Polyzene-F nanoscale coating in a porcine kidney model. Thirty-six minipigs were enrolled for superselective renal embolization. Polyzene-F-coated PMMA particles and uncoated PMMA particles with a diameter of 300-600 mum were used. Either 4 or 12 weeks post-embolization, arteriography of the embolized kidneys was performed and then compared with pre- and immediate post-embolization arteriograms using a specific recanalization score to determine the extent of recanalization. Using a microscopic inflammation score (Banff classification), the embolized organs were examined for local inflammatory effects which occurred in response to the embolic agent. In Polyzene-F-coated particles, the Banff classification showed an average inflammation score of 0.26 +/- 0.58 at 4 weeks and of 0.08 +/- 0.28 at 12 weeks. In uncoated particles, the Banff score measured 0.37 +/- 0.6 at 4 weeks, which was higher, but without a statistically significant difference. According to the recanalization score used in this study, mild angiographic recanalization was evident in all groups, without statistically significant differences (3.0 +/- 0.71 in coated particles, 3.09 +/- 0.81 in uncoated particles; p = 0.74). We conclude that both uncoated hydrogel particles and Polyzene-F-coated embolic agents triggered virtually no inflammatory response and effectively occluded target arteries. This study demonstrates good biocompatibility of the new embolic material. As in other spherical embolic agents, recanalization can occur to some degree.
Asunto(s)
Arteritis/patología , Materiales Biocompatibles Revestidos , Embolización Terapéutica/métodos , Polimetil Metacrilato/farmacología , Arteria Renal/patología , Resinas Acrílicas , Angiografía/métodos , Animales , Arteritis/diagnóstico por imagen , Modelos Animales de Enfermedad , Gelatina , Hidrogeles/farmacología , Riñón/irrigación sanguínea , Riñón/diagnóstico por imagen , Riñón/patología , Tamaño de la Partícula , Polímeros/farmacología , Probabilidad , Distribución Aleatoria , Arteria Renal/diagnóstico por imagen , Circulación Renal/fisiología , Medición de Riesgo , Sensibilidad y Especificidad , Estadísticas no Paramétricas , Porcinos , Porcinos EnanosRESUMEN
Molecular ultrasound is capable of elucidating the expression of angiogenic markers in vivo. However, the capability of the method for volumetric "multitarget quantification" and for the assessment of antiangiogenic therapy response has rather been investigated. Therefore, we generated cyanoacrylate microbubbles linked to vascular endothelial growth factor receptor 2 (VEGFR2) and alphavbeta3 integrin binding ligands and quantified their accumulation in squamous cell carcinoma xenografts (HaCaT-ras-A-5RT3) in mice with the quantitative volumetric ultrasound scanning technique, sensitive particle acoustic quantification. Specificity of VEGFR2 and alphavbeta3 integrin binding microbubbles was shown, and changes in marker expression during matrix metalloproteinase inhibitor treatment were investigated. In tumors, accumulation of targeted microbubbles was significantly higher compared with nonspecific ones and could be inhibited competitively by addition of the free ligand in excess. Also, multimarker imaging could successfully be done during the same imaging session. Molecular ultrasound further indicated a significant increase of VEGFR2 and alphavbeta3 integrin expression during tumor growth and a considerable decrease in both marker densities after matrix metalloproteinase inhibitor treatment. Histologic data suggested that the increasing VEGFR2 and alphavbeta3 integrin concentrations in tumors during growth are related to an up-regulation of its expression by the endothelial cells, whereas its decrease under therapy is more related to the decreasing relative vessel density. In conclusion, targeted ultrasound appears feasible for the longitudinal molecular profiling of tumor angiogenesis and for the sensitive assessment of therapy effects in vivo.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias/irrigación sanguínea , Neoplasias/diagnóstico por imagen , Neovascularización Patológica/diagnóstico por imagen , Neovascularización Patológica/tratamiento farmacológico , Animales , Línea Celular Tumoral , Humanos , Inmunohistoquímica , Integrina alfaVbeta3/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Desnudos , Microtúbulos/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Ultrasonografía , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We report a rare case of late transjugular intrahepatic portosystemic stent shunt (TIPSS) occlusion due to progressive stent protrusion into the periportal liver parenchyma, which was a result of delayed liver shrinkage 2 years after TIPSS. The initial TIPSS procedure had been carried out in a 52-year-old man as a bridge for liver transplantation because of post-alcoholic liver cirrhosis. We describe the applied TIPSS recanalization and revision technique. Immediately after TIPSS revision acute liver failure developed, which required emergency liver transplantation.
Asunto(s)
Fallo Hepático Agudo/etiología , Derivación Portosistémica Intrahepática Transyugular/efectos adversos , Complicaciones Posoperatorias/etiología , Bilirrubina/sangre , Tratamiento de Urgencia/métodos , Resultado Fatal , Humanos , Hiperbilirrubinemia/complicaciones , Hiperbilirrubinemia/diagnóstico , Hígado/diagnóstico por imagen , Hígado/lesiones , Hígado/cirugía , Cirrosis Hepática Alcohólica/cirugía , Fallo Hepático Agudo/diagnóstico , Fallo Hepático Agudo/cirugía , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/métodos , Masculino , Arteria Mesentérica Superior/diagnóstico por imagen , Persona de Mediana Edad , Tamaño de los Órganos , Vena Porta/diagnóstico por imagen , Portografía , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/cirugía , Falla de Prótesis , Embolia Pulmonar/etiología , Reoperación , Trombosis/complicaciones , Trombosis/diagnóstico , Tiempo , Transaminasas/sangre , UltrasonografíaRESUMEN
We report a rare case of two communicating pseudoaneurysms of the common hepatic artery 1 month postoperatively following pylorus-preserving pancreaticoduodenectomy due an abscess formation. We describe the superselective transcatheteral embolization technique with deployment of interlocking detachable coils and Histoacryl-Lipiodol in this case and discuss the recent literature. Despite the technical success by achieving hemodynamic stability with initial preservation of liver function, the patient died 23 days postembolization due to multiorgan failure.