RESUMEN
In this paper, we review the value of phantoms for body MRI in the context of their uses for quantitative MRI methods research, clinical trials, and clinical imaging. Certain uses of phantoms are common throughout the body MRI community, including measuring bias, assessing reproducibility, and training. In addition to these uses, phantoms in body MRI methods research are used for novel methods development and the design of motion compensation and mitigation techniques. For clinical trials, phantoms are an essential part of quality management strategies, facilitating the conduct of ethically sound, reliable, and regulatorily compliant clinical research of both novel MRI methods and therapeutic agents. In the clinic, phantoms are used for development of protocols, mitigation of cost, quality control, and radiotherapy. We briefly review phantoms developed for quantitative body MRI, and finally, we review open questions regarding the most effective use of a phantom for body MRI.
RESUMEN
Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B and an inhibitor of microtubule dynamics. Some tubulin-binding drugs are known to have antivascular (antiangiogenesis or vascular-disrupting) activities that can target abnormal tumor vessels. Using dynamic contrast-enhanced MRI analyses, here we show that eribulin induces remodeling of tumor vasculature through a novel antivascular activity in MX-1 and MDA-MB-231 human breast cancer xenograft models. Vascular remodeling associated with improved perfusion was shown by Hoechst 33342 staining and by increased microvessel density together with decreased mean vascular areas and fewer branched vessels in tumor tissues, as determined by immunohistochemical staining for endothelial marker CD31. Quantitative RT-PCR analysis of normal host cells in the stroma of xenograft tumors showed that eribulin altered the expression of mouse (host) genes in angiogenesis signaling pathways controlling endothelial cell-pericyte interactions, and in the epithelial-mesenchymal transition pathway in the context of the tumor microenvironment. Eribulin also decreased hypoxia-associated protein expression of mouse (host) vascular endothelial growth factor by ELISA and human CA9 by immunohistochemical analysis. Prior treatment with eribulin enhanced the anti-tumor activity of capecitabine in the MDA-MB-231 xenograft model. These findings suggest that eribulin-induced remodeling of abnormal tumor vasculature leads to a more functional microenvironment that may reduce the aggressiveness of tumors due to elimination of inner tumor hypoxia. Because abnormal tumor microenvironments enhance both drug resistance and metastasis, the apparent ability of eribulin to reverse these aggressive characteristics may contribute to its clinical benefits.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Furanos/farmacología , Cetonas/farmacología , Moduladores de Tubulina/farmacología , Microambiente Tumoral/efectos de los fármacos , Remodelación Vascular/efectos de los fármacos , Animales , Neoplasias de la Mama/patología , Capecitabina , Línea Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Femenino , Fluorouracilo/análogos & derivados , Fluorouracilo/farmacología , Humanos , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Odanacatib (ODN) is a selective and reversible Cathepsin K (CatK) inhibitor currently being developed as a once weekly treatment for osteoporosis. Here, effects of ODN compared to alendronate (ALN) on bone turnover, DXA-based areal bone mineral density (aBMD), QCT-based volumetric BMD (vBMD) and geometric parameters were studied in ovariectomized (OVX) rhesus monkeys. Treatment was initiated 10 days after ovariectomy and continued for 20 months. The study consisted of four groups: L-ODN (2 mg/kg, daily p.o.), H-ODN (8/4 mg/kg daily p.o.), ALN (15 µg/kg, twice weekly, s.c.), and VEH (vehicle, daily, p.o.). L-ODN and ALN doses were selected to approximate the clinical exposures of the ODN 50-mg and ALN 70-mg once-weekly, respectively. L-ODN and ALN effectively reduced bone resorption markers uNTx and sCTx compared to VEH. There was no additional efficacy with these markers achieved with H-ODN. Conversely, ODN displayed inversely dose-dependent reduction of bone formation markers, sP1NP and sBSAP, and L-ODN reduced formation to a lesser degree than ALN. At month 18 post-OVX, L-ODN showed robust increases in lumbar spine aBMD (11.4%, p<0.001), spine trabecular vBMD (13.7%, p<0.001), femoral neck (FN) integral (int) vBMD (9.0%, p<0.001) and sub-trochanteric proximal femur (SubTrPF) int vBMD, (6.4%, p<0.001) compared to baseline. L-ODN significantly increased FN cortical thickness (Ct.Th) and cortical bone mineral content (Ct.BMC) by 22.5% (p<0.001) and 21.8% (p<0.001), respectively, and SubTrPF Ct.Th and Ct.BMC by 10.9% (p<0.001) and 11.3% (p<0.001) respectively. Compared to ALN, L-ODN significantly increased FN Ct. BMC by 8.7% (p<0.05), and SubTrPF Ct.Th by 7.6% (p<0.05) and Ct.BMC by 6.2% (p<0.05). H-ODN showed no additional efficacy compared to L-ODN in OVX-monkeys in prevention mode. Taken together, the results from this study have demonstrated that administration of ODN at levels which approximate clinical exposure in OVX-monkeys had comparable efficacy to ALN in DXA-based aBMD and QCT-based vBMD. However, FN cortical mineral content clearly demonstrated superior efficacy of ODN versus ALN in this model of estrogen-deficient non-human primates.
Asunto(s)
Alendronato/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Densidad Ósea/efectos de los fármacos , Alendronato/farmacocinética , Animales , Compuestos de Bifenilo/farmacocinética , Conservadores de la Densidad Ósea/farmacocinética , Conservadores de la Densidad Ósea/uso terapéutico , Remodelación Ósea/efectos de los fármacos , Femenino , Haplorrinos , Articulación de la Cadera/diagnóstico por imagen , Articulación de la Cadera/efectos de los fármacos , Ovariectomía , Radiografía , Columna Vertebral/diagnóstico por imagen , Columna Vertebral/efectos de los fármacosRESUMEN
Translational evaluation of disease progression and treatment response is critical to the development of therapies for osteoporosis. In this study, longitudinal in-vivo monitoring of odanacatib (ODN) treatment efficacy was compared to alendronate (ALN) in ovariectomized (OVX) non-human primates (NHPs) using high-resolution peripheral computed tomography (HR-pQCT). Treatment effects were evaluated using several determinants of bone strength, density and quality, including volumetric bone mineral density (vBMD), three-dimensional structure, finite element analysis (FEA) estimated peak force and biomechanical properties at the ultradistal (UD) radius at baseline, 3, 6, 9, 12, and 18 months of dosing in three treatment groups: vehicle (VEH), low ODN (2 mg/kg/day, L-ODN), and ALN (30 µg/kg/week). Biomechanical axial compression tests were performed at the end of the study. Bone strength estimates using FEA were validated by ex-vivo mechanical compression testing experiments. After 18months of dosing, L-ODN demonstrated significant increases from baseline in integral vBMD (13.5%), cortical thickness (24.4%), total bone volume fraction BV/TV (13.5%), FEA-estimated peak force (26.6%) and peak stress (17.1%), respectively. Increases from baseline for L-ODN at 18 months were significantly higher than that for ALN in DXA-based aBMD (7.6%), cortical thickness (22.9%), integral vBMD (12.2%), total BV/TV (10.1%), FEA peak force (17.7%) and FEA peak stress (11.5%), respectively. These results demonstrate a superior efficacy of ODN treatment compared to ALN at the UD radii in ovariectomized NHPs.
Asunto(s)
Alendronato/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Conservadores de la Densidad Ósea/uso terapéutico , Densidad Ósea/efectos de los fármacos , Análisis de Elementos Finitos , Animales , Macaca mulatta , Ovariectomía , Radio (Anatomía) , Tomografía Computarizada por Rayos XRESUMEN
This study aimed to validate finite element analysis (FEA) estimation of strength, identify high-resolution peripheral quantitative computed tomography (HR-pQCT) measures correlating with strength, and evaluate the precision of HR-pQCT measurements to longitudinally monitor effects of osteoporosis treatment in ovariectomized (OVX) non-human primates (NHPs). HR-pQCT images were acquired in three groups of NHPs: Intact (n=10), OVX-odanacatib treated (OVX-ODN 30 mg/kg, n=10) and OVX-vehicle treated (OVX-Veh, n=10) at the ultradistal (UD) and distal 1/3 radii and tibia at 12, 16 and 20 months. FEA estimates of bone strength using the Pistoia criterion were validated by ex-vivo mechanical compression (r(2)=0.95) of the UD radius. Single linear regressions of FEA-determined ultimate stress showed high correlation with HR-pQCT derived parameters: integral vBMD (r(2)=0.86), bone volume fraction (r(2)=0.84) and cortical thickness (r(2)=0.79). Precision of HR-pQCT measurements, obtained from an excised radius and tibia, showed low variation (CV=0.005%-5.6%) and helped identify possible sources of error. Comparison of OVX-Veh and Intact groups showed decreases in bone parameters demonstrating trends consistent with bone loss. Comparison of OVX-ODN and OVX-Veh groups showed a treatment effect with increases in bone parameters: integral vBMD (477±27 vs. 364±22 mgHA/cm(3)) and cortical thickness (Ct.Th) (0.90±0.07 vs. 0.64±0.04 mm) at the UD radius, Ct.Th (2.15±0.28 vs. 1.56±0.08 mm) at the distal 1/3 radius. Axial compression peak stress calculated and obtained experimentally showed the OVX-ODN group was 33% stronger than the OVX-Veh group. We conclude that HR-pQCT and FEA serve as robust techniques to longitudinally monitor bone parameters and strength in NHP's.
Asunto(s)
Compuestos de Bifenilo/uso terapéutico , Osteoporosis/tratamiento farmacológico , Osteoporosis/fisiopatología , Animales , Fenómenos Biomecánicos , Densidad Ósea , Catepsina K/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/uso terapéutico , Modelos Animales de Enfermedad , Femenino , Análisis de Elementos Finitos , Humanos , Macaca mulatta , Osteoporosis/diagnóstico por imagen , Osteoporosis/etiología , Ovariectomía , Microtomografía por Rayos XRESUMEN
Magnetic resonance elastography (MRE) is a technique for quantifying material properties by measuring cyclic displacements of propagating shear waves. As an alternative to dynamic harmonic wave MRE or quasi-steady-state methods, the idea of using a transient impulse for mechanical excitation is introduced. Two processing methods to calculate shear stiffness from transient data were developed. The techniques were tested in phantom studies, and the transient results were found to be comparable to the harmonic wave results. Transient wave based analysis was applied to the brains of six healthy volunteers in order to assess the method in areas of complex wave patterns and geometry. The results demonstrated the feasibility of measuring brain stiffness in vivo using a transient mechanical excitation. Transient and harmonic methods both measure white matter (approximately 12 kPa) to be stiffer than gray matter ( approximately 8 kPa). There were some anatomic differences between harmonic and transient MRE, specifically where the transient results better depicted the deeper structures of the brain.