http://repub.eur.nl/res/aut/33429/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/37978/ 2012-02-13T00:00:00Z Bioluminescence imaging (BLI) has shown its appeal as a sensitive technique for in vivo whole body optical imaging. However, the development of injectable tumor-specific near-infrared fluorescent (NIRF) probes makes fluorescence imaging (FLI) a promising alternative to BLI in situations where BLI cannot be used or is unwanted (e.g., spontaneous transgenic tumor models, or syngeneic mice to study immune effects). In this study, we addressed the questions whether it is possible to detect tumor progression using FLI with appropriate sensitivity and how FLI correlates with BLI measurements. In addition, we explored the possibility to simultaneously detect multiple tumor characteristics by dual-wavelength FLI (~700 and ~800 nm) in combination with spectral unmixing. Using a luciferase-expressing 4T1-luc2 mouse breast cancer model and combinations of activatable and targeting NIRF probes, we showed that the activatable NIRF probes (ProSense680 and MMPSense680) and the targeting NIRF probes (IRDye 800CW 2-DG and IRDye 800CW EGF) were either activated by or bound to 4T1-luc2 cells. In vivo, we implanted 4T1-luc2 cells orthotopically in nude mice and were able to follow tumor progression longitudinally both by BLI and dual-wavelength FLI. We were able to reveal different probe signals within the tumor, which co-localized with immuno-staining. Moreover, we observed a linear correlation between the internal BLI signals and the FLI signals obtained from the NIRF probes. Finally, we could detect pulmonary metastases both by BLI and FLI and confirmed their presence histologically. Taken together, these data suggest that dual-wavelength FLI is a feasible approach to simultaneously detect different features of one tumor and to follow tumor progression with appropriate specificity and sensitivity. This study may open up new perspectives for the detection of tumors and metastases in various experimental models and could also have clinical applications, such as image-guided surgery. http://repub.eur.nl/res/pub/32826/ 2010-09-01T00:00:00Z Background-We imaged the protease activity of matrix metalloproteinases (MMPs) upregulated during aneurysm formation, using protease-activatable near-infrared fluorescence probes. We tested whether these protease-activatable sensors can directly report the in vivo activity of the key biomarkers in aneurysm, using our genetically modified fibulin-4 mouse models for aneurysm formation. Mice homozygous for the fibulin-4 reduced-expression allele (fibulin-4R/R) show dilatation of the ascending aorta and a tortuous, stiffened aorta resulting from disorganized elastic fiber networks. Strikingly, even a moderate reduction in expression of fibulin-4 in the heterozygous fibulin-4+/Rmice occasionally results in modest aneurysm formation. Methods and Results-Aorta transcriptome and protein expression analysis of fibulin-4+/Rand fibulin-4R/Ranimals identified excessive transforming growth factor-β signaling as the critical event in the pathogenesis of aneurysm formation. To determine whether a perturbed elastin lamellar structure arose from induction of transforming growth factor-β-regulated MMPs, we performed gelatin zymography and used a protease-activatable near-infrared fluorescence probe to monitor and quantify MMP upregulation in animals, using various in vivo optical imaging modules and coregistration of the fluorescence signal with CT images of the same animals. Gelatin zymography demonstrated a significant increase in the presence of the active form of MMP-9 in the aortic arch of fibulin-4R/Rmice. In vivo analysis of MMP upregulation using the near-infrared fluorescence probe and subsequent isosurface concentration mapping from reconstructed tomographic images from fibulin-4+/Rand fibulin-4R/Rmice revealed a graded increase in activation of MMPs within the aneurysmal lesions. Conclusions-We aimed to develop molecular imaging procedures for faster, earlier, and easier recognition of aortic aneurysms. We show that in vivo coregistration of MMP activity by noninvasive tomographic imaging methods allows the detection of increased MMP activity, even before the aneurysm has actually formed. http://repub.eur.nl/res/pub/25023/ 2009-01-01T00:00:00Z Purpose: To evaluate the efficacy and toxicity of surgical resection and permanent iodine-125 brachytherapy without adjuvant whole brain radiation therapy (WBRT) for brain metastases. Methods and materials: Forty patients were treated with permanent iodine-125 brachytherapy at the time of resection of brain metastases from 1997 to 2003. Actuarial freedom from progression (FFP) and survival were measured from the date of surgery and estimated using the Kaplan-Meier method, with censoring at last imaging for FFP endpoints. Results: The median survival was 11.3 months overall, 12.0 months in 19 patients with newly diagnosed brain metastases and 7.3 months in 21 patients with recurrent brain metastases. Twenty-two patients (55%) remained free of progression of brain metastases, three failed at the resection cavity (including one with leptomeningeal dissemination), two failed with leptomeningeal spread only, and 13 failed elsewhere in the brain including two who also had leptomeningeal disease. The 1-year resection cavity FFP probabilities were 92%, 86% and 88%; and brain FFP probabilities were 29%, 43% and 37% for the newly diagnosed, recurrent and all patients, respectively. Symptomatic necrosis developed 7.4-40.0 months (median, 19.5 months) after brachytherapy in 9 patients (23%), confirmed by resection in 6 patients. Conclusions: Excellent local control was achieved using permanent iodine-125 brachytherapy for brain metastasis resection cavities, although there is a high risk of radiation necrosis over time. These data support consideration of permanent brachytherapy without adjuvant WBRT as a treatment option in patients with symptomatic or large newly diagnosed or recurrent brain metastases.