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Contains fulltext : 81037.pdf (publisher's version ) (Open Access), PURPOSE: Vascular endothelial growth factor-A (VEGF-A) is one of the most important factors inducing angiogenesis in tumors. Nine splice-variant isoforms of VEGF-A have been identified, each having different properties. Recently, we showed that radiolabeled anti-VEGF monoclonal antibody, bevacizumab, accumulates specifically in VEGF-A expressing tumors. In this study, we investigated in a nude mouse model which VEGF-isoforms are responsible for tumor accretion. MATERIALS AND METHODS: The humanized anti-VEGF-A antibody, A.4.6.1. (bevacizumab), was radiolabeled with In-111. The originally VEGF-negative Mel57 tumor was transfected with different VEGF isoforms (VEGF-121, VEGF-165, and VEGF-189). The obtained melanoma xenografts specifically expressing different VEGF-isoforms were used in mice. The bevacizumab uptake was examined in biodistribution studies and by gamma-camera imaging. RESULTS: The tumor cell line expressing VEGF-121 did not show specific uptake, most likely as a result of the fact that this isoform is freely diffusible. Tumors expressing VEGF-165 and -189 were clearly visualized by using gamma-camera imaging. CONCLUSION: The accumulation of radiolabeled bevacizumab in the tumor is due to interaction with VEGF-A isoforms that are associated with the tumor cell surface and/or the extracellular matrix. Scintigraphic imaging of the expression of these VEGF isoforms may thus be useful to predict response to angiogenic therapy.

Contains fulltext : 80240.pdf (publisher's version ) (Closed access), In murine models, resection of a primary tumor leads to increased vascularization and accelerated growth of metastases that previously had remained microscopic. To study such a potentially inhibitory effect of primary tumors on the outgrowth of distant metastases in humans, we assessed the metabolic activity of liver metastases by 18F-FDG PET before and after resection of primary colorectal tumors. METHODS: Group A consisted of 8 patients with synchronous colorectal liver metastases who were scheduled for resection of their primary tumor. These patients underwent an (18)F-FDG PET scan shortly before resection and 2-3 wk after resection of the primary tumor. The patients in a control group (group B, n = 9) underwent an 18F-FDG PET scan at the time of diagnosis of the liver metastases and a second scan several weeks later, before initiating treatment. There was no surgical intervention between the two 18F-FDG PET scans in this group. RESULTS: In group A, the maximum and mean standardized uptake values of the liver metastases clearly increased after resection of the primary tumor, by 38% +/- 55% and 42% +/- 52%, respectively, as compared with the first 18F-FDG PET scan. In group B, the maximum and mean standardized uptake values of the second 18F-FDG PET scan were not significantly higher than those of the first 18F-FDG PET scan; -11% +/- 23% and 1% +/- 29%, respectively. The difference in standardized uptake value increase between the 2 groups was statistically significant (P < 0.05). CONCLUSION: Our data cannot differentiate between the immunologic sequels caused by the surgical trauma itself and those caused by removal of the primary tumor. The observation itself, however, of increased metabolic activity after surgical resection of the primary tumor may have direct clinical applications and suggests the administration of antiangiogenic therapy after surgery of the primary tumor.

RU Radboud Universiteit Nijmegen, 04 juni 2009, Promotores : Oyen, W.J.G., Boerman, O.C., Laarhoven, C.J.H.M. van Co-promotor : Ruers, T.J.M., Contains fulltext : 80065.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 70965.pdf (publisher's version ) (Closed access), Vascular endothelial growth factor-A (VEGF-A) is one of the most important angiogenic factors. Here, we studied in a nude mouse model whether the expression of VEGF-A in a tumor could be imaged with a radiolabeled anti-VEGF antibody. The humanized anti-VEGF-A antibody A.4.6.1. (bevacizumab), which is reactive with all VEGF-A isoforms, was radiolabeled with In-111 or with I-125. The accumulation of the radiolabeled antibodies in VEGF-A expressing tumors (LS174T) in nude mice was examined in biodistribution studies and by gamma camera imaging. The uptake of the In-111-bevacizumab in the tumor at 3 days p.i. was significantly higher than that of I-125-bevacizumab (19.4 +/- 7.0 %ID/g vs. 9.6 +/- 3.3 %ID/g, p = 0.04). Coinjection of an excess unlabeled antibody resulted in a significant decrease in radioactivity concentration in the tumor (<2.9 +/- 1.9 %ID/g, p < 0.005), indicating VEGF-mediated antibody uptake. Highest uptake in the tumor was observed at relatively low antibody protein doses (<3 microg) (20-25 %ID/g). VEGF-A-expressing tumors could be clearly visualized on planar scintigraphic images from 24-hr post injection onwards. In conclusion, VEGF-A expression in tumors can be visualized specifically with radiolabeled anti-VEGF-A-mAb.

Contains fulltext : 69759.pdf (publisher's version ) (Closed access), In murine models, resection of a primary tumor leads to increased vascularization and accelerated growth of metastases that previously had remained microscopic. To study such a potentially inhibitory effect of primary tumors on the outgrowth of distant metastases in humans, we assessed the metabolic activity of liver metastases by 18F-FDG PET before and after resection of primary colorectal tumors. METHODS: Group A consisted of 8 patients with synchronous colorectal liver metastases who were scheduled for resection of their primary tumor. These patients underwent an (18)F-FDG PET scan shortly before resection and 2-3 wk after resection of the primary tumor. The patients in a control group (group B, n = 9) underwent an 18F-FDG PET scan at the time of diagnosis of the liver metastases and a second scan several weeks later, before initiating treatment. There was no surgical intervention between the two 18F-FDG PET scans in this group. RESULTS: In group A, the maximum and mean standardized uptake values of the liver metastases clearly increased after resection of the primary tumor, by 38% +/- 55% and 42% +/- 52%, respectively, as compared with the first 18F-FDG PET scan. In group B, the maximum and mean standardized uptake values of the second 18F-FDG PET scan were not significantly higher than those of the first 18F-FDG PET scan; -11% +/- 23% and 1% +/- 29%, respectively. The difference in standardized uptake value increase between the 2 groups was statistically significant (P < 0.05). CONCLUSION: Our data cannot differentiate between the immunologic sequels caused by the surgical trauma itself and those caused by removal of the primary tumor. The observation itself, however, of increased metabolic activity after surgical resection of the primary tumor may have direct clinical applications and suggests the administration of antiangiogenic therapy after surgery of the primary tumor.

Contains fulltext : 69878.pdf (publisher's version ) (Closed access), AIM OF THE STUDY: To investigate the correlation between tumour accumulation of In-111-bevacizumab and VEGF-A expression in patients with colorectal liver metastases. METHODS: Two weeks before resection of the liver metastases 12 patients were intravenously injected with In-111-labelled bevacizumab. Ten minutes and 7 d after injection a whole body scan was acquired. Seven days after the injection, 3D acquisition SPECT of the liver was performed. RESULTS: Enhanced uptake of In-111-bevacizumab in the liver metastases was observed in 9 of the 12 patients. The level of antibody accumulation in these lesions varied considerably. There was no correlation between the level of In-111-antibody accumulation and the level of VEGF-A expression in the tissue as determined by in situ hybridisation and ELISA. CONCLUSIONS: In this study, we investigated the correlation between tumour accumulation of radiolabelled bevacizumab and VEGF-A expression in patients with colorectal liver metastases. No clear-cut correlation between the level of antibody accumulation and expression of VEGF-A was found.

Contains fulltext : 52710.pdf (publisher's version ) (Closed access)