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Item does not contain fulltext Bevacizumab (antivascular endothelial growth factor [anti-VEGF]) and cetuximab (antiepidermal growth factor receptor [anti-EGFR]) are approved antibodies for treatment of cancer. However, in advanced colorectal cancer, the combination fails to improve survival. As the reason for the lack of activity is unknown, our study aims to determine the effect of bevacizumab on targeting of anti-EGFR and insulin-like growth factor 1 receptor (IGF-1R) antibodies in tumors with single-photon emission computed tomography (SPECT)/CT imaging. Mice with subcutaneous EGFR and IGF-1R-expressing SUM149 xenografts received a single dose of bevacizumab (10 mg/kg) or saline. After 4 days, mice were injected with radiolabeled cetuximab or R1507, an anti-IGF-1R antibody. A control group received a radiolabeled irrelevant IgG (hLL2). Three days later, SPECT/CT images were acquired and mice were dissected to determine the concentration of antibodies in the tissues. Tumors were analyzed immunohistochemically to determine vascular density (CD34), VEGF, EGFR and IGF-1R expression. SPECT/CT imaging revealed that bevacizumab treatment significantly reduced tumor targeting of radiolabeled cetuximab by 40% from 33.1 +/- 1.1 %ID/g to 19.8 +/- 5.7 %ID/g (p = 0.009) for untreated and bevacizumab-treated tumors, respectively. A similar effect was found for 111 In-R1507: tumor targeting of R1507 decreased by 35%. No significant differences in tumor uptake were observed in mice that received an irrelevant IgG. Uptake in normal organs was not altered by bevacizumab. Immunohistochemical analysis showed that vascular density decreased with 43%, whereas EGFR and IGF-1R expression was unaltered. In conclusion, bevacizumab treatment significantly reduces tumor targeting of anti-EGFR and anti-IGF-1R antibodies. This emphasizes the importance of timing and sequencing of bevacizumab in combination with other antibodies.

Contains fulltext : 118365.pdf (Publisher’s version ) (Closed access) BACKGROUND: Until now, only imatinib and sunitinib have proven clinical benefit in patients with gastrointestinal stromal tumours (GIST), but almost all metastatic GIST eventually develop resistance to these agents, resulting in fatal disease progression. We aimed to assess efficacy and safety of regorafenib in patients with metastatic or unresectable GIST progressing after failure of at least imatinib and sunitinib. METHODS: We did this phase 3 trial at 57 hospitals in 17 countries. Patients with histologically confirmed, metastatic or unresectable GIST, with failure of at least previous imatinib and sunitinib were randomised in a 2:1 ratio (by computer-generated randomisation list and interactive voice response system; preallocated block design (block size 12); stratified by treatment line and geographical region) to receive either oral regorafenib 160 mg daily or placebo, plus best supportive care in both groups, for the first 3 weeks of each 4 week cycle. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was progression-free survival (PFS). At disease progression, patients assigned placebo could crossover to open-label regorafenib. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01271712. RESULTS: From Jan 4, to Aug 18, 2011, 240 patients were screened and 199 were randomised to receive regorafenib (n=133) or matching placebo (n=66). Data cutoff was Jan 26, 2012. Median PFS per independent blinded central review was 4.8 months (IQR 1.4-9.2) for regorafenib and 0.9 months (0.9-1.8) for placebo (hazard ratio [HR] 0.27, 95% CI 0.19-0.39; p

Contains fulltext : 118418.pdf (Publisher’s version ) (Closed access) Because novel therapeutic options are limited in Ewing sarcomas (ES), we investigated the expression, genetic aberrations and clinical relevance of MET and anaplastic lymphoma kinase (ALK) in ES and determined the relevance of targeting these receptors. MET and ALK protein expression was determined immunohistochemically in 31 (50 samples) and 36 (59 samples) ES patients, respectively. Samples included primary tumors, postchemotherapy resections, metastases and relapses. MET and ALK RTK domains were sequenced in respectively 33 and 32 tumors. Five ES cell lines were treated in vitro with the MET/ALK-inhibitor crizotinib, the ALK-inhibitor NVP-TAE684 or the MET-inhibitor cabozantinib and analyzed by MTT assays. Modest to high MET and ALK expression was detected in the majority of ES (86 and 69%, respectively). ALK expression was significantly lower in postchemotherapy resections compared to paired untreated primary tumors (p = 0.031, z = -2.310, n = 11). In primary tumors (n = 20), membranous MET expression significantly correlated with a poor overall survival (OS) (60 vs. 197 months, p = 0.014). There was a trend toward a poor event-free survival (67 vs. 111 months, p = 0.078) and OS (88 vs. 128 months, p = 0.074) in patients with highest ALK levels (n = 29). ALK or MET RTK domain aberrations were demonstrated in 5/32 (16%) and 3/33 (9%) tumors, respectively. Crizotinib (IC50 1.22-3.59 mumol/L), NVP-TAE684 (IC50 0.15-0.79 mumol/L) and cabozantinib (IC50 2.69-8.27 mumol/L) affected ES cell viability in vitro. Altogether, our data suggest that MET and ALK are potential novel therapeutic targets in ES and targeting these receptors may be of great interest to rationally design future studies in ES.

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Contains fulltext : 107703.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext AIM: Insulin-like growth factor-1 receptor (IGF1R) is a tyrosine kinase receptor mediating cell growth and survival of cancer cells. We studied responses to IGF1R tyrosine kinase inhibitor NVP-AEW541 combined with conventional systemic drugs in breast cancer cell lines of different clinical subtype. MATERIALS AND METHODS: Sensitivity to NVP-AEW541, single treatment and combinations with tamoxifen, trastuzumab, doxorubicin or paclitaxel, was tested in MCF7, SKBR3 and T47D cells. Cells were assayed for proliferation, cell death, cell cycle distribution and phosphorylation of proteins downstream of IGF1R. RESULTS: Treatment of NVP-AEW541 resulted in reduced proliferation, G-1 cell cycle arrest and reduced phosphorylation of protein kinase B (AKT) and extracellular-signal-regulated protein kinase (ERK). Sensitivity to IGF1R tyrosine kinase inhibition was low in T47D cells, despite their high IGF1R expression. NVP-AEW541 combined with trastuzumab had synergistic cytotoxic effects in T47D cells, and additive effects were shown in MCF7 and SKBR3 cells. Also, combination with doxorubicin had antagonistic effects in T47D cells. Doxorubicin caused up-regulation of phosphorylated ERK in T47D cells, which was not inhibited by NVP-AEW541. CONCLUSION: Antagonistic effects should be anticipated when IGF1R inhibitors are combined with conventional systemic drugs in a subset of breast tumors. Development of functional biomarkers predicting tumor response to tailored IGF1R therapy is warranted. 01 april 2012

Item does not contain fulltext The insulin-like growth factor 1 receptor (IGF-1R) is a potential new target for the treatment of breast cancer. Patients with breast cancer lesions that express IGF-1R may benefit from treatment with anti-IGF-IR antibodies. IGF-1R expression can be visualized using radiolabeled R1507, a monoclonal antibody directed against IGF-1R. However, antibodies clear slowly from the circulation, resulting in low tumor-to-background ratios early after injection. Therefore, we aimed to accelerate targeting of IGF-1R using radiolabeled R1507 F(ab')(2) and Fab fragments. In vitro, immunoreactivity, binding affinity and internalization of R1507 IgG, F(ab')(2) and Fab were determined using the triple negative IGF-1R-expressing breast cancer cell line SUM149. In vivo, pharmacokinetics of In-111-labeled R1507 IgG, F(ab')(2) and Fab were studied in mice bearing subcutaneous SUM149 xenografts. SPECT/CT images were acquired and the biodistribution was measured ex vivo. The in vitro binding characteristics of radiolabeled R1507 IgG and F(ab')(2) were comparable, whereas the affinity of Fab fragments was significantly lower (K-d: 0.6 nM, 0.7 nM and 3.0 nM for R1507 IgG, F(ab')(2) and Fab, respectively). Biodistribution studies showed that the maximum tumor uptake of In-111-R1507 IgG, F(ab')(2) and Fab was 31.8% ID/g (72 h p.i.), 10.0% ID/g (6 h p.i.), and 1.8% ID/g (1 h p.i.), respectively. However, maximal tumor-to-blood ratios for F(ab')(2) (24 h p.i.: 7.5) were more than twice as high as those obtained with R1507 (72 h p.i.: 2.8) and Fab (6 h p.i.: 2.8). Injection of an excess of unlabeled R1507 significantly reduced tumor uptake, suggesting that the uptake of R1507 IgG and F(ab')(2) was specific for IGF-1R, while the major fraction of the tumor uptake of Fab was nonspecific. IGF-1R-expressing xenografts were visualized with In-111-F(ab')(2) SPECT/CT as early as 6 h p.i., while with R1507 IgG, the tumor could be visualized after 24 h. No specific targeting was observed with In-111-Fab. In-111-F(ab')(2) fragments showed improved targeting of IGF-1R expressing tumors. Tumor-to-blood ratios were twice as high as those obtained with In-111-R1507, and adequate tumor targeting on SPECT/CT images was observed as early as 6 h p.i. For individualization and optimization of IGF-1R targeted therapy, In-111-F(ab')(2) may be the tracer of choice.

Contains fulltext : 109142.pdf (Publisher’s version ) (Open Access) ABSTRACT: BACKGROUND: In this study, pretargeted immuno-positron-emission tomography [PET] with a bispecific monoclonal anti-carcinoembryonic antigen [CEA] (CEACAM5) x anti-hapten antibody (bispecific monoclonal antibody [bsmAb]) and a small (1.5 kD) peptide labeled with 68Ga was compared to fludeoxyglucose [18F-FDG]-PET for detecting intraperitoneal [i.p.] CEA-expressing human colonic tumor xenografts in nude mice. METHODS: Two groups of female BALB/c nude mice were inoculated with LS174T human colonic tumor cells i.p. One group received 5 MBq 18F-FDG, and the other received intravenous injections of the bsmAb, followed 16 h later with 5 MBq of 68Ga-labeled peptide. One hour after the radiolabeled peptide or FDG was given, micro-PET/computed tomography images were acquired. Thereafter, the uptake of the 68Ga or 18F in dissected tissue was determined. RESULTS: Within 1 h, high uptake of the 68Ga-labeled peptide in the tumor lesions (23.4 +/- 7.2% ID/g) and low background activity levels were observed (e.g., tumor-to-intestine ratio, 58 +/- 22). This resulted in a clear visualization of all intra-abdominal tumor lesions >/= 10 muL and even some tumors as small as 5 muL (2 mm diameter). 18F-FDG efficiently localized in the tumors (8.7 +/- 3.1% ID/g) but also showed physiological uptake in various normal tissues (e.g., tumor-to-intestine ratio, 3.9 +/- 1.1). CONCLUSIONS: Pretargeted immuno-PET with bsmAb and a 68Ga-labeled peptide could be a very sensitive imaging method for imaging colonic cancer, disclosing occult lesions.

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Contains fulltext : 88064timmer-bonte.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 87381.pdf (Publisher’s version ) (Closed access) We present two patients with colorectal carcinoma who were admitted with fever and diarrhoea during treatment with chemotherapy. Blood cultures taken from both patients revealed an infection with Listeria monocytogenes. A contaminated ice cream was probably the source of infection in one patient. The other patient died of the listeriosis. Patients with diminished cellular immunity are at risk of invasive listeriosis. Listeriosis has a high mortality rate in this group of patients. Intravenous penicillin or ampicillin for 4 to 6 weeks is the first choice of antibiotic treatment. These antibiotics can be combined with an aminoglycoside or trimethoprim-sulfamethoxazole for a synergistic effect. To prevent invasive listeriosis we recommend strict dietary advice to all patients with diminished cellular immunity.

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Contains fulltext : 81296.pdf (Publisher’s version ) (Closed access) It is uncommon for patients to present with bone metastases while the primary tumor is still unknown. The case of a patient with bone metastases as primary presentation of leiomyosarcoma, who was diagnosed after a 18F-FDG PET-CT and a CT-guided biopsy of the adrenal gland is described. If after routine physical, laboratory and radiological investigations no diagnosis can be made, 18F-FDG PET should be added to the conventional work-up of patients with unknown primary cancer. In this way, unnecessary and enduring suffering of symptomatic patients may be prevented.

Contains fulltext : 80465.pdf (Publisher’s version ) (Closed access)

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Contains fulltext : 111564.pdf (Publisher’s version ) (Open Access) Radboud Universiteit Nijmegen, 27 juni 2013 Promotores : Graaf, W.T.A. van der, Bont, E.S.J.M. de Co-promotor : Versleijen-Jonkers, Y.M.H.

Contains fulltext : 87967.pdf (Publisher’s version ) (Open Access) Radboud Universiteit Nijmegen, 22 december 2010 Promotores : Graaf, W.T.A. van der, Oyen, W.J.G. Co-promotores : Herpen, C.M.L. van, Laarhoven, H.W.M. van 240 p.