Assessment of Angiogenesis and Tumor Response: From Microscope to Clinic
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Principal Investigator for Radiology: Monique R Bernsen, PhD & CF (Kees) van Dijke, MD, PhD
Imaging methods are indispensable for studying angiogenesis and hold promise for assessing (early) response parameters in anti-cancer therapy. They can pinpoint sites of angiogenesis — e.g. determine tumor vessel development and integrity — and can assess indirect functional information of normal and pathological tumor tissue before, during and after treatment. Imaging methods therefore potentially may assess the efficacy of angiogenesis inhibitors.
Evaluating angiogenesis in detail presents a dilemma: while microscopic imaging methods are normally invasive in assessing structural abnormalities, MRI provides non-invasive, structural and functional details of tumor and normal tissue at a lower resolution. MRI cannot (generally) resolve vessels of the microcirculation or sub-microcirculation level. Current estimations of quantitative MR data include assumptions of the pharmacokinetic parameters of vessels and interstitial tissue. The heterogeneity of the angiogenesis within tumor tissue further complicates matters. To bridge this gap we combined MR imaging with other imaging methods, including real time in vivo MR microscopy in collaboration with the Erasmus MC Department of Surgical Oncology.
Monitoring angiogenesis at microscopic level: A correlative study of micro-MR imaging and confocal microscopy using labeled contrast agents
In itself a complex, multifactor process, tumor vessel development is a key factor for tumor growth. MR imaging could be a useful non-invasive tool to visualize vessel development and monitor effects of anti-angiogenic drugs (developed to counteract the development of new vessels in a tumor). To assess the value of MRI for monitoring angiogenesis in tumors, we use an experimental dorsal skinfold window model developed by the Department of Surgical Oncology. Using various high molecular weight contrast agents suitable for MRI and/or fluorescent confocal microscopy, the ability to visualize tumor microvessels and to assess their functionality with MRI is studied, using confocal microscopy images as a reference. The confocal and MR images are currently compared by visual inspection. Quantification techniques for microvasculature structure are being developed in collaboration with the Biomedical Imaging Group Rotterdam (see Biomedical Image Processing).
Figure 1 Matched images of tumor feeding vessels obtained by
MRI and confocal microscopy respectively,
using a dual modality, high molecular weight contrast agent.
MR imaging of chemotherapeutic treatment: Effects on limb-threatening soft tissue tumors
Limb-threatening soft tissue tumors can be treated with high doses of cytostatic drugs. Isolated limb perfusion (ILP) may achieve regional concentrations 15 to 20 times higher than those reached after systemic administration, yet without systemic toxicity. The resulting destruction of tumor cells and vessels then allows for secondary limb-sparing surgery. Treatment effects are evaluated by monitoring the patient before and after ILP treatment. The aim of this project is to assess the added value of DCE-MRI in monitoring the effect of ILP on soft tissue tumors. Static and dynamic MRI and permeability parameter maps calculated from the DCE-MRI data are correlated with clinical and pathological findings.
Figure 2 Dynamic contrast MR images of tumor in leg. Three time points during contrast are shown. The early enhancement demonstrates the high grade component of the sarcoma. Tumor feeding and surrounding vessels are displayed.
MR imaging of early treatment effects of ILP on sarcomas: Comparing different acquisition protocols
The Department of Surgical Oncology has developed an animal model for soft tissue sarcoma that mimics the clinical situation. We use this model to study the effects of ILP on tumor tissue in detail. We recently reported that pharmacokinetic MRI parameters, acquired with DCE-MRI, are suitable to monitor treatment effects 24 hours after ILP (Preda et al. MAGMA 2004). In the current study we evaluate the immediate effects of ILP on the tumor. For this purpose DCE-MRI, blood oxygenation level dependent imaging (BOLD) and diffusion weighted imaging (DWI) are performed 30-60 minutes after treatment. In contrast to the decrease in vascular permeability observed 24 hours post-treatment as reported by Preda et al, we expect a transient increase in permeability immediately early after ILP. The data from the different acquisition protocols will be correlated with histology findings to evaluate their value in depicting tumor changes due to ILP.
Figure 3 Diffusion weighted EPI and enhanced T1-weigted SPGR sequences of a subcutaneous tumor in limb of rat. Regions of low signal intensity in the Bold sequence (left image) correspond to non-enhancing regions on the post contrast t1-weighted SPGR sequence (right image). Enhancing regions are high on the Bold images.
Funding: Erasmus MC Translational Research Grant 2003- 2007: "Intravital microscopy and tumor drug uptake studies to assess the predictive value of a clinically applicable indicator in correlation to dynamic contrast enhanced MRI"
Participating researchers Dept. of Radiology: Marion van Vliet, Piotr Wielopolski, Jifke Veenland, Lejla Alić, Gabriel Krestin, Wiro Niessen
Collaborations:
|
Country |
City (State) |
Institute |
Department |
Collaborator |
|
Germany |
Munich |
GE Medical Systems [ASL Europe] |
Timo Schirmer, PhD |
|
|
the Netherlands |
‘s Hertogenbosch |
GE Medical Systems [ASL Europe] |
Gavin C Houston, PhD |
|
|
the Netherlands |
Delft |
Flick Engineering Solutions |
Herman Flick, MEng |
|
|
the Netherlands |
Delft |
University of Technology |
Reactor Instituut |
Gerben A Koning, PhD |
|
the Netherlands |
Eindhoven |
Technical University |
Biomedical Engineering |
Klaas Nicolay, PhD |
|
the Netherlands |
Eindhoven |
Technical University |
Biomedical Engineering |
Gustav J. Strijkers, PhD |
|
the Netherlands |
Enschede |
University of Twente |
Biomedical Optics |
Kiran Kumar Thumma |
|
the Netherlands |
Rotterdam |
Erasmus MC |
Cardiology |
Heleen MM van Beusekom, PhD |
|
the Netherlands |
Rotterdam |
Erasmus MC |
Cardiology |
Ewout Jan van den Bos, MD, PhD |
|
the Netherlands |
Rotterdam |
Erasmus MC |
Cardiology |
Dirk J Duncker, MD, PhD |
|
the Netherlands |
Rotterdam |
Erasmus MC |
Cardiology |
Wim J van der Giessen, MD, PhD |
|
the Netherlands |
Rotterdam |
Erasmus MC |
Hepatogastroenterology |
Ernst J Kuipers, MD, PhD |
|
the Netherlands |
Rotterdam |
Erasmus MC |
Neonatology |
Ingrid B Renes, PhD |
|
the Netherlands |
Rotterdam |
Erasmus MC |
Nuclear Medicine |
Marion de Jong, PhD |
|
the Netherlands |
Rotterdam |
Erasmus MC |
Orthopedics |
Eric J Farrell, PhD |
|
the Netherlands |
Rotterdam |
Erasmus MC |
Orthopedics |
Gerjo JVM van Osch, PhD |
|
the Netherlands |
Rotterdam |
Erasmus MC |
Orthopedics |
Harrie H Weinans, PhD |
|
the Netherlands |
Rotterdam |
Erasmus MC |
Plastic & Reconstructive Surgery |
Ronald I Siphanto, MD |
|
the Netherlands |
Rotterdam |
Erasmus MC |
Surgical Oncology |
AMM (Lex) Eggermont, MD, PhD |
|
the Netherlands |
Rotterdam |
Erasmus MC |
Surgical Oncology |
Timo LM ten Hagen, PhD |
|
the Netherlands |
Rotterdam |
Erasmus MC |
Surgical Oncology |
Gerben A Koning, PhD |
|
the Netherlands |
Rotterdam |
Erasmus MC |
Virology |
Fiona Read |
|
the Netherlands |
Rotterdam |
Erasmus MC |
Virology |
Thijs Kuiken, DVM, PhD, DACVP |
|
USA |
Milwaukee (WI) |
GE Medical Systems [ASL Central] |
Jason A Polzin, PhD |
|
|
USA |
San Francisco (CA) |
University of California |
Radiology |
Robert C Brasch, MD |