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Final Report Summary - IMAGE-GUIDED SURGERY (Preclinical Protocols For Image-Guided Surgery)

The scientific objective of this grant was the preclinical demonstration that ZW800-1 (a novel zwitterionic Near Infra-Red Fluorescence (NIRF) dye), when conjugated onto a cRGD peptide, can be used to identify a minimum tumour margin distance during intra-operative image-guided surgery. The goal was to validate the ZW800-1-cRGD probe a) in vitro (validation studies to detect integrin αvβ3) and b) in vivo (in rodents and dogs in order to fast track it into the clinic). The technological objectives included that the probe was validated in conjunction with the three clinical hand-held camera systems ArtemisTM, mini-FLARETM and MSOTTM (Multispectral Optoacoustic Tomography) imaging technologies so that a complete image-guided surgical solution to cancer can be of benefit to patients and the healthcare system. As far as networking & training objectives are concerned, Dr. Bierau’s personal goal was to move towards an academic career. After her career break, Dr. Bierau started her new assignment at the LUMC to develop new preclinical imaging strategies in conjunction with imaging hardware manufacturers, surgeons and preclinical scientists so that optical imaging may be used in the context of cancer surgery. The process of bringing a targeted contrast reagent and camera detection system to cancer surgery involves crossing a preclinical-to-clinical translational chasm. The current process involves a multitude of different personnel, skills and regulatory adherence, for which Dr. Bierau shortened this bridge significantly. Optical imaging in particular represents a technology that has the potential to further exploit the current knowledge in this area, whereby it is likely to be used routinely in the clinic within the next 10-15 years. Indeed, it is envisaged that in the future optical imaging will be implemented as the fourth clinical modality in conjunction with the three already established clinical imaging techniques of Magnetic Resonance Imaging (MRI), X-ray Computed Tomography (CT) and Positron Emission Tomography (PET). Dr. Bierau has been further educated by Prof. Lowik, the scientist in charge, as well as by his respective international collaborators, for example TUM: Technical University Munich in Germany), in highly innovative approaches (including MSOTTM). The concept of this highly inter- / multi-disciplinary project was the development of improved imaging technologies for therapeutic intervention of tumours. This is necessary to decrease the morbidity of patients undergoing oncologic surgery and improved postoperative results. For an long-term project impact, the hypothesis was that if one could develop a fluorescently labelled marker that can specifically demarcate healthy from tumour tissue (known as the tumour margin), surgeons would have a more definitive standard for resection of tumours. If this can be achieved, the future impact would be (a) reduced recurrence rates in patients by lowering the risk of residual tumour tissue remaining after surgery and as a consequence improve survival (b) minimised removal of healthy tissues as an undesirable effect for the patient c) reduced patient morbidity and hospital stay and d) significant health cost benefits. Nowadays, the translation of pre-operative imaging to the intraoperative situation is often challenging. Surgeons therefore mostly needs to rely on visual inspection and palpation when discriminating between healthy and tumor tissue. Consequently, tumor positive resection margins are still too high or the other way around too much healthy tissue is removed which can have a serious impact on the quality of life of the patient. Next to the personal point of view, covered in the quality of life, there are also economic implications which force us to improve surgical outcomes. Less invasive surgery leads to reduced hospital stay, less complications and lower reoperation rates due to better margins and smaller defects. More focused on this project the 5 year survival rate of pancreas cancer patients is as less as 5%. Slight improvements can already make a huge difference in here. We wanted to make progress towards this by improving the accuracy of oncologic surgery by using a near infrared fluorescent targeting probe, cRGD-CW800, which is an outstanding progress for this two year project period. During surgery, the fluorescence signal can exactly show the surgeon the boundaries of the tumor which makes it able to improve the precision of surgery in general. In this project we are using two different imaging modalities, fluorescence and MSOT. Both have a high resolution, sensitivity and specificity in general. Based on the experiments performed during this project, we know that this is also true when using cRGD-CW800 as fluorescent contrast agent. We were able to visualise the tumor in vivo with both NIRF and MSOT in a specific manner, which is one of the most significant results of the project period. To summarize, since the beginning of the project we started with the synthesis and validation of the probe. Initial we planned to use cRGD-ZW800-1, nevertheless it turned out that ZW800-1 has stability problems when using it in vivo. This means that this probe is maybe sufficient for the goal of this project but will never reach a clinical trial. For this reason we decided to change the fluorophore with the widely available IRDye800CW. Afterwards we had to validate an appropriate pancreas cancer model which mimics the human situation as close as possible. After extensive testing the cell lines AsPc-1 and BxPC-3 are chosen to be used in orthotopic mouse models. Subsequently, the in vivo testing could start. First we used the Pearl, a preclinical fluorescent imaging system, to visualise the tumors in vivo. When this showed us satisfactory results we moved on to the Artemis, a fluorescent imaging guided surgery system which is also used in the operating theatre nowadays. The most challenging part was the introduction of the MSOT system but in the end we were able to obtain acceptable images. However, MSOT is still in the middle of the development phase related to acquisition parameters and reconstruction algorithms which will improve the quality of the images even more over time and in the future.

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