Periodic Reporting for period 2 - PRISAR (Preclinical Intra-Operative Image-Guided Surgery and Post-Operative Radiotherapy of Tumours) Reporting period: 2017-02-01 to 2019-01-31 Summary of the context and overall objectives of the project Pancreatic cancer is a major cause of cancer-associated mortality, with a dismal overall prognosis that has remained unchanged for many decades. There are several factors that contribute to the poor prognosis of patients with pancreatic cancer. The most important point is that due to the lack of disease-associated symptoms, approximately 50-60% of the patients already have locally advanced or metastatic disease at the time of diagnosis. The median survival of patients with metastatic pancreatic cancer is 3 months. Medical imaging has several important roles to personalize oncological management to the individual patient, ranging from initial diagnosis and staging towards early monitoring of therapy response and assessment of systemic control in metastatic patients. However, adequate visualization of the primary tumour and metastatic lesions using current imaging techniques and protocols is challenging in patients with pancreatic cancer. In a considerable number of patients, the primary tumour cannot be visualized. PRISAR stands for Preclinical Intraoperative Image-Guided Surgery and Postoperative Radionuclide therapy of Tumours and in this context, intraoperative fluorescence imaging is a promising technique which potentially allows a better detection of tumor cells left at the resection margins. Fluorescence guided surgery is the first part of PRISAR and can already lead to an enormous improvement in survival rates. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far In workpackage 1; is the development of a tumor margin specific fluorescent probe with a TCO tag for click chemistry. The first step was the development of the NIRF labelled contrast reagent and TCO tag with optimised affinity and selectivity for neovasculature structures, associated with carcinomas. Nowadays, cRGD-800CW-TCO is synthesized and validated both vitro, and ex vivo. In workpackage 2; the development of an optoacoustic camera system for open surgery. Nowadays it is proved that this can be used for imaging of human subjects in a range of clinical applications. Taken from the lab, the first prototype system was developed alongside a range of different handheld configurations that range in depth/resolution as models for various applications included intraoperative imaging. In workpackage 3; preclinical in vitro and in vivo validation of the probe developed in workpackage 1, the MSOT system in workpackage 2 and the other imaging modalities; Cellvisio, mass spectrometry imaging (MSI) and the small hybrid gamma-optical camera. For validation of the probe we developed and established a suitable, clinically relevant nude mouse model using orthotopic injection of human pancreatic tumor cell suspensions into the pancreas. This proved to be an important step in developing pancreatic tumor models that represent all steps of the metastatic cascade including local growth and vascular and lymphatic invasion at the local site. The AsPc1 model shows this cascade which makes this model highly suitable for the combination of image guided surgery and targeted radionuclide therapy. In workpackage 4; targeted radionuclidetherapy by conjugating onto the probe, the additional value of targeted fluorescence guided surgery in combination with targeted radionuclide therapy should be proved. In the project we are heading towards workpackage 4 which means that we are already thinking about what types of IGS are performed in the clinic nowadays and how should we handle and analyse such big imaging data sets. Fortunately, within the PRISAR project, there is expertise regarding data dimensionality reduction approaches which can assist the interpretation of the data. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) Progress Beyond State-of-ArtThe use of intraoperative gamma imaging has the potential to further improve surgical outcomes. By also fusing optical and gamma images, there are medical advantages of having both anatomical and physiological information during surgical procedures. Furthermore, a handheld device provides practical benefits including bedside imaging for small targeted organs and tissues, such as thyroid gland and lacrimal ducts. Using this hybrid gamma-optical camera unit will provide the surgeon with fused optical and gamma images that can enhance the localisation of tumours and outline margins in critical surgical situations. Furthermore, the device would help to minimise the chance of leaving abnormal tissues behind after the surgical procedure is complete. There is currently no commercially available system that offers hybrid imaging for clinical use that combines fluorescence and gamma imaging into a single fused image. Development of such a system will have significant benefits for cancer diagnosis and treatment, especially in the case of head and neck cancers, and will be a unique offering in the healthcare arena which will make it extremely useful in-theatre for procedures such as sentinel lymph node biopsies. ResultsThe PRISAR project brought to the forefront a new type of hybrid radionuclide-fluorescent imaging to aid the process of image-guided surgery. The visualisation of the probe by different imaging modalities enables the surgeon to identify tumours with far greater precision than current state-of-the-art methods. Where clinical imaging nowadays tend to rely on large single modality instruments, the PRISAR project resulted in the development of a multimodality handheld hybrid gamma-optical camera. Early development of these small field of view (SFOV) cameras was focussed on a single modality imaging. Now the combination of dual optical and gamma detection enables high spatial resolution multi-modal imaging, giving a superimposed scintigraphic and optical image. Hybrid imaging offers new possibilities for assisting clinicians and surgeons in localising the site of uptake in procedures such as sentinel node detection and intraoperative imaging. The hybrid camera concept can be extended to a multimodal detector design which can offer stereoscopic images, depth estimation of gamma-emitting sources, and simultaneous gamma and fluorescence imaging. Socio-Economic ImpactThe project will build upon the current SME expertise available in Europe where such relationships are easier to bridge and where access to academic insight and collaboration is less fraught with difficulties. By empowering people with the knowledge of cross-sector issues and the multidisciplinary requirements of imaging, a new foundation of understanding will be achieved. This will help to build a more competent and employable European molecular imaging work force – ready for the next era of molecular imaging. At the start of this project we already acknowledged the fact that this project had the potential to produce the much-needed multi-disciplinary young professionals by active transfer of knowledge across different disciplines, as well as across an academic-industrial axis. After two years into the project, we can say that there is a high level of interaction and transfer of knowledge between several partners and secondees, partners with different backgrounds can help each other further. For this the highly wanted helicopter view is developed for a truly multi-disciplinary approach. Furthermore, the processing of big data as mentioned under workpackage 4 in the previous section, was not mentioned in the proposal but is additional progress beyond the state of the art which is highly likely to be be used in a broad range of diseases and not only cancer.
