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Early Detection of cancer onset based on sensing field cancerization at the organ level

Periodic Reporting for period 1 - SENSITIVE (Early Detection of cancer onset based on sensing field cancerization at the organ level)

Reporting period: 2018-11-01 to 2019-10-31

Cancer remains a major cause of death worldwide. In fact, because of the ever increasing life expectancy, the percentage of deaths attributed to cancer increases constantly. Not all cancers are equally common or life-threatening. Tumors of the gastrointestinal (GI) tract account for over 20% of newly diagnosed cases, while some of the GI tract tumors are quite deadly. As with most cancer types, prevention and early diagnosis crucial for the clinical outcome. The majority of cancers, however, remain asymptomatic until advanced stage while biomarkers for early detection are sparse. Finally, imaging techniques are either not sensitive enough or too expensive to be used as a routine approach for early diagnosis.
Early stages of cancer are characterized by tissue changes which cannot be easily detected by current means of body scan and imaging. These changes are being referred to as “field cancerization” and imply that a whole region in a tissue/organ can be prone to develop cancer and/or that a tissue segment larger than the tumor itself is affected, leading to tumor reappearance (recurrence) at a later stage. The SENSITIVE project is trying to address exactly this issue: to develop imaging methodologies and modalities that could allow the detection of such tumor-prone regions and allow early detection of cancer and/or assessment of tumor margins during operation. Successful implementation will allow the development of an endoscope especially designed for this purpose that will be used to detect cancerous tissue in humans. This will allow early diagnosis and better treatment of cancer.
"WP1: During the period covered by the report the hybrid Scattering/Raman microscope was developed and characterized, and an imaging protocol was designed to enable coregistered measurements with the existing at HMGU OA/SHG/THG microscope. In specifics, RiverD developed a Raman module, optimized for tissue Raman microscopy in the red and near-infrared region of the electromagnetic spectrum. The control and data pre-processing software was programmed in MATLAB and C#, using a .NET framework, while a software developer kit (SDK) was created by RiverD and RAYFOS for the software of the hybrid microscope. The spectrally resolved depolarization spectra module was developed by UC3M. Spectral measurements are carried out under white-light illumination, using the spectrometer, while depolarization and scattering are measured under reflected laser illumination, using the photodetector. In collaboration with RiverD, UC3M designed the coupling interface of the scattering module for straightforward coupling to the hybrid microscope. A LabVIEW based software was also developed. The integration of these two modalities into a new hybrid microscope was implemented by HMGU in close collaboration with RiverD, UC3M, and RAYFOS. The inverted microscope with epi-illumination was assembled by components that enable high customization and thus direct optical coupling of the two modalities. The requirements for the microscope objective were established by RiverD. Following several iteration and design proposals, the optimal solution was an objective design that allows the combination of Raman spectroscopy and diffuse scattering modalities in one hybrid microscope. Finally, HMGU developed a LabVIEW based graphical user interface that allows full control of the microscope and acquisition of the multimodal data. A large number of tests have been executed to fully characterize the operation of the hybrid microscope, while phantom and tissue measurements were implemented to develop an integrated imaging protocol between the Scattering/Raman and the hybrid OA/SHG/THG microscopes, so that all modalities image the same regions of interest. UC3M has further initiated phantom and tissue measurements to assess the performance and accuracy of the depolarization measurements, while RAYFOS has initiated the design of the software platform to operate the Scattering/Raman microscope in collaboration with all involved partners.

WP2: During the first year of the project, experiments were performed towards the development of mouse models in one hand, and establishing procedures for obtaining human tissues and actual collection of the first biopsies.
Two different mouse for esophageal and colorectal carcinoma have been developed. A small scale breeding program is running at HMGU. This was necessitated by the need for measurements on fresh material. The esophageal model which is going to be measured relies on the overexpression of the IL2 cytokine which is known to lead to inflammation, hyperplasia and eventually metaplasia and cancer. The colorectal model relies on the tissue specific knockout of the tumor suppressor protein APC in the small and large intestine of mice. With respect to human samples, protocols for taking biopsies from patients have been established. Ethical approval for patient work has been obtained from the independent review board (IRB) of the UMCG. First biopsies (n = 32) have already been acquired from patients with Barrett’s esophagus and Lynch syndrome in the first 2 weeks since we are running, and more patients are scheduled."
WP1: To the best of our knowledge this is the first time that Raman spectroscopy will be used for the investigation of field cancerization at the organ level. On top of that, SENSITIVE moves far beyond the current state of the art by developing a never before seen hybrid microscope that integrates scattering (structural information) and Raman (molecular information) to assess field cancerization. The unprecedented technical inventions of SENSITIVE are further strengthened by the development of an integrated imaging protocol that enables imaging of the exact same regions of interest with 5 (and possibly more) modalities interrogating either structural or molecular information. Such a multimodal system will enable systematic investigation of biomarkers related to field effect through scattering (structural and molecular information), anisotropy and interfaces (structural information), and absorption (structural and functional information) without the need of exogenous contrast agents. The derived information will allow for further understanding of tissue microalterations during biomarker development and image changes that histological analysis fails to visualize. In the long-term, the results of WP1, in combination with the results from WP3 and WP4, will define a paradigm shift in early cancer diagnosis, and most importantly in cancer prevention as it would allow for initiating preventive measures or schedule early treatment.

WP2: The mouse models developed are all previously published. This was done on purpose because the consortium wanted to use models that recapitulate to the best possible extent the human disease. Although the models are not novel, this is the first time that such optical measurements will be performed in these models. With respect to human samples, by definition every sample collected from a patient is unique. By the end of the project we expect to generate novel molecular and imaging data from both mouse and human samples which will allow us to identify unique biomarkers for the different stages of the disease. Hopefully, these findings will be translated to the clinic and be used for early diagnosis and/or tumor margin assessment during surgery. This way, better treatment decisons will be made.