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ERC

COMBIOSCOPY Report Summary

Project ID: 637960
Funded under: H2020-EU.1.1.

Periodic Reporting for period 1 - COMBIOSCOPY (Computational Biophotonics for Endoscopic Cancer Diagnosis and Therapy)

Reporting period: 2015-07-01 to 2016-12-31

Summary of the context and overall objectives of the project

Medical Background
Both, cancer diagnosis and tumor therapy are frequently performed using interventional procedures. In this context, replacement of traditional open surgery procedures with minimally-invasive interventions for tumor diagnosis, staging and therapy represents one of the most important challenges in modern healthcare. Minimally-invasive procedures provide numerous advantages in contrast to open surgery, including reduced surgical trauma, less pain medication, earlier convalescence, better cosmetic results, shorter hospitalization terms and lower costs. Furthermore, they are often the only promising treatment option for patients that are not eligible for surgery, due to old age or poor overall medical condition for example. However, to date, these interventional procedures are still subject to the following drawbacks:
Local tissue discrimination: Visually discriminating premalignant or potentially malignant tissue from healthy tissue is extremely challenging given the fact that body tissues are displayed in various shades of pink and red within a very limited spectrum. Another challenge is presented due to the fact that tumors typically lie underneath the visible surface. Some structures may be visible in pre-operative images but mental fusion of the partially visible anatomy with high-resolution preoperative tomographic images is associated with a high level of uncertainty and requires a lot of experience, especially when significant organ deformation is an issue.
Global orientation: Due to a loss of depth perception, difficulty with regard to hand-eye coordination, as well as the limited field of view, the navigation of medical instruments through the patient’s body is extremely challenging, particularly while taking into account critical structures, such as other organs, nerves and vessels. Furthermore, in the context of endoscopic screening and (re-)staging, a limited field of view and the lack of orientation frequently lead to incomplete tissue inspection.
With regard to the clinical outcome, major issues include:
Undertreatment: As tumor boundaries cannot be seen with the naked eye, many interventions suffer from false or incomplete resection or tumor capsule injury leading to tumor cell dissemination which can ultimately result in recurrence of the tumor. Furthermore, incomplete tissue inspection leads to a low level of sensitivity in tumor detection when implementing screening procedures.
Overtreatment: Due to the constraints of resolution and contrast, small pathologies such as micrometastases or metastatic lymph nodes are often not detected. This results in major surgeries lacking benefit to the patient and thus, an unnecessary loss of life quality while simultaneously incurring high costs to the health system.
Intraoperative complications: Similar to cancerous tissue, vital structures cannot easily be distinguished from the surrounding tissue, and severe complications resulting from their injury are common.
As a consequence, inadequate treatment, long procedure times as well as high rates of complication lead to enormous costs to the health system. Hence, interventional imaging can be regarded as one of the key issues that should be addressed in cancer therapy.


State of the Art
A modality suitable for interventional procedures should provide real-time discrimination of local tissue with a high contrast-to-noise-ratio (CNR) and spatio-temporal context for global orientation and instrument guidance. It should ideally be radiation-free to prevent the patient and staff from being exposed to harmful ionizing radiation and facilitate integration into the clinical workflow, in addition to featuring a compact design at a low cost for a wide range of applicability and acceptance. Unfortunately, none of the imaging modalities widely used at a clinical level meets all of these requirements.
Two relatively young and so far separate fields of research, referred to as biophotonics and computer-assisted int

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The achievements of the first two years of the project correspond to five of the seven work packages (WPs) that are part of the COMBIOSCOPY grant; the first set of WPs have been devoted to the development of basic methods and techniques (sec. 2.1; WP1-5) that can potentially be applied for a wide range of applications, while the second set targets specific clinical challenges (sec. 2.2; WP6-7).

2.1 Basic Methodology

Hardware development (COMBIOSCOPY WP1)
Due to their potential to reconstruct the molecular tissue composition beneath the visible surface with high spatio-temporal resolution, spectral imaging techniques are applied within the scope of this project. While multispectral optical imaging is a passive technique that yields 2D reflection images but requires no contact with the tissue and no additional illumination unit, multispectral photoacoustic imaging has the advantage of providing tomographic images at a depth range of several centimeters. The following hardware was developed for this project:

Multispectral endoscopes
In collaboration with our partners at Imperial College London we developed a multi-spectral laparoscope based on fast filter wheel technology. The filters were chosen using the band selection method developed in WP2. We are currently building a new multispectral system based on the xiSpec (XIMEA GmbH) snapshot camera. This setup allows us to record 16 multispectral bands simultaneously. Due to its standard C mount connector the camera can be attached to off-the-shelf laparoscopes and thus easily integrated into clinical workflows. Furthermore it can be connected to a flexible fiberoptic catheter (eg. Polyscope from PolyDiagnost GmbH) and will be used for computer-assisted colonoscopies in the future. We have also developed an optical fiber based hyperspectral imaging system that can acquire high spectral resolution data to further guide the filter selection for multispectral imaging.

Multispectral photoacoustic system
A multispectral photoacoustic imaging system was designed and constructed using the DiPhAS Ultrasound system from Fraunhofer IBMT (St. Ingbert, Germany) (FH) who are among the key players in the field of ultrasound device research and development and have profound experience in photoacoustic imaging. The system uses a fast tunable multispectral laser (opotek, Phocus Mobile) with a wide spectrum (690-950 nm). The ultrasonic probe used for the initial work is a 7.5MHz linear transducer. Live hybrid acoustic (ultrasound) and photoacoustic imaging is now possible, featuring basic fluence correction in a software developed within the MITK framework (cf. WP3).


Computational multispectral imaging (COMBIOSCOPY WP2)
Abnormal blood volume and oxygenation are important indicators for malignant tissue. To enable tissue classification based on these parameters, we have developed new methods to estimate them in real time using multispectral endoscopic images. One major challenge to be addressed was the selection of a suitable set of bands considering the trade-off between information content and acquisition speed. To address this issue, we have developed a new spectral band selection method inspired by the remote sensing community. A new information theory based index, referred to as Endoscopic Sheffield Index allows us to maximize the joint information contained in a number of bands. With this approach, we were able to reduce image acquisition times from 10.5s to 400 ms when applying the hardware setup based on the fast filter wheel technique. Spatio-temporal image registration can be used to compensate for motion.

The second challenge was to convert the spectral data into important tissue parameters. While previous methods for physical parameter estimation are based on either simple linear methods or complex model-based approaches exclusively suited for off-line processing, we proposed a novel approach that combines the high accuracy of model-based approaches with the speed and robustne

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)

The achievements of the project with the greatest potential impact so far are related to the analysis of the multispectral data acquired (cf. previous paragraph).
While previous methods for physical parameter estimation are based on either simple linear methods or complex model-based approaches exclusively suited for off-line processing, we proposed a novel approach that combines the high accuracy of model-based approaches with the speed and robustness of modern machine learning methods. Our current implementation allows for near real-time oxygenation estimation from megapixel multispectral images and is thus well suited for online tissue analysis. First in vivo results are extremely promising. As our concept of interventional imaging is exclusively based on non-ionizing radiation at a physical level, it is inherently safe and low in cost. Therefore, it holds high potential for clinical translation.

The second major contribution is related to quantitative PAT. Current model-based approaches are far from satisfactory as they are either too slow, inaccurate or make assumptions that do not hold when the method is applied to clinical settings. To our knowledge, we are the first to propose a machine learning based approach to overcome one of the greatest challenges in the field of PAT (patent pending). If our method, which yielded excellent results in silico, can be adapted to in vivo settings, the impact will be extremely high.

The methods developed in the scope of the COMBIOSCOPY project have already been presented at several national and international events (cf. Keynotes and Invited Talks) and were awarded several national and international prizes (cf. Awards).

Awards for COMBIOSCOPY
2016: Emil Salzer Prize (Lena Maier-Hein)
2015: Thomas-Gessmann Prize (Justin Iszatt)
2014: KUKA “Certificate for Best Paper Award (2nd place)” awarded at the MICCAI 2014 CARE workshop (Sebastian Wirkert)

Keynotes and Invited Talks on COMBIOSCOPY
03 / 2017 134th Annual Congress of the German Society for Surgery (Munich, Germany)
11 / 2016 First European Workshop of MedTech Alsace (Strasbourg, France)
09 / 2016 European Health Science Match (Heidelberg, Germany)
02 / 2016 Dutch society of Pattern Recognition and Image Processing - Spring 2016 Meeting (Rotterdam, The Netherlands)
02 / 2016 3rd EMBO Conference on Visualizing Biological Data (Heidelberg, Germany)
02 / 2016 BioPro Baden-Württemberg Meet and Match: Optical Imaging: Future Trends in Medical Applications (Mannheim, Germany)
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