Ultrasound-directed diagnosis and targeted treatment of Crohn’s disease using smartbubbles

During the 6 months research stay research collaboration with the group of GRAM D’Haens was initiated. A protocol for a longitudinal ultrasound study of Crohn’s patients was accepted by the local ethics committee at the AMC and the study inclusion initiated in April. In the same period I commuted back to Bergen and Haukeland University Hospital and could include patients in the corresponding clinical study in CS-2. An elongation of my stay in Amsterdam was planned for the period 1st March 2017 to 30th April 2017 to continue inclusion and data analysis. Two technical papers on the bolus-and-burst perfusion method with contrast-enhanced ultrasound was submitted for publication investigating inter-observer variability for the analysis, inter-observer variability for repeated examinations on the same scanner and for repeated measurements on different ultrasound scanners. These are all important features of a perfusion method for it to be repeatable and applicable by different investigators. Currently, there are no ultrasound perfusion methods that can be compared between different ultrasound scanners severely limiting the clinical usefulness. We found that using the bolus-and-burst method perfusions measurements can be compared between different scanners. The first paper was rejected and will be resubmitted to another journal early in 2017. The second paper has been accepted with minor revision. A third paper was also submitted investigating the inter-observer variability for analysis using commercially available perfusion analysis software for contrast-enhanced ultrasound. This paper has been resubmitted after revision and we are awaiting the decision. In the same period recommendations and guidelines for gastrointestinal ultrasound was published by the EFSUMB on which I was the first author, and Hilde von Volkmann published an ultrasound study on a genetic diarrheal disorder as a part of her PhD where I am co-supervisor and 2nd author.

A three week research stay in Bologna was performed, but the clinical study is planned at the Academish Medish Centrum (AMC) in Amsterdam, Holland, in collaboration with Professor GRAM D’Haens. The AMC and GRAM D’Haens have considerable experience and expertise in performing clinical studies on patients with inflammatory bowel disease. This research stay is scheduled from March 1st to August 31st 2016. The modified protocol of clinical study 2 was submitted to the regional ethics comittee at Haukeland University Hospital and inclusion started in May. In part of the protocol Sonazoid is used as the contrast agent. Ethical approval for interobserver analysis have been obtained and the performance of Sonovue and Sonazoid will be compared to see which performs better. A similar protocol was submitted to the AMC enabling a multi-senter trial. Data from CS-1 was analyzed. There was however issues with the quality of the contrast recordings in this study since extensive software changes had been made on the clinical scanner during the trial making comparison problematic. The publication of these data are currently on hold and we are considering writing a paper on the remaining ultrasound data without the contrast data. A phantom study of was published with our international collaborator Radovan Jirik testing different approaches for calculating the arterial input function with contrast-enhanced ultrasound perfusion. This is directly related to laboratory study 2 in WP-1 where we are working on validation 2 D CEUS “Bolus and burst” perfusion model. Also a preliminary study comparing CEUS perfusion in mice tumors with MRI perfusion was published in 2015.

During the first 6 months of the postdoc period I have ended inclusion in CS-1 and CS-2. The inclusion in CS-2 was stopped due to lack of progress. Data of CS-1 and CS-2 was analysed and and a paper was drafted from the data in CS-2 and published. Due to the low number of included patients we could not examine remission as an endpoint. Several patients had treatment failure during the observation period however and for this end point we found very interesting results. Our findings indicate that patients with effective treatment has lower perfusion in the affected gastrointestinal already one month into the treatment. This has implications since we usually evaluate treatment effect after three months. If predictions can be made earlier this may both make the treatment better for the patients but also reduce cost. Data analysis of CS-1 has not been finished and will continue in spring 2015. A modified protocol of CS-2 has been drafted for the Research stay in Bologna in the spring. The hospital in Bologna is serving a large cohort of Crohn's patients and is ideal for making longitudinal studies. More patients included will enable us to examine end points such as clinical and endoscopic remission. In 2014 Sonazoid has been registered in Norway for clinical use. This could be better for studying perfusion than Sonovue as it has a more uniform size distribution. Since it already as been approved for use in humans it has the great advantage that it can be implemented quickly in clinical work if it performs well. Instead of trying to design a new microbubble, we intend to use this in WP-1 for testing of reproducibility of the bolus and burst method and for validation. Two other papers related to perfusion analysis of contrast enhanced ultrasound based on previous work was published in 2014.