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  • Periodic Report Summary 1 - CLEVER (Contrast-enhanced uLtrasound for livEr-disease eValuation: development and validation of a novel E-Health-software for Risk-stratification)

Periodic Report Summary 1 - CLEVER (Contrast-enhanced uLtrasound for livEr-disease eValuation: development and validation of a novel E-Health-software for Risk-stratification)

THE PROBLEM: Liver vascular network is characterized by a highly organized structure. This is progressively deranged due to fibrosis and hepatocyte drop-out in patients with chronic liver diseases, leading to portal hypertension. Non-invasive methods able to quantify objectively and automatically the degree of liver vascular derangement, so estimating portal hypertension are highly needed.
OUR SOLUTION: Temporal analysis of Dynamic Contrast Enhanced Ultrasound (DCE-US) based on non-invasive imaging enables to obtain a personalised graph model of the vascular network of an organ, such as the liver, with high prognostic value. We hypothesised that this vascular network model contains relevant information to stratify risk of individuals and support clinical decisions in a more objective manner. We have successfully proved this hypothesis in a pilot study and blind test with liver cirrhosis patients.
FUTURE: We foresee the expansion of this technology to other fields of biomedicine and clinical applications, from studies in animal models to tailored therapies for cancer and other diseases. We are now developing a new solution applied to fertility which has provided successful results on longitudinal studies for 45 individuals.

DETAILED SUMMARY: Liver cirrhosis is a severe disease developing as a consequence of chronic liver damage (alcohol, hepatitis B and C virus, non-alcoholic steatohepatitis, hemocromatosis...). Chronic liver diseases (CLD) represent a major health burden worldwide. Approximately 6% of European Union (EU) citizens suffer from CLD, summing over 29 million people among the 490 million EU inhabitants.
The CLEVER project is a 4-years training and transfer of knowledge program between a highly innovative company working in advanced biomedical image processing and two renowned academic groups working in the field of liver diseases and ultrasound research. The scientific and industrial aim of CLEVER is to develop, validate and transfer to clinical practice a novel electronic-health system based on the analysis of liver dynamic contrast-enhanced ultrasound images to assess the severity of derangement of the intrahepatic vascular network in cirrhosis. This feature is closely related with portal hypertension and liver failure, which are the two most important complications of cirrhosis. The outputs of CLEVER will allow an objective prognostic stratification of patients with cirrhosis replacing current invasive and more expensive tools, such as measurement of portal pressure or liver biopsy.

Since the beginning of the project we have been working in the following tasks:
The consortium has deployed an electronic Case Report Form (eCRF) for the efiicient management of all patients included in the study. In this eCRF clinicians can assist engineers on how to complete all the required fields (values, units, limits), inform about measured HVPG and upload liver ultrasound videos performed on patients.
We have fully developed a toolkit to correct liver motion, graph mapper of vascular networks, graph analysis and precise and personalised predicitve models for substituting invasive procedure (catheterisation) of HVPG of based on our International patent (WO2014155174) and our background results published in the prestigious journal Radiology.
First precise and personalised model has been successfully completed and integrated for clinical testing: This personalised model predicts the most valuable independent surrogate of risk for cirrhotic patients, HVPG. HVPG has tremendous clinical value but it requires catheterisation, which makes it unfeasible for routinely clinical practice.
CLEVER OnLineService (OLS) has been fully deployed and is currently being used by clinicians at UNIBO and IDIBAPS to further refine its clinical feasibility and precision.
Currently, our blind tests have provided an average error of 2.3mmHg which provides the technology a reasonable clinical agreement compared to HVPG, which has an average error of 1mmHg in reference centers (this error is increased in other centers and is not available in many Hospitals). However, substantial efforts need to be done to increase the efficiency of the processing. We are currently able to analyse 35% of all uploaded DCE-US acquisitions. This can be increased by technological and clinical means. From the technology side, major improvements are expected by motion correction means; and from the clinical side, performing more DCE-US acquisitions is clearly feasible (up to 4, compared to the single acquision done until now). We expect that this two measures will rapidly impact on the efficiency of our technology.
We are open to receive feedback from the community to increase our blind testing pool and tecknological assets. Please contact, to for further details.

The final result expected is the development and validation of a completely novel automatic tool for the analysis of the liver vascular network in real-time by modelling DCE-US images as a tool for risk stratification of cirrhotic patients.
The potential impact will be a significant improvement in management of CLD patients and management of liver transplant, where suboptimal priorization of patients is still a major issue, and a better management of primary liver tumour thank to the library of vascular graphs of the liver in normality and disease, usable for clinical practice and research.
A software like that could be used in ongoing relevant large projects on cirrhosis and liver disease (i.e. methods for screening of new drugs or personalized therapies). We aim to increase safety and feasibility of management of cirrhotic patients, towards a more personalized, predictive and preventive practice and developing further applications by a minimally invasive procedure in a large number of diseases and therapies.
A secondary impact would be to market this technology for liver and other applications. We have already signed a contract for validation of a software based on CLEVER project for fertility applications with a large fertility clinic, which is an end-user and distributor of the technology, and has provided successful results in 45 women.
For medical imaging technology the potential result will suppose a significant advance in acquisition and processing of DCE-US to extract information of local tissue dynamic, in the integration of advanced graph analysis into clinical applications, and will suppose a big advance in bridging the meaning of changes of hepatic vascular tree and measurements from pure graph theory. A development like CLEVER is meant to pave the way of future technologies for monitoring and/or characterizing the role of local vascular networks in normal and diseased tissues/organs, the development of more sophisticated tools will meet new requirements, like molecular imaging, with targeted ultrasound microbubbles, for performing pathophysiological studies and/or find new therapeutic targets.

• The address of the project public website is:


Pastora Martinez Samper, (European Projects Officer)
Tel.: +34 93 227 57 07


Life Sciences
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