3TR is a transdisciplinary consortium made of experts in all areas of medicine, basic sciences and bioinformatics from academic institutions, SMEs, and 8 major pharmaceutical companies, teamed to study a fundamental issue in medicine: the mechanisms of response and non-response to therapies, the major aim of 3TR, both within single disease entities and across diseases, where molecular stratification may identify shared disease taxonomies. The molecular identification of groups of patients to whom a drug will benefit, will allow focusing on those who are drug orphan. Harmonization of data from existing academy or industry-sponsored studies will identify biomarkers to inform a new collection. Specimens of diseased tissues, blood, stools, and other fluids will be obtained in a de novo observational prospective trial with standard of care medication prior, during and after first or second line of treatment. Because the studies will be at different phases of progression, a carrousel model of work was designed for input and output of data to be continuously analysed, and interpreted, to inform those measurements to be undertaken and allow cross-validation of results. The 3TR team will elucidate the role of the microbiome, genetics and regulatory genomic features in disease progression. The working aims of 3TR are: 1) establish a centralized data management platform; 2) perform comprehensive molecular and clinical characterisation of a prospective patient cohort; 3) establish integrated analysis of all data using advanced bioinformatics/statistical and modelling methods; 4) identify sets of predictive biomarkers of response/non-response to therapies; 5) improve the competitiveness of European industry and support development of novel solutions. 3TR will sustain beyond the project end the samples and its knowledge base. 3TR will challenge and revolutionize the conventional single-disease based approach with important implications in future disease treatment.

Liver cancer in the paediatric population is rare with an incidence approximately 1-1.5 per million population. The commonest tumour seen in the childhood population is hepatoblastoma (HB), usually seen in young children and infants. Much rarer (about 10% of paediatric liver cancers) is hepatocellular carcinoma (HCC), usually seen in the teenage population and sometimes associated with underlying cirrhotic liver diseases. The ChiLTERN project relates to topic PHC 18 ‘establishing effectiveness of health care interventions in the paediatric population’. The ChiLTERN project builds on a unique opportunity to undertake a comprehensive research programme linked to an ambitious global partnership which will see the single largest clinical trial (the Paediatric Hepatic International Tumour Trial - PHITT) ever undertaken in this population of patients, with several randomised questions in six subgroups of patients. ChiLTERN will allow us to move towards an era of personalised therapy in which each patient will receive the correct amount of chemotherapy and will undergo has the best surgical operation (surgical resection or liver transplant). By using both clinical and biological information, we can assign patients more accurately to risk groups based on their survival. Using genetic tests and biomarkers, we will determine those children who may be at risk of developing long term side effects (deafness, heart failure, kidney damage). In addition, biomarkers will allow us to monitor during therapy and detect toxicities early before serious damage is done so that we can adapt treatment and prevent these problems. Finally, we will be using imaging technology tools which will help our surgeons plan liver operations more safely and effectively. Ultimately ChiLTERN will allow us to cure more children with liver cancer, expose fewer children to toxic chemotherapy and ensure their surgery is both effective and safe.

Liver cirrhosis is a very common and severe chronic disease, responsible for high morbidity, impaired quality of life, major healthcare costs, and poor survival, causing an estimated 170,000 deaths per year in Europe. Liver cirrhosis is preceded by a long period of slowly developing, asymptomatic, liver fibrosis; most commonly caused by non-alcoholic fatty liver disease (NAFLD, related to obesity and type 2 diabetes), alcohol, and hepatitis B or C virus infection. There is no treatment available to reverse advanced liver cirrhosis. However, if fibrosis could be detected early, all of the major causes are still amenable to prevention and treatment. Early diagnosis of liver fibrosis in the general population is therefore crucial for the estimated 10 million Europeans with undetected liver fibrosis. The LiverScreen project aims to develop a targeted screening methodology to identify persons with asymptomatic liver fibrosis and cirrhosis among the general population. This methodology involves: 1) identification of groups from the general population at high risk of having chronic liver disease, 2) screening their liver stiffness with the innovative transient elastography (TE) technology (until now only validated in patients with known liver disease) for diagnosis, and 3) determining the right follow-up screening regime. Within the LiverScreen project 8 European countries will collaborate and perform research in over 34,000 subjects to develop the screening methodology and demonstrate its accuracy, clinical value, cost-effectiveness, acceptability, and potential to be implemented by healthcare systems throughout Europe. Using the LiverScreen program, diagnosis at an early stage can stop liver disease progression and have a subsequent long-term impact on liver disease morbidity and mortality and the associated societal burdens in terms of economic costs and health inequity. The estimated cost reduction ranges from €850 to €4,000 per quality-adjusted life-year gained.