Colorectal cancer (CRC) ranks fourth in cancer deaths worldwide. Between 20% and 30% of patients with advanced CRC have liver metastases (CRLM). Liver cancer ranks second in cancer deaths worldwide, including hepatocellular carcinoma (HCC). Despite recent advances, liver resection offers the only chance of cure for patients with liver metastases. However, the recurrence rate of these tumours is high even after post-resection. The presence of positive margins in the remaining liver after resection correlates with increased local recurrence and decreased overall survival, the only factor where prognosis could be influenced by the performance of surgery. However, at present, the extent of an R-negative status remains debatable and varies widely from one publication to another. Currently, there are radiofrequency ablation studies that, based on preliminary retrospective human clinical trials, are able to correlate an additional coagulation of tumor margins with a reduction on local recurrence. However, there is no prospective and pragmatic controlled study that accurately measures this additional margin and its impact on oncological outcomes. The aim of LIVERATION is to conduct an ambitious, pragmatic multicenter clinical trial with 720 patients with CRLM and HCC at 24 clinical centres in 6 different countries to determine whether additional ablated margin produced by radiofrequency can decrease the recurrence rate and improve patient survival. We will also evaluate the patient-centredness of the intervention and its comparativeness with other therapeutic alternatives in terms of quality of life and patient experience in real-world settings. To this end, the consortium has been formed by highly experienced, highly qualified and multidisciplinary entities to carry out the project successfully. The results will not only have a major impact on a social and scientific level but also on an economic level for the EU. This action is part of the Cancer Mission cluster of projects on ‘Diagnosis and treatment’.

The objective of the project is to develop novel curative concepts for chronic hepatitis B (CHB). Specific aims will be to: 1) improve the rate of functional cure of CHB by boosting innate immunity with immune modulators and stimulating adaptive immune responses with a novel therapeutic vaccine; ii) characterize immune and viral biomarker signatures for patient stratification and treatment response monitoring; iii) integrate biological and clinical data to model the best combination treatment for future trials; iv) model the effectiveness of novel curative therapies with respect to disease spectrum, patient heterogeneity, and constraints of National Health Systems. The project organization will combine: i) a Proof of Concept clinical trial of a combination of 2 novel compounds stimulating innate immunity; ii) a preclinical immune therapy platform in humanized mice combining immune-modulatory strategies to stimulate innate immunity, rescue exhausted HBV-specific T cells and generate anti-HBV adaptive responses; iii) extensive virologic and immune profiling to identify correlates of cure in patients, iv) the integration of large biological and clinical datasets, v) a cost-effectiveness modelling of new therapeutic interventions, vi) project management, vii) results exploitation and dissemination. The proposal responds to the work program by: i) including the evaluation of emerging concepts in drug and vaccine development to discover a curative strategy for CHB, a major public health concern for Europe, ii) capitalizing on knowledge of host-pathogen interactions to develop novel immune-based therapies, iii) considering age, gender and viral genetic variations, iv) comprising a clinical trial and a pre-clinical platform for the discovery of novel immune interventions, and selection of relevant biomarkers for validation in established clinical cohorts, v) addressing conditions for effective uptake of the new curative interventions by National Health Systems.

Alcohol-related hepatocellular carcinoma (ALD-HCC) is, in Europe, the leading cause of liver cancer (2nd most common cause of cancer-related death worldwide, affecting both men and women). ALD-HCC has a median 5-year survival rate of 15%. Yet, the prognosis is driven by the tumour stage, with curative options providing a 5-year survival exceeding 70% for early-stage HCC (<20% of cases). Therefore, interventions aiming to improve prevention and early detection are key. ALD-HCC results from the interplay between environmental determinants and genetic variations. A comprehensive characterisation of environmental factors (e.g. diet, lifestyle) linked to ALD-HCC is still lacking. We recently performed the 1st genome-wide association study of ALD-HCC and identified predisposing genetic variations. However, their role on alcohol-related liver carcinogenesis needs clarification and the genetic architecture of ALD-HCC remains mostly unknown. GENIAL brings together partners with unique expertise in clinical hepatology, single-cell and spatial multi-omics, artificial intelligence (AI) and communication and dissemination capacities. Our aim is to 1) portray genetic and environmental determinants promoting ALD-HCC; 2) evaluate how they interact at cellular level in human samples and preclinical models to get novel insights into liver carcinogenesis, and identify chemopreventive targets; and 3) assess how these determinants modulate the ALD-HCC risk in prospective cohorts of patients included in HCC surveillance programs. Environmental factors will be comprehensively characterised in an ongoing clinical trial designed to evaluate alternative methods for early-stage HCC detection. Finally, AI models, reaching the minimal viable product stage by the end of GENIAL, will be used to integrate genetic and non-genetic information (including digital imaging) to develop novel cost-effective strategies towards prevention and early-stage detection of ALD-HCC in at-risk individuals. This action is part of the Cancer Mission cluster of projects on ‘‘Understanding’.

Liver transplantation (LT) is a life-saving procedure for decompensated cirrhosis (DC) and hepato-cellular carcinoma (HCC). Its efficacy is hampered by the risk of death/drop-out on the Wait List (WL). This risk is driven by organ shortage and is mitigated by organ offering schemes. According to a sickest first policy, offering schemes prioritize LT candidates with the highest risk of dying, as assessed by predictive models. To drive allocation, Organ Sharing Organizations (OSOs) use a 20-year-old model, the MELD, predicting mortality in DC but not in HCC. Because of a dramatic increase in % of HCC candidates (40% against 10% in early 20ties), MELD schemes are increasingly inaccurate, with persisting 15 to 30% mortality in countries with low/medium donation rate. This scenario, together with advances in prognosis in DC and HCC candidates and statistics, prompts LT community to look for up-dated algorithms to refine offering schemes. To address this issue, key European LT stakeholders including OSOs, experts in LT, Statisticians, Research Labs and SME joined LEOPARD. Building on an innovative, harmonized OSOs pre-LT dataset and advances in modeling, LEOPARD propose to design and validate 1) an AI-based LEOPARD predictive algorithm outperforming current allocation models by better stratifying patients on the risk of mortality, to be proposed OSOs to drive allocation; 2) DC & HCC LEOPARD calculators available for professional for assistance in complex decision-making processes; 3) OMICs/radiomics predictive signatures integrated in a prototype 3rd-generation exploratory model. We expect to generate computational tools improving candidates’ outcomes, with more patients transplanted on time. Adoption of these tools should result in harmonization of European heterogeneous prioritization schemes, and in a signification reduction in disparities of access to LT, a major objective pointed out by EC. LEOPARD should place Europe in leading position for organ offering schemes.

GRIP on MASH will address the unmet public health need of reducing disease burden and comorbidities associated with Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD). Together with seven medical technology, pharmaceutical and biotechnology companies, we will devise a sustainable and scalable GRIP on MASH Platform that will enable access to at-risk patients developing or having MASLD through the early detection of this condition at the primary care level. This Platform will allow A) the early detection of patients with MASLD: distributed in 12 European Centers of Excellence (CoEs), 10,000 patients at high risk of MASLD - defined as patients with type-2 diabetes mellitus, metabolic syndrome, obesity or arterial hypertension - will be screened and characterized; B) better patients’ stratification: the Platform will comprise artificial intelligence-based decision support tools that will make use of existing and novel biomarkers/biomarker combinations. Their predictive accuracy will be tested at the primary care level; there we will perform multi-OMICs analysis (proteomics, lipidomics, metabolomics, genomics, metagenomics and fluxomics) in fasted blood samples and we will explore imaging biomarkers/organ-on-a-chip to find future non-invasive diagnostic alternatives for the current standard (liver biopsies); and C) personalized lifestyle advice, by exploring evidence-based lifestyle features and the effect of nutritional recommendations: among the cohorts at the CoEs, we will use validated questionnaires to assess physical activity, diet, sleep, smoking, alcohol consumption, and perception of stress. Integrating patients’ perspectives with the participation of two patient organizations, the trustworthiness and sustainability of our GRIP on MASH Platform will be assessed by investigating potential economic, ethical and regulatory barriers to its future adoption. GRIP on MASH will change healthcare practice in MASLD and reduce the disease burden for patients.