Cecchini, M. (Michele)

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    The EASL-Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality
    (Elsevier BV, 2022) Yki-Järvinen, H. (Hannele); Christos, L. (Lionis); Verkade, H.J. (Henkjan J.); Karlsen, T.H. (Tom H.); Pryke, R. (Rachel); Flisiak, R. (Robert); Kelly, D. (Deirdre); Simonova, M. (Marieta); Serra-Burriel, M. (Miquel); Ginès, P. (Pere); Lerouge, A. (Alienor); Hutchinson, S.J. (Sharon J.); Barrett, D. (Damon); Manns, M.P. (Michael P.); Burra, P. (Patrizia); Mendive, J.M. (Juan M.); Ma, A.T. (Ann T.); Devaux, M. (Marion); Cecchini, M. (Michele); Belloni, A. (Annalisa); Sheena, B. (Brittney); Sangro, B. (Bruno); Marchesini, G. (Giulio); Ashworth-Dirac, M. (Mae); Reic, T. (Tatjana); Cortez-Pinto, H. (Helena); Zelber-Sagi, S. (Shira); Treloar, C. (Carla); Targher, G. (Giovanni); Cucchetti, A. (Alessandro); Carrieri, P. (Patrizia); Petersen, C. (Claus); Scott, N. (Nick); Byrne, C.D. (Chris D.); Buti, M. (Maria); Fabrellas, N. (Nuria); Rutter, H. (Harry); Hellard, M. (Margaret); Bugianesi, E. (Elisabetta); Schramm, C. (Christoph); Martin, N.K. (Natasha K.); Taylor, A. (Alison); Parés, A. (Albert); Lazarus, J.V. (Jeffrey V.); Sturm, E. (Ekkehard); Ponsioen, C.Y. (Cyriel Y.); Tur-Sinai, A. (Aviad); Pose, E. (Elisa); Johnson, P.J. (Philip J.); Burton, R. (Robyn); Mazzaferro, V. (Vicenzo); Newsome, P. (Philip N.); Ninburg, M. (Michael); Rhodes, T. (Tim); Sheron, N. (Nick); Dusheiko, G. (Geoffrey); Graupera, I. (Isabel)
    Liver diseases have become a major health threat across Europe, and the face of European hepatology is changing due to the cure of viral hepatitis C and the control of chronic viral hepatitis B, the increasingly widespread unhealthy use of alcohol, the epidemic of obesity, and undiagnosed or untreated liver disease in migrant populations. Consequently, Europe is facing a looming syndemic, in which socioeconomic and health inequities combine to adversely affect liver disease prevalence, outcomes, and opportunities to receive care. In addition, the COVID-19 pandemic has magnified pre-existing challenges to uniform implementation of policies and equity of access to care in Europe, arising from national borders and the cultural and historical heterogeneity of European societies. In following up on work from the Lancet Commission on liver disease in the UK and epidemiological studies led by the European Association for the Study of the Liver (EASL), our multidisciplinary Commission, comprising a wide range of public health, medical, and nursing specialty groups, along with patient representatives, set out to provide a snapshot of the European landscape on liver diseases and to propose a framework for the principal actions required to improve liver health in Europe. We believe that a joint European process of thinking, and construction of uniform policies and action, implementation, and evaluation can serve as a powerful mechanism to improve liver care in Europe and set the way for similar changes globally. On the basis of these data, we present ten actionable recommendations, half of which are oriented towards health-care providers and half of which focus primarily on health policy. A fundamental shift must occur, in which health promotion, prevention, proactive casefinding, early identification of progressive liver fibrosis, and early treatment of liver diseases replace the current emphasis on the management of end-stage liver disease complications. A considerable focus should be put on underserved and marginalised communities, including early diagnosis and management in children, and we provide proposals on how to better target disadvantaged communities through health promotion, prevention, and care using multilevel interventions acting on current barriers. Underlying this transformative shift is the need to enhance awareness of the preventable and treatable nature of many liver diseases. Therapeutic nihilism, which is prevalent in current clinical practice across a range of medical specialities as well as in many patients themselves, has to end. We wish to challenge medical specialty protectionism and invite a broad range of stakeholders, including primary care physicians, nurses, patients, peers, and members of relevant communities, along with medical specialists trained in obesity, diabetes, liver disease, oncology, cardiovascular disease, public health, addictions, infectious diseases, and more, to engage in integrated person-centred liver patient care across classical medical specialty boundaries. This shift includes a revision in how we converse about liver disease and speak with our patients, and a reappraisal of disease-related medical nomenclature conducted to increase awareness and reduce the social stigmatisation associated with liver disease. Reimbursement mechanisms and insurance systems must be harmonised to account for patient-centric, multimorbidity models of care across a range of medical specialties, and the World Health Assembly resolution to improve the transparency and fairness of market prices for medicines throughout Europe should be reinforced. Finally, we outline how Europe can move forward with implementation of effective policy action on taxation, food reformulation, and product labelling, advertising, and availability, similar to that implemented for tobacco, to reduce consumption of alcohol, ultraprocessed foods, and foods with added sugar, especially among young people. We should utilise the window of opportunity created by the COVID-19 pandemic to overcome fragmentation and the variability of health prevention policies and research across Europe. We argue that the liver is a window to the 21st-century health of the European population. Through our proposed syndemic approach to liver disease and social and health inequities in Europe, the liver will serve as a sentinel for improving the overall health of European populations.
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    Mutational signature profiling classifies subtypes of clinically different mismatch-repair-deficient tumours with a differential immunogenic response potential
    (Springer, 2022) Giner-Calabuig, M. (Mar); De-León, S. (Seila); Wang, J. (Julián); Fehlmann, T. D. (Tara D.); Ukaegbu, Ch. (Chinedu); Gibson, J. (Joanna); Alustiza, M. (Miren); Picó, M.D. (María Dolores); Alenda, C. (Cristina); Herraiz, M. T. (María Teresa); Carrillo-Palau, M. (Marta); Salces, I. (Inmaculada); Reyes, J. (Josep); Ortega, S. P. (Silvia P.); Obrador-Hevia, A. (Antònia); Cecchini, M. (Michele); Syngal, S. (Sapna); Stoffel, E. (Elena); Nathan, E. (Ellis); Sweasy, J. (Joann); Jover, R. (Rodrigo); Llor, X. (Xavier); Xicola, R.M. (Rosa M.)
    BACKGROUND: Mismatch repair (MMR) deficiency is the hallmark of tumours from Lynch syndrome (LS), sporadic MLH1 hypermethylated and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterisation to identify novel features that can impact tumour behaviour and clinical management. METHODS: We tested 105 MMR-deficient colorectal cancer tumours (25 LS, 35 LLS and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load. RESULTS: Fifty-three percent of tumours showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumours. Thirty-one percent of tumours showed weaker features of MMR deficiency, 62% lost MSH2/MSH6 expression and included 60% of LS and 44% of LLS tumours. Remarkably, 9% of all tumours lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumours that show the strongest contribution of MMR-deficient tumours. CONCLUSIONS: Next-generation sequencing approaches allow for a granular molecular characterisation of MMR-deficient tumours, which can be essential to properly diagnose and treat patients with these tumours in the setting of personalised medicine.