Carrascosa, J. (Juan)

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    Pilot multi-omic analysis of human bile from benign and malignant biliary strictures: A machine-learning approach
    (MDPI AG, 2020) Latasa, M.U. (María Ujué); Banales, J.M. (Jesús M.); Carrascosa, J. (Juan); González, B. (Belén); Corrales, F.J. (Fernando José); Macias, R.I.R. (Rocío I. R.); Berasain, C. (Carmen); Arechederra, M. (María); Fernández-Barrena, M.G. (Maite G.); Pineda-Lucena, A. (Antonio); Bolado, F. (Federico); Urman, J.M. (Jesús M.); Uriarte, I. (Iker); Avila, M.A. (Matías Antonio); Gil, I. (Iñigo); Alonso, C. (Cristina); Rullán, M. (María); Purroy, A. (A.); Iruarrizaga-Lejarreta, M. (Marta); Sangro, B. (Bruno); Fernandez-Urien, I. (Ignacio); Monte, M.J. (María J.); Herranz, J.M. (José M.); Iraburu-Elizalde, M. (María); Vila, J.J. (Juan J.); Álvarez-Sola, G. (Gloria); Oyón, D. (Daniel); Colyn, L. (Leticia); Romero, M. (Marta); Puchades-Carrasco, L. (Leonor); Cubero, F.J. (Francisco Javier); Zabalza, L. (Lucía); Martinez-Chantar, M.L. (María Luz); Marin, J.J.G (Jose J.G.); Carmona, L. (Lorena)
    Cholangiocarcinoma (CCA) and pancreatic adenocarcinoma (PDAC) may lead to the development of extrahepatic obstructive cholestasis. However, biliary stenoses can also be caused by benign conditions, and the identification of their etiology still remains a clinical challenge. We performed metabolomic and proteomic analyses of bile from patients with benign (n = 36) and malignant conditions, CCA (n = 36) or PDAC (n = 57), undergoing endoscopic retrograde cholangiopancreatography with the aim of characterizing bile composition in biliopancreatic disease and identifying biomarkers for the differential diagnosis of biliary strictures. Comprehensive analyses of lipids, bile acids and small molecules were carried out using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (1H-NMR) in all patients. MS analysis of bile proteome was performed in five patients per group. We implemented artificial intelligence tools for the selection of biomarkers and algorithms with predictive capacity. Our machine-learning pipeline included the generation of synthetic data with properties of real data, the selection of potential biomarkers (metabolites or proteins) and their analysis with neural networks (NN). Selected biomarkers were then validated with real data. We identified panels of lipids (n = 10) and proteins (n = 5) that when analyzed with NN algorithms discriminated between patients with and without cancer with an unprecedented accuracy
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    Next-generation sequencing of bile cell-free DNA for the early detection of patients with malignant biliary strictures
    (Asociación Médica Británica​, 2022) Arechederra, M. (María); Rullán, M. (María); Amat, I. (Irene); Oyón, D. (Daniel); Zabalza, L. (Lucía); Elizalde, M. (María); Latasa, M.U. (María Ujué); Mercado-Gómez, M. (Maria); Ruiz-Clavijo, D. (David); Saldaña-Dueñas, C. (Cristina); Fernandez-Urien, I. (Ignacio); Carrascosa, J. (Juan); Jusué, V. (Vanesa); Guerrero-Setas, D. (David); Zazpe, C. (Cruz); Gonzalez, I. (Iranzu); Sangro, B. (Bruno); Herranz, J.M. (José M.); Purroy, A. (A.); Gil-Aldea, I. (I.); Nelson, L.J. (Leonard J.); Vila, J.J. (Juan J.); Krawczyk, M. (Marcin); Zieniewicz, K. (Krzysztof); Patkowski, W. (Waldemar); Milkiewicz, P. (Piotr); Cubero, F.J. (Francisco Javier); Alkorta-Aranburu, G. (Gorka); Fernández-Barrena, M.G. (Maite G.); Urman, J.M. (Jesús M.); Berasain, C. (Carmen); Avila, M.A. (Matías Antonio)
    Objective: Despite significant progresses in imaging and pathological evaluation, early differentiation between benign and malignant biliary strictures remains challenging. Endoscopic retrograde cholangiopancreatography (ERCP) is used to investigate biliary strictures, enabling the collection of bile. We tested the diagnostic potential of next-generation sequencing (NGS) mutational analysis of bile cell-free DNA (cfDNA). Design: A prospective cohort of patients with suspicious biliary strictures (n=68) was studied. The performance of initial pathological diagnosis was compared with that of the mutational analysis of bile cfDNA collected at the time of first ERCP using an NGS panel open to clinical laboratory implementation, the Oncomine Pan-Cancer Cell-Free assay. Results: An initial pathological diagnosis classified these strictures as of benign (n=26), indeterminate (n=9) or malignant (n=33) origin. Sensitivity and specificity of this diagnosis were 60% and 100%, respectively, as on follow-up 14 of the 26 and eight of the nine initially benign or indeterminate strictures resulted malignant. Sensitivity and specificity for malignancy of our NGS assay, herein named Bilemut, were 96.4% and 69.2%, respectively. Importantly, one of the four Bilemut false positives developed pancreatic cancer after extended follow-up. Remarkably, the sensitivity for malignancy of Bilemut was 100% in patients with an initial diagnosis of benign or indeterminate strictures. Analysis of 30 paired bile and tissue samples also demonstrated the superior performance of Bilemut. Conclusion: Implementation of Bilemut at the initial diagnostic stage for biliary strictures can significantly improve detection of malignancy, reduce delays in the clinical management of patients and assist in selecting patients for targeted therapies.