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1. Clinical, biological, and molecular genetic features of Richter syndrome and prognostic significance: a study of the French Innovative Leukemia Organization

Author

Reiner Siebert, Anne Quinquenel, Romain Guieze, Catherine Thieblemont, Frederic Davi, Caroline Dartigeas, Sébastien Hergalant, Mathilde Hunault, Florence Cymbalista, Christof Schneider, Marie-Christine Béné, Cécile Tomowiak, Thomas Remen, Kamel Laribi, Damien Roos-Weil, Julien Broséus, Gregory Lazarian, Francis Guillemin, Odile Blanchet, Florian Bouclet, Elise Chapiro, Eugen Tausch, Stephan Stilgenbauer, Sandra Lomazzi, Florence Nguyen-Khac, Pierre Feugier, Charline Moulin, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'investigation clinique - Epidémiologie clinique [Nancy] (CIC-EC), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Méthodologie Promotion Investigation [CHRU Nancy] (MPI), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Universitaire de Reims (CHU Reims), Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Ulm - Ulm University [Ulm, Allemagne], Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre de Ressources Biologiques - [Nancy] (CRB Nancy), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Avicenne [AP-HP], Centre Hospitalier Le Mans (CH Le Mans), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hergalant, Sébastien, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Oncology, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.medical_specialty, Richter syndrome, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Medicine, Humans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Hematology, medicine.disease, Prognosis, Survival Analysis, 3. Good health, [STAT] Statistics [stat], [STAT]Statistics [stat], Leukemia, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 030220 oncology & carcinogenesis, Cytogenetic Analysis, Mutation, Disease Progression, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, Lymphoma, Large B-Cell, Diffuse, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business
Abstract

International audience

Published
2021

2. A plasma metabolomic signature of Leber hereditary optic neuropathy showing taurine and nicotinamide deficiencies

Author

Victor Le Paih, Odile Blanchet, Patrizia Amati-Bonneau, Pascal Reynier, Guy Lenaers, Judith Kouassy Nzoughet, Juan Manuel Chao de la Barca, Dominique Bonneau, Daniela Géromin, Cinzia Bocca, Christophe Orssaud, Vincent Procaccio, Gilles Simard, Benoit Vedie, LENAERS, Guy, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
AcademicSubjects/SCI01140, Adult, Male, Niacinamide, Retinal Ganglion Cells, medicine.medical_specialty, Taurine, Adolescent, [SDV]Life Sciences [q-bio], Optic Atrophy, Hereditary, Leber, Mitochondrion, Biology, Retinal ganglion, DNA, Mitochondrial, Optic neuropathy, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Metabolomics, Internal medicine, Genetics, medicine, Choline, Humans, Molecular Biology, Genetics (clinical), 030304 developmental biology, Aged, 0303 health sciences, Electron Transport Complex I, Nicotinamide, General Medicine, Middle Aged, medicine.disease, Penetrance, Mitochondria, [SDV] Life Sciences [q-bio], Endocrinology, chemistry, Mutation, Metabolome, Female, General Article, 030217 neurology & neurosurgery
Abstract

Leber’s hereditary optic neuropathy (LHON) is the most common disorder due to mitochondrial DNA mutations and complex I deficiency. It is characterized by an acute vision loss, generally in young adults, with a higher penetrance in males. How complex I dysfunction induces the peculiar LHON clinical presentation remains an unanswered question. To gain an insight into this question, we carried out a non-targeted metabolomic investigation using the plasma of 18 LHON patients, during the chronic phase of the disease, comparing them to 18 healthy controls. A total of 500 metabolites were screened of which 156 were accurately detected. A supervised Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) highlighted a robust model for disease prediction with a Q2 (cum) of 55.5%, with a reliable performance during the permutation test (cross-validation analysis of variance, P-value = 5.02284e−05) and a good prediction of a test set (P = 0.05). This model highlighted 10 metabolites with variable importance in the projection (VIP) > 0.8. Univariate analyses revealed nine discriminating metabolites, six of which were the same as those found in the Orthogonal Projections to Latent Structures Discriminant Analysis model. In total, the 13 discriminating metabolites identified underlining dietary metabolites (nicotinamide, taurine, choline, 1-methylhistidine and hippurate), mitochondrial energetic substrates (acetoacetate, glutamate and fumarate) and purine metabolism (inosine). The decreased concentration of taurine and nicotinamide (vitamin B3) suggest interesting therapeutic targets, given their neuroprotective roles that have already been demonstrated for retinal ganglion cells. Our results show a reliable predictive metabolomic signature in the plasma of LHON patients and highlighted taurine and nicotinamide deficiencies.

Published
2021

3. A Plasma Metabolomic Profiling of Exudative Age-Related Macular Degeneration Showing Carnosine and Mitochondrial Deficiencies

Author

Delphine Mirebeau-Prunier, Vincent Procaccio, Stéphanie Leruez, Adrien Buisset, Jeanne Muller, Lydie Tessier, Guy Lenaers, Dan Milea, Odile Blanchet, Pascal Reynier, Marc Ferré, Juan Manuel Chao de la Barca, Gilles Simard, Laurie Moureauzeau, Stéphanie Chupin, Thibaut Macé, Philippe Gohier, Barnabé Rondet-Courbis, Guillaume Plubeau, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre de Ressources Biologiques [CHU d'Angers] (CRB CHU d'Angers BB-0033-00038), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Stress Oxydant et Pathologies Métaboliques (SOPAM), Rigshospitalet [Copenhagen], and Copenhagen University Hospital

Subjects
medicine.medical_specialty, genetic structures, [SDV]Life Sciences [q-bio], lcsh:Medicine, Carnosine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mitochondrion, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Metabolomics, Valine, Internal medicine, Lipidomics, medicine, Carnitine, Proline, age-related macular degeneration, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, metabolomics, 2. Zero hunger, 0303 health sciences, business.industry, [SDV.BA]Life Sciences [q-bio]/Animal biology, lcsh:R, General Medicine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Macular degeneration, medicine.disease, eye diseases, 3. Good health, Endocrinology, chemistry, 030221 ophthalmology & optometry, lipidomics, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, medicine.drug
Abstract

To determine the plasma metabolomic profile of exudative age-related macular degeneration (AMD), we performed a targeted metabolomics study on the plasma from patients (n = 40, mean age = 81.1) compared to an age- and sex-matched control group (n = 40, mean age = 81.8). All included patients had documented exudative AMD, causing significant visual loss (mean logMAR visual acuity = 0.63), compared to the control group. Patients and controls did not differ in terms of body mass index and co-morbidities. Among the 188 metabolites analyzed, 150 (79.8%) were accurately measured. The concentrations of 18 metabolites were significantly modified in the AMD group, but only six of them remained significantly different after Benjamini&ndash, Hochberg correction. Valine, lysine, carnitine, valerylcarnitine and proline were increased, while carnosine, a dipeptide disclosing anti-oxidant and anti-glycating properties, was, on average, reduced by 50% in AMD compared to controls. Moreover, carnosine was undetectable for 49% of AMD patients compared to 18% in the control group (p-value = 0.0035). Carnitine is involved in the transfer of fatty acids within the mitochondria, proline, lysine and valerylcarnitine are substrates for mitochondrial electrons transferring flavoproteins, and proline is one of the main metabolites supplying energy to the retina. Overall, our results reveal six new metabolites involved in the plasma metabolomic profile of exudative AMD, suggesting mitochondrial energetic impairments and carnosine deficiency.

Published
2020

4. Data-Mining Approach on Transcriptomics and Methylomics Placental Analysis Highlights Genes in Fetal Growth Restriction

Author

Floris Chabrun, Noémie Huetz, Xavier Dieu, Guillaume Rousseau, Guillaume Bouzillé, Juan Manuel Chao de la Barca, Vincent Procaccio, Guy Lenaers, Odile Blanchet, Guillaume Legendre, Delphine Mirebeau-Prunier, Marc Cuggia, Philippe Guardiola, Pascal Reynier, Geraldine Gascoin, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Angers University Hospital, France, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, intrauterine growth restriction, lcsh:QH426-470, Offspring, [SDV]Life Sciences [q-bio], Intrauterine growth restriction, Computational biology, Biology, Transcriptome, 03 medical and health sciences, transcriptomics, 0302 clinical medicine, Insulin resistance, Placenta, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Genetics, Epigenetics, Gene, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Original Research, text-mining, data mining, methylomics, multi-omics, medicine.disease, Phenotype, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, lcsh:Genetics, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Molecular Medicine
Abstract

International audience; Intrauterine Growth Restriction (IUGR) affects 8% of newborns and increases morbidity and mortality for the offspring even during later stages of life. Single omics studies have evidenced epigenetic, genetic, and metabolic alterations in IUGR, but pathogenic mechanisms as a whole are not being fully understood. An in-depth strategy combining methylomics and transcriptomics analyses was performed on 36 placenta samples in a case-control study. Data-mining algorithms were used to combine the analysis of more than 1,200 genes found to be significantly expressed and/or methylated. We used an automated text-mining approach, using the bulk textual gene annotations of the discriminant genes. Machine learning models were then used to explore the phenotypic subgroups (premature birth, birth weight, and head circumference) associated with IUGR. Gene annotation clustering highlighted the alteration of cell signaling and proliferation, cytoskeleton and cellular structures, oxidative stress, protein turnover, muscle development, energy, and lipid metabolism with insulin resistance. Machine learning models showed a high capacity for predicting the sub-phenotypes associated with IUGR, allowing a better description of the IUGR pathophysiology as well as key genes involved.

Published
2020

5. Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial

Author

Vincent Dubée, Pierre-Marie Roy, Bruno Vielle, Elsa Parot-Schinkel, Odile Blanchet, Astrid Darsonval, Caroline Lefeuvre, Chadi Abbara, Sophie Boucher, Edouard Devaud, Olivier Robineau, Patrick Rispal, Thomas Guimard, Emma d’Anglejean, Sylvain Diamantis, Marc-Antoine Custaud, Isabelle Pellier, Alain Mercat, Antoine Brangier, Philippe Codron, Jean Michel Lemée, Virginie Pichon, Robin Dhersin, Geoffrey Urbanski, Christian Lavigne, Roxane Courtois, Hélène Danielou, Jonathan Lebreton, Rémi Vatan, Nicolas Crochette, Jean-Baptiste Lainé, Lucia Perez, Sophie Blanchi, Hikombo Hitoto, Louis Bernard, François Maillot, Sylvain Marchand Adam, Jean-Philippe Talarmin, Emeline Gaigneux, Pauline Motte-Vincent, Marine Morrier, Dominique Merrien, Yves Bleher, Maxime Flori, Amélie Ducet-Boiffard, Orane Colin, Ronan Février, Pauline Thill, Macha Tetart, François Demaeght, Barthelemy Lafond-Desmurs, Maxime Pradier, Agnes Meybeck, Marjorie Picaud, Thierry Prazuck, Guillaume Chapelet, Agnès Rouaud, Paul Le Turnier, Simon Sunder, Aurélien Lorleac'h, Christophe Dollon, Antoine Jacquet, Francois Le Vely, Pierre Gazeau, Séverine Ansart, Hélène Roger, François Laterza, Rodolphe Buzelé, Fella Tahmi, Raphael Lepeule, Karine Lacombe, Bénédicte Lefebvre, Thomas Célarier, Amandine Gagneux-Brunon, Elisabeth Botelho-Nevers, Marc Bernard, Camille Garnier, Morgane Mourguet, Gregory Pugnet, Sara Vienne-Noyes, Guillaume Martin-Blondel, Pierre Delobel, Gaspard Grouteau, Alexa Debard, Laurent Guilleminault, Pauline Arias, Catherine Chakvetadze, Clara Flateau, Aude Kopp, Alain Putot, Jeremy Barben, Suzanne Mouries Martin, Valentine Nuss, Lionel Piroth, Yann-Erick Claessens, Veronique Hentgen, Martin Martinot, Maxime Bach-Bunner, Thomas Bonijoly, Simon Gravier, Jean-Marc Michel, Mathilde Andreu, Mélanie Roriz, Aurélie Baldolli, Julia Brochard, Olivier Grossi, Samuel Pineau, Josselin Brisset, Edouard Desvaux, Guillaume Gondran, Jean-François Faucher, Paul-Antoine Quesnel, Holy Bezanahary, Clément Danthu, Blandine Gutierrez, Kim Ly, Yannick Simonneau, Anne Cypierre, Pauline Pinet, Hélène Durox, Sophie Ducroix-Roubertou, Claire Genet, Guillaume Beraud, Gwenael Le Moal, Blandine Rammaert, Jean-Philippe Lanoix, Claire Andrejak, Cédric Joseph, Sandrine Soriot-Thomas, Robin Dhote, Sébastien Abad, Ruben Benainous, Jean-François Boitiaux, Guillaume Briend, Celine Gonfroy, Stanislas Harent, Aurore Lagrange, Alina Tone, Laura Wayenberg, Sophie Desoutter, Nicolas Ettahar, Thomas Gey, Vincent Leroy, Sacha Gaillard, Andrea Toma, Amaury Broussier, Sandrine Etienne, Yann Spivac, Benoit Martha, Nathalie Roch, Pierre Diaz, Danièle N’guyen Baranoff, Stanislas Rebaudet, François Jourda, Valérie Zeller, Boris Bienvenu, Arnaud Boyer, Marie Briet, Bertrand Guidet, Patrick Mismetti, Eric Vicaut, Olivier Sanchez, Philippe Girard, Antoine Elias, Francis Couturaud, Béatrice Gable, Sybille Lazareff, Loïc Carballido, Catherine Hue, Jean-Marie Chrétien, Adrien Goraguer, Lucie van Eeckhoutte, ATOMycA (CRCINA-ÉQUIPE 6), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Ressources Biologiques [CHU d'Angers] (CRB CHU d'Angers BB-0033-00038), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Département de Pharmacie [CHU d'Angers], Laboratoire de virologie [CHU Angers], Département de Pharmacologie-Toxicologie [CHU Angers], Centre Hospitalier René Dubos [Pontoise], Centre Hospitalier Tourcoing, Service de Médecine Interne [Agen], Centre Hospitalier d'Agen, Centre Hospitalier Départemental Vendée (CHDV), Centre Hospitalier de Versailles André Mignot (CHV), Groupe Hospitalier Sud, Université d'Angers (UA), HYCOVID study group, HYCOVID investigators, Angers University Hospital, Cholet Hospital, Laval Hospital, Le Mans Hospital, Tours University Hospital, Quimper Hospital, La Roche sur Yon Hospital, Tourcoing Hospital, Orléans Hospital, Nantes University Hospital, Niort Hospital, Lorient Hospital, Brest University Hospital, Cherbourg Hospital, Saint-Brieuc Hospital, Créteil – APHP University Hospital, Saint-Antoine – APHP University Hospital, Saint-Etienne University Hospital, Toulouse University Hospital, Melun Hospital, Dijon University Hospital, Princesse Grace – Monaco Hospital, Versailles Hospital, Colmar Hospital, Agen-Nerac Hospital, Caen University Hospital, Saint-Nazaire Hospital, Nantes – Confluent Hospital, Limoges University Hospital, Poitiers University Hospital, Amiens University Hospital, Bobigny – APHP University Hospital, Cergy-Pontoise Hospital, Valencienne Hospital, Valencienne – Clinique Tessier Hospital, Henri-Mondor – APHP University Hospital, Chalon-sur-Saône Hospital, Marseille European Hospital, Auxerre Hospital, Diaconnesses Croix-Saint-Simon Hospital, Marseille – Saint Joseph Hospital, Composition of the HYCOVID management team, Steering committee, Independant data safety and monitoring board, Independent adjudication of clinical events committee, Study management Coordination, Data management., Bernardo, Elizabeth, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service des maladies infectieuses et tropicales [CHU Angers], and Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)

Subjects
0301 basic medicine, Microbiology (medical), medicine.medical_specialty, 030106 microbiology, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Placebo, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, [SDV.CAN] Life Sciences [q-bio]/Cancer, law, Interquartile range, Intensive care, Internal medicine, medicine, Clinical endpoint, 030212 general & internal medicine, education, Severe acute respiratory syndrome coronavirus 2, education.field_of_study, Coronavirus disease 2019, business.industry, Hydroxychloroquine, General Medicine, Placebo-controlled, 3. Good health, Infectious Diseases, Relative risk, business, medicine.drug
Abstract

Objectives To determine whether hydroxychloroquine decreases the risk of adverse outcome in patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk of worsening. Methods We conducted a multicentre randomized double-blind placebo-controlled trial evaluating hydroxychloroquine in COVID-19 patients with at least one of the following risk factors for worsening: need for supplemental oxygen, age ≥75 years, age between 60 and 74 years and presence of at least one co-morbidity. Severely ill patients requiring oxygen therapy >3 L/min or intensive care were excluded. Eligible patients were randomized in a 1:1 ratio to receive either 800 mg hydroxychloroquine on day 0 followed by 400 mg per day for 8 days or a placebo. The primary end point was a composite of death or start of invasive mechanical ventilation within 14 days following randomization. Secondary end points included mortality and clinical evolution at days 14 and 28, and viral shedding at days 5 and 10. Results The trial was stopped after 250 patients were included because of a slowing down of the pandemic in France. The intention-to-treat population comprised 123 and 124 patients in the placebo and hydroxychloroquine groups, respectively. The median age was 77 years (interquartile range 58–86 years) and 151/250 (60.4%) patients required oxygen therapy. The primary end point occurred in 9/124 (7.3%) patients in the hydroxychloroquine group and 8/123 (6.5%) patients in the placebo group (relative risk 1.12; 95% CI 0.45–2.80). The rates of positive SARS-CoV-2 RT-PCR tests at days 5 and 10 were 72.8% (75/103) and 57.1% (52/91) in the hydroxychloroquine group, versus 73.0% (73/100) and 56.6% (47/83) in the placebo group, respectively. No difference was observed between the two groups in any of the other secondary end points. Conclusion In this underpowered trial involving mainly older patients with mild to moderate COVID-19, patients treated with hydroxychloroquine did not experience better clinical or virological outcomes than those receiving the placebo. Trial registration ClinicalTrials.gov Identifier: NCT04325893 ( https://clinicaltrials.gov/ct2/show/NCT04325893 ).

Published
2020

6. Quantitative chimerism in CD3-negative mononuclear cells predicts prognosis in acute myeloid leukemia patients after hematopoietic stem cell transplantation

Author

Sylvie François, Mathilde Hunault-Berger, Bénédicte Ribourtout, Yves Delneste, Alban Villate, Laurane Cottin, Sylvain Thepot, Aurélien Sutra Del Galy, Damien Luque Paz, Odile Blanchet, Marie-Hélène Estienne, Valérie Ugo, Jérémie Riou, Corentin Orvain, Norbert Ifrah, Aline Schmidt, Anne Bouvier, Annaëlle Beucher, Laboratoire d'Hématologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Innate immunity and Immunotherapy (CRCINA - Département INCIT - Equipe 7), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service des maladies du sang [Angers], PRES Université Nantes Angers Le Mans (UNAM), Department of Hematology, CHU, Angers, Laboratoire d'hématologie (Labo Hémato - BREST), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire d'hématologie, Centre de Recherche sur le Cancer Nantes-Angers (LUNAM), Université d'Angers (UA)-Université de Nantes (UN), Hematology Department, Université d'Angers (UA), Laboratoire d'hématologie (Labo Hémato - ANGERS), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), and PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, Neoplasm, Residual, CD3 Complex, medicine.medical_treatment, Cell, Hematopoietic stem cell transplantation, Disease, 0302 clinical medicine, hemic and lymphatic diseases, Medicine, Major complication, ComputingMilieux_MISCELLANEOUS, biology, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, Hematology, Middle Aged, Prognosis, 3. Good health, Survival Rate, [STAT]Statistics [stat], Leukemia, Myeloid, Acute, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cohort, Female, Adult, medicine.medical_specialty, Adolescent, CD3, Chimerism, Peripheral blood mononuclear cell, Young Adult, 03 medical and health sciences, Internal medicine, Biomarkers, Tumor, Humans, Transplantation, Homologous, WT1 Proteins, Aged, Retrospective Studies, business.industry, 030104 developmental biology, biology.protein, Neoplasm Recurrence, Local, business, Follow-Up Studies
Abstract

Relapse is a major complication of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (SCT). The objective of our study was to evaluate chimerism monitoring on the CD3-negative mononuclear cells by RQ-PCR to predict relapse of patients allografted for AML and to compare its performance with WT1 quantification. A cohort of 100 patients undergoing allogenic SCT for AML was retrospectively analyzed in a single institution. Patients without complete chimerism, defined as less than 0.01% of recipient’s DNA in CD3-negative cells, had a significantly higher risk of relapse and a lower overall survival (p

Published
2019

7. Sequential mutational evaluation of CALR ‐mutated myeloproliferative neoplasms with thrombocytosis reveals an association between CALR allele burden evolution and disease progression

Author

Jean-Marie Chrétien, Odile Blanchet, Sophie Sadot-Lebouvier, Yves Delneste, Isabelle Quintin-Roué, Corentin Orvain, Olivier Mansier, Françoise Boyer, Barbara Burroni, Mathilde Hunault-Berger, Matgorzata Truchan-Graczyk, Damien Luque Paz, Maxime Renard, Marie-Christine Rousselet, Anne Murati, Jérémie Riou, Olivier Allangba, Laurane Cottin, Rébecca Jouanneau-Courville, Antoine Martin, Jean Christophe Ianotto, Valérie Ugo, Eric Lippert, Boullé, Christelle, Laboratoire d'hématologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service des maladies du sang [Angers], Département d'Hématologie Clinique (BREST - Hémato Clinique), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service des maladies du sang, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fédération Hospitalo-Universitaire 'Grand Ouest Against Leukemia' (FHU GOAL), Université de Bordeaux (UB), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Pathologie [AP-HP Hôpital Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Pathologie Cellulaire et Tissulaire [Angers] (Laboratoire d’Histopathologie-Cytopathologie), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), Biochimie et Physiologie Moléculaire des Plantes (BPMP), Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Hematopoïèse et Cellules Souches (U362), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Hématologie Biologique, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), CHU Cochin [AP-HP], Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche sur le Cancer Nantes-Angers (LUNAM), Université d'Angers (UA)-Université de Nantes (UN), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)

Subjects
Oncology, Adult, Male, allele burden, medicine.medical_specialty, Myeloid, Adolescent, myeloproliferative neoplasms, 03 medical and health sciences, Young Adult, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Humans, In patient, Allele, Myelofibrosis, CALR, Alleles, Aged, Aged, 80 and over, Thrombocytosis, Myeloproliferative Disorders, business.industry, Disease progression, High-Throughput Nucleotide Sequencing, Hematology, Middle Aged, medicine.disease, Prognosis, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cohort, Mutation, Disease Progression, Female, next-generation sequencing, Bone marrow, business, Calreticulin, 030215 immunology
Abstract

International audience; In myeloproliferative neoplasms (MPN), JAK2V617F allele burden measurement has an impact on prognosis that helps in patient monitoring. Less is known about its usefulness in CALR-mutated cases. Additional mutations found by next-generation sequencing have also shown an impact on prognosis that may drive therapeutic choices, especially in myelofibrosis, but few studies focused on CALR-mutated patients. We performed a molecular evaluation combining next-generation sequencing with a myeloid panel and CALR allele burden measurement at diagnosis and during follow-up in a cohort of 45 patients with CALR-mutated essential thrombocythaemia. The bone marrow histology was also blindly reviewed in order to apply the WHO2016 classification. The most frequently mutated gene was TET2 (11/21 mutations). CALR type 1-like patients appear to have a more complex molecular landscape. We found an association between disease progression and CALR allele burden increase during follow-up, independently of additional mutations and WHO2016-reviewed diagnosis. Patients with disease progression at the time of follow-up showed a significant increase in CALR allele burden (+16·7%, P = 0·005) whereas patients without disease progression had a stable allele burden (+3·7%, P = 0·194). This result argues for clinical interest in CALR allele burden monitoring.

Published
2019

8. Circulating PCSK9 levels are not associated with the severity of hepatic steatosis and NASH in a high-risk population

Author

Bertrand Cariou, Odile Blanchet, Matthieu Wargny, Sarra Smati, L. Arnaud, Matthieu Pichelin, Benjamin Bouillet, Luc Van Gaal, Sven Francque, Philippe Lefebvre, Jean-Michel Petit, Jérôme Boursier, Pierre-Henri Ducluzeau, Cédric Le May, Bart Staels, Adrien Lannes, Bruno Vergès, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Endocrinologie (CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Bourgogne Franche-Comté [COMUE] (UBFC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Département d'hépatologie (CHU Angers), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre de Ressources Biologiques [CHU d'Angers] (CRB CHU d'Angers BB-0033-00038), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Gastroenterology and Hepatology (Antwerp University Hospital), Antwerp University Hospital [Edegem] (UZA), Department of Endocrinology, Diabetology and Metabolism (Antwerp University Hospital), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), LUNAM Université, F-49933 Angers, France, Plateforme PACeM (Plateforme d'Analyse Cellulaire et Moléculaire), SFR ICAT4208, F-49933 Angers, France., PACeM Angers, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Unité de recherche de l'institut du thorax (ITX-lab), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Plateforme d'Analyse Cellulaire et Moléculaire [SFR ICAT - UA] (PACEM), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Université d'Angers (UA)-Université d'Angers (UA), ANR-16-RHUS-0007,CHOPIN,CHOPIN(2016), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Male, Biopsy, Liver steatosis, Type 2 diabetes, 030204 cardiovascular system & hematology, Gastroenterology, Severity of Illness Index, PCSK9, 0302 clinical medicine, Fibrosis, Non-alcoholic Fatty Liver Disease, LDL-cholesterol, ComputingMilieux_MISCELLANEOUS, education.field_of_study, medicine.diagnostic_test, Middle Aged, Liver biopsy, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Magnetic Resonance Imaging, 3. Good health, Liver, Female, France, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, MRI, Adult, Risk, medicine.medical_specialty, Population, Liver fibrosis, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, education, Aged, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatology, medicine.disease, Fatty Liver, 030104 developmental biology, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Linear Models, Human medicine, Steatosis, Steatohepatitis, business
Abstract

Background and aims: Some studies suggested that proprotein convertase subtilisin kexin type 9 (PCSK9) is linked to liver steatosis severity and non-alcoholic steatohepatitis (NASH). We aimed to assess whether circulating PCSK9 levels are associated with either liver fat content (LFC) or histological markers of NASH in high-risk patients. Methods: We present results from three cross-sectional studies from two French Hospitals: Dijon and Numevox (departments of Endocrinology) and Angers (department of Hepatology). Only patients without lipid-lowering therapy were included. All 132 patients had type 2 diabetes in Dijon, compared to 55/224 in Numevox (25%) and 39/122 in Angers (32%). LFC was assessed on MRI (Dijon and Numevox), and NASH lesion on liver biopsy (Angers). Additionally, we included mRNA results from 138 overweight patients of a Belgian Hospital (Antwerp). Results: While circulating levels of PCSK9 were positively correlated with total cholesterol, LDL-C, triglycerides and non-HDL-C in all 3 cohorts, no significant association was found between PCSK9 and transaminases. Furthermore, no association was found between plasma PCSK9 levels and LFC in both Numevox (beta(adjusted) = 0.71 +/- 1.33, p = 0.60) and Dijon (beta(adjusted) = 1.03 +/- 0.90, p = 0.25). There was no correlation between circulating PCSK9 and histological liver lesions: steatosis severity (beta(adjusted) = -3.95 +/- 2.75, p = 0.15), NASH activity score (beta(adjusted) = -0.31 +/- 0.17, p = 0.082), lobular (beta = -0.067 +/- 0.055, p = 0.22) or portal inflammation (beta = -0.088 +/- 0.079, p = 0.27), ballooning (beta = -0.025 +/- 0.065, p = 0.70) and fibrosis (beta = -0.17 +/- 0.11, p = 0.12). Finally, hepatic PCSK9 mRNA levels were not correlated with NASH histological severity. Conclusions: Circulating PCSK9 concentrations are not associated with the severity of liver steatosis or histological markers of NASH. These data are reassuring regarding the clinical use of PCSK9 inhibitors in cardiovascular diseases.

Published
2018

9. Study of mitochondrial function in placental insufficiency

Author

Valérie Seegers, Geraldine Gascoin, Vincent Procaccio, Naïg Gueguen, Guillaume Legendre, Majida Cherif, Valérie Desquiret-Dumas, Salim Khiati, Tiphaine Lefebvre, Guillaume Geffroy, Ombeline Roche, Guy Lenaers, Odile Blanchet, Pascal Reynier, Laboratoire d'Ecologie Alpine (LECA ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), ARN : régulations naturelle et artificielle, Université Bordeaux Segalen - Bordeaux 2-Institut Européen de Chimie et de Biologie-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CEntre de REcherches en MAthématiques de la DEcision (CEREMADE), Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), PRES Université Nantes Angers Le Mans (UNAM), and Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)

Subjects
0301 basic medicine, Adult, medicine.medical_specialty, Mitochondrial DNA, Placenta, [SDV]Life Sciences [q-bio], Respiratory chain, Placental insufficiency, Mitochondrion, DNA, Mitochondrial, Polymerase Chain Reaction, Preeclampsia, Electron Transport, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Pregnancy, Internal medicine, medicine, Humans, reproductive and urinary physiology, ComputingMilieux_MISCELLANEOUS, 030219 obstetrics & reproductive medicine, Fetal Growth Retardation, business.industry, Obstetrics and Gynecology, medicine.disease, Placental Insufficiency, Mitochondria, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Reproductive Medicine, Haplotypes, Case-Control Studies, embryonic structures, Female, business, Maternal Serum Screening Tests, Developmental Biology, Human mitochondrial DNA haplogroup
Abstract

Introduction It has been suggested that mitochondria play a crucial role in sustaining pregnancy and foetal growth. The aim of the study was to assess the influence of mitochondrial functions and genetics on placental insufficiency diseases. Methods A total of 115 patients were recruited, subdivided into 74 placenta samples and 41 maternal blood samples: placental insufficiency diseases including intra uterine growth restriction (IUGR) (n = 35), preeclampsia (PE) (n = 13), IUGR associated to PE (PER) (n = 25); and controls (n = 42). Haplogroups were determined for all patients. Eighty-six placenta samples were studied for quantitative and qualitative analyses of mtDNA: IUGR (n = 25), PE (n = 1), PER (n = 18) and controls (n = 42). Sixteen placenta samples were selected for functional analysis: IUGR (n = 6), PER (n = 2) and controls (n = 8). Results Mitochondrial DNA copy numbers and rearrangements and haplogroup distribution were not significantly altered in the patient group. Enzyme activity and expression of respiratory chain complexes were also comparable between both groups. Discussion Our results do not argue in favour of a mitochondrial involvement in placental insufficiency, suggesting that the glycolytic pathway may represent a key energetic source in placental insufficiency diseases.

Published
2018

10. Concomitant CALR and LNK mutations leading to essential thrombocythemia with erythrocytosis

Author

Odile Blanchet, Mathilde Hunault, Diane K. Lambert, Anne Bouvier, Rébecca Jouanneau-Courville, Philippe Guardiola, Françoise Boyer, Valérie Ugo, Yves Delneste, Damien Luque Paz, Annaëlle Beucher, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Laboratoire d'hématologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université d'Angers (UA), Fédération Hospitalo-Universitaire 'Grand Ouest Against Leukemia' (FHU GOAL), Service des maladies du sang [CHU Angers], Service de Génomique Onco-Hématologique [CHU Angers], Centre de Ressources Biologiques [CHU d'Angers] (CRB CHU d'Angers BB-0033-00038), This study is part of the clinical and biological database 'FIMBANK' project supported by a grant of the French National Cancer Institute (INCa-BCB-2013)., Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Male, LNK, [SDV.CAN]Life Sciences [q-bio]/Cancer, Polycythemia, Essential thrombocythemia, Myeloproliferative neoplasms, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Genetic Predisposition to Disease, CALR, Molecular Biology, Genetic Association Studies, ComputingMilieux_MISCELLANEOUS, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, business.industry, Intracellular Signaling Peptides and Proteins, Proteins, Cell Biology, Hematology, Janus Kinase 2, medicine.disease, Erythrocytosis, 3. Good health, 030220 oncology & carcinogenesis, Concomitant, Mutation, Cancer research, Molecular Medicine, Calreticulin, business, Thrombocythemia, Essential
Abstract

International audience; no abstract

Published
2018

11. Prospective long-term minimal residual disease monitoring using RQ-PCR in RUNX1-RUNX1T1-positive acute myeloid leukemia: results of the French CBF-2006 trial

Author

Odile Blanchet, Eric Jourdan, Pascale Cornillet-Lefebvre, Nicolas Boissel, Aline Renneville, Hervé Dombret, Claude Preudhomme, Christophe Willekens, Norbert Ifrah, Romain Guieze, Cécile Pautas, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth

Subjects
Male, 0301 basic medicine, Neoplasm, Residual, Myeloid, Chromosomes, Human, Pair 22, Gene Expression, Gastroenterology, Translocation, Genetic, RUNX1 Translocation Partner 1 Protein, 0302 clinical medicine, Bone Marrow, Recurrence, Cumulative incidence, Prospective Studies, Remission Induction, Myeloid leukemia, Articles, Hematology, Middle Aged, 3. Good health, Leukemia, Myeloid, Acute, Leukemia, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Core Binding Factor Alpha 2 Subunit, Female, France, Chromosomes, Human, Pair 8, Adult, medicine.medical_specialty, Adolescent, Subsequent Relapse, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Real-Time Polymerase Chain Reaction, Lower risk, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Proto-Oncogene Proteins, Internal medicine, Biomarkers, Tumor, medicine, Humans, Adaptor Proteins, Signal Transducing, Monitoring, Physiologic, Blood Cells, business.industry, medicine.disease, Survival Analysis, Minimal residual disease, Surgery, Consolidation Chemotherapy, Cytoskeletal Proteins, 030104 developmental biology, Bone marrow, business, Transcription Factors
Abstract

In t(8;21)(q22;q22) acute myeloid leukemia, the prognostic value of early minimal residual disease assessed with real-time quantitative polymerase chain reaction is the most important prognostic factor, but how long-term minimal residual disease monitoring may contribute to drive individual patient decisions remains poorly investigated. In the multicenter CBF-2006 study, a prospective monitoring of peripheral blood and bone marrow samples was performed every 3 months and every year, respectively, for 2 years following intensive chemotherapy in 94 patients in first complete remission. A complete molecular remission was defined as a (RUNX1-RUNX1T1/ABL1)×100 ≤ 0.001%. After the completion of consolidation therapy, a bone marrow complete molecular remission was observed in 30% of the patients, but was not predictive of subsequent relapse. Indeed, 8 patients (9%) presented a positive bone marrow minimal residual disease for up to 2 years of follow-up while still remaining in complete remission. Conversely, a peripheral blood complete molecular remission was statistically associated with a lower risk of relapse whatever the time-point considered after the completion of consolidation therapy. During the 2-year follow-up, the persistence of peripheral blood complete molecular remission was associated with a lower risk of relapse (4-year cumulative incidence, 8.2%), while molecular relapse confirmed on a subsequent peripheral blood sample predicted hematological relapse (4-year cumulative incidence, 86.9%) within a median time interval of 3.9 months. In t(8;21)(q22;q22) acute myeloid leukemia, minimal residual disease monitoring on peripheral blood every 3 months allows for the prediction of hematological relapse, and to identify patients who could potentially benefit from intervention therapy. (ClinicalTrials.gov ID #NCT00428558).

Published
2016

12. Dasatinib in high-risk core binding factor acute myeloid leukemia in first complete remission: a French Acute Myeloid Leukemia Intergroup trial

Author

Hervé Dombret, Stephane Girault, Odile Blanchet, Romain Guieze, Céline Berthon, Christian Recher, Stéphane Leprêtre, Patrice Chevallier, Caroline Bonmati, Chantal Himberlin, Claude Preudhomme, Edouard Randriamalala, Cécile Pautas, Thomas Prebet, Eric Jourdan, Aline Renneville, Nicolas Boissel, Norbert Ifrah, Thibaut Leguay, Pascale Cornillet Lefebvre, Eric Delabesse, Thibaud Lecerf, Service d'hématologie-oncologie adultes, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), Laboratoire d'Hématologie [CHRU Lille] (Centre de Biologie et de Pathologie), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Equipe 3 - Facteurs de persistance des cellules leucémique - (INSERM U837), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille]-Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Service d’Hématologie [Hôpital Haut-Lévèque, CHU Bordeaux], CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU de Bordeaux], Laboratoire Central d'Hématologie [Hôpital Robert Debré, CHU Reims], Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital universitaire Robert Debré [Reims], Service d'Hématologie [CHU Toulouse], CHU Toulouse [Toulouse], Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service des maladies du sang [CHU Angers], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Laboratoire d'Hématologie [Purpan], Service des Maladies du Sang [CHU Lille] (SMS), Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire d'Hématologie [CHU Angers], Service d’Hématologie [Institut Paoli Calmettes, Marseille], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'Hématologie Biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Hématologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'hématologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Service d’Hématologie Adulte [Hôpitaux de Brabois, CHU Nancy], Centre Hospitalier Universitaire de Nancy (CHU Nancy), Service d’Hématologie Biologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Service d’Hématologie [Hôpital Robert Debré, CHU Reims], Service d'Hématologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'Hématologie Clinique et Oncologie Médicale [CHU de Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), The authors would like to thank Bristol-Myers Squibb and the Association Laurette Fugain for their financial support., Service d’Hématologie [CHU Purpan, Toulouse], Centre Hospitalier Universitaire de Purpan (CHU Purpan), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Service des Maladies du Sang [CHRU Lille], Bernardo, Elizabeth, Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Myeloid, Population, Dasatinib, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cohort Studies, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Maintenance therapy, Risk Factors, Internal medicine, hemic and lymphatic diseases, Humans, Medicine, education, Core binding factor acute myeloid leukemia, 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, Core Binding Factors, Remission Induction, Myeloid leukemia, Articles, Hematology, Middle Aged, medicine.disease, 3. Good health, Leukemia, Myeloid, Acute, Leukemia, medicine.anatomical_structure, RUNX1, chemistry, 030220 oncology & carcinogenesis, Immunology, Female, France, business, Follow-Up Studies, medicine.drug
Abstract

International audience; Core-binding factor acute myeloid leukemia is a favorable acute myeloid leukemia subset cytogenetically defined by t(8;21) or inv(16)/t(16;16) rearrangements, disrupting RUNX1 (previously CBFA/AML1) or CBFB transcription factor functions. The receptor tyrosine kinase KIT is expressed in the vast majority of these acute myeloid leukemias and frequent activating KIT gene mutations have been associated with a higher risk of relapse. This phase II study aimed to evaluate dasatinib as maintenance therapy in patients with core-binding factor acute myeloid leukemia in first hematologic complete remission, but at higher risk of relapse due to molecular disease persistence or recurrence. A total of 26 patients aged 18-60 years old previously included in the CBF-2006 trial were eligible to receive dasatinib 140 mg daily if they had a poor initial molecular response (n=18) or a molecular recurrence (n=8). The tolerance of dasatinib as maintenance therapy was satisfactory. The 2-year disease-free survival in this high-risk population of patients was 25.7%. All but one patient with molecular recurrence presented subsequent hematologic relapse. Patients with slow initial molecular response had a similar disease-free survival when treated with dasatinib (40.2% at 2 years) or without any maintenance (50.0% at 2 years). The disappearance of KIT gene mutations at relapse suggests that clonal devolution may in part explain the absence of efficacy observed with single-agent dasatinib in these patients (n. EudraCT: 2006-006555-12).

Published
2015

13. Early matched sibling hematopoietic cell transplantation for adult AML in first remission using an age-adapted strategy: long-term results of a prospective GOELAMS study

Author

Bruno Lioure, Odile Blanchet, Christian Berthou, Mario Ojeda-Uribe, Jean-Luc Harousseau, Didier Bouscary, Martin Carre, Marie C. Béné, Fabrice Larosa, Mathilde Hunault, Isabelle Luquet, Luc Fornecker, Patrice Chevallier, Brigitte Witz, Norbert Ifrah, Didier Blaise, Pascale Cornillet-Lefebvre, Thierry Lamy, Jérôme Cornillon, Anne Huynh, Martine Delain, Arnaud Pigneux, Edouard Randriamalala, Nathalie Fegueux, Jean-Yves Cahn, Service d'onco-hématologie, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service d'hématologie et oncologie médicale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Hôpital Haut-Lévêque, Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux], Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Laboratoire d'hématologie, Centre Hospitalier Universitaire de Reims (CHU Reims), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'hématologie clinique [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Sciences et Technologies - Bordeaux 1 (UB)-CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], and Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, MESH: Remission Induction, Transplantation Conditioning, Myeloid, medicine.medical_treatment, Graft vs Host Disease, Kaplan-Meier Estimate, Hematopoietic stem cell transplantation, MESH: Peripheral Blood Stem Cell Transplantation, Biochemistry, MESH: Proportional Hazards Models, 0302 clinical medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Medicine, Cumulative incidence, MESH: Incidence, MESH: Bone Marrow Transplantation, Bone Marrow Transplantation, MESH: Transplantation Conditioning, MESH: Middle Aged, Incidence, Incidence (epidemiology), Remission Induction, Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, 3. Good health, Leukemia, Myeloid, Acute, Leukemia, MESH: Antineoplastic Combined Chemotherapy Protocols, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, MESH: Leukemia, Myeloid, Acute, medicine.medical_specialty, Immunology, MESH: Graft vs Host Disease, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Internal medicine, Humans, MESH: Hematopoietic Stem Cell Transplantation, MESH: Kaplan-Meier Estimate, Proportional Hazards Models, Peripheral Blood Stem Cell Transplantation, MESH: Humans, business.industry, Proportional hazards model, Siblings, Cell Biology, medicine.disease, Confidence interval, MESH: Male, Surgery, MESH: Siblings, Transplantation, business, MESH: Female, 030215 immunology
Abstract

The LAM2001 phase 3 trial, involving 832 patients with acute myeloid leukemia (AML; median: 46 years) proposed HLA-identical sibling allograft HSCT for all patients with an identified donor. The trial compared reduced-intensity conditioning (RIC) for patients older than 50 years of age (N = 47) and myeloablative conditioning for younger patients (N = 117). BM HSCT was performed in the younger patients, while the older ones received a consolidation course, followed by peripheral blood allo-HSCT using RIC. The incidence of grade II-IV acute GVHD, was 51.9% (95% confidence interval [CI]: 42.1-61.8) and 11.3% (1.6-21.2) after myeloablative or RIC, respectively (P < .0001) and that of chronic GVHD 45.8% (95% CI: 34.8-56.7) and 41.7% (24.7-58.6; NS). Cumulative incidence of nonrelapse mortality at 108 months was 15.8% (95% CI: 9.8-23.2) for myeloablative, and 6.5% (0.2-16.2) for RIC (NS). CI of relapse at 108 months was 21.7% (95% CI: 13.9-28.6) and 28.6% (16.5-43.4; NS). Overall survival at 108 months was 63.4% (95% CI: 54.6-72.2) and 65.8% (52.2-72.2), respectively, after myeloablative or RIC (NS). RIC peripheral blood stem cell allo-HSCT is prospectively feasible for patients between the ages of 51 and 60 years without excess of relapse or nonrelapse mortality, and compares favorably with myeloablative marrow allo-HSCT proposed to younger patients. This study was registered at clinicaltrials.gov as no. NCT01015196.

Published
2012

14. Routine use of microarray-based gene expression profiling to identify patients with low cytogenetic risk acute myeloid leukemia: accurate results can be obtained even with suboptimal samples

Author

Yves Delneste, Norbert Ifrah, Diane Raingeard de la Blétière, Mathilde Hunault-Berger, Marc Zandecki, Anne Coutolleau, Isabelle Luquet, Philippe Guardiola, Laurence Baranger, Pascale Cornillet-Lefebvre, Annaëlle Beucher, Odile Blanchet, Aline Schmidt-Tanguy, Franck Geneviève, BMC, Ed., Plateforme SNP, Transcriptome & Epigénomique, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'hématologie, Centre Hospitalier Universitaire de Reims (CHU Reims), Laboratoire de génétique, Service des maladies du sang, and PhG from Plateforme SNP, Transcriptome & Epigénomique received a grant from La Ligue Contre le Cancer/Comité Départemental 49 to support this work.

Subjects
Adult, Male, Quality Control, Acute promyelocytic leukemia, lcsh:Internal medicine, Myeloid, lcsh:QH426-470, Adolescent, Microarray, Biology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, hemic and lymphatic diseases, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Humans, Genetics(clinical), Genetic Predisposition to Disease, lcsh:RC31-1245, Genetics (clinical), Aged, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, Gene Expression Profiling, Myeloid leukemia, Middle Aged, medicine.disease, Confidence interval, Gene expression profiling, lcsh:Genetics, Leukemia, Myeloid, Acute, Leukemia, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cytogenetic Analysis, Immunology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, DNA microarray, Research Article
Abstract

Background Gene expression profiling has shown its ability to identify with high accuracy low cytogenetic risk acute myeloid leukemia such as acute promyelocytic leukemia and leukemias with t(8;21) or inv(16). The aim of this gene expression profiling study was to evaluate to what extent suboptimal samples with low leukemic blast load (range, 2-59%) and/or poor quality control criteria could also be correctly identified. Methods Specific signatures were first defined so that all 71 acute promyelocytic leukemia, leukemia with t(8;21) or inv(16)-AML as well as cytogenetically normal acute myeloid leukemia samples with at least 60% blasts and good quality control criteria were correctly classified (training set). The classifiers were then evaluated for their ability to assign to the expected class 111 samples considered as suboptimal because of a low leukemic blast load (n = 101) and/or poor quality control criteria (n = 10) (test set). Results With 10-marker classifiers, all training set samples as well as 97 of the 101 test samples with a low blast load, and all 10 samples with poor quality control criteria were correctly classified. Regarding test set samples, the overall error rate of the class prediction was below 4 percent, even though the leukemic blast load was as low as 2%. Sensitivity, specificity, negative and positive predictive values of the class assignments ranged from 91% to 100%. Of note, for acute promyelocytic leukemia and leukemias with t(8;21) or inv(16), the confidence level of the class assignment was influenced by the leukemic blast load. Conclusion Gene expression profiling and a supervised method requiring 10-marker classifiers enable the identification of favorable cytogenetic risk acute myeloid leukemia even when samples contain low leukemic blast loads or display poor quality control criterion.

Published
2012

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