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1. Efficacy, safety and patient reported outcomes in patients with active relapsing multiple sclerosis treated with ocrelizumab: Final results from the PRO-MSACTIVE study

Author: Eric Manchon, David Laplaud, Sandra Vukusic, Pierre Labauge, Thibault Moreau, Gisela Kobelt, Jean-Marie Grouin, Marie Lotz, David Pau, Lebrun Frenay Christine, Centre Hospitalier de Gonesse, Team 5 : Neuroinflammation, mechanisms, therapeutic options (NEMO) (U1064 Inserm - CR2TI), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Nantes Université (Nantes Univ), Service de Neurologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Nord Laënnec, 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), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Fondation Eugène Devic EDMUS, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), European Health Economics [Stockholm, Sweden] (EHE), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Roche France, Hôpital Pasteur [Nice] (CHU), CRCSEP Nice Hopital Pasteur, Unité de Recherche Clinique de la Côte d’Azur [Nice] (URRIS UR2CA), Université Côte d'Azur (UCA), and KERANDEL-DION, Céline
Subjects: [SDV] Life Sciences [q-bio], Neurology, [SDV]Life Sciences [q-bio], Relapsing multiple sclerosis, Neurology (clinical), General Medicine, Ocrelizumab, Phase IV
Abstract: International audience; Background: Ocrelizumab, a humanized anti-CD20 monoclonal antibody, has been approved in Europe for the treatment of adult patients with active relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS), on the basis of previous phase III studies. However, limited data were available on ocrelizumab efficacy in RMS according to the Lublin definition of activity (clinical and/or imaging features) used in the current drug label. The PRO-MSACTIVE study was thus designed to provide additional data on ocrelizumab efficacy according to this definition, and also on safety and patient reported outcomes (PROs).Methods: PRO-MSACTIVE is a national, multicenter, open-label, single-arm phase IV French study, conducted in patients with active RMS (relapsing-remitting multiple sclerosis, RRMS, or secondary progressive multiple sclerosis, SPMS). The primary endpoint, which was assessed at week (W) 48, was defined as the proportion of patients free of disease activity (defined by no relapses and no T1 gadolinium-enhancing nor new and/or enlarging T2 lesions using brain MRI). Disease activity, disability and PROs using 6 questionnaires for disease severity, quality of life, impact on work productivity, and treatment satisfaction were described at W24 and W48. Adverse events were described until W72.Results: Among the 422 analyzed patients (RRMS: 376, SPMS: 46), 63.3% (95% CI [58.5%; 67.9%]) were free of disease activity at W48 (RRMS: 62.2% [57.1%; 67.2%], SPMS: 71.7% [56.5%; 84.0%]). A total of 358 patients (84.8%; RRMS: 84.6%, SPMS: 87.0%) were relapse-free up to W48, and the overall adjusted annualized relapse rate was 0.14 (RRMS: 0.15, SPMS: 0.09). Overall, 67.8% of patients (RRMS: 66.8%, SPMS: 76.1%) had no evidence of MRI activity (no T1 gadolinium-enhancing lesions [83.4%] and no new/enlarging T2 lesions [75.1%]); 58.5% of patients (RRMS: 57.7%, SPMS: 65.2%) achieved No Evidence of Disease Activity (NEDA: no relapses, no confirmed disability progression, and no MRI activity) at W48. All PRO scores were stable between the first dose of ocrelizumab and W48 and better outcomes were seen for patients having an EDSS score ≥4. Overall, 89.3% of patients reported adverse events, 62.3% adverse events assessed as related to ocrelizumab, and 8.5% serious adverse events. No serious infusion-related reactions, opportunistic infections, progressive multifocal leukoencephalopathy, nor deaths were reported. No new safety signal was identified.Conclusion: These data confirm the efficacy of ocrelizumab in a pragmatic setting and its favorable benefit-risk profile in patients with RMS. (ClinicalTrials.gov identifier: NCT03589105; EudraCT identifier: 2018-000780-91).
Published: 2022

2. Multiresistant Enterobacteriaceae in yellow‐legged gull chicks in their first weeks of life

Author: Marion Vittecoq, Lionel Brazier, Eric Elguero, Ignacio G. Bravo, Nicolas Renaud, Alejandro Manzano‐Marín, Franck Prugnolle, Sylvain Godreuil, Thomas Blanchon, François Roux, Patrick Durand, François Renaud, Frédéric Thomas, Institut de recherche de la Tour du Valat, Evolution of host-microbe communities (MIVEGEC-EVCO), Processus Écologiques et Évolutifs au sein des Communautés (PEEC), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), Virostyle (MIVEGEC-Virostyle), Perturbations, Evolution, Virulence (PEV), Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Ecologie et Evolution de la Santé (CREES), Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Nelson Mandela University [Port Elizabeth], Équipe Photonique (LAAS-PHOTO), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées, Centre de Recherches Ecologiques et Evolutives sur le Cancer (MIVEGEC-CREEC), Cette étude a été financée par la Fondation Gecina, Roche France, et l'INEE-CNRS à travers le programme de recherche Ecosan., European Project: 609398,EC:FP7:PEOPLE,FP7-PEOPLE-2013-COFUND,AGREENSKILLSPLUS(2014), Laboratoire Synlab Provence, and University of Vienna [Vienna]
Subjects: Third‐generation cephalosporin, third-generation cephalosporin, Ecology, Whole‐genome sequencing, whole-genome sequencing, Enterobacteria, [SDE]Environmental Sciences, Larus, Antimicrobial resistance, Ecology, Evolution, Behavior and Systematics, Nature and Landscape Conservation, Wild birds
Abstract: International audience; Wild animal species living in anthropogenic areas are commonly carriers of antimicrobial-resistant bacteria (AMRB), but their role in the epidemiology of these bacteria is unclear. Several studies on AMRB in wildlife have been cross-sectional in design and sampled individual animals at only one point in time. To further understand the role of wildlife in maintaining and potentially transmitting these bacteria to humans and livestock, longitudinal studies are needed in which samples are collected from individual animals over multiple time periods. In Europe, free-ranging yellow-legged gulls (Larus michahellis) commonly live in industrialized areas, forage in landfills, and have been found to carry AMRB in their feces. Using bacterial metagenomics and antimicrobial resistance characterization, we investigated the spatial and temporal patterns of AMRB in a nesting colony of yellow-legged gulls from an industrialized area in southern France. We collected 54 cloacal swabs from 31 yellow-legged gull chicks in 20 nests on three dates in 2016. We found that AMRB in chicks increased over time and was not spatially structured within the gull colony. This study highlights the complex occurrence of AMRB in a free-ranging wildlife species and contributes to our understanding of the public health risks and implications associated with ARMB-carrying gulls living in anthropogenic areas.
Published: 2022

3. 'Doctor, can I have less frequent injection with highly efficient treatment?' A patient centered study using an electronic choice-based conjoint analysis (ePRO) to assess real world preferences regarding erythropoiesis stimulating agent to treat anaemia in chronic kidney disease (PERCEPOLIS study)

Author: Cécile Vigneau, Olivier Moranne, D Pau, Corinne Isnard-Bagnis, Sophie Pibre, Gabriel Choukroun, Gilles Sinnasse-Raymond, CHU Pontchaillou [Rennes], CHU Amiens-Picardie, Service de Néphrologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Roche France, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de néphrologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, medicine.medical_specialty, Real world data, medicine.drug_class, [SDV]Life Sciences [q-bio], medicine.medical_treatment, 030232 urology & nephrology, Electronic patient reported outcomes, Renal anaemia, 03 medical and health sciences, 0302 clinical medicine, Patient-Centered Care, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Prospective Studies, Patient preference, Renal Insufficiency, Chronic, Conjoint analysis, Erythropoietin, Dialysis, Aged, Aged, 80 and over, Digital tablet, business.industry, Anemia, Middle Aged, CERA, Electronic patient-reported outcome, Erythropoiesis stimulating agent, Erythropoiesis-stimulating agent, medicine.disease, 3. Good health, Continuous erythropoietin receptor activator, Nephrology, Hematinics, Female, business, Chronic kidney disease not on dialysis, Patient centered, Kidney disease, medicine.drug
Abstract: International audience; Objectives Patient's perception analysis appears recently in numerous studies. Conjoint analysis has been used extensively by market researchers for studying how people value the characteristics of products and services. This technique was used in a clinical study to describe perceptions and preferences of anaemic patients suffering from chronic kidney disease not on dialysis (CKDnd), regarding erythropoietin stimulating agents (ESA). Methods PERCEPOLIS was a French multicenter prospective non-interventional study designed to describe the relative importance of ESA attributes according to CKDnD patients. Patients fulfilled questionnaires using an electronic device (digital tablet) at baseline and after 6 months under continuous erythropoietin receptor activator (CERA) treatment. Choice-based conjoint (CBC) questionnaires were developed with multiple components: 7 ESA attributes (2 or 3 levels per attribute), 2 partial profiles per task (2 out of the 7 attributes), and 7 tasks per questionnaire. Analyses were performed according to previous ESA treatment or not. Results From 789 analyzed patients, 433 non ESA-naive patients were more than 80% to declare treatment efficacy as the most important expectative in ESA choice process (direct question) but CBC analyses revealed that frequency of injections was more crucial (relative mean weight: ∼30% versus ∼20% for efficacy). Pain at injection site and haemoglobin not exceeding the recommended target were confirmed as important criteria for patients (relative mean weights: ∼15%). No new or unexplained safety signals were noted. Conclusions Using CBC design for the first time in a non-interventional ESA study with an electronic Patient Reported Outcome (ePRO) in an elderly population, these data showed that monthly injections and treatment efficacy were key patients’ expectations relative to ESAs. CERA efficacy to maintain stable haemoglobin within the recommended range was confirmed in real-life conditions.
Published: 2019

4. Impact des comorbidités sur la stabilité de l’hémoglobine chez des patients insuffisants rénaux chroniques en hémodialyse, traités par CERA en pratique courante : l’étude MIRIADE

Author: Jean-Paul Jaulin, Mustapha Amirou, Luc Frimat, Gilles Sinnasse-Raymond, D Pau, Guy Rostoker, Philippe Zaoui, au nom des investigateurs participant à l’étude Miriade, Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), and Roche France
Subjects: Gynecology, medicine.medical_specialty, business.industry, [SDV]Life Sciences [q-bio], medicine.medical_treatment, 030232 urology & nephrology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Nephrology, Current practice, medicine, In patient, Hemodialysis, Hemoglobin, Chronic Kidney Insufficiency, business
Abstract: Resume Cette etude nationale, prospective et multicentrique vise a decrire en pratique medicale courante l’impact des comorbidites sur la stabilite du taux d’hemoglobine chez des patients insuffisants renaux chroniques hemodialyses, traites par methoxy polyethylene glycol-epoetine beta (CERA) en relais d’un agent stimulant l’erythropoiese. Les comorbidites des patients ont ete definies par l’index de Charlson ajuste sur l’âge, le taux d’hemoglobine stable par une variation de ±1 g/dL apres 6 mois de traitement. Les 585 patients analyses etaient repartis selon l’index de Charlson ajuste de la facon suivante : score ≤ 3 (12 % des patients), 4 ≤ score ≤ 5 (17 %), 6 ≤ score ≤ 7 (31 %), score ≥ 8 (40 %). A l’instauration de CERA, sa dose mensuelle mediane etait de 100 μg, sans changement au cours du suivi et avec peu de variations selon le score de comorbidite. Les patients avec un taux d’hemoglobine stable (56 %, 67 % si score ≤ 3) etaient plus nombreux a atteindre la cible therapeutique entre 10 et 12 g/dL apres 6 mois (85 % versus 43 % si hemoglobine non stable). Les patients avec une faible valeur de proteine C-reactive (≤ 5 mg/L ; p = 0,04), sans transfusion sanguine (p = 0,03), peu ou pas de fer intraveineux (≤ 200 mg ; p = 0,03), avaient plus de chance d’atteindre un taux d’hemoglobine stable apres 6 mois. Parmi les 644 patients traites par CERA, 4 (
Published: 2019

5. Partial breast resection for multifocal lower quadrant breast tumour using virtual reality

Author: Laas, Enora, El Beheiry, Mohamed, Masson, Jean-Baptiste, Malhaire, Caroline, Departement de chirurgie [Institut Curie], Institut Curie [Paris], Décision et processus Bayesiens - Decision and Bayesian Computation, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Département d'Imagerie Médicale [Institut Curie], and Roche France
Subjects: Adult, Mammaplasty, [SDV]Life Sciences [q-bio], Virtual Reality, Case Report, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, breast surgery, Mastectomy, Segmental, radiology, breast cancer, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, Breast
Abstract: International audience; Oncoplastic surgery allows an increase in the number of indications for conservative breast cancer treatments. However, uncertainty as to whether it can be performed still exists in certain situations such as with multicentric or multifocal lesions, even when the breast volume can accommodate it. With the aid of a virtual reality software, DIVA, allowing the precise visualisation of tumours and breast volumes based entirely on the patient’s MRI, we report the ability to rapidly confirm and secure an indication for partial surgery of multiple lesions in a 31-year-old patient. With the described approach, the patient did not have to suffer significant disfigurement from cancerous breast surgery without compromising safety.
Published: 2021

6. Unresectable HCC patients disposal in the new era of immunotherapy from the elitor study based on the french chief cohort

Author: Nguyen-Khac, Eric, Nahon, Pierre, Ganry, Olivier, Ben Khadhra, Hajer, Merle, Philippe, Amaddeo, Giuliana, Ganne, Nathalie, Silvain, Christine, Peron, Jean-Marie, Mathurin, Philippe, Anty, Rodolphe, Uguen, Thomas, Riachi, Ghassan, Bouattour, Mohamed, Baron, Aurore, Gilberg, Melina, Tanang, Alexandre, Dupin, Julien, Ducournau, Gerard, Blanc, Jean-Frederic, DESSAIVRE, Louise, Groupe de Recherche sur l'alcool et les pharmacodépendances - UMR INSERM_S 1247 (GRAP), Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Amiens-Picardie, CHU Henri Mondor, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Département de Santé Publique [Avicenne], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Toulouse [Toulouse], Physiopathologie des Maladies Inflammatoires de l'Intestin, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Centre méditerranéen de médecine moléculaire (C3M), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), CHU Pontchaillou [Rennes], CHU Rouen, Normandie Université (NU), Hôpital Beaujon [AP-HP], Roche France, Département d'Oncologie [CHU Bordeaux] (Cancérologie/Oncologie/Digestive), and Hôpital Haut-Lévêque - CHU de Bordeaux (Centre médico chirurgical Magellan)-Hôpital Saint-André [CHU de Bordeaux]
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2021

7. Evolution in the real-world therapeutic strategies in more than 20,000 women with breast cancer having received human epidermal growth factor receptor 2–targeted treatments: Results from the french personalized reimbursement model database (2011–2018)

Author: Xavier Pivot, Anne Doly, Julien Manson, L. Samelson, Paul Cottu, Olivier Aujoulat, Hugues Barletta, Nassera Chalabi, Bruno Coudert, David Pérol, Département d'Oncologie Médicale [Institut Curie, Paris], Institut Curie [Paris], Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Département cancer environnement (Centre Léon Bérard - Lyon), Centre Léon Bérard [Lyon], Université Clermont Auvergne (UCA), Centre Hospitalier René Dubos [Pontoise], Groupe hospitalier de la région de Mulhouse et Sud-Alsace, Hôpital privé Drôme Ardèche, groupe Ramsay générale de santé, site Pasteur, Roche France, CRLCC Paul Strauss, Neuro-Dol (Neuro-Dol), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])
Subjects: Adult, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Receptor, ErbB-2, [SDV]Life Sciences [q-bio], Breast Neoplasms, Pharmacy, Antibodies, Monoclonal, Humanized, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, Antineoplastic Agents, Immunological, 0302 clinical medicine, Breast cancer, Trastuzumab, Internal medicine, HER2, Antineoplastic Combined Chemotherapy Protocols, Humans, Medicine, Molecular Targeted Therapy, Stage (cooking), skin and connective tissue diseases, Reimbursement, Trastuzumab emtansine, Aged, Retrospective Studies, Aged, 80 and over, Pertuzumab, Retrospective real-world data study, business.industry, Cancer, Middle Aged, medicine.disease, 3. Good health, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Female, France, business, medicine.drug
Abstract: International audience; Background: There is a growing need for real-world data on cancer treatments usage, especially to assess compliance with recommendations. We developed a French project using hospital data to analyse evolution in the therapeutic strategies implemented in patients with human epidermal growth factor receptor 2 (HER2)-overexpressed (HER2+) breast cancer (BC) and exposed to injectable HER2-targeted therapies, i.e. trastuzumab, pertuzumab or trastuzumab emtansine (T-DM1).Patients and methods: Data from 26,350 women with BC were extracted in September 2018 from the Electronic Pharmacy Record systems of 120 French randomly recruited hospitals. Evolution in the treatments used, and combination regimens were described from 2011, in accordance with the BC stage and treatment line.Results: Overall, 21,119 patients treated since 2011 were analysed: 16,398 patients with early BC (eBC) and 6030 patients with metastatic BC (mBC) including patients treated at both stages. In eBC, 89.2% of patients received trastuzumab combined with at least taxanes (trastuzumab-taxane-anthracycline: 62.6%). Patients with mBC were treated in the first line (80.3%) and/or the second line (40.1%) and/or ≥ the third line (28.3%). After its approval in 2014, pertuzumab was first used in first-line therapy combinations in 67.4% of the total cases, while trastuzumab-taxane decreased from 47.2% to 9.2%. Similarly, T-DM1 was used as the second-line treatment in 53.8% of cases.Conclusions: Given recent changes in available treatments for patients with HER2+ BC, this large French project provides robust information on real-world evolution in therapeutic strategies. Our data suggest there is room for significant improvement in optimal drug utilisation. Such data will be useful to build drug-related indicators for future value-based pricing solutions.
Published: 2020

8. Long-term outcomes in patients with PET-predicted poor-responsive HER2-positive breast cancer treated with neoadjuvant bevacizumab added to trastuzumab and docetaxel: 5-year follow-up of the randomised Avataxher study

Author: Jean-Yves Pierga, Alina Berriolo-Riedinger, Thierry Petit, Laurent Arnould, David Coeffic, Abdennour Ferhat, Gilles Paintaud, Jean-Briac Prevost, Pierre-Francois Dupre, Fanny Le Du, Thomas Bachelot, Marie-Pierre Chauvet, Jean-Marc Ferrero, Gilles Thibault, Kaldoun Kerrou, Philippe Gabelle, Catherine Barbe, Julien Dupin, Bruno Coudert, Marie-Ange Mouret-Reynier, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut Curie [Paris], Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Paul Strauss, CRLCC Paul Strauss, Centre Eugène Marquis (CRLCC), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Centre Léon Bérard [Lyon], Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Roche France, Département d'information médicale [Centre Georges-François Leclerc] (DIM), UNICANCER-UNICANCER, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université de Lille-UNICANCER
Subjects: Oncology, medicine.medical_specialty, Positron emission tomography, Early pet assessment, Bevacizumab, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 01 natural sciences, Group B, 03 medical and health sciences, Her-2 positive breast cancer, 0302 clinical medicine, Breast cancer, Trastuzumab, Internal medicine, medicine, Adjuvant therapy, 030212 general & internal medicine, 0101 mathematics, Adverse effect, Long-term follow-up, Neoadjuvant therapy, lcsh:R5-920, business.industry, 010102 general mathematics, General Medicine, medicine.disease, 3. Good health, Docetaxel, pathological complete response, Δsuvmax, Neoadjuvant, lcsh:Medicine (General), business, Research Paper, medicine.drug
Abstract: Background: The open-label, randomised Phase 2 AVATAXHER study (NCT01142778) demonstrated that early PET assessment identified HER2-positive breast cancer patients who responded poorly to neoadjuvant docetaxel plus trastuzumab. Adding neoadjuvant bevacizumab for PET-predicted poor-responders improved pathological complete response (pCR) rates (43.8% vs 24.0%). We investigated long-term study outcomes. Methods: Patients were treated in three groups. All patients initially received two cycles of standard neoadjuvant therapy with [¹⁸F]-FDG PET conducted before each cycle. Those with ≥70% change in the maximum standardised uptake value (∆SUVmax) received four further cycles of standard neoadjuvant therapy (PET responders). PET-predicted poor-responders (∆SUVmax
Published: 2020

9. Serum Detection of Nonadherence to Adjuvant Tamoxifen and Breast Cancer Recurrence Risk

Author: Léonor Fasse, Charles Coutant, Laurence Vanlemmens, A. Bardet, Arlindo R. Ferreira, Alexandra L. Dima, Angelo Paci, Agnès Dumas, Olivier Tredan, Florence Lerebours, Christelle Jouannaud, Fabrice Andre, Nan Lin, Patrick Soulié, Ann H. Partridge, Suzette Delaloge, Stefan Michiels, Ines Vaz-Luis, Gwenn Menvielle, Sandrine Pinto, Antonio Di Meglio, Barbara Pistilli, Sarah Dauchy, Anne Laure Martin, Paul Cottu, A. Lesur, Vianney Poinsignon, Sibille Everhard, Patrick Arveux, Christelle Levy, Institut Gustave Roussy (IGR), Pharmacologie, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Champalimaud Centre for the Unknown [Lisbon], Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Roche France, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Interdisciplinaire de Soins de Support aux Patients en Onco-hématologie [Gustave Roussy] (DISSPO), Département de médecine oncologique [Gustave Roussy], Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], and Direction de la recherche [Gustave Roussy]
Subjects: Adult, Oncology, Cancer Research, medicine.medical_specialty, Antineoplastic Agents, Hormonal, medicine.medical_treatment, Breast Neoplasms, Medication Adherence, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, Breast Cancer, medicine, Humans, Prospective Studies, 030212 general & internal medicine, Medical prescription, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, Chemotherapy, [SHS.SOCIO]Humanities and Social Sciences/Sociology, medicine.diagnostic_test, business.industry, Hazard ratio, ORIGINAL REPORTS, Middle Aged, medicine.disease, 3. Good health, Tamoxifen, Treatment Outcome, Chemotherapy, Adjuvant, Therapeutic drug monitoring, 030220 oncology & carcinogenesis, Cohort, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, medicine.drug
Abstract: PURPOSE Nonadherence to long-term treatments is often under-recognized by physicians and there is no gold standard for its assessment. In breast cancer, nonadherence to tamoxifen therapy after surgery constitutes a major obstacle to optimal outcomes. We sought to evaluate the rate of biochemical nonadherence to adjuvant tamoxifen using serum assessment and to examine its effects on short-term, distant disease-free survival (DDFS). PATIENTS AND METHODS We studied 1,177 premenopausal women enrolled in a large prospective study (CANTO/NCT01993498). Definition of biochemical nonadherence was based on a tamoxifen serum level < 60 ng/mL, assessed 1 year after prescription. Self-reported nonadherence to tamoxifen therapy was collected at the same time through semistructured interviews. Survival analyses were conducted using an inverse probability weighted Cox proportional hazards model, using a propensity score based on age, staging, surgery, chemotherapy, and center size. RESULTS Serum assessment of tamoxifen identified 16.0% of patients (n = 188) below the set adherence threshold. Patient-reported rate of nonadherence was lower (12.3%). Of 188 patients who did not adhere to the tamoxifen prescription, 55% self-reported adherence to tamoxifen. After a median follow-up of 24.2 months since tamoxifen serum assessment, patients who were biochemically nonadherent had significantly shorter DDFS (for distant recurrence or death, adjusted hazard ratio, 2.31; 95% CI, 1.05 to 5.06; P = .036), with 89.5% of patients alive without distant recurrence at 3 years in the nonadherent cohort versus 95.4% in the adherent cohort. CONCLUSION Therapeutic drug monitoring may be a useful method to promptly identify patients who do not take adjuvant tamoxifen as prescribed and are at risk for poorer outcomes. Targeted interventions facilitating patient adherence are needed and have the potential to improve short-term breast cancer outcomes.
Published: 2020

10. Factors associated with compliance to cervical cancer screening in France: The EDIFICE 6 survey

Author: Thibault De La Motte Rouge, Chantal Touboul, Christine Lhomel, Morgan Rouprêt, Jean-François Morère, Centre Eugène Marquis (CRLCC), Roche France, Groupe de Recherche Clinique Onco-Urologie Prédictive [CHU Tenon] (GRC 5), CHU Tenon [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Adult, [SDV]Life Sciences [q-bio], Uterine Cervical Neoplasms, Asymptomatic, 03 medical and health sciences, 0302 clinical medicine, Surveys and Questionnaires, Cancer screening, medicine, Humans, 030212 general & internal medicine, Social Factors, Mass screening, Early Detection of Cancer, Aged, Cervical cancer, business.industry, Age Factors, Obstetrics and Gynecology, Cancer, Stepwise regression, Middle Aged, Patient Acceptance of Health Care, medicine.disease, 3. Good health, Test (assessment), Treatment Adherence and Compliance, Oncology, 030220 oncology & carcinogenesis, Female, France, medicine.symptom, business, Social vulnerability, Demography, Papanicolaou Test
Abstract: A nationwide cervical cancer (CC) screening program was implemented in France in 2018. Asymptomatic women are invited for a cytological test once every 3 years (age, 25-29 years), and an HPV test every 5 years (age, 30-65 years). We investigated the characteristics of women who are resistant to CC screening.Since 2005, the EDIFICE survey program has assessed attitudes toward cancer screening in France. The 6th edition (2017) included 12,046 representative women (age, 18-69 years). Social vulnerability was assessed using the EPICES score. Multivariate stepwise logistic regression analysis identified factors correlated with nonuptake of CC screening.Questionnaires from 4499 women (age, 25-65 years) with no history of cancer were analyzed; 88% (N = 3960) reported at least one test in their lifetime, and 73% (N = 3262) did the test in the previous 3 years. Compared to ever-screened women, never-screened women were younger (38 ± 11 yrs. vs 44 ± 12 yrs., P 0.05), and more likely to be single (48% vs 20%, P 0.05) and/or socially vulnerable (59% vs 38%, P 0.05). In multivariate analysis, items significantly (P 0.05) associated with never screening included living alone (OR = 2.26, 95% CI [1.85-2.75]) and social vulnerability (OR = 1.95 [1.59-2.40]). Women who were not compliant with recommendations were more likely to be older (mean age, 49.2 yrs. vs. 43.2 yrs), living alone (single, widowed or divorced, 40% vs. 30%, P 0.05), and/or socially vulnerable (55% vs. 35%, P 0.05; OR = 1.78, 95% CI [1.49-2.12]).This analysis identified several factors associated with never screening and under-screening. Effective prevention messages should specifically target these populations.
Published: 2020

11. Prognostic value of the Residual Cancer Burden index according to breast cancer subtype: Validation on a cohort of BC patients treated by neoadjuvant chemotherapy

Author: Marie Osdoit, Jean-Guillaume Feron, Marick Laé, Jean-Yves Pierga, Florence Lerebours, Clemence Evrevin, Lauren Darrigues, Anne-Sophie Hamy, Fabien Reyal, Lucie Laot, Lucian Topciu, Enora Laas, Diane De Croze, Matthieu Faron, Sonia Rozette, Giang-Thanh Lam, Residual Tumor & Response to Treatment Laboratory [Paris] (RT2Lab), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical Oncology [Saint-Cloud], Institut Curie [Saint-Cloud], Department of Surgery [Paris], Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris], Department of Tumor Biology [Saint-Cloud], Department of Tumor Biology [Paris], Institut Curie [Paris], Geneva University Hospital (HUG), Department of biostatistics and epidemiology [Villejuif], Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Oncostat team [Villejuif], Institut Gustave Roussy (IGR), We thank Roche France for financial support for the construction of the Institut Curie neoadjuvant database (NEOREP). Funding was also obtained from the Site de Recherche Integrée en Cancérologie/Institut National du Cancer (Grant No. INCa-DGOS-4654). A-S Hamy-Petit was supported by an ITMO-INSERM-AVIESAN translational cancer research grant., Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, and Bodescot, Myriam
Subjects: 0301 basic medicine, Oncology, Neoplasm, Residual, Receptor, ErbB-2, Residual cancer, medicine.medical_treatment, Cancer Treatment, Triple Negative Breast Neoplasms, Disease, Pathology and Laboratory Medicine, Biochemistry, 0302 clinical medicine, Breast Tumors, Medicine and Health Sciences, Lipid Hormones, Triple negative, Progesterone, Aged, 80 and over, 0303 health sciences, Multidisciplinary, Pharmaceutics, Middle Aged, Prognosis, 3. Good health, 030220 oncology & carcinogenesis, Cohort, Medicine, Female, Adjuvant, Research Article, Clinical Oncology, Adult, medicine.medical_specialty, Clinical Pathology, Science, Residual cancer burden index, Surgical and Invasive Medical Procedures, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Cancer Chemotherapy, 03 medical and health sciences, Breast cancer, Drug Therapy, [SDV.CAN] Life Sciences [q-bio]/Cancer, Diagnostic Medicine, Internal medicine, Breast Cancer, medicine, Chemotherapy, Humans, Survival analysis, Aged, Retrospective Studies, 030304 developmental biology, business.industry, Cancers and Neoplasms, Biology and Life Sciences, Estrogens, Retrospective cohort study, Breast cancer subtype, medicine.disease, Survival Analysis, Hormones, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 030104 developmental biology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Clinical Medicine, Neoplasm Recurrence, Local, business
Abstract: IntroductionThe Residual Cancer Burden (RCB) quantifies residual disease after neoadjuvant chemotherapy (NAC). Its predictive value has not been validated on large cohorts with long-term follow up. The objective of this work is to independently evaluate the prognostic value of the RCB index depending on BC subtypes (Luminal, HER2-positive and triple negative (TNBCs)).MethodsWe retrospectively evaluated the RCB index on surgical specimens from a cohort of T1-T3NxM0 BC patients treated with NAC between 2002 and 2012. We analyzed the association between RCB index and relapse-free survival (RFS), overall survival (OS) among the global population, after stratification by BC subtypes.Results717 patients were included (luminal BC (n = 222, 31%), TNBC (n = 319, 44.5%), HER2-positive (n = 176, 24.5%)). After a median follow-up of 99.9 months, RCB index was significantly associated with RFS. The RCB-0 patients displayed similar prognosis when compared to the RCB-I group, while patients from the RCB-II and RCB-III classes were at increased risk of relapse (RCB-II versus RCB-0: HR=3.25 CI [2.1-5.1] pversus RCB-0: HR=5.6 CI [3.5-8.9] pHER2-positive cancers; but not for luminal cancers (Pinteraction = 0.07). The prognosis of RCB-III patients was poor (8-years RFS: 52.7%, 95% CI [44.8 – 62.0]) particularly in the TNBC subgroup, where the median RFS was 12.7 months.ConclusionRCB index is a reliable prognostic score. RCB accurately identifies patients at a high risk of recurrence (RCB-III) with TNBC or HER2-positive BC who must be offered second-line adjuvant therapies.
Published: 2020

12. A retrospective study on the management of patients with rituximab refractory follicular lymphoma

Author: Pierre Leconte, Aurélie Bardet, Xavier Troussard, Philippe Solal-Celigny, Juana Hernandez, Normandie, Université, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Roche France, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Clinical Decision-Making, Follicular lymphoma, Comorbidity, 03 medical and health sciences, 0302 clinical medicine, International Prognostic Index, Antineoplastic Agents, Immunological, rituximab, follicular lymphoma, immune system diseases, Internal medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Lymphoma, Follicular, Aged, Neoplasm Staging, Retrospective Studies, Aged, 80 and over, relapse, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Retrospective cohort study, Hematology, Middle Aged, medicine.disease, Combined Modality Therapy, 3. Good health, Transplantation, Regimen, 030104 developmental biology, disease management, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Retreatment, Rituximab, Female, France, Refractory Follicular Lymphoma, business, Idelalisib, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract: Given that there are currently no clear recommendations regarding therapeutic options for rituximab refractory/relapsed follicular lymphoma patients, this study aimed to describe the real-life management of patients with refractory follicular lymphoma after systemic rituximab-containing regimens (rFL), and rFL patient characteristics. In this retrospective, national, multicentre study, descriptive analyses were mainly performed according to rituximab-containing regimen at rFL diagnosis [rituximab monotherapy (R-MONO), rituximab + chemotherapy (R-COMBO), and ongoing rituximab maintenance (R-MAINTAIN)]. The 459 analysed patients experienced rituximab-refractoriness between October 2013 and September 2015: R-MONO: 58 (13%), R-COMBO: 197 (43%), R-MAINTAIN: 204 (44%). Post-refractoriness strategies were heterogeneous: idelalisib ± rituximab (22%), without anti-lymphoma treatment (21%), rituximab-chemotherapy (21%) and stem cell transplantation (18%). Rituximab was continued in combination in 41% of cases. Chosen strategies varied according to patient age (without anti-lymphoma treatment: 28% of patients if ≥65 years vs. 12% if
Published: 2018

13. Causal Attribution of Breast Cancer by Survivors in French West Indies

Author: Philippe Kadhel, Eustase Janky, Ali Ghassani, Caroline Schuster, Nathalie Grossat, CHU Pointe-à-Pitre/Abymes [Guadeloupe], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), Hôpital Albert Clarac [CHU de la Martinique], CHU de la Martinique [Fort de France], Roche France(R), and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 )
Subjects: medicine.medical_specialty, West Indies, Pharmacology toxicology, Breast Neoplasms, Health information sources, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, Surveys and Questionnaires, Psychological support, medicine, Humans, 030212 general & internal medicine, Survivors, West indies, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Cancer risk factors, Causal attribution, business.industry, Public Health, Environmental and Occupational Health, Life events, Cancer, Middle Aged, medicine.disease, Causality, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Family medicine, Female, France, business, Attribution, Social psychology
Abstract: International audience; Patients frequently ask about the cause of their breast cancer. To answer, physicians refer to breast cancer risk factors based on medical reports. We aim to assess these risk factors for the point of view of survivors, a point of view which seems to differ from that of medical references. We ran a survey with open- and closed-ended questionnaires on patients' opinions about risks factors both for women in general and for their own case. We also collected data on their sources of information on this subject. Most patients had no opinion. The most frequently cited risk factors were stress, then genetic causes, and poor diet. Internet was the leading source of information for patients, followed by physicians and magazines. Our study highlights the mismatch between breast cancer risk factors as perceived by scientists and by survivors. Survivors tend to focus on non-controllable risk factors. Taking into account attribution theories of life events, an awareness of patient opinion may be valuable for psychological support of survivors, and it may be informative to record the way in which patients attribute causality for life events such as breast cancer and, more generally, all type of cancer.
Published: 2018

14. DICER1andFOXL2mutations in ovarian sex cord-stromal tumours: a GINECO Group study

Author: Mojgan Devouassoux-Shisheboran, Isabelle Ray-Coquard, Germain Gillet, Véronique Haddad, Ruth Rimokh, Denis Maillet, Isabelle Treilleux, Eric Pujade-Laurraine, Thibault Goulvent, Stéphane Borel, Ariel Savina, Marie-Cécile Vacher-Lavenu, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche et Médecine Translationnelle [Boulogne-Billancourt] (IRRMT), Roche France, Service d'Anatomo-Pathologie [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], and Institut Roche
Subjects: Forkhead Box Protein L2, Ribonuclease III, Adult, 0301 basic medicine, Oncology, medicine.medical_specialty, Pathology, Histology, Gonadal cord, Adolescent, Patients, diagnosis, Stromal tumours, Granulosa cell, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Ovary, Biology, Medical Oncology, medicine.disease_cause, methods, Pathology and Forensic Medicine, DEAD-box RNA Helicases, Sertoli-Leydig Cell Tumor, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Sex Cord-Gonadal Stromal Tumors, Aged, Granulosa Cell Tumor, Ovarian Neoplasms, Mutation, Paraffin Embedding, Group study, General Medicine, Middle Aged, Prognosis, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cohort, Female, pathology, France
Abstract: International audience; AIMS: FOXL2 mutation has been consistently identified in adult granulosa cell tumours (A-GCTs). DICER1 mutations have been described predominantly in Sertoli-Leydig cell tumours (SLCTs). The prognostic implication of these mutations remains uncertain, as moderately sized studies have yielded variable outcomes. Our aim was to determine the implications of DICER1 and FOXL2 mutations in 156 ovarian sex cord-stromal tumours (SCSTs). METHODS AND RESULTS: FOXL2 mutations were found in 94% of pathologically confirmed A-GCTs (95/101), in one of eight juvenile granulosa cell tumours (J-GCTs), and in two of 19 SLCTs. DICER1 mutations in the RNase IIIb domain were found in six of 19 SLCTs, two of eight J-GCTs, and one of 12 undifferentiated SCSTs (Und-SCSTs). Comparison of DICER1-mutated SLCTs with DICER1-non-mutated SLCTs showed that patient age at diagnosis was lower and oestrogen receptor expression was more frequent in DICER1-mutated tumours. With a median follow-up of 22 months, two of five DICER1-mutated SLCTs relapsed, in contrast to none of eight DICER1-non-mutated tumours. CONCLUSIONS: Our results suggest that, in contrast to FOXL2 mutations in A-GCT, DICER1 mutations in SLCT might be more useful for prognosis than for diagnosis. However, study of a larger cohort of patients is necessary to establish this. Identification of genetic alterations in SCST offers promising therapeutic options
Published: 2015

15. Effects of alcohol withdrawal on monocyte subset defects in chronic alcohol users

Author: Jean-François Eliaou, Florence Apparailly, Pierre Portales, Pascal Perney, Martine Bouthier, Hélène Donnadieu-Rigole, Isabelle Duroux-Richard, Thibault Mura, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital de la Colombière, CHU Montpellier, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), and This work was funded by Institut National de la Santé et Recherche Médicale (INSERM U1183), the University of Montpellier, and Roche France. The authors thank Pr. Pierre Corbeau for editing the manuscript before publication.
Subjects: Adult, Lipopolysaccharides, Male, CD14, [SDV]Life Sciences [q-bio], Immunology, Lipopolysaccharide Receptors, Stimulation, Peptidoglycan, Biology, CD16, GPI-Linked Proteins, Monocytes, Immunophenotyping, 03 medical and health sciences, 0302 clinical medicine, Immune system, TLR, mental disorders, medicine, Humans, Immunology and Allergy, immune function, Ethanol, Tumor Necrosis Factor-alpha, Interleukins, Monocyte, Receptors, IgG, Cell Biology, Middle Aged, Toll-Like Receptor 2, cytokines, Substance Withdrawal Syndrome, Toll-Like Receptor 4, Alcoholism, TLR2, medicine.anatomical_structure, TLR4, Female, 030211 gastroenterology & hepatology, Tumor necrosis factor alpha, 030217 neurology & neurosurgery
Abstract: Excessive alcohol consumption has a modulating effect on immune functions that may contribute to decreased immunity and host defense. It is associated with increased intestinal permeability to endotoxins that is normalized after 14 d of abstinence. Whether and how blood monocyte subsets are impaired in patients with an AUD and what their evolution is after alcohol withdrawal are the paper’s objectives. With the use of flow cytometry, blood monocyte subsets were quantified in AUDs before (n = 40) and 2 wk after (n = 33) alcohol withdrawal and compared with HC donors (n = 20). Expression of TLR2 and TLR4 on monocyte subsets was also quantified. Cytokine response of monocytes was monitored following PGN and LPS stimulation. The CD14+CD16− subset was decreased, whereas the CD14dimCD16+ subset was expanded (P < 0.001) in AUD compared with HC. The frequencies of TLR2- and TLR4-expressing monocytes were reduced in AUD compared with HC. Although the basal production of IL-1, IL-6, and TNF by monocytes in AUD was compared with HC, the PGN- and LPS-mediated IL-6 and TNF production was increased in AUD. Frequencies of IL-6-expressing monocytes were higher in AUD than HC. Alcohol withdrawal partially restored the distribution of monocyte subsets and the frequency of IL-6-producing monocytes and increased the frequency of TNF-producing cells in response to LPS and PGN stimulation to levels compared with those in HC. Our findings indicate that chronic alcohol use alters the distribution as well as the phenotypic and functional characteristics of blood monocyte subsets, which are partially restored following 2 wk of alcohol withdrawal.
Published: 2016

16. Efficacy and Safety of Two Neoadjuvant Strategies With Bevacizumab in MRI-Defined Locally Advanced T3 Resectable Rectal Cancer: Final Results of a Randomized, Noncomparative Phase 2 INOVA Study

Author: Emmanuel Rio, Christophe Borg, François Ghiringhelli, Mathieu Coudert, Meher Ben Abdelghani, Yves François, Françoise Mornex, Alexandre Tanang, Thierry Conroy, Bernard Roullet, Frank Boudghène, Laurent Quero, Véronique Vendrely, Dominique Spaeth, Antoine Adenis, Thierry André, Miruna Ionescu-Goga, D. Azria, Zaher Lakkis, Jean-Baptiste Bachet, Jacques Balosso, Georges Mantion, Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service de Médecine Nucléaire, Centre Georges-François Leclerc [Dijon] (CGFL), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Institut du Cancer de Montpellier (ICM), Centre Paul Strauss, CRLCC Paul Strauss, Service d'oncologie médicale [ICL Alexis Vautrin], Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Oncologie médicale [Polyclinique de Gentilly, Nancy], Polyclinique de Gentilly, Roche France, Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Bevacizumab, Colorectal cancer, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Leucovorin, Adenocarcinoma, Anastomosis, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Adverse effect, Capecitabine, Aged, Rectal Neoplasms, business.industry, Gastroenterology, Chemoradiotherapy, Adjuvant, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Total mesorectal excision, Neoadjuvant Therapy, Confidence interval, 3. Good health, Surgery, Oxaliplatin, Survival Rate, Radiation therapy, Clinical trial, Oncology, Lymphatic Metastasis, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, Fluorouracil, Neoplasm Recurrence, Local, business, Follow-Up Studies, medicine.drug
Abstract: Background Recurrence and distant metastases remain a significant issue in locally advanced rectal cancer (LARC). Several multimodal strategies are assessed in clinical trials. Patients and Methods Patients with mid/low magnetic resonance imaging–defined high-risk LARC were randomized to arm A (12-week bevacizumab + FOLFOX-4 then bevacizumab–5-fluorouracil [5-FU]–radiotherapy [RT] before total mesorectal excision [TME]) or arm B (bevacizumab-5-FU–RT then TME). Long-term efficacy and safety up to 5 years’ follow-up are reported. No comparison between arms was planned. Results Overall, 91 patients (46 in arm A and 45 in arm B) were included. Main results have been presented previously. During the late follow-up period (> 4 weeks after surgery), 4 patients (8.7%) in arm A and 4 (8.9%) in arm B experienced grade 3/4 adverse events related to bevacizumab; the most frequent were 2 anastomotic fistulas (both in arm A) and abscesses (1 in arm A and 2 in arm B). At 5 years’ follow-up, 9 (19.6%) and 11 (24.4%) patients in arms A and B developed a fistula in the year after surgery, and 2 (4.3%) in arm A at > 1 year after surgery. Most resolved before study end. Five-year disease-free survival was 70% and 64.3% in arms A and B, respectively. Five-year overall survival was 90.5% (95% confidence interval, 76.7, 96.3) in arm A and 72.7% (95% confidence interval, 56.0, 83.9) in arm B. Conclusion Neoadjuvant bevacizumab + FOLFOX-4 may have the potential to increase survival outcomes when followed by bevacizumab–5-FU–RT and TME in LARC. Bevacizumab–5-FU–RT then TME was associated with a higher-than-projected rate of anastomotic fistulas. Further research of neoadjuvant strategies in LARC is encouraged.
Published: 2019

17. Serum IL-33, a new marker predicting response to rituximab in rheumatoid arthritis

Author: Martin Soubrier, Houria Hendel Chavez, Elodie Rivière, Barbara Tolusso, Bineta Ly, Maxime Dougados, Alice Courties, Paul-Olivier Rouzaire, Edward M Vital, Gianfranco Ferraciolli, Yassine Taoufik, Xavier Mariette, Jérémie Sellam, Paul Emery, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de rhumatologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Clermont-Ferrand, Rheumatology Department, Catholic University of the Sacred Heart, University of Leeds, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Rhumatologie [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, This work was supported by Roche France, who sponsored the study but were not involved in the interpretation of the data or in the preparation of the manuscript., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Service de rhumatologie, inflammation-immunopathologie- biothérapie [CHU Saint-Antoine] (DHU i2B ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de rhumatologie, inflammation-immunopathologie- biothérapie [CHU Saint-Antoine] ( DHU i2B ), CHU Saint-Antoine [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP), Immunologie des Maladies Virales et Autoimmunes ( IMVA - U1184 ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Saint-Antoine [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: 0301 basic medicine, medicine.medical_specialty, Population, [ SDV.IMM.IMM ] Life Sciences [q-bio]/Immunology/Immunotherapy, Gastroenterology, [ SDV.MHEP.RSOA ] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Rheumatoid factor, education, 030203 arthritis & rheumatology, education.field_of_study, business.industry, Odds ratio, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Rheumatology, 3. Good health, 030104 developmental biology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Rheumatoid arthritis, Immunology, Cohort, Rituximab, business, Rheumatism, medicine.drug
Abstract: International audience; Background: Recent works have suggested a possible link between interleukin (IL)-33 and B-cell biology. We aimed to study the possible association between serum IL-33 detection and response to rituximab (RTX) in rheumatoid arthritis (RA) patients in different cohorts with an accurate enzyme-linked immunosorbent assay (ELISA).Methods: Serum IL-33, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), and high serum immunoglobulin (Ig)G levels were assessed in 111 RA patients receiving a first course of 2 g RTX (cohort 1) in an observational study and in 74 RA patients treated with the same schedule in routine care (cohort 2). Univariate and multivariate analyses identified factors associated with a European League Against Rheumatism (EULAR) response at 24 weeks.Results: At week 24, 84/111 (76%) and 54/74 (73%) patients reached EULAR response in cohorts 1 and 2, respectively. Serum IL-33 was detectable in only 33.5% of the patients. In the combined cohorts, the presence of RF or anti-CCP (odds ratio (OR) 3.27, 95% confidence interval (CI) 1.13–9.46; p = 0.03), high serum IgG (OR 2.32, 95% CI 1.01–5.33; p = 0.048), and detectable serum IL-33 (OR 2.40, 95% CI 1.01–5.72; p = 0.047) were all associated with RTX response in multivariate analysis. The combination of these three factors increased the likelihood of response to RTX. When serum IL-33 detection was added to seropositivity and serum IgG level, 100% of the patients with the three risk factors (corresponding to 9% of the population) responded to RTX (OR versus patients with none of the three risk factors 29.61, 95% CI 1.30–674.79; p = 0.034).Conclusion: Detectable serum IL-33 may predict clinical response to RTX independently of, and synergistically with, auto-antibodies and serum IgG level.
Published: 2016

18. HER3 as biomarker and therapeutic target in pancreatic cancer: new insights in pertuzumab therapy in preclinical models

Author: Thomas, Gaëlle, Chardès, Thierry, Gaborit, Nadège, Mollevi, Caroline, Leconet, Wilhem, Robert, Bruno, Kharrat, Abdelhakim, Radosevic-Robin, Nina, Penault-Llorca, Frédérique, Gongora, Céline, Colombo, Pierre-Emmanuel, Lazrek, Yassamine, Bras-Goncalves, Rui, Savina, Ariel, Azria, David, Bazin, Hervé, Pèlegrin, André, Larbouret, Christel, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Institut de Recherche et Médecine Translationnelle [Boulogne-Billancourt] (IRRMT), Roche France, Unité de biostatistiques, CRLCC Val d'Aurelle - Paul Lamarque, Centre Jean Perrin, CRLCC Jean Perrin, Equipe de recherche sur les traitements individualisés des cancers (ERTICa), Université d'Auvergne - Clermont-Ferrand I (UdA), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunociblage des Tumeurs et Ingenierie des Anticorps, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cis Bio International, This work was supported by the program 'Investissement d’avenir' grant agreement: Labex MabImprove, ANR-10-LABX-53-01 and INCa-DGOS-Inserm 6045., We thank G. Heintz, S. Bousquié, V. Garambois, I. Aït-Arsa and A. Ho-pun-cheung for excellent technical assistance. Flow cytometry analysis was performed thanks to N. Vié using equipment at the Montpellier IRO imaging facility. We thank F. Bibeau for providing pancreatic tumor samples, and A. Cayre and F. Boissière for pathology technical assistance., Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Roche de Recherche et Médecine Translationnelle (IRRMT), Millegen SA, MILEGEN-Immeuble BIOSTEP, ROCHE SAS, Roche SAS, Cisbio, Research Department, CIS BIOINTERNATIONAL, This work was supported by the program 'Investissement d’avenir' grant agreement: Labex MabImprove, ANR-10-LABX-53-01 and INCa- DGOS-Inserm 6045., CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Radosevic-Robin, Nina
Subjects: MESH: Signal Transduction, Receptor, ErbB-3, MESH: Random Allocation, pancreatic cancer, MESH: Receptor, ErbB-3/metabolism, medicine.disease_cause, Mice, Random Allocation, MESH: Pancreatic Neoplasms/enzymology, MESH: Cell Proliferation/drug effects, MESH: Animals, skin and connective tissue diseases, 3. Good health, MESH: Antibodies, Monoclonal, Humanized/pharmacology, MESH: Pancreatic Neoplasms/drug therapy, Oncology, Monoclonal, Biomarker (medicine), Female, Pertuzumab, MESH: Biomarkers, Tumor, MESH: Receptor, ErbB-3/antagonists & inhibitors, Research Paper, Signal Transduction, medicine.drug, MESH: Xenograft Model Antitumor Assays, medicine.drug_class, Mice, Nude, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Antibodies, Monoclonal, Humanized, Monoclonal antibody, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Antineoplastic Agents/pharmacology, pertuzumab, HER3, Pancreatic cancer, HER2, Biomarkers, Tumor, medicine, MESH: Mice, Nude, Animals, Humans, MESH: Mice, Cell Proliferation, MESH: Humans, Cancer, medicine.disease, Xenograft Model Antitumor Assays, Pancreatic Neoplasms, body regions, Tumor progression, Cancer research, Carcinogenesis, MESH: Female, MESH: Pancreatic Neoplasms/pathology
Abstract: // Gaelle Thomas 1,2 , Thierry Chardes 1 , Nadege Gaborit 1 , Caroline Mollevi 5 , Wilhem Leconet 1 , Bruno Robert 1 , Nina Radosevic-Robin 3 , Frederique Penault-Llorca 3 , Celine Gongora 1 , Pierre-Emmanuel Colombo 1 , Yassamine Lazrek 1,4 , Rui Bras-Goncalves 1 , Ariel Savina 6 , David Azria 1 , Herve Bazin 7 , Andre Pelegrin 1 and Christel Larbouret 1 1 IRCM, Institut de Recherche en Cancerologie de Montpellier, Montpellier, F-34298, France; INSERM, Unit 896, Montpellier, F-34298, France; Universite Montpellier1, Montpellier, F-34298, France; ICM, Montpellier, France 2 Institut Roche de Recherche et Medecine Translationnelle, Boulogne Bilancourt, France 3 Department of Biopathology, The Jean Perrin Comprehensive Cancer Center and ERTICa Research Group, University of Auvergne EA4677, Clermont-Ferrand, France 4 Millegen SA, F-31681, Labege, France 5 Unite de Biostatistiques, ICM Val d’Aurelle, Montpellier, France 6 Roche SAS Scientific Partnerships, Boulogne Billancourt, France 7 CisBio Bioassays, Le Codolet, France Correspondence: Christel Larbouret, email: // Keywords : HER3; HER2; pertuzumab; pancreatic cancer Received : June 30, 2014 Accepted : July 16, 2014 Published : July 17, 2014 Abstract The anti-HER2 antibody pertuzumab inhibits HER2 dimerization and affects HER2/HER3 dimer formation and signaling. As HER3 and its ligand neuregulin are implicated in pancreatic tumorigenesis, we investigated whether HER3 expression could be a predictive biomarker of pertuzumab efficacy in HER2 low -expressing pancreatic cancer. We correlated in vitro and in vivo HER3 expression and neuregulin dependency with the inhibitory effect of pertuzumab on cell viability and tumor progression. HER3 knockdown in BxPC-3 cells led to resistance to pertuzumab therapy. Pertuzumab treatment of HER3-expressing pancreatic cancer cells increased HER3 at the cell membrane, whereas the anti-HER3 monoclonal antibody 9F7-F11 down-regulated it. Both antibodies blocked HER3 and AKT phosphorylation and inhibited HER2/HER3 heterodimerization but affected differently HER2 and HER3 homodimers. The pertuzumab/9F7-F11 combination enhanced tumor inhibition and the median survival time in mice xenografted with HER3-expressing pancreatic cancer cells. Finally, HER2 and HER3 were co-expressed in 11% and HER3 alone in 27% of the 45 pancreatic ductal adenocarcinomas analyzed by immunohistochemistry. HER3 is essential for pertuzumab efficacy in HER2 low -expressing pancreatic cancer and HER3 expression might be a predictive biomarker of pertuzumab efficacy in such cancers. Further studies in clinical samples are required to confirm these findings and the interest of combining anti-HER2 and anti-HER3 therapeutic antibodies.
Published: 2014

19. Cell growth in aggregates determines gene expression, proliferation, survival, chemoresistance, and sensitivity to immune effectors in follicular lymphoma

Author: Amandine Blanc, Ariel Savina, Christine Bezombes-Cagnac, Julien Familiades, Jean-Jacques Fournié, Pauline Gravelle, Christine Jean, Emilie Decaup, Guy Laurent, Camille Laurent, Jean Jacques Fournié, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche et Médecine Translationnelle [Boulogne-Billancourt] (IRRMT), Roche France, Jean-Jacques Fournié, Laboratoire d'Anatomopathologie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Laboratoire d'Hématologie [Purpan], Gravelle, Pauline, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse]
Subjects: MESH: Cell Line, Tumor, MESH: Immunophenotyping, Cell Survival, Follicular Lymphoma, Blotting, Western, Follicular lymphoma, Cell Culture Techniques, MESH: Flow Cytometry, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Pathology and Forensic Medicine, Immunophenotyping, MESH: Lymphoma, Follicular, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Transduction, Genetic, Cell Line, Tumor, MESH: Cell Proliferation, medicine, Humans, MESH: Blotting, Western, Lymphoma, Follicular, Cell Proliferation, MESH: Cell Culture Techniques, MESH: Humans, Cell growth, hypoxia, MESH: Transcriptome, chemoresistance, MESH: Immunohistochemistry, Cell cycle, medicine.disease, Flow Cytometry, MESH: Transduction, Genetic, Immunohistochemistry, BCL10, MESH: Drug Resistance, Neoplasm, Lymphoma, Cell biology, MESH: Cell Survival, Cell culture, Drug Resistance, Neoplasm, gene expression, MESH: Tumor Escape, Tumor Escape, Transcriptome, 3D
Abstract: International audience; Lymphomas grow as dense aggregates in patients, but whether this spatial organization affects lymphoma cell biology is unknown. We grew follicular lymphoma (FL) cells in vitro as multicellular aggregates of lymphoma cells to investigate this question. Gene expression analysis revealed that 612 genes were differentially expressed when cells grew in multicellular aggregates of lymphoma cells rather than in suspension. These genes correspond to several GO biological processes, such as hypoxia, activation of NF-κB pathway, and negative regulation of cell cycle, a gene signature also found in the transcriptomes from FL biopsies. Pimonidazole staining, HIF-1A accumulation, and VEGFA release confirmed that cells in multicellular aggregates of lymphoma cells actually respond to hypoxia. In adaptation to such conditions, they also displayed an activated NF-κB pathway and a quiescent status far more frequently than in suspension. When cultured in three dimensions, FL cells display resistance to doxorubicin and bendamustine, two drugs largely used in FL therapy, compared to FL cultured in suspension. Finally, multicellular aggregates of lymphoma cells were also found to be less sensitive to purified natural killer cells. To conclude, our study shows that in FL, spatial organization results in dramatic changes in FL biology, including gene expression, proliferation, drug resistance, and immune escape.
Published: 2014

20. Improvement of the quality of BRAF testing in melanomas with nationwide external quality assessment, for the BRAF EQA group

Author: KARINE DURAND, Jean-Christophe Pages, Paul Hofman, Stephanie Trudel, Marc Denis, Jean-Luc Prétet, Michel Peoc'h, Francoise Galateau salle, Karen Leroy, Florence De Fraipont, Frédéric Charlotte, Pierre Laurent-Puig, Pierre-Jean Lamy, Service d'anatomie pathologique [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Roche, Institut national du cancer [Boulogne] (INCA), CHU Rouen, Normandie Université (NU), Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Pathologie Clinique et Expérimentale, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Hôpital pasteur [Colmar]-Centre Hospitalier Universitaire de Nice (CHU Nice), Roche France, BRAF EQA group, BMC, Ed., Université Nice Sophia Antipolis (1965 - 2019) (UNS), Service d'anatomie pathologique, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Institut national du cancer [Boulogne] ( INCA ), Bases moléculaires de la réponse aux xénobiotiques ( U775 (IFR95) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Nice Sophia Antipolis ( UNS ), and Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Hôpital pasteur [Colmar]-CHU Nice
Subjects: Proto-Oncogene Proteins B-raf, Quality Control, Oncology, medicine.medical_specialty, Cancer Research, media_common.quotation_subject, DNA Mutational Analysis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gene mutation, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Surgical oncology, Internal medicine, External quality assessment, medicine, Genetics, Humans, Quality (business), Genetic Testing, Codon, Vemurafenib, Melanoma, neoplasms, 030304 developmental biology, Genetic testing, media_common, 0303 health sciences, medicine.diagnostic_test, business.industry, Cancer, medicine.disease, 3. Good health, Surgery, 030220 oncology & carcinogenesis, Mutation, France, business, Research Article, medicine.drug
Abstract: International audience; BACKGROUND: Knowledge about tumour gene mutation status is essential for the treatment of increasing numbers of cancer patients, and testing quality has a major impact on treatment response and cost. In 2012, 4,629 tests for BRAF p.V600 were performed in France, in patients with melanomas. METHODS: Two batches of unstained melanoma sections were sent, in May and November 2012, to the 46 laboratories supported by the French National Institute of Cancer (INCa). An external quality assessment (EQA) evaluated mutation status, response times and compliance with INCa recommendations. RESULTS: All the French laboratories involved in testing participated in the EQA. Fourteen different methods were used to detect BRAF mutations, most consisting of combinations of in-house techniques. False responses were noted in 25/520 cases (4.8%), 11 of which concerned confusion between p.V600E and p.V600K. Thus, 2.7% of responses would have led to inappropriate treatment. Within six months, mean response times decreased from 22 to 12 days (P
Published: 2013

21. Genotype 1 hepatitis C virus envelope features that determine antiviral response assessed through optimal covariance networks

Author: Françoise Stoll-Keller, Michel Doffoel, Isabel Fofana, Evelyne Schvoerer, Thomas F. Baumert, Aurélie Velay, François Habersetzer, Jean-Pierre Gut, Mirjam B. Zeisel, Rémy Moenne-Loccoz, John M. Murray, SCHVOERER, Evelyne, School of Mathematics and Statistics, University of New South Wales [Sydney] (UNSW), The Kirby Institute for Infection and Immunity in Society (UNSW), Pôle Hépato-digestif [Strasbourg] (HUS - Nouvel Hôpital Civil), Les Hôpitaux Universitaires de Strasbourg (HUS), Stress, Immunité, Pathogènes (SIMPA), Université de Lorraine (UL), Service de Virologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg (UNISTRA), Laboratoire de Virologie [Strasbourg], and This work was supported by the European Union (ERC-2008-AdG-233130-HEPCENT, INTERREG-IV-Rhin Supe´rieur-FEDER-Hepato-Regio-Net 2009), the chair of excellence program of the Agence Nationale de la Recherche France (ANR-05-CEXC-008), ANRS (2011/132, 2011/154, 2012/239&319, 2012/318), DGOS Inserm A12027MS, the University of Strasbourg and Laboratoire d’excellence LabEx HEPSYS (ANR-10-LAB-28). E. Schvoerer thanks the Fondation Transplantation (France), Region Alsace (France), Region Lorraine (France), Abbott Molecular (France) and Roche (France) for unrestricted financial support.
Subjects: Gastroenterology and hepatology, Hepacivirus, lcsh:Medicine, medicine.disease_cause, Hepatitis, 0302 clinical medicine, Viral Envelope Proteins, Genotype, lcsh:Science, Mathematical Computing, Phylogeny, Genetics, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, Mutation, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Systems Biology, Applied Mathematics, Viral Envelope Gene, virus diseases, Hepatitis C, 3. Good health, Infectious hepatitis, Treatment Outcome, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Medicine, Infectious diseases, 030211 gastroenterology & hepatology, Research Article, Hepatitis C virus, Alpha interferon, Viral diseases, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Antiviral Agents, Models, Biological, 03 medical and health sciences, Viral entry, Ribavirin, medicine, Humans, Biology, Liver diseases, 030304 developmental biology, Models, Statistical, lcsh:R, Interferon-alpha, Computational Biology, biology.organism_classification, Virology, Hypervariable region, Multivariate Analysis, lcsh:Q, Mathematics, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; The poor response to the combined antiviral therapy of pegylated alfa-interferon and ribavarin for hepatitis C virus (HCV) infection may be linked to mutations in the viral envelope gene E1E2 (env), which can result in escape from the immune response and higher efficacy of viral entry. Mutations that result in failure of therapy most likely require compensatory mutations to achieve sufficient change in envelope structure and function. Compensatory mutations were investigated by determining positions in the E1E2 gene where amino acids (aa) covaried across groups of individuals. We assessed networks of covarying positions in E1E2 sequences that differentiated sustained virological response (SVR) from non-response (NR) in 43 genotype 1a (17 SVR), and 49 genotype 1b (25 SVR) chronically HCV-infected individuals. Binary integer programming over covariance networks was used to extract aa combinations that differed between response groups. Genotype 1a E1E2 sequences exhibited higher degrees of covariance and clustered into 3 main groups while 1b sequences exhibited no clustering. Between 5 and 9 aa pairs were required to separate SVR from NR in each genotype. aa in hypervariable region 1 were 6 times more likely than chance to occur in the optimal networks. The pair 531-626 (EI) appeared frequently in the optimal networks and was present in 6 of 9 NR in one of the 1a clusters. The most frequent pairs representing SVR were 431-481 (EE), 500-522 (QA) in 1a, and 407-434 (AQ) in 1b. Optimal networks based on covarying aa pairs in HCV envelope can indicate features that are associated with failure or success to antiviral therapy.
Published: 2013

22. Bevacizumab combined with chemotherapy in the second-line treatment of metastatic colorectal cancer: results from the phase II BEVACOLOR study

Author: Jaafar Bennouna, Roger Faroux, Eric Francois, Véronique Trillet-Lenoir, François Goldwasser, Hélène Senellart, F. Husseini, Sandrine Kraemer, Christophe Borg, Jean-Yves Douillard, Marc Ychou, Olivier Bouché, Jean-Pierre Delord, Centre René Gauducheau, CRLCC René Gauducheau, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Institut Claudius Regaud, Hôpital pasteur [Colmar], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Départemental La Roche sur Yon, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CHU de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Roche France, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (HOTE GREFFON), Université de Franche-Comté (UFC) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté]), CRLCC Institut Claudius Regaud, Hospices Civils de Lyon / Centre hospitalier Lyon Sud (HCL), Hospices Civils de Lyon, Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, CHU Cochin [APHP], Hôpital Robert Debré - CHU Reims, Roche, Saas, Philippe, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)
Subjects: Oncology, Male, Organoplatinum Compounds, MESH: Lymphatic Metastasis, Leucovorin, Deoxycytidine, 0302 clinical medicine, MESH: Aged, 80 and over, FOLFOX, MESH: Liver Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Prospective Studies, MESH: Treatment Outcome, Aged, 80 and over, MESH: Aged, MESH: Middle Aged, Liver Neoplasms, MESH: Organoplatinum Compounds, Gastroenterology, MESH: Follow-Up Studies, MESH: Neoplasm Staging, Middle Aged, 3. Good health, MESH: Salvage Therapy, Bevacizumab, Oxaliplatin, Survival Rate, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, 030220 oncology & carcinogenesis, Lymphatic Metastasis, FOLFIRI, MESH: Camptothecin, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030211 gastroenterology & hepatology, Female, Fluorouracil, Colorectal Neoplasms, medicine.drug, Adult, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Survival Rate, Antibodies, Monoclonal, Humanized, Irinotecan, 03 medical and health sciences, Folinic acid, Internal medicine, medicine, Humans, Survival rate, Capecitabine, Aged, Neoplasm Staging, Salvage Therapy, XELIRI, MESH: Humans, business.industry, MESH: Deoxycytidine, MESH: Adult, digestive system diseases, MESH: Male, MESH: Prospective Studies, MESH: Antibodies, Monoclonal, Humanized, Camptothecin, business, MESH: Leucovorin, MESH: Female, MESH: Fluorouracil, MESH: Colorectal Neoplasms, Follow-Up Studies
Abstract: International audience; BACKGROUND: This prospective phase II study assessed the efficacy and safety of bevacizumab plus chemotherapy regimens commonly used in the second-line treatment of metastatic colorectal cancer (mCRC). METHODS: Patients with mCRC who progressed or relapsed after first-line oxaliplatin-based or irinotecan-based treatment received bevacizumab 2.5 mg/kg/week plus chemotherapy until disease progression. The primary endpoint was disease-control rate (DCR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety. RESULTS: Fifty-three patients (66% men; median age, 62 years old) received second-line bevacizumab plus folinic acid, fluorouracil, and irinotecan (FOLFIRI; 57%), folinic acid, fluorouracil, oxaliplatin (FOLFOX; 26%), irinotecan (15%), or capecitabine plus irinotecan (XELIRI; 2%). The DCR was 87% (95% CI, 77%-97%); ORR was 32% (95% CI, 19%-46%). Median PFS was 6.5 months (95% CI, 5.8-7.8 months) and median OS 19.3 months, (95% CI, 14.2-25.1 months).The most frequent grade 3/4 adverse events included neutropenia (21%), diarrhea (15%), asthenia, and vomiting (9% each). Five patients (9%) had grade 3/4 targeted toxicities: grade 3 hypertension (n = 2), grade 3 venous thromboembolism (n = 2), and grade 4 arterial thromboembolism (n = 1). None of these events led to death during the study. CONCLUSION: Bevacizumab plus standard second-line chemotherapy is highly active in patients with mCRC and has an acceptable safety profile.
Published: 2012

23. High-Dose Pegylated Interferon-α and Ribavirin in Nonresponder Hepatitis C Patients and Relationship With IL-28B Genotype (SYREN Trial)

Author: Chevaliez, Stéphane, Hézode, Christophe, Soulier, Alexandre, Costes, Bruno, Bouvier-Alias, Magali, Rouanet, Stéphanie, Foucher, Juliette, Bronowicki, Jean-Pierre, Tran, Albert, Rosa, Isabelle, Mathurin, Philippe, Alric, Laurent, Leroy, Vincent, Couzigou, Patrice, Mallat, Ariane, Charaf-Eddine, Mariem, Babany, Gérard, Pawlotsky, Jean-Michel, Centre National de Référence Virus des hépatites B, C et Delta, Institut National de la Transfusion Sanguine [Paris] (INTS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Service d'hépato-gastro-entérologie [APHP Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Biochimie [Mondor], Produits Roche, Roche, Département d'hépatologie et de gastroentérologie, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Pôle Digestif, Hôpital Archet 2 [Nice] (CHU), Service d'hépato-gastro-entérologie, CHI Créteil, Service d'Hépato-gastroentérologie, Hôpital Huriez-Université de Lille, Service de médecine interne et maladies digestives, CHU Toulouse [Toulouse], Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, This study is investigator-initiated. It has been funded by Roche France, which provided the study drugs, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service Médecine Interne et immunologie clinique [CHU Toulouse], Pôle Maladies de l'appareil digestif [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Hepatitis C virus, nonresponder, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, IL28B genotype, high-dose pegylated IFN-α
Abstract: International audience; BACKGROUND & AIMS: In patients with chronic hepatitis C who failed to respond to standard therapy, high-dose pegylated interferon (IFN)-α and/or ribavirin could induce a stronger antiviral response and prevent treatment failure and HCV resistance when combined with direct-acting antivirals. The influence of genetic determinants in this context remains unknown. METHODS: Eighty-three patients infected with HCV genotype 1 who were nonresponsive to standard therapy received pegylated IFN-α2a (360 μg once per week or 180 μg twice per week) with ribavirin (1.0-1.2 or 1.2-1.6 g/d) for up to 72 weeks. Virological responses were assessed at different time points, and the influence of the IL-28B genotype was studied. RESULTS: At weeks 12 and 24, respectively, 47 (56.6%) and 50 (60.2%) patients achieved a ≥2-Log(10) decrease of HCV RNA levels; 8 (9.6%) and 21 (25.3%) patients had undetectable HCV RNA after 12 and 24 weeks of treatment, respectively. Patients with a CT IL-28B genotype responded significantly better and earlier than those with a TT genotype. In multivariate analysis, the IL-28B genotype was an independent predictor of the virological responses at weeks 4, 12, and 24. CONCLUSIONS: High-dose pegylated IFN-α with standard or high doses of ribavirin induces a potent antiviral response in a substantial number of patients who did not respond to standard therapy. The IL-28B genotype is an independent predictor of the antiviral response. High-dose pegylated IFN-α in combination with ribavirin and protease inhibitors appears as an attractive option for future study in this population.
Published: 2011

24. High-Dose Pegylated Interferon-α and Ribavirin in Nonresponder Hepatitis C Patients and Relationship With IL-28B Genotype (SYREN Trial).: High-Dose peg-IFN and Ribavirin and IL28B in HCV nonresponders

Author: Laurent Alric, Vincent Leroy, Bruno Costes, Magali Bouvier–Alias, Patrice Couzigou, Mariem Charaf–Eddine, Stéphanie Rouanet, Jean-Pierre Bronowicki, Stéphane Chevaliez, Jean-Michel Pawlotsky, Isabelle Rosa, Christophe Hézode, Philippe Mathurin, Juliette Foucher, Alexandre Soulier, Gérard Babany, Albert Tran, Ariane Mallat, Centre National de Référence Virus des hépatites B, C et Delta, Institut National de la Transfusion Sanguine [Paris] (INTS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Service d'hépato-gastro-entérologie [APHP Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Biochimie [Mondor], Produits Roche, Roche, Département d'hépatologie et de gastroentérologie, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Pôle Digestif, Hôpital Archet 2 [Nice] (CHU), Service d'hépato-gastro-entérologie, CHI Créteil, Service d'Hépato-gastroentérologie, Hôpital Huriez-Université de Lille, Service de médecine interne et maladies digestives, CHU Toulouse [Toulouse], Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, This study is investigator-initiated. It has been funded by Roche France, which provided the study drugs, and Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
Subjects: Male, Time Factors, Hepacivirus, medicine.disease_cause, Gastroenterology, Polyethylene Glycols, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Interferon, Pegylated interferon, nonresponder, Genotype, Odds Ratio, Medicine, 0303 health sciences, education.field_of_study, Hepatitis C virus, Hepatitis C, Middle Aged, Viral Load, Recombinant Proteins, 3. Good health, Phenotype, Treatment Outcome, RNA, Viral, Drug Therapy, Combination, Female, 030211 gastroenterology & hepatology, high-dose pegylated IFN-α, medicine.drug, Adult, medicine.medical_specialty, Population, Context (language use), IL28B genotype, Interferon alpha-2, Antiviral Agents, Risk Assessment, 03 medical and health sciences, Internal medicine, Drug Resistance, Viral, Ribavirin, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, education, Aged, 030304 developmental biology, Chi-Square Distribution, Hepatology, business.industry, Interleukins, Interferon-alpha, Hepatitis C, Chronic, medicine.disease, Logistic Models, chemistry, Immunology, Linear Models, Interferons, business
Abstract: International audience; BACKGROUND & AIMS: In patients with chronic hepatitis C who failed to respond to standard therapy, high-dose pegylated interferon (IFN)-α and/or ribavirin could induce a stronger antiviral response and prevent treatment failure and HCV resistance when combined with direct-acting antivirals. The influence of genetic determinants in this context remains unknown. METHODS: Eighty-three patients infected with HCV genotype 1 who were nonresponsive to standard therapy received pegylated IFN-α2a (360 μg once per week or 180 μg twice per week) with ribavirin (1.0-1.2 or 1.2-1.6 g/d) for up to 72 weeks. Virological responses were assessed at different time points, and the influence of the IL-28B genotype was studied. RESULTS: At weeks 12 and 24, respectively, 47 (56.6%) and 50 (60.2%) patients achieved a ≥2-Log(10) decrease of HCV RNA levels; 8 (9.6%) and 21 (25.3%) patients had undetectable HCV RNA after 12 and 24 weeks of treatment, respectively. Patients with a CT IL-28B genotype responded significantly better and earlier than those with a TT genotype. In multivariate analysis, the IL-28B genotype was an independent predictor of the virological responses at weeks 4, 12, and 24. CONCLUSIONS: High-dose pegylated IFN-α with standard or high doses of ribavirin induces a potent antiviral response in a substantial number of patients who did not respond to standard therapy. The IL-28B genotype is an independent predictor of the antiviral response. High-dose pegylated IFN-α in combination with ribavirin and protease inhibitors appears as an attractive option for future study in this population.
Published: 2011

25. Evolution of obesity prevalence in France: an age-period-cohort analysis

Author: Pierre Ducimetière, Evelyne Eschwege, Arnaud Basdevant, Barbara Heude, Ibrahima Diouf, Marie-Aline Charles, Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Epidémiologie cardiovasculaire et mort subite, Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Nutrition et obésité : approches génétique et transcriptomique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de nutrition, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital de l'Hôtel-Dieu, Department of Nutrition, Assistance publique - Hôpitaux de Paris (AP-HP), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), The ObEpi surveys were funded by Institut Roche, France, with the scientific collaboration of INSERM (National Institute of Health and Medical Research), contracts INSERM-Produits Roche N 97062 and 03114A10., Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital de l'Hôtel-Dieu, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and De Lauzon-Guillain, Blandine
Subjects: Male, Gerontology, Epidemiology, Prevalence, MESH : Aged, 030204 cardiovascular system & hematology, Cohort Studies, 0302 clinical medicine, MESH: Aged, 80 and over, MESH: Health Surveys, Medicine, MESH: Obesity, MESH : Female, 030212 general & internal medicine, Young adult, MESH: Cohort Studies, Aged, 80 and over, MESH: Aged, MESH: Middle Aged, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, Middle Aged, MESH : Adult, 3. Good health, MESH: Young Adult, Female, MESH : Obesity, France, Cohort study, Adult, medicine.medical_specialty, Adolescent, MESH : Male, MEDLINE, MESH : Young Adult, MESH : Health Surveys, MESH : Cohort Studies, Article, Young Adult, 03 medical and health sciences, MESH : Adolescent, Humans, MESH : Middle Aged, Obesity, MESH : Aged, 80 and over, MESH : France, Aged, MESH: Adolescent, MESH: Humans, business.industry, MESH : Humans, Age period cohort, MESH: Adult, medicine.disease, Health Surveys, MESH: Male, MESH: France, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female
Abstract: A rapid increase in the prevalence of obesity has been reported in France since 1990. We investigated the impact of birth cohort on the changes in obesity prevalence after taking into account age and survey period.We analyzed data from 4 national surveys in 1997, 2000, 2003, and 2006. For each survey, self-reported data on weight and height were recorded on mailed questionnaires sent to a sample of 20,000 households, representative of the French population. Obesity was defined according to World Health Organization criteria as body mass indexor=30 kg/m. We modeled the prevalence of obesity using logistic regression with age, cohort, and period as explanatory variables. As these variables are linearly dependent, only nonlinear effects can be estimated uniquely and interpreted, after including specific chosen constraints in the models.There was a progressive increase in the prevalence of obesity between 1997 and 2006, attributable either to a period effect or to a cohort effect. There was a substantial departure from a linear trend for the cohort effect only, which seemed to be stronger in women: there was an acceleration in the prevalence of obesity with birth cohort for individuals born after the mid-1960s, in both sexes.Our results are consistent with previous studies in other countries. Compared with older generations, men and women born in the late 1960s may have been subject to early exposures that increased their lifelong susceptibility to obesity.
Published: 2010

26. Monitoring the obesity epidemic in france: the obepi surveys 1997-2006

Author: Charles, Marie-Aline, Eschwège, Eveline, Basdevant, Arnaud, Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition et obésité : approches génétique et transcriptomique, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Roche, France with the scientific collaboration of INSERM, and De Lauzon-Guillain, Blandine
Subjects: obesity, socioeconomics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, prevalence, adults, epidemiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract: International audience; The objective of the study was to describe the prevalences of obesity in French adults over a 9-year period. Mailed questionnaire surveys, in 1997, 2000, 2003, and 2006, sampled 20,000 representative French households by the method of quotas. Weight, height, and waist circumference were reported by all members of the selected households >/=18-years. Obesity was defined according to the WHO criteria, BMI >30 kg/m(2). The prevalence of adult obesity increased progressively from 8.6% (95% confidence interval: 8.2-8.8) in 1997 to 13.1% (12.7-13.5) in 2006. The increase affected all ages, socioeconomic strata, and regions. Although the prevalence of obesity increased in parallel in men and women from 1997 to 2003, the rate of increase was lower in men between 2003 and 2006. These surveys showed a sharp increase in the prevalence of obesity in France in recent years contrasting with a stable prevalence in the 1980s. The results of the first Obepi surveys prompted the French government to implement a Nutrition and Health National Plan in 2001. Regular monitoring of obesity prevalence in France and neighboring countries is needed to compare future trends.Obesity (2008) 16 9, 2182-2186. doi:10.1038/oby.2008.285.
Published: 2008

27. Monitoring the obesity epidemic in france: the obepi surveys 1997-2006.: Increases in the prevalence of obesity in France

Author: Eveline Eschwège, Marie-Aline Charles, Arnaud Basdevant, Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition et obésité : approches génétique et transcriptomique, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Roche, France with the scientific collaboration of INSERM
Subjects: Gerontology, Male, obesity, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Overweight, Body Mass Index, Disease Outbreaks, 0302 clinical medicine, Endocrinology, Epidemiology, adults, 030212 general & internal medicine, 2. Zero hunger, Aged, 80 and over, Nutrition and Dietetics, Middle Aged, 3. Good health, Female, epidemiology, France, medicine.symptom, Waist Circumference, Adult, medicine.medical_specialty, Waist, Adolescent, prevalence, 030209 endocrinology & metabolism, Article, Obesity in France, 03 medical and health sciences, Young Adult, socioeconomics, medicine, Humans, Socioeconomic status, Aged, business.industry, Body Weight, medicine.disease, Obesity, Confidence interval, Body Height, Socioeconomic Factors, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Body mass index, Demography
Abstract: International audience; The objective of the study was to describe the prevalences of obesity in French adults over a 9-year period. Mailed questionnaire surveys, in 1997, 2000, 2003, and 2006, sampled 20,000 representative French households by the method of quotas. Weight, height, and waist circumference were reported by all members of the selected households >/=18-years. Obesity was defined according to the WHO criteria, BMI >30 kg/m(2). The prevalence of adult obesity increased progressively from 8.6% (95% confidence interval: 8.2-8.8) in 1997 to 13.1% (12.7-13.5) in 2006. The increase affected all ages, socioeconomic strata, and regions. Although the prevalence of obesity increased in parallel in men and women from 1997 to 2003, the rate of increase was lower in men between 2003 and 2006. These surveys showed a sharp increase in the prevalence of obesity in France in recent years contrasting with a stable prevalence in the 1980s. The results of the first Obepi surveys prompted the French government to implement a Nutrition and Health National Plan in 2001. Regular monitoring of obesity prevalence in France and neighboring countries is needed to compare future trends.Obesity (2008) 16 9, 2182-2186. doi:10.1038/oby.2008.285.
Published: 2008

28. Identification of profiles associated with conversions between the Alzheimer's disease stages, using a machine learning approach.

Author: Dauphinot V, Laurent M, Prodel M, Civet A, Vainchtock A, Moutet C, Krolak-Salmon P, and Garnier-Crussard A
Subjects: Humans, Female, Male, Aged, Aged, 80 and over, Middle Aged, Cohort Studies, Neuropsychological Tests, Severity of Illness Index, Alzheimer Disease, Machine Learning, Disease Progression, Cognitive Dysfunction epidemiology
Abstract: Background: The identification of factors involved in the conversion across the different Alzheimer's disease (AD) stages is crucial to prevent or slow the disease progression. We aimed to assess the factors and their combination associated with the conversion across the AD stages, from mild cognitive impairment to dementia, at a mild, moderate or severe stage and to identify profiles associated with earliest/latest conversion across the AD stages., Methods: In this study conducted on the real-life MEMORA cohort data collected from January 1, 2013, and December 31, 2019, three cohorts were selected depending on the baseline neurocognitive stage from a consecutive sample of patients attending a memory center, aged between 50 and 90 years old, with a diagnosis of AD during the follow-up, and with at least 2 visits at 6 months to 1 year of interval. A machine learning approach was used to assess the relationship between factors including socio-demographic characteristics, comorbidities and history of diseases, prescription of drugs, and geriatric hospitalizations, and the censored time to conversion from mild cognitive impairment to AD dementia, from the mild stage of dementia to the moderate or severe stages of AD dementia, and from the moderate stage of AD dementia to the severe stage. Profiles of earliest/latest conversion compared to median time to conversion across stages were identified. The median time to conversion was estimated with a Kaplan-Meier estimator., Results: Overall, 2891 patients were included (mean age 77±9 years old, 65% women). The median time of follow-up was 28 months for mild cognitive impairment (MCI) patients, 33 months for mild AD dementia and 30 months for moderate AD dementia. Among the 1264 patients at MCI stage, 61% converted to AD dementia (median time to conversion: 25 months). Among the 1142 patients with mild AD dementia, 59% converted to moderate/severe stage (median time: 23 months) and among the 1332 patients with moderate AD dementia, 23% converted to severe stage (Q3 time to conversion: 22 months). Among the studied factors, cardiovascular comorbidities, anxiety, social isolation, osteoporosis, and hearing disorders were identified as being associated with earlier conversion across stages. Symptomatic treatment i.e. cholinesterase inhibitors for AD was associated with later conversion from mild stage of dementia to moderate/severe stages., Conclusion: This study based on a machine learning approach allowed to identify potentially modifiable factors associated with conversion across AD stages for which timely interventions may be implemented to delay disease progression., (© 2024. The Author(s).)
Published: 2024
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29. Epithelial-to-mesenchymal transition promotes immune escape by inducing CD70 in non-small cell lung cancer.

Author: Ortiz-Cuaran S, Swalduz A, Foy JP, Marteau S, Morel AP, Fauvet F, De Souza G, Michon L, Boussageon M, Gadot N, Godefroy M, Léon S, Tortereau A, Mourksi NE, Leonce C, Albaret MA, Dongre A, Vanbervliet B, Robert M, Tonon L, Pommier RM, Hofman V, Attignon V, Boyault S, Audoynaud C, Auclair J, Bouquet F, Wang Q, Ménétrier-Caux C, Pérol M, Caux C, Hofman P, Lantuejoul S, Puisieux A, and Saintigny P
Subjects: CD27 Ligand genetics, CD27 Ligand metabolism, Cell Line, Tumor, Epithelial-Mesenchymal Transition genetics, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Ligands, Tumor Microenvironment, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms pathology
Abstract: Introduction: Epithelial-to-mesenchymal transition (EMT) is associated with tumor aggressiveness, drug resistance, and poor survival in non-small cell lung cancer (NSCLC) and other cancers. The identification of immune-checkpoint ligands (ICPLs) associated with NSCLCs that display a mesenchymal phenotype (mNSCLC) could help to define subgroups of patients who may benefit from treatment strategies using immunotherapy., Methods: We evaluated ICPL expression in silico in 130 NSCLC cell lines. In vitro, CRISPR/Cas9-mediated knockdown and lentiviral expression were used to assess the impact of ZEB1 expression on CD70. Gene expression profiles of lung cancer samples from the TCGA (n = 1018) and a dataset from MD Anderson Cancer Center (n = 275) were analyzed. Independent validation was performed by immunohistochemistry and targeted-RNA sequencing in 154 NSCLC whole sections, including a large cohort of pulmonary sarcomatoid carcinomas (SC, n = 55)., Results: We uncover that the expression of CD70, a regulatory ligand from the tumor necrosis factor ligand family, is enriched in mNSCLC in vitro models. Mechanistically, the EMT-inducer ZEB1 impacted CD70 expression and fostered increased activity of the CD70 promoter. CD70 overexpression was also evidenced in mNSCLC patient tumor samples and was particularly enriched in SC, a lung cancer subtype associated with poor prognosis. In these tumors, CD70 expression was associated with decreased CD3 + and CD8 + T-cell infiltration and increased T-cell exhaustion markers., Conclusion: Our results provide evidence on the pivotal roles of CD70 and ZEB1 in immune escape in mNSCLC, suggesting that EMT might promote cancer progression and metastasis by not only increasing cancer cell plasticity but also reprogramming the immune response in the local tumor microenvironment., Competing Interests: Conflict of interest statement SO–C: None. AS: Honoraria for Advisory Boards: Roche, Bristol-Myers Squibb, Takeda Symposiums: Roche, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Pfizer, Takeda. JPF: None. SM: None. APM: None. FF: None. MB: None. AD: None. CL: None. MR: None. NM: None. LM: None. MG: None. SL: None. AT: None. LT: None. SB: None. RMP: None. MAA: None. GDS: None. VH: None. NG: None. VA: None. CA: None. JA: None. BV: None. FB: Current employee at F. Hoffman La Roche. CMC: None. QW: None. MP: None. CC: None. PH: None. SL: consultant fees from MSD, BMS, Astra Zeneca, Abbvie, Bayer, Takeda. AP: None. PS: Research funding from Astra-Zeneca, Roche, Genentech BMS, Novartis and HTG Molecular Diagnostics. Scientific Advisory Board member of HTG Molecular Diagnostics., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
Published: 2022
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30. Long-term outcomes in patients with PET-predicted poor-responsive HER2-positive breast cancer treated with neoadjuvant bevacizumab added to trastuzumab and docetaxel: 5-year follow-up of the randomised Avataxher study.

Author: Coudert B, Pierga JY, Mouret-Reynier MA, Kerrou K, Ferrero JM, Petit T, Du FL, Dupré PF, Bachelot T, Gabelle P, Chauvet MP, Coeffic D, Barbe C, Prevost JB, Paintaud G, Thibault G, Ferhat A, Dupin J, Berriolo-Riedinger A, and Arnould L
Abstract: Background: The open-label, randomised Phase 2 AVATAXHER study (NCT01142778) demonstrated that early PET assessment identified HER2-positive breast cancer patients who responded poorly to neoadjuvant docetaxel plus trastuzumab. Adding neoadjuvant bevacizumab for PET-predicted poor-responders improved pathological complete response (pCR) rates (43.8% vs 24.0%). We investigated long-term study outcomes., Methods: Patients were treated in three groups. All patients initially received two cycles of standard neoadjuvant therapy with [¹⁸F]-FDG PET conducted before each cycle. Those with ≥70% change in the maximum standardised uptake value (∆SUVmax) received four further cycles of standard neoadjuvant therapy (PET responders). PET-predicted poor-responders (∆SUVmax <70%) were randomised (2:1) to neoadjuvant therapy with (Group A) or without (Group B) bevacizumab for cycles 3-6. All patients received one further cycle of trastuzumab before surgery plus adjuvant trastuzumab (11 cycles)., Findings: 142 patients were randomized and treated (PET responders, n = 69; Group A, n = 48; Group B, n = 25). 5-year disease-free survival rates were 90.5% (95% CI: 80.0-95.6%) in PET responders, 90.2% (95% CI: 75.9-96.2%) in Group A, and 76.0% (95% CI: 54.2-88.4%) in Group B. However, no difference was observed between randomised arms in a sensitivity analysis. During adjuvant therapy, the incidence of Grade ≥3 (Group A: 25.6%; Group B 12.5%) and serious adverse events (Group A: 18.6%; Group B 12.5%) was higher in Group A vs Group B, but with no apparent effect on cardiac events., Interpretation: In patients with HER2-positive breast cancer, an intervention based on early PET assessment and improvement of pCR does not modify disease-free survival., Funding: Roche France., Competing Interests: BC reports personal fees and non-financial support from Roche Laboratories France, personal fees from Bristol Myers Laboratories France, and personal fees from AstraZeneca Laboratories. JYP declares research funding received by his institution from Roche and Menarini Silicon Biosystems; honoraria received by his institution from Roche and Sanofi; and personal fees from Roche, Novartis, AstraZeneca, Pfizer, Amgen, Ipsen, Lilly, and Genomic Health. TP is a member of scientific boards for Novartis, Lilly and Pfizer. TB reports personal fees and non-financial support from Roche, Novartis, AstraZeneca, and Pfizer; and personal fees from Seattle Genetics, outside the submitted work. DC reports honorarium from Roche, Pfizer, Novartis, Sanofi, and AstraZeneca. GP acted as consultant for Chugai, Novartis and Shire (Takeda), with remunerations received by his institution. GP's research team received grants for academic studies from Amgen, Genzyme (Sanofi), Lilly, Merck, Novartis, and Roche Pharma. AF and JD are full-time employees of Roche Pharma France. KK, J-MF, and PG report personal fees from Roche during the conduct of the study. LA reports personal fees and non-financial support from Roche Laboratories France and Bristol Myers Laboratories France, and personal fees from AstraZeneca Laboratories and Merck. M-AM-R, FLD, P-FD, M-PC, CB, J-BP, GT, and AB-R declare no conflicts of interest., (© 2020 The Authors.)
Published: 2020
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31. Cost-effectiveness of atezolizumab versus docetaxel and nivolumab in the treatment of non-small cell lung cancer as a second line in France.

Author: Marine S, Stéphane R, Nicolas P, Felizzi F, Paracha N, Benjamin M, and Perol M
Subjects: Antibodies, Monoclonal, Humanized economics, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents adverse effects, Bayes Theorem, Carcinoma, Non-Small-Cell Lung pathology, Cost-Benefit Analysis, Docetaxel economics, Docetaxel therapeutic use, France, Health Expenditures statistics & numerical data, Health Resources economics, Health Resources statistics & numerical data, Humans, Lung Neoplasms pathology, Models, Economic, Neoplasm Staging, Nivolumab economics, Nivolumab therapeutic use, Quality-Adjusted Life Years, Survival Analysis, Antineoplastic Agents economics, Antineoplastic Agents therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
Abstract: Aim: To estimate the cost-effectiveness of atezolizumab compared with docetaxel and nivolumab for the treatment of advanced non-small cell lung cancer (NSCLC), as a second-line treatment, in a French setting. Materials and methods: A three-state partitioned-survival model was developed (progression-free survival, post-progression survival, death) based on the phase IIIOAK trial on a 10-year time horizon. The comparison between nivolumab and atezolizumab came from a network meta-analysis. Utilities were estimated from the OAK trial EQ-5D applying the French utility tariffs. Overall survival (OS), progression-free survival (PFS), and treatment duration were estimated using parametric models selected using Akaike and Bayesian information criterion. Extrapolation beyond the trial duration followed NICE DSU TSD 14. Economic perspective was the one of all payers, discount rate fixed at 4% on benefits and costs. This analysis was aligned with French Haute Autorité de Santé recommendations. Results were expressed in total cost (2019) and €/QALY (Quality Adjusted Life Year). Model robustness was checked through sensitivity analyses, and a probabilistic sensitivity analysis was conducted. Results: In comparison to docetaxel, atezolizumab costs 49,429€ more and increased life expectancy by 8 months, generating 0.47 QALY. Incremental cost-effectiveness ratio was estimated at 104,835€/QALY. When comparing nivolumab to atezolizumab, a cost minimization analysis was conducted since no clear evidence supporting a difference in terms of survival benefit was reported. Using list price, and the Market Access Authorization regimens, atezolizumab saved approximately 6,000€, 9.5% of its total costs. Sensitivity analyses confirmed the robustness of our findings. Conclusion: Atezolizumab is more efficient and more costly than docetaxel in the second-line treatment of NSCLC of stage IIIB or IV, in France, with results consistent to previous French authorities' evaluation of immunotherapies in similar indication. Lastly, atezolizumab is a cost saving alternative to nivolumab, based on list price.
Published: 2020
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32. Relapsed or refractory chronic lymphocytic leukemia retreated with rituximab in daily practice: final results of the PERLE study.

Author: Chaoui D, Hacini M, Fitoussi O, Karlin L, Arkam Y, Jourdan E, Orfeuvre H, Voillat L, Sanhes L, Leprêtre S, Liu KL, Barry M, Tempescul A, Dilhuydy MS, Chaib A, Slama B, Labourey JL, Benbrahim O, Dreyfus B, Mahé B, Maynadié M, Delmer A, Benkanoun C, Boissard F, Gandon S, Veerabudun K, and Choquet S
Subjects: Drug Resistance, Neoplasm, Female, France epidemiology, Humans, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell epidemiology, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Male, Multicenter Studies as Topic, Recurrence, Retreatment, Treatment Outcome, Antineoplastic Agents, Immunological therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Rituximab therapeutic use
Published: 2019
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33. [Second- or third-line treatment with erlotinib in EGFR wild-type non-small cell lung cancer: Real-life data].

Author: Debieuvre D, Moreau L, Coudert M, Locher C, Asselain B, Coëtmeur D, Dayen C, Goupil F, Martin F, Brun P, De Faverges G, Hauss PA, Gally S, Ben Hadj Yahia B, and Grivaux M
Subjects: Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung genetics, ErbB Receptors genetics, Female, Humans, Lung Neoplasms genetics, Male, Middle Aged, Prospective Studies, Survival Rate, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung mortality, Erlotinib Hydrochloride therapeutic use, Lung Neoplasms drug therapy, Lung Neoplasms mortality, Protein Kinase Inhibitors therapeutic use
Abstract: Introduction: The benefit of tyrosine kinase inhibitors for patients with an EGFR wild-type non-small cell lung cancer (NSCLC) remains controversial., Methods: The survival of patients with an EGFR wild-type NSCLC who received second- or third-line erlotinib treatment was assessed using real-life data that had been collected in a prospective, national, multicenter, non-interventional cohort study., Results: Data from 274 patients were analysed, 185 (68%) treated with erlotinib and 89 (32%) treated with supportive care only. The median overall survival was 4.2months (95% CI [3.5; 5.4]) with erlotinib, and 1.3months (95% CI [1.0; 1.8]) with supportive care. Survival rate at 3, 6, and 12months was 62%, 37%, and 17%, respectively, with erlotinib, versus 20%, 8%, et 3%, with exclusive supportive care. Significant predictive factors for longer overall survival were the presence of adenocarcinoma, and use of 1st line chemotherapy including either taxanes, pemetrexed or vinorelbine (P<0.05)., Conclusion: Erlotinib remains a valuable therapeutic option to treat inoperable locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen in fragile patients who are not eligible for chemotherapy., (Copyright © 2019 SPLF. Published by Elsevier Masson SAS. All rights reserved.)
Published: 2019
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34. Early access to health products in France: Major advances of the French "Conseil stratégique des industries de santé" (CSIS) to be implemented (modalities, regulations, funding).

Author: Albin N, Chassagnol F, and Bergmann JF
Subjects: Clinical Trials as Topic legislation & jurisprudence, Device Approval, Diffusion of Innovation, Drug Approval, France, Health Systems Agencies, Hospitals, Humans, Health Care Sector legislation & jurisprudence
Abstract: In a context of perpetual evolution of treatments, access to therapeutic innovation is a major challenge for patients and the various players involved in the procedures of access to medicines. The revolutions in genomic and personalized medicine, artificial intelligence and biotechnology will transform the medicine of tomorrow and the organization of our health system. It is therefore fundamental that France prepares for these changes and supports the development of its companies in these new areas. The recent "Conseil stratégique des industries de santé" launched by Matignon makes it possible to propose a regulatory arsenal conducive to the implementation and diffusion of therapeutic innovations. In this workshop, we present a number of proposals, our approach having remained pragmatic with a permanent concern to be effective in the short term for the patients and to simplify the procedures as much as possible. This was achieved thanks to the participation in this workshop of most of the players involved (industrial companies, "Agence nationale de sécurité du médicament et des produits de santé", "Haute Autorité de santé", "Institut national du cancer", "Les entreprises du médicament", hospitals, "Observatoire du médicament, des dispositifs médicaux et de l'innovation thérapeutique"…). The main proposals tend to favor the implementation of clinical trials on our territory, especially the early phases, a wider access to innovations by favoring early access programs and setting up a process called "autorisation temporaire d'utilisation d'extension" (ATUext) that make it possible to prescribe a medicinal product even if the latter has a marketing authorisation in another indication. In addition, we propose a conditional reimbursement that will be available based on preliminary data but will require re-evaluation based on consolidated data from clinical trials and/or real-life data. Finally, in order to better carry out these assessments, with a view to access or care, we propose the establishment of partnership agreements with health agencies/hospitals in order to encourage the emergence of field experts, in order to prioritize an ascending expertise closer to patients' needs and to real life., (Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)
Published: 2019
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35. Accès précoce aux produits de santé en France : des avancées majeures du CSIS (Conseil stratégique des industries de santé) à concrétiser (modalités, réglementations, financements).

Author: Albin N, Chassagnol F, and Bergmann JF
Published: 2019
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36. A retrospective study on the management of patients with rituximab refractory follicular lymphoma.

Author: Solal-Céligny P, Leconte P, Bardet A, Hernandez J, and Troussard X
Subjects: Aged, Aged, 80 and over, Antineoplastic Agents, Immunological administration & dosage, Antineoplastic Agents, Immunological adverse effects, Antineoplastic Agents, Immunological therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Clinical Decision-Making, Combined Modality Therapy, Comorbidity, Disease Management, Drug Resistance, Neoplasm, Female, Humans, Lymphoma, Follicular diagnosis, Lymphoma, Follicular mortality, Male, Middle Aged, Neoplasm Staging, Retreatment, Retrospective Studies, Rituximab administration & dosage, Rituximab adverse effects, Rituximab therapeutic use, Lymphoma, Follicular therapy
Abstract: Given that there are currently no clear recommendations regarding therapeutic options for rituximab refractory/relapsed follicular lymphoma patients, this study aimed to describe the real-life management of patients with refractory follicular lymphoma after systemic rituximab-containing regimens (rFL), and rFL patient characteristics. In this retrospective, national, multicentre study, descriptive analyses were mainly performed according to rituximab-containing regimen at rFL diagnosis [rituximab monotherapy (R-MONO), rituximab + chemotherapy (R-COMBO), and ongoing rituximab maintenance (R-MAINTAIN)]. The 459 analysed patients experienced rituximab-refractoriness between October 2013 and September 2015: R-MONO: 58 (13%), R-COMBO: 197 (43%), R-MAINTAIN: 204 (44%). Post-refractoriness strategies were heterogeneous: idelalisib ± rituximab (22%), without anti-lymphoma treatment (21%), rituximab-chemotherapy (21%) and stem cell transplantation (18%). Rituximab was continued in combination in 41% of cases. Chosen strategies varied according to patient age (without anti-lymphoma treatment: 28% of patients if ≥65 years vs. 12% if <65 years old; stem-cell transplantation: 4% vs. 38%), treatment line at rFL, FL International Prognostic Index score and prior treatment. This French retrospective study, the first one conducted in a large cohort of rFL patients, showed that further strategies were highly heterogeneous, depending notably on patient characteristics and previous treatment. These data are the basis for a better understanding of rFL management and for the design of clinical trials in these patients., (© 2017 John Wiley & Sons Ltd.)
Published: 2018
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37. Relapsed chronic lymphocytic leukemia retreated with rituximab: interim results of the PERLE study.

Author: Chaoui D, Choquet S, Sanhes L, Mahé B, Hacini M, Fitoussi O, Arkam Y, Orfeuvre H, Dilhuydy MS, Barry M, Jourdan E, Dreyfus B, Tempescul A, Leprêtre S, Bardet A, Leconte P, Maynadié M, and Delmer A
Subjects: Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Immunological administration & dosage, Antineoplastic Agents, Immunological adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Drug Resistance, Neoplasm, Female, France epidemiology, Humans, Leukemia, Lymphocytic, Chronic, B-Cell epidemiology, Male, Middle Aged, Recurrence, Retreatment, Rituximab administration & dosage, Rituximab adverse effects, Treatment Outcome, Antineoplastic Agents, Immunological therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Rituximab therapeutic use
Abstract: This prospective non-interventional study assessed the management of relapsed/refractory CLL after one or two treatments with rituximab, and retreatment with a rituximab-based regimen. An interim analysis was performed at the end of the induction period in 192 evaluable patients. Median age was 72 years [35-89], first relapse (55%), and second relapse (45%). Rituximab administered during first (68%), second (92%), or both treatment lines (20%). R-bendamustine administered in 56% of patients, R-purine analogs (21%), and R-alkylating agents (19%). The overall response rate (ORR) was 74.6%, in favor of R-purine analogs (90%), R-bendamustine (75%), and R-alkylating agents (69%). Lower ORR in Del 17p patients (43%) and third time rituximab (31%). Most frequent adverse events were hematological (23% patients) including neutropenia (11%) and infections (12%); grade 3/4 AEs (23% patients), mainly hematological (18%); death during induction treatment (7%). This first large study focusing on relapsed/refractory CLL patients retreated with rituximab-based regimens is still ongoing.
Published: 2017
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38. Daily Practice Management of pT1a-b pN0 Breast Carcinoma: A Prospective French ODISSEE Cohort Study.

Author: Dalenc F, Penault-Llorca F, Cohen M, Houvenaeghel G, Piat JM, Liegeois P, Puyuelo L, Suchaud JP, Zouai M, Lacroix-Triki M, Radosevic-Robin N, Benkanoun C, Attar-Rabia H, Chauvet MP, Gligorov J, and Belkacemi Y
Subjects: Adult, Aged, Aged, 80 and over, Biomarkers, Tumor analysis, Breast Neoplasms mortality, Chemotherapy, Adjuvant, Disease-Free Survival, Estrogen Receptor alpha metabolism, Female, Follow-Up Studies, France epidemiology, Humans, Middle Aged, Neoplasm Grading, Neoplasm Recurrence, Local epidemiology, Neoplasm Staging, Practice Guidelines as Topic, Prognosis, Prospective Studies, Radiotherapy, Adjuvant, Receptor, ErbB-2 metabolism, Self Report, Treatment Outcome, Young Adult, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms pathology, Breast Neoplasms therapy, Trastuzumab therapeutic use
Abstract: Background: Most breast cancer (BC) tumors ≤10 mm have an excellent prognosis. The subgroups with a higher risk for distant recurrence requiring adjuvant systemic therapy are not precisely defined in current international guidelines., Patients and Methods: The OBSERVATOIRE DES PETITS CANCERS DU SEIN HER2 +/- (ODISSEE) study was a prospective, multicenter, cohort study that aimed to describe the daily adjuvant management and outcome of 616 patients with unifocal, invasive pT1a-b pN0 nonmetastatic BC who underwent surgery., Results: At the time of diagnosis, the median age of patients was 61 years. Tumor was detected on imaging or during a screening program in 397 patients (64.6%). Most patients (96%) underwent conservative surgery with sentinel node biopsy (89%), completed with axillary lymph node dissection in 15%. At inclusion, 82% of tumors were pT1b, 73% were pN0 (i-), 53% were Scarff-Bloom-Richardson Grade I, 91% were estrogen receptor (ER)-positive, 5% overexpressed/amplified HER2, and 5% were triple negative (TNBC). Adjuvant treatments were radiotherapy (95%), hormone therapy (82%), chemotherapy (7%), and trastuzumab (3.5%). In patients with TNBC and HER2-positive BC, chemotherapy and trastuzumab (if needed) were administered in 45% and 68%, respectively. After 5 years of follow-up, 7 patients had contralateral BC, 7 had locoregional recurrence, and 1 had distant metastasis. At 5 years, overall survival, disease-free survival, and recurrence-free survival were: 98.4% (96.9%-99.1%), 94.7% (92.4%-96.3%), and 97.1% (95.2%-98.2%), respectively., Conclusion: This prospective cohort study showed that in France, the routine practice in pT1a-b pN0 breast cancers follows international standard guidelines for practice including conservative surgery followed by radiotherapy and endocrine therapy for ER-positive patients. Adjuvant chemotherapy with or without trastuzumab was used but their benefit in breast cancer of ≤10 mm remains controversial., (Copyright © 2016 Elsevier Inc. All rights reserved.)
Published: 2017
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39. Real-life effectiveness of erlotinib as second-line treatment of stage IIIB/IV squamous non-small cell lung cancer: Results of the PEPiTA observational study.

Author: Monnet I, Audigier-Valette C, Girard N, Vergnenègre A, Molinier O, Souquet PJ, Blanchon F, Bonnetain F, Taguieva-Pioger N, Lamour C, and Wislez M
Subjects: Aged, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Squamous Cell mortality, Erlotinib Hydrochloride administration & dosage, Erlotinib Hydrochloride adverse effects, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, Prognosis, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors adverse effects, Quality of Life, Retreatment, Treatment Outcome, Antineoplastic Agents therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell pathology, Erlotinib Hydrochloride therapeutic use, Protein Kinase Inhibitors therapeutic use
Abstract: Objectives: Erlotinib, an inhibitor of tyrosine kinase activity of the epidermal growth factor receptor, is effective in non-small cell lung cancer (NSCLC). Data on erlotinib use in squamous NSCLC are limited. This observational study aimed at evaluating the efficacy and safety of second-line erlotinib in patients with stage IIIB/IV squamous NSCLC in a real-life setting., Material and Methods: Patients with predominantly squamous stage IIIB/IV NSCLC, who failed first-line platinum-based therapy, were recruited and followed-up for 12 months. Patients underwent visits each trimester. Data were derived from case report forms, and functional assessment of cancer therapy-lung (FACT-L) questionnaires., Results: A total of 152 patients were enrolled; the majority were males (90%) and mean age was 67.7 years. All patients had squamous (97%) or predominantly squamous (3%) NSCLC, of stage IIIB (21%) or IV (79%). Median progression free survival (PFS) and overall survival were 3 and 5.8 months, respectively. Disease progression was observed in the majority of the patients, mostly due to progression of primary tumour and/or metastatic sites, and led to death in 91/107 of patients. Of the 107 deaths reported, none were due to erlotinib. FACT-L questionnaires were interpretable up to the first visit and were in line with PFS data, showing a relatively good quality of life up to Month 3 (mean total score=78.8). No new or unexpected safety issues were reported., Conclusions: The results of this real-life cohort study like those of previous phase III/IV subgroups study analyses indicate that erlotinib is a valuable option for second-line treatment of stage IIIB/IV squamous NSCLC., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)
Published: 2016
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40. Fatigue in rheumatoid arthritis: quantitative findings on the efficacy of tocilizumab and on factors associated with fatigue. The French multicentre prospective PEPS Study.

Author: Gossec L, Steinberg G, Rouanet S, and Combe B
Subjects: Adult, Aged, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Antirheumatic Agents administration & dosage, Antirheumatic Agents adverse effects, Arthritis, Rheumatoid complications, Arthritis, Rheumatoid diagnosis, Arthritis, Rheumatoid physiopathology, Arthritis, Rheumatoid psychology, Drug Administration Schedule, Fatigue diagnosis, Fatigue physiopathology, Fatigue psychology, Female, France, Humans, Infusions, Intravenous, Linear Models, Logistic Models, Male, Middle Aged, Multivariate Analysis, Prospective Studies, Remission Induction, Risk Factors, Severity of Illness Index, Surveys and Questionnaires, Time Factors, Treatment Outcome, Antibodies, Monoclonal, Humanized therapeutic use, Antirheumatic Agents therapeutic use, Arthritis, Rheumatoid drug therapy, Fatigue etiology
Abstract: Objectives: Fatigue is an important aspect of rheumatoid arthritis (RA). The objective was to assess fatigue levels and its determinants over the first 4 months of tocilizumab (TCZ) treatment in RA patients., Methods: We performed a multicentre prospective study of RA patients treated with intravenous TCZ in open-label prescription conditions. The first 5 infusions (4 months) were assessed. The primary endpoint was the percentage of patients with variation of the FACIT fatigue scale from inclusion to 4 months, above the minimal clinically important difference (MCID) of 4 points. Fatigue was also assessed by the patient acceptable symptom state for fatigue (PASS) question. Variables related with fatigue and with fatigue improvement including other patient reported outcomes, depression and anxiety, and disease activity, were assessed before and after treatment., Analyses: univariate and multivariate logistic regressions., Results: Of 719 patients, 610 had evaluable data: mean age 56±13 years, disease duration 12±10 years, 490 (81%) women. At baseline, fatigue levels were high: 73% patients had unacceptable fatigue. At 4 months, 378 patients (62%) reached MCID improvement for fatigue. Fatigue reduction was rapid, seen as early as after 2 weeks. Fatigue was mainly related to functional status (HAQ score), depression and anxiety, both before and after TCZ treatment. Moderate predictors of fatigue improvement were evidenced., Conclusions: In these long-standing RA patients, fatigue levels were high and mainly explained by HAQ and psychological distress but improved with treatment indicating a link with disease activity. The pathophysiological basis of RA fatigue should be further explored.
Published: 2015

41. Radiotherapy associated with concurrent bevacizumab in patients with non-metastatic breast cancer.

Author: Pernin V, Belin L, Cottu P, Bontemps P, Lemanski C, De La Lande B, Baumann P, Missohou F, Levy C, Peignaux K, Bougnoux P, Denis F, Bollet M, Dendale R, Vago NA, Campana F, Fourquet A, and Kirova YM
Subjects: Adult, Aged, Bevacizumab, Breast Neoplasms pathology, Carcinoma, Ductal, Breast pathology, Carcinoma, Lobular pathology, Dermatitis etiology, Dyspnea etiology, Esophagitis etiology, Female, Fibrosis, Humans, Lymphedema etiology, Middle Aged, Neoadjuvant Therapy, Prospective Studies, Radiation-Sensitizing Agents adverse effects, Telangiectasis etiology, Angiogenesis Inhibitors adverse effects, Antibodies, Monoclonal, Humanized adverse effects, Breast Neoplasms therapy, Carcinoma, Ductal, Breast therapy, Carcinoma, Lobular therapy, Chemoradiotherapy, Adjuvant adverse effects, Radiation Injuries etiology, Skin pathology
Abstract: The purpose of this multicenter prospective and descriptive study was to determine late toxicities and outcomes among patients with non-metastatic breast cancer receiving concurrent bevacizumab (BV) and radiation therapy (RT) in the clinical trials. Early and late toxicities were assessed and evaluation was available for 63 patients (pts) at 12 months. Acute radiation dermatitis was observed in 48 (76%): grade 1 for 27, grade 2 for 17 and grade 3 for 4 pts. Grade 2 acute oesophagitis was observed in one patient (2%). Little toxicity was described 1 year after the completion of RT: 7 pts (12%): grade 1-2 pain, 3 (5%) presented grade 1 fibrosis, and 2 pts (4%) - telangiectasia. One patient (2%) experienced grade 1 dyspnoea. Five grade 1-2 lymphoedema occurred. Only one patient experienced a LEVF value less than 50% one year after the end of RT. In conclusion, the concurrent BV with locoregional RT provides acceptable toxicities., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
Published: 2014
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42. Comparison of sympathetic modulation induced by single oral doses of mibefradil, amlodipine, and nifedipine in healthy volunteers.

Author: Ragueneau I, Sao AB, Démolis JL, Darné B, Funck-Brentano C, and Jaillon P
Subjects: Administration, Oral, Adult, Aldosterone blood, Cross-Over Studies, Double-Blind Method, Electrocardiography drug effects, Epinephrine blood, Humans, Male, Amlodipine pharmacology, Calcium Channel Blockers pharmacology, Hemodynamics drug effects, Mibefradil pharmacology, Nifedipine pharmacology, Sympathetic Nervous System drug effects
Abstract: Objective: Our objective was to compare the sympathetic modulation induced by oral administration of a single dose of 20 mg of standard nifedipine, of 10 mg of amlodipine, and of 100 mg of mibefradil., Methods: Sixteen healthy male volunteers participated in this double-blind, randomized, placebo-controlled, crossover four-period study. The sympathetic modulation induced by treatments was evaluated during 24 hours after drug administration by neurohormonal dosages, hemodynamic parameter measurements, and spectral analysis of heart rate and blood pressure., Results: We observed a significant (P <.05) decrease in diastolic blood pressure 1 hour after the administration of nifedipine (62 +/- 9 to 59 +/- 5 mm Hg) with concomitant increases in heart rate (59 +/- 5 to 74 +/- 8 bpm) and neurohormones (53 +/- 18 to 83 +/- 50 pg/mL for aldosterone, 157 +/- 56 to 282 +/- 119 pg/mL for norepinephrine, and 9.8 +/- 5.5 to 40.2 +/- 97.1 pg/mL for active renin). No significant modification of these parameters was observed with amlodipine and mibefradil, except an isolated increase of norepinephrine plasma level 2 hours after the administration of mibefradil (133.1 +/- 67.1 to 210.9 +/- 92.5 pg/mL). The spectral analysis over 24 hours of Mayer waves of systolic blood pressure did not show any significant change over time in the different groups. When the analysis was performed during the first 4 hours after treatment administration, we observed a decrease of Mayer waves of systolic blood pressure with nifedipine (2.21 +/- 1.45 mm Hg(2) versus 3.53 +/- 1.85 mm Hg(2) with placebo). These results indicate that oral single doses of mibefradil and amlodipine do not induce baroreflex-mediated clinical changes in healthy volunteers. The single oral dose of nifedipine resulted in a marked increase in sympathetic tone and a decrease in systolic blood pressure variability early after oral administration., Conclusion: Mibefradil, the nondihydropyridine calcium antagonist, exerts much less sympathetic stimulation than nifedipine.
Published: 2001
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