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51. Assessment of sentinel lymph node biopsy in patients receiving neoadjuvant chemotherapy in breast cancer: before or after?

Author

Coutant , Charles, Jankowski , Clémentine, Portha , H., Barranger , Emmanuel, Service de chirurgie [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), UFR des Sciences de Santé (Université de Bourgogne), Université de Bourgogne ( UB ), Pôle de Chirurgie Oncologique générale, Gynécologique et Mammaire [Centre Antoine-Lacassagne], CRLCC Antoine Lacassagne, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Université de Bourgogne (UB), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), and UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA)

Subjects
Ganglion sentinelle, Breast cancer, Preoperative chemotherapy, Chimiothérapie néoadjuvante, Cancers du sein, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sentinel lymph node, [ SDV.CAN ] Life Sciences [q-bio]/Cancer
Abstract

International audience; The main goal of preoperative chemotherapy is to reduce the size of the tumor and allow conservative treatment. Neoadjuvant treatment can affect axillary status with a downstaging in one third of the cases. For these patients, the benefit of axillary node dissection is questioned and the sentinel node biopsy (SLNB) seems to be a relevant option. However, the timing of performing SLNB is still debated especially for clinical negative patients with negative axillary ultrasound before preoperative chemotherapy. For axillary positive nodes proved by biopsy/cytology before preoperative chemotherapy, SLNB can be an option if there is a good clinical and radiological response.; La chimiothérapie néoadjuvante (CNA) peut permettre une réduction de la taille de la tumeur en vue d’un traitement conservateur impossible initialement. Elle permet également une réponse ganglionnaire axillaire histologique complète dans un tiers des cas. La pertinence du curage axillaire (CA) systématique après CNA est remise en question, en faveur de la procédure du ganglion sentinelle (GS). Cependant, le moment optimal par rapport à la CNA est encore débattu dans la littérature pour les patientes n’ayant pas d’envahissement ganglionnaire évalué par échographie avant la chimiothérapie. Pour les patientes avec envahissement ganglionnaire prouvé avant CNA, la réalisation d’un GS après CNA paraît envisageable en cas de réponse radio-clinique.

Published
2016

52. An Evolution-Guided Analysis Reveals a Multi-Signaling Regulation of Fas by Tyrosine Phosphorylation and its Implication in Human Cancers

Author

Jérôme Durivault, Angélique Bole, Benoit Dérijard, Eszter Doma, Anne-Odile Hueber, Sébastien Huault, Krittalak Chakrabandhu, Ly Ta Ngoc, Kévin Lang, Michel Pierres, Jean-Pierre Gérard, Institut de Biologie Valrose (IBV), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Radiothérapie [CAL, Nice], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), This work was supported by institutional funds from the Centre National de la Recherche Scientifique (CNRS) and the Institut National de la Santé et de la Recherche Médicale (INSERM), and by grants from the Institut National du Cancer (INCa, PLBIO09-317), the University of Nice, the Agence Nationale de la Recherche (ANR-10-BLAN-1226, ANR-11-LABX-0028-01). KL was supported by funding from the Canceropole PACA, and LTN was supported by a scholarship from the ministry and education of training of the socialist republic of Vietnam., ANR-10-BLAN-1226,PLAF,Etude du rôle de la plasticité de la signalisation du récepteur Fas dans les adénocarcinomes colo-rectaux.(2010), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), Université Nice Sophia Antipolis (... - 2019) (UNS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), VAFFIDES, Chantal, BLANC - Etude du rôle de la plasticité de la signalisation du récepteur Fas dans les adénocarcinomes colo-rectaux. - - PLAF2010 - ANR-10-BLAN-1226 - BLANC - VALID, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, UNICANCER-Université Côte d'Azur (UCA), and HUEBER, Anne-Odile

Subjects
0301 basic medicine, Cell viability testing, [SDV]Life Sciences [q-bio], Apoptosis, Protein tyrosine phosphatase, Biochemistry, Fas ligand, chemistry.chemical_compound, Aromatic Amino Acids, 0302 clinical medicine, Cell Signaling, Neoplasms, Small interfering RNAs, Post-Translational Modification, Amino Acids, Tyrosine, Biology (General), Phosphorylation, Animal Signaling and Communication, Cell Analysis, ComputingMilieux_MISCELLANEOUS, Cell Death, Animal Behavior, Organic Compounds, Kinase, Protein Tyrosine Phosphatase, Non-Receptor Type 6, General Neuroscience, Fas receptor, Endocytosis, Signaling Cascades, 3. Good health, Cell biology, Nucleic acids, [SDV] Life Sciences [q-bio], Chemistry, src-Family Kinases, Bioassays and Physiological Analysis, Cell Processes, 030220 oncology & carcinogenesis, Physical Sciences, Cell lines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Biological cultures, General Agricultural and Biological Sciences, Research Article, Signal Transduction, [SDV.IMM] Life Sciences [q-bio]/Immunology, QH301-705.5, Molecular Sequence Data, Immunoblotting, macromolecular substances, Biology, General Biochemistry, Genetics and Molecular Biology, Evolution, Molecular, 03 medical and health sciences, Apoptotic signaling cascade, Hydroxyl Amino Acids, Genetics, Humans, Amino Acid Sequence, fas Receptor, Non-coding RNA, Archived Twee, Behavior, General Immunology and Microbiology, Organic Chemistry, Chemical Compounds, Biology and Life Sciences, Proteins, Tyrosine phosphorylation, Cell Biology, Protein Structure, Tertiary, Gene regulation, Research and analysis methods, 030104 developmental biology, SW480 cells, chemistry, Mutagenesis, Site-Directed, RNA, Gene expression, Zoology
Abstract

Demonstrations of both pro-apoptotic and pro-survival abilities of Fas (TNFRSF6/CD95/APO-1) have led to a shift from the exclusive “Fas apoptosis” to “Fas multisignals” paradigm and the acceptance that Fas-related therapies face a major challenge, as it remains unclear what determines the mode of Fas signaling. Through protein evolution analysis, which reveals unconventional substitutions of Fas tyrosine during divergent evolution, evolution-guided tyrosine-phosphorylated Fas proxy, and site-specific phosphorylation detection, we show that the Fas signaling outcome is determined by the tyrosine phosphorylation status of its death domain. The phosphorylation dominantly turns off the Fas-mediated apoptotic signal, while turning on the pro-survival signal. We show that while phosphorylations at Y232 and Y291 share some common functions, their contributions to Fas signaling differ at several levels. The findings that Fas tyrosine phosphorylation is regulated by Src family kinases (SFKs) and the phosphatase SHP-1 and that Y291 phosphorylation primes clathrin-dependent Fas endocytosis, which contributes to Fas pro-survival signaling, reveals for the first time the mechanistic link between SFK/SHP-1-dependent Fas tyrosine phosphorylation, internalization route, and signaling choice. We also demonstrate that levels of phosphorylated Y232 and Y291 differ among human cancer types and differentially respond to anticancer therapy, suggesting context-dependent involvement of Fas phosphorylation in cancer. This report provides a new insight into the control of TNF receptor multisignaling by receptor phosphorylation and its implication in cancer biology, which brings us a step closer to overcoming the challenge in handling Fas signaling in treatments of cancer as well as other pathologies such as autoimmune and degenerative diseases., Signalling by the tumor necrosis factor receptor (TNFR) superfamily member Fas can promote either survival or death of a cell, but the mechanism underlying this choice is unclear. This study reveals that the outcome of Fas signalling (death versus survival) is determined by the tyrosine phosphorylation status of its death domain., Author Summary The versatility of the tumor necrosis factor receptor superfamily members in cell fate regulation is well illustrated by the dual signaling generated by one of the most extensively studied members of the family, Fas (CD95/TNFSFR6). Upon binding its ligand, Fas is able to elicit both pro-death and pro-survival signals. Until now, we have lacked mechanistic knowledge about when and how one signaling output of Fas is favored over the other. We demonstrate here that the outcome of Fas signaling is determined by the phosphorylation status of two tyrosine residues (Y232 and Y291) within the death domain. Dephosphorylation of Fas tyrosines by SHP-1 tyrosine phosphatase turns on the pro-apoptotic signal whereas the tyrosine phosphorylation by Src family kinases (SFKs) turns off the pro-apoptotic signal and turns on the pro-survival signal. Furthermore, we provide evidence that Fas tyrosine phosphorylation status may vary among different cancer types and influence the response to anti-cancer treatments. This information reveals an opportunity to use the screening of Fas tyrosine phosphorylation, a newly discovered direct molecular indicator of Fas functional output, to aid the design of Fas-related cancer therapies.

Published
2016

53. A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers

Author

Marta Gut, Iris Pauporté, Cécile Mannina, Sancha Martin, Michael R. Stratton, Frédérique Penault-Llorca, Vincent Le Texier, Laurent Arnould, Pierre Saintigny, Marie-Christine Mathieu, P. Fumoleau, Xavier Pivot, Jean-François Deleuze, Hélène Blanché, Anthony Ferrari, Janice Kielbassa, Eskeatnaf Mulugeta, Olivier Tredan, Sandrine Boyault, Anne Vincent-Salomon, Thomas Bachelot, Emilie Thomas, Jean-Yves Pierga, Odette Mariani, Suzette Delaloge, Ivo Gut, Hervé Bonnefoi, Fabien Calvo, Frédéric Bibeau, Alain Viari, Serena Nik-Zainal, Anne-Sophie Sertier, Gilles Romieu, Maria Rios, Gaëtan MacGrogan, Jocelyne Jacquemier, Laurie Tonon, Gilles Thomas, Jean-Marc Ferrero, Isabelle Treilleux, Daniel Birnbaum, Catherine Bouteille, Carole Tarpin, Centre Léon Bérard [Lyon], Génétique et Biologie du Développement, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Département de Biologie et pathologie des tumeurs [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Gustave Roussy (IGR), 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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Ressources Biologiques [Paris], Institut Curie [Paris], Département de pathologie, Physico-Chimie-Curie (PCC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Department of Medical Oncology [Lyon], UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, UNICANCER, Pathologie mammaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Pôle de Chirurgie Oncologique générale, Gynécologique et Mammaire [Centre Antoine-Lacassagne], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chirurgie gynécologique, mammaire et réparatrice [Saint-Etienne], Clinique Mutualiste Chirurgicale [Saint-Étienne], Direction de la recherche [Gustave Roussy], Centre for Genomic Regulation [Barcelona] (CRG), Universitat Pompeu Fabra [Barcelona] (UPF)-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), The Wellcome Trust Sanger Institute [Cambridge], Institut National du Cancer [Boulogne Billancourt] (INC), 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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS ), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) ( HOTE GREFFON ), Université de Franche-Comté ( UFC ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Validation et identification de nouvelles cibles en oncologie ( VINCO ), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Institut Gustave Roussy ( IGR ), Equipe de recherche sur les traitements individualisés des cancers ( ERTICa ), Université d'Auvergne - Clermont-Ferrand I ( UdA ), UNICANCER - Institut régional du Cancer [Montpellier] ( ICM ), Institut Curie, Institut Bergonié - CRLCC Bordeaux, Physico-Chimie-Curie ( PCC ), Centre National de la Recherche Scientifique ( CNRS ) -INSTITUT CURIE-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Institut de Cancérologie de Lorraine - Alexis Vautrin ( ICL ), CRLCC Antoine Lacassagne, Centre de Recherche en Cancérologie de Marseille ( CRCM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université ( AMU ), Centre for Genomic Regulation [Barcelona] ( CRG ), Universitat Pompeu Fabra [Barcelona]-Centro Nacional de Analisis Genomico [Barcelona] ( CNAG ), Institut National du Cancer [Boulogne Billancourt] ( INC ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale ( ERABLE ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ), Nik-Zainal Abidin, Serena [0000-0001-5054-1727], Apollo - University of Cambridge Repository, 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), Sagot, Marie-France, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), 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 National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Institut Paoli Calmettes, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Paoli-Calmettes-Aix Marseille Université ( AMU ), Université Claude Bernard Lyon 1 ( UCBL ), and Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
0301 basic medicine, DNA Copy Number Variations, Receptor, ErbB-2, Science, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Breast Neoplasms, Biology, Genome, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Germline mutation, Gene duplication, medicine, Humans, Copy-number variation, skin and connective tissue diseases, Genetics, Multidisciplinary, Whole Genome Sequencing, [ SDV ] Life Sciences [q-bio], Gene Expression Profiling, Estrogen Receptor alpha, Gene Amplification, General Chemistry, Amplicon, medicine.disease, 3. Good health, Gene expression profiling, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Human genome, Female, Receptors, Progesterone, Transcriptome
Abstract

HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal–basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage–fusion–bridge mechanism., Breast cancer is separated into multiple subtypes based on the expression of HER2 and hormone receptors. Here, the authors report the whole genome sequence of 64 HER2 positive tumours and show that these can be further separated into four groups with different gene expression profiles and genomic features.

Published
2016

54. Epidermal Growth Factor Receptor Protein Detection in Head and Neck Cancer Patients: A Many-Faceted Picture

Author

Ellen Van Obberghen-Schilling, Jean-Louis Formento, Dominique Grall, Anne Cayre, Dominique de Raucourt, Philippe Giraud, Olivier Dassonville, Sylvain Morinière, Frédérique Penault-Llorca, Marie-Christine Etienne-Grimaldi, René-Jean Bensadoun, Séverine Racadot, Mireille Francoual, Gérard Milano, Juliette Thariat, Laurence Veracini, Lionel Geoffrois, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Dept of Oncopharmacology, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Service d'ORL, Centre Alexis Vautrin (CAV), and Département de pharmacogénomique

Subjects
Cancer Research, Pathology, medicine.medical_specialty, MESH: Receptor, Epidermal Growth Factor, 03 medical and health sciences, 0302 clinical medicine, MESH: Polymorphism, Genetic, medicine, Carcinoma, Humans, Epidermal growth factor receptor, Phosphorylation, [SDV.BDD]Life Sciences [q-bio]/Development Biology, 030304 developmental biology, 0303 health sciences, MESH: Humans, Polymorphism, Genetic, Tissue microarray, MESH: Phosphorylation, biology, business.industry, Head and neck cancer, Cancer, MESH: Carcinoma, Squamous Cell, MESH: Gene Expression Regulation, Neoplastic, medicine.disease, Head and neck squamous-cell carcinoma, MESH: Head and Neck Neoplasms, ErbB Receptors, Gene Expression Regulation, Neoplastic, Oncology, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Cancer research, biology.protein, Biomarker (medicine), Immunohistochemistry, business
Abstract

Purpose: Epidermal growth factor receptor (EGFR) overexpression is associated with poor prognosis in head and neck squamous cell carcinoma (HNSCC). Despite intensive biomarker studies, a consensual method for assessing EGFR protein expression is still lacking. Here we set out to compare three EGFR detection methods in tumor specimens from HNSCC patients. Experimental Design: Tumors were prospectively excised from a series of 79 high-risk HNSCC patients enrolled in a GORTEC-sponsored clinical trial. EGFR expression was determined using a ligand-binding assay on membranes, Western blotting (WB) on membranes and total homogenates, and immunohistochemistry (IHC) on tissue microarrays. In addition, phosphorylated EGFR (pEGFR) was measured by WB on membranes. Results: Distributions and ranges of tumor EGFR expression were method dependent. Moderate positive correlations (Spearman coefficient r ≈ 0.50) were observed between EGFR expression measured by the binding assay and WB or IHC. pEGFR levels positively and significantly correlated with total EGFR expression measured by WB or ligand binding, but not by IHC. The highest correlation (r = 0.85) was observed between EGFR and pEGFR levels, both measured by WB on membranes. Interestingly, the fraction of phosphorylated receptor (pEGFR/EGFR both measured by WB on membranes) significantly declined with increasing tumor EGFR expression, by all assessment methods used. Conclusion: This study shows significant correlations between EGFR detection methods. The observed relationships between EGFR and pEGFR indicate that high-throughput pEGFR/EGFR analyses merit further investigations and consideration for routine use in patient samples. Clin Cancer Res; 18(5); 1313–22. ©2012 AACR.

Published
2012

55. Abiraterone acetate in patients with metastatic castration-resistant prostate cancer: long term outcome of the Temporary Authorization for Use programme in France

Author

Remy Delva, Philippe Beuzeboc, Stéphane Oudard, Nadine Houédé, Brigitte Laguerre, Delphine Topart, Sophie Gourgou, Igor Latorzeff, Hanane Agherbi, Gwenaelle Gravis, Xavier Rebillard, Guilhem Roubaud, Sophie Tartas, Aude Fléchon, Laura Moise, Diego Tosi, Jean-Marc Ferrero, David Azria, Service d'Oncologie Médicale [Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service d'Oncologie Médicale [Paris], Institut Curie [Paris], Service d'Oncologie Médicale [Caen], Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Service d'Oncologie Médicale [Marseille], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'Oncologie Médicale [Angers], Centre Paul Papin, Service d'Oncologie Médicale [Lyon], UNICANCER - Centre Léon Bérard Lyon (Rhône), Clinique Pasteur, Toulouse, Service d'Oncologie Médicale [Nice], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Service d'oncologie médicale [CHU HEGP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'Oncologie Médicale [Rennes], CRLCC Eugène Marquis (CRLCC), Service d'oncologie médicale [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'Oncologie Médicale [Bordeaux], Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Service d'urologie, Clinique Beausoleil, BMC, BMC, Service d'Oncologie médicale [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Clinique Beau Soleil [Montpellier], Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nîmes ( CHRU Nîmes ), Institut de Recherche en Cancérologie de Montpellier ( IRCM - U1194 Inserm - UM ), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), INSTITUT CURIE, Centre Régional de Lutte contre le Cancer François Baclesse ( CRLC François Baclesse ), UNICANCER - Centre Antoine Lacassagne [Nice], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), CRLCC Eugène Marquis ( CRLCC ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), and UNICANCER - Institut Bergonié [Bordeaux]

Subjects
Oncology, Male, Cancer Research, Multivariate analysis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Metastasis, Cohort Studies, chemistry.chemical_compound, Prostate cancer, 0302 clinical medicine, Surgical oncology, Antineoplastic Combined Chemotherapy Protocols, Neoplasm Metastasis, Aged, 80 and over, 0303 health sciences, Prognostic factor, Abiraterone acetate, Middle Aged, Prognosis, 3. Good health, [SDV] Life Sciences [q-bio], Prostatic Neoplasms, Castration-Resistant, Treatment Outcome, Docetaxel, 030220 oncology & carcinogenesis, France, medicine.drug, Cohort study, Research Article, medicine.medical_specialty, Efficacy, Antineoplastic Agents, 03 medical and health sciences, Internal medicine, medicine, Genetics, Humans, 030304 developmental biology, Aged, Gynecology, Chemotherapy, [ SDV ] Life Sciences [q-bio], business.industry, medicine.disease, Metastatic castration-resistant prostate cancer, chemistry, Neoplasm Grading, business, Follow-Up Studies
Abstract

International audience; AbstractBackgroundCOU-AA-301 trial has proved that abiraterone acetate (AA), a selective inhibitor of androgen biosynthesis, improved overall survival (OS) of patients with metastatic castration resistant prostate cancer (mCRPC) after a first line of docetaxel. Based on this result, a Temporary Authorization for Use (TAU) was performed between December 2010 and July 2011 to provide patients with mCRPC the opportunity to receive AA before its commercialization. The aim of this study was to evaluate safety and efficacy of AA treatment in this TAU.MethodsBetween December 2010 and July 2011, we conducted an ambispective, multicentric cohort study and investigated data from 20 centres participating to the AA TAU for patients presenting mCRPC and already treated by a first line of chemotherapy (CT). Statistical analyses of the data were performed using the Stata software v13 to identify predictive and prognostic factors.ResultsAmong the 408 patients, 306 were eligible with a follow-up at 3 years. Median OS was 37.1 months from beginning of CT and 14.6 months from AA introduction. 211 patients (69%) received ≥ 3 months of AA and 95 patients (31%) were treated less than 3 months. In the multivariate analyses, duration of AA was significantly correlated with PSA decrease at 3 months. Additionally, shorter time under AA treatment, presence of multiple sites of metastasis and previous hormonal treatment duration were three independent factors associated with poorer OS. At the time of analysis ten patients were still under treatment for more than 3 years.ConclusionsBiochemical response monitored by PSA changes at 3 months is a strong predictive factor for AA treatment duration. Some high responders’ patients could beneficiate from AA for more than 3 years.

Published
2015

56. Incidence and Characteristics of Pseudoprogression in IDH-mutant High-Grade Gliomas: A POLA Network Study

Author

Antoine Seyve, Caroline Dehais, Olivier Chinot, Apolline Djelad, Elisabeth Cohen-Moyal, Charlotte Bronnimann, Carole Gourmelon, Evelyne Emery, Philippe Colin, Mathieu Boone, Elodie Vauléon, Olivier Langlois, Anna-Luisa di Stefano, Romuald Seizeur, François Ghiringhelli, Anne D’Hombres, Loic Feuvret, Jacques Guyotat, Laurent Capelle, Catherine Carpentier, Louis Garnier, Jérôme Honnorat, David Meyronet, Karima Mokhtari, Dominique Figarella-Branger, François Ducray, Hospices Civils de Lyon, Departement de Neurologie (HCL), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Bordeaux [Bordeaux], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Service de Neurochirurgie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), 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), CHU Amiens-Picardie, CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), Université de Picardie Jules Verne (UPJV), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Culture et Environnements, Préhistoire, Antiquité, Moyen-Age (CEPAM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Service de neurochirurgie [Brest], Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Laboratoire de Traitement de l'Information Medicale (LaTIM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Hospices Civils de Lyon (HCL), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Référence Maladie Rare 'Syndromes neurologiques Paranéoplasiques', Hospices Civils de Lyon (HCL)-Hopital Neurologique, and Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL]

Subjects
Cancer Research, High-grade glioma, Oncology, pseudoprogression, Neurology (clinical), IDH-mutant, chemotherapy, radiotherapy, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background Incidence and characteristics of pseudoprogression in isocitrate dehydrogenase-mutant high-grade gliomas (IDHmt HGG) remain to be specifically described. Methods We analyzed pseudoprogression characteristics and explored the possibility of pseudoprogression misdiagnosis in IDHmt HGG patients, treated with radiotherapy (RT) (with or without chemotherapy [CT]), included in the French POLA network. Pseudoprogression was analyzed in patients with MRI available for review (reference cohort, n = 200). Pseudoprogression misdiagnosis was estimated in this cohort and in an independent cohort (control cohort, n = 543) based on progression-free survival before and after first progression. Results In the reference cohort, 38 patients (19%) presented a pseudoprogression after a median time of 10.5 months after RT. Pseudoprogression characteristics were similar across IDHmt HGG subtypes. In most patients, it consisted of the appearance of one or several infracentimetric, asymptomatic, contrast-enhanced lesions occurring within 2 years after RT. The only factor associated with pseudoprogression occurrence was adjuvant PCV CT. Among patients considered as having a first true progression, 7 out of 41 (17%) in the reference cohort and 35 out of 203 (17%) in the control cohort were retrospectively suspected to have a misdiagnosed pseudoprogression. Patients with a misdiagnosed pseudoprogression were characterized by a time to event and an outcome similar to that of patients with a pseudoprogression but presented with larger and more symptomatic lesions. Conclusion In patients with an IDHmt HGG, pseudoprogression occurs later than in IDH-wildtype glioblastomas and seems not only frequent but also frequently misdiagnosed. Within the first 2 years after RT, the possibility of a pseudoprogression should be carefully considered.

Published
2023

57. A high sensitivity Cherenkov detector for prompt gamma timing and time imaging

Author

M. Jacquet, S. Ansari, M-L. Gallin Martel, A. André, Y. Boursier, M. Dupont, J. Es‐smimih, L. Gallin-Martel, J. Hérault, C. Hoarau, J-P. Hofverberg, D. Maneval, C. Morel, J-F. Muraz, F. Salicis, S. Marcatili, Laboratoire de Physique Subatomique et de Cosmologie (LPSC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Centre de Physique des Particules de Marseille (CPPM), Aix Marseille Université (AMU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), and UNICANCER-Université Côte d'Azur (UCA)

Subjects
[PHYS]Physics [physics], Multidisciplinary, Protontherapy, Fast timing, [PHYS.PHYS.PHYS-INS-DET]Physics [physics]/Physics [physics]/Instrumentation and Detectors [physics.ins-det], Prompt Gamma Time Imaging
Abstract

We recently proposed a new approach for the real-time monitoring of particle therapy treatments with the goal of achieving high sensitivities on the particle range measurement already at limited counting statistics. This method extends the Prompt Gamma (PG) timing technique to obtain the PG vertex distribution from the exclusive measurement of particle Time-Of-Flight (TOF). It was previously shown, through Monte Carlo simulation, that an original data reconstruction algorithm (Prompt Gamma Time Imaging) allows to combine the response of multiple detectors placed around the target. The sensitivity of this technique depends on both the system time resolution and the beam intensity. At reduced intensities (Single Proton Regime—SPR), a millimetric proton range sensitivity can be achieved, provided the overall PG plus proton TOF can be measured with a 235 ps (FWHM) time resolution. At nominal beam intensities, a sensitivity of a few mm can still be obtained by increasing the number of incident protons included in the monitoring procedure. In this work we focus on the experimental feasibility of PGTI in SPR through the development of a multi-channel, Cherenkov-based PG detector with a targeted time resolution of 235 ps (FWHM): the TOF Imaging ARrAy (TIARA). Since PG emission is a rare phenomenon, TIARA design is led by the concomitant optimisation of its detection efficiency and Signal to Noise Ratio (SNR). The PG module that we developed is composed of a small PbF$$_{2}$$ 2 crystal coupled to a silicon photoMultiplier to provide the time stamp of the PG. This module is currently read in time coincidence with a diamond-based beam monitor placed upstream the target/patient to measure the proton time of arrival. TIARA will be eventually composed of 30 identical modules uniformly arranged around the target. The absence of a collimation system and the use of Cherenkov radiators are both crucial to increase the detection efficiency and the SNR, respectively. A first prototype of the TIARA block detector was tested with 63 MeV protons delivered from a cyclotron: a time resolution of 276 ps (FWHM) was obtained, resulting in a proton range sensitivity of 4 mm at 2$$\sigma$$ σ with the acquisition of only 600 PGs. A second prototype was also evaluated with 148 MeV protons delivered from a synchro-cyclotron obtaining a time resolution below 167 ps (FWHM) for the gamma detector. Moreover, using two identical PG modules, it was shown that a uniform sensitivity on the PG profiles would be achievable by combining the response of gamma detectors uniformly distributed around the target. This work provides the experimental proof-of-concept for the development of a high sensitivity detector that can be used to monitor particle therapy treatments and potentially act in real-time if the irradiation does not comply to treatment plan.

Published
2023

58. Role of the HER2 [Ile655Val] genetic polymorphism in tumorogenesis and in the risk of trastuzumab-related cardiotoxicity

Author

Emmanuel Chamorey, Patricia Formento, Jean-Louis Fischel, Rémy Largillier, W. Lescaut, Paul Hofman, Gérard Milano, Gilles Pagès, Sophie Beauclair, J-M Ferrero, Unité de ciblage pharmacologique dans les cancers ORL, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Medical Oncology Department, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Biostatistics Unit, INSERM ESPRI 2006, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
Oncology, Receptor, ErbB-2, MESH: Protein Isoforms, MESH: Base Sequence, Polymerase Chain Reaction, MESH: Antibodies, Monoclonal, Mice, MESH: Aged, 80 and over, 0302 clinical medicine, Trastuzumab, Genotype, Protein Isoforms, MESH: Animals, skin and connective tissue diseases, Aged, 80 and over, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH: Heart Diseases, Antibodies, Monoclonal, Heart, Hematology, Middle Aged, Immunohistochemistry, 3. Good health, MESH: Mutagenesis, Site-Directed, Cell Transformation, Neoplastic, MESH: Neoplasms, Experimental, MESH: Receptor, erbB-2, 030220 oncology & carcinogenesis, Monoclonal, Experimental pathology, Female, Polymorphism, Restriction Fragment Length, medicine.drug, Adult, medicine.medical_specialty, Heart Diseases, Blotting, Western, Molecular Sequence Data, Mice, Nude, Antineoplastic Agents, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antibodies, Monoclonal, Humanized, Transfection, 03 medical and health sciences, Breast cancer, Internal medicine, MESH: Polymorphism, Genetic, MESH: Mice, Nude, medicine, Animals, Humans, MESH: Blotting, Western, MESH: Mice, neoplasms, Aged, 030304 developmental biology, Cardiotoxicity, Polymorphism, Genetic, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, MESH: Polymorphism, Restriction Fragment Length, business.industry, MESH: Transfection, MESH: Adult, MESH: Immunohistochemistry, MESH: Polymerase Chain Reaction, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Neoplasms, Experimental, medicine.disease, MESH: Heart, MESH: Cell Transformation, Neoplastic, Pharmacodynamics, Immunology, Mutagenesis, Site-Directed, MESH: Antineoplastic Agents, Gene polymorphism, business, MESH: Female, MESH: Breast Neoplasms
Abstract

Background To examine the impact of a frequent her2 gene polymorphism (Ile655Val) on tumor growth and on the pharmacodynamics of treatment by trastuzumab. Patients and methods Experimental study: The growth characteristics of cells expressing the Ile or Val isoform were examined in vitro and after injection into nude mice. The effect of trastuzumab was determined in both experimental models. Clinical study: 61 patients with advanced breast cancers and treated by trastuzumab were genotyped for HER2 by PCR–RFLP. The influence of HER2 genotype on the trastuzumab treatment was examined. Results Experimental study: HER2-expressing cells acquired the characteristics of tumor cells. The Val isoform-expressing cells showed the highest growth capacity and developed aggressive tumors sensitive to trastuzumab. Clinical study: There was no link between tumor response or survival and HER2 genotype. All cases of treatment-related cardiotoxicity were found in the Ile/Val group and there was no cardiac toxicity in the Val/Val and Ile/Ile patients. Conclusions This study establishes a clear-cut difference between the two HER2 isoforms regarding their tumorogenic potential with an advantage for the Val/HER2 isoform. In breast cancer patients treated with trastuzumab, the presence of a Val allele may constitute a risk factor for cardiac toxicity.

Published
2007

59. A new subtype of high-grade mandibular osteosarcoma with RASAL1/MDM2 amplification

Author

Sébastien Lepreux, Christine Galant, Isabelle Peyrottes, Julie Meilleroux, Séverine Valmary-Degano, Corinne Bouvier, Mounia Ouali, Juliette Thariat, Gonzague de Pinieux, Anne Gomez-Brouchet, Anne-Valérie Decouvelaere, Sébastien Aubert, Frédérique Larousserie, Maxime Guérin, Nathalie Stock, Jean-Michel Coindre, Elisabeth Cassagnau, Fabrice Projetti, Béatrice Marie, Institut de pharmacologie et de biologie structurale ( IPBS ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Toulouse [Toulouse], Centre Antoine Lacassagne de Nice, Hôpital de la Timone [CHU - APHM] ( TIMONE ), Département d'anatomopathologie, biopathologie, Centre Léon Bérard [Lyon], Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), CHU Bordeaux [Bordeaux], Service de Pathologie, Institut Bergonié, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Laboratoire d'anatomie pathologique [Besancon], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz-Université de Franche-Comté ( UFC ), Department of Pathology, Teaching Hospital Cochin, Université Paris Descartes - Paris 5 ( UPD5 ), CHU Pontchaillou [Rennes], Cliniques Universitaires Saint-Luc [Bruxelles], Service de Pathologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Department of Pathology, CRLCC Antoine Lacassagne, CHRU Tours, Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital de Rangueil, Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) ( CEF2P / CARCINO ), Université Bourgogne Franche-Comté [COMUE] ( UBFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), CHU Cochin [AP-HP], Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), 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 d'Anatomie pathologique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO)

Subjects
0301 basic medicine, Male, Pathology, Rare Cancer Network, [SDV]Life Sciences [q-bio], Long bone, DNA Mutational Analysis, Réseau d’Expertise Français des Cancers ORL Rares, Mandibular Neoplasms, bone tumor, Polymerase Chain Reaction, 0302 clinical medicine, RASAL1, Gene duplication, GTP-Binding Protein alpha Subunits, Gs, Groupe Français de Pathologistes Osseux, Aged, 80 and over, ossifying fibroma, Groupe Sarcome Français – Groupe d’Etude des Tumeurs Osseuses, Réseau de référence en sarcomes osseux, GTPase-Activating Proteins, Cell Differentiation, Proto-Oncogene Proteins c-mdm2, Middle Aged, Prognosis, Immunohistochemistry, GSF-GETO, 3. Good health, RCN, Real-time polymerase chain reaction, medicine.anatomical_structure, Phenotype, 030220 oncology & carcinogenesis, Osteosarcoma, Female, Adult, musculoskeletal diseases, medicine.medical_specialty, AbbreviationsGFPO, Adolescent, Biology, Pathology and Forensic Medicine, 03 medical and health sciences, Young Adult, MDM2, osteosarcoma, medicine, GNAS complex locus, Biomarkers, Tumor, Chromogranins, Humans, Genetic Predisposition to Disease, molecular analysis, neoplasms, Aged, Retrospective Studies, [ SDV ] Life Sciences [q-bio], Fibrous dysplasia, Gene Amplification, RESOS, medicine.disease, REFCOR, stomatognathic diseases, 030104 developmental biology, Mutation, biology.protein
Abstract

International audience; In contrast to long bone osteosarcoma, mandibular osteosarcoma are highly heterogeneous and morphologically overlap with benign tumors, obscuring diagnosis and treatment selection. Molecular characterization is difficult due to the paucity of available specimens of this rare disease. We aimed to characterize the spectrum of mandibular osteosarcoma using immunohistochemistry and molecular techniques (quantitative polymerase chain reaction, sequencing) and compare them with benign fibro-osseous lesions. Forty-nine paraffin-embedded mandible osteosarcoma tissue samples were collected retrospectively and compared with 10 fibrous dysplasia and 15 ossifying fibroma cases. These were analyzed for molecular markers thought to differ between the different diseases and subtypes: MDM2 (murine double-minute type-2) overexpression; GNAS (guanine nucleotide-binding protein/alpha subunit) mutations; and amplification of MDM2 and/or RASAL1 (RAS protein activator like-1). Five fibroblastic high-grade osteosarcoma subtypes showed MDM2 amplification, including two with a microscopic appearance of high-grade osteosarcoma with part low-grade osteosarcoma (differentiated/dedifferentiated osteosarcoma) and MDM2 overexpression. The other three contained a co-amplification of MDM2 and RASAL1, a signature also described for juvenile ossifying fibroma, with no overexpression of MDM2. These were of the giant cell-rich high-grade osteosarcoma, with areas mimicking juvenile ossifying fibroma (ossifying-fibroma-like osteosarcoma). Our results show that some diagnosed high-grade osteosarcoma are differentiated/dedifferentiated osteosarcomas and harbor an overexpression and amplification of MDM2. In addition, juvenile ossifying fibromas can potentially evolve into giant cell-rich high-grade osteosarcomas and are characterized by a RASAL1 amplification (osteosarcoma with juvenile ossifying fibroma-like genotype). Thus, the presence of a RASAL1 amplification in ossifying fibroma may indicate a requirement for closer follow-up and more aggressive management

Published
2015

60. Nodular lymphocyte predominant Hodgkin lymphoma: a Lymphoma Study Association retrospective study

Author

Emmanuelle Nicolas-Virelizier, Emmanuel Gyan, Peggy Dartigues, Serge Bologna, Florence Broussais-Guillaumot, Emmanuel Bachy, Julien Lazarovici, Marc André, Mathilde Hunault-Berger, Jean Gabarre, Christophe Fermé, Pauline Brice, Richard Delarue, Luc-Matthieu Fornecker, Olivier Casasnovas, Virginie Roland, Thomas Gastinne, Aspasia Stamatoullas, Isabelle Gaillard, Frédérique Orsini-Piocelle, Lucie Oberic, Nicolas Mounier, Frederic Peyrade, Mohamed Touati, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (MGD) Service d'hématologie, Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité des hémopathies lymphoïdes [CHU Henri Mondor], CHU Henri Mondor, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service des maladies du sang [CHU Angers], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service d’Hématologie [Institut Paoli Calmettes, Marseille], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'Hématologie et thérapie cellulaire [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Service d'hématologie biologique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'hématologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie [CH Annecy], CH Annecy, Département d’Hématologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Service d'Hématologie Biologique [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), Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Centre hospitalier universitaire de Nantes (CHU Nantes), Département Oncologie Médicale [Nice], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Service d'Hématologie [CH Perpignan], CH Perpignan, CHU Dinant-Godinne UCL Namur [Yvoir, Belgique], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hématologie, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Institut Gustave Roussy ( IGR ), Laboratoire de Psychologie et NeuroCognition ( LPNC ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Université Grenoble Alpes ( UGA ), Institut Universitaire du Cancer de Toulouse - Oncopole ( IUCT Oncopole - UMR 1037 ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Etude et de Recherche Travail Organisation Pouvoir ( CERTOP ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès ( UT2J ) -Institut national universitaire Champollion - Albi ( INU Champollion ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers, Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), CIC - Tours, CHRU Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Orange Labs [Paris], Telecom Orange, Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CRLCC Henri Becquerel, Service d'Hématologie Clinique [Nantes] ( Unité d'Investigation Clinique ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, AGROCAMPUS OUEST, Centre International de Recherche en Infectiologie ( CIRI ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Swedish Institute of Space Physics [Uppsala] ( IRF ), Bernardo, Elizabeth, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Oncology, Adult, Male, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Models, Biological, Disease-Free Survival, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, immune system diseases, Risk Factors, Internal medicine, hemic and lymphatic diseases, Medicine, Humans, education, Survival rate, Retrospective Studies, Aged, education.field_of_study, Chemotherapy, business.industry, Hazard ratio, Articles, Hematology, Middle Aged, medicine.disease, Combined Modality Therapy, Hodgkin Disease, 3. Good health, Surgery, Lymphoma, Radiation therapy, Survival Rate, Rituximab, Female, business, Watchful waiting, medicine.drug
Abstract

International audience; Nodular lymphocyte predominant Hodgkin lymphoma represents a distinct entity from classical Hodgkin lymphoma. We conducted a retrospective study to investigate the management of patients with nodular lymphocyte predominant Hodgkin lymphoma. Clinical characteristics, treatment and outcome of adult patients with nodular lymphocyte predominant Hodgkin lymphoma were collected in Lymphoma Study Association centers. Progression-free survival (PFS) and overall survival (OS) were analyzed, and the competing risks formulation of a Cox regression model was used to control the effect of risk factors on relapse or death as competing events. Among 314 evaluable patients, 82.5% had early stage nodular lymphocyte predominant Hodgkin lymphoma. Initial management consisted in watchful waiting (36.3%), radiotherapy (20.1%), rituximab (8.9%), chemotherapy or immuno-chemotherapy (21.7%), combined modality treatment (12.7%), or radiotherapy plus rituximab (0.3%). With a median follow-up of 55.8 months, the 10-year PFS and OS estimates were 44.2% and 94.9%, respectively. The 4-year PFS estimates were 79.6% after radiotherapy, 77.0% after rituximab alone, 78.8% after chemotherapy or immuno-chemotherapy, and 93.9% after combined modality treatment. For the whole population, early treatment with chemotherapy or radiotherapy, but not rituximab alone (Hazard ratio 0.695 [0.320-1.512], P=0.3593) significantly reduced the risk of progression compared to watchful waiting (HR 0.388 [0.234-0.643], P=0.0002). Early treatment appears more beneficial compared to watchful waiting in terms of progression-free survival, but has no impact on overall survival. Radiotherapy in selected early stage nodular lymphocyte predominant Hodgkin lymphoma, and combined modality treatment, chemotherapy or immuno-chemotherapy for other patients, are the main options to treat adult patients with a curative intent.

Published
2015

61. Vascular endothelial growth factor-A and Poly(A) binding protein-interacting protein 2 expression in human head and neck carcinomas: correlation and prognostic significance

Author

Emmanuel Chamorey, Jean-Louis Formento, C. Onesto, Ramaioli A, Gilles Pagès, Hannoun-Lévi Jm, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Dept of Radiation Oncology, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Dept. of Statistics, and Dept of Oncopharmacology

Subjects
Male, Vascular Endothelial Growth Factor A, Cancer Research, Pathology, Cellular differentiation, medicine.medical_treatment, Cell, MESH: Laryngeal Neoplasms, MESH: Aged, 80 and over, 0302 clinical medicine, MESH: RNA, Small Interfering, Tumor Cells, Cultured, RNA, Small Interfering, vascular endothelial growth factor-A, MESH: Aged, Aged, 80 and over, 0303 health sciences, MESH: Middle Aged, RNA-Binding Proteins, Cell Differentiation, Middle Aged, Prognosis, Poly(A) binding protein-interacting protein 2, head and neck carcinoma, 3. Good health, Survival Rate, Vascular endothelial growth factor A, Cytokine, medicine.anatomical_structure, Oncology, MESH: Repressor Proteins, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Female, MESH: Cell Differentiation, Adult, medicine.medical_specialty, MESH: Survival Rate, Blotting, Western, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Prognosis, 03 medical and health sciences, medicine, MESH: Blotting, Northern, MESH: Blotting, Western, Humans, prognostic value, MESH: Tumor Cells, Cultured, Laryngeal Neoplasms, Molecular Diagnostics, Survival rate, Aged, Retrospective Studies, 030304 developmental biology, MESH: Humans, MESH: Vascular Endothelial Growth Factor A, Growth factor, Head and neck cancer, MESH: Adult, MESH: Retrospective Studies, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Blotting, Northern, medicine.disease, human tumour specimens, Head and neck squamous-cell carcinoma, MESH: Male, MESH: Head and Neck Neoplasms, Repressor Proteins, MESH: RNA-Binding Proteins, Cancer research, MESH: Female
Abstract

International audience; Vascular endothelial growth factor-A (VEGF-A) has been demonstrated to play an important role in tumour angiogenesis and to influence prognosis in many cancers. However its prognostic value in head and neck squamous cell carcinomas (HNSCCs) remains controversial. Therefore, we investigated the clinical relevance of VEGF-A expression in HNSCCs and analysed whether its expression was associated with PAIP2 protein levels, a VEGF-A mRNA-binding partner that strongly regulates VEGF-A expression in tissue culture. We determined the correlation of VEGF-A and PAIP2 protein levels, quantitatively evaluated in tumour tissue homogenates from 54 patients with HNSCC, to clinicopathological parameters. We showed that VEGF-A expression in HNSCC is correlated to the stage of tumour differentiation (P=0.050) and is an independent prognostic factor for progression-free survival (P=0.001) and overall survival (P=0.0004). In a pharynx carcinoma cell line, we demonstrated by RNA interference that VEGF-A expression is closely controlled by PAIP2. Moreover, in human HNSCCs, VEGF-A expression is significantly correlated to PAIP2 protein levels (P=0.0018). Nevertheless, PAIP2 expression is associated with neither clinicopathological factors nor patient's survival. Our data suggest that, in contrast to PAIP2 protein levels, which are unrelated to tumour prognosis, VEGF-A expression could serve as a prognostic marker in head and neck cancer and may be helpful for targeted therapies.

Published
2006

62. Intensive chemotherapy followed by autologous stem cell transplantation in primary central nervous system lymphomas (PCNSLs). Therapeutic outcomes in real life—experience of the French Network

Author

Schenone, Laurence, Houillier, Caroline, Tanguy, Marie Laure, Choquet, Sylvain, Agbetiafa, Kossi, Ghesquières, Hervé, Damaj, Gandhi, Schmitt, Anna, Bouabdallah, Krimo, Ahle, Guido, Gressin, Remy, Cornillon, Jérôme, Houot, Roch, Marolleau, Jean-Pierre, Fornecker, Luc-Matthieu, Chinot, Olivier, Peyrade, Frédéric, Bouabdallah, Reda, Moluçon-Chabrot, Cécile, Gyan, Emmanuel, Chauchet, Adrien, Casasnovas, Olivier, Oberic, Lucie, Delwail, Vincent, Abraham, Julie, Roland, Virginie, Waultier-Rascalou, Agathe, Willems, Lise, Morschhauser, Franck, Fabbro, Michel, Ursu, Renata, Thieblemont, Catherine, Jardin, Fabrice, Tempescul, Adrian, Malaise, Denis, Touitou, Valérie, Nichelli, Lucia, Le Garff-Tavernier, Magali, Plessier, Aurélie, Bourget, Philippe, Bonmati, Caroline, Wantz-Mézières, Sophie, Giordan, Quentin, Dorvaux, Véronique, Charron, Cyril, Jabeur, Waliyde, Hoang-Xuan, Khê, Taillandier, Luc, Soussain, Carole, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département d'hématologie, Institut Curie, Site Saint-Cloud, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut Bergonié [Bordeaux], UNICANCER, CHU Bordeaux [Bordeaux], Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Centre Hospitalier Universitaire [Grenoble] (CHU), Institut de Cancérologie Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Strasbourg, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d’Hématologie Biologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Dupuytren [CHU Limoges], Centre Hospitalier Saint Jean de Perpignan, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut du Cancer de Montpellier (ICM), Hopital Saint-Louis [AP-HP] (AP-HP), NF-kappaB, Différenciation et Cancer (OncokappaB (URP_7324)), Université Paris Cité (UPCité), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Département d'Oncologie Chirurgicale [Institut Curie], Institut Curie [Paris], Laboratoire d'Imagerie Translationnelle en Oncologie (LITO ), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Beaujon [AP-HP], CHU Necker - Enfants Malades [AP-HP], Biology, genetics and statistics (BIGS), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Élie Cartan de Lorraine (IECL), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut Élie Cartan de Lorraine (IECL), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Hôpital de Mercy, Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Hôpital Ambroise Paré [AP-HP], Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche en Automatique de Nancy (CRAN), Institut Curie - Saint Cloud (ICSC), Immunité et cancer (U932), and We thank the clinicians involved in the French National 'Lymphome Oculo-Cérébral' LOC network, part of the network for rare cancers of the central nervous system, 'RENOCLIP-LOC Network', approved by the French National Institute of Cancer (INCa).

Subjects
Transplantation, Hematology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; We analysed the therapeutic outcomes of all consecutive patients with primary central nervous system lymphoma (PCNSL) registered in the prospective French database for PCNSL and treated with intensive chemotherapy (IC) followed by autologous stem cell transplantation (IC-ASCT) between 2011 and November 2019 (271 patients recruited, 266 analysed). In addition, treatment-related complications of thiotepa-based IC-ASCT were analysed from the source files of 85 patients from 3 centers. Patients had received IC-ASCT either in first-line treatment (n\,=\,147) or at relapse (n\,=\,119). The median age at IC-ASCT was 57 years (range: 22-74). IC consisted of thiotepa-BCNU (n\,=\,64), thiotepa-busulfan (n\,=\,24), BCNU-etoposide-cytarabine-melphalan (BEAM, n\,=\,36) and thiotepa-busulfan-cyclophosphamide (n\,=\,142). In multivariate analysis, BEAM and ASCT beyond the first relapse were adverse prognostic factors for relapse risk. The risk of treatment-related mortality was higher for ASCT performed beyond the first relapse and seemed higher for thiotepa-busulfan-cyclophosphamide. Thiotepa-BCNU tends to result in a higher relapse rate than thiotepa-busulfan-cyclophosphamide and thiotepa-busulfan. This study confirms the role of IC-ASCT in first-line treatment and at first-relapse PCNSL (5-year overall survival rates of 80 and 50%, respectively). The benefit/risk ratio of thiotepa-busulfan/thiotepa-busulfan-cyclophosphamide-ASCT could be improved by considering ASCT earlier in the course of the disease and dose adjustment of the IC.

Published
2022

63. Are labels informative in semi-supervised learning?Estimating and leveraging the missing-data mechanism

Author

Sportisse, Aude, Schmutz, Hugo, Humbert, Olivier, Bouveyron, Charles, Mattei, Pierre-Alexandre, Modèles et algorithmes pour l’intelligence artificielle (MAASAI), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-Laboratoire Jean Alexandre Dieudonné (LJAD), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Scalable and Pervasive softwARe and Knowledge Systems (Laboratoire I3S - SPARKS), Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA), UMR E4320 (TIRO-MATOs), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA), Laboratoire Jean Alexandre Dieudonné (LJAD), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), and UNICANCER-Université Côte d'Azur (UCA)

Subjects
semi-supervised learning, missing data, deep learning, [STAT.OT]Statistics [stat]/Other Statistics [stat.ML], MNAR
Abstract

Semi-supervised learning is a powerful technique for leveraging unlabeled data to improve machine learning models, but it can be affected by the presence of “informative” labels, which occur when some classes are more likely to be labeled than others. In the missing data literature, such labels are called missing not at random. In this paper, we propose a novel approach to address this issue by estimating the missing-data mechanism and using inverse propensity weighting to debias any SSL algorithm, including those using data augmentation. We also propose a likelihood ratio test to assess whether or not labels are indeed informative. Finally, we demonstrate the performance of the proposed methods on different datasets, in particular on two medical datasets for which we design pseudo-realistic missing data scenarios.

Published
2023

64. Learning a confidence score and the latent space of a new supervised autoencoder for diagnosis and prognosis in clinical metabolomic studies

Author

David Chardin, Cyprien Gille, Thierry Pourcher, Olivier Humbert, Michel Barlaud, Université Côte d'Azur (UCA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), UMR E4320 (TIRO-MATOs), 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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA), and ANR-19-P3IA-0002,3IA@cote d'azur,3IA Côte d'Azur(2019)

Subjects
Machine Learning, Structural Biology, [MATH.MATH-ST]Mathematics [math]/Statistics [math.ST], Applied Mathematics, Computational Biology, Humans, Metabolomics, Neural Networks, Computer, Molecular Biology, Biochemistry, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Algorithms, Computer Science Applications
Abstract

Background Presently, there is a wide variety of classification methods and deep neural network approaches in bioinformatics. Deep neural networks have proven their effectiveness for classification tasks, and have outperformed classical methods, but they suffer from a lack of interpretability. Therefore, these innovative methods are not appropriate for decision support systems in healthcare. Indeed, to allow clinicians to make informed and well thought out decisions, the algorithm should provide the main pieces of information used to compute the predicted diagnosis and/or prognosis, as well as a confidence score for this prediction. Methods Herein, we used a new supervised autoencoder (SAE) approach for classification of clinical metabolomic data. This new method has the advantage of providing a confidence score for each prediction thanks to a softmax classifier and a meaningful latent space visualization and to include a new efficient feature selection method, with a structured constraint, which allows for biologically interpretable results. Results Experimental results on three metabolomics datasets of clinical samples illustrate the effectiveness of our SAE and its confidence score. The supervised autoencoder provides an accurate localization of the patients in the latent space, and an efficient confidence score. Experiments show that the SAE outperforms classical methods (PLS-DA, Random Forests, SVM, and neural networks (NN)). Furthermore, the metabolites selected by the SAE were found to be biologically relevant. Conclusion In this paper, we describe a new efficient SAE method to support diagnostic or prognostic evaluation based on metabolomics analyses.

Published
2022

65. A New KIT Mutation (N505I) in Acral Melanoma Confers Constitutive Signaling, Favors Tumorigenic Properties, and Is Sensitive to Imatinib

Author

Maryline Allegra, Damien Giacchero, Jean-Philippe Lacour, Philippe Bahadoran, Paul Hofman, Robert Ballotti, Catherine Butori, Coralie Segalen, Corine Bertolotto, Véronique Hofman, Nicolas Dumaz, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Medical Oncology Department [Nice], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), 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), Laboratory of Clinical and Experimental Pathology, Louis Pasteur Hospital, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de référence de dermatologie pédiatrique, Centre Hospitalier Universitaire de Nice (CHU Nice), Centre méditérannéen de médecine moléculaire (C3M), 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 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), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), and BERTOLOTTO-BALLOTTI, BERTOLOTTO-BALLOTTI

Subjects
business.industry, Imatinib, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Biology, Dermatology, Kit mutation, Biochemistry, 3. Good health, [SDV.CAN] Life Sciences [q-bio]/Cancer, Acral melanoma, Cancer research, medicine, business, Molecular Biology, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), ComputingMilieux_MISCELLANEOUS, medicine.drug
Abstract

International audience; no abstract

Published
2014

66. Long-term hospitalisations in survivors of paediatric solid tumours in France

Author

Daniel, Bejarano-Quisoboni, Nathalie, Pelletier-Fleury, Rodrigue S, Allodji, Brice, Fresneau, Majorie, Boussac, Hélène, Pacquement, François, Doz, Delphine, Berchery, Claire, Pluchart, Piere-Yves, Bondiau, Julie, Nys, Angela, Jackson, Charlotte, Demoor-Goldschmidt, Agnes, Dumas, Cécile, Thomas-Teinturier, Boris, Schwartz, Neige, Journy, Carole, Rubino, Giao, Vu-Bezin, Dominique, Valteau-Couanet, Chiraz, El-Fayech, Christelle, Dufour, Nadia, Haddy, Florent, de Vathaire, 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, Institut Gustave Roussy (IGR), Caisse primaire d'assurance maladie (CPAM), Institut Curie [Paris], Université Paris Cité (UPCité), Institut Claudius Regaud, Centre Hospitalier Universitaire de Reims (CHU Reims), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), 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 Paris Cité (UPCité), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Agence Nationale de la Recherche, ANR, Fondation ARC pour la Recherche sur le Cancer, ARC, Ligue Contre le Cancer: RAB20035LLA, Université Paris-Saclay: 9R_2019_PSU000101141_Upsud, École Polytechnique, Université Paris-Saclay, Sciences et Technologies de l'information et de la Communication, Université Paris-Saclay, STIC DS, fr:STIC, Fondation Gustave Roussy, This work were supported by Université Paris-Saclay (Grant no. 9R_2019_PSU000101141_Upsud), Ligue Contre le Cancer (Grant no. N°RAB20035LLA), French Society of Cancer in Children and adolescents, Fondation Gustave Roussy (Grant no. PSI Interval), Fondation ARC pour la Recherche sur le Cancer (Grant no. POPHarC program), Agence Nationale de la Recherche (Grant no. ANR, HOPE-EPI project)., and HAL UVSQ, Équipe

Subjects
Hospitalization, [SDV] Life Sciences [q-bio], Cross-Sectional Studies, Multidisciplinary, Risk Factors, Neoplasms, [SDV]Life Sciences [q-bio], Humans, Multimorbidity, Survivors, Child
Abstract

The late effects of treatments for childhood cancers may lead to severe and multiple health conditions requiring hospitalisation. We aimed to estimate the hospitalisation rate among childhood cancer survivors (CCS) in France, to compare them with the general population and to investigate the associated factors. We matched total of 5439 5-year solid CCS diagnosed before the age of 21 between 1945 and 2000 by sex, birth year and region of residence to 386,073 individuals of the French general population. After linkage with the national hospital discharge database, we estimated the relative hospitalisation rate (RHR), the absolute excess risks (AERs) and the relative bed-day ratio (RBDR) during 2006–2018. We used generalised linear models to estimate associations between hospitalisation and survivor characteristics. Overall, the RHR was 2.49 (95% confidence interval [CI] 2.46–2.52) and the RBDR was 3.49 (95% CI 3.46–3.51). We found that neoplasm-related hospitalisations had the highest AER (105.8 per 1000 person-years), followed by genitourinary system diseases (34.4 per 1000 person-years) and cardiovascular diseases (19.2 per 1000 person-years). In adjusted analysis, CCS treated with chemotherapy (risk ratio [RR] 1.62, 95% CI 1.53–1.70), radiotherapy (RR 2.11, 95% CI 1.99–2.24) or both (RR 2.59, 95% CI 2.46–2.73) had a higher risk of hospitalisation than the ones who had not received any of these treatments. CCS treated during the past decades by chemotherapy and/or radiotherapy now had a higher hospitalisation risk for all main categories of diagnosis than the general population. Prevention strategies and medical surveillance programmes may promote a long-term decrease in the hospitalisation rate among CSS.

Published
2022

67. Autofluorescence identifies highly phagocytic tissue-resident macrophages in mouse and human skin and cutaneous squamous cell carcinoma

Author

Pierre Bourdely, Luciana Petti, Sokchea Khou, Aida Meghraoui-Kheddar, Roxane Elaldi, Julie Cazareth, Noushine Mossadegh-Keller, Julien Boyer, Michael H. Sieweke, Gilles Poissonnet, Anne Sudaka, Veronique M. Braud, Fabienne Anjuère, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biotechnology Center, and Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden = Dresden University of Technology (TU Dresden), Institut Universitaire de la Face et du Cou [Nice], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), and ANR-15-IDEX-0001,UCA JEDI,Idex UCA JEDI(2015)

Subjects
squamous cell carcinoma, Adult, function, skin, Skin Neoplasms, [SDV]Life Sciences [q-bio], Macrophages, Immunology, autofluorescence, Monocytes, Mice, Phagocytosis, Carcinoma, Squamous Cell, Humans, Animals, Immunology and Allergy
Abstract

Macrophages from human and mouse skin share phenotypic and functional features, but remain to be characterized in pathological skin conditions. Skin-resident macrophages are known to derive from embryonic precursors or from adult hematopoiesis. In this report, we investigated the origins, phenotypes and functions of macrophage subsets in mouse and human skin and in cutaneous squamous cell carcinoma (cSCC) using the spectral flow cytometry technology that enables cell autofluorescence to be considered as a full-fledged parameter. Autofluorescence identifies macrophage subsets expressing the CD206 mannose receptor in human peri-tumoral skin and cSCC. In mouse, all AF+ macrophages express the CD206 marker, a subset of which also displaying the TIM-4 marker. While TIM-4-CD206+ AF+ macrophages can differentiate from bone-marrow monocytes and infiltrate skin and tumor, TIM-4 identifies exclusively a skin-resident AF+ macrophage subset that can derive from prenatal hematopoiesis which is absent in tumor core. In mouse and human, AF+ macrophages from perilesional skin and cSCC are highly phagocytic cells contrary to their AF- counterpart, thus identifying autofluorescence as a bona fide marker for phagocytosis. Our data bring to light autofluorescence as a functional marker characterizing subsets of phagocytic macrophages in skin and cSCC. Autofluorescence can thus be considered as an attractive marker of function of macrophage subsets in pathological context.

Published
2022
Full Text
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68. 18FDG PET/CT and Machine Learning for the prediction of lung cancer response to immunotherapy

Author

Schmutz, Hugo, Mattei, Pierre-Alexandre, Contu, Sara, Chardin, David, Humbert, Olivier, Modèles et algorithmes pour l’intelligence artificielle (MAASAI), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-Laboratoire Jean Alexandre Dieudonné (LJAD), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Scalable and Pervasive softwARe and Knowledge Systems (Laboratoire I3S - SPARKS), Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA), UMR E4320 (TIRO-MATOs), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA), Laboratoire Jean Alexandre Dieudonné (LJAD), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), and UNICANCER-Université Côte d'Azur (UCA)

Subjects
[SDV]Life Sciences [q-bio], [INFO]Computer Science [cs]
Abstract

International audience; In patients with non-small cell lung cancer (NSCLC) treated with immunotherapy, individual biological and PET imaging prognostic biomarkers have been recently identified. However, combination of biomarkers has not been studied yet. The purpose of this study is to combine clinical, biological and 18FDG PET/CT parameters and use machine-learning algorithms to build more accurate prognostic models of NSCLC response to immunotherapy

Published
2022

69. Development and validation of a radiomic model for the diagnosis of dopaminergic denervation on [18F]FDOPA PET/CT

Author

Victor Comte, Hugo Schmutz, David Chardin, Fanny Orlhac, Jacques Darcourt, Olivier Humbert, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Modèles et algorithmes pour l’intelligence artificielle (MAASAI), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-Laboratoire Jean Alexandre Dieudonné (LJAD), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Scalable and Pervasive softwARe and Knowledge Systems (Laboratoire I3S - SPARKS), Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA), UMR E4320 (TIRO-MATOs), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA), and ANR-19-P3IA-0002,3IA@cote d'azur,3IA Côte d'Azur(2019)

Subjects
Parkinsonian Disorders, Positron Emission Tomography Computed Tomography, Positron-Emission Tomography, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Humans, Radiology, Nuclear Medicine and imaging, General Medicine, Radiopharmaceuticals, Denervation, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
Abstract

Purpose FDOPA PET shows good performance for the diagnosis of striatal dopaminergic denervation, making it a valuable tool for the differential diagnosis of Parkinsonism. Textural features are image biomarkers that could potentially improve the early diagnosis and monitoring of neurodegenerative parkinsonian syndromes. We explored the performances of textural features for binary classification of FDOPA scans. Methods We used two FDOPA PET datasets: 443 scans for feature selection, and 100 scans from a different PET/CT system for model testing. Scans were labelled according to expert interpretation (dopaminergic denervation versus no dopaminergic denervation). We built LASSO logistic regression models using 43 biomarkers including 32 textural features. Clinical data were also collected using a shortened UPDRS scale. Results The model built from the clinical data alone had a mean area under the receiver operating characteristics (AUROC) of 63.91. Conventional imaging features reached a maximum score of 93.47 but the addition of textural features significantly improved the AUROC to 95.73 (p p Conclusion A simple model with three radiomic features can identify pathologic FDOPA PET scans with excellent sensitivity and specificity. Textural features show promise for the diagnosis of parkinsonian syndromes.

Published
2022

70. Coupling live-cell imaging and in situ isolation of the same single cell to profile the transient states of predicted drug-tolerant cells

Author

Benjamin Bian, Agnès Paquet, Marie-Jeanne Arguel, Mickael Meyer, Ludovic Peyre, Asma Chalabi, Marielle Péré, Kevin Lebrigand, Rainer Waldmann, Pascal Barbry, Paul Hofman, Jérémie Roux, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Biological control of artificial ecosystems (BIOCORE), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'océanographie de Villefranche (LOV), Institut national des sciences de l'Univers (INSU - CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de la Mer de Villefranche (IMEV), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de la Mer de Villefranche (IMEV), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA), Interdisciplinary Institute for Artificial Intelligence (3iA Côte d’Azur), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), and UNICANCER-Université Côte d'Azur (UCA)

Subjects
General Immunology and Microbiology, General Neuroscience, [SDV]Life Sciences [q-bio], [MATH.MATH-DS]Mathematics [math]/Dynamical Systems [math.DS], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, General Biochemistry, Genetics and Molecular Biology, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], [INFO.INFO-LG]Computer Science [cs]/Machine Learning [cs.LG], [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.IB]Life Sciences [q-bio]/Bioengineering, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [INFO.INFO-BT]Computer Science [cs]/Biotechnology
Abstract

International audience; Cell response variability is a starting point in cancer drug resistance that has been difficult to analyze because the tolerant cell states are short lived. Here, we present fate-seq, an approach to isolate single cells in their transient states of drug sensitivity or tolerance before profiling. The drug response is predicted in live cells, which are laser-captured by microdissection before any drug-induced change can alter their states. This framework enables the identification of the cell-state signatures causing differential cell decisions upon treatment.

Published
2022

71. Radiation-enhanced cell migration/invasion process: a review

Author

Antonin Levy, Jean-Baptiste Guy, Gersende Alphonse, Nicolas Magné, Jane-Chloé Trone, Coralie Moncharmont, Dominique Ardail, Marion Gilormini, Matthieu Guilbert, Claire Rodriguez-Lafrasse, Alexander T. Falk, Robert-Alain Toillon, Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Department of Radiotherapy, Institut de cancérologie Lucien Neuwirth, Radiothérapie moléculaire (UMR 1030), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Plasticité Cellulaire et Cancer - U908 (CPAC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Cancérologie Lucien Neuwirth, CHU Saint-Etienne, Laboratoire de Physique Nucléaire et de Hautes Énergies (LPNHE), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Pierre et Marie Curie - Paris 6 (UPMC), UNICANCER-Université Côte d'Azur (UCA), Médicaments : Dynamique Intracellulaire et Architecture Nucléaire (MéDIAN), Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Inserm U908, Growth factor signalling in breast cancer, functional proteomics, IFR-147, and Université de Lille, Sciences et Technologies-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Pathology, medicine.medical_specialty, Epithelial-Mesenchymal Transition, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, [PHYS.NEXP]Physics [physics]/Nuclear Experiment [nucl-ex], Biology, Metastasis, Extracellular matrix, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, Cell Movement, Neoplasms, Radiation, Ionizing, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, medicine, Humans, Neoplasm Invasiveness, Epithelial–mesenchymal transition, [INFO.INFO-DB]Computer Science [cs]/Databases [cs.DB], Intravasation, Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell migration, Hematology, medicine.disease, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Radiation therapy, Oncology, Cancer cell, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Cancer research, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Neoplasm Recurrence, Local
Abstract

International audience; Radiation therapy is a keystone treatment in cancer. Photon radiation has proved its benefits in overall survival in many clinical studies. However, some patients present local recurrences or metastases when cancer cells survive to treatment. Metastasis is a process which includes adhesion of the cell to the extracellular matrix, degradation of the matrix by proteases, cell motility, intravasation in blood or lymphatic vessels, extravasation in distant parenchyma and development of cell colonies. Several studies demonstrated that ionizing radiation might promote migration and invasion of tumor cells by intricate implications in the micro-environment, cell-cell junctions, extracellular matrix junctions, proteases secretion, and induction of epithelial-mesenchymal transition. This review reports various cellular pathways involved in the photon-enhanced cell invasion process for which potential therapeutic target may be employed for enhancing antitumor effectiveness. Understanding these mechanisms could lead to therapeutic strategies to counter the highly invasive cell lines via specific inhibitors or carbon-ion therapy.

Published
2013

72. Impact of dose-rate on the low-dose hyper-radiosensitivity and induced radioresistance (HRS/IRR) response

Author

Jennifer H. Martin, Clément Devic, Michel Diserbo, Juliette Thariat, Charles Thomas, Nicolas Foray, Elke Bräuer-Krisch, 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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), European Synchrotron Radiation Facility (ESRF), IRBA, Institut de Recherche Biomédicale des Armées (IRBA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Thomas, Charles, groupe Foray-équipe Ansiau/Puisieux, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Microbeam Radiation Therapy, Unité de Radiothérapie, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Centre de Lutte contre le Cancer, E02, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA)-Centre de Lutte contre le Cancer

Subjects
Clonogenic survival, DNA Repair, MESH: DNA Breaks, Double-Stranded, Radiation Tolerance, DSB repair, 030218 nuclear medicine & medical imaging, 0302 clinical medicine, DNA Breaks, Double-Stranded, MESH: Animals, Cobalt Radioisotopes, MESH: Cobalt Radioisotopes, MESH: DNA Repair, MESH: Radiation Tolerance, Radiological and Ultrasound Technology, Chemistry, Low dose, 030220 oncology & carcinogenesis, Dna breaks, Hyper-radiosensitivity (HRS) response, MESH: Radiation Dosage, MESH: Cell Line, Tumor, MESH: Rats, Colon, induced radioresistance (IRR) response, tumor cells, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Radiation Dosage, [SDV.IB.MN] Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Andrology, 03 medical and health sciences, MESH: X-Rays, Radioresistance, Cell Line, Tumor, Animals, Humans, Radiology, Nuclear Medicine and imaging, Radiosensitivity, MESH: Colon, radiotherapy, dose-rate, MESH: Humans, business.industry, X-Rays, MESH: Gamma Rays, Rats, Cell culture, Gamma Rays, Hyper radiosensitivity, Dose rate, Nuclear medicine, business
Abstract

International audience; PURPOSE: To ask whether dose-rate influences low-dose hyper- radiosensitivity and induced radioresistance (HRS/IRR) response in rat colon progressive (PRO) and regressive (REG) cells. METHODS: Clonogenic survival was applied to tumorigenic PRO and non-tumorigenic REG cells irradiated with (60)Co γ-rays at 0.0025-500 mGy.min(-1). Both clonogenic survival and non-homologous end-joining (NHEJ) pathway involved in DNA double-strand breaks (DSB) repair assays were applied to PRO cells irradiated at 25 mGy.min(-1) with 75 kV X-rays only. RESULTS: Irrespective of dose-rates, marked HRS/IRR responses were observed in PRO but not in REG cells. For PRO cells, the doses at which HRS and IRR responses are maximal were dependent on dose-rate; conversely exposure times during which HRS and IRR responses are maximal (t(HRSmax) and t(IRRmax)) were independent of dose-rate. The t(HRSmax) and t(IRRmax) values were 23 ± 5 s and 66 ± 7 s (mean ± standard error of the mean [SEM], n = 7), in agreement with literature data. Repair data show that t(HRSmax) may correspond to exposure time during which NHEJ is deficient while t(IRRmax) may correspond to exposure time during which NHEJ is complete. CONCLUSION: HRS response may be maximal if exposure times are shorter than t(HRSmax) irrespective of dose, dose-rate and cellular model. Potential application of HRS response in radiotherapy is discussed.

Published
2013

73. Spatial-temporal Variations of Bovine Tuberculosis Incidence in France between 1965 and 2000

Author

L. Azizi, J.-J. Bénet, M. E. A. Bekara, Benoit Durand, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Unité de Recherche d'Épidémiologie Animale (UR EpiA), Institut National de la Recherche Agronomique (INRA), Biostatistics Unit, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), and École nationale vétérinaire d'Alfort (ENVA)

Subjects
0301 basic medicine, Veterinary medicine, 040301 veterinary sciences, [SDV]Life Sciences [q-bio], 030106 microbiology, Population, Tuberculin, Biology, Article, 0403 veterinary science, 03 medical and health sciences, specialization, Risk Factors, professionalization, Prevalence, Milk quota, Animals, bovine tuberculosis, education, spatiotemporal, 2. Zero hunger, education.field_of_study, General Veterinary, General Immunology and Microbiology, business.industry, Tuberculin Test, Incidence (epidemiology), Incidence, Bayes Theorem, 04 agricultural and veterinary sciences, General Medicine, Animal husbandry, Models, Theoretical, Mycobacterium bovis, Deviance information criterion, Space-Time Clustering, Herd, Livestock, Cattle, Female, France, business, Tuberculosis, Bovine
Abstract

International audience; We analysed the spatiotemporal variations of bovine tuberculosis (bTB) incidence between 1965 and 2000 in France at the department level (95 areas). Using a Bayesian space-time model, we studied the association between the evolution of bTB incidence and changes of cattle population structure and of herd management practices. Several spatiotemporal hierarchical Bayesian models were compared, and the deviance information criterion was used to select the best of them. Southern France remained a high-risk area over the analysed period, whereas central and western regions were low-risk areas. Besides the frequency of tuberculin skin testing (fixed according to bTB incidence in the preceding years), four factors were associated with an increased risk of bTB: the average herd density and size, the percentage of dairy cows in the cattle population, and the percentage of permanent grassland in cultivated surfaces area. These four factors are linked to the progressive professionalization and specialization of cattle farming, with the disappearance of family farms and of the intensification of breeding systems (especially in dairy farms after the application of the milk quota system in the 1980s). Both trends probably played a significant role in reducing the risk of bTB in France between 1965 and 2000, besides mandatory detection and control procedures.

Published
2013

74. Real-time online monitoring of the ion range by means of prompt secondary radiations

Author

J.-L. Ley, M. Chabot, Ilaria Rinaldi, M. Magne, Joel Herault, C. La Tessa, M. Dahoumane, Damien Prieels, H. Mathez, L. Lestand, M. De Rydt, Stephan Brons, V. Reithinger, L. Caponetto, C. Insa, L. Balleyguier, Voichita Maxim, D. Lambert, Baptiste Joly, Marco Pinto, J. Krimmer, R. Della Negra, R. Pleskac, Denis Dauvergne, George Dedes, Marc Winter, Jean Michel Létang, Gerard Montarou, Katia Parodi, Rémy Prost, P. Force, S. Deng, Julien Smeets, Nicolas Freud, J. Baudot, Y. Zoccarato, X. Lojacono, Etienne Testa, M. Vanstalle, M. H. Richard, Cédric Ray, F. Roellinghoff, X. Chen, Institut de Physique Nucléaire de Lyon (IPNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Heidelberg Ion Beam Therapy Center - HIT, Heidelberg University Clinic, Institut de Physique Nucléaire d'Orsay (IPNO), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique Corpusculaire - Clermont-Ferrand (LPC), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Imagerie Tomographique et Radiothérapie, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cyclotron Biomédical, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Biophysics Department [Darmstadt], Helmholtz Centre for Heavy Ion Research (GSI), Radiation Therapy and Radiation Oncology, University clinic Heidelberg, Ion Beam Applications SA, IBA, Images et Modèles, Rayet, Béatrice, Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris-Sud - Paris 11 (UP11), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), and Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Physics, Range (particle radiation), medicine.medical_specialty, [PHYS.PHYS.PHYS-MED-PH] Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], [PHYS.NEXP] Physics [physics]/Nuclear Experiment [nucl-ex], 010308 nuclear & particles physics, Astrophysics::High Energy Astrophysical Phenomena, Physics::Medical Physics, Detector, Gamma ray, [PHYS.NEXP]Physics [physics]/Nuclear Experiment [nucl-ex], 01 natural sciences, 3. Good health, 030218 nuclear medicine & medical imaging, Ion, Nuclear physics, 03 medical and health sciences, 0302 clinical medicine, 0103 physical sciences, [PHYS.PHYS.PHYS-MED-PH]Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], medicine, Dosimetry, Medical physics, Gamma ray detection
Abstract

International audience; Prompt secondary radiations such as gamma rays and protons can be used for ion-range monitoring during ion therapy either on an energy-slice basis or on a pencil-beam basis. We present a review of the ongoing activities in terms of detector developments, imaging, experimental and theoretical physics issues concerning the correlation between the physical dose and hadronic processes

Published
2013

75. A French prospective pilot study for identifying dihydropyrimidine dehydrogenase (DPD) deficiency in breast cancer patients (pts) receiving capecitabine (cap)

Author

Marie-Christine Etienne-Grimaldi, Gilles Romieu, Henri Roché, Christophe Ferrand, Xavier Pivot, Jean-Marc Ferrero, Anthony Gonçalves, Gérard Milano, Véronique Diéras, Jacques Bonneterre, Fabienne Thomas, Thomas Bachelot, Beatrice De Clercq, Jean-Louis Merlin, Christine Bobin-Dubigeon, Jean-Christophe Boyer, Rémy Largillier, Frédéric Pinguet, Mireille Mousseau, Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, Centre de Recherche en Automatique de Nancy ( CRAN ), Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Alexis Vautrin ( CAV ), Centre d'Investigation Clinique 1432 (Dijon) - Module Plurithématique : Périnatalité Cancérologie Handicap et Ophtalmologie ( CIC-P803 ), Université de Bourgogne ( UB ) -Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire de Nîmes ( CHRU Nîmes ), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Oncogénèse et progression tumorale, Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Département de Médecine Nucléaire, Centre Léon Bérard [Lyon], Service d'oncologie Médicale, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Institute Curie, Service d'oncologie médicale, CHU Grenoble-Hôpital Michallon, Centre de Recherche en Cancérologie de Marseille ( CRCM ), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Département de Sénologie, CRLCC Oscar Lambret, Département de pharmacogénomique, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre Alexis Vautrin (CAV), Centre d'Investigation Clinique 1432 (Dijon) - Module Plurithématique : Périnatalité Cancérologie Handicap et Ophtalmologie (CIC-P803), Université de Bourgogne (UB)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER, UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Merlin, Jean-Louis, Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Direction Générale de l'Organisation des Soins (DGOS)-Université de Bourgogne (UB), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), and Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER

Subjects
Cancer Research, medicine.medical_specialty, macromolecular substances, 030226 pharmacology & pharmacy, Gastroenterology, [SPI.AUTO]Engineering Sciences [physics]/Automatic, Capecitabine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Breast cancer, Internal medicine, [ SPI.AUTO ] Engineering Sciences [physics]/Automatic, medicine, Dihydropyrimidine dehydrogenase, Prospective cohort study, business.industry, Dihydrouracil, medicine.disease, Metastatic breast cancer, 3. Good health, Surgery, [SPI.AUTO] Engineering Sciences [physics]/Automatic, Oncology, chemistry, 030220 oncology & carcinogenesis, Relative risk, Toxicity, bacteria, Published in Journal of Clinical Oncology, vol. 31 : 2013 (Suppl, abstr e13519), business, medicine.drug
Abstract

e13519 Background: For fluoropyrimidines, and especially cap, Health Authorities point out that DPD deficiency confers a significant risk of major toxicity (tox). Identification of at-risk pts is thus relevant. This multicentric prospective study of the French GPCO group (Groupe de Pharmacologie Clinique Oncologique, Unicancer) evaluated the sensitivity, specificity and predictive values of DPD phenotyping and genotyping for predicting severe cap-related tox in metastatic breast cancer pts. Methods: 303 pts were included (15 institutions), 88% received cap as monotherapy, 28% were treated as first line (mean dose at 1st cycle 1957 mg/m2/d). Pre-treatment dihydrouracil (UH2) and uracil (U) plasma concentrations were measured in 286 pts (HPLC assay). DPD genotyping (IVS14+1G>A, 2846A>T, 1679T>G, 464T>A) was done on 281 pts. Severe tox (G3-4 CTCAE v3 criteria) was measured over cycles 1-2. Results: Grade 3-4 tox (diarrhea, vomiting, hematoxicity, hand-foot syndrome) was observed in 19.6% of pts (one toxic death). A marked trend for higher U (median 12.7 vs 10.2 ng/ml, p=0.014) and UH2 (median 110 vs 93 ng/ml, p=0.011) concentrations was observed in pts developing severe tox vs those who didn’t. However, ROC curves showed that these differences were too small for use as reliable tox predictors. The distribution of UH2/U ratio was similar between pts with or without tox (median 9.1 vs 9.6, respectively, p=0.80). The patient with toxic death had a UH2/U ratio of 6.5 and U concentration of 17 ng/ml. Among the 7 pts with a DPD mutation (3 pts IVS14+1, 3 pts 2846A>T, one 1679T>G, all heterozygous), 5 developed severe tox (including toxic death, 2846A>T), one did not, and the last one was not documented. Relative risk for developing severe tox was 4.60 in mut pts vs wt pts (95%CI 2.95-7.16, p=0.001); positive and negative predictive values were 83.3% and 81.9%, respectively; specificity was 99.5% and sensitivity was 9.8%. Conclusions: These data point out that breast cancer pts harbouring a DPD variant allele are candidate to develop severe, up to lethal, cap-related tox. In contrast, pre-treatment UH2/U ratio and U measurements are not reliable predictors of cap tox. Clinical trial information: Eudract 2008-004136-20.

Published
2013

76. Image-based motion detection in 4D images and application to respiratory motion suppression

Author

Julien Guglielmi, M. Breuilly, Grégoire Malandain, Philippe Franken, J. Darcourt, N. Ayache, Thierry Pourcher, Analysis and Simulation of Biomedical Images (ASCLEPIOS), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Transporteurs et Imagerie, Radiothérapie en Oncologie et Mécanismes biologiques des Altérations du Tissu Osseux (TIRO-MATOs - UMR E4320), UMR E4320 (TIRO-MATOs), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Morphologie et Images (MORPHEME), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut de Biologie Valrose (IBV), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)-Signal, Images et Systèmes (Laboratoire I3S - SIS), Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Département de Médecine Nucléaire [Nice] (CHU-Nice), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-UMR E4320 (TIRO-MATOs), 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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Signal, Images et Systèmes (Laboratoire I3S - SIS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS)

Subjects
Image fusion, Tomographic reconstruction, medicine.diagnostic_test, Computer science, business.industry, 3D reconstruction, Motion detection, Iterative reconstruction, Single-photon emission computed tomography, Signal, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, 030220 oncology & carcinogenesis, medicine, Computer vision, Artificial intelligence, business, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Image restoration
Abstract

International audience; Respiratory motion may blur the tomographic reconstruction of PET or SPECT images, which subsequently impairs quantitative measurements, e.g. in the upper abdomen area. Respiratory phase-based gated reconstruction addresses this problem for CT images, but deteriorates the signal-to-noise ratio and other intensity-based quality measures for ET images. This article describes an image-based motion detection method for dynamic images, which works for both 4D-CT and 4D-SPECT images. This method allowed us to identify the motionless phases from the image-based motion signal. Interestingly, we found that the peak of motion according to the pressure signal, recorded during the acquisition and considered as a reference, is temporally shifted compared to the motion-phases identified by the proposed method. Moreover, these observations permit to reconstruct a breath hold like 3D SPECT image improving the quality of the 3D reconstruction compared to both 4D reconstruction and standard 3D reconstruction.

Published
2013

77. Amplitude-based data selection for optimal retrospective reconstruction in micro-SPECT

Author

J. Darcourt, Robert Marsault, Grégoire Malandain, Philippe Franken, Julien Guglielmi, Marine Breuilly, Thierry Pourcher, Analysis and Simulation of Biomedical Images (ASCLEPIOS), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Transporteurs et Imagerie, Radiothérapie en Oncologie et Mécanismes biologiques des Altérations du Tissu Osseux (TIRO-MATOs - UMR E4320), UMR E4320 (TIRO-MATOs), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Morphologie et Images (MORPHEME), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut de Biologie Valrose (IBV), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)-Signal, Images et Systèmes (Laboratoire I3S - SIS), Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Département de Médecine Nucléaire [Nice] (CHU-Nice), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-UMR E4320 (TIRO-MATOs), 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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Signal, Images et Systèmes (Laboratoire I3S - SIS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS)

Subjects
Computer science, Standardized uptake value, Iterative reconstruction, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Mice, 0302 clinical medicine, Imaging, Three-Dimensional, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, medicine, Animals, Radiology, Nuclear Medicine and imaging, Computer vision, Peritoneal Neoplasms, Retrospective Studies, Tomography, Emission-Computed, Single-Photon, Tomographic reconstruction, Radiological and Ultrasound Technology, medicine.diagnostic_test, Noise (signal processing), business.industry, Respiration, 3D reconstruction, Intensity (physics), Rats, Positron emission tomography, 030220 oncology & carcinogenesis, Female, Artificial intelligence, business, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Emission computed tomography
Abstract

Respiratory motion can blur the tomographic reconstruction of positron emission tomography or single-photon emission computed tomography (SPECT) images, which subsequently impair quantitative measurements, e.g. in the upper abdomen area. Respiratory signal phase-based gated reconstruction addresses this problem, but deteriorates the signal-to-noise ratio (SNR) and other intensity-based quality measures. This paper proposes a 3D reconstruction method dedicated to micro-SPECT imaging of mice. From a 4D acquisition, the phase images exhibiting motion are identified and the associated list-mode data are discarded, which enables the reconstruction of a 3D image without respiratory artefacts. The proposed method allows a motion-free reconstruction exhibiting both satisfactory count statistics and accuracy of measures. With respect to standard 3D reconstruction (non-gated 3D reconstruction) without breathing motion correction, an increase of 14.6% of the mean standardized uptake value has been observed, while, with respect to a gated 4D reconstruction, up to 60% less noise and an increase of up to 124% of the SNR have been demonstrated.

Published
2013

78. Performance and cost efficiency of KRAS mutation testing for metastatic colorectal cancer in routine diagnosis: the MOKAECM study, a nationwide experience

Author

Pierre Laurent-Puig, Jean-François Emile, Marie-Claude Gorisse, Pascaline Aucouturier, Jean-Philippe Merlio, Florence de Fraipont, Jean-Louis Merlin, Isabelle Durand-Zaleski, Frédérique Nowak, Karen Leroy, Thierry Frebourg, Alain Morel, Hélène Blons, Delphine Le Corre, Gilles Chatellier, Jean-François Côté, Jean-Christophe Sabourin, L'Houcine Ouafik, Etienne Rouleau, Jean-Christophe Boyer, Nathanaël Charrier, Jean-Christophe Pages, Gérard Milano, Patricia de Cremoux, 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 d'Oncogénétique, CRLCC René Huguenin, Service de Santé Publique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherches Cliniques de Montréal (IRCM), Université de Montréal (UdeM), Virus, pseudo-virus: Morphogénèse et Antigénicité, Université de Tours (UT)-EA3856, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CHU Bordeaux [Bordeaux], Oppelia, Institut Jean Godinot [Reims], UNICANCER, Hôpital Saint Louis, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Département de pharmacogénomique, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre Alexis Vautrin (CAV), CHU Rouen, Normandie Université (NU), Institut national du cancer [Boulogne] (INCA), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Service d'anatomie pathologique [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Département de la recherche clinique et du développement, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Unité de Recherche Clinique en Economie de la santé d'Ile de France (URC Eco), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours-EA3856, Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherches Cliniques de Montréal, Université de Montréal, Université de Montréal [Montréal], Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Institut Jean Godinot, CRLCC Jean Godinot, CHU Saint Louis [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CRLCC Antoine Lacassagne, Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service d'anatomie pathologique, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Unité de Recherche Clinique en Economie de la santé d'Ile de France (URC Eco), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), 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 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques de l'Hopital Europeen Georges Pompidou, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Montréal, CHRU Tours, Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Biochimie et Physiologie Moléculaire des Plantes ( BPMP ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ) -Centre international d'études supérieures en sciences agronomiques ( Montpellier SupAgro ) -Institut national d’études supérieures agronomiques de Montpellier ( Montpellier SupAgro ) -Institut national de la recherche agronomique [Montpellier] ( INRA Montpellier ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Centre de Recherches en Oncologie biologique et Oncopharmacologie ( CRO2 ), Aix Marseille Université ( AMU ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche en Automatique de Nancy ( CRAN ), Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Alexis Vautrin ( CAV ), Institut national du cancer [Boulogne] ( INCA ), Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Unité de Recherche Clinique en Economie de la santé d'Ile de France (URC Eco), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique ( MEPPOT - U1147 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Merlin, Jean-Louis

Subjects
Oncology, Colorectal cancer, Epidemiology, Molecular oncology, MESH: Antibodies, Monoclonal, 0302 clinical medicine, MESH : Fixatives, MESH: Fixatives, Neoplasm Metastasis, lcsh:Science, MESH: Tissue Embedding, 0303 health sciences, MESH: Genetic Testing, Antibodies, Monoclonal, 3. Good health, MESH: Reproducibility of Results, ErbB Receptors, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030220 oncology & carcinogenesis, MESH : Neoplasm Metastasis, MESH : Proto-Oncogene Proteins, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Medicine, MESH : Colorectal Neoplasms, MESH : Sensitivity and Specificity, MESH: ras Proteins, medicine.medical_specialty, MESH: Receptor, Epidermal Growth Factor, Gastroenterology and Hepatology, Sensitivity and Specificity, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Fixatives, MESH : Genetic Testing, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], External quality assessment, Gastrointestinal Tumors, Cancer Detection and Diagnosis, Humans, Genetic Testing, Genotyping, Biology, MESH: Humans, Tissue Embedding, MESH : Reproducibility of Results, MESH : Humans, lcsh:R, medicine.disease, MESH: Neoplasm Metastasis, MESH: Sensitivity and Specificity, MESH : Biopsy, ras Proteins, lcsh:Q, MESH : Sequence Analysis, DNA, MESH: Sequence Analysis, DNA, Biopsy, Cancer Treatment, lcsh:Medicine, Bioinformatics, medicine.disease_cause, MESH : Tissue Embedding, MESH: Biopsy, MESH : Receptor, Epidermal Growth Factor, Gastrointestinal Cancers, Sanger sequencing, Multidisciplinary, Drug development, MESH : Antibodies, Monoclonal, symbols, KRAS, France, Colorectal Neoplasms, Research Article, MESH: Cell Line, Tumor, Clinical Research Design, Rectal Cancer, symbols.namesake, Antibody Therapy, Diagnostic Medicine, Molecular genetics, Internal medicine, Cell Line, Tumor, Proto-Oncogene Proteins, medicine, MESH : France, 030304 developmental biology, Population Biology, MESH : Cell Line, Tumor, business.industry, Reproducibility of Results, Cancers and Neoplasms, Sequence Analysis, DNA, MESH: France, MESH: Proto-Oncogene Proteins, Gastric Cancer, MESH : ras Proteins, business, MESH: Colorectal Neoplasms
Abstract

International audience; PURPOSE: Rapid advances in the understanding of cancer biology have transformed drug development thus leading to the approval of targeted therapies and to the development of molecular tests to select patients that will respond to treatments. KRAS status has emerged as a negative predictor of clinical benefit from anti-EGFR antibodies in colorectal cancer, and anti-EGFR antibodies use was limited to KRAS wild type tumors. In order to ensure wide access to tumor molecular profiling, the French National Cancer Institute (INCa) has set up a national network of 28 regional molecular genetics centers. Concurrently, a nationwide external quality assessment for KRAS testing (MOKAECM) was granted to analyze reproducibility and costs. METHODS: 96 cell-line DNAs and 24 DNA samples from paraffin embedded tumor tissues were sent to 40 French laboratories. A total of 5448 KRAS results were collected and analyzed and a micro-costing study was performed on sites for 5 common methods by an independent team of health economists. RESULTS: This work provided a baseline picture of the accuracy and reliability of KRAS analysis in routine testing conditions at a nationwide level. Inter-laboratory Kappa values were >0.8 for KRAS results despite differences detection methods and the use of in-house technologies. Specificity was excellent with only one false positive in 1128 FFPE data, and sensitivity was higher for targeted techniques as compared to Sanger sequencing based methods that were dependent upon local expertise. Estimated reagent costs per patient ranged from €5.5 to €19.0. CONCLUSION: The INCa has set-up a network of public laboratories dedicated to molecular oncology tests. Our results showed almost perfect agreements in KRAS testing at a nationwide level despite different testing methods ensuring a cost-effective equal access to personalized colorectal cancer treatment.

Published
2013

79. Treatment, outcome, and prognostic factors in non-metastatic anal cancer: The French nationwide cohort study FFCD-ANABASE

Author

Vendrely, Véronique, Lemanski, Claire, Pommier, Pascal, Le Malicot, Karine, Saint, Angélique, Rivin del Campo, Eleonor, Regnault, Pauline, Baba-Hamed, Nabil, Ronchin, Philippe, Crehange, Gilles, Tougeron, David, Menager-Tabourel, Elodie, Diaz, Olivia, Hummelsberger, Michael, Minsat, Mathieu, Drouet, Franck, Larrouy, Anne, Peiffert, Didier, Lievre, Astrid, Zasadny, Xavier, Hautefeuille, Vincent, Mornex, Françoise, Lepage, Côme, Quero, Laurent, BoRdeaux Institute in onCology (Inserm U1312 - BRIC), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Institut du Cancer de Montpellier (ICM), Centre Léon Bérard [Lyon], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Clinique Tivoli Ducos [Bordeaux], Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Azuréen de Cancérologie [Mougins, France], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Institut Daniel Hollard [Grenoble], Centre de radiothérapie et d'oncologie médicale privée (Béziers), Institut Curie - Saint Cloud (ICSC), Clinique Mutualiste de l'Estuaire (Saint Nazaire), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Polyclinique de Limoges - site François Chénieux [Limoges], CHU Amiens-Picardie, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), and Fédération Francophone de Cancérologie Digestive.

Subjects
Oncology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Radiology, Nuclear Medicine and imaging, Chemoradiotherapy, Hematology, Anal cancer, IMRT, Observational cohort
Abstract

International audience; Introduction: International guidelines regarding the treatment of squamous cell carcinoma of the anus (SCCA) recommend intensity-modulated radiotherapy (IMRT) combined with mitomycin-based chemotherapy (CT). The French FFCD-ANABASE cohort aimed at evaluating clinical practices, treatment, and outcomes of SCCA patients.Methods: This prospective multicentric observational cohort included all non-metastatic SCCA patients treated in 60 French centers from January 2015 to April 2020. Patients and treatment characteristics, colostomy-free survival (CFS), disease-free survival (DFS), overall survival (OS), and prognostic factors were analyzed.Results: Among 1015 patients (male: 24.4 %; female: 75.6 %; median age: 65 years), 43.3 %presented with early-stage(T1-2, N0) and 56.7 % with locally advanced stage (T3-4 or N + ) tumors. IMRT was used for 815 patients (80.3 %) and a concurrent CT was administered in 781 patients, consisting of mitomycin-based CT for 80 %. The median follow-up was 35.5 months. DFS, CFS, and OS at 3 years were 84.3 %, 85.6 %, and 91.7 % respectively in the early-stage group compared to 64.4 %, 66.9 %, and 78.2 % in the locally-advanced group (p < 0.001). In multivariate analyses, male gender, locally-advanced stage, and ECOG PS ≥ 1 were associated with poorer DFS, CFS, and OS. IMRT was significantly associated with a better CFS in the whole cohort and almost reached significance in the locally-advanced group.Conclusion: Treatment of SCCA patients showed good respect for current guidelines. Significant differences in outcomes advocate for personalized strategies by either de-escalation for early-stage tumors or treatment intensification for locally-advanced tumors.

Published
2023

80. Upfront surgery or definitive radiotherapy for p16+ oropharyngeal cancer. A GETTEC multicentric study

Author

Laure Santini, Agnès Dupret-Bories, Haitham Mirghani, Aicha Ben Lakdar, Pascal Roger, Guillaume Chambon, Olivier Dassonville, Françoise Chapel, Emmanuel Chamorey, Julien Viotti, Sébastien Vergez, Thibault Galissier, Karen Benezery, Valérie Coste, Benjamin Lallemant, Stéphane Temam, D. Culié, Alexandre Bozec, Nicolas Fakhry, Bruno Guelfucci, Frederic Peyrade, Anne Sophie Ramay, Anne Sudaka, Florence Jourdan-Soulier, P. Gorphe, Alain Bizeau, Gilles Poissonnet, Joanne Guerlain, Renaud Garrel, Esma Saada-Bouzid, A. Modesto, Renaud Schiappa, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer - Hôpital Sainte-Musse, Assistance Publique - Hôpitaux de Marseille (APHM), Laboratoire Parole et Langage (LPL), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Institut Gustave Roussy (IGR), Pathologie morphologique, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Département de cancérologie cervico-faciale [Gustave Roussy] (CCF), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université de Montpellier (UM), Université Côte d'Azur (UCA)-UNICANCER, CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, medicine.medical_specialty, Multivariate analysis, Survival, medicine.medical_treatment, Oropharynx, Cetuximab, [SDV.CAN]Life Sciences [q-bio]/Cancer, Human papilloma virus, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, Humans, Medicine, In patient, 030223 otorhinolaryngology, Definitive radiotherapy, Cyclin-Dependent Kinase Inhibitor p16, Cancer, Aged, Neoplasm Staging, Retrospective Studies, Chemotherapy, Radiotherapy, business.industry, Papillomavirus Infections, Univariate, Chemoradiotherapy, Adjuvant, Induction Chemotherapy, General Medicine, Middle Aged, medicine.disease, 3. Good health, Surgery, Survival Rate, Radiation therapy, Oropharyngeal Neoplasms, Oncology, 030220 oncology & carcinogenesis, Propensity score matching, Female, Radiotherapy, Adjuvant, Cisplatin, Neoplasm Recurrence, Local, business
Abstract

International audience; Background: The aim of this study was to assess the impact of the initial therapeutic strategy on oncologic outcomes in patients with HPV-positive OPSCC.Methods: All p16-positive OPSCCs treated from 2009 to 2014 in 7 centers were retrospectively included and classified according to the therapeutic strategy: surgical strategy (surgery ± adjuvant radiotherapy and chemotherapy) vs. non-surgical strategy (definitive radiotherapy ± chemotherapy). Univariate, multivariate propensity score matching analyses were performed to compare overall (OS), disease-specific (DSS) and recurrence-free survival (RFS).Results: 382 patients were included (surgical group: 144; non-surgical group: 238). Five-year OS, DSS and RFS were 89.2, 96.8 and 83.9% in the surgical group and 84.2, 87.1 and 70.4% in the non-surgical group, respectively. These differences were statistically significant for DSS and RFS after multivariate analysis, but only for RFS after propensity score matching analysis.Conclusion: In p16+ OPSCC patients, upfront surgery results in higher RFS than definitive radiotherapy ± chemotherapy but does not impact OS.

Published
2021

81. Efficacy and safety of regorafenib in patients with metastatic or locally advanced chondrosarcoma: Results of a non-comparative, randomised, double-blind, placebo controlled, multicentre phase II study

Author

Loic Chaigneau, Mathilde Cancel, Corinne Delcambre, Corinne Bouvier, Emannuelle Bompas, Olivier Collard, Antoine Italiano, Christine Chevreau, Alice Hervieu, Pascaline Boudou-Rouquette, Vincent Vidal, Sylvie Chabaud, Olivier Mir, Esma Saada-Bouzid, Nicolas Penel, Maria Rios, Florence Duffaud, Camille Schiffler, Jean-Yves Blay, Christophe Perrin, Sophie Piperno-Neumann, Laure Monard, François Bertucci, Hôpital de la Timone [CHU - APHM] (TIMONE), Institut Bergonié [Bordeaux], UNICANCER, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), University of Lille, Institut Gustave Roussy (IGR), Département interdisciplinaire d’organisation des parcours patients (DIOPP), Department of Medical Oncology, Institut Curie, Paris 75248, France, Institut Claudius Regaud, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cancer Research and Personalized Medicine - CARPEM [Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Eugène Marquis (CRLCC), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Léon Bérard [Lyon], Hôpital JeanMinjoz, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Institut de Cancérologie de la Loire Lucien Neuwirth, and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, business.industry, Phases of clinical research, [SDV.CAN]Life Sciences [q-bio]/Cancer, Placebo, medicine.disease, Clinical trial, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, Oncology, chemistry, 030220 oncology & carcinogenesis, Regorafenib, Internal medicine, Cohort, Clinical endpoint, medicine, business, Adverse effect, ComputingMilieux_MISCELLANEOUS, Progressive disease
Abstract

Background This multi-cohort trial explored the efficacy and safety of regorafenib for patients with advanced sarcomas of bone origin; this report details the cohort of patients with metastatic or locally advanced chondrosarcoma (CS), progressing after prior chemotherapy. Patients and methods Patients with CS, progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progressive disease. The primary endpoint was progression-free rate (PFR) at 12 weeks. With one-sided α of 0.05, and 80% power, at least 16/24 progression-free patients at 12 weeks were needed for success (P0 = 50%, P1 = 75%). Results From September 2014 to February 2019, 46 patients were included in the CS cohort, and 40 patients were evaluable for efficacy: 16 on placebo and 24 on regorafenib. Thirteen patients (54.2%; 95% CI [35.8%-[) were non-progressive at 12 weeks on regorafenib versus 5 (31.3%; 95% CI [13.2%-[);) on placebo. Median PFS was 19.9 weeks on regorafenib, and 8.0 on placebo. Fourteen placebo patients crossed over to regorafenib after progression. The most common grade ≥3 treatment-related adverse events on regorafenib included hypertension (12%), asthenia (8%), thrombocytopenia (8%) and diarrhoea (8%). One episode of fatal liver dysfunction occurred on regorafenib. Conclusion Although the primary endpoint was not met statistically in this small randomised cohort, there is modest evidence to suggest that regorafenib might slow disease progression in patients with metastatic CS after the failure of prior chemotherapy. Clinical trial registration The trial is registered at ClinicalTrials.gov ( NCT02389244 ).

Published
2021

82. Compared performances of high-sensitivity cameras dedicated to myocardial perfusion tomoscintigraphy: a comprehensive analysis of phantom and human images

Author

Antoine Verger, Gilles Karcher, Alain Noel, Olivier Morel, Pierre-Yves Marie, Sylvain Poussier, Didier Wolf, Laetitia Imbert, Bernard Songy, Philippe R. Franken, Centre Alexis Vautrin (CAV), Service de Médecine Nucléaire [Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre de Recherche en Automatique de Nancy (CRAN), Université Henri Poincaré - Nancy 1 (UHP)-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS), Département de Médecine Nucléaire [Nice] (CHU-Nice), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice), Centre cardiolologique du nord, Centre cardiologqiue du Nord, service de médecine nucleaire-Centre cardiologique du nord, service de médecine nucléaire, Risque cardiovasculaire, rigidité-fibrose et hypercoagulabilité (RCV), and Université Henri Poincaré - Nancy 1 (UHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, high-speed SPECT, 030204 cardiovascular system & hematology, Sensitivity and Specificity, Imaging phantom, Collimated light, count sensitivity, 030218 nuclear medicine & medical imaging, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Humans, Radiology, Nuclear Medicine and imaging, Gamma Cameras, Image resolution, CZT-cameras, Physics, Tomography, Emission-Computed, Single-Photon, business.industry, Phantoms, Imaging, Collimator, Middle Aged, myocardial perfusion imaging, 3. Good health, Anger Camera, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Tomography, Nuclear medicine, business, Sensitivity (electronics), Perfusion
Abstract

published in European Journal of Nuclear Medicine and Molecular Imaging, 39(Suppl 2):S208; International audience; Differences in the performances of cadmium‐zinc‐telluride (CZT) cameras and/or collimation systems, which have recently been commercialized for myocardial SPECT, remain unclear. In the present study, the performances of three of these systems were compared by a comprehensive analysis of phantom and human SPECT images. Methods. We evaluated the Discovery‐NM530c (1) and DSPECT (2) CZT‐cameras, as well as Anger Symbia cameras equipped with an astigmatic (IQSPECT (3)) or parallel‐hole (Conventional‐SPECT (4)) collimator. Physical performances were compared on conventionally reconstructed SPECT images from phantoms and from comparable groups of normal subjects. Results. Classifications were as follows, in order of performance: 1) for count sensitivity on cardiac phantom images (count.sec‐1.MBq‐1): DSPECT (850), Discovery‐NM530c (460), IQSPECT (390) and Conventional‐SPECT (130). This classification was similar to that of myocardial counts normalized to injected activities from human images (respective mean values in count.sec‐1.MBq‐1: 11.4±2.6, 5.6±1.4, 2.7±0.7, and 0.6±0.1); 2) for central spatial resolution: Discovery‐NM530c (6.7mm), DSPECT (8.6mm), IQSPECT (15.0mm) and Conventional‐SPECT (15.3mm), also in accordance with the analysis of the sharpness of myocardial contours on human images (in cm‐ 1: 1.02±0.17, 0.92±0.11, 0.64±0.12 and 0.65±0.06, respectively); and 3) for contrast‐ to‐noise ratio on phantom: Discovery‐NM530c (4.6), DSPECT (4.1), IQSPECT (3.9), Conv‐SPECT (3.5), similarly to that documented on human images (5.2±1.0, 4.5±0.5, 3.9±0.6 and 3.4±0.3, respectively). Conclusion. The performances of CZT cameras are dramatically higher than those from Anger cameras, even in conditions of human SPECT images. However, CZT cameras differ in that spatial resolution and contrast‐to‐noise ratio are better with the Discovery‐NM530c, whereas count sensitivity is markedly higher with the DSPECT.

Published
2012

83. Contrasted outcomes to gefitinib on tumoral IGF1R expression in head and neck cancer patients receiving postoperative chemoradiation (GORTEC trial 2004-02)

Author

René-Jean Bensadoun, Anne Sudaka, Anne Cayre, Marie-Christine Etienne-Grimaldi, Juliette Thariat, Lionnel Geoffrois, Dominique Grall, François Bertucci, Philippe Giraud, Sylvain Morinière, Ellen Van Obberghen-Schilling, Dominique de Raucourt, Olivier Dassonville, Gérard Milano, Séverine Racadot, Frédérique Penault-Llorca, Pascal Finetti, Institut de Biologie Valrose (IBV), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Service d'ORL, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Alexis Vautrin (CAV), Département de pharmacogénomique, Université Nice Sophia Antipolis (... - 2019) (UNS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)

Subjects
Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, Randomization, Antineoplastic Agents, Placebo, law.invention, Receptor, IGF Type 1, 03 medical and health sciences, 0302 clinical medicine, Gefitinib, Randomized controlled trial, law, Internal medicine, medicine, Biomarkers, Tumor, Humans, Postoperative Period, skin and connective tissue diseases, Protein Kinase Inhibitors, neoplasms, [SDV.BDD]Life Sciences [q-bio]/Development Biology, 030304 developmental biology, Aged, Neoplasm Staging, Cisplatin, 0303 health sciences, business.industry, Head and neck cancer, Middle Aged, medicine.disease, Prognosis, 3. Good health, respiratory tract diseases, Clinical trial, Treatment Outcome, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Quinazolines, Biomarker (medicine), Female, business, medicine.drug, Signal Transduction
Abstract

Purpose: Intermediate/high-risk operated patients with head and neck cancer may benefit from the addition of EGF receptor (EGFR) inhibitor gefitinib to chemoradiation. This study was designed to assess improved outcomes and identify predictive biomarkers. Experimental Design: Patients provided informed consent for tumor biomarker analyses and, when eligible, were further enrolled in the therapeutic CARISSA multicenter randomized phase II trial of postoperative irradiation with cisplatin + gefitinib (GORTEC 2004-02-NCT00169221). Results: Seventy-nine patients were included in the biomarker study, whereas 27 did not meet prerequisites for randomization between gefitinib and placebo. Two-year disease-free survival (DFS) rate was 65.0% and did not differ between randomized patients treated with gefitinib or placebo (P = 0.85). The similarity of DFS curves between nonrandomized patients (n = 27), randomized patients without gefitinib (n = 27), and randomized patients receiving gefitinib (n = 25), and similar histoclinical parameter distributions for all groups, allowed us to conduct statistical analyses on the entire population. On multivariate analysis, elevated expression of PAK1 by Western blotting, CD31 and membranous insulin-like growth factor 1 receptor (IGF1R) both by immunohistochemistry was significantly associated with shorter DFS. There was a significant interaction between IGF1R and gefitinib. Gefitinib abolished the prognostic discriminative power of high IGF1R expression; patients with elevated IGF1R expression benefited from gefitinib whereas those with low IGF1R fared worse. Conclusion: Gefitinib treatment affords no significant clinical benefit on DFS in an unselected population of patients with head and neck cancer. Our results point to the potential advantage of personalizing treatment for gefitinib based on tumoral IGF1R expression. This should foster confirmatory analyses in trials involving EGFR-targeting agents. Clin Cancer Res; 18(18); 5123–33. ©2012 AACR.

Published
2012

84. Variation in breast cancer risk associated with factors related to pregnancies according to truncating mutation location, in the French National BRCA1/2 carrier cohort (GENEPSO)

Author

Michel Longy, Elisabeth Luporsi, Laurence Gladieff, Catherine Noguès, Pascaline Berthet, Alain Lortholary, Olivier Caron, Chrystelle Colas, Emmanuelle Mouret-Fourme, Marion Gauthier-Villars, Pascal Pujol, Jean-Pierre Fricker, Catherine Dugast, Julie Lecarpentier, Paul Gesta, Dominique Stoppa-Lyonnet, Valérie Bonadona, Julie Tinat, François Eisinger, Isabelle Coupier, Christine Lasset, Nadine Andrieu, Rosette Lidereau, Bruno Buecher, Laurence Faivre, Marc Frenay, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Santé Publique, Institut Curie [Paris]-Hôpital René HUGUENIN (Saint-Cloud), Service de Génétique Oncologique, Institut Curie [Paris], Equipe de prévention et épidémiologie génétique, Centre Léon Bérard [Lyon], Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Département de médecine oncologique, CRLCC Paul Strauss, Génétique oncologique (GO - UMR 8125), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Consultation d'Oncogénétique, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'oncogénétique [Centre georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Pôle pédiatrie, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Hôpital d'enfants, Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Unité d'Oncogénétique, CRLCC Val d'Aurelle - Paul Lamarque, Département d'oncologie médicale, Institut Claudius Regaud, Pôle Oncologie, Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Anticipation et de Suivi du Cancer (DASC), Consultation d'oncogénétique, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Service d'oncologie médicale [ICL Alexis Vautrin], Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Unité d'oncologie gynécologique, Centre Catherine-de-Sienne [Nantes] (CCS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département d'oncologie médicale [Rennes], CRLCC Eugène Marquis (CRLCC), Département de pathologie, Institut Bergonié [Bordeaux], Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), The GENEPSO study is supported by the Fondation de France and the Ligue Nationale Contre le Cancer., GENEPSO, Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, INSTITUT CURIE-Hôpital René HUGUENIN (Saint-Cloud), INSTITUT CURIE, Laboratoire de Biométrie et Biologie Evolutive ( LBBE ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ), Génétique oncologique ( GO - UMR 8125 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le Cancer François Baclesse ( CRLC François Baclesse ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Hôpital d'enfants, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Centre Hospitalier Georges Renon [Niort] ( CH Georges Renon Niort ), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale ( SESSTIM - U912 INSERM - AMU - IRD ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ), Département d'Anticipation et de Suivi du Cancer ( DASC ), CRLCC Antoine Lacassagne, Service d'oncologie médicale, Centre Alexis Vautrin ( CAV ), Centre Catherine de Sienne, Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], CRLCC Eugène Marquis ( CRLCC ), Institut Bergonié - CRLCC Bordeaux, CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Institut Curie, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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)-Université Paris Descartes - Paris 5 (UPD5), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), BMC, Ed., Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
Oncology, Adult, Risk, Pediatrics, medicine.medical_specialty, Heterozygote, endocrine system diseases, Genes, BRCA2, Genes, BRCA1, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Surgical oncology, Pregnancy, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Young adult, Allele, skin and connective tissue diseases, 030304 developmental biology, Aged, Medicine(all), 0303 health sciences, business.industry, Middle Aged, medicine.disease, 3. Good health, Pregnancy Complications, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Cohort, Mutation, Female, business, Cohort study, Research Article
Abstract

International audience; ABSTRACT: INTRODUCTION: Mutations in BRCA1 and BRCA2 confer a high risk of breast cancer (BC), but the magnitude of this risk seems to vary according to the study and various factors. Although controversial, there are data to support the hypothesis of allelic risk heterogeneity. METHODS: We assessed variation in BC risk according to factors related to pregnancies by location of mutation in homogeneous risk region of BRCA1 and BRCA2 in 990 women of the French study GENEPSO by using a weighted Cox regression model. RESULTS: Our results confirm the existence of a protective effect of an increasing number of full-term pregnancies (FTPs) toward BC among BRCA1 and BRCA2 mutation carriers ([greater than or equal to]3 vs. 0 FTPs: HR=0.51, 95% CI=0.33-0.81). Additionally, hazard ratio (HR) show an association between incomplete pregnancies and a higher BC risk, which reached 2.39 (95% CI=1.28-4.45) among women who had at least three incomplete pregnancies when compared with women with zero incomplete pregnancies. This increased risk appeared to be restricted to incomplete pregnancies occurring before the first FTP (HR=1.77, 95% CI=1.19-2.63). We defined the TMAP score (defined as the Time of breast Mitotic Activity during Pregnancies) to take into account simultaneously the opposite effect of full-term and interrupted pregnancies. Compared with women with a TMAP score of less than 0.35, an increasing TMAP score was associated with a statistically significant increase in the risk of BC (P trend=0.02) which reached 1.97 (95% CI=1.19-3.29) for a TMAP score > 0.5 (vs. TMAP less than or equal to 0.35). All these results appeared to be similar in BRCA1 and BRCA2. Nevertheless, our results suggest a variation in BC risk associated with parity according to the location of the mutation in BRCA1. Indeed, parity seems to be associated with a significantly decreased risk of BC only among women with a mutation in the central region of BRCA1 (low-risk region) (greater than or equal to 1 vs. 0 FTP: HR=0.27, 95% CI=0.13-0.55) (pinteraction

Published
2012

85. Osteosarcomas of the mandible: Are they different from other tumor sites?

Author

G. Odin, Isabelle Peyrottes-Birstwisles, Alexis Lacout, Anne Brouchet, Morbize Julieron, Nicolas Isambert, Pierre Yves Marcy, Thomas Schouman, Antoine Italiano, Olivier Dassonville, Antoine Thyss, Juliette Thariat, Robert C. Miller, Institute of Developmental Biology and Cancer (IBDC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Département d'oncologie médicale, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'ORL et de chirurgie maxillofaciale, Hôpital Pasteur [Nice] (CHU), Service d'ORL, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Royal Free and University College Medical School, Haematology, and Centre Hospitalier Universitaire de Nice (CHU Nice)

Subjects
Adult, Diagnostic Imaging, musculoskeletal diseases, Reconstructive surgery, medicine.medical_specialty, Histology, medicine.medical_treatment, Osteogenic sarcoma, Bone Neoplasms, Mandible, 03 medical and health sciences, Head and neck, 0302 clinical medicine, Risk Factors, Osteosarcomas, Humans, Medicine, Chemotherapy, Treatment Failure, Intermediate Grade, Survival rate, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Cause of death, Osteosarcoma, Radiotherapy, business.industry, Soft tissue, 030206 dentistry, Hematology, Databases, Bibliographic, Occult, Neoadjuvant Therapy, 3. Good health, Surgery, Survival Rate, Radiation therapy, Oncology, Jaw, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Radiotherapy, Adjuvant, Radiology, Neoplasm Grading, business
Abstract

International audience; BACKGROUND: Osteosarcomas of the mandible (MOS) affect 1/10millionpersons/year, mostly the young adult. Due to lack of specific data, the treatment of MOS is extrapolated from that of extragnathic OS but varies widely between institutions. MATERIALS AND METHODS: We aimed at providing a focused description of MOS histologies and grades through the English literature, at determining the evidence-based role of chemotherapy, of adjuvant radiation therapy and the potential of reconstructive surgery tailored through modern pre-operative multi-modal imaging. RESULTS: The estimated proportion of high grade MOS was 58%. However, low-grade MOS may be underestimated as they are mostly reported as case reports. The intermediate grade was hardly found in the literature. Estimated weighted-mean proportions of chondroblastic and osteoblastic MOS were 37% and 46%, respectively. Multimodal imaging modalities including MRI has a great potential for accurate pre-operative assessment of tumor extensions into bone and soft tissues. Surgery is the mainstay of treatment and margins the most important factor. The role of neoadjuvant chemotherapy in treating occult systemic metastases and in increasing the probability of clear margins is controversial, as well as the histology-dependent response to chemotherapy. The role of adjuvant radiotherapy (mostly proposed for positive margins) and/or adjuvant chemotherapy is still controversial. Crude survival is around 77% and local control around 67%. Local failure is the main cause of death in MOS compared to extragnathic sites.

Published
2012

86. Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines

Author

Jérôme Durivault, Gilles Pagès, Negrier S, Jean-Yves Scoazec, Chamorey E, Cindy Serdjebi, Marie A. Jacquin, Mélanie Guyot, Lacarelle B, Simonnet H, Sudaka A, Renaud Grépin, RHODIA RECHERCHES ET TECHNOLOGIES CENTRE DE RECHERCHES ET TECHNOLOGIES D'AUBERVILLIERS, RHODIA RECHERCHES ET TECHNOLOGIES, Biostatistics Unit, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), 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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Probabilités et Modèles Aléatoires (LPMA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Equipe 4, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Vascular Endothelial Growth Factor A, Cancer Research, Angiogenesis Inhibitors, Mice, chemistry.chemical_compound, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, MESH: Animals, MESH: Angiogenesis Inhibitors, 0303 health sciences, MESH: Carcinoma, Renal Cell, Kidney Neoplasms, 3. Good health, Lymphangiogenesis, Bevacizumab, Vascular endothelial growth factor, MESH: Antineoplastic Combined Chemotherapy Protocols, Paclitaxel, 030220 oncology & carcinogenesis, Monoclonal, Female, medicine.drug, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, In vivo, MESH: Cell Proliferation, Genetics, medicine, MESH: Mice, Nude, Animals, Humans, MESH: Paclitaxel, Carcinoma, Renal Cell, Molecular Biology, MESH: Mice, Cell Proliferation, 030304 developmental biology, MESH: Humans, Cell growth, MESH: Vascular Endothelial Growth Factor A, Interleukin-8, medicine.disease, MESH: Interleukin-8, Clear cell renal cell carcinoma, chemistry, MESH: Antibodies, Monoclonal, Humanized, Immunology, Cancer research, MESH: Kidney Neoplasms, MESH: Female, Neoplasm Transplantation, MESH: Neoplasm Transplantation
Abstract

International audience; The anti-VEGF targeted antibody bevacizumab (BVZ) has been approved for treating renal cell carcinomas (RCCs). Although BVZ increases the progression-free survival of patients with metastatic RCC, the effect on overall survival is poor. To gain insight into the limited efficacy of BVZ on overall survival, we analyzed patient samples of RCC for angiogenic factors that may participate in escape from anti-VEGF therapy. Our study shows that the level of vascular endothelial growth factor (VEGF) in tumors was increased compared with normal tissue. The level of interleukin-8/CXCL8, a pro-angiogenic member of the CXCL family of cytokines, was also increased in tumors. These observations gave us a good reason to analyze the combined effects of BVZ and anti-CXCL8 antibodies on tumor growth. Surprisingly, we report that BVZ accelerates the growth of RCC in nude mice with in vivo selection of tumor cells with an increased growth capacity. Downregulation of receptor tyrosine phosphatase-κ, a phosphatase implicated in EGF receptor regulation, may partly explain this phenomenon. Modification of the vascular network and development of lymphatic vessels through VEGF-C production and compensatory production of pro-angiogenic CXCL cytokines were also observed. The apparent normalization of the vascular network prompted us to associate BVZ with the chemotherapeutic agent paclitaxel. While efficient in vitro, paclitaxel did not reverse the anti-VEGF effects in vivo. Anti-CXCL8-targeting antibodies were promising as they decreased intra-tumor VEGF production; decreased the pro-angiogenic CXCL/anti-angiogenic CXCL ratio and did not induce lymphangiogenesis. These observations hold clinical implication as they highlight putative markers implicated in escape from BVZ treatment. They also recommend proceeding with caution in the use of anti-VEGF therapy alone for treatment of RCC.

Published
2012

87. Pharmacogenetic profiling and cetuximab outcome in patients with advanced colorectal cancer

Author

Jean-François Seitz, Jean-Louis Formento, Laetitia Dahan, L'Houcine Ouafik, Marie-Christine Etienne-Grimaldi, Isabelle Nanni, Jean Gaudart, Emmanuelle Norguet, Stéphane Garcia, Gérard Milano, Mohamed Gasmi, Digestive Oncology, Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Transfert d'Oncologie Biologique [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pharmacogénomique, UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU)

Subjects
Male, Oncology, Candidate gene, Cancer Research, Colorectal cancer, clinical outcome, 0302 clinical medicine, Epidermal growth factor, Surgical oncology, hemic and lymphatic diseases, cetuximab, Cyclin D1, ComputingMilieux_MISCELLANEOUS, EGFR inhibitors, Aged, 80 and over, 0303 health sciences, Cetuximab, Antibodies, Monoclonal, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, ErbB Receptors, 030220 oncology & carcinogenesis, Disease Progression, Female, Colorectal Neoplasms, Research Article, medicine.drug, Adult, medicine.medical_specialty, Antineoplastic Agents, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antibodies, Monoclonal, Humanized, Skin Diseases, lcsh:RC254-282, 03 medical and health sciences, Internal medicine, medicine, Carcinoma, Genetics, Humans, neoplasms, Aged, 030304 developmental biology, Polymorphism, Genetic, Epidermal Growth Factor, business.industry, Receptors, IgG, medicine.disease, Survival Analysis, Introns, digestive system diseases, polymorphisms, business, Pharmacogenetics
Abstract

Background We analyzed the influence of 8 germinal polymorphisms of candidate genes potentially related to EGFR signalling (EGFR, EGF, CCND1) or antibody-directed cell cytotoxicity (FCGR2A and FCGR3A) on outcome of colorectal cancer (CRC) patients receiving cetuximab-based therapy. Methods Fifty-eight advanced CRC patients treated with cetuximab-irinotecan salvage therapy between 2001 and 2007 were analyzed (mean age 60; 50 PS 0-1). The following polymorphisms were analyzed on blood DNA: EGFR (CA repeats in intron 1, -216 G > T, -191C > A, R497K), EGF (A61G), CCND1 (A870G), FCGR2A (R131H), FCGR3A (F158V). Statistical analyses were conducted on the total population and on patients with wt KRas tumors. All SNPs were considered as ternary variables (wt/wt vs wt/mut vs mut/mut), with the exception of -191C > A EGFR polymorphism (AA patient merged with CA patients). Results Analysis of skin toxicity as a function of EGFR intron 1 polymorphism showed a tendency for higher toxicity in patients with a low number of CA-repeats (p = 0.058). CCND1 A870G polymorphism was significantly related to clinical response, both in the entire population and in KRas wt patients, with the G allele being associated with a lack of response. In wt KRas patients, time to progression (TTP) was significantly related to EGFR -191C > A polymorphism with a longer TTP in CC patients as compared to others, and to CCND1 A870G polymorphism with the G allele being associated with a shorter TTP; a multivariate analysis including these two polymorphisms only retained CCND1 polymorphism. Overall survival was significantly related to CCND1 polymorphism with a shorter survival in patients bearing the G allele, and to FCGR3A F158V polymorphism with a shorter survival in VV patients (in the entire population and in KRas wt patients). FCGR3A F158V and CCND1 A870G polymorphisms were significant independent predictors of overall survival. Conclusions Present original data obtained in wt KRas patients corresponding to the current cetuximab-treated population clearly suggest that CCND1 A870G polymorphism may be used as an additional marker for predicting cetuximab efficacy, TTP and overall survival. In addition, FCGR3A F158V polymorphism was a significant independent predictor of overall survival.

Published
2011

88. A synonymous polymorphism of the Tristetraprolin (TTP) gene, an AU-rich mRNA-binding protein, affects translation efficiency and response to Herceptin treatment in breast cancer patients

Author

Corinne Hieblot, Gilles Pagès, Paola Griseri, Khadija Essafi-Benkhadir, Christian Touriol, Emmanuel Chamorey, Christine Bourcier, Institute of Developmental Biology and Cancer (IBDC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP), Dept. of Statistics, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), and UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA)

Subjects
Vascular Endothelial Growth Factor A, Tristetraprolin, MESH: Base Sequence, MESH: Mutant Proteins, 0302 clinical medicine, Trastuzumab, Gene expression, MESH: Angiogenesis Inducing Agents, heterocyclic compounds, skin and connective tissue diseases, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Regulation of gene expression, Genetics, 0303 health sciences, MESH: Polymorphism, Single Nucleotide, RNA-Binding Proteins, General Medicine, MESH: Gene Expression Regulation, Neoplastic, MESH: Case-Control Studies, 3. Good health, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, MESH: HEK293 Cells, MESH: Protein Biosynthesis, MESH: Tristetraprolin, Female, medicine.drug, MESH: Cell Line, Tumor, Breast Neoplasms, Biology, Antibodies, Monoclonal, Humanized, Transfection, Polymorphism, Single Nucleotide, 03 medical and health sciences, Breast cancer, Cell Line, Tumor, MESH: Cell Proliferation, medicine, Humans, ZFP36, Neoplasm Invasiveness, RNA, Messenger, Allele, Molecular Biology, Gene, Cell Proliferation, 030304 developmental biology, MESH: RNA, Messenger, MESH: Humans, Base Sequence, MESH: Transfection, MESH: Vascular Endothelial Growth Factor A, Interleukin-8, MESH: Clone Cells, MESH: Neoplasm Invasiveness, medicine.disease, Clone Cells, MESH: Interleukin-8, HEK293 Cells, MESH: RNA-Binding Proteins, MESH: Antibodies, Monoclonal, Humanized, Case-Control Studies, Protein Biosynthesis, Cancer research, Angiogenesis Inducing Agents, Mutant Proteins, MESH: Female, MESH: Breast Neoplasms
Abstract

International audience; Post-transcriptional regulation plays a central role in cell differentiation and proliferation. Among the regulatory factors involved in this mechanism, Tristetraprolin (ZFP36 or TTP) is the prototype of a family of RNA-binding proteins that bind to adenylate and uridylate (AU)-rich sequences in the 3'UTR of mRNAs, which promotes their physiological decay. Here, we investigated whether TTP correlates with tumor aggressiveness in breast cancer and is a novel prognostic factor for this neoplasia. By immunoblot analysis, we determined the amount of TTP protein in different breast cancer cell lines and found an inverse correlation between aggressiveness and metastatic potential. TTP mRNA levels were very variable among cells lines and did not correlate with protein levels. Interestingly, by sequencing the entire TTP coding region in Hs578T cells that do not express the TTP protein, we identified a synonymous polymorphism (rs3746083) that showed a statistically significant association with a lack of response to Herceptin/Trastuzumab in HER2-positive-breast cancer patients. Even though this genetic change did not modify the corresponding amino acid, we performed functional studies and showed an effect on protein translation associated with the variant allele with respect to the wild-type. These data underline the importance of synonymous variants on gene expression and the potential role of TTP genetic polymorphisms as a prognostic marker for breast cancer.

Published
2011

89. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

Author

Antoniou, A. C., Kartsonaki, C., Sinilnikova, O. M., Soucy, P., Mcguffog, L., Healey, S., Lee, A., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Cattaneo, E., Barile, M., Pensotti, V., Pasini, B., Dolcetti, R., Giannini, Giuseppe, Laura Putignano, A., Varesco, L., Radice, P., Mai, P. L., Greene, M. H., Andrulis, I. L., Glendon, G., Ozcelik, H., Thomassen, M., Gerdes, A. M., Kruse, T. A., Jensen, U. B., Cruger, D. G., Caligo, M. A., Laitman, Y., Milgrom, R., Kaufman, B., Paluch Shimon, S., Friedman, E., Loman, N., Harbst, K., Lindblom, A., Arver, B., Ehrencrona, H., Melin, B., Nathanson, K. L., Domchek, S. M., Rebbeck, T., Jakubowska, A., Lubinski, J., Gronwald, J., Huzarski, T., Byrski, T., Cybulski, C., Gorski, B., Osorio, A., Cajal, T. R., Fostira, F., Andres, R., Benitez, J., Hamann, U., Hogervorst, F. B., Rookus, M. A., Hooning, M. J., Nelen, M. R., Van Der Luijt, R. B., Van Os, T. A. M., Van Asperen, C. J., Devilee, P., Meijers Heijboer, H. E. J., Garcia, E. B. G., Peock, S., Cook, M., Frost, D., Platte, R., Leyland, J., Evans, D. G., Lalloo, F., Eeles, R., Izatt, L., Adlard, J., Davidson, R., Eccles, D., Ong, K. R., Cook, J., Douglas, F., Paterson, J., John Kennedy, M., Miedzybrodzka, Z., Godwin, A., Stoppa Lyonnet, D., Buecher, B., Belotti, M., Tirapo, C., Mazoyer, S., Barjhoux, L., Lasset, C., Leroux, D., Faivre, L., Bronner, M., Prieur, F., Nogues, C., Rouleau, E., Pujol, P., Coupier, I., Frenay, M., Hopper, J. L., Daly, M. B., Terry, M. B., John, E. M., Buys, S. S., Yassin, Y., Miron, A., Goldgar, D., Singer, C. F., Tea, M. K., Pfeiler, G., Catharina Dressler, A., Hansen, T. V. O., Jonson, L., Ejlertsen, B., Barkardottir, R. B., Kirchhoff, T., Offit, K., Piedmonte, M., Rodriguez, G., Small, L., Boggess, J., Blank, S., Basil, J., Azodi, M., Toland, A. E., Montagna, M., Tognazzo, S., Agata, S., Imyanitov, E., Janavicius, R., Lazaro, C., Blanco, I., Pharoah, P. D. P., Sucheston, L., Karlan, B. Y., Walsh, C. S., Olah, E., Bozsik, A., Teo, S. H., Seldon, J. L., Beattie, M. S., Van Rensburg, E. J., Sluiter, M. D., Diez, O., Schmutzler, R. K., Wappenschmidt, B., Engel, C., Meindl, A., Ruehl, I., Varon Mateeva, R., Kast, K., Deissler, H., Niederacher, D., Arnold, N., Gadzicki, D., Schonbuchner, I., Caldes, T., De La Hoya, M., Nevanlinna, H., Aittomaki, K., Dumont, M., Chiquette, J., Tischkowitz, M., Chen, X. Q., Beesley, J., Spurdle, A. B., Neuhausen, S. L., Ding, Y. C., Fredericksen, Z., Wang, X., Pankratz, V. S., Couch, F., Simard, J., Easton, D. F., Chenevix Trench, G., Karlsson, P., Nordling, M., Bergman, A., Einbeigi, Z., Stenmark Askmalm, M., Liedgren, S., Borg, A., Olsson, H., Kristoffersson, U., Jernstrom, H., Henriksson, K., Von Wachenfeldt, A., Liljegren, A., Barbany Bustinza, G., Rantala, J., Gronberg, H., Stattin, E. L., Emanuelsson, M., Brandell, R. R., Dahl, N., Hogervorst, F. B. L., Verhoef, S., Verheus, M., Veer, L. V., Van Leeuwen, F. E., Collee, M., Van Den Ouweland, A. M. W., Jager, A., Tilanus Linthorst, M. M. A., Seynaeve, C., Wijnen, J. T., Vreeswijk, M. P., Tollenaar, R. A., Ligtenberg, M. J., Hoogerbrugge, N., Ausems, M. G., Aalfs, C. M., Van Os, T. A., Gille, J. J. P., Waisfisz, Q., Gomez Garcia, E. B., Van Roozendaal, C. E., Blok, M. J., Caanen, B., Oosterwijk, J. C., Van Der Hout, A. H., Mourits, M. J., Vasen, H. F., Gregory, H., Morrison, P., Jeffers, L., Cole, T., Mckeown, C., Hoffman, J., Donaldson, A., Downing, S., Taylor, A., Murray, A., Rogers, M. T., Mccann, E., Kennedy, M. J., Barton, D., Porteous, M., Drummond, S., Brewer, C., Kivuva, E., Searle, A., Goodman, S., Hill, K., Murday, V., Bradshaw, N., Snadden, L., Longmuir, M., Watt, C., Gibson, S., Haque, E., Tobias, E., Duncan, A., Jacobs, C., Langman, C., Whaite, A., Dorkins, H., Barwell, J., Chu, C., Miller, J., Ellis, I., Houghton, C., Taylor, J., Side, L., Male, A., Berlin, C., Eason, J., Collier, R., Claber, O., Jobson, I., Walker, L., Mcleod, D., Halliday, D., Durell, S., Stayner, B., Shanley, S., Rahman, N., Houlston, R., Bancroft, E., D'Mello, L., Page, E., Ardern Jones, A., Kohut, K., Wiggins, J., Castro, E., Mitra, A., Robertson, L., Quarrell, O., Bardsley, C., Hodgson, S., Goff, S., Brice, G., Winchester, L., Eddy, C., Tripathi, V., Attard, V., Lucassen, A., Crawford, G., Mcbride, D., Smalley, S., University of Groningen, Clinical Genetics, Medical Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] ( CAM ), Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, Queensland Institute of Medical Research, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT)-Fondazione Istituto FIRC di Oncologia Molecolare, Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Consortium for Genomics Technology (Cogentech), Department of Genetics, Biology and Biochemistry, University of Turin, Cancer Bioimmunotherapy Unit, IRCCS-Centro di Riferimento Oncologico, Department of Experimental Medicine, Università degli Studi di Roma 'La Sapienza' [Rome], Medical Genetics Unit, Department of Clinical Physiopathology, University of Florence, Unit of Hereditary Cancers, Istituto Nazionale per la Ricerca sul Cancro, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health ( NIH ) -National Cancer Institute ( NIH ), Ontario Cancer Genetics Network, Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Samuel Lunenfeld Research Institute, Mount Sinai Hospital ( MSH ), Department of Clinical Genetics, Odense University Hospital, Rigshospitalet [Copenhagen]-University of Copenhagen ( KU ), The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Department of Oncology, Lund University Hospital, Karolinska University Hospital [Stockholm], Departament of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Department of Radiation Sciences and Oncology, Umeå University, Depts of Medicine and Biostatistics and Epidemology, Abramson Family Cancer Research Institute-University of Pennsylvania School of Medicine, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine-Abramson Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University-International Hereditary Cancer Centre, Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, International Hereditary Cancer Center, Pomeranian Medical University, Human Genetics Group, Spanish National Cancer Research Centre, Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Department of Medical Oncology, Hospital Sant Pau, Medical Oncology Division, Hospital Clínico de Zaragoza, Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum ( DKFZ ), Department of Genetic Epidemiology, Leiden University Medical Center (LUMC), Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Guy's and St. Thomas' NHS Foundation Trust, Yorkshire Regional Genetics Service, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Wessex Clinical Genetics Service, Princess Anne Hospital, West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Newcastle Upon Tyne Hospitals NHS Trust, Addenbrookes Hospital, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Service de Génétique Oncologique, INSTITUT CURIE, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), génétique, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ), Laboratoire de Biométrie et Biologie Evolutive ( LBBE ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ), Equipe de prévention et épidémiologie génétique, Centre Léon Bérard [Lyon], Service d'onco-hématologie et génétique, CHU Grenoble, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne, Santé Publique, Hôpital René HUGUENIN (Saint-Cloud)-INSTITUT CURIE, Laboratoire d'Oncogénétique, CRLCC René Huguenin, 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 ), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Unité d'Oncogénétique, CRLCC Val d'Aurelle - Paul Lamarque, Consultation d'oncogénétique, CRLCC Antoine Lacassagne, Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], Department of Surgery, Harvard Medical School [Boston] ( HMS ), Department of Dermatology, University of Utah School of Medicine [Salt Lake City], Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Division of Special Gynecology, Medical University of Vienna-Department of OB/GYN, Department of Clinical Biochemistry, Rigshospitalet [Copenhagen], Copenhagen University Hospital-Rigshospitalet [Copenhagen], Department of Pathology, Landspitali-University Hospital, Department of Environmental Medicine, New York University School of Medicine-NYU Cancer Institute, Clinical Genetics Service, Memorial Sloane Kettering Cancer Center [New York], Statistical and Data Center, Roswell Park Cancer Institute [Buffalo], Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santariskiu Clinics, State Research Institute Innovative Medicine Center, Molecular Diagnostic Unit, IDIBELL-Catalan Institute of Oncology, Genetic Counselling Unit, Department of Molecular Genetics, National Institute of Oncology, Cancer Research Initiatives Foundation, Sime Darby Medical Centre-Malaysia and University Malaya Cancer Research Institute-University Malaya Medical Centre, Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] ( IMISE ), University of Leipzig, Technical University of Munich ( TUM ), Ludwig-Maximillians University, Charite berlin, University Hospital Carl Gustav Carus, University Hospital Ulm, University Hospital Düsseldorf-Heinrich-Heine-Universität Düsseldorf [Düsseldorf], University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel ( CAU ), Institute of Cell and Molecular Pathology, Hannover Medical School [Hannover] ( MHH ), University of Würzburg, Molecular Oncology Laboratory, Hospital Clínico San Carlos, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Department of Genetics, Portuguese Oncology Institute, Department of Medical Genetics, Mayo Clinic, Department of Laboratory Medicine and Pathology, Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Laboratory, Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Università degli Studi di Firenze = University of Florence (UniFI), National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Mount Sinai Hospital [Toronto, Canada] (MSH), Department of Clinical Genetics [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Tel Aviv University (TAU), Uppsala University, Abramson Family Cancer Research Institute-Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Abramson Cancer Center-Perelman School of Medicine, International Hereditary Cancer Centre-Pomeranian Medical University [Szczecin] (PUM), Pomeranian Medical University [Szczecin] (PUM), Hospital de la Santa Creu i Sant Pau, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Universiteit Leiden-Universiteit Leiden, Birmingham Women's and Children's NHS Foundation Trust, Sheffield Children's NHS Foundation Trust, Newcastle Upon Tyne Hospitals NHS Foundation Trust, University of Kansas Medical Center [Kansas City, KS, USA], Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), 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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Institut Curie [Paris]-Hôpital René HUGUENIN (Saint-Cloud), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), 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 Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Harvard Medical School [Boston] (HMS), Medizinische Universität Wien = Medical University of Vienna, Medizinische Universität Wien = Medical University of Vienna-Department of OB/GYN, Department of Clinical Biochemistry [Rigshospitalet], Copenhagen University Hospital, New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-NYU Cancer Institute, Roswell Park Cancer Institute [Buffalo] (RPCI), Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Universitätsklinikum Ulm - University Hospital of Ulm, University Hospital Düsseldorf-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel (CAU), Hannover Medical School [Hannover] (MHH), Julius-Maximilians-Universität Würzburg (JMU), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], University of Kansas Medical Center [Lawrence], Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital René HUGUENIN (Saint-Cloud)-Institut Curie [Paris], 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), Universität Leipzig [Leipzig], Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), University of Florence (UNIFI), Mount Sinai Hospital (MSH), Institut Curie, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie-Hôpital René HUGUENIN (Saint-Cloud), Technical University of Munich (TUM), Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Human genetics, CCA - Oncogenesis, Human Genetics, Klinische Genetica, and RS: GROW - School for Oncology and Reproduction

Subjects
MESH : BRCA2 Protein, MESH : Aged, Estrogen receptor, Genome-wide association study, MESH : Breast Neoplasms, VARIANTS, MESH : Chromosomes, Human, Pair 1, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH : Chromosomes, Human, Pair 6, MESH: BRCA2 Protein, 0302 clinical medicine, MESH: Risk Factors, Risk Factors, Genotype, CONFER SUSCEPTIBILITY, Chromosomes, Human, MESH : Female, skin and connective tissue diseases, Genetics (clinical), POPULATION, MESH: Heterozygote, MESH: Aged, 0303 health sciences, education.field_of_study, MESH: Middle Aged, BRCA1 Protein, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, Association Studies Articles, MESH: Genetic Predisposition to Disease, General Medicine, MESH : Adult, Middle Aged, MESH : Risk Factors, 3. Good health, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 6, Female, MESH : Mutation, Adult, MESH : Heterozygote, Heterozygote, MESH: Mutation, MESH: Chromosomes, Human, Pair 6, MESH: Chromosomes, Human, Pair 1, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Single-nucleotide polymorphism, Breast Neoplasms, Biology, MESH: Chromosomes, Human, Polymorphism, Single Nucleotide, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Genetics, medicine, LOCUS, SNP, Humans, MESH : Middle Aged, MESH : BRCA1 Protein, Genetic Predisposition to Disease, Allele, GENOME-WIDE ASSOCIATION, education, Molecular Biology, Alleles, MESH: BRCA1 Protein, 030304 developmental biology, Aged, BRCA2 Protein, MESH: Humans, 2Q35, MESH: Alleles, MESH : Humans, MESH: Adult, medicine.disease, MESH : Chromosomes, Human, ESTROGEN-RECEPTOR, Mutation, Cancer research, MESH : Genetic Predisposition to Disease, GENETIC MODIFIERS, MESH : Alleles, MESH: Female, MESH: Breast Neoplasms
Abstract

Item does not contain fulltext Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 x 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 x 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

Published
2011

90. Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients Age 60 Years and Younger: Long-Term Results of the Randomized Phase II PRECIS Study

Author

Houillier, Caroline, Dureau, S, Taillandier, Luc, Houot, Roch, Chinot, O., Molucon-Chabrot, Cécile, Schmitt, Anna, Gressin, Rémy, Choquet, Sylvain, Damaj, Gandhi, Peyrade, Frédéric, Abraham, Julie, Delwail, V, Gyan, Emmanuel, Sanhes, Laurence, Cornillon, Jerome, Garidi, Reda, Delmer, Alain, Al Jijakli, Ahmad, Morel, Pierre, Waultier, Agathe, Paillassa, Jérôme, Chauchet, A, Gastinne, Thomas, Laadhari, Mouna, Plissonnier, Anne-Sophie, Feuvret, Loïc, Cassoux, Nathalie, Touitou, Valerie, Ricard, Jean-Damien, Hoang-Xuan, Khe, Soussain, Carole, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Curie [Paris], Centre Hospitalier Universitaire de Nancy (CHU Nancy), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Louise Michel [Clermont-Ferrand], CHU Clermont-Ferrand, Institut Bergonié [Bordeaux], UNICANCER, Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Amiens-Picardie, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CHU Limoges, CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d’Investigation Clinique [Tours] CIC 1415 (CIC ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Saint Jean de Perpignan, Institut de Cancérologie Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier de Lens, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Immunité et cancer (U932), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Cancer Research, Adolescent, Lymphoma, [SDV]Life Sciences [q-bio], Hematopoietic Stem Cell Transplantation, Middle Aged, Transplantation, Autologous, Combined Modality Therapy, Central Nervous System Neoplasms, Young Adult, Oncology, Antineoplastic Combined Chemotherapy Protocols, Humans, Neoplasm Recurrence, Local
Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We previously reported the results of a randomized phase II study in patients with newly diagnosed primary CNS lymphoma (age 18-60 years). Patients were treated with high-dose methotrexate-based induction chemotherapy followed by whole-brain radiotherapy (WBRT) or high-dose chemotherapy (thiotepa-busulfan-cyclophosphamide) with autologous stem-cell transplantation (ASCT). The median follow-up was 33 months. In this report, we provide long-term data (median follow-up, 8 years) regarding the outcomes and toxicities. Fifty-three and 44 patients received induction chemotherapy followed by WBRT or ASCT, respectively. Their 8-year event-free survival from random assignment was 67% and 39% in the ASCT and WBRT arms, respectively ( P = .03), with a significantly lower risk of relapse after ASCT (hazard ratio, 0.13; P < .001). One third of patients who relapsed after WBRT were alive after salvage treatment. Five and four patients died of ASCT and WBRT-related toxicities, respectively. The 8-year overall survival was 69% and 65% in the ASCT and WBRT arms, respectively (not significant). Balance (52% v 10%, P ≤ 0.001) and neurocognition (64% v 13%, P < .001) significantly deteriorated after WBRT compared with ASCT during the follow-up. This study shows that 40 Gy WBRT should be avoided in first-line treatment because of its neurotoxicity and suboptimal efficacy in reducing relapses while ASCT appears to be highly efficient in preventing relapses.

Published
2022

91. Optimal timing of interval debulking surgery for advanced epithelial ovarian cancer: A retrospective study from the ESME national cohort

Author

Quentin Dominique Thomas, Amal Boussere, Jean-Marc Classe, Christophe Pomel, Hélène Costaz, Manuel Rodrigues, Isabelle Ray-Coquard, Laurence Gladieff, Roman Rouzier, Thibault De La Motte Rouge, Sébastien Gouy, Emmanuel Barranger, Renaud Sabatier, Anne Floquet, Frédéric Marchal, Cécile Guillemet, Valentine Polivka, Anne-Laure Martin, Pierre-Emmanuel Colombo, Frédéric Fiteni, Institut du Cancer de Montpellier (ICM), CRLCC René Gauducheau, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Service de chirurgie [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Institut Curie [Paris], Centre Léon Bérard [Lyon], Institut Claudius Regaud, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Eugène Marquis (CRLCC), Institut Gustave Roussy (IGR), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Bergonié [Bordeaux], UNICANCER, Service d'oncogénétique [Vandoeuvre-Lès-Nancy] (Institut de Cancérologie de Lorraine - CLCC Alexis Vautrin), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Desbrest de santé publique (IDESP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Ovarian Neoplasms, Survival, Propensity score, Obstetrics and Gynecology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cytoreduction Surgical Procedures, Carcinoma, Ovarian Epithelial, Prognosis, Neoadjuvant Therapy, Cytoreduction, Oncology, Chemotherapy, Adjuvant, Humans, Female, Neoadjuvant, Neoplasm Staging, Retrospective Studies
Abstract

International audience; Objective. Interval debulking surgery is recommended after 3–4 cycles (standard IDS) of neoadjuvant chemotherapy (NACT) for epithelial ovarian cancer (EOC) not able to received upfront complete debulking surgery. However, real world practices frequently report performing IDS after ≥5 NAC cycles (delayed IDS). The aim of this work was to evaluate the impact on survival of the number of NACT cycles before IDS.Methods. We identified from a French national database, women with newly diagnosed EOC who underwent IDS from January 2011 to December 2016. Progression free survival (PFS) and overall survival (OS) were compared using Cox model with adjustments for confounding factors provided by two propensity score methods: inverse probability of treatment weighting (IPTW) and matched-pair analysis.Results. 928 patients treated by IDS for which our propensity score could be applied were identified. After a median follow-up of 49.0 months (95% CI [46.0;52.9]); from the IPTW analysis, median PFS was 17.6 months and 11.5 months (HR = 1.42; CI 95% [1.22–1.67]; p < 0.0001); median OS was 51.2 months and 44.3 months (HR = 1.29; CI 95% [1.06–1.56]; p = 0.0095) for the standard and delayed IDS groups. From the matched-pair analysis (comparing 352 patients for each group), standard IDS was associated with better PFS (HR = 0,77; CI 95% [0.65–0.90]; p = 0.018) but not significantly associated with better OS (HR = 0,84; CI 95% [0.68–1,03]; p = 0.0947).Conclusions. Carrying IDS after ≥5 NACT cycles seems to have a negative effect on patients survival. The goal of IDS surgery is complete resection and should not be performed after >3–4 NACT cycles.

Published
2022

92. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial

Author

François-Clément Bidard, Anne-Claire Hardy-Bessard, Florence Dalenc, Thomas Bachelot, Jean-Yves Pierga, Thibault de la Motte Rouge, Renaud Sabatier, Coraline Dubot, Jean-Sébastien Frenel, Jean Marc Ferrero, Sylvain Ladoire, Christelle Levy, Marie-Ange Mouret-Reynier, Alain Lortholary, Julien Grenier, Camille Chakiba, Laetitia Stefani, Jérôme Edouard Plaza, Florian Clatot, Luis Teixeira, Véronique D'Hondt, Hélène Vegas, Olfa Derbel, Claire Garnier-Tixidre, Jean-Luc Canon, Barbara Pistilli, Fabrice André, Laurent Arnould, Anne Pradines, Ivan Bièche, Céline Callens, Jérôme Lemonnier, Frédérique Berger, Suzette Delaloge, Francois-Clement BIDARD, Barbara PISTILLI, Florence DALENC, Thomas BACHELOT, Thibault DE LA MOTTE ROUGE, Renaud SABATIER, Coraline DUBOT, Jean-Sébastien FRENEL, Jean-Marc FERRERO, Sylvain LADOIRE, Christelle LEVY, Marie-Ange MOURET-REYNIER, Anne-Claire HARDY-BESSARD, Alain LORTHOLARY, Julien GRENIER, Camille CHAKIBA, Laetitia STEFANI, Patrick SOULIE, Jean-Philippe JACQUIN, Jérôme Edouard PLAZA, Florian CLATOT, Luis TEIXEIRA, Véronique D'HONDT, Hélène VEGAS, Olfa DERBEL, Claire GARNIER TIXIDRE, Catherine DELBALDO, Lionel MOREAU, Caroline CHENEAU, Jean-François PAITEL, Chantal BERNARD-MARTY, Dominique SPAETH, Dominique GENET, Isabelle MOULLET, Nathalie BONICHON-LAMICHHANE, Laura DEIANA, Charlotte GREILSAMER, Laurence VENAT-BOUVET, Valérie DELECROIX, Adrien MELIS, Hubert ORFEUVRE, Suzanne NGUYEN, Eric LEGOUFFE, Alain ZANNETTI, Romuald LE SCODAN, Nadine DOHOLLOU, Philippe DALIVOUST, Olivier ARSENE, Nathalie MARQUES, Thierry PETIT, Delphine MOLLON, Jérôme DAUBA, Nathalie BONNIN, François MORVAN, Miriam GARDNER, Adina MARTI, Charles-Briac LEVACHE, Emma LACHAIER, Mihaela ACHILLE, Christophe VALMAR, Ryan BOUAITA, Jacques MEDIONI, Cyril FOA, Francesco DEL PIANO, Michel GOZY, Anne ESCANDE, Nicolas LEDUC, Brigitte LUCAS, Dominique MILLE, Hanifa AMMARGUELLAT, Abeer NAJEM, Fanny TROUBOUL, Philippe BARTHELEMY, Hervé DESCLOS, Didier MAYEUR, Fabrice LORCHEL, François GUINET, Anne-Pascale LAURENTY, Axelle BOUDRANT, Olivier GISSEROT, Corinne ALLEAUME, Aimery DE GRAMONT, Institut Curie [Paris], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre Armoricain de Radiothérapie, d'Imagerie médicale et d'Oncologie [Plérin, Saint-Brieuc] (CARIO), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département cancer environnement (Centre Léon Bérard - Lyon), Centre Léon Bérard [Lyon], Centre Eugène Marquis (CRLCC), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Service d'oncogénétique [Centre georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Radiothérapie [Centre François Baclesse], Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Hôpital privé du Confluent [Nantes], Institut Sainte Catherine [Avignon], Institut Bergonié [Bordeaux], Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cancer de Montpellier (ICM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital privé Jean Mermoz [Lyon], Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL), and Pfizer

Subjects
Adult, Neutropenia, Adolescent, Aromatase Inhibitors, Receptor, ErbB-2, [SDV]Life Sciences [q-bio], Breast Neoplasms, Disease-Free Survival, Oncology, Receptors, Estrogen, Lymphopenia, Antineoplastic Combined Chemotherapy Protocols, Mutation, Humans, Female, Prospective Studies, Fulvestrant
Abstract

In advanced oestrogen receptor-positive, HER2-negative breast cancer, acquired resistance to aromatase inhibitors frequently stems from ESR1-mutated subclones, which might be sensitive to fulvestrant. The PADA-1 trial aimed to show the efficacy of an early change in therapy on the basis of a rising ESR1 mutation in blood (bESR1We did a randomised, open-label, phase 3 trial in 83 hospitals in France. Women aged at least 18 years with oestrogen receptor-positive, HER2-negative advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited and monitored for rising bESR1From March 22, 2017, to Jan 31, 2019, 1017 patients were included, of whom 279 (27%) developed a rising bESR1PADA-1 is the first prospective randomised trial showing that the early therapeutic targeting of bESR1Pfizer.

Published
2022

93. Comparison of two high-dose cyclophosphamide, doxorubicin, vincristine, and prednisone derived regimens in patients aged under 60 years with low-intermediate risk aggressive lymphoma: a final analysis of the multicenter LNH93-2 protocol

Author

Pierre, Morel, Jean-Nicolas, Munck, Bertrand, Coiffier, Christian, Gisselbrecht, Dana, Ranta, Andre, Bosly, Hervé, Tilly, Bruno, Quesnel, Antoine, Thyss, Nicolas, Mounier, Josette, Brière, Thierry, Molina, Felix, Reyes, C, Traulle, Ganivet, Agnès, Service d'Hématologie Clinique, Centre Hospitalier Schaffner, Service d'Hématologie, Oncologie Médicale, CRLCC René Huguenin, Service d'Hematologie, Hospices Civils de Lyon (HCL)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service d'Hémato-Oncologie, Assistance Publique-Hopitaux de Paris, Service d'Hematologie et Médecine Interne, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Hématologie, Université Catholique de Louvain = Catholic University of Louvain (UCL), Département d'Hématologie, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service des maladies du Sang, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Service d'onco-hématologie, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Service d'anatomo-pathologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Anatomo-Pathologie, Université Catholique de Louvain (UCL), Centre Antoine Lacassagne de Nice, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre René Huguenin, Hospices Civils de Lyon ( HCL ) -Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Université Catholique de Louvain ( UCL ), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen ( CLCC Henri Becquerel ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), CHU Nice-Hôpital l'Archet, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP)

Subjects
Male, Oncology, Cancer Research, Vindesine, Aggressive lymphoma, Aggressive Non-Hodgkin Lymphoma, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Prospective Studies, Etoposide, 0303 health sciences, Cytarabine, Aggressive non-Hodgkin lymphoma, Hematology, Middle Aged, Prognosis, Chemotherapy regimen, 3. Good health, Survival Rate, Clinical trial, 030220 oncology & carcinogenesis, Female, Rituximab, Lymphoma, Large B-Cell, Diffuse, medicine.drug, Epirubicin, Adult, medicine.medical_specialty, Adolescent, Chemotherapy model, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bleomycin, Young Adult, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Ifosfamide, Cyclophosphamide, Survival rate, Neoplasm Staging, 030304 developmental biology, Dose escalation, business.industry, Surgery, Regimen, Methotrexate, Doxorubicin, Prednisone, business, Follow-Up Studies
Abstract

One-third of patients aged

Published
2010

94. Genetic identification of patients with AML older than 60 years achieving long-term survival with intensive chemotherapy

Author

P. Rousselot, Lionel Ades, Hubert Serve, Sylvain Chantepie, Xavier Thomas, Delphine Lebon, Kevin-James Wattebled, Raphael Itzykson, Cécile Pautas, Hervé Dombret, Karine Celli-Lebras, Olivier Nibourel, Thorsten Braun, Elise Fournier, Nicolas Boissel, Thomas Cluzeau, Emilie Lemasle, Christine Terré, Lauris Gastaud, Nicolas Duployez, Claude Gardin, Alice Marceau-Renaut, Christian Thiede, Jean-Baptiste Micol, Emmanuel Raffoux, Christoph Röllig, Céline Berthon, Jean-Valère Malfuson, Laure Goursaud, Claude Preudhomme, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Claude Huriez [Lille], CHU Lille, Technische Universität Dresden = Dresden University of Technology (TU Dresden), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Transfusion Sanguine des Armées (CTSA), Service de Santé des Armées, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Etablissement français du sang [Rennes] (EFS Bretagne), CH Dunkerque, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre Hospitalier de Versailles André Mignot (CHV), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Institut d'Hématologie de Basse-Normandie (IHBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, XLIM (XLIM), Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS), Universitätsklinikum Frankfurt am Main [Germany], Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), and Hôpital Avicenne [AP-HP]

Subjects
Male, Neuroblastoma RAS viral oncogene homolog, Oncology, NPM1, medicine.medical_specialty, Standard of care, [SDV]Life Sciences [q-bio], Immunology, Intensive chemotherapy, medicine.disease_cause, Biochemistry, Disease-Free Survival, Cytogenetics, Internal medicine, Long term survival, Humans, Medicine, Aged, Aged, 80 and over, business.industry, Cell Biology, Hematology, Middle Aged, Neoplasm Proteins, Survival Rate, Leukemia, Myeloid, Acute, Mutation, Prognostic model, Female, KRAS, business, Follow-Up Studies
Abstract

To design a simple and reproducible classifier predicting the overall survival (OS) of patients with acute myeloid leukemia (AML) ≥60 years of age treated with 7 + 3, we sequenced 37 genes in 471 patients from the ALFA1200 (Acute Leukemia French Association) study (median age, 68 years). Mutation patterns and OS differed between the 84 patients with poor-risk cytogenetics and the 387 patients with good (n = 13), intermediate (n = 339), or unmeasured (n = 35) cytogenetic risk. TP53 (hazards ratio [HR], 2.49; P = .0003) and KRAS (HR, 3.60; P = .001) mutations independently worsened the OS of patients with poor-risk cytogenetics. In those without poor-risk cytogenetics, NPM1 (HR, 0.57; P = .0004), FLT3 internal tandem duplications with low (HR, 1.85; P = .0005) or high (HR, 3.51; P < 10−4) allelic ratio, DNMT3A (HR, 1.86; P < 10−4), NRAS (HR, 1.54; P = .019), and ASXL1 (HR, 1.89; P = .0003) mutations independently predicted OS. Combining cytogenetic risk and mutations in these 7 genes, 39.1% of patients could be assigned to a “go-go” tier with a 2-year OS of 66.1%, 7.6% to the “no-go” group (2-year OS 2.8%), and 3.3% of to the “slow-go” group (2-year OS of 39.1%; P < 10−5). Across 3 independent validation cohorts, 31.2% to 37.7% and 11.2% to 13.5% of patients were assigned to the go-go and the no-go tiers, respectively, with significant differences in OS between tiers in all 3 trial cohorts (HDF [Hauts-de-France], n = 141, P = .003; and SAL [Study Alliance Leukemia], n = 46; AMLSG [AML Study Group], n = 223, both P < 10−5). The ALFA decision tool is a simple, robust, and discriminant prognostic model for AML patients ≥60 years of age treated with intensive chemotherapy. This model can instruct the design of trials comparing the 7 + 3 standard of care with less intensive regimens.

Published
2021

95. FOLFIRINOX-R study design: a phase I/II trial of FOLFIRINOX plus regorafenib as first line therapy in patients with unresectable RAS-mutated metastatic colorectal cancer

Author

Antoine Adenis, Stephanie Clisant Delaine, Ludovic Evesque, Julien Fraisse, Brice Pastor, Marc Ychou, Caroline Mollevi, François Ghiringhelli, Thibault Mazard, Patrick Chalbos, Malbec, Odile, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut du Cancer de Montpellier (ICM), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), and UNICANCER

Subjects
Oncology, Male, Cancer Research, FOLFIRINOX, Colorectal cancer, Pyridines, [SDV]Life Sciences [q-bio], ClinicalTrials.gov: NCT03828799 Colorectal cancer, Leucovorin, Chemotherapy triplet, chemistry.chemical_compound, Study Protocol, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Multicenter Studies as Topic, 030212 general & internal medicine, Prospective Studies, RC254-282, Regorafenib, FOLFOXIRI, Clinical Trials, Phase I as Topic, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Progression-Free Survival, 3. Good health, [SDV] Life Sciences [q-bio], Oxaliplatin, Phase 1–2 trial, 030220 oncology & carcinogenesis, RAS-mutated metastatic colorectal cancer. Trial registration: EudraCT: 2018-003541-42, Female, Fluorouracil, Colorectal Neoplasms, medicine.drug, Adult, medicine.medical_specialty, Bevacizumab, Adolescent, Irinotecan, Drug Administration Schedule, 03 medical and health sciences, Folinic acid, Phase 1-2 trial, Young Adult, Clinical Trials, Phase II as Topic, Internal medicine, Genetics, medicine, Humans, business.industry, Phenylurea Compounds, medicine.disease, chemistry, ras Proteins, business
Abstract

Background The chemotherapy triplet FOLFOXIRI combined to the anti-VEGF antibody bevacizumab is an option in selected patients with metastatic colorectal cancer. In this setting, RAS-mutated metastatic colorectal cancer do not benefit the same from treatment than RAS-wildtype metastatic colorectal cancer do. Together with its antiangiogenic properties, the tyrosine-kinase inhibitor regorafenib has also anti-proliferative activities whatever the RAS status is. The present trial aims at studying the safety and the efficacy of regorafenib in combination with FOLFIRINOX – a chemotherapy triplet using a different dosing schedule than FOLFOXIRI - in patients with RAS-mutated metastatic colorectal cancer. Methods FOLFIRINOX-R is a prospective, multicentric, non-randomised, dose-finding phase 1–2 trial. The primary endpoints are the determination of the maximum tolerated dose, the recommended phase 2 dose, and the proportion of patients achieving disease control at 48-weeks. Phase 1 follows a 3 + 3 design (12 to 24 patients to be included). Sixty nine patients will be necessary in phase 2, including 5% non-evaluable ones, with the following assumptions, one-stage Fleming design, α = 5%, β = 20%, p0 = 35% and p1 = 50%. Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS-mutated metastatic colorectal cancer not amenable to surgery with curative intent and not previously treated for metastatic disease. FOLFIRINOX (oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, irinotecan 150–180 mg/m2, 5-fluorouracil: 400 mg/m2 then 2400 mg/m2 over 46 h) is administered every 14 days. Regorafenib (80 to 160 mg, as per dose-level) is administered orally, once daily on days 4 to 10 of each cycle. Discussion FOLFIRINOX-R is the first phase I/II study to evaluate the safety and efficacy of regorafenib in combination with FOLFIRINOX as frontline therapy for patients with RAS-mutated metastatic colorectal cancer. Trial registration EudraCT: 2018-003541-42; ClinicalTrials.gov: NCT03828799.

Published
2021

96. Modulation of cellular redox state underlies antagonism between oxaliplatin and cetuximab in human colorectal cancer cell lines

Author

Dahan, Laetitia, Sadok, Amine, Formento, Jean-Louis, Seitz, Jean François, Kovacic, Hervé, Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dept of Oncopharmacology, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), and Fédération Francophone de la Cancérologie Digestive, FFCD

Subjects
Organoplatinum Compounds, Cell Survival, [SDV]Life Sciences [q-bio], Cetuximab, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Antibodies, Monoclonal, Humanized, Inhibitory Concentration 50, Cell Line, Tumor, Humans, neoplasms, Antibodies, Monoclonal, NADPH Oxidases, Hydrogen Peroxide, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Research Papers, digestive system diseases, ErbB Receptors, Gene Expression Regulation, Neoplastic, Oxaliplatin, Genes, ras, Mutation, NADPH Oxidase 1, Caco-2 Cells, Colorectal Neoplasms, Drug Antagonism, Oxidation-Reduction
Abstract

Oxaliplatin is the first platinum-based compound effective in the treatment of colorectal cancer. Oxaliplatin combined with cetuximab for metastatic colorectal cancer is under evaluation. The preliminary results seem controversial, particularly for the use of cetuximab in K-Ras mutated patients. K-Ras mutation is known to affect redox homeostasis. Here we evaluated how the efficacy of oxaliplatin alone or combined with cetuximab varied according to the Ras mutation and redox status in a panel of colorectal tumour cell lines.Viability was evaluated by methylthiazoletetrazolium assay, reactive oxygen species production by DCFDA and lucigenin on HT29-D4, Caco-2, SW480 and SW620 cell lines.Combination of oxaliplatin and cetuximab was less cytotoxic than oxaliplatin alone in colorectal cells harbouring wild-type Ras and membrane expression of receptors for epidermal growth factor receptor (EGFR), such as HT29-D4 and Caco-2 cells. In contrast, cetuximab did not affect oxaliplatin efficiency in cells harbouring K-Ras(V12) mutation, irrespective of membrane EGFR expression (SW620 and SW480 cells). Transfection of HT29-D4 with K-Ras(V12) decreased oxaliplatin IC(50) and impaired cetuximab sensitivity, without affecting expression of membrane EGFR compared with HT29-D4 control. Oxaliplatin efficacy relies on endogenous production of H(2)O(2). Cetuximab inhibits H(2)O(2) production inhibiting the EGFR/Nox1 NADPH oxidase pathway. Oxaliplatin efficacy was impaired by short hairpin RNA for Nox1 and by catalase (H(2)O(2) scavenger).Cetuximab limited oxaliplatin efficiency by affecting the redox status of cancer cells through Nox1. Such combined therapy might be improved by controlling H(2)O(2) elimination.

Published
2009

97. Influence of the VEGF-A 936C>T germinal polymorphism on tumoral VEGF expression in head and neck cancer

Author

Jean-Louis Formento, Marie-Christine Etienne-Grimaldi, Gérard Milano, Patricia Formento, Gilles Pagès, Gilles Poissonnet, Cercina Onesto, Mireille Francoual, Olivier Dassonville, Emmanuel Chamorey, Dept of Oncopharmacology, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Unité de ciblage pharmacologique dans les cancers ORL, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Dept. of Statistics, and Service d'ORL

Subjects
Adult, Male, Vascular Endothelial Growth Factor A, Genotype, Angiogenesis, Enzyme-Linked Immunosorbent Assay, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Disease-Free Survival, law.invention, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Predictive Value of Tests, law, Genetics, medicine, Humans, Allele frequency, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Polymerase chain reaction, Aged, Proportional Hazards Models, Retrospective Studies, 030304 developmental biology, Aged, 80 and over, Pharmacology, 0303 health sciences, business.industry, Head and neck cancer, DNA, Neoplasm, Middle Aged, medicine.disease, Vascular endothelial growth factor A, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Predictive value of tests, Immunology, Cancer research, Molecular Medicine, Female, Gene polymorphism, business
Abstract

Aims: Elevated tumoral vascular endothelial growth factor A (VEGF-A) expression is linked to poor survival in head and neck cancer patients. The aim of the present study was to analyze the influence of VEGF-A gene polymorphisms on tumoral VEGF-A expression and to test their prognostic value in head and neck cancer patients. Materials & methods: VEGF-A polymorphisms at position -2578C>A, -1498T>C, -1154G>A, -634G>C and 936C>T were analyzed (PCR-RFLP) in tumoral DNA, along with tumoral VEGF-A expression (ELISA), in 49 Caucasian head and neck cancer patients. Results: A trend towards a difference in tumoral VEGF-A expression depending on 936C>T polymorphism was observed, with a median at 540 pg/mg prot in CT + TT patients (n = 5) versus 940 pg/mg prot in CC patients (n = 44) (p = 0.064). VEGF-A expression was not related to any other polymorphism. Unlike tumoral VEGF-A expression, the analyzed genotypes were not related to patient survival. Conclusion: As opposed to tumoral VEGF-A expression, VEGF-A gene polymorphisms are not of prognostic value in head and neck cancer patients. Further studies aimed at confirming the influence of VEGF-A 936C>T germinal polymorphism on tumoral VEGF-A expression are needed.

Published
2009

98. [Study of aberrant methylation of TSG in saliva in case of upper-aerodigestive-tract cancer.]

Author

C A, Righini, F, de Fraipont, J-F, Timsit, O, Dassonville, G, Milano, D, Moro-Sibilot, INSERM U823, équipe 5 (cibles diagnostiques ou thérapeutiques et vectorisation de drogues dans le cancer du poumon), Service d'ORL et de chirurgie cervicale, CHU Grenoble-CHU Grenoble-Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-Université Joseph Fourier - Grenoble 1 (UJF), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Département de biologie intégrée, CHU Grenoble-Hôpital Michallon-Hôpital Michallon, INSERM U823, équipe 11 (Epidémiologie des cancers et des affections graves), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Service d'ORL, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Unité de ciblage pharmacologique dans les cancers ORL, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Département de biologie intégrée, CHU Grenoble-Hôpital Michallon, Centre d'Investigation Clinique [Grenoble] (CIC Grenoble), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon-Institut National de la Santé et de la Recherche Médicale (INSERM), Hurbin, Amandine, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de biologie intégrée, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)

Subjects
Male, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Biomarkers, Tumor, Humans, Genes, Tumor Suppressor, Single-Blind Method, Prospective Studies, Saliva, DNA Modification Methylases, Tissue Inhibitor of Metalloproteinase-3, Genes, p16, Tumor Suppressor Proteins, DNA Methylation, Cadherins, Death-Associated Protein Kinases, DNA Repair Enzymes, Early Diagnosis, Head and Neck Neoplasms, Calcium-Calmodulin-Dependent Protein Kinases, Carcinoma, Squamous Cell, Feasibility Studies, Female, Neoplasm Recurrence, Local, Apoptosis Regulatory Proteins, Follow-Up Studies
Abstract

International audience; CURRENT SITUATION: Early detection of the relapse in case of tumor located in the upper aerodigestive tract (UADT) is an important point for improving prognosis. Clinical control has not been efficient and, until today, no biological biomarker has been validated for surveillance of patients. In a preliminary study, we have shown the benefit of the methylation status of six tumor suppressor genes (TSG): TIMP3, ECAD, p16, MGMT, DAPK, and RASSF1A in saliva for early diagnosis of tumor relapse. The main objective of this second study is to confirm the initial results. MATERIAL AND METHODS: This is a bicenter, prospective, diagnostic, single-blind study. The study started in December 2007, running for one year. The main inclusion criterion is a patient with squamous-cell carcinoma of the oral cavity or the oropharynx, stages I to II, without previous treatment for this location. Eighty patients will be included. The data analysis will use a multivariate Cox model. EXPECTED RESULTS: If our preliminary results are confirmed, identification of methylations in saliva would be able to constitute the first usuable biomarker, for the follow-up of patients with UADT cancer.

Published
2008

99. HMGA2 is the partner of MDM2 in well-differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon

Author

Florence Pedeutour, Dominique Ranchère-Vince, Isabelle Peyrottes, S. Bonnafous, Agnès Leroux, Jean-Michel Coindre, Philippe Terrier, Philippe Gual, Nathalie Cardot-Leccia, Claire Mainguené, Frédérique Keslair, Jean-Marc Dumollard, Albert Tran, Paul Hofman, Laurence Bianchini, Antoine Italiano, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Laboratory of Solid Tumors Genetics, Nice University Hospital, Signalisation moléculaire et obésité, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pathology, Laboratoire d'anatomopathologie, Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Saint Etienne University Hospital, Laboratory of Clinical and Experimental Pathology, Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Alexis Vautrin (CAV), Monaco, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Département d'anatomopathologie, biopathologie, Centre Léon Bérard [Lyon], Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), and Hepatology Federation

Subjects
Male, MESH: Neoplasm Proteins, Cancer Research, MESH: Gene Amplification, 0302 clinical medicine, MESH: Aged, 80 and over, MESH: Reverse Transcriptase Polymerase Chain Reaction, Gene duplication, MESH: In Situ Hybridization, Fluorescence, In Situ Hybridization, Fluorescence, Aged, 80 and over, Transcription Factor CHOP, MESH: Aged, 0303 health sciences, MESH: Middle Aged, medicine.diagnostic_test, Reverse Transcriptase Polymerase Chain Reaction, Cell Differentiation, Proto-Oncogene Proteins c-mdm2, Liposarcoma, MESH: Transcription Factors, Middle Aged, Amplicon, Neoplasm Proteins, Oncology, 030220 oncology & carcinogenesis, Mdm2, MESH: Transcription Factor CHOP, Female, Lipoma, Adult, MESH: Cell Differentiation, MESH: Cyclin-Dependent Kinase 4, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, MESH: Proto-Oncogene Proteins c-mdm2, MESH: Liposarcoma, medicine, Humans, RNA, Messenger, Gene, neoplasms, Aged, 030304 developmental biology, MESH: RNA, Messenger, MESH: Lipoma, Myxoid liposarcoma, Chromosomes, Human, Pair 12, MESH: Humans, HMGA2 Protein, Gene Amplification, Cyclin-Dependent Kinase 4, MESH: Adult, medicine.disease, Molecular biology, MESH: Male, enzymes and coenzymes (carbohydrates), [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, Cancer research, MESH: Chromosomes, Human, Pair 12, MESH: HMGA2 Protein, MESH: Female, Transcription Factors, Fluorescence in situ hybridization
Abstract

Data concerning the fine structure of the 12q13-15 amplicon which contains MDM2 and CDK4 in well-differentiated and dedifferentiated liposarcomas (WDLPS/DDLPS) are scarce. We investigated a series of 38 WDLPS/DDLPS using fluorescence in situ hybridization analysis with 17 probes encompassing the 12q13-15 region. In addition, using quantitative RT-PCR we studied the expression of MDM2, CDK4, DDIT3 (CHOP/GADD153), DYRK2, HMGA2, TSPAN31 and YEATS4 (GAS41) in 11 cases. We showed that CDK4 (12q14.1) belonged to a distinct amplicon than MDM2 (12q15). There was no continuity in the amplified sequences between MDM2 and CDK4. Moreover, while MDM2 was amplified and overexpressed in all cases, CDK4 was not amplified or overexpressed in 13% of cases. The centromeric border of the CDK4 amplicon was located immediately downstream the 5' end of DDIT3, a gene known for being involved in myxoid liposarcoma translocations. DDIT3 was amplified in 3 cases and overexpressed in 9 cases. The overexpression of DDIT3 was correlated to the CDK4 amplification and not to its own amplification status. This suggested that the CDK4 amplicon, as well as the overexpression of DDIT3, might be generated by the disruption of a fragile region in 5' DDIT3. HMGA2 was always amplified and rearranged indicating that it plays a central role in WDLPS/DDLPS. HMGA2 rearrangement frequently resulted in a loss of the 3' end region that is a binding site for let-7. We also found a frequent amplification and overexpression of YEATS4, an oncogene that inactivates P53, suggesting that YEATS4 might play an important role together with MDM2 in WDLPS/DDLPS oncogenesis.

Published
2008

100. HIF-1alpha and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome

Author

Jacques Pouysségur, Edurne Berra, Alain Ramaioli, Emmanuel Benizri, Cynthia Trastour, Emmanuel Chamorey, F. Ettore, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Dept. of Pathology, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), and Dept. of Biostatistics

Subjects
Male, Cancer Research, Pathology, MESH: Carcinoma, Medullary, medicine.medical_treatment, MESH: Antigens, Neoplasm, Immunoenzyme Techniques, Mice, 0302 clinical medicine, MESH: Aged, 80 and over, MESH: Carcinoma, Lobular, MESH: Animals, Carbonic Anhydrases, MESH: Treatment Outcome, Aged, 80 and over, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Carcinoma, Ductal, Breast, Middle Aged, Prognosis, 3. Good health, Survival Rate, Treatment Outcome, Oncology, Chemotherapy, Adjuvant, MESH: Chemotherapy, Adjuvant, Carcinoma, Medullary, 030220 oncology & carcinogenesis, Female, Adult, medicine.medical_specialty, MESH: Carbonic Anhydrases, MESH: Survival Rate, Mice, Nude, CA 15-3, Antineoplastic Agents, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Adenocarcinoma, MESH: Hypoxia-Inducible Factor 1, alpha Subunit, MESH: Prognosis, 03 medical and health sciences, Breast cancer, Antigens, Neoplasm, Biomarkers, Tumor, medicine, Adjuvant therapy, Carcinoma, MESH: Mice, Nude, Animals, Humans, Neoplasm Invasiveness, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Carbonic Anhydrase IX, MESH: Immunoenzyme Techniques, Survival rate, MESH: Mice, Aged, 030304 developmental biology, MESH: Humans, business.industry, Carcinoma in situ, MESH: Adenocarcinoma, Cancer, MESH: Adult, MESH: Neoplasm Invasiveness, Hypoxia-Inducible Factor 1, alpha Subunit, medicine.disease, MESH: Male, Radiation therapy, MESH: Carcinoma, Ductal, Breast, Carcinoma, Lobular, MESH: Tumor Markers, Biological, Cancer research, MESH: Antineoplastic Agents, business, MESH: Female, MESH: Breast Neoplasms
Abstract

Hypoxia stabilizes HIF-1alpha (Hypoxia Inducible Factor-1alpha), which then triggers the expression of several genes involved in many aspects of cancer progression, including metabolic adaptation, cell survival and angiogenesis. The aim of our study was to evaluate the impact of HIF-1alpha and CA IX (carbonic anhydrase IX) (one of its target genes) expression on prognosis and treatment outcome of patients with breast cancer. Because of the extreme O2-dependent instability of the protein, we first validated HIF-1alpha staining using xenograft tumours that were subjected to experimental conditions mimicking surgical clamping or sitting at room temperature under normoxic conditions after surgical excision but before fixation. Afterwards, the immunohistochemical staining of HIF-1alpha and CA IX was evaluated in 132 invasive breast carcinomas with a 10-year follow-up, and correlated to classical clinicopathological parameters and response to adjuvant therapy. No significant correlation was found between tumour size or nodal status and the expression of HIF-1alpha or CA IX. Statistically significant association was found between HIF-1alpha or CA IX staining and the grade, hormonal receptors loss and the presence of carcinoma in situ. Overexpression of HIF-1alpha and CA IX correlates with a poor prognosis in breast cancer. We show that HIF-1alpha is an independent prognostic factor for distant metastasis-free survival and disease-free survival in multivariate analysis. Furthermore, overexpression of HIF-1alpha or CA IX correlates with a poor outcome after conventional adjuvant therapy. CA IX is, however, a weaker prognostic and predictive factor than HIF-1alpha, and its association with HIF-1alpha does not modify the survival curve neither response to therapy, compared to HIF-1alpha alone.

Published
2007

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