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1. Expression Map of the Human Exome in CD34+ Cells and Blood Cells: Increased Alternative Splicing in Cell Motility and Immune Response Genes

Author

S Tondeur, Said Assou, Céline Pangault, Thierry Fest, Jean-François Schved, Tanguy Le Carrour, Samir Hamamah, Bernard Klein, Yoann Lannay, Aurélie Cubizolle, John De Vos, Rima Benmahdi, Véronique Pantesco, Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service d'hématologie clinique, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Microenvironnement et cancer (MiCa), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Unité d'AMP/DPI, Département de Médecine et biologie de la reproduction, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Laboratoire d'immunologie, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), This work was supported by Roche, the Groupe Ouest Est des Leuce´mies et Autres Maladies du Sang (GOELAMS) group and the Socie´te´ Franc¸aise d'He´matologie (SFH)., Frei, Monique, Université de Rennes (UR)-Hôpital Pontchaillou, 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 ), and This work was supported by Roche, the Groupe Ouest Est des Leucémies et Autres Maladies du Sang (GOELAMS) group and the Société Française d'Hématologie (SFH).

Subjects
Male, Cellular differentiation, CD34, Antigens, CD34, [SDV.GEN] Life Sciences [q-bio]/Genetics, Kidney, Exon, 0302 clinical medicine, Cell Movement, Breast, Oligonucleotide Array Sequence Analysis, Principal Component Analysis, 0303 health sciences, Multidisciplinary, Reverse Transcriptase Polymerase Chain Reaction, Prostate, Genetics and Genomics/Gene Expression, Hematology, Exons, Cell biology, Haematopoiesis, medicine.anatomical_structure, Liver, 030220 oncology & carcinogenesis, Medicine, Female, Algorithms, Research Article, Science, Biology, CD19, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, Computational Biology/Alternative Splicing, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Progenitor cell, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Blood Cells, Gene Expression Profiling, Alternative splicing, Immunity, Hematopoietic Stem Cells, Molecular biology, Alternative Splicing, biology.protein, Bone marrow
Abstract

International audience; BACKGROUND: Hematopoietic cells are endowed with very specific biological functions, including cell motility and immune response. These specific functions are dramatically altered during hematopoietic cell differentiation, whereby undifferentiated hematopoietic stem and progenitor cells (HSPC) residing in bone marrow differentiate into platelets, red blood cells and immune cells that exit into the blood stream and eventually move into lymphoid organs or inflamed tissues. The contribution of alternative splicing (AS) to these functions has long been minimized due to incomplete knowledge on AS events in hematopoietic cells. PRINCIPAL FINDINGS: Using Human Exon ST 1.0 microarrays, the entire exome expression profile of immature CD34+ HSPC and mature whole blood cells was mapped, compared to a collection of solid tissues and made freely available as an online exome expression atlas (Amazonia Exon! : http://amazonia.transcriptome.eu/exon.php). At a whole transcript level, HSPC strongly expressed EREG and the pluripotency marker DPPA4. Using a differential splicing index scheme (dsi), a list of 849 transcripts differentially expressed between hematopoietic cells and solid tissues was computed, that included NEDD9 and CD74. Some of these genes also underwent alternative splicing events during hematopoietic differentiation, such as INPP4B, PTPLA or COMMD6, with varied contribution of CD3+ T cells, CD19+ B cells, CD14+ or CD15+ myelomonocytic populations. Strikingly, these genes were significantly enriched for genes involved in cell motility, cell adhesion, response to wounding and immune processes. CONCLUSION: The relevance and the precision provided by this exon expression map highlights the contribution of alternative splicing to key feature of blood cells differentiation and function.

Published
2010

2. Influence of BRAF and PIK3CA mutations on the efficacy of FOLFIRI plus bevacizumab or cetuximab as first-line therapy in patients with RAS wild-type metastatic colorectal carcinoma and <3 baseline circulating tumour cells: the randomised phase II VISNÚ-2 study

Author

J. Sastre, P. García-Alfonso, J.M. Viéitez, M.T. Cano, F. Rivera, J.J. Reina-Zoilo, A. Salud-Salvia, G. Quintero, L. Robles-Díaz, M.J. Safont, A. La Casta, S. Gil, E. Polo, E. Asensio-Martínez, B. García-Paredes, R.L. López, M. Guillot, M. Valladares-Ayerbes, E. Aranda, E. Díaz-Rubio, P. Jiménez, E. Aranda Aguilar, A. Gómez, S. Gil Calle, A. Salud, M. Valladares, B. Graña, J.J. Reina, E. González Flores, M. Salgado, E. Grande, C. Guillén, R. Garcia Carbonero, M.J. Flor, S. Arévalo, R. López López, H. Manzano, X. Hernández Yagüe, A. Arrivi, E. Falcó, J. Gallego, P. Escudero, I. Cabezas, A. Juárez, E. Gálvez, C. Grávalos, L. Robles, R. Dueñas, J.M. Campos, A. Albert, P. Salinas, C. Montagut, M. Provencio, A. Ruiz Casado, J. Muñoz, M. Gil Raga, M.R. Chilet, F.J. González González, B. Massutí, A. López, J. Aparicio, M. Marín, J. Alfaro, M. Zanui, D. Gutiérrez Abad, A.M. García Tapiador, C. García-Girón, J. Molina Saera, E. Torres Sánchez, I. López, C. Bosch, J. Valero, P. Martínez de Prado, Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD), [Sastre,J, García-Paredes,B, Díaz-Rubio,E] Medical Oncology, Hospital Clínico San Carlos, Instituto de Investigación Hospital Clínico San Carlos (IdISSC). [García-Alfonso,P] Medical Oncology, Hospital Universitario Gregorio Marañón, Madrid. [Viéitez,JM] Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, [Cano,MT, Aranda,E] Medical Oncology, IMIBIC, Reina Sofía Hospital, University of Córdoba, CIBERONC, Instituto de Salud Carlos III, Cordoba. [Rivera,F] Medical Oncology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander. [Reina-Zoilo,JJ] Medical Oncology, Complejo Hospitalario Virgen de la Macarena, Seville. [Salud-Salvia,A] Hospital Universitario Arnau de Vilanova de Lleida, Lleida. [Quintero,G] Medical Oncology, Hospital Lucus Augusti, Lugo. [Robles-Díaz,L] Medical Oncology, Hospital 12 de Octubre, Madrid. [Safont,MJ] Medical Oncology, Hospital General Universitario de Valencia, Valencia. [La Casta,A] Medical Oncology, Hospital de Donostia, Guipúzcoa. [Gil,S] Medical Oncology, Hospital Universitario Regional y Virgen de la Victoria, Malaga. [Polo,E] Medical Oncology, Hospital Miguel Servet, Zaragoza. [Asensio-Martínez,E] Medical Oncology, Hospital General Universitario de Elche, Alicante. [López,RL] Medical Oncology, University Clinical Hospital and Health Research Institute (IDIS), CIBERONC, Santiago de Compostela University School of Medicine, Santiago de Compostela. [Guillot,M] Medical Oncology, Hospital Son Espases, Palma de Mallorca. [Valladares-Ayerbes,M] Medical Oncology, Complejo Hospitalario Universitario A Coruña, Instituto de Investigación Biomédica (INIBIC), A Coruña, Spain., This work was supported by Roche Farma S.A (no grant number). Medical writing support was funded by Roche Farma S.A and provided by H. Lamb and L. Miller of Miller Medical Communications Ltd., and UAM. Departamento de Medicina

Subjects
Oncology, Cancer Research, Colorectal cancer, Terapia dirigida, Cetuximab, Phases of clinical research, Chemicals and Drugs::Heterocyclic Compounds::Alkaloids::Camptothecin [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Confidence Intervals [Medical Subject Headings], Targeted therapy, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Neoplasias colorrectales, Antineoplastic Combined Chemotherapy Protocols, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Pyrimidines::Pyrimidinones::Uracil::Fluorouracil [Medical Subject Headings], Original Research, Hazard ratio, Neoplastic Cells, Circulating, targeted therapy, Bevacizumab, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Phosphatidylinositol 3-Kinases::Phosphatidylinositol 3-Kinase::Class I Phosphatidylinositol 3-Kinases [Medical Subject Headings], FOLFIRI, Diseases::Hemic and Lymphatic Diseases::Hematologic Diseases::Leukocyte Disorders::Leukopenia::Agranulocytosis::Neutropenia [Medical Subject Headings], Colorectal Neoplasms, Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Asthenia [Medical Subject Headings], medicine.drug, Diseases::Neoplasms::Neoplastic Processes::Neoplasm Metastasis::Neoplastic Cells, Circulating [Medical Subject Headings], Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Medicina, Class I Phosphatidylinositol 3-Kinases, colorectal cancer, Neutropenia, Neoplastic cells circulating, BRAF, Internal medicine, medicine, Humans, neoplasms, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Drug Therapy::Antineoplastic Protocols::Antineoplastic Combined Chemotherapy Protocols [Medical Subject Headings], business.industry, Chemicals and Drugs::Enzymes and Coenzymes::Coenzymes::Tetrahydrofolates::Formyltetrahydrofolates::Leucovorin [Medical Subject Headings], Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [Medical Subject Headings], PIK3CA, medicine.disease, digestive system diseases, Irinotecan, Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Signs and Symptoms, Digestive::Diarrhea [Medical Subject Headings], Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinases::MAP Kinase Kinase Kinases::raf Kinases::Proto-Oncogene Proteins B-raf [Medical Subject Headings], Camptothecin, business, Células neoplásicas circulantes, RAS
Abstract

Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiere, y los autores pertenecientes a la UAM, Background We explored the influence of BRAF and PIK3CA mutational status on the efficacy of bevacizumab or cetuximab plus 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) as first-line therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC). Patients and methods VISNÚ-2 was a multicentre, randomised, phase II study. Patients with RAS wild-type mCRC and 1), and allocated to bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m2 then 250 mg/m2 weekly) plus FOLFIRI [irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 (bolus) then 2400 mg/m2 (46-h continuous infusion) every 2 weeks]. The primary endpoint was progression-free survival (PFS). All analyses were exploratory. Results Two hundred and forty patients with BRAF/PIK3CA wild-type (n = 196) or BRAF- and/or PIK3CA-mutated tumours (n = 44) were enrolled. Median PFS was 12.7 and 8.8 months in patients with BRAF/PIK3CA wild-type and BRAF/PIK3CA-mutated tumours, respectively [hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.80-1.85; P = 0.3602]. In the BRAF- and/or PIK3CA-mutated cohort, median PFS was 2.8, 8.8 and 15.0 months in patients with BRAF/PI3KCA-mutated (n = 8), BRAF-mutated/PI3KCA wild-type (n = 16) and BRAF wild-type/PI3KCA-mutated (n = 20) tumours, respectively (P = 0.0002). PFS was similar with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in BRAF/PIK3CA wild-type (HR = 0.99; 95% CI 0.67-1.45; P = 0.9486) and BRAF/PIK3CA-mutated tumours (HR = 1.11; 95% CI 0.53-2.35; P = 0.7820). The most common grade 3/4 treatment-related adverse events were neutropenia, diarrhoea and asthenia in both treatment groups. Conclusions BRAF/PIK3CA status influences outcomes in patients with RAS wild-type mCRC but does not appear to assist with the selection of first-line targeted therapy, This work was supported by Roche Farma S.A (no grant number). Medical writing support was funded by Roche Farma S.A and provided by H. Lamb and L. Miller of Miller Medical Communications Ltd.

Published
2021

3. Extracellular vesicle-miRNAs as liquid biopsy biomarkers for disease identification and prognosis in metastatic colorectal cancer patients

Author

Jose Luis Garcia Puche, Alba Rodríguez Martínez, José Exposito Hernandez, Diego Perez, Alba Ortigosa Palomo, Ma Jose Serrano, Agustín Robles Remacho, Francisco Gabriel Ortega Sánchez, Mayte Delgado Ureña, José Antonio Lorente Acosta, [de Miguel Pérez,D, Rodriguez Martínez,A, Ortigosa Palomo,A, Garcia Puche,JL, Robles Remacho,A, Lorente Acosta,JA, Serrano,MJ] GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Liquid biopsy and metastasis research group, PTS Granada, Granada, Spain. [de Miguel Pérez,D, Lorente Acosta,JA] Laboratory of Genetic Identification, Legal Medicine and Toxicology Department, Faculty of Medicine, University of Granada, Granada, Spain. [Delgado Ureña,M, Exposito Hernandez,J, Serrano,MJ] Integral Oncology Division, University Hospital Virgen de las Nieves, IBS Granada, Instituto de Investigación Biosanitaria de Granada, Granada, Spain. [Ortega Sánchez,FG] Balearic Islands Health Research Institute (IdISBa), Palma de Mallorca, Spain. [Ortega Sánchez,FG] Laboratory of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands., and Tis work was supported by Roche Spain, the PhD grant from the University of Granada (DdMP) (2014) and the PhD grant from the Spanish Government (ARM) (FPU) 2014, REF FPU14/05461.

Subjects
0301 basic medicine, Oncology, Male, Colorectal cancer, humanos, lcsh:Medicine, Tumour biomarkers, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Carcinoembryonic antigen, Neoplasias colorrectales, supervivencia sin enfermedad, Neoplasm Metastasis, lcsh:Science, metástasis neoplásica, mediana edad, MicroARNs, Multidisciplinary, biology, Extracellular vesicle, Middle Aged, Bevacizumab, 030220 oncology & carcinogenesis, Female, Colorectal Neoplasms, medicine.drug, medicine.medical_specialty, neoplasias colorrectales, Check Tags::Male [Medical Subject Headings], Context (language use), Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Glycoproteins::Membrane Glycoproteins::Cell Adhesion Molecules::Carcinoembryonic Antigen [Medical Subject Headings], Article, Disease-Free Survival, 03 medical and health sciences, Extracellular Vesicles, Internal medicine, Diseases::Neoplasms::Neoplastic Processes::Neoplasm Metastasis [Medical Subject Headings], Persons::Persons::Volunteers::Healthy Volunteers [Medical Subject Headings], Chemicals and Drugs::Biological Factors::Biological Markers [Medical Subject Headings], medicine, Biomarkers, Tumor, Chemotherapy, Humans, Progression-free survival, Liquid biopsy, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis::Disease-Free Survival [Medical Subject Headings], business.industry, lcsh:R, Cancer, Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [Medical Subject Headings], Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Antisense::MicroRNAs [Medical Subject Headings], microARN, medicine.disease, Vesículas extracelulares, Chemicals and Drugs::Complex Mixtures::Biological Products [Medical Subject Headings], MicroRNAs, 030104 developmental biology, Check Tags::Female [Medical Subject Headings], biology.protein, lcsh:Q, Quimioterapia, business
Abstract

We would like to extend our gratitude to the all the patients and the healthy volunteers who participated in the study, as well as the University of Granada, Biomedicine PhD program. This work was supported by Roche Spain, the PhD grant from the University of Granada (DdMP) (2014) and the PhD grant from the Spanish Government (ARM) (FPU) 2014, REF FPU14/05461., Disseminated disease is present in ≈50% of colorectal cancer patients upon diagnosis, being responsible for most of cancer deaths. Addition of biological drugs, as Bevacizumab, to chemotherapy, has increased progression free survival and overall survival of metastatic colorectal cancer (mCRC) patients. However, these benefits have been only reported in a small proportion of patients. To date, there are not biomarkers that could explain the heterogeneity of this disease and would help in treatment selection. Recent findings demonstrated that microRNAs (miRNAs) play an important role in cancer and they can be encapsulated with high stability into extracellular vesicles (EVs) that are released in biological fluids. EVs can act as cell-to-cell communicators, transferring genetic information, such as miRNAs. In this context, we aimed to investigate serum EV associated miRNAs (EV-miRNAs) as novel non-invasive biomarkers for the diagnosis and prognosis of Bevacizumab-treated mCRC patients. We observed that baseline miRNA-21 and 92a outperformed carcinoembryonic antigen levels in the diagnosis of our 44 mCRC patients, compared to 17 healthy volunteers. In addition, patients who died presented higher levels of miRNA-92a and 222 at 24 weeks. However, in the multivariate Cox analysis, higher levels of miRNA-222 at 24 weeks were associated with lower overall survival. Altogether, these data indicate that EV-miRNAs have a strong potential as liquid biopsy biomarkers for the identification and prognosis of mCRC., Roche Spain, University of Granada (DdMP), Spanish Government REF FPU14/05461

Published
2020

4. Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on BRAFV600E Melanoma Lines with Vemurafenib

Author

Eric Pasmant, Brigitte Dréno, Houssem Benlalam, Marina Colombo, Antoine Toubert, Emmanuelle Fourmentraux-Neves, Frédéric Vély, Florence Faure, Fanny Bouquet, Ariel Savina, Marie-Françoise Avril, Sylvie Rusakiewicz, Laurence Zitvogel, Meriem Messaoudene, Anne Caignard, Alexandra Frazao, Eric Vivier, Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 d'Immunologie [AP-HM], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Immunité et cancer (U932), 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 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), Institut ROCHE [Boulogne-Billancourt], Roche S.A.S, Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Dermatologie [CHU Cochin], This work was supported by Roche Pharmaceuticals, Fondation ARC, Institut National du Cancer (2011-PLBIO-06, for M. Colombo and E. Fourmentraux-Neves, and PAIR Melanoma 2013-066), Ligue Nationale Contre le Cancer (for M. Messaoudene), and Cancerop^ole Ile de France (for A. Frazao)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Alloimmunité-Autoimmunité-Transplantation ( A2T ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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 ), Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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, CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], and Bernardo, Elizabeth

Subjects
0301 basic medicine, MAPK/ERK pathway, Cancer Research, NK Cell Lectin-Like Receptor Subfamily K, Melanoma, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Natural killer T cell, NKG2D, medicine.disease, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 3. Good health, 03 medical and health sciences, 030104 developmental biology, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cancer research, medicine, Receptor, Vemurafenib, neoplasms, V600E, medicine.drug
Abstract

Over 60% of human melanoma tumors bear a mutation in the BRAF gene. The most frequent mutation is a substitution at codon 600 (V600E), leading to a constitutively active BRAF and overactivation of the MAPK pathway. Patients harboring mutated BRAF respond to kinase inhibitors such as vemurafenib. However, these responses are transient, and relapses are frequent. Melanoma cells are efficiently lysed by activated natural killer (NK) cells. Melanoma cells express several stress-induced ligands that are recognized by activating NK-cell receptors. We have investigated the effect of vemurafenib on the immunogenicity of seven BRAF-mutated melanoma cells to NK cells and on their growth and sensitivity to NK-cell–mediated lysis. We showed that vemurafenib treatment modulated expression of ligands for two activating NK receptors, increasing expression of B7-H6, a ligand for NKp30, and decreasing expression of MICA and ULBP2, ligands for NKG2D. Vemurafenib also increased expression of HLA class I and HLA-E molecules, likely leading to higher engagement of inhibitory receptors (KIRs and NKG2A, respectively), and decreased lysis of vemurafenib-treated melanoma cell lines by cytokine-activated NK cells. Finally, we showed that whereas batimastat (a broad-spectrum matrix metalloprotease inhibitor) increased cell surface ULBP2 by reducing its shedding, vemurafenib lowered soluble ULBP2, indicating that BRAF signal inhibition diminished expression of both cell-surface and soluble forms of NKG2D ligands. Vemurafenib, inhibiting BRAF signaling, shifted the balance of activatory and inhibitory NK ligands on melanoma cells and displayed immunoregulatory effects on NK-cell functional activities. Cancer Immunol Res; 5(7); 582–93. ©2017 AACR.

Published
2017

5. R-CHOP 14 with or without radiotherapy in non-bulky limited-stage diffuse large B-cell lymphoma (DLBCL)

Author

Gandhi Damaj, Katell Le Du, J. Fleury, Jean Pierre Marolleau, Vincent Delwail, Krimo Bouabdallah, Anne Devillers, Guillaume Cartron, Pierre Soubeyran, Valérie Costes, Olivier Tournilhac, Pascal Godmer, Emmanuel Gyan, Marie C. Béné, Steven Le Gouill, Marie-Pierre Moles, Jean Philippe Vuillez, Mohamed Benchalal, Philippe Colombat, Jérôme Cornillon, Thierry Fest, Hervé Maisonneuve, Eric Deconinck, Kamel Laribi, Vanessa Szablewski, Roch Houot, Bernard Branger, Thierry Lamy, Remy Gressin, Anne Banos, CHU Pontchaillou [Rennes], 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 ), Centre de référence des mastocytoses (CEREMAST), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plateforme de génétique moléculaire des cancers d'Aquitaine, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Service d'hématologie, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service d'hématologie et oncologie médicale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux], CHU Grenoble-Hôpital Michallon, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Hôpital de Bayonne, Centre Hospitalier de la Côte Basque (CHCB), Centre Eugène Marquis (CRLCC), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de médecine interne [CHU Bretagnes Atlantique], CHU Bretagnes Atlantique, Centre hospitalier La Roche-Sur-Yon, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'hématologie clinique, Université de Rennes (UR)-Hôpital Pontchaillou, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Réseau Sécurité Naissance - Naître Ensemble, Nantes, Département de médecine nucléaire [Rennes], CRLCC Eugène Marquis (CRLCC), Service d'hématologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogénèse et contrôle des infections chroniques (PCCI), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Anatomie et de Cytologie Pathologiques [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), 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), This work was supported by Roche., Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), CHU Saint-Etienne, CH de la Côte Basque, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), BOUAKAZ, Amel, Centre de référence des mastocytoses, Institut Bergonié - CRLCC Bordeaux, Regulation of Bcl2 and p53 networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA - Département NOHMAD - Equipe 10), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias - Clermont Auvergne (CHELTER), Université Clermont Auvergne (UCA), and Centre Hospitalier Universitaire de Montpellier (CHU Montpellier )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, genetic structures, Clinical Trials and Observations, [SDV]Life Sciences [q-bio], Kaplan-Meier Estimate, Biochemistry, Gastroenterology, law.invention, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, International Prognostic Index, Randomized controlled trial, law, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Prospective Studies, Child, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Hazard ratio, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Middle Aged, Chemotherapy regimen, Progression-Free Survival, 3. Good health, [SDV] Life Sciences [q-bio], Treatment Outcome, Vincristine, 030220 oncology & carcinogenesis, Female, Lymphoma, Large B-Cell, Diffuse, Rituximab, medicine.drug, Adult, medicine.medical_specialty, Randomization, Immunology, 03 medical and health sciences, Internal medicine, medicine, Humans, Progression-free survival, Cyclophosphamide, business.industry, Patient Selection, Cell Biology, medicine.disease, Surgery, Doxorubicin, Prednisone, business, Diffuse large B-cell lymphoma, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract

International audience; The benefit of radiotherapy (RT) after chemotherapy in limited-stage diffuse large B-cell lymphoma (DLBCL) remains controversial. We conducted a randomized trial in patients with nonbulky limited-stage DLBCL to evaluate the benefit of RT after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients were stratified according to the modified International Prognostic Index, including lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, age, and disease stage. The patients received 4 or 6 consecutive cycles of R-CHOP delivered once every 2 weeks, followed or not by RT at 40 Gy delivered 4 weeks after the last R-CHOP cycle. All patients were evaluated by fluorodeoxyglucose-positron emission tomography scans performed at baseline, after 4 cycles of R-CHOP, and at the end of treatment. The primary objective of the trial was event-free survival (EFS) from randomization. The trial randomly assigned 165 patients in the R-CHOP arm and 169 in the R-CHOP plus RT arm. In an intent-to-treat analysis with a median follow-up of 64 months, 5-year EFS was not statistically significantly different between the 2 arms, with 89% ± 2.9% in the R-CHOP arm vs 92% ± 2.4% in the R-CHOP plus RT arm (hazard ratio, 0.61; 95% confidence interval [CI], 0.3-1.2; = .18). Overall survival was also not different at 92% (95% CI, 89.5%-94.5%) for patients assigned to R-CHOP alone and 96% (95% CI, 94.3%-97.7%) for those assigned to R-CHOP plus RT ( = not significant). R-CHOP alone is not inferior to R-CHOP followed by RT in patients with nonbulky limited-stage DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT00841945.

Published
2018

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

Author

Martin Soubrier, Houria Hendel Chavez, Elodie Rivière, Barbara Tolusso, Bineta Ly, Maxime Dougados, Alice Courties, Paul-Olivier Rouzaire, Edward M Vital, Gianfranco Ferraciolli, Yassine Taoufik, Xavier Mariette, Jérémie Sellam, Paul Emery, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de rhumatologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Clermont-Ferrand, Rheumatology Department, Catholic University of the Sacred Heart, University of Leeds, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Rhumatologie [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, This work was supported by Roche France, who sponsored the study but were not involved in the interpretation of the data or in the preparation of the manuscript., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Service de rhumatologie, inflammation-immunopathologie- biothérapie [CHU Saint-Antoine] (DHU i2B ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de rhumatologie, inflammation-immunopathologie- biothérapie [CHU Saint-Antoine] ( DHU i2B ), CHU Saint-Antoine [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP), Immunologie des Maladies Virales et Autoimmunes ( IMVA - U1184 ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Saint-Antoine [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
0301 basic medicine, medicine.medical_specialty, Population, [ SDV.IMM.IMM ] Life Sciences [q-bio]/Immunology/Immunotherapy, Gastroenterology, [ SDV.MHEP.RSOA ] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Rheumatoid factor, education, 030203 arthritis & rheumatology, education.field_of_study, business.industry, Odds ratio, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Rheumatology, 3. Good health, 030104 developmental biology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Rheumatoid arthritis, Immunology, Cohort, Rituximab, business, Rheumatism, medicine.drug
Abstract

International audience; Background: Recent works have suggested a possible link between interleukin (IL)-33 and B-cell biology. We aimed to study the possible association between serum IL-33 detection and response to rituximab (RTX) in rheumatoid arthritis (RA) patients in different cohorts with an accurate enzyme-linked immunosorbent assay (ELISA).Methods: Serum IL-33, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), and high serum immunoglobulin (Ig)G levels were assessed in 111 RA patients receiving a first course of 2 g RTX (cohort 1) in an observational study and in 74 RA patients treated with the same schedule in routine care (cohort 2). Univariate and multivariate analyses identified factors associated with a European League Against Rheumatism (EULAR) response at 24 weeks.Results: At week 24, 84/111 (76%) and 54/74 (73%) patients reached EULAR response in cohorts 1 and 2, respectively. Serum IL-33 was detectable in only 33.5% of the patients. In the combined cohorts, the presence of RF or anti-CCP (odds ratio (OR) 3.27, 95% confidence interval (CI) 1.13–9.46; p = 0.03), high serum IgG (OR 2.32, 95% CI 1.01–5.33; p = 0.048), and detectable serum IL-33 (OR 2.40, 95% CI 1.01–5.72; p = 0.047) were all associated with RTX response in multivariate analysis. The combination of these three factors increased the likelihood of response to RTX. When serum IL-33 detection was added to seropositivity and serum IgG level, 100% of the patients with the three risk factors (corresponding to 9% of the population) responded to RTX (OR versus patients with none of the three risk factors 29.61, 95% CI 1.30–674.79; p = 0.034).Conclusion: Detectable serum IL-33 may predict clinical response to RTX independently of, and synergistically with, auto-antibodies and serum IgG level.

Published
2016

7. The role of organic anion-transporting polypeptides and their common genetic variants in mycophenolic acid pharmacokinetics

Author

Nicolas Picard, Kathleen M. Giacomini, Y. Le Meur, Sook Wah Yee, Pierre Marquet, Jean-Baptiste Woillard, Yvon Lebranchu, Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges, Department of Bioengineering and Therapeutic Sciences, University of California [San Francisco] (UCSF), University of California-University of California, Service de néphrologie et immunologie clinique [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT), Service de néphrologie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), This work was supported by Roche Pharma and the Region Limousin., Marquet, Pierre, Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Service de néphrologie et immunologie clinique, and Hôpital Bretonneau-Université de Tours-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
Organic anion transporter 1, medicine.medical_treatment, Organic Anion Transporters, transporters, Pharmacology, Mycophenolate, 030226 pharmacology & pharmacy, immunosuppressive agents, Article, Mycophenolic acid, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, MESH: Polymorphism, Genetic, medicine, Humans, Pharmacology (medical), MESH: Genetic Variation, pharmacogenetics, MESH: Mycophenolic Acid, MESH: Organic Anion Transporters, Kidney, Polymorphism, Genetic, MESH: Humans, biology, MESH: Peptides, HEK 293 cells, Genetic Variation, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, mycophenolic acid, 3. Good health, MESH: Cell Line, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, medicine.anatomical_structure, Immunosuppressive drug, 030220 oncology & carcinogenesis, Sirolimus, biology.protein, Peptides, medicine.drug, transplantation
Abstract

International audience; The goal of this study was to determine the roles of the organic anion-transporting polypeptides (OATPs) OATP1A2, OATP1B1, and OATP1B3 and their genetic variants in the pharmacokinetics of the immunosuppressive drug mycophenolate mofetil (MMF). Using OATP-transfected human embryonic kidney (HEK) cells, we measured the uptake of mycophenolic acid (MPA) and its glucuronide (MPAG). MPAG, but not MPA, significantly accumulated in cells expressing OATP1B3 or OATP1B1 (P < 0.05). The pharmacokinetics of both MPA and MPAG were significantly influenced by the OATP1B3 polymorphism 334T>G/699G>A in 70 renal transplant patients receiving combination treatment of MMF with either tacrolimus or sirolimus, but not in 115 patients receiving MMF and cyclosporine. The decrease in dose-normalized (dn) MPA exposure and the concomitant increase in the MPAG/MPA metabolic ratio are consistent with reduced enterohepatic cycling in patients carrying the OATP1B3 334G-699A haplotype. Further studies demonstrated that this variant of OATP1B3 exhibited a reduced maximal velocity (V(max)) in transfected HEK cells, thereby providing functional evidence to support our clinical findings.

Published
2010

8. Role of Kras Status in Patients with Metastatic Colorectal Cancer Receiving First-Line Chemotherapy plus Bevacizumab: A TTD Group Cooperative Study

Author

Eduardo Díaz-Rubio, Auxiliadora Gómez-España, Bartomeu Massutí, Javier Sastre, Margarita Reboredo, José Luis Manzano, Fernando Rivera, M José Safont, Clara Montagut, Encarnación González, Manuel Benavides, Eugenio Marcuello, Andrés Cervantes, Purificación Martínez de Prado, Carlos Fernández-Martos, Antonio Arrivi, Inmaculada Bando, Enrique Aranda, Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD), The Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD), [Díaz-Rubio,E, Sastre,J, Bando,I] Department of Medical Oncology, Hospital Clínico San Carlos (HCSC), Red Temática de Investigación Cooperativa en Cáncer (RD06/0020/0021), Facultad de Medicina, Universidad Complutense, Instituto de Investigación Sanitaria del HCSC (IdISSC), Madrid, Spain. [Gómez-España,A, Aranda,E] Department of Medical Oncology, Hospital Reina Sofía, Córdoba, Spain. [Massutí,B] Department of Medical Oncology, Hospital General, Alicante, Spain. [Reboredo,M] Department of Medical Oncology, Complejo Hospitalario Universitario La Coruña, La Coruña, Spain. [Manzano, JL] Department of Medical Oncology, Instituto Catalán de Oncología, Hospital Germans Trias I Pujol, Badalona, Spain. [Rivera,F] Department of Medical Oncology, Hospital Marqués de Valdecilla, Santander, Spain. [Safont,MJ] Department of Medical Oncology, Hospital General de Valencia, Valencia, Spain. [Montagut,C] Department of Medical Oncology, Hospital del Mar, Barcelona, Spain. [González,E] Department of Medical Oncology, Hospital Virgen de las Nieves, Granada, Spain. [Benavides,M] Department of Medical Oncology, Hospital Universitario Carlos Haya, Málaga, Spain. [Marcuello,E] Department of Medical Oncology, Hospital Santa Creu i Sant Pau, Barcelona, Spain. [Cervantes,A] Department of Medical Oncology, Institute of Health Research INCLIVA. University of Valencia, Valencia, Spain. [Martínez de Prado, P] Department of Medical Oncology, Hospital de Basurto, Vizcaya, Spain. [Fernández-Martos, C] Department of Medical Oncology, Instituto Valenciano de Oncología, Valencia, Spain. [Arrivi,A] Department of Medical Oncology, Fundación Hospital Son Llatzer, Palma de Mallorca, Spain., and This work was supported by Roche

Subjects
Male, Oncology, Organoplatinum Compounds, endocrine system diseases, Epidemiology, Colorectal cancer, Named Groups::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Deoxycytidine, Metastasis, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Antineoplastic Combined Chemotherapy Protocols, Pathology, Medicine, Neoplasm Metastasis, genes, lcsh:Science, mediana edad, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Clinical Protocols::Antineoplastic Protocols::Antineoplastic Combined Chemotherapy Protocols [Medical Subject Headings], Aged, 80 and over, anciano, Chemicals and Drugs::Organic Chemicals::Organometallic Compounds::Organoplatinum Compounds [Medical Subject Headings], Cancer Risk Factors, Clinical Pharmacology, protocolos de quimioterapia antineoplásica combinada, Colon Adenocarcinoma, Pronóstico, Combination chemotherapy, adulto, Prognosis, Bevacizumab, Oxaliplatin, pronóstico, Oncology Agents, medicine.medical_specialty, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation [Medical Subject Headings], Fluorouracilo, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Pyrimidines::Pyrimidine Nucleosides::Cytidine::Deoxycytidine [Medical Subject Headings], Check Tags::Male [Medical Subject Headings], Molecular Genetics, Capecitabine, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Antibodies, Monoclonal::Antibodies, Monoclonal, Humanized [Medical Subject Headings], Gastrointestinal Tumors, Genetics, Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], Humans, Clinical Trials, Biology, neoplasms, Aged, lcsh:R, Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes, Neoplasm::Oncogenes::Proto-Oncogenes::Genes, ras [Medical Subject Headings], medicine.disease, digestive system diseases, Check Tags::Female [Medical Subject Headings], Pharmacogenetics, Mutation, lcsh:Q, fluorouracilo, Multivariate analysis, Desoxicitidina, humanos, Cancer Treatment, Named Groups::Persons::Age Groups::Adult::Aged::Aged, 80 and over [Medical Subject Headings], lcsh:Medicine, medicine.disease_cause, Neoplasias colorrectales, Surgical oncology, Basic Cancer Research, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Pyrimidines::Pyrimidinones::Uracil::Fluorouracil [Medical Subject Headings], Clinical Trials (Cancer Treatment), metástasis neoplásica, Metástasis neoplásica, Multidisciplinary, Middle Aged, Genetic Epidemiology, Protocolos de quimioterapia antineoplásica combinada, Female, Antiangiogenesis Therapy, Fluorouracil, KRAS, Colorectal Neoplasms, Research Article, medicine.drug, Adult, Drugs and Devices, Clinical Pathology, neoplasias colorrectales, Clinical Research Design, Genetic Causes of Cancer, Antibodies, Monoclonal, Humanized, Antibodies, Rectal Cancer, Antibody Therapy, Diagnostic Medicine, Internal medicine, Diseases::Neoplasms::Neoplastic Processes::Neoplasm Metastasis [Medical Subject Headings], Named Groups::Persons::Age Groups::Adult::Aged [Medical Subject Headings], mutación, Clinical Genetics, Mutación, business.industry, Pharmacoepidemiology, Cancers and Neoplasms, Human Genetics, Chemotherapy and Drug Treatment, desoxicitidina, Genes, ras, anticuerpos, Genetics of Disease, business, compuestos organoplatino
Abstract

Background: In the MACRO study, patients with metastatic colorectal cancer (mCRC) were randomised to first-line treatment with 6 cycles of capecitabine and oxaliplatin (XELOX) plus bevacizumab followed by either single-agent bevacizumab or XELOX plus bevacizumab until disease progression. An additional retrospective analysis was performed to define the prognostic value of tumour KRAS status on progression-free survival (PFS), overall survival (OS) and response rates. Methodology/Principal Findings: KRAS data (tumour KRAS status and type of mutation) were collected by questionnaire from participating centres that performed KRAS analyses. These data were then cross-referenced with efficacy data for relevant patients in the MACRO study database. KRAS status was analysed in 394 of the 480 patients (82.1%) in the MACRO study. Wild-type (WT) KRAS tumours were found in 219 patients (56%) and mutant (MT) KRAS in 175 patients (44%). Median PFS was 10.9 months for patients with WT KRAS and 9.4 months for patients with MT KRAS tumours (p = 0.0038; HR: 1.40; 95% CI: 1.12-1.77). The difference in OS was also significant: 26.7 months versus 18.0 months for WT versus MT KRAS, respectively (p = 0.0002; HR: 1.55; 95% CI: 1.23-1.96). Univariate and multivariate analyses showed that KRAS was an independent variable for both PFS and OS. Responses were observed in 126 patients (57.5%) with WT KRAS tumours and 76 patients (43.4%) with MT KRAS tumours (p = 0.0054; OR: 1.77; 95% CI: 1.18-2.64). Conclusions/Significance: This analysis of the MACRO study suggests a prognostic role for tumour KRAS status in patients with mCRC treated with XELOX plus bevacizumab. For both PFS and OS, KRAS status was an independent factor in univariate and multivariate analyses., This work was supported by Roche (www.roche.es) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Published
2012

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