Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial.
Identifieur interne : 002F62 ( Main/Exploration ); précédent : 002F61; suivant : 002F63Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial.
Auteurs : Georgina V. Long [Australie] ; Daniil Stroyakovskiy [Russie] ; Helen Gogas [Grèce] ; Evgeny Levchenko [Russie] ; Filippo De Braud [Italie] ; James Larkin [Royaume-Uni] ; Claus Garbe [Allemagne] ; Thomas Jouary [France] ; Axel Hauschild [Allemagne] ; Jean-Jacques Grob [France] ; Vanna Chiarion-Sileni [Italie] ; Celeste Lebbe [France] ; Mario Mandalà [Italie] ; Michael Millward [Australie] ; Ana Arance [Espagne] ; Igor Bondarenko [Ukraine] ; John B A G. Haanen [Pays-Bas] ; Johan Hansson [Suède] ; Jochen Utikal [Allemagne] ; Virginia Ferraresi [Italie] ; Nadezhda Kovalenko [Russie] ; Peter Mohr [Allemagne] ; Volodymr Probachai [Ukraine] ; Dirk Schadendorf [Allemagne] ; Paul Nathan [Royaume-Uni] ; Caroline Robert [France] ; Antoni Ribas [États-Unis] ; Douglas J. Demarini [États-Unis] ; Jhangir G. Irani [États-Unis] ; Suzanne Swann [États-Unis] ; Jeffrey J. Legos [États-Unis] ; Fan Jin [États-Unis] ; Bijoyesh Mookerjee [États-Unis] ; Keith Flaherty [États-Unis]Source :
- Lancet (London, England) [ 1474-547X ] ; 2015.
Descripteurs français
- KwdFr :
- Adulte, Adulte d'âge moyen, Association de médicaments, Femelle, Humains, Imidazoles (administration et posologie), Jeune adulte, Mâle, Mélanome (traitement médicamenteux), Méthode en double aveugle, Oximes (administration et posologie), Protéines proto-oncogènes B-raf (génétique), Pyridones (administration et posologie), Pyrimidinones (administration et posologie), Résultat thérapeutique, Sujet âgé, Sujet âgé de 80 ans ou plus, Survie sans rechute.
- MESH :
- administration et posologie : Imidazoles, Oximes, Pyridones, Pyrimidinones.
- génétique : Protéines proto-oncogènes B-raf.
- traitement médicamenteux : Mélanome.
- Adulte, Adulte d'âge moyen, Association de médicaments, Femelle, Humains, Jeune adulte, Mâle, Méthode en double aveugle, Résultat thérapeutique, Sujet âgé, Sujet âgé de 80 ans ou plus, Survie sans rechute.
English descriptors
- KwdEn :
- Adult, Aged, Aged, 80 and over, Disease-Free Survival, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Imidazoles (administration & dosage), Male, Melanoma (drug therapy), Middle Aged, Oximes (administration & dosage), Proto-Oncogene Proteins B-raf (genetics), Pyridones (administration & dosage), Pyrimidinones (administration & dosage), Treatment Outcome, Young Adult.
- MESH :
- chemical , administration & dosage : Imidazoles, Oximes, Pyridones, Pyrimidinones.
- drug therapy : Melanoma.
- chemical , genetics : Proto-Oncogene Proteins B-raf.
- Adult, Aged, Aged, 80 and over, Disease-Free Survival, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Treatment Outcome, Young Adult.
Abstract
Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article.
DOI: 10.1016/S0140-6736(15)60898-4
PubMed: 26037941
Affiliations:
- Allemagne, Australie, Espagne, France, Grèce, Italie, Pays-Bas, Royaume-Uni, Russie, Suède, Ukraine, États-Unis
- Angleterre, Aquitaine, Attique (région), Bade-Wurtemberg, Californie, Catalogne, District de Karlsruhe, District de Tübingen, District fédéral central, Grand Londres, Hollande-Septentrionale, Latium, Lombardie, New Jersey, Nouvelle-Aquitaine, Nouvelle-Galles du Sud, Provence-Alpes-Côte d'Azur, Schleswig-Holstein, Svealand, Île-de-France
- Amsterdam, Athènes, Barcelone, Bordeaux, Heidelberg, Kiel, Londres, Marseille, Milan, Moscou, Paris, Rome, Stockholm, Sydney, Tübingen
- Université de Sydney
Links toward previous steps (curation, corpus...)
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- to stream PubMed, to step Checkpoint: 002A37
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Le document en format XML
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xml:lang="fr">Italie</country><wicri:regionArea>Papa Giovanni XXIII Cancer Center Hospital, Bergamo</wicri:regionArea><wicri:noRegion>Bergamo</wicri:noRegion></affiliation></author><author><name sortKey="Millward, Michael" sort="Millward, Michael" uniqKey="Millward M" first="Michael" last="Millward">Michael Millward</name><affiliation wicri:level="1"><nlm:affiliation>Sir Charles Gairdner Hospital, Hospital Avenue, Perth, WA, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Sir Charles Gairdner Hospital, Hospital Avenue, Perth, WA</wicri:regionArea><wicri:noRegion>WA</wicri:noRegion></affiliation></author><author><name sortKey="Arance, Ana" sort="Arance, Ana" uniqKey="Arance A" first="Ana" last="Arance">Ana Arance</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Oncology, Hospital Clinic and Translational Genomics and Targeted Therapeutics in Solid Tumors, Barcelona, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Medical Oncology, Hospital Clinic and Translational Genomics and Targeted Therapeutics in Solid Tumors, Barcelona</wicri:regionArea><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author><author><name sortKey="Bondarenko, Igor" sort="Bondarenko, Igor" uniqKey="Bondarenko I" first="Igor" last="Bondarenko">Igor Bondarenko</name><affiliation wicri:level="1"><nlm:affiliation>Dnepropetrovsk State Medical Academy, Dnepropetrovsk, Ukraine.</nlm:affiliation><country xml:lang="fr">Ukraine</country><wicri:regionArea>Dnepropetrovsk State Medical Academy, Dnepropetrovsk</wicri:regionArea><wicri:noRegion>Dnepropetrovsk</wicri:noRegion></affiliation></author><author><name sortKey="Haanen, John B A G" sort="Haanen, John B A G" uniqKey="Haanen J" first="John B A G" last="Haanen">John B A G. 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German Cancer Research Center, Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>University Medical Center Mannheim, Heidelberg University, Mannheim, Germany; German Cancer Research Center, Heidelberg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Heidelberg</settlement></placeName></affiliation></author><author><name sortKey="Ferraresi, Virginia" sort="Ferraresi, Virginia" uniqKey="Ferraresi V" first="Virginia" last="Ferraresi">Virginia Ferraresi</name><affiliation wicri:level="3"><nlm:affiliation>Istituto Nazionale Tumori Regina Elena, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto Nazionale Tumori Regina Elena, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Kovalenko, Nadezhda" sort="Kovalenko, Nadezhda" uniqKey="Kovalenko N" first="Nadezhda" last="Kovalenko">Nadezhda Kovalenko</name><affiliation wicri:level="1"><nlm:affiliation>Volograd Regional Oncology Dispensary #3, Volzhsky, Russia.</nlm:affiliation><country xml:lang="fr">Russie</country><wicri:regionArea>Volograd Regional Oncology Dispensary #3, Volzhsky</wicri:regionArea><wicri:noRegion>Volzhsky</wicri:noRegion></affiliation></author><author><name sortKey="Mohr, Peter" sort="Mohr, Peter" uniqKey="Mohr P" first="Peter" last="Mohr">Peter Mohr</name><affiliation wicri:level="1"><nlm:affiliation>Elbe Klinikum Stade, Stade, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Elbe Klinikum Stade, Stade</wicri:regionArea><wicri:noRegion>Stade</wicri:noRegion><wicri:noRegion>Stade</wicri:noRegion><wicri:noRegion>Stade</wicri:noRegion></affiliation></author><author><name sortKey="Probachai, Volodymr" sort="Probachai, Volodymr" uniqKey="Probachai V" first="Volodymr" last="Probachai">Volodymr Probachai</name><affiliation wicri:level="1"><nlm:affiliation>Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council, Dnipropetrovsk, Ukraine.</nlm:affiliation><country xml:lang="fr">Ukraine</country><wicri:regionArea>Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council, Dnipropetrovsk</wicri:regionArea><wicri:noRegion>Dnipropetrovsk</wicri:noRegion></affiliation></author><author><name sortKey="Schadendorf, Dirk" sort="Schadendorf, Dirk" uniqKey="Schadendorf D" first="Dirk" last="Schadendorf">Dirk Schadendorf</name><affiliation wicri:level="1"><nlm:affiliation>University Hospital Essen, Essen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>University Hospital Essen, Essen</wicri:regionArea><wicri:noRegion>Essen</wicri:noRegion><wicri:noRegion>Essen</wicri:noRegion><wicri:noRegion>Essen</wicri:noRegion></affiliation></author><author><name sortKey="Nathan, Paul" sort="Nathan, Paul" uniqKey="Nathan P" first="Paul" last="Nathan">Paul Nathan</name><affiliation wicri:level="1"><nlm:affiliation>Mount Vernon Cancer Centre, Northwood, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Mount Vernon Cancer Centre, Northwood</wicri:regionArea><wicri:noRegion>Northwood</wicri:noRegion></affiliation></author><author><name sortKey="Robert, Caroline" sort="Robert, Caroline" uniqKey="Robert C" first="Caroline" last="Robert">Caroline Robert</name><affiliation wicri:level="1"><nlm:affiliation>Gustave Roussy, Villejuif-Paris-Sud, France; Paris Sud University, Le Kremlin Bicêtre, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Gustave Roussy, Villejuif-Paris-Sud, France; Paris Sud University, Le Kremlin Bicêtre</wicri:regionArea><wicri:noRegion>Le Kremlin Bicêtre</wicri:noRegion><wicri:noRegion>Le Kremlin Bicêtre</wicri:noRegion></affiliation></author><author><name sortKey="Ribas, Antoni" sort="Ribas, Antoni" uniqKey="Ribas A" first="Antoni" last="Ribas">Antoni Ribas</name><affiliation wicri:level="2"><nlm:affiliation>David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>David Geffen School of Medicine, UCLA, Los Angeles, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Demarini, Douglas J" sort="Demarini, Douglas J" uniqKey="Demarini D" first="Douglas J" last="Demarini">Douglas J. Demarini</name><affiliation wicri:level="2"><nlm:affiliation>Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Novartis Pharmaceuticals Corporation, East Hanover, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Irani, Jhangir G" sort="Irani, Jhangir G" uniqKey="Irani J" first="Jhangir G" last="Irani">Jhangir G. Irani</name><affiliation wicri:level="2"><nlm:affiliation>Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Novartis Pharmaceuticals Corporation, East Hanover, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Swann, Suzanne" sort="Swann, Suzanne" uniqKey="Swann S" first="Suzanne" last="Swann">Suzanne Swann</name><affiliation wicri:level="2"><nlm:affiliation>Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Novartis Pharmaceuticals Corporation, East Hanover, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Legos, Jeffrey J" sort="Legos, Jeffrey J" uniqKey="Legos J" first="Jeffrey J" last="Legos">Jeffrey J. Legos</name><affiliation wicri:level="2"><nlm:affiliation>Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Novartis Pharmaceuticals Corporation, East Hanover, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Jin, Fan" sort="Jin, Fan" uniqKey="Jin F" first="Fan" last="Jin">Fan Jin</name><affiliation wicri:level="2"><nlm:affiliation>Merck & Co, Kenilworth, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Merck & Co, Kenilworth, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Mookerjee, Bijoyesh" sort="Mookerjee, Bijoyesh" uniqKey="Mookerjee B" first="Bijoyesh" last="Mookerjee">Bijoyesh Mookerjee</name><affiliation wicri:level="2"><nlm:affiliation>Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Novartis Pharmaceuticals Corporation, East Hanover, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Flaherty, Keith" sort="Flaherty, Keith" uniqKey="Flaherty K" first="Keith" last="Flaherty">Keith Flaherty</name><affiliation wicri:level="1"><nlm:affiliation>Massachusetts General Hospital Cancer Center, Boston MA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Massachusetts General Hospital Cancer Center, Boston MA</wicri:regionArea><wicri:noRegion>Boston MA</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="RBID">pubmed:26037941</idno><idno type="pmid">26037941</idno><idno type="doi">10.1016/S0140-6736(15)60898-4</idno><idno type="wicri:Area/PubMed/Corpus">002B08</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002B08</idno><idno type="wicri:Area/PubMed/Curation">002A37</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">002A37</idno><idno type="wicri:Area/PubMed/Checkpoint">002A37</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">002A37</idno><idno type="wicri:Area/Ncbi/Merge">002661</idno><idno type="wicri:Area/Ncbi/Curation">002661</idno><idno type="wicri:Area/Ncbi/Checkpoint">002661</idno><idno type="wicri:Area/Main/Merge">002F63</idno><idno type="wicri:Area/Main/Curation">002F62</idno><idno type="wicri:Area/Main/Exploration">002F62</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial.</title><author><name sortKey="Long, Georgina V" sort="Long, Georgina V" uniqKey="Long G" first="Georgina V" last="Long">Georgina V. Long</name><affiliation wicri:level="4"><nlm:affiliation>Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Mater Hospital, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Mater Hospital, Sydney, NSW</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Stroyakovskiy, Daniil" sort="Stroyakovskiy, Daniil" uniqKey="Stroyakovskiy D" first="Daniil" last="Stroyakovskiy">Daniil Stroyakovskiy</name><affiliation wicri:level="3"><nlm:affiliation>Moscow City Oncology Hospital, Moscow, Russia.</nlm:affiliation><country xml:lang="fr">Russie</country><wicri:regionArea>Moscow City Oncology Hospital, Moscow</wicri:regionArea><placeName><settlement type="city">Moscou</settlement><region>District fédéral central</region></placeName></affiliation></author><author><name sortKey="Gogas, Helen" sort="Gogas, Helen" uniqKey="Gogas H" first="Helen" last="Gogas">Helen Gogas</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medicine, University of Athens, Medical School, Athens, Greece.</nlm:affiliation><country xml:lang="fr">Grèce</country><wicri:regionArea>Department of Medicine, University of Athens, Medical School, Athens</wicri:regionArea><placeName><settlement type="city">Athènes</settlement><region nuts="2" type="region">Attique (région)</region></placeName></affiliation></author><author><name sortKey="Levchenko, Evgeny" sort="Levchenko, Evgeny" uniqKey="Levchenko E" first="Evgeny" last="Levchenko">Evgeny Levchenko</name><affiliation wicri:level="1"><nlm:affiliation>Petrov Research Institute of Oncology, Saint Petersburg, Russia.</nlm:affiliation><country xml:lang="fr">Russie</country><wicri:regionArea>Petrov Research Institute of Oncology, Saint Petersburg</wicri:regionArea><wicri:noRegion>Saint Petersburg</wicri:noRegion></affiliation></author><author><name sortKey="De Braud, Filippo" sort="De Braud, Filippo" uniqKey="De Braud F" first="Filippo" last="De Braud">Filippo De Braud</name><affiliation wicri:level="3"><nlm:affiliation>Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Fondazione IRCCS Istituto Nazionale Tumori, Milan</wicri:regionArea><placeName><settlement type="city">Milan</settlement><region nuts="2">Lombardie</region></placeName></affiliation></author><author><name sortKey="Larkin, James" sort="Larkin, James" uniqKey="Larkin J" first="James" last="Larkin">James Larkin</name><affiliation wicri:level="3"><nlm:affiliation>Royal Marsden Hospital, London, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Royal Marsden Hospital, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Garbe, Claus" sort="Garbe, Claus" uniqKey="Garbe C" first="Claus" last="Garbe">Claus Garbe</name><affiliation wicri:level="3"><nlm:affiliation>Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Dermatology, University Hospital Tuebingen, Tuebingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation></author><author><name sortKey="Jouary, Thomas" sort="Jouary, Thomas" uniqKey="Jouary T" first="Thomas" last="Jouary">Thomas Jouary</name><affiliation wicri:level="3"><nlm:affiliation>Department of Dermatology, Hôpital Saint André, CHU Bordeaux, Bordeaux, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Dermatology, Hôpital Saint André, CHU Bordeaux, Bordeaux</wicri:regionArea><placeName><region type="region">Nouvelle-Aquitaine</region><region type="old region">Aquitaine</region><settlement type="city">Bordeaux</settlement></placeName></affiliation></author><author><name sortKey="Hauschild, Axel" sort="Hauschild, Axel" uniqKey="Hauschild A" first="Axel" last="Hauschild">Axel Hauschild</name><affiliation wicri:level="3"><nlm:affiliation>University Hospital Schleswig-Holstein, Kiel, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>University Hospital Schleswig-Holstein, Kiel</wicri:regionArea><placeName><region type="land" nuts="2">Schleswig-Holstein</region><settlement type="city">Kiel</settlement></placeName></affiliation></author><author><name sortKey="Grob, Jean Jacques" sort="Grob, Jean Jacques" uniqKey="Grob J" first="Jean-Jacques" last="Grob">Jean-Jacques Grob</name><affiliation wicri:level="3"><nlm:affiliation>Aix-Marseille University and APHM Hospital CHU Timone, Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Aix-Marseille University and APHM Hospital CHU Timone, Marseille</wicri:regionArea><placeName><region type="region">Provence-Alpes-Côte d'Azur</region><region type="old region">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName></affiliation></author><author><name sortKey="Chiarion Sileni, Vanna" sort="Chiarion Sileni, Vanna" uniqKey="Chiarion Sileni V" first="Vanna" last="Chiarion-Sileni">Vanna Chiarion-Sileni</name><affiliation wicri:level="1"><nlm:affiliation>Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padua, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padua</wicri:regionArea><wicri:noRegion>Padua</wicri:noRegion></affiliation></author><author><name sortKey="Lebbe, Celeste" sort="Lebbe, Celeste" uniqKey="Lebbe C" first="Celeste" last="Lebbe">Celeste Lebbe</name><affiliation wicri:level="3"><nlm:affiliation>APHP Dermatology CIC Hôpital Saint Louis, University Paris Diderot, INSERM U976, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>APHP Dermatology CIC Hôpital Saint Louis, University Paris Diderot, INSERM U976, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Mandala, Mario" sort="Mandala, Mario" uniqKey="Mandala M" first="Mario" last="Mandalà">Mario Mandalà</name><affiliation wicri:level="1"><nlm:affiliation>Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Papa Giovanni XXIII Cancer Center Hospital, Bergamo</wicri:regionArea><wicri:noRegion>Bergamo</wicri:noRegion></affiliation></author><author><name sortKey="Millward, Michael" sort="Millward, Michael" uniqKey="Millward M" first="Michael" last="Millward">Michael Millward</name><affiliation wicri:level="1"><nlm:affiliation>Sir Charles Gairdner Hospital, Hospital Avenue, Perth, WA, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Sir Charles Gairdner Hospital, Hospital Avenue, Perth, WA</wicri:regionArea><wicri:noRegion>WA</wicri:noRegion></affiliation></author><author><name sortKey="Arance, Ana" sort="Arance, Ana" uniqKey="Arance A" first="Ana" last="Arance">Ana Arance</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Oncology, Hospital Clinic and Translational Genomics and Targeted Therapeutics in Solid Tumors, Barcelona, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Medical Oncology, Hospital Clinic and Translational Genomics and Targeted Therapeutics in Solid Tumors, Barcelona</wicri:regionArea><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author><author><name sortKey="Bondarenko, Igor" sort="Bondarenko, Igor" uniqKey="Bondarenko I" first="Igor" last="Bondarenko">Igor Bondarenko</name><affiliation wicri:level="1"><nlm:affiliation>Dnepropetrovsk State Medical Academy, Dnepropetrovsk, Ukraine.</nlm:affiliation><country xml:lang="fr">Ukraine</country><wicri:regionArea>Dnepropetrovsk State Medical Academy, Dnepropetrovsk</wicri:regionArea><wicri:noRegion>Dnepropetrovsk</wicri:noRegion></affiliation></author><author><name sortKey="Haanen, John B A G" sort="Haanen, John B A G" uniqKey="Haanen J" first="John B A G" last="Haanen">John B A G. Haanen</name><affiliation wicri:level="3"><nlm:affiliation>Netherlands Cancer Institute, Amsterdam, Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Netherlands Cancer Institute, Amsterdam</wicri:regionArea><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region></placeName></affiliation></author><author><name sortKey="Hansson, Johan" sort="Hansson, Johan" uniqKey="Hansson J" first="Johan" last="Hansson">Johan Hansson</name><affiliation wicri:level="3"><nlm:affiliation>Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Karolinska Institutet, Karolinska University Hospital Solna, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Utikal, Jochen" sort="Utikal, Jochen" uniqKey="Utikal J" first="Jochen" last="Utikal">Jochen Utikal</name><affiliation wicri:level="3"><nlm:affiliation>University Medical Center Mannheim, Heidelberg University, Mannheim, Germany; German Cancer Research Center, Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>University Medical Center Mannheim, Heidelberg University, Mannheim, Germany; German Cancer Research Center, Heidelberg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Heidelberg</settlement></placeName></affiliation></author><author><name sortKey="Ferraresi, Virginia" sort="Ferraresi, Virginia" uniqKey="Ferraresi V" first="Virginia" last="Ferraresi">Virginia Ferraresi</name><affiliation wicri:level="3"><nlm:affiliation>Istituto Nazionale Tumori Regina Elena, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto Nazionale Tumori Regina Elena, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Kovalenko, Nadezhda" sort="Kovalenko, Nadezhda" uniqKey="Kovalenko N" first="Nadezhda" last="Kovalenko">Nadezhda Kovalenko</name><affiliation wicri:level="1"><nlm:affiliation>Volograd Regional Oncology Dispensary #3, Volzhsky, Russia.</nlm:affiliation><country xml:lang="fr">Russie</country><wicri:regionArea>Volograd Regional Oncology Dispensary #3, Volzhsky</wicri:regionArea><wicri:noRegion>Volzhsky</wicri:noRegion></affiliation></author><author><name sortKey="Mohr, Peter" sort="Mohr, Peter" uniqKey="Mohr P" first="Peter" last="Mohr">Peter Mohr</name><affiliation wicri:level="1"><nlm:affiliation>Elbe Klinikum Stade, Stade, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Elbe Klinikum Stade, Stade</wicri:regionArea><wicri:noRegion>Stade</wicri:noRegion><wicri:noRegion>Stade</wicri:noRegion><wicri:noRegion>Stade</wicri:noRegion></affiliation></author><author><name sortKey="Probachai, Volodymr" sort="Probachai, Volodymr" uniqKey="Probachai V" first="Volodymr" last="Probachai">Volodymr Probachai</name><affiliation wicri:level="1"><nlm:affiliation>Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council, Dnipropetrovsk, Ukraine.</nlm:affiliation><country xml:lang="fr">Ukraine</country><wicri:regionArea>Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council, Dnipropetrovsk</wicri:regionArea><wicri:noRegion>Dnipropetrovsk</wicri:noRegion></affiliation></author><author><name sortKey="Schadendorf, Dirk" sort="Schadendorf, Dirk" uniqKey="Schadendorf D" first="Dirk" last="Schadendorf">Dirk Schadendorf</name><affiliation wicri:level="1"><nlm:affiliation>University Hospital Essen, Essen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>University Hospital Essen, Essen</wicri:regionArea><wicri:noRegion>Essen</wicri:noRegion><wicri:noRegion>Essen</wicri:noRegion><wicri:noRegion>Essen</wicri:noRegion></affiliation></author><author><name sortKey="Nathan, Paul" sort="Nathan, Paul" uniqKey="Nathan P" first="Paul" last="Nathan">Paul Nathan</name><affiliation wicri:level="1"><nlm:affiliation>Mount Vernon Cancer Centre, Northwood, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Mount Vernon Cancer Centre, Northwood</wicri:regionArea><wicri:noRegion>Northwood</wicri:noRegion></affiliation></author><author><name sortKey="Robert, Caroline" sort="Robert, Caroline" uniqKey="Robert C" first="Caroline" last="Robert">Caroline Robert</name><affiliation wicri:level="1"><nlm:affiliation>Gustave Roussy, Villejuif-Paris-Sud, France; Paris Sud University, Le Kremlin Bicêtre, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Gustave Roussy, Villejuif-Paris-Sud, France; Paris Sud University, Le Kremlin Bicêtre</wicri:regionArea><wicri:noRegion>Le Kremlin Bicêtre</wicri:noRegion><wicri:noRegion>Le Kremlin Bicêtre</wicri:noRegion></affiliation></author><author><name sortKey="Ribas, Antoni" sort="Ribas, Antoni" uniqKey="Ribas A" first="Antoni" last="Ribas">Antoni Ribas</name><affiliation wicri:level="2"><nlm:affiliation>David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>David Geffen School of Medicine, UCLA, Los Angeles, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Demarini, Douglas J" sort="Demarini, Douglas J" uniqKey="Demarini D" first="Douglas J" last="Demarini">Douglas J. Demarini</name><affiliation wicri:level="2"><nlm:affiliation>Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Novartis Pharmaceuticals Corporation, East Hanover, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Irani, Jhangir G" sort="Irani, Jhangir G" uniqKey="Irani J" first="Jhangir G" last="Irani">Jhangir G. Irani</name><affiliation wicri:level="2"><nlm:affiliation>Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Novartis Pharmaceuticals Corporation, East Hanover, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Swann, Suzanne" sort="Swann, Suzanne" uniqKey="Swann S" first="Suzanne" last="Swann">Suzanne Swann</name><affiliation wicri:level="2"><nlm:affiliation>Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Novartis Pharmaceuticals Corporation, East Hanover, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Legos, Jeffrey J" sort="Legos, Jeffrey J" uniqKey="Legos J" first="Jeffrey J" last="Legos">Jeffrey J. Legos</name><affiliation wicri:level="2"><nlm:affiliation>Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Novartis Pharmaceuticals Corporation, East Hanover, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Jin, Fan" sort="Jin, Fan" uniqKey="Jin F" first="Fan" last="Jin">Fan Jin</name><affiliation wicri:level="2"><nlm:affiliation>Merck & Co, Kenilworth, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Merck & Co, Kenilworth, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Mookerjee, Bijoyesh" sort="Mookerjee, Bijoyesh" uniqKey="Mookerjee B" first="Bijoyesh" last="Mookerjee">Bijoyesh Mookerjee</name><affiliation wicri:level="2"><nlm:affiliation>Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Novartis Pharmaceuticals Corporation, East Hanover, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Flaherty, Keith" sort="Flaherty, Keith" uniqKey="Flaherty K" first="Keith" last="Flaherty">Keith Flaherty</name><affiliation wicri:level="1"><nlm:affiliation>Massachusetts General Hospital Cancer Center, Boston MA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Massachusetts General Hospital Cancer Center, Boston MA</wicri:regionArea><wicri:noRegion>Boston MA</wicri:noRegion></affiliation></author></analytic><series><title level="j">Lancet (London, England)</title><idno type="eISSN">1474-547X</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>Aged</term><term>Aged, 80 and over</term><term>Disease-Free Survival</term><term>Double-Blind Method</term><term>Drug Therapy, Combination</term><term>Female</term><term>Humans</term><term>Imidazoles (administration & dosage)</term><term>Male</term><term>Melanoma (drug therapy)</term><term>Middle Aged</term><term>Oximes (administration & dosage)</term><term>Proto-Oncogene Proteins B-raf (genetics)</term><term>Pyridones (administration & dosage)</term><term>Pyrimidinones (administration & dosage)</term><term>Treatment Outcome</term><term>Young Adult</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adulte</term><term>Adulte d'âge moyen</term><term>Association de médicaments</term><term>Femelle</term><term>Humains</term><term>Imidazoles (administration et posologie)</term><term>Jeune adulte</term><term>Mâle</term><term>Mélanome (traitement médicamenteux)</term><term>Méthode en double aveugle</term><term>Oximes (administration et posologie)</term><term>Protéines proto-oncogènes B-raf (génétique)</term><term>Pyridones (administration et posologie)</term><term>Pyrimidinones (administration et posologie)</term><term>Résultat thérapeutique</term><term>Sujet âgé</term><term>Sujet âgé de 80 ans ou plus</term><term>Survie sans rechute</term></keywords><keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Imidazoles</term><term>Oximes</term><term>Pyridones</term><term>Pyrimidinones</term></keywords><keywords scheme="MESH" qualifier="administration et posologie" xml:lang="fr"><term>Imidazoles</term><term>Oximes</term><term>Pyridones</term><term>Pyrimidinones</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Melanoma</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Proto-Oncogene Proteins B-raf</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Protéines proto-oncogènes B-raf</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Mélanome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Aged</term><term>Aged, 80 and over</term><term>Disease-Free Survival</term><term>Double-Blind Method</term><term>Drug Therapy, Combination</term><term>Female</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Treatment Outcome</term><term>Young Adult</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adulte</term><term>Adulte d'âge moyen</term><term>Association de médicaments</term><term>Femelle</term><term>Humains</term><term>Jeune adulte</term><term>Mâle</term><term>Méthode en double aveugle</term><term>Résultat thérapeutique</term><term>Sujet âgé</term><term>Sujet âgé de 80 ans ou plus</term><term>Survie sans rechute</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>Espagne</li><li>France</li><li>Grèce</li><li>Italie</li><li>Pays-Bas</li><li>Royaume-Uni</li><li>Russie</li><li>Suède</li><li>Ukraine</li><li>États-Unis</li></country><region><li>Angleterre</li><li>Aquitaine</li><li>Attique (région)</li><li>Bade-Wurtemberg</li><li>Californie</li><li>Catalogne</li><li>District de Karlsruhe</li><li>District de Tübingen</li><li>District fédéral central</li><li>Grand Londres</li><li>Hollande-Septentrionale</li><li>Latium</li><li>Lombardie</li><li>New Jersey</li><li>Nouvelle-Aquitaine</li><li>Nouvelle-Galles du Sud</li><li>Provence-Alpes-Côte d'Azur</li><li>Schleswig-Holstein</li><li>Svealand</li><li>Île-de-France</li></region><settlement><li>Amsterdam</li><li>Athènes</li><li>Barcelone</li><li>Bordeaux</li><li>Heidelberg</li><li>Kiel</li><li>Londres</li><li>Marseille</li><li>Milan</li><li>Moscou</li><li>Paris</li><li>Rome</li><li>Stockholm</li><li>Sydney</li><li>Tübingen</li></settlement><orgName><li>Université de Sydney</li></orgName></list><tree><country name="Australie"><region name="Nouvelle-Galles du Sud"><name sortKey="Long, Georgina V" sort="Long, Georgina V" uniqKey="Long G" first="Georgina V" last="Long">Georgina V. Long</name></region><name sortKey="Millward, Michael" sort="Millward, Michael" uniqKey="Millward M" first="Michael" last="Millward">Michael Millward</name></country><country name="Russie"><region name="District fédéral central"><name sortKey="Stroyakovskiy, Daniil" sort="Stroyakovskiy, Daniil" uniqKey="Stroyakovskiy D" first="Daniil" last="Stroyakovskiy">Daniil Stroyakovskiy</name></region><name sortKey="Kovalenko, Nadezhda" sort="Kovalenko, Nadezhda" uniqKey="Kovalenko N" first="Nadezhda" last="Kovalenko">Nadezhda Kovalenko</name><name sortKey="Levchenko, Evgeny" sort="Levchenko, Evgeny" uniqKey="Levchenko E" first="Evgeny" last="Levchenko">Evgeny Levchenko</name></country><country name="Grèce"><region name="Attique (région)"><name sortKey="Gogas, Helen" sort="Gogas, Helen" uniqKey="Gogas H" first="Helen" last="Gogas">Helen Gogas</name></region></country><country name="Italie"><region name="Lombardie"><name sortKey="De Braud, Filippo" sort="De Braud, Filippo" uniqKey="De Braud F" first="Filippo" last="De Braud">Filippo De Braud</name></region><name sortKey="Chiarion Sileni, Vanna" sort="Chiarion Sileni, Vanna" uniqKey="Chiarion Sileni V" first="Vanna" last="Chiarion-Sileni">Vanna Chiarion-Sileni</name><name sortKey="Ferraresi, Virginia" sort="Ferraresi, Virginia" uniqKey="Ferraresi V" first="Virginia" last="Ferraresi">Virginia Ferraresi</name><name sortKey="Mandala, Mario" sort="Mandala, Mario" uniqKey="Mandala M" first="Mario" last="Mandalà">Mario Mandalà</name></country><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Larkin, James" sort="Larkin, James" uniqKey="Larkin J" first="James" last="Larkin">James Larkin</name></region><name sortKey="Nathan, Paul" sort="Nathan, Paul" uniqKey="Nathan P" first="Paul" last="Nathan">Paul Nathan</name></country><country name="Allemagne"><region name="Bade-Wurtemberg"><name sortKey="Garbe, Claus" sort="Garbe, Claus" uniqKey="Garbe C" first="Claus" last="Garbe">Claus Garbe</name></region><name sortKey="Hauschild, Axel" sort="Hauschild, Axel" uniqKey="Hauschild A" first="Axel" last="Hauschild">Axel Hauschild</name><name sortKey="Mohr, Peter" sort="Mohr, Peter" uniqKey="Mohr P" first="Peter" last="Mohr">Peter Mohr</name><name sortKey="Schadendorf, Dirk" sort="Schadendorf, Dirk" uniqKey="Schadendorf D" first="Dirk" last="Schadendorf">Dirk Schadendorf</name><name sortKey="Utikal, Jochen" sort="Utikal, Jochen" uniqKey="Utikal J" first="Jochen" last="Utikal">Jochen Utikal</name></country><country name="France"><region name="Nouvelle-Aquitaine"><name sortKey="Jouary, Thomas" sort="Jouary, Thomas" uniqKey="Jouary T" first="Thomas" last="Jouary">Thomas Jouary</name></region><name sortKey="Grob, Jean Jacques" sort="Grob, Jean Jacques" uniqKey="Grob J" first="Jean-Jacques" last="Grob">Jean-Jacques Grob</name><name sortKey="Lebbe, Celeste" sort="Lebbe, Celeste" uniqKey="Lebbe C" first="Celeste" last="Lebbe">Celeste Lebbe</name><name sortKey="Robert, Caroline" sort="Robert, Caroline" uniqKey="Robert C" first="Caroline" last="Robert">Caroline Robert</name></country><country name="Espagne"><region name="Catalogne"><name sortKey="Arance, Ana" sort="Arance, Ana" uniqKey="Arance A" first="Ana" last="Arance">Ana Arance</name></region></country><country name="Ukraine"><noRegion><name sortKey="Bondarenko, Igor" sort="Bondarenko, Igor" uniqKey="Bondarenko I" first="Igor" last="Bondarenko">Igor Bondarenko</name></noRegion><name sortKey="Probachai, Volodymr" sort="Probachai, Volodymr" uniqKey="Probachai V" first="Volodymr" last="Probachai">Volodymr Probachai</name></country><country name="Pays-Bas"><region name="Hollande-Septentrionale"><name sortKey="Haanen, John B A G" sort="Haanen, John B A G" uniqKey="Haanen J" first="John B A G" last="Haanen">John B A G. Haanen</name></region></country><country name="Suède"><region name="Svealand"><name sortKey="Hansson, Johan" sort="Hansson, Johan" uniqKey="Hansson J" first="Johan" last="Hansson">Johan Hansson</name></region></country><country name="États-Unis"><region name="Californie"><name sortKey="Ribas, Antoni" sort="Ribas, Antoni" uniqKey="Ribas A" first="Antoni" last="Ribas">Antoni Ribas</name></region><name sortKey="Demarini, Douglas J" sort="Demarini, Douglas J" uniqKey="Demarini D" first="Douglas J" last="Demarini">Douglas J. Demarini</name><name sortKey="Flaherty, Keith" sort="Flaherty, Keith" uniqKey="Flaherty K" first="Keith" last="Flaherty">Keith Flaherty</name><name sortKey="Irani, Jhangir G" sort="Irani, Jhangir G" uniqKey="Irani J" first="Jhangir G" last="Irani">Jhangir G. Irani</name><name sortKey="Jin, Fan" sort="Jin, Fan" uniqKey="Jin F" first="Fan" last="Jin">Fan Jin</name><name sortKey="Legos, Jeffrey J" sort="Legos, Jeffrey J" uniqKey="Legos J" first="Jeffrey J" last="Legos">Jeffrey J. Legos</name><name sortKey="Mookerjee, Bijoyesh" sort="Mookerjee, Bijoyesh" uniqKey="Mookerjee B" first="Bijoyesh" last="Mookerjee">Bijoyesh Mookerjee</name><name sortKey="Swann, Suzanne" sort="Swann, Suzanne" uniqKey="Swann S" first="Suzanne" last="Swann">Suzanne Swann</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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