Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer: results of the ring studies of the international immuno-oncology biomarker working group.
Identifieur interne : 001712 ( Main/Exploration ); précédent : 001711; suivant : 001713Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer: results of the ring studies of the international immuno-oncology biomarker working group.
Auteurs : Carsten Denkert [Allemagne] ; Stephan Wienert [Allemagne] ; Audrey Poterie [France] ; Sibylle Loibl [Allemagne] ; Jan Budczies [Allemagne] ; Sunil Badve [États-Unis] ; Zsuzsanna Bago-Horvath [Autriche] ; Anita Bane [Canada] ; Shahinaz Bedri [Qatar] ; Jane Brock [États-Unis] ; Ewa Chmielik [Pologne] ; Matthias Christgen [Allemagne] ; Cecile Colpaert [Belgique] ; Sandra Demaria [États-Unis] ; Gert Van Den Eynden [Belgique] ; Giuseppe Floris [Belgique] ; Stephen B. Fox [Australie] ; Dongxia Gao [Canada] ; Barbara Ingold Heppner [Allemagne] ; S Rim Kim [États-Unis] ; Zuzana Kos [Canada] ; Hans H. Kreipe [Allemagne] ; Sunil R. Lakhani [Australie] ; Frederique Penault-Llorca [France] ; Giancarlo Pruneri [Italie] ; Nina Radosevic-Robin [France] ; David L. Rimm [États-Unis] ; Stuart J. Schnitt [États-Unis] ; Bruno V. Sinn [Allemagne] ; Peter Sinn [Allemagne] ; Nicolas Sirtaine [Belgique] ; Sandra A. O'Toole [Australie] ; Giuseppe Viale [Italie] ; Koen Van De Vijver [Pays-Bas] ; Roland De Wind [Belgique] ; Gunter Von Minckwitz [Allemagne] ; Frederick Klauschen [Allemagne] ; Michael Untch [Allemagne] ; Peter A. Fasching [Allemagne] ; Toralf Reimer [Allemagne] ; Karen Willard-Gallo [Belgique] ; Stefan Michiels [France] ; Sherene Loi [Australie] ; Roberto Salgado [Belgique]Source :
- Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc [ 1530-0285 ] ; 2016.
Abstract
Multiple independent studies have shown that tumor-infiltrating lymphocytes (TIL) are prognostic in breast cancer with potential relevance for response to immune-checkpoint inhibitor therapy. Although many groups are currently evaluating TIL, there is no standardized system for diagnostic applications. This study reports the results of two ring studies investigating TIL conducted by the International Working Group on Immuno-oncology Biomarkers. The study aim was to determine the intraclass correlation coefficient (ICC) for evaluation of TIL by different pathologists. A total of 120 slides were evaluated by a large group of pathologists with a web-based system in ring study 1 and a more advanced software-system in ring study 2 that included an integrated feedback with standardized reference images. The predefined aim for successful ring studies 1 and 2 was an ICC above 0.7 (lower limit of 95% confidence interval (CI)). In ring study 1 the prespecified endpoint was not reached (ICC: 0.70; 95% CI: 0.62-0.78). On the basis of an analysis of sources of variation, we developed a more advanced digital image evaluation system for ring study 2, which improved the ICC to 0.89 (95% CI: 0.85-0.92). The Fleiss' kappa value for <60 vs ≥60% TIL improved from 0.45 (ring study 1) to 0.63 in RS2 and the mean concordance improved from 88 to 92%. This large international standardization project shows that reproducible evaluation of TIL is feasible in breast cancer. This opens the way for standardized reporting of tumor immunological parameters in clinical studies and diagnostic practice. The software-guided image evaluation approach used in ring study 2 may be of value as a tool for evaluation of TIL in clinical trials and diagnostic practice. The experience gained from this approach might be applicable to the standardization of other diagnostic parameters in histopathology.
DOI: 10.1038/modpathol.2016.109
PubMed: 27363491
Affiliations:
- Allemagne, Australie, Autriche, Belgique, Canada, France, Italie, Pays-Bas, Pologne, Qatar, États-Unis
- Auvergne (région administrative), Auvergne-Rhône-Alpes, Bade-Wurtemberg, Basse-Saxe, Bavière, Berlin, Connecticut, District de Karlsruhe, District de Moyenne-Franconie, Hollande-Septentrionale, Indiana, Lombardie, Massachusetts, Ontario, Pennsylvanie, Région de Bruxelles-Capitale, Vienne (Autriche), État de New York
- Amsterdam, Berlin, Bruxelles, Clermont-Ferrand, Erlangen, Hamilton (Ontario), Hanovre, Heidelberg, Milan, Vienne (Autriche)
- Université McMaster
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Cornell Medical College, Doha</wicri:regionArea><wicri:noRegion>Doha</wicri:noRegion></affiliation></author><author><name sortKey="Brock, Jane" sort="Brock, Jane" uniqKey="Brock J" first="Jane" last="Brock">Jane Brock</name><affiliation wicri:level="2"><nlm:affiliation>Harvard Medical School, Boston, MA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Harvard Medical School, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Chmielik, Ewa" sort="Chmielik, Ewa" uniqKey="Chmielik E" first="Ewa" last="Chmielik">Ewa Chmielik</name><affiliation wicri:level="1"><nlm:affiliation>Tumor Pathology Department, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Tumor Pathology Department, Maria Sklodowska-Curie Memorial Cancer Center and Institute 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xml:lang="fr">Belgique</country><wicri:regionArea>Pathology, GZA Ziekenhuizen, Sint-Augustinus, Wilrijk</wicri:regionArea><wicri:noRegion>Wilrijk</wicri:noRegion></affiliation></author><author><name sortKey="Demaria, Sandra" sort="Demaria, Sandra" uniqKey="Demaria S" first="Sandra" last="Demaria">Sandra Demaria</name><affiliation wicri:level="2"><nlm:affiliation>Radiation Oncology and Pathology, Weill Cornell Medical College, New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Radiation Oncology and Pathology, Weill Cornell Medical College, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Van Den Eynden, Gert" sort="Van Den Eynden, Gert" uniqKey="Van Den Eynden G" first="Gert" last="Van Den Eynden">Gert Van Den Eynden</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology and Cytology GZA Hospitals, Wilrijk, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Pathology and Cytology GZA Hospitals, Wilrijk</wicri:regionArea><wicri:noRegion>Wilrijk</wicri:noRegion></affiliation></author><author><name sortKey="Floris, Giuseppe" sort="Floris, Giuseppe" uniqKey="Floris G" first="Giuseppe" last="Floris">Giuseppe Floris</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology University Hospitals Leuven, Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Pathology University Hospitals Leuven, Leuven</wicri:regionArea><wicri:noRegion>Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Fox, Stephen B" sort="Fox, Stephen B" uniqKey="Fox S" first="Stephen B" last="Fox">Stephen B. Fox</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC</wicri:regionArea><wicri:noRegion>VIC</wicri:noRegion></affiliation></author><author><name sortKey="Gao, Dongxia" sort="Gao, Dongxia" uniqKey="Gao D" first="Dongxia" last="Gao">Dongxia Gao</name><affiliation wicri:level="1"><nlm:affiliation>Anatomical Pathology, Vancouver Hospital, Vancouver, BC, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Anatomical Pathology, Vancouver Hospital, Vancouver, BC</wicri:regionArea><wicri:noRegion>BC</wicri:noRegion></affiliation></author><author><name sortKey="Ingold Heppner, Barbara" sort="Ingold Heppner, Barbara" uniqKey="Ingold Heppner B" first="Barbara" last="Ingold Heppner">Barbara Ingold Heppner</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Kim, S Rim" sort="Kim, S Rim" uniqKey="Kim S" first="S Rim" last="Kim">S Rim Kim</name><affiliation wicri:level="2"><nlm:affiliation>Division of Pathology, NSABP, Pittsburgh, PA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Pathology, NSABP, Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Kos, Zuzana" sort="Kos, Zuzana" uniqKey="Kos Z" first="Zuzana" last="Kos">Zuzana Kos</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Kreipe, Hans H" sort="Kreipe, Hans H" uniqKey="Kreipe H" first="Hans H" last="Kreipe">Hans H. Kreipe</name><affiliation wicri:level="3"><nlm:affiliation>Institut für Pathologie, Medizinische Hochschule Hannover, Hannover, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut für Pathologie, Medizinische Hochschule Hannover, Hannover</wicri:regionArea><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Hanovre</settlement></placeName></affiliation></author><author><name sortKey="Lakhani, Sunil R" sort="Lakhani, Sunil R" uniqKey="Lakhani S" first="Sunil R" last="Lakhani">Sunil R. Lakhani</name><affiliation wicri:level="1"><nlm:affiliation>UQ School of Medicine and Pathology Queensland, The University of Queensland Centre for Clinical Research, Brisbane, QLD, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>UQ School of Medicine and Pathology Queensland, The University of Queensland Centre for Clinical Research, Brisbane, QLD</wicri:regionArea><wicri:noRegion>QLD</wicri:noRegion></affiliation></author><author><name sortKey="Penault Llorca, Frederique" sort="Penault Llorca, Frederique" uniqKey="Penault Llorca F" first="Frederique" last="Penault-Llorca">Frederique Penault-Llorca</name><affiliation wicri:level="3"><nlm:affiliation>ERTICa Research Team, Department of Pathology, Jean Perrin Comprehensive Cancer Center, University of Auvergne EA4677, Clermont-Ferrand, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>ERTICa Research Team, Department of Pathology, Jean Perrin Comprehensive Cancer Center, University of Auvergne EA4677, Clermont-Ferrand</wicri:regionArea><placeName><region type="region">Auvergne-Rhône-Alpes</region><region type="old region">Auvergne (région administrative)</region><settlement type="city">Clermont-Ferrand</settlement></placeName></affiliation></author><author><name sortKey="Pruneri, Giancarlo" sort="Pruneri, Giancarlo" uniqKey="Pruneri G" first="Giancarlo" last="Pruneri">Giancarlo Pruneri</name><affiliation wicri:level="3"><nlm:affiliation>Division of Pathology and Laboratory Medicine, University of Milan, Milan, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Division of Pathology and Laboratory Medicine, University of Milan, Milan</wicri:regionArea><placeName><settlement type="city">Milan</settlement><region nuts="2">Lombardie</region></placeName></affiliation></author><author><name sortKey="Radosevic Robin, Nina" sort="Radosevic Robin, Nina" uniqKey="Radosevic Robin N" first="Nina" last="Radosevic-Robin">Nina Radosevic-Robin</name><affiliation wicri:level="3"><nlm:affiliation>ERTICa Research Team, Department of Pathology, Jean Perrin Comprehensive Cancer Center, University of Auvergne EA4677, Clermont-Ferrand, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>ERTICa Research Team, Department of Pathology, Jean Perrin Comprehensive Cancer Center, University of Auvergne EA4677, Clermont-Ferrand</wicri:regionArea><placeName><region type="region">Auvergne-Rhône-Alpes</region><region type="old region">Auvergne (région administrative)</region><settlement type="city">Clermont-Ferrand</settlement></placeName></affiliation></author><author><name sortKey="Rimm, David L" sort="Rimm, David L" uniqKey="Rimm D" first="David L" last="Rimm">David L. Rimm</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, Yale University School of Medicine, New Haven, CT</wicri:regionArea><placeName><region type="state">Connecticut</region></placeName></affiliation></author><author><name sortKey="Schnitt, Stuart J" sort="Schnitt, Stuart J" uniqKey="Schnitt S" first="Stuart J" last="Schnitt">Stuart J. Schnitt</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Sinn, Bruno V" sort="Sinn, Bruno V" uniqKey="Sinn B" first="Bruno V" last="Sinn">Bruno V. Sinn</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Sinn, Peter" sort="Sinn, Peter" uniqKey="Sinn P" first="Peter" last="Sinn">Peter Sinn</name><affiliation wicri:level="3"><nlm:affiliation>Sektion Gynäkopathologie, Pathologisches Institut, University of Heidelberg, Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Sektion Gynäkopathologie, Pathologisches Institut, University of Heidelberg, 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="Sirtaine, Nicolas" sort="Sirtaine, Nicolas" uniqKey="Sirtaine N" first="Nicolas" last="Sirtaine">Nicolas Sirtaine</name><affiliation wicri:level="3"><nlm:affiliation>Anatomie Pathologique, Institut Jules Bordet, Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Anatomie Pathologique, Institut Jules Bordet, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName></affiliation></author><author><name sortKey="O Toole, Sandra A" sort="O Toole, Sandra A" uniqKey="O Toole S" first="Sandra A" last="O'Toole">Sandra A. O'Toole</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Diagnostic Oncology, Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Molecular Diagnostic Oncology, Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW</wicri:regionArea><wicri:noRegion>NSW</wicri:noRegion></affiliation></author><author><name sortKey="Viale, Giuseppe" sort="Viale, Giuseppe" uniqKey="Viale G" first="Giuseppe" last="Viale">Giuseppe Viale</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, European Institute of Oncology, University of Milan, Milan, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Pathology, European Institute of Oncology, University of Milan, Milan</wicri:regionArea><placeName><settlement type="city">Milan</settlement><region nuts="2">Lombardie</region></placeName></affiliation></author><author><name sortKey="Van De Vijver, Koen" sort="Van De Vijver, Koen" uniqKey="Van De Vijver K" first="Koen" last="Van De Vijver">Koen Van De Vijver</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pathology, 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="De Wind, Roland" sort="De Wind, Roland" uniqKey="De Wind R" first="Roland" last="De Wind">Roland De Wind</name><affiliation wicri:level="3"><nlm:affiliation>Jules Bordet Institute, Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Jules Bordet Institute, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName></affiliation></author><author><name sortKey="Von Minckwitz, Gunter" sort="Von Minckwitz, Gunter" uniqKey="Von Minckwitz G" first="Gunter" last="Von Minckwitz">Gunter Von Minckwitz</name><affiliation wicri:level="1"><nlm:affiliation>German Breast Group (GBG), Neu-Isenburg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Breast Group (GBG), Neu-Isenburg</wicri:regionArea><wicri:noRegion>Neu-Isenburg</wicri:noRegion><wicri:noRegion>Neu-Isenburg</wicri:noRegion><wicri:noRegion>Neu-Isenburg</wicri:noRegion></affiliation></author><author><name sortKey="Klauschen, Frederick" sort="Klauschen, Frederick" uniqKey="Klauschen F" first="Frederick" last="Klauschen">Frederick Klauschen</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Untch, Michael" sort="Untch, Michael" uniqKey="Untch M" first="Michael" last="Untch">Michael Untch</name><affiliation wicri:level="3"><nlm:affiliation>Department of Gynecology, Helios-Klinikum Berlin-Buch, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gynecology, Helios-Klinikum Berlin-Buch, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Fasching, Peter A" sort="Fasching, Peter A" uniqKey="Fasching P" first="Peter A" last="Fasching">Peter A. Fasching</name><affiliation wicri:level="3"><nlm:affiliation>Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen EMN, Friedrich-Alexander University Erlangen, Erlangen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen EMN, Friedrich-Alexander University Erlangen, Erlangen</wicri:regionArea><placeName><settlement type="city">Erlangen</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Moyenne-Franconie</region></placeName></affiliation></author><author><name sortKey="Reimer, Toralf" sort="Reimer, Toralf" uniqKey="Reimer T" first="Toralf" last="Reimer">Toralf Reimer</name><affiliation wicri:level="1"><nlm:affiliation>Department of Gynecology, Klinikum Südstadt Rostock, Rostock, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gynecology, Klinikum Südstadt Rostock, Rostock</wicri:regionArea><wicri:noRegion>Rostock</wicri:noRegion><wicri:noRegion>Rostock</wicri:noRegion><wicri:noRegion>Rostock</wicri:noRegion></affiliation></author><author><name sortKey="Willard Gallo, Karen" sort="Willard Gallo, Karen" uniqKey="Willard Gallo K" first="Karen" last="Willard-Gallo">Karen Willard-Gallo</name><affiliation wicri:level="3"><nlm:affiliation>Molecular Immunology Unit, Institut Jules Bordet, Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Molecular Immunology Unit, Institut Jules Bordet, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName></affiliation></author><author><name sortKey="Michiels, Stefan" sort="Michiels, Stefan" uniqKey="Michiels S" first="Stefan" last="Michiels">Stefan Michiels</name><affiliation wicri:level="1"><nlm:affiliation>Service de Biostatistique et d'Epidémiologie, Gustave Roussy, CESP, Inserm U1018, Univ. Paris Sud, Univ. Paris-Saclay, Villejuif, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Service de Biostatistique et d'Epidémiologie, Gustave Roussy, CESP, Inserm U1018, Univ. Paris Sud, Univ. Paris-Saclay, Villejuif</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Loi, Sherene" sort="Loi, Sherene" uniqKey="Loi S" first="Sherene" last="Loi">Sherene Loi</name><affiliation wicri:level="1"><nlm:affiliation>Division of Research and Clinical Medicine, Peter MacCallum Cancer Center, Melbourne, VIC, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Division of Research and Clinical Medicine, Peter MacCallum Cancer Center, Melbourne, VIC</wicri:regionArea><wicri:noRegion>VIC</wicri:noRegion></affiliation></author><author><name sortKey="Salgado, Roberto" sort="Salgado, Roberto" uniqKey="Salgado R" first="Roberto" last="Salgado">Roberto Salgado</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology and Cytology GZA Hospitals, Wilrijk, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Pathology and Cytology GZA Hospitals, Wilrijk</wicri:regionArea><wicri:noRegion>Wilrijk</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:27363491</idno><idno type="pmid">27363491</idno><idno type="doi">10.1038/modpathol.2016.109</idno><idno type="wicri:Area/PubMed/Corpus">001755</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001755</idno><idno type="wicri:Area/PubMed/Curation">001732</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001732</idno><idno type="wicri:Area/PubMed/Checkpoint">001732</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">001732</idno><idno type="wicri:Area/Ncbi/Merge">003783</idno><idno type="wicri:Area/Ncbi/Curation">003783</idno><idno type="wicri:Area/Ncbi/Checkpoint">003783</idno><idno type="wicri:Area/Main/Merge">001707</idno><idno type="wicri:Area/Main/Curation">001712</idno><idno type="wicri:Area/Main/Exploration">001712</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer: results of the ring studies of the international immuno-oncology biomarker working group.</title><author><name sortKey="Denkert, Carsten" sort="Denkert, Carsten" uniqKey="Denkert C" first="Carsten" last="Denkert">Carsten Denkert</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Wienert, Stephan" sort="Wienert, Stephan" uniqKey="Wienert S" first="Stephan" last="Wienert">Stephan Wienert</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Poterie, Audrey" sort="Poterie, Audrey" uniqKey="Poterie A" first="Audrey" last="Poterie">Audrey Poterie</name><affiliation wicri:level="1"><nlm:affiliation>Service de Biostatistique et d'Epidémiologie; Institute Gustave Roussy, Villejuif, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Service de Biostatistique et d'Epidémiologie; Institute Gustave Roussy, Villejuif</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Loibl, Sibylle" sort="Loibl, Sibylle" uniqKey="Loibl S" first="Sibylle" last="Loibl">Sibylle Loibl</name><affiliation wicri:level="1"><nlm:affiliation>German Breast Group (GBG), Neu-Isenburg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Breast Group (GBG), Neu-Isenburg</wicri:regionArea><wicri:noRegion>Neu-Isenburg</wicri:noRegion><wicri:noRegion>Neu-Isenburg</wicri:noRegion><wicri:noRegion>Neu-Isenburg</wicri:noRegion></affiliation></author><author><name sortKey="Budczies, Jan" sort="Budczies, Jan" uniqKey="Budczies J" first="Jan" last="Budczies">Jan Budczies</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Badve, Sunil" sort="Badve, Sunil" uniqKey="Badve S" first="Sunil" last="Badve">Sunil Badve</name><affiliation wicri:level="2"><nlm:affiliation>Indiana University School of Medicine, Indianapolis, IN, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Indiana University School of Medicine, Indianapolis, IN</wicri:regionArea><placeName><region type="state">Indiana</region></placeName></affiliation></author><author><name sortKey="Bago Horvath, Zsuzsanna" sort="Bago Horvath, Zsuzsanna" uniqKey="Bago Horvath Z" first="Zsuzsanna" last="Bago-Horvath">Zsuzsanna Bago-Horvath</name><affiliation wicri:level="3"><nlm:affiliation>Clinical Institute of Pathology, Medizinische Universität Wien, Wien, Austria.</nlm:affiliation><country xml:lang="fr">Autriche</country><wicri:regionArea>Clinical Institute of Pathology, Medizinische Universität Wien, Wien</wicri:regionArea><placeName><settlement type="city">Vienne (Autriche)</settlement><region nuts="2" type="province">Vienne (Autriche)</region></placeName></affiliation></author><author><name sortKey="Bane, Anita" sort="Bane, Anita" uniqKey="Bane A" first="Anita" last="Bane">Anita Bane</name><affiliation wicri:level="4"><nlm:affiliation>Department of Pathology & Molecular Medicine, McMaster University, Hamilton, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pathology & Molecular Medicine, McMaster University, Hamilton, ON</wicri:regionArea><orgName type="university">Université McMaster</orgName><placeName><settlement type="city">Hamilton (Ontario)</settlement><region type="state">Ontario</region></placeName></affiliation></author><author><name sortKey="Bedri, Shahinaz" sort="Bedri, Shahinaz" uniqKey="Bedri S" first="Shahinaz" last="Bedri">Shahinaz Bedri</name><affiliation wicri:level="1"><nlm:affiliation>Weill Cornell Medical College, Doha, Qatar.</nlm:affiliation><country xml:lang="fr">Qatar</country><wicri:regionArea>Weill Cornell Medical College, Doha</wicri:regionArea><wicri:noRegion>Doha</wicri:noRegion></affiliation></author><author><name sortKey="Brock, Jane" sort="Brock, Jane" uniqKey="Brock J" first="Jane" last="Brock">Jane Brock</name><affiliation wicri:level="2"><nlm:affiliation>Harvard Medical School, Boston, MA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Harvard Medical School, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Chmielik, Ewa" sort="Chmielik, Ewa" uniqKey="Chmielik E" first="Ewa" last="Chmielik">Ewa Chmielik</name><affiliation wicri:level="1"><nlm:affiliation>Tumor Pathology Department, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Tumor Pathology Department, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice</wicri:regionArea><wicri:noRegion>Gliwice</wicri:noRegion></affiliation></author><author><name sortKey="Christgen, Matthias" sort="Christgen, Matthias" uniqKey="Christgen M" first="Matthias" last="Christgen">Matthias Christgen</name><affiliation wicri:level="3"><nlm:affiliation>Institut für Pathologie, Medizinische Hochschule Hannover, Hannover, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut für Pathologie, Medizinische Hochschule Hannover, Hannover</wicri:regionArea><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Hanovre</settlement></placeName></affiliation></author><author><name sortKey="Colpaert, Cecile" sort="Colpaert, Cecile" uniqKey="Colpaert C" first="Cecile" last="Colpaert">Cecile Colpaert</name><affiliation wicri:level="1"><nlm:affiliation>Pathology, GZA Ziekenhuizen, Sint-Augustinus, Wilrijk, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Pathology, GZA Ziekenhuizen, Sint-Augustinus, Wilrijk</wicri:regionArea><wicri:noRegion>Wilrijk</wicri:noRegion></affiliation></author><author><name sortKey="Demaria, Sandra" sort="Demaria, Sandra" uniqKey="Demaria S" first="Sandra" last="Demaria">Sandra Demaria</name><affiliation wicri:level="2"><nlm:affiliation>Radiation Oncology and Pathology, Weill Cornell Medical College, New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Radiation Oncology and Pathology, Weill Cornell Medical College, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Van Den Eynden, Gert" sort="Van Den Eynden, Gert" uniqKey="Van Den Eynden G" first="Gert" last="Van Den Eynden">Gert Van Den Eynden</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology and Cytology GZA Hospitals, Wilrijk, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Pathology and Cytology GZA Hospitals, Wilrijk</wicri:regionArea><wicri:noRegion>Wilrijk</wicri:noRegion></affiliation></author><author><name sortKey="Floris, Giuseppe" sort="Floris, Giuseppe" uniqKey="Floris G" first="Giuseppe" last="Floris">Giuseppe Floris</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology University Hospitals Leuven, Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Pathology University Hospitals Leuven, Leuven</wicri:regionArea><wicri:noRegion>Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Fox, Stephen B" sort="Fox, Stephen B" uniqKey="Fox S" first="Stephen B" last="Fox">Stephen B. Fox</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC</wicri:regionArea><wicri:noRegion>VIC</wicri:noRegion></affiliation></author><author><name sortKey="Gao, Dongxia" sort="Gao, Dongxia" uniqKey="Gao D" first="Dongxia" last="Gao">Dongxia Gao</name><affiliation wicri:level="1"><nlm:affiliation>Anatomical Pathology, Vancouver Hospital, Vancouver, BC, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Anatomical Pathology, Vancouver Hospital, Vancouver, BC</wicri:regionArea><wicri:noRegion>BC</wicri:noRegion></affiliation></author><author><name sortKey="Ingold Heppner, Barbara" sort="Ingold Heppner, Barbara" uniqKey="Ingold Heppner B" first="Barbara" last="Ingold Heppner">Barbara Ingold Heppner</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Kim, S Rim" sort="Kim, S Rim" uniqKey="Kim S" first="S Rim" last="Kim">S Rim Kim</name><affiliation wicri:level="2"><nlm:affiliation>Division of Pathology, NSABP, Pittsburgh, PA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Pathology, NSABP, Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Kos, Zuzana" sort="Kos, Zuzana" uniqKey="Kos Z" first="Zuzana" last="Kos">Zuzana Kos</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Kreipe, Hans H" sort="Kreipe, Hans H" uniqKey="Kreipe H" first="Hans H" last="Kreipe">Hans H. Kreipe</name><affiliation wicri:level="3"><nlm:affiliation>Institut für Pathologie, Medizinische Hochschule Hannover, Hannover, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut für Pathologie, Medizinische Hochschule Hannover, Hannover</wicri:regionArea><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Hanovre</settlement></placeName></affiliation></author><author><name sortKey="Lakhani, Sunil R" sort="Lakhani, Sunil R" uniqKey="Lakhani S" first="Sunil R" last="Lakhani">Sunil R. Lakhani</name><affiliation wicri:level="1"><nlm:affiliation>UQ School of Medicine and Pathology Queensland, The University of Queensland Centre for Clinical Research, Brisbane, QLD, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>UQ School of Medicine and Pathology Queensland, The University of Queensland Centre for Clinical Research, Brisbane, QLD</wicri:regionArea><wicri:noRegion>QLD</wicri:noRegion></affiliation></author><author><name sortKey="Penault Llorca, Frederique" sort="Penault Llorca, Frederique" uniqKey="Penault Llorca F" first="Frederique" last="Penault-Llorca">Frederique Penault-Llorca</name><affiliation wicri:level="3"><nlm:affiliation>ERTICa Research Team, Department of Pathology, Jean Perrin Comprehensive Cancer Center, University of Auvergne EA4677, Clermont-Ferrand, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>ERTICa Research Team, Department of Pathology, Jean Perrin Comprehensive Cancer Center, University of Auvergne EA4677, Clermont-Ferrand</wicri:regionArea><placeName><region type="region">Auvergne-Rhône-Alpes</region><region type="old region">Auvergne (région administrative)</region><settlement type="city">Clermont-Ferrand</settlement></placeName></affiliation></author><author><name sortKey="Pruneri, Giancarlo" sort="Pruneri, Giancarlo" uniqKey="Pruneri G" first="Giancarlo" last="Pruneri">Giancarlo Pruneri</name><affiliation wicri:level="3"><nlm:affiliation>Division of Pathology and Laboratory Medicine, University of Milan, Milan, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Division of Pathology and Laboratory Medicine, University of Milan, Milan</wicri:regionArea><placeName><settlement type="city">Milan</settlement><region nuts="2">Lombardie</region></placeName></affiliation></author><author><name sortKey="Radosevic Robin, Nina" sort="Radosevic Robin, Nina" uniqKey="Radosevic Robin N" first="Nina" last="Radosevic-Robin">Nina Radosevic-Robin</name><affiliation wicri:level="3"><nlm:affiliation>ERTICa Research Team, Department of Pathology, Jean Perrin Comprehensive Cancer Center, University of Auvergne EA4677, Clermont-Ferrand, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>ERTICa Research Team, Department of Pathology, Jean Perrin Comprehensive Cancer Center, University of Auvergne EA4677, Clermont-Ferrand</wicri:regionArea><placeName><region type="region">Auvergne-Rhône-Alpes</region><region type="old region">Auvergne (région administrative)</region><settlement type="city">Clermont-Ferrand</settlement></placeName></affiliation></author><author><name sortKey="Rimm, David L" sort="Rimm, David L" uniqKey="Rimm D" first="David L" last="Rimm">David L. Rimm</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, Yale University School of Medicine, New Haven, CT</wicri:regionArea><placeName><region type="state">Connecticut</region></placeName></affiliation></author><author><name sortKey="Schnitt, Stuart J" sort="Schnitt, Stuart J" uniqKey="Schnitt S" first="Stuart J" last="Schnitt">Stuart J. Schnitt</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Sinn, Bruno V" sort="Sinn, Bruno V" uniqKey="Sinn B" first="Bruno V" last="Sinn">Bruno V. Sinn</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Sinn, Peter" sort="Sinn, Peter" uniqKey="Sinn P" first="Peter" last="Sinn">Peter Sinn</name><affiliation wicri:level="3"><nlm:affiliation>Sektion Gynäkopathologie, Pathologisches Institut, University of Heidelberg, Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Sektion Gynäkopathologie, Pathologisches Institut, University of Heidelberg, 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="Sirtaine, Nicolas" sort="Sirtaine, Nicolas" uniqKey="Sirtaine N" first="Nicolas" last="Sirtaine">Nicolas Sirtaine</name><affiliation wicri:level="3"><nlm:affiliation>Anatomie Pathologique, Institut Jules Bordet, Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Anatomie Pathologique, Institut Jules Bordet, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName></affiliation></author><author><name sortKey="O Toole, Sandra A" sort="O Toole, Sandra A" uniqKey="O Toole S" first="Sandra A" last="O'Toole">Sandra A. O'Toole</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Diagnostic Oncology, Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Molecular Diagnostic Oncology, Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW</wicri:regionArea><wicri:noRegion>NSW</wicri:noRegion></affiliation></author><author><name sortKey="Viale, Giuseppe" sort="Viale, Giuseppe" uniqKey="Viale G" first="Giuseppe" last="Viale">Giuseppe Viale</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, European Institute of Oncology, University of Milan, Milan, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Pathology, European Institute of Oncology, University of Milan, Milan</wicri:regionArea><placeName><settlement type="city">Milan</settlement><region nuts="2">Lombardie</region></placeName></affiliation></author><author><name sortKey="Van De Vijver, Koen" sort="Van De Vijver, Koen" uniqKey="Van De Vijver K" first="Koen" last="Van De Vijver">Koen Van De Vijver</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pathology, 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="De Wind, Roland" sort="De Wind, Roland" uniqKey="De Wind R" first="Roland" last="De Wind">Roland De Wind</name><affiliation wicri:level="3"><nlm:affiliation>Jules Bordet Institute, Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Jules Bordet Institute, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName></affiliation></author><author><name sortKey="Von Minckwitz, Gunter" sort="Von Minckwitz, Gunter" uniqKey="Von Minckwitz G" first="Gunter" last="Von Minckwitz">Gunter Von Minckwitz</name><affiliation wicri:level="1"><nlm:affiliation>German Breast Group (GBG), Neu-Isenburg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Breast Group (GBG), Neu-Isenburg</wicri:regionArea><wicri:noRegion>Neu-Isenburg</wicri:noRegion><wicri:noRegion>Neu-Isenburg</wicri:noRegion><wicri:noRegion>Neu-Isenburg</wicri:noRegion></affiliation></author><author><name sortKey="Klauschen, Frederick" sort="Klauschen, Frederick" uniqKey="Klauschen F" first="Frederick" last="Klauschen">Frederick Klauschen</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Untch, Michael" sort="Untch, Michael" uniqKey="Untch M" first="Michael" last="Untch">Michael Untch</name><affiliation wicri:level="3"><nlm:affiliation>Department of Gynecology, Helios-Klinikum Berlin-Buch, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gynecology, Helios-Klinikum Berlin-Buch, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Fasching, Peter A" sort="Fasching, Peter A" uniqKey="Fasching P" first="Peter A" last="Fasching">Peter A. Fasching</name><affiliation wicri:level="3"><nlm:affiliation>Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen EMN, Friedrich-Alexander University Erlangen, Erlangen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen EMN, Friedrich-Alexander University Erlangen, Erlangen</wicri:regionArea><placeName><settlement type="city">Erlangen</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Moyenne-Franconie</region></placeName></affiliation></author><author><name sortKey="Reimer, Toralf" sort="Reimer, Toralf" uniqKey="Reimer T" first="Toralf" last="Reimer">Toralf Reimer</name><affiliation wicri:level="1"><nlm:affiliation>Department of Gynecology, Klinikum Südstadt Rostock, Rostock, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gynecology, Klinikum Südstadt Rostock, Rostock</wicri:regionArea><wicri:noRegion>Rostock</wicri:noRegion><wicri:noRegion>Rostock</wicri:noRegion><wicri:noRegion>Rostock</wicri:noRegion></affiliation></author><author><name sortKey="Willard Gallo, Karen" sort="Willard Gallo, Karen" uniqKey="Willard Gallo K" first="Karen" last="Willard-Gallo">Karen Willard-Gallo</name><affiliation wicri:level="3"><nlm:affiliation>Molecular Immunology Unit, Institut Jules Bordet, Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Molecular Immunology Unit, Institut Jules Bordet, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName></affiliation></author><author><name sortKey="Michiels, Stefan" sort="Michiels, Stefan" uniqKey="Michiels S" first="Stefan" last="Michiels">Stefan Michiels</name><affiliation wicri:level="1"><nlm:affiliation>Service de Biostatistique et d'Epidémiologie, Gustave Roussy, CESP, Inserm U1018, Univ. Paris Sud, Univ. Paris-Saclay, Villejuif, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Service de Biostatistique et d'Epidémiologie, Gustave Roussy, CESP, Inserm U1018, Univ. Paris Sud, Univ. Paris-Saclay, Villejuif</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Loi, Sherene" sort="Loi, Sherene" uniqKey="Loi S" first="Sherene" last="Loi">Sherene Loi</name><affiliation wicri:level="1"><nlm:affiliation>Division of Research and Clinical Medicine, Peter MacCallum Cancer Center, Melbourne, VIC, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Division of Research and Clinical Medicine, Peter MacCallum Cancer Center, Melbourne, VIC</wicri:regionArea><wicri:noRegion>VIC</wicri:noRegion></affiliation></author><author><name sortKey="Salgado, Roberto" sort="Salgado, Roberto" uniqKey="Salgado R" first="Roberto" last="Salgado">Roberto Salgado</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology and Cytology GZA Hospitals, Wilrijk, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Pathology and Cytology GZA Hospitals, Wilrijk</wicri:regionArea><wicri:noRegion>Wilrijk</wicri:noRegion></affiliation></author></analytic><series><title level="j">Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc</title><idno type="eISSN">1530-0285</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Multiple independent studies have shown that tumor-infiltrating lymphocytes (TIL) are prognostic in breast cancer with potential relevance for response to immune-checkpoint inhibitor therapy. Although many groups are currently evaluating TIL, there is no standardized system for diagnostic applications. This study reports the results of two ring studies investigating TIL conducted by the International Working Group on Immuno-oncology Biomarkers. The study aim was to determine the intraclass correlation coefficient (ICC) for evaluation of TIL by different pathologists. A total of 120 slides were evaluated by a large group of pathologists with a web-based system in ring study 1 and a more advanced software-system in ring study 2 that included an integrated feedback with standardized reference images. The predefined aim for successful ring studies 1 and 2 was an ICC above 0.7 (lower limit of 95% confidence interval (CI)). In ring study 1 the prespecified endpoint was not reached (ICC: 0.70; 95% CI: 0.62-0.78). On the basis of an analysis of sources of variation, we developed a more advanced digital image evaluation system for ring study 2, which improved the ICC to 0.89 (95% CI: 0.85-0.92). The Fleiss' kappa value for <60 vs ≥60% TIL improved from 0.45 (ring study 1) to 0.63 in RS2 and the mean concordance improved from 88 to 92%. This large international standardization project shows that reproducible evaluation of TIL is feasible in breast cancer. This opens the way for standardized reporting of tumor immunological parameters in clinical studies and diagnostic practice. The software-guided image evaluation approach used in ring study 2 may be of value as a tool for evaluation of TIL in clinical trials and diagnostic practice. The experience gained from this approach might be applicable to the standardization of other diagnostic parameters in histopathology.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>Autriche</li><li>Belgique</li><li>Canada</li><li>France</li><li>Italie</li><li>Pays-Bas</li><li>Pologne</li><li>Qatar</li><li>États-Unis</li></country><region><li>Auvergne (région administrative)</li><li>Auvergne-Rhône-Alpes</li><li>Bade-Wurtemberg</li><li>Basse-Saxe</li><li>Bavière</li><li>Berlin</li><li>Connecticut</li><li>District de Karlsruhe</li><li>District de Moyenne-Franconie</li><li>Hollande-Septentrionale</li><li>Indiana</li><li>Lombardie</li><li>Massachusetts</li><li>Ontario</li><li>Pennsylvanie</li><li>Région de Bruxelles-Capitale</li><li>Vienne (Autriche)</li><li>État de New York</li></region><settlement><li>Amsterdam</li><li>Berlin</li><li>Bruxelles</li><li>Clermont-Ferrand</li><li>Erlangen</li><li>Hamilton (Ontario)</li><li>Hanovre</li><li>Heidelberg</li><li>Milan</li><li>Vienne (Autriche)</li></settlement><orgName><li>Université McMaster</li></orgName></list><tree><country name="Allemagne"><region name="Berlin"><name sortKey="Denkert, Carsten" sort="Denkert, Carsten" uniqKey="Denkert C" first="Carsten" last="Denkert">Carsten Denkert</name></region><name sortKey="Budczies, Jan" sort="Budczies, Jan" uniqKey="Budczies J" first="Jan" last="Budczies">Jan Budczies</name><name sortKey="Christgen, Matthias" sort="Christgen, Matthias" uniqKey="Christgen M" first="Matthias" last="Christgen">Matthias Christgen</name><name sortKey="Fasching, Peter A" sort="Fasching, Peter A" uniqKey="Fasching P" first="Peter A" last="Fasching">Peter A. Fasching</name><name sortKey="Ingold Heppner, Barbara" sort="Ingold Heppner, Barbara" uniqKey="Ingold Heppner B" first="Barbara" last="Ingold Heppner">Barbara Ingold Heppner</name><name sortKey="Klauschen, Frederick" sort="Klauschen, Frederick" uniqKey="Klauschen F" first="Frederick" last="Klauschen">Frederick Klauschen</name><name sortKey="Kreipe, Hans H" sort="Kreipe, Hans H" uniqKey="Kreipe H" first="Hans H" last="Kreipe">Hans H. Kreipe</name><name sortKey="Loibl, Sibylle" sort="Loibl, Sibylle" uniqKey="Loibl S" first="Sibylle" last="Loibl">Sibylle Loibl</name><name sortKey="Reimer, Toralf" sort="Reimer, Toralf" uniqKey="Reimer T" first="Toralf" last="Reimer">Toralf Reimer</name><name sortKey="Sinn, Bruno V" sort="Sinn, Bruno V" uniqKey="Sinn B" first="Bruno V" last="Sinn">Bruno V. Sinn</name><name sortKey="Sinn, Peter" sort="Sinn, Peter" uniqKey="Sinn P" first="Peter" last="Sinn">Peter Sinn</name><name sortKey="Untch, Michael" sort="Untch, Michael" uniqKey="Untch M" first="Michael" last="Untch">Michael Untch</name><name sortKey="Von Minckwitz, Gunter" sort="Von Minckwitz, Gunter" uniqKey="Von Minckwitz G" first="Gunter" last="Von Minckwitz">Gunter Von Minckwitz</name><name sortKey="Wienert, Stephan" sort="Wienert, Stephan" uniqKey="Wienert S" first="Stephan" last="Wienert">Stephan Wienert</name></country><country name="France"><noRegion><name sortKey="Poterie, Audrey" sort="Poterie, Audrey" uniqKey="Poterie A" first="Audrey" last="Poterie">Audrey Poterie</name></noRegion><name sortKey="Michiels, Stefan" sort="Michiels, Stefan" uniqKey="Michiels S" first="Stefan" last="Michiels">Stefan Michiels</name><name sortKey="Penault Llorca, Frederique" sort="Penault Llorca, Frederique" uniqKey="Penault Llorca F" first="Frederique" last="Penault-Llorca">Frederique Penault-Llorca</name><name sortKey="Radosevic Robin, Nina" sort="Radosevic Robin, Nina" uniqKey="Radosevic Robin N" first="Nina" last="Radosevic-Robin">Nina Radosevic-Robin</name></country><country name="États-Unis"><region name="Indiana"><name sortKey="Badve, Sunil" sort="Badve, Sunil" uniqKey="Badve S" first="Sunil" last="Badve">Sunil Badve</name></region><name sortKey="Brock, Jane" sort="Brock, Jane" uniqKey="Brock J" first="Jane" last="Brock">Jane Brock</name><name sortKey="Demaria, Sandra" sort="Demaria, Sandra" uniqKey="Demaria S" first="Sandra" last="Demaria">Sandra Demaria</name><name sortKey="Kim, S Rim" sort="Kim, S Rim" uniqKey="Kim S" first="S Rim" last="Kim">S Rim Kim</name><name sortKey="Rimm, David L" sort="Rimm, David L" uniqKey="Rimm D" first="David L" last="Rimm">David L. Rimm</name><name sortKey="Schnitt, Stuart J" sort="Schnitt, Stuart J" uniqKey="Schnitt S" first="Stuart J" last="Schnitt">Stuart J. Schnitt</name></country><country name="Autriche"><region name="Vienne (Autriche)"><name sortKey="Bago Horvath, Zsuzsanna" sort="Bago Horvath, Zsuzsanna" uniqKey="Bago Horvath Z" first="Zsuzsanna" last="Bago-Horvath">Zsuzsanna Bago-Horvath</name></region></country><country name="Canada"><region name="Ontario"><name sortKey="Bane, Anita" sort="Bane, Anita" uniqKey="Bane A" first="Anita" last="Bane">Anita Bane</name></region><name sortKey="Gao, Dongxia" sort="Gao, Dongxia" uniqKey="Gao D" first="Dongxia" last="Gao">Dongxia Gao</name><name sortKey="Kos, Zuzana" sort="Kos, Zuzana" uniqKey="Kos Z" first="Zuzana" last="Kos">Zuzana Kos</name></country><country name="Qatar"><noRegion><name sortKey="Bedri, Shahinaz" sort="Bedri, Shahinaz" uniqKey="Bedri S" first="Shahinaz" last="Bedri">Shahinaz Bedri</name></noRegion></country><country name="Pologne"><noRegion><name sortKey="Chmielik, Ewa" sort="Chmielik, Ewa" uniqKey="Chmielik E" first="Ewa" last="Chmielik">Ewa Chmielik</name></noRegion></country><country name="Belgique"><noRegion><name sortKey="Colpaert, Cecile" sort="Colpaert, Cecile" uniqKey="Colpaert C" first="Cecile" last="Colpaert">Cecile Colpaert</name></noRegion><name sortKey="De Wind, Roland" sort="De Wind, Roland" uniqKey="De Wind R" first="Roland" last="De Wind">Roland De Wind</name><name sortKey="Floris, Giuseppe" sort="Floris, Giuseppe" uniqKey="Floris G" first="Giuseppe" last="Floris">Giuseppe Floris</name><name sortKey="Salgado, Roberto" sort="Salgado, Roberto" uniqKey="Salgado R" first="Roberto" last="Salgado">Roberto Salgado</name><name sortKey="Sirtaine, Nicolas" sort="Sirtaine, Nicolas" uniqKey="Sirtaine N" first="Nicolas" last="Sirtaine">Nicolas Sirtaine</name><name sortKey="Van Den Eynden, Gert" sort="Van Den Eynden, Gert" uniqKey="Van Den Eynden G" first="Gert" last="Van Den Eynden">Gert Van Den Eynden</name><name sortKey="Willard Gallo, Karen" sort="Willard Gallo, Karen" uniqKey="Willard Gallo K" first="Karen" last="Willard-Gallo">Karen Willard-Gallo</name></country><country name="Australie"><noRegion><name sortKey="Fox, Stephen B" sort="Fox, Stephen B" uniqKey="Fox S" first="Stephen B" last="Fox">Stephen B. Fox</name></noRegion><name sortKey="Lakhani, Sunil R" sort="Lakhani, Sunil R" uniqKey="Lakhani S" first="Sunil R" last="Lakhani">Sunil R. Lakhani</name><name sortKey="Loi, Sherene" sort="Loi, Sherene" uniqKey="Loi S" first="Sherene" last="Loi">Sherene Loi</name><name sortKey="O Toole, Sandra A" sort="O Toole, Sandra A" uniqKey="O Toole S" first="Sandra A" last="O'Toole">Sandra A. O'Toole</name></country><country name="Italie"><region name="Lombardie"><name sortKey="Pruneri, Giancarlo" sort="Pruneri, Giancarlo" uniqKey="Pruneri G" first="Giancarlo" last="Pruneri">Giancarlo Pruneri</name></region><name sortKey="Viale, Giuseppe" sort="Viale, Giuseppe" uniqKey="Viale G" first="Giuseppe" last="Viale">Giuseppe Viale</name></country><country name="Pays-Bas"><region name="Hollande-Septentrionale"><name sortKey="Van De Vijver, Koen" sort="Van De Vijver, Koen" uniqKey="Van De Vijver K" first="Koen" last="Van De Vijver">Koen Van De Vijver</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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