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1. Slow integrin-dependent migration organizes networks of tissue-resident mast cells

Author

Kaltenbach, Lukas, Martzloff, Paloma, Bambach, Sarah K., Aizarani, Nadim, Mihlan, Michael, Gavrilov, Alina, Glaser, Katharina M., Stecher, Manuel, Thünauer, Roland, Thiriot, Aude, Heger, Klaus, Kierdorf, Katrin, Wienert, Stephan, von Andrian, Ulrich H., Schmidt-Supprian, Marc, Nerlov, Claus, Klauschen, Frederick, Roers, Axel, Bajénoff, Marc, Grün, Dominic, and Lämmermann, Tim

Published
2023
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2. Towards computational fluorescence microscopy: Machine learning-based integrated prediction of morphological and molecular tumor profiles

Author

Binder, Alexander, Bockmayr, Michael, Hägele, Miriam, Wienert, Stephan, Heim, Daniel, Hellweg, Katharina, Stenzinger, Albrecht, Parlow, Laura, Budczies, Jan, Goeppert, Benjamin, Treue, Denise, Kotani, Manato, Ishii, Masaru, Dietel, Manfred, Hocke, Andreas, Denkert, Carsten, Müller, Klaus-Robert, and Klauschen, Frederick

Subjects
Computer Science - Computer Vision and Pattern Recognition
Abstract

Recent advances in cancer research largely rely on new developments in microscopic or molecular profiling techniques offering high level of detail with respect to either spatial or molecular features, but usually not both. Here, we present a novel machine learning-based computational approach that allows for the identification of morphological tissue features and the prediction of molecular properties from breast cancer imaging data. This integration of microanatomic information of tumors with complex molecular profiling data, including protein or gene expression, copy number variation, gene methylation and somatic mutations, provides a novel means to computationally score molecular markers with respect to their relevance to cancer and their spatial associations within the tumor microenvironment.

Published
2018

5. Dynamics of the Intratumoral Immune Response during Progression of High-Grade Serous Ovarian Cancer

Author

Stanske, Mandy, Wienert, Stephan, Castillo-Tong, Dan Cacsire, Kreuzinger, Caroline, Vergote, Ignace, Lambrechts, Sandrijne, Gabra, Hani, Gourley, Charlie, Ganapathi, Ram N., Kolaschinski, Ivonne, Budczies, Jan, Sehouli, Jalid, Ruscito, Ilary, Denkert, Carsten, Kulbe, Hagen, Schmitt, Wolfgang, Jöhrens, Korinna, Braicu, Ioana, and Darb-Esfahani, Silvia

Published
2018
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6. Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Author

Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K., Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H., Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M., Horlings, Hugo M., Hudeček, Jan, Ciompi, Francesco, Moore, David A., Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K., Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P., Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J., Lakhani, Sunil R., Rojo, Federico, Comerma, Laura, Badve, Sunil S., Khojasteh, Mehrnoush, Symmans, W. Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L., Kim, Rim S., Rimm, David L., Viale, Giuseppe, Hewitt, Stephen M., Bartlett, John M. S., Penault-Llorca, Frédérique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G., Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O., Lazar, Alexander J., Bago-Horvath, Zsuzsanna, Kooreman, Loes F. S., van der Laak, Jeroen A. W. M., Saltz, Joel, Gallas, Brandon D., Kurkure, Uday, Barnes, Michael, Salgado, Roberto, and Cooper, Lee A. D.

Published
2020
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7. Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Author

Kos, Zuzana, Roblin, Elvire, Kim, Rim S., Michiels, Stefan, Gallas, Brandon D., Chen, Weijie, van de Vijver, Koen K., Goel, Shom, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O., Badve, Sunil S., Symmans, W. Fraser, Sotiriou, Christos, Rimm, David L., Hewitt, Stephen, Denkert, Carsten, Loibl, Sibylle, Luen, Stephen J., Bartlett, John M. S., Savas, Peter, Pruneri, Giancarlo, Dillon, Deborah A., Cheang, Maggie Chon U., Tutt, Andrew, Hall, Jacqueline A., Kok, Marleen, Horlings, Hugo M., Madabhushi, Anant, van der Laak, Jeroen, Ciompi, Francesco, Laenkholm, Anne-Vibeke, Bellolio, Enrique, Gruosso, Tina, Fox, Stephen B., Araya, Juan Carlos, Floris, Giuseppe, Hudeček, Jan, Voorwerk, Leonie, Beck, Andrew H., Kerner, Jen, Larsimont, Denis, Declercq, Sabine, Van den Eynden, Gert, Pusztai, Lajos, Ehinger, Anna, Yang, Wentao, AbdulJabbar, Khalid, Yuan, Yinyin, Singh, Rajendra, Hiley, Crispin, Bakir, Maise al, Lazar, Alexander J., Naber, Stephen, Wienert, Stephan, Castillo, Miluska, Curigliano, Giuseppe, Dieci, Maria-Vittoria, André, Fabrice, Swanton, Charles, Reis-Filho, Jorge, Sparano, Joseph, Balslev, Eva, Chen, I-Chun, Stovgaard, Elisabeth Ida Specht, Pogue-Geile, Katherine, Blenman, Kim R. M., Penault-Llorca, Frédérique, Schnitt, Stuart, Lakhani, Sunil R., Vincent-Salomon, Anne, Rojo, Federico, Braybrooke, Jeremy P., Hanna, Matthew G., Soler-Monsó, M. Teresa, Bethmann, Daniel, Castaneda, Carlos A., Willard-Gallo, Karen, Sharma, Ashish, Lien, Huang-Chun, Fineberg, Susan, Thagaard, Jeppe, Comerma, Laura, Gonzalez-Ericsson, Paula, Brogi, Edi, Loi, Sherene, Saltz, Joel, Klaushen, Frederick, Cooper, Lee, Amgad, Mohamed, Moore, David A., and Salgado, Roberto

Published
2020
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8. Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer: results of the ring studies of the international immuno-oncology biomarker working group

Author

Denkert, Carsten, Wienert, Stephan, Poterie, Audrey, Loibl, Sibylle, Budczies, Jan, Badve, Sunil, Bago-Horvath, Zsuzsanna, Bane, Anita, Bedri, Shahinaz, Brock, Jane, Chmielik, Ewa, Christgen, Matthias, Colpaert, Cecile, Demaria, Sandra, Van den Eynden, Gert, Floris, Giuseppe, Fox, Stephen B, Gao, Dongxia, Ingold Heppner, Barbara, Kim, S Rim, Kos, Zuzana, Kreipe, Hans H, Lakhani, Sunil R, Penault-Llorca, Frederique, Pruneri, Giancarlo, Radosevic-Robin, Nina, Rimm, David L, Schnitt, Stuart J, Sinn, Bruno V, Sinn, Peter, Sirtaine, Nicolas, O'Toole, Sandra A, Viale, Giuseppe, Van de Vijver, Koen, de Wind, Roland, von Minckwitz, Gunter, Klauschen, Frederick, Untch, Michael, Fasching, Peter A, Reimer, Toralf, Willard-Gallo, Karen, Michiels, Stefan, Loi, Sherene, and Salgado, Roberto

Published
2016
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9. Supplemental Methods, Figures 1-2, Table S1 from Standardized Ki67 Diagnostics Using Automated Scoring—Clinical Validation in the GeparTrio Breast Cancer Study

Author

Klauschen, Frederick, primary, Wienert, Stephan, primary, Schmitt, Wolfgang D., primary, Loibl, Sibylle, primary, Gerber, Bernd, primary, Blohmer, Jens-Uwe, primary, Huober, Jens, primary, Rüdiger, Thomas, primary, Erbstößer, Erhard, primary, Mehta, Keyur, primary, Lederer, Bianca, primary, Dietel, Manfred, primary, Denkert, Carsten, primary, and von Minckwitz, Gunter, primary

Published
2023
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12. Slow integrin-dependent migration organizes networks of tissue-resident mast cells

Author

Bambach, Sarah K., primary, Kaltenbach, Lukas, additional, Aizarani, Nadim, additional, Martzloff, Paloma, additional, Gavrilov, Alina, additional, Glaser, Katharina M., additional, Thünauer, Roland, additional, Mihlan, Michael, additional, Stecher, Manuel, additional, Thiriot, Aude, additional, Wienert, Stephan, additional, von Andrian, Ulrich, additional, Schmidt-Supprian, Marc, additional, Nerlov, Claus, additional, Klauschen, Frederick, additional, Roers, Axel, additional, Bajénoff, Marc, additional, Grün, Dominic, additional, and Lämmermann, Tim, additional

Published
2022
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13. Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non–Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors

Author

Hendry, Shona, Salgado, Roberto, Gevaert, Thomas, Russell, Prudence A., John, Tom, Thapa, Bibhusal, Christie, Michael, van de Vijver, Koen, Estrada, M.V., Gonzalez-Ericsson, Paula I., Sanders, Melinda, Solomon, Benjamin, Solinas, Cinzia, Van den Eynden, Gert G.G.M., Allory, Yves, Preusser, Matthias, Hainfellner, Johannes, Pruneri, Giancarlo, Vingiani, Andrea, Demaria, Sandra, Symmans, Fraser, Nuciforo, Paolo, Comerma, Laura, Thompson, E.A., Lakhani, Sunil, Kim, Seong-Rim, Schnitt, Stuart, Colpaert, Cecile, Sotiriou, Christos, Scherer, Stefan J., Ignatiadis, Michail, Badve, Sunil, Pierce, Robert H., Viale, Giuseppe, Sirtaine, Nicolas, Penault-Llorca, Frederique, Sugie, Tomohagu, Fineberg, Susan, Paik, Soonmyung, Srinivasan, Ashok, Richardson, Andrea, Wang, Yihong, Chmielik, Ewa, Brock, Jane, Johnson, Douglas B., Balko, Justin, Wienert, Stephan, Bossuyt, Veerle, Michiels, Stefan, Ternes, Nils, Burchardi, Nicole, Luen, Stephen J., Savas, Peter, Klauschen, Frederick, Watson, Peter H., Nelson, Brad H., Criscitiello, Carmen, O’Toole, Sandra, Larsimont, Denis, de Wind, Roland, Curigliano, Giuseppe, André, Fabrice, Lacroix-Triki, Magali, van de Vijver, Mark, Rojo, Federico, Floris, Giuseppe, Bedri, Shahinaz, Sparano, Joseph, Rimm, David, Nielsen, Torsten, Kos, Zuzana, Hewitt, Stephen, Singh, Baljit, Farshid, Gelareh, Loibl, Sibylle, Allison, Kimberly H., Tung, Nadine, Adams, Sylvia, Willard-Gallo, Karen, Horlings, Hugo M., Gandhi, Leena, Moreira, Andre, Hirsch, Fred, Dieci, Maria V., Urbanowicz, Maria, Brcic, Iva, Korski, Konstanty, Gaire, Fabien, Koeppen, Hartmut, Lo, Amy, Giltnane, Jennifer, Rebelatto, Marlon C., Steele, Keith E., Zha, Jiping, Emancipator, Kenneth, Juco, Jonathan W., Denkert, Carsten, Reis-Filho, Jorge, Loi, Sherene, and Fox, Stephen B.

Published
2017
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14. Assessing Tumor-infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method From the International Immunooncology Biomarkers Working Group: Part 1: Assessing the Host Immune Response, TILs in Invasive Breast Carcinoma and Ductal Carcinoma In Situ, Metastatic Tumor Deposits and Areas for Further Research

Author

Hendry, Shona, Salgado, Roberto, Gevaert, Thomas, Russell, Prudence A., John, Tom, Thapa, Bibhusal, Christie, Michael, van de Vijver, Koen, Estrada, M.V., Gonzalez-Ericsson, Paula I., Sanders, Melinda, Solomon, Benjamin, Solinas, Cinzia, Van den Eynden, Gert G.G.M., Allory, Yves, Preusser, Matthias, Hainfellner, Johannes, Pruneri, Giancarlo, Vingiani, Andrea, Demaria, Sandra, Symmans, Fraser, Nuciforo, Paolo, Comerma, Laura, Thompson, E.A., Lakhani, Sunil, Kim, Seong-Rim, Schnitt, Stuart, Colpaert, Cecile, Sotiriou, Christos, Scherer, Stefan J., Ignatiadis, Michail, Badve, Sunil, Pierce, Robert H., Viale, Giuseppe, Sirtaine, Nicolas, Penault-Llorca, Frederique, Sugie, Tomohagu, Fineberg, Susan, Paik, Soonmyung, Srinivasan, Ashok, Richardson, Andrea, Wang, Yihong, Chmielik, Ewa, Brock, Jane, Johnson, Douglas B., Balko, Justin, Wienert, Stephan, Bossuyt, Veerle, Michiels, Stefan, Ternes, Nils, Burchardi, Nicole, Luen, Stephen J., Savas, Peter, Klauschen, Frederick, Watson, Peter H., Nelson, Brad H., Criscitiello, Carmen, O’Toole, Sandra, Larsimont, Denis, de Wind, Roland, Curigliano, Giuseppe, André, Fabrice, Lacroix-Triki, Magali, van de Vijver, Mark, Rojo, Federico, Floris, Giuseppe, Bedri, Shahinaz, Sparano, Joseph, Rimm, David, Nielsen, Torsten, Kos, Zuzana, Hewitt, Stephen, Singh, Baljit, Farshid, Gelareh, Loibl, Sibylle, Allison, Kimberly H., Tung, Nadine, Adams, Sylvia, Willard-Gallo, Karen, Horlings, Hugo M., Gandhi, Leena, Moreira, Andre, Hirsch, Fred, Dieci, Maria V., Urbanowicz, Maria, Brcic, Iva, Korski, Konstanty, Gaire, Fabien, Koeppen, Hartmut, Lo, Amy, Giltnane, Jennifer, Rebelatto, Marlon C., Steele, Keith E., Zha, Jiping, Emancipator, Kenneth, Juco, Jonathan W., Denkert, Carsten, Reis-Filho, Jorge, Loi, Sherene, and Fox, Stephen B.

Published
2017
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15. Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: A report of the International Immuno- Oncology Biomarker Working Group on Breast Cancer

Author

Dieci, Maria Vittoria, Radosevic-Robin, Nina, Fineberg, Susan, Van den Eynden, Gert, Ternes, Nils, Pénault-Llorca, Frederique, Pruneri, Giancarlo, D'Alfonso, Timothy TM, Demaria, Sandra, Castaneda, Carlos, Sanchez, Joselyn, Badve, Sunil, Michiels, Stefan, Bossuyt, Veerle Ilse Julie, Rojo, Federico, Singh, Baljit, Nielsen, Torsten, Viale, Giuseppe, Kim, Seong-Rim, Hewitt, Stephen M, Wienert, Stephan, Loibl, Sibylle, Rimm, David D.L., Symmans, Fraser, Denkert, Carsten, Adams, Sylvia, Loi, Sherene, Salgado, Roberto, International Immuno-Oncology Biomarker Working Group on Breast Cancer, Universita degli Studi di Padova, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), European Institute of Oncology [Milan] (ESMO), Ctr Biomol Struct & Org, University of Maryland [College Park], University of Maryland System-University of Maryland System, Università degli Studi di Padova = University of Padua (Unipd), Equipe de recherche sur les traitements individualisés des cancers (ERTICa), Université d'Auvergne - Clermont-Ferrand I (UdA), Méthodologie et épidémiologie clinique en oncologie moléculaire (U1018 (Équipe 2)), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR), Division of Pathology and Laboratory Medicine, Università degli Studi di Milano = University of Milan (UNIMI)-European Institute of Oncology [Milan] (ESMO), Charité, Institute of Pathology, Translational Tumorpathology Unit, Breast Cancer Translational Research Laboratory, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), and Università degli Studi di Milano [Milano] (UNIMI)-European Institute of Oncology [Milan] (ESMO)

Subjects
0301 basic medicine, Oncology, Cancer Research, Neoplasm, Residual, medicine.medical_treatment, Carcinoma in Situ -- immunology, Medical Oncology, Tumor-infiltrating lymphocytes, Biomarkers, Tumor -- immunology, Breast cancer, 0302 clinical medicine, Trastuzumab, Neoplasm, Residual -- immunology, Neoadjuvant therapy, hemic and immune systems, Neoadjuvant Therapy -- methods, Sciences bio-médicales et agricoles, Neoadjuvant Therapy, 3. Good health, 030220 oncology & carcinogenesis, Breast Neoplasms -- immunology, Female, Neoadjuvant, Carcinoma in Situ, medicine.drug, Residual cancer burden, medicine.medical_specialty, Medical Oncology -- methods, Breast Neoplasms, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, breast cancer, ductal carcinoma in situ, neoadjuvant, residual cancer burden, residual disease, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Internal medicine, Biomarkers, Tumor, medicine, Humans, Cancer staging, Tumor marker, business.industry, Carcinoma in situ, Ductal carcinoma in situ, Residual disease, Ductal carcinoma, medicine.disease, Minimal residual disease, 030104 developmental biology, business, Lymphocytes, Tumor-Infiltrating -- immunology
Abstract

Morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer is gaining momentum as evidence strengthens the clinical relevance of this immunological biomarker. TILs in the post-neoadjuvant residual disease setting are acquiring increasing importance as a stratifying marker in clinical trials, considering the raising interest on immunotherapeutic strategies after neoadjuvant chemotherapy. TILs in ductal carcinoma in situ, with or without invasive carcinoma, represent an emerging area of clinical breast cancer research. The aim of this report is to update pathologists, clinicians and researchers on TIL assessment in both the post-neoadjuvant residual disease and the ductal carcinoma in situ settings. The International Immuno-Oncology Working Group proposes a method for assessing TILs in these settings, based on the previously published International Guidelines on TIL Assessment in Breast Cancer. In this regard, these recommendations represent a consensus guidance for pathologists, aimed to achieve the highest possible consistency among future studies., info:eu-repo/semantics/published

Published
2018

16. Epidermal gamma delta T cells originate from yolk sac hematopoiesis and clonally self-renew in the adult

Author

Gentek, Rebecca, Ghigo, Clement, Hoeffel, Guillaume, Jorquera, Audrey, Msallam, Rasha, Wienert, Stephan, Klauschen, Frederick, Ginhoux, Florent, Bajenoff, Marc, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
integumentary system, [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract

The murine epidermis harbors two immune cell lineages, Langerhans cells (LCs) and gamma delta T cells known as dendritic epidermal T cells (DETCs). LCs develop from both early yolk sac (YS) progenitors and fetal liver monocytes before locally self-renewing in the adult. For DETCs, the mechanisms of homeostatic maintenance and their hematopoietic origin are largely unknown. Here, we exploited multicolor fate mapping systems to reveal that DETCs slowly turn over at steady state. Like for LCs, homeostatic maintenance of DETCs is achieved by clonal expansion of tissue-resident cells assembled in proliferative units. The same mechanism, albeit accelerated, facilitates DETC replenishment upon injury. Hematopoietic lineage tracing uncovered that DETCs are established independently of definitive hematopoietic stem cells and instead originate from YS hematopoiesis, again reminiscent of LCs. DETCs thus resemble LCs concerning their maintenance, replenishment mechanisms, and hematopoietic development, suggesting that the epidermal microenvironment exerts a lineage-independent influence on the initial seeding and homeostatic maintenance of its resident immune cells.

Published
2018

17. Tissue clonality of dendritic cell subsets and emergency DCpoiesis revealed by multicolor fate mapping of DC progenitors

Author

Cabeza-Cabrerizo, Mar, primary, van Blijswijk, Janneke, additional, Wienert, Stephan, additional, Heim, Daniel, additional, Jenkins, Robert P., additional, Chakravarty, Probir, additional, Rogers, Neil, additional, Frederico, Bruno, additional, Acton, Sophie, additional, Beerling, Evelyne, additional, van Rheenen, Jacco, additional, Clevers, Hans, additional, Schraml, Barbara U., additional, Bajénoff, Marc, additional, Gerner, Michael, additional, Germain, Ronald N., additional, Sahai, Erik, additional, Klauschen, Frederick, additional, and Reis e Sousa, Caetano, additional

Published
2019
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20. Integration and acceleration of virtual microscopy as the key to successful implementation into the routine diagnostic process

Author

Hufnagl Peter, Saeger Kai, Beil Michael, Wienert Stephan, and Schrader Thomas

Subjects
Pathology, RB1-214
Abstract

Abstract Background The virtual microscopy is widely accepted in Pathology for educational purposes and teleconsultation but is far from the routine use in surgical pathology due to the technical requirements and some limitations. A technical problem is the limited bandwidth of a usual network and the delayed transmission rate and presentation time on the screen. Methods In this study the process of secondary diagnostic was evaluated using the "T.Konsult Pathologie" service of the Professional Association of German Pathologists within the German breast cancer screening program. The characteristics of the access to the WSI (Whole Slide Images) have been analyzed to explore the possibilities of prefetching and caching to reduce the presentation and transfer time with the goal to increase user acceptance. The log files of the web server were analyzed to reconstruct the movements of the pathologist on the WSI and to create the observation path. Using a specialized tool the observation paths were extracted automatically from the log files. The attributes linearity, 3-point-linearity, changes per request, and number of consecutive requests were calculated to design, develop and evaluate different caching and prefetching strategies. Results The analysis of the observation paths showed that a complete accordance of two image requests is a very rare event. But more frequently a partial covering of two requested image areas can be found. In total 257 diagnostic paths from 131 WSI have been extracted and analysed. On average a diagnostic path consists of 16 image requests and takes 189 seconds between first and last image request. The mean linearity was 0,41 and the mean 3-point-linearity 0,85. Three different caching algorithms have been compared with respect to hit rate and additional image requests on the WSI server. Tests demonstrated that 95% of the diagnostic paths could be loaded without any deletion of entries in the cache (cache size 12,2 Megapixel). If the image parts are stored after JPEG compression this complies with less than 2 MB. Discussion WSI telepathology is a technology which offers the possibility to break the limitations of conventional static telepathology. The complete histological slide may be investigated instead of sets of images of lesions sampled by the presenting pathologist. The benefit is demonstrated by the high diagnostic security of 95% accordance between first and second diagnosis.

Published
2009
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21. Assessing Tumor-infiltrating Lymphocytes in Solid Tumors

Author

John, Maria, Salgado, Roberto, Gevaert, Thomas, Russell, Prudence A, John, Tom, Thapa, Bibhusal, Christie, Michael, van de Vijver, Koen, Estrada, M V, Gonzalez-Ericsson, Paula I, Sanders, Melinda, Solomon, Benjamin, Solinas, Cinzia, van den Eynden, Gert G G M, Allory, Yves, Preusser, Matthias, Hainfellner, Johannes, Pruneri, Giancarlo, Vingiani, Andre, Demaria, Sandra, Symmans, Fraser, Nuciforo, Paolo, Comerma, Laura, Thompson, E A, Lakhani, Sunil, Kim, Seong-Rim, Schnitt, Stuart, Colpaert, Cecile, Sotiriou, Christos, Scherer, Stefan, Ignatiadis, Michail, Badve, Sunil, Pierce, Robert H, Viale, Giuseppe, Sirtaine, Nicolas, Penault-Llorca, Fred, Sugie, Tomohagu, Fineberg, Susan, Paik, Soonmyung, Srinivasan, Ashok, Richardson, Andre, Wang, Yihong, Chmielik, Ewa, Brock, Jane, Johnson, Douglas B, Balko, Justin, Wienert, Stephan, Bossuyt, Veerle, Michiels, Stefan, Ternès, Nils, Burchardi, Nicole, Luen, Stephen, Savas, Peter, Klauschen, Fred, Watson, Peter H, Nelson, Brad H, Criscitiello, Carmen, O'Toole, Sandra, Larsimont, Denis, de Wind, Roland, Curigliano, Giuseppe, André, Fabrice, Lacroix-Triki, Magali, van de Vijver, Mark, Rojo, Federico, Floris, Giuseppe, Bedri, Shahinaz, Sparano, Joseph, Rimm, David, Nielsen, Torsten, Kos, Zuzana, Hewitt, Stephen, Singh, Baljit, Farshid, Gelareh, Loi, Sibylle, Allison, Kimberly H, Tung, Nadine, Adams, Sylvia, Willard-Gallo, Karen, Horlings, Hugo M, Gandhi, Leena, Moreira, Andre, Hirsch, Fred, Dieci, Maria, Urbanowicz, Maria, Brcic, Iva, Korski, Konstanty, Gaire, Fabien, Koeppen, Hartmut, Lo, Amy, Giltnane, Jennifer, Rebelatto, Marlon C, Steele, Keith E, Zha, Jiping, Emancipator, Kenneth, Juco, Jonathan W, Denkert, Carsten, Reis-Filho, Jorge, Loi, Sherene, Fox, Stephen B, Hendry, Shona, Russell, Prudence A., Estrada, M.V., Gonzalez-Ericsson, Paula I., van den Eynden, Gert G.G.M., Thompson, E.A., Pierce, Robert H., Johnson, Douglas B., Watson, Peter H., Nelson, Brad H., O’toole, Sandra, Allison, Kimberly H., Horlings, Hugo M., Rebelatto, Marlon C., Steele, Keith E., Juco, Jonathan W., Fox, Stephen B., Breast Cancer Translational Research Laboratory, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Cancer Genetics Branch, National Institute of Health (NIH)-National Human Genome Research Institute (NHGRI), Service d'urologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Division of Pathology and Laboratory Medicine, European Institute of Oncology [Milan] (ESMO), FIRC, Institute of Molecular Oncology Foundation, Trinity College Dublin, Department of medical oncology, Università degli Studi di Milano = University of Milan (UNIMI)-European Institute of Oncology [Milan] (ESMO), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Méthodologie et épidémiologie clinique en oncologie moléculaire (U1018 (Équipe 2)), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR), Trev and Joyce Deeley Research Center, Vancouver Island Center, Division of Medical Oncology, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Département de Biologie et de Pathologie, Institut Claudius Regaud, Department of Dermatology, Helsinki University Hospital-Skin and Allergy Hospital, University of Colorado Cancer Center, University of Colorado [Denver], Charité, Institute of Pathology, Translational Tumorpathology Unit, Breakthrough Breast Cancer Centre, London Institute of Cancer, Department of Experimental Pathology & Pharmacology, Vanderbilt University School of Medicine [Nashville], Department of Pathology, Peter MacCallum Cancer Center, Università degli Studi di Milano [Milano] (UNIMI)-European Institute of Oncology [Milan] (ESMO), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)

Subjects
hemic and immune systems, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract

International audience; Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.

Published
2017

23. Long-Term Application Of Automated Ki67 Quantification In Routine Breast Cancer Diagnostics

Author

Wienert, Stephan, Klauschen, F., Loibl, S., von Minckwitz, G., and Denkert, C.

Subjects
lcsh:R5-920, lcsh:Medical technology, lcsh:R855-855.5, lcsh:R858-859.7, lcsh:Medicine (General), lcsh:Computer applications to medicine. Medical informatics
Abstract

Introduction/ Background The measurement of cell proliferation via Ki67 immunohistochemistry is an important part of tumor diagnostics leading to treatment decisions. The assessment according to the current guidelines is very time consuming which likely leads to counting only few cells or making the analysis completely estimated in many cases. Here, automated image analysis promises a standardized, time-saving and reproducible assessment. Aims We prior developed a computerized method that allows for an automated scoring of Ki67. This approach was validated with a study cohort of more than 1000 patients and showed a very high significance in both overall and disease free survival. The aim of this study was to test the capability of this method for the application in the daily routine diagnostics with the concomitant time pressure and huge variability in the patient material and staining results. Methods The developed computer algorithm and software was applied in daily routine breast cancer diagnostics under real conditions over more than one year. More than 100 cases have been analyzed. Results The retrospective analysis showed that the method was capable of accurately processing most of the images. Problems occurred when the counter staining was too weak which made it even difficult to conventionally assess those images. A user interaction was required in some cases to exclude falsely counted non-tumor cells., Diagnostic Pathology, Vol 1 No 8 (2016): 13. European Congress on Digital Pathology

Published
2016

28. Quantitative Analyse von Zell- und Gewebeeigenschaften in histologischen Bilddaten

Author

Wienert, Stephan

Subjects
histology, image analysis, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit, quantification
Abstract

Einleitung Aufgrund technischer Entwicklungen und einem wachsenden Bedarf an einer Standardisierung der qualitativen und quantitativen Auswertungen in der histopathologischen Forschung und Routinediagnostik hat das Forschungsfeld der automatisierten Mikroskop-Bild-Analyse in jüngster Zeit neue Impulse erhalten. Die automatische Detektion und Segmentierung der relevanten Strukturen, zumeist Zellkerne, ist die Grundlage für die computergestützte Messung von Zell- und Gewebeeigenschaften. Bis heute existiert hierfür allerdings keine universelle Standard-Lösung, die wichtigste Herausforderung ist hier die Heterogenität der verschiedenen Gewebe- und Tumortypen. Desweiteren ist die Pixel-basierte Modellierung von Bildanalyse-Datenstrukturen nach wie vor der weit verbreitete Standard, obwohl die Verwendung von Bild-Objekten als primäre Verarbeitungseinheit eher der menschlichen Wahrnehmung entspricht und besser für die Berechnung von Objektmerkmalen sowie für die Analyse von Nachbarschafts-Beziehungen geeignet ist. Ergebnisse In dieser Arbeit wurde eine neue Methode zur Detektion und Segmentierung von Zellkernen entwickelt, die nur minimale a-priori Informationen verwendet und dadurch auch auf typischerweise heterogene histologische Bilddaten robust anwendbar ist. Weiterhin wurde die Open-Source Software-Plattform CognitionMaster entworfen und implementiert, die eine Bild-Objekt-basierte Modellierung der Datenstrukturen enthält und damit Limitierungen der konventionellen Pixel- basierten Systeme überwindet. Dieses Framework wurde für die computergestützte Bestimmung der Anzahl von CD3-positiven T-Lymphozyten in extranodalen Marginalzonen-Lymphomen, zur Untersuchung der Homöostase von Langerhans-Zellen der Epidermis sowie zur Analyse des Ursprungs und der Funktion von follikulären Dendritischen Zellen des Lymphknotens verwendet. Schlussfolgerungen Es wurde gezeigt, dass die neu entwickelte Minimum-Modell- Methode eine robuste Detektion von Zellkernen auch bei morphologisch heterogenen Bilddaten ermöglicht. Mit der CognitionMaster Software-Plattform konnten für drei zum Teil sehr unterschiedliche Fragestellungen aus der Biologie und Pathologie erfolgreich Quantifizierungsverfahren implementiert werden, womit der proof-of-concept bereits für mehrere Problemklassen erbracht wurde., Introduction Due to technical developments and an increased demand for a standardization of qualitative and quantitative analyses in histopathological research and routine diagnostics the field of automated analysis of microscopic images has recently received new impetus. The automatic detection and segmentation of the relevant structures, mostly cell nuclei, is pivotal for the computer-aided measurement of cell and tissue features. Until today, no universal standard solution exists for this task. Here, the heterogeneity of the different tissue and tumor types is the biggest challenge. Furthermore, pixel-based modeling of data structures is still the widespread standard in digital image analysis although the usage of image objects as primary processing unit relates well to human perception and is more suitable for the computation of object features and the analysis of neighbourhood relationships. Results This thesis describes a novel approach for the detection and segmentation of cell nuclei. This method requires only minimal a-priori information and is therefore capable of dealing with typically morphologically heterogeneous histological image data. Additionally, the open source software platform CognitionMaster was designed and implemented. This framework features an image object-based modeling of data structures and therefore overcomes limitations of conventional pixel-based systems. The platform was used for the computer-aided quantification of CD3-positive T-lymphocytes in extranodal marginal zone lymphomas, for the analysis of the homeostasis of epidermal Langerhans cells and to study origin and dynamics of lymph node follicular Dendritic Cells. Conclusions It was shown that the newly developed minimum-model method allows for a robust detection of cell nuclei in morphologically heterogeneous image data. Based on the CognitionMaster platform quantification systems were set up for three different tasks in biology and pathology whereby the proof-of-concept was already provided for multiple classes of problems.

Published
2015
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30. Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma

Author

Darb-Esfahani, Silvia, primary, Kunze, Catarina Alisa, additional, Kulbe, Hagen, additional, Sehouli, Jalid, additional, Wienert, Stephan, additional, Lindner, Judith, additional, Budczies, Jan, additional, Bockmayr, Michael, additional, Dietel, Manfred, additional, Denkert, Carsten, additional, Braicu, Ioana, additional, and Jöhrens, Korinna, additional

Published
2015
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31. Standardized Ki67 Diagnostics Using Automated Scoring—Clinical Validation in the GeparTrio Breast Cancer Study

Author

Klauschen, Frederick, primary, Wienert, Stephan, additional, Schmitt, Wolfgang D., additional, Loibl, Sibylle, additional, Gerber, Bernd, additional, Blohmer, Jens-Uwe, additional, Huober, Jens, additional, Rüdiger, Thomas, additional, Erbstößer, Erhard, additional, Mehta, Keyur, additional, Lederer, Bianca, additional, Dietel, Manfred, additional, Denkert, Carsten, additional, and von Minckwitz, Gunter, additional

Published
2015
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32. Tumor-Infiltrating Lymphocytes and Response to Neoadjuvant Chemotherapy With or Without Carboplatin in Human Epidermal Growth Factor Receptor 2–Positive and Triple-Negative Primary Breast Cancers

Author

Denkert, Carsten, primary, von Minckwitz, Gunter, additional, Brase, Jan C., additional, Sinn, Bruno V., additional, Gade, Stephan, additional, Kronenwett, Ralf, additional, Pfitzner, Berit M., additional, Salat, Christoph, additional, Loi, Sherene, additional, Schmitt, Wolfgang D., additional, Schem, Christian, additional, Fisch, Karin, additional, Darb-Esfahani, Silvia, additional, Mehta, Keyur, additional, Sotiriou, Christos, additional, Wienert, Stephan, additional, Klare, Peter, additional, André, Fabrice, additional, Klauschen, Frederick, additional, Blohmer, Jens-Uwe, additional, Krappmann, Kristin, additional, Schmidt, Marcus, additional, Tesch, Hans, additional, Kümmel, Sherko, additional, Sinn, Peter, additional, Jackisch, Christian, additional, Dietel, Manfred, additional, Reimer, Toralf, additional, Untch, Michael, additional, and Loibl, Sibylle, additional

Published
2015
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34. Fibrosis in low-grade follicular lymphoma – a link to the TH2 immune reaction.

Author

Lohneis, Philipp, Wienert, Stephan, Klauschen, Frederick, Anagnostopoulos, Ioannis, and Jöhrens, Korinna

Subjects
*IMMUNE response, *CYTOKINES, *FIBROSIS, *IMMUNOHISTOCHEMISTRY, *CELLS, *CANCER
Abstract

There is evidence from studies on fibrotic diseases that a TH2 polarized immune response, characterized by the production of cytokines like IL-4, IL-5, and IL-13 is important for fibrosis development. Data concerning the role of TH2 polarized immune response for fibrogenesis in lymphomas are scarce. Using immunohistochemistry, we investigated paraffin embedded tissue specimens of 58 follicular lymphomas (FL) grade 1/2 with and without fibrosis. In FL with fibrosis, we detected more interfollicular GATA-3 positive lymphocytes and a shift towards a TH2 immune response. In areas of fibrosis, which were enriched with myofibroblasts, we observed a polarization of macrophages towards a M2 phenotype with expression of CD163. Our results hold some evidence that a polarization of the adaptive immune system towards a TH2 immune response in the tumor microenvironment is associated with increased fibrosis, which may indicate its functional relevance for either development or maintenance of fibrosis in FL. [ABSTRACT FROM PUBLISHER]

Published
2017
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36. Multicolor fate mapping of Langerhans cell homeostasis

Author

Ghigo, Clément, primary, Mondor, Isabelle, additional, Jorquera, Audrey, additional, Nowak, Jonathan, additional, Wienert, Stephan, additional, Zahner, Sonja P., additional, Clausen, Björn E., additional, Luche, Hervé, additional, Malissen, Bernard, additional, Klauschen, Frederick, additional, and Bajénoff, Marc, additional

Published
2013
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38. CognitionMaster: an object-based image analysis framework

Author

Wienert, Stephan, primary, Heim, Daniel, additional, Kotani, Manato, additional, Lindequist, Björn, additional, Stenzinger, Albrecht, additional, Ishii, Masaru, additional, Hufnagl, Peter, additional, Beil, Michael, additional, Dietel, Manfred, additional, Denkert, Carsten, additional, and Klauschen, Frederick, additional

Published
2013
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42. Marginal zone lymphomas with monocytoid morphology express T-bet and are associated with a low number of T cells in extranodal locations.

Author

Lohneis, Philipp, Wienert, Stephan, Klauschen, Frederick, Ullrich, Andrea, Anagnostopoulos, Ioannis, and Jöhrens, Korinna

Subjects
*LYMPHOMAS, *TUMORS, *B cell lymphoma, *LYMPHOCYTES, *HEMATOLOGIC malignancies, *PHYSIOLOGY, *TUMOR risk factors
Abstract

The presence of tumor cells with monocytoid morphology in marginal zone lymphoma (MZL) has been described previously. Reactive monocytoid B cells bear a distinct immunophenotype and typically express T-bet, which clearly distinguishes them from nodal marginal zone B cells. The latter are positive for CD27 and negative for T-bet. We analyzed 74 MZLs for the expression of T-bet and correlated these results with the presence of monocytoid morphology. Expression of T-bet correlated with the presence of monocytoid morphology in MZLs. In analogy to reactive monocytoid B lymphocytes, we also found a significantly lower relative amount of intratumoral T lymphocytes in extranodal MZL with monocytoid morphology. [ABSTRACT FROM AUTHOR]

Published
2014
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43. Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Author

Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K., Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H., Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M., Horlings, Hugo M., Hudeček, Jan, Ciompi, Francesco, Moore, David A., Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K., Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P., Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J., Lakhani, Sunil R., Rojo, Federico, Comerma, Laura, Badve, Sunil S., Khojasteh, Mehrnoush, Symmans, W. Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L., Kim, Rim S., Rimm, David L., Viale, Giuseppe, Hewitt, Stephen M., Bartlett, John M. S., Penault-Llorca, Frédérique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G., Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O., Lazar, Alexander J., Bago-Horvath, Zsuzsanna, Kooreman, Loes F. S., Van Der Laak, Jeroen A. W. M., Saltz, Joel, Gallas, Brandon D., Kurkure, Uday, Barnes, Michael, Salgado, Roberto, Cooper, Lee A. D., Hyytiäinen, Aini, Hida, Akira I., Thompson, Alastair, Lefevre, Alex, Gown, Allen, Lo, Amy, Sapino, Anna, Moreira, Andre, Richardson, Andrea, Vingiani, Andrea, Bellizzi, Andrew M., Tutt, Andrew, Guerrero-Zotano, Angel, Grigoriadis, Anita, Ehinger, Anna, Garrido-Castro, Anna C., Vincent-Salomon, Anne, Laenkholm, Anne-Vibeke, Cimino-Mathews, Ashley, Srinivasan, Ashok, Acs, Balazs, Singh, Baljit, Calhoun, Benjamin, Haibe-Kans, Benjamin, Solomon, Benjamin, Thapa, Bibhusal, Nelson, Brad H., Castaneda, Carlos, Ballesteroes-Merino, Carmen, Criscitiello, Carmen, Boeckx, Carolien, Colpaert, Cecile, Quinn, Cecily, Chennubhotla, Chakra S., Swanton, Charles, Solinas, Cinzia, Hiley, Crispin, Drubay, Damien, Bethmann, Daniel, Dillon, Deborah A., Larsimont, Denis, Sabanathan, Dhanusha, Peeters, Dieter, Zardavas, Dimitrios, Höflmayer, Doris, Johnson, Douglas B., Thompson, E. Aubrey, Brogi, Edi, Perez, Edith, ElGabry, Ehab A., Blackley, Elizabeth F., Reisenbichler, Emily, Bellolio, Enrique, Chmielik, Ewa, Gaire, Fabien, Andre, Fabrice, Lu, Fang-I, Azmoudeh-Ardalan, Farid, Gruosso, Forbius Tina, Peale, Franklin, Hirsch, Fred R., Klaushen, Frederick, Acosta-Haab, Gabriela, Farshid, Gelareh, Van Den Eynden, Gert, Curigliano, Giuseppe, Floris, Giuseppe, Broeckx, Glenn, Koeppen, Harmut, Haynes, Harry R., McArthur, Heather, Joensuu, Heikki, Olofsson, Helena, Cree, Ian, Nederlof, Iris, Frahm, Isabel, Brcic, Iva, Chan, Jack, Hall, Jacqueline A., Ziai, James, Brock, Jane, Wesseling, Jelle, Giltnane, Jennifer, Lemonnier, Jerome, Zha, Jiping, M. Ribeiro, Joana, Carter, Jodi M., Hainfellner, Johannes, Quesne, John Le, Juco, Jonathan W., Reis-Filho, Jorge, Van Den Berg, Jose, Sanchez, Joselyn, Sparano, Joseph, Cucherousset, Joël, Araya, Juan Carlos, Adam, Julien, Balko, Justin M., Saeger, Kai, Siziopikou, Kalliopi, Willard-Gallo, Karen, Sikorska, Karolina, Weber, Karsten, Steele, Keith E., Emancipator, Kenneth, El Bairi, Khalid, Blenman, Kim R. M., Allison, Kimberly H., Van De Vijver, Koen K., Korski, Konstanty, Pusztai, Lajos, Buisseret, Laurence, Shi, Leming, Shi-Wei, Liu, Molinero, Luciana, Estrada, M. Valeria, Van Seijen, Maartje, Lacroix-Triki, Magali, Cheang, Maggie C. U., Bakir, Maise Al, Van De Vijver, Marc, Dieci, Maria Vittoria, Rebelatto, Marlon C., Piccart, Martine, Goetz, Matthew P., Preusser, Matthias, Sanders, Melinda E., Regan, Meredith M., Christie, Michael, Misialek, Michael, Ignatiadis, Michail, De Maaker, Michiel, Van Bockstal, Mieke, Castillo, Miluska, Harbeck, Nadia, Tung, Nadine, Laudus, Nele, Sirtaine, Nicolas, Burchardi, Nicole, Ternes, Nils, Radosevic-Robin, Nina, Gluz, Oleg, Grimm, Oliver, Nuciforo, Paolo, Jank, Paul, Jelinic, Petar, Watson, Peter H., Francis, Prudence A., Russell, Prudence A., Pierce, Robert H., Hills, Robert, Leon-Ferre, Roberto, De Wind, Roland, Shui, Ruohong, Declercq, Sabine, Leung, Sam, Tabbarah, Sami, Souza, Sandra C., O’Toole, Sandra, Swain, Sandra, Willis, Scooter, Ely, Scott, Kim, Seong- Rim, Bedri, Shahinaz, Irshad, Sheeba, Liu, Shi-Wei, Hendry, Shona, Bianchi, Simonetta, Bragança, Sofia, Paik, Soonmyung, Fox, Stephen B., Luen, Stephen J., Naber, Stephen, Luz, Sua, Fineberg, Susan, Soler, Teresa, Gevaert, Thomas, D’Alfons, Timothy, John, Tom, Sugie, Tomohagu, Bossuyt, Veerle, Manem, Venkata, Cámaea, Vincente Peg, Tong, Weida, Yang, Wentao, Tran, William T., Wang, Yihong, Allory, Yves, and Husain, Zaheed

Subjects
631/67/580, 692/4028/67/1857, 631/67/2321, 692/53/2422, review-article, Review Article, 631/67/1347, humanities, 3. Good health
Abstract

Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI), Funder: National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University., Funder: Susan G Komen Foundation (CCR CCR18547966) and a Young Investigator Grant from the Breast Cancer Alliance., Funder: The Canadian Cancer Society, Funder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194, Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.

44. Tissue clonality of dendritic cell subsets and emergency DCpoiesis revealed by multicolor fate mapping of DC progenitors

Author

Cabeza-Cabrerizo, Mar, Blijswijk, Janneke Van, Wienert, Stephan, Heim, Daniel, Jenkins, Robert P, Probir Chakravarty, Rogers, Neil, Frederico, Bruno, Acton, Sophie, Beerling, Evelyne, Rheenen, Jacco Van, Clevers, Hans, Schraml, Barbara U, Bajénoff, Marc, Gerner, Michael, Germain, Ronald N, Sahai, Erik, Klauschen, Frederick, and Sousa, Caetano Reis E

Subjects
Model organisms, Chemical Biology & High Throughput, FOS: Clinical medicine, Genome Integrity & Repair, Immunology, Infectious Disease, Cell Biology, Tumour Biology, Genetics & Genomics, 3. Good health, Imaging, Computational & Systems Biology
Abstract

Conventional dendritic cells (cDCs) are found in all tissues and play a key role in immune surveillance. They comprise two major subsets, cDC1 and cDC2, both derived from circulating precursors of cDCs (pre-cDCs), which exited the bone marrow. We show that, in the steady-state mouse, pre-cDCs entering tissues proliferate to give rise to differentiated cDCs, which themselves have residual proliferative capacity. We use multicolor fate mapping of cDC progenitors to show that this results in clones of sister cDCs, most of which comprise a single cDC1 or cDC2 subtype, suggestive of pre-cDC commitment. Upon infection, a surge in the influx of pre-cDCs into the affected tissue dilutes clones and increases cDC numbers. Our results indicate that tissue cDCs can be organized in a patchwork of closely positioned sister cells of the same subset whose coexistence is perturbed by local infection, when the bone marrow provides additional pre-cDCs to meet increased tissue demand.

45. Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Author

Kos, Zuzana, Roblin, Elvire, Kim, Rim S, Michiels, Stefan, Gallas, Brandon D, Chen, Weijie, Van De Vijver, Koen K, Goel, Shom, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O, Badve, Sunil S, Symmans, W Fraser, Sotiriou, Christos, Rimm, David L, Hewitt, Stephen, Denkert, Carsten, Loibl, Sibylle, Luen, Stephen J, Bartlett, John MS, Savas, Peter, Pruneri, Giancarlo, Dillon, Deborah A, Cheang, Maggie Chon U, Tutt, Andrew, Hall, Jacqueline A, Kok, Marleen, Horlings, Hugo M, Madabhushi, Anant, Van Der Laak, Jeroen, Ciompi, Francesco, Laenkholm, Anne-Vibeke, Bellolio, Enrique, Gruosso, Tina, Fox, Stephen B, Araya, Juan Carlos, Floris, Giuseppe, Hudeček, Jan, Voorwerk, Leonie, Beck, Andrew H, Kerner, Jen, Larsimont, Denis, Declercq, Sabine, Van Den Eynden, Gert, Pusztai, Lajos, Ehinger, Anna, Yang, Wentao, AbdulJabbar, Khalid, Yuan, Yinyin, Singh, Rajendra, Hiley, Crispin, Bakir, Maise Al, Lazar, Alexander J, Naber, Stephen, Wienert, Stephan, Castillo, Miluska, Curigliano, Giuseppe, Dieci, Maria-Vittoria, André, Fabrice, Swanton, Charles, Reis-Filho, Jorge, Sparano, Joseph, Balslev, Eva, Chen, I-Chun, Stovgaard, Elisabeth Ida Specht, Pogue-Geile, Katherine, Blenman, Kim RM, Penault-Llorca, Frédérique, Schnitt, Stuart, Lakhani, Sunil R, Vincent-Salomon, Anne, Rojo, Federico, Braybrooke, Jeremy P, Hanna, Matthew G, Soler-Monsó, M Teresa, Bethmann, Daniel, Castaneda, Carlos A, Willard-Gallo, Karen, Sharma, Ashish, Lien, Huang-Chun, Fineberg, Susan, Thagaard, Jeppe, Comerma, Laura, Gonzalez-Ericsson, Paula, Brogi, Edi, Loi, Sherene, Saltz, Joel, Klaushen, Frederick, Cooper, Lee, Amgad, Mohamed, Moore, David A, Salgado, Roberto, and International Immuno-Oncology Biomarker Working Group

Subjects
Prognostic markers, Immunosurveillance, 3. Good health
Abstract

Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.

46. Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Author

Kos, Zuzana, Roblin, Elvire, Kim, Rim S., Michiels, Stefan, Gallas, Brandon D., Chen, Weijie, Van De Vijver, Koen K., Goel, Shom, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O., Badve, Sunil S., Symmans, W. Fraser, Sotiriou, Christos, Rimm, David L., Hewitt, Stephen, Denkert, Carsten, Loibl, Sibylle, Luen, Stephen J., Bartlett, John M. S., Savas, Peter, Pruneri, Giancarlo, Dillon, Deborah A., Cheang, Maggie Chon U., Tutt, Andrew, Hall, Jacqueline A., Kok, Marleen, Horlings, Hugo M., Madabhushi, Anant, Van Der Laak, Jeroen, Ciompi, Francesco, Laenkholm, Anne-Vibeke, Bellolio, Enrique, Gruosso, Tina, Fox, Stephen B., Araya, Juan Carlos, Floris, Giuseppe, Hudeček, Jan, Voorwerk, Leonie, Beck, Andrew H., Kerner, Jen, Larsimont, Denis, Declercq, Sabine, Van Den Eynden, Gert, Pusztai, Lajos, Ehinger, Anna, Yang, Wentao, AbdulJabbar, Khalid, Yuan, Yinyin, Singh, Rajendra, Hiley, Crispin, Bakir, Maise Al, Lazar, Alexander J., Naber, Stephen, Wienert, Stephan, Castillo, Miluska, Curigliano, Giuseppe, Dieci, Maria-Vittoria, André, Fabrice, Swanton, Charles, Reis-Filho, Jorge, Sparano, Joseph, Balslev, Eva, Chen, I-Chun, Stovgaard, Elisabeth Ida Specht, Pogue-Geile, Katherine, Blenman, Kim R. M., Penault-Llorca, Frédérique, Schnitt, Stuart, Lakhani, Sunil R., Vincent-Salomon, Anne, Rojo, Federico, Braybrooke, Jeremy P., Hanna, Matthew G., Soler-Monsó, M. Teresa, Bethmann, Daniel, Castaneda, Carlos A., Willard-Gallo, Karen, Sharma, Ashish, Lien, Huang-Chun, Fineberg, Susan, Thagaard, Jeppe, Comerma, Laura, Gonzalez-Ericsson, Paula, Brogi, Edi, Loi, Sherene, Saltz, Joel, Klaushen, Frederick, Cooper, Lee, Amgad, Mohamed, Moore, David A., Salgado, Roberto, Hyytiäinen, Aini, Hida, Akira I., Thompson, Alastair, Lefevre, Alex, Gown, Allen, Lo, Amy, Sapino, Anna, Moreira, Andre M., Richardson, Andrea, Vingiani, Andrea, Bellizzi, Andrew M., Guerrero, Angel, Grigoriadis, Anita, Garrido-Castro, Ana C., Cimino-Mathews, Ashley, Srinivasan, Ashok, Acs, Balazs, Singh, Baljit, Calhoun, Benjamin, Haibe-Kans, Benjamin, Solomon, Benjamin, Thapa, Bibhusal, Nelson, Brad H., Ballesteroes-Merino, Carmen, Criscitiello, Carmen, Boeckx, Carolien, Colpaert, Cecile, Quinn, Cecily, Chennubhotla, Chakra S., Solinas, Cinzia, Drubay, Damien, Sabanathan, Dhanusha, Peeters, Dieter, Zardavas, Dimitrios, Höflmayer, Doris, Johnson, Douglas B., Thompson, E. Aubrey, Perez, Edith, ElGabry, Ehab A., Blackley, Elizabeth F., Reisenbichler, Emily, Chmielik, Ewa, Gaire, Fabien, Lu, Fang-I, Azmoudeh-Ardalan, Farid, Peale, Franklin, Hirsch, Fred R., Acosta-Haab, Gabriela, Farshid, Gelareh, Broeckx, Glenn, Koeppen, Harmut, Haynes, Harry R., McArthur, Heather, Joensuu, Heikki, Olofsson, Helena, Cree, Ian, Nederlof, Iris, Frahm, Isabel, Brcic, Iva, Chan, Jack, Ziai, James, Brock, Jane, Weseling, Jelle, Giltnane, Jennifer, Lemonnier, Jerome, Zha, Jiping, Ribeiro, Joana, Lennerz, Jochen K., Carter, Jodi M., Hartman, Johan, Hainfellner, Johannes, Le Quesne, John, Juco, Jonathan W., Van Den Berg, Jose, Sanchez, Joselyn, Cucherousset, Joël, Adam, Julien, Balko, Justin M., Saeger, Kai, Siziopikou, Kalliopi, Sikorska, Karolina, Weber, Karsten, Steele, Keith E., Emancipator, Kenneth, El Bairi, Khalid, Allison, Kimberly H., Korski, Konstanty, Buisseret, Laurence, Shi, Leming, Kooreman, Loes F. S., Molinero, Luciana, Estrada, M. Valeria, Van Seijen, Maartje, Lacroix-Triki, Magali, Sebastian, Manu M., Balancin, Marcelo L., Mathieu, Marie-Christine, Van De Vijver, Mark, Rebelatto, Marlon C., Piccart, Martine, Goetz, Matthew P., Preusser, Matthias, Khojasteh, Mehrnoush, Sanders, Melinda E., Regan, Meredith M., Barnes, Michael, Christie, Michael, Misialek, Michael, Ignatiadis, Michail, De Maaker, Michiel, Van Bockstal, Mieke, Harbeck, Nadia, Tung, Nadine, Laudus, Nele, Sirtaine, Nicolas, Burchardi, Nicole, Ternes, Nils, Radosevic-Robin, Nina, Gluz, Oleg, Grimm, Oliver, Nuciforo, Paolo, Jank, Paul, Kirtani, Pawan, Watson, Peter H., Jelinic, Peter, Francis, Prudence A., Russell, Prudence A., Pierce, Robert H., Hills, Robert, Leon-Ferre, Roberto, De Wind, Roland, Shui, Ruohong, Leung, Samuel, Tabbarah, Sami, Souza, Sandra C., O’Toole, Sandra, Swain, Sandra, Dudgeon, Sarah, Willis, Scooter, Ely, Scott, Bedri, Shahinaz, Irshad, Sheeba, Liu, Shiwei, Hendry, Shona, Bianchi, Simonetta, Bragança, Sofia, Paik, Soonmyung, Luz, Sua, Gevaert, Thomas, D’Alfons, Timothy, John, Tom, Sugie, Tomohagu, Kurkure, Uday, Bossuyt, Veerle, Manem, Venkata, Cámaea, Vincente Peg, Tong, Weida, Tran, William T., Wang, Yihong, Allory, Yves, Husain, Zaheed, and Bago-Horvath, Zsuzsanna

Subjects
692/53/2422, article, 3. Good health, 631/67/580/1884
Abstract

Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.

47. Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Author

Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K, Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H, Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M, Horlings, Hugo M, Hudeček, Jan, Ciompi, Francesco, Moore, David A, Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K, Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P, Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J, Lakhani, Sunil R, Rojo, Federico, Comerma, Laura, Badve, Sunil S, Khojasteh, Mehrnoush, Symmans, W Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L, Kim, Rim S, Rimm, David L, Viale, Giuseppe, Hewitt, Stephen M, Bartlett, John MS, Penault-Llorca, Frédérique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G, Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O, Lazar, Alexander J, Bago-Horvath, Zsuzsanna, Kooreman, Loes FS, Van Der Laak, Jeroen AWM, Saltz, Joel, Gallas, Brandon D, Kurkure, Uday, Barnes, Michael, Salgado, Roberto, Cooper, Lee AD, and International Immuno-Oncology Biomarker Working Group

Subjects
Tumour biomarkers, Prognostic markers, Breast cancer, Tumour immunology, Cancer imaging, humanities, 3. Good health
Abstract

Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI), Funder: National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University., Funder: Susan G Komen Foundation (CCR CCR18547966) and a Young Investigator Grant from the Breast Cancer Alliance., Funder: The Canadian Cancer Society, Funder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194, Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.

48. Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Author

Hudeček, Jan, Voorwerk, Leonie, Van Seijen, Maartje, Nederlof, Iris, De Maaker, Michiel, Van Den Berg, Jose, Van De Vijver, Koen K., Sikorska, Karolina, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O., Badve, Sunil S., Michiels, Stefan, Symmans, William Fraser, Sotiriou, Christos, Rimm, David L., Hewitt, Stephen M., Denkert, Carsten, Loibl, Sibylle, Loi, Sherene, Bartlett, John M. S., Pruneri, Giancarlo, Dillon, Deborah A., Cheang, Maggie C. U., Tutt, Andrew, Hall, Jacqueline A., Kos, Zuzana, Salgado, Roberto, Kok, Marleen, Horlings, Hugo M., Hyytiäinen, Aini, Hida, Akira I., Thompson, Alastair, Lefevre, Alex, Lazar, Alexander J., Gown, Allen, Lo, Amy, Sapino, Anna, Madabhushi, Anant, Moreira, Andre, Richardson, Andrea, Vingiani, Andrea, Beck, Andrew H., Bellizzi, Andrew M., Guerrero, Angel, Grigoriadis, Anita, Ehinger, Anna, Garrido-Castro, Ana, Vincent-Salomon, Anne, Laenkholm, Anne-Vibeke, Sharma, Ashish, Cimino-Mathews, Ashley, Srinivasan, Ashok, Acs, Balazs, Singh, Baljit, Calhoun, Benjamin, Haibe-Kans, Benjamin, Solomon, Benjamin, Thapa, Bibhusal, Nelson, Brad H., Gallas, Brandon D., Castaneda, Carlos, Ballesteros-Merino, Carmen, Criscitiello, Carmen, Boeckx, Carolien, Colpaert, Cecile, Quinn, Cecily, Chennubhotla, Chakra S., Swanton, Charles, Solinas, Cinzia, Hiley, Crispin, Drubay, Damien, Bethmann, Daniel, Moore, David A., Larsimont, Denis, Sabanathan, Dhanusha, Peeters, Dieter, Zardavas, Dimitrios, Höflmayer, Doris, Johnson, Douglas B., Thompson, E. Aubrey, Brogi, Edi, Perez, Edith, ElGabry, Ehab A., Stovgaard, Elisabeth Specht, Blackley, Elizabeth F., Roblin, Elvire, Reisenbichler, Emily, Bellolio, Enrique, Balslev, Eva, Chmielik, Ewa, Gaire, Fabien, Andre, Fabrice, Lu, Fang-I, Azmoudeh-Ardalan, Farid, Rojo, Federico, Gruosso, Tina, Ciompi, Francesco, Peale, Franklin, Hirsch, Fred R., Klauschen, Frederick, Penault-Llorca, Frédérique, Acosta Haab, Gabriela, Farshid, Gelareh, Van Den Eynden, Gert, Curigliano, Giuseppe, Floris, Giuseppe, Broeckx, Glenn, Gonzalez-Ericsson, Koeppen, Harmut, Haynes, Harry R., McArthur, Heather, Joensuu, Heikki, Olofsson, Helena, Lien, Huang-Chun, Chen, I-Chun, Cree, Ian, Frahm, Isabel, Brcic, Iva, Chan, Jack, Ziai, James, Brock, Jane, Wesseling, Jelle, Giltnane, Jennifer, Kerner, Jennifer K., Thagaard, Jeppe, Braybrooke, Jeremy P., Van Der Laak, Jeroen A. W. M., Lemonnier, Jerome, Zha, Jiping, Ribeiro, Joana, Lennerz, Jochen K., Carter, Jodi M., Saltz, Joel, Hartman, Johan, Hainfellner, Johannes, Quesne, John Le, Juco, Jonathon W., Reis-Filho, Jorge, Sanchez, Joselyn, Sparano, Joseph, Cucherousset, Joël, Araya, Juan Carlos, Adam, Julien, Balko, Justin M., Saeger, Kai, Siziopikou, Kalliopi, Willard-Gallo, Karen, Weber, Karsten, Pogue-Geile, Katherine L., Steele, Keith E., Emancipator, Kenneth, AbdulJabbar, Khalid, El Bairi, Khalid, Blenman, Kim R. M., Allison, Kimberly H., Korski, Konstanty, Pusztai, Lajos, Comerma, Laura, Buisseret, Laurence, Cooper, Lee A. D., Shi, Leming, Kooreman, Loes F. S., Molinero, Luciana, Estrada, M. Valeria, Lacroix-Triki, Magali, Al Bakir, Maise, Sebastian, Manu M., Van De Vijver, Marc, Balancin, Marcelo Luiz, Dieci, Maria Vittoria, Mathieu, Marie-Christine, Rebelatto, Marlon C., Piccart, Martine, Hanna, Matthew G., Goetz, Matthew P., Preusser, Matthias, Khojasteh, Mehrnoush, Sanders, Melinda E., Regan, Meredith M., Barnes, Michael, Christie, Michael, Misialek, Michael, Ignatiadis, Michail, Van Bockstal, Mieke, Castillo, Miluska, Amgad, Mohamed, Harbeck, Nadia, Tung, Nadine, Laudus, Nele, Sirtaine, Nicolas, Burchardi, Nicole, Ternes, Nils, Radosevic-Robin, Nina, Gluz, Oleg, Grimm, Oliver, Nuciforo, Paolo, Jank, Paul, Gonzalez-Ericsson, Paula, Kirtani, Pawan, Jelinic, Petar, Watson, Peter H., Savas, Peter, Francis, Prudence A., Russell, Prudence A., Singh, Rajendra, Kim, Rim S., Pierce, Robert H., Hills, Robert, Leon-Ferre, Roberto, De Wind, Roland, Shui, Ruohong, De Clercq, Sabine, Leung, Sam, Tabbarah, Sami, Souza, Sandra C., O’Toole, Sandra, Swain, Sandra, Dudgeon, Sarah, Willis, Scooter, Ely, Scott, Kim, Seong-Rim, Bedri, Shahinaz, Irshad, Sheeba, Liu, Shi-Wei, Goel, Shom, Hendry, Shona, Bianchi, Simonetta, Bragança, Sofia, Paik, Soonmyung, Wienert, Stephan, Fox, Stephen B., Luen, Stephen J., Naber, Stephen, Schnitt, Stuart J., Sua, Luz F., Lakhani, Sunil R., Fineberg, Susan, Soler, Teresa, Gevaert, Thomas, D’Alfonso, Timothy, John, Tom, Sugie, Tomohagu, Kurkure, Uday, Bossuyt, Veerle, Manem, Venkata, Cámara, Vincente Peg, Tong, Weida, Chen, Weijie, Yang, Wentao, Tran, William T., Wang, Yihong, Yuan, Yinyin, Allory, Yves, Husain, Zaheed, and Bago-Horvath, Zsuzsanna

Subjects
692/53, review-article, Review Article, 631/67/1347, 692/4028/67/580, 631/67/1857, 3. Good health
Abstract

Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006, Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting.

49. Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer.

Author

Dieci MV, Radosevic-Robin N, Fineberg S, van den Eynden G, Ternes N, Penault-Llorca F, Pruneri G, D'Alfonso TM, Demaria S, Castaneda C, Sanchez J, Badve S, Michiels S, Bossuyt V, Rojo F, Singh B, Nielsen T, Viale G, Kim SR, Hewitt S, Wienert S, Loibl S, Rimm D, Symmans F, Denkert C, Adams S, Loi S, and Salgado R

Subjects
Female, Humans, Medical Oncology methods, Neoadjuvant Therapy methods, Biomarkers, Tumor immunology, Breast Neoplasms immunology, Carcinoma in Situ immunology, Lymphocytes, Tumor-Infiltrating immunology, Neoplasm, Residual immunology
Abstract

Morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer is gaining momentum as evidence strengthens the clinical relevance of this immunological biomarker. TILs in the post-neoadjuvant residual disease setting are acquiring increasing importance as a stratifying marker in clinical trials, considering the raising interest on immunotherapeutic strategies after neoadjuvant chemotherapy. TILs in ductal carcinoma in situ, with or without invasive carcinoma, represent an emerging area of clinical breast cancer research. The aim of this report is to update pathologists, clinicians and researchers on TIL assessment in both the post-neoadjuvant residual disease and the ductal carcinoma in situ settings. The International Immuno-Oncology Working Group proposes a method for assessing TILs in these settings, based on the previously published International Guidelines on TIL Assessment in Breast Cancer. In this regard, these recommendations represent a consensus guidance for pathologists, aimed to achieve the highest possible consistency among future studies., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2018
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50. Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma.

Author

Darb-Esfahani S, Kunze CA, Kulbe H, Sehouli J, Wienert S, Lindner J, Budczies J, Bockmayr M, Dietel M, Denkert C, Braicu I, and Jöhrens K

Subjects
B7-H1 Antigen genetics, Biomarkers, Tumor genetics, Carcinoma genetics, Carcinoma immunology, Carcinoma therapy, Databases, Genetic, Disease-Free Survival, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating pathology, Middle Aged, Neoplasm Grading, Neoplasms, Cystic, Mucinous, and Serous genetics, Neoplasms, Cystic, Mucinous, and Serous immunology, Neoplasms, Cystic, Mucinous, and Serous therapy, Ovarian Neoplasms genetics, Ovarian Neoplasms immunology, Ovarian Neoplasms therapy, Programmed Cell Death 1 Receptor genetics, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Tissue Array Analysis, B7-H1 Antigen analysis, Biomarkers, Tumor analysis, Carcinoma chemistry, Lymphocytes, Tumor-Infiltrating chemistry, Neoplasms, Cystic, Mucinous, and Serous chemistry, Ovarian Neoplasms chemistry, Programmed Cell Death 1 Receptor analysis
Abstract

Aims: Antibodies targeting the checkpoint molecules programmed cell death 1 (PD-1) and its ligand PD-L1 are emerging cancer therapeutics. We systematically investigated PD-1 and PD-L1 expression patterns in the poor-prognosis tumor entity high-grade serous ovarian carcinoma., Methods: PD-1 and PD-L1 protein expression was determined by immunohistochemistry on tissue microarrays from 215 primary cancers both in cancer cells and in tumor-infiltrating lymphocytes (TILs). mRNA expression was measured by quantitative reverse transcription PCR. An in silico validation of mRNA data was performed in The Cancer Genome Atlas (TCGA) dataset., Results: PD-1 and PD-L1 expression in cancer cells, CD3+, PD-1+, and PD-L1+ TILs densities as well as PD-1 and PD-L1 mRNA levels were positive prognostic factors for progression-free (PFS) and overall survival (OS), with all factors being significant for PFS (p < 0.035 each), and most being significant for OS. Most factors also had prognostic value that was independent from age, stage, and residual tumor. Moreover, high PD-1+ TILs as well as PD-L1+ TILs densities added prognostic value to CD3+TILs (PD-1+: p = 0.002,; PD-L1+: p = 0.002). The significant positive prognostic impact of PD-1 and PD-L1 mRNA expression could be reproduced in the TCGA gene expression datasets (p = 0.02 and p < 0.0001, respectively)., Conclusions: Despite their reported immune-modulatory function, high PD-1 and PD-L1 levels are indicators of a favorable prognosis in ovarian cancer. Our data indicate that PD-1 and PD-L1 molecules are biologically relevant regulators of the immune response in high-grade serous ovarian carcinoma, which is an argument for the evaluation of immune checkpoint inhibiting drugs in this tumor entity.

Published
2016
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