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1. The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group

Author

El Bairi, K., Haynes, H. R., Blackley, E., Fineberg, S., Shear, J., Turner, S., de Freitas, J. R., Sur, D., Amendola, L. C., Gharib, M., Kallala, A., Arun, I., Azmoudeh-Ardalan, F., Fujimoto, L., Sua, L. F., Liu, S. -W., Lien, H. -C., Kirtani, P., Balancin, M., El Attar, H., Guleria, P., Yang, W., Shash, E., Chen, I. -C., Bautista, V., Do Prado Moura, J. F., Rapoport, B. L., Castaneda, C., Spengler, E., Acosta-Haab, G., Frahm, I., Sanchez, J., Castillo, M., Bouchmaa, N., Md Zin, R. R., Shui, R., Onyuma, T., Husain, Z., Willard-Gallo, K., Coosemans, A., Perez, E. A., Provenzano, E., Ericsson, P. G., Richardet, E., Mehrotra, R., Sarancone, S., Ehinger, A., Rimm, D. L., Bartlett, J. M. S., Viale, G., Denkert, C., Hida, A. I., Sotiriou, C., Loibl, S., Hewitt, S. M., Badve, S., Symmans, W. F., Kim, R. S., Pruneri, G., Goel, S., Francis, P. A., Inurrigarro, G., Yamaguchi, R., Garcia-Rivello, H., Horlings, H., Afqir, S., Salgado, R., Adams, S., Kok, M., Dieci, M. V., Michiels, S., Demaria, S., Loi, S., Schelfhout, V., Arbzadeh, E., Bondanar, A., Reyes, S. A. G., Ruz, J. R., Kang, J., Xiang, L., Zimovjanova, M., Togores, P., Ozturk, T., Patil, A., Corpa, M., Whitehouse, A., Tan, B., de Paula, A., Rossetti, C., Lang-Schwarz, C., Mahon, S., Giacometti, C., Linderholm, B., Deman, F., Montagna, G., Gong, G., Pavcovich, M., Chaer, Y., Cabrero, I. A., de Brito, M. L., Ilieva, N., Fulop, A., Souza, M., Bilancia, D., Idowu, M., Johri, R., Szpor, J., Bachani, L., Schmitt, F., Giannotti, M., Kurebayashi, Y., Ramirez, B. E. A., Salido, E., Bortesi, L., Bonetto, S., Elomina, K., Lopez, P., Sharma, V., Edirisinghe, A., Mathur, D., Sahay, A., Mouloud, M. A., Giang, C. H., Mukolwe, E., Kiruka, E., Samberg, N., Abe, N., Brown, M., Millar, E., X. B., Li, Yuan, Z., Pasupathy, A., Miele, R., Luff, R., e Porfirio, M. M. A., Ajemba, O., Soni, R., Orvieto, E., Dimaio, M., Thomas, J., Merard, R., Subramaniam, M. M., Apolinario, T., Preda, O., Preda, R., Makanga, A., Maior, M. S., Li, L., Saghatchian, M., Saurine, T., Janssen, E., Cochran, J., Vlada, N., Cappellesso, R., Elfer, K., Hollick, M., Desai, S., Oner, G., Schreurs, A., Liu, S., Perera, R., Mercurio, P., Garcia, F., Hosny, K., Matsumoto, H., van Deurzen, C., Bianchini, G., Coban, I., Jahangir, A., Rahman, A., Stover, D., Luz, P., Martel, A., Waumans, Y., Stenzinger, A., Cortes, J., Dimitrova, P., Nauwelaers, I., Velasco, M., Fan, F., Akturk, G., Firer, M., Roxanis, I., Schneck, M., Wen, H., Cockenpot, V., Konstantinov, A., Calatrava, A., Vidya, M. N., Choi, H. J., Jank, P., Ciinen, A. H., Sabanathan, D., Floris, G., Hoeflmayer, D., Hamada, T., Laudus, N., Grigoriadis, A., Porcellato, I., Acs, B., Miglietta, F., Parrodi, J., Clunie, D., Calhoun, B., F. -I., Lu, Lefevre, A., Tabbarah, S., Tran, W., Garcia-murillas, I., Jelinic, P., Boeckx, C., Souza, S., Cebollero, M. C., Felip, E., Rendon, J. L. S., El Gabry, E., Saltz, J., Bria, E., Garufi, G., Hartman, J., Sebastian, M., Olofsson, H., Kooreman, L., Cucherousset, J., Mathieu, M. -C., Ballesteros-Merino, C., Siziopikou, P., Fong, J., Klein, M., Qulis, I. R. I., Wesseling, J., Bellolio, E., Araya, J. C., Naber, S., Cheang, M., Castellano, I., Ales, A., Laenkholm, A. -V., Kulka, J., Quinn, C., Sapino, A., Amendoeira, I., Marchio, C., Braybrooke, J., Vincent-Salomon, A., Korski, K. P., Sofopoulos, M., Stovgaard, E. I. S., Bianchi, S., Bago-Horvath, Z., Yu, C., Regitnig, P., Hall, S., Kos, Z., Sant, S., Tille, J. -C., Gallas, B., Bethmann, D., Savas, P., Mendes, L., Soler, T., van Seijen, M., Gruosso, T., Quintana, A., Giltnane, J., Van den Eynden, G., Duregon, E., de Cabo, R., Recamo, P. C., Gaboury, L., Zimmerman, J., Pop, C. S., Wernicke, A., Williams, D., Gill, A., Solomon, B., Thapa, B., Farshid, G., Gilham, L., Christie, M., O'Toole, S., Hendry, S., Fox, S. B., Luen, S. J., Lakhani, S. R., Fuchs, T., John, T., Brcic, I., Hainfellner, J., Sigurd, L., Preusser, M., Poortmans, P., Decaluwe, A., Carey, C., Colpaert, C., Larsimont, D., Peeters, D., Broeckx, G., van de Vijver, K., Buisseret, L., Dirix, L., Hertoghs, M., Piccart, M., Ignatiadis, M., Van Bockstal, M., Sirtaine, N., Vermeulen, P., de Wind, R., Declercq, S., Gevaert, T., Haibe-Kans, B., Nelson, B. H., Watson, P. H., Leung, S., Nielsen, T., Shi, L., Balslev, E., Thagaard, J., Almangush, A., Makitie, A., Joensuu, H., Lundin, J., Drubay, D., Roblin, E., Andre, F., Penault-Llorca, F., Lemonnier, J., Adam, J., Lacroix-Triki, M., Ternes, N., Radosevic-Robin, N., Klaushen, F., Weber, K., Harbeck, N., Gluz, O., Wienert, S., Cserni, G., Vingiani, A., Criscitiello, C., Solinas, C., Curigliano, G., Konishi, E., Suzuki, E., Yoshikawa, K., Kawaguchi, K., Takada, M., Toi, M., Ishida, M., Shibata, N., Saji, S., Kogawa, T., Sakatani, T., Okamoto, T., Moriya, T., Kataoka, T., Shimoi, T., Sugie, T., Mukohara, T., Shu, Y., Kikawa, Y., Kozuka, Y., Sayed, S., Rahayu, R., Ramsaroop, R., Senkus-Konefka, E., Chmielik, E., Cardoso, F., Ribeiro, J., Chan, J., Dent, R., Martin, M., Hagen, C., Guerrero, A., Rojo, F., Comerma, L., Nuciforo, P., Serrano, V. V., Camaea, V. P., Steenbruggen, T., Ciompi, F., Nederlof, I., Jan, Hudecek, van der Laak, J., van den Berg, J., Voorwerk, L., van de Vijver, M., de Maaker, M., Linn, S., Mckenzie, H., Somaiah, N., Tutt, A., Swanton, C., Hiley, C., Moore, D. A., Hall, J. A., Le Quesne, J., Jabbar, K. A., al Bakir, M., Hills, R., Irshad, S., Yuan, Y., Li, Z., Liu, M., Klein, J., Fadare, O., Thompson, A., Lazar, A. J., Gown, A., Lo, A., Garrido Castro, A. C., Madabhushi, A., Moreira, A., Richardson, A., Beck, A. H., Bellizzi, A. M., Wolff, A., Harbhajanka, A., Sharma, A., Cimino-Mathews, A., Srinivasan, A., Singh, B., Chennubhotla, C. S., Chauhan, C., Dillon, D. A., Zardavas, D., Johnson, D. B., Thompson, A. E., Brogi, E., Reisenbichler, E., Huang, E., Hirsch, F. R., Mcarthur, H., Ziai, J., Brock, J., Kerner, J., Zha, J., Lennerz, J. K., Carter, J. M., Reis-Filho, J., Sparano, J., Balko, J. M., Pogue-Geile, K., Steele, K. E., Blenman, K. R. M., Allison, K. H., Pusztai, L., Cooper, L., Estrada, V. M., Flowers, M., Robson, M., Rebelatto, M. C., Hanna, M. G., Goetz, M. P., Khojasteh, M., Sanders, M. E., Regan, M. M., Misialek, M., Amgad, M., Tung, N., Singh, R., Huang, R., Pierce, R. H., Leon-Ferre, R., Swain, S., Ely, S., Kim, S. -R., Bedri, S., Paik, S., Schnitt, S., D'Alfons, T., Kurkure, U., Bossuyt, V., Tong, W., Wang, Y., Dos Anjos, C. H., Gaire, F., Van Diest, P. J., El Bairi, Khalid [0000-0002-8414-4145], de Freitas, Juliana Ribeiro [0000-0003-4978-7273], Sur, Daniel [0000-0002-0926-4614], Amendola, Luis Claudio [0000-0002-6404-450X], Azmoudeh-Ardalan, Farid [0000-0003-4701-0532], Kirtani, Pawan [0000-0002-2343-7016], Yang, Wenxian [0000-0002-5349-9680], Castillo, Miluska [0000-0002-0111-3176], Provenzano, Elena [0000-0003-3345-3965], Mehrotra, Ravi [0000-0001-9453-1408], Ehinger, Anna [0000-0001-9225-7396], Rimm, David L [0000-0001-5820-4397], Bartlett, John MS [0000-0002-0347-3888], Denkert, Carsten [0000-0002-2249-0982], Hida, Akira I [0000-0002-4486-8819], Sotiriou, Christos [0000-0002-5745-9977], Hewitt, Stephen M [0000-0001-8283-1788], Badve, Sunil [0000-0001-8861-9980], Symmans, William Fraser [0000-0002-1526-184X], Goel, Shom [0000-0001-8329-9084], Francis, Prudence A [0000-0002-7207-9286], Horlings, Hugo [0000-0003-4782-8828], Salgado, Roberto [0000-0002-1110-3801], Demaria, Sandra [0000-0003-4426-0499], Loi, Sherene [0000-0001-6137-9171], Apollo - University of Cambridge Repository, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), and UNICANCER

Subjects
Oncology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], TRASTUZUMAB, Improved survival, MICROENVIRONMENT, Review Article, SUBTYPES, NEOADJUVANT CHEMOTHERAPY, 0302 clinical medicine, Breast cancer, Ecology,Evolution & Ethology, PROGNOSTIC-SIGNIFICANCE, Medicine and Health Sciences, Pharmacology (medical), TUMOR-INFILTRATING LYMPHOCYTES, Stage (cooking), RC254-282, Chemical Biology & High Throughput, 0303 health sciences, Human Biology & Physiology, Genome Integrity & Repair, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, ASSOCIATION, 3. Good health, 030220 oncology & carcinogenesis, Biomarker (medicine), Life Sciences & Biomedicine, Genetics & Genomics, medicine.medical_specialty, chemical and pharmacologic phenomena, International Immuno-Oncology Biomarker Working Group, Predictive markers, 03 medical and health sciences, Signalling & Oncogenes, SDG 3 - Good Health and Well-being, Internal medicine, 692/53/2423, medicine, Radiology, Nuclear Medicine and imaging, In patient, 030304 developmental biology, Computational & Systems Biology, Science & Technology, IDENTIFICATION, business.industry, review-article, Cancer, 03.01. Általános orvostudomány, Immunotherapy, Tumour Biology, medicine.disease, PREDICTIVE-VALUE, 692/4028/67/1347, Programmed death 1, business, FREE SURVIVAL
Abstract

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC. ispartof: NPJ BREAST CANCER vol:7 issue:1 ispartof: location:United States status: published

Published
2021
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7. Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Author

Kos, Z., Roblin, E., Kim, R. S., Michiels, S., Gallas, B. D., Chen, W., van de Vijver, K. K., Goel, S., Adams, S., Demaria, S., Viale, G., Nielsen, T. O., Badve, S. S., Symmans, W. F., Sotiriou, C., Rimm, D. L., Hewitt, S., Denkert, C., Loibl, S., Luen, S. J., Bartlett, J. M. S., Savas, P., Pruneri, G., Dillon, D. A., Cheang, M. C. U., Tutt, A., Hall, J. A., Kok, M., Horlings, H. M., Madabhushi, A., van der Laak, J., Ciompi, F., Laenkholm, A. -V., Bellolio, E., Gruosso, T., Fox, S. B., Araya, J. C., Floris, G., Hudecek, J., Voorwerk, L., Beck, A. H., Kerner, J., Larsimont, D., Declercq, S., Van den Eynden, G., Pusztai, L., Ehinger, A., Yang, W., Abduljabbar, K., Yuan, Y., Singh, R., Hiley, C., Bakir, M., Lazar, A. J., Naber, S., Wienert, S., Castillo, M., Curigliano, G., Dieci, M. -V., Andre, F., Swanton, C., Reis-Filho, J., Sparano, J., Balslev, E., Chen, I. -C., Stovgaard, E. I. S., Pogue-Geile, K., Blenman, K. R. M., Penault-Llorca, F., Schnitt, S., Lakhani, S. R., Vincent-Salomon, A., Rojo, F., Braybrooke, J. P., Hanna, M. G., Soler-Monso, M. T., Bethmann, D., Castaneda, C. A., Willard-Gallo, K., Sharma, A., Lien, H. -C., Fineberg, S., Thagaard, J., Comerma, L., Gonzalez-Ericsson, P., Brogi, E., Loi, S., Saltz, J., Klaushen, F., Cooper, L., Amgad, M., Moore, D. A., Salgado, R., Hyytiainen, A., Hida, A. I., Thompson, A., Lefevre, A., Gown, A., Lo, A., Sapino, A., Moreira, A. M., Richardson, A., Vingiani, A., Bellizzi, A. M., Guerrero, A., Grigoriadis, A., Garrido-Castro, A. C., Cimino-Mathews, A., Srinivasan, A., Acs, B., Singh, B., Calhoun, B., Haibe-Kans, B., Solomon, B., Thapa, B., Nelson, B. H., Ballesteroes-Merino, C., Criscitiello, C., Boeckx, C., Colpaert, C., Quinn, C., Chennubhotla, C. S., Solinas, C., Drubay, D., Sabanathan, D., Peeters, D., Zardavas, D., Hoflmayer, D., Johnson, D. B., Thompson, E. A., Perez, E., Elgabry, E. A., Blackley, E. F., Reisenbichler, E., Chmielik, E., Gaire, F., F. -I., Lu, Azmoudeh-Ardalan, F., Peale, F., Hirsch, F. R., Acosta-Haab, G., Farshid, G., Broeckx, G., Koeppen, H., Haynes, H. R., Mcarthur, H., Joensuu, H., Olofsson, H., Cree, I., Nederlof, I., Frahm, I., Brcic, I., Chan, J., Ziai, J., Brock, J., Weseling, J., Giltnane, J., Lemonnier, J., Zha, J., Ribeiro, J., Lennerz, J. K., Carter, J. M., Hartman, J., Hainfellner, J., Le Quesne, J., Juco, J. W., van den Berg, J., Sanchez, J., Cucherousset, J., Adam, J., Balko, J. M., Saeger, K., Siziopikou, K., Sikorska, K., Weber, K., Steele, K. E., Emancipator, K., El Bairi, K., Allison, K. H., Korski, K., Buisseret, L., Shi, L., Kooreman, L. F. S., Molinero, L., Estrada, M. V., Van Seijen, M., Lacroix-Triki, M., Sebastian, M. M., Balancin, M. L., Mathieu, M. -C., van de Vijver, M., Rebelatto, M. C., Piccart, M., Goetz, M. P., Preusser, M., Khojasteh, M., Sanders, M. E., Regan, M. M., Barnes, M., Christie, M., Misialek, M., Ignatiadis, M., de Maaker, M., Van Bockstal, M., Harbeck, N., Tung, N., Laudus, N., Sirtaine, N., Burchardi, N., Ternes, N., Radosevic-Robin, N., Gluz, O., Grimm, O., Nuciforo, P., Jank, P., Kirtani, P., Watson, P. H., Jelinic, P., Francis, P. A., Russell, P. A., Pierce, R. H., Hills, R., Leon-Ferre, R., de Wind, R., Shui, R., Leung, S., Tabbarah, S., Souza, S. C., O'Toole, S., Swain, S., Dudgeon, S., Willis, S., Ely, S., Bedri, S., Irshad, S., Liu, S., Hendry, S., Bianchi, S., Braganca, S., Paik, S., Luz, S., Gevaert, T., D'Alfons, T., John, T., Sugie, T., Kurkure, U., Bossuyt, V., Manem, V., Camaea, V. P., Tong, W., Tran, W. T., Wang, Y., Allory, Y., Husain, Z., Bago-Horvath, Z., Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR), Division of Pathology and Laboratory Medicine, Università degli Studi di Milano [Milano] (UNIMI)-European Institute of Oncology [Milan] (ESMO), Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Charité, Institute of Pathology, Translational Tumorpathology Unit, German Breast Group, University of the Sunshine Coast (USC), European Institute of Oncology [Milan] (ESMO), Breakthrough Breast Cancer Centre, London Institute of Cancer, Department of Pathology, The Netherlands Cancer Institute, Division of Experimental Therapy, The Netherlands Cancer Institute NKI/AvL, Odense University Hospital, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Breast Medical Oncology [Houston], The University of Texas M.D. Anderson Cancer Center [Houston], Helsingborg Hospital, Division of Experimental Therapeutics [Milan, Italy], Département de médecine oncologique [Gustave Roussy], Cancer Research UK Lung Cancer Centre of Excellence [Londres, Royaume-Uni], University College of London [London] (UCL), Memorial Sloane Kettering Cancer Center [New York], Herlev and Gentofte Hospital, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Southern Queensland (USQ), Pharmacogenomics Unit [Paris], Department of Genetics [Paris], Institut Curie [Paris]-Institut Curie [Paris], Instituto de Física Teórica UAM/CSIC (IFT), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Ctr Biomol Struct & Org, University of Maryland [College Park], University of Maryland System-University of Maryland System, The University of Sydney, Breast Cancer Translational Research Laboratory, Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Innovation North - Faculty of Information and Technology, Leeds Metropolitan University, Int Immuno-Oncology Biomarker, Graduate School, CCA - Cancer biology and immunology, Pathology, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Università degli Studi di Milano = University of Milan (UNIMI)-European Institute of Oncology [Milan] (ESMO), German Breast Group (GBG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Gallas, Brandon D [0000-0001-7332-1620], van de Vijver, Koen K [0000-0002-2026-9790], Demaria, Sandra [0000-0003-4426-0499], Badve, Sunil S [0000-0001-8861-9980], Symmans, W Fraser [0000-0002-1526-184X], Rimm, David L [0000-0001-5820-4397], Savas, Peter [0000-0001-5999-428X], Hall, Jacqueline A [0000-0003-0708-1360], Horlings, Hugo M [0000-0003-4782-8828], van der Laak, Jeroen [0000-0001-7982-0754], Bellolio, Enrique [0000-0003-0079-5264], Araya, Juan Carlos [0000-0003-3501-8203], Floris, Giuseppe [0000-0003-2391-5425], Hudeček, Jan [0000-0003-1071-5686], Ehinger, Anna [0000-0001-9225-7396], Lazar, Alexander J [0000-0002-6395-4499], Castillo, Miluska [0000-0002-0111-3176], Curigliano, Giuseppe [0000-0003-1781-2518], Sparano, Joseph [0000-0002-9031-2010], Braybrooke, Jeremy P [0000-0003-1943-7360], Hanna, Matthew G [0000-0002-7536-1746], Willard-Gallo, Karen [0000-0002-1150-1295], Sharma, Ashish [0000-0002-1011-6504], Comerma, Laura [0000-0002-0249-4636], Gonzalez-Ericsson, Paula [0000-0002-6292-6963], Loi, Sherene [0000-0001-6137-9171], Cooper, Lee [0000-0002-3504-4965], Apollo - University of Cambridge Repository, Research Programs Unit, Heikki Joensuu / Principal Investigator, HUS Comprehensive Cancer Center, Department of Oncology, Medicum, Gallas, Brandon D. [0000-0001-7332-1620], van de Vijver, Koen K. [0000-0002-2026-9790], Badve, Sunil S. [0000-0001-8861-9980], Symmans, W. Fraser [0000-0002-1526-184X], Rimm, David L. [0000-0001-5820-4397], Hall, Jacqueline A. [0000-0003-0708-1360], Horlings, Hugo M. [0000-0003-4782-8828], Lazar, Alexander J. [0000-0002-6395-4499], Braybrooke, Jeremy P. [0000-0003-1943-7360], and Hanna, Matthew G. [0000-0002-7536-1746]

Subjects
Oncology, [SDV]Life Sciences [q-bio], THERAPY, Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], Prognostic markers, 0302 clinical medicine, Breast cancer, Medicine and Health Sciences, Pharmacology (medical), Lymphocytes, Stromal tumor, health care economics and organizations, 0303 health sciences, CHEMOTHERAPY, Sciences bio-médicales et agricoles, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], PROGNOSTIC VALUE, Clinical Practice, 030220 oncology & carcinogenesis, Educational resources, Immunosurveillance, medicine.medical_specialty, 3122 Cancers, [SDV.CAN]Life Sciences [q-bio]/Cancer, IMMUNITY, lcsh:RC254-282, Article, Limfòcits, Càncer de mama, 03 medical and health sciences, Gastrointestinal cancer, SDG 3 - Good Health and Well-being, Internal medicine, 692/53/2422, medicine, Radiology, Nuclear Medicine and imaging, Càncer gastrointestinal, 030304 developmental biology, Predictive biomarker, Tumor-infiltrating lymphocytes, business.industry, Médecine pathologie humaine, medicine.disease, Cancérologie, Human medicine, business, SYSTEM, 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., info:eu-repo/semantics/published

Published
2020
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8. The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group

Author

El Bairi, K, Haynes, HR, Blackley, E, Fineberg, S, Shear, J, Turner, S, de Freitas, JR, Sur, D, Amendola, LC, Gharib, M, Kallala, A, Arun, I, Azmoudeh-Ardalan, F, Fujimoto, L, Sua, LF, Liu, S-W, Lien, H-C, Kirtani, P, Balancin, M, El Attar, H, Guleria, P, Yang, W, Shash, E, Chen, I-C, Bautista, V, Do Prado Moura, JF, Rapoport, BL, Castaneda, C, Spengler, E, Acosta-Haab, G, Frahm, I, Sanchez, J, Castillo, M, Bouchmaa, N, Zin, RRM, Shui, R, Onyuma, T, Husain, Z, Willard-Gallo, K, Coosemans, A, Perez, EA, Provenzano, E, Ericsson, PG, Richardet, E, Mehrotra, R, Sarancone, S, Ehinger, A, Rimm, DL, Bartlett, JMS, Viale, G, Denkert, C, Hida, AI, Sotiriou, C, Loibl, S, Hewitt, SM, Badve, S, Symmans, WF, Kim, RS, Pruneri, G, Goel, S, Francis, PA, Inurrigarro, G, Yamaguchi, R, Garcia-Rivello, H, Horlings, H, Afqir, S, Salgado, R, Adams, S, Kok, M, Dieci, MV, Michiels, S, Demaria, S, Loi, S, El Bairi, K, Haynes, HR, Blackley, E, Fineberg, S, Shear, J, Turner, S, de Freitas, JR, Sur, D, Amendola, LC, Gharib, M, Kallala, A, Arun, I, Azmoudeh-Ardalan, F, Fujimoto, L, Sua, LF, Liu, S-W, Lien, H-C, Kirtani, P, Balancin, M, El Attar, H, Guleria, P, Yang, W, Shash, E, Chen, I-C, Bautista, V, Do Prado Moura, JF, Rapoport, BL, Castaneda, C, Spengler, E, Acosta-Haab, G, Frahm, I, Sanchez, J, Castillo, M, Bouchmaa, N, Zin, RRM, Shui, R, Onyuma, T, Husain, Z, Willard-Gallo, K, Coosemans, A, Perez, EA, Provenzano, E, Ericsson, PG, Richardet, E, Mehrotra, R, Sarancone, S, Ehinger, A, Rimm, DL, Bartlett, JMS, Viale, G, Denkert, C, Hida, AI, Sotiriou, C, Loibl, S, Hewitt, SM, Badve, S, Symmans, WF, Kim, RS, Pruneri, G, Goel, S, Francis, PA, Inurrigarro, G, Yamaguchi, R, Garcia-Rivello, H, Horlings, H, Afqir, S, Salgado, R, Adams, S, Kok, M, Dieci, MV, Michiels, S, Demaria, S, and Loi, S

Abstract

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

Published
2021

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

Author

Hudecek, J., Voorwerk, L., van Seijen, M., Nederlof, I., de Maaker, M., van den Berg, J., van de Vijver, K. K., Sikorska, K., Adams, S., Demaria, S., Viale, G., Nielsen, T. O., Badve, S. S., Michiels, S., Symmans, W. F., Sotiriou, C., Rimm, D. L., Hewitt, S. M., Denkert, C., Loibl, S., Loi, S., Bartlett, J. M. S., Pruneri, G., Dillon, D. A., Cheang, M. C. U., Tutt, A., Hall, J. A., Kos, Z., Salgado, R., Kok, M., Horlings, H. M., Hyytiainen, A., Hida, A. I., Thompson, A., Lefevre, A., Lazar, A. J., Gown, A., Lo, A., Sapino, A., Madabhushi, A., Moreira, A., Richardson, A., Vingiani, A., Beck, A. H., Bellizzi, A. M., Guerrero, A., Grigoriadis, A., Ehinger, A., Garrido-Castro, A., Vincent-Salomon, A., Laenkholm, A. -V., Sharma, A., Cimino-Mathews, A., Srinivasan, A., Acs, B., Singh, B., Calhoun, B., Haibe-Kans, B., Solomon, B., Thapa, B., Nelson, B. H., Gallas, B. D., Castaneda, C., Ballesteros-Merino, C., Criscitiello, C., Boeckx, C., Colpaert, C., Quinn, C., Chennubhotla, C. S., Swanton, C., Solinas, C., Hiley, C., Drubay, D., Bethmann, D., Moore, D. A., Larsimont, D., Sabanathan, D., Peeters, D., Zardavas, D., Hoflmayer, D., Johnson, D. B., Thompson, E. A., Brogi, E., Perez, E., Elgabry, E. A., Stovgaard, E. S., Blackley, E. F., Roblin, E., Reisenbichler, E., Bellolio, E., Balslev, E., Chmielik, E., Gaire, F., Andre, F., F. -I., Lu, Azmoudeh-Ardalan, F., Rojo, F., Gruosso, T., Ciompi, F., Peale, F., Hirsch, F. R., Klauschen, F., Penault-Llorca, F., Acosta Haab, G., Farshid, G., van den Eynden, G., Curigliano, G., Floris, G., Broeckx, G., Gonzalez-Ericsson, Koeppen, H., Haynes, H. R., Mcarthur, H., Joensuu, H., Olofsson, H., Lien, H. -C., Chen, I. -C., Cree, I., Frahm, I., Brcic, I., Chan, J., Ziai, J., Brock, J., Wesseling, J., Giltnane, J., Kerner, J. K., Thagaard, J., Braybrooke, J. P., van der Laak, J. A. W. M., Lemonnier, J., Zha, J., Ribeiro, J., Lennerz, J. K., Carter, J. M., Saltz, J., Hartman, J., Hainfellner, J., Quesne, J. L., Juco, J. W., Reis-Filho, J., Sanchez, J., Sparano, J., Cucherousset, J., Araya, J. C., Adam, J., Balko, J. M., Saeger, K., Siziopikou, K., Willard-Gallo, K., Weber, K., Pogue-Geile, K. L., Steele, K. E., Emancipator, K., Abduljabbar, K., El Bairi, K., Blenman, K. R. M., Allison, K. H., Korski, K., Pusztai, L., Comerma, L., Buisseret, L., Cooper, L. A. D., Shi, L., Kooreman, L. F. S., Molinero, L., Estrada, M. V., Lacroix-Triki, M., Al Bakir, M., Sebastian, M. M., van de Vijver, M., Balancin, M. L., Dieci, M. V., Mathieu, M. -C., Rebelatto, M. C., Piccart, M., Hanna, M. G., Goetz, M. P., Preusser, M., Khojasteh, M., Sanders, M. E., Regan, M. M., Barnes, M., Christie, M., Misialek, M., Ignatiadis, M., van Bockstal, M., Castillo, M., Amgad, M., Harbeck, N., Tung, N., Laudus, N., Sirtaine, N., Burchardi, N., Ternes, N., Radosevic-Robin, N., Gluz, O., Grimm, O., Nuciforo, P., Jank, P., Gonzalez-Ericsson, P., Kirtani, P., Jelinic, P., Watson, P. H., Savas, P., Francis, P. A., Russell, P. A., Singh, R., Kim, R. S., Pierce, R. H., Hills, R., Leon-Ferre, R., de Wind, R., Shui, R., De Clercq, S., Leung, S., Tabbarah, S., Souza, S. C., O'Toole, S., Swain, S., Dudgeon, S., Willis, S., Ely, S., Kim, S. -R., Bedri, S., Irshad, S., Liu, S. -W., Goel, S., Hendry, S., Bianchi, S., Braganca, S., Paik, S., Wienert, S., Fox, S. B., Luen, S. J., Naber, S., Schnitt, S. J., Sua, L. F., Lakhani, S. R., Fineberg, S., Soler, T., Gevaert, T., D'Alfonso, T., John, T., Sugie, T., Kurkure, U., Bossuyt, V., Manem, V., Camara, V. P., Tong, W., Chen, W., Yang, W., Tran, W. T., Wang, Y., Yuan, Y., Allory, Y., Husain, Z., Bago-Horvath, Z., Division of Pathology and Laboratory Medicine, Università degli Studi di Milano [Milano] (UNIMI)-European Institute of Oncology [Milan] (ESMO), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR), Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Charité, Institute of Pathology, Translational Tumorpathology Unit, German Breast Group, Breast Cancer Translational Research Laboratory, Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), University of the Sunshine Coast (USC), European Institute of Oncology [Milan] (ESMO), Breakthrough Breast Cancer Centre, London Institute of Cancer, Department of Pathology, The Netherlands Cancer Institute, Division of Experimental Therapy, The Netherlands Cancer Institute NKI/AvL, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Hudeček, Jan [0000-0003-1071-5686], van de Vijver, Koen K [0000-0002-2026-9790], Demaria, Sandra [0000-0003-4426-0499], Badve, Sunil S [0000-0001-8861-9980], Symmans, William Fraser [0000-0002-1526-184X], Rimm, David L [0000-0001-5820-4397], Loi, Sherene [0000-0001-6137-9171], Hall, Jacqueline A [0000-0003-0708-1360], Horlings, Hugo M [0000-0003-4782-8828], Apollo - University of Cambridge Repository, van de Vijver, Koen K. [0000-0002-2026-9790], Badve, Sunil S. [0000-0001-8861-9980], Rimm, David L. [0000-0001-5820-4397], Hall, Jacqueline A. [0000-0003-0708-1360], Horlings, Hugo M. [0000-0003-4782-8828], Università degli Studi di Milano = University of Milan (UNIMI)-European Institute of Oncology [Milan] (ESMO), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, German Breast Group (GBG), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], medicine.medical_treatment, MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review Article, lcsh:RC254-282, 631/67/1857, Tumour biomarkers, Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], 03 medical and health sciences, 0302 clinical medicine, Breast cancer, 692/53, Internal medicine, Medicine and Health Sciences, medicine, Pharmacology (medical), Radiology, Nuclear Medicine and imaging, 692/4028/67/580, Stromal tumor, Biomarkers, Tumour immunology, business.industry, Risk management framework, review-article, Médecine pathologie humaine, 631/67/1347, Immunotherapy, Sciences bio-médicales et agricoles, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Review article, Clinical trial, Cancérologie, 030104 developmental biology, 030220 oncology & carcinogenesis, Biomarker (medicine), business
Abstract

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., info:eu-repo/semantics/published

Published
2020
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17. Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Author

Amgad, M, Stovgaard, ES, Balslev, E, Thagaard, J, Chen, W, Dudgeon, S, Sharma, A, Kerner, JK, Denkert, C, Yuan, Y, AbdulJabbar, K, Wienert, S, Savas, P, Voorwerk, L, Beck, AH, Madabhushi, A, Hartman, J, Sebastian, MM, Horlings, HM, Hudecek, J, Ciompi, F, Moore, DA, Singh, R, Roblin, E, Balancin, ML, Mathieu, M-C, Lennerz, JK, Kirtani, P, Chen, I-C, Braybrooke, JP, Pruneri, G, Demaria, S, Adams, S, Schnitt, SJ, Lakhani, SR, Rojo, F, Comerma, L, Badve, SS, Khojasteh, M, Symmans, WF, Sotiriou, C, Gonzalez-Ericsson, P, Pogue-Geile, KL, Kim, RS, Rimm, DL, Viale, G, Hewitt, SM, Bartlett, JMS, Penault-Llorca, F, Goel, S, Lien, H-C, Loibl, S, Kos, Z, Loi, S, Hanna, MG, Michiels, S, Kok, M, Nielsen, TO, Lazar, AJ, Bago-Horvath, Z, Kooreman, LFS, van der Laak, JAWM, Saltz, J, Gallas, BD, Kurkure, U, Barnes, M, Salgado, R, Cooper, LAD, Amgad, M, Stovgaard, ES, Balslev, E, Thagaard, J, Chen, W, Dudgeon, S, Sharma, A, Kerner, JK, Denkert, C, Yuan, Y, AbdulJabbar, K, Wienert, S, Savas, P, Voorwerk, L, Beck, AH, Madabhushi, A, Hartman, J, Sebastian, MM, Horlings, HM, Hudecek, J, Ciompi, F, Moore, DA, Singh, R, Roblin, E, Balancin, ML, Mathieu, M-C, Lennerz, JK, Kirtani, P, Chen, I-C, Braybrooke, JP, Pruneri, G, Demaria, S, Adams, S, Schnitt, SJ, Lakhani, SR, Rojo, F, Comerma, L, Badve, SS, Khojasteh, M, Symmans, WF, Sotiriou, C, Gonzalez-Ericsson, P, Pogue-Geile, KL, Kim, RS, Rimm, DL, Viale, G, Hewitt, SM, Bartlett, JMS, Penault-Llorca, F, Goel, S, Lien, H-C, Loibl, S, Kos, Z, Loi, S, Hanna, MG, Michiels, S, Kok, M, Nielsen, TO, Lazar, AJ, Bago-Horvath, Z, Kooreman, LFS, van der Laak, JAWM, Saltz, J, Gallas, BD, Kurkure, U, Barnes, M, Salgado, R, and Cooper, LAD

Abstract

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.

Published
2020

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

Author

Kos, Z, Roblin, E, Kim, RS, Michiels, S, Gallas, BD, Chen, W, van de Vijver, KK, Goel, S, Adams, S, Demaria, S, Viale, G, Nielsen, TO, Badve, SS, Symmans, WF, Sotiriou, C, Rimm, DL, Hewitt, S, Denkert, C, Loibl, S, Luen, SJ, Bartlett, JMS, Savas, P, Pruneri, G, Dillon, DA, Cheang, MCU, Tutt, A, Hall, JA, Kok, M, Horlings, HM, Madabhushi, A, van der Laak, J, Ciompi, F, Laenkholm, A-V, Bellolio, E, Gruosso, T, Fox, SB, Araya, JC, Floris, G, Hudecek, J, Voorwerk, L, Beck, AH, Kerner, J, Larsimont, D, Declercq, S, Van den Eynden, G, Pusztai, L, Ehinger, A, Yang, W, AbdulJabbar, K, Yuan, Y, Singh, R, Hiley, C, al Bakir, M, Lazar, AJ, Naber, S, Wienert, S, Castillo, M, Curigliano, G, Dieci, M-V, Andre, F, Swanton, C, Reis-Filho, J, Sparano, J, Balslev, E, Chen, I-C, Stovgaard, EIS, Pogue-Geile, K, Blenman, KRM, Penault-Llorca, F, Schnitt, S, Lakhani, SR, Vincent-Salomon, A, Rojo, F, Braybrooke, JP, Hanna, MG, Soler-Monso, MT, Bethmann, D, Castaneda, CA, Willard-Gallo, K, Sharma, A, Lien, H-C, Fineberg, S, Thagaard, J, Comerma, L, Gonzalez-Ericsson, P, Brogi, E, Loi, S, Saltz, J, Klaushen, F, Cooper, L, Amgad, M, Moore, DA, Salgado, R, Kos, Z, Roblin, E, Kim, RS, Michiels, S, Gallas, BD, Chen, W, van de Vijver, KK, Goel, S, Adams, S, Demaria, S, Viale, G, Nielsen, TO, Badve, SS, Symmans, WF, Sotiriou, C, Rimm, DL, Hewitt, S, Denkert, C, Loibl, S, Luen, SJ, Bartlett, JMS, Savas, P, Pruneri, G, Dillon, DA, Cheang, MCU, Tutt, A, Hall, JA, Kok, M, Horlings, HM, Madabhushi, A, van der Laak, J, Ciompi, F, Laenkholm, A-V, Bellolio, E, Gruosso, T, Fox, SB, Araya, JC, Floris, G, Hudecek, J, Voorwerk, L, Beck, AH, Kerner, J, Larsimont, D, Declercq, S, Van den Eynden, G, Pusztai, L, Ehinger, A, Yang, W, AbdulJabbar, K, Yuan, Y, Singh, R, Hiley, C, al Bakir, M, Lazar, AJ, Naber, S, Wienert, S, Castillo, M, Curigliano, G, Dieci, M-V, Andre, F, Swanton, C, Reis-Filho, J, Sparano, J, Balslev, E, Chen, I-C, Stovgaard, EIS, Pogue-Geile, K, Blenman, KRM, Penault-Llorca, F, Schnitt, S, Lakhani, SR, Vincent-Salomon, A, Rojo, F, Braybrooke, JP, Hanna, MG, Soler-Monso, MT, Bethmann, D, Castaneda, CA, Willard-Gallo, K, Sharma, A, Lien, H-C, Fineberg, S, Thagaard, J, Comerma, L, Gonzalez-Ericsson, P, Brogi, E, Loi, S, Saltz, J, Klaushen, F, Cooper, L, Amgad, M, Moore, DA, and Salgado, R

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.

Published
2020

30. Effect of Cisapride on Gastric Dysrhythmia and Emptying of Indigestible Solids in Type-II Diabetic Patients.

Author

CHANG, C.-S., LIEN, H.-C., YEH, H.-Z., POON, S.-K., TUNG, C.-F., and CHEN, G.-H.

Subjects
*CISAPRIDE, *GASTRIC diseases
Abstract

Background: Abnormal gastric slow-wave frequencies have been observed in diabetic gastroparesis. To evaluate the effect of cisapride on gastric dysrhythmia and emptying of indigestible solids, 20 type-II diabetic patients with symptoms suggestive of gastroparesis were enrolled in this study. Methods: Cutaneous electrogastrography, gastric emptying of radiopaque markers, and evaluation of upper gastrointestinal symptoms were performed before and after administration of an 8-week course of cisapride. Results: The fasting-state percentages of dominant frequency in normal and tachygastric ranges improved significantly after an 8-week course of cisapride treatment (P < 0.01 and P < 0.05, respectively). The post-meal percentages of dominant frequency in the tachygastric range also improved significantly after cisapride treatment (P < 0.05). The upper gastrointestinal symptoms score decreased significantly, and gastric emptying of radiopaque markers also increased significantly after 8 weeks of cisapride treatment (P < 0.01). Conclusions: In conclusion, this study showed that cisapride can improve gastric dysrhythmia during both fasting and post-meal phases in patients with diabetic gastroparesis. In addition, upper GI symptoms and gastric emptying of indigestible solids may also show significant improvement after 8 weeks of cisapride treatment. [ABSTRACT FROM AUTHOR]

Published
1998
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31. Gastric Dysrhythmia in Uremic Patients on Maintenance Hemodialysis.

Author

Ko, C.-W., Chang, C.-S., Lien, H.-C., Wu, M.-J., and Chen, G.-H.

Subjects
GASTROINTESTINAL diseases, HEMODIALYSIS patients
Abstract

Background: Dyspeptic symptoms are common in uremic patients receiving hemodialysis. Investigators have placed emphasis on the changes in histopathology and physiology of the gastrointestinal tract. But not much data about the gastric myoelectric activity are available. The aim of this study was to assess gastric myoelectric activity in uremic patients undergoing hemodialysis. Methods: Fifty-eight subjects were enrolled. They were assigned to: group I, uremic patients undergoing hemodialysis with dyspeptic complaints (n = 20); group II, non-uremic patients with matched dyspeptic complaints (n = 20); and group III, healthy volunteers without dyspeptic complaints (n = 18). Gastric myoelectric activity was measured with abdominal surface electrodes in each person. Patients in group I were measured twice, before (group Ia) and after (group Ib) hemodialysis. The data were compared between the groups. Results: In the pre-hemodialysis period there was a significantly lower percentage of normal slow-wave frequency when compared with group III (fasting, 66.54% ± 5.39% versus 84.58% ± 3.63%; P < 0.005; fed, 72.25% ± 4.16% versus 89.06% ± 2.57%; P < 0.01). In the post-hemodialysis period the difference was even more profound (fasting, 46.52% ± 4.26% versus 84.58% ± 3.63%; P < 0.001; fed, 51.49% ± 6.89% versus 89.06% ± 2.57%; P < 0.005). Yet, when compared with group II, a significant difference existed only in the post-hemodialysis period (fasting, 46.52% ± 4.26% versus 67.30% ± 3.46%; P < 0.001; fed, 51.49% ± 6.89% versus 70.41% ± 4.39%; P < 0.01). Another finding is that hemodialysis decreased the gastric myoelectric activity after hemodialysis (fasting, 66.54% ± 5.39% versus 46.52% ± 4.26%; P < 0.001; fed, 72.25% ± 4.16% versus 51.49% ± 6.89%; P < 0.005). Conclusions: Uremic patients undergoing hemodialysis have impaired gastric myoelectric activity. Interestingly, hemodialysis seems to cause deterioration in gastric myoelectric activity. [ABSTRACT FROM AUTHOR]

Published
1998
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32. Endoscopic treatment of bleeding gastric varices by N-butyl-2-cyanoacrylate (Histoacryl) injection: Long-term efficacy and safety

Author

Huang, Y.-H., Yeh, H.-Z., Chen, G.-H., Chang, C.-S., Wu, C.-Y., Poon, S.-K., Lien, H.-C., and Yang, S.-S.

Abstract

Background: The long-term efficacy and safety of the endoscopic injection of N-butyl-2-cyanoacrylate (Histoacryl) were evaluated to define its role as the initial treatment for bleeding gastric varices. Methods: Ninety patients with bleeding gastric varices underwent endoscopic injections of Histoacryl for hemostasis within a 6-year period. Histoacryl was injected intravariceally as a 1:1 mixture with Lipiodol. Among the 90 patients, 5 had active bleeding and 85 had recent bleeding. Most of the varices were large (F2 or F3, 85 cases). The most common locations were the fundus and the posterior wall of the proximal body (94.4%). After Histoacryl injection, patients were followed endoscopically with retreatment as necessary. Results: The rate of hemostasis at 1 week was 94.4%. Recurrent bleeding occurred in 23.3% of the patients from 3 days to 16 months after the initial injection. Recurrent bleeding was stopped with reinjections of Histoacryl in 16.7% of the patients. The rate of definitive hemostasis was 93.3% (84 of 90). The treatment failure-related mortality rate was 2.2% (2 of 90). To date, 35 patients have died, mostly as a result of malignancy or liver failure, and 55 are still alive. The determining factor for long-term survival was the underlying disease leading to portal hypertension. There were few long-term complications except for Histoacryl cast extrusion-related mucosal defects. Conclusions: Endoscopic injection of Histoacryl is highly effective for the treatment of bleeding gastric varices, with rare complications both acutely and long term. This treatment modality is appropriate as the first choice for bleeding gastric varices. (Gastrointest Endosc 2000;52:160-7.)

Published
2000
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35. Phosphorylation of ezh2 at t416 by cdk2 contributes to the malignancy of triple negative breast cancers

Author

Yang, C. -C, Labaff, A., Wei, Y., Nie, L., Xia, W., Huo, L., Yamaguchi, H., Hsu, Y. -H, Hsu, J. L., Liu, D., Lang, J., Du, Y., Lien, H. -C, Li, L. -Y, Deng, R., Li-Chuan Chan, Yao, J., Kleer, C. G., Hortobagyi, G. N., and Hung, M. -C

Subjects
Original Article, macromolecular substances
Abstract

Triple-negative breast cancer (TNBC), which is closely related to basal-like breast cancer, is a highly aggressive subtype of breast cancer that initially responds to chemotherapy but eventually develops resistance. This presents a major clinical challenge as there are currently no effective targeted therapies available due to its lack of HER2 and estrogen receptor expression. Here, we show that cyclin E and the enhancer of zeste 2 (EZH2) are closely co-expressed in TNBC patients, and cyclin E/CDK2 phosphorylates EZH2 at T416 (pT416-EZH2) in vivo. Phosphorylation of EZH2 at T416 enhances the ability of EZH2 to promote TNBC cell migration/invasion, tumorsphere formation, and in vivo tumor growth. In addition, high pT416-EZH2 correlates with poorer survival in TNBC patients. These findings suggest that pT416 has the potential to serve as a therapeutic biomarker for the aggressive forms of breast cancer and provide a rationale for the use of CDK2 inhibitors to treat TNBC.

40. Electrogastrographic Study of the Effect of Transcatheter Arterial Chemoembolization on Gastric Myoelectric Activity.

Author

CHANG, C.-S., LIEN, H.-C., YEH, H.-Z., POON, S.-K., YANG, S.-S., and CHEN, G.-H.

Subjects
*ELECTROGASTROGRAPHY, *LIVER cancer
Abstract

Examines the use of electrogastrography (EGG) to determine the effect of transcatheter arterial chemoembolization (TACE) on gastric myoelectric activity. Relationship between the changes in myoelectric activity and the occurrence of gastrointestinal symptoms; Use of TACE in the treatment of hepatocellular carcinoma; Identification of the abnormalities of EGG.

Published
1998

41. Genetic polymorphisms from genome-wide association study associated with the metabolic and cell proliferation pathways affect the time to distant metastases of hormone receptor-positive and Her2-negative early breast cancer.

Author

Huang, C.-S., Kuo, S.-H., Yang, S.-Y., Lien, H.-C., Lin, C.-H., Lu, Y.-S., Cheng, A.-L., and Chang, K.-J.

Subjects
*SINGLE nucleotide polymorphisms, *BREAST cancer research, *TAMOXIFEN, *HORMONE therapy, *ESTRONE, *ESTRADIOL
Abstract

Background: Single nucleotide polymorphisms (SNPs) identified from genome-wide association study (GWAS) have been found to be associated with breast cancer risk. We hypothesized that candidate genes and genes derived from GWAS involving in the Estrone/Estradiol (E2)/Tamoxifen biosynthesis may influence the adjuvant hormonal therapy effect and the survival. In this study, we sought to investigate whether these SNPs are associated with prognosis of hormone receptor (HR)-positive breast cancer patients, especially in HER2-negative patients. Patients and methods: We selected breast cancer susceptibility SNPs identified by GWAS, SNPs in tamoxifen metabolizing related genes, and SNPs in estrogen receptor genes and estrogen metabolism genes, and genotyped for variations of above genes, including ALDH3A1, CYP2C19, COMT, CYP19, MAP3K1, FGFR2, TNRC9, HCN1, ERCC4, CYP3A5, UGT1A1, ER, ABCG2, CYP2B6, CYP2D6, 5p12 in 171 hormone receptor-positive, and Her2-negative early breast cancer patients (127 with negative lymph node [LN], and 44 with 1-3 positive LN). All patients received adjuvant hormonal therapy. The associations were examined between SNPs and distance disease-free survival (DDFS), and overall survival (OS) by using the log-rank test and Cox's proportional hazard model. Furthermore, we combined clinicopathologic features and SNPs into the risk score analysis to further validate above identified genetic markers. Results: We found that SNPs of CYP2B6 (rs3211371), FGFR2 (rs2981582), and MAP3K1 (rs889312 ) were significantly associated with DDFS and OS. Furthermore, in lymph node-negative patients, CYP2B6 (rs3211371), FGFR2 (rs2981582), MAP3K1 (rs889312 ) and 5p12 (rs10941679 and rs4415084) were significantly associated with DDFS and OS, while CYP3A5 (rs776746 ) was significantly associated with OS but not DDFS. We further assessed the associations of disease prognosis with the number of high-risk genotypes in CYP3A5, FGFR2, and MAP3K1, and showed significant dose-response relationships between the number of high-risk alleles at these 3 loci and DDFS (P = 0.005 for trend) and OS (P = 0.0008 for trend). When combining the clinicopathologic features and SNPs into the risk score analysis, patients were divided into 3 subgroups (subgroup 1, risk score<- 1.438, n=43 [LN-positive, n=7]; subgroup 2, risk score between -1.438 and 1.708, n=85 [LN-positive, n=26]; subgroup 3, risk score>1.708, n=43 [LN-positive, n=11]). We found that around 20 % of subgroup 3 patients had early development of distant metastases (DM) in the upfront 3 years (the trend of DM appeared to persist at least 10 years), and subgroup 2 patients had higher risk of DM after 5 years, whereas subgroup 1 patients had no development of DM even after 12 years. Conclusion: Our results indicate that in addition to drug metabolic genes, genes related to cell proliferation, anti-apoptosis, and signaling transduction, for example, CYP3A5, CYP2B6, FGFR2, and MAP3K1 genes were associated with DDFS and OS in HR- positive/Her2-negative breast cancer patients. These findings provide additional insight that the genetic variants, or host factors, may affect the prognosis of breast cancer. [ABSTRACT FROM AUTHOR]

Published
2012
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42. Nizatidine enhances the gastrocolonic response and the colonic peristaltic reflex in humans.

Author

Sun WM, Hasler WL, Lien HC, Montague J, and Owyang C

Subjects
Adult, Female, Humans, Male, Manometry, Mechanoreceptors drug effects, Middle Aged, Stimulation, Chemical, Anti-Ulcer Agents pharmacology, Colon drug effects, Nizatidine pharmacology, Peristalsis drug effects, Stomach drug effects
Abstract

Animal studies demonstrate that nizatidine, an H2-receptor inhibitor, may enhance colonic activity independent of its effect on acid secretion. The effect of nizatidine on human colonic motility is unknown. We evaluated the potential prokinetic property of nizatidine in 12 healthy subjects (10 men and 2 women, age 21-46 years). Each subject received either nizatidine (600 mg), famotidine (80 mg, a H2-receptor inhibitor used as a control), or a placebo, on separate days in randomized order at least 3 days apart. Following an overnight fast, a three-lumen catheter fitted with a stimulus balloon and two barostat bags was placed in the descending colon. The gastrocolonic response was tested by antral balloon inflation and the colonic peristaltic reflex was evaluated by colonic distension. Changes in colonic motility were assessed by volume changes in the barostat bags. Antral distension evoked volume-dependent increases in colonic motility, maximal at a 300-ml inflation, as demonstrated by a reduced bag volume. Nizatidine enhanced colonic motility in response to antral distension at 200 and 300 ml, compared with famotidine and placebo. Colonic distension evoked volume-dependent increases in colonic motility proximal to the stimulus balloon. Compared with famotidine and placebo, nizatidine enhanced the ascending and descending contractile limbs of the peristaltic reflex but did not affect relaxation distal to the balloon. In conclusion, nizatidine enhanced the gastrocolonic response and the colonic peristaltic reflex in healthy subjects. Further research on the prokinetic action of nizatidine in the colon may lead to novel treatments for idiopathic constipation.

Published
2001

43. Predominant Th2/Tc2 polarity of tumor-infiltrating lymphocytes in human cervical cancer.

Author

Sheu BC, Lin RH, Lien HC, Ho HN, Hsu SM, and Huang SC

Subjects
Cytokines biosynthesis, Cytokines genetics, Female, Humans, Immune Tolerance, Immunity, Cellular, In Vitro Techniques, Interleukin-10 biosynthesis, Interleukin-10 genetics, Interleukin-10 immunology, Interleukin-10 pharmacology, Lymphocytes, Tumor-Infiltrating pathology, Neutralization Tests, Phenotype, Recombinant Proteins pharmacology, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets pathology, T-Lymphocytes, Cytotoxic pathology, Th2 Cells pathology, Transforming Growth Factor beta biosynthesis, Transforming Growth Factor beta genetics, Transforming Growth Factor beta immunology, Transforming Growth Factor beta pharmacology, Uterine Cervical Neoplasms genetics, Uterine Cervical Neoplasms pathology, Lymphocytes, Tumor-Infiltrating immunology, T-Lymphocytes, Cytotoxic immunology, Th2 Cells immunology, Uterine Cervical Neoplasms immunology
Abstract

Cytotoxic T lymphocytes (Tc) play a central role in cellular immunity against cancers. The cytotoxic potential of freshly isolated tumor-infiltrating lymphocytes (TILs) is usually not expressed. This suggests the possible existence of as yet unspecified and perhaps complex immunosuppressive factors or cytokines that affect the anti-tumor capacity of these TILs in the tumor milieu. In the present study, we demonstrated for the first time that TILs derived from human cervical cancer tissue consist mainly of Th2/Tc2 phenotypes. In vitro kinetic assays further revealed that cancer cells could direct the tumor-encountered T cells toward the Th2/Tc2 polarity. Cancer cells promote the production of IL-4 and down-regulate the production of IFN-gamma in cancer-encountered T cells. The regulatory effects of cervical cancer cells are mediated mainly by IL-10, and TGF-beta plays only a synergistic role. The cancer-derived effects can be reversed by neutralizing anti-IL-10 and anti-TGF-beta Abs. IL-10 and TGF-beta are present in cancer tissue and weakly expressed in precancerous tissue, but not in normal cervical epithelial cells. Our study strongly suggests important regulatory roles of IL-10 and TGF-beta in cancer-mediated immunosuppression.

Published
2001
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44. A novel role of metalloproteinase in cancer-mediated immunosuppression.

Author

Sheu BC, Hsu SM, Ho HN, Lien HC, Huang SC, and Lin RH

Subjects
Cervix Uteri cytology, Coculture Techniques, Down-Regulation, Epithelial Cells, Female, Gene Expression Regulation, Neoplastic, Humans, Immune Tolerance immunology, Interleukin-2, Isoenzymes biosynthesis, Lymphocyte Activation immunology, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Metalloendopeptidases antagonists & inhibitors, Metalloendopeptidases metabolism, Receptors, Interleukin-2 biosynthesis, Receptors, Interleukin-2 metabolism, Stromal Cells, T-Lymphocytes immunology, T-Lymphocytes metabolism, Tissue Inhibitor of Metalloproteinase-1 pharmacology, Tissue Inhibitor of Metalloproteinase-2 pharmacology, Transcription, Genetic, Metalloendopeptidases immunology, Receptors, Interleukin-2 immunology, Uterine Cervical Neoplasms enzymology, Uterine Cervical Neoplasms immunology
Abstract

Depressed immune responses have been observed frequently in cancer patients. In a variety of human malignancies, the expression of interleukin-2 receptor alpha (IL-2R alpha) on activated tumor-infiltrating lymphocytes was down-regulated. Because IL-2R alpha plays a pivotal role in the development and propagation of functional T cells, its depressed expression may result in poor function of tumor-reactive cytotoxic lymphocytes. For elucidating the mechanism responsible for down-regulation of IL-2R alpha, a coculture model of in vitro mixed autologous lymphocytes and tumor cells was established. Kinetic analysis showed that cervical cancer cells down-regulated IL-2R alpha expression on encountered T cells. The amount of IL-2R alpha mRNA in tumor-infiltrating lymphocytes-derived CD8+ T cells was compatible with that in the corresponding activated CD8+ T cells. Additional evidence showed that cervical cancer cells could induce the release of soluble IL-2R alpha expression on encountered T cells. By using protease inhibition assays we demonstrated that tissue inhibitors of metalloproteinase abrogated the cancer-mediated IL-2R alpha proteolytic process and restored the T-cell proliferation function. Immunohistochemical stainings further revealed prominent metalloproteinase (MMP) expressions, including MMP-1, MMP-2, and MMP-9, in cervical cancer tissues. Additional in vitro studies showed that MMP-9 mediates cleavage of IL-2R alpha and down-regulates the proliferative capability of cancer-encountered T cells. Our findings suggest a new role of MMPs in tumor-mediated immunosuppression and provide a possible therapeutic potential for patients with cervical cancer.

Published
2001

45. Can percutaneous endoscopic jejunostomy prevent gastroesophageal reflux in patients with preexisting esophagitis?

Author

Lien HC, Chang CS, and Chen GH

Subjects
Aged, Enteral Nutrition, Food, Formulated, Humans, Hydrogen-Ion Concentration, Male, Monitoring, Physiologic, Pneumonia, Aspiration prevention & control, Stroke complications, Esophagitis, Peptic complications, Gastroesophageal Reflux prevention & control, Jejunostomy methods
Abstract

Objective: Percutaneous endoscopic jejunostomy has been used for preventing pulmonary aspiration arising from gastric contents by concomitant jejunal feeding and gastric decompression in susceptible patients. Our objective was to evaluate gastroesophageal reflux in patients with percutaneous endoscopic jejunostomy tube feeding., Methods: Eight cerebrovascular accident patients with percutaneous endoscopic jejunostomy tube placement caused by reflux esophagitis with hematemesis, food regurgitation or vomiting, and/or recurrent aspiration pneumonia were tested for gastroesophageal reflux using 24-h esophageal pH monitoring during continuous jejunal liquid meal or saline infusion with concomitant gastric decompression. Twenty-four hour pH monitoring was also performed during intragastric feeding on a different day., Results: During the liquid meal feeding period, percutaneous endoscopic jejunostomy feeding reduced esophageal acid exposure 46% [12.9% (4.9-28.2%) versus 24.0% (19.0-40.6%), p = 0.01], compared to intragastric feeding. However, in the period of the jejunal tube infusion, esophageal acid exposure was significantly lower during saline infusion than during meal infusion [3.2 (0.0%-10.8%) versus 12.9% (4.9-28.2%), p = 0.008]., Conclusion: Percutaneous endoscopic jejunostomy feeding reduced but did not eliminate gastroesophageal reflux, compared to intragastric feeding in patients with severe gastroesophageal reflux. However, gastroesophageal reflux during percutaneous jejunal feeding was associated with meal infusion. This might, in part, explain the failure of percutaneous endoscopic jejunostomy tube placement to prevent pulmonary aspiration.

Published
2000
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46. Metastatic carcinoma to the jugular foramen.

Author

Chao CK, Sheen TS, Lien HC, and Hsu MM

Subjects
Adenocarcinoma diagnosis, Fatal Outcome, Glomus Jugulare Tumor diagnosis, Humans, Lung Neoplasms diagnosis, Magnetic Resonance Imaging, Male, Middle Aged, Skull Neoplasms diagnosis, Tomography, X-Ray Computed, Adenocarcinoma secondary, Glomus Jugulare Tumor secondary, Lung Neoplasms pathology, Skull Neoplasms secondary, Temporal Bone
Published
2000
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47. Expression of cyclin-dependent kinase 6 (cdk6) and frequent loss of CD44 in nasal-nasopharyngeal NK/T-cell lymphomas: comparison with CD56-negative peripheral T-cell lymphomas.

Author

Lien HC, Lin CW, Huang PH, Chang ML, and Hsu SM

Subjects
Adult, Aged, Cyclin-Dependent Kinase 6, Female, Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor, Humans, Killer Cells, Natural immunology, Lymphoma, T-Cell genetics, Lymphoma, T-Cell immunology, Lymphoma, T-Cell, Peripheral genetics, Lymphoma, T-Cell, Peripheral immunology, Male, Middle Aged, Nasopharyngeal Neoplasms genetics, Nasopharyngeal Neoplasms immunology, Nose Neoplasms genetics, Nose Neoplasms immunology, Protein Serine-Threonine Kinases genetics, Retrospective Studies, Antigens, CD analysis, CD56 Antigen analysis, Cyclin-Dependent Kinases, Hyaluronan Receptors analysis, Killer Cells, Natural pathology, Lymphoma, T-Cell pathology, Lymphoma, T-Cell, Peripheral pathology, Nasopharyngeal Neoplasms pathology, Nose Neoplasms pathology, Protein Serine-Threonine Kinases analysis
Abstract

Lymphomas involving the nasal and nasopharyngeal region mainly include CD56-positive natural killer (NK)/T-cell lymphomas, CD56-negative peripheral T-cell lymphomas (PTL), and B-cell lymphomas. Among these, the CD56-positive lymphoma, presumably of an NK/T-cell nature, is frequently seen in Asian, Mexican, and South American patients. NK cells are proposed to be closer developmentally to T cells than to other lymphoid cells, because bipotential common progenitor cells of NK/T-cell lineage have been isolated. In this study, we collected 47 cases of nasal lymphoma and investigated the phenotypic difference between NK/T-cell lymphoma and PTL by examining the pattern of the developmentally differentially expressed molecules cdk6 (cyclin-dependent kinase 6), CD44, CD117, and by examining the rearrangement of the T-cell receptor gene (TcR-GR). cdk6, an essential regulator of the cell cycle in G1 progression, was over-expressed in a subset of cortical thymocytes, but absent in mature thymocytes. In contrast, CD44, a glycosylated adhesion molecule, was absent in cortical thymocytes, but present in mature thymocytes and peripheral activated T cells. We found both over-expression of nuclear cdk6 (n-cdk6) and frequent absence of CD44 in nasal CD56-positive NK/T-cell lymphomas, in contrast to most nasal CD56-negative PTL, which were CD44-immunoreactive with weak or no expression of n-cdk6. Almost all tested cases of NK/T-cell lymphoma displayed a germ-line configuration of TcR, without evidence of gene rearrangement. Thus, there seems to be a useful distinction between the classical NK/T type of nasal lymphoma (CD56+/n-cdk6+/CD44-/TcR-GR-) and PTL (CD56-/n-cdk6-/CD44+/TcR-GR+) involving the nasal region. The presence of Epstein-Barr virus does not seem to be a good marker for distinguishing between NK/T lymphoma and PTL involving the nasal region.

Published
2000
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48. Helicobacter pylori infection and gastric emptying in cirrhotic patients with symptoms of dyspepsia.

Author

Chang CS, Kao CH, Yeh HZ, Lien HC, Chen GH, and Wang SJ

Subjects
Adult, Aged, Breath Tests, Chronic Disease, Dyspepsia complications, Dyspepsia diagnosis, Endoscopy, Digestive System, Female, Helicobacter Infections complications, Helicobacter Infections epidemiology, Humans, Incidence, Liver Cirrhosis complications, Liver Cirrhosis diagnosis, Male, Middle Aged, Severity of Illness Index, Taiwan epidemiology, Urea analysis, Dyspepsia physiopathology, Gastric Emptying physiology, Helicobacter Infections physiopathology, Liver Cirrhosis physiopathology
Abstract

Background/aims: Chronic gastric Helicobacter pylori infection is common in patients with dyspeptic symptoms. The effect of H. pylori infection on gastric emptying, in cirrhotic patients with dyspeptic symptoms, has never been studied. Therefore, we investigated the incidence of H. pylori infection and its relationship with gastric emptying in cirrhotic patients with dyspepsia., Methodology: A solid-phase gastric emptying study and 14C urea breath test were performed in 80 cirrhotic patients with dyspepsia. The severity of cirrhosis was assessed according to Child-Pugh's classification., Results: The overall incidence of delayed gastric emptying was 75%. Delayed gastric emptying incidences according to severity of cirrhosis were 71.4% for Child-A, 73.1% for Child-B, and 80.8% for Child-C. The differences were not significant. The incidence of H. pylori infection was 52.5% overall. H. pylori infection rates were 46.4% for Child-A, 42.3% for Child-B, and 69.2% for Child-C. Although there was a tendency for the infection rate to increase with the severity of liver cirrhosis, the difference was not significant. In addition, there were no significant differences in the incidences of H. pylori infection among patients with normal and delayed gastric emptying., Conclusions: Delayed gastric emptying is common in cirrhotic patients with dyspepsia. However, the status of H. pylori infection does not seem to play a role in delayed gastric emptying in these patients.

Published
1999

49. Merkel cell carcinoma and chronic arsenicism.

Author

Lien HC, Tsai TF, Lee YY, and Hsiao CH

Subjects
Aged, Aged, 80 and over, Carcinoma, Merkel Cell epidemiology, Chronic Disease, Endemic Diseases, Environmental Exposure, Female, Humans, Male, Middle Aged, Poisoning epidemiology, Skin Neoplasms epidemiology, Taiwan epidemiology, Arsenic Poisoning, Carcinoma, Merkel Cell chemically induced, Skin Neoplasms chemically induced
Abstract

Arsenic is a well-documented human carcinogen. Bowen's disease, squamous cell carcinoma, and basal cell carcinoma are the most common skin cancers found in patients exposed to arsenic over the long term. Merkel cell carcinoma has been documented in Taiwanese patients who resided in an endemic area of black foot disease, another condition found in patients with chronic arsenicism. We collected all cases of Merkel cell carcinoma diagnosed at two medical centers in Taiwan (N = 11) to find a possible association between chronic arsenicism and Merkel cell carcinoma. In our study 6 of the 11 patients were residents of the endemic areas for chronic arsenicism.

Published
1999

50. The effect of intragastric acidity on Helicobacter pylori eradication with bismuth-metronidazole-amoxicillin.

Author

Chang CS, Yang CY, Wong FN, Chen GH, Lien HC, Yeh HZ, and Poon SK

Subjects
Adult, Aged, Anti-Ulcer Agents administration & dosage, Drug Therapy, Combination, Duodenal Ulcer metabolism, Duodenal Ulcer microbiology, Female, Gastrins blood, Helicobacter Infections complications, Helicobacter Infections microbiology, Humans, Male, Middle Aged, Monitoring, Physiologic, Pepsinogen A blood, Ranitidine administration & dosage, Amoxicillin administration & dosage, Antacids administration & dosage, Anti-Bacterial Agents administration & dosage, Bismuth administration & dosage, Duodenal Ulcer drug therapy, Gastric Acidity Determination, Helicobacter Infections drug therapy, Helicobacter pylori isolation & purification, Metronidazole administration & dosage, Organometallic Compounds administration & dosage, Penicillins administration & dosage, Salicylates administration & dosage
Abstract

Background/aims: Adding an acid secretion inhibitor to anti-H. pylori regimens may be potentially valuable for enhancing the effectiveness of antimicrobials that exhibit markedly reduced activity at low pH. This study was conducted to evaluate intragastric acidity as a factor in H. pylori eradication with bismuth-based triple therapy., Methodology: Forty patients with duodenal ulcer and H. pylori infection were included. The patients were divided into 2 groups--normacid (n = 20) and hyperacid (n = 20)--based on the amount of time that 24-hour intragastric pH took to reach the level pH > or = 3. All patients received bismuth subsalicylate (600 mg 3 times daily), metronidazole (500 mg 3 times daily) and amoxicillin (500 mg 3 times daily) for 2 weeks. Then, all patients continued treatment with ranitidine (150 mg twice daily) for 8 weeks prior to the follow-up examination. Blood samples were collected before treatment for measurement of fasting gastrin and pepsinogen-I., Results: Nine patients (45%) in the normacid group and 8 patients (40%) in the hyperacid group reported side effects. However, there were only 2 patients (10%) in each group who withdrew from the study due to intolerance of side-effects. There was no difference in the H. pylori eradication rate between the normacid and hyperacid groups (16/18, 88.9% vs. 15/18, 83.3%)., Conclusions: Without co-administration of anti-secretary agents, intragastric acid is not a significant factor in the effectiveness of H. pylori eradication with bismuth-based triple therapy.

Published
1999

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