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1. Diagnosis and management of isolated serous tubal intraepithelial carcinoma: A qualitative focus group study

Author

Negri, S, Fisch, C, de Hullu, J, van Bommel, M, Simons, M, Bogaerts, J, Apperloo, M, Baiocchi, G, Bakker, J, Bart, J, van Beekhuizen, H, Bernardini, M, Boere, I, Bulten, J, Chen, L, Chrzan, A, Dorum, A, Ewing-Graham, P, Ferrero, A, Floter Radestad, A, Fruscio, R, Gaarenstroom, K, Garcia, C, Harter, P, Hoogstad-van Evert, J, de Iaco, P, Klooster, A, Kooreman, L, Jacobsen, M, Kruse, A, Kwon, J, Lawson, B, Lax, S, van Lonkhuijzen, L, Lu, K, Manchanda, R, Marchetti, C, Mccluggage, W, Mcnally, O, Mourits, M, Nicum, S, Norquist, B, Perrone, A, Piek, J, Polastro, L, Polee, M, Rabban, J, Reesink, N, de los Reyes Oliver Perez, M, Roes, E, Rychlik, A, Shih, I, Soong, T, Speiser, P, Stone, R, Tamussino, K, Tognon, G, Tuninetti, V, Valabrega, G, Vos, M, Welz, J, Zizioli, V, Hermens, R, Steenbeek, M, Negri S., Fisch C., de Hullu J. A., van Bommel M., Simons M., Bogaerts J., Apperloo M. J. A., Baiocchi G., Bakker J. L., Bart J., van Beekhuizen H. J., Bernardini M. Q., Boere I., Bulten J., Chen L. -M., Chrzan A., Dorum A., Ewing-Graham P. C., Ferrero A., Floter Radestad A., Fruscio R., Gaarenstroom K. N., Garcia C., Harter P., Hoogstad-van Evert J. S., de Iaco P., Klooster A., Kooreman L. F. S., Jacobsen M., Kruse A. -J., Kwon J. S., Lawson B. C., Lax S. F., van Lonkhuijzen L. R. C. W., Lu K. H., Manchanda R., Marchetti C., McCluggage W. G., McNally O. M., Mourits M. J. E., Nicum S., Norquist B. M., Perrone A. M., Piek J. M. J., Polastro L., Polee M. B., Rabban J. T., Reesink N., de los Reyes Oliver Perez M., Roes E. -M., Rychlik A., Shih I. -M., Soong T. R., Speiser P., Stone R. L., Tamussino K., Tognon G., Tuninetti V., Valabrega G., Vos M. C., Welz J., Zizioli V., Hermens R. P. M. G., Steenbeek M. P., Negri, S, Fisch, C, de Hullu, J, van Bommel, M, Simons, M, Bogaerts, J, Apperloo, M, Baiocchi, G, Bakker, J, Bart, J, van Beekhuizen, H, Bernardini, M, Boere, I, Bulten, J, Chen, L, Chrzan, A, Dorum, A, Ewing-Graham, P, Ferrero, A, Floter Radestad, A, Fruscio, R, Gaarenstroom, K, Garcia, C, Harter, P, Hoogstad-van Evert, J, de Iaco, P, Klooster, A, Kooreman, L, Jacobsen, M, Kruse, A, Kwon, J, Lawson, B, Lax, S, van Lonkhuijzen, L, Lu, K, Manchanda, R, Marchetti, C, Mccluggage, W, Mcnally, O, Mourits, M, Nicum, S, Norquist, B, Perrone, A, Piek, J, Polastro, L, Polee, M, Rabban, J, Reesink, N, de los Reyes Oliver Perez, M, Roes, E, Rychlik, A, Shih, I, Soong, T, Speiser, P, Stone, R, Tamussino, K, Tognon, G, Tuninetti, V, Valabrega, G, Vos, M, Welz, J, Zizioli, V, Hermens, R, Steenbeek, M, Negri S., Fisch C., de Hullu J. A., van Bommel M., Simons M., Bogaerts J., Apperloo M. J. A., Baiocchi G., Bakker J. L., Bart J., van Beekhuizen H. J., Bernardini M. Q., Boere I., Bulten J., Chen L. -M., Chrzan A., Dorum A., Ewing-Graham P. C., Ferrero A., Floter Radestad A., Fruscio R., Gaarenstroom K. N., Garcia C., Harter P., Hoogstad-van Evert J. S., de Iaco P., Klooster A., Kooreman L. F. S., Jacobsen M., Kruse A. -J., Kwon J. S., Lawson B. C., Lax S. F., van Lonkhuijzen L. R. C. W., Lu K. H., Manchanda R., Marchetti C., McCluggage W. G., McNally O. M., Mourits M. J. E., Nicum S., Norquist B. M., Perrone A. M., Piek J. M. J., Polastro L., Polee M. B., Rabban J. T., Reesink N., de los Reyes Oliver Perez M., Roes E. -M., Rychlik A., Shih I. -M., Soong T. R., Speiser P., Stone R. L., Tamussino K., Tognon G., Tuninetti V., Valabrega G., Vos M. C., Welz J., Zizioli V., Hermens R. P. M. G., and Steenbeek M. P.

Abstract

Objective: A Serous Tubal Intraepithelial Carcinoma (STIC) without concomitant invasive carcinoma is occasionally identified and associated with a high risk of subsequent peritoneal carcinomatosis. Management needs optimisation. This study explores professionals' opinions and clinical practices regarding the diagnosis, counselling, treatment and follow-up of isolated STIC to facilitate clinical decision making and optimise the direction of future research. A secondary aim is to assess international clinical guidelines. Design: Focus group study. Setting: Four online sessions. Population: International panel (n = 12 countries) of gynaecologists, gynaecologic oncologists, pathologists and medical oncologists (n = 49). Methods: A semi-structured interview guide was used. Two independent researchers analysed transcripts by open and axial coding. Results were organised in domains. Relevant (inter)national guidelines were screened for recommendations regarding isolated STIC. Main Outcome Measures: Professionals' opinions and clinical practices regarding isolated STIC management. Results: Regarding pathology, most professionals identified the SEE-FIM protocol as standard of care for high-risk patients, whereas variation exists in the histopathological examination of fallopian tubes in the general population. Confirmation of STIC diagnosis by a specialised pathologist was recommended. Regarding work-up and follow-up after STIC diagnosis, there was variety and discordance. Data on outcomes is limited. As for treatment, chemotherapy and PARP inhibitors were not recommended by most. Eleven guidelines provided limited recommendations. Conclusions: We identified recommendations and highlighted knowledge gaps in the diagnosis and management of isolated STIC. Moreover, recommendations in clinical guidelines are limited. There is an agreed need for international collaboration for the prospective registration of isolated STIC.

Published
2024

7. 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

9. Exploring the Potential of Breast Microbiota as Biomarker for Breast Cancer and Therapeutic Response

Author

Dieleman, S., Aarnoutse, Romy, Ziemons, J., Kooreman, L., Boleij, A., Smidt, M., Dieleman, S., Aarnoutse, Romy, Ziemons, J., Kooreman, L., Boleij, A., and Smidt, M.

Abstract

Contains fulltext : 235760.pdf (Publisher’s version ) (Closed access), Breast cancer tissue contains its own unique microbiota. Emerging preclinical data indicates that breast microbiota dysbiosis contributes to breast cancer initiation and progression. Furthermore, the breast microbiota may be a promising biomarker for treatment selection and prognosis. Differences in breast microbiota composition have been found between breast cancer subtypes and disease severities that may contribute to immunosuppression, enabling tumor cells to evade immune destruction. Interactions between breast microbiota, gut microbiota, and immune system are proposed, all forming potential targets to increase therapeutic efficacy. In addition, because the gut microbiota affects the host immune system and systemic availability of estrogen and bile acids known to influence tumor biology, gut microbiota modulation could be used to manipulate breast microbiota composition. Identifying breast and gut microbial compositions that respond positively to certain anticancer therapeutics could significantly reduce cancer burden. Additional research is needed to unravel the complexity of breast microbiota functioning and its interactions with the gut and the immune system. In this review, developments in the understanding of breast microbiota and its interaction with the immune system and the gut microbiota are discussed. Furthermore, the biomarker potential of breast microbiota is evaluated in conjunction with possible strategies to target microbiota in order to improve breast cancer treatment.

Published
2021

10. A Distinctive Adnexal (Usually Paratubal) Neoplasm Often Associated with Peutz-Jeghers Syndrome and Characterized by STK11 Alterations (STK11 Adnexal Tumor): A Report of 22 Cases

Author

Bennett, J. A., Young, R. H., Howitt, B. E., Croce, S., Wanjari, P., Zhen, C., Da Cruz Paula, A., Meserve, E., Schoolmeester, J. K., Westbom-Fremer, S., Benzi, E., Patil, N. M., Kooreman, L., El-Bahrawy, M., Zannoni, Gian Franco, Krausz, T., Mccluggage, W. G., Weigelt, B., Ritterhouse, L. L., Oliva, E., Zannoni G. F. (ORCID:0000-0003-1809-129X), Bennett, J. A., Young, R. H., Howitt, B. E., Croce, S., Wanjari, P., Zhen, C., Da Cruz Paula, A., Meserve, E., Schoolmeester, J. K., Westbom-Fremer, S., Benzi, E., Patil, N. M., Kooreman, L., El-Bahrawy, M., Zannoni, Gian Franco, Krausz, T., Mccluggage, W. G., Weigelt, B., Ritterhouse, L. L., Oliva, E., and Zannoni G. F. (ORCID:0000-0003-1809-129X)

Abstract

We describe 22 examples of a novel, usually paratubal, adnexal tumor associated with Peutz-Jeghers syndrome in nearly 50% of cases that harbored STK11 alterations in all tested (n=21). The patients ranged from 17 to 66 years (median=39 y) and the tumors from 4.5 to 25.5 cm (median=11 cm). Most (n=18) were paratubal, with metastases noted in 11/22 (50%) and recurrences in 12/15 (80%). Morphologically, they were characterized by interanastomosing cords and trabeculae of predominantly epithelioid cells, set in a variably prominent myxoid to focally edematous stroma, that often merged to form tubular, cystic, cribriform, and microacinar formations, reminiscent of salivary gland-type tumors. The tumor cells were uniformly atypical, often with prominent nucleoli and a variable mitotic index (median=9/10 HPFs). The tumors were usually positive to a variable extent for epithelial (CAM5.2, AE1/AE3, cytokeratin 7), sex cord (calretinin, inhibin, WT1), and mesothelial (calretinin, D2-40) markers, as well as hormone receptors. PAX8, SF1, and GATA-3 were rarely positive, while claudin-4, FOXL2, and TTF-1 were consistently negative. All sequenced tumors (n=21) harbored alterations in STK11, often with a loss of heterozygosity event. There were no other recurrently mutated genes. Recurrent copy number alterations included loss of 1p and 11q, and gain of 1q, 15q, and 15p. Despite an extensive morphologic, immunohistochemical, and molecular evaluation, we are unable to determine with certainty the histogenesis of this unique tumor. Wolffian, sex cord stromal, epithelial, and mesothelial origins were considered. We propose the term STK11 adnexal tumor to describe this novel entity and emphasize the importance of genetic counseling in these patients as a significant number of neoplasms occur in association with Peutz-Jeghers syndrome.

Published
2021

11. 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

12. 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

14. Female adnexal tumors of probable Wolffian origin: morphological, immunohistochemical, and molecular analysis of 15 cases

Author

Bennett, J. A., Ritterhouse, L. L., Furtado, L. V., Lastra, R. R., Pesci, Riccardo, Newell, J. M., Burandt, E., Kooreman, L., Van de Vijver, K., Krausz, T., Felix, A., Zannoni, Gian Franco, Young, R. H., Oliva, E., Pesci A., Zannoni G. F. (ORCID:0000-0003-1809-129X), Bennett, J. A., Ritterhouse, L. L., Furtado, L. V., Lastra, R. R., Pesci, Riccardo, Newell, J. M., Burandt, E., Kooreman, L., Van de Vijver, K., Krausz, T., Felix, A., Zannoni, Gian Franco, Young, R. H., Oliva, E., Pesci A., and Zannoni G. F. (ORCID:0000-0003-1809-129X)

Abstract

Female adnexal tumors of probable Wolffian origin are rare and present a diagnostic challenge due to their morphological and immunohistochemical overlap with more common ovarian and broad ligament entities. We evaluated the morphological, immunohistochemical, and molecular features of 15 tumors of probable Wolffian origin. Patients ranged from 32 to 69 (mean 47) years and tumors from 1.8 to 30 (mean 10) cm. All except one arose in para-adnexal soft tissues. Follow-up was available for six patients, five of whom were alive and well, while the sixth, who had extra-adnexal disease at diagnosis, died from unrelated causes. The following patterns were noted: tubular (all tumors), solid 11/15 (73%), sieve-like 7/15 (47%), and reticular 1/15 (7%). A myxoid background was present in 3/15 (20%) of tumors and eosinophilic luminal secretions in 11/15 (73%). Most tumors (12/15, 80%) had low-grade nuclear atypia, while three showed foci with scattered high-grade atypia. Mitotic index ranged from 0 to 17 (mean 4) per ten high-power fields. Tumors were positive for pankeratin and negative for TTF-1. EMA, GATA3, and PAX8 were positive in 2/10 (20%; focal), 3/15 (20%; focal), and 1/15 (7%; focal) of tumors, respectively. CD10, SF-1, calretinin, inhibin, ER, PR, cytokeratin 7, and WT1 were variably expressed. Pathogenic mutations were rare and included STK11 (n = 3), APC (n = 1), and MBD4 (n = 1). Copy number variations were detected in the three tumors with STK11 mutations and a myxoid background. These data demonstrate that female adnexal tumors of probable Wolffian origin are morphologically and immunohistochemically diverse, but infrequently harbor pathogenic mutations. However, their lack of mutations in contrast to their mimickers may be a valuable tool in diagnostically difficult cases.

Published
2020

17. EP1245 Topical Imiquimod treatment of high-grade cervical intraepithelial neoplasia (TOPIC-3) study: a multicentre, non-randomized controlled study

Author

Hendriks, N, primary, Koeneman, M, additional, van de Sande, M, additional, Kooreman, L, additional, van Kuijk, S, additional, Hoosemans, L, additional, Sep, S, additional, van Gorp, T, additional, Slangen, B, additional, Piek, J, additional, van Beekhuizen, H, additional, Nijman, H, additional, Kruitwagen, R, additional, and Kruse, A, additional

Published
2019
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19. The sulfatase pathway as estrogen supply in endometrial cancer

Author

Cornel, K. M. C., Delvoux, B., Saya, T., Xanthoulea, S., Konings, G. F. J., Kruitwagen, R. P. F. M., Bongers, M. Y., Kooreman, L., Romano, A., Cornel, K. M. C., Delvoux, B., Saya, T., Xanthoulea, S., Konings, G. F. J., Kruitwagen, R. P. F. M., Bongers, M. Y., Kooreman, L., and Romano, A.

Abstract

Objective: Contradictory results are reported about the level of steroid sulfatase (STS), estrogen sulfotransferase (SULT1E1; together, the sulfatase pathway) and aromatase (CYP19A1) in endometrial cancer (EC). The aim of this study was to explore the levels of these enzymes in a well-characterized cohort of EC patients and postmenopausal controls.Materials and Methods: Endometrial tissues from 31 EC patients (21 grade 1 and 10 grade 2-3) and 19 postmenopausal controls were collected. Levels of mRNA (RT-qPCR) and protein (immunohistochemistry) were determined. STS enzyme activity was measured by HPLC, whereas SULT1E1 enzyme activity was determined using a novel method based on liquid chromatography-mass spectrometry (LC-MS/MS).Results: No significant differences in STS, SULT1E1 mRNA or protein levels and STS:SULT1E1 ratio were found. STS enzyme activity and STS:SULT1E1 activity ratio were significantly decreased in ECs compared with controls. CYP19A1 mRNA levels were lower in ECs than in controls.Conclusion: A novel highly sensitive and accurate protocol to assess SULT1E1 activity is presented. STS enzyme activity and the STS:SULT1E1 activity ratio seem to be lower in ECs than in controls. STS is an important route for estrogen supply in endometrial cells.

Published
2018

22. Preliminary stop of the TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC) trial

Author

Koeneman, M. M., Kruse, A. J., Kooreman, L. F S, zur Hausen, A., Hopman, A. H N, Sep, S. J S, Van Gorp, T., Slangen, B. F M, van Beekhuizen, H. J., van de Sande, A. J M, Gerestein, C. G., Nijman, H. W., Kruitwagen, R. F P M, Koeneman, M. M., Kruse, A. J., Kooreman, L. F S, zur Hausen, A., Hopman, A. H N, Sep, S. J S, Van Gorp, T., Slangen, B. F M, van Beekhuizen, H. J., van de Sande, A. J M, Gerestein, C. G., Nijman, H. W., and Kruitwagen, R. F P M

Published
2017

23. Preliminary stop of the TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC) trial

Author

MS Gynaecologische Oncologie, Koeneman, M. M., Kruse, A. J., Kooreman, L. F S, zur Hausen, A., Hopman, A. H N, Sep, S. J S, Van Gorp, T., Slangen, B. F M, van Beekhuizen, H. J., van de Sande, A. J M, Gerestein, C. G., Nijman, H. W., Kruitwagen, R. F P M, MS Gynaecologische Oncologie, Koeneman, M. M., Kruse, A. J., Kooreman, L. F S, zur Hausen, A., Hopman, A. H N, Sep, S. J S, Van Gorp, T., Slangen, B. F M, van Beekhuizen, H. J., van de Sande, A. J M, Gerestein, C. G., Nijman, H. W., and Kruitwagen, R. F P M

Published
2017

24. Preliminary stop of the TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC) trial

Author

Koeneman, MM, Kruse, AJ, Kooreman, L F S, zur Hausen, A, Hopman, AHN, Sep, S J S, Van Gorp, T, Slangen, BFM, van Beekhuizen, Heleen, Sande, Meike, Gerestein, CG, Nijman, HW, Kruitwagen, R, Koeneman, MM, Kruse, AJ, Kooreman, L F S, zur Hausen, A, Hopman, AHN, Sep, S J S, Van Gorp, T, Slangen, BFM, van Beekhuizen, Heleen, Sande, Meike, Gerestein, CG, Nijman, HW, and Kruitwagen, R

Published
2017

25. Preliminary stop of the TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC) trial

Author

Koeneman, M. M., primary, Kruse, A. J., additional, Kooreman, L. F. S., additional, zur Hausen, A., additional, Hopman, A. H. N., additional, Sep, S. J. S., additional, Van Gorp, T., additional, Slangen, B. F. M., additional, van Beekhuizen, H. J., additional, van de Sande, A. J. M., additional, Gerestein, C. G., additional, Nijman, H. W., additional, and Kruitwagen, R. F. P. M., additional

Published
2017
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26. TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC trial) : Study protocol for a randomized controlled trial

Author

Koeneman, M. M., Kruse, A. J., Kooreman, L. F S, zur Hausen, A., Hopman, A. H N, Sep, S. J S, Van Gorp, T., Slangen, B. F M, van Beekhuizen, H. J., van de Sande, M., Gerestein, C. G., Nijman, H. W., Kruitwagen, R. F P M, Koeneman, M. M., Kruse, A. J., Kooreman, L. F S, zur Hausen, A., Hopman, A. H N, Sep, S. J S, Van Gorp, T., Slangen, B. F M, van Beekhuizen, H. J., van de Sande, M., Gerestein, C. G., Nijman, H. W., and Kruitwagen, R. F P M

Published
2016

27. TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC trial): Study protocol for a randomized controlled trial

Author

MS Gynaecologische Oncologie, Koeneman, M. M., Kruse, A. J., Kooreman, L. F S, zur Hausen, A., Hopman, A. H N, Sep, S. J S, Van Gorp, T., Slangen, B. F M, van Beekhuizen, H. J., van de Sande, M., Gerestein, C. G., Nijman, H. W., Kruitwagen, R. F P M, MS Gynaecologische Oncologie, Koeneman, M. M., Kruse, A. J., Kooreman, L. F S, zur Hausen, A., Hopman, A. H N, Sep, S. J S, Van Gorp, T., Slangen, B. F M, van Beekhuizen, H. J., van de Sande, M., Gerestein, C. G., Nijman, H. W., and Kruitwagen, R. F P M

Published
2016

28. TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC trial): study protocol for a randomized controlled trial

Author

Koeneman, MM, Kruse, AJ, Kooreman, L F S, zur Hausen, A, Hopman, AHN, Sep, S J S, Gorp, Renée, Slangen, BFM, van Beekhuizen, Heleen, Sande, Michiel, Gerestein, Cees, Nijman, HW, Kruitwagen, RFPM, Koeneman, MM, Kruse, AJ, Kooreman, L F S, zur Hausen, A, Hopman, AHN, Sep, S J S, Gorp, Renée, Slangen, BFM, van Beekhuizen, Heleen, Sande, Michiel, Gerestein, Cees, Nijman, HW, and Kruitwagen, RFPM

Published
2016

29. TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC trial): study protocol for a randomized controlled trial

Author

Koeneman, M. M., primary, Kruse, A. J., additional, Kooreman, L. F. S., additional, zur Hausen, A., additional, Hopman, A. H. N., additional, Sep, S. J. S., additional, Van Gorp, T., additional, Slangen, B. F. M., additional, van Beekhuizen, H. J., additional, van de Sande, M., additional, Gerestein, C. G., additional, Nijman, H. W., additional, and Kruitwagen, R. F. P. M., additional

Published
2016
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31. Added value of dedicated axillary hybrid 18F-FDG PET/MRI for improved axillary nodal staging in clinically node-positive breast cancer patients: a feasibility study.

Author

van Nijnatten, Thiemo J. A., Goorts, B., Vöö, S., de Boer, M., Kooreman, L. F. S., Heuts, E. M., Wildberger, J. E., Mottaghy, F. M., Lobbes, M. B. I., and Smidt, M. L.

Subjects
BREAST cancer, POSITRON emission tomography, FLUORODEOXYGLUCOSE F18, AXILLA, LYMPH nodes
Abstract

Purpose: To investigate the feasibility and potential added value of dedicated axillary 18F-FDG hybrid PET/MRI, compared to standard imaging modalities (i.e. ultrasound [US], MRI and PET/CT), for axillary nodal staging in clinically node-positive breast cancer. Methods: Twelve patients with clinically node-positive breast cancer underwent axillary US and dedicated axillary hybrid 18F-FDG PET/MRI. Nine of the 12 patients also underwent whole-body PET/CT. Maximum standardized uptake values (SUVmax) were measured for the primary breast tumor and the most FDG-avid axillary lymph node. A positive axillary lymph node on dedicated axillary hybrid PET/MRI was defined as a moderate to very intense FDG-avid lymph node. The diagnostic performance of dedicated axillary hybrid PET/MRI was calculated by comparing quantitative and its qualitative measurements to results of axillary US, MRI and PET/CT. The number of suspicious axillary lymph nodes was subdivided as follows: N0 (0 nodes), N1 (1-3 nodes), N2 (4-9 nodes) and N3 (≥ 10 nodes). Results: According to dedicated axillary hybrid PET/MRI findings, seven patients were diagnosed with N1, four with N2 and one with N3. With regard to mean SUVmax, there was no significant difference in the primary tumor (9.0 [±5.0] vs. 8.6 [±5.7], p = 0.678) or the most FDG-avid axillary lymph node (7.8 [±5.3] vs. 7.7 [±4.3], p = 0.767) between dedicated axillary PET/MRI and PET/CT. Compared to standard imaging modalities, dedicated axillary hybrid PET/MRI resulted in changes in nodal status as follows: 40% compared to US, 75% compared to T2-weighted MRI, 40% compared to contrast-enhanced MRI, and 22% compared to PET/CT. Conclusions: Adding dedicated axillary 18F-FDG hybrid PET/MRI to diagnostic work-up may improve the diagnostic performance of axillary nodal staging in clinically node-positive breast cancer patients. [ABSTRACT FROM AUTHOR]

Published
2018
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32. Hibernoma with metabolic impact?

Author

Vijgen, G. H. E. J., primary, Bouvy, N. D., additional, Smidt, M., additional, Kooreman, L., additional, Schaart, G., additional, and van Marken Lichtenbelt, W., additional

Published
2012
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34. Assessing the impact of deep-learning assistance on the histopathological diagnosis of serous tubal intraepithelial carcinoma (STIC) in fallopian tubes.

Author

Bogaerts JM, Steenbeek MP, Bokhorst JM, van Bommel MH, Abete L, Addante F, Brinkhuis M, Chrzan A, Cordier F, Devouassoux-Shisheboran M, Fernández-Pérez J, Fischer A, Gilks CB, Guerriero A, Jaconi M, Kleijn TG, Kooreman L, Martin S, Milla J, Narducci N, Ntala C, Parkash V, de Pauw C, Rabban JT, Rijstenberg L, Rottscholl R, Staebler A, Van de Vijver K, Zannoni GF, van Zanten M, de Hullu JA, Simons M, and van der Laak JA

Subjects
Humans, Female, Cystadenocarcinoma, Serous diagnosis, Cystadenocarcinoma, Serous pathology, Reproducibility of Results, Observer Variation, Image Interpretation, Computer-Assisted, Deep Learning, Fallopian Tube Neoplasms pathology, Fallopian Tube Neoplasms diagnosis, Carcinoma in Situ pathology, Carcinoma in Situ diagnosis
Abstract

In recent years, it has become clear that artificial intelligence (AI) models can achieve high accuracy in specific pathology-related tasks. An example is our deep-learning model, designed to automatically detect serous tubal intraepithelial carcinoma (STIC), the precursor lesion to high-grade serous ovarian carcinoma, found in the fallopian tube. However, the standalone performance of a model is insufficient to determine its value in the diagnostic setting. To evaluate the impact of the use of this model on pathologists' performance, we set up a fully crossed multireader, multicase study, in which 26 participants, from 11 countries, reviewed 100 digitalized H&E-stained slides of fallopian tubes (30 cases/70 controls) with and without AI assistance, with a washout period between the sessions. We evaluated the effect of the deep-learning model on accuracy, slide review time and (subjectively perceived) diagnostic certainty, using mixed-models analysis. With AI assistance, we found a significant increase in accuracy (p < 0.01) whereby the average sensitivity increased from 82% to 93%. Further, there was a significant 44 s (32%) reduction in slide review time (p < 0.01). The level of certainty that the participants felt versus their own assessment also significantly increased, by 0.24 on a 10-point scale (p < 0.01). In conclusion, we found that, in a diverse group of pathologists and pathology residents, AI support resulted in a significant improvement in the accuracy of STIC diagnosis and was coupled with a substantial reduction in slide review time. This model has the potential to provide meaningful support to pathologists in the diagnosis of STIC, ultimately streamlining and optimizing the overall diagnostic process., (© 2024 The Author(s). The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

Published
2024
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35. Breast Cancer in the Tissue of the Contralateral Breast Reduction.

Author

Kuijlaars ZMA, Hillberg NS, Kooreman L, Severens Rijvers CAH, and Qiu SS

Abstract

Breast cancer is the most prevalent malignancy among women worldwide, and the increasing number of survivors is due to advances in early diagnosis and treatment efficacy. Consequently, the risk of developing contralateral breast cancer (CBC) among these survivors has become a concern. While surgical intervention with lumpectomy is a widely used primary approach for breast cancer, post-operative breast asymmetry is a potential concern. Many women opt for symmetrizing reduction procedures to improve aesthetic outcomes and quality of life. However, despite careful radiological screening, there is a chance of accidentally finding CBC. To address this, tissue excised during symmetrizing surgery is examined pathologically. In some cases, CBC or in situ lesions have been incidentally discovered in these specimens, prompting a need for a more thorough examination. Resection in pieces and the absence of surgical marking and pathological inking of the margin have made it challenging to precisely identify tumor location and assess tumor size and margin status, hampering adjuvant treatment decisions. A new protocol introduced in July 2022 aims to enhance the precision of CBC diagnosis, allowing for tailored treatment plans, including re-excision, systemic adjuvant therapy, or radiation therapy.

Published
2024
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36. Axillary lymph node response to neoadjuvant systemic therapy with dedicated axillary hybrid 18 F-FDG PET/MRI in clinically node-positive breast cancer patients: a pilot study.

Author

de Mooij CM, Samiei S, Mitea C, Lobbes MBI, Kooreman LFS, Heuts EM, Beets-Tan RGH, van Nijnatten TJA, and Smidt ML

Subjects
Axilla diagnostic imaging, Axilla pathology, Female, Humans, Lymph Nodes diagnostic imaging, Lymph Nodes pathology, Lymphatic Metastasis diagnostic imaging, Lymphatic Metastasis pathology, Magnetic Resonance Imaging methods, Neoadjuvant Therapy, Neoplasm Micrometastasis pathology, Pilot Projects, Positron-Emission Tomography, Radiopharmaceuticals, Breast Neoplasms diagnostic imaging, Breast Neoplasms drug therapy, Breast Neoplasms surgery, Fluorodeoxyglucose F18
Abstract

Aim: To investigate the diagnostic performance of dedicated axillary hybrid 18 F-2-[ 18 F]-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/magnetic resonance imaging (MRI) in detecting axillary pathological complete response (pCR) following neoadjuvant systemic therapy (NST) in clinically node-positive breast cancer patients., Materials and Methods: Ten prospectively included clinically node-positive breast cancer patients underwent dedicated axillary hybrid 18 F-FDG PET/MRI after completing NST followed by axillary surgery. PET images were reviewed by a nuclear medicine physician and coronal T1-weighted and T2-weighted MRI images by a radiologist. All axillary lymph nodes visible on PET/MRI were matched with those removed during axillary surgery. Diagnostic performance parameters were calculated based on patient-by-patient and node-by-node validation with histopathology of the axillary surgical specimen as the reference standard., Results: Six patients achieved axillary pCR at final histopathology. A total of 84 surgically harvested axillary lymph nodes were matched with axillary lymph nodes depicted on PET/MRI. Histopathological examination of the matched axillary lymph nodes resulted in 10 lymph nodes with residual axillary disease of which eight contained macrometastases and two micrometastases. The patient-by-patient analysis yielded a sensitivity, specificity, positive predictive value, and negative predictive value of 25%, 100%, 100%, and 67%, respectively. The diagnostic performance parameters of the node-by-node analysis were 0%, 96%, 0%, and 88%, respectively. Excluding micrometastases from the node-by-node analysis increased the negative predictive value to 90%., Conclusion: This pilot study suggests that the negative predictive value and sensitivity of dedicated axillary 18 F-FDG PET/MRI are insufficiently accurate to detect axillary pCR or exclude residual axillary disease following NST in clinically node-positive breast cancer patients., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Published
2022
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37. Inter-observer agreement for the histological diagnosis of invasive lobular breast carcinoma.

Author

Christgen M, Kandt LD, Antonopoulos W, Bartels S, Van Bockstal MR, Bredt M, Brito MJ, Christgen H, Colpaert C, Cserni B, Cserni G, Daemmrich ME, Danebrock R, Dedeurwaerdere F, van Deurzen CH, Erber R, Fathke C, Feist H, Fiche M, Gonzalez CA, Ter Hoeve ND, Kooreman L, Krech T, Kristiansen G, Kulka J, Laenger F, Lafos M, Lehmann U, Martin-Martinez MD, Mueller S, Pelz E, Raap M, Ravarino A, Reineke-Plaass T, Schaumann N, Schelfhout AM, De Schepper M, Schlue J, Van de Vijver K, Waelput W, Wellmann A, Graeser M, Gluz O, Kuemmel S, Nitz U, Harbeck N, Desmedt C, Floris G, Derksen PW, van Diest PJ, Vincent-Salomon A, and Kreipe H

Subjects
Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Female, Humans, Immunohistochemistry, Observer Variation, Breast Neoplasms diagnosis, Breast Neoplasms genetics, Breast Neoplasms metabolism, Carcinoma, Lobular diagnosis, Carcinoma, Lobular genetics
Abstract

Invasive lobular breast carcinoma (ILC) is the second most common breast carcinoma (BC) subtype and is mainly driven by loss of E-cadherin expression. Correct classification of BC as ILC is important for patient treatment. This study assessed the degree of agreement among pathologists for the diagnosis of ILC. Two sets of hormone receptor (HR)-positive/HER2-negative BCs were independently reviewed by participating pathologists. In set A (61 cases), participants were provided with hematoxylin/eosin (HE)-stained sections. In set B (62 cases), participants were provided with HE-stained sections and E-cadherin immunohistochemistry (IHC). Tumor characteristics were balanced. Participants classified specimens as non-lobular BC versus mixed BC versus ILC. Pairwise inter-observer agreement and agreement with a pre-defined reference diagnosis were determined with Cohen's kappa statistics. Subtype calls were correlated with molecular features, including CDH1/E-cadherin mutation status. Thirty-five pathologists completed both sets, providing 4,305 subtype calls. Pairwise inter-observer agreement was moderate in set A (median κ = 0.58, interquartile range [IQR]: 0.48-0.66) and substantial in set B (median κ = 0.75, IQR: 0.56-0.86, p < 0.001). Agreement with the reference diagnosis was substantial in set A (median κ = 0.67, IQR: 0.57-0.75) and almost perfect in set B (median κ = 0.86, IQR: 0.73-0.93, p < 0.001). The median frequency of CDH1/E-cadherin mutations in specimens classified as ILC was 65% in set A (IQR: 56-72%) and 73% in set B (IQR: 65-75%, p < 0.001). Cases with variable subtype calls included E-cadherin-positive ILCs harboring CDH1 missense mutations, and E-cadherin-negative ILCs with tubular elements and focal P-cadherin expression. ILCs with trabecular growth pattern were often misclassified as non-lobular BC in set A but not in set B. In conclusion, subtyping of BC as ILC achieves almost perfect agreement with a pre-defined reference standard, if assessment is supported by E-cadherin IHC. CDH1 missense mutations associated with preserved E-cadherin protein expression, E- to P-cadherin switching in ILC with tubular elements, and trabecular ILC were identified as potential sources of discordant classification., (© 2021 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland & John Wiley & Sons, Ltd.)

Published
2022
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38. The percentage of residual DCIS in patients diagnosed with primary invasive breast cancer treated with neoadjuvant systemic therapy: A nationwide retrospective study.

Author

Ploumen RAW, Keymeulen KBMI, Kooreman LFS, van Kuijk SMJ, Siesling S, Smidt ML, and van Nijnatten TJA

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Breast Neoplasms pathology, Carcinoma, Ductal, Breast pathology, Carcinoma, Intraductal, Noninfiltrating pathology, Female, Humans, Logistic Models, Mastectomy, Mastectomy, Segmental, Middle Aged, Neoplasm Grading, Neoplasm Staging, Neoplasm, Residual, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms pathology, Young Adult, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Carcinoma, Ductal, Breast drug therapy, Carcinoma, Intraductal, Noninfiltrating drug therapy, Neoadjuvant Therapy
Abstract

Introduction: Neoadjuvant systemic therapy (NST) is increasingly applied in breast cancer to improve surgical and oncological outcome. Approximately 21% of patients receiving NST achieve pathological complete response (pCR) of the breast. There is disagreement on the definition of pCR with respect to residual DCIS (ypT0 versus ypT0/is). The aim of this retrospective study was to determine the percentage of breast pCR (ypT0) and residual DCIS (ypTis), and its association with clinicopathological variables, in patients treated with NST and surgery., Materials and Methods: Patients with invasive breast cancer treated with neoadjuvant chemotherapy, with or without targeted therapy, in the period of 2010-2019 were selected from the Netherlands Cancer Registry (NCR). Descriptive statistics and multivariable logistic regression analyses were used to analyse the percentage of ypT0 and ypTis and its association with clinicopathological variables., Results: From the NCR database, 20495 patients were included, of whom 5847 (28.5%) achieved breast pCR (ypT0) and 881 (4.3%) showed residual DCIS (ypTis). The percentage of ypTis was highest in HER2+ tumour subtypes (ER+HER2+ 7.9%, ER-HER2+ 9.8%, ER+HER2- 2.1%, triple negative 3.3%, p < 0.001). Multivariable logistic regression analyses demonstrated high tumour grade (OR 2.00, p = 0.003) and HER2+ tumour subtype (ER+HER2+ OR 3.58, ER-HER2+ OR 4.37, p < 0.001) as independent predictors for ypTis., Conclusion: pCR (ypT0) was achieved in 5847 (28.5%) patients receiving NST and residual DCIS (ypTis) was found in 881 (4.3%) patients. Consequently, the rate of pCR may be affected by ypTis when not excluded from the definition. The percentage of ypTis is highest in HER2+ subtypes., Competing Interests: Declaration of competing interest None declared., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2022
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39. Interobserver Agreement of PD-L1/SP142 Immunohistochemistry and Tumor-Infiltrating Lymphocytes (TILs) in Distant Metastases of Triple-Negative Breast Cancer: A Proof-of-Concept Study. A Report on Behalf of the International Immuno-Oncology Biomarker Working Group.

Author

Van Bockstal MR, Cooks M, Nederlof I, Brinkhuis M, Dutman A, Koopmans M, Kooreman L, van der Vegt B, Verhoog L, Vreuls C, Westenend P, Kok M, van Diest PJ, Nauwelaers I, Laudus N, Denkert C, Rimm D, Siziopikou KP, Ely S, Zardavas D, Roberts M, Floris G, Hartman J, Acs B, Peeters D, Bartlett JMS, Dequeker E, Salgado R, Giudici F, Michiels S, Horlings H, and van Deurzen CHM

Abstract

Patients with advanced triple-negative breast cancer (TNBC) benefit from treatment with atezolizumab, provided that the tumor contains ≥1% of PD-L1/SP142-positive immune cells. Numbers of tumor-infiltrating lymphocytes (TILs) vary strongly according to the anatomic localization of TNBC metastases. We investigated inter-pathologist agreement in the assessment of PD-L1/SP142 immunohistochemistry and TILs. Ten pathologists evaluated PD-L1/SP142 expression in a proficiency test comprising 28 primary TNBCs, as well as PD-L1/SP142 expression and levels of TILs in 49 distant TNBC metastases with various localizations. Interobserver agreement for PD-L1 status (positive vs. negative) was high in the proficiency test: the corresponding scores as percentages showed good agreement with the consensus diagnosis. In TNBC metastases, there was substantial variability in PD-L1 status at the individual patient level. For one in five patients, the chance of treatment was essentially random, with half of the pathologists designating them as positive and half negative. Assessment of PD-L1/SP142 and TILs as percentages in TNBC metastases showed poor and moderate agreement, respectively. Additional training for metastatic TNBC is required to enhance interobserver agreement. Such training, focusing on metastatic specimens, seems worthwhile, since the same pathologists obtained high percentages of concordance (ranging from 93% to 100%) on the PD-L1 status of primary TNBCs.

Published
2021
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40. A Distinctive Adnexal (Usually Paratubal) Neoplasm Often Associated With Peutz-Jeghers Syndrome and Characterized by STK11 Alterations (STK11 Adnexal Tumor): A Report of 22 Cases.

Author

Bennett JA, Young RH, Howitt BE, Croce S, Wanjari P, Zhen C, Da Cruz Paula A, Meserve E, Schoolmeester JK, Westbom-Fremer S, Benzi E, Patil NM, Kooreman L, El-Bahrawy M, Zannoni GF, Krausz T, McCluggage WG, Weigelt B, Ritterhouse LL, and Oliva E

Subjects
AMP-Activated Protein Kinase Kinases, Adolescent, Adult, Aged, Female, Humans, Middle Aged, Mutation, Peutz-Jeghers Syndrome complications, Young Adult, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Protein Serine-Threonine Kinases genetics, Sex Cord-Gonadal Stromal Tumors genetics, Sex Cord-Gonadal Stromal Tumors pathology
Abstract

We describe 22 examples of a novel, usually paratubal, adnexal tumor associated with Peutz-Jeghers syndrome in nearly 50% of cases that harbored STK11 alterations in all tested (n=21). The patients ranged from 17 to 66 years (median=39 y) and the tumors from 4.5 to 25.5 cm (median=11 cm). Most (n=18) were paratubal, with metastases noted in 11/22 (50%) and recurrences in 12/15 (80%). Morphologically, they were characterized by interanastomosing cords and trabeculae of predominantly epithelioid cells, set in a variably prominent myxoid to focally edematous stroma, that often merged to form tubular, cystic, cribriform, and microacinar formations, reminiscent of salivary gland-type tumors. The tumor cells were uniformly atypical, often with prominent nucleoli and a variable mitotic index (median=9/10 HPFs). The tumors were usually positive to a variable extent for epithelial (CAM5.2, AE1/AE3, cytokeratin 7), sex cord (calretinin, inhibin, WT1), and mesothelial (calretinin, D2-40) markers, as well as hormone receptors. PAX8, SF1, and GATA-3 were rarely positive, while claudin-4, FOXL2, and TTF-1 were consistently negative. All sequenced tumors (n=21) harbored alterations in STK11, often with a loss of heterozygosity event. There were no other recurrently mutated genes. Recurrent copy number alterations included loss of 1p and 11q, and gain of 1q, 15q, and 15p. Despite an extensive morphologic, immunohistochemical, and molecular evaluation, we are unable to determine with certainty the histogenesis of this unique tumor. Wolffian, sex cord stromal, epithelial, and mesothelial origins were considered. We propose the term STK11 adnexal tumor to describe this novel entity and emphasize the importance of genetic counseling in these patients as a significant number of neoplasms occur in association with Peutz-Jeghers syndrome., Competing Interests: Conflicts of Interest and Source of Funding: B.W. was funded in part by Breast Cancer Research Foundation, Cycle for Survival and Stand Up To Cancer grants. Research reported in this publication was supported in part by a Cancer Center Support Grant of the NIH/NCI (Grant No. P30CA008748; MSKCC). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Published
2021
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41. Exploring the Potential of Breast Microbiota as Biomarker for Breast Cancer and Therapeutic Response.

Author

Dieleman S, Aarnoutse R, Ziemons J, Kooreman L, Boleij A, and Smidt M

Subjects
Female, Humans, Biomarkers, Tumor, Breast Neoplasms microbiology, Microbiota
Abstract

Breast cancer tissue contains its own unique microbiota. Emerging preclinical data indicates that breast microbiota dysbiosis contributes to breast cancer initiation and progression. Furthermore, the breast microbiota may be a promising biomarker for treatment selection and prognosis. Differences in breast microbiota composition have been found between breast cancer subtypes and disease severities that may contribute to immunosuppression, enabling tumor cells to evade immune destruction. Interactions between breast microbiota, gut microbiota, and immune system are proposed, all forming potential targets to increase therapeutic efficacy. In addition, because the gut microbiota affects the host immune system and systemic availability of estrogen and bile acids known to influence tumor biology, gut microbiota modulation could be used to manipulate breast microbiota composition. Identifying breast and gut microbial compositions that respond positively to certain anticancer therapeutics could significantly reduce cancer burden. Additional research is needed to unravel the complexity of breast microbiota functioning and its interactions with the gut and the immune system. In this review, developments in the understanding of breast microbiota and its interaction with the immune system and the gut microbiota are discussed. Furthermore, the biomarker potential of breast microbiota is evaluated in conjunction with possible strategies to target microbiota in order to improve breast cancer treatment., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Published
2021
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42. Female adnexal tumors of probable Wolffian origin: morphological, immunohistochemical, and molecular analysis of 15 cases.

Author

Bennett JA, Ritterhouse LL, Furtado LV, Lastra RR, Pesci A, Newell JM, Burandt E, Kooreman L, Van de Vijver K, Krausz T, Felix A, Zannoni GF, Young RH, and Oliva E

Subjects
Adult, Aged, Biopsy, Female, Gene Dosage, Genetic Predisposition to Disease, Humans, Middle Aged, Mutation, Phenotype, Predictive Value of Tests, Adenoma genetics, Adenoma metabolism, Adenoma pathology, Adnexa Uteri chemistry, Adnexa Uteri pathology, Adnexal Diseases genetics, Adnexal Diseases metabolism, Adnexal Diseases pathology, Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, Genital Neoplasms, Female chemistry, Genital Neoplasms, Female genetics, Genital Neoplasms, Female pathology, Immunohistochemistry, Molecular Diagnostic Techniques
Abstract

Female adnexal tumors of probable Wolffian origin are rare and present a diagnostic challenge due to their morphological and immunohistochemical overlap with more common ovarian and broad ligament entities. We evaluated the morphological, immunohistochemical, and molecular features of 15 tumors of probable Wolffian origin. Patients ranged from 32 to 69 (mean 47) years and tumors from 1.8 to 30 (mean 10) cm. All except one arose in para-adnexal soft tissues. Follow-up was available for six patients, five of whom were alive and well, while the sixth, who had extra-adnexal disease at diagnosis, died from unrelated causes. The following patterns were noted: tubular (all tumors), solid 11/15 (73%), sieve-like 7/15 (47%), and reticular 1/15 (7%). A myxoid background was present in 3/15 (20%) of tumors and eosinophilic luminal secretions in 11/15 (73%). Most tumors (12/15, 80%) had low-grade nuclear atypia, while three showed foci with scattered high-grade atypia. Mitotic index ranged from 0 to 17 (mean 4) per ten high-power fields. Tumors were positive for pankeratin and negative for TTF-1. EMA, GATA3, and PAX8 were positive in 2/10 (20%; focal), 3/15 (20%; focal), and 1/15 (7%; focal) of tumors, respectively. CD10, SF-1, calretinin, inhibin, ER, PR, cytokeratin 7, and WT1 were variably expressed. Pathogenic mutations were rare and included STK11 (n = 3), APC (n = 1), and MBD4 (n = 1). Copy number variations were detected in the three tumors with STK11 mutations and a myxoid background. These data demonstrate that female adnexal tumors of probable Wolffian origin are morphologically and immunohistochemically diverse, but infrequently harbor pathogenic mutations. However, their lack of mutations in contrast to their mimickers may be a valuable tool in diagnostically difficult cases.

Published
2020
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43. Does the subtype of breast cancer affect the diagnostic performance of axillary ultrasound for nodal staging in breast cancer patients?

Author

Vane MLG, van Nijnatten TJA, Nelemans PJ, Lobbes MBI, van Roozendaal LM, Kooreman LFS, Keymeulen KBMI, Smidt ML, and Schipper RJ

Subjects
Adult, Aged, Aged, 80 and over, False Negative Reactions, Female, Humans, Lymph Nodes pathology, Lymph Nodes surgery, Lymphatic Metastasis, Middle Aged, Neoplasm Staging, Predictive Value of Tests, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Retrospective Studies, Sentinel Lymph Node Biopsy, Young Adult, Lymph Nodes diagnostic imaging, Triple Negative Breast Neoplasms metabolism, Triple Negative Breast Neoplasms pathology, Ultrasonography, Unilateral Breast Neoplasms metabolism, Unilateral Breast Neoplasms pathology
Abstract

Introduction: Imaging findings can be affected by histopathological characteristics, such as breast cancer subtypes. The aim was to determine whether the diagnostic performance, in particular negative predictive value (NPV), of axillary US differs per subtype of breast cancer., Methods: All patients diagnosed between 2008 and 2016 in our hospital with primary invasive breast cancer and an axillary US prior to axillary surgery were included. Histopathology of axillary surgery specimens served as gold standard. The NPV, sensitivity, specificity, positive predictive value (PPV) and accuracy of the axillary US were determined for the overall population and for each subtype (ER+/PR+HER2-,HER2+, triple negative tumors). The Chi-square test was used to determine the difference in diagnostic performance parameters between the subtypes., Results: A total of 1094 breast cancer patients were included. Of these, 35 were diagnosed with bilateral breast cancer, resulting in 1129 cancer cases. Most common subtype was ER+/PR+HER2- in 858 cases (76.0%), followed by 150 cases of HER2+ tumors (13.3%) and 121 cases of triple negative tumors (10.7%). Sensitivity, specificity and accuracy of axillary US did not significantly differ between the subtypes. There was a significant difference for NPV between triple negative tumors and HER2+ tumors (90.3% vs. 80.2%, p = 0.05) and between HER2+ and ER/PR+HER2- tumors (80.2% vs. 87.2%, p = 0.04)., Conclusion: There was no significant difference in the diagnostic performance of axillary US between the subtypes, except for NPV. This was highest in triple negative subtype and lowest in HER2+ tumors. This can be explained by the difference in prevalence of axillary lymph node metastases in our cohort., (Copyright © 2019. Published by Elsevier Ltd.)

Published
2019
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44. Development of an Image-Guided Orthotopic Xenograft Mouse Model of Endometrial Cancer with Controllable Estrogen Exposure.

Author

Konings GF, Saarinen N, Delvoux B, Kooreman L, Koskimies P, Krakstad C, Fasmer KE, Haldorsen IS, Zaffagnini A, Häkkinen MR, Auriola S, Dubois L, Lieuwes N, Verhaegen F, Schyns LE, Kruitwagen RF, Xanthoulea S, and Romano A

Subjects
Animals, Estrogens administration & dosage, Female, Heterografts, Humans, Image Enhancement, Luminescent Measurements, Mice, Tomography, X-Ray Computed, Tumor Burden, X-Ray Microtomography, Disease Models, Animal, Endometrial Neoplasms etiology, Endometrial Neoplasms pathology, Estrogens adverse effects
Abstract

Endometrial cancer (EC) is the most common gynaecological malignancy in Western society and the majority of cases are estrogen dependent. While endocrine drugs proved to be of insufficient therapeutic value in the past, recent clinical research shows promising results by using combinational regimens and pre-clinical studies and identified potential novel endocrine targets. Relevant pre-clinical models can accelerate research in this area. In the present study we describe an orthotopic and estrogen dependent xenograft mouse model of EC. Tumours were induced in one uterine horn of female athymic nude mice using the well-differentiated human endometrial adenocarcinoma Ishikawa cell line-modified to express the luciferase gene for bioluminescence imaging (BLI). BLI and contrast-enhanced computed-tomograph (CE-CT) were used to measure non-invasive tumour growth. Controlled estrogen exposure was achieved by the use of MedRod implants releasing 1.5 μg/d of 17β-estradiol (E2) in ovariectomized mice. Stable E2 serum concentration was demonstrated by LC-MS/MS. Induced tumours were E2 responsive as increased tumour growth was observed in the presence of E2 but not placebo, assessed by BLI, CE-CT, and tumour weight at sacrifice. Metastatic spread was assessed macroscopically by BLI and histology and was seen in the peritoneal cavity, in the lymphovascular space, and in the thoracic cavity. In conclusion, we developed an orthotopic xenograft mouse model of EC that exhibits the most relevant features of human disease, regarding metastatic spread and estrogen dependency. This model offers an easy to manipulate estrogen dosage (by simply adjusting the MedRod implant length), image-guided monitoring of tumour growth, and objectively measurable endpoints (including tumour weight). This is an excellent in vivo tool to further explore endocrine drug regimens and novel endocrine drug targets for EC.

Published
2018
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45. Blocking 17β-hydroxysteroid dehydrogenase type 1 in endometrial cancer: a potential novel endocrine therapeutic approach.

Author

Konings GF, Cornel KM, Xanthoulea S, Delvoux B, Skowron MA, Kooreman L, Koskimies P, Krakstad C, Salvesen HB, van Kuijk K, Schrooders YJ, Vooijs M, Groot AJ, Bongers MY, Kruitwagen RF, and Romano A

Subjects
Aged, Aged, 80 and over, Animals, Cell Line, Tumor, Chick Embryo, Cyclin A metabolism, Endometrial Neoplasms enzymology, Endometrial Neoplasms genetics, Endometrial Neoplasms pathology, Estradiol metabolism, Estradiol pharmacology, Estradiol Dehydrogenases genetics, Estradiol Dehydrogenases metabolism, Estrone metabolism, Estrone pharmacology, Female, Humans, Middle Aged, Molecular Targeted Therapy, Signal Transduction drug effects, Antineoplastic Agents pharmacology, Cell Proliferation drug effects, Endometrial Neoplasms drug therapy, Enzyme Inhibitors pharmacology, Estradiol Dehydrogenases antagonists & inhibitors
Abstract

The enzyme type 1 17β-hydroxysteroid dehydrogenase (17β-HSD-1), responsible for generating active 17β-estradiol (E2) from low-active estrone (E1), is overexpressed in endometrial cancer (EC), thus implicating an increased intra-tissue generation of E2 in this estrogen-dependent condition. In this study, we explored the possibility of inhibiting 17β-HSD-1 and impairing the generation of E2 from E1 in EC using in vitro, in vivo, and ex vivo models. We generated EC cell lines derived from the well-differentiated endometrial adenocarcinoma Ishikawa cell line and expressing levels of 17β-HSD-1 similar to human tissues. In these cells, HPLC analysis showed that 17β-HSD-1 activity could be blocked by a specific 17β-HSD-1 inhibitor. In vitro, E1 administration elicited colony formation similar to E2, and this was impaired by 17β-HSD-1 inhibition. In vivo, tumors grafted on the chicken chorioallantoic membrane (CAM) demonstrated that E1 upregulated the expression of the estrogen responsive cyclin A similar to E2, which was impaired by 17β-HSD-1 inhibition. Neither in vitro nor in vivo effects of E1 were observed using 17β-HSD-1-negative cells (negative control). Using a patient cohort of 52 primary ECs, we demonstrated the presence of 17β-HSD-1 enzyme activity (ex vivo in tumor tissues, as measured by HPLC), which was inhibited by over 90% in more than 45% of ECs using the 17β-HSD-1 inhibitor. Since drug treatment is generally indicated for metastatic/recurrent and not primary tumor, we next demonstrated the mRNA expression of the potential drug target, 17β-HSD-1, in metastatic lesions using a second cohort of 37 EC patients. In conclusion, 17β-HSD-1 inhibition efficiently blocks the generation of E2 from E1 using various EC models. Further preclinical investigations and 17β-HSD-1 inhibitor development to make candidate compounds suitable for the first human studies are awaited. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Published
2018
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46. Contrast-enhanced spectral mammography as work-up tool in patients recalled from breast cancer screening has low risks and might hold clinical benefits.

Author

Houben IPL, Van de Voorde P, Jeukens CRLPN, Wildberger JE, Kooreman LF, Smidt ML, and Lobbes MBI

Subjects
Aged, Breast Density, Breast Neoplasms pathology, Early Detection of Cancer, Female, Humans, Middle Aged, Netherlands, Radiation Exposure, Reproducibility of Results, Retrospective Studies, Risk, Breast Neoplasms diagnostic imaging, Contrast Media, Image Enhancement methods, Mammography methods
Abstract

Objective: Contrast-enhanced spectral mammography (CESM) is a reliable problem solving tool in the work-up of women recalled from breast cancer screening. We evaluated additional findings caused by CESM alone and outweighed them against the disadvantages of this technique., Methods: From December 2012 to December 2015, all women recalled from screening who underwent CESM were considered for this study. Radiation exposure and number of adverse contrast reactions were analysed. An experienced breast radiologist reviewed all exams and identified cases with lesions detected by CESM alone and scored their conspicuity. From these cases, data on breast density and final diagnosis were collected. For malignant cases, tumour grade and receptor characteristics were also collected., Results: During this study, 839 women underwent CESM after a screening recall, in which five minor adverse contrast reactions were observed. Median radiation dose per exam was 6.0mGy (0.9-23.4mGy). Seventy CESM-only lesions were detected in 65 patients. Of these 70 lesions, 54.3% proved to be malignant, most commonly invasive ductal carcinomas. The remaining CESM-only lesions were benign, predominantly fibroadenomas. No complications were observed during biopsy of these lesions. Retrospectively, the majority of the lesions were either occult or a 'minimal sign' on low-energy CESM images or the screening mammogram., Conclusion: Using CESM as a work-up tool for women recalled from screening carries low risk for the patient, while additionally detected tumour foci might hold important clinical implications which need to be further studied in large, randomized controlled trials., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Published
2017
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47. Hibernoma with metabolic impact?

Author

Vijgen GH, Bouvy ND, Smidt M, Kooreman L, Schaart G, and van Marken Lichtenbelt W

Subjects
Adipose Tissue, Brown chemistry, Buttocks, Energy Metabolism, Humans, Ion Channels analysis, Lipoma chemistry, Lipoma surgery, Magnetic Resonance Imaging, Male, Middle Aged, Mitochondrial Proteins analysis, Muscle Neoplasms chemistry, Muscle Neoplasms surgery, Tomography, X-Ray Computed, Uncoupling Protein 1, Adipose Tissue, Brown metabolism, Lipoma pathology, Muscle Neoplasms pathology
Abstract

A hibernoma is a benign tumour of brown adipose tissue (BAT). BAT is also present in physiological depots, previously considered residual. However, in 2009 functional BAT in adults was reported. Metabolically active BAT is suggested to significantly influence the energy balance and increasing BAT activity could possibly treat obesity. This strongly increased the interest in BAT in man and currently more research is conducted. We describe the case of an intramuscular hibernoma and illustrate the pathophysiology of the observed hibernoma in relation to recent insights on physiological BAT. Immunofluorescence staining of the hibernoma showed the presence of uncoupling-protein-1, a protein specific for active BAT. This suggests that this hibernoma contains BAT that could possibly contribute to the human energy balance.

Published
2012
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