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2. Artificial Intelligence and Hepatocellular Carcinoma (ARTIHCC)

Author

San Gerardo Hospital, Ospedale 'Carlo Poma' - Mantova, Ospedale Centrale di Bolzano, University of Pavia, Morgagni Pierantoni Hospital, Regina Elena Cancer Institute, Universita di Verona, University of Milano Bicocca, Treviso Regional Hospital, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Miulli General Hospital, Federico II University, Research Institute Against Digestive Cancer IRCAD, and Simone Famularo, MD, Principal Investigator

Published
2024

3. Segmentectomy vs Lobectomy

Author

Regina Elena Cancer Institute, Istituto Europeo di Oncologia, University of Pisa, A.O.U. Città della Salute e della Scienza - Molinette Hospital, Azienda Ospedaliera 'Sant'Andrea', and CHIAPPETTA MARCO, Dr

Published
2023

5. Longitudinal Evaluation of Intestinal, Haematological and Urinary Toxicity From Pelvic Irradiation for Prostate Cancer (IHU-WPRT-TOX)

Author

Associazione Italiana per la Ricerca sul Cancro, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Regina Elena Cancer Institute, Azienda Ospedaliero Universitaria, Santa Maria della Misericordia di Udine, Italy, Cliniche Humanitas Gavazzeni, Centro AKTIS Diagnostica e Terapia, Azienda Sanitaria dell'Alto Adige, Azienda Sanitaria Locale To4, Arcispedale Santa Maria Nuova-IRCCS, Candiolo Cancer Institute - IRCCS, Azienda Sanitaria Locale di Biella, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo di Alessandria, Azienda U.S.L. della Valle d'Aosta, IRCCS Centro di Riferimento Oncologico della Basilicata, and Cesare Cozzarini, MD

Published
2023

7. National Project on Vaccines, COVID-19 and Frail Patients (VAX4FRAIL)

Author

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Istituto Clinico Humanitas, IRCCS San Raffaele, Regina Elena Cancer Institute, Istituto Nazionale per le Malattie Infettive 'Lazzaro Spallanzani' IRCCS, University of Roma La Sapienza, Fondazione IRCCS Policlinico San Matteo di Pavia, Istituti Fisioterapici Ospitalieri, Istituto Tumori Giovanni Paolo II, BARI, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy, and IRCCS Azienda Ospedaliero-Universitaria di Bologna

Published
2021

8. Revision of the EORTC QLQ-BN20 Questionnaire (QLQBN20)

Author

Medical Center Haaglanden, Regina Elena Cancer Institute, San Giovanni Addolorata Hospital, NHS Lothian, University Hospital Regensburg, University Hospital, Bonn, University of Zurich, National Cancer Center, Japan, King Hussein Cancer Center, Clinical Hospital Center Rijeka, Leeds Cancer Centre at St. James's University Hospital, and LindaDirven, Principal Investigator

Published
2020

9. OMEGA, Local Ablative Therapy in Oligometastatic NSCLC (OMEGA)

Author

A.O.U. Città della Salute e della Scienza - Molinette Hospital, San Luigi Gonzaga Hospital, Regina Elena Cancer Institute, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Azienda Ospedaliera San Camillo Forlanini, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, and Humanitas Research Hospital Milan

Published
2020

12. Laser cavity-soliton microcombs

Author

Marco Peccianti, David J. Moss, Gian-Luca Oppo, Juan Sebastian Totero Gongora, Benjamin Wetzel, Luigi Di Lauro, Maxwell Rowley, Hualong Bao, Andrew Cooper, Brent E. Little, Alessia Pasquazi, Sai T. Chu, Roberto Morandotti, University of Ulster, Department of Medical Oncology, Regina Elena Cancer Institute, City University of Hong Kong [Hong Kong] (CUHK), Karlsruhe Institute of Technology (KIT), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Field (physics), FOS: Physical sciences, Soliton (optics), 02 engineering and technology, 01 natural sciences, law.invention, Semiconductor laser theory, 010309 optics, QC350, Optics, [NLIN.NLIN-PS]Nonlinear Sciences [physics]/Pattern Formation and Solitons [nlin.PS], law, 0103 physical sciences, ComputingMilieux_MISCELLANEOUS, Physics, [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics], business.industry, [PHYS.PHYS.PHYS-ATM-PH]Physics [physics]/Physics [physics]/Atomic and Molecular Clusters [physics.atm-clus], QC0446.2, 021001 nanoscience & nanotechnology, Laser, [PHYS.PHYS.PHYS-GEN-PH]Physics [physics]/Physics [physics]/General Physics [physics.gen-ph], Atomic and Molecular Physics, and Optics, Electronic, Optical and Magnetic Materials, Optical cavity, Photonics, 0210 nano-technology, business, Order of magnitude, Physics - Optics, Optics (physics.optics)
Abstract

Microcavity-based frequency combs, or ‘microcombs’1,2, have enabled many fundamental breakthroughs3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 through the discovery of temporal cavity-solitons. These self-localized waves, described by the Lugiato–Lefever equation22, are sustained by a background of radiation usually containing 95% of the total power23. Simple methods for their efficient generation and control are currently being investigated to finally establish microcombs as out-of-the-lab tools24. Here, we demonstrate microcomb laser cavity-solitons. Laser cavity-solitons are intrinsically background-free and have underpinned key breakthroughs in semiconductor lasers22,25,26,27,28. By merging their properties with the physics of multimode systems29, we provide a new paradigm for soliton generation and control in microcavities. We demonstrate 50-nm-wide bright soliton combs induced at average powers more than one order of magnitude lower than the Lugiato–Lefever soliton power threshold22, measuring a mode efficiency of 75% versus the theoretical limit of 5% for bright Lugiato–Lefever solitons23. Finally, we can tune the repetition rate by well over a megahertz without any active feedback.

Published
2019
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13. TRF2 positively regulates SULF2 expression increasing VEGF-A release and activity in tumor microenvironment

Author

Paola Ostano, Erica Salvati, Chiara Cingolani, Isabella Sperduti, Eleonora Petti, Roberto Dinami, Annamaria Biroccio, Giovanna Chiorino, Marcella Mottolese, Carmen D'Angelo, Giovanni Blandino, Eric Gilson, Manuela Porru, Carla Azzurra Amoreo, Angela Maria Rizzo, Pasquale Zizza, Rosita Russo, Angela Chambery, Carlo Leonetti, Julien Cherfils-Vicini, Andrea Sacconi, Zizza, Pasquale, Dinami, Roberto, Porru, Manuela, Cingolani, Chiara, Salvati, Erica, Rizzo, Angela, D'Angelo, Carmen, Petti, Eleonora, Amoreo, Carla Azzurra, Mottolese, Marcella, Sperduti, Isabella, Chambery, Angela, Russo, Rosita, Ostano, Paola, Chiorino, Giovanna, Blandino, Giovanni, Sacconi, Andrea, Cherfils-Vicini, Julien, Leonetti, Carlo, Gilson, Eric, Biroccio, Annamaria, Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathology, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon

Subjects
Male, Vascular Endothelial Growth Factor A, Angiogenesis, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease_cause, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Neovascularization, 03 medical and health sciences, Mice, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Genetics, medicine, Tumor Microenvironment, Animals, Humans, Telomeric Repeat Binding Protein 2, Neoplasm Metastasis, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, 0303 health sciences, Tumor microenvironment, Neovascularization, Pathologic, Heparin, Gene regulation, Chromatin and Epigenetics, Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Xenograft Model Antitumor Assays, 3. Good health, Telomere, Vascular endothelial growth factor A, Cancer cell, Colonic Neoplasms, Cancer research, medicine.symptom, Sulfatases, Sulfotransferases, Carcinogenesis, 030217 neurology & neurosurgery, Heparan Sulfate Proteoglycans
Abstract

The telomeric protein TRF2 is overexpressed in several human malignancies and contributes to tumorigenesis even though the molecular mechanism is not completely understood. By using a high-throughput approach based on the multiplexed Luminex X-MAP technology, we demonstrated that TRF2 dramatically affects VEGF-A level in the secretome of cancer cells, promoting endothelial cell-differentiation and angiogenesis. The pro-angiogenic effect of TRF2 is independent from its role in telomere capping. Instead, TRF2 binding to a distal regulatory element promotes the expression of SULF2, an endoglucosamine-6-sulfatase that impairs the VEGF-A association to the plasma membrane by inducing post-synthetic modification of heparan sulfate proteoglycans (HSPGs). Finally, we addressed the clinical relevance of our findings showing that TRF2/SULF2 expression is a worse prognostic biomarker in colorectal cancer (CRC) patients. The telomeric protein TRF2 is overexpressed in several human malignancies and contributes to tumorigenesis even though the molecular mechanism is not completely understood. By using a high-throughput approach based on the multiplexed Luminex X-MAP technology, we demonstrated that TRF2 dramatically affects VEGF-A level in the secretome of cancer cells, promoting endothelial cell-differentiation and angiogenesis. The pro-angiogenic effect of TRF2 is independent from its role in telomere capping. Instead, TRF2 binding to a distal regulatory element promotes the expression of SULF2, an endoglucosamine-6-sulfatase that impairs the VEGF-A association to the plasma membrane by inducing post-synthetic modification of heparan sulfate proteoglycans (HSPGs). Finally, we addressed the clinical relevance of our findings showing that TRF2/SULF2 expression is a worse prognostic biomarker in colorectal cancer (CRC) patients.

Published
2019

16. Thermo-optical pulsing in a microresonator filtered fiber-laser: a route towards all-optical control and synchronization

Author

Hualong Bao, Marco Peccianti, Leonardo Del Bino, Luigi Di Lauro, Jonathan M. Silver, Benjamin Wetzel, Juan Sebastian Totero Gongora, Maxwell Rowley, Pascal Del Haye, Alessia Pasquazi, XLIM (XLIM), Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS), University of Sussex, Department of Medical Oncology, and Regina Elena Cancer Institute

Subjects
Materials science, FOS: Physical sciences, Physics::Optics, 02 engineering and technology, Optical field, 01 natural sciences, law.invention, 010309 optics, Synchronization (alternating current), Resonator, law, Fiber laser, 0103 physical sciences, [NLIN]Nonlinear Sciences [physics], Fiber, ComputingMilieux_MISCELLANEOUS, QC, [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics], business.industry, 021001 nanoscience & nanotechnology, Laser, Atomic and Molecular Physics, and Optics, Microsecond, Optical cavity, [SPI.OPTI]Engineering Sciences [physics]/Optics / Photonic, Optoelectronics, 0210 nano-technology, business, Optics (physics.optics), Physics - Optics
Abstract

We report on 'slow' pulsing dynamics in a silica resonator-based laser system: by nesting a high-Q rod-resonator inside an amplifying fiber cavity, we demonstrate that trains of microsecond pulses can be generated with repetition rates in the hundreds of kilohertz. We show that such pulses are produced with a period equivalent to several hundreds of laser cavity roundtrips via the interaction between the gain dynamics in the fiber cavity and the thermo-optical effects in the high-Q resonator. Experiments reveal that the pulsing properties can be controlled by adjusting the amplifying fiber cavity parameters. Our results, confirmed by numerical simulations, provide useful insights on the dynamical onset of complex self-organization phenomena in resonator-based laser systems where thermo-optical effects play an active role. In addition, we show how the thermal state of the resonator can be probed and even modified by an external, counter-propagating optical field, thus hinting towards novel approaches for all-optical control and sensing applications. Published by The Optical Society under the terms of the Creative Commons Attribution 4.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.

Published
2019
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17. Cancer cells induce immune escape via glycocalyx changes controlled by the telomeric protein TRF2

Author

Nicolas Soubeiran, François Ghiringhelli, Pasquale Zizza, Eric Gilson, Charlene Iltis, Annamaria Biroccio, Fabrice Allain, Marina Shkreli, Romy Collet, Ludovic Cervera, Eric Vivier, Sabrina Pisano, Balázs Győrffy, Carlo Leonetti, Martin Rey-Millet, Julien Cherfils-Vicini, Olivier Croce, Nori Sadouni, Valérie M. Renault, Semmelweis University [Budapest], Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Innate Pharma, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Université Côte d'Azur (UCA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Université de Lille, CNRS, and Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF]

Subjects
Male, HSPG, immunosurveillance, MDSC, NK cells, TRF2, Mice, Nude, Biology, Glycocalyx, General Biochemistry, Genetics and Molecular Biology, Metastasis, 03 medical and health sciences, Mice, 0302 clinical medicine, Downregulation and upregulation, Neoplasms, medicine, Animals, Humans, Telomeric Repeat Binding Protein 2, STAT3, Molecular Biology, Cells, Cultured, 030304 developmental biology, 0303 health sciences, General Immunology and Microbiology, General Neuroscience, Myeloid-Derived Suppressor Cells, Articles, Telomere, medicine.disease, 3. Good health, Immunosurveillance, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, TLR2, HEK293 Cells, Tumor progression, Cancer cell, Cancer research, biology.protein, NIH 3T3 Cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Tumor Escape, 030217 neurology & neurosurgery
Abstract

International audience; Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with strong immunosuppressive activity that promote tumor growth. In this study, we describe a mechanism by which cancer cells control MDSCs in human cancers by upregulating TRF2, a protein required for telomere stability. Specifically, we showed that the TRF2 upregulation in cancer cells has extratelomeric roles in activating the expression of a network of genes involved in the biosynthesis of heparan sulfate proteoglycan, leading to profound changes in glycocalyx length and stiffness, as revealed by atomic force microscopy. This TRF2-dependent regulation facilitated the recruitment of MDSCs, their activation via the TLR2/MyD88/IL-6/STAT3 pathway leading to the inhibition of natural killer recruitment and cytotoxicity, and ultimately tumor progression and metastasis. The clinical relevance of these findings is supported by our analysis of cancer cohorts, which showed a correlation between high TRF2 expression and MDSC infiltration, which was inversely correlated with overall patient survival.

Published
2019
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18. Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry

Author

Maria Elena Maccari, Hassan Abolhassani, Asghar Aghamohammadi, Alessandro Aiuti, Olga Aleinikova, Catherine Bangs, Safa Baris, Federica Barzaghi, Helen Baxendale, Matthew Buckland, Siobhan O. Burns, Caterina Cancrini, Andrew Cant, Pascal Cathébras, Marina Cavazzana, Anita Chandra, Francesca Conti, Tanya Coulter, Lisa A. Devlin, J. David M. Edgar, Saul Faust, Alain Fischer, Marina Garcia Prat, Lennart Hammarström, Maximilian Heeg, Stephen Jolles, Elif Karakoc-Aydiner, Gerhard Kindle, Ayca Kiykim, Dinakantha Kumararatne, Bodo Grimbacher, Hilary Longhurst, Nizar Mahlaoui, Tomas Milota, Fernando Moreira, Despina Moshous, Anna Mukhina, Olaf Neth, Benedicte Neven, Alexandra Nieters, Peter Olbrich, Ahmet Ozen, Jana Pachlopnik Schmid, Capucine Picard, Seraina Prader, William Rae, Janine Reichenbach, Stephan Rusch, Sinisa Savic, Alessia Scarselli, Raphael Scheible, Anna Sediva, Svetlana O. Sharapova, Anna Shcherbina, Mary Slatter, Pere Soler-Palacin, Aurelie Stanislas, Felipe Suarez, Francesca Tucci, Annette Uhlmann, Joris van Montfrans, Klaus Warnatz, Anthony Peter Williams, Phil Wood, Sven Kracker, Alison Mary Condliffe, Stephan Ehl, Federal Ministry of Education and Research (Germany), Novartis, GlaxoSmithKline, University of Tehran, Service de Médecine Interne, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Department of Medical Oncology, Regina Elena Cancer Institute, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Istanbul University, Addenbrookes Hospital, Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité d'Immunologie Hématologie et Rhumatologie Pédiatrique [Necker, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Division of Clinical Epidemiology, Deutches Krebsforschungszentrum, Faculty of Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dmitry Rogachev Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, European Laboratory for Food Induced Diseases, Università degli studi di Napoli Federico II, Imagine - Institut des maladies génétiques (IMAGINE - U1163), CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Maccari, Maria Elena, Abolhassani, Hassan, Aghamohammadi, Asghar, Aiuti, Alessandro, Aleinikova, Olga, Bangs, Catherine, Baris, Safa, Barzaghi, Federica, Baxendale, Helen, Buckland, Matthew, Burns, Siobhan O., Cancrini, Caterina, Cant, Andrew, Cathebras, Pascal, Cavazzana, Marina, Chandra, Anita, Conti, Francesca, Coulter, Tanya, Devlin, Lisa A., Edgar, J. David M., Faust, Saul, Fischer, Alain, Prat, Marina Garcia, Hammarstrom, Lennart, Heeg, Maximilian, Jolles, Stephen, Karakoc-Aydiner, Elif, Kindle, Gerhard, Kiykim, Ayca, Kumararatne, Dinakantha, Grimbacher, Bodo, Longhurst, Hilary, Mahlaoui, Nizar, Milota, Tomas, Moreira, Fernando, Moshous, Despina, Mukhina, Anna, Neth, Olaf, Neven, Benedicte, Nieters, Alexandra, Olbrich, Peter, Ozen, Ahmet, Schmid, Jana Pachlopnik, Picard, Capucine, Prader, Seraina, Rae, William, Reichenbach, Janine, Rusch, Stephan, Savic, Sinisa, Scarselli, Alessia, Scheible, Raphael, Sediva, Anna, Sharapova, Svetlana O., Shcherbina, Anna, Slatter, Mary, Soler-Palacin, Pere, Stanislas, Aurelie, Suarez, Felipe, Tucci, Francesca, Uhlmann, Annette, van Montfrans, Joris, Warnatz, Klaus, Williams, Anthony Peter, Wood, Phil, Kracker, Sven, Condliffe, Alison Mary, Ehl, Stephan, Cathébras, Pascal, Hammarström, Lennart, Milota, Toma, Montfrans, Joris van, and Warnatz, Klau

Subjects
0301 basic medicine, Oncology, activated phosphoinositide 3-kinase δ syndrome, [SDV]Life Sciences [q-bio], SIROLIMUS, registry, Activated phosphoinositide 3-kinase δ syndrome, Immunology and Allergy, Registries, Young adult, Non-U.S. Gov't, Child, MUTATION, Societies, Medical, ComputingMilieux_MISCELLANEOUS, Research Support, Non-U.S. Gov't, Middle Aged, PIK3R1, 3. Good health, Europe, Settore MED/02, natural history, Child, Preschool, Perspective, Cohort, Sirolimus/therapeutic use, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, Immunosuppressive Agents, medicine.drug, Adult, lcsh:Immunologic diseases. Allergy, medicine.medical_specialty, Registry, activated phosphoinositide 3-kinase delta syndrome, Adolescent, Class I Phosphatidylinositol 3-Kinases, Primary Immunodeficiency Diseases, Immunology, Natural history, Research Support, Asymptomatic, 03 medical and health sciences, Young Adult, Medical, Internal medicine, Journal Article, medicine, Humans, Rapamycin, Preschool, Sirolimus, Immunologic Deficiency Syndromes/drug therapy, Cytopenia, [SDV.GEN]Life Sciences [q-bio]/Genetics, Bronchiectasis, business.industry, rapamycin, Immunologic Deficiency Syndromes, PIK3CD, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autoimmune lymphoproliferative syndrome, Primary immunodeficiency, Immunosuppressive Agents/therapeutic use, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Societies, business, lcsh:RC581-607
Abstract

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2–3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies., This study was supported by the German Federal Ministry of Education and Research (BMBF 01E01303). The ESID-APDS registry is supported by the pharmaceutical companies Novartis, GlaxoSmithKline, and UCB UK.

Published
2018
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19. The Dilemma of HER2 Double-equivocal Breast Carcinomas

Author

Marchio, Caterina, Dell'Orto, Patrizia, Annaratone, Anna, Geyer, Felipe, Venesio, Tiziana, Berrino, Enrico, Verdun di Cantogno, Ludovica, Garofoli, Andrea, Rangel, Nelson, Casorzo, Laura, dell'Aglio, Carmine, Gugliotta, Patrizia, Trisolini, Elena, Beano, Alessandra, Pietribiasi, Francesca, Orlassino, Renzo, Cassoni, Paola, Pich, Achille, Montemurro, Filippo, Mottolese, Marcella, Vincent-Salomon, Anne, Penault-Llorca, Frédérique, Medico, Enzo, Ng, Charlotte, Viale, Giuseppe, Sapino, Anna, Dell’Orto, Patrizia, dell’Aglio, Carmine, Ng, Charlotte K.Y., Breakthrough Breast Cancer Centre, London Institute of Cancer, Division of Pathology and Laboratory Medicine, Università degli Studi di Milano = University of Milan (UNIMI)-European Institute of Oncology [Milan] (ESMO), Unit of Pathology, Università degli studi di Torino = University of Turin (UNITO), Department of Biomedical Sciences and Human Oncology, University of Turin Med. School, Pathology, Regina Elena Cancer Institute, Département de Pathologie, Institut Curie [Paris], Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Department of Oncological Sciences and Laboratory of Oncogenomics, Università degli Studi di Milano [Milano] (UNIMI)-European Institute of Oncology [Milan] (ESMO), Institute for Cancer Research (IRCC), University of Turin Med. School, Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli studi di Torino (UNITO), and University of Turin

Subjects
Adult, Receptor, ErbB-2, Gene Expression Profiling, Carcinoma, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Original Articles, Middle Aged, molecular subtype, mutations, risk of recurrence, HER2, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Biomarkers, Tumor, Humans, Female, breast carcinoma, skin and connective tissue diseases, equivocal result, neoplasms
Abstract

Supplemental Digital Content is available in the text., The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2013 guidelines for HER2 assessment have increased the number of HER2 equivocal breast carcinomas following in situ hybridization reflex testing, that is, HER2 “double equivocal” (equivocal protein expression and equivocal gene copy number). Forty-five double-equivocal carcinomas were subjected to Prosigna analysis. Twenty-seven cases were investigated for the expression of genes found to be differentially expressed between estrogen receptor (ER)-positive/HER2-positive (N=22) and ER-positive/HER2-negative (N=22) control cases. Twenty-nine of the 45 cases were also analyzed by targeted sequencing using a panel of 14 genes. We then explored the pathologic complete response rates in an independent series of double-equivocal carcinoma patients treated with trastuzumab-containing chemotherapy. All cases were ER-positive, with a mean Ki67 of 28%. Double-equivocal carcinomas were predominantly luminal B (76%); 9 cases (20%) were luminal A, and 2 cases (4%) HER2-enriched. The majority (73%) showed a high risk of recurrence by Prosigna, even when the carcinomas were small (

Published
2018
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20. TRF2 and Apollo Cooperate with Topoisomerase 2α to Protect Human Telomeres from Replicative Damage

Author

Annamaria Biroccio, Eric Gilson, Anaïs Poulet, Christelle Lenain, Anna Bizard, Delphine Benarroch, Arturo Londoño-Vallejo, Erica Salvati, Laure Sabatier, Els Verhoeyen, Julia Morere, Jing Ye, Sébastien Britton, Bernard Salles, Yunlin Wu, Angela Maria Rizzo, Marc Nadal, Patrick Calsou, Adelaïde Saint-Léger, Marie Josèphe Giraud-Panis, Frédérique Magdinier, Simon Amiard, Serge Bauwens, Shanghai Jiao Tong University School of Medicine, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie et pathologie des génomes, Institut National de la Santé et de la Recherche Médicale (INSERM), Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Laboratoire Joliot Curie, École normale supérieure de Lyon (ENS de Lyon)-Centre National de la Recherche Scientifique (CNRS), Virologie humaine, École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et microbiologie [Orsay] (IGM), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Radiobiologie et d'Oncologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Department of Medical Genetics, Centre Hospitalier Universitaire de Nice (CHU Nice), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Laboratory of Biology and Pathology of Genomes, Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
[SDV]Life Sciences [q-bio], MESH: Antigens, Neoplasm, MESH: DNA Replication, chemistry.chemical_compound, MESH: Protein Structure, Tertiary, 0302 clinical medicine, Telomeric Repeat Binding Protein 2, ComputingMilieux_MISCELLANEOUS, Cellular Senescence, Genetics, Telomere-binding protein, 0303 health sciences, Nuclear Proteins, MESH: Telomeric Repeat Binding Protein 2, Telomere, DNA-Binding Proteins, MESH: DNA Repair Enzymes, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Cell Aging, 030220 oncology & carcinogenesis, DNA supercoil, Cell aging, DNA Replication, DNA damage, DNA repair, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Antigens, Neoplasm, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH: DNA Topoisomerases, Type II, Eukaryotic, MESH: DNA Damage, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), DNA replication, DNA, Protein Structure, Tertiary, DNA Repair Enzymes, DNA Topoisomerases, Type II, Exodeoxyribonucleases, chemistry, MESH: Telomere, MESH: Nuclear Proteins, MESH: DNA-Binding Proteins, DNA Damage
Abstract

International audience; Human telomeres are protected from DNA damage by a nucleoprotein complex that includes the repeat-binding factor TRF2. Here, we report that TRF2 regulates the 5' exonuclease activity of its binding partner, Apollo, a member of the metallo-beta-lactamase family that is required for telomere integrity during S phase. TRF2 and Apollo also suppress damage to engineered interstitial telomere repeat tracts that were inserted far away from chromosome ends. Genetic data indicate that DNA topoisomerase 2alpha acts in the same pathway of telomere protection as TRF2 and Apollo. Moreover, TRF2, which binds preferentially to positively supercoiled DNA substrates, together with Apollo, negatively regulates the amount of TOP1, TOP2alpha, and TOP2beta at telomeres. Our data are consistent with a model in which TRF2 and Apollo relieve topological stress during telomere replication. Our work also suggests that cellular senescence may be caused by topological problems that occur during the replication of the inner portion of telomeres.

Published
2010
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21. Design and synthesis of a new dimeric xanthone derivative: enhancement of G-quadruplex selectivity and telomere damage

Author

Armandodoriano Bianco, Alessandro Altieri, Chiara Cingolani, Annamaria Biroccio, Alessandro Venditti, Daniele Nocioni, Stefano Cacchione, Marco Franceschin, Pasquale Zizza, Emanuela Micheli, Department of Biochemical Sciences, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Department of Biology and Biotechnology 'Charles Darwin', Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Réseau International des Instituts Pasteur (RIIP), and This work has been financially supported by Ministero dell’Istruzione,dell’Università e della Ricerca (MIUR, PRIN 2009), by Universitàdi Roma 'La Sapienza', by Istituto Pasteur-FondazioneCenci Bolognetti and by the Italian Association for CancerResearch (A.I.R.C., #11567). C.C. is the recipient of a fellowshipfrom the Italian Foundation for Cancer Research (F.I.R.C.).

Subjects
Stereochemistry, Xanthones, Antineoplastic Agents, G-quadruplex, Biochemistry, Cell Line, chemistry.chemical_compound, Cell Line, Tumor, Neoplasms, Xanthone, Side chain, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Physical and Theoretical Chemistry, Cell Proliferation, Xanthene, Tumor, Ligand, Medicine (all), Organic Chemistry, Dimerization, G-Quadruplexes, Molecular Docking Simulation, Telomere, In vitro, chemistry, Selectivity
Abstract

International audience; Following the results we previously reported on a series of xanthene and xanthone derivatives as G-quad-ruplex stabilizing ligands, in order to obtain a more selective compound with respect to the previous generation of derivatives, we decided to modify the structure of the core ligand, specifically its aromatic extension. In particular, here we report the design, synthesis and activity data of a new compound obtained by dimerization of the xanthene core (HELIXA4C). The reported results show that extension of the aromatic core and the increase of the number of polar side chains led to a great enhancement of G-quadruplex selectivity and telomere damage capability, as derived using ESI-MS evaluation, in vitro cancer screening and specific immunofluorescence assays.

Published
2014
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22. TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells

Author

Ludovic Cervera, Eric Vivier, Eric Gilson, Antonella Stoppacciaro, Karine Jamet, Thomas Kuilman, Laure Sabatier, François-Loïc Cosset, Jacqueline Marvel, Jean-Yves Scoazec, Jing Ye, Daniel S. Peeper, Angela Maria Rizzo, Annamaria Biroccio, Béatrice Horard, Thomas Simonet, Claire T Kint De Rodenbeeke, Carlo Leonetti, Els Verhoeyen, Renée Grataroli, Helene Duret, Mark J. Smyth, Aaron Mendez-Bermudez, Adeline Augereau, Gilles Pagès, Pasquale Zizza, Vincent Picco, Florian Lepinasse, Julien Cherfils-Vicini, Delphine Poncet, Erica Salvati, Arturo Londoño-Vallejo, Serge Bauwens, Michelle Ricoul, Céline Cognet, Sébastien Pinte, Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Énergies et Mécanique Théorique et Appliquée (LEMTA ), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université Nice Sophia Antipolis (1965 - 2019) (UNS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio], Cell, Melanoma, Experimental, Apoptosis, MESH: Flow Cytometry, medicine.disease_cause, Mice, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: RNA, Small Interfering, Tumor Cells, Cultured, Telomeric Repeat Binding Protein 2, MESH: Animals, MESH: Discoidin Domain Receptor 1, RNA, Small Interfering, MESH: Lymphocytes, Tumor-Infiltrating, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, MESH: Real-Time Polymerase Chain Reaction, ZAP70, MESH: Telomeric Repeat Binding Protein 2, Natural killer T cell, Flow Cytometry, 3. Good health, Cell biology, Killer Cells, Natural, MESH: Melanoma, Experimental, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Colonic Neoplasms, Interleukin 12, Female, MESH: Receptor Protein-Tyrosine Kinases, Sulfotransferases, MESH: Killer Cells, Natural, MESH: DNA Primers, Blotting, Western, Mice, Nude, Breast Neoplasms, Biology, Real-Time Polymerase Chain Reaction, MESH: Cell Adhesion, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Discoidin Domain Receptor 1, MESH: Cell Proliferation, medicine, Cell Adhesion, MESH: Mice, Nude, Animals, Humans, MESH: Blotting, Western, RNA, Messenger, MESH: Tumor Cells, Cultured, MESH: Mice, 030304 developmental biology, Cell Proliferation, DNA Primers, MESH: RNA, Messenger, MESH: Colonic Neoplasms, Lymphokine-activated killer cell, MESH: Humans, Cell growth, MESH: Apoptosis, Receptor Protein-Tyrosine Kinases, Cell Biology, MESH: Sulfotransferases, Cancer cell, MESH: HeLa Cells, Carcinogenesis, MESH: Female, MESH: Breast Neoplasms, HeLa Cells
Abstract

International audience; Dysfunctional telomeres suppress tumour progression by activating cell-intrinsic programs that lead to growth arrest. Increased levels of TRF2, a key factor in telomere protection, are observed in various human malignancies and contribute to oncogenesis. We demonstrate here that a high level of TRF2 in tumour cells decreased their ability to recruit and activate natural killer (NK) cells. Conversely, a reduced dose of TRF2 enabled tumour cells to be more easily eliminated by NK cells. Consistent with these results, a progressive upregulation of TRF2 correlated with decreased NK cell density during the early development of human colon cancer. By screening for TRF2-bound genes, we found that HS3ST4--a gene encoding for the heparan sulphate (glucosamine) 3-O-sulphotransferase 4--was regulated by TRF2 and inhibited the recruitment of NK cells in an epistatic relationship with TRF2. Overall, these results reveal a TRF2-dependent pathway that is tumour-cell extrinsic and regulates NK cell immunity.

Published
2013
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23. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Mulligan, Anna Marie, Couch, Fergus J, Barrowdale, Daniel, Domchek, Susan M, Eccles, Diana, Nevanlinna, Heli, Ramus, Susan J, Robson, Mark, Sherman, Mark, Spurdle, Amanda B, Wappenschmidt, Barbara, Lee, Andrew, McGuffog, Lesley, Healey, Sue, Sinilnikova, Olga M, Janavicius, Ramunas, Hansen, Thomas vO, Nielsen, Finn C, Ejlertsen, Bent, Osorio, Ana, Muñoz-Repeto, Iván, Durán, Mercedes, Godino, Javier, Pertesi, Maroulio, Benítez, Javier, Peterlongo, Paolo, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, Cattaneo, Elisa, Bonanni, Bernardo, Viel, Alessandra, Pasini, Barbara, Papi, Laura, Ottini, Laura, Savarese, Antonella, Bernard, Loris, Radice, Paolo, Hamann, Ute, Verheus, Martijn, Meijers-Heijboer, Hanne EJ, Wijnen, Juul, Gómez García, Encarna B, Nelen, Marcel R, Kets, C Marleen, Seynaeve, Caroline, Tilanus-Linthorst, Madeleine MA, van der Luijt, Rob B, van Os, Theo, Rookus, Matti, Frost, Debra, Jones, J Louise, Evans, D Gareth, Lalloo, Fiona, Eeles, Ros, Izatt, Louise, Adlard, Julian, Davidson, Rosemarie, Cook, Jackie, Donaldson, Alan, Dorkins, Huw, Gregory, Helen, Eason, Jacqueline, Houghton, Catherine, Barwell, Julian, Side, Lucy E, McCann, Emma, Murray, Alex, Peock, Susan, Godwin, Andrew K, Schmutzler, Rita K, Rhiem, Kerstin, Engel, Christoph, Meindl, Alfons, Ruehl, Ina, Arnold, Norbert, Niederacher, Dieter, Sutter, Christian, Deissler, Helmut, Gadzicki, Dorothea, Kast, Karin, Preisler-Adams, Sabine, Varon-Mateeva, Raymonda, Schoenbuchner, Ines, Fiebig, Britta, Heinritz, Wolfram, Schäfer, Dieter, Gevensleben, Heidrun, Caux-Moncoutier, Virginie, Fassy-Colcombet, Marion, Cornelis, François, Mazoyer, Sylvie, Léoné, Mélanie, Boutry-Kryza, Nadia, Hardouin, Agnès, Berthet, Pascaline, Muller, Danièle, Fricker, Jean-Pierre, Mortemousque, Isabelle, Pujol, Pascal, Coupier, Isabelle, Lebrun, Marine, Kientz, Caroline, Longy, Michel, Sevenet, Nicolas, Stoppa-Lyonnet, Dominique, Isaacs, Claudine, Caldes, Trinidad, de la Hoya, Miguel, Heikkinen, Tuomas, Aittomäki, Kristiina, Blanco, Ignacio, Lazaro, Conxi, Barkardottir, Rosa B, Soucy, Penny, Dumont, Martine, Simard, Jacques, Montagna, Marco, Tognazzo, Silvia, D'Andrea, Emma, Fox, Stephen, Yan, Max, Rebbeck, Tim, Olopade, Olufunmilayo, Weitzel, Jeffrey N, Lynch, Henry T, Ganz, Patricia A, Tomlinson, Gail E, Wang, Xianshu, Fredericksen, Zachary, Pankratz, Vernon S, Lindor, Noralane M, Szabo, Csilla, Offit, Kenneth, Sakr, Rita, Gaudet, Mia, Bhatia, Jasmine, Kauff, Noah, Singer, Christian F, Tea, Muy-Kheng, Gschwantler-Kaulich, Daphne, Fink-Retter, Anneliese, Mai, Phuong L, Greene, Mark H, Imyanitov, Evgeny, O'Malley, Frances P, Ozcelik, Hilmi, Glendon, Gordon, Toland, Amanda E, Gerdes, Anne-Marie, Thomassen, Mads, Kruse, Torben A, Jensen, Uffe Birk, Skytte, Anne-Bine, Caligo, Maria A, Soller, Maria, Henriksson, Karin, Wachenfeldt, von Anna, Arver, Brita, Stenmark-Askmalm, Marie, Karlsson, Per, Ding, Yuan Chun, Neuhausen, Susan L, Beattie, Mary, Pharoah, Paul DP, Moysich, Kirsten B, Nathanson, Katherine L, Karlan, Beth Y, Gross, Jenny, John, Esther M, Daly, Mary B, Buys, Saundra M, Southey, Melissa C, Hopper, John L, Terry, Mary Beth, Chung, Wendy, Miron, Alexander F, Goldgar, David, Chenevix-Trench, Georgia, Easton, Douglas F, Andrulis, Irene L, Antoniou, Antonis C, Breast Cancer Family Registry, EMBRACE, GEMO Study Collaborators, HEBON, kConFab Investigators, Ontario Cancer Genetics Network, SWE-BRCA, CIMBA, Pediatric Surgery, Neurology, Medical Oncology, Surgery, Clinical Genetics, Department of Laboratory Medicine, St Michael's Hospital-Keenan Research Centre of the Li Ka Shing Knowledge Institute [Toronto], Department of Laboratory Medicine and Pathobiology, University of Toronto, Department of Laboratory Medicine and Pathology, Mayo Clinic, Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] (CAM), Department of Medicine, University of Pennsylvania [Philadelphia]-Abramson Cancer Center, Faculty of Medicine, University of Southampton-University Hospital Southampton, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Department of Preventive Medicine, University of Southern California (USC)-Keck School of Medicine [Los Angeles], University of Southern California (USC), Memorial Sloane Kettering Cancer Center [New York]-Weill Medical College of Cornell University [New York], Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Queensland Institute of Medical Research, Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santariskiu Clinics, State Research Institute Innovative Medicine Center, Center for Genomic Medicine, Copenhagen University Hospital-Rigshospitalet [Copenhagen], Copenhagen University Hospital, Department of Oncology, Human Genetics Group, Spanish National Cancer Research Centre-Spain and the Spanish Network on Rare Diseases, Institute of Biology and Molecular Genetics, Universidad de Valladolid (IBGM-UVA), Instituto de investigación sanitaria de Aragón (IIS), Hospital clinico Universitario 'Lozano Blesa', Molecular Diagnostics Laboratory, National Center for Scientific Research 'Demokritos' (NCSR)-IRRP, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Fondazione Istituto FIRC di Oncologia Molecolare, IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Unit of Medical Genetics, Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Unit of Experimental Oncology 1, Centro di Riferimento Oncologico, Department of Genetics, Biology and Biochemistry, University of Turin, Medical Genetics Unit, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Molecular Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Division of Medical Oncology, Regina Elena Cancer Institute, Department of Experimental Oncology, Consortium for Genomics Technology (Cogentech)-Istituto Europeo di Oncologia. Milan, Molecular Genetics of Breast Cancer, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Epidemiology, Netherlands Cancer Institute, Department of Clinical Genetics, VU Medical Center, Department of Human Genetics and Department of Clinical Genetics, Leiden University Medical Center (LUMC), Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, Department of Human Genetics, Radboud University Medical Center [Nijmegen], Department of Medical Oncology, Erasmus University Medical Center [Rotterdam] (Erasmus MC)-Family Cancer Clinic, Department of Surgical Oncology, Department of Clinical Molecular Genetics, University Medical Center [Utrecht], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Barts Cancer Institute, Queen Mary University of London (QMUL), Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden, Guy's and St. Thomas' NHS Foundation Trust, Yorkshire Regional Genetics Service, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Clinical Genetics Department, St Michael's Hospital, North West Thames Regional Genetics Service, Kennedy-Galton Centre, North of Scotland Regional Genetics Service, University of Aberdeen-NHS Grampian, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Cheshire and Merseyside Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Leicestershire Clinical Genetics Service, University Hospitals Leicester, North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children [London] (GOSH), All Wales Medical Genetics Services, Singleton Hospital, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center [Lawrence], Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Klinikum Rechts der Isar, Ludwig-Maximillians University, University Hospital of Schleswig-Holstein (UKSH), University Hospital Düsseldorf, Institute of Human Genetics, Heidelberg University Hospital [Heidelberg], Universitätsklinikum Ulm - University Hospital of Ulm, Institute of Cell and Molecular Pathology, Hannover Medical School [Hannover] (MHH), University Hospital Carl Gustav Carus, Westfälische Wilhelms-Universität Münster (WWU), Campus Virchov Klinikum, Department of Medical Genetic, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU)-Institute of Human Genetics-Centre of Familial Breast and Ovarian Cancer, Universität Regensburg (UR), University Hospital, Frankfurt, Breakthrough Breast Cancer Research Centre, Institute of cancer research, Service de Génétique Oncologique, Institut Curie [Paris], Service de génétique [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Sud Francilien, CH Evry-Corbeil, CHU Clermont-Ferrand, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Unité d'oncogénétique, CRLCC Paul Strauss, Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne, Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Lombardi Comprehensive Cancer Center, Georgetown University, Molecular Oncology Laboratory, Hospital Clínico San Carlos, Hereditary Cancer Program, Institut Català d'Oncologia-Hospital Duran i Reynals, Department of Pathology, Landspitali University Hospital, University of Iceland [Reykjavik], Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, Research Chair in Oncogenetics, Université Laval [Québec] (ULaval), Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Department of Oncology and Surgical Sciences, Universita degli Studi di Padova, Peter MacCallum Cancer Centre, Peter MacCallum Cancer Center, Department of Anatomical Pathology, Prince of Wales Hospital, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], University of Chicago, City of Hope Comprehensive Cancer Center and Department of Population Sciences, Beckman Research Institute, Departments of Medicine, and Preventive Medicine and Public Health, Creighton University, Jonsson Comprehensive Cancer Center, University of California [Los Angeles] (UCLA), University of California-University of California, Department of Internal Medicine, The University of Texas Health Science Center at Houston (UTHealth)-Harold C. Simmons Comprehensive Cancer Center, Department of Pediatrics, The University of Texas Health Science Center at Houston (UTHealth), Department of Medical Genetics, University of Delaware [Newark], Epidemiology Research Program, American Cancer Society, Department of Obstetrics/Gynaecology and Comprehensive Cancer Center, Medizinische Universität Wien = Medical University of Vienna, Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital [Toronto, Canada] (MSH), Prevention & Cancer Control, Cancer Care Ontario, Departments of Molecular VirologyImmunology and Medical Genetics and Internal Medicine, Ohio State University [Columbus] (OSU), University of Copenhagen = Københavns Universitet (KU)-Rigshospital, Odense University Hospital, Aarhus University Hospital, Vejle Hospital, Section of Genetic Oncology, University of Pisa - Università di Pisa, Lund University Hospital, Oncological Centre, Karolinska University Hospital [Stockholm], Department of Clinical and Experimental Medicine, Linköping University (LIU), Sahlgrenska University Hospital [Gothenburg], Department of Population Sciences, Beckman Research Institute of the City of Hope, UCSF Cancer Risk Program and Departments of Medicine and Epidemiology and Biostatistics, University of California [San Francisco] (UCSF), Department of Cancer Prevention and Control, Roswell Park Cancer Institute [Buffalo], Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention Institute of California, Fox Chase Cancer Center, Department of Oncological Sciences, University of Utah-Huntsman Cancer Institute, Genetic Epidemiology Laboratory, University of Melbourne, Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Columbia University [New York], Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], Department of Dermatology, University of Utah School of Medicine [Salt Lake City], This work was supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. The research leading to these results has received funding from the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175). ACA is a CR-UK Senior Cancer Research Fellow, DFE is CR-UK Principal Research Fellow., for Breast Cancer Family Registry, for EMBRACE, for Ontario Cancer Genetics Network, for SWE-BRCA, for CIMBA, European Project: 223175,EC:FP7:HEALTH,FP7-HEALTH-2007-B,COGS(2009), BMC, Ed., Collaborative Oncological Gene-environment Study - COGS - - EC:FP7:HEALTH2009-05-01 - 2014-01-31 - 223175 - VALID, University of Pennsylvania-Abramson Cancer Center, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Firenze = University of Florence (UniFI), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Consortium for Genomics Technology (Cogentech)-Istituto Europeo di Oncologia [Milano] (IEO), University of Kansas Medical Center [Kansas City, KS, USA], Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Julius-Maximilians-Universität Würzburg (JMU)-Institute of Human Genetics-Centre of Familial Breast and Ovarian Cancer, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Georgetown University [Washington] (GU), Università degli Studi di Padova = University of Padua (Unipd), University of Pennsylvania-University of Pennsylvania, University of California (UC)-University of California (UC), Rigshospital-University of Copenhagen = Københavns Universitet (UCPH), Vejle Hospital [Danemark], University of California [San Francisco] (UC San Francisco), Lee, Andrew [0000-0003-0677-0252], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, University of Cambridge [UK] ( CAM ), University of Southampton [Southampton]-University Hospital Southampton, University of Southern California ( USC ) -Keck School of Medicine [Los Angeles], Memorial Sloan-Kettering Cancer Center-Weill Medical College of Cornell University [New York], National Cancer Institute ( NIH ), Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Instituto de investigación sanitaria de Aragón ( IIS ), National Center for Scientific Research 'Demokritos' ( NCSR ) -IRRP, IFOM, University of Florence, Università degli Studi di Roma 'La Sapienza' [Rome], Deutsches Krebsforschungszentrum ( DKFZ ), Erasmus University Medical Center-Family Cancer Clinic, University Medical Center Utrecht, Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ) -University of Amsterdam [Amsterdam] ( UvA ), Queen Mary University of London ( QMUL ), Sheffield Children's Hospital, University Hospitals of Leicester, Great Ormond Street Hospital for Children [London] ( GOSH ), University of Kansas Medical Center, Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] ( IMISE ), University of Leipzig, University Hospital Ulm, Hannover Medical School [Hannover] ( MHH ), Westfälische Wilhelms-Universität Münster ( WWU ), University Wurzburg-Institute of Human Genetics-Centre of Familial Breast and Ovarian Cancer, University Regensburg, INSTITUT CURIE, Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Centre Hospitalier Universitaire Clermont-Ferrand, Centre François Baclesse, Hôpital Bretonneau-CHRU Tours, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Validation et identification de nouvelles cibles en oncologie ( VINCO ), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laval University [Québec], University of Padua and Istituto Oncologico Veneto IOV - IRCCS, University of Pennsylvania Perelman School of Medicine, University of California at Los Angeles [Los Angeles] ( UCLA ), University of Texas at Houston [Houston] ( UTHealth ) -Harold C. Simmons Comprehensive Cancer Center, University of Texas Health Science, Medical University of Vienna, Mount Sinai Hospital, The Ohio State University Comprehensive Cancer Center, University of Copenhagen ( KU ) -Rigshospital, University of Pisa [Pisa], Linköping University ( LIU ), Sahlgrenska University Hospital, the Beckman Research Institute of the City of Hope, University of California [San Francisco] ( UCSF ), European Project : 223175,EC:FP7:HEALTH,FP7-HEALTH-2007-B,COGS ( 2009 ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2, Human Genetics, Universiteit Leiden-Universiteit Leiden, Nottingham University Hospitals NHS Trust (NUH), Universität Leipzig, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and Roswell Park Cancer Institute [Buffalo] (RPCI)

Subjects
Risk, Heterozygote, endocrine system diseases, Population, Genes, BRCA2, Genes, BRCA1, Social Sciences, Estrogen receptor, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 610 Medical sciences Medicine, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, SDG 3 - Good Health and Well-being, Genotype, medicine, Humans, Genetic Predisposition to Disease, education, skin and connective tissue diseases, Estrogen Receptor Status, Alleles, 030304 developmental biology, Medicine(all), 0303 health sciences, education.field_of_study, Samhällsvetenskap, medicine.disease, 3. Good health, TOX3, Receptors, Estrogen, Cancer and Oncology, 030220 oncology & carcinogenesis, Mutation, Cancer research, Female, Ovarian cancer, Receptors, Progesterone, Research Article
Abstract

[Introduction]: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. [Methods]: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. [Results]: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. [Conclusions]: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

Published
2011
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24. Poly(ADP-ribosyl)ation affects stabilization of Che-1 protein in response to DNA damage

Author

Claudio Passananti, Paola Caiafa, Tiziana Guastafierro, Maurizio Fanciulli, Angela Catizone, Debora Di Lonardo, Michele Zampieri, Maria Giulia Bacalini, Roberta Calabrese, Anna Reale, Fabio Ciccarone, Tiziana Bruno, Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), Department of Cellular Biotechnologies and Haematology, Section of Clinical Biochemistry, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Laboratory B, Department of Therapeutic Programs Development, Regina Elena Cancer Institute, CNR - National Research Council of Italy, Institute of Molecular Biology and Pathology, This work was supported by funds from Ministero della Salute [IFO2007-813232] and from Ministero dell’Istruzione, dell’Università edella Ricerca, Italy [PRIN 2008-812131]., Bacalini, Maria Giulia, Di Lonardo, Debora, Catizone, Angela, Ciccarone, Fabio, Bruno, Tiziana, Zampieri, Michele, Guastafierro, Tiziana, Calabrese, Roberta, Fanciulli, Maurizio, Passananti, Claudio, Caiafa, Paola, and Reale, Anna

Subjects
Cell Cycle Proteins, che-1, Ataxia Telangiectasia Mutated Proteins, Protein-Serine-Threonine Kinase, Biochemistry, Antineoplastic Agent, Ataxia Telangiectasia Mutated Protein, Mice, Cell Cycle Protein, MESH: Animals, Promoter Regions, Genetic, MESH: Ataxia Telangiectasia Mutated Proteins, Poly(ADP-ribose) Polymerase, Polymerase, 0303 health sciences, Apoptosis Regulatory Protein, Kinase, Protein Stability, 030302 biochemistry & molecular biology, MESH: Gene Expression Regulation, Neoplastic, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, dna damage response, PARP inhibitor, Phosphorylation, Poly(ADP-ribose) Polymerases, Human, Protein Binding, MESH: Enzyme Activation, DNA damage, Poly ADP ribose polymerase, DNA-Binding Protein, Recombinant Fusion Proteins, Antineoplastic Agents, Biology, Protein Serine-Threonine Kinases, MESH: Protein-Serine-Threonine Kinases, Cell Line, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, MESH: Proto-Oncogene Proteins p21(ras), MESH: Cell Cycle Proteins, MESH: Protein Stability, MESH: Promoter Regions, Genetic, parp inhibitor, MESH: Recombinant Fusion Proteins, Animals, Humans, MESH: Protein Binding, MESH: Tumor Suppressor Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Settore BIO/10, Gene, Molecular Biology, MESH: Mice, parp-1, 030304 developmental biology, MESH: DNA Damage, Tumor Suppressor Protein, MESH: Humans, Animal, MESH: Apoptosis Regulatory Proteins, Tumor Suppressor Proteins, post-translational modification, MESH: Poly(ADP-ribose) Polymerases, Cell Biology, Molecular biology, In vitro, MESH: Cell Line, Enzyme Activation, biology.protein, MESH: Antineoplastic Agents, Apoptosis Regulatory Proteins, MESH: DNA-Binding Proteins, Recombinant Fusion Protein, DNA Damage
Abstract

International audience; Poly(ADP-ribose) polymerase 1 (PARP-1) catalyzes a post-translational modification that plays a crucial role in coordinating the signalling cascade in response to stress stimuli. During the DNA damage response, phosphorylation by ataxia telangiectasia mutated (ATM) kinase and checkpoint kinase Chk2 induces the stabilization of Che-1 protein, which is critical for the maintenance of G2/M arrest. In this study we showed that poly(ADP-ribosyl)ation, beyond phosphorylation, is involved in the regulation of Che-1 stabilization following DNA damage. We demonstrated that Che-1 accumulation upon doxorubicin treatment is reduced after the inhibition of PARP activity in HCT116 cells and in PARP-1 knock-out or silenced cells. In accordance, impairment in Che-1 accumulation by PARP inhibition reduced Che-1 occupancy at p21 promoter and affected the expression of the corresponding gene. Epistasis experiments showed that the effect of poly(ADP-ribosyl)ation on Che-1 stabilization is independent from ATM kinase activity. Indeed we demonstrated that Che-1 protein co-immunoprecipitates with ADP-ribose polymers and that PARP-1 directly interacts with Che-1, promoting its modification in vitro and in vivo.

Published
2011
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25. Phase I–II trial of prolonged gemcitabine infusion plus paclitaxelas a biweekly schedule for advanced breast cancer patientspretreated with anthracyclines

Author

Francesco Cognetti, Patrizia Vici, Gerold Bepler, Giulio Metro, Domenico Sergi, Alessandra Fabi, Francesca Conti, Massimo Lopez, Federica Tomao, Diana Giannarelli, Luigi Di Lauro, Department of Medical Oncology, Regina Elena Cancer Institute, Statistical Unit, Department of Thoracic Oncology, Moffit Cancer Center, Department of Gynecology, and Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]

Subjects
Cancer Research, Time Factors, Survival, endocrine system diseases, medicine.medical_treatment, Phases of clinical research, Toxicology, Deoxycytidine, Gastroenterology, paclitaxel, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Anthracyclines, Pharmacology (medical), ComputingMilieux_MISCELLANEOUS, advanced breast cancer, 0303 health sciences, BRCA1 Protein, gemcitabine, Middle Aged, 3. Good health, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Female, Breast disease, medicine.drug, Adult, medicine.medical_specialty, Ribonucleoside Diphosphate Reductase, medicine.drug_class, Breast Neoplasms, Antimetabolite, Disease-Free Survival, Drug Administration Schedule, Young Adult, 03 medical and health sciences, Breast cancer, breast cancer, Internal medicine, medicine, Humans, her2-negative breast cancer, Progression-free survival, Aged, 030304 developmental biology, Pharmacology, Chemotherapy, fixed-dose rate, business.industry, Tumor Suppressor Proteins, medicine.disease, Gemcitabine, Regimen, Neoplasm Recurrence, Local, Nuclear medicine, business
Abstract

Paclitaxel (PACL) plus gemcitabine (GEM) is an effective regimen for advanced breast cancer patients pretreated with anthracyclines. A prolonged GEM infusion at a fixed dose rate (FDR) of 10 mg/m2/min produces higher levels of intracellular active metabolites of GEM when compared with a standard 30-min infusion. In the present phase I/II trial, we investigated the association of FDR GEM plus PACL. 1,200 mg/m2 was the dose of GEM recommended for the phase II study, in which patients received PACL at 150 mg/m2, followed by FDR GEM at 1,200 mg/m2 (total GEM infusion time = 120 min), both drugs administered biweekly. Forty-two anthracycline-pretreated advanced breast cancer patients with disease recurrence following at least one line of chemotherapy were enrolled. Two (4.8%) and 12 (33.3%) patients experienced a complete and partial response, respectively, for an overall response rate of 38.1% (95% CI 23.4–52.8%). Median progression free survival and overall survival were 5 and 19.9 months, respectively. No statistically significant association was noted between in situ protein expression of RRM1 and BRCA1 (as assessed by immunofluorescence combined with automated quantitative analysis) and response to treatment in 15 patients with tissue available for analysis. Toxicity was mostly mild to moderate, mainly consisting of G3–G4 neutropenia (9.6%) and hypertransaminasemia (9.5%). Biweekly FDR GEM in combination with PACL is an active and safe regimen for advanced breast cancer patients pretreated with anthracyclines. A prolonged infusion regimen of GEM does not seem to improve the efficacy of a standard 30-min infusion.

Published
2011
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26. The rs3834129 polymorphism and breast cancer risk in mutation carriers

Author

Catucci, Irene, Verderio, Paolo, Pizzamiglio, Sara, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, Roversi, Gaia, Ripamonti, Carla B., Pasini, Barbara, Barile, Monica, Viel, Alessandra, Giannini, Giuseppe, Papi, Laura, Varesco, Liliana, Martayan, Aline, Riboni, Mirko, Volorio, Sara, Radice, Paolo, Peterlongo, Paolo, IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Unit of Genetic Susceptibility to Cancer, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Unit of Medical Statistics and Biometry, Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino (UNITO), Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Unit of Experimental Oncology 1, Centro di Riferimento Oncologico, IRCCS, Department of Experimental Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Medical Genetics Unit, Department of Clinical Physiopathology, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Unit of Hereditary Cancers, Istituto Nazionale per la Ricerca sul Cancro, Laboratory of Immunology, Regina Elena Cancer Institute, and Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine

Subjects
rs3834129, BRCA mutation carriers, CASP8, Polymorphism, Breast cancer risk
Abstract

International audience; The rs3834129 polymorphism, in the promoter of CASP8 gene, has been recently reported as associated with breast cancer risk in the general population, with the minor allele del having a protective effect. Some of the genetic variants found associated with breast cancer risk were reported as risk modifiers in individuals with mutations in and genes. Here, we tested the effect of the rs3834129 del allele on breast cancer risk in BRCA mutation carriers. The rs3834129 was genotyped in a total of 1,207 Italian female mutation carriers. Of these, 740 carried a mutation and 467 a mutation. Overall, 699 were affected with breast cancer and 508 were unaffected. When considering class 1 (loss-of-function) BRCA mutations, hazard ratios estimated by weighted multivariable Cox regression model, for individuals with at least one copy of the del allele, were 1.46 (95% confidence interval (CI): 1.08–1.99) for and mutation carriers combined, 1.74 (95% CI: 1.24–2.46) for mutation carriers, and 1.09 (95% CI: 0.66–1.80) for mutation carriers. These results suggest that the minor allele del of rs3834129 is associated under a dominant model with increased breast cancer risk in carriers of mutations but not in carriers of mutations.

Published
2010
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27. Deregulation of Aurora kinase gene expression in human testicular germ cell tumours

Author

Baldini, Enke, Arlot-Bonnemains, Yannick, Mottolese, Marcella, Sentinelli, Steno, Antoniani, Barbara, Sorrenti, Salvatore, Salducci, M., Comini, E., Ulisse, Salvatore, D'Armiento, Massimino, Department of Experimental Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Department of Pathology, Regina Elena Cancer Institute, Department of Surgical Sciences, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), De Villemeur, Hervé, Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
Adult, Male, mitosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Middle Aged, Neoplasms, Germ Cell and Embryonal, Protein Serine-Threonine Kinases, genomic instability, Seminoma, Up-Regulation, Gene Expression Regulation, Neoplastic, aneuploidy, aurora kinases, testicular germ cell tumour, Testicular Neoplasms, [SDV.CAN] Life Sciences [q-bio]/Cancer, Testis, Aurora Kinase B, Humans, Aurora Kinase C, RNA, Messenger, [SDV.BC] Life Sciences [q-bio]/Cellular Biology
Abstract

International audience; The Aurora kinases regulate chromosome segregation and cytokinesis, and alterations in their expression associate with cell malignant transformation. In this study, we demonstrated by qRT-PCR analysis of 14 seminomas that Aurora-A mRNA was, with respect to control tissues, augmented in five of 14 tumour tissues by 2.17 +/- 0.30 fold (P < 0.05) and reduced in 9 to 0.38 +/- 0.10 (P < 0.01). Aurora-B mRNA was increased in 11 tumour tissues by 4.33 +/- 0.82 fold (P < 0.01) and reduced in 3 to 0.41 +/- 0.11 fold. Aurora-C mRNA was reduced to 0.20 +/- 0.32 fold (P < 0.01) in 13 seminomas and up-regulated in one case. Western blot experiments, performed on protein extracts of nine seminomas and six normal testes, showed an up-regulation of Aurora-B protein by 10.14 +/- 3.51 fold (P < 0.05), while Aurora-A protein was found increased in four seminomas by 2.16 +/- 0.43 (P < 0.05), unchanged in three and reduced in two tumour tissues. Aurora-C protein was increased by 9.2 +/- 2.90 fold (P < 0.05), suggesting that post-transcriptional mechanisms modulate its expression. In conclusion, we demonstrated that expression of Aurora kinases is deregulated in seminomas, suggesting that they may play a role in the progression of testicular cancers.

Published
2010
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28. Exploring the link between MORF4L1 and risk of breast cancer

Author

Martrat, G., Maxwell, C.A., Tominaga, E., Porta-de-la-Riva, M., Bonifaci, N., Gomez-Baldo, L., Bogliolo, M., Lazaro, C., Blanco, I., Brunet, J., Aguilar, H., Fernandez-Rodriguez, J., Seal, S., Renwick, A., Rahman, N., Kuhl, J., Neveling, K., Schindler, D., Ramirez, M.J., Castella, M., Hernandez, G., Easton, D.F., Peock, S., Cook, M., Oliver, C.T., Frost, D., Platte, R., Evans, D.G., Lalloo, F., Eeles, R., Izatt, L., Chu, C., Davidson, R., Ong, K.R., Cook, J., Douglas, F., Hodgson, S., Brewer, C., Morrison, P.J., Porteous, M., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Roversi, G., Barile, M., Viel, A., Pasini, B., Ottini, L., Putignano, A.L., Savarese, A., Bernard, L., Radice, P., Healey, S., Spurdle, A., Chen, X.Q., Beesley, J., Rookus, M.A., Verhoef, S., Tilanus-Linthorst, M.A., Vreeswijk, M.P., Asperen, C.J., Bodmer, D., Ausems, M.G.E.M., Os, T.A. van, Blok, M.J., Meijers-Heijboer, H.E.J., Hogervorst, F.B.L., Goldgar, D.E., Buys, S., John, E.M., Miron, A., Southey, M., Daly, M.B., Harbst, K., Borg, A., Rantala, J., Barbany-Bustinza, G., Ehrencrona, H., Stenmark-Askmalm, M., Kaufman, B., Laitman, Y., Milgrom, R., Friedman, E., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Oskar, T., Couch, F.J., Wang, X.S., Fredericksen, Z., Cuadras, D., Moreno, V., Pientka, F.K., Depping, R., Caldes, T., Osorio, A., Benitez, J., Bueren, J., Heikkinen, T., Nevanlinna, H., Hamann, U., Torres, D., Caligo, M.A., Godwin, A.K., Imyanitov, E.N., Janavicius, R., Sinilnikova, O.M., Stoppa-Lyonnet, D., Mazoyer, S., Verny-Pierre, C., Castera, L., Pauw, A. de, Bignon, Y.J., Uhrhammer, N., Peyrat, J.P., Vennin, P., Ferrer, S.F., Collonge-Rame, M.A., Mortemousque, I., McGuffog, L., Chenevix-Trench, G., Pereira-Smith, O.M., Antoniou, A.C., Ceron, J., Tominaga, K., Surralles, J., Pujana, M.A., EMBRACE, kConFab, HEBON, BCFR, SWE-BRCA, GEMO Study Collaborators, Human Genetics, BMC, Ed., Translational Research Laboratory, Catalan Institute of Oncology-Bellvitge Institute for Biomedical Research, Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Catalan Institute of Oncology, Department of Cellular and Structural Biology, The University of Texas Health Science Center at Houston (UTHealth)-Sam and Ann Barshop Institute for Longevity and Aging Studies, Chemoresistance and Predictive Factors of Tumor Response and Stromal Microenvironment, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Biomarkers and Susceptibility Unit, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona (UAB), Biomedical Research Centre Network for Rare Diseases (CIBERER), Genetic Counseling and Hereditary Cancer Programme, Section of Cancer Genetics, Institute of cancer research, Department of Human Genetics, Julius-Maximilians-Universität Würzburg (JMU), Strangeways Research Laboratory, University of Cambridge [UK] (CAM)-Department of Public Health and Primary Care-Centre for Cancer Genetic Epidemiology, Centre for Cancer Genetic Epidemiology [Cambridge], University of Cambridge [UK] (CAM)-Department of Oncology, Genetic Medicine, St Mary's Hospital-NHS Foundation Trust-Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Clinical Genetics Department, Guy's and St Thomas NHS Foundation Trust, Yorkshire Regional Genetics Service, St James's hospital, Ferguson-Smith Centre for Clinical Genetics, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Institute of Human Genetics, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Queen Mary University of London (QMUL)-St George's Hospital, Department of Clinical Genetics, Royal Devon & Exeter Hospital, Northern Ireland Regional Genetics Centre, Belfast City Hospital, South East of Scotland Regional Genetics Service, Western General Hospital, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine-Fondazione IRCCS Istituto Nazionale Tumori (INT), Department of Preventive and Predictive Medicine, IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Unit of Medical Genetics, Fondazione IRCCS INT, Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Division of Experimental Oncology 1, Centro di Riferimento Oncologico (CRO), Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Department of Molecular Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Università degli Studi di Firenze = University of Florence (UniFI), Fiorgen Foundation for Pharmacogenomics, Division of Medical Oncology, Regina Elena Cancer Institute, Department of Experimental Oncology, IEO, Division of Genetics and Population Health, Queensland Institute of Medical Research, Department of Epidemiology, The Netherlands Cancer Institute, Family Cancer Clinic, Department of Surgical Oncology, Erasmus University Medical Center [Rotterdam] (Erasmus MC)-Family Cancer Clinic, Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), DNA Diagnostics, Radboud University Medical Center [Nijmegen], Department of Medical Genetics, University Medical Center [Utrecht], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), University Hospital Maastricht, VU Medical Center, Department of Dermatology, University of Utah School of Medicine [Salt Lake City], Department of Internal Medicine, Huntsman Cancer Institute, Cancer Prevention Institute of California, Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], Department of Surgery, Harvard Medical School [Boston] (HMS), Centre for Molecular, Environmental, Genetic and Analytic Epidemiology (MEGA), University of Melbourne-Melbourne School of Population Health, Division of Population Science, Fox Chase Cancer Center, Department of Oncology, Clinical Sciences, Lund University [Lund]-Skåne University Hospital, Karolinska University Hospital [Stockholm], Department of Genetics and Pathology, Uppsala University, Department of Oncology, University Hospital-Hälsouniversitetet Universitetssjukhuset, The Institute of Oncology, Chaim Sheba Medical Center, The Susanne Levy Gertner Oncogenetics Unit, Sackler Faculty of Medicine, Tel Aviv University (TAU), Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Department of Medicine, Medical Genetics, Abramson Cancer Center-Perelman School of Medicine, Center for Clinical Epidemiology and Biostatistics, Faculty of Medicine, University of Iceland [Reykjavik], Department of Laboratory Medicine and Pathology, Mayo Clinic, Department of Health Sciences Research, Statistical Assessment Service, Department of Physiology, Universität zu Lübeck = University of Lübeck [Lübeck]-Center for Structural and Cell Biology in Medicine, Medical Oncology Branch, Hospital Clínico San Carlos, Human Cancer Genetics Programme, CIBER de Enfermedades Raras (CIBERER)-Spanish National Cancer Research Centre, Division of Hematopoiesis and Gene Therapy, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas [Madrid] (CIEMAT), Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Molecular Genetics of Breast Cancer, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Instituto de Genética Humana, Pontificia Universidad Javeriana (PUJ), Section of Genetic Oncology, University of Pisa - Università di Pisa, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center [Kansas City, KS, USA], Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion, Vilnius University [Vilnius]-Hospital Santariskiu Clinics, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Oncologique, Institut Curie [Paris], 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), Département d'Oncogénétique, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-UNICANCER, Laboratoire d'Oncologie Moléculaire Humaine, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER, Consultation d'Oncogénétique, Laboratoire de Génétique Chromosomique, CH Chambéry, Département de Génétique et Reproduction, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, The CIMBA data management is supported by Cancer Research - UK., kConFab, HEBON, BCFR, SWE-BRCA, GEMO Study Collaborators, Autonomous University of Barcelona, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Department of Oncology-University of Cambridge [UK] (CAM), University of Turin, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Departament of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Tel Aviv University [Tel Aviv], University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Universität zu Lübeck [Lübeck]-Center for Structural and Cell Biology in Medicine, University of Kansas Medical Center [Lawrence], Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, Universiteit Leiden-Universiteit Leiden, Skåne University Hospital-Lund University [Lund], University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Abramson Cancer Center, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Clinical Genetics, Faculteit der Geneeskunde, Klinische Genetica, RS: GROW - School for Oncology and Reproduction, Genetica & Celbiologie, Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Martrat, G, Maxwell, C, Tominaga, E, Porta de la Riva, M, Bonifaci, N, Gómez Baldó, L, Bogliolo, M, Lázaro, C, Blanco, I, Brunet, J, Aguilar, H, Fernández Rodríguez, J, Seal, S, Renwick, A, Rahman, N, Kühl, J, Neveling, K, Schindler, D, Ramírez, M, Castellà, M, Hernández, G, Embrace, Easton, D, Peock, S, Cook, M, Oliver, C, Frost, D, Platte, R, Evans, D, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Davidson, R, Ong, K, Cook, J, Douglas, F, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Pasini, B, Ottini, L, Putignano, A, Savarese, A, Bernard, L, Radice, P, Healey, S, Spurdle, A, Chen, X, Beesley, J, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Asperen, C, Bodmer, D, Ausems, M, van Os, T, Blok, M, Meijers Heijboer, H, Hogervorst, F, Goldgar, D, Buys, S, John, E, Miron, A, Southey, M, Daly, M, Harbst, K, Borg, A, Rantala, J, Barbany Bustinza, G, Ehrencrona, H, Stenmark Askmalm, M, Kaufman, B, Laitman, Y, Milgrom, R, Friedman, E, Domchek, S, Nathanson, K, Rebbeck, T, Johannsson, O, Couch, F, Wang, X, Fredericksen, Z, Cuadras, D, Moreno, V, Pientka, F, Depping, R, Caldés, T, Osorio, A, Benítez, J, Bueren, J, Heikkinen, T, Nevanlinna, H, Hamann, U, Torres, D, Caligo, M, Godwin, A, Imyanitov, E, Janavicius, R, Sinilnikova, O, Stoppa Lyonnet, D, Mazoyer, S, Verny Pierre, C, Castera, L, de Pauw, A, Bignon, Y, Uhrhammer, N, Peyrat, J, Vennin, P, Ferrer, S, Collonge Rame, M, Mortemousque, I, Mcguffog, L, Chenevix Trench, G, Pereira Smith, O, Antoniou, A, Cerón, J, Tominaga, K, Surrallés, J, Pujana, M, Human genetics, CCA - Oncogenesis, Biomedical Research Centre Network for Epidemiology and Public Health ( CIBERESP ), The University of Texas Health Science Center at San Antonio-Sam and Ann Barshop Institute for Longevity and Aging Studies, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] ( IDIBELL ), Biomedical Research Centre Network for Rare Diseases ( CIBERER ), University of Würzburg, University of Cambridge [UK] ( CAM ) -Department of Public Health and Primary Care-Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] ( CAM ) -Department of Oncology, Birmingham Women's Hospital Healthcare NHS Trust, Sheffield Children's Hospital, Newcastle Upon Tyne Hospitals NHS Trust, Queen Mary University of London ( QMUL ) -St George's Hospital, IFOM, Istituto FIRC di Oncologia Molecolare ( IFOM ), Università degli Studi di Roma 'La Sapienza' [Rome], University of Florence, Erasmus MC-Daniel den Hoed Cancer Center-Family Cancer Clinic, University Medical Center Utrecht, Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ) -University of Amsterdam [Amsterdam] ( UvA ), Harvard Medical School [Boston] ( HMS ), Centre for Molecular, Environmental, Genetic and Analytic Epidemiology ( MEGA ), University of Pennsylvania School of Medicine, University of Pennsylvania School of Medicine-Abramson Cancer Center, Centro de Investigaciones Energéticas, Deutsches Krebsforschungszentrum ( DKFZ ), Pontificia Universidad Javeriana, University of Pisa [Pisa], University of Kansas Medical Center, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), INSTITUT CURIE, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), CRLCC Jean Perrin, CRLCC Oscar Lambret, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Saint-Jacques, Hôpital Bretonneau-CHRU Tours, and Universitat de Barcelona

Subjects
DNA Repair, Genes, BRCA2, RAD51, Genes, BRCA1, Germ-Cell, Helicase Brip1, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 0302 clinical medicine, Breast cancer, Fanconi anemia, Risk Factors, Replication Protein A, Teknik och teknologier, Homologous Recombination, skin and connective tissue diseases, C-Elegans, Genetics, Medicine(all), ddc:616, 0303 health sciences, Mutation, Fanconi Anemia Complementation Group D2 Protein, Nuclear Proteins, Anèmia aplàstica, 3. Good health, 030220 oncology & carcinogenesis, Chromodomain Protein, Engineering and Technology, Female, RNA Interference, Fanconi Anemia Complementation Group N Protein, Aplastic anemia, Research Article, BRCA2 Mutation Carrier, DNA repair, PALB2, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Cell Line, Càncer de mama, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, SDG 3 - Good Health and Well-being, [SDV.CAN] Life Sciences [q-bio]/Cancer, Two-Hybrid System Techniques, medicine, Genetic predisposition, Animals, Humans, Genetic Predisposition to Disease, Caenorhabditis elegans, Gene, 030304 developmental biology, Phenocopy, Caenorhabditis-Elegan, Tumor Suppressor Proteins, medicine.disease, BRCA1, BRCA2, Pancreatic-Cancer, Fanconi Anemia, Genes, Cancer and Oncology, Fanconi-Anemia, Cancer research, Rad51 Recombinase, Susceptibility Gene, DNA Damage, Transcription Factors
Abstract

Introduction Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to γ-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively. Conclusions While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.

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29. Observation of laser-cavity solitons in micro-resonators

Author

Gian-Luca Oppo, Alessia Pasquazi, Marco Peccianti, Juan Sebastian Totero Gongora, Luigi Di Lauro, Brent E. Little, Andrew Cooper, Benjamin Wetzel, Hualong Bao, Maxwell Rowley, Sai T. Chu, David J. Moss, Roberto Morandotti, University of Ulster, Department of Medical Oncology, Regina Elena Cancer Institute, City University of Hong Kong [Hong Kong] (CUHK), Karlsruhe Institute of Technology (KIT), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Physics::Optics, 02 engineering and technology, 01 natural sciences, law.invention, 010309 optics, Resonator, [NLIN.NLIN-PS]Nonlinear Sciences [physics]/Pattern Formation and Solitons [nlin.PS], law, 0103 physical sciences, Spectroscopy, Quantum, ComputingMilieux_MISCELLANEOUS, Physics, [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics], business.industry, [PHYS.PHYS.PHYS-ATM-PH]Physics [physics]/Physics [physics]/Atomic and Molecular Clusters [physics.atm-clus], Ranging, 021001 nanoscience & nanotechnology, Laser, [PHYS.PHYS.PHYS-GEN-PH]Physics [physics]/Physics [physics]/General Physics [physics.gen-ph], Metrology, Power (physics), Optical cavity, Optoelectronics, 0210 nano-technology, business
Abstract

Optical frequency combs based on micro-cavity resonators, also known as ‘micro-combs’, are ready to achieve the full capability of their bulk counterparts but on an integrated footprint [1]. They have enabled major breakthroughs in spectroscopy, communications, microwave photonics, frequency synthesis, optical ranging, quantum sources and metrology. Of particular relevance was the recent experimental implementation of temporal cavity-solitons [2,3]. Temporal cavity-solitons in micro-resonators are described by the well-known Lugiato-Lefever equation. Currently, these self-localised waves form on top of a strong background of radiation, usually containing 95% of the total power [4] and require active control of an external driving laser — a complex process which limits the choice of fundamental parameters such as the repetition-rate. Developing simple methods for controlling and generating highly efficient, self-localised pulses is one of the most compelling challenges to overcome, in anticipation of the widespread use of micro-combs outside of laboratory environments.

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30. Thermo-optical pulsing in a resonator-based laser

Author

Leonardo Del Bino, Luigi Di Lauro, Maxwell Rowley, Hualong Bao, Marco Peccianti, Pascal Dela Haye, Jonathan M. Silver, Benjamin Wetzel, Juan Sebastian Totero Gongora, Alessia Pasquazi, Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Department of Medical Oncology, and Regina Elena Cancer Institute

Subjects
Materials science, Kerr effect, Bistability, Physics::Optics, 02 engineering and technology, 01 natural sciences, law.invention, 010309 optics, Resonator, 020210 optoelectronics & photonics, [NLIN.NLIN-PS]Nonlinear Sciences [physics]/Pattern Formation and Solitons [nlin.PS], law, 0103 physical sciences, 0202 electrical engineering, electronic engineering, information engineering, ComputingMilieux_MISCELLANEOUS, Optical amplifier, Mode volume, [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics], business.industry, [PHYS.PHYS.PHYS-ATM-PH]Physics [physics]/Physics [physics]/Atomic and Molecular Clusters [physics.atm-clus], Laser, [PHYS.PHYS.PHYS-GEN-PH]Physics [physics]/Physics [physics]/General Physics [physics.gen-ph], Optoelectronics, business, Lasing threshold, Refractive index
Abstract

Over the past decades there has been significant effort to develop novel laser sources utilizing small-footprint integrated optics. In particular, micro-resonator devices have been of much interest due to their strong field enhancement which enables access to nonlinear optical processes at relatively low power levels, thus unlocking numerous functionalities. Importantly, the Kerr effect has been utilized to generate optical frequency combs in these devices [1,2]. However, such a desired nonlinear effect is often paired with more detrimental ones. Ubiquitously, these devices are affected by thermal nonlinearities [3], which yield a modification of the refractive index and/or mode volume of the resonator. Significant efforts have been invested in active means to compensate for this effect [4], which can destabilize the desired lasing operation and presents an important challenge to overcome. Understanding this dynamical behavior is of key importance to the suppression or even the beneficial use of this thermal effect within such optical systems. Here, we make use of a laser architecture, which has previously been shown capable of generating self-starting frequency combs, consisting of a micro-resonator nested in an external erbium-doped fiber amplifier (EDFA) cavity loop [5]. We show that with the correct tuning of cavity static parameters, namely amplifier gain and cavity losses, we are able to enter a regime of ‘slow’ pulsing — a stable generation of microsecond pulses with a repetition rate of 100 kHz. We show that the pulsing, operating at a period equivalent to several hundreds of cavity roundtrips, is in fact driven by the thermal bistability in the fused-silica resonator interacting with the non-instantaneous gain response of the EDFA.

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33. Letter to Editor Regarding Article "Initial Experience Using Laparoscopic HIPEC for Gastric Cancer with Peritoneal Metastasis: Safety and Outcomes".

Author

Carboni F, Corona F, and Zazza S

Subjects
Humans, Cytoreduction Surgical Procedures methods, Survival Rate, Prognosis, Peritoneal Neoplasms secondary, Peritoneal Neoplasms therapy, Stomach Neoplasms pathology, Stomach Neoplasms surgery, Stomach Neoplasms therapy, Laparoscopy methods, Hyperthermic Intraperitoneal Chemotherapy methods
Published
2024
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34. Enhanced recovery after surgery (ERAS) implementation in cytoreductive surgery (CRS) and hyperthermic IntraPEritoneal chemotherapy (HIPEC): Insights from Italian peritoneal surface malignancies expert centers.

Author

Robella M, Vaira M, Ansaloni L, Asero S, Bacchetti S, Borghi F, Casella F, Coccolini F, De Cian F, di Giorgio A, Framarini M, Gelmini R, Graziosi L, Kusamura S, Lippolis P, Lo Dico R, Macrì A, Marrelli D, Sammartino P, Sassaroli C, Scaringi S, Tonello M, Valle M, and Sommariva A

Subjects
Humans, Italy, Guideline Adherence, Surveys and Questionnaires, Practice Guidelines as Topic, Cytoreduction Surgical Procedures methods, Peritoneal Neoplasms therapy, Hyperthermic Intraperitoneal Chemotherapy, Enhanced Recovery After Surgery
Abstract

Background: Cytoreductive surgery (CRS) combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is a complex procedure that involves extensive peritoneal and visceral resections followed by intraperitoneal chemotherapy. The Enhanced Recovery After Surgery (ERAS) program aims to achieve faster recovery by maintaining pre-operative organ function and reducing the stress response following surgery. A recent publication introduced dedicated ERAS guidelines for CRS and HIPEC with the aim of extending the benefits to patients with peritoneal surface malignancies., Methods: A survey was conducted among 21 Italian centers specializing in peritoneal surface malignancies (PSM) treatment to assess adherence to ERAS guidelines. The survey covered pre/intraoperative and postoperative ERAS items and explored attitudes towards ERAS implementation., Results: All centers completed the survey, demonstrating expertise in PSM treatment. However, less than 30 % of centers adopted ERAS protocols despite being aware of dedicated guidelines. Preoperative optimization was common, with variations in bowel preparation methods and fasting periods. Intraoperative normothermia control was consistent, but fluid management practices varied. Postoperative practices, including routine abdominal drain placement and NGT management, varied greatly among centers. The majority of respondents expressed an intention to implement ERAS, citing concerns about feasibility and organizational challenges., Conclusions: The study concludes that Italian centers specialized in PSM treatment have limited adoption of ERAS protocols for CRS ± HIPEC, despite being aware of guidelines. The variability in practice highlights the need for standardized approaches and further evaluation of ERAS applicability in this complex surgical setting to optimize patient care., Competing Interests: Declaration of competing interest The authors have no conflicts of interest or financial ties to disclose., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Published
2024
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36. Prognostic value of specific KRAS mutations in patients with colorectal peritoneal metastases.

Author

Tonello M, Baratti D, Sammartino P, Di Giorgio A, Robella M, Sassaroli C, Framarini M, Valle M, Macrì A, Graziosi L, Coccolini F, Lippolis PV, Gelmini R, Deraco M, Biacchi D, Aulicino M, Vaira M, De Franciscis S, D'Acapito F, Carboni F, Milone E, Donini A, Fugazzola P, Faviana P, Sorrentino L, Pizzolato E, Cenzi C, Del Bianco P, and Sommariva A

Subjects
Humans, Male, Female, Middle Aged, Prognosis, Aged, Adult, Hyperthermic Intraperitoneal Chemotherapy, Disease-Free Survival, Retrospective Studies, Cytoreduction Surgical Procedures, Aged, 80 and over, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Colorectal Neoplasms mortality, Peritoneal Neoplasms secondary, Peritoneal Neoplasms genetics, Proto-Oncogene Proteins p21(ras) genetics, Mutation
Abstract

Background: There is little evidence on KRAS mutational profiles in colorectal cancer (CRC) peritoneal metastases (PM). This study aims to determine the prevalence of specific KRAS mutations and their prognostic value in a homogeneous cohort of patients with isolated CRC PM treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy., Materials and Methods: Data were collected from 13 Italian centers, gathered in a collaborative group of the Italian Society of Surgical Oncology. KRAS mutation subtypes have been correlated with clinical and pathological characteristics and survival [overall survival (OS), local (peritoneal) disease-free survival (LDFS) and disease-free survival (DFS)]., Results: KRAS mutations occurred in 172 patients (47.5%) out of the 362 analyzed. Two different prognostic groups of KRAS mutation subtypes were identified: KRAS MUT1 (G12R, G13A, G13C, G13V, Q61H, K117N, A146V), median OS > 120 months and KRAS MUT2 (G12A, G12C, G12D, G12S, G12V, G13D, A59E, A59V, A146T), OS: 31.2 months. KRAS MUT2 mutations mainly occurred in the P-loop region (P < 0.001) with decreased guanosine triphosphate (GTP) hydrolysis activity (P < 0.001) and were more frequently related to size (P < 0.001) and polarity change (P < 0.001) of the substituted amino acid (AA). When KRAS MUT1 and KRAS MUT2 were combined with other known prognostic factors (peritoneal cancer index, completeness of cytoreduction score, grading, signet ring cell, N status) in multivariate analysis, KRAS MUT1 showed a similar survival rate to KRAS WT patients, whereas KRAS MUT2 was independently associated with poorer prognosis (hazard ratios: OS 2.1, P < 0.001; DFS 1.9, P < 0.001; LDFS 2.5, P < 0.0001)., Conclusions: In patients with CRC PM, different KRAS mutation subgroups can be determined according to specific codon substitution, with some mutations (KRAS MUT1 ) that could have a similar prognosis to wild-type patients. These findings should be further investigated in larger series., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2024
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37. Is Systemic Chemotherapy Useful in Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Colorectal Peritoneal Metastases? A Propensity-Score Analysis.

Author

Tonello M, Baratti D, Sammartino P, Di Giorgio A, Robella M, Sassaroli C, Framarini M, Valle M, Macrì A, Graziosi L, Coccolini F, Lippolis PV, Gelmini R, Deraco M, Biacchi D, Santullo F, Vaira M, Di Lauro K, D'Acapito F, Carboni F, Milone E, Donini A, Fugazzola P, Faviana P, Sorrentino L, Pizzolato E, Cenzi C, Del Bianco P, and Sommariva A

Subjects
Humans, Hyperthermic Intraperitoneal Chemotherapy, Cytoreduction Surgical Procedures, Combined Modality Therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Survival Rate, Retrospective Studies, Colorectal Neoplasms pathology, Peritoneal Neoplasms secondary, Hyperthermia, Induced
Abstract

Purpose: Multimodal treatment of colorectal (CRC) peritoneal metastases (PM) includes systemic chemotherapy (SC) and surgical cytoreduction (CRS), eventually with hyperthermic intraperitoneal chemotherapy (HIPEC), in select patients. Considering lack of clear guidelines, this study was designed to analyze the role of chemotherapy and its timing in patients treated with CRS-HIPEC., Methods: Data from 13 Italian centers with PM expertise were collected by a collaborative group of the Italian Society of Surgical Oncology (SICO). Clinicopathological variables, SC use, and timing of administration were correlated with overall survival (OS), disease-free survival (DFS), and local (peritoneal) DFS (LDFS) after propensity-score (PS) weighting to reduce confounding factors., Results: A total of 367 patients treated with CRS-HIPEC were included in the propensity-score weighting. Of the total patients, 19.9% did not receive chemotherapy within 6 months of surgery, 32.4% received chemotherapy before surgery (pregroup), 28.9% after (post), and 18.8% received both pre- and post-CRS-HIPEC treatment (peri). SC was preferentially administered to younger (p = 0.02) and node-positive (p = 0.010) patients. Preoperative SC is associated with increased rate of major complications (26.9 vs. 11.3%, p = 0.0009). After PS weighting, there were no differences in OS, DFS, or LDFS (p = 0.56, 0.50, and 0.17) between chemotherapy-treated and untreated patients. Considering SC timing, the post CRS-HIPEC group had a longer DFS and LDFS than the pre-group (median DFS 15.4 vs. 9.8 m, p = 0.003; median LDFS 26.3 vs. 15.8 m, p = 0.026)., Conclusions: In patients with CRC-PM treated with CRS-HIPEC, systemic chemotherapy was not associated with overall survival benefit. The adjuvant schedule was related to prolonged disease-free intervals. Additional, randomized studies are required to clarify the role and timing of systemic chemotherapy in this patient subset., (© 2023. Society of Surgical Oncology.)

Published
2024
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38. A Prospective Study Evaluating Health-Related Quality of Life Following a Multimodal Treatment for Colorectal Cancer.

Author

Perrone M, Garufi C, Cosimelli M, Graziano F, Falcicchio C, Bonucci A, Fotia L, Giannarelli D, Giacomelli L, Ciliberto G, and Pugliese P

Subjects
Humans, Female, Prospective Studies, Surveys and Questionnaires, Combined Modality Therapy, Quality of Life psychology, Colorectal Neoplasms therapy, Colorectal Neoplasms psychology
Abstract

Purpose: The major improvements in the diagnosis and treatment of colorectal cancer (CRC) over the past decades increased the patients' survival rates. Despite this, patients and clinicians still need to address the long-term physical and psychosocial effects over time. This paper aims to prospectively assess CRC patients' HR-QoL psychological distress and sexual functioning and identify clinical, demographic, and psychological predictors., Methods: In total, 55 patients were evaluated from diagnosis to 5-year follow-up with the following instruments: EORTC QLQ-C30 and QLQ-C38 for QoL and sexuality; HADS for psychological distress; and specific questions to detect psychological variables., Results: QoL worsened after diagnosis and returned to baseline values after 5 years. Sexual function significantly deteriorated over time (with no recovery, especially in women), while borderline/severe anxiety and depression decreased. A better HR-QoL at baseline was associated with better physical, social and sexual functioning, positive body image and sexual pleasure after 5 years., Conclusion: HR-QoL allows the early detection of patients at risk, favoring prompt patient-centered interventions., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2023
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41. Cancer Cure and Consequences on Survivorship Care: Position Paper from the Italian Alliance Against Cancer (ACC) Survivorship Care Working Group.

Author

Dal Maso L, Santoro A, Iannelli E, De Paoli P, Minoia C, Pinto M, Bertuzzi AF, Serraino D, De Angelis R, Trama A, Haupt R, Pravettoni G, Perrone M, De Lorenzo F, and Tralongo P

Abstract

A multidisciplinary panel of experts and cancer patients developed a position paper to highlight recent evidence on "cancer cure" (ie, the possibility of achieving the same life expectancy as the general population) and discuss the consequences of this concept on follow-up and rehabilitation strategies. The aim is to inform clinicians, patients, and health-care policy makers about strategies of survivorship care for cured cancer patients and consequences impacting patient lives, spurring public health authorities and research organizations to implement resources to the purpose. Two identifiable, measurable, and reproducible indicators of cancer cure are presented. Cure fraction (CF) is >60% for breast and prostate cancer patients, >50% for colorectal cancer patients, and >70% for patients with melanoma, Hodgkin lymphoma, and cancers of corpus uteri, testis (>90%), and thyroid. CF was >65% for patients diagnosed at ages 15-44 years and 30% for those aged 65-74 years. Time-to-cure was consistently <1 year for thyroid and testicular cancer patients and <10 years for patients with colorectal and cervical cancers, melanoma, and Hodgkin lymphoma. The working group agrees that the evidence allows risk stratification of cancer patients and implementation of personalized care models for timely diagnosis, as well as treatment of possible cancer relapses or related long-term complications, and preventive measures aimed at maintaining health status of cured patients. These aspects should be integrated to produce an appropriate follow-up program and survivorship care plan(s), avoiding stigma and supporting return to work, to a reproductive life, and full rehabilitation. The "right to be forgotten" law, adopted to date only in a few European countries, may contribute to these efforts for cured patients., Competing Interests: Prof. Armando Santoro’s Conflict of Interest Disclosure: Advisory Board: BMS (BRISTOL-MYERS-SQUIBB)/SERVIER/GILEAD/PFIZER/EISAI/BAYER/MSD (MERCK SHARP & DOHME). Consultancy: ARQULE/SANOFI/ INCYTE. Speaker’s Bureau: TAKEDA/BMS/ROCHE/ABB-VIE/AMGEN/CELGENE/SERVIER/GILEAD/ASTRAZENECA/PFIZER/ARQULE/LILLY/SANDOZ/EISAI/NOVARTIS/BAYER/MSD. Paolo Tralongo is the Coordinator of Survivorship Guidelines for AIOM (Italian Association of Medical Oncology). The other authors declare no competing interests in this work., (© 2022 Dal Maso et al.)

Published
2022
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42. Chronic Cancer Pain: Opioids within Tumor Microenvironment Affect Neuroinflammation, Tumor and Pain Evolution.

Author

Santoni A, Santoni M, and Arcuri E

Abstract

Pain can be a devastating experience for cancer patients, resulting in decreased quality of life. In the last two decades, immunological and pain research have demonstrated that pain persistence is primarily caused by neuroinflammation leading to central sensitization with brain neuroplastic alterations and changes in pain responsiveness (hyperalgesia, and pain behavior). Cancer pain is markedly affected by the tumor microenvironment (TME), a complex ecosystem consisting of different cell types (cancer cells, endothelial and stromal cells, leukocytes, fibroblasts and neurons) that release soluble mediators triggering neuroinflammation. The TME cellular components express opioid receptors (i.e., MOR) that upon engagement by endogenous or exogenous opioids such as morphine, initiate signaling events leading to neuroinflammation. MOR engagement does not only affect pain features and quality, but also influences directly and/or indirectly tumor growth and metastasis. The opioid effects on chronic cancer pain are also clinically characterized by altered opioid responsiveness (tolerance and hyperalgesia), a hallmark of the problematic long-term treatment of non-cancer pain. The significant progress made in understanding the immune-mediated development of chronic pain suggests its exploitation for novel alternative immunotherapeutic approaches.

Published
2022
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43. Replacement and Immunomodulatory Activities of 20% Subcutaneous Immunoglobulin Treatment: A Single-Center Retrospective Study in Autoimmune Myositis and CVID Patients.

Author

Danieli MG, Verga JU, Mezzanotte C, Terrenato I, Svegliati S, Bilo MB, and Moroncini G

Subjects
Adolescent, Adult, Aged, Autoimmune Diseases diagnosis, Biomarkers, Clinical Decision-Making, Disease Management, Disease Susceptibility, Female, Humans, Immunoglobulins, Intravenous, Infusions, Subcutaneous, Male, Middle Aged, Myositis diagnosis, Polymyositis diagnosis, Polymyositis etiology, Polymyositis therapy, Prognosis, Retrospective Studies, Severity of Illness Index, Symptom Assessment, Treatment Outcome, Young Adult, Autoimmune Diseases etiology, Autoimmune Diseases therapy, Immunization, Passive adverse effects, Immunization, Passive methods, Myositis etiology, Myositis therapy
Abstract

Background: Immunoglobulin (Ig) replacement therapy represents a life-saving treatment in primary antibody deficiencies. The introduction of subcutaneous Ig (SCIg) administration brings a major improvement in quality of life for patients, compared to the traditional intravenous administration. In recent years, an additional role has been proposed for Ig therapy for various inflammatory and immune-mediated diseases. Consequently, the use of SCIg has expanded from immunodeficiencies to immune-mediated diseases, such as polymyositis (PM) and dermatomyositis (DM). Given the rarity of these conditions, it is still difficult to evaluate the real impact of SCIg treatment on PM and DM, and additional data are constantly required on this topic, particularly for long-term treatments in real-life settings., Aim: This study aimed to increase the knowledge about the anti-inflammatory and immunomodulatory effects of SCIg treatment for myositis. To this aim, a long-term evaluation of the effectiveness of 20% human SCIg treatment (20% SCIg, Hizentra ® , CSL Behring) was carried out in patients with PM/DM in care at our Center. In addition, an evaluation of the 20% SCIg therapy in CVID patients was provided. This analysis, beside adding knowledge about the use of SCIg therapy in this real-life setting, was intended as a term of comparison, regarding the safety profile., Results: Results support the beneficial effect and tolerability of long-term 20% SCIg therapy in PM/DM patients, reporting a significant improvement in creatine kinase levels, muscle strength, skin conditions, dysphagia, disease activity (MITAX score) and disability (HAQ-DI score). None of the patients reported systemic reactions. The duration of the reported local reactions was a few hours in 80% of the patients, and all resolved spontaneously. CVID patients reported an improvement in all the considered effectiveness parameters at the end of 20% SCIg therapy. The frequency of the adverse events reported by PM/DM patients was not different from what reported in CVID patients, where the use of SCIg therapy is more consolidated., Conclusions: This study suggests that 20% SCIg treatment represents a viable and safe treatment for PM/DM patients and a valid therapeutic alternative to IVIg, with important advantages for patients' quality of life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Danieli, Verga, Mezzanotte, Terrenato, Svegliati, Bilo and Moroncini.)

Published
2022
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44. How direct measurements of worker eyes with a Scheimpflug camera can affect lensdose coefficients in interventional radiology.

Author

Iori M, Isolan L, Piergallini L, Chendi A, Lasagni L, Cucchi G, Bertolini M, Fioroni F, Piccagli V, Moramarco A, Romano MG, Fontana L, Strigari L, D'Alessio D, Bruzzaniti V, Sgura A, Udroiu I, Rosi A, Grande S, Palma A, Giliberti C, and Sumini M

Subjects
Humans, Monte Carlo Method, Radiation Dosage, Radiation Dosimeters, Radiology, Interventional, Lens, Crystalline, Occupational Exposure analysis
Abstract

The 2013/59/Euratom Directive reduced the occupational exposure limits for the lens. Since it has become crucial to estimate the dose absorbed by the lens, we have studied the individual variability of exposed workers' ocular conformations with respect to the data estimated from their personal dosimetry. The anterior eye conformations of 45 exposed workers were acquired using Scheimpflug imaging and classified according to their sight conditions (emmetropia, myopia or hypermetropia). Three eye models were computed, with two lens reconstructions, and implemented in an interventional radiology scenario using Monte Carlo code. The models were dosimetrically analysed by simulating setup A, a theoretical monoenergetic and isotropic photon source (10-150 keV) and setup B, a more realistic interventional setting with an angiographic x-ray unit (50, 75, 100 kV peak). Scheimpflug imaging provided an average anterior chamber depth of (6.4 ± 0.5) mm and a lens depth of (3.9 ± 0.3) mm, together with a reconstructed equatorial lens length of (7.1-10.1) mm. Using these data for model reconstruction, dose coefficients (DCs) were simulated for all ocular structures. Regardless of the eye model used, the DCs showed a similar trend with radiation energy, which highlighted that for the same energy and setup, no significant dependence on ocular morphology and workers' visual conditions was observed. The maximum difference obtained did not exceed 1% for all eye models or structures analysed. Therefore, the individual variabilities of worker ocular anatomy do not require any additional correction, compared to the personal dosimetry data measured with a dedicated lens dosimeter. To estimate the dose absorbed by the other eye structures, it is, instead, essential to know the spectrum of the source that has generated the irradiation, since there are differences between monoenergetic sources and more realistic angiographic units., (© 2021 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights reserved.)

Published
2021
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45. Coping Style in Glioma Patients and Their Caregiver: Evaluation During Disease Trajectory.

Author

Guariglia L, Ieraci S, Villani V, Tanzilli A, Benincasa D, Sperati F, Terrenato I, and Pace A

Abstract

Background: Patients with glioma have a poor prognosis and, in a short period of time, have to deal with severe forms of disability, which compromise their psychological distress and quality of life. The caregivers of these patients consequently carry a heavy burden in terms of emotional and patient care. The study aims to evaluate the coping strategies of patients and their caregivers during the course of the disease in order to frame the adaptation process in a rapidly progressing pathology. Methods: A prospective study on 24 dyads of patients affected by malignant glioma and their caregivers was conducted between May 2016 and July 2018. Questionnaires designed to identify the coping style (MINI-MaC Scale) and psychological distress (HADS scores) and assess QOL (EQ-5D) were administered at two time points: at first lines of treatment and at disease recurrence. Results: Patients and their caregiver structure adaptive coping strategies during the disease: a coping style oriented toward a fighting spirit prevails at baseline (Mini-Mac Mean 3.23); fatalism prevails at recurrence (Mini-Mac Mean 3.03). Psychological distress affects the coping style expressed: high levels of anxiety symptoms were found to be significantly associated with a coping style oriented toward anxious preoccupation, helpless-hopeless, and fatalism; low depressive symptoms were inversely correlated with fighting spirit coping style. Patients' and caregivers' perceptions of quality of life were correlated between them and with performance status assessed by clinicians. In a dyadic perspective, the adaptation of a member of the couple varies as a function of the other partner's coping style. Conclusions: Our data are in line with previous literature on cancer patients, demonstrating that coping style is not a persistent dimension of personality, but can change depending on the situation. Despite the disease rapid course, patients and their caregivers can structure adaptive and functional defenses to manage the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Guariglia, Ieraci, Villani, Tanzilli, Benincasa, Sperati, Terrenato and Pace.)

Published
2021
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46. Patient-reported outcomes in a phase II randomised study of regorafenib compared with lomustine in patients with relapsed glioblastoma (the REGOMA trial).

Author

Lombardi G, Del Bianco P, Brandes AA, Eoli M, Rudà R, Ibrahim T, Lolli I, Rizzato S, Daniele B, Pace A, Pasqualetti F, Caccesse M, Bergo E, Magni G, De Salvo GL, and Zagonel V

Subjects
Aged, Female, Glioblastoma pathology, Humans, Lomustine pharmacology, Male, Middle Aged, Patient Reported Outcome Measures, Phenylurea Compounds pharmacology, Prospective Studies, Pyridines pharmacology, Recurrence, Surveys and Questionnaires, Glioblastoma drug therapy, Lomustine therapeutic use, Phenylurea Compounds therapeutic use, Pyridines therapeutic use
Abstract

Background: The REGOMA trial showed that regorafenib significantly improved overall survival in patients with recurrent glioblastoma compared with lomustine. Patients treated with regorafenib experienced a higher occurrence of grade 3-4 drug-related adverse events than those receiving the standard treatment. Because this safety profile was expected, it was considered of great importance to assess the patient point of view regarding the disease and treatment impact on different aspects of life and patient well-being. We here report the final results of the health-related quality of life (HRQoL) assessment, a secondary end-point of the study. This trial is registered with ClinicalTrials.gov, NCT02926222., Methods: Patient-reported outcomes were assessed, within a prospective, randomised, multicentre, open-label phase II trial, by the European Organisation for Research and Treatment of Cancer core questionnaire and brain module at baseline and every 8-weekly neuroradiological assessment till disease progression. Mixed-effect linear models were fitted for each of the HRQoL domain to examine the change over progression-free time within and between arms. Furthermore, differences were also classified as clinically meaningful changes. To correct for multiple comparisons and avoid type I errors, the level of significance was set at P = 0.01 (2-sided)., Results: Of 119 enrolled patients, 56/59 (95%) patients and 58/60 (97%) patients treated with regorafenib and lomustime completed questionnaires at baseline, respectively. No significant differences were observed in any generic or cancer-specific domain during treatment in both arms, or between the two arms, except for the appetite loss and diarrhoea scales which were significantly worse in patients treated with regorafenib. The rate of patients with a clinically meaningful worsening for appetite loss, diarrhoea and for any other domain was not statistically different between the two arms., Conclusions: Regorafenib did not negatively affect HRQoL in patients with recurrent glioblastoma. These data combined with the survival benefit shown in the REGOMA trial support the use of regorafenib as a treatment option for these patients., Competing Interests: Conflict of interest statement GL has declared a consulting or advisory role for funding from Bayer, AbbVie, Orbus Therapeutics and BrainFarm; travel funding from Roche and Bayer; RR has declared research funding from Mundipharma, Novocure, UCB; BD has declared personal fees from EISAI, ELI LILLY, ASTRA ZENECA, MSD, ROCHE, AMGEN, personal grants and non-financial support from IPSEN, SANOFI and BAYER; VZ has declared consulting or advisory role funding from Bristol-Myers Squibb and Merck, Speakers Bureau funding from Bayer, Roche, Bristol-Myers Squibb, Astellas Pharma, Servier, AstraZeneca and Lilly, travel and accommodation funding from Bayer, Roche and Servier. All remaining authors have declared no conflict of interest to declare., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Published
2021
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47. Peptide Platform as a Powerful Tool in the Fight against COVID-19.

Author

Murdocca M, Citro G, Romeo I, Lupia A, Miersch S, Amadio B, Bonomo A, Rossi A, Sidhu SS, Pandolfi PP, Alcaro S, Sangiuolo FC, and Novelli G

Subjects
Angiotensin-Converting Enzyme 2 chemistry, Angiotensin-Converting Enzyme 2 metabolism, Animals, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Broadly Neutralizing Antibodies immunology, COVID-19 prevention & control, COVID-19 Vaccines immunology, Chlorocebus aethiops, Dipeptidyl Peptidase 4 metabolism, Epitopes, T-Lymphocyte immunology, Humans, Mice, Mice, Inbred BALB C, Models, Molecular, Molecular Docking Simulation, Molecular Dynamics Simulation, Peptide Fragments chemistry, Peptide Fragments metabolism, Protein Binding, Protein Domains, Receptors, Coronavirus chemistry, Receptors, Coronavirus metabolism, SARS-CoV-2 chemistry, SARS-CoV-2 physiology, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus metabolism, Vero Cells, Virus Internalization, COVID-19 Drug Treatment, Dipeptidyl Peptidase 4 chemistry, Peptide Fragments immunology, Peptide Fragments pharmacology, SARS-CoV-2 drug effects, SARS-CoV-2 immunology, Spike Glycoprotein, Coronavirus immunology
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a global pandemic causing over 195 million infections and more than 4 million fatalities as of July 2021.To date, it has been demonstrated that a number of mutations in the spike glycoprotein (S protein) of SARS-CoV-2 variants of concern abrogate or reduce the neutralization potency of several therapeutic antibodies and vaccine-elicited antibodies. Therefore, the development of additional vaccine platforms with improved supply and logistic profile remains a pressing need. In this work, we have validated the applicability of a peptide-based strategy focused on a preventive as well as a therapeutic purpose. On the basis of the involvement of the dipeptidyl peptidase 4 (DPP4), in addition to the angiotensin converting enzyme 2 (ACE2) receptor in the mechanism of virus entry, we analyzed peptides bearing DPP4 sequences by protein-protein docking and assessed their ability to block pseudovirus infection in vitro. In parallel, we have selected and synthetized peptide sequences located within the highly conserved receptor-binding domain (RBD) of the S protein, and we found that RBD-based vaccines could better promote elicitation of high titers of neutralizing antibodies specific against the regions of interest, as confirmed by immunoinformatic methodologies and in vivo studies. These findings unveil a key antigenic site targeted by broadly neutralizing antibodies and pave the way to the design of pan-coronavirus vaccines.

Published
2021
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48. Prospective Evaluation of Health Care Provider and Patient Assessments in Chemotherapy-Induced Peripheral Neurotoxicity.

Author

Alberti P, Bernasconi DP, Cornblath DR, Merkies ISJ, Park SB, Velasco R, Bruna J, Psimaras D, Koeppen S, Pace A, Dorsey SG, Argyriou AA, Kalofonos HP, Briani C, Schenone A, Faber CG, Mazzeo A, Grisold W, Valsecchi M, and Cavaletti G

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Humans, Middle Aged, Neurotoxicity Syndromes etiology, Nurses, Patients, Peripheral Nervous System Diseases chemically induced, Physicians, Prospective Studies, Psychometrics instrumentation, Young Adult, Antineoplastic Agents toxicity, Diagnostic Techniques, Neurological standards, Neoplasms drug therapy, Neurotoxicity Syndromes diagnosis, Peripheral Nervous System Diseases diagnosis, Psychometrics standards, Severity of Illness Index
Abstract

Background and Objective: There is no agreement on the gold standard for detection and grading of chemotherapy-induced peripheral neurotoxicity (CIPN) in clinical trials. The objective is to perform an observational prospective study to assess and compare patient-based and physician-based methods for detection and grading of CIPN., Methods: Consecutive patients, aged 18 years or older, candidates for neurotoxic chemotherapy, were enrolled in the United States, European Union, or Australia. A trained investigator performed physician-based scales (Total Neuropathy Score-clinical [TNSc], used to calculate Total Neuropathy Score-nurse [TNSn]) and supervised the patient-completed questionnaire (Functional Assessment of Cancer Treatment/Gynecologic Oncology Group-Neurotoxicity [FACT/GOG-NTX]). Evaluations were performed before and at the end of chemotherapy. On participants without neuropathy at baseline, we assessed the association between TNSc, TNSn, and FACT/GOG-NTX. Considering a previously established minimal clinically important difference (MCID) for FACT/GOG-NTX, we identified participants with and without a clinically important deterioration according to this scale. Then, we calculated the MCID for TNSc and TNSn as the difference in the mean change score of these scales between the 2 groups., Results: Data from 254 participants were available: 180 (71%) had normal neurologic status at baseline. At the end of the study, 88% of participants developed any grade of neuropathy. TNSc, TNSn, and FACT/GOG-NTX showed good responsiveness (standardized mean change from baseline to end of chemotherapy >1 for all scales). On the 153 participants without neuropathy at baseline and treated with a known neurotoxic chemotherapy regimen, we verified a moderate correlation in both TNSc and TNSn scores with FACT/GOG-NTX (Spearman correlation index r = 0.6). On the same sample, considering as clinically important a change in the FACT/GOG-NTX score of at least 3.3 points, the MCID was 3.7 for TNSc and 2.8 for the TNSn., Conclusions: MCID for TNSc and TNSn were calculated and the TNSn can be considered a reliable alternative objective clinical assessment if a more extended neurologic examination is not possible. The FACT/GOG-NTX score can be reduced to 7 items and these items correlate well with the TNSc and TNSn., Classification of Evidence: This study provides Class III evidence that a patient-completed questionnaire and nurse-assessed scale correlate with a physician-assessed scale., (© 2021 American Academy of Neurology.)

Published
2021
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50. Results of Adrenalectomy for Isolated, Metachronous Metastasis of Breast Cancer: A Retrospective Cohort Study.

Author

Illuminati G, Pasqua R, D'Ermo G, Girolami M, Cerbelli B, D'Amati G, Carboni F, and Fiori E

Abstract

Background and Aim: Metachronous, isolated adrenal metastases from breast cancer are extremely rare. The aim of this study was to evaluate the results of adrenalectomy as a treatment of this uncommon condition. Methods: Twelve female patients (median age: 68 years) underwent 13 adrenalectomies for isolated, metachronous metastases of breast cancer. Ten resections were performed thorugh open surgery and two were preformed through a laparoscopic approach. As main study endpoints, postoperative mortality, postoperative morbidity and disease-free survival were considered. Median length of follow-up was 40 months. Results: Postoperative mortality was absent. Postoperative morbidity was 17%: one patient presented a postoperative pneumothorax requiring drainage and one patient required re-hospitalization 8 days after contralateral adrenalectomy for electrolyte imbalance. Two patients died of recurrent metastatic disease, 28 and 33 months respectively after adrenalectomy. One patient remained alive with hepatic metastases at 32 months from resection of adrenal recurrence. All in all, disease-free survival at 48 months was 75%. Conclusions: Adrenalectomy for metachronous, isolated metastases of breast cancer can be performed with no postoperative mortality and minimal postoperative morbidity, enabling good long-term disease-free survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Illuminati, Pasqua, D'Ermo, Girolami, Cerbelli, D'Amati, Carboni and Fiori.)

Published
2021
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