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1. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Author: [ 1 ] Harvard TH Chan Sch Publ Hlth, Boston, MA USA Show more [ 2 ] Chaim Sheba Med Ctr, Inst Human Genet, Susanne Levy Gertner Oncogenet Unit, IL-52621 Ramat Gan, Israel Show more [ 3 ] Tel Aviv Univ, Sackler Sch Med, Tel Aviv, Israel Show more [ 4 ] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany Show more [ 5 ] Univ Chicago, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 6 ] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China Show more [ 7 ] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary Show more [ 8 ] Univ Buenos Aires, CONICET, Fac Med, INBIOMED, Buenos Aires, DF, Argentina Show more [ 9 ] CEMIC, Dept Clin Chem, Med Direct, Buenos Aires, DF, Argentina [ 10 ] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Malaysia Show more [ 11 ] Odense Univ Hosp, Dept Clin Genet, Odense, Denmark Show more [ 12 ] City Hope Canc Ctr, Div Clin Canc Genom, Duarte, CA USA [ 13 ] Hong Kong Sanat & Hosp, Dept Pathol, Div Mol Pathol, Happy Valley, Hong Kong, Peoples R China [ 14 ] Dept Lab Med & Pathol, Rochester, MN USA Show more [ 15 ] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT USA Show more [ 16 ] Barretos Canc Hosp, Mol Oncol Res Ctr, Sao Paulo, Brazil Show more [ 17 ] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea Show more [ 18 ] Seoul Natl Univ, Grad Sch, Dept Biomed Sci, Seoul, South Korea Show more [ 19 ] Seoul Natl Univ, Canc Res Ctr, Seoul, South Korea Show more [ 20 ] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia Show more [ 21 ] Univ Pretoria, Dept Genet, Canc Genet Lab, Pretoria, South Africa Show more [ 22 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England Show more [ 23 ] QIMR Berghofer Med Res Inst, Genet & Computat Biol Dept, Brisbane, Qld, Australia [ 24 ] Acad Med Ctr, Dept Clin Genet, Amsterdam, Netherlands [ 25 ] City Hope Clin Canc Genom Community Res Network, D, Harvard TH Chan School of Public Health and Dana Farber Cancer Institute; Boston USA, The Susanne Levy Gertner Oncogenetics Unit; Institute of Human Genetics; Chaim Sheba Medical Center, Ramat Gan 52621, and the Sackler School of Medicine; Tel-Aviv University; Tel-Aviv Israel, Molecular Genetics of Breast Cancer; German Cancer Research Center (DKFZ); Heidelberg Germany, Center for Clinical Cancer Genetics and Global Health; University of Chicago; Chicago USA, The Hong Kong Hereditary Breast Cancer Family Registry; Cancer Genetics Center; Hong Kong Sanatorium and Hospital; Hong Kong China, Department of Molecular Genetics; National Institute of Oncology; Budapest Hungary, INBIOMED; Faculty of Medicine, University of Buenos Aires/CONICET and CEMIC, Department of Clinical Chemistry; Medical Direction; Buenos Aires Argentina, Cancer Research Initiatives Foundation; Sime Darby Medical Centre; Subang Jaya Malaysia, Department of Clinical Genetics; Odense University Hospital; Odense Denmark, Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty; University Hospital Cologne; Cologne Germany, Clinical Genetics Services; Dept. of Medicine; Memorial Sloan-Kettering Cancer Center; New York USA, Division of Gynecologic Oncology; North Shore University Health System; University of Chicago; Evanston USA, All Wales Medical Genetics Services; University Hospital of Wales; Cardiff UK, Department of Gynecology; Vilnius University Hospital Santariskiu Clinics; Centre of Woman's Health and pathology; Vilnius Lithuania, Center for Genomic Medicine; Rigshospitalet; University of Copenhagen; Copenhagen Denmark, Clinical Cancer Genetics Program; Division of Human Genetics; Department of Internal Medicine; The Comprehensive Cancer Center; The Ohio State University; Columbus USA, Cancer Genetics Laboratory, Department of Genetics; University of Pretoria; South Africa, Department of Genetics and Pathology; Pomeranian Medical University; Szczecin Poland, Department of Medicine, Abramson Cancer Center; Perelman School of Medicine at the University of Pennsylvania; Philadelphia USA, Department of Internal Medicine; Division of Oncology; University of Kansas Medical Center; Westwood USA, North East Thames Regional Genetics Service; Great Ormond Street Hospital for Children NHS Trust; London UK, Genomics Center; Centre Hospitalier Universitaire de Québec Research Center and Laval University; Quebec City Canada, Dept of OB/GYN and Comprehensive Cancer Center; Medical University of Vienna; Vienna Austria, Department of Clinical Genetics; Aarhus University Hospital; Aarhus N Denmark, Division of Clinical Cancer Genomics; City of Hope Cancer Center; California USA, Medical Genetics Unit; University of London; St George's UK, Département Oncologie Génétique; Prévention et Dépistage; Institut Paoli-Calmettes; Marseille Medical School-AM University; Marseille France, Department of Breast Medical Oncology and Clinical Cancer Genetics Program; University Of Texas MD Anderson Cancer Center; Houston USA, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care; University of Cambridge; Cambridge UK, Department of Population Sciences; Beckman Research Institute of City of Hope; Duarte USA, Institute of Cell and Molecular Pathology; Hannover Medical School; Hannover Germany, Institute of Human Genetics; University Hospital Heidelberg; Heidelberg Germany, National Human Genome Research Institute; National Institutes of Health; Bethesda USA, Dept of OB/GYN, Comprehensive Cancer Center; Medical University of Vienna; Vienna Austria, Department of Genetics; Portuguese Oncology Institute of Porto (IPO Porto); Porto Portugal, Department of Epidemiology; Columbia University; New York USA, Genetic Counseling Unit; Hereditary Cancer Program; IDIBELL (Bellvitge Biomedical Research Institute); Catalan Institute of Oncology, CIBERONC; Gran Via de l'Hospitalet; Barcelona Spain, Department of Health Sciences Research; Mayo Clinic; Rochester USA, Genetics and Computational Biology Department; QIMR Berghofer Medical Research Institute; Brisbane Australia, Department of Medicine; Magee-Womens Hospital; University of Pittsburgh School of Medicine; Pittsburgh USA, Program in Cancer Genetics; Departments of Human Genetics and Oncology; McGill University; Montreal Canada, Immunology and Molecular Oncology Unit; Veneto Institute of Oncology IOV - IRCCS; Padua Italy, Division of Human Genetics; Departments of Internal Medicine and Cancer Biology and Genetics; Comprehensive Cancer Center; The Ohio State University; Columbus USA, Clinical Genetics Research Laboratory, Dept. of Medicine; Memorial Sloan-Kettering Cancer Center; New York USA, Parkville Familial Cancer Centre; Royal Melbourne Hospital; Melbourne Australia, Department of Medical Oncology; Beth Israel Deaconess Medical Center; Massachusetts USA, Department of Clinical Genetics; Leiden University Medical Center; Leiden The Netherlands, Department of Genetics; University Medical Center; Groningen University; Groningen The Netherlands, Family Cancer Clinic; Netherlands Cancer Institute; Amsterdam The Netherlands, Department of Medical Genetics; University Medical Center; Utrecht The Netherlands, Center for Medical Genetics; Ghent University; Gent Belgium, Unit of Hereditary Cancer; Department of Epidemiology, Prevention and Special Functions; IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro; Genoa Italy, Institute of Human Genetics; Campus Virchov Klinikum; Berlin Germany, Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela; Spain, Departamento de Investigacion y de Tumores Mamarios del; Instituto Nacional de Cancerologia; Mexico City Mexico, Department of Oncology; Karolinska University Hospital; Stockholm Sweden, Institute of Genetic Medicine; Centre for Life; Newcastle Upon Tyne Hospitals NHS Trust; Newcastle upon Tyne UK, Oxford Regional Genetics Service; Churchill Hospital; Oxford UK, Department of Gynaecology and Obstetrics; University Hospital; Ulm Germany, Department of Clinical Genetics; Academic Medical Center; Amsterdam The Netherlands, Institute of Human Genetics; Regensburg University; Regensburg Germany, Molecular Diagnostics Laboratory, INRASTES (Institute of Nuclear and Radiological Sciences and Technology); National Centre for Scientific Research “Demokritos”; Athens Greece, Unit of Medical Genetics, Department of Medical Oncology and Hematology; Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Instituto Nazionale Tumori (INT); Milan Italy, Institute of Oncology; Rivka Ziv Medical Center; Zefat Israel, Magee-Womens Hospital; University of Pittsburgh School of Medicine; Pittsburgh USA, Institute of Human Genetics; University Leipzig; Leipzig Germany, Center for Medical Genetics; North Shore University Health System; Evanston USA, Medical Director, Center for Medical Genetics, NorthShore University HealthSystem, Clinical Assistant Professor of Medicine; University of Chicago Pritzker School of Medicine; Evanston USA, City of Hope Clinical Cancer Genomics Community Research Network; Duarte USA, Yorkshire Regional Genetics Service; Chapel Allerton Hospital; Leeds UK, Department of Clinical Genetics; Helsinki University Hospital; Helsinki Finland, Hereditary Cancer Clinic; Prince of Wales Hospital; Randwick Australia, Lunenfeld-Tanenbaum Research Institute; Toronto Canada, Laboratory of Cell Biology, Department of Pathology, hus 9, Landspitali-LSH v/Hringbraut, 101 Reykjavik, Iceland and BMC (Biomedical Centre), Faculty of Medicine; University of Iceland; Reykjavik Iceland, Department of Gynaecology & Oncology; Medical University of Vienna; Austria, Department of Medical Oncology; Vall d'Hebron University Hospital; Barcelona Spain, Division of Cancer Prevention and Genetics; Istituto Europeo di Oncologia (IEO); Milan Italy, Department of Gynaecology and Obstetrics; University Hospital Düsseldorf, Heinrich-Heine University; Düsseldorf Germany, Human Genetics Group and Genotyping Unit (CEGEN), Human Cancer Genetics Programme; Spanish National Cancer Research Centre (CNIO); Madrid Spain, The Institute of Oncology; Chaim Sheba Medical Center; Ramat Gan Israel, UCSF Cancer Genetics and Prevention Program; San Francisco USA, Department of Clinical Genetics; Maastricht University Medical Center; Maastricht The Netherlands, Unité de Prévention et d'Epidémiologie Génétique; Centre Léon Bérard, 28 rue Laënnec; Lyon France, N.N. Petrov Institute of Oncology; St. Petersburg Russia, Department of Clinical Genetics; Royal Devon & Exeter Hospital; Exeter UK, Service de Génétique; Institut Curie, 26 rue d'Ulm; Paris France, Department of Medicine; Huntsman Cancer Institute; Salt Lake City USA, Molecular Oncology Laboratory; Hospital Clinico San Carlos; Instituto de Investigación Sanitaria San Carlos (IdISSC); Centro Investigación Biomédica en Red de Cáncer (CIBERONC); Madrid Spain, Institute of Human Genetics; University Hospital of Schleswig-Holstein; Kiel Germany, Section of Molecular Genetics, Dept. of Laboratory Medicine; University Hospital of Pisa; Pisa Italy, Research Division; Peter MacCallum Cancer Centre; Melbourne Australia, CRCHU de Quebec-oncologie, Centre des maladies du sein Deschênes-Fabia; Hôpital du Saint-Sacrement; Sainte-Foy Canada, Lombardi Comprehensive Cancer Center; Georgetown University; Washington USA, Departments of Pediatrics and Medicine; Columbia University; New York USA, Department of Clinical Genetics, Family Cancer Clinic; Erasmus University Medical Center; Rotterdam The Netherlands, Sheffield Clinical Genetics Service; Sheffield Children's Hospital; Sheffield UK, Department of Clinical Genetics; South Glasgow University Hospitals; Glasgow UK, Unité d'oncogénétique; ICO-Centre René Gauducheau; Saint Herblain France, Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Clinical and Molecular Genetics Area; Vall d'Hebron University Hospital; Barcelona Spain, Department of Gynaecology and Obstetrics; Ludwig-Maximilian University; Munich Germany, Cáncer Hereditario, Instituto de Biología y Genética Molecular, IBGM; Universidad de Valladolid; Valladolid Spain, Institute of Human Genetics; University of Münster; Münster Germany, Nottingham Clinical Genetics Service; Nottingham University Hospitals NHS Trust; Nottingham UK, Oncogenetics Team; The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; London UK, Department of Clinical Genetics; Lund University Hospital; Lund Sweden, Clinical Genetics; Guy's and St. Thomas’ NHS Foundation Trust; London UK, Department of Oncology, Rigshospitalet; Copenhagen University Hospital; Copenhagen Denmark, Institute for Medical Informatics, Statistics and Epidemiology; University of Leipzig; Leipzig Germany, Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar; Technical University; Munich Germany, Genomic Medicine, Manchester Academic Health Sciences Centre, Division of Evolution and Genomic Sciences; University of Manchester, Central Manchester University Hospitals NHS Foundation Trust; Manchester UK, Centre de Lutte Contre le Cancer Georges François Leclerc, France and Genomic and Immunotherapy Medical Institute; Dijon University Hospital; Dijon France, Molecular Diagnostic Unit, Hereditary Cancer Program, ICO-IDIBELL (Catalan Institute of Oncology-Bellvitge Biomedical Research Institute); Barcelona Spain, Laboratoire de Génétique Chromosomique; Hôtel Dieu Centre Hospitalier; Chambéry France, Department of Cancer Epidemiology and Genetics; Masaryk Memorial Cancer Institute; Brno Czech Republic, Columbus Cancer Council, Ohio State University; Columbus USA, Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona); Catalan Institute of Oncology; Girona Spain, Oncogenetics Department; Barretos Cancer Hospital; Barretos Brazil, UCLA Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research; Jonsson Comprehensive Cancer Center; Los Angeles USA, Cancer Risk and Prevention Clinic; Dana-Farber Cancer Institute; Boston USA, Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics; University of Würzburg, Germany; Würzburg, Department of Clinical Genetics; Copenhagen Denmark, Service Régional Oncogénétique Poitou-Charentes; Centre Hospitalier; Niort France, Department of Molecular Medicine; University La Sapienza, and Istituto Pasteur - Fondazione Cenci-Bolognetti; Rome Italy, Bâtiment Cheney D; Centre Léon Bérard; Lyon France, Ontario Cancer Genetics Network: Lunenfeld-Tanenbaum Research Institute; Mount Sinai Hospital; Toronto Canada, Department of Pathology and Laboratory Medicine; University of Kansas Medical Center; Kansas City USA, Clinical Genetics Branch, DCEG, NCI; NIH; Bethesda USA, Parkville Familial Cancer Centre; Peter MacCallum Cancer Centre; Melbourne Australia, Hematology, oncology and transfusion medicine center, Dept. of Molecular and Regenerative Medicine; Vilnius University Hospital Santariskiu Clinics; Vilnius Lithuania, Department of Epidemiology, Cancer Prevention Institute of California; Fremont USA, Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute; Cedars-Sinai Medical Center; Los Angeles USA, Division of Molecular Pathology; Department of Pathology; Hong Kong Sanatorium & Hospital; Happy Valley Hong Kong, Department of Gynecology and Obstetrics; Medical Faculty and University Hospital Carl Gustav Carus; Dresden Germany, Research Department, Peter MacCallum Cancer Centre, Melbourne, Victoria; Australia and The Sir Peter MacCallum Department of Oncology University of Melbourne; Parkville Australia, Department of Surgery; Daerim St. Mary's Hospital; Seoul Korea, The Gyneco-Oncology Department; Chaim Sheba Medical Center; Ramat Gan Israel, Servicio de Genética-CIBERER U705; Hospital de la Santa Creu i Sant Pau; Barcelona Spain, The Feinstein Institute for Medical Research; Manhasset USA, Department of Laboratory Medicine and Pathology; and Health Sciences Research; Rochester USA, Department of Surgery; Soonchunhyang University and Seoul Hospital; Seoul Korea, Inserm U900, Institut Curie; PSL Research University; Paris France, Department of Oncology Radiumhemmet and Institution of Oncology and Patology; Karolinska University Hospital and Karolinska Institutet; Solna Sweden, Department of Health Sciences Research; Mayo Clinic; Scottsdale USA, Oncogénétique; Institut Bergonié; Bordeaux France, Clinical Genetics Branch, DCEG, NCI, NIH; Bethesda USA, Department of Gynecological Oncology and Clinical Cancer Genetics Program; University Of Texas MD Anderson Cancer Center; Houston USA, Department of Dermatology; University of Utah School of Medicine; Salt Lake City USA, Centre Antoine Lacassagne; Nice France, Laboratorio de Genética Molecular, Servicio de Genética; Hospital Universitario Cruces, BioCruces Health Research Institute; Barakaldo Spain, Department of Surgery; National Institute of Oncology; Budapest Hungary, Department of Clinical Genetics; VU University Medical Center; Amsterdam The Netherlands, Department of Human Genetics; Radboud University Medical Center; Nijmegen The Netherlands, Vilnius university Santariskiu hospital; National Center of Pathology; Vilnius Lithuania, NRG Oncology; Statistics and Data Management Center; Roswell Park Cancer Institute; Buffalo USA, Department of Cancer Prevention and Control; Roswell Park Cancer Institute; Buffalo USA, Department of Laboratory Medicine and Pathobiology; University of Toronto; Toronto Canada, Department of Obstetrics and Gynecology; University of Helsinki and Helsinki University Hospital; HUS Finland, Cancer Genetics Service; Division of Medical Oncology; National Cancer Centre Singapore; Bukit Merah Singapore, Institute of Medical Genetics and Applied Genomics; University of Tuebingen; Tuebingen Germany, Molecular Oncology Research Center; Barretos Cancer Hospital; São Paulo Brazil, Cancer Genetics and Prevention Program; University of California San Francisco; San Francisco USA, Clinical Genetics Research Laboratory; Dept. of Medicine; Cancer Biology and Genetics; Memorial Sloan-Kettering Cancer Center; New York USA, Department of Clinical Genetics; Sahlgrenska University Hospital; Gothenburg Sweden, West Midlands Regional Genetics Service; Birmingham Women's Hospital Healthcare NHS Trust; Edgbaston UK, Human Genetics Group; Human Cancer Genetics Programme; Spanish National Cancer Research Centre (CNIO); Biomedical Network on Rare Diseases (CIBERER); Madrid Spain, Unit of Medical Genetics; Department of Biomedical; Experimental and Clinical Sciences; University of Florence; Florence Italy, Department of Medical Sciences; University of Turin; Turin Italy, Section of Molecular Diagnostics; Department of Biochemistry; Aalborg University Hospital; Aalborg Denmark, Department of Preventive Medicine; Seoul National University College of Medicine; Seoul Korea, IFOM; The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology; Milan Italy, Service de Génétique Clinique Chromosomique et Moléculaire; Hôpital Nord; St Etienne France, Unité d'Oncogénétique; CHU Arnaud de Villeneuve; Montpellier France, Unit of Molecular Bases of Genetic Risk and Genetic Testing; Department of Research; Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico), Istituto Nazionale Tumori (INT); Milan Italy, School of Women's and Children's Health; UNSW; Sydney Australia, Department of Clinical Genetics; Karolinska University Hospital; Stockholm Sweden, Rebbeck, Timothy R., Friebel, Tara M., Friedman, Eitan, Hamann, Ute, Huo, Dezheng, Kwong, Ava, Olah, Edith, Olopade, Olufunmilayo I., Solano, Angela R., Teo, Soo-Hwang, Thomassen, Mads, Rashid, Muhammad Usman, Rhiem, Kerstin, Robson, Mark, Rodriguez, Gustavo C., Rogers, Mark T., Rudaitis, Vilius, Schmidt, Ane Y., Schmutzler, Rita Katharina, Senter, Leigha, van Rensburg, Elizabeth J., Gronwald, Jacek, Shah, Payal D., Sharma, Priyanka, Side, Lucy E., Simard, Jacques, Singer, Christian F., Skytte, Anne-Bine, Slavin, Thomas P., Snape, Katie, Sobol, Hagay, Southey, Melissa, Gutierrez-Barrera, Angelica, McGuffog, Lesley, Steele, Linda, Steinemann, Doris, Sukiennicki, Grzegorz, Sutter, Christian, Szabo, Csilla I., Tan, Yen Y., Teixeira, Manuel R., Terry, Mary Beth, Teulé, Alex, Hahnen, Eric, Thomas, Abigail, Parsons, Michael T., Thull, Darcy L., Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda Ewart, Topka, Sabine, Trainer, Alison H, Tung, Nadine, van Asperen, Christi J., Hauke, Jan, van der Hout, Annemieke H., van der Kolk, Lizet E., Leslie, Goska, van der Luijt, Rob B., Van Heetvelde, Mattias, Varesco, Liliana, Varon-Mateeva, Raymonda, Vega, Ana, Villarreal-Garza, Cynthia, von Wachenfeldt, Anna, Henderson, Alex, Walker, Lisa, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Aalfs, Cora M., Weber, Bernhard H. F., Yannoukakos, Drakoulis, Yoon, Sook-Yee, Zanzottera, Cristina, Zidan, Jamal, Zorn, Kristin K., Hentschel, Julia, Hutten Selkirk, Christina G., Hulick, Peter J., Chenevix-Trench, Georgia, Spurdle, Amanda B., Abugattas, Julio, Antoniou, Antonis C., Nathanson, Katherine L., Adlard, Julian, Agata, Simona, Aittomäki, Kristiina, Hogervorst, Frans B.L., Andrews, Lesley, Andrulis, Irene L., Arason, Adalgeir, Arnold, Norbert, Arun, Banu K., Asseryanis, Ella, Auerbach, Leo, Azzollini, Jacopo, Balmaña, Judith, Barile, Monica, Honisch, Ellen, Barkardottir, Rosa B., Barrowdale, Daniel, Benitez, Javier, Berger, Andreas, Berger, Raanan, Blanco, Amie M., Blazer, Kathleen R., Blok, Marinus J., Bonadona, Valérie, Bonanni, Bernardo, Imyanitov, Evgeny N., Bradbury, Angela R., Brewer, Carole, Buecher, Bruno, Buys, Saundra S., Caldes, Trinidad, Caliebe, Almuth, Caligo, Maria A., Campbell, Ian, Caputo, Sandrine M., Chiquette, Jocelyne, Isaacs, Claudine, Chung, Wendy K., Claes, Kathleen B.M., Collée, J. Margriet, Cook, Jackie, Davidson, Rosemarie, de la Hoya, Miguel, De Leeneer, Kim, de Pauw, Antoine, Delnatte, Capucine, Diez, Orland, Weitzel, Jeffrey N., Ding, Yuan Chun, Ditsch, Nina, Domchek, Susan M., Dorfling, Cecilia M., Velazquez, Carolina, Dworniczak, Bernd, Eason, Jacqueline, Easton, Douglas F., Eeles, Ros, Ehrencrona, Hans, Izatt, Louise, Ejlertsen, Bent, Engel, Christoph, Engert, Stefanie, Evans, D. Gareth, Faivre, Laurence, Feliubadaló, Lidia, Ferrer, Sandra Fert, Foretova, Lenka, Fowler, Jeffrey, Frost, Debra, Izquierdo, Angel, Galvão, Henrique C. R., Ganz, Patricia A., Garber, Judy, Gauthier-Villars, Marion, Gehrig, Andrea, Gerdes, Anne-Marie, Gesta, Paul, Giannini, Giuseppe, Giraud, Sophie, Glendon, Gord, Jakubowska, Anna, Godwin, Andrew K., Greene, Mark H., James, Paul, Janavicius, Ramunas, Jensen, Uffe Birk, John, Esther M., Vijai, Joseph, Kaczmarek, Katarzyna, Karlan, Beth Y., Chan, TL, Kast, Karin, Investigators, KConFab, Kim, Sung-Won, Konstantopoulou, Irene, Korach, Jacob, Laitman, Yael, Lasa, Adriana, Lasset, Christine, Lázaro, Conxi, Lee, Annette, Couch, Fergus J., Lee, Min Hyuk, Lester, Jenny, Lesueur, Fabienne, Liljegren, Annelie, Lindor, Noralane M., Longy, Michel, Loud, Jennifer T., Lu, Karen H., Lubinski, Jan, Machackova, Eva, Goldgar, David E., Manoukian, Siranoush, Mari, Véronique, Martínez-Bouzas, Cristina, Matrai, Zoltan, Mebirouk, Noura, Meijers-Heijboer, Hanne E.J., Meindl, Alfons, Mensenkamp, Arjen R., Mickys, Ugnius, Miller, Austin, Kruse, Torben A., Montagna, Marco, Moysich, Kirsten B., Mulligan, Anna Marie, Musinsky, Jacob, Neuhausen, Susan L., Nevanlinna, Heli, Ngeow, Joanne, Nguyen, Huu Phuc, Niederacher, Dieter, Nielsen, Henriette Roed, Palmero, Edenir Inêz, Nielsen, Finn Cilius, Nussbaum, Robert L., Offit, Kenneth, Öfverholm, Anna, Ong, Kai-ren, Osorio, Ana, Papi, Laura, Papp, Janos, Pasini, Barbara, Pedersen, Inge Sokilde, Park, Sue Kyung, Peixoto, Ana, Peruga, Nina, Peterlongo, Paolo, Pohl, Esther, Pradhan, Nisha, Prajzendanc, Karolina, Prieur, Fabienne, Pujol, Pascal, Radice, Paolo, Ramus, Susan J., Torres, Diana, Rantala, Johanna, [ 1 ] Harvard TH Chan Sch Publ Hlth, Boston, MA USA Show more [ 2 ] Chaim Sheba Med Ctr, Inst Human Genet, Susanne Levy Gertner Oncogenet Unit, IL-52621 Ramat Gan, Israel Show more [ 3 ] Tel Aviv Univ, Sackler Sch Med, Tel Aviv, Israel Show more [ 4 ] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany Show more [ 5 ] Univ Chicago, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 6 ] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China Show more [ 7 ] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary Show more [ 8 ] Univ Buenos Aires, CONICET, Fac Med, INBIOMED, Buenos Aires, DF, Argentina Show more [ 9 ] CEMIC, Dept Clin Chem, Med Direct, Buenos Aires, DF, Argentina [ 10 ] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Malaysia Show more [ 11 ] Odense Univ Hosp, Dept Clin Genet, Odense, Denmark Show more [ 12 ] City Hope Canc Ctr, Div Clin Canc Genom, Duarte, CA USA [ 13 ] Hong Kong Sanat & Hosp, Dept Pathol, Div Mol Pathol, Happy Valley, Hong Kong, Peoples R China [ 14 ] Dept Lab Med & Pathol, Rochester, MN USA Show more [ 15 ] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT USA Show more [ 16 ] Barretos Canc Hosp, Mol Oncol Res Ctr, Sao Paulo, Brazil Show more [ 17 ] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea Show more [ 18 ] Seoul Natl Univ, Grad Sch, Dept Biomed Sci, Seoul, South Korea Show more [ 19 ] Seoul Natl Univ, Canc Res Ctr, Seoul, South Korea Show more [ 20 ] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia Show more [ 21 ] Univ Pretoria, Dept Genet, Canc Genet Lab, Pretoria, South Africa Show more [ 22 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England Show more [ 23 ] QIMR Berghofer Med Res Inst, Genet & Computat Biol Dept, Brisbane, Qld, Australia [ 24 ] Acad Med Ctr, Dept Clin Genet, Amsterdam, Netherlands [ 25 ] City Hope Clin Canc Genom Community Res Network, D, Harvard TH Chan School of Public Health and Dana Farber Cancer Institute; Boston USA, The Susanne Levy Gertner Oncogenetics Unit; Institute of Human Genetics; Chaim Sheba Medical Center, Ramat Gan 52621, and the Sackler School of Medicine; Tel-Aviv University; Tel-Aviv Israel, Molecular Genetics of Breast Cancer; German Cancer Research Center (DKFZ); Heidelberg Germany, Center for Clinical Cancer Genetics and Global Health; University of Chicago; Chicago USA, The Hong Kong Hereditary Breast Cancer Family Registry; Cancer Genetics Center; Hong Kong Sanatorium and Hospital; Hong Kong China, Department of Molecular Genetics; National Institute of Oncology; Budapest Hungary, INBIOMED; Faculty of Medicine, University of Buenos Aires/CONICET and CEMIC, Department of Clinical Chemistry; Medical Direction; Buenos Aires Argentina, Cancer Research Initiatives Foundation; Sime Darby Medical Centre; Subang Jaya Malaysia, Department of Clinical Genetics; Odense University Hospital; Odense Denmark, Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty; University Hospital Cologne; Cologne Germany, Clinical Genetics Services; Dept. of Medicine; Memorial Sloan-Kettering Cancer Center; New York USA, Division of Gynecologic Oncology; North Shore University Health System; University of Chicago; Evanston USA, All Wales Medical Genetics Services; University Hospital of Wales; Cardiff UK, Department of Gynecology; Vilnius University Hospital Santariskiu Clinics; Centre of Woman's Health and pathology; Vilnius Lithuania, Center for Genomic Medicine; Rigshospitalet; University of Copenhagen; Copenhagen Denmark, Clinical Cancer Genetics Program; Division of Human Genetics; Department of Internal Medicine; The Comprehensive Cancer Center; The Ohio State University; Columbus USA, Cancer Genetics Laboratory, Department of Genetics; University of Pretoria; South Africa, Department of Genetics and Pathology; Pomeranian Medical University; Szczecin Poland, Department of Medicine, Abramson Cancer Center; Perelman School of Medicine at the University of Pennsylvania; Philadelphia USA, Department of Internal Medicine; Division of Oncology; University of Kansas Medical Center; Westwood USA, North East Thames Regional Genetics Service; Great Ormond Street Hospital for Children NHS Trust; London UK, Genomics Center; Centre Hospitalier Universitaire de Québec Research Center and Laval University; Quebec City Canada, Dept of OB/GYN and Comprehensive Cancer Center; Medical University of Vienna; Vienna Austria, Department of Clinical Genetics; Aarhus University Hospital; Aarhus N Denmark, Division of Clinical Cancer Genomics; City of Hope Cancer Center; California USA, Medical Genetics Unit; University of London; St George's UK, Département Oncologie Génétique; Prévention et Dépistage; Institut Paoli-Calmettes; Marseille Medical School-AM University; Marseille France, Department of Breast Medical Oncology and Clinical Cancer Genetics Program; University Of Texas MD Anderson Cancer Center; Houston USA, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care; University of Cambridge; Cambridge UK, Department of Population Sciences; Beckman Research Institute of City of Hope; Duarte USA, Institute of Cell and Molecular Pathology; Hannover Medical School; Hannover Germany, Institute of Human Genetics; University Hospital Heidelberg; Heidelberg Germany, National Human Genome Research Institute; National Institutes of Health; Bethesda USA, Dept of OB/GYN, Comprehensive Cancer Center; Medical University of Vienna; Vienna Austria, Department of Genetics; Portuguese Oncology Institute of Porto (IPO Porto); Porto Portugal, Department of Epidemiology; Columbia University; New York USA, Genetic Counseling Unit; Hereditary Cancer Program; IDIBELL (Bellvitge Biomedical Research Institute); Catalan Institute of Oncology, CIBERONC; Gran Via de l'Hospitalet; Barcelona Spain, Department of Health Sciences Research; Mayo Clinic; Rochester USA, Genetics and Computational Biology Department; QIMR Berghofer Medical Research Institute; Brisbane Australia, Department of Medicine; Magee-Womens Hospital; University of Pittsburgh School of Medicine; Pittsburgh USA, Program in Cancer Genetics; Departments of Human Genetics and Oncology; McGill University; Montreal Canada, Immunology and Molecular Oncology Unit; Veneto Institute of Oncology IOV - IRCCS; Padua Italy, Division of Human Genetics; Departments of Internal Medicine and Cancer Biology and Genetics; Comprehensive Cancer Center; The Ohio State University; Columbus USA, Clinical Genetics Research Laboratory, Dept. of Medicine; Memorial Sloan-Kettering Cancer Center; New York USA, Parkville Familial Cancer Centre; Royal Melbourne Hospital; Melbourne Australia, Department of Medical Oncology; Beth Israel Deaconess Medical Center; Massachusetts USA, Department of Clinical Genetics; Leiden University Medical Center; Leiden The Netherlands, Department of Genetics; University Medical Center; Groningen University; Groningen The Netherlands, Family Cancer Clinic; Netherlands Cancer Institute; Amsterdam The Netherlands, Department of Medical Genetics; University Medical Center; Utrecht The Netherlands, Center for Medical Genetics; Ghent University; Gent Belgium, Unit of Hereditary Cancer; Department of Epidemiology, Prevention and Special Functions; IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro; Genoa Italy, Institute of Human Genetics; Campus Virchov Klinikum; Berlin Germany, Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela; Spain, Departamento de Investigacion y de Tumores Mamarios del; Instituto Nacional de Cancerologia; Mexico City Mexico, Department of Oncology; Karolinska University Hospital; Stockholm Sweden, Institute of Genetic Medicine; Centre for Life; Newcastle Upon Tyne Hospitals NHS Trust; Newcastle upon Tyne UK, Oxford Regional Genetics Service; Churchill Hospital; Oxford UK, Department of Gynaecology and Obstetrics; University Hospital; Ulm Germany, Department of Clinical Genetics; Academic Medical Center; Amsterdam The Netherlands, Institute of Human Genetics; Regensburg University; Regensburg Germany, Molecular Diagnostics Laboratory, INRASTES (Institute of Nuclear and Radiological Sciences and Technology); National Centre for Scientific Research “Demokritos”; Athens Greece, Unit of Medical Genetics, Department of Medical Oncology and Hematology; Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Instituto Nazionale Tumori (INT); Milan Italy, Institute of Oncology; Rivka Ziv Medical Center; Zefat Israel, Magee-Womens Hospital; University of Pittsburgh School of Medicine; Pittsburgh USA, Institute of Human Genetics; University Leipzig; Leipzig Germany, Center for Medical Genetics; North Shore University Health System; Evanston USA, Medical Director, Center for Medical Genetics, NorthShore University HealthSystem, Clinical Assistant Professor of Medicine; University of Chicago Pritzker School of Medicine; Evanston USA, City of Hope Clinical Cancer Genomics Community Research Network; Duarte USA, Yorkshire Regional Genetics Service; Chapel Allerton Hospital; Leeds UK, Department of Clinical Genetics; Helsinki University Hospital; Helsinki Finland, Hereditary Cancer Clinic; Prince of Wales Hospital; Randwick Australia, Lunenfeld-Tanenbaum Research Institute; Toronto Canada, Laboratory of Cell Biology, Department of Pathology, hus 9, Landspitali-LSH v/Hringbraut, 101 Reykjavik, Iceland and BMC (Biomedical Centre), Faculty of Medicine; University of Iceland; Reykjavik Iceland, Department of Gynaecology & Oncology; Medical University of Vienna; Austria, Department of Medical Oncology; Vall d'Hebron University Hospital; Barcelona Spain, Division of Cancer Prevention and Genetics; Istituto Europeo di Oncologia (IEO); Milan Italy, Department of Gynaecology and Obstetrics; University Hospital Düsseldorf, Heinrich-Heine University; Düsseldorf Germany, Human Genetics Group and Genotyping Unit (CEGEN), Human Cancer Genetics Programme; Spanish National Cancer Research Centre (CNIO); Madrid Spain, The Institute of Oncology; Chaim Sheba Medical Center; Ramat Gan Israel, UCSF Cancer Genetics and Prevention Program; San Francisco USA, Department of Clinical Genetics; Maastricht University Medical Center; Maastricht The Netherlands, Unité de Prévention et d'Epidémiologie Génétique; Centre Léon Bérard, 28 rue Laënnec; Lyon France, N.N. Petrov Institute of Oncology; St. Petersburg Russia, Department of Clinical Genetics; Royal Devon & Exeter Hospital; Exeter UK, Service de Génétique; Institut Curie, 26 rue d'Ulm; Paris France, Department of Medicine; Huntsman Cancer Institute; Salt Lake City USA, Molecular Oncology Laboratory; Hospital Clinico San Carlos; Instituto de Investigación Sanitaria San Carlos (IdISSC); Centro Investigación Biomédica en Red de Cáncer (CIBERONC); Madrid Spain, Institute of Human Genetics; University Hospital of Schleswig-Holstein; Kiel Germany, Section of Molecular Genetics, Dept. of Laboratory Medicine; University Hospital of Pisa; Pisa Italy, Research Division; Peter MacCallum Cancer Centre; Melbourne Australia, CRCHU de Quebec-oncologie, Centre des maladies du sein Deschênes-Fabia; Hôpital du Saint-Sacrement; Sainte-Foy Canada, Lombardi Comprehensive Cancer Center; Georgetown University; Washington USA, Departments of Pediatrics and Medicine; Columbia University; New York USA, Department of Clinical Genetics, Family Cancer Clinic; Erasmus University Medical Center; Rotterdam The Netherlands, Sheffield Clinical Genetics Service; Sheffield Children's Hospital; Sheffield UK, Department of Clinical Genetics; South Glasgow University Hospitals; Glasgow UK, Unité d'oncogénétique; ICO-Centre René Gauducheau; Saint Herblain France, Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Clinical and Molecular Genetics Area; Vall d'Hebron University Hospital; Barcelona Spain, Department of Gynaecology and Obstetrics; Ludwig-Maximilian University; Munich Germany, Cáncer Hereditario, Instituto de Biología y Genética Molecular, IBGM; Universidad de Valladolid; Valladolid Spain, Institute of Human Genetics; University of Münster; Münster Germany, Nottingham Clinical Genetics Service; Nottingham University Hospitals NHS Trust; Nottingham UK, Oncogenetics Team; The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; London UK, Department of Clinical Genetics; Lund University Hospital; Lund Sweden, Clinical Genetics; Guy's and St. Thomas’ NHS Foundation Trust; London UK, Department of Oncology, Rigshospitalet; Copenhagen University Hospital; Copenhagen Denmark, Institute for Medical Informatics, Statistics and Epidemiology; University of Leipzig; Leipzig Germany, Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar; Technical University; Munich Germany, Genomic Medicine, Manchester Academic Health Sciences Centre, Division of Evolution and Genomic Sciences; University of Manchester, Central Manchester University Hospitals NHS Foundation Trust; Manchester UK, Centre de Lutte Contre le Cancer Georges François Leclerc, France and Genomic and Immunotherapy Medical Institute; Dijon University Hospital; Dijon France, Molecular Diagnostic Unit, Hereditary Cancer Program, ICO-IDIBELL (Catalan Institute of Oncology-Bellvitge Biomedical Research Institute); Barcelona Spain, Laboratoire de Génétique Chromosomique; Hôtel Dieu Centre Hospitalier; Chambéry France, Department of Cancer Epidemiology and Genetics; Masaryk Memorial Cancer Institute; Brno Czech Republic, Columbus Cancer Council, Ohio State University; Columbus USA, Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona); Catalan Institute of Oncology; Girona Spain, Oncogenetics Department; Barretos Cancer Hospital; Barretos Brazil, UCLA Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research; Jonsson Comprehensive Cancer Center; Los Angeles USA, Cancer Risk and Prevention Clinic; Dana-Farber Cancer Institute; Boston USA, Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics; University of Würzburg, Germany; Würzburg, Department of Clinical Genetics; Copenhagen Denmark, Service Régional Oncogénétique Poitou-Charentes; Centre Hospitalier; Niort France, Department of Molecular Medicine; University La Sapienza, and Istituto Pasteur - Fondazione Cenci-Bolognetti; Rome Italy, Bâtiment Cheney D; Centre Léon Bérard; Lyon France, Ontario Cancer Genetics Network: Lunenfeld-Tanenbaum Research Institute; Mount Sinai Hospital; Toronto Canada, Department of Pathology and Laboratory Medicine; University of Kansas Medical Center; Kansas City USA, Clinical Genetics Branch, DCEG, NCI; NIH; Bethesda USA, Parkville Familial Cancer Centre; Peter MacCallum Cancer Centre; Melbourne Australia, Hematology, oncology and transfusion medicine center, Dept. of Molecular and Regenerative Medicine; Vilnius University Hospital Santariskiu Clinics; Vilnius Lithuania, Department of Epidemiology, Cancer Prevention Institute of California; Fremont USA, Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute; Cedars-Sinai Medical Center; Los Angeles USA, Division of Molecular Pathology; Department of Pathology; Hong Kong Sanatorium & Hospital; Happy Valley Hong Kong, Department of Gynecology and Obstetrics; Medical Faculty and University Hospital Carl Gustav Carus; Dresden Germany, Research Department, Peter MacCallum Cancer Centre, Melbourne, Victoria; Australia and The Sir Peter MacCallum Department of Oncology University of Melbourne; Parkville Australia, Department of Surgery; Daerim St. Mary's Hospital; Seoul Korea, The Gyneco-Oncology Department; Chaim Sheba Medical Center; Ramat Gan Israel, Servicio de Genética-CIBERER U705; Hospital de la Santa Creu i Sant Pau; Barcelona Spain, The Feinstein Institute for Medical Research; Manhasset USA, Department of Laboratory Medicine and Pathology; and Health Sciences Research; Rochester USA, Department of Surgery; Soonchunhyang University and Seoul Hospital; Seoul Korea, Inserm U900, Institut Curie; PSL Research University; Paris France, Department of Oncology Radiumhemmet and Institution of Oncology and Patology; Karolinska University Hospital and Karolinska Institutet; Solna Sweden, Department of Health Sciences Research; Mayo Clinic; Scottsdale USA, Oncogénétique; Institut Bergonié; Bordeaux France, Clinical Genetics Branch, DCEG, NCI, NIH; Bethesda USA, Department of Gynecological Oncology and Clinical Cancer Genetics Program; University Of Texas MD Anderson Cancer Center; Houston USA, Department of Dermatology; University of Utah School of Medicine; Salt Lake City USA, Centre Antoine Lacassagne; Nice France, Laboratorio de Genética Molecular, Servicio de Genética; Hospital Universitario Cruces, BioCruces Health Research Institute; Barakaldo Spain, Department of Surgery; National Institute of Oncology; Budapest Hungary, Department of Clinical Genetics; VU University Medical Center; Amsterdam The Netherlands, Department of Human Genetics; Radboud University Medical Center; Nijmegen The Netherlands, Vilnius university Santariskiu hospital; National Center of Pathology; Vilnius Lithuania, NRG Oncology; Statistics and Data Management Center; Roswell Park Cancer Institute; Buffalo USA, Department of Cancer Prevention and Control; Roswell Park Cancer Institute; Buffalo USA, Department of Laboratory Medicine and Pathobiology; University of Toronto; Toronto Canada, Department of Obstetrics and Gynecology; University of Helsinki and Helsinki University Hospital; HUS Finland, Cancer Genetics Service; Division of Medical Oncology; National Cancer Centre Singapore; Bukit Merah Singapore, Institute of Medical Genetics and Applied Genomics; University of Tuebingen; Tuebingen Germany, Molecular Oncology Research Center; Barretos Cancer Hospital; São Paulo Brazil, Cancer Genetics and Prevention Program; University of California San Francisco; San Francisco USA, Clinical Genetics Research Laboratory; Dept. of Medicine; Cancer Biology and Genetics; Memorial Sloan-Kettering Cancer Center; New York USA, Department of Clinical Genetics; Sahlgrenska University Hospital; Gothenburg Sweden, West Midlands Regional Genetics Service; Birmingham Women's Hospital Healthcare NHS Trust; Edgbaston UK, Human Genetics Group; Human Cancer Genetics Programme; Spanish National Cancer Research Centre (CNIO); Biomedical Network on Rare Diseases (CIBERER); Madrid Spain, Unit of Medical Genetics; Department of Biomedical; Experimental and Clinical Sciences; University of Florence; Florence Italy, Department of Medical Sciences; University of Turin; Turin Italy, Section of Molecular Diagnostics; Department of Biochemistry; Aalborg University Hospital; Aalborg Denmark, Department of Preventive Medicine; Seoul National University College of Medicine; Seoul Korea, IFOM; The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology; Milan Italy, Service de Génétique Clinique Chromosomique et Moléculaire; Hôpital Nord; St Etienne France, Unité d'Oncogénétique; CHU Arnaud de Villeneuve; Montpellier France, Unit of Molecular Bases of Genetic Risk and Genetic Testing; Department of Research; Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico), Istituto Nazionale Tumori (INT); Milan Italy, School of Women's and Children's Health; UNSW; Sydney Australia, Department of Clinical Genetics; Karolinska University Hospital; Stockholm Sweden, Rebbeck, Timothy R., Friebel, Tara M., Friedman, Eitan, Hamann, Ute, Huo, Dezheng, Kwong, Ava, Olah, Edith, Olopade, Olufunmilayo I., Solano, Angela R., Teo, Soo-Hwang, Thomassen, Mads, Rashid, Muhammad Usman, Rhiem, Kerstin, Robson, Mark, Rodriguez, Gustavo C., Rogers, Mark T., Rudaitis, Vilius, Schmidt, Ane Y., Schmutzler, Rita Katharina, Senter, Leigha, van Rensburg, Elizabeth J., Gronwald, Jacek, Shah, Payal D., Sharma, Priyanka, Side, Lucy E., Simard, Jacques, Singer, Christian F., Skytte, Anne-Bine, Slavin, Thomas P., Snape, Katie, Sobol, Hagay, Southey, Melissa, Gutierrez-Barrera, Angelica, McGuffog, Lesley, Steele, Linda, Steinemann, Doris, Sukiennicki, Grzegorz, Sutter, Christian, Szabo, Csilla I., Tan, Yen Y., Teixeira, Manuel R., Terry, Mary Beth, Teulé, Alex, Hahnen, Eric, Thomas, Abigail, Parsons, Michael T., Thull, Darcy L., Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda Ewart, Topka, Sabine, Trainer, Alison H, Tung, Nadine, van Asperen, Christi J., Hauke, Jan, van der Hout, Annemieke H., van der Kolk, Lizet E., Leslie, Goska, van der Luijt, Rob B., Van Heetvelde, Mattias, Varesco, Liliana, Varon-Mateeva, Raymonda, Vega, Ana, Villarreal-Garza, Cynthia, von Wachenfeldt, Anna, Henderson, Alex, Walker, Lisa, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Aalfs, Cora M., Weber, Bernhard H. F., Yannoukakos, Drakoulis, Yoon, Sook-Yee, Zanzottera, Cristina, Zidan, Jamal, Zorn, Kristin K., Hentschel, Julia, Hutten Selkirk, Christina G., Hulick, Peter J., Chenevix-Trench, Georgia, Spurdle, Amanda B., Abugattas, Julio, Antoniou, Antonis C., Nathanson, Katherine L., Adlard, Julian, Agata, Simona, Aittomäki, Kristiina, Hogervorst, Frans B.L., Andrews, Lesley, Andrulis, Irene L., Arason, Adalgeir, Arnold, Norbert, Arun, Banu K., Asseryanis, Ella, Auerbach, Leo, Azzollini, Jacopo, Balmaña, Judith, Barile, Monica, Honisch, Ellen, Barkardottir, Rosa B., Barrowdale, Daniel, Benitez, Javier, Berger, Andreas, Berger, Raanan, Blanco, Amie M., Blazer, Kathleen R., Blok, Marinus J., Bonadona, Valérie, Bonanni, Bernardo, Imyanitov, Evgeny N., Bradbury, Angela R., Brewer, Carole, Buecher, Bruno, Buys, Saundra S., Caldes, Trinidad, Caliebe, Almuth, Caligo, Maria A., Campbell, Ian, Caputo, Sandrine M., Chiquette, Jocelyne, Isaacs, Claudine, Chung, Wendy K., Claes, Kathleen B.M., Collée, J. Margriet, Cook, Jackie, Davidson, Rosemarie, de la Hoya, Miguel, De Leeneer, Kim, de Pauw, Antoine, Delnatte, Capucine, Diez, Orland, Weitzel, Jeffrey N., Ding, Yuan Chun, Ditsch, Nina, Domchek, Susan M., Dorfling, Cecilia M., Velazquez, Carolina, Dworniczak, Bernd, Eason, Jacqueline, Easton, Douglas F., Eeles, Ros, Ehrencrona, Hans, Izatt, Louise, Ejlertsen, Bent, Engel, Christoph, Engert, Stefanie, Evans, D. Gareth, Faivre, Laurence, Feliubadaló, Lidia, Ferrer, Sandra Fert, Foretova, Lenka, Fowler, Jeffrey, Frost, Debra, Izquierdo, Angel, Galvão, Henrique C. R., Ganz, Patricia A., Garber, Judy, Gauthier-Villars, Marion, Gehrig, Andrea, Gerdes, Anne-Marie, Gesta, Paul, Giannini, Giuseppe, Giraud, Sophie, Glendon, Gord, Jakubowska, Anna, Godwin, Andrew K., Greene, Mark H., James, Paul, Janavicius, Ramunas, Jensen, Uffe Birk, John, Esther M., Vijai, Joseph, Kaczmarek, Katarzyna, Karlan, Beth Y., Chan, TL, Kast, Karin, Investigators, KConFab, Kim, Sung-Won, Konstantopoulou, Irene, Korach, Jacob, Laitman, Yael, Lasa, Adriana, Lasset, Christine, Lázaro, Conxi, Lee, Annette, Couch, Fergus J., Lee, Min Hyuk, Lester, Jenny, Lesueur, Fabienne, Liljegren, Annelie, Lindor, Noralane M., Longy, Michel, Loud, Jennifer T., Lu, Karen H., Lubinski, Jan, Machackova, Eva, Goldgar, David E., Manoukian, Siranoush, Mari, Véronique, Martínez-Bouzas, Cristina, Matrai, Zoltan, Mebirouk, Noura, Meijers-Heijboer, Hanne E.J., Meindl, Alfons, Mensenkamp, Arjen R., Mickys, Ugnius, Miller, Austin, Kruse, Torben A., Montagna, Marco, Moysich, Kirsten B., Mulligan, Anna Marie, Musinsky, Jacob, Neuhausen, Susan L., Nevanlinna, Heli, Ngeow, Joanne, Nguyen, Huu Phuc, Niederacher, Dieter, Nielsen, Henriette Roed, Palmero, Edenir Inêz, Nielsen, Finn Cilius, Nussbaum, Robert L., Offit, Kenneth, Öfverholm, Anna, Ong, Kai-ren, Osorio, Ana, Papi, Laura, Papp, Janos, Pasini, Barbara, Pedersen, Inge Sokilde, Park, Sue Kyung, Peixoto, Ana, Peruga, Nina, Peterlongo, Paolo, Pohl, Esther, Pradhan, Nisha, Prajzendanc, Karolina, Prieur, Fabienne, Pujol, Pascal, Radice, Paolo, Ramus, Susan J., Torres, Diana, and Rantala, Johanna
Abstract: To access publisher's full text version of this article click on the hyperlink below, The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

2. Nivolumab and Relatlimab in Patients With Advanced Melanoma That Had Progressed on Anti–Programmed Death-1/Programmed Death Ligand 1 Therapy: Results From the Phase I/IIa RELATIVITY-020 Trial

Author: Paolo Antonio Ascierto, Evan J. Lipson, Reinhard Dummer, James Larkin, Georgina V. Long, Rachel E. Sanborn, Vanna Chiarion-Sileni, Brigitte Dréno, Stéphane Dalle, Dirk Schadendorf, Margaret K. Callahan, Marta Nyakas, Victoria Atkinson, Carlos Alberto Gomez-Roca, Naoya Yamazaki, Hussein A. Tawbi, Naomey Sarkis, Deepti Warad, Sonia Dolfi, Priyam Mitra, Satyendra Suryawanshi, Jean-Jacques Grob, University of Zurich, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale [Naples, Italy] (INT-FGP), Johns Hopkins University (JHU), Universität Zürich [Zürich] = University of Zurich (UZH), The institute of cancer research [London], The University of Sydney, Providence Cancer Center, Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Immunology and New Concepts in ImmunoTherapy (INCIT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), 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), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Memorial Sloan Kettering Cancer Center (MSKCC), Oslo University Hospital [Oslo], Greenslopes Private Hospital [QLD, Australia] (GPH), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Cancer Center Research Institute [Tokyo], The University of Texas M.D. Anderson Cancer Center [Houston], Bristol-Myers Squibb [Princeton], Service de dermatologie, vénéreologie et cancérologie cutanée [Hôpital de la Timone - APHM], and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)
Subjects: Cancer Research, Oncology, [SDV]Life Sciences [q-bio], Medizin, 10177 Dermatology Clinic, 610 Medicine & health, 2730 Oncology, 1306 Cancer Research
Abstract: PURPOSE Nivolumab and relatlimab activity in advanced melanoma with prior progression on anti–programmed death-1/programmed death ligand 1 (PD-(L)1)-containing regimens is under investigation. RELATIVITY-047 demonstrated significantly improved progression-free survival (PFS) for nivolumab and relatlimab over nivolumab in previously untreated advanced melanoma. METHODS The phase I/IIa, open-label RELATIVITY-020 trial part D assessed efficacy and safety of nivolumab and relatlimab in advanced melanoma with progression during, or within 3 months of, 1 (D1) or ≥ 1 (D2) anti–PD-(L)1-containing regimens. Safety was a primary end point. Objective response rate (coprimary end point) and PFS by blinded independent central review (BICR) were assessed. RESULTS Five hundred eighteen patients (D1 = 354; D2 = 164) received nivolumab and relatlimab. Among evaluable patients, the objective response rate by BICR was 12.0% (95% CI, 8.8 to 15.8) in D1 (n = 351) and 9.2% (95% CI, 5.2 to 14.7) in D2 (n = 163). Responses appeared to be enriched among patients with tumors expressing programmed death ligand 1 or lymphocyte activation gene 3; however, responses were observed regardless of programmed death ligand 1 and lymphocyte activation gene 3 expression (1%). The median duration of response was not reached (95% CI, 12.9 to not reached) in D1 and 12.8 months (95% CI, 6.9 to 12.9) in D2. The median PFS by BICR was 2.1 months (95% CI, 1.9 to 3.5) in D1 and 3.2 months (95% CI, 1.9 to 3.6) in D2; the 6-month PFS rate was 29.1% (95% CI, 24.2 to 34.1) and 27.7% (95% CI, 20.5 to 35.4), respectively. The grade 3-4 treatment-related adverse event incidence was 15.0% in D1 and 12.8% in D2. One case of grade 3 myocarditis and no treatment-related deaths occurred across part D. CONCLUSION Nivolumab and relatlimab had a manageable safety profile and demonstrated durable clinical activity in a proportion of patients with heavily pretreated advanced melanoma with prior progression on anti–PD-(L)1-containing regimens. [Media: see text]
Published: 2023
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3. Quality control in PET/CT and PET/MRI: Results of a survey amongst European countries

Author: Reynés-Llompart, Gabriel, Zorz, Alessandra, Boellaard, Ronald, Ptáček, Jaroslav, Pike, Lucy, Soret, Marine, Vandenberghe, Stefaan, Matheoud, Roberta, Radiology and nuclear medicine, Amsterdam Neuroscience - Brain Imaging, Institut Català d'Oncologia [Barcelona], Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Amsterdam UMC - Amsterdam University Medical Center, University Hospital Olomouc [Czech Republic], King‘s College London, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University (UGENT), University Hospital 'Maggiore della Carità' [Novara, Italy], and Soret, Marine
Subjects: Quality Control, MESH: Quality Control, Biophysics, General Physics and Astronomy, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, MESH: Magnetic Resonance Imaging, [SDV.IB.MN] Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Positron Emission Tomography Computed Tomography, Surveys and Questionnaires, Humans, Radiology, Nuclear Medicine and imaging, MESH: Surveys and Questionnaires, Survey, [SPI.SIGNAL] Engineering Sciences [physics]/Signal and Image processing, MESH: Humans, Phantoms, Imaging, General Medicine, Magnetic Resonance Imaging, MESH: Positron-Emission Tomography, Europe, MESH: Phantoms, Imaging, Positron-Emission Tomography, MESH: Europe, MESH: Positron Emission Tomography Computed Tomography, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Positron Emission Tomography
Abstract: International audience; Purpose: An EFOMP Working Group (WG) was created in 2020 to establish recommendations for PET/CT/MRI Quality Control (QC). The WG's intention was to create a document containing a set of measurements suitable for routine practice. In order to map the current situation in PET facilities, the WG prepared a survey addressed to European Medical Physics Experts (MPE).Methods: The survey was conducted using an electronic questionnaire with 10 sections, for a total of 43 multiple choice or open questions. Data regarding general information, model of installed scanners, contract of maintenance and phantoms available were collected. The focal part of the questionnaire concerned the QC protocol adopted and accreditation programs.Results: 123 answers from 24 countries were collected. 90.2% of the respondents are affiliated as staff MPEs; 45% have non-digital TOF PET/CT scanners with a contract of maintenance (97.6%). In 98.4% and 86.8% of responding centres a sealed source for daily QC and the NEMA Image Quality Phantom were present. 94.3% of respondents perform daily QC according to manufacturer recommendations, while NEMA Tests are not performed routinely (51.2%). 56.1% of the respondents have scanners accredited by a national or international organization. 56% of the centres perform annual CT tests, while more than 90% do not perform any MRI QCs.Conclusions: The results of the survey show that there is a lack of harmonization in the PET QC procedures across Europe. The information obtained will guide the WG in proposing a guideline containing a set of measurements suitable for the clinical routine.
Published: 2022
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4. Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers

Author: Fucà, Giovanni, Cohen, Romain, Lonardi, Sara, Shitara, Kohei, Elez, Elena, Fakih, Marwan, Chao, Joseph, Klempner, Samuel J., Emmett, Matthew, Jayachandran, Priya, Bergamo, Francesca, García, Marc Díez, Mazzoli, Giacomo, Provenzano, Leonardo, Colle, Raphael, Svrcek, Magali, Ambrosini, Margherita, Randon, Giovanni, Shah, Aakash Tushar, Salati, Massimiliano, Fenocchio, Elisabetta, Salvatore, Lisa, Chida, Keigo, Kawazoe, Akihito, Conca, Veronica, Curigliano, Giuseppe, Corti, Francesca, Cremolini, Chiara, Overman, Michael, Andre, Thierry, Pietrantonio, Filippo, Universitat Autònoma de Barcelona, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Instabilité des microsatellites et cancers [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Department of Gastroenterology and Gastrointestinal Oncology [Kashiwa, Japon], National Cancer Center Hospital East, Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], City of Hope Comprehensive Cancer Center [Duarte], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), USC/Norris Comprehensive Cancer Center, University of Southern California (USC), Baylor College of Medicine (BCM), Baylor University, Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Candiolo Cancer Institute (IRCCS), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Azienda Ospedaliero-Universitaria Pisana [Pisa, Italy], Department of Translational Research on New Technologies in Medicine and Surgery, University of Pisa - Università di Pisa, European Institute of Oncology [Milan] (ESMO), Università degli Studi di Milano = University of Milan (UNIMI), The University of Texas M.D. Anderson Cancer Center [Houston], Gestionnaire, Hal Sorbonne Université, Institut Català de la Salut, [Fucà G] Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. [Cohen R] Sorbonne Université, Department of Medical Oncology, Hôpital Saint-Antoine, APHP and INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France. [Lonardi S] Medical Oncology 3 Medical Oncology 1, Istituto Oncologico Veneto IOV-IRCSS, Padua, Italy. [Shitara K] Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. [Elez ME, Díez García M] Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Fakih M] Department of Medical Oncology and Therapeutic Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Male, Cancer Research, Immunology, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], [SDV.CAN]Life Sciences [q-bio]/Cancer, gastrointestinal neoplasms, immunotherapy, translational medical research, tumor biomarkers, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Còlon - Càncer - Tractament, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES], [SDV.CAN] Life Sciences [q-bio]/Cancer, Stomach Neoplasms, Recte - Càncer - Tractament, Immunology and Allergy, Humans, Neoplasm Metastasis, Immune Checkpoint Inhibitors, RC254-282, Aged, Retrospective Studies, Pharmacology, Settore MED/06 - ONCOLOGIA MEDICA, acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS], Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Ascites, Tumor biomarkers, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES], Gastrointestinal neoplasms, Survival Analysis, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, afecciones patológicas, signos y síntomas::procesos patológicos::ascitis [ENFERMEDADES], Oncology, Molecular Medicine, Female, Microsatellite Instability, Immunotherapy, Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS], Translational medical research, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Colorectal Neoplasms, Pathological Conditions, Signs and Symptoms::Pathologic Processes::Ascites [DISEASES]
Abstract: BackgroundDespite unprecedented benefit from immune checkpoint inhibitors (ICIs) in patients with mismatch repair deficient (dMMR)/microsatellite instability high (MSI-H) advanced gastrointestinal cancers, a relevant proportion of patients shows primary resistance or short-term disease control. Since malignant effusions represent an immune-suppressed niche, we investigated whether peritoneal involvement with or without ascites is a poor prognostic factor in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC) and gastric cancer (mGC) receiving ICIs.MethodsWe conducted a global multicohort study at Tertiary Cancer Centers and collected clinic-pathological data from a cohort of patients with dMMR/MSI-H mCRC treated with anti-PD-(L)1 ±anti-CTLA-4 agents at 12 institutions (developing set). A cohort of patients with dMMR/MSI-high mGC treated with anti-PD-1 agents±chemotherapy at five institutions was used as validating dataset.ResultsThe mCRC cohort included 502 patients. After a median follow-up of 31.2 months, patients without peritoneal metastases and those with peritoneal metastases and no ascites had similar outcomes (adjusted HR (aHR) 1.15, 95% CI 0.85 to 1.56 for progression-free survival (PFS); aHR 0.96, 95% CI 0.65 to 1.42 for overall survival (OS)), whereas inferior outcomes were observed in patients with peritoneal metastases and ascites (aHR 2.90, 95% CI 1.70 to 4.94; aHR 3.33, 95% CI 1.88 to 5.91) compared with patients without peritoneal involvement. The mGC cohort included 59 patients. After a median follow-up of 17.4 months, inferior PFS and OS were reported in patients with peritoneal metastases and ascites (aHR 3.83, 95% CI 1.68 to 8.72; aHR 3.44, 95% CI 1.39 to 8.53, respectively), but not in patients with only peritoneal metastases (aHR 1.87, 95% CI 0.64 to 5.46; aHR 2.15, 95% CI 0.64 to 7.27) when compared with patients without peritoneal involvement.ConclusionsPatients with dMMR/MSI-H gastrointestinal cancers with peritoneal metastases and ascites should be considered as a peculiar subgroup with highly unfavorable outcomes to current ICI-based therapies. Novel strategies to target the immune-suppressive niche in malignant effusions should be investigated, as well as next-generation ICIs or intraperitoneal approaches.
Published: 2022
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5. Editorial: Cancer Immunotherapies: From Efficacy to Resistance Mechanisms

Author: Janin Chandra, Morten Hansen, Nathalie Labarriere, Ilaria Marigo, Fernando Souza-Fonseca-Guimaraes, Lazar Vujanovic, Yoshinobu Koguchi, Nicolas Jacquelot, University of Queensland - The Diamantina Institute, University of Queensland [Brisbane], Copenhagen University Hospital, Immunology and New Concepts in ImmunoTherapy (INCIT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Università degli Studi di Padova = University of Padua (Unipd), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Earle A. Chiles Research Institute [Portland, OR, USA], Providence Portland Medical Center-Robert W. Franz Cancer Research Center, Princess Margaret Cancer Centre [Toronto, Canada], and Pecqueret, Valérie
Subjects: Biochemical Phenomena, [SDV]Life Sciences [q-bio], Immunology, adoptive T cell therapy, cancer, immune checkpoint blockers, immunotherapy, tumor microenvironment, [SDV] Life Sciences [q-bio], Neoplasms, Immunology and Allergy, Humans, ComputingMilieux_MISCELLANEOUS
Abstract: International audience; No abstract available
Published: 2022
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6. Microsatellite instability in stage III colon cancer patients receiving fluoropyrimidine ± oxaliplatin: an

Author: Cohen, Romain, Taieb, Julien, Fiskum, Jack, Yothers, Greg, Goldberg, Richard, Yoshino, Takayuki, Alberts, Steven, Allegra, Carmen, De Gramont, Aimery, Seitz, Jean-Francois, O'Connell, Michael, Haller, Daniel, Wolmark, Norman, Erlichman, Charles, Zaniboni, Alberto, Lonardi, Sara, Kerr, Rachel, Grothey, Axel, Sinicrope, Franck, André, Thierry, Shi, Qian, Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Mayo Clinic [Rochester], University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Center for Climate Systems Research [New York] (CCSR), Columbia University [New York], University of Tokyo [Kashiwa Campus], The University of Florida College of Medicine, Service d'Oncologie Médicale [Institut Hospitalier Franco-Britannique], Division of Medical Oncology - Institut Hospitalier Franco-Britannique, Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Fondazione Poliambulanza, Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], University of Oxford [Oxford], and West German Cancer Center [Essen, Germany]
Subjects: deficient mismatch repair, oxaliplatin, microsatellite instability, [SDV.CAN]Life Sciences [q-bio]/Cancer, prognosis, neoplasms, digestive system diseases, Colon cancer
Abstract: International audience; PURPOSE:In patients with stage III colon cancer (CC) whose tumors demonstrate microsatellite instability (MSI), the efficacy of adjuvant fluoropyrimidine (FP) with or without oxaliplatin has not been clearly demonstrated and the prognostic value of MSI remains uncertain.MATERIALS AND METHODS:Individual patient data from the ACCENT database were used to evaluate the effect of FP with or without oxaliplatin on disease-free survival (DFS) and overall survival (OS) among patients with MSI stage III CC and the prognostic value of MSI in patients treated with FP plus oxaliplatin, by stratified Cox models adjusted for demographic and clinicopathological factors.RESULTS:MSI status was available for 5,457 patients (609 MSI, 11.2%; 4848 microsatellite stable [MSS], 88.8%) from 12 randomized clinical trials (RCTs). Oxaliplatin significantly improved OS of MSI patients from the two RCTs testing FP with or without oxaliplatin (n = 185; adjusted hazard ratio [aHR] = 0.52, 95% CI, 0.28 to 0.93). Among the 4,250 patients treated with FP plus oxaliplatin (461 MSI and 3789 MSS), MSI was associated with better OS in the N1 group compared with MSS (aHR = 0.66; 95% CI, 0.46 to 0.95) but similar survival in the N2 population (aHR = 1.13; 95% CI, 0.86 to 1.48; P interaction = .029). The main independent prognosticators of MSI patients treated with FP plus oxaliplatin were T stage (aHR = 2.09; 95% CI, 1.29 to 3.38) and N stage (aHR = 3.57; 95% CI, 2.32 to 5.48). Similar results were observed for DFS in all analyses.CONCLUSION:Adding oxaliplatin to FP improves OS and DFS in patients with MSI stage III CC. Compared with MSS, MSI patients experienced better outcomes in the N1 group but similar survival in the N2 group.
Published: 2021
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7. Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study

Author: Daniil Stroyakovskiy, Yu Guo, Isabelle Rooney, P. Francesco Ferrucci, Keith T. Flaherty, Zeynep Eroglu, Jacopo Pigozzo, S. Troutman, Jacek Mackiewicz, S. Mulla, Athina Voulgari, Piotr Rutkowski, Bethany Pitcher, Brigitte Dréno, Lev V. Demidov, J.M.G. Larkin, A. Arance, M. Castro, Helen Gogas, Yibing Yan, National and Kapodistrian University of Athens (NKUA), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Royal Marsden NHS Foundation Trust, N.N. Blokhin Russian Cancer Research Center, Moscow City Oncology Hospital No. 62 [Moscow, Russia] (MCOH), H. Lee Moffitt Cancer Center and Research Institute, European Institute of Oncology [Milan] (ESMO), Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Maria Sklodowska-Curie National Research Institute of Oncology [Krakow, Poland], Poznan University of Medical Sciences [Poland] (PUMS), Genentech, Inc. [San Francisco], Roche Products Ltd, F. Hoffmann-La Roche [Basel], Massachusetts General Hospital Cancer Center [Boston, MA, USA], Harvard Medical School [Boston] (HMS), Hospital Clinic [Barcelona, Spain], and Malbec, Odile
Subjects: 0301 basic medicine, atezolizumab, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Population, Pembrolizumab, Gastroenterology, BRAF wild-type, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Atezolizumab, Interquartile range, Internal medicine, medicine, melanoma, education, Adverse effect, cobimetinib, Cobimetinib, education.field_of_study, business.industry, Hazard ratio, Hematology, Rash, [SDV] Life Sciences [q-bio], 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, pembrolizumab, medicine.symptom, business
Abstract: International audience; Background: Emerging data suggest that the combination of MEK inhibitors and immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAF V600 wild-type advanced melanoma. Patients and methods: IMspire170 was an international, randomized, open-label, phase III study. Patients were randomized 1 : 1 to receive cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population. Results: Between 11 December 2017, and 29 January 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n ¼ 222) or pembrolizumab (n ¼ 224). Median follow-up was 7.1 months [interquartile range (IQR) 4.8-9.9] for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab. Median PFS was 5.5 months [95% confidence interval (CI) 3.8-7.2] with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab [stratified hazard ratio 1.15 (95% CI 0.88-1.50); P ¼ 0.30]. Hazard ratios for PFS were consistent across prespecified subgroups. In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms. The most common grade 3-5 adverse events (AEs) were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab versus 0.9% with pembrolizumab), diarrhea (7.7% versus 1.9%), rash (6.8% versus 0.9%), hypertension (6.4% versus 3.7%), and dermatitis acneiform (5.0% versus 0). Serious AEs occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab. Conclusion: Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAF V600 wild-type advanced melanoma.
Published: 2020
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8. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Author: Daniel R. Barnes, Matti A. Rookus, Lesley McGuffog, Goska Leslie, Thea M. Mooij, Joe Dennis, Nasim Mavaddat, Julian Adlard, Munaza Ahmed, Kristiina Aittomäki, Nadine Andrieu, Irene L. Andrulis, Norbert Arnold, Banu K. Arun, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Daniel Barrowdale, Javier Benitez, Pascaline Berthet, Katarzyna Białkowska, Amie M. Blanco, Marinus J. Blok, Bernardo Bonanni, Susanne E. Boonen, Åke Borg, Aniko Bozsik, Angela R. Bradbury, Paul Brennan, Carole Brewer, Joan Brunet, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Lise Lotte Christensen, Wendy K. Chung, Kathleen B.M. Claes, Chrystelle Colas, Marie-Agnès Collonge-Rame, Capucine Delnatte, Laurence Faivre, Sophie Giraud, Christine Lasset, Véronique Mari, Noura Mebirouk, Emmanuelle Mouret-Fourme, Hélène Schuster, Dominique Stoppa-Lyonnet, Antonis Antoniou, Jackie Cook, Rosemarie Davidson, Douglas Easton, Ros Eeles, D. Gareth Evans, Debra Frost, Helen Hanson, Louise Izatt, Kai-ren Ong, Lucy Side, Aoife O’Shaughnessy-Kirwan, Marc Tischkowitz, Lisa Walker, Mary B. Daly, Miguel de la Hoya, Robin de Putter, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Cecilia M. Dorfling, Martine Dumont, Bent Ejlertsen, Christoph Engel, Lenka Foretova, Florentia Fostira, Michael Friedlander, Eitan Friedman, Patricia A. Ganz, Judy Garber, Andrea Gehrig, Anne-Marie Gerdes, Paul Gesta, Gord Glendon, Andrew K. Godwin, David E. Goldgar, Anna González-Neira, Mark H. Greene, Daphne Gschwantler-Kaulich, Eric Hahnen, Ute Hamann, Julia Hentschel, Frans B.L. Hogervorst, Maartje J. Hooning, Judit Horvath, Chunling Hu, Peter J. Hulick, Evgeny N. Imyanitov, Georgia Chenevix-Trench, Kelly-Anne Phillips, Amanda Spurdle, Marinus Blok, Frans Hogervorst, Maartje Hooning, Marco Koudijs, Arjen Mensenkamp, Hanne Meijers-Heijboer, Matti Rookus, Klaartje van Engelen, Catherine Noguès, Claudine Isaacs, Angel Izquierdo, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Esther M. John, Vijai Joseph, Beth Y. Karlan, Karin Kast, Torben A. Kruse, Ava Kwong, Yael Laitman, Conxi Lazaro, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Jennifer T. Loud, Jan Lubiński, Phuong L. Mai, Siranoush Manoukian, Hanne E.J. Meijers-Heijboer, Alfons Meindl, Arjen R. Mensenkamp, Austin Miller, Marco Montagna, Semanti Mukherjee, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Dieter Niederacher, Finn Cilius Nielsen, Liene Nikitina-Zake, Edith Olah, Olufunmilayo I. Olopade, Ana Osorio, Claus-Eric Ott, Laura Papi, Sue K. Park, Michael T. Parsons, Inge Sokilde Pedersen, Bernard Peissel, Ana Peixoto, Paolo Peterlongo, Georg Pfeiler, Karolina Prajzendanc, Miquel Angel Pujana, Paolo Radice, Juliane Ramser, Susan J. Ramus, Johanna Rantala, Gad Rennert, Harvey A. Risch, Mark Robson, Karina Rønlund, Ritu Salani, Leigha Senter, Payal D. Shah, Priyanka Sharma, Lucy E. Side, Christian F. Singer, Thomas P. Slavin, Penny Soucy, Melissa C. Southey, Amanda B. Spurdle, Doris Steinemann, Zoe Steinsnyder, Christian Sutter, Yen Yen Tan, Manuel R. Teixeira, Soo Hwang Teo, Darcy L. Thull, Silvia Tognazzo, Amanda E. Toland, Alison H. Trainer, Nadine Tung, Elizabeth J. van Rensburg, Ana Vega, Jeroen Vierstraete, Gabriel Wagner, Shan Wang-Gohrke, Barbara Wappenschmidt, Jeffrey N. Weitzel, Siddhartha Yadav, Xin Yang, Drakoulis Yannoukakos, Dario Zimbalatti, Kenneth Offit, Mads Thomassen, Fergus J. Couch, Rita K. Schmutzler, Jacques Simard, Douglas F. Easton, Antonis C. Antoniou, Pediatric surgery, Human genetics, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, Amsterdam Reproduction & Development (AR&D), Apollo - University of Cambridge Repository, University of Cambridge [UK] (CAM), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Chapel Allerton Hospital, Great Ormond Street Hospital for Children [London] (GOSH), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Université Paris sciences et lettres (PSL), Mount Sinai Hospital [Toronto, Canada] (MSH), University of Toronto (University of Toronto), Christian-Albrechts University of Kiel, The University of Texas M.D. Anderson Cancer Center [Houston], Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Landspitali National University Hospital of Iceland, University of Iceland [Reykjavik], CIBER de Enfermedades Raras (CIBERER), Spanish National Cancer Research Center (CNIO), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Pomeranian Medical University [Szczecin] (PUM), University of California (UC), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], European Institute of Oncology IRCCS [Milan, Italy] (EIO), Zealand University Hospital [Roskilde, Denmark], Lund University [Lund], National Institute of Oncology [Budapest, Hungary], Abramson Cancer Center [philadelphia], University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Institute of Genetic Medicine [Newcastle], Newcastle University [Newcastle], Royal Devon & Exeter Hospital, Exeter, UK, Catalan Institute of Oncology [Barcelone, Espagne], Huntsman Cancer Institute [Salt Lake City], University of Utah, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Pisa University Hospital, Peter MacCallum Cancer Centre [Melbourne, Australie], University of Melbourne, Aarhus University Hospital, Columbia University [New York], Ghent University Hospital, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Sheffield Children's NHS Foundation Trust, Fox Chase Cancer Center, Queen Elizabeth University Hospital (Glasgow), Centre hospitalier universitaire de Nantes (CHU Nantes), Leiden University Medical Center (LUMC), Beckman Research Institute of the City of Hope, Abramson Cancer Center, University of Pretoria [South Africa], Centre Hospitalier Universitaire de Québec Research Center [Canada], Royal Marsden NHS Foundation Trust, Copenhagen University Hospital, Leipzig University, University of Manchester [Manchester], Manchester Academic Health Science Centre (MAHSC), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Masaryk Memorial Cancer Institute (MMCI), Institute of Nuclear and Radiological Sciences and Technology, Energy and Safety (INRASTES), National Center for Scientific Research 'Demokritos' (NCSR), NHMRC Clinical Trials Centre [Camperdown NSW 2050, Australie], Chaim Sheba Medical Center, Tel Aviv University (TAU), Jonsson Comprehensive Cancer Center, University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Dana-Farber Cancer Institute [Boston], University of Würzburg, Rigshospitalet [Copenhagen], Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Hospices Civils de Lyon (HCL), University of Kansas [Kansas City], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Medizinische Universität Wien = Medical University of Vienna, University of Cologne, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Lancashire NHS Foundation Trust, University Hospital Leipzig, Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Mayo Clinic, NorthShore University HealthSystem [Evanston, IL, USA], The University of Chicago Medicine [Chicago], N. N. Petrov Institute of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Guy's and St Thomas' NHS Foundation Trust [London, UK], Peter MacCallum Cancer Center, East Melbourne, Peter MacCallum Cancer Center, Vilnius University [Vilnius], The State Scientific Research Institute Nature Research Centre, Vilnius, Lithuania, Stanford University School of Medicine [CA, USA], Memorial Sloane Kettering Cancer Center [New York], Cedars-Sinai Medical Center, Technische Universität Dresden = Dresden University of Technology (TU Dresden), University Medical Center [Utrecht], Odense University Hospital [Odense, Denmark], The Hong Kong Hereditary Breast Cancer Family Registry, The University of Hong Kong (HKU), Hong Kong Sanatorium and Hospital [Hong Kong] (HKSH), Equipe de prévention et épidémiologie génétique, Centre Léon Bérard [Lyon], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), David Geffen School of Medicine [Los Angeles], Fondation MINES ParisTech, Karolinska Institutet [Stockholm], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Amsterdam UMC - Amsterdam University Medical Center, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Radboud University Medical Center [Nijmegen], Roswell Park Cancer Institute [Buffalo], Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], University of Toronto, University Health Network, University Hospital Düsseldorf, Latvian Biomedical Research and Study Centre [Rīga], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), University of Chicago, Birmingham Women's and Children's NHS Foundation Trust, Cambridge University Hospitals - NHS (CUH), Charité Campus Virchow-Klinikum (CVK), Università degli Studi di Firenze = University of Florence (UniFI), Seoul National University College of Medicine [Séoul, Corée du Sud] (SNUCM), Seoul National University [Seoul] (SNU), QIMR Berghofer Medical Research Institute, Aalborg University [Denmark] (AAU), IRCCS Istituto Nazionale dei Tumori [Milano], Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto (IPO Porto), IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Klinikum rechts der Isar [Munich, Germany], University of New South Wales [Sydney] (UNSW), Garvan Institute of medical research, Technion Faculty of Medicine [Haifa, Israel], Yale School of Medicine [New Haven, Connecticut] (YSM), Vejle Hospital [Danemark], Ohio State University [Columbus] (OSU), Centre de lutte contre le cancer Paul-Strauss, Institut de Cancérologie de Strasbourg Europe (ICANS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Kansas Medical Center [Kansas City, KS, USA], Princess Anne Hospital, City of Hope Comprehensive Cancer Center [Duarte], Monash University [Clayton], Cancer Council Victoria [Melbourne, VIC, Australia], Hannover Medical School [Hannover] (MHH), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Heidelberg University Hospital [Heidelberg], Institute of Biomedical Sciences Abel Salazar - ICBAS [Porto, Portugal], Malaysia and University Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya [Kuala Lumpur, Malaisie], University of Malaya = Universiti Malaya [Kuala Lumpur, Malaisie] (UM), McGill University = Université McGill [Montréal, Canada], Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), Fundación Pública Galega Medicina Xenómica - SERGAS [Santiago de Compostela, Spain] (Grupo de Medicina Xenómica), CIBER de Enfermedades Raras (CIBERER)-Universidade de Santiago de Compostela [Spain] (USC ), Instituto de Investigaciones Sanitarias, Universidade de Santiago de Compostela [Spain] (USC ), Universiteit Gent = Ghent University (UGENT), Oxford University Hospitals NHS Trust, University of Oxford, Universitätsklinikum Ulm - University Hospital of Ulm, University Hospital of Cologne [Cologne], Mayo Clinic [Rochester], Collaborators : Pascaline Berthet, Chrystelle Colas, Marie-Agnès Collonge-Rame, Capucine Delnatte, Laurence Faivre, Sophie Giraud, Christine Lasset, Véronique Mari, Noura Mebirouk, Emmanuelle Mouret-Fourme, Hélène Schuster, Dominique Stoppa-Lyonnet, Julian Adlard, Munaza Ahmed, Antonis Antoniou, Daniel Barrowdale, Paul Brennan, Carole Brewer, Jackie Cook, Rosemarie Davidson, Douglas Easton, Ros Eeles, D Gareth Evans, Debra Frost, Helen Hanson, Louise Izatt, Kai-Ren Ong, Lucy Side, Aoife O'Shaughnessy-Kirwan, Marc Tischkowitz, Lisa Walker, Georgia Chenevix-Trench, Kelly-Anne Phillips, Amanda Spurdle, Marinus Blok, Peter Devilee, Frans Hogervorst, Maartje Hooning, Marco Koudijs, Arjen Mensenkamp, Hanne Meijers-Heijboer, Matti Rookus, Klaartje van Engelen, Nadine Andrieu, Catherine Noguès, Dupuis, Christine, Institut Català de la Salut, [Barnes DR, McGuffog L, Leslie G, Dennis J] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Rookus MA, Mooij TM] The Netherlands Cancer Institute, Department of Epidemiology (PSOE), Amsterdam, The Netherlands. [Balmaña J] High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Barnes, Daniel [0000-0002-3781-7570], Leslie, Goska [0000-0001-5756-6222], Dennis, Joe [0000-0003-4591-1214], Mavaddat, Nasim [0000-0003-0307-055X], RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Universiteit Leiden, Roswell Park Cancer Institute [Buffalo] (RPCI), Medical Oncology, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, Helsinki University Hospital Area, Department of Obstetrics and Gynecology, Biosciences, HUS Gynecology and Obstetrics, University of Helsinki, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Pomeranian Medical University, University of California, University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], University of Leipzig [Leipzig, Allemagne], Masaryk Memorial Cancer Institute (RECAMO), Tel Aviv University [Tel Aviv], University of California-University of California, University of Münster, Amsterdam UMC, Technical University of Munich (TUM), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Garvan Institute of Medical Research [Sydney, Australia], Yale University School of Medicine, Vejle Hospital, University of Kansas Medical Center [Lawrence], Université Paris Descartes (Paris 5), University of Malaya [Kuala Lumpur, Malaisie], Universiteit Gent = Ghent University [Belgium] (UGENT), and University of Oxford [Oxford]
Subjects: 0301 basic medicine, Oncology, endocrine system diseases, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], [SDV]Life Sciences [q-bio], Càncer d'ovari, Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], MODIFIERS, Diàtesi, SUSCEPTIBILITY, Carcinoma, Ovarian Epithelial, PRS, 0302 clinical medicine, Breast cancer, 3123 Gynaecology and paediatrics, Risk Factors, Medicine and Health Sciences, Medicine, Genetics(clinical), genetics, Prospective Studies, Prospective cohort study, skin and connective tissue diseases, Genetics (clinical), Ovarian Neoplasms, education.field_of_study, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], BRCA1 Protein, Hazard ratio, Absolute risk reduction, 1184 Genetics, developmental biology, physiology, article, ASSOCIATION, neoplasias::neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas::carcinoma epitelial de ovario [ENFERMEDADES], ddc, 3. Good health, [SDV] Life Sciences [q-bio], ovarian cancer, 030220 oncology & carcinogenesis, Female, Cohort study, medicine.medical_specialty, Heterozygote, Population, 3122 Cancers, Single-nucleotide polymorphism, Breast Neoplasms, MUTATION CARRIERS, Ovaris - Càncer - Aspectes genètics, Càncer de mama, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, Ovarian cancer, BRCA1/2, Internal medicine, Humans, Genetic Predisposition to Disease, education, Retrospective Studies, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], BRCA2 Protein, IDENTIFICATION, business.industry, Neoplasms::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms::Carcinoma, Ovarian Epithelial [DISEASES], Retrospective cohort study, ALLELES, medicine.disease, BRCA1, BRCA2, MODEL, PATHOLOGY, 030104 developmental biology, Mutation, Mama - Càncer - Aspectes genètics, 3111 Biomedicine, business
Abstract: Contains fulltext : 229292.pdf (Publisher’s version ) (Open Access) PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10(-72)). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10(-22)) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10(-12)) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
Published: 2020
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9. Identifying the Steps Required to Effectively Implement Next-Generation Sequencing in Oncology at a National Level in Europe

Author: Denis Horgan, Giuseppe Curigliano, Olaf Rieß, Paul Hofman, Reinhard Büttner, Pierfranco Conte, Tanja Cufer, William M. Gallagher, Nadia Georges, Keith Kerr, Frédérique Penault-Llorca, Ken Mastris, Carla Pinto, Jan Van Meerbeeck, Elisabetta Munzone, Marlene Thomas, Sonia Ujupan, Gilad W. Vainer, Janna-Lisa Velthaus, Fabrice André, Division of Medical Oncology, European Institute of Oncology [Milan] (ESMO), Laboratory of Clinical and Experimental Pathology, Centre Hospitalier Universitaire de Nice (CHU Nice), University Hospital of Cologne [Cologne], Department of Surgery, Oncology and Gastroenterology, University of Padova, Istituto Oncologico Veneto IOV IRCCS, 35128 Padova, University Clinic Golnik, University College Dublin [Dublin] (UCD), Ministère de la santé, Department of Pathology, Aberdeen University Medical School, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, University of Antwerp (UA), Division of Medical Senology [Milan, Italy], Protéines de défense des réponses immune et inflammatoire : identification, régulation et rôles physiopathologiques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Pathologie mammaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi di Milano = University of Milan (UNIMI), University of Tübingen, Université Côte d'Azur (UCA), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), Hôpital Pasteur [Nice] (CHU), Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Università degli Studi di Padova = University of Padua (Unipd), University of Ljubljana, University of Aberdeen, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), F. Hoffmann-La Roche [Basel], The Hebrew University of Jerusalem (HUJ), Institut Gustave Roussy (IGR), and Direction de la recherche [Gustave Roussy]
Subjects: Evropski načrt za premagovanje raka, [SDV]Life Sciences [q-bio], testing infrastructure, Medicine (miscellaneous), [SDV.CAN]Life Sciences [q-bio]/Cancer, ozaveščanje in izobraževanje deležnikov, pravično povračilo, klinična standardizacija, sekvenciranje naslednje generacije, testiranje infrastrukture, molekularno vodene možnosti zdravljenja, clinical standardization, European Alliance for Personalised Medicine, Europe’s Beating Cancer Plan, stakeholder awareness and education, pridobivanje dokazov, Evropska zveza za personalizirano medicino, evidence generation, governance, Perspective, Medicine, molecularly guided treatment options, next-generation sequencing, Human medicine, equitable reimbursement, upravljanje
Abstract: International audience; Next-generation sequencing (NGS) may enable more focused and highly personalized cancer treatment, with the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines now recommending NGS for daily clinical practice for several tumor types. However, NGS implementation, and therefore patient access, varies across Europe; a multi-stakeholder collaboration is needed to establish the conditions required to improve this discrepancy. In that regard, we set up European Alliance for Personalised Medicine (EAPM)-led expert panels during the first half of 2021, including key stakeholders from across 10 European countries covering medical, economic, patient, industry, and governmental expertise. We describe the outcomes of these panels in order to define and explore the necessary conditions for NGS implementation into routine clinical care to enable patient access, identify specific challenges in achieving them, and make short- and long-term recommendations. The main challenges identified relate to the demand for NGS tests (governance, clinical standardization, and awareness and education) and supply of tests (equitable reimbursement, infrastructure for conducting and validating tests, and testing access driven by evidence generation). Recommendations made to resolve each of these challenges should aid multi-stakeholder collaboration between national and European initiatives, to complement, support, and mutually reinforce efforts to improve patient care.
Published: 2022
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10. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial

Author: Piotr Rutkowski, Lars Bastholt, Ralf Gutzmer, Claus Garbe, Virginia Ferraresi, Marta Nyakas, Omid Hamid, Joanna Pikiel, Jean-Jacques Grob, Paolo A. Ascierto, Céleste Lebbé, Caroline Robert, Delphine Hennicken, Vanna Chiarion-Sileni, Michael Smylie, Gabriella Liszkay, Florent Grange, Catriona M. McNeil, Luc Thomas, Dirk Schadendorf, Andrzej Mackiewicz, Michele Del Vecchio, Christoph Hoeller, Carmen Loquai, Michele Maio, Inge Marie Svane, Anila Qureshi, Brigitte Dréno, Ana Arance, Laurent Mortier, Istituto Nazionale Tumori Fondazione Pascale [Naples, Italy], Medical Oncology, National Cancer Institute [Milan, Italy], Institut Gustave Roussy ( IGR ), Department of Diagnostics and Cancer Immunology [Poznan, Poland], Greater Poland Cancer Centre [Poznan, Poland]-Poznan Medical University [Poland], Melanoma Oncology Unit [Padova, Italy], Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Institut d'Investigacions Biomèdiques August Pi I Sunyer [Barcelona, Spain] ( Hospital Clinic ), Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées ( DIO U976 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Odense University Hospital [Odense, Denmark], The Angeles Clinic and Research Institute [Los Angeles, CA, USA], Maria Sklodowska-Curie Memorial Cancer Center [Warsaw, Poland], Royal Prince Alfred Hospital ( RPAH - SYDNEY ), Melanoma Institute Australia [Sydney, NSW, Australia], Eberhard Karls University [Tübingen, Germany], University Medical Center [Mainz, Germany], Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Département de Dermatologie [CH Lyon-Sud, Pierre-Bénite], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Hôpital de la Timone [CHU - APHM] ( TIMONE ), National Institute of Oncology [Budapest, Hungary], Oslo University Hospital [Oslo, Norway], Medizinische Hochschule Hannover [Hannover, Germany], Wojewodzkie Centrum Oncologii [Gdańsk, Poland], Département de Dermatologie [CHU de Reims], Centre Hospitalier Universitaire de Reims ( CHU Reims ), Medical University of Vienna [Austria], Istituti Fisioterapici Ospitalieri [Rome, Italy], Cross Cancer Institute [Edmonton, AB, Canada], University Hospital [Essen, Germany], Hôspital Claude Huriez [Lille, France], Herlev Hospital [Herlev, Denmark], University of Copenhagen ( KU ), Bristol-Myers Squibb [Princeton, NJ, USA], Istituto Toscano Tumori [Siena, Italy], University Hospital of Siena [Italy], Bristol-Myers Squibb., Institut Gustave Roussy (IGR), Institut d'Investigacions Biomèdiques August Pi I Sunyer [Barcelona, Spain] (Hospital Clinic ), Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cedars-Sinai Medical Center, Royal Prince Alfred Hospital (RPAH - SYDNEY), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Hôpital de la Timone [CHU - APHM] (TIMONE), Oslo University Hospital [Oslo], Centre Hospitalier Universitaire de Reims (CHU Reims), Medizinische Universität Wien = Medical University of Vienna, Hôpital Claude Huriez [Lille], CHU Lille, Herlev and Gentofte Hospital, Bristol-Myers Squibb [Princeton], and Bernardo, Elizabeth
Subjects: Male, 0301 basic medicine, Medizin, Gastroenterology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Clinical endpoint, Melanoma, education.field_of_study, Hazard ratio, Antibodies, Monoclonal, Alanine Transaminase, Middle Aged, Colitis, Intention to Treat Analysis, 3. Good health, Survival Rate, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Female, medicine.drug, Diarrhea, medicine.medical_specialty, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Ipilimumab, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Double-Blind Method, Internal medicine, Journal Article, medicine, Humans, Hypophysitis, Adverse effect, education, Survival rate, Aged, Intention-to-treat analysis, business.industry, Surgery, 030104 developmental biology, business, Follow-Up Studies
Abstract: BACKGROUND: A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3-4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit-risk profile of ipilimumab 10 mg/kg versus 3 mg/kg.METHODS: This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189.FINDINGS: Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6-42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9-29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6-17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9-13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70-0·99; p=0·04). The most common grade 3-4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (INTERPRETATION: In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment.FUNDING: Bristol-Myers Squibb.
Published: 2017
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11. A new landscape for systemic pharmacotherapy of recurrent glioblastoma?

Author: Emilie Le Rhun, Ahmed Idbaih, Pim J. French, Giuseppe Lombardi, Matthias Preusser, Vittorina Zagonel, Neurology, Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Zürich [Zürich] = University of Zurich (UZH), Medizinische Universität Wien = Medical University of Vienna, Erasmus University Medical Center [Rotterdam] (Erasmus MC), INSERM, Université de Lille, 146992|||Universität Zürich [Zürich] = University of Zurich [UZH], Erasmus University Medical Center [Rotterdam] [Erasmus MC], Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Malignant brain tumor, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Pharmacotherapy, Internal medicine, Medicine, neoplasms, Adult patients, business.industry, Recurrent glioblastoma, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, nervous system diseases, n/a, 030104 developmental biology, Editorial, 030220 oncology & carcinogenesis, business, Glioblastoma
Abstract: International audience; Glioblastoma is the most common and aggressive primary malignant brain tumor in adult patients. Despite multimodal treatment with maximal safe surgical resection followed by concurrent radiochemotherapy and adjuvant chemotherapy with temozolomide, the prognosis remains poor with a median survival of 1 year. The survival rate at 5 years is 5% and, theoretically, all glioblastomas relapse [1]. Once tumors progress, treatment options are limited, and the management of recurrent glioblastoma remains challenging. The standard of care for second-line treatment has not been defined; options include surgery, re-irradiation, systemic pharmacotherapy, and, in Europe, mostly lomustine [2,3]. The general and neurological health status of the patient, the molecular findings, the time to first recurrence, the pattern of recurrence, and previous treatment have to be considered. Nitrosoureas or temozolomide rechallenge show limited efficacy. Anti-vascular endothelial growth factor (VEGF) bevacizumab prolonged progression-free survival (PFS), but did not improve overall survival (OS) [4].Because the treatment of recurrent glioblastoma remains a highly unmet clinical need, deeper mechanistic insight into the molecular changes present in these tumors is required. The enrollment of recurrent glioblastoma patients in clinical trials investigating new therapeutic options should be considered carefully whenever possible. In this Special Issue, we present some of the exciting updates on recurrent glioblastomas, which may help shape future treatment options.
Published: 2020
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12. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Author: Eduardo Nagore, Caroline Hayward, Christopher I. Amos, Douglas F. Easton, Zaida García-Casado, Julie Lang, Anjali K. Henders, Veronica Höiom, Lisa Bowdler, Kathryn P. Burdon, Laura Del Regno, Nick Orr, Per Arne Andresen, Tongwu Zhang, Rose Yang, Myriam Brossard, Eric K. Moses, Dirk Schadendorf, Laura Cattaneo, Casey Rowe, Essen-Heidelberg Investigators, Hans-Joachim Schulze, Jamie E Craig, D. Timothy Bishop, Anne E. Cust, Johan Hansson, David E. Elder, Nelleke A. Gruis, Donato Calista, Wei V. Chen, Abrar A. Qureshi, Amy Hutchinson, Pilar Galan, Leanne Wallace, Jennifer H. Barrett, Nilesh J. Samani, Maria Teresa Landi, Per Helsing, Andreas Hadjisavvas, Fengju Song, Celia Requena, Elizabeth M. Gillanders, Arantxa Rodriguez, Joan Anton Puig-Butille, Blair H. Smith, Mark Smithers, Michael Malasky, Marianna Sanna, Miriam Potrony, Maria A. Loizidou, Evangelos Evangelou, Richard A. Scolyer, Karen A. Pooley, Rachel E. Neale, Mario Falchi, Adèle C. Green, Monica Rodolfo, Ketty Peris, Licia Rivoltini, Mark M. Iles, Catherine M. Olsen, Alexander J. Stratigos, Tadeusz Dębniak, Weiyin Zhou, H. Peter Soyer, Xin Li, Margaret A. Tucker, Rajesh Kumar, Håkan Olsson, Anders Molven, Nicholas G. Martin, Anthony J. Swerdlow, Aurelie Vogt, Lars A. Akslen, Stuart MacGregor, Sarah V. Ward, Hamida Mohamdi, Bruna Dalmasso, Grant W. Montgomery, Rona M. MacKie, Esther Azizi, Gonçalo R. Abecasis, Chiara Menin, Alison M. Dunning, Ibd investigators, Kevin M. Brown, Jiali Han, Veryan Codd, Graham J. Mann, Nicholas K. Hayward, Marko Hočevar, Eitan Friedman, Richard A. Sturm, Paola Queirolo, Qtwin Investigators, Lawrie Wheeler, Lars G. Fritsche, Shenying Fang, Kiarash Khosrotehrani, Nicole A Kukutsch, Pol Gimenez-Xavier, Belynda Hicks, Matthew Zawistowski, Alessia Visconti, Jessica Harris, Chad M. Brummett, Paola Ghiorzo, andMe, David G. Hunter, Veronique Bataille, Julia Newton-Bishop, Srdjan Novaković, Amfs Investigators, Siranoush Manoukian, Jianxin Shi, Mitchell J. Machiela, G. Mark Lathrop, Josep Malvehy, Katerina P. Kypreou, Susana Puig, Dale R. Nyholt, I. Stefanaki, Maria Concetta Fargnoli, Lisa A. Simms, Kerrie McAloney, M. Malt, Adam J. Trower, Matthew Law, Lei Song, Paul D.P. Pharoah, Christian Ingvar, Jiyeon Choi, Alisa M. Goldstein, Jeffrey E. Lee, Mark Harland, Cristina Pellegrini, Daniela Massi, Sarah Simi, Scott D. Gordon, Jacobo Martinez, Florence Demenais, Kristine Jones, Graham L. Radford-Smith, David C. Whiteman, Lorenza Pastorino, Lisa Elefanti, Arcangela De Nicolo, Mario Mandalà, Juliette Randerson-Moor, Q-Mega, Jan Lubinski, Stephen J. Chanock, Marie-Françoise Avril, David L. Duffy, Helen Gogas, Nienke van der Stoep, Peter A. Kanetsky, Georgina V. Long, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), University of Leeds, QIMR Berghofer Medical Research Institute, National and Kapodistrian University of Athens (NKUA), Ospedale Policlinico San Martino [Genoa], Universita degli studi di Genova, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Maurizio Bufalini Hospital, University of L'Aquila [Italy] (UNIVAQ), Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana [Espagne] (FISABIO), Cyprus Institute of Neurology and Genetics, University of Athens Medical School [Athens], The University of Sydney, Universitat de Barcelona (UB), Azienda Ospedaliera Ospedale Papa Giovanni XXIII [Bergamo, Italy], University of Michigan [Ann Arbor], University of Michigan System, Instituto Valenciano de Oncologia, Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], IRCCS Istituto Nazionale dei Tumori [Milano], Ninewells Hospital and Medical School [Dundee], Cyprus Institute (CyI), Fondazione 'Policlinico Universitario A. Gemelli' [Rome], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University of Queensland [Brisbane], Haukeland University Hospital, University of Bergen (UiB), Geisel School of Medicine at Dartmouth, Oslo University Hospital [Oslo], Service de Dermatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], King‘s College London, Menzies School of Health Research [Australia], Charles Darwin University, The University of Texas M.D. Anderson Cancer Center [Houston], University of Leicester, Flinders University [Adelaide, Australia], West Pomeranian University of Technology Szczecin, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), National Human Genome Research Institute (NHGRI), Leiden University Medical Center (LUMC), Karolinska Institutet [Stockholm], Queensland University of Technology [Brisbane] (QUT), Institute of Oncology Ljubljana, Harvard T.H. Chan School of Public Health, Lund University [Lund], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University of Glasgow, Statistical Genetics, and Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health (NIH) United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USAU19CA148112SEARCH team (Cancer Research UK) C490/A16561AOCS (US Army Medical Research and Material Command) DAMD17-01-1-0729Canadian Institutes of Health Research (CIHR)Cancer Council Victoria Queensland Cancer Fund Cancer Council New South Wales Cancer Council South Australia Cancer Council Western Australia Cancer Council Tasmania National Health and Medical Research Council of AustraliaID400413ID400281National Health and Medical Research Council of Australia National Health and Medical Research Council of Australia National Health and Medical Research Council of Australia National Health and Medical Research Council of Australia Intramural Research Program of the Division of Cancer Epidemiology and Genetics, NCI, NIH, DHHS Ministry of Health, Italy Associazione Italiana per la Ricerca sul Cancro (AIRC)IG 15460Spanish Fondo de Investigaciones Sanitarias grant - FEDER 'Una manera de hacer Europa' PI15/00716PI15/00956CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain - European Development Regional Fund 'A way to achieve Europe' ERDF AGAUR of the Catalan Government, Spain 2014_SGR_603European CommissionEuropean Commission Joint Research CentreLSHC-CT-2006-018702European Union (EU) 'Fundacio La Marato de TV3', Catalonia, Spain 201331-30'Fundacion Cientifica de la Asociacion Espanola Contra el Cancer', Spain GCB15152978SOENCERCA Programme/Generalitat de Catalunya Italian Ministry of the University and Scientific Research (PRIN-2012 grant) 2012JJX494Melanoma Research Alliance United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI)CA88363CA83115CA122838CA87969CA055075CA100264CA133996CA49449National Health and Medical Research Council of Australia200071241944339462380385389927389875389891389892389938443036442915442981496610496675496739552485552498APP1049894Cancer Council Queensland Cancer Institute New South Wales Australian GovernmentDepartment of Industry, Innovation and ScienceCooperative Research Centres (CRC) Programme Australian Cancer Research Foundation Wellcome TrustWT084766/Z/08/ZNational Health and Medical Research Council of Australia Australian Research Council Department of Health and Human Services (DHHS)
Subjects: Sequence Variants, Male, medicine.medical_specialty, Skin Neoplasms, Genotype, Medizin, Identifies 3, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Malignant-melanoma, 0302 clinical medicine, Genetics, medicine, Genetic predisposition, Nevus, Humans, Hla Class-i, Genetic Predisposition to Disease, Polymorphism, Melanoma, 030304 developmental biology, Telomere Length, Cancer, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Loci, Pigmentation, E-cadherin, Single Nucleotide, medicine.disease, Genetic architecture, Attributable Fraction, 3. Good health, Phenotype, Female, Genetic Loci, Genome-Wide Association Study, Cutaneous melanoma, Medical genetics, Settore MED/35 - MALATTIE CUTANEE E VENEREE, 030217 neurology & neurosurgery, Familial Melanoma
Abstract: Meta-analysis of 36,760 cases and 375,188 controls identifies 54 loci associated with susceptibility to cutaneous melanoma. Further analysis combining nevus count and hair color GWAS results provide insights into the genetic architecture of melanoma.Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 x 10(-8)) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
Published: 2020
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13. Preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): a multicentre, open-label, randomised, phase 3 trial

Author: Sandrine Marreaud, Hans Gelderblom, Pierre Meeus, Marco Rastrelli, Antonino De Paoli, Claudia Sangalli, Alessandro Gronchi, Elizabeth H. Baldini, Piotr Rutkowski, Jean-Yves Blay, Chandrajit P. Raut, Frits van Coevorden, Charles Honoré, Marco Fiore, Aisha Miah, Rick L. Haas, Angelo Paolo Dei Tos, Carol Jane Swallow, Dirk C. Strauss, Daphne Hompes, Eberhard Stoeckle, Sylvie Bonvalot, Cécile Le Péchoux, Jean Jacques Stelmes, Saskia Litière, Peter Chung, Stephan Stoldt, Université Paris sciences et lettres (PSL), Fondazione Ospedale San Camillo [Venezia] (IRCCS), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Département de radiothérapie [Gustave Roussy], Princess Margaret Hospital, University of Toronto, Centre Léon Bérard [Lyon], Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Dana-Farber Cancer Institute [Boston], Harvard Medical School [Boston] (HMS), Centro San Giovanni di Dio, Fatebenefratelli, Brescia (IRCCS), Università degli Studi di Brescia [Brescia], European Organisation for Research and Treatment of Cancer [Bruxelles] (EORTC), European Cancer Organisation [Bruxelles] (ECCO), and Leiden University Medical Center (LUMC)
Subjects: Male, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Population, Phases of clinical research, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Clinical endpoint, Medicine, Humans, 030212 general & internal medicine, Retroperitoneal Neoplasms, Adverse effect, education, ComputingMilieux_MISCELLANEOUS, Aged, education.field_of_study, Performance status, business.industry, Hazard ratio, Sarcoma, Middle Aged, Neoadjuvant Therapy, 3. Good health, Surgery, Clinical trial, Radiation therapy, Europe, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, North America, Female, Radiotherapy, Adjuvant, Radiotherapy, Conformal, business
Abstract: Summary Background Unlike for extremity sarcomas, the efficacy of radiotherapy for retroperitoneal sarcoma is not established. The aim of this study was to evaluate the impact of preoperative radiotherapy plus surgery versus surgery alone on abdominal recurrence-free survival. Methods EORTC-62092 is an open-label, randomised, phase 3 study done in 31 research institutions, hospitals, and cancer centres in 13 countries in Europe and North America. Adults (aged ≥18 years) with histologically documented, localised, primary retroperitoneal sarcoma that was operable and suitable for radiotherapy, who had not been previously treated and had a WHO performance status and American Society of Anesthesiologists score of 2 or lower, were centrally randomly assigned (1:1), using an interactive web response system and a minimisation algorithm, to receive either surgery alone or preoperative radiotherapy followed by surgery. Randomisation was stratified by hospital and performance status. Radiotherapy was delivered as 50·4 Gy (in 28 daily fractions of 1·8 Gy) in either 3D conformal radiotherapy or intensity modulated radiotherapy, and the objective of surgery was a macroscopically complete resection of the tumour mass with en-bloc organ resection as necessary. The primary endpoint was abdominal recurrence-free survival, as assessed by the investigator, and was analysed in the intention-to-treat population. Safety was analysed in all patients who started their allocated treatment. This trial is registered with ClinicalTrials.gov , NCT01344018 . Findings Between Jan 18, 2012 and April 10, 2017, 266 patients were enrolled, of whom 133 were randomly assigned to each group. The median follow-up was 43·1 months (IQR 28·8–59·2). 128 (96%) patients from the surgery alone group had surgery, and 119 (89%) patients in the radiotherapy and surgery group had both radiotherapy and surgery. Median abdominal recurrence-free survival was 4·5 years (95% CI 3·9 to not estimable) in the radiotherapy plus surgery group and 5·0 years (3·4 to not estimable) in the surgery only group (hazard ratio 1·01, 95% CI 0·71–1·44; log rank p=0·95). The most common grade 3–4 adverse events were lymphopenia (98 [77%] of 127 patients in the radiotherapy plus surgery group vs one [1%] of 128 patients in the surgery alone group), anaemia (15 [12%] vs ten [8%]), and hypoalbuminaemia (15 [12%] vs five [4%]). Serious adverse events were reported in 30 (24%) of 127 patients in the radiotherapy plus surgery group, and in 13 (10%) of 128 patients in the surgery alone group. One (1%) of 127 patients in the radiotherapy plus surgery group died due to treatment-related serious adverse events (gastropleural fistula), and no patients in the surgery alone group died due to treatment-related serious adverse events. Interpretation Preoperative radiotherapy should not be considered as standard of care treatment for retroperitoneal sarcoma. Funding European Organisation for Research and Treatment of Cancer, and European Clinical Trials in Rare Sarcomas.
Published: 2020
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14. Ramucirumab in elderly patients with hepatocellular carcinoma and elevated alpha-fetoprotein after sorafenib in REACH and REACH-2

Author: Arndt Vogel, Christophe Borg, Vincenzo Dadduzio, Reigetsu Yoshikawa, Eric Assenat, Giovanni Brandi, Min-Hua Jen, Kenta Shinozaki, Marc Pracht, Kenta Motomura, Masatoshi Kudo, Philippe Merle, Takuji Okusaka, Jiří Tomášek, Nora Drove Ubreva, Ryan C. Widau, Richard S. Finn, Bruno Daniele, Manabu Morimoto, Andrew X. Zhu, Josep M. Llovet, Peter R. Galle, Kindai University, University Medical Center [Mainz], Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Icahn School of Medicine at Mount Sinai [New York] (MSSM), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Medizinische Hochschule Hannover (MHH), Lizuka Hospital, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), S. Orsola-Malpighi Polyclinic, G Rummo Hospital, National Cancer Center Research Institute [Tokyo], Masaryk University [Brno] (MUNI), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Kanagawa Cancer Center, Centre Eugène Marquis (CRLCC), Eli Lilly and Company Limited [Windlesham], Eli Lilly Office Kobe, Eli Lilly and Company [Indianapolis], Eli Liily Office Kobe, Massachusetts General Hospital [Boston, MA, USA], Harvard Medical School [Boston] (HMS), Kudo M., Galle P.R., Llovet J.M., Finn R.S., Vogel A., Motomura K., Assenat E., Merle P., Brandi G., Daniele B., Okusaka T., Tomasek J., Borg C., Dadduzio V., Morimoto M., Pracht M., Jen M.-H., Drove Ubreva N., Widau R.C., Shinozaki K., Yoshikawa R., and Zhu A.X.
Subjects: Sorafenib, medicine.medical_specialty, Carcinoma, Hepatocellular, Hepatocellular carcinoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sorafenib intolerance, Placebo, Antibodies, Monoclonal, Humanized, Gastroenterology, Ramucirumab, Càncer de fetge, 03 medical and health sciences, 0302 clinical medicine, Elderly, Internal medicine, Cox proportional hazards regression, Medicine, Humans, Aged, Hepatology, Elevated alpha-fetoprotein, business.industry, Persones grans dependents, Hazard ratio, Liver Neoplasms, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, medicine.disease, Frail elderly, 3. Good health, VEGFR2, Treatment Outcome, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 030211 gastroenterology & hepatology, Monoclonal antibodies, Alpha-fetoprotein (AFP), alpha-Fetoproteins, business, Anticossos monoclonals, Liver cancer, medicine.drug
Abstract: Background & Aims: Limited data on treatment of elderly patients with hepatocellular carcinoma (HCC) increase the unmet need. REACH and REACH-2 were global phase III studies of ramucirumab in patients with HCC after prior sorafenib, where patients with alpha-fetoprotein (AFP) ≥400ng/mL showed an overall ssurvival (OS) benefit for ramucirumab. These post-hoc analyses examined efficacy and safety of ramucirumab in patients with HCC and baseline AFP≥400ng/mL by three prespecified age subgroups (
Published: 2019
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15. A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma

Author: Gaetano Finocchiaro, Rodica Anghel, Hans Joerg Urban, George Fountzilas, Warren Mason, Martina Makrutzki, O. L. Chinot, Dana Cernea, François Ghiringhelli, Alba A. Brandes, Miguel Gil-Gil, Enrico Franceschi, Giuseppe Lombardi, Patrick Beauchesne, Chiedzo Mpofu, Josef Pichler, Antoine F. Carpentier, François Dubois, Vittorina Zagonel, Frank Saran, Anna K. Nowak, Department of Medical Oncology (AUSL di Bologna), Azienda Unità Sanitaria Locale di Bologna (AUSL), Institut Català d' Oncologia, IDIBELL, Royal Marsden NHS Foundation Trust, Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), School of medecine (University of Western Australia), The University of Western Australia (UWA), Cancer Clinical Research Unit (CCRU), University of Toronto, Princess Margaret Cancer Centre, Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Aristotle University of Thessaloniki, The Oncology Institute 'Prof. Dr. Ion Chiricuta', Assistance Publique - Hôpitaux de Marseille (APHM), Institute of Oncology Prof. Dr. Alexandru Trestioreanu (IOB), University of Medicine and Pharmacy 'Carol Davila' Bucharest (UMPCD), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Service de Neuro-Oncologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), F. Hoffmann-La Roche [Basel], Konsiliardienstes Innere Medizin mit Neuroonkologie, and Johannes Kepler Universität
Subjects: 0301 basic medicine, Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, Randomization, Bevacizumab, [SDV.CAN]Life Sciences [q-bio]/Cancer, Placebo, Continuous bevacizumab, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Agents, Immunological, Double-Blind Method, Internal medicine, Multicenter trial, Clinical endpoint, Recurrent glioblastoma, Medicine, Humans, Overall survival, Neuro‐Oncology, Aged, Temozolomide, business.industry, Brain Neoplasms, Hazard ratio, Lomustine, Middle Aged, Prognosis, 3. Good health, Clinical trial, Survival Rate, 030104 developmental biology, 030220 oncology & carcinogenesis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, Neoplasm Recurrence, Local, business, Glioblastoma, medicine.drug, Follow-Up Studies
Abstract: Background We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV. Patients and Methods TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety. Results Of the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61; CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33%, placebo 31%). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.69–1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70; 95% CI, 0.48–1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70; 95% CI, 0.37–1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76; 95% CI, 0.52–1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19% (CCNU + BEV) versus 15% (CCNU + placebo). Conclusion There was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma. Implications for Practice Previous research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy.
Published: 2018
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16. Generation of fluorescently labeled tracers – which features influence the translational potential?

Author: Frederico Caobelli, Marion de Jong, Latifa Rbah-Vidal, Bart Cornelissen, Silvana Del Vecchio, Jacques Barbet, Catarina Xavier, Laura Evangelista, Fijs W. B. van Leeuwen, Radiology & Nuclear Medicine, Clinical sciences, Supporting clinical sciences, Medical Imaging, Interventional Molecular Imaging Laboratory [Leiden, the Netherlands], Department of Radiology [Leiden, the Netherlands], Leiden University Medical Center (LUMC)-Leiden University Medical Center (LUMC), Department of Oncology [Oxford, UK] (CRUK/MRC), University of Oxford, Department of Nuclear Medicine [Basel, Switzerland], University Hospital Basel [Basel, Switzerland], Nuclear Medicine and Molecular Imaging Unit [Padua, Italy], Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Endothelium Radiobiology and Targeting (CRCINA-ÉQUIPE 14), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Advanced Biomedical Sciences [Naples, Italy], University of Naples Federico II = Università degli studi di Napoli Federico II, In vivo Cellular and Molecular Imaging Laboratory [Brussel, Belgium] (ICMI), Vrije Universiteit Brussel (VUB), Department of Radiology & Nuclear Medicine [Rotterdam, the Netherlands], Erasmus University Medical Center [Rotterdam] (Erasmus MC), EANM board., Bernardo, Elizabeth, University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and University of Naples Federico II
Subjects: lcsh:Medical physics. Medical radiology. Nuclear medicine, 0301 basic medicine, Dual-modality, Computer science, lcsh:R895-920, Molecular imaging, [SDV.CAN]Life Sciences [q-bio]/Cancer, Computational biology, Fluorescence, Analytical Chemistry, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Tracers, Image guided surgery, Pharmacology (medical), Radiology, Nuclear Medicine and imaging, Pharmacology, lcsh:RM1-950, 3. Good health, lcsh:Therapeutics. Pharmacology, 030104 developmental biology, Photon emission, Nuclear medicine, Dual modality, Position Paper
Abstract: International audience; Given the increasing exploration of fluorescent tracers in the field of nuclear medicine, a need has risen for practical development guidelines that can help improve the translation aspects of fluorescent tracers. This editorial discusses the does and don'ts in developing fluorescence tracers. It has been put forward by the European Association of Nuclear Medicine (EANM) Translational Molecular Imaging & Therapy committee and has been approved by the EANM board.
Published: 2018
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17. Histone deacetylase 6 controls Notch3 trafficking and degradation in T-cell acute lymphoblastic leukemia cells

Author: Sonia Minuzzo, Stefano Indraccolo, Carolina Venturoli, Yari Ciribilli, Alberto Amadori, Laura Pezzè, Margherita Ghisi, Gianluca Fossati, Vincenzo Ciminale, Giorgia Pilotto, Marica Pinazza, Valentina Agnusdei, Ghisi, Margherita, Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Università degli Studi di Padova = University of Padua (Unipd), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Italfarmaco S.p.A., and University of Trento [Trento]
Subjects: 0301 basic medicine, Cancer Research, [SDV]Life Sciences [q-bio], T-Lymphocytes, Cell, Messenger, Apoptosis, Leukemia-Lymphoma, Mice, SCID, Histone Deacetylase 6, Hydroxamic Acids, Jurkat cells, Jurkat Cells, Mice, Mice, Inbred NOD, Cell Movement, Leukemia-Lymphoma, Adult T-Cell, Adult T-Cell, RNA, Small Interfering, Receptor, Notch3, Molecular Biology, Genetics, Tumor, Cell biology, Gene Expression Regulation, Neoplastic, [SDV] Life Sciences [q-bio], Protein Transport, medicine.anatomical_structure, medicine.drug, Receptor, Signal Transduction, T cell, Notch signaling pathway, Biology, SCID, Small Interfering, Article, Cell Line, Paediatric cancer, 03 medical and health sciences, Cell Line, Tumor, Target identification, medicine, Animals, Humans, RNA, Messenger, Cell Proliferation, Neoplastic, Acute lymphocytic leukaemia, Notch3, Lysosomes, 030104 developmental biology, Trichostatin A, Gene Expression Regulation, Cell culture, Cancer cell, Inbred NOD, RNA
Abstract: International audience; Several studies have revealed that endosomal sorting controls the steady-state levels of Notch at the cell surface in normal cells and prevents its inappropriate activation in the absence of ligands. However, whether this highly dynamic physiologic process can be exploited to counteract dysregulated Notch signaling in cancer cells remains unknown. T-ALL is a malignancy characterized by aberrant Notch signaling, sustained by activating mutations in Notch1 as well as overexpression of Notch3, a Notch paralog physiologically subjected to lysosome-dependent degradation in human cancer cells. Here we show that treatment with the pan-HDAC inhibitor Trichostatin A (TSA) strongly decreases Notch3 full-length protein levels in T-ALL cell lines and primary human T-ALL cells xenografted in mice without substantially reducing NOTCH3 mRNA levels. Moreover, TSA markedly reduced the levels of Notch target genes, including pTα, CR2, and DTX-1, and induced apoptosis of T-ALL cells. We further observed that Notch3 was post-translationally regulated following TSA treatment, with reduced Notch3 surface levels and increased accumulation of Notch3 protein in the lysosomal compartment. Surface Notch3 levels were rescued by inhibition of dynein with ciliobrevin D. Pharmacologic studies with HDAC1, 6, and 8-specific inhibitors disclosed that these effects were largely due to inhibition of HDAC6 in T-ALL cells. HDAC6 silencing by specific shRNA was followed by reduced Notch3 expression and increased apoptosis of T-ALL cells. Finally, HDAC6 silencing impaired leukemia outgrowth in mice, associated with reduction of Notch3 full-length protein in vivo. These results connect HDAC6 activity to regulation of total and surface Notch3 levels and suggest HDAC6 as a potential novel therapeutic target to lower Notch signaling in T-ALL and other Notch3-addicted tumors.
Published: 2018
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18. Characterization of XR-RV3 GafChromic® films in standard laboratory and in clinical conditions and means to evaluate uncertainties and reduce errors

Author: Novák, L., Pinto, M., Siiskonen, T., Waryn, M.J., Knežević, Ž., Farah, J., Trianni, A., Ciraj-Bjelac, O., Clairand, I., De Angelis, C., Delle Canne, S., Hadid, L., Huet, C., Jarvinen, H., Negri, A., Istituto Nazionale di Metrologia delle Radiazioni Ionizzanti (ENEA-INMRI), Radiation and Nuclear Safety Authority [Helsinki] (STUK), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Vinča Institute of Nuclear Sciences, University of Belgrade [Belgrade], Istituto Superiore di Sanita` (ISS), and Veneto Institute of Oncology IOV-IRCCS [Padua, Italy]
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience; Purpose To investigate the optimal use of XR-RV3 GafChromic® films to assess patient skin dose in interventional radiology while addressing the means to reduce uncertainties in dose assessment. Methods XR-Type R GafChromic films have been shown to represent the most efficient and suitable solution to determine patient skin dose in interventional procedures. As film dosimetry can be associated with high uncertainty, this paper presents the EURADOS WG 12 initiative to carry out a comprehensive study of film characteristics with a multisite approach. The considered sources of uncertainties include scanner, film, and fitting-related errors. The work focused on studying film behavior with clinical high-dose-rate pulsed beams (previously unavailable in the literature) together with reference standard laboratory beams. Results First, the performance analysis of six different scanner models has shown that scan uniformity perpendicular to the lamp motion axis and that long term stability are the main sources of scanner-related uncertainties. These could induce errors of up to 7% on the film readings unless regularly checked and corrected. Typically, scan uniformity correction matrices and reading normalization to the scanner-specific and daily background reading should be done. In addition, the analysis on multiple film batches has shown that XR-RV3 films have generally good uniformity within one batch (
Published: 2015
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19. DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Osorio, Ana, Milne, Roger L., Kuchenbaecker, Karoline, Vaclová, Tereza, Pita, Guillermo, Alonso, Rosario, Peterlongo, Paolo, Blanco Guillermo, Ignacio, De la Hoya, Miguel, Durán, Mercedes, Diez, Orland, Ramon y Cajal, Teresa, Konstantopoulou, Irene, Martínez-Bouzas, Cristina, Andrés Conejero, Raquel, Soucy, Penny, McGuffog, Lesley, Barrowdale, Daniel, Lee, Andrew, SWE-BRCA, None, Arver, Brita, Rantala, Johanna, Loman, Niklas, Ehrencrona, Hans, Olopade, Olufunmilayo I., Beattie, Mary S., Domchek, Susan M., Nathanson, Katherine, Rebbeck, Timothy R., Arun, Banu K., Karlan, Beth Y., Walsh, Christine, Lester, Jenny, John, Esther M., Whittemore, Alice S., Daly, Mary B., Southey, Melissa, Hopper, John L, Terry, Mary Beth, Buys, Saundra, Janavicius, Ramunas, Dorfling, Cecilia M., van Rensburg, Elizabeth J., Steele, Linda, Neuhausen, Susan L., Ding, Yuan Chun, Hansen, Thomas v. O., Jønson, Lars, Ejlertsen, Bent, Gerdes, Anne-Marie, Infante, Mar, Herráez, Belén, Moreno, Leticia Thais, Weitzel, Jeffrey N., Herzog, Josef, Weeman, Kisa, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, Scuvera, Giulietta, Bonanni, Bernardo, Mariette, Frederique, Volorio, Sara, Viel, Alessandra, Varesco, Liliana, Papi, Laura, Ottini, Laura, Tibiletti, Maria Grazia, Radice, Paolo, Yannoukakos, Drakoulis, Garber, Judy, Ellis, Steve, Frost, Debra, Platte, Radka, Fineberg, Elena, Evans, Gareth, Lalloo, Fiona, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Eccles, Diana M, Cook, Jackie, Hodgson, Shirley, Brewer, Carole, Tischkowitz, Marc, Douglas, Fiona, Porteous, Mary, Side, Lucy, Walker, Lisa, Morrison, Patrick, Donaldson, Alan, Kennedy, John, Foo, Claire, Godwin, Andrew K., Schmutzler, Rita Katharina, Wappenschmidt, Barbara, Rhiem, Kerstin, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hans Jörg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Gehrig, Andrea, Stoppa-Lyonnet, Dominique, Sinilnikova, Olga M., Mazoyer, Sylvie, Damiola, Francesca, Poppe, Bruce, Claes, Kathleen, Piedmonte, Marion, Tucker, Kathy, Backes, Floor, Rodríguez, Gustavo, Brewster, Wendy, Wakeley, Katie, Rutherford, Thomas, Caldes, Trinidad, Nevanlinna, Heli, Aittomäki, Kristiina, Rookus, Matti A., van Os, Theo A. M., van der Kolk, Lizet, de Lange, J. L., Meijers-Heijboer, Hanne E. J., van der Hout, A. H., van Asperen, Christi J., Gómez Garcia, Encarna B., Hoogerbrugge, Nicoline, Collée, J. Margriet, van Deurzen, Carolien H. M., van der Luijt, Rob B., Devilee, Peter, HEBON, None, Olah, Edith, Lázaro, Conxi, Teulé, Alex, Menéndez, Mireia, Jakubowska, Anna, Cybulski, Cezary, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Johannsson, Oskar Th., Maugard, Christine, Montagna, Marco, Tognazzo, Silvia, Teixeira, Manuel R., Healey, Sue, Investigators, kConFab, Olswold, Curtis, Guidugli, Lucia, Lindor, Noralane, Slager, Susan, Szabo, Csilla I., Vijai, Joseph, Robson, Mark, Kauff, Noah, Zhang, Liying, Rau-Murthy, Rohini, Fink-Retter, Anneliese, Singer, Christian F., Rappaport, Christine, Geschwantler Kaulich, Daphne, Pfeiler, Georg, Tea, Muy-Kheng, Berger, Andreas, Phelan, Catherine M., Greene, Mark H., Mai, Phuong L., Lejbkowicz, Flavio, Andrulis, Irene L., Mulligan, Anna Marie, Glendon, Gord, Toland, Amanda Ewart, Bojesen, Anders, Pedersen, Inge Sokilde, Sunde, Lone, Thomassen, Mads, Kruse, Torben A., Jensen, Uffe Birk, Friedman, Eitan, Laitman, Yael, Shimon, Shani Paluch, Simard, Jacques, Easton, Douglas F., Offit, Kenneth, Couch, Fergus J., Chenevix-Trench, Georgia, Antoniou, Antonis C., Benitez, Javier, Universitat Autònoma de Barcelona, Pediatric Surgery, Clinical Genetics, Pathology, Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain, Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain. 2Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia. 3Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 4Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain. 5Genotyping Unit (CeGen), Spanish National Cancer Centre (CNIO), Madrid, Spain. 6IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy. 7Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain. 8Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain. 9Institute of Biology and Molecular Genetics, Universidad de Valladolid (IBGM-UVA), Valladolid, Spain. 10Oncogenetics Laboratory, University Hospital Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Institut de Recerca (VHIR), and Universitat Autonoma de Barcelona, Barcelona, Spain. 11Oncology Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 12Molecular Diagnostics Laboratory IRRP, National Centre for Scientific Research Demokritos Aghia Paraskevi Attikis, Athens, Greece. 13Molecular Genetics Laboratory (Department of Biochemistry), Cruces Hospital Barakaldo, Bizkaia, Spain. 14Medical Oncology Service, Hospital Clínico Lozano Blesa, San Juan Bosco, Zaragoza, Spain. 15Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Canada. 16Department of Oncology, Lund University, Lund, Sweden. 17Department of Oncology, Karolinska University Hospital, Stockholm, Sweden. 18Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. 19Department of Oncology, Lund University Hospital, Lund, Sweden. 20Department of Clinical Genetics, Lund University Hospital, Lund, Sweden. 21Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois, United States of America. 22Departments of Medicine, Epidemiology, and Biostatistics, University of California, San Francisco, San Francisco, California, United States of America. 23Abramson Cancer Center and Department of Medicine, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America. 24Abramson Cancer Center and Center for Clinical Epidemiology and Biostatistics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America. 25University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. 26Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America. 27Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, United States of America. 28Department of Health Research & Policy, Stanford University School of Medicine, Stanford, California, United States of America. 29Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America. 30Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Australia. 31Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Victoria, Australia. 32Department of Epidemiology, Columbia University, New York, New York, United States of America. 33Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America. 34Vilnius University Hospital Santariskiu Clinics, Hematology, oncology and transfusion medicine center, Department of Molecular and Regenerative Medicine, Vilnius, Lithuania. 35Department of Genetics, University of Pretoria, Pretoria, South Africa. 36Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, United States of America. 37Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 38Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 39Department of Clinical Genetics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 40Clinical Cancer Genetics, City of Hope, Duarte, California, United States of America. 41Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy. 42Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy. 43IFOM, Fondazione Istituto FIRC di Oncologia Molecolare and Cogentech Cancer Genetic Test Laboratory, Milan, Italy. 44Division of Experimental Oncology 1, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy. 45Unit of Hereditary Cancer, Department of Epidemiology, Prevention and Special Functions, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. 46Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy. 47Department of Molecular Medicine, 'Sapienza' University, Rome, Italy. 48UO Anatomia Patologica, Ospedale di Circolo-Università dell'Insubria, Varese, Italy. 49Unit of Molecular bases of genetic risk and genetic testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy. 50Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. 51Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom. 52South East Thames Regional Genetics Service, Guy's Hospital London, United Kingdom. 53Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, United Kingdom. 54Yorkshire Regional Genetics Service, Leeds, United Kingdom. 55Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, United Kingdom. 56West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, United Kingdom. 57Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom. 58Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom. 59Clinical Genetics Department, St Georges Hospital, University of London, London, United Kingdom. 60Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, United Kingdom. 61Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, United Kingdom. 62Institute of Human Genetics, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom. 63South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, United Kingdom. 64North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom. 65Oxford Regional Genetics Service, Churchill Hospital, Oxford, United Kingdom. 66Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, United Kingdom. 67South West Regional Genetics Service, Bristol, United Kingdom. 68Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St James's Hospital, Dublin, Eire. 69Cheshire & Merseyside Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Liverpool, United Kingdom. 70Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, United States of America. 71Centre of Familial Breast and Ovarian Cancer and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany. 72Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. 73Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany. 74Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 75Institute of Human Genetics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 76Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany. 77Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany. 78Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany. 79Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany. 80Institute of Human Genetics, University of Münster, Münster, Germany. 81Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany. 82Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Berlin, Germany. 83Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Würzburg, Germany. 84Institut Curie, Department of Tumour Biology, Paris, France, Institut Curie, INSERM U830, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 85Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon, France, INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France. 86INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France. 87Center for Medical Genetics, Ghent University, Ghent, Belgium. 88Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, New York, United States of America. 89Prince of Wales Hospital. Sydney, Australia. 90Ohio State University, Columbus Cancer Council, Columbus, Ohio, United States of America. 91Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, Illinois, United States of America. 92Division of Gynecologic Oncology, NorthShore University HealthSystem, Chicago, Illinois, United States of America. 93For Tufts Medical Center, Boston, Massachusetts, United States of America. 94Yale University School of Medicine, New Haven, Connecticut, United States of America. 95Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. 96Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 97Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands. 98Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands. 99Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands. 100University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands. 101Department of Clinical Genetics, Leiden University Medical Center Leiden, Leiden, The Netherlands. 102Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands. 103Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 104Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands. 105Department of Pathology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands. 106Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 107Department of Human Genetics & Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. 108The Hereditary Breast and Ovarian Cancer Research Group, Netherlands Cancer Institute, Amsterdam, The Netherlands. 109Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary. 110Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain. 111Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland. 112Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland, Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland. 113Department of Oncology, Landspitali University Hospital and BMC, Faculty of Medicine, University of Iceland, Reykjavik Iceland. 114Laboratoire de Diagnostic Génétique et Service d'Onco-hématologie, Hopitaux Universitaire de Strasbourg, CHRU Nouvel Hôpital Civil, Strasbourg, France. 115Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. 116Department of Genetics, Portuguese Oncology Institute, Porto, and Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal. 117Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia. 118Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Center, Melbourne, Australia. 119Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America. 120Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America. 121Center for Individualized Medicine, Mayo Clinic, Scottsdale, Arizona, United States of America. 122Center for Translational Cancer Research, Department of Biological Sciences, University of Delaware, Newark, Delaware, United States of America. 123Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 124Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 125Diagnostic Molecular Genetics Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 126Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. 127Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America. 128Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America. 129Clalit National Israeli Cancer Control Center, Haifa, Israel. 130Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, and Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. 131Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada, Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada. 132Ontario Cancer Genetics Network: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. 133Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America. 134Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark. 135Section of Molecular Diagnostics, Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark. 136Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark. 137Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. 138Sheba Medical Center, Tel Aviv, Israel. 139Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Canada. 140Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America. 141Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain, Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain, Genotyping Unit (CeGen), Spanish National Cancer Centre (CNIO), Madrid, Spain., SWE-BRCA, Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, Unión Europea, Cancer Research UK (Reino Unido), United States of Department of Health & Human Services, Canadian Institutes of Health Research, Susan G. Komen Breast Cancer Foundation, Ralph and Marion Falk Medical Research Trust, Research Council (Lituania), University of Kansas. Cancer Center (Estados Unidos), National Institute for Health Research (Reino Unido), Deutsche Krebshilfe, Finlands Akademi (Finlandia), Dutch Cancer Society (Holanda), Dutch Research Council (Holanda), Pink Ribbons Project, Hungarian Scientific Research Fund (Hungría), Canadian Breast Cancer Network, Ministère du Développement économique, de Innovation et de Exportation (Canadá), Westat (Estados Unidos), Department of Obstetrics and Gynecology, Clinicum, Universitat de Barcelona, Human Genetics, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Human genetics, CCA - Oncogenesis, Fundación Mutua Madrileña Automovilista, Fundacion Asociacion Espanola Contra el Cancer (AECC), Instituto de Salud Carlos III - ISCIII, European Union (EU), Cancer Research UK, United States Department of Health & Human Services National Institutes of Health (NIH) - USA, Canadian Institutes of Health Research (CIHR), Research Council of Lithuania, University of Kansas Cancer Center, National Institute for Health Research (NIHR), Academy of Finland, KWF Kankerbestrijding, Netherlands Organization for Scientific Research (NWO), Pink Ribbon grant, Orszagos Tudomanyos Kutatasi Alapprogramok (OTKA), Canadian Breast Cancer Research Alliance-grant, Ministry of Economic Development, Innovation and Export Trade, and Westat, Inc, Rockville, MD
Subjects: Cancer Research, 24 Ciencias de la Vida, DNA Repair, endocrine system diseases, ADN, Càncer d'ovari, Synthetic lethality, BRCA1 Protein/genetics, DNA Glycosylases, 0302 clinical medicine, DNA Glycosylases/genetics, Brjóstakrabbamein, Genotype, Medicine and Health Sciences, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Glicosilasas, INVESTIGATORS, skin and connective tissue diseases, OGG1, Genetics (clinical), Genetics, DAMAGE, Aged, 80 and over, Ovarian Neoplasms, 0303 health sciences, BRCA1 Protein, SINGLE-NUCLEOTIDE POLYMORPHISMS, COMMON VARIANTS, Base excision repair, Middle Aged, BRCA2 Protein, 3. Good health, 030220 oncology & carcinogenesis, NEIL2, Female, Medical Genetics, Research Article, BRCA1, BRCA2, Adult, Risk, Ovarian Neoplasms/genetics, lcsh:QH426-470, Adolescent, DNA repair, education, Single-nucleotide polymorphism, Breast Neoplasms, DNA Repair/genetics, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, OVARIAN-CANCER, 03 medical and health sciences, Polymorphism, Single Nucleotide/genetics, SDG 3 - Good Health and Well-being, Ovarian cancer, Cancer Genetics, BREAST-CANCER, Humans, Genetic Predisposition to Disease, ddc:610, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Aged, BRCA2 Protein/genetics, CONSORTIUM, Biology and Life Sciences, Arfgengi, lcsh:Genetics, DNA glycosylase, Cancer research, 3111 Biomedicine, GENETIC MODIFIERS, Genètica
Abstract: Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p, Author Summary Women harboring a germ-line mutation in the BRCA1 or BRCA2 genes have a high lifetime risk to develop breast and/or ovarian cancer. However, not all carriers develop cancer and high variability exists regarding age of onset of the disease and type of tumor. One of the causes of this variability lies in other genetic factors that modulate the phenotype, the so-called modifier genes. Identification of these genes might have important implications for risk assessment and decision making regarding prevention of the disease. Given that BRCA1 and BRCA2 participate in the repair of DNA double strand breaks, here we have investigated whether variations, Single Nucleotide Polymorphisms (SNPs), in genes participating in other DNA repair pathway may be associated with cancer risk in BRCA carriers. We have selected the Base Excision Repair pathway because BRCA defective cells are extremely sensitive to the inhibition of one of its components, PARP1. Thanks to a large international collaborative effort, we have been able to identify at least two SNPs that are associated with increased cancer risk in BRCA1 and BRCA2 mutation carriers respectively. These findings could have implications not only for risk assessment, but also for treatment of BRCA1/2 mutation carriers with PARP inhibitors.
Published: 2014
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20. Intercomparison of Gafchromic™ films, TL detectors and TL foils for the measurements of skin dose in Interventional Radiology

Author: L. Novák, Françoise Malchair, C. De Angelis, Hannu Järvinen, Jérémie Dabin, A. Negri, Renata Kopeć, S. Haruz Waschitz, J Farah, Željka Knežević, Agnieszka Szumska, Eleftheria Carinou, Marija Majer, Isabelle Clairand, H. Datz, Christelle Huet, Teemu Siiskonen, Filip Vanhavere, Annalisa Trianni, Greek Atomic Energy Commission, PSE-SANTE/SDOS/LDRI, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), National Institute of Health, Radiation and Nuclear Safety Authority [Helsinki] (STUK), Centre Hospitalier Universitaire de Liège (CHU-Liège), Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Assaf Harofeh Medical Center, Partenaires INRAE, and European Commission, ECFundacja na rzecz Nauki Polskiej, FNP
Subjects: Radiation, medicine.diagnostic_test, business.industry, [SDV]Life Sciences [q-bio], Detector, Interventional radiology, Skin dose, radiochromic films, thermoluminescence detectors (TLD), TL foils, skin doses in interventional radiology, 030218 nuclear medicine & medical imaging, Chemistry, 03 medical and health sciences, 0302 clinical medicine, Optics, Quality (physics), 030220 oncology & carcinogenesis, Reference beam, medicine, Calibration, Laser beam quality, Nuclear medicine, business, Instrumentation, Beam (structure)
Abstract: International audience; Several passive solid state dosemeters, such as Gafchromic™ films and thermoluminescence (TL) detectors, are used to estimate and monitor patient skin doses in interventional radiology. To determine the suitability of XR-TypeR Gafchromic™ films and of detectors based on TL materials pellets, chips and foils to measure skin dose, an intercomparison exercise has been organized within European Dosimetry Radiation Group - Working Group 12 "European Medical ALARA Network" (EURADOS WG12). To test response detectors were exposed to X-ray beams of energies and qualities applied clinically. A blind test was also performed to investigate the accuracy of the dose estimate by detectors exposed to unknown doses. We found the response of films to be strongly dependent on beam quality and filtration (increasing by up to 80% with respect to reference beam quality). The response of TL detectors was found to be less dependent on beam quality (less than 25% variation), with TL foils showing less than 10% variation with respect to reference beam quality. To accurately estimate patient skin doses in interventional radiology it is important to choose the quality of the calibration beam to be as close as possible to the quality of beams actually applied in clinical work. © 2014 Elsevier Ltd. All rights reserved.
Published: 2014
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21. Updated EANO guideline on rational molecular testing of gliomas, glioneuronal, and neuronal tumors in adults for targeted therapy selection-Update 1.

Author: van den Bent MJ, Franceschi E, Touat M, French PJ, Idbaih A, Lombardi G, Rudà R, Schweizer L, Capper D, Sanson M, Wesseling P, Weller M, Eoli M, Anghileri E, Bielle F, Euskirchen P, Geurts M, Wen PY, and Preusser M
Subjects: Humans, Adult, Biomarkers, Tumor genetics, Practice Guidelines as Topic standards, Mutation, Glioma genetics, Glioma therapy, Glioma drug therapy, Brain Neoplasms genetics, Brain Neoplasms therapy, Brain Neoplasms drug therapy, Molecular Targeted Therapy methods
Abstract: The standard of care for adult patients with gliomas, glioneuronal, and neuronal tumors consists of combinations of surgery, radiotherapy, and chemotherapy. For many systemic cancers, targeted treatments are a major part of the standard treatment; however, the predictive significance of most of the targets for treatment in systemic cancer is less well-established in central nervous system tumors. In 2023 the European Association for NeuroOncology (EANO) Guideline Committee presented evidence-based recommendations for rational testing of molecular targets for targeted treatments. From all targets reviewed, only testing for BRAF V600E mutations was of proven clinical benefit; despite regulatory approvals for tumor agnostic treatment of NTRK gene fusions and high tumor mutational burden (TMB) for patients with adult brain tumors, the evidence of clinical benefit for adult patients was still limited. This guideline has a modular structure, allowing regular updating of individual sections and adding new ones. The present version (Update 1) presents a review of the rationale of testing for PTEN, H3F3A, MTAP, RET and IDH, and presents an update of the text on TMB high and mismatch repair deficiency. It also presents an overview of the therapeutic yield of routine next-generation sequencing for mutations and fusion detection. The Supplemental File II accompanying this version contains an in-depth review of all targets, whereas, in the main manuscript, the final recommendations of the revised and new targets are presented. Updates will be made on a regular basis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Published: 2025
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22. Computational pathology applied to clinical colorectal cancer cohorts identifies immune and endothelial cell spatial patterns predictive of outcome.

Author: Trahearn N, Sakr C, Banerjee A, Lee SH, Baker AM, Kocher HM, Angerilli V, Morano F, Bergamo F, Maddalena G, Intini R, Cremolini C, Caravagna G, Graham T, Pietrantonio F, Lonardi S, Fassan M, and Sottoriva A
Subjects: Humans, Microsatellite Instability, Endothelial Cells pathology, Endothelial Cells immunology, Biomarkers, Tumor genetics, Female, Male, Aged, Proto-Oncogene Proteins B-raf genetics, Middle Aged, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating pathology, Computational Biology, Mutation, Treatment Outcome, Colorectal Neoplasms pathology, Colorectal Neoplasms genetics, Colorectal Neoplasms immunology, Colorectal Neoplasms mortality, Tumor Microenvironment
Abstract: Colorectal cancer (CRC) is a histologically heterogeneous disease with variable clinical outcome. The role the tumour microenvironment (TME) plays in determining tumour progression is complex and not fully understood. To improve our understanding, it is critical that the TME is studied systematically within clinically annotated patient cohorts with long-term follow-up. Here we studied the TME in three clinical cohorts of metastatic CRC with diverse molecular subtype and treatment history. The MISSONI cohort included cases with microsatellite instability that received immunotherapy (n = 59, 24 months median follow-up). The BRAF cohort included BRAF V600E mutant microsatellite stable (MSS) cancers (n = 141, 24 months median follow-up). The VALENTINO cohort included RAS/RAF WT MSS cases who received chemotherapy and anti-EGFR therapy (n = 175, 32 months median follow-up). Using a Deep learning cell classifier, trained upon >38,000 pathologist annotations, to detect eight cell types within H&E-stained sections of CRC, we quantified the spatial tissue organisation and colocalisation of cell types across these cohorts. We found that the ratio of infiltrating endothelial cells to cancer cells, a possible marker of vascular invasion, was an independent predictor of progression-free survival (PFS) in the BRAF+MISSONI cohort (p = 0.033, HR = 1.44, CI = 1.029-2.01). In the VALENTINO cohort, this pattern was also an independent PFS predictor in TP53 mutant patients (p = 0.009, HR = 0.59, CI = 0.40-0.88). Tumour-infiltrating lymphocytes were an independent predictor of PFS in BRAF+MISSONI (p = 0.016, HR = 0.36, CI = 0.153-0.83). Elevated tumour-infiltrating macrophages were predictive of improved PFS in the MISSONI cohort (p = 0.031). We validated our cell classification using highly multiplexed immunofluorescence for 17 markers applied to the same sections that were analysed by the classifier (n = 26 cases). These findings uncovered important microenvironmental factors that underpin treatment response across and within CRC molecular subtypes, while providing an atlas of the distribution of 180 million cells in 375 clinically annotated CRC patients. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)
Published: 2025
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23. Safety and Efficacy of 177 Lu-PSMA Therapy Following 223 Radium Treatment: A Retrospective Multinational Real-World Analysis.

Author: Giannini G, Kafka M, Neuwirt H, Artamonova N, Santo GD, Virgolini I, Dotzauer R, Deiss E, Paffenholz P, Heidenreich A, Rasul S, Tsaur I, Rausch S, Einspieler H, la Fougère C, Trautwein NF, Zattoni F, Sepulcri M, and Heidegger I
Subjects: Humans, Male, Retrospective Studies, Aged, Middle Aged, Treatment Outcome, Aged, 80 and over, Radioisotopes therapeutic use, Radioisotopes adverse effects, Radioisotopes administration & dosage, Radiopharmaceuticals therapeutic use, Radiopharmaceuticals adverse effects, Radiopharmaceuticals administration & dosage, Prostate-Specific Antigen blood, Europe, Prostatic Neoplasms, Castration-Resistant radiotherapy, Prostatic Neoplasms, Castration-Resistant pathology, Prostatic Neoplasms, Castration-Resistant mortality, Lutetium therapeutic use, Lutetium adverse effects, Radium therapeutic use, Radium adverse effects
Abstract: Background: 177 Lu PSMA therapy is increasingly used for metastatic castration-resistant prostate cancer (mCRPC) treatment. However, data on its efficacy and safety in patients previously treated with 223 Ra remain limited., Methods: This retrospective, multicenter study evaluated 233 mCRPC patients treated with 177 Lu PSMA at 5 European centers. The cohort included 27 patients previously treated with 223 Ra and 206 Radium-naive patients. Statistical analyses, including Chi-squared, Mann-Whitney U tests, and multivariate logistic regression, were used to assess response and mortality. Predictors of response and mortality were identified using multivariate models., Results: Patients who experienced a longer interval between castration resistance and the initiation of 177 Lu PSMA therapy demonstrated better responses (median 17 months in responders vs. 8.5 months in progressors, P = .001). Platelet counts were significantly lower in the progressive group compared to the responsive group (P = .01). Multivariate regression confirmed lower platelet levels as a predictor of poor response (P = .029). The overall response rate to 177 Lu PSMA was 54%, similar between the 223 Ra-pretreated and Radium-naive groups. However, mortality was significantly higher in the 223 Ra-pretreated group (86%) compared to the Radium-naive group (51%, P = .003). ECOG performance status (P = .004) and ALP levels (P = .030) were significant predictors of mortality, while CRP showed a trend towards significance (P = .064). Tolerability of 177 Lu PSMA was comparable to the safety profile reported in the literature, with 44% of 223 Ra-pretreated patients experiencing AEs and 22% experiencing severe AEs (Grade ≥ 3)., Conclusions: 177 Lu PSMA therapy is effective and well-tolerated in mCRPC patients pretreated with 223 Ra. However, higher mortality was observed in the 223 Ra-pretreated group. ECOG PS, ALP, and platelet counts were significant predictors of response and mortality, and a longer interval between therapies was associated with better outcomes. These findings underscore the importance of treatment sequencing and monitoring prognostic markers., Competing Interests: Disclosure There are no disclosures to provide., (Copyright © 2024. Published by Elsevier Inc.)
Published: 2025
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24. Emerging therapeutic strategies in Lynch syndrome-associated colorectal cancer and the role of MMR testing.

Author: Negro S, Perissinotto E, Mammi I, Crivellari G, Schiavi F, Cappello F, Spolverato G, Ferrari D, Rausa E, Vitellaro M, Fassan M, Cavestro GM, Mannucci A, Lonardi S, Bergamo F, and Urso EDL
Abstract: Lynch syndrome is the most common hereditary cancer predisposition, accounting for 1-5% of colorectal cancer cases, and is driven by germline mutations in DNA mismatch repair genes. Despite established diagnostic criteria, such as the Amsterdam guidelines, Lynch syndrome remains largely underdiagnosed. To address this gap, universal tumour screening has been introduced for all newly diagnosed cases of colorectal cancer and endometrial cancer, significantly improving early detection. The surgical management of colorectal cancer in patients with Lynch syndrome remains controversial. While extended colectomy reduces the risk of metachronous colorectal cancer, surgical strategies must be carefully individualised based on patient-specific factors. Chemoprevention with aspirin has shown promise in reducing the risk of colorectal cancer, with ongoing trials investigating optimal dosing. Immunotherapy, particularly immune checkpoint inhibitors, has revolutionised the treatment of Microsatellite Instability-High/deficient Mismatch Repair colorectal cancer, offering durable responses and significant survival benefits. In addition, the neoadjuvant use of immune checkpoint inhibitors is paving the way for non-surgical interventions, potentially transforming the management of colorectal cancer in patients with Lynch syndrome. A multidisciplinary approach and continued research are essential to optimise cancer prevention, treatment and quality of life for people with Lynch syndrome., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Published: 2025
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25. Local ablation disrupts immune evasion in pancreatic cancer.

Author: Musiu C, Adamo A, Caligola S, Agostini A, Frusteri C, Lupo F, Boschi F, Busato A, Poffe O, Anselmi C, Vella A, Wang T, Dusi S, Piro G, Carbone C, Tortora G, Marzola P, D'Onofrio M, Crinò SF, Corbo V, Scarpa A, Salvia R, Malleo G, Lionetto G, Sartoris S, Ugel S, Bassi C, Bronte V, Paiella S, and De Sanctis F
Subjects: Animals, Humans, Mice, Cell Line, Tumor, Tumor Escape, Immunotherapy methods, Mice, Inbred C57BL, Pancreatic Neoplasms immunology, Pancreatic Neoplasms pathology, Tumor Microenvironment immunology, HMGB1 Protein metabolism
Abstract: Background: Pancreatic cancer (PC) is characterised by late diagnosis, tumour heterogeneity, and a peculiar immunosuppressive microenvironment, leading to poor clinical outcomes. Local ablative techniques have been proposed to treat unresectable PC patients, although their impact on activating the host immune system and overcoming resistance to immunotherapy remains elusive., Methods: We dissected the immune-modulatory abilities triggered by local ablation in mouse and human PC models and human specimens, integrating phenotypic and molecular technologies with functional assays., Results: Local ablation treatment performed in mice bearing orthotopic syngeneic PC tumours triggered tumour necrosis and a short-term inflammatory process characterised by the prompt increase of HMGB1 plasma levels, coupled with an enhanced amount of circulating and tumour infiltrating myeloid cells and increased MHCII expression in splenic myeloid antigen-presenting cells. Local ablation synergised with immunotherapy to restrict tumour progression and improved the survival of PC-bearing mice by evoking a T lymphocyte-dependent anti-tumour immune response. By integrating spatial transcriptomics with histological techniques, we pinpointed how combination therapy could reshape TME towards an anti-tumour milieu characterised by the preferential entrance and colocalization of activated T lymphocytes and myeloid cells endowed with antigen presentation features instead of T regulatory lymphocytes and CD206-expressing tumour-associated macrophages. In addition, treatment-dependent TME repolarization extended to neoplastic cells, promoting a shift from squamous to a more differentiated classical phenotype. Finally, we validated the immune regulatory properties induced by local ablation in PC patients and identified an association of the short-term treatment-dependent increase of neutrophils, NLR and HMGB1 with a longer time to progression., Conclusion: Therefore, local ablation might overcome the current limitations of immunotherapy in PC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: VB reports personal fees from Codiak BioSciences and IO Biotech ApS outside of the submitted work. SP receives consultancy honoraria from AlphaTau Medical. The other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Published: 2025
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26. Atezolizumab plus bevacizumab as first-line treatment of unresectable hepatocellular carcinoma: interim analysis results from the phase IIIb AMETHISTA trial.

Author: Piscaglia F, Masi G, Martinelli E, Cabibbo G, Di Maio M, Gasbarrini A, Iavarone M, Antonuzzo L, Mazzaferro V, Ballestrero A, Garufi C, Bergamo F, Celsa C, Marino D, Tovoli F, Ponziani FR, Pressiani T, Astolfi C, Gazzoli GC, Ciardiello F, Daniele B, and Rimassa L
Abstract: Background: The treatment of advanced hepatocellular carcinoma (HCC) with atezolizumab and bevacizumab led to significant improvements in overall survival (OS), progression-free survival (PFS), and response rate compared with sorafenib in the phase III IMbrave150 trial. The etiology of background liver disease can differ between Eastern and Western populations, leading to a potentially different impact of systemic therapies; therefore the unequal representation must be considered in the IMbrave150 trial. To provide further data on the safety and effectiveness of atezolizumab and bevacizumab, the phase IIIb AMETHISTA (Atezolizumab plus bevacizumab in METastatic HCC Italian Safety TriAl) ran in a Western (Italian) population of patients with advanced HCC. The results of the interim analysis are presented in this paper., Methods: AMETHISTA is a multicenter, phase IIIb, single-arm study evaluating the safety and effectiveness of atezolizumab and bevacizumab in an Italian population of patients with systemic treatment-naive HCC (ClinicalTrials.gov: NCT04487067). The primary objective was safety (incidence of grade 3-5 bleeding/hemorrhages). The main secondary objective was effectiveness., Results: A total of 152 patients were enrolled and 149 were treated. At the cut-off date, the median observation time was 13.4 months (interquartile range 8.3-15.5 months). The incidence of grade 3-5 bleeding/hemorrhages was 11.4%. Besides, results of other safety endpoints were consistent with the safety profile of atezolizumab plus bevacizumab, and the underlying disease, without any new safety observation. The median OS was 18.2 months (95% confidence interval 15.4 months to not evaluable); the median PFS was 8.5 months (95% confidence interval 7.5-11.2 months)., Conclusion: Results from the interim analysis are consistent with data from the IMbrave150 trial, and further confirm first-line atezolizumab plus bevacizumab as a standard of care for patients with systemic treatment-naive advanced and unresectable HCC., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Published: 2025
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27. Impact of Pre-Treatment Comorbidity Burden on Survival in Patients Receiving Venetoclax Plus Hypomethylating Agents.

Author: Marconi G, Petracci E, Lanzarone G, Vetro C, Martelli MP, Papayannidis C, Audisio E, Minetto P, Riva C, Guolo F, Martini G, Zappasodi P, Vincenzo F, Gigli F, Griguolo D, Rondoni M, Ciotti G, Borlenghi E, Ciccone N, Palumbo FE, Nanni J, Mattei D, Bernardi M, Cignetti A, Zingaretti C, Vertogen B, Cerchione C, Lanza F, Cilloni D, Brunetti L, Palmieri R, Curti A, Giannini MB, Todisco E, Fracchiolla N, and Martinelli G
Abstract: Expectation of survival of patients receiving HMA + VEN is influenced by pre-treatment comorbidity burden., (© 2025 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)
Published: 2025
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28. Multi-institutional Knowledge-Based (KB) plan prediction benchmark models for whole breast irradiation.

Author: Tudda A, Castriconi R, Placidi L, Benecchi G, Buono RC, Cagni E, Cicchetti A, Landoni V, Malatesta T, Mazzilli A, Meffe G, Moretti E, Mori M, Oliviero C, Guidasci GR, Scaggion A, Trojani V, Vecchio AD, and Fiorino C
Abstract: Purpose: To train and validate KB prediction models by merging a large multi-institutional cohort of whole breast irradiation (WBI) plans using tangential fields., Methods: Ten institutions (INST1-INST10, 1481 patients) developed their KB-institutional models for left/right WBI (ten models for right and eight models for left). The transferability of models among centers was assessed based on the overlap of the geometric Principal Component (PC1) of each model when applied to other institutions and/or on the presence of significantly different optimization policies. Centers corresponding to transferable models were asked to join the building of two KB-benchmark models for right/left breast. Dose-volume histogram (DVH) prediction bands (lung/heart) were compared against those of the KB-institutional models., Results: All models were transferable except INST6 (right breast) and INST1 (left breast). Planning data from 6 institutions for right breast and 5 institutions for left breast (out of 9 and 7 institutions with transferable models, respectively) were combined, totaling data from 850 patients. Prediction bands on the test cohorts (n = 30/25 right/left) showed a large overlap with bands of each institution model: for the right-breast, the KB-benchmark model predicts slightly lower lung D mean when compared to KB-institution models, except for INST7. Regarding the left-breast, even greater similarity between KB-benchmark and KB-institution model predictions was found., Conclusions: Multi-institutional KB-benchmark models for WBI were successfully generated. They may be employed by other users, representing the performances reached in a multi-institutional context of experienced centers. KB-benchmark models can also have significant applications for large-scale automatic plan optimization, QA/audit and tutoring/education purposes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)
Published: 2025
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29. Current insights on PSMA PET/CT in intermediate-risk prostate cancer: a literature review.

Author: Guglielmo P, Buffi N, Porreca A, Setti L, Aricò D, Muraglia L, and Evangelista L
Abstract: The purpose of this systematic review was to evaluate the role of PSMA PET/CT in intermediate-risk prostate cancer (PCa) patients, to determine whether it could help improve treatment strategy and prognostic stratification. A systematic literature search up to May 2024 was conducted in the PubMed, Embase and Scopus databases. Articles with mixed risk patient populations, review articles, editorials, letters, comments, or case reports were excluded. The quality of the papers was assessed by using the CASP criteria. The literature search returned 1111 studies; however, 1105 articles were excluded, and therefore 6 full-text papers were retrieved for the final analysis. Three out of six papers focused on the utility of SUVmax in identifying high ISUP grade in patients with intermediate-risk PCa. The latest three papers discussed the controversial role of PSMA PET/CT in predicting the lymph node involvement, mainly in the case of favorable subset. PSMA PET has completely changed the management of patients with PCa; indeed its role is still undefined in patients with intermediate-risk disease. Future perspective is to investigate larger cohorts of intermediate-risk PCa patients, to fully recognize the added value offered by PSMA PET in this category of subjects., (© 2025. The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)
Published: 2025
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30. Prognostic impact of depth of response and early tumour shrinkage in patients with BRAF V600E -mutated metastatic colorectal cancer treated with targeted therapy.

Author: Vetere G, Germani MM, Antoniotti C, Salvatore L, Pietrantonio F, Lonardi S, Bensi M, Ghelardi F, Calegari MA, Intini R, Minelli A, Sullo FG, Boccaccio C, Taravella A, Puccini A, Lavacchi D, Noto L, Salati M, Scartozzi M, and Cremolini C
Abstract: Background: Encorafenib plus cetuximab (EC) is the standard of care for pre-treated BRAF mutated metastatic colorectal cancer (mCRC). Depth of response (DpR) and early tumour shrinkage (ETS) previously showed a strong correlation with survival outcomes of first-line chemotherapy ± biological agents. V600E mutated metastatic colorectal cancer (mCRC). Depth of response (DpR) and early tumour shrinkage (ETS) previously showed a strong correlation with survival outcomes of first-line chemotherapy ± biological agents., Objectives: We aimed to assess potential predictors of primary resistance to EC ± binimetinib (B) and relationships of DpR/ETS with survival outcomes and clinical characteristics., Design: This is a retrospective real-world cohort study of BRAF V600E mutated mCRC patients treated with second-line EC ± B at 20 Italian centres., Methods: Measurable disease according to Response Evaluation Criteria In Solid Tumour (RECIST) 1.1 at baseline and at least one subsequent computed tomography (CT) scan were mandatory for inclusion. Clinical features associated with primary resistance, DpR and ETS were investigated. Relationships of DpR and ETS, both as binary, according to conventional (30% for DpR and 20% for ETS) and median cut-off values, and continuous variables, with progression-free (PFS), overall survival (OS) and duration of response (DoR) were assessed in non-primary resistant patients., Results: A total of 105 patients were included. The primary resistance rate was 28% (29/105) and was associated with baseline peritoneal metastases ( p = 0.04). Disease control and overall response rates were 72% (76/105) and 24% (25/105), respectively, with a median DpR of 15% and an ETS rate of 37% (28/76). Mucinous histology was associated with a significantly lower magnitude of DpR ( p = 0.005) and a lower rate of ETS ( p = 0.002). In the multivariable models, DpR significantly correlated with longer PFS as a dichotomous variable, according both to conventional (hazard ratio (HR) DpR ⩾ 30% : 0.52, 95% CI: 0.30-0.90, p = 0.02) and median cut-off values (HR DpR⩾15% : 0.55, 95% CI: 0.33-0.92, p = 0.03), and as a continuous variable (HR per 10% increment: 0.88, 95% CI: 0.78-0.98, p = 0.02), while correlations with OS were not confirmed. DpR was also significantly associated with longer DoR ( p DpR⩾30% = 0.02), whereas no relationships of ETS with PFS, OS or DoR were detected.p DpR⩾15% = 0.04; p cont. = 0.02), whereas no relationships of ETS with PFS, OS or DoR were detected., Conclusion: A DpR of at least 15% independently predicts PFS benefit in BRAF V600E mutated mCRC patients treated with second-line EC ± B., Competing Interests: L. S. reported current support by the Associazione Italiana per la Ricerca sul Cancro (AIRC) under My First Grant (MFAG) No. MFAG27367 and consulting or advisory role for Pierre-Fabre, AstraZeneca, Bayer, SERVIER, Merck, Amgen, GSK, Incyte, Leopharma, MSD, Takeda. F. P. reported institutional research grants from BMS, Incyte, Agenus, Amgen, Lilly and AstraZeneca, and personal fees from BMS, MSD, Amgen, Merck-Serono, Pierre-Fabre, Servier, Bayer, Takeda, Astellas, Johnson&Johnson, Rottapharm, Ipsen, AstraZeneca, GSK, Daiichi-Sankyo, Seagen/Pfizer, Beigene. S. L. reported consulting or advisory roles for Amgen, Merck Serono, Eli Lilly, AstraZeneca, Incyte, Daiichi-Sankyo, Bristol Myers Squibb, Servier, Merck Sharp & Dohme, Astellas, and Takeda; is on the speakers’ bureau for Roche, Eli Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, and Amgen; research funding from Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, and Bristol-Myers Squibb. L. N. reported advisory board/honoraria from Astra-Zeneca, Pierre-Fabre, Bayer and travel grants from Astra-Zeneca, MSD. C. C. reported honoraria from Amgen, Bayer, Merck, Merck, MSD, Pierre Fabre, Roche, and Servier; consulting or advisory roles for Amgen, Bayer, MSD, Nordic Bioscience, Pierre Fabre, and Roche; is on the speakers’ bureau for Merck, Pierre Fabre, Servier; research funding from Bayer, Merck, Roche, and Servier. All other authors have declared no conflicts of interest., (© The Author(s), 2025.)
Published: 2025
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31. Early treatment discontinuation in patients with deficient mismatch repair or microsatellite instability high metastatic colorectal cancer receiving immune checkpoint inhibitors.

Author: Taieb J, Ambrosini M, Alouani E, Lonardi S, Sinicrope FA, Decraecker M, Boileve A, Hafliger E, Mazard T, Pernot S, Parent P, Ros J, Overman MJ, Jayachandran P, Nasca V, Salvatore L, Guimbaud R, Cremolini C, Tougeron D, and Pietrantonio F
Subjects: Humans, Male, Female, Middle Aged, Aged, Adult, Neoplasm Metastasis, Aged, 80 and over, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Immune Checkpoint Inhibitors therapeutic use, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors adverse effects, Microsatellite Instability, DNA Mismatch Repair
Abstract: Background: Immune checkpoint inhibitors (ICIs) are recommended to treat patients with deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) metastatic colorectal cancer (mCRC). Pivotal trials have fixed a maximum ICI duration of 2 years, without a compelling rationale. A shorter treatment duration has the potential to improve patients' quality of life and reduce both toxicity and cost without compromising efficacy. Here we examine whether early treatment discontinuation (ETD) before 13 months in patients without progressive disease (PD) can lead to similar long-term disease control compared with a longer treatment duration (LTD)., Methods: To assess whether ETD is associated with similar outcomes compared with LTD, we assembled an international cohort of patients with dMMR/MSI-H mCRC treated with ICIs who stopped treatment for a reason other than PD within 395 days (ETD group) and compared them to those who continued for >395 days (LTD group). Outcomes were adjusted for patient/tumor characteristics. Primary endpoint was progression-free survival (PFS) and secondary endpoints were objective response rate (ORR), overall survival (OS) and safety., Results: Of 976 patients, 137 and 394 were allocated to the ETD and LTD groups, respectively. In the ETD group, treatment was discontinued due to toxicity (n=56), objective response (n=43), surgery (n=28), patient decision (n=2) or other reasons (n=8). Baseline characteristics were well balanced between the two groups: 22% in both groups received both anti-programmed death-(ligand) 1 (anti-PD-(L)1) + anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4); all others received anti-PD-(L)1 monotherapy. ORR to ICIs was 81% in both groups. Median duration of treatment was ~7 months in the ETD and ~24 months in the LTD group. After a median follow-up of 44 months (IQR: 30-67), similar PFS (HR: 0.92, 95% CI: 0.60 to 1.40, p=0.69) and OS (HR: 1.15, 95% CI: 0.66 to 1.99, p=0.62) from the start of ICIs were observed in ETD and LTD patients. In the ETD group, 28 (20%) patients had a PFS event and 9 restarted ICIs with a disease control rate of 66%., Conclusions: In our international series of dMMR/MSI-H mCRC, ETD of ICIs in the absence of PD did not seem detrimental in terms of PFS and OS compared with continuing treatment beyond 1 year. Randomized clinical trials to compare short and long treatment duration are now warranted., Competing Interests: Competing interests: JT declares personal fees for advisory and speaker roles from Astellas, Amgen, BMS, MSD, Merck-Serono, Pierre-Fabre, Servier, Takeda, ONO pharmaceuticals, Rottapharm, Novartis, and Boehringer. EA reports consultancy fees and honoraria from Servier, AMGEN, MSD, and Merck Serono. SL declares personal fees as a speaker from Amgen, Astra Zeneca, Bristol-Myers Squibb, Incyte, GSK, Lilly, Merck Serono, MSD, Pierre-Fabre, Roche, and Servier, has participated on advisory boards for Amgen, Astellas, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, GSK, Incyte, Lilly, Merck Serono, MSD, Servier, Takeda, Rottapharm, and Beigene, and has received institutional research funding from Amgen, Astellas, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche, and Servier. FAS declares consulting fees from Hoffman LaRoche and Guardant Health. FAS has a copatent with the Mayo Foundation for Medical Education and Research and Ventana Medical Systems, Inc. (US20210373024A1). AB declares financial interests from Merck Serono, Ipsen, Pfizer. TM has received honoraria for speaking or consulting roles from Servier, Pierre Fabre, Merck Serono, Galapagos, and MSD, and research grants from Amgen. He has also received travel grants from Pierre Fabre and Merck Serono. SP reports consultancy and honoraria from Servier, Sanofi, Bayer, Amgen, Merck, Pierre Fabre, Astrazeneca, MSD, BMS, Takeda. JR declares personal financial interests in the form of speaking/travel grants or accommodation from Amgen, Merck, Pierre-Fabre, Servier, and Sanofi. MJO declares research funding from Takeda, Roche, Lilly, Merck, Medimmune, BMS, Nouscom, and Phanes, and consulting fees from Roche, Astellas, Medimmune, Merck, Amgen, Takeda, Janssen, Pfizer, Array, Gritstone, Simcere, Atreca, and Bayer. LS is currently supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) under My First Grant (MFAG) No. MFAG27367 and declares personal fees for advisory and speaker roles from Pierre-Fabre, AstraZeneca, Bayer, SERVIER, Merck, Amgen, GSK, Incyte, Leopharma, MSD, and Takeda. CC declares personal fees for advisory board or consultant roles with Astra Zeneca, Merck Serono, MSD, Nordic Pharma, Roche, Pierre Fabre, Takeda, and Tempus, invited speaker role for Amgen, Bayer, Merck Serono, MSD, Pierre Fabre Servier, and Takeda and research grants from Amgen, Merck, Pierre Fabre, Roche, Seagen (Pfizer), Servier, and Tempus. DT declares personal fees for advisory and speaker roles from Amgen, Roche, Merck Serono, MSD, BMS, Pierre Fabre, Servier, Takeda, and Astra Zeneca. FP reports receiving institutional research grants from BMS, Incyte, Agenus, Amgen, Lilly, and AstraZeneca, and personal fees from BMS, MSD, Amgen, Merck-Serono, Pierre-Fabre, Servier, Bayer, Takeda, Astellas, Johnson & Johnson, Rottapharm, Ipsen, AstraZeneca, GSK, Daiichi-Sankyo, Seagen/Pfizer, and Beigene. MA, MD, EH, PP, PJ, VN, RG declare no competing interests., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)
Published: 2025
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32. Stemness and hybrid epithelial-mesenchymal profiles guide peritoneal dissemination of malignant mesothelioma and pseudomyxoma peritonei.

Author: Lazzari N, Rigotto G, Montini B, Del Bianco P, Moretto E, Palladino F, Cappellesso R, Tonello M, Cenzi C, Scapinello A, Piano MA, Rossi CR, Dalerba P, Pilati P, Sommariva A, and Calabrò ML
Subjects: Humans, Male, Female, Middle Aged, Aged, Aldehyde Dehydrogenase 1 Family metabolism, Aldehyde Dehydrogenase 1 Family genetics, Mesothelioma pathology, Mesothelioma genetics, Prognosis, Lung Neoplasms pathology, Lung Neoplasms genetics, Hyperthermic Intraperitoneal Chemotherapy, Tumor Cells, Cultured, Retinal Dehydrogenase metabolism, Retinal Dehydrogenase genetics, Adult, Peritoneal Neoplasms secondary, Peritoneal Neoplasms pathology, Epithelial-Mesenchymal Transition, Neoplastic Stem Cells pathology, Neoplastic Stem Cells metabolism, Mesothelioma, Malignant pathology, Pseudomyxoma Peritonei pathology, Pseudomyxoma Peritonei metabolism
Abstract: Intrabdominal dissemination of malignant mesothelioma (MM) and pseudomyxoma peritonei (PMP) is poorly characterized with respect to the stemness window which malignant cells activate during their reshaping on the epithelial-mesenchymal (E/M) axis. To gain insights into stemness properties and their prognostic significance in these rarer forms of peritoneal metastases (PM), primary tumor cultures from 55 patients selected for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy were analyzed for cancer stem cells (CSC) by aldehyde dehydrogenase 1 (ALDH1) and spheroid formation assays, and for expression of a set of plasticity-related genes to measure E/M transition (EMT) score. Intratumor heterogeneity was also analyzed. Samples from PM of colorectal cancer were included for comparison. Molecular data were confirmed using principal component and cluster analyses. Associations with survival were evaluated using Kaplan-Meier and Cox regression models. The activity of acetylsalicylic acid (ASA), a stemness modifier, was tested in five cultures. Significantly increased amounts of ALDH1 bright -cells identified high-grade PMP, and discriminated solid masses from ascitic/mucin-embedded tumor cells in both forms of PM. Epithelial/early hybrid EMT scores and an early hybrid expression pattern correlated with pluripotency factors were significantly associated with early peritoneal progression (p = .0343 and p = .0339, respectively, log-rank test) in multivariable models. ASA impaired spheroid formation and increased cisplatin sensitivity in all five cultures. These data suggest that CSC subpopulations and hybrid E/M states may guide peritoneal spread of MM and PMP. Stemness could be exploited as targetable vulnerability to increase chemosensitivity and improve patient outcomes. Additional research is needed to confirm these preliminary data., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
Published: 2025
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33. Perfusion Instability During Hyperthermic Intraperitoneal Chemotherapy: The Utility of a Problem-solving Flowchart.

Author: Soligo C, Cenzi C, Foscaro F, Bordignon B, Savi S, Perdonò P, Munaretto G, Visentin F, Tarantino T, Cerato A, Pilati P, Cabianca R, and Sommariva A
Subjects: Humans, Female, Middle Aged, Male, Aged, Adult, Retrospective Studies, Cytoreduction Surgical Procedures methods, Peritoneal Neoplasms therapy, Peritoneal Neoplasms drug therapy, Perfusion methods, Combined Modality Therapy, Hyperthermic Intraperitoneal Chemotherapy methods
Abstract: Background/aim: During hyperthermic intra-peritoneal chemotherapy (HIPEC), perfusion instability (PI) is defined as the inability to maintain a proper perfusion flow without impairment of the target temperature. The management and resolution of this adverse event is underreported and poorly investigated. The study aimed to evaluate the incidence of PI during closed cytoreductive surgery (CRS)-HIPEC and how a problem-solving approach might limit the effects of this adverse event., Patients and Methods: A retrospective analysis of patients who underwent CRS-HIPEC at our Institution was performed. PI was defined when the patient's outflow pressure of the circuit was not able to maintain target flow and temperature (1,100 ml/min and 41°C). A step-by-step problem-solving flowchart, which included checking the drain position, proper muscle relaxation, changing the bed position, adjusting the perfusion volume and switching the drain flow switch, was used., Results: A total of 208 HIPEC procedures were reviewed between May 2018 and January 2023. PI occurred in 21 cases (10.1%). Patients with PI had a significantly longer perfusion time (p<0.001). Although the mean outflow pressure and flow rate were significantly lower in patients with PI (p<0.001), the target temperature was maintained until the end of HIPEC., Conclusion: A scheduled problem-solving approach by HIPEC perfusionist team was able to resolve most cases of PI. Further research on perfusion technical details and volume calculation is needed to prevent and limit the effects of this complication., (Copyright © 2025, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
Published: 2025
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34. Medullary carcinomas of the nonampullary small intestine: association with coeliac disease, mismatch repair deficiency, PD-L1 expression, and favourable prognosis.

Author: Vanoli A, Grillo F, De Lisi G, Guerini C, Arpa G, Klersy C, Fassan M, Parente P, Mastracci L, Biletta E, Nesi G, Macciomei MC, Lenti MV, Quaquarini E, Chiaravalli AM, Furlan D, La Rosa S, Paulli M, and Di Sabatino A
Subjects: Humans, Female, Male, Aged, Middle Aged, Prognosis, Adult, Intestine, Small pathology, Intestine, Small metabolism, DNA Mismatch Repair, Aged, 80 and over, Neoplastic Syndromes, Hereditary pathology, Immunohistochemistry, Adenocarcinoma pathology, Adenocarcinoma metabolism, Adenocarcinoma genetics, Brain Neoplasms, Colorectal Neoplasms, B7-H1 Antigen metabolism, Celiac Disease pathology, Celiac Disease complications, Celiac Disease metabolism, Intestinal Neoplasms pathology, Intestinal Neoplasms metabolism, Biomarkers, Tumor analysis, Biomarkers, Tumor metabolism, Biomarkers, Tumor genetics, Carcinoma, Medullary pathology, Carcinoma, Medullary metabolism, Carcinoma, Medullary genetics
Abstract: Aim: Gastrointestinal medullary carcinoma is a rare histologic subtype of adenocarcinoma. As nonampullary small bowel medullary carcinomas (SB-MCs) are poorly characterized, we aimed to analyse their clinicopathologic and immunohistochemical features and to compare them with nonmedullary small bowel adenocarcinomas (NM-SBAs)., Methods and Results: Surgically resected SBAs collected through the Small Bowel Cancer Italian Consortium were classified as SB-MCs (carcinomas with ≥50% of tumour fulfilling the typical histologic criteria of MC) or NM-SBAs. Immunohistochemistry for cytokeratin (CK)7, CK20, CDX2, programmed death-ligand 1 (PD-L1) and mismatch repair proteins was performed in both SB-MCs and NM-SBAs. SB-MCs were also tested for CK8/18, synaptophysin, SMARCB1, SMARCA2, SMARCA4, and ARID1A and for Epstein-Barr virus (EBV)-encoded RNAs by in-situ hybridization. MLH1 promoter methylation status was evaluated in MLH1-deficient cases. Eleven SB-MCs and 149 NM-SBAs were identified. One (9%) SB-MC was EBV-positive, while 10 (91%) harboured mismatch repair deficiency (dMMR). MLH1 promoter hypermethylation was found in all eight dMMR SB-MCs tested. Switch/sucrose nonfermentable deficiency was seen in two (18%) SB-MCs, both with isolated loss of ARID1A. Compared with NM-SBAs, SB-MCs exhibited an association with coeliac disease (P < 0.001), higher rates of dMMR (P < 0.001), and PD-L1 positivity by both tumour proportion score and combined positive score (P < 0.001 for both), and a lower rate of CK20 expression (P = 0.024). Survival analysis revealed a better prognosis of SB-MC patients compared to NM-SBA cases (P = 0.02)., Conclusion: SB-MCs represent a distinct histologic subtype, with peculiar features compared to NM-SBAs, including association with coeliac disease, dMMR, PD-L1 expression, and better prognosis., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)
Published: 2025
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35. Corrigendum to "PARP inhibitors in gliomas: Mechanisms of action, current trends and future perspectives" [Cancer Treat. Rev. 131 (2024) 102850].

Author: Cella E, Bosio A, Persico P, Caccese M, Padovan M, Losurdo A, Maccari M, Cerretti G, Ius T, Minniti G, Idbaih A, Sanai N, Weller M, Preusser M, Simonelli M, and Lombardi G
Published: 2025
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36. Critical role of protein kinase CK2 in chronic myeloid leukemia cells harboring the T315I BCR::ABL1 mutation.

Author: Quezada Meza CP, Salizzato V, Calistri E, Basso M, Zavatti M, Marmiroli S, Salvi M, Carter BZ, Donella-Deana A, Borgo C, and Ruzzene M
Subjects: Humans, Protein Kinase Inhibitors pharmacology, Cell Proliferation drug effects, Drug Resistance, Neoplasm genetics, Cell Line, Tumor, Signal Transduction, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Casein Kinase II genetics, Casein Kinase II metabolism, Casein Kinase II antagonists & inhibitors, Fusion Proteins, bcr-abl genetics, Fusion Proteins, bcr-abl metabolism, Mutation, Apoptosis drug effects, Apoptosis genetics
Abstract: Chronic myeloid leukemia (CML) is characterized by the fusion protein BCR::ABL1, a constitutively active tyrosine kinase. The frontline treatment, represented by tyrosine kinase inhibitors (TKIs), has dramatically improved the clinical outcomes of patients. However, TKI resistance through various mechanisms has been reported. In particular, the BCR::ABL11 T315I mutation is associated with resistance to first- and second-generation TKIs and poor survival outcomes. For patients harboring this mutation, treatments with third generation TKIs are indicated, which are however accompanied by adverse events. Protein kinase CK2 is implicated in several human diseases. Although its role in CML has already been proven, its essentialness in T315I-mediated TKI resistance has yet to be investigated. Here we show that CK2 contributes to the aberrantly high signaling pathways in T315I-cells, and that its pharmacological or genetic targeting diminishes those signals, induces apoptosis, and reduces the proliferation and clonogenic potential of T315I-cells. The effects of CK2 inhibition are also observed in the presence of bone marrow stromal cells and under hypoxic conditions, and, remarkably, in patient-derived cells. Moreover, CK2 inhibition or genetic ablation of the CK2α catalytic subunit sensitizes T315I-cells towards TKIs. Collectively, our results suggest the potential benefit of inhibiting CK2 in CML characterized by T315I-dependent resistance., Competing Interests: Declaration of competing interest The authors have nothing to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Published: 2025
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37. Real-world multicentre observational study of effectiveness and toxicity in patients with advanced cutaneous squamous cell carcinoma treated with cemiplimab.

Author: Faoro L, Salizzato V, Coppola M, Carpanese D, Fabozzi A, Tondulli L, Marconcini R, Spagnolo F, Del Bianco P, Chiarion-Sileni V, and Piccin L
Published: 2025
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38. Perception of health and illness and quality of life after total thyroidectomy for differentiated thyroid carcinoma: the PERSAM study.

Author: Groff E, Soccal B, Carrossa F, Vianello F, Talomo S, Feltrin A, Scarzello G, Ocagli H, Gregori D, and Martinato M
Subjects: Humans, Female, Male, Middle Aged, Adult, Surveys and Questionnaires, Aged, Perception, Cross-Sectional Studies, Italy epidemiology, Thyroidectomy, Thyroid Neoplasms surgery, Thyroid Neoplasms psychology, Thyroid Neoplasms pathology, Quality of Life
Abstract: Background: Differentiated thyroid carcinoma is the most common endocrine neoplasm; several studies have shown that individuals perceive the disease as being more severe than it actually is, resulting in a reduced quality of life. The primary aim of this study is to assess the quality of life and perception of illness among patients admitted for radiometabolic therapy, post total thyroidectomy for differentiated thyroid carcinoma. The secondary aim is to identify which patient characteristics are associated with a lower quality of life in order to improve and personalize care., Methods: The study was conducted at the UOC of Radiotherapy Veneto Institute of Oncology IOV-IRCCS in Padua, Italy. Three questionnaires were administered: Psychological General Well-Being Index (PGWBI), the Illness Perception Questionnaire (IPQ-R) and the Short Form Survey (SF-12). A descriptive statistics analysis and multiple linear regression models were performed to explore the relationship between some of the variables., Results: Significant associations emerged between the type of surgery and higher values on the PGWBI questionnaire (P = 0.022) and the score obtained in the 'emotional representations' dimension of the IPQ-R questionnaire (P = 0.028). Pathology staging was statistically significantly (P = 0.026) associated with the score obtained in the dimension 'identity'; age with the scores obtained in the dimensions 'emotional representations' (P = 0.035), 'personal control' (P = 0.004), 'consistency with pathology' (P < 0.001) and 'causes' (P = 0.004)., Conclusions: There is evidence of moderate distress in psychological well-being and good perception of pathology. There is less understanding of the disease in individuals with stage 3 and 4 thyroid cancer, in those who have undergone total thyroidectomy without lymphadenectomy and who are aged over 60. Physical well-being: limitations in self-care and moderately physically demanding activities. Mental health: more information to patients decreases the degree of stress and promotes 'positive' emotions. Physical health status: a long-term activity program, characterized by aerobic exercises to be performed in groups or at home, is useful. This study allows to transpose the results into clinical practice, evaluating the possibility and methods of providing personalized care to patients., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Groff, Soccal, Carrossa, Vianello, Talomo, Feltrin, Scarzello, Ocagli, Gregori and Martinato.)
Published: 2024
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39. MLH1 gene promoter methylation status partially overlaps with CpG methylator phenotype (CIMP) in colorectal adenocarcinoma.

Author: Ceccon C, Borga C, Angerilli V, Bergamo F, Munari G, Sabbadin M, Gasparello J, Schiavi F, Zovato S, Scarpa M, Urso EDL, Dei Tos AP, Luchini C, Grillo F, Lonardi S, Parente P, and Fassan M
Abstract: Background: RAS/BRAF mutations, mismatch DNA repair complex deficiency (MMRd)/microsatellite instability (MSI), and CpG methylator phenotype (CIMP) are key molecular actors in colorectal carcinogenesis. To date, conflicting evidence about the correlations between these molecular features has been reported., Materials and Methods: A retrospectively selected cohort of 123 CRCs was divided into 3 groups based on the molecular characteristics: MMR proficient (MMRp)/BRAF p.V600E mutated (BRAF mut ), MMRd/BRAF mut , and MMRd/BRAF wild type (BRAF wt ). MLH1 promoter (pMLH1) methylation status was assessed by pyrosequencing. For 82 samples the CIMP phenotype was evaluated using the EpiTect® MethyLight kit., Results: The MMRd/BRAF mut group showed a higher pMLH1 methylation rate compared to both the MMRd/BRAF wt and the MMRp/BRAF mut groups. Overall, the two MMRd groups had a higher methylation rate compared to the MMRp cases independently from the mutational status of BRAF (p-value <0.0001). The MMRd/BRAF mut group was characterized by a 90.0 % of CIMP high (CIMP-H) tumors of which 97.2 % were pMLH1 methylated. Instead, the MMRd/BRAF wt group presented 50.0 % of CIMP-H adenocarcinomas., Conclusions: Our study demonstrates that pMLH1 hypermethylation, MMRd, BRAF mut and CIMP phenotype do not completely overlap in CRC. These findings further refine the knowledge on the molecular landscape of CRC and may have critical implications also for the clinical management of the disease., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest regarding the publishing paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)
Published: 2024
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40. Management model of caregiver's grief in a tertiary oncological center Hospice, from anticipatory mourning to condolence conversation: preliminary observations.

Author: Gallio I, Lorusso M, Moscato M, Miranti C, Pasalic M, Formaglio F, Feltrin A, and Ruggiero E
Subjects: Humans, Male, Female, Middle Aged, Aged, Adult, Qualitative Research, Tertiary Care Centers organization & administration, Adaptation, Psychological, Hospices methods, Communication, Aged, 80 and over, Grief, Caregivers psychology
Abstract: Background: Bereavement is a crucial physiological process in palliative care; grief-processing disorders can be diagnosed at least 6 months after death and can have severe clinical or psychological consequences. This study aims to verify how adequate management of anticipatory mourning and condolence conversations can be protective in the early stages of grief., Methods: Patients and caregivers are supported by a multidisciplinary team through semi-structured interviews. In condolence conversations within one month of the death, we identify signs of psychological fragility that require support for adequate processing of the loss., Results: From the condolence conversations, only 2-4% of caregivers who had received psychological support during the hospital stay and showed a good level of acceptance of their relative's end of life exhibited grief problems within 1 month of death; none showed excessive avoidance of memories, difficulties with trust, or feelings of emotional loneliness., Conclusions: Despite the limitations, the preliminary data of our study clearly suggest the protective potential of multidisciplinary support, particularly in reducing the risk of developing grief processing disorders. These considerations encourage us to implement our model of clinical and psychological support systems and develop pathways dedicated to caregivers experiencing greater difficulty., Competing Interests: Declarations. Ethics approval and consent to partecipate: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of Veneto Institute of Oncology IOV–IRCCS, Padua, Italy (L04P10 - cod. int. CET ANV 2024-19). Informed consent was obtained from all subjects and/or their legal guardian(s). Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)
Published: 2024
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41. Pathogenic mitochondrial DNA variants are associated with response to anti-VEGF therapy in ovarian cancer PDX models.

Author: Boso D, Piga I, Trento C, Minuzzo S, Angi E, Iommarini L, Lazzarini E, Caporali L, Fiorini C, D'Angelo L, De Luise M, Kurelac I, Fassan M, Porcelli AM, Navaglia F, Billato I, Esposito G, Gasparre G, Romualdi C, and Indraccolo S
Subjects: Humans, Female, Mice, Animals, Xenograft Model Antitumor Assays, Disease Models, Animal, Genetic Variation, Ovarian Neoplasms genetics, Ovarian Neoplasms drug therapy, Ovarian Neoplasms pathology, DNA, Mitochondrial genetics, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism
Abstract: Background: Mitochondrial DNA (mtDNA) pathogenic variants have been reported in several solid tumors including ovarian cancer (OC), the most lethal gynecologic malignancy, and raised interest as they potentially induce mitochondrial dysfunction and rewiring of cellular metabolism. Despite advances in recent years, functional characterization of mtDNA variants in cancer and their possible modulation of drug response remain largely uncharted., Methods: Here, we characterized mtDNA variants in OC patient derived xenografts (PDX) and investigated their impact on cancer cells at multiple levels., Results: Genetic analysis revealed that mtDNA variants predicted as pathogenic, mainly involving complex I and IV genes, were present in all but one PDX (n = 20) at different levels of heteroplasmy, including 7 PDXs with homoplasmic variants. Functional analyses demonstrated that pathogenic mtDNA variants impacted on respiratory complexes activity and subunits abundance as well as on mitochondrial morphology. Moreover, PDX cells bearing homoplasmic mtDNA variants behaved as glucose-addicted and could barely survive glucose starvation in vitro. RNA-seq analysis indicated that mtDNA mutated (heteroplasmy > 50%) PDXs were endowed with upregulated glycolysis and other pathways connected with cancer metabolism. These findings led us to investigate whether pathogenic mtDNA variants correlated with response to anti-VEGF therapy, since the latter was shown to reduce glucose availability in tumors. Strikingly, PDXs bearing homoplasmic pathogenic mtDNA variants associated with improved survival upon anti-VEGF treatment in mice, compared with mtDNA wild type or low heteroplasmy PDXs., Conclusions: These results hint at mtDNA variants as potential biomarkers of response to antiangiogenic drugs., Competing Interests: Declarations. Ethics approval and consent to participate: All procedures involving animals and their care adhere to institutional guidelines that comply with national and international laws and policies (EEC Council Directive 2010/63/EU, OJ L 276, 20.10.2010). The animal study was reviewed and approved by the Italian Ministry of Health (Authorization n. 617/2016-PR), in accordance with the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: The authors declares that they have no competing interests., (© 2024. The Author(s).)
Published: 2024
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42. Assessment of the Addition of Oxaliplatin to Fluoropyrimidine-Based Adjuvant Chemotherapy in Patients With High-Risk Stage II Colon Cancer: An ACCENT Pooled Analysis.

Author: Chibaudel B, Raeisi M, Cohen R, Yothers G, Goldberg RM, Bachet JB, Wolmark N, Yoshino T, Schmoll HJ, Kerr R, Lonardi S, George TJ, Shacham-Shmueli E, Shi Q, André T, and de Gramont A
Subjects: Humans, Male, Female, Chemotherapy, Adjuvant, Middle Aged, Aged, Risk Factors, Leucovorin administration & dosage, Leucovorin therapeutic use, Adult, Kaplan-Meier Estimate, Proportional Hazards Models, Prognosis, Capecitabine administration & dosage, Colonic Neoplasms drug therapy, Colonic Neoplasms pathology, Colonic Neoplasms mortality, Oxaliplatin administration & dosage, Oxaliplatin therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Organoplatinum Compounds administration & dosage, Organoplatinum Compounds therapeutic use, Neoplasm Staging, Fluorouracil administration & dosage, Fluorouracil therapeutic use
Abstract: Purpose: The adjuvant treatment for stage III colon cancer (CC) is chemotherapy combining fluoropyrimidine (FP) and oxaliplatin (OX). FP regimen plus OX (FPOX) may benefit in high-risk stage II CC. We performed a pooled analysis of pivotal MOSAIC and C-07 studies evaluating FPOX for the treatment of high-risk stage II CC according to prognostic factors, number of high-risk factors, and current clinicopathologic risk classification on the basis of T stage, tumor perforation, and number of lymph nodes examined., Patients and Methods: One thousand five hundred and ninety-five patients with stage II CC receiving FP or FPOX were pooled. The overall survival (OS) benefit of OX was analyzed using Kaplan-Meier curves and unadjusted Cox models stratified by study. Three thousand and fifty-nine patients with stage III CC were used only for interaction tests between the allocated chemotherapy and stage., Results: In the pooled analysis of stage II patients, independent prognostic factors in multivariable analysis were sex, age, perforation/obstruction, and tumor sidedness. There was a significant interaction in OS between stage and allocated chemotherapy with hazard ratios (HRs) of 1.03 for stage II (95% CI, 0.82 to 1.29; P = .813) and 0.82 for stage III (95% CI, 0.73 to 0.92; P = .001; P = .073). There was no benefit from the addition of OX to FP for any of the prognostic factors. The number of high-risk factors tested was not predictive of OX benefit. According to the currently agreed clinicopathologic risk classification, no OS benefit of OX was observed, as HR was 0.86 (95% CI, 0.63 to 1.18; int = .073). There was no benefit from the addition of OX to FP for any of the prognostic factors. The number of high-risk factors tested was not predictive of OX benefit. According to the currently agreed clinicopathologic risk classification, no OS benefit of OX was observed, as HR was 0.86 (95% CI, 0.63 to 1.18; P = .349)., Conclusion: No OS benefit of adjuvant OX was found in high-risk stage II CC, regardless of the definition used to characterize tumors as having a high risk for recurrence. Hence, our analysis suggests that OX should not be the standard of care for adjuvant chemotherapy for stage II CC, even in high-risk patients.
Published: 2024
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43. Suboptimal outcomes of sorafenib as a second-line treatment after atezolizumab-bevacizumab for unresectable hepatocellular carcinoma.

Author: Tovoli F, Pallotta DP, Vivaldi C, Campani C, Federico P, Palloni A, Dalbeni A, Soldà C, Lani L, Svegliati-Baroni G, Garajova I, Ielasi L, De Lorenzo S, Granito A, Stefanini B, Masi G, Marra F, Lonardi S, Brandi G, Daniele B, Auriemma A, Schiadà L, Chen R, and Piscaglia F
Subjects: Humans, Male, Female, Middle Aged, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Progression-Free Survival, Prospective Studies, Aged, 80 and over, Adult, Carcinoma, Hepatocellular drug therapy, Carcinoma, Hepatocellular mortality, Sorafenib therapeutic use, Liver Neoplasms drug therapy, Liver Neoplasms mortality, Bevacizumab administration & dosage, Bevacizumab therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects
Abstract: Background: Most patients receiving atezolizumab-bevacizumab (AB) for hepatocellular carcinoma will eventually experience disease progression. Randomized clinical trials (RCTs) are undergoing to identify second-line treatments. Where RCTs are unavailable or patients are non-eligible, sorafenib is often prescribed based on approval and reimbursement policies. However, evidence supporting this approach is minimal., Objective: To assess the efficacy and safety of sorafenib in patients who permanently discontinued AB., Methods: The ARTE database prospectively collects patients treated with AB in a real-life setting. We analysed the outcome of patients who received sorafenib as second-line treatment., Results: Amongst 213 patients, 130 (61.0 %) permanently discontinued AB. Of them, 54 received second- line treatments, and sorafenib was prescribed in 40 patients. The disease control rate (DCR) was 10.0 %. The median progression-free (PFS) and overall survival were 3.3 (95 % confidence interval [CI] 2.7-3.9) and 6.9 months (95 % CI 2.7-11.1), respectively., Conclusions: In patients progressing under AB, the efficacy of sorafenib on different outcomes is limited., Competing Interests: Conflict of interest FT: Consultant for Ipsen, Roche, Eisai, AstraZeneca, Bayer; AG: consultant for Bayer; FM: Consultant for Ipsen, Roche, MSD, AstraZeneca, Bayer; BD: consultant for Astrazeneca, IPSEN, EISAI, MSD, Roche, Amgen, Incyte, Sanofi; FP: honoraria for lecturing or advisory boards from Astrazeneca, Bayer, Bracco, ESAOTE, EISAI, Exact Sciences, IPSEN, MSD, Roche, Samsung, Siemens Healthineers. The other authors have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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44. Long-Term Survivor of Intrahepatic Cholangiocarcinoma for over 18 Years: Case Study with Longitudinal Histo-molecular and Tumor Immune Microenvironment Characterization and Systematic Review of the Literature.

Author: Mattiolo P, De Bellis M, Mafficini A, Fassan M, Bevere M, Ciulla C, Bersani S, Lawlor RT, Milella M, Scarpa A, Luchini C, and Ruzzenente A
Subjects: Humans, Female, Adult, Neoplasm Recurrence, Local pathology, Hepatectomy, Cancer Survivors, Cholangiocarcinoma pathology, Cholangiocarcinoma surgery, Cholangiocarcinoma immunology, Cholangiocarcinoma genetics, Bile Duct Neoplasms pathology, Bile Duct Neoplasms surgery, Bile Duct Neoplasms immunology, Bile Duct Neoplasms genetics, Tumor Microenvironment immunology
Abstract: Background: Intrahepatic cholangiocarcinoma is a biliary neoplasm usually showing a dismal prognosis. In early stages, surgical resection is the best treatment option, significantly increasing the overall survival. This approach is also recommended in the case of relapsing disease. In this study, we report the case of a patient affected by intrahepatic cholangiocarcinoma with multiple relapses and still alive for over 18 years. We also provide a systematic review regarding long-survivor (> 60 months) of intrahepatic cholangiocarcinoma., Case Presentation: A 41-year-old woman with no pathological history was diagnosed with localized intrahepatic cholangiocarcinoma and surgically treated with left hepatectomy. After the first intervention, the patients underwent three further surgical resections because of locoregional recurrences. Histologically, there were some significant similarities among all neoplasms, including the tubule-glandular architecture, but also morphological heterogeneity. The tumor immune microenvironment remained stable across the different lesions. The molecular analysis with next-generation sequencing demonstrated that all neoplasms shared the same genomic profile, including NBN and NOTCH3 mutations and chromosomes 1 and 3 alterations., Conclusions: This case study highlights the essential role of a stringent follow-up after resection of intrahepatic cholangiocarcinoma for detecting early relapsing tumors. Moreover, it shows the importance of the molecular characterization of multiple tumors for understanding their real nature. The accurate study of long-surviving patients highlights the features that are critical for outcome improvement., (© 2024. The Author(s).)
Published: 2024
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45. Endoscopic or combined management of post-surgical biliary leaks: a two-center recent experience.

Author: Quintini D, Rizzo GEM, Tarantino I, Sarzo G, Fantin A, Miraglia R, Maruzzelli L, Ligresti D, Carrozza L, Rancatore G, Gruttadauria S, Cillo U, Ferrara F, and Traina M
Subjects: Humans, Retrospective Studies, Female, Male, Middle Aged, Aged, Postoperative Complications etiology, Postoperative Complications therapy, Postoperative Complications surgery, Adult, Biliary Tract Surgical Procedures methods, Treatment Outcome, Stents, Length of Stay statistics & numerical data, Biliary Tract Diseases surgery, Cholangiopancreatography, Endoscopic Retrograde methods, Anastomotic Leak therapy, Anastomotic Leak surgery, Anastomotic Leak etiology
Abstract: Background and Aims: Post-surgical biliary leaks (PSBL) are one of the most prevalent and significant adverse events emerging after liver or biliary tract surgeries. Endoscopic retrograde cholangiopancreatography (ERCP) alone or combined with another approach (Rendez Vous) as treatment of PSBL obtains optimal outcomes due to the possibility of modifying the resistances in the biliary tree., Methods: A retrospective double-center study was conducted in two tertiary centers. Consecutive patients who underwent at least one attempt of PSBL correction by ERCP or Rendez Vous procedure between January 2018 and August 2023 were included. The primary outcome was overall endoscopic clinical success. In contrast, the secondary outcomes were hospital stay exceeding five days and endoscopic clinical success with the first endoscopic procedure at the tertiary center. Both univariate and multivariate analyses were used to assess outcomes., Results: 65 patients were included. Patients with one or multiple) leaks had more possibility to achieve the endoscopic clinical success compared to those affected by the association of leaks and stricture (96% vs 67%, p value 0.005). Leaks occurring in the main biliary duct had less probability (67%) to achieve the overall endoscopic clinical success compared to those in the end-to-end anastomosis (90%), in the resection plane or biliary stump (96%) or first or secondary order biliary branches (100%, p value 0.038). A leak-bridging stent positioning had more probability of achieving the endoscopic clinical success than a not leak-bridging stent (91% vs 53%, p value 0.005)., Conclusions: ERCP and Rendez Vous procedures are safe and effective for treating PSBL, regardless of the type of preceding surgery, even if technical or clinical success was not achieved on the first attempt. A stent should be placed, if feasible, leak-bridging to enhance treatment efficacy., Competing Interests: Declarations. Disclosures: Drs. Dario Quintini, Dr. Giacomo Emanuele Maria Rizzo, Dr. Ilaria Tarantino, Dr. Giacomo Sarzo, Dr. Alberto Fantin, Dr. Roberto Miraglia, Dr. Luigi Maruzzelli, Dr. Dario Ligresti, Dr. Lucio Carrozza, Dr. Gabriele Rancatore, Dr. Salvatore Gruttadauria, Dr. Umberto Cillo, Dr. Francesco Ferrara, and Dr Mario Traina have no conflicts of interest or financial ties to disclose., (© 2024. The Author(s).)
Published: 2024
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46. Ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line oxaliplatin-based chemotherapy in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer (ARMANI): a randomised, open-label, multicentre, phase 3 trial.

Author: Randon G, Lonardi S, Fassan M, Palermo F, Tamberi S, Giommoni E, Ceccon C, Di Donato S, Fornaro L, Brunetti O, De Vita F, Bittoni A, Chini C, Spallanzani A, Nappo F, Bethaz V, Strippoli A, Latiano T, Cardellino GG, Giuliani F, Morano F, Niger M, Raimondi A, Prisciandaro M, Pircher CC, Sciortino C, Marchesi S, Garattini SK, Airò G, Miceli R, Di Bartolomeo M, and Pietrantonio F
Subjects: Humans, Female, Male, Middle Aged, Aged, Adult, Progression-Free Survival, Italy, Fluorouracil administration & dosage, Maintenance Chemotherapy, Stomach Neoplasms drug therapy, Stomach Neoplasms pathology, Stomach Neoplasms mortality, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Paclitaxel administration & dosage, Paclitaxel adverse effects, Esophagogastric Junction pathology, Esophagogastric Junction drug effects, Ramucirumab, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Receptor, ErbB-2 metabolism, Oxaliplatin administration & dosage, Esophageal Neoplasms drug therapy, Esophageal Neoplasms pathology, Esophageal Neoplasms mortality
Abstract: Background: Paclitaxel plus ramucirumab is recommended as a second-line treatment regimen in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer. We aimed to assess whether switch maintenance or early second-line therapy with paclitaxel plus ramucirumab improved outcomes compared with continuation of oxaliplatin and fluoropyrimidine doublet chemotherapy as a first-line strategy., Methods: ARMANI was a multicentre, open-label, randomised, phase 3 trial done in 31 hospitals in Italy. We enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and locally advanced unresectable or metastatic HER2-negative gastric or gastro-oesophageal junction cancer, who had disease control after 3 months of FOLFOX (leucovorin, fluorouracil, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin). Patients were randomly assigned (1:1) to either paclitaxel 80 mg/m 2 on days 1, 8, and 15 plus ramucirumab at 8 mg/kg on days 1 and 15 every 28 days intravenously (switch maintenance group) or continuation of oxaliplatin-based doublet chemotherapy (FOLFOX or CAPOX) for an additional 12 weeks, followed by fluoropyrimidine monotherapy maintenance (control group). Randomisation was stratified by previous gastrectomy (no vs yes), peritoneal carcinomatosis (yes vs no), and primary tumour location (gastro-oesophageal junction vs gastric). Treatment group allocation was done using a web-based system with a minimisation algorithm implementing a random component. The primary endpoint was progression-free survival, analysed on an intention-to-treat basis. The safety population included patients who received at least one dose of the study treatment. This study is registered with ClinicalTrials.gov, NCT02934464, and is complete., Findings: Between Jan 1, 2017, and Oct 2, 2023, 280 patients were randomly assigned to receive paclitaxel plus ramucirumab (switch maintenance group; n=144) or to continue FOLFOX or CAPOX (control group; n=136). All patients were White. 180 (64%) of 280 patients were male and 100 (36%) were female. At a median follow-up of 43·7 months (IQR 24·0-57·9), 253 (90%) of 280 patients had a progression-free survival event: 131 (91%) of 144 patients in the switch maintenance group and 122 (90%) of 136 patients in the control group. Median progression-free survival was 6·6 months (95% CI 5·9-7·8) in the switch maintenance group and 3·5 months (2·8-4·2) in the control group (HR 0·61, 95% CI 0·48-0·79; p=0·0002). The assumption of proportional hazards was violated; in an analysis of 24-month restricted mean survival time, restricted mean progression-free survival was 8·8 months (95% CI 7·7-9·9) in the switch maintenance group and 6·1 months (5·0-7·2) in the control group (p=0·0010). The most frequent grade 3-4 treatment-related adverse events were neutropenia (37 [26%] patients in the switch maintenance group vs 13 [10%] patients in the control group), peripheral neuropathy (eight [6%] vs nine [7%]) and arterial hypertension (nine [6%] vs none). Serious adverse events occurred in 28 (20%) of 141 patients in the experimental group and 15 (11%) of 135 patients in the control group; these events were treatment-related in two (1%) patients in the switch maintenance group (pulmonary embolism) and two (1%) patients in the control group (mucositis and anaemia). No treatment-related deaths occurred., Interpretation: Paclitaxel and ramucirumab switch maintenance could be a potential treatment strategy in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer who are not eligible for immunotherapy or targeted agents., Funding: Partly funded by Eli Lilly., Competing Interests: Declaration of interests SL reports participation in advisory boards for Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, GSK, Incyte, Lilly, Merck Serono, MSD, Servier, Takeda, Rottapharm, and Beigene; personal honoraria as invited speaker from Amgen, AstraZeneca, Bristol-Myers Squibb, Incyte, GSK, Lilly, Merck Serono, MSD, Pierre Fabre, Roche, and Servier; and research funding (to their institution) from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche, and Servier. MF reports research funding (to their institution) from Roche, Astellas, and Diaceutics; personal honoraria as an invited speaker from Roche, Astellas, AstraZeneca, Lilly, Incyte, Bristol-Myers Squibb, Sanofi, Agilent, Merck Serono, Pierre Fabre, GSK, Novartis, and Amgen; and participation in advisory boards for Amgen, Astellas, Roche, Merck Serono, GSK, Novartis, and Janssen. EG reports payment or honoraria from Servier, Amgen, Viatris, Pierre Fabre, Daiichi Sankyo, and AstraZeneca and support for attending meetings from Servier, Roche, Ipsen, and Viatris. LF reports grants or contracts from MSD, Bristol-Myers Squibb, AstraZeneca, Incyte, BeiGene, Astellas, Daiichi Sankyo, and Roche; consulting fees from MSD, AstraZeneca, Incyte, Taiho Oncology, Servier, Daiichi Sankyo, Eli Lilly, and BeiGene; and payment or honoraria from Incyte, Bristol-Myers Squibb, Eli Lilly, AstraZeneca, and MSD. FDV reports consulting fees from Daiichi Sankyo and payment or honoraria from Servier, Amgen, Roche, Eli Lilly, Daiichi Sankyo, and AstraZeneca. AS reports honoraria (advisory board member or invited speaker) from AstraZeneca, MSD, Daiichi, Jazz Pharma, and Astellas. FG reports payments or honoraria from Servier, Amgen, Novartis, Lilly, Eisai, and Daichi Sankyo and support for attending meetings and travel from Lilly, Roche, Amgen, and Servier. FM reports honoraria from Pierre Fabre and Servier; research grants from Incyte (to their institution), and travel grants from Amgen and Pierre Fabre. MN reports travel expenses from AstraZeneca, speaker honoraria from Accademia della Medicina and Incyte; honoraria from Sandoz, Medpoint, Incyte, AstraZeneca, and Servier for editorial collaboration; and consultant honoraria from EMD Serono, Basilea Pharmaceutica, Incyte, MSD Italia, Servier, Astra Zeneca, and Taiho. AR reports honoraria for speaker bureau or advisory board participation from Servier and MSD. FiP repors receiving research funding (to their institution) from Lilly, Bristol-Myers Squibb, Incyte, AstraZeneca, Amgen, and Agenus; personal honoraria as an invited speaker from BeiGene, Daiichi Sankyo, Seagen, Astellas, Ipsen, AstraZeneca, Servier, Bayer, Takeda, Johnson & Johnson, Bristol-Myers Squibb, MSD, Amgen, Merck Serono, Pierre Fabre; and advisory or consultancy fees from Bristol-Myers Squibb, MSD, Amgen, Pierre Fabre, Johnson & Johnson, Servier, Bayer, Takeda, Astellas, GSK, Daiichi Sankyo, Pfizer, BeiGene, Jazz Pharmaceuticals, Incyte, Rottapharm, and Merck Serono. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)
Published: 2024
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47. Impact of metabolism-related markers on outcomes in ovarian cancer patients: Findings of the MITO16A/MaNGO-OV2 trial.

Author: Indraccolo S, Signoriello S, Piga I, Esposito G, Ferrarini F, Boscolo Bragadin A, Salutari V, Pisano C, Califano D, Bignotti E, Tognon G, Simeon V, Artioli G, Ferrero A, Cinieri S, Bologna A, Chiodini P, Scognamiglio G, Bottoni C, Spina A, Russo D, Arenare L, Perrone F, and Pignata S
Subjects: Humans, Female, Prognosis, Carbonic Anhydrase IX metabolism, Bevacizumab therapeutic use, Bevacizumab administration & dosage, Middle Aged, Antigens, Neoplasm, Muscle Proteins, Monocarboxylic Acid Transporters, Symporters, Ovarian Neoplasms metabolism, Ovarian Neoplasms drug therapy, Ovarian Neoplasms pathology, Biomarkers, Tumor metabolism
Abstract: Introduction: In ovarian cancer, expression of metabolism-related markers has been investigated in several studies focusing on individual markers; however, a parallel quantitative evaluation of markers mapping to distinct metabolic processes and their prognostic value in large patient cohorts is still lacking., Methods: Here, by using immunohistochemistry followed by digital pathology, we investigated the expression of several markers related to glycolysis including monocarboxylate transporter 1 and 4 (MCT1, MCT4), glutamine metabolism (glutaminase, GLS) and hypoxia/acidosis (carbonic anhydrase 9, CA IX) in tissue microarrays of > 300 patients recruited in the MITO16A clinical trial, which involved treatment of ovarian cancer patients with carboplatin/taxol plus bevacizumab., Results: Regarding the prognostic impact of these markers, results indicate that GLS expression correlated with progression-free survival, but this effect disappeared when data were corrected for multiple testing. All other markers showed no correlation with clinical outcome., Conclusion: These results indicate marked heterogeneity of expression of metabolism-associated markers in ovarian cancer; however, there was a lack of association with clinical benefit after chemotherapy/anti-vascular endothelial growth factor treatment. Notwithstanding the lack of prognostic value, knowledge of the pattern of expression of these biomarkers in tumors can be useful for patient stratification purposes when new drugs targeting these metabolic pathways will be tested., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Published: 2024
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48. A schedule for tapering glucocorticoid treatment in patients with severe SARS-CoV 2 infection can prevent acute adrenal insufficiency in the geriatric population.

Author: Tizianel I, Ruggiero E, Torchio M, Simonato M, Seresin C, Bigolin F, Botta IP, Bano G, Lo Storto MR, Scaroni C, and Ceccato F
Subjects: Humans, Male, Female, Aged, Aged, 80 and over, Hydrocortisone blood, COVID-19 Drug Treatment, SARS-CoV-2, Dexamethasone administration & dosage, Dexamethasone therapeutic use, Drug Tapering, Prednisone administration & dosage, Prednisone therapeutic use, Sodium blood, Adrenal Insufficiency blood, Adrenal Insufficiency drug therapy, Adrenal Insufficiency diagnosis, COVID-19 complications, COVID-19 blood, Glucocorticoids administration & dosage
Abstract: Objective and Design: Glucocorticoids (GCs) have been widely used in symptomatic patients for the treatment of COVID-19. The risk for adrenal insufficiency must be considered after GC withdrawal given that it is a life-threatening condition if left unrecognized and untreated. Our study aimed to diagnose adrenal insufficiency early on through a GC reduction schedule in patients with COVID-19 infection., Patients and Measurements: From November 2021 to May 2022, 233 patients were admitted to the Geriatric Division of the University Hospital of Padova with COVID-19 infection. A total of 122 patients were treated with dexamethasone, after which the GC tapering was performed according to a structured schedule. It consists of step-by-step GC tapering with prednisone, from 25 mg to 2.5 mg over 2 weeks. Morning serum sodium, potassium, and cortisol levels were assessed 3 days after the last dose of prednisone., Results: At the end of GC withdrawal, no adrenal crisis or signs/symptoms of acute adrenal insufficiency were reported. Median serum cortisol, sodium, and potassium levels after GC discontinuation were, respectively, 427 nmol/L, 140 nmol/L, and 4 nmol/L (interquartile range 395-479, 138-142, and 3.7-4.3). A morning serum cortisol level below the selected threshold of 270 nmol/L was observed in two asymptomatic cases (respectively, 173 and 239 nmol/L, reference range 138-690 nmol/L). Mild hyponatremia (serum sodium 132 to 134 nmol/L, reference range 135-145 nmol/L) was detected in five patients, without being related to cortisol levels., Conclusions: A structured schedule for the tapering of GC treatment used in patients with severe COVID-19 can reduce the risk of adrenal crisis and acute adrenal insufficiency., (© 2024. The Author(s).)
Published: 2024
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49. PARP inhibitors in gliomas: Mechanisms of action, current trends and future perspectives.

Author: Cella E, Bosio A, Persico P, Caccese M, Padovan M, Losurdo A, Maccari M, Cerretti G, Ius T, Minniti G, Idbaih A, Sanai N, Weller M, Preusser M, Simonelli M, and Lombardi G
Subjects: Humans, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Glioma drug therapy, Brain Neoplasms drug therapy
Abstract: Gliomas are the most common primary malignant brain tumours in adults. Despite decades of research into novel therapeutic approaches, the prognosis remains poor. PARP1-2 are critical for DNA repair, cell survival and genomic stability and PARP inhibition (PARPi) may be a promising therapeutic approach for gliomas. Inhibition of PARP activity leads to homologous recombination deficiency (HRD), which, in combination with DNA damage, results in cell death. This review summarises the current knowledge and future perspectives of PARPi in glioma. The available literature was reviewed using PubMed, recent major international oncology congresses were consulted, and ongoing clinical trials were searched using ClinicalTrials.gov. In translational research, PARPi have demonstrated a strong scientific rationale for their use in the treatment of glioma. They have been evaluated both alone and in combination with radiotherapy, temozolomide, anti-angiogenic agents, immunotherapy and other new drugs in newly diagnosed or recurrent glioma. Most studies were open-label, non-randomised, dose-escalation phase I-II trials. Early results show promising anti-tumour activity, and key challenges include identifying predictive biomarkers, elucidating synergistic effects in combination therapies, addressing the development of resistance, and managing hematological toxicity. In conclusion, early phase studies have shown promising anti-tumour activity of PARPi that should be confirmed in larger prospective and randomised trials. In addition, the development of novel PARPi with improved blood brain barrier (BBB) penetration and PARP inhibitor activity with new synergistic treatment combinations seems promising and needs to be further explored., Competing Interests: Declaration of Competing Interest Ahmed Idbaih reports a relationship with Research grants from Carthera, Transgene, Sanofi, Air Liquide, Servier, Nutritheragene, advisory board for Leo Pharma, Novocure and Boehringer Ingelheim Int, travel funding from Novocure, Carthera and Leo Pharma. Michael Weller reports a relationship with research grants from Novartis, Quercis and Versameb, and honoraria for lectures or advisory board participation or consulting from Anheart, Bayer, Curevac, Medac, Neurosense, Novartis, Novocure, Orbus, Pfizer, Philogen, Roche and Servier. Matteo Simonelli reports a relationship with honoraria for lectures or advisory board participation or consulting from Incyte, Bristol Myers Squibb, Servier, GlaxoSmithKline, Sanofi and travel funding from Roche, Pfizer, Sanofi. Giuseppe Lombardi reports a relationship with consulting or advisory role funding from ABBVIE, Bayer, Novartis, Orbus Therapeutics, BrainFarm, Celgene, CureTeq, GlaxoSmithKline, Health4U, Braun, Janssen, BioRegio Stern, Servier, Novocure, and travel funding from Roche and Bayer, Servier. Matthias Preusser has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Böhringer-Ingelheim, Telix, Medscape, OncLive., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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50. IMMUNOREACT 9 metachronous rectal cancers have high HLA-ABC expression on healthy epithelium but a lower infiltration of CD3+ T cells than primary lesions.

Author: Salmaso B, Scarpa M, Pellegrini V, Stepanyan A, Salmaso R, Kotsafti A, Scognamiglio F, Gregori D, Rivella G, De Simoni O, Becherucci G, Negro S, Vignotto C, Spolverato G, Ruffolo C, Angriman I, Bergamo F, Chiminazzo V, Maretto I, Zizzo M, Marchegiani F, Facci L, Brignola S, Businello G, Licia L, Guzzardo V, Dal Santo L, Carlotta C, Massani M, Pozza A, Cataldo I, Stecca T, Dei Tos AP, Zagonel V, Pilati P, Franzato B, Scapinello A, Pozza G, Godina M, Pirozzolo G, Recordare A, Mondi I, Lio CD, Merenda R, Bordignon G, Verdi D, Saadeh L, Guerriero S, Piccioli A, Noaro G, Cola R, Portale G, Cipollari C, Zuin M, Candioli S, Gavagna L, Ricagna F, Ortenzi M, Guerrieri M, Tagliente G, Tomassi M, Tedeschi U, Porzionato A, Agostini M, Bao RQ, Cavallin F, Tussardi G, Di Camillo B, Bardini R, Castagliuolo I, Pucciarelli S, Fassan M, and Scarpa M
Subjects: Humans, Male, Female, Middle Aged, Aged, CD3 Complex metabolism, Tumor Microenvironment immunology, Neoplasms, Second Primary immunology, Neoplasms, Second Primary metabolism, Neoplasms, Second Primary pathology, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Retrospective Studies, Intestinal Mucosa metabolism, Intestinal Mucosa immunology, Intestinal Mucosa pathology, Adult, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Rectal Neoplasms immunology, Rectal Neoplasms pathology, Rectal Neoplasms metabolism, Rectal Neoplasms genetics
Abstract: Lynch syndrome is rarely associated with rectal cancer (RC) and thus, metachronous RC has been scarcely investigated. This study aimed to analyze the mucosal immune microenvironment in sporadic and metachronous RC. We analyzed the mucosal immune microenvironment in the 25 metachronous RCs present in the IMMUNOREACT 1 and 2 multicentre observational studies (624 patients). A panel of immune markers was retrospectively investigated at immunohistochemistry: CD3, CD4, CD8, CD8b, Tbet, FoxP3, PD-L1, MSH6, and PMS2 and CD80. Single-cell suspensions were subjected to flow-cytometry to determine the proportion of epithelial cells (pan-cytokeratin) acting as antigen-presenting cells (expressing CD80, CD86, HLA-ABC) and the proportion of activated CD8 + T cells (CD8 + positive for CD28, CD38), inhibitory T cells (CD3 + CTLA-4+) of activated CD4 + T helper cells (CD4 + CD25+) and activated T regulatory cells (CD4 + CD25 + FoxP3+). No mismatch repair gene deficiencies were observed in the patients. The previous history of colorectal adenoma was significantly more frequent in metachronous RC. In healthy epithelial cells, HLA-ABC expression was significantly higher in patients with metachronous RC. In therapy-naïve metachronous RC patients, a significantly lower level of circulating lymphocytes and CD3 + T-cell infiltration in the healthy mucosa surrounding the RC was observed compared to patients with non-metachronous cancer. Our study supports the hypothesis that metachronous RC can occur in a cancerization field in patients with weak systemic and local immune systems. The peculiar site of RC makes the mismatch-repair genes deficiency in metachronous cancer onset less relevant., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)
Published: 2024
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