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1. Human metapneumovirus infection is associated with a substantial morbidity and mortality burden in adult inpatients

Author

Quentin Philippot, Blandine Rammaert, Gaëlle Dauriat, Cédric Daubin, Frédéric Schlemmer, Adrien Costantini, Yacine Tandjaoui-Lambiotte, Mathilde Neuville, Emmanuelle Desrochettes, Alexis Ferré, Laetitia Bodet Contentin, François-Xavier Lescure, Bruno Megarbane, Antoine Belle, Jean Dellamonica, Sylvain Jaffuel, Jean-Luc Meynard, Jonathan Messika, Nicolas Lau, Nicolas Terzi, Isabelle Runge, Olivier Sanchez, Benjamin Zuber, Emmanuel Guerot, Anahita Rouze, Patricia Pavese, François Bénézit, Jean-Pierre Quenot, Xavier Souloy, Anne Lyse Fanton, David Boutoille, Vincent Bunel, Astrid Vabret, Jacques Gaillat, Anne Bergeron, Nathanaël Lapidus, Muriel Fartoukh, and Guillaume Voiriot

Subjects
Human metapneumovirus, Pneumonia, Viral pneumonia, Respiratory viruses, Science (General), Q1-390, Social sciences (General), H1-99
Abstract

Background: Human metapneumovirus (hMPV) is one of the leading respiratory viruses. This prospective observational study aimed to describe the clinical features and the outcomes of hMPV-associated lower respiratory tract infections in adult inpatients. Methods: Consecutive adult patients admitted to one of the 31 participating centers with an acute lower respiratory tract infection and a respiratory multiplex PCR positive for hMPV were included. A primary composite end point of complicated course (hospital death and/or the need for invasive mechanical ventilation) was used. Results: Between March 2018 and May 2019, 208 patients were included. The median age was 74 [62–84] years. Ninety-seven (47 %) patients were men, 187 (90 %) had at least one coexisting illness, and 67 (31 %) were immunocompromised. Median time between first symptoms and hospital admission was 3 [2–7] days. The two most frequent symptoms were dyspnea (86 %) and cough (85 %). The three most frequent clinical diagnoses were pneumonia (42 %), acute bronchitis (20 %) and acute exacerbation of chronic obstructive pulmonary disease (16 %). Among the 52 (25 %) patients who had a lung CT-scan, the most frequent abnormality was ground glass opacity (41 %). While over four-fifths of patients (81 %) received empirical antibiotic therapy, a bacterial coinfection was diagnosed in 61 (29 %) patients. Mixed flora (16 %) and enterobacteria (5 %) were the predominant documentations. The composite criterion of complicated course was assessable in 202 (97 %) patients, and present in 37 (18 %) of them. In the subpopulation of pneumonia patients (42 %), we observed a more complicated course in those with a bacterial coinfection (8/24, 33 %) as compared to those without (5/60, 8 %) (p = 0.02). Sixty (29 %) patients were admitted to the intensive care unit. Among them, 23 (38 %) patients required invasive mechanical ventilation. In multivariable analysis, tachycardia and alteration of consciousness were identified as risk factors for complicated course. Conclusion: hMPV-associated lower respiratory tract infections in adult inpatients mostly involved elderly people with pre-existing conditions. Bacterial coinfection was present in nearly 30 % of the patients. The need for mechanical ventilation and/or the hospital death were observed in almost 20 % of the patients.

Published
2024
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2. Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection

Author

Astrid Marchal, Elizabeth T. Cirulli, Iva Neveux, Evangelos Bellos, Ryan S. Thwaites, Kelly M. Schiabor Barrett, Yu Zhang, Ivana Nemes-Bokun, Mariya Kalinova, Andrew Catchpole, Stuart G. Tangye, András N. Spaan, Justin B. Lack, Jade Ghosn, Charles Burdet, Guy Gorochov, Florence Tubach, Pierre Hausfater, Clifton L. Dalgard, Shen-Ying Zhang, Qian Zhang, Christopher Chiu, Jacques Fellay, Joseph J. Grzymski, Vanessa Sancho-Shimizu, Laurent Abel, Jean-Laurent Casanova, Aurélie Cobat, Alexandre Bolze, Alessandro Aiuti, Saleh Al-Muhsen, Fahd Al-Mulla, Ali Amara, Mark S. Anderson, Evangelos Andreakos, Andrés A. Arias, Lisa M. Arkin, Hagit Baris Feldman, Paul Bastard, Alexandre Belot, Catherine M. Biggs, Dusan Bogunovic, Anastasiia Bondarenko, Alessandro Borghesi, Ahmed A. Bousfiha, Petter Brodin, Yenan Bryceson, Manish J. Butte, Giorgio Casari, John Christodoulou, Roger Colobran, Antonio Condino-Neto, Stefan N. Constantinescu, Megan A. Cooper, Murkesh Desai, Beth A. Drolet, Xavier Duval, Jamila El Baghdadi, Philippine Eloy, Sara Espinosa-Padilla, Carlos Flores, José Luis Franco, Antoine Froidure, Peter K. Gregersen, Bodo Grimbacher, Filomeen Haerynck, David Hagin, Rabih Halwani, Lennart Hammarström, James R. Heath, Elena W.Y. Hsieh, Eystein Husebye, Kohsuke Imai, Yuval Itan, Emmanuelle Jouanguy, Elżbieta Kaja, Timokratis Karamitros, Kai Kisand, Cheng-Lung Ku, Yu-Lung Lau, Yun Ling, Carrie L. Lucas, Tom Maniatis, Davood Mansouri, László Maródi, France Mentré, Isabelle Meyts, Joshua D. Milner, Kristina Mironska, Trine H. Mogensen, Tomohiro Morio, Lisa F.P. Ng, Luigi D. Notarangelo, Antonio Novelli, Giuseppe Novelli, Cliona O'Farrelly, Satoshi Okada, Keisuke Okamoto, Tayfun Ozcelik, Qiang Pan-Hammarström, Jean W. Pape, Rebeca Perez de Diego, Jordi Perez-Tur, David S. Perlin, Graziano Pesole, Anna M. Planas, Carolina Prando, Aurora Pujol, Anne Puel, Lluis Quintana-Murci, Sathishkumar Ramaswamy, Laurent Renia, Igor Resnick, Carlos Rodríguez-Gallego, Anna Sediva, Mikko R.J. Seppänen, Mohammad Shahrooei, Anna Shcherbina, Ondrej Slaby, Andrew L. Snow, Pere Soler-Palacín, Vassili Soumelis, Ivan Tancevski, Ahmad Abou Tayoun, Şehime Gülsün Temel, Christian Thorball, Pierre Tiberghien, Sophie Trouillet-Assant, Stuart E. Turvey, K. M. Furkan Uddin, Mohammed J. Uddin, Diederik van de Beek, Donald C. Vinh, Horst von Bernuth, Joost Wauters, Mayana Zatz, Pawel Zawadzki, Serge Bureau, Yannick Vacher, Anne Gysembergh-Houal, Lauren Demerville, Abla Benleulmi-Chaachoua, Sebastien Abad, Radhiya Abassi, Abdelrafie Abdellaoui, Abdelkrim Abdelmalek, Hendy Abdoul, Helene Abergel, Fariza Abeud, Sophie Abgrall, Noemie Abisror, Marylise Adechian, Nordine Aderdour, Hakeem Farid Admane, Frederic Adnet, Sara Afritt, Helene Agostini, Claire Aguilar, Sophie Agut, Tommaso Francesco Aiello, Marc Ait Kaci, Hafid Ait Oufella, Gokula Ajeenthiravasan, Virginie Alauzy, Fanny Alby-Laurent, Lucie Allard, Marie-Alexandra Alyanakian, Blanca Amador Borrero, Sabrina Amam, Lucile Amrouche, Marc Andronikof, Dany Anglicheau, Nadia Anguel, Djillali Annane, Mohammed Aounzou, Caroline Aparicio, Gladys Aratus, Jean-Benoit Arlet, Jeremy Arzoine, Elisabeth Aslangul, Mona Assefi, Adeline Aubry, Laetitia Audiffred, Etienne Audureau, Christelle Nathalie Auger, Jean-Charles Auregan, Celine Awotar, Sonia Ayllon Milla, Delphine Azan, Laurene Azemar, Billal Azzouguen, Marwa Bachir Elrufaai, Aïda Badsi, Prissile Bakouboula, Coline Balcerowiak, Fanta Balde, Elodie Baldivia, Eliane-Flore Bangamingo, Amandine Baptiste, Fanny Baran-Marszak, Caroline Barau, Nathalie Barget, Flore Baronnet, Romain Barthelemy, Jean-Luc Baudel, Camille Baudry, Elodie Baudry, Laurent Beaugerie, Adel Belamri, Nicolas Belaube, Rhida Belilita, Pierre Bellassen, Rawan Belmokhtar, Isabel Beltran, Ruben Benainous, Mourad Benallaoua, Robert Benamouzig, Amélie Benbara, Jaouad Benhida, Anis Benkhelouf, Jihene Benlagha, Chahinez Benmostafa, Skander Benothmane, Miassa Bentifraouine, Laurence Berard, Quentin Bernier, Enora Berti, Astrid Bertier, Laure Berton, Simon Bessis, Alexandra Beurton, Celine Bianco, Clara Bianquis, Frank Bidar, Philippe Blanche, Clarisse Blayau, Alexandre Bleibtreu, Emmanuelle Blin, Coralie Bloch-Queyrat, Marie-Christophe Boissier, Diane Bollens, Marion Bolzoni, Rudy pierre Bompard, Nicolas Bonnet, Justine Bonnouvrier, Shirmonecrystal Botha, Wissam Boucenna, Fatiha Bouchama, Olivier Bouchaud, Hanane Bouchghoul, Taoueslylia Boudjebla, Noel Boudjema, Catherine Bouffard, Adrien Bougle, Meriem Bouguerra, Leila Bouras, Agnes Bourcier, Anne Bourgarit Durand, Anne Bourrier, Fabrice Bouscarat, Diane Bouvry, Nesrine Bouziri, Ons Bouzrara, Sarah Bribier, Delphine Brugier, Melanie Brunel, Eida Bui, Anne Buisson, Iryna Bukreyeva, Côme Bureau, Jacques Cadranel, Johann Cailhol, Ruxandra Calin, Clara Campos Vega, Pauline Canavaggio, Marta Cancella, Delphine Cantin, Albert Cao, Lionel Carbillon, Nicolas Carlier, Clementine Cassard, Guylaine Castor, Marion Cauchy, Olivier Cha, Benjamin Chaigne, Salima Challal, Karine Champion, Patrick Chariot, Julie Chas, Simon Chauveau, Anthony Chauvin, Clement Chauvin, Nathalie Chavarot, Kamélia Chebbout, Mustapha Cherai, Ilaria Cherubini, Amelie Chevalier, Thibault Chiarabini, Thierry Chinet, Richard Chocron, Pascaline Choinier, Juliette Chommeloux, Christophe Choquet, Laure Choupeaux, Benjamin Chousterman, Dragosmarius Ciocan, Ada Clarke, Gaëlle Clavere, Florian Clavier, Karine Clement, Sebastien Clerc, Yves Cohen, Fleur Cohen, Adrien Cohen, Audrey Coilly, Hester Colboc, Pauline Colin, Magalie Collet, Chloé Comarmond, Emeline Combacon, Alain Combes, Celine Comparon, Jean-Michel Constantin, Hugues Cordel, Anne-Gael Cordier, Adrien Costantini, Nathalie Costedoat Chalumeau, Camille Couffignal, Doriane Coupeau, Alain Creange, Yannie Cuvillier Lamarre, Charlène Da Silveira, Sandrine Dautheville Guibal El Kayani, Nathalie De Castro, Yann De Rycke, Lucie Del Pozo, Quentin Delannoy, Mathieu Delay, Robin Deleris, Juliette Delforge, Laëtitia Delphine, Noemie Demare, Sophie Demeret, Alexandre Demoule, Aurore Deniau, François Depret, Sophie Derolez, Ouda Derradji, Nawal Derridj, Vincent Descamps, Lydia Deschamps, Celine Desconclois, Cyrielle Desnos, Karine Desongins, Robin Dhote, Benjamin Diallo, Morgane Didier, Myriam Diemer, Stephane Diez, Juliette Djadi-Prat, Fatima-Zohra Djamouri Monnory, Siham Djebara, Naoual Djebra, Minette Djietcheu, Hadjer Djillali, Nouara Djouadi, Severine Donneger, Catarina Dos Santos, Nathalie Dournon, Martin Dres, Laura Droctove, Marie Drogrey, Margot Dropy, Elodie Drouet, Valérie Dubosq, Evelyne Dubreucq, Estelle Dubus, Boris Duchemann, Thibault Duchenoy, Emmanuel Dudoignon, Romain Dufau, Florence Dumas, Clara Duran, Emmanuelle Duron, Antoine Durrbach, Claudine Duvivier, Nathan Ebstein, Jihane El Khalifa, Alexandre Elabbadi, Caroline Elie, Gabriel Ernotte, Anne Esling, Martin Etienne, Xavier Eyer, Muriel Sarah Fartoukh, Takoua Fayali, Marion Fermaut, Arianna Fiorentino, Souha Fliss, Marie-Céline Fournier, Benjamin Fournier, Hélène Francois, Olivia Freynet, Yvann Frigout, Isaure Fromont, Axelle Fuentes, Thomas Furet, Joris Galand, Marc Garnier, Agnes Gaubert, Stéphane Gaudry, Samuel Gaugain, Damien Gauthier, Maxime Gautier, Sophie Georgin-Lavialle, Daniela Geromin, Mohamed Ghalayini, Bijan Ghaleh, Myriam Ghezal, Aude Gibelin, Linda Gimeno, Benoit Girard, Bénédicte Giroux Leprieur, Doryan Gomes, Elisabete Gomes-Pires, Anne Gouge, Amel Gouja, Helene Goulet, Sylvain Goupil, Jeanne Goupil De Bouille, Julien Gras, Segolene Greffe, Lamiae Grimaldi, Paul Guedeney, Bertrand Guidet, Matthias Guillo, Mariechristelle Gulczynski, Tassadit Hadjam, Didier Haguenauer, Soumeya Hammal, Nadjib Hammoudi, Olivier Hanon, Anarole Harrois, Coraline Hautem, Guillaume Hekimian, Nicholas Heming, Olivier Hermine, Sylvie Ho, Marie Houllier, Benjamin Huot, Tessa Huscenot, Wafa Ibn Saied, Ghilas Ikherbane, Meriem Imarazene, Patrick Ingiliz, Lina Iratni, Stephane Jaureguiberry, Jean-Francois Jean-Marc, Deleena Jeyarajasingham, Pauline Jouany, Veronique Jouis, Clement Jourdaine, Ouifiya Kafif, Rim Kallala, Sandrine Katsahian, Lilit Kelesyan, Vixra Keo, Flora Ketz, Warda Khamis, Enfel Khelili, Mehdi Khellaf, Christy Gaëlla Kotokpo Youkou, Ilias Kounis, Gaelle Kpalma, Jessica Krause, Vincent Labbe, Karine Lacombe, Jean-Marc Lacorte, Anne Gaelle Lafont, Emmanuel Lafont, Lynda Lagha, Lionel Lamhaut, Aymeric Lancelot, Cecilia Landman, Fanny Lanternier, Cecile Larcheveque, Caroline Lascoux Combe, Ludovic Lassel, Benjamin Laverdant, Christophe Lavergne, Jean-Rémi Lavillegrand, Pompilia Lazureanu, Loïc Le Guennec, Lamia Leberre, Claire Leblanc, Marion Leboyer, Francois Lecomte, Marine Lecorre, Romain Leenhardt, Marylou Lefebvre, Bénédicte Lefebvre, Paul Legendre, Anne Leger, Laurence Legros, Justyna Legrosse, Sébastien Lehuunghia, Julien Lemarec, Jeremie Leporrier-Ext, Manon Lesein, Hubert Lesur, Vincent Levy, Albert Levy, Edwige Lopes, Amanda Lopes, Vanessa Lopez, Julien Lopinto, Olivier Lortholary, Badr Louadah, Bénédicte Loze, Marie-Laure Lucas, Axelle Lucasamichi, Liem Binh Luong, Arouna Magazimama-Ext, David Maingret, Lakhdar Mameri, Philippe Manivet, Cylia Mansouri, Estelle Marcault, Jonathan Marey, Nathalie Marin, Clémence Marois, Olivier Martin, Lou Martineau, Cannelle Martinez-Lopez, Pierre Martyniuck, Pauline Mary De Farcy, Nessrine Marzouk, Rafik Masmoudi, Alexandre Mebazaa, Frédéric Mechai, Fabio Mecozzi, Chamseddine Mediouni, Bruno Megarbane, Mohamed Meghadecha, Élodie Mejean, Arsene Mekinian, Nour Mekki Abdelhadi, Rania Mekni, Thinhinan Sabrina Meliti, Breno Melo Lima, Paris Meng, Soraya Merbah, Fadhila Messani, Yasmine Messaoudi, Baboo-Irwinsingh Mewasing, Lydia Meziane, Carole Michelot-Burger, Françoise Mignot, Fadi Hillary Minka, Makoto Miyara, Pierre Moine, Jean-Michel Molina, Anaïs Montegnies-Boulet, Alexandra Monti, Claire Montlahuc, Anne-Lise Montout, Alexandre Moores, Caroline Morbieu, Helene Mortelette, Stéphane Mouly, Rosita Muzaffar, Cherifa Iness Nacerddine, Marine Nadal, Hajer Nadif, Kladoum Nassarmadji, Pierre Natella, Sandrine Ndingamondze, Stefan Neraal, Caroline Nguyen, Bao N'Guyen, Isabelle Nion Larmurier, Luc Nlomenyengue, Nicolas Noel, Hilario Nunes, Edris Omar, Zineb Ouazene, Elise Ouedraogo, Wassila Ouelaa, Anissa Oukhedouma, Yasmina Ould Amara, Herve Oya, Johanna Oziel, Thomas Padilla, Elena Paillaud, Solenne Paiva, Beatrice Parfait, Perrine Parize, Christophe Parizot, Antoine Parrot, Arthur Pavot, Laetitia Peaudecerf, Frédéric Pene, Marion Pepin, Julie Pernet, Claire Pernin, Mylène Petit, Olivier Peyrony, Marie-Pierre Pietri, Olivia Pietri, Marc Pineton De Chambrun, Michelle Pinson, Claire Pintado, Valentine Piquard, Christine Pires, Benjamin Planquette, Sandrine Poirier, Anne-Laure Pomel, Stéphanie Pons, Diane Ponscarme, Annegaelle Pourcelot, Valérie Pourcher, Anne Pouvaret, Florian Prever, Miresta Previlon, Margot Prevost, Marie-Julie Provoost, Cyril Quemeneur, Cédric Rafat, Agathe Rami, Brigitte Ranque, Maurice Raphael, Jean Herle Raphalen, Anna Rastoin, Mathieu Raux, Amani Rebai, Michael Reby, Alexis Regent, Asma Regrag, Matthieu Resche-Rigon, Quentin Ressaire, Christian Richard, Mariecaroline Richard, Maxence Robert, Benjamin Rohaut, Camille Rolland-Debord, Jacques Ropers, Anne-Marie Roque-Afonso, Charlotte Rosso, Mélanie Rousseaux, Nabila Rousseaux, Swasti Roux, Lorène Roux, Claire Rouzaud, Antoine Rozes, Emma Rubenstein, Jean-Marc Sabate, Sheila Sabet, Sophie-Caroline Sacleux, Nathalie Saidenberg Kermanach, Faouzi Saliba, Dominique Salmon, Laurent Savale, Guillaume Savary, Rebecca Sberro, Anne Scemla, Frederic Schlemmer, Mathieu Schwartz, Saïd Sedfi, Samia Sefir-Kribel, Philippe Seksik, Pierre Sellier, Agathe Selves, Nicole Sembach, Luca Semerano, Marie-Victoire Senat, Damien Sene, Alexandra Serris, Lucile Sese, Naima Sghiouar, Johanna Sigaux, Martin Siguier, Johanne Silvain, Noémie Simon, Tabassome Simon, Lina Innes Skandri, Miassa Slimani, Aurélie Snauwaert, Harry Sokol, Heithem Soliman, Nisrine Soltani, Benjamin Soyer, Gabriel Steg, Lydia Suarez, Tali-Anne Szwebel, Kossi Taffame, Yacine Tandjaoui-Lambiotte, Claire Tantet, Mariagrazia Tateo, Igor Theodose, Pierre clement Thiebaud, Caroline Thomas, Kelly Tiercelet, Julie Tisserand, Carole Tomczak, Krystel Torelino, Fatima Touam-Ext, Lilia Toumi, Gustave Toury, Mireille Toy-Miou, Olivia Tran Dinh Thanh Lien, Alexy Trandinh, Jean-Marc Treluyer, Baptiste Trinque, Jennifer Truchot, Sarah Tubiana, Simone Tunesi, Matthieu Turpin, Agathe Turpin, Tomas Urbina, Rafael Usubillaga Narvaez, Yurdagul Uzunhan, Prabakar Vaittinadaayar, Arnaud Valent, Maelle Valentian, Nadia Valin, Hélène Vallet, Marina Vaz, Miguel-Alejandro Vazquezibarra, Benoit Vedie, Laetitia Velly, Celine Verstuyft, Cedric Viallette, Eric Vicaut, Dorothee Vignes, Damien Vimpere, Myriam Virlouvet, Guillaume Voiriot, Lena Voisot, Emmanuel Weiss, Nicolas Weiss, Anaïs Winchenne, Youri Yordanov, Lara Zafrani, Mohamad Zaidan, Wissem Zaidi, Cathia Zak, Aida Zarhrate-Ghoul, Ouassila Zatout, Suzanne Zeino, Michel Zeitouni, Naïma Zemirli, Lorene Zerah, Ounsa Zia, Marianne Ziol, Oceane Zolario, Julien Zuber, Claire Andrejak, François Angoulvant, Delphine Bachelet, Marie Bartoli, Romain Basmaci, Sylvie Behillil, Marine Beluze, Dehbia Benkerrou, Krishna Bhavsar, Lila Bouadma, Sabelline Bouchez, Maude Bouscambert, Minerva Cervantes-Gonzalez, Anissa Chair, Catherine Chirouze, Alexandra Coelho, Sandrine Couffin-Cadiergues, Eric d’Ortenzio, Marie-Pierre Debray, Laurene Deconinck, Dominique Deplanque, Diane Descamps, Mathilde Desvallée, Alpha Diallo, Alphonsine Diouf, Céline Dorival, François Dubos, Brigitte Elharrar, Vincent Enouf, Hélène Esperou, Marina Esposito-Farese, Manuel Etienne, Eglantine Ferrand Devouge, Nathalie Gault, Alexandre Gaymard, Tristan Gigante, Morgane Gilg, Jérémie Guedj, Alexandre Hoctin, Isabelle Hoffmann, Ikram Houas, Jean-Sébastien Hulot, Salma Jaafoura, Florentia Kaguelidou, Sabrina Kali, Antoine Khalil, Coralie Khan, Cédric Laouénan, Samira Laribi, Minh Le, Quentin Le Hingrat, Soizic Le Mestre, Hervé Le Nagard, François-Xavier Lescure, Sophie Letrou, Yves Levy, Bruno Lina, Guillaume Lingas, Jean-Christophe Lucet, Denis Malvy, Marina Mambert, Amina Meziane, Hugo Mouquet, Jimmy Mullaert, Nadège Neant, Duc Nguyen, Marion Noret, Saad Nseir, Aurélie Papadopoulos, Christelle Paul, Nathan Peiffer-Smadja, Thomas Perpoint, Ventzislava Petrov-Sanchez, Gilles Peytavin, Huong Pham, Olivier Picone, Oriane Puéchal, Christian Rabaud, Manuel Rosa-Calatrava, Bénédicte Rossignol, Patrick Rossignol, Carine Roy, Marion Schneider, Richa Su, Coralie Tardivon, Marie-Capucine Tellier, François Téoulé, Olivier Terrier, Jean-François Timsit, Christelle Tual, Sylvie Van Der Werf, Noémie Vanel, Aurélie Veislinger, Benoit Visseaux, Aurélie Wiedemann, Yazdan Yazdanpanah, Loubna Alavoine, Charlotte Charpentier, Aline Dechanet, Jean-Luc Ecobichon, Wahiba Frezouls, Nadhira Houhou, Jonathan Lehacaut, Pauline Manchon, Mariama Nouroudine, Caroline Quintin, Michael Thy, Sylvie van der Werf, Valérie Vignali, Abir Chahine, Nawal Waucquier, Maria-Claire Migaud, Félix Djossou, Mayka Mergeay-Fabre, Aude Lucarelli, Magalie Demar, Léa Bruneau, Patrick Gérardin, Adrien Maillot, Christine Payet, Bruno Laviolle, Fabrice Laine, Christophe Paris, Mireille Desille-Dugast, Julie Fouchard, Thierry Pistone, Pauline Perreau, Valérie Gissot, Carole L.E. Goas, Samatha Montagne, Lucie Richard, Kévin Bouiller, Maxime Desmarets, Alexandre Meunier, Marilou Bourgeon, Benjamin Lefévre, Hélène Jeulin, Karine Legrand, Sandra Lomazzi, Bernard Tardy, Amandine Gagneux-Brunon, Frédérique Bertholon, Elisabeth Botelho-Nevers, Christelle Kouakam, Leturque Nicolas, Layidé Roufai, Karine Amat, Hélène Espérou, Samia Hendou, Giuseppe Foti, Giuseppe Citerio, Ernesto Contro, Alberto Pesci, Maria Grazia Valsecchi, Marina Cazzaniga, Giacomo Bellani, Jorge Abad, Giulia Accordino, Micol Angelini, Sergio Aguilera-Albesa, Aina Aguiló-Cucurull, Esra Akyüz Özkan, Ilad Alavi Darazam, Jonathan Antonio Roblero Albisures, Juan C. Aldave, Miquel Alfonso Ramos, Taj Ali Khan, Anna Aliberti, Seyed Alireza Nadji, Gulsum Alkan, Suzan A. AlKhater, Jerome Allardet-Servent, Luis M. Allende, Rebeca Alonso-Arias, Mohammed S. Alshahrani, Laia Alsina, Zahir Amoura, Arnau Antolí, Romain Arrestier, Mélodie Aubart, Teresa Auguet, Iryna Avramenko, Gökhan Aytekin, Axelle Azot, Seiamak Bahram, Fanny Bajolle, Fausto Baldanti, Aurélie Baldolli, Maite Ballester, Benoit Barrou, Federica Barzaghi, Sabrina Basso, Gulsum Iclal Bayhan, Liliana Bezrodnik, Agurtzane Bilbao, Geraldine Blanchard-Rohner, Ignacio Blanco, Adeline Blandinières, Daniel Blázquez-Gamero, Marketa Bloomfield, Mireia Bolivar-Prados, Raphael Borie, Elisabeth Botdhlo-Nevers, Aurore Bousquet, David Boutolleau, Claire Bouvattier, Oksana Boyarchuk, Juliette Bravais, M. Luisa Briones, Marie-Eve Brunner, Raffaele Bruno, Maria Rita P. Bueno, Huda Bukhari, Jacinta Bustamante, Juan José Cáceres Agra, Ruggero Capra, Raphael Carapito, Maria Carrabba, Carlos Casasnovas, Marion Caseris, Irene Cassaniti, Martin Castelle, Francesco Castelli, Martín Castillo de Vera, Mateus V. Castro, Emilie Catherinot, Jale Bengi Celik, Alessandro Ceschi, Martin Chalumeau, Bruno Charbit, Cécile Boulanger, Père Clavé, Bonaventura Clotet, Anna Codina, Cloé Comarmond, Patrizia Comoli, Angelo G. Corsico, Taner Coşkuner, Aleksandar Cvetkovski, Cyril Cyrus, David Dalmau, François Danion, David Ross Darley, Vincent Das, Nicolas Dauby, Stéphane Dauger, Paul De Munte, Loic de Pontual, Amin Dehban, Geoffroy Delplancq, Isabelle Desguerre, Antonio Di Sabatino, Jean-Luc Diehl, Stephanie Dobbelaere, Elena Domínguez-Garrido, Clément Dubost, Olov Ekwall, Şefika Elmas Bozdemir, Marwa H. Elnagdy, Melike Emiroglu, Akifumi Endo, Emine Hafize Erdeniz, Selma Erol Aytekin, Maria Pilar Etxart Lasa, Romain Euvrard, Giovanna Fabio, Laurence Faivre, Antonin Falck, Muriel Fartoukh, Morgane Faure, Miguel Fernandez Arquero, Ricard Ferrer, Jose Ferreres, Bruno Francois, Victoria Fumadó, Kitty S.C. Fung, Francesca Fusco, Alenka Gagro, Blanca Garcia Solis, Pierre Garçon, Pascale Gaussem, Zeynep Gayretli, Juana Gil-Herrera, Laurent Gilardin, Audrey Giraud Gatineau, Mònica Girona-Alarcón, Karen Alejandra Cifuentes Godínez, Jean-Christophe Goffard, Nacho Gonzales, Luis I. Gonzalez-Granado, Rafaela González-Montelongo, Antoine Guerder, Belgin Gülhan, Victor Daniel Gumucio, Leif Gunnar Hanitsch, Jan Gunst, Marta Gut, Jérôme Hadjadj, Selda Hancerli, Tetyana Hariyan, Nevin Hatipoglu, Deniz Heppekcan, Elisa Hernandez-Brito, Po-ki Ho, María Soledad Holanda-Peña, Juan P. Horcajada, Sami Hraiech, Linda Humbert, Ivan F.N. Hung, Alejandro D. Iglesias, Antonio Íñigo-Campos, Matthieu Jamme, María Jesús Arranz, Marie-Thérèse Jimeno, Iolanda Jordan, Saliha Kanık-Yüksek, Yalcin Kara, Aydın Karahan, Adem Karbuz, Kadriye Kart Yasar, Ozgur Kasapcopur, Kenichi Kashimada, Sevgi Keles, Yasemin Kendir Demirkol, Yasutoshi Kido, Can Kizil, Ahmet Osman Kılıç, Adam Klocperk, Antonia Koutsoukou, Zbigniew J. Król, Hatem Ksouri, Paul Kuentz, Arthur M.C. Kwan, Yat Wah M. Kwan, Janette S.Y. Kwok, Jean-Christophe Lagier, David S.Y. Lam, Vicky Lampropoulou, Fleur Le Bourgeois, Yee-Sin Leo, Rafael Leon Lopez, Daniel Leung, Michael Levin, Michael Levy, Romain Lévy, Zhi Li, Daniele Lilleri, Edson Jose Adrian Bolanos Lima, Agnes Linglart, Eduardo López-Collazo, José M. Lorenzo-Salazar, Céline Louapre, Catherine Lubetzki, Kwok-Cheung Lung, Charles-Edouard Luyt, David C. Lye, Cinthia Magnone, Enrico Marchioni, Carola Marioli, Majid Marjani, Laura Marques, Jesus Marquez Pereira, Andrea Martín-Nalda, David Martínez Pueyo, Javier Martinez-Picado, Iciar Marzana, Carmen Mata-Martínez, Alexis Mathian, Larissa R.B. Matos, Gail V. Matthews, Julien Mayaux, Raquel McLaughlin-Garcia, Philippe Meersseman, Jean-Louis Mège, Armand Mekontso-Dessap, Isabelle Melki, Federica Meloni, Jean-François Meritet, Paolo Merlani, Özge Metin Akcan, Mehdi Mezidi, Isabelle Migeotte, Maude Millereux, Matthieu Million, Tristan Mirault, Clotilde Mircher, Mehdi Mirsaeidi, Yoko Mizoguchi, Bhavi P. Modi, Francesco Mojoli, Elsa Moncomble, Abián Montesdeoca Melián, Antonio Morales Martinez, Francisco Morandeira, Pierre-Emmanuel Morange, Clémence Mordacq, Guillaume Morelle, Stéphane J. Mouly, Adrián Muñoz-Barrera, Cyril Nafati, Shintaro Nagashima, Yu Nakagama, Bénédicte Neven, João Farela Neves, Yuk-Yung Ng, Hubert Nielly, Yeray Novoa Medina, Esmeralda Nuñez Cuadros, Semsi Nur Karabela, J. Gonzalo Ocejo-Vinyals, Mehdi Oualha, Amani Ouedrani, Tayfun Özçelik, Aslinur Ozkaya-Parlakay, Michele Pagani, Maria Papadaki, Philippe Parola, Tiffany Pascreau, Stéphane Paul, Estela Paz-Artal, Sigifredo Pedraza, Nancy Carolina González Pellecer, Silvia Pellegrini, Rebeca Pérez de Diego, Xosé Luis Pérez-Fernández, Aurélien Philippe, Quentin Philippot, Adrien Picod, Marc Pineton de Chambrun, Antonio Piralla, Laura Planas-Serra, Dominique Ploin, Julien Poissy, Géraldine Poncelet, Garyphallia Poulakou, Marie S. Pouletty, Persia Pourshahnazari, Jia Li Qiu-Chen, Paul Quentric, Thomas Rambaud, Didier Raoult, Violette Raoult, Anne-Sophie Rebillat, Claire Redin, Léa Resmini, Pilar Ricart, Jean-Christophe Richard, Raúl Rigo-Bonnin, Nadia Rivet, Jacques G. Rivière, Gemma Rocamora-Blanch, Mathieu P. Rodero, Carlos Rodrigo, Luis Antonio Rodriguez, Carlos Rodriguez-Gallego, Agustí Rodriguez-Palmero, Carolina Soledad Romero, Anya Rothenbuhler, Damien Roux, Nikoletta Rovina, Flore Rozenberg, Yvon Ruch, Montse Ruiz, Maria Yolanda Ruiz del Prado, Juan Carlos Ruiz-Rodriguez, Joan Sabater-Riera, Kai Saks, Maria Salagianni, Oliver Sanchez, Adrián Sánchez-Montalvá, Silvia Sánchez-Ramón, Laire Schidlowski, Agatha Schluter, Julien Schmidt, Matthieu Schmidt, Catharina Schuetz, Cyril E. Schweitzer, Francesco Scolari, Luis Seijo, Analia Gisela Seminario, Piseth Seng, Sevtap Senoglu, Mikko Seppänen, Alex Serra Llovich, Virginie Siguret, Eleni Siouti, David M. Smadja, Nikaia Smith, Ali Sobh, Xavier Solanich, Jordi Solé-Violán, Catherine Soler, Betül Sözeri, Giulia Maria Stella, Yuriy Stepanovskiy, Annabelle Stoclin, Fabio Taccone, Jean-Luc Taupin, Simon J. Tavernier, Loreto Vidaur Tello, Benjamin Terrier, Guillaume Thiery, Karolina Thorn, Caroline Thumerelle, Imran Tipu, Martin Tolstrup, Gabriele Tomasoni, Julie Toubiana, Josep Trenado Alvarez, Vasiliki Triantafyllia, Jesús Troya, Owen T.Y. Tsang, Liina Tserel, Eugene Y.K. Tso, Alessandra Tucci, Şadiye Kübra Tüter Öz, Matilde Valeria Ursini, Takanori Utsumi, Pierre Vabres, Juan Valencia-Ramos, Ana Maria Van Den Rym, Isabelle Vandernoot, Valentina Velez-Santamaria, Silvia Patricia Zuniga Veliz, Mateus C. Vidigal, Sébastien Viel, Cédric Villain, Marie E. Vilaire-Meunier, Judit Villar-García, Audrey Vincent, Dimitri Van der Linden, Alla Volokha, Fanny Vuotto, Els Wauters, Alan K.L. Wu, Tak-Chiu Wu, Aysun Yahşi, Osman Yesilbas, Mehmet Yildiz, Barnaby E. Young, Ufuk Yükselmiş, Marco Zecca, Valentina Zuccaro, Jens Van Praet, Bart N. Lambrecht, Eva Van Braeckel, Cédric Bosteels, Levi Hoste, Eric Hoste, Fré Bauters, Jozefien De Clercq, Catherine Heijmans, Hans Slabbynck, Leslie Naesens, Benoit Florkin, Mary-Anne Young, Amanda Willis, Paloma Lapuente-Suanzes, Ana de Andrés-Martín, Matilda Berkell, Valerio Carelli, Alessia Fiorentino, Surbhi Malhotra, Alessandro Mattiaccio, Tommaso Pippucci, Marco Seri, Evelina Tacconelli, Michiel van Agtmael, Anne Geke Algera, Brent Appelman, Frank van Baarle, Diane Bax, Martijn Beudel, Harm Jan Bogaard, Marije Bomers, Peter Bonta, Lieuwe Bos, Michela Botta, Justin de Brabander, Godelieve de Bree, Sanne de Bruin, David T.P. Buis, Marianna Bugiani, Esther Bulle, Osoul Chouchane, Alex Cloherty, Mirjam Dijkstra, Dave A. Dongelmans, Romein W.G. Dujardin, Paul Elbers, Lucas Fleuren, Suzanne Geerlings, Theo Geijtenbeek, Armand Girbes, Bram Goorhuis, Martin P. Grobusch, Florianne Hafkamp, Laura Hagens, Jorg Hamann, Vanessa Harris, Robert Hemke, Sabine M. Hermans, Leo Heunks, Markus Hollmann, Janneke Horn, Joppe W. Hovius, Menno D. de Jong, Rutger Koning, Endry H.T. Lim, Niels van Mourik, Jeaninne Nellen, Esther J. Nossent, Frederique Paulus, Edgar Peters, Dan A.I. Pina-Fuentes, Tom van der Poll, Bennedikt Preckel, Jan M. Prins, Jorinde Raasveld, Tom Reijnders, Maurits C.F. J. de Rotte, Michiel Schinkel, Marcus J. Schultz, Femke A.P. Schrauwen, Alex Schuurmans, Jaap Schuurmans, Kim Sigaloff, Marleen A. Slim, Patrick Smeele, Marry Smit, Cornelis S. Stijnis, Willemke Stilma, Charlotte Teunissen, Patrick Thoral, Anissa M. Tsonas, Pieter R. Tuinman, Marc van der Valk, Denise P. Veelo, Carolien Volleman, Heder de Vries, Lonneke A. Vught, Michèle van Vugt, Dorien Wouters, A.H. Zwinderman, Matthijs C. Brouwer, W. Joost Wiersinga, Alexander P.J. Vlaar, Miranda F. Tompkins, Camille Alba, Daniel N. Hupalo, John Rosenberger, Gauthaman Sukumar, Matthew D. Wilkerson, Xijun Zhang, Justin Lack, Andrew J. Oler, Kerry Dobbs, Ottavia M. Delmonte, Jeffrey J. Danielson, Andrea Biondi, Laura Rachele Bettini, Mariella D’Angiò, Ilaria Beretta, Luisa Imberti, Alessandra Sottini, Virginia Quaresima, Eugenia Quiros-Roldan, Camillo Rossi, Riccardo Castagnoli, Daniela Montagna, Amelia Licari, and Gian Luigi Marseglia

Subjects
HLA, association, asymptomatic infection, COVID-19, population stratification, Genetics, QH426-470
Abstract

Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

Published
2024
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3. Acute generalized exanthematous pustulosis caused by gemcitabine after nivolumab in metastatic lung adenocarcinoma followed by a dramatic tumor response: A case report

Author

Pierre Magdelaine, Adrien Costantini, Lucie Fabre, and Etienne Giroux‐Leprieur

Subjects
acute generalized exanthematous pustulosis, gemcitabine, lung adenocarcinoma, nivolumab, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Herein, we report a case of a 73‐year‐old female patient diagnosed with cT4N0M1a lung adenocarcinoma with KRAS G12C mutation, PDL1

Published
2022
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4. Electrocardiogram abnormalities and prognosis in COVID-19

Author

Gabriel Chevrot, Marie Hauguel-Moreau, Marion Pépin, Antoine Vieillard-Baron, Anne-Sophie Lot, Mounir Ouadahi, Hélène Hergault, Vincent Aïdan, Ségolène Greffe, Adrien Costantini, Olivier Dubourg, Sébastien Beaune, and Nicolas Mansencal

Subjects
ECG, COVID-19, prognosis, SARS-CoV-2, repolarization, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

BackgroundCOVID-19 is a major pandemic with potential cardiovascular complications. Few studies have focused on electrocardiogram (ECG) modifications in COVID-19 patients.Method and resultsWe reviewed from our database all patients referred to our hospital for COVID-19 between January 1st, 2020, and December 31st, 2020: 669 patients were included and 98 patients died from COVID-19 (14.6%). We systematically analyzed ECG at admission and during hospitalization if available. ECG was abnormal at admission in 478 patients (71.4%) and was more frequently abnormal in patients who did not survive (88.8 vs. 68.5%, p < 0.001). The most common ECG abnormalities associated with death were left anterior fascicular block (39.8 vs. 20.0% among alive patients, p < 0.001), left and right bundle branch blocks (p = 0.002 and p = 0.02, respectively), S1Q3 pattern (14.3 vs. 6.0%, p = 0.006). In multivariate analysis, at admission, the presence of left bundle branch block remained statistically related to death [OR = 3.82, 95% confidence interval (CI): 1.52–9.28, p < 0.01], as well as S1Q3 pattern (OR = 3.17, 95% CI: 1.38–7.03, p < 0.01) and repolarization abnormalities (OR = 2.41, 95% CI: 1.40–4.14, p < 0.01).On ECG performed during hospitalization, the occurrence of new repolarization abnormality was significantly related to death (OR = 2.72, 95% CI: 1.14–6.54, p = 0.02), as well as a new S1Q3 pattern (OR = 13.23, 95% CI: 1.49–286.56, p = 0.03) and new supraventricular arrhythmia (OR = 3.8, 95% CI: 1.11–13.35, p = 0.03).ConclusionThe presence of abnormal ECG during COVID-19 is frequent. Physicians should be aware of the usefulness of ECG for risk stratification during COVID-19.

Published
2022
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5. Corrigendum: High Circulating Sonic Hedgehog Protein Is Associated With Poor Outcome in EGFR-Mutated Advanced NSCLC Treated With Tyrosine Kinase Inhibitors

Author

Paul Takam Kamga, Aurélie Swalduz, Adrien Costantini, Catherine Julié, Jean-François Emile, Maurice Pérol, Virginie Avrillon, Sandra Ortiz-Cuaran, Pierre De Saintigny, and Etienne Giroux-Leprieur

Subjects
non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR), Sonic Hedgehog (Shh), biomarker, tyrosine kinase inhibitor (TKI), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2022
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6. High Circulating Sonic Hedgehog Protein Is Associated With Poor Outcome in EGFR-Mutated Advanced NSCLC Treated With Tyrosine Kinase Inhibitors

Author

Paul Takam Kamga, Aurélie Swalduz, Adrien Costantini, Catherine Julié, Jean-François Emile, Maurice Pérol, Virginie Avrillon, Sandra Ortiz-Cuaran, Pierre de Saintigny, and Etienne Giroux-Leprieur

Subjects
non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR), Sonic Hedgehog (Shh), biomarker, tyrosine kinase inhibitor (TKI), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

IntroductionGrowing preclinical evidence has suggested that the Sonic hedgehog (Shh) pathway is involved in resistance to tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). However, little is known concerning the prognostic value of this pathway in this context.Materials and MethodsWe investigated the relationship between plasma levels of Shh and EGFRm NSCLC patients’ outcome with EGFR TKIs. We included 74 consecutive patients from two institutions with EGFRm advanced NSCLC treated by EGFR TKI as first-line therapy. Plasma samples were collected longitudinally for each patient and were analyzed for the expression of Shh using an ELISA assay. The activation of the Shh–Gli1 pathway was assessed through immunohistochemistry (IHC) of Gli1 and RT-qPCR analysis of the transcripts of Gli1 target genes in 14 available tumor biopsies collected at diagnosis (baseline).ResultsAmong the 74 patients, only 61 had baseline (diagnosis) plasma samples, while only 49 patients had plasma samples at the first evaluation. Shh protein was detectable in all samples at diagnosis (n = 61, mean = 1,041.2 ± 252.5 pg/ml). Among the 14 available tumor biopsies, nuclear expression of Gli1 was observed in 57.1% (8/14) of patients’ biopsies. Shh was significantly (p < 0.05) enriched in youth (age < 68), male, nonsmokers, patients with a PS > 1, and patients presenting more than 2 metastatic sites and L858R mutation. Higher levels of Shh correlated with poor objective response to TKI, shorter progression-free survival (PFS), and T790M-independent mechanism of resistance. In addition, the rise of plasma Shh levels along the treatment was associated with the emergence of drug resistance in patients presenting an initial good therapy response.ConclusionThese data support that higher levels of plasma Shh at diagnosis and increased levels of Shh along the course of the disease are related to the emergence of TKI resistance and poor outcome for EGFR-TKI therapy, suggesting that Shh levels could stand both as a prognostic and as a resistance biomarker for the management of EGFR-mutated NSCLC patients treated with EGFR-TKI.

Published
2021
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8. ERS International Congress, Madrid, 2019: highlights from the Thoracic Oncology Assembly

Author

Adrien Costantini, Clementine Bostantzoglou, and Torsten Gerriet Blum

Subjects
Medicine
Abstract

Lung cancer is a devastating disease affecting hundreds of thousands of patients in Europe. Despite recent advances in treatment, its prognosis remains poor. This is mainly attributed to the late stages that diagnoses are usually established at, consequently excluding curative treatment options. During the 2019 European Respiratory Society International Congress in Madrid, Spain, lung cancer experts presented the most recent aspects of lung cancer early detection with low-dose computed tomography.

Published
2020
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9. Sequential ctDNA whole-exome sequencing in advanced lung adenocarcinoma with initial durable tumor response on immune checkpoint inhibitor and late progression

Author

Coraline Dumenil, Jennifer Dumoulin, Violaine Giraud, Sylvie Labrune, Catherine Julie, Etienne Giroux Leprieur, Paul Takam Kamga, Adrien Costantini, Alexandre Corjon, and Simon Garinet

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background Despite prolonged tumor response to immune checkpoint inhibitors (ICIs) for a subset of patients with advanced non-small cell lung cancer (NSCLC), a secondary resistance will occur for a majority of these patients. The understanding of late progression mechanisms with ICIs is important to improve future treatment strategies.Methods We performed whole-exome sequencing (WES) on circulating tumor DNA and compared molecular profiles between the beginning of ICI treatment and tumor progression in patients with advanced NSCLC treated with ICIs and who had initial and prolonged tumor response with secondary progression, after at least 6 months of treatment.Results We identified eight patients who experienced initial and durable tumor response, and secondary tumor progression after 6 months of treatment, with available paired blood samples (diagnosis and progression). All had lung adenocarcinoma, three had programmed-death ligand-1 expression ≥50% in immunohistochemistry and all presented low blood tumor mutational burden (bTMB). Seven patients received nivolumab in second-line or more, and one received pembrolizumab as first-line treatment. WES at progression showed clonal selection with molecular alterations of Wnt pathway-related genes, increase of copy number aberrations in cancer-related genes and loss of tumor-suppressor genes (such as PTEN) or of genes associated with immune response (such as B2M). No difference in term of bTMB was observed at progression.Conclusions This is the first study describing putative molecular mechanisms associated with late progression under ICI in lung cancer. Studies on treatment strategies adapted to these mechanisms are needed.

Published
2020
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10. The electronic nose: emerging biomarkers in lung cancer diagnostics

Author

Wouter H. van Geffen, Kevin Lamote, Adrien Costantini, Lizza E.L. Hendriks, Najib M. Rahman, Torsten G. Blum, and Jan van Meerbeeck

Subjects
Diseases of the respiratory system, RC705-779
Abstract

Lung cancer is very common and the most common cause of cancer death worldwide. Despite recent progress in the systemic treatment of lung cancer (checkpoint inhibitors and tyrosine kinase inhibitors), each year, >1.5 million people die due to this disease. Most lung cancer patients already have advanced disease at the time of diagnosis. Computed tomography screening of high-risk individuals can detect lung cancer at an earlier stage but at a cost of false-positive findings. Biomarkers could lead towards a reduction of these false-positive findings and earlier lung cancer diagnosis, and have the potential to improve outcomes and treatment monitoring. To date, there is a lack of such biomarkers for lung cancer and other thoracic malignancies, although electronic nose (e-nose)-derived biomarkers are of interest. E-nose techniques using exhaled breath component measurements can detect lung cancer with a sensitivity ranging from 71% to 96% and specificity from 33 to 100%. In some case series, such results have been validated but this is mostly using internal validation and hence, more work is needed. Furthermore, standardised sampling and analysis methods are lacking, impeding interstudy comparison and clinical implementation. In this narrative review, we provide an overview of the currently available data on E-nose technology for lung cancer detection.

Published
2019
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11. Positive plasma cotinine during platinum-based chemotherapy is associated with poor response rate in advanced non-small cell lung cancer patients.

Author

Philippine Dacosta-Noble, Adrien Costantini, Coraline Dumenil, Jennifer Dumoulin, Pierre Helly de Tauriers, Violaine Giraud, Sylvie Labrune, Jean-François Emile, Jean-Claude Alvarez, Thierry Chinet, and Etienne Giroux Leprieur

Subjects
Medicine, Science
Abstract

INTRODUCTION:Patients with advanced non-small cell lung cancer (NSCLC) are most of the time treated with a first-line cytotoxic chemotherapy. Tobacco use is responsible for 90% of lung cancer. The aim of this study was to evaluate the impact of smoking continuation during first-line chemotherapy on tumor response in advanced-stage NSCLC. MATERIALS AND METHODS:All patients with an advanced-stage NSCLC (IIIb or IV), treated with first-line platinum-based chemotherapy in our Department between June 2013 and July 2017 were included. Smoking status was assessed at inclusion by self-report, then at the tumor assessment consultation after 2 months of treatment, by both self-report and plasmatic cotinine measurement. Chemotherapy response, progression-free survival (PFS), overall survival (OS) and stage 3-4 toxicity were registered. RESULTS:Ninety-seven patients were included: 8 (8%) declared to be non-smokers, 56 (58%) current smokers and 33 (34%) former smokers at diagnosis. At the first tumor evaluation, 24 (25%) self-reported as active smokers and 73 (75%) as non-smokers; overall response rate (ORR) was respectively 38% and 48% (p = 0.373). Fifty-four patients had a plasmatic cotinine evaluation at the first tumor evaluation. Seventeen patients (32%) had a positive cotinine rate (median 108ng/mL, IQR 31-236). Six patients (35%) had positive cotinine rate whereas declaring to be non-smokers at the first tumor evaluation. ORR was 18% in case of positive cotinine rate, and 57% when negative (p = 0.007). Regardless of the method for smoking status evaluation, PFS, OS and grade 3-4 toxicities were similar between smoker and non-smoker patients at the first tumor evaluation. CONCLUSION:Smoking continuation during platinum-based chemotherapy, reflected by positive plasma cotinine rate, was associated with a poor ORR.

Published
2019
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12. Predictive role of plasmatic biomarkers in advanced non-small cell lung cancer treated by nivolumab

Author

Adrien Costantini, Catherine Julie, Coraline Dumenil, Zofia Hélias-Rodzewicz, Julie Tisserand, Jennifer Dumoulin, Violaine Giraud, Sylvie Labrune, Thierry Chinet, Jean-François Emile, and Etienne Giroux Leprieur

Subjects
nivolumab, non-small cell lung cancer, plasma, pd-l1, pd-l2, granzyme b, interleukine-2, interferon-γ, microrna, biomarker, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Immune checkpoint inhibitors, as nivolumab, are used in advanced non-small cell lung cancer (NSCLC). However, no associated biomarker is validated in clinical practice with this drug. We investigated herein immune-related blood markers in patients with advanced NSCLC treated with nivolumab. Plasma of 43 consecutive patients were prospectively collected at time of the diagnosis of cancer, at the initiation of nivolumab and at the first tumour evaluation (2 months). Concentrations of PD-L1 (sPD-L1), soluble PD-L2 (sPD-L2), Interleukine-2 (sIl-2), Interferon-gamma (sIFN-γ), and Granzyme B (sGranB) were quantified by ELISA. Cell free RNA was quantified by Reverse Transcriptase -PCR), and plasmatic microRNAs (miRNAs) were evaluated by targeted sequencing. Expression of PD-L1 on tumour biopsies was performed by immunohistochemistry using E13LN. High sPD-L1 at 2 months and increase of sPD-L1 concentrations were associated with poor response and absence of clinical benefit (nivolumab treatment less than 6 months). The variation of sPD-L1 concentrations were confirmed by RNA quantification. sPD-L1 concentrations were not correlated with PD-L1 expression on corresponding tumour samples. Low sGranB at nivolumab initiation was also associated with poor response. High sPD-L1 and low sGranB were associated with poor progression-free survival (PFS) and overall survival (OS). Low sPD-L2, low sIl-2 and high sIFN-γ were associated with grade 3–4 toxicities. Finally, miRNA screening showed that patients with clinical benefit (n = 9) had down-expression of miRNA-320b and -375 compared to patients with early progression at 2 months (n = 9). In conclusion, our results highlight the interest of circulating biomarkers in patients treated with nivolumab.

Published
2018
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13. Efficacy of next treatment received after nivolumab progression in patients with advanced nonsmall cell lung cancer

Author

Adrien Costantini, Jennifer Corny, Vincent Fallet, Sophie Renet, Sylvie Friard, Christos Chouaid, Boris Duchemann, Etienne Giroux-Leprieur, Laurent Taillade, Ludovic Doucet, Marina Nguenang, Stéphane Jouveshomme, Marie Wislez, Jean Tredaniel, and Jacques Cadranel

Subjects
Medicine
Abstract

Nivolumab for the treatment of advanced nonsmall cell lung cancer (NSCLC) evaluated in phase III trials showed 50% progression at first evaluation, but better overall survival (OS), suggesting regained efficacy of treatments given thereafter. We aimed to evaluate the efficacy of nivolumab and of next treatment received after nivolumab progression in patients with advanced NSCLC. Our multicentre retrospective study included all patients receiving nivolumab between January and December 2015. The primary end-point was progression-free survival (PFS) of treatment given after nivolumab. The 303 patients had the following characteristics: median age 63 years, 69% males, 92% smokers, 67% performance status 0–1 and 61% adenocarcinoma. Nivolumab was given as second-line treatment in 40% of patients. With 13.7 months of median follow-up, nivolumab PFS and OS were 2.6 and 11.3 months, respectively. At the cut-off analysis 18% were controlled under nivolumab, 14% were deceased and 5% were lost to follow-up under nivolumab. Among the 191 (63%) patients eligible for post-nivolumab (PN) treatment, 115 (38%) received further treatment and were characterised by better performance status (p=0.028) and by receiving more injections of nivolumab (p=0.001). Global PN-OS and PN-PFS were 5.2 and 2.8 months, respectively. Drugs most frequently used after nivolumab were gemcitabine (23%), docetaxel (22%) and erlotinib (16%), with median PFS of 2.8, 2.7 and 2.0 months, respectively. Nivolumab produced similar efficacy as in phase III trials, although patients received nivolumab later and had worse performance status. 38% received treatment after nivolumab progression with efficacy comparable to historical second-line trials.

Published
2018
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14. Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance

Author

Etienne Giroux-Leprieur, Adrien Costantini, Vivianne W. Ding, and Biao He

Subjects
Sonic Hedgehog, lung cancer, oncogenesis, cancer stem cell, chemoresistance, Epidermal Growth Factor Receptor (EGFR), tyrosine kinase inhibitor, radiotherapy, immune checkpoint inhibitor, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Hedgehog signaling pathway is physiologically activated during embryogenesis, especially in lung development. It is also reactivated in many solid tumors. In lung cancer, Hedgehog pathway is closely associated with cancer stem cells (CSCs). Recent works have shown that CSCs produced a full-length Sonic Hedgehog (Shh) protein, with paracrine activity and induction of tumor development. Hedgehog pathway is also involved in tumor drug resistance in lung cancer, as cytotoxic chemotherapy, radiotherapy, and targeted therapies. This review proposes to describe the activation mechanisms of Hedgehog pathway in lung cancer, the clinical implications for overcoming drug resistance, and the perspectives for further research.

Published
2018
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15. Severe sotorasib-related hepatotoxicity and non-liver adverse events associated with sequential anti-PD(L)1 and sotorasib therapy in KRASG12C-mutant lung cancer

Author

Ali Chour, Julie Denis, Céline Mascaux, Maeva Zysman, Laurence Bigay-Game, Aurélie Swalduz, Valérie Gounant, Alexis Cortot, Marie Darrason, Vincent Fallet, Edouard Auclin, Clémence Basse, Claire Tissot, Chantal Decroisette, Pierre Bombaron, Etienne Giroux-Leprieur, Luc Odier, Solenn Brosseau, Quentin Creusot, Marina Gueçamburu, Corentin Meersseman, Adrien Rochand, Adrien Costantini, Claire Marine Gaillard, Eric Wasielewski, Nicolas Girard, Jacques Cadranel, Claire Lafitte, Fanny Lebossé, and Michael Duruisseaux

Subjects
Pulmonary and Respiratory Medicine, Oncology
Published
2023

16. Gene expression profile of high PD-L1 non-small cell lung cancers refractory to pembrolizumab

Author

Jamila, Talb, Paul, Takam Kamga, Marie, Mayenga, Adrien, Costantini, Catherine, Julié, Coraline, Dumenil, Jennifer, Dumoulin, Julia, Ouaknine, Violaine, Giraud, Cécile, Dujon, Reza, Azarian, Claire, Glaser, Jean-François, Emile, and Etienne, Giroux Leprieur

Subjects
Male, Cancer Research, Lung Neoplasms, Programmed Cell Death 1 Receptor, Immunology, Antibodies, Monoclonal, Humanized, B7-H1 Antigen, Interferon-gamma, Oncology, Drug Resistance, Neoplasm, Albumins, Carcinoma, Non-Small-Cell Lung, Toll-Like Receptor 9, Humans, Immunology and Allergy, Female, Transcriptome, Retrospective Studies
Abstract

Despite high expression of PD-L1, around half of advanced non-small cell lung cancer (NSCLC) will not experience tumor response with pembrolizumab. There is an need for a better understanding of the resistance mechanisms in this setting.This bi-centric retrospective study included all consecutive patients with PDL1 ≥ 50% advanced NSCLC treated with pembrolizumab in first-line treatment between 2016 and 2020. We compared the clinical characteristics of patients with early progression (refractory) vs others. We performed a comprehensive gene expression profile screening by RNAseq capture on tumor samples.We included 46 patients. Twenty-two patients were refractory to pembrolizumab, mainly women, with poor performance status and lower albumin concentration. RNAseq analysis was performed on 19 samples. Hierarchical clustering allowed the identification of 3 clusters with various proportion of refractory tumors: intermediate (C1: 57%), high (C2: 71%) and low proportion (C3: 40%). Comparative analysis between C2 and C3 allowed the identification of overexpressed (n = 137) and underexpressed (n = 40) genes. Among the genes of interest, C2 exhibits higher activation of pathways associated with stemness phenotype (Hedgehog, Notch and Hippo pathways) and pathways associated with loss of PTEN and JAK2. In C2, genes associated with PD-1, toll-like receptor-9 (TLR-9), major histocompatibility complex (MHC) and interferon-γ pathways were underexpressed.This study gives an overview of activated and downregulated pathways in high PD-L1 NSCLC refractory to pembrolizumab. These tumors showed activation of pathways associated with cancer stem cells, loss of PTEN and JAK2, and inhibition of both priming and effector phases of the immune response.

Published
2022

17. Landmark Studies of Targeted Therapies for Advanced Non-Small Cell Lung Cancer: A Guide for Pulmonologists

Author

Adrien Costantini, Theodoros Katsikas, and Clementine Bostantzoglou

Subjects
Pulmonary and Respiratory Medicine, Oncology, medicine.medical_specialty, business.industry, 030204 cardiovascular system & hematology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, Non small cell, Lung cancer, business, Pulmonologists
Abstract

Over the past decade, major breakthroughs in the understanding of lung cancer histology and mutational pathways have radically changed diagnosis and management. More specifically, in non-small cell lung cancer (NSCLC), tumour characterisation has shifted from differentiating based solely on histology to characterisation that includes genetic profiling and mutational status of Epidermal Growth Factor (EGFR), Anaplastic Lymphoma Kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF. These genetic alterations can be targeted by specific drugs that result in improved progression-free survival, as well as higher response rates and are currently standard of care for NSCLC patients harbouring these mutations. In this a narrative, non-systematic review we aim to handpick through the extensive literature and critically present the ground-breaking studies that lead to the institution of tailored treatment options as the standard of care for the main targetable genetic alterations.

Published
2020

18. ERS International Congress, Madrid, 2019: highlights from the Thoracic Oncology Assembly

Author

Torsten Blum, Clementine Bostantzoglou, and Adrien Costantini

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, medicine.diagnostic_test, business.industry, General surgery, lcsh:R, Congress Highlights, lcsh:Medicine, Computed tomography, Disease, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Curative treatment, 030220 oncology & carcinogenesis, Thoracic Oncology, International congress, Lung cancer early detection, Medicine, business, Lung cancer
Abstract

Lung cancer is a devastating disease affecting hundreds of thousands of patients in Europe. Despite recent advances in treatment, its prognosis remains poor. This is mainly attributed to the late stages that diagnoses are usually established at, consequently excluding curative treatment options. During the 2019 European Respiratory Society International Congress in Madrid, Spain, lung cancer experts presented the most recent aspects of lung cancer early detection with low-dose computed tomography., Key thoracic oncology highlights from #ERSCongress Madrid 2019 https://bit.ly/3dQZtv7

Published
2020

19. Baseline hedgehog pathway activation and increase of plasma wnt1 protein are associated with resistance to immune checkpoint inhibitors in advanced non-small-cell lung cancer

Author

Thierry Chinet, Camille Mehlman, Violaine Giraud, Adrien Costantini, Coraline Dumenil, Jean-François Emile, J. Ouaknine, Jennifer Dumoulin, Etienne Giroux Leprieur, Paul Takam Kamga, Catherine Julie, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, and Hôpital Ambroise Paré [AP-HP]

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Gli1, Resistance, [SDV.CAN]Life Sciences [q-bio]/Cancer, Immune checkpoint inhibitor, lcsh:RC254-282, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Article, 03 medical and health sciences, Wnt, Plasma, 0302 clinical medicine, Non-small cell lung cancer, GLI1, WNT2, Interquartile range, Internal medicine, medicine, Sonic hedgehog, Lung cancer, Hedgehog, 030304 developmental biology, 0303 health sciences, biology, business.industry, Wnt signaling pathway, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Hedgehog signaling pathway, 3. Good health, Sonic Hedgehog, 030220 oncology & carcinogenesis, Beta-catenin, biology.protein, business
Abstract

Simple Summary Wnt and Hedgehog (Hh) pathways are associated with stemness profile and with resistance to anti-tumor therapies. Pre-clinical data have suggested a role of these pathways in resistance to immune checkpoint inhibitors (ICIs). Here we evaluated the expression and levels of Shh and Wnt molecules both in plasma and tumor samples in a prospective cohort of 63 consecutive NSCLC patients treated with ICIs. We found that baseline Hh activation as assessed by nuclear staining of Gli1 was associated with poor outcome and high primary resistance rate. Increase of plasma Wnt1 during treatment was associated with resistance to ICIs. This is the first study to our knowledge to find an association between the Hh and Wnt pathways and resistance to ICIs in advanced NSCLC patients. We believe that these results are important to understand the molecular mechanisms associated with resistance to ICIs, and ultimately to improve future treatment strategies. Abstract Hedgehog (Hh) and Wingless-type (Wnt) pathways are associated with resistance to immune checkpoint inhibitors (ICIs) in preclinical studies. This study aimed to assess the association between expression and activation levels of Wnt and Sonic Hedgehog (Shh) pathways and resistance to ICIs in advanced NSCLC patients treated with ICI. Hh and Wnt pathways activation was assessed by immunohistochemistry (Gli1 and beta-catenin) on corresponding tumor tissues, and by plasma concentrations of Shh and Wnt (Wnt1, Wnt2 and Wnt3) at ICI introduction and at the first clinical evaluation. Sixty-three patients were included, with 36 patients (57.1%) with available tissue. Response rate was lower in Gli1+ NSCLC (20.0%) compared to Gli1 negative (Gli-) NSCLC (55.6%) (p = 0.015). Rate of primary resistance was 69.8%, vs. 31.2%, respectively (p = 0.04), and median progression-free survival (PFS) was 1.9 months (interquartile range (IQR) 1.2–5.7) vs. 6.1 months (1.6–26.0), respectively (p = 0.08). Median PFS and overall survival were shorter in case of increase of Wnt1 concentration during ICI treatment compared to other patients: 3.9 months vs. 11.2 months (p = 0.008), and 15.3 months vs. not reached (p = 0.003). In conclusion, baseline activation of Hh pathway and increase of Wnt1 concentrations during ICI treatment were associated with poor outcome in NSCLC patients treated with ICIs.

Published
2021

20. Plasma Biomarkers Screening by Multiplex ELISA Assay in Patients with Advanced Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors

Author

Jennifer Dumoulin, Adrien Costantini, Violaine Giraud, Catherine Julie, Coraline Dumenil, Thierry Chinet, Jean-François Emile, Alexandre Corjon, Martin Rottman, J. Ouaknine, Etienne Giroux Leprieur, Paul Takam Kamga, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), HAL UVSQ, Équipe, Hôpital Ambroise Paré [AP-HP], and Hôpital Raymond Poincaré [AP-HP]

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Fibroblast growth factor, immune checkpoint inhibitor, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pembrolizumab, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, lcsh:RC254-282, Article, resistance, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Medicine, Multiplex, 030212 general & internal medicine, Adverse effect, Lung cancer, non-small cell lung cancer, plasma, interleukine-12, business.industry, toxicity, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, respiratory tract diseases, hepatocyte growth factor, 030220 oncology & carcinogenesis, Toxicity, Biomarker (medicine), [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, biomarker, Nivolumab, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business
Abstract

Immune checkpoint inhibitors (ICIs) are commonly used in patients with advanced non-small cell lung cancer (NSCLC). An unmet need remains for new biomarkers associated with ICIs. In this study, consecutive patients with advanced NSCLC treated with nivolumab or pembrolizumab were included. Plasma at ICIs initiation was prospectively collected and a multiplex ELISA assay testing 48 cytokines and growth factors was performed. Exploratory endpoints were the association between plasma biomarkers with outcome and grade III&ndash, IV immune related adverse events (irAEs). Thirty-five patients were included. Patients without clinical benefit (n = 22) had higher pre-ICI soluble Hepatocyte Growth Factor (sHGF) (210.9 vs. 155.8 pg/mL, p = 0.010), lower pre-ICI soluble Fibroblast Growth Factor (sFGF) (4.0 vs. 4.8 pg/mL, p = 0.043) and lower pre-ICI interleukine-12 (IL-12) (1.3 vs. 2.2 pg/mL, p = 0.043) concentrations. Patients with early progression (n = 23) had higher pre-ICIs sHGF (206.2 vs. 155.8 pg/mL, p = 0.025) concentrations. Patients with low sHGF levels at ICIs initiation had longer progression-free survival and overall survival than those with high sHGF levels: respectively 2.5 vs. 8.0 months (p = 0.002), and 5.5 vs. 35.0 months (p = 0.001). TNF-&alpha, IL-16, IL-12p40 and MCP3 were associated with high grade irAEs. This study shows the potential association between several plasma biomarkers with outcome and grade 3&ndash, 4 IrAEs in advanced NSCLC treated with ICIs.

Published
2020

21. Sequential ctDNA whole-exome sequencing in advanced lung adenocarcinoma with initial durable tumor response on immune checkpoint inhibitor and late progression

Author

Adrien Costantini, Paul Takam Kamga, Thierry Chinet, Jean-François Emile, Etienne Giroux Leprieur, Simon Garinet, Sylvie Labrune, Alexandre Corjon, Zofia Hélias-Rodzewicz, Coraline Dumenil, Catherine Julie, Violaine Giraud, Jennifer Dumoulin, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Ambroise Paré [AP-HP], Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, Lung Neoplasms, Time Factors, DNA Mutational Analysis, Programmed Cell Death 1 Receptor, Pembrolizumab, B7-H1 Antigen, Circulating Tumor DNA, 0302 clinical medicine, biomarkers, tumor, Carcinoma, Non-Small-Cell Lung, Immunology and Allergy, Immune Checkpoint Inhibitors, Lung, Exome sequencing, RC254-282, Clinical/Translational Cancer Immunotherapy, Aged, 80 and over, biology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Middle Aged, Progression-Free Survival, 3. Good health, Nivolumab, 030220 oncology & carcinogenesis, Disease Progression, Molecular Medicine, Adenocarcinoma, Female, Microsatellite Instability, Drug Monitoring, Adult, tumor, medicine.medical_specialty, DNA Copy Number Variations, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Immune system, Internal medicine, Exome Sequencing, medicine, Humans, PTEN, Lung cancer, Aged, Neoplasm Staging, Retrospective Studies, Pharmacology, business.industry, biomarkers, medicine.disease, 030104 developmental biology, Drug Resistance, Neoplasm, Tumor progression, Mutation, biology.protein, business
Abstract

BackgroundDespite prolonged tumor response to immune checkpoint inhibitors (ICIs) for a subset of patients with advanced non-small cell lung cancer (NSCLC), a secondary resistance will occur for a majority of these patients. The understanding of late progression mechanisms with ICIs is important to improve future treatment strategies.MethodsWe performed whole-exome sequencing (WES) on circulating tumor DNA and compared molecular profiles between the beginning of ICI treatment and tumor progression in patients with advanced NSCLC treated with ICIs and who had initial and prolonged tumor response with secondary progression, after at least 6 months of treatment.ResultsWe identified eight patients who experienced initial and durable tumor response, and secondary tumor progression after 6 months of treatment, with available paired blood samples (diagnosis and progression). All had lung adenocarcinoma, three had programmed-death ligand-1 expression ≥50% in immunohistochemistry and all presented low blood tumor mutational burden (bTMB). Seven patients received nivolumab in second-line or more, and one received pembrolizumab as first-line treatment. WES at progression showed clonal selection with molecular alterations of Wnt pathway-related genes, increase of copy number aberrations in cancer-related genes and loss of tumor-suppressor genes (such as PTEN) or of genes associated with immune response (such as B2M). No difference in term of bTMB was observed at progression.ConclusionsThis is the first study describing putative molecular mechanisms associated with late progression under ICI in lung cancer. Studies on treatment strategies adapted to these mechanisms are needed.

Published
2020

22. Effect of Ruxolitinib on Lung Function after Allogeneic Stem Cell Transplantation

Author

Louise Bondeelle, Jean-David Bouaziz, Sylvie Chevret, Abdellatif Tazi, Gérard Socié, Laila Samy, Charlotte Hurabielle, Tiphaine Goletto, Flore Sicre de Fontbrune, Anne Bergeron, David Michonneau, Adrien Costantini, 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), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), CCSD, Accord Elsevier, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Equipe 2 : ECSTRA - Epidémiologie Clinique, STatistique, pour la Recherche en Santé (CRESS - U1153), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), and Université Paris Cité (UPCité)

Subjects
Oncology, medicine.medical_specialty, Vital capacity, Ruxolitinib, Sclerodermatous chronic graft-versus-host disease, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Bronchiolitis obliterans, Graft vs Host Disease, Hematopoietic stem cell transplantation, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Internal medicine, Nitriles, medicine, Humans, Restrictive lung disease, Bronchiolitis Obliterans, Lung, Retrospective Studies, Transplantation, business.industry, Hematopoietic Stem Cell Transplantation, Hematology, Total body irradiation, medicine.disease, Sclerotic-type skin cGVHD, 3. Good health, [SDV] Life Sciences [q-bio], Pyrimidines, 030220 oncology & carcinogenesis, Pulmonary graft-versus-host disease, Pyrazoles, business, 030215 immunology, medicine.drug
Abstract

International audience; Ruxolitinib, a selective Janus kinase (JAK)1/2 inhibitor, has recently been proposed for steroid-refractory chronic graft-versus host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT), particularly in severe skin cGVHD. Lung function impairment is common in severe skin cGVHD through concomitant bronchiolitis obliterans syndrome (BOS) or restrictive lung disease (RLD) from skin sclerosis. To date, no treatment has shown a benefit on lung function in this context. We retrospectively assessed the effect of ruxolitinib on lung function in a cohort of 70 patients diagnosed with sclerotic-type skin cGVHD between March 2015 and April 2018. Among these patients, 36 received ruxolitinib. To handle confounding by indication bias, exposure groups were matched on the propensity score to receive ruxolitinib, incorporating age, myeloablative conditioning, total body irradiation, BOS, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and tobacco use at the time of cohort entry, as well as the time from transplantation. The 1:1 matching used a greedy-matching algorithm with replacement, with a caliper of 0.10. FVC and FEV1 trajectories during follow-up were compared in the matched samples, using linear mixed-effects models. The median duration of follow-up of the 46 matched patients was 58 months (interquartile range, 32 to 84 months). Ten patients had an RLD (6 exposed, 4 unexposed), and 13 patients were diagnosed with BOS (8 exposed, 5 unexposed). FEV1 decreased significantly over time independent of exposure to ruxolitinib (P < .0001). The FEV1 trajectory was similar in the exposed patients and the unexposed patients (P = .11). In conclusion, ruxolitinib administration did not demonstrate any improvement in the course of respiratory function in allogeneic HSCT recipients with sclerotic-type skin cGVHD.

Published
2020

23. Positive plasma cotinine during platinum-based chemotherapy is associated with poor response rate in advanced non-small cell lung cancer patients

Author

Violaine Giraud, Thierry Chinet, Etienne Giroux Leprieur, Sylvie Labrune, Pierre Helly de Tauriers, Coraline Dumenil, Philippine Dacosta-Noble, Adrien Costantini, Jean-Claude Alvarez, Jean-François Emile, Jennifer Dumoulin, Department of Respiratory Diseases and Thoracic Oncology [Boulogne-Billancourt], Hôpital Ambroise Paré [AP-HP], Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Centre de Ressources Biologiques [Boulogne-Billancourt], Service de Pharmacologie Toxicologie [Garches], Hôpital Raymond Poincaré [AP-HP], Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Bodescot, Myriam

Subjects
0301 basic medicine, Oncology, Male, Lung Neoplasms, medicine.medical_treatment, Cancer Treatment, Social Sciences, Platinum Compounds, Kaplan-Meier Estimate, Toxicology, Pathology and Laboratory Medicine, Lung and Intrathoracic Tumors, Diagnostic Radiology, Nicotine, chemistry.chemical_compound, Habits, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Smoking Habits, Medicine and Health Sciences, Psychology, Prospective Studies, Prospective cohort study, Cotinine, Tomography, Aged, 80 and over, Multidisciplinary, Radiology and Imaging, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Middle Aged, Prognosis, 3. Good health, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Chemistry, 030220 oncology & carcinogenesis, Physical Sciences, Medicine, Female, France, medicine.drug, Research Article, Chemical Elements, Adult, medicine.medical_specialty, Imaging Techniques, Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, Neuroimaging, Antineoplastic Agents, Research and Analysis Methods, Disease-Free Survival, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Diagnostic Medicine, Internal medicine, medicine, Carcinoma, Cancer Detection and Diagnosis, Tobacco Smoking, Humans, Lung cancer, Platinum, Aged, Retrospective Studies, Chemotherapy, Behavior, Toxicity, business.industry, Biology and Life Sciences, Cancers and Neoplasms, Retrospective cohort study, medicine.disease, Nicotine replacement therapy, respiratory tract diseases, Non-Small Cell Lung Cancer, Computed Axial Tomography, 030104 developmental biology, chemistry, business, Biomarkers, Neuroscience
Abstract

Introduction Patients with advanced non-small cell lung cancer (NSCLC) are most of the time treated with a first-line cytotoxic chemotherapy. Tobacco use is responsible for 90% of lung cancer. The aim of this study was to evaluate the impact of smoking continuation during first-line chemotherapy on tumor response in advanced-stage NSCLC. Materials and methods All patients with an advanced-stage NSCLC (IIIb or IV), treated with first-line platinum-based chemotherapy in our Department between June 2013 and July 2017 were included. Smoking status was assessed at inclusion by self-report, then at the tumor assessment consultation after 2 months of treatment, by both self-report and plasmatic cotinine measurement. Chemotherapy response, progression-free survival (PFS), overall survival (OS) and stage 3-4 toxicity were registered. Results Ninety-seven patients were included: 8 (8%) declared to be non-smokers, 56 (58%) current smokers and 33 (34%) former smokers at diagnosis. At the first tumor evaluation, 24 (25%) self-reported as active smokers and 73 (75%) as non-smokers; overall response rate (ORR) was respectively 38% and 48% (p = 0.373). Fifty-four patients had a plasmatic cotinine evaluation at the first tumor evaluation. Seventeen patients (32%) had a positive cotinine rate (median 108ng/mL, IQR 31-236). Six patients (35%) had positive cotinine rate whereas declaring to be non-smokers at the first tumor evaluation. ORR was 18% in case of positive cotinine rate, and 57% when negative (p = 0.007). Regardless of the method for smoking status evaluation, PFS, OS and grade 3-4 toxicities were similar between smoker and non-smoker patients at the first tumor evaluation. Conclusion Smoking continuation during platinum-based chemotherapy, reflected by positive plasma cotinine rate, was associated with a poor ORR.

Published
2019

24. 2014TiP REBIMMUNE trial: A prospective study of REBiopsy at progression during IMMUNothErapy in advanced lung cancer

Author

M. Humbert, Jennifer Dumoulin, F. Parent, Catherine Julie, Thierry Chinet, Antoinette Lemoine, A. Seferian, Etienne Giroux-Leprieur, Adrien Costantini, Violaine Giraud, Coraline Dumenil, J. Ouaknine, P. Takam Kamga, and J.F. Emile

Subjects
Oncology, medicine.medical_specialty, business.industry, Internal medicine, medicine.medical_treatment, medicine, Hematology, Immunotherapy, Lung cancer, medicine.disease, business, Prospective cohort study
Published
2020

25. Nivolumab-refractory patients with advanced non-small-cell lung cancer

Author

Christos Chouaid, Vincent Fallet, Laurent Taillade, B. Duchemann, Sylvie Friard, Etienne Giroux-Leprieur, Jennifer Corny, Ludovic Doucet, Marie Wislez, Jean Trédaniel, Jacques Cadranel, Solenn Brosseau, Adrien Costantini, Gestionnaire, Hal Sorbonne Université, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Foch [Suresnes], Centre Hospitalier Intercommunal de Créteil (CHIC), Hôpital Avicenne [AP-HP], Hôpital Ambroise Paré [AP-HP], CHU Pitié-Salpêtrière [AP-HP], Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CIC Hôpital Bichat, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine-AP-HP - Hôpital Bichat - Claude Bernard [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, Lung Neoplasms, [SDV]Life Sciences [q-bio], Disease, Cohort Studies, 0302 clinical medicine, Antineoplastic Agents, Immunological, Carcinoma, Non-Small-Cell Lung, Prospective Studies, Aged, 80 and over, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Nivolumab, Treatment Outcome, 030220 oncology & carcinogenesis, Cohort, Disease Progression, Female, Non small cell, France, Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, Adolescent, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Young Adult, Refractory, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Lung cancer, Aged, business.industry, Cancer, Retrospective cohort study, medicine.disease, Survival Analysis, Treatment, 030104 developmental biology, Drug Resistance, Neoplasm, business, Non-small-cell lung cancer
Abstract

International audience; Introduction: Immune checkpoint inhibitors (ICIs) have revolutionised cancer care especially in lung cancer. New response patterns have been described under ICIs such as pseudo-progression or hyper-progressive disease (HPD). The definition of HPD is yet to be consensual. The aim of this study was to suggest a clinical definition of nivolumab-refractory patients and find factors associated with this entity.Methods: We performed a multi centric retrospective study including all patients who received nivolumab for the treatment of advanced non-small cell lung cancer (NSCLC) during the French authorisation for temporary use in 2015.Results: 303 patients were included in the cohort and 292 had details on the number of nivolumab injections received. 57 patients (20%) were nivolumab-refractory. These patients had worse PS at nivolumab initiation (p

Published
2018

26. Predictive role of plasmatic biomarkers in advanced non-small cell lung cancer (NSCLC) treated with nivolumab (nivo)

Author

Coraline Dumenil, Jennifer Dumoulin, Etienne Giroux-Leprieur, Adrien Costantini, Zofia Hélias-Rodzewicz, Jean-François Emile, Catherine Julié, Violaine Giraud, Thierry Chinet, and Sylvie Labrune

Subjects
Oncology, medicine.medical_specialty, biology, business.industry, non-small cell lung cancer (NSCLC), Cancer, medicine.disease, Granzyme B, Internal medicine, microRNA, medicine, biology.protein, Immunohistochemistry, In patient, Antibody, Nivolumab, business
Abstract

Background: Nivolumab (nivo) is an anti-PD1 antibody, used in second line treatment in non-small cell lung cancer (NSCLC). We investigated the potential interest of immune-related blood markers in patients with advanced NSCLC treated with nivo. Patients and methods: Plasma samples of 43 consecutive patients were prospectively collected at the time of diagnosis of cancer, at the initiation of nivo and at the first tumour evaluation (2 months). Concentrations of soluble PD-L1 (sPD-L1), soluble PD-L2 (sPD-L2), Interleukine-2 (Il-2), Interferon-gamma (IFN-γ), and Granzyme B (GranB) were quantified by ELISA. Plasmatic miRNA screening was also performed at the initiation of nivo. Expression of PD-L1 on tumour biopsies was evaluated by immunohistochemistry (IHC) using E13LN. Tumour response was evaluated by iRECIST. Results: High sPD-L1 at 2 months and increase of sPD-L1 concentrations at the beginning of nivo treatment were associated with poor response and tumour progression within 6 months of treatment. sPD-L1 concentrations at diagnosis were not correlated with PD-L1 expression on corresponding tumour samples. Low GranB at nivo initiation was also associated with poor response. High sPD-L1 and low GranB were associated with poor progression-free survival (PFS) and overall survival (OS). Low sPD-L2, low Il-2 and high IFN-γ were associated with grade 3-4 toxicities. miRNA screening showed that patients with long-term clinical benefit (n=9) had down-expression of miRNA-320b and -375 compared to patients with early progression at 2 months (n=9). Conclusion: Our results showed the predictive value of circulating biomarkers in patients with NSCLC treated with nivo.

Published
2018

27. Hyper-progressive disease in patients with advanced non-small cell lung cancer (NSCLC) treated with nivolumab (nivo)

Author

Jennifer Corny, Stéphane Jouveshomme, Adrien Costantini, Marie Wislez, Vincent Fallet, Sylvie Friard, Sophie Renet, Christos Chouaid, Jean Trédaniel, Laurent Taillade, Ludovic Doucet, Jacques Cadranel, Etienne Giroux-Leprieur, Marina Nguenang, and Boris Duchemann

Subjects
Oncology, medicine.medical_specialty, business.industry, non-small cell lung cancer (NSCLC), Histology, Retrospective cohort study, medicine.disease, Baseline characteristics, Internal medicine, medicine, Adenocarcinoma, In patient, Nivolumab, business, Progressive disease
Abstract

Background: Nivo is the gold standard for second line treatment of advanced NSCLC. Hyper-progression (HP) is a form of early progression observed during treatment by immune checkpoint inhibitors and usually fatal which has been poorly evaluated. Aim: To determine factors associated with HP in patients with advanced NSCLC treated with nivo. Methods: Our multi-center retrospective study included all patients with advanced NSCLC receiving nivo during the French authorisation for temporary use between January and December 2015. HP was defined as progression or death occurring before any tumour evaluation or before 3 injections of nivo. Results: 263 patients were included with 14.6-months median follow-up. Median overall survival (OS) at the date of cut-off was 10.1 months [95% CI (7.7 – 13.0)]. Baseline characteristics were as follows: 65 years, 68% male, 92% smokers, 62% with adenocarcinoma histology, 28% with squamous cell carcinoma and 10% with other, 66% with PS 0-1 at nivo initiation. Fifty-one patients (19%) had progressed before receiving 3 injections of nivo and a further 51 (19%) before receiving 5. Patients who presented with more rapid progression had worse PS at nivo initiation (p=0.042), worse PS at first nivo evaluation (p Conclusion: Nearly 20% of our patients experienced HP before 3 injections of nivo resulting in worsening OS. HP needs to be further studied in order to better select patients who will truly benefit from immune checkpoint inhibitors.

Published
2018

28. Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance

Author

Biao He, Vivianne W. Ding, Etienne Giroux-Leprieur, and Adrien Costantini

Subjects
0301 basic medicine, Lung Neoplasms, Carcinogenesis, medicine.medical_treatment, Drug Resistance, immune checkpoint inhibitor, Drug resistance, Review, Epidermal Growth Factor Receptor, medicine.disease_cause, Radiation Tolerance, Tyrosine-kinase inhibitor, lcsh:Chemistry, 0302 clinical medicine, tyrosine kinase inhibitor, Medicine, Sonic hedgehog, Lung, lcsh:QH301-705.5, Spectroscopy, Cancer, biology, Lung Cancer, chemoresistance, General Medicine, Hedgehog signaling pathway, Epidermal Growth Factor Receptor (EGFR), Computer Science Applications, Sonic Hedgehog, 030220 oncology & carcinogenesis, embryonic structures, Stem Cell Research - Nonembryonic - Non-Human, Signal Transduction, cancer stem cell, animal structures, medicine.drug_class, Catalysis, Inorganic Chemistry, 03 medical and health sciences, Rare Diseases, Cancer stem cell, oncogenesis, Genetics, Animals, Humans, Hedgehog Proteins, Physical and Theoretical Chemistry, Lung cancer, Molecular Biology, radiotherapy, Chemical Physics, business.industry, Organic Chemistry, medicine.disease, Stem Cell Research, Radiation therapy, lung cancer, 030104 developmental biology, Orphan Drug, lcsh:Biology (General), lcsh:QD1-999, Drug Resistance, Neoplasm, biology.protein, Cancer research, Neoplasm, Other Biological Sciences, business, Other Chemical Sciences
Abstract

Hedgehog signaling pathway is physiologically activated during embryogenesis, especially in lung development. It is also reactivated in many solid tumors. In lung cancer, Hedgehog pathway is closely associated with cancer stem cells (CSCs). Recent works have shown that CSCs produced a full-length Sonic Hedgehog (Shh) protein, with paracrine activity and induction of tumor development. Hedgehog pathway is also involved in tumor drug resistance in lung cancer, as cytotoxic chemotherapy, radiotherapy, and targeted therapies. This review proposes to describe the activation mechanisms of Hedgehog pathway in lung cancer, the clinical implications for overcoming drug resistance, and the perspectives for further research.

Published
2018

29. Increased Response Rates to Salvage Chemotherapy Administered after PD-1/PD-L1 Inhibitors in Patients with Non-Small Cell Lung Cancer

Author

Adrien Costantini and Jacques Cadranel

Subjects
Pulmonary and Respiratory Medicine, Oncology, medicine.medical_specialty, Lung Neoplasms, Salvage treatment, Programmed Cell Death 1 Receptor, Salvage therapy, B7-H1 Antigen, 03 medical and health sciences, 0302 clinical medicine, Text mining, Internal medicine, PD-L1, Carcinoma, Non-Small-Cell Lung, Carcinoma, Medicine, Humans, In patient, 030212 general & internal medicine, Lung cancer, Salvage Therapy, biology, business.industry, medicine.disease, 030220 oncology & carcinogenesis, biology.protein, business
Published
2017

30. Immunotherapy: a new standard of care in thoracic malignancies? A summary of the European Respiratory Society research seminar of the Thoracic Oncology Assembly

Author

Franck Pagès, Jorge Moisés, Anne-Pascale Meert, Frances A. Shepherd, Adrien Costantini, Marina Chiara Garassino, H. Bouchaab, Marta Grynovska, Julien Mazieres, Francesca Lucibello, Thierry Berghmans, Jacques Cadranel, Michele Mondini, Joachim G.J.V. Aerts, and Ming-Sound Tsao

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Paris, Standard of care, Lung Neoplasms, medicine.medical_treatment, MEDLINE, Cancer Vaccines, B7-H1 Antigen, 03 medical and health sciences, 0302 clinical medicine, Thoracic Oncology, Carcinoma, Non-Small-Cell Lung, Biomarkers, Tumor, Pulmonary Medicine, Medicine, Humans, Intensive care medicine, Lung cancer, Adverse effect, Societies, Medical, Clinical Trials as Topic, Antitumor immunity, business.industry, Patient Selection, Antibodies, Monoclonal, Standard of Care, Immunotherapy, Oncogenes, Congresses as Topic, Thoracic Neoplasms, medicine.disease, Immunohistochemistry, Radiation therapy, Europe, 030104 developmental biology, 030220 oncology & carcinogenesis, business
Abstract

In May 2017, the second European Respiratory Society research seminar of the Thoracic Oncology Assembly entitled “Immunotherapy, a new standard of care in thoracic malignancies?” was held in Paris, France. This seminar provided an opportunity to review the basis of antitumour immunity and to explain how immune checkpoint inhibitors (ICIs) work. The main therapeutic trials that have resulted in marketing authorisations for use of ICIs in lung cancer were reported. A particular focus was on the toxicity of these new molecules in relation to their immune-related adverse events. The need for biological selection, currently based on immunohistochemistry testing to identify the tumour expression of programmed death ligand (PD-L)1, was stressed, as well as the need to harmonise PD-L1 testing and techniques. Finally, sessions were dedicated to the combination of ICIs and radiotherapy and the place of ICIs in nonsmall cell lung cancer with oncogenic addictions. Finally, an important presentation was dedicated to the future of antitumour vaccination and of all ongoing trials in thoracic oncology.

Published
2017

31. Efficacy of next treatment received after nivolumab progression in patients with advanced nonsmall cell lung cancer

Author

Jennifer Corny, Adrien Costantini, Christos Chouaid, Jean Trédaniel, Sophie Renet, Sylvie Friard, Laurent Taillade, Stéphane Jouveshomme, Marina Nguenang, Vincent Fallet, Ludovic Doucet, Jacques Cadranel, Marie Wislez, Etienne Giroux-Leprieur, and Boris Duchemann

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, Oncology, medicine.medical_specialty, lcsh:Medicine, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, In patient, Performance status, business.industry, lcsh:R, Lung Cancer, Retrospective cohort study, Original Articles, medicine.disease, Gemcitabine, 030104 developmental biology, Docetaxel, 030220 oncology & carcinogenesis, Adenocarcinoma, Erlotinib, Nivolumab, business, medicine.drug
Abstract

Nivolumab for the treatment of advanced nonsmall cell lung cancer (NSCLC) evaluated in phase III trials showed 50% progression at first evaluation, but better overall survival (OS), suggesting regained efficacy of treatments given thereafter. We aimed to evaluate the efficacy of nivolumab and of next treatment received after nivolumab progression in patients with advanced NSCLC. Our multicentre retrospective study included all patients receiving nivolumab between January and December 2015. The primary end-point was progression-free survival (PFS) of treatment given after nivolumab. The 303 patients had the following characteristics: median age 63 years, 69% males, 92% smokers, 67% performance status 0–1 and 61% adenocarcinoma. Nivolumab was given as second-line treatment in 40% of patients. With 13.7 months of median follow-up, nivolumab PFS and OS were 2.6 and 11.3 months, respectively. At the cut-off analysis 18% were controlled under nivolumab, 14% were deceased and 5% were lost to follow-up under nivolumab. Among the 191 (63%) patients eligible for post-nivolumab (PN) treatment, 115 (38%) received further treatment and were characterised by better performance status (p=0.028) and by receiving more injections of nivolumab (p=0.001). Global PN-OS and PN-PFS were 5.2 and 2.8 months, respectively. Drugs most frequently used after nivolumab were gemcitabine (23%), docetaxel (22%) and erlotinib (16%), with median PFS of 2.8, 2.7 and 2.0 months, respectively. Nivolumab produced similar efficacy as in phase III trials, although patients received nivolumab later and had worse performance status. 38% received treatment after nivolumab progression with efficacy comparable to historical second-line trials., Efficacy of nivolumab in nonsmall cell lung cancer http://ow.ly/k2uX30iGZbY

Published
2017

32. Efficacy of next treatment received after Nivolumab (Nivo) progression in patients (pts) with non-small-cell lung cancer (NSCLC)

Author

Laurent Taillade, Ludovic Doucet, Jacques Cadranel, Adrien Costantini, Vincent Fallet, Sophie Renet, Jean Trédaniel, Marie Wislez, Etienne Giroux-Leprieur, Boris Duchemann, Sylvie Friard, Christos Chouaid, Stéphane Jouveshomme, and Jennifer Corny

Subjects
medicine.medical_specialty, education.field_of_study, business.industry, Population, non-small cell lung cancer (NSCLC), medicine.disease, Gastroenterology, Gemcitabine, Docetaxel, Internal medicine, medicine, Clinical endpoint, Progression-free survival, Erlotinib, Nivolumab, business, education, medicine.drug
Abstract

Background: Nivo is authorised for 2nd line treatment of advanced NSCLC. Although 50% of pts progressed at 1st Nivo evaluation in phase III trials overall survival (OS) favoured Nivo suggesting better efficacy of treatments given post Nivo. Aim: To evaluate the efficacy of the next treatment received after Nivo progression in advanced NSCLC patients receiving Nivo. Methods: Our multi-center retrospective study included all pts receiving Nivo during the French authorisation for temporary use (ATU) between Jan and Dec 2015. Primary end point was progression free survival (PFS) on the next treatment given post Nivo. Results: Characteristics of the 297 pts included at Nivo initiation: 65 years, 69% males, 90% smokers; 61% adenocarcinoma, 29% squamous and 10% others; 68% PS 0-1. Nivo was given in 40%, 29% and 31% in 2nd, 3rd or ≥4th line treatment respectively. With a 22 months (mos) median follow-up, PFS on Nivo was 2,6 mos (95%CI [2.1-3.5]) and OS 10,9 mos [8,5 -NR]. 32% of pts died before further treatment, 4% were lost of follow-up, 24% were controlled, 5% were progressive but did not receive post Nivo treatment and 34% (n=101) received post Nivo treatment. Characteristics of these pts did not differ from that of the overall population. Most frequent drugs used were: 24% gemcitabine (G), 21% docetaxel (D) and 15% Erlotinib (E). The PFS after Nivo was 2.7 mos [2.1-3.4]; 2.7 mos for G, 2.7 mos for D and 1.8 mos for E. Treatment duration was >5 mos for G and >4 mos for D in 25% of pts. Conclusion: Nivo produced similar efficacy as in phase III trials. Although only 34% of pts received post Nivo treatment, 25% had longer treatment duration on G or D.

Published
2017

33. Plasma Biomarkers and Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer: New Tools for Better Patient Selection?

Author

Adrien Costantini, Jean-François Emile, Coraline Dumenil, Etienne Giroux Leprieur, Thierry Chinet, and Paul Takam Kamga

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Immune checkpoint inhibitors, immune checkpoint inhibitor, Review, Disease, Plasma biomarkers, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Microbiome, Lung cancer, Adverse effect, non-small cell lung cancer, plasma, business.industry, biomarkers, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, Biomarker (medicine), Non small cell, business
Abstract

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for patients with non-small cell lung cancer (NSCLC). Although some patients can experience important response rates and improved survival, many others do not benefit from ICIs developing hyper-progressive disease or immune-related adverse events. This underlines the need to select biomarkers for ICIs use in order to better select patients. There is currently no universally validated robust biomarker for daily use of ICIs. Programmed death-ligand 1 (PD-L1) or tumor mutational burden (TMB) are sometimes used but still have several limitations. Plasma biomarkers are a promising approach in ICI treatment. This review will describe the development of novel plasma biomarkers such as soluble proteins, circulating tumor DNA (ctDNA), blood TMB, and blood microbiome in NSCLC patients treated with ICIs and their potential use in predicting response and toxicity.

Published
2019

34. Efficacité du nivolumab (Nivo) et du traitement reçu après progression sous Nivo chez les patients atteints de cancer bronchique non à petites cellules (CBNPC) de stade avancé

Author

Adrien Costantini, Jennifer Corny, Boris Duchemann, S. Jouveshomme, Marie Wislez, Etienne Giroux-Leprieur, Jean Trédaniel, Vincent Fallet, Sylvie Friard, Laurent Taillade, Christos Chouaid, Jacques Cadranel, G. Zalcman, S. Renet, and L. Doucet

Subjects
Pulmonary and Respiratory Medicine
Abstract

Introduction Le Nivo (Ac anti-PD-1) est actuellement autorise pour le traitement de deuxieme ligne du CBNPC de stade avance. Malgre des taux de progression proches de 50 % lors de la premiere evaluation tumorale dans les etudes de phase III, les analyses de survie globale (SG) favorisent le Nivo par rapport a la chimiotherapie (CT) suggerant une meilleure efficacite des traitements recus apres le Nivo. Le but de cette etude etait d’evaluer l’efficacite des traitements recus apres progression sous Nivo chez les patients atteints de CBNPC de stade avance traites par Nivo. Methodes Une etude multicentrique (neuf centres), retrospective a ete realisee incluant les patients consecutifs recevant le Nivo dans le cadre de l’autorisation temporaire d’utilisation (ATU) entre janvier et decembre 2015. Les dossiers des patients etaient revus de maniere retrospective et les donnees collectees. Resultats Les caracteristiques des 303 patients inclus sont les suivantes : 63 ans, 69 % de sexe masculin, 92 % de fumeurs ou anciens fumeurs, 90 % de stade avance au diagnostic. L’histologie principale etait l’adenocarcinome (61 %) suivie du carcinome epidermoide (28 %). Lors de l’initiation du Nivo, 67 % des patients etaient de PS 0–1 et 20 % de PS 2. Les principaux sites metastatiques etaient pulmonaire (40 %), pleural (29 %) et cerebral (20 %). Le Nivo etait donne en deuxieme ligne dans 40 % des cas, en troisieme ligne dans 29 % des cas et en quatrieme ligne ou plus dans 31 % des cas. Le suivi median etait de 14,6 mois (m) avec sous Nivo 18 % de patients controles, 14 % decedes et 5 % perdus de vue. 191 patients (63 %) ont progresse et etaient eligibles a un traitement ulterieur dont 115 (38 %) en ont recu un. La SSP et SG sous Nivo etaient respectivement 2,6 m (IC95 % [2,1–3,5]) et 11,3 m (IC95 % [8,5–13,8]). Les patients recevant un traitement apres Nivo avaient un meilleur PS (p = 0,028) et etaient plus jeunes (âge median 63 vs 65,5, p = 0,11). Les traitements les plus utilises apres progression etaient : gemcitabine (23 %), docetaxel (22 %) et erlotinib (16 %) avec respectivement des PFS de 2,8 m, 2,7 m et 2,0 m. Conclusion Le Nivo semble aussi efficace dans la vraie vie que dans les essais cliniques malgre un PS plus eleve et une ligne de traitement plus avancee. 38 % des patients ont recu un traitement apres progression sous Nivo avec des survies proches des etudes historiques malgre la ligne plus avancee de traitement. Apres progression sous Nivo, la CT demeure le traitement standard. Un effet post traitement du Nivo reste a demontrer.

Published
2018

35. Real-life use of nivolumab in non-small cell lung cancer: A multicentric cohort to determine its clinical efficacy and predictive factors of early progression

Author

Laurent Taillade, Ludovic Doucet, Jacques Cadranel, Meryam Jardin, Jennifer Corny, Boris Duchemann, Solenn Brosseau, Sophie Renet, Vincent Fallet, Linda Hajouiji, Etienne Giroux Leprieur, Sylvie Friard, Hélène Beaussier, Jean Trédaniel, Gérard Zalcman, Shobanya Selvarathnam, Adrien Costantini, Stéphane Jouveshomme, and Marie Wislez

Subjects
Oncology, Cancer Research, medicine.medical_specialty, business.industry, medicine.disease, Internal medicine, Cohort, medicine, Non small cell, Clinical efficacy, Nivolumab, business, Lung cancer
Abstract

e20543 Background: Nivolumab (NIV) is now widely used in ≥ 2ndline of advanced non-small cell lung cancer (NSCLC). The aims of this real-life study were (1) to evaluate its efficacy, (2) to identify predictive factors of worsening under NIV. Methods: This retrospective multicentric study (8 Thoracic Oncology regional centers) included all patients treated by NIV in 2015 (follow-up until 2016, June 30th). Demographics and tumor characteristics were extracted. Objective tumor response was assessed by computerized tomography (RECIST v1.1). Median NIV treatment duration and overall survival (OS) were calculated. Clinical and biological factors evaluated as predictive markers of earlyprogression (discontinuation before 1stevaluation) were: NSCLC histology, PS, smoking-history, number of previous chemotherapy received and initial albumine (alb), C-reactive protein (CRP) and lactate dehydrogenase (LDH) serum levels. For these factors, patients quickly worsened and responders were compared (Student’s t-test, Chi-2 test). Results: Our cohort included 297 patients (non-squamous NSCLC n = 181 [61%]; PS > 1 n = 66 [22%]). At first evaluation, partial response was observed in 16% (n = 47), stable disease in 18% (n = 54) and progression in 49% (n = 144). A total of 45 patients (15%) were early progressors and no evaluation could be performed. Median NIV duration of treatment was 2.8 months [0-15], OS 6.9 months [0-16] (n = 146 still alive on June 30th, 2016). Early progressor patients were PS > 1 in 42% versus (vs) 21% for responders (mean PS 1.7 vs 1.0 for responders (p < 0.001)) and an alb level of 29.9 g/L vs 33.6 (p = 0.03). Mean CRP (p = 0.06) and LDH (p = 0.08) serum levels, NSCLC histology (p = 0.64), smoking-history (p = 0.08), number of previous chemotherapy (p = 0.90) were non-significant. Conclusions: This study confirms that NIV may be effective in NSCLC, with a 16% objective response rate. However early progression observed in 15% of patients was associated with a lower initial alb level and a higher PS. Missing data for LDH and CRP levels may have influenced their non-significance. Further studies must be realized to determine the interest of these factors as predictive markers.

Published
2017

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