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1. Initial clinical and treatment patterns of advanced differentiated thyroid cancer: ERUDIT study

Author

Juan Antonio Vallejo Casas, Marcel Sambo, Carlos López López, Manuel Durán-Poveda, Julio Rodríguez-Villanueva García, Rita Joana Santos, Marta Llanos, Elena Navarro-González, Javier Aller, Virginia Pubul, Sonsoles Guadalix, Guillermo Crespo, Cintia González, Carles Zafón, Miguel Navarro, Javier Santamaría-Sandi, Ángel Segura, Pablo Gajate, Marcelino Gómez-Balaguer, Javier Valdivia, Manel Puig-Domingo, Juan Carlos Galofré, Beatriz Castelo, María José Villanueva, Iñaki Argüelles, and Lorenzo Orcajo-Rincón

Subjects
advanced differentiated thyroid cancer, relapsing differentiated thyroid cancer, radioiodine-refractory differentiated thyroid cancer, epidemiological study, relapsing prognostic factors, survival prognostic factors, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Background: Up to 30% of differentiated thyroid cancer (DTC) will develop advanced-stage disease (aDTC) with reduced overall survival (OS). Objective: The aim of this study is to characterize initial diagnosis of aDTC, its therapeutic management, and prognosis in Spain and Portugal. Methods: A multicentre, longitudinal, retrospective study of adult patients diagnosed with aDTC in the Iberian Peninsula was conducted between January 2007 and December 2012. Analyses of baseline characteristics and results of initial treatments, relapse- or progression-free survival ((RP)FS) from first DTC diagnosis, OS, and prognostic factors impacting the evolution of advanced disease were evaluated. Results: Two hundred and thirteen patients (median age: 63 years; 57% female) were eligible from 23 hospitals. Advanced disease presented at first diagnosis (de novo aDTC) included 54% of patients, while 46% had relapsed from early disease (recurrent/progressive eDTC). At initial stage, most patients received surgery (98%) and/or radioiodine (RAI) (89%), with no differences seen between median OS (95% CI) (10.4 (7.3–15.3) years) and median disease-specific-survival (95% CI) (11.1 (8.7–16.2) years; log-rank test P = 0.4737). Age at diagnosis being

Published
2023
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2. Proposal and validation of a method to classify genetic subtypes of diffuse large B cell lymphoma

Author

Lucía Pedrosa, Ismael Fernández-Miranda, David Pérez-Callejo, Cristina Quero, Marta Rodríguez, Paloma Martín-Acosta, Sagrario Gómez, Julia González-Rincón, Adrián Santos, Carlos Tarin, Juan F. García, Francisco R. García-Arroyo, Antonio Rueda, Francisca I. Camacho, Mónica García-Cosío, Ana Heredero, Marta Llanos, Manuela Mollejo, Miguel Piris-Villaespesa, José Gómez-Codina, Natalia Yanguas-Casás, Antonio Sánchez, Miguel A. Piris, Mariano Provencio, and Margarita Sánchez-Beato

Subjects
Medicine, Science
Abstract

Abstract Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease whose prognosis is associated with clinical features, cell-of-origin and genetic aberrations. Recent integrative, multi-omic analyses had led to identifying overlapping genetic DLBCL subtypes. We used targeted massive sequencing to analyze 84 diagnostic samples from a multicenter cohort of patients with DLBCL treated with rituximab-containing therapies and a median follow-up of 6 years. The most frequently mutated genes were IGLL5 (43%), KMT2D (33.3%), CREBBP (28.6%), PIM1 (26.2%), and CARD11 (22.6%). Mutations in CD79B were associated with a higher risk of relapse after treatment, whereas patients with mutations in CD79B, ETS1, and CD58 had a significantly shorter survival. Based on the new genetic DLBCL classifications, we tested and validated a simplified method to classify samples in five genetic subtypes analyzing the mutational status of 26 genes and BCL2 and BCL6 translocations. We propose a two-step genetic DLBCL classifier (2-S), integrating the most significant features from previous algorithms, to classify the samples as N12-S, EZB2-S, MCD2-S, BN22-S, and ST22-S groups. We determined its sensitivity and specificity, compared with the other established algorithms, and evaluated its clinical impact. The results showed that ST22-S is the group with the best clinical outcome and N12-S, the more aggressive one. EZB2-S identified a subgroup with a worse prognosis among GCB-DLBLC cases.

Published
2021
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3. La figura de la mujer en programas de infoentretenimiento en España: el resistente techo de cristal

Author

Marta Llanos and Carme Ferré-Pavia

Subjects
género, mujer y medios, infoentretenimiento, televisión, Social Sciences, Communication. Mass media, P87-96
Abstract

Objetivo del estudio: Este artículo tiene como objetivo analizar la figura de la mujer y las manifestaciones de su rol de género en cinco programas de infoentretenimiento de éxito en España. Diseño/metodología/enfoque: Mediante el análisis cuantitativo y cualitativo de los atributos de cada una de sus intervenciones, este estudio trata de demostrar empíricamente la existencia de estos roles. Centrados en el número de apariciones de ambos sexos en cinco programas de infoentretenimiento (El Intermedio, El Hormiguero, La Resistencia, Late Motiv y Polònia), así como su vestimenta, sus personalidades o el evidente fenómeno de sexualización del cuerpo de la mujer. Resultados: Se puede sintetizar que la presencia de hombres y de mujeres en los programas analizados es acentuadamente dispar, así como que existe un patrón en la vestimenta de hombres y mujeres, por no mencionar que la cosificación del sexo femenino se hace patente en cada uno de los productos televisivos. Limitaciones e implicaciones: las elevadas audiencias de dichos programas pueden generar repercusión sobre la imagen de la mujer para la sociedad. Al revisar solo un grupo finito de episodios de cinco programas, se puede decir que es una investigación exploratoria. Originalidad/contribución: Este texto contribuye a los estudios de género en la televisión española contemporánea, en uno de los campos menos abordados, el del infoentretenimiento. Se muestra que en este macrogénero sigue existiendo un techo de cristal no solo porque los principales conductores del programa son hombres, sino por los roles de género enquistados.

Published
2020
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4. Evolution of RAS Mutations in Cell-Free DNA of Patients with Tissue RAS Wild-Type Metastatic Colorectal Cancer Receiving First-Line Treatment: The PERSEIDA Study

Author

Manuel Valladares-Ayerbes, Pilar Garcia-Alfonso, Jorge Muñoz Luengo, Paola Patricia Pimentel Caceres, Oscar Alfredo Castillo Trujillo, Rosario Vidal-Tocino, Marta Llanos, Beatriz Llorente Ayala, Maria Luisa Limon Miron, Antonieta Salud, Luis Cirera Nogueras, Rocio Garcia-Carbonero, Maria Jose Safont, Esther Falco Ferrer, Jorge Aparicio, Maria Angeles Vicente Conesa, Carmen Guillén-Ponce, Paula Garcia-Teijido, Maria Begoña Medina Magan, Isabel Busquier, Mercedes Salgado, and Ariadna Lloansí Vila

Subjects
colorectal cancer, cell-free DNA, RAS mutations, solid biopsy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA RAS (KRAS/NRAS) mutational status evolution in first-line, metastatic CRC, RAS wild-type (according to baseline tumor tissue biopsy) patients. Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. One hundred and nineteen patients were included (102 received panitumumab and chemotherapy as first-line treatment—panitumumab subpopulation). Fifteen (12.6%) patients presented baseline cfDNA RAS mutations (n = 14 [13.7%], panitumumab subpopulation) (mutant allele fraction ≥0.02 for all results). No patients presented emergent mutations (cfDNA RAS mutations not present at baseline) at 20 weeks. At disease progression, 11 patients (n = 9; panitumumab subpopulation) presented emergent mutations (RAS conversion rate: 19.0% [11/58]; 17.7% [9/51], panitumumab subpopulation). In contrast, three (5.2%) patients presenting baseline cfDNA RAS mutations were RAS wild-type at disease progression. No significant associations were observed between overall response rate or progression-free survival and cfDNA RAS mutational status in the total panitumumab subpopulation. Although, in patients with left-sided tumors, a significantly longer progression-free survival was observed in cfDNA RAS wild-type patients compared to those presenting cfDNA RAS mutations at any time. Continuous evaluation of RAS mutations may provide valuable insights on tumor molecular dynamics that can help clinical practice.

Published
2022
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5. Unraveling transformation of follicular lymphoma to diffuse large B-cell lymphoma.

Author

Julia González-Rincón, Miriam Méndez, Sagrario Gómez, Juan F García, Paloma Martín, Carmen Bellas, Lucía Pedrosa, Socorro M Rodríguez-Pinilla, Francisca I Camacho, Cristina Quero, David Pérez-Callejo, Antonio Rueda, Marta Llanos, José Gómez-Codina, Miguel A Piris, Santiago Montes-Moreno, Carmen Bárcena, Delvys Rodríguez-Abreu, Javier Menárguez, Luis de la Cruz-Merino, Silvia Monsalvo, Consuelo Parejo, Ana Royuela, Ivo Kwee, Luciano Cascione, Alberto Arribas, Francesco Bertoni, Manuela Mollejo, Mariano Provencio, and Margarita Sánchez-Beato

Subjects
Medicine, Science
Abstract

Follicular lymphoma (FL) is an indolent but largely incurable disease. Some patients suffer histological transformation to a more aggressive subtype with poorer prognosis. This study aimed to improve our understanding of the genetics underlying FL histological transformation, and to identify genetic drivers or promoters of the transformation by elucidating the differences between FL samples from patients who did and did not transform. We conducted targeted massive parallel sequencing of 22 pre-transformed FL/transformed diffuse large B-cell lymphoma pairs and 20 diagnostic samples from non-transformed FL patients. Additionally, 22 matched samples from 11 transformed FL patients (pre-transformed FL and diffuse large B-cell lymphoma) and 9 non-transformed FLs were studied for copy number variation using SNP arrays. We identified recurrently mutated genes that were enriched at transformation, most notably LRP1B, GNA13 and POU2AF1, which have roles in B-cell differentiation, GC architecture and migration. Mutations in POU2AF1 might be associated with lower levels of expression, were more frequent in transformed FLs, and seemed to be specific to transformed- compared with de novo-diffuse large B-cell lymphomas. Pre-transformed FLs carried more mutations per sample and had greater subclonal heterogeneity than non-transformed FLs. Finally, we identified four mutated genes in FL samples that differed between patients who did and did not transform: NOTCH2, DTX1, UBE2A and HIST1H1E. The presence of mutations in these genes was associated with shorter time to transformation when mutated in the FL biopsies. This information might be useful for identifying patients at higher risk of transformation.

Published
2019
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6. Impact of treatment in long-term survival patients with follicular lymphoma: A Spanish Lymphoma Oncology Group registry.

Author

Mariano Provencio, Pilar Sabín, Jose Gomez-Codina, Maria Torrente, Virginia Calvo, Marta Llanos, Josep Gumá, Cristina Quero, Ana Blasco, Miguel Angel Cruz, David Aguiar, Francisco García-Arroyo, Javier Lavernia, Natividad Martinez, Manuel Morales, Alvaro Saez-Cusi, Delvys Rodriguez, Luis de la Cruz, Jose Javier Sanchez, Antonio Rueda, and GOTEL (Spanish Lymphoma Oncology Group)

Subjects
Medicine, Science
Abstract

BACKGROUND:Follicular lymphoma is the second most common non-Hodgkin lymphoma in the United States and Europe. However, most of the prospective randomized studies have very little follow-up compared to the long natural history of the disease. The primary aim of this study was to investigate the long-term survival of our series of patients with follicular lymphoma. PATIENTS AND METHODS:A total of 1074 patients with newly diagnosed FL were enrolled. Patients diagnosed were prospectively enrolled from 1980 to 2013. RESULTS:Median follow-up was 54.9 months and median overall survival is over 20 years in our series. We analyzed the patients who are still alive beyond 10 years from diagnosis in order to fully assess the prognostic factors that condition this group. Out of 166 patients who are still alive after more than 10 years of follow-up, 118 of them (73%) are free of evident clinical disease. Variables significantly associated with survival at 10 years were stage < II (p

Published
2017
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7. Risk adapted high-dose and dose-dense therapies modulate the impact of biological classification in diffuse large B-cell lymphoma prognosis

Author

Santiago Montes-Moreno, Ana Batlle, Sonia González de Villambrosía, Beatriz Sánchez-Espiridión, Laura Cereceda, Eva González-Barca, Noelia Purroy, Emilia Pardal, Alejandro Martín, Carlos Grande, Francisco Mazorra, Andrés Insunza, Cristina Quero, David Aguiar, Miguel Angel Cruz, Antonio Rueda, Marta Llanos, José Gómez Codina, Francisco Ramón García Arroyo, Dolores Caballero, Eulogio Conde, Andrés López, Mariano Provencio, and Miguel Piris

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2014
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8. Sequential RAS mutations evaluation in cell-free DNA of patients with tissue RAS wild- type metastatic colorectal cancer: The PERSEIDA (Cohort 2) Study

Author

Valladares-Ayerbes, Manuel, primary, Safont, Maria José, additional, Flores, Encarnación González, additional, García-Alfonso, Pilar, additional, Aranda, Enrique, additional, Muñoz, Ana-Maria López, additional, Ferrer, Esther Falcó, additional, Nogueras, Luís Cirera, additional, Rodríguez-Salas, Nuria, additional, Aparicio, Jorge, additional, Muñoz, Marta Llanos, additional, Cáceres, Paola Patricia Pimentel, additional, Trujillo, Oscar Alfredo Castillo, additional, Tocino, Rosario Vidal, additional, Fernández, Mercedes Salgado, additional, Salud-Salvia, Antonieta, additional, Sureda, Bartomeu Massuti, additional, Garcia-Carbonero, Rocio, additional, Conesa, Maria Ángeles Vicente, additional, and Vila, Ariadna Lloansí, additional

Published
2023
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9. Prospective validation of a lymphocyte infiltration prognostic test in stage III colon cancer patients treated with adjuvant FOLFOX

Author

Thaler, Josef, Greil, Richard, Gaenzer, Johannes, Eisterer, Wolfgang, Tschmelitsch, Joerg, Keil, Felix, Samonigg, Hellmut, Zabernigg, August, Schmid, Franz, Steger, Günther, Steinacher, Robert, Andel, Johannes, Jagdt, Björn, Lang, Alois, Fridrik, Michael, Függer, Reinhold, Hofbauer, Friedrich, Woell, Ewald, Geissler, Dietmar, Lenauer, Alfred, Prager, Manfred, D'Haens, Geert, Demolin, Gauthier, Kerger, Joseph, Deboever, Guido, Ghillebert, Gilbert, Polus, Marc, Van Cutsem, Eric, Kalantari, Hassan Rezaie, Delaunoit, Thierry, Goeminne, Jean Charles, Peeters, Marc, Vergauwe, Philippe, Houbiers, Ghislain, Humblet, Yves, Janssens, Jos, Schrijvers, Dirk, Vanderstraeten, Erik, Van Laethem, Jean-Luc, Vermorken, Jan, Van Daele, Daniel, Ferrante, Michel, Forget, Frederic, Hendlisz, Alain, Yilmaz, Mette, Nielsen, Svend Erik, Vestermark, Lene, Larsen, Jim, Zawadi, Mohamed-Ayman, Bouche, Olivier, Mineur, Laurent, Bennouna-Louridi, Jaafar, Dourthe, Louis Marie, Ychou, Marc, Boucher, Eveline, Taieb, Julien, Pezet, Denis, Desseigne, Francoise, Ducreux, Michel, Texereau, Patrick, Miglianico, Laurent, Rougier, Philippe, Fratte, Serge, Levache, Charles-Briac, Merrouche, Yacine, Ellis, Stephen, Locher, Christophe, Ramee, Jean-Francois, Garnier, Claire, Viret, Frederic, Chauffert, Bruno, Cojean-Zelek, Isabelle, Michel, Pierre, Lecaille, Cedric, Borel, Christian, Seitz, Jean-Francois, Smith, Denis, Lombard-Bohas, Catherine, Andre, Thierry, Gornet, Jean-Marc, Fein, Francine, Coulon-Sfairi, Marie-Aude, Kaminsky, Marie-Christine, Lagasse, Jean-Paul, Luet, Dominique, Etienne, Pierre-Luc, Gasmi, Mohamed, Vanoli, Andre, Nguyen, Suzanne, Aparicio, Thomas, Perrier, Hervé, Stremsdoerfer, Noel, Laplaige, Philippe, Arsene, Dominique, Auby, Dominique, Bedenne, Laurent, Coriat, Romain, Denis, Bernard, Geoffroy, Patrick, Piot, Gilles, Becouarn, Yves, Bordes, Gilbert, Deplanque, Gael, Dupuis, Olivier, Fruge, Frederic, Guimbaud, Rosine, Lecomte, Thierry, Lledo, Gérard, Sobhani, Iradej, Asnacios, Amani, Azzedine, Ahmed, Desauw, Christophe, Galais, Marie-Pierre, Gargot, Dany, Lam, You-Heng, Abakar-Mahamat, Abakar, Berdah, Jean-Francois, Catteau, Sylviane, Clavero-Fabri, Marie-Christine, Codoul, Jean-Francois, Legoux, Jean-Louis, Goldfain, Denis, Guichard, Pierre, Verge, Denis Pere, Provencal, Jocelyne, Vedrenne, Bruno, Brezault-Bonnet, Catherine, Cleau, Denis, Desir, Jean-Paul, Fallik, David, Garcia, Bruno, Gaspard, Marie-Hélène, Genet, Dominique, Hartwig, Johannes, Krummel, Yves, Budnik, Tamara Matysiak, Palascak-Juif, Vanessa, Randrianarivelo, Harizo, Rinaldi, Yves, Aleba, Albert, Darut-Jouve, Ariane, de Gramont, Aimery, Hamon, Herve, Wendehenne, Frederic, Matzdorff, Axel, Stahl, Michael Konrad, Schepp, Wolfgang, Burk, Martin, Mueller, Lothar, Folprecht, Gunnar, Geissler, Michael, Mantovani-Loeffler, Luisa, Hoehler, Thomas, Asperger, Walter, Kroening, Hendrik, von Weikersthal, Ludwig Fischer, Fuxius, Stefan, Groschek, Matthias, Meiler, Johannes, Trarbach, Tanja, Rauh, Jacqueline, Ziegenhagen, Nicolas, Kretzschmar, Albrecht, Graeven, Ullrich, Nusch, Arnd, von Wichert, Goetz, Hofheinz, Ralf-Dieter, Kleber, Gerhard, Schmidt, Karl-Heinz, Vehling-Kaiser, Ursula, Baum, Claudia, Schuette, Jochen, Haag, Georg Martin, Holtkamp, Wilhelm, Potenberg, Jochen, Reiber, Tobias, Schliesser, Georg, Schmoll, Hans-Joachim, Schneider-Kappus, Wolfgang, Abenhardt, Wolfgang, Denzlinger, Claudio, Henning, Jan, Marxsen, Bartscht, Derigs, Hans Guenter, Lambertz, Helmut, Becker-Boost, Ingulf, Caca, Karel, Constantin, Christian, Decker, Thomas, Eschenburg, Henning, Gabius, Sigrun, Hebart, Holger, Hoffmeister, Albrecht, Horst, Heinz-August, Kremers, Stephan, Leithaeuser, Malte, Mueller, Sebastian, Wagner, Siegfried, Daum, Severin, Schlegel, Frank, Stauch, Martina, Heinemann, Volker, Maiello, Evaristo, Latini, Luciano, Zaniboni, Alberto, Amadori, Dino, Aprile, Giuseppe, Barni, Sandro, Mattioli, Rodolfo, Martoni, Andrea, Passalacqua, Rodolfo, Nicolini, Mario, Pasquini, Enzo, Rabbi, Carla, Aitini, Enrico, Ravaioli, Alberto, Barone, Carlo, Biasco, Guido, Tamberi, Stefano, Gambi, Angelo, Verusio, Claudio, Marzola, Marina, Lelli, Giorgio, Boni, Corrado, Cascinu, Stefano, Bidoli, Paolo, Vaghi, Massimo, Cruciani, Giorgio, Di Costanzo, Francesco, Sobrero, Alberto, Mini, Enrico, Petrioli, Roberto, Aglietta, Massimo, Alabiso, Oscar, Capuzzo, Federico, Falcone, Alfredo, Corsi, Domenico Cristi, Labianca, Roberto, Salvagni, Stefania, Chiara, Silvana, Ciuffreda, Libero, Ferraù, Francesco, Giuliani, Francesco, Lonardi, Sara, Gebbia, Nicola, Mantovani, Giovanni, Sanches, Evaristo, Mellidez, Juan Carlos, Santos, Pedro, Freire, Joao, Sarmento, Cristina, Costa, Luis, Pinto, Antonio Moreira, Barroso, Sergio, Santo, Jorge Espirito, Guedes, Fátima, Monteiro, Amélia, Sa, Anabela, Furtado, Irene, Salazar, Ramon, Aguilar, Enrique Aranda, Herrero, Fernando Rivera, Tabernero, Josep, Valera, Javier Sastre, Ayerbes, Manuel Valladares, Batlle, Jaime Feliu, Gil, Silvia, Esteve, Albert Abad, Garcia-Giron, Carlos, Vivanco, Guillermo Lopez, Salvia, Antonia Salud, Orduña, Vicente Alonso, Garcia, Ruth Vera, Gallego, Javier, Sureda, Bartomeu Massuti, Remon, Jordi, Safont Aguilera, Maria Jose, Nogueras, Luis Cirera, Merino, Bernado Queralt, Castro, Cristina Gravalos, de Prado, Purificacion Martinez, Pericay, Carlos Pijaume, Figueiras, Manuel Constenla, Jordan, Inmaculada Guasch, Gome Reina, Maria Jose, Garcia, Amelia Lopez-Ladron, Garcia-Ramos, Antonio Arrivi, Cervantes, Andres, Martos, Carlos Fernandez, Gaspar, Eugenio Marcuello, Montero, Ines Cabezas, Emperador, Pilar Escudero, Carbonero, Ana Leon, Castillo, Manuel Gallen, Garcia, Teresa Garcia, Lopez, Jose Garcia, Flores, Encarnacion Gonzalez, Morales, Monica Guillot, Muñoz, Marta Llanos, Martín, Ana López, Maurel, Joan, Camara, Juan Carlos, Garcia, Rosario Dueñas, Salgado, Mercedes, Busquier, Isabel Hernandez, Ruiz, Teresa Checa, Muñoa, Adelaida Lacasta, Aliguer, Miquel Nogue, de Taranco, Amalia Velasco Ortiz, Ureña, Miguel Mendez, Gaspa, Ferran Losa, Ponce, Jose Juan, Roig, Carlos Bosch, Jimenez, Pedro Valero, Brotons, Antonio Galan, Rodriguez, Santiago Albiol, Martinez, Jose Ales, Ruiz, Liliana Canosa, Ruiz, Margarita Centelles, Bridgewater, John, Glynne-Jones, Rob, Tahir, Saad, Hickish, Tamas, Cassidy, Jim, Samuel, Leslie, Emile, Jean-François, Julié, Catherine, Le Malicot, Karine, Lepage, Come, Dimet, Stéphanie, Boulagnon-Rombi, Camille, Allard, Marc-Antoine, Penault-Llorca, Frédérique, Bennouna, Jaafar, and Laurent-Puig, Pierre

Published
2017
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10. Data from Monitoring of Circulating Tumor DNA Predicts Response to Treatment and Early Progression in Follicular Lymphoma: Results of a Prospective Pilot Study

Author

Margarita Sánchez-Beato, Mariano Provencio, Antonio Rueda-Domínguez, Virginia Calvo, Natalia Yanguas-Casás, Marta Navarro, Silvia Sequero, Miguel Marín, Natividad Martínez, Laura Gálvez, Ana K. Ballesteros, Beatriz Horcajo, Josep Gumá, Francisco R. García-Arroyo, Paloma Martín-Acosta, Sagrario Gómez, Fernando F. Franco, Marta Llanos, Lucía Pedrosa, and Ismael Fernández-Miranda

Abstract

Purpose:Follicular lymphoma (FL) is the most frequent indolent non-Hodgkin lymphoma. Around 20% of patients suffer early disease progression within 24 months (POD24) of diagnosis. This study examined the significance of circulating tumor DNA (ctDNA) in predicting response to therapy and POD24 in patients with FL.Experimental Design:We collected 100 plasma samples, before and during the treatment, from 36 patients with FL prospectively enrolled in 8 Spanish hospitals. They were treated with a chemotherapy-rituximab regimen and followed up for a median of 3.43 years. We performed targeted deep sequencing in cell-free DNA (cfDNA) and tumor genomic DNA from 31 diagnostic biopsy samples.Results:Of the alterations detected in the diagnostic tissue samples, 73% (300/411) were also identified in basal cfDNA. The mean numbers of alterations per basal cfDNA sample in patients who suffered progression of disease within 24 months (POD24-pos) or did not achieve complete response (non-CR) were significantly higher than in POD24-neg or CR patients (unpaired samples t test, P = 0.0001 and 0.001, respectively). Pretreatment ctDNA levels, as haploid genome equivalents per milliliter of plasma, were higher in patients without CR (P = 0.02) and in POD24-pos patients compared with POD24-neg patients (P < 0.001). Dynamic analysis showed that ctDNA levels decreased dramatically after treatment, although the reduction was more significant in patients with CR and POD24-neg patients.Conclusions:Basal ctDNA levels are associated with the risk of early progression and response to treatment in FL. cfDNA monitoring and genotyping during treatment and follow-up predict response to treatment and early progression.

Published
2023

11. Supplementary Data 2 from Monitoring of Circulating Tumor DNA Predicts Response to Treatment and Early Progression in Follicular Lymphoma: Results of a Prospective Pilot Study

Author

Margarita Sánchez-Beato, Mariano Provencio, Antonio Rueda-Domínguez, Virginia Calvo, Natalia Yanguas-Casás, Marta Navarro, Silvia Sequero, Miguel Marín, Natividad Martínez, Laura Gálvez, Ana K. Ballesteros, Beatriz Horcajo, Josep Gumá, Francisco R. García-Arroyo, Paloma Martín-Acosta, Sagrario Gómez, Fernando F. Franco, Marta Llanos, Lucía Pedrosa, and Ismael Fernández-Miranda

Abstract

Supplementary Data 2

Published
2023

12. Supplementary Data 1 from Monitoring of Circulating Tumor DNA Predicts Response to Treatment and Early Progression in Follicular Lymphoma: Results of a Prospective Pilot Study

Author

Margarita Sánchez-Beato, Mariano Provencio, Antonio Rueda-Domínguez, Virginia Calvo, Natalia Yanguas-Casás, Marta Navarro, Silvia Sequero, Miguel Marín, Natividad Martínez, Laura Gálvez, Ana K. Ballesteros, Beatriz Horcajo, Josep Gumá, Francisco R. García-Arroyo, Paloma Martín-Acosta, Sagrario Gómez, Fernando F. Franco, Marta Llanos, Lucía Pedrosa, and Ismael Fernández-Miranda

Abstract

Supplementary Data 1

Published
2023

13. Evolution of

Author

Manuel, Valladares-Ayerbes, Pilar, Garcia-Alfonso, Jorge, Muñoz Luengo, Paola Patricia, Pimentel Caceres, Oscar Alfredo, Castillo Trujillo, Rosario, Vidal-Tocino, Marta, Llanos, Beatriz, Llorente Ayala, Maria Luisa, Limon Miron, Antonieta, Salud, Luis, Cirera Nogueras, Rocio, Garcia-Carbonero, Maria Jose, Safont, Esther, Falco Ferrer, Jorge, Aparicio, Maria Angeles, Vicente Conesa, Carmen, Guillén-Ponce, Paula, Garcia-Teijido, Maria Begoña, Medina Magan, Isabel, Busquier, Mercedes, Salgado, and Ariadna, Lloansí Vila

Abstract

The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA

Published
2022

14. Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin: the phase II DUNE trial (GETNE 1601)

Author

Jaume Capdevila, Jorge Hernando, Alex Teule, Carlos Lopez, Rocío Garcia-Carbonero, Marta Benavent, Ana Custodio, Alejandro Garcia-Alvarez, Antonio Cubillo, Vicente Alonso, Alberto Carmona-Bayonas, Teresa Alonso-Gordoa, Guillermo Crespo, Paula Jimenez-Fonseca, Montserrat Blanco, Antonio Viudez, Adelaida La Casta, Isabel Sevilla, Angel Segura, Marta Llanos, Stefania Landolfi, Paolo Nuciforo, and Jose Luis Manzano

Abstract

Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort (C) 1), G1/2 gastrointestinal (C2), G1/2 pancreatic (C3) and G3 gastroenteropancreatic (GEP) (C4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month (m) disease control rate (DCR) for C1-3 and 9-m overall survival (OS) rate for C4. Median follow-up was 16.5 m; 9-m DCR was 25.9%/35.5%/25% for C1, 2, and 3 respectively. The 9-m OS rate for C4 was 36.1%. Benefit in C4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab was safe in NENs and showed modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS.

Published
2022

15. Monitoring of circulating tumor DNA predicts response to treatment and early progression in follicular lymphoma: results of a prospective pilot study

Author

Ismael Fernández-Miranda, Lucía Pedrosa, Marta Llanos, Fernando F. Franco, Sagrario Gómez, Paloma Martín-Acosta, Francisco R. García-Arroyo, Josep Gumá, Beatriz Horcajo, Ana K. Ballesteros, Laura Gálvez, Natividad Martínez, Miguel Marín, Silvia Sequero, Marta Navarro, Natalia Yanguas-Casás, Virginia Calvo, Antonio Rueda-Domínguez, Mariano Provencio, and Margarita Sánchez-Beato

Subjects
Cancer Research, Oncology
Abstract

Purpose: Follicular lymphoma (FL) is the most frequent indolent non-Hodgkin lymphoma. Around 20% of patients suffer early disease progression within 24 months (POD24) of diagnosis. This study examined the significance of circulating tumor DNA (ctDNA) in predicting response to therapy and POD24 in patients with FL. Experimental Design: We collected 100 plasma samples, before and during the treatment, from 36 patients with FL prospectively enrolled in 8 Spanish hospitals. They were treated with a chemotherapy-rituximab regimen and followed up for a median of 3.43 years. We performed targeted deep sequencing in cell-free DNA (cfDNA) and tumor genomic DNA from 31 diagnostic biopsy samples. Results: Of the alterations detected in the diagnostic tissue samples, 73% (300/411) were also identified in basal cfDNA. The mean numbers of alterations per basal cfDNA sample in patients who suffered progression of disease within 24 months (POD24-pos) or did not achieve complete response (non-CR) were significantly higher than in POD24-neg or CR patients (unpaired samples t test, P = 0.0001 and 0.001, respectively). Pretreatment ctDNA levels, as haploid genome equivalents per milliliter of plasma, were higher in patients without CR (P = 0.02) and in POD24-pos patients compared with POD24-neg patients (P < 0.001). Dynamic analysis showed that ctDNA levels decreased dramatically after treatment, although the reduction was more significant in patients with CR and POD24-neg patients. Conclusions: Basal ctDNA levels are associated with the risk of early progression and response to treatment in FL. cfDNA monitoring and genotyping during treatment and follow-up predict response to treatment and early progression.

Published
2022

16. Usefulness of an immunohistochemical score in advanced pancreatic neuroendocrine tumors treated with CAPTEM or everolimus

Author

Leyre Pérez-Ricarte, Marta Benavent, A. Viudez, Maria Del Carmen Riesco, Paula Jiménez-Fonseca, Juan Jesús Marín-Méndez, Iranzu González-Borja, Marta Llanos, Saioa Goñi, Jaume Capdevila, Beatriz García-Paredes, Vicente Alonso, Ana Custodio, Maika Durantez, J. Hernando, Rocio Garcia-Carbonero, Imanol Arozarena, Isabel Sevilla, Ana De Jesus Acosta, Irene Hernández-García, Guillermo Crespo, Alberto Carmona-Bayonas, Jairo Pérez-Sanz, Maria Luisa Gomez Dorronsoro, Ruth Vera, Borja Lopez De San Vicente, and Carlos F. Lopez

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Cell Cycle Proteins, Neuroendocrine tumors, Capecitabine, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, medicine, Humans, In patient, Everolimus, DNA Modification Methylases, Domain family, Aged, Aged, 80 and over, Temozolomide, Hepatology, business.industry, Tumor Suppressor Proteins, Intracellular Signaling Peptides and Proteins, Gastroenterology, Nuclear Proteins, Middle Aged, Prognosis, medicine.disease, Immunohistochemistry, Survival Analysis, Progression-Free Survival, Pancreatic Neoplasms, Neuroendocrine Tumors, DNA Repair Enzymes, 030220 oncology & carcinogenesis, Biomarker (medicine), Female, 030211 gastroenterology & hepatology, Neoplasm Recurrence, Local, business, Immunosuppressive Agents, medicine.drug
Abstract

Background Pancreatic neuroendocrine tumors are rare neoplasms for which few predictive and/or prognostic biomarkers have been validated. Our previous work suggested the potential of the combined expression of N-myc downstream-regulated gen-1 (NDRG-1), O6-methylguanine DNA methyltransferase (MGMT) and Pleckstrin homology-like domain family A member 3 (PHLDA-3) as prognostic factors for relapse and survival. Methods In this new multicenter study we evaluated immunohistochemistry expression in 76 patients with advanced PanNET who were treated with capecitabine-temozolomide or everolimus. Based on the immunohistochemistry panel, an immunohistochemistry prognostic score (IPS) was developed. Results In patients treated with capecitabine and temozolomide, low IPS was an independent prognostic factor for progression-free-survival and overall-survival. Similar findings were observed with highest IPS for overall-survival in patients treated with everolimus. Conclusion From our knowledge, it is the first time that a simple IPS could be useful to predict outcome for patients with metastatic pancreatic neuroendocrine tumors treated with everolimus or capecitabine and temozolomide.

Published
2021

17. External Validity of Somatostatin Analogs Trials in Advanced Neuroendocrine Neoplasms: The GETNE-TRASGU Study

Author

Teresa Alonso-Gordoa, Juan W. Valle, Carlos F. Lopez, José A. Díaz, Marta Benavent, Rocio Garcia-Carbonero, Felip Vilardell, Adelaida La Casta, Vicente Alonso, Ángel Segura, Angela Lamarca, J. Hernando, Javier Gallego, A Castaño, Mónica Marazuela, Juan Carlos Percovich, Enrique Grande, Marta Llanos, Jorge Barriuso, Manuel Cánovas, Jaume Capdevila, Eduardo Feliciangeli, Guillermo Crespo, Ana Montes, Alberto Carmona-Bayonas, Paula Jiménez-Fonseca, Ana Custodio, Maria Del Carmen Riesco, Novartis, Ipsen, Pfizer, Conquer Cancer Foundation, Christie Charity, and European Neuroendocrine Tumor Society

Subjects
Male, Survival, Endocrinology, Diabetes and Metabolism, Octreotide, Neuroendocrine tumors, Lanreotide, Gastroenterology, Bayesian method, 030218 nuclear medicine & medical imaging, law.invention, Somatostatin analog, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Randomized controlled trial, law, Medicine, Registries, Neoplasm Metastasis, Randomized Controlled Trials as Topic, Aged, 80 and over, Manchester Cancer Research Centre, Hazard ratio, Middle Aged, Prognosis, Primary tumor, Progression-Free Survival, Neuroendocrine Tumors, Somatostatin, Female, Neuroendocrine tumor, medicine.drug, Adult, medicine.medical_specialty, Antineoplastic Agents, Hormonal, 030209 endocrinology & metabolism, Peptides, Cyclic, 03 medical and health sciences, Cellular and Molecular Neuroscience, Stomach Neoplasms, Internal medicine, Intestinal Neoplasms, Humans, Aged, Endocrine and Autonomic Systems, business.industry, Proportional hazards model, ResearchInstitutes_Networks_Beacons/mcrc, Reproducibility of Results, medicine.disease, Pancreatic Neoplasms, chemistry, Spain, business
Abstract

[Introduction] Somatostatin analogs (SSA) prolong progression-free survival (PFS) in patients with well-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, the eligibility criteria in randomized clinical trials (RCTs) have been restricted, which contrasts with the vast heterogeneity found in NENs., [Methods] We identified patients with well-differentiated (Ki-67% ≤20%), metastatic GEP-NENs treated in first line with SSA monotherapy from the Spanish R-GETNE registry. The therapeutic effect was evaluated using a Bayesian Cox model. The objective was to compare survival-based outcomes from real-world clinical practice versus RCTs., [Results] The dataset contained 535 patients with a median age of 62 years (range: 26–89). The median Ki-67% was 4 (range: 0–20). The most common primary tumor sites were as follows: midgut, 46%; pancreas, 34%; unknown primary, 10%; and colorectal, 10%. Half of the patients received octreotide LAR (n = 266) and half, lanreotide autogel (n = 269). The median PFS was 28.0 months (95% CI: 22.1–32.0) for octreotide versus 30.1 months (95% CI: 23.1–38.0) for lanreotide. The overall hazard ratio for lanreotide versus octreotide was 0.90 (95% credible interval: 0.71–1.12). The probability of effect sizes >30% with lanreotide versus octreotide was 2 and 6% for midgut and foregut NENs, respectively., [Conclusion] Our study evaluated the external validity of RCTs examining SSAs in the real world, as well as the main effect-modifying factors (progression status, symptoms, tumor site, specific metastases, and analytical data). Our results indicate that both octreotide LAR and lanreotide autogel had a similar effect on PFS. Consequently, both represent valid alternatives in patients with well-differentiated, metastatic GEP-NENs., The study has been funded by a restricted grant from Novartis Farmacéutica, S.A. RGETNE and the GETNE group is partially funded by Ipsen, Novartis, Pfizer and AAA. Dr Angela Lamarca received funding from ASCO Conquer Cancer Foundation Young Investigator Award and The Christie Charity. Dr Jorge Barriuso received funding from the received funding from the ENETS Centre of Excellence Fellowship Grant Award.

Published
2022

18. A GENE SIGNATURE TO PREDICT RISK OF TRANSFORMATION IN PATIENTS WITH FOLLICULAR LYMPHOMA

Author

Paloma Martín-Acosta, Francisco R García-Arroyo, Fina Climent, S. Sequero, Antonio Salar, N. Yanguas, F. de la Cruz, Julia González-Rincón, Sagrario Gómez, Marta Llanos, Margarita Sánchez-Beato, Lucia Pedrosa, Manuela Mollejo, Blanca Espinet, M. Dominguez, Santiago Mercadal, Mónica García-Cosío, Belen Navarro, Luis Colomo, Mariano Provencio, M A Piris, and Ismael Fernández-Miranda

Subjects
Cancer Research, Transformation (genetics), Oncology, Follicular lymphoma, medicine, Cancer research, In patient, Hematology, General Medicine, Biology, medicine.disease, Signature (topology), Gene
Published
2021

19. Transformed follicular lymphoma in the rituximab era: A report from the<scp>S</scp>panish<scp>L</scp>ymphoma<scp>O</scp>ncology<scp>G</scp>roup

Author

Julia González-Rincón, Mariano Provencio, Antonio Rueda, Marta Llanos, Miriam Mendez, Margarita Sánchez-Beato, José Gómez-Codina, Luis de la Cruz-Merino, Silvia Monsalvo, Pilar Sabin, Ana Royuela, Cristina Quero, Josep Gumá, Maria Torrente, and Delvys Rodriguez-Abreu

Subjects
Male, Oncology, Cancer Research, medicine.medical_specialty, Time Factors, medicine.medical_treatment, Follicular lymphoma, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, International Prognostic Index, Risk Factors, Internal medicine, medicine, Humans, Cumulative incidence, Prospective Studies, Registries, Lymphoma, Follicular, Aged, Chemotherapy, business.industry, Hematology, General Medicine, Odds ratio, Middle Aged, medicine.disease, Lymphoma, Survival Rate, B symptoms, Spain, 030220 oncology & carcinogenesis, Female, Rituximab, medicine.symptom, business, Follow-Up Studies, 030215 immunology, medicine.drug
Abstract

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) subtype. The histological transformation (HT) of FL is an event considered frequent in the natural history of this tumor. We studied the transformation rates, predictive factors, and treatment characteristics that may impact in the survival of patients with FL and HT. A total of 1074 patients diagnosed with FL were prospectively enrolled from 1990 to 2016 in a Spanish registry. Sixty-four HTs were recorded based on clinical criteria (55%) or histological confirmation (45%). The cumulative incidence rate of transformation at 5 years is 7.3%. The 5-year overall survival (OS) without HT was 85% (95% confidence interval [CI], 70%-90%) vs 66% (95% CI, 51%-76%; P = 0.0012) with HT. Factors associated with HT were elevated lactate dehydrogenase (LDH) (odds ratio [OR] 1.83), intermediate-high Follicular lymphoma international prognostic index (FLIPI) (OR 2.16-OR 3.21), B symptoms (OR 2.46), or Eastern Cooperative Oncology Group (ECOG) 1 (OR 2.35). Treatment options related to HT were "watch and wait" or no rituximab or anthracyclines initially. A 5-year OS for patients treated with chemotherapy before HT was 55% (95% CI, 38%-69%) versus 81% (95% CI, 53%-93%; P = 0.009) for those who had not received it. The HT rate has decreased after the introduction of rituximab, as has been previously described. The timing of this treatment had an impact on the survival of these patients.

Published
2019

20. Prospective evaluation of the prognostic value of circulating tumor DNA in patients with follicular lymphoma: A pilot study

Author

Ismael Fernández-Miranda, Ana K Ballesteros, Marta Llanos, Fabio Franco, Paloma Martin-Acosta, Lucía Pedrosa, Francisco Ramon Garcia Arroyo, Josep Guma, Laura Galvez Carvajal, Natividad Martinez Banaclocha, Miguel Marin, Silvia Sequero, Sagrario Gomez, Beatriz Horcajo Morera, Marta Navarro Fernández-Clemente, Natalia Yanguas-Casás, Virginia Calvo, Antonio Rueda Dominguez, Mariano Provencio, and Margarita Sanchez-Beato

Subjects
Cancer Research, Oncology
Abstract

7569 Background: Follicular lymphoma (FL) is the most frequently occurring indolent non-Hodgkin lymphoma, with generally favorable outcomes but a variable clinical course. Around 20% of patients suffer progression of disease within 24 months (POD24) of chemoimmunotherapy. In this prospective study, we examined the prognostic value of circulating tumor DNA (ctDNA), before and during treatment, to predict response and POD24 in FL patients. Methods: We collected 110 plasma samples from 39 patients diagnosed with FL, prospectively enrolled in 8 Spanish hospitals and treated with Chemotherapy-Rituximab regimen from April 2017 to November 2020 with a median follow-up of 41 months (m). Samples were collected before treatment (basal), mid-treatment (3m), at the end of treatment (EOT) (6m) and relapse or follow-up. We performed targeted deep sequencing in cell-free DNA and paired genomic DNA from 30 formalin-fixed paraffin-embedded tumoral (FFPET) samples with the same gene panel. Results: Before treatment, ctDNA levels, measured as haploid genome equivalents per milliliter of plasma (hGE/mL), were detected in 17/30 patients. Basal ctDNA levels were higher in patients without complete response (CR) than in CR patients [18 vs 14 log2(hGE/mL); Mann-Whitney P = 0.007] and in patients with POD24 compared to those not-POD24 [18 vs 13 log2(hGE/mL); P = 0.005]. None of the 13 patients with zero basal ctDNA levels, experienced POD24. Patients with at least one mutation detected in basal ctDNA had an inferior 24-months PFS than patients without alterations (64 vs 100%, log-rank test P = 0.027). In addition, basal ctDNA levels were detected in one patient with low FLIPI, but partial response and POD24, and by contrast, no ctDNA was detected in another patient with CR and no progression event but high FLIPI. From the alterations detected in FFPET samples, 66% were also identified in basal ctDNA. No alterations were detected in basal ctDNA from 7 patients with CR and 3 patients with watch-and-wait strategy. Dynamic analysis showed that ctDNA levels decreased after treatment for every patient (3 mo), but the reduction at EOT was higher in patients achieving CR than in non-CR patients (12 vs 3 log-reduction) and in not-POD24 patients compared to those with POD24 (10 vs 8). Furthermore, patients with at least one mutation detected in ctDNA at EOT had a shorter 24-months PFS than those without alterations (50 vs 90%). The sensitivity to detect alterations in ctDNA at EOT was 94% in patients not achieving a CR and no mutation was detected in patients with CR. Conclusions: In a real-life, prospective-based population, we showed that pre-treatment and dynamic molecular response measured by ctDNA, could be useful to stratify patients and predict response to treatment and early relapse in FL patients.

Published
2022

21. Efficacy of the combination of rituximab-bendamustine as a second-line treatment in patients with follicular lymphoma who progress after immunochemotherapy: a phase II trial of the Spanish Lymphoma Oncology Group

Author

Joaquin Herrero, Francisco R García-Arroyo, Antonio Rueda, Cristina Quero, Delvys Rodriguez-Abreu, Ana Blasco, Marta Llanos, María José Casanova, Natividad Martínez-Banaclocha, Jesús Alfaro, David Aguiar, Ruth Alvarez, Luis Merino, Virginia Calvo, and Mariano Provencio

Subjects
Oncology, Bendamustine, Cancer Research, medicine.medical_specialty, business.industry, Follicular lymphoma, Hematology, medicine.disease, Lymphoma, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, Refractory, immune system diseases, hemic and lymphatic diseases, 030220 oncology & carcinogenesis, Internal medicine, Medicine, Rituximab, Progression-free survival, business, Prospective cohort study, 030215 immunology, medicine.drug
Abstract

Bendamustine is a drug widely used in the treatment of follicular lymphoma. Although it was initially approved as monotherapy in patients refractory to rituximab [1], better results were obtained w...

Published
2018

22. Efecto de los polimorfismos en UGT, SLCO, ABCB y ABCC en la toxicidad del tratamiento con irinotecán

Author

Ruth Ramos Díaz, Braulio Martin Calero, Marta Llanos Muñoz, Sara García Gil, Fernando Gutiérrez Nicolás, Gloria Julia Nazco Casariego, María Micaela Viña Romero, and José A. Pérez

Subjects
0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, business.industry, 030220 oncology & carcinogenesis, Medicine, General Medicine, business, Molecular biology
Abstract

Resumen Antecedentes y objetivos Evaluar la relacion entre la presencia de polimorfismos en los genes implicados en la farmacodinamia del irinotecan (UGT1A, SLCO1B1, ABCB1 y ABCC2) y la seguridad asociada al mismo en el tratamiento del cancer colorrectal metastasico (CCRm) Pacientes y metodos Estudio prospectivo observacional y unicentrico de 30 meses de duracion, en el que se incluyeron los pacientes diagnosticados de CCRm tratados con el esquema FOLFIRI. La toxicidad fue evaluada en cada ciclo de tratamiento segun la Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 NCI. La obtencion del ADN genomico se realizo mediante una muestra de sangre periferica a partir de un metodo de extraccion basado en lisis alcalina. La caracterizacion genetica se realizo empleando la plataforma LigthCycler®480 y sondas fluorescentes HybProbe® especificas de alelo. Los polimorfismos analizados fueron: UGT1A1*28, UGT1A1*60, UGT1A7*1,*2,*3,*4, UGT1A7*12, UGT1A9*22, SLCO1B1 (rs11045879), ABCC2 (rs717620) y ABCB1 (rs1045642). Resultados Fueron incluidos 34 pacientes (el 73,5% eran hombres, con una edad media de 59,9 anos [27-81]). Los polimorfismos: rs8175347, rs17868323, rs3832043, rs11692021 y rs7577677 se relacionaron con una mayor incidencia de efectos adversos. Por otro lado, se observo que aquellos pacientes wild-type, en la serie de genes de la familia UGT analizada, presentan unas menores tasas de toxicidad asociada al tratamiento con irinotecan que aquellos que poseen alguno de los polimorfismos analizados (p = 0,010). Conclusiones Estos resultados sugieren que la presencia de determinados polimorfismos en la familia de genes UGT1A se encuentra relacionada con el desarrollo de toxicidad en el tratamiento con irinotecan en dosis para el esquema FOLFIRI.

Published
2018

23. Effect of UGT, SLCO, ABCB and ABCC polymorphisms on irinotecan toxicity

Author

Marta Llanos Muñoz, Ruth Ramos Díaz, José A. Pérez, Sara García Gil, María Micaela Viña Romero, Fernando Gutiérrez Nicolás, Gloria Julia Nazco Casariego, and Braulio Martin Calero

Subjects
Adult, Male, 0301 basic medicine, Oncology, medicine.medical_specialty, ATP Binding Cassette Transporter, Subfamily B, Colorectal cancer, Irinotecan, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Prospective Studies, Glucuronosyltransferase, Neoplasm Metastasis, Adverse effect, Aged, Aged, 80 and over, Polymorphism, Genetic, biology, Liver-Specific Organic Anion Transporter 1, business.industry, Common Terminology Criteria for Adverse Events, Middle Aged, medicine.disease, Multidrug Resistance-Associated Protein 2, 030104 developmental biology, 030220 oncology & carcinogenesis, Pharmacodynamics, UDP-Glucuronosyltransferase 1A9, Toxicity, biology.protein, FOLFIRI, Female, Multidrug Resistance-Associated Proteins, Colorectal Neoplasms, SLCO1B1, business, medicine.drug
Abstract

Background and objectives Evaluate the relationship between the presence of polymorphisms in genes involved in the pharmacodynamics of irinotecan (UGT1A, SLCO1B1, ABCB1 and ABCC2) and the safety of irinotecan in the treatment of metastatic colorectal cancer (mCRC). Patients and methods Prospective observational, single-centre study of 30 months duration, which included patients diagnosed with mCRC treated with FOLFIRI was carried out. Toxicity was evaluated in each treatment cycle according to the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 NCI. Genomic DNA was obtained with a peripheral blood sample from an extraction method based on alkaline lysis. Genetic characterisation was performed using the LigthCycler®480 platform and allele-specific HybProbe® fluorescent probes. Analysed polymorphisms were: UGT1A1*28, UGT1A1*60, UGT1A7*1,*2,*3,*4, UGT1A7*12, UGT1A9*22, SLCO1B1 (rs11045879), ABCC2 (rs717620) and ABCB1 (rs1045642). Results Thirty-four patients were included (73.5% were male, mean age 59.9 years [27–81]) in the study. Polymorphisms rs8175347, rs17868323, rs3832043, rs11692021 and rs7577677 were associated with a higher incidence of adverse effects. Furthermore, it was observed that those patients with wild-type in UGT family genes analysed have lower rates of toxicity associated with irinotecan treatment than those with certain mutated allele (p = 0.010). Conclusions These results suggest that the presence of certain polymorphisms in the UGT1A family of genes is related to the development of toxicity during treatment with irinotecan.

Published
2018

24. Proposal and validation of a method to classify genetic subtypes of diffuse large B cell lymphoma

Author

Manuela Mollejo, Julia González-Rincón, Francisca I. Camacho, Miguel Piris-Villaespesa, Lucia Pedrosa, Ana Heredero, Marta Llanos, Juan F. García, David Pérez-Callejo, Paloma Martín-Acosta, Mónica García-Cosío, Francisco R García-Arroyo, M. Rodriguez, Adrian Santos, Antonio García Sánchez, Antonio Rueda, Ismael Fernández-Miranda, Mariano Provencio, Carlos Tarin, Cristina Quero, José Gómez-Codina, Sagrario Gómez, Natalia Yanguas-Casás, Margarita Sánchez-Beato, and Miguel A. Piris

Subjects
Male, 0301 basic medicine, Oncology, Lymphoma, PATHOGENESIS, Chromosomal translocation, Disease, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Outcome Assessment, Health Care, Receptor, Notch1, In Situ Hybridization, Fluorescence, Multidisciplinary, Molecular medicine, Middle Aged, CHEMOTHERAPY, Prognosis, BCL6, Neoplasm Proteins, DNA-Binding Proteins, GENOME, 030220 oncology & carcinogenesis, Cohort, Medicine, Female, Lymphoma, Large B-Cell, Diffuse, Rituximab, Algorithms, CD79 Antigens, Adult, EXPRESSION, medicine.medical_specialty, Science, CD58, SECRETASE INHIBITOR PF-03084014, Article, CLASSIFICATION, MALIGNANCIES, 03 medical and health sciences, Internal medicine, medicine, Humans, Aged, MUTATIONS, business.industry, Reproducibility of Results, CD79B, medicine.disease, 030104 developmental biology, DLBCL, Mutation, Next-generation sequencing, business, IPI, Diffuse large B-cell lymphoma
Abstract

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease whose prognosis is associated with clinical features, cell-of-origin and genetic aberrations. Recent integrative, multi-omic analyses had led to identifying overlapping genetic DLBCL subtypes. We used targeted massive sequencing to analyze 84 diagnostic samples from a multicenter cohort of patients with DLBCL treated with rituximab-containing therapies and a median follow-up of 6 years. The most frequently mutated genes were IGLL5 (43%), KMT2D (33.3%), CREBBP (28.6%), PIM1 (26.2%), and CARD11 (22.6%). Mutations in CD79B were associated with a higher risk of relapse after treatment, whereas patients with mutations in CD79B, ETS1, and CD58 had a significantly shorter survival. Based on the new genetic DLBCL classifications, we tested and validated a simplified method to classify samples in five genetic subtypes analyzing the mutational status of 26 genes and BCL2 and BCL6 translocations. We propose a two-step genetic DLBCL classifier (2-S), integrating the most significant features from previous algorithms, to classify the samples as N12-S, EZB2-S, MCD2-S, BN22-S, and ST22-S groups. We determined its sensitivity and specificity, compared with the other established algorithms, and evaluated its clinical impact. The results showed that ST22-S is the group with the best clinical outcome and N12-S, the more aggressive one. EZB2-S identified a subgroup with a worse prognosis among GCB-DLBLC cases.

Published
2021

25. Relapsed Differentiated Thyroid Cancer, clinical presentation, treatment, and prognostic factors (ERUDIT Study)

Author

Sambo, Marcel, primary, Elena, Navarro González, additional, Aller, Pardo Javier, additional, Guadalix, Iglesias Sonsoles, additional, Carles, Zafón Llopis, additional, Cintia, González Blanco, additional, Javier, Santamaría Sandi, additional, Marcelino, Gómez Balaguer, additional, Puig, Domingo Manel, additional, Juan, C. Galofré Ferrater, additional, Iñaki, Argüelles Jiménez, additional, Santos, Rita, additional, Marta, Llanos Muñoz, additional, Juan, Antonio Vallejo Casas, additional, Virginia, Pubul Núñez, additional, Crespo, Herrero Guillermo, additional, Ángel, Segura Huerta, additional, Miguel, Navarro Martín, additional, Gajate, Borau Pablo, additional, Valdivia, Bautista Javier, additional, Beatriz, Castelo Fernández, additional, Carlos, López López, additional, María, J. Villanueva Silva, additional, Orcajo, Lorenzo, additional, and Julio, Rodríguez-Villanueva García, additional

Published
2021
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26. 1099MO Durvalumab plus tremelimumab influence on response to subsequent treatments in patients with neuroendocrine neoplasms (NENs) of gastroenteropancreatic and lung origins: Results from the phase II DUNE trial (GETNE 1601)

Author

Ángel Segura, V. Alonso, Marta Llanos, J. Hernando, M. Benavent Viñuales, Antonio Cubillo, Jose Luis Manzano, A. Viudez, Alexandre Teule, Rocio Garcia-Carbonero, C. López, Gustavo Crespo, A. La Casta, T. Alonso-Gordoa, Alberto Carmona-Bayonas, Isabel Sevilla, Jaume Capdevila, M. Blanco, Paula Jiménez-Fonseca, and Ana Custodio

Subjects
Oncology, medicine.medical_specialty, Lung, Durvalumab, business.industry, Hematology, medicine.anatomical_structure, Internal medicine, medicine, In patient, business, Tremelimumab, medicine.drug
Published
2021

27. 575TiP Cabozantinib plus atezolizumab in advanced and progressive neoplasms of the endocrine system: A multicohort phase II trial (CABATEN trial / GETNE-T1914)

Author

Jaume Capdevila, Ana Custodio, J. Hernando, Paula Jiménez-Fonseca, J.C. Ruffinelli, C. Lopez, Alexandre Teule, I. Gallego Jimenez, Alberto Carmona-Bayonas, B. Antón Pascual, Enrique Grande, Isabel Sevilla, Cinta Hierro, M. Benavent Viñuales, J. Molina-Cerrillo, Jesús Gallego, Rocio Garcia-Carbonero, Vicente Alonso, F. Lista, and Marta Llanos

Subjects
Oncology, medicine.medical_specialty, chemistry.chemical_compound, Cabozantinib, chemistry, business.industry, Atezolizumab, Internal medicine, Medicine, Endocrine system, Hematology, business
Published
2021

28. Incidence of hand–foot syndrome with capecitabine in combination with chemotherapy as first-line treatment in patients with advanced and/or metastatic gastric cancer suitable for treatment with a fluoropyrimidine-based regimen

Author

Gómez-Martin, Carlos, Sánchez, Antonio, Irigoyen, Antonio, Llorente, Beatriz, Pérez, Begoña, Serrano, Raquel, Safont, Mª José, Falcó, Esther, Lacasta, Adelaida, Reboredo, Margarita, Aparicio, Jorge, Dueñas, Rosario, Muñoz, Marta Llanos, Regueiro, Pilar, Sanchez-Viñes, Elena, and López, Rafael López

Published
2012
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29. Diagnostic patterns of relapsed differentiated thyroid cancer (DTC) and the efficacy of rescue therapies (ERUDIT Study)

Author

Iñaki Argüelles, Carlos F. Lopez, Javier Aller, Marta Llanos, Javier Santamaría, Juan C. Galofré, Julio Rodríguez-Villanueva, Manel Puig, Beatriz Castelo, Guillermo Crespo, Marcelino González, Virginia Pubul, Fábia Araujo, María J. Villanueva, Lorenzo Orcajo, Sonsoles Guadalix, Javier Valdivia, Ángel Segura, Cristina Y. González, Miguel Navarro, Marcel Sambo, Juan A. Vallejo, Carlos Zafón, Pablo Gajate, Elena Navarro, and Rita Santos

Subjects
Oncology, medicine.medical_specialty, business.industry, Internal medicine, medicine, business, medicine.disease, Thyroid cancer
Published
2020

30. Pharmacokinetics of Trastuzumab After Subcutaneous and Intravenous Administration in Obese Patients

Author

Matías Llabres Martinez, José Norberto Batista López, Marta Llanos Muñoz, Ruth Ramos Díaz, Isaac Ceballos Lenza, Josefina Cruz Jurado, Alejandro Jiménez Sosa, María Micaela Viña Romero, Fernando Gutiérrez Nicolás, Gloria Julia Nazco Casariego, and Jonathan González García

Subjects
Adult, medicine.medical_specialty, Receptor, ErbB-2, Injections, Subcutaneous, Population, Breast Neoplasms, Gastroenterology, Body Mass Index, 03 medical and health sciences, Cmin, 0302 clinical medicine, Breast cancer, Antineoplastic Agents, Immunological, Pharmacokinetics, Trastuzumab, Internal medicine, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Obesity, Prospective Studies, Prospective cohort study, education, Infusions, Intravenous, education.field_of_study, business.industry, Body Weight, Middle Aged, medicine.disease, Regimen, 030220 oncology & carcinogenesis, Administration, Intravenous, Female, business, Body mass index, medicine.drug
Abstract

Background: Subcutaneous trastuzumab (T-SC) administration does not allow the historical target concentration of 20 µg/mL for efficacy to be reached, from the start of treatment in patients with a body mass index (BMI) >30 kg/m2. Objectives: To analyze the influence of the strategy of dosification (fixed vs adjusted patient’s body weight dose) on the initial minimum plasma concentration ( Cmin) of trastuzumab in obese patients. Methods: This was an observational, prospective study, which included patients with HER2-positive nonmetastatic breast cancer treated with trastuzumab. The determination of the Cmin of trastuzumab was performed on day +21 of the first cycle using the ELISA technique. Patients were stratified according to the strategy of dosification and BMI. Results: A total of 50 patients were included; 16 patients received the drug intravenously and 34 in a fixed dosage subcutaneous (T-SC) regimen. The proportion of patients who achieved an adequate plasma concentration since the beginning of treatment was significantly higher when the drug was administered intravenously (93.8% vs 67.6%, P = 0.042). These differences are especially greater in T-SC patients with BMI >30 kg/m2, with only 20% of patients exceeding the pharmacokinetic target. Conclusion and Relevance: Our study suggests that trastuzumab SC fixed dose of 600 mg is not equivalent to IV administration, especially in obese patients. An adequate trastuzumab exposure in this population needs patient weight–adjusted IV dosage in the first administration. The clinical relevance of these findings remains to be elucidated, and further research, including larger controlled trials, is warranted.

Published
2020

31. Consolidation treatment with yttrium-90 ibritumomab tiuxetan after new induction regimen in advanced stage follicular lymphoma: update results from the Spanish Lymphoma Oncology Group trial after a median follow-up of 8.5-years

Author

José Ignacio Chacón, Ruth Alvarez, Ana Royuela, Francisco R García-Arroyo, Cristina Quero Blanco, Juan Ramón Delgado, Luis de la Cruz, Josep Gumá, Marta Llanos, Fernando Franco, Mariano Provencio, José Gómez-Codina, and Antonio Rueda

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Follicular lymphoma, Kaplan-Meier Estimate, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, Median follow-up, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Molecular Targeted Therapy, Neoplasm Metastasis, Lymphoma, Follicular, Neoplasm Staging, Group trial, business.industry, Advanced stage, Antibodies, Monoclonal, Induction chemotherapy, Consolidation Chemotherapy, Induction Chemotherapy, Hematology, medicine.disease, Lymphoma, Regimen, Treatment Outcome, Spain, 030220 oncology & carcinogenesis, Retreatment, business, Follow-Up Studies, 030215 immunology
Abstract

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) and represents ∼35% of all NHLs. In the United States there are estimated to be 3.18 cases per 100,000 populations per ...

Published
2018

32. A phase II trial of gemcitabine and weekly high-dose 5-fluorouracil in a 48-hour continuous-infusion schedule in patients with advanced pancreatic carcinoma. A study of the Spanish Cooperative Group for Gastrointestinal Tumour Therapy (TTD)

Author

Santasusana, Joan Maurel, García López, José Luis, Bretón García, Juan José, León Carbonero, Ana Isabel, Plazas, Javier Gallego, Rovira, Pedro Sánchez, Martos, Carlos Fernández, Galán Guzmán, Ma Carmen, Jericó, Jesús Florián, Dorta Delgado, Francisco Javier, Espinosa, Javier Casinello, Muñoz, Marta Llanos, Aguilar, Enrique Aranda, Valera, Javier Sastre, Ribas, Ignacio García, and Mena, Alfredo Carrato

Published
2005
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34. 829MO A gene signature to predict risk of transformation in patients with follicular lymphoma

Author

Manuela Mollejo, Antonio Salar, Blanca Espinet, Margarita Sánchez-Beato, N. Yanguas, Mónica García-Cosío, Paloma Martín-Acosta, Francisco R García-Arroyo, Fina Climent, Luis Colomo, Lucia Pedrosa, M. Provencio Pulla, Ismael Fernández-Miranda, Belen Navarro, Sophie Gomez, Santiago Mercadal, F. de la Cruz, Marta Llanos, S. Lopez, and Julia González-Rincón

Subjects
Transformation (genetics), Oncology, business.industry, Cancer research, Follicular lymphoma, medicine, In patient, Hematology, medicine.disease, Signature (topology), business, Gene
Published
2021

35. 455P Concordance of baseline RAS mutational status (ms) between tissue and cell-free DNA (cfDNA) and association with overall response rate (ORR) in first-line (1L) metastatic colorectal cancer (mCRC) patients (pts): PERSEIDA study (cohort 2) (NCT02792478)

Author

P. García-Alfonso, L. Cirera Nogueras, A.M. López Muñoz, Manuel Valladares-Ayerbes, E. González-Flores, M. Salgado Fernández, Rocio Garcia-Carbonero, Juan J. Cruz-Hernández, Jorge Aparicio, E. Aranda Aguilar, A. Salud Salvia, O.A. Castillo Trujillo, E. Falco Ferrer, A. Lloansi Vila, P. Pimentel Cáceres, M.A. Vicente Conesa, N Rodríguez Salas, Marta Llanos, B. Massuti Sureda, and Maria Jose Safont

Subjects
Oncology, medicine.medical_specialty, Colorectal cancer, business.industry, Concordance, First line, Hematology, medicine.disease, Overall response rate, Cell-free fetal DNA, Internal medicine, Cohort, medicine, Mutational status, business
Published
2021

36. P-50 Prognostic factors in patients receiving trifluridine/tipiracil for refractory metastatic colorectal cancer in the real-life setting: The ROS study

Author

F. Rivera Herrero, V. Alonso Orduña, C. Grávalos Castro, E. Mata Velasco, M.T. Delgado Urena, R. Grandez, M.J. Safont Aguilera, Marta Llanos, Enrique Aranda, P. García-Alfonso, A. Illán Varella, J. J. Reina Zoilo, I. Fernandez Rañada, J. Rodriguez-Pascual, Mireia Moreno, J. Mendez, P. Pimentel, C. Castañón, Beatriz García-Paredes, R. Afonso, I. Siso, and A.M. López Muñoz

Subjects
Oncology, medicine.medical_specialty, Refractory, business.industry, Colorectal cancer, Internal medicine, Medicine, In patient, Hematology, business, medicine.disease, Real life setting
Published
2021

39. Diffuse Large B Cell Lymphoma Genetic Classification By Targeted Sequencing and Associations with Immunochemotherapy-Treated Patients' Clinical Outcome

Author

Manuela Mollejo, Antonio García Sánchez, Juan F. García, Natalia Yanguas-Casás, José Gómez Codina, Marta Llanos, M. Rodriguez, Francisca I. Camacho, Mónica García-Cosío, Mariano Provencio, Adrian Santos, Miguel A. Piris, D. Callejo, Julia González-Rincón, Miguel Piris-Villaespesa, Paloma Martín-Acosta, Ana Heredero, Francisco R García-Arroyo, Sagrario Gómez, Margarita Sánchez-Beato, Cristina Quero, Antonio Rueda, Lucia Pedrosa Perez, Ismael Fernández-Miranda, and Carlos Tarin

Subjects
Oncology, medicine.medical_specialty, education.field_of_study, business.industry, Immunology, Population, Cell Biology, Hematology, Disease, Gene mutation, Lower risk, medicine.disease, BCL6, Biochemistry, Median follow-up, Internal medicine, Cohort, medicine, education, business, Diffuse large B-cell lymphoma
Abstract

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous disease with variable prognosis associated with clinical features, cell-of-origin and genetic aberrations. The main problems for DLBCL patients are that a substantial percentage of them (30-40%) are refractory to treatment or relapse and the lack of accurate predictive markers that adequately determine which patients will benefit from immunochemotherapy. Several recent deep-sequencing studies have proposed new genetic subtypes based on the DLBCL genomic profile (Wright et al., 2020; Lacy et al. 2020) and associated with clinical outcome. However, a consensus and validated classification is still needed. The aim was to determine whether genetic alterations of individual genes or genes clustered in pathways are associated with clinical outcome in immunochemotherapy-treated patients. We used targeted massive sequencing to analyze 84 diagnostic samples from a multicentric cohort of patients with DLBCL treated with rituximab-containing therapies with a median follow up of 6 years. A two-step genetic classifier was built with mutation information from 27 genes and BCL2/BCL6 translocations, based on recently proposed genetic subtypes (Wright et al., 2020; Lacy et al. 2020). Logistic regression and Kaplan-Meier analyses for survival and risk of relapse were performed to assess the potential clinical value of the classifier. Moreover, this two-step classifier was validated in an external cohort and its specificity and sensitivity were tested to determine its accuracy in classifying patients compared to the previous approaches. We found that the most frequently mutated genes were IGLL5 (43%), KMT2D (33.3%), CREBBP (28.6%), PIM1 (26.2%), and CARD11 (22.6%). Mutations in CD79B, PRDM1, and NOTCH2 were associated with a higher risk of relapse after treatment, whereas patients with mutations in CD79B, ETS1, PRDM1, and TNFAIP3 had significantly shorter survival. Analyzing the impact of gene mutations on predefined gene sets related to lymphomagenesis revealed that mutations in genes involved in B-cell development, and BCR-PI3K and MAPK-ERK pathways were significantly associated with a higher risk of relapse and/or shorter overall survival. These results confirmed the current landscape of genetic alterations in DLBCL. According to the two-step classifier, we categorized the samples into MCD, BN2, EZB, ST2, and N1 genetic subgroups (Figure). We tested the accuracy of our classification in an external series (UK population-based Haematological Malignancy Research Network cohort [HMRN]) to determine its specificity and sensitivity compared with their own classification (Lacy et al. 2020) and the LymphGen algorithm (Wright et al., 2020). The comparison demonstrated (Wright et al., 2020; Lacy et al. 2020), a specificity and sensitivity higher than 85% for each subtype, except for BN2. This controversy may be explained by the fact that BN2 is less strongly defined than the other subtypes. We then tested their clinical impact and found the EZB and ST2 subtypes to have a better clinical course and a lower risk of relapse. The BN2 group had the worst clinical outcome of our series, unlike other published studies (Figure). These results were validated in the HMRN cohort, in which N1 showed a higher risk of relapse and shorter overall survival, whereas ST2 is the group with the most favorable outcome. Although N1 was not included for clinical outcome analysis in our cohort due to the small number of cases, the validation of our classifier defined N1 as the most aggressive subtype. In summary, we propose and validate a feasible genetic DLBCL classifier based on an optimized panel of genes that unifies previous genetic classification algorithms in such a way as to facilitate its implementation as part of pathology laboratories for routine patient management. This genetic classifier, combined with clinical data and other molecular characteristics, should eventually help develop improved risk models for DLBCL patients, and guide precision therapy. Figure Disclosures Perez Callejo: F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company.

Published
2020

40. Prognostic value of event-free survival at 12 and 24 months and long-term mortality for non-Hodgkin follicular lymphoma patients: A study report from the Spanish Lymphoma Oncology Group

Author

Ana Royuela, Natividad Martínez, Antonio Rueda, Miguel Cruz, Ana Blasco, Luis de la Cruz-Merino, Maria Torrente, Marta Llanos, Delvys Rodriguez, Manuel Morales, Cristina Quero, David Aguiar, Javier Lavernia, Pilar Sabin, Virginia Calvo, Francisco R García-Arroyo, Mariano Provencio, Marina Pollán, José Gómez-Codina, Josep Gumá, and Álvaro Saenz-Cusi

Subjects
Cancer Research, Pediatrics, medicine.medical_specialty, education.field_of_study, business.industry, Mortality rate, Population, Follicular lymphoma, Cancer, medicine.disease, Confidence interval, 03 medical and health sciences, 0302 clinical medicine, Standardized mortality ratio, Oncology, 030220 oncology & carcinogenesis, medicine, Young adult, education, business, 030215 immunology, Cause of death
Abstract

BACKGROUND Relatively few studies have analyzed the mortality of follicular lymphoma (FL) patients in comparison with a sex- and age-matched general population. This study analyzed the overall survival (OS) of patients with FL and compared their survival with the expected survival of a general population. METHODS Patients diagnosed with FL were prospectively enrolled from 1980 to 2013. Standardized mortality ratios (SMRs) were obtained from yearly sex- and age-specific mortality rates in Spain, and OS was compared with age- and sex-matched general population data. RESULTS A total of 1074 patients with newly diagnosed FL were enrolled. The median OS was 231 months (95% confidence interval [CI], 195-267 months). Event-free survival at 12 months (EFS12) and event-free survival at 24 months (EFS24) were associated with an increased probability of early death, with an SMR of 10.27 (95% CI, 8.26-12.77) for EFS12. The overall SMR, including all causes of death, was 2.55 (95% CI, 2.23-2.92), and it was higher for women (SMR, 3.02; 95% CI, 2.48-3.67) and young adults (SMR, 6.01; 95% CI, 3.13-11.55). More than 10 years after the diagnosis, mortality rates for FL patients were lower than those for the general population (SMR, 0.47; 95% CI, 0.28-0.78). When FL was excluded as a cause of death, the overall SMR was 1.35 (95% CI, 1.11-1.65) without a statistically significant mortality increase in the >60-year-old group in comparison with age- and sex-matched general population data. More than 15% of the patients included in the study (n = 158) had more than 10 years of follow-up. CONCLUSIONS EFS12 and EFS24 predict an early increase in mortality. The long-term SMR, over the course of 10 years of follow-up, shows that patients with FL have a risk of dying similar to that of a sex- and age-matched general population. Cancer 2017. © 2017 American Cancer Society.

Published
2017

41. 1157O A multi-cohort phase II study of durvalumab plus tremelimumab for the treatment of patients (pts) with advanced neuroendocrine neoplasms (NENs) of gastroenteropancreatic or lung origin: The DUNE trial (GETNE 1601)

Author

Alexandre Teule, Jaume Capdevila, Antonio Cubillo, A. Viudez, T. Alonso Gordoa, Isabel Sevilla, P. Jiménez-Fonseca, Ángel Segura, Ana Custodio, V. Alonso, Marta Benavent, Rocio Garcia-Carbonero, Jorge Hernando-Cubero, Marta Llanos, A. La Casta Muñoa, Jose Luis Manzano, Gustavo Crespo, Alberto Carmona-Bayonas, M. Blanco-Codesido, and C. López

Subjects
Oncology, medicine.medical_specialty, Durvalumab, Lung, business.industry, Phases of clinical research, Hematology, medicine.anatomical_structure, Internal medicine, Cohort, medicine, business, Tremelimumab, medicine.drug
Published
2020

42. Unraveling transformation of follicular lymphoma to diffuse large B-cell lymphoma

Author

Paloma Martín, Mariano Provencio, Manuela Mollejo, David Pérez-Callejo, Lucia Pedrosa, José Gómez-Codina, Juan F. García, Javier Menárguez, Carmen Bárcena, Luis de la Cruz-Merino, Antonio Rueda, Sagrario Gómez, Margarita Sánchez-Beato, Ana Royuela, Francisca I. Camacho, Cristina Quero, Consuelo Parejo, Alberto J. Arribas, Delvys Rodriguez-Abreu, Julia González-Rincón, Luciano Cascione, Ivo Kwee, Francesco Bertoni, Marta Llanos, Silvia Monsalvo, Carmen Bellas, Santiago Montes-Moreno, Socorro María Rodríguez-Pinilla, Miriam Mendez, and Miguel A. Piris

Subjects
Male, B Cells, Cell Lines, Biopsy, Follicular lymphoma, medicine.disease_cause, Hematologic Cancers and Related Disorders, White Blood Cells, Animal Cells, Medicine and Health Sciences, Copy-number variation, Frameshift Mutation, Lymphoma, Follicular, B-Lymphocytes, Mutation, Multidisciplinary, Massive parallel sequencing, Cell Differentiation, Hematology, Genomics, Diffuse large B-cell lymphoma, Middle Aged, Copy Number Variation, Neoplasm Proteins, Cell Transformation, Neoplastic, Oncology, Medicine, Lymphomas, Female, Biological Cultures, Lymphoma, Large B-Cell, Diffuse, Cellular Types, Raji Cells, Research Article, Adult, Follicular Lymphoma, Immune Cells, Science, Immunology, Surgical and Invasive Medical Procedures, Biology, Research and Analysis Methods, Genome Complexity, Genetics, medicine, Humans, Antibody-Producing Cells, Aged, Blood Cells, Biology and Life Sciences, Cancers and Neoplasms, Computational Biology, Cell Biology, medicine.disease, GNA13, Lymphoma, Transformation (genetics), Cancer research, Follow-Up Studies
Abstract

Follicular lymphoma (FL) is an indolent but largely incurable disease. Some patients suffer histological transformation to a more aggressive subtype with poorer prognosis. This study aimed to improve our understanding of the genetics underlying FL histological transformation, and to identify genetic drivers or promoters of the transformation by elucidating the differences between FL samples from patients who did and did not transform. We conducted targeted massive parallel sequencing of 22 pre-transformed FL/transformed diffuse large B-cell lymphoma pairs and 20 diagnostic samples from non-transformed FL patients. Additionally, 22 matched samples from 11 transformed FL patients (pre-transformed FL and diffuse large B-cell lymphoma) and 9 non-transformed FLs were studied for copy number variation using SNP arrays. We identified recurrently mutated genes that were enriched at transformation, most notably LRP1B, GNA13 and POU2AF1, which have roles in B-cell differentiation, GC architecture and migration. Mutations in POU2AF1 might be associated with lower levels of expression, were more frequent in transformed FLs, and seemed to be specific to transformed- compared with de novo-diffuse large B-cell lymphomas. Pre-transformed FLs carried more mutations per sample and had greater subclonal heterogeneity than non-transformed FLs. Finally, we identified four mutated genes in FL samples that differed between patients who did and did not transform: NOTCH2, DTX1, UBE2A and HIST1H1E. The presence of mutations in these genes was associated with shorter time to transformation when mutated in the FL biopsies. This information might be useful for identifying patients at higher risk of transformation.

Published
2019

43. 1159MO Survival and prognostic factors analysis of 535 grade 3 gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN): Data from the Spanish Taskforce of Neuroendocrine Tumours Registry (R-GETNE)

Author

Carles Pericay, C. Villabona, Marta Llanos, A Castaño, R. Garcia Centeno, Alexandre Teule, A. Lopez de Sa, M. Sánchez Cánovas, L. Oliva Fernandez, J. Gallego Plazas, Gustavo Crespo, I. Torres, A. La Salvia, P. Jimenez Fonseca, Teresa Alonso, Jaume Capdevila, Ana Custodio, Vicente Alonso-Orduña, M. Benavent, and C. López

Subjects
Oncology, medicine.medical_specialty, business.industry, Internal medicine, Neuroendocrine neoplasm, medicine, Hematology, business
Published
2020

44. GETNE-SILVELUL study: A new immunohistochemical score (SPI) in patients (pts) with pancreatic neuroendocrine tumors (PanNET) treated with everolimus or captem

Author

M. Benavent, Guillermo Crespo, Antonio Viudez, Jairo Pérez-Sanz, Alberto Carmona, Saioa Goñi, Maria Luisa Gomez-Dorronsoro, Carlos F. Lopez, Marta Llanos, Vicente Alonso, J. Hernando, Isabel Sevilla, Iranzu González-Borja, Ana De Jesus-Acosta, Irene Hernandez, Borja Lopez De San Vicente, Beatriz Roig García, and Ana Custodio

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Everolimus, business.industry, Neuroendocrine tumors, medicine.disease, Internal medicine, medicine, Immunohistochemistry, In patient, business, medicine.drug
Abstract

e16707 Background: Previously our group showed the potential use of a score based (SPI) on MGMT, NDRG-1 and PHLDA-3 immunohistochemistry (IHC) expression as predictor of outcome in operated PanNET (Viúdez et al. Oncotarget 2016). The present retrospective multicenter project is analyzing the predictive/prognosis role of MGMT, NDRG-1 and PHLDA-3 in patients treated with advanced PanNET treated CAPTEM or everolimus. Methods: IHC nuclear staining for MGMT and PHLDA-3 is being scored as 0, 1-5%, 6-50% and ≥ 51%. For NDRG-1, we are using a cytoplasmic score from 0 to 2 based on distribution pattern (null, patched or diffuse). Results: 60 of 105 pts have been fully analyzed., most of then women (53%) and median age of 63 (27-79). 30 pts were treated with CAPTEM and 30 pts with everolimus. Median previous lines were 1 (21,7% received chemotherapy previously), and 91,7% pf pts had ki67 < 20%. 65,5%, 10,2% and 29,1% were null for MGMT, NDRG-1 and PHLDA-3 IHC analysis. In the entire cohort K-M analysis showed significant differences for PFS or OS based on best response observed (p = 0,0001) and number previous lines received (p = 0,05), respectively. In pts treated with CAPTEM, log rank analysis showed significant differences for PFS (p = 0,047 HR:4,63 CI95%: 1,023-20,990) and OS (p = 0,040 HR:5,433 CI95%: 1,082-27,266) based on our SPI. Similar, although not significant, results were observed in everolimus-treated cohort for PFS (p = 0,529) and OS (p = 0,592) according to SPI. Conclusions: As it was described previously in operated PanNET, our SPI also seems to own predictive role in pts with advanced PanNET treated with CAPTEM or everolimus. More mature results of our work are needed and will be presented during 2020 ASCO Annual Meeting.

Published
2020

45. SILVELUL project: Immunohistochemical panel analyses as potential predictive and prognostic factors in pancreatic neuroendocrine tumours (PanNET) treated with CAPTEM or everolimus

Author

Imanol Arozarena, Maria Luisa Gomez-Dorronsoro, Saioa Goñi, M. Benavent, A. De Jesus-Acosta, V. Alonso, G. Crespo Herrero, V. Arrazubi Arrula, Marta Llanos, Ana Custodio, Marina Baretti, Iranzu González-Borja, B. López de San Vicente, C. López, R. Grandez, M.C. Riesco Martínez, A. Viudez, A. Carmona Bayonas, and P. Jiménez-Fonseca

Subjects
Oncology, medicine.medical_specialty, Prognostic factor, Everolimus, Clinical variables, business.industry, O-6-methylguanine-DNA methyltransferase, Hematology, Prognostic score, Internal medicine, Distribution pattern, medicine, Immunohistochemistry, In patient, business, medicine.drug
Abstract

Background Previously our group showed the potential use of a score based on MGMT, NDRG-1 and PHLDA-3 immunohistochemistry (IHC) expression as predictor of outcome in operated PanNET. The present multicenter project is retrospectively analyzing the predictive/prognosis role of MGMT, NDRG-1 and PHLDA-3 in patients with advanced PanNET treated CAPTEM or everolimus. Methods IHC nuclear staining for MGMT and PHLDA-3 is being scored as 0, 1-5%, 6-50% and ≥ 51%. For NDRG-1, we are using a cytoplasmic score from 0 to 3 based on staining intensity and distribution pattern (patched or diffuse). Results Until now, clinical and samples data from 96 patients (110 samples) has been collected ad are currently being analyzed. Based on our previous results, we will develop an imunohistochemistry prognostic score (IPS, score from 0 to 4) and try to correlate it with clinical variables collected in our database. Conclusions As we described previously in operated PanNET, we will try to describe the potential role of IPS as predictive/ prognostic factor in advanced PanNET. More mature results of this work will be presented during 2019 ESMO Congress. Legal entity responsible for the study Navarrabiomed Biomedical Research Center, Pamplona, Navarra, Spain. Funding GETNE. Disclosure All authors have declared no conflicts of interest.

Published
2019

46. Sequential RAS mutation testing in cfDNA in RAS wild type (wt) metastatic colorectal cancer (mCRC) patients (pt) treated with panitumumab (P) and chemotherapy (CT) in first-line (1L): PERSEIDA study

Author

Manuel Valladares-Ayerbes, C. García Girón, A. Lloansi Vila, Marta Llanos, P. Pimentel Cáceres, Juan J. Cruz-Hernández, P. García-Alfonso, J. Muñoz Luengo, L. Cirera, and J.M. Viéitez

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Chemotherapy, business.industry, Colorectal cancer, First line, medicine.medical_treatment, Disease progression, Stock options, Hematology, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, RAS Mutation, medicine, Panitumumab, Progression-free survival, business, medicine.drug
Abstract

Background Genotyping on cfDNA offers potential advantages in clinical practice for pt selection and serial monitoring of treatment (Tx) efficacy. Clinical relevance of sequential RASmut in cfDNA at different time points during 1L of pt with RASwt solid biopsies (SB) was evaluated. Methods Prospective, multi-center study in mCRC pt with RASwt according to SB and treated following standard practice. Liquid biopsies (LB) were collected before starting 1L, at 20 (± 2) weeks (w) and at disease progression (PD). Beaming PCR was used for cfDNA analysis; 3 mutant allele fraction (MAF) cutoffs were considered: 1%, 0.1% & 0.02%. Results Median progression-free survival (PFS) was 11.7 months (m) (9.9-13.0) (n = 102). There were no differences in the overall response rate (ORR) according to baseline LB at any cut off, being at MAF 0.02%: 78.7% (68.2- 87.1) in RASwt pt (n = 80) vs 61.5% (31.6 - 86.1) in RASmut pt (n = 13) (OR: 2.32; p = 0.180). MAF was not correlated with total cfDNA levels (p = 0.957). The % of mut cfDNA pt varied along time, with the smallest % at 20 w (Table). There were no emergent mutations at 20 w. Ten pt wt according to baseline LB presented mutations at PD. ORR was 76.9% (63.2 - 87.5) in pt always wt (n = 52) vs 76.2% (52.8 - 91.8) in pt with mut cfDNA at any time point (n = 21) (p = 1.0). There were also no differences in PFS between these 2 groups of pt: 13.0 m (10.9 - 15.4) vs 11.4 m (7.1 – 13.7) at MAF 0.02% (p = 0.095). Table . 531PD MAF≥1% MAF≥0.1% MAF≥0.02% Baseline 3 (2.9%) n = 102 6 (5.9%) n = 102 14 (13.7%) n = 102 PFS RASwt: 11.7 m (9.9-13.0) RASmt: NR (5.9-NR) (p = 0.689) PFS RASwt: 11.7 m (9.9-13.1) RASmt: 7.8 m (5.9-NR) (p = 0.662) PFS RASwt: 11.7 m (9.9-13.1) RASmt: 11.4 m (5.9-18.5) (p = 0.495) 20 ± 2 weeks 0 (0%) n = 76 3 (4.0%) n = 76 4 (5.3%) n = 76 PD 1 (2.0%) n = 49 9 (18.4%) n = 49 12 (24.5%) n = 49 Proportions of mutated patients based on the number of samples analysed at each time point and progression-free survival (PFS) according to the baseline plasma sample PD Progression of the disease; MAF: Mutant Allele Fraction; NR: not reached Conclusions RAS mutational status assessed in cfDNA before starting 1L or sequentially during P+CT Tx in pt with RASwt SB was not a significant predictor of PFS and ORR in none of the cutoffs considered, although in RASmut pt clinical results tended to increase as MAF decreased. The highest proportion of mutated pt was observed at PD, which may be linked to the emergence of resistance. Mutated cfDNA by itself did not predict a lack of clinical benefit to CT and P in our study. Editorial acknowledgement Marta Munoz-Tuduri (TFS, S.L.). Legal entity responsible for the study Amgen S.A. Funding Amgen S.A. Disclosure M. Valladares-Ayerbes: Honoraria (self): Amgen, Merck, Roche, Servier, Bayer, Bristol-Myers; Advisory / Consultancy: Merck, Sanofi, Amgen; Speaker Bureau / Expert testimony: Roche, Servier, Bayer; Research grant / Funding (self): Roche; Travel / Accommodation / Expenses: Merck, Servier, Amgen, Roche. J.M. Vieitez: Travel / Accommodation / Expenses, attendance at conferences: Amgen, Roche, Servier; Research grant / Funding (self): Roche, Amgen. J.J. Cruz-Hernandez: Honoraria (self): Amgen, AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer, Roche Farma; Advisory / Consultancy, Advisory Board: Bristol-Myers Squibb, Merck, MSD, Roche Farma, Pfizer, Janssen Cilag; Advisory / Consultancy, Consulting: Roche Farma. M. Llanos: Advisory / Consultancy, collaboration in lectures: Servier, Roche, Ipsen, Merck, Bristol, Sanofi, Eisai; Advisory / Consultancy: Amgen. A. Lloansi Vila: Shareholder / Stockholder / Stock options, employee and stakeholder of Amgen S.A: Amgen. All other authors have declared no conflicts of interest.

Published
2019

47. Neuroendocrine Tumor Heterogeneity Adds Uncertainty to the World Health Organization 2010 Classification: Real-World Data from the Spanish Tumor Registry (R-GETNE)

Author

Jose Javier Pi Barrio, Carlos F. Lopez, Daniel Castellano, Vicente Alonso, Ángel Castaño‐Pascual, Ángel Segura, Paula Jiménez-Fonseca, Alex Teulé, Barbara Nuñez‐Valdovinos, Alberto Carmona-Bayonas, Ana Custodio, Jose Angel Diaz‐Perez, Mónica Marazuela, Isabel Sevilla, Marta Llanos, Adolfo Beguiristain, Teresa Alonso, Marta Benavent, Rocio Garcia-Carbonero, Maria Purificacion Martinez del Prado, and Jaume Capdevila

Subjects
Oncology, Male, Cancer Research, Proliferation index, Neuroendocrine tumors, 0302 clinical medicine, Gastrointestinal Cancer, Registries, Child, Aged, 80 and over, biology, Cell Differentiation, Middle Aged, Prognosis, Survival Rate, Neuroendocrine Tumors, 030220 oncology & carcinogenesis, Ki-67, Female, Adult, medicine.medical_specialty, Registry, Adolescent, 030209 endocrinology & metabolism, Tumor differentiation, World Health Organization 2010, World Health Organization, Tumor heterogeneity, World health, Gastroenteropancreatic, 03 medical and health sciences, Young Adult, Stomach Neoplasms, Internal medicine, Intestinal Neoplasms, medicine, Humans, Grading (tumors), Ki‐67, Aged, Neoplasm Staging, Proportional Hazards Models, business.industry, medicine.disease, Tumor registry, Carcinoma, Neuroendocrine, Clinical trial, Pancreatic Neoplasms, Ki-67 Antigen, Spain, Neuroendocrine neoplasms, biology.protein, Heterogeneity, Neoplasm Grading, business
Abstract

BackgroundGastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a complex family of tumors of widely variable clinical behavior. The World Health Organization (WHO) 2010 classification provided a valuable tool to stratify neuroendocrine neoplasms (NENs) in three prognostic subgroups based on the proliferation index. However, substantial heterogeneity remains within these subgroups, and simplicity sometimes entails an ambiguous and imprecise prognostic stratification. The purpose of our study was to evaluate the prognostic impact of histological differentiation within the WHO 2010 grade (G) 1/G2/G3 categories, and explore additional Ki-67 cutoff values in GEP-NENs.Subjects, Materials, and MethodsA total of 2,813 patients from the Spanish National Tumor Registry (RGETNE) were analyzed. Cases were classified by histological differentiation as NETs (neuroendocrine tumors [well differentiated]) or NECs (neuroendocrine carcinomas [poorly differentiated]), and by Ki-67 index as G1 (Ki-67 20%). Patients were stratified into five cohorts: NET-G1, NET-G2, NET-G3, NEC-G2, and NEC-G3.ResultsFive-year survival was 72%. Age, gender, tumor site, grade, differentiation, and stage were all independent prognostic factors for survival. Further subdivision of the WHO 2010 grading improved prognostic stratification, both within G2 (5-year survival: 81% [Ki-67 3%–5%], 72% [Ki-67 6%–10%], 52% [Ki-67 11%–20%]) and G3 NENs (5-year survival: 35% [Ki-67 21%–50%], 22% [Ki-67 51%–100%]). Five-year survival was significantly greater for NET-G2 versus NEC-G2 (75.5% vs. 58.2%) and NET-G3 versus NEC-G3 (43.7% vs. 25.4%).ConclusionSubstantial clinical heterogeneity is observed within G2 and G3 GEP-NENs. The WHO 2010 classification can be improved by including the additive effect of histological differentiation and the proliferation index.Implications for PracticeGastroenteropancreatic neuroendocrine neoplasms are tumors of widely variable clinical behavior, roughly stratified by the World Health Organization (WHO) 2010 classification into three subgroups based on proliferation index. Real-world data from 2,813 patients of the Spanish Registry RGETNE demonstrated substantial clinical heterogeneity within grade (G) 2 and G3 neuroendocrine neoplasms. Tumor morphology and further subdivision of grading substantially improves prognostic stratification of these patients and may help individualize therapy. This combined, additive effect shall be considered in future classifications of neuroendocrine tumors and incorporated for stratification purposes in clinical trials.

Published
2018

48. Prospective validation of a lymphocyte infiltration prognostic test in stage III colon cancer patients treated with adjuvant FOLFOX

Author

Jean-François Emile, Catherine Julié, Karine Le Malicot, Come Lepage, Josep Tabernero, Enrico Mini, Gunnar Folprecht, Jean-Luc Van Laethem, Stéphanie Dimet, Camille Boulagnon-Rombi, Marc-Antoine Allard, Frédérique Penault-Llorca, Jaafar Bennouna, Pierre Laurent-Puig, Julien Taieb, Josef Thaler, Richard Greil, Johannes Gaenzer, Wolfgang Eisterer, Joerg Tschmelitsch, Felix Keil, Hellmut Samonigg, August Zabernigg, Franz Schmid, Günther Steger, Robert Steinacher, Johannes Andel, Björn Jagdt, Alois Lang, Michael Fridrik, Reinhold Függer, Friedrich Hofbauer, Ewald Woell, Dietmar Geissler, Alfred Lenauer, Manfred Prager, Geert D'Haens, Gauthier Demolin, Joseph Kerger, Guido Deboever, Gilbert Ghillebert, Marc Polus, Eric Van Cutsem, Hassan Rezaie Kalantari, Thierry Delaunoit, Jean Charles Goeminne, Marc Peeters, Philippe Vergauwe, Ghislain Houbiers, Yves Humblet, Jos Janssens, Dirk Schrijvers, Erik Vanderstraeten, Jan Vermorken, Daniel Van Daele, Michel Ferrante, Frederic Forget, Alain Hendlisz, Mette Yilmaz, Svend Erik Nielsen, Lene Vestermark, Jim Larsen, Mohamed-Ayman Zawadi, Olivier Bouche, Laurent Mineur, Jaafar Bennouna-Louridi, Louis Marie Dourthe, Marc Ychou, Eveline Boucher, Denis Pezet, Francoise Desseigne, Michel Ducreux, Patrick Texereau, Laurent Miglianico, Philippe Rougier, Serge Fratte, Charles-Briac Levache, Yacine Merrouche, Stephen Ellis, Christophe Locher, Jean-Francois Ramee, Claire Garnier, Frederic Viret, Bruno Chauffert, Isabelle Cojean-Zelek, Pierre Michel, Cedric Lecaille, Christian Borel, Jean-Francois Seitz, Denis Smith, Catherine Lombard-Bohas, Thierry Andre, Jean-Marc Gornet, Francine Fein, Marie-Aude Coulon-Sfairi, Marie-Christine Kaminsky, Jean-Paul Lagasse, Dominique Luet, Pierre-Luc Etienne, Mohamed Gasmi, Andre Vanoli, Suzanne Nguyen, Thomas Aparicio, Hervé Perrier, Noel Stremsdoerfer, Philippe Laplaige, Dominique Arsene, Dominique Auby, Laurent Bedenne, Romain Coriat, Bernard Denis, Patrick Geoffroy, Gilles Piot, Yves Becouarn, Gilbert Bordes, Gael Deplanque, Olivier Dupuis, Frederic Fruge, Rosine Guimbaud, Thierry Lecomte, Gérard Lledo, Iradej Sobhani, Amani Asnacios, Ahmed Azzedine, Christophe Desauw, Marie-Pierre Galais, Dany Gargot, You-Heng Lam, Abakar Abakar-Mahamat, Jean-Francois Berdah, Sylviane Catteau, Marie-Christine Clavero-Fabri, Jean-Francois Codoul, Jean-Louis Legoux, Denis Goldfain, Pierre Guichard, Denis Pere Verge, Jocelyne Provencal, Bruno Vedrenne, Catherine Brezault-Bonnet, Denis Cleau, Jean-Paul Desir, David Fallik, Bruno Garcia, Marie-Hélène Gaspard, Dominique Genet, Johannes Hartwig, Yves Krummel, Tamara Matysiak Budnik, Vanessa Palascak-Juif, Harizo Randrianarivelo, Yves Rinaldi, Albert Aleba, Ariane Darut-Jouve, Aimery de Gramont, Herve Hamon, Frederic Wendehenne, Axel Matzdorff, Michael Konrad Stahl, Wolfgang Schepp, Martin Burk, Lothar Mueller, Michael Geissler, Luisa Mantovani-Loeffler, Thomas Hoehler, Walter Asperger, Hendrik Kroening, Ludwig Fischer von Weikersthal, Stefan Fuxius, Matthias Groschek, Johannes Meiler, Tanja Trarbach, Jacqueline Rauh, Nicolas Ziegenhagen, Albrecht Kretzschmar, Ullrich Graeven, Arnd Nusch, Goetz von Wichert, Ralf-Dieter Hofheinz, Gerhard Kleber, Karl-Heinz Schmidt, Ursula Vehling-Kaiser, Claudia Baum, Jochen Schuette, Georg Martin Haag, Wilhelm Holtkamp, Jochen Potenberg, Tobias Reiber, Georg Schliesser, Hans-Joachim Schmoll, Wolfgang Schneider-Kappus, Wolfgang Abenhardt, Claudio Denzlinger, Jan Henning, Bartscht Marxsen, Hans Guenter Derigs, Helmut Lambertz, Ingulf Becker-Boost, Karel Caca, Christian Constantin, Thomas Decker, Henning Eschenburg, Sigrun Gabius, Holger Hebart, Albrecht Hoffmeister, Heinz-August Horst, Stephan Kremers, Malte Leithaeuser, Sebastian Mueller, Siegfried Wagner, Severin Daum, Frank Schlegel, Martina Stauch, Volker Heinemann, Evaristo Maiello, Luciano Latini, Alberto Zaniboni, Dino Amadori, Giuseppe Aprile, Sandro Barni, Rodolfo Mattioli, Andrea Martoni, Rodolfo Passalacqua, Mario Nicolini, Enzo Pasquini, Carla Rabbi, Enrico Aitini, Alberto Ravaioli, Carlo Barone, Guido Biasco, Stefano Tamberi, Angelo Gambi, Claudio Verusio, Marina Marzola, Giorgio Lelli, Corrado Boni, Stefano Cascinu, Paolo Bidoli, Massimo Vaghi, Giorgio Cruciani, Francesco Di Costanzo, Alberto Sobrero, Roberto Petrioli, Massimo Aglietta, Oscar Alabiso, Federico Capuzzo, Alfredo Falcone, Domenico Cristi Corsi, Roberto Labianca, Stefania Salvagni, Silvana Chiara, Libero Ciuffreda, Francesco Ferraù, Francesco Giuliani, Sara Lonardi, Nicola Gebbia, Giovanni Mantovani, Evaristo Sanches, Juan Carlos Mellidez, Pedro Santos, Joao Freire, Cristina Sarmento, Luis Costa, Antonio Moreira Pinto, Sergio Barroso, Jorge Espirito Santo, Fátima Guedes, Amélia Monteiro, Anabela Sa, Irene Furtado, Ramon Salazar, Enrique Aranda Aguilar, Fernando Rivera Herrero, Javier Sastre Valera, Manuel Valladares Ayerbes, Jaime Feliu Batlle, Silvia Gil, Albert Abad Esteve, Carlos Garcia-Giron, Guillermo Lopez Vivanco, Antonia Salud Salvia, Vicente Alonso Orduña, Ruth Vera Garcia, Javier Gallego, Bartomeu Massuti Sureda, Jordi Remon, Maria Jose Safont Aguilera, Luis Cirera Nogueras, Bernado Queralt Merino, Cristina Gravalos Castro, Purificacion Martinez de Prado, Carlos Pijaume Pericay, Manuel Constenla Figueiras, Inmaculada Guasch Jordan, Maria Jose Gome Reina, Amelia Lopez-Ladron Garcia, Antonio Arrivi Garcia-Ramos, Andres Cervantes, Carlos Fernandez Martos, Eugenio Marcuello Gaspar, Ines Cabezas Montero, Pilar Escudero Emperador, Ana Leon Carbonero, Manuel Gallen Castillo, Teresa Garcia Garcia, Jose Garcia Lopez, Encarnacion Gonzalez Flores, Monica Guillot Morales, Marta Llanos Muñoz, Ana López Martín, Joan Maurel, Juan Carlos Camara, Rosario Dueñas Garcia, Mercedes Salgado, Isabel Hernandez Busquier, Teresa Checa Ruiz, Adelaida Lacasta Muñoa, Miquel Nogue Aliguer, Amalia Velasco Ortiz de Taranco, Miguel Mendez Ureña, Ferran Losa Gaspa, Jose Juan Ponce, Carlos Bosch Roig, Pedro Valero Jimenez, Antonio Galan Brotons, Santiago Albiol Rodriguez, Jose Ales Martinez, Liliana Canosa Ruiz, Margarita Centelles Ruiz, John Bridgewater, Rob Glynne-Jones, Saad Tahir, Tamas Hickish, Jim Cassidy, Leslie Samuel, UE 1373 Fourrages Environnement Ruminants Lusignan, Institut National de la Recherche Agronomique ( INRA ) -Physiologie Animale et Systèmes d'Elevage ( PHASE ) -Environnement et Agronomie ( E.A. ) -Biologie et Amélioration des Plantes ( BAP ) -Fourrages Environnement Ruminants Lusignan ( FERLUS ), Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Service de Biostatistique, Fédération Francophone de la Cancérologie Digestive, FFCD, Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'hépato-gastroentérologie et cancérologie digestive (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Vall d'Hebron University Hospital [Barcelona], Dpt of Internal Medicine, Section of Immunoallergology and Respiratory [Florence] Diseases, University of Florence, Carl Gustav Carus University Hospital, Erasme Hospital, Brussels, Centre Hepato-Biliaire, AP-HP Hôpital Paul Brousse, Modèles de Cellules Souches Malignes et Thérapeutiques, Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne ( IMoST ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ), Institut de cancérologie de l'Ouest - Nantes ( ICO Nantes ), CRLCC Paul Papin-CRLCC René Gauducheau, Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université de Nantes ( UN ), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique ( MEPPOT - U1147 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Klinikum Wels Grieskirchen, Oncology department [Salzburg], Salzburger Landesklinikum - Uniklinikum Salzburg ( SALK ), Institute of Chemical Reaction Engineering, Hamburg University of Technology, Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar- und Meeresforschung ( AWI ), Department of Medical Oncology, Medical University Vienna, Department of Internal Medicine, Hospital of Steyr, Department Internal Medicine 3, Centre for Hematology and Medical Oncology, General Hospital Linz, Department Medicine LKH, Institut für Festköperfirschung, Institut des Sciences Moléculaires de Marseille ( ISM2 ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Centrale de Marseille ( ECM ) -Aix Marseille Université ( AMU ), University Hospitals Leuven [Leuven], Katholieke Universiteit Leuven ( KU Leuven ), Pharmacology and Toxicology, Ahvaz Jundishapur University of Medical Sciences, Institut de Biologie Computationnelle ( IBC ), Centre de Coopération Internationale en Recherche Agronomique pour le Développement ( CIRAD ) -Institut National de la Recherche Agronomique ( INRA ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Sciences Moléculaires ( ISM ), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique ( CNRS ), Faculty of Veterinary Medicine, Ghent University [Belgium] ( UGENT ), Medical Oncology, Antwerp University Hospital [Edegem], Recombinaison et Expression Génétique, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier de L'Ardenne (Libramont), Department of Cardiology [Sivas, Turkey], Cumhuriyet University [Sivas, Turkey], Department of Earth Sciences, Durham University, Department of Oncology, Rigshospitalet [Copenhagen], Odense Hospital, CP Kelco ApS, Centre Hospitalier Universitaire de Reims ( CHU Reims ), Institut de Recherche en Cancérologie de Montpellier ( IRCM - U1194 Inserm - UM ), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Université du Québec à Montréal ( UQAM ), Université Panthéon-Sorbonne ( UP1 ), École nationale supérieure d'architecture de Nantes ( ENSA Nantes ), Department of Hepatogastroenterology and Oncology, Hopital Ambroise Pare, 9, Avenue Charles de Gaulle, 92104, Boulogne Cedex, France., Hôpital Ambroise Paré, CH Belfort-Montbéliard, Polyclinique Francheville, Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne ( CHU de Saint-Etienne ), Centre Hospitalier de Meaux, Service d'hématologie, Clinique Catherine de Sienne, Unité de recherche sur les Biopolymères, Interactions Assemblages ( BIA ), Institut National de la Recherche Agronomique ( INRA ), Université de la Méditerranée - Aix-Marseille 2, Centre hospitalier universitaire d'Amiens ( CHU Amiens-Picardie ), CHU Amiens-Picardie, Pôle oncologie médicale, Hôpital des Diaconesses, Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bretagne Occidentale - École de sages-femmes ( UBO UFR MSS ESF ), Université de Brest ( UBO ) -Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Service Gastro-Entérologie, CHU Besançon, Université de Franche-Comté ( UFC ) -Université de Franche-Comté ( UFC ), Centre Alexis Vautrin ( CAV ), Ecophysiologie Végétale, Agronomie et Nutritions ( EVA ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Recherche Agronomique ( INRA ), Image et ville ( IV ), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Département informatique ( INFO ), Université européenne de Bretagne ( UEB ) -Télécom Bretagne-Institut Mines-Télécom [Paris], Service de Gastro-entérologie [Avicenne], Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Agence de l'Environnement et de la Maîtrise de l'Energie - ADEME, Service d'hépato-gastroentérologie, CHU Caen-Hôpital côte de nacre, Département de Médecine, Centre hospitalier de Libourne, Service d'Hépato-Gastro-Entérologie (CHU de Dijon), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Fondation FondaMental, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor, Variabilité de réponse aux psychotropes ( VariaPsy - U1144 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ), Département d'oncologie digestive, Institut Bergonié - CRLCC Bordeaux, Hôpital St Joseph, Service de Gynécologie et d'Obstétrique ( CHU Lyon ), Hospices Civils de Lyon ( HCL ), Gastro - Entérologie et Nutrition, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Génétique, Immunothérapie, Chimie et Cancer ( GICC ), Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Université Montpellier 1 ( UM1 ), Service de gastro-entérologie - Hôpital Henri Mondor, Laboratoire Matière et Systèmes Complexes ( Laboratoire MSC ), Université Paris Diderot - Paris 7 ( UPD7 ) -UFR de Physique, France, Amériques, Espagne – Sociétés, pouvoirs, acteurs ( FRAMESPA ), Université Toulouse - Jean Jaurès ( UT2J ) -Centre National de la Recherche Scientifique ( CNRS ), Regional Hospital of Orleans, Histoire, Archéologie et littératures des Mondes chrétiens et musulmans médiévaux ( CIHAM ), École normale supérieure - Lyon ( ENS Lyon ) -Université Lumière - Lyon 2 ( UL2 ) -École des hautes études en sciences sociales ( EHESS ) -Université Jean Moulin - Lyon III ( UJML ) -Université d'Avignon et des Pays de Vaucluse ( UAPV ) -Centre National de la Recherche Scientifique ( CNRS ), Neurobiologie des signaux intercellulaires ( NSI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Dept Med Genet, Hôpital Erasme (Bruxelles), Polyclinique de Limoges - site François Chénieux [Limoges], Clinique Médicale B, CHU Strasbourg, Service de gastro-entérologie, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Hôpital Européen [Fondation Ambroise Paré - Marseille], Asklepios Klinikum Uckermark GmbH, DESY, Notkestr 85, D-22607 Hamburg, Germany, NASA Ames Research Center ( ARC ), Department of Chemistry, Center for Structural Biology, Vanderbilt University [Nashville], Biostatistique et Processus Spatiaux ( BIOSP ), Institute of Ecology [Jena], Friedrich-Schiller-Universität Jena, University of Rostock [Germany], Universität Stuttgart [Stuttgart], Oneonta, Zentrum für Innere Medizin, Klinikum Schwäbisch Gmünd/Stauferklinik, Physiopathologie du stress pancréatique, Institut Armand Frappier ( INRS-IAF ), Institut National de la Recherche Scientifique [Québec] ( INRS ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut Armand Frappier, Institut de Mathématiques de Marseille ( I2M ), Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Department of Computer Science [Freiburg], University of Freiburg [Freiburg], Institut für Mathematik [Berlin], Technische Universität Berlin ( TUB ), Department of Information Engineering, Computer Science and Mathematics, Università degli Studi dell'Aquila [L'Aquila] ( UNIVAQ.IT ), Department of Animal Sciences, North Carolina Agricultural and Technical State University, FEEM, Romagna Cancer Registry, IRST, Luigi Pierantoni Hospital, Observatoire sociologique du changement ( OSC ), Sciences Po-Centre National de la Recherche Scientifique ( CNRS ), Dipartimento di Chimica, Fisica e Ambiente, Università degli Studi di Udine - University of Udine [Italie], Department of Nuclear Medicine, PET/CT Centre, Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Clinica di Oncologia Medica, AO Ospedali Riuniti, Università Politecnica delle Marche [Ancona] ( UNIVPM ), Universidade Nova de Lisboa ( UNINOVA ), Ottawa Hospital Research Institute [Ottawa] ( OHRI ), Oncologia Medica, Ospedali Riuniti, Ospedale 'San Vincenzo', NIPE, CIPES, European Synchrotron Radiation Facility ( ESRF ), Departamento de Engenharia Informática, Faculdade de Engenharia [Porto] ( FEUP ), Universidade do Porto [Porto]-Universidade do Porto [Porto], 3Decide, Unité de recherche Amélioration, Génétique et Physiologie Forestières ( UAGPF ), Universidade Federal de Campina Grande [Campina Grande] ( UFCG ), Instituto de Engenharia de Sistemas e Computadores ( INESC ), Departamento de Ciências Biológicas, Universidade Regional do Cariri ( URCA Brasil ), Department of Biochemistry and Molecular Biology [Barcelona, Spain], Universitat de Barcelona ( UB ), Associated Unit to Consejo Superior de Investigaciones Científicas - CSIC [Barcelona, Spain], University of Barcelona-Institute of Biomedicine - IBUB [Barcelona, Spain], IRCELYON-Caractérisation et remédiation des polluants dans l'air et l'eau ( CARE ), Institut de recherches sur la catalyse et l'environnement de Lyon ( IRCELYON ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'analyse et d'architecture des systèmes [Toulouse] ( LAAS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse ( INSA Toulouse ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Institut National Polytechnique [Toulouse] ( INP ), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier ( ICGM ICMMM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Instituto de Ciencia de Materiales de Madrid [Madrid] ( ICMM ), Interactions, Corpus, Apprentissages, Représentations ( ICAR ), École normale supérieure - Lyon ( ENS Lyon ) -Université Lumière - Lyon 2 ( UL2 ) -INRP-Ecole Normale Supérieure Lettres et Sciences Humaines-Centre National de la Recherche Scientifique ( CNRS ), Institut d'Investigacions Biomèdiques August Pi i Sunyer ( IDIBAPS ), North Region Cancer Registry of Portugal, UMR 5805 Environnements et Paléoenvironnements Océaniques et Continentaux ( EPOC ), Observatoire aquitain des sciences de l'univers ( OASU ), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Paediatrics and Intensive Care, Hospital Universitari Sant Joan de Deu, Laboratoire de Psychologie Sociale ( LPS ), Aix Marseille Université ( AMU ), Universitat de València ( UV ), Instituto de Cienca de Materiales de Madrid [Madrid] ( ICMM ), Biology, New Mexico State University, New Mexico State University, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Centre de recherche sur les Ions, les MAtériaux et la Photonique ( CIMAP - UMR 6252 ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Nationale Supérieure d'Ingénieurs de Caen ( ENSICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ), Institut d'Electronique et de Télécommunications de Rennes ( IETR ), Université de Nantes ( UN ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National des Sciences Appliquées - Rennes ( INSA Rennes ) -CentraleSupélec-Centre National de la Recherche Scientifique ( CNRS ), Computer Science Department - Carnegie Mellon University, University of Pittsburgh, Laboratoire de Sciences Actuarielle et Financière ( SAF ), Université de Lyon-Université de Lyon, Instituto de Oncologia Corachan ( IDOC ), Laboratoire d'informatique de l'école normale supérieure ( LIENS ), École normale supérieure - Paris ( ENS Paris ) -Centre National de la Recherche Scientifique ( CNRS ), Experimental Quantum Optics and Photonics Group, University of Strathclyde, Institut de recherches Asiatiques ( IrAsia ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Européen de Réalité Virtuelle ( CERV ), École Nationale d'Ingénieurs de Brest ( ENIB ), Sol Agro et hydrosystème Spatialisation ( SAS ), Institut National de la Recherche Agronomique ( INRA ) -AGROCAMPUS OUEST, Grenoble Institut des Neurosciences ( GIN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Grenoble-Université Joseph Fourier - Grenoble 1 ( UJF ), Centre de recherche cerveau et cognition ( CERCO ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire Géomatériaux et Environnement ( LGE ), Université Paris-Est Marne-la-Vallée ( UPEM ), Hôpital Ambroise Paré [AP-HP], Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre hépato-biliaire (CHB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Université de Nantes (UN), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Salzburger Landesklinikum - Uniklinikum Salzburg (SALK), Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar- und Meeresforschung (AWI), Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institut de Biologie Computationnelle (IBC), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Moléculaires (ISM), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University [Belgium] (UGENT), Antwerp University Hospital [Edegem] (UZA), Hillerød Hospital, Copenhagen University Hospital-Copenhagen University Hospital, Centre Hospitalier Universitaire de Reims (CHU Reims), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Université Paris 1 Panthéon-Sorbonne (UP1), École nationale supérieure d'architecture de Nantes (ENSA Nantes), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), Institut National de la Recherche Agronomique (INRA), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bretagne Occidentale - École de sages-femmes (UBO UFR MSS ESF), Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Alexis Vautrin (CAV), Ecophysiologie Végétale, Agronomie et Nutritions (EVA), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Recherche Agronomique (INRA), Image et ville (IV), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Département informatique (INFO), Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Agence de l'Environnement et de la Maîtrise de l'Energie (ADEME), Service d'Hépato-Gastro-Enterologie et Nutrition [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Libourne, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation FondaMental [Créteil], Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Service de Gynécologie et d'Obstétrique (CHU Lyon), Hospices Civils de Lyon (HCL), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1), Service de gastro-entérologie [Henri Mondor AP-HP, Créteil], Hôpital Henri Mondor-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Hôpital privé Toulon Hyères : Sainte Marguerite, Clinique des Quatre Pavillons, Lormont, France, Neurobiologie des signaux intercellulaires (NSI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), NASA Ames Research Center (ARC), Biostatistique et Processus Spatiaux (BioSP), Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], University of Rostock, State University of New York at Oneonta (SUNY Oneonta), State University of New York (SUNY), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Institut de Mathématiques de Marseille (I2M), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Klinikum Deggendorf, Technische Universität Berlin (TU), Università degli Studi dell'Aquila (UNIVAQ), North Carolina A&T State University, University of North Carolina System (UNC)-University of North Carolina System (UNC), Observatoire sociologique du changement (OSC), Sciences Po (Sciences Po)-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Università Politecnica delle Marche [Ancona] (UNIVPM), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Ottawa Hospital Research Institute [Ottawa] (OHRI), European Synchrotron Radiation Facility (ESRF), Departamento de Engenharia Informática [Porto], Faculdade de Engenharia da Universidade do Porto (FEUP), Universidade do Porto-Universidade do Porto, Universidade Federal de Campina Grande [Campina Grande] (UFCG), Instituto de Engenharia de Sistemas e Computadores (INESC), Universidade Regional do Cariri (URCA Brasil), Universitat de Barcelona (UB), IRCELYON-Catalytic and Atmospheric Reactivity for the Environment (CARE), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Interactions, Corpus, Apprentissages, Représentations (ICAR), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-INRP-Ecole Normale Supérieure Lettres et Sciences Humaines (ENS LSH)-Centre National de la Recherche Scientifique (CNRS), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), UMR 5805 Environnements et Paléoenvironnements Océaniques et Continentaux (EPOC), Observatoire aquitain des sciences de l'univers (OASU), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Hospital Universitario de Valme, Anenida de Bellavista s/n, Sevilla 41014, Spain, Hospital Son Llatzer, Universitat de València (UV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hospital Universitari Son Espases, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Instituto de Oncologia Corachan (IDOC), Laboratoire d'informatique de l'école normale supérieure (LIENS), École normale supérieure - Paris (ENS Paris), Institut de recherches Asiatiques (IrAsia), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre Européen de Réalité Virtuelle (CERV), École Nationale d'Ingénieurs de Brest (ENIB), Sol Agro et hydrosystème Spatialisation (SAS), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche cerveau et cognition (CERCO), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Géomatériaux et Environnement (LGE), Université Paris-Est Marne-la-Vallée (UPEM), Fédération Francophone de Cancérologie Digestive (FFCD), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Recherche Agronomique (INRA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Department of Information Engineering, Computer Science and Mathematics = Dipartimento di Ingegneria e Scienze dell'Informazione e Matematica [L'Aquila] (DISIM), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département d'informatique - ENS Paris (DI-ENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU), Institute of Biomedicine - IBUB [Barcelona, Spain]-University of Barcelona, Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC), AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de la Recherche Agronomique (INRA)-Environnement et Agronomie (E.A.)-Biologie et Amélioration des Plantes (BAP)-Fourrages Environnement Ruminants Lusignan (FERLUS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, University of Florence (UNIFI), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut de cancérologie de l'Ouest - Nantes (ICO Nantes), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique (CNRS), Ghent University [Belgium] (UGENT), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université du Québec à Montréal (UQAM), Université Panthéon-Sorbonne (UP1), Centre hospitalier universitaire d'Amiens (CHU Amiens-Picardie), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université de Franche-Comté (UFC)-Université de Franche-Comté (UFC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Avicenne, Optimisation Thérapeutique en Neuropsychopharmacologie (VariaPsy - U1144), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Biostatistique et Processus Spatiaux (BIOSP), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Technische Universität Berlin (TUB), Università degli Studi dell'Aquila [L'Aquila] (UNIVAQ.IT), Universidade Nova de Lisboa (NOVA), Faculdade de Engenharia [Porto] (FEUP), Unité de recherche Amélioration, Génétique et Physiologie Forestières (UAGPF), IRCELYON-Caractérisation et remédiation des polluants dans l'air et l'eau (CARE), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Consejo Superior de Investigaciones Científicas [Spain] (CSIC), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-INRP-Ecole Normale Supérieure Lettres et Sciences Humaines-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM), Emile, J, Julie, C, Le Malicot, K, Lepage, C, Tabernero, J, Mini, E, Folprecht, G, Van Laethem, J, Dimet, S, Boulagnon-Rombi, C, Allard, M, Penault-Llorca, F, Bennouna, J, Laurent-Puig, P, Taieb, J, Bidoli, P, Emile, J. -F., Julie, C., Le Malicot, K., Lepage, C., Tabernero, J., Mini, E., Folprecht, G., Van Laethem, J. -L., Dimet, S., Boulagnon-Rombi, C., Allard, M. -A., Penault-Llorca, F., Bennouna, J., Laurent-Puig, P., Taieb, J., Thaler, J., Greil, R., Gaenzer, J., Eisterer, W., Tschmelitsch, J., Keil, F., Samonigg, H., Zabernigg, A., Schmid, F., Steger, G., Steinacher, R., Andel, J., Jagdt, B., Lang, A., Fridrik, M., Fugger, R., Hofbauer, F., Woell, E., Geissler, D., Lenauer, A., Prager, M., D'Haens, G., Demolin, G., Kerger, J., Deboever, G., Ghillebert, G., Polus, M., Van Cutsem, E., Kalantari, H. R., Delaunoit, T., Goeminne, J. C., Peeters, M., Vergauwe, P., Houbiers, G., Humblet, Y., Janssens, J., Schrijvers, D., Vanderstraeten, E., Vermorken, J., Van Daele, D., Ferrante, M., Forget, F., Hendlisz, A., Yilmaz, M., Nielsen, S. E., Vestermark, L., Larsen, J., Zawadi, M. -A., Bouche, O., Mineur, L., Bennouna-Louridi, J., Dourthe, L. M., Ychou, M., Boucher, E., Pezet, D., Desseigne, F., Ducreux, M., Texereau, P., Miglianico, L., Rougier, P., Fratte, S., Levache, C. -B., Merrouche, Y., Ellis, S., Locher, C., Ramee, J. -F., Garnier, C., Viret, F., Chauffert, B., Cojean-Zelek, I., Michel, P., Lecaille, C., Borel, C., Seitz, J. -F., Smith, D., Lombard-Bohas, C., Andre, T., Gornet, J. -M., Fein, F., Coulon-Sfairi, M. -A., Kaminsky, M. -C., Lagasse, J. -P., Luet, D., Etienne, P. -L., Gasmi, M., Vanoli, A., Nguyen, S., Aparicio, T., Perrier, H., Stremsdoerfer, N., Laplaige, P., Arsene, D., Auby, D., Bedenne, L., Coriat, R., Denis, B., Geoffroy, P., Piot, G., Becouarn, Y., Bordes, G., Deplanque, G., Dupuis, O., Fruge, F., Guimbaud, R., Lecomte, T., Lledo, G., Sobhani, I., Asnacios, A., Azzedine, A., Desauw, C., Galais, M. -P., Gargot, D., Lam, Y. -H., Abakar-Mahamat, A., Berdah, J. -F., Catteau, S., Clavero-Fabri, M. -C., Codoul, J. -F., Legoux, J. -L., Goldfain, D., Guichard, P., Verge, D. P., Provencal, J., Vedrenne, B., Brezault-Bonnet, C., Cleau, D., Desir, J. -P., Fallik, D., Garcia, B., Gaspard, M. -H., Genet, D., Hartwig, J., Krummel, Y., Budnik, T. M., Palascak-Juif, V., Randrianarivelo, H., Rinaldi, Y., Aleba, A., Darut-Jouve, A., de Gramont, A., Hamon, H., Wendehenne, F., Matzdorff, A., Stahl, M. K., Schepp, W., Burk, M., Mueller, L., Geissler, M., Mantovani-Loeffler, L., Hoehler, T., Asperger, W., Kroening, H., von Weikersthal, L. F., Fuxius, S., Groschek, M., Meiler, J., Trarbach, T., Rauh, J., Ziegenhagen, N., Kretzschmar, A., Graeven, U., Nusch, A., von Wichert, G., Hofheinz, R. -D., Kleber, G., Schmidt, K. -H., Vehling-Kaiser, U., Baum, C., Schuette, J., Haag, G. M., Holtkamp, W., Potenberg, J., Reiber, T., Schliesser, G., Schmoll, H. -J., Schneider-Kappus, W., Abenhardt, W., Denzlinger, C., Henning, J., Marxsen, B., Derigs, H. G., Lambertz, H., Becker-Boost, I., Caca, K., Constantin, C., Decker, T., Eschenburg, H., Gabius, S., Hebart, H., Hoffmeister, A., Horst, H. -A., Kremers, S., Leithaeuser, M., Mueller, S., Wagner, S., Daum, S., Schlegel, F., Stauch, M., Heinemann, V., Maiello, E., Latini, L., Zaniboni, A., Amadori, D., Aprile, G., Barni, S., Mattioli, R., Martoni, A., Passalacqua, R., Nicolini, M., Pasquini, E., Rabbi, C., Aitini, E., Ravaioli, A., Barone, C., Biasco, G., Tamberi, S., Gambi, A., Verusio, C., Marzola, M., Lelli, G., Boni, C., Cascinu, S., Bidoli, P., Vaghi, M., Cruciani, G., Di Costanzo, F., Sobrero, A., Petrioli, R., Aglietta, M., Alabiso, O., Capuzzo, F., Falcone, A., Corsi, D. C., Labianca, R., Salvagni, S., Chiara, S., Ciuffreda, L., Ferrau, F., Giuliani, F., Lonardi, S., Gebbia, N., Mantovani, G., Sanches, E., Mellidez, J. C., Santos, P., Freire, J., Sarmento, C., Costa, L., Pinto, A. M., Barroso, S., Santo, J. E., Guedes, F., Monteiro, A., Sa, A., Furtado, I., Salazar, R., Aguilar, E. A., Herrero, F. R., Valera, J. S., Ayerbes, M. V., Batlle, J. F., Gil, S., Esteve, A. A., Garcia-Giron, C., Vivanco, G. L., Salvia, A. S., Orduna, V. A., Garcia, R. V., Gallego, J., Sureda, B. M., Remon, J., Safont Aguilera, M. J., Nogueras, L. C., Merino, B. Q., Castro, C. G., de Prado, P. M., Pericay, C. P., Figueiras, M. C., Jordan, I. G., Gome Reina, M. J., Garcia, A. L. -L., Garcia-Ramos, A. A., Cervantes, A., Martos, C. F., Gaspar, E. M., Montero, I. C., Emperador, P. E., Carbonero, A. L., Castillo, M. G., Garcia, T. G., Lopez, J. G., Flores, E. G., Morales, M. G., Munoz, M. L., Martin, A. L., Maurel, J., Camara, J. C., Garcia, R. D., Salgado, M., Busquier, I. H., Ruiz, T. C., Munoa, A. L., Aliguer, M. N., de Taranco, A. V. O., Urena, M. M., Gaspa, F. L., Ponce, J. J., Roig, C. B., Jimenez, P. V., Brotons, A. G., Rodriguez, S. A., Martinez, J. A., Ruiz, L. C., Ruiz, M. C., Bridgewater, J., Glynne-Jones, R., Tahir, S., Hickish, T., Cassidy, J., and Samuel, L.

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, Organoplatinum Compounds, Colorectal cancer, medicine.medical_treatment, Medizin, Leucovorin, Prospective cohort study, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, FOLFOX, Organoplatinum Compounds/therapeutic use, Antineoplastic Combined Chemotherapy Protocols, tudy, Lymphocytes, Prospective Studies, Leucovorin/therapeutic use, Middle Aged, Prognosis, 3. Good health, Colorectal carcinoma, Fluorouracil, 030220 oncology & carcinogenesis, Predictive value of tests, Colonic Neoplasms, Biomarker (medicine), Lymphocytes/pathology, Female, Adjuvant, medicine.drug, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Fluorouracil/therapeutic use, Biomarkers, Tumor/analysis, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Predictive Value of Tests, Biomarker, Immune response, Internal medicine, medicine, Biomarkers, Tumor, Humans, Survival analysis, Aged, business.industry, medicine.disease, Survival Analysis, Surgery, 030104 developmental biology, Prospective cohort&nbsp, Multivariate Analysis, Colonic Neoplasms/diagnosis, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, business
Abstract

IF 6.029; International audience; BackgroundThe prognostic value of lymphocyte infiltration (LI) of colorectal carcinoma (CC) has been demonstrated by several groups. However, no validated test is currently available for clinical practice. We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use.Patients and methodsAccording to National Institutes of Health criteria, we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study. Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI (#NCT02364024). Associations of LI with patient recurrence and survival were analysed, and multivariable models were adjusted for treatment and relevant factors. Automated testing of LI was performed on virtual slides without access to clinical data.ResultsAmong the 1220 CC patients enrolled, LI was high, low and not evaluable in 241 (19.8%), 790 (64.8%) and 189 (15.5%), respectively. Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in patients with high and low LI, respectively (p = 0.02). Patients with high LI also had better disease free survival (DFS) and overall survival (OS). Tumour stage, grade, RAS status and BRAF status were with LI the only prognostic markers in multivariable analysis for OS. Subgroup analyses revealed that high LI had better DFS and OS in mismatch repair (MMR) proficient patients, and in patients without RAS mutation, but not in MMR deficient and RAS mutated patients.ConclusionAlthough this is the first validation with high level of evidence (IIB) of the prognostic value of a LI test in colon cancers, it still needs to be confirmed in independent series of colon cancer patients.

Published
2017

49. Risk adapted high-dose and dose-dense therapies modulate the impact of biological classification in diffuse large B-cell lymphoma prognosis

Author

Dolores Caballero, Antonio Rueda, Emilia Pardal, Sonia González de Villambrosia, Eva González-Barca, Carlos Grande, Francisco Ramon Garcia Arroyo, David Aguiar, Eulogio Conde, Marta Llanos, Laura Cereceda, Beatriz Sanchez-Espiridion, Noelia Purroy, Andrés Insunza, José Gómez Codina, Miguel Cruz, Santiago Montes-Moreno, Ana Batlle, Francisco Mazorra, Andres Lopez, Alejandro Martín, Cristina Quero, Mariano Provencio, and Miguel A. Piris

Subjects
Male, Oncology, Limfomes, Pathology, Stem cells, Disease, Diagnòstic, Prednisone, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Quimioteràpia, Diagnosis, Young adult, Aged, 80 and over, high-dose, Hematology, Middle Aged, Prognosis, Vincristine, Female, Risk Adjustment, Lymphomas, Lymphoma, Large B-Cell, Diffuse, Cèl·lules mare, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Cyclophosphamide, Cèl·lules B, diffuse large B-cell lymphoma, Young Adult, biological classification, Internal medicine, medicine, Humans, Chemotherapy, Doxorubicin, Online Only Articles, dose-dense therapies, Aged, B cells, Dose-Response Relationship, Drug, business.industry, medicine.disease, Lymphoma, business, Diffuse large B-cell lymphoma, Follow-Up Studies, Stem Cell Transplantation
Abstract

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous disease entity. Young patients with high-intermediate and high aa-IPI score seem to be good candidates to receive alternative treatments to standard RCHOP-21 including EPOCH-R,2 R-ACVBP+HDT-ASCT3 and upfront autologous stem cell transplantation. Other risk factors can be used to identify patients for the use of more doseintense regimens including bulky disease, interim PET positivity and, importantly, molecular profiles.

Published
2014

50. Prognostic value of event-free survival at 12 and 24 months and long-term mortality for non-Hodgkin follicular lymphoma patients: A study report from the Spanish Lymphoma Oncology Group

Author

Mariano, Provencio, Ana, Royuela, María, Torrente, Marina, Pollán, José, Gómez-Codina, Pilar, Sabín, Marta, Llanos, Josep, Gumá, Cristina, Quero, Ana, Blasco, David, Aguiar, Francisco Ramón, García-Arroyo, Javier, Lavernia, Natividad, Martínez, Manuel, Morales, Álvaro, Saenz-Cusi, Delvys, Rodríguez, Virginia, Calvo, Luis, de la Cruz-Merino, Miguel Ángel, de la Cruz, and Antonio, Rueda

Subjects
Adult, Male, Time Factors, Age Factors, Antineoplastic Agents, Kaplan-Meier Estimate, Middle Aged, Prognosis, Disease-Free Survival, Sex Factors, Spain, Case-Control Studies, Cause of Death, Confidence Intervals, Humans, Female, Prospective Studies, Rituximab, Lymphoma, Follicular
Abstract

Relatively few studies have analyzed the mortality of follicular lymphoma (FL) patients in comparison with a sex- and age-matched general population. This study analyzed the overall survival (OS) of patients with FL and compared their survival with the expected survival of a general population.Patients diagnosed with FL were prospectively enrolled from 1980 to 2013. Standardized mortality ratios (SMRs) were obtained from yearly sex- and age-specific mortality rates in Spain, and OS was compared with age- and sex-matched general population data.A total of 1074 patients with newly diagnosed FL were enrolled. The median OS was 231 months (95% confidence interval [CI], 195-267 months). Event-free survival at 12 months (EFS12) and event-free survival at 24 months (EFS24) were associated with an increased probability of early death, with an SMR of 10.27 (95% CI, 8.26-12.77) for EFS12. The overall SMR, including all causes of death, was 2.55 (95% CI, 2.23-2.92), and it was higher for women (SMR, 3.02; 95% CI, 2.48-3.67) and young adults (SMR, 6.01; 95% CI, 3.13-11.55). More than 10 years after the diagnosis, mortality rates for FL patients were lower than those for the general population (SMR, 0.47; 95% CI, 0.28-0.78). When FL was excluded as a cause of death, the overall SMR was 1.35 (95% CI, 1.11-1.65) without a statistically significant mortality increase in the60-year-old group in comparison with age- and sex-matched general population data. More than 15% of the patients included in the study (n = 158) had more than 10 years of follow-up.EFS12 and EFS24 predict an early increase in mortality. The long-term SMR, over the course of 10 years of follow-up, shows that patients with FL have a risk of dying similar to that of a sex- and age-matched general population. Cancer 2017;123:3709-3716. © 2017 American Cancer Society.

Published
2016

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