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1. Phase II randomized trial of capecitabine with bevacizumab and external beam radiation therapy as preoperative treatment for patients with resectable locally advanced rectal adenocarcinoma: long term results

Author: Ramón Salazar, Jaume Capdevila, Jose Luis Manzano, Carles Pericay, Mercedes Martínez-Villacampa, Carlos López, Ferrán Losa, María José Safont, Auxiliadora Gómez-España, Vicente Alonso-Orduña, Pilar Escudero, Javier Gallego, Beatriz García-Paredes, Amalia Palacios, Sebastiano Biondo, Cristina Grávalos, Enrique Aranda, and on behalf of the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD)
Subjects: Locally-advanced rectal cancer, Bevacizumab, Neoadjuvant, Chemoradiotherapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Preoperative chemoradiotherapy with capecitabine is considered as a standard of care for locally advanced rectal cancer. The “Tratamiento de Tumores Digestivos” group (TTD) previously reported in a randomized Ph II study that the addition of Bevacizumab to capecitabine-RT conferred no differences in the pre-defined efficacy endpoint (pathological complete response). We present the follow-up results of progression-free survival, distant relapse-free survival, and overall survival data at 3 and 5 years. Methods Patients (pts) were randomized to receive 5 weeks of radiotherapy (45 Gy/25 fractions) with concurrent Capecitabine 825 mg/m2 twice daily, 5 days per week with (arm A) or without (arm b) bevacizumab (5 mg/kg once every 2 weeks). Results In our study, the addition of bevacizumab to capecitabine and radiotherapy in the neoadjuvant setting shows no differences in pathological complete response (15.9% vs 10.9%), distant relapse-free survival (81.0 vs 80.4 and 76.2% vs 78.2% at 3 and 5 years respectively), disease-free survival (75% vs 71.7 and 68.1% vs 69.57% at 3 and 5 years respectively) nor overall survival at 5-years of follow-up (81.8% vs 86.9%). Conclusions the addition of bevacizumab to capecitabine plus radiotherapy does not confer statistically significant advantages neither in distant relapse-free survival nor in disease-free survival nor in Overall Survival in the short or long term. Trial registration EudraCT number: 2009–010192-24 . Clinicaltrials.gov number: NCT01043484 .
Published: 2020
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2. Coexpression of p-IGF-1R and MMP-7 Modulates Panitumumab and Cetuximab Efficacy in RAS Wild-Type Metastatic Colorectal Cancer Patients

Author: Vicente Alonso, Pilar Escudero, Carlos Fernández-Martos, Antonia Salud, Miguel Méndez, Javier Gallego, Jose-R. Rodriguez, Marta Martín-Richard, Julen Fernández-Plana, Hermini Manzano, José-Carlos Méndez, Monserrat Zanui, Esther Falcó, Mireia Gil-Raga, Federico Rojo, Miriam Cuatrecasas, Jaime Feliu, Xabier García-Albéniz, and Joan Maurel
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: INTRODUCTION: The coexpression of pIGF-1R and MMP-7 (double-positive phenotype, DP) correlates with poor overall survival (OS) in KRAS wild-type (WT) (exon 2) metastatic colorectal cancer (mCRC) patients treated with irinotecan-cetuximab in second/third line. METHODS: We analyzed two prospective biomarker design trials of newly diagnosed RAS-WT mCRC patients treated with panitumumab-FOLFOX6 (PULSE trial; NCT01288339) or cetuximab plus either FOLFOX6/FOLFIRI (POSIBA trial; NCT01276379). The main exposure was DP phenotype (DP/non-DP), as assessed by two independent pathologists. DP cases were defined by immunohistochemistry as >70% expression of moderate or strong intensity for both MMP-7 and pIGF-1R. Primary endpoint: progression-free survival (PFS); secondary endpoints: OS and response rate. PFS and OS were adjusted by baseline characteristics using multivariate Cox models. RESULTS: We analyzed 67 patients (30 non-DP, 37 DP) in the PULSE trial and 181 patients in the POSIBA trial (158 non-DP, 23 DP). Response rates and PFS were similar between groups in both studies. DP was associated with prolonged OS in PULSE (adjusted HR: 0.23; 95%CI: 0.11-0.52; P=.0004) and with shorter OS in POSIBA (adjusted HR: 1.67; 95%CI: 0.96-2.90; P=.07). CONCLUSION: A differential effect of anti-EGFRs on survival by DP phenotype was observed. Panitumumab might be more beneficial for RAS-WT mCRC patients with DP phenotype, whereas cetuximab might improve OS in non-DP.
Published: 2018
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3. Correlation of hypertension and proteinuria with outcome in elderly bevacizumab-treated patients with metastatic colorectal cancer.

Author: Jaime Feliu, Antonieta Salud, Maria J Safont, Carlos García-Girón, Jorge Aparicio, Ferran Losa, Carlos Bosch, Pilar Escudero, Enrique Casado, Monica Jorge, Uriel Bohn, Ramon Pérez-Carrión, Alberto Carmona, Ana B Custodio, and Joan Maurel
Subjects: Medicine, Science
Abstract: BACKGROUND:Studies suggest a relationship between hypertension and outcome in bevacizumab-treated patients with metastatic colorectal cancer (mCRC). We performed a retrospective analysis of two phase II studies (BECA and BECOX) to determine if hypertension and proteinuria predict outcome in elderly patients with mCRC treated with bevacizumab. PATIENTS AND METHODS:Patients ≥ 70 years of age received either capecitabine 1250 mg/m(2) bid days 1-14 + bevacizumab 7.5 mg/kg day 1 every 21 days (BECA study) or capecitabine 1000 mg/m(2) bid days 1-14 with bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m(2) day 1 (BECOX study). The primary objective was to correlate hypertension and proteinuria with overall response rate (ORR), time to progression (TTP) and overall survival (OS). Secondary objectives included identification of risk factors associated with the development of hypertension and proteinuria and determining whether development of hypertension or proteinuria in the first 2 cycles was related to ORR, disease-control rate (DCR), TTP or OS. RESULTS:In total, 127 patients (median age 75.5 years) were included in the study. Hypertension correlated with DCR and OS; proteinuria correlated with ORR and DCR. Proteinuria or hypertension in the first 2 cycles did not correlate with efficacy. Risk factors for hypertension were female gender (odds ratio [OR] 0.241; P = 0.011) and more bevacizumab cycles (OR 1.112; P = 0.002); risk factors for proteinuria were diabetes (OR 3.869; P = 0.006) and more bevacizumab cycles (OR 1.181; P
Published: 2015
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4. Los aparatos de Bunsen y su aplicación didáctica

Author: Rosa Domínguez Gómez, Rosario Torralba Marco, Pilar Escudero González, and Manuela Martín Sánchez
Subjects: Robert Bunsen, Historia de la Química y de la Física, Enseñanza de la Química y de la Física, Chemistry, QD1-999
Abstract: Con motivo de celebrarse en el año 2011 el bicentenario del nacimiento de Robert Wilhelm Bunsen (1811-1899) hemos hecho un estudio histórico de todos los instrumentos o aparatos que utilizó y las mejoras que introdujo en ellos. El principal objetivo de nuestro estudio es ayudar a los estudiantes de química (de bachillerato y de primer curso de universidad) a trabajar en este tema. De esta forma, nuestro trabajo tiene dos partes diferentes: primero un estudio histórico y, en segundo lugar, una aplicación didáctica.
Published: 2012

5. 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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6. Is aflibercept an optimal treatment for wt RAS mCRC patients after progression to first line containing anti-EGFR?

Author: Ignacio Juez, Ana Ruiz-Casado, Carles Pericay, Vicente Alonso, José M Cabrera, Maria Jose Safont, M. Salgado, Pilar Escudero, Ruth Vera, Fernando Rivera, Patricia Iranzo, E. González, Nieves P Martínez, Elena Mata, Carlos F. Lopez, and Beatriz González
Subjects: Male, medicine.medical_specialty, Colorectal cancer, Recombinant Fusion Proteins, Perforation (oil well), Leucovorin, Gastroenterology, Disease-Free Survival, Capecitabine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Regorafenib, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Aflibercept, business.industry, Middle Aged, Hepatology, Prognosis, medicine.disease, Survival Analysis, Primary tumor, ErbB Receptors, Receptors, Vascular Endothelial Growth Factor, chemistry, 030220 oncology & carcinogenesis, Multivariate Analysis, Toxicity, ras Proteins, Camptothecin, Female, 030211 gastroenterology & hepatology, Fluorouracil, Colorectal Neoplasms, business, medicine.drug
Abstract: To determine the efficacy and safety data of aflibercept + FOLFIRI in wt RAS mCRC patients after progression to standard chemotherapy + anti-EGFR treatment. Retrospective, observational study in real life conducted in wt RAS mCRC patients treated with FOLFIRI-aflibercept after progression to standard first line chemotherapy + anti-EGFR treatment. A total of 120 patients from 12 Spanish hospitals were enrolled. Median age is 60 years (62.5%/37.5%male/female). Primary tumor site is 24.1%/75.9% right/left-side colon, and 40.8% of patients had a prior resection. All patients had wild-type RAS tumors including 5% of patients with BRAF mutations and received anti-EGFR treatment. At the time aflibercept was initiated, ECOG PS is 0/1 in 96% of patients. Median number of FOLFIRI-aflibercept cycles is 12. Efficacy results: Overall response rate is 33%; progression-free survival (PFS) is 6.9 months (95%CI: 6.1–7.8). Primary tumor resection was the only significant variable related to PFS in the multivariate analysis. Median overall survival (OS) is 14.5 months (95%CI: 9.7–19.3). ECOG and number of metastatic sites were related to OS in multivariate analysis. About 54.1% of patients received a third-line therapy including TAS-102 (23%), regorafenib (18.5%), and capecitabine (9.2%). Toxicity: Grade 3–4 toxicities were observed in 37.5% of the patients (hematologic 16.6%, hypertension 7.5%, asthenia 5.9%, and perforation 2.5%). Aflibercept dose was reduced in 18.3% of patients. The results show that patients with wt RAS mCRC who received an anti-EGFR as part of the first-line treatment achieved similar RR, PFS, OS, and toxicities to those reported in VELOUR trial. These results suggest that FOLFIRI-aflibercept after first-line treatment with anti-EGFR is an appropriated option for RAS wt mCRC.
Published: 2020
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7. Prospective Biomarker Study in Advanced RAS Wild-Type Colorectal Cancer: POSIBA Trial (GEMCAD 10-02)

Author: Miriam Cuatrecasas, Pilar Escudero, Hermini Manzano, José Ramón Muñoz Rodríguez, Montserrat Zanui, Mireia Gil, Carlos Fernández-Martos, Xabier García-Albéniz, Julen Fernández-Plana, Carmen Alonso, Vicente Alonso, Miguel Cadena Méndez, Federico Rojo, Uriel Bohn, Ester Falcó, Joan Maurel, Antonia Salud, Jaime Feliu, Javier Gallego, and V. Calderero
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Clinical score, Colorectal cancer, Cetuximab, Metastasis, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Gastrointestinal Cancer, Biomarkers, Tumor, medicine, Humans, PTEN, Prospective Studies, neoplasms, Aged, Receiver operating characteristic, biology, business.industry, Area under the curve, Middle Aged, Prognosis, medicine.disease, Progression-Free Survival, ErbB Receptors, Clinical trial, 030104 developmental biology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Mutation, ras Proteins, biology.protein, Biomarker (medicine), Female, Colorectal Neoplasms, business, Biomarkers, medicine.drug
Abstract: This articles compares the capacity of several biomarkers (BRAF mutation, PIK3CA mutation/PTEN loss and DP phenotype) to predict 12‐month progression‐free survival and compares it with that of clinical variables, Background. RAS testing is used to select patients with anti‐epidermal growth factor receptor (EGFR) therapies sensitivity in metastatic colorectal cancer (mCRC). However, other biomarkers such as BRAF, PIK3CA/PTEN, and p‐IGF‐1R+/MMP7+ (double positive [DP] phenotype) have not been prospectively assessed to predict anti‐EGFR resistance. Materials and Methods. We designed a multicenter prospective trial (NCT01276379) to evaluate whether the biomarkers BRAF mutation, PIK3CA mutation/PTEN loss, and DP phenotype can improve the prediction for 12‐months progression‐free survival (PFS) over the use of clinical variables exclusively in patients with RAS wild‐type (WT) mCRC treated with standard chemotherapy plus biweekly cetuximab as first‐line therapy. The planned sample size was 170 RAS WT patients to detect a 20% difference in 12‐month PFS based on the analysis of clinical and selected biomarkers (α = .05, β = .2). The discriminatory capacity of the biomarkers was evaluated using receiver operating characteristic curves. Results. We included 181 RAS WT patients. The biomarker distribution was as follows: BRAF mutant, 20 patients (11%); PIK3CA mutated/PTEN loss, 98 patients (58%); DP, 23 patients (12.7%). The clinical variables in the clinical score were progression status >0, left‐sided tumor, and resectable liver metastasis as the only metastatic site. The area under the curve (AUC) of the score containing the clinical variables was 0.67 (95% confidence interval [CI], 0.60–0.75). The AUC of the score with clinical variables and BRAF mutational status was 0.68 (0.61–0.75, p = .37). The AUC of the score with clinical variables and PI3KCA mutation/PTEN status was 0.69 (0.61–0.76, p = .32). The AUC of the score with clinical variables and DP phenotype was 0.66 (0.58–0.73, p = .09). Conclusion. The addition of BRAF, PIK3CA/PTEN, and DP to a clinical score does not improve the discrimination of 12‐month PFS. Implications for Practice. This prospective biomarker design study has important clinical implications because many prospective clinical trials are designed with the hypothesis that BRAF mutation per se and MEK and PIK3CA downstream pathways are critical for colorectal tumor survival. The results lead to the question of whether these pathways should be considered as passengers instead of drivers.
Published: 2019
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8. Metastatic Colorectal Cancer. First Line Therapy for Unresectable Disease

Author: E. Falcó, Ana Fernandez-Montes, Francis Esposito, Hermini Manzano, Pilar Escudero, Sara Serrano, Ana Ruiz-Casado, and Jorge Aparicio
Subjects: Oncology, medicine.medical_specialty, targeted agents, Bevacizumab, Colorectal cancer, medicine.medical_treatment, lcsh:Medicine, Unresectable disease, colorectal cancer, Review, Malignancy, chemotherapy, law.invention, 03 medical and health sciences, 0302 clinical medicine, First line therapy, Growth factor receptor, Randomized controlled trial, law, Internal medicine, medicine, 030212 general & internal medicine, Chemotherapy, business.industry, lcsh:R, General Medicine, medicine.disease, 030220 oncology & carcinogenesis, business, metastatic disease, medicine.drug
Abstract: Colorectal cancer (CRC) is a commonly diagnosed malignancy. The prognosis of patients with unresectable, metastatic colorectal cancer (mCRC) is dismal and medical treatment is mainly palliative in nature. Although chemotherapy remains the backbone of treatment, the landscape is changing with the understanding of its heterogeneity and molecular biology. First-line therapy relies on a combination of chemotherapy and targeted therapies, according to clinical patient characteristics and tumor molecular profile. Here we review current evidence from randomized clinical trials for using chemotherapy doublets or triplets, and for the addition of bevacizumab or anti-epidermal growth factor receptor (EGFR) agents. Novel therapies developed for small, selected populations are also discussed.
Published: 2020
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9. Adjuvant radiochemotherapy in rectal cancer: analysis of acute and late-onset toxicity

Author: Julve, Javier Valencia, Jaime, Sonia Polo, Orduña, Vicente Alonso, Emperador, Pilar Escudero, Millán, Carmen Velilla, and Baron, Ricardo Escó
Published: 2004
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10. Tumour location and efficacy of first-line EGFR inhibitors in

Author: Manuel, Benavides, Eduardo, Díaz-Rubio, Alfredo, Carrato, Albert, Abad, Carmen, Guillén, Pilar, Garcia-Alfonso, Silvia, Gil, María Teresa, Cano, María José, Safont, Cristina, Gravalos, José Luis, Manzano, Antonio, Sánchez, Julia, Alcaide, Rafael, López, Bartomeu, Massutí, Javier, Sastre, Eva, Martínez, Pilar, Escudero, Miguel, Méndez, and Enrique, Aranda
Subjects: Adult, Aged, 80 and over, Male, Time Factors, Panitumumab, Cetuximab, Membrane Proteins, Correction, Middle Aged, Irinotecan, Prognosis, Progression-Free Survival, GTP Phosphohydrolases, ErbB Receptors, Oxaliplatin, Proto-Oncogene Proteins p21(ras), Antineoplastic Agents, Immunological, Antineoplastic Combined Chemotherapy Protocols, Disease Progression, Humans, Female, Colorectal Neoplasms, Aged, Retrospective Studies
Abstract: Metastatic colorectal cancer (mCRC) is a group of distinct diseases, with clinical and molecular differences between right-sided and left-sided tumours driving varying prognosis.Patients withPatients withWe observed significantly improved efficacy outcomes in patients withNCT01161316 and NCT00885885.
Published: 2019

11. First-line biological agents plus chemotherapy in elderly patients with metastatic colorectal cancer: A retrospective pooled analysis

Author: Pilar García-Alfonso, Jose María Vieitez, Gema Durán, Encarnación González Flores, Albert Abad, Eduardo Díaz-Rubio, Jose Luis Manzano, Reyes Ferreiro Monteagudo, Maria Jose Safont Aguilera, Manuel Valladares-Ayerbes, Beatriz García Paredes, Cristina Gravalos Castro, Vicente Alonso Orduña, Pilar Escudero, Eva Martínez de Castro, Enrique Aranda, Alfredo Carrato, Bartomeu Massuti, Rosa Rodríguez Alonso, and Andres J. Muñoz Martín
Subjects: Oncology, Cancer Research, Chemotherapy, medicine.medical_specialty, business.industry, Colorectal cancer, medicine.medical_treatment, First line, medicine.disease, Pooled analysis, Internal medicine, Medicine, business
Abstract: 4017 Background: Biological agents, in combination with chemotherapy, are recommended as first-line treatment of metastatic colorectal cancer (mCRC); however, evidence guiding appropriate management of elderly patients with mCRC is lacking. This study compared the efficacy and safety outcomes in older versus younger patients with mCRC who received first-line biological therapy. Methods: This retrospective analysis used pooled data from five Spanish TTD collaborative group studies of adults with advanced CRC who received first-line treatment with bevacizumab, cetuximab or panitumumab, stratified by age (≥65 vs < 65 years). Endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and safety. Results: In total, 999 patients from five studies were included in the analysis; 480 (48%) were aged ≥65 years and 519 (52%) were aged < 65 years; 733 (73.37%) were treated with bevacizumab, 189 (18.92%) received cetuximab and 77 (7.71%) received panitumumab. Median PFS did not significantly differ between patients aged ≥65 versus < 65 years (9.9 vs 9.4 months; hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.88–1.17). Median OS was significantly shorter in older versus younger patients (21.3 vs 25.0 months; HR 1.21; 95% CI 1.04–1.41; P = 0.0132). There was no significant difference between older versus younger patients in ORR (59% vs 62%). Older patients experienced more treatment-related grade ≥3 adverse events. Conclusions: Biological agents are an effective first-line treatment option for elderly patients with mCRC, with comparable efficacy in PFS and ORR to that observed in younger patients and a manageable safety profile.
Published: 2020
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12. Clinical Impact of Circulating Tumor RAS and BRAF Mutation Dynamics in Patients With Metastatic Colorectal Cancer Treated With First-Line Chemotherapy Plus Anti-Epidermal Growth Factor Receptor Therapy

Author: Marta Martin-Richard, Carlos Fernández-Martos, Veronica Fernández, Xabier García-Albéniz, José Ramón Muñoz Rodríguez, Antonieta Salud, Bart Claes, Mireia Gil-Raga, E. Falcó, Jaime Feliu, Federico Rojo, Òscar Reig, Vicente Alonso, Joan Maurel, Beatriz Bellosillo, Marta Mendiola, Jorge Aparicio, Miguel M. Méndez, Hermini Manzano, Pilar Escudero, Bart Jacobs, Ferran Torres, Clara Montagut, Javier Gallego, Erwin Sablon, Geert Maertens, Montserrat Zanui, Julen Fernández-Plana, and Jose Carlos Mendez
Subjects: 0301 basic medicine, Cancer Research, Mutation, Mechanism (biology), Colorectal cancer, business.industry, medicine.disease_cause, medicine.disease, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, Acquired resistance, Oncology, chemistry, 030220 oncology & carcinogenesis, Anti-Epidermal Growth Factor Receptor, Cancer research, medicine, In patient, First line chemotherapy, business, DNA
Abstract: PURPOSE RAS and BRAF mutations can be detected as a mechanism of acquired resistance in circulating tumor (ct) DNA in patients with metastatic colorectal cancer treated with anti–epidermal growth factor receptor therapy. METHODS RAS and BRAF mutational status was assessed in ctDNA in a baseline plasma sample and a serum sample collected at the time of the last available determination (named secondary extraction) from patients with KRAS exon 2 wild-type metastatic colorectal cancer treated in two first-line prospective biomarker-designed clinical trials (PULSE, ClinicalTrials.gov identifier: NCT01288339; and POSIBA, ClincialTrials.gov identifier: NCT01276379). RESULTS Analysis of extended RAS and BRAF in tissue and plasma from 178 patients with KRAS exon 2 wild-type metastatic colorectal cancer showed a sensitivity of 64.1% and a specificity of 90%. The median overall survival (OS) of baseline patients with RAS and BRAF mutations in ctDNA was 22.3 months (95% CI, 15.6 to 29 months) and 8.9 months (95% CI, 6.3 to 11.4 months), respectively, which was significantly inferior to the median OS of 40.4 months (95% CI, 35.9 to 44.9 months) in two patients with wild-type disease ( P < .001). Acquisition of RAS/BRAF mutations occurred in nine of 63 patients (14%) with progressive disease (PD; ie, blood draw within 1 month before PD or after PD) compared with six of 73 patients (8%) with no PD or blood extraction for ctDNA analysis before 1 month of PD ( P = .47). Median OS in patients with RAS/BRAF acquisition was 23.9 months (95% CI, 19.7 to 27.9 months) compared with 40.6 months (95% CI, not reached to not reached) in patients who remained free of mutations ( P = .016). CONCLUSION Our results confirm that baseline RAS and BRAF testing in ctDNA discriminates survival. The emergence of RAS/BRAF mutations has limited relevance for the time to progression to anti–epidermal growth factor receptor therapy.
Published: 2019

13. Clinical impact of circulating tumor RAS and BRAF mutation dynamics in metastatic colorectal cancer patients treated with first-line chemotherapy plus anti-EGFR therapy: Combined analysis of two prospective clinical trials

Author: J. Feliu Batlle, B.A.W. Jacobs, Jorge Aparicio, José Remesal Rodríguez, V. Fernández, A. Salud Salvia, X. García de Albéniz, Federico Rojo, Pilar Escudero, Carlos Fernández-Martos, Geert Maertens, J. Fernández-Plana, V. Alonso, J. Gallego Plazas, Marta Martin-Richard, Erwin Sablon, C. Montagut, Bart Claes, M. Méndez, Juan Maurel, and Academic Medical Center
Subjects: Clinical trial, Oncology, medicine.medical_specialty, Colorectal cancer, business.industry, Internal medicine, Mutation (genetic algorithm), medicine, Hematology, First line chemotherapy, medicine.disease, business
Published: 2018

14. Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish Task Force Group for Neuroendocrine Tumors (GETNE)

Author: María Apellániz-Ruiz, Teresa Alonso-Gordoa, Enrique Grande, Javier Sastre, Alfredo Carrato, Isabel Sevilla, Ignacio Duran, Daniel Castellano, Julie Earl, Cristina Rodríguez-Antona, José Luis Fuster, Juan J. Díez, Rocio Garcia-Carbonero, Pilar Escudero, Jaume Capdevila, Oriol Casanovas, Alexandre Teule, Luis Ortega, and Jesús García-Donas
Subjects: Adult, Male, Oncology, medicine.medical_specialty, Indazoles, Phases of clinical research, Angiogenesis Inhibitors, Antineoplastic Agents, Kaplan-Meier Estimate, Neuroendocrine tumors, Polymorphism, Single Nucleotide, Disease-Free Survival, Pazopanib, Circulating tumor cell, Internal medicine, Biomarkers, Tumor, Clinical endpoint, Humans, Medicine, Progression-free survival, Aged, Proportional Hazards Models, Aged, 80 and over, Sulfonamides, business.industry, Hazard ratio, Hematology, Middle Aged, Neoplastic Cells, Circulating, Vascular Endothelial Growth Factor Receptor-3, medicine.disease, Vascular Endothelial Growth Factor Receptor-2, Surgery, Pancreatic Neoplasms, Clinical trial, Neuroendocrine Tumors, Pyrimidines, Treatment Outcome, Female, business, medicine.drug
Abstract: Background The management of advanced neuroendocrine tumors (NETs) has recently changed. We assessed the activity of pazopanib after failure of other systemic treatments in advanced NETs. Methods This was a multicenter, open-label, phase II study evaluating pazopanib as a single agent in advanced NETs (PAZONET study). The clinical benefit rate (CBR) at 6 months was the primary end point. Translational correlation of radiological response and progression-free survival (PFS) with circulating and tissue biomarkers was also evaluated. Results A total of 44 patients were enrolled. Twenty-five patients (59.5%) were progression-free at 6 months (4 partial responses, 21 stable diseases) with a median PFS of 9.5 months [95% confidence interval (CI) 4.8–14.1]. The CBR varied according to prior therapy received, with 73%, 60% and 25% in patients treated with prior multitarget inhibitors, prior mTOR inhibitors and both agents, respectively. A nonsignificant increase in PFS was observed in patients presenting lower baseline circulating tumor cell (CTC) counts (9.1 versus 5.8 months; P = 0.22) and in those with decreased levels of soluble-vascular endothelial growth factor receptor-2 (sVEGFR-2) (12.6 versus 9.1 months; P = 0.067). A trend toward reduced survival was documented in patients with VEGFR3 rs307821 and rs307826 missense polymorphisms [hazard ratio (HR): 12.3; 95% CI 1.09–139.2; P = 0.042 and HR: 6.9; 95% CI 0.96–49.9; P = 0.055, respectively]. Conclusions Pazopanib showed clinical activity in patients with advanced NETs regardless of previous treatments. Additionally, CTCs, soluble-s VEFGR-2 and VEGFR3 gene polymorphisms constitute potential biomarkers for selecting patients for pazopanib (NCT01280201). Clinical trial number NCT01280201.
Published: 2015
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15. Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: long-term results of the Spanish GCR-3 phase II randomized trial

Author: M.J. Safont, Bruce D. Minsky, Vicente Alonso, B. Massuti, Jorge Aparicio, Antonieta Salud, Carlos Fernández-Martos, Juan Maurel, Carlos Bosch, Carles Pericay, C. Montagut, Marta Martin, Xabier García-Albéniz, R. Vera, and Pilar Escudero
Subjects: Adult, Male, medicine.medical_specialty, Organoplatinum Compounds, Adenocarcinoma, Preoperative care, Disease-Free Survival, law.invention, Capecitabine, Randomized controlled trial, locally advanced rectal cancer, law, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Cumulative incidence, induction chemotherapy, Aged, Rectal Neoplasms, business.industry, Rectum, Induction chemotherapy, phase II randomized trial, Chemoradiotherapy, Induction Chemotherapy, Hematology, Middle Aged, Chemotherapy regimen, Oxaliplatin, Surgery, adjuvant chemotherapy, Oncology, Chemotherapy, Adjuvant, Female, Neoplasm Recurrence, Local, business, medicine.drug
Abstract: Background The primary results of our phase II randomized trial suggested that compared with conventional preoperative chemoradiation (CRT), the addition of chemotherapy (CT) before CRT and surgery allows most patients receive their planned treatment with a better toxicity profile without compromising the pathological complete response and complete resection rates. We now report the 5-year outcomes. Patients and methods Patients with distal or middle third, T3–T4 and/or N+ rectal adenocarcinoma selected by magnetic resonance imaging, were randomly assigned to arm A—preoperative CRT followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)—or arm B—four cycles of CAPOX followed by CRT and surgery. The following 5-year actuarial outcomes were assessed: the cumulative incidence of local relapse (LR) and distant metastases (DM), disease-free (DFS) and overall survival (OS). Results A total of 108 eligible patients were randomly assigned to arm A (n = 52) or arm B (n = 56). With a median follow-up of 69.5 months, 5-year DFS was 64% in arm A and 62% in arm B (P = 0.85) and 5-year OS was 78% in arm A and 75% in arm B (P = 0.64). The 5-year cumulative incidence of LR was 2% and 5% (P = 0.61) and 5-year cumulative incidence of DM was 21% and 23%; (P = 0.79) in arms A and B, respectively. Conclusion Both treatment approaches yield similar outcomes. Given the lower acute toxicity and improved compliance with induction CT compared with adjuvant CT, integrating effective systemic therapy before CRT and surgery is a promising strategy and should be examined in phase III trials.
Published: 2015
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16. Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset

Author: Josef Thaler, Richard Greil, Johannes Gaenzer, Wolfgang Eisterer, Joerg Tschmelitsch, Hellmut Samonigg, August Zabernigg, Franz Schmid, Günther Steger, Robert Steinacher, Johannes Andel, Alois Lang, Reinhold Függer, Friedrich Hofbauer, Ewald Woell, Dietmar Geissler, Alfred Lenauer, Manfred Prager, Jean-Luc Van Laethem, Eric Van Cutsem, Geert D'Haens, Gauthier Demolin, Joseph Kerger, Guido Deboever, Gilbert Ghillebert, Marc Polus, Hassan RezaieKalantari, 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, Marc Ychou, Ayman Zawadi, Mohamed-Ayman Zawadi, Olivier Bouche, Laurent Mineur, Jaafar Bennouna-Louridi, Louis Marie Dourthe, Eveline Boucher, Julien Taieb, 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 MatysiakBudnik, 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, Gunnar Folprecht, 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 GuenterDerigs, 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, Roberto Labianca, Giuseppe Colucci, Dino Amadori, Enrico Mini, Alfredo Falcone, Corrado Boni, Evaristo Maiello, Luciano Latini, Alberto Zaniboni, 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, Stefano Cascinu, Paolo Bidoli, Massimo Vaghi, Giorgio Cruciani, Francesco Di Costanzo, Alberto Sobrero, Roberto Petrioli, Massimo Aglietta, Oscar Alabiso, Federico Capuzzo, Domenico Cristi Corsi, Stefania Salvagni, Silvana Chiara, 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, Josep Tabernero, Ramon Salazar, Enrique Aranda Aguilar, Fernando Rivera Herrero, Javier Sastre Valera, Manuel ValladaresAyerbes, Jaime FeliuBatlle, Silvia Gil, 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 CireraNogueras, BernadoQueralt Merino, Cristina Gravalos Castro, Purificacion Martinez de Prado, Carlos PijaumePericay, Manuel ConstenlaFigueiras, InmaculadaGuasch Jordan, Maria Jose GomeReina, Amelia Lopez-Ladron Garcia, Antonio Arrivi Garcia-Ramos, Andres Cervantes, Carlos Fernandez Martos, Eugenio MarcuelloGaspar, Ines Cabezas Montero, Pilar Escudero Emperador, Ana Leon Carbonero, Manuel Gallen Castillo, Teresa Garcia Garcia, Jose Garcia Lopez, Encarnacion Gonzalez Flores, Monica GuillotMorales, Marta LlanosMuñoz, Ana López Martín, Joan Maurel, Juan Carlos Camara, Rosario Dueñas Garcia, Mercedes Salgado, Isabel HernandezBusquier, Teresa Checa Ruiz, Adelaida LacastaMuñoa, MiquelNogue Aliguer, Amalia Velasco Ortiz de Taranco, Miguel Mendez Ureña, Ferran Losa Gaspa, Jose Juan Ponce, Carlos Bosch Roig, Pedro Valero Jimenez, Antonio GalanBrotons, Santiago AlbiolRodriguez, Jose Ales Martinez, Liliana Canosa Ruiz, Margarita CentellesRuiz, John Bridgewater, Rob Glynne-Jones, Saad Tahir, Tamas Hickish, Jim Cassidy, and Leslie Samuel
Subjects: Oncology, Hematology
Published: 2015
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17. Coexpression of p-IGF-1R and MMP-7 Modulates Panitumumab and Cetuximab Efficacy in RAS Wild-Type Metastatic Colorectal Cancer Patients

Author: Jose-R. Rodriguez, José-Carlos Méndez, Carlos Fernández-Martos, Hermini Manzano, Marta Martin-Richard, Jaime Feliu, Federico Rojo, Monserrat Zanui, Miguel Cadena Méndez, Antonia Salud, Xabier García-Albéniz, Pilar Escudero, Javier Gallego, Mireia Gil-Raga, Vicente Alonso, E. Falcó, Julen Fernández-Plana, Miriam Cuatrecasas, and Joan Maurel
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, modelos de riesgos proporcionales, Colorectal cancer, humanos, Cetuximab, Gene Expression, Kaplan-Meier Estimate, medicine.disease_cause, Receptor, IGF Type 1, proteínas protooncogénicas B-raf, 0302 clinical medicine, Clinical endpoint, mediana edad, proteínas ras, anciano, Panitumumab, Antibodies, Monoclonal, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prognosis, pronóstico, Matrix Metalloproteinase 7, 030220 oncology & carcinogenesis, FOLFIRI, Biomarker (medicine), Female, KRAS, Colorectal Neoplasms, medicine.drug, Proto-Oncogene Proteins B-raf, estimación de Kaplan-Meier, Original article, medicine.medical_specialty, neoplasias colorrectales, lcsh:RC254-282, Antibodies, 03 medical and health sciences, expresión génica, Internal medicine, medicine, Humans, metaloproteinasa 7 de la matriz, neoplasms, mutación, Aged, Proportional Hazards Models, Proportional hazards model, business.industry, medicine.disease, digestive system diseases, 030104 developmental biology, anticuerpos, Mutation, ras Proteins, business
Abstract: INTRODUCTION: The coexpression of pIGF-1R and MMP-7 (double-positive phenotype, DP) correlates with poor overall survival (OS) in KRAS wild-type (WT) (exon 2) metastatic colorectal cancer (mCRC) patients treated with irinotecan-cetuximab in second/third line. METHODS: We analyzed two prospective biomarker design trials of newly diagnosed RAS-WT mCRC patients treated with panitumumab-FOLFOX6 (PULSE trial; NCT01288339) or cetuximab plus either FOLFOX6/FOLFIRI (POSIBA trial; NCT01276379). The main exposure was DP phenotype (DP/ non-DP), as assessed by two independent pathologists. DP cases were defined by immunohistochemistry as N70% expression of moderate or strong intensity for both MMP-7 and pIGF-1R. Primary endpoint: progression-free survival (PFS); secondary endpoints: OS and response rate. PFS and OS were adjusted by baseline characteristics using multivariate Cox models. RESULTS: We analyzed 67 patients (30 non-DP, 37 DP) in the PULSE trial and 181 patients in the POSIBA trial (158 non-DP, 23 DP). Response rates and PFS were similar between groups in both studies. DP was associated with prolonged OS in PULSE (adjusted HR: 0.23; 95% CI: 0.11-0.52; P =. 0004) and with shorter OS in POSIBA (adjusted HR: 1 .67; 95% CI: 0.96-2.90; P =. 07). CONCLUSION: A differential effect of anti-EGFRs on survival by DP phenotype was observed. Panitumumab might be more beneficial for RAS-WT mCRC patients with DP phenotype, whereas cetuximab might improve OS in non-DP., Amgen supported the PULSE trial and Merck supported the POSIBA trial. Neither Amgen nor Merck had any role in the present analysis design, analysis and interpretation of data, writing the report, and the decision to submit the report for publication.
Published: 2018

18. 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
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19. Phase III randomized sequential open-label study to evaluate the efficacy of FOLFOX + panitumumab followed by FOLFIRI + bevacizumab (Sequence 1) versus FOLFOX+ bevacizumab followed by FOLFIRI + panitumumab (Sequence 2) in untreated patients with wild-type RAS metastatic, primary left (L)-sided, unresectable colorectal cancer (CRC): The CR-SEQUENCE

Author: Teresa Rodriguez, Antonieta Salud Salvia, Ramon Salazar, Clara Montagut, Josep Tabernero, Ferran Losa, Cristina Gravalos Castro, Carles Pericay, T. García, Begoña Graña Suárez, Rosario Vidal, David Marrupe, Auxiliadora Gómez-España, Enrique Aranda, Maria Jose Safont, Javier Gallego Plazas, Helder Mansinho, Alfredo Carrato, Jose Luis Manzano Mozo, and M. Pilar Escudero
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Bevacizumab, business.industry, Colorectal cancer, Wild type, medicine.disease, Open label study, FOLFOX, Internal medicine, FOLFIRI, medicine, Panitumumab, business, medicine.drug, Sequence (medicine)
Abstract: TPS3618 Background: Both anti-EGFR and anti-VEGF therapies have shown clinical benefit when they are added in first and second-line in L-sided CRC. The conflicting results in anti-VEGF vs. anti-EGFR studies (FIRE-3, PEAK and CALGB/SWOG 80405 studies) suggest that the sequence of targeted therapies added to FOLFOX or FOLFIRI regimens in first- and second-line treatment could be an important factor in the overall survival (OS) of mCRC patients. Currently, there are no randomized data on the sequential use of an anti-EGFR followed by an anti-VEGF or vice versa. Therefore, the aim of this randomized clinical trial is to compare the efficacy of two treatment sequences, panitumumab followed by bevacizumab versus bevacizumab followed by panitumumab in combination with FOLFOX chemotherapy in first-line and with FOLFIRI in second-line in patients with wild-type RAS, primary L-sided, metastatic colorectal cancer (mCRC). Methods: A phase III, multicentre, open-label and randomized two-arm clinical trial. Untreated patients with wild-type RAS mCRC (determined locally), primary L-sided and unresectable will be screened for this trial. Eligible patients will be randomized 1:1 to receive first-line (1L) panitumumab plus FOLFOX and then bevacizumab plus FOLFIRI as second-line (2L) treatment (Seq. 1) or bevacizumab plus FOLFOX as 1L and then panitumumab plus FOLFIRI as 2L treatment (Seq. 2). Randomization will be stratified by number of metastatic organs involved (1 vs > 1). Primary objective is the comparison of the progression free survival (PFS) rate at 35 months (m) of Seq 1 vs Seq. 2. Secondary objectives: PFS from randomization to 2nd progression or death, OS rate at 35 months and OS of Seq. 1 vs Seq. 2; PFS, objective response rate, disease control rate, early tumour shrinkage, Depth of Response, duration and time to response and safety in 1L treatment and in 2L treatment in each Sequence arm. Exploratory objectives: impact of baseline biomarkers predictive of the efficacy in each Sequence arm and the clinical impact of clonal dynamics by longitudinal analysis of circulating tumour deoxyribonucleic acid (ctDNA) in plasma. The trial is in progress; 28 of up to 370 planned patients have been recruited at the end of January 2019 (first patient in 31 October 2018). Clinical trial information: NCT03635021.
Published: 2019
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20. Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer

Author: Marta Martin-Richard, Lydia Gaba, Michele Rubini, Javier Gallego, Jordi Camps, Xabier García-Albéniz, Antonieta Salud, Vicente Alonso, Jose Carlos Mendez, Antoni Castells, Mercedes Marín-Aguilera, Federico Rojo, Jaime Feliu, Carla Montironi, Carlos Fernández-Martos, Elena Asensio, Pedro Jares, Miguel Cadena Méndez, Carlos Horndler, Iván Victoria, Pilar Escudero, Jordi Codony-Servat, Joan Maurel, Òscar Reig, Aleix Prat, Rafael Rosell, Eva Martinez-Balibrea, Miriam Cuatrecasas, and Anna Martínez-Cardús
Subjects: 0301 basic medicine, Oncology, Male, IGF-1R, Chemotherapy, Colorectal cancer, Metastasis, Cancer, Phosphorylation, Nuclear location, PIAS3, Cancer Research, Organoplatinum Compounds, Colorectal cancer, medicine.medical_treatment, Dasatinib, Leucovorin, PIAS3, Cetuximab, Metastasis, Targeted therapy, Receptor, IGF Type 1, Economica, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Molecular Targeted Therapy, Phosphorylation, Cancer, Panitumumab, Antibodies, Monoclonal, Middle Aged, Sorafenib, Protein Inhibitors of Activated STAT, Bevacizumab, Oxaliplatin, Protein Transport, Editorial, 030220 oncology & carcinogenesis, Fatty Acids, Unsaturated, Female, Fluorouracil, Colorectal Neoplasms, HT29 Cells, medicine.drug, Signal Transduction, Niacinamide, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Curcumin, Cell Survival, Socio-culturale, Antineoplastic Agents, colorectal cancer, Antibodies, Monoclonal, Humanized, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Internal medicine, medicine, Chemotherapy, Humans, Pyrroles, Gene Silencing, Aged, Cell Nucleus, business.industry, Phenylurea Compounds, nuclear internalisation, acquired resistance, Ambientale, medicine.disease, HCT116 Cells, digestive system diseases, Nuclear location, 030104 developmental biology, Pyrimidines, BRAF mutation, Drug Resistance, Neoplasm, Camptothecin, business, IGF-1R, Molecular Chaperones
Abstract: Altres ajuts: Mutua Madrileña (AP75002010); Porgrama CERCA; CIBERehd Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving. We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation. Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R. Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.
Published: 2017

21. Impact of tumor location on the efficacy of first-line anti-EGFR monoclonal antibody plus chemotherapy in patients (pts) with metastatic colorectal cancer (mCRC): Retrospective analyses of the randomized MACRO-2 and PLANET trials from TTD Group

Author: E. Martínez de Castro, B. Massuti Sureda, Alfredo Carrato, M.T. Cano Osuna, M.J. Safont, Julia Sastre, M. Benavides, M. Méndez-Ureña, Ariadna Sánchez, J.L. Manzano-Mozo, R. López, J. Alcaide-Garcia, Carmen Guillén-Ponce, E. Aranda Aguilar, Pilar Escudero, Cristina Grávalos, Albert Abad, P. García-Alfonso, Sara Gil, and E. Diaz Rubio
Subjects: Oncology, Chemotherapy, medicine.medical_specialty, Colorectal cancer, business.industry, medicine.medical_treatment, First line, Hematology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, 030211 gastroenterology & hepatology, In patient, Tumor location, Anti-EGFR Monoclonal Antibody, business
Published: 2017

22. Dynamic soluble changes in sVEGFR1, HGF, and VEGF promote chemotherapy and bevacizumab resistance: A prospective translational study in the BECOX (GEMCAD 09-01) trial

Author: Beatriz Llorente, R. Perez-Carrion, Jaime Feliu, Estela Pineda, Uriel Bohn, Jorge Aparicio, Pilar Escudero, Elena Vila-Navarro, A. Carmona, Antonieta Salud, Maria Jose Safont, Meritxell Gironella, Rosa Bouzas, Xabier García-Albéniz, T. Ripolles, Carlos Bosch, Juan Ramón Ayuso, Ruth Vera, Enrique Casado, Juan Maurel, UAM. Departamento de Medicina, and Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ)
Subjects: Serum, 0301 basic medicine, Oncology, Male, Vascular Endothelial Growth Factor A, Organoplatinum Compounds, medicine.medical_treatment, VEGF receptors, Angiogenesis Inhibitors, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, RC254-282, Colorectal, Cancer, biology, Neovascularization, Pathologic, Hepatocyte Growth Factor, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, General Medicine, Middle Aged, Bevacizumab, Oxaliplatin, 030220 oncology & carcinogenesis, biomarker, Female, Colorectal Neoplasms, medicine.drug, Adult, medicine.medical_specialty, Medicina, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Internal medicine, medicine, Humans, cancer, Aged, Chemotherapy, business.industry, Biomarker, medicine.disease, Vascular Endothelial Growth Factor Receptor-2, Surgery, 030104 developmental biology, Drug Resistance, Neoplasm, biology.protein, business, serum
Abstract: Despite initial responsiveness, acquired resistance to both bevacizumab and chemotherapy in metastatic colorectal cancer is universal. We have recently published that in vitro, chronically oxaliplatin resistance upregulates soluble vascular endothelial growth factor receptor 1, downregulates vascular endothelial growth factor, and also promotes c-MET, b-ca catenin/transcription factor 4, and AKT activation. We tested whether variation in three serum biomarkers such as the natural c-MET ligand (hepatocyte growth factor), soluble vascular endothelial growth factor receptor 1, and vascular endothelial growth factor-A was associated with efficacy in metastatic colorectal cancer patients treated in the prospective BECOX study. Serum levels of vascular endothelial growth factor-A165, soluble vascular endothelial growth factor receptor 1, and hepatocyte growth factor were assessed by enzyme-linked immunosorbent assay method basally and every 3 cycles (at the time of computed tomography evaluation) in a preplanned translational study in the first-line BECOX trial in metastatic colorectal cancer patients treated with CAPOX plus bevacizumab. Response was evaluated by routine contrast-enhanced computed tomography by RECIST 1.1 by investigator assessment and by three blinded independent radiologists. Ratios between soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A and hepatocyte growth factor/vascular endothelial growth factor-A were established and variations through time were related to RECIST 1.1 by investigator assessment and independent radiologist. The BECOX trial included 68 patients, and 27 patients were analyzed in the translational trial. A total of 80 RECIST 1.1 evaluations were done by investigator assessment and 56 by independent radiologist. We found that a 3.22-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by investigator assessment and a 3.06-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by independent radiologist from previous determination were associated with responses compared with 1.38-fold increase by investigator assessment and 1.59 by independent radiologist in non-responders (p= 0.0009 and p = 0.03, respectively). Responders had a 3.36-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A from previous determination by investigator assessment and 3.66-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A by independent radiologist compared with 1.43-fold increase by investigator assessment and 1.53 by independent radiologist for non-responders (p = 0.002 and 0.003, respectively). In conclusion, a decrease in vascular endothelial growth factor-A and an increase in soluble vascular endothelial growth factor receptor 1 during chemotherapy and bevacizumab exposure can contribute to both chemotherapy (due to c- MET/b-catenin activation) and bevacizumab (due to low vascular endothelial growth factor requirements) resistance. Because hepatocyte growth factor levels decrease also during acquired resistance, alternative strategies to hepatocyte growth factor–ligand inhibition should be investigated, This work was supported by “beca SEOM a Jóvenes Investigadores 2009” and by the Emili Letang fellowship to Estela Pineda.
Published: 2017

23. Panitumumab and irinotecan every 3 weeks is an active and convenient regimen for second-line treatment of patients with wild-type K-RAS metastatic colorectal cancer

Author: Alfredo Carrato, B. Massuti, Javier Gallego, Ferran Losa, R. Dueñas, J. Luis Manzano, Auxiliadora Gómez, Eugenio Marcuello, Jorge Aparicio, Joan Maurel, M. Chaves, Manuel Constenla, Fernando Rivera, Pilar Escudero, Cristina Grávalos, E. González, Antonio Antón, and Enrique Aranda
Subjects: Adult, Male, Oncology, Cancer Research, medicine.medical_specialty, Time Factors, Colorectal cancer, Antineoplastic Agents, Neutropenia, Irinotecan, Disease-Free Survival, Drug Administration Schedule, Internal medicine, Humans, Medicine, Panitumumab, Prospective Studies, Prospective cohort study, neoplasms, Aged, Aged, 80 and over, business.industry, Antibodies, Monoclonal, General Medicine, Middle Aged, medicine.disease, Antineoplastic Agents, Phytogenic, Rash, digestive system diseases, Oxaliplatin, Regimen, Genes, ras, Treatment Outcome, ras Proteins, Camptothecin, Female, medicine.symptom, Colorectal Neoplasms, business, medicine.drug
Abstract: To evaluate the efficacy and safety profile of the combination of panitumumab and irinotecan every 3 weeks in a phase II trial as second-line treatment in patients with advanced wild-type (WT) K-RAS colorectal cancer (CRC). Fifty-three patients received 9 mg/kg of panitumumab followed by 350 mg/m2 of irinotecan every 21 days until disease progression, unacceptable toxicity or consent withdrawal. Median age of patients included was 67 years. All patients had previously received 5-fluorouracil, 84 % oxaliplatin and 8 % irinotecan as first-line treatment. Patients received a median of five infusions of panitumumab and irinotecan. On an intention-to-treat analysis, 12 patients (23 %) achieved partial responses and 22 patients (41 %) achieved disease stabilization. Median progression-free survival and overall survival were 4.5 and 15.1 months, respectively. The most frequent treatment-related severe toxicities per patient were diarrhoea (35.8 %), followed by skin rash (32.1 %), asthenia (18.9 %) and neutropenia (13.2 %). A significant association between clinical response and incidence and grade of skin toxicity was observed (p = 0.0032). This study shows that the administration of panitumumab plus irinotecan every 3 weeks is safe, active and feasible as second-line treatment in patients with advanced WT K-RAS CRC.
Published: 2013
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24. Phase II study of preoperative radiotherapy and concomitant weekly intravenous oxaliplatin combined with oral capecitabine for stages II–III rectal cancer

Author: Vicente Alonso, Manuel Benavides, Bartomeu Massuti, Manel Gallén, Margarita Majem, Enrique Aranda, Encarnación González, Ramon Salazar, Fernando Rivera, Matilde Navarro, Ferran Losa, Pilar Escudero, and Auxiliadora Gómez
Subjects: Adult, Male, Cancer Research, medicine.medical_specialty, Organoplatinum Compounds, Colorectal cancer, medicine.medical_treatment, Phases of clinical research, Deoxycytidine, Gastroenterology, Drug Administration Schedule, Capecitabine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Neoadjuvant therapy, Aged, Rectal Neoplasms, business.industry, Chemoradiotherapy, General Medicine, Middle Aged, medicine.disease, Neoadjuvant Therapy, Oxaliplatin, Surgery, Oncology, Tolerability, Concomitant, Administration, Intravenous, Female, Fluorouracil, business, medicine.drug
Abstract: A prospective phase II study was conducted to assess the clinical activity and tolerability of oxaliplatin, capecitabine, and radiotherapy (RT) for neoadjuvant therapy of stages II-III rectal cancer.Patients with histologically confirmed stages II-III (T3-T4 and/or N+) resectable rectal adenocarcinoma were eligible. Capecitabine was administered at 825 mg/m(2) twice daily for 5 days/week and oxaliplatin at 50 mg/m(2) on day 1 weekly for 5 weeks starting the first day of RT (before RT). RT consisted of a total dose of 45 Gy delivered in 25 fractions of 1.8 Gy, 5 days per week, for 5 weeks.A total of 46 patients were included (35 male, 10 female, median age 62 years). TNM Stage was T3 in 43 patients and T4 in 2. Twenty-eight patients had suspected nodal involvement. The intended chemoradiation treatment was completed in 94 % patients. Grade 3/4 toxicity included lymphocytopenia (6 patients), diarrhea (4 patients), emesis (2 patients), asthenia (3 patients), anorexia (1 patient), and hepatic toxicity (1 patient). Grade 1 neurotoxicity occurred in 18 patients, Grade 2 neurotoxicity in 3, and Grade 1 palmoplantar erythrodysesthesia in 2. Forty-two patients underwent surgery (complete resection 95 %, sphincter-saving operation 55 %). The overall pathologic response rate was 83 %, with a pathologic complete response (pCR) rate of 11.9 % (95 % CI 4.0-25.6).The pCR rate observed with oxaliplatin plus capecitabine and RT did not reach the pre-specified criteria of efficacy in this trial, which is in line with recent results of randomized phase III trials.
Published: 2012
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25. Open-label trial on efficacy and security of treatment with gemcitabine and oral modulation with tegafur and levofolinic acid (GEMTG) in patients with advanced pancreatic cancer

Author: Gaspar Esquerdo Galiana, Emma Dotor Navarro, Pilar Escudero Emperador, Juan Manuel Campos Cervera, Inmaculada Guasch Jordan, Carles Pericay Pijaume, Manuel Gallén Castillo, Román Bastús Piulats, Eugeni Saigi Grau, Aleydis Pisa Gatell, and Jordi Alfaro Gamero
Subjects: Male, Oncology, Cancer Research, medicine.medical_specialty, Leucovorin, Administration, Oral, Antineoplastic Agents, Adenocarcinoma, Deoxycytidine, Tegafur, Internal medicine, Pancreatic cancer, Antineoplastic Combined Chemotherapy Protocols, Humans, Medicine, In patient, Survival analysis, business.industry, General Medicine, Middle Aged, medicine.disease, Survival Analysis, Gemcitabine, Surgery, Pancreatic Neoplasms, Clinical trial, Treatment Outcome, Toxicity, Disease Progression, Female, business, Levofolinic acid, medicine.drug
Abstract: Advanced pancreatic cancer has a bad prognosis, with a median overall survival (OS) no longer than 4-6 months. Since the end of last century, monotherapy with gemcitabine has remained the elective therapy, but new schedules are needed in order to improve these results. We aim to evaluate the efficacy of tegafur and levofolinic acid (LV) associated with gemcitabine, as well as its toxicity, progression-free survival and OS in advanced pancreatic cancer.An open-label, multicentric, prospective, non-controlled trial was carried out on patients with advanced or disseminated pancreatic cancer. Gemcitabine 1250 mg/m² was administered on the 1st and 8th days of the cycle, tegafur 750 mg/m²/day for 21 consecutive days and LV 25 mg/day continuously, every 28 days, with a maximum of six cycles. The primary variable was tumour overall response rate (ORR). Secondarily, time to progression (TTP), OS and scheme toxicity were determined.Forty patients were recruited; the male/female ratio was 30:10, with a mean age of 61 years. Forty percent had a Karnofsky index of 90% or 100%. Only 11 patients (27%) completed the six cycles of treatment, but more than 50% received three or more cycles. Dose intensity was 89.56% for gemcitabine and 87.36% for tegafur. Efficacy ORR was 22.5% (CI 95%, 6-37%). TTP was 3.87 months (CI 95%, 2.1-5.6), time to treatment failure was 2.97 months (CI 95%, 2.43-4.67) and OS 6.3 months (CI 95%, 4-7). The chemotherapeutic combination was well accepted; most haematologic and non-haematologic toxicities were grade 1 or 2. The most prevalent grade 3/4 toxicities were asthenia (30%), liver biochemistry disorders (25%), diarrhoea (15%) and stomatitis (12%).The administration of gemcitabine, associated with oral tegafur and leucovorin, has activity against advanced pancreatic cancer, with an adequate toxicity profile.
Published: 2011
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26. Prospective biomarker study in advanced RAS wild-type colorectal cancer: POSIBA trial

Author: X. García de Albéniz, Miriam Cuatrecasas, José Remesal Rodríguez, V. Calderero Aragón, M.C. Alonso López, M. Méndez, M. Zanui, Federico Rojo, U. Bohn Sarmiento, Carlos Fernández-Martos, J. Fernández-Plana, Pilar Escudero, V. Alonso, J. Gallego Plazas, H. Manzano Alemany, J. Feliu Batlle, A. Salud Salvia, M. Gil-Raga, Juan Maurel, and E. Falcó
Subjects: Oncology, medicine.medical_specialty, business.industry, Colorectal cancer, Internal medicine, medicine, Wild type, Biomarker (medicine), Hematology, business, medicine.disease
Published: 2018
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27. AVEVAC: A phase I-II trial with avelumab plus autologous dendritic cell (ADC) vaccine in pre-treated mismatch repair-proficient (MSS) metastatic colorectal cancer (mCRC) patients (GEMCAD 16-02)

Author: J. Garcia-Corbacho, M. Español Rego, R. Cabezón, Jorge Aparicio, Miquel Lozano, Carlos Fernández-Martos, Juan Maurel, E. Elez Fernandez, A. Ruiz Casado, Jessica Cid, X. García de Albéniz, Nohra Cecilia Rodríguez, D. Benitez Ribas, Pilar Escudero, A. Ginés, V. Alonso, and L. Bianchi
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, business.industry, Colorectal cancer, Hematology, Dendritic cell, medicine.disease, Avelumab, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Phase i ii, 030220 oncology & carcinogenesis, Internal medicine, Medicine, DNA mismatch repair, business, medicine.drug
Published: 2018
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28. In the pathway to response: Is aflibercept an optimal treatment for RASwt mCRC patients after progression to 1st line containing anti-EGFR?

Author: M.J. Safont Aguilera, J.M. Cabrera Romero, M. Salgado Fernandez, F. Rivera Herrero, A. Ruiz Casado, C. Pericay Pijaume, E. Mata Velasco, P. Iranzo Gomez, B. Gonzalez Astorga, I. Juez Martel, V. Alonso, C. López, Pilar Escudero, R. Vera, N. Martinez Lago, and E. González-Flores
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, business.industry, Optimal treatment, Hematology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Medicine, Line (text file), business, Aflibercept, medicine.drug
Published: 2018
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29. Development and internal validation of a predictive nomogram of progression-free survival in well-differentiated stage IV gastroenteropancreatic neuroendocrine tumours treated with somatostatin analogues: GETNE-TRASGU study

Author: José A. Díaz, Pilar Escudero, M. Benavent, M. Llanos-Munoz, M. Sánchez Cánovas, V. Alonso, A. La Casta, G. Crespo Herrero, C. López, J. Gallego Plazas, P. Jiménez-Fonseca, Mónica Marazuela, Juan Carlos Percovich, Rocio Garcia-Carbonero, Teresa Alonso, Jaume Capdevila, Alberto Carmona-Bayonas, Ana Custodio, M.C. Riesco Martínez, and J. Hernando
Subjects: Oncology, medicine.medical_specialty, business.industry, Hematology, Well differentiated, Predictive nomogram, Somatostatin, Internal medicine, medicine, Progression-free survival, Internal validation, Stage iv, business
Published: 2018
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30. First-line treatment with panitumumab plus FOLFIRI in elderly patients with RAS/BRAF wild-type unresectable metastatic colorectal cancer and good performance status: OPALO trial

Author: Estela Pineda Losada, Carmen Castañon Lopez, Pilar Escudero, Vicente Alonso, Gemma Soler Gonzalez, Monica Guillot Morales, Jaime Feliu, Alberto Carmona, Jorge Aparicio, Brenzo Martinez-Amores, Ana Ruíz Casado, Gemma Soler, Antonio Cubillo, Cristina Llorca, Antonieta Salud, and Ismael Macias Declara
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Performance status, business.industry, Colorectal cancer, Wild type, medicine.disease, Metastasis, First line treatment, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, FOLFIRI, Panitumumab, 030212 general & internal medicine, business, medicine.drug
Abstract: TPS3618Background: Approximately 60% of colorectal cancer (CRC) patients are ≥ 70 years, of whom 50-60% already have metastasis at the time of diagnosis. Available data indicate that elderly patien...
Published: 2018
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31. Phase II trial of induction irinotecan-cisplatin followed by concurrent irinotecan-cisplatin and radiotherapy for unresectable, locally advanced gastric and oesophageal-gastric junction adenocarcinoma

Author: Bartomeu Massuti, Javier Gallego, Maica Galán, Ana Lucia Yuste, Pilar Escudero, Alfredo Carrato, Adelaida Cardenal, Berta Laquente, Jordi Giralt, A. Sáenz, Maria Eugenia Vega-Villegas, Fernando Rivera, Enrique Aranda, Antonio Antón, Andrés Cervantes, Josep Tabernero, Edith Rodríguez, and Vicente Alonso-Orduña
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Esophageal Neoplasms, medicine.medical_treatment, Adenocarcinoma, Irinotecan, Toxicology, Gastroenterology, Stomach Neoplasms, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Clinical endpoint, Humans, Pharmacology (medical), Stage (cooking), Survival rate, Pharmacology, Cisplatin, business.industry, Cancer, medicine.disease, Combined Modality Therapy, Survival Rate, Radiation therapy, Camptothecin, Esophagogastric Junction, business, Follow-Up Studies, medicine.drug
Abstract: The prognosis of patients with unresectable M0 gastric cancer remains very poor. We performed a phase II trial to explore the efficacy and toxicity of induction irinotecan-cisplatin (IC) followed by concurrent irinotecan-cisplatin and radiotherapy (IC/RT) in this setting.Patients with unresectable M0 gastric (GC) or oesophageal-gastric junction (EGJC) adenocarcinomas were treated with two courses of IC (irinotecan, 65 mg/m(2); cisplatin, 30 mg/m(2) on days 1 and 8 every 21 days) followed by IC/RT (daily radiotherapy-45 Gy-with concurrent IC: irinotecan, 65 mg/m(2), and cisplatin, 30 mg/m(2), on days 1, 8, 15, and 22). Resectability was reassessed after this treatment, and surgical resection was performed if feasible. The primary endpoint was the R0 resection rate after induction treatment.Seventeen patients were included in the study (EGJC: 6; GC: 11). An R0 resection was achieved in only 5 patients (29%), and according to the design of the trial (Simon's optimal two-stage) accrual of patients was terminated after the first stage. No patient died during IC, whereas 3 patients (24%) died during IC/RT and one of 5 resected patients (20%) died during the first 30 days after resection. The median survival was 10.5 months, and the actuarial 2-year survival rate was 27%.Induction IC followed by IC/RT showed poor efficacy and significant toxicity in patients with unresectable GC/EGJC.
Published: 2010
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32. A Phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens

Author: István Láng, Tae-You Kim, Katalin Boér, Clive Morris, Antoine Adenis, Pilar Escudero, Gillian M. Pover, Manuel Valladares-Ayerbes, Jaafar Bennouna, and Jean-Yves Douillard
Subjects: Adult, Male, Oncology, medicine.medical_specialty, Colorectal cancer, Antineoplastic Agents, Deoxycytidine, Disease-Free Survival, Capecitabine, Internal medicine, medicine, Clinical endpoint, Humans, Pharmacology (medical), Treatment Failure, Adverse effect, Protein Kinase Inhibitors, Aged, Demography, Proportional Hazards Models, Aged, 80 and over, Mitogen-Activated Protein Kinase Kinases, Pharmacology, Dose-Response Relationship, Drug, business.industry, Middle Aged, medicine.disease, Oxaliplatin, Irinotecan, Clinical trial, Fluorouracil, Disease Progression, Benzimidazoles, Female, Colorectal Neoplasms, business, medicine.drug
Abstract: Objectives To assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) in patients with metastatic colorectal cancer who had failed one or two previous chemotherapeutic regimens that included oxaliplatin and/or irinotecan. Methods This was a Phase II, multicentre, open-label, randomised, two-arm, parallel-group study comparing AZD6244 with capecitabine monotherapy. Patients received either 100 mg twice daily oral AZD6244 free-base suspension every day or 1,250 mg/m2 twice daily oral capecitabine, for 2 weeks, followed by a 1-week rest period, in 3-weekly cycles. The primary endpoint was the number of patients experiencing disease progression events. Results Sixty-nine patients were randomised in the study (34 and 35 patients in the AZD6244 and capecitabine groups, respectively). Disease progression events were experienced by 28 patients (∼80%) in both the AZD6244 and capecitabine treatment groups. Median progression-free survival was 81 days and 88 days in the AZD6244 and capecitabine groups, respectively. Ten patients in the AZD6244 treatment arm had a best response of stable disease. For capecitabine, best response was a partial response in one patient, with stable disease in a further 15 patients. The most frequently observed adverse events reported with AZD6244 were acneiform dermatitis, diarrhoea, asthenia and peripheral oedema, compared with hand-foot syndrome, diarrhoea, nausea and abdominal pain with capecitabine. Conclusions AZD6244 showed similar efficacy to capecitabine in terms of the number of patients with a disease progression event and of progression-free survival. AZD6244 is currently undergoing evaluation in Phase II trials in combination with other chemotherapeutic agents.
Published: 2010
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33. Cetuximab Given Every 2 Weeks plus Irinotecan Is an Active and Safe Option for Previously Treated Patients with Metastatic Colorectal Cancer

Author: Antonieta Salud, Carles Pericay, Carlos Grande, P. Vicente, Pilar Escudero, Antonio Arrivi, José-María Roca, Isabel Moreno, Pilar Baca García, Guillermo Quintero-Aldana, Isabel Antón, Luis Cirera, Cristina Martin, Imma Guasch, Luis-Jesús López, Miguel Cadena Méndez, A. Yubero, Manuel Constenla, Ferran Losa, and Vicente Alonso
Subjects: Adult, Diarrhea, Male, Oncology, medicine.medical_specialty, Colorectal cancer, Cetuximab, Antibodies, Monoclonal, Humanized, Irinotecan, Disease-Free Survival, Metastasis, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Drug Discovery, medicine, Humans, Pharmacology (medical), Prospective Studies, Karnofsky Performance Status, Neoplasm Metastasis, Prospective cohort study, neoplasms, Aged, Aged, 80 and over, Pharmacology, business.industry, Antibodies, Monoclonal, General Medicine, Middle Aged, medicine.disease, digestive system diseases, Clinical trial, Regimen, Treatment Outcome, Infectious Diseases, Monoclonal, Camptothecin, Female, Drug Eruptions, Colorectal Neoplasms, business, medicine.drug
Abstract: Background: We gathered data from multiple institutions on the cetuximab regimen of patients with metastatic colorectal cancer. Methods: 126 patients from 19 centers were included from July 2006 to July 2007 in this prospective non-controlled study. Irinotecan-refractory metastatic colorectal cancer patients with Karnofsky ≧70 received cetuximab 500 mg/m2 every 2 weeks (q2w) in combination with irinotecan 180 mg/m2 q2w until disease progression or unacceptable toxicity. The primary endpoint was the progression-free rate at 12 weeks. Results: Median age was 65 years; 65.9% male; colon/rectum 64.3/34.1%; Karnofsky status ≤80/≧90% in 45.3/54.7% of the patients. The progression-free rate was 42.7 (95% CI 32.8–52.6) and 22.4% (95% CI 14.2–30.7) at 12 and 24 weeks, respectively. The main grade 3 or 4 toxicities were: diarrhea 13.5% and acne-like rash 10.3%. No grade 3 or 4 infusional or allergic reactions were reported. Conclusions: The progression-free rates confirm that cetuximab q2w in combination with irinotecan is an option, and is as active and safe as the standard weekly regimen.
Published: 2010
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34. Phase II Trial of Preoperative Irinotecan–Cisplatin Followed by Concurrent Irinotecan–Cisplatin and Radiotherapy for Resectable Locally Advanced Gastric and Esophagogastric Junction Adenocarcinoma

Author: Bartomeu Massuti, Pilar Escudero, Andrés Cervantes, Jordi Giralt, Josep Tabernero, M. Eugenia Vega-Villegas, Adelaida Cardenal, Enrique Aranda, Ana Lucia Yuste, Antonio Antón, Javier Gallego, Alfredo Carrato, Edith Rodríguez, Berta Laquente, A. Sáenz, Vicente Alonso-Orduña, Maica Galán, and Fernando Rivera
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Esophageal Neoplasms, medicine.medical_treatment, Adenocarcinoma, Neutropenia, Irinotecan, Gastroenterology, Drug Administration Schedule, Stomach Neoplasms, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Humans, Medicine, Radiology, Nuclear Medicine and imaging, Prospective Studies, Prospective cohort study, Survival rate, Cisplatin, Chemotherapy, Radiation, business.industry, Remission Induction, medicine.disease, Combined Modality Therapy, Survival Rate, Radiation therapy, Spain, Preoperative Period, Camptothecin, Esophagogastric Junction, business, Algorithms, medicine.drug
Abstract: Purpose To determine in a Phase II trial whether preoperative irinotecan–cisplatin (IC) followed by concurrent IC therapy and radiotherapy (IC/RT) improved outcome in patients with resectable, locally advanced gastric adenocarcinoma (GC) or esophagogastric junction cancer (EGJC). Patients and Methods Patients with resectable Stage II–IV, M0 GC or EGJC made up the study population. The primary endpoint was pathologic complete response (pCR). Two courses of IC (irinotecan, 65mg/m 2 ; cisplatin, 30mg/m 2 on Days 1 and 8 every 21 days) were given. Patients without progression then received IC/RT, consisting of daily radiotherapy (45Gy) with concurrent IC (irinotecan, 65mg/m 2 ; cisplatin, 30mg/m 2 on Days 1, 8, 15, and 22). Surgical resection was performed, if feasible, 5–8 weeks after the end of radiotherapy. Results Twenty-three patients were included in the study: 10 with EGJC and 13 with GC. Two patients (9%) achieved pCR. The incidences of Grade 3–4 toxicities were as follows: IC: neutropenia 35% (febrile 13%), anemia 22%, diarrhea 22%, emesis 8%; IC/RT: neutropenia 52% (febrile 5%), asthenia 19%, anemia 9%, emesis 9%, diarrhea 5%, cardiotoxicity 5%. No patients died during IC or IC/RT. R0 resection was achieved in 15 patients (65%). Median survival was 14.5 months, and the actuarial 2-year survival rate was 35%. Conclusions Preoperative IC followed by IC/RT resulted in moderate response and resection rates with mild toxicity in patients with GC and EGJC.
Published: 2009
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35. Prospective validation of a lymphocyte infiltration prognostic test in stage III colon cancer patients treated with adjuvant FOLFOX

Author: Emile, Jean-François, primary, Julié, Catherine, additional, Le Malicot, Karine, additional, Lepage, Come, additional, Tabernero, Josep, additional, Mini, Enrico, additional, Folprecht, Gunnar, additional, Van Laethem, Jean-Luc, additional, Dimet, Stéphanie, additional, Boulagnon-Rombi, Camille, additional, Allard, Marc-Antoine, additional, Penault-Llorca, Frédérique, additional, Bennouna, Jaafar, additional, Laurent-Puig, Pierre, additional, Taieb, Julien, additional, Thaler, Josef, additional, Greil, Richard, additional, Gaenzer, Johannes, additional, Eisterer, Wolfgang, additional, Tschmelitsch, Joerg, additional, Keil, Felix, additional, Samonigg, Hellmut, additional, Zabernigg, August, additional, Schmid, Franz, additional, Steger, Günther, additional, Steinacher, Robert, additional, Andel, Johannes, additional, Jagdt, Björn, additional, Lang, Alois, additional, Fridrik, Michael, additional, Függer, Reinhold, additional, Hofbauer, Friedrich, additional, Woell, Ewald, additional, Geissler, Dietmar, additional, Lenauer, Alfred, additional, Prager, Manfred, additional, D'Haens, Geert, additional, Demolin, Gauthier, additional, Kerger, Joseph, additional, Deboever, Guido, additional, Ghillebert, Gilbert, additional, Polus, Marc, additional, Van Cutsem, Eric, additional, Kalantari, Hassan Rezaie, additional, Delaunoit, Thierry, additional, Goeminne, Jean Charles, additional, Peeters, Marc, additional, Vergauwe, Philippe, additional, Houbiers, Ghislain, additional, Humblet, Yves, additional, Janssens, Jos, additional, Schrijvers, Dirk, additional, Vanderstraeten, Erik, additional, Vermorken, Jan, additional, Van Daele, Daniel, additional, Ferrante, Michel, additional, Forget, Frederic, additional, Hendlisz, Alain, additional, Yilmaz, Mette, additional, Nielsen, Svend Erik, additional, Vestermark, Lene, additional, Larsen, Jim, additional, Zawadi, Mohamed-Ayman, additional, Bouche, Olivier, additional, Mineur, Laurent, additional, Bennouna-Louridi, Jaafar, additional, Dourthe, Louis Marie, additional, Ychou, Marc, additional, Boucher, Eveline, additional, Pezet, Denis, additional, Desseigne, Francoise, additional, Ducreux, Michel, additional, Texereau, Patrick, additional, Miglianico, Laurent, additional, Rougier, Philippe, additional, Fratte, Serge, additional, Levache, Charles-Briac, additional, Merrouche, Yacine, additional, Ellis, Stephen, additional, Locher, Christophe, additional, Ramee, Jean-Francois, additional, Garnier, Claire, additional, Viret, Frederic, additional, Chauffert, Bruno, additional, Cojean-Zelek, Isabelle, additional, Michel, Pierre, additional, Lecaille, Cedric, additional, Borel, Christian, additional, Seitz, Jean-Francois, additional, Smith, Denis, additional, Lombard-Bohas, Catherine, additional, Andre, Thierry, additional, Gornet, Jean-Marc, additional, Fein, Francine, additional, Coulon-Sfairi, Marie-Aude, additional, Kaminsky, Marie-Christine, additional, Lagasse, Jean-Paul, additional, Luet, Dominique, additional, Etienne, Pierre-Luc, additional, Gasmi, Mohamed, additional, Vanoli, Andre, additional, Nguyen, Suzanne, additional, Aparicio, Thomas, additional, Perrier, Hervé, additional, Stremsdoerfer, Noel, additional, Laplaige, Philippe, additional, Arsene, Dominique, additional, Auby, Dominique, additional, Bedenne, Laurent, additional, Coriat, Romain, additional, Denis, Bernard, additional, Geoffroy, Patrick, additional, Piot, Gilles, additional, Becouarn, Yves, additional, Bordes, Gilbert, additional, Deplanque, Gael, additional, Dupuis, Olivier, additional, Fruge, Frederic, additional, Guimbaud, Rosine, additional, Lecomte, Thierry, additional, Lledo, Gérard, additional, Sobhani, Iradej, additional, Asnacios, Amani, additional, Azzedine, Ahmed, additional, Desauw, Christophe, additional, Galais, Marie-Pierre, additional, Gargot, Dany, additional, Lam, You-Heng, additional, Abakar-Mahamat, Abakar, additional, Berdah, Jean-Francois, additional, Catteau, Sylviane, additional, Clavero-Fabri, Marie-Christine, additional, Codoul, Jean-Francois, additional, Legoux, Jean-Louis, additional, Goldfain, Denis, additional, Guichard, Pierre, additional, Verge, Denis Pere, additional, Provencal, Jocelyne, additional, Vedrenne, Bruno, additional, Brezault-Bonnet, Catherine, additional, Cleau, Denis, additional, Desir, Jean-Paul, additional, Fallik, David, additional, Garcia, Bruno, additional, Gaspard, Marie-Hélène, additional, Genet, Dominique, additional, Hartwig, Johannes, additional, Krummel, Yves, additional, Budnik, Tamara Matysiak, additional, Palascak-Juif, Vanessa, additional, Randrianarivelo, Harizo, additional, Rinaldi, Yves, additional, Aleba, Albert, additional, Darut-Jouve, Ariane, additional, de Gramont, Aimery, additional, Hamon, Herve, additional, Wendehenne, Frederic, additional, Matzdorff, Axel, additional, Stahl, Michael Konrad, additional, Schepp, Wolfgang, additional, Burk, Martin, additional, Mueller, Lothar, additional, Geissler, Michael, additional, Mantovani-Loeffler, Luisa, additional, Hoehler, Thomas, additional, Asperger, Walter, additional, Kroening, Hendrik, additional, von Weikersthal, Ludwig Fischer, additional, Fuxius, Stefan, additional, Groschek, Matthias, additional, Meiler, Johannes, additional, Trarbach, Tanja, additional, Rauh, Jacqueline, additional, Ziegenhagen, Nicolas, additional, Kretzschmar, Albrecht, additional, Graeven, Ullrich, additional, Nusch, Arnd, additional, von Wichert, Goetz, additional, Hofheinz, Ralf-Dieter, additional, Kleber, Gerhard, additional, Schmidt, Karl-Heinz, additional, Vehling-Kaiser, Ursula, additional, Baum, Claudia, additional, Schuette, Jochen, additional, Haag, Georg Martin, additional, Holtkamp, Wilhelm, additional, Potenberg, Jochen, additional, Reiber, Tobias, additional, Schliesser, Georg, additional, Schmoll, Hans-Joachim, additional, Schneider-Kappus, Wolfgang, additional, Abenhardt, Wolfgang, additional, Denzlinger, Claudio, additional, Henning, Jan, additional, Marxsen, Bartscht, additional, Derigs, Hans Guenter, additional, Lambertz, Helmut, additional, Becker-Boost, Ingulf, additional, Caca, Karel, additional, Constantin, Christian, additional, Decker, Thomas, additional, Eschenburg, Henning, additional, Gabius, Sigrun, additional, Hebart, Holger, additional, Hoffmeister, Albrecht, additional, Horst, Heinz-August, additional, Kremers, Stephan, additional, Leithaeuser, Malte, additional, Mueller, Sebastian, additional, Wagner, Siegfried, additional, Daum, Severin, additional, Schlegel, Frank, additional, Stauch, Martina, additional, Heinemann, Volker, additional, Maiello, Evaristo, additional, Latini, Luciano, additional, Zaniboni, Alberto, additional, Amadori, Dino, additional, Aprile, Giuseppe, additional, Barni, Sandro, additional, Mattioli, Rodolfo, additional, Martoni, Andrea, additional, Passalacqua, Rodolfo, additional, Nicolini, Mario, additional, Pasquini, Enzo, additional, Rabbi, Carla, additional, Aitini, Enrico, additional, Ravaioli, Alberto, additional, Barone, Carlo, additional, Biasco, Guido, additional, Tamberi, Stefano, additional, Gambi, Angelo, additional, Verusio, Claudio, additional, Marzola, Marina, additional, Lelli, Giorgio, additional, Boni, Corrado, additional, Cascinu, Stefano, additional, Bidoli, Paolo, additional, Vaghi, Massimo, additional, Cruciani, Giorgio, additional, Di Costanzo, Francesco, additional, Sobrero, Alberto, additional, Petrioli, Roberto, additional, Aglietta, Massimo, additional, Alabiso, Oscar, additional, Capuzzo, Federico, additional, Falcone, Alfredo, additional, Corsi, Domenico Cristi, additional, Labianca, Roberto, additional, Salvagni, Stefania, additional, Chiara, Silvana, additional, Ciuffreda, Libero, additional, Ferraù, Francesco, additional, Giuliani, Francesco, additional, Lonardi, Sara, additional, Gebbia, Nicola, additional, Mantovani, Giovanni, additional, Sanches, Evaristo, additional, Mellidez, Juan Carlos, additional, Santos, Pedro, additional, Freire, Joao, additional, Sarmento, Cristina, additional, Costa, Luis, additional, Pinto, Antonio Moreira, additional, Barroso, Sergio, additional, Santo, Jorge Espirito, additional, Guedes, Fátima, additional, Monteiro, Amélia, additional, Sa, Anabela, additional, Furtado, Irene, additional, Salazar, Ramon, additional, Aguilar, Enrique Aranda, additional, Herrero, Fernando Rivera, additional, Valera, Javier Sastre, additional, Ayerbes, Manuel Valladares, additional, Batlle, Jaime Feliu, additional, Gil, Silvia, additional, Esteve, Albert Abad, additional, Garcia-Giron, Carlos, additional, Vivanco, Guillermo Lopez, additional, Salvia, Antonia Salud, additional, Orduña, Vicente Alonso, additional, Garcia, Ruth Vera, additional, Gallego, Javier, additional, Sureda, Bartomeu Massuti, additional, Remon, Jordi, additional, Safont Aguilera, Maria Jose, additional, Nogueras, Luis Cirera, additional, Merino, Bernado Queralt, additional, Castro, Cristina Gravalos, additional, de Prado, Purificacion Martinez, additional, Pericay, Carlos Pijaume, additional, Figueiras, Manuel Constenla, additional, Jordan, Inmaculada Guasch, additional, Gome Reina, Maria Jose, additional, Garcia, Amelia Lopez-Ladron, additional, Garcia-Ramos, Antonio Arrivi, additional, Cervantes, Andres, additional, Martos, Carlos Fernandez, additional, Gaspar, Eugenio Marcuello, additional, Montero, Ines Cabezas, additional, Emperador, Pilar Escudero, additional, Carbonero, Ana Leon, additional, Castillo, Manuel Gallen, additional, Garcia, Teresa Garcia, additional, Lopez, Jose Garcia, additional, Flores, Encarnacion Gonzalez, additional, Morales, Monica Guillot, additional, Muñoz, Marta Llanos, additional, Martín, Ana López, additional, Maurel, Joan, additional, Camara, Juan Carlos, additional, Garcia, Rosario Dueñas, additional, Salgado, Mercedes, additional, Busquier, Isabel Hernandez, additional, Ruiz, Teresa Checa, additional, Muñoa, Adelaida Lacasta, additional, Aliguer, Miquel Nogue, additional, de Taranco, Amalia Velasco Ortiz, additional, Ureña, Miguel Mendez, additional, Gaspa, Ferran Losa, additional, Ponce, Jose Juan, additional, Roig, Carlos Bosch, additional, Jimenez, Pedro Valero, additional, Brotons, Antonio Galan, additional, Rodriguez, Santiago Albiol, additional, Martinez, Jose Ales, additional, Ruiz, Liliana Canosa, additional, Ruiz, Margarita Centelles, additional, Bridgewater, John, additional, Glynne-Jones, Rob, additional, Tahir, Saad, additional, Hickish, Tamas, additional, Cassidy, Jim, additional, and Samuel, Leslie, additional
Published: 2017
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36. A randomized phase II study of capecitabine-based chemoradiation with or without bevacizumab in resectable locally advanced rectal cancer: clinical and biological features

Author: Cristina Grávalos, Ramon Salazar, Javier Sastre, Javier Gallego, Carles Pericay, A. Gomez, Sebastiano Biondo, Jose Luis Manzano, Carlos López, Enrique Aranda, Jaume Capdevila, Amalia Palacios, Ferran Losa, Berta Laquente, M.J. Safont, Pilar Escudero, Vicente Alonso, and Mercedes Martinez Villacampa
Subjects: Male, Oncology, Cancer Research, genetic structures, Colorectal cancer, Resectable, Phases of clinical research, law.invention, Randomized controlled trial, Surgical oncology, law, Antineoplastic Combined Chemotherapy Protocols, Rectal cancer, Radiotherapy Dosage, Chemoradiotherapy, Middle Aged, Malalts de càncer, Bevacizumab, Treatment Outcome, Preoperative Period, Female, Cancer chemotherapy, Research Article, medicine.drug, Adult, medicine.medical_specialty, Locally-advanced, Drug Administration Schedule, Capecitabine, Quimioteràpia del càncer, Càncer colorectal, Internal medicine, Biomarkers, Tumor, Genetics, medicine, Humans, Aged, Rectal Neoplasms, business.industry, Cancer patients, Chemoradiotherapy, Adjuvant, medicine.disease, Surgery, Clinical trial, Patient Compliance, Monoclonal antibodies, business, Anticossos monoclonals
Abstract: Background Perioperatory chemoradiotherapy (CRT) improves local control and survival in patients with locally advanced rectal cancer (LARC). The objective of the current study was to evaluate the addition of bevacizumab (BEV) to preoperative capecitabine (CAP)-based CRT in LARC, and to explore biomarkers for downstaging. Methods Patients (pts) were randomized to receive 5 weeks of radiotherapy 45 Gy/25 fractions with concurrent CAP 825 mg/m2 twice daily 5 days per week and BEV 5 mg/kg once every 2 weeks (3 doses) (arm A), or the same schedule without BEV (arm B). The primary end point was pathologic complete response (ypCR: ypT0N0). Results Ninety pts were included in arm A (44) or arm B (46). Grade 3–4 treatment-related toxicity rates were 16% and 13%, respectively. All patients but one (arm A) proceeded to surgery. The ypCR rate was 16% in arm A and 11% in arm B (p =0.54). Fifty-nine percent vs 39% of pts achieved T-downstaging (arm A vs arm B; p =0.04). Serial samples for biomarker analyses were obtained for 50 out of 90 randomized pts (arm A/B: 22/28). Plasma angiopoietin-2 (Ang-2) levels decreased in arm A and increased in arm B (p
Published: 2015
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37. Phase II randomised trial of raltitrexed–oxaliplatin vs raltitrexed–irinotecan as first-line treatment in advanced colorectal cancer

Author: A Pelegrín, Luis Lopez-Gomez, J. Lizón, J. Feliu, F. Juárez, M Ruiz, Antonieta Salud, C. Castañón, Pilar Escudero, E González, Manuel González-Barón, J R Mel, and Javier de Castro
Subjects: Adult, Male, Cancer Research, medicine.medical_specialty, Randomization, Organoplatinum Compounds, Colorectal cancer, colorectal cancer, Thiophenes, Irinotecan, Thymidylate synthase, Gastroenterology, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Clinical Studies, medicine, Humans, Infusions, Intravenous, Survival analysis, Aged, biology, business.industry, raltitrexed, oxaliplatin, toxicity, Middle Aged, medicine.disease, Survival Analysis, Oxaliplatin, Surgery, Treatment Outcome, Oncology, Toxicity, Quinazolines, biology.protein, Camptothecin, Female, Colorectal Neoplasms, business, Raltitrexed, medicine.drug
Abstract: The purpose of this phase II randomised trial was to determine which of two schemes, raltitrexed-irinotecan or raltitrexed-oxaliplatin, offered better activity and less toxicity in patients with advanced colorectal cancer (CRC). A total of 94 patients with previously untreated metastatic CRC were included and randomised to receive raltitrexed 3 mg m(-2) followed by oxaliplatin 130 mg m(-2) on day 1 (arm A), or CPT-11 350 mg m(-2) followed by raltitrexed 3 mg m(-2) (arm B). In both arms treatment was repeated every 3 weeks. Intent-to-treat (ITT) analysis showed an overall response rate of 46% (95% CI, 29.5-57.7%) for arm A, and 34% (95% CI, 19.8-48.4%) for arm B. Median time to progression was 8.2 months for arm A and 8.8 months for arm B. After a median follow-up of 14 months, 69% of patients included in arm A were still alive, compared to 59% of those included in arm B. Overall, 31 patients (65%) experienced some episode of toxicity in arm A and 32 patients (70%) in arm B, usually grade 1-2. The most common toxicity was hepatic, with 29 patients (60%) in arm A and 24 patients (62%) in arm B, and was grade 3-4 in four (8%) and four (9%) patients, respectively. In all, 14 patients (29%) from arm A and 24 patients (52%) from arm B had some grade of diarrhoea (P0.03). Neurologic toxicity was observed in 31 patients (64%) in arm A, and was grade 3-4 in five patients (10%), while a cholinergic syndrome was detected in nine patients (19%) in arm B. There were no differences in haematologic toxicity. One toxic death (2%) occurred in arm A and three (6.5%) in arm B. In conclusion, both schemes have high efficacy as first-line treatment in metastatic CRC and their total toxicity levels are similar. Regimens with raltitrexed seem a reasonable alternative to fluoropyrimidines.
Published: 2005
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38. Deletions Affecting Codons 557-558 of the c-KIT Gene Indicate a Poor Prognosis in Patients With Completely Resected Gastrointestinal Stromal Tumors: A Study by the Spanish Group for Sarcoma Research (GEIS)

Author: Javier, Martín, Andrés, Poveda, Antonio, Llombart-Bosch, Rafael, Ramos, José A, López-Guerrero, Javier, García del Muro, Joan, Maurel, Silvia, Calabuig, Antonio, Gutierrez, José L, González de Sande, Javier, Martínez, Ana, De Juan, Nuria, Laínez, Ferrán, Losa, Valentín, Alija, Pilar, Escudero, Antonio, Casado, Paula, García, Pilar, García, Remei, Blanco, and José M, Buesa
Subjects: Adult, Male, Cancer Research, medicine.medical_specialty, Pathology, Receptor, Platelet-Derived Growth Factor alpha, Stromal cell, Gastrointestinal Stromal Tumors, Gastroenterology, Metastasis, Internal medicine, medicine, Humans, In patient, Codon, Aged, Retrospective Studies, Aged, 80 and over, Univariate analysis, GiST, business.industry, Retrospective cohort study, Middle Aged, Prognosis, medicine.disease, Proto-Oncogene Proteins c-kit, Oncology, Multivariate Analysis, Female, Sarcoma, business, Immunostaining
Abstract: Purpose To explore the prognostic value of mutations in c-KIT and PDGFR-α genes with respect to relapse-free survival (RFS) in patients with gastrointestinal stromal tumors (GIST). We have investigated the prognostic relevance of the type and position of the mutations, in addition to other clinicopathologic factors, in a large series of patients with GIST. Methods For this study, 162 patients were selected according to the following criteria: completely resected tumors with negative margins attended between 1994 and 2001; no metastasis at diagnosis; tumor larger than 2 cm, c-KIT–positive immunostaining; and no other primary tumors. Results The median follow-up was 42 months for patients free of recurrence. Mutations were detected in 96 tumors (60%): 82 cases involving c-KIT and 14 cases involving PDFGR-α. Univariate analysis demonstrated the following as poor prognostic factors for RFS: tumors larger than 10 cm (P < .0001); mitotic count higher than 10 mitoses per 50 high-power fields (P < .0001); high risk index (P < .0001); intestinal GIST location (P = .0041); high cellularity (P < .0001); tumor necrosis (P < .0001); deletions affecting exon 11 (P = .0007); and deletions affecting codons 557 to 558 (P < .0001). After the multivariate analysis, only the high risk index (relative risk [RR], 12.36), high cellularity (RR, 3.97), and deletions affecting codons 557 to 558 of c-KIT (RR, 2.57) corresponded to independent prognostic factors for RFS in GIST patients. Conclusion Deletions affecting codons 557 to 558 are relevant for the prognosis of RFS in GIST patients. This critical genetic alteration should be considered to be a new prognostic stratification variable for randomized trials exploring imatinib mesylate in the adjuvant setting in GIST patients.
Published: 2005
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39. Gemcitabine/Capecitabine in Patients with Metastatic Breast Cancer Pretreated with Anthracyclines and Taxanes

Author: R. Lastra, E. Polo, Dolores Isla, R. Lara, Eugenia Ortega, Beth Andres, Alberto Saenz-Cusi, Alejandro Tres, J. Lambea, Pilar Escudero, and Jose I. Mayordomo
Subjects: Adult, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Breast Neoplasms, Neutropenia, Vinorelbine, Deoxycytidine, Gastroenterology, Capecitabine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Anthracyclines, Infusions, Intravenous, Aged, Chemotherapy, business.industry, Middle Aged, medicine.disease, Gemcitabine, Metastatic breast cancer, Surgery, Treatment Outcome, Oncology, Drug Resistance, Neoplasm, Concomitant, Disease Progression, Female, Taxoids, Fluorouracil, Neoplasm Recurrence, Local, business, Progressive disease, medicine.drug
Abstract: Purpose Gemcitabine and capecitabine are 2 anticancer drugs with a mechanism of action involving metabolism of pyrimidine nucleotides. Both are among the few agents active in patients with metastatic breast cancer (MBC) progressing after therapy with anthracyclines and taxanes. We have conducted a phase II trial of gemcitabine/capecitabine in patients with disease progression after treatment with anthracyclines and taxanes. Patients and Methods Treatment included gemcitabine 2000 mg/m 2 on day 1 every 3 weeks and capecitabine 2500 mg/m 2 daily (divided into 2 doses) on days 1–14 every 3 weeks; treament was administered until disease progression or unacceptable toxicity was documented. All patients received concomitant oral pyridoxine 300 mg twice daily to prevent hand-foot syndrome (HFS). Of 39 patients treated, 33 had received previous treatment with anthracyclines, 6 had medical contraindication to anthracyclines, 35 had previously received taxanes, and 23 had received vinorelbine. Fourteen patients had previous high-dose chemotherapy with stem cell rescue and 5 had previously received trastuzumab. Patients were 31–79 years of age (median, 55 years) and, altogether, were given 386 courses of therapy (range, 1–36 courses per patient; median, 6 courses). Results Grade 3/4 toxicities included HFS (11 courses, 6 patients), stomatitis (6 courses, 2 patients), diarrhea (5 courses, 4 patients), anemia (5 courses, 2 patients), thrombocytopenia (5 courses, 2 patients), and neutropenia (1 course, 1 patient). Response rate (all 39 patients were evaluable) was 48.7% (partial response, n = 19; stable disease, n = 7; progressive disease, n = 13). Thirty-six patients died because of disease progression, and 3 are alive with progressive disease. Median follow-up was 26 months or until death. Median duration of response was 15 months (range, 3–26 months). Median time to disease progression was 5 months (range, 1–26 months). Median overall survival duration was 10 months (range, 1–37 months). Conclusion In this cohort of patients heavily pretreated with anthracyclines and taxanes, the response rate to gemcitabine/capecitabine is encouraging, although response duration is limited.
Published: 2005
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40. Capecitabine As First-Line Treatment for Patients Older Than 70 Years With Metastatic Colorectal Cancer: An Oncopaz Cooperative Group Study

Author: A. Yubero, Pilar Escudero, Matilde Bolaños, Enrique Casado, Ferrán Llosa, Luis Lopez-Gomez, Manuel González-Barón, Jaime Feliu, Jose-Manuel Vicent, María-José Gómez-Reina, Jose-Javier Sanz-Lacalle, and Rafael López
Subjects: Male, Antimetabolites, Antineoplastic, Cancer Research, medicine.medical_specialty, Colorectal cancer, Administration, Oral, Renal function, Deoxycytidine, Gastroenterology, Metastasis, Capecitabine, Stable Disease, Internal medicine, medicine, Humans, Aged, Aged, 80 and over, business.industry, Age Factors, Combination chemotherapy, medicine.disease, Surgery, Clinical trial, Oncology, Tolerability, Disease Progression, Female, Fluorouracil, Colorectal Neoplasms, business, medicine.drug
Abstract: Purpose To determine the tolerability of capecitabine in elderly patients with advanced colorectal cancer (CRC). Patients and Methods Fifty-one patients with advanced CRC who were ≥ 70 years and considered ineligible for combination chemotherapy received oral capecitabine 1,250 mg/m2 twice daily on days 1 to 14 every 3 weeks. Patients with a creatinine clearance of 30 to 50 mL/min received a dose of 950 mg/m2 twice daily. Results A total of 248 cycles of capecitabine were administered (median, five cycles; range, one to eight cycles). The overall response rate was 24% (95% CI, 15% to 41%), including two complete responses (CR; 4%) and 10 partial responses (PR; 20%). Disease control (CR + PR + stable disease) was achieved in 67% of patients. The median times to disease progression and overall survival were 7 months (95% CI, 6.4 to 9.5 months) and 11 months (95% CI, 8.6 to 13.3 months), respectively. Of the 35 patients evaluated for clinical benefit response, 14 (40%; 95% CI, 24% to 58%) showed clinical benefit. Capecitabine was well tolerated. Treatment-related grade 3 and 4 adverse events were observed in only six patients (12%), and the most common events were diarrhea, hand-foot syndrome, and thrombocytopenia. One patient (2%) had an episode of angina, but no treatment-related deaths were reported. Conclusion Our findings suggest that capecitabine is effective and well tolerated in elderly patients with advanced CRC who are considered ineligible for combination chemotherapy.
Published: 2005
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41. Phase II Clinical Trial With Pegylated Liposomal Doxorubicin (CAELYX®/Doxil®) and Quality of Life Evaluation (EORTC QLQ-C30) in Adult Patients With Advanced Soft Tissue Sarcomas: A study of the Spanish Group for Research in Sarcomas (GEIS)

Author: M. D. Menéndez, D. Menéndez, Antonio Casado, Pilar Escudero, Andres Poveda, R. Bernabé, J. M. Buesa, Josefina Cruz, Elena Belyakova, J. García del Muro, Antonio Lopez-Pousa, Carmen Balana, O. Sanmartín, and Javier Martín
Subjects: Oncology, medicine.medical_specialty, GiST, business.industry, Soft tissue sarcoma, Neutropenia, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, Surgery, Clinical trial, Regimen, Internal medicine, Toxicity, polycyclic compounds, Medicine, Radiology, Nuclear Medicine and imaging, Doxorubicin, lipids (amino acids, peptides, and proteins), business, Stomatitis, Research Article, medicine.drug
Abstract: Background:Pegylated liposomal doxorubicin (PLD), a formulation with pharmacokinetic differences with respect to doxorubicin (DXR), might benefit patients with advanced soft tissue sarcoma (STS) pretreated with DXR.Patients and methods:Patients with measurable and progressive STS received PLD at 35 mg/m2every 3 weeks. Quality of life before and during treatment was assessed with EORTC QLQ-C30.Results:Twenty-eight patients, 22 DXR-pretreated, were given 140 cycles (median 3, range 1–18). Activity in 27 patients (5 GIST): one complete and one partial remission (both non-GIST and without prior DXR), 12 stabilizations and 13 progressions (response rate 7.4%, 95% CI: 0–17%). Grade 3 toxicity: palmar-plantar erythrodysesthesia (19% of patients), stomatitis (4%) or cutaneous (4%). Neutropenia grade≥3 was detected in 16% of patients. Median relative dose intensity was 95%. Progression-free rate at 3 and 6 months was, respectively, 48 and 22%, median progression-free survival 5.8 months and median overall survival 8.7 months. QLQ-C30 at baseline and at weeks 6–11 in 23 and 13 patients, respectively, showed good reliability and validity. Quality of life did not seem to worsen during therapy.Conclusions:PLD did not induce objective remissions in 22 STS patients pretreated with DXR, but progression-free rate figures support the use of this agent in patients who have not progressed under a DXR-containing regimen. The toxicity observed was comparable to that of other PLD schedules.
Published: 2005

42. Prognostic Value of Serum S-100B in Malignant Melanoma

Author: Raquel Andrés, Pedro Zaballos, A. Saenz, Luis Elosegui, Pilar Escudero, Dolores Isla, Alejandro Tres, Elena Filipovich, E. Polo, Javier Rodino, and Jose I. Mayordomo
Subjects: Adult, Male, Cancer Research, medicine.medical_specialty, Pathology, Skin Neoplasms, S100 Calcium Binding Protein beta Subunit, Normal values, Gastroenterology, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Internal medicine, Biomarkers, Tumor, Humans, Medicine, Nerve Growth Factors, Stage (cooking), Melanoma, Aged, Neoplasm Staging, Tumor marker, business.industry, S100 Proteins, General Medicine, Middle Aged, Prognosis, medicine.disease, Oncology, 030220 oncology & carcinogenesis, Predictive value of tests, Mann–Whitney U test, Female, business, Stage iv, Median survival
Abstract: Aims and Background Although there is no established tumor marker of proven value for patients with melanoma, high serum levels of S-100B protein have been found in patients with melanoma and distant metastases. This study was performed to assess the prognostic value of this marker. Methods and Study Design Serum S-100B protein was measured by means of the LIA-mat System 300 (Sangtec S-100B LIA, AB Sangtec Medical, Bromma, Sweden) in 85 patients with melanoma. Results Mean serum S-100B protein was 0.075 μg/L (range, 0.001-0.470) in 66 patients with non-metastatic melanoma (stage I-III) versus 0.441 μg/L (range, 0.001-16.840) in 19 patients with metastatic melanoma (stage IV) (P Conclusion Serum S-100B is a useful tumor marker in melanoma.
Published: 2004
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43. Irinotecan plus raltitrexed as first-line treatment in advanced colorectal cancer: a phase II study

Author: C. Castañón, Luis Lopez-Gomez, M. González Barón, Carles Pericay, Antonieta Salud, Pilar Escudero, J. J. Sánchez, J M Rodríguez-García, M. Martinez, J. Feliu, M Sanz Martín, and M R López de Tejada
Subjects: Adult, Male, Cancer Research, medicine.medical_specialty, Nausea, medicine.medical_treatment, Phases of clinical research, colorectal cancer, Thiophenes, chemotherapy, Irinotecan, Gastroenterology, Clinical, Internal medicine, CPT-11, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Infusions, Intravenous, Aged, Chemotherapy, business.industry, raltitrexed, Middle Aged, medicine.disease, Survival Analysis, Surgery, Regimen, Treatment Outcome, Oncology, Vomiting, Disease Progression, Quinazolines, Camptothecin, Female, medicine.symptom, business, Colorectal Neoplasms, Raltitrexed, Febrile neutropenia, medicine.drug
Abstract: To evaluate the efficacy and toxicity of irinotecan (CPT-11) in combination with raltitrexed as first-line treatment of advanced colorectal cancer (CRC). A total of 91 previously untreated patients with advanced CRC and measurable disease were enrolled in this phase II study. The median age was 62 years (range 31-77); male/female 54/37; ECOG performance status was 0 in 50 patients (55%), one in 39 (43%) and two in two (2%). Treatment consisted of CPT-11 350 mg x m(-2) in a 30-min intravenous infusion on day 1, followed after 30 min by a 15-min infusion of raltitrexed 3 mg x m(-2). Measurements of efficacy included the following: response rate, time to disease progression and overall survival. Of the 83 evaluable patients valuable to objective response, there were five complete responses (6%) and 23 partial responses (28%), for an overall response rate of 34% (95% CI: 25.9-46.5%). In all, 36 patients (43%) had stable disease, whereas 19 (23%) had a progression. The median time to progression was 11.1 months and the median overall survival was 15.6 months. A total of 487 cycles of chemotherapy were delivered with a median of five per patient. Grade 3-4 WHO toxicities were as follows: diarrhoea in 13 patients (15%), nausea/vomiting in four (4%), transaminase increase in six (7%), stomatitis in two (2%), febrile neutropenia in three (3%), anaemia in five (6%) and asthenia in three (3%). The combination CPT-11-raltitrexed is an effective, well-tolerated and convenient regimen as front-line treatment of advanced CRC.
Published: 2004

44. Activity and Safety of Oxaliplatin with Weekly 5-Fluorouracil Bolus and Low-Dose Leucovorin as First-Line Treatment for Advanced Colorectal Cancer

Author: Alberto Arcediano, Ricardo González del Val, Antonio Colmenarejo, Antonieta Salud, Xavier Marfà, Mauro Oruezabal, V. Guillem, Javier Cassinello, Pilar Escudero, Eduardo Pujol, José Valero, Fernando Marcos, Inés García, and Ramón Pérez-Carrión
Subjects: Adult, Diarrhea, Male, medicine.medical_specialty, Neutropenia, Organoplatinum Compounds, Colorectal cancer, Leucovorin, Phases of clinical research, Antineoplastic Agents, Adenocarcinoma, Gastroenterology, Drug Administration Schedule, Bolus (medicine), Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Infusions, Intravenous, Aged, business.industry, Middle Aged, medicine.disease, Oxaliplatin, Regimen, Treatment Outcome, Oncology, Tolerability, Fluorouracil, Anesthesia, Injections, Intravenous, Disease Progression, Female, Colorectal Neoplasms, business, medicine.drug
Abstract: This study was designed to evaluate the safety and tolerability of oxaliplatin combined with weekly boluses of 5-fluorouracil (5-FU) and low doses of leucovorin (LV) and to determine objective response, progression-free survival, and overall survival of patients with previously untreated advanced colorectal cancer. Seventy-nine patients enrolled in an observational, multicenter, prospective, open-label phase II study received intravenous (I.V.) infusions of oxaliplatin 85 mg/m 2 over the course of 2 hours on days 1 and 14 and LV 20 mg/m 2 over the course of 2 hours and 5-FU 500 mg/m 2 as a bolus on days 1, 7, and 14 every 4 weeks until disease progression or unacceptable toxicity occurred. Seventy-nine patients were evaluable for safety, and data from 70 patients were used for efficacy analysis. The objective response rate was 51.4%. Complete responses occurred in 7 patients (10%), and partial responses occurred in 29 patients (41.4%). Disease control, defined as response or stable disease, was obtained in 56 of 70 patients (80%). The median duration of response was 8.34 weeks (range, 7.3-11.5 weeks). The median time to progression was 7.13 months (range, 6.28–7.72 months), and median overall survival time was 15 months (range, 12.32-18.37 months). Acute dose-limiting toxicities were grade 3/4 diarrhea and neutropenia, which occurred in 10.5% and 3.9% of patients, respectively. Among the 70 patients who experienced neurosensory toxicity, it was estimated that only 1.3% had grade 3 symptoms. Preliminary data showed that the regimen is at least as active as other regimens combining oxaliplatin and infusional schedules of 5-FU and might be more convenient for patients because it avoids the need for I.V. catheter implantation.
Published: 2003
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45. Correlation of hypertension and proteinuria with outcome in elderly bevacizumab treated patients with metastatic colorectal cancer

Author: Ramon Perez-Carrion, Jaime Feliu, Alberto Carmona, Maria Jose Safont, Ana Custodio, Joan Maurel, Ferran Losa, Carlos Bosch, Pilar Escudero, Jorge Aparicio, Mónica Jorge, Carlos García-Girón, Antonieta Salud, Uriel Bohn, Enrique Casado, [Feliu, Jaime, Custodio, Ana B.] Hosp Univ La Paz, Serv Oncol Med, Madrid, Spain, and [Casado, Enrique] Hosp Infanta Sofia, Serv Oncol Med, Madrid, Spain
Subjects: Oncology, Male, Pathology, genetic structures, Organoplatinum Compounds, Colorectal cancer, Secondary hypertension, lcsh:Medicine, Deoxycytidine, Metastasis, Antineoplastic Combined Chemotherapy Protocols, lcsh:Science, Aged, 80 and over, Multidisciplinary, Proteinuria, humanities, Bevacizumab, Oxaliplatin, Treatment Outcome, Hypertension, Female, Fluorouracil, medicine.symptom, Colorectal Neoplasms, medicine.drug, Research Article, medicine.medical_specialty, Antibodies, Monoclonal, Humanized, Disease-Free Survival, Clinical Trials, Phase II as Topic, Internal medicine, medicine, Humans, Capecitabine, Aged, Retrospective Studies, business.industry, lcsh:R, Retrospective cohort study, medicine.disease, eye diseases, digestive system diseases, Clinical trial, Multivariate Analysis, lcsh:Q, business
Abstract: Background Studies suggest a relationship between hypertension and outcome in bevacizumab-treated patients with metastatic colorectal cancer (mCRC). We performed a retrospective analysis of two phase II studies (BECA and BECOX) to determine if hypertension and proteinuria predict outcome in elderly patients with mCRC treated with bevacizumab. Patients and Methods Patients >= 70 years of age received either capecitabine 1250 mg/m(2) bid days 1-14 + bevacizumab 7.5 mg/kg day 1 every 21 days (BECA study) or capecitabine 1000 mg/m(2) bid days 1-14 with bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m(2) day 1 (BECOX study). The primary objective was to correlate hypertension and proteinuria with overall response rate (ORR), time to progression (TTP) and overall survival (OS). Secondary objectives included identification of risk factors associated with the development of hypertension and proteinuria and determining whether development of hypertension or proteinuria in the first 2 cycles was related to ORR, disease-control rate (DCR), TTP or OS. Results In total, 127 patients (median age 75.5 years) were included in the study. Hypertension correlated with DCR and OS; proteinuria correlated with ORR and DCR. Proteinuria or hypertension in the first 2 cycles did not correlate with efficacy. Risk factors for hypertension were female gender (odds ratio [OR] 0.241; P = 0.011) and more bevacizumab cycles (OR 1.112; P = 0.002); risk factors for proteinuria were diabetes (OR 3.869; P = 0.006) and more bevacizumab cycles (OR 1.181; P
Published: 2015

46. Phase II study of a fixed dose-rate infusion of gemcitabine associated with uracil/tegafur in advanced carcinoma of the pancreas

Author: J. Dorta, R. Mel, M. González Barón, M. Bolaños, Eugenia Espinosa, L. López Gómez, J. Feliu, P. Borrega, Pilar Escudero, Javier de Castro, and Sergio Vazquez-Estevez
Subjects: Adult, Male, medicine.medical_specialty, Pancreatic disease, Maximum Tolerated Dose, medicine.medical_treatment, Phases of clinical research, Adenocarcinoma, Neutropenia, Deoxycytidine, Gastroenterology, Tegafur, Statistics, Nonparametric, Metastatic carcinoma, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Humans, Medicine, Neoplasm Invasiveness, Infusions, Intravenous, Uracil, Survival analysis, Aged, Neoplasm Staging, Probability, Chemotherapy, Dose-Response Relationship, Drug, business.industry, Biopsy, Needle, Hematology, Middle Aged, medicine.disease, Survival Analysis, Gemcitabine, Surgery, Pancreatic Neoplasms, Treatment Outcome, Oncology, Female, business, Follow-Up Studies, medicine.drug
Abstract: Background: The objectives of this study were to evaluate the efficacy and toxicity of a fixed doserate infusion of gemcitabine associated with uracil/tegafur (UFT) in patients with advanced adenocarcinoma of the pancreas. Patients and methods: Forty-three chemotherapy-naive patients with adenocarcinoma of the pancreas were included in this phase II study. All of whom had a Karnofsky performance status ≥50 and bidimensionally measurable disease (either advanced non-resectable or metastatic); median age 59 years (range 39–77); male:female ratio 29:14. Eight patients (19%) had locally advanced disease and 35 (81%) distant metastases. Treatment consisted of gemcitabine 1200 mg/m 2 given as a 120-min infusion weekly for 3 consecutive weeks, plus oral UFT 400 mg/m 2 /day (in 2–3 doses per day) on days 1–21, cycles were given every 28 days. Measurements of efficacy included response rate, clinical benefit response, time to disease progression and overall survival. Results: A total of 192 cycles of chemotherapy were delivered with a median of four per patient. There were two complete responses (5%) and 12 partial responses (28%), producing an overall response rate of 33% [95% confidence interval (CI) 16% to 49%]. Thirteen patients (30%) had stable disease, whereas 16 (37%) had a progression. The median time to progression was 6 months and the median overall survival was 11 months. Twenty-five patients (64%, 95% CI 47% to 78%) experienced a clinical benefit response. Grade 3–4 WHO toxicities were: neutropenia in nine patients (21%); thrombocytopenia in four (9%); anaemia in five (12%); diarrhoea in four (9%); and asthenia in one (2%). Conclusions: A fixed dose-rate infusion of gemcitabine associated with UFT was well tolerated and showed promising activity in patients with locally advanced or metastatic carcinoma of the pancreas. This is an appropriate palliative treatment in this setting.
Published: 2002
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47. Phase II randomized trial of capecitabine + radiation therapy with/without bevacizumab as preoperative treatment for patients with resectable locally advanced rectal adenocarcinoma: Final results of 3 and 5-year disease free survival, distant relapse free survival and overall survival

Author: Amalia Palacios, Sebastiano Biondo, Beatriz García-Paredes, E. Aranda Aguilar, Ferran Losa, Jesús Gallego, Vicente Alonso, M.J. Safont, Laura Layos, Auxiliadora Gómez-España, Pilar Escudero, Cristina Grávalos, Jaume Capdevila, Carles Pericay, R. Salazar, M. Martínez-Villacampa, and C. López López
Subjects: Oncology, medicine.medical_specialty, Bevacizumab, business.industry, medicine.medical_treatment, Locally advanced, Distant relapse, Hematology, Surgery, law.invention, Radiation therapy, Capecitabine, Randomized controlled trial, law, Internal medicine, Overall survival, medicine, Rectal Adenocarcinoma, business, medicine.drug
Published: 2017
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48. Role of circulating tumor cells as prognostic marker in resected stage III colorectal cancer

Author: M.L. Maestro, C. Lopez, Javier Sastre, Eduardo Díaz-Rubio, Silvia Veganzones, Ruth Vera, Elena Elez, Pilar García-Alfonso, Jose María Vieitez, J. Gallego-Plazas, P. Ballesteros, Cristina Grávalos, Miguel Sotelo, Enrique Aranda, Amelia López-Ladrón, Pilar Escudero, Carles Pericay, P. Vicente, Antonio Arrivi, and Vicente Alonso
Subjects: Oncology, Adult, Male, medicine.medical_specialty, Colorectal cancer, Population, CA 15-3, Circulating tumor cell, Internal medicine, Adjuvant therapy, Biomarkers, Tumor, Medicine, Humans, Prospective Studies, Stage (cooking), education, neoplasms, Aged, Neoplasm Staging, Aged, 80 and over, education.field_of_study, business.industry, Hematology, Middle Aged, medicine.disease, Neoplastic Cells, Circulating, Prognosis, Primary tumor, digestive system diseases, CA19-9, Female, business, Colorectal Neoplasms, Follow-Up Studies
Abstract: This is the first study that seeks to establish the prognostic value of circulating tumor cell (CTC) (determined by CellSearch system) in patients with stage III CRC. Our results suggest that given the low number of CTC in patients with localized CRC and the particular pattern of metastatic dissemination in patients with CRC, it is likely that CTC does not have a prognostic role in this setting. Background The prognostic role of circulating tumor cells (CTC) in early colorectal cancer (CRC) has not been determined yet. We evaluated the potential prognostic value of CTC in stage III CRC patients. Patients and methods Prospective multicenter study of 519 patients with stage III CRC recruited between January 2009 and June 2010. CTC were enumerated with the CellSearch System after primary tumor resection and before the start of adjuvant therapy. A total of 472 patients were included in the analysis. Results CTC ≥1, ≥2, ≥3 and ≥5 were detected in 166 (35%), 93 (20%), 57 (12%) and 34 (7%) patients, respectively. Median follow-up was 40 months. In the overall population, CTC ≥1 (disease-free survival (DFS): HR 0.97,P = 0.85; overall survival (OS): HR 1.03,P = 0.89), ≥2 (DFS: HR 1.07,P = 0.76; OS: HR 1.02,P = 0.95), ≥3 (DFS: HR 0.96,P = 0.87; OS: HR 0.74,P = 0.41) and ≥5 (DFS: HR 0.72,P = 0.39; OS: HR 0.48,P = 0.21) were not associated with worse DFS and OS. No clinicopathological characteristics were significantly associated with the presence of CTC. In patients with disease relapse, the proportion with CTC ≥1 was not significantly different between those with single versus multiple metastatic locations (37.9% versus 31.4%,P = 0.761). In the multivariate analysis, CTC ≥1 was not an independent prognostic factor for DFS (HR 0.97,P = 0.87) and OS (HR 0.96,P = 0.89). Conclusion CTC detection was not associated with worse DFS and OS in patients with stage III CRC. Given the scarcity of CTC in these patients, it is likely that CTC determined by CellSearch system does not have a prognostic role in this setting. However, a longer follow-up is needed.
Published: 2014

49. Protective effects of melatonin in reducing oxidative stress and in preserving the fluidity of biological membranes: a review

Author: Laura López-Pingarrón, J. M. Ramirez, Joaquin J. Garcia, Pilar Escudero, Alejandro Tres, Dun Xian Tan, Milagros Bernal-Pérez, Francisco A. García-Gil, Priscilla Almeida-Souza, and Russel J. Reiter
Subjects: Aging, Antioxidant, Free Radicals, Membrane Fluidity, medicine.medical_treatment, Lipid Bilayers, Biology, medicine.disease_cause, Antioxidants, Melatonin, Lipid peroxidation, chemistry.chemical_compound, Mice, Endocrinology, medicine, Membrane fluidity, Animals, Humans, chemistry.chemical_classification, Glutathione Peroxidase, Glutathione peroxidase, Biological membrane, Glutathione, Oxidative Stress, Glutathione Reductase, chemistry, Biochemistry, Lipid Peroxidation, Oxidative stress, medicine.drug
Abstract: Free radicals generated within subcellular compartments damage macromolecules which lead to severe structural changes and functional alterations of cellular organelles. A manifestation of free radical injury to biological membranes is the process of lipid peroxidation, an autooxidative chain reaction in which polyunsaturated fatty acids in the membrane are the substrate. There is considerable evidence that damage to polyunsaturated fatty acids tends to reduce membrane fluidity. However, adequate levels of fluidity are essential for the proper functioning of biological membranes. Thus, there is considerable interest in antioxidant molecules which are able to stabilize membranes because of their protective effects against lipid peroxidation. Melatonin is an indoleamine that modulates a wide variety of endocrine, neural and immune functions. Over the last two decades, intensive research has proven this molecule, as well as its metabolites, to possess substantial antioxidant activity. In addition to their ability to scavenge several reactive oxygen and nitrogen species, melatonin increases the activity of the glutathione redox enzymes, that is, glutathione peroxidase and reductase, as well as other antioxidant enzymes. These beneficial effects of melatonin are more significant because of its small molecular size and its amphipathic behaviour, which facilitates ease of melatonin penetration into every subcellular compartment. In the present work, we review the current information related to the beneficial effects of melatonin in maintaining the fluidity of biological membranes against free radical attack, and further, we discuss its implications for ageing and disease.
Published: 2014

50. Phase I trial of weekly irinotecan combined with UFT as second-line treatment for advanced colorectal cancer

Author: Antonio Antón, A. Sáenz, M.D. Isla, Pilar Escudero, Jose I. Mayordomo, Vicente Alonso, J Martinez-Trufero, Alejandro Tres, M Zorrilla, and A. Herrero
Subjects: Adult, Diarrhea, Male, Cancer Research, medicine.medical_specialty, Colorectal cancer, medicine.drug_class, medicine.medical_treatment, Administration, Oral, Irinotecan, Antimetabolite, Gastroenterology, Tegafur, Cohort Studies, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Infusions, Intravenous, Uracil, Aged, Chemotherapy, Dose-Response Relationship, Drug, business.industry, Middle Aged, medicine.disease, Surgery, Oncology, Toxicity, Disease Progression, Camptothecin, Female, Colorectal Neoplasms, business, Febrile neutropenia, Progressive disease, Follow-Up Studies, medicine.drug
Abstract: The aim of this study was to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly Irinotecan (CPT-11) plus UFT, and to assess the antitumour activity of this combination as second-line chemotherapy in patients with advanced colorectal carcinoma, 31 patients with measurable advanced colorectal carcinoma were treated. Cohorts of 3 patients received increasing dose levels of the combination. Levels 1 to 4 included a fixed dose of oral (p.o.) UFT (250 mg/m(2)/day) for 21 days of a 28-day cycle combined with increasing intravenous (i.v.) doses of CPT-11 (80, 100, 110 and 120 mg/m(2)) on days 1, 8 and 15. Levels 5 and 6 included a higher fixed dose of oral UFT (300 mg/m(2)) combined with increasing i.v. doses of CPT-11 (100 and 110 mg/m(2)) on days 1, 8 and 15. 147 courses were administered. MTD were reached at level 4 (2 cases of grade 4 diarrhoea and 1 grade 3 asthenia), and level 6 (1 grade 4 diarrhoea, 1 grade 3 diarrhoea and 1 grade 3 febrile neutropenia). Responses in 30 evaluable patients were: 3 partial responses (10%), 15 stable disease (50%) and progressive disease in 12 patients (40%). Median time to progression was 4.5 months (95% Confidence Interval (CI): 3.4-6.6 months) and median survival was 11 months (95% CI: 7.9-14.1 months). The recommended doses for phase II trials are: (a) CPT-11 110 mg/m(2) i.v. on days 1, 8 and 15 every 28 days plus UFT 250 mg/m(2) p.o. on days 1 through to 21 or (b) CPT-11 100 mg/m(2) and UFT 300 mg/m(2).
Published: 2001
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