Imaging heterogeneity of peptide delivery and binding in solid tumors using SPECT imaging and MRI

Background: As model system, a solid-tumor patient-derived xenograft (PDX) model characterized by high peptide receptor expression and histological tissue homogeneity was used to study radiopeptide targeting. In this solid-tumor model, high tumor uptake of targeting peptides was expected. However, in vivo SPECT images showed substantial heterogeneous radioactivity accumulation despite homogenous receptor distribution in the tumor xenografts as assessed by in vitro autoradiography. We hypothesized that delivery of peptide to the tumor cells is dictated by adequate local tumor perfusion. To study this relationship, sequential SPECT/CT and MRI were performed to assess the role of vascular functionality in radiopeptide accumulation. Methods: High-resolution SPECT and dynamic contrast-enhanced (DCE)-MRI were acquired in six mice bearing PC295 PDX tumors expressing the gastrin-releasing peptide (GRP) receptor. Two hours prior to SPECT imaging, animals received 25 MBq 111In(DOTA-(βAla)2-JMV594) (25 pmol). Images were acquired using multipinhole SPECT/CT. Directly after SPECT imaging, MR images were acquired on a 7.0-T dedicated animal scanner. DCE-MR images were quantified using semi-quantitative and quantitative models. The DCE-MR and SPECT images were spatially aligned to compute the correlations between radioactivity and DCE-MRI-derived parameters over the tumor. Results: Whereas histology, in vitro autoradiography, and multiple-weighted MRI scans all showed homogenous tissue characteristics, both SPECT and DCE-MRI showed heterogeneous distribution patterns throughout the tumor. The average Spearman’s correlation coefficient between SPECT and DCE-MRI ranged from 0.57 to 0.63 for the “exchange-related” DCE-MRI perfusion parameters. Conclusions: A positive correlation was shown between exchange-related DCE-MRI perfusion parameters and the amount of radioactivity accumulated as measured by SPECT, demonstrating that vascular function was an important aspect of radiopeptide distribution in solid tumors. The combined use of SPECT and MRI added crucial information on the perfusion efficiency versus radiopeptide upt

Benefit and Risks of Aspirin in Addition to Ticagrelor in Acute Coronary Syndromes:A Post Hoc Analysis of the Randomized GLOBAL LEADERS Trial

Key PointsQuestionWhat are the benefits and risks of continuing aspirin in addition to P2Y12 receptor inhibition with ticagrelor among patients with acute coronary syndrome between 1 month and 12 months after percutaneous coronary intervention? FindingsIn this nonprespecified, post hoc analysis of the GLOBAL LEADERS randomized clinical trial, beyond 1 month after percutaneous coronary intervention in acute coronary syndrome, aspirin was associated with increased bleeding risk and appeared not to add to the benefit of ticagrelor on ischemic events. MeaningThe findings of this hypothesis-generating analysis pave the way for further trials evaluating aspirin-free antiplatelet strategies after percutaneous coronary intervention. ImportanceThe role of aspirin as part of antiplatelet regimens in acute coronary syndromes (ACS) needs to be clarified in the context of newer potent P2Y12 antagonists. ObjectiveTo evaluate the benefit and risks of aspirin in addition to ticagrelor among patients with ACS beyond 1 month after percutaneous coronary intervention (PCI). Design, Setting, and ParticipantsThis is a nonprespecified, post hoc analysis of GLOBAL LEADERS, a randomized, open-label superiority trial comparing 2 antiplatelet treatment strategies after PCI. The trial included 130 secondary/tertiary care hospitals in different countries, with 15991 unselected patients with stable coronary artery disease or ACS undergoing PCI. Patients had outpatient visits at 1, 3, 6, 12, 18, and 24 months after index procedure. InterventionsThe experimental group received aspirin plus ticagrelor for 1 month followed by 23-month ticagrelor monotherapy; the reference group received aspirin plus either clopidogrel (stable coronary artery disease) or ticagrelor (ACS) for 12 months, followed by 12-month aspirin monotherapy. In this analysis, we examined the clinical outcomes occurring between 31 days and 365 days after randomization, specifically in patients with ACS who, within this time frame, were assigned to receive either ticagrelor alone or ticagrelor and aspirin. Main Outcomes and MeasuresThe primary outcome was the composite of all-cause death or new Q-wave myocardial infarction. ResultsOf 15968 participants, there were 7487 patients with ACS enrolled; 3750 patients were assigned to the experimental group and 3737 patients to the reference group. Between 31 and 365 days after randomization, the primary outcome occurred in 55 patients (1.5%) in the experimental group and in 75 patients (2.0%) in the reference group (hazard ratio [HR], 0.73; 95% CI, 0.51-1.03; P=.07); investigator-reported Bleeding Academic Research Consortium-defined bleeding type 3 or 5 occurred in 28 patients (0.8%) in the experimental group and in 54 patients (1.5%) in the reference arm (HR, 0.52; 95% CI, 0.33-0.81; P=.004). Conclusions and RelevanceBetween 1 month and 12 months after PCI in ACS, aspirin was associated with increased bleeding risk and appeared not to add to the benefit of ticagrelor on ischemic events. These findings should be interpreted as exploratory and hypothesis generating; however, they pave the way for further trials evaluating aspirin-free antiplatelet strategies after PCI. Trial RegistrationClinicalTrials.gov identifier: NCT01813435. This secondary analysis of the GLOBAL LEADERS randomized clinical trial evaluates the benefit and risks of aspirin in addition to ticagrelor among patients with acute coronary syndrome beyond 1 month after percutaneous coronary intervention

Preclinical Comparison of Al18F- and 68Ga-Labeled Gastrin-Releasing Peptide Receptor Antagonists for PET Imaging of Prostate Cancer

International audienceGastrin-releasing peptide receptor (GRPR) is overexpressed in human prostate cancer and is being used as a target for molecular imaging. In this study, we report on the direct comparison of 3 novel GRPR-targeted radiolabeled tracers: Al18F-JMV5132, 68Ga-JMV5132, and 68Ga-JMV4168 (JMV5132 is NODA-MPAA-βAla-βAla-[H-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2], JMV4168 is DOTA-βAla-βAla-[H-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2], and NODA-MPAA is 2-[4-(carboxymethyl)-7-{[4-(carboxymethyl)phenyl]methyl}-1,4,7-triazacyclononan-1-yl]acetic acid). Methods: The GRPR antagonist JMV594 (H-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) was conjugated to NODA-MPAA for labeling with Al18F. JMV5132 was radiolabeled with 68Ga and 18F, and JMV4168 was labeled with 68Ga for comparison. The inhibitory concentration of 50% values for binding GRPR of JMV4168, JMV5132, natGa-JMV4168, and natGa-JMV5132 were determined in a competition-binding assay using GRPR-overexpressing PC-3 tumors. The tumor-targeting characteristics of the compounds were assessed in mice bearing subcutaneous PC-3 xenografts. Small-animal PET/CT images were acquired, and tracer biodistribution was determined by ex vivo measurements. Results: JMV5132 was labeled with 18F in a novel 1-pot, 1-step procedure within 20 min, without need for further purification and resulting in a specific activity of 35 MBq/nmol. Inhibitory concentration of 50% values (in nM) for GRPR binding of JMV5132, JMV4168, natGa-JMV5132, natGa-JMV4168, and AlnatF-JMV5132 were 6.8 (95% confidence intervals [CIs], 4.6–10.0), 13.2 (95% CIs, 5.9–29.3), 3.0 (95% CIs, 1.5–6.0), 3.2 (95% CIs, 1.8–5.9), and 10.0 (95% CIs, 6.3–16.0), respectively. In mice with subcutaneous PC-3 xenografts, all tracers cleared rapidly from the blood, exclusively via the kidneys for 68Ga-JMV4168 and partially hepatobiliary for 68Ga-JMV5132 and Al18F-JMV5132. Two hours after injection, the uptake of 68Ga-JMV4168, 68Ga-JMV5132, and Al18F-JMV5132 in PC-3 tumors was 5.96 ± 1.39, 5.24 ± 0.29, 5.30 ± 0.98 (percentage injected dose per gram), respectively. GRPR specificity was confirmed by significantly reduced tumor uptake of the 3 tracers after coinjection of a 100-fold excess of unlabeled JMV4168 or JMV5132. Small-animal PET/CT clearly visualized PC-3 tumors, with the highest resolution observed for Al18F-JMV5132. Conclusion: JMV5132 could be rapidly and efficiently labeled with 18F. Al18F-JMV5132, 68Ga-JMV5132, and 68Ga-JMV4168 all showed comparable high and specific accumulation in GRPR-positive PC-3 tumors. These new PET tracers are promising candidates for future clinical translation

Blunting periprocedural myocardial necrosis: Rationale and design of the randomized ALPHEUS study

International audienceBackground: Clopidogrel associated with aspirin is the recommended treatment for patients undergoing elective percutaneous coronary intervention (PCI). Although severe PCI-related events are rare, evidence suggests that PCI-related myocardial infarction and myocardial injury are frequent complications that can impact the clinical prognosis of the patients. Antiplatelet therapy with a potent P2Y12 receptor inhibitor such as ticagrelor may reduce periprocedural ischemic complications while maintaining a similar safety profile as compared with conventional dual antiplatelet therapy by aspirin and clopidogrel in this setting. Methods: Assessment of Loading with the P2Y12 inhibitor ticagrelor or clopidogrel to Halt ischemic Events in patients Undergoing elective coronary Stenting (ALPHEUS) (NCT02617290) is an international, multicenter, randomized, parallel-group, open-label study in patients with stable coronary artery disease who are planned for an elective PCI. In total, 1,900 patients will be randomized before a planned PCI to a loading dose of ticagrelor 180 mg or a loading dose of clopidogrel (300 or 600 mg) in addition to aspirin. Patients will then receive a dual antiplatelet therapy with aspirin and ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 30 days. The primary ischemic end point is PCI-related myocardial infarction (myocardial infarction type 4a or 4b) or major myocardial injury within 48 hours (or at hospital discharge if earlier) after elective PCI/stent. Safety will be evaluated by major bleeding events (Bleeding Academic Research Consortium type 3 or 5) at 48 hours (or discharge if it occurs earlier). Conclusion: ALPHEUS is the first properly sized trial comparing ticagrelor to clopidogrel in the setting of elective PCI and is especially designed to show a reduction in periprocedural events, a surrogate end point for mortality

Benefit and risks of aspirin in addition to ticagrelor in acute coronary syndromes: a post hoc analysis of the randomized global leaders trial

What are the benefits and risks of continuing aspirin in addition to P2Y12 receptor inhibition with ticagrelor among patients with acute coronary syndrome between 1 month and 12 months after percutaneous coronary intervention? FindingsIn this nonprespecified, post hoc analysis of the GLOBAL LEADERS randomized clinical trial, beyond 1 month after percutaneous coronary intervention in acute coronary syndrome, aspirin was associated with increased bleeding risk and appeared not to add to the benefit of ticagrelor on ischemic events. MeaningThe findings of this hypothesis-generating analysis pave the way for further trials evaluating aspirin-free antiplatelet strategies after percutaneous coronary intervention. ImportanceThe role of aspirin as part of antiplatelet regimens in acute coronary syndromes (ACS) needs to be clarified in the context of newer potent P2Y12 antagonists. ObjectiveTo evaluate the benefit and risks of aspirin in addition to ticagrelor among patients with ACS beyond 1 month after percutaneous coronary intervention (PCI). Design, Setting, and ParticipantsThis is a nonprespecified, post hoc analysis of GLOBAL LEADERS, a randomized, open-label superiority trial comparing 2 antiplatelet treatment strategies after PCI. The trial included 130 secondary/tertiary care hospitals in different countries, with 15991 unselected patients with stable coronary artery disease or ACS undergoing PCI. Patients had outpatient visits at 1, 3, 6, 12, 18, and 24 months after index procedure. InterventionsThe experimental group received aspirin plus ticagrelor for 1 month followed by 23-month ticagrelor monotherapy; the reference group received aspirin plus either clopidogrel (stable coronary artery disease) or ticagrelor (ACS) for 12 months, followed by 12-month aspirin monotherapy. In this analysis, we examined the clinical outcomes occurring between 31 days and 365 days after randomization, specifically in patients with ACS who, within this time frame, were assigned to receive either ticagrelor alone or ticagrelor and aspirin. Main Outcomes and MeasuresThe primary outcome was the composite of all-cause death or new Q-wave myocardial infarction. ResultsOf 15968 participants, there were 7487 patients with ACS enrolled; 3750 patients were assigned to the experimental group and 3737 patients to the reference group. Between 31 and 365 days after randomization, the primary outcome occurred in 55 patients (1.5%) in the experimental group and in 75 patients (2.0%) in the reference group (hazard ratio [HR], 0.73; 95% CI, 0.51-1.03; P=.07); investigator-reported Bleeding Academic Research Consortium-defined bleeding type 3 or 5 occurred in 28 patients (0.8%) in the experimental group and in 54 patients (1.5%) in the reference arm (HR, 0.52; 95% CI, 0.33-0.81; P=.004). Conclusions and RelevanceBetween 1 month and 12 months after PCI in ACS, aspirin was associated with increased bleeding risk and appeared not to add to the benefit of ticagrelor on ischemic events. These findings should be interpreted as exploratory and hypothesis generating; however, they pave the way for further trials evaluating aspirin-free antiplatelet strategies after PCI. Trial RegistrationClinicalTrials.gov identifier: NCT01813435. This secondary analysis of the GLOBAL LEADERS randomized clinical trial evaluates the benefit and risks of aspirin in addition to ticagrelor among patients with acute coronary syndrome beyond 1 month after percutaneous coronary intervention.4111092110

Correction to: Surgery and outcome of infective endocarditis in octogenarians: prospective data from the ESC EORP EURO-ENDO registry (Infection, (2022), 50, 5, (1191-1202), 10.1007/s15010-022-01792-0)

In this article the “EURO-ENDO Investigators group” member U. Y. Sinan was incorrectly written as U.S. Yasar. The original article has been corrected

Surgery and outcome of infective endocarditis in octogenarians: prospective data from the ESC EORP EURO-ENDO registry

none912Purpose: High mortality and a limited performance of valvular surgery are typical features of infective endocarditis (IE) in octogenarians, even though surgical treatment is a major determinant of a successful outcome in IE. Methods: Data from the prospective multicentre ESC EORP EURO-ENDO registry were used to assess the prognostic role of valvular surgery depending on age. Results: As compared to < 80 yo patients, ≥ 80 yo had lower rates of theoretical indication for valvular surgery (49.1% vs. 60.3%, p < 0.001), of surgery performed (37.0% vs. 75.5%, p < 0.001), and a higher in-hospital (25.9% vs. 15.8%, p < 0.001) and 1-year mortality (41.3% vs. 22.2%, p < 0.001). By multivariable analysis, age per se was not predictive of 1-year mortality, but lack of surgical procedures when indicated was strongly predictive (HR 2.98 [2.43-3.66]). By propensity analysis, 304 ≥ 80 yo were matched to 608 < 80 yo patients. Propensity analysis confirmed the lower rate of indication for valvular surgery (51.3% vs. 57.2%, p = 0.031) and of surgery performed (35.3% vs. 68.4%, p < 0.0001) in ≥ 80 yo. Overall mortality remained higher in ≥ 80 yo (in-hospital: HR 1.50[1.06-2.13], p = 0.0210; 1-yr: HR 1.58[1.21-2.05], p = 0.0006), but was not different from that of < 80 yo among those who had surgery (in-hospital: 19.7% vs. 20.0%, p = 0.4236; 1-year: 27.3% vs. 25.5%, p = 0.7176). Conclusion: Although mortality rates are consistently higher in ≥ 80 yo patients than in < 80 yo patients in the general population, mortality of surgery in ≥ 80 yo is similar to < 80 yo after matching patients. These results confirm the importance of a better recognition of surgical indication and of an increased performance of surgery in ≥ 80 yo patients.nonePazdernik, Michal; Iung, Bernard; Mutlu, Bulent; Alla, François; Riezebos, Robert; Kong, William; Nunes, Maria Carmo Pereira; Pierard, Luc; Srdanovic, Ilija; Yamada, Hirotsugu; De Martino, Andrea; Miglioranza, Marcelo Haertel; Magne, Julien; Piper, Cornelia; Laroche, Cécile; Maggioni, Aldo P; Lancellotti, Patrizio; Habib, Gilbert; Selton-Suty, Christine, EURO-ENDO Investigators group: R Ronderos, G Avegliano, P Fernandez Oses, E Filipini, I Granada, A Iribarren, M Mahia, F Nacinovich, S Ressi, R Obregon, M Bangher, J Dho, L Cartasegna, M L Plastino, V Novas, C Shigel, G Reyes, M De Santos, N Gastaldello, M Granillo Fernandez, M Potito, G Streitenberger, P Velazco, J H Casabé, C Cortes, E Guevara, F Salmo, M Seijo, F Weidinger, M Heger, R Brooks, C Stöllberger, C-Y Ho, L Perschy, L Puskas, G Goliasch, C Binder, R Rosenhek, M Schneider, M-P Winter, E Hoffer, M Melissopoulou, E Lecoq, D Legrand, S Jacquet, M Massoz, P Lancellotti, L Pierard, R Dulgheru, S Marchetta, C D Emal, C Oury, B Cosyns, S Droogmans, D Kerkhove, A Motoc, D Plein, B Roosens, L Soens, C Weytjens, I Lemoine, I Rodrigus, B Paelinck, B Amsel, P Unger, D Konopnicki, C Beauloye, A Pasquet, S Pierard, D Vancraeynest, J L Vanoverschelde, F Sinnaeve, J L Andrade, A C Tude Rodrigues, K Staszko, R Dos Santos Monteiro, M H Miglioranza, D L Shuha, M Alcantara, V Cravo, L Fazzio, A Felix, M Iso, C Musa, A P Siciliano, F Villaca Filho, J Braga, A Rodrigues, R Silva, F Vilela, D Rodrigues, L Silva, S Morhy, C Fischer, R Silva, M Vieira, T Afonso, J Abreu, S N Falcao, V Moises, A Gouvea, G João, F Mancuso, C Silva, A C Souza, C S Abboud, R Bellio de Mattos Barretto, A Ramos, R Arnoni, J E Assef, D J Della Togna, D Le Bihan, L Miglioli, A P Romero Oliveira, R Tadeu Magro Kroll, D Cortez, C L Gelape, M D C Peirira Nunes, T C De Abreu Ferrari, K-L Chan, K Hay, V Le, M Page, F Poulin, C Sauve, K Serri, C Mercure, J Beaudoin, P Pibarot, I Sebag, L Rudski, G Ricafort, B Barsic, V Krajinovic, M Vargovic, J Separovic-Hanzevacki, D Lovric, V Reskovic-Luksic, J Vincelj, S Jaksic Jurinjak, V Yiannikourides, M Ioannides, C Kyriakou, C Pofaides, V Masoura, K Yiangou, J Pudich, A Linhart, M Siranec, J Marek, K Blechova, M Kamenik, M Pazdernik, R Pelouch, Z Coufal, M Mikulica, M Griva, E Jancova, M Mikulcova, M Taborsky, J Precek, M Jecmenova, J Latal, J Widimsky, T Butta, S Machacek, R Vancata, J Spinar, M Holicka, F Pow Chon Long, N Anzules, A Bajana Carpio, G Largacha, E Penaherrera, D Moreira, E Mahfouz, E Elsafty, A Soliman, Y Zayed, J Aboulenein, M Abdel-Hay, A Almaghraby, M Abdelnaby, M Ahmed, B Hammad, Y Saleh, H Zahran, O Elgebaly, A Saad, M Ali, A Zeid, R El Sharkawy, M Meshaal, A Al Kholy, R Doss, D Osama, H Rizk, A Elmogy, M Mishriky, P Assayag, S El Hatimi, Saint- E Botelho-Nevers, S Campisi, J-F Fuzellier, A Gagneux-Brunon, R Pierrard, C Tulane, M Detoc, T Mehalla, D Boutoille, O Al Habash, N Asseray-Madani, C Biron, J Brochard, J Caillon, C Cueff, T Le Tourneau, A S Lecompte, R Lecomte, M Lefebvre, M M Magali Michel, S Pattier, S Delarue, M Le Bras, J Orain, J-F Faucher, V Aboyans, A Beeharry, H Durox, M Lacoste, J Magne, D Mohty, A David, V Pradel, V Sierra, A Neykova, B Bettayeb, S Elkentaoui, B Tzvetkov, G Landry, C Strady, K Ainine, S Baumard, C Brasselet, C Tassigny, V Valente-Pires, M Lefranc, B Hoen, B Lefevre, E Curlier, C Callier, N Fourcade, Y Jobic, S Ansard, R Le Berre, P Le Roux, F Le Ven, M-C Pouliquen, G Prat, F Bouchart, A Savoure, C Alarcon, C Chapuzet, I Gueit, C Tribouilloy, Y Bohbot, F Peugnet, M Gun, B Iung, X Duval, X Lescure, E Ilic-Habensus, N Sadoul, C Selton-Suty, F Alla, E Chevalier, F Goehringer, O Huttin, R Garcia, V Le Marcis, P Tattevin, E Donal, E Flecher, M Revest, G Habib, S Hubert, J-P Casalta, F Gouriet, F Arregle, S Cammilleri, L Tessonnier, A Riberi, C Chirouze, K Bouiller, A-S Brunel, D Fournier, L Hustache-Mathieu, T Klopfenstein, J Moreau, P Lim, L Oliver, J Ternacle, A Moussafeur, P Chavanet, L Piroth, M Buisson, S Mahy, C Martins, A Salmon-Rousseau, S Gohier, C Piper, J Börgermann, D Guckel, D Horstkotte, B Brockmeier, E Winkelmann, A Hagendorff, D Grey, G Nickenig, R Schueler, C Öztürk, E Stöhr, C Hamm, T Walther, R Brandt, A-C Frühauf, C T Hartung, C Hellner, C Wild, M Becker, S Hamada, W Kaestner, K Stangl, F Knebel, G Baldenhofer, A Brecht, H Dreger, C Isner, F Pfafflin, M Stegemann, R Zahn, B Fraiture, C Kilkowski, A-K Karcher, S Klinger, H Tolksdorf, D Tousoulis, C Aggeli, G Sarri, S Sideris, E Venieri, G Athanassopoulos, D Tsiapras, I Armenis, A Koutsiari, G Floros, C Grassos, S Dragasis, L Rallidis, C Varlamos, L Michalis, K Naka, A Bechlioulis, A Kotsia, L Lakkas, K Pappas, C Papadopoulos, S Kiokas, A Lioni, S Misailidou, J Barbetseas, M Bonou, C Kapelios, I Tomprou, K Zerva, A Manolis, E Hamodraka, D Athanasiou, G Haralambidis, L Poulimenos, H Samaras, A Nagy, A Bartykowszki, E Gara, S Sengupta, K Mungulmare, R Kasliwal, M Bansal, A Bhan, S Ranjan, M Kyavar, M Maleki, F Noohi Bezanjani, A Sadeghpour, A Alizadehasl, S Boudagh, A Ghavidel, P Moradnejad, H R Pasha, B Ghadrdoost, D Gilon, J Strahilevitz, S Israel, M Wanounou, C d'Agostino, P Colonna, L De Michele, F Fumarola, M Stante, N Marchionni, V Scheggi, B Alterini, S Del Pace, P Stefano, C Sparano, L P Badano, D Muraru, N Ruozi, R Tenaglia, U Limbruno, A Cresti, P Baratta, M Solari, C Giannattasio, A Moreo, B De Chiara, B Lopez Montero, F Musca, C A Orcese, F Panzeri, C F Russo, F Spano, O Alfieri, M De Bonis, E Agricola, E Busnardo, S Carletti, B Castiglioni, S Chiappetta, B Del Forno, D Ferrara, M Guffanti, G Iaci, E Lapenna, T Nisi, C Oltolini, U Pajoro, R Pasciuta, M Ripa, P Scarpellini, C Tassan Din, R Meneghin, D Schiavi, F Piscione, R Citro, R M Benvenga, L Greco, C Prota, I Radano, L Soriente, M Bellino, D Di Vece, F Santini, A Salsano, G M Olivieri, F Turrini, R Messora, S Tondi, A Olaru, V Agnoletto, L Grassi, C Leonardi, S Sansoni, S Del Ponte, G M Actis Dato, A De Martino, N Ohte, S Kikuchi, K Wakami, K Aonuma, Y Seo, T Ishizu, T Machino-Ohtsuka, M Yamamoto, N Iida, H Nakajima, Y Nakagawa, C Izumi, M Amano, M Miyake, K Takahashi, I Shiojima, Y Miyasaka, H Maeba, Y Suwa, N Taniguchi, S Tsujimoto, T Kitai, M Ota, S Yuda, S Sasaki, N Hagiwara, K Yamazaki, K Ashihara, K Arai, C Saitou, S Saitou, G Suzuki, Y Shibata, N Watanabe, S Nishino, K Ashikaga, N Kuriyama, K Mahara, K Abe, H Fujimaki, T Okubo, H Shitan, S Takanashi, M Terada, H Yamamoto, M Sata, H Yamada, K Kusunose, Y Saijo, H Seno, O Yuichiro, Y Sakata, H Mizuno, S Nakatani, T Onishi, K Sengoku, F Sera, S W Park, K Eun Kyoung, L Ga Yeon, J-W Hwang, C Jin-Oh, S-J Park, L Sang-Chol, C Sung-A, S Y Jang, D-H Kang, R Heo, S Lee, J-M Song, E Jung, J Plisiene, A Dambrauskaite, G Gruodyte, R Jonkaitiene, J Vaskelyte, V Mizariene, J Atkocaityte, R Zvirblyte, R Sow, A Codreanu, E C L De la Vega, C Michaux, T Staub, L Jacobs-Orazi, C Mallia Azzopardi, R G Xuereb, T Piscopo, D Borg, R Casha, J Farrugia, M Fenech, E Pllaha, C Vella, K Yamagata, L Grib, E Raevschi, A Grejdieru, G Balan, I Cardaniuc, L Cardaniuc, V Corcea, A Feodorovici, V Gaina, L Girbu, P Jimbei, D Kravcenco, E Panfile, E Prisacari, E Samohvalov, S Samohvalov, N Sceglova, I Benesco, V Marian, N Sumarga, M Mirocevic, B Bozovic, N Bulatovic, P Lakovic, L Music, J Roos-Hesselink, R Budde, T Gamela, A Wahadat, O Kamp, T Meijers, J P Van Melle, V M Deursen, H Crijns, S Bekkers, E Cheriex, M Gilbers, B Kietselaer, C Knackstedt, R Lorusso, S Schalla, S Streukens, S Chamuleau, M-J Cramer, A Teske, T Van der Spoel, A Wind, O Liesbek, J Lokhorst, H Van Heusden, W Tanis, I Van der Bilt, J Vriend, H De Lange-van Bruggen, E Karijodikoro, R Riezebos, E van Dongen, J Schoep, V Stolk, O Axler, F Baumann, S Lebras, T Edvardsen, J T Offstad, J O Beitnes, T Helle-Valle, H Skulstad, R Skardal, N Qamar, S Furnaz, B Ahmed, M H Butt, M F Khanzada, T Saghir, A Wahid, T Hryniewiecki, P Szymanski, K Marzec, M Misztal-Ogonowska, W Kosmala, M Przewlocka-Kosmala, A Rojek, K Woznicka, J Zachwyc, A Lisowska, M Kaminska, J Kasprzak, E Kowalczyk, D F Strzecka, P Wejner-Mik, M Trabulo, P Freitas, S Ranchordas, G Rodrigues, P Pinto, C Queiros, J Azevedo, L Marques, D Seabra, L Branco, J Abreu, M Cruz, A Galrinho, R Moreira, P Rio, A T Timoteo, M Selas, N M Cardim, V Carmelo, B Duque Neves, H Pereira, I Cruz, A Guerra, A Marques, I Pintassilgo, M C Tomescu, N-M Trofenciuc, M Andor, A Bordejevic, H S Branea, F Caruntu, L Cirin, I M Citu, C A Cotoraci, D Darabantiu, R Farcas, I Marincu, A Mavrea, M F Onel, T Parvanescu, D Pop, A L Pop-Moldovan, M I Puticiu, L A Velcean, A Ionac, D Cozma, C Mornos, F Goanta, I Popescu, R Beyer, R Mada, R Rancea, H Rosianu, R Tomoaia, C Stanescu, Z Kobalava, J Karaulova, E Kotova, A Milto, A Pisaryuk, N Povalyaev, M Sorokina, J Alrahimi, A Elshiekh, A Jamiel, A Ahmed, M Al-Mallah, N Attia, B Putnikovic, A Neskovic, A Dimic, B Ivanovic, S Matic, D Trifunovic, J Petrovic, D Kosevic, P Dabic, P Milojevic, I Petrovic, I Stojanovic, I Srdanovic, M Kovacevic, A Redzek, M Stefanovic, S Susak, L Velicki, A Vulin, T C Yeo, W K F Kong, K K Poh, I Vilacosta, M Abd El- Nasser, C Ferrera, C Olmos, F Calvo Iglesias, E Blanco-Gonzalez, M Bravo Amaro, A N Germinas, E Lopez-Rodriguez, J Lugo Adan, P Pazos-Lopez, M Pereira Loureiro, M T Perez, S Raposeiras-Roubin, S Rasheed Yas, M-M Suarez-Varela, F Vasallo Vidal, D Garcia-Dorado, A Sambola, N Fernandez-Hidalgo, T Gonzalez-Alujas, J Lozano, O Maisterra, N Pizzi, R Rios, P Tornos, A Bayes-Genis, L Pedro Botet, N Vallejo, E Berastegui, C Llibre, L Mateu, R Nunez, D Quesada, D Bosch Portell, J Aboal Vinas, X Albert Bertran, R Brugada Tarradellas, P Loma-Osorio Ricon, C Tiron de Llano, M A Arnau, A Bel, M Blanes, A Osa, M Anguita, F Carrasco, J Castillo, J L Zamorano, J L Moya Mur, M Alvaro, C Fernandez-Golfin, J M Monteagudo, E Navas Elorza, M C Farinas Alvarez, J Aguero Balbin, C Arminanzas, F Arnaiz de Las Revillas, A Arnaiz Garcia, M Cobo Belaustegui, M Fernandez Sampedro, M Gutierrez Cuadra, J F Gutierrez-Diez, J Zarauza, L Garcia Cuello, C Gonzalez Rico, R Rodriguez-Alvarez, J Goikoetxea, M Montejo, J Miro, M Almela, J Ambrosioni, C Falces, D Fuster, C Garcia-de-la-Maria, M Hernandez-Meneses, J Llopis, F Marco, A Moreno, E Quintana, E Sandoval, A Tellez, J M Tolosana, B Vidal, I Ruiz-Zamora, A Bardaji Ruiz, E Sanz Girgas, G Garcia-Pardo, M Guillen Marzo, A Rodriguez Oviedo, A Villares Jimenez, L Abid, R Hammami, S Kammoun, M S Mourali, F Mghaieth Zghal, M Ben Hlima, S Boudiche, S Ouali, L Zakhama, S Antit, I Slama, O Gulel, M Sahin, L E Sade, E Karacaglar, S Kucukoglu, O Cetinarslan, U S Yasar, U Canpolat, B Mutlu, H Atas, R Dervishova, C Ileri, H Zaky, J Alhashmi, F Baslib, J Tahir, P Zarger, S Woldman, L Menezes, C Primus, R Uppal, I Bvekerwa, B Chandrasekaran, A Kopanska, B Prendergast, S Cannata, J Chambers, J Hancock, J Klein, R Rajani, M P Ursi, R Dworakowski, A Fife, J Breeze, M Browne-Morgan, M Gunning, S Streather, F Asch, M Zemedkun, B Alyavi, J UzokovMichal, Pazdernik; Bernard, Iung; Bulent, Mutlu; François, Alla; Robert, Riezebos; William, Kong; Maria Carmo Pereira, Nunes; Luc, Pierard; Ilija, Srdanovic; Hirotsugu, Yamada; Andrea, De Martino; Marcelo Haertel, Miglioranza; Julien, Magne; Cornelia, Piper; Cécile, Laroche; Aldo P, Maggioni; Patrizio, Lancellotti; Gilbert, Habib; Christine, Selton-Suty; R Ronderos, EURO-ENDO Investigators group:; Avegliano, G; Fernandez Oses, P; Filipini, E; Granada, I; Iribarren, A; Mahia, M; Nacinovich, F; Ressi, S; Obregon, R; Bangher, M; Dho, J; Cartasegna, L; L Plastino, M; Novas, V; Shigel, C; Reyes, G; De Santos, M; Gastaldello, N; Granillo Fernandez, M; Potito, M; Streitenberger, G; Velazco, P; H Casabé, J; Cortes, C; Guevara, E; Salmo, F; Seijo, M; Weidinger, F; Heger, M; Brooks, R; Stöllberger, C; Ho, C-Y; Perschy, L; Puskas, L; Goliasch, G; 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