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1. GRAd-COV2 vaccine provides potent and durable humoral and cellular immunity to SARS-CoV-2 in randomized placebo-controlled phase 2 trial

Author

Capone, S, Fusco, F, Milleri, S, Borre, S, Carbonara, S, Lo Caputo, S, Leone, S, Gori, G, Maggi, P, Cascio, A, Lichtner, M, Cauda, R, Dal Zoppo, S, Cossu, M, Gori, A, Roda, S, Confalonieri, P, Bonora, S, Missale, G, Codeluppi, M, Mezzaroma, I, Capici, S, Pontali, E, Libanore, M, Diani, A, Lanini, S, Battella, S, Contino, A, Piano Mortari, E, Genova, F, Parente, G, Dragonetti, R, Colloca, S, Visani, L, Iannacone, C, Carsetti, R, Folgori, A, Camerini, R, Ziviani, L, Malescio, F, Turrini, I, Lawlor, R, Romano, A, Nunziata, M, Armato, S, Mazzeo, N, Carleo, M, Dell'Isola, C, Pisapia, R, Pontarelli, A, Olivani, A, Grasselli, S, Laccabue, D, Leoni, M, Paolillo, F, Mancini, A, Ruaro, B, Confalonieri, M, Salton, F, Mancarella, G, Marocco, R, De Masi, M, Belvisi, V, Lamonica, S, Cingolani, A, Seguiti, C, Brambilla, P, Ferraresi, A, Lupi, M, Ludovisi, S, Renisi, G, Massafra, R, Pellicciotta, M, Armiento, L, Vimercati, S, Piacenza, M, Bonfanti, P, Columpsi, P, Cazzaniga, M, Rovelli, C, Ceresini, M, Previtali, L, Trentini, L, Alcantarini, C, Rugge, W, Biffi, S, Poletti, F, Rostagno, R, Moglia, R, De Negri, F, Fini, E, Cangialosi, A, Bruno, S, Rizzo, M, Niglio, M, Stritto, A, Matano, A, Petruzziello, A, Valsecchi, P, Pieri, T, Altamura, M, Calamo, A, Giannelli, A, Menolascina, S, Di Bari, S, Mauro, V, Aronica, R, Segala, D, Cultrera, R, Sighinolfi, L, Abbott, M, Gizzi, A, Marascia, F, Valenti, G, Feasi, M, Bobbio, N, Del Puente, F, Nicosia, A, Frasca, M, Mazzoleni, M, Garofalo, N, Ammendola, V, Grazioli, F, Napolitano, F, Vitelli, A, Marcellini, V, Capone S., Fusco F. M., Milleri S., Borre S., Carbonara S., Lo Caputo S., Leone S., Gori G., Maggi P., Cascio A., Lichtner M., Cauda R., Dal Zoppo S., Cossu M. V., Gori A., Roda S., Confalonieri P., Bonora S., Missale G., Codeluppi M., Mezzaroma I., Capici S., Pontali E., Libanore M., Diani A., Lanini S., Battella S., Contino A. M., Piano Mortari E., Genova F., Parente G., Dragonetti R., Colloca S., Visani L., Iannacone C., Carsetti R., Folgori A., Camerini R., Ziviani L., Malescio F., Turrini I., Lawlor R., Romano A., Nunziata M., Armato S., Mazzeo N., Carleo M. A., Dell'Isola C., Pisapia R., Pontarelli A., Olivani A., Grasselli S., Laccabue D., Leoni M. C., Paolillo F., Mancini A., Ruaro B., Confalonieri M., Salton F., Mancarella G., Marocco R., De Masi M., Belvisi V., Lamonica S., Cingolani A., Seguiti C., Brambilla P., Ferraresi A., Lupi M., Ludovisi S., Renisi G., Massafra R., Pellicciotta M., Armiento L., Vimercati S., Piacenza M., Bonfanti P., Columpsi P., Cazzaniga M. E., Rovelli C., Ceresini M., Previtali L., Trentini L., Alcantarini C., Rugge W., Biffi S., Poletti F., Rostagno R., Moglia R., De Negri F., Fini E., Cangialosi A., Bruno S. R., Rizzo M., Niglio M., Stritto A. D., Matano A., Petruzziello A., Valsecchi P., Pieri T., Altamura M., Calamo A., Giannelli A., Menolascina S., Di Bari S., Mauro V., Aronica R., Segala D., Cultrera R., Sighinolfi L., Abbott M., Gizzi A., Marascia F. G., Valenti G., Feasi M., Bobbio N., Del Puente F., Nicosia A., Frasca M., Mazzoleni M., Garofalo N., Ammendola V., Grazioli F., Napolitano F., Vitelli A., Marcellini V., Capone, S, Fusco, F, Milleri, S, Borre, S, Carbonara, S, Lo Caputo, S, Leone, S, Gori, G, Maggi, P, Cascio, A, Lichtner, M, Cauda, R, Dal Zoppo, S, Cossu, M, Gori, A, Roda, S, Confalonieri, P, Bonora, S, Missale, G, Codeluppi, M, Mezzaroma, I, Capici, S, Pontali, E, Libanore, M, Diani, A, Lanini, S, Battella, S, Contino, A, Piano Mortari, E, Genova, F, Parente, G, Dragonetti, R, Colloca, S, Visani, L, Iannacone, C, Carsetti, R, Folgori, A, Camerini, R, Ziviani, L, Malescio, F, Turrini, I, Lawlor, R, Romano, A, Nunziata, M, Armato, S, Mazzeo, N, Carleo, M, Dell'Isola, C, Pisapia, R, Pontarelli, A, Olivani, A, Grasselli, S, Laccabue, D, Leoni, M, Paolillo, F, Mancini, A, Ruaro, B, Confalonieri, M, Salton, F, Mancarella, G, Marocco, R, De Masi, M, Belvisi, V, Lamonica, S, Cingolani, A, Seguiti, C, Brambilla, P, Ferraresi, A, Lupi, M, Ludovisi, S, Renisi, G, Massafra, R, Pellicciotta, M, Armiento, L, Vimercati, S, Piacenza, M, Bonfanti, P, Columpsi, P, Cazzaniga, M, Rovelli, C, Ceresini, M, Previtali, L, Trentini, L, Alcantarini, C, Rugge, W, Biffi, S, Poletti, F, Rostagno, R, Moglia, R, De Negri, F, Fini, E, Cangialosi, A, Bruno, S, Rizzo, M, Niglio, M, Stritto, A, Matano, A, Petruzziello, A, Valsecchi, P, Pieri, T, Altamura, M, Calamo, A, Giannelli, A, Menolascina, S, Di Bari, S, Mauro, V, Aronica, R, Segala, D, Cultrera, R, Sighinolfi, L, Abbott, M, Gizzi, A, Marascia, F, Valenti, G, Feasi, M, Bobbio, N, Del Puente, F, Nicosia, A, Frasca, M, Mazzoleni, M, Garofalo, N, Ammendola, V, Grazioli, F, Napolitano, F, Vitelli, A, Marcellini, V, Capone S., Fusco F. M., Milleri S., Borre S., Carbonara S., Lo Caputo S., Leone S., Gori G., Maggi P., Cascio A., Lichtner M., Cauda R., Dal Zoppo S., Cossu M. V., Gori A., Roda S., Confalonieri P., Bonora S., Missale G., Codeluppi M., Mezzaroma I., Capici S., Pontali E., Libanore M., Diani A., Lanini S., Battella S., Contino A. M., Piano Mortari E., Genova F., Parente G., Dragonetti R., Colloca S., Visani L., Iannacone C., Carsetti R., Folgori A., Camerini R., Ziviani L., Malescio F., Turrini I., Lawlor R., Romano A., Nunziata M., Armato S., Mazzeo N., Carleo M. A., Dell'Isola C., Pisapia R., Pontarelli A., Olivani A., Grasselli S., Laccabue D., Leoni M. C., Paolillo F., Mancini A., Ruaro B., Confalonieri M., Salton F., Mancarella G., Marocco R., De Masi M., Belvisi V., Lamonica S., Cingolani A., Seguiti C., Brambilla P., Ferraresi A., Lupi M., Ludovisi S., Renisi G., Massafra R., Pellicciotta M., Armiento L., Vimercati S., Piacenza M., Bonfanti P., Columpsi P., Cazzaniga M. E., Rovelli C., Ceresini M., Previtali L., Trentini L., Alcantarini C., Rugge W., Biffi S., Poletti F., Rostagno R., Moglia R., De Negri F., Fini E., Cangialosi A., Bruno S. R., Rizzo M., Niglio M., Stritto A. D., Matano A., Petruzziello A., Valsecchi P., Pieri T., Altamura M., Calamo A., Giannelli A., Menolascina S., Di Bari S., Mauro V., Aronica R., Segala D., Cultrera R., Sighinolfi L., Abbott M., Gizzi A., Marascia F. G., Valenti G., Feasi M., Bobbio N., Del Puente F., Nicosia A., Frasca M., Mazzoleni M., Garofalo N., Ammendola V., Grazioli F., Napolitano F., Vitelli A., and Marcellini V.

Abstract

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and heterologous immunization approaches implemented worldwide for booster doses call for diversified vaccine portfolios. GRAd-COV2 is a gorilla adenovirus-based COVID-19 vaccine candidate encoding prefusion-stabilized spike. The safety and immunogenicity of GRAd-COV2 is evaluated in a dose- and regimen-finding phase 2 trial (COVITAR study, ClinicalTrials.gov: NCT04791423) whereby 917 eligible participants are randomized to receive a single intramuscular GRAd-COV2 administration followed by placebo, or two vaccine injections, or two doses of placebo, spaced over 3 weeks. Here, we report that GRAd-COV2 is well tolerated and induces robust immune responses after a single immunization; a second administration increases binding and neutralizing antibody titers. Potent, variant of concern (VOC) cross-reactive spike-specific T cell response peaks after the first dose and is characterized by high frequencies of CD8s. T cells maintain immediate effector functions and high proliferative potential over time. Thus, GRAd vector is a valuable platform for genetic vaccine development, especially when robust CD8 response is needed.

Published
2023

2. GRAd-COV2 vaccine provides potent and durable humoral and cellular immunity to SARS-CoV-2 in randomized placebo-controlled phase 2 trial

Author

Capone S., Fusco F. M., Milleri S., Borre S., Carbonara S., Lo Caputo S., Leone S., Gori G., Maggi P., Cascio A., Lichtner M., Cauda R., Dal Zoppo S., Cossu M. V., Gori A., Roda S., Confalonieri P., Bonora S., Missale G., Codeluppi M., Mezzaroma I., Capici S., Pontali E., Libanore M., Diani A., Lanini S., Battella S., Contino A. M., Piano Mortari E., Genova F., Parente G., Dragonetti R., Colloca S., Visani L., Iannacone C., Carsetti R., Folgori A., Camerini R., Ziviani L., Malescio F., Turrini I., Lawlor R., Romano A., Nunziata M., Armato S., Mazzeo N., Carleo M. A., Dell'Isola C., Pisapia R., Pontarelli A., Olivani A., Grasselli S., Laccabue D., Leoni M. C., Paolillo F., Mancini A., Ruaro B., Confalonieri M., Salton F., Mancarella G., Marocco R., De Masi M., Belvisi V., Lamonica S., Cingolani A., Seguiti C., Brambilla P., Ferraresi A., Lupi M., Ludovisi S., Renisi G., Massafra R., Pellicciotta M., Armiento L., Vimercati S., Piacenza M., Bonfanti P., Columpsi P., Cazzaniga M. E., Rovelli C., Ceresini M., Previtali L., Trentini L., Alcantarini C., Rugge W., Biffi S., Poletti F., Rostagno R., Moglia R., De Negri F., Fini E., Cangialosi A., Bruno S. R., Rizzo M., Niglio M., Stritto A. D., Matano A., Petruzziello A., Valsecchi P., Pieri T., Altamura M., Calamo A., Giannelli A., Menolascina S., Di Bari S., Mauro V., Aronica R., Segala D., Cultrera R., Sighinolfi L., Abbott M., Gizzi A., Marascia F. G., Valenti G., Feasi M., Bobbio N., Del Puente F., Nicosia A., Frasca M., Mazzoleni M., Garofalo N., Ammendola V., Grazioli F., Napolitano F., Vitelli A., Marcellini V., Capone, Stefania, Fusco, Francesco M, Milleri, Stefano, Borrè, Silvio, Carbonara, Sergio, Lo Caputo, Sergio, Leone, Sebastiano, Gori, Giovanni, Maggi, Paolo, Cascio, Antonio, Lichtner, Miriam, Cauda, Roberto, Dal Zoppo, Sarah, Cossu, Maria V, Gori, Andrea, Roda, Silvia, Confalonieri, Paola, Bonora, Stefano, Missale, Gabriele, Codeluppi, Mauro, Mezzaroma, Ivano, Capici, Serena, Pontali, Emanuele, Libanore, Marco, Diani, Augusta, Lanini, Simone, Battella, Simone, Contino, Alessandra M, Piano Mortari, Eva, Genova, Francesco, Parente, Gessica, Dragonetti, Rosella, Colloca, Stefano, Visani, Luigi, Iannacone, Claudio, Carsetti, Rita, Folgori, Antonella, Camerini, Roberto, Capone, S, Fusco, F, Milleri, S, Borre, S, Carbonara, S, Lo Caputo, S, Leone, S, Gori, G, Maggi, P, Cascio, A, Lichtner, M, Cauda, R, Dal Zoppo, S, Cossu, M, Gori, A, Roda, S, Confalonieri, P, Bonora, S, Missale, G, Codeluppi, M, Mezzaroma, I, Capici, S, Pontali, E, Libanore, M, Diani, A, Lanini, S, Battella, S, Contino, A, Piano Mortari, E, Genova, F, Parente, G, Dragonetti, R, Colloca, S, Visani, L, Iannacone, C, Carsetti, R, Folgori, A, Camerini, R, Ziviani, L, Malescio, F, Turrini, I, Lawlor, R, Romano, A, Nunziata, M, Armato, S, Mazzeo, N, Carleo, M, Dell'Isola, C, Pisapia, R, Pontarelli, A, Olivani, A, Grasselli, S, Laccabue, D, Leoni, M, Paolillo, F, Mancini, A, Ruaro, B, Confalonieri, M, Salton, F, Mancarella, G, Marocco, R, De Masi, M, Belvisi, V, Lamonica, S, Cingolani, A, Seguiti, C, Brambilla, P, Ferraresi, A, Lupi, M, Ludovisi, S, Renisi, G, Massafra, R, Pellicciotta, M, Armiento, L, Vimercati, S, Piacenza, M, Bonfanti, P, Columpsi, P, Cazzaniga, M, Rovelli, C, Ceresini, M, Previtali, L, Trentini, L, Alcantarini, C, Rugge, W, Biffi, S, Poletti, F, Rostagno, R, Moglia, R, De Negri, F, Fini, E, Cangialosi, A, Bruno, S, Rizzo, M, Niglio, M, Stritto, A, Matano, A, Petruzziello, A, Valsecchi, P, Pieri, T, Altamura, M, Calamo, A, Giannelli, A, Menolascina, S, Di Bari, S, Mauro, V, Aronica, R, Segala, D, Cultrera, R, Sighinolfi, L, Abbott, M, Gizzi, A, Marascia, F, Valenti, G, Feasi, M, Bobbio, N, Del Puente, F, Nicosia, A, Frasca, M, Mazzoleni, M, Garofalo, N, Ammendola, V, Grazioli, F, Napolitano, F, Vitelli, A, and Marcellini, V

Subjects
immunological memory, phase 2 clinical trial, safety, Sars-CoV-2 vaccine, COVID-19, CD8, T cell response, simian adenoviral vector, General Biochemistry, Genetics and Molecular Biology, CD4, neutralizing antibodie
Abstract

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and heterologous immunization approaches implemented worldwide for booster doses call for diversified vaccine portfolios. GRAd-COV2 is a gorilla adenovirus-based COVID-19 vaccine candidate encoding prefusion-stabilized spike. The safety and immunogenicity of GRAd-COV2 is evaluated in a dose- and regimen-finding phase 2 trial (COVITAR study, ClinicalTrials.gov: NCT04791423) whereby 917 eligible participants are randomized to receive a single intramuscular GRAd-COV2 administration followed by placebo, or two vaccine injections, or two doses of placebo, spaced over 3weeks. Here, we report that GRAd-COV2 is well tolerated and induces robust immune responses after a single immunization; a second administration increases binding and neutralizing antibody titers. Potent, variant of concern (VOC) cross-reactive spike-specific Tcell response peaks after the first dose and is characterized by high frequencies of CD8s. Tcells maintain immediate effector functions and high proliferative potential over time. Thus, GRAd vector is a valuable platform for genetic vaccine development, especially when robust CD8 response is needed.

Published
2023

4. Comorbidities, cardiovascular therapies, and COVID-19 mortality: A nationwide, italian observational study (ItaliCO)

Author

Polverino, F, Stern, D, Ruocco, G, Balestro, E, Bassetti, M, Candelli, M, Cirillo, B, Contoli, M, Corsico, A, D'Amico, F, D'Elia, E, Falco, G, Gasparini, S, Guerra, S, Harari, S, Kraft, M, Mennella, L, Papi, A, Parrella, R, Pelosi, P, Poletti, V, Polverino, M, Tana, C, Terribile, R, Woods, J, Di Marco, F, Martinez, F, Zhang, S, Geelhoed, B, Sinning, C, Agarossi, A, Agati, S, Agosteo, E, Ando', F, Andreoni, M, Angelillo, I, Arcoleo, G, Arena, C, Baiamonte, P, Ball, L, Banfi, P, Bartoletti, G, Bartolotta, R, Battaglini, D, Bellan, M, Benzoni, I, Bertolini, R, Bevilacqua, M, Bezzi, M, Bianco, A, Bisbano, A, Bobbio, F, Bocchialini, G, Bonetti, F, Boni, F, Bonifazi, M, Borgonovo, G, Borre', S, Bosio, M, Brachini, G, Brunetti, I, Calagna, L, Calo, F, Capuozzo, A, Carr, T, Castellani, A, Catalano, F, Catania, G, Catena, E, Cattaneo, M, Cattelan, A, Ceruti, V, Chiumiento, F, Cicchitto, G, Confalonieri, M, Confalonieri, P, Coppola, N, Cosentina, R, Costantino, R, Crimi, C, Curra, A, D'Abbraccio, M, Dalbeni, A, Daleffe, F, Davide, R, Del Donno, M, Di Pastena, F, Di Perna, F, Di Rosa, Z, Di Sabatino, A, Elesbani, O, Elia, D, Esposito, V, Fabiani, L, Falo, G, Fanelli, C, Fantin, A, Ferrigno, F, Fiorentino, G, Franceschi, F, Fronza, M, Gardenghi, G, Giacobbe, D, Giannotti, C, Giannotti, G, Gidari, A, Giovanardi, F, Gnerre, P, Gonnelli, F, Graziano, M, Greco, S, Grosso, A, Guarino, S, Iannarelli, A, Imitazione, P, Inglese, F, Iodice, V, Izzo, A, La Greca, C, Lax, A, Legittimo, F, Leo, A, Leone, S, Lepidini, V, Leto, M, Licata, F, Locati, F, Lorini, L, Lucchetti, B, Maida, I, Macera, M, Manzillo, E, March, A, Mascheroni, D, Mastroianni, A, Mauro, I, Mazzitelli, M, Mazzuca, E, Micheletto, C, Mingoli, A, Minuz, P, Moioli, M, Monti, L, Morgagni, R, Mucci, L, Muselli, M, Negri, S, Nobile, C, Oldani, S, Olivieri, C, Parati, G, Parodi, L, Pastorelli, E, Patruno, V, Pellegrino, F, Pengo, M, Pepe, D, Perotti, A, Petrino, R, Petrucci, M, Piane, R, Pignataro, G, Pino, M, Pirisi, M, Porru, F, Pugliese, F, Punzi, R, Ramaroli, D, Robba, C, Rostagno, R, Sabatini, U, Sainaghi, P, Salton, F, Salzano, C, Sanduzzi, A, Zamparelli, S, Sangiovanni, V, Santopuoli, D, Sapienza, P, Sarmati, L, Schiaroli, E, Scienza, F, Senni, M, Serchisu, L, Sgherzi, S, Soddu, D, Soranna, D, Sorino, C, Spadaro, S, Stirpe, E, Tardivo, S, Tartaglia, S, Teopompi, E, Tomchaney, M, Torelli, E, Torlasco, C, Torti, C, Tupputi, E, Ugolinelli, C, Vatrella, A, Versace, A, Villani, M, Vincenzo, L, Volta, C, Voraphani, N, Zekaj, E, Zoppellari, R, Polverino F., Stern D. A., Ruocco G., Balestro E., Bassetti M., Candelli M., Cirillo B., Contoli M., Corsico A., D'Amico F., D'Elia E., Falco G., Gasparini S., Guerra S., Harari S., Kraft M., Mennella L., Papi A., Parrella R., Pelosi P., Poletti V., Polverino M., Tana C., Terribile R., Woods J. C., Di Marco F., Martinez F. D., Zhang S., Geelhoed B., Sinning C., Agarossi A., Agati S., Agosteo E., Ando' F., Andreoni M., Angelillo I. F., Arcoleo G., Arena C., Baiamonte P., Ball L., Banfi P., Bartoletti G., Bartolotta R., Battaglini D., Bellan M., Benzoni I., Bertolini R., Bevilacqua M., Bezzi M., Bianco A., Bisbano A., Bobbio F., Bocchialini G., Bonetti F., Boni F., Bonifazi M., Borgonovo G., Borre' S., Bosio M., Brachini G., Brunetti I., Calagna L., Calo F., Capuozzo A., Carr T., Castellani A., Catalano F., Catania G., Catena E., Cattaneo M., Cattelan A., Ceruti V., Chiumiento F., Cicchitto G., Confalonieri M., Confalonieri P., Coppola N., Cosentina R., Costantino R., Crimi C., Curra A., D'Abbraccio M., Dalbeni A., Daleffe F., Davide R., Del Donno M., Di Pastena F., Di Perna F., Di Rosa Z., Di Sabatino A., Elesbani O., Elia D., Esposito V., Fabiani L., Falo G., Fanelli C., Fantin A., Ferrigno F., Fiorentino G., Franceschi F., Fronza M., Gardenghi G. G., Giacobbe D. R., Giannotti C., Giannotti G., Gidari A., Giovanardi F., Gnerre P., Gonnelli F., Graziano M., Greco S., Grosso A., Guarino S., Iannarelli A., Imitazione P., Inglese F., Iodice V., Izzo A., La Greca C., Lax A., Legittimo F., Leo A., Leone S., Lepidini V., Leto M., Licata F., Locati F., Lorini L., Lucchetti B., Maida I., Macera M., Manzillo E., March A., Mascheroni D., Mastroianni A., Mauro I., Mazzitelli M., Mazzuca E., Micheletto C., Mingoli A., Minuz P., Moioli M., Monti L., Morgagni R., Mucci L., Muselli M., Negri S., Nobile C. G. A., Oldani S., Olivieri C., Parati G., Parodi L., Pastorelli E., Patruno V., Pellegrino F., Pengo M. F., Pepe D., Perotti A., Petrino R., Petrucci M., Piane R. M., Pignataro G., Pino M., Pirisi M., Porru F., Pugliese F., Punzi R., Ramaroli D. A., Robba C., Rostagno R., Sabatini U., Sainaghi P. P., Salton F., Salzano C., Sanduzzi A., Zamparelli S. S., Sangiovanni V., Santopuoli D., Sapienza P., Sarmati L., Schiaroli E., Scienza F., Senni M., Serchisu L., Sgherzi S., Soddu D., Soranna D., Sorino C., Spadaro S., Stirpe E., Tardivo S., Tartaglia S., Teopompi E., Tomchaney M., Torelli E., Torlasco C., Torti C., Tupputi E., Ugolinelli C., Vatrella A., Versace A. G., Villani M., Vincenzo L., Volta C. A., Voraphani N., Zekaj E., Zoppellari R., Polverino, F, Stern, D, Ruocco, G, Balestro, E, Bassetti, M, Candelli, M, Cirillo, B, Contoli, M, Corsico, A, D'Amico, F, D'Elia, E, Falco, G, Gasparini, S, Guerra, S, Harari, S, Kraft, M, Mennella, L, Papi, A, Parrella, R, Pelosi, P, Poletti, V, Polverino, M, Tana, C, Terribile, R, Woods, J, Di Marco, F, Martinez, F, Zhang, S, Geelhoed, B, Sinning, C, Agarossi, A, Agati, S, Agosteo, E, Ando', F, Andreoni, M, Angelillo, I, Arcoleo, G, Arena, C, Baiamonte, P, Ball, L, Banfi, P, Bartoletti, G, Bartolotta, R, Battaglini, D, Bellan, M, Benzoni, I, Bertolini, R, Bevilacqua, M, Bezzi, M, Bianco, A, Bisbano, A, Bobbio, F, Bocchialini, G, Bonetti, F, Boni, F, Bonifazi, M, Borgonovo, G, Borre', S, Bosio, M, Brachini, G, Brunetti, I, Calagna, L, Calo, F, Capuozzo, A, Carr, T, Castellani, A, Catalano, F, Catania, G, Catena, E, Cattaneo, M, Cattelan, A, Ceruti, V, Chiumiento, F, Cicchitto, G, Confalonieri, M, Confalonieri, P, Coppola, N, Cosentina, R, Costantino, R, Crimi, C, Curra, A, D'Abbraccio, M, Dalbeni, A, Daleffe, F, Davide, R, Del Donno, M, Di Pastena, F, Di Perna, F, Di Rosa, Z, Di Sabatino, A, Elesbani, O, Elia, D, Esposito, V, Fabiani, L, Falo, G, Fanelli, C, Fantin, A, Ferrigno, F, Fiorentino, G, Franceschi, F, Fronza, M, Gardenghi, G, Giacobbe, D, Giannotti, C, Giannotti, G, Gidari, A, Giovanardi, F, Gnerre, P, Gonnelli, F, Graziano, M, Greco, S, Grosso, A, Guarino, S, Iannarelli, A, Imitazione, P, Inglese, F, Iodice, V, Izzo, A, La Greca, C, Lax, A, Legittimo, F, Leo, A, Leone, S, Lepidini, V, Leto, M, Licata, F, Locati, F, Lorini, L, Lucchetti, B, Maida, I, Macera, M, Manzillo, E, March, A, Mascheroni, D, Mastroianni, A, Mauro, I, Mazzitelli, M, Mazzuca, E, Micheletto, C, Mingoli, A, Minuz, P, Moioli, M, Monti, L, Morgagni, R, Mucci, L, Muselli, M, Negri, S, Nobile, C, Oldani, S, Olivieri, C, Parati, G, Parodi, L, Pastorelli, E, Patruno, V, Pellegrino, F, Pengo, M, Pepe, D, Perotti, A, Petrino, R, Petrucci, M, Piane, R, Pignataro, G, Pino, M, Pirisi, M, Porru, F, Pugliese, F, Punzi, R, Ramaroli, D, Robba, C, Rostagno, R, Sabatini, U, Sainaghi, P, Salton, F, Salzano, C, Sanduzzi, A, Zamparelli, S, Sangiovanni, V, Santopuoli, D, Sapienza, P, Sarmati, L, Schiaroli, E, Scienza, F, Senni, M, Serchisu, L, Sgherzi, S, Soddu, D, Soranna, D, Sorino, C, Spadaro, S, Stirpe, E, Tardivo, S, Tartaglia, S, Teopompi, E, Tomchaney, M, Torelli, E, Torlasco, C, Torti, C, Tupputi, E, Ugolinelli, C, Vatrella, A, Versace, A, Villani, M, Vincenzo, L, Volta, C, Voraphani, N, Zekaj, E, Zoppellari, R, Polverino F., Stern D. A., Ruocco G., Balestro E., Bassetti M., Candelli M., Cirillo B., Contoli M., Corsico A., D'Amico F., D'Elia E., Falco G., Gasparini S., Guerra S., Harari S., Kraft M., Mennella L., Papi A., Parrella R., Pelosi P., Poletti V., Polverino M., Tana C., Terribile R., Woods J. C., Di Marco F., Martinez F. D., Zhang S., Geelhoed B., Sinning C., Agarossi A., Agati S., Agosteo E., Ando' F., Andreoni M., Angelillo I. F., Arcoleo G., Arena C., Baiamonte P., Ball L., Banfi P., Bartoletti G., Bartolotta R., Battaglini D., Bellan M., Benzoni I., Bertolini R., Bevilacqua M., Bezzi M., Bianco A., Bisbano A., Bobbio F., Bocchialini G., Bonetti F., Boni F., Bonifazi M., Borgonovo G., Borre' S., Bosio M., Brachini G., Brunetti I., Calagna L., Calo F., Capuozzo A., Carr T., Castellani A., Catalano F., Catania G., Catena E., Cattaneo M., Cattelan A., Ceruti V., Chiumiento F., Cicchitto G., Confalonieri M., Confalonieri P., Coppola N., Cosentina R., Costantino R., Crimi C., Curra A., D'Abbraccio M., Dalbeni A., Daleffe F., Davide R., Del Donno M., Di Pastena F., Di Perna F., Di Rosa Z., Di Sabatino A., Elesbani O., Elia D., Esposito V., Fabiani L., Falo G., Fanelli C., Fantin A., Ferrigno F., Fiorentino G., Franceschi F., Fronza M., Gardenghi G. G., Giacobbe D. R., Giannotti C., Giannotti G., Gidari A., Giovanardi F., Gnerre P., Gonnelli F., Graziano M., Greco S., Grosso A., Guarino S., Iannarelli A., Imitazione P., Inglese F., Iodice V., Izzo A., La Greca C., Lax A., Legittimo F., Leo A., Leone S., Lepidini V., Leto M., Licata F., Locati F., Lorini L., Lucchetti B., Maida I., Macera M., Manzillo E., March A., Mascheroni D., Mastroianni A., Mauro I., Mazzitelli M., Mazzuca E., Micheletto C., Mingoli A., Minuz P., Moioli M., Monti L., Morgagni R., Mucci L., Muselli M., Negri S., Nobile C. G. A., Oldani S., Olivieri C., Parati G., Parodi L., Pastorelli E., Patruno V., Pellegrino F., Pengo M. F., Pepe D., Perotti A., Petrino R., Petrucci M., Piane R. M., Pignataro G., Pino M., Pirisi M., Porru F., Pugliese F., Punzi R., Ramaroli D. A., Robba C., Rostagno R., Sabatini U., Sainaghi P. P., Salton F., Salzano C., Sanduzzi A., Zamparelli S. S., Sangiovanni V., Santopuoli D., Sapienza P., Sarmati L., Schiaroli E., Scienza F., Senni M., Serchisu L., Sgherzi S., Soddu D., Soranna D., Sorino C., Spadaro S., Stirpe E., Tardivo S., Tartaglia S., Teopompi E., Tomchaney M., Torelli E., Torlasco C., Torti C., Tupputi E., Ugolinelli C., Vatrella A., Versace A. G., Villani M., Vincenzo L., Volta C. A., Voraphani N., Zekaj E., and Zoppellari R.

Abstract

Background: Italy has one of the world’s oldest populations, and suffered one the highest death tolls from Coronavirus disease 2019 (COVID-19) worldwide. Older people with cardiovascular diseases (CVDs), and in particular hypertension, are at higher risk of hospitalization and death for COVID-19. Whether hypertensionmedicationsmay increase the risk for death in older COVID 19 inpatients at the highest risk for the disease is currently unknown. Methods: Data from 5,625 COVID-19 inpatients were manually extracted from medical charts from 61 hospitals across Italy. From the initial 5,625 patients, 3,179 were included in the study as they were either discharged or deceased at the time of the data analysis. Primary outcome was inpatient death or recovery. Mixed effects logistic regression models were adjusted for sex, age, and number of comorbidities, with a random effect for site. Results: A large proportion of participating inpatients were ≥65 years old (58%), male (68%), non-smokers (93%) with comorbidities (66%). Each additional comorbidity increased the risk of death by 35% [adjOR = 1.35 (1.2, 1.5) p < 0.001]. Use of ACE inhibitors, ARBs, beta-blockers or Ca-antagonists was not associated with significantly increased risk of death. There was a marginal negative association between ARB use and death, and a marginal positive association between diuretic use and death. Conclusions: This Italian nationwide observational study of COVID-19 inpatients, the majority of which ≥65 years old, indicates that there is a linear direct relationship between the number of comorbidities and the risk of death. Among CVDs, hypertension and pre-existing cardiomyopathy were significantly associated with risk of death. The use of hypertension medications reported to be safe in younger cohorts, do not contribute significantly to increased COVID-19 related deaths in an older population that suffered one of the highest death tolls worldwide.

Published
2020

5. Comorbidities, cardiovascular therapies, and COVID-19 mortality: A nationwide, italian observational study (ItaliCO)

Author

Polverino, F., Phd, Md, Stern, D., Polverino, M., D'Amico, F., D'Elia, E., Agarossi, A., Agati, S., Agosteo, E., Ando', F., Andreoni, M., Angelillo, If., Dds, Mph, Arcoleo, G., Arena, C., Baiamonte, P., Balestro, E., Ball, L., Banfi, P., Bartoletti, G., Bartolotta, R., Bassetti, M., Battaglini, D., Bellan, M., Benzoni, I., Bertolini, R., Bevilacqua, M., Bezzi, M., Bianco, A., Bisbano, A., Bobbio, F., Bocchialini, G., Bonetti, F., Boni, F., Bonifazi, M., Borgonovo, G., Borre', S., Bosio, M., Brachini, G., Brunetti, I., Calagna, L., Calò, F., Candelli, M., Capuozzo, A., Carr, T., Castellani, A., Catalano, F., Catania, G., Catena, E., Cattaneo, M., Cattelan, A., Ceruti, V., Chiumiento, F., Cicchitto, G., Cirillo, B., Confalonieri, M., Confalonieri, P., Contoli, M., Coppola, N., Corsico, A., Cosentina, R., Costantino, R., Crimi, C., Currà, A., D'Abbraccio, M., Dalbeni, A., Daleffe, F., Davide, R., Del Donno, M., Di Marco, F., Di Pastena, F., Di Perna, F., Di Rosa, Z., Di Sabatino, A., Elesbani, O., Elia, D., Esposito, V., Fabiani, L., Falco, G., Falo, G., Fanelli, C., Fantin, A., Ferrigno, F., Fiorentino, G., Franceschi, F., Fronza, M., Gardini Gardenghi, G., Gasparini, S., Giacobbe, D. R., Giannotti, C., Giannotti, G., Gidari, A., Giovanardi, F., Gnerre, P., Gonnelli, F., Graziano, M., Greco, S., Grosso, A., Phd, Guarino, S., Guerra, S., Harari, S., Iannarelli, A., Imitazione, P., Inglese, F., Iodice, V., Izzo, A., La Greca, C., Kraft, M., Lax, A., Legittimo, F., Leo, A., Leone, S., Lepidini, V., Leto, M., Licata, F., Locati, F., Lorini, L., Lucchetti, B., Maida, I., Macera, M., Manzillo, E., March, A., Mascheroni, D., Mastroianni, A., Mauro, I., Mazzitelli, M., Mazzuca, E., Mennella, L., Micheletto, C., Mingoli, A., Minuz, P., Moioli, M., Monti, L., Morgagni, R., Mucci, L., Muselli, M., Negri, S., Nobile, C. G. A., Oldani, S., Olivieri, C., Papi, A., Parati, G., Parodi, L., Parrella, R., Pastorelli, E., Patruno, V., Pellegrino, F., Pelosi, P., Fers, Md, Pengo, M. F., Pepe, D., Perotti, A., Petrino, R., Petrucci, M., Piane, R. M., Pignataro, G., Pino, M., Pirisi, M., Poletti, V., Porru, F., Pugliese, F., Punzi, R., Ramaroli, D. A., Robba, C., Rostagno, R., Ruocco, G., Sabatini, U., Sainaghi, P. P., Salton, F., Salzano, C., Sanduzzi, A., Sanduzzi Zamparelli, S., Sangiovanni, V., Santopuoli, D., Sapienza, P., Sarmati, L., Schiaroli, E., Scienza, F., Senni, M., Serchisu, L., Sgherzi, S., Soddu, D., Soranna, D., Sorino, C., Spadaro, S., Stirpe, E., Tana, C., Tardivo, S., Tartaglia, S., Teopompi, E., Terribile, R., Tomchaney, M., Torelli, E., Torlasco, C., Torti, C., Tupputi, E., Ugolinelli, C., Vatrella, A., Versace, A. G., Villani, M., Vincenzo, L., Volta, C. A., Voraphani, N., Woods, J. C., Zekaj, E., Zoppellari, R., Martinez, and F. D., Polverino, Francesca, Stern, Debra A, Ruocco, Gaetano, Balestro, Elisabetta, Bassetti, Matteo, Candelli, Marcello, Cirillo, Bruno, Contoli, Marco, Corsico, Angelo, D'Amico, Filippo, D'Elia, Emilia, Falco, Giuseppe, Gasparini, Stefano, Guerra, Stefano, Harari, Sergio, Kraft, Monica, Mennella, Luigi, Papi, Alberto, Parrella, Roberto, Pelosi, Paolo, Poletti, Venerino, Polverino, Mario, Tana, Claudio, Terribile, Roberta, Woods, Jason C, Di Marco, Fabiano, Martinez, Fernando D, Angelillo, Italo Francesco, Stern, Debra A., C Woods, Jason, Martinez, Fernando D., Polverino, F., Stern, D., Polverino, M., D'Amico, F., D'Elia, E., Agarossi, A., Agati, S., Agosteo, E., Ando', F., Andreoni, M., Angelillo, If., Arcoleo, G., Arena, C., Baiamonte, P., Balestro, E., Ball, L., Banfi, P., Bartoletti, G., Bartolotta, R., Bassetti, M., Battaglini, D., Bellan, M., Benzoni, I., Bertolini, R., Bevilacqua, M., Bezzi, M., Bianco, A., Bisbano, A., Bobbio, F., Bocchialini, G., Bonetti, F., Boni, F., Bonifazi, M., Borgonovo, G., Borre', S., Bosio, M., Brachini, G., Brunetti, I., Calagna, L., Calò, F., Candelli, M., Capuozzo, A., Carr, T., Castellani, A., Catalano, F., Catania, G., Catena, E., Cattaneo, M., Cattelan, A., Ceruti, V., Chiumiento, F., Cicchitto, G., Cirillo, B., Confalonieri, M., Confalonieri, P., Contoli, M., Coppola, N., Corsico, A., Cosentina, R., Costantino, R., Crimi, C., Currà, A., D'Abbraccio, M., Dalbeni, A., Daleffe, F., Davide, R., Del Donno, M., Di Marco, F., Di Pastena, F., Di Perna, F., Di Rosa, Z., Di Sabatino, A., Elesbani, O., Elia, D., Esposito, V., Fabiani, L., Falco, G., Falo, G., Fanelli, C., Fantin, A., Ferrigno, F., Fiorentino, G., Franceschi, F., Fronza, M., Gardini Gardenghi, G., Gasparini, S., Giacobbe, D. R., Giannotti, C., Giannotti, G., Gidari, A., Giovanardi, F., Gnerre, P., Gonnelli, F., Graziano, M., Greco, S., Grosso, A., Guarino, S., Guerra, S., Harari, S., Iannarelli, A., Imitazione, P., Inglese, F., Iodice, V., Izzo, A., La Greca, C., Kraft, M., Lax, A., Legittimo, F., Leo, A., Leone, S., Lepidini, V., Leto, M., Licata, F., Locati, F., Lorini, L., Lucchetti, B., Maida, I., Macera, M., Manzillo, E., March, A., Mascheroni, D., Mastroianni, A., Mauro, I., Mazzitelli, M., Mazzuca, E., Mennella, L., Micheletto, C., Mingoli, A., Minuz, P., Moioli, M., Monti, L., Morgagni, R., Mucci, L., Muselli, M., Negri, S., Nobile, C. G. A., Oldani, S., Olivieri, C., Papi, A., Parati, G., Parodi, L., Parrella, R., Pastorelli, E., Patruno, V., Pellegrino, F., Pelosi, P., Pengo, M. F., Pepe, D., Perotti, A., Petrino, R., Petrucci, M., Piane, R. M., Pignataro, G., Pino, M., Pirisi, M., Poletti, V., Porru, F., Pugliese, F., Punzi, R., Ramaroli, D. A., Robba, C., Rostagno, R., Ruocco, G., Sabatini, U., Sainaghi, P. P., Salton, F., Salzano, C., Sanduzzi, A., Sanduzzi Zamparelli, S., Sangiovanni, V., Santopuoli, D., Sapienza, P., Sarmati, L., Schiaroli, E., Scienza, F., Senni, M., Serchisu, L., Sgherzi, S., Soddu, D., Soranna, D., Sorino, C., Spadaro, S., Stirpe, E., Tana, C., Tardivo, S., Tartaglia, S., Teopompi, E., Terribile, R., Tomchaney, M., Torelli, E., Torlasco, C., Torti, C., Tupputi, E., Ugolinelli, C., Vatrella, A., Versace, A. G., Villani, M., Vincenzo, L., Volta, C. A., Voraphani, N., Woods, J. C., Zekaj, E., Zoppellari, R., Martinez, F. D., Public Health, Polverino, F, Stern, D, Ruocco, G, Balestro, E, Bassetti, M, Candelli, M, Cirillo, B, Contoli, M, Corsico, A, D'Amico, F, D'Elia, E, Falco, G, Gasparini, S, Guerra, S, Harari, S, Kraft, M, Mennella, L, Papi, A, Parrella, R, Pelosi, P, Poletti, V, Polverino, M, Tana, C, Terribile, R, Woods, J, Di Marco, F, Martinez, F, Zhang, S, Geelhoed, B, Sinning, C, Agarossi, A, Agati, S, Agosteo, E, Ando', F, Andreoni, M, Angelillo, I, Arcoleo, G, Arena, C, Baiamonte, P, Ball, L, Banfi, P, Bartoletti, G, Bartolotta, R, Battaglini, D, Bellan, M, Benzoni, I, Bertolini, R, Bevilacqua, M, Bezzi, M, Bianco, A, Bisbano, A, Bobbio, F, Bocchialini, G, Bonetti, F, Boni, F, Bonifazi, M, Borgonovo, G, Borre', S, Bosio, M, Brachini, G, Brunetti, I, Calagna, L, Calo, F, Capuozzo, A, Carr, T, Castellani, A, Catalano, F, Catania, G, Catena, E, Cattaneo, M, Cattelan, A, Ceruti, V, Chiumiento, F, Cicchitto, G, Confalonieri, M, Confalonieri, P, Coppola, N, Cosentina, R, Costantino, R, Crimi, C, Curra, A, D'Abbraccio, M, Dalbeni, A, Daleffe, F, Davide, R, Del Donno, M, Di Pastena, F, Di Perna, F, Di Rosa, Z, Di Sabatino, A, Elesbani, O, Elia, D, Esposito, V, Fabiani, L, Falo, G, Fanelli, C, Fantin, A, Ferrigno, F, Fiorentino, G, Franceschi, F, Fronza, M, Gardenghi, G, Giacobbe, D, Giannotti, C, Giannotti, G, Gidari, A, Giovanardi, F, Gnerre, P, Gonnelli, F, Graziano, M, Greco, S, Grosso, A, Guarino, S, Iannarelli, A, Imitazione, P, Inglese, F, Iodice, V, Izzo, A, La Greca, C, Lax, A, Legittimo, F, Leo, A, Leone, S, Lepidini, V, Leto, M, Licata, F, Locati, F, Lorini, L, Lucchetti, B, Maida, I, Macera, M, Manzillo, E, March, A, Mascheroni, D, Mastroianni, A, Mauro, I, Mazzitelli, M, Mazzuca, E, Micheletto, C, Mingoli, A, Minuz, P, Moioli, M, Monti, L, Morgagni, R, Mucci, L, Muselli, M, Negri, S, Nobile, C, Oldani, S, Olivieri, C, Parati, G, Parodi, L, Pastorelli, E, Patruno, V, Pellegrino, F, Pengo, M, Pepe, D, Perotti, A, Petrino, R, Petrucci, M, Piane, R, Pignataro, G, Pino, M, Pirisi, M, Porru, F, Pugliese, F, Punzi, R, Ramaroli, D, Robba, C, Rostagno, R, Sabatini, U, Sainaghi, P, Salton, F, Salzano, C, Sanduzzi, A, Zamparelli, S, Sangiovanni, V, Santopuoli, D, Sapienza, P, Sarmati, L, Schiaroli, E, Scienza, F, Senni, M, Serchisu, L, Sgherzi, S, Soddu, D, Soranna, D, Sorino, C, Spadaro, S, Stirpe, E, Tardivo, S, Tartaglia, S, Teopompi, E, Tomchaney, M, Torelli, E, Torlasco, C, Torti, C, Tupputi, E, Ugolinelli, C, Vatrella, A, Versace, A, Villani, M, Vincenzo, L, Volta, C, Voraphani, N, Zekaj, E, and Zoppellari, R

Subjects
0301 basic medicine, COVID-19, comorbidities, ACE inhibitors, mortality, cohort study, medicine.medical_specialty, comorbiditie, lcsh:Diseases of the circulatory (Cardiovascular) system, ACE inhibitors, Coronavirus disease 2019 (COVID-19), COVID-19, cohort study, comorbidities, mortality, Cardiomyopathy, Socio-culturale, Disease, 030204 cardiovascular system & hematology, Cardiovascular Medicine, Logistic regression, Older population, Comorbidities, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Internal medicine, ACE inhibitor, medicine, Mortality, Original Research, business.industry, Cohort study, medicine.disease, Comorbidity, 030104 developmental biology, lcsh:RC666-701, Observational study, Erratum, Cardiology and Cardiovascular Medicine, business
Abstract

Background: Italy has one of the world’s oldest populations, and suffered one the highest death tolls from Coronavirus disease 2019 (COVID-19) worldwide. Older people with cardiovascular diseases (CVDs), and in particular hypertension, are at higher risk of hospitalization and death for COVID-19. Whether hypertensionmedicationsmay increase the risk for death in older COVID 19 inpatients at the highest risk for the disease is currently unknown. Methods: Data from 5,625 COVID-19 inpatients were manually extracted from medical charts from 61 hospitals across Italy. From the initial 5,625 patients, 3,179 were included in the study as they were either discharged or deceased at the time of the data analysis. Primary outcome was inpatient death or recovery. Mixed effects logistic regression models were adjusted for sex, age, and number of comorbidities, with a random effect for site. Results: A large proportion of participating inpatients were ≥65 years old (58%), male (68%), non-smokers (93%) with comorbidities (66%). Each additional comorbidity increased the risk of death by 35% [adjOR = 1.35 (1.2, 1.5) p < 0.001]. Use of ACE inhibitors, ARBs, beta-blockers or Ca-antagonists was not associated with significantly increased risk of death. There was a marginal negative association between ARB use and death, and a marginal positive association between diuretic use and death. Conclusions: This Italian nationwide observational study of COVID-19 inpatients, the majority of which ≥65 years old, indicates that there is a linear direct relationship between the number of comorbidities and the risk of death. Among CVDs, hypertension and pre-existing cardiomyopathy were significantly associated with risk of death. The use of hypertension medications reported to be safe in younger cohorts, do not contribute significantly to increased COVID-19 related deaths in an older population that suffered one of the highest death tolls worldwide.

Published
2020

7. Simple parameters from complete blood count predict in-hospital mortality in covid-19

Author

Bellan, M., Azzolina, D., Hayden, E., Gaidano, G., Pirisi, M., Acquaviva, A., Aimaretti, G., Valletti, P. A., Angilletta, R., Arioli, R., Avanzi, G. C., Avino, G., Balbo, P. E., Baldon, G., Baorda, F., Barbero, E., Baricich, A., Barini, M., Barone-Adesi, F., Battistini, S., Beltrame, M., Bertoli, M., Bertolin, S., Bertolotti, M., Betti, M., Bobbio, F., Boffano, P., Boglione, L., Borre, S., Brucoli, M., Calzaducca, E., Cammarata, E., Cantaluppi, V., Cantello, R., Capponi, A., Carriero, A., Casciaro, G. F., Castello, L. M., Ceruti, F., Chichino, G., Chirico, E., Cisari, C., Cittone, M. G., Colombo, C., Comi, C., Croce, E., Daffara, T., Danna, P., Corte, F. D., de Vecchi, S., Dianzani, U., Benedetto, D. D., Esposto, E., Faggiano, F., Falaschi, Z., Ferrante, D., Ferrero, A., Gagliardi, I., Galbiati, A., Gallo, S., Garavelli, P. L., Gardino, C. A., Garzaro, M., Gastaldello, M. L., Gavelli, F., Gennari, A., Giacomini, G. M., Giacone, I., Via, V. G., Giolitti, F., Gironi, L. C., Gramaglia, C., Grisafi, L., Inserra, I., Invernizzi, M., Krengli, M., Labella, E., Landi, I. C., Landi, R., Leone, I., Lio, V., Lorenzini, L., Maconi, A., Malerba, M., Manfredi, G. F., Martelli, M., Marzari, L., Marzullo, P., Mennuni, M., Montabone, C., Morosini, U., Mussa, M., Nerici, I., Nuzzo, A., Olivieri, C., Padelli, S. A., Panella, M., Parisini, A., Pasche, A., Patrucco, F., Patti, G., Pau, A., Pedrinelli, A. R., Percivale, I., Ragazzoni, L., Re, R., Rigamonti, C., Rizzi, E., Rognoni, A., Roveta, A., Salamina, L., Santagostino, M., Saraceno, M., Savoia, P., Sciarra, M., Schimmenti, A., Scotti, L., Spinoni, E., Smirne, C., Tarantino, V., Tillio, P. A., Tonello, S., Vaschetto, R., Vassia, V., Zagaria, D., Zavattaro, E., Zeppegno, P., Zottarelli, F., Sainaghi, P. P., Aiosa, G., Airoldi, A., Barco, A., Bargiacchi, O., Bazzano, S., Berni, P., Bianchi, B., Bianco, S., Biffi, S., Binda, V., Bolgeo, T., Bolla, C., Bonato, V., Bonizzoni, G., Bragantini, A., Brustia, D., Bullara, V., Burlone, M., Brustia, F., Caccia, S., Calareso, A., Cammarota, G., Cancelliere, L., Carbone, R., Cassinari, A., Ceriani, E., Cena, T., Clivati, E., Collimedaglia, L., Colombatto, A., Cornella, C., Costanzo, M., Croce, A., de Benedittis, C., Delorenzi, S., Dionisio, R., Donato, P., Esposito, M., Fangazio, S., Feggi, A., Ferrillo, S., Foci, V., Fra, G. P., Gaggino, C., Gambaro, E., Gattoni, E., Gattoni, L., Giacchero, F., Gianfreda, R., Giubertoni, A., Grecu, L., Grossi, F., Guglielmetti, G., Guido, S., Iannantuoni, G., Ingrao, S., Jona, A., Lazzarich, E., Lissandrin, R., Maduli, E., Magne, F., Mantia, E., Marangon, D., Massara, M., Matino, E., Mauri, M. G., Menegatti, M., Moglia, R., Molinari, R., Morelli, S., Morlino, P., Naldi, P., Nebbiolo, C., Omodeo, P., Palmieri, D., Panero, A., Parodi, M., Pedrazzoli, R., Pelazza, C., Penpa, S., Perucca, R., Pirovano, A., Pittau, S., Pochetti, P., Poletti, F., Polla, B., Prandi, P., Prodam, F., Prosperini, P., Puma, A., Quaglia, M., Raie, A., Rapetti, R., Ravera, S., Re, A., Reale, M., Rossati, A., Rossi, M., Rossi, P., Rostagno, R., Salomoni, G., Sama, M. T., Sarchi, E., Sarcoli, M., Sarda, C., Sguazzotti, I., Soddu, D., Sola, D., Stobbione, P., Todoerti, M., Vallese, G. C., Varrasi, C., Veia, A., Vignazia, G. L., Zanotti, I., Zecca, E., Zichittella, D., Zisa, G., and Zoppis, E.

Subjects
Adult, Male, medicine.medical_specialty, Medicine (General), Multivariate analysis, Article Subject, Clinical Decision Rules, COVID-19, Prognosis, Blood Cell Count, Hospital Mortality, Severity of Illness Index, Clinical Biochemistry, Asymptomatic, Severity of Illness Index, NO, R5-920, Internal medicine, Clinical Decision Rules, Severity of illness, Genetics, 80 and over, Medicine, Humans, Hospital Mortality, Molecular Biology, Aged, Retrospective Studies, Aged, 80 and over, medicine.diagnostic_test, business.industry, Biochemistry (medical), Complete blood count, COVID-19, Retrospective cohort study, Red blood cell distribution width, General Medicine, Odds ratio, Middle Aged, Prognosis, Female, Italy, Multivariate Analysis, Blood Cell Count, Cohort, medicine.symptom, business, Research Article
Abstract

Introduction. The clinical course of Coronavirus Disease 2019 (COVID-19) is highly heterogenous, ranging from asymptomatic to fatal forms. The identification of clinical and laboratory predictors of poor prognosis may assist clinicians in monitoring strategies and therapeutic decisions. Materials and Methods. In this study, we retrospectively assessed the prognostic value of a simple tool, the complete blood count, on a cohort of 664 patients ( F 260; 39%, median age 70 (56-81) years) hospitalized for COVID-19 in Northern Italy. We collected demographic data along with complete blood cell count; moreover, the outcome of the hospital in-stay was recorded. Results. At data cut-off, 221/664 patients (33.3%) had died and 453/664 (66.7%) had been discharged. Red cell distribution width (RDW) ( χ 2 10.4; p < 0.001 ), neutrophil-to-lymphocyte (NL) ratio ( χ 2 7.6; p = 0.006 ), and platelet count ( χ 2 5.39; p = 0.02 ), along with age ( χ 2 87.6; p < 0.001 ) and gender ( χ 2 17.3; p < 0.001 ), accurately predicted in-hospital mortality. Hemoglobin levels were not associated with mortality. We also identified the best cut-off for mortality prediction: a NL ratio > 4.68 was characterized by an odds ratio for in-hospital mortality OR = 3.40 (2.40-4.82), while the OR for a RDW > 13.7 % was 4.09 (2.87-5.83); a platelet count > 166,000 /μL was, conversely, protective (OR: 0.45 (0.32-0.63)). Conclusion. Our findings arise the opportunity of stratifying COVID-19 severity according to simple lab parameters, which may drive clinical decisions about monitoring and treatment.

Published
2021

8. Is oral antibiotic therapy as effective as intravenous treatment in bacterial osteomyelitis? A real-life experience.

Author

MELIS, F., DE VITO, A., FIORE, V., ROSTAGNO, R., RAVERA, L., BABUDIERI, S., BORRÈ, S., and MADEDDU, G.

Abstract

OBJECTIVE: Osteomyelitis is a relatively understudied disease with no standardized and evidence-based approach to treatment. We aimed to evaluate a cohort of patients with osteomyelitis, comparing the outcomes between intravenous (IV) and oral treatment. PATIENTS AND METHODS: We performed an observational retrospective study on osteomyelitis cases in adult patients seen for care between 2017 and 2019. We collected information on patient characteristics, microbiological etiology, infection treatment, and outcome. In addition, we divided osteomyelitis cases by antibiotic regimens [oral (OTG) vs. intravenous±oral (ITG)] and therapy durations to evaluate outcomes differences. RESULTS: A total of 235 episodes of osteomyelitis were evaluated, with a higher prevalence in male gender. Staphylococci, especially S. aureus, were the most common strains. Out of the 235 evaluated episodes, we selected 142 cases. Of these, 75 were treated with OTG and 67 with ITG. Gram-positive bacteria were the most frequent aetiological agents, with 81 isolates (61.8%). Full recovery was observed in 79 (55.6%) cases; of these, 36 (53.7%) were in the ITG and 43 (57.3%) in the OTG (p = 0.666). At the logistic regression, a polymicrobial infection [OR 4.16 (95%CI 1.28-13.4), p = 0.017] and a less than six weeks treatment duration [OR 4.24 (95%CI 1.38-5.43) p = 0.004] were significantly associated with a higher risk of treatment failure. CONCLUSIONS: Our study suggests that oral treatment efficacy is comparable to ITG therapy for osteomyelitis, confirming the most recent evidence suggesting that oral therapy is non-inferior to intravenous therapy to treat osteomyelitis. [ABSTRACT FROM AUTHOR]

Published
2022

12. Epidemiological and clinical features of prosthetic joint infections caused by gram-negative bacteria.

Author

FANTONI, M., BORRÈ, S., ROSTAGNO, R., RICCIO, G., CARREGA, G., GIOVANNENZE, F., and TACCARI, F.

Abstract

OBJECTIVE: To review the clinical literature focusing on epidemiology, clinical presentation and outcomes of prosthetic joint infections (PJIs) due to gram-negative bacteria (GNB) and to report the experience of a multicentric cohort. PATIENTS AND METHODS: A retrospective, observational, cohort study was performed in three Italian hospitals. All consecutive PJIs caused by GNB over a 12-year period (from May 2007 to March 2018) were enrolled. Epidemiological, clinical, microbiological and therapeutic features were described. Factors related to treatment failure (defined as the occurrence of death, amputation or starting long-term antimicrobial suppression therapy) were analysed with a Cox regression model. RESULTS: A total of 82 PJIs due to GNB (42.7% men; median age 73 years) were studied. The implants included 65 (79.3%) hip, 16 (19.5%) knee and one (1.2%) shoulder. An early PJI was diagnosed in 16.2% of patients, a delayed PJI in 29.4% and a late PJI in 54.4%. The most common isolated organisms were Escherichia coli (21.7%) and Pseudomonas spp. (20.9%). 13.4% of the isolates were carbapenem-resistant bacteria (CRB). In 53.8% of cases a two-stage exchange arthroplasty was performed and in 32.5% a Girdlestone excision arthroplasty. The average therapeutic failure occurred in 17.7% of cases. The therapeutic failure rate of the two-stage was 10%. PJI due to CRB was identified as a potential risk factor for failure (aHR 4.90; IC 95%, 0.96-25.08; p=0.05). The therapeutic failure rate in the CRB group was 50%. CONCLUSIONS: The treatment with the two-stage procedure for PJIs caused by GNB seems to be associated with a low rate of failure, while PJI due to CRB seems to be related to the worst outcome. [ABSTRACT FROM AUTHOR]

Published
2019

13. Dried plasma/blood spots for monitoring antiretroviral treatment efficacy and pharmacokinetics: a cross-sectional study in rural Burundi

Author

Calcagno, Andrea, Motta, Ilaria, Milia, M, Rostagno, R, Simiele, Marco, Libanore, V, Fontana, S, D'Avolio, Antonio, Ghisetti, V, DI PERRI, Giovanni, and Bonora, Stefano

Subjects
Adult, Male, Rural Population, Anti-HIV Agents, Burundi, HIV Infections, Viral Load, Cross-Sectional Studies, Treatment Outcome, Blood Stains, Drug Resistance, Viral, HIV-1, Humans, Female, Pharmacokinetics, Nevirapine, Drug Monitoring, Child
Abstract

In limited resource settings monitoring antiretroviral (ARV) treatment efficacy is restrained by the lack of access to technological equipment. The aim of the study was to assess the use of dried plasma (DPS) and blood spots (DBS) to facilitate ARV monitoring in remote settings where clinical monitoring is the primary strategy.A cross-sectional study in HIV-positive ARV-treated patients in Kiremba, Burundi was performed. DBS were used for HIV-1 viral load (limit of the assay 250 copies ml(-1)) and genotypic drug resistance tests and dried plasma spots were used for concentration measurements.Three hundred and seven patients [201 female (88.6%), 14 children (4.5%)] were enrolled. HIV-1 viral load was250, 250-1000 and1000 copies ml(-1) in 250 (81.7%), 33 (10.8%) and 23 patients (7.5%). Eleven samples out of 23 were successfully amplified revealing nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistance associated mutations [in seven (58.3%) and six patients (50%)]. Nevirapine trough concentrations were3000 ng ml(-1) in 28/189 patients (14.8%) and efavirenz 12 h concentrations were1000 ng ml(-1) in 2/16 patients (12.5%). Children and patients with nevirapine exposure3000 ng ml(-1) presented a higher risk of viral replication.Viral loads250 copies ml(-1) were observed in 81.7% of patients (83.6% adults and 42.9% children). Children and patients with low nevirapine concentrations had higher risk of viral replication. Dried blood and plasma spots may be useful for monitoring HIV-positive patients including viral load and drug level measurement as part of treatment management in remote areas.

Published
2014

14. Randomised study comparing 48 and 96 weeks peginterferon α-2a therapy in genotype D HBeAg-negative chronic hepatitis B

Author

Pegbeliver, Study Group, Colombo, M, Facchetti, F, Massetto, B, Regep, L, Iannacone, C, Giuberti, T, Fargion, S, Farci, P, Boninsegna, S, Di Marco, V, Fasano, M, Sagnelli, E, Di Costanzo, Gg, Viganò, M, Lampertico, P, Andreone, P, Riili, A, Scuteri, A, Cursaro, C, Andriulli, A, Niro, Ga, Angarano, G, Santantonio, Ta, Palattella, Ms, Brunetto, MAURIZIA ROSSANA, Colombatto, P, Coco, B, Ciccorossi, P, Oliveri, F, Sacco, R, Bruno, S, Bollani, S, Chiesa, A, Carosi, G, Baiguera, C, Rossi, S, Zaltron, S, Puoti, M, Cozzolongo, R, Giannuzzi, V, Craxì, A, Calvaruso, V, Venezia, G, Lanza, Ag, Di Perri, G, Cariti, G, Mollaretti, O, De Blasi, T, Kulmiye, C, Rostagno, R, Lai, Me, Serra, G, Chessa, L, Balestrieri, C, Cauli, C, Fargion, Sr, Bertelli, C, Fatta, E, Fattovich, G, Pasino, M, Zanni, S, Olivari, N, Zagni, I, Ferrari, C, Schivazappa, S, Laccabue, D, Penna, A, Gaeta, G, Stanzione, M, Stornaiuolo, G, Martines, D, Raimondo, G, Caccamo, G, Squadrito, G, Isgrò, G, Rizzetto, M, Lagget, M, Carenzi, S, Ruggiero, G, Marrone, A, Messina, V, Di Caprio, Du, Selva, V, Toniutto, P., Lampertico, P, Viganò, M, Di Costanzo, GG, Sagnelli, E, Fasano, M, Di Marco, V, Boninsegna, S, Farci, P, Fargion, S, Giuberti, T, Iannacone, C, Regep, L, Massetto, B, Facchetti, F, Colombo, M, and Calvaruso, V

Subjects
Adult, Male, HBsAg, medicine.medical_specialty, Hepatitis B virus, Time Factors, Anti-HIV Agents, medicine.disease_cause, Gastroenterology, Antiviral Agents, Group B, law.invention, Polyethylene Glycols, Pharmacotherapy, Hepatitis B, Chronic, Randomized controlled trial, law, Pegylated interferon, Internal medicine, medicine, Humans, Hepatitis B e Antigens, business.industry, Lamivudine, Interferon-alpha, Alanine Transaminase, Hepatitis B, Middle Aged, medicine.disease, Recombinant Proteins, Treatment Outcome, Immunology, DNA, Viral, Interferon, Drug Therapy, Combination, Female, business, medicine.drug
Abstract

Treatment with peginterferon α-2a (PegIFN) for 48 weeks is the standard of care for selected HBeAg-negative patients chronically infected with hepatitis B virus (HBV), but with limited treatment efficacy. A study was undertaken to investigate whether treatment extension to 96 weeks improves the outcome in this patient population.128 HBeAg-negative patients (120 genotype D) were randomised to weekly 180 μg PegIFN for 48 weeks (group A, n=51), 180 μg PegIFN for 48 weeks followed by 135 μg weekly for an additional 48 weeks (group B, n=52) or 180 μg PegIFN plus lamivudine (100 mg/day) for 48 weeks then 135 μg PegIFN for 48 weeks (group C, n=25). Endpoints were alanine aminotransferase normalisation plus HBV DNA3400 IU/ml (primary), HBV DNA2000 IU/ml and HBsAg clearance at 48 weeks after treatment.Forty-eight weeks after treatment, six patients in group A and 13 in group B achieved alanine aminotransferase normalisation plus HBV DNA3400 IU/ml (11.8% vs 25.0%, p=0.08), 6 vs 15 patients had HBV DNA2000 IU/ml (11.8% vs 28.8%, p=0.03), 0 vs 3 achieved HBsAg clearance (0% vs 5.8%, p=0.24) and 0 vs 5 had HBsAg10 IU/ml (0% vs 9.6%, p=0.06). While extended PegIFN treatment was the strongest independent predictor of response, the combination with lamivudine did not improve responses. Discontinuation rates were similar among the groups (19.6%, 23.1%, 32.0%, p=0.81) and were mostly due to PegIFN-related adverse events.In HBeAg-negative genotype D patients with chronic hepatitis B, PegIFN treatment for 96 weeks was well tolerated and the post-treatment virological response improved significantly compared with 48 weeks of treatment.http://ClinicalTrials.gov registration number: NCT01095835.

Published
2013

15. A filter‐based cross‐sectional analysis of an HIV‐positive, HAART‐treated cohort in rural Burundi: pharmacokinetics, pharmacogenetics and viral load

Author

Calcagno, A, Milia, Mg, D' Avolio, A, Ndayishimiyae, P, Dusabimana, P, Bonora, S, Cusato, J, Simiele, M, Rostagno, R, Siccardi, M, Audagnotto, S, Ghisetti, V, and Di Perri, G

Subjects
Pharmacokinetics -- Testing, Nevirapine -- Dosage and administration, Pharmacogenetics -- Testing, HIV infection -- Development and progression -- Drug therapy, Health
Abstract

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK, Background In Burundi Triomune® is the first‐line HIV treatment and it is estimated to reach 30% of those in need, but efficacy monitoring does not rely on viral load (VL) [...]

Published
2010
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16. Influence of CYP2B6 and ABCB1 SNPs on nevirapine plasma concentrations in Burundese HIV-positive patients using dried sample spot devices

Author

Calcagno, Andrea, D'Avolio, Antonio, Simiele, Marco, Cusato, Jessica, Rostagno, R., Libanore, V., Baietto, Lorena, Siccardi, Marco, Bonora, Stefano, and DI PERRI, Giovanni

Subjects
Adult, Male, Blood Specimen Collection, ATP Binding Cassette Transporter, Subfamily B, Anti-HIV Agents, Burundi, HIV Infections, Oxidoreductases, N-Demethylating, Middle Aged, Polymorphism, Single Nucleotide, Cytochrome P-450 CYP2B6, Pharmacogenetics, Humans, Female, ATP Binding Cassette Transporter, Subfamily B, Member 1, Aryl Hydrocarbon Hydroxylases, Dried Blood Spot Testing, Nevirapine
Abstract

• Nevirapine pharmacokinetics are affected by several factors including CYP2B6 single nucleotide polymorphisms (SNPs). These genetic profiles are more common in African patients and they affect the drug clearance being associated with higher trough concentrations. Pharmacokinetic/pharmacogenetic (PK/PG) studies are difficult to perform in remote areas where refrigeration is not available, although dried plasma and dried blood methods have been validated.• Dried plasma spots are useful tools for studying nevirapine PK with a good association to plasma concentrations and they can be used in rural areas since a cold chain is not necessary. Dried blood spots can be used to store and analyze patients' DNA for PG polymorphisms. Nevirapine trough concentrations in Burundese patients, not studied so far, are above the target concentration (3000 ng ml(-1) ) in 84% of patients. CYP2B6 (both at position 516 and 983) but not ABCB1 (3435 and 1236) SNPs as well as age correlate with higher nevirapine exposure.The pharmacokinetics (PK) and pharmacogenetics (PG) of nevirapine have been studied in rich and limited-resource countries. CYP2B6 single nucleotide polymorphisms (SNPs) have been associated with decreased drug clearance. We evaluated the PG determinants of nevirapine trough concentrations in a rural cohort in Burundi using easy to store and transport dried sample spot devices.A cross-sectional analysis in HIV-positive nevirapine-treated patients in Kiremba, north of Burundi, was performed in 2009. After blood withdrawal whole blood was stored on dried blood spots and plasma (after centrifugation) was placed on dried plasma spot devices and stored at room temperature. Nevirapine plasma and dried sample spot concentrations were compared to test the clinical usefulness of this method. SNPs in CYP2B6 and ABCB1 (using a real time PCR technique) were analyzed and associated with nevirapine plasma trough concentrations.Nevirapine concentrations measured on dried plasma spot devices were highly related to plasma concentrations in 60 patients, although a negative bias was observed (-18%). Nevirapine trough concentrations were above the target concentration (3000 ng ml(-1) ) in 84% of patients and they were associated with CYP2B6 SNPs (both at position 516 and 983). No effect of ABCB1 SNPs was noted.Dried plasma spot devices are accurate tools for measuring nevirapine concentrations in rural settings where refrigeration is not available, despite a moderate underestimation bias. They allowed the evaluation of nevirapine concentrations in a cohort of HIV-infected people in rural Burundi, confirming very good exposure and correlation with PG polymorphisms in the CYP2B6 encoding gene.

Published
2012

18. Whole-Exome Sequencing Data - Identifying Somatic Mutations

Author

Spinelli, R, Piazza, RG, Pirola, A, Valletta, S, Rostagno, R, Mogavero, A, Marega, M, Kundaningattu Raman, H, Gambacorti Passerini, C, Kasabov, N, Piazza, R, Roberta, R, KUNDANINGATTU RAMAN, H, GAMBACORTI PASSERINI, C, SPINELLI, ROBERTA, PIAZZA, ROCCO GIOVANNI, PIROLA, ALESSANDRA, VALLETTA, SIMONA, MOGAVERO, ANGELA, MAREGA, MANUELA, KUNDANINGATTU RAMAN, HIMA, GAMBACORTI PASSERINI, CARLO, Spinelli, R, Piazza, RG, Pirola, A, Valletta, S, Rostagno, R, Mogavero, A, Marega, M, Kundaningattu Raman, H, Gambacorti Passerini, C, Kasabov, N, Piazza, R, Roberta, R, KUNDANINGATTU RAMAN, H, GAMBACORTI PASSERINI, C, SPINELLI, ROBERTA, PIAZZA, ROCCO GIOVANNI, PIROLA, ALESSANDRA, VALLETTA, SIMONA, MOGAVERO, ANGELA, MAREGA, MANUELA, KUNDANINGATTU RAMAN, HIMA, and GAMBACORTI PASSERINI, CARLO

Abstract

The use of next-generation sequencing instruments to study hematological malignancies generates a tremendous amount of sequencing data. This leads to a challenging bioinformatics problem to store, manage, and analyze terabytes of sequencing data, often generated from extremely different data sources. Our project is mainly focused on sequence analysis of human cancer genomes, in order to identify the genetic lesions underlying the development of tumors. However, the automated detection procedure of somatic mutations and the statistical testing procedure to identify genetic lesions are still an open problem. Therefore, we propose a computational procedure to handle large-scale sequencing data in order to detect exonic somatic mutations in a tumor sample. The proposed pipeline includes several steps based on open-source software and the R language: alignment, detection of mutations, annotation, functional classification, and visualization of results. We analyzed Illumina whole-exome sequencing data from five leukemic patients and five paired controls plus one colon cancer sample and paired control. The results were validated by Sanger sequencing.

Published
2014

19. A bioinformatics procedure to identify and annotate somatic mutations in whole-exome sequencing data

Author

Biganzoli, E, Vellido, A, Ambrogi, F, Tagliaferri, R, Spinelli, R, Piazza, R, Pirola, A, Valletta, S, Rostagno, R, Mogavero, A, Marega, M, KUNDANINGATTU RAMAN, H, GAMBACORTI PASSERINI, C, SPINELLI, ROBERTA, PIAZZA, ROCCO GIOVANNI, PIROLA, ALESSANDRA, VALLETTA, SIMONA, ROSTAGNO, ROBERTA, MOGAVERO, ANGELA, MAREGA, MANUELA, KUNDANINGATTU RAMAN, HIMA, GAMBACORTI PASSERINI, CARLO, Biganzoli, E, Vellido, A, Ambrogi, F, Tagliaferri, R, Spinelli, R, Piazza, R, Pirola, A, Valletta, S, Rostagno, R, Mogavero, A, Marega, M, KUNDANINGATTU RAMAN, H, GAMBACORTI PASSERINI, C, SPINELLI, ROBERTA, PIAZZA, ROCCO GIOVANNI, PIROLA, ALESSANDRA, VALLETTA, SIMONA, ROSTAGNO, ROBERTA, MOGAVERO, ANGELA, MAREGA, MANUELA, KUNDANINGATTU RAMAN, HIMA, and GAMBACORTI PASSERINI, CARLO

Abstract

The application of next-generation sequencing instruments generates a tremendous amount of sequencing data. This leads to a challenging bioinformatics problem to store, manage and analyze terabytes of sequencing data often generated from extremely different data-sources. Our project is mainly focused on the sequence analysis of human cancer genomes, in order to identify the genetic lesions underlying the development of tumors. However, the automated detection procedure of somatic mutations and a statistical based testing procedure to identify genetic lesions are still an open problem. Therefore, we propose a computational procedure to manage large scale sequencing data in order to detect exonic somatic mutations in a tumor sample. The proposed pipeline includes several steps based on open-source softwares and R language: alignment, detection of mutations, annotation, functional classification and visualization of results. We analyzed whole exome sequencing data from 3 leukemic patients and 3 paired controls plus 1 colon cancer sample and paired control. The results were validated by Sanger sequencing. © Springer-Verlag 2012.

Published
2012

20. Three novel patients derived BCR/ABL mutants show different sensitivity to second and third generation tyrosine kinase inhibitors

Author

Redaelli, S, Mologni, L, Rostagno, R, Piazza, R, Magistroni, V, Ceccon, M, Viltadi, M, Flynn, D, GAMBACORTI PASSERINI, C, REDAELLI, SARA, MOLOGNI, LUCA, ROSTAGNO, ROBERTA, PIAZZA, ROCCO GIOVANNI, MAGISTRONI, VERA, CECCON, MONICA, VILTADI, MICHELA, GAMBACORTI PASSERINI, CARLO, Redaelli, S, Mologni, L, Rostagno, R, Piazza, R, Magistroni, V, Ceccon, M, Viltadi, M, Flynn, D, GAMBACORTI PASSERINI, C, REDAELLI, SARA, MOLOGNI, LUCA, ROSTAGNO, ROBERTA, PIAZZA, ROCCO GIOVANNI, MAGISTRONI, VERA, CECCON, MONICA, VILTADI, MICHELA, and GAMBACORTI PASSERINI, CARLO

Abstract

BCR/ABL (Breakpoint Cluster Region protein/Abelson tyrosine-protein kinase 1) kinase domain (KD) mutations represent the most frequently described mechanism of resistance to the treatment with tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukemia (CML). Mutations may impair TKI activity by directly or indirectly impairing the drug binding to the protein. We report the discovery of three new BCR/ABL mutations, L248R, T315V, and F317R identified in two patients with CML (L248R and T315V) and in one patient with Ph1 acute lymphoblastic leukemia (ALL) (F317R). Mutations were screened against second-generation (bosutinib, nilotinib, and dasatinib), as well as third-generation TKIs (ponatinib/AP-24534 and DCC-2036). Furthermore, the activity profile of ponatinib and DCC-2036 against a panel of 24 clinically relevant BCR/ABL mutants is presented and compared to the other TKIs. The IC50 values for each TKI against the mutants and the IC50 increase over wild type BCR/ABL (relative resistance, RR) were calculated to define four resistance levels: sensitive (RR 2), moderately resistant (2 < RR 4), resistant (4 < RR 10), or highly resistant (RR > 10). L248R and T315V showed high resistance to imatinib, bosutinib, dasatinib, and nilotinib, intermediate resistance to ponatinib, but were sensitive to DCC-2036. Interestingly, F317R showed a moderate resistance to imatinib and nilotinib, but is resistant/highly resistant to dasatinib, bosutinib, ponatinib, and DCC-2036. The availability of drugs activity profiles may become a useful tool for clinicians dealing with the treatment of drug-resistant CML patients

Published
2012

21. A computational procedure to identify and annotate somatic mutations in next-generation sequencing data

Author

Biganzoli, E, Tettamanzi, A, Vellido, A, Spinelli, R, Piazza, R, Pirola, A, Valletta, S, Rostagno, R, Mogavero, A, Marega, M, KUNDANINGATTU RAMAN, H, GAMBACORTI PASSERINI, C, SPINELLI, ROBERTA, PIAZZA, ROCCO GIOVANNI, PIROLA, ALESSANDRA, VALLETTA, SIMONA, ROSTAGNO, ROBERTA, MOGAVERO, ANGELA, MAREGA, MANUELA, KUNDANINGATTU RAMAN, HIMA, GAMBACORTI PASSERINI, CARLO, Biganzoli, E, Tettamanzi, A, Vellido, A, Spinelli, R, Piazza, R, Pirola, A, Valletta, S, Rostagno, R, Mogavero, A, Marega, M, KUNDANINGATTU RAMAN, H, GAMBACORTI PASSERINI, C, SPINELLI, ROBERTA, PIAZZA, ROCCO GIOVANNI, PIROLA, ALESSANDRA, VALLETTA, SIMONA, ROSTAGNO, ROBERTA, MOGAVERO, ANGELA, MAREGA, MANUELA, KUNDANINGATTU RAMAN, HIMA, and GAMBACORTI PASSERINI, CARLO

Published
2011

22. A New BCR-ABL1 Mutation (L248R) Is Highly Resistant to Imatinib, Bosutinib, Nilotinib and Dasatinib, but Can Be Inhibited by AP-24534 and DCC-2036

Author

Redaelli, S, Mologni, L, Rostagno, R, Piazza, R, Viltadi, M, Wise, S, Flynn, D, GAMBACORTI PASSERINI, C, REDAELLI, SARA, MOLOGNI, LUCA, ROSTAGNO, ROBERTA, PIAZZA, ROCCO GIOVANNI, VILTADI, MICHELA, GAMBACORTI PASSERINI, CARLO, Redaelli, S, Mologni, L, Rostagno, R, Piazza, R, Viltadi, M, Wise, S, Flynn, D, GAMBACORTI PASSERINI, C, REDAELLI, SARA, MOLOGNI, LUCA, ROSTAGNO, ROBERTA, PIAZZA, ROCCO GIOVANNI, VILTADI, MICHELA, and GAMBACORTI PASSERINI, CARLO

Published
2010

23. WHOLE-EXOME SEQUENCING OF A PHILADELPHIA NEGATIVE CHRONIC MYELOID LEUKEMIA PATIENT THROUGH THE EXON-CAPTURE TECHNIQUE

Author

Piazza, R, Spinelli, R, Pirola, A, Valletta, S, Rostagno, R, Mogavero, A, Marega, M, GAMBACORTI PASSERINI, C, PIAZZA, ROCCO GIOVANNI, SPINELLI, ROBERTA, PIROLA, ALESSANDRA, VALLETTA, SIMONA, ROSTAGNO, ROBERTA, GAMBACORTI PASSERINI, CARLO, Mogavero A, Marega M, Piazza, R, Spinelli, R, Pirola, A, Valletta, S, Rostagno, R, Mogavero, A, Marega, M, GAMBACORTI PASSERINI, C, PIAZZA, ROCCO GIOVANNI, SPINELLI, ROBERTA, PIROLA, ALESSANDRA, VALLETTA, SIMONA, ROSTAGNO, ROBERTA, GAMBACORTI PASSERINI, CARLO, Mogavero A, and Marega M

Published
2010

24. Reply to P. Laneuville et al

Author

Gambacorti-Passerini, C, Piazza, R, Perini, P, Rostagno, R, Redaelli, S, Gambacorti-Passerini, Carlo, Piazza, Rocco, Perini, Pietro, Rostagno, Roberta, Redaelli, Sara, Gambacorti-Passerini, C, Piazza, R, Perini, P, Rostagno, R, Redaelli, S, Gambacorti-Passerini, Carlo, Piazza, Rocco, Perini, Pietro, Rostagno, Roberta, and Redaelli, Sara

Published
2010

25. Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors

Author

Mologni, L, Rostagno, R, Brussolo, S, Knowles, P, Kjaer, S, Murray Rust, J, Rosso, E, Zambon, A, Scapozza, L, Mcdonald, N, Lucchini, V, GAMBACORTI PASSERINI, C, MOLOGNI, LUCA, ROSTAGNO, ROBERTA, Knowles, PP, McDonald, NQ, GAMBACORTI PASSERINI, CARLO, Mologni, L, Rostagno, R, Brussolo, S, Knowles, P, Kjaer, S, Murray Rust, J, Rosso, E, Zambon, A, Scapozza, L, Mcdonald, N, Lucchini, V, GAMBACORTI PASSERINI, C, MOLOGNI, LUCA, ROSTAGNO, ROBERTA, Knowles, PP, McDonald, NQ, and GAMBACORTI PASSERINI, CARLO

Abstract

The synthesis, structure-activity relationships (SAR) and structural data of a series of indolin-2-one inhibitors of RET tyrosine kinase are described. These compounds were designed to explore the available space around the indolinone scaffold within RET active site. Several substitutions at different positions were tested and biochemical data were used to draw a molecular model of steric and electrostatic interactions, which can be applied to design more potent and selective RET inhibitors. The crystal structures of RET kinase domain in complex with three inhibitors were solved. All three compounds bound in the ATP pocket and formed two hydrogen bonds with the kinase hinge region. Crystallographic analysis confirmed predictions from molecular modelling and helped refine SAR results. These data provide important information for the development of indolinone inhibitors for the treatment of RET-driven cancers

Published
2010

26. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants

Author

Redaelli, S, Piazza, R, Rostagno, R, Magistroni, V, Perini, P, Marega, M, GAMBACORTI PASSERINI, C, Boschelli, F, REDAELLI, SARA, PIAZZA, ROCCO GIOVANNI, ROSTAGNO, ROBERTA, MAGISTRONI, VERA, PERINI, PIETRO, MAREGA, MANUELA, GAMBACORTI PASSERINI, CARLO, Boschelli, F., Redaelli, S, Piazza, R, Rostagno, R, Magistroni, V, Perini, P, Marega, M, GAMBACORTI PASSERINI, C, Boschelli, F, REDAELLI, SARA, PIAZZA, ROCCO GIOVANNI, ROSTAGNO, ROBERTA, MAGISTRONI, VERA, PERINI, PIETRO, MAREGA, MANUELA, GAMBACORTI PASSERINI, CARLO, and Boschelli, F.

Published
2009

27. Determination of the Activity Profile of Bosutinib, Dasatinib and Nilotinib against 18 Imatinib Resistant Bcr/Abl Mutants

Author

Redaelli, S, Piazza, R, Rostagno, R, Sassone, M, Magistroni, V, Perini, P, Marega, M, Boschelli, F, GAMBACORTI PASSERINI, C, REDAELLI, SARA, PIAZZA, ROCCO GIOVANNI, ROSTAGNO, ROBERTA, SASSONE, MARIANNA CAROLINA, MAGISTRONI, VERA, PERINI, PIETRO, MAREGA, MANUELA, GAMBACORTI PASSERINI, CARLO, Redaelli, S, Piazza, R, Rostagno, R, Sassone, M, Magistroni, V, Perini, P, Marega, M, Boschelli, F, GAMBACORTI PASSERINI, C, REDAELLI, SARA, PIAZZA, ROCCO GIOVANNI, ROSTAGNO, ROBERTA, SASSONE, MARIANNA CAROLINA, MAGISTRONI, VERA, PERINI, PIETRO, MAREGA, MANUELA, and GAMBACORTI PASSERINI, CARLO

Published
2008

28. Inhibition of RET tyrosine kinase by SU5416

Author

Mologni, L, Sala, E, Cazzaniga, S, Rostagno, R, Kuoni, T, Puttini, M, Bain, J, Cleris, L, Redaelli, S, Riva, B, Formelli, F, Scapozza, L, GAMBACORTI PASSERINI, C, MOLOGNI, LUCA, ROSTAGNO, ROBERTA, PUTTINI, MIRIAM, REDAELLI, SARA, GAMBACORTI PASSERINI, CARLO, Mologni, L, Sala, E, Cazzaniga, S, Rostagno, R, Kuoni, T, Puttini, M, Bain, J, Cleris, L, Redaelli, S, Riva, B, Formelli, F, Scapozza, L, GAMBACORTI PASSERINI, C, MOLOGNI, LUCA, ROSTAGNO, ROBERTA, PUTTINI, MIRIAM, REDAELLI, SARA, and GAMBACORTI PASSERINI, CARLO

Abstract

Thyroid neoplasia is frequently associated with rearranged during transfection (RET) proto-oncogene mutations that cause hyperactivation of RET kinase activity. Selective inhibition of RET-mediated signaling should lead to an efficacious therapy. SU5416 is a potent inhibitor of vascular endothelial cell growth factor receptor, c-Kit, and FLT-3 receptor tyrosine kinases presently used in clinical trials. We found that SU5416 inhibits RET with similar potency, both in cell-free assays and in cells, thus causing proliferation arrest in oncogenic RET-transfected cells and in papillary thyroid carcinoma (PTC) cells expressing the RET/PTC1 oncogene, but not in RET-negative control cells. SU5416 inhibited RET-mediated signaling through the extracellular signal regulated kinase (ERK) and JNK pathways. In addition, we show that a naturally occurring MEN2 mutation at codon 804 confers resistance to SU5416, but not to the related compound SU4984. We provide a possible explanation to these results by using molecular docking. Finally, SU5416 was also assessed against an array of 52 tyrosine and serine/threonine kinases.

Published
2006

29. Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias

Author

GAMBACORTI PASSERINI, C, Gunby, R, Piazza, R, Galietta, A, Rostagno, R, Scapozza, L, GAMBACORTI PASSERINI, CARLO, PIAZZA, ROCCO GIOVANNI, ROSTAGNO, ROBERTA, Scapozza, L., GAMBACORTI PASSERINI, C, Gunby, R, Piazza, R, Galietta, A, Rostagno, R, Scapozza, L, GAMBACORTI PASSERINI, CARLO, PIAZZA, ROCCO GIOVANNI, ROSTAGNO, ROBERTA, and Scapozza, L.

Abstract

Imatinib (STI571 or CGP57148B) is an innovative treatment for tumours with a constitutively activated form of c-ABL, c-KIT, or PDGFR. Such tumours include Philadelphia-chromosome-positive (Ph-positive) leukaemias, gastrointestinal stromal tumours, and PDGFR-positive leukaemias. Diseases such as primary hypereosinophilia and dermatofibrosarcoma protuberans also seem to respond to imatinib. Clinical trials assessing the therapeutic effects of imatinib have shown that the drug is highly effective with few associated side-effects, achieving durable cytogenetic responses in many patients with chronic-phase BCR-ABL-positive leukaemias. However, the emergence of resistance, particularly in patients with acute leukaemias, has prompted intense research, and many are concerned about the future prospects for imatinib. The resistance has been found in patients with acute-phase disease, but may also occur in patients with chronic-phase disease. Two cellular mechanisms for resistance to imatinib have been identified: amplification of BCR-ABL gene and mutations in the catalytic domain of the protein. In addition, suboptimum inhibition of BCR-ABL in vivo could contribute to the selection of resistant cells. We have summarised all currently available data on resistance to imatinib, both published and unpublished, including the mechanisms of resistance identified so far, and their clinical relevance to the different forms of Ph-positive leukaemias is discussed. Furthermore, we discuss strategies to overcome or prevent the development of resistance

Published
2003

45. Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias.

Author

Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L, Gambacorti-Passerini, Carlo B, Gunby, Rosalind H, Piazza, Rocco, Galietta, Annamaria, Rostagno, Roberta, and Scapozza, Leonardo

Abstract

Imatinib (STI571 or CGP57148B) is an innovative treatment for tumours with a constitutively activated form of c-ABL, c-KIT, or PDGFR. Such tumours include Philadelphia-chromosome-positive (Ph-positive) leukaemias, gastrointestinal stromal tumours, and PDGFR-positive leukaemias. Diseases such as primary hypereosinophilia and dermatofibrosarcoma protuberans also seem to respond to imatinib. Clinical trials assessing the therapeutic effects of imatinib have shown that the drug is highly effective with few associated side-effects, achieving durable cytogenetic responses in many patients with chronic-phase BCR-ABL-positive leukaemias. However, the emergence of resistance, particularly in patients with acute leukaemias, has prompted intense research, and many are concerned about the future prospects for imatinib. The resistance has been found in patients with acute-phase disease, but may also occur in patients with chronic-phase disease. Two cellular mechanisms for resistance to imatinib have been identified: amplification of BCR-ABL gene and mutations in the catalytic domain of the protein. In addition, suboptimum inhibition of BCR-ABL in vivo could contribute to the selection of resistant cells. We have summarised all currently available data on resistance to imatinib, both published and unpublished, including the mechanisms of resistance identified so far, and their clinical relevance to the different forms of Ph-positive leukaemias is discussed. Furthermore, we discuss strategies to overcome or prevent the development of resistance. [ABSTRACT FROM AUTHOR]

Published
2003
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46. Whole-Exome Sequencing Data - Identifying Somatic Mutations

Author

M Marega, Hima Raman, Angela Mogavero, Simona Valletta, Roberta Spinelli, Roberta Rostagno, Alessandra Pirola, Rocco Piazza, Carlo Gambacorti-Passerini, Spinelli, R, Piazza, RG, Pirola, A, Valletta, S, Rostagno, R, Mogavero, A, Marega, M, Kundaningattu Raman, H, Gambacorti Passerini, C, Kasabov, N, Piazza, R, Roberta, R, KUNDANINGATTU RAMAN, H, and GAMBACORTI PASSERINI, C

Subjects
Sanger sequencing, Genetics, R language, Annotation, symbols.namesake, Germline mutation, Sequence analysis, Somatic cell, symbols, R language, somatic mutation, aCML, CML, Biology, Genome, Exome sequencing
Abstract

The use of next-generation sequencing instruments to study hematological malignancies generates a tremendous amount of sequencing data. This leads to a challenging bioinformatics problem to store, manage, and analyze terabytes of sequencing data, often generated from extremely different data sources. Our project is mainly focused on sequence analysis of human cancer genomes, in order to identify the genetic lesions underlying the development of tumors. However, the automated detection procedure of somatic mutations and the statistical testing procedure to identify genetic lesions are still an open problem. Therefore, we propose a computational procedure to handle large-scale sequencing data in order to detect exonic somatic mutations in a tumor sample. The proposed pipeline includes several steps based on open-source software and the R language: alignment, detection of mutations, annotation, functional classification, and visualization of results. We analyzed Illumina whole-exome sequencing data from five leukemic patients and five paired controls plus one colon cancer sample and paired control. The results were validated by Sanger sequencing.

Published
2014

47. A bioinformatics procedure to identify and annotate somatic mutations in whole-exome sequencing data

Author

Angela Mogavero, Simona Valletta, Alessandra Pirola, M Marega, Roberta Rostagno, Roberta Spinelli, Hima Raman, Rocco Piazza, Carlo Gambacorti-Passerini, Biganzoli, E, Vellido, A, Ambrogi, F, Tagliaferri, R, Spinelli, R, Piazza, R, Pirola, A, Valletta, S, Rostagno, R, Mogavero, A, Marega, M, KUNDANINGATTU RAMAN, H, and GAMBACORTI PASSERINI, C

Subjects
Sanger sequencing, symbols.namesake, Annotation, Computer science, Somatic cell, Sequence analysis, symbols, Next-Generation Sequencing, leukemia, colon cancer, somatic mutation, Bioinformatics, Large-Scale Sequencing, Genome, DNA sequencing, Exome sequencing
Abstract

The application of next-generation sequencing instruments generates a tremendous amount of sequencing data. This leads to a challenging bioinformatics problem to store, manage and analyze terabytes of sequencing data often generated from extremely different data-sources. Our project is mainly focused on the sequence analysis of human cancer genomes, in order to identify the genetic lesions underlying the development of tumors. However, the automated detection procedure of somatic mutations and a statistical based testing procedure to identify genetic lesions are still an open problem. Therefore, we propose a computational procedure to manage large scale sequencing data in order to detect exonic somatic mutations in a tumor sample. The proposed pipeline includes several steps based on open-source softwares and R language: alignment, detection of mutations, annotation, functional classification and visualization of results. We analyzed whole exome sequencing data from 3 leukemic patients and 3 paired controls plus 1 colon cancer sample and paired control. The results were validated by Sanger sequencing. © Springer-Verlag 2012.

Published
2012

48. Three novel patients derived BCR/ABL mutants show different sensitivity to second and third generation tyrosine kinase inhibitors

Author

Luca Mologni, Roberta Rostagno, Michela Viltadi, Vera Magistroni, Rocco Piazza, Carlo Gambacorti-Passerini, Daniel L. Flynn, Sara Redaelli, Monica Ceccon, Redaelli, S, Mologni, L, Rostagno, R, Piazza, R, Magistroni, V, Ceccon, M, Viltadi, M, Flynn, D, and GAMBACORTI PASSERINI, C

Subjects
Cell Culture Techniques, Fusion Proteins, bcr-abl, Antineoplastic Agents, Transfection, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Sequence Analysis, Protein, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, hemic and lymphatic diseases, Tumor Cells, Cultured, medicine, Animals, Humans, Protein Kinase Inhibitors, ABL, business.industry, Ponatinib, breakpoint cluster region, BCR/ABL, TK inhibitors, Imatinib, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Protein-Tyrosine Kinases, Dasatinib, Nilotinib, chemistry, Drug Resistance, Neoplasm, Mutation, Mutagenesis, Site-Directed, Cancer research, business, Bosutinib, Tyrosine kinase, medicine.drug
Abstract

BCR/ABL (Breakpoint Cluster Region protein/Abelson tyrosine-protein kinase 1) kinase domain (KD) mutations represent the most frequently described mechanism of resistance to the treatment with tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukemia (CML). Mutations may impair TKI activity by directly or indirectly impairing the drug binding to the protein. We report the discovery of three new BCR/ABL mutations, L248R, T315V, and F317R identified in two patients with CML (L248R and T315V) and in one patient with Ph1 acute lymphoblastic leukemia (ALL) (F317R). Mutations were screened against second-generation (bosutinib, nilotinib, and dasatinib), as well as third-generation TKIs (ponatinib/AP-24534 and DCC-2036). Furthermore, the activity profile of ponatinib and DCC-2036 against a panel of 24 clinically relevant BCR/ABL mutants is presented and compared to the other TKIs. The IC50 values for each TKI against the mutants and the IC50 increase over wild type BCR/ABL (relative resistance, RR) were calculated to define four resistance levels: sensitive (RR 2), moderately resistant (2 < RR 4), resistant (4 < RR 10), or highly resistant (RR > 10). L248R and T315V showed high resistance to imatinib, bosutinib, dasatinib, and nilotinib, intermediate resistance to ponatinib, but were sensitive to DCC-2036. Interestingly, F317R showed a moderate resistance to imatinib and nilotinib, but is resistant/highly resistant to dasatinib, bosutinib, ponatinib, and DCC-2036. The availability of drugs activity profiles may become a useful tool for clinicians dealing with the treatment of drug-resistant CML patients

Published
2012

49. A computational procedure to identify and annotate somatic mutations in next-generation sequencing data

Author

SPINELLI, ROBERTA, PIAZZA, ROCCO GIOVANNI, PIROLA, ALESSANDRA, VALLETTA, SIMONA, ROSTAGNO, ROBERTA, MOGAVERO, ANGELA, MAREGA, MANUELA, KUNDANINGATTU RAMAN, HIMA, GAMBACORTI PASSERINI, CARLO, Biganzoli, E, Tettamanzi, A, Vellido, A, Spinelli, R, Piazza, R, Pirola, A, Valletta, S, Rostagno, R, Mogavero, A, Marega, M, KUNDANINGATTU RAMAN, H, and GAMBACORTI PASSERINI, C

Subjects
next-generation sequencing, computational procedure, somatic mutations, leukemia, colon cancer, MED/09 - MEDICINA INTERNA
Published
2011

50. WHOLE-EXOME SEQUENCING OF A PHILADELPHIA NEGATIVE CHRONIC MYELOID LEUKEMIA PATIENT THROUGH THE EXON-CAPTURE TECHNIQUE

Author

PIAZZA, ROCCO GIOVANNI, SPINELLI, ROBERTA, PIROLA, ALESSANDRA, VALLETTA, SIMONA, ROSTAGNO, ROBERTA, GAMBACORTI PASSERINI, CARLO, Mogavero A, Marega M, Piazza, R, Spinelli, R, Pirola, A, Valletta, S, Rostagno, R, Mogavero, A, Marega, M, and GAMBACORTI PASSERINI, C

Subjects
MED/15 - MALATTIE DEL SANGUE, Whole-Exome Sequencing, Atypical Chronic Myeloid Leukemia, Somatic variantsm high-throughput sequencing
Published
2010

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