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19 results on '"Spina, E."'

1. Effect of centre volume on pathological outcomes and postoperative complications after surgery for colorectal cancer: results of a multicentre national study

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Rottoli, M, Spinelli, A, Pellino, G, Gori, A, Calini, G, Flacco, M, Manzoli, L, Poggioli, G, Romano, A, Belvedere, A, Lanci, A, Parlanti, D, Vago, G, Pezzuto, A, Canavese, A, Dajti, G, Cardelli, S, Catalioto, C, Russo, I, Violante, T, Morezzi, D, Maurino, L, Filippone, E, Cuicchi, D, Bernante, P, Jovine, E, Lombardi, R, Masetti, M, Cipressi, C, Offi, M, Larotonda, C, Puglisi, S, Barbosa, A, Vaiana, R, Bianchi, P, Tonti, C, Codignola, C, Zorcolo, L, Restivo, A, Deidda, S, Marchetti, M, Ippolito, L, Spolverato, G, Pucciarelli, S, Marchegiani, F, Ghio, G, Zagolin, G, Glavas, D, Tomassi, M, Rosati, R, Elmore, U, Gozzini, L, Calef, R, Puccetti, F, Cossu, A, Vignali, A, Morino, M, Allaix, M, Cannata, G, Lombardi, E, Ammirati, C, Piceni, C, Buccianti, P, Balestri, R, Puccini, M, Pezzati, D, D'Ischia, R, Asta, V, Sargenti, B, Taddei, G, Bonari, F, Boni, G, Ferrero, A, Mineccia, M, Gonella, F, Palisi, M, Danese, F, Cherubini, V, Perotti, S, Carvello, M, Carbone, F, Luberto, A, Calafiore, E, De Lucia, F, Sacchi, M, Sasia, D, Giuffrida, M, Ballauri, E, Cardile, M, Armentano, S, Beltrami, E, Preve, G, Vercellone, B, Mozzon, M, Folliero, C, Lirusso, C, Vecchiato, M, Ziccarelli, A, Gattesco, D, Moretti, L, Crestale, S, Banchini, F, Capelli, P, Romboli, A, Palmieri, G, Conti, L, Rizzi, N, Bonfili, D, De Manzini, N, Germani, P, Osenda, E, Cortinovis, S, Giunta, C, Fracon, S, Abdallah, H, Bogoni, S, Portolani, N, Nascimbeni, R, Molfino, S, Tiberio, G, Garosio, I, Lamperti, G, Rigosa, D, Ercolani, G, Solaini, L, Cavaliere, D, Avanzolini, A, D'Acapito, F, Chiarella, L, Di Pietrantonio, D, Annunziata, D, Piccolo, R, Sorrentino, M, Pansini, M, Cojutti, A, Graziano, M, Callegari, F, Balzarotti, L, Dameno, V, Cattaneo, A, Santolamazza, G, Altieri, C, Magarini, R, Pietrabissa, A, Dominioni, T, Pugliese, L, Peri, A, Botti, M, Salvetti, F, Boni, L, Cassinotti, E, Baldari, L, Messina, V, D'Abrosca, V, Cianci, P, Tumolo, R, Gattulli, D, Restini, E, Minafra, M, Sederino, M, Bottalico, B, Pilati, P, Franzato, B, Mattara, G, De Simoni, O, Barina, A, Tonello, M, Muratore, A, Calabro, M, Federico Pipitone, N, Cuzzola, B, Van Nood, E, Passuello, N, Frasson, A, Mammano, E, Faccio, L, Vittadello, F, Bressan, A, Sarzo, G, Tamini, N, Oldani, M, Cigagna, L, Carissimi, F, De Carlo, G, Baccalini, E, Nespoli, L, Giordano, A, Cantafio, S, Grifoni, L, Matani, D, Livi, S, Delogu, D, Scognamillo, F, Marrosu, A, Guerrini, L, Ugolini, G, Ghignone, F, Frascaroli, G, Albertini, N, Zattoni, D, Taffurelli, G, Montroni, I, Colombo, F, Danelli, P, Bondurri, A, Maffioli, A, Bonomi, A, Pezzoli, I, Cammarata, F, Goletti, O, Molteni, M, Assisi, A, Quartierini, G, Da Lio, C, Verdi, D, Mondi, I, Peluso, C, Macchi, L, Tanzanu, M, Zanzi, F, Pellegrini, S, Andreuccetti, J, D'Alessio, R, Pignata, G, De Capua, M, Canfora, I, Ottaviani, L, Lepiane, P, Balla, A, De Carlo, A, Saraceno, F, Scaramuzzo, R, Guida, A, Aguzzi, D, Bellora, P, Gentilli, S, Monni, M, Nikaj, H, Cillara, N, Cannavera, A, Deserra, A, Margiani, C, Cabula, R, Dettori, M, Gramignano, G, Lezoche, G, Ortenzi, M, Orlandoni, E, Curzi, F, Vitali, F, Capomagi, P, Palmieri, M, Del Rio, P, Bonati, E, Loderer, T, Cozzani, F, Rossini, M, Agnesi, S, Capolupo, G, Caricato, M, Carannante, F, Masciana, G, Marrelli, M, Miacci, V, Lauricella, S, Tonini, V, Cervellera, M, Pisconti, S, Lozito, C, Shahu, J, Mongelli, C, Morelli, G, Sartarelli, L, Sica, G, Siragusa, L, Bagaglini, G, Franceschilli, M, Bellato, V, Fiorani, C, Taddei, A, Risaliti, M, Bartolini, I, Ringressi, M, Tirloni, L, Laface, L, Abate, E, Casati, M, Gobbi, P, Opocher, E, Mariani, N, Ceretti, A, Giovenzana, M, Giuliani, B, Sironi, M, Grossi, U, Zanus, G, Santoro, G, Brizzolari, M, De Leo, E, Novello, S, Aquilino, K, Milardi, F, Olmi, S, Uccelli, M, Bonaldi, M, Cesana, G, Bindi, M, Galleano, R, Langone, A, Botto, M, Franceschi, A, Gambino, E, Ronconi, M, Casiraghi, S, Casole, G, Ciulla, S, Terrosu, G, Calandra, S, Scarpa, E, Cherchi, V, Martinuzzo, L, Clocchiatti, L, Muschitiello, D, Romanzi, A, Vignati, B, Vannelli, A, Scolaro, R, Milanesi, M, Rossi, F, Canonico, G, Anastasi, A, Nelli, T, Barlettai, M, Fratarcangeli, R, Di Martino, C, Damigella, A, Adinolfi, E, Birindelli, A, Taglietti, L, Dester, S, Fleres, F, Cucinotta, E, Viscosi, F, Biondo, S, Badessi, G, Catarsini, N, Mazzeo, C, Rega, D, Delrio, P, Cervone, C, Aversano, A, De Franciscis, S, Di Marzo, M, Marra, B, Pace, U, Amato, A, Batistotti, P, Mina, E, Serventi, A, Lapolla, P, Mingoli, A, Sapienza, P, Brachini, G, Cirillo, B, Fiori, E, Crocetti, D, Clementi, I, Martines, G, Picciariello, A, Tomasicchio, G, Dibra, R, Trigiante, G, Rinaldi, M, Lantone, G, Porcu, A, Perra, T, Scanu, A, Feo, C, Fancellu, A, Cossu, M, Ginesu, G, Patriti, A, Coletta, D, Petrelli, F, Greco, P, Spadoni, C, Cassiani, G, Bianchini, F, Arganini, M, Bianchini, M, Perotti, B, Palmeri, M, Scabini, S, Deiana, S, Carganico, G, Pertile, D, Soriero, D, Fioravanti, E, Sperotto, B, Nardo, B, Paglione, D, Crocco, V, Doni, M, Osso, M, Perri, R, Sampietro, G, Corbellini, C, Lorusso, L, Manzo, C, Cigognini, M, Baldi, C, Palomba, G, Aprea, G, Capuano, M, Basile, R, Tutino, R, Massani, M, Marinelli, L, Canitano, N, Pilia, T, Podda, M, Pisanu, A, Murzi, V, Incani, S, Frongia, F, Esposito, G, Luglio, G, Tropeano, F, Pagano, G, Spina, E, De Simone, G, Cricri, M, Catena, F, Vallicelli, C, Zanini, N, Ronconi, D, Favi, F, Mazzucchelli, C, Convertini, G, Vincenti, L, Andriola, V, Bizzoca, C, Fabbri, N, Fazzin, M, Pesce, A, Gennari, S, Torchiaro, M, Severi, S, Frontali, A, Bracchetti, G, Granieri, S, Cotsoglou, C, Carlini, M, Lisi, G, Spoletini, D, Mastrangeli, M, Campanelli, M, Manigrasso, M, Milone, M, De Palma, G, Vertaldi, S, Chini, A, Maione, F, Marello, A, Selvaggi, F, Sciaudone, G, Selvaggi, L, Tasselli, F, Fuschillo, G, Oddis, L, Grande, S, Grande, M, Ascanelli, S, Chimisso, L, Aisoni, F, Rossin, E, Pepe, F, Marchetti, F, Picardi, B, Rossi, S, Del Monte, S, Picarelli, M, Muttillo, I, Ratto, C, Marra, A, Parello, A, Litta, F, Campenni, P, De Simone, V, Pata, F, Riboni, C, Rausa, E, Celentano, V, Rottoli M., Spinelli A., Pellino G., Gori A., Calini G., Flacco M. E., Manzoli L., Poggioli G., Romano A., Belvedere A., Lanci A. L., Parlanti D., Vago G., Pezzuto A. P., Canavese A., Dajti G., Cardelli S., Catalioto C., Russo I. S., Violante T., Morezzi D., Maurino L., Filippone E., Cuicchi D., Bernante P., Jovine E., Lombardi R., Masetti M., Cipressi C., Offi M. F., Larotonda C., Puglisi S. B., Barbosa A., Vaiana R., Bianchi P. M., Tonti C., Codignola C., Zorcolo L., Restivo A., Deidda S., Marchetti M. E., Ippolito L., Spolverato G., Pucciarelli S., Marchegiani F., Ghio G., Zagolin G., Glavas D., Tomassi M., Rosati R., Elmore U., Gozzini L., Calef R., Puccetti F., Cossu A., Vignali A., Morino M., Allaix M. E., Cannata G., Lombardi E., Ammirati C. A., Piceni C., Buccianti P., Balestri R., Puccini M., Pezzati D., D'Ischia R., Asta V. F., Sargenti B., Taddei G., Bonari F., Boni G., Ferrero A., Mineccia M., Gonella F., Palisi M., Danese F., Cherubini V., Perotti S., Carvello M., Carbone F., Luberto A., Calafiore E., De Lucia F., Sacchi M., Sasia D., Giuffrida M. C., Ballauri E., Cardile M., Armentano S., Beltrami E., Preve G., Vercellone B., Mozzon M., Folliero C., Lirusso C., Vecchiato M., Ziccarelli A., Gattesco D., Moretti L., Crestale S., Banchini F., Capelli P., Romboli A., Palmieri G., Conti L., Rizzi N., Bonfili D., De Manzini N., Germani P., Osenda E., Cortinovis S., Giunta C., Fracon S., Abdallah H., Bogoni S., Portolani N., Nascimbeni R., Molfino S., Tiberio G. A. M., Garosio I., Lamperti G., Rigosa D., Ercolani G., Solaini L., Cavaliere D., Avanzolini A., D'Acapito F., Chiarella L. L., Di Pietrantonio D., Annunziata D., Piccolo R., Sorrentino M., Pansini M., Cojutti A., Graziano M., Callegari F., Balzarotti L., Dameno V. R., Cattaneo A., Santolamazza G., Altieri C., Magarini R., Pietrabissa A., Dominioni T., Pugliese L., Peri A., Botti M., Salvetti F., Boni L., Cassinotti E., Baldari L., Messina V., D'Abrosca V., Cianci P., Tumolo R., Gattulli D., Restini E., Minafra M., Sederino M. G., Bottalico B., Pilati P., Franzato B., Mattara G., De Simoni O., Barina A., Tonello M., Muratore A., Calabro M., Federico Pipitone N. S., Cuzzola B., Van Nood E. H., Passuello N., Frasson A., Mammano E., Faccio L., Vittadello F., Bressan A., Sarzo G., Tamini N., Oldani M., Cigagna L., Carissimi F., De Carlo G., Baccalini E., Nespoli L., Giordano A., Cantafio S., Grifoni L., Matani D., Livi S., Delogu D., Scognamillo F., Marrosu A., Guerrini L., Ugolini G., Ghignone F., Frascaroli G., Albertini N., Zattoni D., Taffurelli G., Montroni I., Colombo F., Danelli P., Bondurri A., Maffioli A., Bonomi A., Pezzoli I., Cammarata F., Goletti O., Molteni M., Assisi A., Quartierini G., Da Lio C., Verdi D., Mondi I., Peluso C., MacChi L., Tanzanu M., Zanzi F., Pellegrini S., Andreuccetti J., D'Alessio R., Pignata G., De Capua M., Canfora I., Ottaviani L., Lepiane P., Balla A., De Carlo A., Saraceno F., Scaramuzzo R., Guida A., Aguzzi D., Bellora P., Gentilli S., Monni M., Nikaj H., Cillara N., Cannavera A., Deserra A., Margiani C., Cabula R., Dettori M., Gramignano G., Lezoche G., Ortenzi M., Orlandoni E. S., Curzi F., Vitali F., Capomagi P., Palmieri M., Giuffrida M., Del Rio P., Bonati E., Loderer T., Cozzani F., Rossini M., Agnesi S., Capolupo G. T., Caricato M., Carannante F., Masciana G., Marrelli M., Miacci V., Lauricella S., Tonini V., Cervellera M., Pisconti S., Lozito C., Shahu J., Mongelli C., Morelli G., Sartarelli L., Sica G. S., Siragusa L., Bagaglini G., Guida A. M., Franceschilli M., Bellato V., Fiorani C., Taddei A., Risaliti M., Bartolini I., Ringressi M. N., Tirloni L., Laface L., Abate E., Casati M., Gobbi P., Opocher E., Mariani N. M., Ceretti A. P., Giovenzana M., Giuliani B., Sironi M., Grossi U., Zanus G., Santoro G. A., Brizzolari M., De Leo E., Novello S., Aquilino K., Milardi F., Olmi S., Uccelli M., Bonaldi M., Cesana G. C., Bindi M., Galleano R., Langone A., Botto M., Franceschi A., Gambino E., Ronconi M., Casiraghi S., Casole G., Ciulla S. L., Terrosu G., Calandra S., Scarpa E., Cherchi V., Martinuzzo L., Clocchiatti L., Muschitiello D., Romanzi A., Vignati B., Vannelli A., Scolaro R., Milanesi M., Rossi F., Canonico G., Anastasi A., Nelli T., Barlettai M., Fratarcangeli R., Di Martino C., Damigella A., Adinolfi E., Birindelli A., Taglietti L., Dester S. E., Fleres F., Cucinotta E., Viscosi F., Biondo S. A., Badessi G., Catarsini N., Mazzeo C., Rega D., Delrio P., Cervone C., Aversano A., De Franciscis S., Di Marzo M., Marra B., Pace U., Amato A., Batistotti P., Mina E., Serventi A., Lapolla P., Mingoli A., Sapienza P., Brachini G., Cirillo B., Fiori E., Crocetti D., Clementi I., Martines G., Picciariello A., Tomasicchio G., Dibra R., Trigiante G., Rinaldi M., Lantone G., Porcu A., Perra T., Scanu A. M., Feo C. F., Fancellu A., Cossu M. L., Ginesu G. C., Patriti A., Coletta D., Petrelli F., Greco P. A., Spadoni C., Cassiani G., Bianchini F., Arganini M., Bianchini M., Perotti B., Palmeri M., Scabini S., Deiana S., Carganico G., Pertile D., Soriero D., Fioravanti E., Sperotto B., Nardo B., Paglione D., Crocco V., Doni M., Osso M., Perri R., Sampietro G. M., Corbellini C., Lorusso L., Manzo C. A., Cigognini M., Baldi C., Palomba G., Aprea G., Capuano M., Basile R., Tutino R., Massani M., Marinelli L., Canitano N., Pilia T., Podda M., Pisanu A., Murzi V., Incani S., Frongia F., Esposito G., Luglio G., Tropeano F. P., Pagano G., Spina E., De Simone G., Cricri M., Catena F., Vallicelli C., Zanini N., Ronconi D., Favi F., Mazzucchelli C., Convertini G., Vincenti L., Andriola V., Bizzoca C., Feo C. V., Fabbri N., Fazzin M., Pesce A., Gennari S., Torchiaro M., Severi S., Frontali A., Bracchetti G., Granieri S., Cotsoglou C., Carlini M., Lisi G., Spoletini D., Mastrangeli M. R., Campanelli M., Manigrasso M., Milone M., De Palma G. D., Vertaldi S., Chini A., Maione F., Marello A., Selvaggi F., Sciaudone G., Selvaggi L., Tasselli F. M., Fuschillo G., Oddis L., Grande S., Grande M., Ascanelli S., Chimisso L., Aisoni F., Rossin E., Pepe F., Marchetti F., Picardi B., Rossi S., Del Monte S. R., Picarelli M., Muttillo I. A., Ratto C., Marra A. A., Parello A., Litta F., Campenni P., De Simone V., Pata F., Riboni C., Rausa E., Celentano V., Rottoli, M, Spinelli, A, Pellino, G, Gori, A, Calini, G, Flacco, M, Manzoli, L, Poggioli, G, Romano, A, Belvedere, A, Lanci, A, Parlanti, D, Vago, G, Pezzuto, A, Canavese, A, Dajti, G, Cardelli, S, Catalioto, C, Russo, I, Violante, T, Morezzi, D, Maurino, L, Filippone, E, Cuicchi, D, Bernante, P, Jovine, E, Lombardi, R, Masetti, M, Cipressi, C, Offi, M, Larotonda, C, Puglisi, S, Barbosa, A, Vaiana, R, Bianchi, P, Tonti, C, Codignola, C, Zorcolo, L, Restivo, A, Deidda, S, Marchetti, M, Ippolito, L, Spolverato, G, Pucciarelli, S, Marchegiani, F, Ghio, G, Zagolin, G, Glavas, D, Tomassi, M, Rosati, R, Elmore, U, Gozzini, L, Calef, R, Puccetti, F, Cossu, A, Vignali, A, Morino, M, Allaix, M, Cannata, G, Lombardi, E, Ammirati, C, Piceni, C, Buccianti, P, Balestri, R, Puccini, M, Pezzati, D, D'Ischia, R, Asta, V, Sargenti, B, Taddei, G, Bonari, F, Boni, G, Ferrero, A, Mineccia, M, Gonella, F, Palisi, M, Danese, F, Cherubini, V, Perotti, S, Carvello, M, Carbone, F, Luberto, A, Calafiore, E, De Lucia, F, Sacchi, M, Sasia, D, Giuffrida, M, Ballauri, E, Cardile, M, Armentano, S, Beltrami, E, Preve, G, Vercellone, B, Mozzon, M, Folliero, C, Lirusso, C, Vecchiato, M, Ziccarelli, A, Gattesco, D, Moretti, L, Crestale, S, Banchini, F, Capelli, P, Romboli, A, Palmieri, G, Conti, L, Rizzi, N, Bonfili, D, De Manzini, N, Germani, P, Osenda, E, Cortinovis, S, Giunta, C, Fracon, S, Abdallah, H, Bogoni, S, Portolani, N, Nascimbeni, R, Molfino, S, Tiberio, G, Garosio, I, Lamperti, G, Rigosa, D, Ercolani, G, Solaini, L, Cavaliere, D, Avanzolini, A, D'Acapito, F, Chiarella, L, Di Pietrantonio, D, Annunziata, D, Piccolo, R, Sorrentino, M, Pansini, M, Cojutti, A, Graziano, M, Callegari, F, Balzarotti, L, Dameno, V, Cattaneo, A, Santolamazza, G, Altieri, C, Magarini, R, Pietrabissa, A, Dominioni, T, Pugliese, L, Peri, A, Botti, M, Salvetti, F, Boni, L, Cassinotti, E, Baldari, L, Messina, V, D'Abrosca, V, Cianci, P, Tumolo, R, Gattulli, D, Restini, E, Minafra, M, Sederino, M, Bottalico, B, Pilati, P, Franzato, B, Mattara, G, De Simoni, O, Barina, A, Tonello, M, Muratore, A, Calabro, M, Federico Pipitone, N, Cuzzola, B, Van Nood, E, Passuello, N, Frasson, A, Mammano, E, Faccio, L, Vittadello, F, Bressan, A, Sarzo, G, Tamini, N, Oldani, M, Cigagna, L, Carissimi, F, De Carlo, G, Baccalini, E, Nespoli, L, Giordano, A, Cantafio, S, Grifoni, L, Matani, D, Livi, S, Delogu, D, Scognamillo, F, Marrosu, A, Guerrini, L, Ugolini, G, Ghignone, F, Frascaroli, G, Albertini, N, Zattoni, D, Taffurelli, G, Montroni, I, Colombo, F, Danelli, P, Bondurri, A, Maffioli, A, Bonomi, A, Pezzoli, I, Cammarata, F, Goletti, O, Molteni, M, Assisi, A, Quartierini, G, Da Lio, C, Verdi, D, Mondi, I, Peluso, C, Macchi, L, Tanzanu, M, Zanzi, F, Pellegrini, S, Andreuccetti, J, D'Alessio, R, Pignata, G, De Capua, M, Canfora, I, Ottaviani, L, Lepiane, P, Balla, A, De Carlo, A, Saraceno, F, Scaramuzzo, R, Guida, A, Aguzzi, D, Bellora, P, Gentilli, S, Monni, M, Nikaj, H, Cillara, N, Cannavera, A, Deserra, A, Margiani, C, Cabula, R, Dettori, M, Gramignano, G, Lezoche, G, Ortenzi, M, Orlandoni, E, Curzi, F, Vitali, F, Capomagi, P, Palmieri, M, Del Rio, P, Bonati, E, Loderer, T, Cozzani, F, Rossini, M, Agnesi, S, Capolupo, G, Caricato, M, Carannante, F, Masciana, G, Marrelli, M, Miacci, V, Lauricella, S, Tonini, V, Cervellera, M, Pisconti, S, Lozito, C, Shahu, J, Mongelli, C, Morelli, G, Sartarelli, L, Sica, G, Siragusa, L, Bagaglini, G, Franceschilli, M, Bellato, V, Fiorani, C, Taddei, A, Risaliti, M, Bartolini, I, Ringressi, M, Tirloni, L, Laface, L, Abate, E, Casati, M, Gobbi, P, Opocher, E, Mariani, N, Ceretti, A, Giovenzana, M, Giuliani, B, Sironi, M, Grossi, U, Zanus, G, Santoro, G, Brizzolari, M, De Leo, E, Novello, S, Aquilino, K, Milardi, F, Olmi, S, Uccelli, M, Bonaldi, M, Cesana, G, Bindi, M, Galleano, R, Langone, A, Botto, M, Franceschi, A, Gambino, E, Ronconi, M, Casiraghi, S, Casole, G, Ciulla, S, Terrosu, G, Calandra, S, Scarpa, E, Cherchi, V, Martinuzzo, L, Clocchiatti, L, Muschitiello, D, Romanzi, A, Vignati, B, Vannelli, A, Scolaro, R, Milanesi, M, Rossi, F, Canonico, G, Anastasi, A, Nelli, T, Barlettai, M, Fratarcangeli, R, Di Martino, C, Damigella, A, Adinolfi, E, Birindelli, A, Taglietti, L, Dester, S, Fleres, F, Cucinotta, E, Viscosi, F, Biondo, S, Badessi, G, Catarsini, N, Mazzeo, C, Rega, D, Delrio, P, Cervone, C, Aversano, A, De Franciscis, S, Di Marzo, M, Marra, B, Pace, U, Amato, A, Batistotti, P, Mina, E, Serventi, A, Lapolla, P, Mingoli, A, Sapienza, P, Brachini, G, Cirillo, B, Fiori, E, Crocetti, D, Clementi, I, Martines, G, Picciariello, A, Tomasicchio, G, Dibra, R, Trigiante, G, Rinaldi, M, Lantone, G, Porcu, A, Perra, T, Scanu, A, Feo, C, Fancellu, A, Cossu, M, Ginesu, G, Patriti, A, Coletta, D, Petrelli, F, Greco, P, Spadoni, C, Cassiani, G, Bianchini, F, Arganini, M, Bianchini, M, Perotti, B, Palmeri, M, Scabini, S, Deiana, S, Carganico, G, Pertile, D, Soriero, D, Fioravanti, E, Sperotto, B, Nardo, B, Paglione, D, Crocco, V, Doni, M, Osso, M, Perri, R, Sampietro, G, Corbellini, C, Lorusso, L, Manzo, C, Cigognini, M, Baldi, C, Palomba, G, Aprea, G, Capuano, M, Basile, R, Tutino, R, Massani, M, Marinelli, L, Canitano, N, Pilia, T, Podda, M, Pisanu, A, Murzi, V, Incani, S, Frongia, F, Esposito, G, Luglio, G, Tropeano, F, Pagano, G, Spina, E, De Simone, G, Cricri, M, Catena, F, Vallicelli, C, Zanini, N, Ronconi, D, Favi, F, Mazzucchelli, C, Convertini, G, Vincenti, L, Andriola, V, Bizzoca, C, Fabbri, N, Fazzin, M, Pesce, A, Gennari, S, Torchiaro, M, Severi, S, Frontali, A, Bracchetti, G, Granieri, S, Cotsoglou, C, Carlini, M, Lisi, G, Spoletini, D, Mastrangeli, M, Campanelli, M, Manigrasso, M, Milone, M, De Palma, G, Vertaldi, S, Chini, A, Maione, F, Marello, A, Selvaggi, F, Sciaudone, G, Selvaggi, L, Tasselli, F, Fuschillo, G, Oddis, L, Grande, S, Grande, M, Ascanelli, S, Chimisso, L, Aisoni, F, Rossin, E, Pepe, F, Marchetti, F, Picardi, B, Rossi, S, Del Monte, S, Picarelli, M, Muttillo, I, Ratto, C, Marra, A, Parello, A, Litta, F, Campenni, P, De Simone, V, Pata, F, Riboni, C, Rausa, E, Celentano, V, Rottoli M., Spinelli A., Pellino G., Gori A., Calini G., Flacco M. E., Manzoli L., Poggioli G., Romano A., Belvedere A., Lanci A. L., Parlanti D., Vago G., Pezzuto A. P., Canavese A., Dajti G., Cardelli S., Catalioto C., Russo I. S., Violante T., Morezzi D., Maurino L., Filippone E., Cuicchi D., Bernante P., Jovine E., Lombardi R., Masetti M., Cipressi C., Offi M. F., Larotonda C., Puglisi S. B., Barbosa A., Vaiana R., Bianchi P. M., Tonti C., Codignola C., Zorcolo L., Restivo A., Deidda S., Marchetti M. E., Ippolito L., Spolverato G., Pucciarelli S., Marchegiani F., Ghio G., Zagolin G., Glavas D., Tomassi M., Rosati R., Elmore U., Gozzini L., Calef R., Puccetti F., Cossu A., Vignali A., Morino M., Allaix M. E., Cannata G., Lombardi E., Ammirati C. A., Piceni C., Buccianti P., Balestri R., Puccini M., Pezzati D., D'Ischia R., Asta V. F., Sargenti B., Taddei G., Bonari F., Boni G., Ferrero A., Mineccia M., Gonella F., Palisi M., Danese F., Cherubini V., Perotti S., Carvello M., Carbone F., Luberto A., Calafiore E., De Lucia F., Sacchi M., Sasia D., Giuffrida M. C., Ballauri E., Cardile M., Armentano S., Beltrami E., Preve G., Vercellone B., Mozzon M., Folliero C., Lirusso C., Vecchiato M., Ziccarelli A., Gattesco D., Moretti L., Crestale S., Banchini F., Capelli P., Romboli A., Palmieri G., Conti L., Rizzi N., Bonfili D., De Manzini N., Germani P., Osenda E., Cortinovis S., Giunta C., Fracon S., Abdallah H., Bogoni S., Portolani N., Nascimbeni R., Molfino S., Tiberio G. A. M., Garosio I., Lamperti G., Rigosa D., Ercolani G., Solaini L., Cavaliere D., Avanzolini A., D'Acapito F., Chiarella L. L., Di Pietrantonio D., Annunziata D., Piccolo R., Sorrentino M., Pansini M., Cojutti A., Graziano M., Callegari F., Balzarotti L., Dameno V. R., Cattaneo A., Santolamazza G., Altieri C., Magarini R., Pietrabissa A., Dominioni T., Pugliese L., Peri A., Botti M., Salvetti F., Boni L., Cassinotti E., Baldari L., Messina V., D'Abrosca V., Cianci P., Tumolo R., Gattulli D., Restini E., Minafra M., Sederino M. G., Bottalico B., Pilati P., Franzato B., Mattara G., De Simoni O., Barina A., Tonello M., Muratore A., Calabro M., Federico Pipitone N. S., Cuzzola B., Van Nood E. H., Passuello N., Frasson A., Mammano E., Faccio L., Vittadello F., Bressan A., Sarzo G., Tamini N., Oldani M., Cigagna L., Carissimi F., De Carlo G., Baccalini E., Nespoli L., Giordano A., Cantafio S., Grifoni L., Matani D., Livi S., Delogu D., Scognamillo F., Marrosu A., Guerrini L., Ugolini G., Ghignone F., Frascaroli G., Albertini N., Zattoni D., Taffurelli G., Montroni I., Colombo F., Danelli P., Bondurri A., Maffioli A., Bonomi A., Pezzoli I., Cammarata F., Goletti O., Molteni M., Assisi A., Quartierini G., Da Lio C., Verdi D., Mondi I., Peluso C., MacChi L., Tanzanu M., Zanzi F., Pellegrini S., Andreuccetti J., D'Alessio R., Pignata G., De Capua M., Canfora I., Ottaviani L., Lepiane P., Balla A., De Carlo A., Saraceno F., Scaramuzzo R., Guida A., Aguzzi D., Bellora P., Gentilli S., Monni M., Nikaj H., Cillara N., Cannavera A., Deserra A., Margiani C., Cabula R., Dettori M., Gramignano G., Lezoche G., Ortenzi M., Orlandoni E. S., Curzi F., Vitali F., Capomagi P., Palmieri M., Giuffrida M., Del Rio P., Bonati E., Loderer T., Cozzani F., Rossini M., Agnesi S., Capolupo G. T., Caricato M., Carannante F., Masciana G., Marrelli M., Miacci V., Lauricella S., Tonini V., Cervellera M., Pisconti S., Lozito C., Shahu J., Mongelli C., Morelli G., Sartarelli L., Sica G. S., Siragusa L., Bagaglini G., Guida A. M., Franceschilli M., Bellato V., Fiorani C., Taddei A., Risaliti M., Bartolini I., Ringressi M. N., Tirloni L., Laface L., Abate E., Casati M., Gobbi P., Opocher E., Mariani N. M., Ceretti A. P., Giovenzana M., Giuliani B., Sironi M., Grossi U., Zanus G., Santoro G. A., Brizzolari M., De Leo E., Novello S., Aquilino K., Milardi F., Olmi S., Uccelli M., Bonaldi M., Cesana G. C., Bindi M., Galleano R., Langone A., Botto M., Franceschi A., Gambino E., Ronconi M., Casiraghi S., Casole G., Ciulla S. L., Terrosu G., Calandra S., Scarpa E., Cherchi V., Martinuzzo L., Clocchiatti L., Muschitiello D., Romanzi A., Vignati B., Vannelli A., Scolaro R., Milanesi M., Rossi F., Canonico G., Anastasi A., Nelli T., Barlettai M., Fratarcangeli R., Di Martino C., Damigella A., Adinolfi E., Birindelli A., Taglietti L., Dester S. E., Fleres F., Cucinotta E., Viscosi F., Biondo S. A., Badessi G., Catarsini N., Mazzeo C., Rega D., Delrio P., Cervone C., Aversano A., De Franciscis S., Di Marzo M., Marra B., Pace U., Amato A., Batistotti P., Mina E., Serventi A., Lapolla P., Mingoli A., Sapienza P., Brachini G., Cirillo B., Fiori E., Crocetti D., Clementi I., Martines G., Picciariello A., Tomasicchio G., Dibra R., Trigiante G., Rinaldi M., Lantone G., Porcu A., Perra T., Scanu A. M., Feo C. F., Fancellu A., Cossu M. L., Ginesu G. C., Patriti A., Coletta D., Petrelli F., Greco P. A., Spadoni C., Cassiani G., Bianchini F., Arganini M., Bianchini M., Perotti B., Palmeri M., Scabini S., Deiana S., Carganico G., Pertile D., Soriero D., Fioravanti E., Sperotto B., Nardo B., Paglione D., Crocco V., Doni M., Osso M., Perri R., Sampietro G. M., Corbellini C., Lorusso L., Manzo C. A., Cigognini M., Baldi C., Palomba G., Aprea G., Capuano M., Basile R., Tutino R., Massani M., Marinelli L., Canitano N., Pilia T., Podda M., Pisanu A., Murzi V., Incani S., Frongia F., Esposito G., Luglio G., Tropeano F. P., Pagano G., Spina E., De Simone G., Cricri M., Catena F., Vallicelli C., Zanini N., Ronconi D., Favi F., Mazzucchelli C., Convertini G., Vincenti L., Andriola V., Bizzoca C., Feo C. V., Fabbri N., Fazzin M., Pesce A., Gennari S., Torchiaro M., Severi S., Frontali A., Bracchetti G., Granieri S., Cotsoglou C., Carlini M., Lisi G., Spoletini D., Mastrangeli M. R., Campanelli M., Manigrasso M., Milone M., De Palma G. D., Vertaldi S., Chini A., Maione F., Marello A., Selvaggi F., Sciaudone G., Selvaggi L., Tasselli F. M., Fuschillo G., Oddis L., Grande S., Grande M., Ascanelli S., Chimisso L., Aisoni F., Rossin E., Pepe F., Marchetti F., Picardi B., Rossi S., Del Monte S. R., Picarelli M., Muttillo I. A., Ratto C., Marra A. A., Parello A., Litta F., Campenni P., De Simone V., Pata F., Riboni C., Rausa E., and Celentano V.

Abstract

Background: The association between volume, complications and pathological outcomes is still under debate regarding colorectal cancer surgery. The aim of the study was to assess the association between centre volume and severe complications, mortality, less-than-radical oncologic surgery, and indications for neoadjuvant therapy. Methods: Retrospective analysis of 16,883 colorectal cancer cases from 80 centres (2018-2021). Outcomes: 30-day mortality; Clavien-Dindo grade >2 complications; removal of ≥ 12 lymph nodes; non-radical resection; neoadjuvant therapy. Quartiles of hospital volumes were classified as LOW, MEDIUM, HIGH, and VERY HIGH. Independent predictors, both overall and for rectal cancer, were evaluated using logistic regression including age, gender, AJCC stage and cancer site. Results: LOW-volume centres reported a higher rate of severe postoperative complications (OR 1.50, 95% c.i. 1.15-1.096, P = 0.003). The rate of ≥ 12 lymph nodes removed in LOW-volume (OR 0.68, 95% c.i. 0.56-0.85, P < 0.001) and MEDIUM-volume (OR 0.72, 95% c.i. 0.62-0.83, P < 0.001) centres was lower than in VERY HIGH-volume centres. Of the 4676 rectal cancer patients, the rate of ≥ 12 lymph nodes removed was lower in LOW-volume than in VERY HIGH-volume centres (OR 0.57, 95% c.i. 0.41-0.80, P = 0.001). A lower rate of neoadjuvant chemoradiation was associated with HIGH (OR 0.66, 95% c.i. 0.56-0.77, P < 0.001), MEDIUM (OR 0.75, 95% c.i. 0.60-0.92, P = 0.006), and LOW (OR 0.70, 95% c.i. 0.52-0.94, P = 0.019) volume centres (vs. VERY HIGH). Conclusion: Colorectal cancer surgery in low-volume centres is at higher risk of suboptimal management, poor postoperative outcomes, and less-than-adequate oncologic resections. Centralisation of rectal cancer cases should be taken into consideration to optimise the outcomes.

Published
2024

2. Some minutes matter more: Groin-to-recanalization is the main time-related predictor of outcome in acute ischemic stroke.

Author

De Mase A, Spina E, Servillo G, Barbato S, Leone G, Giordano F, Renna R, Ranieri A, Iorio WD, Muto M, Guarnieri G, Muto M, Candelaresi P, and Andreone V

Abstract

Introduction: Endovascular thrombectomy (EVT) is the standard of care for selected patients with acute ischemic stroke (AIS) and large vessel occlusion (LVO), associated with intravenous thrombolysis, when indicated. While many studies focused on pre-hospital and in-hospital pathways, only few analyzed the relationship between groin-to-recanalization (GTR) time and functional outcome., Aim: To explore whether GTR time is an independent predictor of outcome in patients undergoing EVT., Methods: All patients with anterior circulation stroke treated with EVT at a high-volume center from January 2021 to December 2023 were included. The cohort was divided into two groups according to GTR time shorter or longer than 30 min. Regression analysis assessed the association between GTR time and 3-month good outcome, defined as modified Rankin Scale 0-2., Results: The study included 419 patients. The groups had similar baseline characteristics and similar onset to recanalization (OTR) time. Regression analysis showed shorter GTR time is an independent predictor of favorable outcome (OR 2.49 [95% CI 1.26-4.94]). Age, baseline NIHSS, ASPECT score and bridging IVT were also found to be independently associated with outcome., Discussion and Conclusions: Our study showed GTR time is an independent predictor of good outcome in patients undergoing EVT with similar OTR time, emphasizing procedural time as a key prognostic factor, even greater than other well-known pre-hospital and in-hospital time-dependent variables. These findings may raise the issue of developing alternative approaches or early "rescue" strategies for complicated procedures., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Published
2024
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3. PI-QUAL version 2: A Multi-Reader reproducibility study on multiparametric MRI from a tertiary referral center.

Author

Ponsiglione A, Cereser L, Spina E, Mannacio L, Negroni D, Russo L, Muto F, Di Costanzo G, Stanzione A, Cuocolo R, Imbriaco M, and Girometti R

Abstract

Purpose: To assess the inter-reader and intra-reader agreement of the Prostate imaging quality version 2 (PI-QUAL v.2) for multiparametric magnetic resonance imaging (mpMRI) among radiologists with varying levels of expertise., Methods: Fifty men underwent 3 T mpMRI scans in a tertiary referral center. Images were anonymized and assessed by six readers of different expertise (2 expert, 2 basic and 2 beginners) in two sessions: first using PI-QUAL v.2, and then using both PI-QUAL v.2 and v.1 after a 2-week interval. PI-QUAL v.2 scores were considered overall and, for comparison with PI-QUAL v.1, dichotomized according to the threshold of acceptable image quality. Gwet AC 1 index was used to calculate the inter-reader and intra-reader agreement of the scores., Results: The inter-reader agreement for PI-QUAL v.2 scores was overall moderate (Gwet's AC 1  = 0.55), being higher for expert readers compared to the beginner and basic ones (Gwet's AC 1  = 0.66 versus 0.45-0-58). Intra-reader agreement varied from moderate to perfect (Gwet's AC 1  = 0.43-1.00) and improved with increasing levels of expertise. The ratings were more reproducible for DWI and DCE sequences (Gwet's AC 1  = 0.62-1.00) compared to T2w (Gwet's AC 1  = 0.24-0.70). The intra-reader agreement between PI-QUAL v.2 and v.1 scores across readings ranged from almost perfect to perfect (Gwet's AC 1  = 0.96-1.00)., Conclusions: In a tertiary referral center context, PI-QUAL v.2 is a moderately reliable tool for standardizing prostate mpMRI quality evaluations among readers with varying expertise., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Published
2024
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4. Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: Focus on antipsychotics.

Author

Hart XM, Gründer G, Ansermot N, Conca A, Corruble E, Crettol S, Cumming P, Hefner G, Frajerman A, Howes O, Jukic MM, Kim E, Kim S, Maniscalco I, Moriguchi S, Müller DJ, Nakajima S, Osugo M, Paulzen M, Ruhe HG, Scherf-Clavel M, Schoretsanitis G, Serretti A, Spina E, Spigset O, Steimer W, Süzen SH, Uchida H, Unterecker S, Vandenberghe F, Verstuyft C, Zernig G, Hiemke C, and Eap CB

Abstract

Background: For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialised tools are used. Three tools have been proven useful to personalise drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging., Methods: In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 45 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET))., Results: Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings., Conclusion: All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimise treatment effects, minimise side effects and ultimately reduce the global burden of diseases, personalised drug treatment has not yet become the standard of care in psychiatry.

Published
2024
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5. TGF-β and RAS jointly unmask primed enhancers to drive metastasis.

Author

Lee JH, Sánchez-Rivera FJ, He L, Basnet H, Chen FX, Spina E, Li L, Torner C, Chan JE, Yarlagadda DVK, Park JS, Sussman C, Rudin CM, Lowe SW, Tammela T, Macias MJ, Koche RP, and Massagué J

Abstract

Epithelial-to-mesenchymal transitions (EMTs) and extracellular matrix (ECM) remodeling are distinct yet important processes during carcinoma invasion and metastasis. Transforming growth factor β (TGF-β) and RAS, signaling through SMAD and RAS-responsive element-binding protein 1 (RREB1), jointly trigger expression of EMT and fibrogenic factors as two discrete arms of a common transcriptional response in carcinoma cells. Here, we demonstrate that both arms come together to form a program for lung adenocarcinoma metastasis and identify chromatin determinants tying the expression of the constituent genes to TGF-β and RAS inputs. RREB1 localizes to H4K16acK20ac marks in histone H2A.Z-loaded nucleosomes at enhancers in the fibrogenic genes interleukin-11 (IL11), platelet-derived growth factor-B (PDGFB), and hyaluronan synthase 2 (HAS2), as well as the EMT transcription factor SNAI1, priming these enhancers for activation by a SMAD4-INO80 nucleosome remodeling complex in response to TGF-β. These regulatory properties segregate the fibrogenic EMT program from RAS-independent TGF-β gene responses and illuminate the operation and vulnerabilities of a bifunctional program that promotes metastatic outgrowth., Competing Interests: Declaration of interests J.M. owns company stock in Scholar Rock. C.M.R. has consulted regarding oncology drug development with Amgen, Astra Zeneca, Chugai, Daiichi Sankyo, Hoffman-La Roche, and Jazz Pharmaceuticals; C.M.R. serves on the scientific advisory boards of Auron, Bridge Medicines, DISCO, Earli, and Harpoon Therapeutics. S.W.L. is a consultant and holds equity in Blueprint Medicines, ORIC Pharmaceuticals, Mirimus, PMV Pharmaceuticals, Faeth Therapeutics, and Senecea Therapeutics, and is a consultant for Fate Therapeutics. T.T. is a consultant and holds equity in Lime Therapeutics; the Tammela Lab receives research support from Ono Pharmaceuticals Co., Ltd. (unrelated to this work). T.T.’s spouse is an employee of Recursion Pharmaceuticals. R.P.K. is a co-founder of and consultant for Econic Biosciences., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Published
2024
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6. Investigating in VigiBase over 6000 cases of pneumonia in clozapine-treated patients in the context of the literature: focus on high lethality and the association with aspiration pneumonia.

Author

de Leon J, Ruan CJ, Schoretsanitis G, Villasante-Tezanos AG, Spina E, Sanz EJ, Betancort M, and De Las Cuevas C

Subjects
Humans, Female, Male, Middle Aged, Adult, Aged, Clozapine adverse effects, Clozapine administration & dosage, Pneumonia, Aspiration chemically induced, Antipsychotic Agents adverse effects, Antipsychotic Agents administration & dosage, Pharmacovigilance, Pneumonia chemically induced, Pneumonia epidemiology, Adverse Drug Reaction Reporting Systems statistics & numerical data, Databases, Factual
Abstract

Background: The literature associates clozapine with pneumonia/aspiration pneumonia., Research Design and Methods: The international pharmacovigilance database (VigiBase™) uses the information component (IC) as statistical signal. VigiBase clozapine reports were analyzed for pneumonia/aspiration pneumonia from introduction to 10 May 2023., Results: There were 6392 cases of all types of pneumonia (5572 cases of pneumonia, 775 of aspiration pneumonia, and 45 combined). The IC was 3.52 for aspiration pneumonia, introduced as a VigiBase label in 2003, and 1.91 for pneumonia. Patients were reclassified as 3628 with no signs of aspiration and 1533 with signs. Signs of aspiration were strongly associated with some co-medications: olanzapine, odds ratio (OR) = 23.8, 95% confidence interval (CI), 14.9-38.0; risperidone OR = 18.6, CI, 11.4-30.4; valproic acid, OR = 5.5, CI, 4.5-6.6; and benzodiazepines OR = 5.5, CI, 4.5-6.6. In 2415 cases with completed data, fatal outcomes made up 45% (signs of aspiration made no difference), but there was wide variability from 0% (females <45 years of age; duration ≤30 days) to 76% (males >64 years of age; duration >1 year). During the first week, pneumonia was associated with 1) very high titration doses, 2) very small doses in Parkinson's disease, and 3) Japan vs other countries., Conclusions: In clozapine-treated patients: 1) at least 30% of pneumonia cases may be aspiration pneumonia, 2) stopping some co-medications may decrease the risk of aspiration pneumonia, 3) average lethality in pneumonia was 45% but may be around 75% in geriatric patients with long-term treatment, and 4) safer titrations may sometimes require 5-mg tablets.

Published
2024
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7. Effectiveness and safety profile of mepolizumab in chronic rhinosinusitis with nasal polyps: Real life data in a tertiary care.

Author

Galletti C, Ciodaro F, Barbieri MA, Gambino F, Ferrisi MG, Portelli D, Catalano N, Spina E, Freni F, and Galletti B

Subjects
Humans, Male, Female, Chronic Disease, Middle Aged, Treatment Outcome, Adult, Prospective Studies, Tertiary Healthcare, Cohort Studies, Aged, Sino-Nasal Outcome Test, Rhinosinusitis, Sinusitis drug therapy, Sinusitis complications, Nasal Polyps drug therapy, Nasal Polyps complications, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized adverse effects, Rhinitis drug therapy, Rhinitis complications
Abstract

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a type 2 pattern of inflammation. Mepolizumab was approved for the treatment of CRSwNP in 2021, it may be useful to evaluate its safety profile in a real-world setting., Aim: This work aimed to prospectively highlight the effectiveness and safety profile of Mepolizumab in patients with CRSwNP enrolled in the Otorhinolaryngology Unit of the University Hospital of Messina., Methods: An observational cohort study was carried out considering all patients treated with Mepolizumab. A descriptive analysis was conducted reporting all demographic characteristics, endoscopic evaluations, and symptom conditions., Results: A total of 30 patients were treated with Mepolizumab, one patient discontinued the treatment. A statistically significant reduction in the Sino-Nasal Outcome Tests-22 (SNOT-22) and nasal polyp score (NPS) was shown at the 6th and 12th months compared to baseline values (SNOT-22, -33 and - 43, p < 0.001 for both comparisons; NPS, 0 and - 1, p < 0.001 for both comparisons). The median (Q1-Q3) sniffin' sticks test score increased from 7 (6-8) at the 6th month to 11 (10-13) at the 12th month. Seven patients (24.1 %) reported pain at the injection site, accompanied by redness, warmth, and tenderness within the first 24 h post-injection with a median duration of three days from the onset., Conclusions: Given the optimal treatment response and the minimal adverse effects observed, clinicians should consider Mepolizumab a safe and effective treatment in CRSwNP patients. Further studies in real-life setting are necessary to better understand the long-term effects., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Published
2024
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8. (+)Alpha-Lipoic Acid Regulates Lipid Metabolism Gene Expression and Lipidic Profile in a Cellular Model of Fatty Acid Overload.

Author

Longhitano L, Tibullo D, Zuppelli T, Ronsisvalle S, La Spina E, Nicolosi A, Antoci M, Sipala FM, Galvano F, Currenti W, Santisi A, Alanazi AM, Zanghì G, Tropea E, Li Volti G, and Barbagallo IA

Subjects
Humans, Hep G2 Cells, Gene Expression Regulation drug effects, Fatty Acids metabolism, PPAR gamma metabolism, Lipid Droplets metabolism, Lipid Droplets drug effects, PPAR alpha metabolism, PPAR alpha genetics, Uncoupling Protein 2 metabolism, Uncoupling Protein 2 genetics, Thioctic Acid pharmacology, Lipid Metabolism drug effects, Non-alcoholic Fatty Liver Disease metabolism, Non-alcoholic Fatty Liver Disease drug therapy, Non-alcoholic Fatty Liver Disease genetics, Oleic Acid pharmacology, Oleic Acid metabolism, Palmitic Acid pharmacology, Palmitic Acid metabolism
Abstract

Background: Nonalcoholic fatty liver disease (NAFLD) is a prevalent condition characterized by hepatic fat accumulation, often progressing to severe liver injury, for which approved treatments are currently lacking. This study explores the potential therapeutic impact of alpha-lipoic acid (ALA), a natural compound crucial in lipid metabolism, on NAFLD using an in vitro model., Methods: HepG2 cells were treated with a palmitic acid:oleic acid (PA:OA) mixture, representing a cellular model of steatosis. Subsequent treatment with ALA at concentrations of 1 µM and 5 µM aimed to evaluate its effects on lipid content and metabolism. Real-time polymerase chain reaction (PCR), BODIPY staining, cytofluorimetric analysis, and lipidomics were used to assess gene expression, lipid droplet accumulation, and fatty acid profiles., Results: Our results showed that ALA significantly reduced lipid droplets in PA:OA-treated HepG2 cells, with a concentration-dependent effect. Analysis of fatty acid profiles demonstrated a decrease in palmitic acid levels with ALA treatment, while oleic acid reduction was observed only at the higher concentration. Moreover, ALA modulated the expression of genes involved in cholesterol biosynthesis and low-density lipoprotein (LDL) metabolism, indicating a potential role in lipid homeostasis. Further insights into molecular mechanisms revealed that ALA modulated peroxisome proliferator activated receptors (PPARs), specifically PPAR-alpha and PPAR-gamma, involved in fatty acid metabolism and insulin sensitivity. Finally, ALA counteracted the overexpression of thermogenic genes induced by exogenous fatty acids, suggesting a regulatory role in energy dissipation pathways., Conclusion: In conclusion, this study highlights ALA as a therapeutic agent in mitigating lipid accumulation and dysregulation in NAFLD., Competing Interests: Given their role as Guest Editor, GLV had no involvement in the peer-review of this article and have no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Margaret O. James. The authors declare no other conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Published
2024
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9. Exploring low clozapine C/D ratios, inverted clozapine-norclozapine ratios and undetectable concentrations as measures of non-adherence in clozapine patients: A literature review and a case series of 17 patients from 3 studies.

Author

Ruan CJ, Olmos I, Ricciardi C, Schoretsanitis G, Vincent PD, Anıl Yağcıoğlu AE, Eap CB, Baptista T, Clark SR, Fernandez-Egea E, Kim SH, Lane HY, Leung J, Maroñas Amigo O, Motuca M, Every-Palmer S, Procyshyn RM, Rohde C, Suhas S, Schulte PFJ, Spina E, Takeuchi H, Verdoux H, Correll CU, Molden E, De Las Cuevas C, and de Leon J

Subjects
Humans, Female, Male, Adult, Middle Aged, Drug Monitoring, Medication Adherence statistics & numerical data, Clozapine blood, Clozapine pharmacokinetics, Clozapine therapeutic use, Clozapine analogs & derivatives, Antipsychotic Agents blood, Antipsychotic Agents pharmacokinetics, Antipsychotic Agents administration & dosage, Schizophrenia drug therapy, Schizophrenia blood
Abstract

Background: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable., Methods: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study., Results: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11)., Conclusion: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented)., Competing Interests: Declaration of competing interest GS has received speaker/consultation fees from HLS Therapeutics and Thermo Fisher. AEAY has received speaker/advisory board fees from Janssen, Abdi İbrahim Otsuka and Nobel, and has received investigator fees from Janssen. CBE received honoraria for conferences from Forum pour la formation médicale, Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Sysmex Suisse AG, Takeda, Vifor-Pharma, and Zeller in the past 3 years. SRC received speaker/consultation fees from: Janssen-Cilag, Lundbeck, Otsuka and Servier and research funding from Janssen-Cilag, Lundbeck, Otsuka and Gilead. SHK has received research grants from Janssen and Dongwha. JGL has consulted/spoken on behalf of Saladax Biomedical. RMP has received speaker/consultation fees from Eisai, HLS Therapeutics, Jansen, Lundbeck, and Otsuka. HT has received grants from Daiichi Sankyo and Novartis Pharma; speaker's fees from EA. Pharma, Eisai, Kyowa, Janssen, Lundbeck, Meiji Seika Pharma, MSD, Otsuka, Sumitomo Pharma, Takeda, and Yoshitomiyakuhin; and consulting fees from Janssen, Mitsubishi Tanabe Pharma, Ono, and Sumitomo Pharma. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic. In the last 3 years, the remaining authors report no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Published
2024
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10. Comparing major and mild cognitive impairment risks in older type-2 diabetic patients: a Danish register-based study on dipeptidyl peptidase-4 inhibitors vs. glucagon-like peptide-1 analogues.

Author

Battini V, Barbieri MA, Carnovale C, Spina E, Clementi E, and Sessa M

Subjects
Humans, Male, Female, Denmark epidemiology, Aged, Hypoglycemic Agents adverse effects, Aged, 80 and over, Follow-Up Studies, Middle Aged, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 epidemiology, Diabetes Mellitus, Type 2 complications, Dipeptidyl-Peptidase IV Inhibitors adverse effects, Dipeptidyl-Peptidase IV Inhibitors therapeutic use, Cognitive Dysfunction epidemiology, Cognitive Dysfunction etiology, Glucagon-Like Peptide 1, Registries
Abstract

Introduction: The prevalence of major and mild cognitive impairment (CI) in type-2 diabetes older patients is 15-25% and 30-60%, respectively, thus affecting quality of life and health outcomes. There is, therefore, the need of head-to-head studies aiming at identifying the optimal treatment for individuals with type-2 diabetes at increased risk of mild and major CI. This study focuses on the risk of developing mild and major CI in Danish patients treated with dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 analogues (GLP-1a) using administrative and healthcare registers., Methods: An active comparator design with a 3-year follow-up period was used. The main outcome was the hospital admission with a diagnosis of mild CI or major CI. Multivariate Cox Regression analysis was performed using the high-dimensional propensity score to obtain adjusted Hazard Ratio (HR) estimates. Inverse probability of treatment weighting (IPTW) and marginal structured model were used to calculate risk differences while accounting for the variations of confounders throughout the follow-up period., Results: Our results show a significant higher risk of major CI between DPP-4i and GLP-1a in unadjusted [HR (95% CI) = 3.13 (2.45-4.00), p < 0.001] and adjusted analyses [HR (95% CI) = 1.58 (1.22-2.06), p = 0.001]. No statistically significant differences were observed for mild CI. IPTW resulted stable throughout the follow-up period. Marginal structure modeling (β (95% CI) = 0.022 (0.020-0.024), p < 0.001) resulted in a higher risk of major CI for DPP-4i when compared to GLP-1a., Discussion: DPP-4i was associated with an increased risk of developing major CI when compared to GLP-1a among older individuals with type-2 diabetes., (© 2024. The Author(s).)

Published
2024
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11. Clozapine ultrarapid metabolism during weak induction probably exists but requires careful diagnosis. A literature review, five new cases and a proposed definition.

Author

Schoretsanitis G, Anıl Yağcıoğlu AE, Ruan CJ, Eap CB, Molden E, Baptista T, Clark SR, Fernandez-Egea E, Kim SH, Lane HY, Leung J, Maroñas Amigo O, Motuca M, Olmos I, Every-Palmer S, Procyshyn RM, Rohde C, Satish S, Schulte PFJ, Spina E, Takeuchi H, Verdoux H, Correll CU, and de Leon J

Subjects
Humans, Male, Adult, Schizophrenia drug therapy, Smoking, Clozapine administration & dosage, Clozapine pharmacokinetics, Clozapine adverse effects, Antipsychotic Agents pharmacology, Antipsychotic Agents administration & dosage
Abstract

During weak induction (from smoking and/or valproate co-prescription), clozapine ultrarapid metabolizers (UMs) need very high daily doses to reach the minimum therapeutic concentration of 350 ng/ml in plasma; clozapine UMs need clozapine doses higher than: 1) 900 mg/day in patients of European/African ancestry, or 2) 600 mg/day in those of Asian ancestry. Published clozapine UMs include 10 males of European/African ancestry, mainly assessed with single concentrations. Five new clozapine UMs (two of European and three of Asian ancestry) with repeated assessments are described. A US double-blind randomized trial included a 32-year-old male smoking two packages/day with a minimum therapeutic dose of 1,591 mg/day from a single TDM during open treatment of 900 mg/day. In a Turkish inpatient study, a 30-year-old male smoker was a possible clozapine UM needing a minimum therapeutic dose of 1,029 mg/day estimated from two trough steady-state concentrations on 600 mg/day. In a Chinese study, three possible clozapine UMs (all male smokers) were identified. The clozapine minimum therapeutic dose estimated with trough steady-state concentrations >150 ng/ml was: 1) 625 mg/day, based on a mean of 20 concentrations in Case 3; 2) 673 mg/day, based on a mean of 4 concentrations in Case 4; and 3) 648 mg/day, based on a mean of 11 concentrations in Case 5. Based on these limited studies, clozapine UMs during weak induction may account for 1-2% of clozapine-treated patients of European ancestry and <1% of those of Asian ancestry. A clozapine-to-norclozapine ratio <0.5 should not be used to identify clozapine UMs., Competing Interests: Declaration of competing interest GS has received speaker/consultation fees from HLS Therapeutics and Thermo Fisher. SRC received speaker/consultation fees from: Janssen-Cilag, Lundbeck, Otsuka and Servier and research funding from Janssen-Cilag, Lundbeck, Otsuka and Gilead. SH Kim has received research grants from Janssen and Dongwha. HT has received grants from Daiichi Sankyo and Novartis Pharma; speaker's fees from EA. Pharma, Eisai, Kyowa, Janssen, Lundbeck, Meiji Seika Pharma, MSD, Otsuka, Sumitomo Pharma, Takeda, and Yoshitomiyakuhin; and consulting fees from Janssen, Mitsubishi Tanabe Pharma, Ono, and Sumitomo Pharma. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic. In the last 3 years, the remaining authors report no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Published
2024
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12. Assessment of diagnostic criteria for multifocal motor neuropathy in patients included in the Italian database.

Author

Doneddu PE, Gentile L, Cocito D, Fazio R, Luigetti M, Briani C, Filosto M, Siciliano G, Benedetti L, Antonini G, Matà S, Marfia GA, Inghilleri M, Manganelli F, Cosentino G, Brighina F, Carpo M, Carta F, Mazzeo A, Peci E, Strano C, Romano A, Campagnolo M, Cotti-Piccinelli S, Viola DV, Germano F, Leonardi L, Sperti M, Mataluni G, Ceccanti M, Spina E, Vegezzi E, Di Stefano V, and Nobile-Orazio E

Subjects
Humans, Peripheral Nerves, Magnetic Resonance Imaging, Immunoglobulin M, Italy, Neural Conduction physiology, Polyneuropathies diagnosis, Motor Neuron Disease diagnosis, Motor Neuron Disease drug therapy
Abstract

Background and Purpose: This study aimed to assess the diagnostic criteria, ancillary investigations and treatment response using real-life data in multifocal motor neuropathy (MMN) patients., Methods: Clinical and laboratory data were collected from 110 patients enrolled in the Italian MMN database through a structured questionnaire. Twenty-six patients were excluded due to the unavailability of nerve conduction studies or the presence of clinical signs and symptoms and electrodiagnostic abnormalities inconsistent with the MMN diagnosis. Analyses were conducted on 73 patients with a confirmed MMN diagnosis and 11 patients who did not meet the diagnostic criteria., Results: The European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria were variably applied., Author: When applying the American Association of Electrodiagnostic Medicine criteria, an additional 17% of patients fulfilled the criteria for probable/definite diagnosis whilst a further 9.5% missed the diagnosis. In 17% of the patients only compound muscle action potential amplitude, but not area, was measured and subsequently recorded in the database by the treating physician. Additional investigations, including anti-GM1 immunoglobulin M antibodies, cerebrospinal fluid analysis, nerve ultrasound and magnetic resonance imaging, supported the diagnosis in 46%-83% of the patients. Anti-GM1 immunoglobulin M antibodies and nerve ultrasound demonstrated the highest sensitivity. Additional tests were frequently performed outside the EFNS/PNS guideline recommendations., Conclusions: This study provides insights into the real-world diagnostic and management strategies for MMN, highlighting the challenges in applying diagnostic criteria., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Published
2024
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13. Targeted Metabolomics Highlights Dramatic Antioxidant Depletion, Increased Oxidative/Nitrosative Stress and Altered Purine and Pyrimidine Concentrations in Serum of Primary Myelofibrosis Patients.

Author

Mangione R, Giallongo C, Duminuco A, La Spina E, Longhitano L, Giallongo S, Tibullo D, Lazzarino G, Saab MW, Sbriglione A, Palumbo GA, Graziani A, Alanazi AM, Di Pietro V, Tavazzi B, Amorini AM, and Lazzarino G

Abstract

To date, little is known concerning the circulating levels of biochemically relevant metabolites (antioxidants, oxidative/nitrosative stress biomarkers, purines, and pyrimidines) in patients with primary myelofibrosis (PMF), a rare form of myeloproliferative tumor causing a dramatic decrease in erythropoiesis and angiogenesis. In this study, using a targeted metabolomic approach, serum samples of 22 PMF patients and of 22 control healthy donors were analyzed to quantify the circulating concentrations of hypoxanthine, xanthine, uric acid (as representative purines), uracil, β-pseudouridine, uridine (as representative pyrimidines), reduced glutathione (GSH), ascorbic acid (as two of the main water-soluble antioxidants), malondialdehyde, nitrite, nitrate (as oxidative/nitrosative stress biomarkers) and creatinine, using well-established HPLC method for their determination. Results showed that PMF patients have dramatic depletions of both ascorbic acid and GSH (37.3- and 3.81-times lower circulating concentrations, respectively, than those recorded in healthy controls, p < 0.0001), accompanied by significant increases in malondialdehyde (MDA) and nitrite + nitrate (4.73- and 1.66-times higher circulating concentrations, respectively, than those recorded in healthy controls, p < 0.0001). Additionally, PMF patients have remarkable alterations of circulating purines, pyrimidines, and creatinine, suggesting potential mitochondrial dysfunctions causing energy metabolism imbalance and consequent increases in these cell energy-related compounds. Overall, these results, besides evidencing previously unknown serum metabolic alterations in PMF patients, suggest that the determination of serum levels of the aforementioned compounds may be useful to evaluate PMF patients on hospital admission for adjunctive therapies aimed at recovering their correct antioxidant status, as well as to monitor patients' status and potential pharmacological treatments.

Published
2024
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14. Impact of 2021 European Academy of Neurology/Peripheral Nerve Society diagnostic criteria on diagnosis and therapy of chronic inflammatory demyelinating polyradiculoneuropathy variants.

Author

De Lorenzo A, Liberatore G, Doneddu PE, Manganelli F, Cocito D, Briani C, Fazio R, Mazzeo A, Schenone A, Di Stefano V, Cosentino G, Marfia GA, Benedetti L, Carpo M, Filosto M, Antonini G, Clerici AM, Luigetti M, Matà S, Rosso T, Lucchetta M, Siciliano G, Lauria Pinter G, Cavaletti G, Inghilleri M, Cantisani T, Notturno F, Ricciardi D, Habetswallner F, Spina E, Peci E, Salvalaggio A, Falzone Y, Strano C, Gentile L, Vegezzi E, Mataluni G, Cotti Piccinelli S, Leonardi L, Romano A, and Nobile-Orazio E

Subjects
Humans, Peripheral Nerves, Neural Conduction physiology, Databases, Factual, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating diagnosis
Abstract

Background and Purpose: There are different criteria for the diagnosis of different variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guidelines provide specific clinical criteria for each CIDP variant even if their therapeutical impact has not been investigated., Methods: We applied the clinical criteria for CIDP variants of the 2021 EAN/PNS guidelines to 369 patients included in the Italian CIDP database who fulfilled the 2021 EAN/PNS electrodiagnostic criteria for CIDP., Results: According to the 2021 EAN/PNS clinical criteria, 245 patients achieved a clinical diagnosis of typical CIDP or CIDP variant (66%). We identified 106 patients with typical CIDP (29%), 62 distal CIDP (17%), 28 multifocal or focal CIDP (7%), four sensory CIDP (1%), 27 sensory-predominant CIDP (7%), 10 motor CIDP (3%), and eight motor-predominant CIDP (2%). Patients with multifocal, distal, and sensory CIDP had milder impairment and symptoms. Patients with multifocal CIDP had less frequently reduced conduction velocity and prolonged F-wave latency and had lower levels of cerebrospinal fluid protein. Patients with distal CIDP more frequently had reduced distal compound muscle action potentials. Patients with motor CIDP did not improve after steroid therapy, whereas those with motor-predominant CIDP did. None of the patients with sensory CIDP responded to steroids, whereas most of those with sensory-predominant CIDP did., Conclusions: The 2021 EAN/PNS criteria for CIDP allow a better characterization of CIDP variants, permitting their distinction from typical CIDP and more appropriate treatment for patients., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Published
2024
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15. Heterogenous electrophysiological features in early stage of hereditary transthyretin amyloidosis neuropathy.

Author

Tozza S, Palumbo G, Severi D, Iovino A, Spina E, Aruta F, Cassano E, Iodice R, Dubbioso R, Ruggiero L, Nolano M, Santoro L, and Manganelli F

Subjects
Aged, Humans, Male, Middle Aged, Affect, Neural Conduction, Prealbumin genetics, Retrospective Studies, Female, Amyloid Neuropathies, Familial complications, Amyloid Neuropathies, Familial diagnosis, Amyloid Neuropathies, Familial genetics
Abstract

Introduction: Hereditary transthyretin-mediated amyloidosis (ATTRv, v for variant) is a progressive disease caused by mutations in the TTR gene, leading to sensory-motor, axonal and length-dependent neuropathy. However, some patients may show variable electrophysiological pattern. The aim of this study was to evaluate the electrophysiological features of TTR amyloid neuropathy at the time of the first nerve conduction study (NCS) to assess whether there were distinguishing features useful for early diagnosis., Methods: We retrospectively revised the first electrophysiological findings of ATTRv patients, and we categorized the neuropathy based on nerve conduction slowing, type of involved fibres and distribution pattern of PNS involvement. Cluster analysis was performed to evaluate the prevalence of neuropathy features between the early and late stage of disease, based on disease duration and disability burden assessed by NIS., Results: We recruited 33 patients (27 males) with mean age 63.9 ± 10.8 years, mean disease duration 2.8 ± 2.4 years and mean NIS 47.6 ± 41.8. Overall, the frequency analysis showed that the most common features of ATTRv neuropathy included the categories of axonal, sensory-motor and neuronopathic-like pattern. This electrophysiological pattern of PNS involvement was constant in patients in late stage of disease, whereas ATTRv patients in early stage of disease displayed variable electrophysiological pattern of PNS involvement., Discussion: Our findings demonstrated that ATTRv neuropathy may present at first NCS in a variable way, and it changes over the course of disease. Such heterogeneity makes the suspicion of ATTRv even more challenging at the time of first electrophysiological examination., (© 2023. The Author(s).)

Published
2024
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16. Effects of immediate thrombolytic treatment in imaging area on functional outcome in patients with acute ischemic stroke.

Author

De Mase A, Spina E, Servillo G, Barbato S, Leone G, Giordano F, Muto M, Guarnieri G, Alfieri G, Longo K, Di Iorio W, Muto M, Candelaresi P, and Andreone V

Subjects
Humans, Thrombolytic Therapy methods, Fibrinolytic Agents therapeutic use, Treatment Outcome, Ischemic Stroke etiology, Brain Ischemia diagnostic imaging, Brain Ischemia drug therapy, Brain Ischemia etiology, Stroke diagnostic imaging, Stroke drug therapy
Abstract

Introduction: Door-to-needle time (DNT) is an established predictor of outcome in acute ischemic stroke (AIS) patients treated with intravenous thrombolysis (IVT). Several strategies have been proposed to streamline in-hospital pathways, among which treatment at CT/MR bed., Aim: To explore the impact of treatment at CT/MR bed, here defined as imaging area (IA), on functional outcome in stroke patients treated with IVT alone., Methods: All AIS patients treated with IVT alone at our center in 2020, 2021, and 2022 were included. Patients with any previous disability were excluded. The cohort was divided into two groups, depending on the treatment site. One group received IVT at IA, the other at emergency room or stroke unit (non-IA). Regression analysis assessed the association between treatment site and 3-month outcome., Results: A total of 327 patients who received IVT alone were included in the analysis. One hundred thirty-three (40.7%) were in the IA group and 194 (59.3%) in the non-IA group. The groups showed similar baseline characteristics. In the IA group, DNT was 45 min shorter. Despite similar rates of functional independence (mRS 0-2), the IA group showed higher rates of excellent outcome (mRS 0-1) compared to the non-IA group (60.1% vs 42.8%, p<0.01). Immediate treatment at IA was independently associated to excellent outcome (OR 1.78 [1.03-3.08])., Conclusions: Thrombolytic treatment at IA lowers DNT and is an independent predictor of excellent outcome after AIS. Our study emphasizes the importance of immediate thrombolytic treatment at IA, soon after radiological eligibility is confirmed. Immediate treatment at IA should be a standard-of-care for AIS., (© 2023. Fondazione Società Italiana di Neurologia.)

Published
2024
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17. Safety of Dual Orexin Receptor Antagonist Daridorexant: A Disproportionality Analysis of Publicly Available FAERS Data.

Author

Cicala G, Barbieri MA, Russo G, Salvo F, and Spina E

Abstract

Daridorexant (dari), as the first dual orexin receptor antagonist (DORA) marketed in Europe, offers a novel therapeutic approach to insomnia. However, data regarding its real-world safety are scarce. Thus, this study was aimed at assessing its safety profile using a large-scale pharmacovigilance database. Dari-related adverse drug reaction (ADR) reports from the Food and Drug Administration Adverse Event Reporting System were scrutinized, and ADRs were selected using reporting odds ratio (ROR) as a measure of disproportionality. Frequencies of events related to dari were compared to all other drugs (reference group, RG1) and only to other DORAs (RG2). Only significant disproportionalities to both RGs were evaluated in-depth. A total of 845 dari-related reports were selected; nightmares ( n = 146; dari vs. RG1: ROR = 113.74; 95%CI [95.13, 136]; dari vs. RG2: ROR = 2.35; 95 CI% [1.93, 2.85]), depression ( n = 22; dari vs. RG1: 2.13; [1.39, 3.25]; dari vs. RG2: ROR = 2.31; 95 CI% [1.45, 3.67]), and hangover ( n = 20; dari vs. RG1: ROR = 127.92; 95 CI% [81.98, 199.62]; and dari vs. RG2: 3.38; [2.04, 5.61]) were considered as safety signals. These data provide valuable insights into the real-world safety profile of daridorexant, supporting the existence of safety signals related to nightmares, depression, and hangovers.

Published
2024
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18. Cardiovascular Adverse Drug Reactions of Anti-Calcitonin Gene-Related Peptide Monoclonal Antibodies for Migraine Prevention: An Analysis from the European Spontaneous Adverse Event Reporting System.

Author

Sorbara EE, Barbieri MA, Russo G, Cicala G, and Spina E

Subjects
Humans, Female, Calcitonin Gene-Related Peptide, Pallor, Antibodies, Monoclonal therapeutic use, Atrial Fibrillation drug therapy, Drug-Related Side Effects and Adverse Reactions epidemiology, Drug-Related Side Effects and Adverse Reactions prevention & control, Migraine Disorders drug therapy, Hypertension, Myocardial Infarction, Venous Thrombosis drug therapy
Abstract

Introduction: Anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP-mAbs) have recently been approved for the prevention of migraine, and their safety profile is not fully characterized., Objective: The aim of this study was to evaluate the adverse drug reactions (ADRs) of anti-CGRP-mAbs through the analysis of individual case safety reports (ICSRs) collected in the EudraVigilance (EV) database, with a specific focus on cardiovascular (CV) ADRs., Methods: Data on ICSRs recorded between July 2018 and December 2022 in the EV database, involving one of the anti-CGRP-mAbs for migraine prevention-erenumab (ERE), galcanezumab (GMB), fremanezumab (FMB), and eptinezumab (EPT)-were included in the analysis. All ICSRs reporting at least one CV ADR, as identified within the MedDRA ® System Organ Classes (SOCs) "cardiac disorders" or "vascular disorders," were selected for the analysis. The frequency of disproportionate reporting was expressed as the reporting odds ratio (ROR) with its 95% confidence interval (CI), to evaluate the frequency of reporting of CV ADRs for each anti-CGRP-mAb compared with all other monoclonal antibodies (mAbs). A case-by-case analysis was conducted paying particular attention to serious CV ADR reports, focusing on the type of seriousness, age group, sex, and concomitant drugs., Results: A total of 9441 ICSRs were recorded in the EV database from 2018 to 2022, of which more than half were related to ERE (58.9%), followed by GMB (21.4%), FMB (19.0%), and EPT (0.7%). CV ICSRs accounted for 1205 cases (12.8%), with a total of 1599 CV ADRs. The CV ICSRs were mainly related to female patients (82.6%) aged 18-64 years (73.4%). Of the reported CV ADRs, 67.5% were considered serious. Among the total number of ICSRs related to each anti-CGRP-mAb, those associated with FMB had a higher percentage of CV ADRs (n = 253; 14.1%), followed by ERE (n = 707; 12.7%), EPT (n = 8; 12.7%), and GMB (n = 237; 11.7%). A higher frequency of reporting hypertension was shown for ERE (ROR = 1.45; 95% CI = 1.14-1.85). Pallor was mainly observed with FMB (5.00; 1.68-14.89), as well as deep vein thrombosis (3.86; 1.57-9.51), hot flush (2.16; 1.43-3.25), and palpitations (1.48; 1.05-2.08). Atrial fibrillation (2.36; 1.02-5.46) and myocardial infarction (2.21; 1.37-3.58) were mostly reported for GMB., Conclusion: The analysis of anti-CGRP-related CV ADRs was consistent with the information reported in the literature. However, hypertension with ERE, atrial fibrillation and myocardial infarction with GMB, as well as pallor, deep vein thrombosis, hot flush, and palpitations with FMB were not reported in the Summary of Product Characteristics (SmPCs). Considering this, more post-marketing analyses are needed to improve knowledge on the CV safety profiles of anti-CGRP-mAbs, especially for the last approved medication, EPT., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Published
2024
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19. Environmental effects on genetic variance are likely to constrain adaptation in novel environments.

Author

Walter GM, Monro K, Terranova D, la Spina E, Majorana M, Pepe G, Clark J, Cozzolino S, Cristaudo A, Hiscock SJ, and Bridle J

Abstract

Adaptive plasticity allows populations to cope with environmental variation but is expected to fail as conditions become unfamiliar. In novel conditions, populations may instead rely on rapid adaptation to increase fitness and avoid extinction. Adaptation should be fastest when both plasticity and selection occur in directions of the multivariate phenotype that contain abundant genetic variation. However, tests of this prediction from field experiments are rare. Here, we quantify how additive genetic variance in a multivariate phenotype changes across an elevational gradient, and test whether plasticity and selection align with genetic variation. We do so using two closely related, but ecologically distinct, sister species of Sicilian daisy ( Senecio , Asteraceae) adapted to high and low elevations on Mt. Etna. Using a quantitative genetic breeding design, we generated and then reciprocally planted c. 19,000 seeds of both species, across an elevational gradient spanning each species' native elevation, and then quantified mortality and five leaf traits of emergent seedlings. We found that genetic variance in leaf traits changed more across elevations than between species. The high-elevation species at novel lower elevations showed changes in the distribution of genetic variance among the leaf traits, which reduced the amount of genetic variance in the directions of selection and the native phenotype. By contrast, the low-elevation species mainly showed changes in the amount of genetic variance at the novel high elevation, and genetic variance was concentrated in the direction of the native phenotype. For both species, leaf trait plasticity across elevations was in a direction of the multivariate phenotype that contained a moderate amount of genetic variance. Together, these data suggest that where plasticity is adaptive, selection on genetic variance for an initially plastic response could promote adaptation. However, large environmental effects on genetic variance are likely to reduce adaptive potential in novel environments., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Society for the Study of Evolution (SSE) and European Society for Evolutionary Biology (ESEN).)

Published
2024
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