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2. Adolescent gender dysphoria management: position paper from the Italian Academy of Pediatrics, the Italian Society of Pediatrics, the Italian Society for Pediatric Endocrinology and Diabetes, the Italian Society of Adolescent Medicine and the Italian Society of Child and Adolescent Neuropsychiatry

Author

Calcaterra, V, Tornese, G, Zuccotti, G, Staiano, A, Cherubini, V, Gaudino, R, Fazzi, E, Barbi, E, Chiarelli, F, Corsello, G, Esposito, S, Ferrara, P, Iughetti, L, Laforgia, N, Maghnie, M, Marseglia, G, Perilongo, G, Pettoello-Mantovani, M, Ruggieri, M, Russo, G, Salerno, M, Striano, P, Valerio, G, Wasniewska, M, Agosti, M, Agostoni, C, Aiuti, A, Azzari, C, Badolato, R, Balduzzi, A, Baraldi, E, Canani, R, Biffi, A, Biondi, A, Bisogno, G, Pierri, N, Carnielli, V, Cianfarani, S, Cogo, P, Corvaglia, L, Dani, C, Di Salvo, G, Fagioli, F, Fanos, V, Ferrero, G, Francavilla, R, Galli, L, Gazzolo, D, Giaquinto, C, Giordano, P, Gitto, E, Grosso, S, Guarino, A, Indrio, F, Lanari, M, Lionetti, P, Locatelli, F, Lombardo, F, Maffeis, C, Marino, B, Midulla, F, Del Giudice, E, Del Giudice, M, Montini, G, Parenti, G, Parisi, P, Peroni, D, Perrotta, S, Piacentini, G, Pietrobelli, A, Raimondi, F, Ramenghi, U, Ravelli, A, Romano, C, Rossi, F, Rossi, P, Damiano, V, Spalice, A, Suppiej, A, Troncone, R, Verrotti, A, Null, N, Calcaterra, Valeria, Tornese, Gianluca, Zuccotti, Gianvincenzo, Staiano, Annamaria, Cherubini, Valentino, Gaudino, Rossella, Fazzi, Elisa Maria, Barbi, Egidio, Chiarelli, Francesco, Corsello, Giovanni, Esposito, Susanna Maria Roberta, Ferrara, Pietro, Iughetti, Lorenzo, Laforgia, Nicola, Maghnie, Mohamad, Marseglia, Gianluigi, Perilongo, Giorgio, Pettoello-Mantovani, Massimo, Ruggieri, Martino, Russo, Giovanna, Salerno, Mariacarolina, Striano, Pasquale, Valerio, Giuliana, Wasniewska, Malgorzata, Agosti, Massimo, Agostoni, Carlo Virginio, Aiuti, Alessandro, Azzari, Chiara, Badolato, Raffaele, Balduzzi, Adriana, Baraldi, Eugenio, Canani, Roberto Berni, Biffi, Alessandra, Biondi, Andrea, Bisogno, Gianni, Pierri, Nicola Brunetti, Carnielli, Virginio, Cianfarani, Stefano, Cogo, Paola, Corvaglia, Luigi, Dani, Carlo, Di Salvo, Giovanni, Fagioli, Franca, Fanos, Vassilios, Ferrero, Giovanni Battista, Francavilla, Ruggiero, Galli, Luisa, Gazzolo, Diego, Giaquinto, Carlo, Giordano, Paola, Gitto, Eloisa, Grosso, Salvatore, Guarino, Alfredo, Indrio, Flavia, Lanari, Marcello, Lionetti, Paolo, Locatelli, Franco, Lombardo, Fortunato, Maffeis, Claudio, Marino, Bruno, Midulla, Fabio, Del Giudice, Emanuele Miraglia, Del Giudice, Michele Miraglia, Montini, Giovanni, Parenti, Giancarlo, Parisi, Pasquale, Peroni, Diego, Perrotta, Silverio, Piacentini, Giorgio, Pietrobelli, Angelo, Raimondi, Francesco, Ramenghi, Ugo, Ravelli, Angelo, Romano, Claudio, Rossi, Francesca, Rossi, Paolo, Damiano, Vincenzo Salpietro, Spalice, Alberto, Suppiej, Agnese, Troncone, Riccardo, Verrotti, Alberto, null, null, Calcaterra, V, Tornese, G, Zuccotti, G, Staiano, A, Cherubini, V, Gaudino, R, Fazzi, E, Barbi, E, Chiarelli, F, Corsello, G, Esposito, S, Ferrara, P, Iughetti, L, Laforgia, N, Maghnie, M, Marseglia, G, Perilongo, G, Pettoello-Mantovani, M, Ruggieri, M, Russo, G, Salerno, M, Striano, P, Valerio, G, Wasniewska, M, Agosti, M, Agostoni, C, Aiuti, A, Azzari, C, Badolato, R, Balduzzi, A, Baraldi, E, Canani, R, Biffi, A, Biondi, A, Bisogno, G, Pierri, N, Carnielli, V, Cianfarani, S, Cogo, P, Corvaglia, L, Dani, C, Di Salvo, G, Fagioli, F, Fanos, V, Ferrero, G, Francavilla, R, Galli, L, Gazzolo, D, Giaquinto, C, Giordano, P, Gitto, E, Grosso, S, Guarino, A, Indrio, F, Lanari, M, Lionetti, P, Locatelli, F, Lombardo, F, Maffeis, C, Marino, B, Midulla, F, Del Giudice, E, Del Giudice, M, Montini, G, Parenti, G, Parisi, P, Peroni, D, Perrotta, S, Piacentini, G, Pietrobelli, A, Raimondi, F, Ramenghi, U, Ravelli, A, Romano, C, Rossi, F, Rossi, P, Damiano, V, Spalice, A, Suppiej, A, Troncone, R, Verrotti, A, Null, N, Calcaterra, Valeria, Tornese, Gianluca, Zuccotti, Gianvincenzo, Staiano, Annamaria, Cherubini, Valentino, Gaudino, Rossella, Fazzi, Elisa Maria, Barbi, Egidio, Chiarelli, Francesco, Corsello, Giovanni, Esposito, Susanna Maria Roberta, Ferrara, Pietro, Iughetti, Lorenzo, Laforgia, Nicola, Maghnie, Mohamad, Marseglia, Gianluigi, Perilongo, Giorgio, Pettoello-Mantovani, Massimo, Ruggieri, Martino, Russo, Giovanna, Salerno, Mariacarolina, Striano, Pasquale, Valerio, Giuliana, Wasniewska, Malgorzata, Agosti, Massimo, Agostoni, Carlo Virginio, Aiuti, Alessandro, Azzari, Chiara, Badolato, Raffaele, Balduzzi, Adriana, Baraldi, Eugenio, Canani, Roberto Berni, Biffi, Alessandra, Biondi, Andrea, Bisogno, Gianni, Pierri, Nicola Brunetti, Carnielli, Virginio, Cianfarani, Stefano, Cogo, Paola, Corvaglia, Luigi, Dani, Carlo, Di Salvo, Giovanni, Fagioli, Franca, Fanos, Vassilios, Ferrero, Giovanni Battista, Francavilla, Ruggiero, Galli, Luisa, Gazzolo, Diego, Giaquinto, Carlo, Giordano, Paola, Gitto, Eloisa, Grosso, Salvatore, Guarino, Alfredo, Indrio, Flavia, Lanari, Marcello, Lionetti, Paolo, Locatelli, Franco, Lombardo, Fortunato, Maffeis, Claudio, Marino, Bruno, Midulla, Fabio, Del Giudice, Emanuele Miraglia, Del Giudice, Michele Miraglia, Montini, Giovanni, Parenti, Giancarlo, Parisi, Pasquale, Peroni, Diego, Perrotta, Silverio, Piacentini, Giorgio, Pietrobelli, Angelo, Raimondi, Francesco, Ramenghi, Ugo, Ravelli, Angelo, Romano, Claudio, Rossi, Francesca, Rossi, Paolo, Damiano, Vincenzo Salpietro, Spalice, Alberto, Suppiej, Agnese, Troncone, Riccardo, Verrotti, Alberto, and null, null

Abstract

Background In response to the imperative need for standardized support for adolescent Gender Dysphoria (GD), the Italian Academy of Pediatrics, in collaboration with the Italian Society of Pediatrics, the Italian Society for Pediatric Endocrinology and Diabetes, Italian Society of Adolescent Medicine and Italian Society of Child and Adolescent Neuropsychiatry is drafting a position paper. The purpose of this paper is to convey the author's opinion on the topic, offering foundational information on potential aspects of gender-affirming care and emphasizing the care and protection of children and adolescents with GD.Main body Recognizing that adolescents may choose interventions based on their unique needs and goals and understanding that every individual within this group has a distinct trajectory, it is crucial to ensure that each one is welcomed and supported. The approach to managing individuals with GD is a multi-stage process involving a multidisciplinary team throughout all phases. Decisions regarding treatment should be reached collaboratively by healthcare professionals and the family, while considering the unique needs and circumstances of the individual and be guided by scientific evidence rather than biases or ideologies. Politicians and high court judges should address discrimination based on gender identity in legislation and support service development that aligns with the needs of young people. It is essential to establish accredited multidisciplinary centers equipped with the requisite skills and experience to effectively manage adolescents with GD, thereby ensuring the delivery of high-quality care.Conclusion Maintaining an evidence-based approach is essential to safeguard the well-being of transgender and gender diverse adolescents.

Published
2024

5. Does morbid obesity influence perioperative outcomes after video-assisted thoracic surgery (VATS) lobectomy for non-small cell lung cancer? Analysis of the Italian VATS group registry

Author

Guerrera, F., Lyberis, P., Lausi, P. O., Cristofori, R. C., Giobbe, R., Molinatti, M., Filosso, P. L., Curcio, C., Crisci, R., Ruffini, E., Maurizio, M., Fausto, P., Majed, R., Franco, S., Desideria, A., Giuseppe, M., Angela, D. P., Luigi, B., Giovanna, R., Piergiorgio, S., Giampiero, D., Reinhold, P., Francesco, Z., Roberto, B. M., Diego, G., Roberto, C., Albino, F. P., Felice, M., Pierpaolo, C., Giulio, M., Federico, M., Giorgio, C., Pio, M., Luca, V., Alessandro, G., Francesco, S., Pia, A. N., Luca, P. G., Carlo, R., Corrado, S., Camillo, L., Andrea, D., Michele, G., Cristiano, B., Fabio, L. G., Marco, A., Edoardo, B., Lorenzo, S., Roberto, G., Massimo, T., Alessandro, R., Mario, N., Davide, T., Giampeiro, N., Alessandro, B., Federico, R., Alessandro, S., Pamela, N., Marco, S., Emanuele, P., Carlo, C., Dario, A., Ottavio, R., Samuele, N., Andrea, D. A., Giorgia, T., Luca, A., Paolo, C., Francesco, P., Damiano, V., Giuseppe, C., Francesco, C., Stefano, M., Elisa, M., Piero, P., Marco, G., Duilio, D., Diego, F., Vittorio, D. B., Angelo, M., Francesco, L., Andrea, I., Nicola, R., Alberto, Andrea, V., and Maurizio, I.

Subjects
medicine.medical_specialty, Surgical margin, Lung Neoplasms, medicine.medical_treatment, VATS lobectomy, Video-assisted thoracic surgery, Blood Loss, Surgical, Lobectomy, Lung Cancer, Morbidity, Mortality, Obesity, Postoperative Complications, Carcinoma, Non-Small-Cell Lung, medicine, Humans, Thoracotomy, Registries, Lung cancer, Pneumonectomy, Retrospective Studies, business.industry, Thoracic Surgery, Video-Assisted, Margins of Excision, Perioperative, Length of Stay, medicine.disease, Surgery, Obesity, Morbid, Chest tube, Treatment Outcome, Cardiothoracic surgery, business, Abdominal surgery
Abstract

Objectives Obesity in Europe, and worldwide, has been an increasing epidemic during the past decades. Moreover, obesity has important implications regarding technical issues and the risks associated with surgical interventions. Nevertheless, there is a lack of evidence assessing the influence of obesity on video-assisted thoracic surgery (VATS) lobectomy results. Our study aimed to assess the impact of morbid obesity on perioperative clinical and oncological outcomes after VATS lobectomy using a prospectively maintained nationwide registry. Methods The Italian VATS lobectomy Registry was used to collect all consecutive cases from 55 Institutions. Explored outcome parameters were conversion to thoracotomy rates, complication rates, intra-operative blood loss, surgical time, hospital postoperative length of stay, chest tube duration, number of harvested lymph-node, and surgical margin positivity. Results From 2016 to 2019, a total of 4412 patients were collected. 74 patients present morbid obesity (1.7%). Multivariable-adjusted analysis showed that morbid obesity was associated with a higher rate of complications (32.8% vs 20.3%), but it was not associated with a higher rate of conversion, and surgical margin positivity rates. Moreover, morbid obesity patients benefit from an equivalent surgical time, lymph-node retrieval, intraoperative blood loss, hospital postoperative length of stay, and chest tube duration than non-morbid obese patients. The most frequent postoperative complications in morbidly obese patients were pulmonary-related (35%). Conclusion Our results showed that VATS lobectomy could be safely and satisfactorily conducted even in morbidly obese patients, without an increase in conversion rate, blood loss, surgical time, hospital postoperative length of stay, and chest tube duration. Moreover, short-term oncological outcomes were preserved.

Published
2021

11. Core curriculum. Oncologia clinica

Author

Antonelli, M, Zora, Baretta, Bianco, C, Bianco, R, Bria, E, Cancello, G, Ciardiello, F, Cingarlini, S, Condello, C, Damiano, V, Nullm, nullDe Laurentiis, Nullg, nullDella Vittoria Scarpati, Dieci, Mv, Forestieri, V, Nullg, nullDi Lorenzo, Nullm, nullDi Maio, Guarneri, V, Massari, F, Melisi, D, Morabito, A, Palmieri, G, Pensabene, M, Pepe, S, Perrone, F, Piccirillo, Mc, ARPINO, GRAZIA, CARLOMAGNO, Chiara, BIANCO, ANGELO RAFFAELE, CONTEGIACOMO, ALMA, LAURIA, ROSSELLA, MARINELLI, ALFREDO, MATANO, ELIDE, PERSICO, GIOVANNI, Antonelli M, Arpino G, Zora Baretta, Bianco C, Bianco R, Bria E, Cancello G, Carlomagno C, Bianco AR, Ciardiello F, Cingarlini S, Condello C, Contegiacomo A, Damiano V, De Laurentiis M, Della Vittoria Scarpati G, Dieci MV, Forestieri V, Di Lorenzo G, Di Maio M, Guarneri V, Lauria R, Marinelli A, Massari F, Matano E, Melisi D, Morabito A, Palmieri G, Pensabene M, Pepe S, Perrone F, Persico G, Piccirillo MC, Angelo Raffaele Bianco, Sabino De Placido, Giampaolo Tortora e Pierfranco Conte, Antonelli, M, Arpino, Grazia, Zora, Baretta, Bianco, C, Bianco, Roberto, Bria, E, Cancello, G, Carlomagno, Chiara, Bianco, ANGELO RAFFAELE, Ciardiello, F, Cingarlini, S, Condello, C, Contegiacomo, Alma, Damiano, V, Nullm, nullDe Laurentii, Nullg, nullDella Vittoria Scarpati, Dieci, Mv, Forestieri, Valeria, Nullg, nullDi Lorenzo, Nullm, nullDi Maio, Guarneri, V, Lauria, Rossella, Marinelli, Alfredo, Massari, F, Matano, Elide, Melisi, D, Morabito, A, Palmieri, G, Pensabene, M, Pepe, S, Perrone, F, Persico, Giovanni, Piccirillo, Mc, Lauria E, Bianco, R, and Forestieri, V

Published
2015

14. Letter: The response to somatostatin analogues in neuroendocrine tumours is influenced by the Ki67 score

Author

Faggiano, A, Carratù, A, Guadagno, E, Tafuto, S, Tatangelo, F, Riccardi, F, Mocerino, C, Palmieri, G, Damiano, V, Siciliano, R, Leo, S, Mauro, A, Tozzi, L, Battista, C, GUADAGNO, ELIA, DE ROSA, GAETANO, COLAO, ANNAMARIA, Faggiano, A, Carratù, A, Guadagno, E, Tafuto, S, Tatangelo, F, Riccardi, F, Mocerino, C, Palmieri, G, Damiano, V, Siciliano, R, Leo, S, Mauro, A, Tozzi, L, Battista, C, DE ROSA, Gaetano, Colao, Annamaria, and Guadagno, Elia

Subjects
Gastritis, Atrophic, medicine.medical_specialty, Hepatology, business.industry, Medicine (all), Gastroenterology, Neuroendocrine tumors, Bioinformatics, medicine.disease, Somatostatin, Text mining, Endocrinology, Stomach Neoplasm, Internal medicine, medicine, Pharmacology (medical), business, Neuroendocrine Tumor, Human
Published
2015

21. Efficacy and safety of pasireotide LAR or everolimus alone, or in combination in patients with advanced carcinoids (NET) of the lung/thymus : Results from the randomized, phase 2 LUNA study

Author

Ferolla, P., Brizzi, M. P., Meyer, T., Mansoor, W., Mazieres, J., Cao, C. D., Lena, H., Berruti, A., Damiano, V., Buikhuisen, W., Stankovic, M., Singh, N., Chiodini, E., Gislimberti, G., Öberg, Kjell E., Baudin, E., Ferolla, P., Brizzi, M. P., Meyer, T., Mansoor, W., Mazieres, J., Cao, C. D., Lena, H., Berruti, A., Damiano, V., Buikhuisen, W., Stankovic, M., Singh, N., Chiodini, E., Gislimberti, G., Öberg, Kjell E., and Baudin, E.

Published
2016
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22. SPHINGOSINE KINASE 1 (SPHK1) CONTRIBUTES TO RESISTANCE TO EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) INHIBITORS IN COLORECTAL CANCER MODELS

Author

Nappi L., Rosa R., Damiano V., Formisano L., Gelardi T., D’Amato C., Marciano R., De Maio A. P., Ferrara R., Tortora G., DE PLACIDO, SABINO, BIANCO, ROBERTO, VENEZIANI, BIANCA MARIA, Nappi, L., Rosa, R., Damiano, V., Formisano, L., Gelardi, T., D’Amato, C., Marciano, R., De Maio, A. P., Ferrara, R., Tortora, G., Veneziani, BIANCA MARIA, DE PLACIDO, Sabino, and Bianco, Roberto

Published
2011

23. INHIBITION OF CANCER CELL GROWTH AND INVASION BY TARGETING C-SRC IN BREAST CANCER MODELS RESISTANT TO ANTI-HER2 DRUGS

Author

Formisano L., Damiano V., Nappi L., Rosa R., Gelardi T., D’Amato C., Marciano R., De Maio A. P., Ferrara R., Tortora G., DE PLACIDO, SABINO, BIANCO, ROBERTO, VENEZIANI, BIANCA MARIA, Formisano, L., Damiano, V., Nappi, L., Rosa, R., Gelardi, T., D’Amato, C., Marciano, R., De Maio, A. P., Ferrara, R., Tortora, G., Veneziani, BIANCA MARIA, DE PLACIDO, Sabino, and Bianco, Roberto

Published
2011

24. Adherence issues related to sublingual immunotherapy as perceived by allergists

Author

Scurati, S., Frati, F., Passalacqua, G., Puccinelli, P., Hilaire, C., Incorvaia, C., D Avino, G., Comi, R., Lo Schiavo, M., Pezzuto, F., Montera, C., Pio, A., Teresa Ielpo, M., Cellini, F., Vicentini, L., Pecorari, R., Aresu, T., Capra, L., Benedictis, E., Bombi, C., Zauli, D., Vanzi, A., Alberto Paltrinieri, C., Bondioli, A., Paletta, I., Ventura, D., Mei, F., Paolini, F., Colangelo, C., Cavallucci, E., Cucinelli, F., Tinari, R., Ermini, G., Beltrami, V., Novembre, E., Begliomini, C., Marchese, E., Solito, E., Ammannati, V., Molino, G., Galli, E., Baldassini, M., Di Michele, L., Calvani, M., Gidaro, M., Venuti, A., Li Bianchi, E., Benassi, F., Pocobelli, D., Zangari, P., Rocco, M. G., Lo Vecchio, A., Pingitore, G., Grimaldi, O., Schiavino, D., Perrone, N., Antonietta Frieri, M., Di Rienzo, V., Tripodi, S., Scarpa, A., Tomsic, M., Bonaguro, R., Enrico Senna, G., Sirena, A., Turatello, F., Crescioli, S., Favero, E., Billeri, L., Chieco Bianchi, F., Gemignani, C., Zanforlin, M., Angiola Crivellaro, M., Hendrick, B., Maltauro, A., Masieri, S., Elisabetta Conte, M., Fama, M., Pozzan, M., Bonadonna, P., Casanova, S., Vallerani, E., Schiappoli, M., Borghesan, F., Giro, G., Casotto, S., Berardino, L., Zanoni, G., Ariano, R., Aquilina, R., Pellegrino, R., Marsico, P., Del Giudice, A., Narzisi, G., Tomaselli, V., Fornaca, G., Favro, M., Loperfido, B., Gallo, C., Buffoni, S., Gani, F., Raviolo, P., Faggionato, S., Truffelli, T., Vivalda, L., Albano, M., Enzo Rossi, R., Lattuada, G., Bona, F., Quaglio, L., Chiesa, A., Trapani, M., Seminara, R., Cucchi, B., Oderda, S., Borio, G., Galeasso, G., Garbaccio, P., Marco, A., Marengo, F., Cadario, G., Manzoni, S., Vinay, C., Curcio, A., Silvestri, A., Peduto, A., Riario-Sforza, G. G., Maria Forgnone, A., Barocelli, P., Tartaglia, N., Feyles, G., Giacone, A., Ricca, V., Guida, G., Nebiolo, F., Bommarito, L., Heffler, E., Vietti, F., Galimberti, M., Savi, E., Pappacoda, A., Bottero, P., Porcu, S., Felice, G., Berra, D., Francesca Spina, M., Pravettoni, V., Calamari, A. M., Varin, E., Iemoli, E., Lietti, D., Ghiglioni, D., Alessandro Fiocchi, Tosi, A., Poppa, M., Caviglia, A., Restuccia, M., Russello, M., Alciato, P., Manzotti, G., Ranghino, E., Luraschi, G., Rapetti, A., Rivolta, F., Allegri, F., Terracciano, L., Agostinis, F., Paolo Piras, P., Ronchi, G., Gaspardini, G., Caria, V., Tolu, F., Fantasia, D., Carta, P., Moraschini, A., Quilleri, R., Santelli, A., Prandini, P., Del Giudice, G., Apollonio, A., Bonazza, L., Teresa Franzini, M., Branchi, S., Zanca, M., Rinaldi, S., Catelli, L., Zanoletti, T., Cosentino, C., Della Torre, F., Cremonte, L., Musazzi, D., Suli, C., Rivolta, L., Ottolenghi, A., Marino, G., Sterza, G., Sambugaro, R., Orlandini, A., Minale, P., Voltolini, S., Bignardi, D., Omodeo, P., Tiri, A., Milani, S., Ronchi, B., Licardi, G., Bruni, P., Scibilia, J., Schroeder, J., Crosti, F., Maltagliati, A., Alesina, M. R., Mosca, M., Leone, G., Napolitano, G., Di Gruttola, G., Scala, G., Mascio, S., Valente, A., Marchetiello, I., Catello, R., Gazulli, A., Del Prete, A., Varricchio, A. M., Carbone, A., Forestieri, A., Stillitano, M., Leonetti, L., Tirroni, E., Castellano, F., Abbagnara, F., Romano, F., Levanti, C., Cilia, M., Longo, R., Ferrari, A., Merenda, R., Di Ponti, A., Guercio, E., Surace, L., Ammendola, G., Tansella, F., Peccarisi, L., Stragapede, L., Minenna, M., Granato, M., Fuiano, N., Pannofino, A., Ciuffreda, S., Giannotta, A., Morero, G., D Oronzio, L., Taddeo, G., Nettis, E., Cinquepalmi, G., Lamanna, C., Mastrandrea, F., Minelli, M., Salamino, F., Muratore, L., Latorre, F., Quarta, C., Ventura, M., D Ippolito, G., Giannoccaro, F., Dambra, P., Pinto, L., Triggiani, M., Munno, G., Manfredi, G., Lonero, G., Damiano, V., Errico, G., Di Leo, E., Manzari, F., Spagna, V., Arsieni, A., Matarrese, A., Mazzarella, G., Scarcia, G., Scarano, R., Ferrannini, A., Pastore, A., Maionchi, P., Filannino, L., Tria, M., Giuliano, G., Damiani, E., Scichilone, N., Marchese, M., Lucania, A., Marino, M., Strazzeri, L., Tumminello, S., Vitale, G. I., Gulotta, S., Gragotto, G., Zambito, M., Greco, D., Valenti, G., Licitra, G., Cannata, E., Filpi, R., Contraffatto, M., Sichili, S., Randazzo, S., Scarantino, G., Lo Porto, B., Pavone, F., Di Bartolo, C., Paternò, A., Rapisarda, F., Laudani, E., Leonardi, S., Padua, V., Cabibbo, G., Marino Guzzardi, G., Deluca, F., Agozzino, C., Pettinato, R., Ghini, M., Scurati S., Frati F., Passalacqua G., Puccinelli P., Hilaire C., Incorvaia C., D'Avino G., Comi R., Lo Schiavo M., Pezzuto F., Montera C., Pio A., Teresa Ielpo M., Cellini F., Vicentini L., Pecorari R., Aresu T., Capra L., De Benedictis E., Bombi C., Zauli D., Vanzi A., Alberto Paltrinieri C., Bondioli A., Paletta I., Ventura D., Mei F., Paolini F., Colangelo C., Cavallucci E., Cucinelli F., Tinari R., Ermini G., Beltrami V., Novembre E., Begliomini C., Marchese E., Solito E., Ammannati V., Molino G., Galli E., Baldassini M., Di Michele L., Calvani M., Gidaro M., Venuti A., Li Bianchi E., Benassi F., Pocobelli D., Zangari P., De Rocco M.G., Lo Vecchio A., Pingitore G., Grimaldi O., Schiavino D., Perrone N., Antonietta Frieri M., Di Rienzo V., Tripodi S., Scarpa A., Tomsic M., Bonaguro R., Enrico Senna G., Sirena A., Turatello F., Crescioli S., Favero E., Billeri L., Chieco Bianchi F., Gemignani C., Zanforlin M., Angiola Crivellaro M., Hendrick B., Maltauro A., Masieri S., Elisabetta Conte M., Fama M., Pozzan M., Bonadonna P., Casanova S., Vallerani E., Schiappoli M., Borghesan F., Giro G., Casotto S., Berardino L., Zanoni G., Ariano R., Aquilina R., Pellegrino R., Marsico P., Del Giudice A., Narzisi G., Tomaselli V., Fornaca G., Favro M., Loperfido B., Gallo C., Buffoni S., Gani F., Raviolo P., Faggionato S., Truffelli T., Vivalda L., Albano M., Enzo Rossi R., Lattuada G., Bona F., Quaglio L., Chiesa A., Trapani M., Seminara R., Cucchi B., Oderda S., Borio G., Galeasso G., Garbaccio P., De Marco A., Marengo F., Cadario G., Manzoni S., Vinay C., Curcio A., Silvestri A., Peduto A., Riario-Sforza G.G., Maria Forgnone A., Barocelli P., Tartaglia N., Feyles G., Giacone A., Ricca V., Guida G., Nebiolo F., Bommarito L., Heffler E., Vietti F., Galimberti M., Savi E., Pappacoda A., Bottero P., Porcu S., Felice G., Berra D., Francesca Spina M., Pravettoni V., Calamari A.M., Varin E., Iemoli E., Lietti D., Ghiglioni D., Fiocchi A., Tosi A., Poppa M., Caviglia A., Restuccia M., Russello M., Alciato P., Manzotti G., Ranghino E., Luraschi G., Rapetti A., Rivolta F., Allegri F., Terracciano L., Agostinis F., Paolo Piras P., Ronchi G., Gaspardini G., Caria V., Tolu F., Fantasia D., Carta P., Moraschini A., Quilleri R., Santelli A., Prandini P., Del Giudice G., Apollonio A., Bonazza L., Teresa Franzini M., Branchi S., Zanca M., Rinaldi S., Catelli L., Zanoletti T., Cosentino C., Della Torre F., Cremonte L., Musazzi D., Suli C., Rivolta L., Ottolenghi A., Marino G., Sterza G., Sambugaro R., Orlandini A., Minale P., Voltolini S., Bignardi D., Omodeo P., Tiri A., Milani S., Ronchi B., Licardi G., Bruni P., Scibilia J., Schroeder J., Crosti F., Maltagliati A., Alesina M.R., Mosca M., Leone G., Napolitano G., Di Gruttola G., Scala G., Mascio S., Valente A., Marchetiello I., Catello R., Gazulli A., Del Prete A., Varricchio A.M., Carbone A., Forestieri A., Stillitano M., Leonetti L., Tirroni E., Castellano F., Abbagnara F., Romano F., Levanti C., Cilia M., Longo R., Ferrari A., Merenda R., Di Ponti A., Guercio E., Surace L., Ammendola G., Tansella F., Peccarisi L., Stragapede L., Minenna M., Granato M., Fuiano N., Pannofino A., Ciuffreda S., Giannotta A., Morero G., D'Oronzio L., Taddeo G., Nettis E., Cinquepalmi G., Lamanna C., Mastrandrea F., Minelli M., Salamino F., Muratore L., Latorre F., Quarta C., Ventura M., D'Ippolito G., Giannoccaro F., Dambra P., Pinto L., Triggiani M., Munno G., Manfredi G., Lonero G., Damiano V., Errico G., Di Leo E., Manzari F., Spagna V., Arsieni A., Matarrese A., Mazzarella G., Scarcia G., Scarano R., Ferrannini A., Pastore A., Maionchi P., Filannino L., Tria M., Giuliano G., Damiani E., Scichilone N., Marchese M., Lucania A., Marino M., Strazzeri L., Tumminello S., Vitale G.I., Gulotta S., Gragotto G., Zambito M., Greco D., Valenti G., Licitra G., Cannata E., Filpi R., Contraffatto M., Sichili S., Randazzo S., Scarantino G., Lo Porto B., Pavone F., Di Bartolo C., Paterno A., Rapisarda F., Laudani E., Leonardi S., Padua V., Cabibbo G., Marino Guzzardi G., Deluca F., Agozzino C., Pettinato R., Ghini M., Scurati S, Frati F, Passalacqua G, Puccinelli P, Hilaire C, Incorvaia I, D'Avino G, Comi R, Lo Schiavio M, Pezzuto F, Montera C, Pio A, Ielpo MT, Cellini F, Vicentini L, Pecorari R, Aresu T, Capra L, De Benedictis E, Bombi C, Zauli D, and et al

Subjects
medicine.medical_specialty, Pathology, genetic structures, efficacy, Alternative medicine, Medicine (miscellaneous), Adherence, Cost, Efficacy, Side effects, Sublingual immunotherapy, Settore MED/10 - Malattie Dell'Apparato Respiratorio, sublingual immunotherapy, ALLERGEN, cost, medicine, Subcutaneous immunotherapy, Sublingual immunotherapy, adherence, Clinical efficacy, Intensive care medicine, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), sublingual immunoterapy, Original Research, Asthma, AEROALLERGENS, side effects, business.industry, Health Policy, medicine.disease, Slit, eye diseases, Clinical trial, Patient Preference and Adherence, immunotherapy, sense organs, Allergists, ADHERENCE TO TREATMENT, business, Social Sciences (miscellaneous)
Abstract

Silvia Scurati1, Franco Frati1, Gianni Passalacqua2, Paola Puccinelli1, Cecile Hilaire1, Cristoforo Incorvaia3, Italian Study Group on SLIT Compliance 1Scientific and Medical Department, Stallergenes, Milan, Italy; 2Allergy and Respiratory Diseases, Department of Internal Medicine, Genoa; 3Allergy/Pulmonary Rehabilitation, ICP Hospital, Milan, ItalyObjectives: Sublingual immunotherapy (SLIT) is a viable alternative to subcutaneous immunotherapy to treat allergic rhinitis and asthma, and is widely used in clinical practice in many European countries. The clinical efficacy of SLIT has been established in a number of clinical trials and meta-analyses. However, because SLIT is self-administered by patients without medical supervision, the degree of patient adherence with treatment is still a concern. The objective of this study was to evaluate the perception by allergists of issues related to SLIT adherence.Methods: We performed a questionnaire-based survey of 296 Italian allergists, based on the adherence issues known from previous studies. The perception of importance of each item was assessed by a VAS scale ranging from 0 to 10.Results: Patient perception of clinical efficacy was considered the most important factor (ranked 1 by 54% of allergists), followed by the possibility of reimbursement (ranked 1 by 34%), and by the absence of side effects (ranked 1 by 21%). Patient education, regular follow-up, and ease of use of SLIT were ranked first by less than 20% of allergists.Conclusion: These findings indicate that clinical efficacy, cost, and side effects are perceived as the major issues influencing patient adherence to SLIT, and that further improvement of adherence is likely to be achieved by improving the patient information provided by prescribers.Keywords: adherence, sublingual immunotherapy, efficacy, cost, side effects

Published
2010

25. Vascular endothelial growth factor receptor-1 contributes to resistance to anti-epidermal growth factor receptor drugs in human cancer cells

Author

BIANCO R, ROSA R, DAMIANO V, DANIELE G, GELARDI T, GAROFALO S, TARALLO V, FALCO S, MELISI D, BENELLI R, ALBINI A, RYAN A, TORTORA G., CIARDIELLO, Fortunato, Bianco, R, Rosa, R, Damiano, V, Daniele, G, Gelardi, T, Garofalo, S, Tarallo, V, De, Falco, S, Melisi, D, Benelli, R, Albini, A, Ryan, A, Ciardiello, Fortunato, and Tortora, G.

Published
2008

26. VEGF Receptor 1 contributes to resistance to anti-EGFR drugs in human cancer cells

Author

BIANCO, ROBERTO, TORTORA, GIAMPAOLO, Rosa R, Damiano V, Daniele G, Gelardi T, Garofalo S, Tarallo V, De Falco S, Melisi D, Benelli R, Albini A, Ryan A, Ciardiello F, Bianco, Roberto, Rosa, R, Damiano, V, Daniele, G, Gelardi, T, Garofalo, S, Tarallo, V, De Falco, S, Melisi, D, Benelli, R, Albini, A, Ryan, A, Ciardiello, F, and Tortora, Giampaolo

Subjects
resistance, EGFR, VEGFR-1
Published
2008

28. Mechanisms of resistance to HER/erbB inhibitors

Author

BIANCO, ROBERTO, TORTORA, GIAMPAOLO, Damiano V, Gelardi T, Ciardiello F, Benjamin Bonavida, Bianco, Roberto, Damiano, V, Gelardi, T, Ciardiello, F, and Tortora, Giampaolo

Published
2007

31. Novel toll-like receptor 9 agonist induces epidermal growth factor receptor (EGFR) inhibition and synergistic antitumour activity with EGFR inhibitors

Author

Damiano, V., Caputo, R, ., Fp, F. P., A, ., Placido, De, S, ., Ar, A. R., F, ., G, ., Labianca, BIANCO, ROBERTO, D'ARMIENTO, FRANCESCO PAOLO, LEONARDI, ANTONIO, BIANCO, ANGELO RAFFAELE, AGRAWAL, ASHWINI, CIARDIELLO, FORTUNATO, TORTORA, GIAMPAOLO, Damiano, V., Caputo, R, ., Bianco, Roberto, D'Armiento, FRANCESCO PAOLO, Fp, F. P., Leonardi, Antonio, A, ., Placido, De, S, ., Bianco, ANGELO RAFFAELE, Ar, A. R., Agrawal, Ashwini, Ciardiello, Fortunato, F, ., Tortora, Giampaolo, G, ., and Labianca

Published
2006

32. Efficacy and safety of pasireotide LAR or everolimus alone, or in combination in patients with advanced carcinoids (NET) of the lung/thymus: Results from the randomized, phase 2 LUNA study

Author

Ferolla, P., primary, Brizzi, M.P., additional, Meyer, T., additional, Mansoor, W., additional, Mazieres, J., additional, Cao, C.D., additional, Lena, H., additional, Berruti, A., additional, Damiano, V., additional, Buikhuisen, W., additional, Stankovic, M., additional, Singh, N., additional, Chiodini, E., additional, Gislimberti, G., additional, Oberg, K., additional, and Baudin, E., additional

Published
2016
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35. Antitumor activity ofZD6126, a novel vascular-targeting agent, is enhanced when combined with ZD1839, an epidermal growth factor receptor tyrosine kinase inhibitor, and potentiatesthe effects of radiation in a human non-small cell lung cancer xenograft model

Author

Raben D, Bianco C, Damiano V, Bianco R, Melisi D, Mignogna C, D'Armiento FP, Cionini L, Bianco AR, Tortora G, Bunn P., CIARDIELLO, Fortunato, Raben, D, Bianco, C, Damiano, V, Bianco, R, Melisi, D, Mignogna, C, D'Armiento, Fp, Cionini, L, Bianco, Ar, Tortora, G, Ciardiello, Fortunato, and Bunn, P.

Published
2004

37. COMBINED TARGETING OF EGFR AND MDM2 BY GEFITINIB AND ANTISENSE MDM2 COOPERATIVELY INHIBIT HORMONE-INDEPENDENT PROSTATE CANCER

Author

BIANCO, ROBERTO, DE PLACIDO, SABINO, CAPUTO R, DAMIANO V, FICORELLA C, AGRAWAL S, BIANCO AR, CIARDIELLO F, G. TORTORA, Bianco, Roberto, Caputo, R, Damiano, V, DE PLACIDO, Sabino, Ficorella, C, Agrawal, S, Bianco, Ar, Ciardiello, F, and G., Tortora

Subjects
mdm2, EGFR, prostate cancer
Abstract

EGFR) may play a relevant role in the progression, hormone therapy resistance, and prognosis of prostate cancer patients. Also MDM2, a negative p53 regulator that interacts with retinoblastoma (Rb), E2F, p19arf and the rasmitogen- activated protein kinase(MAPK) cascade plays an important role in prostate cancer progression and prognosis. On the basis of the EGFR and MDM2 role in integrating signaling pathways critical for prostate cancer progression, we investigated whether their selective combined blockade may have a cooperative antitumor effect in prostate cancer. For this purpose, we have used the EGFR tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) and a second generation hybrid oligonucleotide antisense MDM2 (AS-MDM2), respectively. Experimental Design: Gefitinib and AS-MDM2 were administered to hormone-refractory and hormone-dependent human prostate cancer cells in vitro and to mice bearing tumor xenografts, evaluating the effects on growth, apoptosis, and protein expression, in vitro and in vivo. Results: We demonstrated that the combination of gefitinib and AS-MDM2 synergistically inhibits the growth of hormone-independent prostate cancer cells in vitro. This effect is accompanied by the inhibition of MDM2, phosphorylated Akt (pAkt), phosphorylated MAPK (pMAPK), and vascular endothelial growth factor (VEGF) expression and by Rb hypophosphorylation. The combination of the two agents in nude mice bearing the same hormone-independent tumors caused a potent cooperative antitumor effect. Tumor samples analysis confirmed the inhibition of MDM2, pAkt, pMAPK, VEGF, and basic fibroblast growth factor expression. Conclusions: This study shows that EGFR and MDM2 play a critical role in the growth of prostate cancer, especially hormone-dependent, and that their combined blockade by gefitinib and AS-MDM2 causes a cooperative antitumor effect, supporting the clinical development of this therapeutic strategy.

Published
2004

39. Combined targeted inhibition of bcl-2, bcl-XL, epidermal growth factor receptor, and protein kinase A type I causes potent antitumor, apoptotic, and antiangiogenic activity

Author

Tortora, G., Caputo, R., Damiano, V., Troiani, T., Bianca Maria VENEZIANI, Placido, S., Bianco, A. R., Zangemeister-Wittke, U., Ciardiello, F., Tortora, G, Caputo, R, Damiano, V, Troiani, Teresa, Veneziani, Bm, DE PLACIDO, S, Bianco, Ar, ZANGEMEISTER WITTKE, U, Ciardiello, Fortunato, Giampaolo, Tortora, Rosa, Caputo, Vincenzo, Damiano, Roberta, Caputo, Teresa, Troiani, Veneziani, BIANCA MARIA, DE PLACIDO, Sabino, Angelo Raffaele, Bianco, Uwe Zangemeister, Wittke, and Fortunato, Ciardiello

Subjects
Vascular Endothelial Growth Factor A, Transplantation, Heterologous, Oligonucleotides, bcl-X Protein, Mice, Nude, Antineoplastic Agents, Apoptosis, Breast Neoplasms, Endothelial Growth Factors, Transfection, Mice, Tumor Cells, Cultured, Animals, Humans, Lymphokines, Cell Death, Neovascularization, Pathologic, Vascular Endothelial Growth Factors, Gefitinib, Oligonucleotides, Antisense, Cyclic AMP-Dependent Protein Kinases, ErbB Receptors, Proto-Oncogene Proteins c-bcl-2, Colonic Neoplasms, Quinazolines, Intercellular Signaling Peptides and Proteins, Female, Cell Division
Abstract

PURPOSE: This study investigated whether the functional and structural interactions between epidermal growth factor receptor (EGFR), protein kinase AI (PKAI), and bcl-2/bcl-xL could be exploited to obtain cooperative antitumor effects against models of human colon and breast cancer. EXPERIMENTAL DESIGN: Antisense bcl-2/bcl-xL (4625), antisense PKAI (AS-PKAI), and ZD1839 ("Iressa"), a selective EGFR tyrosine kinase inhibitor, were administered as single agents and in combination against GEO colon and ZR-75-1 breast cancer cell lines in vitro and to mice bearing s.c. GEO human tumor xenografts in vivo. Effects on growth inhibition, vascular endothelial growth factor secretion, and induction of apoptosis were assessed. RESULTS: Antisense bcl-2/bcl-xL inhibited the growth of GEO and ZR-75-1 cells in vitro, reducing bcl-2 and bcl-xL expression and vascular endothelial growth factor secretion. Supra-additive growth inhibition and apoptosis induction were observed when 4625 was combined with ZD1839 or AS-PKAI. Combining all three agents resulted in a complete growth inhibitory effect in vitro. Antisense bcl-2/bcl-xL, AS-PKAI, and ZD1839 administered in vivo as single agents caused growth inhibition of GEO xenografts. Combining all three agents caused a marked and sustained effect, with 50\% growth inhibition and 50\% of mice tumor free 5 weeks after treatment withdrawal. The combination was well tolerated. CONCLUSIONS: The combination of 4625, AS-PKAI, and ZD1839 resulted in a strong antiproliferative, proapoptotic, and antiangiogenic response, suggestive of a functional interaction between EGFR, PKAI, and bcl-2/bcl-xL and providing a rationale for the selection of specific molecular treatments for the development of therapeutic strategies. Iressa is a trademark of the AstraZeneca group of companies.

Published
2003

40. Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase

Author

Ciardiello F, Caputo R, Damiano V, Troiani T, Vitagliano D, Carlomagno F, Bianca Maria VENEZIANI, Fontanini G, Ar, Bianco, Tortora G, Ciardiello, Fortunato, Caputo, R, Damiano, V, Troiani, Teresa, Vitagliano, D, Carlomagno, F, Veneziani, Bm, Fontanini, G, Bianco, Ar, Tortora, G., Ciardiello, F, Troiani, T, Carlomagno, Francesca, Veneziani, BIANCA MARIA, Fortunato, Ciardiello, Rosa, Caputo, Vincenzo, Damiano, Roberta, Caputo, Teresa, Troiani, Donatella, Vitagliano, Gabriella, Fontanini, A., Raffaele Bianco, and Giampaolo, Tortora

Subjects
Time Factors, Paclitaxel, Blotting, Western, Apoptosis, Mice, Piperidines, Cell Line, Tumor, Neoplasms, Animals, Humans, Enzyme Inhibitors, Phosphorylation, Mice, Inbred BALB C, Dose-Response Relationship, Drug, Antibodies, Monoclonal, Protein-Tyrosine Kinases, Flow Cytometry, Immunohistochemistry, Vascular Endothelial Growth Factor Receptor-2, ErbB Receptors, Agar, Receptors, Vascular Endothelial Growth Factor, NIH 3T3 Cells, Quinazolines, Electrophoresis, Polyacrylamide Gel, Cell Division, Neoplasm Transplantation
Abstract

PURPOSE: Vascular endothelial growth factor (VEGF) is a major mitogen for endothelial cells and enhances vascular permeability. Enhanced VEGF secretion is found in human cancers and correlates with increased tumor neovascularization. ZD6474 is a p.o. bioavailable, VEGF flk-1/KDR receptor (VEGFR-2) tyrosine kinase inhibitor with antitumor activity in many human cancer xenografts and is currently in Phase I clinical development. EXPERIMENTAL DESIGN: We tested the effects of ZD6474 on EGFR phosphorylation in cell expressing functional epidermal growth factor receptor (EGFR) and the antiproliferative and the proapoptotic activity of ZD6474 alone or in combination taxanes in human cancer cell lines with functional EGFR but lacking VEGFR-2. The antitumor activity of this drug was also tested in nude mice bearing established GEO colon cancer xenografts. RESULTS: ZD6474 causes a dose-dependent inhibition of EGFR phosphorylation in mouse NIH-EGFR fibroblasts and human MCF-10A ras breast cancer cells, two cell lines that overexpress the human EGFR. ZD6474 treatment resulted in a dose-dependent inhibition of soft agar growth in seven human cell lines (breast, colon, gastric, and ovarian) with functional EGFR but lacking VEGFR-2. A dose-dependent supra-additive effect in growth inhibition and in apoptosis in vitro was observed by the combined treatment with ZD6474 and paclitaxel or docetaxel. ZD6474 treatment of nude mice bearing palpable GEO colon cancer xenografts (which are sensitive to inhibition of EGFR signaling) induced dose-dependent tumor growth inhibition. Immunohistochemical analysis revealed a significant dose-dependent reduction of neoangiogenesis. The antitumor activity of ZD6474 in GEO tumor xenografts was also found to be enhanced when combined with paclitaxel. Tumor regression was observed in all mice after treatment with ZD6474 plus paclitaxel, and it was accompanied by a significant potentiation in inhibition of angiogenesis. Six of 20 mice had no histological evidence of tumors after treatment with ZD6474 plus paclitaxel. CONCLUSIONS: This study suggests that in addition to inhibiting endothelial cell proliferation by blocking VEGF-induced signaling, ZD6474 may also be able to inhibit cancer cell growth by blocking EGFR autocrine signaling. These results provide also a rationale for the clinical evaluation of ZD6474 combined with taxanes in cancer patients.

Published
2003

41. Combined targeted inhibition of Bcl-2, Bcl-xL, EGFR and Protein Kinase A Type I causes potent antitumor, apoptotic and antiangiogenic activity

Author

TORTORA G, CAPUTO R, DAMIANO V, TROIANI T, BIANCO AR, ZANGEMEISTER WITTKE U, CIARDIELLO F., VENEZIANI, BIANCA MARIA, DE PLACIDO, SABINO, Tortora, Giampaolo, Caputo, R, Damiano, Vincenzo, Troiani, T, Veneziani, BIANCA MARIA, DE PLACIDO, Sabino, Bianco, Ar, ZANGEMEISTER WITTKE, U, Ciardiello, F., Tortora, G, and Damiano, V

Subjects
EGFR, bcl-2, Protein Kinase A
Published
2003

44. Inhibition of growth factors production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor

Author

Ciardiello F, Caputo R, Bianco R, Damiano V, Fontanini G, Cuccato S, De Placido S, Ar, Bianco, Giampaolo Tortora, Ciardiello, F, Caputo, R, Bianco, Roberto, Damiano, V, Fontanini, G, Cuccato, S, DE PLACIDO, Sabino, Bianco, Ar, Tortora, G., Damiano, Vincenzo, Tortora, Giampaolo, Ciardiello, Fortunato, Bianco, R, and DE PLACIDO, S

Subjects
Vascular Endothelial Growth Factor A, EGFR, gefitinib, Mice, Nude, Angiogenesis Inhibitors, Antineoplastic Agents, Endothelial Growth Factors, Inhibitory Concentration 50, Mice, angiogenesis, Tumor Cells, Cultured, Animals, Humans, Growth Substances, Lymphokines, Mice, Inbred BALB C, Neovascularization, Pathologic, Vascular Endothelial Growth Factors, Drug Synergism, Neoplasms, Experimental, Protein-Tyrosine Kinases, Transforming Growth Factor alpha, Immunohistochemistry, Xenograft Model Antitumor Assays, ErbB Receptors, Disease Models, Animal, Quinazolines, Female, Fibroblast Growth Factor 2
Abstract

The transforming growth factor-alpha/epidermal growth factor receptor (TGF-alpha-EGFR) autocrine pathway, which is involved in the development and the progression of human epithelial cancers, controls, in part, the production of angiogenic factors. These angiogenic factors, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), are secreted by cancer cells to stimulate normal endothelial cell growth through paracrine mechanisms. ZD1839 (Iressa) is a p.o.-active, selective EGFR-tyrosine kinase inhibitor (TKI) in clinical trials in cancer patients. In this study, we evaluated the antiangiogenic and antitumor activity of ZD1839 in human colon (GEO, SW480, and CaCo2), breast (ZR-75-1 and MCF-7 ADR), ovarian (OVCAR-3), and gastric (KATO III and N87) cancer cells that coexpress TGF-alpha and EGFR. ZD1839 treatment determined a dose- and time-dependent growth inhibition accompanied by the decrease of VEGF, bFGF and TGF-alpha production in vitro. Treatment of immunodeficient mice bearing well-established, palpable GEO xenografts with ZD1839 determined a cytostatic dose-dependent tumor growth inhibition. Immunohistochemical analysis of GEO tumor xenografts after ZD1839 treatment revealed a significant dose-dependent reduction of TGF-alpha, bFGF, and VEGF expression in cancer cells and of neoangiogenesis, as determined by microvessel count. Furthermore, the antitumor activity of ZD1839 was potentiated in combination with the cytotoxic drug paclitaxel in GEO tumor xenografts. Tumor regression was observed in all mice after treatment with ZD1839 plus paclitaxel, and it was accompanied by a significant potentiation in inhibition of TGF-alpha, VEGF, and bFGF expression with a few or no microvessels. Furthermore, 6 of 16 mice bearing well-established, palpable GEO xenografts had no histological evidence of GEO tumors at the end of treatment with ZD1839 plus paclitaxel. These results demonstrate that the antitumor effect of ZD1839 is accompanied by inhibition in the production of autocrine and paracrine growth factors that sustain autonomous local growth and facilitate angiogenesis, and that this effect can be potentiated by the combined treatment with certain cytotoxic drugs, such as paclitaxel.

Published
2001

47. Oral antisense targeting protein kinase A cooperates with taxol and inhibits tumor growth, angiogenesis and growth factors production

Author

TORTORA G., BIANCO, ROBERTO, DAMIANO V., FONTANINI G., DE PLACIDO, SABINO, CIARDIELLO F., BIANCO, ANGELO RAFFAELE, Tortora, Giampaolo, Bianco, Roberto, Damiano, Vincenzo, Fontanini, G, DE PLACIDO, Sabino, Bianco, Ar, Ciardiello, F., Tortora, G., Damiano, V., Fontanini, G., and Bianco, ANGELO RAFFAELE

Subjects
angiogenesis, protein kinase A, targeted therapy
Published
2000

48. Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells

Author

Ciardiello, F., Bianco, R., Damiano, V., Fontanini, G., Caputo, R., Pomatico, G., Placido, S., Bianco, A. R., Mendelsohn, J., Giampaolo Tortora, Ciardiello, Fortunato, Bianco, R, Damiano, V, Fontanini, G, Caputo, R, Pomatico, G, DE PLACIDO, S, Bianco, Ar, Mendelsohn, J, and Tortora, G.

Subjects
Vascular Endothelial Growth Factor A, Lymphokines, Mice, Inbred BALB C, Dose-Response Relationship, Drug, Neovascularization, Pathologic, Vascular Endothelial Growth Factors, Blotting, Western, Antibodies, Monoclonal, Mice, Nude, Endothelial Growth Factors, Oligonucleotides, Antisense, Thionucleotides, Transforming Growth Factor alpha, Immunohistochemistry, Xenograft Model Antitumor Assays, ErbB Receptors, Mice, Colonic Neoplasms, Tumor Cells, Cultured, Animals, Humans, Female, Fibroblast Growth Factor 2
Abstract

Angiogenesis plays a key role in tumor growth and metastasis. The transforming growth factor alpha (TGF-alpha)-epidermal growth factor receptor (EGFR) autocrine pathway controls in part the production of angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in cancer cells. In this study, we have evaluated the antiangiogenic and antitumor activity of monoclonal antibody (MAb) C225, an anti-EGFR chimeric human-mouse MAb, alone and in combination with a human VEGF antisense (AS) 21-mer phosphorothioate oligonucleotide (VEGF-AS) in human GEO colon cancer cells. MAb C225 treatment determined a dose-dependent inhibition of VEGF, bFGF, and TGF-alpha production by GEO cells in vitro. Treatment with VEGF-AS caused a selective inhibition in VEGF expression by GEO cells in vitro. Treatment of immunodeficient mice bearing established, palpable GEO xenografts for 3 weeks with VEGF-AS or with MAb C225 determined a cytostatic reversible inhibition of tumor growth. In contrast, a prolonged inhibition of tumor growth was observed in all mice treated with the two agents, in combination with a significant improvement in mice survival compared with controls (P.001), to MAb C225 (P.001), or to VEGF-AS (P.001) treated mice. All mice died within 4, 6, and 8 weeks after tumor cell injection in the control, VEGF-AS and MAb C225 groups, respectively. In contrast, 50% of mice treated with the combination of VEGF-AS and MAb C225 were alive at 13 weeks. Ten % of mice treated with VEGF-AS plus MAb C225 were alive at 20 weeks and had no histological evidence of GEO tumors. Immunohistochemical analysis of GEO tumor xenografts demonstrated a significant reduction of VEGF expression after treatment with VEGF-AS with a parallel reduction in microvessel count. MAb C225 treatment determined a reduction in the expression of VEGF, bFGF, and TGF-alpha with a reduction in microvessel count. Finally, a significant potentiation in inhibition of VEGF expression and little or no microvessels were observed in GEO tumors after the combined treatment with the two agents.

Published
2000

49. Oral antisense that targets protein kinase A cooperates with taxol and inhibits tumor growth, angiogenesis, and growth factor production

Author

Giampaolo Tortora, Bianco, R., Damiano, V., Fontanini, G., Placido, S., Bianco, A. R., Ciardiello, F., Tortora, G, Bianco, R, Damiano, V, Fontanini, G, DE PLACIDO, S, Bianco, Ar, and Ciardiello, Fortunato

Subjects
Mice, Inbred BALB C, Time Factors, Neovascularization, Pathologic, Paclitaxel, Tumor Suppressor Proteins, Administration, Oral, Mice, Nude, Cell Cycle Proteins, Oligonucleotides, Antisense, Antineoplastic Agents, Phytogenic, Cyclic AMP-Dependent Protein Kinases, Immunohistochemistry, Mice, Ki-67 Antigen, Colonic Neoplasms, Tumor Cells, Cultured, Animals, Humans, Female, Growth Substances, Microtubule-Associated Proteins, Cyclin-Dependent Kinase Inhibitor p27, Neoplasm Transplantation
Abstract

Protein kinase A type I (PKAI) transduces mitogenic signals from different growth factors and oncogenes and is overexpressed in the majority of human cancers. We and other investigators previously have reported that different PKAI inhibitors, including antisense oligonucleotides, have antitumor activity. In this study, we used a novel hybrid DNA/RNA mixed-backbone oligonucleotide (MBO) targeting the PKAI subunit RIalpha. We demonstrated that after oral administration, the MBO antisense RIalpha inhibited the growth of human colon cancer xenografts in nude mice and showed a cooperative antitumor effect with Taxol, which outlasted treatment withdrawal and significantly prolonged survival of mice compared with untreated controls or to single-agent-treated mice. Immunohistochemical analysis of tumor specimens showed inhibition of target protein RIalpha and of growth factor expression along with a marked inhibition of angiogenesis and an increase in p27 expression. In conclusion, a novel MBO that targets PKAI, administered p.o., is effective and cooperates with the anticancer drug Taxol on both tumor growth and expression of factors involved in the control of cell proliferation, cell cycle, and angiogenesis. Because the MBO described has completed a phase I trial involving i.v. injection in cancer patients, these results provide the biological rationale of its activity after oral administration and may be translated into a therapeutic strategy in a clinical setting.

Published
2000

50. Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225

Author

Fortunato Ciardiello, Bianco, R., Damiano, V., Lorenzo, S., Pepe, S., Placido, S., Fan, Z., Mendelsohn, J., Bianco, A. R., Tortora, G., Ciardiello, F, Bianco, Roberto, Damiano, Vincenzo, DE LORENZO, Sonya, Pepe, Stefano, DE PLACIDO, Sabino, Fan, Z, Mendelsohn, J, Bianco, A. R., Tortora, Giampaolo, Ciardiello, Fortunato, Bianco, R, Damiano, V, DE LORENZO, S, Pepe, S, DE PLACIDO, S, Bianco, Ar, and Tortora, G.

Subjects
Mice, Inbred BALB C, Dose-Response Relationship, Drug, EGFR, Antibodies, Monoclonal, Cetuximab, Mice, Nude, Antineoplastic Agents, Drug Synergism, Neoplasms, Experimental, Antibodies, Monoclonal, Humanized, Drug Administration Schedule, ErbB Receptors, Mice, Tumor Cells, Cultured, topotecan, cetuximab, Animals, Humans, Topotecan, Neoplasm Transplantation, Tumor Stem Cell Assay
Abstract

Epidermal growth factor (EGF)-related proteins such as transforming growth factor alpha (TGF-alpha) control cancer cell growth through autocrine and paracrine pathways. Overexpression of TGF-alpha and/or its receptor (EGFR) has been associated with a more aggressive disease and a poor prognosis. The blockade of EGFR activation has been proposed as a target for anticancer therapy. Monoclonal antibody (MAb) C225 is an anti-EGFR humanized chimeric mouse MAb that is presently in Phase II clinical trials in cancer patients. Previous studies have suggested the potentiation of the antitumor activity of certain cytotoxic drugs, such as cisplatin and doxorubicin, in human cancer cell lines by treatment with anti-EGFR antibodies. We have evaluated in human ovarian, breast, and colon cancer cell lines, which express functional EGFR, the antiproliferative activity of MAb C225 in combination with topotecan, a cytotoxic drug that specifically inhibits topoisomerase I and that has shown antitumor activity in these malignancies. A dose-dependent supraadditive increase of growth inhibition in vitro was observed when cancer cells were treated with topotecan and MAb C225 in a sequential schedule. In this respect, the cooperativity quotient, defined as the ratio between the actual growth inhibition obtained by treatment with topotecan followed by MAb C225 and the sum of the growth inhibition achieved by each agent, ranged from 1.2 to 3, depending on drug concentration and cancer cell line. Treatment with MAb C225 also markedly enhanced apoptotic cell death induced by topotecan. For example, in GEO colon cancer cells, 5 nM topotecan, followed by 0.5 microg/ml MAb C225, induced apoptosis in 45% cells as compared with untreated cells (6%) or to 5 nM topotecan-treated cells (22%). Treatment of mice bearing established human GEO colon cancer xenografts with topotecan or with MAb C225 determined a transient inhibition of tumor growth because GEO tumors resumed the growth rate of untreated tumors at the end of the treatment period. In contrast, an almost complete tumor regression was observed in all mice treated with the two agents in combination. This determined a prolonged life span of the mice that was significantly different as compared with controls (P0.001), to MAb C225-treated group (P0.001), or to the topotecan-treated group (P0.001). All mice of the topotecan plus MAb C225 group were the only animals alive 14 weeks after tumor cell injection. Furthermore, 20% of mice in this group were still alive after 19 weeks. The combined treatment with MAb C225 and topotecan was well tolerated by mice with no signs of acute or delayed toxicity. These results provide a rationale for the evaluation of the anticancer activity of the combination of topoisomerase I inhibitors and anti-EGFR blocking MAbs in clinical trials.

Published
1999

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