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101. Human neural stem cells drug product: Microsatellite instability analysis

Author

Valentina Grespi, Cecilia Caprera, Claudia Ricciolini, Ilaria Bicchi, Gianmarco Muzi, Matteo Corsi, Stefano Ascani, Angelo Luigi Vescovi, Maurizio Gelati, Grespi, V, Caprera, C, Ricciolini, C, Bicchi, I, Muzi, G, Corsi, M, Ascani, S, Vescovi, A, and Gelati, M

Subjects
Multidisciplinary, Neural Stem Cells, Humans, Neural Stem Cell, Cell Differentiation, Microsatellite Instability, Human, Stem Cell Transplantation
Abstract

Introduction In central nervous system neurodegenerative disorders, stem cell-based therapies should be considered as a promising therapeutic approach. The safe use of human Neural Stem Cells (hNSCs) for the treatment of several neurological diseases is currently under evaluation of phase I/II clinical trials. Clinical application of hNSCs require the development of GMP standardized protocols capable of generating high quantities of reproducible and well characterized stem cells bearing stable functional and genetic properties. Aim The aim of this study was to evaluate possible instabilities or modifications of the microsatellite loci in different culture passages because high culture passages represent an in vitro replicative stress leading to senescence. Experimental method: The hNSCs were characterized at different culture time points, from passage 2 to passage 25, by genetic typing at ten microsatellite loci. Conclusion We showed that genetic stability at microsatellite loci is maintained by the cells even at high passages adding a further demonstration of the safety of our hNSCs GMP culture method.

Published
2022

102. What do we have to know about pd-l1 expression in prostate cancer? A systematic literature review. part 2: Clinic–pathologic correlations

Author

Sofia Canete-Portillo, Magda Zanelli, Giacomo Santandrea, Daniel M. Berney, Luigi Cormio, Guido Giordano, Cristina Magi-Galluzzi, Stefania Croci, Stefano Ascani, Alcides Chaux, Eleonora Zanetti, Loredana De Marco, Matteo Landriscina, Maria Carolina Gelli, Alessandra Bisagni, Maurizio Zizzo, Giuseppe Carrieri, Beatrice Melli, Jatin Gandhi, Alessandro Tafuni, Antonio De Leo, Martina Bonacini, Alessandra Soriano, Dario de Biase, Maria Paola Bonasoni, Francesca Sanguedolce, Andrea Palicelli, Carolina Castro Ruiz, Moira Ragazzi, Palicelli A., Bonacini M., Croci S., Magi-Galluzzi C., Canete-Portillo S., Chaux A., Bisagni A., Zanetti E., De Biase D., Melli B., Sanguedolce F., Zanelli M., Bonasoni M.P., De Marco L., Soriano A., Ascani S., Zizzo M., Ruiz C.C., De Leo A., Giordano G., Landriscina M., Carrieri G., Cormio L., Berney D.M., Gandhi J., Santandrea G., Gelli M.C., Tafuni A., and Ragazzi M.

Subjects
Male, Oncology, PD-L1, medicine.medical_specialty, QH301-705.5, Adenocarcinoma, Cancer, Checkpoint inhibitors, Im-munotherapy, Immunohistochemistry, Prostate, Target-therapy, Ipilimumab, Review, B7-H1 Antigen, Prostate cancer, chemistry.chemical_compound, Castration Resistance, Checkpoint inhibitor, Internal medicine, Carcinoma, Humans, Medicine, Degarelix, Biology (General), Neoplasm Staging, business.industry, Prostatic Neoplasms, Lymphatic Metastasi, General Medicine, medicine.disease, Survival Analysis, GVAX, chemistry, Lymphatic Metastasis, Prostatic Neoplasm, immunotherapy, Neoplasm Grading, Neoplasm Recurrence, Local, business, checkpoint inhibitors, Human, medicine.drug
Abstract

Many studies have investigated the potential prognostic and predictive role of PD-L1 in prostatic carcinoma (PC). We performed a systematic literature review (PRISMA guidelines) to critically evaluate human tissue-based studies (immunohistochemistry, molecular analysis, etc.), experimental research (cell lines, mouse models), and clinical trials. Despite some controversial results and study limitations, PD-L1 expression by tumor cells may be related to clinic–pathologic features of adverse outcome, including advanced tumor stage (high pT, presence of lymph node, and distant metastases), positivity of surgical margins, high Grade Group, and castration resistance. Different PD-L1 positivity rates may be observed in matched primary PCs and various metastatic sites of the same patients. Over-fixation, type/duration of decalcification, and PD-L1 antibody clone may influence the immunohistochemical analysis of PD-L1 on bone metastases. PD-L1 seemed expressed more frequently by castration-resistant PCs (49%) as compared to hormone-sensitive PCs (17%). Some series found that PD-L1 positivity was associated with decreased time to castration resistance. Treatment with ipilimumab, cyclophosphamide/GVAX/degarelix, or degarelix alone may increase PD-L1 expression. Correlation of PD-L1 positivity with overall survival and outcomes related to tumor recurrence were rarely investigated; the few analyzed series produced conflicting results and sometimes showed limitations. Further studies are required. The testing and scoring of PD-L1 should be standardized.

Published
2021

103. Impact of COVID-19 Pandemic on Cardiovascular Testing in Asia

Author

Takashi Kudo, Ryan Lahey, Cole B. Hirschfeld, Michelle C. Williams, Bin Lu, Mirvat Alasnag, Mona Bhatia, Hee-Seung Henry Bom, Tairkhan Dautov, Reza Fazel, Ganesan Karthikeyan, Felix Y.J. Keng, Ronen Rubinshtein, Nathan Better, Rodrigo Julio Cerci, Sharmila Dorbala, Paolo Raggi, Leslee J. Shaw, Todd C. Villines, João V. Vitola, Andrew D. Choi, Eli Malkovskiy, Benjamin Goebel, Yosef A. Cohen, Michael Randazzo, Thomas N.B. Pascual, Yaroslav Pynda, Maurizio Dondi, Diana Paez, Andrew J. Einstein, Rodrigo Cerci, Joao V. Vitola, Gerd Hinterleitner, Yao Lu, Olga Morozova, Zhuoran Xu, Yosef Cohen, Andrew Choi, Juan Lopez-Mattei, Purvi Parwani, Mohammad Nawaz Nasery, Artan Goda, Ervina Shirka, Rabie Benlabgaa, Salah Bouyoucef, Abdelkader Medjahedi, Qais Nailli, Mariela Agolti, Roberto Nicolas Aguero, Maria del Carmen Alak, Lucia Graciela Alberguina, Guillermo Arroñada, Andrea Astesiano, Alfredo Astesiano, Carolina Bas Norton, Pablo Benteo, Juan Blanco, Juan Manuel Bonelli, Jose Javier Bustos, Raul Cabrejas, Jorge Cachero, Roxana Campisi, Alejandro Canderoli, Silvia Carames, Patrícia Carrascosa, Ricardo Castro, Oscar Cendoya, Luciano Martin Cognigni, Carlos Collaud, Claudia Cortes, Javier Courtis, Daniel Cragnolino, Mariana Daicz, Alejandro De La Vega, Silvia Teresa De Maria, Horacio Del Riego, Fernando Dettori, Alejandro Deviggiano, Laura Dragonetti, Mario Embon, Ruben Emilio Enriquez, Jorge Ensinas, Fernando Faccio, Adolfo Facello, Diego Garofalo, Ricardo Geronazzo, Natalia Gonza, Lucas Gutierrez, Miguel Angel Guzzo, Victor Hasbani, Melina Huerin, Victor Jäger, Julio Manuel Lewkowicz, Maria Nieves A. López De Munaín, Jose Maria Lotti, Alejandra Marquez, Osvaldo Masoli, Osvaldo Horacio Masoli, Edgardo Mastrovito, Matias Mayoraz, Graciela Eva Melado, Anibal Mele, Maria Fernanda Merani, Alejandro Horacio Meretta, Susana Molteni, Marcos Montecinos, Eduardo Noguera, Carlos Novoa, Claudio Pereyra Sueldo, Sebastian Perez Ascani, Pablo Pollono, Maria Paula Pujol, Alejandro Radzinschi, Gustavo Raimondi, Marcela Redruello, Marina Rodríguez, Matías Rodríguez, Romina Lorena Romero, Arturo Romero Acuña, Federico Rovaletti, Lucas San Miguel, Lucrecia Solari, Bruno Strada, Sonia Traverso, Sonia Simona Traverzo, Maria del Huerto Velazquez Espeche, Juan Sebastian Weihmuller, Juan Wolcan, Susana Zeffiro, Mari Sakanyan, Scott Beuzeville, Raef Boktor, Patrick Butler, Jennifer Calcott, Loretta Carr, Virgil Chan, Charles Chao, Woon Chong, Mark Dobson, D'Arne Downie, Girish Dwivedi, Barry Elison, Jean Engela, Roslyn Francis, Anand Gaikwad, Ashok Gangasandra Basavaraj, Bruce Goodwin, Robert Greenough, Christian Hamilton-Craig, Victar Hsieh, Subodh Joshi, Karin Lederer, Kenneth Lee, Joseph Lee, John Magnussen, Nghi Mai, Gordon Mander, Fiona Murton, Dee Nandurkar, Johanne Neill, Edward O'Rourke, Patricia O'Sullivan, George Pandos, Kunthi Pathmaraj, Alexander Pitman, Rohan Poulter, Manuja Premaratne, David Prior, Lloyd Ridley, Natalie Rutherford, Hamid Salehi, Connor Saunders, Luke Scarlett, Sujith Seneviratne, Deepa Shetty, Ganesh Shrestha, Jonathan Shulman, Vijay Solanki, Tony Stanton, Murch Stuart, Michael Stubbs, Ian Swainson, Kim Taubman, Andrew Taylor, Paul Thomas, Steven Unger, Anthony Upton, Shankar Vamadevan, William Van Gaal, Johan Verjans, Demetrius Voutnis, Victor Wayne, Peter Wilson, David Wong, Kirby Wong, John Younger, Gudrun Feuchtner, Siroos Mirzaei, Konrad Weiss, Natallia Maroz-Vadalazhskaya, Olivier Gheysens, Filip Homans, Rodrigo Moreno-Reyes, Agnès Pasquet, Veronique Roelants, Caroline M. Van De Heyning, Raúl Araujo Ríos, Valentina Soldat-Stankovic, Sinisa Stankovic, Maria Helena Albernaz Siqueira, Augusto Almeida, Paulo Henrique Alves Togni, Jose Henrique Andrade, Luciana Andrade, Carlos Anselmi, Roberta Araújo, Guilherme Azevedo, Sabbrina Bezerra, Rodrigo Biancardi, Gabriel Blacher Grossman, Simone Brandão, Diego Bromfman Pianta, Lara Carreira, Bruno Castro, Tien Chang, Fernando Cunali, Roberto Cury, Roberto Dantas, Fernando de Amorim Fernandes, Andrea De Lorenzo, Robson De Macedo Filho, Fernanda Erthal, Fabio Fernandes, Juliano Fernandes, Thiago Ferreira De Souza, Wilson Furlan Alves, Bruno Ghini, Luiz Goncalves, Ilan Gottlieb, Marcelo Hadlich, Vinícius Kameoka, Ronaldo Lima, Adna Lima, Rafael Willain Lopes, Ricardo Machado e Silva, Tiago Magalhães, Fábio Martins Silva, Luiz Eduardo Mastrocola, Fábio Medeiros, José Claudio Meneghetti, Vania Naue, Danilo Naves, Roberto Nolasco, Cesar Nomura, Joao Bruno Oliveira, Eduardo Paixao, Filipe Penna De Carvalho, Ibraim Pinto, Priscila Possetti, Mayra Quinta, Rodrigo Rizzo Nogueira Ramos, Ricardo Rocha, Alfredo Rodrigues, Carlos Rodrigues, Leila Romantini, Adelina Sanches, Sara Santana, Leonardo Sara da Silva, Paulo Schvartzman, Cristina Sebastião Matushita, Tiago Senra, Afonso Shiozaki, Maria Eduarda Menezes de Siqueira, Cristiano Siqueira, Paola Smanio, Carlos Eduardo Soares, José Soares Junior, Marcio Sommer Bittencourt, Bernardo Spiro, Cláudio Tinoco Mesquita, Jorge Torreao, Rafael Torres, Marly Uellendahl, Guilherme Urpia Monte, Otávia Veríssimo, Estevan Vieira Cabeda, Felipe Villela Pedras, Roberto Waltrick, Marcello Zapparoli, Hamid Naseer, Marina Garcheva-Tsacheva, Irena Kostadinova, Youdaline Theng, Gad Abikhzer, Rene Barette, Benjamin Chow, Dominique Dabreo, Matthias Friedrich, Ria Garg, Mohammed Nassoh Hafez, Chris Johnson, Marla Kiess, Jonathon Leipsic, Eugene Leung, Robert Miller, Anastasia Oikonomou, Stephan Probst, Idan Roifman, Gary Small, Vikas Tandon, Adwait Trivedi, James White, Katherine Zukotynski, Jose Canessa, Gabriel Castro Muñoz, Carmen Concha, Pablo Hidalgo, Cesar Lovera, Teresa Massardo, Luis Salazar Vargas, Pedro Abad, Harold Arturo, Sandra Ayala, Luis Benitez, Alberto Cadena, Carlos Caicedo, Antonio Calderón Moncayo, Sharon Gomez, Claudia T. Gutierrez Villamil, Claudia Jaimes, Juan Londoño, Juan Luis Londoño Blair, Luz Pabon, Mauricio Pineda, Juan Carlos Rojas, Diego Ruiz, Manuel Valencia Escobar, Andres Vasquez, Damiana Vergel, Alejandro Zuluaga, Isabel Berrocal Gamboa, Gabriel Castro, Ulises González, Ana Baric, Tonci Batinic, Maja Franceschi, Maja Hrabak Paar, Mladen Jukic, Petar Medakovic, Viktor Persic, Marina Prpic, Ante Punda, Juan Felipe Batista, Juan Manuel Gómez Lauchy, Yamile Marcos Gutierrez, Rayner Menéndez, Amalia Peix, Luis Rochela, Christoforos Panagidis, Ioannis Petrou, Vaclav Engelmann, Milan Kaminek, Vladimír Kincl, Otto Lang, Milan Simanek, Jawdat Abdulla, Morten Bøttcher, Mette Christensen, Lars Christian Gormsen, Philip Hasbak, Søren Hess, Paw Holdgaard, Allan Johansen, Kasper Kyhl, Bjarne Linde Norgaard, Kristian Altern Øvrehus, Niels Peter Rønnow Sand, Rolf Steffensen, Anders Thomassen, Bo Zerahn, Alfredo Perez, Giovanni Alejandro Escorza Velez, Mayra Sanchez Velez, Islam Shawky Abdel Aziz, Mahasen Abougabal, Taghreed Ahmed, Adel Allam, Ahmed Asfour, Mona Hassan, Alia Hassan, Ahmed Ibrahim, Sameh Kaffas, Ahmed Kandeel, Mohamed Mandour Ali, Ahmad Mansy, Hany Maurice, Sherif Nabil, Mahmoud Shaaban, Ana Camila Flores, Anne Poksi, Juhani Knuuti, Velipekka Kokkonen, Martti Larikka, Valtteri Uusitalo, Matthieu Bailly, Samuel Burg, Jean-François Deux, Vincent Habouzit, Fabien Hyafil, Olivier Lairez, Franck Proffit, Hamza Regaieg, Laure Sarda-Mantel, Vania Tacher, Roman P. Schneider, Harold Ayetey, George Angelidis, Aikaterini Archontaki, Sofia Chatziioannou, Ioannis Datseris, Christina Fragkaki, Panagiotis Georgoulias, Sophia Koukouraki, Maria Koutelou, Eleni Kyrozi, Evangelos Repasos, Petros Stavrou, Pipitsa Valsamaki, Carla Gonzalez, Goleat Gutierrez, Alejandro Maldonado, Klara Buga, Ildiko Garai, Pál Maurovich-Horvat, Erzsébet Schmidt, Balint Szilveszter, Edit Várady, Nilesh Banthia, Jinendra Kumar Bhagat, Rishi Bhargava, Vivek Bhat, Partha Choudhury, Vijay Sai Chowdekar, Aparna Irodi, Shashank Jain, Elizabeth Joseph, Sukriti Kumar, Prof Dr Girijanandan Mahapatra, Deepanjan Mitra, Bhagwant Rai Mittal, Ahmad Ozair, Chetan Patel, Tapan Patel, Ravi Patel, Shivani Patel, Sudhir Saxena, Shantanu Sengupta, Santosh Singh, Bhanupriya Singh, Ashwani Sood, Atul Verma, Erwin Affandi, Padma Savenadia Alam, Edison Edison, Gani Gunawan, Habusari Hapkido, Basuki Hidayat, Aulia Huda, Anggoro Praja Mukti, Djoko Prawiro, Erwin Affandi Soeriadi, Hilman Syawaluddin, Amjed Albadr, Majid Assadi, Farshad Emami, Golnaz Houshmand, Majid Maleki, Maryam Tajik Rostami, Seyed Rasoul Zakavi, Eed Abu Zaid, Svetlana Agranovich, Yoav Arnson, Rachel Bar-Shalom, Alex Frenkel, Galit Knafo, Rachel Lugassi, Israel Shlomo Maor Moalem, Maya Mor, Noam Muskal, Sara Ranser, Aryeh Shalev, Domenico Albano, Pierpaolo Alongi, Gaspare Arnone, Elisa Bagatin, Sergio Baldari, Matteo Bauckneht, Paolo Bertelli, Francesco Bianco, Rachele Bonfiglioli, Roberto Boni, Andrea Bruno, Isabella Bruno, Elena Busnardo, Elena Califaretti, Luca Camoni, Aldo Carnevale, Roberta Casoni, Armando Ugo Cavallo, Giorgio Cavenaghi, Franca Chierichetti, Marcello Chiocchi, Corrado Cittanti, Mauro Colletta, Umberto Conti, Alberto Cossu, Alberto Cuocolo, Marco Cuzzocrea, Maria Luisa De Rimini, Giuseppe De Vincentis, Eleonora Del Giudice, Alberico Del Torto, Veronica Della Tommasina, Rexhep Durmo, Paola Anna Erba, Laura Evangelista, Riccardo Faletti, Evelina Faragasso, Mohsen Farsad, Paola Ferro, Luigia Florimonte, Viviana Frantellizzi, Fabio Massimo Fringuelli, Marco Gatti, Angela Gaudiano, Alessia Gimelli, Raffaele Giubbini, Francesca Giuffrida, Salvatore Ialuna, Riccardo Laudicella, Lucia Leccisotti, Lucia Leva, Riccardo Liga, Carlo Liguori, Giampiero Longo, Margherita Maffione, Maria Elisabetta Mancini, Claudio Marcassa, Elisa Milan, Barbara Nardi, Sara Pacella, Giovanna Pepe, Gianluca Pontone, Sabina Pulizzi, Natale Quartuccio, Lucia Rampin, Fabrizio Ricci, Pierluigi Rossini, Giuseppe Rubini, Vincenzo Russo, Gian Mauro Sacchetti, Gianmario Sambuceti, Massimo Scarano, Roberto Sciagrà, Massimiliano Sperandio, Antonella Stefanelli, Guido Ventroni, Stefania Zoboli, Dainia Baugh, Duane Chambers, Ernest Madu, Felix Nunura, Hiroshi Asano, Chimura Misato Chimura, Shinichiro Fujimoto, Koichiro Fujisue, Tomohisa Fukunaga, Yoshimitsu Fukushima, Kae Fukuyama, Jun Hashimoto, Yasutaka Ichikawa, Nobuo Iguchi, Masamichi Imai, Anri Inaki, Hayato Ishimura, Satoshi Isobe, Toshiaki Kadokami, Takao Kato, Shinichiro Kumita, Hirotaka Maruno, Hiroyuki Mataki, Masao Miyagawa, Ryota Morimoto, Masao Moroi, Shigeki Nagamachi, Kenichi Nakajima, Tomoaki Nakata, Ryo Nakazato, Mamoru Nanasato, Masanao Naya, Takashi Norikane, Yasutoshi Ohta, Satoshi Okayama, Atsutaka Okizaki, Yoichi Otomi, Hideki Otsuka, Masaki Saito, Sakata Yasushi Sakata, Masayoshi Sarai, Daisuke Sato, Shinya Shiraishi, Yoshinobu Suwa, Kentaro Takanami, Kazuya Takehana, Junichi Taki, Nagara Tamaki, Yasuyo Taniguchi, Hiroki Teragawa, Nobuo Tomizawa, Kenichi Tsujita, Kyoko Umeji, Yasushi Wakabayashi, Shinichiro Yamada, Shinya Yamazaki, Tatsuya Yoneyama, Mohammad Rawashdeh, Daultai Batyrkhanov, Khalid Makhdomi, Kevin Ombati, Faridah Alkandari, Masoud Garashi, Tchoyoson Lim Coie, Sonexay Rajvong, Artem Kalinin, Marika Kalnina, Mohamad Haidar, Renata Komiagiene, Giedre Kviecinskiene, Mindaugas Mataciunas, Donatas Vajauskas, Christian Picard, Noor Khairiah A. Karim, Luise Reichmuth, Anthony Samuel, Mohammad Aaftaab Allarakha, Ambedhkar Shantaram Naojee, Erick Alexanderson-Rosas, Erika Barragan, Alejandro Becerril González-Montecinos, Manuel Cabada, Daniel Calderon Rodriguez, Isabel Carvajal-Juarez, Violeta Cortés, Filiberto Cortés, Erasmo De La Peña, Manlio Gama-Moreno, Luis González, Nelsy Gonzalez Ramírez, Moisés Jiménez-Santos, Luis Matos, Edgar Monroy, Martha Morelos, Mario Ornelas, Jose Alberto Ortga Ramirez, Andrés Preciado-Anaya, Óscar Ulises Preciado-Gutiérrez, Adriana Puente Barragan, Sandra Graciela Rosales Uvera, Sigelinda Sandoval, Miguel Santaularia Tomas, Lilia M. Sierra-Galan, Silvia Siu, Enrique Vallejo, Mario Valles, Marc Faraggi, Erdenechimeg Sereegotov, Srdja Ilic, Nozha Ben-Rais, Nadia Ismaili Alaoui, Sara Taleb, Khin Pa Pa Myo, Phyo Si Thu, Ram Kumar Ghimire, Bijoy Rajbanshi, Peter Barneveld, Andor Glaudemans, Jesse Habets, Klaas Pieter Koopmans, Jeroen Manders, Stefan Pool, Arthur Scholte, Asbjørn Scholtens, Riemer Slart, Paul Thimister, Erik-Jan Van Asperen, Niels Veltman, Derk Verschure, Nils Wagenaar, John Edmond, Chris Ellis, Kerryanne Johnson, Ross Keenan, Shaw Hua (Anthony) Kueh, Christopher Occleshaw, Alexander Sasse, Andrew To, Niels Van Pelt, Calum Young, Teresa Cuadra, Hector Bladimir Roque Vanegas, Idrissa Adamou Soli, Djibrillou Moussa Issoufou, Tolulope Ayodele, Chibuzo Madu, Yetunde Onimode, Elen Efros-Monsen, Signe Helene Forsdahl, Jenni-Mari Hildre Dimmen, Arve Jørgensen, Isabel Krohn, Pål Løvhaugen, Anders Tjellaug Bråten, Humoud Al Dhuhli, Faiza Al Kindi, Naeema Al-Bulushi, Zabah Jawa, Naima Tag, Muhammad Shehzad Afzal, Shazia Fatima, Muhammad Numair Younis, Musab Riaz, Mohammad Saadullah, Yariela Herrera, Dora Lenturut-Katal, Manuel Castillo Vázquez, José Ortellado, Afroza Akhter, Dianbo Cao, Stephen Cheung, Xu Dai, Lianggeng Gong, Dan Han, Yang Hou, Caiying Li, Tao Li, Dong Li, Sijin Li, Jinkang Liu, Hui Liu, Ming Yen Ng, Kai Sun, Gongshun Tang, Jian Wang, Ximing Wang, Zhao-Qian Wang, Yining Wang, Yifan Wang, Jiang Wu, Zhifang Wu, Liming Xia, Jiangxi Xiao, Lei Xu, Youyou Yang, Wu Yin, Jianqun Yu, Li Yuan, Tong Zhang, Longjiang Zhang, Yong-Gao Zhang, Xiaoli Zhang, Li Zhu, Ana Alfaro, Paz Abrihan, Asela Barroso, Eric Cruz, Marie Rhiamar Gomez, Vincent Peter Magboo, John Michael Medina, Jerry Obaldo, Davidson Pastrana, Christian Michael Pawhay, Alvin Quinon, Jeanelle Margareth Tang, Bettina Tecson, Kristine Joy Uson, Mila Uy, Magdalena Kostkiewicz, Jolanta Kunikowska, Nuno Bettencourt, Guilhermina Cantinho, Antonio Ferreira, Ghulam Syed, Samer Arnous, Said Atyani, Angela Byrne, Tadhg Gleeson, David Kerins, Conor Meehan, David Murphy, Mark Murphy, John Murray, Julie O'Brien, Ji-In Bang, Henry Bom, Sang-Geon Cho, Chae Moon Hong, Su Jin Jang, Yong Hyu Jeong, Won Jun Kang, Ji-Young Kim, Jaetae Lee, Chang Kyeong Namgung, Young So, Kyoung Sook Won, Venjamin Majstorov, Marija Vavlukis, Barbara Gužic Salobir, Monika Štalc, Theodora Benedek, Imre Benedek, Raluca Mititelu, Claudiu Adrian Stan, Alexey Ansheles, Olga Dariy, Olga Drozdova, Nina Gagarina, Vsevolod Milyevich Gulyaev, Irina Itskovich, Anatoly Karalkin, Alexander Kokov, Ekaterina Migunova, Viktor Pospelov, Daria Ryzhkova, Guzaliya Saifullina, Svetlana Sazonova, Vladimir Sergienko, Irina Shurupova, Tatjana Trifonova, Wladimir Yurievich Ussov, Margarita Vakhromeeva, Nailya Valiullina, Konstantin Zavadovsky, Kirill Zhuravlev, Subhani Okarvi, Dragana Sobic Saranovic, Felix Keng, Jia Hao Jason See, Ramkumar Sekar, Min Sen Yew, Andrej Vondrak, Shereen Bejai, George Bennie, Ria Bester, Gerrit Engelbrecht, Osayande Evbuomwan, Harlem Gongxeka, Magritha Jv Vuuren, Mitchell Kaplan, Purbhoo Khushica, Hoosen Lakhi, Lizette Louw, Nico Malan, Katarina Milos, Moshe Modiselle, Stuart More, Mathava Naidoo, Leonie Scholtz, Mboyo Vangu, Santiago Aguadé-Bruix, Isabel Blanco, Antonio Cabrera, Alicia Camarero, Irene Casáns-Tormo, Hug Cuellar-Calabria, Albert Flotats, Maria Eugenia Fuentes Cañamero, María Elia García, Amelia Jimenez-Heffernan, Rubén Leta, Javier Lopez Diaz, Luis Lumbreras, Juan Javier Marquez-Cabeza, Francisco Martin, Anxo Martinez de Alegria, Francisco Medina, Maria Pedrera Canal, Virginia Peiro, Virginia Pubul-Nuñez, Juan Ignacio Rayo Madrid, Cristina Rodríguez Rey, Ricardo Ruano Perez, Joaquín Ruiz, Gertrudis Sabatel Hernández, Ana Sevilla, Nahla Zeidán, Damayanthi Nanayakkara, Chandraguptha Udugama, Magnus Simonsson, Hatem Alkadhi, Ronny Ralf Buechel, Peter Burger, Luca Ceriani, Bart De Boeck, Christoph Gräni, Alix Juillet de Saint Lager Lucas, Christel H. Kamani, Nadine Kawel-Boehm, Robert Manka, John O. Prior, Axel Rominger, Jean-Paul Vallée, Benjapa Khiewvan, Teerapon Premprabha, Tanyaluck Thientunyakit, Ali Sellem, Kemal Metin Kir, Haluk Sayman, Mugisha Julius Sebikali, Zerida Muyinda, Yaroslav Kmetyuk, Pavlo Korol, Olena Mykhalchenko, Volodymyr Pliatsek, Maryna Satyr, Batool Albalooshi, Mohamed Ismail Ahmed Hassan, Jill Anderson, Punit Bedi, Thomas Biggans, Anda Bularga, Russell Bull, Rajesh Burgul, John-Paul Carpenter, Duncan Coles, David Cusack, Aparna Deshpande, John Dougan, Timothy Fairbairn, Alexia Farrugia, Deepa Gopalan, Alistair Gummow, Prasad Guntur Ramkumar, Mark Hamilton, Mark Harbinson, Thomas Hartley, Benjamin Hudson, Nikhil Joshi, Michael Kay, Andrew Kelion, Azhar Khokhar, Jamie Kitt, Ken Lee, Chen Low, Sze Mun Mak, Ntouskou Marousa, Jon Martin, Elisa Mcalindon, Leon Menezes, Gareth Morgan-Hughes, Alastair Moss, Anthony Murray, Edward Nicol, Dilip Patel, Charles Peebles, Francesca Pugliese, Jonathan Carl Luis Rodrigues, Christopher Rofe, Nikant Sabharwal, Rebecca Schofield, Thomas Semple, Naveen Sharma, Peter Strouhal, Deepak Subedi, William Topping, Katharine Tweed, Jonathan Weir-Mccall, Suhny Abbara, Taimur Abbasi, Brian Abbott, Shady Abohashem, Sandra Abramson, Tarek Al-Abboud, Mouaz Al-Mallah, Omar Almousalli, Karthikeyan Ananthasubramaniam, Mohan Ashok Kumar, Jeffrey Askew, Lea Attanasio, Mallory Balmer-Swain, Richard R. Bayer, Adam Bernheim, Sabha Bhatti, Erik Bieging, Ron Blankstein, Stephen Bloom, Sean Blue, David Bluemke, Andressa Borges, Kelley Branch, Paco Bravo, Jessica Brothers, Matthew Budoff, Renée Bullock-Palmer, Angela Burandt, Floyd W. Burke, Kelvin Bush, Candace Candela, Elizabeth Capasso, Joao Cavalcante, Donald Chang, Saurav Chatterjee, Yiannis Chatzizisis, Michael Cheezum, Tiffany Chen, Jennifer Chen, Marcus Chen, James Clarcq, Ayreen Cordero, Matthew Crim, Sorin Danciu, Bruce Decter, Nimish Dhruva, Neil Doherty, Rami Doukky, Anjori Dunbar, William Duvall, Rachael Edwards, Kerry Esquitin, Husam Farah, Emilio Fentanes, Maros Ferencik, Daniel Fisher, Daniel Fitzpatrick, Cameron Foster, Tony Fuisz, Michael Gannon, Lori Gastner, Myron Gerson, Brian Ghoshhajra, Alan Goldberg, Brian Goldner, Jorge Gonzalez, Rosco Gore, Sandra Gracia-López, Fadi Hage, Agha Haider, Sofia Haider, Yasmin Hamirani, Karen Hassen, Mallory Hatfield, Carolyn Hawkins, Katie Hawthorne, Nicholas Heath, Robert Hendel, Phillip Hernandez, Gregory Hill, Stephen Horgan, Jeff Huffman, Lynne Hurwitz, Ami Iskandrian, Rajesh Janardhanan, Christine Jellis, Scott Jerome, Dinesh Kalra, Summanther Kaviratne, Fernando Kay, Faith Kelly, Omar Khalique, Mona Kinkhabwala, George Kinzfogl Iii, Jacqueline Kircher, Rachael Kirkbride, Michael Kontos, Anupama Kottam, Joseph Krepp, Jay Layer, Steven H. Lee, Jeffrey Leppo, John Lesser, Steve Leung, Howard Lewin, Diana Litmanovich, Yiyan Liu, Kathleen Magurany, Jeremy Markowitz, Amanda Marn, Stephen E. Matis, Michael Mckenna, Tony Mcrae, Fernando Mendoza, Michael Merhige, David Min, Chanan Moffitt, Karen Moncher, Warren Moore, Shamil Morayati, Michael Morris, Mahmud Mossa-Basha, Zorana Mrsic, Venkatesh Murthy, Prashant Nagpal, Kyle Napier, Katarina Nelson, Prabhjot Nijjar, Medhat Osman, Edward Passen, Amit Patel, Pravin Patil, Ryan Paul, Lawrence Phillips, Venkateshwar Polsani, Rajaram Poludasu, Brian Pomerantz, Thomas Porter, Ryan Prentice, Amit Pursnani, Mark Rabbat, Suresh Ramamurti, Florence Rich, Hiram Rivera Luna, Austin Robinson, Kim Robles, Cesar Rodríguez, Mark Rorie, John Rumberger, Raymond Russell, Philip Sabra, Diego Sadler, Mary Schemmer, U. 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Subjects
medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Heart disease, business.industry, cardiac testing, coronavirus, COVID-19, global health, Disease, medicine.disease_cause, medicine.disease, coronaviru, cardiovascular disease, RC666-701, Emergency medicine, Pandemic, medicine, Global health, Diseases of the circulatory (Cardiovascular) system, business, Coronavirus
Abstract

Background: The coronavirus disease-2019 (COVID-19) pandemic significantly affected management of cardiovascular disease around the world. The effect of the pandemic on volume of cardiovascular diagnostic procedures is not known. Objectives: This study sought to evaluate the effects of the early phase of the COVID-19 pandemic on cardiovascular diagnostic procedures and safety practices in Asia. Methods: The International Atomic Energy Agency conducted a worldwide survey to assess changes in cardiovascular procedure volume and safety practices caused by COVID-19. Testing volumes were reported for March 2020 and April 2020 and were compared to those from March 2019. Data from 180 centers across 33 Asian countries were grouped into 4 subregions for comparison. Results: Procedure volumes decreased by 47% from March 2019 to March 2020, showing recovery from March 2020 to April 2020 in Eastern Asia, particularly in China. The majority of centers cancelled outpatient activities and increased time per study. Practice changes included implementing physical distancing and restricting visitors. Although COVID testing was not commonly performed, it was conducted in one-third of facilities in Eastern Asia. The most severe reductions in procedure volumes were observed in lower-income countries, where volumes decreased 81% from March 2019 to April 2020. Conclusions: The COVID-19 pandemic in Asia caused significant reductions in cardiovascular diagnostic procedures, particularly in low-income countries. Further studies on effects of COVID-19 on cardiovascular outcomes and changes in care delivery are warranted.

Published
2021

104. What do we have to know about pd-l1 expression in prostate cancer? A systematic literature review. part 7: Pd-l1 expression in liquid biopsy

Author

Andrea Palicelli, Martina Bonacini, Stefania Croci, Alessandra Bisagni, Eleonora Zanetti, Dario De Biase, Francesca Sanguedolce, Moira Ragazzi, Magda Zanelli, Alcides Chaux, Sofia Cañete-Portillo, Maria Paola Bonasoni, Stefano Ascani, Antonio De Leo, Jatin Gandhi, Alessandro Tafuni, Beatrice Melli, Palicelli A., Bonacini M., Croci S., Bisagni A., Zanetti E., de Biase D., Sanguedolce F., Ragazzi M., Zanelli M., Chaux A., Canete-Portillo S., Bonasoni M.P., Ascani S., De Leo A., Gandhi J., Tafuni A., and Melli B.

Subjects
PD-L1, Liquid biopsy, Circulating tumor cell, Circulating tumor cells, Prostate, Medicine (miscellaneous), Review, exosomes, circulating tumor cells, Exosomes, Exosome, Checkpoint inhibitor, Medicine, Cancer, Checkpoint inhibitors, Immunotherapy, checkpoint inhibitors
Abstract

Liquid biopsy is an accessible, non-invasive diagnostic tool for advanced prostate cancer (PC) patients, potentially representing a real-time monitoring test for tumor evolution and response to treatment through the analysis of circulating tumor cells (CTCs) and exosomes. We performed a systematic literature review (PRISMA guidelines) to describe the current knowledge about PD-L1 expression in liquid biopsies of PC patients: 101/159 (64%) cases revealed a variable number of PD-L1+ CTCs. Outcome correlations should be investigated in larger series. Nuclear PD-L1 expression by CTCs was occasionally associated with worse prognosis. Treatment (abiraterone, enzalutamide, radiotherapy, checkpoint-inhibitors) influenced PD-L1+ CTC levels. Discordance in PD-L1 status was detected between primary vs. metastatic PC tissue biopsies and CTCs vs. corresponding tumor tissues. PD-L1 is also released by PC cells through soluble exosomes, which could inhibit the T cell function, causing immune evasion. PD-L1+ PC-CTC monitoring and genomic profiling may better characterize the ongoing aggressive PC forms compared to PD-L1 evaluation on primary tumor biopsies/prostatectomy specimens (sometimes sampled a long time before recurrence/progression). Myeloid-derived suppressor cells and dendritic cells (DCs), which may have immune-suppressive effects in tumor microenvironment, have been found in PC patients circulation, sometimes expressing PD-L1. Occasionally, their levels correlated to clinical outcome. Enzalutamide-progressing castration-resistant PC patients revealed increased PD-1+ T cells and circulating PD-L1/2+ DCs.

Published
2021

105. What do we have to know about PD-L1 expression in prostate cancer? A systematic literature review. part 4: Experimental treatments in pre-clinical studies (cell lines and mouse models)

Author

Alessandra Bisagni, Sofia Canete-Portillo, Alcides Chaux, Giacomo Santandrea, Guido Giordano, Francesca Sanguedolce, Maurizio Zizzo, Dario de Biase, Andrea Palicelli, Beatrice Melli, Moira Ragazzi, Alessandra Soriano, Luigi Cormio, Daniel M. Berney, Stefania Croci, Carolina Castro Ruiz, Eleonora Zanetti, Stefano Ascani, Antonio De Leo, Giuseppe Carrieri, Maria Paola Bonasoni, Martina Bonacini, Matteo Landriscina, Jatin Gandhi, Magda Zanelli, Palicelli A., Croci S., Bisagni A., Zanetti E., De Biase D., Melli B., Sanguedolce F., Ragazzi M., Zanelli M., Chaux A., Canete-Portillo S., Bonasoni M.P., Soriano A., Ascani S., Zizzo M., Ruiz C.C., De Leo A., Giordano G., Landriscina M., Carrieri G., Cormio L., Berney D.M., Gandhi J., Santandrea G., and Bonacini M.

Subjects
Male, Signaling pathways, medicine.medical_treatment, Cell, Review, B7-H1 Antigen, Prostate cancer, Mice, Checkpoint inhibitor, Biology (General), STAT3, Spectroscopy, Cancer, biology, Signaling pathway, Prostate, General Medicine, Computer Science Applications, Gene Expression Regulation, Neoplastic, Chemistry, medicine.anatomical_structure, Immunotherapy, Signal transduction, Tyrosine kinase, Checkpoint inhibitors, Human, Signal Transduction, PD-L1, Microenvironment, QH301-705.5, Catalysis, Inorganic Chemistry, Cell Line, Tumor, medicine, Animals, Humans, Physical and Theoretical Chemistry, Molecular Biology, QD1-999, PI3K/AKT/mTOR pathway, business.industry, Animal, Organic Chemistry, Prostatic Neoplasms, Target-therapy, medicine.disease, signaling pathways, Disease Models, Animal, Prostatic Neoplasm, biology.protein, Cancer research, business, checkpoint inhibitors
Abstract

In prostate cancer (PC), the PD-1/PD-L1 axis regulates various signaling pathways and it is influenced by extracellular factors. Pre-clinical experimental studies investigating the effects of various treatments (alone or combined) may discover how to overcome the immunotherapy-resistance in PC-patients. We performed a systematic literature review (PRISMA guidelines) to delineate the landscape of pre-clinical studies (including cell lines and mouse models) that tested treatments with effects on PD-L1 signaling in PC. NF-kB, MEK, JAK, or STAT inhibitors on human/mouse, primary/metastatic PC-cell lines variably down-modulated PD-L1-expression, reducing chemoresistance and tumor cell migration. If PC-cells were co-cultured with NK, CD8+ T-cells or CAR-T cells, the immune cell cytotoxicity increased when PD-L1 was downregulated (opposite effects for PD-L1 upregulation). In mouse models, radiotherapy, CDK4/6-inhibitors, and RB deletion induced PD-L1-upregulation, causing PC-immune-evasion. Epigenetic drugs may reduce PD-L1 expression. In some PC experimental models, blocking only the PD-1/PD-L1 pathway had limited efficacy in reducing the tumor growth. Anti-tumor effects could be increased by combining the PD-1/PD-L1 blockade with other approaches (inhibitors of tyrosine kinase, PI3K/mTOR or JAK/STAT3 pathways, p300/CBP; anti-RANKL and/or anti-CTLA-4 antibodies; cytokines; nitroxoline; DNA/cell vaccines; radiotherapy/Radium-223).

Published
2021

106. Reproducibility of the WHO histological criteria for the diagnosis of Philadelphia chromosome-negative myeloproliferative neoplasms

Author

Ada Maria Florena, Elena Sabattini, Riccardo Valli, Alessia Moro, Vito Franco, Ivan Cortinovis, Emanuela Boveri, Maurilio Ponzoni, Stefano Ascani, Alessandra Iurlo, Giulio Fraternali Orcioni, Luigi Gugliotta, Claudio Tripodo, Emanuela Bonoldi, Anna Bossi, Umberto Gianelli, Gianelli, U, Bossi, A, Cortinovis, I, Sabattini, E, Tripodo, C, Boveri, E, Moro, A, Valli, R, Ponzoni, M, Florena, AM, Orcioni, FG, Ascani, S, Bonoldi, E, Iurlo, A, Gugliotta, L, Franco, V., Ponzoni, Maurilio, M., Florena A, and F., Orcioni G

Subjects
Adult, Male, Polycythaemia, Pathology, medicine.medical_specialty, myeloproliferative neoplasm, Philadelphia Chromosome Negative, essential thrombocythaemia, World Health Organization, polycythaemia vera, myeloproliferative neoplasms, Pathology and Forensic Medicine, Young Adult, Cohen's kappa, Bone Marrow, hemic and lymphatic diseases, Biopsy, Humans, Medicine, Philadelphia Chromosome, Myelofibrosis, Polycythemia Vera, Aged, Aged, 80 and over, Observer Variation, WHO classification, medicine.diagnostic_test, business.industry, primary myelofibrosi, Reproducibility of Results, Middle Aged, medicine.disease, primary myelofibrosis, Female, Who criteria, Differential diagnosis, business, Who classification, Thrombocythemia, Essential
Abstract

This study, performed on behalf of the Italian Registry of Thrombocythaemias (Registro Italiano Trombocitemie), aimed to test the inter-observer reproducibility of the histological parameters proposed by the WHO classification for the diagnosis of the Philadelphia chromosome-negative myeloproliferative neoplasms. A series of 103 bone marrow biopsy samples of Philadelphia chromosome-negative myeloproliferative neoplasms consecutively collected in 2004 were classified according to the WHO criteria as follows: essential thrombocythaemia (n=34), primary myelofibrosis (n=44) and polycythaemia vera (n=25). Two independent groups of pathologists reviewed the bone marrow biopsies. The first group was asked to reach a collegial 'consensus' diagnosis. The second group reviewed individually all the cases to recognize the main morphological parameters indicated by the WHO classification and report their results in a database. They were subsequently instructed to individually build a 'personal' diagnosis of myeloproliferative neoplasms subtype just assembling the parameters collected in the database. Our results indicate that high levels of agreement (≥70%) have been reached for about all of the morphological features. Moreover, among the 18 evaluated histological features, 11 resulted statistically more useful for the differential diagnosis among the different Philadelphia chromosome-negative myeloproliferative neoplasms. Finally, we found a high percentage of agreement (76%) between the 'personal' and 'consensus' diagnosis (Cohen's kappa statistic >0.40). In conclusion, our results support the use of the histological criteria proposed by the WHO classification for the Philadelphia chromosome-negative myeloproliferative neoplasms to ensure a more precise and early diagnosis for these patients.

Published
2014

107. Variations in clinical presentation, frequency of hemophagocytosis and clinical behavior of intravascular lymphoma diagnosed in different geographical regions

Author

Ferreri, Andrés J. M., Dognini, Giuseppina P., Elías Campo, Rein Willemze, Seymour, John F., Osnat Bairey, Maurizio Martelli, Renz, Amalia O., Claudio Doglioni, Carlos Montalbán, Alberto Tedeschi, Astrid Pavlovsky, Sue Morgan, Lilj Uziel, Massimo Ferracci, Stefano Ascani, Umberto Gianelli, Carlo Patriarca, Fabio Facchetti, Alessio Dalla Libera, Barbara Pertoldi, Barbara Horváth, Arpad Szomor, Emanuele Zucca, Franco Cavalli, Maurilio Ponzoni, International Extranodal Lymphoma Study Group (IELSG), Translational Immunology Groningen (TRIGR), Ferreri, Ajm, Dognini, Gr, Campo, E, Willemze, R, Seymour, Jf, Bairey, O, Martelli, M, De Renzo, A, Doglioni, C, Montalan, C, Tedeschi, A, Pavlovsky, A, Morgan, S, Uziel, L, Ferracci, M, Ascani, S, Gianelli, U, Patriarca, C, Facchetti, F, Libera, Ad, Pertoldi, B, Horvath, B, Szomor, A, Zucca, E, Cavalli, F, and Ponzoni, Maurilio

Subjects
Questionnaires, Male, Pathology, Skin Neoplasms, intravascular lymphoma, Cutaneous lymphoma, Japan, Surveys and Questionnaires, Antineoplastic Combined Chemotherapy Protocols, Anthracyclines, Aged, 80 and over, Hematology, Brain Neoplasms, Middle Aged, Prognosis, Vascular Neoplasms, Europe, Histiocytosis, Phenotype, Treatment Outcome, Organ Specificity, Disease Progression, Female, Lymphoma, Large B-Cell, Diffuse, Hemophagocytosis, brain lymphoma, cutaneous lymphoma, hemophagocytosis, Asian Continental Ancestry Group, Adult, medicine.medical_specialty, Asia, Adolescent, Anemia, European Continental Ancestry Group, Lymphohistiocytosis, Hemophagocytic, White People, Asian People, Internal medicine, medicine, Humans, Aged, Retrospective Studies, Intravascular large B-cell lymphoma, business.industry, Retrospective cohort study, medicine.disease, Lymphoma, business, Follow-Up Studies, Forecasting
Abstract

Background and Objectives This study explored variations in the clinical manifestations of intravascular lymphoma (IVL) on the bases of the association with hemophagocytosis and the country where the diagnosis was made. Design and Methods The clinical features of 50 Western patients with IVL were compared with those of 123 patients with IVL diagnosed in Eastern countries (87 diagnosed in Japan and 36 in other Asian countries), previously reported in English literature, and collected by an electronic bibliographic search. Results Hemophagocytosis was absent in Western patients, but reported in 38 (44%) Japanese patients ( p =0.00001) and in seven (19%) patients from other Asian countries ( p =0.002). No clinical differences were evident between patients with hemophagocytosis-negative IVL diagnosed in Western countries, Japan and other Asian Countries. Conversely, Japanese and non-Japanese patients with hemophagocytosis-related IVL more frequently had stage IV disease, fever, hepato-splenic involvement, marrow infiltration, dyspnea, anemia, and thrombocytopenia, and rarely exhibited cutaneous or central nervous system involvement. Lymph node and peripheral blood involvement was uncommon in all subgroups. In Western patients, anthracycline-based chemotherapy was associated with a 52% remission rate, and a 2-year overall survival of 46%. Interpretation and Conclusions The clinical features of IVL vary according to the association with hemophagocytosis, regardless of the country in which the diagnosis is made. Western, Japanese and other Asian patients with hemophagocytosis-negative IVL display similar clinical characteristics and should be considered as having classical IVL. Patients with hemophagocytosis-related IVL show significantly different clinical features. Both forms have a poor prognosis. Extensive molecular studies are needed to explore whether these clinical differences might reflect discordant biological entities within IVL.

Published
2007

108. Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia

Author

Martin S. Tallman, L. De Carolis, Sasinya N. Scott, Enrico Tiacci, Maria Paola Martelli, Alessandro Pulsoni, Antonella Anastasia, Monia Capponi, A. M. Carella, Robert Foa, Alessandro Broccoli, S. A. Pileri, Brunangelo Falini, Pietro Leoni, Franca Falzetti, Marzia Varettoni, Michael R. Grever, Davide Rossi, Kanti R. Rai, Vincenzo Fraticelli, Giovanna Motta, Jae H. Park, Achille Ambrosetti, M.F. Berger, Alan Saven, Young Rock Chung, Omar Abdel-Wahab, Ross L. Levine, Christopher Y. Park, Stefano Ascani, Neal Rosen, Pier Luigi Zinzani, Mario E. Lacouture, Alessandro Rambaldi, Francesco Zaja, Eunhee Kim, Michele Cimminiello, Stephen S. Chung, Jessica K. Altman, Sean M. Devlin, Richard Stone, Tiacci, E, Park, J.H., De Carolis, L., Chung, S.S., Broccoli, A., Scott, S., Zaja, F., Devlin, S., Pulsoni, A., Chung, Y.R., Cimminiello, M., Kim, E., Rossi, D., Stone, R.M., Motta, G., Saven, A., Varettoni, M., Altman, J.K., Anastasia, A., Grever, M.R., Ambrosetti, A., Rai, K.R., Fraticelli, V., Lacouture, M.E., Carella, A.M., Levine, R.L., Leoni, P., Rambaldi, A., Falzetti, F., Ascani, S., Capponi, M., Martelli, M.P., Park, C.Y., Pileri, S.A., Rosen, N., Foà, R., Berger, M.F., Zinzani, P.L., Abdel-Wahab, O., Falini, B., Tallman, M.S., Park, J. H., Chung, S. S., Zaja, Francesco, Chung, Y. R., Stone, R. M., Altman, J. K., Grever, M. R., Rai, K. R., Lacouture, M. E., Carella, A. M., Levine, R. L., Martelli, M. P., Park, C. Y., Pileri, S. A., Berger, M. F., Zinzani, P. L., Abdel Wahab, O., and Tallman, M. S.

Subjects
Oncology, Male, Indoles, Hairy Cell, Drug Resistance, Administration, Oral, Drug resistance, Antineoplastic Agent, Moxetumomab pasudotox, Bone Marrow, Recurrence, 80 and over, Vemurafenib, Aged, 80 and over, Leukemia, Hairy Cell, Proto-Oncogene Protein, Sulfonamides, Leukemia, Medicine (all), Remission Induction, General Medicine, Middle Aged, HCL, Arthralgia, Administration, Biological Markers, Female, Adult, Aged, Antineoplastic Agents, Biomarkers, Disease-Free Survival, Drug Resistance, Neoplasm, Exanthema, Humans, Mutation, Proto-Oncogene Proteins, Proto-Oncogene Proteins B-raf, ras Proteins, medicine.drug, Human, Oral, medicine.medical_specialty, Purine analogue, BRAF, leukemia, hairy cell, cladribine, Sulfonamide, Article, Proto-Oncogene Proteins p21(ras), Refractory, Internal medicine, medicine, business.industry, Biomarker, medicine.disease, ras Protein, Surgery, Clinical trial, Indole, Neoplasm, business, V600E
Abstract

BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues.We conducted two phase 2, single-group, multicenter studies of vemurafenib (at a dose of 960 mg twice daily)--one in Italy and one in the United States. The therapy was administered for a median of 16 weeks in the Italian study and 18 weeks in the U.S. study. Primary end points were the complete response rate (in the Italian trial) and the overall response rate (in the U.S. trial). Enrollment was completed (28 patients) in the Italian trial in April 2013 and is still open (26 of 36 planned patients) in the U.S. trial.The overall response rates were 96% (25 of 26 patients who could be evaluated) after a median of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12 weeks in the U.S. study. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in the two trials, respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free survival was 19 months among patients with a complete response and 6 months among those with a partial response; the median treatment-free survival was 25 months and 18 months, respectively. In the U.S. trial, at 1 year, the progression-free survival rate was 73% and the overall survival rate was 91%. Drug-related adverse events were usually of grade 1 or 2, and the events most frequently leading to dose reductions were rash and arthralgia or arthritis. Secondary cutaneous tumors (treated with simple excision) developed in 7 of 50 patients. The frequent persistence of phosphorylated ERK-positive leukemic cells in bone marrow at the end of treatment suggests bypass reactivation of MEK and ERK as a resistance mechanism.A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy-cell leukemia. (Funded by the Associazione Italiana per la Ricerca sul Cancro and others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number NCT01711632.).

Published
2015

109. Identification of Novel Cryptic Chromosomal Abnormalities in Primary Myelofibrosis by Single-Nucleotide Polymorphism Oligonucleotide Microarray

Author

Alessandro Isidori, Stefania Paolini, Meris Donati, Elena Sabattini, Simona Righi, Claudia Mannu, Antonella Laginestra, Anna Gazzola, Nicola Vianelli, Claudio Agostinelli, Roberto Emiliani, Carlo Finelli, Michele De Nictolis, Massimo Valentini, Francesco Alesiani, Maura Rossi, Pier Paolo Piccaluga, Stefano Pileri, Stefano Ascani, Maria Rosaria Sapienza, Giovanni Martinelli, Giuseppe Visani, Ilaria Iacobucci, Visani G., Isidori A., Sapienza MR., Righi S., Laginestra A., Agostinelli C., Sabattini E., De Nictolis M., Valentini M., Donati M., Emiliani R., Gazzola A., Mannu C., Rossi M., Alesiani F., Martinelli G., Iacobucci I., Paolini S., Ascani S., Finelli C., Vianelli N., Pileri SA., and Piccaluga PP.

Subjects
Genetics, Immunology, Single-Nucleotide Polymorphism, Single-nucleotide polymorphism, Cell Biology, Hematology, Biology, medicine.disease, Biochemistry, Uniparental disomy, Loss of heterozygosity, Primary Myelofibrosi, Germline mutation, Chromosome abnormality, medicine, Copy-number variation, Genotyping, Oligonucleotide Microarray, SNP array
Abstract

Abstract 1890 Poster Board I-913 Background. Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm (MPN) characterised by a proliferation of predominantly megakaryocytes and granulocytes in bone marrow that in fully developed disease is replaced by fibrous tissue. At molecular level, no specific defect has been identified yet. Cytogenetic abnormalities occur in up to 30% of patients, the commonest including del(13)(q12-22), der(6)t(1;6)(q21-23;p21.3), del (20q), and partial trisomy 1q. In addition, approximately 50% of patients with PMF exhibit a single, recurrent, somatic mutation in the gene encoding the cytoplasmic tyrosine kinase Janus kinase 2 (JAK2). However, such mutation is not specific, also occurring in other MPN. Recently a couple of reports dealt with single-nucleotide polymorphism (SNP) array karyotyping of MPD, including some PMF. Importantly, such studies could identify previously uncovered genetic lesions, highlighting the importance of novel high resolution technologies for the detection of formerly unknown, cryptic aberrations. In this study we performed high resolution karyotyping by SNP oligonucleotide microarray by using the most updated Affymetrix array (Genome-Wide Human SNP Array 6.0) in 20 cases of myelofibrosis (MF) in order to identify novel cryptic genomic aberrations. Methods. DNA (500 ng) was extracted from peripheral blood cells (PBMNC) of 14 primary and 6 secondary MF patients. PBMNC were depleted from lymphocytes by magnetic beads. Briefly, CD3+ cells were labeled with anti-CD3 MoAb directly coupled to magnetic microbeads (Miltenyi Biotech), washed and subsequently purified using Mini-MACS technology. After selection, cell present in the positive (CD3) and negative (PBMNC) fractions were counted and submitted to flow cytometry analysis. DNA was processed and hybridized to the Affymetrix SNP arrays 6.0 as for manufacturer instruction. A whole-genome copy number variation (CNV), genotyping, loss of heterozygosity (LOH) and uniparental disomy (UPD) analyses were performed using the Partek Suite 6.0. Ten lab-specific as well as 90 HapMap samples relative to Caucasian healthy donor were used as control reference. Genomic abnormalities were defined as recurrent when occurring in at least 25% of cases. JAK2 mutational status was assessed as reported, by alle-specific PCR. Clinical information and complete follow up were retrieved for all cases. Direct sequencing, FISH, qPCR and immunohistochemistry (IHC) has been chosen for validation. Results. In all patients we could detect several CNV. The median number of CNV was 60 (range, 34-72), including 46 amplifications (A) and 14 deletions (D). All commonest previously described abnormalities were detected. In addition, several formerly uncovered recurrent lesions were identified, mainly involving 1p, 1q, 2p, 4p, 4q, 5q, 6p, 6q, 7q, 8p, 9q 10q, 11p 11q, 12p, 14q, 15q, 16p, 16q, 17q, 18q, 19q, 20p, 22q. The median size of such CNV was 424,582 Kbp (1,379 Kbp-71,277 Mbp). We then compared JAK2+ vs. JAK2− cases. Of note, we found numerous definite aberrations (A or D) distinguishing the two groups and specifically affecting 16q23.1, 1p36.13, 3q26, 14q13.2, 5q33.2, 6q14.1, 7q33, 8p23.1, and 9p11.2. Grippingly, several genes of potential interest for PMF pathogenesis were identified within the involved loci, including RET, SCAPER, WWOX and SIRPB1. Among others, the product of such genes has been selected for validation by IHC. Similarly, many miRNA were recognized, which may deserve further investigation. Conclusions. By using a newly developed highly sensitive array we identified novel cryptic lesions in patients affected by MF. Future studies on larger series, as well as functional analyses will definitely assess their role in the pathogenesis of the disease. Of note, consistent differences were recorded in JAK2+ vs. JAK2−, supporting the hypothesis of different genetic mechanisms occurring in the two sub-groups. Acknowledgments: this work was supported by AIL Pesaro Onlus, Centro Interdipartimentale per la Ricerca sul Cancro “G. Prodi”, BolognAIL, AIRC, FIRB, RFO, Fondazione Cassa di Risparmio in Bologna, Fondazione della Banca del Monte e Ravenna, Progetto Strategico di Ateneo 2006.*GV and MRS equally contributed to this work. Disclosures: No relevant conflicts of interest to declare.

Published
2009

110. Myeloid sarcoma of liver: an unusual cause of jaundice. Report of three cases and review of literature

Author

Michele Baccarani, Claudio Agostinelli, Pier Paolo Piccaluga, Cristina Papayannidis, Stefano Ascani, Claudio Laterza, Giuseppe Visani, Stefano Pileri, Stefania Paolini, Giovanni Martinelli, Piccaluga PP, Ascani S, Agostinelli C, Paolini S, Laterza C, Papayannidis C, Martinelli G, Visani G, Baccarani M, and Pileri SA.

Subjects
Pathology, medicine.medical_specialty, Histology, business.industry, GRANULOCYTIC SARCOMA, General Medicine, Jaundice, medicine.disease, Pathology and Forensic Medicine, MYELOID SARCOMA, medicine, Myeloid sarcoma, medicine.symptom, business
Published
2007

111. Marker expression in peripheral T-cell lymphoma: a proposed clinical-pathologic prognostic score

Author

Francesco Bacci, Brunangelo Falini, Stefano Ascani, Marco Paulli, Pier Paolo Piccaluga, Elena Sabattini, Teresio Motta, Pier Luigi Zinzani, Andrea Gallamini, Stefano Pileri, Claudio Agostinelli, Tullio Artusi, Philip Went, Milena Piccioli, Went P, Agostinelli C, Gallamini A, Piccaluga PP, Ascani S, Sabattini E, Bacci F, Falini B, Motta T, Paulli M, Artusi T, Piccioli M, Zinzani PL, and Pileri SA.

Subjects
Male, Cancer Research, Pathology, CD3 Complex, CD30, Antigens, CD7, REAL CLASSIFICATION, Multicenter Studies as Topic, EPSTEIN-BARR-VIRUS, In Situ Hybridization, IMMUNOHISTOCHEMICAL ANALYSIS, Aged, 80 and over, Clinical Trials as Topic, Tissue microarray, NON-HODGKINS-LYMPHOMAS, Middle Aged, Prognosis, Immunohistochemistry, MALIGNANT-LYMPHOMAS, Gene Expression Regulation, Neoplastic, Phenotype, Oncology, CD4 Antigens, Female, Neprilysin, Adult, medicine.medical_specialty, PROLIFERATIVE ACTIVITY, CD8 Antigens, CD2 Antigens, Ki-1 Antigen, Lewis X Antigen, Peripheral T-cell lymphoma not otherwise specified, CD15, CD5 Antigens, Antigens, CD, Predictive Value of Tests, CLINICOPATHOLOGICAL FEATURES, Biomarkers, Tumor, medicine, Humans, ANGIOIMMUNOBLASTIC LYMPHADENOPATHY, TISSUE MICROARRAY, Survival analysis, Aged, Proportional Hazards Models, Retrospective Studies, MONOCLONAL-ANTIBODIES, business.industry, Lymphoma, T-Cell, Peripheral, Antigens, CD20, medicine.disease, Survival Analysis, Peripheral T-cell lymphoma, Lymphoma, Ki-67 Antigen, Tissue Array Analysis, CD5, business, Follow-Up Studies
Abstract

PurposeAlthough peripheral T-cell lymphoma, unspecified (PTCL/U), is the most common T-cell tumor in Western countries, no study to date has been based on the application of a wide panel of markers to a large series of patients and assessed the impact of phenotype on survival. We evaluated the expression of 19 markers in 148 PTCLs/U and 45 PTCLs of the angioimmunoblastic type (AILD).Patients and MethodsThe analysis was performed on tissue microarrays by immunohistochemistry and in situ hybridization. Clinical data were available in 93 PTCL/U patients, most of whom had been included in a previous study proposing a prognostic index (PIT).ResultsAn aberrant phenotype with frequent loss of CD5 and/or CD7 was typical for PTCLs, irrespective of whether they were U or AILD. Aberrantly expressed proteins rarely included CD20, CD15, and CD30. Positivity for Epstein-Barr virus–associated small RNAs and CD15 expression emerged as adverse prognostic factors. Among PTCLs/U, the proliferation-associated protein Ki-67 turned out to be prognostically relevant and was integrated in a new predictive score, incorporating age (> 60 years), high lactate dehydrogenase, poor performance status, and Ki-67 ≥ 80%. This score was associated with the patient outcome (P < .0001) and was found to be more robust than PIT (P = .0043) in the present series.ConclusionOur retrospective analysis shows a wide range of protein expression in PTCLs and proposes a new prognostic index. The latter represents one of the first examples of mixed score (including patient- and tumor-specific factors) applied to malignant lymphomas and may be the basis for future prospective therapeutic trials.

Published
2006

112. Successful resumption of epoetin alfa after rituximab treatment in a patient with pure red cell aplasia

Author

Marcora Mandreoli, Carlo Finelli, Antonia Lopez, Stefano Ascani, Nicola Vianelli, Michele Baccarani, Antonio Santoro, MANDREOLI M, FINELLI C, LOPEZ A, ASCANI S, VIANELLI N, BACCARANI M., and SANTORO A.

Subjects
Aged, 80 and over, Male, hronic renal failure (CRF), pure red cell aplasia (PRCA), rituximab, recombinant human erythropoietin (rHuEPO), anti-rHuEPO antibodies, Antibodies, Monoclonal, Antigens, CD20, Red-Cell Aplasia, Pure, Recombinant Proteins, Epoetin Alfa, Antibodies, Monoclonal, Murine-Derived, Nephrology, Hematinics, Humans, Kidney Failure, Chronic, Rituximab, Erythropoietin, Aged
Abstract

An 80-year-old man with chronic renal failure (CRF) had pure red cell aplasia (PRCA) 9 months after starting the subcutaneous administration of recombinant human erythropoietin alfa (rHuEPO-alpha). Owing to the advanced renal failure, conventional immunosuppressive therapies were not practicable. It was decided to administer rituximab (4 cycles of 375 mg/m2/wk). PRCA was treated successfully with rituximab. The administration of rHuEPO-alpha then was resumed via the intravenous route with a satisfactory correction of anemia (12 months after the EPO-alpha rechallenge the patient is still transfusion independent). To the authors' knowledge, this is the first report of (1) a successful treatment with rituximab with CD20 depletion in a CRF patient with PRCA and (2) a successful intravenous resumption of the same rHuEPO-alpha.

Published
2004

113. Nodal marginal-zone lymphoma associated with monoclonal light-chain and heavy-chain deposition disease

Author

Maurizio Musso, Sverre Henning Brorson, Brunangelo Falini, Erik H. Strøm, Stefano Ascani, Pier Luigi Zinzani, Stephan Dirnhofer, Philip Went, Stefano Pileri, WENT P, ASCANI S, STROM E, BRORSON SH, MUSSO M, ZINZANI P., FALINI B, DIRNHOFER S, and PILERI S.

Subjects
Pathology, medicine.medical_specialty, idarubicin, Periodic acid–Schiff stain, vincristine, Immunoglobulin D, Risk Assessment, Antineoplastic Combined Chemotherapy Protocols, immunoglobulin M, Medicine, Humans, Lymph node, Hyaline, immunoglobulin light chain, cyclophosphamide, immunoglobulin heavy chain, prednisolone, biology, business.industry, Biopsy, Needle, Lymphoma, B-Cell, Marginal Zone, Middle Aged, medicine.disease, BCL6, Immunohistochemistry, Lymphoma, medicine.anatomical_structure, Oncology, biology.protein, Phosphatase complex, Clathrin Light Chains, Female, Lymph Nodes, CD5, business, Follow-Up Studies, Heavy Chain Disease
Abstract

In February, 2003, a 61-year-old woman presented at our hospital with abdominal pain. Her past medical history was unremarkable. A physical examination and CT scan showed generalised lymphadenopathy with a retroperitoneal bulky tumour without the involvement of any other organ. Laboratory tests showed moderate anaemia (haemoglobin concentration 11·2 g/L) and an IgM/ monoclonal gammopathy (7·33 mg/L). No signs of nephrotic syndrome, renal failure, arthritis, congestive heart-failure, or coagulopathy were detected. A supraclavicular lymph node and a bone-marrow trephine were taken, fixed in 10% buffered formalin for 24 h, and then paraffin-embedded. The patient was diagnosed with nodal marginal-zone lymphoma (NMZL) stage IVA and received eight cycles of CIOP chemotherapy (cyclophosphamide, idarubicin, vincristine, prednisolone). At the patient’s last follow-up (October, 2003), she was in a good condition with stable disease, although the lymph node was only slightly smaller. The IgM/ value had decreased (3·90 g/L) compared with the concentration measured at presentation. Histological analysis of the lymph-node biopsy sample showed almost complete destruction of the normal structure because of the deposition of hyaline material, which stained positively with periodic acid Schiff (with and without diastase digestion), Van Gieson, and toluidine blue, but not with Congo red. Furthermore, the hyaline material was more abundant around the small vessels (figure 1A, 1B). Atypical lymphoid elements with a monocytoid profile were mixed with the hyaline deposition, either singly or in small aggregates, and contained some blast cells and numerous plasma cells (figure 1C). By use of the paraffin-embedded sections of biopsied lymph-node tissue, immunohistochemical analysis, and the alkaline phosphatase antialkaline phosphatase complex (APAAP) technique, the atypical elements were found to express the IRTA1 (immunoglobulin superfamily receptor translocationassociated 1) molecule, CD20, CD79a, CD45RA, CD27, IgM/ , and BCL2. The tissue was negative for IgG, IgD, Ig light-chain, BCL6, CD10, DBA44, CD5, and CD3 (figure 1D–G and figure 2A–C). About 15% of the cells expressed Nodal marginal-zone lymphoma associated with monoclonal light-chain and heavy-chain deposition disease

Published
2004

114. Clear-cell proliferation of the lung with lymphangioleiomyomatosis-like change

Author

M Schiavina, Franco Bonetti, Elena Sabattini, Stefano Pileri, T V Colby, M Pederzoli, Stefano Ascani, A Cavazza, Gianandrea Pasquinelli, M Goldfischer, Maurizio Zompatori, PILERI SA, CAVAZZA A, SCHIAVINA M, ZOMPATORI M, PEDERZOLI M, GOLDFISCHER M, SABATTINI E, ASCANI S, PASQUINELLI G., BONETTI F, and COLBY TV

Subjects
Adult, Lung Diseases, Male, Pathology, medicine.medical_specialty, Histology, phenotype, Antigens, CD34, tuberous sclerosis complex, Biology, S100 protein, Perivascular Epithelioid Cell, Pathology and Forensic Medicine, Diagnosis, Differential, Tuberous sclerosis, Antigens, Neoplasm, Tuberous Sclerosis, morphology, medicine, molecular biology, Humans, Lymphangioleiomyomatosis, lymphangioleiomyomatosis, clear-cell 'sugar' tumour of the lung, perivascular epithelioid cell, Lung, Cysts, General Medicine, Middle Aged, medicine.disease, Immunohistochemistry, Neoplasm Proteins, Microscopy, Electron, medicine.anatomical_structure, Desmin, Female, Tomography, X-Ray Computed, Epithelioid cell, Melanoma-Specific Antigens, Clear cell
Abstract

Aims : To describe two cases of a peculiar pulmonary lesion, which expand both the morphological and the immunophenotypic spectrum of perivascular epithelioid cell (PEC)-related disorders. Methods and results : One man and one female, with and without the tuberous sclerosis complex (TSC), respectively, showed pulmonary cysts and small nodules on computed tomography scan. In the former, lymphangioleiomyomatosis (LAM) was suspected. In both cases, an open lung biopsy was performed, whose cut surface displayed numerous cysts lined by thin/thick septa. Microscopically, the septa were associated with micronodular or interstitial proliferation of medium/large-sized elements with abundant clear (periodic acid–Schiff-positive/diastase-sensitive) cytoplasm and distinct cell borders, embedded in fibrous tissue. The elements were CD34+, vimentin-positive and, to a lesser extent, HMB-45+ and MART-1+. The stains for specific muscle actin, desmin, S100 protein, CD31, FVIIIRAg, cytokeratins, CD45, CD68, oestrogen and progesterone receptors were all negative. Ki67 labelling was

Published
2004

115. CLINICAL PRESENTATION, BEHAVIOR, MANAGEMENT, AND OUTCOME OF AN INTERNATIONAL SERIES OF 40 CASES OF INTRAVASCULAR LYMPHOMA

Author

Ponzoni, Maurilio, Ambrosetti, Achille, Lestani, Massimo, Ilariucci, Fiorella, Asioli, Silvia, Zucca, Emanuele, Rossi, Giuseppe, Ungari, Marco, Facchetti, Fabio, Berti, Emilio, Iuzzolino, Paolo, Martelli, Maurizio, Federico, Massimo, Artusi, Tulio, anna candoni, Cortelazzo, Sergio, Motta, Teresio, Renzo, Amalia, Milani, Mario, Rossi, Roberta, Ascani, Stefano, Pileri, Stefano, Oro, Stefania, Frungillo, Niccolo, Doglioni, Claudio, Ferreri, Andres J. M., Ponzoni, M, Ambrosetti, A, Lestani, M, Ilariucci, F, Asioli, S, Zucca, E, Rossi, G, Ungari, M, Facchetti, F, Berti, E, Iuzzolino, P, Martelli, M, Federico, M, Artusi, T, Candoni, A, Cortelazzo, S, Motta, T, De Renzo, A, Milani, M, Rossi, R, Ascani, S, Pileri, S, Dell'Oro, S, Frungillo, N, Doglioni, C, and Ferreri, Ajm

Published
2004

116. Identification of a novel t(1;9)(q11;q34) in acute myelocytic leukemia

Author

Michele Baccarani, Michela Rondoni, Nicoletta Testoni, Pier Paolo Piccaluga, Stefano Pileri, Stavroula Gaitani, Stefano Ascani, Simona Luatti, Michele Malagola, Michele Bianchini, Giuseppe Visani, Giovanni Martinelli, PICCALUGA PP, LUATTI S, ASCANI S, BIANCHINI M, MALAGOLA M, RONDONI M, GAITANI S, TESTONI N., PILERI SA, BACCARANI M, MARTINELLI G, and VISANI G

Subjects
Cancer Research, ACUTE MYELOID-LEUKEMIA, Biology, Middle Aged, Translocation, Genetic, RESIDUAL DISEASE, ADULT, Immunophenotyping, Leukemia, Myeloid, Acute, Chromosomes, Human, Pair 1, Karyotyping, Genetics, Cancer research, Humans, Identification (biology), Myelocytic leukemia, Female, Chromosomes, Human, Pair 9, Molecular Biology
Published
2004

117. CD27 distinguishes two phases in bone marrow infiltration of splenic marginal zone lymphoma

Author

Stefano Pileri, Vito Franco, Marco Paulli, Stefano Ascani, M. Salvato, A. M. Florena, FRANCO V, FLORENA AM, ASCANI S, PAULLI M, SALVATO M, and PILERI SA

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Histology, bone marrow, Lymphoma, Biopsy, Naive B cell, splenic marginal zone lymphoma, Splenic Neoplasm, Spleen, Pathology and Forensic Medicine, intrasinusoidal infiltration, medicine, Humans, Splenic marginal zone lymphoma, CD27, naive and memory B cells, Aged, Aged, 80 and over, medicine.diagnostic_test, business.industry, Splenic Neoplasms, General Medicine, Middle Aged, medicine.disease, Bone Marrow Neoplasm, Immunohistochemistry, Tumor Necrosis Factor Receptor Superfamily, Member 7, medicine.anatomical_structure, Bone marrow neoplasm, Female, Bone marrow, business, Bone Marrow Neoplasms, Infiltration (medical)
Abstract

Aims: To investigate CD27 expression in splenic marginal zone lymphoma (SMZL), an indolent low-grade B-cell lymphoma with constant involvement of the bone marrow, especially with an intrasinusoidal pattern. It is not clear if the neoplastic clone is composed of virgin or somatically mutated B cells. CD27 is reported to be a hallmark of memory B cells. Methods and results: We evaluated 64 bone marrow biopsy specimens (BMBs) from 36 patients with SMZL for the expression of CD27. For comparison, splenectomy specimens of patients with traumatic splenic rupture or with SMZL were used. All BMBs showed lymphomatous infiltration. When located in the marrow sinusoids, neoplastic cells were CD27– in all cases and therefore corresponded to naive B cells. In nodular/interstitial infiltration, the cells were CD27+ and therefore corresponded to memory B cells. No difference in immunohistochemical expression of B and T antibodies was found between intrasinusoidal and interstitial/nodular infiltration. CD27 was constantly expressed in the splenic marginal zone of normal spleen, surgically removed for trauma, and in seven out of 10 spleens with SMZL. Conclusion: We propose the existence of two different phases of neoplastic progression with, first, expansion of a virgin B clone in the bone marrow and, following exposure to antigen, a re-colonization of the bone marrow.

Published
2004

118. Difficult Diagnostic and Therapeutic Cases

Author

Stefano Pileri, Pier Paolo Piccaluga, Philip Went, Pier Luigi Zinzani, Anna Marina Liberati, Stefano Ascani, ASCANI S, WENT P, LIBERATI AM, PICCALUGA PP, ZINZANI P., and PILERI SA

Subjects
Adult, Cancer Research, Pathology, medicine.medical_specialty, Fatal outcome, THYMIC HYPERPLASIA, Lymphoma, T-Cell, Risk Assessment, True Thymic Hyperplasia, Diagnosis, Differential, Fatal Outcome, Antineoplastic Combined Chemotherapy Protocols, Biopsy, medicine, Humans, T-cell lymphoma, Bone Marrow Transplantation, medicine.diagnostic_test, business.industry, Biopsy, Needle, Thymus Neoplasms, T lymphocyte, Hyperplasia, medicine.disease, Combined Modality Therapy, Immunohistochemistry, Magnetic Resonance Imaging, Lymphoma, Oncology, Female, Thymus Hyperplasia, business, Tomography, Emission-Computed
Published
2004

119. A targeted gene signature stratifying mediastinal gray zone lymphoma into classical HL-like or PMBL-like subtypes.

Author

Gargano G, Vegliante MC, Esposito F, Pappagallo SA, Sabattini E, Agostinelli C, Pileri SA, Tabanelli V, Ponzoni M, Lorenzi L, Facchetti F, Di Napoli A, Lucioni M, Paulli M, Leoncini L, Lazzi S, Ascani S, Opinto G, Zaccaria GM, Volpe G, Mondelli P, Bucci A, Selicato L, Negri A, Loseto G, Clemente F, Scattone A, Zito AF, Nassi L, Del Buono N, Guarini A, and Ciavarella S

Abstract

Not available.

Published
2024
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120. HELLS regulates transcription in T-cell lymphomas by reducing unscheduled R-loops and by facilitating RNAPII progression.

Author

Tameni A, Mallia S, Manicardi V, Donati B, Torricelli F, Vitale E, Salviato E, Gambarelli G, Muccioli S, Zanelli M, Ascani S, Martino G, Sanguedolce F, Sauta E, Tamagnini I, Puccio N, Neri A, Ciarrocchi A, and Fragliasso V

Subjects
Humans, Cell Line, Tumor, Genomic Instability genetics, Lymphoma, Large-Cell, Anaplastic genetics, Lymphoma, Large-Cell, Anaplastic pathology, Lymphoma, Large-Cell, Anaplastic metabolism, Gene Expression Regulation, Neoplastic, DNA Helicases genetics, DNA Helicases metabolism, Promoter Regions, Genetic, Lymphoma, T-Cell genetics, Lymphoma, T-Cell metabolism, Lymphoma, T-Cell pathology, RNA Polymerase II metabolism, R-Loop Structures, Transcription, Genetic, DNA Damage
Abstract

Chromatin modifiers are emerging as major determinants of many types of cancers, including Anaplastic Large Cell Lymphomas (ALCL), a family of highly heterogeneous T-cell lymphomas for which therapeutic options are still limited. HELLS is a multifunctional chromatin remodeling protein that affects genomic instability by participating in the DNA damage response. Although the transcriptional function of HELLS has been suggested, no clues on how HELLS controls transcription are currently available. In this study, by integrating different multi-omics and functional approaches, we characterized the transcriptional landscape of HELLS in ALCL. We explored the clinical impact of its transcriptional program in a large cohort of 44 patients with ALCL. We demonstrated that HELLS, loaded at the level of intronic regions of target promoters, facilitates RNA Polymerase II (RNAPII) progression along the gene bodies by reducing the persistence of co-transcriptional R-loops and promoting DNA damage resolution. Importantly, selective knockdown of HELLS sensitizes ALCL cells to different chemotherapeutic agents, showing a synergistic effect. Collectively, our work unveils the role of HELLS in acting as a gatekeeper of ALCL genome stability providing a rationale for drug design., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Published
2024
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121. Programmed Death Ligand 1 (PD-L1) Expression in Lymphomas: State of the Art.

Author

Zanelli M, Fragliasso V, Parente P, Bisagni A, Sanguedolce F, Zizzo M, Broggi G, Ricci S, Palicelli A, Foroni M, Gozzi F, Gentile P, Morini A, Koufopoulos N, Caltabiano R, Cimino L, Fabozzi M, Cavazza A, Neri A, and Ascani S

Subjects
Humans, Biomarkers, Tumor metabolism, Gene Expression Regulation, Neoplastic, Immune Checkpoint Inhibitors therapeutic use, B7-H1 Antigen metabolism, B7-H1 Antigen genetics, Lymphoma metabolism, Lymphoma genetics, Lymphoma pathology
Abstract

The interaction of programmed death-1 (PD-1) on T lymphocytes with its ligands Programmed Death Ligand 1 (PD-L1) and Programmed Death Ligand 2 (PD-L2) on tumor cells and/or tumor-associated macrophages results in inhibitory signals to the T-cell receptor pathway, consequently causing tumor immune escape. PD-L1/PD-L2 are currently used as predictive tissue biomarkers in clinical practice. Virtually PD-L1 levels expressed by tumor cells are associated with a good response to immune checkpoint blockade therapies targeting the PD-1/PD-L1 axis. These therapies restore T-cell antitumor immune response by releasing T-lymphocytes from the inhibitory effects of tumor cells. Immune checkpoint therapies have completely changed the management of patients with solid cancers. This therapeutic strategy is less used in hematological malignancies, although good results have been achieved in some settings, such as refractory/relapsed classic Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Variable results have been obtained in diffuse large B-cell lymphoma and T-cell lymphomas. Immunohistochemistry represents the main technique for assessing PD-L1 expression on tumor cells. This review aims to describe the current knowledge of PD-L1 expression in various types of lymphomas, focusing on the principal mechanisms underlying PD-L1 overexpression, its prognostic significance and practical issues concerning the evaluation of PD-L1 immunohistochemical results in lymphomas.

Published
2024
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123. Chronic myeloproliferative neoplasms with concomitant CALR mutation and BCR::ABL1 translocation: diagnostic and therapeutic implications of a rare hybrid disease.

Author

Zanelli M, Fragliasso V, Loscocco GG, Sanguedolce F, Broggi G, Zizzo M, Palicelli A, Ricci S, Ambrogi E, Martino G, Aversa S, Coppa F, Gentile P, Gozzi F, Caltabiano R, Koufopoulos N, Asaturova A, Cimino L, Cavazza A, Orcioni GF, and Ascani S

Abstract

Myeloproliferative neoplasms (MPNs) are subdivided into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. BCR::ABL1 translocation is essential for the development and diagnosis of CML; on the other hand, the majority of Ph-negative MPNs are characterized by generally mutually exclusive mutations of Janus kinase 2 ( JAK2 ), calreticulin ( CALR ), or thrombopoietin receptor/myeloproliferative leukemia ( MPL ). CALR mutations have been described essentially in JAK2 and MPL wild-type essential thrombocythemia and primary myelofibrosis. Rarely coexisting CALR and MPL mutations have been found in Ph-negative MPNs. BCR::ABL1 translocation and JAK2 mutations were initially considered mutually exclusive genomic events, but a discrete number of cases with the combination of these genetic alterations have been reported. The presence of BCR::ABL1 translocation with a coexisting CALR mutation is even more uncommon. Herein, starting from a routinely diagnosed case of CALR -mutated primary myelofibrosis subsequently acquiring BCR::ABL1 translocation, we performed a comprehensive review of the literature, discussing the clinicopathologic and molecular features, as well as the outcome and treatment of cases with BCR::ABL1 and CALR co-occurrence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Zanelli, Fragliasso, Loscocco, Sanguedolce, Broggi, Zizzo, Palicelli, Ricci, Ambrogi, Martino, Aversa, Coppa, Gentile, Gozzi, Caltabiano, Koufopoulos, Asaturova, Cimino, Cavazza, Orcioni and Ascani.)

Published
2024
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124. Prognostic Value of P63 Expression in Muscle-Invasive Bladder Cancer and Association with Molecular Subtypes-Preliminary Report.

Author

Sanguedolce F, Falagario UG, Zanelli M, Palicelli A, Zizzo M, Ascani S, Tortorella S, Busetto GM, Cormio A, Carrieri G, and Cormio L

Abstract

There is an ongoing need for biomarkers that could reliably predict the outcome of BC and that could guide the management of this disease. In this setting, we aimed to explore the prognostic value of the transcription factor P63 in patients with muscle-invasive bladder cancer (MIBC) having undergone radical cystectomy. The correlation between P63 expression and clinicopathological features (tumor stage, nodes involvement, patterns of muscularis propria invasion, papillary architecture, anaplasia, concomitant carcinoma in situ, lymphovascular invasion, perineural invasion, necrosis) and molecular subtyping (basal and luminal type tumors) was tested in 65 radical cystectomy specimens and matched with cancer-specific survival (CSS) and overall survival (OS). P63-negative tumors displayed significantly higher rates of pattern 2 of muscularis propria invasion (50% vs. 14%, p = 0.002) and variant histology (45% vs. 19%, p = 0.022) compared to P63-positive ones. According to the combined expression of CK5/6 and CK20 (Algorithm #1), P63-positive and P63-negative tumors were mostly basal-like and double-negative, respectively ( p = 0.004). Using Algorithm #2, based on the combined expression of CK5/6 and GATA3, the vast majority of tumors were luminal overall and in each group ( p = 0.003). There was no significant difference in CSS and OS between P63-positive and P63-negative tumors, but the former featured a trend towards longer OS. Though associated with pathological features harboring negative prognostic potential, P63 status as such failed to predict CSS and OS. That said, it may contribute to better molecular subtyping of MIBC.

Published
2024
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125. An unusual form of BRAF-V600E mutated hairy cell neoplasm with clinical resistance to BRAF inhibition: Challenging precision medicine.

Author

Marra A, Santi A, Pucciarini A, Venanzi A, De Carolis L, Zaja F, Ascani S, Canzonieri V, Ballanti S, Falini B, and Tiacci E

Subjects
Humans, Precision Medicine, Mutation, Proto-Oncogene Proteins B-raf genetics, Neoplasms
Abstract

Distinct outcomes of BRAF inhibition in BRAF-mutated hairy cell neoplasms with wild-type or mutant TP53, and alternative strategies to overcome mutant TP53., (© 2024 Wiley Periodicals LLC.)

Published
2024
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126. TROP-2, NECTIN-4 and predictive biomarkers in sarcomatoid and rhabdoid bladder urothelial carcinoma.

Author

Brunelli M, Gobbo S, Malpeli G, Sirgiovanni G, Caserta C, Munari E, Francesconi S, Caliò A, Martignoni G, Cimadamore A, Veccia A, Antonelli A, Tucci M, Pierconti F, Hattab IM, Eccher A, Ascani S, Milella M, Buffoni L, Cheng L, and Bracarda S

Subjects
Humans, B7-H1 Antigen, Nectins genetics, Urinary Bladder pathology, In Situ Hybridization, Fluorescence, Biomarkers, Tumor analysis, Carcinoma, Transitional Cell pathology, Urinary Bladder Neoplasms diagnosis, Urinary Bladder Neoplasms genetics
Abstract

Introduction: The surface protein TROP-2/TACSTD2 and the cell adhesion protein NECTIN-4/NECTIN4 are responsible for the efficacy of anticancer therapies based on antibody-drug conjugates (ADC) targeting intracellular microtubules. In contrast with common histologic subtypes of bladder urothelial carcinoma (BUC), little is known of TROP-2 and NECTIN-4 expression in sarcomatoid and rhabdoid BUC., Aims: In this study, we aimed to analyze TROP-2 and NECTIN-4 expression and additional predictive biomarkers by immunohistochemistry and fluorescence in situ hybridization (FISH) on 35 undifferentiated BUC (28 sarcomatoid and 7 rhabdoid). Wide genomic investigation was also performed on 411 BUC cases of the PanCancer Atlas, focusing on genes related to the microtubule pathways., Results: Seven of 35 (20%) undifferentiated BUC showed expression of TROP-2. NECTIN-4 was expressed in 10 cases (29%). Seven cases (20%) co-expressed TROP-2 and NECTIN-4. HER-2 FISH was amplified in 5 cases (14%) while HER-2 immunoexpression was observed in 14 cases (40%). PD-L1 scored positive for combined proportion score (CPS) in 66% of cases and for tumor proportion score (TPS) in 51% of cases. Pan-NTRK1-2/3 was elevated in 9 cases (26%) and FGFR-2/3 was broken in 7 of 35 cases (20%). Of 28 sarcomatoid BUC, 9 (32%) were negative for all (TROP-2, NECTIN-4, PD-L1, HER-2, FGFR and pan-NTRK) biomarkers and 3 (11%) expressed all five biomarkers. Among cases with rhabdoid dedifferentiation, 1 of 7 (14%) showed activation of all biomarkers, whereas 2 of 7 (28%) showed none. The mRNA analysis identified microtubule-related genes and pathways suitable for combined ADC treatments in BUC., Conclusion: Sarcomatoid and rhabdoid BUC do harbor positive expression of the ADC targets TROP-2 or NECTIN-4 in a relatively modest subset of cases, whereas the majority do not. Different combinations of other positive biomarkers may help the choice of medical therapies. Overall, these findings have important clinical implications for targeted therapy for BUC., (Copyright © 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Published
2024
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127. Co-occurrence of JAK2-V617 F mutation and BCR::ABL1 translocation in chronic myeloproliferative neoplasms: a potentially confounding genetic combination.

Author

Zanelli M, Bisagni A, Sanguedolce F, Broggi G, Fragliasso V, Zizzo M, Palicelli A, Martino G, Cresta C, Caprera C, Corsi M, Gentile P, Gozzi F, Trombetta D, Parente P, Caltabiano R, Koufopoulos N, Cimino L, Cavazza A, Fraternali Orcioni G, and Ascani S

Abstract

Myeloproliferative neoplasms (MPNs) are classified into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. BCR::ABL1 translocation is the key genetic event of CML, whereas JAK2/MPL/CALR mutations are molecular aberrations of Ph-negative MPNs. Despite initially considered mutually exclusive genetic aberrations, the co-occurrence of BCR::ABL1 and JAK2 has been reported in a limited number of cases. The two genetic alterations may be identified either at the same time or JAK2 aberration may be detected in patients with a previous CML treated with tyrosine kinase inhibitors or, finally, BCR::ABL1 translocation occurs in patients with a history of JAK2 -positive MPN. This combination of genomic alterations is potentially confounding with clinical manifestations often misinterpreted either as disease progression or drug resistance, therefore leading to inappropriate patient's treatment. Our systematic review aims to improve hematologist and pathologist knowledge on this rare subset of patients. Starting from the presentation of two additional cases from our routine daily practice, we focus mainly on clinical, laboratory, and bone marrow histological findings, which may represent useful clues of BCR::ABL1 and JAK2 co-occurrence. The interaction between JAK2 and BCR::ABL1 clones during the disease course as well as therapy and outcome are presented., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Zanelli, Bisagni, Sanguedolce, Broggi, Fragliasso, Zizzo, Palicelli, Martino, Cresta, Caprera, Corsi, Gentile, Gozzi, Trombetta, Parente, Caltabiano, Koufopoulos, Cimino, Cavazza, Fraternali Orcioni and Ascani.)

Published
2024
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128. Long non-coding RNA mitophagy and ALK-negative anaplastic lymphoma-associated transcript: a novel regulator of mitophagy in T-cell lymphoma.

Author

Mularoni V, Donati B, Tameni A, Manicardi V, Reggiani F, Sauta E, Zanelli M, Tigano M, Vitale E, Torricelli F, Ascani S, Martino G, Inghirami G, Sanguedolce F, Ruffini A, Bavieri A, Luminari S, Pizzi M, Dei Tos AP, Fesce C, Neri A, Ciarrocchi A, and Fragliasso V

Subjects
Humans, Receptor Protein-Tyrosine Kinases genetics, Anaplastic Lymphoma Kinase genetics, Mitophagy genetics, Retrospective Studies, RNA, Long Noncoding genetics, Lymphoma, T-Cell, Peripheral, Lymphoma, Large-Cell, Anaplastic pathology
Abstract

Long non-coding RNA (lncRNA) are emerging as powerful and versatile regulators of transcriptional programs and distinctive biomarkers of progression of T-cell lymphoma. Their role in the aggressive anaplastic lymphoma kinase-negative (ALK-) subtype of anaplastic large cell lymphoma (ALCL) has been elucidated only in part. Starting from our previously identified ALCL-associated lncRNA signature and performing digital gene expression profiling of a retrospective cohort of ALCL, we defined an 11 lncRNA signature able to discriminate among ALCL subtypes. We selected a not previously characterized lncRNA, MTAAT, with preferential expression in ALK- ALCL, for molecular and functional studies. We demonstrated that lncRNA MTAAT contributes to an aberrant mitochondrial turnover restraining mitophagy and promoting cellular proliferation. Functionally, lncRNA MTAAT acts as a repressor of a set of genes related to mitochondrial quality control via chromatin reorganization. Collectively, our work demonstrates the transcriptional role of lncRNA MTAAT in orchestrating a complex transcriptional program sustaining the progression of ALK- ALCL.

Published
2023
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129. Concomitant myeloproliferative neoplasm with eosinophilia, B and T cell lymphoblastic lymphoma/leukemia and mast cell proliferation driven by ZMYM2::FGFR1 rearrangement.

Author

Loscocco GG, Ascani S, Mannelli F, Zanelli M, Rotunno G, Santi R, and Vannucchi AM

Subjects
Humans, Cell Proliferation, T-Lymphocytes, Receptor, Fibroblast Growth Factor, Type 1 genetics, Translocation, Genetic, DNA-Binding Proteins, Transcription Factors, Myeloproliferative Disorders complications, Myeloproliferative Disorders genetics, Eosinophilia genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
Published
2023
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130. CD47 expression in acute myeloid leukemia varies according to genotype.

Author

Marra A, Akarca AU, Martino G, Ramsay A, Ascani S, Perriello VM, O'Nions J, Wilson AJ, Gupta R, Childerhouse A, Proctor I, Rodriguez-Justo M, Pomplun S, Martelli MP, Lo Celso C, Falini B, and Marafioti T

Subjects
Humans, Antibodies, Monoclonal, Genotype, CD47 Antigen genetics, CD47 Antigen metabolism, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism
Published
2023
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133. Skin Involvement by Hematological Neoplasms with Blastic Morphology: Lymphoblastic Lymphoma, Blastoid Variant of Mantle Cell Lymphoma and Differential Diagnoses.

Author

Zanelli M, Sanguedolce F, Zizzo M, Fragliasso V, Broggi G, Palicelli A, Loscocco GG, Cresta C, Caprera C, Corsi M, Martino G, Bisagni A, Marchetti M, Koufopoulos N, Parente P, Caltabiano R, and Ascani S

Abstract

Hematological neoplasms sharing a blastic morphology may involve the skin. The skin may be either the primary site of occurrence of hematological malignancies with blastic features or cutaneous lesions are the first manifestation of an underlying systemic malignancy. The assessment of skin biopsies of hematological neoplasms with blastic features poses diagnostic problems and requires expert hematopathologists considering a wide range of differential diagnoses. The precise diagnosis of diseases sharing blastic features but with different outcomes and requiring distinct therapies is essential for patient management. The present paper mainly focuses on cutaneous involvement of the blastoid variant of mantle cell lymphoma and lymphoblastic lymphoma of B-cell or T-cell origin. The relevant literature has been reviewed and the clinical aspects, pathological features, prognosis, and therapy of both blastoid mantle cell lymphoma and lymphoblastic lymphoma involving the skin are discussed. A focus on other hematological entities with blastic features, which may involve the skin, to be taken into consideration in differential diagnosis is also given.

Published
2023
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135. Myelodysplastic/myeloproliferative neoplasm with neutrophilia (atypical chronic myeloid leukemia-aCML).

Author

Martino G, Quintini M, Martelli MP, Ascani S, Lazzi S, and Mecucci C

Subjects
Humans, Leukocytosis, Mutation, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative genetics, Myelodysplastic-Myeloproliferative Diseases genetics
Abstract

A case of myelodysplastic/myeloproliferative neoplasm with neutrophilia (aCML) with SETBP1 and ASXL1 mutations., (© 2023 Wiley Periodicals LLC.)

Published
2023
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136. Short-Term Outcomes in Patients Undergoing Virtual/Ghost Ileostomy or Defunctioning Ileostomy after Anterior Resection of the Rectum: A Meta-Analysis.

Author

Zizzo M, Morini A, Zanelli M, Tumiati D, Sanguedolce F, Palicelli A, Mereu F, Ascani S, and Fabozzi M

Abstract

Background and Objectives: Anterior rectal resection (ARR) represents one of the most frequently performed methods in colorectal surgery, mainly carried out for rectal cancer (RC) treatment. Defunctioning ileostomy (DI) has long been chosen as a method to "protect" colorectal or coloanal anastomosis after ARR. However, DI does not rule out risks of more or less serious complications. A proximal intra-abdominal closed-loop ileostomy, the so-called virtual/ghost ileostomy (VI/GI), could limit the number of DIs and the associated morbidity., Materials and Methods: We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines. Meta-analysis was performed by use of RevMan [Computer program] Version 5.4., Results: The five included comparative studies (VI/GI or DI) covering an approximately 20-year study period (2008-2021). All included studies were observational ones and originated from European countries. Meta-analysis indicated VI/GI as significantly associated with lower short-term morbidity rates related to VI/GI or DI after primary surgery (RR: 0.21, 95% CI: 0.07-0.64, p = 0.006), fewer dehydration (RR: 0.17, 95% CI: 0.04-0.75, p = 0.02) and ileus episodes after primary surgery (RR: 0.20, 95% CI: 0.05-0.77, p = 0.02), fewer readmissions after primary surgery (RR: 0.17, 95% CI: 0.07-0.43, p = 0.0002) and readmissions after primary surgery plus stoma closure surgery (RR: 0.14, 95% CI: 0.06-0.30, p < 0.00001) than the DI group. On the contrary, no differences were identified in terms of AL after primary surgery, short-term morbidity after primary surgery, major complications (CD ≥ III) after primary surgery and length of hospital stay after primary surgery. Conclusions : Given the significant biases among meta-analyzed studies (small overall sample size and the small number of events analyzed, in particular), our results require careful interpretation. Further randomized, possibly multi-center trials may be of paramount importance in confirming our results.

Published
2023
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138. Clinicopathological Features and Survival Analysis in Molecular Subtypes of Muscle-Invasive Bladder Cancer.

Author

Sanguedolce F, Falagario UG, Zanelli M, Palicelli A, Zizzo M, Ascani S, Tortorella S, Mancini V, Cormio A, Carrieri G, and Cormio L

Subjects
Humans, Survival Analysis, Biomarkers, Tumor metabolism, Urinary Bladder Neoplasms metabolism
Abstract

Molecular subtyping of bladder cancer (BC) aims to capture the biological heterogeneity of this complex disease in order to provide better patient risk stratification. Immunohistochemical (IHC) markers are regarded as promising surrogates to classify BCs into luminal and basal subtypes in routine practice. We investigated the correlation between the molecular subclassification, assessed through IHC, and the conventional prognostic variables of a cohort of 93 muscle-invasive BCs (MIBCs), with a focus on the pattern of muscularis propria (MP) invasion, and evaluated their association with outcome. Basal, luminal, double-positive (DP), and double-negative (DN) phenotypes were identified according to the coordinate expression of 1 basal (CK5/6) and 2 luminal (CK20, GATA3) markers, and accounted for 33.3%, 32.3%, 3.2%, and 31.2% (Scheme #1) and 9.7%, 60.2%, 26.9%, and 3.2% (Scheme #2). There was a significant association between the pattern of MP invasion and the molecular subtypes according to Scheme #2, in that all 8 basal and DN cases, as well as 83% of DP cases, had a non-infiltrative invasion pattern. No consistent differences were observed in terms of OS and CSS between the molecular subtypes obtained through surrogate IHC markers. In keeping with previous studies, we report the correlation between the identification of BC subtypes and the presence of morphological prognostic factors, supporting the need for a comprehensive pathological evaluation, including clinicopathological and molecular parameters, in order to improve the diagnosis and management of MIBC.

Published
2023
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139. CIC-rearranged sarcoma presenting with superior vena cava syndrome: case report.

Author

Ascione A, Martino G, Di Donato F, Casini B, Covello R, and Ascani S

Subjects
Humans, Male, Middle Aged, Biomarkers, Tumor genetics, Oncogene Proteins, Fusion genetics, Sarcoma complications, Sarcoma diagnosis, Sarcoma genetics, Sarcoma, Small Cell diagnosis, Sarcoma, Small Cell genetics, Sarcoma, Small Cell pathology, Superior Vena Cava Syndrome genetics
Abstract

CIC-rearranged sarcomas are rare mesenchymal neoplasms belonging to the family of undifferentiated small round cell sarcomas. This report details the case of a 45-year-old man presenting with symptoms of mediastinal compression, radiological diagnosis of a mediastinal mass and rapid evolution to full-blown superior vena cava syndrome. The emergency was successfully managed with a pharmacological approach. Formulation of a pathological diagnosis of CIC-rearranged sarcoma was initially supported by fluorescence in situ hybridisation findings and later validated by next-generation sequencing, which showed CIC-DUX4 gene fusion. A chemotherapy regimen was started with immediate benefits for the patient. The spectrum of pathological entities able to cause superior vena cava syndrome is wide, and recognition of rare causes is important to tailor the therapeutic approach to the specific disease. This is, to the best of our knowledge, the first report of CIC-rearranged sarcoma presenting with superior vena cava syndrome., (Copyright © 2023 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Published
2023
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140. Mast Cell Leukemia: An Update with a Practical Review.

Author

Zanelli M, Quintini M, Magnasco S, Aprile L, Palicelli A, Zizzo M, Sanguedolce F, Ricci S, Pancetti S, Zuccalà V, Martino V, Broggi G, Caltabiano R, Cavazza A, Parente P, Mecucci C, Martino G, and Ascani S

Abstract

Mast cell leukemia (MCL) is the leukemic form of SM with at least 20% mostly immature mast cells on bone marrow aspirate. MCL may develop de novo, in the absence of a prior SM, or it may represent a progression from a previous SM. MCL may be sub-divided into the more frequent, aggressive acute form with signs of organ damage (C-findings) and the chronic form lacking C-findings and presenting a more stable course, although over time, progression to acute MCL is common. The 2022 WHO subtype of MCL with an associated hematological neoplasm was renamed MCL with an associated myeloid neoplasm in the 2022 International Consensus Classification (ICC). The relevance of the distinction between the leukemic and aleukemic forms based on the percentage of circulating mast cells is a matter of debate. The current knowledge on MCL is restricted mainly to single reports or case series with a limited number of larger studies. Our aim is to provide a comprehensive overview of this rare disease in terms of clinical manifestations, morphology, phenotype, molecular characteristics, differential diagnosis, outcome and treatment. A general overview on mastocytosis is also included.

Published
2023
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141. HER2 Expression in Bladder Cancer: A Focused View on Its Diagnostic, Prognostic, and Predictive Role.

Author

Sanguedolce F, Zanelli M, Palicelli A, Bisagni A, Zizzo M, Ascani S, Pedicillo MC, Cormio A, Falagario UG, Carrieri G, and Cormio L

Subjects
Humans, Biomarkers, Tumor metabolism, Prognosis, Urinary Bladder pathology, Receptor, ErbB-2 genetics, Receptor, ErbB-2 metabolism, Urinary Bladder Neoplasms genetics, Urinary Bladder Neoplasms pathology
Abstract

Bladder cancer (BC) is a heterogeneous disease from a molecular, morphological, and clinical standpoint. HER2 is a known oncogene involved in bladder carcinogenesis. Assessing HER2 overexpression as a result of its molecular changes in a routine pathology practice using immunohistochemistry might be a useful adjunct in several scenarios, namely (1) to correctly identify flat urothelial lesions and inverted urothelial lesions in the diagnostic setting; (2) to provide prognostic hints in both non-muscle invasive (NMI) and muscle invasive (MI) tumors, thus supplementing risk stratification tools, especially when evaluating higher-risk tumors such as those with variant morphology; (3) to improve antibody panels as a surrogate marker of BC molecular subtyping. Furthermore, the potential of HER2 as a therapeutic target has been only partly explored so far, in light of the ongoing development of novel target therapies.

Published
2023
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142. CD5-Negative Primary Mantle Cell Lymphoma Presenting with a Bilateral Conjunctival Mass: A Potential Diagnostic Pitfall.

Author

Zanelli M, Lugli A, Palicelli A, Sanguedolce F, Zizzo M, Cresta C, Biancafarina S, Martino G, Crescenzi B, Pancetti S, Broggi G, Caltabiano R, Cimino L, Mecucci C, and Ascani S

Subjects
Adult, Humans, Lymph Nodes pathology, CD5 Antigens metabolism, Lymphoma, B-Cell, Marginal Zone diagnosis, Lymphoma, B-Cell, Marginal Zone pathology, Lymphoma, Mantle-Cell diagnosis
Abstract

Mantle cell lymphoma is a B-cell malignancy, which, in its classic form, usually involves lymph nodes and extranodal sites, and, among the extranodal sites, the gastrointestinal tract and the Waldeyer's ring are most prevalent. MCL is rarely reported in the ocular adnexa, a site more frequently affected by extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, which is a form of low-grade malignancy. The diagnosis of MCL presenting in the ocular adnexa requires special attention as its rarity in this location combined with the not uncommon CD5 negativity of the disease when occurring in the ocular adnexa, may lead the pathologist to overlook the diagnosis and misinterpret MCL as marginal zone B cell lymphoma, which has a totally different behavior. Herein, we present a case of primary bilateral conjunctival CD5-negative MCL in a patient having no other sites affected by lymphoma and we discuss possible diagnostic pitfalls.

Published
2023
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143. What does MYC, BCL2, and BCL6 genes 'rearranged' mean in large cell/diffuse B-cell lymphomas?

Author

Trombetta D, Zanelli M, Garuti A, Carosi I, Mastracci L, Ascani S, Graziano P, and Parente P

Subjects
Humans, Proto-Oncogene Proteins c-bcl-6 genetics, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-myc genetics, Gene Rearrangement, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse pathology
Abstract

Competing Interests: Conflict of interest The Authors have no conflicts of interest to declare.

Published
2022
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144. Intravascular NK/T-Cell Lymphoma: What We Know about This Diagnostically Challenging, Aggressive Disease.

Author

Zanelli M, Parente P, Sanguedolce F, Zizzo M, Palicelli A, Bisagni A, Carosi I, Trombetta D, Mastracci L, Ricci L, Pancetti S, Martino G, Broggi G, Caltabiano R, Cavazza A, and Ascani S

Abstract

Intravascular lymphoma is a form of lymphoid malignancy characterized by neoplastic cells growing almost exclusively within the lumina of small- to medium-sized blood vessels. Most cases are of B-cell origin with rare cases of natural killer or T-cell lineage. Extranodal sites are affected, mainly the skin and central nervous system, although any organ may be involved. Intravascular NK/T-cell lymphoma deserves special attention because of its clinicopathologic features and the need for adequate immunophenotyping combined with clonality test for a proper diagnosis. Moreover, intravascular NK/T-cell lymphoma is strongly linked to Epstein-Barr virus (EBV), which is considered to play a role in tumorigenesis and to be responsible for the aggressive behavior of the disease. In this paper, we review the current knowledge on this rare lymphoma and, in particular, the most recent advances about its molecular landscape. The main distinguishing features with other EBV-related entities, such as extranodal NK/T-cell lymphoma, EBV-positive primary nodal T/NK-cell lymphoma, and aggressive NK-cell leukemia, are discussed to help pathologists obtain the correct diagnosis and consequently develop an adequate and prompt therapy response.

Published
2022
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146. Primary Vitreoretinal Lymphoma: Current Diagnostic Laboratory Tests and New Emerging Molecular Tools.

Author

Melli B, Gentile P, Nicoli D, Farnetti E, Croci S, Gozzi F, Bolletta E, De Simone L, Sanguedolce F, Palicelli A, Zizzo M, Ricci S, Ilariucci F, Rossi C, Cavazza A, Ascani S, Cimino L, and Zanelli M

Subjects
Humans, Vitreous Body pathology, Myeloid Differentiation Factor 88, Immunoglobulin Heavy Chains, Steroids, Retinal Neoplasms diagnosis, Retinal Neoplasms genetics, Retinal Neoplasms pathology, Lymphoma diagnosis, Lymphoma genetics, Uveitis pathology
Abstract

Primary vitreoretinal lymphoma (PVRL), a rare aggressive malignancy primarily involving the retina and/or the vitreous, is a major diagnostic challenge for clinicians (who commonly misdiagnose it as chronic uveitis) as well as for pathologists (for biological and technical reasons). Delays in diagnosis and treatment are responsible for visual impairments and life-threatening consequences, usually related to central nervous system involvement. The identification of lymphoma cells in vitreous fluid, obtained by vitrectomy, is required for diagnosis. Of note, the scarcity of neoplastic cells in small volumes of vitreous sample, and the fragility of lymphoma cells with degenerative changes caused by previous steroid use for presumed uveitis makes diagnosis based on cytology plus immunophenotyping difficult. Interleukin levels, immunoglobulin heavy chain or T-cell receptor gene rearrangements, and MYD88 mutation are applied in combination with cytology to support diagnosis. We aim to describe the current laboratory technologies for PVRL diagnosis, focusing on the main issues that these methods have. In addition, new emerging diagnostic strategies, such as next-generation sequencing analysis, are discussed. The genetic profile of PVRL remains largely unexplored. Better knowledge of genetic alterations is critical for precision medicine interventions with target-based treatments of this lymphoma for which no standardised treatment protocol currently exists.

Published
2022
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147. Pediatric Thymoma: A Review and Update of the Literature.

Author

Rossi C, Zanelli M, Sanguedolce F, Zizzo M, Palicelli A, Ricci L, Corsi M, Caprera C, Cresta C, Sollitto F, Broggi G, Caltabiano R, Cavazza A, Lococo F, Loizzi D, and Ascani S

Abstract

Pediatric thymomas are extremely rare and slow-growing malignant tumors. The recent publication of the first Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis (TNM) stage classification and updated treatment guidelines for thymomas has prompted us to perform a review of the literature on pediatric thymomas. A search of English-language articles in the PubMed, Cochrane, Web of Science, and Embase databases was conducted. Additional articles were identified through reference lists of retrieved publications. Thirty-two articles involving 82 pediatric thymomas were included. Males comprised 60% of patients, and 13% manifested myasthenia gravis (MG). Histotype B1 (45%) and stage I (52% Masaoka-Koga and 71% UICC/AJCC TNM) were the most frequent. Of note is the possibility that the lack of cases with mixed histologies in the reviewed publications might be related to a sampling issue, as it is well known that the more sections are available for review, the more likely it is that the majority of these neoplasms will show mixed histologies. Both staging systems showed a gradual increase in the percentage of cases, with more advanced stages of disease moving from type A to B3 thymomas. Complete surgical resection (R0) was the main therapeutic approach in Masaoka-Koga stage I (89%) and UICC/AJCC TNM stage I (70%) thymomas. Advanced stages of disease and incomplete surgical resection were most often associated with recurrence and death. An association between stage and outcome, and completeness of resection and outcome, was found. Interestingly, though an association between histotype and staging was found, this does not take into account the possibility of mixed histologies which would reduce the clinical impact of histologic subtyping over staging.

Published
2022
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148. Gastrectomy with or without Complete Omentectomy for Advanced Gastric Cancer: A Meta-Analysis.

Author

Zizzo M, Zanelli M, Sanguedolce F, Palicelli A, Ascani S, Morini A, Tumiati D, Mereu F, Zuliani AL, Nardecchia M, Gatto F, Zanni M, and Giunta A

Subjects
Gastrectomy methods, Humans, Omentum pathology, Omentum surgery, Retrospective Studies, Treatment Outcome, Laparoscopy methods, Stomach Neoplasms pathology, Stomach Neoplasms surgery
Abstract

Background and Objectives : Surgery remains the only possible curative treatment for advanced gastric cancer (AGC). Peritoneal metastases are estimated to occur in approximately 55-60% AGC patients. Greater omentum is the most common metastatic area in AGC. At present, omentectomy alone or bursectomy are usually carried out during gastric cancer surgery. We performed a meta-analysis in order to evaluate long-term and short-term outcomes among AGC patients, who have undergone radical gastrectomy with or without complete omentectomy (CO). Materials and Methods : We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Meta-analysis was performed by use of RevMan (Computer program) Version 5.4. Results : The eight included studies covered an approximately 20 years long study period (2000-2018). Almost all included studies were retrospective ones and originated from Asian countries. Meta-analysis indicated gastrectomy without CO as significantly associated with longer 3-year (RR: 0.94, 95% CI: 0.90-0.98, p = 0.005) and 5-year overall survivals (OS) (RR: 0.93, 95% CI: 0.88-0.98, p = 0.007). Moreover, we found longer operative time (MD: 24.00, 95% CI: -0.45-48.45, p = 0.05) and higher estimated blood loss (MD: 194.76, 95% CI: 96.40-293.13, p = 0.0001) in CO group. Conclusions : Non-complete omentectomy (NCO) group had a statistically greater rate in 3-year and 5-year OSs than the CO group, while the CO group had significantly longer operative time and higher estimated blood loss than the NCO group. Further randomized, possibly multi-center trials may turn out of paramount importance in confirming our results.

Published
2022
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149. Collision nodal metastasis of bladder cancer and melanoma: The first reported case and literature review.

Author

Sanguedolce F, Troiano F, Musci G, Zanelii M, Zizzo M, Ascani S, Carrieri G, and Cormio L

Abstract

Collision metastasis is a rare phenomenon of concomitant localization of 2 or more different tumors in the same lymph node. In most cases, primary malignancies are synchronous carcinomas arising in the same organ or area of the body. A 82-year-old man presented with hematuria and acute renal failure; he had undergone dermatological consultation ten months ago because of a large deep brown skin lesion in his dorso-lumbar region, which was not excised upon patient's request. He underwent radical cystectomy with extended pelvic lymphadenectomy due to nonpapillary high-grade urothelial carcinoma, with focal squamous features, infiltrating the bladder wall and prostate gland. In one left iliac lymph node, small foci of metastatic urothelial carcinoma (positive for P63 and CK34betaE12) were close to melanoma cells (positive for HMB45). The patient refused further treatment and died of metastatic disease 12 months after cystectomy. There is no specific clinical feature for nodal collision metastasis. A polymorphic histologic appearance poses the suspect, but immunohistochemical stains are needed to define the primary tumors. Collision metastases are thought to carry a poor prognosis. Their clinical relevance is linked to the fact that the patient faces 2 different metastatic tumors that may require specific multidisciplinary approach once diagnosed as metastatic. We present, to the best of our knowledge, the first case of collision nodal metastasis from bladder cancer and melanoma, and describe its clinical and histopathological characteristics to raise awareness on this rare occurrence, which portends a poorer prognosis than each single tumor., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc.)

Published
2022
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150. Human neural stem cells drug product: Microsatellite instability analysis.

Author

Grespi V, Caprera C, Ricciolini C, Bicchi I, Muzi G, Corsi M, Ascani S, Vescovi AL, and Gelati M

Subjects
Cell Differentiation, Humans, Stem Cell Transplantation, Microsatellite Instability, Neural Stem Cells
Abstract

Introduction: In central nervous system neurodegenerative disorders, stem cell-based therapies should be considered as a promising therapeutic approach. The safe use of human Neural Stem Cells (hNSCs) for the treatment of several neurological diseases is currently under evaluation of phase I/II clinical trials. Clinical application of hNSCs require the development of GMP standardized protocols capable of generating high quantities of reproducible and well characterized stem cells bearing stable functional and genetic properties., Aim: The aim of this study was to evaluate possible instabilities or modifications of the microsatellite loci in different culture passages because high culture passages represent an in vitro replicative stress leading to senescence. Experimental method: The hNSCs were characterized at different culture time points, from passage 2 to passage 25, by genetic typing at ten microsatellite loci., Conclusion: We showed that genetic stability at microsatellite loci is maintained by the cells even at high passages adding a further demonstration of the safety of our hNSCs GMP culture method., Competing Interests: The authors have declared that no competing interests exist.

Published
2022
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