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5. Gut microbiota diversity before allogeneic hematopoietic stem cell transplantation as a predictor of mortality in children

Author

Masetti, Riccardo, Leardini, Davide, Muratore, Edoardo, Fabbrini, Marco, D’Amico, Federica, Zama, Daniele, Baccelli, Francesco, Gottardi, Francesca, Belotti, Tamara, Ussowicz, Marek, Fraczkiewicz, Jowita, Cesaro, Simone, Zecca, Marco, Merli, Pietro, Candela, Marco, Pession, Andrea, Locatelli, Franco, Prete, Arcangelo, Brigidi, Patrizia, and Turroni, Silvia

Published
2023
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6. Impact of Inflammatory Burden on Voriconazole Exposure in Oncohematological Pediatric Patients Receiving Antifungal Prophylaxis after Allogeneic HCT.

Author

Gatti, Milo, Campoli, Caterina, Muratore, Edoardo, Belotti, Tamara, Masetti, Riccardo, Lanari, Marcello, Viale, Pierluigi, and Pea, Federico

Subjects
HEMATOPOIETIC stem cell transplantation, DRUG monitoring, DRUG dosage, BLOOD proteins, CHILD patients
Abstract

(1) Background: The impact of inflammation on voriconazole exposure in oncohematological pediatric patients represents a debated issue. We aimed to investigate the impact of serum C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) levels on voriconazole exposure in oncohematological pediatric patients requiring allogeneic hematopoietic stem cell transplantation (HCT). (2) Methods: Pediatric patients undergoing allogeneic HCT and receiving therapeutic drug monitoring (TDM)-guided voriconazole as primary antifungal prophylaxis between January 2021 and December 2023 were included. The ratio between concentration and dose (C/D) of voriconazole was used as a surrogate marker of total clearance. A receiving operating characteristic curve analysis was performed by using CRP, PCT, or IL-6 values as the test variable and voriconazole C/D ratio > 0.188 or >0.375 (corresponding to a trough concentration value [Cmin] of 3 mg/L normalized to the maintenance dose of 16 mg/kg/day in patients of age < 12 years and of 8 mg/kg/day in those ≥12 years, respectively) as the state variable. Area under the curve (AUC) and 95% confidence interval (CI) were calculated. (3) Results: Overall, 39 patients were included. The median (IQR) voriconazole Cmin was 1.7 (0.7–3.0) mg/L. A CRP value > 8.49 mg/dL (AUC = 0.72; 95%CI 0.68–0.76; p < 0.0001), a PCT value > 2.6 ng/mL (AUC = 0.71; 95%CI 0.63–0.77; p < 0.0001), and an IL-6 value > 27.9 pg/mL (AUC = 0.80; 95%CI 0.71–0.88; p < 0.0001) were significantly associated with voriconazole overexposure. Consistent results were found in patients aged <12 and ≥12 years. (4) Conclusions: A single specific threshold of inflammatory biomarkers may be linked to a significantly higher risk of voriconazole exposure in oncohematological pediatric patients after HCT, irrespective of age. Adopting a TDM-guided strategy could be useful for minimizing the risk of voriconazole overexposure. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Gut microbiota diversity before allogeneic hematopoietic stem cell transplantation as predictor of mortality in children

Author

Masetti, Riccardo, primary, Leardini, Davide, additional, Muratore, Edoardo, additional, Fabbrini, Marco, additional, D'Amico, Federica, additional, Zama, Daniele, additional, Baccelli, Francesco, additional, Gottardi, Francesca, additional, Belotti, Tamara, additional, Ussowicz, Marek, additional, Fraczkiewicz, Jowita, additional, Cesaro, Simone, additional, Zecca, Marco, additional, Merli, Pietro, additional, Candela, Marco, additional, Pession, Andrea, additional, Locatelli, Franco, additional, Prete, Arcangelo, additional, Brigidi, Patrizia, additional, and Turroni, Silvia, additional

Published
2023
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10. In-Depth Immunological Typization of Children with Sickle Cell Disease: A Preliminary Insight into Its Plausible Correlation with Clinical Course and Hydroxyurea Therapy

Author

Giulietti, Giulia, primary, Zama, Daniele, additional, Conti, Francesca, additional, Moratti, Mattia, additional, Presutti, Maria Teresa, additional, Belotti, Tamara, additional, Cantarini, Maria Elena, additional, Facchini, Elena, additional, Bassi, Mirna, additional, Selva, Paola, additional, Magrini, Elisabetta, additional, Lanari, Marcello, additional, and Pession, Andrea, additional

Published
2022
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11. Febrile Neutropenia Duration Is Associated with the Severity of Gut Microbiota Dysbiosis in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients

Author

Masetti, Riccardo, primary, D’Amico, Federica, additional, Zama, Daniele, additional, Leardini, Davide, additional, Muratore, Edoardo, additional, Ussowicz, Marek, additional, Fraczkiewicz, Jowita, additional, Cesaro, Simone, additional, Caddeo, Giulia, additional, Pezzella, Vincenza, additional, Belotti, Tamara, additional, Gottardi, Francesca, additional, Tartari, Piero, additional, Brigidi, Patrizia, additional, Turroni, Silvia, additional, and Prete, Arcangelo, additional

Published
2022
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12. Off-Label Use of Letermovir as Preemptive Anti-Cytomegalovirus Therapy in a Pediatric Allogeneic Peripheral Blood Stem Cell Transplant

Author

Chiereghin,Angela, Belotti,Tamara, Borgatti,Eva Caterina, Fraccascia,Nicola, Piccirilli,Giulia, Fois,Maura, Borghi,Michele, Turello,Gabriele, Gabrielli,Liliana, Masetti,Riccardo, Prete,Arcangelo, Fanti,Stefano, Lazzarotto,Tiziana, Chiereghin,Angela, Belotti,Tamara, Borgatti,Eva Caterina, Fraccascia,Nicola, Piccirilli,Giulia, Fois,Maura, Borghi,Michele, Turello,Gabriele, Gabrielli,Liliana, Masetti,Riccardo, Prete,Arcangelo, Fanti,Stefano, and Lazzarotto,Tiziana

Abstract

Angela Chiereghin,1,2 Tamara Belotti,3 Eva Caterina Borgatti,4 Nicola Fraccascia,5 Giulia Piccirilli,6 Maura Fois,3 Michele Borghi,4 Gabriele Turello,4 Liliana Gabrielli,6 Riccardo Masetti,3 Arcangelo Prete,3 Stefano Fanti,5 Tiziana Lazzarotto4 1Section of Microbiology, Department of Specialized, Experimental, and Diagnostic Medicine, University of Bologna, Bologna, Italy; 2Department of Public Health, Local Health Authority of Bologna, Bologna, Italy; 3Pediatric Oncology and Haematology Unit “Lalla Seragnoli”, Department of Pediatrics, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy; 4Microbiology Unit, Department of Specialized, Experimental, and Diagnostic Medicine, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy; 5Nuclear Medicine Unit, Department of Specialized, Experimental, and Diagnostic Medicine, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy; 6Microbiology Unit, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, ItalyCorrespondence: Tiziana LazzarottoMicrobiology Unit, Department of Specialized, Experimental, and Diagnostic Medicine, IRCCS St. Orsola Polyclinic, University of Bologna, via Massarenti 9, Bologna, 40138, ItalyTel +39 0512143360Fax +39 0512143514Email tiziana.lazzarotto@unibo.itAbstract: Despite the effectiveness of the currently available antiviral drugs in treating cytomegalovirus (CMV) infection, high rates of adverse effects are associated with their use. Moreover, a problem of increasing importance is the emergence of drug-resistant CMV infection. Here, we describe the first case of off-label use of letermovir (LMV) as preemptive antiviral therapy, in a pediatric allogeneic peripheral blood stem cell transplant recipient with ganciclovir-resistant CMV infection who was intolerant to foscarnet and unable to achieve viral clearance after seven doses of cidofovir. After the administration of LMV, a gradual reduction in viral load was observed and within 6

Published
2021

13. Off-Label Use of Letermovir as Preemptive Anti-Cytomegalovirus Therapy in a Pediatric Allogeneic Peripheral Blood Stem Cell Transplant

Author

Chiereghin, Angela, primary, Belotti, Tamara, additional, Borgatti, Eva Caterina, additional, Fraccascia, Nicola, additional, Piccirilli, Giulia, additional, Fois, Maura, additional, Borghi, Michele, additional, Turello, Gabriele, additional, Gabrielli, Liliana, additional, Masetti, Riccardo, additional, Prete, Arcangelo, additional, Fanti, Stefano, additional, and Lazzarotto, Tiziana, additional

Published
2021
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14. Incidence, Risk Factors and Outcome of Pre-engraftment Gram-Negative Bacteremia After Allogeneic and Autologous Hematopoietic Stem Cell Transplantation: An Italian Prospective Multicenter Survey

Author

Girmenia, Corrado, Bertaina, Alice, Piciocchi, Alfonso, Perruccio, Katia, Algarotti, Alessandra, Busca, Alessandro, Cattaneo, Chiara, Raiola, Anna Maria, Guidi, Stefano, Iori, Anna Paola, Candoni, Anna, Irrera, Giuseppe, Milone, Giuseppe, Marcacci, Giampaolo, Scimè, Rosanna, Musso, Maurizio, Cudillo, Laura, Sica, Simona, Castagna, Luca, Corradini, Paolo, Marchesi, Francesco, Pastore, Domenico, Alessandrino, Emilio Paolo, Annaloro, Claudio, Ciceri, Fabio, Santarone, Stella, Nassi, Luca, Farina, Claudio, Viscoli, Claudio, Rossolini, Gian Maria, Bonifazi, Francesca, Rambaldi, Alessandro, Capria, Saveria, Bertaina, A., Mastronuzzi, Angela, Pagliara, Daria, Bernaschi, Paola, Amico, Lucia, Carotti, Alessandra, Mencacci, Antonella, Busca, A., Bruno, Benedetto, Costa, Cristina, Passi, Angela, Ravizzola, Giuseppe, Angelucci, Emanuele, Marchese, Anna, Pecile, Patrizia, Candoni, A., Ventura, Giovanna, Fanin, Renato, Scarparo, Claudio, Barbaro, Angelo, Milone, G., Leotta, Salvatore, Marchese, Anna Elisa, Marcacci, G., Becchimanzi, Cristina, Donnarumma, Daniela, Tringali, Stefania, Baldi, Maria Teresa, Scalone, Renato, Cudillo, L., Picardi, Alessandra, Arcese, William, Fontana, Carla, Sica, S., Giammarco, Sabrina, Spanu, Teresa, Castagna, L., Crocchiolo, Roberto, Casari, Erminia, Mussetti, Alberto, Conte, Eutilia, Ensoli, Fabrizio, Miragliotta, Giuseppe, Marone, Piero, Arghittu, Milena, Greco, Raffaella, Forcina, Alessandra, Chichero, Paola, Santarone, S., Di Bartolomeo, Paolo, Fazii, Paolo, Kroumova, Vesselina, Decembrino, Nunzia, Zecca, Marco, Pisapia, Giovanni, Palazzo, Giulia, Lanino, Edoardo, Faraci, Maura, Castagnola, Elio, Bandettini, Roberto, Pastano, Rocco, Sammassimo, Simona, Passerini, Rita, Stefani, Piero Maria, Gherlinzoni, Filippo, Rigoli, Roberto, Prezioso, Lucia, Cambò, Benedetta, Calderaro, Adriana, Carella, Angelo Michele, Cascavilla, Nicola, Labonia, Maria Teresa, Celeghini, Ivana, Mordini, Nicola, Piana, Federica, Vacca, Adriana, Sanna, Marco, Podda, Giovanni, Corsetti, Maria Teresa, Rocchetti, Andrea, Cilloni, Daniela, De Gobbi, Marco, Bianco, Ornella, Fagioli, Franca, Carraro, Francesca, De Intinis, Gianfranco, Severino, Alessandro, Proia, Anna, Parisi, Gabriella, Vallisa, Daniele, Confalonieri, Massimo, Russo, Domenico, Malagola, Michele, Galieni, Piero, Falcioni, Sadia, Travaglini, Valeria, Raimondi, Roberto, Borghero, Carlo, Pavan, Giacomina, Prete, Arcangelo, Belotti, Tamara, Ambretti, Simone, Imola, Manuela, Mianulli, Anna Maria, Pedna, Maria Federica, Cesaro, Simone, Lo Cascio, Giuliana, Ferrari, Antonella, Piedimonte, Monica, Santino, Iolanda, Calandrelli, Monica, Olivieri, Attilio, Orecchioni, Francesca, Mirabile, Milena, Centurioni, Riccardo, Gironacci, Luciana, Caravelli, Daniela, Gallo, Susanna, De Filippi, Marco, Cupelli, Luca, Dentamaro, Teresa, Falco, Silvana, Eugenio, Ospedale S, Marotta, Serena, Risitano, Antonio, Lula, Dora, Musto, Pellegrino, Pietrantuono, Giuseppe, Traficante, Antonio, Cerchiara, Elisabetta, Tirindelli, Maria Cristina, Dicuonzo, Giordano, Chierichini, Anna, Anaclerico, Barbara, Placanica, Paola, Girmenia, C, Bertaina, A, Piciocchi, A, Perruccio, K, Algarotti, A, Busca, A, Cattaneo, C, Raiola, Am, Guidi, S, Iori, Ap, Candoni, A, Irrera, G, Milone, G, Marcacci, G, Scimè, R, Musso, M, Cudillo, L, Sica, S, Castagna, L, Corradini, P, Marchesi, F, Pastore, D, Alessandrino, Ep, Annaloro, C, Ciceri, F, Santarone, S, Nassi, L, Farina, C, Viscoli, C, Rossolini, Gm, Bonifazi, F, Rambaldi, A, for the Gruppo Italiano Trapianto di Midollo Osseo, (GITMO), Associazione Microbiologi Clinici Italiani, (AMCLI), Girmenia, Corrado, Bertaina, Alice, Piciocchi, Alfonso, Perruccio, Katia, Algarotti, Alessandra, Busca, Alessandro, Cattaneo, Chiara, Raiola, Anna Maria, Guidi, Stefano, Iori, Anna Paola, Candoni, Anna, Irrera, Giuseppe, Milone, G., Marcacci, Giampaolo, Scimè, Rosanna, Musso, Maurizio, Cudillo, Laura, Sica, Simona, Castagna, Luca, Corradini, Paolo, Marchesi, Francesco, Pastore, Domenico, Alessandrino, Emilio Paolo, Annaloro, Claudio, Ciceri, Fabio, Santarone, Stella, Nassi, Luca, Farina, Claudio, Viscoli, Claudio, Rossolini, Gian Maria, Bonifazi, Francesca, Rambaldi, Alessandro, Capria, Saveria, Bertaina, A., Mastronuzzi, Angela, Pagliara, Daria, Bernaschi, Paola, Amico, Lucia, Carotti, Alessandra, Mencacci, Antonella, Busca, A., Bruno, Benedetto, Costa, Cristina, Passi, Angela, Ravizzola, Giuseppe, Angelucci, Emanuele, Marchese, Anna, Pecile, Patrizia, Candoni, A., Ventura, Giovanna, Fanin, Renato, Scarparo, Claudio, Barbaro, Angelo, Leotta, Salvatore, Marchese, Anna Elisa, Marcacci, G., Becchimanzi, Cristina, Donnarumma, Daniela, Tringali, Stefania, Baldi, Maria Teresa, Scalone, Renato, Cudillo, L., Picardi, Alessandra, Arcese, William, Fontana, Carla, Sica, S., Giammarco, Sabrina, Spanu, Teresa, Castagna, L., Crocchiolo, Roberto, Casari, Erminia, Mussetti, Alberto, Conte, Eutilia, Ensoli, Fabrizio, Miragliotta, Giuseppe, Marone, Piero, Arghittu, Milena, Greco, Raffaella, Forcina, Alessandra, Chichero, Paola, Santarone, S., Di Bartolomeo, Paolo, Fazii, Paolo, Kroumova, Vesselina, Decembrino, Nunzia, Zecca, Marco, Pisapia, Giovanni, Palazzo, Giulia, Lanino, Edoardo, Faraci, Maura, Castagnola, Elio, Bandettini, Roberto, Pastano, Rocco, Sammassimo, Simona, Passerini, Rita, Stefani, Piero Maria, Gherlinzoni, Filippo, Rigoli, Roberto, Prezioso, Lucia, Cambò, Benedetta, Calderaro, Adriana, Carella, Angelo Michele, Cascavilla, Nicola, Labonia, Maria Teresa, Celeghini, Ivana, Mordini, Nicola, Piana, Federica, Vacca, Adriana, Sanna, Marco, Podda, Giovanni, Corsetti, Maria Teresa, Rocchetti, Andrea, Cilloni, Daniela, De Gobbi, Marco, Bianco, Ornella, Fagioli, Franca, Carraro, Francesca, De Intinis, Gianfranco, Severino, Alessandro, Proia, Anna, Parisi, Gabriella, Vallisa, Daniele, Confalonieri, Massimo, Russo, Domenico, Malagola, Michele, Galieni, Piero, Falcioni, Sadia, Travaglini, Valeria, Raimondi, Roberto, Borghero, Carlo, Pavan, Giacomina, Prete, Arcangelo, Belotti, Tamara, Ambretti, Simone, Imola, Manuela, Mianulli, Anna Maria, Pedna, Maria Federica, Cesaro, Simone, Lo Cascio, Giuliana, Ferrari, Antonella, Piedimonte, Monica, Santino, Iolanda, Calandrelli, Monica, Olivieri, Attilio, Orecchioni, Francesca, Mirabile, Milena, Centurioni, Riccardo, Gironacci, Luciana, Caravelli, Daniela, Gallo, Susanna, De Filippi, Marco, Cupelli, Luca, Dentamaro, Teresa, Falco, Silvana, Eugenio, Ospedale S, Marotta, Serena, Risitano, Antonio, Lula, Dora, Musto, Pellegrino, Pietrantuono, Giuseppe, Traficante, Antonio, Cerchiara, Elisabetta, Tirindelli, Maria Cristina, Dicuonzo, Giordano, Chierichini, Anna, Anaclerico, Barbara, and Placanica, Paola

Subjects
0301 basic medicine, Male, Transplantation Conditioning, Drug Resistance, Bacteremia, 0302 clinical medicine, epidemiology, Gram negative bacteremia, multidrug resistance, stem cell transplant, survival, Risk Factors, Drug Resistance, Multiple, Bacterial, Epidemiology, Medicine, Age Factor, Prospective Studies, Prospective cohort study, Child, Transplantation, Homologou, education.field_of_study, Incidence (epidemiology), Incidence, Bacterial, Age Factors, Hematopoietic Stem Cell Transplantation, Middle Aged, Transplantation, Autologou, surgical procedures, operative, Infectious Diseases, Italy, Child, Preschool, Female, medicine.symptom, Multiple, Autologous, Human, Homologous, Microbiology (medical), Adult, medicine.medical_specialty, Adolescent, 030106 microbiology, Population, Transplantation, Autologous, 03 medical and health sciences, Young Adult, Internal medicine, Gram-Negative Bacteria, Gram-Negative Bacterial Infection, Escherichia coli, Humans, Transplantation, Homologous, Preschool, education, Aged, Gram-Negative Bacterial Infections, Infant, Transplantation, business.industry, Risk Factor, medicine.disease, Prospective Studie, Carriage, Otitis, business, Settore MED/15 - Malattie del Sangue, 030215 immunology
Abstract

Background Gram-negative bacteremia (GNB) is a major cause of illness and death after hematopoietic stem cell transplantation (HSCT), and updated epidemiological investigation is advisable. Methods We prospectively evaluated the epidemiology of pre-engraftment GNB in 1118 allogeneic HSCTs (allo-HSCTs) and 1625 autologous HSCTs (auto-HSCTs) among 54 transplant centers during 2014 (SIGNB-GITMO-AMCLI study). Using logistic regression methods. we identified risk factors for GNB and evaluated the impact of GNB on the 4-month overall-survival after transplant. Results The cumulative incidence of pre-engraftment GNB was 17.3% in allo-HSCT and 9% in auto-HSCT. Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa were the most common isolates. By multivariate analysis, variables associated with GNB were a diagnosis of acute leukemia, a transplant from a HLA-mismatched donor and from cord blood, older age, and duration of severe neutropenia in allo-HSCT, and a diagnosis of lymphoma, older age, and no antibacterial prophylaxis in auto-HSCT. A pretransplant infection by a resistant pathogen was significantly associated with an increased risk of posttransplant infection by the same microorganism in allo-HSCT. Colonization by resistant gram-negative bacteria was significantly associated with an increased rate of infection by the same pathogen in both transplant procedures. GNB was independently associated with increased mortality at 4 months both in allo-HSCT (hazard ratio, 2.13; 95% confidence interval, 1.45–3.13; P Conclusions Pre-engraftment GNB is an independent factor associated with increased mortality rate at 4 months after auto-HSCT and allo-HSCT. Previous infectious history and colonization monitoring represent major indicators of GNB. Clinical Trials registration NCT02088840.

Published
2017

15. Clonal evolution in relapsed pediatric acute myeloid leukemia without recurrent cytogenetic alterations revealed by whole-exome massively parallel sequencing

Author

Belotti, Tamara

Subjects
MED/38 Pediatria generale e specialistica
Abstract

Nonostante la prognosi dei bambini con leucemia acuta mieloide (LAM) sia migliorata in modo significativo nel corso degli ultimi 30 anni, circa il 30% dei bambini recidiva, facendo di quest’ultima la principale causa di fallimento terapeutico e di morte. Per indagare i meccanismi molecolari alla base recidiva, è stato eseguito il sequenziamento massivo dell’esoma dei campioni di esordio, remissione e recidiva di 4 LAM pediatriche a citogenetica normale mediate tecnologia Illumina, seguito da sequenziamento mirato high coverage (7000X) delle mutazioni somatiche con possibile ruolo patogenetico nello sviluppo della recidiva. La mutazione biCEBPα è stabile e altamente penetrante durante il decorso della malattia (>80% nel clone di esordio e recidiva). Al contrario, le mutazioni di WT1 risultano estremamente instabili. Si configurano specifici pattern molecolari sottostanti alla recidiva, tra i quali l’aberrante attivazione dei segnali proliferativi cellulari (conferito dalle mutazioni di PTPN11 e FLT3-TKD) e l’aumentata resistenza all’apoptosi (iperattivazione di TYK2). Si osserva inoltre un’instabilità genomica conferita dall’inattivazione di SETD2, una metiltransferasi implicata nel mismatch repair, alla base di una maggior plasticità della malattia che contribuisce alla sua evoluzione. Il conseguente accumulo di nuove mutazioni promuove l'adattabilità della leucemia, contribuendo alla selezione clonale. E’ stata inoltre identificata una nuova mutazione di ASXL3, presente in un clone minoritario alla diagnosi (, Despite significant improvement in treatment of childhood acute myeloid leukemia (AML), 30% of patients experience disease recurrence, which is still the major cause of treatment failure and death in these patients. To investigate molecular mechanisms underlying relapse, we performed whole-exome sequencing of diagnosis-relapse pairs and matched remission samples from 4 pediatric AML patients without recurrent cytogenetic alterations. Candidate driver mutations were selected for targeted deep sequencing at high coverage, suitable to detect small subclones (0.12%). BiCEBPa mutation was found to be stable and highly penetrant, representing a separate biological and clinical entity, unlike WT1 mutations, which were extremely unstable. Among the mutational patterns underlying relapse, we detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TKD mutations) and the increased resistance to apoptosis (hyperactivation of TYK2). We also found a previously undescribed feature of AML, consisting of a hypermutator phenotype caused by SETD2 inactivation. The consequent accumulation of new mutations promotes the adaptability of the leukemia, contributing to clonal selection. We report a novel ASXL3 mutation characterizing a very small subclone (

Published
2017

16. Evoluzione clonale nella recidiva della leucemia acuta mieloide nell'eta pediatrica mediante sequenziamento dell'esoma tramite Next Generation Sequencing

Author

Pession, Andrea, Belotti, Tamara <1982>, Pession, Andrea, and Belotti, Tamara <1982>

Abstract

Nonostante la prognosi dei bambini con leucemia acuta mieloide (LAM) sia migliorata in modo significativo nel corso degli ultimi 30 anni, circa il 30% dei bambini recidiva, facendo di quest’ultima la principale causa di fallimento terapeutico e di morte. Per indagare i meccanismi molecolari alla base recidiva, è stato eseguito il sequenziamento massivo dell’esoma dei campioni di esordio, remissione e recidiva di 4 LAM pediatriche a citogenetica normale mediate tecnologia Illumina, seguito da sequenziamento mirato high coverage (7000X) delle mutazioni somatiche con possibile ruolo patogenetico nello sviluppo della recidiva. La mutazione biCEBPα è stabile e altamente penetrante durante il decorso della malattia (>80% nel clone di esordio e recidiva). Al contrario, le mutazioni di WT1 risultano estremamente instabili. Si configurano specifici pattern molecolari sottostanti alla recidiva, tra i quali l’aberrante attivazione dei segnali proliferativi cellulari (conferito dalle mutazioni di PTPN11 e FLT3-TKD) e l’aumentata resistenza all’apoptosi (iperattivazione di TYK2). Si osserva inoltre un’instabilità genomica conferita dall’inattivazione di SETD2, una metiltransferasi implicata nel mismatch repair, alla base di una maggior plasticità della malattia che contribuisce alla sua evoluzione. Il conseguente accumulo di nuove mutazioni promuove l'adattabilità della leucemia, contribuendo alla selezione clonale. E’ stata inoltre identificata una nuova mutazione di ASXL3, presente in un clone minoritario alla diagnosi (<1%) con espansione alla recidiva (60%). In conclusione, la LAM pediatrica è caratterizzata da notevole complessità genomica ed evoluzione clonale. Nello sviluppo della recidiva contribuiscono diversi pathway molecolari che causano aumentata proliferazione, resistenza all’apoptosi e ipermutabilità somatica e si configurano come possibili bersagli di terapie mirate., Despite significant improvement in treatment of childhood acute myeloid leukemia (AML), 30% of patients experience disease recurrence, which is still the major cause of treatment failure and death in these patients. To investigate molecular mechanisms underlying relapse, we performed whole-exome sequencing of diagnosis-relapse pairs and matched remission samples from 4 pediatric AML patients without recurrent cytogenetic alterations. Candidate driver mutations were selected for targeted deep sequencing at high coverage, suitable to detect small subclones (0.12%). BiCEBPa mutation was found to be stable and highly penetrant, representing a separate biological and clinical entity, unlike WT1 mutations, which were extremely unstable. Among the mutational patterns underlying relapse, we detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TKD mutations) and the increased resistance to apoptosis (hyperactivation of TYK2). We also found a previously undescribed feature of AML, consisting of a hypermutator phenotype caused by SETD2 inactivation. The consequent accumulation of new mutations promotes the adaptability of the leukemia, contributing to clonal selection. We report a novel ASXL3 mutation characterizing a very small subclone (<1%) present at diagnosis and undergoing expansion (60%) at relapse. Taken together, these findings provide molecular clues for designing optimal therapeutic strategies, in terms of target selection, adequate schedule design and reliable response-monitoring techniques.

Published
2017

17. A New Formulation of an Old Drug: A Potential New Therapy in the Management of Oral cGvHD

Author

Bertelli, L, Di Nardo, G, Zama, D, Bardasi, G, Morello, W, Masetti, R, Belotti, T, Forchielli, M, Prete, A, Pession, A, Bertelli, Luca, Di Nardo, Giovanni, Zama, Daniele, Bardasi, Giulia, Morello, William, Masetti, Riccardo, Belotti, Tamara, Forchielli, Maria Luisa, Prete, Arcangelo, Pession, Andrea, Bertelli, L, Di Nardo, G, Zama, D, Bardasi, G, Morello, W, Masetti, R, Belotti, T, Forchielli, M, Prete, A, Pession, A, Bertelli, Luca, Di Nardo, Giovanni, Zama, Daniele, Bardasi, Giulia, Morello, William, Masetti, Riccardo, Belotti, Tamara, Forchielli, Maria Luisa, Prete, Arcangelo, and Pession, Andrea

Abstract

Oral chronic graft versus host disease (cGVHD) is often refractory to systemic therapies. Additional topical treatment is commonly required. The potency of the agent, the vehicle and formulation in which it is delivered are all critical factors in determining the effectiveness of topical therapies. High potency of budesonide, combined with its very low bioavailability when absorbed through mucosal surfaces, increased the potential role in topical application for oral cGVHD. Viscous formulation increases mucosal contact time resulting in a greater decrease in mucosal inflammation. This short communication suggests that oral viscous budesonide should be considered as a potential new therapy in the management of oral cGVHD.

Published
2016

18. Genomic complexity and dynamics of clonal evolution in childhood acute myeloid leukemia studied with whole-exome sequencing

Author

Masetti, Riccardo, primary, Castelli, Ilaria, additional, Astolfi, Annalisa, additional, Bertuccio, Salvatore Nicola, additional, Indio, Valentina, additional, Togni, Marco, additional, Belotti, Tamara, additional, Serravalle, Salvatore, additional, Tarantino, Giuseppe, additional, Zecca, Marco, additional, Pigazzi, Martina, additional, Basso, Giuseppe, additional, Pession, Andrea, additional, and Locatelli, Franco, additional

Published
2016
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20. Levofloxacin prophylaxis and parenteral nutrition have a detrimental effect on intestinal microbial networks in pediatric patients undergoing HSCT

Author

Marco Fabbrini, Federica D’Amico, Davide Leardini, Edoardo Muratore, Monica Barone, Tamara Belotti, Maria Luisa Forchielli, Daniele Zama, Andrea Pession, Arcangelo Prete, Patrizia Brigidi, Simone Rampelli, Marco Candela, Silvia Turroni, Riccardo Masetti, Fabbrini, Marco, D'Amico, Federica, Leardini, Davide, Muratore, Edoardo, Barone, Monica, Belotti, Tamara, Forchielli, Maria Luisa, Zama, Daniele, Pession, Andrea, Prete, Arcangelo, Brigidi, Patrizia, Rampelli, Simone, Candela, Marco, Turroni, Silvia, and Masetti, Riccardo

Subjects
microbiota, HSCT, network, metagenomics, Medicine (miscellaneous), General Agricultural and Biological Sciences, General Biochemistry, Genetics and Molecular Biology
Abstract

The gut microbiome (GM) has shown to influence hematopoietic stem cell transplantation (HSCT) outcome. Evidence on levofloxacin (LVX) prophylaxis usefulness before HSCT in pediatric patients is controversial and its impact on GM is poorly characterized. Post-HSCT parenteral nutrition (PN) is oftentimes the first-line nutritional support in the neutropenic phase, despite the emerging benefits of enteral nutrition (EN). In this exploratory work, we used a global-to-local networking approach to obtain a high-resolution longitudinal characterization of the GM in 30 pediatric HSCT patients receiving PN combined with LVX prophylaxis or PN alone or EN alone. By evaluating the network topology, we found that PN, especially preceded by LVX prophylaxis, resulted in a detrimental effect over the GM, with low modularity, poor cohesion, a shift in keystone species and the emergence of modules comprising several pathobionts, such as Klebsiella spp., [Ruminococcus] gnavus, Flavonifractor plautii and Enterococcus faecium. Our pilot findings on LVX prophylaxis and PN-related disruption of GM networks should be considered in patient management, to possibly facilitate prompt recovery/maintenance of a healthy and well-wired GM. However, the impact of LVX prophylaxis and nutritional support on short- to long-term post-HSCT clinical outcomes has yet to be elucidated.

Published
2023

21. Musculoskeletal manifestations of childhood cancer and differential diagnosis with juvenile idiopathic arthritis (ONCOREUM): a multicentre, cross-sectional study

Author

Giovanna Russo, Valentino Conter, M Caniglia, A Garaventa, Giulia Stabile, MF Gicchino, Elisa Rossi, Annalisa Arlotta, S Ladogana, C Atzeni, Rita Consolini, Luciana Vinti, Daniela Onofrillo, Roberto Rondelli, Nicola Santoro, Loredana Lepore, F Locatelli, Elisa Coassin, Monica Ficara, Micol Romano, S Martino, Roberta Burnelli, I Fontanili, Francesca Soscia, Eleonora Prete, Francesca Santarelli, Romina Gallizzi, Patrizia Barone, MG Cefalo, E Cortis, Giovanni Filocamo, M Amatruda, Angela Miniaci, Anna Maria Caroleo, Massimo Eraldo Abate, Maria Cristina Maggio, M Mascarin, Simone Cesaro, E Fabbri, F De Benedetti, Angelo Ravelli, Alma Nunzia Olivieri, C Micalizzi, A Magnolato, B Bigucci, Francesca Ricci, Elisa Tirtei, Antonella Colombini, Luciana Breda, Tamara Belotti, Raffaela De Santis, Roberta Pericoli, Serena Pastore, Silvia Magni-Manzoni, Rosa Anna Podda, Chiara Mainardi, Donato Rigante, Federico Verzegnassi, C Messina, Adele Civino, Cristina Pizzato, M Marsili, Chiara Gorio, Rossella Mura, M Cattalini, Andrea Pession, M Cappella, A Di Cataldo, Francesco La Torre, Assunta Tornesello, Andrea Roncadori, F Porta, Maria Antonietta Pelagatti, F Fagioli, P Bertolini, Ilaria Capolsini, C Rizzari, M Cellini, Bianca Lattanzi, Alessandro De Fanti, S Davì, Carmela De Fusco, Giovanni Alighieri, Andrea Biondi, Civino, Adele, Alighieri, Giovanni, Prete, Eleonora, Maria Caroleo, Anna, SilviaMagni-Manzoni, Vinti, Luciana, Romano, Micol, Santoro, Nicola, Filocamo, Giovanni, Belotti, Tamara, Santarelli, Francesca, Gorio, Chiara, Ricci, Francesca, Colombini, Antonella, Pastore, Serena, Cesaro, Simone, Barone, Patrizia, Verzegnassi, Federico, Olivieri, Alma Nunzia, Ficara, Monica, Miniaci, Angela, Russo, Giovanna, Gallizzi, Romina, Pericoli, Roberta, Breda, Luciana, Mura, Rossella, Annapodda, Rosa, Onofrillo, Daniela, Lattanzi, Bianca, Elisatirtei, Cristina Maggio, Maria, De Santis, Raffaela, Ritaconsolini, Arlotta, Annalisa, La Torre, Francesco, Mainardi, Chiara, Antonietta Pelagatti, Maria, Coassin, Elisa, Capolsini, Ilaria, Burnelli, Roberta, Tornesello, Assunta, Soscia, Francesca, De Fanti, Alessandro, Donatorigante, Pizzato, Cristina, De Fusco, Carmela, Eraldo Abate, Massimo, Roncadori, Andrea, Rossi, Elisa, Stabile, Giulia, Biondi, Andrea, Lepore, Loredana, Conter, Valentino, Rondelli, Roberto, Pession, Andrea, Ravelli, Angelo, Association of Paediatric Haematology and Oncology†and the Italian Paediatric Rheumatology Study Group†, Italian, Amatruda, M, Atzeni, C, Pbertolini, Bigucci, B, Caniglia, M, Cappella, M, Cattalini, M, Cefalo, Mg, Cellini, M, Cortis, E, Davì, S, De Benedetti, F, Di Cataldo, A, Fabbri, E, Fagioli, F, Fontanili, I, Garaventa, A, Gicchino, MARIA FRANCESCA, Ladogana, S, Locatelli, F, Magnolato, A, Marsili, M, Martino, S, Mascarin, M, Messina, C, Micalizzi, C, Porta, F, Rizzari, C, Civino A., Alighieri G., Prete E., Caroleo A.M., Magni-Manzoni S., Vinti L., Romano M., Santoro N., Filocamo G., Belotti T., Santarelli F., Gorio C., Ricci F., Colombini A., Pastore S., Cesaro S., Barone P., Verzegnassi F., Olivieri A.N., Ficara M., Miniaci A., Russo G., Gallizzi R., Pericoli R., Breda L., Mura R., Podda R.A., Onofrillo D., Lattanzi B., Tirtei E., Maggio M.C., De Santis R., Consolini R., Arlotta A., La Torre F., Mainardi C., Pelagatti M.A., Coassin E., Capolsini I., Burnelli R., Tornesello A., Soscia F., De Fanti A., Rigante D., Pizzato C., De Fusco C., Abate M.E., Roncadori A., Rossi E., Stabile G., Biondi A., Lepore L., Conter V., Rondelli R., Pession A., Ravelli A., Amatruda M., Atzeni C., Bertolini P., Bigucci B., Caniglia M., Cappella M., Cattalini M., Cefalo M.G., Cellini M., Cortis E., Davi S., De Benedetti F., Di Cataldo A., Fabbri E., Fagioli F., Fontanili I., Garaventa A., Gicchino M.F., Ladogana S., Locatelli F., Magnolato A., Marsili M., Martino S., Mascarin M., Messina C., Micalizzi C., Porta F., Rizzari C., Civino, A, Alighieri, G, Prete, E, Caroleo, A, Magni-Manzoni, S, Vinti, L, Romano, M, Santoro, N, Filocamo, G, Belotti, T, Santarelli, F, Gorio, C, Ricci, F, Colombini, A, Pastore, S, Cesaro, S, Barone, P, Verzegnassi, F, Olivieri, A, Ficara, M, Miniaci, A, Russo, G, Gallizzi, R, Pericoli, R, Breda, L, Mura, R, Podda, R, Onofrillo, D, Lattanzi, B, Tirtei, E, Maggio, M, De Santis, R, Consolini, R, Arlotta, A, La Torre, F, Mainardi, C, Pelagatti, M, Coassin, E, Capolsini, I, Burnelli, R, Tornesello, A, Soscia, F, De Fanti, A, Rigante, D, Pizzato, C, De Fusco, C, Abate, M, Roncadori, A, Rossi, E, Stabile, G, Biondi, A, Lepore, L, Conter, V, Rondelli, R, Pession, A, Ravelli, A, Bertolini, P, Cefalo, M, Davi, S, and Gicchino, M

Subjects
medicine.medical_specialty, business.industry, Immunology, Arthritis, Cancer, Odds ratio, Musculoskeletal manifestation, Juvenile idiopathic arthritis, medicine.disease, Histiocytosis, Rheumatology, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Prednisone, Internal medicine, Joint pain, Arthropathy, Musculoskeletal manifestations, childhood cancer, juvenile idiopathic arthritis, medicine, childhood cancer, Immunology and Allergy, Differential diagnosis, medicine.symptom, business, medicine.drug
Abstract

Summary Background Presenting symptoms of childhood cancers might mimic those of rheumatic diseases. However, the evidence available to guide differential diagnosis remains scarce. Preventing wrong or delayed diagnosis is therefore important to avoid incorrect administration of glucocorticoid or immunosuppressive therapy and worsening of prognosis. As such, we aimed to assess the prevalence and characteristics of presenting musculoskeletal manifestations in patients at cancer onset and to identify the factors that differentiate childhood malignancies with arthropathy from juvenile idiopathic arthritis. Methods We did a multicentre, cross-sectional study at 25 paediatric haemato-oncology centres and 22 paediatric rheumatology centres in Italy. We prospectively recruited patients who were younger than 16 years that were newly diagnosed with cancer or juvenile idiopathic arthritis. We excluded patients with glucocorticoid pre-treatment (>1 mg/kg per day of oral prednisone or equivalent for ≥2 consecutive weeks). We collected data for patients with a new diagnosis of cancer or juvenile idiopathic arthritis using an electronic case report form on a web-based platform powered by the Cineca Interuniversity Consortium. The primary outcome was to describe the frequency and characteristics of musculoskeletal manifestations at cancer onset; and the secondary outcome was to identify factors that could discriminate malignancies presenting with arthropathy, with or without other musculoskeletal symptoms, from juvenile idiopathic arthritis using multivariable logistic regression analysis. Findings Between May 1, 2015, and May 31, 2018, 1957 patients were eligible, of which 1277 (65%) had cancer and 680 (35%) had juvenile idiopathic arthritis. Musculoskeletal symptoms occurred in 324 (25% [95% CI 23·0–27·8]) of 1277 patients with cancer, of whom 207 had arthropathy. Patients with malignant bone tumours had the highest frequency of musculoskeletal symptoms (53 [80%] of 66), followed by patients with Langerhans histiocytosis (16 [47%] of 34), leukaemia (189 [32%] of 582), soft-tissue sarcomas (16 [24%] of 68), and neuroblastoma (21 [19%] of 109). In the 324 patients with cancer and musculoskeletal symptoms, the most common complaints were joint pain (199 [61%]), followed by limb bone pain (112 [35%]). Joint involvement had a prevalent monoarticular pattern (100 [48%] of 207) and oligoarticular pattern (86 [42%] had 2–4 joints involved and 20 [10%] had >4 joints involved), with the most frequently involved joints being the hip (88 [43%] of 207) and knee (81 [39%]). On multivariable analysis, limb bone pain was the independent variable most strongly associated with cancer (odds ratio [OR] 87·80 [95% CI 18·89–408·12]), followed by weight loss (59·88 [6·34–565·53]), thrombocytopenia (12·67 [2·40–66·92]), monoarticular involvement (11·30 [4·09–31·19]), hip involvement (3·30 [1·13–9·61]), and male sex (2·40 [1·03–5·58]). Factors independently associated with juvenile idiopathic arthritis were morning stiffness (OR 0·04 [95% CI 0·01–0·20]), joint swelling (0·03 [0·01–0·09]), and involvement of the small hand joints (0·02 [0–1·05]). Interpretation Our study provides detailed information about presenting musculoskeletal manifestations of childhood cancers and highlights the clinical and laboratory features that are most helpful in the differential diagnosis with juvenile idiopathic arthritis. Funding Associazione Lorenzo Risolo.

Published
2021

22. Genomic complexity and dynamics of clonal evolution in childhood acute myeloid leukemia studied with whole-exome sequencing

Author

Martina Pigazzi, Giuseppe Tarantino, Annalisa Astolfi, Tamara Belotti, Andrea Pession, Salvatore Serravalle, Giuseppe Basso, Valentina Indio, Marco Togni, Franco Locatelli, Salvatore Nicola Bertuccio, Marco Zecca, Riccardo Masetti, Ilaria Castelli, Masetti, Riccardo, Castelli, Ilaria, Astolfi, Annalisa, Bertuccio, SALVATORE NICOLA, Indio, Valentina, Togni, Marco, Belotti, Tamara, Serravalle, Salvatore, Tarantino, Giuseppe, Zecca, Marco, Pigazzi, Martina, Basso, Giuseppe, Pession, Andrea, and Locatelli, Franco

Subjects
0301 basic medicine, Oncology, Male, medicine.medical_specialty, Adolescent, Pediatric Hematology/Oncology, DNA Mutational Analysis, acute myeloid leukemia relapse, Somatic evolution in cancer, NO, Clonal Evolution, 03 medical and health sciences, Acute myeloid leukemia relapse, FLT3-TKD mutation, Pediatric acute myeloid leukemia, SETD2 mutation, Whole-exome massively parallel sequencing, Internal medicine, medicine, Humans, Exome, Child, Exome sequencing, Massive parallel sequencing, business.industry, Childhood Acute Myeloid Leukemia, Remission Induction, pediatric acute myeloid leukemia, Myeloid leukemia, High-Throughput Nucleotide Sequencing, Genomics, medicine.disease, PTPN11, flt3-tkd mutation, setd2 mutation, whole-exome massively parallel sequencing, Leukemia, Leukemia, Myeloid, Acute, 030104 developmental biology, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Child, Preschool, Immunology, Female, Neoplasm Recurrence, Local, business, Research Paper
Abstract

// Riccardo Masetti 1, * , Ilaria Castelli 1, * , Annalisa Astolfi 2 , Salvatore Nicola Bertuccio 1 , Valentina Indio 2 , Marco Togni 1, 3 , Tamara Belotti 1 , Salvatore Serravalle 1 , Giuseppe Tarantino 2 , Marco Zecca 4 , Martina Pigazzi 5 , Giuseppe Basso 5 , Andrea Pession 1, # , Franco Locatelli 6, 7, # 1 Department of Pediatrics “Lalla Seragnoli”, Hematology-Oncology Unit, University of Bologna, Bologna, Italy 2 Interdepartmental Centre of Cancer Research “G. Prodi”, University of Bologna, Bologna, Italy 3 Current address: Stem Cell Group, University College London Cancer Institute, University College London, London, United Kingdom 4 Department of Pediatric Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy 5 Department of Woman and Child Health, Laboratory of Hematology-Oncology, University of Padova, Padova, Italy 6 Department of Pediatric Hematology-Oncology, IRCCS Ospedale Bambino Gesu, Rome, Italy 7 University of Pavia, Pavia, Italy * These authors have contributed equally to this work # Both authors have shared co-senior authorship Correspondence to: Riccardo Masetti, email: riccardo.masetti@gmail.com Keywords: pediatric acute myeloid leukemia, acute myeloid leukemia relapse, whole-exome massively parallel sequencing, SETD2 mutation, FLT3-TKD mutation Received: April 19, 2016 Accepted: July 10, 2016 Published: July 22, 2016 ABSTRACT Despite significant improvement in treatment of childhood acute myeloid leukemia (AML), 30% of patients experience disease recurrence, which is still the major cause of treatment failure and death in these patients. To investigate molecular mechanisms underlying relapse, we performed whole-exome sequencing of diagnosis-relapse pairs and matched remission samples from 4 pediatric AML patients without recurrent cytogenetic alterations. Candidate driver mutations were selected for targeted deep sequencing at high coverage, suitable to detect small subclones (0.12%). BiCEBPα mutation was found to be stable and highly penetrant, representing a separate biological and clinical entity, unlike WT1 mutations, which were extremely unstable. Among the mutational patterns underlying relapse, we detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TKD mutations) and the increased resistance to apoptosis (hyperactivation of TYK2). We also found a previously undescribed feature of AML, consisting of a hypermutator phenotype caused by SETD2 inactivation. The consequent accumulation of new mutations promotes the adaptability of the leukemia, contributing to clonal selection. We report a novel ASXL3 mutation characterizing a very small subclone (

Published
2016

23. Treatment of steroid-refractory graft versus host disease in children.

Author

Gottardi F, Leardini D, Muratore E, Baccelli F, Cerasi S, Venturelli F, Zanaroli A, Belotti T, Prete A, and Masetti R

Abstract

Systemic steroids are still the first-line approach in acute graft-versus-host disease (aGvHD), and the backbone of chronic GvHD management. Refractoriness to steroid represent a major cause of morbidity and non-relapse mortality after hematopoietic stem cell transplantation (HSCT). In both backgrounds, several second-line immunosuppressive agents have been tested with variable results in terms of efficacy and toxicity. Solid evidence regarding these approaches is still lacking in the pediatric setting where results are mainly derived from adult experiences. Furthermore, the number of treated patients is limited and the incidence of acute and chronic GvHD is lower, resulting in a very heterogeneous approach to this complication by pediatric hematologists. Some conventional therapies and anti-cytokine monoclonal antibodies used in the adult setting have been evaluated in children. In recent years, the increasing understanding of the biological mechanisms underpinning the pathogenesis of GvHD justified the efforts toward the adoption of targeted therapies and non-pharmacologic approaches, with higher response rates and lower immunosuppressive effects. Moreover, many questions regarding the precise timing and setting in which to integrate these new approaches remain unanswered. This Review aims to critically explore the current evidence regarding novel approaches to treat SR-GvHD in pediatric HSCT recipients., Competing Interests: The author (RM) declared that he was an editorial board member of Frontiers at the time of submission. This had no impact on the peer review process and the final decision. The remaining 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., (© 2023 Gottardi, Leardini, Muratore, Baccelli, Cerasi, Venturelli, Zanaroli, Belotti, Prete and Masetti.)

Published
2023
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