87 results on '"Matteo G. Della Porta"'
Search Results
2. Pretransplant active disease status and HLA class II mismatching are associated with increased incidence and severity of cytokine release syndrome after haploidentical transplantation with posttransplant cyclophosphamide
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Clara Di Vito, Lucio Morabito, Carmelo Carlo-Stella, Armando Santoro, Matteo G. Della Porta, Stefania Bramanti, Chiara De Philippis, Jacopo Mariotti, Luca Castagna, Domenico Mavilio, Daniela Taurino, Fabrizio Marino, and Barbara Sarina
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0301 basic medicine ,Male ,Cancer Research ,HLA mismatch ,Transplantation Conditioning ,Graft vs Host Disease ,Kaplan-Meier Estimate ,Gastroenterology ,Severity of Illness Index ,disease burden ,0302 clinical medicine ,Risk Factors ,Cumulative incidence ,Bone Marrow Transplantation ,Original Research ,Univariate analysis ,Incidence (epidemiology) ,Histocompatibility Testing ,Incidence ,Hazard ratio ,haploidentical stem cell transplant with posttransplant cyclophosphamide ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cytokine release syndrome ,Oncology ,030220 oncology & carcinogenesis ,Hematologic Neoplasms ,Female ,Immunosuppressive Agents ,medicine.drug ,Adult ,medicine.medical_specialty ,Cyclophosphamide ,Side effect ,Adolescent ,Risk Assessment ,lcsh:RC254-282 ,03 medical and health sciences ,Young Adult ,Internal medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Aged ,Retrospective Studies ,Peripheral Blood Stem Cell Transplantation ,business.industry ,Clinical Cancer Research ,cytokine release syndrome ,medicine.disease ,Transplantation ,030104 developmental biology ,Transplantation, Haploidentical ,business ,HLA-DRB1 Chains - Abstract
Cytokine release syndrome (CRS) represents a life‐threatening side effect after haploidentical stem cell transplantation (Haplo‐SCT) with posttransplant cyclophosphamide (PT‐Cy). Factors predictive of CRS development is still a matter of debate. We retrospectively analyzed 102 consecutive patients receiving a bone marrow (BM) (n = 42) or peripheral blood stem cells (PBSC) (n = 60) Haplo‐SCT with PT‐Cy. The two cohorts were similar in main patients’ characteristics besides disease type (P = .02). Cumulative incidence of grades 1, 2, and ≥3 CRS was 80%, 52%, and 15% at a median of 2, 4, and 7 days, respectively. Moderate/High‐grade fever (39°‐41°), grade 1 and grade ≥3 CRS occurred more frequently after PBSC relative to BM grafts (68% vs 33%, P = .0005; 87% vs 71%, P = .009; 20% vs 7%, P = .07). Only patients experiencing grade ≥3 CRS had a worse outcome in terms of 1‐year overall survival (OS) and nonrelapse mortality (NRM): 39% vs 80% (P = .002) and 40% vs 8% (P = .005), respectively. By univariate analysis the only factors associated with the increased risk of ≥3 CRS were pretransplant disease status (8% for complete remission, 11% for partial remission, and 38% for active disease, P = .002), HLA‐DRB1 mismatching (57% vs 14%, P = .007), and PBSC graft (P = .07). By multivariable analysis, only pretransplant disease status (hazard ratio, HR: 6.84, P = .005) and HLA‐DRB1 mismatching (HR: 17.19, P = .003) remained independent predictors of grade ≥3 CRS. Only grade ≥3 CRS is clinically relevant for the final outcome of patients receiving Haplo‐SCT with PT‐Cy, is more frequent after a PBSC graft and is associated with pretransplant active disease and HLA‐DRB1 mismatching., Severe cytokine release syndrome (CRS) may occur after T‐cell‐replete haploidentical stem cell transplantation and conditions nonrelapse mortality. Disease burden and HLA mismatch in the graft‐vs‐host‐disease direction are the main factors affecting the occurrence of severe CRS.
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- 2020
3. A prognostic model for patients with lymphoma and COVID-19: a multicentre cohort study
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Francesco Merli, Carlo Visco, Annarita Conconi, Daniele Vallisa, Elettra Ortu La Barbera, Sara Galimberti, Roberto Mina, Marianna Sassone, Anna Guidetti, Adriano Venditti, Alessandro Corso, Francesco Marchesi, Pellegrino Musto, Agostino Tafuri, Valentina Bonuomo, Filippo Gherlinzoni, Francesco Lanza, Monia Marchetti, Safaa M. Ramadan, Marco Salvini, Massimo Massaia, Elisa Coviello, Alessandro Busca, Luigi Petrucci, Daniele Armiento, Mauro Turrini, Alessandra Romano, Chiara Cattaneo, Francesco Passamonti, Matteo G. Della Porta, Anna Candoni, Luigi Rigacci, Luca Arcaini, Livio Trentin, Valeria Cardinali, Maria Chiara Tisi, Carmine Selleri, Carlo Gambacorti-Passerini, Andrés J.M. Ferreri, Patrizia Tosi, Riccardo Bruna, Mauro Krampera, Antonio Cuneo, Nicola Stefano Fracchiolla, Daniela Cilloni, Lorenza Bertù, Paolo Corradini, Annamaria Scattolin, Roberto Cairoli, Giuseppe Visani, Domenico Penna, Marco Ladetto, Antonello Pinto, Michele Cavo, Monica Bocchia, Sofia Pilerci, Luigi Marcheselli, Visco, C, Marcheselli, L, Mina, R, Sassone, M, Guidetti, A, Penna, D, Cattaneo, C, Bonuomo, V, Busca, A, Ferreri, A, Bruna, R, Petrucci, L, Cairoli, R, Salvini, M, Bertu, L, Ladetto, M, Pilerci, S, Pinto, A, Ramadan, S, Marchesi, F, Cavo, M, Arcaini, L, Coviello, E, Romano, A, Musto, P, Massaia, M, Fracchiolla, N, Marchetti, M, Scattolin, A, Tisi, M, Cuneo, A, Porta, M, Trentin, L, Turrini, M, Gherlinzoni, F, Tafuri, A, Galimberti, S, Bocchia, M, Cardinali, V, Cilloni, D, Corso, A, Armiento, D, Rigacci, L, La Barbera, E, Gambacorti Passerini, C, Visani, G, Vallisa, D, Venditti, A, Selleri, C, Conconi, A, Tosi, P, Lanza, F, Candoni, A, Krampera, M, Corradini, P, Passamonti, F, and Merli, F
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Adult ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Aged ,Aged, 80 and over ,Cohort Studies ,Humans ,Middle Aged ,Prognosis ,SARS-CoV-2 ,Young Adult ,COVID-19 ,Lymphoma ,Lymphocyte ,medicine.medical_treatment ,Disease ,NO ,lymphoma, COVID-19, multicentre cohort study, SARS-CoV-2 ,Internal medicine ,medicine ,80 and over ,lymphoma ,covid-19 ,anti-cd20 ,business.industry ,Regular Article ,Immunosuppression ,Hematology ,Settore MED/15 ,medicine.disease ,medicine.anatomical_structure ,Cohort ,Prognostic model ,business ,Cohort study - Abstract
Lymphoma represents a heterogeneous hematological malignancy (HM), which is characterized by severe immunosuppression. Patients diagnosed of coronavirus disease 2019 (COVID-19) during the course of HM have been described to have poor outcome, with only few reports specifically addressing lymphoma patients. Here, we investigated the clinical behavior and clinical parameters of a large multicenter cohort of adult patients with different lymphoma subtypes, with the aim of identifying predictors of death. The study included 856 patients, of whom 619 were enrolled prospectively in a 1-year frame and were followed-up for a median of 66 days (range 1-395). Patients were managed as outpatient (not-admitted cohort, n = 388) or required hospitalization (n = 468), and median age was 63 years (range 19-94). Overall, the 30- and 100-days mortality was 13% (95% confidence interval (CI), 11% to 15%) and 23% (95% CI, 20% to 27%), respectively. Antilymphoma treatment, including anti-CD20 containing regimens, did not impact survival. Patients with Hodgkin’s lymphoma had the more favorable survival, but this was partly related to significantly younger age. The time interval between lymphoma diagnosis and COVID-19 was inversely related to mortality. Multivariable analysis recognized 4 easy-to-use factors (age, gender, lymphocyte, and platelet count) that were associated with risk of death, both in the admitted and in the not-admitted cohort (HR 3.79 and 8.85 for the intermediate- and high-risk group, respectively). Overall, our study shows that patients should not be deprived of the best available treatment of their underlying disease and indicates which patients are at higher risk of death. This study was registered with ClinicalTrials.gov, NCT04352556.
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- 2022
4. Prognostic impact of somatic mutations on time to first treatment: Results of targeted next-generation sequencing in 211 patients with early stage chronic lymphocytic leukemia
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Chiara Cavalloni, Massimo Gentile, Fabio Bergamini, Silvia Zibellini, Matteo G. Della Porta, Anna Gallì, Luca Arcaini, Marzia Varettoni, Sara Rattotti, Ettore Rizzo, Elena Flospergher, Ester Orlandi, Caterina Cristinelli, Nicole Fabbri, Marianna Rossi, and Virginia Valeria Ferretti
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Oncology ,medicine.medical_specialty ,Somatic cell ,business.industry ,Time to first treatment ,Chronic lymphocytic leukemia ,High-Throughput Nucleotide Sequencing ,Hematology ,medicine.disease ,Prognosis ,Leukemia, Lymphocytic, Chronic, B-Cell ,DNA sequencing ,Cohort Studies ,Internal medicine ,Mutation ,medicine ,Humans ,Stage (cooking) ,business - Published
- 2021
5. Thiotepa, Fludarabine, and Busulfan Conditioning Regimen before T Cell–Replete Haploidentical Transplantation with Post-Transplant Cyclophosphamide for Acute Myeloid Leukemia: A Bicentric Experience of 100 Patients
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Matteo G. Della Porta, Raynier Devillier, Angela Granata, Claude Lemarie, Boris Calmels, Samia Harbi, Lucas Castagna, Thomas Pagliardini, Colombe Saillard, Sabine Furst, Pierre-Jean Weiller, Catherine Faucher, Djamel Mokart, Faezeh Legrand, Christian Chabannon, Stefania Bramanti, Didier Blaise, Wang Lining, Norbert Vey, Valerio Maisano, Aude Charbonnier, and Jerome Rey
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,Cyclophosphamide ,T-Lymphocytes ,Graft vs Host Disease ,Disease ,ThioTEPA ,Disease-Free Survival ,hemic and lymphatic diseases ,Internal medicine ,Humans ,Medicine ,Busulfan ,Aged ,Transplantation ,business.industry ,Incidence (epidemiology) ,Myeloid leukemia ,Hematology ,Middle Aged ,Allografts ,Fludarabine ,Survival Rate ,Leukemia, Myeloid, Acute ,surgical procedures, operative ,Chronic Disease ,Female ,business ,Thiotepa ,Vidarabine ,Stem Cell Transplantation ,medicine.drug - Abstract
Haploidentical stem cell transplantation (haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) is an alternative treatment for acute myeloid leukemia (AML) patients who lack HLA-matched donors. Relapse after haplo-SCT remains a major concern, especially after nonmyeloablative conditioning regimens. Promising results were reported for TBF-based conditioning regimens (thiotepa, busulfan, and fludarabine) in patients transplanted from different categories of donors and for various disease types but not specifically in PT-Cy haplo-SCT for AML. Here we evaluate the outcome of 100 AML patients who received haplo-SCT with PT-Cy after TBF conditioning regimens (reduced-intensity conditioning, n = 77; myeloablative conditioning, n = 23) in 2 transplant programs. Cumulative incidences of grades III to IV acute and moderate or severe chronic graft-versus-host disease (GVHD) were 7% and 14%, respectively. NRM at 2 years was 28%, significantly influenced by disease status at haplo-SCT (first complete response [CR1] versus advanced AML: 16% versus 38%, P = .016) but not by conditioning intensity or age. The cumulative incidences of relapse at 2 years were 17% and 24% in CR1 and advanced AML, respectively (not significant). Progression-free survival, overall survival, and GVHD and relapse-free survival at 2 years were 67%, 71%, and 49% in CR1 patients, respectively, whereas comparative values in patients with advanced disease were 37%, 41%, and 32%. Our study suggests that TBF conditioning for PT-Cy haplo-SCT is safe and effective for AML patients in CR1. In patients with more advanced disease, the relatively low incidence of relapse seems counterbalanced by a high nonrelapse mortality, underlining the need for alternative strategies to decrease relapse risk, without increasing the intensity of conditioning regimen.
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- 2019
6. Bortezomib-based therapy in non-transplant multiple myeloma patients: a retrospective cohort study from the FABIO project
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Salvatore Scondotto, Mirko Di Martino, Marilena Romero, Donatella Garau, Ilenia De Carlo, Claudia Vener, Matteo Franchi, Matteo G. Della Porta, Giovanni Corrao, Francesco Passamonti, Ursula Kirchmayer, Chiara Stival, Franchi, M, Vener, C, Garau, D, Kirchmayer, U, Di Martino, M, Romero, M, De Carlo, I, Scondotto, S, Stival, C, Della Porta, M, Passamonti, F, and Corrao, G
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Oncology ,medicine.medical_specialty ,real-world ,Cost effectiveness ,cost-effectivene ,effectiveness ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,Medicine ,030212 general & internal medicine ,cost-effectiveness ,Multiple myeloma ,Original Research ,lcsh:RC633-647.5 ,business.industry ,Bortezomib ,Disease progression ,bortezomib ,multiple myeloma ,Retrospective cohort study ,lcsh:Diseases of the blood and blood-forming organs ,Hematology ,medicine.disease ,030220 oncology & carcinogenesis ,Conventional chemotherapy ,business ,effectivene ,medicine.drug - Abstract
Introduction: Randomized clinical trials showed that bortezomib, in addition to conventional chemotherapy, improves survival and disease progression in multiple myeloma (MM) patients not eligible for stem cell transplantation. The aim of this retrospective population-based cohort study is the evaluation of both clinical and economic profile of bortezomib-based versus conventional chemotherapy in daily clinical practice. Methods: Healthcare utilization databases of six Italian regions were used to identify adult patients with non-transplant MM, who started a first-line therapy with bortezomib-based or conventional chemotherapy. Patients were matched by propensity score and were followed from treatment start until death, lost to follow-up or study end-point. Overall survival (OS) and restricted mean survival time (RMST) were estimated using the Kaplan–Meier method. Association between first-line treatment and risk of death was estimated by a conditional Cox proportional regression model. Average mean cumulative costs were estimated and compared between groups. Results: In the period 2010–2016, 3509 non-transplant MM patients met the inclusion criteria, of which 1157 treated with bortezomib-based therapy were matched to 1826 treated with conventional chemotherapy. Median OS and RMST were 33.9 and 27.9 months, and 42.9 and 38.4 months, respectively, in the two treatment arms. Overall, these values corresponded to a HR of death of 0.79 (95% CI 0.71–0.89) over a time horizon of 84 months. Average cumulative cost were 83,839 € and 54,499 €, respectively, corresponding to an incremental cost-effectiveness ratio of 54,333 € per year of life gained, a cost coherent with the willingness-to-pay thresholds frequently adopted from Western countries. Conclusions: These data suggested that, in a large cohort of non-transplant MM patients treated outside the experimental setting, first-line treatment with bortezomib-based therapy was associated with a favourable effectiveness and cost-effectiveness profile.
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- 2021
7. What changed in the Italian internal medicine and geriatric wards during the lockdown
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M. C. Nava, Ligia J. Dominguez, F. Giofre, S. Dassi, Stella Provini, Roberto Castello, Maria Elena Pipita, Raffaele Landolfi, I. Indiano, S. Schiavone, Renzo Rozzini, Matteo G. Della Porta, A. Cespiati, F. Perticone, G. Bartelloni, Miriam Gino, Maurizio Corsi, Lina Falanga, R. Di Quattro, G. Orio, Salvatore Piro, Antonio Mirijello, Alessio Molfino, L. Biondi, Leonardo A. Sechi, Luciano Ottonello, Marco Bertolotti, C. Sidoli, G. Colombo, C. Bussolino, A. Delitala, P. M. Mannucci, Luigina Guasti, Antonio Nouvenne, Marta Di Pasquale, P. Peasso, E. Favale, A. Volpini, Giulia Costanzo, C. Margaria, S. Morganti, Guido Moreo, F. Nasso, S. Dolenti, Enrico Strocchi, Laura Stefani, Cristian Petri, M. M. De Amicis, Maria Domenica Cappellini, E. Magnolfi, G. Principato, Fabio Fabbian, G. D'Aurizio, M. V. Libbra, Fabrizio Fabris, Michela Zanetti, P. Tarsitani, V. Piccinelli, R. Caruso, Andrea Artoni, G. Argiolas, A. D. Di Mauro, C. Custodero, Angela Sciacqua, Gabriella Gruden, Anna Ludovica Fracanzani, A. Falcetta, M. L. Matacena, E. Ianniello, G. Bogoni, M. Soldati, P. Agosti, Patrizia Mecocci, Benedetta Marigliano, Chiara Lonati, Luca Zanoli, Massimo Raspanti, F. Gandolfo, C. Catena, Paolo Rossi, Francesco Salerno, Carlotta Franchi, A. Gennaro, P. Bocchi, Elena Silvestri, R. Leonardi, Raffaella Rossio, M. Vanoli, V. Gioffre, L. Fondrieschi, B. D'Avanzo, N. Scaramellini, S. Del Giacco, A. da Porto, G. Serafini, I. Rossi, Giuseppe Palasciano, R. Gonella, Alice Valoriani, Antonella Afeltra, Filippo Alessandro Montalto, C. Antonucci, Giorgio Galanti, F. Montecucco, I. Aiello, Giuseppe Natoli, Antonio Brucato, C. Di Gennaro, Marco Zoli, Teresa Salvatore, Maria Ester Modeo, Mosè Bartone, Ilaria Ardoino, Flora Peyvandi, E. Simeone, Y. Grassi, Paolo Gallo, S. Leoni, S. Buffelli, Giacomo Emmi, Antonio Cittadini, Maria Teresa Guagnano, F. Corica, Giorgio Basile, G. Oberti, Giulia Grignani, G. Vannini, B. Graziella, A De Giorgi, Roberto Tarquini, G. M. De Vincenzo, M. Fogliati, G. Famularo, Antonio Picardi, Chiara Mussi, Andrea Maria Maresca, M. Pisati, Silvia Prolo, Domenico Girelli, Maurizio Muscaritoli, E. Amoruso, Silvia Ghidoni, Marco Vincenzo Lenti, Caterina Mengoli, Vanessa Bianconi, Carlo Vigorito, M. Galassi, A. Di Pino, M. Bellan, M. Girino, F. Bellone, V. Beccati, Luigi Anastasio, Laura Cortesi, M. Mattioli, Giuseppe Montalto, Gino Roberto Corazza, S. Fragapani, M. V. Rabuini, Pietro Minuz, Lara Caserza, R. Battaglia, F. Cacioppo, D. Cerminara, S. Di Marca, Gian Paolo Ceda, V. Beneduce, A. Ballestrero, Giuseppe Montrucchio, G. De Luca, G. P. Fra, Vincenzo Stanghellini, Raffaele Maio, A. Cavarape, N. Passariello, F. Berti, Patrizia Suppressa, Benedetta Stancanelli, A. Giorgi, Marta Rizzo, L. Colangelo, Massimo Montalto, A. Pilotto, Anna Licata, Francesco Violi, M. S. Pisciotta, Maria Perticone, Giuseppe Zuccalà, Virginia Boccardi, L. Ricevuti, Alessandra Marengoni, Giuseppe Romanelli, V. Saracco, Paola Riva, Giuseppe Paolisso, Alessandro Nobili, Francesco Saverio Vella, S. Tiraboschi, G. Pallini, G. Vischi, Nicola Lucio Liberato, R. Tiseo, Valter Monzani, Marcello Maggio, G. Damiani, G. Leoncini, M. Sanino, M. Cesari, Luana Castiglioni, G. Miglio, Luciano Rinaldi, M. Cilli, T. de Falco, C. Ricozzi, F. Tolloso, R. D. Diprizio, M. Berria, S. Mularo, A. Comitangelo, Carmelinda Ruggiero, Eugenio Ruggeri, Claudio Borghi, Tiziana Tognin, Antonino Catalano, A. Simili, Agostino Gaudio, Mario Barbagallo, Emanuela Miceli, Luca Pasina, A. Vignali, Alessandro Salvi, Giuseppe Delitala, Elena Succurro, Maria Antonietta Bleve, Alessio Novella, Sergio Harari, D. Sola, A. Dal Col, A. Di Sabatino, F. Ferrando, Enrico Petrillo, Francesco Baffa Bellucci, Andrea Ticinesi, L. La Malfa, Davide Firinu, Franco Arturi, Umberto Vespasiani Gentilucci, Lorenzo Malatino, Alessandra Bettiol, Valeria Savojardo, Francesca Mete, R. Quadri, Mancuso G, G. Pina, C. Poletto, G. Colussi, Sarah Damanti, Ginevra De Marchi, Graziana Lupattelli, Mario Pirisi, Pietro Castellino, A. Greco, Marta Clerici, Michela Novelli, Giulia Lancellotti, R. Volpi, R. Scurti, T. Prandini, Marco Carbone, E.A. Pulixi, Gianni Biolo, S. del Vecchio, W. Capeci, Tiziana Meschi, Luigi Fenoglio, Giovanna Fabio, R. Ghio, Francesco Cipollone, Leonardo Campiotti, G. P. Martino, Michela Pasino, Maria Grazia Serra, A. Bragagni, Roberto Pontremoli, Salvatore Corrao, Mauro Tettamanti, C. Catalano, L. Monaco, S. Berra, Alice Grossi, Giuseppe Bellelli, G. N. Imperiale, C. Principato, Gabriele Mascherini, E. Larovere, A. Pietrangelo, Giancarlo Labbadia, Fabiana Busti, I. Bertozzi, F. Napoli, Domenico Prisco, G. Nobili, Carlo Sabbà, Francesco Purrello, P. Pettinari, B. Tassone, G. Ceriani, G. Scanzi, S. Baldassarre, I. Mattioli, G. Sigon, Costanza Caccia Dominioni, Alessandro Squizzato, C. Gracin, Benedetta Boari, Roberto Manfredini, M. Grossi, Salvatore Minisola, Daniela Calipari, R. Alcidi, D. Lucente, V. Terranova, D'Avanzo B., Nobili A., Tettamanti M., Pasina L., Mannucci P.M., Pietrangelo A., Perticone F., Violi F., Corazza G.R., Corrao S., Marengoni A., Salerno F., Cesari M., Franchi C., Cortesi L., Miglio G., Ardoino I., Novella A., Prisco D., Silvestri E., Emmi G., Bettiol A., Mattioli I., Biolo G., Zanetti M., Bartelloni G., Vanoli M., Grignani G., Pulixi E.A., Lupattelli G., Bianconi V., Alcidi R., Girelli D., Busti F., Marchi G., Barbagallo M., Dominguez L., Beneduce V., Cacioppo F., Natoli G., Mularo S., Raspanti M., Zoli M., Matacena M.L., Orio G., Magnolfi E., Serafini G., Simili A., Palasciano G., Modeo M.E., Di Gennaro C., Cappellini M.D., Fabio G., de Amicis M.M., de Luca G., Scaramellini N., Rossi P.D., Damanti S., Clerici M., Leoni S., Di Mauro A.D., Di Sabatino A., Miceli E., Lenti M.V., Pisati M., Dominioni C.C., Pontremoli R., Beccati V., Nobili G., Leoncini G., Anastasio L., Carbone M., Cipollone F., Guagnano M.T., Rossi I., Mancuso G., Calipari D., Bartone M., Delitala G., Berria M., Delitala A., Muscaritoli M., Molfino A., Petrillo E., Giorgi A., Gracin C., Zuccala G., D'Aurizio G., Romanelli G., Volpini A., Lucente D., Picardi A., Gentilucci U.V., Gallo P., Bellelli G., Corsi M., Antonucci C., Sidoli C., Principato G., Arturi F., Succurro E., Tassone B., Giofre F., Serra M.G., Bleve M.A., Brucato A., de Falco T., Fabris F., Bertozzi I., Bogoni G., Rabuini M.V., Prandini T., Manfredini R., Fabbian F., Boari B., de Giorgi A., Tiseo R., Paolisso G., Rizzo M.R., Catalano C., Borghi C., Strocchi E., Ianniello E., Soldati M., Schiavone S., Bragagni A., Sabba C., Vella F.S., Suppressa P., de Vincenzo G.M., Comitangelo A., Amoruso E., Custodero C., Fenoglio L., Falcetta A., Fracanzani A.L., Tiraboschi S., Cespiati A., Oberti G., Sigon G., Peyvandi F., Rossio R., Colombo G., Agosti P., Monzani V., Savojardo V., Ceriani G., Pallini G., Montecucco F., Ottonello L., Caserza L., Vischi G., Liberato N.L., Tognin T., Purrello F., Di Pino A., Piro S., Rozzini R., Falanga L., Pisciotta M.S., Bellucci F.B., Buffelli S., Montrucchio G., Peasso P., Favale E., Poletto C., Margaria C., Sanino M., Guasti L., Castiglioni L., Maresca A., Squizzato A., Campiotti L., Grossi A., Diprizio R.D., Bertolotti M., Mussi C., Lancellotti G., Libbra M.V., Galassi M., Grassi Y., Greco A., Sciacqua A., Perticone M., Battaglia R., Maio R., Stanghellini V., Ruggeri E., del Vecchio S., Salvi A., Leonardi R., Damiani G., Capeci W., Mattioli M., Martino G.P., Biondi L., Pettinari P., Ghio R., Dal Col A., Minisola S., Colangelo L., Cilli M., Labbadia G., Afeltra A., Marigliano B., Pipita M.E., Castellino P., Zanoli L., Gennaro A., Gaudio A., Saracco V., Fogliati M., Bussolino C., Mete F., Gino M., Vigorito C., Cittadini A., Moreo G., Prolo S., Pina G., Ballestrero A., Ferrando F., Gonella R., Cerminara D., Berra S., Dassi S., Nava M.C., Graziella B., Baldassarre S., Fragapani S., Gruden G., Galanti G., Mascherini G., Petri C., Stefani L., Girino M., Piccinelli V., Nasso F., Gioffre V., Pasquale M., Sechi L., Catena C., Colussi G., Cavarape A., da Porto A., Passariello N., Rinaldi L., Berti F., Famularo G., Tarsitani P., Castello R., Pasino M., Ceda G.P., Maggio M.G., Morganti S., Artoni A., Grossi M., Del Giacco S., Firinu D., Costanzo G., Argiolas G., Montalto G., Licata A., Montalto F.A., Corica F., Basile G., Catalano A., Bellone F., Principato C., Malatino L., Stancanelli B., Terranova V., Di Marca S., Di Quattro R., la Malfa L., Caruso R., Mecocci P., Ruggiero C., Boccardi V., Meschi T., Ticinesi A., Nouvenne A., Minuz P., Fondrieschi L., Imperiale G.N., Pirisi M., Fra G.P., Sola D., Bellan M., Porta M., Riva P., Quadri R., Larovere E., Novelli M., Scanzi G., Mengoli C., Provini S., Ricevuti L., Simeone E., Scurti R., Tolloso F., Tarquini R., Valoriani A., Dolenti S., Vannini G., Volpi R., Bocchi P., Vignali A., Harari S., Lonati C., Napoli F., Aiello I., Landolfi R., Montalto M., Mirijello A., Ghidoni S., Salvatore T., Monaco L., Ricozzi C., Pilotto A., Indiano I., Gandolfo F., D'Avanzo, B, Nobili, A, Tettamanti, M, Pasina, L, Mannucci, P, Bellelli, G, D'Avanzo, B., Nobili, A., Tettamanti, M., Pasina, L., Mannucci, P. M., Pietrangelo, A., Perticone, F., Violi, F., Corazza, G. R., Corrao, S., Marengoni, A., Salerno, F., Cesari, M., Franchi, C., Cortesi, L., Miglio, G., Ardoino, I., Novella, A., Prisco, D., Silvestri, E., Emmi, G., Bettiol, A., Mattioli, I., Biolo, G., Zanetti, M., Bartelloni, G., Vanoli, M., Grignani, G., Pulixi, E. A., Lupattelli, G., Bianconi, V., Alcidi, R., Girelli, D., Busti, F., Marchi, G., Barbagallo, M., Dominguez, L., Beneduce, V., Cacioppo, F., Natoli, G., Mularo, S., Raspanti, M., Zoli, M., Matacena, M. L., Orio, G., Magnolfi, E., Serafini, G., Simili, A., Palasciano, G., Modeo, M. E., Di Gennaro, C., Cappellini, M. D., Fabio, G., de Amicis, M. M., de Luca, G., Scaramellini, N., Rossi, P. D., Damanti, S., Clerici, M., Leoni, S., Di Mauro, A. D., Di Sabatino, A., Miceli, E., Lenti, M. V., Pisati, M., Dominioni, C. C., Pontremoli, R., Beccati, V., Nobili, G., Leoncini, G., Anastasio, L., Carbone, M., Cipollone, F., Guagnano, M. T., Rossi, I., Mancuso, G., Calipari, D., Bartone, M., Delitala, G., Berria, M., Delitala, A., Muscaritoli, M., Molfino, A., Petrillo, E., Giorgi, A., Gracin, C., Zuccala, G., D'Aurizio, G., Romanelli, G., Volpini, A., Lucente, D., Picardi, A., Gentilucci, U. V., Gallo, P., Bellelli, G., Corsi, M., Antonucci, C., Sidoli, C., Principato, G., Arturi, F., Succurro, E., Tassone, B., Giofre, F., Serra, M. G., Bleve, M. A., Brucato, A., de Falco, T., Fabris, F., Bertozzi, I., Bogoni, G., Rabuini, M. V., Prandini, T., Manfredini, R., Fabbian, F., Boari, B., de Giorgi, A., Tiseo, R., Paolisso, G., Rizzo, M. R., Catalano, C., Borghi, C., Strocchi, E., Ianniello, E., Soldati, M., Schiavone, S., Bragagni, A., Sabba, C., Vella, F. S., Suppressa, P., de Vincenzo, G. M., Comitangelo, A., Amoruso, E., Custodero, C., Fenoglio, L., Falcetta, A., Fracanzani, A. L., Tiraboschi, S., Cespiati, A., Oberti, G., Sigon, G., Peyvandi, F., Rossio, R., Colombo, G., Agosti, P., Monzani, V., Savojardo, V., Ceriani, G., Pallini, G., Montecucco, F., Ottonello, L., Caserza, L., Vischi, G., Liberato, N. L., Tognin, T., Purrello, F., Di Pino, A., Piro, S., Rozzini, R., Falanga, L., Pisciotta, M. S., Bellucci, F. B., Buffelli, S., Montrucchio, G., Peasso, P., Favale, E., Poletto, C., Margaria, C., Sanino, M., Guasti, L., Castiglioni, L., Maresca, A., Squizzato, A., Campiotti, L., Grossi, A., Diprizio, R. D., Bertolotti, M., Mussi, C., Lancellotti, G., Libbra, M. V., Galassi, M., Grassi, Y., Greco, A., Sciacqua, A., Perticone, M., Battaglia, R., Maio, R., Stanghellini, V., Ruggeri, E., del Vecchio, S., Salvi, A., Leonardi, R., Damiani, G., Capeci, W., Mattioli, M., Martino, G. P., Biondi, L., Pettinari, P., Ghio, R., Dal Col, A., Minisola, S., Colangelo, L., Cilli, M., Labbadia, G., Afeltra, A., Marigliano, B., Pipita, M. E., Castellino, P., Zanoli, L., Gennaro, A., Gaudio, A., Saracco, V., Fogliati, M., Bussolino, C., Mete, F., Gino, M., Vigorito, C., Cittadini, A., Moreo, G., Prolo, S., Pina, G., Ballestrero, A., Ferrando, F., Gonella, R., Cerminara, D., Berra, S., Dassi, S., Nava, M. C., Graziella, B., Baldassarre, S., Fragapani, S., Gruden, G., Galanti, G., Mascherini, G., Petri, C., Stefani, L., Girino, M., Piccinelli, V., Nasso, F., Gioffre, V., Pasquale, M., Sechi, L., Catena, C., Colussi, G., Cavarape, A., da Porto, A., Passariello, N., Rinaldi, L., Berti, F., Famularo, G., Tarsitani, P., Castello, R., Pasino, M., Ceda, G. P., Maggio, M. G., Morganti, S., Artoni, A., Grossi, M., Del Giacco, S., Firinu, D., Costanzo, G., Argiolas, G., Montalto, G., Licata, A., Montalto, F. A., Corica, F., Basile, G., Catalano, A., Bellone, F., Principato, C., Malatino, L., Stancanelli, B., Terranova, V., Di Marca, S., Di Quattro, R., la Malfa, L., Caruso, R., Mecocci, P., Ruggiero, C., Boccardi, V., Meschi, T., Ticinesi, A., Nouvenne, A., Minuz, P., Fondrieschi, L., Imperiale, G. N., Pirisi, M., Fra, G. P., Sola, D., Bellan, M., Porta, M., Riva, P., Quadri, R., Larovere, E., Novelli, M., Scanzi, G., Mengoli, C., Provini, S., Ricevuti, L., Simeone, E., Scurti, R., Tolloso, F., Tarquini, R., Valoriani, A., Dolenti, S., Vannini, G., Volpi, R., Bocchi, P., Vignali, A., Harari, S., Lonati, C., Napoli, F., Aiello, I., Landolfi, R., Montalto, M., Mirijello, A., Ghidoni, S., Salvatore, T., Monaco, L., Ricozzi, C., Pilotto, A., Indiano, I., and Gandolfo, F.
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2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Aged ,Humans ,Italy ,Hospitals ,Internal Medicine ,MEDLINE ,geriatric ,Socio-culturale ,law.invention ,lockdown ,Hospital ,Patient Transport ,law ,Pandemic ,Hospital discharge ,medicine ,Aged, Hospitals, Humans, Internal Medicine, Italy ,Letter to the Editor ,Internal medicine ,LS7_9 ,business.industry ,geriatric patients ,medicine.disease ,Intensive care unit ,Internal medicine, geriatric patients, lockdown, covid-19 ,covid-19 ,Medical emergency ,business ,Human - Abstract
A total of 48 internal medicine or geriatric wards among the 93 adhering to the register REPOSI answered an online questionnaire aimed to investigate the characteristics and activities of converted and non-converted wards in the crucial period of the first wave of the epidemic, 22 February-4 May 2020
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- 2021
8. Clinical relevance of clonal hematopoiesis in persons aged ≥80 years
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Aurelio Malabaila, Maria De Santis, Paolo Detoma, Erica Travaglino, Alessia A. Galbussera, Elena Saba, Emma Riva, Rocco Piazza, Marta Ubezio, Maria Elena Bicchieri, Armando Santoro, Gianluigi Condorelli, Matteo Bersanelli, Sara Mandelli, Chiara Chiereghin, George S. Vassiliou, Stefano Duga, Paola Allavena, Francesco Passamonti, Efrem Civilini, Claudia Sala, Matteo Zampini, Luca Sala, Giovanni Corrao, Francesc Solé, Uwe Platzbecker, Karolina Malik, Ettore Mosca, N. Manes, Matteo G. Della Porta, Ugo Lucca, Alessia Campagna, Claudia Saitta, Mauro Tettamanti, Torsten Haferlach, Gastone Castellani, Wolfgang Kern, Laura Giordano, Clelia Peano, Giulia Soldà, Cristina Astrid Tentori, Giulia Maggioni, Stefano Rosso, Manja Meggendorfer, Roberto Zanetti, Chiara Milanesi, Elena Riva, Rosanna Asselta, Pierre Fenaux, Alberto Termanini, Marianna Rossi, Niccolo Bolli, Carlo Selmi, Lucio Morabito, Antonio Russo, Rossi M., Meggendorfer M., Zampini M., Tettamanti M., Riva E., Travaglino E., Bersanelli M., Mandelli S., Antonella Galbussera A., Mosca E., Saba E., Chiereghin C., Manes N., Milanesi C., Ubezio M., Morabito L., Peano C., Solda G., Asselta R., Duga S., Selmi C., De Santis M., Malik K., Maggioni G., Bicchieri M., Campagna A., Tentori C.A., Russo A., Civilini E., Allavena P., Piazza R., Corrao G., Sala C., Termanini A., Giordano L., Detoma P., Malabaila A., Sala L., Rosso S., Zanetti R., Saitta C., Condorelli G., Passamonti F., Santoro A., Sole F., Platzbecker U., Fenaux P., Bolli N., Castellani G., Kern W., Vassiliou G.S., Haferlach T., Lucca U., Della Porta M.G., Rossi, M, Meggendorfer, M, Zampini, M, Tettamanti, M, Riva, E, Travaglino, E, Bersanelli, M, Mandelli, S, Galbussera, A, Mosca, E, Saba, E, Chiereghin, C, Manes, N, Milanesi, C, Ubezio, M, Morabito, L, Peano, C, Soldà, G, Asselta, R, Duga, S, Selmi, C, De Santis, M, Malik, K, Maggioni, G, Bicchieri, M, Campagna, A, Tentori, C, Russo, A, Civilini, E, Allavena, P, Piazza, R, Corrao, G, Sala, C, Termanini, A, Giordano, L, Detoma, P, Malabaila, A, Sala, L, Rosso, S, Zanetti, R, Saitta, C, Condorelli, G, Passamonti, F, Santoro, A, Sole, F, Platzbecker, U, Fenaux, P, Bolli, N, Castellani, G, Kern, W, Vassiliou, G, Haferlach, T, Lucca, U, and Della Porta, M
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Oncology ,Male ,Myeloid ,Coronary Disease ,Biochemistry ,Arthritis, Rheumatoid ,hemic and lymphatic diseases ,aged adult ,80 and over ,follow-up ,cytopenia ,Age Factor ,Aged, 80 and over ,Myeloid Neoplasia ,medicine.diagnostic_test ,Age Factors ,leukemia ,vascular disease ,Hematology ,anemia ,myeloid neoplasms ,Leukemia ,Haematopoiesis ,medicine.anatomical_structure ,Leukemia, Myeloid ,hematopoiesi ,Female ,Human ,medicine.medical_specialty ,Anemia ,Immunology ,Myelodysplastic Syndrome ,Myeloid Neoplasm ,Internal medicine ,medicine ,clonal hematopoiesis ,Humans ,mean corpuscular volume analyse ,Clinical significance ,coronary heart disease ,Red blood cell indices ,Cytopenia ,business.industry ,mutational screening ,Cell Biology ,medicine.disease ,Myelodysplastic Syndromes ,Mutation ,Clonal Hematopoiesi ,business ,hematologic neoplasm - Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.
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- 2021
9. COVID-19 elicits an impaired antibody response against SARS-CoV-2 in patients with haematological malignancies
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Francesco Zaja, Filippo Gherlinzoni, Anna Maria Scattolin, Luca Arcaini, Roberto Cairoli, Mario Luppi, Carmen Fava, Patrizia Zappasodi, Matteo G. Della Porta, Monica Bocchia, Valeria Cardinali, Nicola Stefano Fracchiolla, Francesco Passamonti, Giuseppe Visani, M. Ladetto, Enrico Derenzini, Lorenza Bertù, Roberto Mina, Daniele Armiento, B. Mora, Anna Candoni, Alessandro Corso, A. M. Vannucchi, Paolo Corradini, Francesco Lanza, Pellegrino Musto, Agostino Tafuri, Carlo Visco, E. Coviello, Francesco Marchesi, Roberto M. Lemoli, Chiara Cattaneo, Alessandro Busca, Marco Salvini, Sara Galimberti, I. Romano, M. Merli, Mauro Krampera, Alessandra Romano, Paolo Grossi, Michele Cavo, E. O. La Barbera, Mauro Turrini, Livio Pagano, Adriano Venditti, Antonio Pinto, Patrizia Tosi, F. Farina, Riccardo Bruna, L. Petrucci, Massimo Massaia, Monia Marchetti, Carlo Gambacorti Passerini, Francesco Merli, Passamonti, F, Romano, A, Salvini, M, Merli, F, Porta, M, Bruna, R, Coviello, E, Romano, I, Cairoli, R, Lemoli, R, Farina, F, Venditti, A, Busca, A, Ladetto, M, Massaia, M, Pinto, A, Arcaini, L, Tafuri, A, Marchesi, F, Fracchiolla, N, Bocchia, M, Armiento, D, Candoni, A, Krampera, M, Luppi, M, Cardinali, V, Galimberti, S, Cattaneo, C, La Barbera, E, Mina, R, Lanza, F, Visani, G, Musto, P, Petrucci, L, Zaja, F, Grossi, P, Bertu, L, Pagano, L, Corradini, P, Derenzini, E, Marchetti, M, Scattolin, A, Corso, A, Tosi, P, Gherlinzoni, F, Gambacorti Passerini, C, Cavo, M, Fava, C, Turrini, M, Visco, C, Zappasodi, P, Merli, M, Mora, B, Vannucchi, A, Passamonti F., Romano A., Salvini M., Merli F., Porta M.G.D., Bruna R., Coviello E., Romano I., Cairoli R., Lemoli R., Farina F., Venditti A., Busca A., Ladetto M., Massaia M., Pinto A., Arcaini L., Tafuri A., Marchesi F., Fracchiolla N., Bocchia M., Armiento D., Candoni A., Krampera M., Luppi M., Cardinali V., Galimberti S., Cattaneo C., La Barbera E.O., Mina R., Lanza F., Visani G., Musto P., Petrucci L., Zaja F., Grossi P.A., Bertu L., Pagano L., Corradini P., Derenzini E., Marchetti M., Scattolin A.M., Corso A., Tosi P., Gherlinzoni F., Passerini C.G., Cavo M., Fava C., Turrini M., Visco C., Zappasodi P., Merli M., Mora B., Vannucchi A.M., Passamonti, F., Romano, A., Salvini, M., Merli, F., Porta, M. G. D., Bruna, R., Coviello, E., Romano, I., Cairoli, R., Lemoli, R., Farina, F., Venditti, A., Busca, A., Ladetto, M., Massaia, M., Pinto, A., Arcaini, L., Tafuri, A., Marchesi, F., Fracchiolla, N., Bocchia, M., Armiento, D., Candoni, A., Krampera, M., Luppi, M., Cardinali, V., Galimberti, S., Cattaneo, C., La Barbera, E. O., Mina, R., Lanza, F., Visani, G., Musto, P., Petrucci, L., Zaja, F., Grossi, P. A., Bertu, L., Pagano, L., Corradini, P., Derenzini, E., Marchetti, M., Scattolin, A. M., Corso, A., Tosi, P., Gherlinzoni, F., Passerini, C. G., Cavo, M., Fava, C., Turrini, M., Visco, C., Zappasodi, P., Merli, M., Mora, B., and Vannucchi, A. M.
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Male ,Myeloid ,Antibodies, Viral ,Gastroenterology ,SARS‐CoV‐2 ,80 and over ,Covid-19 ,SARS-CoV-2 ,leukemia ,lymphoma ,myeloma ,Viral ,Covid‐19 ,Aged, 80 and over ,biology ,Hematology ,Plasma cell neoplasm ,Middle Aged ,Adult ,Aged ,COVID-19 ,Female ,Hematologic Neoplasms ,Humans ,Immunoglobulin G ,Seroconversion ,Young Adult ,Antibody Formation ,Leukemia ,medicine.anatomical_structure ,Antibody ,Human ,medicine.medical_specialty ,Short Report ,Antibodies ,NO ,Chemoimmunotherapy ,Internal medicine ,medicine ,Hematologic Neoplasm ,business.industry ,Odds ratio ,Settore MED/15 ,medicine.disease ,Covid-19, SARS-CoV-2, leukemia, lymphoma, myeloma ,Lymphoma ,Settore MED/15 - MALATTIE DEL SANGUE ,biology.protein ,business - Abstract
COVID-19 is associated with high mortality in patients with haematological malignancies (HM) and rate of seroconversion is unknown. The ITA-HEMA-COV project (NCT04352556) investigated patterns of seroconversion for SARS-CoV-2 IgG in patients with HMs. A total of 237 patients, SARS-CoV-2 PCR-positive with at least one SARS-CoV-2 IgG test performed during their care, entered the analysis. Among these, 62 (26·2%) had myeloid, 121 (51·1%) lymphoid and 54 (22·8%) plasma cell neoplasms. Overall, 69% of patients (164 of 237) had detectable IgG SARS-CoV-2 serum antibodies. Serologically negative patients (31%, 73 of 237) were evenly distributed across patients with myeloid, lymphoid and plasma cell neoplasms. In the multivariable logistic regression, chemoimmunotherapy [odds ratio (OR), 3·42; 95% confidence interval (CI), 1·04–11·21; P=0·04] was associated with a lower rate of seroconversion. This effect did not decline after 180days from treatment withdrawal (OR, 0·35; 95% CI: 0·11–1·13; P=0·08). This study demonstrates a low rate of seroconversion in HM patients and indicates that treatment-mediated immune dysfunction is the main driver. As a consequence, we expect a low rate of seroconversion after vaccination and thus we suggest testing the efficacy of seroconversion in HM patients.
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- 2021
10. The SPID-GBA study: Sex distribution, Penetrance, Incidence, and Dementia in GBA-PD
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Valeria Rimoldi, Giada Melistaccio, Ugo Lucca, Anna Zecchinelli, Stefano Duga, Alessio Di Fonzo, Gianni Pezzoli, Letizia Straniero, Rosanna Asselta, Matteo G. Della Porta, Roberto Cilia, Giulia Solda, Massimo Aureli, and Salvatore Bonvegna
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0301 basic medicine ,medicine.medical_specialty ,Disease ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,mental disorders ,medicine ,Dementia ,Genetics (clinical) ,business.industry ,Dementia with Lewy bodies ,Incidence (epidemiology) ,Parkinsonism ,Odds ratio ,medicine.disease ,Penetrance ,Confidence interval ,030104 developmental biology ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
ObjectiveTo provide a variant-specific estimate of incidence, penetrance, sex distribution, and association with dementia of the 4 most common Parkinson disease (PD)-associated GBA variants, we analyzed a large cohort of 4,923 Italian unrelated patients with primary degenerative parkinsonism (including 3,832 PD) enrolled in a single tertiary care center and 7,757 ethnically matched controls.MethodsThe p.E326K, p.T369M, p.N370S, and p.L444P variants were screened using an allele-specific multiplexed PCR approach. All statistical procedures were performed using R or Plink v1.07.ResultsAmong the 4 analyzed variants, the p.L444P confirmed to be the most strongly associated with disease risk for PD, PD dementia (PDD), and dementia with Lewy bodies (DLB) (odds ratio [OR] for PD 15.63, 95% confidence interval [CI] = 8.04–30.37, p = 4.97*10−16; OR for PDD 29.57, 95% CI = 14.07–62.13, p = 3.86*10−19; OR for DLB 102.7, 95% CI = 31.38–336.1, p = 1.91*10−14). However, an unexpectedly high risk for dementia was conferred by p.E326K (OR for PDD 4.80, 95% CI = 2.87–8.02, p = 2.12*10−9; OR for DLB 12.24, 95% CI = 4.95–30.24, p = 5.71*10−8), which, on the basis of the impact on glucocerebrosidase activity, would be expected to be mild. The 1.5–2:1 male sex bias described in sporadic PD was lost in p.T369M carriers. We also showed that PD penetrance for p.L444P could reach the 15% at age 75 years.ConclusionsWe report a large monocentric study on GBA-PD assessing mutation-specific data on the sex distribution, penetrance, incidence, and association with dementia of the 4 most frequent deleterious variants in GBA.
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- 2020
11. Platelet count predicts driver mutations' co-occurrence in low JAK2 mutated essential thrombocythemia and myelofibrosis
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Daniela Barraco, Matteo G. Della Porta, Raffaella Accetta, Daniela Pietra, Marta Ubezio, Francesco Pallotti, Barbara Mora, Margherita Maffioli, Laura Libera, Rosario Casalone, Francesco Passamonti, Michele Merli, Chiara Trotti, Ilaria Carola Casetti, Luca Arcaini, Silvia Uccella, Marianna Rossi, Lorenza Bertù, Claudia Siracusa, and Elisa Rumi
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Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Text mining ,Internal medicine ,Medicine ,Humans ,Platelet ,Myelofibrosis ,Aged ,Aged, 80 and over ,business.industry ,Essential thrombocythemia ,Platelet Count ,Hematology ,Janus Kinase 2 ,Middle Aged ,medicine.disease ,Primary Myelofibrosis ,Mutation ,Female ,business ,Thrombocythemia, Essential - Published
- 2020
12. Clinical Relevance of Clonal Hematopoiesis in the Oldest-Old Population
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Aurelio Malabaila, Lucio Morabito, Rocco Piazza, Chiara Chiereghin, Marilena Bicchieri, Maria De Santis, Paolo Detoma, Matteo G. Della Porta, Sara Mandelli, Wolfgang Kern, Alberto Termanini, Rosanna Asselta, Uwe Platzbecker, Nicla Manes, Alessia A. Galbussera, Matteo Bersanelli, Niccolo Bolli, Chiara Milanesi, Erica Travaglino, Marta Ubezio, Elena Saba, George S. Vassiliou, Emma Riva, Manja Meggendorfer, Giovanni Corrao, Claudia Sala, Torsten Haferlach, Pierre Fenaux, Giulia Maggioni, Mauro Tettamanti, Armando Santoro, Roberto Zanetti, Alessia Campagna, Stefano Duga, Marianna Rossi, Laura Giordano, Claudia Saitta, Giulia Soldà, Francesc Solé, Matteo Zampini, Luca Sala, Efrem Civilini, Karolina Malik, Gianluigi Condorelli, Paola Allavena, Francesco Passamonti, Ugo Lucca, Ettore Mosca, Clelia Peano, Stefano Rosso, Gastone Castellani, and Carlo Selmi
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education.field_of_study ,medicine.medical_specialty ,Cytopenia ,Myeloid ,medicine.diagnostic_test ,business.industry ,Anemia ,Population ,medicine.disease ,Myeloid Neoplasm ,medicine.anatomical_structure ,Internal medicine ,Medicine ,media_common.cataloged_instance ,European union ,business ,education ,Red blood cell indices ,Blood sampling ,media_common - Abstract
Background: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. The phenomenon becomes very common in oldest-old individuals, in whom the implications of CHIP are not well defined. Here we investigate the relationships between CHIP and associated pathologies in people aged >80 years. Methods: We performed a mutational screening in 1794 oldest-old individuals enrolled in two population-based studies (“Health_&_Anemia” and “Monzino_80+”). Findings: Clonal mutations were observed in one third of oldest-old individuals and were associated with reduced survival and increased risk of cancers. Mutations in JAK2 and splicing genes (SF3B1, SRSF2, U2AF1, ZRSR2), multiple mutations (DNMT3A, TET2, ASXL1) combined with additional genetic lesions) and variant allele frequency ≥0.14 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1 or JAK2 (most occurring as single lesion) were associated with coronary heart disease and rheumatoid arthritis. Cytopenia (most including anemia) was a common finding in oldest-old population (>20%), the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly-specific mutation patterns was associated with a myeloid neoplasms-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of oldest-old subjects with cytopenia had presumptive evidence of myeloid neoplasm. Interpretation: Specific mutational patterns define different risk of developing cancers vs. inflammatory-associated diseases in oldest-old population. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms. Trial Registration: (ClinicalTrials.gov number:NCT03907553) Funding: Supported by European Union; Cariplo Foundation, Italy; Italian Association for Cancer Research; Italian Ministry of Health and Research. Declaration of Interests: The Authors declare no competing interests. Ethics Approval Statement: Study procedures were in accordance with the Declaration of Helsinki. Ethics Committees of Humanitas Research Hospital and Mario Negri Pharmacological Institute, Milan Italy approved the study. Written informed consent was obtained prior to blood sampling.
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- 2020
13. The SPID- GBA Study: The Largest Monocentric Study on Sex Distribution, Penetrance, Incidence, and Association with Dementia of GBA Mutations in Parkinson's Disease
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Giulia Soldà, Roberto Cilia, Stefano Duga, Letizia Straniero, Valeria Rimoldi, Gianni Pezzoli, Matteo G. Della Porta, Massimo Aureli, Anna Zecchinelli, Salvatore Bonvegna, Ugo Lucca, Rosanna Asselta, and Alessio Di Fonzo
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medicine.medical_specialty ,Parkinson's disease ,Dementia with Lewy bodies ,business.industry ,Incidence (epidemiology) ,Parkinsonism ,Disease ,medicine.disease ,Penetrance ,Internal medicine ,Attributable risk ,medicine ,Dementia ,business - Abstract
Background: Despite GBA mutations are considered the most frequent genetic risk factor for Parkinson’s disease (PD), uncertainty still exists on their impact on PD risk. This is mostly due to underpowered studies, genotyping inaccuracies, ethnic differences and underrating of mutation- age- and sex- specific effects. Methods: We studied a large cohort of 4,923 Italian unrelated patients with primary degenerative parkinsonism (including 3,832 PD) enrolled in a single tertiary care center and 7,757 ethnically-matched controls. The four most common PD-associated GBA variants (p.E326K, p.T369M, p.N370S, p.L444P) were screened by multiple methods (next-generation sequencing, Sanger sequencing, allele-specific PCR). Findings: We provide for the first time an accurate mutation-specific estimate of penetrance, incidence, sex distribution, and association with dementia of p.E326K, p.T369M, p.N370S, and p.L444P variants in GBA. p.L444P confirmed to show by far the strongest association with disease risk for PD, PD dementia (PDD), and Dementia with Lewy bodies (DLB) (OR for PD 17.08, 95%CI=8.56-34.08, P=7.86*10-16; OR for PDD 32.05, 95%CI=14.89-68.99, P=7.80*10-19; OR for DLB 111.7, 95%CI=33.07-377.1, P=3.09*10-14). However, an unexpectedly high risk for dementia was conferred by p.E326K (OR for PDD 4.861 95%CI=2.90-8.13, P=1.76*10-9; OR for DLB 12.37 95%CI=4.99-30.61, P=5.37*10-8), which, purely on the basis of the impact on glucocerebrosidase activity, would be expected to be mild. The 1.5-2:1 male sex bias described in sporadic PD was lost or even reverted in GBA carriers, suggesting that genetics is completely overriding the effect of sex in disease predisposition. Interpretation: Understanding the mutation-specific attributable risk is fundamental to instruct future research on disease therapy and design effective clinical trials. Age- and sex-specific penetrance for GBA variants in PD and associated phenotypes are crucial for neurologists to properly counsel patients and implement their care. Funding Statement: This work was supported by PRIN (Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale, Grant n. 2017228L3J, Program coordinator SD) and by the “Fondazione Grigioni per il Morbo di Parkinson”, Milan, Italy. LS was supported by fellowships from the “Fondazione Veronesi” and “Fondazione Grigioni per il Morbo di Parkinson.” Declaration of Interests: No conflict of interest to disclose. Ethics Approval Statement: The study was approved by the “Comitato Etico Milano Area 2” the 6th of March 2018, (ID 483).
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- 2020
14. Revising flow cytometric mini-panel for diagnosing low-grade myelodysplastic syndromes: Introducing a parameter quantifying CD33 expression on CD34+ cells
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Yumi Yamamoto, Kiyoyuki Ogata, Leonie Saft, Nicolas Chapuis, Matteo G. Della Porta, Kazuma Sei, and Naoya Kawahara
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Scoring system ,Cd34 cells ,Sialic Acid Binding Ig-like Lectin 3 ,CD33 ,Antigens, CD34 ,Bone Marrow Cells ,Objective data ,Sensitivity and Specificity ,Immunophenotyping ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Humans ,Medicine ,Aged ,Aged, 80 and over ,business.industry ,Myelodysplastic syndromes ,Hematology ,Middle Aged ,Flow Cytometry ,medicine.disease ,Multivariate logistic regression model ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Female ,business ,Biomarkers ,Granulocytes ,030215 immunology - Abstract
Diagnosis of myelodysplastic syndromes (MDS) is not straightforward when objective data, such as blast excess and abnormal cytogenetics, are lacking. Expert laboratories use flow cytometry (FCM) to help diagnose MDS. However, most of FCM protocols for MDS are complex, requiring a high level of expertise and high cost. We have reported a FCM mini-panel consisting of four FCM parameters (so-called Ogata score), which is simple to conduct and inexpensive. In this paper, to refine this mini-panel, we have introduced a new FCM parameter, which quantifies CD33 expression on CD34+ cells (called Granulocyte/CD34 cell CD33 ratio). Bone marrow cells from MDS without blast excess (low-grade MDS) and controls were stained with CD34, CD45, and CD33 and analyzed for five parameters ("Granulocyte/CD34 cell CD33 ratio" plus four parameters in the Ogata score). By a multivariate logistic regression model, only three parameters, including "Granulocyte/CD34 cell CD33 ratio" had statistically significant power for diagnosing low-grade MDS. Based on the results, we constructed a new scoring system, which showed approximately 50% sensitivity and more than 95% specificity in diagnosing low-grade MDS. Our revised mini-panel is suitable for screening samples suspected for MDS and provides a basis for further improvement in diagnostic FCM protocols for MDS.
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- 2018
15. Multicenter Prospective Evaluation of Diagnostic Potential of Flow Cytometric Aberrancies in Myelodysplastic Syndromes
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Matteo G. Della Porta, Dolores Subirá, Kate Burbury, Arjan A. van de Loosdrecht, Sergio Matarraz, Leonie Saft, Anna Porwit, Lisa Eidenschink Brodersen, Ulrika Johansson, Uta Oelschlaegel, Elisabeth Weiss, Marie C. Béné, Peter Bettelheim, Katherina Psarra, Frauke Bellos, Alan Stewart Dunlop, Sung-Chao Chu, Wolfgang Kern, Theresia M. Westers, Kiyoyuki Ogata, Frank Preijers, and Matthew J. Cullen
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Oncology ,medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Prospective evaluation ,hemic and lymphatic diseases ,Internal medicine ,Medicine ,business - Abstract
Background: Myelodysplastic syndromes (MDS) are considered clonal diseases and are diagnosed according to WHO by cytomorphology and cytogenetics. The diagnostic potential of flow cytometric aberrancies has not yet been comprehensively evaluated. Aim: Multicenter prospective evaluation of diagnostic potential of flow cytometric aberrancies predefined according to European LeukemiaNet (ELN). Methods: 1682 patients undergoing diagnostics for suspected MDS according to WHO 2016 criteria were analyzed in parallel by flow cytometry according to ELN recommendations. Results: Median age was 72 years (18-97). MDS, MPN-RS-T or CMML were confirmed by cytomophology in 1029 (61%) cases, 653 (39%) were non-MDS. IPSS-R data was available in 857 (51%). An overall flow cytometric readout was available in 1679 (99.8%). 1001 (60%) were in agreement with MDS while 678 (40%) were not. Flow cytometric readout significantly correlated with cytomorphologic diagnosis (p Non-MDS cases had a fewer myeloid progenitor cells (MPC) (mean±SD, 0.8±0.9%) compared to low-risk MDS (1.7±2.3%, p3% was strongly associated with MDS/CMML (286/293, 98%, p Neutrophil aberrancies were found more frequently in neoplastic cases than in non-MDS cases (table 1). Again, frequencies of aberrations were higher for high-risk MDS as compared to low-risk MDS while this was not the case for CMML showing frequencies rather similar to low-risk MDS. Frequencies of aberrancies in monocytes revealed a similar figure as in neutrophils with higher rates in neoplastic cases but clearly significant numbers positive in non-MDS cases. Interestingly, frequencies were not higher in high-risk MDS as compared to low-risk MDS. As anticipated, frequencies were highest in CMML (table 1). Regarding erythroid cells only an aberrant percentage of them and aberrant CD71 expression were found in a reasonable number of cases. Importantly, rates of positivity were rather high in non-MDS cases which did not differ from CMML cases (table 1). In order to identify the diagnostic value of each individual aberrancy multivariate analyses were performed in the three subgroups, low-risk MDS, high-risk MDS and CMML, as well as in the total cohort. In low-risk MDS ten aberrancies were independently related to MDS (table 2). Five of these aberrancies were found in MPCs, two each in neutrophils and monocytes and one in erythroid cells. In high-risk MDS 11 aberrancies were independently related to MDS (table 2). Eight were found in MPCs, two in neutrophils, none in monocytes and one in erythroid cells. In CMML 12 aberrancies were independently related to CMML (table 2). Four were found in MPCs, neutrophils and monocytes, respectively, and none in erythroid cells. Considering all these three groups together and all aberrancies identified significantly related to MDS/CMML in at least one group in univariate analysis, multivariate analysis identified 12 aberrancies independently related to MDS/CMML (table 2). Six were found in MPCs, two in neutrophils, three in monocytes and one in erythroid cells. Taking into consideration only aberrancies independently associated with MDS/CMML, three such aberrancies resulted in an 80% agreement with the cytomorphologic diagnosis of MDS/CMML, i.e. 20% concordantly negative and 60% concordantly positive. Importantly, this applies without need of at least two cell compartments being affected as specified in the ELN recommendations. Conclusions: This multicenter prospective evaluation confirms the diagnostic potential of flow cytometric aberrancies. A core set of 17 markers identified as independently related to a diagnosis of MDS/CMML is suggested mandatory for flow cytometric evaluation of suspected MDS. An MPC count >3% should be considered indicative of MDS/CMML. Figure 1 Figure 1. Disclosures Kern: MLL Munich Leukemia Laboratory: Other: Part ownership. Eidenschink Brodersen: Hematologics, Inc.: Current Employment, Other: Equity Ownership. Van de Loosdrecht: Celgene: Consultancy, Research Funding; Amgen: Consultancy; Roche: Consultancy; Novartis: Consultancy; Alexion: Consultancy.
- Published
- 2021
16. Acute Myeloid Leukemia with Isocitrate Dehydrogenases (IDH) 1 and 2 Mutations. a Real-World Study from the European IDH Research Group
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Marcus Hentrich, Jordi Esteve, Matteo G. Della Porta, Mar Tormo, Sigrid Machherndl-Spandl, Ana Garrido, Sonia Matos, Annika Dufour, Olga Salamero, Jorge Sierra, Marta Pratcorona, Lisa Pleyer, Federico Lussana, Maria Carmo-Fonseca, Francesco Passamonti, Paola Fazi, Albertina Nunes, Sonja Heibl, Susana Vives, Christoph Sippel, Nicola Stefano Fracchiolla, Alfonso Piciocchi, Joana M. P. Desterro, Montserrat Arnan, Pamela Acha, Erica Travaglino, Aida Botelho de Sousa, Friedrich Stölzel, Maria Teresa Voso, Giulia Maggioni, Christian Thiede, Claudia Basilico, Cristina Astrid Tentori, Francesc Solé, Karsten Spiekermann, Marcos Lemos, Klaus H. Metzeler, Elisabetta Todisco, Bernhard Heilmeier, Jan Moritz Middeke, Marina Diaz, Valentina Mancini, and David Gallardo
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Response rate (survey) ,education.field_of_study ,NPM1 ,medicine.medical_specialty ,IDH1 ,business.industry ,Immunology ,Population ,Myeloid leukemia ,Context (language use) ,Cell Biology ,Hematology ,Biochemistry ,IDH2 ,Isocitrate dehydrogenase ,Internal medicine ,Medicine ,business ,education - Abstract
Introduction. Mutations in genes encoding the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and 2 are found in 10-20% of patients with acute myeloid leukemia (AML). Recently, IDH inhibitors have shown good clinical response in patient's refractory to standard treatments, providing evidence for a new treatment paradigm. Comprehensive real-world studies are needed to explore genotype-to-phenotype correlations and prognosis of IDH mutated AML, which may influence targeted treatment strategies. Patients. From a retrospective, European, real-word population (ClinicalTrials.gov Identifier: NCT04369287) we studied 477 IDH mutated patients and 954 IDH wild type patients matched for age, sex and type of treatment with a 1:2 ratio. Results. Median age of IDH mutated patients was 67 years; IDH1 mutations were found in 202 patients (89% carried R132 mutation), while IDH2 mutations were found in 275 cases (51% and 28% carried R140 and R172 mutations, respectively). At diagnosis, IDH mutated patients had lower neutrophil and higher platelet count and higher percentage of marrow blasts (P Considering cytogenetic risk according to ELN criteria, the great majority of IDH1 and IDH2 mutated patients had an intermediate cytogenetic risk (84% and 86%, respectively, P We then analysed the most common co-mutational patterns in IDH mutated patients. A total of 53% of IDH1 mutated patients carried NPM1 mutations (without FLT3 mutations), while the majority of IDH2 mutated patients had wild type NPM1 gene (P Median overall survival from diagnosis (OS) was 14 months for IDH1 mutated patients, 23 for IDH2 mutated patients and 19 for IDH wild type patients (P IDH mutated patients receiving hypomethylating agents (n=211) had a lower response rate vs. wild type patients (56% vs. 36% of treatment failure, respectively, P=.04), while no significant different probability of response to intensive chemotherapy was noticed. In patients who received allogeneic transplantation (n=345), IDH1 mutated patients shower higher relapse rate vs. wild type and IDH2 mutated patients (53% vs. 34%, P Conclusion. In a real world context, AML patients with IDH1 and 2 mutations have high marrow blasts percentage, frequently present normal karyotype and show specific co-mutational patterns with respect to NPM1, FLT3 and ASXL1 genes. IDH1 mutations were an independent predictor of unfavorable outcome with high rate of disease recurrence under currently available treatment options, and could be considered as an additional marker to improve personalized prognostic assessment within ELN risk groups. Dissection of prognosis of IDH mutated AML may influence targeted treatment strategies in clinical practice. Disclosures Voso: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Heibl:Takeda: Honoraria; AOP orphan: Consultancy, Honoraria, Research Funding; BMS/celgene: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria. Metzeler:Astellas: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharma: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Thiede:AgenDix GmbH: Other: Co-owner and CEO. Fracchiolla:ABBVIE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau. Todisco:Jannsen, Abbvie, Jazz: Membership on an entity's Board of Directors or advisory committees. Passamonti:Novartis: Speakers Bureau; BMS: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support.
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- 2020
17. Clinical characteristics and treatment outcome of an 86-year-old patient with acute myeloid leukaemia with acute promyelocytic-like morphology and uncommon RARA fusion variant
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Valentina Rossi, Riccardo Schiavon, Matteo G. Della Porta, Francesco Lo Coco, Marco Barchiesi, Laura Cicconi, and Roberto Castelli
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Hematology ,Oncogene Proteins ,business.industry ,Treatment outcome ,General Medicine ,medicine.disease ,03 medical and health sciences ,Leukemia ,030104 developmental biology ,0302 clinical medicine ,Text mining ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Myeloid leukaemia ,business - Published
- 2018
18. Second primary malignancies in ruxolitinib-treated myelofibrosis: Real-world evidence from 219 consecutive patients
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Elena Maria Elli, Toni Giorgino, Lorenza Bertù, Elisa Rumi, Chiara Cavalloni, Marianna Caramella, Alessandro Vismara, Daniela Barraco, Margherita Maffioli, Maria Chiara Finazzi, Mariella D'Adda, Francesco Spina, Daniele Cattaneo, Francesco Passamonti, Nicola Polverelli, Simona Malato, Maria Cristina Carraro, Alfredo Molteni, Barbara Mora, Alessandra Iurlo, Maria Luisa Pioltelli, Marianna Rossi, Rossella Renso, Raffaella Accetta, Matteo G. Della Porta, Michela Anghilieri, Marta Bellini, and Cinzia Sissa
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Ruxolitinib ,Population ,Aggressive lymphoma ,myelofibrosis ,Young Adult ,Mutation Rate ,Internal medicine ,Neoplasms ,Nitriles ,medicine ,80 and over ,Humans ,Janus Kinase Inhibitors ,Cumulative incidence ,Aged ,Aged, 80 and over ,Biomarkers ,Duration of Therapy ,Female ,Italy ,Middle Aged ,Mutation ,Neoplasms, Second Primary ,Primary Myelofibrosis ,Pyrazoles ,Myelofibrosis ,education ,education.field_of_study ,Essential thrombocythemia ,business.industry ,hematology ,Gandotinib ,medicine.disease ,Stimulus Report ,Second Primary ,Pyrimidines ,International Prognostic Scoring System ,business ,medicine.drug - Abstract
Myeloproliferative neoplasms (MPNs) are clonal disorders that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Patients with MPNs have a higher risk than the general population of developing a lymphoid neoplasm.1 It is still unclear whether this holds true for nonhematological second primary malignancies (SPMs).2-4 However, among 20 250 MPN patients included in the Surveillance, Epidemiology, and End Results (SEER) Program database, the 10-year cumulative incidence of SPMs was 12.7%, significantly higher than that expected in the general US population.5 Ruxolitinib (RUX) is an oral JAK inhibitor (JAKi) approved for International Prognostic Scoring System (IPSS)/Dynamic IPSS (DIPSS) intermediate- and high-risk myelofibrosis (MF)6,7 and for inadequately controlled PV. More than 2600 RUX-treated MF patients have been prospectively observed for at least 2 years within the 2 pivotal COMFORT trials8,9 and the expanded-access JUMP trial.10,11 Safety data from these trials underline a possibly increased incidence of nonmelanoma skin cancers (NMSCs), but no significant increase of lymphoproliferative neoplasms, similarly to what occurs in PV.12,13 Recently, Porpaczy et al alerted, however, on the possible 16-fold increased risk of developing aggressive lymphomas in MPN patients treated with JAKis, especially in the presence of a preexisting B-cell clone.14 The publication included a total of 1555 MPN patients, 126 of whom were treated with a JAKi (ruxolitinib, gandotinib, fedratinib, momelotinib), obtained assembling 2 broad academic data sets. In the well-described Viennese cohort, 3 of 31 MF patients treated with JAKi developed lymphomas. Median time from JAKi initiation to lymphoma diagnosis was 25 months. Subsequent analyses of other large academic data sets did, however, not confirm an increased risk of aggressive lymphoma development under JAKis in MPNs15,16 and in post-PV and post-ET MF (secondary MF [SMF]).17 These contradictory results were derived either from clinical trials with strict eligibility criteria, possibly at the expense of uncertainty about the generalizability of results, or from highly selected data sets of patients evaluated at referral centers, thus highlighting the need for real-world data (RWD). We consequently set out to assess the occurrence of SPMs, including lymphoproliferative neoplasms, in RUX-treated MF patients on the basis of RWD provided by the health authority of the Lombardy Region, integrated with institutional data.
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- 2019
19. Additional prognostic impact of the percentage of erythroid cells in the bone marrow of patients with myelodysplastic syndromes
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Aspasia Stamatoullas, Judith Neukirchen-Strapatsas, Rosa Sapena, Corinna Strupp, Peter Valent, Matteo G. Della Porta, Marianna Rossi, Ulrich Germing, Heinz Tuechler, Rainer Haas, John M. Bennett, Agnès Guerci, Wolfgang R. Sperr, and Pierre Fenaux
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Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Risk category ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Erythroid Cells ,Bone Marrow ,Risk Factors ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Overall survival ,Humans ,In patient ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Myelodysplastic syndromes ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,Survival Rate ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Female ,Bone marrow ,business ,030215 immunology ,Follow-Up Studies - Abstract
In patients with myelodysplastic syndromes (MDS) the impact of the percentage of erythroid precursors in the bone marrow has been the subject of considerable debate, especially with regard to prognosis. We examined the prognostic impact of the percentage of erythroid cells in the bone marrow (bmery) in 2453 primary untreated MDS patients in a retrospective multi-center analysis. Bmery were quantified in bone marrow smears at the time of diagnosis and were correlated with overall survival (OS) and AML evolution. We identified three distinct risk categories: " = 10% bmery" (poor), "11-25 or45% bmery" (intermediate), and "26-45% bmery" (good) with distinct OS of 23, 40 and 48 months, respectively. The percentage of bmery showed prognostic significance concerning OS (Dxy = 0.08, p 0.001) and AML-free survival (Dxy = 0.15, p 0.001). Considering the IPSS-R by stratification, the Dxy were 0.09 for survival, and 0.18 for transformation (p 0.001). Added to the IPSS-R, bmery enhances the prognostic power for both survival (Dxy = 0.39) and time to AML (Dxy = 0.59). Survival and time to AML differ in MDS according to the percentage of bmery. The best outcome was found in those who had normal or near normal bmery counts. Moreover, adding bmery as differentiating feature to the IPSS-R may enhance its prognostic significance.
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- 2018
20. A Multicenter, Italian Trial of Early Iron Chelation Therapy with Low Dose Deferasirox (Exjade®) in Patients with Low/Intermediate-1 Risk MDS at the Beginning of Transfusional Story
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Gian Luca Forni, Esther Oliva, Federica Pilo, Mario Capasso, Daniela Cilloni, Emanuele Angelucci, Valeria Santini, Marta Riva, Elena Crisà, Annamaria Pelizzari, Gianni Binotto, Marino Clavio, Matteo G. Della Porta, Pasquale Niscola, and Domenico Girelli
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0301 basic medicine ,medicine.medical_specialty ,Blood transfusion ,medicine.diagnostic_test ,Transferrin saturation ,business.industry ,medicine.medical_treatment ,Immunology ,Deferasirox ,Transfusion History ,Cell Biology ,Hematology ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Internal medicine ,medicine ,Serum iron ,Transfusion therapy ,Chelation therapy ,Packed red blood cells ,business ,030215 immunology ,medicine.drug - Abstract
Background Most MDS patients require regular packed red blood cells (RBC) transfusions and finally most become transfusion dependent. One of the unavoidable consequences of transfusion therapy is iron overload which has been found to be deleterious for different categories of patients including MDS patients. So far tissue and organ damage have been directly and strictly connected to the amount of tissue iron deposition (i.e. a "bulky" disease). All the studies performed in the last years have linked survival to markers of iron accumulation (mainly indirect markers) such as serum ferritin (PLoS One 2017;12: e0179016 17). Recent data support the notion that iron disease is not only a "bulky" disease exclusively secondary to iron accumulation but rather it is a toxic disease in which tissue damage is due to toxic iron forms (Non-Transferrin-Bound-Iron, NTBI, and Labile Plasma Iron, LPI) (Free Radic Biol Med 2014; 72: 23-40). These tissue reactive iron species are present in plasma since early phase of transfusion therapy or even before (Hematology 2017; 22: 9-15. Clin Biochem 2017 Nov;50: 911-7). NTBI and LPI emerge in the serum only once iron binding capacity is saturated in a rate over 60-70% (Haematologica 2016; 101: 38-45). Notably these iron fractions are chelatable and can be removed from circulation by a chelator (Blood. 2003; 102: 2670-7). The scientific rationale for this study (ClinicalTrials.gov: NCT03920657; CICL670AIT17T) is the notion that iron-induced tissue damage is not only a process of progressive organs bulking through high-volumes iron deposition, but also a reactive iron species related "toxic" damage. Therefore, a timely early initiation of iron chelation may be of benefit before overt iron overload is seen. Our hypothesis is that early and low dose Deferasirox film coated tablets (DFX-FCT) is well tolerated and is able to prevent iron accumulation, oxidative stress and related tissue damage, by consistently suppressing iron reactive oxygen species (NTBI and LPI). Study design and Methods. For inclusion, patients must be affected by Myelodysplastic Syndrome (MDS), aged ≥ 18 years, with very low, low and intermediate revised IPSS stage. They must have a limited history of transfusions (5-20 RBC units) and be chelation naïve. Additional inclusion criteria are serum ferritin levels >350 ng/mL and transferrin saturation >60%. In a recruitment period of 1 years, 60 patients from 10 Italian centers will be included in the study. DFX-FCT will be administered at the fixed dose of 3.5 mg/kg/day for the entire study year. The primary efficacy objective and end point is to evaluate impact on of iron burden in one-year treatment in early phase of transfusion requirement by low dose DFX-FCT acting as prevention of iron accumulation as demonstrated by hepatic iron concentration determined by liver MRI (end of study versus baseline). Most relevant secondary objectives and endpoints are 1) Definition of iron overload and oxidative stress in MDS at beginning of transfusion history. 2) demonstrating presence and quantitative changes of toxic serum iron forms and oxidative stress under low dose DFX-FCT therapy by regular NTBI, LPI and serum Malonildialdehyde (MDA) monitoring. 3) Verify if regular suppression of the "free iron forms" prevent tissue iron accumulation by absolute change in hepatic iron concentration end of study versus baseline 4) Evaluate the overall safety of low DFX-FCT dose in patients with lower risk MDS at the beginning of their transfusion history 5) hemopoietic response Conclusions This prospective multicenter study has been designed to investigate the clinical benefit and safety of early chelation therapy with DFX-FCT in patients with MDS at the beginning of their transfusion history to verify the possibility to continually suppress tissue NTBI, LPI and Oxidative stress thus preventing iron accumulation and tissue damage. Disclosures Angelucci: Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorporated, and CRISPR Therapeutics: Other: Partecipation in DMC; Jazz Pharmaceuticals: Other: Local advisory board; Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Partecipation in DMC; BlueBirdBio: Other: Local advisory board. Forni:Novartis, Iron chelation: Research Funding; Roche, Erithropoiesis Stimulation: Research Funding; BlueBirdBio: Consultancy; Celgene, Erithropoiesis Stimulation: Research Funding. Girelli:Vifor Pharma: Other: honoraria for lectures; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; La Jolla Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Oliva:Novartis: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy. Pilo:Novartis: Other: Advisory board. Cilloni:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Crisà:Jannsen: Honoraria. Santini:Menarini: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.
- Published
- 2019
21. Cdx Report Program: Heterogeneity Revealed in Current Reporting Practices for Hemato-Oncology Companion Diagnostic (CDx) Markers in Multiple Countries
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Sabit Delic, Devon Chabot-Richards, Christian Thiede, Maria Teresa Voso, William Stevenson, María José Calasanz, Torsten Haferlach, Jay Patel, Paul Evans, Piers Blombery, Dolors Colomer, Jordan Clark, Joanne Mason, and Matteo G. Della Porta
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Oncology ,medicine.medical_specialty ,business.industry ,Chronic lymphocytic leukemia ,Immunology ,Equity (finance) ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Leukemia ,hemic and lymphatic diseases ,Internal medicine ,medicine ,business ,Protein p53 ,Companion diagnostic - Abstract
Introduction: In the current era of precision medicine, CDx tests have become the basis for optimal patient care and targeted treatment. While technical aspects of a CDx assay's performance are audited regularly by participation in external quality assessment (EQA) programs, the reporting of these CDx markers is rarely scrutinized. The aim of this first of its kind CDx report program is to get a detailed picture of hemato-oncology CDx marker reporting across multiple countries. Therefore, we evaluated multiple laboratory parameters and reviewed actual content of clinical CDx reports. Methods: Thirty-four clinical labs from Germany, Italy, Spain, and the United Kingdom provided information for 7 biomarkers used for treatment decisions in hemato-oncology. An identical program is already running in Australia and the United States and will be initiated shortly in India and China. The CDx markers covered in this CDx report program were: BCR-ABL1 in chronic myeloid leukemia (CML), at diagnosis; BCR-ABL1 in CML, minimal residual disease (MRD); IDH1/2 in acute myeloid leukemia (AML); FLT3-ITD in AML; FLT3-TKD in AML; IGHV in chronic lymphocytic leukemia (CLL); and TP53 in CLL. The information requested from participating laboratories included two anonymized or blank reports: one with a positive/mutant result and one with a negative/wild-type result. The received anonymized reports were reviewed by experts within each country according to pre-agreed criteria. In addition, labs participated in a short online survey evaluating test volumes, turnaround times (TATs), positivity rates, participation in an EQA program, and status regarding accreditation and reimbursement. The results of the questionnaires were forwarded as anonymized and aggregated data to reviewing experts. Results: Overall, we received 184 survey datasets and 179 sets of anonymized reports. The review of the anonymized reports according to pre-defined criteria revealed differences in the way CDx results are represented and interpreted in clinical reports. Since not all markers covered in this program were tested by all participating labs, the number of survey datasets per CDx marker ranged from 16 to 34 (IGHV: 16; TP53: 19; IDH1/2: 24; FLT3-TKD: 28; FLT3-ITD: 30; BCR-ABL1 [MRD]: 33; and BCR-ABL1 [diagnosis]: 34). The 184 survey datasets represented more than 7000 tests per month (Figure). The stated average TAT across all covered markers was 6.9 days, ranging from 5.3 days to 8.6 days in the covered countries. The TATs for the individual markers ranged from 4.4 days to 9.4 days (FLT3-ITD: 4.4 days; FLT3-TKD: 4.6 days; BCR-ABL1 [diagnosis]: 5.3 days; BCR-ABL1 [MRD]: 6.9 days; IDH1/2: 8.4 days; IGHV: 9.3 days; and TP53: 9.4 days). In 103/179 (58%) datasets labs participated in EQA programs, and in 76/179 (42%) datasets labs did not participate in EQA programs. For 84/180 (47%) datasets, labs were ISO15189-accredited; for 12/180 (7%) datasets, labs were College of American Pathologists (CAP)-accredited; and for 84/180 (47%) datasets, labs were not accredited by either ISO15189 or CAP. Conclusion: CDx report program results reveal a broad range globally in CDx reporting practices. The identified differences in laboratory parameters, such as TAT and the actual content of clinical CDx reports, suggest a need for international harmonization of CDx reporting. The anonymized and aggregated data generated provide the basis for other initiatives and may support guideline updates and the international harmonization of CDx reporting. Figure. Estimated number of companion diagnostic tests per month covered in the CDx report program. Figure Disclosures Delic: Diaceutics: Employment, Equity Ownership. Blombery:Janssen: Honoraria; Novartis: Consultancy; Invivoscribe: Honoraria. Calasanz:Janssen: Honoraria; Diaceutics: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria. Colomer:Novartis: Honoraria; Incyte: Honoraria. Evans:Diaceutics: Honoraria; Novartis: Honoraria. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Mason:Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria; AbbVie: Honoraria. Thiede:Daiichi Sankyo: Honoraria; Diaceutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; AgenDix GmbH: Employment, Equity Ownership. Clark:Diaceutics: Employment, Equity Ownership.
- Published
- 2019
22. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts
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Anna Gallì, Mario Cazzola, Luca Malcovati, Martin Jädersten, Matteo G. Della Porta, Daniela Pietra, Monika Jansson, Klaus Kallenbach, Chiara Elena, Simona Conte, Ilaria Ambaglio, Rosangela Invernizzi, Eva Hellstrom Lindberg, Viktor Ljungström, Peter J. Campbell, Mohsen Karimi, Klas Raaschou-Jensen, Richard Rosenquist, Erica Travaglino, Elli Papaemmanuil, Gunilla Walldin, and Emanuela Boveri
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Adolescent ,Immunology ,Erythroid dysplasia ,Biology ,medicine.disease_cause ,Biochemistry ,Diagnosis, Differential ,Young Adult ,Internal medicine ,medicine ,Humans ,Aged ,Aged, 80 and over ,Mutation ,Hematology ,Myelodysplastic Syndrome with Ring Sideroblasts ,Myelodysplastic syndromes ,Cell Biology ,Middle Aged ,Ribonucleoprotein, U2 Small Nuclear ,Phosphoproteins ,Prognosis ,medicine.disease ,Anemia, Sideroblastic ,Myelodysplastic Syndromes ,Refractory anemia with ring sideroblasts ,Mutation testing ,Female ,RNA Splicing Factors ,Refractory cytopenia with multilineage dysplasia - Abstract
Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome (MDS) characterized by isolated erythroid dysplasia and 15% or more bone marrow ring sideroblasts. Ring sideroblasts are found also in other MDS subtypes, such as refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). A high prevalence of somatic mutations of SF3B1 was reported in these conditions. To identify mutation patterns that affect disease phenotype and clinical outcome, we performed a comprehensive mutation analysis in 293 patients with myeloid neoplasm and 1% or more ring sideroblasts. SF3B1 mutations were detected in 129 of 159 cases (81%) of RARS or RCMD-RS. Among other patients with ring sideroblasts, lower prevalence of SF3B1 mutations and higher prevalence of mutations in other splicing factor genes were observed (P < .001). In multivariable analyses, patients with SF3B1 mutations showed significantly better overall survival (hazard ratio [HR], .37; P = .003) and lower cumulative incidence of disease progression (HR = 0.31; P = .018) compared with SF3B1-unmutated cases. The independent prognostic value of SF3B1 mutation was retained in MDS without excess blasts, as well as in sideroblastic categories (RARS and RCMD-RS). Among SF3B1-mutated patients, coexisting mutations in DNA methylation genes were associated with multilineage dysplasia (P = .015) but had no effect on clinical outcome. TP53 mutations were frequently detected in patients without SF3B1 mutation, and were associated with poor outcome. Thus, SF3B1 mutation identifies a distinct MDS subtype that is unlikely to develop detrimental subclonal mutations and is characterized by indolent clinical course and favorable outcome.
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- 2015
23. Antitumour activity of trabectedin in myelodysplastic/myeloproliferative neoplasms
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Simonetta Andrea Licandro, Elisa Bonetti, Carlos M. Galmarini, Laura Mannarino, Eugenio Erba, Vittorio Rosti, Richard Tancredi, Marianna Rossi, Matteo G. Della Porta, Mario Cazzola, Paola Allavena, Anna Gallì, Maurizio D'Incalci, Marco Zecca, M. Romano, Franco Locatelli, Andrea Biondi, Nicolò Panini, Alberto Zambelli, Ezia Bello, Ilaria Craparotta, Sergio Marchini, Alessandro Rambaldi, Luca Porcu, Romano, M, della Porta, M, Gallì, A, Panini, N, Licandro, S, Bello, E, Craparotta, I, Rosti, V, Bonetti, E, Tancredi, R, Rossi, M, Mannarino, L, Marchini, S, Porcu, L, Galmarini, C, Zambelli, A, Zecca, M, Locatelli, F, Cazzola, M, Biondi, A, Rambaldi, A, Allavena, P, Erba, E, and D'Incalci, M
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,CD34 ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,Tetrahydroisoquinolines ,Rho GTPases ,apoptosis ,cmml ,cytotoxicity ,gene expression ,jmml ,rho gtpases ,trabectedin ,Trabectedin ,Tumor Stem Cell Assay ,JMML ,Chemistry ,Rho GTPase ,Leukemia, Myelomonocytic, Chronic ,Leukemia ,Haematopoiesis ,medicine.anatomical_structure ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,030220 oncology & carcinogenesis ,Female ,medicine.drug ,medicine.medical_specialty ,Mice, Nude ,Dioxoles ,03 medical and health sciences ,Internal medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Progenitor cell ,Antineoplastic Agents, Alkylating ,Cell Proliferation ,CMML ,Cell growth ,Myelodysplastic syndromes ,Gene Expression Profiling ,medicine.disease ,apoptosi ,030104 developmental biology ,Leukemia, Myelomonocytic, Juvenile ,Myelodysplastic Syndromes ,Cancer research ,Bone marrow ,Translational Therapeutics - Abstract
Background: Juvenile myelomonocytic leukaemia (JMML) and chronic myelomonocytic leukaemia (CMML) are myelodysplastic myeloproliferative (MDS/MPN) neoplasms with unfavourable prognosis and without effective chemotherapy treatment. Trabectedin is a DNA minor groove binder acting as a modulator of transcription and interfering with DNA repair mechanisms; it causes selective depletion of cells of the myelomonocytic lineage. We hypothesised that trabectedin might have an antitumour effect on MDS/MPN. Methods: Malignant CD14+ monocytes and CD34+ haematopoietic progenitor cells were isolated from peripheral blood/bone marrow mononuclear cells. The inhibition of CFU-GM colonies and the apoptotic effect on CD14+ and CD34+ induced by trabectedin were evaluated. Trabectedin's effects were also investigated in vitro on THP-1, and in vitro and in vivo on MV-4-11 cell lines. Results: On CMML/JMML cells, obtained from 20 patients with CMML and 13 patients with JMML, trabectedin - at concentration pharmacologically reasonable, 1-5 nM - strongly induced apoptosis and inhibition of growth of haematopoietic progenitors (CFU-GM). In these leukaemic cells, trabectedin downregulated the expression of genes belonging to the Rho GTPases pathway (RAS superfamily) having a critical role in cell growth and cytoskeletal dynamics. Its selective activity on myelomonocytic malignant cells was confirmed also on in vitro THP-1 cell line and on in vitro and in vivo MV-4-11 cell line models. Conclusions: Trabectedin could be good candidate for clinical studies in JMML/CMML patients.
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- 2017
24. Vascular endothelial growth factor overexpression in myelodysplastic syndrome bone marrow cells: biological and clinical implications
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Matteo G. Della Porta, Raffaella Bastia, Rosangela Invernizzi, Anna Gallì, Ilaria Ambaglio, Vittorio Rosti, Mariella Ciola, Emanuela Boveri, Erica Travaglino, Mario Cazzola, and Luca Malcovati
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0301 basic medicine ,Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,VEGF receptors ,Gene Expression ,Antigens, CD34 ,Apoptosis ,Bone Marrow Cells ,Kaplan-Meier Estimate ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Hematology ,biology ,Vascular Endothelial Growth Factors ,Disease progression ,Prognosis ,Immunohistochemistry ,Vascular endothelial growth factor ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Phenotype ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,biology.protein ,Female ,Bone marrow ,Biomarkers - Abstract
In myelodysplastic syndrome (MDS), vascular endothelial growth factor (VEGF) may have regulatory effects on the hematopoietic system and contribute to disease progression. We analyzed by immunocytochemistry VEGF expression in bone marrow (BM) cells from 188 patients with MDS and 96 non-hemopathic subjects. We also measured VEGF BM plasma levels and in vitro VEGF release. Our aims were to evaluate whether VEGF expression abnormalities were associated with relevant laboratory or clinical findings and their possible prognostic value. In MDS, VEGF expression was higher than in controls (p .0001) and VEGF release was significantly higher in the low-risk cases. A trend to a positive correlation between VEGF myeloid expression and apoptotic rate was observed. High myeloid VEGF levels were independently associated with longer overall survival (p .0001) and progression-free survival (p = .0002). Our findings suggest that, in MDS, VEGF production and release may contribute to ineffective hematopoiesis, with a potential prognostic role.
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- 2016
25. Performance of hormone assays in EQAS 'Buenos Aires' ProgBa – Cemic
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S. Quiroga, C.A. Fenili, L. Del Vecchio, Matteo G. Della Porta, and M. Torres
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medicine.medical_specialty ,Endocrinology ,business.industry ,Internal medicine ,Biochemistry (medical) ,Clinical Biochemistry ,medicine ,General Medicine ,business ,Biochemistry ,Hormone - Published
- 2019
26. Therapy-Related MDS Can be Separated into Different Risk-Groups According to Tools for Classification and Prognostication of Primary MDS
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María López-Pavía, Amy E. DeZern, Francesc Cobo, Hartmut Döhner, Michael Lübbert, Jordi Esteve, Sabine Blum, Arjan A. van de Loosdrecht, Brayan Merchan, Mario Cazzola, Benet Nomdedeu, Christina Ganster, Guillermo Sanz, Dolors Costa, Claudia D. Baldus, María Teresa Cedena, Carme Pedro, Peter L. Greenberg, Detlef Haase, Thomas Schroeder, Guillermo Garcia-Manero, Luis Benlloch, Meritxell Nomdedeu, Xavier Calvo, Francesc Solé, Arturo Pereira, Montserra Martinez-de-Sola, Peter Valent, María Díez-Campelo, David P. Steensma, Barbara Hildebrandt, Ulrich Germing, Javier Grau, Alan F. List, Mikkael A. Sekeres, Gail J. Roboz, Reinhard Stauder, Uwe Platzbecker, Itziar Oiartzabal, Heinz Tuechler, Andrea Kuendgen, Rami S. Komrokji, Aristoteles Giagounidis, Matteo G. Della Porta, Rainer Haas, and Sigrid Machherndl-Spandl
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Oncology ,0303 health sciences ,medicine.medical_specialty ,Primary (chemistry) ,Surrogate endpoint ,business.industry ,Immunology ,Cytogenetics ,Chromosomal translocation ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Clinical research ,Internal medicine ,Persistent Müllerian duct syndrome ,medicine ,Specific Learning Disorder ,Risk assessment ,business ,030304 developmental biology ,030215 immunology - Abstract
The current classification system for Myelodysplastic Syndromes lumps all therapy-related (tMDS) into one subgroup assuming all tMDS had the same poor prognosis. We have put together a database including 2032 patients with a diagnosis of tMDS from several different IWG centers and the MDS clinical research consortium. With the idea of developing an individual scoring system for tMDS, we decided to start by optimizing the cytogenetic part of the IPSSR. First, we did an extensive review of karyotypes. Finally, 1245 patients had complete data and correct ISCN formula to be used for score development. We could show regarding karyotypes there are very limited differences between primary and tMDS. Mainly the distribution of risk groups differs with complex occurring more (37%) and normal karyotypes occurring less frequent, although still accounting for 30%. There are few exceptions that are relatively special for tMDS, like translocations including 11q23. A few karyotypes are less frequent; therefore, we could not evaluate the value of IPSS-R cytogenetics for all karyotypes. However, if we apply IPSS-R cytogenetics to our patient cohort, we can separate 5 different risk groups as in pMDS. We tested the performance of the score by using the Dxy. As main endpoint we chose transformation-free survival giving better information about the severity of the disease compared to the single endpoints survival and AML transformation that where calculated for completeness as well. The Dxy for the IPSS-R cytogenetic part is 0.31 for transformation-free survival. This indicates an effective prognostic performance although not as good as in pMDS. Several attempts were done to develop a tMDS specific cytogenetic score. The best draft scoring component achieves a Dxy of 0.33. Counting the number of aberrations achieves a score of 0.30. If normal clone present or not is added, the performance of this very simple model is improved with a Dxy of 0.32. As we could show, all these different approaches lead to a comparable performance. One can argue that still regarding a few karyotypes the prognostic impact is slightly different between p and tMDS (e.g. +8). On the other hand, the most practical approach seems to be to adopt the original cytogenetic part of the IPSS-R for further score development since clinicians do not need to use different scoring systems for different MDS subtypes. While the final analyses for the development of a tMDS specific risk score are currently under way, extensive calculations regarding the performance of different scores like WHO- (Dxy 0.24), FAB-classification (Dxy 0.19), WPSS-R (Dxy 0.35), IPSS-R (Dxy 0.37), and IPSS-R+age (Dxy 0.36), show all these systems can separate different risk groups within our cohort. However, these results also show an inferior performance of the scoring systems in t compared to pMDS. There are multiple possible reasons for this. The most important seem to be tMDS patients are often not cured from the primary disease and its disease specific risk of death should ideally be considered. Unfortunately, we don't have that data. And second, we included treated as well as untreated patients. It seems not to be feasible otherwise since the selection bias for old unfit patients would be unacceptable. We could show already in pMDS that the score performances are considerably worse if we analyze treated patients and the score performance in our cohort is better if limited to untreated patients. To conclude, we can say existing classification and scoring systems work in tMDS and can separate groups with clearly different risk for death and transformation. Although we could not develop a tMDS specific cytogenetic score this could be seen positively since it underlines tMDS do not seem to be much different regarding disease specific risk. This should initiate a discussion of a revision of the WHO-classification and encourage clinicians to use the existing tools for risk assessment and treatment decisions. A simple solution could be to use the WHO classification for pMDS and precede each subgroup with a t, like tMDS-SLD, and so on. Such an approach would be of importance for patients falsely classified as tMDS. After all this classification is done according to anamnestic information only and sporadic cases cannot be excluded. Until now, in the first analyzes performed with the final tMDS-database, we did not find any indication that risk factors established in pMDS would lose or change their meaning in tMDS. Figure. Figure. Disclosures Komrokji: Celgene: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. List:Celgene: Research Funding. Roboz:Orsenix: Consultancy; Eisai: Consultancy; Novartis: Consultancy; Celltrion: Consultancy; Astex Pharmaceuticals: Consultancy; Argenx: Consultancy; Janssen Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Argenx: Consultancy; Janssen Pharmaceuticals: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Daiichi Sankyo: Consultancy; Sandoz: Consultancy; Otsuka: Consultancy; Daiichi Sankyo: Consultancy; Eisai: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Novartis: Consultancy; Celltrion: Consultancy; Celgene Corporation: Consultancy; Cellectis: Research Funding; Orsenix: Consultancy; Aphivena Therapeutics: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; Roche/Genentech: Consultancy; Aphivena Therapeutics: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Bayer: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy. Döhner:Jazz: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Pfizer: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Celator: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Astellas: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Valent:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Platzbecker:Celgene: Research Funding. Lübbert:TEVA: Other: Study drug; Celgene: Other: Travel Support; Cheplapharm: Other: Study drug; Janssen: Honoraria, Research Funding. Díez-Campelo:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Stauder:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Research Funding. Germing:Janssen: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.
- Published
- 2018
27. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia
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Ignacio Lorenzo, Leonor Arenillas, José Cervera, David Valcárcel, Benet Nomdedeu, Luca Malcovati, Mari Luz Amigo, Matteo G. Della Porta, Barbara Hildebrandt, Blanca Xicoy, Elisa Luño, Esperanza Such, Guillermo Sanz, Ilaria Ambaglio, Ulrich Germing, Mario Cazzola, Andrea Kuendgen, and Kathrin Nachtkamp
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Multivariate analysis ,Acute myeloblastic leukemia ,Immunology ,Chronic myelomonocytic leukemia ,Risk Assessment ,Biochemistry ,Cohort Studies ,Hemoglobins ,Young Adult ,Risk Factors ,hemic and lymphatic diseases ,Internal medicine ,Outcome Assessment, Health Care ,medicine ,Humans ,Intensive care medicine ,Survival analysis ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,business.industry ,Proportional hazards model ,Myelodysplastic syndromes ,Reproducibility of Results ,Leukemia, Myelomonocytic, Chronic ,Cell Biology ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Leukemia ,Leukemia, Myeloid ,Acute Disease ,Multivariate Analysis ,Female ,Erythrocyte Transfusion ,business ,Cohort study - Abstract
The natural course of chronic myelomonocytic leukemia (CMML) is highly variable but a widely accepted prognostic scoring system for patients with CMML is not available. The main aim of this study was to develop a new CMML-specific prognostic scoring system (CPSS) in a large series of 558 patients with CMML (training cohort, Spanish Group of Myelodysplastic Syndromes) and to validate it in an independent series of 274 patients (validation cohort, Heinrich Heine University Hospital, Dusseldorf, Germany, and San Matteo Hospital, Pavia, Italy). The most relevant variables for overall survival (OS) and evolution to acute myeloblastic leukemia (AML) were FAB and WHO CMML subtypes, CMML-specific cytogenetic risk classification, and red blood cell (RBC) transfusion dependency. CPSS was able to segregate patients into 4 clearly different risk groups for OS (P < .001) and risk of AML evolution (P < .001) and its predictive capability was confirmed in the validation cohort. An alternative CPSS with hemoglobin instead of RBC transfusion dependency offered almost identical prognostic capability. This study confirms the prognostic impact of FAB and WHO subtypes, recognizes the importance of RBC transfusion dependency and cytogenetics, and offers a simple and powerful CPSS for accurately assessing prognosis and planning therapy in patients with CMML.
- Published
- 2013
28. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms
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Simona Conte, Sudhir Tauro, Jacqueline Boultwood, Erica Travaglino, Peter J. Campbell, Michael J. Groves, Norene Keenan, Eva Hellström-Lindberg, Elli Papaemmanuil, Anna L. Godfrey, Mario Cazzola, P. Andrew Futreal, Jonathan Hinton, Ann Hyslop, Cristiana Pascutto, Ilaria Ambaglio, Matteo G. Della Porta, Luca Malcovati, James S. Wainscoat, Anna Gallì, Matteo Claudio Da Via, David T. Bowen, Michael R. Stratton, and Laura Mudie
- Subjects
Male ,Oncology ,medicine.medical_specialty ,Erythroblasts ,DNA Mutational Analysis ,Immunology ,Plenary Paper ,Biology ,medicine.disease_cause ,Lower risk ,Biochemistry ,Myelodysplastic–myeloproliferative diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Clinical significance ,Codon ,Alleles ,Genetic Association Studies ,Survival analysis ,Aged ,Sex Characteristics ,Mutation ,Myelodysplastic syndromes ,Hazard ratio ,Cell Biology ,Hematology ,Middle Aged ,Ribonucleoprotein, U2 Small Nuclear ,Phosphoproteins ,Prognosis ,medicine.disease ,Myelodysplastic-Myeloproliferative Diseases ,Survival Analysis ,Leukemia, Myeloid, Acute ,Myelodysplastic Syndromes ,Refractory anemia with ring sideroblasts ,Female ,RNA Splicing Factors ,Follow-Up Studies - Abstract
In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS.
- Published
- 2016
29. The influence of disease and comorbidity risk assessments on the survival of MDS and oligoblastic AML patients treated with 5-azacitidine: A retrospective analysis in ten centers of the 'Rete Ematologica Lombarda'
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Alessandra Freyrie, Emanuele Ravano, Enrica Morra, Roberto Cairoli, Jacopo Mariotti, Marta Ubezio, Rosa Greco, Matteo G. Della Porta, Domenica Caramazza, Massimo Bernardi, Marta Riva, Simona Guarco, Alfredo Molteni, Lorenza Borin, Giulia Quaresmini, Michele Nichelatti, Federica Gigli, Anna Maria Pelizzari, Molteni, A, Riva, M, Borin, L, Bernardi, M, Pelizzari, A, Freyrie, A, Della Porta, M, Nichelatti, M, Ravano, E, Quaresmini, G, Mariotti, J, Caramazza, D, Ubezio, M, Guarco, S, Gigli, F, Greco, R, Cairoli, R, and Morra, E
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Antimetabolites, Antineoplastic ,Azacitidine ,Disease ,Comorbidity ,Kaplan-Meier Estimate ,Prognostic indice ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Humans ,Young adult ,Psychiatry ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Myelodysplastic syndromes ,Retrospective cohort study ,5-Azacytidine ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Myeloid, Acute ,Oncology ,ROC Curve ,International Prognostic Scoring System ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,High risk myelodysplastic syndrome ,Oligoblastic acute myeloid leukemia ,Female ,business ,Risk assessment ,030215 immunology ,medicine.drug - Abstract
5-Azacytidine is an effective therapy in high risk MDS and oligoblastic AML. This "real life" analysis was made on 185 patients treated with 5-azacytidine in 10 centers afferent to REL ("Rete Ematologica Lombarda"), a network in Lombardia region. The aim was to assess the influence of disease and comorbidity risk assessments on the survival. The results confirm the utility of 5-azacitidine in prolonging OS regardless of advanced age and the presence of comorbidities. They also encourage an early treatment since patients with IPSS-R High risk MDS have better outcome with respect to Very High risk ones. According to the IPSS cytogenetic risk, there was no difference in the outcome between Intermediate and High risk patients. Nevertheless, a poorer cytogenetic risk, according to the IPSS-R cytogenetic stratification, negatively influenced the outcome.
- Published
- 2016
30. Clinical effects of driver somatic mutations on the outcomes of patients with myelodysplastic syndromes treated with allogeneic hematopoietic stem-cell transplantation
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Cristina Tresoldi, Mariella Cuzzola, Orietta Spinelli, Mario Cazzola, Andrea Bacigalupo, Silvia Luchetti, Ettore Rizzo, Silvia Zibellini, Laura Pezzetti, Silvia Catricalà, Benedetto Bruno, Marianna Rossi, Marta Ubezio, Simona Sica, Chiara Milanesi, Maria Teresa Voso, Emilio Paolo Alessandrino, Riccardo Bellazzi, Anna Gallì, Sarah Pozzi, Armando Santoro, Virginia Valeria Ferretti, Massimo Bernardi, Emanuele Angelucci, Alessandro Rambaldi, Alberto Bosi, Pietro Pioltelli, Paola Marenco, Ivan Limongelli, Fabio Ciceri, Matteo G. Della Porta, Alberto Malovini, Elli Papaemmanuil, Maria Teresa Van Lint, Francesca Bonifazi, Bernardino Allione, Alberto Riva, Della Porta, Matteo G., Gallì, Anna, Bacigalupo, Andrea, Zibellini, Silvia, Bernardi, Massimo, Rizzo, Ettore, Allione, Bernardino, Van Lint, Maria Teresa, Pioltelli, Pietro, Marenco, Paola, Bosi, Alberto, Voso, Maria Teresa, Sica, Simona, Cuzzola, Mariella, Angelucci, Emanuele, Rossi, Marianna, Ubezio, Marta, Malovini, Alberto, Limongelli, Ivan, Ferretti, Virginia V., Spinelli, Orietta, Tresoldi, Cristina, Pozzi, Sarah, Luchetti, Silvia, Pezzetti, Laura, Catricalà, Silvia, Milanesi, Chiara, Riva, Alberto, Bruno, Benedetto, Ciceri, Fabio, Bonifazi, Francesca, Bellazzi, Riccardo, Papaemmanuil, Elli, Santoro, Armando, Alessandrino, Emilio P., Rambaldi, Alessandro, and Cazzola, Mario
- Subjects
Oncology ,medicine.medical_specialty ,Cancer Research ,Myeloid ,Somatic cell ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,business.industry ,Myelodysplastic syndromes ,Myeloid leukemia ,ORIGINAL REPORTS ,medicine.disease ,Transplantation ,Haematopoiesis ,Settore MED/15 - MALATTIE DEL SANGUE ,medicine.anatomical_structure ,RUNX1 ,chemistry ,030220 oncology & carcinogenesis ,Immunology ,business ,030215 immunology - Abstract
Purpose The genetic basis of myelodysplastic syndromes (MDS) is heterogeneous, and various combinations of somatic mutations are associated with different clinical phenotypes and outcomes. Whether the genetic basis of MDS influences the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) is unclear. Patients and Methods We studied 401 patients with MDS or acute myeloid leukemia (AML) evolving from MDS (MDS/AML). We used massively parallel sequencing to examine tumor samples collected before HSCT for somatic mutations in 34 recurrently mutated genes in myeloid neoplasms. We then analyzed the impact of mutations on the outcome of HSCT. Results Overall, 87% of patients carried one or more oncogenic mutations. Somatic mutations of ASXL1, RUNX1, and TP53 were independent predictors of relapse and overall survival after HSCT in both patients with MDS and patients with MDS/AML (P values ranging from .003 to .035). In patients with MDS/AML, gene ontology (ie, secondary-type AML carrying mutations in genes of RNA splicing machinery, TP53-mutated AML, or de novo AML) was an independent predictor of posttransplantation outcome (P = .013). The impact of ASXL1, RUNX1, and TP53 mutations on posttransplantation survival was independent of the revised International Prognostic Scoring System (IPSS-R). Combining somatic mutations and IPSS-R risk improved the ability to stratify patients by capturing more prognostic information at an individual level. Accounting for various combinations of IPSS-R risk and somatic mutations, the 5-year probability of survival after HSCT ranged from 0% to 73%. Conclusion Somatic mutation in ASXL1, RUNX1, or TP53 is independently associated with unfavorable outcomes and shorter survival after allogeneic HSCT for patients with MDS and MDS/AML. Accounting for these genetic lesions may improve the prognostication precision in clinical practice and in designing clinical trials.
- Published
- 2016
31. Harmonemia: a universal strategy for flow cytometry immunophenotyping-A European LeukemiaNet WP10 study
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M C Béné, S Couzens, Ulf Johansson, Kaoutar Allou, Wolfgang Kern, Richard Ratei, Thomas Matthes, Matteo G. Della Porta, Anna Porwit, Frank Preijers, Marion G. Macey, C Palacio, David Bloxham, Sanna Siitonen, E Bernal, Artur Paiva, Ricardo Morilla, and Francis Lacombe
- Subjects
0301 basic medicine ,Oncology ,Citometria de Fluxo ,Cancer Research ,medicine.medical_specialty ,Imunofenotipagem ,Bioinformatics ,Immunophenotyping ,Flow cytometry ,03 medical and health sciences ,European LeukemiaNet ,0302 clinical medicine ,Internal medicine ,Humans ,Medicine ,ddc:616 ,medicine.diagnostic_test ,business.industry ,Hematology ,Flow Cytometry ,Europe ,030104 developmental biology ,Hematologic Neoplasms ,030220 oncology & carcinogenesis ,business - Abstract
Harmonemia: a universal strategy for flow cytometry immunophenotyping—A European LeukemiaNet WP10 study
- Published
- 2016
32. Multicenter validation of a reproducible flow cytometric score for the diagnosis of low-grade myelodysplastic syndromes: results of a European LeukemiaNET study
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Matteo G. Della Porta, Hideto Tamura, Anna Porwit, Canan Alhan, Claudia Cali, Leonie Saft, Magdalena Czader, Theresia M. Westers, Hiroshi Handa, Arjan A. van de Loosdrecht, Luca Malcovati, Cristina Picone, Sylvie D. Freeman, Cristiana Pascutto, Kiyoyuki Ogata, Paresh Vyas, Hematology laboratory, Hematology, and CCA - Disease profiling
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Pathology ,Adolescent ,CD34 ,Bone Marrow Cells ,Sensitivity and Specificity ,Immunophenotyping ,Young Adult ,Internal medicine ,Myeloblast ,medicine ,Humans ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Myelodysplastic syndromes ,Cytogenetics ,Reproducibility of Results ,Retrospective cohort study ,Hematology ,Middle Aged ,Flow Cytometry ,medicine.disease ,medicine.anatomical_structure ,Dysplasia ,Myelodysplastic Syndromes ,Cohort ,Female ,Neoplasm Grading ,Original Articles and Brief Reports ,business - Abstract
BACKGROUND: The current World Health Organization classification of myelodysplastic syndromes is based morphological evaluation of bone marrow dysplasia. In clinical practice, the reproducibility of the recognition of dysplasia is usually poor especially in cases that lack specific markers such as ring sideroblasts and clonal cytogenetic abnormalities. DESIGN AND METHODS: We aimed to develop and validate a flow cytometric score for the diagnosis of myelodysplastic syndrome. Four reproducible parameters were analyzed: CD34(+) myeloblast-related and B-progenitor-related cluster size (defined by CD45 expression and side scatter characteristics CD34(+) marrow cells), myeloblast CD45 expression and granulocyte side scatter value. The study comprised a "learning cohort" (n=538) to define the score and a "validation cohort" (n=259) to confirm its diagnostic value. RESULTS: With respect to non-clonal cytopenias, patients with myelodysplastic syndrome had increased myeloblast-related cluster size, decreased B-progenitor-related cluster size, aberrant CD45 expression and reduced granulocyte side scatter (P
- Published
- 2012
33. Predicting and preventing cardiotoxicity in the era of breast cancer targeted therapies. Novel molecular tools for clinical issues
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Alberto Riccardi, Carlo Tondini, Matteo G. Della Porta, Luciana De Giuli, Alberto Zambelli, Ermanno Eleuteri, and Oronzo Catalano
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Niacinamide ,Oncology ,Pathology ,medicine.medical_specialty ,Indoles ,Bevacizumab ,Pyridines ,medicine.medical_treatment ,Angiogenesis Inhibitors ,Antineoplastic Agents ,Breast Neoplasms ,Antibodies, Monoclonal, Humanized ,Lapatinib ,Cardiotoxins ,Risk Assessment ,Targeted therapy ,Breast cancer ,Trastuzumab ,Internal medicine ,Sunitinib ,medicine ,Humans ,Pyrroles ,Molecular Targeted Therapy ,Protein Kinase Inhibitors ,Heart Failure ,Cardiotoxicity ,business.industry ,Phenylurea Compounds ,Benzenesulfonates ,Antibodies, Monoclonal ,Cancer ,General Medicine ,Sorafenib ,medicine.disease ,Clinical trial ,Cardiovascular Diseases ,Quinazolines ,Female ,Surgery ,business ,Biomarkers ,medicine.drug - Abstract
Treatment of breast cancer (BC) has changed over the last decade with the advent of targeted therapies. Whereas traditional chemotherapy was directed toward all rapidly dividing cells (cancerous or not), several new anti-cancer drugs are mainly tailored to specific genetic pathways of cancer cells. Ideally, the goal of these new therapies is to improve the management of cancer with a specific targeting of the malignant cell and fewer side effects than traditional chemotherapy. Due to the initial success of this approach, an increasing number of targeted drugs entered into clinical development. However, unanticipated side effects of the new drugs, such as cardiotoxicity and heart failure, emerged from several clinical trials. The mechanisms of cardiotoxicity due to traditional chemotherapy and the one due to new drugs seem to be inherently different. In the case of BC, available targeted therapies are probably associated with the abrogation of normal molecular pathways involved in cardiomyocytes and endothelial cells survival/proliferation. The cardiac safety profile of these new drugs asks for a careful patient monitoring and follow up. Herein we will review the cardiotoxicity of BC patients receiving antiERBB2 treatment (Trastuzumab, Lapatinib), VEGF inhibitors (Bevacizumab) and tirosin-kinase inhibitors (Sorafenib, Sunitinib). We will discuss the molecular mechanisms that underlie the risk of cardiotoxicity, and we will examine the molecular tools useful for prediction of heart failure and for identification of subgroups of BC patients more susceptible to cardiac side effects induced by targeted therapies. Attention will be paid in particular to ERBB2 gene and its polymorphisms, as well as to the possible genetic risk stratification of BC patients. Finally, we will discuss the possible clinical strategies to prevent and minimizing the cardiotoxicity of targeted therapies in BC patients, focusing in particular on new drugs combination and on the emerging role of a tight partnership between cardiologists and oncologists.
- Published
- 2011
34. From cancer patients to cancer survivors: The issue of Cardioncology – A biological perspective
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Matteo G. Della Porta, Vittorio Rosti, and Alberto Zambelli
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Oncology ,Tumor angiogenesis ,Cancer Research ,medicine.medical_specialty ,Antineoplastic Agents ,Lower risk ,Metastasis ,Neoplasms ,Internal medicine ,medicine ,Humans ,Neoplasm Metastasis ,Progenitor cell ,Cardiotoxicity ,Neovascularization, Pathologic ,business.industry ,Stem Cells ,Regeneration (biology) ,Endothelial Cells ,Cancer ,medicine.disease ,Cardiovascular Diseases ,Concomitant ,Immunology ,Endothelium, Vascular ,business - Abstract
Long-term survival of cancer patients can be worsened by cardiovascular morbidity and mortality due to anticancer treatments based on cardiotoxic or antiangiogenic regimens. Growing scientific evidences support a role for circulating endothelial progenitor cells (EPCs) both in cancer pathogenesis and in cardiovascular diseases. High frequency of circulating EPCs seems to play a role in cancer growth and dissemination by favouring tumor angiogenesis and estabilishment of sites of metastasis. On the other hand, high level of circulating EPCs seems to be associated with a lower risk of developing cardiovascular diseases and with improved vascular regeneration after cardiovascular damage. Here, the possibile opposing roles of circulating EPCs in cancer patients suffering from therapy related-cardiovascular diseases are discussed, under the light of the potential modulation of their levels for therapeutic purposes. This can become a relevant issue in the field of cardioncology, the discipline that deals with the managing and treatment of cancer patients suffering from concomitant cardiovascular diseases or who are exposed to an increased risk to develop therapy related-cardiovascular complications.
- Published
- 2010
35. Diagnostic utility of flow cytometry in low-grade myelodysplastic syndromes: a prospective validation study
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Matteo G. Della Porta, Kiyoyuki Ogata, Hideto Tamura, Kazuo Dan, Luca Malcovati, Cristina Picone, Norio Yokose, Akira Matsuda, Junichi Tsukada, and Taishi Yamashita
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Multiple abnormalities ,medicine.medical_specialty ,Pathology ,Cytopenia ,Hematology ,business.industry ,Myelodysplastic syndromes ,Reference range ,medicine.disease ,Gastroenterology ,medicine.anatomical_structure ,Immunophenotyping ,Internal medicine ,Myeloblast ,medicine ,Original Article ,business ,Prospective cohort study - Abstract
Background The diagnosis of myelodysplastic syndromes is not always straightforward when patients lack specific diagnostic markers, such as blast excess, karyotype abnormality, and ringed sideroblasts.Design and Methods We designed a flow cytometry protocol applicable in many laboratories and verified its diagnostic utility in patients without those diagnostic markers. The cardinal parameters, analyzable from one cell aliquot, were myeloblasts (%), B-cell progenitors (%), myeloblast CD45 expression, and channel number of side scatter where the maximum number of granulocytes occurs. The adjunctive parameters were CD11b, CD15, and CD56 expression (%) on myeloblasts. Marrow samples from 106 control patients with cytopenia and 134 low-grade myelodysplastic syndromes patients, including 81 lacking both ringed sideroblasts and cytogenetic aberrations, were prospectively analyzed in Japan and Italy.Results Data outside the predetermined reference range in 2 or more parameters (multiple abnormalities) were common in myelodysplastic syndromes patients. In those lacking ringed sideroblasts and cytogenetic aberrations, multiple abnormalities were observed in 8/26 Japanese (30.8%) and 37/55 Italians (67.3%) when the cardinal parameters alone were considered, and in 17/26 Japanese (65.4%) and 42/47 Italians (89.4%) when all parameters were taken into account. Multiple abnormalities were rare in controls. When data from all parameters were used, the diagnostic sensitivities were 65% and 89%, specificities were 98% and 90%, and likelihood ratios were 28.1 and 8.5 for the Japanese and Italian cohorts, respectively.Conclusions This protocol can be used in the diagnostic work-up of low-grade myelodysplastic syndromes patients who lack specific diagnostic markers, although further improvement in diagnostic power is desirable.
- Published
- 2009
36. Clinical Relevance of Bone Marrow Fibrosis and CD34-Positive Cell Clusters in Primary Myelodysplastic Syndromes
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Erica Travaglino, Emanuela Boveri, Umberto Magrini, Mario Lazzarino, Mario Cazzola, Matteo G. Della Porta, Rosangela Invernizzi, A. Castello, Francesco Passamonti, Cristiana Pascutto, Luca Malcovati, and Daniela Pietra
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Myelodysplastic syndromes ,CD34 ,Antigens, CD34 ,bone marrow biopsy ,Gastroenterology ,Leukemia, Myelomonocytic, Acute ,Diagnosis, Differential ,Bone Marrow ,Fibrosis ,Internal medicine ,Humans ,Medicine ,Clinical significance ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Cytogenetics ,Cancer ,Middle Aged ,Prognosis ,medicine.disease ,Leukemia ,medicine.anatomical_structure ,Oncology ,Female ,Bone marrow ,business - Abstract
Purpose We studied bone marrow (BM) histologic abnormalities in myelodysplastic syndromes (MDS) classified according to WHO criteria to determine their clinical correlates and prognostic value. Patients and Methods Three hundred one consecutive patients were retrospectively evaluated for BM fibrosis and CD34 immunoreactivity. Marrow fibrosis was assessed following the European consensus guidelines. Results Moderate to severe BM fibrosis was detected in 17% of cases and was associated with multilineage dysplasia (P = .001), high transfusion requirement (P < .001), and poor-risk cytogenetics (P = .007). CD34+ cell clusters were found in 23% of patients and were associated with WHO categories with excess of blasts (P < .001) and poor-risk cytogenetics (P = .001). In multivariable analysis, BM fibrosis and presence of CD34+ cell clusters had independent negative impact on overall survival (P < .001 and P = .019, respectively) and leukemia-free survival (P < .001 and P = .004, respectively). A hierarchical clustering analysis identified three subsets of patients with distinct clinical features. One cluster consisted mainly of patients with BM fibrosis, multilineage dysplasia, and high transfusion requirement; these individuals had lower overall survival and leukemia-free survival (P = .001 and P < .001, respectively). Within patients stratified according to International Prognostic Scoring System and WHO classification–based Prognostic Scoring System categories, BM fibrosis involved a shift to a one-step more advanced risk group. Conclusion BM fibrosis identifies a distinct subgroup of MDS with multilineage dysplasia, high transfusion requirement, and poor prognosis and represents an independent prognostic factor that may be useful in clinical decision making. Furthermore, the presence of CD34+ cell clusters is an independent risk factor for progression to acute leukemia.
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- 2009
37. Methylenetetrahydrofolate reductase C677T and A1298C gene variants in adult non-Hodgkin's lymphoma patients: association with toxicity and survival
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Matteo G. Della Porta, Giuseppe Gilli, Agnese Pellati, Silvia Tognazzo, Alessia Ongaro, Endri Mauro, Angelo Caruso, Monica De Mattei, Donato Gemmati, Diana Campioni, Antonella Bardi, Linda Catozzi, Federica Federici, and Gian L. Scapoli
- Subjects
Male ,medicine.medical_treatment ,Leucovorin ,Kaplan-Meier Estimate ,CHOP ,Gastroenterology ,Antineoplastic Combined Chemotherapy Protocols ,pharmacogenetics ,Aged, 80 and over ,biology ,Hematology ,Middle Aged ,Neoplasm Proteins ,Treatment Outcome ,Vincristine ,Toxicity ,Female ,Lymphoma, Large B-Cell, Diffuse ,Chemical and Drug Induced Liver Injury ,medicine.drug ,Adult ,Mucositis ,Risk ,Antimetabolites, Antineoplastic ,medicine.medical_specialty ,Adolescent ,Genotype ,Polymorphism, Single Nucleotide ,survival ,NO ,Bleomycin ,Internal medicine ,medicine ,Humans ,Cyclophosphamide ,Methylenetetrahydrofolate Reductase (NADPH2) ,Survival analysis ,Aged ,Chemotherapy ,toxicity ,non-Hodgkin’s lymphoma ,MTHFR SNP ,medicine.disease ,Hematologic Diseases ,Survival Analysis ,Non-Hodgkin's lymphoma ,Methotrexate ,Amino Acid Substitution ,Doxorubicin ,Methylenetetrahydrofolate reductase ,Immunology ,biology.protein ,Prednisone - Abstract
Background and Objectives Common methylenetetrahydrofolate reductase gene variants (MTHFR C677T and A1298C) have been described to have opposite effects on cancer patients. They may reduce cancer susceptibility and increase drug-related toxicity when folate antagonists (e.g. methotrexate) are utilized. We analyzed 110 patients with high-grade non-Hodgkin’s lymphoma (NHL), 68 of whom were eligible for a chemotherapy combination containing methotrexate (MACOP-B) and 42 for chemotherapy without methotrexate (CHOP).Design and Methods Patients were genotyped by polymerase chain reaction and stratified by MTHFR variants. These data were related to the toxicity (WHO grade GO-4) that the patients suffered and their survival. Overall 64 cases (58.2%) developed some form of toxicity and 23 (20.9%) had grade 3/4 toxicity.Results When considering toxicity of any grade (grade 1–4), the 677TT genotype was significantly over-represented among cases with mucositis (OR=4.85; 95%CI, 1.47–15.97; p=0.009) and those with hepatic toxicity (OR=3.43; 95%CI, 0.99–11.86; p=0.052). Sub-analyses in the group treated with MACOP-B showed a slight increase in the risk of developing mucositis (OR=5.22; 95%CI, 1.20–27.27; p=0.03), and a strong increase in the risk of hepatic toxicity (OR=7.08; 95%CI, 1.38–36.2; p=0.019) and thrombocytopenia (OR=7.69, 95%CI 1.0–58.94; p=0.05). Interestingly, compared to the risk of developing toxicity of any grade, the risk of developing severe (grade 3/4) mucositis was almost doubled in the whole group of cases with 677TT (OR=8.13; 95%CI 1.61–41.04; p=0.011) and dramatically increased in the MACOP-B-treated cases with this gene variant (OR=24.6; 95%CI 2.49–87.41; p=0.001). There were significant results for 1298CC cases exclusively for mucositis (any grade, OR=5.33; 95%CI, 1.25–22.70; p=0.023 and OR=9.15; 95%CI, 1.14–73.41; p=0.037; for the whole group and the MACOP-B-treated group, respectively). Similarly, the risk of 1298CC patients developing severe mucositis increased (OR=9.24; 95%CI, 1.47–58.0; p=0.017 and OR=11.53; 0.93–143.18; p=0.057; in the whole group and in the MACOP-B-treated group, respectively). Event-free survival analysis revealed a lower probability of event-free survival at 5 years for 677T-carriers (log-ranks, p=0.05 and p=0.07 in the whole group and in the MACOP-B-treated group, respectively). More significant results were obtained when 1298CC cases were excluded from the reference group (log-ranks, p=0.03 and p=0.04, respectively). No significant associations were found in the CHOP-treated group.Interpretation and Conclusions Our data suggest that MTHFR gene variants play a critical role in NHL outcome, possibly by interfering with the action of methotrexate with significant effects on toxicity and survival. Genotyping of folate pathway gene variants might be useful to enable reduction of chemotherapy toxicity and/or to improve survival by indicating when dose adjustments or alternative treatments are necessary.
- Published
- 2007
38. Prognostic models in myelodysplastic syndromes
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Matteo G. Della Porta
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Oncology ,medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,Hematology ,medicine.disease ,Prognosis ,Text mining ,Internal medicine ,Myelodysplastic Syndromes ,medicine ,Humans ,business ,Prognostic models - Published
- 2015
39. Correlation of the FLIPI score for follicular lymphoma with period of diagnosis and type of treatment
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Francesco Passamonti, Francesca Montanari, Cristiana Pascutto, Matteo G. Della Porta, Sara Burcheri, Ercole Brusamolino, Nora Colombo, Marco Paulli, Ester Orlandi, Luca Arcaini, Elisa Rumi, and Mario Lazzarino
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Adult ,Male ,Research design ,Cancer Research ,medicine.medical_specialty ,Pathology ,Adolescent ,Anthracycline ,Follicular lymphoma ,Antineoplastic Agents ,Severity of Illness Index ,Disease-Free Survival ,Correlation ,Risk groups ,Risk Factors ,hemic and lymphatic diseases ,Internal medicine ,Severity of illness ,Humans ,Medicine ,Anthracyclines ,Lymphoma, Follicular ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Retrospective cohort study ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,FLIPI ,IPI ,Lymphoma ,Oncology ,Research Design ,Female ,business - Abstract
Objectives Follicular lymphoma (FL) is generally considered an indolent disorder but a significant subset of patients shows a worse outcome. Aim of this study was to validate the FLIPI score in an independent series of follicular lymphoma patients and to correlate prognostic categories with the period of diagnosis and the use of anthracycline. Methods We evaluated the clinical characteristics, prognostic stratification, and outcome of 338 patients with follicular lymphoma consecutively diagnosed and followed at our Institution between 1975 and 2002. Results The distribution of patients within the prognostic categories of the IPI and FLIPI score, while confirming the indolent outcome of follicular lymphoma, shows that a subset of patients has a worse prognosis. With the IPI score, 62% of patients are in the low risk, 26% in the low-intermediate, and 12% in the high (high-intermediate + high) risk group. With the FLIPI score, 48% of patients are categorized as low risk, 31% as intermediate risk, and 21% as poor risk. With the IPI score, median OS is 17.3 years for the low risk; 6.3 for the intermediate risk, and 5.2 years for the high risk group (p = 0.0004). With the FLIPI system, median OS is 15.5 years for the low risk, 8.3 years for the intermediate risk, and 5.2 for the poor risk group (p = 0.0002). Prognostic scores were calculated also after dividing patients according to the time of diagnosis: in three periods (before 1987, between 1988 and 1997, and from 1998), as well as in two periods (before and after 1998). In all the periods studied survival of patients classified according to IPI and FLIPI categories was significantly different. Conclusion This study shows in an independent series that the FLIPI score is a reproducible prognostic index of clinical utility for the initial assessment of patients with follicular lymphoma.
- Published
- 2006
40. Prognostic Factors and Life Expectancy in Myelodysplastic Syndromes Classified According to WHO Criteria: A Basis for Clinical Decision Making
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Erica Travaglino, Margherita Maffioli, Matteo G. Della Porta, Luca Malcovati, Cristiana Pascutto, Mario Cazzola, Mario Lazzarino, Rosangela Invernizzi, Paolo Bernasconi, Luca Arcaini, Francesco Passamonti, and Marina Boni
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Pediatrics ,Anemia ,acute myeloid leukemia ,decision making ,Life Expectancy ,Bone Marrow ,Internal medicine ,medicine ,Humans ,Blood Transfusion ,Aged ,Demography ,Retrospective Studies ,transfusion ,Aged, 80 and over ,Myelodysplastic syndrome ,anemia ,chromosomal aberration ,prognosis ,risk assessment ,Hematology ,business.industry ,Myelodysplastic syndromes ,Middle Aged ,medicine.disease ,Leukemia ,Standardized mortality ratio ,Oncology ,International Prognostic Scoring System ,Karyotyping ,Myelodysplastic Syndromes ,Life expectancy ,Female ,Refractory cytopenia with multilineage dysplasia ,business - Abstract
Purpose The aim of this study was to evaluate the prognostic value of the WHO proposal, to assess the role of the main prognostic factors in myelodysplastic syndromes (MDSs) classified into WHO subgroups, and to estimate mortality (standardized mortality ratio [SMR]) and life expectancy in these groups as a basis for clinical decision making. Patients and Methods Four hundred sixty-seven patients who were diagnosed as having de novo MDS at the Division of Hematology, University of Pavia (Pavia, Italy), between 1992 and 2002, were evaluated retrospectively for clinical and hematologic features at diagnosis, overall survival (OS), and progression to leukemia (leukemia-free survival). Results Significant differences in survival were noted between patients with refractory anemia (RA), refractory cytopenia with multilineage dysplasia, RA with excess blasts, type 1 (RAEB-1), and RAEB-2. The effect of demographic factors on OS was observed in MDS patients without excess blasts (age, P = .001; sex, P = .006), as in the general population. The mortality of RA patients 70 years or older did not differ significantly from that of the general population (SMR, 1.62; P = .06). Cytogenetics was the only International Prognostic Scoring System variable showing a prognostic value in MDS classified into WHO subgroups. Transfusion-dependent patients had a significantly shorter survival than patients who did not require transfusions (P < .001). Developing a secondary iron overload significantly affected the survival of transfusion-dependent patients (P = .003). Conclusion These data show that the WHO classification of MDSs has a relevant prognostic value. This classification, along with cytogenetics, might be useful in decisions regarding transplantation. MDS with isolated erythroid lineage dysplasia identifies a subset of truly low-risk patients, for whom a conservative approach is advisable.
- Published
- 2005
41. Leukemic transformation of polycythemia vera
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Paolo Bernasconi, Carlo Castagnola, Elisa Rumi, Mario Lazzarino, Francesco Passamonti, Mario Cazzola, Matteo G. Della Porta, Cristiana Pascutto, Monia Lunghi, Nora Columbo, and Luca Arcaini
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Cancer Research ,medicine.medical_specialty ,Myeloproliferative neoplasm ,Essential thrombocythemia ,Single Center ,Gastroenterology ,Polycythemia vera ,Internal medicine ,medicine ,Humans ,Acute myeloid leukemia ,Myelofibrosis ,Aged ,Chromosome Aberrations ,Acute leukemia ,Leukemia ,business.industry ,Induction chemotherapy ,Middle Aged ,medicine.disease ,Surgery ,Transplantation ,Regimen ,Oncology ,Karyotyping ,Acute Disease ,Cytarabine ,business ,medicine.drug - Abstract
BACKGROUND Acute leukemia (AL) may occur as rare and late event of polycythemia vera (PV). METHODS The current study included 23 patients who developed acute leukemia in a cohort of 414 consecutive PV patients with long-term observation (3208 person years of follow-up). Kaplan–Meier Product-Limit method was used to estimate the cumulative probability of survival; Gehan–Wilcoxon test was applied to compare survival in different groups of patients. RESULTS Median age was 68 years, and 18 patients (78%) were > 60 years of age. At diagnosis of AL, most patients had a white blood count > 10 × 109/L (n = 17; 74%), Hgb 50 × 109/L (n = 17; 74%). Of 14 patients in whom cytogenetic analysis was available at leukemic transformation, 12 showed high-risk abnormalities including complex karyotype (n = 10), del (7)(q22) sole (n = 1) and del (X)(q26) sole (n = 1), whereas 2 had a normal karyotype. In patients whose karyotype was available at diagnosis of PV, cytogenetic evolution was documented at progression to AL. Treatment consisted of supportive care and/or low-dose chemotherapy (n = 15), or induction chemotherapy (n = 8). This included idarubicin plus cytarabine (n = 3), high-dose cytarabine (n = 4), and fludarabine-based regimen (n = 1). Allogenic stem cell transplantation was offered to a single patient, who is alive at Day + 70. The outcome of patients was poor, with a median survival of 2.9 months (range, 0.6–20.1 mos), with no significant differences between palliation and intensive treatments. CONCLUSIONS AL following PV has distinct clinical and biologic features. Outcome of patients is poor irrespective of the treatment employed. Cancer 2005. © 2005 American Cancer Society.
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- 2005
42. Flow cytometric detection of accelerated telomere shortening in myelodysplastic syndromes: correlations with aetiological and clinical-biological findings*
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Antonio Cuneo, Anna Maria Bugli, Maria Ciccone, Gian Matteo Rigolin, Endri Mauro, Gianluigi Castoldi, Barbara Castagnari, Matteo G. Della Porta, and Letizia Zenone Bragotti
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Oncology ,medicine.medical_specialty ,medicine.diagnostic_test ,Myelodysplastic syndromes ,Cytogenetics ,CD34 ,Hematology ,General Medicine ,Biology ,medicine.disease ,Flow cytometry ,Telomere ,Apoptosis ,International Prognostic Scoring System ,Internal medicine ,Immunology ,medicine ,Clinical significance - Abstract
Using quantitative fluorescence in situ hybridisation and flow cytometry (flow-FISH), we investigated the biological and clinical relevance of telomere length in 55 patients affected by myelodysplastic syndromes (MDS) compared with 55 sex- and age-matched controls. We found that telomere fluorescence in MDS granulocytes, and CD34+ cells did not decline with age as in normal controls and that MDS granulocytes and CD34+ cells had significantly shorter telomeres than healthy controls. A significant higher incidence of cases with intermediate-unfavourable cytogenetics and International Prognostic Scoring System (IPSS) int-2/high-risk group was observed among patients with lower telomere fluorescence. We also found that apoptosis in CD34+ cells was significantly higher in IPSS int-1 low-risk patients when compared with IPSS int-2 high-risk cases and healthy controls and that CD34+ cell telomere fluorescence directly correlated with CD34+ cell apoptosis. Reduced telomere fluorescence was associated with a history of occupational exposure to toxic agents and with worse survival in univariate and multivariate analyses. Our results suggest that flow-cytometry assessment of telomere dynamics may represent a valuable tool in the biological and clinical–prognostic characterisation of MDS disorders.
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- 2004
43. Clinical significance of neutrophil CD177 mRNA expression in Ph-negative chronic myeloproliferative disorders
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Matteo G. Della Porta, Lucia Malabarba, Maurizio Bonfichi, Daniela Pietra, Elisa Rumi, Mario Lazzarino, Cristiana Pascutto, Francesco Passamonti, Mario Cazzola, and Luca Malcovati
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Polycythaemia ,medicine.medical_specialty ,Myeloid ,Hematology ,Granulocyte ,Biology ,medicine.disease ,Polycythemia vera ,medicine.anatomical_structure ,Internal medicine ,Immunology ,medicine ,Bone marrow ,Gene polymorphism ,Myelofibrosis - Abstract
The PRV-1 gene has been proposed as a marker of polycythaemia vera (PV). PRV-1 and NB1 are alleles of the polymorphic gene CD177, which belongs to the Ly-6/uPAR superfamily, and their coding regions differ at only four nucleotides. We studied neutrophil CD177 mRNA levels in normal subjects and in 235 patients with Ph-negative chronic myeloproliferative disorders (CMD), including PV, essential thrombocythaemia and myelofibrosis with myeloid metaplasia. Additional disease states were investigated for comparison. Highly variable neutrophil CD177 mRNA levels were observed in normal individuals. Neutrophils isolated from the bone marrow, or from peripheral blood following granulocyte colony-stimulating factor administration showed markedly higher CD177 expression than circulating granulocytes on steady state. Increased neutrophil CD177 mRNA levels were detected in all CMD. Elevated values were also found in reactive conditions and in disorders such as chronic myeloid leukaemia and myelodysplastic syndromes. In the differential diagnosis between PV and secondary erythrocytosis, the assay sensitivity was 68% while its specificity was 60%. These findings indicate that an elevated neutrophil CD177 mRNA level is not a specific marker for the diagnosis of PV nor for that of CMD. From a clinical viewpoint, neutrophil CD177 mRNA overexpression is rather a marker of abnormal neutrophil production and/or release in patients with CMD.
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- 2004
44. In patients with myelodysplastic syndromes response to rHuEPO and G-CSF treatment is related to an increase of cytogenetically normal CD34+ cells
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Matteo G. Della Porta, Gianluigi Castoldi, Maria Ciccone, Letizia Zenone Bragotti, Anna Maria Bugli, Chiara Fraulini, Antonio Cuneo, Endri Mauro, Antonella Bardi, Gian Matteo Rigolin, and Antonella Russo Rossi
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medicine.medical_specialty ,Hematology ,medicine.diagnostic_test ,Myelodysplastic syndromes ,CD34 ,Biology ,medicine.disease ,Granulocyte colony-stimulating factor ,Endocrinology ,Antigen ,Erythropoietin ,Internal medicine ,medicine ,Progenitor cell ,medicine.drug ,Fluorescence in situ hybridization - Abstract
The in vivo effect of recombinant human erythropoietin (rHuEpo) and granulocyte colony-stimulating factor (G-CSF) combined treatment on CD34(+) cells was evaluated by fluorescence in situ hybridization (FISH) in 13 myelodysplastic syndrome (MDS) patients with known cytogenetic abnormalities. After treatment, responsive patients presented a significantly lower proportion of FISH abnormal CD34(+) cells than before treatment (P = 0.003), and in comparison with unresponsive cases (P = 0.007). Response to treatment was associated with a reduced degree of apoptosis in CD34(+) cells (P = 0.021): however, no difference in telomere length was observed in responsive patients after growth factor administration. Although the number of patients analysed was relatively small, the present data suggest that, in MDS patients, response to rHuEpo and G-CSF may be related to the proliferation of karyotypically normal but potentially defective CD34(+) progenitor cells.
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- 2004
45. Soluble urokinase-type plasminogen activator receptor (suPAR) as an independent factor predicting worse prognosis and extra-bone marrow involvement in multiple myeloma patients
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Antonio Cuneo, Giovanni Guerra, Gianluigi Castoldi, Rosanna Carroccia, Alessia Tieghi, Matteo G. Della Porta, Barbara Castagnari, Maria Ciccone, Gian Matteo Rigolin, Francesco Cavazzini, and Letizia Zenone Bragotti
- Subjects
Urokinase ,medicine.medical_specialty ,Angiogenesis ,Hematology ,Biology ,Plasma cell ,medicine.disease ,Urokinase receptor ,medicine.anatomical_structure ,Endocrinology ,SuPAR ,Internal medicine ,medicine ,Bone marrow ,Plasminogen activator ,Multiple myeloma ,medicine.drug - Abstract
The urokinase-type plasminogen activator (uPA) system, which consists of a proteinase (uPA), a receptor (uPAR or CD87) and inhibitors, is involved in proteolysis, cell migration, tissue remodelling, angiogenesis and cell adhesion. Recent findings suggest that malignant plasma cells express uPA and uPAR. The expression of these factors could represent a process by which myeloma plasma cells interact with the bone marrow (BM) environment and influence important biological events such as bone matrix degradation, plasma cell invasion and homing and, possibly, clinical evolution. We evaluated uPAR (CD87) and its soluble form (suPAR) in 49 multiple myeloma (MM) patients and correlated their expression and levels with clinico-biological characteristics of the disease. Flow cytometric analysis demonstrated that CD87 was expressed in all MM patients. High CD87 expression was associated with higher intensity of expression of CD56 (P = 0.038), CD38 (P = 0.058) and CD138 (P = 0.054) and CD45bright positivity (P = 0.014). suPAR levels correlated positively with soluble serum CD138 (P = 0.001), creatinine (P = 0.001), beta2-microglobulin (P < 0.001), disease stage (P = 0.017) and extra-BM involvement (P = 0.002). In the 46 evaluable patients, multivariate analysis showed that high levels of suPAR (P = 0.0214) and disease stage (P = 0.0064) were predictive of extra-BM involvement. In multivariate Cox analysis, 13q deletion (P = 0.0278), high soluble serum CD138 (P = 0.0201) and high suPAR (P = 0.0229) were the only parameters that independently affected survival. We conclude that CD87 is expressed on myeloma plasma cells and that suPAR, which predicts extra-BM involvement and poor prognosis, possibly represents a molecule with a relevant role in the biology of MM.
- Published
- 2003
46. Predictive factors for the outcome of allogeneic transplantation in patients with MDS stratified according to the revised IPSS-R
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Francesco Onida, Alessandro Rambaldi, Matteo G. Della Porta, Massimo Bernardi, Anna Paola Iori, Raffaella Cerretti, Michele Falda, Francesco Ripamonti, Emilio Paolo Alessandrino, Alberto Bosi, Mario Cazzola, Maria Teresa Van Lint, Luca Malcovati, Pietro Pioltelli, Stefano Guidi, Cristiana Pascutto, Rosi Oneto, Andrea Bacigalupo, Paolo Bernasconi, Paola Marenco, and Emanuele Angelucci
- Subjects
Oncology ,Adult ,Male ,medicine.medical_specialty ,Allogeneic transplantation ,Adolescent ,medicine.medical_treatment ,Immunology ,Hematopoietic stem cell transplantation ,Kaplan-Meier Estimate ,Biochemistry ,Young Adult ,Recurrence ,Risk Factors ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Young adult ,Intensive care medicine ,Aged ,Proportional Hazards Models ,Hematology ,business.industry ,Proportional hazards model ,Myelodysplastic syndromes ,Hematopoietic Stem Cell Transplantation ,Cell Biology ,Middle Aged ,medicine.disease ,Allografts ,Prognosis ,Transplantation ,surgical procedures, operative ,Treatment Outcome ,International Prognostic Scoring System ,Myelodysplastic Syndromes ,Female ,business - Abstract
Approximately one-third of patients with myelodysplastic syndrome (MDS) receiving allogeneic hematopoietic stem cell transplantation (HSCT) are cured by this treatment. Treatment failure may be due to transplant complications or relapse. To identify predictive factors for transplantation outcome, we studied 519 patients with MDS or oligoblastic acute myeloid leukemia (AML
- Published
- 2014
47. Driver Somatic Mutations and Transplantation Decision Making in Patients with Myelodysplastic Syndrome
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Paola Marenco, Bernardino Allione, Benedetto Bruno, Emanuele Angelucci, Silvia Zibellini, Massimo Bernardi, Mario Cazzola, Emilio Paolo Alessandrino, Maria Cuzzola, Maria Teresa Van Lint, Matteo G. Della Porta, Andrea Bacigalupo, Chiara Milanesi, Alberto Bosi, Alessandro Rambaldi, Armando Santoro, Simona Sica, Anna Gallì, Marianna Rossi, Francesca Bonifazi, Fabio Ciceri, Ettore Rizzo, Pietro Pioltelli, and Maria Teresa Voso
- Subjects
Oncology ,medicine.medical_specialty ,Myeloid ,medicine.medical_treatment ,Immunology ,Hematopoietic stem cell transplantation ,Disease ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Cumulative incidence ,business.industry ,Myelodysplastic syndromes ,Induction chemotherapy ,Cell Biology ,Hematology ,medicine.disease ,Comorbidity ,Transplantation ,medicine.anatomical_structure ,business ,030215 immunology - Abstract
The genetic basis of myelodysplastic syndromes (MDS) is heterogeneous, and various somatic mutations are associated with different phenotypes and clinical outcomes. The only curative treatment for MDS patients is allogeneic hematopoietic stem cell transplantation (HSCT) which is considered as a therapeutic option until the age of 65-70 in eligible patients. Whether the genetic basis influences the outcome of HSCT is currently unclear. Recently, we observed that mutations on ASXL1, RUNX1 and TP53 genes are independent predictors of relapse and overall survival in MDS patients after HSCT, and that the integration of these mutations into currently available predictive models increases the capability to capture prognostic information at individual patient level (Della Porta MG et al. J Clin Oncol, 2016 in press). In this study, we explored the possibility of developing a clinical/molecular predictive model to specifically estimate the outcome after HSCT in patients with MDS or acute myeloid leukemia evolving from MDS (MDS/AML). We studied 401 patients undergoing allogeneic HSCT for primary MDS or MDS/AML between 1997 and 2013 and reported to the GITMO registry. We used massively parallel sequencing to examine tumor samples collected before HSCT for somatic mutations in 34 recurrently mutated genes in myeloid neoplasms. In multivariable analysis with probability of relapse as endpoint the following factors showed independent prognostic value: percentage of marrow blasts (>10% vs. ≤10%, HR 1.43, P=0.04), cytogenetic risk according to IPSSR (poor/very poor vs. very low/low/intermediate risk, HR 1.85, P=.002), disease status at transplant (refractoriness to induction chemotherapy vs. complete remission, HR 2.4, P40 vs. ≤40 years, HR 1.68, P=.001), comorbidity risk according to HCT-CI (high vs. low/intermediate risk 2.10, P Based on regression coefficients, we developed a clinical/molecular model predictive for the risk of relapse after transplantation in MDS and MDS/AML. Accordingly, a score value of 1 was assigned for each of the following risk factors: marrow blasts >10%, poor/very poor cytogenetic risk according to IPSSR, refractoriness to induction chemotherapy, and driver mutations in ASLX1/RUNX1/TP53 genes. A relapse risk index was calculated as the sum of these weighted scores, and was then categorized into 4 risk groups: low (score=0), intermediate (score=1-2), high (score=3), and very high (score=4). The cumulative incidence of relapse was estimated by a competing risks approach with TRM. In patients receiving standard conditioning, 5-year probability of survival after allogeneic HSCT was 61%, 43%, 39% and 19% for low, intermediate, high and very high risk (P This model serves as a proof of concept that the integration of somatic mutations significantly increase the capability to capture prognostic information in MDS and MDS/AML patients receiving allogeneic HSCT, and may provide a basis for improving clinical decision-making. Possible interventions in patients with high risk of disease relapse after HSCT according to genotype may include the anticipation of the transplant procedure in early disease phase, the use of innovative conditioning regimens to increase the probability to eradicate MDS clone, and prophylaxis of disease recurrence after transplantation by donor leukocyte infusions and targeted/novel therapies Disclosures Ciceri: MolMed SpA: Consultancy.
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- 2016
48. Inappropriately low hepcidin levels in patients with myelodysplastic syndrome carrying a somatic mutation of SF3B1
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Luca Malcovati, Matteo G. Della Porta, Coby M. Laarakkers, Dorine W. Swinkels, Marta Ubezio, Peter J. Campbell, Elisa Bono, Matteo Claudio Da Via, Mario Cazzola, Anna Gallì, Riccardo Albertini, Erica Travaglino, Elli Papaemmanuil, and Ilaria Ambaglio
- Subjects
Ineffective erythropoiesis ,Male ,medicine.medical_specialty ,Iron ,Iron metabolism Pathogenesis and modulation of inflammation [IGMD 7] ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Hepcidins ,Hepcidin ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Alleles ,Soluble transferrin receptor ,Aged ,Aged, 80 and over ,Mutation ,biology ,Myelodysplastic syndromes ,Hematology ,Articles ,Middle Aged ,Ribonucleoprotein, U2 Small Nuclear ,Iron metabolism Aetiology, screening and detection [IGMD 7] ,medicine.disease ,Phosphoproteins ,Ferritin ,Endocrinology ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Ferritins ,biology.protein ,Female ,GDF15 ,RNA Splicing Factors ,030215 immunology - Abstract
Contains fulltext : 118639.pdf (Publisher’s version ) (Open Access) Somatic mutations of the RNA splicing machinery have been recently identified in myelodysplastic syndromes. In particular, a strong association has been found between SF3B1 mutation and refractory anemia with ring sider-oblasts, a condition characterized by ineffective erythropoiesis and parenchymal iron overload. We studied the relationship between SF3B1 mutation, erythroid activity and hepcidin levels in myelodysplastic syndrome patients. Erythroid activity was evaluated through the proportion of marrow erythroblasts, soluble transferrin receptor and serum growth differentiation factor 15. Significant relationships were found between SF3B1 mutation and marrow erythroblasts (P=0.001), soluble transferrin receptor (P=0.003) and serum growth differentiation factor 15 (P=0.033). Serum hepcidin varied considerably, and multivariable analysis showed that the hepcidin to ferritin ratio, a measure of adequacy of hepcidin levels relative to body iron stores, was inversely related to the SF3B1 mutation (P=0.013). These observations suggest that patients with SF3B1 mutation have inappropriately low hepcidin levels, which may explain their propensity to parenchymal iron loading.
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- 2013
49. Rationale for the clinical application of flow cytometry in patients with myelodysplastic syndromes: position paper of an International Consortium and the European LeukemiaNet Working Group
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Detlef Haase, David T. Bowen, Jeroen G. te Marvelde, Alberto Orfao, Denise A. Wells, Spencer S. C. Chu, Peter Bettelheim, Luca Malcovati, Lisa Eidenschink, Shahram Kordasti, Katherina Psarra, Patricia Font, Florian Zettl, Gert J. Ossenkoppele, Pierre Fenaux, Vincent H.J. van der Velden, Arjan A. van de Loosdrecht, Ghulam J. Mufti, Dolores Subirá, Sergio Matarraz, Theo de Witte, John F. Seymour, Peter Valent, Mario Cazzola, B. Moshaver, Ulrich Germing, Stephen J. Richards, Anna Porwit, Wolfgang Kern, Veselka Nikolova, Ulrika Johansson, Vicky Tindell, Eva Hellström-Lindberg, Canan Alhan, Kate Burbury, Jean Feuillard, Uwe Platzbecker, Uta Oelschlaegel, Angelika M. Dräger, Teresa Vallespi, Jan Sebastian Balleisen, Matthew J. Cullen, Theresia M. Westers, Robin M. Ireland, Michael R. Loken, Marie C. Béné, Kiyoyuki Ogata, Matteo G. Della Porta, Jevon Cutler, T. Milne, Frank Preijers, Munich Leukemia Laboratory, MLL, Otto Wagner Hospital, 3.Central Laboratory, Department of Internal Medicine, Università degli Studi di Roma Tor Vergata [Roma], Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Service d'hématologie clinique [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Haematology, Oncology and Clinical Immunology, Centre for Haematology and Oncology, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Georg-August-University [Göttingen], Department of Medicine, Centre for Experimental Haematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Division of Hematology, Università degli Studi di Pavia, OF MEDICINE, FUNDACIÓN CENTRO DE INVESTIGACIÓN DEL CÁNCER, Department of Pathology, Karolinska University Hospital [Stockholm], Universitätsklinikum Carl Gustav Carus, Haematology, Vall d'Hebron University Hospital [Barcelona], Division of Hematology/Hemostaseology, Medical University Vienna, Ludwig Boltzmann Cluster Oncology, Hematology, Hematology laboratory, CCA - Disease profiling, Immunology, and Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS)
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Oncology ,Societies, Scientific ,Cancer Research ,medicine.medical_specialty ,Disease ,Outcome assessment ,Sensitivity and Specificity ,Flow cytometry ,03 medical and health sciences ,European LeukemiaNet ,0302 clinical medicine ,Translational research [ONCOL 3] ,Internal medicine ,Outcome Assessment, Health Care ,medicine ,Humans ,In patient ,medicine.diagnostic_test ,business.industry ,Myelodysplastic syndromes ,Translational research Immune Regulation [ONCOL 3] ,International Agencies ,Reproducibility of Results ,Hematology ,International working group ,medicine.disease ,Flow Cytometry ,Prognosis ,3. Good health ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Physical therapy ,Position paper ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,business ,030215 immunology - Abstract
Item does not contain fulltext An international working group within the European LeukemiaNet gathered, aiming to determine the role of flow cytometry (FC) in myelodysplastic syndromes (MDS). It was agreed that FC has a substantial application in disease characterization, diagnosis and prognosis. FC may also be useful in predicting treatment responses and monitoring novel and standard therapeutic regimens. In this article the rationale is discussed that flow cytometry should be integrated as a part of diagnostic and prognostic scoring systems in MDS.
- Published
- 2013
50. Hematologic responses to deferasirox therapy in transfusion-dependent patients with myelodysplastic syndromes
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Carlo Finelli, Bernard Roubert, Kerry Taylor, Pierre Fenaux, Agnès Guerci-Bresler, Dany Habr, Christian Rose, Matthias Schmid, Andrea Marcellari, Norbert Gattermann, Matteo G. Della Porta, Michael Stadler, and D. Vassilieff
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Adult ,Blood Platelets ,Male ,medicine.medical_specialty ,Blood transfusion ,Iron Overload ,Adolescent ,Neutrophils ,medicine.medical_treatment ,Iron Chelating Agents ,Gastroenterology ,Benzoates ,Hemoglobins ,Young Adult ,Internal medicine ,Medicine ,Humans ,Prospective Studies ,Prospective cohort study ,Child ,Survival rate ,Aged ,Aged, 80 and over ,business.industry ,Myelodysplastic syndromes ,Deferasirox ,Transfusion Reaction ,Hematology ,Middle Aged ,Triazoles ,medicine.disease ,Prognosis ,Hematologic Response ,Surgery ,Survival Rate ,Concomitant ,Myelodysplastic Syndromes ,Cohort ,Female ,Original Articles and Brief Reports ,Neoplasm Recurrence, Local ,business ,medicine.drug ,Follow-Up Studies - Abstract
Background Reductions in transfusion requirements/improvements in hematologic parameters have been associated with iron chelation therapy in transfusion-dependent patients, including those with myelodysplastic syndromes; data on these reductions/improvements have been limited to case reports and small studies. Design and Methods To explore this observation in a large population of patients, we report a post-hoc analysis evaluating hematologic response to deferasirox in a cohort of iron-overloaded patients with myelodysplastic syndromes enrolled in the Evaluation of Patients’ Iron Chelation with Exjade® (EPIC) study using International Working Group 2006 criteria. Results Two-hundred and forty-seven, 100 and 50 patients without concomitant medication for myelodysplastic syndromes were eligible for analysis of erythroid, platelet and neutrophil responses, respectively. Erythroid, platelet and neutrophil responses were observed in 21.5% (53/247), 13.0% (13/100) and 22.0% (11/50) of the patients after a median of 109, 169 and 226 days, respectively. Median serum ferritin reductions were greater in hematologic responders compared with non-responders at end of study, although these differences were not statistically significant. A reduction in labile plasma iron to less than 0.4 μmol/L was observed from week 12 onwards; this change did not differ between hematologic responders and non-responders. Conclusions This analysis suggests that deferasirox treatment for up to 1 year could lead to improvement in hematologic parameters in some patients with myelodysplastic syndromes.
- Published
- 2012
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