441 results on '"Paola Guglielmelli"'
Search Results
2. Age-stratified analysis reveals arterial thrombosis as a predictor for gender-related second cancers in myeloproliferative neoplasms: a case-control study
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Arianna Ghirardi, Alessandra Carobbio, Paola Guglielmelli, Alessandro Rambaldi, Valerio De Stefano, Alessandro M. Vannucchi, Ayalew Tefferi, and Tiziano Barbui
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2024
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3. One thousand patients with essential thrombocythemia: the Florence-CRIMM experience
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Giuseppe G. Loscocco, Francesca Gesullo, Giulio Capecchi, Alessandro Atanasio, Chiara Maccari, Francesco Mannelli, Alessandro M. Vannucchi, and Paola Guglielmelli
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract We describe 1000 patients with essential thrombocythemia seen at the Center Research and Innovation of Myeloproliferative Neoplasms (CRIMM), Florence, Italy, between 1980 and 2023: median age 59 years (18–95), females 65%, JAK2/CALR/MPL-mutated 66%/19%/4%, triple-negative (TN) 11%. Extreme thrombocytosis (ExT, platelets ≥1000 × 109/L) in 16%, leukocytosis (leukocytes >11 × 109/L) in 16%, and at least one cardiovascular risk factor in 52% of cases. JAK2-mutated patients were older (median 62 years) and CALR-mutated and TN (53 years for both) younger (p
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- 2024
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4. Validation and molecular integration of the RR6 model to predict survival after 6 months of therapy with ruxolitinib
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Giacomo Coltro, Giulio Capecchi, Margherita Maffioli, Francesco Mannelli, Barbara Mora, Alessandro Atanasio, Alessandra Iurlo, Chiara Maccari, Mirko Farina, Elena Nacca, Marianna Caramella, Leonardo Signori, Miriam Borella, Lorenza Bertù, Maria Esposito, Paola Guglielmelli, Francesco Passamonti, and Alessandro Maria Vannucchi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Not available.
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- 2024
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5. Incidence of blast phase in myelofibrosis according to anemia severity
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Barbara Mora, Margherita Maffioli, Elisa Rumi, Paola Guglielmelli, Marianna Caramella, Andrew Kuykendall, Francesca Palandri, Alessandra Iurlo, Valerio De Stefano, Jean‐Jacques Kiladjian, Elena M. Elli, Nicola Polverelli, Jason Gotlib, Francesco Albano, Richard T. Silver, Giulia Benevolo, David M. Ross, Timothy Devos, Oscar Borsani, Tiziano Barbui, Matteo G. Della Porta, Lorenza Bertù, Rami Komrokji, Alessandro M. Vannucchi, and Francesco Passamonti
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acute myeloid leukemia ,essential thrombocythemia ,myelofibrosis ,polycythemia vera ,ruxolitinib ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract Myelofibrosis (MF) is a clonal malignancy frequently characterized by anemia and in 10%–20% of cases it can evolve into blast phase (BP). Anemia in MF is associated with reduced survival and ‐in primary MF‐ also with an increased probability of BP. Conventional treatments for anemia have limited effectiveness in MF. Within a dataset of 1752 MF subjects largely unexposed to ruxolitinib (RUX), BP incidence was 2.5% patients per year (p‐y). This rate reached respectively 4.3% and 4.5% p‐y in case of patients with common terminology criteria for adverse events (CTCAE) grade 3/4 and grade 2 anemia, respectively, that represented together 32% of the cohort. Among 273 MF cases treated with RUX, BP incidence was 2.89% p‐y and it reached 4.86% p‐y in subjects who started RUX with CTCAE grade 2 anemia (one third of total). Within patients with red blood cell transfusion‐dependency at 6 months of RUX (21% of the exposed), BP rate was 4.2% p‐y. Our study highlights a relevant incidence of BP in anemic MF patients, with a similar rate whether treated with or without RUX. These findings will help treating physicians to make decisions on the safety profile of innovative anemia treatments.
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- 2023
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6. Assessment of the efficacy and tolerability of ruxolitinib for the treatment of myelofibrosis patients in a real‐life setting: An Italian MYNERVA Project
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Giacomo Coltro, Emanuela Sant'Antonio, Giuseppe A. Palumbo, Francesco Mannelli, Valerio De Stefano, Marco Ruggeri, Elena M. Elli, Roberta Zanotti, Oscar Borsani, Irene Bertozzi, Andrea Duminuco, Silvia Betti, Giuseppe Carli, Fabrizio Cavalca, Ilaria Tanasi, Elisa Rumi, Maria L. Randi, Bruno Garibaldi, Giuseppe G. Loscocco, Paola Guglielmelli, and Alessandro M. Vannucchi
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efficacy ,myelofibrosis ,ruxolitinib ,safety ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Incorporating real‐world data in the drug development process allows the improvement of health outcomes by providing better representation of actual patterns of drug safety and efficacy. Aims and Methods Here, we present the results of a retroprospective, observational real‐life study of 154 patients with myelofibrosis treated with ruxolitinib in a real‐life setting in seven Italian centers of the MYNERVA project. Results Median drug exposure was 29 (range, 3–98) months. Discontinuation rate was 27% after a median time of 13 (range, 3–61). While hematological toxicities were in line with previous findings, infections occurred frequently, representing a not negligible cause of discontinuation and death. Anemia, symptoms, and spleen responses were obtained at any time in 23%, 91%, and 68% of patients, respectively; most patients achieved their responses by week 24. Larger splenomegaly and delayed treatment initiation correlated with lower spleen response at 24 weeks. Spleen response was associated with a superior overall survival, regardless of DIPSS. Of interest, both achievement and loss of spleen response had prognostic implications. Discussion and Conclusion Overall, our findings provide insights on the efficacy and safety of ruxolitinib in a real‐world, multicenter cohort of Italian MF patients.
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- 2023
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7. The clinical experience of compassionate use program for avapritinib: implications for drug positioning in the therapeutic scenario of systemic mastocytosis
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Francesco Mannelli, Francesca Crupi, Roberta Zanotti, Livio Pagano, Davide Rapezzi, Ilaria Tanasi, Marianna Criscuolo, Massimiliano Bonifacio, Alberto Fresa, Paola Guglielmelli, and Alessandro M. Vannucchi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
In systemic mastocytosis, cytoreductive treatment is indicated for advanced systemic mastocytosis (AdvSM) variants. The treatment scenario is rapidly diversifying especially with the introduction of KIT tyrosine kinase inhibitors. Avapritinib is a second-generation potent and selective inhibitor of the mutant KIT D816V that, based on the results of pivotal clinical trials, was approved for the treatment of adults with AdvSM by the regulatory agencies US FDA and EMA. The present article reports the experience of treating SM patients with avapritinib in an Italian compassionate use program. The data from our case series confirm the drug as being active after multiple lines of treatment allowing rapid achievement of profound responses, making it also an effective bridging strategy to allogeneic transplant in eligible patients. However, the anticipated wider use of avapritinib in the near future will require careful monitoring of side effects, especially in heavily pretreated patients.
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- 2023
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8. Phenotypic correlations of CALR mutation variant allele frequency in patients with myelofibrosis
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Paola Guglielmelli, Chiara Maccari, Benedetta Sordi, Manjola Balliu, Alessandro Atanasio, Carmela Mannarelli, Giulio Capecchi, Ilaria Sestini, Giacomo Coltro, Giuseppe Gaetano Loscocco, Giada Rotunno, Eva Angori, Filippo C. Borri, Ayalew Tefferi, and Alessandro M. Vannucchi
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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9. P529: THE EFFECT OF AGE AND TREATMENT ON THE PREDICTIVE VALUE OF MEASURABLE RESIDUAL DISEASE: IMPLICATIONS FOR THE CLINICAL MANAGEMENT OF ADULT PATIENTS WITH ACUTE MYELOID LEUKEMIA
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Francesco Mannelli, Matteo Piccini, Sara Bencini, Giacomo Gianfaldoni, Benedetta Peruzzi, Roberto Caporale, Barbara Scappini, Laura Fasano, Elisa Quinti, Gaia Ciolli, Andrea Pasquini, Francesca Crupi, Sofia Pilerci, Fabiana Pancani, Leonardo Signori, Danilo Tarantino, Chiara Maccari, Vivian Paradiso, Francesco Annunziato, Paola Guglielmelli, and Alessandro Maria Vannucchi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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10. P1041: LEUKOCYTOSIS SELECTS A SUBGROUP OF LOW-RISK PV PATIENTS IN WHOM PHLEBOTOMY-ALONE MAY BE INSUFFICIENT
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Alessandra Carobbio, Alessandro Vannucchi, Valerio De Stefano, Arianna Ghirardi, Greta Carioli, Arianna Masciulli, Elena Rossi, Fabio Ciceri, Massimiliano Bonifacio, Alessandra Iurlo, Francesca Palandri, Giulia Benevolo, Fabrizio Pane, Alessandra Ricco, Giuseppe Carli, Marianna Caramella, Davide Rapezzi, Caterina Musolino, Sergio Siragusa, Elisa Rumi, Andrea Patriarca, Nicola Cascavilla, Barbara Mora, Emma Cacciola, Carmela Mannarelli, Giuseppe Gaetano Loscocco, Paola Guglielmelli, Francesca Gesullo, Silvia Betti, Francesca Lunghi, Luigi Scaffidi, Cristina Bucelli, Nicola Vianelli, Marta Bellini, Maria Chiara Finazzi, Gianni Tognoni, Alessandro Rambaldi, and Tiziano Barbui
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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11. P1022: PHASE 1/2 STUDY OF THE ACTIVIN RECEPTOR-LIKE KINASE 2 (ALK2) INHIBITOR ZILURGISERTIB (INCB000928, LIMBER-104) AS MONOTHERAPY OR WITH RUXOLITINIB IN PATIENTS WITH ANEMIA DUE TO MYELOFIBROSIS
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Prithviraj Bose, Sanjay Mohan, Stephen Oh, Jason Gotlib, Ellen Ritchie, Taizo Shimomura, Haris Ali, Francoise Boyer, Paola Guglielmelli, Anthony M. Hunter, Betty Lamothe, Yi Cui, Francis Seguy, Amanda Mcbride, Francesca Palandri, Masahiro Takeuchi, and Jean-Jacques Kiladjian
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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12. Breakthrough infections in MPN-COVID vaccinated patients
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Tiziano Barbui, Alessandra Carobbio, Arianna Ghirardi, Alessandra Iurlo, Valerio De Stefano, Marta Anna Sobas, Elisa Rumi, Elena Maria Elli, Francesca Lunghi, Mercedes Gasior Kabat, Beatriz Cuevas, Paola Guglielmelli, Massimiliano Bonifacio, Monia Marchetti, Alberto Alvarez-Larran, Laura Fox, Marta Bellini, Rosa Daffini, Giulia Benevolo, Gonzalo Carreno-Tarragona, Andrea Patriarca, Haifa Kathrin Al-Ali, Maria Marcio Miguel Andrade-Campos, Francesca Palandri, Claire Harrison, Maria Angeles Foncillas, Santiago Osorio, Steffen Koschmieder, Elena Magro Mazo, Jean-Jacques Kiladjian, Estefanía Bolaños Calderón, Florian H. Heidel, Keina Quiroz Cervantes, Martin Griesshammer, Valentin Garcia-Gutierrez, Alberto Marin Sanchez, Juan Carlos Hernandez-Boluda, Emma Lopez Abadia, Giuseppe Carli, Miguel Sagues Serrano, Rajko Kusec, Blanca Xicoy Cirici, Margarita Guenova, Begona Navas Elorza, Anna Angona, Edyta Cichocka, Anna Kulikowska de Nałęcz, Daniele Cattaneo, Cristina Bucelli, Silvia Betti, Oscar Borsani, Fabrizio Cavalca, Sara Carbonell, Natalia Curto-Garcia, Lina Benajiba, Alessandro Rambaldi, and Alessandro Maria Vannucchi
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2022
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13. Increased risk of thrombosis in JAK2 V617F-positive patients with primary myelofibrosis and interaction of the mutation with the IPSS score
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Tiziano Barbui, Arianna Ghirardi, Alessandra Carobbio, Arianna Masciulli, Greta Carioli, Alessandro Rambaldi, Maria Chiara Finazzi, Marta Bellini, Elisa Rumi, Daniele Vanni, Oscar Borsani, Francesco Passamonti, Barbara Mora, Marco Brociner, Paola Guglielmelli, Chiara Paoli, Alberto Alvarez-Larran, Ana Triguero, Marta Garrote, Helna Pettersson, Björn Andréasson, Giovanni Barosi, and Alessandro Maria Vannucchi
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2022
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14. Differential prognostic impact of cytopenic phenotype in prefibrotic vs overt primary myelofibrosis
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Giacomo Coltro, Francesco Mannelli, Giuseppe Gaetano Loscocco, Carmela Mannarelli, Giada Rotunno, Chiara Maccari, Fabiana Pancani, Alessandro Atanasio, Alessandro Maria Vannucchi, and Paola Guglielmelli
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2022
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15. Management of Myelofibrosis during Treatment with Ruxolitinib: A Real-World Perspective in Case of Resistance and/or Intolerance
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Massimo Breccia, Francesca Palandri, Paola Guglielmelli, Giuseppe Alberto Palumbo, Alessandra Malato, Francesco Mendicino, Alessandra Ricco, Emanuela Sant’Antonio, Mario Tiribelli, and Alessandra Iurlo
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anemia ,infection ,intolerance ,myelofibrosis ,non-melanoma skin cancer ,resistance ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The development and approval of ruxolitinib, the first JAK1/2 inhibitor indicated to treat myelofibrosis, has improved patient outcomes, with higher spleen and symptoms responses, improved quality of life, and overall survival. Despite this, several unmet needs remain, including the absence of resistance criteria, suboptimal response, the timing of allogeneic transplant, and the management of patients in case of intolerance. Here, we report the results of the second survey led by the “MPN Lab” collaboration, which aimed to report physicians’ perspectives on these topics. As in our first survey, physicians were selected throughout Italy, and we included those with extensive experience in treating myeloproliferative neoplasms and those with less experience representing clinical practice in the real world. The results presented here, summarized using descriptive analyses, highlight the need for a clear definition of response to ruxolitinib as well as recommendations to guide the management of ruxolitinib under specific conditions including anemia, thrombocytopenia, infections, and non-melanoma skin cancers.
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- 2022
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16. Effect of age and treatment on predictive value of measurable residual disease: implications for clinical management of adult patients with acute myeloid leukemia
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Francesco Mannelli, Matteo Piccini, Sara Bencini, Giacomo Gianfaldoni, Benedetta Peruzzi, Roberto Caporale, Barbara Scappini, Laura Fasano, Elisa Quinti, Gaia Ciolli, Andrea Pasquini, Francesca Crupi, Sofia Pilerci, Fabiana Pancani, Leonardo Signori, Danilo Tarantino, Chiara Maccari, Vivian Paradiso, Francesco Annunziato, Paola Guglielmelli, and Alessandro M. Vannucchi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Measurable residual disease (MRD) is a powerful predictor of outcome in acute myeloid leukemia. In the early phases of treatment, MRD refines initial disease risk stratification and is used for the allocation to allogeneic transplant. Despite its well-established role, a relatively high fraction of patients eventually relapses albeit achieving MRDneg status. The aim of this work was to assess specifically the influence of baseline features and treatment intensity on the predictive value of an MRDneg status, particularly focusing on MRD2, measured after two consecutive chemotherapy cycles. Among baseline features, younger MRD2neg patients (
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- 2023
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17. Neutrophil-to-lymphocyte ratio is a novel predictor of venous thrombosis in polycythemia vera
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Alessandra Carobbio, Alessandro Maria Vannucchi, Valerio De Stefano, Arianna Masciulli, Paola Guglielmelli, Giuseppe Gaetano Loscocco, Francesco Ramundo, Elena Rossi, Yogendra Kanthi, Ayalew Tefferi, and Tiziano Barbui
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract We investigated the neutrophil-to-lymphocyte ratio (NLR) as a predictor of thrombosis in polycythemia vera (PV). After a median follow-up of 2.51 years, of 1508 PV patients enrolled in the ECLAP study, 82 and 84 developed arterial and venous thrombosis, respectively. Absolute counts of total leukocytes, neutrophils, lymphocytes, platelets, and the NLR were tested by generalized additive models (GAM) to evaluate their trend in continuous scale of thrombotic risk. Only for venous thrombosis, we showed that baseline absolute neutrophil and lymphocyte counts were on average respectively higher (median: 6.8 × 109/L, p = 0.002) and lower (median: 1.4 × 109/L, p = 0.001), leading to increased NLR values (median: 5.1, p = 0.002). In multivariate analysis, the risk of venous thrombosis was independently associated with previous venous events (HR = 5.48, p ≤ 0.001) and NLR values ≥5 (HR = 2.13, p = 0.001). Moreover, the relative risk in both low- and high-standard risk groups was almost doubled in the presence of NLR ≥ 5. These findings were validated in two Italian independent external cohorts (Florence, n = 282 and Rome, n = 175) of contemporary PV patients. Our data support recent experimental work that venous thrombosis is controlled by innate immune cells and highlight that NLR is an inexpensive and easily accessible prognostic biomarker of venous thrombosis.
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- 2022
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18. JAK2V617F variant allele frequency >50% identifies patients with polycythemia vera at high risk for venous thrombosis
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Paola Guglielmelli, Giuseppe G. Loscocco, Carmela Mannarelli, Elena Rossi, Francesco Mannelli, Francesco Ramundo, Giacomo Coltro, Silvia Betti, Chiara Maccari, Sara Ceglie, Patrizia Chiusolo, Chiara Paoli, Tiziano Barbui, Ayalew Tefferi, Valerio De Stefano, and Alessandro M. Vannucchi
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Arterial (AT) and venous (VT) thrombotic events are the most common complications in patients with polycythemia vera (PV) and are the leading causes of morbidity and mortality. In this regard, the impact of JAK2V617F variant allele frequency (VAF) is still debated. The purpose of the current study was to analyze the impact of JAK2V617F VAF in the context of other established risk factors for thrombosis in a total of 865 2016 WHO-defined PV patients utilizing two independent cohorts: University of Florence (n = 576) as a training cohort and Policlinico Gemelli, Catholic University, Rome (n = 289) as a validation cohort. In the training cohort VT free-survival was significantly shorter in the presence of a JAK2V617F VAF > 50% (HR 4; p 50% (HR 3.8, p = 0.001) and previous VT (HR 2.2; p = 0.04) as independent risk factors for future VT whereas diabetes (HR 2.4; p = 0.02), hyperlipidemia (HR 2.3; p = 0.01) and previous AT (HR 2; p = 0.04) were independent risk factors for future AT. Similarly, JAK2V617F VAF > 50% (HR 2.4; p = 0.01) and previous VT (HR 2.8; p = 0.005) were confirmed as independent predictors of future VT in the validation cohort. Impact of JAK2V617F VAF > 50% on VT was particularly significant in conventional low-risk patients, both in Florence (HR 10.6, p = 0.005) and Rome cohort (HR 4; p = 0.02). In conclusion, we identified JAK2V617F VAF > 50% as an independent strong predictor of VT, supporting that AT and VT are different entities which might require distinct management.
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- 2021
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19. Nanopore sequencing for the screening of myeloid and lymphoid neoplasms with eosinophilia and rearrangement of PDGFRα, PDGFRβ, FGFR1 or PCM1-JAK2
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Simone Romagnoli, Niccolò Bartalucci, Francesca Gesullo, Manjola Balliu, Stefania Bonifacio, Anair Graciela Lema Fernandez, Francesco Mannelli, Davide Bolognini, Elisabetta Pelo, Cristina Mecucci, Paola Guglielmelli, and Alessandro Maria Vannucchi
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Primary eosinophilic disorders ,Nanopore sequencing ,PDGFRα ,PDGFRβ ,FGFR1 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract Eosinophilia represents a group of diseases with heterogeneous pathobiology and clinical phenotypes. Among the alterations found in primary Eosinophilia, gene fusions involving PDGFRα, PDGFRβ, FGFR1 or JAK2 represent the biomarkers of WHO-defined “myeloid and lymphoid neoplasms with eosinophilia”. The heterogeneous nature of genomic aberrations and the promiscuity of fusion partners, may limit the diagnostic accuracy of current cytogenetics approaches. To address such technical challenges, we exploited a nanopore-based sequencing assay to screen patients with primary Eosinophilia. The comprehensive sequencing approach described here enables the identification of genomic fusion in 60 h, starting from DNA purified from whole blood.
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- 2021
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20. Efficacy and safety of ruxolitinib in patients with myelofibrosis and low platelet count (50 × 10/L to
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Paola Guglielmelli, Jean-Jacques Kiladjian, Alessandro M. Vannucchi, Minghui Duan, Haitao Meng, Ling Pan, Guangsheng He, Srdan Verstovsek, Françoise Boyer, Fiorenza Barraco, Dietger Niederwieser, Ester Pungolino, Anna Marina Liberati, Claire Harrison, Pantelia Roussou, Monika Wroclawska, Divyadeep Karumanchi, Karen Sinclair, Peter A.W. te Boekhorst, and Heinz Gisslinger
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background: Thrombocytopenia is a common feature of myelofibrosis (MF), a myeloproliferative neoplasm driven by dysregulated JAK/STAT signaling; however, pivotal trials assessing the efficacy of ruxolitinib (a JAK1/2 inhibitor) excluded MF patients with low platelet counts (
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- 2022
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21. Benefit of Early Ruxolitinib Initiation Regardless of Fibrosis Grade in Patients with Primary Myelofibrosis: A Post Hoc Analysis of the Single-Arm Phase 3b JUMP Study
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Francesca Palandri, Haifa Kathrin Al-Ali, Paola Guglielmelli, Mike W. Zuurman, Rajendra Sarkar, and Vikas Gupta
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primary myelofibrosis ,ruxolitinib ,bone marrow fibrosis ,spleen response ,phase 3b trial ,JAK1/2 inhibition ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Bone marrow fibrosis (BMF) is an adverse prognostic factor for myelofibrosis (MF). The single-arm, open-label, phase 3b JUMP trial (NCT01493414) assessed the safety and efficacy of the JAK1/JAK2 inhibitor ruxolitinib in patients with symptomatic MF. This post hoc analysis investigated the impact of BMF grade on response and outcomes in patients with primary MF (PMF) from the JUMP study. BMF was assessed by biopsy and graded from 0 to 3; grades 0–1 were considered low-grade fibrosis (LGF) and grades 2–3 were considered high-grade fibrosis (HGF). Patients with LGF (n = 268) had lower rates of cytopenias at baseline but showed comparable disease burden vs. patients with HGF (n = 852). The proportion of patients achieving a spleen response was greater in the LGF group vs. the HGF group at Week 24 and at any time during the study, while overall survival estimates were improved in patients with LGF vs. patients with HGF. Early initiation of ruxolitinib therapy (within 2 years of diagnosis) was associated with increased response rates in all patients. These results highlight the efficacy of ruxolitinib in symptomatic patients with PMF, with the greatest clinical improvements observed in patients with LGF and in patients who received early treatment.
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- 2023
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22. Long-term follow-up of recovered MPN patients with COVID-19
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Tiziano Barbui, Alessandra Iurlo, Arianna Masciulli, Alessandra Carobbio, Arianna Ghirardi, Giuseppe Rossi, Claire Harrison, Alberto Alvarez-Larran, Elena Maria Elli, Jean-Jaques Kiladjian, Mercedes Gasior Kabat, Alberto Marin Sanchez, Francesca Palandri, Marcio Miguel Andrade-Campos, Alessandro Maria Vannucchi, Gonzalo Carreno-Tarragona, Petros Papadopoulos, Keina Quiroz Cervantes, Maria Angeles Foncillas, Maria Laura Fox, Miguel Sagues Serrano, Elisa Rumi, Santiago Osorio, Giulia Benevolo, Andrea Patriarca, Begona Navas Elorza, Valentin Garcia-Gutierrez, Elena Magro Mazo, Francesca Lunghi, Massimiliano Bonifacio, Valerio De Stefano, Juan Carlos Hernandez-Boluda, Emma Lopez Abadia, Anna Angona, Blanca Xicoy Cirici, Marco Ruggeri, Steffen Koschmieder, Marta Anna Sobas, Beatriz Cuevas, Daniele Cattaneo, Rosa Daffini, Marta Bellini, Natalia Curto-Garcia, Marta Garrote, Fabrizio Cavalca, Lina Benajiba, Beatriz Bellosillo, Paola Guglielmelli, Oscar Borsani, Silvia Betti, Silvia Salmoiraghi, and Alessandro Rambaldi
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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23. Mutations and thrombosis in essential thrombocythemia
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Paola Guglielmelli, Naseema Gangat, Giacomo Coltro, Terra L. Lasho, Giuseppe Gaetano Loscocco, Christy M. Finke, Erika Morsia, Benedetta Sordi, Natasha Szuber, Curtis A. Hanson, Animesh Pardanani, Alessandro M. Vannucchi, and Ayalew Tefferi
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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24. JAK inhibitors and COVID-19
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Gabriel Levy, Paola Guglielmelli, Peter Langmuir, and Stefan Constantinescu
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2022
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25. Among classic myeloproliferative neoplasms, essential thrombocythemia is associated with the greatest risk of venous thromboembolism during COVID-19
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Tiziano Barbui, Valerio De Stefano, Alberto Alvarez-Larran, Alessandra Iurlo, Arianna Masciulli, Alessandra Carobbio, Arianna Ghirardi, Alberto Ferrari, Valeria Cancelli, Elena Maria Elli, Marcio Miguel Andrade-Campos, Mercedes Gasior Kabat, Jean-Jaques Kiladjian, Francesca Palandri, Giulia Benevolo, Valentin Garcia-Gutierrez, Maria Laura Fox, Maria Angeles Foncillas, Carmen Montoya Morcillo, Elisa Rumi, Santiago Osorio, Petros Papadopoulos, Massimiliano Bonifacio, Keina Susana Quiroz Cervantes, Miguel Sagues Serrano, Gonzalo Carreno-Tarragona, Marta Anna Sobas, Francesca Lunghi, Andrea Patriarca, Begoña Navas Elorza, Anna Angona, Elena Magro Mazo, Steffen Koschmieder, Giuseppe Carli, Beatriz Cuevas, Juan Carlos Hernandez-Boluda, Emma Lopez Abadia, Blanca Xicoy Cirici, Paola Guglielmelli, Marta Garrote, Daniele Cattaneo, Rosa Daffini, Fabrizio Cavalca, Beatriz Bellosillo, Lina Benajiba, Natalia Curto-Garcia, Marta Bellini, Silvia Betti, Claire Harrison, Alessandro Rambaldi, and Alessandro Maria Vannucchi
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract In a multicenter European retrospective study including 162 patients with COVID-19 occurring in essential thrombocythemia (ET, n = 48), polycythemia vera (PV, n = 42), myelofibrosis (MF, n = 56), and prefibrotic myelofibrosis (pre-PMF, n = 16), 15 major thromboses (3 arterial and 12 venous) were registered in 14 patients, of whom all, but one, were receiving LMW-heparin prophylaxis. After adjustment for the competing risk of death, the cumulative incidence of arterial and venous thromboembolic events (VTE) reached 8.5% after 60 days follow-up. Of note, 8 of 12 VTE were seen in ET. Interestingly, at COVID-19 diagnosis, MPN patients had significantly lower platelet count (p
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- 2021
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26. Second primary malignancies in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 2233 patients
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Barbara Mora, Elisa Rumi, Paola Guglielmelli, Daniela Barraco, Margherita Maffioli, Alessandro Rambaldi, Marianna Caramella, Rami Komrokji, Jason Gotlib, Jean Jacques Kiladjian, Francisco Cervantes, Timothy Devos, Francesca Palandri, Valerio DeStefano, Marco Ruggeri, Richard T. Silver, Giulia Benevolo, Francesco Albano, Chiara Cavalloni, Daniela Pietra, Tiziano Barbui, Giada Rotunno, Mario Cazzola, Alessandro Maria Vannucchi, Toni Giorgino, and Francesco Passamonti
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JAK inhibitors ,second malignancy ,secondary myelofibrosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Patients with myeloproliferative neoplasms (MPN) are known to have higher incidence of nonhematological second primary malignancies (SPM) compared to general population. In the MYSEC study on 781 secondary myelofibrosis (SMF) patients, the incidence of SPM after SMF diagnosis resulted 0.98/100 patient‐years. When including non‐melanoma skin cancers (NMSC), the incidence arose to 1.56/100 patient‐years. In SMF, JAK inhibitor treatment was associated only with NMSC occurrence. Then, we merged the MYSEC cohort with a large dataset of PV and ET not evolving into SMF. In this subanalysis, we did not find any correlation between SPM and SMF occurrence. These findings highlight the need of studies aimed at identifying MPN patients at higher risk of SPM.
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- 2019
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27. Role of TGF‐β1/miR‐382‐5p/SOD2 axis in the induction of oxidative stress in CD34+ cells from primary myelofibrosis
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Chiara Rossi, Roberta Zini, Sebastiano Rontauroli, Samantha Ruberti, Zelia Prudente, Greta Barbieri, Elisa Bianchi, Simona Salati, Elena Genovese, Niccolò Bartalucci, Paola Guglielmelli, Enrico Tagliafico, Vittorio Rosti, Giovanni Barosi, Alessandro M. Vannucchi, Rossella Manfredini, and the AGIMM (AIRC‐Gruppo Italiano Malattie Mieloproliferative) investigators
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miR‐382‐5p ,oxidative stress ,primary myelofibrosis ,reactive oxygen species ,superoxide dismutase ,TGF‐β1 signaling ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by an excessive production of pro‐inflammatory cytokines resulting in chronic inflammation and genomic instability. Besides the driver mutations in JAK2, MPL, and CALR genes, the deregulation of miRNA expression may also contribute to the pathogenesis of PMF. To this end, we recently reported the upregulation of miR‐382‐5p in PMF CD34+ cells. In order to unveil the mechanistic details of the role of miR‐382‐5p in pathogenesis of PMF, we performed gene expression profiling of CD34+ cells overexpressing miR‐382‐5p. Among the downregulated genes, we identified superoxide dismutase 2 (SOD2), which is a predicted target of miR‐382‐5p. Subsequently, we confirmed miR‐382‐5p/SOD2 interaction by luciferase assay and we showed that miR‐382‐5p overexpression in CD34+ cells causes the decrease in SOD2 activity leading to reactive oxygen species (ROS) accumulation and oxidative DNA damage. In addition, our data indicate that inhibition of miR‐382‐5p in PMF CD34+ cells restores SOD2 function, induces ROS disposal, and reduces DNA oxidation. Since the pro‐inflammatory cytokine transforming growth factor‐β1 (TGF‐β1) is a key player in PMF pathogenesis, we further investigated the effect of TGF‐β1 on ROS and miR‐382‐5p levels. Our data showed that TGF‐β1 treatment enhances miR‐382‐5p expression and reduces SOD2 activity leading to ROS accumulation. Finally, inhibition of TGF‐β1 signaling in PMF CD34+ cells by galunisertib significantly reduced miR‐382‐5p expression and ROS accumulation and restored SOD2 activity. As a whole, this study reports that TGF‐β1/miR‐382‐5p/SOD2 axis deregulation in PMF cells is linked to ROS overproduction that may contribute to enhanced oxidative stress and inflammation. Our results suggest that galunisertib may represent an effective drug reducing abnormal oxidative stress induced by TGF‐β1 in PMF patients. Database linking GEO: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE103464.
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- 2018
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28. Shared and Distinctive Ultrastructural Abnormalities Expressed by Megakaryocytes in Bone Marrow and Spleen From Patients With Myelofibrosis
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Maria Zingariello, Vittorio Rosti, Alessandro M. Vannucchi, Paola Guglielmelli, Maria Mazzarini, Giovanni Barosi, Maria Luisa Genova, and Anna Rita Migliaccio
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myeloproliferative neoplasms ,myelofibrosis ,megakaryocytes ,ultrastructural analyses ,cell metabolism ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Numerous studies have documented ultrastructural abnormalities in malignant megakaryocytes from bone marrow (BM) of myelofibrosis patients but the morphology of these cells in spleen, an important extramedullary site in this disease, was not investigated as yet. By transmission-electron microscopy, we compared the ultrastructural features of megakaryocytes from BM and spleen of myelofibrosis patients and healthy controls. The number of megakaryocytes was markedly increased in both BM and spleen. However, while most of BM megakaryocytes are immature, those from spleen appear mature with well-developed demarcation membrane systems (DMS) and platelet territories and are surrounded by platelets. In BM megakaryocytes, paucity of DMS is associated with plasma (thick with protrusions) and nuclear (dilated with large pores) membrane abnormalities and presence of numerous glycosomes, suggesting a skewed metabolism toward insoluble polyglucosan accumulation. By contrast, the membranes of the megakaryocytes from the spleen were normal but these cells show mitochondria with reduced crests, suggesting deficient aerobic energy-metabolism. These distinctive morphological features suggest that malignant megakaryocytes from BM and spleen express distinctive metabolic impairments that may play different roles in the pathogenesis of myelofibrosis.
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- 2020
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29. The Response to Oxidative Damage Correlates with Driver Mutations and Clinical Outcome in Patients with Myelofibrosis
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Elena Genovese, Margherita Mirabile, Sebastiano Rontauroli, Stefano Sartini, Sebastian Fantini, Lara Tavernari, Monica Maccaferri, Paola Guglielmelli, Elisa Bianchi, Sandra Parenti, Chiara Carretta, Selene Mallia, Sara Castellano, Corrado Colasante, Manjola Balliu, Niccolò Bartalucci, Raffaele Palmieri, Tiziana Ottone, Barbara Mora, Leonardo Potenza, Francesco Passamonti, Maria Teresa Voso, Mario Luppi, Alessandro Maria Vannucchi, Enrico Tagliafico, Rossella Manfredini, and on behalf of the Mynerva (MYeloid NEoplasms Research Venture AIRC)
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myelofibrosis ,calreticulin ,janus kinase 2 ,oxidative stress ,reactive oxygen species ,superoxide dismutase ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Myelofibrosis (MF) is the Philadelphia-negative myeloproliferative neoplasm characterized by the worst prognosis and no response to conventional therapy. Driver mutations in JAK2 and CALR impact on JAK-STAT pathway activation but also on the production of reactive oxygen species (ROS). ROS play a pivotal role in inflammation-induced oxidative damage to cellular components including DNA, therefore leading to greater genomic instability and promoting cell transformation. In order to unveil the role of driver mutations in oxidative stress, we assessed ROS levels in CD34+ hematopoietic stem/progenitor cells of MF patients. Our results demonstrated that ROS production in CD34+ cells from CALR-mutated MF patients is far greater compared with patients harboring JAK2 mutation, and this leads to increased oxidative DNA damage. Moreover, CALR-mutant cells show less superoxide dismutase (SOD) antioxidant activity than JAK2-mutated ones. Here, we show that high plasma levels of total antioxidant capacity (TAC) correlate with detrimental clinical features, such as high levels of lactate dehydrogenase (LDH) and circulating CD34+ cells. Moreover, in JAK2-mutated patients, high plasma level of TAC is also associated with a poor overall survival (OS), and multivariate analysis demonstrated that high TAC classification is an independent prognostic factor allowing the identification of patients with inferior OS in both DIPSS lowest and highest categories. Altogether, our data suggest that a different capability to respond to oxidative stress can be one of the mechanisms underlying disease progression of myelofibrosis.
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- 2022
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30. An agenda for future research projects in polycythemia vera and essential thrombocythemia
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Tiziano Barbui, Alessandro Maria Vannucchi, Paola Guglielmelli, Valerio De Stefano, and Alessandro Rambaldi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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31. Results from HARMONY: an open-label, multicenter, 2-arm, phase 1b, dose-finding study assessing the safety and efficacy of the oral combination of ruxolitinib and buparlisib in patients with myelofibrosis
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Simon T. Durrant, Arnon Nagler, Paola Guglielmelli, David Lavie, Philipp le Coutre, Heinz Gisslinger, Charles Chuah, Margherita Maffioli, Savita Bharathy, Tuochuan Dong, Monika Wroclawska, and Joaquin Martinez Lopez
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2019
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32. Increased Plasma Levels of lncRNAs LINC01268, GAS5 and MALAT1 Correlate with Negative Prognostic Factors in Myelofibrosis
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Sebastian Fantini, Sebastiano Rontauroli, Stefano Sartini, Margherita Mirabile, Elisa Bianchi, Filippo Badii, Monica Maccaferri, Paola Guglielmelli, Tiziana Ottone, Raffaele Palmieri, Elena Genovese, Chiara Carretta, Sandra Parenti, Selene Mallia, Lara Tavernari, Costanza Salvadori, Francesca Gesullo, Chiara Maccari, Michela Zizza, Alexis Grande, Silvia Salmoiraghi, Barbara Mora, Leonardo Potenza, Vittorio Rosti, Francesco Passamonti, Alessandro Rambaldi, Maria Teresa Voso, Cristina Mecucci, Enrico Tagliafico, Mario Luppi, Alessandro Maria Vannucchi, and Rossella Manfredini
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lncRNAs ,myelofibrosis ,MPN ,biomarkers ,prognosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Long non-coding RNAs (lncRNAs) have been recently described as key mediators in the development of hematological malignancies. In the last years, circulating lncRNAs have been proposed as a new class of non-invasive biomarkers for cancer diagnosis and prognosis and to predict treatment response. The present study is aimed to investigate the potential of circulating lncRNAs as non-invasive prognostic biomarkers in myelofibrosis (MF), the most severe among Philadelphia-negative myeloproliferative neoplasms. We detected increased levels of seven circulating lncRNAs in plasma samples of MF patients (n = 143), compared to healthy controls (n = 65). Among these, high levels of LINC01268, MALAT1 or GAS5 correlate with detrimental clinical variables, such as high count of leukocytes and CD34+ cells, severe grade of bone marrow fibrosis and presence of splenomegaly. Strikingly, high plasma levels of LINC01268 (p = 0.0018), GAS5 (p = 0.0008) or MALAT1 (p = 0.0348) are also associated with a poor overall-survival while high levels of LINC01268 correlate with a shorter leukemia-free-survival. Finally, multivariate analysis demonstrated that the plasma level of LINC01268 is an independent prognostic variable, suggesting that, if confirmed in future in an independent patients’ cohort, it could be used for further studies to design an updated classification model for MF patients.
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- 2021
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33. Integration of Molecular Information in Risk Assessment of Patients with Myeloproliferative Neoplasms
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Giuseppe G. Loscocco, Giacomo Coltro, Paola Guglielmelli, and Alessandro M. Vannucchi
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myeloproliferative neoplasms ,polycythemia vera ,essential thrombocythemia ,myelofibrosis ,JAK2 ,CALR ,Cytology ,QH573-671 - Abstract
Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are clonal disorders of a hematopoietic stem cell, characterized by an abnormal proliferation of largely mature cells driven by mutations in JAK2, CALR, and MPL. All these mutations lead to a constitutive activation of the JAK-STAT signaling, which represents a target for therapy. Beyond driver ones, most patients, especially with myelofibrosis, harbor mutations in an array of “myeloid neoplasm-associated” genes that encode for proteins involved in chromatin modification and DNA methylation, RNA splicing, transcription regulation, and oncogenes. These additional mutations often arise in the context of clonal hematopoiesis of indeterminate potential (CHIP). The extensive characterization of the pathologic genome associated with MPN highlighted selected driver and non-driver mutations for their clinical informativeness. First, driver mutations are enlisted in the WHO classification as major diagnostic criteria and may be used for monitoring of residual disease after transplantation and response to treatment. Second, mutation profile can be used, eventually in combination with cytogenetic, histopathologic, hematologic, and clinical variables, to risk stratify patients regarding thrombosis, overall survival, and rate of transformation to secondary leukemia. This review outlines the molecular landscape of MPN and critically interprets current information for their potential impact on patient management.
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- 2021
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34. Driver mutations (JAK2V617F, MPLW515L/K or CALR), pentraxin-3 and C-reactive protein in essential thrombocythemia and polycythemia vera
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Federico Lussana, Alessandra Carobbio, Silvia Salmoiraghi, Paola Guglielmelli, Alessandro Maria Vannucchi, Barbara Bottazzi, Roberto Leone, Alberto Mantovani, Tiziano Barbui, and Alessandro Rambaldi
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Polycythemia vera ,Essential thrombocythemia ,Mutations ,Inflammation ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The driver mutations JAK2V617F, MPLW515L/K and CALR influence disease phenotype of myeloproliferative neoplasms (MPNs) and might sustain a condition of chronic inflammation. Pentraxin 3 (PTX3) and high-sensitivity C-reactive protein (hs-CRP) are inflammatory biomarkers potentially useful for refining prognostic classification of MPNs. Methods We evaluated 305 with essential thrombocythemia (ET) and 172 polycythemia vera (PV) patients diagnosed according to the 2016 WHO criteria and with full molecular characterization for driver mutations. Results PTX3 levels were significantly increased in carriers of homozygous JAK2V617F mutation compared to all the other genotypes and triple negative ET patients, while hs-CRP levels were independent of the mutational profile. The risk of haematological evolution and death from any cause was about 2- and 1.5-fold increased in individuals with high PTX-3 levels, while the thrombosis rate tended to be lower. High hs-CRP levels were associated with risk of haematological evolution, death and also major thrombosis. After sequential adjustment for potential confounders (age, gender, diagnosis and treatments) and the presence of JAK2V617F homozygous status, high hs-CRP levels remained significant for all outcomes, while JAK2V617F homozygous status as well as treatments were the factors independently accounting for adverse outcomes among patients with high PTX3 levels. Conclusions These results provide evidence that JAK2V617F mutation influences MPN-associated inflammation with a strong correlation between allele burden and PTX3 levels. Plasma levels of hs-CRP and PTX3 might be of prognostic value for patients with ET and PV, but their validation in future prospective studies is needed.
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- 2017
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35. Targeted deep sequencing in polycythemia vera and essential thrombocythemia
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Ayalew Tefferi, Terra L. Lasho, Paola Guglielmelli, Christy M. Finke, Giada Rotunno, Yoseph Elala, Annalisa Pacilli, Curtis A. Hanson, Alessandro Pancrazzi, Rhett P. Ketterling, Carmela Mannarelli, Daniela Barraco, Tiziana Fanelli, Animesh Pardanani, Naseema Gangat, and Alessandro M. Vannucchi
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Specialties of internal medicine ,RC581-951 - Abstract
Abstract: Polycythemia vera (PV) is characterized by JAK2 and essential thrombocythemia (ET) by JAK2, calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) mutations; we describe the occurrence and prognostic relevance of DNA sequence variants/mutations other than JAK2/CALR/MPL. A myeloid neoplasm–relevant 27-gene panel was used for next-generation sequencing of bone marrow or whole blood DNA and conventional tools were used for analysis. “Adverse variants/mutations” were identified by age-adjusted multivariable analysis of impact on overall, leukemia-free, or myelofibrosis-free survival. Fifty-three percent of 133 Mayo Clinic patients with PV and 53% of 183 with ET harbored 1 or more sequence variants/mutations other than JAK2/CALR/MPL; the most frequent were TET2 and ASXL1. “Adverse variants/mutations” in PV included ASXL1, SRSF2, and IDH2 and in ET SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2; combined prevalence was 15% and 15%, respectively. Adverse variants/mutations were associated with inferior survival in both PV (median, 7.7 vs 16.9 years) and ET (median, 9 vs 22 years) and the effect was independent of conventional prognostic models with respective hazard ratio (95% confidence interval) of 2.8 (1.5-5.1) and 2.6 (1.4-4.8); these observations were validated in 215 Italian patients with PV and 174 with ET. In both Mayo Clinic and Italian cohorts, leukemic or fibrotic progression was also predicted by adverse variants/mutations. Number of mutations did not provide additional prognostic information. We conclude that targeted deep sequencing in PV and ET allows for genetic risk stratification that is independent of clinically derived prognostic models.
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- 2016
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36. CircRNAs Are Here to Stay: A Perspective on the MLL Recombinome
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Anna Dal Molin, Silvia Bresolin, Enrico Gaffo, Caterina Tretti, Elena Boldrin, Lueder H. Meyer, Paola Guglielmelli, Alessandro M. Vannucchi, Geertruij te Kronnie, and Stefania Bortoluzzi
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circRNA ,leukemia ,MLL rearrangements ,fusion-circRNA ,translocation breakpoint region ,blood cells ,Genetics ,QH426-470 - Abstract
Chromosomal translocations harbored by cancer genomes are important oncogenic drivers. In MLL rearranged acute leukemia (MLLre) MLL/KMT2A fuses with over 90 partner genes. Mechanistic studies provided clues of MLL fusion protein leukemogenic potential, but models failed to fully recapitulate the disease. Recently, expression of oncogenic fusion circular RNAs (f-circ) by MLL-AF9 fusion was proven. This discovery, together with emerging data on the importance and diversity of circRNAs formed the incentive to study the circRNAs of the MLL recombinome. Through interactions with other RNAs, such as microRNAs, and with proteins, circRNAs regulate cellular processes also related to cancer development. CircRNAs can translate into functional peptides too. MLL and most of the 90 MLL translocation partners do express circRNAs and exploration of our RNA-seq dataset of sorted blood cell populations provided new data on alternative circular isoform generation and expression variability of circRNAs of the MLL recombinome. Further, we provided evidence that rearrangements of MLL and three of the main translocation partner genes can impact circRNA expression, supported also by preliminary observations in leukemic cells. The emerging picture underpins the view that circRNAs are worthwhile to be considered when studying MLLre leukemias and provides a new perspective on the impact of chromosomal translocations in cancer cells at large.
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- 2019
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37. Essential Thrombocythemia and Acquired von Willebrand Syndrome: The Shadowlands between Thrombosis and Bleeding
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Hassan Awada, Maria Teresa Voso, Paola Guglielmelli, and Carmelo Gurnari
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essential thrombocythemia ,cytoreductive therapy ,excessive thrombocytosis ,acquired von Willebrand syndrome ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Over the past decade, new insights have emerged on the pathophysiology of essential thrombocythemia (ET), its clinical management, and associated thrombohemostatic disturbances. Here, we review the latest diagnostic and risk stratification modalities of ET and its therapeutics. Moreover, we discuss the clinical evidence-based benefits, deriving from major clinical trials, of using cytoreductive therapy and antiplatelet agents to lower the risk of fatal vascular events. Also, we focus on the condition of extreme thrombocytosis (>1000 × 109/L) and bleeding risk, the development and pathogenesis of acquired von Willebrand syndrome, and the clinical approach to this paradoxical scenario in ET.
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- 2020
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38. Drug-Related Cutaneous Adverse Events in Philadelphia Chromosome-Negative Myeloproliferative Neoplasms: A Literature Review
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Alessandra Malato, Elena Rossi, Giuseppe Alberto Palumbo, Paola Guglielmelli, and Novella Pugliese
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adverse events ,Philadelphia chromosome-negative myeloproliferative neoplasms ,cytoreductive agents ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Since myeloproliferative neoplasms (MPN) pose a significant risk for vascular and thrombotic complications, cytoreductive therapies, such as hydroxyurea (HU), interferon (IFN) inhibitors, and Janus kinase (JAK) inhibitors are recommended for patients at high risk. However, these agents also place patients at increased risk for drug-related cutaneous adverse events. Herein, we review the literature on skin toxicity related to the use of drugs for the treatment of MPN. Overall, the cytoreductive agents used for MPN are generally well tolerated and considered to be safe, except IFN, for which dropout rates as high as 25% have been reported. While IFN is known to give rise to flu syndrome, it rarely leads to hematological alterations. The most common hematological side effects of HU are mild and include granulocytopenia, anemia, and thrombocytopenia. The JAK inhibitor ruxolitinib has been associated with cytopenia and a higher incidence of viral infections, as well as increased risk for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Based on the present analysis, it can be concluded that cutaneous toxicity is not a negligible complication of commonly used treatments for MPN. While further research is needed, patients on these agents, and especially those with a history of cutaneous malignancies, should undergo thorough skin examination before and during therapy. In addition, detailed history is critical since many patients who develop non-melanoma skin cancer have multiple preexisting risk factors for cutaneous carcinogenesis.
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- 2020
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39. Value of cytogenetic abnormalities in post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a study of the MYSEC project
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Barbara Mora, Toni Giorgino, Paola Guglielmelli, Elisa Rumi, Margherita Maffioli, Alessandro Rambaldi, Marianna Caramella, Rami Komrokji, Jason Gotlib, Jean Jacques Kiladjian, Francisco Cervantes, Timothy Devos, Francesca Palandri, Valerio De Stefano, Marco Ruggeri, Richard T. Silver, Giulia Benevolo, Francesco Albano, Chiara Cavalloni, Daniela Barraco, Michele Merli, Daniela Pietra, Rosario Casalone, Tiziano Barbui, Giada Rotunno, Mario Cazzola, Alessandro Maria Vannucchi, and Francesco Passamonti
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2018
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40. Antiplatelet therapy versus observation in low-risk essential thrombocythemia with a CALR mutation
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Alberto Alvarez-Larrán, Arturo Pereira, Paola Guglielmelli, Juan Carlos Hernández-Boluda, Eduardo Arellano-Rodrigo, Francisca Ferrer-Marín, Alimam Samah, Martin Griesshammer, Ana Kerguelen, Bjorn Andreasson, Carmen Burgaleta, Jiri Schwarz, Valentín García-Gutiérrez, Rosa Ayala, Pere Barba, María Teresa Gómez-Casares, Chiara Paoli, Beatrice Drexler, Sonja Zweegman, Mary F. McMullin, Jan Samuelsson, Claire Harrison, Francisco Cervantes, Alessandro M. Vannucchi, and Carlos Besses
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The role of antiplatelet therapy as primary prophylaxis of thrombosis in low-risk essential thrombocythemia has not been studied in randomized clinical trials. We assessed the benefit/risk of low-dose aspirin in 433 patients with low-risk essential thrombocythemia (271 with a CALR mutation, 162 with a JAK2V617F mutation) who were on antiplatelet therapy or observation only. After a follow up of 2215 person-years free from cytoreduction, 25 thrombotic and 17 bleeding episodes were recorded. In CALR-mutated patients, antiplatelet therapy did not affect the risk of thrombosis but was associated with a higher incidence of bleeding (12.9 versus 1.8 episodes per 1000 patient-years, P=0.03). In JAK2V617F-mutated patients, low-dose aspirin was associated with a reduced incidence of venous thrombosis with no effect on the risk of bleeding. Coexistence of JAK2V617F-mutation and cardiovascular risk factors increased the risk of thrombosis, even after adjusting for treatment with low-dose aspirin (incidence rate ratio: 9.8; 95% confidence interval: 2.3–42.3; P=0.02). Time free from cytoreduction was significantly shorter in CALR-mutated patients with essential thrombocythemia than in JAK2V617F-mutated ones (median time 5 years and 9.8 years, respectively; P=0.0002) and cytoreduction was usually necessary to control extreme thrombocytosis. In conclusion, in patients with low-risk, CALR-mutated essential thrombocythemia, low-dose aspirin does not reduce the risk of thrombosis and may increase the risk of bleeding.
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- 2016
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41. STAT1 activation in association with JAK2 exon 12 mutations
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Anna L. Godfrey, Edwin Chen, Charles E. Massie, Yvonne Silber, Francesca Pagano, Beatriz Bellosillo, Paola Guglielmelli, Claire N. Harrison, John T. Reilly, Frank Stegelmann, Fontanet Bijou, Eric Lippert, Jean-Michel Boiron, Konstanze Döhner, Alessandro M. Vannucchi, Carlos Besses, and Anthony R. Green
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2016
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42. Tie2 Expressing Monocytes in the Spleen of Patients with Primary Myelofibrosis.
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Rita Campanelli, Gabriela Fois, Paolo Catarsi, Valentina Poletto, Laura Villani, Benedetta Gaia Erba, Luigi Maddaluno, Basilio Jemos, Silvia Salmoiraghi, Paola Guglielmelli, Vittorio Abbonante, Christian Andrea Di Buduo, Alessandra Balduini, Alessandra Iurlo, Giovanni Barosi, Vittorio Rosti, Margherita Massa, and AGIMM Investigators
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Medicine ,Science - Abstract
Primary myelofibrosis (PMF) is a Philadelphia-negative (Ph-) myeloproliferative disorder, showing abnormal CD34+ progenitor cell trafficking, splenomegaly, marrow fibrosis leading to extensive extramedullary haematopoiesis, and abnormal neoangiogenesis in either the bone marrow or the spleen. Monocytes expressing the angiopoietin-2 receptor (Tie2) have been shown to support abnormal angiogenic processes in solid tumors through a paracrine action that takes place in proximity to the vessels. In this study we investigated the frequency of Tie2 expressing monocytes in the spleen tissue samples of patients with PMF, and healthy subjects (CTRLs), and evaluated their possible role in favouring spleen angiogenesis. We show by confocal microscopy that in the spleen tissue of patients with PMF, but not of CTRLs, the most of the CD14+ cells are Tie2+ and are close to vessels; by flow cytometry, we found that Tie2 expressing monocytes were Tie2+CD14lowCD16brightCDL62-CCR2- (TEMs) and their frequency was higher (p = 0.008) in spleen tissue-derived mononuclear cells (MNCs) of patients with PMF than in spleen tissue-derived MNCs from CTRLs undergoing splenectomy for abdominal trauma. By in vitro angiogenesis assay we evidenced that conditioned medium of immunomagnetically selected spleen tissue derived CD14+ cells of patients with PMF induced a denser tube like net than that of CTRLs; in addition, CD14+Tie2+ cells sorted from spleen tissue derived single cell suspension of patients with PMF show a higher expression of genes involved in angiogenesis than that found in CTRLs. Our results document the enrichment of Tie2+ monocytes expressing angiogenic genes in the spleen of patients with PMF, suggesting a role for these cells in starting/maintaining the pathological angiogenesis in this organ.
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- 2016
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43. Small RNA Sequencing Uncovers New miRNAs and moRNAs Differentially Expressed in Normal and Primary Myelofibrosis CD34+ Cells.
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Paola Guglielmelli, Andrea Bisognin, Claudia Saccoman, Carmela Mannarelli, Alessandro Coppe, Alessandro M Vannucchi, and Stefania Bortoluzzi
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Medicine ,Science - Abstract
Myeloproliferative neoplasms (MPN) are chronic myeloid cancers thought to arise at the level of CD34+ hematopoietic stem/progenitor cells. They include essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). All can progress to acute leukemia, but PMF carries the worst prognosis. Increasing evidences indicate that deregulation of microRNAs (miRNAs) might plays an important role in hematologic malignancies, including MPN. To attain deeper knowledge of short RNAs (sRNAs) expression pattern in CD34+ cells and of their possible role in mediating post-transcriptional regulation in PMF, we sequenced with Illumina HiSeq2000 technology CD34+ cells from healthy subjects and PMF patients. We detected the expression of 784 known miRNAs, with a prevalence of miRNA up-regulation in PMF samples, and discovered 34 new miRNAs and 99 new miRNA-offset RNAs (moRNAs), in CD34+ cells. Thirty-seven small RNAs were differentially expressed in PMF patients compared with healthy subjects, according to microRNA sequencing data. Five miRNAs (miR-10b-5p, miR-19b-3p, miR-29a-3p, miR-379-5p, and miR-543) were deregulated also in PMF granulocytes. Moreover, 3'-moR-128-2 resulted consistently downregulated in PMF according to RNA-seq and qRT-PCR data both in CD34+ cells and granulocytes. Target predictions of these validated small RNAs de-regulated in PMF and functional enrichment analyses highlighted many interesting pathways involved in tumor development and progression, such as signaling by FGFR and DAP12 and Oncogene Induced Senescence. As a whole, data obtained in this study deepened the knowledge of miRNAs and moRNAs altered expression in PMF CD34+ cells and allowed to identify and validate a specific small RNA profile that distinguishes PMF granulocytes from those of normal subjects. We thus provided new information regarding the possible role of miRNAs and, specifically, of new moRNAs in this disease.
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- 2015
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44. Role of miR-34a-5p in Hematopoietic Progenitor Cells Proliferation and Fate Decision: Novel Insights into the Pathogenesis of Primary Myelofibrosis
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Elisa Bianchi, Samantha Ruberti, Sebastiano Rontauroli, Paola Guglielmelli, Simona Salati, Chiara Rossi, Roberta Zini, Enrico Tagliafico, Alessandro Maria Vannucchi, and Rossella Manfredini
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miR-34a-5p ,nuclear receptor subfamily 4, group A, member 2 (NR4A2) ,lymphoid enhancer-binding factor 1 (LEF1) ,MYB ,hematopoetic progenitor cells ,hematopoietic differentiation ,megakaryopoiesis ,primary myelofibrosis ,myeloproliferative neoplasms ,macrophage ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Primary Myelofibrosis (PMF) is a chronic Philadelphia-negative myeloproliferative neoplasm characterized by a skewed megakaryopoiesis and an overproduction of proinflammatory and profibrotic mediators that lead to the development of bone marrow (BM) fibrosis. Since we recently uncovered the upregulation of miR-34a-5p in PMF CD34+ hematopoietic progenitor cells (HPCs), in order to elucidate its role in PMF pathogenesis here we unravelled the effects of miR-34a-5p overexpression in HPCs. We showed that enforced expression of miR-34a-5p partially constrains proliferation and favours the megakaryocyte and monocyte/macrophage commitment of HPCs. Interestingly, we identified lymphoid enhancer-binding factor 1 (LEF1) and nuclear receptor subfamily 4, group A, member 2 (NR4A2) transcripts as miR-34a-5p-targets downregulated after miR-34a-5p overexpression in HPCs as well as in PMF CD34+ cells. Remarkably, the knockdown of NR4A2 in HPCs mimicked the antiproliferative effects of miR-34a-5p overexpression, while the silencing of LEF1 phenocopied the effects of miR-34a-5p overexpression on HPCs lineage choice, by favouring the megakaryocyte and monocyte/macrophage commitment. Collectively our data unravel the role of miR-34a-5p in HPCs fate decision and suggest that the increased expression of miR-34a-5p in PMF HPCs could be important for the skewing of megakaryopoiesis and the production of monocytes, that are key players in BM fibrosis in PMF patients.
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- 2017
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45. Transcriptome analysis of bone marrow mesenchymal stromal cells from patients with primary myelofibrosis
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Christophe Martinaud, Christophe Desterke, Johanna Konopacki, Alessandro M. Vannucchi, Lisa Pieri, Paola Guglielmelli, Brigitte Dupriez, Jean-Christophe Ianotto, Laetitia Boutin, Jean-Jacques Lataillade, and Marie-Caroline Le Bousse-Kerdilès
- Subjects
Genetics ,QH426-470 - Abstract
Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm whose severity and treatment complexity are attributed to the presence of bone marrow (BM) fibrosis and alterations of stroma impairing the production of normal blood cells. Despite the recently discovered mutations including the JAK2V617F mutation in about half of patients, the primitive event responsible for the clonal proliferation is still unknown. In the highly inflammatory context of PMF, the presence of fibrosis associated with a neoangiogenesis and an osteosclerosis concomitant to the myeloproliferation and to the increase number of circulating hematopoietic progenitors suggests that the crosstalk between hematopoietic and stromal cells is deregulated in the PMF BM microenvironmental niches. Within these niches, mesenchymal stromal cells (BM-MSC) play a hematopoietic supportive role in the production of growth factors and extracellular matrix which regulate the proliferation, differentiation, adhesion and migration of hematopoietic stem/progenitor cells. A transcriptome analysis of BM-MSC in PMF patients will help to characterize their molecular alterations and to understand their involvement in the hematopoietic stem/progenitor cell deregulation that features PMF.
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- 2015
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46. Infrequent occurrence of mutations in the PH domain of LNK in patients with JAK2 mutation-negative ‘idiopathic’ erythrocytosis
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Ambra Spolverini, Lisa Pieri, Paola Guglielmelli, Alessandro Pancrazzi, Tiziana Fanelli, Chiara Paoli, Alberto Bosi, Ilaria Nichele, Marco Ruggeri, and Alessandro M. Vannucchi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2013
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47. Complex patterns of chromosome 11 aberrations in myeloid malignancies target CBL, MLL, DDB1 and LMO2.
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Thorsten Klampfl, Jelena D Milosevic, Ana Puda, Andreas Schönegger, Klaudia Bagienski, Tiina Berg, Ashot S Harutyunyan, Bettina Gisslinger, Elisa Rumi, Luca Malcovati, Daniela Pietra, Chiara Elena, Matteo Giovanni Della Porta, Lisa Pieri, Paola Guglielmelli, Christoph Bock, Michael Doubek, Dana Dvorakova, Nada Suvajdzic, Dragica Tomin, Natasa Tosic, Zdenek Racil, Michael Steurer, Sonja Pavlovic, Alessandro M Vannucchi, Mario Cazzola, Heinz Gisslinger, and Robert Kralovics
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Medicine ,Science - Abstract
Exome sequencing of primary tumors identifies complex somatic mutation patterns. Assignment of relevance of individual somatic mutations is difficult and poses the next challenge for interpretation of next generation sequencing data. Here we present an approach how exome sequencing in combination with SNP microarray data may identify targets of chromosomal aberrations in myeloid malignancies. The rationale of this approach is that hotspots of chromosomal aberrations might also harbor point mutations in the target genes of deletions, gains or uniparental disomies (UPDs). Chromosome 11 is a frequent target of lesions in myeloid malignancies. Therefore, we studied chromosome 11 in a total of 813 samples from 773 individual patients with different myeloid malignancies by SNP microarrays and complemented the data with exome sequencing in selected cases exhibiting chromosome 11 defects. We found gains, losses and UPDs of chromosome 11 in 52 of the 813 samples (6.4%). Chromosome 11q UPDs frequently associated with mutations of CBL. In one patient the 11qUPD amplified somatic mutations in both CBL and the DNA repair gene DDB1. A duplication within MLL exon 3 was detected in another patient with 11qUPD. We identified several common deleted regions (CDR) on chromosome 11. One of the CDRs associated with de novo acute myeloid leukemia (P=0.013). One patient with a deletion at the LMO2 locus harbored an additional point mutation on the other allele indicating that LMO2 might be a tumor suppressor frequently targeted by 11p deletions. Our chromosome-centered analysis indicates that chromosome 11 contains a number of tumor suppressor genes and that the role of this chromosome in myeloid malignancies is more complex than previously recognized.
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- 2013
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48. mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms.
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Costanza Bogani, Niccolò Bartalucci, Serena Martinelli, Lorenzo Tozzi, Paola Guglielmelli, Alberto Bosi, Alessandro M Vannucchi, and Associazione Italiana per la Ricerca sul Cancro AGIMM Gruppo Italiano Malattie Mieloproliferative
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Medicine ,Science - Abstract
BACKGROUND:Dysregulated signaling of the JAK/STAT pathway is a common feature of chronic myeloproliferative neoplasms (MPN), usually associated with JAK2V617F mutation. Recent clinical trials with JAK2 inhibitors showed significant improvements in splenomegaly and constitutional symptoms in patients with myelofibrosis but meaningful molecular responses were not documented. Accordingly, there remains a need for exploring new treatment strategies of MPN. A potential additional target for treatment is represented by the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway that has been found constitutively activated in MPN cells; proof-of-evidence of efficacy of the mTOR inhibitor RAD001 has been obtained recently in a Phase I/II trial in patients with myelofibrosis. The aim of the study was to characterize the effects in vitro of mTOR inhibitors, used alone and in combination with JAK2 inhibitors, against MPN cells. FINDINGS:Mouse and human JAK2V617F mutated cell lines and primary hematopoietic progenitors from MPN patients were challenged with an allosteric (RAD001) and an ATP-competitive (PP242) mTOR inhibitor and two JAK2 inhibitors (AZD1480 and ruxolitinib). mTOR inhibitors effectively reduced proliferation and colony formation of cell lines through a slowed cell division mediated by changes in cell cycle transition to the S-phase. mTOR inhibitors also impaired the proliferation and prevented colony formation from MPN hematopoietic progenitors at doses significantly lower than healthy controls. JAK2 inhibitors produced similar antiproliferative effects in MPN cell lines and primary cells but were more potent inducers of apoptosis, as also supported by differential effects on cyclinD1, PIM1 and BcLxL expression levels. Co-treatment of mTOR inhibitor with JAK2 inhibitor resulted in synergistic activity against the proliferation of JAK2V617F mutated cell lines and significantly reduced erythropoietin-independent colony growth in patients with polycythemia vera. CONCLUSIONS/SIGNIFICANCE:These findings support mTOR inhibitors as novel potential drugs for the treatment of MPN and advocate for clinical trials exploiting the combination of mTOR and JAK2 inhibitor.
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- 2013
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49. Inflammation and thrombosis in essential thrombocythemia and polycythemia vera: different role of C-reactive protein and pentraxin 3
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Tiziano Barbui, Alessandra Carobbio, Guido Finazzi, Alessandro M. Vannucchi, Giovanni Barosi, Elisabetta Antonioli, Paola Guglielmelli, Alessandro Pancrazzi, Silvia Salmoiraghi, Pio Zilio, Cosimo Ottomano, Roberto Marchioli, Ivan Cuccovillo, Barbara Bottazzi, Alberto Mantovani, and Alessandro Rambaldi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
We tested the hypothesis that levels of pentraxin high sensitivity C-reactive protein and pentraxin 3 might be correlated with cardiovascular complications in patients with essential thrombocythemia and polycythemia vera. High sensitivity C-reactive protein and pentraxin 3 were measured in 244 consecutive essential thrombocythemia and polycythemia vera patients in whom, after a median follow up of 5.3 years (range 0–24), 68 cardiovascular events were diagnosed. The highest C-reactive protein tertile was compared with the lowest (>3 vs.
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- 2011
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50. Molecular mechanisms associated with leukemic transformation of MPL-mutant myeloproliferative neoplasms
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Philip A. Beer, Christina A. Ortmann, Frank Stegelmann, Paola Guglielmelli, John T. Reilly, Thomas S. Larsen, Hans C. Hasselbalch, Alessandro M. Vannucchi, Peter Möller, Konstanze Döhner, and Anthony R. Green
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Somatic activating mutations in MPL, the thrombopoietin receptor, occur in the myeloproliferative neoplasms, although virtually nothing is known about their role in evolution to acute myeloid leukemia. In this study, the MPL T487A mutation, identified in de novo acute myeloid leukemia, was not detected in 172 patients with a myeloproliferative neoplasm. In patients with a prior MPL W515L-mutant myeloproliferative neoplasm, leukemic transformation was accompanied by MPL-mutant leukemic blasts, was seen in the absence of prior cytoreductive therapy and often involved loss of wild-type MPL by mitotic recombination. Moreover, clonal analysis of progenitor colonies at the time of leukemic transformation revealed the presence of multiple genetically distinct but phylogenetically-related clones bearing different TP53 mutations, implying a mutator-phenotype and indicating that leukemic transformation may be preceded by the parallel expansion of diverse hematopoietic clones.
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- 2010
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