27 results on '"Criscuolo, Marianna"'
Search Results
2. In vitro effect of eltrombopag alone and in combination with azacitidine on megakaryopoiesis in patients with myelodysplastic syndrome.
- Author
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D'Alò F, Zangrilli I, Cupelli E, Fianchi L, Criscuolo M, Falconi G, Fabiani E, Pagano L, Hohaus S, and De Stefano V
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- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols pharmacology, Azacitidine pharmacology, Benzoates pharmacology, Humans, Hydrazines pharmacology, Middle Aged, Myelodysplastic Syndromes pathology, Pyrazoles pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Azacitidine therapeutic use, Benzoates therapeutic use, Hydrazines therapeutic use, Myelodysplastic Syndromes drug therapy, Pyrazoles therapeutic use, Thrombopoiesis drug effects
- Abstract
Thrombocytopenia is a severe complication for patients with myelodysplastic syndrome (MDS). Eltrombopag increases platelet count in MDS patients but its combination with azacitidine elicited controversial results. We aimed to quantify the colony forming units of megakaryocytes (CFU-Mk) obtained from CD34+ bone marrow cells isolated from patients with MDS and from healthy donors that were cultured in vitro in the presence or absence of azacitidine and with or without the sequential addition of eltrombopag to the culture medium. CD34+ bone marrow cells from 6 MDS patients and 3 controls were expanded in vitro and cultured for 3 days with or without azacitidine. Subsequently, a CFU-Mk assay was performed in presence or absence of eltrombopag. The addition of eltrombopag in the CFU-Mk assay after mock treatment of CD34+ cells increased the number of CFU-Mk in both controls and patients. On the contrary, using azacitidine pretreated CD34+ cells, eltrombopag minimally increased CFU-Mk in controls and produced heterogeneous response in MDS patients with no change in two patients and CFU-Mk increase in four patients. In vitro CFU-Mk assay suggest that some MDS patients are likely to benefit from the sequential addition of eltrombopag after azacitidine treatment, in the context of a personalized medicine.
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- 2021
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3. WT1 evaluation in higher-risk myelodysplastic syndrome patients treated with azacitidine.
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Falconi G, Fabiani E, Ottone T, Piciocchi A, Lavorgna S, Criscuolo M, Fianchi L, Gurnari C, Postorino M, Picardi A, Palmieri R, Lo-Coco F, and Voso MT
- Subjects
- Antimetabolites, Antineoplastic therapeutic use, Humans, WT1 Proteins, Azacitidine therapeutic use, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics
- Published
- 2020
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4. Pulmonary infections in patients with myelodysplastic syndromes receiving frontline azacytidine treatment.
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Latagliata R, Niscola P, Fianchi L, Aloe Spiriti MA, Maurillo L, Carmosino I, Cesini L, Sarlo C, Piccioni A, Campagna A, De Luca ML, De Benedittis D, Mancini M, Breccia M, Criscuolo M, Buccisano F, Voso MT, Avvisati G, Tafuri A, De Fabritiis P, Foà R, and Girmenia C
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- Aged, Female, Follow-Up Studies, Humans, Lung drug effects, Male, Middle Aged, Myelodysplastic Syndromes pathology, Prognosis, Respiratory Tract Infections chemically induced, Retrospective Studies, Survival Rate, Antimetabolites, Antineoplastic adverse effects, Azacitidine adverse effects, Lung microbiology, Myelodysplastic Syndromes drug therapy, Respiratory Tract Infections etiology
- Abstract
Pulmonary infections (PIs) are a major complication of patients with myelodysplastic syndromes (MDS). We retrospectively evaluated 234 MDS patients treated with azacytidine (AZA). The total number of AZA cycles was 2886 (median 8 cycles per patient). There were 111 episodes of PI (3.8% of AZA cycles) in 81 patients (34.6%). PIs were considered of fungal origin in 27 cases (24.3%), associated to bacteremia in 11 cases (9.9%), to influenza infection in two cases (1.8%) and of unknown origin in the remaining 71 cases (64.0%). Forty-five PI episodes were documented in cycles 1 to 4 of AZA (5.1% of 875 cycles) and the remaining 66 episodes beyond the fourth cycle (3.2% of 2011 cycles) (P = .017). Overall, a fungal PI was documented in 13/875 (1.5%) cycles 1 to 4 and in 13/2011 (0.6%) cycles beyond the fourth cycle (P = .001). A baseline chronic pulmonary disease was significantly associated to a higher risk of severe PIs. In the survival analysis, cases of PI in patients who progressed to acute leukemia (PAL) were excluded, in view of the predominant influence of PAL on the outcome of the patients. A PI unrelated to PAL documented during the first 4 AZA cycles was an independent factor predicting lower survival (OR, 2.13; 95% CI, 1.37-3.33; P = .001). In conclusion, PIs are common in MDS patients receiving AZA, in particular during the first cycles of treatment and are associated with an unfavorable outcome. The results of our study raise the issue of the need of a tailored infection prevention strategy., (© 2019 John Wiley & Sons Ltd.)
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- 2020
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5. Transcription factors implicated in late megakaryopoiesis as markers of outcome after azacitidine and allogeneic stem cell transplantation in myelodysplastic syndrome.
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Falconi G, Fabiani E, Criscuolo M, Fianchi L, Finelli C, Cerqui E, Pelosi E, Screnci M, Gurnari C, Zangrilli I, Postorino M, Laurenti L, Piciocchi A, Testa U, Lo-Coco F, and Voso MT
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- Adult, Aged, Cell Differentiation genetics, Combined Modality Therapy, Female, GATA1 Transcription Factor genetics, GATA1 Transcription Factor metabolism, GATA2 Transcription Factor genetics, GATA2 Transcription Factor metabolism, Gene Expression, Humans, Male, Middle Aged, Myelodysplastic Syndromes diagnosis, Transcription Factors metabolism, Transplantation, Homologous, Treatment Outcome, Azacitidine therapeutic use, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes therapy, Thrombopoiesis genetics, Transcription Factors genetics
- Abstract
The hypomethylating agent azacitidine (AZA) is used to treat higher-risk myelodysplastic syndromes (HR-MDS) and elderly patients with low-blast count acute myeloid leukemia (LBC-AML). Platelet recovery is an early predictor of AZA response. We prospectively studied the expression profile of transcription factors, critical for late megakaryopoiesis and changes in their expression after AZA treatment in patients with HR-MDS and LBC-AML enrolled in the BMT-AZA trial (EudraCT number 2010-019673-15). Twenty-five additional patients with low-risk (LR)-MDS were also studied. At the time of diagnosis, GATA2 mRNA levels were significantly higher in MDS as compared to controls, with increasing levels from LR- to HR-MDS/AML. RUNX1 expression was also significantly higher in MDS, as compared to controls, but no differences were found between LR- and HR-MDS. Looking at biomarkers of response, we found that patients AZA responsive had higher basal GATA1 and lower FLI1 expression, compared to those with stable or progressive disease after treatment. Univariate analysis showed that increased GATA2 mRNA expression was associated with a worse overall survival. Our findings suggest that high GATA2 expression is a poor prognostic marker for survival in patients with HR-MDS and LBC-AML treated with azacitidine. Moreover, GATA1 and FLI1 mRNA expression may predict response to AZA treatment., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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6. Mutational profile and haematological response to iron chelation in myelodysplastic syndromes (MDS).
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Fabiani E, Calabrese C, Niscola P, Balleari E, Molteni A, Finelli C, Falconi G, Fenu S, Fianchi L, Criscuolo M, Salvi F, Lavorgna S, Buccisano F, Maurillo L, Lo Coco F, Cilloni D, and Voso MT
- Subjects
- Adult, Aged, Aged, 80 and over, Humans, Iron Chelating Agents pharmacology, Middle Aged, Mutation, Hematology methods, Iron Chelating Agents therapeutic use, Myelodysplastic Syndromes drug therapy
- Published
- 2019
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7. Somatic mutations as markers of outcome after azacitidine and allogeneic stem cell transplantation in higher-risk myelodysplastic syndromes.
- Author
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Falconi G, Fabiani E, Piciocchi A, Criscuolo M, Fianchi L, Lindfors Rossi EL, Finelli C, Cerqui E, Ottone T, Molteni A, Parma M, Santarone S, Candoni A, Sica S, Leone G, Lo-Coco F, and Voso MT
- Subjects
- Adult, Aged, Female, Hematopoietic Stem Cell Transplantation methods, Humans, Male, Middle Aged, Young Adult, Azacitidine therapeutic use, Biomarkers, Tumor genetics, Mutation drug effects, Mutation genetics, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics
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- 2019
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8. Real-life use of erythropoiesis-stimulating agents in myelodysplastic syndromes: a "Gruppo Romano Mielodisplasie (GROM)" multicenter study.
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Buccisano F, Piccioni AL, Nobile C, Criscuolo M, Niscola P, Tatarelli C, Fianchi L, Villivà N, Neri B, Carmosino I, Gumenyuk S, Mancini S, Voso MT, Maurillo L, Breccia M, Zini G, Venditti A, Fenu S, Spiriti MA, and Latagliata R
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- Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Italy epidemiology, Male, Myelodysplastic Syndromes mortality, Retrospective Studies, Survival Rate trends, Hematinics therapeutic use, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes drug therapy
- Abstract
The Gruppo Romano Mielodisplasie (GROM) conducted a retrospective study in 543 patients with myelodysplastic syndromes (MDS) to evaluate the safety and efficacy of erythropoiesis-stimulating agents (ESAs) in "real-life" clinical practice. The 40.000-UI/week erythropoietin (EPO)-alpha and 30.000-UI/week EPO-beta starting dose were defined "standard," and 80,000 UI/week EPO-alpha and 60.000 UI/week EPO-beta were defined "high." Response was defined according to International Working Group (IWG) 2006 criteria. At ESA's start, median age was 74.2 years (interquartile range (IR) 67.8-79.5) and median hemoglobin was 8.9 g/dl (IR 8.2-9.6). Median time from diagnosis to ESAs start was 3.8 months (IR 0.8-13.2). ESA starting dose was "standard" in 361 patients (66.5 %) and "high" in 182 patients (33.5 %). Erythroid response was observed in 82/185 (44.3 %) transfusion dependent (TD) patients as compared with 226/329 (68.6 %) transfusion independent (TI) ones (p < 0.001). At multivariate analysis, in TD patients, only endogenous EPO levels <50 mU/l were significant (p = 0.046), whereas in TI patients, high-dose ESAs (p < 0.001), abnormal creatinine levels (0.009), and endogenous EPO levels <50 mU/l (p = 0.014) were predictors of response. Responders showed a higher 5-year overall survival (OS) (57.8 vs. 32.2 %, p < 0.001) and leukemia-free survival (76.0 vs. 49.8 %, p < 0.001). At multivariable analysis for OS, response to ESA, low International Prognostic Scoring System (IPSS), no transfusion need, and female sex showed an independent favorable prognostic role. Our results confirm that treatment with ESAs is effective in a real-life MDS setting, particularly at high dose and in TI patients. Prospective studies are needed to define the optimal starting dose.
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- 2016
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9. Standard dose and prolonged administration of azacitidine are associated with improved efficacy in a real-world group of patients with myelodysplastic syndrome or low blast count acute myeloid leukemia.
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Voso MT, Niscola P, Piciocchi A, Fianchi L, Maurillo L, Musto P, Pagano L, Mansueto G, Criscuolo M, Aloe-Spiriti MA, Buccisano F, Venditti A, Tendas A, Piccioni AL, Zini G, Latagliata R, Filardi N, Fragasso A, Fenu S, and Breccia M
- Subjects
- Adult, Aged, Aged, 80 and over, Cell Count, Disease Management, Drug Administration Schedule, Female, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Multivariate Analysis, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes mortality, Myelodysplastic Syndromes pathology, Retrospective Studies, Survival Analysis, Treatment Outcome, Antimetabolites, Antineoplastic therapeutic use, Azacitidine therapeutic use, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy
- Abstract
Objective: Azacitidine is the standard of care for higher-risk myelodysplastic syndromes (MDS). We evaluated factors affecting the outcome of azacitidine treatment in 196 'real-world' patients, retrospectively collected by two Italian cooperative groups., Methods: The study included 184 MDS and 12 low blast count acute myeloid leukemia (AML). Azacitidine was administered at the standard dose of 75 mg/m(2)/d for 7 d (SD) in 163 patients and 100 mg/d for 5-7 d in 33 patients., Results: After a median of 4.5 azacitidine cycles (range 7-15 cycles), 182 patients were evaluable for response. Nineteen percent achieved complete remission (CR), 17% partial remission (PR), and 21% hematological improvement (HI). The disease was stable or progressive in 29% and 14% of patients, respectively. The probability of response was significantly higher in patients who received the 75 mg/m(2)/7 d compared with 100 mg through 5-7 d dose (CR/PR/HI: 63 vs. 29%, P = 0.0005). Median overall survival was 17.1 months. Low MDS-CI and achievement of CR/PR/HI were significant predictors of survival in the multivariable analysis., Conclusions: Our data show that maximal azacitidine efficacy is associated with the standard dose and with prolonged treatment, beyond 4-6 cycles, with the goal of also improving the 'quality' of response. Lower MDS-CI and IPSS-R scores, hematologic response and disease stability, are associated with longer survival. The risk of febrile events is highest during the first treatment cycles and is associated with active disease., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2016
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10. Impairment of PI3K/AKT and WNT/β-catenin pathways in bone marrow mesenchymal stem cells isolated from patients with myelodysplastic syndromes.
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Falconi G, Fabiani E, Fianchi L, Criscuolo M, Raffaelli CS, Bellesi S, Hohaus S, Voso MT, D'Alò F, and Leone G
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- Aged, Aged, 80 and over, Bone Marrow Cells enzymology, Female, Humans, Male, Mesenchymal Stem Cells enzymology, Middle Aged, Myelodysplastic Syndromes enzymology, Myelodysplastic Syndromes metabolism, Bone Marrow Cells metabolism, Mesenchymal Stem Cells metabolism, Myelodysplastic Syndromes pathology, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Wnt Proteins metabolism, beta Catenin metabolism
- Abstract
Bone marrow mesenchymal stem cells (BM-MSCs) exhibit multiple abnormalities in myelodysplastic syndromes (MDS), including impaired proliferative and clonogenic capacity, altered morphology, increased senescence, impaired immunoregulatory properties, and reduced hematopoietic support capacity. Common signaling pathways, such as PI3K/AKT and WNT/β-catenin, regulate multiple MSC properties, including proliferation, differentiation, and cell-cell interaction. Here, with polymerase chain reaction arrays, we investigated the expression of 84 genes belonging to the PI3K/AKT signaling pathways in BM-MSCs isolated from patients with MDS, acute myeloid leukemia, and therapy-related myeloid neoplasms, using as a control BM-MSCs isolated from patients with untreated early-stage lymphomas without BM involvement. Statistically significant downregulation of GSK3β, SOS1, RASA1, and MTCP1 gene expression was observed in BM-MSCs isolated from patients with de novo MDS, as compared with controls. Moreover, expression of the GSK3β protein was reduced in MDS-derived MSCs, and was associated with concomitant reduction of phosphorylation at Ser-9. The role of GSK3β in the downstream WNT/β-catenin signaling pathway was assessed. We investigated β-catenin protein levels and expression of 84 genes belonging to the WNT target gene pathway using PCR arrays in MDS BM-MSCs, as compared with control BM-MSCs. GSK3β impairment translated into decreased β-catenin protein levels and downregulation of several WNT/β-catenin target genes (SOX9, EGR1, WISP1). These findings suggest that deregulation of genes involved in the PI3K/AKT and WNT signaling pathways may contribute to the phenotypical abnormalities of MDS BM-MSCs., (Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)
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- 2016
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11. Deferasirox chelation therapy in patients with transfusion-dependent MDS: a 'real-world' report from two regional Italian registries: Gruppo Romano Mielodisplasie and Registro Basilicata.
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Maurillo L, Breccia M, Buccisano F, Voso MT, Niscola P, Trapè G, Tatarelli C, D'Addosio A, Latagliata R, Fenu S, Piccioni AL, Fragasso A, Aloe Spiriti MA, Refrigeri M, Criscuolo M, Musto P, and Venditti A
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- Adult, Aged, Aged, 80 and over, Deferasirox, Female, Ferritins blood, Hematopoiesis drug effects, Humans, Iron blood, Iron Overload blood, Iron Overload etiology, Iron Overload pathology, Italy, Male, Middle Aged, Myelodysplastic Syndromes blood, Myelodysplastic Syndromes pathology, Retrospective Studies, Treatment Outcome, Benzoates therapeutic use, Iron Chelating Agents therapeutic use, Iron Overload drug therapy, Myelodysplastic Syndromes therapy, Registries, Transfusion Reaction, Triazoles therapeutic use
- Abstract
Deferasirox (DFX) is an orally administered iron chelator approved for use in patients with transfusion-dependent iron overload due to myelodysplastic syndromes (MDS). The safety and efficacy of DFX has been explored in clinical trial settings, but there is little data on unselected patients with MDS. The aim of this study was to retrospectively evaluate the safety, compliance, efficacy and effect on haematopoiesis of DFX in a large 'real-world' MDS population. One hundred and eighteen patients with transfusion-dependent MDS were treated with DFX across 11 centres in Italy. Serum ferritin levels, haematological response, dosing, adverse events and transfusion dependence were recorded at baseline, 3, 6, 12 and 24 months following initiation of treatment. DFX reduced mean serum ferritin levels from 1790 to 1140 ng/mL (P < 0.001), with 7.1% of patients achieving transfusion independence. Significant haematological improvement was seen in erythroid (17.6%), platelet (5.9%) and neutrophil counts (7.1%). Adverse events were reported in 47.5% of patients, including gastrointestinal and renal toxicity. Regression analysis showed that higher starting doses of DFX are associated with transfusion independence at 24 months. DFX is a safe, effective treatment for transfusion-dependent MDS that can lead to transfusion independence and haematological improvement in a subset of patients., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2015
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12. Prevalence, severity and correlates of fatigue in newly diagnosed patients with myelodysplastic syndromes.
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Efficace F, Gaidano G, Breccia M, Criscuolo M, Cottone F, Caocci G, Bowen D, Lübbert M, Angelucci E, Stauder R, Selleslag D, Platzbecker U, Sanpaolo G, Jonasova A, Buccisano F, Specchia G, Palumbo GA, Niscola P, Wan C, Zhang H, Fenu S, Klimek V, Beyne-Rauzy O, Nguyen K, and Mandelli F
- Subjects
- Adult, Aged, Aged, 80 and over, Dyspnea epidemiology, Dyspnea etiology, Europe epidemiology, Fatigue blood, Fatigue epidemiology, Female, Hemoglobins metabolism, Humans, Male, Middle Aged, Myelodysplastic Syndromes blood, Myelodysplastic Syndromes epidemiology, Pain epidemiology, Pain etiology, Prevalence, Psychometrics, Quality of Life, Severity of Illness Index, Fatigue etiology, Myelodysplastic Syndromes complications
- Abstract
The primary objective of this study was to investigate factors associated with fatigue severity in newly diagnosed patients with higher-risk myelodysplastic syndromes (MDS). The secondary objectives were to assess symptom prevalence and to examine the relationships between fatigue, quality of life (QoL) and overall symptom burden in these patients. The analyses were conducted in 280 higher-risk MDS patients. Pre-treatment patient-reported fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale and QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Female gender (P = 0·018), poor performance status (i.e., ECOG of 2-4) (P < 0·001) and lower levels of haemoglobin (Hb) (P = 0·026) were independently associated with higher fatigue severity. The three most prevalent symptoms were as follows: fatigue (92%), dyspnoea (63%) and pain (55%). Patients with higher levels of fatigue also had greater overall symptom burdens. The mean global QoL scores of patients with the highest versus those with the lowest levels of fatigue were 29·2 [standard deviation (SD), 18·3] and 69·0 (SD, 18·8), respectively and this difference was four times the magnitude of a clinically meaningful difference. Patient-reported fatigue severity revealed the effects of disease burden on overall QoL more accurately than did degree of anaemia. Special attention should be given to the female patients in the management of fatigue., (© 2014 John Wiley & Sons Ltd.)
- Published
- 2015
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13. Methylenetetrahydrofolate reductase polymorphisms in myelodysplastic syndromes and therapy-related myeloid neoplasms.
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Criscuolo M, Chiusolo P, Giammarco S, Giachelia M, Fianchi L, Fabiani E, Falconi G, Hohaus S, Sica S, Leone G, and Voso MT
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- Genetic Predisposition to Disease, Genotype, Humans, Myelodysplastic Syndromes therapy, Polymorphism, Single Nucleotide, Leukemia, Myeloid etiology, Methylenetetrahydrofolate Reductase (NADPH2) genetics, Myelodysplastic Syndromes genetics, Neoplasms, Second Primary etiology, Polymorphism, Genetic
- Published
- 2014
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14. SETBP1 mutations in 106 patients with therapy-related myeloid neoplasms.
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Fabiani E, Falconi G, Fianchi L, Criscuolo M, Leone G, and Voso MT
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- Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Female, Gamma Rays adverse effects, Humans, Leukemia, Myeloid, Acute chemically induced, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Myelodysplastic Syndromes chemically induced, Myelodysplastic Syndromes pathology, Neoplasms drug therapy, Neoplasms genetics, Neoplasms pathology, Neoplasms radiotherapy, Carrier Proteins genetics, Leukemia, Myeloid, Acute genetics, Mutation, Myelodysplastic Syndromes genetics, Nuclear Proteins genetics
- Published
- 2014
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15. Recombinant human erythropoietin in very elderly patients with myelodysplastic syndromes: results from a retrospective study.
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Tatarelli C, Piccioni AL, Maurillo L, Naso V, Battistini R, D'Andrea M, Criscuolo M, Nobile C, Villivà N, Mancini S, Neri B, Breccia M, Fenu S, Buccisano F, Voso MT, Latagliata R, and Aloe Spiriti MA
- Subjects
- Age Factors, Aged, Aged, 80 and over, Anemia etiology, Blood Transfusion statistics & numerical data, Drug Evaluation, Epoetin Alfa, Erythropoietin adverse effects, Female, Ferritins blood, Gastrointestinal Diseases chemically induced, Hematocrit, Humans, Hypertension chemically induced, Kaplan-Meier Estimate, Male, Multicenter Studies as Topic statistics & numerical data, Myelodysplastic Syndromes complications, Myelodysplastic Syndromes mortality, Prognosis, Proportional Hazards Models, Recombinant Proteins adverse effects, Recombinant Proteins therapeutic use, Retrospective Studies, Thrombosis chemically induced, Anemia drug therapy, Erythropoietin therapeutic use, Myelodysplastic Syndromes drug therapy
- Abstract
Myelodysplastic syndromes (MDS) are common in elderly patients. Recombinant human erythro-poietin (rHuEPO) has been widely used to treat anemia in lower risk MDS patients, but few data are known about rHuEPO treatment in the very elderly patient group. In order to investigate the role of rHuEPO treatment in terms of response, overall survival (OS), and toxicity in a very elderly MDS patient group, 93 MDS patients treated with rHuEPO when aged ≥80 years were selected among MDS cases enrolled in a retrospective multicenter study by the cooperative group Gruppo Romano Mielodisplasie (GROM) from Jan 2002 to Dec 2010. At baseline, median age was 82.7 (range 80-99.1) with a median hemoglobin (Hb) level of 9 g/dl (range 6-10.8). The initial dose of rHuEPO was standard (epoetin alpha 40,000 IU/week or epoetin beta 30,000 IU/week) in 59 (63.4 %) patients or high in 34 (36.6 %) (epoetin alpha 80,000 IU/week) patients. We observed an erythroid response (ER) in 59 (63.4 %) patients. No thrombotic event was reported. Independent predictive factors for ER were low transfusion requirement before treatment (p = 0.004), ferritin <200 ng/ml (p = 0.017), Hb >8 g/dl (p = 0.034), and a high-dose rHuEPO treatment (p = 0.032). Median OS from rHuEPO start was 49.3 months (95 % CI 27.5-68.4) in responders versus 30.6 months (95 % CI 7.3-53.8) in resistant patients (p = 0.185). In conclusion, rHuEPO treatment is safe and effective also in the very elderly MDS patients. However, further larger studies are warranted to evaluate if EPO treatment could be worthwhile in terms of quality of life and cost-efficacy in very old patients.
- Published
- 2014
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16. The BCL2L10 Leu21Arg variant and risk of therapy-related myeloid neoplasms and de novo myelodysplastic syndromes.
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Fabiani E, Fianchi L, Falconi G, Boncompagni R, Criscuolo M, Guidi F, La Brocca A, Hohaus S, Leone G, and Voso MT
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Amino Acid Substitution, Bone Marrow pathology, Case-Control Studies, DNA Mutational Analysis, Female, Gene Frequency, Genotype, Humans, Leukemia, Myeloid, Acute diagnosis, Male, Middle Aged, Myelodysplastic Syndromes diagnosis, Neoplasms, Second Primary diagnosis, Odds Ratio, Polymorphism, Genetic, Risk, Young Adult, Leukemia, Myeloid, Acute etiology, Mutation, Myelodysplastic Syndromes etiology, Neoplasms, Second Primary etiology, Proto-Oncogene Proteins c-bcl-2 genetics
- Abstract
Therapy-related myeloid neoplasms (t-MNs) are an increasingly recognized complication in patients previously treated with radiotherapy and/or chemotherapy for cancer or autoimmune disease. Single nucleotide variants (SNVs) in genes involved in the cellular pathways of detoxification, DNA repair and apoptosis may modify the individual risk of developing a t-MN. We studied the frequency of the SNVs of six genes involved in xenobiotic detoxification (CYP3A4, NQO1, GSTA1, GSTM1, GSTP1 and GSTT1), two DNA repair genes (RAD51 and XRCC3) and one key regulator of apoptosis (BCL2L10) in a case-control study including 111 cases of t-MN and 259 controls. This is the first report on the prevalence of BCL2L10 Leu21Arg polymorphism in myeloid malignancies. In this line, we also tested 146 cases of de novo myelodysplastic syndrome (MDS) and 109 cases of de novo acute myeloid leukemia (AML). Our results showed a significantly lower frequency of the BCL2L10-21Arg allele in patients with t-MN and de novo MDS compared to controls (Leu/Arg + Arg/Arg: 50.6% vs. 65.9%, p = 0.017 and 45.8% vs. 65.9%, p = 0.0003, respectively). Carriers of the BCL2L10-21Arg variant have a reduced risk of developing t-MN and de novo MDS.
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- 2014
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17. Why methylation is not a marker predictive of response to hypomethylating agents.
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Voso MT, Santini V, Fabiani E, Fianchi L, Criscuolo M, Falconi G, Guidi F, Hohaus S, and Leone G
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- Animals, Apoptosis drug effects, Apoptosis genetics, Biomarkers, Epigenesis, Genetic drug effects, Humans, Mutation, Prognosis, Treatment Outcome, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, DNA Methylation drug effects, DNA Modification Methylases antagonists & inhibitors, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics
- Abstract
The azanucleotides azacitidine and decitabine have been shown to induce hematologic response and prolong survival in higher-risk myelodysplastic syndromes. They are inhibitors of DNA methyltransferase-1 and induce DNA-hypomethylation. Induction of apoptosis is also clinically relevant, in particular during the first treatment cycles, when cytopenia is a frequent side-effect. Since the hypomethylating effect is reversible, and the malignant clone has been shown to persist in most responding patients, several cycles are necessary to achieve and maintain responses, while treatment interruption is associated with rapid relapse. Methylation studies have shown global and gene-specific hypermethylation in myelodysplastic syndromes, but there seems to be little relation between the degree of demethylation following hypomethylating treatment and hematologic response. The presence of concurrent genomic hypermethylation and hypomethylation may impair the predictive power of current detection techniques. This scenario has been complicated by the identification of epigenetic enzyme mutations, including TET2, IDH1/2, DNMT3A and EZH2, which are important for response to hypomethylating treatment. Changes in azanucleotide metabolism genes may also play a role. In the future, methylation analysis concentrating not only on promoters, but also on gene bodies and intergenic regions, may identify key genes in patients with the highest probability of response to azanucleotides and allow a patient-tailored approach.
- Published
- 2014
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18. Revised International Prognostic Scoring System (IPSS) predicts survival and leukemic evolution of myelodysplastic syndromes significantly better than IPSS and WHO Prognostic Scoring System: validation by the Gruppo Romano Mielodisplasie Italian Regional Database.
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Voso MT, Fenu S, Latagliata R, Buccisano F, Piciocchi A, Aloe-Spiriti MA, Breccia M, Criscuolo M, Andriani A, Mancini S, Niscola P, Naso V, Nobile C, Piccioni AL, D'Andrea M, D'Addosio A, Leone G, and Venditti A
- Subjects
- Adult, Aged, Aged, 80 and over, Disease Progression, Female, Humans, International Cooperation, Male, Middle Aged, Myelodysplastic Syndromes blood, Prognosis, Research Design, Retrospective Studies, Risk Factors, Survival Analysis, Treatment Outcome, World Health Organization, Young Adult, Myelodysplastic Syndromes diagnosis
- Abstract
Purpose: The definition of disease-specific prognostic scores plays a fundamental role in the treatment decision-making process in myelodysplastic syndrome (MDS), a group of myeloid disorders characterized by a heterogeneous clinical behavior., Patients and Methods: We applied the recently published Revised International Prognostic Scoring System (IPSS-R) to 380 patients with MDS, registered in an Italian regional database, recruiting patients from the city of Rome (Gruppo Romano Mielodisplasie). Patients were selected based on the availability of IPSS-R prognostic factors, including complete peripheral-blood and bone marrow counts, informative cytogenetics, and follow-up data., Results: We validated the IPSS-R score as a significant predictor of overall survival (OS) and leukemia-free survival (LFS) in MDS (P < .001 for both). When comparing the prognostic value of the International Prognostic Scoring System (IPSS), WHO Prognostic Scoring System (WPSS), and IPSS-R, using the Cox regression model and the likelihood ratio test, a significantly higher predictive power for LFS and OS became evident for the IPSS-R, compared with the IPSS and WPSS (P < .001 for both). The multivariate analysis, including IPSS, WPSS, age, lactate dehydrogenase, ferritin concentration, Eastern Cooperative Oncology Group performance status, transfusion dependency, and type of therapy, confirmed the significant prognostic value of IPSS-R subgroups for LFS and OS. Treatment with lenalidomide and erythropoiesis-stimulating agents was shown to be an independent predictor of survival in the multivariate analysis., Conclusion: Our data confirm that the IPSS-R is an excellent prognostic tool in MDS in the era of disease-modifying treatments. The early recognition of patients at high risk of progression to aggressive disease may optimize treatment timing in MDS.
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- 2013
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19. Outcome of therapy-related myeloid neoplasms treated with azacitidine.
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Fianchi L, Criscuolo M, Lunghi M, Gaidano G, Breccia M, Levis A, Finelli C, Santini V, Musto P, Oliva EN, Leoni P, Aloe Spiriti A, D'Alò F, Hohaus S, Pagano L, Leone G, and Voso MT
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Myelodysplastic Syndromes mortality, Neoplasms, Second Primary mortality, Prognosis, Remission Induction, Retrospective Studies, Survival Rate, Antimetabolites, Antineoplastic therapeutic use, Azacitidine therapeutic use, DNA Methylation drug effects, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy, Neoplasms, Second Primary drug therapy
- Abstract
Background: Therapy-related myeloid neoplasms (t-MN), including myelodysplastic syndromes and acute myeloid leukemia (t-MDS and t-AML) are associated to clinical and biologic unfavorable prognostic features, including high levels of DNA methylation., Methods: We retrospectively evaluated 50 t-MN patients (34 MDS and 16 AML) selected among all patients receiving azacitidine (AZA) at 10 Italian Hematology Centers. Patients had developed a t-MN at a median of 6.5 years (range 1.7- 29) after treatment of the primary tumor (hematological neoplasm, 27 patients; solid tumor, 23 patients)., Results: The overall response rate was 42% (complete remission: 10 patients, partial remission: 2 and hematological improvement: 8 patients) and was obtained after a median of 3 cycles (range 1-6). Median overall survival (OS) was 21 months (range 1-53.6+) from AZA start. OS was significantly better in patients with less than 20% blasts, in normal karyotype t-AML and when AZA was used as front-line treatment. This was confirmed by the multivariate analysis., Conclusions: This study reports efficacy of AZA in the largest series of therapy-related MN patients treated with 5-AZA. Our data show that blasts and karyotype maintain their important prognostic role in t-MN also in the azacitidine era.
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- 2012
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20. Promoter methylation of DAPK1, E-cadherin and thrombospondin-1 in de novo and therapy-related myeloid neoplasms.
- Author
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Greco M, D'Alò F, Scardocci A, Criscuolo M, Fabiani E, Guidi F, Di Ruscio A, Migliara G, Pagano L, Fianchi L, Chiusolo P, Hohaus S, Leone G, and Voso MT
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antigens, CD, Death-Associated Protein Kinases, Female, Humans, Male, Middle Aged, Apoptosis Regulatory Proteins, Cadherins, Calcium-Calmodulin-Dependent Protein Kinases, DNA Methylation, Leukemia, Myeloid, Acute metabolism, Myelodysplastic Syndromes metabolism, Neoplasms, Second Primary metabolism, Promoter Regions, Genetic, Thrombospondin 1
- Abstract
DNA methylation is one of the major epigenetic changes in human cancers, leading to silencing of tumor suppressor genes, with a pathogenetic role in tumor development and progression in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Methylation of key promoter regions, induced by cytotoxic therapy together with complex genetic changes, is important in the biology of therapy-related myeloid neoplasms (t-MN). We were interested in the characterization of the methylation pattern of AML and MDS de novo and therapy-related. We studied 385 patients (179 females, 206 males), of a median age of 66 years (range 16-98 years). There were 105 MDS, 208 de novo AML and 72 t-MN (45 MDS and 27 AML). Using a methylation-specific PCR, we studied the promoter methylation status of E-cadherin (CDH1), TSP1 and DAP-Kinase 1. These genes have been shown to be involved in the malignant transformation, interfering with angiogenesis, interaction with micro-environment, apoptosis and xenobiotic detoxification. We found no associations between promoter hypermethylation and gender or age at the time of initial diagnosis. In patients with MDS, there were no associations between hypermethylation and clinical characteristics, including IPSS score, WHO classification and cytogenetics. DAPK1 was more frequently methylated in t-MDS/AML when compared to de novo MDS and AML (39% vs 15.3% and 24.4%, p=0.0001), while methylation of CDH1 was similar in t-MDS/AML and AML (51% and 53.4%), but less frequent in de novo MDS (29%) (p=0.003). In the t-MDS/AML group, we found that the methylation pattern appeared to be related to the primary tumor, with DAPK1 more frequently methylated in patients with a previous lymphoproliferative disease (75% vs 32%, p=0.006). On the other hand, methylation of CDH1 was associated to radiotherapy for the primary malignancy (84.5% vs 38%, p=0.003). TSP1 hypermethylation was rare and not characteristic of t-MDS/AML. In 177 patients studied for concurrent methylation of several promoters, t-MN and AML de novo were significantly more frequently hypermethylated in 2 or more promoter regions than de novo MDS (20% vs 12.4%, p<0.001). Chemotherapy and individual genetic predisposition have a role in t-MDS/AML development, the identification of specific epigenetic modifications may explain complexity and genomic instability of these diseases and give the basis for targeted-therapy. The significant association with previous malignancy subtypes may underlie a likely susceptibility to methylation of specific targets and a role for constitutional epimutations as predisposing factors for the development of therapy-related myeloid neoplasm., (Copyright © 2010 Elsevier Inc. All rights reserved.)
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- 2010
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21. Epigenetic changes in therapy-related MDS/AML.
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Voso MT, D'Alò F, Greco M, Fabiani E, Criscuolo M, Migliara G, Pagano L, Fianchi L, Guidi F, Hohaus S, and Leone G
- Subjects
- DNA Damage, DNA Methylation, Humans, Leukemia, Myeloid, Acute therapy, Myelodysplastic Syndromes therapy, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes genetics
- Abstract
Therapy-related Myelodysplastic Syndromes/Acute Myeloid Leukemias (t-MDS/AML) are one of the most compelling long term adverse events occurring in cancer survivors treated with chemo-radiotherapy regimes. Beside several well-described genetic lesions, a growing amount of data suggests that abnormalities in DNA methylation profile contribute to multistep secondary leukemogenesis. Two distinct alterations of normal DNA methylation patterns may occur in cancer: a global hypomethylation resulting in chromosomal instability and loss of genetic integrity, and promoter specific DNA hypermethylation which leads to silencing of tumor suppressor genes. Cytotoxic drugs and radiation have been shown to affect tissue DNA methylation profile. Radiation is able to induce a stable DNA hypomethylation in both target and bystander tissues. Gene promoter methylation is a common finding in t-MDS/AML and has been associated to a shorter latency period from the treatment of the primary tumor. Among the studied genes, p15 methylation correlated to monosomy/deletion of chromosome 7q, suggesting that it could be a relevant event in alkylating agent-induced leukemogenesis. We found frequent methylation of DAPK in the t-MDS/AML group, especially in patients with a previous lymphoproliferative disease. In patients studied for concurrent methylation of several promoters, t-MDS/AML were significantly more frequently hypermethylated in 2 or more promoter regions than de novo MDS or AML suggesting that promoter hypermethylation of genes involved in cell cycle control, apoptosis and DNA repair pathways is a frequent finding in t-MDS/AML and may contribute to secondary leukemogenesis. However, how the epigenetic machinery is disrupted after chemo/radiotherapy and during secondary carcinogenesis is still unknown, warranting further studies., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)
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- 2010
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22. Polymorphisms of detoxification and DNA repair enzymes in myelodyplastic syndromes.
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Fabiani E, D'Alò F, Scardocci A, Greco M, Di Ruscio A, Criscuolo M, Fianchi L, Pagano L, Hohaus S, Leone G, and Voso MT
- Subjects
- Aged, Case-Control Studies, Cohort Studies, Disease-Free Survival, Female, Humans, Male, Myelodysplastic Syndromes mortality, Risk Factors, Survival Rate, Xenobiotics, Alleles, DNA Repair genetics, Myelodysplastic Syndromes genetics, Polymorphism, Genetic
- Abstract
The genetic background may modify the individual's risk of developing cancer. We performed a case-control study to test the impact of genomic polymorphisms of 9 genes involved in xenobiotics detoxification and DNA repair in myelodysplastic syndromes (MDS). Frequencies of polymorphic variants of RAD51, XRCC3, NQO1, GSTA1, GSTM1, GSTT1, CYP3A4 and XPD enzymes were similar in patients and controls. On the other hand, the GSTP1-105Val allele was associated to an increased risk of MDS (O.R. 1.66; p=0.04) and to higher probability of overall survival in the low/intermediate-1 IPSS risk group (p=0.008). The GSTP1-Ile105Val polymorphism is likely to influence MDS risk and prognosis.
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- 2009
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23. Myelodysplastic Syndromes with Isolated 20q Deletion: A New Clinical–Biological Entity?
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Campagna, Alessia, De Benedittis, Daniela, Fianchi, Luana, Scalzulli, Emilia, Rizzo, Lorenzo, Niscola, Pasquale, Piccioni, Anna Lina, Di Veroli, Ambra, Mancini, Stefano, Villivà, Nicoletta, Martini, Tiziano, Mohamed, Sara, Carmosino, Ida, Criscuolo, Marianna, Fenu, Susanna, Aloe Spiriti, Maria Antonietta, Buccisano, Francesco, Mancini, Marco, Tafuri, Agostino, and Breccia, Massimo
- Subjects
MYELODYSPLASTIC syndromes ,ACUTE myeloid leukemia ,BONE marrow ,22Q11 deletion syndrome - Abstract
Aims: To define the peculiar features of patients with the deletion of the chromosome 20 long arm (del20q), data from 69 patients with myelodysplastic syndromes (MDSs) and isolated del20q, followed by the Gruppo Romano-Laziale Sindromi Mielodisplastiche (GROM-L) and Ospedale Torrette of Ancona, were collected and compared with those of 502 MDS patients with normal karyotype (NK-MDS). Results: Compared to the NK-MDS group, patients with del20q at diagnosis were older (p = 0.020) and mainly male (p = 0.006). They also had a higher rate of bone marrow blast < 5% (p = 0.004), a higher proportion of low and int-1 risk according to IPSS score (p = 0.023), and lower median platelet (PLT) count (p < 0.001). To date, in the del20q cohort, 21 patients (30.4%) received no treatment, 42 (61.0%) were treated with erythropoiesis-stimulating agents (ESA), 3 (4.3%) with hypomethylating agents, and 3 (4.3%) with other treatments. Among 34 patients evaluable for response to ESA, 21 (61.7%) achieved stable erythroid response according to IWG 2006 criteria and 13 (38.2%) were resistant. Nine patients (13.0%) progressed to acute myeloid leukaemia (AML) after a median time from diagnosis of 28 months (IR 4.1–51.7). The median overall survival (OS) of the entire cohort was 60.6 months (95% CI 54.7–66.4). the 5-year cumulative OS was 55.9% (95% CI 40.6–71.2). Conclusion: According to our results, we hypothesize that MDSs with isolated del 20q may represent a distinct biological entity, with peculiar clinical and prognostic features. The physio-pathological mechanisms underlying the deletion of the chromosome 20 long arm are still unclear and warrant future molecular analysis. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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24. Treatment of Low-Blast Count AML using Hypomethylating Agents
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De Bellis, Eleonora, Fianchi, Luana, Buccisano, Francesco, Criscuolo, Marianna, Maurillo, Luca, Cicconi, Laura, Brescini, Mattia, Del Principe, Maria Ilaria, Di Veroli, Ambra, Venditti, Adriano, Amadori, Sergio, Arcese, William, Lo-Coco, Francesco, and Voso, Maria Teresa
- Subjects
Oncology ,NPM1 ,medicine.medical_specialty ,azacitidine ,Azacitidine ,Decitabine ,Review Article ,acute myeloid leukemia ,03 medical and health sciences ,0302 clinical medicine ,AML ,White blood cell ,Internal medicine ,hemic and lymphatic diseases ,medicine ,MDS ,business.industry ,lcsh:RC633-647.5 ,Myelodysplastic syndromes ,Myeloid leukemia ,Cancer ,Hematology ,lcsh:Diseases of the blood and blood-forming organs ,medicine.disease ,Infectious Diseases ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Bone marrow ,business ,Settore MED/15 - Malattie del Sangue ,decitabine ,030215 immunology ,medicine.drug - Abstract
In 2002, the WHO classification reduced the proportion of blasts in the bone marrow (BM) necessary for the diagnosis of acute myeloid leukemia (AML) from 30% to 20%, eliminating the RAEB-t subtype of myelodysplastic syndromes (MDS). However, this AML subtype, defined as low-blast count AML (LBC-AML, with 20-30% BM-blasts) is characterized by peculiar features, as increased frequency in elderly individuals and after cytotoxic treatment for a different primary disease (therapy-related), poor-risk cytogenetics, lower white blood cell counts, and less frequent mutations of NPM1 and FLT3 genes. The clinical course of this entity is often similar to MDS with 10-19% BM-blasts. The hypomethylating agents azacitidine and decitabine have been shown to induce responses and prolong survival both in MDS and LBC-AML. The role of these agents has been also demonstrated in AML with >30% BM-blasts, particularly in patients with poor-risk cytogenetics and in AML with myelodysplasia related changes. Most recent studies are evaluating strategies to improve outcome, including combinations of hypomethylating agents with immune-response checkpoint inhibitors, which have a role in cancer immune surveillance. Efforts are also ongoing to identify mutations which may predict response and survival in these patients.
- Published
- 2017
25. A population-based study on myelodysplastic syndromes in the Lazio Region (Italy), medical miscoding and 11-year mortality follow-up. The Gruppo Romano-Laziale Mielodisplasie experience of retrospective multicentric registry
- Author
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Mayer, Flavia, Faglioni, Laura, Agabiti, Nera, Fenu, Susanna, Buccisano, Francesco, Latagliata, Roberto, Ricci, Roberto, Aloe Spiriti, Maria Antonietta, Tatarelli, Caterina, Breccia, Massimo, Cimino, Giuseppe, Fianchi, Luana, Criscuolo, Marianna, Gumenyuk, Svitlana, Mancini, Stefano, Maurillo, Luca, Nobile, Carolina, Niscola, Pasquale, Piccioni, Anna Lina, Tafuri, Agostino, Trapã, Giulio, Andriani, Alessandro, De Fabritiis, Paolo, Voso, Maria Teresa, Davoli, Marina, and Zini, Gina
- Subjects
Hospital information system ,Pediatrics ,medicine.medical_specialty ,Disease ,infectious diseases ,Health informatics ,medical miscoding ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Health care ,medicine ,Hematology ,lcsh:RC633-647.5 ,business.industry ,hematology ,Myelodysplastic syndromes ,epidemiology ,myelodysplastic syndromes ,lcsh:Diseases of the blood and blood-forming organs ,Original Articles ,medicine.disease ,Comorbidity ,030220 oncology & carcinogenesis ,Cohort ,Epidemiology ,Medical miscoding ,business ,Settore MED/15 - Malattie del Sangue ,030215 immunology - Abstract
Results on myelodysplastic syndromes (MDS) from population-based studies are rare and these data are infrequently collected by cancer registries because diagnostic difficulties and under-reported data.Our is the first regional Lazio study about medical coding, diagnosis, classification and mortality of MDS patients. This study is aimed at evaluating MDS medical miscoding and conducting a mortality follow-up in a cohort of 644 MDS patients enrolled in the Gruppo Romano-Laziale Mielodisplasie (GROM-L) registry from 2002 to 2010.We linked the MDS cohort with 2 regional health information systems: the Hospital Information System (HIS) and the regional Mortality Information System (MIS).About the first objective 92% of the patients had at most 12 hospitalization, but 28.5% of them had no hospitalization with the 238.7 ICD-9-CM. About the second objective we observed 45.5% of death during the follow-up, Myelodysplastic Syndrome was the second cause of death, other frequent causes of death were myeloid leukemia and aplastic anemia.This study highlights for the first time in Lazio that a disease like MDS, involving many resources for care assistance, tends to be under-documented in the HIS archive. This may be due to the evolution of the disease over the time, the inappropriate use of existing ICD-9-CM and the limitations of current ICD-9-CM classification. Moreover, the most frequent causes of death other than MDS might suggest a miscoding of MDS in the death causes too.In conclusion our registry could be a useful investigational tool to make a continued surveillance on medical miscoding and collect epidemiological data.
- Published
- 2017
26. Impairment of PI3K/AKT and WNT/β-catenin pathways in bone marrow mesenchymal stem cells isolated from patients with myelodysplastic syndromes
- Author
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Falconi, Giulia, Fabiani, Emiliano, Fianchi, Luana, Criscuolo, Marianna, Raffaelli, Cs, Bellesi, Silvia, Hohaus, Stefan, Voso, Mt, D'Alò, F, Leone, Giuseppe, and D'Alo', Francesco
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Myeloid ,Beta-catenin ,bone marrow ,Myelodysplastic Syndrome ,Bone Marrow Cells ,03 medical and health sciences ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Genetics ,medicine ,Humans ,Molecular Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,beta Catenin ,Aged ,Aged, 80 and over ,mesenchymal stem cells ,biology ,Wnt signaling pathway ,Myeloid leukemia ,LRP5 ,Cell Biology ,Hematology ,Middle Aged ,Wnt Proteins ,Settore MED/15 - MALATTIE DEL SANGUE ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Catenin ,Myelodysplastic Syndromes ,Immunology ,biology.protein ,Cancer research ,Female ,Proto-Oncogene Proteins c-akt - Abstract
Bone marrow mesenchymal stem cells (BM-MSCs) exhibit multiple abnormalities in myelodysplastic syndromes (MDS), including impaired proliferative and clonogenic capacity, altered morphology, increased senescence, impaired immunoregulatory properties, and reduced hematopoietic support capacity. Common signaling pathways, such as PI3K/AKT and WNT/β-catenin, regulate multiple MSC properties, including proliferation, differentiation, and cell-cell interaction. Here, with polymerase chain reaction arrays, we investigated the expression of 84 genes belonging to the PI3K/AKT signaling pathways in BM-MSCs isolated from patients with MDS, acute myeloid leukemia, and therapy-related myeloid neoplasms, using as a control BM-MSCs isolated from patients with untreated early-stage lymphomas without BM involvement. Statistically significant downregulation of GSK3β, SOS1, RASA1, and MTCP1 gene expression was observed in BM-MSCs isolated from patients with de novo MDS, as compared with controls. Moreover, expression of the GSK3β protein was reduced in MDS-derived MSCs, and was associated with concomitant reduction of phosphorylation at Ser-9. The role of GSK3β in the downstream WNT/β-catenin signaling pathway was assessed. We investigated β-catenin protein levels and expression of 84 genes belonging to the WNT target gene pathway using PCR arrays in MDS BM-MSCs, as compared with control BM-MSCs. GSK3β impairment translated into decreased β-catenin protein levels and downregulation of several WNT/β-catenin target genes (SOX9, EGR1, WISP1). These findings suggest that deregulation of genes involved in the PI3K/AKT and WNT signaling pathways may contribute to the phenotypical abnormalities of MDS BM-MSCs.
- Published
- 2016
27. Therapy-related myeloid neoplasms: clinical perspectives.
- Author
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Fianchi, Luana, Criscuolo, Marianna, Fabiani, Emiliano, Falconi, Giulia, Maraglino, Alessio Maria Edoardo, Voso, Maria Teresa, and Pagano, Livio
- Subjects
- *
MYELODYSPLASTIC syndromes , *TUMOR treatment , *ANTINEOPLASTIC agents , *CANCER chemotherapy , *ACUTE myeloid leukemia - Abstract
Therapy-related myeloid neoplasms (t-MNs) are a complication of cytotoxic treatment for primary tumors and autoimmune diseases. t-MNs result from a complex interaction between individual predisposition and exposition to toxic agents. Some different biological and clinical characteristics can be recognized according to the type of anticancer drug. Compared to de novo myeloid neoplasms, prognosis of t-MN is dismal. Age and karyotype are the most important prognostic factors for t-MN, which should be treated with frontline chemotherapy treatments that are appropriate for patients with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML) with similar disease characteristics. Allogeneic stem cell transplantation should be considered particularly for unfavorable karyotypes and younger patients with aggressive disease. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
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