44 results on '"DE STEFANO, V"'
Search Results
2. A randomized phase 3 trial of interferon-α vs hydroxyurea in polycythemia vera and essential thrombocythemia.
- Author
-
Mascarenhas J, Kosiorek HE, Prchal JT, Rambaldi A, Berenzon D, Yacoub A, Harrison CN, McMullin MF, Vannucchi AM, Ewing J, O'Connell CL, Kiladjian JJ, Mead AJ, Winton EF, Leibowitz DS, De Stefano V, Arcasoy MO, Kessler CM, Catchatourian R, Rondelli D, Silver RT, Bacigalupo A, Nagler A, Kremyanskaya M, Levine MF, Arango Ossa JE, McGovern E, Sandy L, Salama ME, Najfeld V, Tripodi J, Farnoud N, Penson AV, Weinberg RS, Price L, Goldberg JD, Barbui T, Marchioli R, Tognoni G, Rampal RK, Mesa RA, Dueck AC, and Hoffman R
- Subjects
- Disease Progression, Humans, Hydroxyurea adverse effects, Interferon-alpha adverse effects, Polycythemia Vera drug therapy, Polycythemia Vera genetics, Thrombocythemia, Essential drug therapy, Thrombocythemia, Essential genetics, Thrombosis chemically induced, Thrombosis prevention & control
- Abstract
The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856., (© 2022 by The American Society of Hematology.)
- Published
- 2022
- Full Text
- View/download PDF
3. Thrombosis in myeloproliferative neoplasms during cytoreductive and antithrombotic drug treatment.
- Author
-
Barbui T, Carobbio A, and De Stefano V
- Abstract
A state-of-the-art lecture titled "Myeloproliferative Neoplasm-associated Thrombosis" was presented at the ISTH congress in 2021. We summarize here the main points of the lecture with two purposes: to report the incidence rates of major thrombosis in polycythemia vera and essential thrombocythemia and to discuss to what extent cytoreductive therapy and antithrombotic drugs have reduced the incidence of these events. Unfortunately, the incidence rate of thrombosis remains high, ranging between 2 and 5/100 person-years. It is likely that new drugs such as interferon and ruxolitinib can be more efficacious given their cytoreductive and anti-inflammatory activities. Despite prophylaxis with vitamin K antagonists and direct oral anticoagulants after venous thrombosis in either common sites or splanchnic or cerebral sites, the incidence rate is still elevated, as high as 4 to 5/100 person-years. Future studies with new drugs or new strategies should consider thrombosis as the primary endpoint or surrogate biomarkers only if previously validated., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)
- Published
- 2022
- Full Text
- View/download PDF
4. Real-world use of thrombopoietin receptor agonists in older patients with primary immune thrombocytopenia.
- Author
-
Palandri F, Rossi E, Bartoletti D, Ferretti A, Ruggeri M, Lucchini E, Carrai V, Barcellini W, Patriarca A, Rivolti E, Consoli U, Cantoni S, Oliva EN, Chiurazzi F, Caocci G, Giuffrida G, Borchiellini A, Auteri G, Baldacci E, Carli G, Nicolosi D, Sutto E, Carpenedo M, Cavo M, Mazzucconi MG, Zaja F, De Stefano V, Rodeghiero F, and Vianelli N
- Subjects
- Aged, Aged, 80 and over, Female, Follow-Up Studies, Hemorrhage chemically induced, Hemorrhage epidemiology, Humans, Male, Middle Aged, Retrospective Studies, Benzoates administration & dosage, Benzoates adverse effects, Hydrazines administration & dosage, Hydrazines adverse effects, Purpura, Thrombocytopenic, Idiopathic drug therapy, Purpura, Thrombocytopenic, Idiopathic mortality, Pyrazoles administration & dosage, Pyrazoles adverse effects, Receptors, Fc administration & dosage, Receptors, Thrombopoietin antagonists & inhibitors, Recombinant Fusion Proteins administration & dosage, Recombinant Fusion Proteins adverse effects, Thrombopoietin administration & dosage, Thrombopoietin adverse effects, Thrombosis chemically induced, Thrombosis mortality
- Abstract
The efficacy and safety of thrombopoietin receptor agonists (TRAs) in older patients with primary immune thrombocytopenia (ITP) are unknown. We investigated TRA response and switch, thrombotic/hemorrhagic risk, and sustained responses off-treatment (SROTs) in 384 patients with ITP aged ≥60 years. After 3 months, 82.5% and 74.3% of eltrombopag- and romiplostim-treated patients, respectively, achieved a response; 66.7% maintained the response (median follow-up, 2.7 years). Eighty-five (22.2%) patients switched to the alternative TRA; although no cross-toxicity was observed, 83.3% of resistant patients had a response after the switch. Thirty-four major thromboses (3 fatal) and 14 major hemorrhages (none fatal) occurred in 18 and 10 patients, respectively, while on TRAs and were associated with thrombosis history (subdistribution hazard ratio, 2.04, P = .05) and platelet count <20 × 109/L (subdistribution hazard ratio, 1.69; P = .04), respectively, at TRA start. A recurrent event occurred in 15.6% of patients surviving thrombosis, in all cases but 1 during persisting TRA treatment (incidence rate, 7.7 per 100 patient-years). All recurrences occurred in the absence of adequate antithrombotic secondary prophylaxis. Sixty-two (16.5%) responding patients discontinued TRAs; 53 (13.8%) patients maintained SROTs, which were associated with TRA discontinuation in complete response (P < .001). Very old age (≥75 years; 41.1%) was associated with the more frequent start of TRAs in the persistent/acute phase but not with response or thrombotic/hemorrhagic risk. TRAs are effective in older patients with ITP, with no fatal hemorrhages and with SROTs in a significant portion of patients. Caution is warranted in patients with a history of thrombosis, and a careful risk/benefit balance should be considered., (© 2021 by The American Society of Hematology.)
- Published
- 2021
- Full Text
- View/download PDF
5. Progression to Symptomatic Multiple Myeloma Predicted by Texture Analysis-Derived Parameters in Patients Without Focal Disease at 18 F-FDG PET/CT.
- Author
-
Ripani D, Caldarella C, Za T, Rossi E, De Stefano V, and Giordano A
- Subjects
- Aged, Disease Progression, Female, Fluorodeoxyglucose F18 pharmacokinetics, Humans, Male, Middle Aged, Multiple Myeloma metabolism, Positron Emission Tomography Computed Tomography, ROC Curve, Radiopharmaceuticals, Retrospective Studies, Fluorodeoxyglucose F18 therapeutic use, Multiple Myeloma diagnostic imaging, Multiple Myeloma pathology
- Abstract
This retrospective study is focused on the possible clinical implications of texture analysis-derived PET parameters in patients with smoldering multiple myeloma. Several texture features are significantly associated with progression to symptomatic multiple myeloma and with a shorter time to progression. The results of this study may lead to early identification of patients who could benefit from specific therapies., Background: The aim of the study was to determine whether positron emission tomography parameters derived from texture analysis of axial and peripheral skeleton predict progression to symptomatic multiple myeloma (MM) in patients undergoing 18F-fluorodeoxyglucose positron emission tomography/computed tomography (
18 F-FDG PET/CT) without evidence of focal sites of18 F-FDG uptake., Patients and Methods: Patients with smoldering MM who underwent18 F-FDG PET/CT from May 2014 to June 2018 were retrospectively reviewed. Volumes of interest (VOIs) were placed on T5-T7 and L2-L4, iliac crests, and femoral diaphyses. Dedicated software (LIFEx) allowed us to obtain PET-derived first-, second-, and higher order texture features. Possible associations between PET parameters and progression to symptomatic MM were determined. Kaplan-Meier curves allowed to assess time to progression (TTP) based on the PET parameters., Results: Forty-five patients were included: 26 patients (58%) did not meet the criteria for symptomatic MM, but 19 patients (42%) progressed to symptomatic MM. Several texture features extracted from VOIs placed on iliac crests and femoral diaphyses were significantly associated with progression to symptomatic MM and with a shorter TTP (P < .05); conversely, the above-mentioned parameters extracted from VOIs placed on T5-T7 and L2-L4 did not significantly differ among the patients with regard to their progression to symptomatic MM and length of TTP, except for the gray-level zone length matrix-short-zone low-gray-level emphasis and gray-level zone length matrix-low gray-level zone emphasis. Particularly, second- and higher order texture features showed a significant association with the above-mentioned outcomes., Conclusion: Texture features derived from PET may be an expression of subtle disease distribution in the axial and peripheral bone marrow., (Copyright © 2021. Published by Elsevier Inc.)- Published
- 2021
- Full Text
- View/download PDF
6. A randomized double-blind trial of 3 aspirin regimens to optimize antiplatelet therapy in essential thrombocythemia.
- Author
-
Rocca B, Tosetto A, Betti S, Soldati D, Petrucci G, Rossi E, Timillero A, Cavalca V, Porro B, Iurlo A, Cattaneo D, Bucelli C, Dragani A, Di Ianni M, Ranalli P, Palandri F, Vianelli N, Beggiato E, Lanzarone G, Ruggeri M, Carli G, Elli EM, Carpenedo M, Randi ML, Bertozzi I, Paoli C, Specchia G, Ricco A, Vannucchi AM, Rodeghiero F, Patrono C, and De Stefano V
- Subjects
- Adult, Aged, Aspirin pharmacokinetics, Cyclooxygenase 1 blood, Cyclooxygenase Inhibitors pharmacology, Double-Blind Method, Epoprostenol urine, Humans, Middle Aged, Platelet Aggregation Inhibitors pharmacokinetics, Thrombocythemia, Essential blood, Thrombocythemia, Essential urine, Aspirin administration & dosage, Cyclooxygenase Inhibitors administration & dosage, Platelet Aggregation Inhibitors administration & dosage
- Abstract
Essential thrombocythemia (ET) is characterized by abnormal megakaryopoiesis and enhanced thrombotic risk. Once-daily low-dose aspirin is the recommended antithrombotic regimen, but accelerated platelet generation may reduce the duration of platelet cyclooxygenase-1 (COX-1) inhibition. We performed a multicenter double-blind trial to investigate the efficacy of 3 aspirin regimens in optimizing platelet COX-1 inhibition while preserving COX-2-dependent vascular thromboresistance. Patients on chronic once-daily low-dose aspirin (n = 245) were randomized (1:1:1) to receive 100 mg of aspirin 1, 2, or 3 times daily for 2 weeks. Serum thromboxane B2 (sTXB2), a validated biomarker of platelet COX-1 activity, and urinary prostacyclin metabolite (PGIM) excretion were measured at randomization and after 2 weeks, as primary surrogate end points of efficacy and safety, respectively. Urinary TX metabolite (TXM) excretion, gastrointestinal tolerance, and ET-related symptoms were also investigated. Evaluable patients assigned to the twice-daily and thrice-daily regimens showed substantially reduced interindividual variability and lower median (interquartile range) values for sTXB2 (ng/mL) compared with the once-daily arm: 4 (2.1-6.7; n = 79), 2.5 (1.4-5.65, n = 79), and 19.3 (9.7-40; n = 85), respectively. Urinary PGIM was comparable in the 3 arms. Urinary TXM was reduced by 35% in both experimental arms. Patients in the thrice-daily arm reported a higher abdominal discomfort score. In conclusion, the currently recommended aspirin regimen of 75 to 100 once daily for cardiovascular prophylaxis appears to be largely inadequate in reducing platelet activation in the vast majority of patients with ET. The antiplatelet response to low-dose aspirin can be markedly improved by shortening the dosing interval to 12 hours, with no improvement with further reductions (EudraCT 2016-002885-30)., (© 2020 by The American Society of Hematology.)
- Published
- 2020
- Full Text
- View/download PDF
7. Arterial thrombosis in Philadelphia-negative myeloproliferative neoplasms predicts second cancer: a case-control study.
- Author
-
De Stefano V, Ghirardi A, Masciulli A, Carobbio A, Palandri F, Vianelli N, Rossi E, Betti S, Di Veroli A, Iurlo A, Cattaneo D, Finazzi G, Bonifacio M, Scaffidi L, Patriarca A, Rumi E, Casetti IC, Stephenson C, Guglielmelli P, Elli EM, Palova M, Rapezzi D, Erez D, Gomez M, Wille K, Perez-Encinas M, Lunghi F, Angona A, Fox ML, Beggiato E, Benevolo G, Carli G, Cacciola R, McMullin MF, Tieghi A, Recasens V, Isfort S, Marchetti M, Griesshammer M, Alvarez-Larran A, Vannucchi AM, Rambaldi A, and Barbui T
- Subjects
- Case-Control Studies, Follow-Up Studies, Humans, Kaplan-Meier Estimate, Multivariate Analysis, Arteries pathology, Myeloproliferative Disorders pathology, Neoplasms, Second Primary pathology, Philadelphia Chromosome, Thrombosis pathology
- Abstract
Patients with Philadelphia-negative myeloproliferative neoplasm (MPN) are prone to the development of second cancers, but the factors associated with these events have been poorly explored. In an international nested case-control study, we recruited 647 patients with carcinoma, nonmelanoma skin cancer, hematological second cancer, and melanoma diagnosed concurrently or after MPN diagnosis. Up to 3 control patients without a history of cancer and matched with each case for center, sex, age at MPN diagnosis, date of diagnosis, and MPN disease duration were included (n = 1234). Cases were comparable to controls for MPN type, driver mutations and cardiovascular risk factors. The frequency of thrombosis preceding MPN was similar for cases and controls (P = .462). Thrombotic events after MPN and before second cancer were higher in cases than in controls (11.6% vs 8.1%; P = .013), because of a higher proportion of arterial thromboses (6.2% vs 3.7%; P = .015). After adjustment for confounders, the occurrence of arterial thrombosis remained independently associated with the risk of carcinoma (odds ratio, 1.97; 95% confidence interval, 1.14-3.41), suggesting that MPN patients experiencing arterial events after MPN diagnosis deserve careful clinical surveillance for early detection of carcinoma. This study was registered at www.clinicaltrials.gov as NCT03745378., (© 2020 by The American Society of Hematology.)
- Published
- 2020
- Full Text
- View/download PDF
8. Multiple Myeloma Treatment in Real-world Clinical Practice: Results of a Prospective, Multinational, Noninterventional Study.
- Author
-
Mohty M, Terpos E, Mateos MV, Cavo M, Lejniece S, Beksac M, Bekadja MA, Legiec W, Dimopoulos M, Stankovic S, Durán MS, De Stefano V, Corso A, Kochkareva Y, Laane E, Berthou C, Salwender H, Masliak Z, Pečeliūnas V, Willenbacher W, Silva J, Louw V, Nemet D, Borbényi Z, Abadi U, Pedersen RS, Černelč P, Potamianou A, Couturier C, Feys C, Thoret-Bauchet F, and Boccadoro M
- Subjects
- Adult, Aged, Aged, 80 and over, Boronic Acids administration & dosage, Bortezomib administration & dosage, Dexamethasone administration & dosage, Female, Follow-Up Studies, Humans, Lenalidomide administration & dosage, Male, Middle Aged, Multiple Myeloma pathology, Neoplasm Recurrence, Local pathology, Prospective Studies, Survival Rate, Thalidomide administration & dosage, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Multiple Myeloma drug therapy, Neoplasm Recurrence, Local drug therapy, Practice Patterns, Physicians', Salvage Therapy
- Abstract
Background: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients., Patients and Methods: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months., Results: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide., Conclusion: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
9. Platelet indices and glucose control in type 1 and type 2 diabetes mellitus: A case-control study.
- Author
-
Zaccardi F, Rocca B, Rizzi A, Ciminello A, Teofili L, Ghirlanda G, De Stefano V, and Pitocco D
- Subjects
- Adult, Biomarkers blood, Blood Glucose drug effects, Diabetes Mellitus, Type 1 diagnosis, Diabetes Mellitus, Type 1 drug therapy, Diabetes Mellitus, Type 2 diagnosis, Diabetes Mellitus, Type 2 drug therapy, Female, Glycated Hemoglobin metabolism, Humans, Hypoglycemic Agents therapeutic use, Kinetics, Male, Mean Platelet Volume, Middle Aged, Platelet Count, Retrospective Studies, Blood Glucose metabolism, Blood Platelets metabolism, Diabetes Mellitus, Type 1 blood, Diabetes Mellitus, Type 2 blood
- Abstract
Background and Aims: The relationship between platelet indices and glucose control may differ in type 1 (T1DM) and type 2 (T2DM) diabetes. We aimed to investigate differences in mean platelet volume (MPV), platelet count, and platelet mass between patients with T1DM, T2DM, and healthy controls and to explore associations between these platelet indices and glucose control., Methods and Results: A total of 691 T1DM and 459 T2DM patients and 943 control subjects (blood donors) were included. HbA1c was measured in all subjects with diabetes and 36 T1DM patients further underwent 24 h-continuous glucose monitoring to estimate short-term glucose control (glucose mean and standard deviation). Adjusting for age and sex, platelet count was higher and MPV lower in both T1DM and T2DM patients vs control subjects, while platelet mass (MPV × platelet count) resulted higher only in T2DM. Upon further adjustment for HbA1c, differences in platelet count and mass were respectively 19.5 × 10
9 /L (95%CI: 9.8-29.3; p < 0.001) and 101 fL/nL (12-191; p = 0.027) comparing T2DM vs T1DM patients. MPV and platelet count were significantly and differently related in T2DM patients vs both T1DM and control subjects; this difference was maintained also accounting for HbA1c, age, and sex. Platelet mass and the volume-count relationship were significantly related to HbA1c only in T1DM patients. No associations were found between platelet indices and short-term glucose control., Conclusion: By accounting for confounders and glucose control, our data evidenced higher platelet mass and different volume-count kinetics in subjects with T2DM vs T1DM. Long-term glucose control seemed to influence platelet mass and the volume-count relationship only in T1DM subjects. These findings suggest different mechanisms behind platelet formation in T1DM and T2DM patients with long-term glycaemic control being more relevant in T1DM than T2DM., (Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)- Published
- 2017
- Full Text
- View/download PDF
10. External validation of the DASH prediction rule: a retrospective cohort study.
- Author
-
Tosetto A, Testa S, Martinelli I, Poli D, Cosmi B, Lodigiani C, Ageno W, De Stefano V, Falanga A, Nichele I, Paoletti O, Bucciarelli P, Antonucci E, Legnani C, Banfi E, Dentali F, Bartolomei F, Barcella L, and Palareti G
- Subjects
- Administration, Oral, Adult, Age Factors, Aged, Anticoagulants administration & dosage, Biomarkers blood, Decision Support Techniques, Female, Fibrin Fibrinogen Degradation Products metabolism, Humans, Incidence, Italy epidemiology, Male, Middle Aged, Predictive Value of Tests, Pulmonary Embolism blood, Pulmonary Embolism drug therapy, Pulmonary Embolism epidemiology, Recurrence, Reproducibility of Results, Retrospective Studies, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, Venous Thromboembolism blood, Venous Thromboembolism drug therapy, Venous Thromboembolism epidemiology, Venous Thrombosis blood, Venous Thrombosis drug therapy, Venous Thrombosis epidemiology, Pulmonary Embolism diagnosis, Venous Thromboembolism diagnosis, Venous Thrombosis diagnosis
- Abstract
Essentials Predicting recurrences may guide therapy after unprovoked venous thromboembolism (VTE). We evaluated the DASH score in 827 patients with unprovoked VTE to verify prediction accuracy. A DASH score ≤ 1 had a cumulative recurrence risk at 1 year of 3.6%, as predicted by the model. The DASH score performed better in younger (< 65 years old) subjects., Summary: Background The DASH prediction model has been proposed as a guide to identify patients at low risk of recurrence of venous thromboembolism (VTE), but has never been validated in an independent cohort. Aims To validate the calibration and discrimination of the DASH prediction model, and to evaluate the DASH score in a predefined patient subgroup aged > 65 years. Methods Patients with a proximal unprovoked deep vein thrombosis (DVT) or pulmonary embolism (PE) who received a full course of vitamin K antagonist or direct oral anticoagulant (> 3 months) and had D-dimer measured after treatment withdrawal were eligible. The DASH score was computed on the basis of the D-dimer level after therapy withdrawal and personal characteristics at the time of the event. Recurrent VTE events were symptomatic proximal or distal DVT/PE, and were analyzed with a time-dependent analysis. Observed 12-month and 24-month recurrence rates were compared with recurrence rates predicted by the DASH model. Results We analyzed a total of 827 patients, of whom 100 (12.1%) had an objectively documented recurrence. As compared with the original DASH cohort, there was a greater proportion of subjects with a 'low-risk' (≤ 1) DASH score (66.3% versus 51.6%, P < 0.001). The slope of the observed versus expected cumulative incidence at 2 years was 0.71 (95% confidence interval 0.51-1.45). The c-statistic was lower for subjects aged > 65 years (0.54) than for younger subjects (0.72). Conclusions These results confirm the validity of DASH prediction model, particularly in young subjects. The recurrence risk in elderly patients (> 65 years) was, however, > 5% even in those with the lowest DASH scores., (© 2017 International Society on Thrombosis and Haemostasis.)
- Published
- 2017
- Full Text
- View/download PDF
11. Thrombotic risk in patients with primary immune thrombocytopenia is only mildly increased and explained by personal and treatment-related risk factors.
- Author
-
Ruggeri M, Tosetto A, Palandri F, Polverelli N, Mazzucconi MG, Santoro C, Gaidano G, Lunghi M, Zaja F, De Stefano V, Sartori R, Fazi P, and Rodeghiero F
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Female, Humans, Male, Middle Aged, Retrospective Studies, Risk Factors, Thrombosis immunology, Young Adult, Purpura, Thrombocytopenic, Idiopathic complications, Thrombosis etiology
- Abstract
Background: An increased risk of thrombosis has been reported in primary immune thrombocytopenia (ITP) and with the use of thrombopoietin (TPO) receptor agonists, on the basis of population studies using administrative databases., Objectives: To evaluate if the incidence of venous and arterial thrombosis in patients with primary ITP is higher than a clinically significant cut-off set at of 3% and 6.4%., Patients/methods: We undertook a retrospective multicenter investigation in a large cohort of patients requiring at least one treatment for ITP, enrolled from the major tertiary Italian centers treating ITP. A total of 986 patients were analyzed., Results: During a 3888 patient-year follow-up, 43 first thrombotic events occurred: 28 arterial and 15 venous, resulting in a cumulative incidence of 3.2% for arterial (95% CI, 2.0-5.0) and 1.4% (95% CI, 0.8-2.5) for venous thrombosis at 5 years. The annualized rates for 100 patient-years were 1.14 (95% CI, 0.84-1.54), 0.39 (95% CI, 0.23-0.65) and 0.71 (95% CI, 0.49-1.04) for total, venous and arterial thrombosis. Splenectomy, performed in 136 patients (13.7%), increased thrombotic risk (HR = 3.5, 95% CI) compared with non-splenectomized patients. Age > 60 years, more than two risk factors for thrombosis at diagnosis and steroid use were independently associated with an increased risk of thrombosis., Conclusions: In this study, we demonstrate that the 5-year cumulative incidence of venous and arterial thrombosis in ITP is well below the predefined thresholds. Venous and arterial thromboembolism are not frequent complications in ITP, except in particular settings, such as in splenectomized and elderly patients., (© 2014 International Society on Thrombosis and Haemostasis.)
- Published
- 2014
- Full Text
- View/download PDF
12. Influence of proband's characteristics on the risk for venous thromboembolism in relatives with factor V Leiden or prothrombin G20210A polymorphisms.
- Author
-
Bucciarelli P, De Stefano V, Passamonti SM, Tormene D, Legnani C, Rossi E, Castaman G, Simioni P, Cini M, and Martinelli I
- Subjects
- Adult, Disease-Free Survival, Female, Genetic Predisposition to Disease epidemiology, Genetic Predisposition to Disease genetics, Genotype, Humans, Male, Middle Aged, Polymorphism, Genetic genetics, Risk Factors, Venous Thromboembolism blood, Factor V genetics, Prothrombin genetics, Venous Thromboembolism epidemiology, Venous Thromboembolism genetics
- Abstract
In family studies, the risk for venous thromboembolism (VTE) in relatives with factor V Leiden (FVL) or G20210A prothrombin (PT20210A) gene polymorphisms may differ according to genotype and clinical presentation of the proband. To address this hypothesis, a retrospective cohort family study was carried out on 192 kindreds with at least one member with homozygous FVL or PT20210A, for a total of 886 relatives. The proband of the family was heterozygous in 68 and homozygous or with both polymorphisms in 124 kindreds. Twenty-three probands were asymptomatic, 11 had had arterial thrombosis, 7 obstetrical complications, and 151 venous thrombosis (122 VTE and 29 superficial vein thrombosis). The incidence of VTE (per 1000 patient-years) in relatives was higher when the proband had heterozygous rather than homozygous polymorphism (1.25 [95% confidence interval (CI), 0.73-1.91] vs 0.44 [0.19-0.78]) and when the proband had had VTE instead of other or no clinical manifestations (0.95 [0.57-1.42] vs 0.50 [0.19-0.96]). Compared with relatives belonging to kindreds with homozygous probands without VTE, the adjusted hazard ratio of VTE for relatives selected from kindreds with heterozygous probands with VTE was 4.14 (95% CI, 1.17-14.71). The genotype and clinical presentation of the proband influence the risk for VTE in relatives with FVL or PT20210A.
- Published
- 2013
- Full Text
- View/download PDF
13. Recommendations for prophylaxis of pregnancy-related venous thromboembolism in carriers of inherited thrombophilia. Comment on the 2012 ACCP guidelines.
- Author
-
De Stefano V, Grandone E, and Martinelli I
- Subjects
- Female, Humans, Pregnancy, Evidence-Based Medicine, Fibrinolytic Agents adverse effects, Fibrinolytic Agents therapeutic use, Pregnancy Complications, Cardiovascular drug therapy, Pregnancy Complications, Cardiovascular prevention & control, Societies, Medical, Thrombophilia drug therapy, Venous Thromboembolism drug therapy, Venous Thromboembolism prevention & control
- Published
- 2013
- Full Text
- View/download PDF
14. Platelet activation and inhibition in polycythemia vera and essential thrombocythemia.
- Author
-
Patrono C, Rocca B, and De Stefano V
- Subjects
- Clinical Trials as Topic, Humans, Platelet Aggregation Inhibitors therapeutic use, Polycythemia Vera etiology, Risk Factors, Thrombocythemia, Essential etiology, Platelet Activation drug effects, Polycythemia Vera prevention & control, Thrombocythemia, Essential prevention & control
- Abstract
Persistently enhanced platelet activation has been characterized in polycythemia vera (PV) and essential thrombocythemia (ET) and shown to contribute to a higher risk of both arterial and venous thrombotic complications. The incidence of major bleeding complications is also somewhat higher in PV and ET than in the general population. Although its efficacy and safety was assessed in just 1 relatively small trial in PV, low-dose aspirin is currently recommended in practically all PV and ET patients. Although for most patients with a thrombosis history the benefit/risk profile of antiplatelet therapy is likely to be favorable, in those with no such history this balance will depend critically on the level of thrombotic and hemorrhagic risks of the individual patient. Recent evidence for a chemopreventive effect of low-dose aspirin may tilt the balance of benefits and harm in favor of using aspirin more broadly, but the potential for additional benefits needs regulatory scrutiny and novel treatment guidelines. A clear pharmacodynamic rationale and analytical tools are available for a personalized approach to antiplatelet therapy in ET, and an improved regimen of low-dose aspirin therapy should be tested in a properly sized randomized trial.
- Published
- 2013
- Full Text
- View/download PDF
15. Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis).
- Author
-
Barbui T, Finazzi G, Carobbio A, Thiele J, Passamonti F, Rumi E, Ruggeri M, Rodeghiero F, Randi ML, Bertozzi I, Gisslinger H, Buxhofer-Ausch V, De Stefano V, Betti S, Rambaldi A, Vannucchi AM, and Tefferi A
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Female, Humans, International Classification of Diseases, Male, Middle Aged, Prognosis, Research Design, Thrombocythemia, Essential pathology, Young Adult, Severity of Illness Index, Thrombocythemia, Essential classification, Thrombocythemia, Essential diagnosis, World Health Organization
- Abstract
Accurate prediction of thrombosis in essential thrombocythemia (ET) provides the platform for prospective studies exploring preventive measures. Current risk stratification for thrombosis in ET is 2-tiered and considers low- and high-risk categories based on the respective absence or presence of either age > 60 years or history of thrombosis. In an international study of 891 patients with World Health Organization (WHO)-defined ET, we identified additional independent risk factors including cardiovascular risk factors and JAK2V617F. Accordingly, we assigned risk scores based on multivariable analysis-derived hazard ratios (HRs) to age > 60 years (HR = 1.5; 1 point), thrombosis history (HR = 1.9; 2 points), cardiovascular risk factors (HR = 1.6; 1 point), and JAK2V617F (HR = 2.0; 2 points) and subsequently devised a 3-tiered prognostic model (low-risk = < 2 points; intermediate-risk = 2 points; and high-risk = > 2 points) using a training set of 535 patients and validated the results in the remaining cohort (n = 356; internal validation set) and in an external validation set (n = 329). Considering all 3 cohorts (n = 1220), the 3-tiered new prognostic model (low-risk n = 474 vs intermediate-risk n = 471 vs high-risk n = 275), with a respective thrombosis risk of 1.03% of patients/y versus 2.35% of patients/y versus 3.56% of patients/y, outperformed the 2-tiered (low-risk 0.95% of patients/y vs high-risk 2.86% of patients/y) conventional risk stratification in predicting future vascular events.
- Published
- 2012
- Full Text
- View/download PDF
16. Abdominal thromboses of splanchnic, renal and ovarian veins.
- Author
-
De Stefano V and Martinelli I
- Subjects
- Anticoagulants pharmacology, Anticoagulants therapeutic use, Biomarkers, Tumor metabolism, Budd-Chiari Syndrome complications, Budd-Chiari Syndrome drug therapy, Budd-Chiari Syndrome pathology, Female, Heparin pharmacology, Heparin therapeutic use, Humans, Janus Kinase 2 metabolism, Leukemia complications, Leukemia drug therapy, Leukemia pathology, Nephrotic Syndrome complications, Nephrotic Syndrome drug therapy, Nephrotic Syndrome pathology, Ovary pathology, Portal Vein pathology, Splanchnic Circulation, Vena Cava, Inferior pathology, Venous Thrombosis complications, Venous Thrombosis drug therapy, Venous Thrombosis pathology, Vitamin K antagonists & inhibitors, Budd-Chiari Syndrome diagnosis, Leukemia diagnosis, Nephrotic Syndrome diagnosis, Venous Thrombosis diagnosis
- Abstract
Thromboses of abdominal veins outside the iliac-caval axis are rare but clinically relevant. Early deaths after splanchnic vein thrombosis occur in 5-30% of cases. Sequelae can be liver failure or bowel infarction after splanchnic vein thrombosis, renal insufficiency after renal vein thrombosis, ovarian infarction after ovarian vein thrombosis. Local cancer or infections are rare in Budd-Chiari syndrome, and common for other sites. Inherited thrombophilia is detected in 30-50% of patients. Myeloproliferative neoplasms are the main cause of splanchnic vein thrombosis: 20-50% of patients have an overt myeloproliferative neoplasm and/or carry the molecular marker JAK2 V617F. Renal vein thrombosis is closely related to nephrotic syndrome; finally, ovarian vein thrombosis can complicate puerperium. Heparin is used for acute treatment, sometimes in conjunction with systemic or local thrombolysis. Vitamin K-antagonists are recommended for 3-6 months, and long-term in patients with Budd-Chiari syndrome, unprovoked splanchnic vein thrombosis, or renal vein thrombosis with a permanent prothrombotic state such as nephrotic syndrome., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
17. Extra-abdominal venous thromboses at unusual sites.
- Author
-
Martinelli I and De Stefano V
- Subjects
- Anticoagulants pharmacology, Anticoagulants therapeutic use, Catheters adverse effects, Contraceptives, Oral adverse effects, Heparin pharmacology, Heparin therapeutic use, Humans, Postthrombotic Syndrome diagnosis, Postthrombotic Syndrome drug therapy, Postthrombotic Syndrome etiology, Pulmonary Embolism diagnosis, Pulmonary Embolism drug therapy, Pulmonary Embolism etiology, Retinal Vein Occlusion diagnosis, Retinal Vein Occlusion drug therapy, Retinal Vein Occlusion etiology, Risk Factors, Thrombophilia diagnosis, Thrombophilia drug therapy, Thrombophilia etiology, Upper Extremity Deep Vein Thrombosis diagnosis, Upper Extremity Deep Vein Thrombosis drug therapy, Upper Extremity Deep Vein Thrombosis etiology, Vitamin K antagonists & inhibitors, Warfarin pharmacology, Warfarin therapeutic use, Postthrombotic Syndrome pathology, Pulmonary Embolism pathology, Retinal Vein Occlusion pathology, Thrombophilia pathology, Upper Extremity Deep Vein Thrombosis pathology
- Abstract
Venous thrombosis typically involves the lower extremities. Rarely, it can occur in cerebral, splanchnic, or renal veins, with a frightening clinical impact. Other rare manifestations are upper-extremity deep vein thrombosis, that can complicate with pulmonary embolism and post-thrombotic syndrome, and retinal vein occlusion, significantly affecting the quality of life. This review is focused on venous thromboses at unusual extra-abdominal sites. Local infections or cancer are frequent in cerebral sinus-venous thrombosis. Upper-extremity deep vein thrombosis is mostly due to catheters or effort-related factors. Common risk factors are inherited thrombophilia and oral contraceptive use. Acute treatment is based on heparin; in cerebral sinus-venous thrombosis, local or systemic fibrinolysis should be considered in case of clinical deterioration. Vitamin-K antagonists are recommended for 3-6 months; indefinite anticoagulation is suggested for recurrent thrombosis or unprovoked thrombosis and permanent risk factors. However, such recommendations mainly derive from observational studies; there are no data about long-term treatment of retinal vein occlusion., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
18. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma.
- Author
-
Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, and Palumbo A
- Subjects
- Antineoplastic Agents administration & dosage, Antineoplastic Agents, Hormonal administration & dosage, Boronic Acids administration & dosage, Bortezomib, Combined Modality Therapy, Dexamethasone administration & dosage, Disease-Free Survival, Female, Humans, Immunosuppressive Agents administration & dosage, Kaplan-Meier Estimate, Male, Middle Aged, Multiple Myeloma diagnosis, Prognosis, Pyrazines administration & dosage, Thalidomide administration & dosage, Transplantation, Autologous, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Hematopoietic Stem Cell Transplantation methods, Multiple Myeloma drug therapy
- Abstract
In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD-treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484.
- Published
- 2012
- Full Text
- View/download PDF
19. Long-term outcomes of patients with cerebral vein thrombosis: a multicenter study.
- Author
-
Dentali F, Poli D, Scoditti U, Di Minno MN, De Stefano V, Siragusa S, Kostal M, Palareti G, Sartori MT, Grandone E, Vedovati MC, Ageno W, Falanga A, Lerede T, Bianchi M, Testa S, Witt D, McCool K, Bucherini E, Grifoni E, Coalizzo D, Benedetti R, Marietta M, Sessa M, Guaschino C, di Minno G, Tufano A, Barbar S, Malato A, Pini M, Castellini P, Barco S, Barone M, Paciaroni M, Alberti A, Agnelli G, Giorgi Pierfranceschi M, Dulicek P, Silingardi M, Federica L, Ghirarduzzi A, Tiraferri E, di Lazzaro V, Rossi E, Ciminello A, Pasca S, Barillari G, Rezoagli E, Galli M, Squizzato A, and Tosetto A
- Subjects
- Adult, Cohort Studies, Female, Humans, Male, Middle Aged, Recurrence, Cerebral Veins pathology, Thrombosis pathology
- Abstract
Background: Little information is available on the long-term clinical outcome of cerebral vein thrombosis (CVT)., Objectives and Methods: In an international, retrospective cohort study, we assessed the long-term rates of mortality, residual disability and recurrent venous thromboembolism (VTE) in a cohort of patients with a first CVT episode., Results: Seven hundred and six patients (73.7% females) with CVT were included. Patients were followed for a total of 3171 patient-years. Median follow-up was 40 months (range 6, 297 months). At the end of follow-up, 20 patients had died (2.8%). The outcome was generally good: 89.1% of patients had a complete recovery (modified Rankin Score [mRS] 0-1) and 3.8% had a partial recovery and were independent (mRS 2). Eighty-four per cent of patients were treated with oral anticoagulants and the mean treatment duration was 12 months. CVT recurred in 31 patients (4.4%), and 46 patients (6.5%) had a VTE in a different site, for an overall incidence of recurrence of 23.6 events per 1000 patient-years (95% confidence Interval [CI] 17.8, 28.7) and of 35.1 events/1000 patient-years (95% CI, 27.7, 44.4) after anticoagulant therapy withdrawal. A previous VTE was the only significant predictor of recurrence at multivariate analysis (hazard ratio [HR] 2.70; 95% CI 1.25, 5.83)., Conclusions: The long-term risk of mortality and recurrent VTE appears to be low in patients who survived the acute phase of CVT. A previous VTE history independently predicts recurrent events., (© 2012 International Society on Thrombosis and Haemostasis.)
- Published
- 2012
- Full Text
- View/download PDF
20. Primary plasma cell leukemia: a retrospective multicenter study of 73 patients.
- Author
-
Pagano L, Valentini CG, De Stefano V, Venditti A, Visani G, Petrucci MT, Candoni A, Specchia G, Visco C, Pogliani EM, Ferrara F, Galieni P, Gozzetti A, Fianchi L, De Muro M, Leone G, Musto P, and Pulsoni A
- Subjects
- Adult, Aged, Aged, 80 and over, Anthracyclines administration & dosage, Boronic Acids administration & dosage, Bortezomib, Cohort Studies, Combined Modality Therapy, Female, Follow-Up Studies, Hematopoietic Stem Cell Transplantation, Humans, Male, Middle Aged, Pyrazines administration & dosage, Retrospective Studies, Survival Rate, Thalidomide administration & dosage, Transplantation, Autologous, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Plasma Cell therapy, Neoplasm Recurrence, Local therapy
- Abstract
Background: Epidemiological and clinical information on primary plasma cell leukemia (pPCL) are rarely reported. The aims are to evaluate the clinical features, prognostic factors, and efficacy of treatments in pPCL., Patients and Methods: A multicenter retrospective cohort study was carried out from January 2000 to December 2008 in 26 Italian hematology divisions. A total of 128 cases of plasma cell leukemia were collected, and 73 of them (57%) were classified as primary (male/female 43/30)., Results: Sixty-four patients had at least 1 sign of end-organ damage and 10 had extramedullary localization. One patient died early; of the remaining patients, 36 (50%) received anthracycline-based regimens as first-line therapy, 17 (24%) single alkylating agents, and 30 (42%) bortezomib or thalidomide as additional (n = 11) or unique treatments (n = 19). Twenty-three patients (31%) underwent autologous and/or allogeneic hematopoietic stem cell transplantation (HSCT). The median overall survival (OS) was 12.6 months; complete or partial response was achieved in 22 (30%) and 18 patients (25%), respectively; the median duration of response (DOR) was 16.4 months. HSCT patients had a longer OS and DOR (median 38.1 and 25.8 months, respectively) compared with nontransplanted patients (9.1 and 7.3 months, respectively, P < 0.001). OS was influenced by nonresponse to treatment, hypoalbuminemia, and HSCT. DOR was favorably influenced only by HSCT., Conclusions: pPCL is an aggressive disease with a poor prognosis and a low response rate to conventional therapy. HSCT is effective, increasing OS and DOR by 69% and 88%, respectively. The use of bortezomib and thalidomide may improve outcomes.
- Published
- 2011
- Full Text
- View/download PDF
21. Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia.
- Author
-
Zaja F, Baccarani M, Mazza P, Bocchia M, Gugliotta L, Zaccaria A, Vianelli N, Defina M, Tieghi A, Amadori S, Campagna S, Ferrara F, Angelucci E, Usala E, Cantoni S, Visani G, Fornaro A, Rizzi R, De Stefano V, Casulli F, Battista ML, Isola M, Soldano F, Gamba E, and Fanin R
- Subjects
- Adult, Aged, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Murine-Derived, Antineoplastic Combined Chemotherapy Protocols adverse effects, Dexamethasone adverse effects, Female, Humans, Male, Middle Aged, Platelet Count, Purpura, Thrombocytopenic, Idiopathic blood, Rituximab, Time Factors, Antibodies, Monoclonal administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Dexamethasone administration & dosage, Purpura, Thrombocytopenic, Idiopathic drug therapy, Salvage Therapy methods
- Abstract
Previous observational studies suggest that rituximab may be useful in the treatment of primary immune thrombocytopenia (ITP). This randomized trial investigated rituximab efficacy in previously untreated adult ITP patients with a platelet count of 20 x 10(9)/L or less. One hundred three patients were randomly assigned to receive 40 mg/d dexamethasone for 4 days with or without 375 mg/m(2) rituximab weekly for 4 weeks. Patients who were refractory to dexamethasone alone received salvage therapy with dexamethasone plus rituximab. Sustained response (ie, platelet count > or = 50 x 10(9)/L at month 6 after treatment initiation), evaluable in 101 patients, was greater in patients treated with dexamethasone plus rituximab (n = 49) than in those treated with dexamethasone alone (n = 52; 63% vs 36%, P = .004, 95% confidence interval [95% CI], 0.079-0.455). Patients in the experimental arm showed increased incidences of grade 3 to 4 adverse events (10% vs 2%, P = .082, 95% CI, -0.010 to 0.175), but incidences of serious adverse events were similar in both arms (6% vs 2%, P = .284, 95% CI, -0.035 to 0.119). Dexamethasone plus rituximab was an effective salvage therapy in 56% of patients refractory to dexamethasone. The combination of dexamethasone and rituximab improved platelet counts compared with dexamethasone alone. Thus, combination therapy may represent an effective treatment option before splenectomy. This study is registered at http://clinicaltrials.gov as NCT00770562.
- Published
- 2010
- Full Text
- View/download PDF
22. Melphalan 200 mg/m(2) versus melphalan 100 mg/m(2) in newly diagnosed myeloma patients: a prospective, multicenter phase 3 study.
- Author
-
Palumbo A, Bringhen S, Bruno B, Falcone AP, Liberati AM, Grasso M, Ria R, Pisani F, Cangialosi C, Caravita T, Levi A, Meloni G, Nozza A, Pregno P, Gabbas A, Callea V, Rizzo M, Annino L, De Stefano V, Musto P, Baldi I, Cavallo F, Petrucci MT, Massaia M, and Boccadoro M
- Subjects
- Adult, Aged, Algorithms, Antigens, CD34 metabolism, Antineoplastic Agents, Alkylating administration & dosage, Bone Marrow Transplantation immunology, Bone Marrow Transplantation methods, Combined Modality Therapy, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Multiple Myeloma mortality, Myeloablative Agonists administration & dosage, Neoadjuvant Therapy, Transplantation Conditioning methods, Transplantation, Autologous, Melphalan administration & dosage, Multiple Myeloma therapy
- Abstract
High-dose (200 mg/m(2), MEL200) and intermediate-dose melphalan (100 mg/m(2), MEL100) showed significant activity in myeloma. In a phase 3 study, 298 patients were randomly assigned to receive 2 autologous transplantations after conditioning with MEL200 or MEL100. Ninety-six of 149 (64%) completed MEL200 and 103 of 149 (69%) MEL100. Best response to MEL200 was: complete remission 22 of 149 (15%); partial remission 95 of 149 (64%), for an overall response rate of 79%. Best response to MEL100 was: complete remission 12 of 149 (8%); partial remission 95 of 149 (64%), for an overall response rate of 72%. Overall survival did not differ (P = .13); median progression-free survival (31.4 vs 26.2 months, P = .01), median time to progression (34.4 vs 27.0 months, P = .014) were longer in the MEL200. Treatment-related mortality was 3.1% in the MEL200 and 2.9% in the MEL100 group. Severe neutropenia and infections were marginally superior, whereas severe thrombocytopenia, mucositis, gastrointestinal adverse events, and the overall occurrence of at least 1 nonhematologic grade 3 or 4 adverse event were significantly higher in the MEL200 cohort. We conclude that MEL200 leads to longer remission duration and should be considered the standard conditioning regimen for autologous transplantation. This study was registered at www.clinicaltrials.gov as #NCT00950768.
- Published
- 2010
- Full Text
- View/download PDF
23. The risk of first venous thromboembolism during pregnancy and puerperium in double heterozygotes for factor V Leiden and prothrombin G20210A.
- Author
-
Martinelli I, Battaglioli T, De Stefano V, Tormene D, Valdrè L, Grandone E, Tosetto A, and Mannucci PM
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Female, Humans, Middle Aged, Postpartum Period, Pregnancy, Risk, Venous Thrombosis blood, Factor V genetics, Heterozygote, Pregnancy Complications, Cardiovascular, Prothrombin genetics, Venous Thrombosis diagnosis, Venous Thrombosis genetics
- Abstract
Background: The risk of venous thromboembolism (VTE) during pregnancy in double heterozygous carriers of factor (F) V Leiden and prothrombin G20210A is not established. Hence, whether or not these women deserve antithrombotic prophylaxis when pregnant is unknown., Patients and Methods: In the frame of a multicenter family study, 52 double heterozygous carriers of FV Leiden and prothrombin G20210A who had remained pregnant at least once before knowledge of thrombophilia, were retrospectively investigated with respect to the occurrence of first VTE during pregnancy and puerperium. They were compared with 104 heterozygous carriers of FV Leiden, 104 of prothrombin G20210A and 104 women without thrombophilia., Results: Double heterozygotes were similar to single heterozygous carriers and non-carriers for the age at first pregnancy, age at testing and rate of full-term pregnancies. No VTE during pregnancy was observed in the four groups of women, whereas in the puerperium it occurred in two double carriers (1.8% of pregnancies, 95% CI: 0.5-6.3), three single FV Leiden carriers (1.5%, 0.5-4.3), two single prothrombin G20210A carriers (1%, 0.2-3.6) and one non-carrier (0.4%, 0-2.5)., Conclusions: The risk of first VTE during pregnancy and puerperium in double heterozygous carriers of FV Leiden and prothrombin G20210A is low and similar to that of single carriers. As for single heterozygotes, antithrombotic prophylaxis in asymptomatic double heterozygous carriers appears to be justified only in puerperium.
- Published
- 2008
- Full Text
- View/download PDF
24. Postsurgery outcomes in patients with polycythemia vera and essential thrombocythemia: a retrospective survey.
- Author
-
Ruggeri M, Rodeghiero F, Tosetto A, Castaman G, Scognamiglio F, Finazzi G, Delaini F, Micò C, Vannucchi AM, Antonioli E, De Stefano V, Za T, Gugliotta L, Tieghi A, Mazzucconi MG, Santoro C, and Barbui T
- Subjects
- Adult, Aged, Aged, 80 and over, Anticoagulants adverse effects, Female, Follow-Up Studies, Heparin adverse effects, Humans, Laparoscopy adverse effects, Male, Middle Aged, Polycythemia Vera mortality, Retrospective Studies, Thrombocythemia, Essential mortality, Thrombosis pathology, Thrombosis prevention & control, Anticoagulants administration & dosage, Heparin administration & dosage, Polycythemia Vera complications, Polycythemia Vera surgery, Postoperative Hemorrhage mortality, Postoperative Hemorrhage prevention & control, Thrombocythemia, Essential complications, Thrombocythemia, Essential surgery, Thrombosis etiology
- Abstract
A multicenter retrospective analysis was performed to estimate the frequency of thrombosis and hemorrhage after surgical procedures in patients with polycythemia vera (PV) and patients with essential thrombocythemia (ET). Data from 105 patients with PV and 150 patients with ET were analyzed, for a total of 311 surgical interventions. An emergency procedure was performed in 25 (8.1%) patients; 194 surgeries were done under general anesthesia, and 21 (23%) of 91 abdominal interventions were done under laparoscopy; 155 (50.1%) were major surgeries. Subcutaneous heparin was administered in 169 (54.3%) of 311 cases and antiplatelet therapy in 48 (15.4%) of 311 case interventions. One hundred eighty-eight (74%) of 255 patients were on cytoreductive therapy before surgery. No events were observed in 259 (83.2%) of 311 procedures during 3 months of follow-up; there were 12 arterial and 12 venous thrombotic events, 23 major and 7 minor hemorrhages, and 5 deaths. Arterial thromboses were more frequent in ET (5.3% vs 1.5%; P=.08), venous events were more frequent in PV (7.7% vs 1.1%; P=.002). There was not a correlation between bleeding episodes and the type of diagnosis, use of antithrombotic prophylaxis, or type of surgery. A high proportion of PV and ET surgeries was complicated by vascular occlusion (7.7%) or by a major hemorrhage (7.3%). Prospective investigations analyzing the optimal prophylaxis in these patients are suggested.
- Published
- 2008
- Full Text
- View/download PDF
25. The G20210A prothrombin variant and the risk of venous thromboembolism or fetal loss in pregnant women: a family study.
- Author
-
Tormene D, De Stefano V, Grandone E, Za T, Perlati M, Rossi E, Margaglione M, and Simioni P
- Subjects
- Adult, Cohort Studies, Family Health, Female, Fetal Death epidemiology, Fetal Death etiology, Genotype, Humans, Pregnancy, Pregnancy Complications, Hematologic epidemiology, Pregnancy Complications, Hematologic etiology, Pulmonary Embolism etiology, Pulmonary Embolism genetics, Retrospective Studies, Risk Factors, Venous Thrombosis etiology, Fetal Death genetics, Polymorphism, Single Nucleotide, Pregnancy Complications, Hematologic genetics, Prothrombin genetics, Venous Thrombosis genetics
- Abstract
Background: The relationship between the G20210A prothrombin variant (PT-G20210A) and adverse pregnancy outcome has been studied by several groups in the last few years. However, because of the different design and sample sizes of these studies the estimated risks have varied., Objective: In this retrospective, multi-center, cohort study we assessed the risk of thromboembolic or obstetric complications in women belonging to families of probands with isolated PT-G20210A and that were symptomatic for venous thromboembolism (VTE)., Methods: Two hundred and eighty-three female family members that had been pregnant at least once were enrolled. The occurrence of VTE and obstetric complications during pregnancy and postpartum were assessed in carriers of PT-G20210A and compared with non- carriers., Results: One thromboembolic event occurred during the postpartum period in the carriers group. In the same group, 48 out of 359 pregnancies resulted in unexplained fetal loss as compared with 50 out of 357 pregnancies in the non-carriers (RR 0.9; 95% CI: 0.7-1.4). After adjustment, carriers of PT-G20210A showed a trend towards a higher risk of late fetal loss as compared with non-carriers (RR 2.2; 95% CI: 0.8-6.2). Furthermore, in pregnancies subsequent to those with previous fetal loss there was not a different risk of adverse outcome regardless of the carrier status., Conclusions: Female family members who are heterozygous carriers of isolated PT-G20210A do not seem to be at significant increased risk for fetal loss as compared with non-carriers. Screening for PT-G20210A of fertile age women belonging to these families is not warranted in this situation.
- Published
- 2007
- Full Text
- View/download PDF
26. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia.
- Author
-
Vannucchi AM, Antonioli E, Guglielmelli P, Rambaldi A, Barosi G, Marchioli R, Marfisi RM, Finazzi G, Guerini V, Fabris F, Randi ML, De Stefano V, Caberlon S, Tafuri A, Ruggeri M, Specchia G, Liso V, Rossi E, Pogliani E, Gugliotta L, Bosi A, and Barbui T
- Subjects
- Adult, Aged, Amino Acid Substitution, Cardiovascular Diseases blood, Cardiovascular Diseases etiology, Cardiovascular Diseases genetics, Cardiovascular Diseases pathology, Female, Hematocrit, Heterozygote, Humans, Leukocyte Count, Male, Middle Aged, Organ Size, Polycythemia Vera complications, Polycythemia Vera genetics, Polycythemia Vera pathology, Pruritus blood, Pruritus etiology, Pruritus genetics, Pruritus pathology, Retrospective Studies, Risk Factors, Spleen pathology, Thrombocythemia, Essential complications, Thrombocythemia, Essential genetics, Thrombocythemia, Essential pathology, Thrombosis blood, Thrombosis etiology, Thrombosis genetics, Thrombosis pathology, Homozygote, Janus Kinase 2 genetics, Mutation, Missense, Polycythemia Vera blood, Thrombocythemia, Essential blood
- Abstract
JAK2 617V>F mutation occurs in a homozygous state in 25% to 30% of patients with polycythemia vera (PV) and 2% to 4% with essential thrombocythemia (ET). Whether homozygosity associates with distinct clinical phenotypes is still under debate. This retrospective multicenter study considered 118 JAK2 617V>F homozygous patients (104 PV, 14 ET) whose clinical characteristics were compared with those of 587 heterozygous and 257 wild-type patients. Irrespective of their clinical diagnosis, homozygous patients were older, displayed a higher leukocyte count and hematocrit value at diagnosis, and presented larger spleen volume. Aquagenic pruritus was significantly more common among homozygous PV patients. JAK2 617V>F homozygosity associated with more frequent evolution into secondary myelofibrosis in both PV and ET. After adjustment for sex, age, leukocyte count, and previous thrombosis in a multivariate analysis, homozygous ET patients displayed a significantly higher risk of cardiovascular events (hazard ratio [HR] 3.97, 95% confidence interval [CI] 1.34-11.7; P = .013) than wild-type (HR = 1.0) or heterozygous patients (HR = 1.49). No significant association of JAK2 617V>F homozygosity with thrombosis risk was observed in PV. Finally, JAK2 617V>F homozygous patients were more likely to receive chemotherapy for control of disease. We conclude that JAK2 617V>F homozygosity identifies PV or ET patients with a more symptomatic myeloproliferative disorder and is associated with a higher risk of major cardiovascular events in patients with ET.
- Published
- 2007
- Full Text
- View/download PDF
27. Incidence of the JAK2 V617F mutation among patients with splanchnic or cerebral venous thrombosis and without overt chronic myeloproliferative disorders.
- Author
-
De Stefano V, Fiorini A, Rossi E, Za T, Farina G, Chiusolo P, Sica S, and Leone G
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Polycythemia Vera epidemiology, Polycythemia Vera genetics, Thrombocythemia, Essential epidemiology, Thrombocythemia, Essential genetics, Venous Thrombosis epidemiology, Cerebral Veins pathology, Janus Kinase 2 genetics, Janus Kinase 2 physiology, Mutation, Myeloproliferative Disorders genetics, Splanchnic Circulation, Venous Thrombosis genetics
- Abstract
Background: Thrombosis of splanchnic or cerebral veins is a typical manifestation of polycythemia vera (PV) or essential thrombocythemia (ET). The recently identified Janus kinase 2 (JAK2) V617F somatic mutation is closely related to chronic myeloproliferative disorders (CMD)., Objective: To assess the incidence of the JAK2 V617F mutation among patients with splanchnic or cerebral venous thrombosis with or without overt CMD., Patients and Methods: We searched for the mutation in 139 adult patients (> 18 years old) with thrombosis of hepatic veins (HVT, n = 15), or extrahepatic portal vein (PVT) and/or mesenteric vein (MVT) (n = 79), or cerebral veins (CVT, n = 45). Only 19 patients fulfilled criteria for diagnosis of PV (n = 8) or ET (n = 11) at the time of thrombosis: four had HVT, 11 PVT and/or MVT, and four CVT., Results: The JAK2 V617F mutation was found in 94.7% [95% CI 75.3-99.0] of the patients with overt CMD at the time of thrombosis, in 21.5% (95% CI 13.8-31.7) of the patients with abdominal venous thrombosis and without overt CMD, and in 4.8% (95% CI 1.3-16.1) of the patients with CVT and without overt CMD. Among the patients without overt CMD or thrombophilia and with unprovoked thrombosis, 29.4% (95% CI 16.8-46.1) with splanchnic venous thrombosis and 42.8% (95% CI 24.4-63.4) with PVT had the JAK2 V617F mutation., Conclusions: A substantial proportion of patients with splanchnic venous thrombosis and a small, but significant, number of patients with CVT can be recognized as carriers of the JAK2 V617F mutation in the absence of overt signs of CMD. The clinical significance of such findings deserves further investigation.
- Published
- 2007
- Full Text
- View/download PDF
28. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera.
- Author
-
Landolfi R, Di Gennaro L, Barbui T, De Stefano V, Finazzi G, Marfisi R, Tognoni G, and Marchioli R
- Subjects
- Aged, Aspirin therapeutic use, Female, Follow-Up Studies, Humans, Leukocyte Count, Leukocytosis epidemiology, Male, Middle Aged, Polycythemia Vera drug therapy, Polycythemia Vera epidemiology, Risk Factors, Thrombosis epidemiology, Leukocytosis complications, Leukocytosis pathology, Polycythemia Vera complications, Polycythemia Vera pathology, Thrombosis etiology, Thrombosis pathology
- Abstract
In polycythemia vera, vascular risk assessment is based on age and thrombotic history, while the role of other potential predictors of this risk is still uncertain. Thus, we exploited the large database collected by the observational study of the European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) to investigate the association of hematologic variables and cardiovascular risk factors with the thrombotic risk. Among 1638 polycythemic patients followed for 2.7 +/- 1.3 years, there were 205 thromboses. Subjects with hypertension had a mild nonsignificant increase in the risk of arterial thrombosis, while this risk was significantly increased by smoking (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.15-3.14; P = .012). The time-dependent analysis adjusted for potential confounders showed that patients with a white blood cell count above 15 x 10(9)/L, compared with those with a white blood cell count below 10 x 10(9)/L, had a significant increase in the risk of thrombosis (HR, 1.71; 95% CI, 1.10-2.65; P = .017), mainly deriving from an increased risk of myocardial infarction (HR, 2.84; 95% CI, 1.25-6.46; P = .013). Thus, leukocyte count may help in defining the vascular risk of polycythemic subjects.
- Published
- 2007
- Full Text
- View/download PDF
29. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial.
- Author
-
Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, Cangialosi C, Grasso M, Rossini F, Galli M, Catalano L, Zamagni E, Petrucci MT, De Stefano V, Ceccarelli M, Ambrosini MT, Avonto I, Falco P, Ciccone G, Liberati AM, Musto P, and Boccadoro M
- Subjects
- Aged, Aged, 80 and over, Antineoplastic Agents, Alkylating administration & dosage, Antineoplastic Agents, Hormonal administration & dosage, Disease-Free Survival, Female, Humans, Male, Melphalan administration & dosage, Middle Aged, Multiple Myeloma mortality, Prednisone administration & dosage, Thalidomide administration & dosage, Antineoplastic Combined Chemotherapy Protocols, Multiple Myeloma drug therapy
- Abstract
Background: Since 1960, oral melphalan and prednisone (MP) has been regarded as the standard of care in elderly multiple myeloma patients. This multicentre randomised trial compared oral MP plus thalidomide (MPT) with MP alone in patients aged 60-85 years., Methods: Patients with newly diagnosed multiple myeloma were randomly assigned to receive oral MP for six 4-week cycles plus thalidomide (n=129; 100 mg per day continuously until any sign of relapse or progressive disease) or MP alone (n=126). Analysis was intention-to-treat. This study is registered at , number NCT00232934., Results: Patients treated with thalidomide had higher response rates and longer event-free survival (primary endpoints) than patients who were not. Combined complete or partial response rates were 76.0% for MPT and 47.6% for MP alone (absolute difference 28.3%, 95% CI 16.5-39.1), and the near-complete or complete response rates were 27.9% and 7.2%, respectively. 2-year event-free survival rates were 54% for MPT and 27% for MP (hazard ratio [HR] for MPT 0.51, 95% CI 0.35-0.75, p=0.0006). 3-year survival rates were 80% for MPT and 64% for MP (HR for MPT 0.68, 95% CI 0.38-1.22, p=0.19). Rates of grade 3 or 4 adverse events were 48% in MPT patients and 25% in MP patients (p=0.0002). Introduction of enoxaparin prophylaxis reduced rate of thromboembolism from 20% to 3% (p=0.005)., Conclusion: Oral MPT is an effective first-line treatment for elderly patients with multiple myeloma. Anticoagulant prophylaxis reduces frequency of thrombosis. Longer follow-up is needed to assess effect on overall survival.
- Published
- 2006
- Full Text
- View/download PDF
30. The risk of thrombosis in patients with acute leukemia: occurrence of thrombosis at diagnosis and during treatment.
- Author
-
De Stefano V, Sorà F, Rossi E, Chiusolo P, Laurenti L, Fianchi L, Zini G, Pagano L, Sica S, and Leone G
- Subjects
- Acute Disease, Adolescent, Adult, Aged, Asparaginase adverse effects, Female, Follow-Up Studies, Genetic Predisposition to Disease, Humans, Incidence, Leukemia epidemiology, Male, Middle Aged, Risk, Thrombosis epidemiology, Leukemia complications, Thrombosis etiology
- Abstract
Background: Thromboembolism can occur during acute leukemia, especially acute lymphoid leukemia (ALL) treated with L-asparaginase. Yet, most reports are anecdotical and scarce data are available on the risk of thrombosis in acute myeloid leukemia (AML)., Objectives: To evaluate the risk of thrombosis in patients with acute leukemia., Patients and Methods: Three-hundred and seventy-nine consecutive adult patients with newly diagnosed acute leukemia were recruited in an observational cohort study conducted from January 1994 to December 2003. Diagnosis was ALL in 69 patients, acute promyelocytic leukemia (APL; FAB subtype M3) in 31, and non-M3 AML in 279. All first or recurrent symptomatic thromboembolic events objectively diagnosed were recorded., Results: Twenty-four patients of the overall 379 (6.3%; 95% CI 4.1%-9.2%) had a first thrombosis, venous in 80% of the cases and arterial in 20%. At diagnosis, thrombosis was a presenting manifestation in 13 cases (3.4% of the whole cohort): 1.4% in ALL, 9.6% in APL, and 3.2% in non-M3 AML patients. Follow-up was carried out on 343 patients without thrombosis at diagnosis and further 11 thrombotic events (3.2%) were recorded. At 6 months from diagnosis, the cumulative incidence of thrombosis was 10.6% in ALL, 8.4% in APL, and 1.7% in non-M3 AML patients. The patients who received L-asparaginase had a 4.9-fold increased risk of thrombosis in comparison with those who did not (95% CI 1.5-16.0). The fatality rate due to thrombosis was 0.8%., Conclusions: In patients with acute leukemia, the risk of thrombosis is not negligible. Thombosis can be a presenting symptom at diagnosis in a significant portion of cases with APL (9.6%) and non-M3 AML (3.2%); a similar rate of thrombosis can occur during the subsequent course of the disease. The incidence of symptomatic thrombosis at diagnosis is relatively low in ALL patients (1.4%), but is significantly increased by further treatment up to 10.6%. Strategies of antithrombotic prophylaxis should be investigated in this setting.
- Published
- 2005
- Full Text
- View/download PDF
31. Inherited thrombophilia and life-time risk of venous thromboembolism: is the burden reducible?
- Author
-
De Stefano V
- Subjects
- Female, Humans, Male, Pregnancy, Risk Factors, Thromboembolism blood, Thromboembolism prevention & control, Thrombophilia blood, Venous Thrombosis blood, Venous Thrombosis prevention & control, Thromboembolism etiology, Thrombophilia complications, Thrombophilia genetics, Venous Thrombosis etiology
- Published
- 2004
- Full Text
- View/download PDF
32. The expression pattern of c-mpl in megakaryocytes correlates with thrombotic risk in essential thrombocythemia.
- Author
-
Teofili L, Pierconti F, Di Febo A, Maggiano N, Vianelli N, Ascani S, Rossi E, Pileri S, Leone G, Larocca LM, and De Stefano V
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, Immunohistochemistry, Male, Megakaryocytes pathology, Middle Aged, Prognosis, Proto-Oncogene Proteins analysis, Receptors, Thrombopoietin, Retrospective Studies, Risk Factors, Thrombocythemia, Essential metabolism, Thrombocythemia, Essential pathology, Thrombosis metabolism, Thrombosis pathology, Megakaryocytes chemistry, Neoplasm Proteins, Proto-Oncogene Proteins metabolism, Receptors, Cytokine, Thrombocythemia, Essential complications, Thrombosis diagnosis
- Abstract
Using immunohistochemistry, we investigated the expression of c-mpl in bone marrow megakaryocytes of 88 patients with essential thrombocythemia (ET), 6 patients with secondary thrombocytosis (ST), and 20 patients with lymphoma (controls). Considering both the pattern of expression and the staining intensity, we identified a uniform and a heterogeneous pattern of c-mpl expression. The uniform pattern was found in all the controls, all the patients with ST, and 28 of the patients with ET, with a strong staining intensity observed in most megakaryocytes (> 80%). In contrast, c-mpl expression was heterogeneous in 60 patients with ET, 18 of whom (30%) presented with thrombosis at diagnosis, a significant difference from patients with a uniform c-mpl pattern (2 of 28; 7%; P =.026). In particular, the overrepresentation of thrombotic complications in patients with a heterogeneous c-mpl expression pattern was found mainly among patients with a significant percentage (10% to 40%) of weakly stained or c-mpl-negative megakaryocytes (heterogeneous-weak pattern; 13 of 30; 43%; P =.002). Accordingly, this pattern was associated with a 6.1-fold increased risk of thrombosis compared with that of patients with a uniform c-mpl pattern. In conclusion, the presence of a heterogeneous pattern of c-mpl distribution in bone marrow megakaryocytes could be a useful diagnostic criterion in the differential diagnosis of thrombocytosis. Furthermore, detection of a significant percentage of weakly stained or c-mpl-negative megakaryocytes can identify patients with a higher risk of thrombosis.
- Published
- 2002
- Full Text
- View/download PDF
33. Use of gemcitabine (GEM) in advanced myelodysplastic syndromes.
- Author
-
Mario AD, Pagano L, Mele L, De Stefano V, and Leone G
- Subjects
- Aged, Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic adverse effects, Deoxycytidine administration & dosage, Deoxycytidine adverse effects, Disease Progression, Female, Humans, Infusions, Intravenous, Male, Myelodysplastic Syndromes pathology, Survival Analysis, Treatment Outcome, Gemcitabine, Antimetabolites, Antineoplastic pharmacology, Deoxycytidine analogs & derivatives, Deoxycytidine pharmacology, Myelodysplastic Syndromes drug therapy
- Published
- 2001
- Full Text
- View/download PDF
34. Acquired and inherited risk factors for splanchnic venous thrombosis.
- Author
-
De Stefano V, Teofili L, and Leone G
- Subjects
- Budd-Chiari Syndrome etiology, Budd-Chiari Syndrome genetics, Chronic Disease, Humans, Myeloproliferative Disorders complications, Risk Factors, Portal Vein, Venous Thrombosis etiology, Venous Thrombosis genetics
- Published
- 2001
- Full Text
- View/download PDF
35. Coinheritance of the HR2 haplotype in the factor V gene confers an increased risk of venous thromboembolism to carriers of factor V R506Q (factor V Leiden).
- Author
-
Faioni EM, Franchi F, Bucciarelli P, Margaglione M, De Stefano V, Castaman G, Finazzi G, and Mannucci PM
- Subjects
- Adolescent, Adult, Aged, Cohort Studies, Female, Haplotypes, Humans, Male, Middle Aged, Mutation, Retrospective Studies, Risk, Factor V genetics, Venous Thrombosis genetics
- Abstract
With the aim of establishing whether the HR2 haplotype in factor V affects the risk of venous thromboembolism, a retrospective multicenter cohort study was performed in 810 family members identified through 174 probands who suffered from at least 1 episode of deep vein thrombosis and/or pulmonary embolism and had an inherited defect associated with thrombophilia (antithrombin, protein C, or protein S deficiency; factor V R506Q or prothrombin G20210A). Fifty-eight percent (468/810) of the family members had an inherited defect and 10% (47/468) were symptomatic. The HR2 haplotype was found in association with factor V R506Q more frequently in family members with venous thromboembolism (18%) than in those without (8%). Double heterozygosity for factor V R506Q and HR2 conferred a 3- to 4-fold increase in the relative risk of venous thromboembolism compared with factor V R506Q alone. The median age at first event was lower when the 2 defects were associated (46 v 52 years). No increase in risk of venous thromboembolism could be demonstrated when the HR2 haplotype was associated with inherited thrombophilic defects other than factor V R506Q. Because both factor V R506Q and the HR2 haplotype are very frequent, the effect of their coinheritance on the risk of venous thromboembolism might represent a clinically relevant issue, and screening for HR2 in carriers of factor V R506Q should be considered.
- Published
- 1999
36. Impaired cotranslational processing as a mechanism for type I antithrombin deficiency.
- Author
-
Fitches AC, Appleby R, Lane DA, De Stefano V, Leone G, and Olds RJ
- Subjects
- Adult, Amino Acid Substitution genetics, Animals, Antithrombins chemistry, COS Cells, Cell-Free System, DNA Mutational Analysis, Dogs, Female, Gene Expression, Glycosylation, Humans, Leucine genetics, Microsomes metabolism, Pancreas metabolism, Point Mutation genetics, Proline genetics, Protein Sorting Signals genetics, Protein Sorting Signals metabolism, Transfection, Antithrombins deficiency, Antithrombins genetics, Protein Processing, Post-Translational
- Abstract
Most secretory proteins, including antithrombin (AT), are synthesized with a signal peptide, which is cleaved before the mature protein is exported from the cell. The signal peptide is important in the process whereby nascent protein is recognized as requiring subsequent modification within the endoplasmic reticulum (ER). We have identified a novel mutation, 2436T-->C L(-10)P, which affects the central hydrophobic domain of the AT signal peptide, in a proband presenting with venous thrombotic disease and type I AT deficiency. We investigated the basis of the phenotype by examining expression in mammalian cells of a range of variant AT cDNAs with mutations affecting the -10 residue. Glycosylated AT was secreted from COS-7 cells transfected with wild-type AT, -10L deletion, -10V or -10M variants, but not variants with P, T, R, or G at -10. Cell-free expression of wild-type and variant AT cDNAs was then performed in the presence of canine pancreatic microsomes, as a substitute for ER. Variant AT proteins with P, T, R, or G at residue -10 did not undergo posttranslational glycosylation, and their susceptibility to trypsin digestion suggested they had not been translocated into microsomes. Our results suggest that the ability of AT signal peptide to direct the protein to ER for cotranslational processing events appears to be critically dependent on maintaining the hydrophobic nature of the region including residue -10. The investigations have defined impaired cotranslational processing as a hitherto unrecognized cause of hereditary AT deficiency.
- Published
- 1998
37. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families.
- Author
-
Martinelli I, Mannucci PM, De Stefano V, Taioli E, Rossi V, Crosti F, Paciaroni K, Leone G, and Faioni EM
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antithrombin III, Arteries, Child, Child, Preschool, Disease Susceptibility, Factor V Deficiency complications, Female, Humans, Infant, Italy epidemiology, Male, Middle Aged, Protein C, Protein S Deficiency complications, Pulmonary Embolism epidemiology, Pulmonary Embolism etiology, Risk, Thrombophilia epidemiology, Thrombophlebitis epidemiology, Thrombophlebitis etiology, Antithrombin III Deficiency genetics, Factor V genetics, Factor V Deficiency genetics, Protein C Deficiency genetics, Protein S Deficiency genetics, Thrombophilia genetics
- Abstract
Deficiency of the naturally occurring anticoagulant proteins, such as antithrombin, protein C and protein S, and activated protein C resistance due to the factor V Leiden gene mutation is associated with inherited thrombophilia. So far, no direct comparison of the thrombotic risk associated with these genetic defects is available. In this study, we wish to compare the lifetime probability of developing thrombosis, the type of thrombotic symptoms, and the role of circumstantial triggering factors in 723 first- and second-degree relatives of 150 index patients with different thrombophilic defects. We found higher risks for thrombosis for subjects with antithrombin (risk ratio 8.1, 95% confidence interval [CI], 3.4 to 19.6), protein C (7.3, 95% CI, 2.9 to 18.4) or protein S deficiency (8.5, 95% CI, 3. 5 to 20.8), and factor V Leiden (2.2, 95% CI, 1.1 to 4.7) than for individuals with normal coagulation. The risk of thrombosis for subjects with factor V Leiden was lower than that for those with all three other coagulation defects (0.3, 95% CI, 0.1 to 1.6), even when arterial and superficial vein thromboses were excluded and the analysis was restricted to deep vein thrombosis (0.3, 95% CI, 0.2 to 0.5). No association between coagulation defects and arterial thrombosis was found. The most frequent venous thrombotic manifestation was deep vein thrombosis with or without pulmonary embolism (90% in antithrombin, 88% in protein C, 100% in protein S deficiency, and 57% in factor V Leiden), but a relatively mild manifestation such as superficial vein thrombosis was common in factor V Leiden (43%). There was a predisposing factor at the time of venous thromboembolism in approximately 50% of cases for each of the four defects. In conclusion, factor V Leiden is associated with a relatively small risk of thrombosis, lower than that for antithrombin, protein C, or protein S deficiency. In addition, individuals with factor V Leiden develop less severe thrombotic manifestations, such as superficial vein thrombosis.
- Published
- 1998
38. Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients.
- Author
-
De Stefano V, Chiusolo P, Paciaroni K, Casorelli I, Rossi E, Molinari M, Servidei S, Tonali PA, and Leone G
- Subjects
- Adolescent, Adult, Age of Onset, Alleles, Brain Ischemia genetics, Child, Child, Preschool, Comorbidity, Deoxyribonuclease HindIII, Disease Susceptibility, Factor V genetics, Female, Genotype, Humans, Male, Methylenetetrahydrofolate Reductase (NADPH2), Odds Ratio, Oxidoreductases Acting on CH-NH Group Donors deficiency, Oxidoreductases Acting on CH-NH Group Donors genetics, Polymorphism, Restriction Fragment Length, Prevalence, Risk Factors, Thrombosis epidemiology, Thrombosis genetics, Brain Ischemia epidemiology, Point Mutation, Prothrombin genetics
- Abstract
The factor II G20210A mutation is a recently identified congenital risk factor for venous thrombosis. Its role in artery disease is still undefined. We investigated 72 patients (35 male and 37 female) with documented ischemic stroke occurred before 50 years of age and without risk factors such as diabetes, hypertension, and hyperlipidemia; 198 thrombosis-free individuals were investigated as the control group. We found 7 heterozygotes (9.7%) and 2 homozygotes (2.7%) for the mutant factor II allele among the patients and 5 heterozygotes (2.5%) among the controls; the mutant factor II allele frequency in the patient group (7.6%, 95% confidence interval [CI], 3.3 to 11.9) was significantly higher than in the controls (1.2%; 95% CI, 0.1 to 2.3; P = .0001). The prevalence of other investigated mutant alleles (factor V G1691A, methylenetetrahydrofolate reductase C677T) did not significantly differ between the two groups. The odds ratio for ischemic stroke associated with the carriership of the mutant factor II allele (both heterozygous and homozygous genotypes) was 5.1 (95% CI, 1.6 to 16.3). Heterozygous genotype was associated with a 3.8-fold increased risk for cerebral ischemia (95% CI, 1.1 to 13.1); in particular, assuming an expected prevalence of homozygotes in the general population of 1.6 to 10,000 according to the Hardy-Weinberg equilibrium, the risk associated with the homozygous genotype was estimated exceedingly high, being increased 208-fold.
- Published
- 1998
39. Pleomorphic xanthoastrocytoma: clinical, imaging and pathological features of four cases.
- Author
-
Bucciero A, De Caro M, De Stefano V, Tedeschi E, Monticelli A, Siciliano A, Cappabianca P, Vizioli L, and Cerillo A
- Subjects
- Adolescent, Aged, Astrocytoma diagnosis, Astrocytoma pathology, Astrocytoma radiotherapy, Brain Neoplasms diagnosis, Brain Neoplasms pathology, Brain Neoplasms radiotherapy, Cerebral Cortex pathology, Cerebral Cortex surgery, Child, Preschool, Combined Modality Therapy, Cranial Irradiation, Female, Humans, Infant, Magnetic Resonance Imaging, Male, Neoplasm Recurrence, Local diagnosis, Neoplasm Recurrence, Local pathology, Neoplasm Recurrence, Local radiotherapy, Neoplasm Recurrence, Local surgery, Prognosis, Radiotherapy, Adjuvant, Thalamic Diseases diagnosis, Thalamic Diseases pathology, Thalamic Diseases radiotherapy, Thalamic Diseases surgery, Thalamus pathology, Thalamus surgery, Astrocytoma surgery, Brain Neoplasms surgery
- Abstract
Four cases of pleomorphic xanthoastrocytoma (PXA) were collected from among 688 glioma patients who underwent operation at the Institute of Neurosurgery, University of Naples "Federico II" between January 1973 and December 1994. Three were females and one male, ranging in age from 10 months to 65 years. Three tumors were superficial in location, appearing as a meningo-cerebral mass in the temporo-parietal region. In one case, the tumor was situated deep within the brain (capsulo-thalamic region), without contact with leptomeninges. Three patients had experienced epileptic seizures, whereas one patient presented with an ictal episode. Tumor excision was grossly total in two cases, and subtotal in the remaining two. In three cases, histological examination demonstrated a "typical" PXA; conversely one tumor (subtotal excised) was an "atypical" PXA. The two patients with incomplete surgical resection were postoperatively treated with fractionated brain radiation therapy. Of the two patients who had grossly total removals, one showed tumor recurrence 6 years after surgery, and underwent operation (the recurrent neoplasm did not exhibit malignant transformation); the second patient was free of tumor at 14 months following craniotomy. Of the two patients who had undergone subtotal removals, one died because of massive regrowth of the lesion 22 months after surgery, whereas the second patient was asymptomatic at 1 year follow up.
- Published
- 1997
- Full Text
- View/download PDF
40. Inherited thrombophilia: pathogenesis, clinical syndromes, and management.
- Author
-
De Stefano V, Finazzi G, and Mannucci PM
- Subjects
- Humans, Thrombosis physiopathology, Thrombosis therapy, Thrombosis genetics
- Published
- 1996
41. Effect of all-trans retinoic acid on procoagulant and fibrinolytic activities of cultured blast cells from patients with acute promyelocytic leukemia.
- Author
-
De Stefano V, Teofili L, Sica S, Mastrangelo S, Di Mario A, Rutella S, Salutari P, Rumi C, d'Onofrio G, and Leone G
- Subjects
- Adolescent, Adult, Aged, Aprotinin pharmacology, Cell Differentiation drug effects, Cysteine Endopeptidases genetics, Female, Hemorrhagic Disorders physiopathology, Humans, Leukemia, Promyelocytic, Acute blood, Leukemia, Promyelocytic, Acute complications, Leukemia, Promyelocytic, Acute genetics, Male, Middle Aged, Neoplasm Proteins genetics, Neoplastic Stem Cells metabolism, Pancreatic Elastase biosynthesis, Pancreatic Elastase genetics, Thromboplastin biosynthesis, Thromboplastin genetics, Tissue Plasminogen Activator biosynthesis, Tissue Plasminogen Activator genetics, Tumor Cells, Cultured, Urokinase-Type Plasminogen Activator biosynthesis, Urokinase-Type Plasminogen Activator genetics, Blood Coagulation drug effects, Cysteine Endopeptidases biosynthesis, Fibrinolysis drug effects, Gene Expression Regulation, Leukemic drug effects, Hemorrhagic Disorders etiology, Leukemia, Promyelocytic, Acute pathology, Neoplasm Proteins biosynthesis, Neoplastic Stem Cells drug effects, Tretinoin pharmacology
- Abstract
The mechanisms underlying acute promyelocytic leukemia (APL) coagulopathy and its reversal by administration of all-trans retinoic acid (ATRA) have been investigated. Bone marrow promyelocytic blasts from nine patients with APL were cultured with or without ATRA 1 mumol/L. Cultured blasts (days 0, 3, 6, and 9) were washed, resuspended in phosphate buffer, lysed by freezing and thawing, and then assayed for procoagulant activity (PCA), elastase activity, tissue factor (TF) antigen, tissue-type plasminogen activator (t-PA) antigen and urokinase-type plasminogen activator (u-PA) antigen. PCA was determined by a recalcification assay. Elastase was measured by an amidolytic assay (S-2484). TF, t-PA, and u-PA antigens were measured by an enzyme-linked immunosorbent assay (ELISA). Malignant promyelocytes isolated from the patients had increased levels of PCA and TF as compared with the control polymorphonucleates, and low levels of elastase, t-PA, and u-PA; the patient blast PCA level was significantly related to the degree of hypofibrinogenemia. In this system, blast PCA depended on the tissue factor and was significantly correlated to the TF antigen values. In the cultures without ATRA, PCA, TF, and u-PA progressively increased, whereas elastase and t-PA levels remained essentially unchanged. In the presence of ATRA, all parameters (except u-PA) decreased during the culture time. Thus, a major role of the promyelocytic blast cell PCA in the pathogenesis of M3-related coagulopathy is suggested; the ATRA effect on coagulopathy seems mainly mediated by a downregulation of the PCA.
- Published
- 1995
42. Hypercoagulability during induction therapy of acute lymphoblastic leukemia is of scarce clinical relevance. Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto.
- Author
-
de Stefano V, Gugliotta L, Mazzucconi MG, Leone G, and Mandelli F
- Subjects
- Adult, Antithrombin III analysis, Asparaginase administration & dosage, Cyclophosphamide administration & dosage, Daunorubicin administration & dosage, Fibrinogen metabolism, Fibrinolysin analysis, Fibrinopeptide A analysis, Humans, Peptide Hydrolases analysis, Prednisone administration & dosage, Prospective Studies, Prothrombin analysis, Vincristine administration & dosage, alpha-2-Antiplasmin analysis, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Blood Coagulation drug effects, Precursor Cell Lymphoblastic Leukemia-Lymphoma blood, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Published
- 1993
43. Mortality related to thrombosis in congenital antithrombin III deficiency.
- Author
-
De Stefano V and Leone G
- Subjects
- Cause of Death, Family, Humans, Italy, Recurrence, Retrospective Studies, Antithrombin III Deficiency, Thrombosis mortality
- Published
- 1991
- Full Text
- View/download PDF
44. Antithrombin III loss in patients with nephrotic syndrome or receiving continuous ambulatory peritoneal dialysis. Evidence of inactive antithrombin III in urine of patients with nephrotic syndrome.
- Author
-
De Stefano V, Triolo L, De Martini D, Ferrelli R, Mori R, and Leone G
- Subjects
- Adult, Aged, Antithrombin III urine, Female, Humans, Hydrogen-Ion Concentration, Immunoelectrophoresis, Two-Dimensional, Isoelectric Focusing, Male, Middle Aged, Nephrotic Syndrome therapy, Nephrotic Syndrome urine, Antithrombin III metabolism, Nephrotic Syndrome metabolism, Peritoneal Dialysis, Continuous Ambulatory
- Abstract
Antithrombin III (AT III) was measured as antigen (Ag) and as heparin cofactor (HC) in plasma and urine or dialysate from nine patients with nephrotic syndrome and nine patients receiving continuous ambulatory peritoneal dialysis (CAPD), respectively. Crossed immunoelectrophoresis on heparin-agarose (H-CIE) and crossed immunoelectrofocusing (CIEF) runs were carried out on plasma and urine or dialysate samples. AT III plasma levels of the patients receiving CAPD were in the normal range, whereas levels in the patients with nephrotic syndrome showed a significant reduction. Nevertheless the AT III Ag daily loss was the same in both patient groups, so that an additional AT III loss caused by renal metabolism was suggested in patients with nephrotic syndrome. No alteration in the isoantithrombin plasma distribution was found in any patient. The AT III recovered in urine was almost all inactive, as demonstrated by the quantitative assays and by the H-CIE runs; on the contrary, the findings obtained by functional assays, H-CIE, and CIEF runs on dialysate samples failed to demonstrate any major alteration in the AT III molecule. In urine the AT III CIEF pattern displayed a more acid distribution (pH 4.9 to 4.5) in respect to the plasma AT III (pH 5.2 to 4.6); this pattern was suggested to be related to the renal AT III functional inactivation, whose exact mechanism remains to be clarified.
- Published
- 1987
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.