Showing papers by "Giovanni Barosi published in 2007"
Mayo Clinic1, University of Cologne2, Indiana University3, University of Texas MD Anderson Cancer Center4, Uppsala University5, Royal Hallamshire Hospital6, Medical University of Vienna7, University of Florence8, University of Barcelona9, University of Illinois at Chicago10, Harvard University11, Ohio State University12, University of Chicago13
TL;DR: In this paper, the authors proposed a revision of the current World Health Organization (WHO) diagnostic criteria for polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), which was subsequently presented by an international expert panel of pathologists and clinical investigators in myeloproliferative disorders.
856 citations
TL;DR: It is concluded 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.
436 citations
TL;DR: The Working Group recommends that the presented criteria for diagnosing clinically significant TAM be adopted in clinical use, especially in scientific trials.
Abstract: Background and Objectives There are no widely accepted criteria for the definition of hematopoietic stem cell transplant-associated microangiopathy (TAM). An International Working Group was formed to develop a consensus formulation of criteria for diagnosing clinically significant TAM.Design and Methods The participants proposed a list of candidate criteria, selected those considered necessary, and ranked those considered optional to identify a core set of criteria. Three obligatory criteria and four optional criteria that ranked highest formed a core set. In an appropriateness panel process, the participants scored the diagnosis of 16 patient profiles as appropriate or not appropriate for TAM. Using the experts’ ratings on the patient profiles as a gold standard, the sensitivity and specificity of 24 candidate definitions of the disorder developed from the core set of criteria were evaluated. A nominal group technique was used to facilitate consensus formation. The definition of TAM with the highest score formed the final proposal.Results The Working Group proposes that the diagnosis of TAM requires fulfilment of all of the following criteria: (i) >4% schistocytes in blood; (ii) de novo, prolonged or progressive thrombocytopenia (platelet count
325 citations
Mayo Clinic1, University of Texas MD Anderson Cancer Center2, Royal Hallamshire Hospital3, Harvard University4, University of Cambridge5, Cornell University6, University of Florence7, Fred Hutchinson Cancer Research Center8, Medical University of Vienna9, University of Chicago10, Stanford University11, University of Pennsylvania12, Memorial Sloan Kettering Cancer Center13, Indiana University14, University of Cologne15
TL;DR: This document summarizes the proceedings from the second meeting of the IWG-MRT, in November 2006, where the group discussed and agreed to standardize the nomenclature referring to CIMF.
289 citations
TL;DR: The JAK2 V617F genotype should be considered in any future risk stratification of patients with PMF and independently predicted the evolution toward large splenomegaly, need of splenectomy, and leukemic transformation.
243 citations
TL;DR: MK hyperplasia in IMF is likely a consequence of both the increased ability of IMF progenitor cells to generate MKs and a decreased rate of MK apoptosis, which contribute to the development of many pathological epiphenomena associated with IMF.
186 citations
TL;DR: Data indicate that MPL mutation in myelofibrosis characterises patients with more severe anaemic phenotype, irrespective of JAK2V617F status.
Abstract: Summary
The clinical and haematological phenotype of patients with myelofibrosis harbouring MPLW515L/K mutation has not been thoroughly investigated. Of 217 myelofibrosis subjects, 18 (8·2%) had an MPL mutation, four of which (22%) co-existed with JAK2V617F mutation. When compared with MPL wild-type patients, irrespective of JAK2V617F status, those with MPLW515L/K, were more frequently female, were older (61 years vs. 57 years; P = 0·02), presented with more severe anaemia (haemoglobin, 101 g/l vs. 121 g/l; P = 0·002) and were more likely to require regular transfusional support (P = 0·012). These data indicate that MPL mutation in myelofibrosis characterises patients with more severe anaemic phenotype.
142 citations
TL;DR: In a long-term horizon, adjuvant trastuzumab is a cost-effective therapy for patients with HER2-positive, high-risk, early breast cancer.
Abstract: Purpose To evaluate the cost-effectiveness of 12-month adjuvant trastuzumab therapy in women with high-risk human epidermal growth factor receptor 2 (HER2) –positive early breast cancer. Methods A Markov model tracked quarterly patients’ transitions between five health states: disease free, local relapse, disease free after local relapse, metastatic disease, and death. Patients were allowed to incur symptomatic or asymptomatic transient cardiac dysfunction during trastuzumab administration. Probabilities were derived mainly from the combined report of the National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 trials (95% node positive) and a meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group. Costs were estimated from the perspective of the Italian and US health care systems. The analysis was run during a 15-year time horizon. A 3% yearly discount rate was applied to both costs and life-years. Second-order Monte-Carlo and probabilis...
131 citations
TL;DR: Molecular profiling of IM CD34+ cells uncovered a limited number of genes with altered expression that, beyond their putative role in disease pathogenesis, are associated with patients' clinical characteristics and may have potential prognostic application.
Abstract: This study was aimed at the characterization of a gene expression signature of the pluripotent hematopoietic CD34(+) stem cell in idiopathic myelofibrosis (IM), which would eventually provide novel pathogenetic insights and/or diagnostic/prognostic information. Aberrantly regulated genes were revealed by transcriptome comparative microarray analysis of normal and IM CD34(+) cells; selected genes were also assayed in granulocytes. One-hundred seventy four differentially expressed genes were identified and in part validated by quantitative polymerase chain reaction. Altered gene expression was corroborated by the detection of abnormally high CD9 or CD164, and low CXCR4, membrane protein expression in IM CD34(+) cells. According to class prediction analysis, a set of eight genes (CD9, GAS2, DLK1, CDH1, WT1, NFE2, HMGA2, and CXCR4) properly recognized IM from normal CD34(+) cells. These genes were aberrantly regulated also in IM granulocytes that could be reliably differentiated from control polycythemia vera and essential thrombocythemia granulocytes in 100% and 81% of cases, respectively. Abnormal expression of HMGA2 and CXCR4 in IM granulocytes was dependent on the presence and the mutational status of JAK2(V617F) mutation. The expression levels of both CD9 and DLK1 were associated with the platelet count, whereas higher WT1 expression levels identified IM patients with more active disease, as revealed by elevated CD34(+) cell count and higher severity score. In conclusion, molecular profiling of IM CD34(+) cells uncovered a limited number of genes with altered expression that, beyond their putative role in disease pathogenesis, are associated with patients' clinical characteristics and may have potential prognostic application.
115 citations
TL;DR: CXCR4 down-regulation was associated with advanced patient age, the presence of severe anemia, thrombocytopenia, and degree of bone marrow fibrosis, and was severely down-regulated in high risk patients and patients with a high "myelodepletion severity index".
Abstract: Purpose: We studied the expression of the chemokine receptor CXCR4 on circulating CD34+ cells of patients with myelofibrosis with myeloid metaplasia (MMM), and examined its relationship to the severity of disease. Patients and methods: Surface and intracellular CXCR4 expression were measured flow cytometrically in 84 consecutive MMM patients, 16 patients with polycythemia vera (PV), and 20 healthy subjects. In 23 MMM patients, CXCR4 gene expression level was also quantitated by real time-RT-PCR in CD34+ cells. Results: The expression of CXCR4 on circulating CD34+ cells was significantly reduced in patients with MMM ( P P = 0.01). The levels of CXCR4 mRNA in CD34+ cells were lower in patients with MMM as compared with normal subjects, and were directly correlated with the degree of CXCR4 surface expression, demonstrating that transcriptional defects were the major cause for receptor down-regulation. No statistical association was found between JAK2V617F mutational status and the extent of CXCR4 down-regulation. CXCR4 expression on CD34+ cells inversely correlated with the number of circulating CD34+ cells ( R = − 0.55; P Conclusions: Reduced expression of CXCR4 by CD34+ cells is a characteristic of MMM which is associated with the constitutive mobilization of CD34+ cells and occurs in patients with advanced forms of the disease.
61 citations
TL;DR: Allogeneic stem cell transplantation is the only curative therapy for PMF, and its standard modality has an associated mortality of 30%, and it is indicated in younger patients with high-risk disease or disease resistant to conventional treatment.
Abstract: The treatment of primary myelofibrosis (PMF) remains essentially palliative. Conventional modalities include a wait-and-see approach for asymptomatic patients, oral cytolytic drugs such as hydroxyurea for the hyperproliferative forms of the disease, androgens or erythropoietin for the anemia, and splenectomy in selected patients. These therapeutic modalities improve the patients' quality of life but have no impact on survival. Newer therapies for PMF are currently being used. Antiangiogenic and immunomodulatory drugs such as thalidomide and lenalidomide are associated with frequent side effects but have shown certain efficacy, especially for the anemia and thrombocytopenia. The association of low-dose thalidomide with prednisone has better tolerability, and it is also effective. Tyrosine kinase inhibitors such as imatinib have also been used, but their efficacy is limited. Tipifarnib, a farnesyltransferase inhibitor, has shown certain effects in the anemia. Allogeneic stem cell transplantation (SCT) is the only curative therapy for PMF. Its standard modality has an associated mortality of 30%, and it is indicated in younger patients with high-risk disease or disease resistant to conventional treatment. Reduced-intensity conditioning allogeneic SCT is associated with low mortality while maintaining a curative potential, and until longer follow-up is available, it can be used in patients aged 45-70 years old with high- or intermediate-risk myelofibrosis or myelofibrosis resistant to treatment. Autologous SCT is a palliative measure that can be considered in patients with resistant disease, who lack a suitable donor. Newer immunomodulatory drugs, proteasome inhibitors, hypomethylating agents, and JAK2 inhibitors are currently being tested.
TL;DR: Allogeneic transplantation is a curative option for patients with idiopathic myelofibrosis and factors which predict a favourable outcome are identified and may be used to select patients for this procedure.
TL;DR: Analyzing the clinical evolution between groups demonstrated persistently higher LDH and worsening thrombocytopenia in the PMF-BP cohort, and clonal evolution are features commonly seen in PMF patients whom evolve to blast phase and may be a harbinger of movement towards PMF BP.
TL;DR: The putative risk of leukaemia associated with HU therapy prompted the evaluation of other drugs thought to lack leukaemogenic potential such as interferon and anagrelide and the need for a unified definition of resistance and intolerance to hydroxyurea.
Abstract: In the treatment of essential thrombocythaemia (ET), cytoreductive agents are used to reduce the risk of thrombosis and other disease-related complications. Hydroxyurea (HU) is the cytoreductive agent most commonly used for the treatment of high-risk ET patients (1). Although the use of HU is supported by evidencebased guidelines (1) and the results of randomised studies (2), it is not an optimal treatment option for all ET patients. It is estimated that 10% of patients receiving it do not achieve the desired reduction in platelet count using recommended doses (clinical resistance) (3). Some patients also experience unacceptable side effects including leg ulcers, other muco-cutaneous manifestations and HU-related fever (clinical intolerance) (1, 2, 4, 5). In such cases, clinicians must decide whether it is appropriate to stop HU therapy and switch to an alternative agent. An important consideration in switching from HU to an alternative ET treatment option is the possible increased risk of leukaemic transformation that may apply if other cytostatic agents are used (6). The putative risk of leukaemia associated with HU therapy prompted the evaluation of other drugs thought to lack leukaemogenic potential such as interferon and anagrelide. In Europe, anagrelide has been approved for ‘at risk patients who are intolerant to their current therapy or whose elevated platelet counts are not reduced to an acceptable level by their current therapy’ (3). This indication highlights clinical intolerance or resistance as the basis for switching a patient’s current therapy to an alternative agent. It does not, however, specify precise criteria for how resistance and intolerance should be defined. The need for a unified definition of resistance and intolerance to hydroxyurea
TL;DR: Results show that bortezomib in MF is clinically tolerable at the 1.3 mg/m2 every 21 days x 6 cycles, and the efficacy of the drug is under examination in a phase II study.
TL;DR: Growing in vitro EPC-derived colonies from the peripheral blood of patients with myelofibrosis show that patients with MF have an increased frequency of EPC in their PB compared to healthy subjects and that these mobilized EPC are not clonally-related to the JAK-2 or MPL mutated clone.