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Giuseppe Leone

Publications and source records attributed to Giuseppe Leone.

At least 19 recordsLinked to original sources
PubMed2026

AML, Myelodysplasia-Related: Beyond Classification-Toward Precision Decision-Making.

Acute myeloid leukemia, myelodysplasia-related (AML-MR), represents a genetically defined and clinically heterogeneous entity characterized by myelodysplasia-related gene (MRG) mutations, specific cytogenetic abnormalities, and frequently a previous history of myelodysplastic syndromes (MDS) or MDS/myeloproliferative neoplasm (MDS-MPN). The transition from the World Health Organization (WHO) 2016 classification to the 2022 WHO and International Consensus Classification (ICC) systems reflects a paradigm shift from morphology-based definitions toward genomics-driven disease entities. However, while diagnostic precision has improved, translation of these classifications into clinically actionable strategies remains incomplete. This review critically examines the biological and prognostic implications of MRG mutations, their interaction with key molecular subgroups such as NPM1- and FLT3-mutated AML, and their impact on therapeutic decision-making. We highlight unresolved issues, including the context-dependent prognostic value of MRG mutations, limitations of static risk stratification, and the need to integrate measurable residual disease (MRD), genomics, and patient fitness into therapeutic algorithms. At the clinical level, many studies have explored the sensitivity of AML-MR to various induction treatments in both younger and older AML patients, with significant improvements in survival. The main objective of these different induction therapy strategies is to achieve a complete remission with minimal toxicity, particularly in older patients, allowing patients to proceed to allogeneic hematopoietic stem cell transplantation, the only curative option so far.

AML MDS-related↗
PubMed2006

The haematocrit and platelet target in polycythemia vera.

Polycythemia vera (PV) is a chronic myeloproliferative disorder whose major morbidity and mortality are thrombohaemorragic events and progression to acute leukaemia or myelofibrosis. Whether the haematocrit and platelet count predict such complications remains unclear. The European Collaboration on Low-dose Aspirin in Polycythemia Vera prospective study included 1638 PV patients. A total of 164 deaths (10%), 145 (8.85%) major thrombosis and 226 (13.8%) total thrombosis were encountered during 4393 person-years follow-up (median 2.8 years). In time-dependent multivariable analysis, a haematocrit in the evaluable range of 40-55% was neither associated with the occurrence of thrombotic events, mortality nor with haematological progression in the studied population. The haematocrit of patients in the highest and lowest deciles at baseline was maintained within a narrow interval of haematocrit values ranging from 40% to 47% throughout follow-up. High platelet count was associated with a lower progression rate to acute leukaemia/myelofibrosis, whereas it had no significant relationship with thrombotic events or mortality. Our findings do not suggest that the range of haematocrit (<55%) and platelet counts (<600 x 10(9)/l) we encountered in our population had an impact on the outcome of PV patients treated by current therapeutic strategies.

Aged↗
PubMed2006

Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience.

In idiopathic thrombocytopenic purpura (ITP), corticosteroids have been widely recognized as the most appropriate first-line treatment, even if the best therapeutic approach is still a matter of debate. Recently, a single high-dose dexamethasone (HD-DXM) course was administered as first-line therapy in adult patients with ITP. In this paper we show the results of 2 prospective pilot studies (monocentric and multicentric, respectively) concerning the use of repeated pulses of HD-DXM in untreated ITP patients. In the monocenter study, 37 patients with severe ITP, age at least 20 years and no more than 65 years, were enrolled. HD-DXM was given in 4-day pulses every 28 days, for 6 cycles. Response rate was 89.2%; relapse-free survival (RFS) was 90% at 15 months; long-term responses, lasting for a median time of 26 months (range 6-77 months) were 25 of 37 (67.6%). In the multicenter study, 95 patients with severe ITP, age at least 2 years and no more than 70 years, were enrolled. HD-DXM was given in 4-day pulses every 14 days, for 4 cycles; 90 patients completed 4 cycles. Response rate (85.6%) was similar in patients classified by age (<18 years, 36 of 42=85.7%; >or=18 years, 41 of 48=85.4%, P=not significant), with a statistically significant difference between the second and third cycle (75.8% vs 89%, P=.018). RFS at 15 months 81%; long-term responses, lasting for a median time of 8 months (range 4-24 months) were 67 of 90 (74.4%). In both studies, therapy was well tolerated. A schedule of 3 cycles of HD-DXM pulses will be compared with standard prednisone therapy (eg, 1 mg/kg per day) in the next randomized Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) trial.

Adolescent↗
PubMed2006

ZAP-70 enhances B-cell-receptor signaling despite absent or inefficient tyrosine kinase activation in chronic lymphocytic leukemia and lymphoma B cells.

Expression of ZAP-70 is an important negative prognostic factor in chronic lymphocytic leukemia (CLL). This protein tyrosine kinase is a key mediator of T-cell receptor (TCR) signaling and is structurally homologous to Syk, which plays an analogous role in B-cell receptor (BCR) signaling. Recent studies indicate that ZAP-70 may participate in BCR signaling as well, but the mechanism of action is not completely understood. We have now compared antigen receptor-induced activation of ZAP-70 in B cells and T cells by analyzing phosphorylation of critical regulatory tyrosine residues. We show that BCR-mediated activation of ZAP-70 is very inefficient in CLL and lymphoma B cells and is negligible when compared to activation of Syk. Despite the inefficient catalytic activation, the ability of ZAP-70 to recruit downstream signaling molecules in response to antigen receptor stimulation appeared relatively preserved. Moreover, ectopic expression of ZAP-70 enhanced and prolonged activation of several key mediators of BCR signaling, such as the Syk, ERK, and Akt kinases, and decreased the rate of ligand-mediated BCR internalization. We conclude that the role of ZAP-70 in BCR signaling is quite distinct from its role in TCR signaling and is likely mediated by inhibition of events that terminate the signaling response.

Adaptor Proteins, Signal Transducing↗
PubMed2006

The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis.

Whether or not pregnant women with a previous episode of venous thromboembolism (VTE) should receive antithrombotic prophylaxis is a matter of debate. In order to estimate the rate of recurrent deep venous thrombosis (DVT) or pulmonary embolism (PE) during pregnancy and puerperium we retrospectively investigated a cohort of 1104 women with previous VTE; after a single DVT or isolated PE, 88 of them became pregnant at least once without receiving antithrombotic prophylaxis. Overall, 155 pregnancies and 120 puerperium periods without prophylaxis were recorded. There were nine recurrences during pregnancy and 10 during puerperium, with a rate of 5.8% [95% confidence interval (CI) 3.0-10.6] and 8.3% (95%CI 4.5-14.6) respectively. In pregnancy, the rate of recurrence was 7.5% (95%CI 4.0-13.7) if the first VTE was unprovoked, related to pregnancy or to oral contraceptive use, whereas no recurrence occurred if the first VTE was related to other transient risk factors. In puerperium, the rate of recurrence was 15.5% (95%CI 7.7-28.7) in women with a pregnancy-related first VTE, with a risk 3.9-times higher than in the remaining women. Inherited thrombophilia was not associated with a statistically significant increase in risk of recurrence in pregnancy or in puerperium, yet the rate of recurrence in puerperium was 14.2% (95%CI 5.7-31.4) in overall carriers of factor V Leiden and 30% (95%CI 10.7-60.3) in carriers with a pregnancy-related first VTE, with a risk 6.8 times higher than in women without thrombophilia and with a non pregnancy-related first VTE.

Adult↗
PubMed2006

Low-dose thalidomide in combination with oral fludarabine and cyclophosphamide is ineffective in heavily pre-treated patients with chronic lymphocytic leukemia.

Elevated levels of TNF-alpha have been associated with progressive disease in patients with chronic lymphocytic leukemia (CLL). Thalidomide has been shown to inhibit production of TNF-alpha. We investigated the effects of thalidomide on clinical outcome and TNF-alpha serum levels in five pre-treated CLL patients. The schedule consisted on daily thalidomide (Thal), oral fludarabine (Flu) and oral cyclophosphamide (CTX). Median duration of treatment was 60 days; four patients stopped treatment for disease progression and one patient for neurological toxicity. Serum TNF-alpha levels did not show any decrease during treatment. Low-dose thalidomide is not effective in CLL patients with refractory disease.

Administration, Oral↗
PubMed2006

Tolerogenic dendritic cells: cytokine modulation comes of age.

Dendritic cells (DCs) include a heterogeneous family of professional APCs involved in initiation of immunity and in immunologic tolerance. Specifically, peripheral tolerance can be achieved and maintained by promoting regulatory T-cell (Treg) responses and/or T-cell anergy or deletion. Until recently, immature developmental stages of DC differentiation were believed to induce T-cell anergy or Treg cells, whereas DCs transformed into mature DCs by activation stimuli were thought to represent immunogenic DCs capable of inciting primary T-cell responses. This paradigm has been challenged by the demonstration of Treg-cell expansion by antigen-bearing, fully mature DCs. Similarly, semimature DCs with a distinctive interleukin 10 (IL-10)+ IL-12- cytokine production profile might be endowed with tolerogenic functions, supporting the concept that DC maturation per se should no longer be considered as a distinguishing feature of immunogenic as opposed to tolerogenic DCs (TDCs). Cytokine-modulated TDCs reflect an incomplete or altered status of monocyte differentiation and promote in vitro induction of Treg cells and/or in vivo protection from autoimmune diseases. Several growth factors, including IL-10, transforming growth factor beta (TGF-beta), granulocyte colony-stimulating factor (G-CSF), hepatocyte growth factor (HGF), and vasoactive intestinal peptide (VIP), modulate DC maturation and favor the differentiation of TDCs. From a therapeutic standpoint, cytokine-modulated TDCs might be beneficial for prevention and/or treatment of posttransplantation graft-versus-host disease (GVHD) and autoimmunity.

Aging↗
PubMed2006

Analysis of MTHFR polymorphisms and P16 methylation and their correlation with clinical-biological features of multiple myeloma.

BACKGROUND: Low folate intake and changes in folate metabolism due to polymorphisms in the methylentetrahydrofolate reductase (MTHFR) gene have been associated with myelomagenesis. However, controversial data have been published regarding a protective role of variant alleles of MTHFR on MM. PATIENTS AND METHODS: To investigate the influence of two common polymorphisms of MTHFR C677T and A1298C on the risk of multiple myeloma (MM), we performed a matched case-control study. The methylation status pattern of p16 was also addressed. RESULTS: The frequency each of 677 CC, 677CT, and 677TT was 31, 44, and 25%, respectively, whereas, the frequency each of 1298 AA, AC, CC was 48, 44, and 8% in MM patients. In the control group, the frequency each of 677CC, 677CT, and 677TT was 36, 45, and 19%, respectively, while the frequency each of 1298 AA, AC, CC was 37, 50, and 13%, respectively. No significant association between susceptibility to MM, 677, and 1298 MTHFR variants was detected. As regards p16 methylation, we confirmed a high prevalence of p16 methylation (40%) in patients affected by MM and demonstrated that MTHFR 677CC is associated with a higher prevalence of p16 hypermethylation. CONCLUSIONS: Our data demonstrated that variant alleles did not play a key role neither in protection nor in increased risk for MM, suggesting that the effect of MTHFR on folate metabolism might be modified by diet intake. Moreover, our findings demonstrated that p16 hypermethylation might be a frequent genetic aberration in MM and may contribute with other molecular aberrations in the pathogenesis of this malignant disorder.

Adult↗
PubMed2006

Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features.

Several hematopoietic growth factors, including interleukin-10 (IL-10) and transforming growth factor-beta1 (TGF-beta1), promote the differentiation of tolerogenic dendritic cells (DCs). Hepatocyte growth factor (HGF) is a pleiotropic cytokine whose effects on human DC differentiation and function have not been investigated. Monocytes cultured with HGF (HGFMo) differentiated into accessory cells with DC-like morphology, released low amounts of IL-12p70 and up-regulated IL-10 both at the mRNA and at the protein level. Upon activation with HGFMo, allogeneic CD4+CD25- T cells expressed the T regulatory (Treg)-associated transcription factor FoxP3, proliferated poorly, and released high levels of IL-10. Interestingly, blockade of surface immunoglobulin-like transcript 3 (ILT3) on HGFMo or neutralization of secreted IL-10 translated into partial restoration of T-cell proliferation. Secondary stimulation of HGFMo-primed CD4+ T cells with immunogenic DCs differentiated with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4 from monocytes of the same donor resulted in measurable T-cell proliferation. HGFMo-primed CD4+ T cells significantly inhibited the proliferation of naive CD4+CD25- T cells in a cell-contact-dependent manner. Finally, DNA microarray analysis revealed a unique gene-expression profile of HGF-activated monocytes. Collectively, our findings point to a novel role for HGF in the regulation of monocyte/DC functions that might be exploited therapeutically.

CD4-Positive T-Lymphocytes↗
PubMed2006

Mitoxantrone, carboplatin, cytosine arabinoside, and methylprednisolone followed by autologous peripheral blood stem cell transplantation: a salvage regimen for patients with refractory or recurrent non-Hodgkin lymphoma.

BACKGROUND: The objective of the current study was to evaluate a salvage chemotherapy regimen consisting of mitoxantrone, carboplatin, cytosine arabinoside, and methylprednisolone (MiCMA) for the treatment of patients with primary refractory or recurrent non-Hodgkin lymphoma (NHL). METHODS: From September 1991 to August 2002, 94 consecutive patients ages 16-60 years who had either recurrent or refractory NHL (mainly diffuse large-cell lymphomas) were treated on the MiCMA protocol. Patients had peripheral blood stem cells collected successfully for autologous stem cell transplantation after two or three cycles of MiCMA. RESULTS: Sixty-four of 85 evaluable patients achieved a response to the MiCMA regimen: 24 patients (26%) achieved a complete response and 40 patients (44%) achieved a partial response, for a total response rate of 70%. Sixty-two patients underwent autologous stem cell transplantation. After a median follow-up of 58 months, 47 patients (55%) remained alive; among these patients, 32 were free of disease (37%). No toxic deaths related to MiCMA were observed. Three patients died of infectious complications after transplantation. CONCLUSIONS: The current results suggested that MiCMA chemotherapy is an effective therapeutic alternative salvage regimen for patients with primary refractory or recurrent NHL. Response rates, overall survival, and freedom from disease progression were found to be associated significantly with response to MiCMA. Peripheral blood stem cell transplantation was feasible in virtually all patients, and its outcome was influenced strongly by chemosensitivity.

Adolescent↗
PubMed2006

Granulocyte colony-stimulating factor enhances the in vitro cytotoxicity of gemtuzumab ozogamicin against acute myeloid leukemia cell lines and primary blast cells.

OBJECTIVE: To evaluate the effects of granulocyte colony-stimulating factor (G-CSF) on the in vitro sensitivity of acute myeloid leukemia (AML) cell lines and primary AML blast cells to gemtuzumab ozogamicin (GO). MATERIALS AND METHODS: AML cell lines and primary blasts from 10 patients with AML were first incubated for 72 hours in the presence of G-CSF (5 or 100 ng/mL) and then exposed to increasing concentrations of GO (1-1,000 ng/mL) for an additional 72 hours. RESULTS: Pretreatment with G-CSF translated into significant enhancement of GO-induced cytotoxicity in the GO-sensitive HL-60 and NB-4 cells. Conversely, the response of GO-insensitive KG-1a, TF-1, and K562 cells was unaffected by in vitro priming with G-CSF. In vitro exposure to G-CSF augmented GO-induced apoptosis in 7 of 10 primary AML samples and rendered blast cells from three refractory patients sensitive to killing effect of GO. The G-CSF-induced increase of the cytocidal activity of GO was independent of effects on the cell cycle and on the expression levels of CD33 antigen. Of potential interest, G-CSF induced dose-dependent inhibition of P-glycoprotein (P-gp/ABCB1) function in the GO-sensitive HL-60 and NB-4 cells and in blasts from three patients with AML that we tested. CONCLUSION: Collectively, our findings point to G-CSF as a potential sensitizing agent that can be exploited therapeutically to improve the clinical efficacy of GO.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Prophylaxis and treatment of venous thromboembolism in individuals with inherited thrombophilia.

Venous thromboembolism (VTE) susceptibility genes are widely diffuse in the general population, but clinical penetrance of genotypes is incomplete and has variable expressivity. Therefore, the indiscriminate search for carriers is of doubtful utility and potentially detrimental for screened individuals. A targeted screening in kindreds in which VTE already occurred can be more fruitful in identifying individuals sharing with the proband one or more known susceptibility genes (possibly cosegregating with other ones still unknown). Clinical penetrance is variable, and is higher in the relatively rare deficiencies of antithrombin (AT), protein C (PC), or protein S (PS), and lower in the presence of the common polymorphisms factor V Leiden and prothrombin G20210A. Women with inherited thrombophilia should be warned about the thrombotic risk associated with the use of oral contraceptives or hormonal replacement treatment. Moreover, prophylaxis during puerperium and surgery or after trauma is warranted. The absolute risk associated with such situations is low but not negligible in the presence of deficiencies of AT, PC, or PS, homozygous conditions, and carriership of multiple defects. In such cases primary prophylaxis should be applied also during pregnancy and in general should be more stringent; moreover, in these patients the option for indefinite duration of secondary anticoagulant prophylaxis after VTE should be considered because of the relevant risk of recurrent VTE. In all cases, a careful balance of benefits and risks associated with prophylactic measures should be achieved, and patient preferences should be considered.

Blood Coagulation Disorders, Inherited↗
PubMed2006

Lower hemoglobin levels in human immunodeficiency virus-infected patients with a positive direct antiglobulin test (DAT): relationship with DAT strength and clinical stages.

BACKGROUND: There are conflicting opinions regarding the effect of positive direct antiglobulin test (DAT) on hemoglobin (Hb) levels in human immunodeficiency virus-infected (HIV+) patients. STUDY DESIGN AND METHODS: A total of 166 samples from HIV+ outpatients were studied. The DAT was performed with the tube test and column agglutination technology (CAT). RESULTS: The DAT was positive in 18.67 percent with the tube method and 33.73 percent with the CAT. Patients with DAT-positive results showed lower Hb levels than DAT-negative patients, 12.3 g per dL versus 14.3 g per dL (p = 0.0002). The univariate logistic regression enabled us to study the phenomenon better and fit the probability of having a DAT-positive result on the basis of the Hb levels. The relationship between the CAT and the tube test when washing the red blood cells (RBC) at 4 degrees C was stronger than when washing these at room temperature (phi = 0.8156; p = 0.000). The Hb levels were significantly lower in the positive DATs of Stage C (acquired immune deficiency syndrome [AIDS]) and Stage B (symptomatic non-AIDS patients), which showed decreasing Hb values for increasing agglutination strengths (p = 0.000). Anemia was related with the DAT results (odds ratio [OR], 8.005; p = 0.000) but not to the AIDS condition (OR, 1.741; p = 0.221). DISCUSSION: Our study indicates that the DAT-positive results may be specifically related to lower Hb levels in HIV+ patients. The immunologic RBC clearance could be part of the anemic multifactorial condition in HIV+ patients.

Anemia↗
PubMed2006

Inherited thrombophilia: treatment during pregnancy.

OBJECTIVE: Inherited thrombophilia is associated with thromboembolic events and/or poor obstetric outcome. We evaluated the pregnancy outcome in women with inherited thrombophilia treated with low-molecular-weight heparin (LMWH). METHODS: 38 thrombophilic women with a history of thromboembolic events and/or poor obstetric outcome were treated during their 39 consecutive pregnancies with LMWH from pregnancy verification until 4-6 weeks in puerperium. A fixed dose of enoxaparin 4,000 IU/day (except 1 case who required nadroparin 0.3 ml/day) was administered in most cases, adopting a higher dose (6,000 IU/day to 6,000 IU twice a day) in those with previous thromboembolic events. RESULTS: In the treated women, all had a good obstetric outcome, whereas in the previous untreated pregnancies (n = 78), the rate of fetal loss (early and late) was 76.9%, only 12 live infants survived (66.6%). Moreover, birth weight resulted significantly higher in live infants born to treated pregnancies in comparison to that of previous untreated pregnancies (p = 0.009). No maternal thrombosis or major bleeding complications were recorded. CONCLUSIONS: The treatment with LMWH improved pregnancy outcome resulting effective and safe in thrombophilic women with a history of thromboembolic events and/or poor obstetric outcome.

Adult↗
PubMed2006

Non-invasive detection of fetal rhesus D status: a comparison between polymerase chain reaction and flow cytometry.

OBJECTIVE: A non-invasive prenatal determination of the fetal RhD status might be useful for the management of pregnancies in RhD-negative women whose partners are RhD positive. METHODS: Maternal peripheral blood of 32 RhD-negative women (17-24 weeks of gestation) was collected, and circulating fetal cells were enriched by CD71 mini-magnetic activated cell sorting. The RhD status of the fetuses was assessed using multiparametric flow cytometry, and results were compared to those of reverse transcriptase (RT)-polymerase chain reaction (PCR), or PCR, which acted as control. Flow-cytometric study of fetal cells employed monoclonal antibodies directed against CD71, glycophorin A (GPA) and RhD antigens. RESULTS: The median percentage of CD71- and RhD-positive cells was 0.83% (range 0.14-6.44%), and that of CD71 and GPA-positive cells was 10.07% (range 0.52-45.84%). Flow-cytometric analysis correlated with RT-PCR results of RNA obtained from whole maternal blood. In 1 case, an incorrect result was due to the failure of the amplification of the specific RhD band on RNA extracted from the CD71-positive fraction. In two instances, we observed false-positive results for RhD in PCR of DNA obtained from maternal plasma. CONCLUSION: Based on our results, flow-cytometric analysis might be proposed as a clinical tool for the non-invasive prenatal determination of the fetal RhD status independently of fetal gender.

Antibodies, Monoclonal↗
PubMed2006

The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C and protein S.

Few data are available on the risk of recurrent venous thromboembolism (VTE) associated with the rare inherited deficiencies of natural anticoagulants. We studied 602 patients with previous VTE: the incidence of first recurrence in the absence of anticoagulation was retrospectively estimated in 64 patients with deficiency of antithrombin (AT, n=14), protein C (PC, n=28), or protein S (PS, n=22) and 538 with no known defect, who acted as the reference group. After adjustment for sex, age, and circumstances of the first event, AT deficiency resulted an independent risk factor for recurrence (hazard ratio 1.9, 95% CI 1.0-3.9); the carriers of PC or PS deficiency had a marginal increase in risk (hazard ratio 1.4, 95% CI 0.9-2.2). In conclusion, patients with AT deficiency are potential candidates for long-term oral anticoagulation.

3' Untranslated Regions↗