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S Sica

Publications and source records attributed to S Sica.

At least 19 recordsLinked to original sources
PubMed2006

The Akt signaling pathway determines the different proliferative capacity of chronic lymphocytic leukemia B-cells from patients with progressive and stable disease.

Chronic lymphocytic leukemia (CLL) B-cells are hyporesponsive to many proliferative signals that induce activation of normal B-lymphocytes. However, a heterogeneous response has recently been observed with immunostimulatory CpG-oligodeoxynucleotides (CpG ODN). We now show that CpG ODN induce proliferation mainly in CLL B-cells from patients with progressive disease and unmutated immunoglobulin V(H) genes, whereas G(1)/S cell cycle arrest and apoptosis are induced in leukemic B-cells from stable/V(H) mutated CLL. Examination of early signaling events demonstrated that all CLL B-cells respond to CpG ODN stimulation by degradation of the NF-kappaB inhibitor IkappaB and activation of the Akt, ERK, JNK and p38 MAPK kinases, but the magnitude and duration of the signaling response was greater in the proliferating cases. Pharmacological inhibition of these pathways showed that simultaneous activation of Akt, ERK and JNK is required for cell cycle progression and proliferation. Conversely, introduction of constitutively active Akt in nonproliferating CLL B-cells resulted in induction of cyclin A following CpG ODN stimulation, indicating that increased Akt activation is sufficient to overcome the hyporesponsiveness of these cells to proliferative signals. Thus, the magnitude of Akt signaling may determine the distinct responses observed in leukemic B-cells belonging to the different prognostic subgroups.

Adult↗
PubMed2006

Treatment of acute leukaemias with monoclonal antibodies: current status and future prospects.

Monoclonal antibodies are a new class of agents targeted at specific receptors on cancer cells. In addition to direct cellular effects, antibodies can carry substances to the targeted cells, such as radioactive isotopes, toxins, and antineoplastic agents. At present monoclonal antibodies, directed against both lymphoid antigens (CD 20 and CD 52) and a myeloid antigen (CD33) are available for clinical use. In ALL, rituximab, a humanized anti CD20 antibody, has been combined to chemotherapy mainly in mature B-ALL and Burkitt's lymphoma and preliminary results are promising. Alemtuzumab is an anti-CD52 humanized antibody, which showed anti-tumour activity in CLL; clinical effects were observed in some patients with relapsed adult ALL. Monoclonal antibodies against myeloid antigens have been prevalently used in acute myeloid leukaemias (AML), where the most utilised immunological target is CD33. The CD33 molecule is expressed by approximately 90% of AMLs but not on CD34(+) bone marrow-resident hematopoietic stem cells. The humanized anti-CD33 monoclonal antibody HuM195 has only modest activity against overt AML, but it can eliminate minimal residual disease. Radioimmunotherapy with beta-particle-emitting isotopes targeting CD33 shows a major efficacy. Targeted chemotherapy with the anti-CD33-calicheamicin construct gemtuzumab ozogamicin (GO) has produced remissions as a single agent in patients with relapsed AML and appears promising when used in combination with standard chemotherapy. GO is composed of a humanized immunoglobulin G(4) (IgG(4)) monoclonal antibody (mAb), targeting the CD33 antigen and linked to a calicheamicin derivative, a cytotoxic anthracycline antibiotic. GO has been approved by FDA as second-line therapy in older patients with AML. The most common adverse effects of monoclonal antibodies are myelosuppression, infusion-related reactions, and hypersensitivity reactions. Rituximab may cause tumour lysis syndrome. Alemtuzumab causes immunosuppression, increasing the risk of infection. GO may cause hepatotoxicity.

Acute Disease↗
PubMed2005

The risk of thrombosis in patients with acute leukemia: occurrence of thrombosis at diagnosis and during treatment.

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.

Acute Disease↗
PubMed2004

Mycobacterial infection: a difficult and late diagnosis in stem cell transplant recipients.

The Infectious Diseases Working Party of the European Blood and Marrow Transplant Group conducted a survey to obtain information about the frequency, presentation, and treatment of mycobacterial infection (MBI) in stem cell transplant (SCT) recipients. Among 29 centers, MBI was diagnosed in 0.79% of 1513 allogeneic and 0.23% of 3012 autologous SCT recipients during 1994-1998 a median of 160 days after transplantation. The mean interval between first symptoms and diagnosis was 29 days and was still longer for patients with atypical MBI or recipients of corticosteroid therapy. The prevalence of MBI was highest among those who received matched unrelated or mismatched STCs from related donors. Of 31 patients, 20 had tuberculosis, 8 had atypical MBI, and 3 had diagnoses based on histological findings only. Five patients (16%) died, all of whom had received an allogeneic SCT. Because of the increased numbers of unmatched donors and transplantation programs in countries with a high prevalence of tuberculosis, constant vigilance is required to early detect MBI in SCT recipients.

Adolescent↗
PubMed2004

Outbreaks of infectious diseases in stem cell transplant units: a silent cause of death for patients and transplant programmes.

Following the closure of the National Blood and Bone Marrow Transplant Unit in Dublin, because of an outbreak of vancomycin-resistant enterococcal infection, a survey was carried out by the EBMT to investigate the occurrence of outbreaks of infection in SCT units and the impact on patient morbidity, mortality and the administration of the transplant programme over a 10-year period from 1991 to 2001. A total of 13 centres reported 23 outbreaks of infection involving 231 patients: 10 bacterial, eight viral and five fungal outbreaks were reported and 56 deaths were attributed to infection. All fungal and bacterial deaths and the majority of viral deaths occurred in allograft recipients. In all outbreaks, the infection was reported to be hospital acquired and in all the viral, and half the bacterial infections, cross-infection was a major factor. All viral, four of 10 bacterial and three of five fungal outbreaks occurred in HEPA filtered rooms. A total of 12 SCT units reported a partial or total closure. The introduction of mandatory quality management systems such as JACIE should result in a change in attitude to 'incident reporting' and together with future surveys should reduce the incidence of infectious outbreaks in SCT units.

Aspergillosis↗
PubMed2003

Efficacy of granulocyte transfusions for neutropenia-related infections: retrospective analysis of predictive factors.

BACKGROUND: The transfusion of G-CSf-primed granulocytes (GTX) might represent an important treatment option for neutropenia-related infections unresponsive to conventional antimicrobial therapies and to recombinant hematopoietic growth factors. However, few studies to date have identified the factors that can predict clinical outcome and the patient populations who are likely to benefit most from GTX. The primary endpoint of the present retrospective study was to evaluate the efficacy of GTX in 22 patients with hematological malignancies who developed neutropenia-related bacterial and fungal infections that were unresponsive to appropriate antimicrobial therapies. METHODS: Peripheral blood granulocytes were collected by continuous-flow leukapheresis from HLA-identical siblings after priming with G-CSF. The response to GTX was classified as 'favorable' if clinical symptoms and signs of infection resolved or 'unfavorable' if clinical symptoms and signs of infection were unchanged or worsened. Control of infection at Day 30 after the enrollment in the GTX program was considered as the outcome variable in multiple regression analysis. RESULTS: Two patients died of infection before receiving the granulocyte concentrates. Bacterial infections (monomicrobial or mixed bacteremias) were documented in 11 patients, whereas fungal infections (fungemia or focal fungal infections) were diagnosed in seven patients. In two patients, no infecting agent could be isolated (clinical infection). Control of infection at Day 30 after the first GTX was achieved in 10 of 20 assemble patients. Overall, 54% of patients with bacterial infections had a favorable response, compared with 57% of patients with fungal infections. No differences in terms of survival were found when comparing patients with bacterial and those with fungal infections at a median follow-up 90 days from the first GTX. In univariate analysis, disease status before GTX, e.g., complete or partial remission, and spontaneous recovery of the neutrophil count were significantly associated with control of infection. when multivariate regression models were formed, the recovery 0.5 x 10 (9)/L PMN was the only parameter that significantly and independently correlated with a favorable response to GTX. DISCUSSION: GTX can be used to successfully treat bacterial as well as fungal infections in severely neutropenic patients when administered early after the onset of febrile neutropenia in patients with remission of the underlying disease and who are likely to recover marrow function.

Adult↗
PubMed2002

Preponderance of methylenetetrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, a common mutation of the gene encoding the enzyme that catalyzes reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a carbon donor in the metabolism of folate, determines a striking reduction in the enzyme activity in carriers of mutation at homozygous status. PATIENTS AND METHODS: We retrospectively analyzed the incidence of MTHFR C677T and the influence of genotype on methotrexate (MTX) toxicity in patients with acute leukemia undergoing maintenance chemotherapy. Seventy-eight patients were analyzed and 61 were evaluable for toxicity. MTX toxicity was assessed on bone marrow, liver and mucosae. RESULTS: The incidence of the C677T mutation was as expected in the general Italian population with 23.08% of patients being TT, 38.46% of patients CT and 38.46% of patients CC. The TT genotype was significantly associated with an increase of toxicity during MTX administration. No specific pattern of toxicity was detected, although in TT patients myelosuppression and liver toxicity were more pronounced. CONCLUSIONS: TT genotype may indicate a need to reduce the dose of MTX during prolonged administration. Considering the high prevalence of homozygous individuals in the Italian population, pretreatment screening may be worthwhile.

Adolescent↗
PubMed2001

Control of oocyte recruitment: regulative role of follicle cells through the release of a diffusible factor.

To determine whether oogonial proliferation and oocyte recruitment are under control of hypophyseal and/or ovarian factors, we carried out a series of investigations using Podarcis sicula, a lizard inhabiting the temperate lowlands of Europe in which oocyte recruitment occurs throughout the year, as animal model. Germinal beds containing oogonia and oocytes in prefollicular stages were cocultured with different ovarian compartments in presence/absence of FSH, and the effects of different treatments were evaluated by counting the number of prelepto-leptotene oocytes. Results revealed that oocyte recruitment from the pool of oogonia is under the control of a factor released by follicle cells while FSH has an indirect effect on modulating oogonial proliferation. SDS-PAGE analyses carried out on media conditioned by follicles suggest that the factor involved in the control of oocyte recruitment may be a small protein (about 21 kDa) and that its release is dependent on the period of the ovarian cycle but apparently not on the circulating levels of FSH.

Animals↗
PubMed2001

Molecular and clinical follow-up after stem cell transplantation for multiple myeloma.

Molecular follow-up has been carried out using immunoglobulin heavy-chain (IgH) gene finger-printing, a polymerase chain reaction (PCR)-based technique with a sensitivity of 0.1-0.01% (10(-3)-10(-4)), in 22 patients affected by multiple myeloma and submitted to stem cell transplantation (SCT). Twelve patients were submitted to either single or double autologous unselected peripheral blood progenitor cell transplantation, eight patients were submitted to autologous CD34+ immunoselected transplantation and two patients were submitted to allogeneic bone marrow (one patient) or peripheral blood CD34+ stem cell (one patient) transplantation. At diagnosis, all patients showed clonal CDIII rearrangement. The molecular analysis performed on leukapheresis products and CD34+ purified fractions proved to be contaminated by myeloma cells. During follow-up after autografting, all but one patient retained clonal rearrangement despite clinical complete remission (CR) in ten of them. These ten patients either relapsed (Rel) or showed progressive disease (PD) after transplantation; four of them died. Only one patient did not retain clonal rearrangement after autologous transplantation; she is currently alive in CR after a follow-up of 100 months. One patient submitted to allogeneic transplantation is currently alive with no evidence of the disease, but still retains clonal rearrangement after a follow-up of 47 months. Another patient died 4 months after transplantation after succumbing to fatal pneumonia showing myeloma progression.

Adult↗
PubMed2001

T-cell apoptosis induced by granulocyte colony-stimulating factor is associated with retinoblastoma protein phosphorylation and reduced expression of cyclin-dependent kinase inhibitors.

Peripheral blood progenitor cells (PBPC) mobilized by granulocyte colony-stimulating factor (G-CSF) promptly engraft allogeneic recipients after myeloablative chemotherapy for hematologic malignancies. Surprisingly, no exacerbation of acute graft-vs-host disease has been observed despite a 10-fold higher T-cell content in PBPC compared with bone marrow allografts. Because G-CSF can suppress T-cell proliferation in response to mitogens and enhance their activation-induced apoptosis, we examined the molecular mechanisms underlying G-CSF-induced immune dysfunction. Normal allogeneic lymphocytes were challenged with phytohemagglutinin in the presence of serum collected after G-CSF administration (postG) to healthy PBPC donors, and the expression of key components of the cell cycle and apoptotic machineries was investigated by flow cytometry and Western blotting. Lymphocyte stimulation was associated with collapse of mitochondrial transmembrane potential, hypergeneration of reactive oxygen intermediates, and activation of caspase-3 and DNA fragmentation. Lymphocytes were arrested in a G(1)-like phase of the cell cycle, as measured by G(1)-phase cyclin expression and bromodeoxyuridine (BrdUrd) incorporation. Cell tracking experiments confirmed the occurrence of a lower number of population doublings in postG compared with preG cultures. Unexpectedly, the phosphorylation state of the protein encoded by the retinoblastoma susceptibility gene (pRB) was unaltered in postG cultures, and the inhibition of cell cycle progression occurred without the recruitment of the cyclin-dependent kinase inhibitors p15(INK4B), p16(INK4A), and p27(Kip1). We eventually evaluated the ability of antioxidant/cytoprotectant agents to prevent the G-CSF-induced mitochondrial dysfunction and inhibition of cell cycle progression. Of interest, both N-acetylcysteine and amifostine reduced apoptotic cell death by 45% on average, inhibited the activation/processing of caspase-3, and increased BrdUrd incorporation in postG cultures. Based on these experimental findings, a model is proposed in which T-cell activation in the presence of serum immunoregulatory factor(s) induced by G-CSF is associated with a molecular phenotype mimicking the G(1)-S transition and consisting of pRB phosphorylation, lack of CDKI recruitment, and reduced cyclin-E expression. The putative relationship between lymphocyte mitogenic unresponsiveness and apoptosis induction would occur at the level of key molecules shared by the cell cycle and apoptotic machineries. Whether the G-CSF-mediated modulation of lymphocyte functions in vitro is beneficial in transplantation medicine remains to be determined.

Acetylcysteine↗
PubMed2001

Clonal hemopoiesis and risk of thrombosis in young female patients with essential thrombocythemia.

OBJECTIVE: Several studies demonstrated a high prevalence of nonrandom X-chromosome inactivation pattern (X-CIP) in essential thrombocythemia (ET). This study explored the incidence of clonal hemopoiesis in myeloid precursors and endogenous erythroid colonies (EECs) in ET patients and its correlation with thrombotic manifestations. MATERIALS AND METHODS: Clonal analysis of hemopoiesis using X-CIP was performed in 40 female patients with ET. Median age was 40.5 years (range 20-64), and median platelet count at testing time was 700 x 10(9)/L (range 220-1300 x 10(9)/L). Patients older than 65 years were excluded to reduce age-related skewing. Clonality was assessed on neutrophils, platelets, EECs, and bone marrow CD34(+) cells. RESULTS: Eight (20%) of 40 patients developed thrombosis mainly at diagnosis. Clonal hemopoiesis was found in 17 (42.5%) patients, 15 (37.5%) had polyclonal hemopoiesis, and 8 (20%) were considered uninterpretable due to constitutive skewing. Clonality was confirmed on purified CD34(+) subpopulations from bone marrow, documenting that clonality does not appear lineage-restricted. There were no statistical differences in age at diagnosis, median platelet count at testing time, and length of follow-up. Thrombotic episodes were significantly more frequent in the monoclonal group (p = 0.04, Fisher exact test). CONCLUSIONS: Young female patients with ET exhibiting a clonal pattern of hemopoiesis by X-CIP analysis are at higher risk for thrombosis. X-CIP analysis may contribute to defining the individual risk leading to appropriate treatment. X-CIP will allow a correct diagnosis in patients with latent myeloproliferative disorders and thrombosis in unusual sites. Clonal hemopoiesis is easily recognized by X-CIP, but its applicability is limited to the female sex and is hampered by the presence of age-related or constitutive skewing.

Adult↗