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Biomedical subjects

Luca Laurenti

Publications and source records attributed to Luca Laurenti.

At least 19 recordsLinked to original sources
PubMed2007

Comprehensive characterization of IGHV3-21-expressing B-cell chronic lymphocytic leukemia: an Italian multicenter study.

IGHV3-21-using chronic lymphocytic leukemia (CLL) is a distinct entity with restricted immunoglobulin gene features and poor prognosis and is more frequently encountered in Northern than Southern Europe. To further investigate this subset and its geographic distribution in the context of a country (Italy) with both continental and Mediterranean areas, 37 IGHV3-21 CLLs were collected out of 1076 cases enrolled by different institutions from Northern or Central Southern Italy. Of the 37 cases, 18 were identified as homologous (hom)HCDR3-IGHV3-21 CLLs and were found almost exclusively (16 of 18) in Northern Italy; in contrast, 19 nonhomHCDR3-IGHV3-21 cases were evenly distributed throughout Italy. Clinically, poor survivals were documented for IGHV3-21 CLLs as well as for subgroups of mutated and homHCDR3-IGHV3-21 CLLs. Negative prognosticators CD38, ZAP-70, CD49d, and CD79b were expressed at higher levels in homHCDR3 than nonhomHCDR3-IGHV3-21 cases. Differential gene expression profiling (GEP) of 13 IGHV3-21 versus 52 non-IGHV3-21 CLLs identified, among 122 best-correlated genes, TGFB2 and VIPR1 as down- and up-regulated in IGHV3-21 CLL cases, respectively. Moreover, GEP of 7 homHCDR3 versus 6 nonhomHCDR3-IGHV3-21 CLLs yielded 20 differentially expressed genes, with WNT-16 being that expressed at the highest levels in homHCDR3-IGHV3-21 CLLs. Altogether, IGHV3-21 CLLs, including those with homHCDR3, had a peculiar global phenotype in part explaining their worse clinical outcome.

Amino Acid Sequence↗
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

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

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

Immunophenotypic characterization of IgVH3-72 B-cell chronic lymphocytic leukaemia (B-CLL).

The frequent expression of the otherwise rare IgVH3-72 gene was demonstrated in highly stable B-cell chronic lymphocytic leukaemias (B-CLLs). Here we describe the immunophenotypic profiles of eleven IgVH3-72 B-CLLs, by investigating expression of ZAP-70 and of a set of surface antigens previously demonstrated to represent the signature of distinct B-CLL prognostic groups. All IgVH3-72 B-CLLs revealed a homogeneous immunophenotypic profile, expressing all the markers associated with good prognosis, but not those representing the signature of bad prognosis B-CLLs, including ZAP-70. Our results corroborate the notion that IgVH3-72 B-CLLs represent a molecularly and immunophenotypically homogeneous disease group with a good prognosis.

Aged↗
PubMed2006

Rituximab therapy for chronic lymphocytic leukemia-associated autoimmune hemolytic anemia.

Autoimmune hemolytic anemia (AIHA) is a well-known complication of chronic lymphocytic leukemia (CLL). In recent years the anti-CD20 monoclonal antibody rituximab has been used for the therapy of steroid-refractory AIHA and autoimmune thrombocytopenia, either idiopathic or in association with CLL. We report the results of rituximab treatment for 14 patients suffering from CLL-associated AIHA. They developed a direct antiglobulin test positive AIHA at a mean time of 47 months (range 0-135 months) from the diagnosis of CLL. In 3 cases AIHA was diagnosed at the same time as CLL. Only 1 patient had fludarabine-related AIHA. All patients received steroids as first-line treatment. At a mean time of 46 days (range 1-210 days) from the diagnosis of AIHA all patients received rituximab at a dosage of 375 mg/m(2)/weekly for 4 weeks. All patients except 3 (2 died of cardiac failure or sepsis soon after the third cycle and 1 HCV-positive patient experienced a rise in serum amino transferases) completed the scheduled four programmed cycles. First injection side effects of rituximab were minimal. All but 2 patients showed an increase in hemoglobin levels in response to rituximab (mean value 3.6 g/dl; range 0.7-10 g/dl) and a reduction in the absolute lymphocyte count and lymph nodes and spleen volume. Nine patients required packed red cell transfusions before starting rituximab; 5 no longer needed transfusions just after the second cycle and another patient after the fourth cycle. Three patients (22%) were considered to fully respond and 7 (50%) only responded partially. At a mean follow-up of 17 months, 8 patients were still alive, 6 of them transfusion-free. Our results prove that the anti-CD20 monoclonal antibody is an effective and well-tolerated alternative treatment for CLL-associated AIHA.

Aged↗
PubMed2006

Relationship between autoimmune phenomena and disease stage and therapy in B-cell chronic lymphocytic leukemia.

The aim of this multicenter GIMEMA study was to correlate autoimmune complications (AIC) in B-cell chronic lymphocytic leukemia (B-CLL) with stage and therapy. Autoimmune hemolytic anemia (129/194 cases) and autoimmune thrombocytopenia (35/194 cases) were typically present in advanced and multi-treated disease. Age over the median, stage C and first and second line therapy were identified as independent risk factors by multivariate analysis. In contrast, non-hematologic AIC (30/194 cases) and the presence of serological markers of autoimmunity were mostly observed in early B-CLL, suggesting different pathogenic mechanisms underlying hematologic and non-hematologic autoimmune phenomena in B-CLL.

Aged↗
PubMed2005

Sustained signaling through the B-cell receptor induces Mcl-1 and promotes survival of chronic lymphocytic leukemia B cells.

The clinical course of chronic lymphocytic leukemia (CLL) differs significantly between patients with mutated (M-CLL) and unmutated (U-CLL) immunoglobulin (Ig) variable heavy-chain (V(H)) genes, implying a role for B-cell receptor (BCR) signaling in the pathogenesis of this disease. We have now investigated activation of downstream BCR signaling pathways in U-CLL and M-CLL B cells using soluble anti-IgM (sol-IgM) and immobilized anti-IgM (imm-IgM) antibodies as models for antigenic stimulation. Ligation of the BCR with sol-IgM induced incomplete responses in both CLL subsets, resembling the pattern described for tolerant B cells. This response was characterized by transient phosphorylation of extracellular signal-related kinase (ERK) and Akt (protein kinase B [PKB]), lack of activation of c-JUN NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), and variable activation of phospholipase Cgamma2 (PLCgamma2) and nuclear factor-kappaB (NF-kappaB). Stimulation with imm-IgM elicited a more complete BCR signal and significantly prolonged phosphorylation of ERK and Akt, indicating persistent or repetitive BCR signaling. Moreover, this type of stimulation increased the levels of the antiapoptotic protein myeloid cell leukemia-1 (Mcl-1) and protected from chemotherapy-induced apoptosis, whereas induction of apoptosis and down-regulation of Mcl-1 was observed following stimulation with sol-IgM. These data demonstrate that only sustained BCR signaling can promote survival of CLL B cells and indicate that the main difference between CLL with mutated and unmutated V(H) genes may reside in the availability of such stimulation.

Apoptosis↗
PubMed2005

Positive selection of cytotoxic T lymphocyte escape variants during acute hepatitis C virus infection.

Cellular immune responses are induced during hepatitis C virus (HCV) infection and acute-phase CD8+ T cells are supposed to play an important role in controlling viral replication. In chimpanzees, failure of CD8+ T cells to control HCV replication has been associated with acquisition of mutations in MHC class I-restricted epitopes. In humans, although selection of escape mutations in an immunodominant CTL epitope has been recently described, the overall impact of immune escape during acute HCV infection is unclear. Here, by performing an in depth analysis of the relationship between early cellular immune responses and viral evolution in a chronically evolving HCV acutely infected individual, we demonstrate: (i) the presence of a potent and focused CD8(+ T cell response against a novel epitope in the NS3 protein, (ii) the elimination of the quasi-species harboring the original amino acid sequence within this epitope, and (iii) the selection for a virus population bearing amino acid changes at a single residue within the cytotoxic T cell epitope that strongly diminished T cell recognition. These results support the view that acute-phase CD8+ T cell responses exert a biologically relevant pressure on HCV replication and that viruses escaping this host response could have a significant survival advantage.

Adult↗
PubMed2005

Low-dose intravenous alemtuzumab therapy in pretreated patients affected by chronic lymphocytic leukemia. A single center experience.

We report the efficacy and safety of intravenous low-dose alemtuzumab (10 mg three times weekly for 10 weeks) in 12 patients with relapsed or refractory chronic lymphocytic leukemia. Low-dose alemtuzumab induced significant responses in these patients (16% complete remission, 25% partial remission), with mild hematologic and extrahematologic side effects and a low rate of infections, even in the presence of long-lasting severe immunosuppression.

Aged↗
PubMed2005

Comparison of ZAP-70/Syk mRNA levels with immunoglobulin heavy-chain gene mutation status and disease progression in chronic lymphocytic leukemia.

BACKGROUND AND OBJECTIVES: The protein tyrosine kinase ZAP-70 has recently emerged as a major prognostic indicator in chronic lymphocytic leukemia (CLL). ZAP-70 is structurally and functionally homologous to Syk, a key mediator of B-cell receptor signaling. We therefore evaluated ZAP-70 expression in CLL B cells using Syk as an intracellular standard. DESIGN AND METHODS: The relative amounts of ZAP-70 and Syk were determined in purified B cells from 92 CLL patients using a novel reverse transcriptase/polymerase chain reaction (RT-PCR) procedure that co-amplifies both transcripts with equal efficiency. The ZAP-70/Syk mRNA ratio was correlated with VH gene mutation status, median treatment-free survival and FACS analysis of ZAP-70 expression. RESULTS: ZAP-70 was expressed in the majority of cases with unmutated VH genes (88%), but also at lower levels in a substantial fraction of cases with mutated VH genes (44%). High levels of ZAP-70, defined as ZAP-70/Syk mRNA ratios above 0.25, were observed mainly in cases with unmutated VH genes and correlated with short treatment-free survival. In contrast, no difference was observed in the median treatment-free survival between patients with low ZAP-70/Syk ratios (0.05-0.25) and patients with no or negligible ZAP-70 expression (ZAP-70/Syk<0.05). In 73 cases ZAP-70 expression was investigated by RT/PCR and FACS analysis; concordance with VH gene mutation status was 86% and 71%, respectively. INTERPRETATION AND CONCLUSIONS: ZAP-70 is frequently expressed in CLL B cells, but only high levels correlate with unmutated VH gene status and progressive disease. Expression of ZAP-70 can be accurately assessed by analysis of the ZAP-70/Syk mRNA ratio, thus providing an alternative to FACS analysis.

Adult↗
PubMed2004

Hormonal replacement therapy after stem cell transplantation.

OBJECTIVE: To evaluate HRT compliance and efficacy in the treatment of symptomatic ovarian failure in pre-menopausal women after stem cell transplantation (SCT) for malignancies. METHODS: Thirty-one females were selected and prospectively followed in a university bone marrow transplantation unit and gynecologic outpatient clinic in a university teaching hospital. The patients received regular gynecological examinations, hormonal assessment every 6 months including plasma levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), 17-beta estradiol (E2), and transvaginal pelvic ultrasonography, mammography, and computerized bone mineralometry every 12 months. Self-assessment form of menopausal symptoms perception was filled in by all patients before HRT and during the observation period. RESULTS: All patients developed gonadal failure after SCT. The menopausal symptoms more frequently reported were: vasomotor (90%), muscleskeletal symptoms (61%), vulvo-vaginal atrophy (54%), and mood changes (54%). Fifteen premenopausal women out of 31 (51.6%) received systemic HRT on the basis of age (<45 years), absence of medical contraindication or subjective refusal, and complete remission of underlying malignancies post-SCT. The remaining patients (48.4%) did not receive HRT mainly for patient's refusal (29%), relapse of malignancy (13%) or liver toxicity (9.6%). HRT was effective in HRT treated patients promptly relieving unpleasant symptoms of gonadal failure. HRT was tolerated without minimal complications or serious side effects. CONCLUSIONS: Dramatic improvement in menopausal symptoms was observed in women on HRT although treatment was feasible only in nearly half of the patients. HRT alleviates unnecessary discomfort and improves the well-being of female patients post-transplant also by preventing menopause related complications. Feasibility and patients' compliance of HRT should be carefully evaluated in long-term survivors after stem cell transplantation.

Adult↗
PubMed2004

Immune recovery of lymphocyte subsets 6 years after autologous peripheral blood stem cell transplantation (PBSCT) for lymphoproliferative diseases. A comparison between NHL, HD and MM in group of 149 patients.

To evaluate the normalization of lymphocyte subsets several years after autologous peripheral blood stem cell transplantation (aPBSCT) and to detect any differences based on the underlying lymphoproliferative diseases, we analyzed the immunological recovery of 149 patients with Non Hodgkin's Lymphoma (NHL), Hodgkin's Disease (HD), Multiple Myeloma (MM). Lymphocyte recovery was assessed before the transplant, on days 15, 30, 60, 90, 120 and on years 1, 2, 4, 6. Analysis of a total of 709 lymphocytes, including total lymphocyte count, CD3 +, CD4 +, CD8 +, CD4 +/CD8 + ratio, CD19 +, CD3 + HLA-DR +, CD16 + 56 +, was performed. The normalization of total lymphocyte counts was achieved between days 14 to 22 following PBSCT. CD3 + cells count showed a normalization after 2 years in the HD and NHL groups and after 4 years in MM group. CD4 + subset achieved normalization during the sixth year in the 3 groups. The CD8 + and CD19 + lymphocytes subsets achieved normal values in the 3 groups at day 60 and at day 120 respectively. CD16 + 56 + and CD3 +/HLA-DR + lymphocytes showed median values above the normal range starting from day 30. Immunological recovery was similar in all 3 groups. Moreover, the recovery of all subsets evaluated was similarly demonstrated within 6 years after aPBSCT.

Adolescent↗
PubMed2004

Production of interferon-gamma by lymphocytes from paroxysmal nocturnal haemoglobinuria patients: relationship with clinical status.

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by the expansion of phosphatidylinositol glycan class A (PIG-A) defective haematopoietic cells, probably due to the immune-mediated alterations of the bone marrow environment selecting PIG-A- stem cells. The present study investigated the presence of alterations of the immune system in a population of 11 PNH patients. The production of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), evaluated by intracellular cytokine analysis, and the frequencies of class I and II human leucocyte antigen (HLA) alleles were studied in comparison with healthy human subjects. Similar percentages of lymphocytes produced cytokines in PNH patients and controls after costimulation-independent activation; however, a negative correlation was found between the percentage of IFN-gamma producing cells and white cell or platelets counts. PNH patients showed an higher percentage, compared with controls, of IFN-gamma producing cells after costimulation-dependent activation. The frequency of HLA-A31 was higher in patients than in controls (27.2% vs. 4%), similarly to that of HLA-B7 (27.2% vs. 6%). With regard to class II alleles, 18% of PNH patients expressed DQB1*04 compared with none of 50 control cases. This study supports the hypothesis that immune alteration are present in PNH and that the immunogenetic background could influence the development of the disease.

Adult↗