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G Gaidano

Publications and source records attributed to G Gaidano.

At least 91 records · Page 5Linked to original sources
PubMed1997

High CD40 membrane expression in AIDS-related lymphoma B cell lines is associated with the CD45RA+, CD45RO+, CD95+ phenotype and high levels of its soluble form in culture supernatants.

CD40 is a membrane glycoprotein expressed on normal and neoplastic B lymphocytes. Stimulation through CD40 regulates important cellular functions, but the effects depend on its membrane density. While extensive studies have characterized CD40 in non-Hodgkin lymphomas of immunocompetent individuals, little is known on the characteristics of this molecule in lymphomas arising in immunocompromised hosts. The aim of this study was to characterize the pattern of CD40 expression in an in vitro model constituted by AIDS small non-cleaved lymphoma (SNCCL) cell lines. The analysis of CD45 isoforms, a group of molecules alternatively spliced during B cell differentiation, has been chosen to correlate this process to the number of CD40 molecules per cell in these cell lines. Since Apo 1/Fas expression is upregulated on B lymphocytes after CD40 ligation and this expression is functionally relevant, we wanted to know whether a different CD40 pattern in AIDS-SNCCL cell lines could influence CD95 expression. We have shown that 3 of these cell lines (PA 682, Es III, and HBL-2) have high membrane CD40 expression (> 100,000 molecules/cell); they release large amounts of soluble CD40 (sCD40) in culture supernatants (>500 pg/ml), are CD45RA/RO double labelled, and express the Apo 1/Fas (CD95) antigen. On the contrary, low CD40 membrane antigen cell lines (BRGIgA, HBL-2, NC 71, AS 283A, and LAM C3+, < 50,000 molecules/cell) release low amounts of sCD40 (<300 pg/ml), are CD45RA+ but CD45RO-, and do not express CD95. EBV has no role in CD40 and CD45 isoform behaviour, because EBV superinfection of the EBV negative, low membrane CD40 HBL-2 cell line does not modify CD40 membrane expression, sCD40 production, or CD45 isoform and CD95 expression. Our data suggest that membrane CD40 in AIDS-SNCCL cell lines might be a key element in the regulation of their pathophysiology by influencing the expression of CD45 isoforms and of CD95, and by the release of its soluble form.

Antigens, CD↗
PubMed1997

Microsatellite instability is rare in B-cell non-Hodgkin's lymphomas.

Microsatellite instability (MSI), a symptom of defect in DNA mismatch repair function, represents a type of genomic instability frequently detected in many types of cancers. However, the involvement of MSI in non-Hodgkin's lymphomas (NHL) has not been conclusively investigated. In this study, we have tested the presence of MSI in 69 cases of B-cell NHL (B-NHL) representative of the various histologic categories of the disease and including 17 cases of acquired immunodeficiency syndrome (AIDS)-related B-NHL (AIDS-NHL). In addition, for selected B-NHL cases, consecutive samples obtained before and after clinical progression (with and without concomitant histologic transformation) were also investigated. Five distinct microsatellite repeats (2 dinucleotide, 2 trinucleotide, and 1 tetranucleotide repeats) were analyzed by polymerase chain reaction in all cases. MSI, defined by the presence of microsatellite alterations in two or more of the five microsatellite loci tested, was not found in NHL. In contrast to a previous study reporting the frequent association between MSI and AIDS-NHL, we found this abnormality in only 1 of 17 cases of AIDS-NHL representative of the major subtypes. Overall, these data indicate that defects in DNA mismatch repair do not contribute significantly to the molecular pathogenesis of B-NHL.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Detection of BCL-6 rearrangements and p53 mutations in Malt-lymphomas.

Twenty-seven lymphomas of mucosa-associated lymphoid tissue (MALT) derived from distinct anatomical sites were tested for the presence of genetic lesions commonly involved in B-cell lymphomagenesis, including activation of proto-oncogenes (BCL-1, BCL-2, BCL-6, and c-MYC), disruption of tumor suppressor loci (p53, 6q), and infection by viruses [Epstein-Barr virus (EBV), and Kaposi's sarcoma-herpesvirus/human herpesvirus-8 (KSHV/HHV-8)]. Sixteen low-grade and 11 high-grade MALT-lymphomas were included in the study. The presence of genetic lesions was tested by a combination of molecular approaches, including Southern blot hybridization, polymerase chain reaction (PCR), and PCR-single strand conformation polymorphism followed by DNA direct sequencing. Alterations of BCL-1, BCL-2, or c-MYC, as well as infection by KSHV/HHV-8, scored negative in all MALT-lymphomas analysed. Conversely, rearrangements of BCL-6 and mutations of p53 clustered with a fraction of high-grade MALT-lymphomas. Deletions of 6q occurred in selected cases of both low- and high-grade MALT-lymphomas, whereas a monoclonal infection by EBV was restricted to one single patient. These data corroborate the notion that the molecular pathogenesis of MALT-lymphomas differs substantially from that of nodal B-cell lymphomas. Occasionally, however, a proportion of high-grade MALT-lymphomas may harbor selected genetic lesions among the ones commonly involved in nodal B-cell lymphomagenesis.

Blotting, Southern↗
PubMed1997

Pathological and immunophenotypic features of adult non-Hodgkin's lymphomas by age group.

To elucidate age-related differences in non-Hodgkin's lymphoma (NHL), the authors evaluated 950 consecutive, human immunodeficiency virus-negative patients (age range, 15 to 96 years) observed between July 1988 and June 1995 in the same Italian cancer institute. Patients were grouped into six age groups and cross-tabulated by Working Formulation (WF) categories and other newly recognized entities according to the Revised European American Lymphoma (REAL) classification, cell immunophenotype, and nodal or extranodal location. There was a tendency of the low-grade category to increase with increasing age (16.8% in the age group 15 to 34 years to 32.4% in the age group 65 to 74 years), although a subsequent decline was seen at age 75 years or older (23.2%). Also the intermediate-grade category was more frequent in the elderly (46.6% and 49.4% at 65 to 74 years and at 75 years or older, respectively). High-grade category showed compared with low and intermediate grade ones, a significant downward trend with age (X2 for trend = 25.31; P < .001), interrupted in only the oldest age group. The relative excess of low-grade NHL in patients older than 55 years. of age was accounted for by the high proportion of small lymphocytic lymphomas, which, however, somewhat declined at age 75 years or older. Conversely, the relative excess of high-grade NHL below age 35 years chiefly derived from the high percentage (28.4%) of CD30-positive anaplastic large cell lymphomas. B- and T-cell lymphomas accounted for 85.9% and 9.0% of all cases, respectively. B- and T- and non-B, non-T-cell and histiocytic NHL accounted for the remaining 5.1%. A highly significant trend of increase in the proportion of B-cell lymphomas with age increase was noted (X2 for trend = 21.90; P < .001); chiefly attributable to the excess of T-cell (15.1%) and undetermined phenotype (18.6%) in patients younger than 35 years of age. Extranodal location was not significantly related to age groups. Thus, the present study showed some interesting differences in NHL morphology and cell phenotype according to age, avoiding, at the same time, the arbitrariness of patients' dichotomization into elderly and nonelderly.

Adolescent↗
PubMed1997

Microsatellite instability in KSHV/HHV-8 positive body-cavity-based lymphoma.

Body-cavity-based lymphoma (BCBL) is a rare non-Hodgkin-'s lymphoma (NHL) type growing in liquid phase in the body cavities. Virtually all BCBL associate with Kaposi's sarcoma-associated herpesvirus/human herpesvirus type-8 infection in the absence of molecular alterations typical of other NHL categories. Microsatellite instability (MSI), a specific variant of genomic instability frequently associated with human cancers, has not been tested in BCBL thus far. In this report, we have analyzed the presence of MSI in the tumor cells of a male patient affected by AIDS-related BCBL. The genomic configuration of 12 distinct microsatellite loci was investigated by polymerase chain reaction amplification of DNA obtained from the patient's tumor cells and from autologous peripheral blood mononuclear cells. MSI was observed at 4/12 microsatellite repeats tested. Absence of the germline allele at one microsatellite locus mapping to chromosome X indicates that, in this BCBL case, MSI represents a clonal genetic lesion affecting virtually all tumor cells. These data suggest that MSI may be potentially involved in the pathogenesis of AIDS-related BCBL.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Intraclonal molecular heterogeneity suggests a hierarchy of pathogenetic events in Burkitt's lymphoma.

BACKGROUND: Burkitt's lymphoma is a B-cell neoplasm characterized by a chromosomal translocation involving the c-myc gene. BL may carry, besides the c-myc translocation, several other lesions including a) mutations in c-myc, b) mutations in bcl-6, c) mutations in p53 and d) EBV genomes. In this report we describe a unique study of the timing of these genetic lesions during the evolution and progression of Burkitt's lymphoma. MATERIALS AND METHODS: From each of two patients with Burkitt's lymphoma, we established three different cell lines from different sites or at different times in the clinical course of the disease (diagnosis and relapse). Chromosomal aberrations were analyzed by karyotyping and the presence of molecular lesions determined by Southern blot, PCR, SSCP and sequence analyses. RESULTS: In each patient all the clones carry identical c-myc translocations, identical bcl-6 status (wild type or mutant) and the same productive VDJ rearrangement. However, within each individual patient, we could demonstrate the presence of intraclonal variation with respect to EBV, p53 mutations and c-myc mutations. CONCLUSIONS: c-myc translocation and bcl-6 mutations appear to be early events, mutations in the coding region of c-myc occur early but are an ongoing event, while mutations in the p53 gene seem to occur later. Discrete clonal bands reflecting independent EBV infection were observed in the cell lines from one HIV-associated Burkitt's lymphoma, suggesting the possibility that EBV infection may occur as a late event, at least in some HIV associated lymphomas.

Adult↗
PubMed1997

Genetic heterogeneity of AIDS-related small non-cleaved cell lymphoma.

AIDS-related small noncleaved cell lymphoma (AIDS-SNCCL) includes Burkitt's lymphoma (BL) and high-grade B-cell Burkitt-like lymphoma (BLL). Due to the marked polymorphism of AIDS-related non-Hodgkin's lymphomas (AIDS-NHL), the morphologic distinction between these two types of lymphomas is frequently controversial, although it may bear clinical relevance. Although the molecular features of AIDS-BL have been clarified to a certain extent, the genetic peculiarities of AIDS-BLL have not been investigated in detail. In this study we have compared morphologic and genetic features of AIDS-BL and AIDS-BLL in a blind coded fashion. Molecular studies were focused on the genetic lesions known to be implicated in AIDS-NHL, including alterations of c-MYC, BCL-6, p53, deletions of 6q, as well as infection by EBV and HHV-8. Alterations of c-MYC occurred in 10/10 AIDS-BL, whereas they were restricted to 2/10 AIDS-BLL (P < 0.01). Mutations of p53 were present in 5/10 AIDS-BL, whereas they were consistently absent among AIDS-BLL (n = 10; P < 0.05). Infection by EBV occurred in 30% of both AIDS-BL and AIDS-BLL. Rearrangements of BCL-6, deletions of 6q and infection by HHV-8 scored consistently negative in both AIDS-BL and AIDS-BLL. Based on the genetic lesions tested, the molecular profile of AIDS-BLL appears to be closer to that of AIDS-related diffuse large cell lymphoma (AIDS-DLCL) than to that of AIDS-BL. In contrast to AIDS-BLL however, AIDS-DLCL carried rearrangements of BCL-6 in a fraction of cases (2/9). This study, the largest of its kind reported so far, suggests that AIDS-BL and AIDS-BLL have a different molecular pathogenesis and that characterization of genetic lesions may help to distinguish between these two lymphomas.

Blotting, Southern↗
PubMed1997

Point mutations of the BCL-6 gene in Burkitt's lymphoma.

BCL-6 codes for a transcription factor implicated in chromosomal translocations of diffuse large cell lymphomas. Recent evidence indicates that BCL-6 may also be altered by mutations of its 5' non-coding regions. In this study we have investigated the distribution of BCL-6 5' mutations among 35 Burkitt's lymphoma cases representative of the epidemiologic variants of the disease. Mutations were detected in 6/21 (28.6%) sporadic Burkitt's lymphomas and 7/14 (50%) endemic Burkitt's lymphomas. These data expand the spectrum of B-cell non-Hodgkin's lymphomas associated with BCL-6 5' mutations and have implications for the pathogenesis, histogenesis and clinical monitoring of Burkitt's lymphoma.

Burkitt Lymphoma↗
PubMed1997

Multigenetic lesions in infant acute leukaemias: correlations with ALL-1 gene status.

In this study we investigated the presence of structural lesions in the ALL-1, p53 and p16 (cyclin-dependent kinase 4 inhibitor) genes in leukaemic cells obtained from 22 patients with infant acute leukaemia (aged < 18 months). Of these, 18 cases were classified as acute lymphoblastic leukaemia (ALL) and four as acute myeloid leukaemia (AML). Tumour DNAs were analysed by a combination of Southern blot. polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP), and direct sequence analyses. The results showed ALL-1 gene rearrangements in 15/22 (68%) cases, p53 gene mutations in 5/22 (26%), and a homozygous deletion of p16 in a single T-ALL case. p53 and p16 alterations were all found in the group of patients with ALL-1 gene rearrangements. p53 mutations were more often associated with a myeloid phenotype (3/5). In summary, multiple molecular alterations were found in 6/15 (40%) infant acute leukaemias with ALL-1 rearrangements. As to the clinical course, patients with additional lesions had similar clinical outcome with respect to patients with ALL-1 gene rearrangement as the sole genetic aberration. This may support the hypothesis that ALL-1 alterations are genetic events per se sufficient to confer a fully malignant phenotype to the leukaemic clone.

Acute Disease↗
PubMed1997

Analysis of human herpesvirus type 8 infection in AIDS-related and AIDS-unrelated primary central nervous system lymphoma.

Human herpesvirus type 8 (HHV-8) has been proposed as a pathogenetic factor for immunosuppression-associated primary central nervous system lymphoma (PCNSL). To verify this hypothesis, HHV-8 infection was investigated in 31 persons with PCNSL (16 AIDS-related, 15 AIDS-unrelated) and in 30 persons with systemic B cell non-Hodgkin's lymphomas (B-NHL; 15 AIDS-related, 15 AIDS-unrelated). All subjects with PCNSL scored negative by single-step polymerase chain reaction (PCR), suggesting a tumor virus load of <100 viral copies/200,000 human haploid genome equivalents (HHGE). By applying Poisson assumptions to nested PCR, 16 of 31 persons with PCNSL were devoid of HHV-8 sequences: 1 subject with AIDS and PCNSL had 1-100 viral copies/200,000 HHGE, and 14 with PCNSL had <1 viral copy/200,000 HHGE. Similarly, 10 of 30 persons with systemic B-NHL were devoid of HHV-8 sequences; 20 had <1 viral copy/200,000 HHGE. The extremely low levels of infection rule out a role of HHV-8 in PCNSL pathogenesis and are consistent with HHV-8 infection of bystander cells contaminating the tumor clone.

AIDS-Related Opportunistic Infections↗
PubMed1997

HIV-associated human herpesvirus 8-positive primary lymphomatous effusions: radiologic findings in six patients.

PURPOSE: To define the imaging features of body cavity-based lymphoma (BCBL) related to the acquired immunodeficiency syndrome. This is a peculiar type of non-Hodgkin lymphoma harboring infection by human herpesvirus 8 (HHV-8) and displaying a peculiar tropism for the serous body cavities. MATERIALS AND METHODS: At diagnosis of BCBL, six consecutive patients were investigated with radiography of the chest and conventional computed tomography (CT) of the chest and abdomen. For all patients, clinical features and results of biologic characterization of the lymphoma were also available. RESULTS: In all patients, chest radiographs displayed bilateral or unilateral pleural effusion in the absence of parenchymal opacities or mediastinal enlargement. CT scans confirmed chest radiographic findings and revealed a slight thickening of the parietal pleura in all patients and a pericardial thickening in four patients. CT also depicted pericardial and abdominal effusions in five and two patients, respectively, in the absence of solid tumor masses or parenchymal abnormalities. CONCLUSION: BCBL must be included among the differential diagnoses of serous effusions detected radiologically in individuals infected with the human immunodeficiency virus (HIV). Since the combination of serous effusion, slight serosal thickening, and absence of solid masses is compatible with, though not specific for, BCBL in the context of HIV infection, radiologic findings need to be complemented by a detailed biologic and virologic characterization of tumor cells.

Adult↗
PubMed1997

Human herpesvirus type-8 (HHV-8) in haematopoietic neoplasia.

Human herpesvirus type-8 (HHV-8) is a lymphotropic herpesvirus originally identified in Kaposi's sarcoma. Among lymphoproliferative disorders, HHV-8 infection is restricted to body-cavity-based lymphoma (BCBL) and multicentric Castleman's disease (MCD). BCBL are B-cell lymphomas growing in liquid phase in the body cavities and most frequently associated with AIDS. BCBL express indeterminate phenotypes, in all cases are associated with HHV-8 infection, and frequently carry Epstein-Barr virus genomes in the absence of c-MYC rearrangements or other genetic lesions characteristic of B-cell lymphomas. The clinical outcome of BCBL is poor with a median survival of only few months. MCD is an atypical lymphoproliferative disorder which displays marked vascular hyperplasia and is commonly associated with Kaposi's sarcoma. HHV-8 infection occurs in 100% of AIDS-related MCD and in approximately 40% of AIDS-unrelated cases. Overall, the consistency of HHV-8 infection in BCBL and MCD, its selectivity throughout the spectrum of lymphoproliferative disorders and the high copy number of HHV-8 DNA sequences in infected cells suggest that the virus plays a pathogenetic role in these disorders.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Molecular pathways in low grade B-cell lymphoma.

Low grade B-cell non-Hodgkin's lymphomas (B-NHL) represent a markedly heterogeneous group of lymphoproliferative disorders, including B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CCL/SLL), lymphoplasmacytoid lymphoma (LPL), follicular lymphoma (FL), mucosa-associated lymphoid tissue lymphoma (MALTL), and splenic lymphoma with villous lymphocytes (SLVL). The molecular pathogenesis of low grade B-NHL is characterized by distinct genetic pathways which selectively associate with each clinicopathologic category. At diagnosis, B-CLL/SLL frequently display deletions of 13q14 and trisomy 12, whereas evolution to Richter's syndrome associates with disruption of p53. LPL carries t(9;14)(p13;q32) in 40-50% of the cases, leading to the deregulated expression of the PAX-5 gene. FL consistently harbors rearrangements of BCL-2 independent of the cytologic variant. With time, a fraction of FL cases accumulates mutations of p53 and evolves into a high grade B-NHL. Low grade MALTL are characterized by the frequent occurrence of trisomy 3 and, occasionally, by p53 mutations. SLVL carries p53 mutations in a fraction of cases. The identification of distinct genetic categories among low grade B-NHL may help in the therapeutic stratification of these disorders. In addition, genetic lesions of low grade B-NHL have proved to be a useful molecular marker for monitoring minimal residual disease.

Antigens, CD↗
PubMed1997

BCL-6 protein expression in AIDS-related non-Hodgkin's lymphomas: inverse relationship with Epstein-Barr virus-encoded latent membrane protein-1 expression.

This study aimed at investigating the expression of the BCL-6 protein in acquired immune deficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (AIDS-NHLs) and at comparing the expression pattern with the presence of Epstein-Barr virus (EBV) infection of the tumor clone. A total of 34 AIDS-NHL biopsies, including 16 AIDS-related diffuse large-cell lymphomas (AIDS-DLCLs) and 18 AIDS-related small-noncleaved-cell lymphomas (AIDS-SNCCLs) as well as 7 AIDS-SNCCL cell lines were immunostained with a BCL-6-specific monoclonal antibody. Expression of BCL-6 protein was detected in 9 of 16 AIDS-DLCLs, 18 of 18 AIDS-SNCCLs, and 3 of 7 AIDS-SNCCL cell lines. Expression of BCL-6 among AIDS-NHLs occurred independently of the presence of molecular lesions of the bcl-6 gene. Notably, among EBV-positive AIDS-NHL biopsies and cell lines, expression of BCL-6 was mutually exclusive with the expression of EBV-encoded transforming antigen latent membrane protein-1. The mutual exclusion between BCL-6 and latent membrane protein-1 expression was further confirmed by in vitro superinfection experiments of an AIDS-SNCCL cell line originally devoid of EBV sequences. Overall, the frequent association between AIDS-NHLs and expression of BCL-6, a protein selectively expressed by germinal center B cells, suggests that these lymphomas may originate from the germinal center.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Involvement of the bcl-6 gene in AIDS-related lymphomas.

BACKGROUND: Non-Hodgkin's lymphoma (NHL) represents a major complication of AIDS. Systemic AIDS-related NHLs (AIDS-NHLs) derive from B cells and are classified into four distinct groups, including small noncleaved-cell lymphoma (SNCCL), diffuse large-cell lymphoma (DLCL), anaplastic large-cell lymphoma (ALCL), and body-cavity-based lymphoma (BCBL). The molecular pathogenesis of AIDS-NHL is characterized by the association of specific genetic lesions with distinct AIDS-NHL categories. Genetic lesions of AIDS-NHL involve proto-oncogenes (c-myc, Ras), tumor suppressor loci (p53, 6q), and viral infection (Epstein-Barr virus, human herpesvirus type 8). DESIGN: The aim of this work was to define the involvement of the bcl-6 gene in AIDS-related lymphomagenesis by investigating the distribution of bcl-6 structural alterations throughout the pathologic spectrum of AIDS-NHL. Both gross rearrangements and mutations in the 5' noncoding regions of the gene were investigated. RESULTS: Gross rearrangements of bcl-6 are confined to a fraction of AIDS-DLCL cases among AIDS-NHLs. Conversely, mutations of the 5' noncoding regions of bcl-6 are detected in a large proportion of AIDS-SNCCLs, AIDS-DLCLs and AIDS-ALCLs independent of the concomitant presence of bcl-6 rearrangements. CONCLUSIONS: Mutations of the 5' noncoding regions of bcl-6 represent the most frequent genetic lesion presently detectable among systemic AIDS-NHLs. The frequency of these mutations and their location in the proximity of bcl-6 regulatory regions suggest that they may play a role in AIDS-related lymphomagenesis.

DNA-Binding Proteins↗
PubMed1997

Genetic lesions associated with blastic transformation of polycythemia vera and essential thrombocythemia.

Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative disorders that may progress to acute leukemia in a subset of patients. This study aimed at investigating the genetic lesions associated with the blastic transformation of PV and ET. A panel of PV and ET cases at different stages of disease was analyzed for the presence of genetic alterations of TP53, NRAS, KRAS, and MDM2 by a combination of mutational analysis and Southern blot hybridization. The occurrence of microsatellite instability (MSI) was also tasted in selected cases. Samples of PV and ET analyzed in chronic phase disease were consistently devoid of all genetic lesions tested, suggesting that alterations of TP53, NRAS, KRAS, and MDM2 do not contribute significantly to development of chronic phase PV and ET. Conversely, mutations of TP53 were detected in 7/15 (46.6%) blastic phase cases, including 3/5 PV and 4/10 ET. In blastic phase patients for whom the corresponding chronic phase DNA was also available, it could be documented that the genetic lesion had arisen at the time of blastic transformation. In addition to TP53 mutations, cases of blastic phase PV and ET occasionally harbored mutations of NRAS (one case of blastic phase ET) or displayed MSI (one case of blastic phase PV). These data indicate that inactivation of TP53 is a relatively frequent event associated with the blastic transformation of PV and ET and may be responsible for the tumor progression of these disorders.

Adult↗