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Biomedical subjects

C Pastore

Publications and source records attributed to C Pastore.

At least 37 records · Page 2Linked to original sources
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

[Diagnosis and treatment of gastrointestinal carcinoid. Report of a clinical case with duodenal site].

Carcinoid tumors are among the most frequently neuroendocrine neoplasms of the gastrointestinal tract. They occur more commonly as benign diseases but malignant ones can also be found. The peak age incidence varies with the location of the tumor, with appendiceal tumors being diagnosed at an overage of 36 years, whereas non appendiceal tumors are found typically in the fifth sixth decades of life. There is no sex predilection of the tumors. Most carcinoid tumors are found within the appendix (40-50%) or small intestine (25%). Less common sites include the rectum (15%), main bronchus (10%), duodenum (3-8%) and stomach (2%). Most carcinoid tumors are found incidentally at operation and cause no symptoms. If symptoms do occur, they can be either non specific include intermittent crampy abdominal pain, vomiting and distension caused by intestinal obstruction. The prognosis depends on the site of the tumor and its size. Most carcinoid tumors (75%) are less than 1 cm in size and only 5% are greater than 2 cm. The incidence of metastatic disease is related directly to the size of the tumor at all locations. Carcinoid tumor with size less than 1 cm give linfonodal metastasis only in 3-5%; the other with size over 2 cm give metastasis in the 70-75% of the cases. The 5-years survival for all carcinoid tumors are approximately 85%. Five years rate is higher (> 80%) in carcinoid tumors of appendix and rectum than in gastroduodenal, ileal and colonic neoplasm (< 60%). In this paper the authors report a case of malignant carcinoid of the duodenum.

Carcinoid Tumor↗
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↗
PubMed1997

[Early infantile epileptic encephalopathy and glycine encephalopathy].

INTRODUCTION: Early infantile epileptic encephalopathy (EIEE) with suppression burst activity in EEG (Ohtahara syndrome) is a rare type of epileptic encephalopathy in infancy and represents the earliest type of age-related symptomatic generalized epilepsy. The main etiologic factors associated to EIEE are cerebral dysgenesia and metabolopathies, principally nonketotic hyperglycinemia. CLINICAL CASE: We report a neonate with EIEE secondary to glycine encephalopathy, diagnosed by increased of LCR/plasma glycine index.

Brain Diseases↗
PubMed1996

Distribution of hyaluronan during extracellular matrix remodeling in human restenotic arteries and balloon-injured rat carotid arteries.

BACKGROUND: The glycosaminoglycan hyaluronan (HA) is present in developing tissues and healing wounds and forms a loose, hydrated extracellular matrix (ECM) that promotes processes such as cell migration. To investigate the potential contribution of HA to the pathogenesis of restenosis, we studied (1) human lesions obtained by directional atherectomy and (2) experimentally induced neointima formation in balloon-injured rat carotid arteries. METHODS AND RESULTS: A biotinylated proteoglycan fragment that binds specifically to HA was used to stain atherectomy specimens from 29 human restenotic lesions (mean restenosis interval, 6.0+/-4.4 months) and 8 human primary lesions. The loose myxoid ECM typical of human restenotic arteries demonstrated intense, diffuse staining for HA. The intensity was inversely related to the density of immunostaining for collagen types I and III and was lowest in hypocellular primary atherosclerotic plaque. Among 24 rat carotid arteries retrieved 3, 7, 14, 28, 42, or 56 days after balloon injury and immunostained as well for proliferating cell nuclear antigen, staining for HA in the neointima reached a maximum 7 days after balloon injury and was associated with the presence of proliferating, PCNA-positive smooth muscle cells. CONCLUSIONS: Hyaluronan is a characteristic constituent of the loose myxoid ECM in human restenotic arteries and of the neointima in experimentally injured arteries. The presence of hyaluronan may be a marker for an initial phase of the extracellular matrix remodeling that occurs during the development of a fibroproliferative lesion and could facilitate biological processes such as cell migration.

Animals↗
PubMed1996

Distribution of TP53 mutations among acute leukemias with MLL rearrangements.

Acute leukemias carrying MLL rearrangements are characterized by a high degree of clinical and immunologic heterogeneity, as demonstrated by variability in their immunophenotype, consistent with lymphoid or myeloid/monoblastic derivation, as well as their occurrence in distinct age groups from infancy to adulthood. Recently, it was shown that inactivation of the TP53 tumor suppressor gene occurs frequently in cases of acute lymphoblastic leukemia carrying MLL rearrangements. In order to assess the extent of TP53 inactivation throughout the immunophenotypic and clinical spectrum of MLL+ acute leukemias, we tested for TP53 mutations 29 cases of MLL+ acute leukemias displaying lymphoid (13 cases) or myeloid/monoblastic (16 cases) features and belonging to different age groups. Mutations were detected in 6/16 myeloid/monoblastic cases and in 3/13 lymphoid cases. Among myeloid/monoblastic leukemias, the TP53 mutations occurred in 3/4 infants, but only in 3/16 cases in other age groups. Overall, our data suggest that (1) TP53 inactivation is a relatively common event in leukemias with MLL rearrangements irrespective of the leukemic phenotype and of the patients' age; (2) at least two genetic lesions (i.e., MLL rearrangement and TP53 mutation) have accumulated in the short time (few weeks after the birth or conception of the child) corresponding to the development of acute leukemias of infancy.

Acute Disease↗
PubMed1996

Molecular heterogeneity of B-lineage diffuse large cell lymphoma.

B-lineage diffuse large cell lymphoma (B-DLCL) arising de novo is characterized by a marked degree of clinical heterogeneity. To determine whether or not the clinical heterogeneity of de novo B-DLCL is reflected by heterogeneity in the molecular features of these tumors, we investigated the pattern of distribution of several genetic lesions in 70 cases of de novo B-DLCL at diagnosis. The panel of genetic lesions tested comprised the molecular alterations most frequently detected in B-DLCL, including rearrangements of BCL2, BCL6, and MYC as well as deletions of 6q and mutations of TP53. One or more genetic lesions were detected in 39/70 cases of B-DLCL. Isolated structural alterations of BCL2, BCL6, 6q or TPS3 were detected in 8/70, 10/70, 11/70, and 3/70 cases, respectively. No isolated MYC lesions were detected. Six cases carried different combinations of two genetic lesions, including lesions of BCL2 + BCL6 (1 case), BCL2 + MYC (1 case), BCL2 + 6q (2 cases), or BCL6 + 6q (2 cases). One case had accumulated three genetic lesions, namely a rearrangement of BCL2 and BCL6 and a mutation of TPS3. Overall, these data show that multiple distinct patterns of genetic lesions may associate with de novo B-DLCL, indicating that the molecular pathogenesis of this group of lymphomas is characterized by a high degree of molecular heterogeneity.

Chromosome Deletion↗
PubMed1996

Analysis of microsatellite instability in chronic lymphoproliferative disorders.

Microsatellite instability (MSI) represents one specific pattern of genomic instability and is one of the genetic lesions most frequently detected in human neoplasia. Although MSI has been found to be associated with a wide variety of solid cancers, its involvement in lymphoid malignancies is virtually unexplored. In this study, we have investigated the presence of MSI in chronic lymphoproliferative disorders by comparing the pattern of nine microsatellite repeats (two tetranucleotides, two trinucleotides, and five dinucleotides) on autologous germline and tumor DNA of 23 patients, including 17 with B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL), four with hairy cell leukemia, one with lymphoplasmacytoid lymphoma, and one with T-cell chronic lymphocytic leukemia. All samples at diagnosis displayed a germline pattern of the microsatellites examined, thus suggesting that MSI is not involved in the pathogenesis of these lymphoproliferations. Also, no microsatellite alterations were observed in consecutive samples of B-CLL/SLL obtained from the same patient at various stages of the disease both before and after chemotherapy. Conversely, alterations in 3/9 microsatellite repeats were detected in one case of Richter's syndrome which had evolved from a pre-existent B-CLL/SLL phase. Overall, the low frequency of MSI among chronic lymphoproliferative disorders adds further weight to the common view that the mechanisms and patterns of genomic instability in lymphoid neoplasia differ markedly from those commonly observed in solid cancers.

Base Sequence↗
PubMed1996

Kaposi's sarcoma-associated herpesvirus DNA sequences in AIDS-related and AIDS-unrelated lymphomatous effusions.

Primary effusions presenting as the sole lymphoma localization are also known as body-cavity-based-lymphoma (BCBL), and have been shown to carry Kaposi's sarcoma herpesvirus (KSHV) DNA sequences. The aim of this study was a comparative analysis of the clinical, pathologic and molecular features of BCBL and lymphomatous effusions secondary to tissue-based lymphomas occurring both in the general population and in HIV-1-infected individuals. All the lymphomatous effusion samples (seven AIDS-related and nine AIDS-unrelated) were subjected to an identical multiparameter investigation, including collection of clinical data, analysis of morphology and immunophenotype, as well as the study of viral sequences and genetic lesions. In six cases defined as BCBL (four AIDS-related and two AIDS-unrelated), the patients exhibited exclusive or predominant involvement of the body cavities. BCBL tended to display indeterminate phenotypes (4/6), whereas all AIDS-related and AIDS-unrelated lymphomatous effusions secondary to tissue-based lymphomas consistently expressed B-cell phenotype. Detection of KSHV DNA sequences was restricted to cases of BCBL (3/4 AIDS-related and 1/2 AIDS-unrelated), whereas EBV association (3/4) and expression of EBV-encoded antigens (LMP-1, 2/3; EBNA-2, 1/3) were confined to the AIDS-related BCBL. Overall, our results confirm that both AIDS-related and AIDS-unrelated BCBL preferentially associate with peculiar clinical, immunophenotypic and molecular features among lymphomatous effusions and therefore should be singled out as a specific clinico-pathologic entity.

Adult↗
PubMed1996

Distribution of human herpesvirus-8 sequences throughout the spectrum of AIDS-related neoplasia.

OBJECTIVE: AIDS frequently associates with certain malignancies, including Kaposi's sarcoma, non-Hodgkin's lymphoma (NHL), and anogenital neoplasia. In this study we aimed to define the frequency of infection by human herpesvirus (HHV)-8 throughout the spectrum of AIDS-related neoplasia in Europe. DESIGN: A tumour panel representative of the distinct types of AIDS-related neoplasms was tested for the presence of HHV-8 DNA sequences. Autologous uninvolved tissues were also tested in selected cases. METHODS: The presence of HHV-8 DNA sequences was assayed by a combination of polymerase chain reaction followed by oligohybridization and Southern blot hybridization of genomic DNA with an HHV-8-specific probe. RESULTS: HHV-8 sequences were detected in 100% of AIDS-related Kaposi's sarcoma (all 35 cases). Among AIDS-related NHL, HHV-8 sequences selectively clustered with body-cavity-based lymphomas (BCBL; all three cases), although they were consistently negative in small non-cleaved cell lymphomas (none in 18 cases), diffuse large cell lymphomas (none in seven), or anaplastic large cell lymphomas (none in three). No HHV-8 sequences were found in cases of anogenital neoplasia (out of 14) or Hodgkin's disease (out of three). HHV-8 DNA sequences were also positive in the uninvolved skin of all six AIDS-related Kaposi's sarcoma patients, but not in the circulating lymphocytes of a BCBL patient. Positivity for HHV-8 sequences occurred in patients belonging to all major AIDS risk categories. CONCLUSIONS: These data confirm that HHV-8 sequences associate at high frequency with selected types of AIDS-related neoplasia, namely Kaposi's sarcoma and BCBL, although they are consistently absent in other types of AIDS-NHL and AIDS-related anogenital neoplasia.

AIDS-Related Opportunistic Infections↗
PubMed1996

AIDS-related non-Hodgkin's lymphomas: molecular genetics, viral infection and cytokine deregulation.

AIDS-related non-Hodgkin's lymphomas (AIDS-NHLs) are almost invariably derived from B cells and are grouped into three distinct histologic categories, including small-non-cleaved-cell lymphoma (SNCCL), diffuse large-cell lymphoma (DLCL), and anaplastic large-cell lymphoma (ALCL). In addition, AIDS-NHLs presenting solely as a body cavity effusion are thought to be a peculiar clinicopathologic entity and are defined as body-cavity-based lymphoma (BCBL). At the biologic level, AIDS-related lymphomagenesis is characterized by activation of proto-oncogenes, inactivation of tumor suppressor genes, viral infection of the tumor clone, and deregulated cytokine production. Distinct AIDS-NHL types associate with specific molecular pathways. The first pathogenetic pathway clusters with AIDS-SNCCL, and is characterized by a relatively mild degree of host immunodeficiency. AIDS-SNCCL consistently associates with c-myc rearrangements and p53 inactivation in 100 and 60% of cases, respectively, whereas infection by Epstein-Barr virus (EBV) is restricted to 30% of the cases. Production of high levels of interleukin-10 is an additional peculiar feature of EBV-positive AIDS-SNCCL. The second pathogenetic pathway associates with AIDS-DLCL, which is usually accompanied by marked host immunodeficiency. AIDS-DLCL is characterized by EBV infection in the large majority of cases and by the mutually exclusive presence of bcl-6 rearrangements and c-myc translocations in 40% of the cases. A third pathway characterizes AIDS-BCBL, which associates in virtually all cases with infection by EBV and with the presence of DNA sequences of the recently identified Kaposi sarcoma herpesvirus in the apparent absence of other known genetic lesions. Finally, the pathogenetic features of AIDS-ALCL are still under investigation.

Cytokines↗
PubMed1996

AIDS-related Burkitt's-type lymphomas are a target for lymphokine-activated killers induced by interleukin-2 and prolactin.

The development of non-Hodgkin's lymphomas (NHL) is one of the major complications of AIDS. Although several biologic aspects of AIDS-related NHL have been clarified, their sensitivity to immune system cytotoxic effectors has not been tested. In this study, we have investigated the susceptibility of one major AIDS-related NHL type, Burkitt's-type lymphoma (BL), to the cytotoxic activity of lymphokine-activated killers (LAK) and prolactin-activated killers (PAK), which were generated from peripheral blood mononuclear cells upon stimulation with interleukin-2 (in the case of LAK cells) and prolactin (in the case of PAK cells). The sensitivity of AIDS-related BL to in vitro raised cytotoxic effectors was compared with that of BL variants of the general population, including sporadic BL and endemic BL. The data show that AIDS-related BL is susceptible to cytolysis by LAK cells, whereas both LAK and PAK cells can efficiently kill endemic BL. In contrast, sporadic BL showed resistance to all cytotoxic effectors tested. Intriguingly, in the case of AIDS-related and endemic BL suboptimal doses of interleukin-2 in combination with prolactin displayed a cytotoxic effect similar to that of LAK cells, suggesting a synergistic activity of the two agents. Overall, these data corroborate the notion that the distinct BL variants differ in their biologic features despite their morphologic and genetic similarity.

Burkitt Lymphoma↗
PubMed1996

Association of 6q deletions with AIDS-related diffuse large cell lymphoma.

Deletions of chromosome 6 at band q27 represent the site of a putative novel tumor suppressor gene in non-Hodgkin's lymphomas (NHL) of the immunocompetent host. Although several genetic lesions have been identified in AIDS-related NHL (AIDS-NHL), the involvement of 6q27 loss has not been investigated in this NHL category. In this report, we tested the presence of a 6q deletion at the molecular level in a panel of AIDS-NHL representative of the major histologic types, including AIDS-related small non-cleaved cell lymphoma (AIDS-SNCCL; n = 10), AIDS-related diffuse large cell lymphoma (AIDS-DLCL; n = 13) and AIDS-related anaplastic large cell lymphoma (AIDS-ALCL; n = 3). We report that 6q deletions occur in 5/26 AIDS-NHL tested (19.2%). Notably, 6q deletions do not randomly distribute throughout the spectrum of AIDS-NHL histologic types, but rather selectively cluster with AIDS-DLCL (5/13; 38.4%). Overall, these data add to the notion that the molecular pathogenesis of AIDS-NHL is heterogeneous and that distinct genetic pathways associate with specific histologic categories of AIDS-NHL.

Blotting, Southern↗