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Biomedical subjects

L Leoncini

Publications and source records attributed to L Leoncini.

At least 37 records · Page 2Linked to original sources
PubMed2001

Performance of cytology and colposcopy in diagnosis of cervical intraepithelial neoplasia (CIN) in HIV-positive and HIV-negative women.

As part of an extensive multi-institutional DIANAIDS-HIV-HPV-SIL project run in Italy (co-ordinated by ISS), the present study compares the performance (sensitivity, specificity, agreement) of routine cervical smear cytology with that of colposcopy in the detection of histologically-confirmed CIN lesions in 37 HIV-positive and 21 HIV-negative women, belonging to the DIANAIDS cohort of 459 women. All women were subjected to a cervical smear, colposcopy and biopsy, making possible the pairwise comparison of these techniques. In the whole series of HIV-positive and HIV-negative women, cytology had a sensitivity of 86.9% and specificity of 83.3%, the sensitivity of grade 2 abnormality on colposcopy against histology being 82.6% and specificity, 33.3%. No statistically significant difference was observed in the performance of Pap smears between the HIV-positive and HIV-negative women. The sensitivity of cytology was 89.7% vs 82.4% and the specificity, 75% vs 100%. For colposcopy, the sensitivity was 79.3% vs 88.2% and the specificity, 75% vs 50%. These data suggest that cervical Pap smear cytology is a highly sensitive and specific diagnostic tool in the clinical monitoring of lower genital tract pathology in HIV-positive women. Colposcopy, on the other hand, proved to be a somewhat less accurate diagnostic tool in these women.

Adolescent↗
PubMed2000

Expression of the ALK protein by anaplastic large-cell lymphomas correlates with high proliferative activity.

A variable fraction of anaplastic large-cell lymphomas (ALCLs) exhibits a t(2;5)(p23;q35) translocation that results in expression of the chimeric hyperphosphorylated protein NPM-ALK (p80). Tumor cells expressing NPM-ALK exhibit markedly enhanced proliferative activity, but comparative cellular kinetic studies on ALK(+) (ALK lymphomas) and ALK(-) lymphomas are lacking. The present study showed that ALK(+) lymphomas, detected with the monoclonal antibody ALKc (n = 17), had significantly higher average values for the proliferation-associated parameters mitotic index, ana/telophase index, growth index (x x mitotic index - apoptotic index, assuming x = 3), percentages of Ki-67(+) cells and fraction of cells expressing cyclin A or B or the cell cycle-regulatory protein p34(cdc2) than did ALK(-) ALCLs (n = 15). Whether this intense proliferative activity contributes to the good response to chemotherapy and favorable outcome of ALK(+) ALCLs remains to be assessed in a larger series of patients. Our findings support the notion that ALK(+) and ALK(-) ALCLs are 2 distinct disease entities.

Adolescent↗
PubMed2000

Mutations in the retinoblastoma-related gene RB2/p130 in lung tumors and suppression of tumor growth in vivo by retrovirus-mediated gene transfer.

The retinoblastoma (Rb) family consists of the tumor suppressor pRb/p105 and related proteins p107 and pRb2/p130. Recent immunohistochemical studies of the retinoblastoma family of proteins in 235 specimens of lung cancer show the tightest inverse association between the histological grading in the most aggressive tumor types and pRb2/p130. This led us to study a panel of human lung cancers for mutations in the RB2/p130 gene. Mutations in the Rb-related gene RB2/p130 were detected in 11 of 14 (78.5%) primary lung tumors by single-strand conformation polymorphism and sequence analysis. A Moloney leukemia virus-based retroviral system was set up, and a comparable viral concentration of 1 x 10(7) infectious units/ml was obtained. Retrovirus-mediated delivery of wild-type RB2/p130 to the lung tumor cell line H23 potently inhibited tumorigenesis in vitro and in vivo, as shown by the dramatic growth arrest observed in a colony assay and the suppression of anchorage-independent growth potential and tumor formation in nude mice. The tumors transduced with the RB2/p130 retrovirus diminished in size after a single injection, and a 12-fold reduction in tumor growth after RB2/p130 transduction compared with the Pac-transduced tumors (92% reduction, P = 0.003) and lacZ-transduced tumors (93% reduction, P < 0.001) was found to be statistically significant. These findings provide the missing confirmation that RB2/p130 is a "bona fide" tumor suppressor gene and strengthen the hypothesis that it may be a candidate for cancer gene therapy for lung cancer.

Adenocarcinoma↗
PubMed2000

Genetic alterations disrupting the nuclear localization of the retinoblastoma-related gene RB2/p130 in human tumor cell lines and primary tumors.

The prototypic tumor suppressor gene, the retinoblastoma gene (RB/ p105), is mutated in a variety of human tumors. However, to date, mutational data on retinoblastoma family members p107 and RB2/p130 in tumors is lacking. We studied the expression of pRb2/p130 by immunocytochemistry and Western blot analysis in a panel of human osteosarcoma and lymphoid cell lines. Only the lymphoid cell lines showed an abnormal cytoplasmic localization of pRb2/p130, suggesting possible alterations within the region of nuclear localization signaling. We screened these cell lines for genetic alterations of the RB2/p130 gene in the region of the putative bipartite nuclear localization signal (NLS). This region is highly homologous with that of the RB/p105 gene. In addition, we screened four primary Burkitt's lymphomas for genetic alterations in the RB2/p130 gene. Naturally occurring mutations, which disrupt the putative bipartite NLS, were found in lymphoma cell lines and primary tumors, but not in the osteosarcoma cell lines, where normal nuclear localization of the protein was detectable. Site-directed mutagenesis and transfection assay using NLS mutants displayed markedly reduced biological activity as measured by flow cytometric analysis. This study clearly describes RB2/ p130 as an important target for mutations and subsequent inactivation in lymphoma pathogenesis, thus validating that RB2/p130 is a classical tumor suppressor gene.

Amino Acid Substitution↗
PubMed2000

Fatal cardiac arrhythmia after infusion of dimethyl sulfoxide-cryopreserved hematopoietic stem cells in a patient with severe primary cardiac amyloidosis and end-stage renal failure.

Amyloidosis (AL) is a rapidly fatal plasma cell dyscrasia causing progressive multiorgan failure. Recently, substantial improvement of survival was reported following high-dose chemotherapy with peripheral blood stem cell (PBSC) rescue. We describe a patient with AL with severe cardiac and renal involvement who received high-dose melphalan followed by fractioned autologous PBSC transplantation (455 ml on day 1 and 350 ml on day 2). Immediately after the second infusion of the PBSCs, life-threatening cardiac arrhythmias occurred and, despite intensive treatment, the patient died less than 24 h later. The infusion of cryopreserved PBSCs may be associated with complications, including cardiac toxicity. Dimethyl sulfoxide (DMSO) is the most frequently used cryopreservation agent. In the present case, we suggest that DMSO could have played an important role in causing the fatal cardiac arrhythmias. The mechanisms of the cardiovascular effects of DMSO and the possible preventive measures are discussed. Given the poor prognosis of AL and the promising results of dose-intensive chemotherapy with autologous PBSC transplantation, careful patient selection and intensive monitoring are mandatory in order to further pursue this therapeutic approach.

Amyloidosis↗
PubMed2000

Genetic alterations of the retinoblastoma-related gene RB2/p130 identify different pathogenetic mechanisms in and among Burkitt's lymphoma subtypes.

Alterations of cell cycle-associated genes probably contribute to the pathogenesis of Burkitt's Lymphoma (BL), in addition to c-myc translocation. Mutations disrupting the nuclear localization signal of the retinoblastoma-related gene RB2/p130 have been documented recently in BL cell lines and primary tumors. Given the importance of the RB2/p130 gene in controlling cell growth, mutations of this gene may result in uncontrolled cell proliferation. We tested the expression and genomic organization of the RB2/p130 gene in relation to the proliferative features of a series of BL samples collected from the endemic and sporadic regions, regardless of whether the samples were acquired immune deficiency syndrome (AIDS)-related. The expression of the Rb2/p130, p107, and cell proliferation-related proteins (cyclin A and B) was determined by immunohistochemistry. The structures of exons 19 through 22 of the RB2/p130 gene, encoding for the B domain and C terminus, were analyzed by polymerase chain reaction (PCR) analysis and single-strand conformation polymorphism (SSCP) technique. The direct PCR products were sequenced to identify the actual mutations. Our results suggest that BL is composed of a mixture of molecular types with distinct genetic and phenotypic patterns, probably resulting from different pathogenetic mechanisms. In endemic BL, the RB2/p130 gene is mutated in most of the cases, and the protein is restricted to the cytoplasm. In AIDS-related BL, high levels of nuclear expression of the wild-type pRb2/p130, p107, and cell proliferation-related proteins were detected. This finding is in line with the molecular mechanisms observed in virus-linked oncogenesis. Sporadic BLs were mainly characterized by the low nuclear values of the wild-type pRb2/p130 and, conversely, the high values of p107. The increased cell proliferation due to different alterations of cell growth control by Rb-related proteins may be the first step in lymphomagenesis, during which additional genetic changes, including missense mutations of c-myc, may subsequently occur.

Adolescent↗
PubMed2000

The pathologist's view point. Part I--indolent lymphomas.

BACKGROUND AND OBJECTIVES: The REAL/WHO classification constitutes a new tool for the better understanding and treatment of malignant lymphomas. The authors focus on the key features of B-cell lymphomas with an indolent behavior, aiming to contribute to the cross-talk between pathologists and clinicians. DATA SOURCES AND METHODS: Each lymphoma entity is analyzed on the basis of the most representative contributions in the literature and the authors' experience gained in studying more than 20,000 lymphoid tumors over a 20-year period. RESULTS: Guidelines for diagnosis and areas of interest for future clinico-pathologic studies are identified and discussed. Within this context, selected data obtained by the application of novel markers are presented. INTERPRETATION AND CONCLUSIONS: The present know- ledge and organization of malignant lymphomas now make the development of tailored therapies a feasible goal.

Humans↗
PubMed2000

The pathologist's view point. Part II --aggressive lymphomas.

BACKGROUND AND OBJECTIVES: The REAL/WHO classification constitutes a new tool for the better understanding and treatment of malignant lymphomas. The authors focus on the key features of aggressive B- and T-cell lymphomas, aiming to contribute to the cross-talk between pathologists and clinicians. DATA SOURCES AND METHODS: Each lymphoma entity is analyzed on the basis of the most representative contributions in the literature and the authors' experience gained in studying more than 20,000 lymphoid tumors over a 20-year period. RESULTS: Guidelines for diagnosis and areas of interest for future clinico-pathologic studies are identified and discussed. Within this context, selected data obtained by the application of novel markers are presented. INTERPRETATION AND CONCLUSIONS: The present know- ledge and organization of malignant lymphomas now make the development of tailored therapies a feasible goal.

Humans↗
PubMed1999

Expression of p34(cdc2) and cyclins A and B compared to other proliferative features of non-Hodgkin's lymphomas: a multivariate cluster analysis.

In view of recent knowledge on proteins regulating the cell cycle, we re-evaluated proliferative features of 98 diffusely growing non-Hodgkin's lymphomas. The combined use of 5 proliferation-associated variables (mitotic indices and percentages of Ki-67(+), p34(cdc2+), cyclin A(+) and cyclin B(+) cells) and their entry into a multivariate cluster analysis separated, without overlaps, the entire cohort into 3 groups (clusters) with (1) low, (2) intermediate and (3) high proliferative activity. Conversely, bivariate plots exposed considerable cluster overlaps. Multivariate stepwise discriminant analysis of all cases revealed a decreasing order of discriminant power for % Ki-67(+) cells > % p34(cdc2+) cells > mitotic index > % cyclin A(+) cells > % cyclin B(+) cells. The combined use of 2 variables only, mitotic index and % p34(cdc2+) cells, allowed a clear-cut separation of clusters 2 and 3. In bivariate plots, correlations were best between % Ki-67(+) cells and % cyclin A(+) cells and between mitotic indices and % cyclin B(+) cells. Except for chronic lymphocytic leukemias, immunocytomas and marginal zone lymphomas (all in cluster 1), individual lymphoma entities were distributed among at least 2 clusters. There was, however, a marked preponderance of mantle cell lymphomas and diffuse follicular center lymphomas in cluster 1 and of diffuse large B-cell lymphomas and peripheral T-cell lymphomas in cluster 2. Anaplastic large-cell lymphomas predominated in cluster 3 and responded best to therapy.

Adolescent↗
PubMed1999

Cell growth and death in malignant lymphomas. A quantitative analysis.

OBJECTIVE: To review the value of biopathologic factors in single lymphomatous patients across the boundaries of histologic classification. STUDY DESIGN: In a series of previous studies, based on a large collection of biopsy samples, the value of the above biopathologic characteristics in individual lymphomatous patients was quantitatively evaluated. RESULTS: The relationships between apoptotic index and growth fraction, in light of the expression of oncogenes, which regulate cell birth and death, were of particular value in determining the growth pattern of different lymphoma cases across the boundaries of histologic classification. CONCLUSION: The study of mechanisms that regulate cell proliferation and death might have therapeutic implications as the proper therapeutic approach should be based on detailed knowledge of the kinetic and molecular characteristics of each tumor.

Apoptosis↗
PubMed1999

Retinoblastoma-related p107 and pRb2/p130 proteins in malignant lymphomas: distinct mechanisms of cell growth control.

pRb/p105, p107, and pRb2/p130 compose the retinoblastoma (RB) family of proteins and regulate cellular growth and differentiation. Because recent functional studies have indicated that the expression of the RB-related proteins p107 and pRb2/p130 are tightly cell cycle regulated, we were interested in investigating their expression along with cellular kinetic characteristics and proliferative features of non-Hodgkin's lymphomas (NHLs). p107 and pRb2/ p130 expression was determined immunohistochemically in biopsy specimens from 83 untreated patients with NHLs of various histiotypes. The expression of these two RB-related proteins was correlated with the mitotic index, apoptotic index, and percentages of Ki-67(+), cyclin A(+), p34(+), and cyclin B(+) cells. The overall survival rate was evaluated according to the Kaplan-Meier method and the log-rank test. We found a positive correlation between the percentages of cells positive for p107 and proliferative features such as mitotic index and percentage of Ki-67(+) and cyclin A(+) cells, whereas such correlation could not be demonstrated for the percentages of pRb2/p130 positive cells. Low immunohistochemical levels of pRb2/p130 detected in untreated patients with NHLs of various histiotypes inversely correlated with a large fraction of cells expressing high levels of p107 and proliferation-associated proteins. Such a pattern of protein expression is normally observed in continuously cycling cells. Interestingly, such cases showed the highest survival percentage (82.5%) after the observation period of 10 years. Thus, down-regulation of the RB-related pRb2/p130 protein could be one of the reasons why these cases display such a high rate of proliferation and why they respond so well to therapy.

Aged↗
PubMed1998

Cellular kinetic differences between Hodgkin's and anaplastic large cell lymphomas: relation to the expression of p34cdc2 and cyclin B-1.

Our study was designed to compare cellular kinetic parameters of classical Hodgkin's disease (HD) with those of anaplastic large cell lymphomas (ALCL-C, common type; and ALCL-HL, Hodgkin's like), with a particular focus on the G2/M transition. These disorders share some phenotypic properties, e.g., CD30 positivity of putative neoplastic cells. The percentages of cells expressing p34cdc2 (p34) and cyclin B-1 (cyclin-B), which form a complex (maturation/mitosis promoting factor, MPF) regulating the G2-M phases of the cell cycle, were also registered. Highly significant differences between HD and ALCL-C were recognized: a) in HD, evidence for abortive mitosis (i.e., difficulty to proceed beyond the metaphase stage) and consequent multinucleation and/or deletion of CD30+ cells was prominent, in contrast to ALCL-C. This was associated with a markedly lower fraction of large atypical cells (LAC) expressing cyclin-B in the cytoplasm and the nucleus (C + N) in HD than in ALCL-C; b) the extent of multinucleation of CD30+ cells in HD, but not in ALCL-C, was correlated with the %p34+ LAC; c) the proportions of LAC expressing p34 and/or cyclin-B (C) were positively related to the percentages of cyclin-B (C + N)+ LAC in ALCL-C but not in HD; d) in HD, in contrast to ALCL-C, the size of the fraction of cyclin-B (C + N)+ LAC did not correlate with the ana/telophase indices (ATI, reflecting successful completion of mitosis) and the magnitude of cell loss; e) in ALCL-C, the percentages of p34+ LAC were positively correlated with ATI or the degree of CD30+ cell deletion, but inversely in HD. With regard to all parameters mentioned above, ALCL-HL tended to take an intermediate position between HD and ALCL-C, but sided more with the latter. In conclusion, our present results suggest a derangement of MPF kinetics and functions that is more profound in HD than in ALCL-C.

CDC2 Protein Kinase↗
PubMed1998

HIV-associated malignant lymphomas in Kenya (Equatorial Africa)

The clinical and pathological features of acquired immune deficiency syndrome (AIDS)-related lymphomas, including their relationship with other viruses, such as Epstein-Barr virus (EBV) and human herpes virus-8 (HHV8), have been the subject of several studies from North America and Europe. No consistent data have been reported in Africa, where AIDS runs an epidemiological and clinical course different from that observed in Western countries. We retrospectively evaluated the presence of human immunodeficiency virus (HIV), HHV8, and EBV in 146 cases of malignant lymphomas collected in Kenya (Equatorial Africa), with the use of polymerase chain reaction (PCR) and in situ hybridization (ISH). The PCR technique confirmed HIV infection in 16 HIV-seropositive subjects (11%) and showed the presence of HIV sequences in five additional cases (3%) in which the occurrence of lymphoma was the only clinical manifestation. Our findings suggest that AIDS-related lymphomas are not pathogenetically homogenous, and different mechanisms may contribute to lymphomagenesis in these severely immunocompromised patients. In our series, no association of Hodgkin's disease (HD) with HIV infection could be shown. Among non-HIV-related lymphomas, EBV was present in 94% of Burkitt lymphoma (BL) occurring in patients younger than 15 years of age, in 87% of HD independently of age, sex, and histological types, in 60% of anaplastic large cell lymphoma (ALCL), and to a lesser extent (13%) in large B-cell lymphoma (LBCL) cases. Only one tumor, a case of HD, showed HHV8 by PCR.

HIV↗