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Biomedical subjects

L M Larocca

Publications and source records attributed to L M Larocca.

At least 55 records · Page 3Linked to original sources
PubMed1999

Expression of thrombospondin receptor (CD36) in B-cell chronic lymphocytic leukemia as an indicator of tumor cell dissemination.

BACKGROUND AND OBJECTIVE: The expression of CD36 antigen has not been conclusively associated with human B-lymphocytes although CD36 was recently detected in a human B-cell angiotropic lymphoma where it might be involved in lymphoblast-endothelial cell adhesion. We investigated the expression of CD36 in B-cell chronic lymphocytic leukemia (CLL) by multiparameter flow cytometry; results were correlated with clinical features. DESIGN AND METHODS: CD36 expression was evaluated on peripheral blood and bone marrow samples from 24 patients affected by CD5+ B-CLL. Mononuclear cells were isolated by Ficoll-Hypaque density gradient centrifugation, were labeled with fluorochrome-conjugated monoclonal antibodies under standard experimental conditions and were analyzed by flow cytometry. CD36 expression was quantified both in terms of frequency of CD19+CD36+ cells and of mean fluorescence intensity (MFI-R) of CD36+ cell populations. The intensity of CD36 expression was arbitrarily classified as weak (MFI-R ranging from 3 to 6; score 0), moderate (MFI-R ranging from 6 to 9; score 1), intermediate (MFI-R ranging from 9 to 11; score 2) or strong (MFI-R ranging from 11 to 17; score 3). RESULTS: CD36 could be detected on 3% (range 2-5) of normal CD19+ B-lymphocytes and on 45% (range 30-75) of neoplastic CD19+ B-cells. When CLL patients were stratified according to CD36 staining intensity, higher hemoglobin levels (Hb) were recorded in patients assigned to score 0 (Hb = 14.3 g/dL; range 13.9-15.1) compared to patients scoring 1-2 (Hb = 11.2; range 10.3-12.2) or 3 (Hb = 9.8; range 9.6-11.6; p=0.0053). Similarly, higher platelet counts (Plt) were found in patients scoring 0 (Plt = 282x10(3)/microL; range 244-319), compared to patients with intermediate (Plt = 175x10(3)/microL; range 144-238) and high scores (Plt = 149x10(3)/microL; range 103-230; p=0.044); lymphocyte count (Ly) was significantly higher in patients assigned to score 3-4 (Ly = 23.3x10(3)/microL, range 13-30) compared to score 0-2 (Ly = 9.8x10(3)/microL, range 8.5-10.8; p=0.045). CLL patients expressing CD36 at intermediate-to-strong intensity (MFI-R = 14, range 9-16) were more frequently assigned to Rai stages III-IV than stages I-II (CD36 MFI-R = 9, range 6.5-11; p=0.005) and stage 0 (CD36 MFI-R = 6, range 4-7.3; p<0.001). Interestingly, bone marrow diffuse histology was strongly associated with higher CD36 expression (MFI-R = 8.7; range 4.7-13.9) compared to non-diffuse patterns of bone marrow infiltration (MFI-R = 6.7; range 5.2-9.3; p=0.0019). In multivariate regression analysis, CD36 staining intensity significantly and independently correlated with diffuse BM histology (p=0.033). INTERPRETATION AND CONCLUSIONS: The present report provides the first evidence of CD36 expression on CD19+ B-cells from CLL; the correlations with clinical parameters strongly support the view that CD36 might favor tumor cell spreading. Whether high CD36 expression levels on CLL CD19+ B-cells identify an aggressive disease subset remains to be further confirmed in larger series of patients.

Aged↗
PubMed1999

Epstein-Barr virus in monitoring the response to therapy of acquired immunodeficiency syndrome-related primary central nervous system lymphoma.

To evaluate the value of Epstein-Barr virus DNA (EBV-DNA) assay in cerebrospinal fluid (CSF) for monitoring the response to treatment in acquired immunodeficiency syndrome-related primary central nervous system lymphoma (AIDS-PCNSL), 9 human immunodeficiency virus-infected patients with biopsy-proven AIDS-PCNSL who underwent multimodal therapy were investigated for EBV-DNA detection in CSF by semiquantitative nested polymerase chain reaction (PCR). Tumoral tissue expression of bcl-6 oncogene protein and of EBV-encoded latent membrane protein (LMP-1) was also investigated. The 2 patients who had a response to chemotherapy showed a reduction of mean EBV-DNA concentration values after chemotherapy and displayed a large noncleaved morphology and a BCL-6+/LMP-1- phenotype. Conversely, the 4 patients with progressive disease after chemotherapy showed increasing mean values of EBV-DNA and displayed an immunoblastic morphology and a BCL-6-/LMP-1+ phenotype. No significant changes were observed for patients with stable disease. EBV-DNA burden reduction was significantly associated with prolonged survival. These results suggest that EBV-DNA monitoring might be helpful in predicting response to chemotherapy and in segregating distinct biological and prognostic categories of AIDS-PCNSL.

Analysis of Variance↗
PubMed1998

The molecular and phenotypic profile of primary central nervous system lymphoma identifies distinct categories of the disease and is consistent with histogenetic derivation from germinal center-related B cells.

Primary central nervous system lymphoma (PCNSL) is a major cause of morbidity and mortality among human immunodeficiency virus (HIV)-infected individuals. The precise histogenetic derivation and the molecular pathogenesis of PCNSL is poorly understood. In an attempt to clarify the histogenesis and pathogenesis of these lymphomas, 49 PCNSL (26 acquired immunodeficiency syndrome [AIDS]-related and 23 AIDS-unrelated) were analyzed for multiple biologic markers, which are known to bear histogenetic and pathogenetic significance for mature B-cell neoplasms. PCNSL associated frequently (50.0%) with mutations of BCL-6 5' noncoding regions, which are regarded as a marker of B-cell transition through the germinal center (GC). Expression of BCL-6 protein, which is restricted to GC B cells throughout physiologic B-cell maturation, was detected in 100% AIDS-unrelated PCNSL and in 56.2% AIDS-related cases. Notably, among AIDS-related PCNSL, expression of BCL-6 was mutually exclusive with expression of Epstein-Barr virus (EBV)-encoded latent membrane protein (LMP)-1 and, with few exceptions, also of BCL-2. All but one PCNSL expressed hMSH2, which among mature B cells selectively stains GC B cells. These data suggest that PCNSL may be frequently related to GC B cells and may be segregated into two major biologic categories based on the expression pattern of BCL-6, LMP-1, and BCL-2. BCL-6(+)/LMP-1(-)/BCL-2(-) PCNSL occur both in the presence and in the absence of HIV infection and consistently display a large noncleaved cell morphology. Conversely, BCL-6(-)/LMP-1(+)/BCL-2(+) PCNSL are restricted to HIV-infected hosts and are represented by lymphomas with immunoblastic features. These data are relevant for the pathogenesis and histogenesis of PCNSL and may be helpful to segregate distinct biologic and prognostic categories of these lymphomas.

B-Lymphocyte Subsets↗
PubMed1998

Minimally invasive diagnosis of acquired immunodeficiency syndrome-related primary central nervous system lymphoma.

BACKGROUND: The detection of Epstein-Barr virus (EBV)-DNA in cerebrospinal fluid (CSF) by means of the polymerase chain reaction (PCR) has been revealed, in retrospective studies, to be a good marker of primary central nervous system lymphoma (PCNSL) related to acquired immunodeficiency syndrome (AIDS); however, the technique's usefulness in the management of AIDS patients with focal brain lesions is still unknown. We studied the clinical usefulness of testing CSF obtained by lumbar puncture for the presence of EBV-DNA as a minimally invasive approach to the diagnosis of AIDS-PCNSL in patients with focal brain lesions. METHODS: Human immunodeficiency virus (HIV)-infected patients with focal brain lesions, observed prospectively during a 30-month period, underwent lumbar puncture if not contraindicated; otherwise, ventricular CSF was obtained at brain biopsy. The presence of EBV-DNA was determined by means of PCR. RESULTS: We evaluated 122 patients: 42 diagnosed with brain lymphoma and the remaining 80 diagnosed with other brain disorders. Cerebrospinal fluid was collected from 101 patients--by lumbar puncture in 95, including 40 patients with AIDS-PCNSL. The sensitivity and specificity of PCR for EBV-DNA detection in lumbar CSF were 80% (95% confidence interval [CI] = 60.9%-91.6%) and 100% (95% CI = 92.6%-100%), respectively. Lumbar puncture and subsequent assessment of EBV-DNA would have allowed a correct diagnosis in 63.2% (95% CI = 46.0%-77.7%) of patients with AIDS-PCNSL and excluded this diagnosis in 76.3% (95% CI = 65.2%-84.8%) of patients without lymphoma (because EBV-DNA was not detected). CONCLUSIONS: The presence of EBV-DNA in lumbar CSF is a sensitive and highly specific diagnostic marker of AIDS-PCNSL, and EBV-DNA detection in this fluid may allow a minimally invasive diagnosis in a large percentage of patients with brain lymphomas.

Adult↗
PubMed1998

Differential expression of BCL-6, CD138/syndecan-1, and Epstein-Barr virus-encoded latent membrane protein-1 identifies distinct histogenetic subsets of acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas.

This study was aimed at defining the histogenesis of the pathologic spectrum of acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas (AIDS-NHL), including AIDS-related small noncleaved cell lymphoma (AIDS-SNCCL), AIDS-related large noncleaved cell lymphoma (AIDS-LNCCL), AIDS-related large cell immunoblastic lymphoma plasmacytoid (AIDS-IBLP), and AIDS-related primary effusion lymphoma (AIDS-PEL). Forty-six cases of AIDS-NHL were investigated for the expression pattern of BCL-6, a protein specifically expressed by germinal center (GC) B-cells, and CD138/syndecan-1 (syn-1), a marker of post-GC B-cell differentiation. Expression of BCL-6 and syn-1 segregated two major phenotypic patterns among AIDS-NHL: (1) the BCL-6+/syn-1- pattern associated with AIDS-SNCCL and AIDS-LNCCL; (2) the BCL-6-/syn-1+ pattern associated with AIDS-IBLP and AIDS-PEL. Among systemic AIDS-NHL infected by Epstein-Barr virus (EBV), expression of the EBV-encoded latent membrane protein-1 (LMP-1) preferentially associated with the BCL-6-/syn-1+ profile. Analysis of nonneoplastic lymph nodes showed that the two phenotypic patterns detected in AIDS-NHL correspond to physiologic stages of B-cell development, i.e., GC B-cells (BCL-6+/syn-1-) and preterminally differentiated post-GC B-cells (BCL-6-/syn-1+). Thus, BCL-6+/syn-1- AIDS-NHL reflects a GC stage of differentiation, whereas AIDS-NHL which are BCL-6-/syn-1+, and LMP-1+ when infected by EBV, derive from B cells that have entered post-GC plasmacell differentiation. These findings are relevant for the pathogenesis and differential diagnosis of AIDS-NHL.

Cell Membrane↗
PubMed1998

Neurofibromatosis type 2: growth stimulation of mixed acoustic schwannoma by concurrent adjacent meningioma: possible role of growth factors. Case report.

The authors report the case of a young man suffering from neurofibromatosis type 2 (NF2) who harbored bilateral acoustic schwannomas and a parasellar meningioma. Neuroimaging studies performed during a 4-year follow-up period showed that the bilateral schwannomas had grown very little and at similar rates. However, after the meningioma had infiltrated the tentorium and approached the ipsilateral schwannoma at the incisura, both Schwann cell tumors started to grow rapidly, particularly the one adjacent to the meningioma, of which the percentage of annual growth rate increased by approximately a factor of 10(2). At the same time, magnetic resonance imaging showed that this tumor also changed its features. During surgery, the acoustic schwannoma was firmly adherent to both meningioma and tentorium. Histological examination revealed meningotheliomatous cells in the schwannoma adjacent to the meningioma. Antiphosphotyrosine immunoblotting of PC12 cells was compatible with the presence of an epidermal growth factor (EGF)-like molecule in the cerebrospinal fluid (CSF) of the patient. This factor was not detected in the CSF of five other NF2 patients, two of whom bore associated bilateral acoustic schwannomas and meningioma in remote locations. It is hypothesized that the meningotheliomatous cells infiltrating the schwannoma triggered an autocrine/paracrine growth-stimulatory mechanism that involved an EGF-like factor.

Adolescent↗
PubMed1998

Expression of p15INK4B in normal hematopoiesis.

The cyclin-dependent kinase inhibitor (CDKI) p15INK4B (p15) induces cell cycle arrest in G0/G1 phase. Several studies report deletion or transcriptional loss of the p15 gene in myeloid and lymphoid hematological malignancies, and a possible role as a tumor suppressor gene has been proposed for this CDKI. In this study we evaluated the expression of p15 by cytofluorometric, immunohistochemical, and reverse transcriptase-polymerase chain reaction (RT-PCR) methods in CD34+ progenitors (both during steady state and after chemotherapy and/or granulocyte-colony stimulating factor [G-CSF] administration) and in cells belonging to different hematopoietic differentiative lineages. We found that p15 is not expressed in normal G0/G1-arrested peripheral blood (PB)- or bone marrow (BM)-CD34+ cells. Moreover, p15 is expressed in G0/G1-blocked CD34+ cells mobilized by chemotherapy and G-CSF but not in CD34+ cells mobilized by G-CSF alone. To clarify the role of p15 in normal hematopoiesis, we used flow cytometry to investigate its expression in normal differentiating BM and PB cells. We found that p15 was expressed in cells belonging to the granulocyte-monocyte lineage and in B and T lymphocytes, whereas erythroid and megakaryocytic cells were p15 negative. These findings, which were confirmed both by immunohistochemical and RT-PCR analysis, definitely establish a linkage between p15 expression and granulocyte-monocyte differentiation.

Antigens, CD34↗
PubMed1997

Differential sensitivity of leukemic and normal hematopoietic progenitors to the killing effect of hyperthermia and quercetin used in combination: role of heat-shock protein-70.

Autologous bone-marrow transplantation (ABMT) is widely used in the treatment of acute leukemias where a matched sibling donor is not available for allogeneic transplantation. However, a major problem in ABMT is relapse, and ex vivo purging may be very important in preventing it. We show here that quercetin enhances the growth-inhibitory effect of hyperthermia (HT) in AML (19 cases) and ALL (6 cases) leukemic blasts. Furthermore, the inhibitory effect of this combined treatment resulted in leukemic-cell apoptosis. On the contrary, normal hematopoietic progenitors were neither growth-inhibited nor induced to apoptosis by HT-plus-quercetin treatment. To explain this difference in sensitivity of leukemic and normal hematopoietic progenitors, we analyzed the effect of quercetin on heat-induced expression of heat-shock protein-70 (HSP-70), which has been shown to be important in regulating thermosensitivity. We found that quercetin inhibits heat-induced HSP-70 expression both at protein and at mRNA levels in AML and ALL blasts. In normal CD34+ progenitors, the combined treatment with HT and quercetin did not reduce HSP-70 expression and did not induce cell apoptosis. Considering the difference in heat sensitivity of normal CD34+ and leukemic progenitors in the presence of quercetin, the combined use of HT and quercetin could constitute a purging protocol for ABMT.

Adult↗
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

Gastric cryptosporidiosis complicating HIV infection: case report and review of the literature.

Gastric cryptosporidiosis is rarely reported despite the fact that Cryptosporidium has been recognized with increasing frequency as an aetiological agent of severe chronic diarrhoeal enteritis in patients with human immunodeficiency virus (HIV) infection. We report a case of gastric cryptosporidiosis that occurred in an AIDS patient. Fifteen previously reported cases of gastric cryptosporidiosis are also reviewed. The review of all cases reported in the literature, including our own, showed that 12 patients had digestive symptoms. In 14 out of 16 patients the diagnosis was achieved by biopsy of the gastric mucosa rather than by examination of the stools. Gastric localization of Cryptosporidium is a rare and severe manifestation of intestinal cryptosporidiosis in patients with AIDS, and no single drug regimen has yet been found to be effective in eradicating this organism.

AIDS-Related Opportunistic Infections↗
PubMed1997

Diagnosis of AIDS-related focal brain lesions: a decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF.

OBJECTIVE: To identify disease patterns in AIDS-related focal brain lesions (FBL) and to design a decision-making strategy for differential diagnosis. DESIGN: Prospective study. Probabilities of CNS disorders were calculated using Bayes' theorem according to clinical variables (mass effect at CT or MRI, Toxoplasma serology, anti-Toxoplasma prophylaxis) and to the results of polymerase chain reaction (PCR) assays. PATIENTS: 136 consecutive HIV-infected patients with a definitive diagnosis of FBL-causing disorder observed from 1991 to 1995 in a single clinical setting. INTERVENTIONS: Patients underwent empiric anti-Toxoplasma therapy. After 3 weeks, patients with progressive/stable disease underwent brain biopsy. In 66 patients Epstein-Barr virus (EBV)-DNA, JC virus (JCV)-DNA, and T gondii-DNA amplification was performed by PCR in CSF. Diagnostic criteria were histopathologic examination of bioptic or autoptic tissue specimens for all disorders and complete/partial resolution of FBL after empiric therapy for toxoplasmic encephalitis (TE). RESULTS: Neuroradiologic characteristics did not discriminate between TE and primary CNS lymphoma (PCNSL). Probability of TE was 0.87 in Toxoplasma-seropositive patients with mass effect who were not receiving anti-Toxoplasma prophylaxis, but only 0.59 if prophylaxis was performed. In seronegative patients with mass effect, the likelihood of PCNSL was 0.74. If EBV-DNA or T gondii-DNA tests were positive, the probability of PCNSL or TE increased to more than 0.96. The absence of T gondii-DNA did not exclude the possibility of a TE diagnosis. Among FBL without mass effect, the probability of progressive multifocal leukoencephalopathy (PML) was 0.81; this increased to 0.99 if JCV-DNA testing was positive. Sensitivity of brain biopsy was 93%, with a perioperative morbidity of 12% and a mortality of 2%. CONCLUSIONS: Due to the low diagnostic capability of clinical variables, PCR amplifications in CSF, especially for EBV-DNA and for JCV-DNA, represent, in most cases, an essential step in the differential diagnosis of AIDS-related FBL. This is particularly true in patients with FBL without mass effect or with mass effect and who are either seronegative or undergoing anti-Toxoplasma prophylaxis. Brain biopsy remains a necessary procedure in EBV-DNA-positive cases and in seronegative patients with FBL displaying a mass effect. Positive JCV-DNA testing may obviate the need for brain biopsy in patients with FBL without mass effect. An advanced diagnostic strategy based on combined clinical criteria and PCR tests may allow rapid and accurate identification of patients for prompt brain biopsy or specific therapy.

AIDS Dementia Complex↗
PubMed1996

Quercetin and the growth of leukemic progenitors.

The bioflavonoid quercetin (3, 3', 4', 5-7-pentahydroxyflavone) inhibits in a dose-dependent manner the in vitro growth of acute leukemias and enhances the anti-proliferative activity of cytosine arabinoside. Quercetin exerts a blocking action of cell transition from the G0/G1 to the S phase of the cell cycle. Acute myeloid leukemias (AML)-M3,-M4 and -M5, and acute lymphoid leukemias (ALL) were more sensitive to quercetin than AML-M1 and -M2 subtypes. The sensitivity of leukemic progenitors to the growth inhibitory effect of quercetin significantly correlated with their clonogenic efficiency. We postulate that quercetin exerts its growth inhibitory action by interaction with type II estrogen binding sites and subsequent induction of Transforming Growth Factor-beta 1 expression and secretion. Finally quercetin is synergistic with hyperthermia in inducing apoptosis of leukemic cells sparing normal stem cell progenitors. Taken together these results stress the potential role of quercetin in the treatment of acute leukemias and its in vitro use in purging procedures for autologous bone marrow transplantation.

Animals↗
PubMed1995

Quercetin inhibits the growth of leukemic progenitors and induces the expression of transforming growth factor-beta 1 in these cells.

We previously showed that quercetin (3,3',4',5,7 pentahydroxyflavone) inhibits in a dose-dependent manner the growth of acute leukemias and is able to enhance the antiproliferative activity of cytosine arabinoside. We show here that quercetin inhibits the clonogenic activity of 20 of 22 acute leukemias (AL; 4 M1-AML, 3 M2-AML, 2 M3-AML, 3 M4-AML, 3 M5-AML, and 7 ALL). In the present report, we show that the induction of transforming growth factor-beta 1 (TGF-beta 1) in leukemic blasts is one of the growth-inhibitory mechanisms of quercetin in these cells. This observation was supported by the following data. (1) Quercetin-sensitive leukemic blasts, when treated with quercetin, secrete large amounts of TGF-beta 1 in the medium and show positivity for TGF-beta 1-immunoreactive material in the cytoplasm. (2) At a concentration of 8 mumol/L, antisense TGF-beta 1 oligonucleotides prevent the growth-inhibitory action of quercetin. (3) Anti-TGF-beta 1 neutralizing monoclonal antibodies can prevent almost completely the growth-inhibitory activity of quercetin. The analysis of quercetin-resistant cases confirmed as well the central role of TGF-beta 1 in the growth-inhibitory activity of quercetin. In conclusion, quercetin can act as a cytostatic agent for leukemic cells by modulating the production of TGF-beta 1.

Bone Marrow↗
PubMed1995

Tamoxifen and quercetin interact with type II estrogen binding sites and inhibit the growth of human melanoma cells.

The mechanism of the antiproliferative activity of tamoxifen on melanoma cells in vitro and in vivo is poorly understood, as it is not mediated by the antiestrogenic properties of tamoxifen. Using a whole-cell assay and nuclear and cytosolic radio-binding experiments with [3H]-estradiol as tracer, we found that MNT1, M10, and M14 melanoma cell lines as well as primary tumors expressed type II estrogen binding sites that bind tamoxifen and the flavonoid quercetin with similar affinity (KD 10-25 nM). Cell count and clonogenic assay showed both compounds to inhibit melanoma cell growth in a concentration-dependent manner in the range of concentrations between 1 nM and 1 microM. Neither the pure antiestrogen ICI-182780 nor the 3-rhamnosylglucoside of quercetin, rutin, bound to type II estrogen binding sites or inhibited cell growth. Our results suggesting that tamoxifen and quercetin can inhibit melanoma cell growth by interacting with type II estrogen binding sites help explain the reported effectiveness of tamoxifen, particularly in estrogen-receptor-negative tumors, and stress the potential role of quercetin in the treatment of melanoma.

Binding Sites↗