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M Raphael

Publications and source records attributed to M Raphael.

At least 73 records · Page 4Linked to original sources
PubMed1994

Visualization of the endogenous NF-kappa B p50 subunit in the nucleus of follicular dendritic cells in germinal centers.

NF-kappa B, a 50 kDa/65 kDa (p50/p65) heterodimer, is a ubiquitous transcription factor involved in the positive regulation of various immune genes. The aim of this study was to determine whether NF-kappa B is related to a particular cell type and/or differentiation step during immunopoiesis. Using in situ hybridization on sections from non HIV hyperplastic lymph nodes, we found that the gene of the 105 kDa precursor of p50 was overexpressed in the light zone of germinal centers, with a network aspect, which suggested the involvement of follicular dendritic cells (FDC). By immunohistochemistry, p50 protein was detected in the cytoplasm and nucleus of FDC, confirming the involvement of FDC. Furthermore, p50 protein was detected in the cytoplasm of all lymphocytes. Thus, we focused our study on isolated FDC clusters from normal tonsils. As showed on tissue sections, we detected the p50 in both cytoplasm and nucleus of FDC. Nuclei of lymphocytes from FDC clusters were negative. We next studied p65 and c-Rel protein expression in FDC clusters. p65 was detected in the cytoplasm of FDC, whereas nuclei were negative. Furthermore, p65 was detected in the nuclei of some lymphocytes. c-Rel protein was detected only in the cytoplasm of lymphocytes and not in the nucleus and cytoplasm of FDC. Our results indicated that, in the context of T cell-dependent B cell immunopoiesis occurring in FDC clusters, p50 is mainly related to FDC with a massive overexpression in the nuclei, whereas p65 is expressed in a scattered manner in the nuclei of lymphocytes and c-Rel protein exclusively in the cytoplasm of lymphocytes from FDC clusters. These results suggested that the two subunits of NF-kappa B and the c-Rel protein have different roles in different cell types during B cell immunopoiesis.

Adolescent↗
PubMed1994

Epstein-Barr virus latent and replicative gene expression in post-transplant lymphoproliferative disorders and AIDS-related non-Hodgkin's lymphomas. French Study Group of Pathology for HIV-associated Tumors.

In acquired immunodeficiency, B-cell proliferation is usually associated with Epstein-Barr virus (EBV), implying the impairment of the normal control of EBV and EBV-infected cells. It has been assumed that EBV infection is latent in lymphoproliferative disorders. In order to determine the type of latency and to investigate whether any lymphoproliferative disorders enter into the lytic cycle, we analyzed the expression of latent and replicative EBV genes in 9 post-transplant lymphoproliferative disorders (PTLD) and in 23 EBV-positive AIDS-related non-Hodgkin's lymphomas (AR-NHL). The PTLD cases were categorized into polyclonal or monoclonal polymorphic tumors and monoclonal monomorphic tumors. The AR-NHL cases included large-cell/immunoblastic (LC/IB) and Burkitt's lymphoma (BL) groups. We demonstrated that varying patterns of latent-viral-gene expression are exhibited showing the 3 forms of latency. Polymorphic PTLD and LC/IB AR-NHL frequently expressed type II or III latency, whereas monomorphic tumors and BL AR-NHL showed type I latency. It is noteworthy that 3 cases of BL AR-NHL expressed latency II form. Induction of lytic cycle highlighted by the expression of BZLF1 occurred in 55.5% of PTLD, 36% of LC/IB and 22% of BL AR-NHL. In contrast, late viral proteins indicating productive cycle were present in 22% of PTLD, 14% of LC/IB, and were absent in BL cases. These data suggest that the impairment of EBV control permits disruption of latency, but the initiation of the lytic cycle may not always lead to viral production.

Gene Expression↗
PubMed1994

[Sarcoidosis and non-Hodgkin's lymphoma. A non-fortuitous association].

The simultaneous disclosure of a lymphoblastic B cell lymphoma and sarcoidosis is reported herein. The initially undiagnosed sarcoidosis leads to discuss the differential diagnosis of a sarcoid-like reaction associated to the lymphoma. The association of sarcoidosis and malignant lymphoproliferative disease is not fortuitous; nevertheless the simultaneity of the two diagnoses, the lymphoblastic type of the lymphoma and the colocalization of granulomatous and lymphomatous lesions in lung and liver are unusual features.

Diagnosis, Differential↗
PubMed1993

Variable morphology of human immunodeficiency virus-associated lymphomas with c-myc rearrangements. The French Study Group of Pathology for Human Immunodeficiency Virus-Associated Tumors, I.

Burkitt lymphoma (BL) and immunoblastic lymphoma (IL) are the most frequent lymphoid tumors encountered in human immunodeficiency virus (HIV)-infected patients. Tumors with a morphology intermediate between BL and IL, and the existence of Burkitt's type translocations in some IL cases makes the classification of these tumors sometimes unclear. We have studied 14 cases of BL and IL in HIV-seropositive individuals with regard to clonality, Epstein-Barr virus (EBV) association, and the presence of c-myc rearrangement. Of seven tumors with morphology of BL, all were monoclonal, six showed a c-myc rearrangement and four were associated with EBV. Five tumors with morphology of IL were associated with EBV and devoid of c-myc rearrangement. Three were polyclonal representing EBV-driven lymphoproliferations similar to those observed in transplant recipients. Two tumors, one with a morphology of IL and the other intermediate between IL and BL were monoclonal, associated with EBV, and harbored a c-myc rearrangement. We propose that these last two tumors represent cases of BL that have adopted an immunoblastic morphotype in the context of acquired immunodeficiency syndrome (AIDS), reflecting the morphologic evolution of Burkitt lymphoma cells observed in culture.

Adult↗
PubMed1993

In situ demonstration of Epstein-Barr virus small RNAs (EBER 1) in acquired immunodeficiency syndrome-related lymphomas: correlation with tumor morphology and primary site.

Some acquired immunodeficiency syndrome (AIDS)-related lymphomas (ARLs) are infected with Epstein-Barr virus (EBV), although the frequency and importance of this association is disputed. Using paraffin section RNA in situ hybridization (ISH) with digoxigenin-labeled riboprobes, we screened 16 central nervous system (CNS) non-Hodgkin's lymphomas (NHLs), 101 systemic NHLs, and 11 Hodgkin's disease cases arising in human immunodeficiency virus-seropositive individuals for EBV-encoded small RNA (EBER 1) expression, an EBV gene product transcribed in abundance during latent infection. Tumor cells contained EBV in 85 of 128 ARLs (66%), but infection rates differed with lymphoma type. EBER 1 was expressed in tumor cells in 11 of 11 Hodgkin's disease cases (100%), 15 of 16 CNS NHLs (94%), and 46 of 60 systemic immunoblast-rich/large-cell lymphomas (77%), but in only 12 of 35 Burkitt-type (small noncleaved cell) (34%) and 1 of 6 monomorphic centroblastic (diffuse large noncleaved cell) (17%) lymphomas. In most EBV-positive ARLs, all recognizable viable tumor cells expressed EBER 1. We conclude that (1) EBV infects tumor cells in all AIDS-related Hodgkin's disease cases, in virtually all primary CNS ARLs, and in most systemic immunoblast-rich/large-cell ARLs; (2) only a minority of Burkitt-type and monomorphic centroblastic lymphomas are associated with EBV; and (3) EBER-ISH is ideal for the histopathologic detection of latent EBV in routine tissue specimens.

B-Lymphocytes↗
PubMed1993

Germinal center analysis with the tools of mathematical morphology on graphs.

Only few studies devoted to quantitative analysis of tissue architecture have been performed. The analysis of neighborhood relationships between cells, using graphs and mathematical morphology (MM), constitutes one approach. We propose to analyse quantitatively the architecture of a tissue with the tools of MM on graphs. The use of graphs seems best suited to take into account the neighborhood relationships between cells, independently from their mutual distances: two cells are considered as neighbors if no interfering cell is placed in a given sense between them. Such neighboring cells are linked by an arc in a graph. On such a graph, all tools of MM may be applied. We investigate two of them in the present work: (1) the distance transforms permits to analyse the repartition of a cellular population A relative to population B, (2) the size distribution permits to analyse the tendancy of a cell population to form clusters. We have applied this method using Gabriel's graph, derived from the Voronoï diagram, to determine the "zone of influence" of a cell. We have analysed the neighborhood relationships between cells in germinal centers (GC) from lymph nodes. Twelve hyperplastic GCs from follicular hyperplasia (FH) and 5 neoplastic GCs from small cleaved cell follicular lymphoma (++SCCFL) have been studied; 2 microns hematoxylin-eosin plastic embedded sections have been analysed. Cell nuclei have been identified manually by the observer by giving a numerical and image color code. Gabriel's graphs have been constructed with all centrofollicular cells. Subgraphs with only lymphoid cells, large cells or small cleaved cells have also been studied. The application of MM transformations on the graphs using software package Morphograph has allowed a quantitative description of cell distribution in the tissue. The distances of centrofollicular lymphoid cells from the periphery of the GCs (mantle zone), from nonlymphoid cells as macrophages located within the GCs and between large lymphoid cells and small lymphoid cells have been determined in FH and SCCFL. Using iterative closings and openings, we have detected aggregates of small and large cells and characterized their size and distribution in the GCs. The application of this method on lymph node biopsy has allowed a quantitative description and comparison of GCs in different pathological conditions.

Biopsy↗
PubMed1993

Human immunodeficiency virus-related lymphoma treatment with intensive combination chemotherapy. French-Italian Cooperative Group.

PURPOSE: An increased risk of high-grade non-Hodgkin's lymphoma is observed in patients who are seropositive for human immunodeficiency virus (HIV). Treatment of such patients is complicated by their underlying acquired immunodeficiency syndrome (AIDS). Intensive strategies such as those used in non-HIV-related lymphoma may be poorly tolerated. However, patients without severe AIDS may derive significant benefits from such an approach. In a prospective multicenter study, treatment outcomes were assessed in 141 cases of HIV-seropositive lymphomas submitted to aggressive chemotherapy. PATIENTS AND METHODS: Adult patients with lymphoma with a performance status less than 3 and no active opportunistic infection were consecutively treated with three cycles of doxorubicin 75 mg/m2, cyclophosphamide 1,200 mg/m2, vindesine 2 mg/m2 for 2 days, bleomycin 10 mg for 2 days, and prednisolone 60 mg/m2 for 5 days (ACVB). This treatment was followed by a consolidation phase of high-dose methotrexate plus leucovorin, ifosfamide, etoposide, asparaginase, and cytarabine (LNH84). Central nervous system prophylaxis with intrathecal methotrexate was routinely used. Zidovudine maintenance therapy was started after chemotherapy. Ninety-three patients had high-grade lymphomas (59 Burkitt's type) and 48 had intermediate-grade lymphomas. Disseminated stage III-IV was present in 86 patients, meningeal involvement in 29, and bone marrow infiltration in 30; 62 patients had more than 2 extranodal localizations. Lactate dehydrogenase levels were above the normal value in 95 cases. The median CD4-positive lymphocyte count was 227 x 10(6)/L. RESULTS: Eighty-nine patients (63%) achieved complete remission (CR) and 19 (13%) partial remission, whereas 13 did not respond and 20 (14%) died during the course of ACVB, 8 of them from progressive disease. With a median follow-up of 28 months, median survival and disease-free survival were 9 and 16 months, respectively. Median survival for nonresponders was 5 months; 23 patients died of opportunistic infections while in persistent CR. In multivariate analysis, four factors were strongly associated with shorter survival: (1) CD4 count less than 100 x 10(6)/L, (2) performance status greater than 1, (3) immunoblastic lymphoma, and (4) prior AIDS. In the absence of all risk factors, the probability of survival at 2 years was 50%. CONCLUSION: In a selected group of HIV-related lymphomas, intensive chemotherapy with LNH84 is feasible and yields a high CR rate. Survival is short due to death from HIV-related infections; however, in a subgroup of patients without adverse prognostic factors, long-term remission was observed.

Adult↗
PubMed1993

Hodgkin's disease during HIV1 infection: the French registry experience. French Registry of HIV-associated Tumors.

BACKGROUND: The first cases of Hodgkin's disease (HD) associated with HIV infection were reported in 1984. Since then, short series of seropositive patients suffering from HD have been published. In order to identify the characteristics, treatment response and outcome of HIV-associated Hodgkin's disease (HIV-HD), the data of HIV-HD patients recorded between 1987 and 1989 were analysed and compared with those of primary HD patient and with those of HIV-associated non-Hodgkin's lymphoma (HIV-NHL), registered during the same period. PATIENTS AND METHODS: The 45 cases of HD collected by the French registry of HIV-associated tumors between January 1987 and December 1989 were included in this study. All patients were clinically staged according to the Ann Arbor system. To compare HIV-HD characteristics with those of primary HD, we used a cohort of 407 patients with clinical stages (CS) IA to IVB, who were enrolled between September 1981 and August 1988 in a multicentric clinical trial. To identify the relationship between HIV-HD and the course of HIV infection we studied, when available, the routes of infection, initial CD4 cell count at the moment of HD diagnostic as well as the CDC class of HIV infection and compared these data with the same parameters observed in 142 HIV-NHL enrolled in the registry during the same period. RESULTS: HIV-HD is characterized by an increase in mixed-cellularity histology (49%), with a predominance of advanced stages (75%) and B symptoms (80%). A unique observation is made regarding mediastinal involvement, present in only 13% of HIV-HD (71% in primary HD). The HIV-HD/HIV-NHL ratio was significantly higher in intravenous drug abusers than in male homosexuals. Median CD4 cell count was 306/microliters at HIV-HD diagnosis, and only 11% of the cases were preceded by an AIDS manifestation. With standard therapy, 79% of the patients achieved complete remission, but hematological and infectious complications were very frequent. The progression to AIDS rate was 94% at two years and opportunistic infections were the most frequent cause of death. Overall two-year survival was 41% with 71% for patients with initial CD 4 cell counts higher than 300/microliter and 0% for those with CD4 cell counts lower than 300/microliter (P < 0.01). CONCLUSION: HIV-HD has a particular clinico-pathological profile when compared to primary HD, with a predominance of mixed-cellularity type, a high frequency of advanced stages and a high proportion of patients without mediastinal involvement. Moreover, HIV-HD seems to occur preferentially in the group of subjects infected by needle sharing. Standard HD therapy seems to be efficient but excessively toxic.

Adolescent↗
PubMed1993

Detection by in situ hybridization of HIV and c-myc RNA in tumour cells of AIDS-related B-cell lymphomas.

The incidence of acquired immune deficiency syndrome (AIDS)-related malignant lymphoma has increased since the disease was first described, but its pathogenesis is still not understood. There have been numerous molecular studies addressing the clonality of these proliferations, the presence of Epstein-Barr virus genome in the tumor cells, and rearrangements of the c-myc oncogene. However, very few in situ hybridization studies have been carried out. We analysed 24 cases of high-grade B-cell malignant lymphomas and two cases of polymorphic B-cell proliferation associated with human immunodeficiency virus (HIV) infection. Human immunodeficiency virus ribonucleic acids were detected in some of the tumour cells in 19 of the 24 cases of malignant lymphomas and in both cases of polymorphic B-cell proliferation, with the in situ hybridization technique and using a specific tritiated copy deoxyribonucleic acid probe. With the same technique, c-myc ribonucleic acid was detected in most of the tumour cells from all the 21 cases of malignant lymphomas tested but not in the polymorphic B-cell proliferation.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Intratumoral production of IL-6 in B cell chronic lymphocytic leukemia and B lymphomas.

Interleukin-6 is a major B lymphocyte growth factor, and may play a role in the proliferation of malignant B lymphocytes. In order to provide arguments supporting such a role, the intratumoral production of IL-6 was studied by in situ hybridization and immunohistochemistry in 53 neoplastic tissues from B cell chronic lymphocytic leukemia or B lymphomas. IL-6-producing cells were detected in all samples but 5. However, the number of IL-6 producing cells was variable amongst the different cases. Increased density of IL-6-producing cells was highly dependent on the presence of malignant immunoblasts within the neoplastic clone. IL-6 was produced in a paracrine way, macrophages and endothelial cells being the main producers of the cytokine while malignant immunoblasts expressed the IL-6 receptor. Taken together, these results suggest that IL-6 may indeed act as a growth factor for malignant cells in some B lymphoproliferations and that this paracrine loop could be the target of new therapeutic approaches.

Gene Expression↗
PubMed1993

Epstein-Barr virus-latent gene expression and tumor cell phenotype in acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma. Correlation of lymphoma phenotype with three distinct patterns of viral latency.

We investigated 49 acquired immunodeficiency syndrome-related lymphomas (ARLs) for Epstein-Barr virus (EBV) by Southern blotting and in situ hybridization and, in positive cases, used cryostat immunohistology to compare EBV-latent gene expression (EBV encoded small RNA-1 [EBER-1], EBV nuclear antigen-2 [EBNA-2], latent membrane protein-1 [LMP-1] and host cell immunophenotype (CD11a, CD18, CD54, CD58, CD21, CD23, CD30, CD39, CDw70, immunoglobulin) patterns with those reported in other EBV infections. EBV+ immunoblast-rich/large cell ARLs (n = 22) showed three patterns of latency: broad (EBER+EBNA-2+/LMP-1+; n = 9), reminiscent of a lymphoblastoid cell line phenotype; restricted (EBER+/EBNA-2-/LMP-1-; n = 6), similar to endemic Burkitt's lymphoma; and intermediate (EBER+/EBNA-2-/LMP-1+; n = 7), a pattern rarely described in vitro but seen in certain EBV-related malignancies. EBNA-2 expression was associated with extranodal lymphomas. EBV+ Burkitt-type ARLs (n = 11) usually showed the restricted latency pattern (n = 8), but some expressed the intermediate form (n = 3). Adhesion (CD54, CD58) and activation (CD30, CD39, CDw70) molecule expression varied with morphology (immunoblast-rich/large cell versus Burkitt-type), but was not independently correlated with EBV-positivity. CD30 and LMP-1 expression were associated. ARLs show heterogeneity regarding both the presence of EBV and latency pattern. Comparison of these phenotypically distinct lymphoma groups with known forms of EBV infection provides clues to their possible pathogenesis.

Adult↗
PubMed1993

Adult T-cell leukemia/lymphoma revealed by a surgically cured cardiac valve lymphomatous involvement in an Iranian woman: clinical, immunopathological and viromolecular studies.

A 60-year-old woman from the town of Mashhad in northeastern Iran developed cardiac failure due to aortic and mitral regurgitations which needed cardiac valve replacement. Histopathological study of the valves revealed a T-cell non-Hodgkin's lymphoma. Blood examination showed leukemic features with 32% of abnormal white blood cells. Human T-cell leukemia/lymphoma virus type I (HTLV-I) antibodies were present in the serum and the specific env HTLV-I sequences were detected in the DNA extracted from the valves and peripheral blood mononuclear cells (PBMC) using polymerase chain reaction technique. Clonal integration of two HTLV-I copies was found in both the valves and PBMC DNA, thus the diagnosis of adult T-cell leukemia/lymphoma (ATL) was established. In contrast to the acute life-threatening cardiac localization, our case met the diagnostic criteria of chronic ATL, this was confirmed by favorable evolution without chemotherapy during the 24 months after diagnosis. According to our knowledge, this is the first report of an isolated lymphomatous cardiac valve involvement, without other cardiac abnormalities. It seems important to underline that the patient originated from Iran where endemicity of HTLV-I has only recently been discovered.

Aortic Valve↗
PubMed1992

Interleukin-6 production in high-grade B lymphomas: correlation with the presence of malignant immunoblasts in acquired immunodeficiency syndrome and in human immunodeficiency virus-seronegative patients.

The mechanisms leading to malignant cell proliferation may differ between the different histologic forms of high-grade non-Hodgkin's lymphomas. To analyze the potential role of interleukin-6 (IL-6) as a growth factor for lymphomatous cells in these different forms, the in situ production of this cytokine was analyzed in lymphomatous samples taken from 24 patients, 18 of whom were human immunodeficiency virus (HIV) infected. Eleven Burkitt's lymphomas (BLs), seven diffuse large-cell lymphomas, and six immunoblastic lymphomas were studied. In situ hybridization experiments showed that the IL-6 gene was expressed in all tissues. The number of IL-6 gene-expressing cells was 7 times higher in the non-BLs than in the BLs, and it was 17 times higher than that of 14 control lymph nodes displaying a benign follicular hyperplasia. Analysis of individual cases indicated that the level of IL-6 gene expression was strongly correlated with the presence of immunoblasts within the malignant clone. In contrast, this level was not correlated with the presence of Epstein-Barr virus genome in the lymphoma or with the HIV status of patients. Immunohistochemical studies with an anti-IL-6 monoclonal antibody showed that IL-6 was produced in non-BLs, but not in BLs. In the former, IL-6 mainly originated from reactive, nonmalignant cells. Immunohistochemical analyses of non-BLs also showed that malignant cells produced the 80-Kd chain of the IL-6 receptor. Taken together, these results suggest that IL-6 may act as a growth factor in some forms of high-grade B lymphomas. The presence of immunoblasts may be an indicator of such forms.

Acquired Immunodeficiency Syndrome↗