The Spectrum of AIDS-Related Lymphoproliferative Disorders.
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Journal Article↗
Biomedical subjects
A Carbone
Publications and source records attributed to A Carbone.
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↗
The role of eosinophils in the pathobiology of Hodgkin's disease.
BACKGROUND: Even though the presence of a prominent tissue eosinophilia represents a common histopathologic feature of Hodgkin's disease (HD), eosinophils have been mainly regarded as 'innocent' bystanders recruited and activated during the cellular reaction typical of HD. To evaluate the putative role of eosinophils or eosinophil-derived cytokines on tumor-cell regulation in HD, we have analyzed these cells for the functional expression of surface ligands (L) of the tumor necrosis factor (TNF) superfamily, whose specific receptors are known to transduce proliferation signals at the surface of Hodgkin (H) and Reed-Sternberg (RS) cells. MATERIALS AND METHODS: Eosinophils from peripheral blood of healthy donors and patients with HD, primary hypereosinophilic syndrome (HES), or secondary hypereosinophilia (HE), were purified by density gradient centrifugation and immunomagnetic depletion of residual granulocytes. RESULTS: By immunostaining and mRNA analysis, we were able to show that eosinophils from normal donors and patients with HD, HES, and HE express a number of receptors and ligands of the TNF superfamily, including CD40, CD40L, CD30L, CD95/Fas, CD95/FasL and 4-1BB. In addition, we provide evidence that cytokines regulating eosinophil proliferation and activation, i.e., interleukin (IL)-5, IL-3, and granulocyte-macrophage colony-stimulating factor, are able to enhance the cellular density of several TNF superfamily ligands and/or receptors at the surface of cultured eosinophils. Finally, we have shown that native CD40L and CD30L at the surface of purified eosinophils are functionally active and able to transduce proliferative signals on CD40+ and CD30+ target cells, including cultured H-RS cells. CONCLUSIONS: Our data suggest that eosinophils may act as important elements in the pathology of HD by providing cellular ligands for TNF-superfamily receptors (CD40, CD30, CD95/Fas) able to transduce proliferation and antiapoptotic signals at the surface of H-RS cells. The presence on eosinophils of receptors for TNF ligands expressed by activated T cells (i.e., OX40L, FasL, CD40L, 4-1BBL), also suggest that eosinophils may contribute to the deregulated network of interactive signals between H-RS cells, T cells, and other surrounding reactive cells.
Antigens, Neoplasm↗
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↗
Embryonic gene expression in nonoverloaded ventricles of hereditary hypertrophic cardiomyopathic hamsters.
Current information regarding the molecular and biochemical mechanisms of myocardial hypertrophy, as obtained from isolated cardiomyocytes and/or healthy animals with aortic banding, does not permit dissection of the hierarchical relationship among different steps and triggers of the pathogenic process in vivo. The aim of the present study was to depict the temporal relationship among myocardial structural and functional characteristics, the embryonic gene program, and transforming growth factor (TGF) beta 1 expression in euthyroid hereditary hypertrophic cardiomyopathic hamsters (CMPH). This investigation was performed using Western and Northern blot and in situ hybridization techniques. The results show that in CMPH, the severity of the hemodynamic overload is not related to any modification in structural myocardial characteristics (cardiac mass, cardiomyocyte dimensions, total RNA, and protein content), whereas an early activation of the embryonic gene program occurs in not yet overloaded 90-day-old CMPH (left ventricular end diastolic pressure < 15 mm Hg). In these animals, a 30% to 90% decrease in the alpha myosin heavy chain (alpha MHC) relative content was found in ventricles, whereas beta MHC increased 5-fold. In addition, the alpha skeletal actin expression was enhanced 2-fold versus age-matched controls. No modifications were observed in myosin function evaluated by in vitro motility assay, whereas the administration of L-thyroxine (100 micrograms/kg intraperitoneally daily) to CMPH was able to reinduce the ventricular expression of the alpha MHC isoform (5-fold increase). Conversely, no changes were found in alpha cardiac actin and myosin light chain 2 (MLC2) expression. A close temporal relationship occurred in CMPH ventricles between the re-expression of the embryonic gene program and a 3-fold enhancement of the expression of TGF beta 1. These results indicate that the CMPH provides a useful model for investigating the expression of embryonic genes in hypertrophic ventricles in the absence of mechanical and hormonal stimuli, and that TGF beta 1 is involved in regulating in vivo the "embryonic step" of myocardial hypertrophy. Furthermore, the study offers new insights into the pathophysiologic mechanisms leading to heart failure.
Actins↗
Proliferating cells in adult cardiomyopathic hamster ventricles.
Myocardium of hereditary hypertrophic cardiomyopathic hamsters UM.X7.1 between 60 and 90 days of life shows large clusters of densely packed, actively proliferating cells with a rhabdoid appearance. Immunohistochemical studies showed that most of proliferating cells express, although with variable patterns, muscular markers such as desmin, alpha-sarcomeric actin, myoglobin and alpha/gamma-smooth muscle actin. The simultaneous occurrence of a poorly differentiated appearance, intense proliferating activity and expression of muscular markers seems to indicate that cluster cells may be muscular in origin and that their proliferation can be a fundamental pathophysiological step in the onset of cardiomyopathy. The possibility that myocardial proliferating cells originated from de-differentiated adult cardiomyocytes, which undergo a short cellular proliferation program, or from not fully matured (fetal) cardiomyocytes scattered throughout the myocardium is discussed.
Animals↗
Detection and distribution of hepatitis C virus-related proteins in lymph nodes of patients with type II mixed cryoglobulinemia and neoplastic or non-neoplastic lymphoproliferation.
The role of hepatitis C virus (HCV) in the pathogenesis of type II mixed cryoglobulinemia (MC) has been strongly emphasized in the last few years. Although MC is a benign lymphoproliferative disorder, the risk of overt B-cell malignancy greatly increases during its course. The occurrence of HCV infection in 10% to 30% of patients with non-Hodgkin's lymphoma (NHL) suggests that this virus may have a role in the development of MC-associated B-cell malignancies. We identified 2 patients with hyperplastic reactive lymphadenopathy (HRL) and 12 with NHL in two series of MC patients chronically infected with HCV collected over a 5-year period. Structural and nonstructural HCV-related proteins were investigated in lymph node sections by immunohistochemistry and their location and distribution were correlated with clinical and histologic findings, viremic state, and HCV genotypes. In HRL, HCV proteins were found in the cytoplasm of lymphoid cells, mainly in interfollicular areas. However, occasional positive cells were found in the mantle zone and in the germinal centers of follicles. In addition, strong reactivity was found in the circulating mononuclear cells of capsular blood vessels. HCV immunodeposits were found in 3 of 12 (25%) NHL cases. Positive cells were frequently restricted to the cortex; if not, they were randomly diffused in the neoplastic tissue. Positivity was related to the low-grade type of NHL; in the 2 composite cases, HCV immunodetection was found in the small cells, whereas large anaplastic cells were regularly negative. Other viruses previously involved in lymphoproliferation, ie, human herpes virus-6 and Epstein-Barr virus, were absent in all tissues. These data emphasize that lymphoid organs may be a site of HCV infection. The demonstration of HCV-related proteins in a nonmalignant condition, namely HRL, indicates that HCV infection precedes the neoplastic transformation and possibly plays a major role in lymphomagenesis in MC.
Adult↗
Human eosinophils express functional CD30 ligand and stimulate proliferation of a Hodgkin's disease cell line.
The presence of a prominent tissue eosinophilia represents a typical histopathologic hallmark of Hodgkin's disease (HD). To evaluate the putative role of eosinophils on tumor cell regulation in HD, we have analyzed these cells for the functional expression of CD30 ligand (CD30L), a surface molecule able to transduce CD30-mediated proliferation signals on Hodgkin's (H) and Reed-Sternberg (RS) cells. The results demonstrate that circulating and tissue eosinophils from normal donors and patients with HD or hypereosinophilic syndrome (HES), display CD30L mRNA and express CD30L protein, as shown by immunostaining with a specific monoclonal antibody (M80) and with a biotinylated soluble CD30-Fc fusion protein. The surface density of CD30L on eosinophils from HD and HES patients was remarkably higher compared with healthy donors, probably reflecting a cytokine-mediated upregulation in these pathologic conditions. Accordingly, we provide evidence that cytokines regulating eosinophils proliferation and activation, ie, interleukin-5 (IL-5), IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF), are able to enhance the cellular density of CD30L on purified eosinophils from normal subjects. Finally, we show that native CD30L on human eosinophils is a functionally active surface structure able to transduce proliferative signals on CD30+ target cells, including cultured H-RS cells. Our data suggest that eosinophils may not merely represent innocent bystanders, but rather act as important elements in the pathology of HD by contributing to the deregulated network of CD30/CD30L-mediated interactive signals between H-RS cells and surrounding reactive cells.
CD30 Ligand↗
Centromeric instability of chromosome 1 resulting in multibranched chromosomes, telomeric fusions, and "jumping translocations" of 1q in a human immunodeficiency virus-related non-Hodgkin's lymphoma.
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Chromosome Aberrations↗
Structural abnormality of 1q in an AIDS-related body-cavity-based lymphoma.
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Cell Line↗
Adjuvant immunotherapy treatment of renal carcinoma patients with autologous tumor cells and bacillus Calmette-Guèrin: five-year results of a prospective randomized study.
BACKGROUND: Active specific immunotherapy (ASI) is a strategy that attempts to boost the host's immune response specifically against its own tumor. The purpose of this study was to investigate the effect of adjuvant ASI in patients with renal carcinoma. METHODS: Of 120 consecutive patients, 60 were randomized to a control group and 60 to receive ASI comprised of 3 intradermal injections of 10(7) autologous irradiated tumor cells mixed with 10(7) Bacillus Calmette-Guèrin (in the first 2 vaccinations) or alone. At randomization and 1, 6, and 12 months after completing immunotherapy, the treated patients were evaluated for the development of delayed type cutaneous hypersensitivity (DTCH) response to autologous tumor and autologous normal renal cells. RESULTS: The baseline DTCH responses were negative in all patients. One month after completing ASI, 38 of 54 immunized patients showed a significant (P<0.01) DTCH response to autologous tumor but not to autologous normal renal cells. The response was persistent at 6 months in 25 of 44 patients and at 12 months in 16 of 28 patients. DTCH response remained negative in the nonimmunized control patients. There was no systemic toxicity but local ulcerations that healed in 2 months were observed. After a median follow-up of 61 months, the probability of 5-year disease free survival (DFS) was 63% for treated patients and 72% for control patients. The corresponding probability of 5-year overall survival (OS) was 69% and 78%, respectively. These differences were not statistically significant. CONCLUSIONS: This is the first prospective randomized study of ASI in a large population of patients with renal carcinoma after radical nephrectomy. Our data clearly indicate that ASI can increase the reactivity to autologous tumor, as measured by the DTCH test, but it appears unable to affect DFS and OS of patients.
Adjuvants, Immunologic↗
CD40: a sensitive marker of Reed-Sternberg cells.
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Antigens, Neoplasm↗
Expression of Epstein-Barr virus-encoded latent membrane protein 1 in nonendemic Burkitt's lymphomas.
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Adult↗
Distinctive expression pattern of the BCL-6 protein in nodular lymphocyte predominance Hodgkin's disease.
The BCL-6 gene encoding a nuclear-located Kruppel-type zinc finger protein is rearranged in about 30% diffuse large B-cell lymphomas and is expressed predominantly in normal germinal center B cells and related lymphomas. These findings suggest that BCL-6 may play a role in regulating differentiation of normal germinal center B cells and that its deregulated expression caused by rearrangements may contribute to lymphomagenesis. This prompted us to investigate the expression of the BCL-6 protein in Hodgkin's disease (HD), focusing on the nodular lymphocyte predominance subtype (NLPHD), which differs from classical HD by virtue of the B-cell nature of the malignant cell population (so-called L&H cells) and its relationship with germinal centers. Forty-one HD samples (19 NLPHD, 12 nodular sclerosis, and 10 mixed cellularity) were immunostained with the monoclonal antibodies PG-B6 and PG-B6p that react with a fixative-sensitive and a formalin-resistant epitope on the aminoterminal region of the BCL-6 gene product, respectively. Strong nuclear positivity for the BCL-6 protein was detected in tumor (L&H) cells in all cases of NLPHD. In contrast, BCL-6 was expressed only in a small percentage of Hodgkin and Reed-Sternberg cells in about 30% of classical HD cases. Notably, the nuclei of reactive CD3+/CD4+ T cells nearby to and rosetting around L&H cells in NLPHD were also strongly BCL-6+, but lacked CD40 ligand (CD40L) expression. This staining pattern clearly differed from that of classical HD, whose cellular background was made up of CD3+/CD4+ T cells showing the BCL-6-/CD40L+ phenotype. These results further support the concept that NLPHD is an histogenetically distinct, B-cell-derived subtype of HD and suggest a role for BCL-6 in its development.
Animals↗
Human herpesvirus 6 in human immunodeficiency virus-infected individuals: association with early histologic phases of lymphadenopathy syndrome but not with malignant lymphoproliferative disorders.
Preliminary evidence suggested that human herpesvirus-6 (HHV-6) may act as a cofactor in acquired immunodeficiency syndrome (AIDS) and may contribute to the pathogenesis of lymphoproliferative disorders occurring in individuals infected with the human immunodeficiency virus (HIV). To understand better the biological and clinical significance of HHV-6 infection in the context of HIV-related immunosuppression, the polymerase chain reaction was used to study the frequency and variant distribution of HHV-6 in peripheral blood mononucleated cells (PBMCs) from HIV-seropositive individuals, either asymptomatic or with lymphadenopathy syndrome (LAS) or with overt AIDS. Non-neoplastic and malignant lymphoproliferative disorders from both HIV-infected and HIV-seronegative patients were also investigated using the same series of samples for the presence of Epstein-Barr virus (EBV). When compared with healthy blood donors (12/42, 29%), HHV-6 prevalence in PBMCs showed a progressive decline in HIV-seropositive individuals with asymptomatic HIV infection (3/26, 11%) and in patients with LAS (1/13, 8%) and a significant reduction in patients with overt AIDS (1/20, 20%; P = 0.02). The decrease correlated with the number of CD4+ cells at the time of examination. In addition, HHV-6 DNA sequences were significantly more prevalent in LAS biopsies (13/20, 65%) than in HIV-unrelated reactive lymphadenopathies (2/10, 20%; P = 0.02) and the presence of HHV-6 sequences correlated closely with a histologic pattern of follicular hyperplasia (13/16, 81%; P = 0.003). Strikingly, HHV-6 prevalence decreased in PBMCs of LAS patients, suggesting that the likelihood of interactions between HHV-6 and HIV varies in different body districts. In particular, the demonstration that all HHV-6-carrying LAS samples were also positive for HIV infection suggests that LAS lymph nodes constitute one of the sites where biologically relevant interactions between the two viruses might occur. Also, the prevalence of EBV was higher in LAS (14/20, 70%) than in non-neoplastic lymph nodes from HIV-seronegative individuals (4/10, 40%), although the difference was not statistically significant. EBV was associated strongly with HIV-related malignant lymphoproliferative disorders, being detected in 100% of patients with Hodgkin's disease (HD) and 53% of B-cell non-Hodgkin's lymphomas (NHL). In contrast, the prevalence of HHV-6 DNA in HD and B-cell NHL arisen in HIV-infected patients (30% and 6% respectively) was remarkably lower and similar to that observed in lymphoproliferative disorders from HIV-seronegative patients. Finally, as observed in healthy individuals, HHV-6 variant B was more prevalent than variant A in benign and malignant lymphoproliferative disorders from bot HIV-infected and HIV-seronegative patients. These results suggest that the interactions between HHV-6 and HIV could be different in the various phases of HIV disease and in different districts; HHV-6 has probably no direct role in the pathogenesis of HIV-associated B-cell NHL and HD cases, and behave differently from EBV; and HIV-related immunosuppression does not alter the distribution of HHV-6 variants in these tissues, as observed in the case of EBV.
AIDS-Related Complex↗
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↗
Long-term survival of patients with HIV-related systemic non-Hodgkin's lymphomas.
BACKGROUND: the overall outcome of patients with HIV-related non-Hodgkin's lymphomas (HIV-NHL) is poor because of the adverse clinico-pathological features of HIV-NHL and the underlying HIV infection. However, the experience of physicians in the management of HIV-NHL has increased, in particular in the use of intensive chemotherapy regimens, leading to an improvement in the prognosis of some of these neoplasms. Because some patients with AIDS may survive up to 5 years, it is possible to evaluate the long-term efficacy of the treatment of patients with HIV-NHL. In the general population, aggressive NHL, that are those occurring in HIV patients, may be considered cured after 2 years of lasting complete remission (CR) after chemotherapy. PATIENTS AND METHODS: we reviewed our monoinstitutional case-series of 73 HIV-infected patients with systemic NHL, observed between April 1985 and February 1993. Two groups of patients were arbitrarily identified, the first one (group A) including patients with a CR lasting for at least 2 years (N = 13) and the other including all remaining patients (group B) (N = 60). RESULTS: the 13 patients of group A differed significantly from the other patients in terms of higher CD4+ cell count and performance status (PS) at the time of diagnosis of NHL. There was no significant difference in the histological subtypes of the HIV-NHLs. The overall survival of the 73 patients was 8 months. In a separate analysis on all patients, age less than 30 years, PS less or equal to 1, a CD4+ cell count equal to or higher than 100/mm3 and the absence of B symptoms were significantly associated with a longer survival. The median survival in patients of group A was 42 months, however none of these patients relapsed during a median observation time of 42 months (range, 24-90). CONCLUSIONS: long-term survival and possibly cure can be obtained in some patients with HIV-NHL, in particular in those with a better PS and a less advanced immune dysfunction. In fact some of these patients are alive without evidence of disease 4 to 7 years after therapy, and others died of causes related to underlying HIV infection, in particular opportunistic infections, rather than relapse of NHL.
Adult↗
A follow-up study of determinants of second tumor and metastasis among subjects with cancer of the oral cavity, pharynx, and larynx.
We conducted a follow-up study of 380 incident cases of cancer of the oral cavity, pharynx, or larynx, who had been included in a previous case-control study. Information pertaining to potential risk factors, clinical characteristics, and evolution of the tumor (vital status, metastases, and second primary tumors) was obtained. From a multivariate proportional hazard model including terms for risk factors and clinical variables, the incidence of metachronous second primary tumors occurring in the head and neck was positively associated with employment as a farmer as opposed to white collar (hazard ratio [HR] = 3.3) and with tobacco smoking before first tumor diagnosis (HR = 4.3 for heavy versus never or very light smoker). The risk of second primary tumor decreased with increasing dietary "beta-carotene" intake (HR = 0.4 for high versus low intake in tertiles). Less differentiated first primary tumors were followed more frequently by second tumors as compared to grade 1 tumors. The incidence of metastases was not associated with etiological factors of the first tumor, but with stage.
Adult↗