Synergistic effects of the fenretinide (4-HPR) and anti-CD20 monoclonal antibodies on apoptosis induction of malignant human B cells.
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Retinoids have been shown to be clinically useful in the biological therapy of certain myeloid and T-cell malignancies, whereas CD20 has proven to be an effective target in B-cell lymphoma immunotherapy. Both retinoic acid derivatives and anti-CD20 monoclonal antibodies have also been shown to induce apoptosis of malignant cells in vitro. Retinoid-induced apoptosis is thought to be mediated by nuclear retinoid receptor binding and transcriptional activation, whereas CD20 ligation appears to initiate transmembrane Ca(2+) influx with resultant programmed cell death. In this report, we evaluate the in vitro effects of N-(4-hydroxyphenyl) retinamide (4-HPR) with and without anti-CD20 antibodies in B-cell lymphoma lines. We demonstrate that 4-HPR inhibits the growth of malignant B-cells beyond that of all-trans-retinoic acid and 13-cis-retinoic acid. We also show that this 4-HPR-mediated growth inhibition is attributable to apoptosis, is consistent across a variety of malignant B-cell lines (Ramos, Ramos AW, SU-DHL4, and Raji), peaks at 96 to 144 h, and is attainable with concentrations as low as 2 microM. As with CD20-mediated apoptosis, we show that the final common pathway includes caspase activation that can be blocked by 2-val-Ala-Asp-fluoromethyl ketone (z-VAD), a specific inhibitor of caspase function. Coincubation of a 2 microM concentration of 4-HPR and the anti-CD20 antibodies rituximab and tositumomab exhibited a supra-additive increase in levels of apoptosis induction of 24% (P = 0.009) and 42% (P = 0.0019) relative to expected additive levels of these same agents. These in vitro findings suggest that the potential in vivo synergy of these well-tolerated drugs may augment the previously demonstrated clinical activity of anti-CD20 monoclonal antibodies in the treatment of B-cell malignancies. (+info)
Increased frequency of pre-germinal center B cells and plasma cell precursors in the blood of children with systemic lupus erythematosus.
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We have analyzed the blood B cell subpopulations of children with systemic lupus erythematosus (SLE) and healthy controls. We found that the normal recirculating mature B cell pool is composed of four subsets: conventional naive and memory B cells, a novel B cell subset with pregerminal center phenotype (IgD(+)CD38(+)centerin(+)), and a plasma cell precursor subset (CD20(-)CD19(+/low)CD27(+/++) CD38(++)). In SLE patients, naive and memory B cells (CD20(+)CD38(-)) are approximately 90% reduced, whereas oligoclonal plasma cell precursors are 3-fold expanded, independently of disease activity and modality of therapy. Pregerminal center cells in SLE are decreased to a lesser extent than conventional B cells, and therefore represent the predominant blood B cell subset in a number of patients. Thus, SLE is associated with major blood B cell subset alterations. (+info)
Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura.
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The role of rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, in the treatment of patients with chronic idiopathic thrombocytopenic purpura (ITP) has not been determined. The effectiveness and side effects of this therapeutic modality were investigated in a cohort of 25 individuals with chronic ITP. All patients had ITP that had been resistant to between 2 and 5 different therapeutic regimens, including 8 patients who had already failed splenectomy. Patients were scheduled to receive intravenous rituximab at the dose of 375 mg/m(2) once weekly for 4 weeks. Rituximab infusion-related side effects were observed in 18 patients, but were of modest intensity and did not require discontinuation of treatment. A complete response (platelet count greater than 100 x 10(9)/L) was observed in 5 cases, a partial response (platelet count between 50 and 100 x 10(9)/L) in 5 cases, and a minor response (platelet count below 50 x 10(9)/L, with no need for continued treatment) in 3 cases, with an overall response rate of 52%. In 7 cases, responses were sustained (6 months or longer). In 2 patients with relapsed disease, repeat challenge with rituximab induced a new response. In patients with a complete or partial response, a significant rise in platelet concentrations was observed early during the course of treatment, usually 1 week after the first rituximab infusion. No clinical or laboratory parameter was found to predict treatment outcome, although there was a suggestion that women and younger patients have a better chance of response. In conclusion, rituximab therapy has a limited but valuable effect in patients with chronic ITP. In view of its mild toxicity and the lack of effective alternative treatments, its use in the setting of chronic refractory ITP is warranted. (Blood. 2001;98:952-957) (+info)
Early phase of intestinal mantle cell lymphoma: a report of two cases associated with advanced colonic adenocarcinoma.
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Intestinal mantle cell lymphoma characteristically produces multiple polyps, a finding reported as multiple lymphomatous polyposis. The early stages of intestinal mantle cell lymphoma before polyp formation and the pattern of initial lymph node invasion, however, have not been described. We recently encountered two cases of intestinal mantle cell lymphoma in their early development found incidentally associated with advanced colonic adenocarcinoma. We present herein the clinical, histopathological, immunohistochemical, and molecular genetic features of these two cases. In one case, a single polypoid mass was found with invasion limited to mucosa and submucosa of the terminal ileum and without lymph node compromise. In the second case, there were multiple mucosal aggregates of neoplastic cells without formation of polyps. Regional lymph nodes in the latter case showed either partial or complete involvement by lymphoma. In both cases, immunohistochemistry (CD20+, CD5+, cyclin D1+, CD10-, and CD23-), and demonstration of clonal immunoglobulin heavy chain and bcl-1 gene rearrangements by PCR analysis confirmed the diagnosis of mantle cell lymphoma. (+info)
Rituximab therapy of patients with B-cell chronic lymphocytic leukemia.
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Rituximab (IDEC-C2B8) is a chimeric antibody that binds to the B-cell surface antigen CD20. Rituximab has significant activity in follicular non-Hodgkin lymphomas. Much less is known about the effects in chronic lymphocytic leukemia (CLL). We have initiated a phase II trial to evaluate the efficacy and safety of rituximab in patients with CD20+ pretreated CLL. To avoid the rituximab-associated toxicity, we restricted the tumor cell load, as measured by the number of circulating lymphocytes and the spleen size, in the first 2 cohorts of patients included in the study. Patients received 4 intravenous infusions of 375 mg/m2 once a week over a period of 1 month. Of the 28 patients evaluable for response, 7 patients showed a partial remission (National Cancer Institute criteria) lasting for a median of 20 weeks, with 1 patient still in remission after 71 weeks. Based on lymphocyte counts only, we found at least a 50% reduction of lymphocyte counts lasting for at least 4 weeks in 13 (45%) of 29 patients. Fifteen patients from 3 institutions were monitored for the immunophenotype profile of lymphocyte subsets. The number of CD5+CD20+ cells decreased significantly and remained low until day 28 after therapy. T-cell counts were not affected. With the exception of one rituximab-related death, adverse events in the remaining patients were mild. The results suggest that rituximab has clinical activity in pretreated patients with B-CLL. Toxicity is tolerable. Response duration after withdrawal of rituximab is rather short. Therefore, other modes of application and the combination with other agents need to be tested. (+info)
Anti-CD20 monoclonal antibody treatment of human herpesvirus 8-associated, body cavity-based lymphoma with an unusual phenotype in a human immunodeficiency virus-negative patient.
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Human herpesvirus 8 (HHV-8), or Kaposi's sarcoma-associated herpesvirus, is a gammaherpesvirus first detected in Kaposi's sarcoma tumor cells and subsequently in primary effusion lymphoma (PEL) tumor cells and peripheral blood mononuclear cells from PEL patients. PEL has been recognized as an individual nosologic entity based on its distinctive features and consistent association with HHV-8 infection. PEL is an unusual form of body cavity-based B-cell lymphoma (BCBL). It occurs predominantly in human immunodeficiency virus (HIV)-positive patients but occasionally also in elderly HIV-negative patients. We describe a case of PEL, with ascites, bilateral pleural effusions, and a small axillary lymphadenopathy, in a 72-year-old HIV-negative man. PCR performed on a lymph node specimen and in liquid effusion was positive for HHV-8 and negative for Epstein-Barr virus. The immunophenotype of the neoplastic cells was B CD19+ CD20+ CD22+ with coexpression of CD10 and CD23 and with clonal kappa light chain rearrangement. The patient was treated with Rituximab, a chimeric (human-mouse) anti-CD20 monoclonal antibody. Thirteen months later, the patient continued in clinical remission. This is the first report of an HHV-8-associated BCBL in an HIV-negative patient in Argentina. (+info)
CD8 T lymphocytes and macrophages infiltrate coronary artery aneurysms in acute Kawasaki disease.
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The pathogenesis of coronary arterial inflammation in acute Kawasaki disease (KD) is unclear. To test the hypothesis that the KD vascular lesion is an activated T lymphocyte-dependent process, immunohistochemical studies were done on coronary artery aneurysms from 8 fatal acute KD cases by using antibodies to CD45RO (activated or memory T lymphocyte), CD8 (cytotoxic T lymphocyte), CD4 (helper T lymphocyte), HAM56 (macrophage), and CD20 (B lymphocyte). Acute KD coronary arteritis was characterized by transmural infiltration of CD45RO T lymphocytes with CD8 T lymphocytes predominating over CD4 T lymphocytes. Macrophages were present primarily in the adventitial layer; B lymphocytes were notably absent. These data lend support to the hypotheses that KD results from infection with an intracellular pathogen, such as a virus, whose antigens are presented by major histocompatibility complex class I molecules, and that CD8 T lymphocytes and macrophages are important in the pathogenesis of KD coronary aneurysms. (+info)
Higher levels of surface CD20 expression on circulating lymphocytes compared with bone marrow and lymph nodes in B-cell chronic lymphocytic leukemia.
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Differential expression of CD20 surface antigen in B-cell neoplasms at different sites is largely unknown. The number of CD20 antibodies bound per cell (CD20 ABC) in bone marrow (BM), peripheral blood (PB), and lymph node aspirate (LNA) samples from patients with B-cell chronic lymphocytic leukemia (B-CLL) or other B-cell disease was studied using quantitative flow cytometry. CD20 ABC differed significantly with the specimen type in B-CLL, being highest in PB (mean, 9,051) and lower in BM (mean, 4,067) and LNA (mean, 3,951). No difference in CD20 ABC between BM and PB samples was found in splenic lymphoma, mantle cell lymphoma, or follicular lymphoma. Also, we found a significant difference of CD20 ABC by type of disease: lowest in B-CLL; higher in splenic, follicular, and mantle cell lymphoma; and highest in hairy cell leukemia. The lower CD20 surface antigen levels in BM and LNA than in PB in B-CLL may have clinical relevance with regard to the efficacy of rituximab therapy. (+info)