Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among the monoclonal antibodies (mAbs) under clinical development, anti-CD20 mAbs have been most extensively investigated and have shown definitive clinical activities. Rituximab is a genetically engineered, chimeric anti-CD20 mAb with mouse variable and human constant regions. Consecutive clinical trials conducted in the United States, Europe, and Japan have revealed that rituximab is an effective agent, with acceptable toxicities, in the treatment of indolent and aggressive B-cell non-Hodgkin's lymphomas (B-NHLs). A recent European phase III study in elderly patients with untreated diffuse large B-cell lymphoma suggested that rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) chemotherapy is superior to CHOP chemotherapy alone in terms of complete response rate and event-free and overall survivals. Lymphoma is inherently a radiosensitive tumor. The aim of radioimmunotherapy is to use the mAb to target radiation to lymphoma tissue while minimizing toxicity to normal cells. Clinical trials of (90)Y-ibritumomab tiuxetan and (131)I-tositumomab showed that they have definitive efficacy in relapsed indolent B-NHL, with acceptable toxicities. A recent comparative study in relapsed indolent B-NHL showed that (90)Y-ibritumomab tiuxetan produced a higher response rate than rituximab. In addition, BL22, a recombinant anti-CD22 immunotoxin, showed significant efficacy in patients with chemotherapy-resistant hairy cell leukemia. Monoclonal antibodies will have significant roles in the treatment of lymphoid malignancies in the future.
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PMID:Rituximab and other emerging antibodies as molecular target-based therapy of lymphoma. 1295 76

Even with routine immunohistochemical evaluation, distinguishing classic Hodgkin lymphoma (CHL) from diffuse large B-cell lymphoma (DLBCL) or anaplastic large cell lymphoma (ALCL) can be difficult. In these cases, the transcription factors (B cell-specific activator protein [BSAP], octamer-binding transcription factor 2 [Oct-2], and B-cell Oct-binding protein 1 [BOB.1]) and the pan-B-cell markers (CD20, CD22, and CD79a) may aid in clarifying the diagnosis. In 57 cases of CHL, 5 cases of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), and 33 cases of non-Hodgkin lymphoma (25 DLBCL and 8 ALCL) we found the transcription factor phenotype BSAP+ and either Oct-2- or BOB.1- to be predictive of CHL; BSAP+/Oct-2+/BOB.1+ was predictive of NLPHL or DLBCL, while BSAP- was predictive of ALCL. Expression of all 3 pan-B-cell markers was seen only in NLPHL and DLBCL; positivity for a single B-cell marker was present only in CHL. Thus, together, the transcription factors and pan-B-cell markers might be useful in the differential diagnosis of CHL.
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PMID:The B-cell transcription factors BSAP, Oct-2, and BOB.1 and the pan-B-cell markers CD20, CD22, and CD79a are useful in the differential diagnosis of classic Hodgkin lymphoma. 1460 5

Non-Hodgkin's lymphomas (NHL) are a diverse group of malignancies that result, in addition to their treatments, in significant morbidity and mortality in the population. The identification of more effective and better tolerated treatments is of vital importance. Immunotherapy using monoclonal antibodies directed against the CD20 protein has had a profound impact on the management of patients with B-cell NHL. Additional antigen targets are being aggressively investigated. The targeting of lymphoma cells with monoclonal antibodies offers a treatment with a potentially noncross-resistant mechanism of action and a more favorable toxicity profile compared to chemotherapy. Epratuzumab (humanized LL2) is a humanized immunoglobulin G1 monoclonal antibody directed against the CD22 protein in which expression is restricted to mature B cells. Because of important differences in the characteristics of CD22 compared to CD20, epratuzumab may become an important component of future therapies for NHL.
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PMID:Epratuzumab in non-Hodgkin's lymphomas. 1523 5

Multiparametric clinical flow cytometry has evolved from two-parameter quantitative assessment of lymphocytes to assessment of many qualitative parameters of suspensions obtained from bone marrow, peripheral blood, and lymph nodes for hematopathology. Nowadays, lymphoma immunophenotyping is a necessary complement to morphology and molecular parameters in the diagnosis and monitoring of human hematopoietic malignancies. The aim of the present study was to determine whether immunophenotypic differences could be used to distinguish between non-Hodgkin's B cell lymphoma (NHL-B) and the normal B cell subpopulation by assessing the variability in the patterns of expression of some lymphoid antigens (CD5, CD19, FMC7, CD23, CD20, CD79b, CD38, CD22, CD10, sIgkappa, sIglambda, mIgA, mIgG, mIgM, and mIgD) in specimens obtained from patients with NHL-B. We have studied peripheral blood samples, lymph node suspensions, and bone marrow specimens from 20 patients with malignant lymphoma and from controls without oncohematologic disease. Some patients showed stable patterns of antigen expression that remained unchanged over time and were consistent from one specimen to another. Other patients showed more variability in the pattern of antigen expression from different specimens. The two-way cluster analysis of antigens revealed three patterns of expression: (1) most cells in most cases positive (CD5, CD19, CD20, CD23, CD45); (2) most cells in most cases negative (CD10, mIgG, CD22, CD23,CD38); and (3) a mixed pattern with a variable number of positive cases and a variable percentage of positive cells in individual cases (CD22, CD38, CD79b, FMC7, mIgD, mIgM, mIgA, mIgG, sIgkappa, sIglambda). The expression of several antigens was strongly interdependent, even when antigens belonged to entirely different gene families. Such antigen pairs were CD19/CD45; CD19/CD79b; CD23/Igkappa; and CD45/CD79b. Our results suggest that different factors may determine the stability or the variability of such multiantigen expression, particularly the biology and function of the different antigens and the mechanisms of disease dissemination and progression.
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PMID:Flow cytometric immunophenotyping analysis of patterns of antigen expression in non-Hodgkin's B cell lymphoma in samples obtained from different anatomic sites. 1565 Feb 71

The transcription factor PU.1 has been shown to be crucial for the early stages of B cell development but its function at later stages of B cell development is less well known. We observed previously that PU.1 is expressed uniformly throughout the mature pre-plasma cell B cell population, the only exception being a subpopulation of germinal centre (GC) cells which showed exceptionally high expression of PU.1. This suggested that PU.1 may also have a role in GC B cell biology. To test this hypothesis and to screen for possible genes regulated by PU.1, we first evaluated semi-quantitatively the possible co-expression of PU.1 with proteins known to be upregulated or downregulated during GC B cell development. Normal lymphoid tissues and 255 B cell non-Hodgkin lymphomas of putative GC B cell origin were evaluated. PU.1 expression was positively associated with CD10 (p < 0.0001), CD20 (p = 0.043), CD22 (p = 0.005), CD79a (p = 0.024) and Bcl-6 (p < 0.0001) and negatively associated with cytoplasmic immunoglobulin light-chain expression (p = 0.036) in diffuse large B cell lymphoma. Identical or nearly identical associations were found in follicular lymphoma. Since CD20 is known to be partly regulated by PU.1 and putative PU.1-binding sites have been described in the regulatory regions of the CD22, CD79a and CD10 genes, we looked for putative PU.1 binding sites in the BCL6 promotor. Four such putative PU.1 binding sites were identified. Further analysis by gel-shift electromobility essay showed that PU.1 protein binds to three of the four putative binding sites in the BCL6 promotor. PU.1 and Bcl-6 were also found to be upregulated in centroblasts in the normal GC, but jointly downregulated in a subpopulation of centrocytes. Our findings support the contention that PU.1 may also have an important role in GC B cell development.
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PMID:PU.1 protein expression has a positive linear association with protein expression of germinal centre B cell genes including BCL-6, CD10, CD20 and CD22: identification of PU.1 putative binding sites in the BCL-6 promotor. 1684 70

The recent approval of rituximab, gemtuzumab ozogamicin, alemtuzumab and ibritumomab tiuxetan by the FDA in the US revealed clear evidence that monoclonal antibodies (mAbs) have significant roles in the current treatment of haematologic malignancies. Among the mAbs under clinical development, anti-CD20 mAbs have been most extensively investigated and have shown definitive clinical efficacy. Rituximab is a genetically engineered chimeric anti-CD20 mAb, with mouse variable and human constant regions. Consecutive clinical trials conducted in the US, Europe and Japan have revealed that rituximab is a highly effective agent with acceptable toxicities against indolent and aggressive B cell non-Hodgkin's lymphomas (B-NHLs) as a single agent and in combination with cytotoxic drugs. A recent French Phase III study in elderly patients with untreated aggressive B-NHL suggested that the addition of rituximab to standard CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy increases the complete response rate and prolongs event-free and overall survival. Lymphoma cells are inherently sensitive to radiation. The aim of radioimmunotherapy is to use the mAb to target radiation to lymphoma tissue while minimising toxicity to normal cells. The clinical trials of 90Y ibritumomab tiuxetan and (131)I tositumomab showed they have definitive efficacy in relapsed indolent B-NHL with acceptable toxicities. A recent comparative study in relapsed indolent B-NHL showed that 90Y ibritumomab tiuxetan produces higher response rates than rituximab. In addition, BL22, a recombinant anti-CD22 immunotoxin, showed significant efficacy in patients with chemotherapy-resistant hairy cell leukaemia. MAbs will have significant roles in the treatment of lymphoid malignancies in the future.
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PMID:Rituximab and other emerging monoclonal antibody therapies for lymphoma. 1598 52

Chronic lymphocytic leukemia (CLL) is characterized by a clonal expansion of low proliferating mature B and T lymphocytes in the bone marrow and peripheral blood. The nuclear antigen Ki 67 is a protein detected in G1, S, G2 and M phases of the cell cycle, but not in G0, and thus, is a widely accepted proliferation marker of Human tumors. The aim of this study was to evaluate Ki 67 monoclonal antibody in CLL. We studied 48 patients diagnosed as CLL on the presence of clinical signs, over 4.109/l circulating lymphoid cells and immunophenotyping by flow cytometry using CD19, CD5, CD22, CD23, FMC7 and immunoglobulin light chains monoclonal antibodies. Ki 67 immunostaining was determined by Avidin Biotin Complex method. Our results allows to characterize between CLL: one group which proliferation rate (percentage of Ki 67 positive cells) was equal or less than 2%, represented by 14 cases (29,2%) with morphological aspect of typical CLL, one group which proliferation rate was between 3% and 9% represented by 32 cases (66,6%) with morphological aspect of polymorph CLL or prolymphocytic leukemia, and a last group with proliferation rate equal or up to 10% and corresponding to two cases (4,2%) of transformation of CLL to high grade Non Hodgkin lymphoma. There were no correlation between Matutes immunological score and proliferation rate, as this rate was 2.9% in score < 3 and 2.7% in score > 3. This study confirm the Ki 67 usefulness in studying cellular proliferation, and underline that CLL with polymorphic cytology are more proliferate than typical CLL. These data reinforce the notion that CLL is a disease with heterogeneity in clinical behavior, immunophenotype, cytogenetic, molecular aspects, and thus, prognostic.
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PMID:[Expression of proliferation marker Ki 67 in chronic lymphocytic leukemia]. 1629 59

DEV is the only cell line derived from nodular lymphocyte predominance type of Hodgkin's lymphoma (NLPHL); however, a comprehensive report about the genetic and immunophenotypic profile of this unique cell line is lacking. We analyzed DEV with respect to immunophenotype and genetic aberrations. The immunostaining revealed positivity for CD45, CD20, CD22, CD79a, IgA2, CD80, CD86, CD74, and BCL6. Cytogenetically, DEV has complex chromosome 3 translocations involving chromosomes 7, 14, and 22. A detailed analysis of the 3q27 breakpoint of the der(3)t(3;14)(p14;q32)t(3;22)(q27;q11.2) revealed a break in the BCL6 alternative breakpoint region. Using array comparative genomic hybridization, a 3-megabase homozygous deletion at 17q24.1-24.2 was identified. Fluorescence in situ hybridization indicated the presence of 2 chromosome 17 homologues, each of which carried a small interstitial deletion. Eight microsatellite markers flanking the homozygously deleted region all showed a homozygous pattern suggesting loss of one of the parental alleles. D17S1809 and D17S1816 could not be amplified using DEV DNA, in keeping with a location within the homozygously deleted segment. In conclusion, DEV has an immunophenotype that is consistent with the neoplastic cells of NLPHL cases, the lymphocytic and histiocytic cells. We demonstrated involvement of the BCL6 gene based on the presence of a breakpoint in the alternative breakpoint region and nuclear staining for BCL6 protein and identified a homozygously deleted region at 17q24.
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PMID:BCL6 alternative breakpoint region break and homozygous deletion of 17q24 in the nodular lymphocyte predominance type of Hodgkin's lymphoma-derived cell line DEV. 1673 7

Epratuzumab is a humanized anti-CD22 monoclonal antibody currently in clinical trials for treatment of non-Hodgkin lymphoma (NHL) and certain autoimmune diseases. Here we report the results of investigations of epratuzumab's mode of action in comparison to and in combination with the anti-CD20 mAb, rituximab. In vitro cell growth inhibition, induction of apoptosis, and the ability of the mAbs to mediate complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) were evaluated. We also investigated the potential activity of epratuzumab in the regulation of B-cell antigen receptor (BCR) activation. Epratuzumab and rituximab displayed very distinct modes of action; epratuzumab acts as an immunomodulatory agent, while rituximab is an acutely cytotoxic therapeutic antibody. Epratuzumab has distinct effects on cell growth from rituximab. For example, rituximab+anti-human IgG Fcgamma yielded marked inhibition of proliferation in human NHL cell lines, while epratuzumab had little or no effect in this assay. However, when cells were immobilized and stimulated with anti-IgM, epratuzumab, but not rituximab, caused a significant antiproliferative effect. Unlike rituximab, no CDC could be detected, and ADCC was modest but significant with epratuzumab. Importantly, combining rituximab and epratuzumab did not decrease rituximab's ability to induce apoptosis, CDC, and ADCC. In fact, the combination is more effective than rituximab alone in inhibiting proliferation of Daudi Burkitt lymphoma cells in the presence of second antibody, and at least equally effective to rituximab in the absence of crosslinking. These observations suggest that it may be possible to enhance clinical efficacy by combination therapy comprised of anti-CD20 and anti-CD22 mAbs.
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PMID:Epratuzumab, a CD22-targeting recombinant humanized antibody with a different mode of action from rituximab. 1681 87

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) differs in histological and clinical presentation from classical Hodgkin lymphoma (cHL). The typical morphologic signs of NLPHL are atypical "lymphocytic and histiocytic" (L&H) cells, which are surrounded by a non-neoplastic nodular background of small lymphocytes of B-cell origin. The NLPHL cells are positive for CD45, CD19, CD20, CD22 and CD79a, but lack expression of CD15 and CD30, the typical markers for cHL. NLPHL patients are predominantly of male gender with a median age of 37 years. Patients often present in early stages (63%) and rarely have B-symptoms (9%). Treatment of NLPHL patients using standard Hodgkin lymphoma (HL) protocols leads to complete remission (CR) in more than 95% of patients. Survival and freedom from treatment failure (FFTF) are worse in advanced-stage patients than in early-stage patients. Thus, patients in advanced and in early stages with unfavorable risk factors are treated similarly to cHL patients. In contrast, patients with early-stage NLPHL without risk factors can be sufficiently treated with reduced intensity programs having less severe adverse effects. As a result, treatment of early NLPHL is less clearly defined, including radiotherapy in extended field (EF) or involved field (IF) technique, combined modality treatment, and, more recently, monoclonal antibody rituximab. Watch and wait strategy plays an important role in pediatric oncology to avoid adverse effects associated with therapy.
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PMID:Biology, clinical course and management of nodular lymphocyte-predominant hodgkin lymphoma. 1712 71


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