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)

Immunophenotyping of hematopoietic malignancies is usually accomplished in frozen sections or cell suspensions. To determine whether this procedure was also feasible in paraffin sections, we performed a double-blind immunoperoxidase study of 65 hematopoietic tumors whose phenotypes had been determined previously in fresh tissue. A selected antibody panel was used, including anti-LN2, UCHL-1, anti-cathepsin B, anti-Leu M1, anti-MB2, and anti-MT1. A correct phenotype was obtained on paraffin sections in 95% of cases. All 31 B-cell malignancies were properly classified, showing reactivity for LN2 and MB2. In 14 of 15 T-cell hematopoietic malignancies, all cells reacted with anti-MT1 and/or UCHL-1; the 1 case negative for these antigens was misdiagnosed as a B-cell tumor because of misinterpreted LN2 reactivity in benign histiocytes. Four of 5 true histiocytic neoplasms were positive for cathepsin B and LN2 but lacked other antigens; the fifth case was wrongly considered a B-cell proliferation because only bland histiocytes displayed cathepsin B. Only 1 of 7 Hodgkin's lymphomas was misdiagnosed (as a T-cell tumor); in the other 6 cases, Reed-Sternberg cells were reactive for LN2 and LEU M1. Five of 6 extramedullary myeloid leukemias also stained for LN2, MT1, and LEU M1. One showed LN2, MB2, and MT1; this case was classified as a B-cell neoplasm and indeed represented a pre-B-cell transformation of chronic myelogenous leukemia. These results show that the specified panel of antibodies may be useful for immunophenotyping of hematopoietic neoplasms when only paraffin sections are available for analysis. However, it cannot supplant traditional cell-marker studies of hematopoietic tumors because of its lesser accuracy.
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PMID:Immunophenotyping of hematopoietic malignancies in paraffin sections. 328 5

Cathepsin B has been demonstrated by immunohistochemical means in the macrophages of palatine tonsils, reactive lymph nodes and in specimens of Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHL). Two cases of genuine histiocytic lymphoma showed strong staining for the enzyme in most cells. In Hodgkin's disease, many Reed-Sternberg cells and Hodgkin cells were positive. Branching and 'tingible body' macrophages (histiocytic reticulum cells, HRCs) were strongly positive in all of the specimens. In reactive lymph nodes, the sinus-lining cells and intrasinusoidal macrophages were positive for cathepsin B. True dendritic reticulum cells (DRCs) appeared to be negative. Unlike muramidase (lysozyme), cathepsin B is not seen in neutrophil polymorph leucocytes.
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PMID:Immunohistochemical demonstration of cathepsin B in the macrophages of benign and malignant lymphoid tissues. 636 77

Histiocytic reticulum cells have been counted in 160 lymph nodes, comprising 50 high grade non-Hodgkin's lymphomas, 90 lymphomas of low grade histology, and 20 specimens exhibiting reactive follicular hyperplasia. The histiocytes were shown immunohistochemically by virtue of their content of the cysteine proteinase cathepsin B. A consistent and striking finding was that high grade lymphomas contain many more histiocytes than low grade lymphomas. Immunoblastic neoplasms contain up to 24.2% of these cells, whereas low grade diffuse lymphomas possess only up to 3.6% histiocytes. Histiocytic reticulum cells were also counted in benign or malignant follicular lesions in standard areas from follicle centres only. No significant differences were found between low grade lymphomas and hyperplastic nodes. These findings are discussed in relation to previous, more limited studies.
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PMID:A quantitative study of histiocytic reticulum cells in diffuse and follicular non-Hodgkin's lymphomas. 638 2

Effective antibody-drug conjugates (ADC) combine high drug-linker stability in circulation and efficient intratumoral release of drug. Conjugation of monomethyl auristatin E (MMAE) to the anti-CD30 monoclonal antibody (mAb), cAC10, produced a selective and potent ADC against CD30(+) anaplastic large cell lymphoma and Hodgkin's disease models. This ADC, cAC10-valine-citrulline-MMAE, uses a protease-sensitive dipeptide linker designed to release MMAE by lysosomal cathepsin B in target cells but maintain a stable linkage and attenuate drug potency in circulation. To evaluate ADC stability in vivo, we developed methods for measuring drug/mAb ratios at progressive times in plasma from ADC-treated mice and nonhuman primates. Anti-idiotype mAb permitted the capture and quantitation of mAb cAC10, whereas antidrug mAb and MMAE-conjugated horseradish peroxidase reporter provided quantitative detection of conjugated drug following its in vitro release by cathepsin B. These data were validated by an alternative ELISA using anti-idiotype and anti-MMAE mAbs for capture and detection, respectively. Both methods differentiated ADC with variable levels of drug loading and were subsequently applied to stability studies in severe combined immunodeficient mice and cynomolgus monkeys. Evaluation of ADC from mouse circulation showed the linker half-life to be approximately 144 hours (6.0 days), significantly greater than that reported for disulfide- or hydrazone-linked ADCs in mice or human trials. In cynomolgus monkey, the apparent linker half-life was approximately 230 hours (9.6 days), suggesting that the drug-linker will be highly stable in humans. These data represent the longest reported drug-linker half-life to date and provide the basis for the pronounced specificity and antitumor activity of cAC10-valine-citrulline-MMAE.
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PMID:In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate. 1570 75

Evaluation of: Younes A, Connors JM, Park SI et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a Phase 1, open-label, dose-escalation study. Lancet Oncol. 14(13), 1348-1356 (2013). With exceptionally high response rates, the CD30-directed antibody-drug conjugate brentuximab vedotin (BV) was US FDA approved for treatment of patients with relapsed/refractory Hodgkin lymphoma (HL). Now in Phase I clinical trial, it has been shown that combining BV with multiagent chemotherapy (excluding bleomycin) as first-line treatment in HL patients with high-risk disease is feasible. Complete response rates were over 90% and toxicity was manageable. Given that the malignant cell population comprises a minority of HL lesions, and that BV releases a diffusible cytotoxin via a cathepsin B-cleavable linker, we argue that a significant proportion of the antitumor activity of BV can be attributed to bystander cytotoxicity in addition to direct killing of CD30-expressing malignant cells.
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PMID:Could bystander killing contribute significantly to the antitumor activity of brentuximab vedotin given with standard first-line chemotherapy for Hodgkin lymphoma? 2423 20