Non-Hodgkin Lymphoma: Diagnosis and Treatment

Ansell, Stephen M.

doi:10.1016/j.mayocp.2015.04.025

Cited by 151 publications

(158 citation statements)

References 97 publications

(83 reference statements)

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“…Collectively, lymphomas constitute the fifth most common cancer in North America, with more than 90% of the patients being affected by lymphomas of B-cell origin (17). Despite overall improvements in outcomes of lymphoma, ∼30-40% of patients have disease that is either refractory or relapses after standard therapy (18). Therefore, a better understanding of the molecular pathobiology of lymphomas is needed for the development of new therapeutic approaches.…”

mentioning

confidence: 99%

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Weissmann¹,

Arvatz²,

Horowitz

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

103

140

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Heparanase is an endoglycosidase that cleaves heparan sulfate side chains of proteoglycans, resulting in disassembly of the extracellular matrix underlying endothelial and epithelial cells and associating with enhanced cell invasion and metastasis. Heparanase expression is induced in carcinomas and sarcomas, often associating with enhanced tumor metastasis and poor prognosis. In contrast, the function of heparanase in hematological malignancies (except myeloma) was not investigated in depth. Here, we provide evidence that heparanase is expressed by human follicular and diffused non-Hodgkin's B-lymphomas, and that heparanase inhibitors restrain the growth of tumor xenografts produced by lymphoma cell lines. Furthermore, we describe, for the first time to our knowledge, the development and characterization of heparanaseneutralizing monoclonal antibodies that inhibit cell invasion and tumor metastasis, the hallmark of heparanase activity. Using luciferase-labeled Raji lymphoma cells, we show that the heparanase-neutralizing monoclonal antibodies profoundly inhibit tumor load in the mouse bones, associating with reduced cell proliferation and angiogenesis. Notably, we found that Raji cells lack intrinsic heparanase activity, but tumor xenografts produced by this cell line exhibit typical heparanase activity, likely contributed by host cells composing the tumor microenvironment. Thus, the neutralizing monoclonal antibodies attenuate lymphoma growth by targeting heparanase in the tumor microenvironment.heparanase | lymphoma | neutralizing antibody | tumor growth | metastasis H eparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains at a limited number of sites, releasing saccharide products with appreciable size (4-7 kDa) and biological potency. Enzymatic degradation of HS leads to disassembly of the extracellular matrix (ECM) and correlates with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of HS cleavage and remodeling of the ECM and basement membrane underlying epithelial and endothelial cells (1, 2). Heparanase expression is induced in human cancer, most often associating with reduced patients' survival postoperation, increased tumor metastasis, and higher vessel density (3-5). In addition, heparanase up-regulation is associated with tumors larger in size (3, 5). Likewise, heparanase over-expression enhanced (6, 7), whereas local delivery of anti-heparanase siRNA inhibited (8), the growth of tumor xenografts. These results imply that heparanase function is not limited to tumor metastasis but is engaged in progression of the primary lesion, thus critically supporting the intimate involvement of heparanase in tumor progression and encouraging the development of heparanase inhibitors as anticancer therapeutics (9-12). As a consequence, heparanase inhibitors are currently evaluated in phase 1 clinical trials (13).Heparanase activity is similarly implicated in the progression of multiple myeloma (14-16), but its significan...

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confidence: 99%

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Weissmann¹,

Arvatz²,

Horowitz

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

103

140

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“…Moreover, as known, all reported IgG4-RDs do not show the symptoms of fever, night sweat and body weight loss, which are often observed in lymphoma. [6] In our case, we observed the obvious body weight loss and thus suspected that this case could be a lymphoma. In addition, some evidence indicates the correlations of IgG4 level elevation to lymphoma.…”

Section: Discussionmentioning

confidence: 48%

A case of IgG4-related disease seemingly presenting as a T-cell lymphoma

et al. 2016

CRCP

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IgG4-related disease (IgG4-RD) is an immune-mediated disorder hallmarked with lymphoplasmacytic tissues infiltrated with abundant IgG4-positive plasma cells, which has various clinical features and easily to be misdiagnosed. Here, we described a case with symptoms of body weight loss and multiple lymph node enlargements in a patient's groin, axilla, mediastinum, and retroperitoneum at the first admission. Both F-fluorodeoxyglucose (FDG)-position emission tomography (PET) and lymph node biopsies supported the possible diagnosis of this case as a T-cell lymphoma, but no TCR gene rearrangement observed. Further examinations showed that serum IgG4 level of the patient was elevated and large amount of IgG4+ plasmocyte infiltration was detected in the involved lymph nodes, indicating this case as a possible IgG4-RD. However, the possibility of this disease as a T-cell lymphoma still could not be excluded. Tentatively, the patient was first treated as IgG4-RD with oral prednisone combined with methotrexate to avoid the unnecessary side effect of chemotherapy and economy burden. After three weeks treatment, the serum IgG4 level of the patient is evidently decreased and the enlarged lymph nodes disappeared as well. Eventually, we characterized this case as an atypical IgG4-related lymphadenopathy with 20 months' follow-up.

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“…Literature suggests that the best treatment outcomes are obtained with the R-CHOP regimen, given at three-week intervals [13]. Intrathecal methotrexate and hydrocortisone reduces CNS recurrence and improves survival in aggressive NHL [14].…”

Section: Discussionmentioning

confidence: 99%