Elevated soluble interleukin-2 receptor (sIL-2R) in sera is observed in patients with malignant lymphoma (ML). Therefore, sIL-2R is commonly used as a diagnostic and prognostic marker for ML, but the mechanisms responsible for the increase in sIL-2R levels in patients with B-cell lymphomas have not yet been elucidated. We first hypothesized that lymphoma cells expressing IL-2R and some proteinases such as matrix metalloproteinases (MMPs) in the tumor microenvironment can give rise to increased sIL-2R in sera. However, flow cytometric studies revealed that few lymphoma cells expressed IL-2R α chain (CD25) in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), and most CD25-expressing cells in the tumor were T-cells. Distinct correlations between CD25 expression on B-lymphoma cells and sIL-2R levels were not observed. We then confirmed that MMP-9 plays an important role in producing sIL-2R in functional studies. Immunohistochemical (IHC) analysis also revealed that MMP-9 is mainly derived from tumor-associated macrophages (TAMs). We therefore evaluated the number of CD68 and CD163 positive macrophages in the tumor microenvironment using IHC analysis. A positive correlation between the levels of sIL-2R in sera and the numbers of CD68 positive macrophages in the tumor microenvironment was confirmed in FL and extranodal DLBCL. These results may be useful in understanding the pathophysiology of B-cell lymphomas.

BackgroundBortezomib offers a novel approach to the treatment of multiple myeloma producing rapid control. The aim of this study was to investigate the outcomes of bortezomib and dexamethasone-treated patients with multiple myeloma.MethodsWe conducted a retrospective study of 44 consecutively-treated multiple myeloma patients with bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle or 1.3 mg/m2 intravenously 1, 8, 15, and 22 of every 35-day cycle) and dexamethasone.ResultsThe median time to progression, progression free survival time, and overall survival time in the treatment groups was 14.9, 14.9, and 38.3 months, respectively. The present study also suggests the possibility that the prognosis of patients with high levels of AST and LDH might be worse.ConclusionsOur results indicate that the treatment of multiple myeloma with bortezomib and dexamethasone is feasible.

Abstract.We investigated the effects of bortezomib (PS-341) and immunomodulatory thalidomide analogs (immunomodulatory compounds; CC-4047, CC-6032, and CC-5013, or lenalidomide) on osteoblast and osteoclast differentiation in vitro using human mesenchymal stem cells (hMSC) to commit to osteoprogenitor cells and peripheral blood mononuclear cells (PBMCs) isolated from healthy donors, respectively. First, the concentration of bortezomib for an anti-myeloma effect was more than 1.0 nM in myeloma cells of multiple myeloma (MM) patients and more than 2.5 nM in myeloma cell lines. In contrast, anti-myeloma effects of immunomodulatory compounds on myeloma cells differed among myeloma cells and these compounds themselves. Subsequently, these agents (bortezomib; 0.5-5.0 nM, immunomodulatory compounds; 10 μM) were added to the osteoprogenitor cell culture media or the media for osteoclast differentiation. Low bortezomib concentrations (0.5 and 1.0 nM) increased ALP activity, and the delayed addition of bortezomib further increased ALP activity. Mineralized nodular formation with <2.5 nM bortezomib was not impaired. BMP2 expression on osteoprogenitor cells was found to increase in a time-dependent manner irrespective of treatment with bortezomib. On the other hand, the antiosteoclast effect with low bortezomib concentration (≤2.5 nM) depended on MM patients. In contrast, immunomodulatory compounds at 10 μM showed an anti-osteoclast effect without cytotoxicity to osteoblast differentiation, at which dose myeloma cells underwent apoptosis. These findings might improve the treatment strategy for MM patients without damaging BM stromal cells by combining bortezomib with immunomodulatory compounds.