Multiple myeloma : new aspects of biology and treatment

Recently, considerable progress has been made in understanding of the biology and treatment of multiple myeloma. Molecular genetic abnormalities such as bcl-2,c-myc, ras, p53, and Rb genes have been identified in this disease and are related to a poor prognosis. Cytokine studies have revealed that interleukin-6 is a potent growth factor for myeloma cells and is also responsible for the progressive bone resorption together with interleukin-1 βand tumor necrosis factor. Myeloablative chemotherapy followed by allogeneic or autologous hematopoietic stem cell transplantation has increased the incidence of complete remission. However, relapses are still observed because of drug resistance of tumor cells. Immunotherapeutic approaches targeting to cell surface antigens andinterleukin-6 signals are being developed to further eliminate myeloma cells. Translating new biological advances into treatment protocols is essential to improve the prognosis of multiple myeloma

Immunotherapy of multiple myeloma with monoclonal antibody

Multiple myeloma is so far an incurable malignancy because of marked resistance of tumor cell to conventional chemotherapeutic agents even if myeloablative treatment has been applied with hematopoietic stem cell transplantation. The challenge remains to develop less toxic, but more effective, targeted therapies. We have generated a monoclonal antibody (mAb), which detects a human plasma cell specific antigen, HM 1.24, to develop a new immunotherapy for multiple myeloma. This mAb has been shown to inhibit the proliferation of human myeloma cells implanted into severe combined immunodeficiency mice by antibody-dependent cell-mediated cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC). Subsequently, for the clinical application to treatment of myeloma patients, the murine mAb was humanized through genetic engineering methods to ameliorate the host humoral response and to mediate ADCC against myeloma cells in the presence of human effector cells, CD 16+ NK cells. Using the humanized anti-HM 1.24 mAb, but not the murine mAb, the peripheral blood mononuclear cells (PBMCs) from myeloma patients exhibited ADCC activity as efficiently as those of healthy donors. These results promise that humanized anti-HM 1.24 has potential as a new therapeutic strategy in refractory multiple myeloma

NADPH oxidase and ROS in kidney growth

Ureteric bud branching and nephrogenesis are performed through large-scale proliferation and apoptosis events during renal development. Reactive oxygen species (ROS), produced by NADPH oxidase, may contribute to cell behaviors, including proliferation and apoptosis. We investigated the role of NADPH oxidase expression and ROS production in developing kidneys. Immunohistochemistry revealed that NADPH oxidase components were expressed on epithelial cells in ureteric bud branches, as well as on immature glomerular cells and epithelial cells in nephrogenic zones. ROS production, detected by dihydroethidium assay, was strongly observed in ureteric bud branches and nephrogenic zones, corresponding with NADPH oxidase localization. Organ culture of E14 kidneys revealed that the inhibition of NADPH oxidase significantly reduced the number of ureteric bud branches and tips, consistent with reduced ROS production. This was associated with reduced expression of phosphorylated ERK1/2 and increased expression of cleaved caspase-3. Organ culture of E18 kidneys showed that the inhibition of NADPH oxidase reduced nephrogenic zone size, accompanied by reduced ROS production, fewer proliferating cell nuclear antigen-positive cells, lower p-ERK1/2 expression, and increased expression of cleaved caspase-3. These results demonstrate that ROS produced by NADPH oxidase might play an important role in ureteric bud branching and nephrogenesis by regulating proliferation and apoptosis

Gene Expression and Localization of High-mobility Group Box Chromosomal Protein-1 (HMGB-1) in Human Osteoarthritic Cartilage

We investigated the expression and localization of high-mobility group box chromosomal protein-1 (HMGB-1) in human osteoarthritic (OA) cartilage in relation to the histopathological grade of cartilage destruction, and examined the role of HMGB-1 in the regulation of proinflammatory cytokine expression in chondrocytes. An immunohistochemical study demonstrated that total HMGB-1-positive cell ratios increase as the Osteoarthritis Research Society International (OARSI) histological grade increased. The population of cytoplasmic HMGB-1-positive chondrocytes was especially increased in the deep layers of higher-grade cartilage. The ratios and localization of receptors for advanced glycation end products (RAGE) expression by chondrocytes in Grade 2, 3, and 4 were significantly higher than those in Grade 1. In vitro stimulation with IL-1β, but not TNFα, significantly upregulated the expression of HMGB-1 mRNA by human OA chondrocytes. Both IL-1β and TNFα promoted the translocation of HMGB-1 from nuclei to cytoplasm. IL-1β and TNFα secretions were stimulated at higher levels of HMGB-1. The results of our study suggest the involvement of HMGB-1 in the pathogenesis of cartilage destruction in OA

Polyclonal Immunoglobulin Recovery after Autologous Stem Cell Transplantation Is an Independent Prognostic Factor for Survival Outcome in Patients with Multiple Myeloma

We retrospectively analyzed multiple myeloma (MM) patients who underwent autologous stem cell transplantation (ASCT) without maintenance therapy to assess the impact of recovery of normal immunoglobulin (Ig) on clinical outcomes. The recovery of polyclonal Ig was defined as normalization of all values of serum IgG, IgA, and IgM 1 year after ASCT. Among 50 patients, 26 patients showed polyclonal Ig recovery; 14 patients were in ≥complete response (CR) and 12 remained in non-CR after ASCT. The patients with Ig recovery exhibited a significantly better progression-free survival (PFS, median, 46.8 vs. 26.7 months, p = 0.0071) and overall survival (OS, median, not reached vs. 65.3 months, p < 0.00001) compared with those without Ig recovery. The survival benefits of Ig recovery were similarly observed in ≥CR patients (median OS, not reached vs. 80.5 months, p = 0.061) and non-CR patients (median OS, not reached vs. 53.2 months, p = 0.00016). Multivariate analysis revealed that non-CR and not all Ig recovery were independent prognostic factors for PFS (HR, 4.284, 95%CI (1.868–9.826), p = 0.00059; and HR, 2.804, 95%CI (1.334–5.896), p = 0.0065, respectively) and also for OS (HR, 8.245, 95%CI (1.528–44.47), p = 0.014; and HR, 36.55, 95%CI (3.942–338.8), p = 0.0015, respectively). Therefore, in addition to the depth of response, the recovery of polyclonal Ig after ASCT is a useful indicator especially for long-term outcome and might be considered to prevent overtreatment with maintenance therapy in transplanted patients with MM

カンセツ リウマチ ニ タイスル メトトレキセート チリョウチュウ ニ コウド ノ ハンケッキュウ ゲンショウ オ キタシ シボウ シタ 5レイ ノ ケントウ

Background : Methotrexate （MTX） is placed as an anchor drug of treatment for rheumatoid arthritis （RA）. However, many cases suffered from side effects of MTX such as interstitial pneumonia and hematological toxicity. We investigated ５ cases that died of severe pancytopenia under treatment with low-dose MTX for RA. Methods : We reviewed the clinical features of ５ cases that developed severe pancytopenia and were transferred to Tokushima Prefectural Central Hospital under treatment with low-dose MTX for RA from ２０１１-２０１５. Results : All the cases were women, and were under treatment with low-dose MTX. The periods of medication of MTX were not clear. All the cases had renal insufficiency, and had a severe infection induced by pancytopenia and some cases developed disseminated intravascular coagulation （DIC）. At once we started intensive care, but all patients died in a short term. Conclusions : Women, the elderly, and renal insufficiency can be risk factors of severe pancytopenia induced by MTX even if low dosage. We should carefully treat these patients with MTX