Safety Profile of Ixazomib in Patients with Relapsed/Refractory Multiple Myeloma in Japan: An All-case Post-marketing Surveillance.

Objective To evaluate the safety profile of ixazomib combined with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM) in clinical practice in Japan through an all-case post-marketing surveillance. Methods This was a nationwide non-interventional observational study conducted in Japan. The study included all patients who received ixazomib from May 24 to September 24, 2017. Ixazomib was administered to RRMM patients according to the Japanese package insert. All enrolled patients were observed until the completion of the sixth treatment cycle or until ixazomib discontinuation. The patient treatment course, including adverse events (AEs), was reported. Results The safety analysis set included 741 patients; the median age was 71 (range 35-92) years old, and the median number of prior treatment lines was 3 (range 1-30). Adverse drug reactions (ADRs) occurred in 572 (77.2%) patients, most commonly being thrombocytopenia (49.9%), diarrhea (29.2%), and nausea (12.4%). Serious ADRs occurred in 193 (26.0%) patients, most commonly being thrombocytopenia (9.9%) and diarrhea (5.9%). Thrombocytopenia, severe gastrointestinal disorders, infections, skin disorders, and peripheral neuropathy were prespecified as ADRs of clinical importance; the frequency of these ADRs (grade ≥3) were 28.5%, 9.4%, 7.4%, 2.2%, and 1.3%, respectively. Treatment discontinuation was most common with thrombocytopenia and severe gastrointestinal disorders (49 and 43 patients, respectively). Eleven patients died due to ADRs (16 events). Conclusion These results suggest that ixazomib has a tolerable safety profile in clinical practice in Japan. However, close AE management for thrombocytopenia and gastrointestinal disorders should be considered.

Follistatin-related protein/follistatin-like 1 evokes an innate immune response via CD14 and toll-like receptor 4.

Follistatin-related protein (FRP)/follistatin-like 1 (FSTL1) has multi-specific binding nature especially with TGF-ß superfamily proteins, and thereby modulates organ development. However, its function in immune systems remains unclear. Previously, we reported FRP interacts with CD14, which is known to mediate toll-like receptor 4 (TLR4) signaling. Here, we investigated whether FRP activates TLR4 signaling. Recombinant FRP induced interleukin 6 or interleukin 8 production from target cells in a CD14- and TLR4-dependent manner. Moreover, similar to lipopolysaccharide (LPS), FRP induced tolerance to the second LPS stimulation. FRP has the function of evoking innate immune responses as one of the endogenous TLR4 agonists.

Overexpression of a minimal domain of calpastatin suppresses IL-6 production and Th17 development via reduced NF-κB and increased STAT5 signals.

Calpain, a calcium-dependent cysteine protease, is reportedly involved in the pathophysiology of autoimmune diseases such as rheumatoid arthritis (RA). In addition, autoantibodies against calpastatin, a natural and specific inhibitor of calpain, are widely observed in RA. We previously reported that E-64-d, a membrane-permeable cysteine protease inhibitor, is effective in treating experimental arthritis. However, the exact role of the calpastatin-calpain balance in primary inflammatory cells remains unclear. Here we investigated the effect of calpain-specific inhibition by overexpressing a minimal functional domain of calpastatin in primary helper T (Th) cells, primary fibroblasts from RA patients, and fibroblast cell lines. We found that the calpastatin-calpain balance varied during Th1, Th2, and Th17 development, and that overexpression of a minimal domain of calpastatin (by retroviral gene transduction) or the inhibition of calpain by E-64-d suppressed the production of IL-6 and IL-17 by Th cells and the production of IL-6 by fibroblasts. These suppressions were associated with reductions in RORγt expression and STAT3 phosphorylation. Furthermore, inhibiting calpain by silencing its small regulatory subunit (CPNS) suppressed Th17 development. We also confirmed that overexpressing a minimal domain of calpastatin suppressed IL-6 by reducing NF-κB signaling via the stabilization of IκBα, without affecting the upstream signal. Moreover, our findings indicated that calpastatin overexpression suppressed IL-17 production by Th cells by up-regulating the STAT5 signal. Finally, overexpression of a minimal domain of calpastatin suppressed IL-6 production efficiently in primary fibroblasts derived from the RA synovium. These findings suggest that inhibiting calpain by overexpressing a minimal domain of calpastatin could coordinately suppress proinflammatory activities, not only those of Th cells but also of synovial fibroblasts. Thus, this strategy may prove viable as a candidate treatment for inflammatory diseases such as RA.

Pharmacological profile of the novel anti-inflammatory corticosteroid NS-126, a therapeutic agent for allergic rhinitis.

NS-126 (9-fluoro-11beta,17,21-trihydroxy-16alpha-methylpregna-1,4-diene-3,20-dione 21-cyclohexanecarboxylate 17-cyclopropanecarboxylate) is a novel, highly lipophilic anti-inflammatory corticosteroid. We compared NS-126 and the widely used intranasal corticosteroid fluticasone propionate (FP) in a guinea-pig model of allergic rhinitis and a rat model of airway eosinophilia. In the allergic rhinitis model, NS-126 and FP reduced sneezing and nasal obstruction to similar extents. In the airway eosinophilia model, both compounds inhibited the infiltration of eosinophils into the bronchoalveolar lavage fluid, but the effect of NS-126 was longer-lasting than that of FP. In vitro, NS-126 showed lower affinity than FP for the glucocorticoid receptor and was a weaker inhibitor of Th(2) cytokine and chemokine production and mast-cell secretory responses. We also investigated DX-17-CPC, a metabolite of NS-126 generated in nasal tissue by carboxylesterase-catalyzed hydrolysis at the 17-position. DX-17-CPC showed greater affinity than NS-126 for the glucocorticoid receptor and was a stronger inhibitor of Th(2) cytokine and chemokine production and mast-cell secretory responses. The long duration of the anti-allergic effects of NS-126 may be explained by its high lipophilicity, while the strength of its anti-allergic effects may be explained by the generation of the active metabolite DX-17-CPC. NS-126 is a long-acting intranasal corticosteroid and a promising therapeutic agent for allergic rhinitis.

[A case of dermatomyositis associated with different types of cancers at intervals of six years].

The patient is a 56-year-old Japanese woman who suffered from breast cancer and ovarian cancer at intervals of 6 years, and was also complicated by two episodes of dermatomyositis, each of which occurred simultaneously with each of two cancers. When she was 51 years old, she developed dermatomyositis for the first time 6 months after the resection of breast cancer, whose histological type was tubular adenocarcinoma. The dermatomyositis remitted without oral corticosteroids in 2 months, and the remission had continued for 6 years. However, at the age of 56, dermatomyositis abruptly recurred with a pruritic generalized rash, Gottron's papules and elevated serum CK levels. Examination for malignancy revealed an ovarian tumor, which was diagnosed as serous papillaly adenocarcinoma, and the surgery was performed. After the resection of the ovarian cancer, skin rash was improved dramatically and CK levels were normalized again without oral corticosteroids. Since there were no evidences of recurrence of the breast cancer, it was considered that each episode of dermatomyositis was associated with each of the cancers, respectively. We report this rare and interesting case to consider the etiology of cancer-associated myositis as a paraneoplastic syndrome, since the two cancers have different histological types.