Sudden elevation of plasma D-dimer levels induced by the combination therapy of dabrafenib and trametinib: Report of two cases.

The combination therapy of dabrafenib and trametinib revolutionized the treatment for BRAF V600-mutated melanoma. Various adverse events have been reported for this treatment, most notably fever. Herein, we report two cases of novel an adverse event, namely sudden and significant elevation of plasma D-dimer level induced by this therapy. In the first case, the remarkable elevation of plasma D-dimer level up to 87.4 mg/dL was noted on day 11, and in the second case, the plasma D-dimer level reached 125.5 mg/dL on day 25. In both cases, D-dimer levels gradually decreased after the cessation of this therapy. Although the exact cause is not clear, we assume two possible hypotheses: the first is that the combination therapy may induce disseminated intravascular coagulation, and the second is that the therapy induced pathological condition of secondary thrombotic microangiopathies. Our cases suggest that this thrombotic adverse event should not be overlooked, and coagulation parameters need to be monitored during the course of this treatment.

Approach for the Derivation of Melanocytes from Induced Pluripotent Stem Cells.

Induced pluripotent stem (iPS) cells have the ability to differentiate into multiple cell types in the body and have an unlimited growth potential. However, iPS cell-derived melanocytes produced by existing protocols have significant limitations in developing novel strategies for regenerative medicine and cell therapies of pigmentation disorders in humans because they involve culture in media containing fetal bovine serum and nonphysiological agents. In this study, we established an in vitro approach to generate iPS cell-derived human melanocytes that have higher proliferation rates and increased melanin production compared with melanocytes prepared by previously reported approaches. Importantly, our iPS cell-derived human melanocytes are prepared in fetal bovine serum-free culture conditions that do not contain any nonphysiological agents. We designed two original methods, transferring black colonies by pipette and recovering black cell pellets from centrifuged medium, and numerous human iPS cell-derived melanocytes proliferated in gelatinous dishes coated with Matrigel after 12 days. We also succeeded in inducing melanin pigmentation in the nude mouse skin in vivo using those human iPS cell-derived melanocytes. We propose that this method using iPS cells established from T cells in the blood of normal human volunteers could be applied clinically to develop regenerative medicine and cell therapies for various forms of human pigmentation disorders.

Serum peptides as putative modulators of inflammation in psoriasis.

BACKGROUND: Psoriasis is a refractory inflammatory disease, however, its pathophysiology is still not fully understood. OBJECTIVE: We tried to identify novel serum peptides associated with the pathophysiology of psoriasis. METHODS: Serum peptides from 24 patients with psoriasis vulgaris (PV), 10 patients with psoriatic arthritis (PsA), 14 patients with atopic dermatitis (AD), and 23 healthy control (HC) subjects were analyzed by mass spectrometry. The effects of some peptides on the secretion of humoral factors from dermal cells were investigated by cytokine arrays and ELISAs. RESULTS: A total of 93 peptides were detected. 24, 20, 23, and 2 peptides showed at least 1.2-fold difference in ion intensity between the psoriasis (PV+PsA) and HC groups, between the PV+PsA and AD groups, between the PV and PsA groups, and between patients with severe-to-moderate PV (n=6) and those with mild PV (n=18), respectively (p<0.05). 13 out of 27 peptides that showed at least 1.5-fold ion intensity difference in the abovementioned 4 comparisons were identified. The parent proteins of the identified peptides included a coagulation factor, proteins involved in the maintenance of skin, and a protein relating to cytoskeleton. We focused on 2 peptides that were increased in the PV+PsA group: a fibrinogen α chain-derived peptide (1462m/z), the unmodified form of which was fibrinopeptide A-des-alanine (FPAdA), and a filaggrin (FLG)-derived peptide (1977m/z), a modified form of FLG2099-2118 (Q2099pE, Q2115E; FLG-pEE). FPAdA stimulation increased the secretion of GROα from dermal microvascular endothelial cells (dMVECs) and decreased the secretion of lipocalin-2 from keratinocytes in comparison to FPAdA-resequenced peptide stimulation (GROα, 280.9±7.3pg/mL vs. 229.6±5.0pg/mL, p<0.001; lipocalin-2, 273±13pg/mL vs. 350±10pg/mL, p<0.01). Interestingly, FLG-pEE stimulation decreased the secretion of GROα, IL-8, and MCP-1 from dMVECs in comparison to FLG-derived control peptide stimulation (GROα, 844.3±47.5pg/mL vs. 1038.5±96.9pg/mL, p<0.05; IL-8, 2240.1±172.6pg/mL vs. 3221.8±523.7pg/mL, p<0.05; MCP-1, 4057.8±157.2pg/mL vs. 4619.1±213.4pg/mL, p<0.05). CONCLUSIONS: The results suggested that some serum peptides are involved in the pathophysiology of psoriasis, regulating the secretion of inflammatory chemokines and an antimicrobial protein. The modulation of serum peptides may be a potential therapeutic strategy for psoriasis.

Presence of anti-phosphatidylserine-prothrombin complex antibodies and anti-moesin antibodies in patients with polyarteritis nodosa.

We measured both serum anti-phosphatidylserine-prothrombin complex (anti-PSPT) antibodies and anti-moesin antibodies, as well as various cytokines (interleukin [IL]-2, IL-4, IL-5, IL-10, IL-13, IL-17, granulocyte macrophage colony-stimulating factor, γ-interferon, tumor necrosis factor-α) levels in polyarteritis nodosa (PAN) patients with cutaneous manifestations. All patients showed the presence of a histological necrotizing vasculitis in the skin specimen. They were treated with i.v. cyclophosphamide pulse therapy (IV-CY) and prednisolone therapy or steroid pulse therapy. The immunological assessments were performed on sera collected prior to and after treatment with IV-CY or steroid pulse therapy. We found a significant positive correlation between serum anti-moesin antibodies and both clinical Birmingham Vasculitis Activity Scores and Vasculitis Damage Index. Anti-PSPT antibody and IL-2 levels after treatment in PAN patients were significantly lower than before treatment. In contrast, anti-moesin antibody levels were higher following IV-CY or steroid pulse therapy compared with the pretreatment levels. In the treatment-resistant PAN patients (n = 8), anti-PSPT antibody levels after treatment were significantly lower than before treatment. In contrast, anti-moesin antibody levels after treatment in the patients were significantly higher compared with the pretreatment levels. Immunohistochemical staining revealed moesin overexpression in mainly fibrinoid necrosis of the affected arteries in the PAN patients. We suggest that measurement of serum anti-PSPT antibody levels could serve as a marker for PAN and aid in earlier diagnosis of PAN. We also propose that elevated serum anti-moesin antibodies could play some role of the exacerbation in patients with PAN.