ABSTRACT
Arsenic trioxide (AsO) is recently found to have therapeutic potential in systemic sclerosis (SSc), a life-threatening multi-system fibrosing autoimmune disease with type I interferon (IFN-I) signature. Chronically activated plasmacytoid dendritic cells (pDCs) are responsible for IFN-I secretion and are closely related with fibrosis establishment in SSc. In this study, we showed that high concentrations of AsO induced apoptosis of pDCs mitochondrial pathway with increased BAX/BCL-2 ratio, while independent of reactive oxygen species generation. Notably, at clinical relevant concentrations, AsO preferentially inhibited IFN- secretion as compared to other cytokines such as TNF-, probably due to potent down-regulation of the total protein and mRNA expression, as well as phosphorylation of the interferon regulatory factor 7 (IRF7). In addition, AsO induced a suppressive phenotype, and in combination with cytokine inhibition, it down-regulated pDCs' capacity to induce CD4 T cell proliferation, Th1/Th22 polarization, and B cell differentiation towards plasmablasts. Moreover, chronically activated pDCs from SSc patients were not resistant to the selective IFN- inhibition, and regulatory phenotype induced by AsO. Collectively, our data suggest that AsO could target pDCs and exert its treatment efficacy in SSc, and more autoimmune disorders with IFN-I signature.
ABSTRACT
The optimal treatment of patients with multiple myeloma [MM] is not well defined, in part because these patients are underrepresented in clinical studies. Autologous stem cell transplantation [auto-SCT] after high-dose melphalan chemotherapy can result in a prolonged response duration and survival in patients under 65 years of age. Single-center, retrospective study of patients treated at Paoli-Chalmette Institute Cancer Centre, between January 1994 and January 2007 [96 months] We compared the outcome of elderly [age >65 years] patients with younger patients aged between 60 and 65 years with MM. We compared 82 elderly patients with 104 younger patients. Except for age, both groups had comparable demographic features, disease characteristics, and prognostic factors. Induction VAD chemotherapy was comparable between the elderly [87%] and younger [94%] group. Prior to auto-SCT, the calculated hematopoietic cell transplantation-specific co-morbidity index was also comparable. With a median follow-up of 41 months [range, 5-227 months] after auto-SCT, 120 patients were still alive. Disease progression [n=40; 61%] was the main cause of death, and it was comparable in the two groups. Auto-SCT-related mortality was 3.8% [n=4/104] in younger and 3.7% [n=3/82] in older patients. Comparing younger/older subjects, progression-free survival was significantly higher in the younger group [P<.0001]. However, disease response rates after the first auto-SCT was comparable and overall survival [OS] was also comparable [57% vs. 54% at 5 years, P=NS; 32% vs. 24% at 10 years, P=NS]. In a Cox multivariate analysis model, none of the relevant characteristics was shown to be a critical prognostic feature for OS. Age was insignificant for both OS and transplant-related mortality. We conclude that there is no biological justification for an age-discriminate policy for MM therapy. Physiologic aging is likely more important than chronologic aging
Subject(s)
Humans , Male , Female , Multiple Myeloma/therapy , Transplantation, Autologous/adverse effects , Age Factors , Melphalan , Hematopoietic Stem Cell Transplantation/methods , Antineoplastic Combined Chemotherapy Protocols , Survival Rate , Multivariate Analysis , Treatment OutcomeABSTRACT
The liposomal formulation of amphotericin B [LAmB] has been shown to cause few and mild infusion-related reactions, while achieving high plasma and tissue concentrations compared with conventional amphotericin B. We investigated the efficacy and safety of high-dose LAmB [7.5 mg/kg once weekly] prophylaxis of fungal infections in allogeneic stem-cell transplanted [allo-SCT] patients with graft-versus-host disease [GvHD]. Retrospective, comparative, single-center. Forty-two patients receiving high-dose prednisone for GvHD after allo-SCT had LAmB prophylaxis; 83 patients in the control group received other antifungal prophylaxis. In the LAmB prophylaxis group, the median duration of treatment was 7 weeks. The cumulative incidence of invasive fungal infection was 8% at 1 year after transplantation, 8% at 2 years and 16% at 3 years in the LAmB group vs. 36% at 1 year, 44% at 2 years and 49% at 3 years in the other prophylaxis group [P=.008]. Fungal infection-related mortality after transplantation was observed in none of the patients in the LAmB prophylaxis group vs. 12 patients [14%] at 1 year, 14 patients [17%] at 2 years and 16 patients [19%] at 3 years in the control group [P = .005]. The tolerance of the treatment was good with only 5 patients [12%] having a reversible nephrotoxicity leading to temporary treatment discontinuation. High-dose LAmB prophylaxis seems effective and well tolerated in this short series of allo-SCT patients with GvHD. Prospective clinical studies are required to confirm these results