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1.
Lupus ; 25(1): 54-60, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26296361

ABSTRACT

OBJECTIVE: We have assessed the effectiveness of tacrolimus for minor flares in systemic lupus erythematosus (SLE) patients. METHODS: The medical records of 313 patients were retrospectively reviewed over a period of seven years, from 2006 to 2013. We enrolled patients with minor flare treated with add-on tacrolimus, without glucocorticoid (GC) intensification (tacrolimus group). Minor flare was defined as a ≥ 1-point increase in a total score between 3 and 11 in the SLE Disease Activity Index (SLEDAI). We enrolled as controls patients who were administered increased doses of GC for minor flare (GC group). All patients were followed for one year. The primary outcome measure was the proportion of responders. RESULTS: There were 14 eligible patients in the tacrolimus group and 20 eligible patients in the GC group. The mean SLEDAI at flare tended to be higher in the tacrolimus group than in the GC group (7.5 vs. 6.2, p = 0.085). A mean dose of 1.6 mg tacrolimus/day was administered for flare, while the mean GC dose was 13.7 mg/day in the GC group. The proportion of responders was 86% (12/14) in the tacrolimus group and 75% (15/20) in the GC group (p = 0.67). The mean dose of GC at 12 months was higher in the GC group than in the tacrolimus group (9.7 mg/day vs. 7.1 mg/day, p < 0.05). Only one patient discontinued tacrolimus because of fatigue after three months. CONCLUSION: Adding tacrolimus without increasing the GC dose may provide an effective treatment option for minor flares in patients with SLE.


Subject(s)
Immunosuppressive Agents/administration & dosage , Lupus Erythematosus, Systemic/drug therapy , Tacrolimus/administration & dosage , Adult , Disease Progression , Drug Therapy, Combination , Female , Glucocorticoids/administration & dosage , Humans , Immunosuppressive Agents/adverse effects , Lupus Erythematosus, Systemic/diagnosis , Male , Medical Records , Middle Aged , Retrospective Studies , Severity of Illness Index , Tacrolimus/adverse effects , Time Factors , Treatment Outcome
2.
Oncogene ; 33(33): 4236-41, 2014 Aug 14.
Article in English | MEDLINE | ID: mdl-24336323

ABSTRACT

Chronic inflammation is frequently associated with tumorigenesis in elderly people. By contrast, young people without chronic inflammation often develop tumors considered independent of chronic inflammation but driven instead by mutations. Thus, whether inflammation has a significant role in tumor progression in tumors driven by mutations remains largely unknown. Here we show that TNFα is required for the tumorigenesis of osteosarcoma, the most common tumor in children and adolescents. We show that transplantation of AX osteosarcoma cells, which harbor mutations driving c-Myc overexpression and Ink4a-deficiency, in wild-type mice promotes lethal tumorigenesis accompanied by ectopic bone formation and multiple metastases, phenotypes seen in osteosarcoma patients. Such tumorigenesis was completely abrogated in TNFα-deficient mice. AX cells have the capacity to undergo osteoblastic differentiation; however, that activity was significantly inhibited by TNFα treatment, suggesting that TNFα maintains AX cells in an undifferentiated state. TNFα inhibition of AX cell osteoblastic differentiation occurred through ERK activation, and a pharmacological TNFα inhibitor effectively inhibited both AX cell tumorigenesis and increased osteoblastic gene expression and increased survival of tumor-bearing mice. Lethal tumorigenesis of AX cells was also abrogated in IL-1α/IL-1ß doubly deficient mice. We found that both TNFα and IL-1 maintained AX cells in an undifferentiated state via ERK activation. Thus, inflammatory cytokines are required to promote tumorigenesis even in mutation-induced tumors, and TNFα/IL-1 and ERK may represent therapeutic targets for osteosarcoma.


Subject(s)
Bone Neoplasms/metabolism , Osteosarcoma/metabolism , Tumor Necrosis Factor-alpha/physiology , Animals , Bone Neoplasms/pathology , Cell Differentiation , Disease Progression , Fibroblasts/physiology , Humans , Interleukin-6/metabolism , MAP Kinase Signaling System , Mice , Mice, Knockout , Neoplasm Transplantation , Osteoblasts/metabolism , Osteosarcoma/pathology , Receptors, Tumor Necrosis Factor/metabolism , Up-Regulation
3.
Cancer ; 82(3): 512-9, 1998 Feb 01.
Article in English | MEDLINE | ID: mdl-9452269

ABSTRACT

BACKGROUND: Carcinosarcoma (malignant mixed mullerian tumor) of the female genital tract is a highly malignant neoplasm. The tumor stage and histologic grade of the carcinomatous component are among the important prognostic indicators cited in the literature for this tumor. METHODS: Twenty-five patients with uterine carcinosarcoma at 4 hospitals in the Kyoto and Nara areas of Japan were studied retrospectively. The clinicopathologic and immunohistochemical data including p53, bcl-2, Ki-67, and proliferating cell nuclear antigen (PCNA) staining were analyzed using univariate and multivariate analysis with the Cox proportional hazards model to investigate potential prognostic indicators for this neoplasm. RESULTS: The 5-year survival rate was 36.4% for all stages, 62.3% for Stage I, and 0% for Stages II-IV. From the univariate analysis, stage (P = 0.0001), endometrioid adenocarcinoma as a carcinomatous component (P = 0.0006), age (P = 0.0355), and a heterologous sarcomatous component (P = 0.0421) were found to be prognostically significant for patient survival. Stage was the only independent significant factor in the multivariate analysis (t = 2.212). None of the other factors (history of pregnancy and gestation, gross appearance of the tumors, grade of the carcinomatous component, mitotic count of the sarcomatous component, Ki-67 and PCNA reactivity, or p53 or bcl-2 positive staining) was found to be a significant prognostic indicator. CONCLUSIONS: Stage appears to be the only definite independent prognostic indicator of survival in patients with uterine carcinosarcoma. It is uncertain whether age, endometrioid adenocarcinoma as a carcinomatous component, or absence of a heterologous component in the sarcomatous area are prognostic factors. Immunohistochemical expression of p53, bcl-2, Ki-67, or PCNA is not a prognostic indicator. The immunohistochemical results of the current study may support the hypothesis of a common stem cell origin of this tumor.


Subject(s)
Carcinosarcoma/pathology , Uterine Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Carcinosarcoma/chemistry , Carcinosarcoma/mortality , Female , Humans , Immunohistochemistry , Ki-67 Antigen/analysis , Middle Aged , Mixed Tumor, Mullerian/chemistry , Mixed Tumor, Mullerian/mortality , Mixed Tumor, Mullerian/pathology , Prognosis , Proliferating Cell Nuclear Antigen/analysis , Proto-Oncogene Proteins c-bcl-2/analysis , Retrospective Studies , Survival Rate , Tumor Suppressor Protein p53/analysis , Uterine Neoplasms/chemistry , Uterine Neoplasms/mortality
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