Objective. To assess the efficacy, safety, and optimal dose of tacrolimus monotherapy in patients with rheumatoid arthritis (RA).Methods. This phase II, randomized, doubleblind, placebo-controlled monotherapy study was set in 12 community sites and 9 university-based sites. Two hundred sixty-eight patients with RA who were resistant to or intolerant of methotrexate (mean dose 15.2 mg/ week) and had active disease for at least 6 months (mean tender joint count 28.2, mean erythrocyte sedimentation rate 46.5 mm/hour) were randomized to receive treatment after discontinuation of methotrexate. Those who received at least 1 dose of tacrolimus were analyzed; 141 completed the study. Stable dosages of nonsteroidal antiinflammatory drugs and low-dose prednisone were allowed during treatment. All patients were given 1, 3, or 5 mg of tacrolimus or placebo once daily for 24 weeks. The American College of Rheumatology definition of 20% improvement (ACR20) and the tender and swollen joint counts at the end of treatment were the primary outcomes.Results. ACR20 response rates demonstrated a clear dose response. The ACR20 response was observed in 15.5% of patients receiving placebo (95% confidence interval [95% CI] 7.1-23.9%), 29% of the 1 mg tacrolimus group (95% CI 18.3-39.7%) (P < 0.058); 34.4% of the 3 mg group (95% CI 22.7-46.0%) (P < 0.013), and 50% of the 5 mg group (95% CI 37.8-62.3%) (P < 0.001). The tender joint count improved statistically significantly in all tacrolimus groups. The swollen joint count, physical function, and patient-assessed pain improved statistically significantly in the 3 mg and 5 mg groups. The incidence of creatinine elevation >40% above baseline levels increased in a dose-dependent manner. Dropout rates were high (41-59%) and were more common for inefficacy in the placebo patients (71.4%), whereas they were more common for toxicity in the high-dose
Introduction:
Definitive chemoradiation (CRT) followed by high-dose-rate (HDR) brachytherapy (BT) represents state-of-the-art treatment for locally-advanced cervical cancer. Despite use of this treatment paradigm, disease-related outcomes have stagnated in recent years, indicating the need for biomarker development and improved patient stratification. Here, we report the association of Polo-like kinase (PLK) 3 expression and Caspase 8 T273 phosphorylation levels with survival among patients with cervical squamous cell carcinoma (CSCC) treated with CRT plus BT.
Methods:
We identified 74 patients with FIGO Stage Ib to IVb cervix squamous cell carcinoma. Baseline immunohistochemical scoring of PLK3 and pT273 Caspase 8 levels was performed on pre-treatment samples. Correlation was then assessed between marker expression and clinical endpoints, including cumulative incidences of local and distant failure, cancer-specific survival (CSS) and overall survival (OS). Data were then validated using The Cancer Genome Atlas (TCGA) dataset.
Results:
PLK3 expression levels were associated with pT273 Caspase 8 levels (
p
= 0.009), as well as N stage (
p
= 0.046), M stage (
p
= 0.026), and FIGO stage (
p
= 0.001). By the same token, pT273 Caspase 8 levels were associated with T stage (
p
= 0.031). Increased PLK3 levels corresponded to a lower risk of distant relapse (
p
= 0.009), improved CSS (
p
= 0.001), and OS (
p
= 0.003). Phospho T273 Caspase 8 similarly corresponded to decreased risk of distant failure (
p
= 0.021), and increased CSS (
p
< 0.001) and OS (
p
< 0.001) and remained a significant predictor for OS on multivariate analysis. TCGA data confirmed the association of low PLK3 expression with resistance to radiotherapy and BT (
p
< 0.05), as well as increased propensity for metastasis (
p
= 0.019). Finally, a combined PLK3 and pT273 Caspase 8 score predicted for decreased distant relapse (
p
= 0.005), and both improved CSS (
p
< 0.001) and OS (
p
< 0.001); this combined score independently predicted distant failure (
p
= 0.041) and CSS (
p
= 0.003) on multivariate analyses.
Conclusion:
Increased pre-treatment tumor levels of PLK3 and pT273 Caspase 8 correspond to improved disease-related outcomes among cervical cancer patients treated with CRT plus BT, representing a potential biomarker in this context.
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