The eIF3a Arg803Lys genetic polymorphism is associated with susceptibility to and chemoradiotherapy efficacy in cervical carcinoma.

We aimed to explore the correlations between eukaryotic translation initiation factor 3, subunit A (eIF3a) polymorphisms and susceptibility to and chemoradiotherapy efficacy in cervical carcinoma. Between August 2007 and August 2011, 176 patients with cervical carcinoma were enrolled as the case group, and 180 healthy individuals were selected as the control group. eIF3a Arg803Lys C>T genotypes were detected by hemi-nested polymerase chain reaction restriction fragment length polymorphism. All patients received chemoradiotherapy and were evaluated for efficacy. Compared with carriers of the CC genotype, carriers of the T genotype of the eIF3a Arg803Lys C>T polymorphism had a higher risk of cervical carcinoma. The eIF3a Arg803Lys C>T polymorphism was associated with tumor size, differentiation degree, Federation of Gynecology and Obstetrics (FIGO) stage, and lymph node metastasis (LNM). The overall response rate of the case group was 69.32% (122/176). The response rate of CC genotype carriers was higher compared to patients with the CT+TT genotypes. Binary-logistic regression analysis showed that tumor size, FIGO stage, LNM, and the eIF3a Arg803Lys C>T polymorphism were influencing factors for chemoradiotherapy efficacy. Univariate analysis revealed that age, eIF3a Arg803Lys C>T polymorphism, differentiation degree, FIGO stage, and LNM were prognostic factors of cervical carcinoma, and multivariate analysis showed that age ≥ 60 years, higher FIGO stage, and LNM, as well as the CT and TT genotypes of the eIF3a Arg803Lys C>T polymorphism, were risk factors related to the prognosis of cervical carcinoma. The eIF3a Arg803Lys C>T polymorphism is connected with a higher susceptibility to cervical carcinoma and may affect chemoradiotherapy efficacy in and prognosis of cervical carcinoma.

Increased expression of miR-15b is associated with clinicopathological features and poor prognosis in cervical carcinoma.

OBJECTIVE: The aims of this study were to explore the expression of microRNA-15b (miR-15b) in cervical carcinoma and to correlate its expression with clinicopathological characteristics and prognosis. METHODS: Quantitative reverse transcriptase polymerase chain reaction analysis was conducted to quantify the expression level of miR-15b in 607 cervical tissues, including 185 cervical carcinoma tissues, 124 CIN I lesions, 148 CIN II-III lesions, and 150 normal cervical tissues. The 5-year overall cumulative survival rates for all patients with cervical carcinoma were calculated using Kaplan-Meier survival analysis, and multivariate survival analysis of these patients was completed using the stepwise Cox proportional hazards regression model. RESULTS: The expression of miR-15b gradually increased from normal cervical tissues to CIN lesions and then to cervical carcinoma tissues (all P < 0.05), and it was strongly correlated with degree of differentiation, clinical stage, tumor diameter, and lymph-node metastases (all P < 0.05). When the median value of miR-15b expression was used as the cut-off point, patients with high miR-15b expression (above the median) had worse 5-year overall cumulative survival rates than those who exhibited low miR-15b expression (below the median; P < 0.05). Multivariate analysis using the Cox regression model identified miR-15b expression, clinical stage, tumor diameter, and lymph-node metastasis as independent risk factors for cervical carcinoma prognosis (all P < 0.05). CONCLUSION: Our results indicate that elevated miRNA-15b expression is a typical feature in cervical carcinoma, which could be a useful clinical predictor for the early diagnosis and evaluation of cervical carcinoma prognosis.

A two-stage design for bridging studies.

The ICH E5 guideline defines a bridging study as a supplementary study conducted in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage, and dose regimen to allow extrapolation of the foreign clinical data to the population of the new region. Therefore, a bridging study is usually conducted in the new region only after the test product has been approved for commercial marketing in the original region based on its proven efficacy and safety. One of the current issues for evaluation of bridging studies is a cross-study comparison. Therefore, bias occurs when the study is not internally valid. A two-stage approach is proposed to overcome the issue of internal validity and at the same time to meet the objective of minimizing unnecessary duplication of clinical data required by the ICH E5 guideline. Under the framework of the proposed two-stage design, the bridging study of the new region is a second-stage substudy of the whole trial, and the patients for the bridging substudy are enrolled only after the data obtained in the original region demonstrate a statistically significantly positive treatment effect. Methods for the determination of the sample size for each region and the critical values at each stage are also proposed.

A group sequential approach to evaluation of bridging studies.

The International Conference on Harmonization (ICH) E5 guideline defines a bridging study as a supplementary study conducted in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage, and dose regimen to allow extrapolation of the foreign clinical data to the population of the new region. Therefore, a bridging study is usually conducted in the new region only after the test product has been approved for commercial marketing in the original region due to its proven efficacy and safety. The issue of analysis of clinical data generated by the bridging study conducted in the new region to evaluate the similarity for extrapolation of the foreign clinical data to the population of the new region is the information on efficacy, safety, dosage, and dose regimen of the original region that cannot be concurrently obtained from the local bridging studies but is available in the trials conducted in the original region. A group sequential approach is therefore proposed to overcome the issue of internal validity. In particular, we use the region as a group sequence to enroll the patients from the original region first and then to enroll patients from the new region subsequently. Methods for sample size determination for the bridging study in the new region are also proposed.