| PART I Preliminary study on the role of microRNA101and microRNA1285in radiosensitivity of advanced squamous cervical carcinoma underwent concurrent chemoradiotherapy[Background and Objectives] Cervical carcinoma is one of the most common malignancies of women worldwide and in developing countries. In China, cervical carcinoma occupies the first place of three female reproductive malignancies, among which, patients of advance stage (≥ⅡB) account for60%-70%. These advanced patients are often of poor reaction to treatment and result in poor prognosis. Based on several large randomized controlled clinical trials, NCCN (National Comprehensive Cancer Network) had recommended concurrent chemoradiotherapy (CCRT) to be the standard treatment for patients of advanced cervical carcinoma, instead of previous simple radiotherapy. However, different patients respond differently to CCRT, and it might attribute to differences in clinicopathological factors and intrinsic reaction of tumor to CCRT. microRNAs (miRNAs) are kind of endogenous non-coding small single-stranded RNAs, involved in the development of different tumors, and the spectrums of miRNAs for predicting treatment response and prognosis are of high stability and specificity. miRNAs had been demonstrated to be a potential tumor marker and target for cancer therapy. Our previous studies of miRNAs microarray analysis showed that170miRNAs expressed significantly differently in tumor tissue of cervical carcinoma between radioresistant group and radiosensitive group. Combined with the prediction analysis of target gene and literature review,6miRNAs were chosen to be the targets for distinction of radioresistant group and radiosensitive group. The6miRNAs were miR-101, miR-125a-5p, miR-365, miR-886-3p, miR-1285and miR-492, of which, the former4were up-regulated in radioresistant group, and the latter2were down-regulated. Hierarchical cluster analysis showed that the6miRNAs could well separate radioresistant group and radiosensitive group. This study, based on previous research, was to analyze the expression of miR-101and miR-1285in tumor tissue of radiosensitive group and radioresistant group of advanced squamous cervical carcinoma underwent CCRT, and to explore the mechanism of the relationship between the two miRNAs and radiosensitivity of cervical carcinoma. The final goal of this study was to provide evidence for individual treatment of cervical carcinoma.[Materials and Methods] Tumor tissue was collected before treatment from patients of advanced squamous cervical carcinoma underwent CCRT between April,2010and December,2013in Cancer Hospital, Chinese Academy of Medical Sciences (CICAMS), and was divided into radioresistant group and radiosensitive group according to the response to treatment. Patients who didn’t achieve complete regression at the end of treatment or had tumor recurrence within12months after the end of treatment were assigned to radioresistant group, and those who achieved complete regression at the end of treatment and were free of tumor recurrence within12months after the end of treatment were assigned to radiosensitive group. The expression of miR-101and miR-1285was compared between the two groups through realtime PCR method, and the expression of their downstream genes EZH2and p53was tested by Western Blotting method.[Results] The expression of miR-101in radioresistant group was significantly higher than that in radiosensitive group (p<0.01); the expression of miR-101was significantly related to tumor stage, higher in IIIB patients than that in ⅡB patients (p<0.05); the expression of EZH2in radioresistant group was significantly lower than that in radiosensitive group (p=0.002); the expression of miR-101was negatively correlated with the levels of EZH2(r=-0.46,p=0.036). The expression of miR-1285and p53did not differ between radioresistant group and radiosensitive group (p>0.05), and there was no correlation between them (p>0.05).[Conclusion] The expression of miR-101in tumor tissue before treatment was related with radioresistance of advanced squamous cervical carcinoma underwent CCRT, maybe through negatively regulation of EZH2. The expression of miR-1285and p53had no relation with radiosensitivity of advanced squamous cervical carcinoma underwent CCRT. PART II Outcomes and prognostic factors of advanced squamous cervical carcinoma after concurrent chemoradiotherapy[Background and Objectives] Cervical carcinoma is one of the most common malignancies of women worldwide and in developing countries. In China, cervical carcinoma occupies the first place of three female reproductive malignancies, among which, patients of advance stage (≥ⅡB) account for60%-70%. These advanced patients are often of poor reaction to treatment and result in poor prognosis. Based on several large randomized controlled clinical trials, NCCN had recommended CCRT to be the standard treatment for patients of advanced cervical carcinoma, instead of previous simple radiotherapy. However, different patients response differently to CCRT, and it might attribute to differences in clinicopathological factors, including clinical stage, local size of tumor, level of squamous cell carcinoma antigen (SCC), retro-peritoneal lymph node status, pathological type, tumor grade, etc. This study was to evaluate the outcomes and the prognostic factors for advanced squamous cervical carcinoma after CCRT.[Materials and Methods]172patients of stage ⅡB-Ⅳ who were treated in CICAMS between January2007and December2008were retrospectively analyzed. All the patients received external radiotherapy, high-dose rate brachytherapy and cisplatin-based chemotherapy concurrently. Univariate analysis (log-rank method) and multivariate analysis (Cox regression) were used for survival analysis of these patients.[Results] The median follow-up period was54.5months. The2-year and5-year overall survival (OS) were separately81.5%and68.8%. The2-year and5-year progress free survival (PFS) were separately69.2%and63.1%. Using univariate analysis followed with multivariate analysis, stage (Ⅲ and above vs. ⅡB, p=0.021, HR=1.95;p=0.020, HR=1.86), maximum diameter of local tumor (>4cm vs.≤4cm,p=0.009, HR=2.55; p=0.033, HR=1.94), SCC level before treatment (>3ng/ml vs.≤3ng/ml,p=0.010, HR=2.47; p=0.013, HR=2.09) and retroperitoneal lymph node status on imaging (para-aortic lymph node positive vs. negative,p=0.009, HR=3.00,p=0.010, HR=2.74; pelvic lymph node positive only vs. negative, p=0.044, HR=1.98, p=0.033, HR=1.92) had a significant effect on OS and PFS. Patients with no above adverse prognostic factor were assigned to Group A (n=18), those with one factor were assigned to Group B (n=43), and those with no less than two factors were assigned to Group C (n=111). The2-year OS of the three groups were separately94.1%,97.7%and73.1%; the5-year OS of the three groups were separately81.4%,90.1%and58.6%; the2-year PFS of the three groups were separately88.2%,90.4%and57.9%; the5-year PFS of the three groups were82.4%,87.9%and50.0%. Group C had significant difference from Group A and B separately on OS and PFS (p<0.05), while Group A had no significant difference from Group B on OS and PFS (p>0.05).[Conclusion] Stage Ⅲ or above, maximum diameter of local tumor>4cm, SCC level>3ng/ml before treatment and positive retroperitoneal lymph nodes on imaging were4independent adverse factors for prognosis of squamous cervical carcinoma of advanced stage after CCRT. The patients who had more than2adverse factors were of poor prognosis. |
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