Significant Efficacy of Additional Concurrent Chemotherapy with Radiotherapy for Postoperative Cervical Cancer with Risk Factors: a Systematic Review and Meta-analysis.

BACKGROUND: Whether concurrent chemotherapy treatment is superior to radiotherapy alone as an adjuvant regimen for postoperative cervical carcinoma with risk factors remains controversial. MATERIALS AND METHODS: A literature search strategy was used to examine Pubmed, Embase, the Cochrane Library, the China National Knowledge Internet Web, the Chinese Biomedical Database and the Wanfang Database. Article reference lists and scientific meeting abstracts were also screened. Controlled trials comparing concurrent chemoradiotherapy versus radiotherapy alone in postoperative cervical cancer were included. The methodological quality of non-randomized controlled trials was evaluated using the Newcastle-Ottawa Scale. Randomized controlled studies were evaluated with the Cochrane handbook. A meta-analysis was performed with RevMan 5.3. RESULTS: A total of 1,073 patients from 11 clinical trials were analysed, with 582 patients in the concurrent chemoradiotherapy group and 491 patients in the radiotherapy group. Hazard ratios (HR) of 0.47 (95% CI 0.31-0.72) and 0.50 (95% CI 0.35-0.72) were observed for overall survival and progression-free survival, indicating a benefit from the additional use of concurrent chemotherapy. Subgroup analyses demonstrated that cervical cancer with high risk factors significantly benefitted from concurrent chemotherapy when examining overall survival (HR 0.44, 95% CI 0.28-0.67) and progression-free survival (HR 0.48, 95% CI 0.33-0.70), but patients with intermediate risk factors showed no benefit from concurrent chemotherapy in overall survival (HR 1.72, 95% CI 0.28-10.41) and progression-free survival (HR 1.09, 95% CI 0.19-6.14). No significant differences were observed for grade 3-4 anaemia (risk ratio (RR) 3.87, 95% CI 0.69-21.84), grade 3-4 thrombocytopenia (RR 3.04, 95% CI 0.88- 10.58), grade 3-4 vomiting or nausea (RR 1.71, 95% CI 0.27-10.96), or grade 3-4 diarrhoea (RR 1.40, 95% CI 0.69-2.83). Significant differences were observed for grade 3-4 neutropenia in favour of the radiotherapy group (RR 7.23, 95% CI 3.94-13.26). CONCLUSIONS: Concurrent chemoradiotherapy improves survival in postoperative cervical cancer cases with high risk factors but not in those with intermediate risk factors.

Pap Smear Combined with HPV Testing: A Reasonable Tool for Women with High-grade Cervical Intraepithelial Neoplasia Treated by LEEP.

BACKGROUND: To evaluate HPV testing by Hybrid Capture II (HCII) in conjunction with cytology in detecting the residual/recurrence disease after treatment of high-grade cervical intraepithelial neoplasia (CIN II-III) with loop electrosurgical excision procedure (LEEP). MATERIALS AND METHODS: A retrospective review of 158 patients with histologically confirmed CIN II-III who underwent LEEP between January 2011 and October 2012 was conducted. Post-treatment control was scheduled at the 3rd, 6th, 12th and 18th month. All patients were followed up by Pap smear and HR-HPV genotype and viral load testing. RESULTS: Pre-treatment, HR-HPV DNA, was detected in all specimens of the patients. At follow-up, 25 patients were diagnosed as the residual/recurrent disease during the FU visit, among whom, 16 patients with positive margin: 13 patients (52%) with HR-HPV DNA+/cytology+, 2 patients (8%) with HR-HPV DNA+/cytology-, 1 patient (4%) with cytology+/ HR-HPV DNA-; 9 patients with clean margin--5 patients (55.6%) with HR-HPV DNA+/cytology+; 2 patients (22.2%) with HR- HPV DNA+/cytology-, 2 patients (22.2%) with cytology+/HR-HPV DNA-. None of them persisting HR-HPV DNA-/cytology- with positive or negative margin was identified as the residual/recurrent disease. The majority of residual/recurrent disease was detected at the 12th and 18th month FU, and there was almost no difference in the sensitivity and negative predictive value (NPV) between at the 3rd month and the 6th month FU visits. 14 residual/recurrence disease (14/46:30.4%) had pre-treatment high viral load (>5,000 RUL/PC) and 11 (11/112, 9.8%) with pre-treatment low viral load, P<0.05. CONCLUSIONS: (1) The persistence HR-HPV DNA is the root cause of the residual/recurrent disease for the women treated for high-grade CIN; the pre-treatment viral load and margin can be seen as the predictor. (2) The FU visit beginning at the 6th month post-treatment and lasting at least 24 months with the combination of cytology and HPV testing. (3) Patients with high pre-treatment HPV load, which is considered as one risk of developing the residual/recurrent disease, should be paid more attention (especially above 500 RUL/PC) to by clinicians.

[Effect of WWOX gene on the attachment and adhesion of ovarian cancer cells].

OBJECTIVE: To explore the relationship between WWOX gene and attachment and adhesion of ovarian cancer. METHODS: The expression of WWOX mRNA was detected by RT-PCR, the expression of the WWOX protein was evaluated by western blot in WWOX-transfected PEO1 cells (H6, H7, H8 cell) and vector-transfected control cells (vec-1, vec-2 cell). Attachment assay was used to assess the adhesion of the transfection in PEO1 cells via culturing the cells on the pre-coated fibronectin wells. RNA interference (RNAi) was used to knockdown the endogenous expression of WWOX in the A2780 ovarian cancer cell line by liposome. Attachment assay was detected the adhesion to fibronectin after gene silencing. RESULTS: RT-PCR showed that expression of mRNA WWOX in exon9 was in all transfection cells (H6, H7, H8, vec-1, vec-2 cell). Western blot showed that expression of WWOX protein was in the WWOX-transfected cells (H6, H7, H8 cell), but not in the vector-transfected cells (vec-1, vec-2 cell). Attachment assay showed that H6, H7, H8 cell (0.098 +/-0. 003, 0.091 +/- 0.004, 0.099 +/- 0.003) adhered more slowly to fibronectin than vec-1, vec-2 cell (0.185 +/- 0.003, 0.175 +/- 0.006) and non-transfected PEO1 cell (0.211 +/- 0.007), and demonstrated significantly reduced adhesion after 2 hours (P < 0.01). A2780 adhesive cells that WWOX gene be knockdown was 0.059 +/- 0.005, adhered more significantly rapid than those untreated cells that was 0.029 +/- 0.003 after treated 30 minutes (P < 0.05). CONCLUSIONS: WWOX gene can suppress adhesion to fibronectin in ovarian cancer cells. This suggests an important role for loss of WWOX gene in promoting attachment and adhesion of ovarian cancer cells on loco-regional peritoneum, and further resulting in enhancing loco-regional peritoneal tumor invasiveness and spread.

[Effects of WWOX on ovarian cancer cell attachment in vitro].

OBJECTIVE: To observe the effects of WWOX on cell attachment in ovarian cancer, and to explore its mechanisms of action. METHODS: Attachment assay was used to assess the adhesion of wwox-transfected PEO1 cells and vector-transfected PEO1 cells that were constructed, as well as PEO1 parent cells. Alpha/beta integrin-mediated cell adhesion assays were designed to identify cells surface integrins in PEO1 clone cells. Integrin function blocking experiments were designed to further determine integrins in PEO1 clone cells according to the integrin that was selected in integrin expression profiling. FACS analysis was used to further detect the level of integrin alpha3 on the cell membrane. RESULTS: Attachment assay showed that adhesion of WWOX-transfected PEO1 cells to fibronectin was significantly slower than that in vector-transfected controls or PEO1 parent cells, cultured on the pre-coated fibronectin for 2 hours (P<0.01). The level of membranous integrins alpha2 and alpha3 in the WWOX-transfected PEO1 cells was significantly decreased, as compared with that in vector-transfected controls (P<0.05), but there was no association with the level of functioning integrins betal or beta2 in clone cells (P>0.05). The attachment assays were repeated after pre-incubating the cells with integrin alpha2 or alpha3 function-blocking antibodies. These results showed that blocking integrin alpha3 significantly reduced the binding to fibronectin of all the PEO1 clonal lines, as compared with cells pre-incubated with a non-specific IgG antibody (P<0.05). In contrast, preincubation with alpha2 blocking antibody had very little effect on fibronectin binding in these cells (P>0.05). FACS analysis showed that membranous integrin alpha3 expression revealed a marked reduction in WWOX-transfected cells than that in vector-transfected cells. CONCLUSION: WWOX acts as an ovarian tumor suppressor by modulating the interaction between tumor cells and the extracellular matrix, decreasing integrin activity and adhesion of tumor cells to fibronectin. This suggests an important role for loss of WWOX tumor suppressor in promoting attachment and adhesion of ovarian cancer cells on locoregional peritoneum, and further resulting in enhancing locoregional peritoneal tumor spread.

[Study on serum vascular endothelial growth factor level in ovarian malignant tumors].

OBJECTIVE: To explore the diagnostic value of serum vascular endothelial growth factor (VEGF) level in patients with ovarian carcinomas, and to evaluate the correlation between serum VEGF level and prognosis of ovarian cancer. METHOD: Serum VEGF level in patients with ovarian neoplasms (120 cases of ovarian carcinomas, 25 cases of benign tumors) and 90 healthy women as controls was determined by enzyme linked immunosorbent assay (ELISA), also the change of preoperative and postoperative serum VEGF level of 25 cases of epithelial ovarian cancer was observed. RESULTS: (1)The preoperative serum VEGF levels were (766 +/- 1237) mg/L in malignant groups, and there was a significant difference compared with normal controls (55 +/- 19) mg/L or patients with benign tumor (56 +/- 23) mg/L (P < 0.05). As a cut-off at 100 mg/L, sensitivity and specificity of preoperative serum VEGF levels for diagnosing ovarian cancer was 77% and 87% respectively. (2) Serum VEGF level were significantly elevated in advanced stage (955 +/- 1716) mg/L and poorly differentiated (991 +/- 1349) mg/L compared with early stage (198 +/- 287) mg/L and well differentiated (280 +/- 552) mg/L (P < 0.05), but there is no significant difference between the VEGF level and pathological types (P > 0.05). (3) The postoperative serum VEGF levels (118 +/- 110) mg/L were significantly lower than that in preoperative (1074 +/- 1211) mg/L. (4) The average total survival-time in patients with VEGF(+) was 28 months, but it in patients with VEGF(-) was 35 months (P < 0.05). CONCLUSION: Serum VEGF values were higher in malignant tumors and preoperative serum VEGF level has a potential as a marker for diagnosing and monitoring in ovarian neoplasms.