Comprehensive Analysis and Experimental Validation of a Novel Estrogen/Progesterone-Related Prognostic Signature for Endometrial Cancer.

Estrogen and progesterone are the major determinants of the occurrence and development of endometrial cancer (EC), which is one of the most common gynecological cancers worldwide. Our purpose was to develop a novel estrogen/progesterone-related gene signature to better predict the prognosis of EC and help discover effective therapeutic strategies. We downloaded the clinical and RNA-seq data of 397 EC patients from The Cancer Genome Atlas (TCGA) database. The "limma" R package was used to screen for estrogen/progesterone-related differentially expressed genes (DEGs) between EC and normal tissues. Univariate and multivariate Cox proportional hazards regression analyses were applied to identify these DEGs that were associated with prognosis; then, a novel estrogen/progesterone-related prognostic signature comprising CDC25B, GNG3, ITIH3, PRXL2A and SDHB was established. The Kaplan-Meier (KM) survival analysis showed that the low-risk group identified by this signature had significantly longer overall survival (OS) than the high-risk group; the receiver operating characteristic (ROC) and risk distribution curves suggested this signature was an accurate predictor independent of risk factors. A nomogram incorporating the signature risk score and stage was constructed, and the calibration plot suggested it could accurately predict the survival rate. Compared with normal tissues, tumor tissues had increased mRNA levels of GNG3 and PRXL2A and a reduced mRNA level of ITIH3. The knockdown of PRXL2A and GNG3 significantly inhibited the proliferation and colony formation of Ishikawa and AN3CA cells, while the inhibition of PRXL2A expression suppressed xenograft growth. In this study, five estrogen/progesterone-related genes were identified and incorporated into a novel signature, which provided a new classification tool for improved risk assessment and potential molecular targets for EC therapies.

Nedaplatin and paclitaxel compared with carboplatin and paclitaxel for patients with platinum-sensitive recurrent ovarian cancer.

This retrospective cohort study was designed to evaluate the efficacy and safety of nedaplatin plus paclitaxel (NP) compared with carboplatin plus paclitaxel (CP) in platinum-sensitive recurrent ovarian cancer. Patients with histologically proven epithelial ovarian cancer with recurrent interval ≥6 months after finishing platinum-based therapies between January 1, 2009 and December 31, 2014 were investigated. Patients received an intravenous infusion of NP (nedaplatin 80 mg/m2 plus paclitaxel 175 mg/m2) or CP (carboplatin at an area under the curve of 5 plus paclitaxel 175 mg/m2) protocols every 3 weeks for at least 6-8 cycles or until disease progression. Primary end point was progression-free survival (PFS); secondary end points were toxicity and overall survival (OS). 436 patients were included in the study, containing 241 cases receiving CP regimen and 195 cases receiving NP regimen, who were all contained in safety analysis. Because of 61 patients with unbearable toxicity and poor compliance, 375 patients were finally included in the efficacy analysis. With median follow-up of 63.5 months, PFS was 11.0 months with NP regimen versus 9.5 months with CP regimen (P=0.109). Subgroup analysis indicated that PFS of the NP arm was statistically superior to the CP arm when recurrent interval was 6-12 months (P=0.048); median PFS was 10.0 versus 8.0 months, respectively. There was no significant difference in overall survival between two groups. More frequent grade 3-4 neutropenia (13.3% vs 33.6%), thrombocytopenia (5.6% vs 14.5%) and hypersensitivity reactions (5.6% vs 21.9% ) were observed in CP arm (P<0.01). Compared to the CP, NP regimen did not improve 5-year overall survival in platinum-sensitive recurrent ovarian cancer, but it had better tolerance. NP obtained significant benefit in progression-free survival when the recurrent interval was between 6 and 12 months, although the efficacy of two regimens were similar when the recurrent interval ≥12 months.

[Clinical analysis for 18 cases of vulvar Bowen's disease].

OBJECTIVE: To analyse the clinical and pathological characteristics, diagnosis, treatment and prognosis of vulvar Bowen's disease. METHODS: Clinical data including pathological characteristics, diagnosis, treatment methods and follow-up of 18 cases with vulvar Bowen's disease admitted to Cancer Hospital, Chinese Academy of Medical Sciences during January 1991 to June 2011 were retrospectively analyzed. RESULTS: The median age of the 18 patients was 37 years (range:23 to 64 years) . Sixteen patients had symptoms of vulvar itching and two patients had no symptom. Five cases were single neoplasm focus and the other 13 cases were multiple focuses. The diagnosis of vulvar Bowen's disease was according to the pathological diagnosis. Its diagnostic characteristic was giant round or ovoid cells with mono nucleolus in the whole layer of epidermis. All the patients received operation, eleven with simple vulvectomy and other seven cases with lumpectomy. The median follow-up time was 123 months (range: 5 to 197 months). Relapse was found in two cases. One patient relapsed five months postoperation and received vulvectomy. Another patient relapsed fifteen moths post-operation and received lumpectomy again. And they were follow-up for 192 months and 55 months respectively after second operation without relapse. CONCLUSIONS: The diagnostic characteristic of vulvar Bowen's disease is giant round or ovoid cell with mono nucleolus in the whole layer of epidermis, itsdiagnosis is according to the pathological diagnosis. Operation could get very good curative effect for patients with primary vulvar Bowen's disease and even for the recurrent patients. The prognosis of vulvar Bowen's disease is good.

[Analysis of 25 cases of brain metastasis from gynecological cancers].

OBJECTIVE: To discuss the clinical characteristics, treatment and prognostic factors of brain metastasis from gynecological cancers. METHODS: Clinical records of 25 brain metastasis patients from gynecological cancers admitted from January 1999 to January 2009 were reviewed retrospectively. The curative effects of different treatments were compared. The prognostic factors were determined using the Cox regression model. RESULTS: There were 14 cases ovarian malignant tumor, 6 cases cervical carcinoma and 5 cases uterine malignant tumor. Seven cases (28%, 7/25) had solitary metastatic lesion in the brain. Extracranial metastases were detected in 18 cases (72%, 18/25). Five patients only received one kind of treatment, and the mean survival time was 4.0 months (0.5 to 9.5 months). Sixteen patients received combined treatment, 3 of them received combined treatment including surgery, and the mean survival time was 8.4 months (4.1 to 13.4 months); 13 of them received chemotherapy and radiotherapy, and the mean survival time was 14.2 months (4.3 to 58.1 months). Four patients received only palliative supportive care, and the survival time was only 0.1 to 1.0 month. The Cox regression model showed that Karnofsky performance status scale, with or without extracranial metastases and the treatment method were the independent prognostic factors of brain metastasis from gynecological cancers (P < 0.05). CONCLUSION: The incidence of brain metastasis from gynecological cancers is low and the prognosis is very poor. Combined treatments may get better effects.

[Analysis of treatment and prognosis of recurrent epithelial ovarian carcinoma].

OBJECTIVE: To discuss the prognostic factors of recurrent ovarian epithelial carcinoma and to analyze the curative effect of post-relapse treatment. METHODS: The clinical records of 293 patients with ovarian epithelial carcinoma were reviewed retrospectively. There were 199 recurrent cases during the following up. RESULTS: All the 199 patients received chemotherapy. And 173 patients only received chemotherapy. 16 patients received surgery and chemotherapy and the other 10 patients received radiotherapy and chemotherapy. 158 patients received platinum-based chemotherapy again and 41 patients received chemotherapy without platinum. The response rate of all the patients was 43.7% (87/199), the response rate of only chemotherapy was 39.9% (69/173), the response rate of surgery and chemotherapy was 75.0% (12/16), and the response rate of radiotherapy and chemotherapy was 60.0% (6/10). The patients were divided into four groups according to the progression free interval (PFI). The response rates in groups that PFI < or = 6 months, 7 - 12 months, 13 - 24 months and > 24 months were 5.1%, 47.2%, 82.1% and 96.0%, respectively. The median survival time in the 16 patients received second cyto-reductive surgery was 41 months. Multivariate analysis revealed that PFI was significantly correlated with prognosis of recurrent ovarian epithelial carcinoma (OR = 0.589, P = 0.021). CONCLUSION: PFI is an individual prognostic factor for survival of recurrent ovarian epithelial carcinoma. PFI is significantly associated with the response rate of chemotherapy. Optimal secondary cytoreductive surgery may improve the overall survival of recurrent patients. The response rate of paclitaxel plus platinum chemotherapy in platinum-sensitive patients is higher than that of other platinum-based chemotherapy.

[Study of the prevention of chemotherapy-induced ovarian damage by gonadotropin-releasing hormone agonist in rat model].

OBJECTIVE: To study the effect of gonadotropin-releasing hormone agonist (GnRHa) against cyclophosphamide (CTX) induced gonado toxicity in female rats. METHODS: Eighty Fischer 344 rats were divided into four groups which received normal saline, CTX, GnRHa and CTX + GnRHa respectively. We measured the serum estradiol and follicle-stimulating hormone (FSH) concentration monthly, and respectively killed half of the rats two months and three months later to compare the weight of the ovary, the numbers of the follicle and the mean diameter of the follicles. RESULTS: After three months, in the rats in the CTX group, the serum estradiol and FSH were (148.3 +/- 16.5) pmol/L and (16.90 +/- 1.90) U/L respectively. They were significantly higher than (91.8 +/- 9.9) pmol/L and (7.60 +/- 0.30) U/L in the rats in the combination therapy group (P < 0.05). The follicle number of rats in the CTX group was 550 +/- 50 and the follicle number in the combination group was 1250 +/- 160. There was significant difference between two groups (P < 0.05). Between rats in the control and combination therapy groups, there was no obvious difference in all the indexes we examined. CONCLUSIONS: Combination of the CTX and GnRHa in the rat model could decrease the CTX-induced damage to the ovarian function.

[Influence of gonadotropin-releasing hormone agonist on the effects of chemotherapy upon ovarian cancer: an experimental study with rat model].

OBJECTIVE: To study the influence of the gonadotropin-releasing hormone agonist (GnRHa) on the expression of the estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), progesterone receptor (PR) and androgen receptor (AR) in the ovarian tissue and on the curative effect of cytoxan (CTX) on ovarian cancer. METHODS: (1) Eighty female Fischer-344 rats were randomly divided into four groups: blank control group receiving normal saline, GnRHa treatment group, CTX treatment group, and CTX + GnRHa treatment group. Two months after the beginning of experiment 10 rats from each group were killed and their bilateral ovaries were taken out to undergo RT-PCR and immunohistochemistry to compare the expression of ERalpha, ERbeta, PR, and AR. The remaining rats were killed after one more month and their ovaries were examined too. (2) Twenty female Fischer-344 rats were injected intraperitoneally with 5 x 10(9) rat ovarian adenocarcinoma cells of the line NuTu-19 and then randomly divided into 3 groups: group 1 (n = 4, used as controls), group 2 (n = 8, receiving CTX 5 weeks after the injection of cancer cells), and group 3 (n = 8, receiving CTX + GnRHa). The survival time was observed among each group. RESULTS: (1) The mRNA expression levels of ERalpha, ERbeta, PR and AR in the four groups were 0.24-0.29, 1.13-1.35, 0.68-0.88, and 1.39-1.63 respectively; The protein expression levels of ERalpha, ERbeta,PR and AR in the four groups were 4.7-5.1, 15.1-15.5, 8.5-9.1, and 17.9-19.0 respectively. There was no significant difference between each group in the expression of these receptors. (2) The mean survival times of the CTX group and CTX + GnRHa group were 76.0 +/- 15.3 days and 79.6 +/- 16.6 days respectively (P > 0.05), both significantly longer than that of the control group (52.0 +/- 3.5 days, both P < 0.05). CONCLUSION: GnRHa has no effect on the expression of ERalpha, ERbeta, PR and AR in the ovarian tissue and does not influence the curative effect of CTX on ovarian cancer in rat model.