Objective:To identify the factors associated with long-term survival and guide the decision for primary surgery in patients with advanced high-grade serous ovarian cancer(HGSOC).Methods:In this case-control study, clinical parameters, including surgical and non-surgical associated factors, were collected and compared between the patients with short-term (<2 years) and long-term (>5 years) survival who all underwent primary debulking surgery (PDS) followed by carboplatin and paclitaxel chemotherapy from January 2004 to December 2016. Univariate analysis was examined by chi-square test and multivariate analysis was performed by logistic regression analysis.Results:There were 95 cases long-term survival (LTS group) and 77 cases short-term survival (STS group) in 698 newly diagnosed HGSOC patients with International Federation of Gynecology and Obstetrics (FIGO) stage Ⅲc and Ⅳ who met include and exclude criteria. (1) Univariate analysis showed that the proportion of complete cytoreduction with no visible residual disease (R0) at PDS and platinum sensitivity in LTS group were significantly higher than those in STS group ( P<0.01). The surgical complexity score (SCS), the preoperative serum CA 125 level and the ascites volume in the LTS group were significantly lower than those of the STS group (all P<0.05). In the LTS group, the preoperative incidence of lesions in retrograde peritoneum of the bladder, serosal and mesangial membrane of the small intestine, upper abdominal peritoneum and liver parenchyma were significantly lower than those in the STS group (all P<0.05). Multivariate logistic regression analysis showed that platinum sensitivity ( OR=0.016, 95% CI: 0.004-0.063, P<0.01), ascites volume >500 ml ( OR=3.193, 95% CI: 1.285-7.930, P=0.012), and SCS ≥8 ( OR=17.433, 95% CI: 2.281-133.25, P=0.003) were independent factors affecting long-term survival ( P>0.05). (2) Totally 37 of 95 in long-term survival and 16 of 77 in short-term survival achieved R0 cytoreduction at PDS. Univariate analysis showed that preoperative serum CA 125 level, preoperative lesion score, preoperative lesion (DS) score, ascites volume, platinum sensitivity,and SCS were significantly correlated with the R0 PDS (all P<0.05). Multivariate analysis showed that ascites volume >500 ml ( OR=5.199, 95% CI: 2.015-13.409, P=0.001), DS >2 ( OR=15.264, 95% CI: 5.843-39.874, P<0.01) and SCS ≥4 ( OR=4.176, 95% CI: 1.618-10.777, P=0.003) were independent factors associated with R0 cytoreduction. In patients with DS ≤2 or SCS <4, but not those with DS >2 or SCS ≥4, R0 cytoreduction was significantly associated with long-term survival. Conclusion:The intrinsic biology of tumor is the factor influencing long-term survival of advanced HGSOC patients, and those who present with wide intraperitoneal metastases and need to remove multiple organs may not benefit from R0 cytoreduction.

Objective:To investigate the inhibitory effect of combined strategy of poly adenosine diphosphate ribose polymerase (PARP) inhibitor and interleukin-1β (IL-1β) inhibitor on homologous recombination deficiency (HRD)-proficient ovarian cancer cells.Methods:(1) HRD-proficient ovarian cancer cell lines OVCAR3 and CAOV3 were treated with PARP inhibitor olaparib. Screening by RNA sequencing analysis, the expression level of IL-1β was validated by enzyme-linked immunosorbent assay (ELISA) and western blot. (2) The dose-response curves of IL-1β inhibitor diacerein were evaluated by cell counting kit-8 (CCK-8) assays in OVCAR3 and CAOV3 cells. CCK-8 assays were further applied to determine the viabilities of OVCAR3 and CAOV3 cells. (3) To evaluate the synergistic effects of olaparib and IL-1β inhibitor in vivo, the transplanted ovarian cancer model was constructed. BALB/c-nude mice ( n=16) were injected intraperitoneally with 1×10 7 OVACR3 cells labelled with luciferase (OVCAR3-Luc). Immunohistochemistry (IHC) assay was performed to determine nuclear antigen associated with cell proliferation (Ki-67) expression. (4) Blood routine tests, kidney and liver function tests were performed to analyze the toxic reaction of different drug treatments. The potential drug-induced injuries of vital organs including heart, liver, spleen, lungs and kidneys of nude mice were determined by hematoxylin-eosin (HE) staining. Results:(1) The RNA sequencing results showed that the mRNA level of IL-1β was the most significantly increased among the 25 differentially expressed genes in OVCAR3 cells treated with olaparib, compared to the negative control group. Olaparib treatment significantly promoted the secretion and expression of IL-1β protein in both OVACR3 and CAOV3 cells by ELISA [(36.2±3.5) and (49.5±3.5) pg/ml, respectively; all P<0.001] and western bolt (2.87±0.37 and 2.05±0.08, respectively; all P<0.01). (2) The half maximal inhibitory concentration (IC 50) value of IL-1β inhibitor was determined as follows: 75 μmol/L for OVACR3 cells and 100 μmol/L for CAOV3 cells. The treatments were divided into four groups including control group, olaparib monotherapy group, IL-1β inhibitor monotherapy group and the combination therapy group. The cell viabilities of each group in OVCAR3 and CAOV3 were determined by CCK-8 assay. The data in each group were showed as follows for OVCAR3 and CAOV3 cells: (100.0±0.4)% and (100.0±3.5)% in control group; (63.1±6.2)% and (63.3±3.8)% in olaparib monotherapy group; (61.6±4.7)% and (63.8±3.5)% in IL-1β inhibitor monotherapy group; and (32.9±5.2)% and (30.0±1.3)% in the combination therapy group. The viability assay showed that the combined strategy exhibited a significant inhibition effect on OVACR3 and CAOV3 cells, compared to the monotherapy group and the control group (all P<0.01). (3) All mice with transplanted tumors of HRD-proficient ovarian cancer cells were randomly divided into four groups, and treated with four different treatments as mentioned above, respectively. After 4 weeks (on day 29), the vivo fluorescence imaging were determined. The results showed that the amount of fluorescence of transplanted tumors was mostly decreased in the combination therapy group [(0.5±0.4)×10 10 p/s], compared to the control group [(4.2±1.0)×10 10 p/s] or the groups treated with any single drug [(3.1±0.9)×10 10, (2.2±0.9)×10 10 p/s; all P<0.05]. Mice were then sacrificed under anesthesia, and all transplanted tumors detached and weighed for further investigation. The weight of transplanted tumors was significantly decreased in the combination therapy group [(0.09±0.03) g], compared to that in control group [(0.25±0.05) g] or groups treated with any single drug [(0.17±0.03), (0.19±0.04) g; all P<0.05]. The measurement of the expression of Ki-67 showed that it was significantly decreased in the combination therapy group (0.33±0.10), compared to that in the control group (1.00±0.20) or monotherapy groups (0.76±0.07, 0.77±0.12; all P<0.05). (4) There were no significant differences of body weights, blood routine test, renal and liver function tests among mice with different treatments (all P>0.05). Moreover, no significant injuries were observed in the vital organs among the four groups. Conclusions:The combination of olaparib and IL-1β inhibitor synergistically exhibits significant cytotoxicity in HRD-proficient ovarian cancer cells. Moreover, the blood routine and blood biochemistry results confirmed the biosafety of the combination of olaparib and IL-1β inhibitor.

OBJECTIVES: The International Federation of Gynecology and Obstetrics (FIGO) 2000 scoring system classifies gestational trophoblastic neoplasia (GTN) patients into low- and high-risk groups, so that single- or multi-agent chemotherapy can be administered accordingly. However, a number of FIGO-defined low-risk patients still exhibit resistance to single-agent regimens, and the risk factors currently adopted in the FIGO scoring system possess inequable values for predicting single-agent chemoresistance. The purpose of this study is therefore to evaluate the efficacy of risk factors in predicting single-agent chemoresistance and explore the feasibility of simplifying the FIGO 2000 scoring system for GTN. METHODS: The clinical data of 578 GTN patients who received chemotherapy between January 2000 and December 2018 were retrospectively reviewed. Univariate and multivariate logistic regression analyses were carried out to identify risk factors associated with single-agent chemoresistance in low-risk GTN patients. Then, simplified models were built and compared with the original FIGO 2000 scoring system. RESULTS: Among the eight FIGO risk factors, the univariate and multivariate analyses identified that pretreatment serum human chorionic gonadotropin (hCG) level and interval from antecedent pregnancy were consistently independent predictors for both first-line and subsequent single-agent chemoresistance. The simplified model with two independent factors showed a better performance in predicting single-agent chemoresistance than the model with the other four non-independent factors. However, the addition of other co-factors did improve the efficiency. Overall, simplified models can achieve favorable performance, but the original FIGO 2000 prognostic system still features the highest discrimination. CONCLUSIONS Pretreatment serum hCG level and interval from antecedent pregnancy were independent predictors for both first-line and subsequent single-agent chemoresistance, and they had greater weight than other non-independent factors in predicting single-agent chemoresistance. The simplified model composed of certain selected factors is a promising alternative to the original FIGO 2000 prognostic system, and it shows comparable performance.
Female ; Gestational Trophoblastic Disease/drug therapy* ; Humans ; Multivariate Analysis ; Pregnancy ; Retrospective Studies ; Risk Factors