LncRNA IDH1-AS1 sponges miR-518c-5p to suppress proliferation of epithelial ovarian cancer cell by targeting RMB47

Long noncoding RNA(lncRNA)IDH1 antisense RNA 1(IDH1-AS1)is involved in the progression of multiple cancers,but its role in epithelial ovarian cancer(EOC)is unknown.Therefore,we investigated the expression levels of IDH1-AS1 in EOC cells and normal ovarian epithelial cells by quantitative real-time PCR(qPCR).We first evaluated the effects of IDH1-AS1 on the proliferation,migration,and invasion of EOC cells through cell counting kit-8,colony formation,EdU,transwell,wound-healing,and xenograft assays.We then explored the downstream targets of IDH1-AS1 and verified the results by a dual-luciferase reporter,qPCR,rescue experiments,and Western blotting.We found that the expression levels of IDH1-AS1 were lower in EOC cells than in normal ovarian epithelial cells.High IDH1-AS1 expression of EOC patients from the Gene Expression Profiling Interactive Analysis database indicated a favorable prognosis,because IDH1-AS1 inhibited cell proliferation and xenograft tumor growth of EOC.IDH1-AS1 sponged miR-518c-5p whose overexpression promoted EOC cell proliferation.The miR-518c-5p mimic also reversed the proliferation-inhibiting effect induced by IDH1-AS1 overexpression.Furthermore,we found that RNA binding motif protein 47(RBM47)was the downstream target of miR-518c-5p,that upregulation of RBM47 inhibited EOC cell proliferation,and that RBM47 overexpressing plasmid counteracted the proliferation-promoting effect caused by the IDH1-AS1 knockdown.Taken together,IDH1-AS1 may suppress EOC cell proliferation and tumor growth via the miR-518c-5p/RBM47 axis.

Epithelial Ovarian Cancer Patients and Clinicopathological Features and Survival: A Comparison of Outcomes of Two Age Cohorts in Bangladesh

Objective: This study compared the clinicopathologic characteristics and overall survival of epithelial ovarian carcinoma in women younger versus older than 45 years in Bangladesh. Methods: A retrospective analysis identified 129 epithelial ovarian carcinoma patients who were admitted to the National Institute of Cancer Research and Hospital, in Dhaka, Bangladesh from 2016 through 2017 for surgery. These patients were grouped into two categories: the younger group (≤45 years) and the older group (>45 years). Clinicopathological features of epithelial ovarian carcinoma were analyzed in each age group. Cox proportional hazards model identified factors affecting survival and Kaplan-Meier survival curves with log rank test compared outcomes for each age group. Results: The median age of the 129 women was 46 years (IQR: 38, 56) and median time of follow-up was 9 months (inter-quartile range: 4, 26.5). We found a significant difference in the CA-125 level (p < 0.044), age of menopause (p < 0.001), follow-up duration (p < 0.016), disease outcome (p < 0.005) and histopathological type (p < 0.021) between the two groups. No significant differences were found in breakdown of Federation of Gynecology and Obstetrics (FIGO) stage of the disease. There was a significant difference in overall survival between the patients of two groups (p = 0.021) where there was a higher probability of death among the older cohort. The 5-year overall survival rates for the younger age versus older group were 34.0%, and 11.7% respectively. Independent prognostic factors by univariate analysis for the overall survival were age, FIGO stage, preoperative CA-125 and CEA level. However, when controlling for stage, survival was similar between age cohorts. Conclusions: Our data suggests that women in Bangladesh with epithelial ovarian cancer who are under the age of 45 years have a different clinical profile and better overall survival than women in the older age cohort.

Adaptor Protein Crk is Implicated in Mucus Formation in Mucinous Epithelial Ovarian Cancer (mEOC) Cells MCAS

Objective： The mucus production is an indicator for the histological grade of mucinous epithelial ovarian cancer （mEOC）. In our previous study, Crk expression was targeted in the human ovarian mucinous adenocarcinoma cell line MCAS through RNA interference, resulting in the establishment of Crk knock down cells. These cells exhibited decreased tumorigenic potential both in vitro and in vivo. The purpose of this study was to investigate if there is any change in the capability of forming mucus in these Crk knock down cells. Methods： Cytoplasmic periodic acid Schiff （PAS） staining and particle excluding assay were conducted to assess the mucus formation within and around cells, respectively. Additionally, the amount of mucus formed in tumor lumps from nude mice model was measured following HE and PAS staining. Results： The increased mucus production in Crk knockdown mEOC cells （MCAS） was manifested by increased number of enlarged cells filled with vacuoles-like mucus observed by phase-contrast microscope and cytoplasmic PAS staining; and enhanced mucus secretion was represented by the assembly of pericellular matrix in particle excluding assay and increased mucus area in tumor lumps from nude mice models. Conclusion： The course of carcinogenesis in mEOC is associated with the altered pattern of mucus production and secretion. The adaptor protein Crk is implicated in both pathways.

Primary ovarian cancer combined with primary fallopian tube cancer:A case report

BACKGROUND Low grade serous carcinoma of the ovary(LGSOC)is a rare type of epithelial ovarian cancer with a low incidence rate.The origin of ovarian cancer has always been a hot topic in gynecological oncology research,and some scholars believe that the origin of ovarian malignant tumors is the fallopian tubes.Primary fallopian tube cancer is the lowest incidence of malignant tumors in the female reproductive system.There are only a few reports in the literature,but the mortality rate is very high.But in clinical practice,fallopian tube cancer is very common,but in most cases,it is classified as ovarian cancer.CASE SUMMARY We report a 54 years old postmenopausal woman who was hospitalized with a lower abdominal mass and underwent surgical treatment.The final pathological confirmation was low-grade serous carcinoma of the right ovary and low-grade serous carcinoma of the left fallopian tube.No special treatment was performed after the surgery,and the patient was instructed to undergo regular follow-up without any signs of disease progression.CONCLUSION The prognosis of LGSOC is relatively good,over 80%of patients still experience disease recurrence.

New Progress of CA125 Surveillance in Diagnosis and Treatment of Ovarian Cancer

The fatality rate of ovarian cancer (OC) is the highest, and the 5-year survival rate is only 50.8%. For more than 40 years, CA125 has been the most concerned and widely used biomarker of OC in clinical practice. In recent years, many researchers have proposed a reliable strategy of multiple markers combined with CA125 to screen OC to make up for the lack of accuracy of CA125, redefine the biochemical recurrence threshold of CA125, and use mathematical model scores to provide help for the feasibility of treatment and survival prognosis. To fully understand the role of CA125 in OC screening, initial treatment, and recurrence prediction, and summarize the limitations of CA125, this review has summarized the new progress of CA125 in the diagnosis and treatment of OC in recent years which can also provide a reference for clinicians.

Overexpression and Immunosuppressive Functions of Transforming Growth Factor 1,Vascular Endothelial Growth Factor and Interleukin-10 in Epithelial Ovarian Cancer

Objective： Transforming growth factor-1 （TGF-βI）, vascular endothelial growth factor （VEGF）, and interleukin-lO （IL-10） may be critical cytokines in the microenvironment of a tumor, playing roles in immune suppression. This study was conducted to elucidate the roles and immunosuppressive functions of these cytokines in epithelial ovarian cancer （EOC）. Methods： The expression levels of TGF-β1, VEGF and IL-10 in malignant tissue were evaluated by immune- histochemistry and compared with corresponding borderline, benign, and tumor-free tissues. Moreover, relationships among the levels of these cytokines and correlations between expression and the prognosis of EOC were analyzed by Pearson rank correlations and multi-factor Logistic regression. The roles of TGF-βI, VEGF, and IL-lO in the immunosuppressive microenvironment of ovarian cancer were studied through dendritic cell （DC） maturation and CD4＋CD25＋FoxP3＋ Treg generation in vitro experiments. Results： TGF-β1, VEGF, and IL-IO were expressed TGF-β1 was an independent prognostic factor for EOC n 100%, 74.69%, and 54.96% of EOC patients, respectively. L-IO was significantly co-expressed with VEGF. In vitro, VEGF and TGF-β31 strongly interfered with DC maturation and consequently led to immature DCs, which secreted high levels of IL-IO that accumulated around the tumor site. TGF-β1 and IL-10 induced Treg generation without antigen presentation in DCs. Conclusions： TGF-βI, VEGF and IL-IO play important roles in EOC and can lead to frequent immune evasion events.

Targeted therapies in epithelial ovarian cancer: Molecular mechanisms of action

Ovarian cancer is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at an advanced stage and have a poor prognosis.Currently, surgical tumor debulking, followed by platinum- and taxane-based chemotherapy is the standard treatment for advanced ovarian cancer. However, these patients are at great risk of recurrence and emerging drug resistance. Therefore, novel treatment strategies are required to improve outcomes for women with advanced ovarian cancer. A variety of molecular targeted agents, the majority of which are monoclonal antibodies and small-molecule protein-kinase inhibitors, have been explored in the management of ovarian cancer. The targets of these agents include angiogenesis, the human epidermal growth factor receptor family, ubiquitinproteasome pathway, epigenetic modulators, poly(ADPribose) polymerase (PARP), and mammalian target of rapamycin (mTOR) signaling pathway, which are aberrant in tumor tissue. The antiangiogenic agent, bevacizumab, has been reported as the most effective targeted agent and should be included in the standard chemotherapeutic regimen for advanced ovarian cancer. PARP inhibitors, which are mainly used in breast and ovarian cancer susceptibility gene-mutated patients, and mTOR inhibitors are also attractive treatment strategies, either alone or combination with chemotherapy, for ovarian cancer. Understanding the tumor molecular biology and identification of predictive biomarkers are essential steps for selection of the best treatment strategies. This article reviews the molecular mechanisms of the most promising targeted agents that are under early phase clinical evaluation for ovarian cancer.

PGC-la induces apoptosis in human epithelial ovarian cancer cells through a PPARy-dependent pathway

Peroxisome proliferator-activated receptor gamma （PPAR）,） coactivator-1 alpha （PGC-1α） coactivates multiple transcription factors and regulates several metabolic processes. The current study investigated the role of PGC-1α in the induction of apoptosis in human epithelial ovarian cancer cells. The PGC-1α mRNA level between human ovaries and human ovarian epithelial tumors was examined by quantitative RT-PCR. Less PGC- 1α expression was found in the surface epithelium of malignant tumors compared with normal ovaries. Overexpression of PGC-1α in human epithelial ovarian cancer cell line Ho-8910 induced cell apoptosis through the coordinated regulation of Bcl-2 and Bax expression. Microarray analyses confirmed that PGC-1α dramatically affected the apoptosis-related genes in Ho-8910 cells. Mitochondrial functional assay showed that the induction of apoptosis was through the terminal stage by the release of cytochrome c. Furthermore, PG-C- 1 α-induced apoptosis was partially, but not completely, blocked by PPAR）, antagonist （GW9662）, and suppression of PPAR）, expression by siRNA also inhibited PGC-1α-induced apoptosis in Ho-8910 cells. These data suggested that PGC-1α exerted its effect through a PPARγ-dependent pathway. Our findings indicated that PGC-1α was involved in the apoptotic signal transduction pathways and downregulation of PGC-1α may be a key point in promoting epithelial ovarian cancer growth and progression.

Epithelial ovarian cancer:An overview

Ovarian cancer is the second most common gyneco-logical cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which accounts for over 95 percent of the ovarian malignancies. We will present various theories about the potential origin of ovarian malignancies. We will discuss the genetic anomalies and syndromes that may cause ovarian cancers with emphasis on Breast cancer type 1/2 mutations. The pathology and pathogenesis of ovarian carcinoma will also be presented. Lastly, we provide a comprehensive overview of treatment strategies and staging of ovarian cancer, conclusions and future directions.

Association of serum lipids and severity of epithelial ovarian cancer：an observational cohort study of 349 Chinese patients

While obesity and fat intake have been associated with the risk and prognosis of epithelial ovarian cancer, the association between the lipid levels and epithelial ovarian cancer phenotype remains controversial. We conducted a retrospective study of 349 epithelial ovarian cancer patients who received treatment at Jiangsu Cancer Hospital, China between 2011 and 2017. We analyzed age at diagnosis, blood pressure, plasma glucose content, body mass index（BMI）, lipid levels and clinical parameters. Severity of epithelial ovarian cancer was classified according to the International Federation of Gynecology and Obstetrics（FIGO） grading system. Univariate analysis of the clinical factors according to the severity of epithelial ovarian cancer was followed by logistic regression analysis to identify clinical factors significantly associated with epithelial ovarian cancer severity. Univariate analysis indicated that age,BMI, triglyceride（TG）, and high density lipoproteins（HDL） differed significantly among different stages of epithelial ovarian cancer（P〈0.05）. In the logistic regression model, elevated TG（OR： 1.883; 95% CI= 1.207-2.937）, and low HDL（OR： 0.497; 95% CI = 0.298-0.829） levels were significantly associated with the high severity epithelial ovarian cancer. Our data indicate that high TG and low HDL levels correlate with a high severity of epithelial ovarian cancer. These data provide important insight into the potential relationship between the lipid pathway and epithelial ovarian cancer phenotype and development.

Establishment of an optimized CTC detection model consisting of EpCAM,MUC1 and WT1 in epithelial ovarian cancer and its correlation with clinical characteristics

Objective:Emerging studies have demonstrated the promising clinical value of circulating tumor cells(CTCs)for diagnosis,disease assessment,treatment monitoring and prognosis in epithelial ovarian cancer.However,the clinical application of CTC remains restricted due to diverse detection techniques with variable sensitivity and specificity and a lack of common standards.Methods:We enrolled 160 patients with epithelial ovarian cancer as the experimental group,and 90 patients including 50 patients with benign ovarian tumor and 40 healthy females as the control group.We enriched CTCs with immunomagnetic beads targeting two epithelial cell surface antigens(EpCAM and MUC1),and used multiple reverse transcription-polymerase chain reaction(RT-PCR)detecting three markers(EpCAM,MUC1 and WT1)for quantification.And then we used a binary logistic regression analysis and focused on EpCAM,MUC1 and WT1 to establish an optimized CTC detection model.Results:The sensitivity and specificity of the optimized model is 79.4%and 92.2%,respectively.The specificity of the CTC detection model is significantly higher than CA125(92.2%vs.82.2%,P=0.044),and the detection rate of CTCs was higher than the positive rate of CA125(74.5%vs.58.2%,P=0.069)in early-stage patients(stage I and II).The detection rate of CTCs was significantly higher in patients with ascitic volume≥500 mL,suboptimal cytoreductive surgery and elevated serum CA125 level after 2 courses of chemotherapy(P<0.05).The detection rate of CTC;and CTC;was significantly higher in chemo-resistant patients(26.3%vs.11.9%;26.4%vs.13.4%,P<0.05).The median progression-free survival time for CTC;patients trended to be longer than CTC;patients,and overall survival was shorter in CTC;patients(P=0.043).Conclusions:Our study presents an optimized detection model for CTCs,which consists of the expression levels of three markers(EpCAM,MUC1 and WT1).In comparison with CA125,our model has high specificity and demonstrates better diagnostic values,especially for early-stage ovarian cancer.Detection of CTC;and CTC;had predictive value for chemotherapy resistance,and the detection of CTC;suggested poor prognosis.

Expression and mechanism of action of miR-196a in epithelial ovarian cancer

Objective:To explore the expression,biological function and possible mechanism of action of microRNA molecular-196a(miR-196a) in epithelial ovarian cancer.Methods:RT-PCR was used to detect the expression quantities of epithelial ovarian tissue,benign ovarian tissue,normal ovary epithelial tissue,ovarian cancer cell lines and miR-196 a in normal ovarian epithelial cells to analyze the relationship between the expression of miR-196 a and the clinical pathologic parameters of ovarian cancer.Among those cell lines,the cell line of which miR-196 a expressed the most or least was selected and transfected the ovarian cancer cell line by using negative control plasma and miR-196 a inhibitor.After transfection,RT-PCR was used to test the expression quantity of miR-196 a,Transwell chamber method was applied to determine the migration and invasion abilities of ovarian carcinoma cells and Western blot was employed to detect the expression of HOXA10 protein.Results:The relative expression quantities of miR-196 a in ovarian cancer tissue and benign ovarian tissue were significantly higher than that in normal ovarian epithelial tissue,and the expression quantity of miR-196 a in ovarian cancer tissue was distinctively higher than that in benign ovarian tissue(P < 0.05).Among 78 cases of epithelial ovarian cancer,the expression quantities of miR-196 a in patients with low differentiation were all significantly higher than those in patients with high differentiation(P< 0.05).The expression of miR-196 a showed no significant relation with age,clinical stage and whether CA125 was positive or not in patients(P > 0.05).Compared with normal ovarian epithelial cell line IOSE80,the expression quantities of miR-196 a of all ovarian cancer cell lines increased obviously and differences were statistically significant(P < 0.05).Among them,the expression of miR-196 a of ovarian cancer cell line SKOV3 was the highest,while it decreased significantly(4.678 ± 0.785 vs.2.131 ± 0.345,t = 2.938,P < 0.05) after the ovarian cancer cell line SKOV3 was transfected by miR-196 a inhibitor.The results of Transwell chamber method showed that the migration and invasion abilities of ovarian cancer cells SKOV3 were declined significantly after the expression of miR-196 a was down-regulated and the difference showed statistical significance(P < 0.05).The results of Western blot revealed that the relative expression of HOXA10 decreased distinctly after the expression of miR-196 a was down-regulated and also the difference showed statistical significance(P < 0.05).Conclusions:The miR-196 a might serve as a cancer-promoting gene to promote the migration and invasion of epithelial ovarian cancer by downstream target gene HOXA10.

Changes of TIZ expression in epithelial ovarian cancer cells

Objective:To study the change of TIZ expression in epithelial ovarian cancer cells.Methods:HO8910 cells were transinfected with siRNA to inhibit the expression of TIZ.pcDNA3.1-TIZ vectors were combined to increase the TIZ expression level.The cell viabilily,colony forming efficiency and cycle distribution of HO8910,HO8910/NC,HO8910/pcDNA3.1-NC,HO8910/ TIZ-573 and HO8910/pcDNA3.l-TIZ were compared,and the invasion rate,migration rate and adhesion rate between 5 groups of cells were compared.Results:Compared with those of HO8910,HO8910/NC and HO8910/pcDNA3.1-NC,the cell viability,colony forming efficiency and cell cycle distribution of HO8910/ TIZ-573 were increased,while the indexes of HO8910/pcDNA3.1-NC were decreased with statistical significant difference(P<0.05).There was no statistical significant difference in the invasion rate,migration rate and adhesion rate between 5 groups of cells(P>0.05).Conclusions:The expression of TIZ can inhibit the proliferation of epithelial ovarian cancer cells.

Prognosis in epithelial ovarian cancer: Clinical analysis of 287 pelvic and para-aortic lymphadenectomy

Objective: To evaluate the relationship between the pelvic and para-aortic lymphadenectomy and the prognosis of epithelial ovarian cancer. Methods: 287 patients suffering from primary epithelial ovarian cancer from 1995 to 2005 were analyzed retrospectively. Results: The 3-, 5-, 10-year survival with systematic lymphadenectomy (SL) were slightly higher than those without SL, but there were no statistically significance (P > 0.05). The 3-, 5-, 10-year survival of clinical stages without SL were lower than those with SL, but there were no significant difference either (P > 0.05). The 3-,5-, and 10-year survival rates with SL were higher than those without SL with no statistically differences (P > 0.05) among the subgroups such as absent, ≤ 2 cm and > 2 cm residual tumor. The survival rates of the groups without residual tumor and the group with ≤ 2 cm residual tumor were significantly higher than that of > 2 cm (P < 0.005). On multivariate analysis, patient staging (P = 0.01) and size of residual disease after primary cytoreductive surgery (P < 0.001 and = 0.002, respectively) retained prognostic significance. SL was not proved to be an independent prognostic factor (P = 0.69). Conclusion: Systematic pelvic and para-aortic lymphadenectomy can not improve and prolong the survival time significantly.

Identification of Novel Epithelial Ovarian Cancer Biomarkers by Cross-laboratory Microarray Analysis

The purpose of this study was to pool information in epithelial ovarian cancer by combining studies using Affymetrix expression microarray datasets made at different laboratories to identify novel biomarkers.Epithelial microarray expression information across laboratories was screened and combined after preprocessing raw microarray data,then ANOVA and unpaired T test statistical analysis was performed for identifying differentially expressed genes(DEGs),followed by clustering and pathway analysis for these DEGs.In this work,we performed a combination analysis on microarrays from three different laboratories using gene expression data on ovarian cancer and obtained a list of differential expression profiles identified as potential candidate in aggressiveness of ovarian cancer.The clustering and pathway analysis explored the different molecular basis of different ovarian cancer stages and potential important regulatory pathways in ovarian cancer development.Our results showed that combination of microarray data from different laboratories in the same platforms may overcome biases derived from probe design and technical features,thereby accelerating the identification of trustworthy DEGs,and demonstrating the advantage of integrative analysis in gene expression studies on epithelial ovarian cancer research.

Combination of docetaxel-carboplatin for adjuvant chemotherapy of epithelial ovarian,primary peritoneal and fallopian tube cancers:a meta-analysis

Objective： The aim of this study was to compare the efficacies and safeties of the combination of docetaxel- carboplatin with the combination of non docetaxel-carboplatin as first-line chemotherapy for advanced epithelial ovarian, pri- mary peritoneal or fallopian tube cancers. Methods： Relevant articles were identified from MEDLINE （1993-2010）, EMBASE （1980-2010）, MEDION, the Cochrane library, Science Citation Index Expanded databases, hand searching of reference lists from primary articles and reviews, conference abstracts and contact with experts in the field. The review included 5 relevant primary studies （1430 women）. Data was extracted for study characteristics and quality. Bivariate random-effect model meta- analysis was used to estimate diagnostic accuracy of the various index tests. A quantitative meta-analysis was carried out by two reviewers based on the inclusion criteria from all available studies. Results： The frequency of the subgroup analysis of toxicity showed that toxicity action of combination of docetaxel-carboplatin was more severe than that of non docetaxel- carboplatin group （OR = 1.33, 95% CI = 1.13-1.56, P = 0.0005）, whereas that of clinical responses was equivalent in com- parison combination of docetaxel-carboplatin with combination of paclitaxel-carboplatin or docetaxel-cisplatin （OR = 1.0, 95% CI = 0.87-1.16, P = 0.95）. There were heterogeneity （X2 = 79.36, P 〈 0.00001） and inconsistency （83.6%） in toxicity analysis among the trials, while neither heterogeneity （x2 = 3.21, P = 0.99） nor inconsistency （F = 0%） in clinical responses among the trials. Conclusion： The safety of combination of docetaxel-carboplatin is less than that of combination of paclitaxel- carboplatin or docetaxel-cisplatin. However, the clinical responses of combination of docetaxel-carboplatin are comparable with combination of paclitaxel-carboplatin or docetaxel-cisplatin.

Pharmacology of cancer chemotherapy drugs for hyperthermic intraperitoneal peroperative chemotherapy in epithelial ovarian cancer

The peritoneal parietal and visceral surfaces of the abdomen and pelvis are an important anatomic site for the dissemination of epithelial ovarian cancer(EOC). The transcoelomic spread of cancer cells gives rise to peritoneal carcinomatosis(PC) which, without special treatments, is a fatal manifestation of EOC. In order to control PC cytoreductive surgery to remove macroscopic disease is combined with perioperative intraperitoneal(IP) and perioperative intravenous chemotherapy to eradicate microscopic residual disease. Chemotherapy agents are selected to be administered by the IP or intravenous route based on their pharmacologic properties. A peritoneal-plasma barrier which retards the clearance of high molecular weight chemotherapy from the peritoneal cavity results in a large exposure of small cancer nodules on abdominal and pelvic surfaces. Tissue penetration is facilitated by moderate hyperthermia(41-42 ℃) of the IP chemotherapy solution. Timing of the chemotherapy as a planned part of the surgical procedure to maximize expo-sure of all peritoneal surfaces is crucial to success.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in epithelial ovarian cancer: State of the art

Advanced stage epithelial ovarian cancer(EOC) is diffi cult to treat with low overall cure rates. A new strategy combining maximal cytoreductive surgery(CRS) with intraoperative hyperthermic intraperitoneal chemotherapy(HIPEC) has been proposed to treat advanced stage EOC in the primary setting. Numerous small, heterogeneous studies have been conducted exploring outcomes in patients with predominantly advanced, recurrent or refractory disease treated with CRS + HIPEC. Although morbidity rates approaching 35% have been reported, oncologic outcomes are promising. Incorporation of HIPEC for the treatment of primary EOC has continued to gain interest. Several prospective phase 2 clinical trials were recently completed evaluating the impact of CRS + HIPEC in the primary setting. This article will briefl y discuss the benefi ts of optimal surgical cytoreduction and the theoretical basis of intraperitoneal chemotherapy in patients with advanced stage EOC, and will then review existing literature describing oncologic outcomes in EOC patients treated with HIPEC in the primary setting.

Fluid Shear Stress-Induced IL-8/CXCR Signaling Promotes Epithelial Mesenchymal Transition of Ovarian Cancer Cells

Objective Epithelial mesenchymal transition(EMT)plays a very important role in ovarian cancer metastasis,and IL-8 released from mechanosensitive cancer cells may contribute to the EMT process of solid carcinomas.In this study,we have explored IL-8 and its receptors signal transduction process of human ovarian cancer cells under conditions of FSS,and simultaneously detected the EMT process of ovarian cancer.Methods After the fluid shear stress was loaded,LightCyclerTM system and ELISA were employed to assay the IL-8 mRNA expression and protein production,respectively.Meanwhile,IL-8 reporter gene pEGFP1-IL8USCS was constructed for determining IL-8 gene transcriptional activation through gene transfer and flow cytometric analysis.RT-PCR,Northern blot and immunofluorescence were used to determine the expression of IL-8 receptor CXCR2 at mRNA and protein levels.IL-8 downstream signaling molecule NF-κB nuclear translocation was observed by immunocytofluoresent staining.Western blot was used to examine IκB phosphorylation and EMT-related protein.Results(1)The increase of IL-8 mRNA expression by shear stress was time-dependent.The expression increased when SKOV3 cells exposed to fluid shear stress for 1 h,reached the summits at 2 h,gradually decreased at 3 h and remained at a constant level at 4~12 h.Additionally,IL-8 expression was negatively associated with the intensity of shear stress.After SKOV3 cells were exposed to low fluid shear stress(1.5 dyne/cm2)for 1 h and 2 h,IL-8 mRNA expression increased near 68 and 52 times respectively as that of SKOV3 cells exposed to a high fluid shear stress of 5.0 dyne/cm^2.(2)The productions of IL-8 protein in SKOV3 cells subjected to shear stress were time-dependent.The secretion reached the summit when SKOV3 cells exposed to fluid shear stress for 5 h,then IL-8 secretion gradually decreased at 8 h of stimulation by shear stress.IL-8 secretion increased obviously when fluid shear stress(0.5,1.5,or 2.0 dyne/cm2)was exerted on SKOV3 cells for 1 h.Notablely,the secretion of IL-8 was the highest when SKOV3 cells subjected to fluid shear stress 1.5dyne/cm^2,which was near 6 or 7 times as that of SKOV3 cells subjected to high fluid shear stress(5.0 dyne/cm^2).(3)There was an increase in enhanced green fluorescent protein expression in pEGFPI-IL8USCS-transfected SKOV3 cells subjected to a fluid shear stress of 1.5 dyne/cm2 for 2 h,suggesting a flow shear stress induced IL-8 gene transcriptional activation;(4)CXCR2,which was constitutively present on the surface of SKOV3 cells,increased following exposure to fluid shear stress for 60 min.(5)Following the application of a shear stress of 1.5 dyne/cm^2,NF-κB p65 became detectable in the cell nuclei and Phosphorylated IκB in cell lysates increased significantly;(6)Compared with the control group,critical EMT-related proteins vimentin was upregulated,E-cadherin was downregulated after the application of the 1.5 dyne/cm2shear stress for 2 h,which suggested the EMT of ovarian cancer.Conclusions FSS triggered IL-8/CXCR2 signaling of SK-OV3 cells represents an early gene activation and the activation can be mediated through NF-κB.When the fluid shear stress-induced IL-8/CXCR signaling activated,the expression of EMT-related proteins changed.This observation suggested that fluid shear stress-induced IL-8 activation and the downstream signal pathways may have important contribution to the EMT process of ovarian cancer cells.

Germline mutations in Thai patients with nonmucinous epithelial ovarian cancer

BACKGROUND Genetic testing is widely recommended for all epithelial ovarian cancer(EOC)patients.However,an increased probability of identifying germline mutations has been reported in selected patients with risk factors such as a family history or personal history of cancer and high-grade serous carcinoma(HGSC)subtype.HGSC has been reported to be the most common subtype of EOC worldwide(approximately 70%).However,this subtype is less prevalent in Thai patients(reported as only 20%).The difference in the distribution of various subtypes of EOC may reflect the incidence of germline mutations in Thai EOC patients.AIM To evaluate the frequencies of germline mutations in EOC patients and to compare the frequencies in those with and without clinical risk factors for hereditary ovarian cancer.METHODS This cross-sectional study included 112 nonmucinous EOC patients who underwent primary surgery at our tertiary care hospital.Clinical risk factors for hereditary ovarian cancer were defined as follows:Age below 40 years,a significant family history of cancer,synchronous ovarian and endometrial cancer,and HGSC.Comprehensive germline mutations were detected by nextgeneration sequencing.RESULTS Of a total of 112 patients,82(73.2%)patients had≥1 risk factor and 30(26.8%)patients had no risk factors.Germline mutations were detected in 26 patients:20(17.8%)patients had BRCA1/2 mutations,but 6(5.4%)patients had mutations in other genes,including 1 in MLH1,1 in MSH2,1 in RAD51C,2 in ATM and 1 in CDH1.Germline mutations were only detected in patients with risk factors(26 of 82,31.7%),not in patients without risk factors(P<0.001).A significant family history of cancer and HGSC were the only two significant risk factors associated with a higher proportion of germline mutations(56.3%vs 10%for those with and without a history of cancer,respectively,40.8%vs 9.5%for those with and without HGSC).Germline BRCA mutations were detected in 38.8%of patients with HGSC but in only 1.6%of those with non-HGSC.An age below 40 years,personal history of breast cancer,and synchronous ovarian and endometrial cancer were not significant factors(14.3%vs 23.5%,33.3%vs 21%,22.2%vs 22.3%).CONCLUSION Approximately one-third of EOC patients with risk factors had germline mutations.Almost all germline BRCA mutations were found in patients with the HGSC subtype.Selected patients with HGSC and a family history of cancer should be initially considered for genetic analysis in Thailand.