Ovarian cancer is the seventh most common cancer and the eighth most common cause of cancer mortality in women. Although standard chemotherapy is the established treatment for ovarian cancer, the prognosis remains poor, and it is highly anticipated that new drugs will be developed. New drugs, such as humanized anti-vascular endothelial growth factor monoclonal antibodies and poly ADP-ribose polymerase inhibitors, are expected to improve clinical outcomes of ovarian cancer. However, long-term, costly research is required to develop such new drugs, and soaring national healthcare costs are becoming a concern worldwide. In this social context, drug repositioning, wherein existing drugs are used to develop drugs with new indications for other diseases, has recently gained attention. Because trials have already confirmed the safety in humans and the pharmacokinetics of such drugs, the development period is shorter than the conventional development of a new drug, thereby reducing costs. This review discusses the available basic experimental and clinical data on drugs used for other types of cancer for which drug repositioning is anticipated to repurpose the drug for the treatment of ovarian cancer. These include statins, which are used to treat dyslipidemia; bisphosphonate, which is used to treat osteoporosis; metformin, which is used to treat diabetes; non-steroidal anti-inflammatory drugs; ivermectin, an antiparasitic agent; and itraconazole, an anti-fungal agent. These drugs will play an important role in future drug repositioning strategies for ovarian cancer. Furthermore, drug repositioning is anticipated to extend not only to ovarian cancer treatment but also to ovarian cancer prevention.
Adenosine Diphosphate Ribose ; Anti-Inflammatory Agents, Non-Steroidal ; Antibodies, Monoclonal ; Drug Repositioning* ; Drug Therapy ; Dyslipidemias ; Endothelial Growth Factors ; Female ; Health Care Costs ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Itraconazole ; Ivermectin ; Metformin ; Mortality ; Osteoporosis ; Ovarian Neoplasms* ; Pharmacokinetics ; Prognosis

OBJECTIVES: We conducted a protocol-based cohort study to evaluate the outcomes of interval debulking surgery (IDS) followed by paclitaxel-based hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of advanced-stage ovarian cancer. METHODS: From October 2015 to May 2018, 65 patients with stages IIIC–IV ovarian cancer were treated according to the study protocol. HIPEC was performed with paclitaxel (175 mg/m2) for 90 minutes, only in cases of optimal cytoreduction. RESULTS: Of 65 patients, 40 (61.5%) patients underwent neoadjuvant chemotherapy (NAC), 34 (52.3%) patients had a high tumor burden with a Fagotti score ≥8 at diagnostic laparoscopy, and 6 (9.2%) had definite stage IV metastasis and/or poor performance status before NAC. Twenty-seven (41.5%) patients underwent IDS followed by HIPEC. The mean duration of IDS with HIPEC was 543.8 (range, 277.0–915.0) minutes. Grade III/IV perioperative complications occurred in 7.4% (n=2)/3.7% (n=1) of patients and no cases of mortality were reported within 30 days postoperatively. The median progression-free survival was 21.3 months, and the median overall survival was not reached for those who received HIPEC. CONCLUSIONS: According to our study protocol, IDS followed by paclitaxel-based HIPEC as a first-line treatment appears to be feasible and safe for the treatment of advanced-stage ovarian cancer. Further evaluations of this procedure are required to assess its survival benefits.
Cohort Studies ; Disease-Free Survival ; Drug Therapy* ; Humans ; Laparoscopy ; Mortality ; Neoplasm Metastasis ; Ovarian Neoplasms* ; Paclitaxel ; Pilot Projects* ; Tumor Burden

OBJECTIVE: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been proposed as a treatment in ovarian cancer. A recently published RCT demonstrated that HIPEC prolongs disease-free survival (DFS) and overall survival (OS) in ovarian cancer. The aim of the study was to investigate oncologic results of cytoreductive surgery+HIPEC compared with cytoreductive surgery alone in advanced primary ovarian cancer with a particular attention to the pattern of recurrence. METHODS: This is a retrospective case control study with a propensity score (PS) matching of the patients. All the patients treated for primary advanced ovarian cancer who underwent interval surgery with or without HIPEC were collected; a PS was calculated in order to match cases to controls. RESULTS: Among 77 eligible patients 56 patients were included in the study. Preoperative patients' characteristics were homogeneous. No difference in morbidity and mortality after surgery were recorded. DFS was not different among the 2 groups (13.2 vs. 13.9 months, p=0.454) but OS was better in patients treated with HIPEC with no median reached vs. 35.5 months (p=0.048). Patients treated with cytoreductive surgery alone were more likely to have a peritoneal recurrence (43% vs. 14%). CONCLUSION: HIPEC seems to affect the relapse pattern with lesser peritoneal recurrence. This difference in relapse pattern seems to affect the OS with better results in patients treated with HIPEC. Further studies are needed to confirm these findings.
Case-Control Studies* ; Disease-Free Survival ; Drug Therapy* ; Humans ; Hyperthermia, Induced ; Mortality ; Ovarian Neoplasms* ; Propensity Score* ; Recurrence* ; Retrospective Studies

BACKGROUND: Asbestos exposure causes asbestos-related diseases (ARDs) including asbestosis, malignant mesothelioma, lung cancer, laryngeal cancer, and ovarian cancer. Although Korea used substantial amounts of asbestos in the past, no study has focused on its occupational burden of disease (OBD). Therefore, this study aimed to determine the OBDs of ARDs in Korea. METHODS: The CARcinogen Exposure (CAREX) database was used to determine the proportion of exposed population. Relative risks for lung cancer, laryngeal cancer, and ovarian cancer were used to determine the population-attributable fraction. Data for deaths caused by ARDs during 1998–2013 were obtained from the World Health Organization mortality database. The potential years of life lost (PYLL) and annual average PYLL (APYLL) indicated OBDs. RESULTS: In Korea, the number of ARD-attributable deaths and PYLL due to all ARDs during 1998–2013 were 4,492 and 71,763.7, respectively. The number of attributable deaths and PYLL due to asbestosis, malignant mesothelioma, lung cancer, laryngeal cancer, and ovarian cancer were 37 and 554.2, 808 and 15,877.0, 3,256 and 47,375.9, 120 and 1,605.5, and 271 and 6,331.1, respectively; additionally, the APYLL were 15.0, 19.7, 14.6, 13.4, and 23.4, respectively, and the average age at death was 70.4, 62.6, 69.1, 69.9, and 61.8, respectively. Our study showed that although the use of asbestos has ceased in Korea, the incidence of ARDs tends to increase. CONCLUSION: Therefore, efforts to reduce future OBDs of ARDs, including early detection and proper management of ARDs, are needed in Korea.
Asbestos ; Asbestosis* ; Incidence ; Korea* ; Laryngeal Neoplasms* ; Lung Neoplasms* ; Lung* ; Mesothelioma* ; Mortality ; Ovarian Neoplasms* ; World Health Organization

Ovarian cancer (OC) has the highest mortality rate among gynecological malignancies. Because chemokine network is involved in OC progression, we evaluated associations between chemokine expression and survival in tumor suppressor protein p53 (TP53) wild-type (TP53WT) and mutant (TP53m) OC datasets. TP53 was highly mutated in OC compared to other cancer types. Among OC subtypes, CXCL14 was predominantly expressed in clear cell OC, and CCL15 and CCL20 in mucinous OC. TP53WT endometrioid OC highly expressed CXCL14 compared to TP53m, showing better progression-free survival but no difference in overall survival (OS). TP53m serous OC highly expressed CCL8, CCL20, CXCL10 and CXCL11 compared to TP53WT. CXCL12 and CCL21 were associated with poor OS in TP53WT serous OC. CXCR2 was associated with poor OS in TP53m serous OC, while CXCL9, CCL5, CXCR4, CXCL11, and CXCL13 were associated with better OS. Taken together, specific chemokine signatures may differentially influence OS in TP53WT and TP53m OC.
Chemokines ; Dataset ; Disease-Free Survival ; Mortality ; Mucins ; Ovarian Neoplasms* ; Tumor Suppressor Protein p53

OBJECTIVE: To examine the trends and survival for women with early-stage epithelial ovarian cancer who underwent adequate lymphadenectomy during surgical treatment. METHODS: This is a retrospective observational study examining the Surveillance, Epidemiology, End Results program between 1988 and 2013. We evaluated 21,537 cases of stage I–II epithelial ovarian cancer including serous (n=7,466), clear cell (n=6,903), mucinous (n=4,066), and endometrioid (n=3,102) histology. A time-trend analysis of the proportion of patients who underwent adequate pelvic lymphadenectomy (≥ 8 per Gynecologic Oncology Group [GOG] criteria, ≥ 12 per Collaborative Group Report [CGR] criteria for bladder cancer, and > 22 per Mayo criteria for endometrial cancer) and a survival analysis associated with adequate pelvic lymphadenectomy were performed. RESULTS: There were significant increases in the proportion of women who underwent adequate lymphadenectomy: GOG criteria 3.6% to 28.6% (1988–2010); CGR criteria 2.4% to 22.4% (1988–2013); and Mayo criteria 0.7% to 9.5% (1988–2013) (all, p < 0.05). On multivariable analysis, adequate lymphadenectomy was independently associated with improved cause-specific survival compared to inadequate lymphadenectomy: GOG criteria, adjusted-hazard ratio (HR)=0.75, CGR criteria, adjusted-HR=0.77, and Mayo criteria, adjusted-HR = 0.85 (all, p < 0.05). Compared to inadequate lymphadenectomy, adequate lymphadenectomy was significantly associated with improved cause-specific survival for serous (HR range = 0.67–0.73), endometrioid (HR range = 0.59–0.61), and clear cell types (HR range = 0.66–0.73) (all, p < 0.05) but not in mucinous type (HR range = 0.80–0.91; p > 0.05). CONCLUSION: Quality of lymphadenectomy during the surgical treatment for early-stage epithelial ovarian cancer has significantly improved. Adequate lymphadenectomy is associated with a 15%–25% reduction in ovarian cancer mortality compared to inadequate lymphadenectomy.
Epidemiology ; Female ; Humans ; Lymph Node Excision* ; Mortality ; Mucins ; Observational Study ; Ovarian Neoplasms* ; Retrospective Studies ; Urinary Bladder Neoplasms

Ovarian cancer is one of the leading causes of cancer-related deaths in gynecological malignancies. Over 70% of ovarian cancer cases are high-grade serous ovarian cancers and have high death rates due to their resistance to chemotherapy. Despite advances in surgical and pharmaceutical therapies, overall survival rates are not good, and making an accurate prediction of the prognosis is not easy because of the highly heterogeneous nature of ovarian cancer. To improve the patient's prognosis through proper treatment, we present a prognostic prediction model by integrating high-dimensional RNA sequencing data with their clinical data through the following steps: gene filtration, pre-screening, gene marker selection, integrated study of selected gene markers and prediction model building. These steps of the prognostic prediction model can be applied to other types of cancer besides ovarian cancer.
Drug Therapy ; Filtration ; Mortality ; Ovarian Neoplasms ; Prognosis ; RNA ; Sequence Analysis, RNA ; Survival Rate

Cervical, endometrial, and ovarian cancers, have both high morbidity and mortality among the gynecologic malignant tumors in Japan. The present study was conducted using both the population-based cancer registry and the gynecologic cancer registry to elucidate the characteristics of gynecologic malignant tumors in Japan. Based on nationwide estimates from the population-based cancer registry in Japan, the morbidities and mortality of cervical, endometrial, and ovarian cancers were obtained and used for analysis. Clinicopathologic factors for cervical cancer, endometrial cancer, ovarian cancer, including age, clinical stage, postsurgical stage, histological type, therapeutic strategy, and prognosis were retrieved from the gynecologic cancer registry published by the Japan Society of Obstetrics and Gynecology and used for analysis. The morbidities of cervical, endometrial, and ovarian cancers were 10,908, 13,606, and 9,384 women in 2012, respectively. The prevalence of endometrial cancer has significantly and consistently been increasing and represents the most common gynecologic malignant tumor in Japan. The mortalities of cervical, endometrial, and ovarian cancers were 2.1, 1.3, and 3.2 per 100,000 in 2012, respectively. In 2014, 52.2% of cervical cancer patients were classified as stage I, 22.5% as stage II, 10.2% as stage III, and 11.2% as stage IV. In addition, 71.9% of endometrial cancer patients were classified as stage I, 6.0% as stage II, 13.3% as stage III, and 7.5% as stage IV. Finally, 43.2% of ovarian cancer patients were classified as stage I, 9.1% as stage II, 27.6% as stage III, and 7.2% as stage IV. Twelve point five percent of ovarian cancer patients received neoadjuvant chemotherapy.
Drug Therapy ; Endometrial Neoplasms ; Female ; Genital Neoplasms, Female ; Gynecology ; Humans ; Japan* ; Mortality ; Obstetrics ; Ovarian Neoplasms ; Prevalence ; Prognosis ; Registries ; Uterine Cervical Neoplasms

Tumor necrosis factor-α (TNF) is well known to be involved in the immune system and ovarian inflammation. Ovarian cancer is an inflammation-related malignancy that lacks early screening strategies, resulting in late diagnosis followed by high mortality. Based on our previous data, TNF induced abundant serum amyloid A (SAA), an acute phase protein linked to inflammation, in ovarian granulosal cells. To date, the regulation and expression of SAA in ovarian cancer is not fully elucidated. Here, we investigated the relationship between TNF and SAA by comparing human normal ovarian tissues and serous ovarian tumors. We found that SAA1/2 was significantly expressed in tumor tissues, but no or trace expression levels in normal tissues. TNF was also significantly upregulated in ovarian tumor tissues compared to normal tissues. Moreover, TNF significantly increased SAA1/2 levels in human ovarian cancer cell lines, OVCAR-3 and SKOV-3, in a time-dependent manner. Since the SAA1 promoter contains two nuclear factor (NF)-κB sites, we examined whether TNF regulates SAA1 promoter activity. Deletion analysis revealed that the proximal NF-κB site (−95/−85) played a critical role in regulating TNF-induced SAA1 promoter activity. Within 2 h after intraperitoneal injection of lipopolysaccharide, a product known to stimulate release of TNF, SAA preferably localized to ovarian epithelial cells and the thecal-interstitial layers compared to granulosal cell layers. Based on Gene Expression Omnibus (GEO) database, SAA1/2 and TNF were dominantly expressed in advanced grade ovarian cancer. Taken together, the accumulation of SAA1/2 in ovarian cancer could be mediated by TNF-induced NF-κB activation.
Acute-Phase Proteins ; Amyloid* ; Cell Line ; Delayed Diagnosis ; Epithelial Cells ; Gene Expression ; Humans* ; Immune System ; Inflammation ; Injections, Intraperitoneal ; Mass Screening ; Mortality ; Necrosis ; Ovarian Neoplasms ; Serum Amyloid A Protein ; Tumor Necrosis Factor-alpha

OBJECTIVE: To investigate the 5-year relative survival rates in gynecological cancers diagnosed and treated in Turkey by year 2009 and to compare the results with developed countries. METHODS: Data of patients diagnosed for ovarian, corpus uteri or cervix uteri cancer at year 2009 are collected from 9 national cancer registry centers. Date of deaths are retracted from governmental Identity Information Sharing System (KPS). In order to calculate relative survival rates, national general population mortality tables are obtained from Turkish Statistical Institute (TurkStat). Hakulinen method is used for computing curves by R program. Data for European, Asian and some developed countries were obtained from official web pages. RESULTS: A total of 1,553 patients are evaluated. Among these, 713 (45.9%) are corpus uteri cancers, while remaining 489 (31.5%) are ovarian and 351 (22.6%) are cervix uteri. Five-year overall relative survival rates are 85%, 50%, and 62% for corpus uteri, ovarian, and cervix uteri, respectively. These figures are between 73%–87% for corpus uteri, 31%–62% for ovarian and 61%–80% for cervix uteri in developed countries. Stage is the most important factor for survival in all cancers. Five-year relative survival rates in corpus uteri cancers are 92%, 66%, and 38% for localized, regional, and distant metastatic disease, respectively. These figures are 77%, 57%, and 29% for ovarian; 80%, 50%, and 22% for cervix uteri. CONCLUSION: This is the first report from Turkey giving national overall relative survival for gynecological cancers from a population based cancer registry system.
Asian Continental Ancestry Group ; Cervix Uteri ; Developed Countries ; Female ; Genital Neoplasms, Female ; Humans ; Information Dissemination ; Methods ; Mortality ; Ovarian Diseases ; Survival Rate ; Turkey* ; Uterus