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Ovarian Cancer

Cancer of the ovaries are the second most common group of gynaecologic cancers, and account for about 5% of all women's cancers. There are two main types; (i) epithelial tumours (carcinomas) which account for 90% of ovarian cancers, and (ii) non-epithelial tumours (eg. Stroma cell and germ cell tumours of the ovary). The epithelial ovarian cancers are usually found in women aged over 40, while the non-epithelial tumours are more common in girls and young women. Epithelial ovarian cancer has few early symptoms, a risk factor is having a family history of the disease. Taking the contraceptive pill is known to be protective against ovarian cancer.

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    MeSH term: Ovarian Neoplasms
    International US National Library of Medicine
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Patch AM, Christie EL, Etemadmoghadam D, et al.
Whole-genome characterization of chemoresistant ovarian cancer.
Nature. 2015; 521(7553):489-94 [PubMed] Related Publications
Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.

Ilić MB, Jovanović DV, Milosavljević MZ, et al.
Hypercalcemic type of small cell carcinoma of the ovary.
Vojnosanit Pregl. 2015; 72(3):295-8 [PubMed] Related Publications
INTRODUCTION: Extrapulmonary small cell carcinoma is a rare, prognostically bad tumor category. Primary, it can be localized in every organ, even in the ovary, where, due to its clinical specificities, it represents a challenge in diagnosis, as well as in therapy. Small cell ovarian carcinoma (SCOC) is biologically very aggressive malignant tumor of unknown histogenesis. We presented a rare case of SCOC with hypercalcemia of aggressive course and fatal outcome in a postmenopausal woman at International Federation of Gynecology and Obstetrics (FIGO) Ia stage.
CASE REPORT: A 60-year-old woman, Caucasian, came to the doctor because of discomfort in the lower abdomen and pain of greater intensity in last few days. Ultrasound examination and CT scan of the abdomen confirmed the presence of large adnexal masses of cystic-solid appearance with the largest diameter of 13 cm, regular structure of the other gynecological organs, without verifying the existence of metastatic deposits. All the results of laboratory analysis gave normal values, except for calcium, which was elevated. Explorative laparotomy with complete hysterectomy, bilateral salpingo-oophorectomy, dissection of lymph nodes and omentectomy were conducted. Based on pathohistological analysis of the operative material, SCOC at FIGO Ia stage was diag- nosed. No complications were observed in a postsurgery period and after 10 days the patient was discharged in a good condition and with normal calcemia. The treatment was continued with concurrent radiotherapy and chemotherapy. However, in spite of overall treatment, the disease progressed, and the patient died of disseminated metastatic disease, 26 months after the diagnosis.
CONCLUSION: Small cell carcinoma localized in the ovary is generally a tumor category with bad prognosis depending on the stage of the disease.

Xia D
Ovarian cancer HO-8910 cell apoptosis induced by crocin in vitro.
Nat Prod Commun. 2015; 10(2):249-52 [PubMed] Related Publications
The effect and mechanism of ovarian cancer HO-8910 cell apoptosis induced by crocin.MTT assay was performed to detect the inhibitory action of crocin on the proliferation of HO-8910 cells. Flow cytometry was used to test the cell cycle distribution and apoptosis rate of ovarian cancer HO-8910 cells. Western blot analysis was utilized to measure the levels of apoptotic proteins such as p53, Fas/APO-1, and Caspase-3. MTT analysis revealed that crocin significantly inhibited the growth of HO-8910 cells. Additionally, flow cytometry illustrated that crocin raised the proportion of HO-8910 cells in the G0/G1 phase and increased their apoptosis rate. Furthermore, Western blot analysis revealed that crocin up-regulated the expression of p53, Fas/APO-1, and Caspase-3. The results of this study showed that crocin can significantly inhibit the growth of HO-8910 cells and arrest them in the G0/G1 phase. Crocin can also promote ovarian cancer HO-8910 cell apoptosis, most likely by increasing p53 and Fas/APO-1 expression, and then activating the apoptotic pathway regulated by Caspase-3.

Bacalbaşa N, Popescu I
Ovarian cancer liver metastases--should we apply the principle of optimal cytoreduction to the liver? A review.
Hepatogastroenterology. 2015 Mar-Apr; 62(138):355-7 [PubMed] Related Publications
Advanced stage ovarian cancer is a common situation at presentation and current medical practice lacks efficient methods of prevention and early diagnosis. Primary maximal cytoreductive surgery followed by adjuvant chemotherapy is currently a generally accepted principle; most patients however undergo recurrence and common therapeutical attitude is secondary cytoreduction based approximately on the same principles as the primary one. Due to the success of liver resections in colorectal metastases and the development of liver surgery in general, different centers worldwide analyzed in the last 20 years liver resections' utility for other primaries, including ovarian tumors.

Reynaers EA, Ezendam NP, Pijnenborg JM
Comparable outcome between endometrioid and non-endometrioid tumors in patients with early-stage high-grade endometrial cancer.
J Surg Oncol. 2015; 111(6):790-4 [PubMed] Related Publications
BACKGROUND: Approximately 25% of endometrial cancer patients present with high-grade tumors. Unlike the clearly defined work-up for non-endometrioid endometrial cancer, no consensus exists for surgical staging and adjuvant therapy in high-grade endometrioid endometrial cancer. We compared the recurrence rate and disease-related mortality (DRM) after treatment between endometrioid and non-endometrioid endometrial cancer.
METHODS: A total of 123 patients diagnosed with early-stage high-grade endometrial cancer at the Dutch Comprehensive Cancer Centre South (CCCS) between January 2005 and December 2011 were included. All patients underwent abdominal hysterectomy and bilateral salpingo-oophorectomy. Patient and tumor characteristics, primary and adjuvant treatment, and outcome were analyzed.
RESULTS: After a median follow-up of 27.9 months, 27.6% (n = 34) of patients had recurrent disease. Distant recurrence rate was equal among endometrioid (14.5%), papillary serous (14.8%), and clear cell (15.4%) types. The total DRM was 15.4% (n = 19). The 5 year recurrence-free survival was not significantly different between early-stage high-grade endometrioid versus non-endometrioid endometrial cancer (P = 0.72).
CONCLUSION: Distant recurrence and DRM was high in patients with endometrial cancer regardless of histological type, suggesting the need for different therapies in early-stage high-grade non-endometrioid and endometrioid tumors.

Androutsopoulos G, Adonakis G, Terzakis E, et al.
Endometrial cancer in a patient with rheumatoid arthritis.
Eur J Gynaecol Oncol. 2015; 36(1):91-3 [PubMed] Related Publications
BACKGROUND: Rheumatoid arthritis is a chronic, systemic, and autoimmune disease. In patients with rheumatoid arthritis, there is increased risk for site-specific malignancies. The authors present a case of endometrial cancer in a patient with rheumatoid arthritis and a review of the current literature.
CASE: The patient, a 60-year-old, postmenopausal Greek woman suffering from rheumatoid arthritis, presented with a complaint of abnormal uterine bleeding. She underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and para-aortic lymphadenectomy. Histopathology revealed endometrial cancer. The final diagnosis was Stage Ib endometrial cancer endometrioid type. She underwent postoperative adjuvant radiotherapy. She remains without evidence of disease, 16 months after initial surgery.
CONCLUSION: Although the present patient was diagnosed at early-stage disease and remains well 16 months after initial surgery, she needs a multidisciplinary treatment approach in order to achieve prolonged survival.

Lubin J, Pawałowska M, Markowska A, Bielas A
Small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT)--case report.
Eur J Gynaecol Oncol. 2015; 36(1):88-90 [PubMed] Related Publications
Small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT) is a very rare malignant disease, seen mostly in young women, with a very poor prognosis. There is no standard treatment for patients with this disease and most literature is limited to short series or case reports. This report describes the case of a 34-year-old woman with aggressive course of SCCOHT and poor outcome. What proved difficult was the process of establishing the diagnosis due to non-specific first symptoms of disease and consequently the combined treatment of surgery and chemotherapy with concurrent side effects.

Tanda ET, Budroni M, Cesaraccio R, et al.
Epidemiology of ovarian cancer in North Sardinia, Italy, during the period 1992-2010.
Eur J Gynaecol Oncol. 2015; 36(1):69-72 [PubMed] Related Publications
INTRODUCTION: The aim of this study was to analyze and describe the incidence and mortality trends of ovarian cancer in North Sardinia, Italy, in the period 1992-2010.
MATERIALS AND METHODS: Data were obtained from the tumor registry of Sassari province which makes part of a wider registry web, coordinated today by the Italian Association for Tumor Registries.
RESULTS: The overall number of ovarian cancer cases registered in the period under investigation was 600. The mean age of the patients was 62 years. The standardized incidence and mortality rates were 11.2/100,000 and 5.1/100,000 respectively. A substantially stable trend in incidence and mortality of ovarian cancer was evidenced. Relative survival at five years from diagnosis was 44.2%.
CONCLUSIONS: The incidence and mortality trends of ovarian cancer in North Sardinia remained relatively stable in the last decades, while prognosis remains relatively poor.

Fukuda T, Imai K, Yamauchi M, et al.
Primary peritoneal cancer: study of 14 cases and comparison with epithelial ovarian cancer.
Eur J Gynaecol Oncol. 2015; 36(1):49-53 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: Primary peritoneal carcinoma (PPC) is histologically similar to ovarian serous carcinoma, but its biochemical features remain obscure. The authors investigated and compared clinical findings, treatments, and outcomes of patients with PPS and those with epithelial ovarian cancer (EOC) patients.
MATERIALS AND METHODS: The authors retrospectively reviewed data from 14 patients with PPC and 219 patients with EOC treated at the present hospital from January 2005 to December 2012, including demographic data, pathologic findings, treatments, and outcomes.
RESULTS: Patients with PPC were significantly older (62.6 ± 8.4 years) than those with EOC (56.3 ± 11.3 years) (p = 0.045). There was no significant difference in serum CA-125 levels. The five-year survival rates did not differ significantly between patients with PPC (61.1%) and those with EOC (60.3%; p = 0.78); nor between patients with PPC and those with Stage III serous EOC (43.8%; p = 0.40).
CONCLUSIONS: Treatment strategies for EOC applied to PPC apparently led to similar survival patterns among the two patient groups. Cytoreductive surgery combined with pre/postoperative platinum-containing chemotherapy may be effective for PPC patients.

Machado-Linde F, Sánchez-Ferrer ML, Cascales P, et al.
Prevalence of endometriosis in epithelial ovarian cancer. Analysis of the associated clinical features and study on molecular mechanisms involved in the possible causality.
Eur J Gynaecol Oncol. 2015; 36(1):21-4 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: To determine the prevalence of endometriosis in patients with epithelial ovarian cancer and explore the differences between women with endometrioid and clear-cell histologic subtypes with and without associated endometriosis.
MATERIALS AND METHODS: The medical charts of 496 patients with epithelial ovarian cancer at the Hospital Virgin de la Arrixaca (Murcia, Spain) between 1971 and 2010 were reviewed.
RESULTS: Endometriosis was present in 27 (5.4%) of the 496 cases (p < 0001), and was associated with the endometrioid histotype in 13/45 cases (29%) and with the clear cell histotype in 7/22 (32%). The prevalence of an association with endometriosis according to histologic type was 28.8% (13/45) for endometrioid carcinoma and 31.8% (7/22) for clear-cell carcinoma.
CONCLUSION: Both endometrioid and clear-cell ovarians tumours are associated with pelvic endometriosis. Patients with endometiosis associated ovarian cancer differ from non-endometiosis associated ovarian cancer in their clinical characteristics.

Ying HC, Xu HY, Lv J, et al.
MicroRNA signatures of platinum-resistance in ovarian cancer.
Eur J Gynaecol Oncol. 2015; 36(1):16-20 [PubMed] Related Publications
OBJECTIVES: The authors utilized a microRNA (miRNA) array to compare the differentially expressed miRNAs in platinum-resistant associated ovarian cancer cells.
MATERIALS AND METHODS: The differential expression of microRNA between COC1 (DDP-sensitive) and platinum-resistant COC1/DDP (DDP-resistant) tumor cell lines was determined using microarray. Expression levels were further validated by real-time quantitive polymerase chain reaction (qRT-PCR).
RESULTS: The authors identified that several miRNAs are altered in collected 86 samples of human ovarian cancer cell-lines, with four significantly deregulated miRNAs and 13 upregulated miRNAs. Of which, miR-141-3p was the most differentially expressed miRNA between COC1 group (1.7833 ± 0.7213) and COC1/DDP group (14.0433 ± 4.4895) (p < 0.05). Additionally, the product curve of PCR amplification indicated that miR-141-3p had a significant higher expression level in chemotherapy resistant group (n = 20) rather than in chemotherapy sensitive group (n = 20) (9.56 ± 1.04 vs. 1.59 ± 0.91, p < 0.05).
CONCLUSIONS: The present results suggest that miR-141-3p might be used as a therapeutic target to modulate platinum-based chemotherapy and as a biomarker to predict chemotherapy response.

Wang Y, Ye Y, Lin J, et al.
Genetic variants in matrix metalloproteinase genes as disposition factors for ovarian cancer risk, survival, and clinical outcome.
Mol Carcinog. 2015; 54(6):430-9 [PubMed] Related Publications
Ovarian cancer is one of the leading female cancers in the United States. Challenges remain in early diagnosis of this deadly disease. Matrix metalloproteinases (MMPs) family genes are paradoxically involved in cancer promotion and suppression. We hypothesize that genetic variants in MMP genes are associated with ovarian cancer development, so they could be potential markers for ovarian cancer diagnosis and prognosis. In this study of 417 ovarian cancer cases and 417 healthy controls, we genotyped a comprehensive panel of 266 single nucleotide polymorphisms (SNPs) in 23 MMP genes and analysed their associations with ovarian cancer risk, overall survival and treatment response in ovarian cancer cases who received platinum-based chemotherapy with surgery. In the analysis on 339 Caucasian cases and 349 Caucasian controls, 4 SNPs were significantly associated with cancer risk. The most significant association was observed for rs2292730 (OR = 2.03, 95% CI = 1.39-2.96, P = 0.0002). Classification and regression tree analysis identified four terminal nodes with differential risk of ovarian cancer. Thirty-four SNPs were significantly associated with overall survival and four of which showed significant association with response to chemotherapy. Unfavourable genotype analysis of top SNPs on overall risk of death showed significant gene-dosage effect, survival tree analysis differentiated patients into distinct risk groups based on their genetic profiles with median survival times (MSTs) ranging from 17.7 to 151.7 months. In conclusion, our results suggest that genetic variants in MMP pathway genes may modulate the risk and clinical outcomes of ovarian cancer, both individually and jointly.

Mizuno M, Kajiyama H, Shibata K, et al.
Prognostic value of histological type in stage IV ovarian carcinoma: a retrospective analysis of 223 patients.
Br J Cancer. 2015; 112(8):1376-83 [PubMed] Article available free on PMC after 14/04/2016 Related Publications
BACKGROUND: Patients with FIGO stage IV epithelial ovarian carcinoma have a poor but non-uniform prognosis. This study aimed to compare the survival of patients with serous or endometrioid tumours (S/E) and clear cell or mucinous tumours (non-S/E).
METHODS: Data for 223 patients who underwent surgery between 1987 and 2010 and were diagnosed by centralized pathology review and were retrospectively analysed. The patients included 169 with S/E tumours and 54 with non-S/E tumours.
RESULTS: The median overall survivals (OSs) of the S/E and non-S/E groups were 3.1 and 0.9 years, respectively (P<0.001). Six patients (2.7%), all with non-S/E tumours, died within 6 weeks after the initial surgery. Multivariate OS analysis revealed that performance status, residual tumor, metastatic sites, no debulking surgery, and non-S/E tumours were independent poor prognostic factors. For patients with non-S/E tumours, prognosis was more favourable for single-organ metastasis, except for liver or distant lymph nodes, no residual tumor, and resection of metastasis (median OS: 4.1, 4.6, and 2.6 years, respectively).
CONCLUSIONS: In stage IV ovarian carcinoma, non-S/E tumours are associated with a significantly poorer prognosis and higher rates of early mortality compared to S/E tumours. Therefore, careful management and development of new strategies are required.

Kreuzinger C, Gamperl M, Wolf A, et al.
Molecular characterization of 7 new established cell lines from high grade serous ovarian cancer.
Cancer Lett. 2015; 362(2):218-28 [PubMed] Related Publications
Cancer cell lines are good in vitro models to study molecular mechanisms underlying chemoresistance and cancer recurrence. Recent works have demonstrated that most of the available ovarian cancer cell lines are most unlikely high grade serous (HGSOC), the major type of epithelial ovarian cancer. We aimed at establishing well characterized HGSOC cell lines, which can be used as optimal models for ovarian cancer research. We successfully established seven cell lines from HGSOC and provided the major genomic alterations and the transcriptomic landscapes of them. They exhibited different gene expression patterns in the key pathways involved in cancer resistance. Each cell line harbored a unique TP53 mutation as their corresponding tumors and expressed cytokeratins 8/18/19 and EpCAM. Two matched lines were established from the same patient, one at diagnosis and being sensitive to carboplatin and the other during chemotherapy and being resistant. Two cell lines presented respective BRCA1 and BRCA2 mutations. To conclude, we have established seven cell lines and well characterized them at genomic and transcriptomic levels. They are optimal models to investigate the molecular mechanisms underlying the progression, chemo resistance and recurrence of HGSOC.

Rebbeck TR, Mitra N, Wan F, et al.
Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.
JAMA. 2015; 313(13):1347-61 [PubMed] Related Publications
IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.
OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2.
DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.
EXPOSURES: Mutations of BRCA1 or BRCA2.
MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks.
RESULTS: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.
CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Bristow RE, Chang J, Ziogas A, et al.
Impact of National Cancer Institute Comprehensive Cancer Centers on ovarian cancer treatment and survival.
J Am Coll Surg. 2015; 220(5):940-50 [PubMed] Related Publications
BACKGROUND: The regional impact of care at a National Cancer Institute Comprehensive Cancer Center (NCI-CCC) on adherence to National Comprehensive Cancer Network (NCCN) ovarian cancer treatment guidelines and survival is unclear.
STUDY DESIGN: We performed a retrospective population-based study of consecutive patients diagnosed with epithelial ovarian cancer between January 1, 1996 and December 31, 2006 in southern California. Patients were stratified according to care at an NCI-CCC (n = 5), non-NCI high-volume hospital (≥ 10 cases/year, HVH, n = 29), or low-volume hospital (<10 cases/year, LVH, n = 158). Multivariable logistic regression and Cox-proportional hazards models were used to examine the effect of NCI-CCC status on treatment guideline adherence and ovarian cancer-specific survival.
RESULTS: A total of 9,933 patients were identified (stage I, 22.8%; stage II, 7.9%; stage III, 45.1%; stage IV, 24.2%), and 8.1% of patients were treated at NCI-CCCs. Overall, 35.7% of patients received NCCN guideline adherent care, and NCI-CCC status (odds ratio [OR] 1.00) was an independent predictor of adherence to treatment guidelines compared with HVHs (OR 0.83, 95% CI 0.70 to 0.99) and LVHs (OR 0.56, 95% CI 0.47 to 0.67). The median ovarian cancer-specific survivals according to hospital type were: NCI-CCC 77.9 (95% CI 61.4 to 92.9) months, HVH 51.9 (95% CI 49.2 to 55.7) months, and LVH 43.4 (95% CI 39.9 to 47.2) months (p < 0.0001). National Cancer Institute Comprehensive Cancer Center status (hazard ratio [HR] 1.00) was a statistically significant and independent predictor of improved survival compared with HVH (HR 1.18, 95% CI 1.04 to 1.33) and LVH (HR 1.30, 95% CI 1.15 to 1.47).
CONCLUSIONS: National Cancer Institute Comprehensive Cancer Center status is an independent predictor of adherence to ovarian cancer treatment guidelines and improved ovarian cancer-specific survival. These data validate NCI-CCC status as a structural health care characteristic correlated with superior ovarian cancer quality measure performance. Increased access to NCI-CCCs through regional concentration of care may be a mechanism to improve clinical outcomes.

Srivastava AK, Han C, Zhao R, et al.
Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells.
Proc Natl Acad Sci U S A. 2015; 112(14):4411-6 [PubMed] Article available free on PMC after 07/10/2015 Related Publications
Cancer stem cells (CSCs) with enhanced tumorigenicity and chemoresistance are believed to be responsible for treatment failure and tumor relapse in ovarian cancer patients. However, it is still unclear how CSCs survive DNA-damaging agent treatment. Here, we report an elevated expression of DNA polymerase η (Pol η) in ovarian CSCs isolated from both ovarian cancer cell lines and primary tumors, indicating that CSCs may have intrinsically enhanced translesion DNA synthesis (TLS). Down-regulation of Pol η blocked cisplatin-induced CSC enrichment both in vitro and in vivo through the enhancement of cisplatin-induced apoptosis in CSCs, indicating that Pol η-mediated TLS contributes to the survival of CSCs upon cisplatin treatment. Furthermore, our data demonstrated a depletion of miR-93 in ovarian CSCs. Enforced expression of miR-93 in ovarian CSCs reduced Pol η expression and increased their sensitivity to cisplatin. Taken together, our data suggest that ovarian CSCs have intrinsically enhanced Pol η-mediated TLS, allowing CSCs to survive cisplatin treatment, leading to tumor relapse. Targeting Pol η, probably through enhancement of miR-93 expression, might be exploited as a strategy to increase the efficacy of cisplatin treatment.

Lojkin I, Rubinek T, Orsulic S, et al.
Reduced expression and growth inhibitory activity of the aging suppressor klotho in epithelial ovarian cancer.
Cancer Lett. 2015; 362(2):149-57 [PubMed] Related Publications
Klotho is an anti-aging transmembrane protein, which can be shed and function as a hormone. Accumulating data indicate klotho as a tumor suppressor in a wide array of malignancies, and we identified klotho as an inhibitor of the insulin-like growth factor (IGF-1) pathway in cancer cells. As this pathway is significant in the development of epithelial ovarian cancer (EOC) we studied klotho expression and activity in this tumor. Klotho mRNA levels were reduced in 16 of 19 EOC cell lines and immunohistochemistry analysis revealed high expression in normal ovaries, and reduced expression in 100 of 241 high grade papillary-serous adenocarcinoma of the ovaries, fallopian tubes and peritoneum. Reduced expression was associated with wild-type BRCA status. Klotho reduced EOC cell viability, enhanced cisplatin sensitivity, and reduced expression of mesenchymal markers. Finally, klotho inhibited IGF-1 pathway activation and inhibited transcriptional activity of the estrogen receptor. In conclusion, klotho is silenced in a substantial subset of the tumors and restoring its expression slows growth of EOC cells and inhibits major signaling pathways. As klotho is a hormone, treatment with klotho may serve as a novel treatment for EOC.

Koti M, Siu A, Clément I, et al.
A distinct pre-existing inflammatory tumour microenvironment is associated with chemotherapy resistance in high-grade serous epithelial ovarian cancer.
Br J Cancer. 2015; 112(7):1215-22 [PubMed] Article available free on PMC after 31/03/2016 Related Publications
BACKGROUND: Chemotherapy resistance is a major determinant of poor overall survival rates in high-grade serous ovarian cancer (HGSC). We have previously shown that gene expression alterations affecting the NF-κB pathway characterise chemotherapy resistance in HGSC, suggesting that the regulation of an immune response may be associated with this phenotype.
METHODS: Given that intrinsic drug resistance pre-exists and is governed by both tumour and host factors, the current study was performed to examine the cross-talk between tumour inflammatory microenvironment and cancer cells, and their roles in mediating differential chemotherapy response in HGSC patients. Expression profiling of a panel of 184 inflammation-related genes was performed in 15 chemoresistant and 19 chemosensitive HGSC tumours using the NanoString nCounter platform.
RESULTS: A total of 11 significantly differentially expressed genes were found to distinguish the two groups. As STAT1 was the most significantly differentially expressed gene (P=0.003), we validated the expression of STAT1 protein by immunohistochemistry using an independent cohort of 183 (52 resistant and 131 sensitive) HGSC cases on a primary tumour tissue microarray. Relative expression levels were subjected to Kaplan-Meier survival analysis and Cox proportional hazard regression models.
CONCLUSIONS: This study confirms that higher STAT1 expression is significantly associated with increased progression-free survival and that this protein together with other mediators of tumour-host microenvironment can be applied as a novel response predictive biomarker in HGSC. Furthermore, an overall underactive immune microenvironment suggests that the pre-existing state of the tumour immune microenvironment could determine response to chemotherapy in HGSC.

François CM, Wargnier R, Petit F, et al.
17β-estradiol inhibits spreading of metastatic cells from granulosa cell tumors through a non-genomic mechanism involving GPER1.
Carcinogenesis. 2015; 36(5):564-73 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Granulosa cell tumor (GCT) is a rare and severe form of sex-cord stromal ovarian tumor that is characterized by its long natural history and tendency to recur years after surgical ablation. Because there is no efficient curative treatment beyond surgery, ~20% of patients die of the consequences of their tumor. However, very little is known of the molecular etiology of this pathology. About 70% of GCT patients present with elevated circulating estradiol (E2). Because this hormone is known to increase tumor growth and progression in a number of cancers, we investigated the possible role of E2 in GCTs. Cell-based studies with human GCT metastases and primary tumor-derived cells, ie KGN and COV434 cells, respectively, aimed at evaluating E2 effect on cell growth, migration and invasion. Importantly, we found that E2 did not affect GCT cell growth, but that it significantly decreased the migration and matrix invasion of metastatic GCT cells. Noteworthy, our molecular studies revealed that this effect was accompanied by the inhibition through non-genomic mechanisms of extracellular signal-regulated kinase 1/2 (ERK1/2), which is constitutively activated in GCTs. By using pharmacological and RNA silencing approaches, we found that E2 action was mediated by G protein-coupled estrogen receptor 1 (GPER1) signaling pathway. Analyses of GPER1 expression on tissue microarrays from human GCTs confirmed its expression in ~90% of GCTs. Overall, our study reveals that E2 would act via non-classical pathways to prevent metastasis spreading in GCTs and also reveals GPER1 as a possible target in this disease.

Chen S, Chen X, Xiu YL, et al.
MicroRNA-490-3P targets CDK1 and inhibits ovarian epithelial carcinoma tumorigenesis and progression.
Cancer Lett. 2015; 362(1):122-30 [PubMed] Related Publications
The expression of microRNA-490-3P has been reported to regulate hepatocellular carcinoma cell proliferation, migration and invasion, and its overexpression significantly inhibits A549 lung cancer cell proliferation. Here, we demonstrated for the first time that miR-490 mRNA expression was significantly lower in ovarian carcinoma and borderline tumors compared to benign tumors, and lower in metastatic ovarian carcinoma (omentum) than primary ovarian carcinoma, and was negatively associated with differentiation and International Federation of Gynecology and Obstetrics (FIGO) staging. MiR-490-3P overexpression promoted G1/S or G2/M arrest and apoptosis; reduced cell proliferation, migration and invasion; reduced CDK1, Bcl-xL, MMP2/9, CCND1, SMARCD1 mRNA or protein expression; and induced P53 expression. Dual-luciferase reporter assay indicated miR-490-3P directly targeted CDK1. In vivo studies showed that miR-490-3P transfection suppressed tumor development and CDK1, Bcl-xL, MMP2/9 expression while inducing P53 expression. These findings indicate that miR-490-3P may target CDK1 and inhibit ovarian epithelial carcinoma tumorigenesis and progression.

Gąsiorowska E, Michalak M, Warchoł W, et al.
Clinical application of HE4 and CA125 in ovarian cancer type I and type II detection and differential diagnosis.
Ginekol Pol. 2015; 86(2):88-93 [PubMed] Related Publications
OBJECTIVES: The aim of this study was to assess the sensitivity and specificity of HE4 in detecting and differentiating between types I and II epithelial ovarian cancer (EOC) in comparison with CA125.
MATERIAL AND METHODS: We measured HE4 and CA125 serum concentrations in 206 samples taken from patients operated in Gynecologic Oncology Department due to ovarian tumors. Ovarian cancer was confirmed in 89 cases divided into type I and type II. 52 healthy patients without any gynecological disease formed the control group. The sensitivity and specificity for type I and type II EOC detection and differentiating between both types was evaluated for HE4 and CA125.
RESULTS: The HE4 and CA125 serum concentrations were significantly higher in type II than in type I EOC (p=0.008696, p=0.000243 respectively). The HE4 and CA125 sensitivity for type I and benign tumors differentiation was 63.16% for both of them and specificity was 87.29% vs 67.89% respectively. For CA125 these differences did not reach statistical significance. The HE4 sensitivity and specificity for type II and benign tumors differentiation were 87.14% and 96.61%, respectively and for CA125 these values were 82.86% and 94.07%, respectively.
CONCLUSIONS: Pretreatment analysis of HE4 serum concentration is superior to CA125 in differential diagnosis of ovarian cancer subtypes (I and II). HE4 is superior to CA125 in detecting ovarian cancer type II. Neither HE4 nor CA125 is an effective diagnostic tool for type I ovarian cancer detection. A new highly specific and highly sensitive tumor marker for type I EOC is needed.

Moradan S
Ovarian immature teratoma during pregnancy: a case report.
J Med Liban. 2014 Oct-Nov; 62(4):245-7 [PubMed] Related Publications
Germ cell tumors are derived from the primordial germ cells of the ovary and immature teratoma is the second most common germ cell malignancy. About 50% of pure immature teratomas of the ovary occur in women between the ages of 10 and 20 years, and they rarely occur in pregnancy. A 21-year-old woman, gravid 1, para 0, at 18 weeks of gestation, was incidentally diagnosed with a right ovarian mass 180 mm by 200 mm, 160 mm in diameter, during a prenatal ultrasound scanning. She underwent surgery by unilateral salpingo-oophorectomy and surgical staging. The result of pathology showed a stage 1a grade 1 immature teratoma of ovary. Her pregnancy continued until term. At 38 weeks she delivered with breech presentation a normal 2900 g male newborn by cesarean section. Although immature teratomas of ovary during pregnancy are rare, clinicians should consider their eventuality in younger pregnant women in asymptomatic cases.

Qiu JJ, Wang Y, Ding JX, et al.
The long non-coding RNA HOTAIR promotes the proliferation of serous ovarian cancer cells through the regulation of cell cycle arrest and apoptosis.
Exp Cell Res. 2015; 333(2):238-48 [PubMed] Related Publications
HOX transcript antisense RNA (HOTAIR) is a well-known long non-coding RNA (lncRNA) whose dysregulation correlates with poor prognosis and malignant progression in many forms of cancer. Here, we investigate the expression pattern, clinical significance, and biological function of HOTAIR in serous ovarian cancer (SOC). Clinically, we found that HOTAIR levels were overexpressed in SOC tissues compared with normal controls and that HOTAIR overexpression was correlated with an advanced FIGO stage and a high histological grade. Multivariate analysis revealed that HOTAIR is an independent prognostic factor for predicting overall survival in SOC patients. We demonstrated that HOTAIR silencing inhibited A2780 and OVCA429 SOC cell proliferation in vitro and that the anti-proliferative effects of HOTAIR silencing also occurred in vivo. Further investigation into the mechanisms responsible for the growth inhibitory effects by HOTAIR silencing revealed that its knockdown resulted in the induction of cell cycle arrest and apoptosis through certain cell cycle-related and apoptosis-related proteins. Together, these results highlight a critical role of HOTAIR in SOC cell proliferation and contribute to a better understanding of the importance of dysregulated lncRNAs in SOC progression.

Celik B, Didem Yalcin A, Esra Genc G, Gumuslu S
Proteomics pattern of peritoneal sApo-2L but not CD200 (OX-2) as a possible screening biomarker for metastatic ovarian, endometrial and breast carcinoma.
J BUON. 2015 Jan-Feb; 20(1):280-6 [PubMed] Related Publications
PURPOSE: The purpose of this study was to evaluate the soluble Apo-2L (sApo-2L) levels in the ascitic fluid and to study its potential in detecting malignant ascites and soluble CD200 (sCD200,sOX-2) levels so as to predict its clinical usage for detecting stage 4 metastatic endometrial, ovarian and breast cancer in serum samples.
METHODS: Ascitic fluid from 53 and blood from 25 subjects without known malignancy on admission were collected. There were 14 breast cancer (BC), 17 ovarian cancer (OC) and 19 endometrial cancer (EC) patients diagnosed later on. Blood samples for sApo-2L, sCD200, liver function tests and CEA, CA-19.9 and CA-125 were always taken and assayed in the morning.
RESULTS: Significantly low levels of sApo-2L were observed in peritoneal fluid from OC and EC patients compared to benign peritoneal fluid from control individuals. Positive correlation was observed between sApo-2L and aspartate aminotransferase (AST) in benign peritoneal fluid and sCD200, and creatinine and sCD200 and platelets in OC patients; also, sCD200 and CEA in EC patients and sCD200 and blood urea nitrogen (BUN) in healthy subjects.
CONCLUSIONS: Our data indicate that low proteomics pattern of sApo-2L but not sCD200 is a good biochemical marker. Further decline in the level of sApo-2L was seen in EC compared to OC. Since higher levels of sApo-2L were seen with higher levels of AST, the liver might be involved in its metabolism. The positive correlation detected between sCD200 and creatinine, platelets, CEA and BUN needs to be elucidated.

Desmeules P, Trudel D, Turcotte S, et al.
Prognostic significance of TIMP-2, MMP-2, and MMP-9 on high-grade serous ovarian carcinoma using digital image analysis.
Hum Pathol. 2015; 46(5):739-45 [PubMed] Related Publications
The objective of this cohort study was to evaluate whether the immunohistochemical expression of tissue inhibitor of metalloprotease 2, matrix metalloproteinase (MMP) 2, and MMP-9 could predict the occurrence of death and progression in women with ovarian high-grade serous carcinoma (HGSC). A total of 100 women with primary HGSC who were treated by cytoreductive surgery and adjuvant chemotherapy at the Centre Hospitalier Universitaire de Québec (Canada) were included. Biomarker expression was evaluated by immunohistochemistry on tissue microarrays constructed from primary tumors. Immunostaining quantification was performed using digital image analysis, from algorithms created with Calopix software, and continuous H-score data were obtained. The cancer antigen-125 and/or the Response Evaluation Criteria In Solid Tumors criteria were used to define progression. Dates of death were obtained by record linkage with the Québec mortality files. Hazard ratios (HRs) of death and progression with their 95% confidence intervals (CIs) were estimated using the Cox proportional hazards regression model. Overall, a low variability of expression was observed for each marker. No association was found between the level of expression and standard prognostic factors. When assessed as a continuous variable, increased MMP-9 expression (10 units of H-score) was associated with death (HR, 1.08; 95% CI, 1.01-1.16; P = .02), but not with progression (HR, 1.03; 95% CI, 0.97-1.10; P = .29). There was no association between the expression of MMP-2 or tissue inhibitor of metalloprotease 2 and death or progression. In conclusion, in a homogeneous cohort of women with HGSC, increased MMP-9 tissue expression, as assessed by automated immunostaining quantification, was associated with a higher risk of death.

How JA, Abitbol J, Lau S, et al.
The impact of qualitative research on gynaecologic oncology guidelines.
J Obstet Gynaecol Can. 2015; 37(2):138-44 [PubMed] Related Publications
OBJECTIVE: Inherent in the care provided to patients with cancer is an important psychosocial element which has been explored scientifically through qualitative research. The purpose of our study was to evaluate the availability of qualitative research in gynaecologic oncology and to measure its integration in gynaecologic oncology practice guidelines.
METHODS: We searched Medline, CINHAL, Scopus, and Web of Science databases to identify the availability of qualitative research conducted in the past 20 years on the three most prevalent gynaecologic cancers: endometrial, ovarian, and cervical cancer. National and international practice guidelines on management of gynaecologic cancers were selected using the National Guideline Clearinghouse website, the Society of Obstetricians and Gynaecologists of Canada website, and the Standards and Guidelines Evidence directory of cancer guidelines. Bibliometric analysis was used to determine the frequency of qualitative references cited in these guidelines.
RESULTS: One hundred thirteen qualitative research papers on gynaecologic cancers were identified focusing on psychological impacts, social dynamics, and doctor-patient interactions during cancer treatment and recovery. Among the 15 national and international clinical practice guidelines identified on management of gynaecologic cancer, there were a total of 2272 references, and of these only three references citing qualitative research were identified (0.1%) in only one of the 15 practice guidelines.
CONCLUSION: Although qualitative research is being carried out in gynaecologic oncology, its integration into clinical practice guidelines is essentially absent. Efforts to narrow the gap between qualitative research and clinical practice are essential in ensuring a comprehensive approach to the treatment of patients with gynaecologic cancer.

Liu L, Chang S, Sun J, et al.
Ultrasound-mediated destruction of paclitaxel and oxygen loaded lipid microbubbles for combination therapy in ovarian cancer xenografts.
Cancer Lett. 2015; 361(1):147-54 [PubMed] Related Publications
We have synthesized multifunctional oxygen and paclitaxel loaded microbubbles (OPLMBs) for ultrasound mediated delivery of combination therapy in an ovarian cancer xenograft model. In comparison with other therapeutic options, intravenous injection of OPLMBs followed by ultrasound mediation yielded a superior therapeutic outcome. Immunohistochemical analyses of the dissected tumor tissue confirmed the increased tumor apoptosis and the reduced VEGF expression after treatment. Western Blot tests further confirmed the decreased expressions of HIF-1α and P-gp. Our experiment suggests that ultrasound mediation of OPLMBs may provide a promising drug delivery strategy for the combination treatment of ovarian cancer.

Bristow RE, Chang J, Ziogas A, et al.
Sociodemographic disparities in advanced ovarian cancer survival and adherence to treatment guidelines.
Obstet Gynecol. 2015; 125(4):833-42 [PubMed] Related Publications
OBJECTIVE: To estimate whether race or ethnic and socioeconomic strata are independently associated with advanced-stage ovarian cancer-specific survival after adjusting for adherence to National Comprehensive Cancer Network treatment guidelines.
METHODS: The design was a retrospective population-based cohort study of patients with stage IIIC-IV epithelial ovarian cancer identified from the Surveillance, Epidemiology, and End Results-Medicare database (1992-2009). Quartile of census tract median household income was used as the measure of socioeconomic status (quartiles 1-4). A multivariable logistic regression model was used to identify characteristics predictive of adherence to National Comprehensive Cancer Network guidelines for surgery and chemotherapy. Cox proportional hazards models and propensity score matching were used for survival analyses.
RESULTS: A total of 10,296 patients were identified, and 30.2% received National Comprehensive Cancer Network guideline-adherent care. Among demographic variables, black race (adjusted odds ratio [OR] 1.53, 95% confidence interval [CI] 1.22-1.92) and low socioeconomic status (quartile 1, adjusted OR 1.32, 95% CI 1.14-1.52) were independently associated with nonguideline care. Stratified multivariate survival analysis using the propensity score-matched sample (n=5,124) revealed that deviation from treatment guidelines was associated with a comparable risk of disease-related death across race-ethnicity: whites (adjusted hazard ratio [HR] 1.59, 95% CI 1.48-1.71), blacks (adjusted HR 1.66, 95% CI 1.19-2.30), Asian or Pacific Islanders (adjusted HR 1.52, 95% CI 0.99-1.92), and Hispanics (adjusted HR 1.91, 95% CI 0.98-3.72). Across socioeconomic status, deviation from treatment guidelines was also associated with a comparable risk of ovarian cancer mortality for quartile 1 (adjusted HR 1.69, 95% CI 1.47-1.95), quartile 2 (adjusted HR 1.63, 95% CI 1.42-1.87), quartile 3 (adjusted HR 1.51, 95% CI 1.32-1.73), and quartile 4 (adjusted HR 1.57, 95% CI 1.38-1.79).
CONCLUSION: Adherence to treatment guidelines for advanced-stage ovarian cancer is associated with equivalent survival benefit across racial or ethnic and socioeconomic strata. Ensuring equal access to standard treatment is a viable strategic approach to reduce survival disparities.

Cybulski M, Jarosz B, Nowakowski A, et al.
Cyclin A correlates with YB1, progression and resistance to chemotherapy in human epithelial ovarian cancer.
Anticancer Res. 2015; 35(3):1715-21 [PubMed] Related Publications
BACKGROUND: Cyclin A is a cell-cycle regulatory gene and its overexpression promotes tumor cell growth. Y-Box-binding protein 1 (YB1) is a transcription/translation factor involved in tumor growth, invasion, and drug resistance. We investigated whether an association exists between protein products of these genes in epithelial ovarian cancer (EOC) specimens and clinicopathological parameters, patient response and EOC sensitivity to platinum-based first-line chemotherapy.
PATIENTS AND METHODS: Cyclin A and YB1 expression were analyzed by immunohistochemistry in 54 human primary EOC tissues. Immunolabeling of both proteins was graded according to their staining intensity (scale 0-3) and the proportion of immunostained cancer cells (scale 0-4) to obtain a staining index (SI; value=0-12).
RESULTS: Significantly higher cyclin A immunostaining (SI≥4) in EOC specimens was discovered in patients with advanced (International Federation of Gynaecology and Obstetrics (FIGO) III and IV, p=0.003), poorly differentiated (G3, p<0.001) tumors, and tumors of those with residual disease>1 cm (p=0.001). YB1 immunostaining was significantly higher in EOCs from patients with suboptimal debulking (p=0.025). Over-expression of cyclin A (SI≥9) in EOCs was significantly linked with poorer patient response (p=0.001) and higher resistance of tumors to platinum-based first-line chemotherapy (p=0.007), while immunolabeling of YB1 in EOCs was not significantly associated with either of these variables (p>0.05). Cyclin A expression was significantly and positively correlated with that of YB1 (R=0.588, p<0.001).
CONCLUSION: Increased cyclin A expression in EOC is related to a more aggressive tumor behavior and predicts the response of patients to first-line platinum-based chemotherapy.

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