Identification and clinical significance of somatic oncogenic mutations in epithelial ovarian cancer.

OBJECTIVE: Epithelial ovarian cancer (EOC) is a heterogeneous disease with diverse clinicopathological features and behaviors, and its heterogeneity may be concerned with the accumulation of multiple somatic oncogenic mutations. The major goals of this study are to systematically perform the comprehensive mutational profiling in EOC patients, and investigate the associations between somatic mutations and clinicopathological characteristics. METHODS: A total of 80 surgical specimens were obtained from EOC patients who had previously undergone primary debulking surgery, and genomic DNAs were extracted from fresh-frozen tissues. We investigated mutational status in hot spot regions of 50 cancer-related genes by targeted next-generation sequencing using an Ion AmpliSeq Cancer Hotspot Panel v2 Kit. RESULTS: Validated mutations were detected in 66 of the 80 tumors (82.5%). The five most frequently mutated genes were TP53 (43.8%), PIK3CA (27.5%), KRAS (23.8%), PTEN (10%) and CTNNB1 (10%). PTEN and CTNNB1 mutations were associated with younger age. PIK3CA1, KRAS and CTNNB1 mutations were observed in early-stage, whereas TP53 mutations were more common in advanced stage. Significant associations were observed between TP53 mutation and serous carcinoma, and between KRAS mutation and mucinous carcinoma. Both PIK3CA mutation and CTNNB1 mutation were also significantly associated with endometrioid and clear cell carcinoma. The patients with PIK3CA and KRAS mutations were significantly associated with favorable progression free survival (PFS). In particular, PIK3CA mutations had more significant associations with favorable PFS than PIK3CA wild-type in the endometrioid subtype (P = 0.012). Patients with mutations only in TP53 were significantly associated with worse PFS. CONCLUSION: EOCs were heterogeneous at the genomic level and harbored somatic oncogenic mutations. Our molecular profiling may have the potential for becoming a novel stratification within histological subtypes of EOC. Further studies are needed to define molecular classification for improved clinical outcomes and treatment of EOC patients in future.

Menopausal symptoms in epithelial ovarian cancer survivors: a GINECO VIVROVAIRE2 study.

OBJECTIVE: We have previously shown that epithelial ovarian cancer (EOC) and its treatments have negative effects on long-term quality of life (QoL) and fatigue. The present multicenter study investigated the main menopausal symptoms and gynecological management of EOC survivors (EOCS). METHODS: 166 patients with relapse-free ≥3 years after the end of treatment attended a consultation with a gynecologist, including a questionnaire related to vasomotor symptoms (VMS) and sexuality, a clinical examination, a blood sample and an osteodensitometry. QoL, fatigue, insomnia and mood disorders were measured with validated questionnaires and correlated to VMS. VMS and QoL were assessed according to natural menopause (NM) or surgical menopause (SM). RESULTS: Mean age at the survey was 62 [21-83] years and stage III/IV (48%). Mean delay since the end of treatment was 6 years. Fifty-nine patients (36%) had SM. Half of patients reported VMS. Seventy-two percent of EOCS with SM had VMS compared to 41% with NM (P < .001). VMS were not associated with poor global QoL, fatigue, insomnia or mood disorders. Two-thirds of EOCS reported a decrease in libido. Patients with SM showed a greater decrease in libido than NM (P < .02). Fourteen percent of them had osteoporosis and 50% osteopenia. Among the 85 patients with VMS, 80 did not receive HRT after cancer treatment. At the time of the survey, only 7 (4%) patients were receiving hormone replacement therapy (HRT). CONCLUSIONS: VMS and sexual disorders are frequently reported by EOCS, particularly among patients with SM. Most EOCS with menopausal symptoms could benefit from HRT to improve these symptoms.

CA125 normalization within 60 days as an independent prognostic factor for patients with advanced epithelial ovarian cancer.

BACKGROUND: CA125 level normalization at different chemotherapy cycles has been reported to be a prognosticator in advanced epithelial ovarian cancer. OBJECTIVE: In the present study, we investigated whether the time (in days) to CA125 normalization or nadir during treatment could be used as markers to predict survival. METHODS: Patients with FIGO stage III-IV epithelial ovarian cancer treated with cytoreductive surgery followed by adjuvant chemotherapy between 2008 and 2016 were enrolled in this retrospective study. Clinicopathological characteristics, changes in CA125 level during treatment, and survival outcomes were analyzed. Time-dependent receiver operating characteristic curve analysis was used to determine the optimal cut-off values of the time to normalization and time to nadir of CA125 levels to predict survival. Univariate and multivariate Cox regression analysis were used to examine the impact of each variable on survival. RESULTS: A total of 106 patients were included in the analysis. The optimal cut-off values for the time to normalization and nadir for predicting survival were 60 and 194 days, respectively. In Kaplan-Meier survival analysis, CA125 level normalization ⩽ 60 days and CA125 ⩽ 35 u/mL after the third cycle, and CA125 level ⩽ 10 u/mL after the sixth cycle of chemotherapy were associated with significantly better 5-year progression-free survival (PFS) and overall survival (OS). In multivariate analysis, only CA125 level normalization > 60 days was significantly associated with poor survival outcomes (PFS, HR 2.62 [95% CI: 1.54, 4.45], p= 0.004; OS, HR 2.40 [95% CI: 1.19, 4.81], p= 0.014). CONCLUSIONS: Normalization of CA125 level within 60 days after cytoreductive surgery followed by adjuvant chemotherapy in patients with advanced ovarian epithelial cancer could be used as a marker to predict survival.

Perioperative fluid balance and major postoperative complications in surgery for advanced epithelial ovarian cancer.

OBJECTIVE: Appropriate fluid balance in the perioperative period is important as both hypo- and hypervolemia are associated with increased risk of complications. Women undergoing cytoreductive surgery (CRS) for advanced epithelial ovarian cancer (EOC) may have major fluid shifts. The optimal perioperative fluid balance in these women is yet to be determined. Our objective was to investigate the association between perioperative fluid balance and major postoperative complications. METHODS: Women with advanced stage EOC who underwent surgery at Karolinska University Hospital, Stockholm, Sweden were identified from the institutional database. Women subjected to surgery with curative intent were included in the analysis. Additional data were retrieved from medical records. The association between perioperative fluid balance and major postoperative complications was investigated by multivariable regression and adjusted for predefined confounders. RESULTS: Of the 270 women identified in the institutional database during 2014-2017, 184 women were included in the analyses. Of these women, 22% (n = 40) experienced a major postoperative complication. The fully adjusted odds of major postoperative complications increased when perioperative fluid balance exceeded >3000 mL, (Odds Ratio (OR) 4.85, 95% Confidence Interval (CI) 1.23-19.2, p = 0.02) and > 5000 mL (OR 33.7, 95% CI 4.13-275, p < 0.01). There was no association between negative fluid balance and major postoperative complications (OR 3.33, 95% CI 0.25-44.1, p = 0.36). CONCLUSIONS: Fluid balance >3000 mL perioperatively during surgery for advanced EOC increased the odds of major postoperative complications. Management of perioperative fluid balance in advanced EOC surgery remains a challenge.

Changes in left ventricular function induced by carboplatin combined with paclitaxel in patients with ovarian cancer identified using three-dimensional spot tracking imaging technology.

OBJECTIVE: To investigate the clinical value of three-dimensional speckle tracking imaging (3D-STI) in evaluating left ventricular (LV) systolic function in patients with ovarian cancer (OC) treated with paclitaxel and carboplatin. METHOD: We studied 30 patients with OC treated with paclitaxel combined with carboplatin chemotherapy. Two-dimensional echocardiography and 3D-STI were performed in the patients before they underwent 2- and 6-cycle chemotherapies, and in 30 normal control subjects. Were measured LV end-diastolic volume (EDV), end-systolic volume (ESV), three-dimensional LV ejection fraction (3D-LVEF), stroke volume (SV), spherical index (SPI), LV end-diastolic mass (LV EDmass), LV end-systolic mass (LV ESmass), LV global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), global area strain (GAS) and cardiac troponin T(cTnT). At the end of chemotherapy, magnetic resonance imaging (MRI) was also performed. RESULT: The 3D conventional strain values (3D-LVEF, SV, LV EDV) after the 2- and 6-cycle chemotherapy were lower than before chemotherapy. LV Edmass, LV ESmass and cTnT were higher while LV GLS, GCS, GRS, GAS were lower after 2- and after 6-cycle chemotherapy than before chemotherapy. There was no significant difference in ESV and EDV between the 3D-STI and MRI parameters. GAS showed a significant negative correlation with cTnT. MRI and 3D-STI variables were significantly correlated, and the receiver operating characteristic curves showed the greater area under the curve for GAS after 2- and after 6-cycle chemotherapy. After 2-cycle chemotherapy, the highest specificity for GAS was 93.3%, and the highest sensitivity for GLS was 70.0%. After 6-cycle chemotherapy, the highest specificity for GAS was 96.7%, and the highest sensitivity for GLS was 96.7%. CONCLUSION: The LV systolic function decreased in OC patients treated with paclitaxel and carboplatin, showing that 3D-STI may detect early LV systolic dysfunction.

Ultrasound, macroscopic and histological features of serous epithelial ovarian carcinomas.

We present a video showing two cases of serous epithelial ovarian carcinomas. The first video shows clinical, ultrasound, macroscopic, and histological features of a patient with high grade serous ovarian carcinoma. The second video presents clinical, ultrasound, macroscopic, and histological features of a patient with low grade serous ovarian carcinoma.

Dietary Inflammatory Index and Epithelial Ovarian Cancer in Southern Chinese Women: A Case-Control Study.

The association between inflammatory properties of diet and ovarian cancer risk has been investigated in some Western populations. However, little evidence is available from Asian women whose ovarian cancer incidence rates are low and dietary and lifestyle patterns are very different from their Western counterparts. We aimed to examine whether more pro-inflammatory diets, as indicated by higher dietary inflammatory index (DII®) scores, are associated with increased odds of epithelial ovarian cancer in southern China. A case-control study was conducted during 2006-2008 in Guangzhou, Guangdong Province. Energy-adjusted DII (E-DII) scores were calculated based on dietary intake assessed by a validated food frequency questionnaire administered to 500 incident epithelial ovarian cancer patients and 500 hospital-based controls. Logistic regression models were used to assess the relationship between E-DII scores and odds of ovarian cancer. Positive associations were observed between higher E-DII scores and ovarian cancer odds, using both continuous DII scores (odds ratio (OR) 1.87; 95% confidence interval (CI) 1.65, 2.13) and by DII tertiles (ORtertile3vs1 7.04, 95% CI: 4.70, 10.54, p for trend < 0.001). Likewise, a more pro-inflammatory diet was associated with a higher chance of serous and mucinous ovarian tumors. Our results suggest that a pro-inflammatory diet was associated with increased odds of developing epithelial ovarian cancer in southern Chinese women. The findings add to epidemiological evidence for the role of dietary inflammatory potential in ovarian cancer development.

Psychosexual morbidity in women with ovarian cancer.

Increasing numbers of women are surviving for longer with epithelial ovarian cancer. Consequently, there is increased focus on long-term quality of life in national guidance. Psychosexual morbidity including vaginal dryness, pain during intercourse (dyspareunia), reduced libido, and negative perceived body image exacerbate stress and anxiety and impact intimate relationships. Although a priority for women with epithelial ovarian cancer, clinicians seldom discuss sexual problems. Therefore, psychosexual morbidity and the associated distress remain unaddressed. We synthesize evidence from primary qualitative and quantitative research studies exploring psychosexual morbidity in women with epithelial ovarian cancer to identify potential risk factors and common symptoms, to facilitate the identification and management of sexual problems in clinic. Literature (2008-19) from 10 databases identified 29 suitable publications (4116 patients). The papers were assessed to answer the question: "What are the key potential risk factors and presentations of psychosexual morbidity in women with epithelial ovarian cancer?" Current literature lacks consensus in defining clinically significant psychosexual morbidity in women with epithelial ovarian cancer. Discrepancies in measurement tools, questionnaires, and primary outcome measures confound result interpretation, limiting wider application. Key potential risk factors identified included: younger age (<53 years); pre-menopausal status at diagnosis; aim of treatment; extent of surgery; more courses of chemotherapy; cardiovascular co-morbidities; and anxiety and depression. Up to 75% of women with epithelial ovarian cancer reported adverse changes in their sex lives following diagnosis and, of the sexually active, vaginal dryness affected 81-87% and pain 77%. Other prevalent symptoms included: reduced sexual desire and activity, impaired orgasm, diminished perceived body image, and reduced partner intimacy. Psychosexual morbidity represents a significant unmet need for women with epithelial ovarian cancer. Effective treatment necessitates a multimodal approach encompassing medical, psychoeducational, and physiotherapy-based strategies. Future studies need agreement in their questionnaires, definitions, thresholds, and primary outcome measures for meaningful interstudy comparisons to be drawn.

Combined Poziotinib with Manidipine Treatment Suppresses Ovarian Cancer Stem-Cell Proliferation and Stemness.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy in women worldwide, with an overall 5 year survival rate below 30%. The low survival rate is associated with the persistence of cancer stem cells (CSCs) after chemotherapy. Therefore, CSC-targeting strategies are required for successful EOC treatment. Pan-human epidermal growth factor receptor 4 (HER4) and L-type calcium channels are highly expressed in ovarian CSCs, and treatment with the pan-HER inhibitor poziotinib or calcium channel blockers (CCBs) selectively inhibits the growth of ovarian CSCs via distinct molecular mechanisms. In this study, we tested the hypothesis that combination treatment with poziotinib and CCBs can synergistically inhibit the growth of ovarian CSCs. Combined treatment with poziotinib and manidipine (an L-type CCB) synergistically suppressed ovarian CSC sphere formation and viability compared with either drug alone. Moreover, combination treatment synergistically reduced the expression of stemness markers, including CD133, KLF4, and NANOG, and stemness-related signaling molecules, such as phospho-STAT5, phospho-AKT, phospho-ERK, and Wnt/ß-catenin. Moreover, poziotinib with manidipine dramatically induced apoptosis in ovarian CSCs. Our results suggest that the combinatorial use of poziotinib with a CCB can effectively inhibit ovarian CSC survival and function.

METTL3 regulates m6A in endometrioid epithelial ovarian cancer independently of METTl14 and WTAP.

N6-methyladenosine (m6A) RNA methylation, one of the common RNA modifications, has been determined to execute crucial functions in tumorigenesis and cancer development. The m6A "writers" including methyltransferase like 3 (METTL3), METTL14, and Wilms tumor 1-associated protein (WTAP) contribute to the m6A modification process initiation. However, the coordination of m6A methyltransferase complex is not fully understood in endometrioid epithelial ovarian cancer (EEOC). In this study, mRNA and protein levels of METTL3, METTL14, and WTAP were detected in 33 EEOC cases using quantitative polymerase chain reaction (qPCR), immunohistochemistry, and western blot analysis. The overall m6A methylation was detected by dot plot. The METTL3 expression and overall m6A level were elevated in EEOC tissues, while the expressions of METTL14 and WTAP have no significant difference in EEOC compared to the adjacent tissues. The expression of METTL3 was an independent factor that correlated with poor malignancy and survival of EEOC patients. Moreover, METTL3 knockdown in TOV-112D and CRL-11731D cells weakened the capability of cell proliferation and migration, and promoted cell apoptosis compared to negative control and cells with WTAP or METTL14 knockdown using CCK-8 assay, transwell assay, wound healing assay, and TUNEL assay. Furthermore, METTL3 knockdown also reduced m6A enrichment of the genes associated with ovarian cancer including EIF3C, AXL, CSF-1, FZD10 in TOV-112D, and CRL-11731D cells by RIP-qPCR assay. Taken together, the high expressed METTL3 indicated poor malignancy and survival of EEOC via modulating the aberrant m6A RNA methylation. METTL3-mediated m6A modification, independent of WTAP and METTL14, was considered as a novel mechanism underlying m6A modulation and a potential therapeutic target of EEOC.

Melatonin suppresses chronic restraint stress-mediated metastasis of epithelial ovarian cancer via NE/AKT/ß-catenin/SLUG axis.

Chronic stress has been shown to facilitate progression of epithelial ovarian cancer (EOC), however, the neuro-endocranial mechanism participating in this process still remains unclear. Here, we reported that chronic restraint stress (CRS) promoted the abdominal implantation metastasis of EOC cells and the expression of epithelial-mesenchymal transition-related markers in tumor-bearing mouse model, including TWIST, SLUG, SNAIL, and ß-catenin. We observed that ß-catenin co-expressed with SLUG and norepinephrine (NE) in tumor tissues obtained from nude mice. Further ex vivo experiments revealed that NE promoted migration and invasion of ovarian cancer cells and SLUG expression through upregulating expression and improving transcriptional function of ß-catenin in vitro. A human phosphor-kinase array suggested that NE activated various kinases in ovarian cancer cells, and we further confirmed that AKT inhibitor reduced NE-mediated pro-metastatic impacts and activation of the ß-catenin/SLUG axis. Furthermore, the expression levels of NE and ß-catenin were examined in ovarian tumor tissues by using tumor tissue arrays. Results showed that the expression levels of both NE and ß-catenin were associated with poor clinical stage of serous EOC. Moreover, we found that melatonin (MLT) effectively reduced the abdominal tumor burden of ovarian cancer induced by CRS, which was partially related to the inhibition of the NE/AKT/ß-catenin/SLUG axis. Collectively, these findings suggest a novel mechanism for CRS-mediated ovarian cancer metastasis and MLT has a potential therapeutic efficacy against ovarian cancer.

Physical activity and exercise in women with ovarian cancer: A systematic review.

OBJECTIVE: A consistent body of evidence supports participating in physical activity (PA) post-cancer diagnosis as beneficial to function, quality-of-life and potentially survival. However, diagnosis of late stage disease, poor prognosis, receipt of high doses of adjuvant therapy and presence of severe acute and persistent treatment-related side-effects may alter how these findings translate to women with ovarian cancer. Therefore, the objectives of this review were to (I) describe PA levels post-diagnosis of ovarian cancer, (II) explore the relationship between PA levels and health outcomes, and (III) evaluate the effect of exercise interventions for women with ovarian cancer. METHODS: PubMed, EMBASE, Scopus and CINAHL were systematically searched to December 31, 2019. Two independent reviewers assessed articles for eligibility. Studies were eligible if they evaluated the relationship between PA levels or an exercise intervention and health outcomes following ovarian cancer. Methodological quality was assessed by two independent reviewers using the Joanna Briggs Institute Critical Appraisal Tools. Descriptive statistics were used to collate relevant data. RESULTS: 34 articles were eligible for inclusion. Results demonstrated that most women decrease PA from pre- to post-diagnosis and remain insufficiently active following diagnosis. Higher levels of PA were associated with higher health-related quality-of-life (HRQOL), and lower levels of anxiety and depression. Exercise appears safe and feasible during and following treatment and leads to improvements in HRQOL, fatigue and additional physical and psychological outcomes. CONCLUSIONS: Findings suggest that PA is relevant to health outcomes for women with ovarian cancer. Interventions that aid women to stay or become sufficiently active, including through exercise interventions during or following treatment have potential to improve the lives of those with ovarian cancer. Future work evaluating targeted interventions that can accommodate disease-specific challenges is now required to ensure scientific findings can translate into improved ovarian cancer care.

Dietary and Circulating Fatty Acids and Ovarian Cancer Risk in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Fatty acids impact obesity, estrogens, and inflammation, which are risk factors for ovarian cancer. Few epidemiologic studies have investigated the association of fatty acids with ovarian cancer. METHODS: Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 1,486 incident ovarian cancer cases were identified. Cox proportional hazard models with adjustment for ovarian cancer risk factors were used to estimate HRs of ovarian cancer across quintiles of intake of fatty acids. False discovery rate was computed to control for multiple testing. Multivariable conditional logistic regression models were used to estimate ORs of ovarian cancer across tertiles of plasma fatty acids among 633 cases and two matched controls in a nested case-control analysis. RESULTS: A positive association was found between ovarian cancer and intake of industrial trans elaidic acid [HR comparing fifth with first quintileQ5-Q1 = 1.29; 95% confidence interval (CI) = 1.03-1.62; P trend = 0.02, q-value = 0.06]. Dietary intakes of n-6 linoleic acid (HRQ5-Q1 = 1.10; 95% CI = 1.01-1.21; P trend = 0.03) and n-3 α-linolenic acid (HRQ5-Q1 = 1.18; 95% CI = 1.05-1.34; P trend = 0.007) from deep-frying fats were also positively associated with ovarian cancer. Suggestive associations were reported for circulating elaidic (OR comparing third with first tertileT3-T1 = 1.39; 95% CI = 0.99-1.94; P trend = 0.06) and α-linolenic acids (ORT3-T1 = 1.30; 95% CI = 0.98-1.72; P trend = 0.06). CONCLUSIONS: Our results suggest that higher intakes and circulating levels of industrial trans elaidic acid, and higher intakes of linoleic acid and α-linolenic acid from deep-frying fat, may be associated with greater risk of ovarian cancer. IMPACT: If causal, eliminating industrial trans-fatty acids could offer a straightforward public health action for reducing ovarian cancer risk.

Chemoresistant ovarian cancer enhances its migration abilities by increasing store-operated Ca2+ entry-mediated turnover of focal adhesions.

BACKGROUND: Among gynecological cancers, ovarian carcinoma has the highest mortality rate, and chemoresistance is highly prevalent in this cancer. Therefore, novel strategies are required to improve its poor prognosis. Formation and disassembly of focal adhesions are regulated dynamically during cell migration, which plays an essential role in cancer metastasis. Metastasis is intricately linked with resistance to chemotherapy, but the molecular basis for this link is unknown. METHODS: Transwell migration and wound healing migration assays were used to analyze the migration ability of ovarian cancer cells. Real-time recordings by total internal reflection fluorescence microscope (TIRFM) were performed to assess the turnover of focal adhesions with fluorescence protein-tagged focal adhesion molecules. SOCE inhibitors were used to verify the effects of SOCE on focal adhesion dynamics, cell migration, and chemoresistance in chemoresistant cells. RESULTS: We found that mesenchymal-like chemoresistant IGROV1 ovarian cancer cells have higher migration properties because of their rapid regulation of focal adhesion dynamics through FAK, paxillin, vinculin, and talin. Focal adhesions in chemoresistant cells, they were smaller and exhibited strong adhesive force, which caused the cells to migrate rapidly. Store-operated Ca2+ entry (SOCE) regulates focal adhesion turnover, and cell polarization and migration. Herein, we compared SOCE upregulation in chemoresistant ovarian cancer cells to its parental cells. SOCE inhibitors attenuated the assembly and disassembly of focal adhesions significantly. Results of wound healing and transwell assays revealed that SOCE inhibitors decreased chemoresistant cell migration. Additionally, SOCE inhibitors combined with chemotherapeutic drugs could reverse ovarian cancer drug resistance. CONCLUSION: Our findings describe the role of SOCE in chemoresistance-mediated focal adhesion turnover, cell migration, and viability. Consequently, SOCE might be a promising therapeutic target in epithelial ovarian cancer.

Sarcopenia as a predictor of survival and chemotoxicity in patients with epithelial ovarian cancer receiving platinum and taxane-based chemotherapy.

OBJECTIVES: Severe skeletal muscle loss (sarcopenia) is associated with poor cancer outcomes, including reduced survival and increased treatment toxicity. Our goal was to evaluate if sarcopenia was associated with worse survival outcomes and chemotoxicity in EOC patients undergoing primary platinum and taxane-based chemotherapy. METHODS: EOC patients diagnosed between 06/2000 and 02/2017 who received treatment with platinum and taxane-based chemotherapy were included. CT abdominal images closest to the time of diagnosis were retrospectively evaluated for skeletal muscle area at the 3rd lumbar vertebrae. Measurements were obtained with use of TomoVision® radiological software (SliceOmatic - version 5.0, Quebec, Canada). Sarcopenia was defined as Skeletal Muscle Index (SMI) ≤ 41. Data analysis included Kaplan-Meier plots to assess survival, and unpaired t-tests were used to compare the means by groups. RESULTS: 201 EOC patients were evaluated. Sixty-four percent (128/201) met criteria for sarcopenia (SMI ≤ 41) at time of diagnosis. The mean overall survival did not differ between patients with SMI > 41 and SMI ≤ 41 (36.5 vs 40.8 months, p = 0.4, respectively). No difference in frequency of dose reduction, dose delay, hospital admissions, changes in regimen, blood transfusion, or toxicity was noted. There was no difference in distribution of toxicity grade. CONCLUSION: Sarcopenia was not associated with worse survival outcomes or chemotoxcity in EOC patients receiving first-line platinum and taxane-based chemotherapy in this cohort. Future prospective studies should focus on interventions to prevent or reverse sarcopenia and possibly increase ovarian cancer survival, performance status, and quality of life.

MiR-203 regulates proliferation and apoptosis of ovarian cancer cells by targeting SOCS3.

OBJECTIVE: Cytokine signal transduction inhibitor 3 (SOCS3) negatively regulates Janus kinases (JAK) - signal transducer and activator of transcription (STAT) pathway. Bioinformatics analysis revealed a targeted relationship between miR-203 and SOCS3 mRNA. This study investigated the role of miR-203 in ovarian cancer cell proliferation and apoptosis. PATIENTS AND METHODS: Ovarian cancer tissues and adjacent tissues were collected to detect the expression of miR-203 and SOCS3. Ovarian cancer HO8910 cells were divided into miR-NC group, miR-203 inhibitor group, and miR-203 mimic group followed by the analysis of the expression of miR-203 and SOCS3 mRNA by quantitative Reverse Transcription-PCR (qRT-PCR), protein expression of p-JAK2 and p-STAT3 by Western blot, cell apoptosis by flow cytometry, and proliferation by 5-Ethynyl-2'-deoxyuridine (EdU) staining chronologically. RESULTS: Compared with adjacent tissues, miR-203 expression was significantly increased in tumor tissues and SCOS3 mRNA expression was decreased. Compared with those with lower miR-203 expression, the prognosis of patients with higher expression of miR-203 was significantly worse. There was a targeted regulatory relationship between miR-203 and SOCS3 mRNA. Compared with IOSE80 cells, miR-203 expression in HO8910 and SKOV3 cells was increased, and its expressions of SOCS3 mRNA and protein were decreased. Compared with miR-NC group, the transfection of miR-203 inhibitor significantly increased SOCS3 expression, and decreased the expression of p-JAK2 and p-STAT3 protein. We draw the conclusion that miR-203 increased cell apoptosis and decreased cell proliferation. However, opposite results were observed after the transfection of miR-203 mimic. CONCLUSIONS: Abnormal miR-203 and SOCS3 expression are related to the pathogenesis of ovarian cancer. MiR-203 affects the proliferation of JAK-STAT pathway and regulates the proliferation and apoptosis of ovarian cancer cells by targeting the inhibition of SOCS3 expression.

PD-L1 expression on stromal tumor-infiltrating lymphocytes is a favorable prognostic factor in ovarian serous carcinoma.

BACKGROUND: PD-L1 expression levels determined by immunostaining are known to be related to the survival rate and prognosis of patients with various types of cancers, as well as to the therapeutic response to immune checkpoint inhibitors. Recently, the U.S. Food and Drug Administration approved an immune checkpoint inhibitor for the treatment of non-small cell lung cancer along with the clones used for PD-L1 immunostaining to predict the resulting response. In this study, we performed PD-L1 immunostaining of tissue microarrays from ovarian epithelial cancer using SP263, an approved clone, and examined the effect of PD-L1 expression on survival rate and prognosis. METHODS: Tissue microarrays were constructed from ovarian epithelial cancer tissues of 248 patients and PD-L1 immunostaining was performed using the SP263 clone. PD-L1 expression levels in tumor cells, intraepithelial tumor-infiltrating lymphocytes, and stromal tumor-infiltrating lymphocytes were evaluated, and the effect of PD-L1 expression on survival and prognosis was analyzed. RESULTS: PD-L1 was detected in tumor cells as well as intraepithelial tumor-infiltrating lymphocytes and stromal tumor-infiltrating lymphocytes. It was most frequently expressed in stromal tumor-infiltrating lymphocytes. The Kaplan-Meier curve analysis and log rank test showed that only high stromal PD-L1 expression was associated with increased overall survival in ovarian serous carcinoma. Multivariate and univariate Cox regression analyses revealed that stromal PD-L1 expression was an independent prognostic factor, especially in ovarian serous carcinoma. CONCLUSIONS: PD-L1 immunostaining using SP263 was observed in tumor cells as well as intraepithelial and stromal tumor-infiltrating lymphocytes. PD-L1-expressing stromal tumor-infiltrating lymphocytes were associated with an increased overall survival rate and may serve as a favorable prognostic factor in ovarian cancer, particularly serous carcinoma.

[Research advances on the role of exosomes in chemotherapy resistance of ovarian cancer].

Chemotherapy resistance is one of the biggest challenges in treatment of ovarian cancer. Mounting evidence shows that the exosomes shedding from tumor cells are considered to be involved in chemotherapy resistance of ovarian cancer by enhanced exosomal export of drugs, transferring RNAs or proteins and interfering with the bioactivity of therapeutic anti-tumor antibodies. In this review, we display the correlation between exosomes and chemotherapy resistance of ovarian cancer, the mechanism of exosomes involved in chemotherapy resistance of ovarian cancer, and discuss the potential clinical values of exosomes in chemotherapy resistance of ovarian cancer.

Long-term fatigue and quality of life among epithelial ovarian cancer survivors: a GINECO case/control VIVROVAIRE I study.

BACKGROUND: Few data are available on long-term fatigue (LTF) and quality of life (QoL) among epithelial ovarian cancer survivors (EOCS). In this case-control study, we compared LTF, symptoms and several QoL domains in EOCS relapse-free ≥3 years after first-line treatment and age-matched healthy women. PATIENTS AND METHODS: EOCS were recruited from 25 cooperative GINECO centers in France. Controls were randomly selected from the electoral rolls. All participants completed validated self-reported questionnaires: fatigue (FACIT-F), QoL (FACT-G/O), neurotoxicity (FACT-Ntx), anxiety/depression (HADS), sleep disturbance (ISI), and physical activity (IPAQ). Severe LTF (SLTF) was defined as a FACIT-F score <37/52. Univariate and multivariate logistic regressions were conducted to analyze SLTF and its influencing factors in EOCS. RESULTS: A total of 318 EOCS and 318 controls were included. EOCS were 63-year-old on average, with FIGO stage I/II (50%), III/IV (48%); 99% had received platinum and taxane chemotherapy, with an average 6-year follow-up. There were no differences between the two groups in socio-demographic characteristics and global QoL. EOCS had poorer FACIT-F scores (40 versus 45, P < 0.0001), lower functional well-being scores (18 versus 20, P = 0.0002), poorer FACT-O scores (31 versus 34 P < 0.0001), and poorer FACT-Ntx scores (35 versus 39, P < 0.0001). They also reported more SLTF (26% versus 13%, P = 0.0004), poorer sleep quality (63% versus 47%, P = 0.0003), and more depression (22% versus 13%, P = 0.01). Fewer than 20% of EOCS and controls exercised regularly. In multivariate analyses, EOCS with high levels of depression, neurotoxicity, and sleep disturbance had an increased risk of developing SLTF (P < 0.01). CONCLUSION: Compared with controls, EOCS presented similar QoL but persistent LTF, EOC-related symptoms, neurotoxicity, depression, and sleep disturbance. Depression, neuropathy, and sleep disturbance are the main conditions associated with severe LTF.