Preoperative ctDNA Levels Are Associated With Poor Overall Survival in Patients With Ovarian Cancer.

BACKGROUND/AIM: Circulating tumor DNA (ctDNA), which is shed from cancer cells into the bloodstream, offers a potential minimally invasive approach for cancer diagnosis and monitoring. This research aimed to assess the preoperative ctDNA levels in ovarian tumors patients' plasma and establish correlations with clinicopathological parameters and patient prognosis. PATIENTS AND METHODS: Tumor DNA was extracted from ovarian tumor tissue from 41 patients. Targeted sequencing using a panel of 127 genes recurrently mutated in cancer was performed to identify candidate somatic mutations in the tumor DNA. SAGAsafe digital PCR (dPCR) assays targeting the candidate mutations were used to measure ctDNA levels in patient plasma samples, obtained prior to surgery, to evaluate ctDNA levels in terms of mutant copy number/ml and variant allele frequency. RESULTS: Somatic mutations were found in 24 tumor samples, 17 of which were from ovarian cancer patients. The most frequently mutated gene was TP53. Preoperative plasma ctDNA levels were detected in 14 of the 24 patients. With higher stage, plasma ctDNA mutant concentration increased (p for trend <0.001). The overall survival of cancer patients with more than 10 ctDNA mutant copies/ml in plasma was significantly worse (p=0.008). CONCLUSION: Pre-operative ctDNA measurement in ovarian cancer patients' plasma holds promise as a predictive biomarker for tumor staging and prognosis.

A Multiplex Biomarker Assay Improves the Prediction of Survival in Epithelial Ovarian Cancer.

BACKGROUND/AIM: Epithelial ovarian cancer (EOC) is usually diagnosed in advanced stages and has a high mortality rate. In this study, we used the proximity extension assay from Olink Proteomics to search for new plasma protein biomarkers to predict overall survival (OS) in patients with EOC. MATERIALS AND METHODS: Peripheral blood samples were obtained preoperatively from 116 EOC patients undergoing primary debulking surgery: 28 early EOC cases (FIGO stage I-II) and 88 advanced EOC cases (FIGO stage III-IV). Proteins were measured using the Olink Oncology II and Inflammation panels. In total, 177 unique protein biomarkers were analysed. Cross-validation and LASSO regression were combined to select prediction models for OS. RESULTS: The model including age and the three-biomarker combination of neurotrophin-3 (NT-3)+transmembrane glycoprotein NMB (GPNMB)+mesothelin (MSLN) predicted worse OS with AUC=0.79 (p=0.004). Adding cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) to the model further improved performance (AUC=0.83; p=0.003). In a postoperative model including age and stage (III+IV vs. I+II), the three-biomarker panel of chemokine (C-C motif) ligand 28 (CCL28)+T-cell leukaemia/lymphoma protein 1A (TCL1A)+GPNMB improved the prediction of OS (from AUC=0.83 to AUC=0.90; p=0.05). In the postoperative model including age and dichotomized stage (III vs. I+II), the biomarkers CCL28 and GPNMB1 improved the prediction of OS (AUC=0.86; p<0.001). The combination of high levels of both CA125 and HE4 predicted worse survival (p=0.05). CONCLUSION: In this explorative study evaluating the performance of plasma protein biomarkers in predicting OS, we found that adding biomarkers, especially NT-3, to the panel improved the prediction of OS.

National survey of donor-conceived individuals who requested information about their sperm donor-experiences from 17 years of identity releases in Sweden.

STUDY QUESTION: What characterizes the group of donor-conceived (DC) individuals who request information about their identity-release sperm donor in Sweden, and what are their experiences of disclosure, information receipt and donor contact? SUMMARY ANSWER: Following three decades of identity-release donation in Sweden, few DC individuals have requested donor information with varying experiences of information receipt and donor contact. WHAT IS KNOWN ALREADY: In 1985, Sweden was the first country worldwide to enact legislation that gave DC individuals the right to obtain identifying information about their donor. Since then, identity-release gamete donation has become available in many countries but there is limited knowledge about the individuals who request donor information. STUDY DESIGN, SIZE, DURATION: A nation-wide cross-sectional survey study was performed at all seven University hospitals that provided donation treatment in Sweden during 1985-2002. During this period only donor insemination to heterosexual couples was permitted. Inclusion criteria were being 18 years of age or older, conceived with donor sperm and having requested information about the donor by December 2020. Recruitment was performed during 2016-2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 60 individuals had requested information about their donor. Of these, 53 were approached and 40 individuals, representing 34 families, accepted study participation (75% response rate). Participants completed a postal survey with the WHO-10 well-being index and study-specific questions about experiences of disclosure, motivations for requesting donor information, receipt of information, as well as intentions and experiences of donor contact. Independent t-test and chi-square tests were used to compare ratings of participants with early and late disclosure. MAIN RESULTS AND ROLE OF CHANCE: Of ∼900 DC individuals who had reached adult age, a total of 60 (≈7%) had requested information about the donor. Most of the 40 study participants (78%) made their requests within 2 years after reaching 18 years of age, or following disclosure at later ages (up to 32 years). Several participants had adult DC siblings in the family who had not requested any donor information. All except five participants received identifying information about the donor from the clinic. However, some donors had died or lacked contact information. Among those participants who were able to contact their donor, 41% had done so at the time of the study, while a third of the participants were unsure about potential contact. Several had met the donor in person and a few were in regular contact. About half of the participants had been informed about their donor conception in adolescence or adulthood (age 12-32), and there were significant differences between participants based on age at disclosure. Compared to those with early disclosure, participants with late disclosure were significantly more likely to be dissatisfied with the timing of their disclosure (P = 0.021), to react with negative emotions (P < 0.001), and to subsequently contact the donor (P = 0.047). LIMITATIONS, REASONS FOR CAUTION: The limited population available for inclusion resulted in a small sample size, despite a high response rate. In addition, men's lower participation rate must be taken into consideration when interpreting the results. WIDER IMPLICATIONS OF THE FINDINGS: The small number of individuals requesting information about their identity-release sperm donor is surprising. While not all DC individuals appear to be interested in donor information, it is reasonable to assume that some are unaware of their donor conception and thus unable to make informed decisions regarding their genetic origins. During the coming years, young women and men in many countries will become eligible to access identifying information about their donor. In order to meet the needs of these individuals, and to support positive outcomes for all involved parties, it is essential that adequate protocols and resources are developed. STUDY FUNDING/COMPETING INTEREST: Financial support from The Swedish Research Council. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Incidence and survival of epithelial ovarian, fallopian tube, peritoneal, and undesignated abdominal/pelvic cancers in Sweden 1960-2014: A population-based cohort study.

BACKGROUND: Despite improved surgical and oncological treatment, ovarian cancer continues to be the most lethal of the gynecologic malignancies. We aimed to analyze survival trends in epithelial ovarian cancer with regard to age, tumor site, and morphology in Sweden 1960 to 2014. METHODS: A nationwide population-based study was conducted using data from the Swedish Cancer Registry on 46,350 women aged 18 or older with a diagnosis of epithelial ovarian, fallopian tube, peritoneal, or undesignated abdominal/pelvic cancer 1960 to 2014. Analyses of age-standardized incidence and relative survival (RS) were performed and time trends modelled according to age, tumor site, and morphology. RESULTS: Overall incidence of ovarian, tubal, peritoneal, and undesignated abdominal/pelvic cancers declined since 1980. Median age at diagnosis increased. Serous carcinoma increased in incidence. RS at 1, 2 and 5 years from diagnosis improved since 1960, although not for the youngest and the oldest patients. Ten-year RS did not improve. The best RS was found for fallopian tube cancer and the worst RS for undesignated abdominal/pelvic cancer. Among the morphologic subgroups, endometrioid carcinoma had the best RS. CONCLUSIONS: Survival in epithelial ovarian, tubal, peritoneal, and undesignated abdominal/pelvic cancers in Sweden has improved over the last six decades. Advances in epithelial ovarian cancer treatment have extended life for the first 5 years from diagnosis but 10-year survival remains poor.

Access to infertility evaluation and treatment in two public fertility clinics and the reasons for withholding it: a prospective survey cohort study of healthcare professionals.

OBJECTIVES: Study the proportion of patients affected by involuntary childlessness who are denied fertility treatment and the reasons behind this in a publicly funded healthcare system. DESIGN: Survey study using prospectively collected information by healthcare professionals. SETTING: Two university-affiliated fertility clinics in Sweden. PARTICIPANTS: Single women and couples in heterosexual and homosexual relationships seeking fertility evaluation and treatment between November 2017 and April 2018 (943 individual cases). PRIMARY AND SECONDARY OUTCOME MEASURES: Number and proportion of individuals who were either denied, delayed or granted fertility treatment directly. Furthermore, the reasons behind delaying or completely withholding treatment. RESULTS: The majority of those seeking evaluation were heterosexual couples (75%), while 14% were single women and 7.5% were same-sex couples. The great majority of those undergoing evaluation were granted treatment either directly (85%) or after in-depth evaluation (7.5%), while 7.5% were denied treatment. Among those who were denied treatment, there were a greater proportion of single women and couples seeking treatment with donated gametes. Among heterosexual couples, gamete origin was not associated with treatment refusal. Although age did not differ between those granted and denied treatment, a higher body mass index (in both recipient and partner, when applicable) was observed among those being refused treatment. Fertility specialists in Sweden focused their assessment on parental factors that may indirectly entail a risk of harm to the future child, such as medical and psychiatric conditions of the individuals involved, their financial constraints and other social reasons, substance abuse and female obesity. CONCLUSION: Being single or receiving treatment with donated gametes can both be reasons for withholding fertility treatment. Although difficult to operationalise, parenting assessment in Sweden is employed interchangeably in treatments with donated gametes (legally mandated assessment) and even autologous gametes (non-legally mandated assessment)-making evident a need for clear official policy guidelines regulating these assessments and the provision of treatment.

A multiplex biomarker assay improves the diagnostic performance of HE4 and CA125 in ovarian tumor patients.

OBJECTIVE: Survival in epithelial ovarian cancer (EOC) remains poor. Most patients are diagnosed in late stages. Early diagnosis increases the chance of survival. We used the proximity extension assay from Olink Proteomics to search for new protein biomarkers with the potential to improve the diagnostic performance of CA125 and HE4 in patients with ovarian tumors. MATERIAL AND METHODS: Plasma samples were obtained from 180 women with ovarian tumors; 30 cases of benign tumor, 28 cases with borderline tumors, 25 early EOC cases (FIGO stage I) and 97 advanced EOC cases (FIGO stages II-IV). Proteins were measured using the Olink® Oncology II and Inflammation panels. For statistical analyses, patients were categorized into benign tumors versus cancer and benign tumors versus borderline + cancer, respectively. RESULTS: We analyzed 177 biomarkers. Thirty-four proteins had ROC AUC > 0.7 for discrimination between benign tumors and cancer. Fifteen proteins had ROC AUC > 0.7 for discrimination between benign tumors and borderline tumors + cancer. HE4 ranked highest for both comparisons. A reference model with HE4, CA125 and age (AUC 0.838 for benign tumors vs. cancer and AUC 0.770 for benign tumors vs. borderline tumors + cancer) was compared to the reference model with the addition of each of the remaining proteins with AUC > 0.7. ITGAV was the only individual biomarker found to improve diagnostic performance of the reference model, to AUC 0.874 for benign tumors vs. cancer and AUC 0.818 for benign tumors vs. borderline tumors + cancer (p < 0.05). Cross-validation and LASSO regression was combined to select multiple biomarker combinations. The best performing model for discrimination between benign tumors and borderline tumors + cancer was a 6-biomarker combination (HE4, CA125, ITGAV, CXCL1, CEACAM1, IL-10RB) and age (AUC 0.868, sensitivity 0.86 and specificity 0.82, p = 0.016 for comparison with the reference model). CONCLUSION: HE4 was the best performing individual biomarker for discrimination between benign ovarian tumors and EOC including borderline tumors. The addition of other carcinogenesis-related biomarkers in a multiplex biomarker panel can improve the diagnostic performance of the established biomarkers HE4 and CA125.

Confounders other than comorbidity explain survival differences in Danish and Swedish ovarian cancer patients - a comparative cohort study.

OBJECTIVE: Danish ovarian cancer (OC) patients have previously been found to have worse prognosis than Swedish patients, and comorbidity has been suggested as a possible explanation for this survival difference. We aimed to investigate the prognostic impact of comorbidity in surgically treated OC patients in Denmark and Sweden. METHODS: This comparative cohort study was based on data from 3118 surgically treated OC patients diagnosed in 2012-2015. The Swedish subcohort (n = 1472) was identified through the Swedish National Quality Register of Gynecological Surgery, whereas the Danish subcohort (n = 1646) originated from the Danish Gynecological Cancer Database. The clinical databases have high coverage and similar variables included. Comorbidity was classified according to the Ovarian Cancer Comorbidity Index and overall survival was the primary outcome. Data were analyzed using Kaplan Meier and Cox regression analyses. Multiple imputation was used to handle missing data. RESULTS: We found comparable frequencies of the following comorbidities: Hypertension, diabetes and 'Any comorbidity'. Arteriosclerotic cardiac disease and chronic pulmonary disease were more common among Swedish patients. Univariable survival analysis revealed a significant better prognosis for Swedish than for Danish patients (HR 0.84 [95% CI 0.74-0.95], p < .01). In adjusted multivariable analysis, Swedish patients had nonsignificant better prognosis compared to Danish patients (HR 0.91 [95% CI 0.80-1.04], p = .16). Comorbidity was associated with survival (p = .02) but comorbidity did not explain the survival difference between the two countries. CONCLUSIONS: Danish OC patients have a poorer prognosis than patients in Sweden but the difference in survival seems to be explained by other factors than comorbidity.

Ovarian Cancer Surgery - A Population-based Registry Study.

BACKGROUND/AIM: To evaluate ovarian cancer surgery in tertiary centers (TC) and regional hospitals (RH). PATIENTS AND METHODS: Data from the GynOp registry on patients undergoing surgery for ovarian cancer or borderline tumor from 2013 to 2015 were analyzed. RESULTS: Four TC and 21 RH reported 1,108 cases of surgery with curative intent, 770 cases (69.5%) in TC and 338 cases (30.5%) in RH. Out of 458 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV disease 396 (86.5%) had surgery in TC. We found differences in selection for primary debulking surgery (PDS) (45% to 93%, p<0.001) and PDS achieving no residual tumor (36% to 70%, p<0.001) between the four TC. Major complications, re-admissions and re-operation rates did not differ between TC and RH. CONCLUSION: Tertiary centers perform more extensive surgery compared to regional hospitals without increased frequency of major complications. Tertiary centers display significant differences among patient selection for PDS, as well as achieving no residual tumor.

A Biomarker Panel Increases the Diagnostic Performance for Epithelial Ovarian Cancer Type I and II in Young Women.

BACKGROUND/AIM: To assess preoperative blood levels of a biomarker panel in relation to the new classification system of epithelial ovarian cancer (EOC) type I and II. PATIENTS AND METHODS: Preoperative plasma levels of B7-family protein homolog 4 (B7-H4), intact and cleaved soluble urokinase plasminogen activator receptor (suPAR), human epididymis protein 4 (HE4) and cancer antigen 125 (CA125) were analyzed in 350 patients with adnexal lesions. RESULTS: The levels of suPAR(II-III), HE4, CA125 were all higher in EOC II than in EOC I, borderline and benign ovarian tumors. B7-H4 was increased in EOC II compared with benign ovarian tumors. The combination of suPAR(II-III), HE4, CA125 and age in premenopausal women discriminates EOC and borderline tumors from benign tumors to higher accuracy compared to the Risk of Ovarian Malignancy Algorithm (p=0.007). CONCLUSION: The biomarker panel suPAR(II-III), HE4, CA125 and age in premenopausal women improved discrimination of malignant and benign ovarian tumors. The plasma levels of B7-H4 were increased in patients with EOC II compared to those with benign ovarian tumors.