School performance and educational achievement in children exposed to maternal cancer in utero.

BACKGROUND: In utero exposure to maternal cancer and cancer treatment might influence the child's cognitive development. This study investigated if exposure to maternal cancer during fetal life impacted school performance and educational achievement as adults. METHODS: This nationwide retrospective cohort study identified all live-born children in Denmark between January 1978 and December 2013. Exposure was defined as maternal cancer diagnosis during pregnancy. Four partly overlapping birth cohorts were constructed depending on the outcome of interest: (1) receiving special educational support for birth years 2001-2013; (2) grade point average (GPA) at the final exams after 10th grade for 1986-2003; (3) educational achievement at 20 years for 1978-1998; and (4) education at 30 years for 1978-1988. Logistic and linear models were adjusted for birth year, maternal age, maternal education and maternal death. RESULTS: The estimated probability of receiving special educational support was similar in the exposed group and the reference (adjusted OR 0.96; 95% CI 0.46 to 1.77, non-significant). The GPA did not statistically differ (0.13 grade points; 95% CI -0.18 to 0.45, non-significant). The achieved educational levels were similar for the exposed group and the reference at 20 years, with an adjusted OR of 1.07 (95% CI 0.82 to 1.40) for low versus medium educational level, and at 30 years with an adjusted OR of 0.73 (95% CI 0.35 to 1.50) for low versus high educational level and of 1.07 (95% CI 0.66 to 1.72) for medium versus high educational level. CONCLUSION: Our findings did not indicate poorer performance in compulsory school nor impairment of adult educational achievement after exposure to maternal cancer in utero.

Cancer in pregnancy - The obstetrical management.

Cancer in pregnancy, defined as a cancer diagnosed during pregnancy, is a rare but severe condition presenting both clinical and ethical challenges. During the last two decades a paradigm shift has occurred towards recommending similar staging and treatment regimens of pregnant and non-pregnant cancer patients. This strategy is a result of an increasing number of reassuring reports on chemotherapy treatment in pregnancy after the first trimester. The management of cancer in pregnancy should be managed in a multidisciplinary team where staging, oncological treatment, social and mental care, timing of delivery, and follow-up of the infant should be planned. Due to the rarity, centralization is recommended to allow experience accumulation. Furthermore, national and international advisory boards are supportive when there is a lack of expertise.

Cancer in pregnancy and the risk of adverse pregnancy and neonatal outcomes: A nationwide cohort study.

OBJECTIVES: To investigate the obstetrical management of cancer in pregnancy and to determine adverse pregnancy and neonatal outcomes. DESIGN: A nationwide cohort study. SETTING AND POPULATION: We included all pregnancies (n = 4 071 848) in Denmark from 1 January 1973 to 31 December 2018. METHODS: Exposure was defined as pregnancies exposed to maternal cancer (n = 1068). The control group comprised pregnancies without cancer. The groups were compared using logistic regression analysis and adjusted for potential confounders. MAIN OUTCOME MEASURES: The outcomes were induced abortion, preterm birth and adverse neonatal outcomes. RESULTS: More women with cancer in pregnancy, as compared with the control group, experienced induced abortion (24.8% vs. 20.0%); first-trimester induced abortion adjusted odds ratio (aOR) 3.5 (95% confidence interval [CI] 2.7-4.5), second-trimester induced abortion; aOR 8.8 (95% CI 6.3-12.3), planned preterm birth (11.8% vs. 1.3%); aOR 10.8 (95% CI 8.0-14.6) and planned preterm birth at <32 gestational weeks; aOR 16.3 (95% CI 8.3-31.7). Neonates born to mothers with cancer in pregnancy had a higher risk of respiratory distress syndrome; aOR 3.5 (95% CI 2.8-4.4), low birthweight; aOR 3.8 (95% CI 3.1-4.8), admission to neonatal intensive care unit for >7 days; aOR 5.1 (95% CI 3.9-6.6), neonatal infection; aOR 1.8 (95% CI1.1-3.1) and neonatal mortality; aOR 4.7 (95% CI 2.7-8.2), but not of SGA; aOR 1.0 (95% CI 0.6-1.5) and malformations; 1.2 (95% CI 0.9-1.7). CONCLUSION: Cancer in pregnancy increases the risk of induced abortion and planned premature birth. Neonates born to mothers with cancer in pregnancy had an increased risk of neonatal morbidity and mortality, presumably due to prematurity. TWEETABLE ABSTRACT: Cancer in pregnancy is associated with an increased risk of premature birth leading to adverse neonatal outcomes.

MicroRNA characteristics in epithelial ovarian cancer.

The purpose of the current study was to clarify differences in microRNA expression according to clinicopathological characteristics, and to investigate if miRNA profiles could predict cytoreductive outcome in patients with FIGO stage IIIC and IV ovarian cancer. Patients enrolled in the Pelvic Mass study between 2004 and 2010, diagnosed and surgically treated for epithelial ovarian cancer, were used for investigation. MicroRNA was profiled from tumour tissue with global microRNA microarray analysis. Differences in miRNA expression profiles were analysed according to histologic subtype, FIGO stage, tumour grade, type I or II tumours and result of primary cytoreductive surgery. One microRNA, miR-130a, which was found to be associated with serous histology and advanced FIGO stage, was also validated using data from external cohorts. Another seven microRNAs (miR-34a, miR-455-3p, miR-595, miR-1301, miR-146-5p, 193a-5p, miR-939) were found to be significantly associated with the clinicopathological characteristics (p ≤ 0.001), in our data, but mere not similarly significant when tested against external cohorts. Further validation in comparable cohorts, with microRNA profiled using newest and similar methods are warranted.

Identification and validation of potential prognostic and predictive miRNAs of epithelial ovarian cancer.

BACKGROUND: Ovarian cancer is the leading cause of death by gynecologic cancers in the Western world. The aim of the study was to identify microRNAs (miRNAs) associated with prognosis and/or resistance to chemotherapy among patients with epithelial ovarian cancer. METHODS: Using information from the Pelvic Mass Study we identified a cohort of women with epithelial ovarian cancer. Tumor tissues were then collected and analyzed by global miRNA microarrays. MiRNA profiling was then linked to survival and time to progression using Cox proportional-hazards regression models. Logistic regression models were used for the analysis of resistance to chemotherapy. Our results were validated using external datasets retrieved from the NCBI Gene Expression Omnibus database. RESULTS: A total of 197 patients with epithelial ovarian cancer were included for miRNA microarray analysis. In multivariate analyses we identified a number of miRNAs significantly correlated with overall survival (miR-1183 (HR: 1.42, 95% CI:1.17-1.74, p = 0.0005), miR-126-3p (HR: 1.38, 95% CI:1.11-1.71, p = 0.0036), time to progression (miR-139-3p (HR: 1.48, 95% CI: 1.13-1.94, p = 0.0047), miR-802 (HR: 0.48, 95% CI: 0.29-0.78, p = 0.0035)), progression free survival (miR-23a-5p (HR:1.32, 95% CI:1.09-1.61, p = 0.004), miR-23a-3p (HR:1.70, 95% CI:1.15-2.51, p = 0.0074), miR-802 (HR: 0.48, 95% CI: 0.29-0.80, p = 0.0048)), and resistance to chemotherapy (miR-1234 (HR: 0.26, 95% CI: 0.11-0.64, p = 0.003)). A few miRNAs identified in our training cohort, were validated in external cohorts with similar results. CONCLUSION: Eight miRNAs were identified as significant predictors of overall survival, progression free survival, time to progression, and chemotherapy resistance. A number of these miRNAs were significantly validated using external datasets. Inter-platform and inter-laboratory variations may have influence on the ability to compare and reproduce miRNA results. The use of miRNAs as potential markers of relapse and survival in ovarian cancer warrants further investigation.

Survival of selected patients with ovarian cancer treated with fertility-sparing surgery.

RESEARCH QUESTION: How many patients in Denmark were treated with fertility-sparing surgery (FSS) for epithelial ovarian cancer (EOC) and what was their prognosis compared with patients treated with radical surgery (RS)? DESIGN: This study was a retrospective Danish nationwide study, evaluating the effect of FSS compared with RS in patients with EOC, age ≤45 years and International Federation of Gynecology and Obstetrics (FIGO) stage ≤IC3 from 2005 to 2016. RESULTS: A total of 106 patients were included. Of these, 13 were treated with FSS and 93 were treated with RS. Median age was 27 versus 42 years (P < 0.0001). Overall survival did not differ significantly between the two groups. Overall survival rate in the FSS group was 100%, while the overall survival in the RS group was 87%. Disease-specific survival was 100% in the FSS group and 91% in the RS group. CONCLUSIONS: This study shows that patients treated with FSS for FIGO stage I EOC do not have an impaired survival compared with patients treated with RS. Nevertheless, the conclusion must be interpreted with caution due to the limited number of patients and the retrospective nature of the study. Larger studies are needed before conclusions can be drawn.

Clinical validation of chemotherapy predictors developed on global microRNA expression in the NCI60 cell line panel tested in ovarian cancer.

OBJECTIVE: Ovarian cancer is the leading cause of death among gynecologic malignancies. This is partly due to a non-durable response to chemotherapy. Prediction of resistance to chemotherapy could be a key role in more personalized treatment. In the current study we aimed to examine if microRNA based predictors could predict resistance to chemotherapy in ovarian cancer, and to investigate if the predictors could be prognostic factors for progression free and overall survival. METHODS: Predictors of chemotherapy-resistance were developed based on correlation between miRNA expression and differences in measured growth inhibition in a variety of human cancer cell lines in the presence of Carboplatin, Paclitaxel and Docetaxel. These predictors were then, retrospectively, blindly validated in a cohort of 170 epithelial ovarian cancer patients treated with Carboplatin and Paclitaxel or Docetaxel as first line treatment. RESULTS: In a multivariate cox proportional analysis the predictors of chemotherapy-resistance were not able to predict time to progression after end of chemotherapy (hazard ratio: 0.64, 95% CI: 0.36-1.12, P = 0.117). However, in a multivariate logistic analysis, where time to progression was considered as either more or less than 6 months, the predictors match clinical observed chemotherapy-resistance (odds ratio: 0.19, 95% CI: 0.05-0.73, P = 0.015). Neither univariate nor multivariate, time-dependent, cox analysis for progression free survival (PFS) or overall survival (OS) in all 170 patients showed to match predicted resistance to chemotherapy (PFS: hazard ratio: 0.69, 95% CI: 0.40-1.19, P = 0.183, OS: hazard ratio: 0.76, 95% CI: 0.42-1.40, P = 0.386). CONCLUSION: In the current study, microRNA based predictors of chemotherapy-resistance did not demonstrate any convincing correlation to clinical observed chemotherapy-resistance, progression free survival, or overall survival, in patients with epithelial ovarian cancer. However the predictors did reflect relapse more or less than 6 months.

A novel index for preoperative, non-invasive prediction of macro-radical primary surgery in patients with stage IIIC-IV ovarian cancer-a part of the Danish prospective pelvic mass study.

The purpose of this study was to develop a novel index for preoperative, non-invasive prediction of complete primary cytoreduction in patients with FIGO stage IIIC-IV epithelial ovarian cancer. Prospectively collected clinical data was registered in the Danish Gynecologic Cancer Database. Blood samples were collected within 14 days of surgery and stored by the Danish CancerBiobank. Serum human epididymis protein 4 (HE4), serum cancer antigen 125 (CA125), age, performance status, and presence/absence of ascites at ultrasonography were evaluated individually and combined to predict complete tumor removal. One hundred fifty patients with advanced epithelial ovarian cancer were treated with primary debulking surgery (PDS). Complete PDS was achieved in 41 cases (27 %). The receiver operating characteristic curves demonstrated an area under the curve of 0.785 for HE4, 0.678 for CA125, and 0.688 for age. The multivariate model (Cancer Ovarii Non-invasive Assessment of Treatment Strategy (CONATS) index), consisting of HE4, age, and performance status, demonstrated an AUC of 0.853. According to the Danish indicator level, macro-radical PDS should be achieved in 60 % of patients admitted to primary surgery (positive predictive value of 60 %), resulting in a negative predictive value of 87.5 %, sensitivity of 68.3 %, specificity of 83.5 %, and cutoff of 0.63 for the CONATS index. Non-invasive prediction of complete PDS is possible with the CONATS index. The CONATS index is meant as a supplement to the standard preoperative evaluation of each patient. Evaluation of the CONATS index combined with radiological and/or laparoscopic findings may improve the assessment of the optimal treatment strategy in patients with advanced epithelial ovarian cancer.

High-risk HPV is not associated with epithelial ovarian cancer in a Caucasian population.

BACKGROUND: High-risk human papillomavirus (HPV) has been suspected to play a role in the carcinogenesis of epithelial ovarian cancer (EOC). However, results from previous studies are conflicting. In most of these studies, the number of tissue samples was small. The current study was therefore undertaken to examine the prevalence of high-risk HPV DNA in EOC in a large series of patients. METHOD: Formalin-fixed, paraffin-imbedded tumor tissue samples from 198 cases consecutively included in the Danish Pelvic Mass Study were analyzed. The material included 163 serous adenocarcinomas, 15 endometrioid adenocarcinomas, 11 mucinous adenocarcinomas and nine clear-cell carcinomas. Genotyping for high-risk HPV DNA was performed by real-time Polymerase chain reaction (PCR) using an in-house TaqMan singleplex assay targeting the E6/E7 region of the HPV 16 and 18 genomes. Additionally, 20 random samples without HPV 16 and/or 18 infections were reanalyzed for HPV subtypes 31, 33, 35, 39, 45, 51 and 52. RESULTS: The quality criteria were fulfilled in 191 samples. HPV 18 DNA was detected in one sample only, while the rest tested negative. The subgroup analysis for seven additional high-risk HPV subtypes was also negative. CONCLUSIONS: Only one in 191 samples was positive for HPV DNA. We therefore conclude that high risk HPV is unlikely to be associated with EOC in a Caucasian population. Future studies should focus on other microorganisms as possible etiological factors in EOC carcinogenesis.

Relapse and disease specific survival in 1143 Danish women diagnosed with borderline ovarian tumours (BOT).

OBJECTIVE: The aim of the study was to evaluate the rate of relapse as well as disease-free, overall, and disease-specific survival in women with borderline ovarian tumour (BOT). Furthermore, the study aims to identify the clinical parameters correlated to relapse. METHODS: National clinical data of women diagnosed with BOT from January 2005 to January 2013 constituted the basis for our study population. The prognostic influence of clinical variables was evaluated using univariate and multivariate analyses. RESULTS: A total of 1143 women were eligible for analysis, with 87.9% in FIGO stage I and 12.1% in FIGO stages II-IV. Relapse of BOT was detected in 3.7%, hereof 40.5% with malignant transformation. The five-year disease-free survival was 97.6% in FIGO stage I and 87.3% in FIGO stages II-IV. Younger age, laparoscopic surgical approach, fertility sparing surgery, FIGO stages II-IV, bilateral tumour presence, serous histology, implants and microinvasion of the tumour were significantly associated with relapse in univariate analyses. The overall five-year survival rate was 92.2% in FIGO stage I and 89.0% in FIGO stages II-IV. Out of 77 deaths in total, only seven women died from BOT. CONCLUSIONS: A general favourable prognosis in women with BOT was confirmed in our study. Our findings indicate that systematic, long-term follow-up does not seem necessary in women treated for FIGO stage IA BOT with no residual disease or microinvasion.

The prognostic value of dividing epithelial ovarian cancer into type I and type II tumors based on pathologic characteristics.

OBJECTIVE: To investigate the prognostic significance of dividing epithelial ovarian cancer (EOC) in type I and type II tumors based on pathologic variables. METHODS: We used the Danish Gynecologic Cancer Database to identify all patients diagnosed with EOC from 2005 to 2012. Information on histologic type and grade were used to classify tumors as either type I or type II. Death, and several prognostic factors were used in the multivariate Cox regression, and Landmark analysis was used to estimate hazard ratios of all-cause mortality. RESULTS: Among 2660 patients diagnosed with EOC, 735 were categorized as type I tumors, and 1925 as type II tumors. Patients with type II EOC were more frequently diagnosed in late FIGO stages (stages III-IV) than patients with type I EOC (78.1% vs. 32.1% respectively; P<0.001). Time dependent multivariate Cox analysis, adjusted for known prognostic variables, showed no significant difference in survival within the first two years after diagnosis, however, after 730days of follow-up a significantly increased overall survival for type I tumors was observed (hazard ratio 1.72, 95% confidence interval: 1.28-2.31, P<0.001). Similarly the Landmark analysis for survival confirmed the increased overall survival for type I tumors after two years of follow-up (hazard ratio: 1.85, 95% confidence interval: 1.35-2.54, P<0.001). CONCLUSION: Classification of EOC in type I and type II tumors based on pathologic variables was associated with an increased risk of death for type II tumors after two years of follow-up, while no increased risk was seen during the first two years of follow-up.

Evaluation of HE4, CA125, risk of ovarian malignancy algorithm (ROMA) and risk of malignancy index (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic mass.

OBJECTIVE: Diagnostic factors are needed to improve the currently used serum CA125 and risk of malignancy index (RMI) in differentiating ovarian cancer (OC) from other pelvic masses, thereby achieving precise and fast referral to a tertiary center and correct selection for further diagnostics. The aim was to evaluate serum Human Epididymis protein 4 (HE4) and the risk of ovarian malignancy algorithm (ROMA) for these purposes. METHODS: Serum from 1218 patients in the prospective ongoing pelvic mass study was collected prior to diagnosis. The HE4 and CA125 data were registered and evaluated separately and combined in ROMA and compared to RMI. RESULTS: 809 benign tumors, 79 borderline ovarian tumors, 252 OC (64 early and 188 late stage), 9 non-epithelial ovarian tumors and 69 non-ovarian cancers were evaluated. Differentiating between OC and benign disease the specificity was 62.2 (CA125), 63.2 (HE4), 76.5 (ROMA) and 81.5 (RMI) at a set sensitivity of 94.4 which corresponds to RMI=200. The areas under the curve (AUC) were 0.854 (CA125), 0.864 (HE4), 0,897 (ROMA) and 0.905 (RMI) for benign vs. early stage OC. For premenopausal benign vs. OC AUC were 0.925 (CA125), 0.905 (HE4), 0.909 (ROMA) and 0.945 (RMI). CONCLUSION: HE4 and ROMA helps differentiating OC from other pelvic masses, even in early stage OC. ROMA performs equally well as the ultrasound depending RMI and might be valuable as a first line biomarker for selecting high risk patients for referral to a tertiary center and further diagnostics. Further improvements of HE4 and ROMA in differentiating pelvic masses are still needed, especially regarding premenopausal women.