The aim of this study was to investigate the value of serum human epididymis protein 4 (HE4) and HE4 tissue protein expression to predict tumor resistance to adjuvant chemotherapy, progression-free survival (PFS), and overall survival in patients with epithelial ovarian cancer (EOC). Consecutive inclusion of 198 patients diagnosed with EOC was conducted. Blood samples were collected prior to surgery and tissue samples during surgery. Patient data were registered prospectively in the Danish Gynecologic Cancer Database. The association between serum HE4 and HE4 tissue protein expression, resistance to adjuvant chemotherapy, PFS, and overall survival were analyzed in univariate analyses and in multivariate analyses adjusted for age, performance score, surgical outcome, stage, grade, and histological subtype. Serum HE4 levels predicted chemotherapy resistance, PFS, and overall survival correlated significantly (p < 0.001) in the univariate analyses; but after adjustment in a multivariate model, serum HE4 was insignificant, except in a subgroup analysis of postmenopausal women, where serum HE4 significantly predicted resistance to chemotherapy and progression-free survival. HE4 tissue protein expression predicted PFS (p = 0.022) and overall survival (p = 0.047) in the univariate analysis, while HE4 tissue protein expression failed to predict these outcomes in the adjusted multivariate analyses. Serum HE4 or HE4 tissue protein expression are not independent factors of chemotherapy resistance or survival in patients with EOC, but serum HE4 might predict chemotherapy resistance and PFS in postmenopausal women.
To evaluate the IOTA classification in patients with endometriosis. Patients, with cysts, were prospectively included at the Gynecologic Department, Rigshospitalet, Denmark from Jan. 2020. Cysts were described using IOTA terminology. Clinical decisions were not based on IOTA classification. We performed a retrospective application of IOTA simple rules in cases w. endometriosis. CA-125 levels were evaluated when available. N= 47 patients (median age 41 years (range 24 – 72)) w. histologically verified endometriosis were included. 3 had co-existing pathology (2 dermoids and 1 borderline ovarian tumour). 34/47 (72.3%) were examined by an IOTA certified gynecologist. Cysts were classified as: 17 unilocular, 2 unilocular solid, 16 multilocular, 7 multilocular solid, and 5 solid. B features present in 35/47 (74.6%) (20 w. 2 B-features and 2 w. 3 B-features): 17 unilocular lesions (B1), 4 w. acoustic shadowing (B3), 10 smooth multilocular lesions w. diameter < 100mm (B4), and 28 w. colour score 1 (B5). M features were present in 4/47 cases (8.5%); 1 w. ascites (M2), 2 w. ≥4 papillary structures (M3), and 1 irregular multilocular solid lesion w. diameter ≥100mm (M4). In 8/47 (17.0%) cases both B and M features were present or not applicable. According to simple rules, 35 should be classified as benign, 4 as malignant & 8 not classifiable. CA125 was ≥ 35 U/ml in 29/38 (76.3%) measured cases (median 62 U/ml (range 7–1490)). Based on routine ultrasound (US) & CA-125, clinicians classified cysts as suspected endometriosis 35/47 (74.5%), benign cyst 5/47 (10.6%) and borderline/malignant 7/47 (14.9%). CA-125 (n = 8) and/or US (n = 7) led to PET-CT scan before surgery in 15/47 (32%) despite endometriosis suspicion. 3/47 (6.4%) were operated by laparotomy because PET-CT scan did not exclude malignancy suspicion. Simple rules classified endometriosis better than routine US and CA-125. Endometriosis is a challenging diagnosis in a tertiary centre, primarily using risk of malignancy index for triage. Positive PET-CT lead to unnecessary laparotomy in 3 cases.
Presence of residual disease (RD) after interval debulking surgery (IDB) is an important negative prognostic factor for patients with advanced stage epithelial ovarian cancer (EOC). Surgery is of limited benefit when the diameter of RD is >1 cm. RD is difficult to predict before surgery. The multivariate model Cancer Ovarii Non-invasive Assessment of Treatment Strategy (CONATS) index, based on serum biomarker Human Epididymis 4 (HE4), age and WHO performance status (PS), predicted no visible RD in patients undergoing primary debulking surgery with an AUC of 0.85. The AUC of predicting RD >1 cm was not reported, although this can be of importance for pre-operative decision making especially in fragile patients. We tested this model for predicting RD >1 cm in patients undergoing IDB.
Methodology
We retrospectively included patients with advanced EOC who underwent IDB between 2010 and 2017 in two tertiary centers in the Netherlands. HE4 was measured with electrochemiluminescence in pre-operative samples. The CONATS-index was used to predict RD. Areas under the curve (AUC) were calculated to predict RD >1 cm.
Results
Two-hundred-seventy-three patients were included. Mean age was 64 years (SD 11 years). Following surgery, 232 patients (85%) had RD ≤1 cm and 41 patients (15%) had RD >1 cm. The AUC was 0.80 for predicting RD >1 cm. In patients ≥70 years of age the AUC was 0.82.
Conclusion
The CONATS-index can help to predict surgical outcome after IDB in addition to radiologic parameters and can be useful in counseling patients about the chance whether a meaningful IDB can be achieved. This could be especially helpful in counseling elderly patients in whom surgery has an increased risk of complications.
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.
Predicting borderline ovarian tumors can be challenging. Despite a favorable prognosis, these patients should not be treated as benign disease as comprehensive surgical staging is needed. In Denmark, RMI is the gold standard for predicting malignancy and referral to PET/CT. We evaluated ultrasound features in accordance to IOTA terminology and risk of malignancy using the ADNEX model.
Methodology
Patients ≥18 years with ovarian lesions were prospectively included at Dept. of Gynecology, Rigshospitalet, Denmark. Gynecologists described lesions using IOTA terminology in a template (EPIC). Clinical decisions were not based on IOTA scores.
Results
N=47 patients with histologically verified borderline ovarian tumors were included (89.4% stage I, 10.6% stage II-III). Median age was 54 years (range 21 – 82). RMI was >200 in 29 (61.7%) and <200 in 18 (38.3%). PET/CT was performed in 36 (79.6%) and concluded malignancy suspicion in 18 (FDG-uptake in 15, suspicious CT in 3). Thus, malignancy was suspected in 18 (38.3%) and benign disease in 29 (61.7%) women preoperatively. A total of 10 (21.3%) women underwent secondary staging surgery. The majority were classified multilocular solid (53.2%) or multilocular (23.4%), and less often unilocular solid (21.3%) and unilocular (2.1%). Papillary projections were present in 59.6%, and 38.3% had ≥4. The largest diameter of lesion was >100 mm in 57.4%. Cystic content was anechoic in 46.8%, low level in 32.0%, ground glass in 10.6%, and mixed in 10.6%. Color score >1 was seen in 55.3%. A total of 41/47 (87.2%) had a malignancy risk >10% using the ADNEX model. All 6/47 (10.6%) with malignancy risk <10% were uni-/multilocular lesions (<10 locules), 2 with diameter >100 mm.
Conclusion
Accurate diagnosis of borderline is essential for planning appropriate management. Ultrasound pattern recognition is a valuable clinical observation. The ADNEX model identified a malignancy risk above 10% in almost 90% of the population.
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.
PURPOSE In utero exposure to maternal cancer and cancer treatment might influence the child's short- and long-term health and development. The objective of the study was to investigate short- and long-term somatic and psychiatric outcomes in children exposed to maternal cancer in utero. METHODS This nationwide cohort study identified all liveborn children in Denmark between January 1978 and December 2018. Exposure was defined as maternal cancer diagnosis during pregnancy, and in a subgroup analysis, exposure to chemotherapy in utero. The main outcomes of interest were overall mortality, somatic diagnoses, and psychiatric diagnoses identified in the National Health Registers. Follow-up started at birth and ended at an event, death, emigration, or end of 2018. Hazard ratios of end points adjusted for potential confounders were estimated using Cox regression analysis. RESULTS Of 2,526,163 included liveborn children, 690 (0.03%) were exposed to maternal cancer in utero. Compared with unexposed fetuses, children exposed in utero had no higher overall mortality, adjusted hazard ratio 0.8 (95% CI, 0.4 to 1.5), nor increased risk of congenital malformations, overall somatic or psychiatric disease. During the period 2002-2018, of 378 (0.03%) children exposed to cancer in utero, 42 (12.5%) were exposed to chemotherapy. Among these 42 children, in utero exposure to chemotherapy was not associated with selected somatic diseases nor to congenital malformations when compared with in utero exposure to maternal cancer without chemotherapy. CONCLUSION Overall, findings did not indicate excess risk of mortality or severe morbidity among children exposed to cancer in utero. Fetal exposure to chemotherapy was not associated with adverse health outcomes in childhood.
