Mona Aarenstrup Karlsen

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.

HE4 Tissue Expression and Serum HE4 Levels in Healthy Individuals and Patients with Benign or Malignant Tumors: A Systematic Review

Human epididymis protein 4 (HE4) has received major attention as a potential tumor marker in epithelial ovarian cancer; however, evidence of significant overexpression of HE4 in several other human cancers is expanding. To assess the possible limitations or benefits of HE4 in a clinical setting, this review aims to systematically outline published results of HE4 tissue expression and serum HE4 levels in healthy individuals and patients with benign or malignant tumors. Our findings suggest scientific basis for a potential diagnostic ability of HE4 in gynecologic cancer and lung cancer, and further research is needed regarding other cancers. Yet, it is important to recognize that other malignancies can cause increased HE4 levels. Furthermore, attention should be paid to the influence of age and renal function on HE4 serum levels in future studies as well as in the clinic for proper interpretation of serum HE4 test results. Cancer Epidemiol Biomarkers Prev; 23(11); 2285–95. ©2014 AACR.

A novel diagnostic index combining HE4, CA125 and age may improve triage of women with suspected ovarian cancer — An international multicenter study in women with an ovarian mass

AIM To develop and validate a biomarker-based index to optimize referral and diagnosis of patients with suspected ovarian cancer. Furthermore, to compare this new index with the Risk of Malignancy Index (RMI) and Risk of Ovarian Malignancy Algorithm (ROMA). PATIENTS AND METHODS A training study, consisting of patients with benign ovarian disease (n=809) and ovarian cancer (n=246), was used to develop the Copenhagen Index (CPH-I) utilizing the variables serum HE4, serum CA125 and patient age. Eight international studies provided the validation population; comprising 1060 patients with benign ovarian masses and 550 patients with ovarian cancer. RESULTS Overall, 2665 patients were included. CPH-I was highly significant in discriminating benign from malignant ovarian disease. At the defined cut-off of 0.070 for CPH-I the sensitivity and specificity were 95.0% and 78.4% respectively in the training cohort and 82.0% and 88.4% in the validation cohort. Comparison of CPH-I, ROMA and RMI demonstrated area-under-curve (AUC) at 0.960, 0.954 and 0.959 respectively in the training study and 0.951, 0.953 and 0.935 respectively in the validation study. Using a sensitivity of 95.0%, the specificities for CPH-I, ROMA and RMI in the training cohort were 78.4%, 71.7% and 81.5% respectively, and in the validation cohort 67.3%, 70.7% and 69.5% respectively. CONCLUSION All three indices perform well at the clinically relevant sensitivity of 95%, but CPH-I, unlike RMI and ROMA, is independent of ultrasound and menopausal status, and may provide a simple index to optimize referral of women with suspected ovarian cancer.

Treatment of bacterial vaginosis in pregnancy in order to reduce the risk of spontaneous preterm delivery: a clinical recommendation

Bacterial vaginosis (BV) is characterized by a dysbiosis of the vaginal microbiota with a depletion of Lactobacillus spp. In pregnancy, prevalences between 7 and 30% have been reported depending on the study population and the definition. BV may be associated with an increased risk of spontaneous preterm delivery (sPTD). However, it is controversial whether or not BV‐positive pregnant women will benefit from treatment to reduce the risk of sPTD. We could not identify any good‐quality guideline addressing this issue. Consequently we aimed to produce this clinical recommendation based on GRADE.

Serous ovarian, fallopian tube and primary peritoneal cancers: a common disease or separate entities - a systematic review.

OBJECTIVE The aim of this systematic review is to analyze data on risk factors, epidemiology, clinicopathology and molecular biology from studies comparing primary peritoneal cancer, fallopian tube cancer and ovarian cancer of serous histology, in order to achieve a greater understanding of whether or not these disorders should be considered as separate entities. METHODS A systematic literature search was conducted in PubMed and MEDLINE. Case-control studies comparing primary serous peritoneal or fallopian tube carcinomas with primary serous ovarian carcinomas or a control group were included. RESULTS Twenty-eight studies were found eligible. Primary peritoneal cancer patients were older, had higher parity, were more often obese and had poorer survival compared to ovarian cancer patients. Differences in protein expression patterns of Her2/neu, estrogen and progestin receptors and frequency of loss of heterozygosity differed between primary peritoneal cancer and primary ovarian cancer patients. No major differences were found between primary fallopian tube cancer and primary ovarian cancer. The proportion of serous tubal intraepithelial carcinomas (STIC) was lower in primary peritoneal cancer and primary ovarian cancer compared to primary fallopian tube cancer. CONCLUSION Except from differences in the proportion of STIC only few differences between primary fallopian tube cancer and primary ovarian cancer have been found. In contrast, observed differences in risk factor profile, clinicopathologic and prognostic factors, as well as in the molecular patterns, indicate that peritoneal cancer and ovarian cancer may be linked to different carcinogenic pathways.

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.

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.

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.

Stability of HE4 and CA125 in blood samples from patients diagnosed with ovarian cancer

Abstract Objective. To investigate the influence of handling and storage on HE4 and CA125 serum and EDTA plasma levels to clarify any important consequences for a clinical setting. Methods. Blood samples from 13 ovarian cancer (OC) patients were collected and allowed to clot or sediment for up to 72 hours at 4°C or 20°C, then processed into serum and EDTA plasma. Furthermore, the effects of up to eight repetitive cycles of freeze/thaw were investigated. HE4 and CA125 were analyzed using a Chemiluminescent Microparticle Immunoassay on the Architect i2000sr System. Results. No significant effect of processing time for HE4 could be shown. HE4 EDTA plasma levels were insignificantly lower (3%) than serum levels (p = 0.41). Similarly, no significant effect of processing time for CA125 could be demonstrated. CA125 levels at 4°C were significantly reduced compared to levels at 20°C (p = 0.024). No significant difference between CA125 serum and plasma levels were found (p = 0.46). Serum and EDTA plasma samples were stable during the eight cycles of freezing and thawing (CA125: all p > 0.2; HE4: all p > 0.5). Conclusion. No systematic difference could be demonstrated for HE4. CA125 is not dependent on processing time, EDTA plasma or serum. Levels of CA125 are significantly reduced at 4°C compared to levels at 20°C, but this difference was less than 6% and is not considered clinically relevant.

Primary hyperaldosteronism diagnosed with adrenal vein sampling. Characteristics and follow-up after adrenalectomy in a Danish study

Abstract Background: Primary hyperaldosteronism (PA), known as Mb Conn, is one of the most common forms of secondary hypertension in middle-aged adults. High plasma aldosterone has been associated with severe organ damage. The unilateral aldosterone-producing adenoma (lateralized disease) is a subtype of PA, which can be fully or partly cured by adrenalectomy. Methods: Retrospective review of data from 50 patients who underwent adrenal venous sampling (AVS) was performed. Medical records, plasma renin and aldosteron, confirmatory tests and medical imaging (predominantly Computed Tomography and Magnetic Resonance Imaging) were available. Patients with lateralized disease (n = 39) underwent adrenalectomy and additional clinical data at least one year after surgery was recorded. Results: Age and gender were widely and equally distributed (median age = 51, age span = 28–73). Patients with lateralized disease had higher blood pressure (BP) and lower serum potassium compared to patients with bilateral hyperplasia. No difference regarding age and gender distribution was detected. Despite lateralized disease diagnosed from AVS, the medical images were normal in 10 patients (28%). Follow-up of 30 patients who underwent adrenalectomy showed that six patients were cured, 17 had better BP control, five patients had no effect and one patient had higher BP but decreased number of antihypertensive drugs. Conclusion: PA is of equal prevalence in men and women, young and old individuals. The agreement between imaging modalities and AVS is limited, and the final diagnosis must rely on AVS. Patients prone for surgery had better BP control after adrenalectomy.