Dorthe Hartwell

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.

Treatment of postmenopausal osteoporosis: is the anabolic steroid nandrolone decanoate a candidate?

Thirty-nine postmenopausal women (aged 55–75 years) with at least one osteoporotic fracture were allocated to one year of treatment with the anabolic steroid nandrolone decanoate (50 mg i.m. every 3 weeks) or placebo injection. Both groups also received a daily intake of 500 mg calcium. Thirty-six women (92%) completed the study. In the nandrolone decanoate-treated group the fat corrected bone mineral content in the proximal part of the distal forearm (measured by single photon absorptiometry) showed a significant increase of 3% compared with placebo (P < 0.01), and the same tendency was seen in the bone mineral content of the distal part of the distal forearm and density of the lumbar spine (measured by dual photon absorptiometry). However, this did not reach significance. In the placebo group all bone mineral measurements remained unchanged. The biochemical estimates of bone formation (plasma bone Gla protein (BGP). serum alkaline phosphatase) and whole body retention (WBR) of 99mTc-diphosphonates were not statistically significantly changed by the nandrolone decanoate therapy. We conclude that treatment with nandrolone decanoate does increase the bone mineral content; however, this may not be due to a direct increase in bone formation. The mechanism may theoretically be a combination of decreased bone resorption and increased muscle mass, which both play a beneficial role in conserving bone.

Vitamin D metabolites - relation to age, menopause and endometriosis.

We investigated the influence of menopause, age and sex on vitamin D metabolism in a large group of healthy women (n=113) and men (n=108) and in a group of early postmenopausal women (n=124). Furthermore, we studied the vitamin D metabolism in 42 women with endometriosis.The vitamin D metabolites did not show dependence on age or on duration of menopause. The serum concentrations of vitamin D metabolites did not differ in normal men and women. There were highly significant seasonal oscillations for 25(OH)D and 24,25(OH)2D3 but not for 1,25(OH)2D. Women with endometriosis had significantly elevated serum 1,25(OH)2D compared to the normal women.Our study indicates that ageing is not associated with a significant depletion of 25(OH)D, 24,25(OH)2D or 1,25(OH)2D in normal men and women up to the age of 75 years. Furthermore, changes in vitamin D metabolism seem not to be an important factor in early postmenopausal bone loss. Our results on patients with endometriosis indicate that these patients may have some ...

Reproductive prognosis in endometriosis. A national cohort study

To assess the reproductive long‐term prognosis of women with and without endometriosis, to explore changes over time, and to quantify the contribution of artificial reproductive techniques.

Risk of malignancy index used as a diagnostic tool in a tertiary centre for patients with a pelvic mass

Abstract  Objective. Risk of malignancy index (RMI), based on a serum cancer antigen 125 level, ultrasound findings and menopausal status, is used to discriminate ovarian cancer from benign pelvic mass. In Denmark, patients with pelvic mass and RMI ≥200 are referred to tertiary gynecologic oncology centers according to the national guidelines for ovarian cancer treatment. The guidelines include recalculation of RMI at the tertiary center and, if indicated, positron emission tomography/computed tomography and fast‐track surgery by specialists in cancer surgery. The aim of this study was to validate the use of RMI ≥200 as a tool for preoperative identification of ovarian cancer at a tertiary center. Design. Prospective observational study. Setting. A tertiary center in Copenhagen, Denmark. Population. One thousand one hundred and fifty‐nine women with pelvic mass. Methods. The RMI was calculated after ultrasound examination and blood sampling for serum cancer antigen 125 analysis within two weeks before surgery. Main outcome measures. Sensitivity, specificity, positive and negative predictive values were calculated to evaluate the ability of RMI to distinguish between ovarian cancer and benign pelvic mass. Results. There were 778 women diagnosed with benign pelvic mass, while 251 had ovarian cancer and 74 had borderline ovarian tumor. Fifty‐six women were diagnosed with other forms of cancer. Sensitivity and specificity for ovarian cancer vs. benign pelvic mass for RMI ≥200 were 92 and 82%, respectively. Corresponding positive and negative predictive values were 62 and 97%. Conclusions. Risk of malignancy index ≥200 is a reliable tool for identifying patients with ovarian cancer pelvic masses at a tertiary centre to select patients for further preoperative examinations.

A novel proteomic biomarker panel as a diagnostic tool for patients with ovarian cancer.

BACKGROUND Previous reports have shown that the proteomic markers apolipoprotein A1, hepcidin, transferrin, inter-alpha trypsin IV internal fragment, transthyretin, connective-tissue activating protein 3 and beta-2 microglobulin may discriminate between a benign pelvic mass and ovarian cancer (OC). The aim was to determine if these serum proteomic biomarkers alone as well as in combination with age and serum CA125, could be helpful in triage of women with a pelvic mass. METHODS We included prospectively 144 patients diagnosed with (OC), 40 with a borderline tumor and 469 with a benign tumor. Surface-enhanced laser desorption/ionization time of flight-mass spectrometry was used for analyses. The Danish Index (DK-Index) based on the proteomic data, age and CA125 was developed using logistic regression models. RESULTS Multivariate logistic regression analysis demonstrated that the selected proteomic markers, CA125 and age were independent predictors of OC and the combination of these is proposed as the DK-index. A sensitivity (SN) of 99% had a specificity (SP) of 57% for DK-index and 49% for CA125. At a SN of 95%, the SP increased to 81% for DK-index compared to 68% for CA125 alone. For stage I+II the SP was 58% for DK-index and 49% for CA125. For stage III+IV the corresponding values were 94% and 86% respectively. CONCLUSIONS The DK-index warrants further evaluation in independent cohorts.

Comparisons between two receptor assays for 1, 25-dihydroxyvitamin D

We present a competitive protein binding assay (CPBA) for 1,25(OH)2D employing 1,25(OH)2D receptor from calf thymus, which was compared with a CPBA-employing receptor from rachitic chick intestine. The thymus receptor assay was more sensitive, specific and precise than the intestinal receptor assay. The thymus receptor assay measured both 1,25(OH)2D2 and 1,25(OH)2D3 with equal affinity, whereas 1,25(OH)2D2 was 1.1 times less potent than 1,25(OH)2D3 in the displacement from the chick intestinal receptor. Mean serum values of 1,25(OH)2D in normal subjects, post-menopausal women, pregnant women, and patients with chronic renal failure measured by the two assay systems did not differ. Furthermore, both assays showed that 1,25(OH)2D was unchanged in post-menopausal women after treatment with vitamin D2 or vitamin D3, 4000 IU/day for 8 weeks. We conclude that the high sensitivity of the thymus receptor and the equal affinity for the D2 and D3 analogue make the thymus receptor assay a reliable alternative to the chick intestinal receptor assay.

Endometriosis increases the risk of obstetrical and neonatal complications

The objective of this study was to assess obstetrical complications and neonatal outcomes in women with endometriosis as compared with women without endometriosis.

Comparison of vitamin D metabolism in early healthy and late osteoporotic postmenopausal women.

SummaryWe studied 20 healthy premenopausal women aged 36.5±4.0 years (mean±1 SD), 123 healthy postmenopausal women aged 50.0±2.4 years, and 103 postmenopausal women aged 65.1±5.6 years with symptomatic osteoporosis (forearm and spinal fracture). Serum levels of vitamin D metabolites [25(OH)D, 24,25(OH)2D3, and 1,25(OH)2D] were compared with (1) bone mass in the forearm (single photon absorptiometry) and in the spine (dual photon absorptiometry); (2) biochemical indices of bone formation (serum alkaline phosphatase, plasma bone Gla protien), and bone resorption (fasting urinary hydroxyproline); and (3) other biochemical estimates of calcium metabolism (serum calcium, serum phosphate, 24-hour urinary calcium, intestinal absorption of calcium). The present study revealed no difference in any of the vitamin D metabolites between the premenopausal women, the healthy postmenopausal women and the osteoporotic women as a group. The concentrations of 1,25(OH)2D and 25(OH)D were significantly lower in patients with spinal fracture than in those with forearm fracture. In the early postmenopausal women, serum 1,25(OH)2D was related to forearm bone mass (r=−0.20;P<0.05), intestinal calcium absorption (r=0.18;P<0.05), and 24-hour urinary calcium (r=0.21;P<0.05); serum 25(OH)D was related to spinal bone mass (r=0.23;P<0.01). In the osteoporotic women, serum vitamin D metabolites were not related to bone mass, but 1,25(OH)2D was related to bone Gla protein (r=0.33;P<0.001), serum phosphate (r=−0.27;P<0.01), and 24-hour urinary calcium (r=0.43;P<0.001). The present study demonstrates that in a population that is apparently not deficient in vitamin D, a disturbance of the vitamin D metabolism is not likely to play a pathogenetic role in early postmenopausal bone loss. Patients with spinal fractures have low levels of vitamin D metabolites, which may aggravate their osteoporosis.

Reproductive prognosis in daughters of women with and without endometriosis

STUDY QUESTION Do daughters of women with endometriosis exhibit an increased risk of endometriosis and impaired long-term reproductive prognosis when compared with daughters of women without endometriosis? SUMMARY ANSWER Daughters of women with endometriosis have over a 2-fold higher risk of endometriosis but no difference in long-term reproductive prognosis compared with controls. WHAT IS KNOWN ALREADY Several studies have found an increased prevalence of endometriosis in sisters and mothers of women with endometriosis, but none have examined the long-term reproductive prognosis in daughters of these patients. STUDY DESIGN, SIZE, DURATION A controlled historical cohort study with a 33-year follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS Among women 15-49 years old during the period 1977-1982, 24 691 were diagnosed with endometriosis during the study period. These women were age matched to 98 764 women without endometriosis. Daughters of these two groups were followed until 31 December 2009 for an endometriosis diagnosis and reproductive outcomes. Women were excluded from the study at death or if they emigrated. MAIN RESULTS AND THE ROLE OF CHANCE Except for 4-6% of emigrated women, the follow-up rate of the study was almost 100%. Daughters of women with endometriosis (n = 12 389) had a 2.12-fold (95% confidence interval 1.89-2.37, P < 0.0001) increased risk of being diagnosed with endometriosis, compared with daughters of women without endometriosis (n = 52 371). Delivery rate, risk of spontaneous abortions and ectopic pregnancies were similar for the two cohorts, whereas induced abortions were slightly more frequent in the exposed cohort. LIMITATIONS, REASONS FOR CAUTION The most important limitation of the study was the lack of data concerning the attempt to become pregnant. Also, some women with endometriosis might never be diagnosed with the condition. This applies to both the control mothers and the control daughters, but also the daughters of mothers with endometriosis. Other limitations are lack of accounting for potential confounders and the lack of data on preterm birth. However, the influence of most confounding factors was expected to be minimal because of the close matching by age of controls. WIDER IMPLICATIONS OF THE FINDINGS The external validity of the study is expected to be high owing to the unselected inclusion criteria. The encouraging finding was that despite the increased risk of being diagnosed with endometriosis, daughters of women with endometriosis have a reproductive prognosis comparable with that of daughters of women without endometriosis. STUDY FUNDING/COMPETING INTEREST(S) The Department of Gynaecology at Rigshospitalet University Hospital, Copenhagen, covered all expenses of the study. Ø.L. has, within the last 3 years, received honoraria for speeches in pharmacoepidemiological issues and has been expert witness in a legal US case in 2011-2012. None of the other authors have any conflicts of interest.