Assessment of protein biomarkers for preoperative differential diagnosis between benign and malignant ovarian tumors.

OBJECTIVE: To estimate the diagnostic value of tumor and immune related proteins in the discrimination between benign and malignant adnexal masses, and between different subgroups of tumors. METHODS: In this exploratory diagnostic study, 254 patients with an adnexal mass scheduled for surgery were consecutively enrolled at the University Hospitals Leuven (128 benign, 42 borderline, 22 stage I, 55 stage II-IV, and 7 secondary metastatic tumors). The quantification of 33 serum proteins was done preoperatively, using multiplex high throughput immunoassays (Luminex) and electrochemiluminescence immuno-assay (ECLIA). We calculated univariable areas under the Receiver Operating Characteristic Curves (AUCs). To discriminate malignant from benign tumors, multivariable ridge logistic regression with backward elimination was performed, using bootstrapping to validate the resulting AUCs. RESULTS: CA125 had the highest univariable AUC to discriminate malignant from benign tumors (0.85, 95% confidence interval 0.79-0.89). Combining CA125 with CA72.4 and HE4 increased the AUC to 0.87. For benign vs borderline tumors, CA125 had the highest univariable AUC (0.74). For borderline vs stage I malignancy, no proteins were promising. For stage I vs II-IV malignancy, CA125, HE4, CA72.4, CA15.3 and LAP had univariable AUCs ≥0.80. CONCLUSIONS: The results confirm the dominant role of CA125 for identifying malignancy, and suggest that other markers (HE4, CA72.4, CA15.3 and LAP) may help to distinguish between stage I and stage II-IV malignancies. However, further research is needed, also to investigate the added value over clinical and ultrasound predictors of malignancy, focusing on the differentiation between subtypes of malignancy.

Impact of predictor measurement heterogeneity across settings on the performance of prediction models: A measurement error perspective.

It is widely acknowledged that the predictive performance of clinical prediction models should be studied in patients that were not part of the data in which the model was derived. Out-of-sample performance can be hampered when predictors are measured differently at derivation and external validation. This may occur, for instance, when predictors are measured using different measurement protocols or when tests are produced by different manufacturers. Although such heterogeneity in predictor measurement between derivation and validation data is common, the impact on the out-of-sample performance is not well studied. Using analytical and simulation approaches, we examined out-of-sample performance of prediction models under various scenarios of heterogeneous predictor measurement. These scenarios were defined and clarified using an established taxonomy of measurement error models. The results of our simulations indicate that predictor measurement heterogeneity can induce miscalibration of prediction and affects discrimination and overall predictive accuracy, to extents that the prediction model may no longer be considered clinically useful. The measurement error taxonomy was found to be helpful in identifying and predicting effects of heterogeneous predictor measurements between settings of prediction model derivation and validation. Our work indicates that homogeneity of measurement strategies across settings is of paramount importance in prediction research.

Subjective assessment versus ultrasound models to diagnose ovarian cancer: A systematic review and meta-analysis.

INTRODUCTION: Many national guidelines concerning the management of ovarian cancer currently advocate the risk of malignancy index (RMI) to characterise ovarian pathology. However, other methods, such as subjective assessment, International Ovarian Tumour Analysis (IOTA) simple ultrasound-based rules (simple rules) and IOTA logistic regression model 2 (LR2) seem to be superior to the RMI. Our objective was to compare the diagnostic accuracy of subjective assessment, simple rules, LR2 and RMI for differentiating benign from malignant adnexal masses prior to surgery. MATERIALS AND METHODS: MEDLINE, EMBASE and CENTRAL were searched (January 1990-August 2015). Eligibility criteria were prospective diagnostic studies designed to preoperatively predict ovarian cancer in women with an adnexal mass. RESULTS: We analysed 47 articles, enrolling 19,674 adnexal tumours; 13,953 (70.9%) benign and 5721 (29.1%) malignant. Subjective assessment by experts performed best with a pooled sensitivity of 0.93 (95% confidence interval [CI] 0.92-0.95) and specificity of 0.89 (95% CI 0.86-0.92). Simple rules (classifying inconclusives as malignant) (sensitivity 0.93 [95% CI 0.91-0.95] and specificity 0.80 [95% CI 0.77-0.82]) and LR2 (sensitivity 0.93 [95% CI 0.89-0.95] and specificity 0.84 [95% CI 0.78-0.89]) outperformed RMI (sensitivity 0.75 [95% CI 0.72-0.79], specificity 0.92 [95% CI 0.88-0.94]). A two-step strategy using simple rules, when inconclusive added by subjective assessment, matched test performance of subjective assessment by expert examiners (sensitivity 0.91 [95% CI 0.89-0.93] and specificity 0.91 [95% CI 0.87-0.94]). CONCLUSIONS: A two-step strategy of simple rules with subjective assessment for inconclusive tumours yielded best results and matched test performance of expert ultrasound examiners. The LR2 model can be used as an alternative if an expert is not available.

Subjective ultrasound assessment, the ADNEX model and ultrasound-guided tru-cut biopsy to differentiate disseminated primary ovarian cancer from metastatic non-ovarian cancer.

OBJECTIVES: To compare subjective ultrasound assessment and the ADNEX model with ultrasound-guided tru-cut biopsy to differentiate disseminated primary ovarian cancer from metastatic non-ovarian cancer. METHODS: This was a prospective study including 143 consecutive women with disseminated malignancy of unknown primary origin, with a pelvic tumor/carcinosis. Women underwent either transvaginal or transrectal ultrasound as well as transabdominal ultrasound examination followed by tru-cut biopsy. The ultrasound examiner assessed tumor morphology, spread in the pelvis and abdomen, and predicted tumor origin as primary ovarian or metastatic using both subjective assessment and the ADNEX model. Histology from tru-cut biopsy served as the gold standard for assessment of diagnostic accuracy. Biopsy adequacy and the complication rate were assessed. RESULTS: Tru-cut biopsy was performed transvaginally in 131/143 (92%) women. Two women needed inpatient care (one had abdominal wall hematoma, and one infection). Biopsy resulted in a conclusive diagnosis in 126/143 (88%) women, amongst whom cytoreductive surgery was performed in 30/126 confirming the diagnosis in all cases. Non-ovarian metastatic cancer was found in 37/126 (29%) women and primary ovarian cancer in 89/126 (71%) women. Subjective ultrasound evaluation had a sensitivity of 82% (73/89) and a specificity of 70% (26/37) in predicting primary ovarian cancer. The ADNEX model had an area under the receiver-operating characteristics curve of 0.891 (95% CI, 0.794-0.946) (in women with an ovarian lesion, n = 104). Tumor origin was associated with age, CA 125, previous neoplasia, presence of omental cake and tumor mobility. CONCLUSIONS: Subjective ultrasound assessment and the ADNEX model can both be used to predict whether a pelvic tumor is metastatic and of non-ovarian origin, indicating the need for tru-cut biopsy, which is associated with very few complications and will provide a conclusive diagnosis in nine out of 10 women. Copyright © 2015 ISUOG.

Multicentre external validation of IOTA prediction models and RMI by operators with varied training.

BACKGROUND: Correct characterisation of ovarian tumours is critical to optimise patient care. The purpose of this study is to evaluate the diagnostic performance of the International Ovarian Tumour Analysis (IOTA) logistic regression model (LR2), ultrasound Simple Rules (SR), the Risk of Malignancy Index (RMI) and subjective assessment (SA) for preoperative characterisation of adnexal masses, when ultrasonography is performed by examiners with different background training and experience. METHODS: A 2-year prospective multicentre cross-sectional study. Thirty-five level II ultrasound examiners contributed in three UK hospitals. Transvaginal ultrasonography was performed using a standardised approach. The final outcome was the surgical findings and histological diagnosis. To characterise the adnexal masses, the six-variable prediction model (LR2) with a cutoff of 0.1, the RMI with cutoff of 200, ten SR (five rules for malignancy and five rules for benignity) and SA were applied. The area under the curves (AUCs) for performance of LR2 and RMI were calculated. Diagnostic performance measures for all models assessed were sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-), and the diagnostic odds ratio (DOR). RESULTS: Nine-hundred and sixty-two women with adnexal masses underwent transvaginal ultrasonography, whereas 255 had surgery. Prevalence of malignancy was 29% (49 primary invasive epithelial ovarian cancers, 18 borderline ovarian tumours, and 7 metastatic tumours). The AUCs for LR2 and RMI for all masses were 0.94 (95% confidence interval (CI): 0.89-0.97) and 0.90 (95% CI: 0.83-0.94), respectively. In premenopausal women, LR2-RMI difference was 0.09 (95% CI: 0.03-0.15) compared with -0.02 (95% CI: -0.08 to 0.04) in postmenopausal women. For all masses, the DORs for LR2, RMI, SR+SA (using SA when SR inapplicable), SR+MA (assuming malignancy when SR inapplicable), and SA were 62 (95% CI: 27-142), 43 (95% CI: 19-97), 109 (95% CI: 44-274), 66 (95% CI: 27-158), and 70 (95% CI: 30-163), respectively. CONCLUSION: Overall, the test performance of IOTA prediction models and rules as well as the RMI was maintained in examiners with varying levels of training and experience.

Does the presence of a Caesarean section scar affect implantation site and early pregnancy outcome in women attending an early pregnancy assessment unit?

STUDY QUESTION: Are there any differences in the location and distance to the internal cervical ostium of the implantation site of the intrauterine gestation sacs, early pregnancy symptoms and pregnancy outcome at 12 weeks gestation between women with and without a previous Caesarean section (CS)? SUMMARY ANSWER: The presence of a CS scar affects the site of implantation, and the distance between implantation site and the scar is related to the risk of spontaneous abortion. WHAT IS KNOWN ALREADY?: Little is known about the impact of a CS scar on implantation other than the risk of Caesarean scar pregnancy (CSP). Furthermore, there is a paucity of information on how the proximity of implantation to the scar impacts on pregnancy outcome in the first trimester. STUDY DESIGN, SIZE, AND DURATION: A prospective cohort study conducted over 15 months in the early pregnancy unit of a London Teaching Hospital. Three hundred and eighty women underwent a transvaginal scan at 6-11 weeks of gestation. A total of 170 women had undergone ≥1 CS, and 210 women had no history of CS. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 380 women were recruited as consecutive non-selected cases. The relationship between the implanted sac and the CS scar was assessed by quantifiable measures and by subjective impression. Logistic regression analysis was used to determine the influence of the presence of a CS scar on pregnancy outcome. The final outcome of the study was the viability of the pregnancy at 12 weeks. MAIN RESULTS AND THE ROLE OF CHANCE: Implantation was most frequently posterior (53%) in the CS group and fundal in the non-CS group (42%). Gestation sac implantation was 8.7 mm lower in the CS group (95% confidence interval (CI) 6.7-10.7, P < 0.0001). Presenting complaints differed in women with and without a previous CS (P = 0.0009). More frequent vaginal bleeding [73 versus 55%, difference -18, 95% CI (-27 to -8%] yet no clearly increased spontaneous abortion rates were noted in the CS group compared with the non-CS group (adjusted odds ratio = 1.1, 95% CI 0.6-1.9, P = 0.74). Subjective impression showed that in eight cases the implantation site crossed the scar, seven of which resulted in spontaneous abortion, while the remaining case survived to term complicated by placenta praevia and post-partum haemorrhage. The subjective impression of the examiner was supported by the measurements of distance between implantation site and CS scar. LIMITATIONS, REASONS FOR CAUTION: A weakness of the study is the lack of a reference technique to verify the location of implantation. WIDER IMPLICATIONS OF THE FINDINGS: This study adds further support to the hypothesis that the presence of a CS on the uterus impacts on the implantation site of a future pregnancy. The possibility that the CS scar has an impact on the risk of spontaneous abortion should be further studied. Caution must be exercised when implantation occurs near to, and crosses, a CS scar as this is not always associated with the diagnosis of CSP. A potential limitation of the study is that we did not examine scar dimensions and morphology.

Pre-sampling ultrasound evaluation and assessment of the tissue yield during sampling improves the diagnostic reliability of office endometrial biopsy.

We evaluated the implementation of a strict procedure for endometrium biopsy, including pre-sampling ultrasound examination and assessment of the tissue yield during sampling, in 257 consecutive women with abnormal bleeding. The tissue yield was assessed during sampling and scored from 1 to 4. The median endometrial thickness as measured by ultrasound was 5.0 mm, 5.1 mm, 10.0 mm and 18.7 mm for a tissue yield score of 1, 2, 3 and 4, respectively. The median endometrial thickness at ultrasound and the median tissue yield score was 18.3 mm and score 4 in the endometrial cancer cases, compared with 3.9 mm and score 1, and 14.8 mm and score 3 in the case of endometrial atrophy and hyperplasia, respectively; and 11.5 mm and score 2 in endometrial polyp cases. Overall, 12 cancers were diagnosed. No endometrial cancer was diagnosed during follow-up (median 447 days). A strict office endometrial biopsy procedure contributes to the diagnostic reliability for intracavitary pathology.