Validation of ADNEX and IOTA two-step strategy and estimation of risk of complications during follow-up of adnexal masses in low-risk population.

OBJECTIVES: To evaluate the ability of the Assessment of Different NEoplasias in the adneXa (ADNEX) model and the International Ovarian Tumour Analysis (IOTA) two-step strategy to predict malignancy in adnexal masses detected in an outpatient low-risk setting, and to estimate the risk of complications in masses with benign ultrasound morphology managed using clinical and ultrasound follow-up. METHODS: This single-center study was performed at Hospital Universitari Dexeus, Barcelona, Spain, using interim data from the ongoing prospective observational IOTA Phase-5 (IOTA5) study. The primary aim of the IOTA5 study is to describe the cumulative incidence of complications during follow-up of adnexal masses classified as benign on ultrasound examination. Consecutive patients with an adnexal mass detected between June 2012 and September 2016 in a private center offering screening for gynecological cancer were included and followed up until February 2020. Tumors were classified as benign or malignant based on histology (if patients underwent surgery) or the outcome of clinical and ultrasound follow-up at 12 (range, 10-14) months. Multiple imputation was used when outcomes were uncertain. The ability of the ADNEX model without CA125 and of the IOTA two-step strategy to distinguish benign from malignant masses was evaluated retrospectively using the prospectively collected data. We assessed performance with regard to discrimination (area under the receiver-operating-characteristics curve (AUC)), calibration, classification (sensitivity and specificity) and clinical utility (Net Benefit). In the group of patients with a mass judged to be benign who were selected for conservative management, we evaluated the occurrence of spontaneous resolution or any mass complication during the first 5 years of follow-up by assessing the cumulative incidence of malignancy, torsion, cyst rupture and minor mass complications (inflammation, infection or adhesions) and the time to occurrence of an event. RESULTS: A total of 2654 patients were recruited to the study. After application of exclusion criteria, 2039 patients with a newly detected mass were included for the model validation. Of those, 1684 (83%) masses were benign, 49 (2%) masses were malignant and, for 306 (15%) masses, the outcome was uncertain and therefore imputed. The AUC was 0.95 (95% CI, 0.89-0.98) for ADNEX without CA125 and 0.94 (95% CI, 0.88-0.97) for the two-step strategy. Calibration performance could not be meaningfully interpreted because the small number of malignancies resulted in very wide confidence intervals. The two-step strategy had better clinical utility than did the ADNEX model at malignancy risk thresholds < 3%. There were 1472 (72%) patients whose mass was judged to be benign based on pattern recognition by an experienced ultrasound examiner and were managed with clinical and ultrasound follow-up. In this group, the 5-year cumulative incidence was 66% (95% CI, 63-69%) for spontaneous resolution of the mass, 0% (95% CI, 0-0.2%) for torsion, 0.1% (95% CI, < 0.1-0.4%) for cyst rupture, 0.2% (95% CI, 0.1-0.6%) for a borderline tumor and 0.2% (95% CI, 0.1-0.6%) for invasive malignancy. CONCLUSIONS: The ADNEX model and IOTA two-step strategy performed well to distinguish benign from malignant adnexal masses detected in a low-risk population. Conservative management is safe for masses with a benign ultrasound appearance in this population. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Estimating risk of endometrial malignancy and other intracavitary uterine pathology in women without abnormal uterine bleeding using IETA-1 multinomial regression model: validation study.

OBJECTIVES: To assess the ability of the International Endometrial Tumor Analysis (IETA)-1 polynomial regression model to estimate the risk of endometrial cancer (EC) and other intracavitary uterine pathology in women without abnormal uterine bleeding. METHODS: This was a retrospective study, in which we validated the IETA-1 model on the IETA-3 study cohort (n = 1745). The IETA-3 study is a prospective observational multicenter study. It includes women without vaginal bleeding who underwent a standardized transvaginal ultrasound examination in one of seven ultrasound centers between January 2011 and December 2018. The ultrasonography was performed either as part of a routine gynecological examination, during follow-up of non-endometrial pathology, in the work-up before fertility treatment or before treatment for uterine prolapse or ovarian pathology. Ultrasonographic findings were described using IETA terminology and were compared with histology, or with results of clinical and ultrasound follow-up of at least 1 year if endometrial sampling was not performed. The IETA-1 model, which was created using data from patients with abnormal uterine bleeding, predicts four histological outcomes: (1) EC or endometrial intraepithelial neoplasia (EIN); (2) endometrial polyp or intracavitary myoma; (3) proliferative or secretory endometrium, endometritis, or endometrial hyperplasia without atypia; and (4) endometrial atrophy. The predictors in the model are age, body mass index and seven ultrasound variables (visibility of the endometrium, endometrial thickness, color score, cysts in the endometrium, non-uniform echogenicity of the endometrium, presence of a bright edge, presence of a single dominant vessel). We analyzed the discriminative ability of the model (area under the receiver-operating-characteristics curve (AUC); polytomous discrimination index (PDI)) and evaluated calibration of its risk estimates (observed/expected ratio). RESULTS: The median age of the women in the IETA-3 cohort was 51 (range, 20-85) years and 51% (887/1745) of the women were postmenopausal. Histology showed EC or EIN in 29 (2%) women, endometrial polyps or intracavitary myomas in 1094 (63%), proliferative or secretory endometrium, endometritis, or hyperplasia without atypia in 144 (8%) and endometrial atrophy in 265 (15%) women. The endometrial sample had insufficient material in five (0.3%) cases. In 208 (12%) women who did not undergo endometrial sampling but were followed up for at least 1 year without clinical or ultrasound signs of endometrial malignancy, the outcome was classified as benign. The IETA-1 model had an AUC of 0.81 (95% CI, 0.73-0.89, n = 1745) for discrimination between malignant (EC or EIN) and benign endometrium, and the observed/expected ratio for EC or EIN was 0.51 (95% CI, 0.32-0.82). The model was able to categorize the four histological outcomes with considerable accuracy: the PDI of the model was 0.68 (95% CI, 0.62-0.73) (n = 1532). The IETA-1 model discriminated very well between endometrial atrophy and all other intracavitary uterine conditions, with an AUC of 0.96 (95% CI, 0.95-0.98). Including only patients in whom the endometrium was measurable (n = 1689), the model's AUC was 0.83 (95% CI, 0.75-0.91), compared with 0.62 (95% CI, 0.52-0.73) when using endometrial thickness alone to predict malignancy (difference in AUC, 0.21; 95% CI, 0.08-0.32). In postmenopausal women with measurable endometrial thickness (n = 848), the IETA-1 model gave an AUC of 0.81 (95% CI, 0.71-0.91), while endometrial thickness alone gave an AUC of 0.70 (95% CI, 0.60-0.81) (difference in AUC, 0.11; 95% CI, 0.01-0.20). CONCLUSION: The IETA-1 model discriminates well between benign and malignant conditions in the uterine cavity in patients without abnormal bleeding, but it overestimates the risk of malignancy. It also discriminates well between the four histological outcome categories. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Diagnostic accuracy of ultrasound signs for detecting adnexal torsion: systematic review and meta-analysis.

OBJECTIVE: To evaluate the diagnostic accuracy of different ultrasound signs for diagnosing adnexal torsion, using surgery as the reference standard. METHODS: This was a systematic review and meta-analysis of studies published between January 1990 and November 2021 evaluating ovarian edema, adnexal mass, ovarian Doppler flow findings, the whirlpool sign and pelvic fluid as ultrasound signs (index tests) for detecting adnexal torsion, using surgical findings as the reference standard. The search for studies was performed in PubMed/MEDLINE, CINAHL, Scopus, The Cochrane Library, ClinicalTrials.gov and Web of Science databases. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to evaluate the quality of the studies. Pooled sensitivity, specificity, and positive and negative likelihood ratios were calculated separately, and the post-test probability of adnexal torsion following a positive or negative test was also determined. RESULTS: The search identified 1267 citations after excluding duplicates. Eighteen studies were ultimately included in the qualitative and quantitative syntheses. Eight studies (809 patients) analyzed the presence of ovarian edema, eight studies (1044 patients) analyzed the presence of an adnexal mass, 14 studies (1742 patients) analyzed ovarian Doppler flow, six studies (545 patients) analyzed the whirlpool sign and seven studies (981 patients) analyzed the presence of pelvic fluid as ultrasound signs of adnexal torsion. Overall, the quality of most studies was considered to be moderate or good. However, there was a high risk of bias in the patient-selection and index-text domains (with the exception of the whirlpool sign) in a significant proportion of studies. Pooled sensitivity, specificity, and positive and negative likelihood ratios of each ultrasound sign were 58%, 86%, 4.0 and 0.49 for ovarian edema, 69%, 46%, 1.3 and 0.67 for adnexal mass, 65%, 91%, 7.6 and 0.38 for the whirlpool sign, 53%, 95%, 11.0 and 0.49 for ovarian Doppler findings and 55%, 69%, 1.7 and 0.66 for pelvic fluid. Heterogeneity was high for all analyses. CONCLUSIONS: The presence of an adnexal mass or pelvic fluid have poor diagnostic accuracy as ultrasound signs of adnexal torsion, while the presence of ovarian edema, the whirlpool sign and decreased or absent ovarian Doppler flow have good specificity but moderate sensitivity for detecting adnexal torsion. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Diagnostic accuracy of transvaginal ultrasound for detection of endometriosis using International Deep Endometriosis Analysis (IDEA) approach: prospective international pilot study.

OBJECTIVE: To evaluate the diagnostic accuracy of transvaginal ultrasound (TVS) in predicting deep endometriosis (DE) following the International Deep Endometriosis Analysis (IDEA) consensus methodology. METHODS: This was an international multicenter prospective diagnostic accuracy study involving eight centers across six countries (August 2018-November 2019). Consecutive participants with endometriosis suspected based on clinical symptoms or historical diagnosis of endometriosis were included. The index test was TVS performed preoperatively in accordance with the IDEA consensus statement. At each center, the index test was interpreted by a single sonologist. Reference standards were: (1) direct visualization of endometriosis at laparoscopy, as determined by a non-blinded surgeon with expertise in endometriosis surgery; and (2) histological assessment of biopsied/excised tissue. Surgery was performed within 12 months following the index TVS. Accuracy, sensitivity, specificity, positive and negative predictive values (PPV and NPV) and positive and negative likelihood ratios (LR+ and LR-) of TVS in the diagnosis of DE were calculated. RESULTS: Included in the study were 273 participants with complete clinical, TVS, laparoscopic and histological data. Of these, based on histology, 256 (93.8%) were confirmed to have endometriosis, including superficial endometriosis, and 190 (69.6%) were confirmed to have DE. Based on surgical visualization, 207/273 (75.8%) patients had DE. For DE overall, the diagnostic performance of TVS based on surgical visualization as the reference standard was as follows: accuracy, 86.1%; sensitivity, 88.4%; specificity, 78.8%; PPV, 92.9%; NPV, 68.4%; LR+, 4.17; LR-, 0.15, and the diagnostic performance of TVS based on histology as the reference standard was as follows: accuracy, 85.9%; sensitivity, 89.8%; specificity, 75.9%; PPV, 90.4%; NPV, 74.6%; LR+, 3.72; LR-, 0.13. CONCLUSIONS: Using the IDEA consensus methodology provides strong diagnostic accuracy for TVS assessment of DE. We found a higher TVS detection rate of DE overall than that reported by the most recent meta-analysis on the topic (sensitivity, 79%), albeit with a lower specificity. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Ultrasound features of endometrial pathology in women without abnormal uterine bleeding: results from the International Endometrial Tumor Analysis study (IETA3).

OBJECTIVES: The primary aim of this study was to describe the ultrasound features of various endometrial and other intracavitary pathologies in women without abnormal uterine bleeding (AUB) using the International Endometrial Tumor Analysis (IETA) terminology. The secondary aim was to compare our findings with published data on women with AUB. METHODS: This was a prospective observational study of women presenting at one of seven centers specialized in gynecological ultrasonography, from 2011 until 2018, for indications unrelated to AUB. All patients underwent transvaginal ultrasound using the IETA examination and measurement techniques. Ultrasonography was performed as part of routine gynecological examination or follow-up of non-endometrial pathology, or as part of the work-up before undergoing treatment for infertility, uterine prolapse or ovarian pathology. Ultrasound findings were described using the IETA terminology. Endometrial sampling was performed after the ultrasound scan. The histological endpoints were endometrial atrophy, proliferative or secretory endometrium, endometrial hyperplasia without atypia, endometrial polyp, intracavitary leiomyoma, endometrial intraepithelial neoplasia (EIN), endometrial cancer (EC) and insufficient tissue. The findings in our cohort of women without AUB were compared with those in a published cohort of women with AUB who were examined with transvaginal ultrasound between 2012 and 2015 using the same IETA examination technique and terminology. RESULTS: In this study (IETA3), we included 1745 women without AUB who underwent a standardized transvaginal ultrasound examination followed by either endometrial sampling with histological diagnosis (n = 1537) or at least 1 year of clinical and ultrasound follow-up (n = 208). Of these, 858 (49.2%) women were premenopausal and 887 (50.8%) were postmenopausal. Histology showed the presence of EC and/or EIN in 29 (1.7%) women, endometrial polyps in 1028 (58.9%), intracavitary myomas in 66 (3.8%), proliferative or secretory changes or hyperplasia without atypia in 144 (8.3%), endometrial atrophy in 265 (15.2%) and insufficient tissue in five (0.3%). Most cases of EC or EIN (25/29 (86.2%)) were diagnosed after menopause. The mean endometrial thickness in women with EC or EIN was 11.2 mm (95% CI, 8.9-13.6 mm), being on average 2.4 mm (95% CI, 0.3-4.6 mm) thicker than their benign counterparts. Women with malignant endometrial pathology manifested more frequently non-uniform echogenicity (22/29 (75.9%)) than did those with benign endometrial pathology (929/1716 (54.1%)) (difference, +21.8% (95% CI, +4.2% to +39.2%)). Moderate to abundant vascularization (color score 3-4) was seen in 31.0% (9/29) of cases with EC or EIN compared with 12.8% (220/1716) of those with a benign outcome (difference, +18.2% (95% CI, -0.5% to +36.9%)). Multiple multifocal vessels were recorded in 24.1% (7/29) women with EC or EIN vs 4.0% (68/1716) of those with a benign outcome (difference, +20.2% (95% CI, +4.6% to +35.7%)). A regular endometrial-myometrial junction was seen less frequently in women with EC or EIN (19/29 (65.5%)) vs those with a benign outcome (1412/1716 (82.3%)) (difference, -16.8% (95% CI, -34.2% to +0.6%)). In women with endometrial polyps without AUB, a single dominant vessel was the most frequent vascular pattern (666/1028 (64.8%)). In women with EC, both in those with and those without AUB, the endometrium usually manifested heterogeneous echogenicity, but the endometrium was on average 8.6 mm (95% CI, 5.2-12.0 mm) thinner and less intensely vascularized (color score 3-4: difference, -26.8% (95% CI, -52.2% to -1.3%)) in women without compared to those with AUB. In both pre- and postmenopausal women, asymptomatic endometrial polyps were associated with a thinner endometrium, and they manifested more frequently a bright edge, a regular endometrial-myometrial junction and a single dominant vessel than did polyps in symptomatic women, and they were less intensely vascularized. CONCLUSIONS: We describe the typical ultrasound features of EC, polyps and other intracavitary histologies using IETA terminology in women without AUB. Our findings suggest that the presence of asymptomatic polyps or endometrial malignancy may be accompanied by thinner and less intensely vascularized endometria than their symptomatic counterparts. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Diagnostic accuracy of sliding sign for detecting pouch of Douglas obliteration and bowel involvement in women with suspected endometriosis: systematic review and meta-analysis.

OBJECTIVE: The aim of this systematic review and meta-analysis was to evaluate the diagnostic accuracy of the sliding sign on transvaginal ultrasound (TVS) in detecting pouch of Douglas obliteration and bowel involvement in patients with suspected endometriosis, using laparoscopy as the reference standard. METHODS: A search for studies evaluating the role of the sliding sign in the assessment of pouch of Douglas obliteration and/or bowel involvement using laparoscopy as the reference standard published from January 2000 to October 2021 was performed in PubMed/MEDLINE, Web of Science, CINAHL, The Cochrane Library, ClinicalTrials.gov and SCOPUS databases. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was used to evaluate the quality of the studies. Analyses were performed using MIDAS and METANDI commands in STATA. RESULTS: A total of 334 citations were identified. Eight studies were included in the analysis, resulting in 938 and 963 patients available for analysis of the diagnostic accuracy of the sliding sign for pouch of Douglas obliteration and bowel involvement, respectively. The mean prevalence of pouch of Douglas obliteration was 37% and the mean prevalence of bowel involvement was 23%. The pooled estimated sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio of the sliding sign on TVS for detecting pouch of Douglas obliteration were 88% (95% CI, 81-93%), 94% (95% CI, 91-96%), 15.3 (95% CI, 10.2-22.9), 0.12 (95% CI, 0.07-0.21) and 123 (95% CI, 62-244), respectively. The heterogeneity was moderate for sensitivity and low for specificity for detecting pouch of Douglas obliteration. The pooled estimated sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio of the sliding sign on TVS for detecting bowel involvement were 81% (95% CI, 64-91%), 95% (95% CI, 91-97%), 16.0 (95% CI, 9.0-28.6), 0.20 (95% CI, 0.10-0.40) and 81 (95% CI, 34-191), respectively. The heterogeneity for the meta-analysis of diagnostic accuracy for bowel involvement was high. CONCLUSION: The sliding sign on TVS has good diagnostic performance for predicting pouch of Douglas obliteration and bowel involvement in women with suspected endometriosis. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Evaluation of the relationship between homocysteine levels and bone mineral density in postmenopausal women.

OBJECTIVE: The current study aimed to evaluate the relationship between homocysteine (Hcy) levels and bone mineral density (BMD) in postmenopausal women. METHODS: The present, cross-sectional study included 760 postmenopausal women. The following variables were recorded: age, age at menopause, body mass index (BMI), BMD (measured by dual-energy X-ray absorptiometry [DXA] scanning and expressed as lumbar, femoral neck and total hip T-scores), smoking status, biochemical parameters (Hcy, creatinine, calcium, phosphorus, vitamin D and parathormone levels) and vitamin D supplementation. RESULTS: The mean age of the sample population was 56.4 ± 5.77 years and the mean age at menopause was 49.9 ± 3.62 years. The mean BMI was 25.2 ± 4.49 kg/m2. In the current study, a comparison of the subjects with osteoporosis, osteopenia and normal BMD revealed that the subjects in the low BMD group were significantly older (p < 0.001), had a lower age at menopause (p < 0.001) and had lower BMI (p < 0.001). There was no statistically significant difference among the groups with regard to the plasma levels of Hcy (p = 0.946). The levels of Hcy were positively correlated to the creatinine levels (r = 0.21). The present study did not observe any significant correlations between the Hcy levels and other parameters. CONCLUSIONS: In the present study, 15.3% of the subjects had hyperhomocysteinemia and 62.11% had low BMD. The current results obtained from a group of postmenopausal women suggest that the plasma levels of Hcy are not related to BMD in the lumbar spine (L1-L4), femoral neck and total hip. In the current study, age, age at menopause and low BMI were observed to be associated with low BMD.

Diagnostic accuracy of transvaginal sonography for detecting parametrial involvement in women with deep endometriosis: systematic review and meta-analysis.

OBJECTIVE: To evaluate the accuracy of transvaginal sonography (TVS) for detecting parametrial deep endometriosis, using laparoscopy as the reference standard. METHODS: A search was performed in PubMed/MEDLINE and Web of Science for studies evaluating TVS for detecting parametrial involvement in women with suspected deep endometriosis, as compared with laparoscopy, from January 2000 to December 2020. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to evaluate the quality of the studies. Pooled sensitivity, specificity and positive and negative likelihood ratios for TVS in the detection of parametrial deep endometriosis were calculated, and the post-test probability of parametrial deep endometriosis following a positive or negative test was determined. RESULTS: The search identified 134 citations. Four studies, comprising 560 patients, were included in the analysis. The mean prevalence of parametrial deep endometriosis at surgery was 18%. Overall, the pooled estimated sensitivity, specificity and positive and negative likelihood ratios of TVS in the detection of parametrial deep endometriosis were 31% (95% CI, 10-64%), 98% (95% CI, 95-99%), 18.5 (95% CI, 8.8-38.9) and 0.70 (95% CI, 0.46-1.06), respectively. The diagnostic odds ratio was 26 (95% CI, 10-68). Heterogeneity was high. Visualization of a lesion suspected to be parametrial deep endometriosis on TVS increased significantly the post-test probability of parametrial deep endometriosis. CONCLUSION: TVS has high specificity but low sensitivity for the detection of parametrial deep endometriosis. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Vessel morphology depicted by three-dimensional power Doppler ultrasound as second-stage test in adnexal tumors that are difficult to classify: prospective diagnostic accuracy study.

OBJECTIVES: To assess whether vessel morphology depicted by three-dimensional (3D) power Doppler ultrasound improves discrimination between benignity and malignancy if used as a second-stage test in adnexal masses that are difficult to classify. METHODS: This was a prospective observational international multicenter diagnostic accuracy study. Consecutive patients with an adnexal mass underwent standardized transvaginal two-dimensional (2D) grayscale and color or power Doppler and 3D power Doppler ultrasound examination by an experienced examiner, and those with a 'difficult' tumor were included in the current analysis. A difficult tumor was defined as one in which the International Ovarian Tumor Analysis (IOTA) logistic regression model-1 (LR-1) yielded an ambiguous result (risk of malignancy, 8.3% to 25.5%), or as one in which the ultrasound examiner was uncertain regarding classification as benign or malignant when using subjective assessment. Even when the ultrasound examiner was uncertain, he/she was obliged to classify the tumor as most probably benign or most probably malignant. For each difficult tumor, one researcher created a 360° rotating 3D power Doppler image of the vessel tree in the whole tumor and another of the vessel tree in a 5-cm3 spherical volume selected from the most vascularized part of the tumor. Two other researchers, blinded to the patient's history, 2D ultrasound findings and histological diagnosis, independently described the vessel tree using predetermined vessel features. Their agreed classification was used. The reference standard was the histological diagnosis of the mass. The sensitivity of each test for discriminating between benign and malignant difficult tumors was plotted against 1 - specificity on a receiver-operating-characteristics diagram, and the test with the point furthest from the reference line was considered to have the best diagnostic ability. RESULTS: Of 2403 women with an adnexal mass, 376 (16%) had a difficult mass. Ultrasound volumes were available for 138 of these cases. In 79/138 masses, the ultrasound examiner was uncertain about the diagnosis based on subjective assessment, in 87/138, IOTA LR-1 yielded an ambiguous result and, in 28/138, both methods gave an uncertain result. Of the masses, 38/138 (28%) were malignant. Among tumors that were difficult to classify as benign or malignant by subjective assessment, the vessel feature 'densely packed vessels' had the best discriminative ability (sensitivity 67% (18/27), specificity 83% (43/52)) and was slightly superior to subjective assessment (sensitivity 74% (20/27), specificity 60% (31/52)). In tumors in which IOTA LR-1 yielded an ambiguous result, subjective assessment (sensitivity 82% (14/17), specificity 79% (55/70)) was superior to the best vascular feature, i.e. changes in the diameter of vessels in the whole tumor volume (sensitivity 71% (12/17), specificity 69% (48/70)). CONCLUSION: Vessel morphology depicted by 3D power Doppler ultrasound may slightly improve discrimination between benign and malignant adnexal tumors that are difficult to classify by subjective ultrasound assessment. For tumors in which the IOTA LR-1 model yields an ambiguous result, subjective assessment is superior to vessel morphology as a second-stage test. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Typical ultrasound features of various endometrial pathologies described using International Endometrial Tumor Analysis (IETA) terminology in women with abnormal uterine bleeding.

OBJECTIVE: To describe the ultrasound features of different endometrial and other intracavitary pathologies inpre- and postmenopausal women presenting with abnormal uterine bleeding, using the International Endometrial Tumor Analysis (IETA) terminology. METHODS: This was a prospective observational multicenter study of consecutive women presenting with abnormal uterine bleeding. Unenhanced sonography with color Doppler and fluid-instillation sonography were performed. Endometrial sampling was performed according to each center's local protocol. The histological endpoints were cancer, atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (EIN), endometrial atrophy, proliferative or secretory endometrium, endometrial hyperplasia without atypia, endometrial polyp, intracavitary leiomyoma and other. For fluid-instillation sonography, the histological endpoints were endometrial polyp, intracavitary leiomyoma and cancer. For each histological endpoint, we report typical ultrasound features using the IETA terminology. RESULTS: The database consisted of 2856 consecutive women presenting with abnormal uterine bleeding. Unenhanced sonography with color Doppler was performed in all cases and fluid-instillation sonography in 1857. In 2216 women, endometrial histology was available, and these comprised the study population. Median age was 49 years (range, 19-92 years), median parity was 2 (range, 0-10) and median body mass index was 24.9 kg/m2 (range, 16.0-72.1 kg/m2 ). Of the study population, 843 (38.0%) women were postmenopausal. Endometrial polyps were diagnosed in 751 (33.9%) women, intracavitary leiomyomas in 223 (10.1%) and endometrial cancer in 137 (6.2%). None (0% (95% CI, 0.0-5.5%)) of the 66 women with endometrial thickness < 3 mm had endometrial cancer or atypical hyperplasia/EIN. Endometrial cancer or atypical hyperplasia/EIN was found in three of 283 (1.1% (95% CI, 0.4-3.1%)) endometria with a three-layer pattern, in three of 459 (0.7% (95% CI, 0.2-1.9%)) endometria with a linear endometrial midline and in five of 337 (1.5% (95% CI, 0.6-3.4%)) cases with a single vessel without branching on unenhanced ultrasound. CONCLUSIONS: The typical ultrasound features of endometrial cancer, polyps, hyperplasia and atrophy and intracavitary leiomyomas, are described using the IETA terminology. The detection of some easy-to-assess IETA features (i.e. endometrial thickness < 3 mm, three-layer pattern, linear midline and single vessel without branching) makes endometrial cancer unlikely. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Two-dimensional transvaginal sonography vs saline contrast sonohysterography for diagnosing endometrial polyps: systematic review and meta-analysis.

OBJECTIVE: To compare the diagnostic performance of two-dimensional transvaginal sonography (TVS) and saline contrast sonohysterography (SCSH) for the diagnosis of endometrial polyps in studies that used both tests in the same group of patients. METHODS: This was a systematic review and meta-analysis. An extensive search was conducted of Medline (PubMed), Cochrane Library and Web of Science, for studies comparing the diagnostic performance of TVS and SCSH for identifying endometrial polyps, published between January 1990 and December 2019, that reported a definition of endometrial polyp on TVS and SCSH and used pathologic analysis as the reference standard. Quality of the included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. A random-effects model was used to determine pooled sensitivity, specificity and positive and negative likelihood ratios of TVS and SCSH in the detection of endometrial polyps. Subanalysis according to menopausal status was performed. RESULTS: In total, 1278 citations were identified; after exclusions, 25 studies were included in the meta-analysis. In the included studies, the risk of bias evaluated using QUADAS-2 was low for most of the four domains, except for flow and timing, which had an unclear risk of bias in 13 studies. Pooled sensitivity, specificity and positive and negative likelihood ratios for TVS in the detection of endometrial polyps were 55.0% (95% CI, 46.0-64.0%), 91.0% (95% CI, 86.0-94.0%), 5.8 (95% CI, 3.9-8.7) and 0.5 (95% CI, 0.41-0.61), respectively. The corresponding values for SCSH were 92.0% (95% CI, 87.0-95.0%), 93.0% (95% CI, 91.0-95.0%), 13.9 (95% CI, 9.9-19.5) and 0.08 (95% CI, 0.05-0.14), respectively. Significant differences were found when comparing the methods in terms of sensitivity (P < 0.001), but not for specificity (P = 0.0918). Heterogeneity was high for TVS and moderate for SCSH. On subanalysis according to menopausal status, SCSH was found to have higher diagnostic accuracy in both pre- and postmenopausal women; sensitivity and specificity did not differ significantly between the groups for either TVS or SCSH. CONCLUSION: Given that SCSH has better diagnostic positive and negative likelihood ratios than does TVS in both pre- and postmenopausal women, those with clinical suspicion of endometrial polyps should undergo SCSH if TVS findings are inconclusive. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Ecografía transvaginal bidimensional vs histerosonografía con contraste salino para el diagnóstico de pólipos endometriales: revisión sistemática y metaanálisis OBJETIVO: Comparar el desempeño del diagnóstico de la ecografía transvaginal bidimensional (TVS, por sus siglas en inglés) y la histerosonografía con contraste salino (SCSH, por sus siglas en inglés) para el diagnóstico de pólipos endometriales en estudios que utilizaron ambas pruebas en el mismo grupo de pacientes. MÉTODOS: Este estudio fue una revisión sistemática y metaanálisis. El estudio realizó una extensa búsqueda en Medline (PubMed), Cochrane Library y Web of Science de estudios en los que se había comparado el desempeño del diagnóstico de la TVS y la SCSH para identificar pólipos endometriales, publicados entre enero de 1990 y diciembre de 2019, que incluyeran una definición de pólipo endometrial en la TVS y la SCSH y utilizaran el análisis patológico como estándar de referencia. La calidad de los estudios incluidos se evaluó mediante la herramienta de Evaluación de Calidad de los Estudios de Precisión en el Diagnóstico-2 (QUADAS-2, por sus siglas en inglés). Se utilizó un modelo de efectos aleatorios para determinar la sensibilidad combinada, la especificidad, los cocientes de verosimilitud positivos y negativos de la TVS y la SCSH en la detección de pólipos endometriales. Se realizó un subanálisis en función del estatus de la menopausia. RESULTADOS: Se identificaron un total de 1278 citas, de las cuales se incluyeron 25 estudios en el metaanálisis. En los estudios incluidos, el riesgo de sesgo evaluado mediante QUADAS-2 fue bajo para la mayoría de los cuatro dominios, excepto para el flujo y el tiempo, que tuvieron un riesgo de sesgo poco claro en 13 estudios. La sensibilidad combinada, la especificidad y los cocientes de verosimilitud positivos y negativos para la TVS en la detección de pólipos endometriales fueron del 55,0% (IC 95%, 46,0-64,0%), 91,0% (IC 95%, 86,0-94,0%), 5,8 (IC 95%, 3,9-8,7) y 0,5 (IC 95%, 0,41-0,61), respectivamente. Los valores correspondientes para la SCSH fueron 92,0% (IC 95%, 87,0-95,0%), 93,0% (IC 95%, 91,0-95,0%), 13,9 (IC 95%, 9,9-19,5) y 0,08 (IC 95%, 0,05-0,14), respectivamente. Se encontraron diferencias significativas al comparar los métodos respecto a la sensibilidad (P<0,001), pero no respecto a la especificidad (P=0,0918). La heterogeneidad fue alta para la TVS y moderada para la SCSH. En el subanálisis según el estado menopáusico, se determinó que la SCSH tenía una mayor precisión en el diagnóstico en las mujeres pre- y posmenopáusicas, mientras que la sensibilidad y la especificidad no difirieron significativamente entre ambos grupos, tanto para la TVS como para la SCSH. CONCLUSIÓN: Dado que la SCSH tiene mejores coeficientes de verosimilitud positivos y negativos de diagnóstico que la TVS en las mujeres pre- y posmenopáusicas, las mujeres con sospecha clínica de pólipos endometriales deberían someterse a una SCSH si los hallazgos de la TVS no son concluyentes.

Imaging in gynecological disease (17): ultrasound features of malignant ovarian yolk sac tumors (endodermal sinus tumors).

OBJECTIVE: To describe the clinical and sonographic characteristics of malignant ovarian yolk sac tumors (YSTs). METHODS: In this retrospective multicenter study, we included 21 patients with a histological diagnosis of ovarian YST and available transvaginal ultrasound images and/or videoclips and/or a detailed ultrasound report. Ten patients identified from the International Ovarian Tumor Analysis (IOTA) studies had undergone a standardized preoperative ultrasound examination, by an experienced ultrasound examiner, between 1999 and 2016. A further 11 patients were identified through medical files, for whom ultrasound images were retrieved from local image workstations and picture archiving and communication systems. All tumors were described using IOTA terminology. The collected ultrasound images and videoclips were used by two observers for additional characterization of the tumors. RESULTS: All cases were pure YSTs, except for one that was a mixed tumor (80% YST and 20% embryonal carcinoma). Median age at diagnosis was 25 (interquartile range (IQR), 19.5-30.5) years. Seventy-six percent (16/21) of women had an International Federation of Gynecology and Obstetrics (FIGO) Stage I-II tumor at diagnosis. Fifty-eight percent (11/19) of women felt pain during the ultrasound examination and one presented with ovarian torsion. Median serum α-fetoprotein (S-AFP) level was 4755 (IQR, 1071-25 303) µg/L and median serum CA 125 level was 126 (IQR, 35-227) kU/L. On ultrasound assessment, 95% (20/21) of tumors were unilateral. The median maximum tumor diameter was 157 (IQR, 107-181) mm and the largest solid component was 110 (IQR, 66-159) mm. Tumors were classified as either multilocular-solid (10/21; 48%) or solid (11/21; 52%). Papillary projections were found in 10% (2/21) of cases. Most (20/21; 95%) tumors were well vascularized (color score, 3-4) and none had acoustic shadowing. Malignancy was suspected in all cases, except in the patient with ovarian torsion, who presented a tumor with a color score of 1, which was classified as probably benign. Image and videoclip quality was considered as adequate in 18/21 cases. On review of the images and videoclips, we found that all tumors contained both solid components and cystic spaces, and that 89% (16/18) had irregular, still fine-textured and slightly hyperechoic solid tissue, giving them a characteristic appearance. CONCLUSION: Malignant ovarian YSTs are often detected at an early stage, in young women usually in the second or third decade of life, presenting with pain and markedly elevated S-AFP. On ultrasound, malignant ovarian YSTs are mostly unilateral, large and multilocular-solid or solid, with fine-textured slightly hyperechoic solid tissue and rich vascularization. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology..

Ultrasonographic soft markers for detection of rectosigmoid deep endometriosis.

OBJECTIVES: The aim of this study was to evaluate the use of ultrasound (US) soft markers as a first-line imaging tool to raise suspicion of rectosigmoid (RS) involvement in women suspected of having deep endometriosis. METHODS: We included in this prospective observational study all patients with clinical suspicion of deep endometriosis who underwent diagnostic transvaginal US evaluation at our unit from January 2016 to February 2017. Several US soft markers were evaluated for prediction of RS involvement (presence of US signs of uterine adenomyosis, presence of an endometrioma, adhesion of the ovary to the uterus (reduced ovarian mobility), presence of 'kissing ovaries' (KO) and absence of the 'sliding sign'), using as the gold standard expert US examination for the presence of RS endometriosis. RESULTS: Included were 333 patients with clinical suspicion of deep endometriosis. Of these, 106 had an US diagnosis of RS endometriosis by an expert. The only significant variables found in the prediction model were absence of the sliding sign (odds ratio (OR), 13.95; 95% CI, 7.7-25.3), presence of KO (OR, 22.5; 95% CI, 4.1-124.0) and the interaction between these two variables (OR, 0.03; 95% CI, 0.004-0.28). Regarding their interaction, RS endometriosis was present when KO was absent and the sliding sign was present in 10% (19/190) of cases, when both KO and the sliding sign were present in 71.4% (5/7) of cases, when both KO and the sliding sign were absent in 60.8% (76/125) of cases and when KO was present and the sliding sign was absent in 54.5% (6/11) of cases. Thus, when the sliding sign was absent and/or KO was present, transvaginal US showed a specificity of 75% (95% CI, 69-80%) and a sensitivity of 82% (95% CI, 73-88%). CONCLUSIONS: US findings of absence of the sliding sign and/or presence of KO in patients with clinical suspicion of endometriosis should raise suspicion of RS involvement and indicate referral for expert US examination, with a low rate of false-negative diagnosis. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Imaging in gynecological disease (15): clinical and ultrasound characteristics of uterine sarcoma.

OBJECTIVE: To describe the clinical and ultrasound characteristics of uterine sarcomas. METHODS: This was a retrospective multicenter study. From the databases of 13 ultrasound centers, we identified patients with a histological diagnosis of uterine sarcoma with available ultrasound reports and ultrasound images who had undergone preoperative ultrasound examination between 1996 and 2016. As the first step, each author collected information from the original ultrasound reports from his/her own center on predefined ultrasound features of the tumors and by reviewing the ultrasound images to identify information on variables not described in the original report. As the second step, 16 ultrasound examiners reviewed the images electronically in a consensus meeting and described them using predetermined terminology. RESULTS: We identified 116 patients with leiomyosarcoma, 48 with endometrial stromal sarcoma and 31 with undifferentiated endometrial sarcoma. Median age of the patients was 56 years (range, 26-86 years). Most patients were symptomatic at diagnosis (164/183 (89.6%)), the most frequent presenting symptom being abnormal vaginal bleeding (91/183 (49.7%)). Patients with endometrial stromal sarcoma were younger than those with leiomyosarcoma and undifferentiated endometrial sarcoma (median age, 46 years vs 57 and 60 years, respectively). According to the assessment by the original ultrasound examiners, the median diameter of the largest tumor was 91 mm (range, 7-321 mm). Visible normal myometrium was reported in 149/195 (76.4%) cases, and 80.0% (156/195) of lesions were solitary. Most sarcomas (155/195 (79.5%)) were solid masses (> 80% solid tissue), and most manifested inhomogeneous echogenicity of the solid tissue (151/195 (77.4%)); one sarcoma was multilocular without solid components. Cystic areas were described in 87/195 (44.6%) tumors and most cyst cavities had irregular walls (67/87 (77.0%)). Internal shadowing was observed in 42/192 (21.9%) sarcomas and fan-shaped shadowing in 4/192 (2.1%). Moderate or rich vascularization was found on color-Doppler examination in 127/187 (67.9%) cases. In 153/195 (78.5%) sarcomas, the original ultrasound examiner suspected malignancy. Though there were some differences, the results of the first and second steps of the analysis were broadly similar. CONCLUSIONS: Uterine sarcomas typically appear as solid masses with inhomogeneous echogenicity, sometimes with irregular cystic areas but only very occasionally with fan-shaped shadowing. Most are moderately or very well vascularized. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Learning curve for ultrasonographic diagnosis of deep infiltrating endometriosis using structured offline training program.

OBJECTIVE: To assess the learning curves of trainees during a structured offline/hands-on training program for the ultrasonographic diagnosis of deep infiltrating endometriosis (DIE). METHODS: Four trainees (all Ob/Gyn postgraduates with at least 5 years' experience in ultrasonography in obstetrics and gynecology, but with no experience of sonographic examination of DIE) participated in the study. They underwent a 2-week training program with a single trainer. Day 1 was devoted to theoretical issues and guided offline analysis of 10 three-dimensional ultrasound volumes. During the following days, four sessions of real-time sonographic examinations were performed in a DIE referral center ultrasound unit. In between these sessions, the trainees analyzed four datasets offline, each containing 25 volumes. At the end of each set, misinterpreted volumes were reassessed with the trainer. Presence or absence of DIE at surgery was considered the gold standard. The trainees' learning process was evaluated by learning-curve cumulative summation (LC-CUSUM) and the deviations of the trainees' level of performance at the control stage was assessed by CUSUM (standard CUSUM), for different locations of DIE. RESULTS: The trainees reached competence after an average of 17 (range, 14-21) evaluations for bladder, 40 (range, 30-60) for rectosigmoid, 25 (range, 14-34) for forniceal, 44 (range, 25-66) for uterosacral ligament (USL) and 21 (range, 14-43) for rectovaginal septum (RVS) locations of DIE, and then kept the process under control, with error levels of less than 4.5% until the end of the test. The overall accuracy for each trainee in diagnosis of DIE at the different locations ranged from 0.91 to 0.98 for bladder DIE, from 0.80 to 0.94 for rectosigmoid DIE, from 0.90 to 0.94 for forniceal DIE, from 0.79 to 0.82 for USL DIE and from 0.89 to 0.98 for RVS DIE. CONCLUSIONS: The suggested 2-week training program, based on a mixture of offline and live scanning sessions, is feasible and apparently provides effective training for the ultrasonographic diagnosis of DIE. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Ultrasound characteristics of endometrial cancer as defined by International Endometrial Tumor Analysis (IETA) consensus nomenclature: prospective multicenter study.

OBJECTIVE: To describe the sonographic features of endometrial cancer in relation to tumor stage, grade and histological type, using the International Endometrial Tumor Analysis (IETA) terminology. METHODS: This was a prospective multicenter study of 1714 women with biopsy-confirmed endometrial cancer undergoing standardized transvaginal grayscale and Doppler ultrasound examination according to the IETA study protocol, by experienced ultrasound examiners using high-end ultrasound equipment. Clinical and sonographic data were entered into a web-based database. We assessed how strongly sonographic characteristics, according to IETA, were associated with outcome at hysterectomy, i.e. tumor stage, grade and histological type, using univariable logistic regression and the c-statistic. RESULTS: In total, 1538 women were included in the final analysis. Median age was 65 (range, 27-98) years, median body mass index was 28.4 (range 16-67) kg/m2 , 1377 (89.5%) women were postmenopausal and 1296 (84.3%) reported abnormal vaginal bleeding. Grayscale and color Doppler features varied according to grade and stage of tumor. High-risk tumors, compared with low-risk tumors, were less likely to have regular endometrial-myometrial junction (difference of -23%; 95% CI, -27 to -18%), were larger (mean endometrial thickness; difference of +9%; 95% CI, +8 to +11%), and were more likely to have non-uniform echogenicity (difference of +7%; 95% CI, +1 to +13%), a multiple, multifocal vessel pattern (difference of +21%; 95% CI, +16 to +26%) and a moderate or high color score (difference of +22%; 95% CI, +18 to +27%). CONCLUSION: Grayscale and color Doppler sonographic features are associated with grade and stage of tumor, and differ between high- and low-risk endometrial cancer. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Transvaginal ultrasound vs magnetic resonance imaging for diagnosing deep infiltrating endometriosis: systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review of studies comparing the accuracy of transvaginal ultrasound (TVS) and magnetic resonance imaging (MRI) in diagnosing deep infiltrating endometriosis (DIE) including only studies in which patients underwent both techniques. METHODS: An extensive search was carried out in PubMed/MEDLINE and Web of Science for papers from January 1989 to October 2016 comparing TVS and MRI in DIE. Studies were considered eligible for inclusion if they reported on the use of TVS and MRI in the same set of patients for the preoperative detection of endometriosis in pelvic locations in women with clinical suspicion of DIE and using surgical data as a reference standard. Quality was assessed using the QUADAS-2 tool. A random-effects model was used to determine pooled sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-) and diagnostic odds ratio (DOR). RESULTS: Of 375 citations identified, six studies (n = 424) were considered eligible. For MRI in the detection of DIE in the rectosigmoid, pooled sensitivity was 0.85 (95% CI, 0.78-0.90), specificity was 0.95 (95% CI, 0.83-0.99), LR+ was 18.4 (95% CI, 4.7-72.4), LR- was 0.16 (95% CI, 0.11-0.24) and DOR was 116 (95% CI, 23-585). For TVS in the detection of DIE in the rectosigmoid, pooled sensitivity was 0.85 (95% CI, 0.68-0.94), specificity was 0.96 (95% CI, 0.85-0.99), LR+ was 20.4 (95% CI, 4.7-88.5), LR- was 0.16 (95% CI, 0.07-0.38) and DOR was 127 (95% CI, 14-1126). For MRI in the detection of DIE in the rectovaginal septum, pooled sensitivity was 0.66 (95% CI, 0.51-0.79), specificity was 0.97 (95% CI, 0.89-0.99), LR+ was 22.5 (95% CI, 6.7-76.2), LR- was 0.38 (95% CI, 0.23-0.52) and DOR was 65 (95% CI, 21-204). For TVS in the detection of DIE in the rectovaginal septum, pooled sensitivity was 0.59 (95% CI, 0.26-0.86), specificity was 0.97 (95% CI, 0.94-0.99), LR+ was 23.5 (95% CI, 9.1-60.5), LR- was 0.42 (95% CI, 0.18-0.97) and DOR was 56 (95% CI, 11-275). For MRI in the detection of DIE in the uterosacral ligaments, pooled sensitivity was 0.70 (95% CI, 0.55-0.82), specificity was 0.93 (95% CI, 0.87-0.97), LR+ was 10.4 (95% CI, 5.1-21.2), LR- was 0.32 (95% CI, 0.20-0.51) and DOR was 32 (95% CI, 12-85). For TVS in the detection of DIE in the uterosacral ligaments, pooled sensitivity was 0.67 (95% CI, 0.55-0.77), specificity was 0.86 (95% CI, 0.73-0.93), LR+ was 4.8 (95% CI, 2.6-9.0), LR- was 0.38 (95% CI, 0.29-0.50) and DOR was 12 (95% CI, 7-24). Confidence intervals of pooled sensitivities, specificities and DOR were wide for both techniques in all the locations considered. Heterogeneity was moderate or high for sensitivity and specificity for both TVS and MRI in most locations assessed. According to QUADAS-2, the quality of the included studies was considered good for most domains. CONCLUSION: The diagnostic performance of TVS and MRI is similar for detecting DIE involving rectosigmoid, uterosacral ligaments and rectovaginal septum. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Transdermal therapeutic systems for memantine delivery. Comparison of passive and iontophoretic transport.

Memantine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist used in the treatment of moderate to severe dementia including the symptoms of Alzheimer's disease (AD). It is administered orally but compliance, swallowing problems and the routine use of multiple medications in elderly AD patients means that an alternative route of administration would be of interest. The aim of the present study was to develop memantine hydrochloride occlusive transdermal therapeutic systems (TTS) for passive and iontophoretic delivery across the skin. Polyvinyl pyrrolidone (PVP) and a mixture with polyvinyl alcohol (PVA) were employed as polymeric matrices. The study involved the TTS characterization in addition to quantification of the memantine transport across porcine skin in vitro. The evaluation of the TTS physical properties suggested that systems were made more mechanically resistant by including PVA (6%) or high concentrations of PVP (24%). Moreover, a linear correlation was observed between the concentration of PVP and the bioadhesion of the systems. Drug delivery experiments showed that the highest transdermal flux provided by a passive TTS (PVP 24% w/w limonene) was 8.89±0.81µgcm-2h-1 whereas the highest iontophoretic transport was 46.4±3.6µgcm-2h-1. These innovative TTS would enable two dosage regimens that could lead to therapeutic plasma concentrations.