Comparison of the ADNEX and ROMA risk prediction models for the diagnosis of ovarian cancer: a multicentre external validation in patients who underwent surgery.

BACKGROUND: Several diagnostic prediction models to help clinicians discriminate between benign and malignant adnexal masses are available. This study is a head-to-head comparison of the performance of the Assessment of Different NEoplasias in the adneXa (ADNEX) model with that of the Risk of Ovarian Malignancy Algorithm (ROMA). METHODS: This is a retrospective study based on prospectively included consecutive women with an adnexal tumour scheduled for surgery at five oncology centres and one non-oncology centre in four countries between 2015 and 2019. The reference standard was histology. Model performance for ADNEX and ROMA was evaluated regarding discrimination, calibration, and clinical utility. RESULTS: The primary analysis included 894 patients, of whom 434 (49%) had a malignant tumour. The area under the receiver operating characteristic curve (AUC) was 0.92 (95% CI 0.88-0.95) for ADNEX with CA125, 0.90 (0.84-0.94) for ADNEX without CA125, and 0.85 (0.80-0.89) for ROMA. ROMA, and to a lesser extent ADNEX, underestimated the risk of malignancy. Clinical utility was highest for ADNEX. ROMA had no clinical utility at decision thresholds <27%. CONCLUSIONS: ADNEX had better ability to discriminate between benign and malignant adnexal tumours and higher clinical utility than ROMA. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT01698632 and NCT02847832.

Patient satisfaction with ultrasound, whole-body CT and whole-body diffusion-weighted MRI for pre-operative ovarian cancer staging: a multicenter prospective cross-sectional survey.

BACKGROUND: In addition to the diagnostic accuracy of imaging methods, patient-reported satisfaction with imaging methods is important. OBJECTIVE: To report a secondary outcome of the prospective international multicenter Imaging Study in Advanced ovArian Cancer (ISAAC Study), detailing patients' experience with abdomino-pelvic ultrasound, whole-body contrast-enhanced computed tomography (CT), and whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) for pre-operative ovarian cancer work-up. METHODS: In total, 144 patients with suspected ovarian cancer at four institutions in two countries (Italy, Czech Republic) underwent ultrasound, CT, and WB-DWI/MRI for pre-operative work-up between January 2020 and November 2022. After having undergone all three examinations, the patients filled in a questionnaire evaluating their overall experience and experience in five domains: preparation before the examination, duration of examination, noise during the procedure, radiation load of CT, and surrounding space. Pain perception, examination-related patient-perceived unexpected, unpleasant, or dangerous events ('adverse events'), and preferred method were also noted. RESULTS: Ultrasound was the preferred method by 49% (70/144) of responders, followed by CT (38%, 55/144), and WB-DWI/MRI (13%, 19/144) (p<0.001). The poorest experience in all domains was reported for WB-DWI/MRI, which was also associated with the largest number of patients who reported adverse events (eg, dyspnea). Patients reported higher levels of pain during the ultrasound examination than during CT and WB-DWI/MRI (p<0.001): 78% (112/144) reported no pain or mild pain, 19% (27/144) moderate pain, and 3% (5/144) reported severe pain (pain score >7 of 10) during the ultrasound examination. We did not identify any factors related to patients' preferred method. CONCLUSION: Ultrasound was the imaging method preferred by most patients despite being associated with more pain during the examination in comparison with CT and WB-DWI/MRI. TRIAL REGISTRATION NUMBER: NCT03808792.

Multiclass risk models for ovarian malignancy: an illustration of prediction uncertainty due to the choice of algorithm.

BACKGROUND: Assessing malignancy risk is important to choose appropriate management of ovarian tumors. We compared six algorithms to estimate the probabilities that an ovarian tumor is benign, borderline malignant, stage I primary invasive, stage II-IV primary invasive, or secondary metastatic. METHODS: This retrospective cohort study used 5909 patients recruited from 1999 to 2012 for model development, and 3199 patients recruited from 2012 to 2015 for model validation. Patients were recruited at oncology referral or general centers and underwent an ultrasound examination and surgery ≤ 120 days later. We developed models using standard multinomial logistic regression (MLR), Ridge MLR, random forest (RF), XGBoost, neural networks (NN), and support vector machines (SVM). We used nine clinical and ultrasound predictors but developed models with or without CA125. RESULTS: Most tumors were benign (3980 in development and 1688 in validation data), secondary metastatic tumors were least common (246 and 172). The c-statistic (AUROC) to discriminate benign from any type of malignant tumor ranged from 0.89 to 0.92 for models with CA125, from 0.89 to 0.91 for models without. The multiclass c-statistic ranged from 0.41 (SVM) to 0.55 (XGBoost) for models with CA125, and from 0.42 (SVM) to 0.51 (standard MLR) for models without. Multiclass calibration was best for RF and XGBoost. Estimated probabilities for a benign tumor in the same patient often differed by more than 0.2 (20% points) depending on the model. Net Benefit for diagnosing malignancy was similar for algorithms at the commonly used 10% risk threshold, but was slightly higher for RF at higher thresholds. Comparing models, between 3% (XGBoost vs. NN, with CA125) and 30% (NN vs. SVM, without CA125) of patients fell on opposite sides of the 10% threshold. CONCLUSION: Although several models had similarly good performance, individual probability estimates varied substantially.

The Risk of Endometrial Malignancy and Other Endometrial Pathology in Women with Abnormal Uterine Bleeding: An Ultrasound-Based Model Development Study by the IETA Group.

OBJECTIVES: The aim of this study was to develop a model that can discriminate between different etiologies of abnormal uterine bleeding. DESIGN: The International Endometrial Tumor Analysis 1 study is a multicenter observational diagnostic study in 18 bleeding clinics in 9 countries. Consecutive women with abnormal vaginal bleeding presenting for ultrasound examination (n = 2,417) were recruited. The histology was obtained from endometrial sampling, D&C, hysteroscopic resection, hysterectomy, or ultrasound follow-up for >1 year. METHODS: A model was developed using multinomial regression based on age, body mass index, and ultrasound predictors to distinguish between: (1) endometrial atrophy, (2) endometrial polyp or intracavitary myoma, (3) endometrial malignancy or atypical hyperplasia, (4) proliferative/secretory changes, endometritis, or hyperplasia without atypia and validated using leave-center-out cross-validation and bootstrapping. The main outcomes are the model's ability to discriminate between the four outcomes and the calibration of risk estimates. RESULTS: The median age in 2,417 women was 50 (interquartile range 43-57). 414 (17%) women had endometrial atrophy; 996 (41%) had a polyp or myoma; 155 (6%) had an endometrial malignancy or atypical hyperplasia; and 852 (35%) had proliferative/secretory changes, endometritis, or hyperplasia without atypia. The model distinguished well between malignant and benign histology (c-statistic 0.88 95% CI: 0.85-0.91) and between all benign histologies. The probabilities for each of the four outcomes were over- or underestimated depending on the centers. LIMITATIONS: Not all patients had a diagnosis based on histology. The model over- or underestimated the risk for certain outcomes in some centers, indicating local recalibration is advisable. CONCLUSIONS: The proposed model reliably distinguishes between four histological outcomes. This is the first model to discriminate between several outcomes and is the only model applicable when menopausal status is uncertain. The model could be useful for patient management and counseling, and aid in the interpretation of ultrasound findings. Future research is needed to externally validate and locally recalibrate the model.

Effect of second-trimester sonographic cervical length on the risk of spontaneous preterm delivery in different risk groups: A prospective observational multicenter study.

INTRODUCTION: The aim of the study is to compare the effect of cervical length measured with transvaginal ultrasound in the second trimester on the risk of spontaneous preterm delivery (PTD) between different risk groups of asymptomatic women with a singleton pregnancy. MATERIAL AND METHODS: This is a pre-planned exploratory analysis of the CERVIX study, a prospective blinded multicenter diagnostic accuracy study. Asymptomatic women with a singleton pregnancy were consecutively recruited at their second-trimester routine ultrasound examination at seven Swedish ultrasound centers. Cervical length was measured with transvaginal ultrasound at 18-20 weeks (Cx1; n = 11 072) and 21-23 weeks (Cx2, optional; n = 6288). The effect of cervical length on the risk of spontaneous PTD and its discriminative ability was compared between women with: (i) previous spontaneous PTD, late miscarriage or cervical conization (high-risk group; n = 1045); (ii) nulliparae without risk factors (n = 5173); (iii) parae without risk factors (n = 4740). Women with previous indicated PTD were excluded (n = 114). Main outcome measures were: effect of cervical length on the risk of spontaneous PTD expressed as odds ratio per 5-mm decrease in cervical length with interaction analysis using logistic regression to test whether the effect differed between groups, area under the receiver operating characteristic curve (AUC), sensitivity, specificity, number needed to screen to detect one spontaneous PTD. RESULTS: The effect of cervical length at Cx2 on the risk of spontaneous PTD <33 weeks was similar in all groups (odds ratios 2.26-2.58, interaction p value 0.91). The discriminative ability at Cx2 was superior to that at Cx1 and was similar in all groups (AUC 0.69-0.76). Cervical length ≤25 mm at Cx2 identified 57% of spontaneous preterm deliveries <33 weeks in the high-risk group with number needed to screen 161. The number needed to screen for groups (ii) and (iii) were 1018 and 843. CONCLUSIONS: The effect of cervical length at 21-23 weeks on the risk of spontaneous PTD <33 weeks is similar in high- and low-risk pregnancies. The differences in number needed to screen should be considered before implementing a screening program.

Second trimester cervical length measurements with transvaginal ultrasound: A prospective observational agreement and reliability study.

INTRODUCTION: Universal screening for preterm delivery by adding transvaginal ultrasound measurement of cervical length to routine second trimester ultrasound has been proposed. The aim is to estimate inter- and intraobserver agreement and reliability of second trimester transvaginal ultrasound measurements of cervical length performed by specially trained midwife sonographers. MATERIAL AND METHODS: This is a prospective reliability and agreement study performed in seven Swedish ultrasound centers. In total, 18 midwife sonographers specially trained to perform ultrasound measurements of cervical length and 286 women in the second trimester were included. In each center, two midwife sonographers measured cervical length a few minutes apart in the same woman, the number of women examined per examiner pair varying between 24 and 30 (LIVE study). Sixteen midwife sonographers measured cervical length twice ≥2 months apart on 93 video clips (CLIPS study). The main outcome measures were mean difference, limits of agreement, intraclass correlation coefficient, intra-individual standard deviation, repeatability, Cohen's kappa and Fleiss kappa. RESULTS: The limits of agreement and intraclass correlation coefficient of the best examiner pair in the LIVE study were -4.06 to 4.72 mm and 0.91, and those of the poorest were -11.11 to 11.39 mm and 0.31. In the CLIPS study, median (range) intra-individual standard deviation was 2.14 mm (1.40-3.46), repeatability 5.93 mm (3.88-9.58), intraclass correlation coefficient 0.84 (0.66-0.94). Median (range) interobserver agreement for cervical length ≤25 mm in the CLIPS study was 94.6% (84.9%-98.9%) and Cohen's kappa 0.56 (0.12-0.92), median (range) intraobserver agreement was 95.2% (87.1%-98.9%) and Cohen's kappa 0.68 (0.27-0.93). CONCLUSIONS: Agreement and reliability of cervical length measurements differed substantially between examiner pairs and examiners. If cervical length measurements are used to guide management there is potential for both over- and under-treatment. Uniform training and rigorous supervision and quality control are advised.

Predictors of complete miscarriage after expectant management or misoprostol treatment of non-viable early pregnancy in women with vaginal bleeding.

PURPOSE: To identify predictors of complete miscarriage after expectant management or misoprostol treatment of non-viable early pregnancy in women with vaginal bleeding. METHODS: This was a planned secondary analysis of data from a published randomized controlled trial comparing expectant management with vaginal single dose of 800 µg misoprostol treatment of women with embryonic or anembryonic miscarriage. Predefined variables-serum-progesterone, serum-ß-human chorionic gonadotropin, parity, previous vaginal deliveries, gestational age, clinical symptoms (bleeding and pain), mean diameter and shape of the gestational sac, crown-rump-length, type of miscarriage, and presence of blood flow in the intervillous space-were tested as predictors of treatment success (no gestational sac in the uterine cavity and maximum anterior-posterior intracavitary diameter was ≤ 15 mm as measured with transvaginal ultrasound on a sagittal view) in univariable and multivariable logistic regression. RESULTS: Variables from 174 women (83 expectant management versus 91 misoprostol) were analyzed for prediction of complete miscarriage at ≤ 17 days. In patients managed expectantly, the rate of complete miscarriage was 62.7% (32/51) in embryonic miscarriages versus 37.5% (12/32) in anembryonic miscarriages (P = 0.02). In multivariable logistic regression, the likelihood of success increased with increasing gestational age, increasing crown-rump-length and decreasing gestational sac diameter. Misoprostol treatment was successful in 80.0% (73/91). No variable predicted success of misoprostol treatment. CONCLUSIONS: Complete miscarriage after expectant management is significantly more likely in embryonic miscarriage than in anembryonic miscarriage. Gestational age, crown-rump-length, and gestational sac diameter are independent predictors of success of expectant management. Predictors of treatment success may help counselling women with early miscarriage.

Risk of complications in patients with conservatively managed ovarian tumours (IOTA5): a 2-year interim analysis of a multicentre, prospective, cohort study.

BACKGROUND: Ovarian tumours are usually surgically removed because of the presumed risk of complications. Few large prospective studies on long-term follow-up of adnexal masses exist. We aimed to estimate the cumulative incidence of cyst complications and malignancy during the first 2 years of follow-up after adnexal masses have been classified as benign by use of ultrasonography. METHODS: In the international, prospective, cohort International Ovarian Tumor Analysis Phase 5 (IOTA5) study, patients aged 18 years or older with at least one adnexal mass who had been selected for surgery or conservative management after ultrasound assessment were recruited consecutively from 36 cancer and non-cancer centres in 14 countries. Follow-up of patients managed conservatively is ongoing at present. In this 2-year interim analysis, we analysed patients who were selected for conservative management of an adnexal mass judged to be benign on ultrasound on the basis of subjective assessment of ultrasound images. Conservative management included ultrasound and clinical follow-up at intervals of 3 months and 6 months, and then every 12 months thereafter. The main outcomes of this 2-year interim analysis were cumulative incidence of spontaneous resolution of the mass, torsion or cyst rupture, or borderline or invasive malignancy confirmed surgically in patients with a newly diagnosed adnexal mass. IOTA5 is registered with ClinicalTrials.gov, number NCT01698632, and the central Ethics Committee and the Belgian Federal Agency for Medicines and Health Products, number S51375/B32220095331, and is ongoing. FINDINGS: Between Jan 1, 2012, and March 1, 2015, 8519 patients were recruited to IOTA5. 3144 (37%) patients selected for conservative management were eligible for inclusion in our analysis, of whom 221 (7%) had no follow-up data and 336 (11%) were operated on before a planned follow-up scan was done. Of 2587 (82%) patients with follow-up data, 668 (26%) had a mass that was already in follow-up at recruitment, and 1919 (74%) presented with a new mass at recruitment (ie, not already in follow-up in the centre before recruitment). Median follow-up of patients with new masses was 27 months (IQR 14-38). The cumulative incidence of spontaneous resolution within 2 years of follow-up among those with a new mass at recruitment (n=1919) was 20·2% (95% CI 18·4-22·1), and of finding invasive malignancy at surgery was 0·4% (95% CI 0·1-0·6), 0·3% (<0·1-0·5) for a borderline tumour, 0·4% (0·1-0·7) for torsion, and 0·2% (<0·1-0·4) for cyst rupture. INTERPRETATION: Our results suggest that the risk of malignancy and acute complications is low if adnexal masses with benign ultrasound morphology are managed conservatively, which could be of value when counselling patients, and supports conservative management of adnexal masses classified as benign by use of ultrasound. FUNDING: Research Foundation Flanders, KU Leuven, Swedish Research Council.

GestaTIonal TrophoblAstic NeoplasIa Ultrasound assessMent: TITANIUM study.

BACKGROUND: There are limited data on ultrasound morphologic features of gestational trophoblastic neoplasia. A predictive model to determine predictors of response to therapy would be ideal in the management of patients with this rare disease. PRIMARY OBJECTIVES AND STUDY HYPOTHESIS: TITANIUM is a prospective, multicenter, observational study aiming to describe ultrasound features of gestational trophoblastic neoplasia and to investigate the role of ultrasound in identifying patients at high risk of resistance to single-drug therapy. The study hypothesis is that ultrasound could improve the International Federation of Gynecology and Obstetrics (FIGO) scoring system for early identification of patients predisposed to single-drug resistance. TRIAL DESIGN AND MAJOR INCLUSION/EXCLUSION CRITERIA: Patients eligible have a diagnosis of gestational trophoblastic neoplasia according to FIGO or the criteria set by Charing Cross Hospital, London, UK. At diagnosis, patients are classified as low-risk (score 0-6) or high-risk (score >6) according to the FIGO risk scoring system, and a baseline ultrasound scan is performed. Patients receive treatment according to local protocol at each institution. Follow-up ultrasound examinations are performed at 1, 4, 10, 16, and 22 months after start of chemotherapy, and at each scan, serum human chorionic gonadotropin (hCG) level, and chemotherapy treatment, if any, are recorded. PRIMARY ENDPOINTS: Our aims are to define ultrasound features of gestational trophoblastic neoplasia and to develop a predictive model of resistance to single-drug therapy in low-risk patients. SAMPLE SIZE: The sample size was calculated assuming that 70% of patients with gestational trophoblastic neoplasia are at low risk, and estimating the rate of resistance to single-drug therapy in this group to be 40%. Assuming a dropout rate of 10%, we should recruit at least 120 patients. With this sample size, we can attempt to create a mathematical model with three variables (either two ultrasound parameters in addition to the risk score or three ultrasound variables statistically significant at univariate analysis) to predict resistance to single-drug therapy in low-risk patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The accrual started in February 2019. Additional referral centers for gestational trophoblastic disease, with similar ultrasound expertise, are welcome to participate in the study. Enrollment should be completed by December 2021, and analysis will be conducted in December 2023. TRIAL REGISTRATION: The study received the Ethical Committee approval of the Coordinator Center (Rome) in January 2019 (Protocol No. 0004668/19).

Endometrial cancer off-line staging using two-dimensional transvaginal ultrasound and three-dimensional volume contrast imaging: Intermethod agreement, interrater reliability and diagnostic accuracy.

OBJECTIVES: The aim is to estimate agreement between two-dimensional transvaginal ultrasound (2D-TVS) and three-dimensional volume contrast imaging (3D-VCI) in diagnosing deep myometrial invasion (MI) and cervical stromal involvement (CSI) of endometrial cancer and to compare the two methods regarding inter-rater reliability and diagnostic accuracy. METHODS: Fifteen ultrasound experts assessed off-line de-identified 3D-VCI volumes and 2D-TVU video clips from 58 patients with biopsy-confirmed endometrial cancer regarding the presence of deep (≥50%) MI and CSI. Video clips and 3D volumes were assessed independently. Interrater reliability was measured using kappa statistics. Histological diagnosis after hysterectomy served as gold standard. Accuracy measurements were correlated to rater experience using Spearman's rank correlation coefficient (ρ). RESULTS: Agreement between 2D-TVU and 3D-VCI for diagnosing MI was median 76% (range 64-93%) and for CSI median 88% (range 79-97%). Interrater reliability was better for 2D-TVU than for 3D-VCI (Fleiss' kappa 0.41 vs. 0.31 for MI and 0.55 vs. 0.45 for CSI). Median accuracy for diagnosing deep MI was 76% (range 59-84%) with 2D-TVU and 69% (range 52-83%) for 3D-VCI; the corresponding figures for CSI were 88% (range 81-93%) and 86% (range 72-95%). Accuracy was significantly correlated to how many cases the raters assessed annually. CONCLUSIONS: Off-line assessment of MI and CSI in women with endometrial cancer using 3D-VCI has lower interrater reliability and lower accuracy than 2D-TVU video clip assessment. Since accuracy was correlated to the number of cases assessed annually it is advised to centralize these examinations to high-volume centres.

Age-related differences in the sonographic characteristics of endometriomas.

STUDY QUESTION: Do sonographic characteristics of ovarian endometriomas vary with age in premenopausal women? SUMMARY ANSWER: With increasing age, multilocular cysts and cysts with papillations and other solid components become more common whereas ground glass echogenicity of cyst fluid becomes less common. WHAT IS KNOWN ALREADY: Expectant or medical management of women with endometriomas is now accepted. Therefore, the accuracy of non-invasive diagnosis of these cysts is pivotal. A clinically relevant question is whether the sonographic characteristics of ovarian endometriomas are the same irrespective of the age of the woman. STUDY DESIGN, SIZE, DURATION: This is a secondary analysis of cross-sectional data in the International Ovarian Tumor Analysis (IOTA) database. The database contains clinical and ultrasound information collected pre-operatively between 1999 and 2012 from 5914 patients with adnexal masses in 24 ultrasound centres in 10 countries. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were 1005 histologically confirmed endometriomas in adult premenopausal patients found in the database and these were used in our analysis. The following ultrasound variables (defined using IOTA terminology) were used to describe the ultrasound appearance of the endometriomas: tender mass at ultrasound, largest diameter of lesion, tumour type (unilocular, unilocular-solid, multilocular, multilocular-solid, solid), echogenicity of cyst content, presence of papillations, number of papillations, height (mm) of largest papillation, presence and proportion of solid tissue and number of cyst locules, as well as vascularity in papillations and colour content of the tumour scan (colour score) on colour or power Doppler ultrasounds. Results are reported as median difference or odds ratio (OR) per 10 years increase in age. MAIN RESULTS AND THE ROLE OF CHANCE: Maximal lesion diameter did not vary substantially with age (+1.3 mm difference per 10 years increase in age, 95% confidence interval (CI) -1.4 to 4.0). Tender mass at scan was less common in the older the woman (OR 0.75, 95% CI 0.63-0.89), as were unilocular cysts relative to multilocular cysts (OR 0.70, 95% CI 0.57-0.85) and to lesions with solid components (OR 0.61, 95% CI 0.48-0.77), and ground glass echogenicity relative to homogeneous low-level echogenicity (OR 0.74, 95% CI 0.58-0.94) and other types of echogenicity of cyst contents (OR 0.64, 95% CI 0.50-0.81). Papillations were more common the older the woman (OR 1.65, 95% CI 1.24-2.21), but their height and vascularization showed no clear relation to age. LIMITATIONS, REASONS FOR CAUTION: It is a limitation that we have little clinical information on the women included, e.g. previous surgery or medical treatment for endometriosis. It is important to emphasize that we do not know the age of the endometrioma itself and that our study is not longitudinal and so does not describe changes in endometriomas over time. The differences in the ultrasound appearance of endometriomas between women of different ages might be explained by previous surgery or medical treatment and might not be an effect of age per se. WIDER IMPLICATIONS OF THE FINDINGS: Awareness of physicians that the ultrasound appearance of endometriomas differs between women of different ages may facilitate a correct diagnosis of endometrioma. STUDY FUNDING/COMPETING INTERESTS: This study was supported in part by the Regione Autonoma della Sardegna (project code CPR-24750). B.V.C., A.C. and D.T. are supported by the Fund for Scientific Research Flanders, Belgium (FWO). The authors declare that there is no conflict of interest.

Predicting the risk of malignancy in adnexal masses based on the Simple Rules from the International Ovarian Tumor Analysis group.

BACKGROUND: Accurate methods to preoperatively characterize adnexal tumors are pivotal for optimal patient management. A recent metaanalysis concluded that the International Ovarian Tumor Analysis algorithms such as the Simple Rules are the best approaches to preoperatively classify adnexal masses as benign or malignant. OBJECTIVE: We sought to develop and validate a model to predict the risk of malignancy in adnexal masses using the ultrasound features in the Simple Rules. STUDY DESIGN: This was an international cross-sectional cohort study involving 22 oncology centers, referral centers for ultrasonography, and general hospitals. We included consecutive patients with an adnexal tumor who underwent a standardized transvaginal ultrasound examination and were selected for surgery. Data on 5020 patients were recorded in 3 phases from 2002 through 2012. The 5 Simple Rules features indicative of a benign tumor (B-features) and the 5 features indicative of malignancy (M-features) are based on the presence of ascites, tumor morphology, and degree of vascularity at ultrasonography. Gold standard was the histopathologic diagnosis of the adnexal mass (pathologist blinded to ultrasound findings). Logistic regression analysis was used to estimate the risk of malignancy based on the 10 ultrasound features and type of center. The diagnostic performance was evaluated by area under the receiver operating characteristic curve, sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), positive predictive value (PPV), negative predictive value (NPV), and calibration curves. RESULTS: Data on 4848 patients were analyzed. The malignancy rate was 43% (1402/3263) in oncology centers and 17% (263/1585) in other centers. The area under the receiver operating characteristic curve on validation data was very similar in oncology centers (0.917; 95% confidence interval, 0.901-0.931) and other centers (0.916; 95% confidence interval, 0.873-0.945). Risk estimates showed good calibration. In all, 23% of patients in the validation data set had a very low estimated risk (<1%) and 48% had a high estimated risk (≥30%). For the 1% risk cutoff, sensitivity was 99.7%, specificity 33.7%, LR+ 1.5, LR- 0.010, PPV 44.8%, and NPV 98.9%. For the 30% risk cutoff, sensitivity was 89.0%, specificity 84.7%, LR+ 5.8, LR- 0.13, PPV 75.4%, and NPV 93.9%. CONCLUSION: Quantification of the risk of malignancy based on the Simple Rules has good diagnostic performance both in oncology centers and other centers. A simple classification based on these risk estimates may form the basis of a clinical management system. Patients with a high risk may benefit from surgery by a gynecological oncologist, while patients with a lower risk may be managed locally.

Gastrointestinal symptoms among endometriosis patients--A case-cohort study.

BACKGROUND: Women with endometriosis often experience gastrointestinal symptoms. Gonadotropin-releasing hormone (GnRH) analogs are used to treat endometriosis; however, some patients develop gastrointestinal dysmotility following this treatment. The aims of the present study were to investigate gastrointestinal symptoms among patients with endometriosis and to examine whether symptoms were associated with menstruation, localization of endometriosis lesions, or treatment with either opioids or GnRH analogs, and if hormonal treatment affected the symptoms. METHODS: All patients with diagnosed endometriosis at the Department of Gynecology were invited to participate in the study. Gastrointestinal symptoms were registered using the Visual Analogue Scale for Irritable Bowel Syndrome (VAS-IBS); socioeconomic and medical histories were compiled using a clinical data survey. Data were compared to a control group from the general population. RESULTS: A total of 109 patients and 65 controls were investigated. Compared to controls, patients with endometriosis experienced significantly aggravated abdominal pain (P = 0.001), constipation (P = 0.009), bloating and flatulence (P = 0.000), defecation urgency (P = 0.010), and sensation of incomplete evacuation (P = 0.050), with impaired psychological well-being (P = 0.005) and greater intestinal symptom influence on their daily lives (P = 0.001). The symptoms were not associated with menstruation or localization of endometriosis lesions, except increased nausea and vomiting (P = 0.010) in patients with bowel-associated lesions. Half of the patients were able to differentiate between abdominal pain from endometriosis and from the gastrointestinal tract. Patients using opioids experienced more severe symptoms than patients not using opioids, and patients with current or previous use of GnRH analogs had more severe abdominal pain than the other patients (P = 0.024). Initiation of either combined oral contraceptives or progesterone for endometriosis had no effect on gastrointestinal symptoms when the patients were followed prospectively. CONCLUSIONS: The majority of endometriosis patients experience more severe gastrointestinal symptoms than controls. A poor association between symptoms and lesion localization was found, indicating existing comorbidity between endometriosis and irritable bowel syndrome (IBS). Treatment with opioids or GnRH analogs is associated with aggravated gastrointestinal symptoms.

ADNEX risk prediction model for diagnosis of ovarian cancer: systematic review and meta-analysis of external validation studies.

Objectives: To conduct a systematic review of studies externally validating the ADNEX (Assessment of Different Neoplasias in the adnexa) model for diagnosis of ovarian cancer and to present a meta-analysis of its performance. Design: Systematic review and meta-analysis of external validation studies. Data sources: Medline, Embase, Web of Science, Scopus, and Europe PMC, from 15 October 2014 to 15 May 2023. Eligibility criteria for selecting studies: All external validation studies of the performance of ADNEX, with any study design and any study population of patients with an adnexal mass. Two independent reviewers extracted the data. Disagreements were resolved by discussion. Reporting quality of the studies was scored with the TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) reporting guideline, and methodological conduct and risk of bias with PROBAST (Prediction model Risk Of Bias Assessment Tool). Random effects meta-analysis of the area under the receiver operating characteristic curve (AUC), sensitivity and specificity at the 10% risk of malignancy threshold, and net benefit and relative utility at the 10% risk of malignancy threshold were performed. Results: 47 studies (17 007 tumours) were included, with a median study sample size of 261 (range 24-4905). On average, 61% of TRIPOD items were reported. Handling of missing data, justification of sample size, and model calibration were rarely described. 91% of validations were at high risk of bias, mainly because of the unexplained exclusion of incomplete cases, small sample size, or no assessment of calibration. The summary AUC to distinguish benign from malignant tumours in patients who underwent surgery was 0.93 (95% confidence interval 0.92 to 0.94, 95% prediction interval 0.85 to 0.98) for ADNEX with the serum biomarker, cancer antigen 125 (CA125), as a predictor (9202 tumours, 43 centres, 18 countries, and 21 studies) and 0.93 (95% confidence interval 0.91 to 0.94, 95% prediction interval 0.85 to 0.98) for ADNEX without CA125 (6309 tumours, 31 centres, 13 countries, and 12 studies). The estimated probability that the model has use clinically in a new centre was 95% (with CA125) and 91% (without CA125). When restricting analysis to studies with a low risk of bias, summary AUC values were 0.93 (with CA125) and 0.91 (without CA125), and estimated probabilities that the model has use clinically were 89% (with CA125) and 87% (without CA125). Conclusions: The results of the meta-analysis indicated that ADNEX performed well in distinguishing between benign and malignant tumours in populations from different countries and settings, regardless of whether the serum biomarker, CA125, was used as a predictor. A key limitation was that calibration was rarely assessed. Systematic review registration: PROSPERO CRD42022373182.

Inter-Rater Agreement for Diagnosing Adenomyosis Using Magnetic Resonance Imaging and Transvaginal Ultrasonography.

Our aim was to compare the inter-rater agreement about transvaginal ultrasonography (TVS) with magnetic resonance imaging (MRI) with regard to diagnosing adenomyosis and for assessing various predefined imaging features of adenomyosis, in the same set of women. The study cohort included 51 women, prospectively, consecutively recruited based on a clinical suspicion of adenomyosis. MRIs and TVS videoclips and 3D volumes were retrospectively assessed by four experienced radiologists and five experienced sonographers, respectively. Each rater subjectively evaluated the presence or absence of adenomyosis, as well as imaging features suggestive of adenomyosis. Fleiss kappa (κ) was used to reflect inter-rater agreement for categorical data, and the intraclass correlation coefficient (ICC) was used to reflect the reliability of quantitative data. Agreement between raters for diagnosing adenomyosis was higher for TVS than for MRI (κ = 0.42 vs. 0.28). MRI had a higher inter-rater agreement in assessing wall asymmetry, irregular junctional zone (JZ), and the presence of myometrial cysts, while TVU had a better agreement for assessing globular shape. MRI showed a moderate to good reliability for measuring the JZ (ICC = 0.57-0.82). For TVS, the JZ was unmeasurable in >50% of cases, and the remaining cases had low reliability (ICC = -0.31-0.08). We found that inter-rater agreement for diagnosing adenomyosis was higher for TVS than for MRI, despite the fact that MRI showed a higher inter-rater agreement in most specific features. Measurements of JZ in the coronal plane with 3D TVS were unreliable and thus unlikely to be useful for diagnosing adenomyosis.

External Validation of the Ovarian-Adnexal Reporting and Data System (O-RADS) Lexicon and the International Ovarian Tumor Analysis 2-Step Strategy to Stratify Ovarian Tumors Into O-RADS Risk Groups.

Importance: Correct diagnosis of ovarian cancer results in better prognosis. Adnexal lesions can be stratified into the Ovarian-Adnexal Reporting and Data System (O-RADS) risk of malignancy categories with either the O-RADS lexicon, proposed by the American College of Radiology, or the International Ovarian Tumor Analysis (IOTA) 2-step strategy. Objective: To investigate the diagnostic performance of the O-RADS lexicon and the IOTA 2-step strategy. Design, Setting, and Participants: Retrospective external diagnostic validation study based on interim data of IOTA5, a prospective international multicenter cohort study, in 36 oncology referral centers or other types of centers. A total of 8519 consecutive adult patients presenting with an adnexal mass between January 1, 2012, and March 1, 2015, and treated either with surgery or conservatively were included in this diagnostic study. Twenty-five patients were excluded for withdrawal of consent, 2777 were excluded from 19 centers that did not meet predefined data quality criteria, and 812 were excluded because they were already in follow-up at recruitment. The analysis included 4905 patients with a newly detected adnexal mass in 17 centers that met predefined data quality criteria. Data were analyzed from January 31 to March 1, 2022. Exposures: Stratification into O-RADS categories (malignancy risk <1%, 1% to <10%, 10% to <50%, and ≥50%). For the IOTA 2-step strategy, the stratification is based on the individual risk of malignancy calculated with the IOTA 2-step strategy. Main Outcomes and Measures: Observed prevalence of malignancy in each O-RADS risk category, as well as sensitivity and specificity. The reference standard was the status of the tumor at inclusion, determined by histology or clinical and ultrasonographic follow-up for 1 year. Multiple imputation was used for uncertain outcomes owing to inconclusive follow-up information. Results: Median age of the 4905 patients was 48 years (IQR, 36-62 years). Data on race and ethnicity were not collected. A total of 3441 tumors (70%) were benign, 978 (20%) were malignant, and 486 (10%) had uncertain classification. Using the O-RADS lexicon resulted in 1.1% (24 of 2196) observed prevalence of malignancy in O-RADS 2, 4% (34 of 857) in O-RADS 3, 27% (246 of 904) in O-RADS 4, and 78% (732 of 939) in O-RADS 5; the corresponding results for the IOTA 2-step strategy were 0.9% (18 of 1984), 4% (58 of 1304), 30% (206 of 690), and 82% (756 of 927). At the 10% risk threshold (O-RADS 4-5), the O-RADS lexicon had 92% sensitivity (95% CI, 87%-96%) and 80% specificity (95% CI, 74%-85%), and the IOTA 2-step strategy had 91% sensitivity (95% CI, 84%-95%) and 85% specificity (95% CI, 80%-88%). Conclusions and Relevance: The findings of this external diagnostic validation study suggest that both the O-RADS lexicon and the IOTA 2-step strategy can be used to stratify patients into risk groups. However, the observed malignancy rate in O-RADS 2 was not clearly below 1%.

Number of antral follicles, ovarian volume, and vascular indices in asymptomatic women 20 to 39 years old as assessed by 3-dimensional sonography: a prospective cross-sectional study.

OBJECTIVES: Our aim was to elicit data representative of normal findings on 3-dimensional (3D) transvaginal gray-scale and power Doppler sonography of ovaries in women of fertile age. METHODS: A total of 303 gynecologically asymptomatic white women 20 to 39 years old with spontaneous regular menstrual cycles were examined with transvaginal 3D gray-scale and power Doppler sonography on cycle days 4 to 8. We used a 6- to 12-MHz transducer. The ovarian volume, number and volume of antral follicles of 2 mm or larger, vascularization index, flow index, and vascularization-flow index were calculated using dedicated software. Results are presented separately for women with follicles of 2.0 to 10.0 mm and for those with at least 1 follicle larger than 10.0 mm for 3 age groups: 20 to 29, 30 to 34, and 35 to 39 years. RESULTS: There were 214 women (71%) with follicles of 2.0 to 10.0 mm and 89 (29%) with follicles larger than 10.0 mm. In women with follicles of 2.0 to 10.0 mm, the right ovary was on average 0.8 cm3 larger and contained on average 1.2 more follicles than the left one. The ovarian volume, number of follicles, and total follicular volume decreased significantly with age in both ovaries (P = .000-.029): for the right ovary ovarian volume, the median (range) decreased from 8.4 (3.7-17.3) cm3 at 20 to 29 years to 6.5 (2.4-12.7) cm(3) at 35 to 39 years, the number of follicles from 14 (1-32) at 20 to 29 years to 8 (1-21) at 35 to 39 years, and the total follicular volume from 1.08 (0.01-3.10) cm3 at 20 to 29 years to 0.84 (0.03-2.00) cm3 at 35 to 39 years. The size of the largest follicle and the vascular indices manifested no clear changes with age in any ovary. In women with follicles larger than 10 mm, the number of follicles decreased with age in both ovaries. CONCLUSIONS: We have elicited data representative of normal findings on 3D trans-vaginal sonography of ovaries in gynecologically asymptomatic white women of fertile age. Our gray-scale sonographic results may be used as reference values for general gynecology in populations similar to ours. Vascular indices must be interpreted with caution because of difficulties with standardization.