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: The aim is to evaluate the ability of the Assessment of Different NEoplasias in the adneXa model (ADNEX) 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 with clinical and ultrasound follow-up. METHODS: This single center (Hospital Universitari Dexeus Barcelona) study was performed using interim data of the ongoing prospective observational IOTA phase 5 study. The primary aim of the IOTA 5 study is to describe the cumulative incidence of complications during follow-up of adnexal masses classified as benign on ultrasound. Consecutive patients with adnexal masses detected between June 2012 and September 2016 in a private center offering screening for gynecological cancers were included and followed-up until February 2020. Tumors were classified as benign or malignant based on histology (if patients underwent surgery) or outcome of clinical and ultrasound follow-up at 12 (±2) months. Multiple imputation was used when follow-up information was 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 describe performance as discrimination (area under the receiver operating characteristic curve, AUC), calibration, classification (sensitivity and specificity) and clinical utility (Net Benefit). In the group of patients with a benign looking mass 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 for malignancy, torsion, cyst rupture, or 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. 1684 (82.6%) masses were benign, 49 (2.4%) masses were malignant and for 306 (15.0%) masses the outcome was uncertain and imputed. The AUC was 0.95 (95% CI 0.89-0.98) for ADNEX and 0.94 (95% CI 0.88-0.97) for the two-step strategy. Calibration performance could not be meaningfully interpreted due to few malignancies resulting in very wide confidence intervals. The two-step strategy had better clinical utility than ADNEX at malignancy risk thresholds < 3%. 1472 (72%) patients had a mass 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% for spontaneous resolution of the mass (95% CI 63-69), 0% for torsion (95%CI 0-0.002), 0.1% for cyst rupture (<0.1-0.6), 0.2% for a borderline tumor (<0.1-0.6), and 0.2% (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 benign ultrasound appearance in such a population. This article is protected by copyright. All rights reserved.

Benign descriptors and ADNEX in two-step strategy to estimate risk of malignancy in ovarian tumors: retrospective validation in IOTA5 multicenter cohort.

OBJECTIVE: Previous work has suggested that the ultrasound-based benign simple descriptors (BDs) can reliably exclude malignancy in a large proportion of women presenting with an adnexal mass. This study aimed to validate a modified version of the BDs and to validate a two-step strategy to estimate the risk of malignancy, in which the modified BDs are followed by the Assessment of Different NEoplasias in the adneXa (ADNEX) model if modified BDs do not apply. METHODS: This was a retrospective analysis using data from the 2-year interim analysis of the International Ovarian Tumor Analysis (IOTA) Phase-5 study, in which consecutive patients with at least one adnexal mass were recruited irrespective of subsequent management (conservative or surgery). The main outcome was classification of tumors as benign or malignant, based on histology or on clinical and ultrasound information during 1 year of follow-up. Multiple imputation was used when outcome based on follow-up was uncertain according to predefined criteria. RESULTS: A total of 8519 patients were recruited at 36 centers between 2012 and 2015. We excluded patients who were already in follow-up at recruitment and all patients from 19 centers that did not fulfil our criteria for good-quality surgical and follow-up data, leaving 4905 patients across 17 centers for statistical analysis. Overall, 3441 (70%) tumors were benign, 978 (20%) malignant and 486 (10%) uncertain. The modified BDs were applicable in 1798/4905 (37%) tumors, of which 1786 (99.3%) were benign. The two-step strategy based on ADNEX without CA125 had an area under the receiver-operating-characteristics curve (AUC) of 0.94 (95% CI, 0.92-0.96). The risk of malignancy was slightly underestimated, but calibration varied between centers. A sensitivity analysis in which we expanded the definition of uncertain outcome resulted in 1419 (29%) tumors with uncertain outcome and an AUC of the two-step strategy without CA125 of 0.93 (95% CI, 0.91-0.95). CONCLUSION: A large proportion of adnexal masses can be classified as benign by the modified BDs. For the remaining masses, the ADNEX model can be used to estimate the risk of malignancy. This two-step strategy is convenient for clinical use. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

ESGO/ISUOG/IOTA/ESGE Consensus Statement on preoperative diagnosis of ovarian tumours.

The European Society of Gynaecological Oncology (ESGO), the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG), the International Ovarian Tumour Analysis (IOTA) group and the European Society for Gynaecological Endoscopy (ESGE) jointly developed clinically relevant and evidence-based statements on the preoperative diagnosis of ovarian tumours, including imaging techniques, biomarkers and prediction models. ESGO/ISUOG/IOTA/ESGE nominated a multidisciplinary international group, including expert practising clinicians and researchers who have demonstrated leadership and expertise in the preoperative diagnosis of ovarian tumours and management of patients with ovarian cancer (19 experts across Europe). A patient representative was also included in the group. To ensure that the statements were evidence-based, the current literature was reviewed and critically appraised. Preliminary statements were drafted based on the review of the relevant literature. During a conference call, the whole group discussed each preliminary statement and a first round of voting was carried out. Statements were removed when a consensus among group members was not obtained. The voters had the opportunity to provide comments/suggestions with their votes. The statements were then revised accordingly. Another round of voting was carried out according to the same rules to allow the whole group to evaluate the revised version of the statements. The group achieved consensus on 18 statements. This Consensus Statement presents these ESGO/ISUOG/IOTA/ESGE statements on the preoperative diagnosis of ovarian tumours and the assessment of carcinomatosis, together with a summary of the evidence supporting each statement.

ESGO/ISUOG/IOTA/ESGE Consensus Statement on preoperative diagnosis of ovarian tumors.

The European Society of Gynaecological Oncology (ESGO), the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG), the International Ovarian Tumour Analysis (IOTA) group and the European Society for Gynaecological Endoscopy (ESGE) jointly developed clinically relevant and evidence-based statements on the preoperative diagnosis of ovarian tumors, including imaging techniques, biomarkers and prediction models. ESGO/ISUOG/IOTA/ESGE nominated a multidisciplinary international group, including expert practising clinicians and researchers who have demonstrated leadership and expertise in the preoperative diagnosis of ovarian tumors and management of patients with ovarian cancer (19 experts across Europe). A patient representative was also included in the group. To ensure that the statements were evidence-based, the current literature was reviewed and critically appraised. Preliminary statements were drafted based on the review of the relevant literature. During a conference call, the whole group discussed each preliminary statement and a first round of voting was carried out. Statements were removed when consensus among group members was not obtained. The voters had the opportunity to provide comments/suggestions with their votes. The statements were then revised accordingly. Another round of voting was carried out according to the same rules to allow the whole group to evaluate the revised version of the statements. The group achieved consensus on 18 statements. This Consensus Statement presents these ESGO/ISUOG/IOTA/ESGE statements on the preoperative diagnosis of ovarian tumors and the assessment of carcinomatosis, together with a summary of the evidence supporting each statement.

Declaración de consenso de ESGO/ISUOG/IOTA/ESGE sobre el diagnóstico preoperatorio de los tumores de ovario La Sociedad Europea de Oncología Ginecológica (ESGO), la Sociedad Internacional de Ecografía en Obstetricia y Ginecología (ISUOG), el Grupo Internacional de Análisis de Tumores de Ovario (IOTA) y la Sociedad Europea de Endoscopia Ginecológica (ESGE) elaboraron conjuntamente declaraciones de importancia para la práctica clínica y con base empírica sobre el diagnóstico preoperatorio de los tumores de ovario, a partir de imágenes, biomarcadores y modelos de predicción, entre otras técnicas. La ESGO/ISUOG/IOTA/ESGE designó a un grupo internacional multidisciplinar, que incluye a personas expertas de la práctica clínica y la investigación que han demostrado liderazgo y experiencia en el diagnóstico preoperatorio de los tumores de ovario y en el tratamiento de las pacientes con cáncer de ovario (19 personas expertas de toda Europa). También se incluyó en el grupo a una representante de las pacientes. Para garantizar que las declaraciones tenían una base empírica, se revisó la literatura actual y se valoró de forma crítica. Se redactaron declaraciones preliminares basadas en la revisión de la literatura pertinente. La totalidad del grupo debatió durante una teleconferencia cada declaración preliminar y se llevó a cabo una primera ronda de votaciones. Las declaraciones se eliminaron cuando no se obtuvo el consenso entre los miembros del grupo. Los votantes tuvieron la oportunidad de aportar comentarios/sugerencias a la par que sus votos. Las declaraciones se revisaron en consecuencia. Se llevó a cabo otra ronda de votaciones según las mismas reglas para que todo el grupo pudiera evaluar la versión revisada de las declaraciones. El grupo logró un consenso sobre 18 declaraciones. Esta Declaración de Consenso presenta estas declaraciones de la ESGO/ISUOG/IOTA/ESGE sobre el diagnóstico preoperatorio de los tumores de ovario y la evaluación de la carcinomatosis, junto con un resumen de la evidencia que apoya cada declaración.

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

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

Imaging in gynecological disease (14): clinical and ultrasound characteristics of ovarian clear cell carcinoma.

OBJECTIVE: To describe the clinical and ultrasound characteristics of ovarian pure clear cell carcinoma. METHODS: This was a retrospective study involving data from 11 ultrasound centers. From the International Ovarian Tumor Analysis (IOTA) database, 105 patients who had undergone preoperative ultrasound examination by an experienced ultrasound examiner between 1999 and 2016 were identified with a histologically confirmed pure clear cell carcinoma of the ovary. An additional 47 patients diagnosed with pure clear cell carcinoma between 1999 and 2016 and with available complete preoperative ultrasound reports were identified retrospectively from the databases of the departments of gynecological oncology in the participating centers. The ultrasound images of all tumors were described using IOTA terminology. Clinical and ultrasound characteristics were analyzed for the whole group, and separately, for patients with and those without histologically confirmed endometriosis, and for patients with evidence of tumor developing from endometriosis. RESULTS: Median age of the 152 patients was 53.5 (range, 28-92) years and 92/152 (60.5%) tumors were FIGO Stage I. Most tumors (128/152, 84.2%) were unilateral. On ultrasound examination, all tumors contained solid components and 36/152 (23.7%) were completely solid masses. The median largest diameter of the lesion was 117 (range, 25-310) mm. Papillary projections were present in 58/152 (38.2%) masses and, in most of these (51/56, 91.1%), vascularized papillary projections were seen. Information regarding the presence, site and type of pelvic endometriosis at histology was available for 130/152 patients. Endometriosis was noted in 54 (41.5%) of these. In 24/130 (18.6%) patients, the tumor was judged to have developed from endometriosis. Patients with, compared to those without, evidence of tumor developing from endometriosis were younger (median 47.5 vs 55.0 years, respectively), and ground-glass echogenicity of cyst fluid was more common in pure clear cell cancers developing from endometriosis (10/20 vs 13/79 (50.0% vs 16.5%), respectively). CONCLUSIONS: Ovarian pure clear cell carcinoma is usually diagnosed at an early stage and typically appears as a large unilateral mass with solid components. Patients with clear cell carcinoma developing from endometriosis are younger than other patients with clear cell carcinoma, and clear cell cancers developing from endometriosis more often manifest ground-glass echogenicity of cyst fluid. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Differences in ultrasound features of papillations in unilocular-solid adnexal cysts: a retrospective international multicenter study.

OBJECTIVES: To identify ultrasound features of papillations or of the cyst wall that can discriminate between benign and malignant unilocular-solid cysts with papillations but no other solid components. METHODS: From the International Ovarian Tumor Analysis (IOTA) database derived from seven ultrasound centers, we identified patients with an adnexal lesion described at ultrasonography as unilocular-solid with papillations but no other solid components. All patients had undergone transvaginal ultrasound between 1999 and 2007 or 2009 and 2012, by an experienced examiner following the IOTA research protocol. Information on four ultrasound features of papillations had been collected prospectively. Information on a further seven ultrasound features was collected retrospectively from electronic or paper ultrasound images of good quality. The histological diagnosis of the surgically removed adnexal lesion was considered the gold standard. RESULTS: Of 204 masses included, 131 (64.2%) were benign, 42 (20.6%) were borderline tumors, 30 (14.7%) were primary invasive tumors and one (0.5%) was a metastasis. Multivariate logistic regression analysis showed the following ultrasound features to be associated independently with malignancy: height of the largest papillation, presence of blood flow in papillations, papillation confluence or dissemination, and shadows behind papillations. Shadows decreased the odds of malignancy, while the other features increased them. CONCLUSION: We have identified ultrasound features that can help to discriminate between benign and malignant unilocular-solid cysts with papillations but no other solid components. Our results need to be confirmed in prospective studies. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Practical guidance for applying the ADNEX model from the IOTA group to discriminate between different subtypes of adnexal tumors.

All gynecologists are faced with ovarian tumors on a regular basis, and the accurate preoperative diagnosis of these masses is important because appropriate management depends on the type of tumor. Recently, the International Ovarian Tumor Analysis (IOTA) consortium published the Assessment of Different NEoplasias in the adneXa (ADNEX) model, the first risk model that differentiates between benign and four types of malignant ovarian tumors: borderline, stage I cancer, stage II-IV cancer, and secondary metastatic cancer. This approach is novel compared to existing tools that only differentiate between benign and malignant tumors, and therefore questions may arise on how ADNEX can be used in clinical practice. In the present paper, we first provide an in-depth discussion about the predictors used in ADNEX and the ability for risk prediction with different tumor histologies. Furthermore, we formulate suggestions about the selection and interpretation of risk cut-offs for patient stratification and choice of appropriate clinical management. This is illustrated with a few example patients. We cannot propose a generally applicable algorithm with fixed cut-offs, because (as with any risk model) this depends on the specific clinical setting in which the model will be used. Nevertheless, this paper provides a guidance on how the ADNEX model may be adopted into clinical practice.

Terms, definitions and measurements to describe sonographic features of myometrium and uterine masses: a consensus opinion from the Morphological Uterus Sonographic Assessment (MUSA) group.

The MUSA (Morphological Uterus Sonographic Assessment) statement is a consensus statement on terms, definitions and measurements that may be used to describe and report the sonographic features of the myometrium using gray-scale sonography, color/power Doppler and three-dimensional ultrasound imaging. The terms and definitions described may form the basis for prospective studies to predict the risk of different myometrial pathologies, based on their ultrasound appearance, and thus should be relevant for the clinician in daily practice and for clinical research. The sonographic features and use of terminology for describing the two most common myometrial lesions (fibroids and adenomyosis) and uterine smooth muscle tumors are presented.

Is chronically dysfunctional yet viable myocardium distal to a severe coronary stenosis hypoperfused?

BACKGROUND: Controversy exists regarding the perfusion status of chronically dysfunctional yet viable myocardium. Studies investigating the pathophysiology of this condition have reached different conclusions, with some suggesting that myocardial blood flow (MBF) in these regions is normal at rest with regional dysfunction resulting from repetitive stress-induced ischemia (stunned myocardium), whereas others have proposed that MBF is chronically reduced at rest (hibernating myocardium). However, adequately powered experimental studies investigating this question in an appropriate animal model using clinically available techniques have not been performed. Based on the mixed results of prior studies, we hypothesized that these chronically dysfunctional yet viable regions may actually represent a mixture of hibernation and stunning. Consequently, the purpose of this study was to quantitatively determine the distribution of MBF in left ventricular regions with chronically impaired resting function but preserved viability in a large population of animals with single-vessel coronary stenosis in an attempt to further elucidate the mechanism(s) responsible for chronic, reversible myocardial dysfunction. METHODS: Fifty-two adult mini-swine with 90% proximal left circumflex (LCx) stenosis underwent dynamic positron emission tomography (PET) with 13N-ammonia and 18F-fluorodeoxyglucose and dobutamine stress echocardiography (DSE) (5 to 40 microg/kg/min) 1 month after stenosis creation. Values of MBF and FDG uptake by PET and wall motion score index (WMSI) by DSE were compared using a standard 16-segment model. RESULTS: Of 312 possible LCx segments seen on PET, 303 (97.1%) were visualized by DSE. Of the 303 LCx segments, 279 (92.1%) had rest dysfunction (WMSI > or = 2) by DSE. One hundred eighty-two segments (60.1%) had decreased (< 85% reference) MBF at rest with preserved to increased (> 60% reference) FDG uptake and were classified as hibernating. Ninety-two segments (30.4%) had preserved MBF (> or = 85% reference) and were classified as stunned. Five segments (1.7%) with reduced (< or = 60% reference) FDG uptake by PET and akinesis or dyskinesis at rest (WMSI > or = 3) and no contractile reserve were considered infarcted. Hibernating segments had significantly higher FDG uptake at rest (360.7+/-48.3 vs 212.3+/-17.7% septal values; p < 0.001) than stunned segments consistent with greater resting ischemia. Likewise, mean rest WMSI was also worse in hibernating versus stunned segments (2.35+/-0.04 vs 2.13+/-0.04; p < 0.001). There was no difference in the percentage of hibernating versus stunned segments exhibiting contractile reserve during dobutamine infusion (55.5 vs 63.7%; p = 0.4), indicating similar degrees of viability. CONCLUSIONS: Myocardial hibernation and stunning appear to frequently coexist in regions served by a stenotic coronary vessel. Hibernating regions appear to have greater resting ischemia based on higher values of FDG uptake and greater resting dysfunction. Reversible left ventricular dysfunction in the setting of chronic coronary artery disease is likely due to a combination of these two mechanisms.

Fenfluramine and phentermine and cardiovascular findings: effect of treatment duration on prevalence of valve abnormalities.

BACKGROUND: The combination of fenfluramine and phentermine was a widely used obesity treatment before the withdrawal of fenfluramine for an association with heart valve regurgitation. The prevalence and clinical significance of regurgitation among patients treated with these medications has yet to be fully established. METHODS AND RESULTS: To evaluate the potential association between the duration of treatment and the prevalence of heart valve abnormalities, we examined 1163 patients who had taken fenfluramine-phentermine and 672 control patients who had not taken the drug combination within 5 years. Mild or greater aortic regurgitation was present in 8.8% of treated patients and 3.6% of control patients (P<0.001). Moderate or greater mitral regurgitation was present in 2.6% of treated patients and 1.5% of control patients (P=0.18). The adjusted odds ratio compared with controls of aortic regurgitation of mild or greater severity increased according to duration of treatment: 90 to 180 days, 1.5 (P=0.23); 181 to 360 days, 2.4 (P=0.002); 361 to 720 days, 4.6 (P<0.001); >720 days, 6.2 (P<0.001). CONCLUSIONS: This is the largest study to demonstrate a relation between the length of treatment with fenfluramine-phentermine and the prevalence of valvular abnormalities. These findings suggest that valvular abnormalities in patients who took fenfluramine-phentermine primarily involve those who had taken these medications for >6 months and predominantly results in mild aortic regurgitation. The valve regurgitation identified by this study was not accompanied by significant differences in cardiovascular symptoms nor physical findings other than a higher prevalence of heart murmurs.

Real-time volumetric echocardiography: the technology and the possibilities.

The heart is a dynamic organ with complexities in its shape. As such, it places special demands on three-dimensional techniques for reconstruction. Real-time volumetric echocardiography, which is based on phased array and parallel processing principles to enhance line density within a scan volume, provides rapid image acquisition. We introduce the principle, potential clinical importance, current limitations, and future of volumetric imaging methods.

Intermediate-term clinical outcome following transmyocardial laser revascularization in patients with refractory angina pectoris.

BACKGROUND: This study was conducted to examine the intermediate-term clinical outcomes in patients with refractory angina pectoris treated with transmyocardial laser revascularization (TMR) at our institution. TMR is an alternative surgical technique for the treatment of myocardial ischemia and angina pectoris not amenable to conventional percutaneous or surgical revascularization. Limited data exist evaluating the natural history and duration of clinical improvement in angina pectoris following TMR. METHODS AND RESULTS: Thirty-four patients with severe coronary artery disease unsuitable for treatment with standard revascularization techniques underwent TMR in myocardial regions determined to be ischemic by preoperative SPECT (201)Tl perfusion imaging following dipyridamole stress. Patients were assessed postoperatively at 3, 6, and 12 months for clinical outcomes including death, myocardial infarction, functional class of angina pectoris, and hospitalizations for unstable angina. Myocardial perfusion imaging by (201)Tl scintigraphy was also assessed at these temporal end points. Overall mortality at 1 year was 14.7% (n=5). Nonfatal myocardial infarction occurred in 3 patients (8.8%). Among the patients with complete 12-month follow-up (n =27), mean anginal class improved from 3.5+/-0. 5 pre-TMR to 2.8+/-0.7 and 2.5+/-0.7 at 3 and 6 months, respectively, and 2.8+/-0.9 at 12 months. Overall improvement in angina pectoris was sustained at 1 year by at least one functional class in 50% of patients. Mean hospitalizations per year for unstable angina declined from 2.4+/-1.6 pre-TMR to 1.7+/-2.0 post-TMR (P=0.01). There was no significant improvement in perfusion by SPECT (201)Tl imaging at any temporal end point post-TMR. CONCLUSIONS: Despite the lack of demonstrable improvement in perfusion by SPECT (201)Tl imaging, TMR improved the functional class of angina pectoris in patients with end stage coronary artery disease to a modest degree. Although the maximal benefit in symptoms occurred at 6 months post-TMR, mild sustained clinical improvement above baseline was evident in 50% of patients at 1 year.