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BACKGROUND: Uterine disorders have clear overlapping symptoms and ultrasound discrimination is not always easy. Accurately measuring vascularity is of diagnostic and prognostic value. Power Doppler is limited to imaging only the larger vessels. Assessment of the microvasculature requires advanced machine settings.OBJECTIVES: In this pilot study, we aimed to test the feasibility of microvascular flow imaging of benign uterine disorders.MATERIAL AND METHODS: Two experienced gynaecologists (JH, RL) randomly applied power Doppler and MV-flowTM mode during a single day, in ten patients each visiting the outpatient clinic. Images of eight patients were labelled with a diagnosis by the attending physicians and collected as coded data.MAIN OUTCOME MEASURES: Microvascular flow images of normal uterine architecture including the fallopian tube, and of benign disorders such as fibroids, adenomyosis, endometriosis and uterine niches were collected. For both Doppler techniques, qualitative descriptive evaluation of the vascular architecture and a quantitative vascular index of fibroids were provided. Finally, we evaluated the effect of the cardiac cycle.RESULTS: All microvascular flow images showed more distinctive vascular structures than visible on power Doppler. Calculating a vascular index for fibroids on 2D MV-flowTM images was easily performed on-site. During the cardiac cycle a higher vascular index (VI 75.2) is obtained in systole as compared with diastole (VI 44.0).CONCLUSION: Microvascular flow imaging allowed detailed visualisation of the uterine vascular architecture and is easy to use.WHAT IS NEW?: Microvascular flow imaging may be of added value for diagnosing uterine disorders, as well as for pre- and post-operative assessment of suited surgical techniques. Yet, validation with histology and clinical outcomes is required.

Objectives: To evaluate whether the Morphological Uterus Sonographic Assessment (MUSA) features of adenomyosis need to be better defined and, if deemed necessary, to reach consensus on the updated definitions. Methods: A modified Delphi procedure was performed among European gynecologists with expertise in ultrasound diagnosis of adenomyosis. To identify MUSA features that might need revision, 15 two-dimensional (2D) video recordings (four recordings also included three-dimensional (3D) still images) of transvaginal ultrasound (TVS) examinations of the uterus were presented in the first Delphi round (online questionnaire). Experts were asked to confirm or refute the presence of each of the nine MUSA features of adenomyosis (described in the original MUSA consensus statement) in each of the 15 videoclips and to provide comments. In the second Delphi round (online questionnaire), the results of the first round and suggestions for revision of MUSA features were shared with the experts before they were asked to assess a new set of 2D and 3D still images of TVS examinations and to provide feedback on the proposed revisions. A third Delphi round (virtual group meeting) was conducted to discuss and reach final consensus on revised definitions of MUSA features. Consensus was predefined as at least 66.7% agreement between experts. Results: Of 18 invited experts, 16 agreed to participate in the Delphi procedure. Eleven experts completed and four experts partly finished the first round. The experts identified a need for more detailed definitions of some MUSA features. They recommended use of 3D ultrasound to optimize visualization of the junctional zone. Fifteen experts participated in the second round and reached consensus on the presence or absence of ultrasound features of adenomyosis in most of the still images. Consensus was reached for all revised definitions except those for subendometrial lines and buds and interrupted junctional zone. Thirteen experts joined the online meeting, in which they discussed and agreed on final revisions of the MUSA definitions. There was consensus on the need to distinguish between direct features of adenomyosis, i.e. features indicating presence of ectopic endometrial tissue in the myometrium, and indirect features, i.e. features reflecting changes in the myometrium secondary to presence of endometrial tissue in the myometrium. Myometrial cysts, hyperechogenic islands and echogenic subendometrial lines and buds were classified unanimously as direct features of adenomyosis. Globular uterus, asymmetrical myometrial thickening, fan-shaped shadowing, translesional vascularity, irregular junctional zone and interrupted junctional zone were classified as indirect features of adenomyosis. Conclusion: Consensus between gynecologists with expertise in ultrasound diagnosis of adenomyosis was achieved regarding revised definitions of the MUSA features of adenomyosis and on the classification of MUSA features as direct or indirect signs of adenomyosis.

Background To illustrate the technical feasibility and diagnostic value of including the assessment of the bladder and the ureters during a standard transvaginal ultrasound examination. Methods We present four cases illustrating ureter and bladder pathology diagnosed by transvaginal ultrasound. Results In a first case, transvaginal ultrasonography in a woman with lower abdominal pain showed a calculus in the left distal ureter. The small echogenic lesion was easily detectable within the ureter lumen. A second patient, presenting with suprapubic pain, urgency and back pain, was also diagnosed with a ureteral calculus and additionally a hydroureter. The presence of a hydroureter is part of the differential diagnosis of any cystic structure in the pelvis. In a third case, an elderly woman, referred with uterine prolapse, transvaginal ultrasound examination showed a tubular anechoic structure lateral in the pelvis due to a hydroureter, illustrating the differential diagnosis with a hydrosalpinx. A fourth patient, presenting with hematuria, showed an irregular and highly vascularized mass in the bladder and was diagnosed with a transitional cell carcinoma. Conclusion The bladder and pelvic part of the ureters are easily identifiable on transvaginal scan. Important pathology of the lower urinary tract and the distal ureters can be readily diagnosed by transvaginal ultrasound examination. The evaluation of the bladder and the ureters should therefore be part of the standard gynecological ultrasound investigation.

Mathematics can be applied in many different fields, oncology being no exception. Mathematical models require data to be constructed, tested and validated, which makes their applications largely driven by opportunity. Furthermore, different hypotheses require different mathematical models. As such, many different kinds of mathematical models can be used depending on the available data and proposed research question. In this work, three distinct aspects of mathematical oncology are studied as a result. In the first part, intra-tumour heterogeneity (ITH) is studied. High ITH is well known to correlate to worse patient prognosis in many cancer types. However, ITH does not have a single definition, as it can be measured through the genome, proteome and the tumour microenvironment. In this work, a measure for chromosomal copy-number ITH (CNH) is constructed. CNH is shown to outperform other ITH-based biomarkers for predicting patient survival across cancer types. Furthermore, a subset of breast cancer patients with low CNH are identified that could benefit from less intensive treatment. In the second part, mathematical models for tissue dynamics are established. In particular, a mathematical model combined with experimental data shows that the healthy endocrine pancreas does not contain stem cells. A different mathematical model applied to colorectal cancer xenografts shows that colorectal tumour stem cells are defined by their environment. In the third part, mathematical models, in particular machine learning models, are used to predict complications and identify risk factors for colorectal cancer resections by exploiting a large clinical audit containing 60,000+ patients.

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/m(2) (range, 16.0-72.1 kg/m(2) ). 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 (C) 2020 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVES: To develop a pre-operative risk model using endometrial biopsy results, clinical and ultrasound variables to predict the individual risk of lymph node metastases in women with endometrial cancer. METHODS: A mixed effects logistic regression model was developed on 1501 prospectively included women with endometrial cancer subjected to transvaginal ultrasound examination before surgery. Missing data, including missing lymph node status, was imputed. Discrimination, calibration and clinical utility were evaluated using leave-center-out cross-validation. The predictive performance was compared with risk classification from endometrial biopsy alone (high-risk = endometrioid cancer grade 3/non-endometrioid cancer) or combined endometrial biopsy and ultrasound (high-risk = endometrioid cancer grade 3/non-endometrioid cancer/deep myometrial invasion/cervical stromal invasion/extrauterine spread). RESULTS: Lymphadenectomy was performed in 691 women, of which 127 had lymph node metastases. The model included the predictors age, duration of abnormal bleeding, endometrial biopsy result, tumor extension and tumor size according to ultrasound and "undefined tumor with an unmeasurable endometrium". The model's AUC was 0.73 (95% CI 0.68 to 0.78), calibration slope 1.06 (95% CI 0.79 to 1.34) and calibration intercept 0.06 (95% CI 0.15 to 0.27). Using risk thresholds for lymph node metastases 5% vs. 20% the model had sensitivity 98% vs. 48% and specificity 11% vs. 80%. The model had higher sensitivity and specificity than high-risk according to endometrial biopsy alone (50% vs. 35% and 80% vs. 77%) or combined endometrial biopsy and ultrasound (80% vs. 75% and 53% vs. 52%). The model's clinical utility was higher than that of endometrial biopsy alone or combined endometrial biopsy and ultrasound at any given risk threshold. CONCLUSIONS: Based on endometrial biopsy results, clinical and ultrasound characteristics, the individual risk of lymph node metastases in women with endometrial cancer can be reliably estimated before surgery. The model is superior to risk classification by endometrial biopsy alone or in combination with ultrasound. This article is protected by copyright. All rights reserved.

BACKGROUND: To illustrate the technical feasibility and diagnostic value of including the assessment of the bladder and the ureters during a standard transvaginal ultrasound examination. METHODS: We present four cases illustrating ureter and bladder pathology diagnosed by transvaginal ultrasound. RESULTS: In a first case, transvaginal ultrasonography in a woman with lower abdominal pain showed a calculus in the left distal ureter. The small echogenic lesion was easily detectable within the ureter lumen. A second patient, presenting with suprapubic pain, urgency and back pain, was also diagnosed with a ureteral calculus and additionally a hydroureter. The presence of a hydroureter is part of the differential diagnosis of any cystic structure in the pelvis. In a third case, an elderly woman, referred with uterine prolapse, transvaginal ultrasound examination showed a tubular anechoic structure lateral in the pelvis due to a hydroureter, illustrating the differential diagnosis with a hydrosalpinx. A fourth patient, presenting with hematuria, showed an irregular and highly vascularized mass in the bladder and was diagnosed with a transitional cell carcinoma. CONCLUSION: The bladder and pelvic part of the ureters are easily identifiable on transvaginal scan. Important pathology of the lower urinary tract and the distal ureters can be readily diagnosed by transvaginal ultrasound examination. The evaluation of the bladder and the ureters should therefore be part of the standard gynecological ultrasound investigation. ispartof: FACTS VIEWS AND VISION IN OBGYN vol:11 issue:4 pages:347-351 ispartof: location:Belgium status: published

OBJECTIVES: To describe the sonographic features of endometrial cancer in relation to stage, grade, and histological type using the International Endometrial Tumor Analysis (IETA) terminology. METHODS: Prospective multicenter study on 1714 women with endometrial cancer undergoing a standardized transvaginal grayscale and Doppler ultrasound examination by an experienced ultrasound examiner using a high-end ultrasound system. Clinical and sonographic data were entered into a web-based protocol. We assessed how strongly sonographic characteristics, according to IETA, were associated to outcome at hysterectomy, i.e. tumor stage, grade, and histological type. RESULTS: After excluding 176 women (no or delayed hysterectomy, final diagnosis other than endometrial cancer, or incomplete data), 1538 women were included in our statistical analysis. Median age was 65 years (range 27-98), and median BMI 28.4 (range 16-67), 1378 (89.7%) women were postmenopausal, and 1296 (84.2%) reported abnormal vaginal bleeding. Grayscale and color Doppler features varied according to grade and stage. High-risk tumors (stage 1A, grade 3 or non-endometrioid or ≥ stage 1B) were less likely to have regular endometrial myometrial border (difference of -23%, 95% CI -27 to -18%), whilst they were larger (mean endometrial thickness; difference of +9 mm, 95% CI +8 to +11 mm), more frequently had non-uniform echogenicity (difference of +10%, 95% CI +5 to +15%), 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%), than low-risk tumors. CONCLUSION: Grayscale and color Doppler ultrasound features are associated with grade and stage, and differ between high and low risk endometrial cancer.

Objectives: The aim of this study was to find the best 3D reconstruction technique to visualize the endometrial-myometrial junction (EMJ). Methods: Retrospective observational study on 240 stored 3D volumes of 80 patients. The first author reconstructed the 2D midcoronal image without volume contrast imaging (VCI), with VCI set at 4 mm and with VCI set at 2 mm. Three images per patient (240 images) were saved and integrated in the web-based electronic data capture software Clinical Data Miner (CDM) (http://cdm.esat.kuleuven.be). Five experienced gynaecologists analysed the images shown in random order. They scored the image quality (good, moderate, poor, insufficient) and described the EMJ of these images using IETA terminology (regular, irregular, interrupted, not defined). One of the examiners (CVP) also re-evaluated the same set of images after 12 days to assess intra-observer variability. Results: The use of VCI significantly improved the recorded subjective image quality. The Fleiss‘ kappa coefficient for evaluating the inter-observer variability of the EMJ description using coronal view without VCI, with VCI at 4 mm and VCI at 2 mm were 0.36 ± 0.05, 0.34 ± 0.05 and 0.42 ± 0.05, respectively. The corresponding figures for the intra-observer variability were 0.58 ± 0.08, 0.36 ± 0.08 and 0.68 ± 0.07, respectively. Discussion: In this study on 3D reconstructed coronal images of the uterine cavity, the 2 mm VCI slices gave the best quality images of the EMJ.

Book Review 1Book Title: The Threatened Medical Identity of Psychiatry: Winds of ChangeBook Author: Theodore PearlmanPp. xxi + 270. Illinois: Charles C Thomas. 1992.Book Review 2Book Title: Operative Laparoscopy. The Masters' TechniquesBook Author: Richard M. Sodenstrom (Ed.)Pp. xv + 245. Illustrated. New York: Raven Press. 1992.Book Review 3Book Title: Bailliere's Clinical Neurology: International Practice and Research: Ocular Motor Disorders of the Brain StemBook Authors: U Büttner & T Brandt (Eds.)Pp. ix + 263-475. Illustrated. London: Bailliere Tindall. 1992.Book Review 4Book Title: Rights and Responsibilities of DoctorsPp. xxviii + 226. Overseas £15, London: BMJ 1992Book Review 5Book Title: MRI of the KneeBook Authors: J.H. Mink, M.A. Reicher, J.V. Crues III & A. L. Deutsch (Eds.)2nd Ed. Pp. xiii + 474. Illustrated. New York: Raven Press. 1993Book Review 6Book Title: April Fool's Day: A Modern TragedyBook Author: B CourtenayPp. xii + 449. Port Melbourne, Australia: William Heinemann. 1993.Book Review 7Book Title: Report on Surrogate MotherhoodPp. xiv + 183. Pretoria: South African Law Commission. 1992.Book Review 8Book Title: Ward's Anaesthetic EquipmentBook Authors: Andrew Davey, John T. B. Moyle & Crispian S. Ward (Eds.)3rd Ed. pp. xiv + 391. Illustrated. London: W. B. Saunders. 1992.Book Review 9Book Title: Inside autism: Nobody NowhereBook Author: Donna WilliamsPp. xvii + 199. Illustrated. London: Doubleday. 1992.Book Review 10Book Title: Medical Negligence in South AfricaBook Authors: N.J. B. Claasens & T. VerschoorPp. 128. Pretoria: Digma Publications. 1992.Book Review 11Book Title: Biopsy Diagnosis of the Digestive Tract. (Biopsy Interpretation Series)Book Authors: Heidrun Rotterdam, Daniel G. Sheahan & Sheldon C. Sommers2nd Ed. Pp. 869. Illustrated. New York: Raven Press. 1992.Book Review 12Book Title: Baby and Child Care HandbookBook Author: Marina PetropulosPp. 334. Illustrated. Camps Bay: Marina Petropulos. 1992.

To assess interobserver reproducibility among ultrasound experts and gynecologists in the prediction by transvaginal ultrasound of deep myometrial and cervical stromal invasion in women with endometrial cancer.Sonographic videoclips of the uterine corpus and cervix of 53 women with endometrial cancer, examined preoperatively by the same ultrasound expert, were integrated into a digitalized survey. Nine ultrasound experts and nine gynecologists evaluated presence or absence of deep myometrial and cervical stromal invasion. Histopathology from hysterectomy specimens was used as the gold standard.Compared with gynecologists, ultrasound experts showed higher sensitivity, specificity and agreement with histopathology in the assessment of cervical stromal invasion (42% (95% CI, 31-53%) vs 57% (95% CI, 45-68%), P 0.01; 83% (95% CI, 78-86%) vs 87% (95% CI, 83-90%), P = 0.02; and kappa, 0.45 (95% CI, 0.40-0.49) vs 0.58 (95% CI, 0.53-0.62), P 0.001, respectively) but not of deep myometrial invasion (73% (95% CI, 66-79%) vs 73% (95% CI, 66-79%), P = 1.0; 70% (95% CI, 65-75%) vs 69% (95% CI, 63-74%), P = 0.68; and kappa, 0.48 (95% CI, 0.44-0.53) vs 0.52 (95% CI, 0.48-0.57), P = 0.11, respectively). Though interobserver reproducibility (in the context of test proportions 'good' and 'very good', according to kappa) regarding deep myometrial invasion did not differ between the groups (experts, 34% vs gynecologists, 22%, P = 0.13), ultrasound experts assessed cervical stromal invasion with significantly greater interobserver reproducibility than did gynecologists (53% vs 14%, P 0.001).Preoperative ultrasound assessment of deep myometrial and cervical stromal invasion in endometrial cancer is best performed by ultrasound experts, as, compared with gynecologists, they showed a greater degree of agreement with histopathology and greater interobserver reproducibility in the assessment of cervical stromal invasion.

Objectives: Our primary aim was to assess how patients’ characteristics, bleeding pattern, sonographic endometrial thickness (ET) and additional features at unenhanced ultrasound examination (UTVS) and at fluid instillation sonography (FIS) contribute to the diagnosis of intracavitary uterine pathology in women presenting with abnormal uterine bleeding (AUB). We further aimed to report the prevalence of pathology in women presenting with AUB. Methods: 1220 consecutive women presenting with AUB underwent UTVS, colour Doppler imaging (CDI) and FIS. Most women (n = 1042) had histological diagnosis. Results: Mean age was 50 years and 37% were postmenopausal. Of 1220 women 54% were normal, polyps were diagnosed in 26%, intracavitary fibroids in 11%, hyperplasia without atypia in 4% and cancer in 3%. All cancers were diagnosed in postmenopausal (7%) or perimenopausal (1%) women. ET had a low predictive value in premenopausal women (LR+ and LR- of 1.34 and 0.74, respectively), while FIS had a LR+ and LR- of 6.20 and 0.24, respectively. After menopause, ET outperformed all patient characteristics for the prediction of endometrial pathology (LR+ and LR- of 3.13 and 0.24). The corresponding LR+ and LR- were 10.85 and 0.71 for CDI and 8.23 and 0.26 for FIS. Conclusion: About half of the women presenting to a bleeding clinic will have pathology. In premenopausal women, benign lesions are often the cause of AUB. For the prediction of intracavitary pathology ET is of little value in premenopausal women. CDI and FIS substantially improve the diagnostic accuracy.

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.

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.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.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.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.

OBJECTIVE: To investigate the association between personal history, anthropometric features and lifestyle characteristics and endometrial malignancy in women with abnormal vaginal bleeding. METHODS: Prospective observational cohort assessed by descriptive and multivariable logistic regression analyses. Three features-age, body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters), and nulliparity-were defined a priori for baseline risk assessment of endometrial malignancy. The following variables were tested for added value: intrauterine contraceptive device, bleeding pattern, age at menopause, coexisting diabetes/hypertension, physical exercise, fat distribution, bra size, waist circumference, smoking/drinking habits, family history, use of hormonal/anticoagulant therapy, and sonographic endometrial thickness. We calculated adjusted odds ratio, optimism-corrected area under the receiver operating characteristic curve (AUC), R2 , and Akaike's information criterion. RESULTS: Of 2417 women, 155 (6%) had endometrial malignancy or endometrial intraepithelial neoplasia. In women with endometrial cancer median age was 67 years (interquartile range [IQR] 56-75 years), median parity was 2 (IQR 0-10), and median BMI was 28 (IQR 25-32). Age, BMI, and parity produced an AUC of 0.82. Other variables marginally affected the AUC, adding endometrial thickness substantially increased the AUC in postmenopausal women. CONCLUSION: Age, parity, and BMI help in the assessment of endometrial cancer risk in women with abnormal uterine bleeding. Other patient information adds little, whereas sonographic endometrial thickness substantially improves assessment. ispartof: INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS vol:159 issue:1 pages:103-110 ispartof: location:United States status: published

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

OBJECTIVE: To develop a preoperative risk model, using endometrial biopsy results and clinical and ultrasound variables, to predict the individual risk of lymph-node metastases in women with endometrial cancer. METHODS: A mixed-effects logistic regression model for prediction of lymph-node metastases was developed in 1501 prospectively included women with endometrial cancer undergoing transvaginal ultrasound examination before surgery, from 16 European centers. Missing data, including missing lymph-node status, were imputed. Discrimination, calibration and clinical utility of the model were evaluated using leave-center-out cross validation. The predictive performance of the model was compared with that of risk classification from endometrial biopsy alone (high-risk defined as endometrioid cancer Grade 3/non-endometrioid cancer) or combined endometrial biopsy and ultrasound (high-risk defined as endometrioid cancer Grade 3/non-endometrioid cancer/deep myometrial invasion/cervical stromal invasion/extrauterine spread). RESULTS: Lymphadenectomy was performed in 691 women, of whom 127 had lymph-node metastases. The model for prediction of lymph-node metastases included the predictors age, duration of abnormal bleeding, endometrial biopsy result, tumor extension and tumor size according to ultrasound and undefined tumor with an unmeasurable endometrium. The model's area under the curve was 0.73 (95% CI, 0.68-0.78), the calibration slope was 1.06 (95% CI, 0.79-1.34) and the calibration intercept was 0.06 (95% CI, -0.15 to 0.27). Using a risk threshold for lymph-node metastases of 5% compared with 20%, the model had, respectively, a sensitivity of 98% vs 48% and specificity of 11% vs 80%. The model had higher sensitivity and specificity than did classification as high-risk, according to endometrial biopsy alone (50% vs 35% and 80% vs 77%, respectively) or combined endometrial biopsy and ultrasound (80% vs 75% and 53% vs 52%, respectively). The model's clinical utility was higher than that of endometrial biopsy alone or combined endometrial biopsy and ultrasound at any given risk threshold. CONCLUSIONS: Based on endometrial biopsy results and clinical and ultrasound characteristics, the individual risk of lymph-node metastases in women with endometrial cancer can be estimated reliably before surgery. The model is superior to risk classification by endometrial biopsy alone or in combination with ultrasound. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. ispartof: ULTRASOUND IN OBSTETRICS & GYNECOLOGY vol:56 issue:3 pages:443-452 ispartof: location:England status: published

OBJECTIVES: To compare the performance of ultrasound measurements and subjective ultrasound assessment (SA) in detecting deep myometrial invasion (MI) and cervical stromal invasion (CSI) in women with endometrial cancer, overall and according to whether they had low- or high-grade disease separately, and to validate published measurement cut-offs and prediction models to identify MI, CSI and high-risk disease (Grade-3 endometrioid or non-endometrioid cancer and/or deep MI and/or CSI). METHODS: The study comprised 1538 patients with endometrial cancer from the International Endometrial Tumor Analysis (IETA)-4 prospective multicenter study, who underwent standardized expert transvaginal ultrasound examination. SA and ultrasound measurements were used to predict deep MI and CSI. We assessed the diagnostic accuracy of the tumor/uterine anteroposterior (AP) diameter ratio for detecting deep MI and that of the distance from the lower margin of the tumor to the outer cervical os (Dist-OCO) for detecting CSI. We also validated two two-step strategies for the prediction of high-risk cancer; in the first step, biopsy-confirmed Grade-3 endometrioid or mucinous or non-endometrioid cancers were classified as high-risk cancer, while the second step encompassed the application of a mathematical model to classify the remaining tumors. The 'subjective prediction model' included biopsy grade (Grade 1 vs Grade 2) and subjective assessment of deep MI or CSI (presence or absence) as variables, while the 'objective prediction model' included biopsy grade (Grade 1 vs Grade 2) and minimal tumor-free margin. The predictive performance of the two two-step strategies was compared with that of simply classifying patients as high risk if either deep MI or CSI was suspected based on SA or if biopsy showed Grade-3 endometrioid or mucinous or non-endometrioid histotype (i.e. combining SA with biopsy grade). Histological assessment from hysterectomy was considered the reference standard. RESULTS: In 1275 patients with measurable lesions, the sensitivity and specificity of SA for detecting deep MI was 70% and 80%, respectively, in patients with a Grade-1 or -2 endometrioid or mucinous tumor vs 76% and 64% in patients with a Grade-3 endometrioid or mucinous or a non-endometrioid tumor. The corresponding values for the detection of CSI were 51% and 94% vs 50% and 91%. Tumor AP diameter and tumor/uterine AP diameter ratio showed the best performance for predicting deep MI (area under the receiver-operating characteristics curve (AUC) of 0.76 and 0.77, respectively), and Dist-OCO had the best performance for predicting CSI (AUC, 0.72). The proportion of patients classified correctly as having high-risk cancer was 80% when simply combining SA with biopsy grade vs 80% and 74% when using the subjective and objective two-step strategies, respectively. The subjective and objective models had an AUC of 0.76 and 0.75, respectively, when applied to Grade-1 and -2 endometrioid tumors. CONCLUSIONS: In the hands of experienced ultrasound examiners, SA was superior to ultrasound measurements for the prediction of deep MI and CSI of endometrial cancer, especially in patients with a Grade-1 or -2 tumor. The mathematical models for the prediction of high-risk cancer performed as expected. The best strategies for predicting high-risk endometrial cancer were combining SA with biopsy grade and the subjective two-step strategy, both having an accuracy of 80%. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. ispartof: ULTRASOUND IN OBSTETRICS & GYNECOLOGY vol:55 issue:1 pages:115-124 ispartof: location:England status: published

We developed a targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the site-specific quantification of lysine acetylation in the N-terminal region of histone H4 by combining chemical derivatization at the protein and peptide levels with digestion using chymotrypsin and trypsin. Unmodified ε-amino groups were first modified with propionic acid anhydride and the derivatized protein digested with trypsin and chymotrypsin. The newly formed peptide N-termini were subjected to a second derivatization step with d6- (heavy) or d0- (light) acetic acid anhydride. Samples were mixed at different ratios and peptides monitored by multiple reaction monitoring (MRM) LC-MS/MS. The method was validated in terms of linearity (R2 ≥ 0.94), precision (RSD ≤ 10 %), and accuracy (≤27 %) and used to assess the effect of the histone deacetylase (HDAC) inhibitors SAHA and MS-275 in the murine macrophage-like cell line RAW 264.7. SAHA and MS-275 showed site-specific effects on the acetylation levels of K5 and K8 with the K5(Ac)–K8 and K5–K8(Ac) peptides increasing 2.5-fold and 5-fold upon treatment with SAHA and MS-275, respectively. Assessing lysine acetylation in a site-specific manner is important for gaining a better understanding of the effects of HDAC inhibitors and for clarifying disease mechanisms where lysine acetylation plays a role. Electronic supplementary material The online version of this article (doi:10.1007/s00216-016-9431-1) contains supplementary material, which is available to authorized users.

The aim of this work was to investigate the behavior of thermophilic esterase EST2 fromAlicyclobacillus acidocaldariusin milk and cheese models. The pure enzyme was used to compare the EST2 hydrolytic activity to the activity of endogenous esterase EstA fromLactococcus lactis. The results indicate that EST2 exhibits 30-fold-higher esterase activity than EstA. As EstA has thioesterase activity, EST2 was assayed for this activity under the optimal conditions determined for EstA (namely, 30°C and pH 7.5). Although it is a thermophilic enzyme, EST2 exhibited eightfold-higher thioesterase activity than EstA withS-methyl thiobutanoate. The abilities of EST2 and EstA to synthesize short-chain fatty acid esters were compared. Two methods were developed to do this. In the first method a spectrophotometric assay was used to monitor the synthesis of esters by the pure enzymes usingp-nitrophenol as the alcohol substrate. The synthetic activities were also evaluated under conditions that mimicked those present in milk and/or cheese. The second method involved evaluation of the synthetic abilities of the enzymes when they were directly added to a model cheese matrix. Substantial ester synthesis by EST2 was observed under both conditions. Finally, esterase and thioesterase activities were evaluated in milk using the purified EST2 enzyme and in the model cheese matrix using a strain ofL. lactisNZ9000 harboring the EST2 gene and thus overproducing EST2. Both the esterase and thioesterase activities measured in milk and in the cheese matrix were much greater than the activities of the controls.