Predictive value of the new ESGO-ESTRO-ESP endometrial cancer risk classification on survival and recurrence in the Danish population.

OBJECTIVE: To compare the performance of the new ESGO-ESTRO-ESP (European Society of Gynecological Oncology-European Society for Radiotherapy & Oncology-European Society for Pathology) 2020 risk classification system with the previous 2016 risk classification in predicting survival and patterns of recurrence in the Danish endometrial cancer population. METHODS: This Danish national cohort study included 4516 patients with endometrial cancer treated between 2005 and 2012. Five-year Kaplan-Meier adjusted and unadjusted survival estimates and actuarial recurrence rates were calculated for the previous and the new classification systems. RESULTS: In the 2020 risk classification system, 81.0% of patients were allocated to low, intermediate, or high-intermediate risk compared with 69.1% in the 2016 risk classification system, mainly due to reclassification of 44.5% of patients previously classified as high risk to either intermediate or especially high-intermediate risk. The survival of the 2020 high-risk group was significantly lower, and the recurrence rate, especially the non-local recurrence rate, was significantly higher than in the 2016 high risk group (2020/2016, overall survival 59%/66%; disease specific 69%/76%; recurrence 40.5%/32.3%, non-local 34.5%/25.8%). Survival and recurrence rates in the other risk groups and the decline in overall and disease-specific survival rates from the low risk to the higher risk groups were similar in patients classified according to the 2016 and 2020 systems. CONCLUSION: The new ESGO-ESTRO-ESP 2020 risk classification system allocated fewer patients to the high risk group than the previous risk classification system. The main differences were lower overall and disease-specific survival and a higher recurrence rate in the 2020 high risk group. The introduction of the new 2020 risk classification will potentially result in fewer patients at high risk and allocation to the new high risk group will predict lower survival, potentially allowing more specific selection for postoperative adjuvant therapy.

Direct access from general practice to transvaginal ultrasound for early detection of ovarian cancer: a feasibility study.

OBJECTIVE: To investigate the feasibility of providing general practitioners (GPs) direct and fast referral access to transvaginal ultrasound (TVUS). DESIGN: A prospective cohort study. SETTING: A total of 232 Danish general practices in parts of the Central Denmark Region. SUBJECTS: Women aged ≥40 years who consulted their GP for vague and non-specific symptoms (n = 479). MAIN OUTCOME MEASURES: The feasibility assessment included the GPs' referral rate, indications for referral, management of test results, and findings from TVUS. RESULTS: A total of 479 women were referred to TVUS. The examinations revealed abnormalities in 104 (21.7%) women. Additional investigations were needed in 68 (14.2%) women of whom seven (1.5%) underwent major surgery. No case of ovarian cancer was diagnosed during the study period or the 6-month follow-up. However, three (0.6%) women with an abnormal transvaginal ultrasound were diagnosed with urogynecological cancer; this yielded a PPV of 4.4% (95% confidence interval: 1.5-12.2) and an NPV of 100.0% (95% confidence interval: 96.7-100.0) for urogynecological cancer. CONCLUSION: Providing GPs with direct access to transvaginal ultrasound was feasible; 80% of the investigated women were referred back to the GP, 14% were further investigated, 0.6% were diagnosed with urogynecological cancer, and 1.5% had major procedures performed without complications. IMPLICATIONS: Direct access to TVUS could be an important pathway to ensure fast evaluation of women presenting with vague non-specific symptoms of potential ovarian cancer. Future studies should explore the patient experience, cancer outcomes, and health economics issues.KEY POINTS Current awareness • GPs have no fast referral option for women presenting with vague non-specific symptoms that could indicate underlying ovarian cancer. Key findings • We offered GPs direct and fast referral access to TVUS; 51.7% of practices used the opportunity. • The GPs referred 479 women to TVUS; 104 had an abnormal TVUS and 68 needed additional investigations. • Seven women underwent major surgery, leading to three cases of urogynecological cancer. No woman had a false negative TVUS result.

Effect of sphingosine-1-phosphate on activation of dormant follicles in murine and human ovarian tissue.

In vitro activation of resting ovarian follicles, with the use of mechanical stress and/or pharmacological compounds, is an emerging and novel approach for infertility treatment. The aim of this study was to assess the sphingolipid, sphingosine-1-phosphate (S1P), as a potential in vitro activation agent in murine and human ovarian tissues and isolated follicles. Juvenile murine ovaries and donated human ovarian tissues, from 10 women undergoing ovarian tissue cryopreservation for fertility preservation, were incubated with or without 12 µM S1P for 3 h for quantitative PCR analysis, and 12 h for xenotransplantation or culture studies. Gene expression analyses were performed for genes downstream of the Hippo signaling pathway. Murine ovaries and isolated murine and human preantral follicles showed significantly increased mRNA expression levels of Ccn2/CCN2 following S1P treatment compared to controls. This increase was shown to be specific for the Hippo signaling pathway and for the S1P2 receptor, as co-treatment with Hippo-inhibitor, verteporfin and S1PR2 antagonist, JTE-013, reduced the S1P-induced Ccn2 gene expression in murine ovaries. Histological evaluation of human cortical tissues (5 × 5 × 1 mm; n = 30; three pieces per patient) xenografted for 6 weeks and juvenile murine ovaries cultured for 4 days (n = 9) or allografted for 2 weeks (n = 48) showed no differences in the distribution of resting or growing follicles in S1P-treated ovarian tissues compared to controls. Collectively, S1P increased Ccn2/CCN2 gene expression in isolated preantral follicles and ovarian tissue from mice and human, but it did not promote follicle activation or growth in vivo. Thus, S1P does not appear to be a potent in vitro activation agent under these experimental conditions.

Imaging for Adenomyosis: Making the Diagnosis by Sonography.

OBJECTIVE: To demonstrate a systematic approach for ultrasound diagnosis of adenomyosis. DESIGN: Stepwise demonstration of the ultrasound features of adenomyosis with narrated video footage. SETTING: In 2015, the International Morphological Uterus Sonographic Assessment group published a consensus on which terminology to use when describing myometrial lesions seen on ultrasonography [12]. However, 2-dimensional (2D) and 3-dimensional (3D) ultrasound features of adenomyosis are demonstrated most optimally using video clips. INTERVENTIONS: A systematic description, including pictograms of individual features of adenomyosis, is correlated to the typical findings of adenomyosis in 2D and 3D ultrasound images and video clips. CONCLUSION: A structured, systematic description of individual 2D and 3D ultrasound features is important for a correct diagnosis of adenomyosis [3-5].

Reduced Complications Following Implementation of Laparoscopic Hysterectomy: A Danish Population-based Cohort Study of Minimally Invasive Benign Gynecologic Surgery between 2004 and 2018.

STUDY OBJECTIVE: To monitor and report nationwide changes in the rates of and complications after different methods for benign hysterectomy, operative hysteroscopy, myomectomy, and embolization in Denmark. To report the national mortality after benign hysterectomy DESIGN: National prospective, observational cohort study. SETTING: The Danish Hysterectomy and Hysteroscopy Database. PATIENTS: Women undergoing surgery for benign gynecologic diseases: 64 818 hysterectomies, 84 175 hysteroscopies, 4016 myomectomies, and 1209 embolizations in Denmark between 2004 and 2018. INTERVENTIONS: National meetings with representatives from all departments, annual working reports of institutional complication rates, workshops, and national guideline initiative to improve minimally invasive surgical methods. MEASUREMENTS AND MAIN RESULTS: Rates of the different methods and complications after each method with follow-up to 5 years as recorded by the database directly in the National Patient Registry. Nationwide, a decline in the use of hysterectomy, myomectomy, embolizations, and endometrial ablation. The total short-term complications were 9.8%, 7.5%, 8.9%, and 2.7% respectively, however, with a persistent risk of approximately 20% for recurrent operations within 5 years after endometrial ablation. Initially, we urged for increased use of vaginal hysterectomy, but only reached 36%. From 2010, we urged for reducing abdominal hysterectomies by implementing laparoscopic hysterectomy and reached 72% laparoscopic and robotic procedures. Since 2015, we used coring or contained morcellation for removal of large uterus at laparoscopic hysterectomy. The major and minor complication rates (modified Clavien-Dindo classification) were reduced significantly from 8.1% to 4.1% and 9.9% to 5.7% respectively. Mortality after benign hysterectomy was 0.27‰. The odds ratio for major complications after abdominal hysterectomy was 1.66 (1.52-1.81) compared to minimally invasive hysterectomy independent of the length of stay, high-volume departments, indications, comorbidity, age, and calendar year. CONCLUSION: Fifteen years with a national database has resulted in a marked quality improvement. Denmark has 85% minimally invasive hysterectomies and has reduced the number of major complications by 50%.

Two- and three-dimensional transvaginal ultrasonography for diagnosis of adenomyosis of the inner myometrium.

RESEARCH QUESTION: How diagnostically accurate is two-dimensional (2D-TVS) compared with three-dimensional transvaginal ultrasonography (3D-TVS) in diagnosing adenomyosis of the inner myometrium. What is the most accurate combination of ultrasonographic features? DESIGN: Premenopausal women (n = 110) scheduled for hysterectomy or transcervical resection of the endomyometrium owing to abnormal uterine bleeding were consecutively enrolled. All participants had real-time 2D-TVS and, later, blinded off-line 3D-TVS to diagnose adenomyosis. Results were compared with a detailed histopathological examination of the inner myometrium as gold standard. RESULTS: Prevalence of adenomyosis of the inner myometrium was 29%. For 2D-TVS and 3D-TVS, respectively, the diagnostic accuracy was sensitivity 72% (95% CI 53 to 86) and 69% (95% CI 50 to 84); specificity 76% (95% CI 65 to 85) and 86% (95% CI 76-93); and area under the curve (AUC) 0.74 (95% CI 0.7 to 0.8) and 0.77 (95% CI 0.7 to 0.9). Specificity of 3D-TVS was not statistically significantly better than 2D-TVS; the difference between them almost reached statistical significance (P = 0.06). The most accurate three-dimensional feature was junctional zone irregularity (JZmax-JZmin ≥5mm) (AUC: 0.78). A combination of two or more two-dimensional and two or more three-dimensional features was highly accurate (AUC: 0.77). CONCLUSIONS: For diagnosing adenomyosis of the inner myometrium, 3D-TVS offers a high accuracy similar to 2D-TVS. Identification of junctional zone irregularity with 3D-TVS may be beneficial to diagnosis. Two or more two-dimensional features and two or more three-dimensional features combined may give a more objective diagnosis, and may be useful for clinical practice and future research.

Location of recurrences in high-risk stage Iendometrial cancer patients not given postoperative radiotherapy: A Danish gynecological cancer group study.

OBJECTIVES: To study recurrence rates in Danish high-risk stage I endometrial cancers not given radiotherapy in accordance with the decision of the Danish Gynecological Cancer Group. METHODS: This prospective national cohort study includes all 4707 endometrial carcinomas diagnosed from 2005 to 2012. Of these, 623 patients had grade 3 endometroid adenocarcinoma with >50% myometrial invasion or serous/clear/undifferentiated carcinoma (with any depth of invasion). In 305 patients with high-risk stage I on final pathology, 14.1% received adjuvant external beam radiotherapy and 9.6% adjuvant chemotherapy. No patients received brachytherapy. 5-year Kaplan-Meier survival estimates and actuarial recurrence rates were calculated, and adjusted Cox regression analysis used for comparison. Recurrence rates were compared with historical Danish population data (DEMCA 98-99). RESULTS: For non-irradiated patients, 5-year overall survival, cancer-specific survival, and progression-free survival rates in high-risk stage I patients were 65%, 78%, and 73%, respectively. For non-irradiated patients, isolated local recurrences were uncommon (vaginal 3.1%, pelvic 0.4%). Death was mainly due to a high occurrence of non-local recurrences, with 8.8% experiencing a first recurrence in the abdominal cavity (outside the field where radiation traditionally have been given) and 13.0% a distant metastasis outside the abdominal cavity. Grade 3 tumors with >50% myometrial invasion seem to be characterized by a different pattern of recurrences, with significantly more isolated vaginal recurrences (7.9% vs 2.2%) and fewer total number of abdominal recurrences (7.9% vs 15.3%) as compared with unfavorable tumor types. CONCLUSION: Isolated vaginal and pelvic recurrences were rare (3-5%) in patients with a final pathologic diagnosis of high-risk stage I endometrial cancer even after the Danish Gynecological Cancer Group decided to omit all types of postoperative radiotherapy and introduce lymph node staging.

The effect of introducing pelvic lymphadenectomy on survival and recurrence rates in Danish endometrial cancer patients at high risk: a Danish Gynecological Cancer Group study.

OBJECTIVES: To evaluate the rate of survival and recurrence related to the introduction of pelvic lymphadenectomy in Danish high-risk endometrial cancer patients. STUDY DESIGN: Data on 713 high-risk patients defined as grade 3 with >50% myometrial invasion or serous/clear/undifferentiated carcinomas stage I-IV endometrial cancer patients diagnosed from 2005 to 2012 were retrieved from the Danish Gynecological Cancer Database. Of these, 305 were high-risk stage I. Five year Kaplan-Meier survival estimates and actuarial recurrence rates were calculated, and adjusted Cox used for comparison. Findings were compared with earlier Danish results. RESULTS: Lymphadenectomy in 390 radically operated high-risk patients resulted in upstaging of 31 patients from stage I to IIIC and 19 patients from stage II to IIIC corresponding to 12.8%. Upstaging from stage I to IIIC had a cancer-specific survival of 77%, almost comparable to lymph node-negative high-risk stage I patients (81%). Lymphadenectomy patients had a significant higher overall survival as compared with non-lymph node resected for all patients, but not for stage I patients. Lymphadenectomy, however, did not significantly affect cancer-specific survival, progression-free survival, recurrence rate or risk of local, distant, or lymph node recurrence. When the survival of high-risk stage I patients was compared with earlier Danish results, a small improvement in overall survival (7%) and cancer-specificsurvival (8%) was demonstrated. CONCLUSION: Only a small number of high-risk patients were upstaged from stage I to III due to lymphadenectomy. These patients showed a surprisingly good survival possibly due to correct stage identification and subsequent relevant adjuvant therapy. However, even though introduction of lymphadenectomy in the Danish high-risk population seems to increase overall survival, no significant change in cancer-specific survival, progression-free survival or recurrence patterns was demonstrated.

Two- and three-dimensional ultrasonographic features related to histopathology of the uterine endometrial-myometrial junctional zone.

INTRODUCTION: Our aim was to correlate junctional zone thickening and irregularity (junctional zone disease) and other ultrasonographic features of adenomyosis with the histopathology of the endometrial-myometrial junctional zone. MATERIAL AND METHODS: Consecutively enrolled premenopausal women (n = 110) scheduled for hysterectomy or transcervical endometrial resection due to abnormal uterine bleeding and/or menstrual pain, underwent two- and three-dimensional transvaginal ultrasonography on the day of surgery with the observer blinded to previous diagnosis. Junctional zone maximum thickness (JZmax ), junctional zone maximum irregularity (JZdif ) and ultrasonographic characteristics of adenomyosis were compared with histopathology of the junctional zone defined as (1) adenomyosis of the inner myometrium, ≥2 mm myometrial invasion without contact to the basal endometrium, (2) serrated junctional zone, >3 mm myometrial invasion with contact to the basal endometrium or (3) linear junctional zone, no or marginal myometrial invasion ≤3 mm with contact to the basal endometrium. RESULTS: Adenomyosis of the inner myometrium, serrated junctional zone and linear junctional zone was present in 29%, 35% and 35% of the women, respectively. Median JZmax and median JZdif expanded from linear junctional zone (8.5 and 3.3 mm) to serrated junctional zone (10.1 and 4.1 mm) to adenomyosis of the inner myometrium (14.6 and 9.2 mm) (P < 0.05). In addition, the median number of characteristic adenomyosis-like ultrasonographic features increased from the linear junctional zone to the serrated junctional zone to adenomyosis of the inner myometrium (P < 0.05). CONCLUSIONS: A slightly thickened and/or irregular junctional zone corresponds to a histopathologically defined serrated junctional zone. This study emphasizes three distinct appearances of the junctional zone: adenomyosis of the inner myometrium, junctional zone disease (serrated junctional zone) and linear junctional zone. This classification may be useful in future clinical studies.

Ultrasound Scoring of Endometrial Pattern for Fast-track Identification or Exclusion of Endometrial Cancer in Women with Postmenopausal Bleeding.

STUDY OBJECTIVE: To evaluate the risk of endometrial cancer (REC) scoring system for the prediction of high and low probability of endometrial cancer (EC) in women with postmenopausal bleeding (PMB). DESIGN: A prospective study (Canadian Task Force classification II-1). SETTING: An academic hospital. PATIENTS: Nine hundred fifty consecutive patients with PMB underwent transvaginal ultrasonography (TVS) and REC scoring between November 2013 and December 2015. INTERVENTIONS: Obstetrics and gynecology residents supervised by trained physicians scored endometrial patterns according to the previously established REC scoring system. The reference standard was endometrial samples, endometrial thickness (ET, 4-4.9 mm), operative hysteroscopy or hysterectomy (ET ≥5 mm), and 1-year follow-up in all patients presenting with ET <4 mm. Diagnostic performance for the prediction of probability of malignancy was assessed using the REC scoring system. MEASUREMENTS AND MAIN RESULTS: The area under the receiver operating characteristic curve of the TVS REC scoring system was 97% (95% confidence interval [CI], 95%-98%) for the prediction of malignancy. In 656 patients with ET ≥4 mm, REC scoring effectively predicted a high probability of malignancy with sensitivity (95% confidence interval) of 92% (95% CI, 87%-95%) and specificity of 94% (95% CI, 91%-96%). An REC score of 0 was present in 206 (32%) patients with ET ≥4 mm and was associated with a low negative likelihood ratio of 0.026 for EC. There were only 7 patients with EC/atypical hyperplasia among these 206 patients. CONCLUSION: The REC scoring system identified or ruled out most ECs, clearly showing that more specific image analysis at first-line TVS can accelerate the diagnosis of EC in patients with PMB and may allow for improved selection of second-line strategies in patients with ET ≥4 mm.

Inter-rater agreement in the diagnosis of adenomyosis by 2- and 3-dimensional transvaginal ultrasonography.

OBJECTIVES: To assess the inter-rater agreement of 2-dimensional (2D) and 3-dimensional (3D) transvaginal ultrasonography (TVUS) in the diagnosis of adenomyosis. METHODS: This prospective study included premenopausal women (n = 96) with heavy menstrual bleeding, menstrual pain, or both who were scheduled for hysterectomy or transcervical resection of the endometrium. All women underwent real-time 2D TVUS and subsequently offline 3D TVUS, which was blinded to 2D TVUS, by a single expert rater and a single nonexpert rater for the diagnosis of adenomyosis based on standardized pattern recognition and junctional zone measurements. Three-dimensional TVUS was done on a computer with 3D volumes recorded during 2D TVUS by both raters. The expert rater reported the image quality of all 3D volumes (n = 192). Inter-rater agreement (Cohen's κ) was assessed for both techniques, and the improvement over time was assessed for 2D TVUS. RESULTS: Diagnosis of adenomyosis showed good (κ = 0.69) and poor (κ = 0.21) inter-rater agreement with 2D and 3D TVUS, respectively (P < .05). The agreement with 2D TVUS improved over time. The agreement with 3D TVUS was slightly better for expert-recorded 3D volumes (κ = 0.40), which also had better image quality (P < .05). The most reproducible 2D and 3D features were anechoic lacunae (κ = 0.52) and junctional zone irregularity (κ = 0.27), respectively. CONCLUSIONS: Standardized pattern recognition during real-time 2D TVUS may result in good agreement between expert and nonexpert raters for the diagnosis of adenomyosis. Offline 3D TVUS is less reproducible, and junctional zone measurements do not improve the inter-rater agreement. The low inter-rater agreement may be related to a lack of experience and low image quality of nonexpert-recorded 3D volumes.

Intra- and Inter-Rater Agreement Describing Myometrial Lesions Using Morphologic Uterus Sonographic Assessment: A Pilot Study.

OBJECTIVES: To evaluate the intra- and inter-rater agreement for myometrial lesions using Morphologic Uterus Sonographic Assessment terminology. METHODS: Thirteen raters with high (n = 6) or medium experience (n = 7) assessed 30 3-dimensional ultrasound clips with (n = 20) and without (n = 10) benign myometrial lesions. Myometrial lesions were reported as poorly or well defined and then systematically evaluated for the presence of individual features. The clips were blindly assessed twice (at a 2-month interval). Intra- and inter-rater agreements were calculated with κ statistics. RESULTS: The reporting of poorly defined lesions reached moderate intra-rater agreement (κ = 0.49 [high experience] and 0.47 [medium experience]) and poor inter-rater agreement (κ = 0.39 [high experience] and 0.25 [medium experience]). The reporting of well-defined lesions reached good to very good intra-rater agreement (κ = 0.73 [high experience] and 0.82 [medium experience]) and good inter-rater agreement (κ = 0.75 [high experience] and 0.63 [medium experience]). Most individual features associated with ill-defined lesions reached moderate intra- and inter-rater agreement among highly experienced raters (κ = 0.41-0.60). The least reproducible features were myometrial cysts, hyperechoic islands, subendometrial lines and buds, and translesional flow (κ = 0.11-0.34). Most individual features associated with well-defined lesions reached moderate to good intra- and inter-rater agreement among all observers (κ = 0.41-0.80). The least reproducible features were a serosal contour, asymmetry, a hyperechoic rim, and fan-shaped shadows (κ = 0.00-0.35). CONCLUSIONS: The reporting of well-defined lesions showed excellent agreement, whereas the agreement for poorly defined lesions was low, even among highly experienced raters. The agreement on identifying individual features varied, especially for features associated with ill-defined lesions. Guidelines on minimum requirements for features associated with ill-defined lesions to be interpreted as poorly defined lesions may improve agreement.

Uterine adenomyosis and infertility, review of reproductive outcome after in vitro fertilization and surgery.

This review includes an analysis of the clinical studies evaluating reproductive outcome and adenomyosis, and a review of studies on reproductive outcome and surgical treatment options for adenomyosis. Strict diagnostic criteria and classification of disease are needed for an image diagnosis of adenomyosis. Studies of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) populations and women with surgically treated deep endometriosis have suggested that adenomyosis has a negative impact on reproductive outcome, although there are substantial variations between studies. Few data are available on the relation between the extent of disease and impact on reproductive outcome, but a correlation appears to exist. Case series seem to confirm a positive effect of gonadotropin-releasing hormone analog treatment and surgery on reproductive outcome, but there are no controlled trials. Evidence is impaired by the poor quality of many studies, a lack of strict image diagnosis, and the absence of a classification of the extent of disease. Selection of the optimal evidence-based treatment options for adenomyosis in the fertility clinic is difficult because of a lack of evidence regarding the relation between fertility and the degree and composition of adenomyosis. Adenomyosis may reduce implantation so severely that surgical or other treatment options should be recommended, but the benefit of these treatment options needs to be verified. Referral of women with adenomyosis and recurrent miscarriage and repeated failure of assisted reproductive technology to centers with a special interest in adenomyosis research and treatment may be critical.

Radiofrequency Thermal Ablation for Uterine Myomas: Long-term Clinical Outcomes and Reinterventions.

STUDY OBJECTIVE: To assess the long-term efficacy and rate of reintervention after ultrasound-guided radiofrequency thermal ablation (RFA) for uterine myomas. DESIGN: A retrospective follow-up, cohort study (Canadian Task Force classification II-2). SETTING: University hospitals and private clinics. PATIENTS: Between November 1, 2007, and February 26, 2010, 66 consecutive women underwent ultrasound-guided RFA. INTERVENTIONS: Patients underwent abdominal or vaginal ultrasound-guided RFA and were contacted for a long-term follow-up to complete the Uterine Fibroid Symptom and Quality of Life Score (UFS-QOL) questionnaire and optional ultrasound and examination. MEASUREMENTS AND MAIN RESULTS: Sixty-six consecutive patients (mean age 45 ± 7 years) with type 2 to 5 symptomatic myomas per the International Federation of Gynecology and Obstetrics (median size = 122.5 cm3 [range, 24-675]) were included. Forty of 62 patients recruited for follow-up underwent no/minor hysteroscopic reinterventions; 35 patients from this group completed the UFS-QOL questionnaire and showed sustained and improved symptom severity scores (100-point scale) from baseline (57.2 ± 16.6) to long-term follow-up (23.8 ± 20.8, p < .001). Twenty-two patients (35%) had major reinterventions (15 hysterectomies and 7 myomectomies). Six of the 22 patients underwent major reinterventions for reasons other than myoma-related complaints. The estimated major reintervention rate because of myoma-related symptoms determined by the Kaplan-Meier method was 13.5% (95% confidence interval [CI], 7%-25%) after 2 years and 29.1% (95% CI, 19%-43%) after 5 years. Women ≥45 years of age had a major reintervention rate of 12% (95% CI, 5%-26%) after 2 years and 19% (95% CI, 10%-35%) after 5 years, and women <45 years had a major reintervention rate of 35.0% (95% CI, 19%-60%) and 73.8% (95% CI, 52%-92%) after 2 and 5 years, respectively. Fewer major reinterventions occurred in women with only 1 RFA-treated myoma (volume ≤180 cm3, diameter <7 cm) than women with more than 1 RFA-treated myoma (>180 cm3, p < .01). The Kaplan-Meier estimates for reintervention in women with only 1 RFA-treated myoma with a volume ≤180 cm3 were 13% (95% CI, 6-28%) and 26% (95% CI, 14%-45%) after 2 and 5 years, respectively. No patients with morphologic myoma characteristics underwent reinterventions. CONCLUSION: Ultrasound-guided RFA for uterine myomas is an alternative treatment option especially for women ≥45 years of age with only 1 myoma (volume ≤180 cm3) and warrants further evaluation.

Assessment of myometrial invasion in endometrial cancer using three-dimensional ultrasound and magnetic resonance imaging.

INTRODUCTION: Preoperative knowledge of myometrial invasion in endometrial cancer is important for surgical planning. This study aimed to assess the diagnostic efficiency of two-dimensional (2D) and three-dimensional (3D) transvaginal ultrasonography (TVS) with and without saline infusion (SIS) and magnetic resonance imaging (MRI) for assessment of myometrial invasion in endometrial cancer. MATERIAL AND METHODS: 110 women with atypical endometrial hyperplasia or endometrial adenocarcinoma underwent preoperative 2D- and 3D-TVS with and without SIS and MRI. Offline 3D-TVS measurement was performed of the minimal tumor-free margin in relation to myometrial thickness expressed as deep (≥ 50%) myometrial invasion and subjective impression of cervix involvement. The quality of images was also evaluated. Diagnostic efficiencies were calculated for myometrial and cervical involvement for each method. The pathologist's final diagnosis served as the reference standard. RESULTS: For myometrial involvement, MRI showed greater accuracy than 3D-TVS or 2D-TVS (83, 71 and 75%, respectively). The efficiency of 3D-TVS was not superior to 2D-TVS and did not improve with SIS. The sensitivities of 2D-TVS and 3D-TVS were similar to that of MRI, and the efficiency of 3D-TVS improved when volumes of inadequate quality (39%) were excluded. For evaluating cervical involvement, the accuracy of 3D-TVS was 85%, comparable to the results of 2D-TVS (80%) and MRI (85%). The results did not improve when saline was added. CONCLUSION: 3D-TVS or 3D-SIS was not more efficient than 2D-TVS or MRI for assessment of myometrial invasion in endometrial cancer. 3D-TVS assessment without 2D-TVS was impeded by difficulties in obtaining 3D-TVS volumes of sufficient quality.

Repeatability of Junctional Zone Measurements Using 3-Dimensional Transvaginal Sonography in Healthy Fertile Women.

OBJECTIVES: To describe the junctional zone and determine the intraobserver and interobserver repeatability of junctional zone measurements using 3-dimensional (3D) transvaginal sonography in healthy fertile women. METHODS: We examined 82 consecutive women with 3D transvaginal sonography. The maximum and minimum junctional zone thickness was measured in all uterine walls. The difference between maximum and minimum thickness and average measurements (maximum thickness + minimum thickness/2) of the anterior, posterior, fundal, and lateral walls were calculated. Among the first 40 consecutive women, intraobserver and interobserver repeatability was evaluated according to the Bland-Altman method and expressed as a coefficient of repeatability. RESULTS: Using 3D transvaginal sonography, we visualized a thin and regular junctional zone in most women. The posterior uterine wall had the largest median maximum junctional zone thickness value of 5.2 (interquartile range, 3.8-6.5) mm. Ten women (12%) had maximum thickness values of 8.0 to 12.0 mm. The maximum thickness in each uterine wall had intraobserver and interobserver coefficients of repeatability of ±2.1 to ±3.4 and ±2.6 to ±3.9 mm, respectively, which were reduced by average measurements: ±1.9 and ±2.0 mm (anterior and posterior walls) and ±1.5 mm (fundal and lateral walls) for intraobserver and interobserver values. Correlations between measurements were poor in the narrow range of junctional zone thickness. CONCLUSIONS: The junctional zone has an indistinct outline on 3D transvaginal sonography, resulting in measurement errors within a broad range of ±2 to ±4 mm, which were only reduced to some extent by average measurements. The thickness of the junctional zone varied within a narrow range in this healthy fertile population, and reliability measurements of junctional zone thickness have to be evaluated in women with a wider range of thickness. The observer repeatability and reliability of junctional zone measurements need to be further evaluated and refined before applying this method in clinical practice.

Structured Hysteroscopic Evaluation of Endometrium in Women With Postmenopausal Bleeding.

STUDY OBJECTIVE: To evaluate visual pattern parameters obtained with hysteroscopy for the prediction of endometrial cancer, to evaluate observer variation of these parameters, and to present a scoring system of the parameters for the prediction of malignancy compared with subjective evaluation. DESIGN: A prospective controlled study (Canadian Task Force classification II-1). SETTING: A university clinic. PATIENTS: One hundred forty-nine consecutive women with postmenopausal bleeding and an endometrium thickness ≥ 5 mm. Sixty-one (41%) had endometrial cancer. Forty-six of 149 women were referred based on suspected malignancy. INTERVENTIONS: Endometrial pattern characteristics for endometrial cancer were evaluated in hysteroscopic video clips. The reference standard was pathologic evaluation of resectoscopic samples or hysterectomy. Using multivariate logistic regression, image parameters were correlated with the presence of endometrial cancer. A scoring system of visual parameters for the prediction of malignancy was compared with subjective evaluation of malignancy. MEASUREMENTS AND MAIN RESULTS: A score for lesion surface, necrosis, and vessels had an area under the curve (AUC) of 0.89, 0.89, and 0.87, respectively. A hysteroscopic cancer (HYCA) scoring system based on unsmooth lesion surface, papillary projections, surface necrosis, "candy floss" necrosis, white hyperintense spots, irregular branching vessels, and irregular distribution of irregular vessels was able to predict cancer (AUC = 0.964) with higher accuracy than subjective evaluation (AUC = 0.859, p < .01). At a score value ≥ 3, sensitivity was 89% and specificity was 92% with moderate agreement between observers (kappa = 0.56 [0.42-0.71]). CONCLUSION: A systematic pattern evaluation of optimal parameters by a HYCA scoring system based on systematically defined terms may increase accuracy in the diagnosis of endometrial cancer and should be further elaborated and external validity tested in unselected women with postmenopausal bleeding.

Reproducibility of Endometrial Pathologic Findings Obtained on Hysteroscopy, Transvaginal Sonography, and Gel Infusion Sonography in Women With Postmenopausal Bleeding.

STUDY OBJECTIVE: To evaluate and compare interobserver variation in endometrial pattern recognition with hysteroscopy (HY) and transvaginal sonography (TVS) and gel infusion sonography (GIS) with regard to the diagnosis of endometrial pathology. DESIGN: Prospective study (Canadian Task Force II-1). SETTING: University clinic. PATIENTS: One hundred twenty-two consecutive women with postmenopausal bleeding and an endometrium thickness ≥ 5 mm. INTERVENTION: Two observers using HY and 2 others using TVS and GIS evaluated the endometrial pattern in recorded video clips. Interobserver agreement regarding findings obtained with TVS, GIS, and HY for a diagnosis of cancer, hyperplasia, polyps, and no endometrial pathology was expressed by κ coefficients and compared. MEASUREMENT AND MAIN RESULTS: Interobserver agreement (κ) was as follows: identification of normal endometrium: HY (.74), TVS (.68), and GIS (.48); diagnosis of cancer: HY (.56), TVS (.59), and GIS (.34); classification in all categories of endometrial pathology: HY (.70), TVS (.47), and GIS (.41) (p < .05 HY vs GIS). The presence of additional endometrial polyps decreased agreement on HY in patients with hyperplasia or cancer. Observer agreement was poor regarding the diagnosis of hyperplasia by all techniques. CONCLUSION: Observer agreement regarding both HY and TVS was reliable for the diagnosis of a normal endometrium but poor with HY, TVS, and especially GIS for a diagnosis of cancer. In patients with hyperplasia or cancer, agreement between observers was especially low in the presence of additional polyps when HY was used. These findings call attention to the need for systematic methods to improve reliability in endometrial pattern recognition.

Dorsomorphin inhibits AMPK, upregulates Wnt and Foxo genes and promotes the activation of dormant follicles.

AMPK is a well-known energy sensor regulating cellular metabolism. Metabolic disorders such as obesity and diabetes are considered detrimental factors that reduce fecundity. Here, we show that pharmacologically induced in vitro activation (by metformin) or inhibition (by dorsomorphin) of the AMPK pathway inhibits or promotes activation of ovarian primordial follicles in cultured murine ovaries and human ovarian cortical chips. In mice, activation of primordial follicles in dorsomorphin in vitro-treated ovaries reduces AMPK activation and upregulates Wnt and FOXO genes, which, interestingly, is associated with decreased phosphorylation of ß-catenin. The dorsomorphin-treated ovaries remain of high quality, with no detectable difference in reactive oxygen species production, apoptosis or mitochondrial cytochrome c oxidase activity, suggesting safe activation. Subsequent maturation of in vitro-treated follicles, using a 3D alginate cell culture system, results in mature metaphase eggs with protruding polar bodies. These findings demonstrate that the AMPK pathway can safely regulate primordial follicles by modulating Wnt and FOXO genes, and reduce ß-catenin phosphorylation.

Preoperative staging of endometrial cancer using TVS, MRI, and hysteroscopy.

OBJECTIVES: To evaluate the accuracy of different preoperative modalities for staging of endometrial cancer to restrict extensive surgery to patients at high risk of metastatic disease. SETTING: Aarhus University Hospital. POPULATION: 156 women referred in 2006-2011 because of atypical endometrial hyperplasia (G0) or endometrial cancer. METHODS: Patients were offered preoperative transvaginal ultrasonography (TVS), magnetic resonance imaging (MRI), and hysteroscopic-directed biopsies from the uterine tumor and cervix. Final pathology of the removed uterus was the reference standard. Patients were divided into low risk (<50% myometrial invasion, and grades 0, 1, 2, and no cervical invasion) or high risk (all others). MAIN OUTCOME MEASURES: Accuracy, sensitivity, specificity, positive/negative predictive value. RESULTS: Patients were aged 32-88 years, with a mean body mass index of 29. At final pathology 81% had cancer and 19% G0 or no residual tumor; 54% were high risk. Hysteroscopy-directed biopsies had a higher accuracy (92%) than endometrial biopsy (58%) for differentiating G0 from cancer (p < 0.001); grade 3 tumor identification had similar accuracy (93 vs. 92%). Deep myometrial invasion was estimated with higher accuracy by MRI (82%) than TVS (74%) (p < 0.02). For cervical involvement, hysteroscopy-directed biopsies had higher accuracy (94%) than MRI (84%,) and TVS (80%) (p < 0.02). Accuracy for identifying high-risk women was highest (83%) using a combination of MRI and hysteroscopic-directed biopsies, compared with TVS and endometrial biopsy (72%) (p < 0.05). CONCLUSION: Preoperative staging with MRI and hysteroscopy-directed biopsy can identify eight of 10 women with high risk of lymph node metastases and spare eight of 10 low-risk women extended surgery.