Publications by authors named "Elisabeth Epstein"

32 Publications

Implementation of the 2021 molecular ESGO/ESTRO/ESP risk groups in endometrial cancer.

Gynecol Oncol 2021 Aug 11;162(2):394-400. Epub 2021 Jun 11.

Department of Oncology-Pathology, Karolinska Institutet, Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden. Electronic address:

Introduction: In 2021, a joint ESGO/ESTRO/ESP committee updated their evidence-based guidelines for endometrial cancer, recommending a new risk grouping incorporating both clinicopathologic and molecular parameters. We applied the new risk grouping and compared the results to those of the prior 2016 clinicopathologic system.

Materials And Methods: We classified molecularly a cohort of 604 women diagnosed with endometrial cancer using immunohistochemistry for TP53 and MMR proteins on a tissue microarray, as well as Sanger sequencing for POLE mutations. These results, combined with clinicopathologic data, allowed the patients to be risk grouped using both the new 2021 molecular/clinicopathologic parameters and the prior 2016 clinicopathologic system.

Results: The application of the 2021 molecular markers shows Kaplan-Meier curves with a significant difference between the groups for all survival. Molecular classification under the 2021 guidelines revealed a total of 39 patients (39/594, 7%) with a change in risk group in relation to the 2016 classification system: the shift was alone due to either P53abn or POLEmut molecular marker. In order to ensure correct 2021 molecular risk classification, not all patients with endometrial cancer need a molecular diagnostic: 433 (72.9%) cases would need to be analyzed by TP53 IHC, only 46 (7.7%) by MMR IHC and 286 (48.1%) POLE sequencing reactions.

Conclusion: Application of the 2021 molecular risk groups is feasible and shows significant differences in survival. IHC for TP53 and MMR and applying POLE sequencing is only needed in selected cases and leads to shifting risk groups both upward and downward for a sizeable number of patients. It is possible to significantly reduce the number of analyses required to implement the classification if resources are limited.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygyno.2021.05.026DOI Listing
August 2021

Vaginal bromocriptine for treatment of adenomyosis: Impact on magnetic resonance imaging and transvaginal ultrasound.

Eur J Obstet Gynecol Reprod Biol 2020 Nov 24;254:38-43. Epub 2020 Aug 24.

Department of Women´s and Children´s Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.

Objective: Vaginal bromocriptine significantly reduces heavy menstrual bleeding and pain in women with diffuse adenomyosis. The aim of this pilot study was to evaluate whether imaging findings of adenomyosis, as assessed by transvaginal ultrasound (TVU) and magnetic resonance imaging (MRI) reflect changes induced by the bromocriptine treatment.

Study Design: Eighteen women, aged 35-50, with heavy menstrual bleeding reporting Pictorial Blood Loss Assessment Chart (PBLAC) scores >100 and diffuse adenomyosis according to both MRI and TVU were included. The subjects underwent treatment with vaginal bromocriptine for 6 months. MRI and TVU were performed at baseline and after 6 months of medication.

Results: Mean age of the participants was 44.8 years, 77.8 % reported PBLAC scores > 250 and 66.7 % reported moderate to severe pain during menstruation at baseline. As compared to baseline, TVU revealed a thinner maximal Junctional Zone (JZmax) (8.5 mm [5.2-14] vs 7.9 mm [5-11.2], p = 0.02) at 6 months. Asymmetric wall thickening was seen in 13 (72 %) at baseline, and in 6 (33 %) women at 6 months, p = 0.02. No significant changes were seen in irregular endometrial-myometrial border, presence of fan-shaped shadowing, cystic changes, striations, hyperechogenic islands or lesion extension. MRI showed no significant difference in JZmax (16.0 mm[12.1-27.7] vs 15.5 mm [9.5-25.8], p = 0.81), JZdifference (9.5 mm[4.8-21.6] vs 8.4[3.8-19.5], p = 1) or Ratio JZ/myometrium (0.6 [0.5-0.8] vs. 0.6[0.4-0.8], p = 0.9) at baseline vs 6 month. Cystic lesions in the JZ were found in 9 women (50 %) before, and in 5 women (28 %) at 6 months, p = 0.13.

Conclusion: TVU showed a significant decrease in JZ max and a reduced number of women with asymmetric myometrial wall thickness. The changes seen in this small pilot study may indicate that vaginal bromocriptine have an impact on adenomyosis that is reflected in radiological appearance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejogrb.2020.08.040DOI Listing
November 2020

Validation of models to diagnose ovarian cancer in patients managed surgically or conservatively: multicentre cohort study.

BMJ 2020 07 30;370:m2614. Epub 2020 Jul 30.

Department of Development and Regeneration, KU Leuven, Herestraat 49 Box 805, 3000 Leuven, Belgium.

Objective: To evaluate the performance of diagnostic prediction models for ovarian malignancy in all patients with an ovarian mass managed surgically or conservatively.

Design: Multicentre cohort study.

Setting: 36 oncology referral centres (tertiary centres with a specific gynaecological oncology unit) or other types of centre.

Participants: Consecutive adult patients presenting with an adnexal mass between January 2012 and March 2015 and managed by surgery or follow-up.

Main Outcome Measures: Overall and centre specific discrimination, calibration, and clinical utility of six prediction models for ovarian malignancy (risk of malignancy index (RMI), logistic regression model 2 (LR2), simple rules, simple rules risk model (SRRisk), assessment of different neoplasias in the adnexa (ADNEX) with or without CA125). ADNEX allows the risk of malignancy to be subdivided into risks of a borderline, stage I primary, stage II-IV primary, or secondary metastatic malignancy. The outcome was based on histology if patients underwent surgery, or on results of clinical and ultrasound follow-up at 12 (±2) months. Multiple imputation was used when outcome based on follow-up was uncertain.

Results: The primary analysis included 17 centres that met strict quality criteria for surgical and follow-up data (5717 of all 8519 patients). 812 patients (14%) had a mass that was already in follow-up at study recruitment, therefore 4905 patients were included in the statistical analysis. The outcome was benign in 3441 (70%) patients and malignant in 978 (20%). Uncertain outcomes (486, 10%) were most often explained by limited follow-up information. The overall area under the receiver operating characteristic curve was highest for ADNEX with CA125 (0.94, 95% confidence interval 0.92 to 0.96), ADNEX without CA125 (0.94, 0.91 to 0.95) and SRRisk (0.94, 0.91 to 0.95), and lowest for RMI (0.89, 0.85 to 0.92). Calibration varied among centres for all models, however the ADNEX models and SRRisk were the best calibrated. Calibration of the estimated risks for the tumour subtypes was good for ADNEX irrespective of whether or not CA125 was included as a predictor. Overall clinical utility (net benefit) was highest for the ADNEX models and SRRisk, and lowest for RMI. For patients who received at least one follow-up scan (n=1958), overall area under the receiver operating characteristic curve ranged from 0.76 (95% confidence interval 0.66 to 0.84) for RMI to 0.89 (0.81 to 0.94) for ADNEX with CA125.

Conclusions: Our study found the ADNEX models and SRRisk are the best models to distinguish between benign and malignant masses in all patients presenting with an adnexal mass, including those managed conservatively.

Trial Registration: ClinicalTrials.gov NCT01698632.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmj.m2614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391073PMC
July 2020

Women with fair phenotypes seem to confer a survival advantage in a low UV milieu. A nested matched case control study.

PLoS One 2020 30;15(1):e0228582. Epub 2020 Jan 30.

Departments of Oncology and Cancer Epidemiology, Lund University Hospital, Lund, Sweden.

Background: Sun exposure in combination with skin pigmentation is the main determinant for vitamin D status. Human skin color seems to be adapted and optimized for regional sun ultraviolet (UV) intensity. However, we do not know if fair, UV-sensitive skin is a survival advantage in regions with low UV radiation.

Methods: A population-based nested case-control study of 29,518 Caucasian women, ages 25 to 64 years from Southern Sweden who responded to a questionnaire regarding risk-factors for malignant melanoma in 1990 and followed for 25 years. For each fair woman, defined as having red hair or freckles (n = 11,993), a control was randomly selected from all non-fair women from within the cohort of similar age, smoking habits, education, marital status, income, and comorbidity, i.e., 11,993 pairs. The main outcome was the difference in all-cause mortality between fair and non-fair women in a low UV milieu, defined as living in Sweden and having low-to-moderate sun exposure habits. Secondary outcomes were mortality by sun exposure, and among those non-overweight.

Results: In a low UV milieu, fair women were at a significantly lower all-cause mortality risk as compared to non-fair women (log rank test p = 0.04) with an 8% lower all-cause mortality rate (hazard ratio [HR] = 0.92, 95% CI 0.84‒1.0), including a 59% greater risk of dying from skin cancer among fair women (HR 1.59, 95% CI 1.26‒2.0). Thus, it seem that the beneficial health effect from low skin coloration outweigh the risk of skin cancer at high latitudes.

Conclusion: In a region with low UV milieu, evolution seems to improve all-cause survival by selecting a fair skin phenotype, i.e., comprising fair women with a survival advantage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228582PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992199PMC
April 2020

Clinicopathological and molecular characterisation of 'multiple-classifier' endometrial carcinomas.

J Pathol 2020 03 12;250(3):312-322. Epub 2020 Jan 12.

Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.

Endometrial carcinoma (EC) molecular classification based on four molecular subclasses identified in The Cancer Genome Atlas (TCGA) has gained relevance in recent years due to its prognostic utility and potential to predict benefit from adjuvant treatment. While most ECs can be classified based on a single classifier (POLE exonuclease domain mutations - POLEmut, MMR deficiency - MMRd, p53 abnormal - p53abn), a small but clinically relevant group of tumours harbour more than one molecular classifying feature and are referred to as 'multiple-classifier' ECs. We aimed to describe the clinicopathological and molecular features of multiple-classifier ECs with abnormal p53 (p53abn). Within a cohort of 3518 molecularly profiled ECs, 107 (3%) tumours displayed p53abn in addition to another classifier(s), including 64 with MMRd (MMRd-p53abn), 31 with POLEmut (POLEmut-p53abn), and 12 with all three aberrations (MMRd-POLEmut-p53abn). MMRd-p53abn ECs and POLEmut-p53abn ECs were mostly grade 3 endometrioid ECs, early stage, and frequently showed morphological features characteristic of MMRd or POLEmut ECs. 18/28 (60%) MMRd-p53abn ECs and 7/15 (46.7%) POLEmut-p53abn ECs showed subclonal p53 overexpression, suggesting that TP53 mutation was a secondary event acquired during tumour progression. Hierarchical clustering of TCGA ECs by single nucleotide variant (SNV) type and somatic copy number alterations (SCNAs) revealed that MMRd-p53abn tumours mostly clustered with single-classifier MMRd tumours (20/23) rather than single-classifier p53abn tumours (3/23), while POLEmut-p53abn tumours mostly clustered with single-classifier POLEmut tumours (12/13) and seldom with single-classifier p53abn tumours (1/13) (both p ≤ 0.001, chi-squared test). Finally, the clinical outcome of patients with MMRd-p53abn and POLEmut-p53abn ECs [stage I 5-year recurrence-free survival (RFS) of 92.2% and 94.1%, respectively] was significantly different from single-classifier p53abn EC (stage I RFS 70.8%, p = 0.024 and p = 0.050, respectively). Our results support the classification of MMRd-p53abn EC as MMRd and POLEmut-p53abn EC as POLEmut. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/path.5373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065184PMC
March 2020

Interpretation of somatic POLE mutations in endometrial carcinoma.

J Pathol 2020 03 29;250(3):323-335. Epub 2020 Jan 29.

Department of Pathology and Laboratory Medicine, University of British Columbia and Vancouver General Hospital, Vancouver, Canada.

Pathogenic somatic missense mutations within the DNA polymerase epsilon (POLE) exonuclease domain define the important subtype of ultramutated tumours ('POLE-ultramutated') within the novel molecular classification of endometrial carcinoma (EC). However, clinical implementation of this classifier requires systematic evaluation of the pathogenicity of POLE mutations. To address this, we examined base changes, tumour mutational burden (TMB), DNA microsatellite instability (MSI) status, POLE variant frequency, and the results from six in silico tools on 82 ECs with whole-exome sequencing from The Cancer Genome Atlas (TCGA). Of these, 41 had one of five known pathogenic POLE exonuclease domain mutations (EDM) and showed characteristic genomic alterations: C>A substitution > 20%, T>G substitutions > 4%, C>G substitutions < 0.6%, indels < 5%, TMB > 100 mut/Mb. A scoring system to assess these alterations (POLE-score) was developed; based on their scores, 7/18 (39%) additional tumours with EDM were classified as POLE-ultramutated ECs, and the six POLE mutations present in these tumours were considered pathogenic. Only 1/23 (4%) tumours with non-EDM showed these genomic alterations, indicating that a large majority of mutations outside the exonuclease domain are not pathogenic. The infrequent combination of MSI-H with POLE EDM led us to investigate the clinical significance of this association. Tumours with pathogenic POLE EDM co-existent with MSI-H showed genomic alterations characteristic of POLE-ultramutated ECs. In a pooled analysis of 3361 ECs, 13 ECs with DNA mismatch repair deficiency (MMRd)/MSI-H and a pathogenic POLE EDM had a 5-year recurrence-free survival (RFS) of 92.3%, comparable to previously reported POLE-ultramutated ECs. Additionally, 14 cases with non-pathogenic POLE EDM and MMRd/MSI-H had a 5-year RFS of 76.2%, similar to MMRd/MSI-H, POLE wild-type ECs, suggesting that these should be categorised as MMRd, rather than POLE-ultramutated ECs for prognostication. This work provides guidance on classification of ECs with POLE mutations, facilitating implementation of POLE testing in routine clinical care. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/path.5372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065171PMC
March 2020

GestaTIonal TrophoblAstic NeoplasIa Ultrasound assessMent: TITANIUM study.

Int J Gynecol Cancer 2019 09 26;29(7):1216-1220. Epub 2019 Jun 26.

Gynecology and Breast Care Center, Mater Olbia Hospital, Olbia, Italy.

Background: There are limited data on ultrasound morphologic features of gestational trophoblastic neoplasia. A predictive model to determine predictors of response to therapy would be ideal in the management of patients with this rare disease.

Primary Objectives And Study Hypothesis: TITANIUM is a prospective, multicenter, observational study aiming to describe ultrasound features of gestational trophoblastic neoplasia and to investigate the role of ultrasound in identifying patients at high risk of resistance to single-drug therapy. The study hypothesis is that ultrasound could improve the International Federation of Gynecology and Obstetrics (FIGO) scoring system for early identification of patients predisposed to single-drug resistance.

Trial Design And Major Inclusion/exclusion Criteria: Patients eligible have a diagnosis of gestational trophoblastic neoplasia according to FIGO or the criteria set by Charing Cross Hospital, London, UK. At diagnosis, patients are classified as low-risk (score 0-6) or high-risk (score >6) according to the FIGO risk scoring system, and a baseline ultrasound scan is performed. Patients receive treatment according to local protocol at each institution. Follow-up ultrasound examinations are performed at 1, 4, 10, 16, and 22 months after start of chemotherapy, and at each scan, serum human chorionic gonadotropin (hCG) level, and chemotherapy treatment, if any, are recorded.

Primary Endpoints: Our aims are to define ultrasound features of gestational trophoblastic neoplasia and to develop a predictive model of resistance to single-drug therapy in low-risk patients.

Sample Size: The sample size was calculated assuming that 70% of patients with gestational trophoblastic neoplasia are at low risk, and estimating the rate of resistance to single-drug therapy in this group to be 40%. Assuming a dropout rate of 10%, we should recruit at least 120 patients. With this sample size, we can attempt to create a mathematical model with three variables (either two ultrasound parameters in addition to the risk score or three ultrasound variables statistically significant at univariate analysis) to predict resistance to single-drug therapy in low-risk patients.

Estimated Dates For Completing Accrual And Presenting Results: The accrual started in February 2019. Additional referral centers for gestational trophoblastic disease, with similar ultrasound expertise, are welcome to participate in the study. Enrollment should be completed by December 2021, and analysis will be conducted in December 2023.

Trial Registration: The study received the Ethical Committee approval of the Coordinator Center (Rome) in January 2019 (Protocol No. 0004668/19).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/ijgc-2019-000434DOI Listing
September 2019

Phenotype of POLE-mutated endometrial cancer.

PLoS One 2019 27;14(3):e0214318. Epub 2019 Mar 27.

Department of Oncology-Pathology, Karolinska Institutet, and Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.

Background And Purpose: Individualized therapy in endometrial cancer, the most common gynaecologic cancer in the developed world, focuses on identifying specific molecular subtypes. Mutations in the exonuclease domain of the DNA polymerase epsilon (POLE) gene define one such subtype, which causes an ultra-mutated tumour phenotype. These tumours may have an improved progression-free survival and may be receptive to specific therapies. However, the clinical phenotype of these tumours is unknown. The objective of this study was to evaluate the clinical and genetic features of POLE-mutated tumours from a large cohort of women whose cases are characterized by: (1) the availability of detailed clinical and lifestyle data; (2) mutation analysis; and (3) long-term follow-up.

Methods: A total of 604 patients with endometrial cancer were included in the study. Data from a detailed questionnaire, including lifestyle and family history information, provided extensive pertinent information on the patients. Sequencing of exons 9-14 of the POLE gene was performed. Follow-up data were gathered and analysed.

Results: Hotspot pathogenic POLE mutations were identified in N = 38/599 patients (6.3%). Patients with a POLE-mutated tumour were significantly younger, were more often nulliparous, and had a history of smoking. POLE-mutated tumours were more frequently aneuploid. Prognosis for patients with hotspot POLE-mutated tumours was significantly better in comparison with patients with non-mutated tumours; however careful selection of pathogenic mutations is essential to the definition of this prognostically favourable group.

Conclusions: This study demonstrates that POLE-mutated endometrial cancer is significantly associated with previously unknown clinicopathologic characteristics. Outcome in POLE-mutated tumours was excellent in cases with hotspot mutations. Our results suggest that prediction of excellent outcome in cases of POLE-mutated EMCA should be restricted to cases of EMCA with hotspot mutations until further data are available on the rising number of mutations with unknown significance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214318PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436745PMC
December 2019

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

J Ultrasound Med 2019 Oct 23;38(10):2673-2683. Epub 2019 Feb 23.

Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jum.14971DOI Listing
October 2019

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

Lancet Oncol 2019 03 5;20(3):448-458. Epub 2019 Feb 5.

Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium. Electronic address:

Background: Ovarian tumours are usually surgically removed because of the presumed risk of complications. Few large prospective studies on long-term follow-up of adnexal masses exist. We aimed to estimate the cumulative incidence of cyst complications and malignancy during the first 2 years of follow-up after adnexal masses have been classified as benign by use of ultrasonography.

Methods: In the international, prospective, cohort International Ovarian Tumor Analysis Phase 5 (IOTA5) study, patients aged 18 years or older with at least one adnexal mass who had been selected for surgery or conservative management after ultrasound assessment were recruited consecutively from 36 cancer and non-cancer centres in 14 countries. Follow-up of patients managed conservatively is ongoing at present. In this 2-year interim analysis, we analysed patients who were selected for conservative management of an adnexal mass judged to be benign on ultrasound on the basis of subjective assessment of ultrasound images. Conservative management included ultrasound and clinical follow-up at intervals of 3 months and 6 months, and then every 12 months thereafter. The main outcomes of this 2-year interim analysis were cumulative incidence of spontaneous resolution of the mass, torsion or cyst rupture, or borderline or invasive malignancy confirmed surgically in patients with a newly diagnosed adnexal mass. IOTA5 is registered with ClinicalTrials.gov, number NCT01698632, and the central Ethics Committee and the Belgian Federal Agency for Medicines and Health Products, number S51375/B32220095331, and is ongoing.

Findings: Between Jan 1, 2012, and March 1, 2015, 8519 patients were recruited to IOTA5. 3144 (37%) patients selected for conservative management were eligible for inclusion in our analysis, of whom 221 (7%) had no follow-up data and 336 (11%) were operated on before a planned follow-up scan was done. Of 2587 (82%) patients with follow-up data, 668 (26%) had a mass that was already in follow-up at recruitment, and 1919 (74%) presented with a new mass at recruitment (ie, not already in follow-up in the centre before recruitment). Median follow-up of patients with new masses was 27 months (IQR 14-38). The cumulative incidence of spontaneous resolution within 2 years of follow-up among those with a new mass at recruitment (n=1919) was 20·2% (95% CI 18·4-22·1), and of finding invasive malignancy at surgery was 0·4% (95% CI 0·1-0·6), 0·3% (<0·1-0·5) for a borderline tumour, 0·4% (0·1-0·7) for torsion, and 0·2% (<0·1-0·4) for cyst rupture.

Interpretation: Our results suggest that the risk of malignancy and acute complications is low if adnexal masses with benign ultrasound morphology are managed conservatively, which could be of value when counselling patients, and supports conservative management of adnexal masses classified as benign by use of ultrasound.

Funding: Research Foundation Flanders, KU Leuven, Swedish Research Council.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(18)30837-4DOI Listing
March 2019

Clinical and Ultrasound Characteristics of the Microcystic Elongated and Fragmented (MELF) Pattern in Endometrial Cancer According to the International Endometrial Tumor Analysis (IETA) criteria.

Int J Gynecol Cancer 2019 01;29(1):119-125

Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

Objectives: To describe sonographic features of the microcystic elongated and fragmented (MELF) pattern of myometrial invasion (MI) using the International Endometrial Tumor Analysis (IETA) criteria; to assess the effect of the MELF pattern on preoperative ultrasound evaluation of MI; and to determine the relationship of the MELF pattern to more advanced stage (≥ IB) and lymph node metastases in women with endometrioid endometrial cancer.

Methods/materials: We included 850 women with endometrioid endometrial cancer from the prospective IETA 4 study. Ultrasound experts performed all ultrasound examinations, according to the IETA protocol. Reference pathologists assessed the presence or absence of the MELF pattern. Sonographic features and accuracy of ultrasound assessment of MI were compared in cases with the presence and the absence of the MELF pattern. The MELF pattern was correlated to more advanced stage (≥IB) and lymph node metastases.

Results: The MELF pattern was present in 197 (23.2%) women. On preoperative ultrasound imaging the endometrium was thicker (p = 0.031), more richly vascularized (p = 0.003) with the multiple multifocal vessel pattern (p < 0.001) and the assessment of adenomyosis was more often uncertain (p < 0.001). The presence or the absence of the MELF pattern did not affect the accuracy of the assessment of MI. The MELF pattern was associated with deep myometrial invasion (≥ 50%) (p < 0.001), cervical stromal invasion (p = 0.037), more advanced stage (≥ IB) (p < 0.001) and lymph node metastases (p = 0.011).

Conclusions: Tumors with the MELF pattern were slightly larger, more richly vascularized with multiple multifocal vessels and assessment of adenomyosis was more uncertain on ultrasound imaging. The MELF pattern did not increase the risk of underestimating MI in preoperative ultrasound staging. Tumors with the MELF pattern were more than twice as likely to have more advanced stage (≥ IB) and lymph node metastases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/ijgc-2018-000045DOI Listing
January 2019

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

Gynecol Oncol 2018 09 18;150(3):438-445. Epub 2018 Jul 18.

Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

Objectives: The aim is to estimate agreement between two-dimensional transvaginal ultrasound (2D-TVS) and three-dimensional volume contrast imaging (3D-VCI) in diagnosing deep myometrial invasion (MI) and cervical stromal involvement (CSI) of endometrial cancer and to compare the two methods regarding inter-rater reliability and diagnostic accuracy.

Methods: Fifteen ultrasound experts assessed off-line de-identified 3D-VCI volumes and 2D-TVU video clips from 58 patients with biopsy-confirmed endometrial cancer regarding the presence of deep (≥50%) MI and CSI. Video clips and 3D volumes were assessed independently. Interrater reliability was measured using kappa statistics. Histological diagnosis after hysterectomy served as gold standard. Accuracy measurements were correlated to rater experience using Spearman's rank correlation coefficient (ρ).

Results: Agreement between 2D-TVU and 3D-VCI for diagnosing MI was median 76% (range 64-93%) and for CSI median 88% (range 79-97%). Interrater reliability was better for 2D-TVU than for 3D-VCI (Fleiss' kappa 0.41 vs. 0.31 for MI and 0.55 vs. 0.45 for CSI). Median accuracy for diagnosing deep MI was 76% (range 59-84%) with 2D-TVU and 69% (range 52-83%) for 3D-VCI; the corresponding figures for CSI were 88% (range 81-93%) and 86% (range 72-95%). Accuracy was significantly correlated to how many cases the raters assessed annually.

Conclusions: Off-line assessment of MI and CSI in women with endometrial cancer using 3D-VCI has lower interrater reliability and lower accuracy than 2D-TVU video clip assessment. Since accuracy was correlated to the number of cases assessed annually it is advised to centralize these examinations to high-volume centres.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygyno.2018.06.027DOI Listing
September 2018

A Pilot Study on Diagnostic Performance of Contrast-Enhanced Ultrasonography for Detection of Early Cervical Cancer.

Ultrasound Med Biol 2018 08 30;44(8):1664-1671. Epub 2018 May 30.

Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Science and Education, Södersjukhuset, Stockholm, Sweden.

In this cohort study of 49 women with all stages of cervical cancer and 21 healthy controls, we compared contrast-enhanced ultrasonography (CEUS) filling pattern and semi-quantitative parameters in the two groups. Participants were examined with conventional grayscale and power Doppler ultrasound (US) followed by CEUS, using a 2.5 mL bolus of intravenous contrast agent. CEUS video clips were analyzed with regard to contrast distribution (focal or global) and semi-quantitative parameters. Focal contrast distribution was found in 3% (1/32) of the women with no tumor versus 89% (34/38) of women with histologically detectable tumor. A semi-quantitative analysis showed that the amount of contrast over a period of the whole tumor (area under the curve [AUC[ 0.92, 95% confidence interval [CI] 0.87-1.0), and the maximal intensity area (AUC 0.94, 95% CI 0.84-1.0) could accurately distinguish tumors from healthy tissue. In conclusion, the CEUS parameters differ significantly between tumors and healthy cervical tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ultrasmedbio.2018.04.018DOI Listing
August 2018

Platelet protein biomarker panel for ovarian cancer diagnosis.

Biomark Res 2018 12;6. Epub 2018 Jan 12.

3Department of Oncology and Pathology, Cancer Centre Karolinska, Karolinska Institute, SE-171 76 Stockholm, Sweden.

Background: Platelets support cancer growth and spread making platelet proteins candidates in the search for biomarkers.

Methods: Two-dimensional (2D) gel electrophoresis, Partial Least Squares Discriminant Analysis (PLS-DA), Western blot, DigiWest.

Results: PLS-DA of platelet protein expression in 2D gels suggested differences between the International Federation of Gynaecology and Obstetrics (FIGO) stages III-IV of ovarian cancer, compared to benign adnexal lesions with a sensitivity of 96% and a specificity of 88%. A PLS-DA-based model correctly predicted 7 out of 8 cases of FIGO stages I-II of ovarian cancer after verification by western blot. Receiver-operator curve (ROC) analysis indicated a sensitivity of 83% and specificity of 76% at cut-off >0.5 (area under the curve (AUC) = 0.831,  < 0.0001) for detecting these cases. Validation on an independent set of samples by DigiWest with PLS-DA differentiated benign adnexal lesions and ovarian cancer, FIGO stages III-IV, with a sensitivity of 70% and a specificity of 83%.

Conclusion: We identified a group of platelet protein biomarker candidates that can quantify the differential expression between ovarian cancer cases as compared to benign adnexal lesions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40364-018-0118-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767003PMC
January 2018

Prediction of Tubal Ectopic Pregnancy Using Offline Analysis of 3-Dimensional Transvaginal Ultrasonographic Data Sets: An Interobserver and Diagnostic Accuracy Study.

J Ultrasound Med 2018 Jun 8;37(6):1467-1472. Epub 2017 Dec 8.

Acute Gynecology, Early Pregnancy, and Advanced Endosurgery Unit, Sydney Medical School Nepean, University of Sydney, Nepean Hospital, Kingswood, New South Wales, Australia.

Objectives: To assess interobserver reproducibility in detecting tubal ectopic pregnancies by reading data sets from 3-dimensional (3D) transvaginal ultrasonography (TVUS) and comparing it with real-time 2-dimensional (2D) TVUS.

Methods: Images were initially classified as showing pregnancies of unknown location or tubal ectopic pregnancies on real time 2D TVUS by an experienced sonologist, who acquired 5 3D volumes. Data sets were analyzed offline by 5 observers who had to classify each case as ectopic pregnancy or pregnancy of unknown location. The interobserver reproducibility was evaluated by the Fleiss κ statistic. The performance of each observer in predicting ectopic pregnancies was compared to that of the experienced sonologist. Women were followed until they were reclassified as follows: (1) failed pregnancy of unknown location; (2) intrauterine pregnancy; (3) ectopic pregnancy; or (4) persistent pregnancy of unknown location.

Results: Sixty-one women were included. The agreement between reading offline 3D data sets and the first real-time 2D TVUS was very good (80%-82%; κ = 0.89). The overall interobserver agreement among observers reading offline 3D data sets was moderate (κ = 0.52). The diagnostic performance of experienced observers reading offline 3D data sets had accuracy of 78.3% to 85.0%, sensitivity of 66.7% to 81.3%, specificity of 79.5% to 88.4%, positive predictive value of 57.1% to 72.2%, and negative predictive value of 87.5% to 91.3%, compared to the experienced sonologist's real-time 2D TVUS: accuracy of 94.5%, sensitivity of 94.4%, specificity of 94.5%, positive predictive value of 85.0%, and negative predictive value of 98.1%.

Conclusions: The diagnostic accuracy of 3D TVUS by reading offline data sets for predicting ectopic pregnancies is dependent on experience. Reading only static 3D data sets without clinical information does not match the diagnostic performance of real time 2D TVUS combined with clinical information obtained during the scan.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jum.14489DOI Listing
June 2018

Clinical Utility of Risk Models to Refer Patients with Adnexal Masses to Specialized Oncology Care: Multicenter External Validation Using Decision Curve Analysis.

Clin Cancer Res 2017 Sep 16;23(17):5082-5090. Epub 2017 May 16.

Department of Development and Regeneration, KU Leuven, Leuven, Belgium.

To evaluate the utility of preoperative diagnostic models for ovarian cancer based on ultrasound and/or biomarkers for referring patients to specialized oncology care. The investigated models were RMI, ROMA, and 3 models from the International Ovarian Tumor Analysis (IOTA) group [LR2, ADNEX, and the Simple Rules risk score (SRRisk)]. A secondary analysis of prospectively collected data from 2 cross-sectional cohort studies was performed to externally validate diagnostic models. A total of 2,763 patients (2,403 in dataset 1 and 360 in dataset 2) from 18 centers (11 oncology centers and 7 nononcology hospitals) in 6 countries participated. Excised tissue was histologically classified as benign or malignant. The clinical utility of the preoperative diagnostic models was assessed with net benefit (NB) at a range of risk thresholds (5%-50% risk of malignancy) to refer patients to specialized oncology care. We visualized results with decision curves and generated bootstrap confidence intervals. The prevalence of malignancy was 41% in dataset 1 and 40% in dataset 2. For thresholds up to 10% to 15%, RMI and ROMA had a lower NB than referring all patients. SRRisks and ADNEX demonstrated the highest NB. At a threshold of 20%, the NBs of ADNEX, SRrisks, and RMI were 0.348, 0.350, and 0.270, respectively. Results by menopausal status and type of center (oncology vs. nononcology) were similar. All tested IOTA methods, especially ADNEX and SRRisks, are clinically more useful than RMI and ROMA to select patients with adnexal masses for specialized oncology care. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-16-3248DOI Listing
September 2017

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

Am J Obstet Gynecol 2016 Apr 19;214(4):424-437. Epub 2016 Jan 19.

Skåne University Hospital Malmö, Lund University, Malmö, Sweden.

Background: Accurate methods to preoperatively characterize adnexal tumors are pivotal for optimal patient management. A recent metaanalysis concluded that the International Ovarian Tumor Analysis algorithms such as the Simple Rules are the best approaches to preoperatively classify adnexal masses as benign or malignant.

Objective: We sought to develop and validate a model to predict the risk of malignancy in adnexal masses using the ultrasound features in the Simple Rules.

Study Design: This was an international cross-sectional cohort study involving 22 oncology centers, referral centers for ultrasonography, and general hospitals. We included consecutive patients with an adnexal tumor who underwent a standardized transvaginal ultrasound examination and were selected for surgery. Data on 5020 patients were recorded in 3 phases from 2002 through 2012. The 5 Simple Rules features indicative of a benign tumor (B-features) and the 5 features indicative of malignancy (M-features) are based on the presence of ascites, tumor morphology, and degree of vascularity at ultrasonography. Gold standard was the histopathologic diagnosis of the adnexal mass (pathologist blinded to ultrasound findings). Logistic regression analysis was used to estimate the risk of malignancy based on the 10 ultrasound features and type of center. The diagnostic performance was evaluated by area under the receiver operating characteristic curve, sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), positive predictive value (PPV), negative predictive value (NPV), and calibration curves.

Results: Data on 4848 patients were analyzed. The malignancy rate was 43% (1402/3263) in oncology centers and 17% (263/1585) in other centers. The area under the receiver operating characteristic curve on validation data was very similar in oncology centers (0.917; 95% confidence interval, 0.901-0.931) and other centers (0.916; 95% confidence interval, 0.873-0.945). Risk estimates showed good calibration. In all, 23% of patients in the validation data set had a very low estimated risk (<1%) and 48% had a high estimated risk (≥30%). For the 1% risk cutoff, sensitivity was 99.7%, specificity 33.7%, LR+ 1.5, LR- 0.010, PPV 44.8%, and NPV 98.9%. For the 30% risk cutoff, sensitivity was 89.0%, specificity 84.7%, LR+ 5.8, LR- 0.13, PPV 75.4%, and NPV 93.9%.

Conclusion: Quantification of the risk of malignancy based on the Simple Rules has good diagnostic performance both in oncology centers and other centers. A simple classification based on these risk estimates may form the basis of a clinical management system. Patients with a high risk may benefit from surgery by a gynecological oncologist, while patients with a lower risk may be managed locally.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajog.2016.01.007DOI Listing
April 2016

Evaluating the risk of ovarian cancer before surgery using the ADNEX model to differentiate between benign, borderline, early and advanced stage invasive, and secondary metastatic tumours: prospective multicentre diagnostic study.

BMJ 2014 Oct 15;349:g5920. Epub 2014 Oct 15.

Department of Development and Regeneration, KU Leuven, Herestraat 49 box 7003, 3000 Leuven, Belgium Department of Obstetrics and Gynaecology, University Hospitals Leuven, Leuven, Belgium.

Objectives: To develop a risk prediction model to preoperatively discriminate between benign, borderline, stage I invasive, stage II-IV invasive, and secondary metastatic ovarian tumours.

Design: Observational diagnostic study using prospectively collected clinical and ultrasound data.

Setting: 24 ultrasound centres in 10 countries.

Participants: Women with an ovarian (including para-ovarian and tubal) mass and who underwent a standardised ultrasound examination before surgery. The model was developed on 3506 patients recruited between 1999 and 2007, temporally validated on 2403 patients recruited between 2009 and 2012, and then updated on all 5909 patients.

Main Outcome Measures: Histological classification and surgical staging of the mass.

Results: The Assessment of Different NEoplasias in the adneXa (ADNEX) model contains three clinical and six ultrasound predictors: age, serum CA-125 level, type of centre (oncology centres v other hospitals), maximum diameter of lesion, proportion of solid tissue, more than 10 cyst locules, number of papillary projections, acoustic shadows, and ascites. The area under the receiver operating characteristic curve (AUC) for the classic discrimination between benign and malignant tumours was 0.94 (0.93 to 0.95) on temporal validation. The AUC was 0.85 for benign versus borderline, 0.92 for benign versus stage I cancer, 0.99 for benign versus stage II-IV cancer, and 0.95 for benign versus secondary metastatic. AUCs between malignant subtypes varied between 0.71 and 0.95, with an AUC of 0.75 for borderline versus stage I cancer and 0.82 for stage II-IV versus secondary metastatic. Calibration curves showed that the estimated risks were accurate.

Conclusions: The ADNEX model discriminates well between benign and malignant tumours and offers fair to excellent discrimination between four types of ovarian malignancy. The use of ADNEX has the potential to improve triage and management decisions and so reduce morbidity and mortality associated with adnexal pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198550PMC
http://dx.doi.org/10.1136/bmj.g5920DOI Listing
October 2014

Imaging in endometrial cancer.

Best Pract Res Clin Obstet Gynaecol 2014 Jul 30;28(5):721-39. Epub 2014 Apr 30.

Department of Diagnostic Radiology, Karolinska University Hospital, Stockholm, Sweden.

The prognosis for women with endometrial cancer is generally good. This is because the disease is often diagnosed at an early treatable stage, as women seek care owing to postmenopausal bleeding. The prognosis is, however, worse for women with high-risk endometrial cancer. These women may benefit from more extensive surgery, including pelvic- and para-aortic lymph-node dissection, whereas such surgery is of no benefit for women with low-risk cancer. It is, therefore, important to correctly identify women with high-risk cancer before surgery. No consensus has been reached on how and when to use imaging to assess local extension of the disease. Nevertheless, evidence shows that imaging will improve the identification of women with high-risk cancer. The primary aim of this review is to present the examination technique, accuracy, imaging findings, benefits, and shortcomings of ultrasound and magnetic resonance imaging in the assessment of local tumour extension, in women with endometrial cancer. A secondary goal is to discuss the role of positron emission tomography and computed tomography, diagnostic modalities that primarily are used to detect lymph node and distant metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bpobgyn.2014.04.007DOI Listing
July 2014

Early-stage cervical cancer: tumor delineation by magnetic resonance imaging and ultrasound - a European multicenter trial.

Gynecol Oncol 2013 Mar 28;128(3):449-53. Epub 2012 Sep 28.

Department of Obstetrics and Gynaecology, Karolinska University Hospital, Stockholm, Sweden.

Objective: To compare the diagnostic accuracy of ultrasound (US) and magnetic resonance imaging (MRI) in the preoperative assessment of early-stage cervical cancer using pathologic findings as the reference standard.

Patients And Methods: Prospective multi-center trial enrolling 209 consecutive women with early-stage cervical cancer (FIGO IA2-IIA) scheduled for surgery. The following parameters were assessed on US and MRI and compared to pathology: remaining tumor, size, tumor stromal invasion<2/3 (superficial) or ≥2/3 (deep), and parametrial invasion.

Results: Complete data were available for 182 patients. The agreement between US and pathology was excellent for detecting tumors, correctly classifying bulky tumors (>4cm), and detecting deep stromal invasion (kappa values 0.84, 0.82, and 0.81 respectively); and good for classifying small tumors (<2cm) and detecting parametrial invasion (kappa values 0.78 and 0.75, respectively). The agreement between MRI and histology was good for classifying tumors as <2cm, or >4cm, and detecting deep stromal invasion (kappa values 0.71, 0.76, and 0.77, respectively). It was moderately accurate in tumor detection, and in assessing parametrial invasion (kappa values 0.52 and 0.45, respectively). The agreement between histology and US was significantly better in assessing residual tumor (p<0.001) and parametrial invasion (p<0.001) than the results obtained by MRI. Imaging methods were not significantly influenced by previous cone biopsy.

Conclusion: US and MRI are highly accurate for the preoperative assessment of women with early-stage cervical cancer, although US may be more accurate in detecting residual tumors and assessing parametrial invasion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygyno.2012.09.025DOI Listing
March 2013

CsgE is a curli secretion specificity factor that prevents amyloid fibre aggregation.

Mol Microbiol 2011 Jul 7;81(2):486-99. Epub 2011 Jun 7.

Department of Molecular Microbiology and Microbial Pathogenesis, Washington University School of Medicine, Campus Box 8230, 660 S. Euclid Avenue, St Louis, MO 63110, USA.

Curli are extracellular amyloid fibres produced by Escherichia coli that are critical for biofilm formation and adhesion to biotic and abiotic surfaces. CsgA and CsgB are the major and minor curli subunits, respectively, while CsgE, CsgF and CsgG direct the extracellular localization and assembly of curli subunits into fibres. The secretion and stability of CsgA and CsgB are dependent on the outer membrane lipoprotein CsgG. Here, we identified functional interactions between CsgG and CsgE during curli secretion. We discovered that CsgG overexpression restored curli production to a csgE strain under curli-inducing conditions. In antibiotic sensitivity and protein secretion assays, CsgG expression alone allowed translocation of erythromycin and small periplasmic proteins across the outer membrane. Coexpression of CsgE with CsgG blocked non-specific protein and antibiotic passage across the outer membrane. However, CsgE did not block secretion of proteins containing a 22-amino-acid putative outer membrane secretion signal of CsgA (A22). Finally, using purified proteins, we found that CsgE prohibited the self-assembly of CsgA into amyloid fibres. Collectively, these data indicate that CsgE provides substrate specificity to the curli secretion pore CsgG, and acts directly on the secretion substrate CsgA to prevent premature subunit assembly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1365-2958.2011.07706.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134098PMC
July 2011

Simple ultrasound rules to distinguish between benign and malignant adnexal masses before surgery: prospective validation by IOTA group.

BMJ 2010 Dec 14;341:c6839. Epub 2010 Dec 14.

Department of Obstetrics and Gynaecology, University Hospitals KU Leuven, 3000 Leuven, Belgium.

Objectives: To prospectively assess the diagnostic performance of simple ultrasound rules to predict benignity/malignancy in an adnexal mass and to test the performance of the risk of malignancy index, two logistic regression models, and subjective assessment of ultrasonic findings by an experienced ultrasound examiner in adnexal masses for which the simple rules yield an inconclusive result.

Design: Prospective temporal and external validation of simple ultrasound rules to distinguish benign from malignant adnexal masses. The rules comprised five ultrasonic features (including shape, size, solidity, and results of colour Doppler examination) to predict a malignant tumour (M features) and five to predict a benign tumour (B features). If one or more M features were present in the absence of a B feature, the mass was classified as malignant. If one or more B features were present in the absence of an M feature, it was classified as benign. If both M features and B features were present, or if none of the features was present, the simple rules were inconclusive.

Setting: 19 ultrasound centres in eight countries.

Participants: 1938 women with an adnexal mass examined with ultrasound by the principal investigator at each centre with a standardised research protocol. Reference standard Histological classification of the excised adnexal mass as benign or malignant.

Main Outcome Measures: Diagnostic sensitivity and specificity.

Results: Of the 1938 patients with an adnexal mass, 1396 (72%) had benign tumours, 373 (19.2%) had primary invasive tumours, 111 (5.7%) had borderline malignant tumours, and 58 (3%) had metastatic tumours in the ovary. The simple rules yielded a conclusive result in 1501 (77%) masses, for which they resulted in a sensitivity of 92% (95% confidence interval 89% to 94%) and a specificity of 96% (94% to 97%). The corresponding sensitivity and specificity of subjective assessment were 91% (88% to 94%) and 96% (94% to 97%). In the 357 masses for which the simple rules yielded an inconclusive result and with available results of CA-125 measurements, the sensitivities were 89% (83% to 93%) for subjective assessment, 50% (42% to 58%) for the risk of malignancy index, 89% (83% to 93%) for logistic regression model 1, and 82% (75% to 87%) for logistic regression model 2; the corresponding specificities were 78% (72% to 83%), 84% (78% to 88%), 44% (38% to 51%), and 48% (42% to 55%). Use of the simple rules as a triage test and subjective assessment for those masses for which the simple rules yielded an inconclusive result gave a sensitivity of 91% (88% to 93%) and a specificity of 93% (91% to 94%), compared with a sensitivity of 90% (88% to 93%) and a specificity of 93% (91% to 94%) when subjective assessment was used in all masses.

Conclusions: The use of the simple rules has the potential to improve the management of women with adnexal masses. In adnexal masses for which the rules yielded an inconclusive result, subjective assessment of ultrasonic findings by an experienced ultrasound examiner was the most accurate diagnostic test; the risk of malignancy index and the two regression models were not useful.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001703PMC
http://dx.doi.org/10.1136/bmj.c6839DOI Listing
December 2010

Endometrial thickness measurement for detecting endometrial cancer in women with postmenopausal bleeding: a systematic review and meta-analysis.

Obstet Gynecol 2010 Jul;116(1):160-167

From the Department of Obstetrics and Gynecology, Academic Medical Centre, Amsterdam, The Netherlands; Department of Clinical Epidemiology and Biostatistics, Academic Medical Centre, Amsterdam, The Netherlands; the Department of Obstetrics and Gynecology, Birmingham Women's Health Care NHS Trust, Birmingham, UK; the Horten Centre, University of Zurich, Zurich, Switzerland; the Department of Obstetrics and Gynecology, Lund University Hospital, Lund, Sweden; the Department of Obstetrics and Gynecology, Birmingham Women's Health Care NHS Trust, Birmingham, UK; the Department of Obstetrics and Gynecology, Birmingham Women's Health Care NHS Trust, Birmingham, UK; the Department of Obstetrics & Gynecology, Sandwell & West Birmingham Hospital NHS Trust, Birmingham, UK; the Department of Obstetrics and Gynecology, University Hospital Leuven, Leuven, Belgium; the Department of Obstetrics and Gynecology, Erasmus Medical Centre, Rotterdam, The Netherlands; the Department of Reproductive and Developmental Sciences, University of Edinburgh, Edinburgh, UK; the Department of Gynecology, Escola Paulista de Medicina, Federal University of Sao Paolo, Brazil; the Department of Gynecology, University of Sassari, Sassari, Italy; the Department of Obstetrics and Gynecology, Rijnstate Hospital, Arnhem, The Netherlands; the Department of General Practice, Academic Medical Centre, Amsterdam, The Netherlands; and the Department of Obstetrics and Gynecology, Academic Medical Centre, Amsterdam, The Netherlands.

Objective: To estimate the accuracy of endometrial thickness measurement in the detection of endometrial cancer among women with postmenopausal bleeding with individual patient data using different meta-analytic strategies.

Data Sources: Original data sets of studies detected after reviewing the included studies of three previous reviews on this subject. An additional literature search of published articles using MEDLINE databases was preformed from January 2000 to December 2006 to identify articles reporting on endometrial carcinoma and sonographic endometrial thickness measurement in women with postmenopausal bleeding.

Methods Of Study Selection: We identified 90 studies reporting on endometrial thickness measurements and endometrial carcinoma in women with postmenopausal bleeding.

Tabulation, Integration, And Results: We contacted 79 primary investigators to obtain the individual patient data of their reported studies, of which 13 could provide data. Data on 2,896 patients, of which 259 had carcinoma, were included. Several approaches were used in the analyses of the acquired data. First, we performed receiver operator characteristics (ROC) analysis per study, resulting in a summary area under the ROC curve (AUC) calculated as a weighted mean of AUCs from original studies. Second, individual patient data were pooled and analyzed with ROC analyses irrespective of study with standardization of distributional differences across studies using multiples of the median and by random effects logistic regression. Finally, we also used a two-stage procedure, calculating sensitivities and specificities for each study and using the bivariate random effects model to estimate summary estimates for diagnostic accuracy. This resulted in rather comparable ROC curves with AUCs varying between 0.82 and 0.84 and summary estimates for sensitivity and specificity located along these curves. These curves indicated a lower AUC than previously reported meta-analyses using conventional techniques.

Conclusion: Previous meta-analyses on endometrial thickness measurement probably have overestimated its diagnostic accuracy in the detection of endometrial carcinoma. We advise the use of cutoff level of 3 mm for exclusion of endometrial carcinoma in women with postmenopausal bleeding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/AOG.0b013e3181e3e7e8DOI Listing
July 2010

Histopathology indicates lymphatic spread of a pelvic retroperitoneal ectopic pregnancy removed by robot-assisted laparoscopy with temporary occlusion of the blood supply.

Acta Obstet Gynecol Scand 2010 Jun;89(6):835-9

Department of Obstetrics and Gynecology, Lund University Hospital and Lund University, Lund, Sweden.

Retroperitoneal ectopic pregnancies are extremely rare and a diagnostic and therapeutic challenge as an early diagnosis is difficult and all treatments entail a risk for severe bleeding. We present a case of a live completely retroperitoneal ectopic pregnancy in the right obturator fossa. Following 3D color Doppler vaginal ultrasonography to evaluate the relation to larger blood vessels the pregnancy was completely removed by robot-assisted laparoscopic surgery. The hypogastric artery was temporarily occluded by removable vessel clips. Time for surgery was 126 minutes, no bleeding occurred. The postoperative course was uneventful and s-betahCG normalized in five weeks. Histopathology of the intact specimen showed trophoblast surrounded by lymphatic tissue. We believe robot-assisted laparoscopic surgery is a feasible and safe technique for surgery of retroperitoneal ectopic pregnancies with similar or other locations allowing occlusion of the main supplying artery. Lymphatic spread may explain retroperitoneal ectopic pregnancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/00016341003623779DOI Listing
June 2010

A population-based cohort study on the use of hormone treatment and endometrial cancer in southern Sweden.

Int J Cancer 2009 Jul;125(2):421-5

Institute of Clinical Sciences Lund, Department of Obstetrics and Gynaecology, Lund University Hospital, University of Lund, Lund, Sweden.

Our aim was to determine the risk of endometrial cancer associated with long-term use of combined hormone therapy (HT) and low-potency estrogens. In this prospective population-based cohort, 40,000 women aged 25-64 years, without prior cancer or hysterectomy, were included. The women answered 2 questionnaires at a 10-year interval regarding HT use and personal details. Women were followed up for an average of 15.5 years through the National Cancer and Causes of Death Registry, representing 236,611 women years. Among the 17,822 postmenopausal women included, 166 cases of endometrial cancer were diagnosed. Only use of combined HT was related to a decreased risk of endometrial cancer (OR 0.3, 95% CI 0.1-0.8), the protective effect was found after 2 years, and increased with extended duration of use. "Only use" of low-potency estrogens increased the risk of endometrial cancer almost to the same extent as use of high-potency estrogens (OR 2.0, 95% CI 1.1-3.6 vs. OR 2.5, 95% CI 1.3-4.8), the increased risk was confined to non-obese women in both groups. The risk was significantly increased for oral but not for local low-potency estrogen users (OR 2.1, 95% CI 1.1-3.6 vs. OR 1.5, 95% CI 0.4-6.2, respectively). In long-term estrogen users the risk was highest during the first 2 years, dropping slightly thereafter. Since low-potency estrogen use increases the risk of endometrial cancer almost as much as high-potency estrogen use, they should only be given if medically indicated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.24284DOI Listing
July 2009

The use of new and old ultrasound techniques in the assessment of women with postmenopausal bleeding.

Australas J Ultrasound Med 2009 Feb 31;12(1):24-27. Epub 2015 Dec 31.

Obstetrics and Gynecology Lund University Hospital Universitetssjukhuset i Lund Lund SE-221 85 Sweden.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/j.2205-0140.2009.tb00003.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024825PMC
February 2009

The relationship between lifestyle factors and venous thromboembolism among women: a report from the MISS study.

Br J Haematol 2009 Jan 19;144(2):234-40. Epub 2008 Nov 19.

Department of Obstetrics and Gynaecology, Clinical Science, Malmö University Hospital, Malmö, Sweden.

There has been a great advance in our knowledge of the role that thrombophilic factors play in the risk of venous thromboembolic events (VTE). However, the effect of lifestyle factors on VTE has been inadequately explored in large scale studies of women. This cohort study comprised one thousand native Swedish women for each age year between 25 and 64 inclusive (total = 40,000) drawn from the South Swedish population registry for 1990 (n = 40,000), who were followed for a mean of eleven years. Seventy-four percent completed a questionnaire at the inception of the study (n = 29,518) and 24,098 women responded to a follow-up inquiry between the years 2000-2002. The main outcome was the relationship between VTE and physical exercise, smoking habits, and alcohol consumption. Moderate drinkers of alcohol (10-15 g/d) and women engaged in strenuous exercise were at half the risk of VTE compared to those who consumed little or no alcohol or lived a sedentary life. Heavy smoking was associated with a 30% increased risk of VTE. Lifestyle factors have a major impact on the risk of VTE. Women non-smokers who were physically active and who consumed alcohol in moderation were at a lower risk of VTE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1365-2141.2008.07460.xDOI Listing
January 2009

Spatial clustering of the curlin secretion lipoprotein requires curli fiber assembly.

J Bacteriol 2009 Jan 14;191(2):608-15. Epub 2008 Nov 14.

Department of Molecular, Cellular and Developmental Biology, University of Michigan, 830 North University, Ann Arbor, MI 48109, USA.

Gram-negative bacteria assemble functional amyloid surface fibers called curli. CsgB nucleates the major curli subunit protein, CsgA, into a self-propagating amyloid fiber on the cell surface. The CsgG lipoprotein is sufficient for curlin transport across the outer membrane and is hypothesized to be the central molecule of the curli fiber secretion and assembly complex. We tested the hypothesis that the curli secretion protein, CsgG, was restricted to certain areas of the cell to promote the interaction of CsgA and CsgB during curli assembly. Here, electron microscopic analysis of curli-producing strains showed that relatively few cells in the population contacted curli fibers and that curli emanated from spatially discrete points on the cell surface. Microscopic analysis revealed that CsgG was surface exposed and spatially clustered around curli fibers. CsgG localization to the outer membrane and exposure of the surface domain were not dependent on any other csg-encoded protein, but the clustering of CsgG required the csg-encoded proteins CsgE, CsgF, CsgA, and CsgB. CsgG formed stable oligomers in all the csg mutant strains, but these oligomers were distinct from the CsgG complexes assembled in wild-type cells. Finally, we found that efficient fiber assembly was required for the spatial clustering of CsgG. These results suggest a new model where curli fiber formation is spatially coordinated with the CsgG assembly apparatus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JB.01244-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2620823PMC
January 2009

Polymerizing the fibre between bacteria and host cells: the biogenesis of functional amyloid fibres.

Cell Microbiol 2008 Jul 26;10(7):1413-20. Epub 2008 Mar 26.

Department of Molecular, Cellular and Developmental Biology, University of Michigan, 830 North University, Ann Arbor, MI 48109, USA.

Amyloid fibres are proteinaceous aggregates associated with several human diseases, including Alzheimer's, Huntington's and Creutzfeldt Jakob's. Disease-associated amyloid formation is the result of proteins that misfold and aggregate into beta sheet-rich fibre polymers. Cellular toxicity is readily associated with amyloidogenesis, although the molecular mechanism of toxicity remains unknown. Recently, a new class of 'functional' amyloid fibres was discovered that demonstrates that amyloids can be utilized as a productive part of cellular biology. These functional amyloids will provide unique insights into how amyloid formation can be controlled and made less cytotoxic. Bacteria produce some of the best-characterized functional amyloids, including a surface amyloid fibre called curli. Assembled by enteric bacteria, curli fibres mediate attachment to surfaces and host tissues. Some bacterial amyloids, like harpins and microcinE492, have exploited amyloid toxicity in a directed and functional manner. Here, we review and discuss the functional amyloids assembled by bacteria. Special emphasis will be paid to the biology of functional amyloid synthesis and the connections between bacterial physiology and pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1462-5822.2008.01148.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674401PMC
July 2008

High risk of cervical pathology among women with postmenopausal bleeding and endometrium

Acta Obstet Gynecol Scand 2006 ;85(11):1368-74

Department of Obstetrics and Gynaecology, Lund University Hospital, Lund, Sweden.

Background: To determine the risk of endometrial and cervical pathology during long-term follow-up in women with postmenopausal bleeding and thin endometrium (
Methods: Retrospective study including all women (n=332) with postmenopausal bleeding and thin endometrium examined at the Department of Obstetrics and Gynaecology at Malmö University Hospital from 1992 until 2002. Follow-up was accomplished by searching the medical records, the local registry of cytology and pathology, and the regional cancer registry up to November 15, 2005.

Results: At the first visit, cervical cancer was diagnosed in 1.5% (5/332) and endometrial cancer in 0.9% (3/332) of the women. During follow-up, cervical cancer was detected in 2/313 (0.6%) of the women; no additional case of endometrial cancer was found. In the region, the expected incidence of cervical and endometrial cancer during follow-up was 0.23 (standard incidence ratio [SIR], 8.7; 95% CI 1.1-31.4) and 1.34 (SIR, 0.0; 95% CI 0.0-2.7), respectively. Thirteen percent (41/313) of the women sought medical care because of re-bleeding. Endometrial pathology was found in 16% (4/25) and cervical pathology in 11% (3/28) of these women.

Conclusions: Cervical cancer was twice as common as endometrial cancer in women with postmenopausal bleeding and a thin endometrium. During follow-up, the risk of endometrial cancer was as expected, whereas the risk of cervical cancer was higher than expected. The results support that the diagnostic focus should be directed at excluding cervical pathology and that repeated diagnostic procedures be performed in cases of re-bleeding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00016340600883435DOI Listing
December 2006
-->