Magnetic resonance scoring system for assessment of adnexal masses: added value of diffusion-weighted imaging including apparent diffusion coefficient map.

OBJECTIVES: To validate prospectively the ADNEX magnetic resonance (MR) scoring system to assess adnexal masses and to evaluate a new, modified ADNEX MR scoring system that incorporates diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping. METHODS: Between January 2015 and September 2018, 323 consecutive women with adnexal masses diagnosed on transvaginal ultrasound (TVS) underwent standardized MR imaging (MRI) including diffusion and dynamic contrast-enhanced sequences. Of these, 131 underwent subsequent surgery. For interpretation of the MRI examinations, we applied the five-category ADNEX MR scoring system, along with a modified scoring system including DWI with ADC mapping. For both scoring systems, a score was given for all adnexal masses. Histological diagnosis was considered as the gold standard and lesions were classified as benign or malignant. The difference between the predictive values for diagnosing malignancy of the classical and modified scoring systems was assessed on the basis of the areas under the receiver-operating-characteristics (AUC) curves. The sensitivity and specificity for diagnosing malignancy of each score were also calculated. RESULTS: Among the 131 women with adnexal mass(es) diagnosed on TVS who underwent MRI and subsequent surgery, the surgery revealed 161 adnexal masses in 126 women; five women had no mass. Histological examination confirmed 161 adnexal masses, of which all had been detected on MRI: 32 malignant tumors, 15 borderline tumors, which were classified as part of the malignant group (n = 47), and 114 benign lesions. The AUC for prediction of a malignant lesion was 0.938 (95% CI, 0.902-0.975) using the classical ADNEX MR scoring system and 0.974 (95% CI, 0.953-0.996) using the modified scoring system. Pairwise comparison of these AUCs revealed a significant difference (P = 0.0032). The sensitivity and specificity for diagnosing malignancy with an ADNEX MR score of 4 or more were 95.5% and 86.6%, respectively, using the classic scoring system, and 95.7% and 93.3%, respectively, using the modified scoring system. CONCLUSION: DWI with ADC mapping could be integrated into the ADNEX MR scoring system to improve specificity, thereby potentially optimizing clinical management by avoiding unnecessary surgery. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Typical ultrasound features of various endometrial pathologies described using International Endometrial Tumor Analysis (IETA) terminology in women with abnormal uterine bleeding.

OBJECTIVE: To describe the ultrasound features of different endometrial and other intracavitary pathologies inpre- and postmenopausal women presenting with abnormal uterine bleeding, using the International Endometrial Tumor Analysis (IETA) terminology. METHODS: This was a prospective observational multicenter study of consecutive women presenting with abnormal uterine bleeding. Unenhanced sonography with color Doppler and fluid-instillation sonography were performed. Endometrial sampling was performed according to each center's local protocol. The histological endpoints were cancer, atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (EIN), endometrial atrophy, proliferative or secretory endometrium, endometrial hyperplasia without atypia, endometrial polyp, intracavitary leiomyoma and other. For fluid-instillation sonography, the histological endpoints were endometrial polyp, intracavitary leiomyoma and cancer. For each histological endpoint, we report typical ultrasound features using the IETA terminology. RESULTS: The database consisted of 2856 consecutive women presenting with abnormal uterine bleeding. Unenhanced sonography with color Doppler was performed in all cases and fluid-instillation sonography in 1857. In 2216 women, endometrial histology was available, and these comprised the study population. Median age was 49 years (range, 19-92 years), median parity was 2 (range, 0-10) and median body mass index was 24.9 kg/m2 (range, 16.0-72.1 kg/m2 ). Of the study population, 843 (38.0%) women were postmenopausal. Endometrial polyps were diagnosed in 751 (33.9%) women, intracavitary leiomyomas in 223 (10.1%) and endometrial cancer in 137 (6.2%). None (0% (95% CI, 0.0-5.5%)) of the 66 women with endometrial thickness < 3 mm had endometrial cancer or atypical hyperplasia/EIN. Endometrial cancer or atypical hyperplasia/EIN was found in three of 283 (1.1% (95% CI, 0.4-3.1%)) endometria with a three-layer pattern, in three of 459 (0.7% (95% CI, 0.2-1.9%)) endometria with a linear endometrial midline and in five of 337 (1.5% (95% CI, 0.6-3.4%)) cases with a single vessel without branching on unenhanced ultrasound. CONCLUSIONS: The typical ultrasound features of endometrial cancer, polyps, hyperplasia and atrophy and intracavitary leiomyomas, are described using the IETA terminology. The detection of some easy-to-assess IETA features (i.e. endometrial thickness < 3 mm, three-layer pattern, linear midline and single vessel without branching) makes endometrial cancer unlikely. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Optimizing the ultrasound visualization of the endometrial-myometrial junction (EMJ).

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

Does three-dimensional power Doppler ultrasound predict histopathological findings of uterine fibroids? A preliminary study.

OBJECTIVES: To compare three-dimensional (3D) power Doppler sonographic characteristics of fibroids with histopathological parameters. METHODS: We evaluated sonographically 73 fibroids before myomectomy or hysterectomy. For each, the total fibroid volume, a shell of 3 mm and a 1-cm(3) spherical sample from the most vascularized area on subjective assessment were captured. 3D power Doppler vascularization index (VI), flow index (FI) and vascularization flow index (VFI) were generated in the acquired volumes. The degree of cellularity, ischemic necrosis and fibrosclerosis, as well as CD31 and Ki-67 staining for vascular density and proliferation index, respectively, were estimated using the surgical sample. Pathological data were considered as dependent variables and ultrasound data as independent variables in multivariable logistic regression models including patients' characteristics. RESULTS: A high histological 'cellular activity score', combining hypercellularity, a fibrosclerosis rate < 25% and positive Ki-67 staining, was statistically related in multivariate analyses to high 3D power Doppler VI in spherical samples (odds ratio (OR), 1.1 (95% CI, 1.0-1.3), P < 0.05) and VFI (OR, 1.3 (95% CI, 1.0-1.8), P < 0.05). Positive CD31 staining was statistically related to high 3D power Doppler VI in spherical samples (OR, 1.1 (95% CI, 1.0-1.3), P < 0.05). In contrast, ischemic necrosis was statistically related to low 3D power Doppler VI in the total volume (OR, 0.6 (95% CI, 0.4-1.0), P < 0.05) and VFI (OR, 0.4 (95% CI, 0.1-1.1), P < 0.05). CONCLUSION: Vascular density, ischemic necrosis and histological cellular activity score are statistically significantly associated with some 3D power Doppler indices.

Topical treatment of CIN 2+ by cidofovir: results of a phase II, double-blind, prospective, placebo-controlled study.

OBJECTIVE: Randomized controlled trial evaluating a topical treatment for cervical intraepithelial neoplasia 2 and 3 (CIN 2+) using cidofovir. METHODS: Fifty-three women with a biopsy-proven CIN 2+ were randomly assigned, 6 weeks before their planned conisation, either 3 applications of 3 ml 2% cidofovir in Intrasite gel in a cervical cap or a placebo (the same volume of Intrasite alone). A cervical sample for high-risk types of human papillomaviruses (HPV) (Hybrid Capture 2 or HC2) was taken before treatment and before conisation. The cone was submitted for pathological examination, and subsequently, along with the initial biopsy, to in situ hybridization (ISH) for high-risk HPV. RESULTS: Forty-eight patients were treated and followed according to the protocol, (23 cidofovir, and 25 placebo). Fourteen of the 23 cones were free of any CIN (60.8%) in the cidofovir group. Only 5 of 25 cones were free of any CIN (20%) in the placebo group (p<0.01). The difference remained significant in the ITT group (p<0.05). In the per-protocol and ITT populations, we observed more frequent viral clearance in the cidofovir group, but the difference was significant only when evaluated by ISH and not by HC2. No systemic toxicity was observed. Cervico-vaginal side effects of cidofovir were limited, and not statistically different from placebo. CONCLUSION: The medical topical treatment with cidofovir, at this point, cannot replace conisation, but it is a promising candidate for topical chemotherapy of CIN 2+ lesions; a larger prospective randomized study is needed to confirm our results.

Ploidy and chromatin pattern analysis as an aid for cervical smear diagnosis.

In the present study we used computer-assisted microscopy to analyze the morphology of Feulgen-stained cell nuclei in cell populations obtained at the same time as routinely performed cervical smears and in the same way. We investigated in a series of 110 cases whether the quantitative morphonuclear description of cytological cervical samples is able to aid pathologists to distinguish between benign and more suspect premalignant lesions. For this task nuclear DNA content, nuclear morphometry (size and anisonucleosis level) and chromatin pattern-related parameters were compiled for each specimen enrolled in the database. A set of 32 normal and 17 high-grade squamous intraepithelial lesion (HSIL) specimens (with diagnostic confirmations) were selected as references and used to establish a discriminant model on the basis of cytometry-generated variables. This model was then used to score the remaining 61 cases in our series (including cases exhibiting benign cellular changes, squamous cells of undetermined significance, low-grade SIL and cancers). The results show that a model discriminating efficiently between normal and HSIL groups can be obtained by combining 5 quantitative features (1 DNA ploidy-related, 2 morphometrical and 2 chromatin texture features). A 97% specificity and an 88% sensitivity characterized the boundary so established. When applied to new cases, the model was in fact able to correct diagnoses for cases which had been down- or up-graded on the basis of the Bethesda system, and provided scores in accordance with histological control.

Varying sensitivity of human mammary carcinoma cells to the toxic effect of parvovirus H-1.

We have previously demonstrated lysis of non-established cultures of human mammary carcinoma cells by parvovirus H-1, which has little effect on the proliferation of corresponding normal cultures. In the present study, we examined this effect in a number of breast-tumour specimens and found them to differ as to the amplitude of their response to parvoviral attack. We first investigated whether the differences in cell sensitivity to parvovirus infection reflected the differentiation level of the initial tumour. Among the biochemical and anatomopathological indicators of original tumour differentiation, the presence of oestrogenic receptors (ER) was found to have a predictive value as to the sensitivity of derived cultures to the cytopathic effect of H-1 virus. The ER+ tumour-derived cultures showed an increased sensitivity to the lytic effect of H-1 virus compared with the ER-tumour-derived cultures, in spite of similar average proliferation rates for the two types of cultures. The proliferation rate was more heterogeneous among ER+ tumour-derived cultures and, in this group, the faster growing cultures were also the most sensitive. This observation was corroborated by the study of established cell lines retaining ER expression under in vitro culture conditions. Oestradiol was found to increase the sensitivity of these cells to the parvovirus in parallel with induction of proliferation. This effect appeared to be mediated by ER activation, since it was not observed in the ER-negative cell line MDA-MB-231. These data point to the importance of hormonal influences and cellular parameters, notably differentiation and proliferation, in determining the extent to which human cancer cells can be targets for the cytopathic effect of parvoviruses.

Parvovirus H-1 inhibits growth of short-term tumor-derived but not normal mammary tissue cultures.

Infection with parvovirus H-1 strongly interfered with the proliferation of non-established tissue cultures derived from human breast tumors, but had little effect on the growth of corresponding normal human mammary cells. Even though tumor cells were always more sensitive to the virus than normal tissue from the same patient, appreciable quantitative differences were observed among tumor specimens. With time and sub-cultures, the killing effect of the virus on tumor cells became amplified. The impaired growth of infected tumor cells was due both to cytotoxic and to cytostatic action of H-1 virus and was associated with their greater capacity for virus-DNA amplification as compared with normal cells.

In vitro infection of normal human keratinocytes by human papillomavirus type 1 followed by amplification of the viral genome in reconstructed epidermis.

Primary cultures of normal human keratinocytes were inoculated in vitro with human papillomavirus type 1 (HPV-1), the agent responsible for deep plantar warts. Upon transfer to dead de-epidermized dermis and growth at the air-liquid interface, keratinocytes reconstituted a pseudoepidermis. Under these highly differentiating conditions, HPV-1 DNA amplification was found to take place in the reconstructed epidermis, being detectable from 7 days after the transfer and persisting for at least 10 days thereafter. The extent of keratinocyte differentiation may be insufficient to allow a complete HPV infectious cycle.

Prevalence of high risk genital papillomaviruses in the Belgian female population determined by fast multiplex polymerase chain reaction.

Because in situ/filter hybridisation is not sensitive enough and because classical polymerase chain reaction (PCR) protocols are generally not sufficiently reproducible and specific, there is little accurate information on the prevalence of human papillomaviruses (HPV) 16, 18, and 33 infections in women without dyskaryotic changes of the cervix. In our hands, our Fast Multiplex PCR protocol has always been the most sensitive, specific, and reproducible DNA detection assay in all the microbiological and haematological applications we attempted (Vandenvelde C, Verstraete M, Van Beers D [1990]: Journal of Virological Methods 30:215-228; Vandenvelde C, Scheen R, Corazza F, Van Beers D [1991a]: Journal of Experimental and Clinical Hematology 33:293-297; Vandenvelde C, Scheen R, Van Beers D, Fondu P [1991b]: Journal of Experimental and Clinical Hematology 30:25-29). Using this new technique, cervical scrapes from 336 Belgian women attending the cervical cancer screening clinic were examined for the presence of these three high-risk genital papillomaviruses. Positive results were confirmed using another set of HPV-specific primers. Exactly one sixth of our population was found positive for one or more of these HPVs. Types 33 and 16 were significantly more prevalent than type 18. The nonparametric statistical analysis of the data suggests that some risk factors such as particular sexual habits, that are inversely related to age, must exist.

From oral contraception to hormone replacement therapy: towards a continuum?

PIP: On the basis of available evidence, it is reasonable to conclude that at this time women between 35-45 years should not be denied the benefit of oral contraception (OC) if they do not smoke. As Upton recently reported, the risk of death due to pregnancy and childbirth, even in a developed country such as the US, is greater than the risk of OC, including the risk for OC users who smoke. Low-dose, or very low-dose, ethinyl-estradiol combined OCs most likely can be prescribed safely for most women up to the time of menopause in the absence of cardiovascular risk factors. The alternative treatments that might be initiated before and then continued during and after the climacteric include: cyclic or continuous combined estrogen-progestogen preparations containing estradiol (in valerate or micronized form); "transdermal therapeutic systems" delivering both estrogen and progestogen, for cyclic or even continuous use; and other newly-developed means of delivering fairly constant doses of steroids, such as pellet implants and microspheres. The combination of estradiol pellet implants with the cyclic or continuous administration of progesterone or a progestogen also might prove to be a promising approach if estrogen accumulation could be avoided. Substantial effort still needs to be made to improve the available preparations and provide the clinician and the women concerned with the best possible formulations for use in the perimenopause, and possibly indefinitely afterwards as true substitution therapy.^ieng