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

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

Response to treatment and prognostic significance of supradiaphragmatic disease in patients with high-grade serous ovarian cancer.

OBJECTIVES: This study was designed to investigate the response to chemotherapy of supradiaphragmatic disease diagnosed by preoperative imaging. As secondary objectives, oncologic outcomes of patients affected by supradiaphragmatic disease and their pattern of recurrence were also evaluated. METHODS: Data of consecutive patients with newly diagnosed FIGO stage IV (for supradiaphragmatic disease) epithelial ovarian cancer undergoing either primary debulking surgery or neoadjuvant chemotherapy plus interval debulking surgery between 2004 and 2021, were retrospectively collected. All patients were preoperatively evaluated by chest/abdominal CT scan or 18F-FDG PET/CT preoperatively and at follow-up to evaluate response to chemotherapy. At follow-up visits, site of recurrence diagnosed by imaging techniques was systematically recorded as it occurred. Progression-free and overall survival were measured by using Kaplan-Meier and Cox models. RESULTS: A total of 130 patients was included in this study with a median (range) follow-up of 32.9 (12.8-176.7) months. Complete or partial response was achieved in most of the patients after 3 cycles (77.7%) and 6 cycles (85.4%) of chemotherapy. At follow-up, recurrence occurred in 96 (73.8%) patients and the main site of recurrence was abdomen only in 64 (66.7%) patients. At multivariate analysis, residual disease after surgery was the only variable influencing survival outcomes. CONCLUSIONS: Supradiaphragmatic disease respond to chemotherapy in most patients affected by advanced EOC and recurrence mainly occurs in the abdomen. Results from this study confirms that abdominal optimal cytoreduction is the main surgical goal in the treatment of women affected by FIGO stage IV EOC.

Imaging in gynecological disease (23): clinical and ultrasound characteristics of ovarian carcinosarcoma.

OBJECTIVE: To describe the clinical and ultrasound characteristics of ovarian carcinosarcoma. METHODS: This was a retrospective multicenter study. Patients with a histological diagnosis of ovarian carcinosarcoma, who had undergone preoperative ultrasound examination between 2010 and 2019, were identified from the International Ovarian Tumor Analysis (IOTA) database. Additional patients who were examined outside of the IOTA study were identified from the databases of the participating centers. The masses were described using the terms and definitions of the IOTA group. Additionally, two experienced ultrasound examiners reviewed all available images to identify typical ultrasound features using pattern recognition. RESULTS: Ninety-one patients with ovarian carcinosarcoma who had undergone ultrasound examination were identified, of whom 24 were examined within the IOTA studies and 67 were examined outside of the IOTA studies. Median age at diagnosis was 66 (range, 33-91) years and 84/91 (92.3%) patients were postmenopausal. Most patients (67/91, 73.6%) were symptomatic, with the most common complaint being pain (51/91, 56.0%). Most tumors (67/91, 73.6%) were International Federation of Gynecology and Obstetrics (FIGO) Stage III or IV. Bilateral lesions were observed on ultrasound in 46/91 (50.5%) patients. Ascites was present in 38/91 (41.8%) patients. The median largest tumor diameter was 100 (range, 18-260) mm. All ovarian carcinosarcomas contained solid components, and most were described as solid (66/91, 72.5%) or multilocular-solid (22/91, 24.2%). The median diameter of the largest solid component was 77.5 (range, 11-238) mm. Moderate or rich vascularization was found in 78/91 (85.7%) cases. Retrospective analysis of ultrasound images and videoclips using pattern recognition in 73 cases revealed that all tumors had irregular margins and inhomogeneous echogenicity of the solid components. Forty-seven of 73 (64.4%) masses appeared as a solid tumor with cystic areas. Cooked appearance of the solid tissue was identified in 28/73 (38.4%) tumors. No pathognomonic ultrasound sign of ovarian carcinosarcoma was found. CONCLUSIONS: Ovarian carcinosarcomas are usually diagnosed in postmenopausal women and at an advanced stage. The most common ultrasound appearance is a large solid tumor with irregular margins, inhomogeneous echogenicity of the solid tissue and cystic areas. The second most common pattern is a large multilocular-solid mass with inhomogeneous echogenicity of the solid tissue. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Developing and validating ultrasound-based radiomics models for predicting high-risk endometrial cancer.

OBJECTIVES: The primary aim of this study was to develop and validate radiomics models, applied to ultrasound images, capable of differentiating from other cancers high-risk endometrial cancer, as defined jointly by the European Society for Medical Oncology, European Society of Gynaecological Oncology and European Society for Radiotherapy & Oncology (ESMO-ESGO-ESTRO) in 2016. The secondary aim was to develop and validate radiomics models for differentiating low-risk endometrial cancer from other endometrial cancers. METHODS: This was a multicenter, retrospective, observational study. From two participating centers, we identified consecutive patients with histologically confirmed diagnosis of endometrial cancer who had undergone preoperative ultrasound examination by an experienced examiner between 2016 and 2019. Patients recruited in Center 1 (Rome) were included as the training set and patients enrolled in Center 2 (Milan) formed the external validation set. Radiomics analysis (extraction of a high number of quantitative features from medical images) was applied to the ultrasound images. Clinical (including preoperative biopsy), ultrasound and radiomics features that were statistically significantly different in the high-risk group vs the other groups and in the low-risk group vs the other groups on univariate analysis in the training set were considered for multivariate analysis and for developing ultrasound-based machine-learning risk-prediction models. For discriminating between the high-risk group and the other groups, a random forest model from the radiomics features (radiomics model), a binary logistic regression model from clinical and ultrasound features (clinical-ultrasound model) and another binary logistic regression model from clinical, ultrasound and previously selected radiomics features (mixed model) were created. Similar models were created for discriminating between the low-risk group and the other groups. The models developed in the training set were tested in the validation set. The performance of the models in discriminating between the high-risk group and the other groups, and between the low-risk group and the other risk groups for both validation and training sets was compared. RESULTS: The training set comprised 396 patients and the validation set 102 patients. In the validation set, for predicting high-risk endometrial cancer, the radiomics model had an area under the receiver-operating-characteristics curve (AUC) of 0.80, sensitivity of 58.7% and specificity of 85.7% (using the optimal risk cut-off of 0.41); the clinical-ultrasound model had an AUC of 0.90, sensitivity of 80.4% and specificity of 83.9% (using the optimal cut-off of 0.32); and the mixed model had an AUC of 0.88, sensitivity of 67.3% and specificity of 91.0% (using the optimal cut-off of 0.42). For the prediction of low-risk endometrial cancer, the radiomics model had an AUC of 0.71, sensitivity of 65.0% and specificity of 64.5% (using the optimal cut-off of 0.38); the clinical-ultrasound model had an AUC of 0.85, sensitivity of 70.0% and specificity of 80.6% (using the optimal cut-off of 0.46); and the mixed model had an AUC of 0.85, sensitivity of 87.5% and specificity of 72.5% (using the optimal cut-off of 0.36). CONCLUSIONS: Radiomics seems to have some ability to discriminate between low-risk endometrial cancer and other endometrial cancers and better ability to discriminate between high-risk endometrial cancer and other endometrial cancers. However, the addition of radiomics features to the clinical-ultrasound models did not result in any notable increase in performance. Other efficacy studies and further effectiveness studies are needed to validate the performance of the models. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Using rADioMIcs and machine learning with ultrasonography for the differential diagnosis of myometRiAL tumors (the ADMIRAL pilot study). Radiomics and differential diagnosis of myometrial tumors.

OBJECTIVE: To develop and evaluate the performance of a radiomics and machine learning model applied to ultrasound (US) images in predicting the risk of malignancy of a uterine mesenchymal lesion. METHODS: Single-center retrospective evaluation of consecutive patients who underwent surgery for a malignant uterine mesenchymal lesion (sarcoma) and a control group of patients operated on for a benign uterine mesenchymal lesion (myoma). Radiomics was applied to US preoperative images according to the International Biomarker Standardization Initiative guidelines to create, validate and test a classification model for the differential diagnosis of myometrial tumors. The TRACE4 radiomic platform was used thus obtaining a full-automatic radiomic workflow. Definitive histology was considered as gold standard. Accuracy, sensitivity, specificity, AUC and standard deviation of the created classification model were defined. RESULTS: A total of 70 women with uterine mesenchymal lesions were recruited (20 with histological diagnosis of sarcoma and 50 myomas). Three hundred and nineteen radiomics IBSI-compliant features were extracted and 308 radiomics features were found stable. Different machine learning classifiers were created and the best classification system showed Accuracy 0.85 ± 0.01, Sensitivity 0.80 ± 0.01, Specificity 0.87 ± 0.01, AUC 0.86 ± 0.03. CONCLUSIONS: Radiomics applied to US images shows a great potential in differential diagnosis of mesenchymal tumors, thus representing an interesting decision support tool for the gynecologist oncologist in an area often characterized by uncertainty.

Imaging in gynecological disease (17): ultrasound features of malignant ovarian yolk sac tumors (endodermal sinus tumors).

OBJECTIVE: To describe the clinical and sonographic characteristics of malignant ovarian yolk sac tumors (YSTs). METHODS: In this retrospective multicenter study, we included 21 patients with a histological diagnosis of ovarian YST and available transvaginal ultrasound images and/or videoclips and/or a detailed ultrasound report. Ten patients identified from the International Ovarian Tumor Analysis (IOTA) studies had undergone a standardized preoperative ultrasound examination, by an experienced ultrasound examiner, between 1999 and 2016. A further 11 patients were identified through medical files, for whom ultrasound images were retrieved from local image workstations and picture archiving and communication systems. All tumors were described using IOTA terminology. The collected ultrasound images and videoclips were used by two observers for additional characterization of the tumors. RESULTS: All cases were pure YSTs, except for one that was a mixed tumor (80% YST and 20% embryonal carcinoma). Median age at diagnosis was 25 (interquartile range (IQR), 19.5-30.5) years. Seventy-six percent (16/21) of women had an International Federation of Gynecology and Obstetrics (FIGO) Stage I-II tumor at diagnosis. Fifty-eight percent (11/19) of women felt pain during the ultrasound examination and one presented with ovarian torsion. Median serum α-fetoprotein (S-AFP) level was 4755 (IQR, 1071-25 303) µg/L and median serum CA 125 level was 126 (IQR, 35-227) kU/L. On ultrasound assessment, 95% (20/21) of tumors were unilateral. The median maximum tumor diameter was 157 (IQR, 107-181) mm and the largest solid component was 110 (IQR, 66-159) mm. Tumors were classified as either multilocular-solid (10/21; 48%) or solid (11/21; 52%). Papillary projections were found in 10% (2/21) of cases. Most (20/21; 95%) tumors were well vascularized (color score, 3-4) and none had acoustic shadowing. Malignancy was suspected in all cases, except in the patient with ovarian torsion, who presented a tumor with a color score of 1, which was classified as probably benign. Image and videoclip quality was considered as adequate in 18/21 cases. On review of the images and videoclips, we found that all tumors contained both solid components and cystic spaces, and that 89% (16/18) had irregular, still fine-textured and slightly hyperechoic solid tissue, giving them a characteristic appearance. CONCLUSION: Malignant ovarian YSTs are often detected at an early stage, in young women usually in the second or third decade of life, presenting with pain and markedly elevated S-AFP. On ultrasound, malignant ovarian YSTs are mostly unilateral, large and multilocular-solid or solid, with fine-textured slightly hyperechoic solid tissue and rich vascularization. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology..

Ultrasound-based risk model for preoperative prediction of lymph-node metastases in women with endometrial cancer: model-development study.

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

Imaging in gynecological disease (15): clinical and ultrasound characteristics of uterine sarcoma.

OBJECTIVE: To describe the clinical and ultrasound characteristics of uterine sarcomas. METHODS: This was a retrospective multicenter study. From the databases of 13 ultrasound centers, we identified patients with a histological diagnosis of uterine sarcoma with available ultrasound reports and ultrasound images who had undergone preoperative ultrasound examination between 1996 and 2016. As the first step, each author collected information from the original ultrasound reports from his/her own center on predefined ultrasound features of the tumors and by reviewing the ultrasound images to identify information on variables not described in the original report. As the second step, 16 ultrasound examiners reviewed the images electronically in a consensus meeting and described them using predetermined terminology. RESULTS: We identified 116 patients with leiomyosarcoma, 48 with endometrial stromal sarcoma and 31 with undifferentiated endometrial sarcoma. Median age of the patients was 56 years (range, 26-86 years). Most patients were symptomatic at diagnosis (164/183 (89.6%)), the most frequent presenting symptom being abnormal vaginal bleeding (91/183 (49.7%)). Patients with endometrial stromal sarcoma were younger than those with leiomyosarcoma and undifferentiated endometrial sarcoma (median age, 46 years vs 57 and 60 years, respectively). According to the assessment by the original ultrasound examiners, the median diameter of the largest tumor was 91 mm (range, 7-321 mm). Visible normal myometrium was reported in 149/195 (76.4%) cases, and 80.0% (156/195) of lesions were solitary. Most sarcomas (155/195 (79.5%)) were solid masses (> 80% solid tissue), and most manifested inhomogeneous echogenicity of the solid tissue (151/195 (77.4%)); one sarcoma was multilocular without solid components. Cystic areas were described in 87/195 (44.6%) tumors and most cyst cavities had irregular walls (67/87 (77.0%)). Internal shadowing was observed in 42/192 (21.9%) sarcomas and fan-shaped shadowing in 4/192 (2.1%). Moderate or rich vascularization was found on color-Doppler examination in 127/187 (67.9%) cases. In 153/195 (78.5%) sarcomas, the original ultrasound examiner suspected malignancy. Though there were some differences, the results of the first and second steps of the analysis were broadly similar. CONCLUSIONS: Uterine sarcomas typically appear as solid masses with inhomogeneous echogenicity, sometimes with irregular cystic areas but only very occasionally with fan-shaped shadowing. Most are moderately or very well vascularized. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

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

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

Imaging in gynecological disease (13): clinical and ultrasound characteristics of endometrioid ovarian cancer.

OBJECTIVE: To describe the clinical and ultrasound characteristics of ovarian pure endometrioid carcinomas. METHODS: This was a retrospective multicenter study of patients with a histological diagnosis of pure endometrioid carcinoma. We identified 161 patients from the International Ovarian Tumor Analysis (IOTA) database who had undergone preoperative ultrasound examination by an experienced ultrasound examiner between 1999 and 2016, and another 78 patients from the databases of the departments of gynecological oncology in the participating centers. All tumors were described using IOTA terminology. In addition, one author reviewed all available ultrasound images and described them using pattern recognition. RESULTS: Median age of the 239 patients was 55 years (range, 19-88 years). On ultrasound examination, two (0.8%) endometrioid carcinomas were described as unilocular cysts, three (1.3%) as multilocular cysts, 37 (15.5%) as unilocular-solid cysts, 115 (48.1%) as multilocular-solid cysts and 82 (34.3%) as solid masses. Median largest tumor diameter was 102.5 mm (range, 20-300 mm) and median largest diameter of the largest solid component was 63 mm (range, 9-300 mm). Papillary projections were present in 70 (29.3%) masses. Most cancers (188 (78.7%)) were unilateral. In 49 (20.5%) cases, the cancer was judged by the pathologist to develop from endometriosis. These cancers, compared with those without evidence of tumor developing from endometriosis, more often manifested papillary projections on ultrasound (46.9% (23/49) vs 24.7% (47/190)), were less often bilateral (8.2% (4/49) vs 24.7% (47/190)) and less often associated with ascites (6.1% (3/49) vs 28.4% (54/190)) and fluid in the pouch of Douglas (24.5% (12/49) vs 48.9% (93/190)). Retrospective analysis of available ultrasound images using pattern recognition revealed that many tumors without evidence of tumor developing from endometriosis (36.3% (41/113)) had a large central solid component entrapped within locules, giving the tumor a cockade-like appearance. CONCLUSIONS: Endometrioid cancers are usually large, unilateral, multilocular-solid or solid tumors. The ultrasound characteristics of endometrioid carcinomas developing from endometriosis differ from those without evidence of tumor developing from endometriosis, the former being more often unilateral cysts with papillary projections and no ascites. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Ultrasound characteristics of endometrial cancer as defined by International Endometrial Tumor Analysis (IETA) consensus nomenclature: prospective multicenter study.

OBJECTIVE: To describe the sonographic features of endometrial cancer in relation to tumor stage, grade and histological type, using the International Endometrial Tumor Analysis (IETA) terminology. METHODS: This was a prospective multicenter study of 1714 women with biopsy-confirmed endometrial cancer undergoing standardized transvaginal grayscale and Doppler ultrasound examination according to the IETA study protocol, by experienced ultrasound examiners using high-end ultrasound equipment. Clinical and sonographic data were entered into a web-based database. We assessed how strongly sonographic characteristics, according to IETA, were associated with outcome at hysterectomy, i.e. tumor stage, grade and histological type, using univariable logistic regression and the c-statistic. RESULTS: In total, 1538 women were included in the final analysis. Median age was 65 (range, 27-98) years, median body mass index was 28.4 (range 16-67) kg/m2 , 1377 (89.5%) women were postmenopausal and 1296 (84.3%) reported abnormal vaginal bleeding. Grayscale and color Doppler features varied according to grade and stage of tumor. High-risk tumors, compared with low-risk tumors, were less likely to have regular endometrial-myometrial junction (difference of -23%; 95% CI, -27 to -18%), were larger (mean endometrial thickness; difference of +9%; 95% CI, +8 to +11%), and were more likely to have non-uniform echogenicity (difference of +7%; 95% CI, +1 to +13%), a multiple, multifocal vessel pattern (difference of +21%; 95% CI, +16 to +26%) and a moderate or high color score (difference of +22%; 95% CI, +18 to +27%). CONCLUSION: Grayscale and color Doppler sonographic features are associated with grade and stage of tumor, and differ between high- and low-risk endometrial cancer. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Is aortic lymphadenectomy indicated in locally advanced cervical cancer after neoadjuvant chemotherapy followed by radical surgery? A retrospective study on 261 women.

OBJECTIVES: The aim of this study was to estimate the rate of aortic lymph nodes (LN) metastases/recurrences among patients affected by locally advanced stage cancer patients (LACC), treated with neoadjuvant chemotherapy (NACT) and radical surgery. METHODS: Retrospective evaluation of consecutive 261 patients affected by LACC (stage IB2-IIB), treated with NACT followed by radical surgery at National Cancer Institute, Milan, Italy, between 1990 and 2011. RESULTS: Stage at presentation included stage IB2, IIA and IIB in 100 (38.3%), 50 (19.2%) and 111 (42.5%) patients, respectively. Squamous cell carcinoma accounted for more than 80%, followed by adenocarcinoma or adenosquamous cancers (20%). Overall, 56 women (21.5%) had LN metastases. Four out of 83 women (5%) who underwent both pelvic and aortic LN dissection had aortic LN metastases, and all women had concomitant pelvic and aortic LN metastases. Only one woman out of 178 (0.5%) who underwent pelvic lymphadenectomy only, had an aortic LN recurrence. Overall 2% of women (5/261) had aortic LN metastases/recurrence. CONCLUSIONS: Our data suggest that aortic lymphadenectomy at the time of surgery is not routinely indicated in LACC after NACT, but should reserved in case of bulky LN in both pelvic and/or aortic area. The risk of isolated aortic LN relapse is negligible. Further prospective studies are warranted.

How often parametrial involvement leads to post-operative adjuvant treatment in locally advanced cervical cancer after neoadjuvant chemotherapy and type C radical hysterectomy?

OBJECTIVE: Parametrial involvement (PMI) is one of the most important factors influencing prognosis in locally advanced stage cervical cancer (LACC) patients. We aimed to evaluate PMI rate among LACC patients undergoing neoadjuvant chemotherapy (NACT), thus evaluating the utility of parametrectomy in tailor adjuvant treatments. METHODS: Retrospective evaluation of consecutive 275 patients affected by LACC (IB2-IIB), undergoing NACT followed by type C/class III radical hysterectomy. Basic descriptive statistics, univariate and multivariate analyses were applied in order to identify factors predicting PMI. Survival outcomes were assessed using Kaplan-Meier and Cox models. RESULTS: PMI was detected in 37 (13%) patients: it was associated with vaginal involvement, lymph node positivity and both in 10 (4%), 5 (2%) and 12 (4%) patients, respectively; while PMI alone was observed in only 10 (4%) patients. Among this latter group, adjuvant treatment was delivered in 3 (1%) patients on the basis of pure PMI; while the remaining patients had other characteristics driving adjuvant treatment. Considering factors predicting PMI we observed that only suboptimal pathological responses (OR: 1.11; 95% CI: 1.01, 1.22) and vaginal involvement (OR: 1.29 (95%) CI: 1.17, 1.44) were independently associated with PMI. PMI did not correlate with survival (HR: 2.0; 95% CI: 0.82, 4.89); while clinical response to NACT (HR: 3.35; 95% CI: 1.59, 7.04), vaginal involvement (HR: 2.38; 95% CI: 1.12, 5.02) and lymph nodes positivity (HR: 3.47; 95% CI: 1.62, 7.41), independently correlated with worse survival outcomes. CONCLUSIONS: Our data suggest that PMI had a limited role on the choice to administer adjuvant treatment, thus supporting the potential embrace of less radical surgery in LACC patients undergoing NACT. Further prospective studies are warranted.

Agreement of two-dimensional and three-dimensional transvaginal ultrasound with magnetic resonance imaging in assessment of parametrial infiltration in cervical cancer.

OBJECTIVES: To compare two-dimensional (2D) and three-dimensional (3D) transvaginal ultrasound with magnetic resonance imaging (MRI) as the gold standard in assessment of parametrial infiltration of cervical cancer and to determine if all parts of the cervix are equally assessable with ultrasound. METHODS: Patients with macroscopically evident and histologically confirmed cervical cancer were staged using International Federation of Gynecology and Obstetrics (FIGO) criteria and underwent MRI and 2D and 3D ultrasound examination before treatment. When assessing parametrial infiltration with 3D ultrasound and MRI, the cervix was (virtually) divided into three cylinders (cranial, middle and caudal) of equal size and each cylinder was then divided into six sectors in a clockwise manner following a consensus between radiologists and ultrasound examiners. The presence and the extent of parametrial invasion were recorded for each sector. Results of 2D ultrasound, 3D ultrasound and MRI were compared and reported in terms of percentage agreement and kappa value. RESULTS: A total of 29 consecutive patients were included in the study. The percentage agreement between 2D ultrasound and MRI in assessing parametrial infiltration (yes or no) was 76% (kappa, 0.459) and that between 3D ultrasound and MRI was 79% (kappa, 0.508). The results of 2D ultrasound showed the following agreement with those of MRI: 90% for the ventral parametrium (kappa, 0.720), 72% for the right lateral parametrium (kappa, 0.494), 69% for the left lateral parametrium (kappa, 0.412) and 58.5% for the dorsal parametrium (kappa, 0.017). The results of 3D ultrasound showed the following agreement with those of MRI: 62.5% for the ventral parametrium (kappa, 0.176), 81% for the right lateral parametrium (kappa, 0.595), 70% for the left lateral parametrium (kappa, 0.326) and 52% for the dorsal parametrium (kappa, 0.132). The best agreement between 3D ultrasound and MRI was for the middle cervical cylinder (76%; kappa, 0.438) and the poorest agreement was for the caudal cylinder (42%; kappa, 0.125). CONCLUSION: The results of 2D and 3D ultrasound showed similar moderate agreement with MRI; 2D and 3D ultrasound examinations are less costly and more readily available than MRI and should be considered in the preoperative work-up for cervical cancer.

Fertility-sparing treatment in young women with endometrial cancer or atypical complex hyperplasia: a prospective single-institution experience of 21 cases.

We conducted a prospective study of conservative treatment in 21 young nulliparous women with grade (G)1 endometrial cancer stage IA (11) or atypical complex hyperplasia (10). All were treated with a low-dose cyclic natural progestin therapy (200 mg/day from day 14-25) and encouraged to attempt pregnancy immediately. No adverse therapy-related effects were recorded. Overall response rate to progestin therapy was 57%. Nine women conceived (43%). There were 13 pregnancies, of which 13 were spontaneous and 8 were in women with persistent disease or partial response to hormonal treatment. Three additional complete responses were observed after delivery. Only women with known primary infertility or severe polycystic ovary syndrome showed inadequate pregnancy rate. Fifteen women underwent definitive surgery after enrolment (median 27 months, range 3-56 months). All 21 women are alive and disease free after a median follow up of 98 months.

The fourth transmembrane segment of the dopamine D2 receptor: accessibility in the binding-site crevice and position in the transmembrane bundle.

The binding site of the dopamine D2 receptor, like that of homologous G-protein-coupled receptors (GPCRs), is contained within a water-accessible crevice formed among its seven transmembrane segments (TMSs). Using the substituted-cysteine-accessibility method (SCAM), we are mapping the residues that contribute to the surface of this binding-site crevice. We have mutated to cysteine, one at a time, 21 consecutive residues in the fourth TMS (TM4). Eleven of these mutants reacted with charged sulfhydryl-specific reagents, and bound antagonist protected nine of these from reaction. For the mutants in which cysteine was substituted for residues in the cytoplasmic half of TM4, treatment with the reagents had no effect on binding, consistent with these residues being inaccessible and with the low-resolution structure of the homologous rhodopsin, in which TM3 and TM5 occlude the cytoplasmic half of TM4. Although hydrophobicity analysis positions the C-terminus of TM4 at 4.64, Pro-Pro and Pro-X-Pro motifs, which are known to disrupt alpha-helices, occur at position 4.59 in a number of homologous GPCRs. The SCAM data were consistent with a C-terminus at 4.58, but it is also possible that the alpha-helix extends one additional turn to 4.62 in the D2 receptor, which has a single Pro at 4.59. In homologous GPCRs, the high degree of sequence variation between 4.59 and 4.68 is more characteristic of a loop domain than a helical segment. This region is shown here to be very conserved within functionally related receptors, suggesting an important functional role for this putative nonhelical domain. This inference is supported by observed ligand-specific effects of mutations in this region and by the predicted spatial proximity of this segment to known ligand binding sites in other TMs.

Dopamine D4/D2 receptor selectivity is determined by A divergent aromatic microdomain contained within the second, third, and seventh membrane-spanning segments.

Conserved features of the sequences of dopamine receptors and of homologous G-protein-coupled receptors point to regions, and amino acid residues within these regions, that contribute to their ligand binding sites. Differences in binding specificities among the catecholamine receptors, however, must stem from their nonconserved residues. Using the substituted-cysteine accessibility method, we have identified the residues that form the surface of the water-accessible binding-site crevice in the dopamine D2 receptor. Of approximately 80 membrane-spanning residues that differ between the D2 and D4 receptors, only 20 were found to be accessible, and 6 of these 20 are conservative aliphatic substitutions. In a D2 receptor background, we mutated the 14 accessible, nonconserved residues, individually or in combinations, to the aligned residues in the D4 receptor. We also made the reciprocal mutations in a D4 receptor background. The combined substitution of four to six of these residues was sufficient to switch the affinity of the receptors for several chemically distinct D4-selective antagonists by three orders of magnitude in both directions (D2- to D4-like and D4- to D2-like). The mutated residues are in the second, third, and seventh membrane-spanning segments (M2, M3, M7) and form a cluster in the binding-site crevice. Mutation of a single residue in this cluster in M2 was sufficient to increase the affinity for clozapine to D4-like levels. We can rationalize the data in terms of a set of chemical moieties in the ligands interacting with a divergent aromatic microdomain in M2-M3-M7 of the D2 and D4 receptors.

Electrostatic and aromatic microdomains within the binding-site crevice of the D2 receptor: contributions of the second membrane-spanning segment.

The binding-site of the dopamine D2 receptor, like that of other homologous G protein-coupled receptors, is contained within a water-accessible crevice formed among its seven membrane-spanning segments. Using the substituted cysteine accessibility method (SCAM), we previously mapped the residues in the third, fifth, sixth, and seventh membrane-spanning segments that contribute to the surface of this binding-site crevice. We have now mutated to cysteine, one at a time, 22 consecutive residues in the second membrane-spanning segment (M2) and expressed the mutant receptors in HEK 293 cells. Eleven of these mutants reacted with charged, hydrophilic, lipophobic, sulfhydryl-specific reagents, added extracellularly, and 9 of these 11 were protected from reaction by a reversible dopamine antagonist, sulpiride. We infer that the side chains of the residues at the 11 reactive loci (D80, L81, V83, V87, P89, W90, V91, V92, L94, E95, V96) are on the water-accessible surface of the binding-site crevice and that 9 of these are occluded by bound antagonist. The pattern of accessibility suggests an alpha-helical conformation. A broadening of the angle of accessibility near the binding site is consistent with the presence of a kink at Pro89. On the basis of the enhanced rates of reaction of positively charged sulfhydryl reagents, we infer the presence of an electrostatic microdomain composed of three acidic residues in M2 and the adjacent M3 that could attract and orient cationic ligands. Furthermore, based on the enhanced reactivity of the hydrophobic cation-containing reagent, we infer the presence of an aromatic microdomain formed between M2, M3, and M7.