Vulvar cancer staging: guidelines of the European Society of Urogenital Radiology (ESUR)

Objective The aim of the Female Pelvic Imaging Working Group of the European Society of Urogenital Radiology (ESUR) was to develop imaging staging guidelines for vulvar cancer and to propose standardised MRI protocols and reporting. Methods The guidelines recommended from the ESUR in this article resulted from a questionnaire analysis regarding imaging staging of vulvar cancer that was answered by all members of the Female Pelvic Imaging Working Group. Only the answers with an agreement equal to or more than 80% were considered. Additionally, the literature was reviewed to complement and further support our conclusions. Results The critical review of the literature and consensus obtained among experts allows for recommendations regarding imaging staging guidelines, patient preparation, MRI protocol, and a structured MRI report. Conclusions Standardising image acquisition techniques and MRI interpretation reduces ambiguity and ultimately improves the contribution of radiology to the staging and management of patients with vulvar cancer. Moreover, structured reporting assists with the communication of clinically relevant information to the referring physician

Structural Basis for Substrate Specificity in Human Monomeric Carbonyl Reductases

Carbonyl reduction constitutes a phase I reaction for many xenobiotics and is carried out in mammals mainly by members of two protein families, namely aldo-keto reductases and short-chain dehydrogenases/reductases. In addition to their capacity to reduce xenobiotics, several of the enzymes act on endogenous compounds such as steroids or eicosanoids. One of the major carbonyl reducing enzymes found in humans is carbonyl reductase 1 (CBR1) with a very broad substrate spectrum. A paralog, carbonyl reductase 3 (CBR3) has about 70% sequence identity and has not been sufficiently characterized to date. Screening of a focused xenobiotic compound library revealed that CBR3 has narrower substrate specificity and acts on several orthoquinones, as well as isatin or the anticancer drug oracin. To further investigate structure-activity relationships between these enzymes we crystallized CBR3, performed substrate docking, site-directed mutagenesis and compared its kinetic features to CBR1. Despite high sequence similarities, the active sites differ in shape and surface properties. The data reveal that the differences in substrate specificity are largely due to a short segment of a substrate binding loop comprising critical residues Trp229/Pro230, Ala235/Asp236 as well as part of the active site formed by Met141/Gln142 in CBR1 and CBR3, respectively. The data suggest a minor role in xenobiotic metabolism for CBR3. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1

Carbonyl reductase 1 catalyzes 20β-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity

Carbonyl Reductase 1 (CBR1) is a ubiquitously expressed cytosolic enzyme important in exogenous drug metabolism but the physiological function of which is unknown. Here, we describe a role for CBR1 in metabolism of glucocorticoids. CBR1 catalyzes the NADPH-dependent production of 20 beta-dihydrocortisol (20 beta-DHF) from cortisol. CBR1 provides the major route of cortisol metabolism in horses and is up-regulated in adipose tissue in obesity in horses, humans and mice. We demonstrate that 20 beta-DHF is a weak endogenous agonist of the human glucocorticoid receptor (GR). Pharmacological inhibition of CBR1 in diet-induced obesity in mice results in more marked glucose intolerance with evidence for enhanced hepatic GR signaling. These findings suggest that CBR1 generating 20 beta-dihydrocortisol is a novel pathway modulating GR activation and providing enzymatic protection against excessive GR activation in obesity

Diagnostic Performance of Computed Tomography for Preoperative Staging of Patients with Non-endometrioid Carcinomas of the Uterine Corpus

Item does not contain fulltextPURPOSE: The aim of this study was to assess the diagnostic performance of computed tomography (CT) for initial staging of non-endometrioid carcinomas of the uterine corpus. MATERIALS AND METHODS: Waiving informed consent, the Institutional Review Board approved this Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective study of 193 women with uterine papillary serous carcinomas, clear cell carcinomas, and carcinosarcomas, who underwent surgical staging between May 1998 and December 2011 and had preoperative CT within 6 weeks before surgery. Two radiologists (R1, R2) independently reviewed all CT images. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and area under the curve were calculated using operative notes and surgical pathology as the reference standard. RESULTS: The respective sensitivities and specificities achieved by R1/R2 were 0.79/0.64 and 0.87/0.75 for detecting deep myometrial invasion (MI) on CT; 0.56/0.63 and 0.93/0.79 for detecting cervical stromal invasion; 0.52/0.45 and 0.95/0.93 for detecting pelvic nodal metastases; and 0.45/0.30 and 0.98/0.98 for detecting para-aortic nodal metastases. Although CT had suboptimal sensitivity for the detection of omental disease, it had high PPV for omental seeding at surgical exploration (1.00 for R1 and 0.92 for R2). Inter-observer agreement ranged from moderate in the detection of deep MI (kappa = 0.42 +/- 0.06) to almost perfect in the detection of para-aortic nodal metastases (kappa = 0.88 +/- 0.08). CONCLUSION: In patients with uterine non-endometrioid carcinomas, CT is only moderately accurate for initial staging but may provide clinically valuable information by 'ruling-in' isolated para-aortic lymph node metastases and omental dissemination

Preoperative CT-based nomogram for predicting overall survival in women with non-endometrioid carcinomas of the uterine corpus

Item does not contain fulltextTo develop a preoperative CT-based nomogram for predicting overall survival (OS) in patients with non-endometrioid carcinomas of the uterine corpus.Waiving informed consent, the institutional review board approved this HIPAA-compliant, retrospective study of 193 women with histopathologically proven uterine papillary serous carcinomas (UPSC), uterine clear cell carcinomas (UCCC), and uterine carcinosarcomas (UCS) who underwent primary surgical resection between May 1998 and December 2011, and had a preoperative CT ≤ 6 weeks before surgery. All CT scans were reviewed for local or/and regional tumor extent, presence of pelvic or/and para-aortic adenopathy, and presence of distant metastases. Univariate survival analysis was performed using log-rank test and Cox regression. Variables shown significant by the univariate analysis were evaluated with the multivariable Cox regression analysis and the results were used to create a nomogram for predicting OS. The predictive accuracy of the nomogram was assessed with the concordance probability index (c-index) and a 3-year calibration plot.Mean patient age was 67.2 years (range 49.0-85.9); histologies included UPSC (n = 116), UCCC (n = 27), and UCS (n = 50). Median follow-up was 38.1 months (0.9-168.5 months). At multivariate analysis, patient age, ascites, and omental implants on CT were significant adverse predictors of OS and were used to build the nomogram. Concordance index for the nomogram was 0.640 ± 0.028.We developed a nomogram with a good concordance probability at predicting OS based on readily available pretreatment clinical and imaging characteristics. This preoperative nomogram has the potential to improve initial treatment planning and patient counseling