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

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.

[Obesity and osteoporosis-connections between adipose tissue and bone.]

The adipose and osseous tissue, although both derived from the connective tissues, perform different functions. In the common opinion, obesity might be a protective factor against bone loss and osteoporosis. The adipose tissue is a recognized major endocrine organ, producing a number of active biological substances, which affect the bone mass. Adipocyte and osteoblast are derived from the same mesenchymal stem cells. Therefore abnormal secretion of adipocytokines may play an important role not only in pathogenesis of the obesity, but also can influence the bone . It is supposed that obesity might have a protective effect on bone tissue in postmenopausal women, by increasing the load on the axial skeleton and because of its hormonal activity.

Understanding the Influence of Flow Velocity, Wall Motion Filter, Pulse Repetition Frequency, and Aliasing on Power Doppler Image Quantification.

OBJECTIVES: Although power Doppler imaging has been used to quantify tissue and organ vascularity, many studies showed that limitations in defining adequate ultrasound machine settings and attenuation make such measurements complex to be achieved. However, most of these studies were conducted by using the output of proprietary software, such as Virtual Organ computer-aided analysis (GE Healthcare, Kretz, Zipf, Austria); therefore, many conclusions may not be generalizable because of unknown settings and parameters used by the software. To overcome this limitation, our goal was to evaluate the impact of the flow velocity, pulse repetition frequency (PRF), and wall motion filter (WMF) on power Doppler image quantification using beam-formed ultrasonic radiofrequency data. METHODS: The setup consisted of a blood-mimicking fluid flowing through a phantom. Radiofrequency signals were collected using PRFs ranging from 0.6 to 10 kHz for 6 different flow velocities (5-40 cm/s). Wall motion filter cutoff frequencies were varied between 50 and 250 Hz. RESULTS: The power Doppler magnitude was deeply influenced by the WMF cutoff frequency. The effect of using different WMF values varied with the PRF; therefore, the power Doppler signal intensity was dependent on the PRF. Finally, we verified that power Doppler quantification can be affected by the aliasing effect, especially when using a PRF lower than 1.3 kHz. CONCLUSIONS: The WMF and PRF greatly influenced power Doppler quantification, mainly when flow velocities lower than 20 cm/s were used. Although the experiments were conducted in a nonclinical environment, the evaluated parameters are equivalent to those used in clinical practice, which makes them valuable for aiding the interpretation of related data in future research.

[Vitamin D - a geriatric point of view].

Elderly people more often suffer from vitamin D insufficiency. It is caused by insufficient supply with diet and scarce sun exposure, due to life style. This is a very common situation in Poland and worldwide. Vitamin D influences functioning of many various organs. Its deficiency may cause bone mineralization disorders, osteomalacia, osteoporosis, muscle weakening, which can result in higher risk of falls. Its influence on cardiovascular diseases, type 2 diabetes and cognitive functions is widely discussed. Supplementation is crucial in elderly population. It should be administrated all year, with adjustement of dose to age and weight. Initial blood concentration is not required. An appropriate sun exposure is recommended. Treatment of vitamin D deficiency should be intensive and last for several months. Although the doses are high, no adverse effects were observed.

Elastography Improves the Diagnostic Accuracy of Sonography in Differentiating Endometrial Polyps and Submucosal Fibroids.

OBJECTIVES: To assess whether strain elastography may be used to visualize the different stiffness of endometrial polyps and submucosal fibroids. METHODS: We conducted a prospective monocentric single-operator study on diagnostic accuracy. Patients who qualified for hysteroscopy because of suspected endometrial polyps and submucosal fibroids were included. Before the procedure, all patients underwent routine sonographic and power Doppler examinations. Additionally, the stiffness of intrauterine lesions was assessed by strain elastography. The enhancement was adjusted to visualize hard myometrium and soft endometrium around the intrauterine lesion. Due to their histologic structure, we assumed that on strain elastography, endometrial polyps should appear as soft lesions, whereas submucosal fibroids should appear as hard lesions. Sonographic, power Doppler, and elastographic findings were verified by pathologic examinations after hysteroscopies. The diagnostic accuracy of sonography, power Doppler imaging, and strain elastography was compared by the McNemar test. RESULTS: Forty-seven patients were included and underwent hysteroscopy. In 29 cases, endometrial polyps were found, and in 18, submucosal fibroids were found. The diagnostic accuracy rates for B-mode sonography, power Doppler imaging, and strain elastography in distinguishing endometrial polyps and submucosal fibroids were 70.2%, 65.9%, and 89.4%, respectively. The proportion of correct findings was significantly higher for strain elastography than for B-mode sonography (P = .0265) and power Doppler imaging (P = .0153). CONCLUSIONS: Strain elastography complements sonography in differentiating intrauterine lesions. Strain elastography may be used to visualize the different stiffness of endometrial polyps and submucosal fibroids.

Ovarian metastasis in a patient with neuroendocrine tumour of the small intestine.

No required for Clinical Vignette.

External Validation of the Ovarian-Adnexal Reporting and Data System (O-RADS) Lexicon and the International Ovarian Tumor Analysis 2-Step Strategy to Stratify Ovarian Tumors Into O-RADS Risk Groups.

Importance: Correct diagnosis of ovarian cancer results in better prognosis. Adnexal lesions can be stratified into the Ovarian-Adnexal Reporting and Data System (O-RADS) risk of malignancy categories with either the O-RADS lexicon, proposed by the American College of Radiology, or the International Ovarian Tumor Analysis (IOTA) 2-step strategy. Objective: To investigate the diagnostic performance of the O-RADS lexicon and the IOTA 2-step strategy. Design, Setting, and Participants: Retrospective external diagnostic validation study based on interim data of IOTA5, a prospective international multicenter cohort study, in 36 oncology referral centers or other types of centers. A total of 8519 consecutive adult patients presenting with an adnexal mass between January 1, 2012, and March 1, 2015, and treated either with surgery or conservatively were included in this diagnostic study. Twenty-five patients were excluded for withdrawal of consent, 2777 were excluded from 19 centers that did not meet predefined data quality criteria, and 812 were excluded because they were already in follow-up at recruitment. The analysis included 4905 patients with a newly detected adnexal mass in 17 centers that met predefined data quality criteria. Data were analyzed from January 31 to March 1, 2022. Exposures: Stratification into O-RADS categories (malignancy risk <1%, 1% to <10%, 10% to <50%, and ≥50%). For the IOTA 2-step strategy, the stratification is based on the individual risk of malignancy calculated with the IOTA 2-step strategy. Main Outcomes and Measures: Observed prevalence of malignancy in each O-RADS risk category, as well as sensitivity and specificity. The reference standard was the status of the tumor at inclusion, determined by histology or clinical and ultrasonographic follow-up for 1 year. Multiple imputation was used for uncertain outcomes owing to inconclusive follow-up information. Results: Median age of the 4905 patients was 48 years (IQR, 36-62 years). Data on race and ethnicity were not collected. A total of 3441 tumors (70%) were benign, 978 (20%) were malignant, and 486 (10%) had uncertain classification. Using the O-RADS lexicon resulted in 1.1% (24 of 2196) observed prevalence of malignancy in O-RADS 2, 4% (34 of 857) in O-RADS 3, 27% (246 of 904) in O-RADS 4, and 78% (732 of 939) in O-RADS 5; the corresponding results for the IOTA 2-step strategy were 0.9% (18 of 1984), 4% (58 of 1304), 30% (206 of 690), and 82% (756 of 927). At the 10% risk threshold (O-RADS 4-5), the O-RADS lexicon had 92% sensitivity (95% CI, 87%-96%) and 80% specificity (95% CI, 74%-85%), and the IOTA 2-step strategy had 91% sensitivity (95% CI, 84%-95%) and 85% specificity (95% CI, 80%-88%). Conclusions and Relevance: The findings of this external diagnostic validation study suggest that both the O-RADS lexicon and the IOTA 2-step strategy can be used to stratify patients into risk groups. However, the observed malignancy rate in O-RADS 2 was not clearly below 1%.

Revisiting the yeast PPR proteins--application of an Iterative Hidden Markov Model algorithm reveals new members of the rapidly evolving family.

Pentatricopeptide repeat (PPR) proteins are the largest known RNA-binding protein family, and are found in all eukaryotes, being particularly abundant in higher plants. PPR proteins localize mostly to mitochondria and chloroplasts, and many were shown to modulate organellar genome expression on the posttranscriptional level. Although the genomes of land plants encode hundreds of PPR proteins, only a few have been identified in Fungi and Metazoa. As the current PPR motif profiles are built mainly on the basis of the predominant plant sequences, they are unlikely to be optimal for detecting fungal and animal members of the family, and many putative PPR proteins in these genomes may remain undetected. In order to verify this hypothesis, we designed a hidden Markov model-based bioinformatic tool called Supervised Clustering-based Iterative Phylogenetic Hidden Markov Model algorithm for the Evaluation of tandem Repeat motif families (SCIPHER) using sequence data from orthologous clusters from available yeast genomes. This approach allowed us to assign 12 new proteins in Saccharomyces cerevisiae to the PPR family. Similarly, in other yeast species, we obtained a 5-fold increase in the detection of PPR motifs, compared with the previous tools. All the newly identified S. cerevisiae PPR proteins localize in the mitochondrion and are a part of the RNA processing interaction network. Furthermore, the yeast PPR proteins seem to undergo an accelerated divergent evolution. Analysis of single and double amino acid substitutions in the Dmr1 protein of S. cerevisiae suggests that cooperative interactions between motifs and pseudoreversion could be the force driving this rapid evolution.

Spatiotemporal image correlation with spherical sampling and high-definition flow: new 4-dimensional method for assessment of tissue vascularization changes during the cardiac cycle: reproducibility analysis.

OBJECTIVES: To describe and assess the interobserver reproducibility of a new method for evaluation of ovarian vascularization using spatiotemporal image correlation-high definition flow (STIC-HDF). METHODS: Stored 4-dimensional (4D) STIC-HDF volume data from 39 healthy pre-menopausal fertile women (aged <35 years) examined in the follicular part of the menstrual cycle by transvaginal sonography were assessed by two different examiners blinded from each other (one in Spain the other in Poland). Using 1-cm(3) spherical sampling, the vascularization index (VI) from the most vascularized part of the ovarian stroma was calculated at two different moments of the cardiac cycle (systole and diastole). System settings were kept constant for all patients (pulse repetition frequency, 0.6 kHz; gain, 0.2) with a depth of 40 mm. Analysis was performed offline using 4D software on a personal computer. On the basis of VI and vascularization-flow index (VFI) values during systole and diastole, 4 new 4D indices were defined: 4D systolic/diastolic volumetric index (4D-SDVI = VI(syst)/VI(diast)), 4D hemodynamic volumetric index (4D-HVI = [VI(syst) + VI(diast)]/[VI(syst) - VI(diast)]), 4D systolic/diastolic vascularization-flow index (4D-SDVFI = VFI(syst)/VFI(diast)), and 4D hemodynamic vascularization-flow index (4D-HVFI = [VFI(syst) + VFI(diast)]/[VFI(syst)- VFI(diast)]). Reproducibility of measurements was estimated by calculating the intraclass correlation coefficient (ICC). RESULTS: The systolic VI, diastolic VI, 4D-SDVI, 4D-HVI, systolic VFI, diastolic VFI, and 4D-HVFI showed good reproducibility (ICC, 0.992, 0.994, 0.879, 0.915, 0.995, 0.995, and 0.893, respectively). The 4D-SDVFI showed moderate reproducibility (ICC, 0.797). CONCLUSIONS: We describe 4 new 4D vascular indices for assessing tissue vascularization using STIC-HDF technology. Assessment of ovarian vascularization using this STIC-HDF spherical sampling is reliable. The calculation of these new indices is reproducible between two different examiners.

The germ cell nuclear proteins hnRNP G-T and RBMY activate a testis-specific exon.

The human testis has almost as high a frequency of alternative splicing events as brain. While not as extensively studied as brain, a few candidate testis-specific splicing regulator proteins have been identified, including the nuclear RNA binding proteins RBMY and hnRNP G-T, which are germ cell-specific versions of the somatically expressed hnRNP G protein and are highly conserved in mammals. The splicing activator protein Tra2beta is also highly expressed in the testis and physically interacts with these hnRNP G family proteins. In this study, we identified a novel testis-specific cassette exon TLE4-T within intron 6 of the human transducing-like enhancer of split 4 (TLE4) gene which makes a more transcriptionally repressive TLE4 protein isoform. TLE4-T splicing is normally repressed in somatic cells because of a weak 5' splice site and surrounding splicing-repressive intronic regions. TLE4-T RNA pulls down Tra2beta and hnRNP G proteins which activate its inclusion. The germ cell-specific RBMY and hnRNP G-T proteins were more efficient in stimulating TLE4-T incorporation than somatically expressed hnRNP G protein. Tra2b bound moderately to TLE4-T RNA, but more strongly to upstream sites to potently activate an alternative 3' splice site normally weakly selected in the testis. Co-expression of Tra2beta with either hnRNP G-T or RBMY re-established the normal testis physiological splicing pattern of this exon. Although they can directly bind pre-mRNA sequences around the TLE4-T exon, RBMY and hnRNP G-T function as efficient germ cell-specific splicing co-activators of TLE4-T. Our study indicates a delicate balance between the activity of positive and negative splicing regulators combinatorially controls physiological splicing inclusion of exon TLE4-T and leads to modulation of signalling pathways in the testis. In addition, we identified a high-affinity binding site for hnRNP G-T protein, showing it is also a sequence-specific RNA binding protein.

4D Doppler Ultrasound in High Grade Serous Ovarian Cancer Vascularity Evaluation-Preliminary Study.

The aim of the study was to evaluate the usefulness of 4D Power Doppler tissue evaluation to discriminate between normal ovaries and ovarian cancer tumors. This was a prospective observational study. Twenty-three cases of surgically confirmed ovarian High Grade Serous Carcinoma (HGSC) were analyzed. The control group consisted of 23 healthy patients, each matching their study-group counterpart age wise (±3 years) and according to their menopausal status. Transvaginal Doppler 4D ultrasound scans were done on every patient and analyzed with 3D/4D software. Two 4D indices-volumetric Systolic/Diastolic Index (vS/D) and volumetric Pulsatility Index (vPI)-were calculated. To keep results standardized and due to technical limitations, virtual 1cc spherical tissue samples taken from the part with highest vascularization as detected by bi-directional Power Doppler were analyzed for both groups of ovaries. Values of volumetric S/D indices and volumetric PI indices were statistically lower in ovarian malignant tumors compared to normal ovaries: 1.096 vs. 1.794 and 0.092 vs. 0.558, respectively (p < 0.001). The 4D bi-directional Power Doppler vascular indices were statistically different between malignant tumors and normal ovaries. These findings could support the rationale for future studies for assessing this technology to discriminate between malignant and benign tumors.

Robust T cell activation requires an eIF3-driven burst in T cell receptor translation.

Activation of T cells requires a rapid surge in cellular protein synthesis. However, the role of translation initiation in the early induction of specific genes remains unclear. Here, we show human translation initiation factor eIF3 interacts with select immune system related mRNAs including those encoding the T cell receptor (TCR) subunits TCRA and TCRB. Binding of eIF3 to the TCRA and TCRB mRNA 3'-untranslated regions (3'-UTRs) depends on CD28 coreceptor signaling and regulates a burst in TCR translation required for robust T cell activation. Use of the TCRA or TCRB 3'-UTRs to control expression of an anti-CD19 chimeric antigen receptor (CAR) improves the ability of CAR-T cells to kill tumor cells in vitro. These results identify a new mechanism of eIF3-mediated translation control that can aid T cell engineering for immunotherapy applications.

Three-dimensional vascular indices calculated using conventional power Doppler and high-definition flow imaging: are there differences?

OBJECTIVE: The purpose of this study was to determine whether there are differences in 3-dimensional (3D) vascular indices when calculated using high-definition flow imaging (HDF) and power Doppler imaging (PD). METHODS: Twenty-five consecutive asymptomatic premenopausal women (mean age, 31 years; range, 28-33 years) without a history of gynecologic disease who attended routine gynecologic checkups were included in the study. All women had regular menstrual cycles, and none had uterine or myometrial disease detected on basal transvaginal sonography. All women underwent 3D transvaginal sonography. In each patient, a first volume using conventional PD was obtained, immediately followed by a second volume using HDF. Volumes were stored and subsequently analyzed for calculating 3D vascular indices (vascularization index [VI], flow index [FI], and vascularization-flow index [VFI]) from the endometrium. RESULTS: The median VI, FI, and VFI were significantly higher when calculated using HDF compared with conventional PD (P < .05). CONCLUSIONS: Three-dimensional vascular indices calculated using HDF are higher than those calculated using conventional PD.

Spatiotemporal image correlation using high-definition flow: a new method for assessing ovarian vascularization.

OBJECTIVE: The purpose of this study was to describe a new method for assessing ovarian vascularization using spatiotemporal image correlation (STIC)-high-definition flow (HDF). METHODS: Thirty healthy premenopausal fertile women were assessed in the follicular part of the menstrual cycle by transvaginal sonography. A 4-dimensional STIC-HDF volume was obtained from the nondominant ovary to assess 3-dimensional (3D) vascular indices (vascularization index [VI] and flow index [FI]) during one cardiac cycle in each women. Using 1-cm(3) spherical sampling, we calculated the VI and FI from the most vascularized part of the ovarian stroma at two different moments of the cardiac cycle (systole and diastole). System settings were kept constant for all of the patients (pulse repetition frequency, 0.9 kHz; gain, 0.8; and depth, 40 mm). We calculated the VI and FI ratios between systole and diastole. RESULTS: The mean VI during systole (11.485%; SD, 6.7%) was significantly higher than during diastole (8.653%; SD, 5.6%; P < .0001). The mean FI values during systole (47.799 [unitless]; SD, 5.8) and diastole (47.791; SD, 6.0) were nearly identical (P = .993). The VI ratio was 1.35 (95% confidence interval, 1.28-1.42), which means that the mean VI was 35% higher during systole compared to diastole, whereas the FI during systole and diastole remained constant (FI ratio, 1.00; 95% confidence interval, 0.96-1.04). There was a high correlation between VI values during systole and diastole (r(2) = 0.94), whereas this correlation was weaker for the FI (r(2) = 0.45). CONCLUSIONS: The STIC-HDF method allows assessment of 3D vascular indices throughout the cardiac cycle. Vascularization index calculation is affected by the moment of the cardiac cycle during which the measurement is taken. However, it seems that FI calculation is not affected by the cardiac cycle in the normal nondominant ovary.

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

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.

Three-dimensional power Doppler angiography of cyclic ovarian blood flow.

OBJECTIVE: The purpose of this study was to assess the vascular indices generated by 3-dimensional (3D) power Doppler angiography by evaluating the cyclic changes in the vascularity of normal ovaries, including those that were ovulating, nonovulating, and hormonally suppressed. METHODS: In this prospective longitudinal observational study, a cohort of premenopausal regularly menstruating women with no known ovarian disease underwent 3D power Doppler imaging every 2 to 3 days for the duration of 1 menstrual cycle. Four indices were generated: vascularization index (VI), flow index (FI), vascularization-flow index (VFI), and mean grayness. Comparisons of vascularity were made between ovulating, nonovulating, and hormonally suppressed ovaries. Normal ranges were established and graphed longitudinally. RESULTS: Eighteen participants (36 ovaries) ages 28 to 45 years underwent an average of 10 examinations, yielding 368 acquired ovarian volumes for analysis. Seven participants used hormonal contraception. The VI, FI, and VFI were closely correlated (Pearson product moment correlation coefficients, 0.52-0.95). The vascular indices of ovulating ovaries were significantly higher than those of nonovulating ovaries (VI, FI, and VFI, all P < .001), with the largest discrepancies during the luteal phase. Hormonally suppressed ovaries had significantly lower vascularity throughout the cycle (VI, P < .002; FI, P < .001; VFI, P < .007). The vascular indices of all groups appeared to drop during the late follicular period and then rise again. CONCLUSIONS: The VI would suffice as the principal vascular parameter for 3D power Doppler analysis. Preovulatory scans may be more useful for distinguishing pathologic vascularization. Hormonally suppressed ovaries have significantly lower vascularity throughout the cycle. Normal-appearing ovaries with vascular indices above the normal ranges established by these data may warrant further investigation.

Spatio-temporal image correlation (STIC) in evaluation of advanced neuroendocrine tumours.

INTRODUCTION: 4D Ultrasound technology merging the Power Doppler option called High-Definition Flow (HDF) with Spatio-Temporal Image Correlation (STIC) is used in gynaecology and obstetrics. It seems to be a promising tool in assessing tissue vascularisation. The aim of the paper was to assess whether HDF STIC technique could be a useful tool for the evaluation of gastro-entero-pancreatic neuroendocrine neoplasm (GEP-NEN) advancement. MATERIAL AND METHODS: Forty-eight patients [mean age 57.7 ± 10.3 years; male 40.9% (n = 18)] diagnosed with metastatic GEP-NENs were included in the analysis. All subjects were enrolled in the Department of Endocrinology and Neuroendocrine Tumours, Medical University of Silesia, Katowice. We analysed liver metastases. Patients with G3 grading or faintly vascularised lesions were excluded. HDF STIC volumes were acquired during USG examination. 4D indices [volumetric pulsatility index (vPI) and volumetric systolic/diastolic index (vS/D)] were calculated using dedicated software. RESULTS: There were no correlations between vS/D and Ki-67 [p = 0.67; r = -0.19; (-0.28-0.19)], CgA [p = 0.47; r = -0.11; (-0.38-0,19)], 5-HIAA [p = 0.52; r = -0.09 (-0.37-0.2)], serotonin [p = 0.83; r = -0.03 (-0.32-0.26)], and VCAM-1 (p = 0.62; r = 0.09 (-03-0.47)]. The were no correlations between vPI and Ki-67 [p = 0.29; r = -0.16 (-0.45-0.14)], CgA (p = 0.46; r = -0.11 (-0.39-0.19)], 5-HIAA [p = 0.52; r = -0.09 (-0.37-0.2)], serotonin [p = 0.82; r = -0.03 (-0.32-0.26)], and VCAM-1 (p = 0.62; r = -0.09 (-03-0.47)]. There was no significant difference between carcinoid versus non-carcinoid patients if compared by vS/D and vPI (p = 0.62, p = 0.61, respectively). CONCLUSIONS: HDF STIC seems not to be an efficient marker to assess advancement of NENs, due to lack of correlation with widely used and approved markers of progression.

MYC-Driven Small-Cell Lung Cancer is Metabolically Distinct and Vulnerable to Arginine Depletion.

PURPOSE: Small-cell lung cancer (SCLC) has been treated clinically as a homogeneous disease, but recent discoveries suggest that SCLC is heterogeneous. Whether metabolic differences exist among SCLC subtypes is largely unexplored. In this study, we aimed to determine whether metabolic vulnerabilities exist between SCLC subtypes that can be therapeutically exploited. EXPERIMENTAL DESIGN: We performed steady state metabolomics on tumors isolated from distinct genetically engineered mouse models (GEMM) representing the MYC- and MYCL-driven subtypes of SCLC. Using genetic and pharmacologic approaches, we validated our findings in chemo-naïve and -resistant human SCLC cell lines, multiple GEMMs, four human cell line xenografts, and four newly derived PDX models. RESULTS: We discover that SCLC subtypes driven by different MYC family members have distinct metabolic profiles. MYC-driven SCLC preferentially depends on arginine-regulated pathways including polyamine biosynthesis and mTOR pathway activation. Chemo-resistant SCLC cells exhibit increased MYC expression and similar metabolic liabilities as chemo-naïve MYC-driven cells. Arginine depletion with pegylated arginine deiminase (ADI-PEG 20) dramatically suppresses tumor growth and promotes survival of mice specifically with MYC-driven tumors, including in GEMMs, human cell line xenografts, and a patient-derived xenograft from a relapsed patient. Finally, ADI-PEG 20 is significantly more effective than the standard-of-care chemotherapy. CONCLUSIONS: These data identify metabolic heterogeneity within SCLC and suggest arginine deprivation as a subtype-specific therapeutic vulnerability for MYC-driven SCLC.

The polycystic ovary syndrome: a position statement from the Polish Society of Endocrinology, the Polish Society of Gynaecologists and Obstetricians, and the Polish Society of Gynaecological Endocrinology.

Polycystic ovary syndrome (PCOS) diagnosis and therapy still arouse a lot of controversy. Each year brings new information, so, having collected the experience of three scientific societies, we present contemporary recommendations concerning PCOS diagnostics and treat-ment. In adult female diagnosis, we still use the Rotterdam criteria, which is two out of three of the follwing characteristics: a) ovulation abnormality, b) clinical or biochemical hyperandrogenism, and c) polycystic ovaries. In the case of teenagers, diagnostic criteria are as follows: menstruation disturbances two years after menarche and clinical or biochemical hyperandrogenism. The presence of polycysti-cally abnormal ovaries is not necessary. The consensus paper presents the threats resulting from imperfect diagnostic methods applied in PCOS (hyperandrogenism diagnostics, ultrasound examination of ovaries). Suggested therapy includes personalised schemes according to the dominant PCOS phenotype, i.e. metabolic, hyperandrogenic, or reproductive ones.