ICSI outcome after microdissection testicular sperm extraction, testicular sperm aspiration and ejaculated sperm.

We conducted a case-controlled single-center cohort study to evaluate the intracytoplasmic sperm injection (ICSI) outcome in severe male infertility with different methods of sperm obtention. The data was compiled from a tertiary university hospital. The micro-TESE procedures were performed from 2008 to 2023, with a sperm recovery rate (SRR) of 45 %. The ICSI treatments were carried out between 2011 and 2023. The aim of the study was to compare the ICSI outcome using sperm obtained by microdissection testicular extraction (micro-TESE), testicular sperm aspiration (TESA), and ejaculated sperm with sperm concentration less than 15 million per milliliter. We included a total of 462 ICSI cycles, of which 340 ICSIs with ejaculated sperm of men with oligozoospermia, with or without asthenozoospermia or teratozoospermia (OAT group), 51 ICSIs with TESA sperm of men with obstructive azoospermia (OA, TESA group), and 71 ICSIs with micro-TESE sperm of men with non-obstructive azoospermia (NOA, micro-TESE group). The patient characteristics, fertilization rate, pregnancy rate, and pregnancy outcome data were similar between the groups. The fertilization rates were 66.0 % in the OAT group, 68.3 % in the TESA group and 62.8 % in the micro-TESE group and live birth rate per embryo transfer were 23.7 %, 28.9 %, and 25.0 %, respectively, without statistical difference. The obstetrical outcome was similar in all the groups. The overall clinical results in all ICSI cycles performed for treating severe male factor infertility were similar, independent of the method of collection of spermatozoa. The results also confirm the efficacy of micro-TESE in the treatment of severe male factor infertility.

Histological findings in resected leiomyomas following MR-HIFU treatment, single-institution data from seven patients with unfavorable focal therapy.

PURPOSE: Magnetic resonance - high-intensity focused ultrasound (MR-HIFU) is a noninvasive treatment option for symptomatic uterine leiomyomas. Currently, pretreatment MRI is used to assess tissue characteristics and predict the most likely therapeutic response for individual patients. However, these predictions still entail significant uncertainties. The impact of tissue properties on therapeutic outcomes remains poorly understood and detailed knowledge of the histological effects of ultrasound ablation is lacking. Investigating these aspects could aid in optimizing patient selection, enhancing treatment effects and improving treatment outcomes. METHODS AND MATERIALS: We present seven patients who underwent MR-HIFU treatment for leiomyoma followed by second-line surgical treatment. Tissue samples obtained during the surgery were stained with hematoxylin and eosin, Masson's trichrome and Herovici to evaluate general morphology, fibrosis and collagen deposition of leiomyomas. Immunohistochemical CD31, Ki-67 and MMP-2 stainings were performed to study vascularization, proliferation and matrix metalloproteinase-2 protein expression in leiomyomas, respectively. RESULTS: The clinical characteristics and radiological findings of the leiomyomas prior to treatment as well as qualitative histological findings after the treatment are presented and discussed in the context of current literature. A tentative model for volume reduction is presented. CONCLUSION: These findings provide insights into potential factors contributing to suboptimal therapeutic outcomes and the variability in histological changes following treatment.

Magnetic resonance guided high intensity focused ultrasound for uterine fibroids and adenomyosis has no effect on ovarian reserve.

INTRODUCTION: Uterine fibroids are the most common benign tumors in healthy women. High Intensity Focused Ultrasound (HIFU) is a modern, noninvasive thermal ablation method for treating uterine fibroids. There is increasing evidence that ultrasound guided HIFU (US-HIFU) has no adverse impact on ovarian reserve but little data exists on magnetic resonance guided HIFU (MR-HIFU). There are different options to estimate ovarian reserve, perhaps the most reliable being the measurement of serum Anti-Müllerian hormone (AMH). MATERIAL AND METHODS: Seventy-four (74) premenopausal women with serum AMH 0.1 ug/L or over, aged 24-48 and with fibroids or adenomyosis treated with MR-HIFU were enrolled in our study. AMH levels were analyzed before and 3 months after the MR-HIFU treatment. Correlations between AMH level changes and position of fibroids, fibroid volume, non-perfused volume ratio, and treatment energies were studied. RESULTS: The median AMH level before the HIFU treatment was 1.20 (range: 0.1-7.75 ug/L) and after the treatment 1.23 (range: 0.1-8.51 ug/L). No significant change was detected (p = .90). The patients were divided in three subgroups depending on the baseline AMH levels. The changes were not significant in any of the subgroups. Neither did the location of the treated fibroid affect the change of AMH levels nor the total energy used during treatment. CONCLUSIONS: MR-HIFU does not compromise the ovarian reserve. Neither the location of the treated fibroid nor the total energy used during MR-HIFU had any effect on the change of AMH levels.

Reproductive Markers of Testicular Function and Size During Puberty in Boys With and Without a History of Cryptorchidism.

CONTEXT: Longitudinal data on levels of hypothalamic-pituitary-gonadal axis hormones and insulin-like growth factor I (IGF-I) during puberty in boys with a history of cryptorchidism are largely missing. OBJECTIVE: We aimed to compare pubertal hormone levels between boys with a history of congenital cryptorchidism who experienced spontaneous testicular descent or underwent orchiopexy and boys without a history of cryptorchidism. METHODS: This was a nested case-control study within a population-based birth cohort, with a prospective, longitudinal pubertal follow-up every 6 months (2005 to 2019). Participants were 109 Finnish boys, including boys with a history of unilateral cryptorchidism who underwent orchiopexy (n = 15), unilateral cryptorchidism who had spontaneous testicular descent (n = 15), bilateral cryptorchidism who underwent orchiopexy (n = 9), bilateral cryptorchidism who had spontaneous testicular descent (n = 7), and controls (n = 63). Serum reproductive hormone levels and testicular volumes were measured. RESULTS: From around onset of puberty, boys with bilateral cryptorchidism who underwent orchiopexy had significantly higher follicle-stimulating hormone (FSH) and lower inhibin B levels than controls. Boys with unilateral cryptorchidism who underwent orchiopexy had significantly higher FSH than controls, whereas inhibin B levels were similar. Testosterone, luteinizing hormone, insulin-like factor 3, and IGF-I were generally similar between groups. Testicular volume of boys with unilateral or bilateral cryptorchidism who underwent orchiopexy was smaller than that of the controls from 1 year after pubertal onset (P < 0.05). CONCLUSION: Cryptorchid boys, particularly those with bilateral cryptorchidism who underwent orchiopexy, had altered levels of serum biomarkers of Sertoli cells and germ cells and smaller testicular volumes compared with controls.

Histone H3K4me3 breadth in hypoxia reveals endometrial core functions and stress adaptation linked to endometriosis.

Trimethylation of histone H3 at lysine 4 (H3K4me3) is a marker of active promoters. Broad H3K4me3 promoter domains have been associated with cell type identity, but H3K4me3 dynamics upon cellular stress have not been well characterized. We assessed this by exposing endometrial stromal cells to hypoxia, which is a major cellular stress condition. We observed that hypoxia modifies the existing H3K4me3 marks and that promoter H3K4me3 breadth rather than height correlates with transcription. Broad H3K4me3 domains mark genes for endometrial core functions and are maintained or selectively extended upon hypoxia. Hypoxic extension of H3K4me3 breadth associates with stress adaptation genes relevant for the survival of endometrial cells including transcription factor KLF4, for which we found increased protein expression in the stroma of endometriosis lesions. These results substantiate the view on broad H3K4me3 as a marker of cell identity genes and reveal participation of H3K4me3 extension in cellular stress adaptation.

Top-quality embryo transfer is associated with lower odds of ectopic pregnancy.

INTRODUCTION: The incidence of ectopic pregnancy is up to four times higher after in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) than in spontaneous pregnancies, and the risk of ectopic pregnancy is increased by tubal factor infertility and the transfer of multiple embryos. However, the effect of embryo quality on the probability of ectopic pregnancy has not been investigated until now and it is not clear whether ovarian stimulation parameters affect the incidence of ectopic pregnancy. MATERIAL AND METHODS: An historical cohort study of 15 006 clinical pregnancies (diagnosed by ultrasound at 6-8 gestational weeks) after non-donor IVF/ICSI with fresh embryo transfer (n = 8952) or frozen-thawed embryo transfer (n = 6054). Treatments were performed during 2000-2017 in Finland. A total of 9207 (61.4%) single and 5799 (38.6%) double embryo transfers of no more than one top-quality embryo were evaluated. We analyzed the effects of multiple factors on ectopic pregnancy by logistic regression, including type of cycle (fresh vs frozen embryo transfer), female age, number and quality of embryos transferred, tubal factor infertility and factors of ovarian response to gonadotropin stimulation. RESULTS: Ectopic pregnancy was observed in 2.3% of cycles. There was no significant difference in ectopic pregnancy rate after fresh embryo transfer and frozen embryo transfer (2.2% vs 2.4%, p = 0.3). The ectopic pregnancy rate was lower in cycles with top-quality embryo transfer (1.9%) than of those where only non-top quality embryos were transferred (2.7%, p < 0.0001). Tubal factor infertility was diagnosed more often in ectopic pregnancy than in intrauterine pregnancies (21.2% vs 11.0%, p < 0.0001). Logistic regression revealed lower odds for ectopic pregnancy after a top-quality embryo transfer than after transfer of a non-top quality embryo (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.56-0.92, p = 0.007). Transfer of two vs one embryo (OR 1.35, 95% CI 1.05-1.70, p = 0.02) and tubal factor infertility (OR 2.21, 95% CI 1.68-2.91, p < 0.0001) significantly increased the risk of ectopic pregnancy. CONCLUSIONS: Transfer of non-top quality embryos is associated with a higher rate of ectopic pregnancy. This is particularly important to keep in mind in treatments with only non-top embryos available even in the absence of tubal factor infertility. To minimize the risk of ectopic pregnancy, the number of embryos transferred should be as low as possible.

Protocol for developing a core outcome set for male infertility research: an international consensus development study.

STUDY QUESTION: We aim to develop, disseminate and implement a minimum data set, known as a core outcome set, for future male infertility research. WHAT IS KNOWN ALREADY: Research into male infertility can be challenging to design, conduct and report. Evidence from randomized trials can be difficult to interpret and of limited ability to inform clinical practice for numerous reasons. These may include complex issues, such as variation in outcome measures and outcome reporting bias, as well as failure to consider the perspectives of men and their partners with lived experience of fertility problems. Previously, the Core Outcome Measure for Infertility Trials (COMMIT) initiative, an international consortium of researchers, healthcare professionals and people with fertility problems, has developed a core outcome set for general infertility research. Now, a bespoke core outcome set for male infertility is required to address the unique challenges pertinent to male infertility research. STUDY DESIGN SIZE DURATION: Stakeholders, including healthcare professionals, allied healthcare professionals, scientists, researchers and people with fertility problems, will be invited to participate. Formal consensus science methods will be used, including the modified Delphi method, modified Nominal Group Technique and the National Institutes of Health's consensus development conference. PARTICIPANTS/MATERIALS SETTING METHODS: An international steering group, including the relevant stakeholders outlined above, has been established to guide the development of this core outcome set. Possible core outcomes will be identified by undertaking a systematic review of randomized controlled trials evaluating potential treatments for male factor infertility. These outcomes will be entered into a modified Delphi method. Repeated reflection and re-scoring should promote convergence towards consensus outcomes, which will be prioritized during a consensus development meeting to identify a final core outcome set. We will establish standardized definitions and recommend high-quality measurement instruments for individual core outcomes. STUDY FUNDING/COMPETING INTERESTS: This work has been supported by the Urology Foundation small project award, 2021. C.L.R.B. is the recipient of a BMGF grant and received consultancy fees from Exscentia and Exceed sperm testing, paid to the University of Dundee and speaking fees or honoraria paid personally by Ferring, Copper Surgical and RBMO. S.B. received royalties from Cambridge University Press, Speaker honoraria for Obstetrical and Gynaecological Society of Singapore, Merk SMART Masterclass and Merk FERRING Forum, paid to the University of Aberdeen. Payment for leadership roles within NHS Grampian, previously paid to self, now paid to University of Aberdeen. An Honorarium is received as Editor in Chief of Human Reproduction Open. M.L.E. is an advisor to the companies Hannah and Ro. B.W.M. received an investigator grant from the NHMRC, No: GNT1176437 is a paid consultant for ObsEva and has received research funding from Ferring and Merck. R.R.H. received royalties from Elsevier for a book, consultancy fees from Glyciome, and presentation fees from GryNumber Health and Aytu Bioscience. Aytu Bioscience also funded MiOXYS systems and sensors. Attendance at Fertility 2020 and Roadshow South Africa by Ralf Henkel was funded by LogixX Pharma Ltd. R.R.H. is also Editor in Chief of Andrologia and has been an employee of LogixX Pharma Ltd. since 2020. M.S.K. is an associate editor with Human Reproduction Open. K.Mc.E. received an honoraria for lectures from Bayer and Pharmasure in 2019 and payment for an ESHRE grant review in 2019. His attendance at ESHRE 2019 and AUA 2019 was sponsored by Pharmasure and Bayer, respectively. The remaining authors declare no competing interests. TRIAL REGISTRATION NUMBER: Core Outcome Measures in Effectiveness Trials (COMET) initiative registration No: 1586. Available at www.comet-initiative.org/Studies/Details/1586. TRIAL REGISTRATION DATE: N/A. DATE OF FIRST PATIENT'S ENROLMENT: N/A.

Oestrogen therapy for postpartum depression: efficacy and adverse effects. A double-blind, randomized, placebo-controlled pilot study.

BACKGROUND: Postpartum depression (PPD) is detrimental to the mother and the family as a whole. Early initiation of appropriate treatment is important. The aim of this pilot study was to evaluate the efficacy and adverse effects of oestradiol treatment. METHODS: We performed a pilot double-blind, randomized, placebo-controlled study. Major depression was diagnosed using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), and the severity of depression was evaluated using the Edinburgh Postnatal Depression Scale (EPDS). The duration of treatment with sublingual oestradiol hemihydrate (1-3 mg/day) was 12 weeks. RESULTS: The treatment group consisted of 16 mothers and the placebo group of 14 mothers. Thirteen mothers in the treatment group and ten in the placebo group recovered from depression during the treatment period as measured with the EPDS (<10). There was no evidence to suggest that oestradiol was more effective than placebo. More mothers in the treatment group than in the placebo group (eight vs. one) received gestagen treatment for irregular bleeding. Oestradiol did not disturb breastfeeding. The mean number of other adverse effects per mother was lower in the treatment group, and these were mostly somatic symptoms. CONCLUSION: Our findings warrant further studies on oestrogen therapy for PPD with and without antidepressant and gestagen therapy, and on adverse effects (including effects on vaginal bleeding and breastfeeding).

Feasibility of T2 relaxation time in predicting the technical outcome of MR-guided high-intensity focused ultrasound treatment of uterine fibroids.

PURPOSE: The aim of this study was to assess the feasibility of T2 relaxation time in predicting the immediate technical outcome i.e., nonperfused volume ratio (NPVr) of magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) treatment of symptomatic uterine fibroids and to compare it with existing T2-weighted imaging methods (Funaki classification and scaled signal intensity, SSI). MATERIALS AND METHODS: 30 patients with 32 uterine fibroids underwent an MRI study including a quantitative T2 relaxation time measurement prior to MRgHIFU treatment. T2 relaxation times were measured with a multi-echo fast imaging-based technique with 16 echoes. The correlation between pretreatment values of the uterine fibroids and treatment outcomes, that is nonperfused volume ratios (NPVr), was assessed with nonparametric statistical measures. T2 relaxation time-based method was compared to existing T2-weighted imaging-based methods using receiver-operating-characteristics (ROC) curve analysis and Chi-square test. RESULTS: Nonparametric measures of association revealed a statistically significant negative correlation between T2 relaxation time values and NPVr. The T2 relaxation time classification (T2 I, T2 II, and T2 III) resulted in the whole model p-value of 0.0019, whereas the Funaki classification resulted in a p-value of 0.56. The T2 relaxation time classification (T2 I and T2 II) achieved a whole model of a p-value of 0.0024, whereas the SSI classification had a p-value of 0.0749. CONCLUSIONS: A longer T2 relaxation time of the fibroid prior to treatment correlated with a lower NPVr. Based on our results, the T2 relaxation time classifications seem to outperform the Funaki classification and the SSI method.

Maternal risk factors for congenital limb deficiencies: A population-based case-control study.

BACKGROUND: Risk factors for congenital limb deficiencies are poorly understood. OBJECTIVE: To investigate risk factors for congenital limb deficiencies. METHODS: We conducted a nationwide population-based case-control (1:5) study in Finland, using national registers on congenital anomalies, births, and induced abortions, cross-linked with data on maternal prescription medicine use obtained from the registers on Reimbursed Drug Purchases and Medical Special Reimbursements. Five hundred and four children with limb deficiencies (241 isolated, 181 syndromic, and 82 other associated anomalies) were identified, and 2,520 controls were matched to cases on residence and year of pregnancy. Non-syndromic cases (n = 323) were subdivided into longitudinal (n = 120), transverse (n = 123), intercalary (n = 24), mixed (n = 18), and unknown (n = 38) deficiencies. RESULTS: Pregestational diabetes was associated with all limb deficiencies (adjusted odds ratio [OR] 12.71, 95% confidence interval [CI] 2.37, 68.25) and with isolated (OR 11.42, 95% CI 2.00, 64.60) deficiencies. Primiparity was associated with increased risk of congenital limb deficiencies among all cases (OR 1.49, 95% CI 1.15, 1.93), isolated cases (OR 1.46, 95% CI 1.09, 1.96), and among cases with longitudinal (OR 1.90, 95% CI 1.24, 2.90) and transverse deficiencies (OR 1.75, 95% CI 1.13, 2.70). Young maternal age (<25 years) was associated with all congenital limb deficiencies (OR 1.40, 95% CI 1.02, 1.90) and transverse deficiencies (OR 1.76, 95% CI 1.05, 2.96). Advanced maternal age (≥35 years) was associated with syndromic (OR 1.82, 95% CI 1.19, 2.78) and transverse deficiencies (OR 1.94, 95% CI 1.06, 3.57). Maternal antiepileptic medication was associated with all (OR 5.77, 95% CI 1.75, 19.04) and with isolated cases (OR 3.83, 95% CI 1.02, 14.34). CONCLUSIONS: It is important that pregnant women taking medications, especially antiepileptics, or women with pregestational diabetes are carefully monitored with regard to the occurrence and risk of limb deficiencies in the fetus.

Feasibility of apparent diffusion coefficient in predicting the technical outcome of MR-guided high-intensity focused ultrasound treatment of uterine fibroids - a comparison with the Funaki classification.

PURPOSE: To investigate the feasibility of using an apparent diffusion coefficient (ADC) classification in predicting the technical outcome of magnetic resonance imaging-guided high-intensity focused ultrasound (MRgHIFU) treatment of symptomatic uterine fibroids and to compare it to the Funaki classification. MATERIALS AND METHODS: Forty-two patients with forty-eight uterine fibroids underwent diffusion-weighted imaging (DWI) before MRgHIFU treatment. The DW images were acquired with five different b-values. Correlations between ADC values and treatment parameters were assessed. Optimal ADC cutoff values were determined to predict technical outcomes, that is, nonperfused volume ratios (NPVr) such that three classification groups were created (NPVr of <30%, 30-80%, or >80%). Results were compared to the Funaki classification using receiver-operating-characteristic (ROC) curve analysis, with statistical significance being tested with the Chi-square test. RESULTS: A statistically significant negative correlation (Spearman's ρ = -0.31, p-value < 0.05) was detected between ADC values and NPV ratios. ROC curve analysis indicated that optimal ADC cutoff values of 980 × 10-6mm2/s (NPVr > 80%) and 1800 × 10-6mm2/s (NPVr < 30%) made it possible to classify fibroids into three groups: ADC I (NPVr > 80%), ADC II (NPVr 30-80%) and ADC III (NPVr < 30%). Analysis of the whole model area under the curve resulted in values of 0.79 for the ADC classification (p-value = 0.0007) and 0.62 for the Funaki classification (p-value = 0.0527). CONCLUSIONS: Lower ADC values prior to treatment correlate with higher NPV ratios. The ADC classification seems to be able to predict the NPV ratio and may even outperform the Funaki classification. Based on these results DWI and ADC maps should be included in the MRI screening protocol.

Oxytocin selectively reduces blood flow in uterine fibroids without an effect on myometrial blood flow: a dynamic contrast enhanced MRI evaluation.

INTRODUCTION: Uterine fibroids are the most common benign neoplasms in women. The administration of intravenous oxytocin is known to increase the efficacy of a non-invasive thermal ablation method (MR-HIFU) for treating fibroids. However, it is not known whether this phenomenon is caused by the effect of the oxytocin on the myometrium or the fibroid itself. The objective of this study was to evaluate the influence of oxytocin on the blood flow of fibroids, myometrium and skeletal muscle using a quantitative perfusion MRI technique. MATERIALS AND METHODS: 17 premenopausal women with fibroids considered to be treated with MR-HIFU and 11 women with no fibroids were enrolled in the study. An extended MRI protocol of the pelvis was acquired for each subject. Later another MRI scan was performed with continuous intravenous infusion of oxytocin. The effect of oxytocin was analyzed from quantitative perfusion imaging. The study was registered in clinicaltrials.gov NCT03937401. RESULTS: Oxytocin decreased the blood flow of each fibroid; the median blood flow of fibroid was 39.9 ml/100 g tissue/min without and 3.5 mL/100 g/min with oxytocin (p ≤ 0.0001). Oxytocin did not affect the blood flow of the myometrium in either group. Oxytocin increased the blood flow of the skeletal muscle in both groups (p = 0.04). CONCLUSION: Oxytocin is effective in decreasing the blood flow in fibroids while having minor or no effect on the blood flow of normal myometrium. Routine use of oxytocin in HIFU therapy may make the therapy suitable to a larger group of women in a safe manner.

A relational database to identify differentially expressed genes in the endometrium and endometriosis lesions.

Endometriosis is a common inflammatory estrogen-dependent gynecological disorder, associated with pelvic pain and reduced fertility in women. Several aspects of this disorder and its cellular and molecular etiology remain unresolved. We have analyzed the global gene expression patterns in the endometrium, peritoneum and in endometriosis lesions of endometriosis patients and in the endometrium and peritoneum of healthy women. In this report, we present the EndometDB, an interactive web-based user interface for browsing the gene expression database of collected samples without the need for computational skills. The EndometDB incorporates the expression data from 115 patients and 53 controls, with over 24000 genes and clinical features, such as their age, disease stages, hormonal medication, menstrual cycle phase, and the different endometriosis lesion types. Using the web-tool, the end-user can easily generate various plot outputs and projections, including boxplots, and heatmaps and the generated outputs can be downloaded in pdf-format.Availability and implementationThe web-based user interface is implemented using HTML5, JavaScript, CSS, Plotly and R. It is freely available from https://endometdb.utu.fi/ .

Glycovariant-based lateral flow immunoassay to detect ovarian cancer-associated serum CA125.

Cancer antigen 125 (CA125) is a widely used biomarker in monitoring of epithelial ovarian cancer (EOC). Due to insufficient cancer specificity of CA125, its diagnostic use is severely compromised. Abnormal glycosylation of CA125 is a unique feature of ovarian cancer cells and could improve differential diagnosis of the disease. Here we describe the development of a quantitative lateral flow immunoassay (LFIA) of aberrantly glycosylated CA125 which is widely superior to the conventional CA125 immunoassay (CA125IA). With a 30 min read-out time, the LFIA showed 72% sensitivity, at 98% specificity using diagnostically challenging samples with marginally elevated CA125 (35-200 U/mL), in comparison to 16% sensitivity with the CA125IA. We envision the clinical use of the developed LFIA to be based on the substantially enhanced disease specificity against the many benign conditions confounding the diagnostic evaluation and against other cancers.

Exploratory Analysis of CA125-MGL and -STn Glycoforms in the Differential Diagnostics of Pelvic Masses.

BACKGROUND: The cancer antigen 125 (CA125) immunoassay (IA) does not distinguish epithelial ovarian cancer (EOC) from benign disease with the sensitivity needed in clinical practice. In recent studies, glycoforms of CA125 have shown potential as biomarkers in EOC. Here, we assessed the diagnostic abilities of two recently developed CA125 glycoform assays for patients with a pelvic mass. Detailed analysis was further conducted for postmenopausal patients with marginally elevated conventionally measured CA125 levels, as this subgroup presents a diagnostic challenge in the clinical setting. METHODS: Our study population contained 549 patients diagnosed with EOC, benign ovarian tumors, and endometriosis. Of these, 288 patients were postmenopausal, and 98 of them presented with marginally elevated serum levels of conventionally measured CA125 at diagnosis. Preoperative serum levels of conventionally measured CA125 and its glycoforms (CA125-MGL and CA125-STn) were determined. RESULTS: The CA125-STn assay identified EOC significantly better than the conventional CA125-IA in postmenopausal patients (85% vs. 74% sensitivity at a fixed specificity of 90%, P = 0.0009). Further, both glycoform assays had superior AUCs compared to the conventional CA125-IA in postmenopausal patients with marginally elevated CA125. Importantly, the glycoform assays reduced the false positive rate of the conventional CA125-IA. CONCLUSIONS: The results indicate that the CA125 glycoform assays markedly improve the performance of the conventional CA125-IA in the differential diagnosis of pelvic masses. This result is especially valuable when CA125 is marginally elevated.

Transcriptomic responses to hypoxia in endometrial and decidual stromal cells.

Human reproductive success depends on a properly decidualized uterine endometrium that allows implantation and the formation of the placenta. At the core of the decidualization process are endometrial stromal fibroblasts (ESF) that differentiate to decidual stromal cells (DSC). As variations in oxygen levels are functionally relevant in endometrium both upon menstruation and during placentation, we assessed the transcriptomic responses to hypoxia in ESF and DSC. In both cell types, hypoxia-upregulated genes in classical hypoxia pathways such as glycolysis and the epithelial mesenchymal transition. In DSC, hypoxia restored an ESF-like transcriptional state for a subset of transcription factors that are known targets of the progesterone receptor, suggesting that hypoxia partially interferes with progesterone signaling. In both cell types, hypoxia modified transcription of several inflammatory transcription factors that are known regulators of decidualization, including decreased transcription of STATs and increased transcription of CEBPs. We observed that hypoxia-upregulated genes in ESF and DSC had a significant overlap with genes previously detected to be upregulated in endometriotic stromal cells. Promoter analysis of the genes in this overlap suggested the hypoxia-upregulated Jun/Fos and CEBP transcription factors as potential drivers of endometriosis-associated transcription. Using immunohistochemistry, we observed increased expression of JUND and CEBPD in endometriosis lesions compared to healthy endometria. Overall, the findings suggest that hypoxic stress establishes distinct transcriptional states in ESF and DSC and that hypoxia influences the expression of genes that contribute to the core gene regulation of endometriotic stromal cells.

Europium Nanoparticle-Based Sialyl-Tn Monoclonal Antibody Discriminates Epithelial Ovarian Cancer-Associated CA125 from Benign Sources.

BACKGROUND: The Sialyl-Thomsen-nouveau antigen (STn) is abundantly produced on many types of human epithelial cancers including epithelial ovarian cancer (EOC). We previously developed an EOC-specific lectin sandwich immunoassay (CA125MGL) using a human macrophage galactose-binding lectin coated on fluorescent europium nanoparticles (Eu+3-NPs) as a tracer and an anti-CA125-specific mAb for capture. Here we have identified a novel STn-mAb that efficiently recognizes the EOC-associated STn antigen on CA125 when coated on Eu+3-NPs. METHOD: CA125 from the ovarian cancer cell line OVCAR-3, placental homogenate, and ascites fluid from patients with liver cirrhosis was captured by anti-CA125 antibody immobilized on microtitration wells and traced with anti-STn-mAb-Eu+3-NPs. Samples from EOC or patients with endometriosis with marginally increased conventional CA125 immunoassay (CA125IA; 35-200 U/mL) and healthy controls were analyzed. RESULTS: An analytically sensitive CA125STn assay that specifically recognized the CA125 isoform produced by OVCAR-3 was achieved. Serum CA125STn concentration was significantly higher in EOC patients than in those with endometriosis (P < 0.001). Furthermore, the sensitivity for detection of EOC with CA125STn assay was 73.3% when 95% of endometriosis cases were undetectable. CONCLUSION: Our findings suggest that Eu+3-NPs-based CA125STn assay could help reduce the false-positive rates of CA125IA to improve differential diagnosis. The results encourage studying further the potential use of CA125STn to detect EOC at earlier clinical stages. This approach warrants further investigation in other cancers as well.

Comprehensive feature selection for classifying the treatment outcome of high-intensity ultrasound therapy in uterine fibroids.

The study aim was to utilise multiple feature selection methods in order to select the most important parameters from clinical patient data for high-intensity focused ultrasound (HIFU) treatment outcome classification in uterine fibroids. The study was retrospective using patient data from 66 HIFU treatments with 89 uterine fibroids. A total of 39 features were extracted from the patient data and 14 different filter-based feature selection methods were used to select the most informative features. The selected features were then used in a support vector classification (SVC) model to evaluate the performance of these parameters in predicting HIFU therapy outcome. The therapy outcome was defined as non-perfused volume (NPV) ratio in three classes: <30%, 30-80% or >80%. The ten most highly ranked features in order were: fibroid diameter, subcutaneous fat thickness, fibroid volume, fibroid distance, Funaki type I, fundus location, gravidity, Funaki type III, submucosal fibroid type and urinary symptoms. The maximum F1-micro classification score was 0.63 using the top ten features from Mutual Information Maximisation (MIM) and Joint Mutual Information (JMI) feature selection methods. Classification performance of HIFU therapy outcome prediction in uterine fibroids is highly dependent on the chosen feature set which should be determined prior using different classifiers.