Analysis of Differentially Expressed MicroRNAs and Circulating Tumor Cells as Predictive Biomarkers of Platinum Chemoresistance in Primary Ovarian Carcinomas: A Prospective Study.

LESSON LEARNED: Circulating tumor cells, microRNA markers, or other biomarkers merit examination as part of correlative scientific analyses in prospective clinical trials. BACKGROUND: Platinum chemotherapy resistance occurs in approximately 25% of patients with ovarian carcinoma; however, no biomarkers of ovarian carcinoma chemoresistance have been validated. We performed a prospective trial designed to identify tumor-based predictive biomarkers of platinum resistance. METHODS: Tumor specimens were collected from 29 women with newly diagnosed histopathologically proven primary ovarian carcinoma. Of these, 23 women had specimens accessible for assessment and outcome data available regarding chemosensitive versus chemoresistance status via review of the medical record. Tumor slices were stained with antibodies against two microRNAs (miRNAs 29b and 199a) differentially expressed in chemoresistant ovarian cancer cell lines. Additionally, blood samples obtained at the time of diagnosis were analyzed for the presence of circulating tumor cells (CTCs). RESULTS: The average age of the patients was 64 years, and 82.6% had high-grade epithelial carcinomas. The baseline median CA-125 was 464 (range 32-2,782). No statistically significant differences were observed in miR29b or 199a expression in platinum-resistant/refractory versus platinum-sensitive tumors. Furthermore, the presence of CTCs was not found to be statistically significantly predictive of eventual platinum resistance. CONCLUSION: Our analysis showed no differences in miR29b and 199a expression, and differences in baseline CTCs in women with newly diagnosed ovarian tumors were not statistically significant.

The evaluation of the predictive value of TNF-alpha concentration in maternal serum in the prediction of neonatal and maternal infection.

INTRODUCTION: The consequences of uncomplicated PPROM are serious, and the presence of overt intraamniotic infection (IAI) is associated with a significant increase in both, the maternal and fetal morbidity and mortality rate. TNF-alpha is a cytokine involved in systemic inflammation and plays an important role in modulating the acute phase reaction. AIM: The aim of this study was to evaluate the predictive value of TNF-alpha levels in maternal serum within 6 hours after pprom and in the period of up to 12 hours after delivery in the prediction of neonatal and maternal infection. MATERIAL AND METHODS: The investigation was conducted on a group of 56 women diagnosed with PPROM between 30+0 and 36+6 weeks gestational age. In the period of up to 6 hrs from pprom first sample of 10 ml of maternal venous blood for laboratory testing was taken and the level of TNF-alpha was measured. A second sample of venous blood was taken within 12 hrs from delivery to reassess the TNF-alpha levels. All the participants were divided retrospectively into four groups depending on the occurrence of adverse neonatal and maternal outcome. Measuring the concentration of TNF-alpha in maternal serum was performed using the elisa method (enzyme-linked immunosorbent assay). RESULTS: A statistically significant difference in the second assay (up to 12 hours after delivery) between the patients with and without signs of maternal infection was observed concerning the TNF-alpha serum level. The concentration of this cytokine in maternal serum after delivery was 1.79 and 1.36 pg/ml (p < 0.05) respectively whereas within 6 hours from the PPROM in those two groups it was comparable (1.25 vs. 7.37 pg/ml - ns). Analogous observations were made in case of adverse neonatal outcome, where the TNF-alpha serum level within 12 hours after delivery was 1.70 and 1.45 pg/ml (p < 0.05) and in the period of up to 6 hours from pprom was 1.25 vs. 1.38 pg/ml (ns) respectively CONCLUSIONS: 1. In our investigation the maternal serum TNF-alpha concentration testing within 6 hours from PPROM between 30+0 and 36+6 weeks of gestation did not allow for the identification of patients who are more likely to develop signs of maternal infection and whose infant was at risk of neonatal infection after delivery 2. In case of pprom between 30+0 and 36+6 weeks of gestation maternal serum TNF-alpha concentration testing in the period of up to 12 hours after delivery may be a useful diagnostic tool for identification of patients with an increased risk of maternal and neonatal infection. 3. The lower the gestational age at PPROM and at delivery the risk of neonatal infection was greater.

Reproductive outcomes after surgical sperm retrieval in couples with male factor subfertility: a 10-year retrospective national cohort.

OBJECTIVE: To determine any significant differences in the reproductive outcome from intracytoplasmic sperm injection (ICSI) with surgical sperm retrieval (SSR) between cycles using fresh and cryopreserved sperm and between cycles using epididymal and testicular sperm. DESIGN: A retrospective national cohort study using data from the UK Human Fertilisation and Embryology Authority, including all ICSI cycles performed in the United Kingdom over a 10-year period. SETTING: Hospital. PATIENT(S): All nondonor ICSI cycles from 2008 to 2017 categorized by sperm source and cryopreservation status. INTERVENTION(S): Intracytoplasmic sperm injection with SSR using fresh or cryopreserved sperm and using ejaculated, testicular, and epididymal sperm. MAIN OUTCOME MEASURE(S): Live birth rate, pregnancy rate, and implantation rate. RESULT(S): We analyzed data from 214,649 ICSI cycles, including 199,818 cycles of ejaculated sperm, 5,646 cycles of epididymal sperm, and 9,185 cycles of testicular sperm. Live births rates per ICSI cycle were 28.5%, 30.6%, and 28.7% for ejaculated, epididymal, and testicular sperm cycles, respectively. Epididymal sperm cycles had a higher live birth rate than that of testicular sperm cycles (odds ratio [OR], 1.067; 95% confidence interval [CI], 1.014-1.123). This was despite a higher mean male age (42.5 vs. 40.6 years; 95% CI of difference, 1.81-1.85 years) and female age (34.3 vs. 34.0 years; 95% CI of difference, 0.32-0.34 years) in epididymal cycles than in testicular cycles. Implantation (61.2% vs. 58.0%; OR, 1.086; 95% CI, 1.041-1.133) and clinical pregnancy rates (34.3% vs. 31.3%; OR, 1.085; 95% CI, 1.039-1.132) were also higher in epididymal cycles than in testicular cycles. There were no statistically significant differences in outcomes between cycles using fresh sperm and those using cryopreserved sperm for SSR-ICSI. CONCLUSION(S): Our study indicates that reproductive outcomes of SSR-ICSI are at least comparable with those of ICSI using ejaculated sperm and does not support the preferential use of fresh sperm over cryopreserved sperm in SSR-ICSI. Births per SSR-ICSI cycle were higher for cycles using epididymal sperm than for cycles using testicular sperm; however, the differences were small, which may provide reassurance to patients undergoing these procedures. The results must be interpreted with caution because multivariable analysis was not possible because of aggregation of data.

[Conservative treatment of endometriosis]. / Leczenie zachowawcze endometriozy--praca pogladowa.

Endometriosis is a common disease concerning 5-10% of women at reproductive age. It may cause sterility and decrease the quality of life. The best known symptoms are dysmenorrhea, dyspareunia, chronic pelvic pain and pain related to ovulation. Endometriosis is a chronic illness which, so far can not be completely cured. Clinical treatment is focused on decreasing symptoms, improving the quality of life, inhibition of endometrial focuses, sustaining sterility and preventing recurrences. Most of the time clinical treatment is not limited only to one possibility but usually joins a few therapeutic options. One of the possibilities is the surgical treatment, usually laparoscopic. Conservative treatment may be its completion. The main medical aim of conservative treatment is to decrease pain by inhibition of inflammation and to reduce or arrest the production of cyclic ovarian hormones, what usually leads to amenorrhea. Drugs used in conservative treatment of endometriosis are often connected with numerous side effects, constituting a serious limitation of a long-term therapy. That is the reason why much research concentrates on finding the optimal medical procedures for patients with endometriosis.

[Concentration of selected cytokines in women with premature rupture of membranes and preterm delivery--preliminary study]. / Stzenie wybranych cytokin u kobiet z przedwczesnym peknieciem blon plodowych i porodem przedwczesnym--badane wstepne.

INTRODUCTION: For years much attention has been paid to the possible role of cytokines in the etiology of preterm delivery (PTD) in relation to anticipation of delivery in women with premature rupture of membranes (PROM). There are no clear indications introducing this observation to clinical practice. The goal of this study was to evaluate interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), G-colony stimulating factor (G-CSF) concentration in serum of women with PROM in connection with the occurrence of the delivery MATERIAL AND METHODS: 35 patients with PROM (average age 29.6 +/- 3.8 years, average time of gestation 35.2 +/- 1.5 weeks) were analyzed. The pregnant women were divided into 2 groups: 15 women delivered < 24 h and 20 women delivered > 24 h since the appearance of PROM. In both analyzed subgroups, the levels of IL-6, TNF-alpha, G-CSF CRP and leucocytosis have been compared. The concentration of IL-6, TNF-alpha and G-CSF in serum was measured by immunoenzymatic ELISA method, CRP concentration by immunoturbimetric method. RESULTS: In the whole group of women with PROM, the differences in average serum concentration of IL-6 before and after delivery (6.01 +/- 3.71 pg/mL and 7.98 +/- 3.44 pg/mL p < 0.05) and G-CSF (130.92 +/- 110.32 pg/mL and 79.59 +/- 52, 13 pg/mL, p < 0,05) have been observed. Moreover, average TNF-alpha concentration before and after the delivery was 1.43 +/- 0.63 pg/mL and 1.72 +/- 1.06 pg/mL (p > 0.05), respectively. It is particularly interesting that the authors have observed higher concentration of G-CSF in women who delivered within 24 h since PROM (147.05 +/- 103.88 pg/mL), if compared to the women who delivered after 24 h since PROM (118.81 +/- 115.71 pg/mL, without statistically significant difference p > 0.05). The same remark was connected with difference of IL-6 concentration in analogical groups of women (6.42 +/- 4.14 pg/mL vs 5.71 +/- 3.42 pg/mL, p > 0.05). Equally interesting observation were statistically significant differences in G-CSF concentration before and after delivery (147.06 +/- 103,88 vs 74.67 +/- 46.84, p < 0.05) in the event of the delivery < 24 h since PROM, such as in IL-6 concentration (5.71 +/- 3.42 vs 8.11 +/- 3.41, p < 0.05) in case of the delivery > 24 h since PROM. CONCLUSIONS: Statistically significant differences in IL-6, G-CSF, and CRP concentration before and after the delivery suggest the participation of these factors in the etiology of preterm delivery in women with PROM. The higher IL-6 and G-CSF concentration in women delivering within 24 h since the appearance of PROM suggest that these cytokines could be involved in the processes leading to delivery Statistically significant differences in IL-6 and G-CSF concentration before and after the delivery in a group of women delivering < 24 h or > 24 could indicate an important contribution of changes in proportions of these cytokines in PTD the etiology in PROM.

Effectiveness of modified downregulation for women with moderate and severe adenomyosis of the uterus prior to frozen thawed embryo transfer (MODA) study protocol: a pragmatic randomised-controlled trial.

INTRODUCTION: Adenomyosis can adversely reduce chances of pregnancy in couples undergoing assisted conception. We aim to evaluate the effect of two different downregulation protocols on the reproductive outcomes in women with moderate and severe adenomyosis undergoing frozen-thawed embryo transfer (FTET). METHODS AND ANALYSIS: We will conduct a two-armed pragmatic randomised clinical trial comparing modified downregulation with gonadotrophin-releasing hormone (GnRH) analogue for 6 weeks to standard downregulation with GnRH analogue for 1 week prior to FTET. Our primary outcome is clinical pregnancy, defined as a viable intrauterine pregnancy confirmed by ultrasound at greater than 6 weeks gestation, with other secondary reproductive, neonatal and safety outcomes. We aim to randomise 162 patients over 3 years to achieve 80% power for detecting a 20% difference in the primary outcome at 5% significance. ETHICS AND DISSEMINATION: To date there is no consensus on the optimal protocol for management of subfertile women with adenomyosis. Modified downregulation could improve the clinical pregnancy rate by reducing the endometrial inflammatory reaction and/or myometrial contractility and their impact on uterine receptivity in women with moderate and severe adenomyosis of the uterus undergoing FTET. The MODA trial is designed to offer pragmatic, real-life evaluation of the optimal protocol for downregulation for this population during assisted conception treatments. Our findings will be published in peer-reviewed journals and presented at national and international scientific meetings and congresses. Ethical approval was granted by the NHS Research Ethics Committees (19/LO/1567). TRIAL REGISTRATION NUMBER: NCT03946722.

[Sacrococcygeal teratoma in foetus--case report]. / Potworniak okolicy krzyzowo-guzicznej u plodu--opis przypadku.

Sacrococcygeal teratoma develops from all three germinal layers (endoderm, mesoderm and ectoderm). Sacrococcygeal teratomas (SCT) are the most common neoplasms in the fetus and newborns, with an estimated prevalence of 1 in 20,000 to 1 in 40,000. Female to male ratio is 3:1. Perinatal mortality rate among fetuses with prenatally diagnosed SCT is high, mainly due to cardiac failure. According to Polish Gynecology Society Recommendation, the main aim of intrauterine intervention or pharmacological treatment in case of prenatally diagnosed SCT is to prevent development of severe fetal cardiac failure. Fetal cardiac failure is one of the most important prognostic factors in surveillance of fetus and newborns with SCT. The following article describes a case report of a 34-year-old pregnant woman, 23 weeks of gestation, with a diagnosis of fetal sacrococcygeal teratoma. Each pregnant woman with suspicion of neoplasm in fetus should be referred to tertiary center of perinatal care to gain access to specific diagnostic methods and medical care of many specialists, such as obstetricians, neonatologists, general practitioners and infant surgeons. The role of psychological care during hospitalization is also invaluable and helps the patient to minimize the mental trauma, due to diagnosed fetal abnormalities.

[Polymorphism in the genes of Toll-like receptors type 2 and type 4 (TLR-2 and TLR-4) and the risk of premature rupture of the membranes--preliminary study]. / Polimorfizm genów receptorów Toll- podobnych typu 2 oraz 4 (TLR-2 i TLR-4) a ryzyko wystapienia przedwczesnego pekniecia blon plodowych--doniesienie wstepne.

INTRODUCTION: Toll-like receptors (TLR) -2 and -4 are a part of basic defence mechanism protecting against bacterial infections. They recognize microbial products and increase immune response of the host organism. The relationship between the expression of TLR receptors and the occurrence of intraamniotic infection (IAI) as well as preterm labour was demonstrated. Therefore, a relationship between TLR-2 and -4 genes polymorphism, premature rupture of membranes (PROM), intraamniotic infection and preterm labour is claimed to exist. AIM: The aim of the following study was to evaluate the frequency of two genetic polymorphisms: Arg753Gln (G20877A) in TLR-2 and Thr399lle (C8993T) in TLR-4 genes in a group of pregnant women with preterm rupture of membranes and preterm labour. MATERIAL AND METHODS: 33 pregnant women with the diagnosis of preterm--between 30 and 36 weeks of gestation--rupture of membranes (study group), and 60 healthy pregnant women (controls) were enrolled into the study. To analyse Arg753Gln polymorphism of TLR-2 gene and Thr399lle polymorphism of TLR-4 gene, polymerase chain reaction and restriction fragments length polymorphism (PCR/RFLP) were used. RESULTS: For G20877A polymorphism in TLR-2 gene, the frequency of heterozygous GA genotype in the study group was 9.1% and was comparable with the control group (8.3%, p = ns). Moreover frequency mutated G allele was comparable in both examined groups (4.6% in the study group and 4.2% in the control group, p = ns). For C8993T polymorphism in TLR-4 gene, heterozygous CT genotype was less frequent in the study group in comparison with the control group (9.1 vs. 16.7%). The homozygous CC genotype was more frequent in the study group (90.0 vs 83.3%, p = ns), with relatively high value of the odds ratio (OR = 2,0). Similar observations were conducted by analysing the frequencies of the alleles in both examined groups. CONCLUSION: Overrepresentation of heterozygous CT genotype and mutated T allele of C8993T polymorphism in TLR-4 gene in the control group may indicate that, possibly, it plays a protective role against PROM. However this hypothesis requires further investigation on a larger group of patients with premature rupture of membranes.

Assessment of Circulating Tumor Cells as a Predictive Biomarker of Histology in Women With Suspected Ovarian Cancer.

BACKGROUND: The clinical assessment of circulating tumor cells (CTCs) as a blood-based biomarker is FDA-approved for use in breast, colorectal, and prostate cancers. The objective of this prospective clinical study was to determine whether pretreatment CTCs are a useful diagnostic biomarker in women with complex pelvic masses. METHODS: Whole blood was collected from 49 women with newly diagnosed pelvic masses. The presence of CTCs was compared between women with and without ovarian cancer histopathologic diagnosis after surgery using a Chi-squared test. RESULTS: CTCs were absent in those with benign disease (0/14), present in 17% (5/29) of patients with a histologic diagnosis of ovarian carcinoma, and present in 80% (4/5) of patients with ovarian metastases from other cancers (P = 0.001). All 5 women with ovarian cancer who had CTCs present presented stage III or IV of the disease (P = 0.13). CONCLUSIONS: CTCs were more prevalent in patients with metastases to the ovary than in primary ovarian carcinomas.