Impact of preimplantation genetic testing for aneuploidies (PGT-A) on first trimester biochemical markers - PAPP-A (placenta-associated plasma protein) and free ß-hCG (human chorionic gonadotropin).

OBJECTIVE: The objective of the study was to study the effect of preimplantation genetic testing for aneuploidies (PGT-A) performed at blastocyst stage on the levels of first trimester biomarkers. METHODS: This is an observational, collaborative, retrospective study. Seven hundred and twenty-eight patients were included in the study. Patients were with singleton pregnancies resulting from either natural conception (NC), or assisted reproductive techniques (ARTs) with PGT-A and frozen embryo transfer (FET) (ART/PGT-A/FET) or after ART without PGT-A and fresh ET (ART/no PGT-A/fresh ET) or FET (ART/no PGT-A/FET), who had first trimester combined screening test between 11 and 14 gestational weeks. They were stratified into four groups: group A (ART/PGT-A/FET) - 143 patients; group B (ART/no PGT-A/FET) - 100 patients; group C (ART/no PGT-A/fresh ET) - 346 patients, and group D (NC) - 139 patients. RESULTS: Statistically significant differences among the examined groups were observed for maternal age, BMI, ethnicity, and parity. The median placenta-associated plasma protein (PAPP-A) was lowest in the group with ART/PGT-A/FET and the highest result was obtained in the group with ART/no PGT-A/FET. Statistically significant difference in the median PAPP-A levels was identified among the examined groups (p = .0186). When a subgroup analysis was performed, a statistically significant difference was observed in the median PAPP-A between ART/PGT-A/FET group versus ART/no PGT-A/FET group (p = .01) and NC versus ART/no PGT-A/FET (p = .01). A similar trend toward statistical significance was noted when comparing NC versus ART/no PGT-A/fresh ET (p = .06). Multivariate analysis elucidated that when age is present in the model, the effect of any method of conception or testing for aneuploidy disappears. The other factors (BMI, ethnicity, and parity) do not influence the levels of PAPP-A. The lowest median free human chorionic gonadotropin (ß-HCG) was recorded in the NC group and the highest result was identified in the group with IVF/PGT-A/FET. No statistically significant difference was observed in the median concentration levels of free ß-hCG among the compared groups (p = .5789) and when subgroup analysis was performed (p>.05). The normality of the distribution of variables was analyzed by the Kolmogorov-Smirnov test and the median PAPP-A and free ßhCG concentration difference by the Wilcoxon rank-sum test with nonparametric ANOVA. CONCLUSIONS: Testing for aneuploidy (PGT-A) and the decision to transfer either fresh or cryopreserved embryos (ET) appear not to affect the levels of first trimester biochemical markers. The findings of the present study should be a baseline for future studies and could be used to improve the antenatal screening counseling for women with ART pregnancies and PGT-A.

Phase 3 trial of coronavir (favipiravir) in patients with mild to moderate COVID-19.

Favipiravir has demonstrated efficacy against the SARS-CoV-2 virus in several preliminary studies. This study aimed to evaluate the efficacy and safety of favipiravir for treatment of mild to moderate COVID-19 in outpatients and hospitalized patients. We conducted an open-label, randomized, active-controlled trial of a generic form of favipiravir in patients with COVID-19 confirmed by PCR-test. Eligible patients (18-60 years) after stratification were randomly assigned (in a 2:1 ratio) to receive either favipiravir (1800 mg BID on day 1, followed by 800 mg BID for up to 9 days), or standard of care (SOC) treatment (umifenovir + intranasal interferon alpha-2b, or hydroxychloroquine) for up to 10 days. The co-primary outcomes were the time to clinical improvement and the time to viral clearance. Among 190 patients assessed for eligibility 168 were randomized to favipiravir (n=112) or to SOC (n=56) group. The median time to clinical improvement was 6.0 days (IQR 4.0; 9.3) in the favipiravir group and 10.0 (IQR 5.0; 21.0) days in the SOC group; the median difference was 4 days (HR 1.63; 95% CI 1.14-2.34; P=0.007). The statistically significant difference in the median time to viral clearance was observed only for hospitalized patients: 3.0 (IQR 3.0; 3.0) days in the favipiravir group vs. 5.0 (IQR 4.5; 5.5) days in the SOC group (HR 2.11; 95% CI 1.04-4.31; P=0.038). The rate of viral elimination on Day 5 in the favipiravir group was significantly higher than in SOC group: 81.2% vs. 67.9% (RR 1.22; 05% CI 1.00-1.48; P=0.022). The rate of clinical improvement on Day 7 in the favipiravir group was 1.5-fold higher than in SOC group: 52.7% vs. 35.8% (RR 1.50; 95% CI 1.02-2.22; P=0.020). Favipiravir was well-tolerated and the most common adverse reactions were asymptomatic hyperuricemia, transient elevation of ALT & AST, and mild gastrointestinal disorders. Favipiravir was superior to the SOC in shortening the time to clinical improvement in patients with mild to moderate COVID-19.

Isthmocele and ovarian stimulation for IVF: considerations for a reproductive medicine specialist.

STUDY QUESTION: What is the risk of developing intracavitary fluid (ICF) during ovarian stimulation in patients with an isthmocele after previous caesarean section (CS) delivery? SUMMARY ANSWER: In patients with an existing isthmocele, the risk of developing ICF during hormonal stimulation for IVF is almost 40%; therefore, special attention has to be paid to exclude fluid accumulation during stimulation and particularly at the time of transfer, in which case the reproductive outcomes of frozen embryo transfer (FET) cycles appear to be uncompromised. WHAT IS KNOWN ALREADY: Lately, there is an increasing focus on the long-term impact of CS delivery on the health and future fertility of the mother. Development of an isthmocele is one of the sequelae of a CS delivery. The presence of ICF in combination with an isthmocele has been described previously, and the adverse effect of endometrial fluid on implantation is well recognised by reproductive medicine specialists. Accumulation of ICF has been previously described in patients with hydrosalpinx, less commonly in patients with polycystic ovary syndrome undergoing ovarian stimulation for IVF/ICSI, and even in some patients without any identifiable reason. Assisted reproductive techniques (ARTs) are a means to overcome infertility. Reproductive medicine specialists commonly see patients with secondary infertility with a history of having had one or more previous CS and with ultrasound confirmation of an isthmocele. However, the available data pertaining to the prevalence of intracavitary fluid during ovarian stimulation in patients with ultrasound confirmation of an isthmocele is limited. Furthermore, data on the influence of ICF in a stimulated cycle on the ART outcome of a subsequent FET cycle is scarce and merits further studies. STUDY DESIGN, SIZE, DURATION: A prospective observational exploratory study was performed in IVI Middle East Fertility Clinic, Abu Dhabi, from June 2018 to March 2019, and retrospective analysis of the reproductive outcomes was performed until July 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients with secondary infertility, defined as a minimum of 1 year of infertility after a previous successful pregnancy, undergoing ovarian stimulation for IVF/ICSI and having a history of one or more previous CS with ultrasonographic visible isthmocele, were included (n = 103). Patients were monitored as a clinical routine with vaginal ultrasound examinations during ovarian stimulation for IVF/ICSI treatment. All patients included in the study were asked to complete a questionnaire regarding their previous obstetric history. Development of ICF was recorded as well as changes in the measurements of the isthmocele during the course of ovarian stimulation. Reproductive outcomes of FET cycles of the patients with an isthmocele were retrospectively compared to those of patients with infertility and without isthmocele in our clinic during the same time period. MAIN RESULTS AND THE ROLE OF CHANCE: Patients with an existing isthmocele after previous CS have a risk of ~40% of developing ultrasonographic visible fluid in the endometrial cavity during the course of ovarian stimulation. Development of ICF was significantly correlated with the depth of the isthmocele on Day 2/3 (P = 0.038) and on the day of trigger (-1/-2 days) (P = 0.049), circumference of the isthmocele on the day of trigger (-1/-2 days) (P = 0.040), distance from the C-scar to the external os (P = 0.036), number of children delivered (P = 0.047) and number of previous CS (P = 0.035). There was a statistically significant increase in the parameters related to the size of the isthmocele during ovarian stimulation. No significant differences in the reproductive outcome (pregnancy rate and rates of biochemical and ectopic pregnancies, miscarriages and ongoing/delivered pregnancies) after FET were found between the patients with and without an isthmocele, when ICF was excluded prior to embryo transfer procedure. LARGE-SCALE DATA: NA. LIMITATIONS, REASONS FOR CAUTION: This study was not primarily designed to investigate the causes of ICF during ovarian stimulation or to evaluate the reproductive outcomes. Further, the small number of reported reproductive outcomes may be seen as a limitation. WIDER IMPLICATIONS OF THE FINDINGS: The data highlights the need for an increased awareness on the part of reproductive medicine specialists towards the potentially adverse impact of an isthmocele on ART treatment, as there is a potential to develop intracavitary fluid during ovarian stimulation for IVF. The increase in the circumference of the isthmocele may increase embryo transfer difficulty. STUDY FUNDING/COMPETING INTEREST(S): No funding of the study has to be reported. The authors have no competing interests. TRIAL REGISTRATION NUMBER: This prospective study was registered with clinicaltrials.gov. under the number NCT03518385.

Quality of life with talazoparib versus physician's choice of chemotherapy in patients with advanced breast cancer and germline BRCA1/2 mutation: patient-reported outcomes from the EMBRACA phase III trial.

Background: In the EMBRACA phase III trial, talazoparib (1 mg daily, orally) demonstrated a statistically significant improvement in PFS versus physician's choice of chemotherapy (PCT; capecitabine, eribulin, gemcitabine, or vinorelbine) in patients with HER2-negative advanced breast cancer carrying a germline BRCA1/2 mutation; we evaluated patient-reported outcomes (PROs). Patients and methods: Patients were randomized 2 : 1 to receive talazoparib or PCT. PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3 weeks), and at the end of treatment, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-30) and its breast cancer module, QLQ-BR23. Prespecified exploratory analyses included a longitudinal mixed-effect model comparing treatment arms and a time to definitive clinically meaningful deterioration (TTD) analysis carried out in the global health status/quality of life (GHS/QoL), and all functional and symptom scales from the EORTC QLQ-C30 and -BR23 questionnaires. Between-arm TTD comparisons were made using a stratified log-rank test and a Cox proportional hazards model. Results: Baseline scores were similar between arms. Statistically significant estimated overall improvement from baseline in GHS/QoL was seen for talazoparib compared with statistically significant deterioration for PCT {3.0 [95% confidence interval (CI) 1.2, 4.8] versus -5.4 [95% CI -8.8, -2.0]; between arms, P < 0.0001}. A statistically significant greater delay was observed in TTD in GHS/QoL, favoring talazoparib over PCT [hazard ratio, 0.38 (95% CI 0.26, 0.55; median, 24.3 versus 6.3 months, respectively; P < 0.0001)]. A statistically significant overall change and a statistically significant delay in TTD, all favoring talazoparib, were also observed in multiple functions and symptoms. Conclusion: Patients who received talazoparib had significant overall improvements and significant delay in TTD in multiple cancer-related and breast cancer-specific symptoms, functions, and GHS/QoL. ClinicalTrials.gov: NCT01945775.

Validation of targeted sequencing of single-nucleotide polymorphisms for non-invasive prenatal detection of aneuploidy of chromosomes 13, 18, 21, X, and Y.

OBJECTIVE: To assess the performance of cell-free DNA (cfDNA) testing in maternal blood for detection of fetal aneuploidy of chromosomes 13, 18, 21, X, and Y using targeted sequencing of single-nucleotide polymorphisms. METHODS: Prospective study in 242 singleton pregnancies undergoing chorionic villus sampling at 11 to 13 weeks. Maternal blood was collected before chorionic villus sampling and sent to Natera (San Carlos, CA, USA). cfDNA was isolated from maternal plasma, and targeted multiplex PCR amplification followed by sequencing of 19 488 polymorphic loci covering chromosomes 13, 18, 21, X, and Y was performed. Sequencing data were analyzed using the NATUS algorithm that determines the copy number and calculates a sample-specific accuracy for each of the five chromosomes tested. Laboratory personnel were blinded to fetal karyotype. RESULTS: Results were provided for 229 (94.6%) of the 242 cases. Thirty-two cases were correctly identified as aneuploid, including trisomy 21 [n = 25; sensitivity = 100% (CI: 86.3-100%), specificity = 100% (CI: 98.2-100%)], trisomy 18 (n = 3), trisomy 13 (n = 1), Turner syndrome (n = 2), and triploidy (n = 1), with no false positive or false negative results. Median accuracy was 99.9% (range: 96.0-100%). CONCLUSIONS: cfDNA testing in maternal blood using targeted sequencing of polymorphic loci at chromosomes 13, 18, 21, X, and Y holds promise for accurate detection of fetal autosomal trisomies, sex chromosome aneuploidies, and triploidy.

[Dopplerometry at prolonged pregnancy].

Prolonged pregnancy, associated with low amniotic fluid is a reason for the increase of fetal mortality and morbidity. There is no a define test at prolonged pregnancy which can determine which pregnancy are at a risk for adverse outcome and complications. Dopplerometry as a noninvasive method for examination of blood circulation, and especially a. cerebri media and a. umbilicalis can be used for the prediction of the outcome of prolonged pregnancy.

[A case of heterotopic pregnancy].

Heterotopic pregnancy is the simultaneous occurrence of intrauterine and ectopic pregnancy. Because of the increasing use of assisted reproductive technology techniques, the frequency of heterotopic pregnancy rises during the past years. We present a case of simultaneous occurrence of ruptured extrauterine /tubal/pregnancy and intrauterine /twin/pregnancy after IVF and ET.

[HELLP syndrome, complicated with DIC syndrome in the third trimester of pregnancy].

Defined as hemolysis, liver dysfunction and low platelets, HELLP syndrome is a severe complication of preeclampsia with worsening seriously the prognosis of mother and foetus. Frequently it is associated with the development of DIC syndrome. We present a case of HELLP syndrome developed in 30 gestational week, complicated with DIC syndrome.

[Mixed gonadal dysgenesis combined with gonadoblastoma].

Gonadal dysgenesis is defined by incomplete or defect forming of gonads, a result of disturbed process of migration of germ cells or and their correct organization in gonadal ridge. The combination of dysgenetic gonads and Y chromosome is a prerequisite for developing ovarian neoplasma--most frequent gonadoblastoma. We present a case of mixed gonadal dysgenesis at a patient with caryotype 46XY in combination with gonadoblastoma.

[A clinical case of twin pregnancy with intrauterine death of one of the twin (foetus papiraceus)].

Multiple pregnancy is associated with some specific syndromes: twin to twin transfusion syndrome, syndrome of the disappeared twin, intrauterine loss of one of the twin, development of foetus papiraceus and syndrome of asymmetric growth of the twin. We present a case of term pregnancy with death of one of the twin and normal delivery of healthy baby and Foetus papiraceus.

[Ovarian cancer with metastatic lesion in the vagina (foetus papiraceus)].

Ovarian cancer spreads primarily by intraperitoneal implantation of exfoliated cancer cells, by lymphatic dissemination, and by haematogenous spread. Very rarely it metastasizes to cervix, vulva and vagina; this type of metastases present a diagnostic challenge to the gynecologist and pathologist. We present a case of ovarian cancer with initial clinical manifestation-lesion of the vagina.

[Immunohistochemical profile of colorectal and ovarian carcinomas--examination with cytokeratin 7, cytokeratin 20, beta catenin and cDX 2].

INTRODUCTION: Metastases from colorectal adenocarcinomas can be histologically similar to serous, mucinous and endometrioid ovarian adenocarcinomas. The differentiation between primary and metastatic ovarian tumours is of great importance for the patients because of the different treatment and prognosis. AIM: The aim of the study was to determine whether the differences in the expression of Cytokeratin 7, Cytokeratin 20, Beta catenin and CDX2 can be used to distinguish the different types of carcinomas and their metastases. MATERIALS AND METHODS: The immunohistochemical expression of the listed above antibodies was examined retrospectively and prospectively in 38 colorectal adenocarcinomas (primary and metastatic) and 32 ovarian adenocarcinomas (primary and metastatic). The metastases in both types of adenocarcinomas are located in the peritoneum. RESULTS: The immunohistochemical expression was evaluated using a semi-quantitative method. The ovarian adenocarcinomas are mostly positive for Cytokeratin 7 (in 63%), while colorectal carcinomas are mostly positive for Cytokeratin 20 (in 73%). Regarding Beta catenin, in colorectal carcinomas the expression is mostly nuclear (in 65%) and in ovarian carcinomas mostly membrane (in 68%). In cases of uncertain expression of the markers mentioned above, CDX2 was used. Positive nuclear expression was observed only in intestinal tumours (in 86%). CONCLUSION: For differential diagnosis between ovarian and colorectal adenocarcinomas, the use of antibodies, determining the intestinal differentiation of the tumours like Cytokeratin 20, Beta catenin and CDX2 is recommended.

[Uterine carcinosarcoma with chondroid differentiation--immuhistochemical examination].

Uterine carcinosarcomas are highly aggressive malignant tumours, consisting of both epithelial and mesenchymal components. They represent 1-3% of the malignant uterine neoplasms. Their histogenesis is unclear. Because of their rarity and the very few clinical data available, the studies of potential therapeutic goals are scarce. We present clinical and pathohistological description of a rare case of a 76-year-old woman with a uterine carcinosarcoma with a chondroid differentiation, examined immunohistochemically with Cytokeratin, Vimentin and S-100 protein.

[CDX2--an immunochystochemistry marker of intestinal differentiation of adenocarcinomas].

CDX2 is a nuclear transcribing factor, important for the development and differentiation of the bowels. According to the recent publications, CDX2 expression is immunochystochemisry detector in the normal enterocytes of the bowels and is normally met in the most, but not at all colorectal carcinomas. Two homeostatic genes are detected at people CDX1 u CDX2. We present examination of CDX2 expression at 15 adenomas and 30 colorectal carcinomas. All the adenomas are positive for CDX2, 27 /90%/ of the adenocarcinomas show nuclear expression of CDX2.

[Frequency of cytolytic vaginosis--examination of 1152 patients].

The aim of the study was to evaluate the frequency of cytolitic vaginosis amongst women with symptoms that mimic vulvovaginal candidiasis. We include 1152 patients, which are microbiologically and citologically tested. We found in 3.9% cytolytic vaginosis. The clinical presentation is suggestive of vulvovaginal candidiasis. The differentiation of these two conditions is essential for appropriate treatment and resolution of chronic vaginal subjective complaints.

[Differential diagnostic importance of immunochistochemistry applied at metastases of adenocarcinomas of the peritoneum].

Patients with metastatic carcinomas with unclear primary tumor site are often clinical and pathological problem. They are diagnosed in about 3-65 of the cases with solid tumors. In 60% of cases the reason is adenocarcinomas. The most frequent reason for peritoneal carcinomas at women is the ovarian cancer. In such cases we must exclude the probability of colorectal cancer. In fact there are not international standards for prove the origin of adenocarcinomas; different research groups use different criteria. We present the use of four antibodies--Cytokeratin 7 and 20, Beta cathenin and CDX2 and define their positiveness at metastases from different groups of adenocarcinomas in the peritoneum.

[Molecular genetics of ovarian cancer].

Ovarian cancer is the most lethal gynecologic neoplasia. The risk of ovarian cancer in Europe is 1 to 80. In 80-90% of cases, the clinical manifestation is in advanced stage. The 5 year survival is for III /IV stage 25%, but for I/II stage is 90%. In the present study we present the molecular and genetic changes of hereditary and sporadic ovarian cancer.

[Adnexal torsion and concominant appendicitis during third trimester of pregnancy--a case report].

Adnexial torsion is a rare, but important cause for abdominal pain during pregnancy. During pregnancy, its frequency is 10-20%, with highest frequency in the first trimester. We present a case of 24 year primigravida, with an acute onset of clinical symptoms with concominant disease chronic pyelonephritis. The initial diagnosis was exacerbation of the concominant disease and acute inflammation of the appendix. The intraoperative diagnosis was right adnexial torsion and inflammation of the appendix; the diagnosis was pathologically proved. Although rare, it can be included in the differential diagnosis of acute abdomen during pregnancy.