Influence on the adult male Leydig cell biomarker insulin-like peptide 3 of maternal exposure to estrogenic and anti-androgenic endocrine disrupting compound mixtures: A retrospective study.

Insulin-like peptide 3 (INSL3) is a peptide biomarker secreted specifically by the mature Leydig cells of the testes. It is constitutive, has low within-individual variance, and effectively measures the functional capacity of Leydig cells to make testosterone. In young adult men there is a large 10-fold range of serum INSL3 concentration, persisting into old age, and implying that later hypogonadal status might be programmed in early life. To determine whether maternal exposure to environmental endocrine disrupting compounds (EDCs) influences adult serum INSL3 concentration, using a retrospective paradigm, INSL3 was measured in young adult male rats (80-90 days) from the F1 generation of females maternally exposed to varied doses of bisphenol A (BPA), butylparaben, epoxiconazole, and fludioxonil as single compounds, as well as estrogenic and anti-androgenic mixtures of BPA and butylparaben, and di(2-ethylhexyl) phthalate and procymidone respectively. A mixture of BPA and butylparaben significantly reduced circulating INSL3 concentration in adult male progeny. The remaining compounds or mixtures tested, though sufficient to induce other effects in the F1 generation were without significant effect. Maternal exposure to low concentrations of some EDCs may be a contributing factor to the variation in the Leydig cell biomarker INSL3 in young adulthood, though caution is warranted translating results from rats to humans.

Unilateral Partial Absence of the Fallopian Tube in a Female Patient With Infertility: A Case Report and Literature Review.

Unilateral partial absence of the fallopian tube is rare, and its clinical importance in fertility is unclear. A 35-year-old nulligravid female patient with infertility was suspected to have a left hydrosalpinx on hysterosalpingography and sonography. Therefore, the patient underwent diagnostic laparoscopy. The left fallopian tube lacked the ampullary portion, and its proximal end had a hydrosalpinx. A left salpingectomy was performed, and the pathological finding was a unilateral partial absence of the ampullary portion of the fallopian tube with hydrosalpinx. Postoperatively, she conceived via in vitro fertilization-embryo transfer-and delivered a healthy baby. Hydrosalpinx is a well-known cause of infertility and can develop due to the partial absence of a fallopian tube. Furthermore, salpingectomy may be effective in improving fertility in female patients with a unilateral partial absence of the fallopian tube.

Male seminal parameters are not associated with Leydig cell functional capacity in men.

BACKGROUND: Insulin-like peptide 3 (INSL3) is a constitutive, secreted peptide produced in the male uniquely by the Leydig cells of the testes. It is a biomarker for Leydig cell functional capacity, which is a measure of the numbers and differentiation status of these steroidogenic cells and lacks the biological and technical variance of the steroid testosterone. This retrospective study was carried out to examine the relationship between seminal parameters and the Leydig cell compartment, and secondarily to assess other factors responsible for determining Leydig cell functional capacity. METHODS: INSL3 was assessed together with seminal, anthropometric, and hormonal parameters in a Swedish cohort of 18-year-old men, representing the average population, and in a smaller, more heterogeneous cohort of men visiting an Australian infertility clinic. RESULTS AND DISCUSSION: Average INSL3 concentration at 18 years is greater than that reported at younger or older ages and indicated a large 10-fold variation. In neither cohort was there a relationship between INSL3 concentration and any semen parameter. For the larger, more uniform Swedish cohort of young men, there was a significant negative relationship between INSL3 and BMI, supporting the idea that adult Leydig cell functional capacity may be established during puberty. In both cohorts, there was a significant relationship between INSL3 and FSH, but not LH concentration. No relationship was found between INSL3 and androgen receptor trinucleotide repeat polymorphisms, reinforcing the notion that Leydig cell functional capacity is unlikely to be determined by androgen influence alone. Nor did INSL3 correlate with the T/LH ratio, an alternative measure of Leydig cell functional capacity, supporting the view that these are independent measures of Leydig cell function.

Placenta previa may acquire invasive nature by factors associated with epithelial-mesenchymal transition and matrix metalloproteinases.

AIM: To investigate the differences in epithelial-mesenchymal transition (EMT)- and matrix metalloproteinases (MMP)-related factors among placenta previa with and without placenta accreta spectrum (PAS) (n = 69), and normal placenta (n = 51). METHODS: The women diagnosed with placenta previa with or without PAS, and normal placentas, who delivered at our institution between 2006 and 2016, were enrolled. The difference of EMT-related factors' expression by immunochemical analysis in chorionic villi and decidual cells between the normal placenta and placenta previa with or without PAS were evaluated. RESULTS: In chorionic villi of placenta previa with and without PAS, E-cadherin expression decreased, while that of ZEB1, SNAIL2 and MMP-9 increased than that in normal placenta. In decidual cells of placenta previa with and without PAS, expression of vimentin, ZEB1 and MMP-9 increased than that in normal placenta. In placenta previa with and without PAS, there was strong co-expression of ZEB1 and vimentin in chorionic villi, of ZEB1 and MMP-2 or MMP-9 in decidual cells, and of SNAIL2 and vimentin or MMP-9 in both chorionic villi and decidual cell. Vimentin expression in both chorionic villi and decidual cells was higher in placenta previa with PAS (n = 18) than in placenta previa without PAS (n = 51). MMP-2 expression in decidual cells was higher in placenta previa with PAS than in placenta previa without PAS. CONCLUSION: This study revealed that EMT- and MMP-associated factors may be related to placenta previa with and without PAS. Furthermore, placenta previa without PAS may acquire invasive nature.

Ovarian Seromucinous Borderline Tumors Are Histologically Different from Mucinous Borderline Tumors.

AIM: To examine the clinicopathological features of ovarian seromucinous borderline tumors (SMBTs) and compare them with those of mucinous borderline/atypical proliferative mucinous tumors (MB/APMTs). PATIENTS AND METHODS: Patients with SMBT between 2014 and 2018 and those with MB/APMT between 1988 and 2018 who underwent surgery at our Institution were identified. Pathological review was conducted using the 2014 World Health Organization criteria. Clinical features were compared retrospectively between SMBT and MB/APMT. RESULTS: In total, 11 (12.9%) patients with SMBT and 74 (87.1%) patients with MB/APMT were included in our study. The diagnosis of six patients with SMBT and 73 patients with MB/APMT was not revised on review. SMBT was diagnosed at a younger age (p=0.04), was of smaller size (p<0.01) and bilateral (p=0.03), coexisted with endometriosis (p<0.01), and more frequently recurred than MB/APMT (p=0.04). CONCLUSION: SMBT might be more aggressive than MB/APMT.

Rapid decrease in serum VEGF-A levels may be a worse prognostic biomarker for patients with platinum-resistant recurrent ovarian cancer treated with bevacizumab and gemcitabine.

PURPOSE: The aim of this study was to investigate the association between changes in the levels of vascular endothelial growth factors (VEGFs) after treatment with bevacizumab and gemcitabine (Bev-Gem) and the clinical outcome. METHODS: Platinum-resistant ovarian cancer patients treated with Bev-Gem therapy at our hospital between 2014 and 2018 were identified. Serum VEGF levels at the first and second treatment cycle were measured by ELISA. All patients were categorized into two groups-patients with > 50% decrease in serum VEGF-A levels (Group A) and patients with < 50% decrease serum VEGF-A levels (Group B). The association between clinical outcome and serum VEGF levels was investigated between the two groups. RESULTS: Among 18 patients, 10 were in Group A and 8 in Group B. Group A exhibited a lower response rate (0% vs.75% p < 0.01) and clinical benefit rate (60% vs.100% p = 0.02) than Group B. The median serum VEGF-A level of Group A before the first cycle of Bev-Gem therapy was higher than that in Group B (61.2 vs. 3.7 pg/mL, p < 0.01). Group A exhibited worse PFS (7 vs., 10 months, p < 0.01) and OS (17 vs. 26 months, p = 0.04) than Group B. There were more patients with > 10% increase in serum VEGF-B levels in Group A than in Group B (p < 0.01). CONCLUSION: The rapid decrease in VEGF-A levels and the resultant increase in serum VEGF-B levels might be associated with an unfavorable clinical outcome. Large-scale studies are needed to further examine these results.

The Haphazard Pattern in Grade-3 Endometrioid Carcinoma Is Associated with Poor Prognosis and Tumor Lymphocyte Infiltration.

The aim of this study was to examine the associations among the haphazard invasive patterns, defined as directionless infiltration into the myometrium; expression of key proteins; tumor infiltrative lymphocytes (TILs); and the prognosis of gade-3 endometrioid carcinoma (G3EC). Between 1990 and 2013, patients with G3EC who underwent surgery at our hospital were identified. Invasive patterns were classified into either haphazard, infiltrative, or expansile patterns. The estrogen, progesterone, androgen receptor, cytokeratin 5/6, epidermal growth factor receptor, E-cadherin, snail-2, vimentin, ZEB1, chromogranin A, synaptophysin, MLH1, MSH2, MSH6, and PMS2 levels were evaluated by immunochemical analysis. The degree of strong or weak lymphocyte infiltration (LI) were evaluated using zone formation of LI at the invasive front. Haphazard, infiltrative, and expansile patterns were discovered in 8 (18%), 6 (13%), and 31 (69%) cases, respectively. Cases with the haphazard patterns were diagnosed at a more advanced stage (p < 0.01) and recurred more frequently (p < 0.01). There were statistical differences in progression-free survival (PFS) and overall survival (OS) between the three groups (PFS; p < 0.01: OS; p < 0.01). In multivariate analysis, only the haphazard pattern was found to be an independent, worse prognostic factor of PFS (Hazard ratio (HR) =10.8, p < 0.01) and OS (HR = 23.3, p < 0.01). Furthermore, the haphazard invasive pattern was related with weak LI (p < 0.01) but not with the expression of all proteins analyzed. The haphazard pattern was found to be a worse prognostic factor and was associated with weak LI in G3EC. The aggressive feature of G3EC might be associated with LI but not tumor biology.

Thrombotic events induce the worse prognosis in ovarian carcinomas and frequently develop in ovarian clear cell carcinoma.

BACKGROUND: This study aimed to examine the clinical significance and risk factors of thromboembolic events (TEEs) in patients with ovarian carcinoma. METHODS: Patients with ovarian carcinoma treated at our hospital between 2000 and 2017 were identified. The risk factors of TEEs, including venous TEEs and arterial TEEs, and the association between TEEs and prognosis were investigated. Patients with TEEs were classified into two groups: those with severe TEEs, defined as patients who required urgent treatment for deep vein thrombosis, massive pulmonary embolism, acute myocardial infarction, and symptomatic cerebral infarction, and those with mild TEEs. The risk factors of severe TEEs and the association between severe TEEs and prognosis were investigated. RESULTS: A total of 369 patients were enrolled. Among them, 53 patients (14.4%) were complicated with TEEs. Clear cell carcinoma (CCC) was a greater risk factor of TEEs than serous carcinoma (hazard ratio [HR] = 2.81, p = 0.03). In multivariate analysis for survival, TEEs were a prognostic factor of poor progression-free survival (PFS; HR = 2.90, p < 0.01) and overall survival (OS; HR = 2.89, p < 0.01). Among 53 patients with TEEs, 17 (32.1%) developed severe TEEs. CCC was strongly associated with severe TEEs (HR = 42.6, p = 0.02). Multivariate analysis for survival demonstrated that severe TEEs were a risk factor of worse PFS (HR = 4.34, p < 0.01) and OS (HR = 3.30, p = 0.03). CONCLUSION: TEEs induced poor prognosis and was associated with CCC. A standard treatment for CCC should be included in the strategy of TEEs.

Zone Formation of Lymphocyte Infiltration at the Invasive Front Results in the Prolonged Survival of Individuals With Endometrial Serous Carcinoma and Endometrioid Carcinoma With Serous Component.

BACKGROUND/AIM: This study aimed to evaluate the clinical significance of lymphocyte infiltration (LI) for patients with endometrial serous carcinoma and those with endometrioid carcinoma including serous component. PATIENTS AND METHODS: Patients who underwent surgery at our hospital between 1990 and 2013 were identified. LI was classified into strong LI, defined as a continuous thick zone of LI, and weak LI, defined as the lack of zone or scattered small foci of LI at the invasive front. RESULTS: Out of a total of 51 patients, 38 cases had weak LI and 13 had strong LI. The progression-free survival of patients with weak LI was worse (p=0.02). No significant difference of overall survival according to the status of LI was noted (p=0.054). Multivariate analysis revealed that LI was a prognostic factor of poorer progression-free survival (hazard ratio(HR)=5.05, p<0.01) and overall survival (HR=6.93, p=0.01). CONCLUSION: LI might be a new biomarker of such conditions.

Pretreatment Neutrophil-to-Lymphocyte Ratio Was a Predictor of Lymph Node Metastasis in Endometrial Cancer Patients.

OBJECTIVE: The pretreatment neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) have been reported to be useful as markers for prognostic factors and metastasis in several cancers. The aim of this study was to identify the predictor of lymph node (LN) metastasis by pretreatment NLR and PLR in patients with endometrial cancer. METHODS: Medical charts of the patients with endometrial cancers that received primary surgery at our hospital between 2007 and 2013 were retrospectively analyzed. The cutoff value was calculated from the receiver operating characteristics (ROC) curve. Clinicopathological parameters including inflammatory markers were evaluated for LN metastasis using multiple logistic regression analysis. RESULTS: Among 197 patients enrolled in the study, LN metastasis was observed in 25 patients (13%). ROC curves demonstrated that the best cutoff value of NLR for predicting LN metastasis was 2.18 and that of PLR was 206. In univariate analysis, several pathological factors, NLR, and PLR were identified as predictors of LN metastasis. In multiple logistic regression analysis, lymphovascular invasion and NLR were found to be significantly correlated with LN metastasis (p = 0.002, 0.039). CONCLUSION: A higher pretreatment NLR was identified as a predictor of LN metastasis in endometrial cancers. Although further study is needed to confirm the results, NLR could be a candidate clinical marker for detection of LN metastasis.

Analysis of prophylactic Bakri balloon tamponade failure in patients with placenta previa.

OBJECTIVE: Recently, Bakri balloon (BBT) was effective for women with placenta previa to reduce hemorrhage. However, about 10% of women needed to receive an invasive strategy. Thus, the identification of risk factors and the development of additional measurements for BBT failure was needed. The aim of our study is to investigate the cause and measurements of failing prophylactic BBT in women with placenta previa. MATERIALS AND METHODS: Women with placenta previa who underwent cesarean section and had a prophylactic BBT inserted during the operation at our institution between January 2015 and December 2017 were enrolled. Patients requiring additional procedures after cesarean section for massive hemorrhage were defined as BBT failures. Additionally, the patterns and risk factors of BBT failure were retrospectively evaluated. RESULTS: Seventy women met the inclusion criteria. Of them, 9 (13%) were in the balloon failure group and 61 (87%), in the balloon success group. Between two groups, the median of postoperative blood loss was 1153 g vs. 70 g (p < 0.01) and the total blood loss 2409 g vs. 971 g (p < 0.01). There were two types of failures in the balloon failure group: balloon prolapse in eight patients (89%) and accidental placental retention in one patient (11%). The hemorrhage was controlled in all patients with balloon prolapse by reinsertion and inflation of the balloon. The patient with placental retention required a uterine artery embolization (UAE). Although three patients required a blood transfusion, none required a hysterectomy. The logistic regression for the risk of balloon failure revealed classification of major previa to be the highest risk factor (Hazard Ratio; 19.1, 95% Confidence Interval; 3.17-367.9, p < 0.01). CONCLUSION: The major cause of BBT failure was balloon prolapse. It could be treated with non-invasive methods; however, patients with placental retention could not avoid invasive treatment to stop the hemorrhage.

Zone Formation of Lymphocyte Infiltration at Invasive Front as a Biomarker of Prognosis in Endometrial Carcinomas.

OBJECTIVE: The clinical significance of lymphocyte infiltration (LI) at the invasive front in endometrial carcinomas (EC) has not been determined. The aim of the current study was to evaluate the association between zone formation of LI at the invasive front of the tumor margin and prognoses of the patients with EC. METHODS: All available pathological slides of the enrolled cases were reviewed, and the degree of LI at the invasive front was categorized into 2 groups: strong LI and weak LI. Clinical significance of LI was evaluated retrospectively. RESULTS: A total of 333 cases with EC were enrolled in the study: 225 cases with weak LI and 108 cases with strong LI. Weak LI was more frequently observed in the patients with grade1/2 endometrioid EC. Multivariate analyses for progression-free survival (PFS) and overall survival (OS) revealed that weak LI was identified as an independent worse prognostic factor for OS (p = 0.004) in addition to PFS (p = 0.022). CONCLUSION: Weak LI at the invasive front of the tumor margin was associated with worse prognoses in EC. Although further studies are needed, it is suggested that LI could be a biomarker of prognoses in EC.

Marginal sinus placenta previa is a different entity in placenta previa: A retrospective study using magnetic resonance imaging.

OBJECTIVE: The current definition of placenta previa does not include whether the placental edge is parenchyma or marginal sinus defined as placenta previa in which the placental marginal sinus just reached the internal os and/or in which the placental parenchyma might be located at > 2 cm from internal os. MATERIALS AND METHODS: Cases with placenta previa were identified through the review of magnetic resonance imaging (MRI) from among 210 cases at our institution between 2007 and 2016. The clinical outcomes of patients with marginal sinus placenta previa (Group A) were compared with patients with low-lying placenta and marginal placenta (Group B) and patients with partial placenta and total placenta previa (Group C), respectively. This study was a retrospective analysis. RESULTS: Twenty-seven (12.7%) cases were included in Group A. The patients in Group B and Group C were 72 and 108 cases, respectively. First, Group A more frequently underwent emergency cesarean section than Group B (p = 0.02). There was no statistical significance with other maternal history, post-or pre-operative hemorrhage, and/or additional treatment for hemorrhage between the two groups. Additionally, Group A delivered at a later gestational age (p < 0.01); were less frequently complicated with antenatal bleeding (p < 0.01); underwent emergency cesarean section (p < 0.01), allogenic blood transfusion (p < 0.01), and uterine artery embolization (p < 0.01) for postpartum hemorrhage less often; and had less perioperative hemorrhage (p < 0.01) than Group C. CONCLUSIONS: Marginal sinus placenta previa may be a mild type of placenta previa. This new classification could be useful in the management of placenta previa.

A case of refeeding syndrome in pregnancy with anorexia nervosa.

Refeeding syndrome very rarely develops during pregnancy. A 35-year-old primiparous woman pregnant with twins complained of severe fatigue at 19 weeks' gestation. She was admitted to our hospital in a malnourished condition because of repeated self-induced vomiting due to anorexia nervosa. Just after hospitalization, she voluntarily increased her caloric intake significantly above the recommended prescribed diet, without medical permission. Nine days later, she developed refeeding syndrome. Electrolyte replacement and calorie restriction were started and her condition gradually improved. The healthy twin babies were born by cesarean section at 36 weeks' gestation. Acute increases in caloric intake by previously malnourished pregnant women with anorexia nervosa may induce refeeding syndrome. Women with the binge eating/purging subtype of anorexia nervosa may be at additional risk due to alternating phases of starvation and overeating.

A Pathological Study Using 2014 WHO Criteria Reveals Poor Prognosis of Grade 3 Ovarian Endometrioid Carcinomas.

BACKGROUND/AIM: The purpose of this study was to compare the clinical behavior of several grades of endometrioid carcinoma (EC) compared to high-grade serous carcinoma (HGSC), based on World Health Organization 2014 criteria. MATERIALS AND METHODS: Clinicopathological features were compared between all grades of EC and HGSC, and between HGSC and either grade 1/2 or grade 3 EC. RESULTS: Sixty-five patients with EC and 214 with HGSC were identified. Among patients with EC, 56 displayed 1/2 EC and nine had grade 3 EC. The progression-free (PFS) and overall (OS) survival of patients with grade 1/2 EC were better than of those of patients with HGSC; however, PFS and OS did not statistically differ between patients with grade 3 EC and those with HGSC. Grade 1/2 EC, but not grade 3, was a better prognostic factor compared with HGSC. CONCLUSION: A grading system for EC would be beneficial for the accurate prognosis of ovarian cancer.