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.

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.

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.

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.

JAK2/STAT3 pathway as a therapeutic target in ovarian cancers.

The activation of JAK2/STAT3 pathway has been reported to have critical roles in several solid tumors. The present study aimed to evaluate the correlation between JAK2/STAT3 activation and clinicopathological parameters in ovarian cancer types. Tissue microarrays made from the patients treated at the National Defense Medical College Hospital between 1984 and 2008 were evaluated using immunohistochemical (IHC) stainings. Medical charts of these patients including IHC results were retrospectively analyzed, and prognostic factors for progression-free survival and overall survival were evaluated. Among 341 enrolled patients, positive expression of p-STAT3 was observed in 95 cases (28%). Positive p-STAT3 was an independent worse prognostic factor for overall survival in all the cases. Additionally, p-STAT3 expression was related with overall survival in patients with clear-cell histology, but not in serous histology. The effect of an inhibitor of STAT3, niclosamide, was evaluated in ovarian clear-cell cancer cells, and niclosamide treatment decreased expression of p-STAT3, leading to increased apoptosis in a dose-dependent manner in vitro. The activation of JAK2/STAT3 pathway had significant impact on survival of ovarian cancers, especially for the cases with clear-cell histology. Although further analyses are needed, suppression of this pathway could be a candidate for the treatment of ovarian cancers.

Addition of bevacizumab to gemcitabine for platinum-resistant recurrent ovarian cancer: a retrospective analysis.

PURPOSE: To compare a cohort of patients with platinum-resistant recurrent ovarian cancer (PROC) treated with bevacizumab and gemcitabine (Bev-Gem) to that of patients treated only with gemcitabine (Gem). METHODS: Between 2011 and 2017, we identified the Bev-Gem and Gem PROC groups. The regimen included 1000 mg/m2 of Gem on days 1, 8, and 15, and 15 mg/m2 of Bev on day 1, every 4 weeks. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of the administration of Bev-Gem or Gem until disease progression or death. RESULTS: The Bev-Gem and Gem groups included 18 and 29 patients, respectively. More patients had advanced stage disease in the Bev-Gem group (p = 0.048); no other characteristics differed between the groups. The response rates [ratio of complete remission (CR) to partial remission (PR)] of Bev-Gem and Gem were 38.9 and 3.4%, respectively (p < 0.01). The clinical benefit rates [combined percentages of CR, PR, and stable disease] of the Bev-Gem and Gem groups were 88.9 and 41.4%, respectively (p = 0.04). PFS and OS of the Bev-Gem group were superior (p < 0.01, p = 0.03, respectively). Bev-Gem was the better prognostic factor of both PFS [hazard ratio (HR) 0.17, p < 0.01] and OS (HR 0.31, p = 0.01). The frequency of hematologic and non-hematologic adverse effects was similar in each group. CONCLUSION: Bev-Gem regimens improved PFS and OS for PROC. Furthermore, the adverse effects of Bev-Gem were tolerable. Thus, Bev-Gem could be a candidate treatment strategy for PROC.

Seromucinous component in endometrioid endometrial carcinoma as a histological predictor of prognosis.

OBJECTIVE: In 2014 World Health Organization criteria, seromucinous carcinoma was defined as a new histological subtype in ovarian carcinomas, but "seromucinous carcinoma" was not defined in endometrial carcinomas. The aim of this study was to identify seromucinous carcinoma resembling ovarian seromucinous carcinoma in endometrial carcinomas, and to evaluate the clinical significance for prognoses of the patients. METHODS: Central pathological review was conducted for patients with endometrioid carcinoma of the endometrium treated by primary surgery at our hospital between 1990 and 2013. RESULTS: Among 340 cases included in the study, no case had all tumor cells resembling ovarian seromucinous carcinoma in all specimens, and 31 cases (9.1%) had seromucinous component in combination with endometrioid carcinomas. Immunohistochemical analysis revealed seromucinous component had positive reactivity for cytokeratin (CK) 7, and negative reactivity for CK20 and caudal type homeobox 2 (CDX2) in all cases. Seromucinous component showed lower immunoreactivity of estrogen receptor and progesterone receptor, compared with endometrioid carcinoma component. Progression-free survival of the cases with seromucinous component was better than those without seromucinous component (p=0.049). CONCLUSION: Seromucinous component was identified in approximately 10% of endometrioid carcinoma, and could be a histological predictor for prognosis.

Low Expression of CD44 Is an Independent Factor of Poor Prognosis in Ovarian Mucinous Carcinoma.

AIM: To determine whether CD44, which is associated with tumor growth and metastasis, is related to carcinogenesis and prognosis in ovarian mucinous carcinomas (MACs). MATERIALS AND METHODS: Tissue blocks from 71 patients with benign mucinous ovarian tumors were used in the study: 35 were from patients with borderline mucinous ovarian tumors, and 60 from patients with MACs. Immunochemical analysis was performed to evaluate the expression of CD44 and examine its association with tumorigenesis and survival. RESULTS: Compared to benign tumors, borderline tumors had high CD44 expression levels (p=0.047). Conversely, MACs had lower expression than borderline tumors (p=0.032). Progression-free and overall survival of patients with MAC with low CD44 expression were worse than those of patients with high expression (p=0.04 and p=0.02, respectively). CONCLUSION: Malignant transformation of mucinous tumors is associated with changes in CD44 expression, with low expression level being a prognostic factor in MAC.

Phenoxodiol Increases Cisplatin Sensitivity in Ovarian Clear Cancer Cells Through XIAP Down-regulation and Autophagy Inhibition.

BACKGROUND/AIM: To investigate whether XIAP down-regulation and autophagy inhibition sensitize ovarian clear cell cancer cells to cisplatin. MATERIALS AND METHODS: The ovarian clear cancer cell line KK was used for in vitro analysis. Hydroxychloroquine (HCQ) and phenoxodiol (PXD) or embelin were used as autophagy and XIAP inhibitors, respectively. Non-specific and XIAP-specific siRNAs were transfected using Lipofectamine. Cytotoxicity was assessed by MTT assays. Protein expression was confirmed by western blotting. RESULTS: In KK, down-regulation of XIAP using specific siRNAs together with HCQ treatment enhanced the anti-tumor effect of cisplatin. Although embelin sensitized KK to cisplatin through XIAP down-regulation, it induced autophagy. However, PXD increased cisplatin sensitivity through XIAP down-regulation and autophagy inhibition. Expression of Atg7, Atg12, and Beclin 1 was decreased after PXD treatment. CONCLUSION: PXD increased cisplatin sensitivity through XIAP down-regulation and autophagy inhibition and could be a new candidate for ovarian clear cell carcinoma treatment.

Efficacy of combination chemotherapy using irinotecan and nedaplatin for patients with recurrent and refractory endometrial carcinomas: preliminary analysis and literature review.

PURPOSE: We aimed to retrospectively evaluate the efficacy and toxicity of an irinotecan hydrochloride (CPT) and nedaplatin (N) combination therapy for recurrent and refractory endometrial carcinoma, administered based on UGT1A1 genotype. METHODS: Between 2009 and 2017, 21 patients who received CPT-N therapy for recurrent endometrial carcinoma as second- or third-line chemotherapy at our hospital were identified. The CPT-N regimen included 40-70 mg/m2 of CPT-11 on days 1, 8, and 15, and 50 mg/m2 of nedaplatin on day 1, q4 weeks. RESULTS: The median patient age was 63 years. The number of prior chemotherapeutic regimens ranged from 1 to 2. Two patients had prior pelvic irradiation. The response rate [ratio of complete remission (CR) to partial remission (PR)] of CPT-N therapy was 3 of 21 (14.3%), and clinical benefit rate (CBR) [the combined percentages of CR, PR, and stable disease (SD)] was 9 of 21 (42.8%). Toxicities included grade 3 neutropenia [4 (19.0%) cases], grade 3 febrile neutropenia [2 (9.5%) cases], and grade 3 diarrhea [3 (14.3%) cases]; all resolved with conservative treatment. Patients with a wild-type UGT1A1 status received higher doses of CPT-11 (p = 0.048) and had similar RR and CBR compared to those with a UGT1A1*6 and *28 status. There were no significant differences in frequencies of hematological or non-hematological toxicities, regardless of UGT1A1 status. CONCLUSIONS: The CPT-N regimen for recurrent and refractory endometrial carcinoma had tolerable side effects and significant efficacy. This regimen is a viable treatment option for endometrial carcinoma.

Role of endometriosis as a prognostic factor for post-progression survival in ovarian clear cell carcinoma.

The clinical significance of coexistence of endometriosis (EM) in ovarian clear cell carcinoma (CCC) has not yet been determined. The aim of the present study was to analyze the correlation of endometriosis with clinicopathological factors in CCC. The cases with CCC that received primary debulking surgery at the present hospital between 1990 and 2013 were identified. Retrospective analysis was conducted to evaluate the association between complications with EM and clinicopathological features in CCC. Of the 105 cases enrolled in the study, 45 cases were complicated with EM, and 60 cases did not have EM (non-EM). The patients with EM were diagnosed at a younger age (P=0.03), and at earlier stages (P<0.01) compared with non-EM cases. Although there was no significant difference of progression-free survival (P=0.36), complications with EM were identified as an independent prognostic factor for overall survival (OS; P<0.01) by multivariate analysis. A total of 48 patients (45.7%) developed recurrence: 18 patients in EM-group and 30 patients in non-EM group. There were no significant differences of clinicopathological factors in the treatment at recurrence between both groups. Recurrent cases in EM had significantly worse post-progression survival (PPS) compared with recurrent non-EM group (P<0.01). Multivariate analysis for PPS demonstrated that complications with EM (P<0.01) were identified as a worse prognostic factor. In CCC, the complication with EM was identified as a significant worse prognostic factor for PPS in recurrent cases. Additionally, EM was significantly associated with OS in all cases with CCC. Novel treatment strategies are therefore necessary for recurrent CCC, particularly for cases exhibiting EM.