Risk factors of retained products of conception after miscarriage or termination with gemeprost in the second trimester of pregnancy: a retrospective case-controlled study in Japanese population.

Retained products of conception (RPOC) is a complication that occurs in the second trimester of pregnancy. We enrolled 98 women who had a miscarriage or termination with gemeprost in the second trimester of pregnancy. Eighteen cases (18.4%) were RPOC-positive. The gestational week at miscarriage or termination was earlier in the RPOC-positive group than those in the RPOC-negative group (p = .003). The period of the third stage of labour was longer in the RPOC-positive group than in RPOC-negative group (p = .040). The proportion of placental forceps use was higher in the RPOC-positive group than in RPOC-negative group (p = .003). Multivariate logistic regression analysis showed that gestational week (OR: 3.53; p = .04) and use of placental forceps at delivery (OR: 2.21; p = .012) were independent risk factors for RPOC. Earlier gestational weeks at miscarriage or termination and use of placental forceps at delivery were predictive factors for RPOC after second trimester miscarriage or termination with gemeprost.Impact StatementWhat is already known on this subject? There have been some reports on risk factors of RPOC. A previous report showed that the termination of pregnancy with misoprostol at earlier periods was associated with an increased risk of RPOC.What the results of this study add? There have been few studies on the risk factors of RPOC after miscarriage or termination with gemeprost. In this study, we evaluated the risk factors of RPOC after miscarriage or termination of pregnancy with gemeprost in the second trimester. We found that an earlier gestational age (between 12 and 17 weeks) at delivery and using placental forceps to remove placenta were significant risk factors of RPOC after miscarriage or termination of pregnancy with gemeprost in the second trimester.What the implications are of these findings for clinical practice and/or further research? An earlier gestational age and using forceps to remove placenta may be significant risk factors for RPOC. The accurate evaluation and treatment for RPOC is important for maternal life-saving efforts and subsequent pregnancies. Further research is needed to draft a standardised protocol for RPOC.

Malignant melanoma treated with pembrolizumab during pregnancy: A case report and review of the literature.

There have been very few reports on the use of immune checkpoint inhibitors for malignant tumors during pregnancy. Herein, the current study reports a case of a patient diagnosed with advanced malignant melanoma who was treated with pembrolizumab during pregnancy. A 40-year-old primigravida underwent noninvasive prenatal testing at 10 weeks of gestation, and the result was inconclusive, suggesting the possibility of maternal malignancy. A biopsy of the gluteal mass led to a diagnosis of malignant melanoma, and computed tomography revealed extensive metastases in her lungs and lymph nodes. She had a strong desire to proceed with pregnancy. In consideration of fetal growth and maturation, monotherapy was administered with pembrolizumab from 21 weeks of gestation, aiming for 28 weeks of gestation. The fetus grew well without maternal complications. At 28 weeks of pregnancy, the patient gave birth to a healthy boy by cesarean section. There was no evidence of metastasis in the placenta. The patient received nivolumab-ipilimumab combination therapy from postpartum day 13, followed by nivolumab monotherapy, and has been alive with controlled disease for 20 months.

Lipid Droplet Accumulation Independently Predicts Poor Clinical Prognosis in High-Grade Serous Ovarian Carcinoma.

High-grade serous ovarian carcinoma (HGSOC) is an epithelial cancer that accounts for most ovarian cancer deaths. Metabolic abnormalities such as extensive aerobic glycolysis and aberrant lipid metabolism are well-known characteristics of cancer cells. Indeed, accumulation of lipid droplets (LDs) in certain types of malignant tumors has been known for more than 50 years. Here, we investigated the correlation between LD accumulation and clinical prognosis. In 96 HGSOC patients, we found that high expression of the LD marker adipophilin was associated with poor progression-free and overall survival (p = 0.0022 and p = 0.014, respectively). OVCAR-3 ovarian carcinoma cells accumulated LDs in a glucose-dependent manner, which suggested the involvement of aerobic glycolysis and subsequently enhanced lipogenesis, with a result being LD accumulation. The acyl-CoA: cholesterol acyltransferase 1 inhibitor K604 and the hydroxymethylglutaryl-CoA reductase inhibitor pitavastatin blocked LD accumulation in OVCAR-3 cells and reduced phosphorylation of the survival-related kinases Akt and ERK1/2, both of which have been implicated in malignancy. Our cell-based assays thus suggested that enhanced aerobic glycolysis resulted in LD accumulation and activation of survival-related kinases. Overall, our results support the idea that cancers with lipogenic phenotypes are associated with poor clinical prognosis, and we suggest that adipophilin may serve as an independent indicator of a poor prognosis in HGSOC.

Short term outcomes of helical tomotherapy during concurrent chemoradiotherapy for advanced cervical cancer.

The aim of the present study was to clarify the feasibility and efficacy of helical tomotherapy during concurrent chemoradiotherapy for treating cervical cancer. The medical records of 13 patients who underwent oncurrent chemoradiotherapy using helical tomotherapy for cervical cancer at Wakayama Medical University Hospital between 2013 and 2015 were retrospectively reviewed. A total of 15 patients who underwent oncurrent chemoradiotherapy using conventional radiotherapy (CRT) between 2008 and 2013 at our institution were also examined for comparison. The median age of patients treated with helical tomotherapy was 60 (range, 35-71), and the median age of patients treated with CRT was 57 (range, 43-77). The median follow-up period was 27 months (range, 3-46) in the tomotherapy group and 35 months (range, 7-88) in the CRT group. The frequency of G3/4 thrombocytopenia in the tomotherapy group was significantly higher than that in the CRT group (P=0.049). However, the platelet count spontaneously recovered without transfusion. There were no significant differences between the groups in terms of frequency of G3/4 neutropenia, diarrhea or late intestine injury. The rate of complete response in the tomotherapy group and the CRT group was 84.6 and 73.3%, respectively, and there was no significant difference in the response rate between the groups. There were no significant differences in the progression-free survival or progression-free rate in the irradiation field between the groups. Adverse events from concurrent chemoradiotherapy using helical tomotherapy were acceptable and clinically controllable. The present results suggest that helical tomotherapy is efficient during concurrent chemoradiotherapy for treatment of advanced cervical cancer.

Programmed cell death ligand 1 disruption by clustered regularly interspaced short palindromic repeats/Cas9-genome editing promotes antitumor immunity and suppresses ovarian cancer progression.

Programmed cell death ligand 1 (PD-L1) on tumor cells suppresses anti-tumor immunity and has an unfavorable prognostic impact in ovarian cancer patients. We herein report the pathophysiological and therapeutic impacts of PD-L1 disruption in ovarian cancer. PD-L1 was genetically disrupted in the murine ovarian cancer cell line ID8 using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated genome editing. PD-L1 knockout (KO) and control ovarian cancer cells were intraperitoneally inoculated into syngeneic mice, and survival and tumor dissemination were evaluated. Survival times were significantly longer in the PD-L1-KO ID8-inoculated groups than in their control groups, and its therapeutic benefit was enhanced in combination with the cisplatin treatment. Tumor weights and ascites volumes were significantly lower in the PD-L1-KO ID8 groups than in their control groups. Immunohistochemical and immunofluorescence analyses showed that intratumoral CD4+ T cells, CD8+ T cells, NK cells and CD11c+ M1 macrophages were significantly increased, whereas regulatory T cells were significantly decreased in the PD-L1-KO ID8 groups compared with those in their control groups. The intratumoral mRNA expression of interferon-γ, tumor-necrosis factor-α, interleukin (IL)-2, IL-12a, CXCL9 and CXCL10 was significantly stronger, while that of IL-10, vascular endothelial growth factor, CXCL1 and CXCL2 was significantly weaker in the PD-L1-KO ID8 groups. These results indicate that CRISPR/Cas9-mediated PD-L1 disruption on tumor cells promotes anti-tumor immunity by increasing tumor-infiltrating lymphocytes and modulating cytokine/chemokine profiles within the tumor microenvironment, thereby suppressing ovarian cancer progression. These results suggest that PD-L1-targeted therapy by genome editing may be a novel therapeutic strategy for ovarian cancer.

Prevention of lipopolysaccharide-induced preterm labor by the lack of CX3CL1-CX3CR1 interaction in mice.

Preterm labor (PTL) is the most common cause of neonatal death and long-term adverse outcome. The pharmacological agents for PTL prevention are palliative and frequently fail to prevent PTL and improve neonatal outcome. It is essential to fully understand the molecular mechanisms of PTL in order to develop novel therapeutic methods against PTL. Several lines of evidence indicate some chemokines are expressed in gestational tissues during labor or PTL. To reveal the pathophysiological roles of the CX3CL1-CX3CR1 axis in PTL, we performed present study using LPS-induced PTL mice model in CX3CR1-deficient (Cx3cr1-/-) mice. We indicated that PTL was suppressed in Cx3cr1-/- mice and immunoneutralization of CX3CL1 in WT mice. From immunohistochemical and the gene expression analyses, the CX3CL1-CX3CR1 axis has detrimental roles in PTL through intrauterine recruitment of macrophages and the enhancement of macrophage-derived inflammatory mediators. Thus, the CX3CL1-CX3CR1 axis may be a good molecular target for preventing PTL.

Levels of serum-circulating angiogenic factors within 1 week prior to delivery are closely related to conditions of pregnant women with pre-eclampsia, gestational hypertension, and/or fetal growth restriction.

AIM: We aimed to investigate maternal serum angiogenic marker profiles within 1 week prior to delivery in cases of gestational hypertension (GH), pre-eclampsia (PE), and/or fetal growth restriction (FGR) with different clinical conditions. METHODS: We enrolled 165 women with singleton pregnancy. The participants were classified based on three characteristics: (i) proteinuria (GH and PE); (ii) FGR (PE with FGR [PE + FGR], PE alone, and FGR alone); and (iii) onset (early onset PE [EO PE] and late-onset PE [LO PE]). All sera were obtained within 1 week prior to delivery, and soluble fms-like tyrosine kinase 1 (sFlt-1), soluble endoglin (sEng), and placental growth factor (PlGF) were measured with enzyme-linked immunosorbent assay. RESULTS: (i) In PE, a significantly increased sFlt-1, sEng, and sFlt-1 to PlGF ratio (sFlt-1/PlGF) and significantly decreased PlGF were observed compared with GH and Term control, whereas in GH, only sFlt-1/PlGF was significantly higher than Term control. (ii) In PE + FGR, similar changes were more markedly shown compared with PE alone. The FGR alone group exhibited similar tendencies as PE, although significant differences were found in PlGF and sEng levels. (iii) In EO PE, significant changes were observed in all factors compared with LO PE or Term control, while no significant change in PlGF levels was observed between LO PE and Term control. CONCLUSION: We demonstrated that the levels of circulating angiogenic factors just before delivery are correlated with the severity of hypertensive disorders of pregnancy and FGR. Profiling these specific markers may contribute to better understanding of the clinical conditions in individual patients and their pathogenesis.

Calreticulin Is Involved in Invasion of Human Extravillous Trophoblasts Through Functional Regulation of Integrin ß1.

Calreticulin (CRT), a molecular chaperone in the endoplasmic reticulum (ER), plays a variety of roles in cell growth, differentiation, apoptosis, immunity, and cancer biology. It has been reported that CRT is expressed in the human placenta, although its function in placental development is poorly understood. Appropriate invasion of extravillous trophoblasts (EVTs) into the maternal decidua is necessary for successful pregnancy. The objective of the present study was to investigate the expression and functional role of CRT in EVTs using the human EVT cell line HTR8/SVneo, in which CRT gene expression was knocked down. We found that CRT was highly expressed in the human placenta in the early stage of pregnancy and localized to the EVTs. CRT knockdown markedly suppressed the invasion ability of HTR8/SVneo cells. Furthermore, the adhesion to fibronectin was suppressed in the CRT-knockdown cells via the dysfunction of integrin α5ß1. In the CRT-knockdown cells, terminal sialylation and fucosylation were decreased, and the core galactose-containing structure was increased in the N-glycans of integrin ß1. In addition, the expression levels of several critical glycosyltransferases were changed in the CRT-knockdown cells, consistent with the changes in the N-glycans. These results showed that CRT regulates the function of integrin ß1 by affecting the synthesis of N-glycans in HTR8/SVneo cells. Collectively, the results of the present study demonstrate that the ER chaperone CRT plays a regulatory role in the invasion of EVTs, suggesting the importance of CRT expression in placental development during early pregnancy.

Rapidly progressing large-cell neuroendocrine carcinoma arising from the uterine corpus: A case report and review of the literature.

Large-cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine tumor. LCNECs arising from the genital organs are highly malignant and rare, with <20 cases of LCNEC developing from the uterine endometrium reported to date. We herein present the case of a patient with LCNEC of the endometrium. The patient was a 52-year-old woman, who exhibited lower abdominal pain and rapid uterine enlargement during outpatient treatment for uterine myoma. The endometrial biopsy suggested a diagnosis of poorly differentiated carcinoma or carcinosarcoma. Based on magnetic resonance imaging and positron emission tomography/computed tomography, endometrial stromal sarcoma was suspected. The serum lactate dehydrogenase level was abnormally high. Due to the suspicion of stage IIIC malignant tumor of the uterine corpus, surgery was performed. The pathological diagnosis was stage IIIC2 LCNEC of the endometrium. Recurrence occurred in the vaginal stump, and concurrent chemoradiotherapy (CCRT) was initiated 1 month after the surgery. The residual lesions markedly shrank, but metastasis to the upper abdominal region and cervix subsequently developed. CCRT was attempted, but the associated adverse effects were severe and was switched to palliative treatment. The patient eventually succumbed to the disease 309 days after surgery.

Prognostic impact of primary tumor SUVmax on preoperative 18F-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography in endometrial cancer and uterine carcinosarcoma.

The objective of the present study was to investigate the usefulness of the maximum standardized uptake value (SUVmax) of the primary tumor on preoperative 18F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography and computed tomography (PET/CT) as a prognostic indicator in patients with endometrial neoplasms. A total of 75 patients with endometrial cancer or uterine carcinosarcoma who underwent surgical treatment were included in the present study. All patients underwent preoperative PET/CT, and the correlation between the SUVmax of the primary tumor and clinical outcomes was analyzed. The SUVmax was significantly higher in patients with stage II/III disease, a histology of grade 3 endometrioid adenocarcinoma and carcinosarcoma, a positive lymph node (LN) status, positive lymph-vascular space involvement (LVSI), and deep (≥1/2) myometrial invasion. Receiver operating characteristic curve analysis revealed that the optimal cut-off values of SUVmax for predicting a positive LN, LVSI and deep myometrial invasion were 7.49, 6.45 and 6.45, respectively. The overall survival (OS) and progression-free survival (PFS) of patients with a high SUVmax were significantly lower compared with those of patients with a low SUVmax using the cut-off value of 7.30. However, no significant difference was observed in the OS or PFS between the high and low SUVmax groups when analyzed in carcinosarcoma patients alone. Finally, multivariate analyses demonstrated that the SUVmax of the primary tumor was an independent prognostic factor for impaired PFS in 55 endometrioid adenocarcinoma patients; however, not in all patients, including those with carcinosarcoma. The present findings demonstrated that the SUVmax of the primary tumor may be a useful biomarker for predicting clinical outcomes of patients with endometrial cancer, although its prognostic impact appears to be limited in patients with uterine carcinosarcoma.

Ovarian steroid cell tumor, not otherwise specified, producing testosterone.

Steroid cell tumor, not otherwise specified, is a rare type of ovarian sex cord-stromal tumor with malignant potential. Some of these tumors produce testosterone. We describe a case of steroid cell tumor of the ovary associated with virilization. A 23-year-old nulliparous woman was found to have an ovarian tumor when she visited her primary doctor for virilization and oligomenorrhea. Magnetic resonance imaging revealed a solid left ovarian tumor 40 mm in size. Her laboratory data revealed elevated testosterone with normal levels of gonadotropins, estradiol, dehydroepiandrosterone sulfate and cortisol. She underwent left adnexectomy. On histopathologic and immunohistochemical analyses, the tumor was diagnosed as steroid cell tumor, not otherwise specified, without malignant behavior. After removal of the tumor, serum testosterone level decreased, and there have been no signs of recurrence.

Indoleamine 2,3-dioxygenase promotes peritoneal metastasis of ovarian cancer by inducing an immunosuppressive environment.

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that has immunoregulatory functions. Our prior study showed that tumoral IDO overexpression is involved in disease progression and impaired patient survival in human ovarian cancer, although its mechanism remains unclear. The purpose of the present study is to clarify the role of IDO during the process of peritoneal dissemination of ovarian cancer. Indoleamine 2,3-dioxygenase cDNA was transfected into the murine ovarian carcinoma cell line OV2944-HM-1, establishing stable clones of IDO-overexpressing cells (HM-1-IDO). Then HM-1-IDO or control vector-transfected cells (HM-1-mock) were i.p. transplanted into syngeneic immunocompetent mice. The HM-1-IDO-transplanted mice showed significantly shortened survival compared with HM-1-mock-transplanted (control) mice. On days 11 and 14 following transplantation, the tumor weight of peritoneal dissemination and ascites volume were significantly increased in HM-1-IDO-transplanted mice compared with those of control mice. This tumor-progressive effect was coincident with significantly reduced numbers of CD8(+) T cells and natural killer cells within tumors as well as increased levels of transforming growth factor-ß and interleukin-10 in ascites. Finally, treatment with the IDO inhibitor 1-methyl-tryptophan significantly suppressed tumor dissemination and ascites with reduced transforming growth factor-ß secretion. These findings showed that tumor-derived IDO promotes the peritoneal dissemination of ovarian cancer through suppression of tumor-infiltrating effector T cell and natural killer cell recruitment and reciprocal enhancement of immunosuppressive cytokines in ascites, creating an immunotolerogenic environment within the peritoneal cavity. Therefore, IDO may be a promising molecular target for the therapeutic strategy of ovarian cancer.