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Objective Angular and interstitial pregnancies have been reported with live births and are often complicated by adherent placentas. Most cases had been treated with hysterectomy or corneal resection. Case report We successfully treated four patients with conservative management (including one reported previously). Case 1 had a vaginal delivery, but the placenta remained attached. We maintained the patient under observation and delivered the placenta on postpartum day 9. Case 2 underwent a C-section. Uterine artery embolization controlled the hemorrhage without placenta removal. The placenta had disappeared by postpartum day 136. Case 3 underwent a C-section. The right uterine angle, where the placenta was attached, was bulging. We manually removed the placenta. Conclusion We propose a new entity in angular or interstitial pregnancies called “angular placenta attachment” that could be diagnosed during C-sections or after vaginal delivery without placental separation. Expectant management may be considered for adherent placentas in these cases.

Background A diagnostic sign on magnetic resonance imaging, suggestive of posterior extrauterine adhesion (PEUA), was identified in patients with placenta previa. However, the clinical features or surgical outcomes of patients with placenta previa and PEUA are unclear. Our study aimed to investigate the clinical characteristics of placenta previa with PEUA and determine whether an altered management strategy improved surgical outcomes. Methods This single institution retrospective study examined patients with placenta previa who underwent cesarean delivery between 2014 and 2019. In June 2017, we recognized that PEUA was associated with increased intraoperative bleeding; thus, we altered the management of patients with placenta previa and PEUA. To assess the relationship between changes in practice and surgical outcomes, a quasi-experimental method was used to examine the difference-in-difference before (pre group) and after (post group) the changes. Surgical management was modified as follows: (i) minimization of uterine exteriorization and adhesion detachment during cesarean delivery and (ii) use of Nelaton catheters for guiding cervical passage during Bakri balloon insertion. To account for patient characteristics, propensity score matching and multivariate regression analyses were performed. Results The study cohort (n = 141) comprised of 24 patients with placenta previa and PEUA (PEUA group) and 117 non-PEUA patients (control group). The PEUA patients were further categorized into the pre (n = 12) and post groups (n = 12) based on the changes in surgical management. Total placenta previa and posterior placentas were more likely in the PEUA group than in the control group (66.7% versus 42.7% [P = 0.04] and 95.8% versus 63.2% [P n = 72), intraoperative blood loss was significantly higher in the PEUA group (n = 24) than in the control group (n = 48) (1515 mL versus 870 mL, P t = 2.46, P = 0.02). Intraoperative blood loss in the post group was successfully reduced, as opposed to in the pre group (1180 mL versus 1827 mL, P = 0.04). Conclusions PEUA was associated with total placenta previa, posterior placenta, and increased intraoperative bleeding in patients with placenta previa. Our altered management could reduce the intraoperative blood loss.

Paclitaxel is a first-line drug for treating epithelial ovarian cancer (EOC). However, prognosis for patients with advanced stage cancer remains poor due to primary or acquired drug resistance. Therefore, overcoming chemoresistance is one of the greatest challenges in treating EOC. In this study, we identified microRNAs (miRNA) that regulate paclitaxel resistance and tested their potential utility as therapeutic targets. Paclitaxel-resistant cell lines were established using two EOC cell lines: SKVO3ip1 and HeyA8. miRNA PCR arrays showed that miR-194-5p was downregulated in paclitaxel-resistant cells. Forced expression of miR-194-5p resensitized resistant cells to paclitaxel. Conversely, miR-194-5p inhibition induced paclitaxel resistance in parental cells. In silico analysis and luciferase reporter assay revealed that MDM2 is a direct target of miR-194-5p. MDM2 was upregulated in paclitaxel resistant cells compared with parental cells. MDM2 inhibition also resensitized resistant cells to paclitaxel and forced MDM2 induced paclitaxel resistance in parental cells. miR-194-5p induced p21 upregulation and G1 phase arrest in resistant cells by downregulating MDM2. Furthermore, a public database showed that high MDM2 expression was associated with a shorter progression-free survival in EOC patients treated with paclitaxel. Collectively, our results show that restoring miR-194-5p expression resensitizes EOCs to paclitaxel, and this may be exploited as a therapeutic option.

Background microRNAs (miRNAs) stably exist in circulating blood and are encapsulated in extracellular vesicles such as exosomes. The aims of this study were to identify which exosomal miRNAs are highly produced from epithelial ovarian cancer (EOC) cells, to analyze whether serum miRNA can be used to discriminate patients with EOC from healthy volunteers, and to investigate the functional role of exosomal miRNAs in ovarian cancer progression. Methods Exosomes were collected from the culture media of serous ovarian cancer cell lines, namely TYK-nu and HeyA8 cells. An exosomal miRNA microarray revealed that several miRNAs including miR-99a-5p were specifically elevated in EOC-derived exosomes. Expression levels of serum miR-99a-5p in 62 patients with EOC, 26 patients with benign ovarian tumors, and 20 healthy volunteers were determined by miRNA quantitative reverse transcription-polymerase chain reaction. To investigate the role of exosomal miR-99a-5p in peritoneal dissemination, neighboring human peritoneal mesothelial cells (HPMCs) were treated with EOC-derived exosomes and then expression levels of miR-99a-5p were examined. Furthermore, mimics of miR-99a-5p were transfected into HPMCs and the effect of miR-99a-5p on cancer invasion was analyzed using a 3D culture model. Proteomic analysis with the tandem mass tag method was performed on HPMCs transfected with miR-99a-5p and then potential target genes of miR-99a-5p were examined. Results The serum miR-99a-5p levels were significantly increased in patients with EOC, compared with those in benign tumor patients and healthy volunteers (1.7-fold and 2.8-fold, respectively). A receiver operating characteristic curve analysis showed with a cut-off of 1.41 showed sensitivity and specificity of 0.85 and 0.75, respectively, for detecting EOC (area under the curve = 0.88). Serum miR-99a-5p expression levels were significantly decreased after EOC surgeries (1.8 to 1.3, p = 0.002), indicating that miR-99a-5p reflects tumor burden. Treatment with EOC-derived exosomes significantly increased miR-99a-5p expression in HPMCs. HPMCs transfected with miR-99a-5p promoted ovarian cancer invasion and exhibited increased expression levels of fibronectin and vitronectin. Conclusions Serum miR-99a-5p is significantly elevated in ovarian cancer patients. Exosomal miR-99a-5p from EOC cells promotes cell invasion by affecting HPMCs through fibronectin and vitronectin upregulation and may serve as a target for inhibiting ovarian cancer progression. Electronic supplementary material The online version of this article (10.1186/s12885-018-4974-5) contains supplementary material, which is available to authorized users.

Aska Toda, Kenjiro Sawada, Akihiko Yoshimura, Erika Nakatsuka, Hiromasa Kuroda, Katsumi Kozasa, Mayuko Miyamoto, Kae Hashimoto, Seiji Mabuchi, Tadashi Kimura Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan Background: In clinical practice, patients with postmenopausal osteoporosis have often shown a poor response to treatment with an antiresorptive agent for several years. The purpose of this study was to investigate the efficacy of switching raloxifene with minodronate in patients who responded poorly to the treatment of postmenopausal osteoporosis with raloxifene. Patients and methods: This observational study was conducted based on a single-arm, non-randomized, open-label design and was approved by the institute’s institutional review board. Postmenopausal women with osteoporosis who became unresponsive in terms of bone mineral density (BMD) after being administered raloxifene for two or more years were enrolled. Patients were treated with 1 mg minodronate daily or 50 mg minodronate monthly. Changes in BMD and serum bone turnover markers were monitored at baseline, 6, 12, and 24 months after switching treatment.Results: Twenty-seven patients were enrolled. Two discontinued treatment because of adverse events related to the study drug. Among the remaining 25 patients, lumbar BMD significantly increased by 3.67%, 5.08%, and 6.97% at 6, 12, and 24 months, respectively, and femoral neck BMD increased by 1.63%, 2.18%, and 3.85% at 6, 12, and 24 months, respectively. Serum bone-specific alkaline phosphatase showed a significant reduction of 30.35% from the baseline (p

In the present study, the therapeutic potential of targeting plasminogen activator inhibitor-1 (PAI-1) in ovarian cancer was tested. Tissues samples from 154 cases of ovarian carcinoma were immunostained with anti-PAI-1 antibody, and the prognostic value was analyzed. Among the samples, 67% (104/154) showed strong PAI-1 expression; this was significantly associated with poor prognosis (progression-free survival: 20 vs. 31 months, P = 0.0033). In particular, among patients with stage II-IV serous adenocarcinoma, PAI-1 expression was an independent prognostic factor. The effect of a novel PAI-1 inhibitor, IMD-4482, on ovarian cancer cell lines was assessed and its therapeutic potential was examined using a xenograft mouse model of ovarian cancer. IMD-4482 inhibited in vitro cell adhesion to vitronectin in PAI-1-positive ovarian cancer cells, followed by the inhibition of extracellular signal-regulated kinase and focal adhesion kinase phosphorylation through dissociation of the PAI-urokinase receptor complex from integrin αVβ3. IMD-4482 caused G0/G1 cell arrest and inhibited the proliferation of PAI-1-positive ovarian cancer cells. In the xenograft model, IMD-4482 significantly inhibited peritoneal dissemination with the reduction of PAI-1 expression and the inhibition of focal adhesion kinase phosphorylation. Collectively, the functional inhibition of PAI-1 significantly inhibited ovarian cancer progression, and targeting PAI-1 may be a potential therapeutic strategy in ovarian cancer.

ObjectiveAberrant activation of nuclear factor-kappa β (NF-κB) signaling has been correlated with poor outcome among patients with ovarian cancer. Although the therapeutic potential of NF-κB pathway disruption in cancers has been extensively studied, most classical NF-κB inhibitors are poorly selective, exhibit off-target effects, and have failed to be applied in clinical use. IMD-0560,N-[2,5-bis (trifluoromethyl) phenyl]-5-bromo-2-hydroxybenzamide, is a novel low-molecular-weight compound that selectively inhibits the IκB kinase complex and works as an inhibitor of NF-κB signaling. The aim of this study was to assess the therapeutic potential of IMD-0560 against ovarian cancer in vitro and in vivo.MethodsNF-κB activity (phosphorylation) was determined in 9 ovarian cancer cell lines and the inhibitory effect of IMD-0560 on NF-κB activation was analyzed by Western blotting. Cell viability, cell cycle, vascular endothelial growth factor (VEGF) expression, and angiogenesis were assessed in vitro to evaluate the effect of IMD-0560 on ovarian cancer cells. In vivo efficacy of IMD-0560 was also investigated using an ovarian cancer xenograft mouse model.ResultsThe NF-κB signaling pathway was constitutively activated in 8 of 9 ovarian cancer cell lines. IMD-0560 inhibited NF-κB activation and suppressed ovarian cancer cell proliferation by inducing G1 phase arrest. IMD-0560 decreased VEGF secretion from cancer cells and inhibited the tube formation of human umbilical vein endothelial cells. IMD-0560 significantly inhibited peritoneal metastasis and prolonged the survival in an ovarian cancer xenograft mice model. Immunohistochemical staining of excised tumors revealed that IMD-0560 suppressed VEGF expression, tumor angiogenesis, and cancer cell proliferation.ConclusionsIMD-0560 showed promising therapeutic efficacy against ovarian cancer xenograft mice by inducing cell cycle arrest and suppressing VEGF production from cancer cells. IMD-0560 may be a potential future option in regimens for the treatment of ovarian cancer.

Background microRNAs (miRNAs) stably exist in circulating blood encapsulated in extracellular vesicles such as exosomes; therefore, serum miRNAs have the potential to serve as novel cancer biomarkers. New diagnostic markers to detect high grade serous ovarian cancer (HGSOC) are urgently needed. The aim of this study was to identify miRNAs specific to HGSOC and analyze whether serum miRNA can discriminate HGSOC patients from healthy controls or patients with ovarian malignancies of other histological types. Methods Exosomes from ovarian cancer cell lines were collected and exosomal miRNAs extracted. miRNA microarray analysis revealed several elevated miRNAs specific to HGSOC. Among these, we focused on miR-1290. Sera from 70 ovarian cancer patients and 13 healthy controls were gathered and its expression levels detected by quantitative real-time polymerase chain reaction. Results In HGSOC patients, serum miR-1290 was significantly overexpressed compared to in healthy controls (3.52 fold; P = 0.03), unlike in patients with ovarian cancers of other histological types. The relative expression of miR-1290 was higher in advanced stages of HGSOC than in early stages (4.23 vs. 1.58; P = 0.23). Its expression significantly decreased after operation (5.87 to 1.17; P

Loss of ovarian function by the treatment for gynecological malignancy results in a drastic decrease of estrogen causing physical and mental symptoms. The purpose of this study is to evaluate the effect of Japanese Kampo Kamikihito (KKT) and Kamishoyosan (KSS) on menopausal symptoms in gynecological cancer patients. Patients who had menopausal symptoms after gynecologic malignancy treatment were enrolled and randomly divided into a KKT or a KSS group. Kupperman Menopausal Index (KI) questionnaires were obtained before tumor treatment, at baseline, and at 4 and 8 weeks. Changes in KI scores and severity of each symptom were evaluated. A total of 33 patients were enrolled: 18 in the KKT group and 15 in the KSS group. The KI scores significantly decreased at 4 and 8 weeks compared with baseline in both groups. Although no significant difference was found in change in KI scores between the KKT and KSS groups, efficacy showed some differences. Both KKT and KSS were effective for insomnia, vertigo, and palpitation. KSS was also effective for vasomotor symptoms and arthralgia/myalgia. In conclusion, both KKT and KSS were effective for menopausal symptoms in patients after gynecological tumor treatment. Tailor-made Kampo therapy may contribute to improve patients’ physical and mental symptoms.

Background: Platinum-paclitaxel combination chemotherapy is standard postoperative treatment of ovarian cancer. Overcoming paclitaxel resistance is a critical issue in ovarian cancer treatment. Objectives: The aim of this study is to identify key miRNAs which regulate paclitaxel resistance and to pursue those potential as therapeutic targets. Methods: Using two serous ovarian cancer cell lines, SKVO3ip1 and HeyA8, paclitaxel resistant cell lines were established by a continuous exposure to paclitaxel. Taqman miRNA PCR array was performed and several miRNAs which were down-regulated in paclitaxel resistant cell lines were picked up. After the validation by miRNA PCR assay, miR-522 was found to be one of those. The clinical impact of miR-522 expression in ovarian cancer tissues was examined using a public database (PROGmiRV2). From a patient who had Stage IC clear cell carcinoma, RNA was extracted from formalin fixed paraffin-embedded (FFPE) tissue by laser microdissection. Thereafter, the miR-522 expression was compared with that from a normal contralateral ovary. Further, the miR-522 expression was analyzed among 4 ovarian cancer cell lines (RMG-1, RMG-2, HAC2 and KOC7C) and each IC50 value of paclitaxel was analyzed. The effect of miR-522 expression was assessed by transducing the precursor miRNA into paclitaxel resistant cells. Results: While the IC50 values of parental SKOV3ip1 and HeyA8 were 6.2 and 1.3 nM respectively, SKOV3ip1-PR and HeyA8-PR were 194.8 and 135.5 nM. MiRNA PCR array revealed 5 miRNAs including miR-522 were down-regulated in both paclitaxel resistant cell lines. Among those, the validation assay by miRNA PCR showed miR-522 was significantly down-regulated. In a public database analyzing 549 patients with serous adenocarcinomas, patients with the low expression of miR-522 had significantly correlated with worse relapse free survival than those with the high expression. In clinical paclitaxel resistant ovarian cancer tissue, the miR-522 expression was significantly down-regulated compared with that of a normal contralateral ovary. Each IC50 value of ovarian cancer cell lines (RMG-1, RMG-2, HAC2 and KOC7C) was 4.8, 222.1, 75.6, 66.9nM, respectively. Among those, IC50 values of 3 cell lines (RMG-2, HAC2 and KOC7C) were more than 50nM. In these cell lines, the expression level of miR-522 was significantly lower than that of paclitaxel sensitive SKOV3ip1. Transduction of miR-522 into paclitaxel resistant cells significantly sensitized to paclitaxel. Conclusion: MiR-522 is down-regulated in paclitaxel resistant cell lines and the low expression of miR-522 is correlated with shorter relapse free survival, indicating that the dysregulation of miR-522 is associated with the acquisition of paclitaxel resistance. The transduction of miR-522 into paclitaxel resistant cells sensitized these to paclitaxel. MiR-522 can be considered a therapeutic target to overcome paclitaxel resistance. Citation Format: Mayuko Miyamoto, Kenjiro Sawada, Akihiko Yoshimura, Erika Nakatsuka, Michiko Kodama, Kae Hashimoto, Seiji Mabuchi, Tadashi Kimura. Low miR-522 expression is correlated with paclitaxel resistance in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 505.

Objective: There is a critical need for improved diagnostic markers to detect ovarian high grade serous cancer (HGSC). microRNAs (miRNAs) stably exist in circulating blood, reflecting tissue or organ conditions and present in circulating microvesicles such as exosomes. We aimed to identify which miRNAs are highly produced from HGSCs and analyze whether serum miRNA can discriminate patients with HGSC from healthy controls. Methods: Secreted exosomes from ovarian cancer cell lines were collected and exosomal miRNAs extracted. miRNA microarray was performed and several elevated miRNAs specific to ovarian cancer cells were picked up. Among these, we focused on miR-99a. Sera were collected from 15 patients with HGSC (stage III and IV) and 10 healthy controls. Expression level of miR-99a was determined by miRNA RT-qPCR. Results: miRNA microarray revealed several miRNAs were highly expressed in exosomes in patients with HGSC. In patients, serum miR-99a levels were significantly increased (4.8 fold) compared with those of healthy controls. ROC analysis showed that at the cut-off of 1.4, the sensitivity and specificity were 73 % and 80 % respectively for detecting HGSC (AUC = 0.85). Conclusion: Exosomal miRNAs can be detected in sera of patients with HGSC and have the potential to predict ovarian cancer. Citation Format: Akihiko Yoshimura, Kenjiro Sawada, Koji Nakamura, Yasuto Kinose, Erika Nakatsuka, Seiji Mabuchi, Tadashi Kimura. Elevated level of serum miR-99a is correlated with serous epithelial ovarian cancer and can be a potential biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4655. doi:10.1158/1538-7445.AM2017-4655