Progesterone Suppresses Uterine Contraction by Reducing Odontogenic Porphyromonas gingivalis Induced Chronic Inflammation in Mice.

Preterm birth is one of the most significant obstetric complications. Inflammation reportedly promotes uterine contraction and weakening of the fetal membrane, which induces preterm birth. Previous studies using animal models of lipopolysaccharide-induced acute inflammation have shown that progesterone (P4) promotes uterine quiescence. However, this effect is not fully understood in chronic inflammation. This study aimed to investigate the effects of P4 on uterine contractility and inflammation of the fetal membrane in mice infected with Porphyromonas gingivalis (P.g.), a major periodontal pathogen as a model of preterm birth caused by chronic inflammation. Mice were injected with 1 mg of P4 from day 15.5 to 17.5. P4 prolonged the mean gestation period of P.g mice from 18.3 to 20.4 days, and no reduction in the gestation period was observed. P4 treatment suppressed spontaneous uterine contractility and decreased oxytocin sensitivity. In addition, the expression of inflammatory cytokines in the fetal membrane was significantly reduced. Thus, P4 prevented preterm birth by suppressing enhanced uterine contractility induced by chronic inflammation in this model. This result describes the effects of P4 in a chronic inflammation model, which may lead to a better understanding of the efficacy of P4 in preventing preterm birth in humans.

Porphyromonas gingivalis, a cause of preterm birth in mice, induces an inflammatory response in human amnion mesenchymal cells but not epithelial cells.

INTRODUCTION: Inflammation and infection, including dental infectious diseases, are factors that can induce preterm birth. We previously reported that mice with dental Porphyromonas gingivalis infection could be used as a model of preterm birth. In this model, cyclooxygenase (COX)-2 and interleukin (IL)-1ß levels are increased, and P. gingivalis colonies are observed in the fetal membrane. However, the mechanism underlying fetal membrane inflammation remains unknown. Therefore, we investigated the immune responses of human amnion to P. gingivalis in vitro. METHODS: Epithelial and mesenchymal cells were isolated from human amnion using trypsin and collagenase, and primary cell cultures were obtained. Confluent cells were stimulated with P. gingivalis lipopolysaccharide (P.g-LPS) or P. gingivalis. mRNA expressions of IL-1ß, IL-8, IL-6 and COX-2, protein expressions of nuclear factor (NF)-κB pathway components and culture medium levels of prostaglandin E2 were evaluated. RESULTS: Following stimulation with 1 µg/mL P.g-LPS, the mRNA expression levels of IL-1ß, IL-8, IL-6 and COX-2 in mesenchymal cells were increased 5.9-, 3.3-, 4.2- and 3.1-fold, respectively. Similarly, the expression levels of IL-1ß, IL-8, IL-6 and COX-2 in mesenchymal cells were increased by 7.6-, 8.2-, 13.4- and 9.3-fold, respectively, after coculture with P. gingivalis. Additionally, stimulation with P.g-LPS or P. gingivalis resulted in the activation of NF-κB signaling and increased production of IL-1ß and prostaglandin E2. In contrast, no significant changes were observed in epithelial cells. DISCUSSION: Our findings suggest that mesenchymal cells might mediate the inflammatory responses to P. gingivalis and P.g-LPS, thereby producing inflammation that contributes to the induction of preterm birth.

Fetal Membrane Inflammation Induces Preterm Birth Via Toll-Like Receptor 2 in Mice With Chronic Gingivitis.

Inflammation is associated with preterm birth. We previously described a mouse model of chronic inflammation-induced preterm birth after dental Porphyromonas gingivalis infection. The aim of this study was to employ this model system to investigate the mechanisms through which enhanced uterine contractility induces preterm birth. Messenger RNA (mRNA) encoding contraction-associated proteins, such as oxytocin receptors, was measured at various gestational time points by real-time polymerase chain reaction (PCR). Spontaneous and oxytocin-induced uterine contractile activity at gestational day 18 was assessed using a tissue organ bath. The expression levels of Toll-like receptor 2 (TLR2), TLR4, cyclooxygenase (COX)-2, nuclear factor-kappa B (NF-κB) p65, and p38 mitogen-activated protein kinase (MAPK) on gestational day 18 were also determined by real-time PCR or Western blotting. Messenger RNA encoding contraction-associated proteins was increased at gestational day 18, and the spontaneous contractile activity (1.6-fold greater area under the contraction curve) and sensitivity to oxytocin (EC50: 8.8 nM vs 2.2 nM) were enhanced in the P gingivalis group compared to those in the control group. In the P gingivalis group, COX-2 mRNA expression was not elevated in the placenta or myometrium but was upregulated 2.3-fold in the fetal membrane. The TLR2 mRNA levels in the fetal membrane were 2.7-fold higher in the P gingivalis group, whereas TLR4 levels were not elevated. Activation of the NF-κB p65 and p38 MAPK pathways was enhanced in the fetal membrane of the P gingivalis group. Thus, in mice with chronic dental P gingivalis infection, TLR2-induced inflammation in the fetal membrane leads to upregulation of uterine contractility, leading to preterm birth.

Two Case Reports of Intravenous Leiomyomatosis with Hyaluronan Expression.

Intravenous leiomyomatosis (IVL) is a rare benign neoplasm. Herein, we describe two cases of IVL at different levels of progression. The tumor in Case 1 was extensive, invading the right atrium after a hysterectomy for a uterine myoma. The tumor temporarily responded to hormonal treatment; however, tumor regrowth occurred. In contrast, the tumor in Case 2 extended only to the pelvic veins and was revealed preoperatively. Hysterectomy and bilateral salpingo-oophorectomy were performed, resulting in the complete surgical resection of the tumor. In Case 2, no recurrence has been observed. Tumor samples were evaluated for hyaluronan expression using Alcian blue staining (with and without hyaluronidase digestion). The tumor in Case 1 stained strongly positive for hyaluronan while the tumor in Case 2 stained weakly positive for hyaluronan. In contrast, a large non-IVL uterine leiomyoma (control) stained negative for hyaluronan. These results suggest a relationship between tumor hyaluronan expression and IVL progression, similar to that in other cancers.

[Outcomes of Tertiary Debulking Surgery(TDS)for Re-Recurrent Ovarian Cancer].

The survival of patients with recurrent ovarian cancer who have completed secondary debulking surgery (SDS) has been shown to increase. However, whether tertiary debulking surgery (TDS) aimed at complete surgery is useful in patients with a second recurrence is unclear. Eight patients who had undergone SDS were treated after a second recurrence in our hospital. Their medical records were retrospectively reviewed. Consequently, TDS was performed in 4 of the patients (TDSgr). All 4 patients underwent complete debulking surgery, 2 patients received blood transfusions, and none had serious postoperative complications. The median treatment free interval (TFI) from recurrence surgery to the second recurrence was 16 months (range, 9-23 months), and the median TFI after the second recurrence was 30.5 months (range, 15-69 months). Meanwhile, the median TFI after the second recurrence was 7.5 months (range, 1-31 months) in the 4 patients who did not undergo TDS (non-TDSgr). The median survival times after the second recurrence in TDSgr and non-TDSgr were 53 months (range, 41-69 months) and 12 months (range, 2-30 months), respectively. When complete surgery is indicated in patients with a second recurrent ovarian cancer after SDS, in case of good physical condition with single or multiple recurrent lesions, TDS may increase survival and TFI.

A case of uterine corpus large cell neuroendocrine carcinoma showing prominent myometrial invasion without any macroscopically clear tumor formation.

Large cell neuroendocrine carcinoma (LCNEC) arising in the uterine corpus is a very rare. Here, we report our experience with a primary LCNEC in the uterine corpus that showed prominent myometrial invasion without exhibiting any macroscopically distinct tumor formation in the uterine cavity. The patient was a 54-year-old woman. She had a past medical history of right breast cancer and was referred to our department with irregular genital bleeding, elevated serum carcinoembryonic antigen in periodic medical examinations and computed tomography (CT) findings of uterine cavity dilation. Endometrial biopsy suggested a poorly differentiated tumor. Although magnetic resonance imaging (MRI) showed hematometra-like findings in the uterine cavity, it did not indicate any clear endometrial lesion. The myometrium was unequally thickened, and the entire muscle layer showed a high signal intensity on diffusion-weighted images. Fluorine-18-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) showed strong FDG accumulation in the whole uterus, and on the bottom of the uterus, there was a ring-shaped accumulation mainly in the muscle layer. The postoperative resected specimen did not show any tumor formation in the uterine cavity, whereas the myometrium was hard and thickened, and colored white overall. Histopathological examination revealed prominent myometrial invasion in most layers, cervical stromal invasion and pelvic lymph node metastasis. The diagnosis was a LCNEC of the uterine corpus, at FIGO stage IIIC1 and pT2N1M0. With these patients, we found that functional metabolic images, such as MRI diffusion-weighted images and FDG-PET/CT, were useful in identifying the lesion. Preoperatively, when a poorly differentiated tumor is estimated and characteristic myometrial invasion is suspected, the possibility of LCNEC should be considered.

Enhanced Expression of Contractile-Associated Proteins and Ion Channels in Preterm Delivery Model Mice With Chronic Odontogenic Porphyromonas Gingivalis Infection.

Inflammation and infection have been reported to induce preterm delivery. We have studied the relationship between inflammation and various ion channels, including the L-type Ca(2+) channel and P2X7 receptor, during acute inflammation of the pregnant rat uterus induced by lipopolysaccharides. Recently, we found that mice with odontogenic Porphyromonas gingivalis (P.g, an important odontogenic pathogen) infection delivered at day 18.3 of gestation (vs. day 20.5 in normal mice). The purpose of this study was to investigate the expression of myometrial contractile-associated proteins inducing contractions and confirm that these mice are useful as a model for preterm delivery induced by chronic inflammation. We examined the expression of the oxytocin receptor, connexin 43, prostaglandin F receptors, L-type Ca(2+) channel, and P2X7 receptor in the myometrium at day 18 of gestation by real-time PCR and western blot analyses. We also measured TNF-α and IL-1ß levels in the blood serum, placenta, fetal membrane and myometrium on the same day. mRNA expression of the oxytocin receptor, connexin 43, prostaglandin F receptors, L-type Ca(2+) channel, and P2X7 receptor was elevated by 5.4, 3.2, 2.4, 2.5, and 1.7 fold, respectively, in the P.g-infected mice. Protein levels of the oxytocin receptor and connexin 43 also increased. Serum levels of TNF-α and IL-1ß were elevated, showing that systemic inflammation continued during pregnancy. IL-1ß levels in the placenta and fetal membrane also increased, suggesting inflammatory reactions were induced. Thus, mice with odontogenic infection may be useful as a model of chronic inflammation-induced preterm delivery.

[A case of platinum-resistant, recurrent ovarian clear cell adenocarcinoma successfully treated with irinotecan (CPT-11) and paclitaxel (PTX) chemotherapy].

A 40-year-old woman presented to a local clinic with abdominal distension. She was referred to our hospital for suspected ovarian cancer. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed an ovarian tumor with mural nodules, ascites, pleural effusion, and peritoneal dissemination. Laparotomy revealed a 20-cm right ovarian tumor with strong adhesion to the uterus and rectum. Bilateral salpingo-oophorectomy was performed as a primary surgery. The histopathological diagnosis was stage IVovarian clear cell adenocarcinoma, and 6 cycles of postoperative chemotherapy with a combination of TC (paclitaxel [PTX] and carboplatin) and the mTOR inhibitor temsirolimus was administered. During maintenance treatment with temsirolimus, the lesion recurred, and progressive disease was confirmed. Because relapse occurred after 5 months from the last TC treatment, the disease was considered platinum-resistant ovarian cancer, and second-line chemotherapy with 6 cycles of irinotecan (CPT-11 ) and PTX was administered. Partial response was observed after 2 cycles, and the response period was 7 months. We suggest that chemotherapy with CPT-11/PTX could be a treatment option for platinum resistant recurrent ovarian clear cell adenocarcinoma.

Maximum standardized uptake value of fluorodeoxyglucose positron emission tomography/computed tomography is a prognostic factor in ovarian clear cell adenocarcinoma.

BACKGROUND: Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is useful for diagnosing malignant tumors. Intracellular FDG uptake is measured as the standardized uptake value (SUV), which differs depending on tumor characteristics. This study investigated differences in maximum SUV (SUVmax) according to histologic type in ovarian epithelial cancer and the relationship of SUVmax with prognosis. METHODS: This study included 80 patients with ovarian epithelial cancer based on histopathologic findings at surgery and who had undergone PET/CT before treatment. Maximum SUV on PET/CT of primary lesions and histopathology were compared based on histologic type, and the prognosis associated with different SUVmax was evaluated. RESULTS: Clinical tumor stage was I in 35 patients, II in 8, III in 25, and IV in 12. Histologic type was serous adenocarcinoma (AC) in 33 patients, clear cell AC in 27, endometrioid AC in 15, and mucinous AC in 5. Median SUVmax was lower in mucinous AC (2.76) and clear cell AC (4.9) than in serous AC (11.4) or endometrioid AC (11.4). Overall, median SUVmax was lower in clinical stage I (5.37) than in clinical stage ≥II (10.3). However, in both clear cell AC and endometrioid AC, when histologic evaluation was possible, no difference was seen between stage I and stage ≥II. Moreover, in clear cell AC, the 5-year survival rate was significantly higher in the low-SUVmax group (100%) than in the high-SUVmax group (43.0%, P = 0.009). CONCLUSIONS: Maximum SUV on preoperative FDG-PET/CT in ovarian epithelial cancer differs according to histologic type. In clear cell AC, SUVmax may represent a prognostic factor.