Bilateral ovarian endometriomas after laparoscopic hysterectomy following adjuvant tamoxifen therapy for breast cancer: A case report.

Tamoxifen, a selective estrogen receptor modulator, is widely used as adjunctive therapy for women with breast cancer. However, tamoxifen has an agonistic effect on the endometrium and may be associated with endometrial proliferation, hyperplasia, polyp formation and carcinoma. The case report describes a 50-year-old woman who developed bilateral ovarian endometriomas while taking tamoxifen for breast cancer after total laparoscopic hysterectomy. She had undergone total laparoscopic hysterectomy for multiple uterine fibroids with no ovarian pathology at age 48 years, had been diagnosed with breast cancer and had commenced tamoxifen as post-mastectomy adjuvant therapy. One year after starting tamoxifen, she developed bilateral ovarian swelling accompanied by acute abdominal pain. At laparoscopic bilateral salpingo-oophorectomy, endometriomas were visible on both ovaries. Pathological examination confirmed endometriotic cysts with no evidence of malignancy. Postoperatively, anastrozole (an aromatase inhibiter) was substituted for tamoxifen as adjuvant therapy for her breast cancer.

Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice.

Cervical cancer (CC) is usually initiated by infection with high-risk types of human papillomavirus (HPV). The HPV E6 and E7 proteins target p53 and RB, respectively, but other cellular targets likely exist. We generated uterus-specific MOB1A/B double KO (uMob1DKO) mice, which immediately developed cervical squamous cell carcinoma in situ. Mutant cervical epithelial cells showed YAP1-dependent hyperproliferation, altered self-renewal, impaired contact inhibition, and chromosomal instability. p53 activation was increased in uMob1DKO cells, and additional p53 loss in uMob1DKO mice accelerated tumor invasion. In human CC, strong YAP1 activation was observed from the precancerous stage. Human cells overexpressing HPV16 E6/E7 showed inactivation of not only p53 and RB but also PTPN14, boosting YAP1 activation. Estrogen, cigarette smoke condensate, and PI3K hyperactivation all increased YAP1 activity in human cervical epithelial cells, and PTPN14 depletion along with PI3K activation or estrogen treatment further enhanced YAP1. Thus, immediate CC onset may initiate when YAP1 activity exceeds an oncogenic threshold, making Hippo-YAP1 signaling a major CC driver.

MOB1 regulates thymocyte egress and T-cell survival in mice in a YAP1-independent manner.

Mammalian STE20-like protein kinase 1/2 (MST1/2) and nuclear Dbf2-related kinase 1/2 (NDR1/2) are core components of Hippo signaling that are also known to be important regulators of lymphocyte trafficking. However, little is understood about the roles of other Hippo pathway molecules in these cells. Here, we present the first analysis of the function of Mps one binder kinase activator-1 (MOB1) in T lymphocytes in vivo. T-cell-specific double knockout (DKO) of MOB1A/B in mice [tMob1 DKO mice] reduces the number of naïve T cells in both the circulation and secondary lymphoid organs, but leads to an accumulation of CD4+ CD8- and CD4- CD8+ single-positive (SP) cells in the thymus. In vitro, naïve MOB1A/B-deficient T cells show increased apoptosis and display impaired trafficking capacity in response to the chemokine CCL19. These defects are linked to suppression of the activation of MST and NDR kinases, but are independent of the downstream transcriptional co-activator Yes-associated protein 1 (YAP1). Thus, MOB1 proteins play an important role in thymic egress and T-cell survival that is mediated by a pathway other than conventional Hippo-YAP1 signaling.

Incidence and risk factors for postpartum hemorrhage among transvaginal deliveries at a tertiary perinatal medical facility in Japan.

Postpartum hemorrhage (PPH) remains a leading cause of maternal death worldwide, and it is important to understand the relative contributions of different risk factors. We assessed the incidence of these among cases of transvaginal delivery. Between June 2013 and July 2016, a prospective cohort study was conducted at a tertiary perinatal medical facility in Japan. Women were administered a questionnaire to ascertain risk factors for PPH, defined as a blood loss of 1,000 ml or more assessed using a calibrated under-buttocks drape and collection vessel at childbirth. We analyzed 1,068 transvaginal deliveries of singleton pregnancies. The incidence of PPH was 8.7%, and of severe PPH (1,500 ml blood loss or more) was 2.1%. Risk factors for postpartum hemorrhage among the deliveries were: fetal macrosomia (over 4000 g); pregnancy-induced hypertension; pregnancy generated by assisted reproductive technology; severe vaginal or perineal lacerations; and weight gain over 15 kg during pregnancy. Such high weight gain significantly increased the incidence of PPH compared with women showing less than 10 kg weight gain during pregnancy. Monitoring these identified risk factors could enable extra vigilance during labor, and preparedness for managing PPH in all women giving birth.

Case of uterine rupture after multiple intrauterine operations and uterine artery embolization.

Uterine rupture is rare but may result in both maternal and fetal death. The factors involved in such deaths depend on each case, but uterine artery embolization (UAE), the common treatment for hemorrhage, is possibly one factor. UAE may be related to uterine rupture or placenta accreta, but few data exist regarding UAE and uterine rupture. Here, we present a case of uterine rupture associated with placenta accreta that occurred after UAE. The case is a 35-year-old woman who became pregnant after undergoing UAE because of treatment for placental polyps twice. She underwent emergency cesarean delivery for uterine rupture. At the same time, she underwent hysterectomy because of placenta accreta. The uterus ruptured at the location where the polyp had emerged previously. Therefore, we present a case where UAE, uterine rupture and placenta accreta are possibly associated, and highlight the need for caution when performing UAE multiple times.

Primary peritoneal carcinosarcoma arising from the Douglas pouch: A case report.

Primary peritoneal carcinosarcoma is extremely rare and only few cases have been reported in the literature to date. We herein present a case of carcinosarcoma of the Douglas pouch in a 73-year-old Japanese woman. The patient complained of fever and lower abdominal pain, and a large pelvic mass (>10 cm in diameter) was detected, with rectal invasion. Laparotomy was performed and revealed a left ovarian abscess and a Douglas pouch mass; however, there was no obvious tumor involvement of the bilateral ovaries or uterus. The patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy and tumor debulking, with a reduction rate of ~30%. Sigmoid colostomy was also performed due to the deep and wide rectal invasion. Histologically, the tumor was composed of a mixture of ovarian high-grade serous carcinoma and spindle-cell sarcoma mimicking leiomyosarcoma. Immunohistochemically, the serous carcinoma component was positive for cytokeratin (CK)7, Wilms' tumor-1 and p53 (null type), while CDX-2 and CK20 were negative. The spindle-cell sarcoma component was positive for vimentin and α-smooth muscle actin. The present case was diagnosed as carcinosarcoma of the homologous type derived from the peritoneum in the Douglas pouch. The patient received several courses of combination chemotherapy with paclitaxel, carboplatin and bevacizumab, and achieved complete remission. The principal treatment for such cases is surgery, and several chemotherapeutic regimens, including paclitaxel and carboplatin, or cisplatin and ifosfamide, have been reported. The accumulation of more clinical cases is crucial for understanding the clinicopathological characteristics of these rare tumors and establishing effective therapeutic strategies.

Malignant lymphoma of the uterine cervix presumptively diagnosed by Pap smear: A case report.

Malignant lymphoma of the uterine cervix is exceedingly rare and is difficult to diagnose by cervical cytology. The current study presents a case of malignant lymphoma of the uterine cervix that was presumptively diagnosed by cervical cancer screening in which the patient had no clinical symptoms. The anterior lip of the uterine cervix was occupied by a macroscopic hemorrhagic tumor. The obtained tumor cells exhibited typical cytological features of malignant lymphoma and were positive for CD20. The final diagnosis was diffuse large B cell lymphoma of the uterine cervix, stage IIEA (Ann Arbor classification). The patient received 6 courses of R-CHOP chemotherapy and achieved complete remission. Despite its rarity, the possibility of malignant lymphoma should be considered while screening for cervical cancers using Pap smears. The Pap test screening may be useful for the early diagnosis of malignant lymphoma of the uterine cervix in certain cases. By reaching a rapid and accurate diagnosis, immediate treatment may be initiated and surgery may be avoided.

Loss of Mob1a/b in mice results in chondrodysplasia due to YAP1/TAZ-TEAD-dependent repression of SOX9.

Hippo signaling is modulated in response to cell density, external mechanical forces, and rigidity of the extracellular matrix (ECM). The Mps one binder kinase activator (MOB) adaptor proteins are core components of Hippo signaling and influence Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ), which are potent transcriptional regulators. YAP1/TAZ are key contributors to cartilage and bone development but the molecular mechanisms by which the Hippo pathway controls chondrogenesis are largely unknown. Cartilage is rich in ECM and also subject to strong external forces - two upstream factors regulating Hippo signaling. Chondrogenesis and endochondral ossification are tightly controlled by growth factors, morphogens, hormones, and transcriptional factors that engage in crosstalk with Hippo-YAP1/TAZ signaling. Here, we generated tamoxifen-inducible, chondrocyte-specific Mob1a/b-deficient mice and show that hyperactivation of endogenous YAP1/TAZ impairs chondrocyte proliferation and differentiation/maturation, leading to chondrodysplasia. These defects were linked to suppression of SOX9, a master regulator of chondrogenesis, the expression of which is mediated by TEAD transcription factors. Our data indicate that a MOB1-dependent YAP1/TAZ-TEAD complex functions as a transcriptional repressor of SOX9 and thereby negatively regulates chondrogenesis.

Choosing the uterine preservation surgery for placental polyp determined by blood flow evaluation: A retrospective cohort study.

BACKGROUND: A placental polyp is an intrauterine polypoid mass or pedunculated mass occurring from residual trophoblastic tissue following abortion, cesarean section or vaginal delivery. Recently uterine preservation surgery represented by transcervical resection (TCR) has been performed for placental polyps. However TCR without intravascular intervention, including uterine artery embolization (UAE) may cause profound bleeding which necessitate emergency laparotomy. METHODS: Seventeen cases of placental polyp were retrospectively examined. We divided cases into two groups: strong vascularity group (n = 13) and weak vascularity group (n = 4). Mass extraction of polyp by TCR was conducted in 16 cases, 6 case without UAE and 10 cases with UAE. RESULTS: As for the weak vascularity group, one case was naturally resolved while planning surgery and 3 cases were treated with TCR without UAE without major intra- and/or postoperative bleeding. On the other hand in the strong vascularity group, 2 out of 3 cases of TCR without UAE resulted in major bleeding during and after the surgery, both needed transfusion and one needing postoperative UAE. Ten cases of strong vascularity group, TCR with UAE were performed and all of them were accomplished without major bleeding. TCR without UAE was safely performed in cases where there was absent or mild to moderate blood flow. CONCLUSIONS: Our report suggests that adding UAE might be safer to treat placental polyps that have strong vascularity.

Mutual contribution of Pten and estrogen to endometrial carcinogenesis in a PtenloxP/loxP mouse model.

OBJECTIVE: An association between estrogen and the risk of type 1 endometrial carcinoma, which shows frequent mutations in the Pten tumor suppressor gene, has consistently been found in many studies. However, such tumors usually arise in perimenopausal or postmenopausal women with decreased serum estrogen levels. This study aimed to reveal the contributions of estrogen to endometrial carcinogenesis in a mouse model of endometrial carcinoma initiated by conditional targeting of Pten. METHODS: The Cre-loxP system was used to achieve Pten inactivation within mouse endometrial epithelium. We delivered a recombinant adenovirus vector expressing Cre recombinase to the endometrial cavity of the Pten mice that had been ovariectomized at 10 weeks old. Mice were subcutaneously injected with 17ß-estradiol (E2) or vehicle, followed by injection of the adenovirus. Two weeks after adenovirus injection, the entire endometrium was analyzed. RESULTS: Mice that did not receive E2 injection notably developed endometrial neoplasia, complex atypical hyperplasia, or carcinoma (7/8, 87.5%). In contrast, hyperplastic but nonneoplastic endometrium was observed in E2-treated mice. In these E2-treated mice, immunohistochemistry revealed that Pten-null glandular epithelial cells clonally proliferate among the hyperplastic endometrium. CONCLUSIONS: The results of this study suggest that estrogen clonally proliferates Pten-null epithelial cells together with surrounding cells, and depletion of estrogen induces predominant growth of Pten-null cells with estrogen-independent capabilities, resulting in abnormal structure of the glandular cells and subsequent neoplasia. This phenomenon might explain why the incidence of human endometrial carcinoma increases with perimenopausal or postmenopausal status, which represents declining ovarian function. Our model mice have partially resolved the issue of endometrial Pten- and estrogen-related carcinogenesis and have potential to represent a valuable tool for developing novel therapies against this carcinoma.