Rapamycin prevents cyclophosphamide-induced ovarian follicular loss and potentially inhibits tumour proliferation in a breast cancer xenograft mouse model.

STUDY QUESTION: To what extent and via what mechanism does the concomitant administration of rapamycin (a follicle activation pathway inhibitor and antitumour agent) and cyclophosphamide (a highly toxic ovarian anticancer agent) prevent cyclophosphamide-induced ovarian reserve loss and inhibit tumour proliferation in a breast cancer xenograft mouse model? SUMMARY ANSWER: Daily concomitant administration of rapamycin and a cyclic regimen of cyclophosphamide, which has sufficient antitumour effects as a single agent, suppressed cyclophosphamide-induced primordial follicle loss by inhibiting primordial follicle activation in a breast cancer xenograft mouse model, suggesting the potential of an additive inhibitory effect against tumour proliferation. WHAT IS KNOWN ALREADY: Cyclophosphamide stimulates primordial follicles by activating the mammalian target of the rapamycin (mTOR) pathway, resulting in the accumulation of primary follicles, most of which undergo apoptosis. Rapamycin, an mTOR inhibitor, regulates primordial follicle activation and exhibits potential inhibitory effects against breast cancer cell proliferation. STUDY DESIGN, SIZE, DURATION: To assess ovarian follicular apoptosis, 3 weeks after administering breast cancer cells, 8-week-old mice were randomized into three treatment groups: control, cyclophosphamide, and cyclophosphamide + rapamycin (Cy + Rap) (n = 5 or 6 mice/group). Mice were treated with rapamycin or vehicle control for 1 week, followed by a single dose of cyclophosphamide or vehicle control. Subsequently, the ovaries were resected 24 h after cyclophosphamide administration (short-term treatment groups). To evaluate follicle abundance and the mTOR pathway in ovaries, as well as the antitumour effects and impact on the mTOR pathway in tumours, 8-week-old xenograft breast cancer transplanted mice were randomized into three treatment groups: vehicle control, Cy, and Cy + Rap (n = 6 or 7 mice/group). Rapamycin (5 mg/kg) or the vehicle was administered daily for 29 days. Cyclophosphamide (120 mg/kg) or the vehicle was administered thrice weekly (long-term treatment groups). The tumour diameter was measured weekly. Seven days after the last cyclophosphamide treatment, the ovaries were harvested, fixed, and sectioned (for follicle counting) or frozen (for further analysis). Similarly, the tumours were resected and fixed or frozen. PARTICIPANTS/MATERIALS, SETTING, METHODS: Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) was performed to examine ovarian follicular apoptosis in the short-term treatment groups. All subsequent experiments were conducted in the long-term treatment groups. Tumour growth was evaluated using the tumour volume index. The tumour volume index indicates the relative volume, compared to the volume 3 weeks after tumour cell injection (at treatment initiation) set to 100%. Tumour cell proliferation was evaluated by Ki-67 immunostaining. Activation of the mTOR pathway in tumours was assessed using the protein extracts from tumours and analysed by western blotting. Haematoxylin and eosin staining of ovaries was used to perform differential follicle counts for primordial, primary, secondary, antral, and atretic follicles. Activation of the mTOR pathway in ovaries was assessed using protein extracts from whole ovaries and analysed by western blotting. Localization of mTOR pathway activation within ovaries was assessed by performing anti-phospho-S6 kinase (downstream of mTOR pathway) immunohistochemistry. MAIN RESULTS AND THE ROLE OF CHANCE: Ovaries of the short-term treatment groups were resected 24 h after cyclophosphamide administration and subjected to TUNEL staining of apoptotic cells. No TUNEL-positive primordial follicles were detected in the control, Cy, and Cy + Rap groups. Conversely, many granulosa cells of growing follicles were TUNEL positive in the Cy group but negative in the control and Cy + Rap groups. All subsequent experimental results were obtained from the long-term treatment groups. The tumour volume index stabilized at a mean of 160-200% in the Cy group and 130% in the Cy + Rap group throughout the treatment period. In contrast, tumours in the vehicle control group grew continuously with a mean tumour volume index of 600%, significantly greater than that of the two treatment groups. Based on the western blot analysis of tumours, the mTOR pathway was activated in the vehicle control group and downregulated in the Cy + Rap group when compared with the control and Cy groups. Ki-67 immunostaining of tumours showed significant inhibition of cell proliferation in the Cy + Rap group when compared with that in the control and Cy groups. The ovarian follicle count revealed that the Cy group had significantly fewer primordial follicles (P < 0.001) than the control group, whereas the Cy + Rap group had significantly higher number of primordial follicles (P < 0.001, 2.5 times) than the Cy group. The ratio of primary to primordial follicles was twice as high in the Cy group than in the control group; however, no significant difference was observed between the control group and the Cy + Rap group. Western blot analysis of ovaries revealed that the mTOR pathway was activated by cyclophosphamide and inhibited by rapamycin. The phospho-S6 kinase (pS6K)-positive primordial follicle rate was 2.7 times higher in the Cy group than in the control group. However, this effect was suppressed to a level similar to the control group in the Cy + Rap group. LARGE SCALE DATA: None. LIMITATIONS, REASONS FOR CAUTION: The combinatorial treatment of breast cancer tumours with rapamycin and cyclophosphamide elicited inhibitory effects on cell proliferative potential compared to cyclophosphamide monotherapy. However, no statistically significant additive effect was observed on tumour volume. Thus, the beneficial antitumour effect afforded by rapamycin administration on breast cancer could not be definitively proven. Although rapamycin has ovarian-protective effects, it does not fully counteract the ovarian toxicity of cyclophosphamide. Nevertheless, rapamycin is advantageous as an ovarian protective agent as it can be used in combination with other ovarian protective agents, such as hormonal therapy. Hence, in combination with other agents, mTOR inhibitors may be sufficiently ovario-protective against high-dose and cyclic cyclophosphamide regimens. WIDER IMPLICATIONS OF THE FINDINGS: Compared with a cyclic cyclophosphamide regimen that replicates human clinical practice under breast cancer-bearing conditions, the combination with rapamycin mitigates the ovarian follicle loss of cyclophosphamide without interfering with the anticipated antitumour effects. Hence, rapamycin may represent a new non-invasive treatment option for cyclophosphamide-induced ovarian dysfunction in breast cancer patients. STUDY FUNDING/COMPETING INTEREST(S): This work was not financially supported. The authors declare that they have no conflict of interest.

Successful ovarian tissue cryopreservation with transvaginal natural orifice transluminal endoscopic surgery: A case report.

Chemotherapy and radiation therapy can cause gonadal dysfunction in women of reproductive age. Ovarian tissue cryopreservation is performed to restore fertility by allowing transplantation of the patient's frozen-thawed ovarian tissue or through future in vitro maturation and in vitro fertilization of frozen-thawed oocytes. Herein, we describe our initial experience with vaginal natural orifice transluminal endoscopic surgery for ovarian tissue preservation in a young woman with malignant tumor. A 23-year-old woman with anaplastic lymphoma kinase-positive malignant lymphoma was scheduled for hematopoietic stem cell transplantation after experiencing relapse following R-cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy. Ovarian tissue cryopreservation was selected as only MII2 oocytes were collected. Vaginal natural orifice transluminal endoscopic surgery was performed to excise the left ovary. Ovarian tissues were frozen using the vitrification method. The operative time was 37 min, and blood loss was minimal. Pathological examination revealed no metastatic findings of malignant lymphoma and no thermal damage to the ovarian tissue due to bipolar disorder. The patient was discharged on the first day postoperatively, and her postoperative course was uneventful. The vaginal natural orifice transluminal endoscopic surgery technique can provide a safe and effective alternative to laparoscopy or laparotomy for the cryopreservation of ovarian tissue in young patients with cancer. We believe this method has potential application in sexually mature female cancer survivors.

Ovarian tissue cryopreservation with vaginal natural orifice transluminal endoscopic surgeryChemotherapy and radiotherapy can affect a woman's ability to have children by reducing ovarian function. This can make it hard to conceive even with fertility treatments. Freezing healthy ovaries before these treatments can help restore fertility. This can be done by freezing and later transplanting ovarian tissue or by fertilizing frozen eggs in a lab. Traditional surgery to remove ovaries can cause cosmetic issues and pain. But now, a new method called vaginal spontaneous opening transperitoneal endoscopic surgery is becoming more common. This surgery is less invasive, quicker, and causes less bleeding. We recently used this method to preserve ovarian tissue in young women with cancer. The surgery was successful with minimal complications. This new approach could offer a safer option for preserving fertility in female cancer survivors.

Cases of pleural effusion possibly due to clinical pleuroperitoneal communication in the perioperative period of emergency gynecologic surgery: Case series and literature review.

Pleuroperitoneal communication poses a respiratory failure risk due to pleural fluid accumulation with thoracic migration of ascites. Here, we discuss the following cases: Case 1: A woman was diagnosed with a ruptured ovarian tumor with right pleural fluid and ascites, without respiratory failure. Ovarian cystectomy was performed with inadequate removal of ascites. Postoperatively, respiratory failure occurred, and thoracentesis detected pleural fluid resembling ascites. Case 2: A woman was diagnosed with a ruptured ectopic pregnancy with right pleural fluid and ascites without respiratory failure. A diagnosis of clinical pleuroperitoneal communication was considered based on computed tomography findings. During laparoscopic salpingectomy, high-pressure ventilation was performed to push the pleural fluid back into the abdominal cavity; a negative-pressure drain was inserted, and the ascites was completely removed. Postoperative radiography revealed the absence of pleural fluid. Therefore, a preoperative diagnosis of clinical pleuroperitoneal communication and appropriate intraoperative techniques can prevent postoperative respiratory failure.

Locally advanced endometrial cancer with multiple immune-related adverse events coinciding with the complete response to radiotherapy after immune checkpoint inhibitor therapy: A case report.

We report a case of a 70-year-old female patient with locally advanced endometrial cancer with primary empty sella who developed multiple immune-related adverse events (irAEs), including hypopituitarism coinciding with the complete response to radiotherapy after receiving immune checkpoint inhibitors. A computed tomography scan acquired after a traffic accident led to the discovery of endometrial cancer that had invaded the vulva and primary empty sella. Following adriamycin and cisplatin, pembrolizumab was administered for three cycles. No irAEs were observed during treatment, but the tumor was progressive. The patient underwent radiotherapy for the residual tumor. Four months after the last dose of pembrolizumab, hypopituitarism caused secondary adrenal insufficiency, primary hypothyroidism, and pseudogout at the end of radiotherapy. The tumor later achieved a complete response. In conclusion, radiotherapy after immune checkpoint inhibitor (ICI) therapy is expected to have an antitumor effect by stimulating tumor-specific immunity. However, proper management of irAEs is necessary. Patients with primary empty sella may be prone to pituitary insufficiency induced by ICIs.

Prevalence, definition, and etiology of cesarean scar defect and treatment of cesarean scar disorder: A narrative review.

Background: Cesarean scar defects (CSD) are caused by cesarean sections and cause various symptoms. Although there has been no previous consensus on the name of this condition for a long time, it has been named cesarean scar disorder (CSDi). Methods: This review summarizes the definition, prevalence, and etiology of CSD, as well as the pathophysiology and treatment of CSDi. We focused on surgical therapy and examined the effects and procedures of laparoscopy, hysteroscopy, and transvaginal surgery. Main findings: The definition of CSD was proposed as an anechoic lesion with a depth of at least 2 mm because of the varied prevalence, owing to the lack of consensus. CSD incidence depends on the number of times, procedure, and situation of cesarean sections. Histopathological findings in CSD are fibrosis and adenomyosis, and chronic inflammation in the uterine and pelvic cavities decreases fertility in women with CSDi. Although the surgical procedures are not standardized, laparoscopic, hysteroscopic, and transvaginal surgeries are effective. Conclusion: The cause and pathology of CSDi are becoming clear. However, there is variability in the prevalence and treatment strategies. Therefore, it is necessary to conduct further studies using the same definitions.

Endometriosis: Cell Death and Cell Signaling Machinery.

Endometriosis is an estrogen-dependent disorder defined as the deposition and growth of endometrial tissue outside the uterus, including but not limited to the pelvic peritoneum, rectovaginal septum, and ovaries. Endometriosis is a substantial contributor to pelvic pain and subfertility and has been associated with an increased incidence of certain cancers, including ovarian. Appropriate treatment of endometriosis can reduce morbidity, but generally is used only to address symptoms, since no cure currently exists. Multifactorial etiologies for endometriosis have been proposed, with significant evidence for genetic, immune, and environmental causes. Recent advances suggest that molecular signaling and programmed cell death pathways are involved in endometriosis, suggesting avenues for future curative treatments. The goal of this review is to examine the pathologic processes of endometriosis, focusing on cell signaling and cell death pathways, stem cells, treatment regimens, and future directions surrounding this gynecologic disorder.

Bovine lactoferrin suppresses inflammatory cytokine expression in endometrial stromal cells in chronic endometritis.

Chronic endometritis (CE) is a type of chronic inflammation in the endometrium that is associated with infertility, which is primarily due to implantation failure. Antibiotics are the most common treatment for CE. However, some patients with CE are resistant to antibiotic treatment, while others refuse this treatment. Therefore, we focused on lactoferrin (Lf), which exhibits antimicrobial and anti-inflammatory properties, and studied its effect on inflammation in endometrial stromal cells (ESCs) from patients with CE. Endometrial tissue was collected from patients with CE, and ESCs were isolated and cultured. When ESCs were cultured with bovine lactoferrin (bLf: 1 mg/mL), the mRNA expression of TNF-α (p < 0.05) and IL-1ß (p < 0.01) was significantly decreased compared with that in cells cultured without bLf. The level of TNF-α protein in the culture medium was significantly decreased (p < 0.01), while that of IL-1ß was also decreased, but not significantly (p < 0.10), when 1 mg/mL of bLf was added to the culture medium. When more inflammation was induced artificially by adding 0.1 ng/mL of TNF-αto ESCs, the addition of bLf (1 mg/mL) to ESCs decreased IL-6 and IL-1ß mRNA expression to levels similar to those in ESCs without TNF-α treatment. Furthermore, it was revealed that the actions of bLf are mediated by the AKT and MAPK intracellular signaling pathways, which are mechanisms by which the increase in TNF-α-induced cytokine expression is suppressed in ESCs. bLf suppresses the expression of inflammatory cytokines in human ESCs and may be a new therapeutic candidate for CE.

The MEK1/2 Pathway as a Therapeutic Target in High-Grade Serous Ovarian Carcinoma.

High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to its high recurrence rate and acquired chemoresistance. RAS/MEK/ERK pathway activation is linked to cell proliferation and therapeutic resistance, but the role of MEK1/2-ERK1/2 pathway in HGSOC is poorly investigated. We evaluated MEK1/2 pathway activity in clinical HGSOC samples and ovarian cancer cell lines using immunohistochemistry, immunoblotting, and RT-qPCR. HGSOC cell lines were used to assess immediate and lasting effects of MEK1/2 inhibition with trametinib in vitro. Trametinib effect on tumor growth in vivo was investigated using mouse xenografts. MEK1/2 pathway is hyperactivated in HGSOC and is further stimulated by cisplatin treatment. Trametinib treatment causes cell cycle arrest in G1/0-phase and reduces tumor growth rate in vivo but does not induce cell death or reduce fraction of CD133+ stem-like cells, while increasing expression of stemness-associated genes instead. Transient trametinib treatment causes long-term increase in a subpopulation of cells with high aldehyde dehydrogenase (ALDH)1 activity that can survive and grow in non-adherent conditions. We conclude that MEK1/2 inhibition may be a promising approach to suppress ovarian cancer growth as a maintenance therapy. Promotion of stem-like properties upon MEK1/2 inhibition suggests a possible mechanism of resistance, so a combination with CSC-targeting drugs should be considered.

An abdominal-sacral approach with preoperative embolisation for vulvar solitary fibrous tumour: a case report.

BACKGROUND: Solitary fibrous tumours (SFTs) in the female genital tract are uncommon. Resection of these tumours is controversial because it can cause life-threatening haemorrhage. We report a case of vulvar SFT that was excised in a combined abdominal-sacral approach after preoperative embolisation. CASE PRESENTATION: At another hospital, an inoperable intrapelvic tumour was diagnosed in a 34-year-old woman. Computed tomography and magnetic resonance imaging showed that the uterus, urinary bladder and rectum were compressed laterally by a pelvic tumour with a maximum diameter of 11 cm. This mass was hypervascular and had a well-defined border. Transperineal biopsy was performed, and immunostaining revealed that the mass was an SFT. The tumour was supplied by feeding vessels from the right iliac arteries. First, we embolised the feeding vessels. Second, we performed surgical resection in a combined abdominal-sacral approach; no blood transfusion was necessary, and no perioperative complications occurred. The final pathological diagnosis was SFT that was positive for CD34 and signal transducer and activator of transcription 6 according to immunohistochemical staining. CONCLUSION: During a year of follow-up, the disease did not recur. Treatment of pelvic SFT should aim at complete resection through various approaches after careful measures are taken to prevent haemorrhage.

Premature ovarian insufficiency: pathogenesis and therapeutic potential of mesenchymal stem cell.

Primary ovarian insufficiency (POI) is defined as a reduction in ovarian function before the expected age of menopause. POI is known to increase the risk of cardiovascular disorders, osteoporosis, cognitive decline, and mood disorders, resulting in a reduced quality of life. Appropriate hormone replacement for premenopausal women decreases these adverse health risks and improves quality of life for women with POI, but does not prolong life expectancy. The potential etiologies of POI include chromosomal abnormalities and genetic mutations, autoimmune factors, and iatrogenic causes, including surgery, chemotherapy, and radiation therapy. A major association is suggested to exist between reproductive longevity and the DNA damage pathway response genes. DNA damage and repair in ovarian granulosa cells is strongly associated with POI. Depletion of oocytes with damaged DNA occurs through different cell death mechanisms, such as apoptosis, autophagy, and necroptosis, mediated by the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/forkhead transcription factors 3 (FOXO3) pathway. Mesenchymal stem cells (MSCs) are characterized by the ability of self-renewal and differentiation and play an important role in the regeneration of injured tissues. Transplantation of MSCs has been shown to functionally restore ovarian reserve in a POI mouse model. Recent advances in stem cell therapy are likely to be translated to new therapeutic options bringing new hope to patients with POI. The aim of this review is to summarize the pathogenic mechanisms that involve cell death and DNA damage and repair pathways and to discuss the stem cell-based therapies as potential therapeutic options for this gynecologic pathology.

The expression of hepatoma upregulated protein in human endometrium during the menstrual cycle.

AIMS: Human endometrium resists embryo implantation except during the window period. Currently, uterine HURP expression is known to be involved in endometrial stromal proliferation during embryo implantation of mice. Thus, we demonstrated hepatoma up-regulated protein (HURP) expression in the human endometrium during the menstrual cycle, as well as HURP regulation in endometrial stromal cells (ESCs). MATERIALS AND METHODS: We collected human endometrial samples from different menstrual cycle phases (early/late proliferative, and early/mid/late secretory), and then analyzed these samples by immunohistochemistry, reverse transcription-polymerase chain reaction, and Western blotting. We also assessed the effects of two sex-steroid hormones, 17ß-estradiol (E2) and 4-pregnene-3,20-dione (P4) on the cultured stromal cells. RESULTS: HURP protein was localized to the nucleus of the endometrial both epithelial and stromal cells in all stages. Also, HURP mRNA and protein in human endometrial tissue was significantly up-regulated during late-proliferative and secretory phase, compared with early-proliferative phase. In ESCs, HURP expression was regulated by E2, but not P4. CONCLUSIONS: We indicated that cyclic changes in HURP expression in human normal ESC strongly suggested up-regulation by estrogen. Taken together, since estrogen responses are fundamental in endometrial biology, uterine expression of HURP may be involved in female reproductive function during the menstrual cycle.

Bevacizumab-associated events in Japanese women with cervical cancer: a multi-institutional survey of Obstetrical Gynecological Society of Kinki district, Japan.

BACKGROUND: The development of perforations or fistulas in the Gastrointestinal (GI) tract or genitourinary (GU) system is a serious adverse effect of bevacizumab. The aim of this study was to investigate the incidences of these GI/GU events as well as their association with previous radiotherapy (RT) in Japanese women with cervical cancer. METHODS: We conducted a written questionnaire survey among 14 gynecological institutions belonging to the Oncology Research Committee of the Obstetrical and Gynecological Society of Kinki District, Japan. The severity of GI/GU events was classified according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0. All data were extracted from survey responses and maintained in an Excel spreadsheet and summarized using descriptive statistics. RESULTS: The information of 224 Japanese women with cervical cancer (152 recurrent and 72 advanced) who were treated with bevacizumab-containing chemotherapy was collected from 14 institutions. Of these, 65% had been previously treated with RT. GI/GU events of any grade developed in 25 (11.2%) patients, leading directly to death in 3 (1.3%) patients. When compared, the incidence of GI/GU events was higher in recurrent disease patients than in advanced disease patients (13.8% vs 5.6%, p = 0.0728). When examined according to the history of RT, the incidence of GI/GU events was greater in patients with a history of RT than in those without (14.5% vs 5.1%, p = 0.044). CONCLUSION: More than 10% of patients experience GI/GU events during or after receiving bevacizumab-containing chemotherapies. Prior RT is a risk factor for bevacizumab-associated GI/GU events.

Laparoscopic Hysterectomy for Benign Pathology Does Not Yield More Perioperative Complications than Abdominal or Vaginal Hysterectomies: Our Experience in Introducing Laparoscopic Hysterectomy.

OBJECTIVES: Total laparoscopic hysterectomy (TLH) is increasing as a substitute for total abdominal hysterectomy (TAH) and total vaginal hysterectomy (TVH) with the growing prevalence of laparoscopic surgery. The aim of this study is to assess perioperative complications of the chosen hysterectomy techniques performed for benign indications when started performing TLH. This was retrospective cohort study. This study was conducted at Nagahama City Hospital. MATERIALS AND METHODS: There were 176 patients who underwent hysterectomy for benign indications from 2013 to 2016. Perioperative and postoperative outcomes were compared for the three different hysterectomy approaches laparoscopic; abdominal; and vaginal. Data were analyzed using the t-test or Chi-square and Fisher's exact test. RESULTS: TAH, TLH, and TVH were performed on 118 patients (67.0%), 32 (18.2%), and 26 (14.8%), respectively. Operation time was significantly longer for the TLH group than for the TAH and TVH groups. Blood loss was lower for the TVH and TLH groups than for the TAH group. Three days after surgery, C-reactive protein was lower in the TVH group than in the TAH group. The average uterus size in the TAH group was larger than in the TVH and TLH groups. Patients undergoing TLH experienced fewer perioperative complications than patients in the TAH and TVH groups; however, this difference was not statistically significant. CONCLUSION: TLH for benign pathology does not yield more perioperative complications than TAH or TVH. However, vaginal hysterectomy is the least invasive approach. The final choice for the route of hysterectomy depends on many factors, including body mass index, uterus size, and experience of the gynecologist.

Pregnancy outcomes after hysteroscopic surgery in women with cesarean scar syndrome.

Cesarean scar defect often causes postmenstrual abnormal uterine bleeding, dysmenorrhea, chronic pelvic pain, and infertility, which are collectively known as cesarean scar syndrome (CSS). Several studies have reported that hysteroscopic surgery can restore fertility in women with CSS. The study aimed to identify factors that influence subsequent pregnancy following hysteroscopic surgery. Therefore, we studied 38 women with secondary infertility due to CSS who underwent hysteroscopic surgery at Shiga University of Medical Hospital between July 2014 and July 2019. Our hysteroscopic procedure included inferior edge resection and superficial cauterization of the cesarean scar defect under laparoscopic guidance. Patients were followed up for 3 to 40 months after surgery. Surgery was successful in all cases and no complications were observed. Twenty-seven patients (71%) became pregnant (pregnant group), while 11 (29%) did not (non-pregnant group). Baseline characteristics of age, body mass index, gravidity, parity, previous cesarean section, presence of endometriosis, retroflex uterus, and preoperative residual myometrial thickness were not significantly different between the groups. However, the median residual myometrium thickness was significantly higher after surgery than before surgery in the pregnant group (1.9 [1.1-3.6] vs 4.9 [3.4-6.6] mm, P<0.0001), whereas this difference was not significant in the non-pregnant group. Of those who became pregnant, 85% conceived within 2 years of surgery. Although three pregnancies resulted in abortion and one is ongoing at the time of writing, 23 pregnancies resulted in healthy babies at 35-38 gestational weeks by scheduled cesarean sections with no obstetrical complications due to hysteroscopic surgery. The average birth weight was 3,076 g. Our findings support that hysteroscopic surgery is a safe and effective treatment for secondary infertility due to CSS. The thickness of the residual myometrium may be a key factor that influences subsequent pregnancy in women with CSS.

Relationship of chronic endometritis with chronic deciduitis in cases of miscarriage.

BACKGROUND: The presence of chronic deciduitis (CD) was determined in patients diagnosed with or without chronic endometritis (CE) before pregnancy. OBJECTIVE: To study the effect of CE on decidua in cases of miscarriage. METHODS: Decidual tissue was obtained from the patients who miscarried at the first pregnancy within a year after the diagnosis of the presence or absence of CE. The number and distribution pattern of plasma cells stained with CD138 in decidual tissue in 10 high-power fields (HPFs) was examined. The prevalence of CD diagnosed with four different grade; grade 0, no plasma cell in 10 HPFs, thus Non-CD;grade 1, rare single plasma cells; grade 2, rare clusters or more than 5 single cells total; and grade 3, many plasma cells with more than 5 clusters, were examined and compared between Non-CE and CE. RESULTS: The incidence rate of CD of grade2 + 3 was significantly higher in CE than Non-CE (53.8%; 7/13 vs. 0%; 0/13, P < 0.01). Presence of clusters or a number of plasma cells in 10 HPFs of decidua showed a sensitivity of 53.8%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 68.4% for the diagnosis of CE. CONCLUSION: Presence of clusters of plasma cells or five or more of plasma cells in decidua was found in more than half of CE, but not found in Non-CE. When CD with cluster or five or more of plasma cells is confirmed histologically in miscarriage decidual tissue, the presence of CE before the pregnancy should be suspected.

Successful conservative treatment for massive uterine bleeding with non-septic disseminated intravascular coagulation after termination of early pregnancy in a woman with huge adenomyosis: case report.

BACKGROUND: Adenomyosis is a benign gynecological condition in which endometrial tissue or endometrial-like tissue develops within the uterine myometrium. Few cases of disseminated intravascular coagulation has been reported in the patients with adenomyosis. Although hysterectomy is indicated for refractory massive uterine bleeding in the patients with advanced uterine adenomyosis, conservative treatment is often desired in women in the late reproductive age. Recently such cases are increasing due to the social trend of late marriage. CASE PRESENTATION: A 37-year-old woman with huge adenomyosis, gravida 2 para 0, was referred to our hospital to terminate her pregnancy. Acute, non-septic, disseminated intravascular coagulation (DIC) developed after early pregnancy was terminated in a woman with huge adenomyosis. Massive bleeding and DIC occurred 3 days after the dilatation and curettage. There was no evidence of infection as the cause of the DIC, because neither bacteria nor endotoxin could be detected in her blood, and antithrombin 3 (AT3), which would be expected to decrease in septic patients, was not decreased. Hemorrhage in the adenomyotic tissue after the termination presumably developed inflammation, with numerous microthrombi and necrosis in the adenomyotic tissue, which subsequently promoted coagulation and fibrinolysis, leading to the onset of massive uterine bleeding and DIC. Although severe hyperfibrinolysis is observed in peripheral blood, the fibrinolysis state in the uterine myometrium is considered to be even more severe. The newly formed clots for hemostasis under the uterine mucosa could be removed due to the excessive activation of fibrinolytic system happened in the adjacent myometrium, leading to the onset of massive uterine bleeding. Massive bleeding and DIC resolved quickly after the patient was treated with nafamostat mesilate, which is effective for both excessive coagulation and fibrinolysis. CONCLUSIONS: Adenomyosis could cause massive bleeding and DIC when pregnancy is terminated. Massive bleeding was considered to occur because the excessive fibrinolysis system inside adenomyosis affected the adjacent endometrium. Before considering hysterectomy to control refractory uterine bleeding, nafamostat mesilate should be considered as one option, thinking the pathophysiology of the massive bleeding due to uterine adenomyosis.

Endometrial Immunity for Embryo Implantation and Pregnancy Establishment.

The uterus is an organ for raising the fetus, and its lumen is lined by the endometrium. The endometrium is an important site for the implantation and maturation of fertilized eggs. The endometrium undergoes repetitive proliferation, maturation (decidualization), and exfoliation changes every menstrual cycle. At the same time, the number and type of endometrial immunocompetent cells vary during the menstrual cycle. At the implantation stage, the immunocompetent cells occupy approximately half of the endometrial cells. Immunocompetent cells normally eliminate pathogenic microorganisms to protect the body; however, they also promote immune tolerance to accept the fetus during pregnancy. The immunocompetent cells in the uterus can perform both these functions. With the establishment of pregnancy, stimuli from the trophoblast (placenta) and fetus can also change the immune environment of the uterus, and pregnancy can be maintained only when the immune system is well adapted to the stimuli of some hormones and the fetus. Immunity for the establishment of pregnancy is not simple because multiple immunocompetent cells are involved in establishing and maintaining pregnancy. To understand the immune mechanisms associated with the establishment of pregnancy, we have to learn about each immune cell. This review, therefore, discusses the roles and distribution of the immunocompetent cells inside the uterus during menstruation and early pregnancy.

How to win the ovarian cancer stem cell battle: destroying the roots.

Ovarian cancer has the highest mortality rate among gynecologic malignancies. The combination of cytoreductive surgery and chemotherapy is the standard regimen for the treatment of ovarian cancer. The initial treatment is usually effective, but many patients with ovarian cancer experience recurrence, and treatment options for recurrent disease remain challenging. Cancer stem cells (CSCs) are suggested to play an essential role in cancer recurrence after initial chemotherapy. Furthermore, they are of great interest as CSCs may also be involved in chemotherapy susceptibility. Thus, understanding the characteristics and mechanisms by which CSCs display resistance to therapeutic agents is important to design effective cancer treatments. In this review, we describe and discuss current therapeutic regimens for ovarian cancer, as well as the various CSC markers, association between CSCs and disease progression, correlation of CSCs with poor prognosis, enrichment of CSCs in tumor tissues following repeated chemotherapy cycles, activation of major signaling pathways following chemotherapy, and potential inhibitors that suppress these signaling cascades. In addition, clinical trials evaluating novel targeted therapies to overcome chemotherapy resistance will be reviewed. The combination of traditional chemotherapy and CSC-targeted therapy could be an effective and promising anticancer treatment for ovarian cancer. Understanding the biological properties of CSCs and the mechanism of chemotherapy resistance are critical to design and develop new therapeutic strategies to overcome CSC-associated chemotherapy resistance.

Successful para-aortic lymph node dissection for endometrial cancer with horseshoe kidney: A case report and review of the literature.

Horseshoe kidney (HSK) is considered to impede para-aortic lymph node dissection. We report the case of a 54-year-old female patient with endometrial cancer and HSK, treated successfully with para-aortic lymph node dissection, and present literature review regarding vascular abnormalities associated with HSK affecting para-aortic lymph node dissection. Three-dimensional computed tomography reconstruction revealed the accessory renal artery, supernumerary renal vein and ventral displacement of the renal pelvis and ureter. Abdominal modified radical hysterectomy, bilateral salpingo-oophorec'tomy, pelvic and para-aortic lymph node dissection and omentectomy were then performed. Lymphadenectomy behind the isthmus of the kidney was performed without separation of the isthmus by lifting the kidneys with vessel tape. There were no intraoperative or postoperative complications. Grasping shifted ureter and complicated vascular network of HSK and securing the operative field without division of the isthmus were key to reducing complications and hemorrhage. This case report can serve as a guide for performing para-aortic lymph node dissection safely and effectively in patients with HSK.