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.

Comparison of postoperative adjuvant platinum-based chemotherapy and no further therapy after radical surgery in intermediate-risk early-stage cervical cancer.

OBJECTIVE: To identify a relatively high-risk population in postoperative intermediate-risk cervical cancer and evaluate the effect of platinum-based adjuvant chemotherapy (CT). METHODS: We retrospectively reviewed the medical records of patients with stage IA2-IIA cervical cancer who had been treated with radical hysterectomy and pelvic lymphadenectomy and classified as the intermediate-risk group for recurrence by postoperative pathological examination from January 2007 to December 2018 at 3 medical centers in Japan. First, patients with intermediate-risk were stratified by histological type and the number of intermediate-risk factors (IRF; large tumor diameter, lymph vascular space invasion, and deep cervical stromal invasion) and then divided into 2 groups: high and low-risk population (estimated 5-year recurrence-free survival [RFS] rate with no further therapy [NFT] <90% and ≥90%, respectively). Second, the efficacy of CT for the high-risk population was evaluated by comparing RFS and overall survival (OS) between the patients receiving CT and those with NFT. RESULTS: In total, 133 patients were included in the analysis. Among patients with squamous cell carcinoma (SCC) with all IRF or those with non-SCC with 2 to 3 IRF, the 5-year estimated RFS was <90% when treated with NFT. In this population, adjuvant CT was significantly superior to NFT regarding RFS (log-rank, p=0.014), although there was no statistical difference in OS. CONCLUSION: Patients with SCC with all 3 IRFs and those with non-SCC with 2 to 3 IRFs were at high risk for recurrence. Adjuvant CT is a valid treatment option for these populations.

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.

Effectiveness of an articulating laparoscopic needle holder for cesarean scar defect repair.

AIM: To evaluate the efficacy of an articulating laparoscopic needle holder in laparoscopic surgery for cesarean scar defect. METHODS: We performed a retrospective case-control study at the Shiga University of Medical Science. Patients who underwent laparoscopic uterine scar repair were divided into an articulating laparoscopic needle holder (ArtiSential®) group and a rigid needle holder (conventional) group to compare the suture and total operative times. Uterine myometrial suturing involves a double-layer interrupted suture, including a modified Gambee suture for the first layer. We measured the residual myometrial thickness using magnetic resonance imaging preoperatively and at 3 months postoperatively. RESULTS: Both groups comprised 10 patients each. The time per stitch for the first and second layers was significantly shorter in the ArtiSential group than in the conventional group (median 208 s vs. 403 s, p < 0.0001 and median 17 s vs. 29 s; p < 0.0001, respectively). The total operating time was significantly shorter in the ArtiSential group (mean 188 min vs. 240 min, p = 0.0015). The postoperative residual myometrial thickness (mean 9.1 mm in the ArtiSential group and 9.6 mm in the conventional group) was significantly higher than the preoperative residual myometrial thickness (mean 1.6 mm in the ArtiSential group and 1.6 mm in the conventional group) (p < 0.0001 in both groups). CONCLUSIONS: An articulating needle holder is useful in laparoscopic surgery for cesarean scar defect, especially when a modified Gambee suture is required.

Management of Pregnant Women with Mental Disorders Requires Attention to Gestational Diabetes Mellitus.

Background: Psychiatric interventions may be required during pregnancy. In the aspect of the management of psychiatric symptoms and the consideration of the need for pharmacotherapy, possibly to manage the effects on the fetus, pregnant women with mental disorders are considered high risk as other physical illnesses. Objective: We investigated the characteristics of pregnant women with psychiatric disorders compared with high-risk pregnant women with physical illnesses at our university hospital and the effects of psychotropic drug use on pregnant women with mental disorders and their children. Materials and Methods: In a multivariate analysis of 1282 pregnant women, excluding those with multiple pregnancies who gave birth at our hospital between January 2017 and the end of December 2019, we evaluated the effects of mental disorders and the use of psychotropic drugs throughout at least the third trimester up to the day of delivery on obstetric complications and infants. All data were collected retrospectively. Results: Ninety-nine pregnant women had mental disorders and 62 took psychotropic drugs. Among multiple factors, pregnant women with mental disorders were associated with significantly higher rates of smoking and gestational diabetes mellitus (GDM) and significantly lower child abnormalities. The cause or effect was difficult to determine; however, the use of antipsychotics or antidepressants was also significantly associated with GDM, while psychotropic use was not related to any of the other factors investigated in this study. Conclusions: Attention to GDM might be important in the management of pregnant women with mental disorders.

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.

Impact of administering umbilical cord-derived mesenchymal stem cells to cynomolgus monkeys with endometriosis.

Purpose: This study aimed to explore whether umbilical cord-derived mesenchymal stem cells (UC-MSCs) could be used as a therapeutic resource for endometriosis. Methods: Of seven cynomolgus monkeys with endometriosis, five were administered UC-MSCs (intervention group) and two were administered saline (control group). First, intravenous US-MSC treatment was administered for three months. Second, weekly intravenous US-MSC administration combined with monthly intraperitoneal US-MSC administration was conducted for 3 months. Finally, weekly intraperitoneal US-MSC administration was conducted for 3 months. The dose of UC-MSCs was set to 2 × 106 cells/kg for all administration routes. Laparoscopic findings and serum cancer antigen 125 (CA125) levels were also evaluated. The Revised American Society for Reproductive Medicine classification was used for laparoscopic evaluation. Results: Laparoscopic findings showed exacerbation of endometriosis after intraperitoneal UC-MSC administration, although no changes were observed in the control group. Intravenous UC-MSC administration decreased the level of CA125 in all monkeys; however, the difference was not significant. Intraperitoneal UC-MSC administration significantly exacerbated endometriosis compared with intravenous administration (p = 0.02). Conclusions: This study revealed that intraperitoneal UC-MSC administration exacerbates endometriosis in a nonhuman primate model of the disease.

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.

Amniotic fluid interleukin-6 and neutrophil gelatinase-associated lipocalin for predicting fetal inflammatory response syndrome based on histological chorioamnionitis and funisitis.

OBJECTIVE: We aimed to analyze the predictive efficacy of amniotic fluid interleukin-6 (IL-6) and neutrophil gelatinase-associated lipocalin (NGAL) for fetal inflammatory response syndrome (FIRS)-related infection. MATERIALS AND METHODS: We included singleton pregnancies classified into FIRS and non-FIRS groups. FIRS was defined as histologic chorioamnionitis and funisitis. Amniotic fluid samples were collected during vaginal delivery (VD) or cesarean section (CS). We compared amniotic fluid IL-6 and NGAL levels between the groups. RESULTS: Forty-six pregnancies were analyzed and classified into 20 (43.5%) FIRS and 26 (56.5%) non-FIRS pregnancies. We observed significant differences in amniotic fluid IL-6 and NGAL. Amniotic fluid collection significantly influenced NGAL levels (p < 0.001). The area under the concentration-time curve (AUC), with optimal cutoff values, for amniotic fluid IL-6 and NGAL (VD and CS) levels was 0.948 (11,344 pg/mL), 0.800 (1180 ng/mL), and 0.946 (708 ng/mL), respectively. CONCLUSION: Amniotic fluid IL-6 and NGAL levels showed equivalent predictive ability for FIRS-related infection.

The efficacy of adjuvant chemotherapy on the survival of early stage endometrial cancer.

OBJECTIVE: No consensus exists on the adjuvant chemotherapy for the International Federation of Gynecology and Obstetrics (FIGO) Stage I-II endometrial cancer with risk factors for recurrence. This study evaluated adjuvant chemotherapy's efficacy in improving these patients' survival. STUDY DESIGN: We conducted a retrospective chart review of patients with FIGO Stage I-II endometrial cancer with recurrence risk factors. The patients received no adjuvant therapy at the National Cancer Center Hospital (NCCH) but received platinum-based chemotherapy at Shiga University of Medical Science (SUMS). RESULTS: Six hundred thirty-eight patients with endometrial cancer were identified. Of these, 118 met the inclusion criteria, 321 were excluded from NCCH, while 49 met the inclusion criteria, and 150 were excluded from SUMS. Multivariate analyses of age, surgery, para-aortic lymphadenectomy, omentectomy, histological type, myometrial invasion, cervical stromal invasion, and adjuvant therapy revealed that in patients aged > 60 years with type II histology, the outer half of myometrial invasion, cervical stromal invasion, and positive peritoneal cytology had significantly worse recurrence-free survival (RFS) rates, and patients aged > 60 years with type II histology, outer half of myometrial invasion, and positive peritoneal cytology had significantly worse overall survival (OS) rates. Patients that received adjuvant chemotherapy showed equivalent effects on RFS (hazard ratio [HR] = 2.13; 95% confidence interval [CI] = 0.82-5.53) and worse on OS ([HR = 5.20; 95 %CI = 1.26-21.50) than patients who did not. CONCLUSION: This study did not show that adjuvant chemotherapy for FIGO Stages I-II endometrial cancer with recurrence risk factors has survival benefit. Further large-scale studies are necessary to validate our findings.

Indication Criteria of Hysteroscopic Surgery for Secondary Infertility due to Symptomatic Cesarean Scar Defect Based on Clinical Outcomes: A Retrospective Cohort Study.

STUDY OBJECTIVE: Hysteroscopic surgery criteria for patients with cesarean scar defect (CSD) are unclear. Therefore, this study aimed to explore the indication of hysteroscopic surgery for secondary infertility owing to CSD. DESIGN: Retrospective cohort study. SETTING: Single university hospital. PATIENTS: Seventy patients with secondary infertility owing to symptomatic CSD who underwent hysteroscopic surgery under laparoscopy between July 2014 and February 2022 were included. INTERVENTIONS: Clinical data, including basic patient information, preoperative residual myometrial thickness (RMT), and postoperative pregnancy status, were collected from medical records. Patients were divided into postoperative pregnancy and nonpregnancy groups. A receiver operating characteristic curve was drawn, and the optimal cutoff value was calculated based on the area under the curve to predict pregnancy after hysteroscopic surgery. MEASUREMENTS AND MAIN RESULTS: No complications were observed in any cases. Among the 70 patients, 49 patients (70%) became pregnant after hysteroscopic surgery. There was no significant difference in patient characteristics between the pregnancy and nonpregnancy groups. In the receiver operating characteristic curve analysis for patients aged <38 years, the value of the area under the curve was 0.77 (sensitivity, 0.83; specificity, 0.78) when optimal cutoff of RMT was 2.2 mm. There was a significant difference in preoperative RMT between the pregnancy and nonpregnancy groups (3.3 mm and 1.7 mm, respectively) in patients aged <38 years. CONCLUSION: For RMT ≥2.2 mm, hysteroscopic surgery was reasonable for secondary infertility owing to symptomatic CSD, particularly in patients aged <38 years.

Transanal total mesorectal excision for primary rectovaginal carcinosarcoma: A case report and literature review.

We report a case of rectovaginal septum carcinosarcoma successfully treated with surgical excision via transanal total mesorectal excision following platinum-based neoadjuvant chemotherapy. A 48-year-old woman presented with a 3-week defecation pain preceding the visit. Pelvic imaging showed an 8-cm sized lesion in the lower rectovaginal septum. Transvaginal biopsy and immunohistochemical analysis were performed. After three courses of carboplatin-paclitaxel-bevacizumab therapy, the mass reduced by half. Subsequently, laparoscopic excision with transanal total mesorectal excision, and radical hysterectomy were performed. The anus was preserved, and dysuria improved within a month. The final histopathological diagnosis was carcinosarcoma of the rectovaginal septum from an uncertain origin, presumably endometriotic or mesonephric. Twelve months following surgery, solitary liver metastasis was confirmed; however, there was no evidence of local recurrence. Total mesorectal excision following platinum-based neoadjuvant chemotherapy may be an ideal treatment for gynecological malignancies in the rectovaginal septum, especially for large tumors localized deep into the pelvis.

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.

Decreased Fertility in Women with Cesarean Scar Syndrome Is Associated with Chronic Inflammation in the Uterine Cavity.

Chronic inflammation in cesarean scar defect contributes to secondary infertility in women with cesarean scar syndrom; however, it remains unclear about the situation of inflammation in uterine cavity in women with cesarean scar syndrome. This ambidirectional cohort study aimed to explore the effect of inflammation in the uterine cavities of women with cesarean scar syndrome on infertility at a single university hospital. The frequency of chronic endometritis in infertile patients was retrospectively compared between the cesarean scar syndrome group and non-cesarean scar syndrome group. The frequency of endometriosis was also investigated in patients with cesarean scar syndrome who underwent laparoscopy. The level of tumor necrosis factor-α and interleukin-1ß in the uterine cavity was prospectively evaluated in the cesarean scar syndrome group and in women with a history of cesarean section (control group) using an enzyme-linked immunosorbent assay. There was a significant difference in the incidence of chronic endometritis between the cesarean scar syndrome and non-cesarean scar syndrome groups (65.8% and 46.0%, respectively, p = 0.0315). Endometriosis was detected in 51 (70%) patients with laparoscopy. Tumor necrosis factor-α and interleukin-1ß levels in the cesarean scar syndrome group were significantly higher than those in the control group (p = 0.0002 and p = 0.0217, respectively). Our findings suggest that one cause of secondary infertility in women with cesarean scar syndrome is embryo implantation failure-associated chronic endometritis, endometriosis, and chronic inflammation in the uterine cavity.

Histopathological evaluation of cesarean scar defect in women with cesarean scar syndrome.

Purpose: To explore the histopathological findings of cesarean scar defect (CSD) and the immunological component in women with cesarean scar syndrome (CSS). Methods: This retrospective study was conducted in a university hospital and a public hospital. A total of 63 patients with secondary infertility due to CSS who underwent laparoscopic resection of the CSD lesion were enrolled (CSS group), and 21 patients who underwent hysterectomy with a history of cesarean section were enrolled as control (non-CSS group). We compared the differences in histopathological findings of CSD lesions by hematoxylin and eosin staining and immunohistochemistry for CD3, CD20, CD56, CD68, CD138, myeloperoxidase, and tryptase between the two groups. Results: The frequency of presence of endometrium on the CSD surface was significantly lower (p = 0.0023) and that of adenomyosis was significantly higher (p = 0.0195) in the CSS group than in the non-CSS group. The number of CD3-, CD20-, CD68-, and tryptase-positive cells was significantly lower in the CSS group than in the non-CSS group; however, the number of CD138-positive cells was significantly higher in the CSS group (p = 0.0042). Conclusions: This study suggested that the absence of endometrium, presence of adenomyosis, and chronic inflammation in CSD contributes to secondary infertility due to CSS.

Current Overview of Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI), or brittle bone disease, is a heterogeneous disorder characterised by bone fragility, multiple fractures, bone deformity, and short stature. OI is a heterogeneous disorder primarily caused by mutations in the genes involved in the production of type 1 collagen. Severe OI is perinatally lethal, while mild OI can sometimes not be recognised until adulthood. Severe or lethal OI can usually be diagnosed using antenatal ultrasound and confirmed by various imaging modalities and genetic testing. The combination of imaging parameters obtained by ultrasound, computed tomography (CT), and magnetic resource imaging (MRI) can not only detect OI accurately but also predict lethality before birth. Moreover, genetic testing, either noninvasive or invasive, can further confirm the diagnosis prenatally. Early and precise diagnoses provide parents with more time to decide on reproductive options. The currently available postnatal treatments for OI are not curative, and individuals with severe OI suffer multiple fractures and bone deformities throughout their lives. In utero mesenchymal stem cell transplantation has been drawing attention as a promising therapy for severe OI, and a clinical trial to assess the safety and efficacy of cell therapy is currently ongoing. In the future, early diagnosis followed by in utero stem cell transplantation should be adopted as a new therapeutic option for severe OI.

Case of adenomyosis causing the activation of the coagulation system after a complete loss of endometrium following microwave endometrial ablation.

The formation of microbleed and minute tissue necrosis inside adenomyosis after the shedding of endometrial or endometrial-like tissue within the myometrium during menstruation is receiving attention as a new pathological condition of uterine adenomyosis. These formations might greatly affect coagulation and fibrinolysis function. However, these modulations might occur due to indirect effects of massive hemorrhage from the uterus with adenomyosis. We present a case of adenomyosis in which the patient's coagulation system was markedly activated despite the absence of menstruation due to previous microwave endometrial ablation to prevent massive uterine hemorrhage. Although no uterine bleeding was observed at all, the patient's serum levels of thrombin-antithrombin complex and soluble fibrin were abnormally elevated at the time when she complained of lower abdominal pain. As the first such case in the world, the present case is valuable for showing that the coagulation function can be modified by uterine adenomyosis.

Amniotic fluid neutrophil gelatinase-associated lipocalin and L-type fatty acid-binding protein in predicting fetal inflammatory response syndrome.

AIM: To analyze the effectiveness of amniotic fluid neutrophil gelatinase-associated lipocalin and L-type fatty acid-binding protein as predictive factors for fetal inflammatory response syndrome. METHODS: We classified single pregnancy cases into the fetal inflammatory response syndrome and nonfetal inflammatory response syndrome groups. We collected amniotic fluid at vaginal delivery and cesarean section and compared the patient characteristics, maternal white blood cell count, C-reactive protein level, and amniotic fluid interleukin-6; neutrophil gelatinase-associated lipocalin; and L-type fatty acid-binding protein levels between the groups. We further analyzed the relationship between L-type fatty acid-binding protein levels and neonatal clinical outcomes. RESULTS: We analyzed 129 pregnancies, of which 36 and 93 (27.9% and 72.1%, respectively) were classified into the fetal inflammatory response syndrome and nonfetal inflammatory response syndrome groups, respectively. We observed significant differences in the maternal white blood cell counts and amniotic fluid interleukin-6 and neutrophil gelatinase-associated lipocalin levels. On the multivariate analysis, the useful predictive factors were maternal white blood cell count and amniotic fluid interleukin-6 and neutrophil gelatinase-associated lipocalin levels. Furthermore, the level of L-type fatty acid-binding protein was significantly higher in the transient tachypnea of the newborn and postnatal respiratory support group than in the control group. CONCLUSIONS: The maternal white blood cell count and amniotic interleukin-6 and neutrophil gelatinase-associated lipocalin levels were effective predictors of fetal inflammatory response syndrome. Amniotic fluid L-type fatty acid-binding protein level was an effective predictor of neonatal respiratory support.