Imiquimod for vaginal intraepithelial neoplasia 2-3: A systematic review and meta-analysis.

OBJECTIVE: The treatment strategy for vaginal intraepithelial neoplasia (VaIN) 2-3 has not been established. This study aimed to investigate the efficacy of imiquimod in VaIN 2-3. METHODS: Electronic databases (PubMed, EMBASE, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials) were searched from their inception until October 2019 and articles reporting imiquimod treatment for VaIN 2-3 were extracted. Additionally, the clinical records of women with VaIN 2-3 who had been treated with imiquimod in Shizuoka General Hospital from January 2016 to May 2020 were investigated. The data from the systematic search and the data from our hospital were analyzed, and a pooled complete response (CR) rate and response rate of imiquimod treatment for VaIN 2-3 were estimated. As a subgroup analysis, the CR rates and response rates were compared between women with and without a history of hysterectomy, and the rate ratio was calculated. RESULTS: Five articles described 28 women with VaIN 2-3 who underwent imiquimod treatment, and nine women with VaIN 2-3 were treated with imiquimod in our hospital. The discontinuation of the treatment was required in only one patient of the reported cases. The pooled CR rate and response rate of imiquimod, regardless of a history of hysterectomy, was 0.76 (95% CI, 0.59-0.87) and 0.89 (95% CI, 0.71-0.97), respectively. In the subgroup analysis, the CR rate in patients with hysterectomy was 0.98 (95% CI, 0.11-1.0) and in those without hysterectomy was 0.60 (95% CI, 0.30-0.84), and the rate ratio was 0.83 (95% CI, 0.48-1.19). The pooled response rates with and without a history of hysterectomy were not estimated, and the rate ratio was 0.83 (95% CI, 0.54-1.09). CONCLUSION: Imiquimod can be an effective treatment for vaginal intraepithelial neoplasia 2-3.

Hepatocyte nuclear factor-1ß (HNF-1ß) promotes glucose uptake and glycolytic activity in ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (OCCC) is a morphologically and biologically distinct subtype of ovarian carcinomas that often arises in ovarian endometriosis. We previously reported that a unique carcinogenic environment, especially iron-induced oxidative stress in endometriotic cysts may promote development of OCCC. We also identified a gene expression profile characteristic of OCCC (the "OCCC signature"). This 320-gene OCCC signature is enriched in genes associated with stress response and sugar metabolism. However, the biological implication of this profile is unclear. In this study, we have focused on the biological role of the HNF-1ß gene within the OCCC signature, which was previously shown to be overexpressed in OCCC. Suppression of HNF-1ß in the HNF-1ß-overexpressing human ovarian cancer cell line RMG2 using short hairpin RNA resulted in a significant increase in proliferation. It also facilitated glucose uptake, glycolytic activity, and lactate secretion along with increased expression of the glucose transporter-1 (GLUT-1) gene and several key enzymes in the glycolytic process. Conversely, forced expression of HNF-1ß in the serous ovarian cancer cell line, Hey, resulted in slowed cellular growth and repressed glycolytic activity. These data suggest that HNF-1ß represses cell growth, and at the same time, it promotes aerobic glycolysis which is known as the "Warburg effect." As the Warburg effect is regarded as a characteristic metabolic process in cancer which may contribute to cell survival under hypoxic conditions or in a stressful environment, overexpression of HNF-1ß may play an inevitable role in the occurrence of OCCC in stressful environment.

Efficacy and safety of bivalent RSVpreF maternal vaccination to prevent RSV illness in Japanese infants: Subset analysis from the pivotal randomized phase 3 MATISSE trial.

BACKGROUND: Maternal vaccination with respiratory syncytial virus prefusion F vaccine (RSVpreF) is effective at preventing RSV-associated lower respiratory tract illness (LRTI) in newborns/infants. METHODS: This subgroup analysis from the global, phase 3, randomized, double-blind, placebo-controlled MATISSE (Maternal Immunization Study for Safety and Efficacy) trial evaluated participants enrolled in Japan. Pregnant women 24-36 weeks' gestation were randomized 1:1 to receive RSVpreF or placebo. Maternal safety endpoints included local reactions/systemic events within 7 days, adverse events (AEs) through 1 month, and serious AEs (SAEs) through 6 months after vaccination. In infants born to maternal participants, safety endpoints included specific birth outcomes, AEs through 1 month after birth, and SAEs and newly diagnosed chronic medical conditions through 12 or 24 months after birth. Vaccine efficacy in infants was assessed against RSV-positive, medically attended LRTI (RSV-MA-LRTI) and severe RSV-MA-LRTI through 180 days after birth. RESULTS: In Japan, 230 maternal participants received RSVpreF and 232 received placebo; 218 and 216 infants born to these mothers, respectively, were analyzed. Observed vaccine efficacy (95 % CIs) against infant RSV-MA-LRTI within 90 and 180 days after birth was 100.0 % (30.9, 100.0; RSVpreF, 0 cases; placebo, 7 cases) and 87.6 % (7.2, 99.7; RSVpreF, 1 case; placebo, 8 cases), respectively. Vaccine efficacy (95 % CIs) against severe RSV-MA-LRTI within 90 and 180 days was 100.0 % (-140.9, 100.0; RSVpreF, 0 cases; placebo, 3 cases) and 75.1 % (-151.5, 99.5; RSVpreF, 1 case; placebo, 4 cases), respectively. No safety concerns were identified. AE rates ≤1 month after vaccination/birth were similar in the RSVpreF (maternal, 16.1 %; infant, 48.6 %) and placebo (19.8 %; 50.5 %) groups. Preterm birth rates were also similar (RSVpreF, 3.2 %; placebo, 6.0 %). CONCLUSIONS: Safety and efficacy data in Japanese participants were consistent with overall MATISSE results, supporting the efficacy of maternal RSVpreF vaccination against severe MA-RSV-LRTI/MA-RSV-LRTI in infants, with no safety concerns. NCT04424316.

Endometrial Cancer Diagnosed at an Early Stage during Lynch Syndrome Surveillance: A Case Report.

Lynch syndrome is an autosomal dominant inherited disorder caused by a germline pathogenic variant in DNA mismatch repair genes, resulting in multi-organ cancer. Annual transvaginal ultrasonography and endometrial biopsy are recommended for endometrial cancer surveillance in patients with Lynch syndrome in several guidelines; however, evidence is limited. Here, we present the case of a 51-year-old woman with endometrial cancer who underwent robot-assisted laparoscopic simple hysterectomy at an early stage detected by Lynch syndrome surveillance. The patient was a 51-year-old gravida zero woman without any medical history or symptoms. Her sister suffered from bladder, breast, rectal, and endometrial cancer and was diagnosed with Lynch syndrome using a hereditary cancer panel test (VistaSeq®). During gynecologic surveillance, the patient's endometrial cytology was classified as Papanicolaou class III. Therefore, she underwent endometrial curettage with hysteroscopy and was diagnosed with atypical endometrial hyperplasia. Robot-assisted hysterectomy was performed with a final pathological diagnosis of endometrial cancer (endometrioid carcinoma, Grade 1), stage 1A. She has remained disease-free for more than 12 months. Owing to advances in genetic medicine, prophylactic and therapeutic surgeries for hereditary cancers are increasing. To achieve an early diagnosis and treatment of Lynch syndrome-associated cancers, the importance of Lynch syndrome surveillance should be more widely recognized.

Imiquimod for Cervical and Vaginal Intraepithelial Neoplasia: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate the treatment efficacy and the risk of adverse events of imiquimod for cervical intraepithelial neoplasia (CIN) and vaginal intraepithelial neoplasia (VAIN), compared with placebo or no intervention. DATA SOURCES: We searched Cochrane, PubMed, ISRCTN registry, ClinicalTrials.gov , and the World Health Organization International Clinical Trials Registry Platform up to November 23, 2022. METHODS OF STUDY SELECTION: We included randomized controlled trials and prospective nonrandomized studies with control arms that investigated the efficacy of imiquimod for histologically confirmed CIN or VAIN. The primary outcomes were histologic regression of the disease (primary efficacy outcome) and treatment discontinuation due to side effects (primary safety outcome). We estimated pooled odds ratios (ORs) of imiquimod, compared with placebo or no intervention. We also conducted a meta-analysis of the proportions of patients with adverse events in the imiquimod arms. TABULATION, INTEGRATION, AND RESULTS: Four studies contributed to the pooled OR for the primary efficacy outcome. An additional four studies were available for meta-analyses of proportions in the imiquimod arm. Imiquimod was associated with increased probability of regression (pooled OR 4.05, 95% CI 2.08-7.89). Pooled OR for CIN in the three studies was 4.27 (95% CI 2.11-8.66); results of one study were available for VAIN (OR, 2.67, 95% CI 0.36-19.71). Pooled probability for primary safety outcome in the imiquimod arm was 0.07 (95% CI 0.03-0.14). The pooled probabilities (95% CI) of secondary outcomes were 0.51 (0.20-0.81) for fever, 0.53 (0.31-0.73) for arthralgia or myalgia, 0.31 (0.18-0.47) for abdominal pain, 0.28 (0.09-0.61) for abnormal vaginal discharge or genital bleeding, 0.48 (0.16-0.82) for vulvovaginal pain, and 0.02 (0.01-0.06) for vaginal ulceration. CONCLUSION: Imiquimod was found to be effective for CIN, whereas data on VAIN were limited. Although local and systemic complications are common, treatment discontinuation is infrequent. Thus, imiquimod is potentially an alternative therapy to surgery for CIN. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42022377982.

Adenoid cystic carcinoma of skene glands: a rare origin in the female genital tract and the characteristic clinical course.

Adenoid cystic carcinoma (ACC) is a relatively uncommon malignancy that most frequently arises in the salivary glands. In the genital tract, approximately 60 cases of ACC that originated from Bartholin glands have been reported to date. In this report, we describe a case of ACC that arose from Skene glands, a very rare origin for this disease. In this patient, the disease had an indolent clinical course, with few symptoms other than localized pain. During the surgical operation, the tumor was found to have invaded more extensively than had been estimated preoperatively, and it required pelvic exenteration with radical vulvectomy. Although the precise preoperative assessment and the preparation for an extended operation are difficult, they are necessary for the successful treatment of this rare disease.

Olaparib-induced cutaneous side effects in a patient with recurrent ovarian cancer.

Over the past decade, the treatment of ovarian cancer has been revolutionised by poly(ADP-ribose polymerase (PARP)) inhibitors. Based on the results from clinical trials, olaparib, a PARP inhibitor, is indicated for use in the first-line treatment for patients with BRCA gene mutations, and as a maintenance treatment in platinum-sensitive relapsed ovarian cancer after a complete or partial response to platinum-based chemotherapy. Although PARP inhibitors have been shown to be well tolerated, adverse side effects can affect the quality of life of patients and lead to the discontinuation of therapy. Here, we report a case of dermatosis of the left dorsal hand as a rare adverse side effect of olaparib. Dermatological adverse side effects may become the crux of a clinical problem that requires the cooperation of professionals in many fields.

Validity of Weekly Administration of Carboplatin after Carboplatin-Induced SIADH: Two Case Reports and Literature Review.

Chemotherapy-induced severe hyponatremia is a life-threatening condition. Platinum-based agents play a key role in ovarian cancer treatment but are more likely to cause hyponatremia than other anticancer agents. The optimal strategy for treating ovarian cancer in cases of severe platinum agent-induced hyponatremia remains unclear. We encountered 2 patients with ovarian cancer who developed syndrome of inappropriate antidiuretic hormone secretion (SIADH) after chemotherapy with involved carboplatin. Case 1 was a recurrent ovarian clear-cell carcinoma with peritoneal dissemination, and the patient developed severe hyponatremia due to SIADH on day 5 after receiving triweekly docetaxel and carboplatin (DC) therapy. The chemotherapy regimen was changed to weekly DC therapy, and she completed six cycles of regimen without electrolyte disturbance or tumor recurrence. Case 2 was a newly diagnosed advanced high-grade serous ovarian carcinoma, stage IIIC, with a BRCA1 mutation. She developed SIADH on day 8 after receiving triweekly paclitaxel and carboplatin (TC) therapy as adjuvant therapy after primary debulking surgery. The regimen was changed to weekly TC therapy, and she completed the schedule of chemotherapy without electrolyte disturbance and transitioned to maintenance therapy with a PARP inhibitor. In conclusion, weekly carboplatin administration might be a promising alternative to triweekly carboplatin administration after the development of carboplatin-induced SIADH.

Risk Factors for Septic Shock After Irinotecan-Containing Chemotherapy: An Exploratory Case-Control Study.

BACKGROUND AND OBJECTIVES: Irinotecan sometimes causes lethal septic shock but the risk factors remain unclear. This retrospective case-control study explored the potential risk factors for septic shock following irinotecan treatment. METHODS: All women who received irinotecan-containing chemotherapy for gynecologic malignancies at Shizuoka General Hospital from October 2014 to September 2020 were investigated. The clinical backgrounds and blood test results of those who developed septic shock after irinotecan-containing chemotherapy were compared with those who did not. Odds ratios (ORs) for developing septic shock after receiving irinotecan were calculated with 95% confidence intervals (CIs), using univariable logistic regression analysis. RESULTS: During the study period, 147 women received irinotecan-containing chemotherapy. Three women developed septic shock due to neutropenic enterocolitis after irinotecan treatment, and 144 did not. The three patients with septic shock had recurrent cervical cancer, heterozygous variants in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene (two patients had *1/*6, one had *1/*28 variants), a history of concurrent chemoradiation therapy, 50-60 Gy of pelvic irradiation, and platinum-combined chemotherapy. A history of pelvic irradiation was identified as a possible risk factor for developing septic shock after irinotecan-containing chemotherapy (OR 63.0, 95% CI 5.71-8635; p < 0.001). The OR of UGT1A1 polymorphism for septic shock was 9.09 (95% CI 0.86-1233; p = 0.070) in the complete case analysis. CONCLUSION: Medical personnel involved in cancer therapy should consider the possible risk of septic shock developing due to neutropenic enterocolitis when administering irinotecan-containing chemotherapy in patients with a history of pelvic irradiation.

A Case of Uterine Lymphangioleiomyomatosis Complicated by Tuberous Sclerosis Complex.

Lymphangioleiomyomatosis (LAM) is one of the presentations of perivascular epithelioid cell neoplasm that is frequently complicated by tuberous sclerosis complex (TSC). Here, we report an uncommon case of uterine LAM treated with everolimus, which is a mechanistic target of rapamycin (mTOR) inhibitor. A 42-year-old female patient (gravida 0) with a history of TSC presented with abdominal pain. Pelvic magnetic resonance imaging showed multiple masses in the uterine myometrium, suggesting tumors that may contain internal hemorrhagic components. The lesions were suspected as the root cause of her symptoms. After everolimus was administered for a previously diagnosed renal angiolipoma, her uterine tumors temporarily decreased in size. Subsequently, laparoscopic hysterectomy and bilateral salpingectomy were performed since she could not tolerate everolimus for a long period due to the medication's side effects. Furthermore, the patient was diagnosed with LAM through histopathological examination after surgical resection. Therefore, it is advisable to suspect and investigate uterine LAM when a patient with a history of TSC presents with irregular genital bleeding or abdominal pain. Moreover, mTOR inhibitors may be a treatment option, in addition to surgery, in cases of uterine LAM exacerbation.

Lower systolic blood pressure levels in early pregnancy are associated with a decreased risk of early-onset superimposed preeclampsia in women with chronic hypertension: a multicenter retrospective study.

To clarify the impact of blood pressure (BP) management ranges on pregnancy outcomes, we conducted a multicenter retrospective analysis of 215 women with singleton pregnancies diagnosed with essential hypertension either before or within 14 weeks of gestation. Patients were classified according to systolic BP (sBP; <130, 130-139, 140-159, and ≥160 mmHg) or diastolic BP (dBP; <80, 80-89, 90-109, and ≥110 mmHg) at 8-11, 12-15, and 16-19 weeks of gestation. The risk of early-onset superimposed preeclampsia and small-for-gestational-age neonates was assessed in each BP group. Moreover, a subgroup analysis was performed in 144 eligible patients whose BP was measured at both 12-13 and 14-15 weeks of gestation. At 16-19 weeks of gestation, higher sBP significantly increased the incidence of early-onset superimposed preeclampsia (13.3%, 24.6%, 32.2% and 75.0%, respectively) and small-for-gestational-age neonates (6.0%, 13.1%, 16.9% and 50.0%, respectively). Multivariate logistic regression analyses showed that women with sBP < 130 mmHg at 16-19 weeks of gestation had a significantly lower risk of early-onset superimposed preeclampsia than women with sBP of 140-159 mmHg. Subgroup analyses also showed that even at 14-15 weeks of gestation, sBP < 130 mmHg was associated with a significantly lower risk of early-onset superimposed preeclampsia than an sBP of 140-159 mmHg. In conclusion, sBP < 130 mmHg within 14 weeks of gestation reduced the risk of developing early-onset superimposed preeclampsia in women with chronic hypertension.

The comprehensive assessment of local immune status of ovarian cancer by the clustering of multiple immune factors.

The aim of this study was to evaluate the local immune status of human ovarian cancers by the comprehensive analysis of tumor-infiltrating immune cells and immunosuppressive factors, and to elucidate the local immunity in clinical course. The numbers of CD1α+, CD4+, CD8+, CD57+, forkhead box P3+ and programmed cell death-1+ cells were counted, and the intensity of immunosuppressive factors, such as programmed cell death-1 ligand (PD-L)1, PD-L2, cyclooxygenase (COX)-1, COX-2 and transforming growth factor ß1, were evaluated in 70 ovarian cancer specimens stained by immunohistochemistry. Then hierarchical clustering of these parameters showed the four clusters into ovarian cancer cases. Cluster 1, which had significantly better prognosis than the others, was characterized by high infiltration of CD4+ and CD8+ cells. In conclusion the comprehensive analysis of local immune status led to subdivide ovarian cancers into groups with better or worse prognoses and may guide precise understanding of the local immunity.

Pregnancy and delivery in women receiving maintenance hemodialysis in Japan: analysis of potential risk factors for neonatal and maternal complications.

INTRODUCTION: Average dialysis vintage in Japan is among the longest in the world, providing a unique opportunity to characterize pregnancy under conditions of long dialysis vintage. In 2017, we carried out a nationwide survey following up on a similar survey in 1996, in which we investigated the prevalence and outcomes of pregnancy in women undergoing dialysis and assessed risk factors associated with neonatal and maternal complications. METHODS: The target population was women aged 15-44 years undergoing maintenance dialysis between 2012 and 2016. The survey was conducted in 2693 dialysis units. RESULTS: A response was obtained from 951 dialysis units, yielding a target population of 1992 women of childbearing age receiving hemodialysis or peritoneal dialysis. Pregnancy occurred only among women receiving hemodialysis, with 25 pregnancies (1.26% in 5 years) being reported for 20 women. Detailed information about 19 pregnancies (mean age 34.6 ± 5.7 years at conception, mean dialysis vintage 8.4 ± 7.3 years) indicated 4 spontaneous abortions, 1 elective abortion, no neonatal deaths, and 14 surviving infants, including 5 full-term (≥ 37 weeks at birth), 2 late preterm (34-36), and 3 extremely preterm (< 28) cases. Neonatal complications occurred in the offspring of 3 mothers who had end-stage renal disease (ESRD) caused by primary glomerulonephritis and serum albumin levels (sAlb) ≤ 3.2 mg/dL in the first trimester. These mothers had started dialysis at 12, 17, and 30 years of age. ESRD caused by diabetic nephropathy or primary glomerulonephritis, age at conception ≥ 38 years, and sAlb ≤ 3.2 mg/dL were associated with maternal complications, although not significantly. CONCLUSIONS: In this study, the pregnancy rate of Japanese women with ESRD was 0.25% per year. The study generates the hypothesis that ESRD caused by diabetic nephropathy and age at conception ≥ 38 years are potential risk factors for maternal complications but not for neonatal complications in dialysis patients, and that hypoalbuminemia is a potential risk factor for both kinds of complications.

Recurrent vaginal intraepithelial neoplasia successfully treated with topical imiquimod: A case report.

Vaginal intraepithelial neoplasia (VAIN) is a rare disease associated with human papillomavirus infection. High-grade VAIN is typically treated with either excisional or ablative therapy. However, recurrent VAIN lesions are common and these treatments cause vaginal scarring. Recent studies have indicated that 5% imiquimod is an effective treatment for VAIN. The present report describes a case of a woman diagnosed with recurrent VAIN 3 who was treated with a 5% topical imiquimod cream and achieved a complete response after excision and CO2 laser vaporization. A 53-year-old, gravida 5, para 2 postmenopausal woman who was diagnosed with papillary squamous cell carcinoma by biopsy underwent conization, total abdominal hysterectomy and bilateral salpingo-oophorectomy. A histological examination revealed grade 3 cervical intraepithelial neoplasia with free surgical margins. At 3 years after the hysterectomy, the vaginal smear revealed atypical squamous cells, leading to a pathological diagnosis of VAIN 3. Partial vaginectomy was performed, and VAIN 3 was detected in the lesion with positive margins. At 4 months into follow-up, the vaginal smear revealed a high-grade squamous intraepithelial lesion (HSIL), and subsequent biopsy during colposcopy revealed a pathological diagnosis of VAIN 3. At 3 months after CO2 laser vaporization, the vaginal smear revealed HSIL with suspected recurrence and imiquimod treatment was initiated. One sachet of 5% imiquimod cream (0.25 g) was placed in the entire vagina three times per week for 14 weeks with no apparent complications. At 3 years after the treatment, there has been no recurrence. This case demonstrated that topical imiquimod with careful follow-up is an effective treatment for VAIN and is well-tolerated. Further clinical evidence of the effectiveness and safety of imiquimod in patients diagnosed with VAIN is required.

Do anticholinergic agents suppress uterine peristalsis and sporadic myometrial contractions at cine MR imaging?

PURPOSE: To prospectively evaluate anticholinergic drug effects on uterine peristalsis and sporadic myometrial contractions, as well as on intestinal motion, with cine magnetic resonance (MR) imaging. MATERIALS AND METHODS: This prospective study was approved by the institutional review board; informed consent was obtained from all participants. Twenty-one women (mean age, 29.3 years +/- 4.0 [standard deviation]) underwent MR imaging during the follicular through periovulatory phases (cycle days 5-26). Before and after injection of an anticholinergic agent, 60 serial half-Fourier rapid acquisition with relaxation enhancement MR images were obtained within 2 minutes in the midsagittal uterine plane. Evaluations were performed independently and separately in random order by two radiologists who were blinded to whether an anticholingeric agent had been administered. Uterine peristalsis was evaluated for frequency (paired t test), predominant direction (McNemar test), degree of endometrial movement, wave conduction in the junctional zone (JZ), and wave conduction toward the outer myometrium (Wilcoxon signed rank test). Degree of sporadic contractions in the outer myometrium and intestinal motion were also evaluated (Wilcoxon signed rank test). RESULTS: On postinjection images, uterine peristalsis decreased in frequency from 4.57 waves per 2 minutes +/- 1.62 to 3.52 waves per 2 minutes +/- 1.59, which is a 23% (95% confidence interval: 8.7%, 37.2%) average reduction (P = .003). There was no significant difference in actual predominant uterine peristalsis direction between pre- and postinjection images (P > .99). Although there were trends toward reduction of the degree of endometrial movement and of wave conduction in the JZ and toward the outer myometrium, these were not significant. The degree of sporadic myometrial contractions (P = .001) and intestinal motion (P < .001) decreased on postinjection images. CONCLUSION: Anticholinergic agents significantly suppress sporadic myometrial contractions and uterine peristalsis, in addition to intestinal motion, all of which may contribute to improved quality of conventional uterine MR images.

Spontaneous regression of congenital cystic adenomatoid malformation of the lung: longitudinal examinations by magnetic resonance imaging.

We report a case of large cystic adenomatoid malformation of the lung (CCAM), which occupied almost the entire left lung with a prominent mediastinal shift at 24 weeks of gestation. The volume of the lesion, determined by magnetic resonance imaging (MRI), was 27.0 cm3. Subsequent MRI and ultrasound examinations revealed a spontaneous resolution of the lesion at 32 and 36 weeks of gestation without a mediastinal shift, when the lesion volume was 12.8 cm3 and 5.6 cm3, respectively. At 37 weeks of gestation, a mature male baby weighing 2638 g with an Apgar score of 7 was delivered by elective cesarean section. A lobectomy of the left upper lobe of the lung was carried out at 3 days of age, due to an enlargement of the CCAM after birth.

New regulatory mechanisms for human extravillous trophoblast invasion.

Human extravillous trophoblasts (EVT) invade maternal deciduas and reconstructed maternal spiral arteries during early placentation. However, the precise regulatory mechanisms to induce EVT invasion toward arteries and/or to protect EVT from further invasion have not been well understood. Recently, it was found that EVT that had already ceased their invasion, specifically expressed cluster of differentiation (CD9) and dipeptidyl peptidase IV (DPPIV) on their cell surface. In addition, EVT migrating to maternal spiral arteries expressed CC chemokine receptor type-1 (CCR-1), which is a chemokine receptor for regulated on activation normal T cell expressed and secreted (RANTES) and so on. CD9 is associated with integrin molecules on the cell surface and is considered to modulate integrin function. In contrast, DPPIV is a cell surface peptidase that can metabolize RANTES at extracellular sites before its accessing to the chemokine receptors. In vitro functional assay showed that CD9, DPPIV and RANTES are involved in the regulation for EVT invasion. From these findings, it can be proposed that CD9 and DPPIV, including chemokines, are new regulatory factors for human extravillous trophoblasts. (Reprod Med Biol 2005; 4: 189-195).

Human blastocysts and endometrial epithelial cells express activated leukocyte cell adhesion molecule (ALCAM/CD166).

Activated leukocyte cell adhesion molecule (ALCAM)/cluster of differentiation (CD166) is a type I transmembrane cell adhesion molecule belonging to the Ig superfamily and a ligand for CD6 that is expressed on T lymphocytes. Recently, homophilic (ALCAM-ALCAM) adhesion was shown to play important roles in tight cell-to-cell interaction and regulation of stem cell differentiation. To investigate the involvement of ALCAM in embryo implantation, the expression of ALCAM was examined in human blastocysts and endometrium. Immunohistochemical study showed that ALCAM was expressed on endometrial luminal and glandular epithelial cells but not on the endometrial stromal cells in either the proliferative or secretory phase. Northern blot analysis of isolated endometrial epithelial cells and stromal cells showed that ALCAM mRNA was expressed in endometrial epithelial cells. Flow cytometry confirmed cell surface expression of ALCAM on endometrial epithelial cells. On the other hand, nested RT-PCR analysis demonstrated that ALCAM mRNA was expressed in human blastocysts but not in the embryos in the 8-cell or morula stages, which were obtained from patients undergoing in vitro fertilization treatment. These findings indicate that ALCAM is expressed on human endometrial epithelial cells and blastocysts. The developing stage-specific expression on the embryo suggests that the ALCAM-ALCAM cell adhesion system is involved in an initial interaction of the embryo with maternal endometrium.

Human chorionic gonadotropin (HCG) activates monocytes to produce interleukin-8 via a different pathway from luteinizing hormone/HCG receptor system.

To investigate immune-endocrine interactions between the embryo and the mother early in pregnancy, we examined the effects of human chorionic gonadotropin (HCG) on IL-8 production by peripheral blood mononuclear cells (PBMC). Recombinant HCG promoted IL-8 secretion by PBMC derived from nonpregnant women. The induction of IL-8 mRNA expression was observed after 30 min of HCG stimulation. Adsorption of the HCG with anti-HCG antibodies confirmed the specificity of this effect. The translocation of nuclear factor kappaB into the nucleus and subsequent IL-8 production were observed mainly in monocytes, and IL-8 production was reduced when a proteasome inhibitor was added to inactivate nuclear factor kappaB. Although fluorescein isothiocyanate-labeled HCG was bound to the majority of monocytes, cell surface expression of HCG receptor was hardly detected. IL-8 production by HCG was not affected by inhibitors of protein kinases A and C. In contrast, this stimulation was attenuated by D-mannose, which inhibits binding to C-type lectins. The basal IL-8 production by PBMC from women early in pregnancy was significantly elevated, compared with that from nonpregnant women. This study showed that human monocytes respond to HCG and secrete IL-8 through a pathway different from the HCG receptor system, suggesting that this glycoprotein hormone can react with not only endocrine cells but also immune cells early in pregnancy, probably via primitive systems such as C-type lectins.

Human endometrial epithelial cells express ephrin A1: possible interaction between human blastocysts and endometrium via Eph-ephrin system.

Eph receptor tyrosine kinases and their cell membrane-bound ligands, ephrins, are well known to function in cell-to-cell interaction and to play an important role in cell migration and adhesion during embryonic development in mammals. To investigate the involvement of the Eph-ephrin system in human embryo implantation, the expression of Eph receptors and ephrins was examined in human blastocysts and the endometrium. Immunohistochemical examination showed that ephrin A1 was expressed on human endometrial luminal and glandular epithelial cells in both the proliferative (cycle d 8-13; n = 8) and secretory (cycle d 18-24; n = 7) phases. RT-PCR analysis of isolated endometrial epithelial cells and stromal cells showed that ephrin A1 mRNA was predominantly expressed in endometrial epithelial cells. Northern blot analysis also confirmed the expression of ephrin A1 mRNA in the endometrium. In addition, nested RT-PCR analysis revealed the mRNA expression of Eph A1, one of the representative receptors for ephrin A1, in human blastocysts obtained from patients undergoing in vitro fertilization treatment. These findings indicate a possible interaction between human blastocysts and endometrial epithelial cells via the Eph-ephrin system. Because intracytoplasmic signals are induced by Eph receptors after ephrin stimulation, this system may be involved in the activation process of the human embryo during the implantation period.