Verification of selective and individual pulmonary thromboembolism prophylaxes for cesarean delivery.

OBJECTIVE: This study aimed to verify the utility of simple, safe, and effective venous thromboembolism (VTE) prophylaxis and implement it with few adverse events during cesarean delivery. METHODS: This single-center, prospective study involved pregnant women who underwent cesarean deliveries from August 3, 2020 to March 31, 2022. Patients with VTE risk factors were initially administered unfractionated heparin (5,000 international unit [IU] subcutaneously, twice daily), 6 hours after cesarean delivery. Subsequently, they were administered enoxaparin (2,000 IU subcutaneously, twice daily). They were not administered anticoagulants if one or more of the exclusion criteria were met. The primary efficacy outcome was the incidence of symptomatic VTE. The primary safety outcome was the incidence of major bleeding. RESULTS: Out of the 850 women eligible for this study, 551 (64.9%) had one or more VTE risk factors and 299 (35.1%) had no risk factors. Of the 551 women with one or more VTE risk factors, 15 met one or more exclusion criteria for enoxaparin administration. A total of 314 women received only perioperative mechanical prophylaxis, including 15 who met the exclusion criteria for anticoagulants and 299 without VTE risk factors. During implementation of the protocol, no woman developed symptomatic VTE after cesarean delivery. Major bleeding occurred in only one woman who received postoperative anticoagulants. CONCLUSION: This protocol, which clarified the administration of anticoagulants according to VTE risk factors and dose reduction/discontinuation criteria, may be an effective and safe VTE prophylaxis for cesarean deliveries.

Involvement of Receptor for Advanced Glycation Endproducts in Hypertensive Disorders of Pregnancy.

Preeclampsia/hypertensive disorders of pregnancy (PE/HDP) is a serious and potentially life-threatening disease. Recently, PE/HDP has been considered to cause adipose tissue inflammation, but the detailed mechanism remains unknown. We exposed human primary cultured adipocytes with serum from PE/HDP and healthy controls for 24 h, and analyzed mRNA expression of several adipokines, cytokines, and ligands of the receptor for advanced glycation endproducts (RAGE). We found that the mRNA levels of interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), high mobility group box 1 (HMGB1), and RAGE were significantly increased by the addition of PE/HDP serum. Among RAGE ligands, advanced glycation endproducts (AGE) and HMGB1 increased mRNA levels of IL-6 and CCL2 in SW872 human adipocytes and mouse 3T3-L1 cells. The introduction of small interfering RNA for RAGE (siRAGE) into SW872 cells abolished the AGE- and HMGB1-induced up-regulation of IL-6 and CCL2. In addition, lipopolysaccharide (LPS), a ligand of RAGE, increased the expression of IL-6 and CCL2 and siRAGE attenuated the LPS-induced expression of IL-6 and CCL2. These results strongly suggest that the elevated AGE, HMGB1, and LPS in pregnant women up-regulate the expression of IL-6 and CCL2 via the RAGE system, leading to systemic inflammation such as PE/HDP.

Comparison of the Different Definition Criteria for the Diagnosis of Amniotic Fluid Embolism.

INTRODUCTION: There are several sets of criteria for the diagnosis of Amniotic Fluid Embolism (AFE), but little is known about their degree of agreement. AIM: To evaluate the concordance of the Japan criteria for AFE in comparison with two definitions: the US AFE registration entry criteria (the US criteria) and UK Obstetric Surveillance System criteria for defining cases of amniotic fluid embolism (the UK criteria). MATERIALS AND METHODS: A retrospective observational study was conducted in which the AFE cases registered in the Obstetrical Gynaecological Society of Kinki District in Japan for the period of April 2005 to December 2012 have been analysed by the expert steering obstetric committee, organized by the members of the Obstetric Research group. Cohen's kappa coefficient was used to calculate the agreement among three clinical diagnoses. For inter-group comparison, the Pearson Chi-square test was used (for categorical) and Mann-Whitney test was used (for continuous variables). RESULTS: Among the 26 cases registered for this period, a total of 18 women were selected as having AFE according to the Japan criteria. Five women died (case fatality rate 27.8%). Agreement between the Japan criteria and the US and UK criteria was k = 0.453 and k = 0.538, respectively, reflecting moderate agreement. However, only 38.9% were given a diagnosis of AFE according to all three criteria. The factor that most often caused disagreement in diagnosis between the Japan criteria and the US criteria was "onset within 30 minutes postpartum". The UK criteria excluded "women with postpartum haemorrhage as the first presenting feature in whom there was no evidence of cardiorespiratory compromise". The case fatality rates in US and UK are higher than in Japan (50.0% and 38.5% vs 27.8%), but this did not result in a significant difference (p=0.497). CONCLUSION: The groups of subjects identified as having AFE by the Japan criteria had a medium agreement with the US (k=0.453) or UK criteria (k=0.538). These three definition criteria identified different subgroups of patients. Such disagreement has serious implications for research and treatment.

Evaluation of vaginal fluid squamous cell carcinoma antigen test in diagnosis of premature rupture of membranes.

OBJECTIVE: Previous studies have reported that concentrations of squamous cell carcinoma (SCC) antigen in amniotic fluid are extremely higher than that in the maternal serum. The aim of this study was to assess the potential clinical utility of vaginal fluid SCC level as a marker for diagnosing premature rupture of membranes (PROM). METHODS: A case-control study was performed using patients admitted to Nara Medical University Hospital, delivery ward, from January 2011 to December 2012. The discriminatory potential of SCC assay was determined using 54 PROM and 108 gestational age-matched control vaginal fluid samples, in a 1:2 ratio. Levels of vaginal fluid SCC in patients with PROM and control pregnant women were quantified by an enzyme-linked immunosorbent assay. RESULTS: The statistical results showed no correlation between gestational age and vaginal fluid SCC levels. There was no significant difference in vaginal fluid SCC levels between patients with PROM and those with control pregnant women (16156.5 ± 10495.8 ng/mL versus 15471.9 ± 11362.2 ng/mL, p = 0.467). CONCLUSION: We conclude that SCC could not be regarded as a potential marker for diagnosis of PROM. SCC may be a physiologic constituent of the vaginal fluid during pregnancy.

Involvement of Visceral Adipose Tissue in Immunological Modulation of Inflammatory Cascade in Preeclampsia.

OBJECTIVES: The pathophysiology of preeclampsia is characterized by abnormal placentation, an exaggerated inflammatory response, and generalized dysfunction of the maternal endothelium. We investigated the effects of preeclampsia serum on the expression of inflammation-related genes by adipose tissue. MATERIALS AND METHODS: Visceral adipose tissue was obtained from the omentum of patients with early ovarian cancer without metastasis. Adipose tissue was incubated with sera obtained from either five women affected with severe preeclampsia or five women from control pregnant women at 37°C in a humidified incubator at 5% CO2 for 24 hours. 370 genes in total mRNA were analyzed with quantitative RT-PCR (Inflammatory Response & Autoimmunity gene set). RESULTS: Gene expression analysis revealed changes in the expression levels of 30 genes in adipose tissue treated with preeclampsia sera. Some genes are related to immune response, oxidative stress, insulin resistance, and adipogenesis, which plays a central role in excessive systemic inflammatory response of preeclampsia. In contrast, other genes have shown beneficial effects in the regulation of Th2 predominance, antioxidative stress, and insulin sensitivity. CONCLUSION: In conclusion, visceral adipose tissue offers protection against inflammation, oxidative insults, and other forms of cellular stress that are central to the pathogenesis of preeclampsia.

Epigenetic dysregulation of endometriosis susceptibility genes (Review).

The aim of the present review was to illustrate how dysregulation of hormonal signaling regulates expressional changes of spatially associated genes in endometriosis. From a multi­platform endometriosis dataset, an integrated analysis was performed of epigenomic changes of several biologically relevant genes that have been validated in the literature. Estrogen receptor (ER) may act as a direct epigenetic driver for endometriosis establishment, maintenance and progression. A majority of endometriosis susceptibility genes may be present in functional downstream targets of ER and located near the known imprinting genes. Previous studies have shed light on the overlapping genetic signatures between endometriosis development and the defective decidualization process. The steroid hormone­mediated decidualization signaling pathway was shown to be frequently dysregulated in endometriosis. DNA methylation is associated with various intragenic or intergenic epigenetic modifications of chromatin. Chromatin architecture may be established in temporal and spatial orchestration of the recruitment of genes specifically downregulated in endometriosis. In conclusion, defective chromatin architecture at the ER target locus may have a key role in endometriosis. Endometriosis represents an interesting model to explore the variation of expression of spatially associated genes.

Genes Downregulated in Endometriosis Are Located Near the Known Imprinting Genes.

There is now accumulating evidence that endometriosis is a disease associated with an epigenetic disorder. Genomic imprinting is an epigenetic phenomenon known to regulate DNA methylation of either maternal or paternal alleles. We hypothesize that hypermethylated endometriosis-associated genes may be enriched at imprinted gene loci. We sought to determine whether downregulated genes associated with endometriosis susceptibility are associated with chromosomal location of the known paternally and maternally expressed imprinting genes. Gene information has been gathered from National Center for Biotechnology Information database geneimprint.com. Several researchers have identified specific loci with strong DNA methylation in eutopic endometrium and ectopic lesion with endometriosis. Of the 29 hypermethylated genes in endometriosis, 19 genes were located near 45 known imprinted foci. There may be an association of the genomic location between genes specifically downregulated in endometriosis and epigenetically imprinted genes.

Evaluation of the relation between patient characteristics and the state of chemotherapy-induced nausea and vomiting in patients with gynecologic cancer receiving paclitaxel and carboplatin.

PURPOSE: An antiemetic regimen for patients taking paclitaxel and carboplatin (TC) includes dexamethasone (20 mg) to protect against hypersensitivity. Chemotherapy-induced nausea and vomiting (CINV), however, is difficult to adequately control in patients receiving TC. In the present study, we retrospectively investigated risk factors for CINV in patients receiving TC with this antiemetic regimen based on a questionnaire. METHODS: Eligible patients were diagnosed with gynecologic cancer and receiving paclitaxel (175 mg/m(2)) intravenously for 3 h and carboplatin (area under the curve 5 mg/mL per min) on day 1 every 3 weeks in our institution, and treated with granisetron (3 mg) and dexamethasone (20 mg) for antiemesis. Data of nausea and vomiting assessed by Common Terminology Criteria for Adverse Events version4.0 were collected from the medical records. Patients were asked to complete a questionnaire including items such as age and hyperemesis. Logistic regression analysis was used to evaluate univariate and independent multivariate associations with items on nausea of grade 2 or greater and vomiting of grade 1 or greater. RESULTS: On univariate logistic analysis, no item was significantly associated with nausea of grade 2 or greater. Hypertension and hyperemesis gravidarum and adjuvant chemotherapy were significantly associated with delayed vomiting of grade 1 or greater. Multivariate analysis was performed with delayed vomiting of grade 1 or greater as an endpoint, and the resulting independent items were hypertension and hyperemesis gravidarum. CONCLUSIONS: The present study showed that the risk factor for delayed vomiting of grade 1 or higher was a history of hyperemesis gravidarum in patients receiving conventional TC with dexamethasone (20 mg) and granisetron. Therefore, in patients with this risk factor, criteria of major organizations should be followed first.

Risk factors for wound complications after surgery for gynecologic malignancies.

INTRODUCTION: Factors in wound complications such as surgical duration and suture methods are surgeon-side problems. The purpose of the present study was to retrospectively evaluate the incidence of wound complications in patients who underwent wound closure with stainless steel staples or subcuticular sutures in surgery for gynecologic malignancies and to retrospectively determine the risk factors for wound complications. PATIENTS AND METHODS: From April 2007 through March 2012, a cohort of 317 consecutive patients undergoing surgery for gynecologic malignancies was evaluated in the retrospective study. The skin was closed with stainless steel staples before March 2010 (staples group). From April 2010, the skin was closed by subcuticular suturing (subcuticular group). We compared the incidence of wound complications between 2 groups and evaluated independent multivariate associations with the effect of clinical parameters on occurrence of wound complications. RESULTS: The incidence of wound disruption was 7.3% (23/317): 12.1% (17/140) in the staples group and 3.4% (6/177) in the subcuticular group (P = 0.0029). The incidence of wound infection was 2.5% (8/317): 5.0% (7/140) in the staples group and 0.6% (1/177) in the subcuticular group (P = 0.0124). Multivariate analyses performed with wound disruption as the end point revealed long-term steroid treatment, subcutaneous thickness, and skin staples as independent predictors. Subcutaneous thickness and skin staples were independent factors significantly associated with the possibility of wound infection. CONCLUSION: The findings of the present study indicated that risk factors for wound complications after surgeries for gynecologic malignancies include, as a surgeon-side problem, the use of staples for skin closure, and as a patient-side problem, a subcutaneous thickness of more than 30 mm.

CA-125 cut-off value as a predictor for complete interval debulking surgery after neoadjuvant chemotherapy in patients with advanced ovarian cancer.

OBJECTIVE: In the present study, we evaluated changes in CA-125 cut-off values predictive of complete interval debulking surgery (IDS) after neoadjuvant chemotherapy (NAC) using receiver operating characteristic (ROC) analysis. METHODS: This retrospective single-institution study included patients with International Federation of Gynecology and Obstetrics (FIGO) stage III epithelial ovarian cancer and a pre-NAC serum CA-125 level of greater than 40 U/mL who were treated with neoadjuvant platinum-based chemotherapy followed by IDS between 1994 and 2009. Logistic regression analysis was used to evaluate univariate and independent multivariate associations with the effect of clinical, pathological, and CA-125 parameters on complete IDS, and ROC analysis was used to determine potential cut-off values of CA-125 for prediction of the possibility of complete IDS. RESULTS: Seventy-five patients were identified. Complete IDS was achieved in 46 (61.3%) patients and non-complete IDS was observed 29 (38.7%). Median pre-NAC CA-125 level was 639 U/mL (range, 57 to 6,539 U/mL) in the complete IDS group and 1,427 U/mL (range, 45 to 10,989 U/mL) in the non-complete IDS group. Median pre-IDS CA-125 level was 15 U/mL (range, 2 to 60 U/mL) in the complete IDS group and 53 U/mL (range, 5 to 980 U/mL) in the non-complete IDS group (p<0.001). Multivariate analyses performed with complete IDS as the endpoint revealed only pre-IDS CA-125 as an independent predictor. The odds ratio of non-complete IDS was 10.861 when the pre-IDS CA-125 level was greater than 20 U/mL. CONCLUSION: The present data suggest that in the setting of IDS after platinum-based NAC for advanced ovarian cancer, a pre-IDS CA-125 level less than 20 U/mL is an independent predictor of complete IDS.

Hepatocyte nuclear factor (HNF)-1ß and its physiological importance in endometriosis.

Endometriosis is associated with pelvic pain and female infertility. Endometriosis induces inflammation and is vulnerable to oxidative stress damage. To update and summarize the literature concerning the mechanisms that serve to protect genomic DNA from the oxidative damage, the present study reviews the English-language literature for biochemical studies on the transcription factor hepatocyte nuclear factor (HNF)-1ß target genes. Findings demonstrated that retrograde flow of the menstrual blood might give rise to endometriosis. Iron may have a significant impact on endometriosis gene expression. HNF-1ß regulates tissue-specific gene expression in endometriosis, as well as the expression of several genes, including CD44v9, which binds several molecules, including hyaluronan, epidermal growth factor receptor (EGFR), leukemia-associated Rho-guanine nucleotide exchange factor (LARG), IQ motif containing GTPase activating protein 1 (IQGAP1), macrophage migration inhibitory factor (MIF), major histocompatibility complex, class II invariant chain (CD74), cystine transporter subunit (xCT), Fas and extracellular matrix (ECM) proteins. The CD44v9 system is involved in cell migration, growth, survival, anti-apoptosis, immune response and anti-oxidative stress through maintaining higher levels of antioxidants. HNF-1ß may serve to alleviate damage and promote survival of cells experiencing stress by upregulating antioxidant protein expression. This review expands current knowledge on the molecular mechanisms underlying the oxidative stress protection provided by HNF-1ß and provides evidence that elevated HNF-1ß activity might be associated with the CD44v9-dependent signaling cascades.

The biology of uterine sarcomas: A review and update.

Uterine sarcoma is a rare neoplasm, accounting for only 5% of uterine malignancies. The pathogenesis of uterine sarcoma remains largely unknown, although recent basic science and pre-clinical animal models have provided a better understanding of tumor biology. The aim of this study was to review the clinical features, imaging characteristics, genetic aberrations and therapeutic approaches in uterine sarcoma. This study reviewed the English-language literature on clinical and basic studies on uterine sarcoma. The common variants of uterine sarcoma are carcinosarcoma, leiomyosarcoma and endometrial stromal sarcoma (ESS). Genetic profiling efforts have identified amplification, overexpression and mutation, while the molecular mechanisms of tumorigenesis driven by these genomic and genetic aberrations have yet to be fully elucidated yet. Recent genome-wide studies have also identified complex chromosomal rearrangements as oncogenic mechanisms. The cell cycle regulators, p16 and p53, are frequently over-expressed and appear to be involved in key modifications of sarcomagenesis. Molecular-targeted therapy has now been evaluated in clinical trials for certain subtypes. In conclusion, aberrations of cell cycle control would be a critical step in the development of uterine sarcoma. This review has provided new areas of study targeting molecular and genetic pathways.

PP029. Genetic change of adipose tissue related to inflammation in preeclampsia: Findings under novel culture method.

INTRODUCTION: Recently, adipose tissue is suggested to contribute to the inflammatory action in preeclampsia(PE), from peripheral increase of cytokines. However, the mechanism of the action in adipose tissue was not clarified yet. OBJECTIVES: In this study, we performed "Gel bottom-captured" adipose tissue culture with PE to show that the adipose tissue is the inflammatory focus in the pathophysiology of PE. METHODS: Under informed consent of the patients, omentum from probe laparotomy for ovarian cancer was captured in Peptide Hydrogel®. After 24h starvation, tissues were cultured with medium containing 10% of severe PE and healthy pregnant maternal serum (n=5 each). M30 (Apoptosis) and M65 (all cell death) were measured with ELISA. After mRNA extraction from tissue, quantitative PCR array (Qiagen, Inc.) was performed on all samples. RESULTS: No significant histological differences were found between each culture. However, M30/M65 ratio was increased in PE (p=0.053). In PCR array, under 2-fold decrease in OSM (p=0.019) was found, and over 2-fold increase in TLR (p<0.01) and other inflammatory genes were defined in PE. CONCLUSION: Inflammatory action in PE via TLR pathway was defined by adipose tissue culture. Apoptosis were shown in PE condition, but total tissue injury include necrosis were suggested to be stronger in normal pregnancy. Increase of inflammatory gene suggested that adipose tissue is one of a main organ of systemic inflammation in PE.

Pathogenesis and malignant transformation of adenomyosis (review).

The aim of our review was to identify the current information with regard to the pathogenesis and malignant transformation of adenomyosis. The current literature was reviewed by searching MEDLINE/PubMed, using the following keywords: adenomyosis, myometrium, stromal cells, malignant transformation, pathogenesis, etiology, genome-wide and microarray. Early signs of the development of adenomyosis are considered to be the penetration of stromal cells into the inner layer of the myometrium. Adenomyosis smooth muscle cells are developed, possibly, through a remodeling pathway via reactivation of coelomic epithelial cells as a result of estrogen-induced epithelial mesenchymal transition. Smooth muscle cell hyperplasia and hypertrophy are a reflection of a reaction of the surrounding tissue. The development of adenocarcinoma arising from adenomyosis is a relatively rare occurrence. In our literature review, to date, 44 cases of malignant tumors arising from adenomyosis have been documented. Studies reporting results of genetic abnormalities, epigenetic changes, monoclonal expansion, mutational analysis and the inactivation of specific tumor suppressor genes are very few in this field. In conclusion, adenomyosis can be a precursor of some carcinomas. The exact molecular mechanisms that lead to the malignant transformation are poorly understood.

Chemokine and free fatty acid levels in insulin-resistant state of successful pregnancy: a preliminary observation.

Increased insulin resistance and inflammatory action are observed in pregnancy-induced hypertension (PIH), but similar insulin resistance is observed also in successful pregnancy. To estimate insulin resistance and inflammatory activity in normal pregnancy and PIH, serum concentrations of free fatty acids (FFA; corrected with albumin to estimate unbound FFA), monocyte chemoattractant protein (MCP)-1, and high-molecular weight (HMW) adiponectin were measured in severe PIH patients with a BMI less than 25 kg/m(2) and were measured 3 times during the course of pregnancy in women with normal pregnancies. FFA/albumin, MCP-1, and HMW adiponectin concentrations were significantly higher in PIH patients than in women with normal pregnancies. The 3 measurements of FFA/albumin showed a significant increase through the course of uncomplicated pregnancies. In contrast, MCP-1 and HMW adiponectin were significantly decreased during the course of pregnancy. These results suggest that the reduced MCP-1 concentration in normal pregnancy may be a pathway to inhibit the induction of pathological features from physiological insulin resistance and homeostatic inflammation.

Peripheral RAGE (receptor for advanced glycation endproducts)-ligands in normal pregnancy and preeclampsia: novel markers of inflammatory response.

Inflammatory response in preeclampsia (PE) is a key feature in its pathophysiology. Advanced Glycation Endproducts (AGEs), receptors for AGEs (RAGE), and RAGE ligands are involved in systemic inflammation in various pathological conditions. In this study, we measured serum RAGE ligands in normal pregnancy controls and PE patients. Levels of Carboxymethyl Lysine (CML), HMGB1 and S100A12/EN-RAGE were measured in thirty-three normal pregnant women 3 times at 10-12 (1st measurement), 28 (2nd measurement), and 36 (3rd measurement) weeks during gestation for paired analysis. We also measured those in serum samples from 17 severe PE patients at admission using ELISA. Early onset (EO, <32 weeks) and late onset (LO, ≥32 weeks) PE patients were compared with the 2nd and 3rd measurements of normal controls, respectively. CML and HMGB1 did not change during normal pregnancy. However, S100A12/EN-RAGE decreased from the 1st to 2nd measurement (P<0.0001). Across all PE patients, serum CML was unaltered, while HMGB1 significantly increased compared to 2nd (P=0.0002) and 3rd (P<0.0001) measurement as well as individually compared to both EO (P=0.018) and LO groups (P=0.0001). S100A12 in all PE patients increased over 2nd (P=0.0015) and 3rd (P=0.0002) measurements, although only LO was significantly increased compared to the 3rd measurement (P=0.0005). Our data suggest that patterns of serum RAGE ligand concentration indicate different inflammatory pathways in normal pregnancy, EO-PE, and LO-PE.