Laparoscopic detorsion of the ovary in ovarian hyperstimulation syndrome during the sixth week of gestation: A case report and review.

INTRODUCTION: Ovarian torsion in ovarian hyperstimulation syndrome (OHSS) is a relatively rare but serious complication in pregnant women. A delay in treatment increases the risk for functional loss of the ovary and early termination of pregnancy. In this report, we present the case of a 40-year-old female with OHSS who experienced ovarian torsion that was successfully treated with laparoscopic detorsion. PRESENTATION OF CASE: A 40-year-old pregnant woman in the 6th week of gestation who had conceived following in vitro fertilization presented to us with severe and persistent lower abdominal pain. Ultrasound examination revealed a viable singleton intrauterine pregnancy and bilateral enlarged ovaries with scanty ascites. Approximately 14 h after symptom onset, exploratory laparoscopy was performed. The right ovary was found to be twisted once around over the pedicle, and laparoscopic detorsion was completed. Postoperative follow-up was uneventful, and she successfully delivered a healthy infant at 38 weeks of gestation. DISCUSSION: Although the reports on successful laparoscopic surgery for pregnant women with ovarian torsion are becoming more frequent, there are few reports on laparoscopic surgery for ovarian torsion in OHSS during the early first trimester. Optimal management of ovarian torsion during pregnancy needs to be explored for these patients. CONCLUSION: Immediate explorative laparoscopic surgery is a potentially safe and useful strategy for treating ovarian torsion during the early first trimester of pregnancy.

Squamous cell carcinoma antigen as a novel candidate marker for amniotic fluid embolism.

AIM: We aimed to evaluate the clinical usefulness of serum squamous cell carcinoma (SCC) antigen for the diagnosis of amniotic fluid embolism (AFE). METHODS: Sera and information of 20 patients with AFE (autopsy-proven AFE, four cases; clinical AFE, 16 cases) were obtained from the Japan Amniotic Fluid Embolism Registration Center at Hamamatsu University School of Medicine. As controls, we included 74 gestational-age-matched healthy women who gave birth to healthy newborns during the period from December 2012 to January 2014. Receiver-operator curves (ROC) were used to evaluate the diagnostic performance of SCC levels for prediction of AFE. RESULTS: Serum SCC antigen levels in women with autopsy-proven AFE (112.0 ± 169.4 ng/mL, P = 0.001) and clinical AFE (9.5 ± 10.3 ng/mL, P = 0.004) were significantly higher than those in healthy controls with normal delivery (4.4 ± 2.2 ng/mL). On ROC analysis, the optimal cut-off value for SCC antigen levels was 7.15 ng/mL, for which the sensitivity and specificity for AFE prediction was 60.0% and 89.2%, respectively (area under the ROC, 0.785; 95% confidence interval, 0.663-0.908; P < 0.001). CONCLUSION: Serum SCC antigen may be a promising predictor of the entry of amniotic fluid into the maternal circulation, potentially serving as a candidate marker for noninvasive diagnosis of AFE.

Case Report of Successful Childbearing after Conservative Surgery for Cervical Mullerian Adenosarcoma.

Mullerian adenosarcoma (MA) is a rare tumor variant with low malignancy potential and is reported to account for 8% of all uterine sarcomas. Cervical MAs are reported to occur in relatively younger patients with the mean age of 27 years, while those in the uterine corpus generally present in postmenopausal women. Due to the rarity of cervical MAs, optimal management for these patients (especially younger women) is still under exploration. Here, we describe a case of cervical MA in a woman of reproductive age who was treated by fertility-preserving surgery and successfully delivered a child 18 months later.

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.

Comparison of Neoadjuvant Intraarterial Chemotherapy Versus Concurrent Chemoradiotherapy in Patients With Stage IIIB Uterine Cervical Cancer.

BACKGROUND: The purpose of this study was to compare the long-term survival of patients with stage IIIB squamous cell carcinoma of the cervix treated with neoadjuvant intraarterial chemotherapy (IA-NAC) versus those treated with concurrent chemoradiotherapy (CCRT). METHODS: We retrospectively reviewed the clinical records of 38 patients with stage IIIB squamous cell carcinoma of the cervix admitted between January 1994 and December 1999 who received IA-NAC followed by abdominal radical hysterectomy (ARH) or radiotherapy (RT). IA-NAC consisted of bilateral infusion via the internal iliac artery of cisplatin, bleomycin and pirarubicin for 2-3 courses. A historical control group of 64 patients who underwent primary CCRT from January 2000 to September 2007 was used for comparison. RESULTS: In the IA-NAC group, 12 patients (31.6%) with operable tumors underwent ARH, and the remaining 26 patients (68.4%) received RT. The response rates were 86.8% (12 complete response + 21 partial response) for IA-NAC and 98.4% (26 complete response + 37 partial response) for CCRT (P = 0.077), respectively. The 5-year overall survival and disease-free survival rates were 62.4 and 44.5% for IA-NAC and 51.1 and 46.9% for CCRT (P = 0.247 and 0.776), respectively. The 5-year overall survival and disease-free survival rates were 75.0 and 58.3% for the patients receiving IA-NAC followed by ARH, and 55.3 and 37.6% for the patients receiving IA-NAC followed by RT (P = 0.368 and 0.262), respectively. CONCLUSIONS: In the present study, IA-NAC followed by ARH or RT and primary CCRT showed similar survival rates for stage IIIB squamous cell carcinoma of the cervix.

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.

Modulation of estrogenic action in clear cell carcinoma of the ovary (Review).

Two histologic types, clear cell carcinoma (CCC) and endometrioid adenocarcinoma (EAC), are the common histology in ovarian cancer patients who have associated endometriosis. However, both tumor types have distinct clinicopathological characteristics and molecular phenotypes. EAC is predominantly positive for estrogen receptor (ER), but CCC specifically exhibits lower ER expression. This study reviews the current understanding of the role of the ER information in the pathogenesis of CCC, as well as the English language literature for biochemical studies on ER expression and estrogenic action in CCC. The iron-mediated oxidative stress occurs due to repeated hemorrhage in endometriosis, then this compound oxidatively modifies genomic DNA and, subsequently, ER depletion may be observed. There are a number of factors that interfere with ER expression and estrogen activity, which include DNA methylation of the promoter region, histone deacetylation, heme and iron binding, chromatin remodeling and ubiquitin ligase activity. Loss of estrogen function may be a turning point in CCC progression and aggressiveness.

A case of early-stage ovarian carcinoid tumor metastasized to the liver.

We report a case of ovarian carcinoid tumor that recurred with multiple liver metastases and was successfully treated with chemoembolization. A 76-year-old woman was admitted to our hospital presented with abdominal distension and abnormal uterine bleeding for about 6 months. She presented with hyperestrogenic and androgenic manifestations such as vaginal bleeding with endometrial hyperplasia and hirsutism. Magnetic resonance (MR) imaging revealed a large solid and cystic ovarian tumor of 17 cm at maximum diameter. On the basis of the clinical diagnosis of sex cord stromal tumor containing a mature cystic teratoma, she underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. The pathology report revealed that the mass in the left ovary was a carcinoid tumor, insular type, with mature cystic teratoma. Two years after surgical treatment, multiple liver metastases were revealed by abdominal CT. Hepatic arterial infusion of cisplatin was performed for 2 courses, and multiple metastatic nodules have remarkably reduced. No established chemotherapy or radiation therapy treatments are currently available for recurrent or advanced carcinoid tumors. Our paper suggests that chemoembolization with cisplatin may be effective in treatment of patients with multiple liver metastases of ovarian carcinoid tumor.

Redox-active iron-induced oxidative stress in the pathogenesis of clear cell carcinoma of the ovary.

OBJECTIVE: Epithelial ovarian cancer (EOC) is the most lethal pelvic gynecologic cancer. Clear cell carcinoma (CCC) and endometrioid adenocarcinoma (EAC) of the ovary have been associated with endometriosis, thus indicating that endometriosis has been believed to increase the risk of developing EOC. The aim of our review was to identify and synthesize the most current information on CCC with regard to molecular and pathophysiological distinctions. METHOD: This article reviews the English-language literature for molecular, pathogenetic, and pathophysiological studies on endometriosis and endometriosis-associated ovarian cancer (EAOC). In this review, we focus on the functions and roles of redox-active iron in CCC carcinogenesis. RESULTS: The iron-induced reactive oxygen species signals can contribute to carcinogenesis via 3 major processes: step 1, by increasing oxidative stress, which promotes DNA mutagenesis, histone modification, chromatin remodeling, and gene products activation/inactivation thus contributing to EAOC initiation; step 2, by activating detoxification and antiapoptotic pathways via the transcription factor hepatocyte nuclear factor 1ß overexpression, thereby contributing to CCC promotion; and step 3, by creating an environment that supports sustained growth, angiogenesis, migration, and invasion of cancer cells via estrogen-dependent (EAC) or estrogen-independent (CCC) mechanisms, thus supporting tumor progression and metastasis. CONCLUSIONS: These aspects of reactive oxygen species biology will be discussed in the context of its relationship to EAOC carcinogenesis.

Signaling pathway involved in cyclooxygenase-2 up-regulation by hepatocyte growth factor in endometrial cancer cells.

Hepatocyte growth factor (HGF) is up-regulated in tissue repair and has been implicated in playing a role in this process through its anti-apoptotic and proliferative activities. Cyclooxygenase-2 (COX-2) is an inducible enzyme in the biosynthetic pathway of prostaglandins, and its activation has been shown to play an important role in cell growth. We previously reported that HGF significantly inhibited anoikis, possibly through the up-regulation of COX-2 expression in the endometrial RL95-2 cancer cell line. Here, we report that i) treatment of RL95-2 cells with HGF resulted in phosphorylation of the HGF receptor c-Met, activation of Akt and IκB, translocation of NF-κB into the nucleus, and up-regulation of COX-2 mRNA; ii) the IκB-α phosphorylation inhibitor BAY11-7082 and the selective COX-2 inhibitor CAY10452 blocked HGF-mediated anoikis resistance in RL95-2 cells; and iii) HGF induced migration and invasion in RL95-2 cells, while the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and CAY10452 blocked these effects of HGF stimulation. Our data suggest that HGF possesses chemotactic ability, has anti-apoptosis action, and induces cellular infiltration via the PI3K/Akt pathway; it also triggers NF-κB activation and up-regulates COX-2 gene expression in endometrial cancer cells.

Risk of carcinoma in women with ovarian endometrioma.

Endometriosis affects an estimated 10% of women in the reproductive-age group. Here, we review current knowledge on molecular genesis of endometriosis-associated epithelial ovarian carcinoma (EOC). This article reviews the English language literature for biology, pathogenesis, and pathophysiological studies on endometriosis-associated EOC. Although endometriosis generally remains a benign condition, it demonstrates somatically acquired genetic alterations. Clear cell carcinoma (CCC) and endometrioid adenocarcinoma (EAC) are the most frequent types of EOC associated with endometriosis. Retrograde menstruation or ovarian hemorrhage carries highly pro-oxidant factors, such as iron, into the peritoneal cavity or ovarian endometrioma. CCC and EAC should be considered separately in studies of endometriosis-associated EOC. The repeated events of hemorrhage in endometriosis can contribute to carcinogenesis and progression via 3 major processes: 1) increasing oxidative stress promotes DNA methylation; 2) activating anti-apoptotic pathways supports tumor promotion; and 3) aberrant expression of stress signaling pathways contributes to tumor progression. This review summarizes recent advances in the understanding of epidemiology, carcinogenesis, pathogenesis, and pathophysiology of endometriosis-associated EOC; and a possible novel model is proposed.

The role of components of the chromatin modification machinery in carcinogenesis of clear cell carcinoma of the ovary (Review).

Recent data have provided information regarding the profiles of clear cell carcinoma of the ovary (CCC) with adenine-thymine rich interactive domain 1A (ARID1A) mutations. The purpose of this review was to summarize current knowledge regarding the molecular mechanisms involved in CCC tumorigenesis and to describe the central role played by the aberrant chromatin remodeling. The present article reviews the English-language literature for biochemical studies on the ARID1A mutation and chromatin remodeling in CCC. ARID1A is responsible for directing the SWI/SNF complex to target promoters and regulates the transcription of certain genes by altering the chromatin structure around those genes. The mutation spectrum of ARID1A was enriched for C to T transitions. CCC and clear cell renal cell carcinoma (ccRCC) resemble each other pathogenetically. Dysfunction of the ARID1A protein, which occurs with VHL mutations in ccRCC, is responsible for loss of the assembly of the ARID1A-mediated histone H2B complex. Therefore, ARID1A acts as a chromatin remodeling modifier, which stimulates cell signaling that can lead to cell cycle arrest and cell death in the event of DNA damage. The dysfunction of ARID1A may result in susceptibility to CCC carcinogenesis through a defect in the repair or replication of damaged DNA.

New insights into pattern recognition receptors and their ligands in gynecologic pathologies.

In the ovary, clear cell carcinoma (CCC) and endometrioid adenocarcinoma occur in the setting of endometriosis. In this review, we discuss the role of innate immune responses, specifically endogenous ligands (also known as "alarmins"), their pattern recognition receptors (PRRs) and their signaling pathways, in the pathogenesis of ovarian cancer, in particular, endometriosis-associated ovarian cancer. This article reviews the English-language literature for pathogenesis and pathophysiological studies on endometriosis and ovarian cancer. Here, we show that iron functions as an endogenous ligand and can induce chromosomal instability through production of reactive oxygen intermediates-induced oxidative stress. Several important CCC-related genes overlap with those known to be associated with hepatocyte nuclear factor-1ß-dependent oxidative stress. Aberrant expression of PRRs and HNF-1ß in endometriosis has been reported in the setting of chronic inflammation and oxidative stress pathways, which lie downstream of these genes. A concerted overexpression of alarmins, their receptors and HNF-1ß might be required for endometriosis carcinogenesis. Recent advances in innate immunity illuminate the molecular mechanism underlying inflammation-induced carcinogenesis. Upregulation of PRRs expression may synergize with activation of HNF-1ß signaling to accelerate endometriosis proliferation and cause carcinogenesis.

Anti-inflammatory actions of serine protease inhibitors containing the Kunitz domain.

INTRODUCTION: Protease inhibitors, including the Kunitz, Kazal, serpin and mucus families, play important roles in inhibiting protease activities during homeostasis, inflammation, tissue injury, and cancer progression. Interestingly, in addition to their anti-protease activity, protease inhibitors also often possess other intrinsic properties that contribute to termination of the inflammatory process, including modulation of cytokine expression, signal transduction and tissue remodeling. In this review we have tried to summarize recent findings on the Kunitz family of serine proteinase inhibitors and their implications in health and disease. MATERIALS AND METHODS: A systematic search was performed in the electronic databases PubMed and ScienceDirect up to October 2009. We tried to limit the review to anti-inflammatory actions and actions not related to protease inhibition. RESULTS AND CONCLUSION: Recent studies have demonstrated that the Kunitz inhibitors are not only protease inhibitors, but can also prevent inflammation and tissue injury and subsequently promote tissue remodeling.

A case of intravenous leiomyomatosis with high levels of hyaluronan.

Intravenous leiomyomatosis (IVL) is a rare benign tumor. The clinical behavior can be life-threatening due to extension through the pelvic veins. A 70-year-old woman was referred to our hospital with IVL originating from a uterine leiomyoma and extending to the inferior vena cava. The patient was diagnosed on the basis of the results of various studies, and the tumor was resected completely through a single-stage approach. The intravascular tumor was 20 cm long, multinodular and rubbery. Microscopic findings showed benign smooth muscle that was partly hyalinized and fibrous. Immunohistochemical studies revealed that hyaluronan was expressed more prominently in IVL than in uterine leiomyomas. IVL has viscoelastic properties and contains a large amount of hyaluronan, which may promote invasion during pathogenesis.

Fatal factors of clinical manifestations and laboratory testing in patients with amniotic fluid embolism.

AIMS: To identify factors leading to fatality of patients with amniotic fluid embolism (AFE). METHODS: Patients who had fatal or nonfatal AFE were registered at the Hamamatsu University School of Medicine in the Department of Obstetrics and Gynecology from 1992 to 2006. Data collected included information about demographics and clinical characteristics. The fatal factors among these data were identified using chi(2) analysis and the Mann-Whitney test. RESULTS: One hundred and thirty-five patients met the criteria, which included fatal (n = 65) and nonfatal AFE (n = 70). Maternal full-term gestational weeks, multiparous and noncesarean sections were the risk factors for death found in this study (p < 0.01). Sialyl Tn levels (mean +/- SD) in the serum of patients with fatal AFE (69.7+/- 126.4 U/ml) were higher compared to those with nonfatal AFE (48.3+/- 161.8 U/ml; p = 0.003). Each of three items (cardiac arrest, dyspnea or loss of consciousness) was more common in fatal AFE (p < 0.01). Maternal pregnancy and labor complications were not associated with the distinction between fatal and nonfatal AFE. CONCLUSION: Factors associated with patients with fatal AFE were identified. These included multiparity, noncesarean section at full-term and the three symptoms mentioned above. Sialyl Tn levels could be a possible prognostic fatality factor.

Clear cell carcinoma of the ovary: potential pathogenic mechanisms (Review).

Epithelial ovarian cancer (EOC) is the most common cause of gynecological cancer-related mortality. Clear cell EOC (cEOC) has a number of clinical features distinguishing it from other EOC because of frequent concurrence of endometriosis and highly chemoresistant nature resulting in a poor prognosis. Recent biochemical studies based on genome-wide expression analysis technology have noted specific expression of a transcription factor, hepatocyte nuclear factor-1beta (HNF-1beta), in cEOC and genetic alteration may be involved in oxidative stress. We describe the HNF-1beta-dependent pathophysiology of cEOC and discuss its role in oxidative stress-induced carcinogenesis. A systematic search was performed in the electronic databases PubMed and ScienceDirect up to July 2009, combining the keywords, genome-wide, microarray, epithelial ovarian cancer, clear cell carcinoma, oxidative stress, and detoxification, with specific expression profiles of genes. The catalog of cEOC-specificity might be a manifestation of six essential alterations in cell physiology: oxidative stress and detoxification, proteases, signal transduction, adhesion, transcription, and metabolism. Among 54 genes highly upregulated in cEOC, 47 genes (87.0%) were associated with the redox-related genes. Several important cEOC-related genes overlap with those known to be regulated by HNF-1beta. Twenty-two (40.7%) of the 54 genes predominantly identified in cEOC were involved in downstream targets of HNF-1beta. The HNF-1beta-dependent pathway might provide new insights into regulation of glycogen synthesis, detoxification and resistance to anticancer agents. This review summarizes recent advances in the understanding of oxidative stress and antioxidant mechanisms in pathogenesis of cEOC. A redox-sensitive subset of cEOC genes linked to oxidative and detoxification pathways was identified and associated with HNF-1beta-specific downstream targets.

The usefulness of photodynamic eye for sentinel lymph node identification in patients with cervical cancer.

AIMS AND BACKGROUND: We studied the potential use of sentinel lymph node identification using a near-infrared fluorescence imaging technique in the treatment of cervical cancer. METHODS AND STUDY DESIGN: Directly before the start of the operation, 0.2 ml of 5 mg/ml indocyanine green was prepared and injected into 4 sites in the cervix using a 26-gauge standard needle, at 3, 6, 9 and 12 o'clock positions. When the operation was advanced to the pelvis, near-infrared fluorescence imaging was performed using photodynamic eye (Hamamatsu Photonics Co., Japan). The sentinel lymph nodes and other dissected lymph nodes were histologically examined to find any metastases. RESULTS: Twelve patients were examined. Their ages ranged from 36 to 68 years (median, 58). Sentinel lymph nodes were identified in 10 patients (83%), and all were bilaterally identified. The median maximum tumor diameter of dissected cervical tumors was 35 mm (22-65); histology was squamous cell carcinoma in 8 patients and adenocarcinoma in 2 patients. Capillary lymphatic space involvement was found in 8 of the 10 patients. The site of the sentinel lymph node was the right external iliac node in 8 patients, the right obturator node in 8, the left external iliac node in 9, and the left obturator node in 8. Lymph node metastasis was found in 2 of the 12 patients, and all were sentinel lymph nodes. No metastasis from lymph nodes other than sentinel lymph nodes was observed. CONCLUSIONS: Photodynamic eye achieved a detection rate similar to that obtained with the blue dye and radioisotope method. It is also easier to use than the other two methods.

Expression profiles of genes involved in poor prognosis of epithelial ovarian carcinoma: a review.

BACKGROUND: Epithelial ovarian cancer (EOC) is the commonest cause of gynecological cancer-related mortality. Although the prognosis for patients with advanced cancer is poor, there is a wide range of outcomes for individual patients. OBJECTIVE: The aim of this study was to review molecular factors predictive of poor prognosis of women with EOC by reviewing microarray research identifying gene expression profiles. METHODS: A systematic search was performed in the electronic databases PubMed and ScienceDirect up to July 2008, combining the keywords "genome-wide," "microarray," "epithelial ovarian cancer" "prognosis," and "epithelial-mesenchymal transition" with specific expression profiles of genes. RESULTS: Many genes that participated in cell signaling, growth factors, transcription factors, proteinases, metabolism, cell adhesion, extracellular matrix component, cell proliferation, and anti-apoptosis were overexpressed in patients with poor prognosis. Several important prognosis-related genes overlap with those known to be regulated by epithelial-mesenchymal transition (EMT). This signaling pathway of EMT (E-cadherin, beta-catenin, receptor tyrosine kinases, NF-kappaB, TGF-beta, or Wnt signalings) will be discussed, as it provides new insights into a new treatment strategy. CONCLUSIONS: This review summarizes recent advances in prognosis-related molecular biology. Collectively, molecular changes possibly through EMT are considered to be a major contributor to the poor prognosis of EOC.