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We herein report a case of clear cell carcinoma arising from endometriosis in the groin in a 53-year-old woman. The findings of MRI and FDG/PET-CT indicated a malignant tumor, and surgical biopsy confirmed adenocarcinoma of the female genital tract. The tumor including a part of the abdominal rectus muscle and rectus sheath, subcutaneous fat, skin, and the right inguinal ligament was resected en bloc. The defect in the abdominal wall was reconstructed with a fascia lata tensor muscle skin flap. The tumor was composed of clear cell adenocarcinoma arising from extrapelvic endometriosis. The patient received chemotherapy with gemcitabine and carboplatin for 6 cycles and had no evidence of recurrence 7 months after the treatment. We herein described the diagnosis and surgical management of endometriosis-associated carcinoma in the groin.

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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.

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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.

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BACKGROUND: High-molecular weight (HMW)-adiponectin is an active multimer for insulin sensitivity and anti-inflammatory reactions. We compared the ratio of serum total and HMW-adiponectin with brain-type natriuretic peptide (BNP) and other adipocytokines in normal pregnancy and pregnancy-induced hypertension (PIH). Effect of BNP on the secretion of adiponectin from cultured adipocytes was also examined. METHODS: The three study groups consisted of 44 non-pregnant women, 40 normal (healthy) pregnant women over 28weeks gestation and 29 patients with severe PIH. Adiponectin (protease-pretreated for HMW), BNP-N-terminal, leptin, and monocyte chemoattractant protein (MCP)-1 were measured with ELISA. Pre-adipocytes were differentiated to matured adipocytes and cultured with recombinant-BNP addition. RESULTS: HMW-to-total adiponectin ratio (HMW-ratio) was lower in normal pregnancy than in non-pregnant, and significantly higher in PIH than normal pregnancies. BNP-N-terminal showed positive correlation with HMW-adiponectin and HMW-ratio. Leptin and MCP-1 showed positive correlation with HMW-adiponectin, but not with HMW-ratio. Adiponectin in the supernatant of adipocyte cultures and intracellular cyclic-GMP was increased in dose-dependent manner in response to BNP. CONCLUSION: The observed increase in the HMW-adponectin ratio in subjects with PIH may reflect a functional increase of adiponectin in the pathophysiology of PIH. Additionally, this increase seemed to be related to BNP via stimulation of adipocytes.

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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.

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OBJECTIVE: Individuals with inflammation have a myriad of pregnancy aberrations including increasing their preterm birth risk. Toll-like receptors (TLRs) and receptor for advanced glycation end products (RAGE) and their ligands were all found to play a key role in inflammation. In the present study, we reviewed TLR and RAGE expression, their ligands, and signaling in preterm birth. RESEARCH DESIGN AND METHODS: A systematic search was performed in the electronic databases PubMed and ScienceDirect up to July 2010, combining the keywords "preterm birth," "TLR", "RAGE", "danger signal", "alarmin", "genomewide," "microarray," and "proteomics" with specific expression profiles of genes and proteins. RESULTS: This paper provides data on TLR and RAGE levels and critical downstream signaling events including NF-kappaB-dependent proinflammatory cytokine expression in preterm birth. About half of the genes and proteins specifically present in preterm birth have the properties of endogenous ligands "alarmin" for receptor activation. The interactions between the TLR-mediated acute inflammation and RAGE-mediated chronic inflammation have clear implications for preterm birth via the TLR and RAGE system, which may be acting collectively. CONCLUSIONS: TLR and RAGE expression and their ligands, signaling, and functional activation are increased in preterm birth and may contribute to the proinflammatory state.

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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.

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PROBLEM: Preterm birth (PTB) is an oxidative stress-related disease that lacks effective therapies partly because of the poor understanding of disease pathogenesis. The aim of this manuscript was to review molecular pathways that could be responsible for the pathogenesis of PTB. Genomic and proteomic studies have started to delineate the wide array of mediators involved in this disorder. Understanding the mechanisms of the development of PTB and elucidating pathogenesis and pathophysiology are intrinsic to prevention and effective therapies for this disorder. METHOD OF STUDY: This article reviews the English language literature for pathogenesis and pathophysiological studies on PTB. Several recent genomic and proteomic studies are discussed in the context of PTB biology. RESULTS: Decidual hemorrhage has been identified histologically in the placentas of patients with PTB, which may result in high levels of free heme and iron. Several important PTB-specific genes and proteins overlap with those known to be regulated by iron. Others were genes involved in oxidative stress and detoxification. Free iron oxidatively modifies lipid and protein, leading to DNA and cell damage. This signaling pathway of PTB will be discussed as it provides new insights into regulation of inflammation, oxidative stress, and detoxification. CONCLUSION: This review summarizes recent advances in heme/iron-mediated signaling, the target genes thereof, and the potential challenges to the understanding of pathogenesis and pathophysiology of PTB. A novel model is proposed. Collectively, decidual hemorrhage and inflammation are considered to be major contributors to the pathogenesis of PTB. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to paraphrase the role of oxidative stress in pathogenesis of preterm birth, explain the idea of preterm birth as a "syndrome," and summarize the potential role of early uterine bleeding in pathophysiology of preterm birth.

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The detection of an ovarian mass during pregnancy is often a diagnostic challenge. We describe 2 cases of ovarian endometrioma during pregnancy with marked mural nodules on the cyst wall. The sonographic and MR imaging findings mimicked ovarian cancer. Surgical intervention may still be inevitable to exclude the possibility of malignancy.

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OBJECTIVE: We performed a detailed molecular analysis of bikunin-mediated anti-inflammation (suppressive effect of cytokine release, MAP kinase activation, and nuclear translocation of NF-kB) using a truncated form of bikunin. MATERIALS AND METHODS: We obtained bikunin derivatives that contained O-glycoside-linked N-terminal glycopeptide (Bik-m1), N-glycoside-linked C-terminal tandem Kunitz domains (Bik-m2), bikunin lacking O-glycoside (Bik-c), asialo bikunin (Bik-a), bikunin lacking N-glycoside (Bik-n), and purified C-terminal Kunitz domain II (kII) of bikunin (HI-8). Enzyme-linked immunosorbent assay and Western blot were carried out to measure secreted TNF-alpha and MAP kinase activation. RESULTS: We examined the TNF-alpha secretion in control and lipopolysaccharide (LPS)-treated neutrophils and did not see any changes of its protein levels in the cells pretreated with Bik-m1, Bik-m2, Bik-c, or HI-8. In all of the derivatives tested, only the derivatives that lacked N-glycoside side chain showed a significant suppression of TNF-alpha secretion by LPS. Only a small (21 amino acids) deletion of the N-terminal portion of bikunin (which corresponds to Bik-m2) abolished its suppressing activity of TNF-alpha secretion, thus suggesting that the N-terminal 21 amino acids play a critical role in anti-inflammation. Bik-m1 alone failed to show anti-inflammatory response. Bikunin failed to inhibit ionomycin-induced phosphorylation of MAP kinases. CONCLUSION: These data allow us to conclude that the cytokine expression was inhibited only by the O-glycoside-linked core protein without the N-glycoside side chain. Our results also suggest a possible role of bikunin for receptor-dependent MAP kinase activation.

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Activated neutrophils contribute to the development of preterm delivery. Because of its ability to suppress inflammation, bikunin, a Kunitz-type protease inhibitor, is currently in clinical trials. To investigate the molecular mechanism of this inhibition, we analyzed the effect of bikunin on pro-inflammatory cytokine production and nuclear factor-kappaB (NF-kappaB) activation in mouse neutrophils stimulated by lipopolysaccharide (LPS), an inflammatory inducer. Here, we show that bikunin: (i) blocks LPS-induced secretion of pro-inflammatory cytokines, including TNF-alpha and IL-1beta, in a dose-dependent manner; (ii) has an inhibitory effect on cytokine production at a concentration of 0.2 microM, reaching 65% inhibition at the highest doses of bikunin tested (5 microM); (iii) has the suppressive capacity of ERK1/2 and p38 signaling pathways; and (iv) inhibited sequentially the LPS-induced phosphorylation of IkappaB-alpha, degradation of IkappaB-alpha, and nuclear translocation of NF-kappaB. When the MAPK data are analyzed, a significant decrease in phosphorylation is not seen at 0.2 microM bikunin but is at 1.0 microM dosing. Bikunin can inhibit LPS-induced neutrophil activation and cytokine release, although it is unlikely that it works primarily through the inhibition of MAPK phosphorylation. These data suggest that such effects are important in vivo and play a major contributory role in abrogation of neutrophil-mediated inflammatory responses, such as preterm delivery.

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