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.

A novel peptide blocking cancer cell invasion by structure-based drug design.

The receptor for the urokinase-type plasminogen activator (uPA), uPAR, facilitates tumor cell invasion and metastasis by focusing on several ligands, including uPA, integrins and vitronectin. With computational prediction algorithms and structure-based drug design, we identified peptides containing the Gly-Lys-Gly-Glu-Gly-Glu-Gly-Lys-Gly sequence (peptide H1), which strongly interacts with uPAR. The aim of the present study was to investigate the effect of allosteric inhibition at the uPAR interface using a novel synthetic peptide and its function on ovarian cancer cell invasion. The molecular and functional mechanisms of H1 were determined by complementary biochemical and biological methods in the promyeloid U937 cell line as well as ovarian cancer cell lines, including serous carcinoma SKOV3 and clear cell carcinoma TOV21G. The effects of H1 treatment on cancer cell invasion were evaluated in vitro. H1 inhibited cancer cell invasion, without affecting cell viability, accompanied by the suppression of extracellular signal-regulated kinase (ERK)-1 phosphorylation and then matrix metalloproteinase (MMP)-9 expression. H1 failed to block the interaction of uPA-uPAR protein-protein interaction in cells, but antagonized the uPA function. H1 failed to disrupt the uPA-uPAR complex, but abolished the invasion of ovarian cancer cells at least through suppression of the ERK-MMP-9 signaling pathway. Further studies are needed to confirm our observations and to describe the underlying molecular mechanism.

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.

Palonosetron in combination with 1-day versus 3-day dexamethasone to prevent nausea and vomiting in patients receiving paclitaxel and carboplatin.

PURPOSE: The aim of the present study was to evaluate the efficacy and toxicity of palonosetron (PAL) and dexamethasone (DEX) on day 1 only in patients with gynecologic cancer receiving paclitaxel combined with carboplatin (TC). The primary endpoint was to evaluate the complete response (CR) rate in the delayed phase. METHODS: This study was a randomized phase 2. Regardless of assignment to either study arm, all patients received an intravenous prophylactic regimen of DEX (20 mg) within 15 min and then an intravenous dose of PAL (0.75 mg) as a bolus given 30 min before initiation of TC on day 1. Patients in the DEX 1-day group received no additional DEX on days 2 and 3. Patients in the DEX 3-day group received DEX (8 mg) orally on days 2 and 3. RESULTS: Eighty-two patients had evaluable data on the primary outcome. The CR rates in the delayed phase between the two groups were not statistically significantly different (3-day group, 76.9 % [30/39]; 1-day group 69.8 % [30/43]; p = 0.4652). The frequency of constipation and insomnia which were antiemetic treatment-related adverse events was similar between two groups, and no serious adverse events occurred. CONCLUSIONS: Administration of a combination of PAL and DEX 1 day may prevent chemotherapy-induced nausea and vomiting (CINV) in the delayed phase for TC as well as administration of DEX 3 days. Further evaluation of the antiemetic regimen of combination of PAL and DEX 1 day for TC is warranted in future phase 3 trials.

Inhibition of cell death and induction of G2 arrest accumulation in human ovarian clear cells by HNF-1ß transcription factor: chemosensitivity is regulated by checkpoint kinase CHK1.

OBJECTIVE: Appropriate cell cycle checkpoints are essential for the maintenance of normal cells and chemosensitivity of cancer cells. Clear cell adenocarcinoma (CCA) of the ovary is highly resistant to chemotherapy. Hepatocyte nuclear factor-1ß (HNF-1ß) is known to be overexpressed in CCA, but its role and clinical significance is unclear. We investigated the role of HNF-1ß in regulation of the cell cycle in CCA. METHODS: To clarify the effects of HNF-1ß on cell cycle checkpoints, we compared the cell cycle distribution and the expression of key proteins involved in CCA cells in which HNF-1ß had been stably knocked down and in vector-control cell lines after treatment with bleomycin. HNF-1ß (+) cells were arrested in G2 phase because of DNA damage. RESULTS: HNF-1ß (-) cells died because of a checkpoint mechanism. G2 arrest of HNF-1ß (+) cells resulted from sustained CHK1 activation, a protein that plays a major role in the checkpoint mechanism. HNF-1ß (+) cells were treated with a CHK1 inhibitor after bleomycin treatment. Flow cytometric analysis of the cell cycle demonstrated that DNA damage-induced G2-arrested cells were released from the checkpoint and killed by a CHK1 inhibitor. CONCLUSIONS: The chemoresistance of CCA may be due to aberrant retention of the G2 checkpoint through overexpression of HNF-1ß. This is the first study demonstrating cell cycle regulation and chemosensitization by a CHK1 inhibitor in CCA.

Outcomes of Laser Conization for Cervical Intraepithelial Neoplasia 2-3 and Microinvasive Cervical Cancer.

BACKGROUND: Currently, there is no standardized follow-up protocol for patients who undergo laser conization. Therefore, we retrospectively investigated the clinical outcomes of laser conization in patients with high-grade cervical intraepithelial neoplasia 2-3 (CIN 2-3) and microinvasive squamous cell carcinoma and assessed the risks of residual and recurrent lesions of the cervix uteri. METHODS: The medical and pathological records of 91 patients with CIN 2, 580 with CIN 3 and 73 with microinvasive cervical cancer (MIC) who underwent laser conization between January 2000 and December 2011 were retrospectively reviewed. RESULTS: Positive margins increased with the extent of disease and were observed in 5.5%, 8.9% and 16.4% patients with CIN 2, CIN 3 and MIC, respectively, while residual or recurrent disease was observed in 0%, 3.2% and 13.6% patients, respectively. Examination of specimens obtained through postconization biopsy or hysterectomy revealed that 1.5% and 20% patients with negative and positive margins, respectively, were diagnosed with residual or recurrent lesions. Among patients who were conservatively managed after conization, seven with CIN 3 exhibited residual or recurrent disease, as evidenced by abnormal cytological findings, within 2 years after conization. CONCLUSIONS: Continuous follow-up by cytology and colposcopy, particularly during the first 2 years after conization, can effectively detect early residual or recurrent disease in CIN 3 and MIC patients, regardless of their margin status.

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.

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.

Endometrioid adenocarcinoma with high-grade transformation with serous and choriocarcinomatous differentiation - a case report.

A choriocarcinoma component with a malignant tumor is relatively rare. We present a case of an 85-year-old woman with mixed carcinoma, which was endometrioid adenocarcinoma with squamous differentiation, choriocarcinoma and a disseminated peritoneal nodule, which was papillary serous adenocarcinoma. The patient received surgery and conservative treatment. Twenty weeks after surgery, a recurring tumor appeared at the Douglas pouch. Histology showed that the recurring tumor was poorly differentiated carcinoma that was very different from the primary tumor. This case represents an unusual uterine corpus cancer with high-grade transformation with serous and choriocarcinomatous differentiation. This case also demonstrates the capacity of tumor cells to differentiate into divergent elements.

Type II versus type III fertility-sparing abdominal radical trachelectomy for early-stage cervical cancer: a comparison of feasibility of surgical outcomes.

OBJECTIVE: The purpose of this study was to compare surgical outcomes using modified (type II) and traditional (type III) abdominal radical trachelectomy (ART) for fertility-sparing surgery in early cervical cancer. METHODS: A prospectively maintained database of ART procedures was analyzed. Data were collected regarding age, stage, histology, operative outcome, surgical complication, and fertility outcome. RESULTS: We performed 23 fertility-sparing ARTs for patients with International Federation of Gynecology and Obstetrics stages IA to IB1 tumors of less than 2 cm between 2006 and 2010. Type III ART was attempted in 8 patients and modified ART in 15 patients. The median operating time was greater in the type III group compared with that in the type II group (305 vs 247 minutes; P < 0.02). The median surgical blood loss was greater in the type III ART group (580 mL; range, 250-988 mL) compared with that in the modified type II group (366 mL; range, 200-850 mL; P < 0.05). The median time to recovery of bladder dysfunction was less in the type II group (9 days; range, 3-10 days) than that in the type III group (13 days; range, 10-23 days; P < 0.01). There were no recurrences at the time of this report. CONCLUSIONS: Type II ART provides surgical and pathological outcomes with better recovery of bladder function similar to those in type III ART. For patients with early cervical cancer who wish to preserve reproductive function, type II ART is a feasible and safe operation.

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.

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.

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.

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.

Theoretical model of treatment strategies for clear cell carcinoma of the ovary: focus on perspectives.

OBJECTIVES: Among epithelial ovarian cancer (EOC), clear cell carcinomas (CCC) differ from the other histologic types with respect to their clinical characteristics, carcinogenesis and prognosis. The aim of this review is to summarize the current knowledge and future perspective on the new therapeutic targets and treatment strategies for CCC. MATERIALS AND METHODS: The present article reviews the English language literature for preclinical and clinical trials and promising molecular targets on CCC of the ovary, based on the gene expression profiling studies. RESULTS: Here, we show that (1) the expression of the genes involved in transcription, signaling, cell cycle, adhesion, matrix, proteinase, and detoxification was greatly increased in the CCC carcinogenesis; (2) upregulation of hepatocyte nuclear factor-1beta (HNF-1beta) and Polo-like kinase (PLK)-Early mitotic inhibitor-1 (Emi1) as well as their downstream targets are specifically found in most CCC. The promising molecular targeting approach will emerge in the context of HNF-1beta and PLK-Emi1 biology; and 3) several significant common pathways observed in CCC of the ovary overlap the datasets identified in CCC of the kidney. To improve the outcome in CCC therapy, we must learn various adaptive treatment strategies for renal CCC, although it is not supported by any preliminary clinical data. CONCLUSION: The inhibitors that target HNF-1beta and PLK-Emi1 and their downstream signaling molecules would be evaluated. In addition, the therapy currently used in renal CCC should be considered as an alternative for the present treatments or an attractive therapeutic option for ovarian CCC. The challenges accompanying the recent advance are described in this review article.

Molecular pathogenesis of endometriosis-associated clear cell carcinoma of the ovary (review).

Epithelial ovarian cancer (EOC) is the leading cause of death in women with gynecological malignancies. Among EOC, clear cell carcinoma (CCC) and endometrioid adenocarcinoma (EAC) differ from the other histological types with respect to their clinical characteristics and carcinogenesis. Both tumor types are often associated with endometriosis. EAC is recently reported to be characterized by K-RAS activation and PTEN dysfunction. However, the molecular changes in CCC remain largely unknown. The aim of this review is to summarize the current knowledge on the molecular mechanisms involved in CCC tumorigenesis. The present article reviews the English language literature for biological, pathogenetic and pathophysiological studies on endometriosis-associated CCC of the ovary. Several recent studies of loss of heterozygosity (LOH), allelic loss, comparative genomic hybridization, mutation, methylation status, microarray gene-expression profiling and proteomics are discussed in the context of CCC biology. Retrograde menstruation or ovarian hemorrhage carries highly pro-oxidant factors, such as heme and iron, into the peritoneal cavity or ovarian endometrioma. A histologically normal ectopic endometrium bears genetic damages caused by iron-dependent oxidative stress. DNA damage or LOH caused by oxidative stress is a critical factor in the carcinogenic process. LOH studies have implicated the involvement of specific chromosomal regions (5q, 6q, 9p, 10q, 11q, 17q and 22q). Furthermore, the PTEN and APC (early event), p53, polo-like kinases, Emi1 and K-RAS (late event) genes may be involved in CCC carcinogenesis. The molecular pathology of CCC is heterogeneous and involves various putative precursor lesions and multiple pathways of development, possibly via genetic alteration by oxidative stress.