Prognostic factors and treatment outcomes for patients with surgically staged uterine clear cell carcinoma focusing on the early stage: A Taiwanese Gynecologic Oncology Group study.

OBJECTIVE: The aim of this study was to investigate the clinical and pathological characteristics of uterine clear cell carcinoma (UCCC) and the treatment of this disease in relation to patient outcomes. METHODS: The clinicopathological data for and the management of all patients with UCCC who presented between 1991 and 2010 at 11 member hospitals of the Taiwanese Gynecologic Oncology Group (TGOG) were retrospectively reviewed. RESULTS: There were no significant differences in 5-year overall survival (OS) rates between patients with pure UCCC (n=100) and non-pure UCCC (n=53) at the same surgical stage, with OS rates of 92.6%, and 87.7% for stage I; 83.3% and 83.3% for stage II; 64.0% and 67.8% for stage III; and 16.7% and 0% for stage IV (n=1), respectively. Tumor stage and age independently influenced the OS rate of UCCC. For the patients with early stage UCCC, the adjuvant therapy modality was the only significant prognostic factor for recurrence-free survival. The patients with early stage UCCC who received adjuvant therapy had excellent 5-year recurrence-free survival and OS rates compared to those who received radiotherapy (100% vs. 74%, p=0.01; 100% vs. 72%, p=0.03). CONCLUSIONS: The 5-year survival rates of patients with pure UCCC and non-pure UCCC were similar. The prognosis for surgical staging of patients with stage I/II UCCC was encouraging. Postoperative adjuvant platinum-based chemotherapy is recommended for patients with early stage UCCC who are at a high risk of recurrence.

Proposal for Practical Approach in Prenatal Diagnosis of Beckwith-Wiedemann Syndrome and Review of the Literature.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is a phenotypically and genetically heterogeneous disorder associated with epigenetic/genetic aberrations on chromosome 11p15.4p15.5. There is no consensus criterion for prenatal diagnosis of BWS. METHODS: Three BWS patients with their clinical histories, prenatal ultrasonographic features, and results of molecular diagnosis were presented. Likewise, by incorporating the findings of our cases and literature review, the phenotypic spectrum and genotype-phenotype correlations of fetal BWS were summarized, and a practical approach in prenatal diagnosis of BWS was proposed. RESULTS: A total of 166 BWS cases with prenatal features were included for analysis. Common fetal features include abdominal wall defects (42.8%), polyhydramnios (33.1%), and macrosomia (32.5%). Molecular pathologies include methylation changes in imprinting control region 1 and 2 (ICR1 and ICR2), paternal uniparental disomy of chromosome 11p15.5, copy number change involving 11p15, etc. Some genotype-phenotype correlations were observed. However, the broad phenotypic spectrum but limited features manifested by affected fetuses rendering ultrasonographic diagnosis not easy. CONCLUSIONS: Molecular tests are used for prenatal diagnosis of BWS suspected by ultrasonography. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is recommended as the first-line molecular tool because it simultaneously detects ICR1/ICR2 methylation statuses and copy numbers that solve the majority of clinical cases in the prenatal scenario.

Anticancer Effects and Molecular Mechanisms of Apigenin in Cervical Cancer Cells.

Cervical cancer is the fourth most frequent malignancy in women. Apigenin is a natural plant-derived flavonoid present in common fruit, vegetables, and herbs, and has been found to possess antioxidant and anti-inflammatory properties as a health-promoting agent. It also exhibits important anticancer effects in various cancers, but its effects are not widely accepted by clinical practitioners. The present study investigated the anticancer effects and molecular mechanisms of apigenin in cervical cancer in vitro and in vivo. HeLa and C33A cells were treated with different concentrations of apigenin. The effects of apigenin on cell viability, cell cycle distribution, migration potential, phosphorylation of PI3K/AKT, the integrin ß1-FAK signaling pathway, and epithelial-to-mesenchymal transition (EMT)-related protein levels were investigated. Mechanisms identified from the in vitro study were further validated in a cervical tumor xenograft mouse model. Apigenin effectively inhibited the growth of cervical cancer cells and cervical tumors in xenograft mice. Furthermore, the apigenin down-regulated FAK signaling (FAK, paxillin, and integrin ß1) and PI3K/AKT signaling (PI3K, AKT, and mTOR), inactivated or activated various signaling targets, such as Bcl-2, Bax, p21cip1, CDK1, CDC25c, cyclin B1, fibronectin, N-cadherin, vimentin, laminin, and E-cadherin, promoted mitochondrial-mediated apoptosis, induced G2/M-phase cell cycle arrest, and reduced EMT to inhibit HeLa and C33A cancer cell migration, producing anticancer effects in cervical cancer. Thus, apigenin may act as a chemotherapeutic agent for cervical cancer treatment.

Updated applications of Ultrasound in Uterine Cervical Cancer.

Cervical cancer is a common gynecologic malignancy worldwide. It is the fourth for both incidence and mortality. For cervical cancer, imaging and pathology assessments are incorporated in the revised 2018 Federation of Gynecology and Obstetrics (FIGO) staging system. Uses of imaging techniques for the pre-treatment work-up of cervical cancer have been increasing. Among imaging techniques for the evaluation of cervical cancer, ultrasound is cheaper, faster and widely available than other imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI). Advanced technique in ultrasound, such as three-dimension (3D) ultrasound and color Doppler, have improved the clinical application of ultrasound in cervical cancer. Ultrasound may provide highly accurate information on detecting tumor presence and evaluating local tumor extent if performed by ultrasound-trained gynecologists; the experience of readers is also critical for correct pretreatment staging and assessment of response to treatment. Sonographic images could be useful to predict response of neoadjuvant chemotherapy, radiotherapy, chemotherapy and concurrent chemoradiotherapy in patients with cervical cancer. This review article attempted to present the most updated specific applications of ultrasound in cervical cancer.

Metformin Potentiates the Anticancer Effect of Everolimus on Cervical Cancer In Vitro and In Vivo.

Cervical cancer is globally the fourth most common cancer in women. Metformin is a widely used drug for the treatment of type II diabetes and has been shown to possess important anticancer properties in cervical cancer. Everolimus is an mTOR inhibitor and is widely used to treat NETs, RCC, TSC, and breast cancers. The present study investigated the anticancer effects of metformin and everolimus in cervical cancer, when used alone or in combination. CaSki and C33A human cervical cancer cells were treated with different concentrations of everolimus alone or in combination with metformin. Cell viability was assessed using a CCK-8 assay. Cell apoptosis, cell-cycle, and mtROS analyses were conducted using flow cytometry. Target protein levels were analyzed by Western blotting. Related mechanisms were confirmed using appropriate inhibitors (z-VAD-fmk and BIRB796). The in vitro results were further confirmed in a xenograft tumor study. Both metformin and everolimus, when used alone, were moderately effective in inhibiting cell proliferation and inducing cell apoptosis of CaSki and C33A cells. When used in combination, these two drugs synergistically inhibited the growth of human cervical cancer cells and xenografts in nude mice, promoted sub-G1- and G0/G1-phase cell-cycle arrest, and enhanced mtROS production. The protein expressions of PI3K (p110α) and p-AKT were significantly downregulated, while P27, P21, p-p38, p-ERK, and p-JNK were upregulated following combined treatment. These results revealed that metformin potentiates the anticancer effect of everolimus on cervical cancer, and combination treatment with metformin and everolimus provides a novel therapeutic strategy for patients with cervical cancer.

Metformin induces apoptosis and inhibits migration by activating the AMPK/p53 axis and suppressing PI3K/AKT signaling in human cervical cancer cells.

Human cervical cancer is the fourth most common malignancy among women worldwide, and it is expected to result in 460,000 deaths per year by 2040. Moreover, patients with cervical cancer often display drug resistance and severe side effects; therefore, the development of effective novel chemotherapeutic agents is important. In the present study, the effects of metformin, a first­line therapeutic drug for type 2 diabetes mellitus, were evaluated in cervical cancer. Compared with the control group, metformin significantly inhibited cell viability and migration, and induced apoptosis and cell cycle arrest in human cervical cancer cell lines (CaSki and HeLa). Following metformin treatment, the protein expression levels of p­AMP­activated protein kinase (p­AMPK), which promotes cell death, and the tumor suppressor protein p­p53 were remarkably upregulated in CaSki and C33A cells compared with the control group. Furthermore, compared with the control group, metformin significantly suppressed the PI3K/AKT signaling pathway in CaSki, C33A and HeLa cells. Compound C (an AMPK inhibitor) significantly reversed the effects of metformin on CaSki, C33A and HeLa cell viability, and AMPK and p53 phosphorylation. The results of the present study suggested that metformin induced AMPK­mediated apoptosis, thus metformin may serve as a chemotherapeutic agent for human cervical cancer.

An Automatic Platform Based on Nanostructured Microfluidic Chip for Isolating and Identification of Circulating Tumor Cells.

Circulating tumor cell (CTC) test is currently used as a biomarker in cancer treatment. Unfortunately, the poor reproducibility and limited sensitivity with the CTC detection have limited its potential impact on clinical application. A reliable automated CTC detection system is therefore needed. We have designed an automated microfluidic chip-based CTC detection system and hypothesize this novel system can reliably detect CTC from clinical specimens. SKOV3 ovarian cancer cell line was used first to test the reliability of our system. Ten healthy volunteers, 5 patients with benign ovarian tumors, and 8 patients with epithelial ovarian cancer (EOC) were recruited to validate the CTC capturing efficacy in the peripheral blood. The capture rates for spiking test in SKOV3 cells were 48.3% and 89.6% by using anti-EpCAM antibody alone and a combination of anti-EpCAM antibody and anti-N-cadherin antibody, respectively. The system was sensitive to detection of low cell count and showed a linear relationship with the cell counts in our test range. The sensitivity and specificity were 62.5% and 100% when CTC was used as a biomarker for EOC. Our results demonstrated that this automatic CTC platform has a high capture rate and is feasible for detection of CTCs in EOC.

Pre-operative diagnosis of a primary uterine mature teratoma.

OBJECTIVE: Mature cystic teratoma is a common benign ovarian tumor. But extragonadal teratomas are very rare. They mainly occur in the midline structure of the body. Uterine teratomas are extremely rare with only few reports. The diagnosis was mainly based on the operative findings. We report a case of uterine mature teratoma in a 37 year-old woman who was diagnosed before the operation. We also review the literature about this exceptional presentation. CASE REPORT: We report a case of uterine teratoma that was initially diagnosed as a uterine tumor under ultrasound examination. But teratoma was highly suspected preoperatively by the abdominal CT scan. She underwent tumor excision via laparotomy. The operative finding and the histological examination confirms the diagnosis of primary uterine teratoma. CONCLUSION: Preoperatively diagnosis of uterine teratoma was difficult. Although there are no gold standard to treat the uterine teratoma, the majority of the treatment choice is surgery. The prognosis of this unusual disease is relatively good in benign lesions.

Complete non-puerperal uterine inversion caused by uterine hemangioma: A case report.

OBJECTIVE: Uterine inversion is a rare postpartum complication. Non-puerperal uterine inversion is extremely rare. It mostly occurs with uterine tumors, especially leiomyoma. In most instances, the inversion may not be noticed until the time of surgery. The preoperative diagnosis is difficult. CASE REPORT: We report a case of non-puerperal complete uterine inversion that was initially diagnosed as cervical cancer. The uterine inversion was diagnosed preoperatively and she underwent total abdominal hysterectomy and bilateral salpingooophorectomy. The histological examination showed uterine hemangioma. CONCLUSION: Accurate diagnosis of the non-puerperal uterine inversion is important. Surgical intervention is necessary and it provides good prognosis. Hemangioma may be one of the causes of non-puerperal uterine inversion.

Genome-Wide Microarray Analysis Suggests Transcriptomic Response May Not Play a Major Role in High- to Low-Altitude Acclimation in Harvest Mouse (Micromys minutus).

The harvest mouse (Micromys minutus) is a small rodent species with a wide range of vertical distribution in Taiwan, extending from the sea level to 3100 m altitude. This species has recently suffered from habitat loss in high-altitude areas due to orchard cultivation, which may have resulted in mouse migration from high to low altitude. To investigate whether there is any physiological mechanism involved in altitude acclimation, rat cDNA microarray was used to compare transcriptomic patterns of the skeletal muscle tissues taken from individuals native to the high-altitude environment and those transferred to the low-altitude captive site. Of the 23,188 genes being analyzed, 47 (33 up-regulated and 14 down-regulated) were found to have differential expression (fold change > 4 or < -4, ANOVA p < 0.05). However, after multiple testing correction with a false discovery rate (FDR), only the result for Tnfrsf12a was found to be statistically significant (fold change = 13, FDR p < 0.05). The result was confirmed by quantitative polymerase chain reaction (q-PCR). The expression of Tnfrsf12a possibly relates to the skeletal muscle biology and thus can be correlated with altitude acclimation. However, finding only one gene transcript with significant alteration suggests that transcriptomic response may not play a major role in high- to low-altitude acclimation in harvest mouse.

Association of Fibroblast Growth Factor Receptor 4 Genetic Polymorphisms With the Development of Uterine Cervical Cancer and Patient Prognosis.

This is the first study to investigate the relationships among fibroblast growth factor receptor 4 (FGFR4) genetic polymorphisms, development of uterine cervical cancer, clinicopathological variables, and patient prognosis in Taiwanese women. Real-time polymerase chain reaction and genotyping were used to detect the genotype frequencies of 4 FGFR4 single-nucleotide polymorphisms (SNPs), rs351855 (C/T, Gly388Arg), rs2011077 (G/A), rs7708357 (G/A), and rs1966265 (Ile10Val), in 138 patients with invasive cancer, 89 with precancerous lesions of uterine cervix, and 335 normal controls. The results showed that there is no significant difference in the frequencies of FGFR4 SNPs rs351855, rs2011077, rs7708357, and 1966265 between women with cervical invasive cancer and normal controls even after controlling for age. However, significant differences existed in the distributions of the FGFR4 genetic polymorphism rs2011077, when mutant homozygotes (AA) were compared using other genotypes (GG/GA) as a reference, as well as rs1966265, when mutant homozygotes (AA) were compared using GG/GA as a reference, between women with cervical precancerous lesions and normal women even after controlling for age. In multivariate analysis, lymph node metastasis was associated with cancer recurrence, and lymph node metastasis and FGFR4 rs351855 were associated with patient survival. In conclusion, our study demonstrated that FGFR4 rs2011077 and rs1966265 are associated with the progression of cervical normal tissues to precancerous lesions in Taiwanese women. Moreover, rs351855 (Gly388Arg) is the only FGFR4 genetic polymorphism that is associated with patient survival.

Clinicopathologic Features and Treatment Outcomes in Patients with Stage I, High-Risk Histology or High-Grade Endometrial Cancer after Primary Staging Surgery: A Taiwanese Gynecologic Oncology Group Study.

To investigate the clinicopathological features and treatment outcomes in patients with stage I, high-risk endometrial cancer. Patients with International Federation of Gynecology and Obstetrics stage I, papillary serous, clear cell, or grade 3 endometrioid carcinoma treated between 2000 and 2012 were analyzed for the clinical and pathological factors in relation to prognosis. A total of 267 patients (stage IA; n = 175, stage IB; n = 92) were included. Among the clinicopathological features, stage and age were significant prognostic factors. The recurrence rate and overall survival for stage IB versus IA were 22.8% versus 9.1% (p = 0.003) and 149.7 months versus 201.8 months (p < 0.001), respectively. The patients >60 years of age also had a higher recurrence rate (21.7% versus 9.7%, p = 0.008) and poorer survival (102.0 months versus 196.8 months, p = 0.001) than those ≤60 years of age. Distant recurrence (64.9%) occurred more frequently than local recurrence (24.3%) and local combined with distant recurrence (10.8%) (p < 0.001). The postoperative treatment modality had no impact on tumor recurrence rate, recurrence site, or overall survival. Distant recurrence is a major cause of treatment failure in patients with stage I, high-risk endometrial cancer. However, current adjuvant treatment appeared to have little effect in preventing its occurrence.

Late onset of large benign ductus arteriosus aneurysm presented with increased nuchal translucency and cystic hygroma at first trimester Down syndrome screening.

OBJECTIVE: Fetal ductus arteriosus aneurysm (DAA) is a rare but potentially risky congenital heart disease. It is often not diagnosed until the third trimester because of its asymptomatic nature and late onset. In rare occasions, DAA may result in serious complications; therefore, prenatal diagnosis is helpful. CASE REPORT: Herein, we report the case of a foetus with cystic hygroma and increased nuchal translucency in the first trimester (but regressed at 20-week anomalous scan). Karyotyping indicated a 46 XY genotype. A large vascular mass was noted at the apex of the left lung by Doppler ultrasound at 38 weeks of gestation, with a diameter of 12.5 mm. After birth, echocardiography showed a patent ductus arteriosus with aneurysmal dilatation (17 mm as the largest diameter); thus, DAA was impressed. Chest computed tomography and three-dimensional angiography confirmed the large aneurysmal dilatation of the ductus arteriosus with a closed end at the pulmonary arterial side. CONCLUSION: The male infant survived, but presented mild respiratory distress at birth. He was discharged at 24 days of age. At that time, DAA had regressed partially (diameter of 8.5 mm and much less blood flow), and it fully regressed at 40 days of age.

Prognostic factors and adjuvant therapy on survival in early-stage cervical adenocarcinoma/adenosquamous carcinoma after primary radical surgery: A Taiwanese Gynecologic Oncology Group (TGOG) study.

OBJECTIVE: We aimed to identify prognostic factors of early-stage cervical adenocarcinoma (AC) and adenosquamous carcinoma (ASC) treated with primary radical surgery, and to evaluate the impact of postoperative adjuvant therapy on outcome. METHODS: The clinical-pathological data of all patients (n = 1132) with stages I-II cervical AC/ASC treated with primary radical surgery at the member hospitals of the Taiwanese Gynecologic Oncology Group were retrospectively reviewed. RESULTS: In multivariate analysis, stage II, deep stromal invasion (DSI), lymphovascular space invasion (LVSI), positive pelvic lymph node (PLN), and parametrial involvement (PI) were significant factors for recurrence-free survival (RFS), while only DSI, PI, and positive PLN were independent factors for cancer-specific survival (CSS). Low- and high-risk groups were defined by prognostic scores derived from the four factors (DSI, LVSI, positive PLN, PI) selected by internal validation. Postoperative adjuvant therapy significantly improved outcome for PLN-positive patients (RFS, p = 0.014; CSS, p = 0.016), but not for PLN-negative high-risk group because of higher mean prognostic score (p = 0.028) of adjuvant+ than adjuvant- patients. CONCLUSIONS: PLN metastasis, PI, DSI, and LVSI were independent prognostic factors. Prospective studies of postoperative adjuvant therapy with prognostic score and nodal status stratification for cervical AC/ASC are necessary.

The prevalence of HPV-18 and variants of E6 gene isolated from cervical cancer patients in Taiwan.

BACKGROUND: Cervical cancer is the second most common cancer in women worldwide. It has been considered that human papillomavirus (HPV) is associated with cervical cancer. Currently, more than 80 different serotypes of HPV have been characterized and they are divided into low- and high-risk groups. The most common types that lead to cervical cancer are HPV-16 and -18. The viral oncogenes E6 and E7 are associated with the development of cervical cancer. In previous study, the variants of HPV-16 E6 gene have been reported. It suggests that variants may influence the morbidity of carcinogenesis, but the variant study on HPV-18 remains unknown. OBJECTIVES: To identify the variants of integrated HPV-18 E6 gene in the prevalent infection of HPV-18 of cervical cancer patients. STUDY DESIGN: 25 cervical cancer patients were clinically identified and the biopsies were obtained. The infectious HPV types were identified by PCR and Southern blotting analysis. The DNA fragments of the integrated HPV-18 E6 were amplified by PCR and cloned. The nucleotide sequences were obtained by sequencing. RESULTS: The prevalence of HPV infection in our 25 cases was HPV-18 (100%) and 7 out of these 25 cases (28%) were co-infected with HPV-16. The most dominant mutation among 25 tested patients was a silence mutation C183G of the E6 coding region. CONCLUSIONS: The prevalent HPV infectious serotype is HPV-18, which differs from the worldwide prevalent type. The identified HPV-18 E6 variants had a unique silence mutation located on C183G in E6 coding region.

Triage of Atypical Glandular Cell by SOX1 and POU4F3 Methylation: A Taiwanese Gynecologic Oncology Group (TGOG) Study.

INTRODUCTION: Invasive procedures including loop electrosurgical excision, cervical conization, and endometrial sampling are often recommended when atypical glandular cells (AGC) are detected on Pap smear with unsatisfactory colposcopy. These invasive procedures may result in patient anxiety, increased medical expense, and increasing the risk of preterm delivery in subsequent pregnancies. This study was performed to assess methylation biomarkers in the triage of AGC on Pap smear for invasive procedures. METHODS: We conducted a multicenter study in 13 medical centers in Taiwan from May 2012 to May 2014. A total of 55 samples diagnosed "AGC not otherwise specified" (AGC-NOS) were included. All patients with AGC underwent colposcopy, cervical biopsy, endometrial sampling, and conization if indicated. Multiplex quantitative methylation-specific polymerase chain reaction (QMSPCR) was performed. Sensitivity, specificity, and accuracy were calculated for detecting CIN3+ and endometrial complex hyperplasia. RESULTS: In 55 patients with AGC, the sensitivity for methylated (m) SOX1m, PAX1 m, ZNF582m,PTPRRm, AJAP1m, HS3ST2m, and POU4F3m for detecting CIN3+ and endometrial complex hyperplasia lesions was 100, 86, 71, 86, 86, 57, and 100%; specificity was 67, 79, 85, 50, 52, 96, and 52%, respectively. Testing for high risk-HPV had a sensitivity of 57% and specificity of 75% for CIN3+ and endometrial complex hyperplasia lesions. CONCLUSION: Methylated (m) SOX1m and POU4F3m could be new methylation biomarkers for detection of CIN3+ and endometrial complex hyperplasia in AGC. Women with AGC and positive SOX1m / POU4F3m, colposcopy, cervical conization or endometrial sampling should be considered.

Genomic analyses of the Formosan harvest mouse (Micromys minutus) and comparisons to the brown Norway rat (Rattus norvegicus) and the house mouse (Mus musculus).

The harvest mouse, Micromys minutus (MMIN), has a very wide range of distribution (from the British Isles across the Euroasian continent to Japan and Taiwan). We studied an isolated population of MMIN in Taiwan, which is at the southeastern margin of the species' geographic distribution, and compared its genetic complement with those of the same species previously reported from other geographic locations and with two model rodent species, the house mouse (Mus musculus) and the brown Norway rat (Rattus norvegicus). The diploid number (2N) of MMIN was 68, consistent with that reported for other populations. However, variations were noted in the fundamental number (FN) and the shape and banding patterns of the individual chromosomes among populations. The FN of MMIN was estimated to be 72, including 2 bi-armed autosomes, 31 one-armed autosomes, and one pair of one-armed sex chromosomes. Here, we propose the first ideogram for MMIN. C-banding, Ag-NOR, and the locations of 18S rRNA gene sequences (MMIN chromosomes no. 10, 14, 19, 29, 31, 33, and X) mapped by fluorescence in situ hybridization (FISH) are also reported. Additionally, we compared the 18S rDNA sequences and performed cross-species X chromosome painting (FISH) for M. minutus, M. musculus, and R. norvegicus. The results indicate that both genetic elements are rather conserved across species. Thus, implications for the phylogenetic position of Micromys were limited.

Aberrant TGFß/SMAD4 signaling contributes to epigenetic silencing of a putative tumor suppressor, RunX1T1 in ovarian cancer.

Aberrant TGFß signaling pathway may alter the expression of down-stream targets and promotes ovarian carcinogenesis. However, the mechanism of this impairment is not fully understood. Our previous study has identified RunX1T1 as a putative SMAD4 target in an immortalized ovarian surface epithelial cell line, IOSE. In this study, we report that transcription of RunX1T1 was confirmed to be positively regulated by SMAD4 in IOSE cells and epigenetically silenced in a panel of ovarian cancer cell lines by promoter hypermethylation and histone methylation at H3 lysine 9. SMAD4 depletion increased repressive histone modifications of RunX1T1 promoter without affecting promoter methylation in IOSE cells. Epigenetic treatment can restore RunX1T1 expression by reversing its epigenetic status in MCP3 ovarian cancer cells. When transiently treated with a demethylating agent, the expression of RunX1T1 was partially restored in MCP3 cells, but gradual re-silencing through promoter re-methylation was observed after the treatment. Interestingly, SMAD4 knockdown accelerated this re-silencing process, suggesting that normal TGF-beta signaling is essential for the maintenance of RunX1T1 expression. In vivo analysis confirmed that hypermethylation of RunX1T1 was detected in 35.7% (34/95) of ovarian tumors with high clinical stages (P=0.035) and in 83% (5/6) of primary ovarian cancer-initiating cells. Additionally, concurrent methylation of RunX1T1 and another SMAD4 target, FBXO32 which was previously found to be hypermethylated in ovarian cancer was observed in this same sample cohort (P< 0.05). Restoration of RunX1T1 inhibited cancer cell growth. Taken together, dysregulated TGFß/SMAD4 signaling may lead to epigenetic silencing of a putative tumor suppressor, RunX1T1, during ovarian carcinogenesis.

Ruptured corpus luteum with hemoperitoneum: case characteristics and demographic changes over time.

OBJECTIVE: Women of reproductive age are at risk of ruptured corpus luteum with hemoperitoneum. We identified the clinical and demographic features of patients recently treated in our institution and compared the findings with those from an earlier series, to detect any changes in disease identity that have occurred over the past 20 years. MATERIALS AND METHODS: Charts of patients treated between January 2001 and December 2003 at Changhua Christian Hospital were reviewed. Clinical parameters were compared with those from our previous study in the 1980s. RESULTS: A total of 91 women were diagnosed with ruptured corpus luteum and hemoperitoneum (mean age, 26 years; range, 15-42 years). Most ruptures (60.4%) occurred during the secretory phase and most women (57.1%) reported recent sexual intercourse prior to the onset of pain. Most patients (81.3%) required laparoscopic intervention to achieve hemostasis. No obvious differences were found between the results of this study and those from the 1985 series, except that our patients were younger, were more often unmarried, chose laparoscopic interventions rather than laparotomy, and that there was an emerging trend towards conservative treatment. CONCLUSION: The manifestations of corpus luteum hemorrhage in this study were similar to those observed in the 1980s at the same medical center. However, the demographic parameters (age, marital status) and the modalities of treatment (conservative treatment, mode of surgical interventions) had changed in line with the evolution of society, culture, and the progress of medical science over the past 20 years.