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The natural history of high-risk human papillomavirus (HRHPV) infection after successful treatment of cervical intraepithelial neoplasia (CIN) is not well known. This study was performed to evaluate the rate and pattern of HRHPV infection clearance after successful conization for CIN and to analyze factors associated with such clearance. A total of 287 patients who underwent loop electrosurgical excision procedures (LEEP) owing to HRHPV-associated CIN were included. All patients had negative resection margins on LEEP specimens and underwent HPV testing with the hybrid capture II system at 3-, 6-, 9-, 12-, 18- and 24-month follow-up visits after LEEP. Persistent HPV infections were detected in 45.6%, 14.3%, 6.3%, 2.2%, 1.5% and 1.1% of patients at 3, 6, 9, 12, 18 and 24 months after LEEP, respectively. Clearance rates did not differ by age, parity or severity of cervical lesion. However, clearance rates were significantly slower in patients with HPV DNA loads500 RLU/PC before LEEP (p = 0.040). During 2 years of follow-up after LEEP, 24 patients had recurrent disease revealed by biopsy. The odds ratios for recurrent disease in patients with persistent HRHPV infection increased gradually from 5.17 at the 3-month follow-up visit to 12.54, 15.69 and 25.90 at 6-, 9-, 12- and 24-month follow-up visits, respectively. We conclude that HRHPV infection cleared gradually in most patients within 6 months of treatment. Clearance rates were significantly slower in patients with HPV DNA loads500 RLU/PC. Persistent HPV infection was a significant positive predictor of recurrence.

Objective. To evaluate whether concurrent chemoradiation therapy (CRT) improves overall survival as compared to radiation therapy (RT) alone in stage III cervical cancers. Design. A multicenter retrospective review. Setting. Nine tertiary medical centers in Korea. Population. A total of 277 patients treated for stage III cervical cancer without para-aortic lymph node (PALN) metastasis based on clinical staging workup from 1996 to 2003. Methods. Medical and histopathological record review. Main outcome measures. Disease-specific overall survival. Results. CRT and RT alone were performed in 172 and 105 patients, respectively. There was no significant difference in disease-specific overall survival between the CRT and RT alone arms based on clinical staging workup, even though the CRT arm was characterized by younger age, more favorable performance status and lower pretreatment blood urea nitrogen level as compared to the RT alone arm. In the CRT arm, three patients succumbed to treatment-related death. Conclusion. CRT does not improve the overall survival rate in stage III cervical cancer as compared to RT alone based on clinical staging workup for PALN status. Special care needs to be taken regarding optimal dose and duration of RT, use of brachytherapy, anemia control and accurate pretreatment staging workup to improve survival outcome in patients with stage III cervical cancer.

Objectives The objective of this study was to determine whether ovarian preservation is feasible in younger endometrial cancer patients. Methods Endometrial cancer patients who underwent ovary-saving surgery were recruited from the tumor registries of 14 tertiary hospitals under the influence of the Korean Gynecologic Oncology Group (KGOG). Information regarding patient age, preoperative and intraoperative evaluations, pathologic reports, and follow-up results was abstracted from medical records. Results One hundred and seventy five patients were eligible for this study. Mean patient age at the time of surgery was 38.5±8.3 years (range 25–57). Ovary-preserving surgery was performed in 101 (57.7%) patients who desired to preserve their ovaries, incidentally in 69 (39.4%) patients with preoperative diagnoses other than endometrial carcinoma, and in 5 patients (2.9%) with unknown reasons. Median duration of follow-up was 55.0 months (range 6.2–180.0 months). Recurrence free survival and overall survival rates were 94.3 and 93.3%, respectively. Seven of the 175 (4.0%) patients had documented recurrence, and no recurrences were observed in stage I patients with endometrioid histology. All 7 recurrences had risk factors that could have reasonably explained recurrence, namely, non-endometrioid histology (4/7), deep myometrial invasion (5/7), cervical stromal invasion (4/7), and inadequate adjuvant treatment (4/7). No metachronous ovarian malignancy occurred during follow-up. Ten (5.8%) deaths occurred during follow-up; five resulted from disease recurrence, and 5 from non-disease related causes. Conclusion Our findings suggest that ovarian preservation does not adversely impact the recurrence of early stage endometrial cancer.

Knowledge of the risk factors for lymph node metastasis (LNM) is necessary to treat patients with endometrioid uterine cancer to optimize and further individualize treatment. This study was designed to determine the risk of LNM based on myometrial invasion and tumor grade in endometrioid uterine cancer.The authors retrospectively reviewed the medical records and pathological findings of 834 patients who underwent surgical staging, including pelvic lymphadenectomy with or without para-aortic lymphadenectomy, for endometrioid uterine cancer from 2002 to 2008 in Korea.Of the 834 patients with endometrioid uterine cancer, 107 (12.8%) patients had LNM. Sixty-one (57%) patients had only pelvic LNM, 39 (36.4%) had pelvic and para-aortic LNM, and 7 (6.6%) had isolated para-aortic LNM. Tumor grade, myometrial invasion, tumor diameter, cervical extension, lymphovascular space invasion, and adnexal involvement were found to be significant predictors of LNM. Of 215 patients with no myometrial invasion and tumor grade I/II, only 1 (0.47%) had LNM. However, in other patients, the risk of LNM was significant and at least3.5%. Furthermore, the risk of LNM was found to be well correlated with increases in myometrial invasion and tumor grade based on subgroup analyses, when patients with no myometrial invasion and tumor grade I/II were used as a reference group (p0.0001).Patients with endometrioid uterine cancers with no myometrial invasion and tumor grade I/II might have minimal risk of LNM, whereas others might require complete pelvic and para-aortic lymphadenectomy for surgical staging.

The aim of this study was to explore the cancer information needs, utilization, and source preferences in South Korean women with cervical cancer. This was a multicenter descriptive study comprising 968 cervical cancer patients (stages 0–IVb; mean age, 55 years; response rate, 34.4% of those who agreed to participate) who had been treated from 1983 through 2004 at any of the six South Korean hospitals. The study data were obtained through a mail-in self-response questionnaire that asked about the patients’ cancer information needs, cancer-information-seeking behavior, information sources, and type of information needed. It also collected data about anxiety and depression. Of the 968 cervical cancer patients, 404 (41.7%) had sought cancer information. When patients felt a need for information, their information-seeking behavior increased (overall risk = 4.053, 95% confidence interval = 2.139–7.680). Television and/or radio were the most frequently cited sources, and narratives about cancer experiences were the most easily understood forms of cancer information. More younger patients preferred booklets and pamphlets, while more older patients preferred television and radio. The most needed cancer information at the time of diagnosis and treatment involved diagnosis, stage, and prognosis while after treatment ended it involved self-care techniques. Cervical cancer patients’ need of cancer information varied with age and treatment phase. These findings should help guide the development of educational materials tailored to the needs of individual patients.

Observations from the authors' laboratory suggest a physiological role for increased cyclin G1 protein levels in human uterine leiomyoma. The hypothesis of the present study is that the strategic modulation of cyclin G1 by antisense technology will inhibit the survival of in vitro-grown uterine leiomyoma cells. Cultured uterine leiomyoma cells were transfected with cyclin G1 ribbon-type antisense oligonucleotide (cyclin G1 RiAS) to effectively reduce cyclin G1 expression. Cell viability, in situ terminal deoxyuridine nick end-labeling (TUNEL) assay, flow cytometry, DNA fragmentation, and expression of cell cycle regulatory-related proteins were evaluated by Western blot. Antisense oligonucleotides compromised uterine leiomyoma cell viability and inducted apoptosis in a caspase-independent mechanism. In situ TUNEL and DNA fragmentation revealed apoptosis induction, and fluorescent-activated cell sorting analysis showed increased sub-G1-phase cells. Furthermore, abrogation of cyclin G1 enhanced p53 accumulation, phosphorylation of p53 at Ser-15 residue, and increased expression of cyclin-dependent kinase inhibitors p21 and p27. These data imply that cyclin G1 expression is associated with growth promotion and the potential utility and novelty of using ribbon-type antisense oligonucleotides as a gene therapy strategy to treat human uterine leiomyoma.

No definitive recommendation is available concerning optimal antithrombotic ther- apy in pregnant women with a mechanical heart valve. The purpose of the current study was to evaluate the clinical results of nadroparin treatment with respect to pre- gnancy outcome and maternal complications. From 1997 to 2005, 31 pregnancies were reviewed in 25 women. Nadroparin (7,500 U, twice daily) was used in 23 preg- nancies between 6 and 12 weeks of gestation and close-to-term only, and coumarin derivatives were used with aspirin at other times. Eight pregnant women treated with coumarin derivatives throughout pregnancy were compared to evaluate the safety and efficacy of nadroparin. No maternal death or bleeding complication occu- rred in either of the two groups, and frequencies of maternal thromboembolism includ- ing valve thrombosis (8.7% vs. 12.5%, p>0.05) were similar. However, the frequen- cies of live born (91.3% vs. 50%, p=0.01) and healthy babies (90.4% vs. 25%, p< 0.01) were significantly higher, and the fetal loss rate was significantly lower (8.7% vs. 50%, p=0.01) in the nadroparin-treated group. Regarding the efficacy and safety of antithrombotic treatment in pregnant women with prosthetic heart valves, nadro- parin treatment during the first trimester is an acceptable regimen and produces better results than coumarin derivatives.

Objective The objective of the study was to analyze the characteristics of cervical cancer associated with pregnancy. Study Design Forty patients with cervical cancer associated with pregnancy were retrospectively identified between 1995-2003. Three controls for each case were matched on the basis of age, stage, histology, and date of treatment. Results Sampling of cervical cytology after the second trimester was the most common cause of delayed diagnosis. Among 12 patients who delayed treatment for fetal maturity, 2 died of disease. There was no difference in overall survival between pregnant and nonpregnant patients with stage Ib tumors. In contrast to nonpregnant patients, the depth of stromal invasion was not correlated with the incidence of lymph vascular space involvement and lymph node metastasis in pregnant patients. Conclusion Thorough evaluation is warranted before deciding whether to delay treatment until fetal maturity. Pregnancy does not adversely affect the prognosis of early-stage cervical cancer significantly.

OBJECTIVES: The recent advances in understanding the relation between cancer and metabolism have highlighted the relevance of serine/glycine biosynthesis and one-carbon metabolism. The aim of this study was to evaluate the expression of enzymes associated with serine/glycine metabolism in ovarian cancer stem like cells (CSCs) and discuss their potential clinical implications. METHODS: We established primary ovarian cancer cell cultures from dissected fresh tumor tissue. To isolate CD117(+) and CD44(+) CSCs from primary ovarian cancer cultures, we have modified and optimized the Magnetic-Activated Cell Sorting (MACS) procedure from Miltenyi resulting in high sorting purity. In the present study, we used Western blotting and immunohistochemistry to examine three serine-/glycine-metabolism-associated proteins (PHGDH, SHMT, and GLDC) in CSCs and ovarian cancer cases using tissue microarray (TMA). The expression of stemness gene (Nanog, Oct3/4, Sox2 and ABCG2) mRNA was determined by RT-PCR and protein expression was detected by Western blot analysis. RESULTS: GLDC, PHGDH and SHMT, associated with serine/ glycine metabolism, showed lower expression in the CSCs. TMA showed that the different expressions of GLDC, PHGDH and SHMT in platinum-sensitive and platinum-resistant ovarian cancer cases (p CONCLUSIONS: Based on our findings, we concluded that the expression of serine-metabolism-associated proteins was related with resistance of ovarian cancer cells and patient's survival. Citation Format: So-Jin Shin, Hye-Won Chung, Hyun-Gyo Lee, Eun Som Choi, Chi-Heum Cho. Differential expression of enzymes associated with glycine metabolism in ovarian cancer stem like cell. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1147. doi:10.1158/1538-7445.AM2015-1147

5527 Background: Belotecan is a camptothecin derivative with anti-tumor properties. Previous studies suggested the feasibility of belotecan-based chemotherapy for patients with primary or recurrent ovarian cancer. Thus, we conducted a phase IIb trial to compare the efficacy and safety between belotecan and another derivative of camptothecin, topotecan, in patients with recurrent or refractory ovarian cancer. Methods: Patients with recurrent or refractory ovarian cancer were randomized to receive belotecan 0.5 mg/m2 (B-arm) or topotecan 1.5 mg/m2(T-arm) intravenously for 5 consecutive days every 3 weeks till 6 cycles or disease progression. The primary endpoint was overall response rate based on RECIST or GCIG criteria, and secondary endpoints were progression-free survival (PFS), overall survival (OS) and adverse events according to NCI-CTCAE version 4.0. Results: One hundred and forty one patients were randomized from January 2011 to June 2014. Among all patients, 140 were eligible in full analysis (FA) ...

The incidence rate of cervical cancer in Korea is still higher than in other developed countries, notwithstanding the national mass-screening program. Furthermore, a new method has been introduced in cervical cancer screening. Therefore, the committee for cervical cancer screening in Korea updated the recommendation statement established in 2002. The new version of the guideline was developed by the committee using evidence-based methods. The committee reviewed the evidence for the benefits and harms of the Papanicolaou test, liquid-based cytology, and human papillomavirus (HPV) testing, and reached conclusions after deliberation. The committee recommends screening for cervical cancer with cytology (Papanicolaou test or liquid-based cytology) every three years in women older than 20 years of age (recommendation A). The cervical cytology combined with HPV test is optionally recommended after taking into consideration individual risk or preference (recommendation C). The current evidence for primary HPV screening is insufficient to assess the benefits and harms of cervical cancer screening (recommendation I). Cervical cancer screening can be terminated at the age of 74 years if more than three consecutive negative cytology reports have been confirmed within 10 years (recommendation D).

Purpose: Sodium butyrate (NaBT) is principally a histone deacetylase (HDAC) inhibitor, and it has the potential to arrest HPV-positive carcinoma cells at the G1 to S phase transition of the cell cycle. The aim of study was to determine whether phosphatidylinositol 3-kinase (PI3K) inhibition can enhance the inhibitory effect of NaBT on a human cervical cancer cell line (HeLa). Materials and Methods: Cervical cancer cells (HeLa) were treated with NaBT alone or in combination with the PI3K inhibitors wortmannin or LY294002. Cell viability analysis and FACS analysis were carried out. The expressions of the cell cycle related proteins were evaluated by Western-blot analysis. Results: Inhibition of PI3K enhanced NaBT-mediated apoptosis and this decreased the HeLa cell viability. Either wortmannin or LY294002, combined with NaBT, enhanced the activation of caspase 3 and caspase 9, and this enhanced the subsequent cleavage of poly (ADP-ribose) polymerase (PARP). Cervical cancer cells were arrested in the subG1 and G2/M phase, as was detected by FACS analysis. NaBT treatment in combination with PI3K inhibitors showed the increased expression of the CDK inhibitors p21Cip1/Waf1 and p27Kip1, in a p53 dependent manner, and also the increased dephosphorylation of Rb whereas there was a reduction in the expression levels of cyclin A, cyclin D1 and cyclin B1. Conclusion: The results demonstrate that inhibition of PI3K enhances NaBT-mediated cervical cancer cell apoptosis through the activation of the caspase pathway. Moreover, these findings will support future investigation using the PI3K inhibitors in combination with adjuvant treatment for treating carcinoma of the cervix. (Cancer Res Treat. 2006;38:112-117)

Previously, we have reported that BRCA1 regulates the expression of various classes of genes, including genes involved in xenobiotic stress responses (Bae, I., Fan, S., Meng, Q., Rih, J. K., Kim, H. J., Kang, H. J., Xu, J., Goldberg, I. D., Jaiswal, A. K., and Rosen, E. M. (2004) Cancer Res. 64, 7893–7909). In the present study, we have investigated the effects of BRCA1 on xenobiotic stress-inducible gene expression. In response to aryl hydrocarbon receptor (AhR) ligands, cytoplasmic AhR becomes activated and then translocates to the nucleus where it forms a complex with the aryl hydrocarbon receptor nuclear translocator (ARNT). Subsequently, the AhR·ARNT complex binds to the enhancer or promoter of genes containing a xenobiotic stress-responsive element and regulates the expression of multiple target genes including cytochrome P450 subfamily polypeptide 1 (CYP1A1). In this study, we have found that endogenous and overexpressed exogenous wild-type BRCA1 affect xenobiotic stress-induced CYP1A1 gene expression. Using a standard chromatin immunoprecipitation assay, we have demonstrated that BRCA1 is recruited to the promoter regions of CYP1A1 and CYP1B1 along with ARNT and/or AhR following xenobiotic exposure. Our findings suggest that BRCA1 may be physiologically important for mounting a normal response to xenobiotic insults and that it may function as a coactivator for ARNT activity. Using immunoprecipitation, Western blotting, and glutathione S-transferase capture assays, a xenobiotic-independent interaction between BRCA1 and ARNT has been identified, although it is not yet known whether this is a direct or indirect interaction. We have also found that the inducibility of CYP1A1 and CYP1B1 transcripts following xenobiotic stress was significantly attenuated in BRCA1 knockdown cells. This reduced inducibility is associated with an altered stability of ARNT and was almost completely reversed in cells transfected with an ARNT expression vector. Finally, we have found that xenobiotic (TCDD) treatments of breast cancer cells containing reduced levels of BRCA1 cause the transcription factor ARNT to become unstable.

A recent study of breast cancer patients with and without BRCA1 gene mutations found significantly lower levels of VEGF in serum from patients with BRCA1 mutations (Tarnowski, B., Chudecka-Glaz, A., Gorski, B., and Rzepka-Gorska, I. (2004) Breast Cancer Res. Treat. 88, 287-288). Here, we describe a possible mechanistic explanation for this correlation. Because hypoxia in tumors stimulates VEGF expression and secretion we hypothesized that altered BRCA1 protein levels in breast tumors could affect hypoxia-stimulated VEGF promoter activity. This possibility was tested in cells transfected with various combinations of expression plasmids for BRCA1, BRCA1 specific inhibitory RNAs (BRCA1-siRNAs), HIF-1alpha, and a VEGF promoter-reporter and then incubated in normoxia (21%, O2) or hypoxia (0.1%, O2). As predicted, increased BRCA1 levels enhanced both hypoxia-stimulated VEGF promoter activity and the amounts of VEGF mRNA, as determined by semiquantitative RT-PCR and quantitative real time PCR. Using the ChIP assay, we discovered that BRCA1 could be recruited to the endogenous human VEGF promoter along with HIF-1alpha following hypoxia. An interaction between BRCA1 and HIF-1alpha was found in human breast cancer cells. We also found that hypoxia-stimulated VEGF promoter activity and secretion was reduced in cells containing reduced amounts of endogenous BRCA1 protein (obtained by transfecting with BRCA1 siRNAs). A mechanistic explanation for these effects is provided by our finding a reduced half-life and reduced accumulation of HIF-1alpha in hypoxic cells transfected with BRCA1-siRNAs and that proteasome inhibitors blocked these effects of BRCA1-siRNAs. Thus, our results suggest that normal amounts of BRCA1 function in hypoxia to regulate HIF-1alpha stability, probably by interacting with HIF-1alpha.

(−)-Epigallocatechin-3-gallate (EGCG), a major polyphenolic substance found in green tea, is well recognized to be beneficial for human health. However, it is still controversial as to what dose of this compound is indeed good for human health. Though some recent studies have interestingly reported various beneficial effects of EGCG in cell culture system, however, plasma levels of EGCG attainable by oral regular intake in humans are normally in nanomolar range. However, potential side effects of EGCG when administered parenterally at higher concentration have not been thoroughly tested. Here, we evaluated the effect of EGCG on ATP-sensitive potassium (K ATP ) channels expressed in Xenopus oocytes. EGCG inhibited the activity of the Kir6.2/SUR1 and Kir6.2ΔC36 channels with IC 50 of 142 ± 37 and 19.9 ± 1.7 μM, respectively. Inhibition of EGCG was also observed in Kir6.2/SUR2A or Kir6.2/SUR2B channels. Notably, (−)-epicatechin-3-gallate (ECG), another major polyphenolic substance in green tea, was found to reduce the channel activity with greater potency than EGCG. In contrast to EGCG and ECG, which have the gallic acid-ester moiety in their own structures, (−)-epigallocatechin and (−)-epicatechin exhibited very weak inhibition of the K ATP channel. Collectively, these results suggest that the gallate-ester moiety of epicatechins may be critical for inhibiting the K ATP channel activity via the pore-forming subunit Kir6.2 and this may be a possible mechanism by which green tea extracts or EGCG may cause unexpected side effects at micromolar plasma level.

This study investigated the acute effects of a peroxisome proliferator-activated receptor (PPAR)-γ ligand, ciglitizone, on cell proliferation and intracellular Ca2+ signaling in human normal myometrium and uterine leiomyoma. Changes in intracellular Ca2+ concentration ([Ca2+]i) were measured with fura-2 AM, and cellular viabilities were determined by viable cell count and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide reduction assay. Ciglitizone (100 μM) induced greater inhibition of cell proliferation in uterine leiomyoma than in myometrium. Ciglitizone also dose-dependently increased [Ca2+]i in both myometrium and uterine leiomyoma; these [Ca2+]i increases were inhibited by PPAR-γ antagonists and raloxifene. Ciglitizone-induced [Ca2+]i increase showed only an initial peak in normal myometrial cells, whereas in uterine leiomyoma there was a second sustained [Ca2+]i increase as well. The initial [Ca2+]i increase in both myometrium and uterine leiomyoma resulted from the release of Ca2+ by the sarcoplasmic reticulum via activation of ryanodine receptors. The second [Ca2+]i increase was observed only in uterine leiomyoma because of a Ca2+ influx via an activation of store-operated Ca2+ channels (SOCCs). Cell proliferation was inhibited and secondary [Ca2+]i increase in uterine leiomyoma was attenuated by cotreatment of ciglitizone with a SOCC blocker, lanthanum. The results suggest that ciglitizone inhibits cell proliferation and increases [Ca2+]i through the activation of SOCCs, especially in human uterine leiomyoma.

Taurine has been found to inhibit ATP-sensitive K+ (KATP) channels in rat pancreatic beta-cells [Park et al., Biochem Pharmacol 2004;67:1089-1096] which could be due to its interaction with a benzamido-binding site on SUR1. In present study, we further evaluated the mechanism of taurine action on the KATP-channel inhibition, using cloned KATP-channels with different types of SUR subunit expressed in Xenopus laevis oocytes. The oocytes were coinjected with Kir6.2 mRNA, and mRNA encoding SUR1, SUR2A or SUR2B. Macroscopic currents were recorded from giant excised inside-out patches. The binding of glibenclamide to SUR1 was assessed by using a glibenclamide-fluorescent probe. Intracellular taurine inhibited all three types of KATP-channels to a similar extent. They were fit to the Hill equation, showing IC50 of 11.0 mM for Kir6.2/SUR1, 10.9 mM for Kir6.2/SUR2A, and 9.0 mM for Kir6.2/SUR2B currents. Taurine at the concentration of 10 mM enhanced the high-affinity bindings of glibenclamide and repaglinide on all types of SUR, whereas the low-affinity binding on Kir6.2 was not affected. The intensity of glibenclamide fluorescence was higher in the plasma membrane of taurine-pretreated oocytes. The high-affinity binding of tolbutamide or gliclazide on SUR was not modified by taurine. These results suggest that the taurine inhibition of KATP-channels is mediated by an interaction with the site on SUR where the benzamido group is bound. Therefore, intracellular concentrations of taurine in different tissues may be more important in determining taurine modulation of the KATP-channel rather than distinct types of SUR subunit.

It has been reported that macrophages produce substantial amounts of nitrite and nitrate after addition of catalase, but the mechanism associated remains unclear. In present study, we investigated whether catalase modulates the expression of inducible nitric oxide synthase (iNOS), an enzyme that produces nitric oxide. Exposure of Raw 264.7 macrophages (Raw cells) to catalase induced high expression of iNOS mRNA as well as protein with enzymatic activity. Data of mechanical analyses, such as iNOS promoter-driven luciferase assay and actinomycin D chase experiments demonstrated that the induction was due to increased iNOS transcription and post-transcriptional iNOS mRNA stability. Of interest, catalase-induced iNOS protein expression was abrogated through inactivation of NF-kappaB pathway by MG132 or BAY 11-7085 and PI3K pathway by LY294002 or wortmannin, respectively. In particular, blockage of PI3K pathway by LY294002 down-regulated iNOS transcription and steady-state iNOS mRNA levels as well as iNOS mRNA stability induced by catalase, suggesting regulation of PI3K pathway in catalase-induced iNOS expression at the levels of iNOS transcription, steady-state mRNA status, and mRNA stability. Additional cell culture works in different types of cells indicated that iNOS expression by catalase might be cell type-specific, based on the facts that catalase induced iNOS expression in BV2 microglial macrophage-like cells, but not in HT-29 or A549, human colon or lung cancer epithelial-like cells. Together, these results demonstrate for the first time that catalase induces iNOS expression in Raw cells, which seems to be associated with the increase of iNOS transcription and mRNA stability as well as the activation of NF-kappaB and PI3K signaling pathways.

Study Objective To evaluate and describe our experience in the management of recurrent second-trimester miscarriage and preterm delivery by laparoscopic transabdominal cervicoisthmic cerclage (LTCC), after failure of transvaginal cervical cerclage. Design Retrospective review (Canadian Task Force classification III). Setting Tertiary care teaching hospital. Patients Twenty women in whom it was not technically possible to perform transvaginal cerclage. Intervention LTCC. Measurements and Main Results Mean operating time was 55 minutes (range 40–75 min). There were no operative or immediate postoperative complications. Mean gestational age at the time of cerclage placement was 12.1weeks (range 11–14wks). Nineteen women successfully delivered 21 live babies (2 sets of twins; live birth rate 95%). One loss occurred after rupture of membrane at 19 weeks' after cerclage. Conclusion LTCC during pregnancy can be safe and effective treatment for well-selected patients with cervical incompetence, and eliminates the need for open laparotomy.

Objective: The purpose of this study was to detect the expression of cyclin G1 in leiomyoma and to investigate the alteration of its expression compared with normal myometrial tissue that was obtained from the same patient. Study Design: With the use of Northern blot analysis, Western blot analysis, and immunohistochemistry, we analyzed the expression of cyclin G1 in 24 patients who underwent hysterectomies. Results: We found that messenger RNA levels of cyclin G1 were elevated in human leiomyomas compared with their adjacent normal myometrial tissues. Consistent with elevated messenger RNA levels, high levels of cyclin G1 protein expression were detected by immunoblot analysis in all leiomyoma samples. Immunohistochemistry revealed that cyclin G1 is located mainly in the nucleus in both normal myometrium and leiomyoma. However, higher levels of cyclin G1 were apparent in tumor regions compared with adjacent normal myometrial regions. In addition, we found the expression levels of other cyclins (A and E) and CDK2 were elevated in leiomyomas compared with normal myometrium. Because cyclin G1 is a transcriptional target of the p53 tumor suppressor, we examined the p53 status of all eight leiomyoma samples and found no p53 mutations. Conclusion: These results suggest that cyclin G1 is frequently overexpressed in uterine leiomyoma in a p53-independent manner and that this abnormality could be attributed to the severe proliferation of human uterine leiomyomas. (Am J Obstet Gynecol 2003;188:634-9.)

OBJECTIVE: Cancer stem cells (CSCs) represent a subpopulation of undifferentiated tumorigenic cells responsible for tumor initiation, maintenance, drug resistance and metastasis of tumors. CSCs involved in drug resistance and relapse of cancers can significantly affect ovarian cancer therapy. The antibiotics salinomycin has recently been shown to be a potent compound to deplete chemoresistant cells in adenocarcinoma. The objective of the present study was to evaluate the effect of salinomycin on ovarian CSC whereby salinomycin mono-and combination treatment with paclitaxol regimend were analyzed. METHODS: The CD44+CD117+CSCs were isolated from the primary ovarian cancer cells derived from ascites fluids of patients with epithelial ovarian cancer by using immune magnetic-activated cell sorting system. To evaluate the effect of salinomycin on ovarian CSC, cells were treated in single and combined treatment. The expression was Nanog, Oct3/4, Sox2 and ABCG2 mRNA was determined by RT-PCR and protein expression was detected by Western blot analysis. The cell viability assay, gelatin zymography and apoptosis assay were applied to evaluate the effects of salinomycin compared with parental tumor cells and CSCs. RESULTS: The combination of salinomycin with paclitaxel (PTX) was enhanced change cell viability or activating apoptosis in CD44+CD117+ cells, whereas the salinomycin monotreatment did not cause significant changes. Salinomycin treatment reduced stemness gene expression and suppressed invasion of CSCs. CONCLUSIONS: Based on our findings, we concluded that anti-cancer effect of salinomycin with PTX reduced stemness and induced apoptosis in ovarian cancer and cancer stem cells. Citation Format: So-Jin Shin, Jin-Young Kim, Hyun-Gyo Lee, Eun-Ji Nam, Chi-Heum Cho. Salinomycin have antiproliferative and apoptotic effects on ovarian cancer stem-like cell. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 217. doi:10.1158/1538-7445.AM2014-217

Myomectomy is common gynecologic procedure performed for the conservative management of leiomyomas. The surgical removal of myomas can be associated with a considerable amount of intra-operative blood loss, which represents an important morbidity that may be associated with the procedure. The purpose of this video presentation is to demonstrate various preoperative and intraoperative measures that may decrease blood loss during a myomectomy. A particular emphasis was placed on demonstrating the evidence-based strategies that have been shown to decrease blood loss in minimally-invasive abdominal myomectomies. The strategies that are covered in this video presentation include the preoperative use of medications, temporary and permanent uterine artery occlusion, injection of vasopressin and use of barbed suture for closure of the uterine defect.

5568 Background: Cremorphor EL, used to enhance drug solubility, may add to paclitaxel’s toxicities such as hypersensitivity reactions or peripheral neuropathy. This multi-institutional phase II trial is to evaluate the efficacy and safety of Cremophor-Free, Polymeric Micelle Formulation of Paclitaxel (Genexol-PM) compared to Paclitaxel (Genexol) as a combined chemotherapy with carboplatin in patients with advanced epithelial ovarian cancer. Methods: In this phase II, randomized, parallel study, patients with FIGO stage IC-IV epithelial ovarian cancer after debulking surgery received intravenously Genexol-PM 260 mg/m2 or Genexol 175 mg/m2 combined with carboplatin iv (AUC 5) on day 1 of every 3-week cycle for a maximum of six cycles. The primary endpoint was composite response by GCIG CA-125 Response and Response Evaluation Criteria In Solid Tumors (RECIST). Secondary and exploratory endpoints included overall survival, progression-free survival, time to tumor progression, and safety and tolerability. Results: A total of 102 patients were randomized to Genexol-PM plus carboplatin (n = 51) or Genexol plus carboplatin (n = 51). Composite response rate in patients with or without measurable disease was 88.0% in the Genexol-PM plus carboplatin group and 77.1% in the Genexol plus carboplatin group. Noninferiority of Genexol-PM plus carboplatin compared with Genexol plus carboplatin was confirmed for composite response rate by CA-125/RECIST criteria. There were no differences in progression-free survival and overall tumor progression between the groups. Although there was a higher rate of grade 3 neutropenia in the Genexol-PM plus carboplatin group, the overall rate of hemodynamic adverse events was comparable between the 2 groups. There was no difference in peripheral neuropathy and hypersensitivity. No unexpected safety concerns were identified in this study. Conclusions: High-dose of Genexol-PM in combination with carboplatin was well tolerated, and its response rate was noninferior to that of Genexol plus carboplatin in patients with advanced epithelial ovarian cancer. Clinical trial information: NCT01276548.

Ovarian cancer has the highest mortality rate among gynecologic malignancies in the world. Drug resistance is the main cause of treatment failure and mortality in cancer patients. The objective of this study was to establish a paclitaxel (PTX)-resistant human ovarian carcinoma cell line (OVCAR3) and to sensitize chemoresistant cells. The drug-resistant tumor cell lines were established in vitro by stepwise sequential exposure to increased concentration of PTX. For sensitization, OVCAR3/PTX cells were treated with different concentration of salinomycin alone or combined with PTX. The cell viability and cell cycle distribution was measured by MTT and flow cytometric analysis. The transcriptional change of mRNA was examined by RT-PCR. The induction of apoptosis was measured by caspase-3 activity test, DNA fragmentation assay and western blot analysis. The cell viability was significantly reduced by combination treatment in a dose dependent manner. The flow cytometry result showed an increase in sub-G1 phase. Combination treatment enhanced the sensitivity of OVCAR3/PTX cells to PTX with down-regulation of P-glycoprotein, XIAP and survivin. Taken together, we demonstrated potential effect of salinomycin in sensitization of PTX resistant ovarian tumor growth. Our results suggest salinomycin in combination with PTX may be a beneficial chemotherapeutic strategy, especially in patients with tumors refractory to PTX alone. Citation Format: Chi-Heum Cho, Hyun-Gyo Lee, Bidur Parajuli, So-Jin Shin, Sang-Hoon Kwon, Soon-Do Cha. Salinomycin sensitized paclitaxel-resistant human ovarian cancer cells and induced apoptosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 973. doi:10.1158/1538-7445.AM2013-973

Ciglitazone is a kind of thiazolidinedione and a potent, selective peroxisome proliferator-activated receptor γ (PPAR γ) ligand and it is active in vivo as an anti-hyperglycemic agent in the murine model. Glucose metabolism plays a key role in the maintenance of energy homeostasis in organisms and changes in cellular glucose uptake rate are found in malignant diseases. Significant increase in glucose consumption can be found in many malignant conditions and research so far has focused on its apoptotic and inhibition of proliferation properties but their role in cell death is unclear. We show that ciglitazone inhibits glucose uptake in ovarian cancer cell through GLUT-1 expression. In this study, we investigated the effect of ciglitazone to GLUT-1 expression and cell proliferation. We further demonstrate that ciglitazone pretreated tumor cell was increased apoptosis dose dependent manner and siGLUT-1 treated tumor cell showed increased apoptosis. Interestingly, not only cancer cell line but also in vivo state, ciglitazone could decrease tumor mass. Specificity protein (Sp) is highly expressed in tissues of prostate cancer, breast carcinomas and lung cancer when compared to normal tissues or cells. Previous studies showed that Sp1 plays an important role in carcinogenesis and metastasis of several human tumor types by regulating growth-related signal transduction, cell cycle control molecules, apoptosis, oncogenes, tumor suppressor genes. In this study there was no relation with apoptosis and SP1 expression. We demonstreated that ciglitazone inhibit glucose uptake in ovarian cancer cell lines and the relationship between ciglitazone and GLUT-1 in ciglitazone induced cell death. Citation Format: Jin Young Kim, So Jin Shin, Keon Uk Park, Young June Jeon, Chi Heum Cho, Eunyoung Ha. Ciglitazone increases ovarian cancer cell death by inhibiting GLUT-1 expression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1865. doi:10.1158/1538-7445.AM2013-1865

Objective: Uterine leiomyomas are the most prevalent benign tumors in women of reproductive age and the leading indication for hysterectomy in premenopausal women. The underlying causes of uterine leiomyomas are poorly understood, as a result, in part, of the absence of a good model system with which to study these tumors. To overcome this problem, this study was undertaken to develop a murine model for human leiomyoma. Study design: Human leiomyoma tissues were cut into small pieces and some of those were cultured. Tissue pieces and cultured cells were inserted subcutaneously in the flank of each severe immunodeficiency (NOD/SCID gamma, NSG) mice (n=6). Estrogen supplement was needed to maintain serum estrogen level 3 days before the tissue or cultured cells transplantation. Xenograft tissues or cells were harvested after 6wks and analyzed. Results: Six uterine leiomyoma xenografts were successfully established with the tumor tissue derived from six patients. The xenografted human uterine leiomyoma tissues retained their gross appearance with small vessels around the implant tissues and did not change in size up to 6wks after implantation. H&E staining showed that xenografts retained major histologic features of the original leiomyoma. The immunohistochemical staining of SMA(smooth muscle actin) revealed strong cytoplasmic and membranous positivity of spindle tumor cells of xenografts.Conclusions: In summary, transplantation of surgical specimens from uterine leiomyoma patients into NSG mice results in an attractive model for the study of the uterine leiomyoma and may also be useful for analysis or new experimental therapeutic approaches for the treatment of this disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1357. doi:1538-7445.AM2012-1357

Objective The aim of this study was to identify a standard for the evaluation of future models for prediction of lymph node metastasis in endometrial cancer through estimation of performance of well-known surgicopathological models. Methods Using the medical records of 947 patients with endometrial cancer who underwent surgical management with lymphadenectomy, we retrospectively assessed the predictive performances of nodal metastasis of currently available models. Results We evaluated three models included: 1) a model modified from the Gynecologic Oncology Group (GOG) pilot study; 2) one from the GOG-33 data; and 3) one from Mayo Clinic data. The three models showed similar negative predictive values ranging from 97.1% to 97.4%. Using Bayes' theorem, this can be translated into 2% of negative post-test probability when 10% of prevalence of lymph node metastasis was assumed. In addition, although the negative predictive value was similar among these models, the proportion that was classified as low-risk was significantly different between the studies (56.4%, 44.8%, and 30.5%, respectively; p

Primary fallopian tube carcinoma is one of the rarest gynecological malignancies, accounting for 0.18% to 1.6% of all malignant neoplasms of the female reproductive tract. Preoperative diagnosis was difficult due to nonspecific symptoms and signs. This case of primary tubal cancer was diagnosed preoperatively on the basis of ultrasonography, computed tomography and magnetic resonance imaging. We have experienced a case of primary fallopian tube carcinoma before operation and so report with brief review of the literature.

Choriocarcinoma is a rapidly growing tumor that characteristically outgrows its blood supply. We report a rare case of metastatic choriocarcinoma presenting with acute right flank pain due to kidney rupture secondary to renal metastasis. The renal metastasis was embolised to stanch blood for control of hemorrhage. A brief review of the imaging features and therapeutic options for the ruptured renal metastases is discussed along with the case.

e15504 Background: Locally advanced bulky cervical cancer (LABCC) is characterized by poor local control. The objective of this study was to identify the clinicopathologic variables associated with...

Objective: To address the growth inhibitory effects of Genistein and Indole 3 carbinol in endometrial cancer cell growth and evaluate its effect on apoptosis using ishikawa endometrial cancer cell line. Methods: Human endometrial cancer cells ishikawa were cultured and treated with various concentrations of Genistein and Indole 3 carbinol alone and in combination. Cell proliferation and growth arrest were evaluated by MTS assay and FACS analysis, respectively. The apoptosis induced was analyzed by DNA fragmentation and western blotting. Results: Combination of Genistein and Indole 3 carbinol significantly inhibited the proliferation of ishikawa cells in dose dependent manner. Cell cycle analysis indicated the increased proportion of cell arrest in sub G1 phase. DNA fragmentation, up regulation of DR5, down regulation of c-Flip, cleavage of caspase-8 and PARP revealed apoptotic progression. Conclusion: Genistein and Indole 3 carbinol synergistically inhibited the growth of endometrial cancer cell. Significant induction of apoptosis is associated with DR5 regulated death dependent pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4762. doi:10.1158/1538-7445.AM2011-4762

Objective : Peroxisome Proliferator-Activated Receptor (PPAR)-gamma ligands constitute important insulin sensitizers that have already been approved for the treatment of human metabolic disorders. It has been previously demonstrated that growth inhibition in human uterine leiomyoma cells mediated by caspase-dependent pathway and death receptor. The present study was designed to further understand the mechanism after uterine leiomyoma and normal myometrial cells were exposed to PPAR gamma agonist, Ciglitizone. Methods : In order to confirm the unknown cellular and biochemical responses to ciglitizone treatment with three uterine leiomyoma and normal myometrial cells, DNA chip analysis were performed. Highly up-regulated genes were confirmed to ascertain effect of PPAR gamma agonist by RT-PCR and Western-blot analysis. To analyze mechanism of invasion and metastasis -associating gene regulation by PPAR-γ ligands, wound healing assay and soft agar assay were performed. Results : DNA chip analysis revealed genes are related with cell adhesion and metastasis genes including plasminogen activating urokinase (PLAU), claudin 1, matrix metallopeptidase 1,2, and 9. Highly down-regulated genes had defense system against cell metastasis in common and was related with adhesion. Treatment with ciglitizone made decrease expression level of above cell adhesion related genes in dose dependent manner by RT-PCR and Western-blot analysis. Furthermore, treatment with ciglitizone in uterine leiomyoma cells decrease the invasion ability of leiomyoma cells and the formation of anchorage-independent colonies in soft agar. Conclusions : These results suggest that PPAR-gamma could be considered as a therapeutic target for diverse disease states in which excessive angiogenesis is implicated, including cancer and uterine leiomyoma. This phenomenon has not been previously reported for PPAR-gamma agonist in uterine leiomyoma. Defining the role of PPARγ in uterine leiomyoma cells will be paramount for a rational design of combinatorial therapy schemes that takes advantage of the potent and well-tolerated PPARγ agonists. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 676.

Objective: To determine the anti-tumor effect of isoliquiritigenin (ISL) on endometrial cancer cell and to evaluate its effect on apoptosis in Hec1A endometrial cancer cell lines. Methods: Human endometrial cancer cell lines (Hec1A) and Ishikawa, and normal endometrial cell line (T-HESCS) were cultured in vitro. The viabilities of three cell lines on ISL were measured. Cell cycle distribution and induction of apoptosis were measured in Hec1A cells after ISL treatment. Results: ISL significantly reduced cell viabilities of endometrial cancer cell lines but not normal cell line in a dose-dependent manner. Cell cycle analysis indicated that ISL treatment increased the proportion of cells in the sub-G0/G1 phase. DNA frag- mentation and fluorometric TUNEL assays also revealed apoptotic cell death after ISL incubation. ISL treatment markedly up-regulated the expression of cyclin-dependent kinase inhibitor, p21 Cip1/Waf1 in a p53 independent manner and down regulated the expressions of cyclins and CDKs, with concomitant increase in FAS and cleavage of caspase 7, caspase 8, and caspase 9. In addition, elevation of caspase 3 activity also observed in a dose and time dependent manner. Conclusion: ISL inhibited cell proliferation and triggered apoptosis in human endometrial cancer cell line Hec1A. Hence, ISL can be used as a potentially potent clinical chemotherapeutic agent for treating endometrial cancer.