Expression and prognostic significance of SP1, KLF4 and p21 in ovarian serous carcinoma / 临床与实验病理学杂志

Purpose To explore the difference of expression and prognostic significance of SP1,KLF4 and p21 in low grade ovarian serous carcinoma (LGSC) and high grade ovarian serous carcinoma (HGSC).Methods The expression of SP1,KLF4 and p21 protein was examined with immunohistochemistry EliVision method in cases with LGSC and HGSC.Kaplan-Meier analysis and Cox multivariate survival analysis were used to assess the impact of SP1,KLF4 and p21 expression on prognosis of LGSC and HGSC.Results SP1,KLF4 and p21 expression were detected respectively in 74.5％,17.0％ and 11.7％ HG-SC cases,and in 65.2％,34.8％ and 26.1％ LGSC cases.Compared to control group,the expression level of SP1 was significantly higher (P ＜ 0.05),but the expression level of KLF4 and p21 were significantly lower (P ＜0.05).There was no significant difference of SP1,KLF4 and p21 expression between HGSC and LGSC (P ＞ 0.05).The expression of SP1,KLF4 and p21 were associated with FIGO stage,meanwhile SP1 associated with residual tumor size in HGSC (P ＜ 0.05).There was a significant negative correlation between SP1 and KLF4,p21 proteins in HGSC (P ＜ 0.05).Kaplan-Meier analysis revealed that there were significantly poor overall survival (OS) of 5 years for patients with HGSC displaying high expression of SP1,or low expression of KLF4 and p21 (P ＜0.05),but no significantly improved OS for patients with LGSC (P ＞ 0.05).Cox analysis showed that SP1 overexpression is an independent prognosis factor for HGSC.Conclusion Overexpression of SP1 and low expresion of KLF4 and p21 contribute to carcinogenesis of HGSC and LGSC.They are associated with a poor prognosis of HGSC,but not LGSC,meanwhile SP1 is an independant prognosis factor for HGSC.

Prognostic Significance of KAI-1 and Survivin Expressions in Ovarian Epithelial Carcinomas / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The purpose of this study was to evaluate the expressions of KAI-1 and survivin, and to investigate their correlation with the clinical stage and survival rate of patients with ovarian carcinomas. MATERIALS AND METHODS: The expressions of survivin and KAI-1 were immunohistochemically determined in 54 serous and mucinous ovarian adenocarcinomas and borderline malignancy tumors. 10 of the 54 cases were also analyzed for the expressions of survivin and KAI-1 using western blot. RESULTS: The down-regulation of the expression of KAI-1 was observed by immunohistochemical staining (IHC) in 53.7% of the ovarian cancers, and a negative reaction in 50% by the western blot analysis. From the IHC, the survivin expression was positive and strongly positive in 51.9 and 18% of the ovarian cancers, respectively. From the western blot analysis, 10% of the ovarian cancer showed positive reactions. The down- regulation of the KAI-1 expression was significantly correlated with the clinical stage (p=0.001) and disease free survival rate (p<0.001), but not with the histological type. The expression of survivin was not correlated with the clinical stage or histological type. However, the patients with a negative survivin expression had a significantly longer disease survival rate than those with a strong positive expression. CONCLUSION: The down- and up-regulation of the KAI-1 and survivin, respectively, might be independent prognostic factors in human ovarian carcinomas.

Expression of Cyclin D1 and CDK4 in DMBA-Induced Rat Ovarian Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Ovarian cancer is a common gynecologic malignancy and the leading cause of death in women. It is typically not diagnosed until it has reached the advanced stages. We performed this study to investigate the roles of the proteins related to the G1 cell cycle in ovarian carcinogenesis. MATERIALS AND METHODS: Immunohistochemistry and Western blot were used to analyse the expression of cyclin Dl and CDK4 in 7, 12-dimethylbenzanthracene- induced ovarian cancer in rats. RESULTS: The Cyclin D1 and CDK4 labelling index was significantly higher in the ovarian cancers than in the normal ovarian surface epithelium of rats. There was no difference among the cancer types. In Western blot analyses, the expression of cyclin Dl and CDK4 in the ovarian cancers was higher than that in the normal ovarian surface epithelium. A positive correlation was observed between the expressions of the CDK4 and Cyclin D1. CONCLUSION: The upregulation of cyclin Dl and CDK4 that occurs in DMBA-induced rat ovarian carcinogenesis is likely to be associated with tumor progression. Further studies are needed to investigate the role and function of cyclin Dl and CDK4 in human ovarian cancer.

Growth Suppression of Ovarian Cancer Cells by Interferon-gama / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Growth regulation of cancer cells very frequently involves tumor suppressor gene p53, Rb and cell cycle regulator, however the molecular biologic mechanisms of growth regulation in ovarian carcinoma cells are not fully defined. To assess the mechanism of growth suppression, we treated IFN-gama in ovarian carcinoma cells. MATERIALS AND METHODS: Growth suppression by treatment of IFN-gama was determined by cell proliferation assay in ovarian carcinoma cell lines. Apoptosis was determined by DNA fragmentation assay and electron microscopy. Molecular mechanism of the apoptosis in ovarian carcinoma cell by IFN-gama was further analyzed by the western blot. RESULTS: We found that IFN-gama had remarkable growth- suppressive effects in PA-1 and A2774 ovarian carcinoma cells in a time-dependent manner. Apoptosis was observed in PA-1 and A2774 cell following treatment of IFN- gama by DNA fragmentation assay and EM. The expression of IRF-1 protein from A2774 and PA-1 cell extracts was elevated by increasing the concentration of IFN-gama. IFN-gama caused an increased expression of the important apoptosis-related gene, ICE (interleukin-1beta-converting enzyme) protein in A2774 and PA-1. CONCLUSION: The coordinate induction of IRF-1 and ICE by IFN-gama in ovarian carcinoma cells suggests a functional relationship between these proteins in programmed cell death. The significance of this study is the molecular biologic background of IFN-gama considered as an alternative treatment trial of ovarian cancers.

Calcified Cavernous Hemangioma of the Ovary: A Case Report

Ovarian hemangiomas are very uncommon and most are of the cavernous type. A few reports have described the radiologic findings of this neoplasm, but as far as the author is aware, the literature contains no description of calcified cavernous hemangioma. A case in which this condition involved the ovary is now reported.

Changes of Telomerase Activity by Protein Kinase C Modulators in Human Ovarian Cancer Cell Lines / 대한암학회지

PURPOSE: This study was designed to find out whether protein kinase C (PKC) may affect telomerase activity in human ovarian cancers. MATERIALS AND METHODS: To determine whether PKC modulators influence PKC activities, NIH: OVCAR-3 and CUMO-2, cells were treated with PKC inhibitors, G 6976 and bisindolyl maleimide I, and PKC activator, 12-O-tetradecanoyl phorbol 13-acetate (TPA). Telomerase acti vity was determined by telomeric repeat amplification protocol (TRAP). Analysis of the expres sion of each telomerase subunits, human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT), was performed by RT-PCR. We also examined the alternative splicing of hTERT. RESULTS: G 6976 and bisindolylmaleimide I inhibited PKC activity. Telomerase activities appeared to be affected in a time-dependent manner by these two PKC inhibitors. PKC activities were increased in parallel with telomerase activity by TPA at the low dose (10 nM), but their activities were down-regulated at the high dose (1 micrometer). RT-PCR demonstrated the presence of hTR and hTERT mRNA before and after the treatment of PKC modulators, respectively, and showed the presence of one alternatively spliced transcript and full-length hTERT transcripts. CONCLUSION: These results showed that telomerase activity was affected by PKC and suggested PKC modulation may serve as an useful tool in the regulation of telomerase activity.

Alterations of HLA Class I and II Antigen Expressions in Borderline, Invasive and Metastatic Ovarian Cancers / 대한암학회지

PURPOSE: The relationship between altered HLA expressions and ovarian carcinogenesis is not fully elucidated. MATERIALS AND METHODS: Histological evaluation comprised 20 serous adenocarcinoma, 5 borderline serous malignancy, 10 mucinous adenocarcinoma, 15 borderline mucinous malignancy. We used monoclonal antibodys to HLA class I beta2-microglobulin, class I B/C and class II heavy chain. RESULTS: There was no statistical difference in HLA expressions between borderline serous malignancy and normal ovarian tissue. In serous adenocarcinoma, beta2-microglobulin, B/C and class II heavy chain expressions were down-regulated. In metastatic cancer, B/C and class II ex pressions were also down-regulated. But the HLA expression of tumor or normal stromal tissue in primary tumor, were not down-regulated compared with the tissues in metastasis. In borderline mucinous malignancy, class II expressions were down-regulated. In mucinous adenocarcinoma, beta2-microglobulin, B/C and class II expressions were down-regulated. In metastatic ovarian cancer, B/C and class II expressions were down-regulated. But, in borderline malignancy, the result failed to reach statistical significance except class II of borderline mucinous malignancy. CONCLUSION: Loss of HLA class I and II molecules in invasive ovarian cancers raises the possibility that this could be a mechanism for tumor cells to have invasiveness.

Differentiation between Ovarian Fibroma and Subserosal Leiomyoma by MR Imaging

PURPOSE: To evaluate the findings and differential points of ovarian fibroma and subserosal leiomyoma, as seen on MR images. MATERIALS AND METHODS: The MR imaging findings of 31 surgically confirmed cases of ovarian fibroma(n=6) and subserosal leiomyoma (n=25 ; 28 lesions) were evaluated. Multiplanar T1- and T2-weighted and postcon-trast T1-weighted images were obtained using a 1.5T MR unit, and histologic examination was also performed. The MR findings were analyzed in terms of signal intensity, the presence and definition of margin, the histo-logic finding of hyperintense lesion on T2-weighted images, the presence of the bridging vessel sign, degree of enhancement, and the presence of ipsilateral ovary and ascites. RESULTS: Both fibromas and leiomyomas showed hypo-or isointensity compared with uterine myometrium on T1-weighted images and compared with skeletal muscle on T2-weighted images. The latter revealed intratu-moral hyperintense lesions in most cases of ovarian fibroma and subserosal leiomyoma. Three of four ovarian fibromas had a well defined margin after cystic change, but in 24 of 26 subserosal leiomyomas the margin was ill defined. The "bridging vessel sign" was visible only in subserosal leiomyomas (22/28), and in all cases the enhancement of ovarian fibromas were less than that of myomtetrium. Subserosal leiomyomas (12/28), seen on enhancement as isointense or hyperintense to myometrium, showed a greater degree of enhancement than ovarian fibromas (0/6). Ipsilateral ovary was rarely seen in ovarian fibromas (1/6), but commonly seen in sub-serosal leiomyomas (20/25). Ascites was present in one case of ovarian fibroma. CONCLUSION: A defined margin of an intratumoral hyperintense lesion, as seen on T2-weighted images, and the presence or absence of the "bridging vessel sign" and ipsilateral ovary are useful signs when differentiating be-tween ovarian fibromas and subserosal leiomyomas.

Radiologic Findings of Ovarian Fibrothe

PURPOSE: To evaluate the radiologic features of fibrothecoma of the ovary, which is a rare solid tumor originating from the ovarian sex cord-stroma. MATERIALS AND METHODS: The radiologic findings of 29 patients with pathologically-proven fibrothecoma of the ovary were retrospectively evaluated for bilaterality, size, shape, margin, echogenecity, CT attenuation, signal intensity on magnetic resonance imaging, calcification, and amount of ascites. RESULTS: All fibrothecomas were unilateral, and had well defined margins. The diameter of the mass was 4-18(mean, 9.6)cms. Elghteen of 29 tumors were round or oval with a smooth margin, and eleven were lobulated. The internal architecture of the tumor was purely solid in 21 patients, predominantly solid in six, and pre-dominantly cystic in two. A broad spectrum of sonographic features was apparent, including a homogeneously hypoechoic mass (with posterior shadowing in four cases, and without posterior shadowing in ten), a homoge-neously hyperechoic mass in seven cases, an anechoic mass with septatations in two, and a mixed echoic mass in six. On precontrast CT scans, the mass was isodense to the uterine myometrium in eight of nine cases, while on postcontrast scans the lesion was slightly hypodense to the myometrium in seven cases and isodense in one. On T1-weighted MR images, nine of ten cases showed a relatively homogeneous low signal intensity, while on T2-weighted images, signal intensity was homogeneously low in two patients and predominantly low with focal high intensity in seven of the other eight. On gadolinium-enhanced T1-weighted images, most tu-mors showed slight heterogeneous enhancement. Calcifications were present in two cases, and in two others there was a large amount of ascites. CONCLUSION: The characteristic finding of ovarian fibrothecomas is a well-defined, oval or lobulated homoge-neously solid mass, which on CT scans enhances less than uterine myometrium and demonstrates a predomi-nantly low signal intensity on both T1- and T2-weighted images. However, a predominantly solid mass with cystic components or a predominantly cystic mass may also be presented.

A Case of Triple-Alkylating Regimen and Peripheral Blood Stem Cell Transplantation for a Patient with Relapsed Ovarian Carcinoma / 대한암학회지

Despite an aggressive surgical debulking followed by front-line chemotherapy, most patients with advanced ovarian carcinoma die of drug-resistant disease. Drug resistance can be overcome in a subset of patients with hematologic malignancies and lymphoma with high-dose therapy (HDT) and hematopoietic stem cell transplantation, suggesting that this therapy may also be value in ovarian carcinoma. We report the successful outcome of HDT and peripheral blood stem cell transplantation (PBSCT) in a 41-year-old nulliparous woman who initially was diagnosed with advanced ovarian carcicnoma with FIGO stage IIIc. Her disease relapsed after 19 months from initial therapy of definitive surgery and intra- and post-operative chemotherapy. Subsequently, she received optimal debulking surgery and salvage chemotherapy followed by HDT with triple- alkylating regimen, composed of cyclophosphamide (100 mg/kg), thiotepa (500 mg/m2), and melphalan (100 mg/m2). Her pretranplant characteristics were platinum-sensitive and complete response state. She showed rapid hematologic recovery and mild regimen-related toxicity (Bear man's toxicity criteria), stomatitis (grade I), cardiac toxicitiy (grade II). She has been followed up for 36 months after the inital therapy and is doing well without relapse.

Chromosomal Aberrations in Ovarian Carcinoma Cell Line, SNU - S , Using Chromosome Painting / 대한암학회지

PURPOSE: The characterization of all recognizable chromosomal rearrangements was dis- turbed by technical limitation of conventional cytogenetic methods. Recently, the strong usefullness of generation of chromosome specific painting probes in identification of marker chromosomes has proven. This study was intended to analyze the chromosomal aberrations in human ovarian cancer cell line, SNU-8, by G-banding and multiple paintings. MATERIALS AND METHODS: Human ovarian cancer cell line, SNU-8 was cultured and harvested for cytogenetic analysis. Routine karyotyping was performed. For complete analysis of chromosomal aberrations, human chromosome-specific painting probes were constructed from somatic hybrid cells. The origins of the unidentified marker chromosomes were analyzed by fluorescent in situ hybridization (FISH) with these painting probes. RESULTS: All chromosome alterations were confirmed by the use of multiple chromosome paintings, which also demonstrated a number of additional alterations. SNU-8 had the karyotype 62-69,XXX, + der(1;10)(q10;p10),der(3;18) (q10;p10)X2,-4,+ 5,+ 7,del(9)(q21)X2,-11,-13,-15,-16,der(17;19)(q10;q10) X2, + 20,-22[cp51]. CONCLUSION: The chromosomal aberrations of SNU-8 cell line was effectively analyzed by FISH with these painting probes, and the approach methods of this study can be applied to cytogenetic analysis of chromosomal aberrations in the other cancers.

Phase I Clinical Trial of Paclitaxel Plus Ifosfamide for the Patients with Refractory Ovarian Cancer / 대한암학회지

PURPOSE: Patients with advanced ovarian carcinoma and refractory to platinum based chemotherapy have a very poor prognosis and effective salvage regimens are needed. This study was conducted in order to determine the maximum tolerated dose (MTD) and dose limiting toxicity of combination with paclitaxel and ifosfamide. MATERIALS AND METHODS: After premedication, patients received paclitaxel (110~225 mg/m2) as a 24 hour IV infusion on day 1. Ifosfamide (1,000~1,500 mg/m2) was given as a 12 hour IV infusion with standard dose of mesna on day 2~6. All patients received G-CSF (granulocyte colony stimulating factor) on day 6~15. RESULTS: 12 patients with advanced ovarian cancer entered this trial. Toxicity included bone marrow suppression, neuromuscular toxicity, urothelial toxicity, gastrointestinal toxicity, which occurred in 84.6%, 65.3%, 30.7%, 88.4% of cycles. CONCLUSION: Neuromuscular toxicity was dose limiting toxicity. Maximum tolerated dose in com bination with paclitaxel and ifosfamide was 175 mg/m2 of paclitaxel and 1,500 mg/m2 of ifosfamide.