Cigarette smoking and epithelial ovarian cancer by histologic type

OBJECTIVE: To examine cigarette smoking as a risk factor for different types of epithelial ovarian cancer. METHODS: We used data from the Cancer and Steroid Hormone Study, a multicenter, population-based, case control investigation. Cases were 447 women aged 20-54 years with diagnoses of epithelial ovarian cancer. Controls were 3868 women selected by random-digit dialing. Conditional logistic regression was used to obtain odds ratios (ORs) and 95% confidence intervals (CIs) as estimators of the relative risk of ovarian cancer. With age and study site as conditioning variables, OR point estimates were additionally adjusted for parity and use of oral contraceptives. RESULTS: The OR of mucinous epithelial ovarian cancer for women who had ever smoked was 2.3 (95% CI 1.4, 3.9) and for current smokers was 2.9 (95% CI 1.7, 4.9). The OR of mucinous tumors for current smokers was significantly elevated regardless of years since first cigarette or age at which women first smoked. The OR of mucinous tumors for current smokers increased slightly as cumulative pack-years of smoking increased, although the trend was not significant. Similar patterns of elevated risk were not observed among serous, endometrioid, or other histologic types. Odds ratio point estimates for former smokers were not significantly elevated for any histologic type. CONCLUSION: Current cigarette smoking was a risk factor for mucinous epithelial ovarian cancer, but not other histologic types.     

Differential gene expression analysis of ovarian cancer in a population isolate

Gene expression products represent candidate biomarkers with the potential for early screening and therapy of patients with ovarian serous carcinoma. The present study, using patients that originate from the population isolate of South Tyrol, Italy, substantiates the feasibility of differential gene expression analysis in a genetically isolated population for the identification of potential markers of ovarian cancer. Gene expression profiles of fresh-frozen ovarian serous papillary carcinoma samples were analyzed and compared to normal ovarian control tissues using oligonucleotide microarrays complementary to 14,500 human genes. Supervised analysis of gene expression profiling data identified 225 genes that are down-regulated and 635 that are up-regulated in malignant compared to normal ovarian tissues. Class-prediction analysis identified 40 differentially expressed genes for further investigation as potential classifiers for ovarian cancer, including 20 novel candidates. Our findings provide a glimpse into the potential of population isolate genomics in oncological research.     

Impact of hormone replacement therapy on the histologic subtype of breast cancer

OBJECTIVE: Postmenopausal hormone replacement therapy (HRT) is associated with an increase in breast cancer risk, which correlates to the duration of HRT use. We wanted to investigate a possible association between HRT use and the risk of a histologic subtype of breast cancer. PATIENTS AND METHODS: From 1995 until 2004, 497 cases of primary ductal, lobular or ductulolobular breast cancer in postmenopausal women were diagnosed at the Department of Gynecology and Obstetrics, University Hospital Basel, Switzerland. The data was derived from patient's records. HRT ever use was defined as HRT use for > or =6 months. RESULTS: Of the 99 cases of lobular cancer 72.7% were invasive lobular cancers, 21.2% were invasive ductulolobular cancers and 6.1% were lobular cancers in situ. Of the 398 cases of ductal cancer, 90.5% were invasive ductal cancers and 9.5% were ductal cancers in situ. Totally 144 women were HRT ever users, and 341 women were HRT never users. HRT status could not be defined in 12 women. HRT ever use was associated with an increased risk for lobular cancer (OR 1.67; 95% CI 1.02-2.73). Also, menopause due to bilateral oophorectomy was associated with an increased risk for lobular cancer (OR 2.42; 95% CI 1.06-5.54). CONCLUSIONS: There is evidence that HRT as well as menopause due to bilateral oophorectomy may be associated with an increased risk for lobular cancer. This association is of major clinical relevance, since lobular breast cancer is more difficult to diagnose clinically and radiologically than ductal breast cancer.     

卵巢癌顺铂耐药细胞模型中14-3-3蛋白的差异表达

目的探讨卵巢癌顺铂化疗耐药模型中14-3-3蛋白的差异表达,为深入研究卵巢癌顺铂耐药机制提供理论依据。方法分别提取卵巢癌顺铂耐药和敏感细胞的蛋白质,应用差异凝胶电泳(DIGE),通过DecyderTM分析软件获得差异表达蛋白质点,进行基质辅助激光解吸/电离飞行时间质谱(MALDI-TOF-MS)分析、鉴定。结果经过二维电泳技术分离,MALDI-TOF-MS成功鉴定出2个14-3-3蛋白亚型,即14-3-3σ和14-3-3ζ,在耐药细胞中表达分别上调31%和38%,t检验P值分别为0.0049和0.0032。结论差异蛋白14-3-3σ和14-3-3ζ的鉴定为探讨这类蛋白在卵巢癌顺铂耐药中的作用奠定了基础,并提供了候选治疗靶点。     

COX-2 expression and ovarian cancer

The aim of the present review is to study the significance of the COX-2 expression for unfavourable prognosis and aggressive clinicopathological parameters in certain malignancies. The main directions for future research on COX-2 as a prognostic factor of decreased survival and predictive factor of chemotherapy resistance in ovarian cancer are discussed.     

Cancer-associated stroma significantly contributes to the mesenchymal subtype signature of serous ovarian cancer

Objective

Mesenchymal (MES) subtype of high-grade serous ovarian cancer (HGSOC) is associated with worse outcomes including survival and resectability compared with other molecular subtypes. Molecular subtypes have historically been derived from ‘tumor’, consisting of both cancer and stromal cells. We sought to determine the origins of multiple MES subtype gene signatures in HGSOC.

Reproducibility and prognostic value of histologic type and grade in early epithelial ovarian cancer

From September 1981 to September 1986, 417 consecutive treated patients with epithelial ovarian cancer FIGO stage I and II were registered by the Danish Ovarian Cancer Group (DACOVA). Typing and grading were primarily performed by several pathologists, with and without training in gynecologic pathology. Review typing by one specially trained pathologist showed an agreement rate of 72% for serous and endometrioid carcinoma, 86% for mucinous and 100% for clear cell carcinoma. The agreement rate was calculated for patients primarily classified by pathologists trained in gynecologic pathology and for patients primarily classified by pathologists with and without training. The agreement rate was not better for the group of pathologists with special training in gynecologic pathology. Grading was performed according to two classifications: one based on architectural pattern and one on combined criteria. Review grading showed an agreement rate of 77% for architectural classification and an agreement rate of 52% for combined classification. The agreement rate between the two grade classifications at review was only 62%. Combined grading showed a significant tendency towards classifying more tumors as low grade. All grade classifications had prognostic value. The poor agreement rate of both type and grade even when performed by pathologists with expertise in gynecologic pathology, calls for a better and more reproducible characterization of malignant ovarian tumors.     

YB-1 protein expression in ovarian cancer

OBJECTIVES: Unfavourable prognosis of ovarian cancer is due to prompt progression, advanced stage at time of diagnosis and chemoresistance. No protein tissue prognosticators of ovarian cancer are in clinical use yet. YB-1 belongs to a family of "cold shock proteins" and participates at gene expression control at several levels. High expression of YB-1 in tumour tissue correlates with unfavourable prognosis and chemoresistance in some malignant neoplasms. THE AIM: of this study was to determine the expression of YB-1 in benign and malignant ovarian neoplasms and to correlate the expression of YB-1 with clinical indicators of cancer progression. METHODS: Specimens of 11 benign ovarian cysts and 14 cystadenocarcinomas of the ovary were obtained.YB-1 expression was determined by immunohistochemistry. Staging of ovarian cancer was performed according to FIGO. RESULTS: Mean YB-1 expression levels in benign and malignant tumours were 5.36 +/- 4.1 and 2.86 +/- 4.18 points respectively and were not significantly different (p=0.18). No correlation between FIGO stage and expression of YB-1 was found in the group of ovarian cancers, either (p=0.32). CONCLUSIONS: This study demonstrates that YB-1 is expressed both in benign and malignant ovarian tumors. Although there we didn't found any correlation between YB-1 expression and FIGO stage, YB-1 could be useful in the prognosis recurrence after chemotherapy.     

Differential expression of CD40 and CD95 in ovarian carcinoma

PURPOSE: The role of CD95 (Fas) as a mediator of apoptosis has been well documented. CD40 ligation has been recently shown to initiate apoptosis and modulate CD95 mediated apoptosis in normal and some neoplastic tissues. Here we report the expression of CD95 and CD40 in cryopreserved cell suspensions from ovarian cancer associated ascites, fresh primary and recurrent ovarian carcinoma (OVCA) specimens, and ten established ovarian cancer cell lines. The effect of CD95 and CD40 receptor binding on apoptosis is described in two cell lines. EXPERIMENTAL DESIGN: Ascites specimens, fresh primary and recurrent OVCA specimens were dissociated to single cell suspensions. Expression of CD95 and CD40 was analyzed using flow cytometry. Apoptosis was determined via annexin uptake by flow cytometry following incubation with anti-CD95 antibody, CH11 and trimeric CD40L. RESULTS: Ascites showed the highest expression of both CD95 and CD40. Recurrent OVCA, in contrast, expressed low levels of CD95 and CD40. Primary OVCA showed moderate expression of both receptors. CD40 expression in ascites was significantly greater when compared to solid specimens (p < 0.05). Both CD40 and CD95 were strongly expressed in eight of ten cell lines studied. Binding of CD40L did not influence CD95 mediated apoptosis. CONCLUSIONS: CD40 is ubiquitously expressed in ovarian carcinomas and expression differs between ascites and solid tumor. There may be differential expression of both CD40 and CD95 in recurrent vs primary ovarian carcinoma, which may contribute to increased clinical malignancy of recurrent disease. In contrast to other epithelial malignancies, CD40 ligation does not appear to modulate CD95 mediated apoptosis.     

Correlation of ascitic fluid cytology with histologic findings before and after treatment of ovarian cancer

One hundred thirteen specimens of ascitic fluid from 97 patients with primary, persistent, or recurrent ovarian cancer were examined cytologically. Advanced stage of disease, involvement of the ovarian surface, a moderate or large volume of fluid, and nonbloody serous ascites were factors that correlated with a high rate of positive findings in ascites in these patients. Other factors influencing the positive rate appeared to be the invasive as opposed to borderline malignant histology of the tumor. Involved external surface and volume of ascites were influencing factors only in advanced cases. Therefore, the most important factor influencing the positive rate of ascites cytology was the proportion of cases in advanced stages to total cases.     

Triple synchronous primary cervical,endometrial and ovarian cancer with four different histologic patterns

Background Double synchronous primary cancers of gynecological cancers is a common event. However, triple synchronous primary gynecological cancers is an extremely rare event. Case A 50-year-old woman, para 0-0-0-0 was admitted to the hospital with a complaint of menorrhagia for 2 months. The preoperative evaluation and diagnosis was myoma uteri with bilateral ovarian tumor. Subtotal hysterectomy with bilateral salpingo-oophorectomy, and omentectomy were performed. The postoperative and pathologic findings were adenosquamous carcinoma of the endocervix, adenocarcinoma of the endometrium, low malignant potential of the right ovary and mucinous cystadenocarcinoma of the left ovary. She received a complete course of whole pelvic radiation. Unfortunately, she died from pulmonary embolism. Conclusion The occurrence of triple synchronous gynecological cancers is a rare and unique event deserving further studies     

In vitro chemoresistance and biomarker profiles are unique for histologic subtypes of epithelial ovarian cancer

OBJECTIVES: To determine whether there is a relationship between histologic subtype of epithelial ovarian cancer and chemoresistance, we evaluated ovarian carcinomas of six histologic subtypes and correlated histology with in vitro drug response. Biomarker profiles (p53, Her-2 neu, and EGFR) were also evaluated to determine if their expression patterns were associated with histology. METHODS: In vitro drug response profiles for different histologic subsets of epithelial ovarian carcinomas exposed to standard relevant chemotherapy agents were determined in the Extreme Drug Resistance assay (EDR). Immunohistochemistry techniques were employed to determine biomarker expression. RESULTS: Of 5195 referred serial cases of epithelial ovarian cancer, there were 2660 papillary serous, 303 endometrioid, 142 mucinous, 102 clear cell, 952 undifferentiated carcinomas, and 42 tumors of low malignant potential. For the samples as a whole, the incidences of extreme drug resistance to the tested chemotherapeutic agents were cisplatin 10%, carboplatin 16%, cyclophosphamide 16%, doxorubicin 40%, gemcitabine 21%, paclitaxel 22%, and topotecan 13%. When compared to papillary serous tumors, mucinous tumors were more frequently resistant to cisplatin (10% vs. 18%) but less frequently resistant to topotecan (13% vs. 5%) and doxorubicin (42% vs. 16%). Endometrioid tumors were less resistant to cisplatin (10% vs. 6%) and doxorubicin (42% vs. 20%). Clear cell and undifferentiated tumors had the lowest rates of EDR to paclitaxel (13% and 18%) and cyclophosphamide (7% and 11%), while borderline tumors showed high rates of EDR to these agents (52% and 63%, respectively). With respect to biomarker profiles, mP53 was detected in 46%, Her-2 neu in 16%, and EGFR in 30% of the cases evaluated. As compared to all other subtypes, clear cell carcinomas had significantly higher Her-2 neu expression (19%). Relative to papillary serous carcinomas, borderline tumors exhibited significantly lower rates of mP53 expression (60% vs.17%). CONCLUSIONS: We found significant differences in the frequencies of extreme drug resistance to chemotherapeutic agents and biomarker expression among histologic subtypes of epithelial ovarian cancer. The data collected in this investigation may provide a guide for stratification of patients entering clinical trials based on histology and biomarker expression.     

Re-assigning the histologic identities of COV434 and TOV-112D ovarian cancer cell lines

ObjectiveThe development of effective cancer treatments depends on the availability of cell lines that faithfully recapitulate the cancer in question. This study definitively re-assigns the histologic identities of two ovarian cancer cell lines, COV434 (originally described as a granulosa cell tumour) and TOV-112D (originally described as grade 3 endometrioid carcinoma), both of which were recently suggested to represent small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), based on their shared gene expression profiles and sensitivity to EZH2 inhibitors.MethodsFor COV434 and TOV-112D, we re-reviewed the original pathology slides and obtained clinical follow-up on the patients, when available, and performed immunohistochemistry for SMARCA4, SMARCA2 and additional diagnostic markers on the original formalin-fixed, paraffin-embedded (FFPE) clinical material, when available. For COV434, we further performed whole exome sequencing and validated SMARCA4 mutations by Sanger sequencing. We studied the growth of the cell lines at baseline and upon re-expression of SMARCA4 in vitro for both cell lines and evaluated the serum calcium levels in vivo upon injection into immunodeficient mice for COV434 cells.ResultsThe available morphological, immunohistochemical, genetic, and clinical features indicate COV434 is derived from SCCOHT, and TOV-112D is a dedifferentiated carcinoma. Transplantation of COV434 into mice leads to increased serum calcium level. Re-expression of SMARCA4 in either COV434 and TOV-112D cells suppressed their growth dramatically.ConclusionsCOV434 represents a bona fide SCCOHT cell line. TOV-112D is a dedifferentiated ovarian carcinoma cell line.