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Background Alterations in nuclear pore complex (NPC) genes have been previously associated with response to chemotherapy. Using agnostic exome sequencing, we envisioned that new alleles in NPC genes, predictive of sensitivity to platinum treatment, could be discovered. Methods Twenty-two platinum-sensitive and six platinum-resistant ovarian cancer patients were tested. Platinum sensitivity was defined as disease-free survival greater than 6 months. Next-generation sequencing of exomes was used to compare platinum-sensitive and platinum-resistant patients. Single nucleotide variants (SNVs) associated with platinum sensitivity in NPC genes (n=30 genes) were identified. Results SNVs in three NPC genes were associated with response to platinum on univariate analysis. SNV rs79419059 (10T>C) in Nucleoporin 107 (Nup107) was associated with platinum resistance (P=0.0061), whereas rs2302811 (3662-4A>G) in Nucleoporin 188 (Nup188) and rs77246077 (3420-67T>A) in Nucleoporin 214 (Nup214) were associated with platinum sensitivity (P=0.0483 and 0.0091, respectively). Controlling for other confounders, multivariate age-adjusted Cox proportional hazard analysis showed rs79419059 to be significantly associated with platinum resistance (odds ratio: 4.519, 95% confidence interval: 1.317-15.501, P=0.0457). Conclusion We identified a variant in the 3'-UTR region Nup107 unique to sensitivity to platinum in ovarian cancer. With validation of this variant, it is possible that a new marker predictive of patient response may be identified.

Purpose Enhancer of zeste homologue 2 (EZH2), a component of the chromatin modification protein complex, is upregulated in pancreatic ductal adenocarcinoma (PDAC), whereas loss of p53 and its downstream target, p21 waf1/cip1 , is also observed frequently. We sought to investigate the role of the p53-p21 waf1/cip1 pathway in relation to EZH2-mediated inhibition of PDAC. Methods The PANC-1 cell line was utilized in chromatin immunoprecipitation, gene profiling, Western blot, cell invasion, cell proliferation, and tumor xenograft assays. Results Western blot analysis with antibodies that recognize both wild-type and mutant p53 did not show any alterations in band intensity; however, antibody that detects only mutant p53 showed a band of significantly lesser intensity with EZH2 knockdown. Western blot analysis further revealed a significant upregulation of p21 waf1/cip1 . Gene expression profile analysis indicated significantly enhanced transcripts of transcriptional inducers of p21 waf1/cip1 , with downregulation of mutant p53 transcript, corroborating the Western blot analysis. PANC-1 cells expressing EZH2-short hairpin RNA displayed markedly attenuated growth in SCID mice. Conclusion Downregulation of mutant p53 with concomitant enhanced expression of p21 waf1/cip1 and its transcriptional trans-activators may contribute toward EZH2-mediated suppression of PDAC.

The enhancer of zeste homolog 2 (EZH2) methyltransferase is a transcriptional repressor. EZH2 is abnormally elevated in epithelial ovarian cancer (EOC). We demonstrated that EZH2 knockdown inhibited cell growth, activated apoptosis, and enhanced chemosensitivity. Further, silencing of EZH2 resulted in re-expression of p21(waf1/cip1) and down-regulation of mutant p53. Finally, EZH2 knockdown contributed to attenuated EOC growth in SCID mice.

We aimed to compare the differences in demographic features, clinicopathologic features, and survival in patients with vulvar/vaginal melanoma versus cutaneous melanoma with a special emphasis on race.Data were obtained from the Surveillance Epidemiology and End Results database from 1973 to 2008. Kaplan-Meier curves and Cox multivariate model were used for statistical analysis.Seven hundred sixty-two patients with vulvar/vaginal melanoma and 55,485 patients with cutaneous melanoma patients were included in the study. Twenty-eight patients of the vulvar/vaginal group and 334 patients of the cutaneous group were black (3.6% vs 0.6%, respectively). The median age at the time of diagnosis was 68 years in the vulvar/vaginal group and 52 years in the cutaneous group (P0.0001). Three hundred fifty patients (45.9%) in the vulvar/vaginal and 46,499 patients (83.8%) in the cutaneous group presented with localized disease (P0.0001), whereas 64 patients (8.4%) in the vulvar/vaginal group and 1520 patients (2.7%) in cutaneous group presented with advanced disease (P = 0.0081). The median survival of the black patients was 16 months in the vulvar/vaginal group and 124 months in the cutaneous melanoma group (P0.0001). The median survival in the nonblack population was 39 months in the vulvar/vaginal group compared to 319 months in the cutaneous melanoma group (P0.0001). In multivariate analysis performed for patients between 1988 and 2008, age, stage, and positive lymph nodes were negative independent prognostic factors for survival in vulvar/vaginal melanoma; whereas age, race, stage, radiation therapy, and lymph node positivity were negative prognostic factors in cutaneous melanoma.These findings emphasize that cutaneous and vulvar/vaginal melanomas have different clinicopathologic features and survival patterns.

The objective of this study was to analyze the clinical and pathologic factors in patients with uterine serous carcinoma confined to the endometrium. A total of 236 uterine serous carcinoma patients from the pathology databases of 4 large academic institutions were included in the study. Clinical and pathologic variables were analyzed, including patient demographics, tumor size (?2 vs. >2 cm), myometrial invasion, lymphovascular invasion, lymph node status, tumor location (endometrium vs. polyp), cervical involvement, lower uterine segment involvement, FIGO stage, pelvic washings, recurrence, overall survival, and progression-free survival. Of 236 patients, 55 (23%) had tumors limited to the endometrium. Forty-four patients (80%) had Stage IA tumors. The tumor was confined to a polyp in 17 (30.9%) patients. Twenty patients (36.4%) had tumor sizes >2 cm and 12 (21.8%) exhibited lymphovascular invasion. Only 3 patients (5.4 %) had cervical stromal involvement. Thirty-three (66%) patients underwent pelvic and para-aortic lymphadenectomy with 2 positive para-aortic lymph nodes identified. Seven (12.7%) patients had positive washings, whereas 8 patients (14.5 %) had disease recurrence. At a median follow-up of 46 months, there was no difference in overall survival (P = 0.216) or progression-free survival (P=0.063) between patients with tumors confined to a polyp, patients with tumors confined to the endometrium, and patients with tumors present in both polyp and the endometrium. Uterine serous carcinoma with only endometrial involvement, even when confined to a polyp, can be associated with poor prognosis, further stressing the importance of complete surgical staging and adjuvant treatment in this setting.

The deregulation of E-cadherin is associated with Src/FAK signaling axis and histone deacetylase (HDAC)/EZH2 activity. However, the association between EZH2 and FAK and its clinical significance in endometrial carcinoma has not been reported.202 archived cases of endometrial carcinoma (1996-2000) were reviewed and divided into two subtypes. TMAs were developed as per established procedures. EZH2, FAK, and pFAK immunohistochemical stains were performed and the expression was scored as negative (0), low (1) and high (2). Proper statistical analysis was used to assess the correlation between the expression profiles and the clinicopathological parameters and clinical outcome.A total of 141 (69.8%) type-1 tumors and 61 (30.2%) type-2 tumors were identified. EZH2 overexpression was identified in 7.6% of type-1 tumors vs. 63% of type-2 tumors (p0.001). FAK and pFAK overexpression was only seen in 24.8% and 1.7% of Type-1 tumors as compared to 72% and 58.8% of type-2 tumors, respectively (p0.001). A positive correlation between the expression of EZH2, FAK, pFAK and PTEN (p0.0001) was found. The overexpression of EZH2, FAK, and pFAK were significantly associated with high histologic grade, angiolymphatic invasion, lymph node metastasis, myometrial invasion and cervical involvement (p0.01). Kaplan-Meier analysis demonstrates that the overexpression of EZH2 (p=0.0024), FAK and pFAK (p=0.0001) was significantly associated with decreased overall survival.The overexpression of EZH2, FAK and pFAK correlates with well established pathologic risk factors and may predict a more aggressive biologic behavior in endometrial carcinoma, transforming these proteins into potential therapeutic targets for treatment of endometrial cancer.

Uterine serous carcinoma (USC) constitutes 10% of uterine cancers but ~40% of deaths. Tumor size is a known prognostic factor in other solid tumors. In endometriod cancers it is one element used to identify the need for complete staging, while its significance in USC is debated. Therefore tumor size was examined as an independent prognostic factor.Clinical and pathologic variables were recorded for 236 institutional patients, and those patients in the SEER database with USC. Chi-square and Fisher exact t-tests were utilized and survival data generated via Kaplan-Meier method; multivariate analysis was performed via cox-regression.The patients' mean age was 67.2 years (range 40-91). Survival ranged from 0 to 184 months (mean 42.8). We used a tumor size cut-off of 1cm and noted significant associations with myometrial invasion (p0.0001), angiolymphatic invasion (p0.0001), peritoneal washings (p=0.03), stage (p=0.015) and positive lymph nodes (p=0.05). Furthermore, recurrence was associated with larger tumors (p=0.03). In multivariate analysis, extra-uterine disease was the only factor associated with both recurrence and survival. Review of the SEER database noted association of larger tumors with lymph node involvement and a significant survival advantage with tumors1cm in both univariate and multivariate analysis.Treatment options for USC are often predicated on the surgical stage and therefore components of the staging are vitally important. The 1cm tumor-size cut-off should be studied prospectively as a prognostic indicator of survival and recurrence in USC and considered for inclusion in USC staging.

ObjectiveOur aim was to evaluate the prognostic significance of the revised 2009 International Federation of Gynecology and Obstetrics (FIGO) staging criteria in patients with uterine serous carcinoma (USC).Materials and MethodsWe retrieved clinical and histopathologic data on women with USC from 2 large academic centers. Age, race, stage, myometrial invasion, angiolymphatic invasion, and adjuvant therapy were analyzed using Kaplan-Meier and Cox regression models.ResultsA total of 168 patients were included. Three-year survival rate was 81% for revised stage I, 52% for stage II, 46% for stage III, and 19% for stage IV. Survival was not significantly different when comparing overall 1988 FIGO stage I or II to 2009 FIGO stage I or II. The 3-year survival rate for 1988 stage IA (93%), IB (75%), and IC (60%) significantly differed (P = 0.02). When patients were restaged using the 2009 staging system, the 3-year overall survival of 2009 stage IA dropped to 83.4% and 68.8% for stage IB. New FIGO stage, myometrial invasion, angiolymphatic invasion, and administration of chemotherapy all remained independent predictors of survival on multivariate analysis (P < 0.05). Of note, extrauterine disease was observed in 22% of patients without myometrial invasion. Age and race were not prognostic factors for either classification.ConclusionsThe streamlined 2009 FIGO criteria do not adequately delineate survival for USC in early-stage disease. The 1988 FIGO classification correctly identified 3 subgroups of stage I USC patients with significantly different survival that is lost with the elimination of the most favorable 1988 stage IA subgroup. Because evaluation for adjuvant therapy and patient planning may change based on survival information, further evaluation of more appropriate USC staging is warranted. Caution should be taken when evaluating therapeutic response and comparing studies using these revised criteria in the future.

Analyze tumor characteristics and outcomes in patients with endometrial carcinoma (EC)40 years of age and compare them to the characteristics of patients ≥ 40 years of age.10,700 patients (305 patients40 years of age) diagnosed between 1988 and 2007 with EC from the Metropolitan Detroit Cancer Surveillance System (MDCSS), and 884 patients (42 patients40 years of age) diagnosed between 1996 and 2008 with EC from our institutional database were identified. Differences in clinical and demographic variables by age (40 vs. ≥ 40) were assessed for statistical significance by chi-square tests. Cox proportional hazards models were used to calculate adjusted hazard ratios (HR) and their 95% confidence intervals (95% CI) to assess the risk of death from all causes.MDCSS based analysis: Patients40 were more likely to present with low grade tumors (p0.0001) and endometroid histology (p=0.0004) but less likely to undergo surgery (p=0.0007) or radiotherapy (p=0.0007). A multivariate analysis confirmed the significance of age, grade, and stage in all patients, and that of histologic type, surgery, and race in patients ≥ 40 as independent prognostic factors for overall survival. Institution based analysis: Patients40 had a higher proportion of patients with BM I ≥ 30 (p=0.04), and presented with a higher frequency of well differentiated (p=0.04) endometrioid tumors (p=0.004) that are less prone to have deep myometrial invasion (p=0.008).This study supports the hypothesis of a disease that is biologically and genetically heterogeneous among women of different ages and ethnicities.

Therapy related acute myeloid leukemia (t-AML) is a potential late complication of cytotoxic therapy, and it is of particular concern in the treatment of patients with epithelial ovarian carcinoma (EOC) exposed to multiple courses of chemotherapy during the course of their disease. This study examines the incidence, characteristics and clinical outcomes of patients who developed secondary myeloid-type leukemia after a diagnosis of EOC.National Cancer Institute's Surveillance, Epidemiology and End Results database was pooled for diagnosis of secondary myeloid leukemia after an initial diagnosis of EOC. This group of patients was compared to patients with de novo AML, and to EOC patients who did not develop secondary myeloid leukemia. Demographic, cytopathological and survival data were recorded. Cox Proportional Hazards model was used to calculate hazard ratios (HR) for developing secondary leukemia and to determine the statistically significant variables impacting survival. Kaplan-Meier estimates of survival were obtained and comparisons between the groups were performed using log-rank test.One hundred and nine myeloid leukemia cases were identified among 63,359 patients with a prior diagnosis of EOC for an overall incidence of 0.17%. The median latency to development of leukemia was 4 years (range 0-27 years). Median survival from the time of secondary leukemia diagnosis was 3 months and significantly worse than the 6 month median survival in patients with de novo AML (p0.001). Age at leukemia diagnosis greater than 65 and development of secondary vs. de novo leukemia had a statistically worse prognosis on multivariate analysis (HR of 2.69, 95%CI 2.60-2.78 and 1.81, 95%CI 1.49-2.20 respectively). The development of secondary leukemia was more common with EOC diagnosis made prior to the platinum/taxane era (HR 6.70, 95%CI 3.69-12.18). There was no difference in median survival between EOC patients who developed AML and those who did not.Development of t-AML is a rare but lethal event among EOC patients, and its incidence has decreased significantly since the use of platinum/taxane-based chemotherapy became the standard of care.

INTRODUCTION: Glucose transporter 1 (Glut-1) is a facilitative glucose transporter expressed in many cancers including breast cancer. Basal-like breast cancer (BLBC) is a high-risk disease associated with poor prognosis and lacks the benefit of targeted therapy. The aim of this study was to characterize the immunohistochemical (IHC) expression of Glut-1 in patients with BLBC compared with non-BLBC. MATERIALS AND METHODS: We identified 523 cases of invasive breast carcinoma from our database. The clinicopathologic findings and the biologic markers including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2) status were reviewed. IHC stains for cytokeratin 5/6 (CK5/6), epidermal growth factor receptor (EGFR), p53, and Glut-1 were performed on tissue microarray using standard procedures. BLBC was defined as ER-,PR-, Her2-, and CK5/6+ and/or EGFR+. RESULTS: Of informative cases, 14.7% were categorized as BLBC versus 85.3% as non-BLBC. Glut-1 was expressed in 42 (76.4%) of 55 BLBCs, whereas only 55 (23.8%) of 231 non-BLBCs showed immunostaining for Glut-1 (P < .001). Overall, Glut-1 expression was significantly associated with high histologic grade, ER negativity, PR negativity, CK5/6 positivity, EGFR expression, and high p53 expression (P < .001). However, there was no correlation between Glut-1 immunostaining and patient's outcome. CONCLUSIONS: Our results show that Glut-1 is significantly associated with BLBC and might be a potential therapeutic target for this aggressive subgroup of breast cancer, and this warrants further investigations.

MicroRNA-101 (miR-101) expression is negatively associated with tumor growth and proliferation in several solid epithelial cancers. Enhancer of zeste homolog 2 (EzH2) appears to be a functional target of miR-101. We explore the role of miR-101 and its interaction with EzH2 in epithelial ovarian carcinoma (EOC). In situ hybridization (ISH) for miR-101 was performed on EOC patient tissues and normal controls. EOC cell lines were transfected with miR-101 and subjected to growth analysis and clonogenic assays. Cell motility was assessed by Boyden chamber and wound-healing assays. P21waf1/cip1 and EzH2 interaction was assessed by Chromatin Immunoprecipitation (ChIP) assay in MDAH-2774 cells. SCID mice were assessed for tumor burden after injection with miR-101 or control vector-treated MDAH-2774 cells. ISH analysis revealed a decrease in miR-101 expression in EOC compared with normal tissue. MiR-101 re-expression in EOC cell lines resulted in increased apoptosis, decreased cellular proliferation, invasiveness, and reduced growth of tumor xenografts. CHIP assays revealed that re-expression of miR-101 inhibited the interaction of EzH2 with p21waf1/cip1 promoter. MiR-101 re-expression appears to have antitumor effects, providing a better understanding of the role of miR-101 in EOC.

Objective GLUT-1 is involved at various steps in the processes of tumor progression. The objective of this study was to examine the relationship between GLUT-1 expression and tumor proliferation and angiogenesis in epithelial ovarian carcinoma. Materials and methods Specimens from 213 patients with epithelial ovarian carcinoma were evaluated by immunohistochemistry for GLUT-1, Ki-67, and vascular endothelial growth factor. Tumor microvessel density was assessed with CD34 immunostaining. We investigated the relationships between GLUT-1 expression and clinicopathologic characteristics, tumor angiogenesis (tumor MVD and vascular endothelial growth factor expression), and tumor proliferation (Ki-67). The effect of GLUT-1 expression on patient survival and on the volume of residual disease after cytoreduction was determined. Results There was a significant positive correlation between expression of GLUT-1, Ki-67, and microvessel density. In univariate survival analysis, high GLUT-1 expression, high Ki-67 expression and high tumor microvessel density showed a significant impact on patient survival (p=0.0001). In multivariate analysis including patients with all tumor stages, after controlling for age, race, stage, grade, MVD, and the 3 markers (GLUT-1, Ki-67 and VEGF), only age (HR 1.5; 95% CI 1–2.3), stage (HR 3.6; 95% CI 1.8–7.5) and grade (HR 2.3; 95% CI 1.2–4.5) retained their significance as independent poor prognostic factors. Tumors simultaneously overexpressing GLUT-1 and Ki-67 were less likely to be optimally cytoreduced as compared to tumors overexpressing only one or neither of those two markers (OR: 3.8, p=0.01). Conclusion Expression of GLUT-1 correlates with tumor proliferation and microvessel density in epithelial ovarian carcinoma. In addition, patients with rapidly proliferating advanced stage tumors overexpressing GLUT-1 have a lesser chance for optimal cytoreduction.

Background:The current International Federation of Gynecology and Obstetrics (FIGO) grade in endometrial carcinomas requires the evaluation of histologic features with proven prognostic value but with questionable reproducibility. This study tests the prognostic power and reproducibility of a new binary grading system.Study Design:Specimens from 254 hysterectomies were graded according to the new 3- and 2-tiered FIGO grading systems described by Alkushi et al. The selected morphologic parameters for the new grading system included the presence of predominant solid or papillary architecture pattern, severe nuclear atypia, tumor necrosis, and vascular invasion. The Cox proportional hazards and κ statistics were used for comparisons.Results:On multivariate analysis, and looking at all tumor cell types, the 4 tested grading systems were independent predictors of survival, with the 3-tiered FIGO grading system being the most predictive (P = 0.005). In the subset of endometrioid tumors, the 3- and 2-tiered FIGO grading systems and the new grading system retained their statistical significance as predictors of survival (P = 0.004, P = 0.03, and P = 0.007, respectively), whereas the grading system of Alkushi et al did not (P = 0.1). In nonendometrioid tumors, the new grading system proved to be the best predictor of survival, reaching near statistical significance (P = 0.06). The new grading system had acceptable intraobserver and interobserver reproducibility assessment (κ = 0.87 and κ = 0.45, respectively).Conclusion:The 3-tiered FIGO grading system retained its superior prognostic power. However, available binary grading systems remain an attractive option by being highly reproducible and by eliminating the clinical ambiguity of intermediate grades of disease.

e17079Background: Studies have found that genetic determinates can predict response to chemotherapy in some cancer patients. However little is known about ovarian cancer. By using exome sequencing,...

Clear cell carcinoma originating in the abdominal wall is rare and usually develops within endometriotic implants in the scar. We describe 2 patients: a 42 year old with a 15 cm mass on the abdominal wall treated with neoadjuvant chemotherapy and excision and a 51 year old with a 6 cm abdominal mass treated with excision and adjuvant radiotherapy.

Purpose To investigate the possibility of inhibiting the progression of pancreatic ductal adenocarcinoma (PDAC) by facilitating the expression of E-cadherin through the enforced expression of microRNA-101 (miR-101). Methods In situ hybridization was conducted with archival tissue using a double digoxigenin-labeled probe. Chromatin immunoprecipitation (ChIP) assay was conducted with EZ-Magna ChIPTM A. Gene profile analysis, Western blot, and immunoprecipitation assays were performed using standard protocols. Results We found that decreased miR-101 expression observed in archival patient tissues was significantly associated with poor prognosis indicated by low-intensity staining in high-grade tumors. ChIP assays using anti-enhancer of zeste homolog 2 (EZH2) antibodies indicated not only the interaction of EZH2 to the CDH1 (E-cadherin) promoter, but also that this interaction was significantly diminished in cells transfected with pre–miR-101. We observed a global downregulation of trimethylated lysine 27 of H3 histone (H3K27me3) along with upregulation of the enzymes histone deacetylase -1 and -2 with the re-expression of miR-101. Further, we observed lesser levels of transcriptional factors that inhibit the CDH1 promoter with pre–miR-101 treatment. Western blot analysis confirmed the enhanced E-cadherin expression. PANC-1 cells transduced with pre–miR-101 displayed markedly attenuated growth in SCID mice. Conclusion These results suggest the potential therapeutic use of miR-101–enforced expression for inhibition of PDAC.

Acquired immunodeficiency syndrome (AIDS) is a disease caused by the infection of human immunodeficiency virus-1 (HIV-1) that primarily impairs immune function by reducing the CD4 T-lymphocyte count. More than two decades after the first clinical evidence of AIDS was reported, AIDS continues to be a major public health problem worldwide with millions of people infected and new infections rising in an alarming rate in third world countries especially in Asia and sub-Saharan Africa.(1, 2) AIDS has become one of the most devastating diseases that the scientific community has ever faced, struggling till today to come up with a therapeutic strategy that successfully controls the disease. AIDS is now the leading cause of death in sub-Saharan Africa, and is presently the fourth biggest killer worldwide. AIDS-related deaths totaled over 5 million by 2009 reaching a cumulative death toll of over 30 million since the beginning of the epidemic. More than 75 million people have been infected with HIV-1, and roughly 2.7 million new HIV-1 infections were diagnosed in 2009(3) even though this rate has decreased from one decade ago. To date, there is no effective treatment and the number of individuals infected with HIV-1 is growing dramatically in the eastern part of the world. Considering its infection rate, it is imperative to devise newer strategies to control progression of the disease. Although newer approaches such as highly active antiretroviral therapy (HAART) have proven to be effective in prolonging life, other constraints associated with their use underscores the need for development of other effective therapies. Protease inhibitors appear to be successful at controlling the viral replication immediately following budding of immature virus particle, but the development of drug resistant viral mutants and toxicity after prolonged therapy contributes to their failure.(4) HAART has considerable toxicity and its inability to

The polycomb group protein, enhancer of zeste homolog 2, is a transcriptional repressor involved in cell cycle regulation and has been linked to aggressive breast cancer. We examined the clinical and biological significance of enhancer of zeste homolog 2 expression in triple-negative breast cancers. Tissue microarrays were constructed with invasive breast cancer cases and stained with the enhancer of zeste homolog 2, cytokeratin 5/6, epidermal growth factor receptor 1, and p53. The expression of these markers was correlated with clinicopathologic variables and patients' outcome. Furthermore, in vivo enhancer of zeste homolog 2 gene silencing was achieved using small interfering RNA incorporated into chitosan nanoparticles. Of 261 cases of invasive breast cancer, high expression of the enhancer of zeste homolog 2 was detected in 87 (33%) cases, and it was strongly associated with a triple-negative breast cancer phenotype (P.001) compared with all other non-triple-negative breast cancers. Furthermore, high enhancer of zeste homolog 2 was significantly associated with high histologic grade (P = .01), estrogen receptor negativity (P.001), progesterone receptor negativity (P.001), epidermal growth factor receptor positivity (P = .04), and high p53 expression (P.001). Survival analysis demonstrated that patients with high enhancer of zeste homolog 2 had a poorer overall survival compared with those with low enhancer of zeste homolog 2 (P = .03), and it retained its significance as an independent prognostic factor (P = .02). In addition, enhancer of zeste homolog 2 gene silencing resulted in a significant reduction in tumor growth (P.01) in the orthotopic MB-231 mouse model of breast carcinoma. Our results show that high enhancer of zeste homolog 2 expression is significantly associated with triple-negative breast cancer and decreased survival. Enhancer of zeste homolog 2 may represent a potential therapeutic target for this aggressive disease, which warrants further investigation.

Objective:To compare the survival of patients with bilateral versus unilateral malignant ovarian germ cell tumors (OGCT).Methods:Patients with a diagnosis of OGCT were identified from the Surveillance, Epidemiology, and End Results Program for the period 1988 to 2006 and were divided into bilateral and unilateral subgroups. Only surgically treated patients were included. Histologic types were grouped into dysgerminoma, malignant teratoma, and mixed germ cell tumors with pure nondysgerminoma cell tumors. Statistical analysis using Wilcoxon rank sum test, Kaplan-Meier survival methods, and Cox proportional hazards regression model were performed.Results:In 1529 patients with OGCT, 1463 (95.7%) were unilateral and 66 (4.3%) were bilateral. Bilaterality was more common with dysgerminomas (6.5%) and mixed germ cell tumors with pure nondysgerminoma cell tumors (6.25%) than with immature teratomas (1.7%),P< 0.001. Most OGCT (67.3%) were stage I. Bilateral OGCT were more likely than unilateral tumors to be associated with advanced-stage disease (FIGO III and IV, 41% vs 20%,P< 0.04). Overall 5-year survival was 93.6% for unilateral OGCT and 80.7% in bilateral OGCT,P< 0.001. In multivariate analysis, bilaterality was not an independent predictor of survival when controlling for age, histology, stage, and surgical staging (hazard ratio, 1.3; 95% confidence interval, 0.7-2.5;P= 0.40).Conclusions:Compared with unilateral tumors, bilateral OGCT are more often associated with advanced-stage disease, high-risk histology, and poor survival. When other prognostic factors are accounted for, bilaterality was not an independent prognostic predictor of survival.

MicroRNA-101 (miR-101) expression is negatively associated with tumor growth and proliferation in several solid epithelial cancers. Enhancer of zeste homolog 2 (EzH2) appears to be a functional target of miR-101. We explore the role of miR-101 and its interaction with EzH2 in epithelial ovarian carcinoma (EOC).In situ hybridization (ISH) for miR-101 was performed on EOC patient tissues and normal controls. EOC cell lines were transfected with miR-101 and subjected to growth analysis and clonogenic assays. Cell motility was assessed by Boyden chamber and wound-healing assays. P21(waf1/cip1) and EzH2 interaction was assessed by Chromatin Immunoprecipitation (ChIP) assay in MDAH-2774 cells. SCID mice were assessed for tumor burden after injection with miR-101 or control vector-treated MDAH-2774 cells.ISH analysis revealed a decrease in miR-101 expression in EOC compared with normal tissue. MiR-101 re-expression in EOC cell lines resulted in increased apoptosis, decreased cellular proliferation, invasiveness, and reduced growth of tumor xenografts. CHIP assays revealed that re-expression of miR-101 inhibited the interaction of EzH2 with p21(waf1/cip1) promoter.MiR-101 re-expression appears to have antitumor effects, providing a better understanding of the role of miR-101 in EOC.

Background The role of frozen section (FS) in intraoperative decision making for surgical staging of endometrial cancer is controversial. Objective of this study is to assess the agreement rate between the FS and paraffin section (PS); and the potential impact of the role of FS in the intra-operative decision making for the complete surgical staging in low risk endometrial cancer. Methods This is a retrospective analysis of patients diagnosed with intra-operative FS stage I, grade I or II endometrial cancer from 1995–2004. FS results were compared with final pathology results with regard to tumor grade, depth of myometrial invasion, cervical involvement, lymphovascular invasion, and lymph node involvement. Agreement statistic with kappa was calculated using SPSS statistical software. Categorical variables were tested using chi-square test with p value of ≤0.05 being statistically significant. Results Of the 457 patients with endometrial cancer, 146 were evaluated by intra-operative FS and met inclusion criteria. FS results were in disagreement with permanent section in 35% for the grade (kappa 0.58, p = 0.003), 28% for depth of myometrial invasion (kappa 0.61, p

Objective Although less common than endometrioid carcinoma, uterine serous carcinoma (USC) accounts for a disproportionate number of endometrial cancer-related deaths. It is relatively more common in black compared to white women. The aim of our study is to analyze the impact of race on survival in USC. Methods We conducted a retrospective review in women with USC managed at two large urban medical centers. Clinical and histopathologic parameters were retrieved. Recurrence and survival data were obtained from medical records and the Surveillance, Epidemiology, and End Results (SEER) registry. Differences in overall survival between African American and Caucasian women were compared using Kaplan–Meier curves and log rank test for univariate analysis. Cox regression models for multivariate analyses were built to evaluate the relative impact of the various prognostic factors. Results One hundred seventy-two women with USC were included in this study, including 65 Caucasian women and 107 African American women. Both groups were similar with respect to age, stage at diagnosis, angiolymphatic invasion ( p =0.79), and the depth of myometrial invasion ( p =0.36). There was no statistical difference in overall survival between African American and Caucasian patients in univariate analysis ( p =0.14). In multivariate analysis, stage at diagnosis, angiolymphatic invasion, and depth of myometrial invasion, but not race, were significantly associated with overall survival. Conclusion In this study, African American women with USC had a similar survival to Caucasian women. This suggests that the racial differences seen in USC at a larger population level may be diminished in hospital-based studies, where women are managed in a uniform way.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a transient process occurring during developmental stages and carcinogenesis, characterized by phenotypic and molecular alterations, resulting in increased invasive and metastatic capabilities of cancer cells and drug resistance. Moreover, emerging evidence suggests that EMT is associated with increased enrichment of cancer stem-like cells in neoplastic tissues. We interrogated the molecular alterations occurring in breast cancer using proposed EMT markers such as E-cadherin, vimentin, epidermal growth factor receptor (EGFR), platelet-derived growth factor (PDGF) D, and nuclear factor κB (NF-κB) to decipher their roles in the EMT and breast cancer progression. METHODS: Fifty-seven invasive ductal adenocarcinomas of the breast were assessed for the expression of E-cadherin, vimentin, EGFR, NF-κB, and PDGF-D using immunohistochemical analysis. Tumors were categorized into three groups: A (ER+, and/or PR+, HER-2/neu-), B (ER+, and/or PR+, HER-2/neu+), and C (triple-negative: ER-, PR-, and HER-2/neu-). Immunostained slides were microscopically evaluated and scored using intensity (0, 1+, 2+, and 3+) and percentage of positive cells, and data were statistically analyzed. RESULTS: Membranous E-cadherin was positive in all 57 cases (100%), whereas cytoplasmic E-cadherin was predominantly positive in groups B and C compared with group A (21%, 7%, and 0%, respectively). All group A cases were negative for vimentin and EGFR. There was statistically significant increased expression of vimentin (P < .0002), EGFR (P < .0001), and NF-κB (P < .02) in triple-negative cases when compared with groups A and B. CONCLUSIONS: Vimentin, EGFR, and NF-κB were significantly increased in triple-negative tumors, which is consistent with the aggressiveness of these tumors. These markers could be useful as markers for EMT in breast cancers and may serve as predictive markers for designing customized therapy in the future.

The objective of the study was to evaluate the prognosis of ovarian cancer arising in endometriosis.We retrospectively compared 42 cases of endometriosis-associated ovarian cancer (EAOC) with 184 cases of ovarian carcinoma without endometriosis (OC).The median age in the EAOC group was 52 vs 59 years in OC (P.05). In comparison with OC, the EAOC patients were more likely to have low-grade (21% vs 8%; P = .04) and early-stage tumors (International Federation of Gynecology and Obstetrics I and II combined) (49% vs 24%; P = .002). Clear cell (21% vs 2%) and endometrioid (14% vs 3%) tumors were more frequent in EAOC, whereas mucinous tumors were more prevalent in OC (P = .001). The median survival (199 vs 62 months) and the 5 year survival (62% vs 51%) were better for EAOC when compared with OC (P = .038). After controlling for age, stage, grade, and treatment, association with endometriosis was not an independent predictor of better survival in ovarian cancer.As such, EAOC has a much better survival rate than OC. This could be explained by the higher prevalence of early-stage and low-grade tumors in EAOC when compared with OC.

Ovarian epithelial carcinomas have recently been classified as slow growing type I tumors and rapidly growing highly aggressive type II tumors. The present study sought to molecularly characterize type I and II tumors using known molecular markers.Specimens from 213 patients with ovarian carcinoma were categorized as type I or type II, and evaluated by immunohistochemistry for the inflammatory markers glucose transporter protein-1 (Glut-1), inducible nitric oxide synthase (iNOS), cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and nuclear factor kappa B. Statistical analysis was performed to investigate whether these molecular markers could distinguish between type I and type II tumors. Kaplan-Meier survival curves and COX regression analysis were used to determine the prognostic effect of these markers on survival in the 2 types of tumors.Overexpression of COX-1, COX-2, iNOS, and Glut-1 was significantly higher in type II tumors (P.05). Women with type II tumors had a poorer median survival (60 months) as compared with those with type I tumors (141 months) (P = .0001). Multivariate analysis revealed type II tumors, late stage, and age60 years as significant predictors of poor survival. For type II tumors, median survival of patients with tumors overexpressing COX-2 was 44 compared with 85 months for those with tumors with low COX-2 expression (P = .029). Looking at both type I and II tumors, the number of markers simultaneously overexpressed in each tumor was a significant predictor of poor patient survival (P = .005).The present study demonstrates that the new proposed histologic classification of ovarian epithelial carcinomas correlates with a distinct expression of inflammatory pathway proteins. High expression of these markers may explain the different biologic behavior of these 2 tumor types and provide targets for therapy.

Background Sulforaphane (SFN), an isothiocyanate phytochemical present predominantly in cruciferous vegetables such as brussels sprout and broccoli, is considered a promising chemo-preventive agent against cancer. In-vitro exposure to SFN appears to result in the induction of apoptosis and cell-cycle arrest in a variety of tumor types. However, the molecular mechanisms leading to the inhibition of cell cycle progression by SFN are poorly understood in epithelial ovarian cancer cells (EOC). The aim of this study is to understand the signaling mechanisms through which SFN influences the cell growth and proliferation in EOC. Results SFN at concentrations of 5 - 20 μM induced a dose-dependent suppression of growth in cell lines MDAH 2774 and SkOV-3 with an IC50 of ~8 μM after a 3 day exposure. Combination treatment with chemotherapeutic agent, paclitaxel, resulted in additive growth suppression. SFN at ~8 μM decreased growth by 40% and 20% on day 1 in MDAH 2774 and SkOV-3, respectively. Cells treated with cytotoxic concentrations of SFN have reduced cell migration and increased apoptotic cell death via an increase in Bak/Bcl-2 ratio and cleavage of procaspase-9 and poly (ADP-ribose)-polymerase (PARP). Gene expression profile analysis of cell cycle regulated proteins demonstrated increased levels of tumor suppressor retinoblastoma protein (RB) and decreased levels of E2F-1 transcription factor. SFN treatment resulted in G1 cell cycle arrest through down modulation of RB phosphorylation and by protecting the RB-E2F-1 complex. Conclusions SFN induces growth arrest and apoptosis in EOC cells. Inhibition of retinoblastoma (RB) phosphorylation and reduction in levels of free E2F-1 appear to play an important role in EOC growth arrest.

e15538 Background: Enhancer of zeste homolog 2 (EzH2), the catalytic subunit of Polycomb group (PcG) of the chromatin modifying complex, is abnormally elevated in several cancers. High levels of Ez...

e15531 Background: Myeloperoxidase (MPO) is a heme protein synthesized during myeloid differentiation. It is an enzymatic mediator of several inflammatory cascades. A link between inflammation and ...