Divergent Metabolic Effects of Metformin Merge to Enhance Eicosapentaenoic Acid Metabolism and Inhibit Ovarian Cancer In Vivo.

Metformin is being actively repurposed for the treatment of gynecologic malignancies including ovarian cancer. We investigated if metformin induces analogous metabolic changes across ovarian cancer cells. Functional metabolic analysis showed metformin caused an immediate and sustained decrease in oxygen consumption while increasing glycolysis across A2780, C200, and SKOV3ip cell lines. Untargeted metabolomics showed metformin to have differential effects on glycolysis and TCA cycle metabolites, while consistent increased fatty acid oxidation intermediates were observed across the three cell lines. Metabolite set enrichment analysis showed alpha-linolenic/linoleic acid metabolism as being most upregulated. Downstream mediators of the alpha-linolenic/linoleic acid metabolism, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were abundant in all three cell lines. EPA was more effective in inhibiting SKOV3 and CaOV3 xenografts, which correlated with inhibition of inflammatory markers and indicated a role for EPA-derived specialized pro-resolving mediators such as Resolvin E1. Thus, modulation of the metabolism of omega-3 fatty acids and their anti-inflammatory signaling molecules appears to be one of the common mechanisms of metformin's antitumor activity. The distinct metabolic signature of the tumors may indicate metformin response and aid the preclinical and clinical interpretation of metformin therapy in ovarian and other cancers.

The role of adjuvant therapy in stage IA serous and clear cell uterine cancer: A multi-institutional pooled analysis.

OBJECTIVE: As the optimal adjuvant management of stage IA serous or clear cell endometrial cancer is controversial, a multi-institutional review was conducted with the objective of evaluating the appropriateness of various strategies including observation. METHODS: Retrospective chart reviews for 414 consecutive patients who underwent hysterectomy for FIGO stage IA endometrial cancer with serous, clear cell or mixed histology between 2004 and 2015 were conducted in 6 North American centers. Time-to-event outcomes were analyzed by Kaplan-Meier estimates, log-rank test, univariable and multivariable cox proportional hazard regression models. RESULTS: Post-operative management included observation (50%), chemotherapy and radiotherapy (RT) (27%), RT only (16%) and chemotherapy only (7%). The 178 RT patients received external beam (EBRT, 16%), vaginal vault brachytherapy (VVB, 56%) or both (28%). Among patients without any adjuvant treatment, 5-year local control (LC), disease free survival (DFS) and cancer-specific survival (CSS) were 82% (95% confidence interval: 74-88), 70% (62-78) and 90% (82-94), respectively. CSS in patients without adjuvant treatment was improved with adequate surgical staging (100% vs. 87% (77-92), log-rank p=0.022). Adjuvant VVB was associated with improved LC (5-year 96% (91-99) vs. 84% (76-89), log-rank p=0.007) and DFS (5-year 79% (66-88) vs. 71% (63-77), log-rank p=0.033). Adjuvant chemotherapy was associated with better LC (5-year 96% (90-98) vs. 84% (77-89), log-rank p=0.014) and DFS (5-year 84% (74-91) vs. 69% (61-76), log-rank p=0.009). On multivariable analysis, adjuvant chemotherapy and VVB were associated with improved LC while adjuvant chemotherapy and age were significant for DFS. CONCLUSIONS: In stage IA serous or clear cell uterine cancer, adjuvant RT and chemotherapy were associated with better LC and DFS. Observation may be appropriate in patients who have had adequate surgical staging.

Does Age-Adjusted Charlson Comorbidity Score Impact Survival Endpoints in Women with Federation of Gynecology and Obstetrics-Stage III Endometrial Cancer?

OBJECTIVES: We sought to evaluate the impact of age-adjusted Charlson comorbidity index (AACCI) score on survival endpoints for women with advanced stage endometrial carcinoma (EC). METHODS AND MATERIALS: We identified 238 women with stage III EC. AACCI score was calculated and 3 groups were created accordingly; group 1 with a score of 0-2, group 2 with score 3-4, and group 3 with score ≥5. Significant predictors of recurrence-free (RFS), disease-specific (DSS) and overall survival (OS) were analyzed. RESULTS: Median follow-up was 54 months and median age was 65 years. Stage IIIC was the most common stage (69%). The 3 groups were well-balanced except for less utilization of adjuvant chemotherapy in group 3 (p = 0.01). Five-year OS was significantly lower in group 3 compared to groups 1 and 2 (23 vs. 65 and 51%, respectively). Similarly, 5-year RFS was 54, 41, and 33% and DSS was 65, 54, and 35% for groups 1, 2, and 3 respectively. On multivariate analyses, AACCI group 3, cervical stromal involvement, positive peritoneal cytology, and higher tumor grade were predictors for shorter OS. Cervical stromal involvement and higher grade were independent predictors for worse RFS and DSS. Additionally, positive cytology, lymphovascular space invasion, and stage IIIC2 were significantly detrimental for RFS. CONCLUSIONS: Our study suggests that comorbidity burden is a strong predictor of worse OS in women with stage III EC. Women with higher AACCI are less likely to receive adjuvant chemotherapy. Comorbidity score can significantly impact survival endpoints for women with advanced EC.

External pelvic and vaginal irradiation vs. vaginal irradiation alone as postoperative therapy in women with early stage uterine serous carcinoma: Results of a National Cancer Database analysis.

PURPOSE: Adjuvant treatment in early stage uterine serous carcinoma (USC) usually consists of chemotherapy with vaginal brachytherapy (VB), pelvic external beam radiation therapy (EBRT), or combination. We compared survival outcomes across these various radiation treatment modalities using the National Cancer Database. METHODS AND MATERIALS: The National Cancer Database was queried for adult females with histologically confirmed International Federation of Gynecology and Obstetrics 1988 Stage I-II USC diagnosed from 2003 to 2013 treated definitively with hysterectomy, adjuvant chemotherapy, and radiation therapy. χ2 tests were used to assess differences by radiation type (VB, pelvic EBRT, and EBRT + VB) and various clinical variables. Kaplan-Meier and log-rank test methods were used to evaluate survival outcomes. Risk factors related to overall survival were identified by univariate and multivariate analysis. RESULTS: We identified 1336 patients with USC who met our inclusion criteria. Most patients were treated with VB (66%) compared with EBRT (21%) or combination EBRT + VB (13%). The proportion of patients who received EBRT (including EBRT + VB) was higher for those who did not have a lymph node dissection or with fewer dissected lymph nodes. Patients treated with VB alone had longer 5-year survival rates (84% [95% confidence interval: 80, 90]) than those treated with EBRT (75% [95% confidence interval: 69, 80]) (p < 0.001). On multivariate analysis, the presence of lymphovascular space invasion (hazard ratio, 2.48; p < 0.001) and the absence of a lymph node dissection (hazard ratio, 2.24; p = 0.047) were independent predictors of overall survival. CONCLUSIONS: This large hospital-based study suggests that VB alone may be sufficient for adjuvant radiation treatment in women with USC treated with adjuvant chemotherapy and who underwent an adequate surgical staging.

Synergistic effect of MEK inhibitor and metformin combination in low grade serous ovarian cancer.

OBJECTIVE: Low-grade serous ovarian cancer (LGSOC) constitutes 5-8% of epithelial ovarian cancers and is refractory to chemotherapy. We and others have shown metformin to cause significant growth inhibition in high-grade ovarian cancer both in vitro and in vivo. Here, we aimed to analyze if metformin was effective in inhibiting proliferation of LGSOC alone and in combination with MEK inhibitor. METHODS: Three LGSOC lines (VOA1056, VOA1312 and VOA5646) were treated with metformin, trametinib or 2-deoxyglucose (2DG) alone or in combination with metformin. Proliferation was measured by MTT assay over a period of four days. Protein expression was measured by western blotting. Seahorse Analyzer was used to measure effect of metformin on glycolysis and mitochondrial respiration. RESULTS: All LGSOC cell lines showed significant inhibition with metformin in a dose- and time-dependent manner. Trametinib significantly inhibited the growth of Ras mutated LGSOC lines (VOA1312 and VOA1056), while VOA5646 cells without RAS mutation did not show any response. Metformin and trametinib combination showed synergistic inhibition of RAS mutated VOA1312 and VOA1056 cells, but not for non-Ras mutated VOA5646 cells. Metformin and trametinib increased phosphorylated AMPK expression in LGSOC lines with combination showing stronger expression. Trametinib decreased 42/44 mitogen activated kinase phosphorylation in all cell lines, while metformin and combination had no significant effect. 2-DG significantly inhibited glycolysis in all LGSOC lines and combination with metformin showed synergistic inhibitory effect. CONCLUSIONS: Metformin alone or in combination with MEK and glycolytic inhibitors may be a potential therapy for LGSOC, a cancer that is indolent but chemo-resistant.

Isatin Derived Spirocyclic Analogues with α-Methylene-γ-butyrolactone as Anticancer Agents: A Structure-Activity Relationship Study.

Design, synthesis, and evaluation of α-methylene-γ-butyrolactone analogues and their evaluation as anticancer agents is described. SAR identified a spirocyclic analogue 19 that inhibited TNFα-induced NF-κB activity, cancer cell growth and tumor growth in an ovarian cancer model. A second iteration of synthesis and screening identified 29 which inhibited cancer cell growth with low-µM potency. Our data suggest that an isatin-derived spirocyclic α-methylene-γ-butyrolactone is a suitable core for optimization to identify novel anticancer agents.

Metformin prevents aggressive ovarian cancer growth driven by high-energy diet: similarity with calorie restriction.

Caloric restriction (CR) was recently demonstrated by us to restrict ovarian cancer growth in vivo. CR resulted in activation of energy regulating enzymes adenosine monophosphate activated kinase (AMPK) and sirtuin 1 (SIRT1) followed by downstream inhibition of Akt-mTOR. In the present study, we investigated the effects of metformin on ovarian cancer growth in mice fed a high energy diet (HED) and regular diet (RD) and compared them to those seen with CR in an immunocompetent isogeneic mouse model of ovarian cancer. Mice either on RD or HED diet bearing ovarian tumors were treated with 200 mg/kg metformin in drinking water. Metformin treatment in RD and HED mice resulted in a significant reduction in tumor burden in the peritoneum, liver, kidney, spleen and bowel accompanied by decreased levels of growth factors (IGF-1, insulin and leptin), inflammatory cytokines (MCP-1, IL-6) and VEGF in plasma and ascitic fluid, akin to the CR diet mice. Metformin resulted in activation of AMPK and SIRT1 and inhibition of pAkt and pmTOR, similar to CR. Thus metformin can closely mimic CR's tumor suppressing effects by inducing similar metabolic changes, providing further evidence of its potential not only as a therapeutic drug but also as a preventive agent.

Tumor size is an independent predictor of lymph node metastasis and survival in early stage endometrioid endometrial cancer.

OBJECTIVE(S): To analyze the impact of tumor size (TS) on risk of lymph node metastasis (PLN) and prognosis in endometrioid endometrial cancer grossly confined to the uterus (EEC). METHOD(S): Patients with EEC grossly confined to the uterus were identified from Surveillance, Epidemiology, and End Results dataset from 1988 to 2007. Only surgically treated patients were included. TS was analyzed as a continuous and categorical variable (TS ≤ 2 cm, >2-5 cm and >5 cm). Multivariable logistic regression and Cox proportional hazards models were used. RESULT(S): 19,692 patients met the inclusion criteria. In patients with TS ≤ 2 cm, only 2.7 % (88/3,244) had PLN; this increased to 5.8 % (372/6,355) with TS > 2-5 cm and 11.1 % (195/1,745) with TS > 5 cm. The odds of PLN increased by 14 % for each 1 cm increase in TS after controlling for age, race, depth of myometrial invasion and grade (HR 1.14, 95 % CI 1.10-1.19, p < 0.001). Further, TS was an independent predictor of disease-specific survival (DSS) even after adjusting for age, race, grade, depth of myometrial invasion, lymph node status and adjuvant radiation therapy (HR 1.13 for each 1 cm increment in TS, 95 % 1.08-1.18, p < 0.001). In multivariable analysis, larger TS (>5 cm) was significantly associated with worse DSS (HR 2.09, 95 % 1.31-3.35, p = 0.002); however, there was no significant difference between TS > 2-5 cm versus ≤2 cm (HR 1.25, 95 % 0.85-1.83, p = 0.25). The impact of TS remained significant on DSS in subset of patients who underwent lymphadenectomy with negative lymph nodes. CONCLUSION(S): TS was an independent predictor of lymph node metastasis and disease-specific survival in patients with EEC grossly confined to the uterus. Tumor >5 cm was a predictor of disease-specific survival but no difference in outcome was noted between tumor >2-5 cm and tumor ≤2 cm.

Sox2 gene amplification significantly impacts overall survival in serous epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer. Recently, the existence of ovarian cancer stem cells has been reported. Sox2, Nanog and Oct4 are key markers of "stemness". The objective of this study was to determine whether Sox2, Nanog, and Oct4 are associated with EOC and poor outcome. The expression of these markers was assessed by immunofluorescence staining and real-time RT-PCR in human EOC cell lines MDAH-2774 and SKOV-3, while the cancer genome atlas (TCGA) dataset was analyzed for associations with survival. Sox2, Nanog and Oct4 (POU5F1) were all detected by immunofluorescence staining and these results were confirmed by real-time RT-PCR. The TCGA dataset revealed a 26%, 9%, and 6% amplification of Sox2, Nanog and POU5F1, respectively. Additionally, K-M survival analyses showed a significant median overall survival difference (41 versus 48.3 months, P = .01) for Sox2 amplification, but not for Nanog (44.1 versus 36.2 months, P > .05) and POU5F1 (43.5 versus 45.0 months, P > .05). Our results suggest that Sox2 gene amplification significantly influences overall survival.

Significance of lymphovascular space invasion in uterine serous carcinoma: what matters more; extent or presence?

To analyze the clinical significance of the extent of lymphovascular space invasion (LVI) in patients with uterine serous carcinoma. After IRB approval, 232 patients with uterine serous carcinoma from the pathology databases of 4 large academic institutions were included. Patients were divided into 3 groups based on extent of LVI. Extensive LVI (E-LVI) was defined as ≥3 vessel involvement; low LVI (L-LVI) was defined <3 vessel involvement; and the third group consisted of tumors with no LVI (A-LVI). The association between LVI and myometrial invasion, cervical involvement, lower uterine segment involvement, positive peritoneal washings, lymph node involvement, stage, and survival were analyzed. Of 232 patients, 47 had E-LVI (20.3%), 83 had L-LVI (35.8%), and 102 had A-LVI (44%). A total of 9.8% of the patients with A-LVI had lymph node involvement as compared with 18.1% in the L-LVI group and 55.4% in the E-LVI group (P<0.0001). Fifty-nine percent of the patients in A-LVI, 85% in L-LVI, and 100% in the E-LVI group demonstrated myometrial invasion (P<0.0001). Cervical involvement was noted in 23%, 43%, 66% (P<0.0001) and lower uterine segment involvement involvement in 31%, 43%, and 42% of A-LVI, L-LVI, and E-LVI (P<0.0001), respectively. Stage III and IV disease were seen in 29%, 38%, and 79% of the patients with A-LVI, L-LVI, and E-LVI, respectively (P<0.0001). The median overall survival was 172, 95, and 39 mo for the A-LVI, L-LVI, and E-LVI groups, respectively (P<0.0001). The racial distribution was significant with African American patients demonstrating significantly more L-LVI (27.8%) and E-LVI (40.4%) when compared with A-LVI (19.6%) (P=0.040). In a subgroup analysis including patients with Stage I and II (n=123) revealed median survivals of 172, 169, and 38 mo in the A-LVI, L-LVI, and E-LVI groups, respectively (P<0.0001). Fifty percent of these patients with E-LVI, 20% in L-LVI group, and 15% in A-LVI group had disease recurrence (P=0.040). The extent of LVI was associated with multiple pathologic factors and was found to be a negative prognostic factor for overall survival and disease recurrence.

Recurrence patterns and survival endpoints in women with stage II uterine endometrioid carcinoma: a multi-institution study.

OBJECTIVE: There is paucity of data in regard to prognostic factors and outcome of women with 2009 FIGO stage II disease. The objective of this study was to investigate prognostic factors, recurrence patterns and survival endpoints in this group of patients. METHODS: Data from four academic institutions were analyzed. 130 women were identified with 2009 FIGO stage II. All patients underwent hysterectomy, oophorectomy and lymph node evaluation with or without pelvic and paraaortic lymph node dissections and peritoneal cytology. The Kaplan-Meier approach and Cox regression analysis were used to estimate recurrence-free (RFS), disease-specific (DSS) and overall survival (OS). RESULTS: Median follow-up was 44months. 120 patients (92%) underwent simple hysterectomy, 78% had lymph node dissection and 95% had peritoneal cytology examination. 99 patients (76%) received adjuvant radiation treatment (RT). 5-year RFS, DSS and OS were 77%, 90%, and 72%, respectively. On multivariate analysis of RFS, adjuvant RT, the presence of lymphovascular space invasion (LVSI) and high tumor grades were significant predictors. For DSS, LVSI and high tumor grades were significant predictors while older age and high tumor grade were the only predictors of OS. CONCLUSIONS: In this multi-institutional study, disease-specific survival for women with FIGO stage II uterine endometrioid carcinoma is excellent. High tumor grade, lymphovascular space invasion, adjuvant radiation treatment and old age are important prognostic factors. There was no significant difference in the outcome between patients who received vaginal cuff brachytherapy compared to those who received pelvic external beam radiation treatment.

Protective effect of bisphosphonates on endometrial cancer incidence in data from the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial.

BACKGROUND: Preclinical studies have demonstrated antitumor effects of bisphosphonates. The objective of the current study was to determine the effect of exposure to bisphosphonate on the incidence of endometrial cancer. METHODS: The authors used data from the National Cancer Institute's Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, which collected data on all cancers. In year 5, all participants were asked to complete a self-administered supplemental questionnaire (SQX) that included questions regarding bone medication use. For women without a cancer diagnosis at the time of the SQX, the authors identified whether a woman reported current or former use of a nitrogenous bisphosphonate (NBP), defined as ever-use, and compared them with women never exposed to an NBP. Women with missing information were excluded as were women who reported undergoing a hysterectomy. Incidence rates and rate ratios were calculated with 95% confidence intervals (95% CIs). Cox proportional hazard ratios were also calculated and adjusted for covariates. RESULTS: A total of 29,254 women were included in the current analysis; an additional 77 cases of endometrial cancer have been diagnosed since the SQX. The incidence rate for endometrial cancer among women exposed to NBPs was 8.7 per 10,000 person-years versus 17.7 per 10,000 person-years among never-exposed women (rate ratio, 0.49; 95% CI, 0.30-0.80). The effect was similar after adjusting for all the covariates in the Cox proportional hazards analysis, with a hazard ratio of 0.56 (95% CI, 0.34-0.93). CONCLUSIONS: The results of the current study suggest that use of NBPs may have a protective effect on the incidence of endometrial cancer. However, additional studies are needed that include other potential confounders and a larger sample.

Dietary energy balance modulates ovarian cancer progression and metastasis.

A high energy balance, or caloric excess, accounts as a tumor promoting factor, while a negative energy balance via caloric restriction, has been shown to delay cancer progression. The effect of energy balance on ovarian cancer progression was investigated in an isogeneic immunocompetent mouse model of epithelial ovarian cancer kept on a regimen of regular diet, high energy diet (HED) and calorie restricted diet (CRD), prior to inoculating the animals intraperitoneally with the mouse ovarian surface epithelial ID8 cancer cells. Tumor evaluation revealed that mice group on HED displayed the most extensive tumor formation with the highest tumor score at all organ sites (diaphragm, peritoneum, bowel, liver, kidney, spleen), accompanied with increased levels of insulin, leptin, insulin growth factor-1 (IGF-1), monocyte chemoattractant protein-1 (MCP-1), VEGF and interleukin 6 (IL-6). On the other hand, the mice group on CRD exhibited the least tumor burden associated with a significant reduction in levels of insulin, IGF-1, leptin, MCP-1, VEGF and IL-6. Immunohistochemistry analysis of tumors from HED mice showed higher activation of Akt and mTOR with decreased adenosine monophosphate activated kinase (AMPK) and SIRT1 activation, while tumors from the CRD group exhibited the reverse profile. In conclusion, ovarian cancer growth and metastasis occurred more aggressively under HED conditions and was significantly curtailed under CRD. The suggested mechanism involves modulated secretion of growth factors, cytokines and altered regulation of AMPK and SIRT1 that converges on mTOR inhibition. While the role of a high energy state in ovarian cancer has not been confirnmed in the literature, the current findings support investigating the potential impact of diet modulation as adjunct to other anticancer therapies and as possible individualized treatment strategy of epithelial ovarian cancer.

Metformin limits the adipocyte tumor-promoting effect on ovarian cancer.

Omental adipocytes promote ovarian cancer by secretion of adipokines, cytokines and growth factors, and acting as fuel depots. We investigated if metformin modulates the ovarian cancer promoting effects of adipocytes. Effect of conditioned media obtained from differentiated mouse 3T3L1 preadipoctes on the proliferation and migration of a mouse ovarian surface epithelium cancer cell line (ID8) was estimated. Conditioned media from differentiated adipocytes increased the proliferation and migration of ID8 cells, which was attenuated by metformin. Metformin inhibited adipogenesis by inhibition of key adipogenesis regulating transcription factors (CEBPα, CEBPß, and SREBP1), and induced AMPK. A targeted Cancer Pathway Finder RT-PCR (real-time polymerase chain reaction) based gene array revealed 20 up-regulated and 2 down-regulated genes in ID8 cells exposed to adipocyte conditioned media, which were altered by metformin. Adipocyte conditioned media also induced bio-energetic changes in the ID8 cells by pushing them into a highly metabolically active state; these effects were reversed by metformin. Collectively, metformin treatment inhibited the adipocyte mediated ovarian cancer cell proliferation, migration, expression of cancer associated genes and bio-energetic changes. Suggesting, that metformin could be a therapeutic option for ovarian cancer at an early stage, as it not only targets ovarian cancer, but also modulates the environmental milieu.

The influence of comorbid conditions on racial disparities in endometrial cancer survival.

OBJECTIVE: There are known disparities in endometrial cancer survival with black women who experience a greater risk of death compared with white women. The purpose of this investigation was to evaluate the role of comorbid conditions as modifiers of endometrial cancer survival by race. STUDY DESIGN: Two hundred seventy-one black women and 356 white women who had been diagnosed with endometrial cancer from 1990-2005 were identified from a large urban integrated health center. A retrospective chart review was conducted to gather information on comorbid conditions and other known demographic and clinical predictors of survival. RESULTS: Black women experienced a higher hazard of death from any cause (hazard ratio [HR] 1.51; 95% confidence interval [CI], 1.22-1.87) and from endometrial cancer (HR, 2.42; 95% CI, 1.63-3.60). After adjustment for known clinical prognostic factors and comorbid conditions, the hazard of death for black women was elevated but no longer statistically significant for overall survival (HR, 1.22; 95% CI, 0.94-1.57), and the hazard of death from endometrial cancer remained significantly increased (HR, 2.27; 95% CI, 1.39-3.68). Both black and white women with a history of hypertension experienced a lower hazard of death from endometrial cancer (HR, 0.47; 95% CI, 0.23-0.98; and HR, 0.35; 95% CI, 0.19-0.67, respectively). CONCLUSION: The higher prevalence of comorbid conditions among black women does not explain fully the racial disparities that are seen in endometrial cancer survival. The association between hypertension and a lower hazard of death from endometrial cancer is intriguing, and further investigation into the underlying mechanism is needed.

Racial disparities in uterine clear cell carcinoma: a multi-institution study.

OBJECTIVE: The aim of this study was to evaluate the impact of race on the overall survival (OS) and progression-free survival (PFS) of white and African-American patients with uterine clear cell carcinoma (UCCC). METHODS: A retrospective review was conducted of all primary UCCC cases treated at 1 of 4 major gynecologic cancer centers between 1982 and 2012. Patients and tumor characteristics were retrieved from the cancer databases of the respective institutions and based on a retrospective review of the medical records. Differences in the OS and PFS between African-American and white women were compared using the Kaplan-Meier curves and log-rank test for univariate analysis. Cox regression models for the multivariate analyses were built to evaluate the relative impact of the various prognostic factors. RESULTS: One hundred seventy women with UCCC were included in the study, including 118 white and 52 African-American women. Both groups were comparable with respect to age (P = 0.9), stage at diagnosis (P = 0.34), angiolymphatic invasion (P = 0.3), and depth of myometrial invasion (P = 0.84). In the multivariate analyses for known prognostic factors, OS and PFS were significantly different between white and African-American patients in the early-stage disease (hazard ratio [HR], 5.4; 95% confidence interval [CI], 1.2-23.2; P = 0.023 and HR, 3.5; 95% CI, 1.60-7.77; P = 0.0016, respectively) but not in the advanced-stage disease (HR, 0.83; 95% CI, 0.40-1.67; P = 0.61 and HR, 1.5; 95% CI, 0.84-2.78; P = 0.15, respectively). CONCLUSIONS: In the current study, African-American patients have a prognosis worse than that of white patients in early-stage UCCC. We could not prove the same difference in advanced-stage disease.

Is the two-tier ovarian serous carcinoma grading system potentially useful in stratifying uterine serous carcinoma? A large multi-institutional analysis.

OBJECTIVE: A subset of uterine serous carcinoma (USC) may have better clinical behavior bringing up the possibility that there may be morphologic features, which would help in their categorization. The aim of this study is to evaluate the potential use of the MD Anderson Cancer Center 2-tier grading system for ovarian carcinoma in USC. METHODS: Tumors assigned a combined score included in this analysis were 1) low-grade: tumors without marked atypia and 12 mitoses/10 high power field (HPF) and 2) high grade: tumors with severe nuclear atypia and >12 mitoses/10 HPF. Clinicopathologic parameters evaluated included patients' age, tumor size, myometrial invasion (MI), lymphovascular invasion (LVI), lymph node (LN), FIGO stage, and patient outcome. RESULTS: 140 patients with USC were included, 30 low grade uterine serous carcinoma (LGUSC) and 110 high grade uterine serous carcinoma (HGUSC). Of all parameters only 2 (MI and stage IA) reached statistical significance. 67% of LGUSC cases showed myometrial invasion versus 93.6% HGUSC cases (p = 0.003). A higher percentage of LGUSC (63.3%) versus HGUSC (32.7%) were in stage IA (p = 0.01). However, by multivariate analysis including age, LVI, stage and tumor grade only stage was an independent prognostic factor. CONCLUSION: The presence of atypia and mitosis across a uterine serous carcinoma is notoriously variable in magnitude and extent, potentially making evaluation of these features difficult and subsequent grading subjective. Our findings thus show that actual prognostic utility of application of MDACC two-tier grading system to uterine serous carcinoma may not be applicable.

Improved survival of baby boomer women with early-stage uterine cancer: A Surveillance, Epidemiology and End Results (SEER) Study.

AIM: To study the prognostic impact of baby boomer (BB) generation on survival end-points of patients with early-stage endometrial carcinoma (EC). PATIENTS AND METHODS: Data were obtained from the SEER registry between 1988-2009. Inclusion criteria included women who underwent hysterectomy for stage I-II EC. Patients were divided into two birth cohorts: BB (women born between 1946 and 1964) and pre-boomers (PB) (born between 1926 and 1945). RESULTS: A total of 30,956 patients were analyzed. Considering that women in the PB group were older than those of the BB generation, the statistical analysis was limited to women 50-59 years of age at the time of diagnosis (n=11,473). Baby boomers had a significantly higher percentage of endometrioid histology (p<0.0001), higher percentage of African American women (p<0.0001), lower tumor grade (p<0.0001), higher number of dissected lymph nodes (LN) (p<0.0001), and less utilization of adjuvant radiation therapy (p=0.0003). Overall survival was improved in women in the BB generation compared to the PB generation (p=0.0003) with a trend for improved uterine cancer-specific survival (p=0.0752). On multivariate analysis, birth cohort (BB vs. PB) was not a significant predictor of survival end-points. Factors predictive of survival included: tumor grade, FIGO stage, African-American race, and increased number of dissected LN. CONCLUSION: Our study suggests that the survival of BB women between 50-60 years of age is better compared to women in the PB generation. As more BB patients are diagnosed with EC, further research is warranted.

Prevalence and prognostic impact of lymphadenectomy and lymph node metastasis in clinically early-stage ovarian clear cell carcinoma.

OBJECTIVES: The objective of this study was to estimate the prevalence and prognostic impact of lymphadenectomy and lymph node involvement in patients with ovarian clear cell carcinoma (OCCC) grossly confined to the ovary. METHODS: Patients with a diagnosis of OCCC grossly confined to the ovary were identified from Surveillance, Epidemiology, and End Results program from 1988 to 2007. Only surgically treated patients were included. Statistical analysis using Student t test, Kaplan-Meier survival methods, and Cox proportional hazards regression were performed. RESULTS: One thousand eight hundred ninety-seven patients with OCCC who have undergone surgical treatment and deemed at time of the surgery to have disease grossly confined to the ovary were included: 538 (28.3%) had no lymphadenectomy (LND -1), and 1359 (71.7%) had lymphadenectomy. Of the 1359 patients who had lymphadenectomy, 1298 (95.5%) were International Federation of Gynecology and Obstetrics (FIGO) surgical stage I (LND +1), and 61 (4.5%) were upstaged to FIGO stage IIIC due to nodal metastasis (LND +3C). The 5-year disease-specific survival was 84.9% for LND -1, 88.0% for LND +1, and 65.0% for LND +3C (P < 0.001). Among those with histologically negative lymph nodes, the 5-year disease-specific survival was 85% for patients with 1 to 10 nodes removed, and 91% for those with more than 10 nodes removed (P = 0.054). On multivariate analysis after controlling for stage, age, and race, lymph node metastasis was an independent predictor of poor disease-specific survival (hazard ratio, 3.1; 95% confidence interval, 1.86-5.28; P < 0.001). On other hand, there was a trend toward an improved survival when more extensive lymphadenectomy is performed in patients with histologically negative nodes (1-10 vs >10 nodes), but it did not reach statistical significance (hazard ratio, 0.71; 95% confidence interval, 0.49-1.02; P = 0.064). CONCLUSIONS: Lymph node metastasis was uncommon in patients diagnosed with OCCC grossly confined to the ovary; however, patients with positive nodes were more likely to die compared to those with negative nodes. More extensive lymphadenectomy plays an important role in providing accurate staging and prognostic information.

EZH2 blockade by RNA interference inhibits growth of ovarian cancer by facilitating re-expression of p21(waf1/cip1) and by inhibiting mutant p53.

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.