Leslie H. Clark

Metformin is associated with improved survival in endometrial cancer.

OBJECTIVE Preclinical evidence suggests that metformin exhibits anti-tumorigenic effects in endometrial cancer. We sought to investigate the association of metformin on endometrial cancer outcomes. METHODS A multi-institutional IRB-approved retrospective cohort analysis was conducted comparing endometrial cancer patients with diabetes mellitus who used metformin (based on medication review at the time of diagnosis) to those who did not use metformin from 2005 to 2010. Metformin use on treatment related outcomes (TTR: time to recurrence; RFS: recurrence free survival; OS: overall survival) were evaluated using univariate and multivariate modeling. RESULTS 24% (363/1495) endometrial cancer patients were diabetic, of whom 54% used metformin. Metformin users were younger and heavier than non-users, though nearly all were postmenopausal and obese. 75% of both groups had endometrioid histology. Stage, grade, and adjuvant therapy distributions were similar. Metformin users had improved RFS and OS. Non-metformin users had 1.8 times worse RFS (95% CI: 1.1-2.9, p = 0.02) and 2.3 times worse OS (95% CI: 1.3-4.2, p = 0.005) after adjusting for age, stage, grade, histology and adjuvant treatment. Metformin use was not associated with TTR. CONCLUSION Metformin use was associated with improved RFS and OS but not TTR, most likely due to improving all-cause mortality. Its role in modifying cancer recurrence remains unclear. Prospective studies that capture metformin exposure prior to, during and post endometrial cancer treatment may help define the role of metformin upon cancer specific and overall health outcomes.

The complex triad of obesity, diabetes and race in Type I and II endometrial cancers: Prevalence and prognostic significance

BACKGROUND We examined the distribution of obesity, diabetes, and race in Type I and Type II endometrial cancers (EC) and their associations with clinical outcomes. METHODS A multi-institutional retrospective analysis of Type I and II EC cases from January 2005 to December 2010 was conducted. Type I (endometrioid), Type II (serous and clear cell), low grade (LG) (grade 1 and 2 endometrioid), and high grade (HG) (grade 3 endometrioid, serous, clear cell) cohorts were compared. Univariate and multivariate analyses were used to determine time-to-recurrence (TTR), recurrence-free survival (RFS), and overall survival (OS). RESULTS Type I EC patients were more frequently obese than Type II (66% versus 51%, p<0.0001) and had similar rates of diabetes (25% versus 23%, p=0.69). African-Americans (AA) had higher median BMI than Caucasians in both Type I (p<0.001) and II (p<0.001) ECs, and were twice as likely to have diabetes (p<0.001). In Type I EC, DM was associated with worse RFS and OS in unadjusted and adjusted models (RFS HR 1.38, 95%CI 1.01-1.89; OS HR 1.86, 95%CI 1.30-2.67), but not with TTR. BMI was associated with improved TTR in the adjusted analysis for Type I EC (HR 0.98, 95%CI 0.95-1.0), but not with RFS or OS. There was no association between DM or BMI and outcomes in Type II or HG EC. AA race was not associated with RFS or OS on adjusted analyses in any group. CONCLUSIONS Obesity and diabetes are highly prevalent in Type I and II ECs, especially in AA. DM was associated with worse RFS and OS in Type I EC. Neither DM nor BMI was associated with outcomes in Type II or HG EC.

Mechanical bowel preparation before laparoscopic hysterectomy: A randomized controlled trial

OBJECTIVE: To examine the influence of mechanical bowel preparation on surgical field visualization during laparoscopic hysterectomy. METHODS: The studys primary outcome was the percentage of operations rated “good” or “excellent” in terms of surgical field visualization at the outset of the case by the primary surgeon. Additional measures included assessment of visualization during the case and patient perioperative comfort. The study was powered to detect a 20% absolute difference in the proportion of cases rated as “good” or “excellent.” RESULTS: Seventy-three patients were assigned to mechanical bowel preparation and 73 to no mechanical bowel preparation. The groups were comparable regarding patient and surgery characteristics. No differences were found for this rating between groups (mechanical bowel preparation, 64 of 73 patients [87.7%], compared with no mechanical bowel preparation, 60 of 73 patients [82.2%], P=.36). Surgeons guessed patient assignment correctly 59% of the time (42 of 71 patients) with mechanical bowel preparation and 55% of the time (41 of 75 patients) with no mechanical bowel preparation. CONCLUSION: Mechanical bowel preparation is well-tolerated but does not influence surgical field visualization for laparoscopic hysterectomy. CLINICAL TRIAL REGISTRATION: ClinialTrials.gov, www.clinicaltrials.gov, NCT01576965. LEVEL OF EVIDENCE: I

Did GOG99 and PORTEC1 change clinical practice in the United States

OBJECTIVE To assess the practice of adjuvant radiation (RT) for endometrial cancer in the United States following the publication of the Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC1), and Gynecologic Oncology Group-Adjuvant Radiation for Intermediate Risk Endometrial Cancers (GOG99). METHODS A retrospective cohort study using the NCI SEER database compared the use of RT pre and post publication of PORTEC1 (1996-99 v 2000-03) and GOG 99 (2000-03 v 2004-07). Criteria for intermediate (IR) and high-intermediate (HIR) risk categories as defined by PORTEC1 and GOG99 were applied. Chi-squared statistics and adjusted multivariable Poisson models were used. RESULTS RT did not increase for HIR (RR 1.05, 95%CI 0.99, 1.11) or IR groups (RR 1.0, 95% CI 0.95, 1.05) following GOG99 publication, or for HIR (RR 1.01, 95% CI 0.86, 1.19) or IR groups (RR 0.88, 95% CI 0.77-1.00) following PORTEC1 publication. Radiation rates changed heterogeneously across the country without a discernible pattern of cause. Among radiated patients, brachytherapy use increased, whereas external beam use decreased after GOG99 publication. CONCLUSIONS As the debate regarding the utility of adjuvant radiation in early stage endometrial cancer continues, we found that overall, clinicians had not adopted GOG99 or PORTEC1 results into their clinical practice in the years immediately after publication. However, we did identify significant variation in practice by geographic location. Given that barely half the women deemed highest risk for recurrence received radiation, these findings illustrate that clinical practice reflects the continued controversy surrounding adjuvant radiation in the treatment of endometrial cancer.

Incidence of trocar site herniation following robotic gynecologic surgery

OBJECTIVE Trocar site herniation is a recognized complication of minimally invasive surgery, but published data on trocar site herniation after robotic surgery are scarce. We sought to determine the incidence of trocar site herniation in women undergoing robotic surgery for gynecologic disease. METHODS A retrospective review of robotic surgeries performed from January 1, 2006, through December 31, 2012, was conducted. Postoperative trocar site herniations were identified, along with time to presentation, location of herniation, and management. Patients were excluded if surgery was converted to laparotomy or traditional laparoscopy. The Wilcoxon rank-sum test was used to compare patients with and without herniation with respect to continuous variables, and Fishers exact test was used to compare these 2 groups with respect to categorical variables. RESULTS The study included 500 patients, 3 of whom experienced herniation at a single trocar site. The patients with and without herniation did not differ with respect to age, body mass index, smoking status, medical comorbidities, operating time, or estimated blood loss. All 3 herniations occurred at 12-mm trocar sites. Two herniations occurred at assistant port sites, and 1 occurred at the umbilical camera port site. The median time to herniation was 21 days (range, 8-38 days). One patient required immediate surgical intervention; the other 2 patients had conservative management. CONCLUSIONS Trocar site herniation is a rare complication following robotic surgery. The most important risk factor for trocar site herniation appears to be larger trocar size, as all herniations occurred at 12-mm port sites.

JQ1 suppresses tumor growth via PTEN/PI3K/AKT pathway in endometrial cancer

Overexpression of c-Myc is associated with worse outcomes in endometrial cancer, indicating that c-Myc may be a promising target for endometrial cancer therapy. A novel small molecule, JQ1, has been shown to block BRD4 resulting in inhibition of c-Myc expression and tumor growth. Thus, we investigated whether JQ1 can inhibit endometrial cancer growth in cell culture and xenograft models. In PTEN-positive endometrial cancer cells, JQ1 significantly suppressed cell proliferation via induction of G1 phase arrest and apoptosis in a dose-dependent manner, accompanied by a sharp decline in cyclin D1 and CDK4 protein expression. However, PTEN-negative endometrial cancer cells exhibited intrinsic resistance to JQ1, despite significant c-Myc inhibition. Moreover, we found that PTEN and its downstream PI3K/AKT signaling targets were modulated by JQ1, as evidenced by microarray analysis. Silencing of PTEN in PTEN-positive endometrial cancer cells resulted in resistance to JQ1, while upregulation of PTEN in PTEN-negative endometrial cancer cells increased sensitivity to JQ1. In xenografts models of PTEN-positive and PTEN-knock-in endometrial cancer, JQ1 significantly upregulated the expression of PTEN, blocked the PI3K/AKT signaling pathway and suppressed tumor growth. These effects were attenuated in PTEN-negative and PTEN-knockdown xenograft models. Thus, JQ1 resistance appears to be highly associated with the status of PTEN expression in endometrial cancer. Our findings suggest that targeting BRD4 using JQ1 might serve as a novel therapeutic strategy in PTEN-positive endometrial cancers.

Endometrial Cancer Survivors' Perceptions of Provider Obesity Counseling and Attempted Behavior Change: Are We Seizing the Moment?

Objective To determine patients’ perceptions of provider-based counseling and behavior changes made by endometrial cancer survivors. Materials and Methods Endometrial cancer survivors (diagnosed from 2011 to 2012) from a single institution were surveyed. Exclusion criteria included persistent or recurrent disease or those actively undergoing treatment. Information collected included demographics, weight assessments, health behaviors, and physician counseling. Statistical analysis was performed using descriptive statistics, Fisher exact test, McNemar test, and the &kgr; statistic as a measure of agreement. Results Of 233 surveys sent, 46% were returned. Median body mass index was 29.8 kg/m2 (range, 17.1–64.8 kg/m2). Comparing primary care providers with gynecologic oncologists (GOs), 47% (n = 46) versus 25% (n = 23) provided dietary counseling and 62% (n = 60) versus 37% (n = 34) provided physical activity counseling (Fisher exact test, P = 0.001 and P < 0.001, respectively). Only 29% (n = 30) reported being told of the link between endometrial cancer and obesity. Fifty-two percent of responders attempted weight loss after their diagnosis. Fifty-nine percent of responders reported making changes in their diet. Fifty-six percent of patients made dietary changes within 3 months of diagnosis. Forty-eight percent of responders increased physical activity, with 62% implementing changes within 3 to 6 months of their diagnosis. The responders most likely to attempt weight loss were those who received counseling by a provider. All patients reporting attempted weight loss after their cancer diagnosis report being counseled by either a primary care provider or a GO to lose weight. Weight loss counseling was significantly associated with attempting weight loss (P < 0.001). Conclusions One third of endometrial cancer survivors report counseling by their GO to lose weight. One half of endometrial cancer survivors reported attempted weight loss. All patients reporting weight loss counseling from their oncologist reported attempted weight loss. Most behavioral change occurred 3 to 6 months after a cancer diagnosis. Obesity in endometrial cancer survivors is not adequately addressed and represents a critical area for improvement.

Deregulated miRNAs in human cervical cancer: functional importance and potential clinical use

Cervical cancer (CC) is one of the most common malignancies affecting women worldwide. While the morbidity and mortality associated with CC are decreasing in western countries, they both remain high in developing countries. Unfortunately, many issues about molecular mechanisms of CC are not clear yet. miRNAs are a group of small noncoding RNAs that could post-transcriptionally modulate the expression of specific genes and participate in the initiation and progression of multiple diseases including CC. In the last decade, mounting evidences suggest an association between miRNAs and human papillomavirus infection, as well as variations in biologic behavior, treatment response and prognosis in CC. Herein, we highlight the latest findings in this area and the potential applications.

Everolimus exhibits anti-tumorigenic activity in obesity-induced ovarian cancer

Everolimus inhibits mTOR kinase activity and its downstream targets by acting on mTORC1 and has anti-tumorigenic activity in ovarian cancer. Clinical and epidemiologic data find that obesity is associated with worse outcomes in ovarian cancer. In addition, obesity leads to hyperactivation of the mTOR pathway in epithelial tissues, suggesting that mTOR inhibitors may be a logical choice for treatment in obesity-driven cancers. However, it remains unclear if obesity impacts the effect of everolimus on tumor growth in ovarian cancer. The present study was aimed at evaluating the effects of everolimus on cytotoxicity, cell metabolism, apoptosis, cell cycle, cell stress and invasion in human ovarian cancer cells. A genetically engineered mouse model of serous ovarian cancer fed a high fat diet or low fat diet allowed further investigation into the inter-relationship between everolimus and obesity in vivo. Everolimus significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, reduced invasion and caused cellular stress via inhibition of mTOR pathways in vitro. Hypoglycemic conditions enhanced the sensitivity of cells to everolimus through the disruption of glycolysis. Moreover, everolimus was found to inhibit ovarian tumor growth in both obese and lean mice. This reduction coincided with a decrease in expression of Ki-67 and phosphorylated-S6, as well as an increase in cleaved caspase 3 and phosphorylated-AKT. Metabolite profiling revealed that everolimus was able to alter tumor metabolism through different metabolic pathways in the obese and lean mice. Our findings support that everolimus may be a promising therapeutic agent for obesity-driven ovarian cancers.

Extremes in body mass index affect overall survival in women with cervical cancer

OBJECTIVE To examine the effect of BMI on pathologic findings, cancer recurrence and survival in cervical cancer patients. METHODS A retrospective cohort study of cervical cancer patients treated from July 2000 to March 2013 was performed. BMI was calculated, and patients were classified by BMI. The primary outcome was overall survival (OS). Secondary outcomes included stage, histopathology, disease-specific survival (DSS) and recurrence free survival (RFS). Kaplan-Meier survival curves were generated and compared using Cox proportional hazard ratios. RESULTS Of 632 eligible patients, 24 (4%) were underweight, 191 (30%) were normal weight, 417 (66%) were overweight/obese. There was no difference in age (p=0.91), stage at presentation (p=0.91), grade (p=0.46), or histology (p=0.76) between weight categories. There were fewer White patients in the underweight (54%) and overweight/obese (58%) groups compared to the normal weight (71%) group (p=0.04). After controlling for prognostic factors, underweight and overweight/obese patients had worse median RFS than normal weight patients (7.6 v 25.0months, p=0.01 and 20.3 v 25.0months, p=0.03). Underweight patients also had worse OS (10.4 v 28.4months, p=0.031) and DSS (13.8 v 28.4months, p=0.04) compared to normal weight patients. Overweight/obese patients had worse OS than normal weight patients (22.2 v 28.4months, p=0.03) and a trend toward worse DSS (21.9 v 28.4months, p=0.09). CONCLUSION Both extremes of weight (underweight and overweight/obesity) were associated with worse survival in patients with cervical cancer. Optimizing weight in cervical cancer patients may improve outcomes in these patients.