Kristy K. Ward

Cardiovascular disease is the leading cause of death among endometrial cancer patients

OBJECTIVE To evaluate the causes of death among women with endometrial cancer. METHODS SEER registries from 1973-1988 were queried to perform a retrospective cohort study of women with invasive epithelial endometrial cancer. Causes of death were compared according to grade and stage. RESULTS 33,232 women with incident cases of endometrial cancer had died at the time of last follow up. Overall, women were most likely to die from cardiovascular disease (35.9%, 95% CI 35.3-36.3%), followed by other causes, other malignancies, and endometrial cancer. Women with low grade localized cancer were most likely to die of cardiovascular disease, while women with high grade advanced cancer were least likely to die of cardiovascular disease and most likely to die of endometrial cancer. For the entire population, risk of death from cardiovascular causes surpasses the risk of death from endometrial cancer 5 years after diagnosis. CONCLUSIONS Higher risk of cardiac death among endometrial cancer patients likely reflects the high probability of curative cancer treatment and the prevalence of cardiac disease and risk factors. As the probability of dying of endometrial cancer decreases with time, the probability of dying of cardiovascular disease increases. Interventions and investigations aimed at addressing risk factors for cardiovascular disease may have the greatest potential to improve survival for women diagnosed with endometrial cancer and should feature prominently in treatment and survivorship plans.

Inhibition of endothelial FAK activity prevents tumor metastasis by enhancing barrier function

Endothelial cell focal adhesion kinase is a key intermediate between c-Src and the regulation of endothelial cell barrier function in the control of tumor metastasis.

Bariatric surgery decreases the risk of uterine malignancy.

OBJECTIVE To describe the risk of uterine malignancy among women who have had weight loss surgery. METHODS We performed a retrospective cohort study among inpatient admissions of women 18years, or older, registered in the University HealthSystem Consortium (UHC) dataset. The rate of uterine malignancy per hospital admission was calculated. Rates were compared according to whether diagnoses at the time of discharge included history of bariatric surgery, and further, according to whether there was a diagnosis of obesity. RESULTS In admissions of patients who did not have a history of prior bariatric surgery, the rate of uterine malignancy was 599/100,000 (95% CI 590 to 610). Among obese women who had not previously undergone bariatric operations, the rate was 1409/100,000 (95% CI 1380 to 1440). Of women admitted who had a history of bariatric surgery, the rate of uterine malignancy was 408/100,000 (95% CI 370 to 450). The relative risk of uterine malignancy in all admissions for women who had prior bariatric surgery, compared to obese women who had not had bariatric surgery, was 0.29 (95% CI 0.26-0.32). Among women who had bariatric surgery and were not currently obese, the relative risk of uterine malignancy was 0.19 (95% CI 0.17-0.22) compared to obese women who had not undergone bariatric surgery. CONCLUSION A history of bariatric surgery is associated with a 71% reduced risk for uterine malignancy overall, and an 81% reduced risk if normal weight is maintained after surgery. This finding suggests that obesity may be a modifiable risk factor related to development of endometrial cancer.

Changing demographics of cervical cancer in the United States (1973-2008).

OBJECTIVE To describe changes in the cervical cancer population. METHODS The SEER database 9 registries from 1973 to 2008 were queried to perform a retrospective cohort study of women with invasive cervical cancer. Estimated annual percent change (EAPC) in incidence rates and 95% confidence intervals (CI) over the entire study period were compared according to age, stage, race, and cell type (squamous [SCC] and adenocarcinoma [ACA]). Proportions and odds ratios (OR) were calculated for patients diagnosed during the second half (1990-2008) compared to first half (1973-89) of the study period. RESULTS 40,363 women with cervical cancer were entered into SEER. The EAPC are falling fastest among those with localized disease (-2.5%; 95% CI -2.8 to -2.1), age≥50 (-3.0%; 95% CI=-3.2 to -2.8), and black women (-3.8%; 95% CI=-4.1 to -3.6). The odds of a newly diagnosed cervical cancer patient having advanced disease are 10% higher, being less than age 50 are 37% higher, and being Asian or Pacific Islander are 68% higher in the second time period as compared to the first. CONCLUSIONS In the US, the population with cervical cancer is changing. Patients are presently significantly more likely to be pre-menopausal, Asian or Pacific Islander, and more frequently have non-squamous histology than previously. These progressive and cumulative changes could be due to the disparate impact of current population based screening and prevention strategies. Understanding the implications of these evolving population characteristics may facilitate planning targeted studies and interventions for cervical cancer prevention, screening and treatment in the future.

The risk of uterine malignancy is linearly associated with body mass index in a cohort of US women

OBJECTIVE We sought to quantify the relationship of uterine malignancy with body mass index (BMI). STUDY DESIGN The University HealthSystem Consortium database was queried to identify all women undergoing total hysterectomy with a recorded BMI in the overweight and obese categories. Least squares regression was applied to evaluate the association between increasing BMI and the proportion of women with a diagnosis of uterine malignancy. Multivariate binary logistic regression was performed to adjust for other known risk factors including age, race, and other comorbidities. RESULTS There were 6905 women who met inclusion criteria; 1891 (27.4%) of these had uterine malignancy. There is a linear relationship (y = 0.015x - 0.23, R(2) = 0.92) of the probability of uterine malignancy vs BMI. After adjusting for other risk factors, we found that each 1-U increase in BMI was significantly, independently associated with an 11% increase in the proportion of patients diagnosed with uterine malignancy (odds ratio, 1.11; 95% confidence interval, 1.09-1.13; P < .001). CONCLUSION In a population of women undergoing hysterectomy, we observed a linear increase in the frequency of uterine cancer associated with increasing BMI. This finding suggests that even relatively modest weight gain may significantly raise cancer risk. In the United States, the mean BMI for women is 26.5 kg/m(2) and it is estimated that more than half of US women have a BMI within the studys range. Our results could, therefore, be relevant to a majority of the population. The findings could increase popular acceptance of weight management as a key component of general health maintenance and, possibly, as an additional approach to cancer risk reduction.

FAK Inhibition Disrupts a β5 Integrin Signaling Axis Controlling Anchorage-Independent Ovarian Carcinoma Growth

Ovarian cancer ascites fluid contains matrix proteins that can impact tumor growth via integrin receptor binding. In human ovarian tumor tissue arrays, we find that activation of the cytoplasmic focal adhesion (FAK) tyrosine kinase parallels increased tumor stage, β5 integrin, and osteopontin matrix staining. Elevated osteopontin, β5 integrin, and FAK mRNA levels are associated with decreased serous ovarian cancer patient survival. FAK remains active within ovarian cancer cells grown as spheroids, and anchorage-independent growth analyses of seven ovarian carcinoma cell lines identified sensitive (HEY, OVCAR8) and resistant (SKOV3-IP, OVCAR10) cells to 0.1 μmol/L FAK inhibitor (VS-4718, formerly PND-1186) treatment. VS-4718 promoted HEY and OVCAR8 G0–G1 cell-cycle arrest followed by cell death, whereas growth of SKOV3-IP and OVCAR10 cells was resistant to 1.0 μmol/L VS-4718. In HEY cells, genetic or pharmacological FAK inhibition prevented tumor growth in mice with corresponding reductions in β5 integrin and osteopontin expression. β5 knockdown reduced HEY cell growth in soft agar, tumor growth in mice, and both FAK Y397 phosphorylation and osteopontin expression in spheroids. FAK inhibitor–resistant (SKOV3-IP, OVCAR10) cells exhibited anchorage-independent Akt S473 phosphorylation, and expression of membrane-targeted and active Akt in sensitive cells (HEY, OVCAR8) increased growth but did not create a FAK inhibitor–resistant phenotype. These results link osteopontin, β5 integrin, and FAK in promoting ovarian tumor progression. β5 integrin expression may serve as a biomarker for serous ovarian carcinoma cells that possess active FAK signaling. Mol Cancer Ther; 13(8); 2050–61. ©2014 AACR.

Ketorolac for Pain Control With Intrauterine Device Placement: A Randomized Controlled Trial.

OBJECTIVE: To evaluate intramuscular ketorolac compared with placebo saline injection for pain control with intrauterine device (IUD) placement. METHODS: We conducted a randomized, double-blind, placebo-controlled trial between July 2012 and March 2014. Patients received 30 mg ketorolac or placebo saline intramuscular injection 30 minutes before IUD placement. The primary outcome was pain with IUD placement on a 10-cm visual analog scale. Sample size was calculated to provide 80% power to show a 2.0-cm difference (&agr;=0.05) in the primary outcome. Secondary outcomes included pain with study drug injection, speculum insertion, tenaculum placement, uterine sounding, and at 5 and 15 minutes after IUD placement. RESULTS: A total of 67 women participated in the study, 33 in the ketorolac arm and 34 in the placebo arm. There were no differences in baseline demographics including age, body mass index, and race. There were no differences in median pain scores for IUD placement in the placebo compared with ketorolac groups (5.2 compared with 3.6 cm, P=.99). There was a decrease in median pain scores at 5 minutes (2.2 compared with 0.3 cm, P⩽.001) and 15 minutes (1.6 compared with 0.1 cm, P⩽.001) after IUD placement but no difference for all other time points. Nulliparous participants (n=16, eight per arm) had a decrease in pain scores with IUD placement (8.1 compared with 5.4 cm, P=.02). In this study, 22% of participants in the placebo group and 18% in the ketorolac group reported injection pain was as painful as IUD placement. CONCLUSION: Ketorolac does not reduce pain with IUD placement but does reduce pain at 5 and 15 minutes after placement. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; www.clinicaltrials.gov, NCT01664559. LEVEL OF EVIDENCE: I

Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer.

OBJECTIVE Focal adhesion kinase (FAK) is overexpressed in serous ovarian cancer. Loss of merlin, a product of the neurofibromatosis 2 tumor suppressor gene, is being evaluated as a biomarker for FAK inhibitor sensitivity in mesothelioma. Connections between merlin and FAK in ovarian cancer remain undefined. METHODS Nine human and two murine ovarian cancer cell lines were analyzed for growth in the presence of a small molecule FAK inhibitor (PF-271, also termed VS-6062) from 0.1 to 1 μM for 72 h. Merlin was evaluated by immunoblotting and immunostaining of a human ovarian tumor tissue array. Growth of cells was analyzed in an orthotopic tumor model and evaluated in vitro after stable shRNA-mediated merlin knockdown. RESULTS Greater than 50% inhibition of OVCAR8, HEY, and ID8-IP ovarian carcinoma cell growth occurred with 0.1 μM PF-271 in anchorage-independent (p<0.001) but not in adherent culture conditions. PF-271-mediated reduction in FAK Y397 phosphorylation occurred independently of growth inhibition. Suspended growth of OVCAR3, OVCAR10, IGROV1, IGROV1-IP, SKOV3, SKOV3-IP, A2780, and 5009-MOVCAR was not affected by 0.1 μM PF-271. Merlin expression did not correlate with serous ovarian tumor grade or stage. PF-271 (30 mg/kg, BID) did not inhibit 5009-MOVCAR tumor growth and merlin knockdown in SKOV3-IP and OVCAR10 cells did not alter suspended cell growth upon PF-271 addition. CONCLUSIONS Differential responsiveness to FAK inhibitor treatment was observed. Intrinsic low merlin protein level correlated with PF-271-mediated anchorage-independent growth inhibition, but reduction in merlin expression did not induce sensitivity to FAK inhibition. Merlin levels may be useful for patient stratification in FAK inhibitor trials.

Using the Theory of Planned Behavior to Understand Cervical Cancer Screening Among Latinas

To reduce the high incidence of cervical cancer among Latinas in the United States it is important to understand factors that predict screening behavior. The aim of this study was to test the utility of theory of planned behavior in predicting cervical cancer screening among a group of Latinas. A sample of Latinas (N = 614) completed a baseline survey about Pap test attitudes subjective norms, perceived behavioral control, and intention to be screened for cervical cancer. At 6 months postbaseline, cervical cancer screening behavior was assessed. Structural equation modeling was used to test the theory. Model fit statistics indicated good model fit: χ2(48) = 54.32, p = .246; comparative fit index = .992; root mean square error of approximation = .015; weighted root mean square residual = .687. Subjective norms (p = .005) and perceived behavioral control (p < .0001) were positively associated with intention to be screened for cervical cancer, and the intention to be screened predicted actual cervical cancer screening (p < .0001). The proportion of variance (R2) in intention accounted for by the predictors was .276 and the R2 in cervical cancer screening accounted for was .130. This study provides support for the use of the theory of planned behavior in predicting cervical cancer screening among Latinas. This knowledge can be used to inform the development of a theory of planned behavior–based intervention to increase cervical cancer screening among Latinas and reduce the high incidence of cervical cancer in this group of women.

Women with gynecologic malignancies have a greater incidence of suicide than women with other cancer types

To evaluate risk of suicide of women with invasive gynecologic malignancies, the National Cancer Institutes Surveillance, Epidemiology, and End Results Program (1973-2007) was queried. Suicide per 100,000 women with gynecologic malignancies was compared with that of women with other malignancies; suicide was 30% more likely in those with gynecologic malignancies. Most suicides occurred within 4 years of diagnosis. Better understanding of the descriptive epidemiology of suicide among women with gynecologic malignancies could lead to improved risk assessment, screening, and prevention of this potentially avoidable cause of death.