Lauren P. Wallner

Inhibition of Interleukin-6 with CNTO328, an Anti-Interleukin-6 Monoclonal Antibody, Inhibits Conversion of Androgen-Dependent Prostate Cancer to an Androgen-Independent Phenotype in Orchiectomized Mice

Initially, prostate cancer is androgen dependent. However, most cases progress to an androgen-independent state through unknown mechanisms. Interleukin-6 (IL-6) has been associated with prostate cancer progression including activation of the androgen receptor (AR). To determine if IL-6 plays a role in the conversion of prostate cancer from androgen dependent to androgen independent, we established androgen-dependent LuCaP 35 human prostate cancer xenografts in nude mice, castrated the mice, and blocked IL-6 activity using a neutralizing antibody (CNT0328) for a period of 18 weeks. IL-6 inhibition increased survival of mice and inhibited tumor growth, as reflected by decreased tumor volume and prostate-specific antigen levels, compared with that in mice receiving isotype control antibody. To test the effect of IL-6 inhibition on the conversion from androgen dependent to androgen independent, tumor cells from the treated mice were assessed for their androgen dependence both in vitro and by implanting them into sham-operated or orchiectomized mice. Tumor cells derived from the isotype-treated animals converted to androgen-independent state, whereas tumor cells from the anti-IL-6 antibody-treated mice were still androgen dependent in vitro and in vivo. Although there was no difference in AR levels between the androgen-independent and androgen-dependent tumors, IL-6 inhibition promoted both apoptosis and inhibited cell proliferation in tumors and blocked the orchiectomy-induced expression of histone acetylases, p300 and CBP, which are AR cofactors. These data show that IL-6 contributes to the development of androgen independence in prostate cancer and suggest that it mediates this effect, in part, through modulation of p300 and CBP.

Bladder Management After Spinal Cord Injury in the United States 1972 to 2005

PURPOSE Studies have shown that bladder management with an indwelling catheter for patients with spinal cord injury is associated with more urological complications such as stones, urinary infection, urethral strictures and bladder cancer. However, little is known about actual bladder management for these patients in clinical practice. MATERIALS AND METHODS Using the National Spinal Cord Injury Database the bladder management method was determined at discharge from rehabilitation and at each 5-year followup period for 30 years. RESULTS At discharge from rehabilitation (24,762 patients) the selection of bladder management with a condom catheter decreased steadily from a peak of 34.6% in 1972 to a low of 1.50% in 2001. The use of clean intermittent catheterization increased from 12.6% in 1972 to a peak of 56.2% in 1991. Indwelling catheter use initially decreased from 33.1% in 1972 to 16.5% in 1991 but increased to 23.1% in 2001. Of 12,984 individuals with followup data those originally using an indwelling catheter for bladder management were unlikely to switch to another method, with 71.1% continuing to use an indwelling catheter at 30 years. Individuals using clean intermittent catheterization and condom catheterization at discharge home did not continue to use these methods with only 20% and 34.6% remaining on the same management, respectively. CONCLUSIONS With time bladder management with clean intermittent catheterization has increased in popularity. However, only 20% of patients initially on clean intermittent catheterization remained on this form of bladder management. More research on the safety of each of these methods needs to be performed to provide better guidance to aid with this decision.

Sexual Functioning among Women with and without Diabetes in the Boston Area Community Health Study

AIM To examine sexual dysfunction among women with and without diabetes in a community-based sample of women aged 30-79 years. METHODS We conducted a cross-sectional analysis of survey responses of female participants in the Boston Area Community Health Study, a community-based random sample, who answered questions regarding sexual functioning and diabetes status and also reported sexual activity (n = 1,291). Associations between diabetes and overall sexual function as well as domain of sexual function were examined in multivariable linear regression models. RESULTS Women with type 2 diabetes (n = 75) were older, less often white, and more likely to have decreased physical activity levels, elevated body mass index, and cardiovascular disease than women without diabetes (n = 1,190). Women with type 1 diabetes (n = 26) were similar to women without diabetes except for higher depression scores and lower levels of activity. Age, marital status, and depressive symptoms were correlated with overall sexual function. After adjustment for age and race, women with and without diabetes had similar arousal, lubrication, orgasm, dyspareunia, satisfaction, and desire. After further adjustment for other factors, including age, depression, and marital status, women with type 1 diabetes had increased dyspareunia compared with women without diabetes, and women with type 2 diabetes had similar functioning to women without diabetes. CONCLUSION Women with type 2 diabetes may have similar sexual functioning to women without diabetes, although women with type 1 diabetes may more often have dyspareunia. Factors such as depression, which are common in women with diabetes, are more strongly related to sexual dysfunction than diabetes status.

Prevalence and severity of undiagnosed urinary incontinence in women.

BACKGROUND Urinary incontinence is a highly prevalent condition in aging women that results in significant morbidity. Less than half of women who suffer from urinary incontinence seek treatment, resulting in a significant proportion of clinically relevant urinary incontinence remaining undiagnosed. Therefore, the purpose of this study was to quantify the prevalence of urinary incontinence in undiagnosed women in a managed care population. METHODS There were 136,457 women aged 25-80 years enrolled in Kaiser Permanente Northwest who were free of genitourinary diagnoses, including urinary incontinence, who were included in this study. Of the 2118 women who were mailed questionnaires ascertaining information on demographic and urinary incontinence characteristics, 875 completed the survey. A chart review of the 234 women who reported moderate to severe urinary incontinence was performed. RESULTS The prevalence of undiagnosed urinary incontinence was 53% in the preceding year, and 39% in the preceding week. The prevalence of undiagnosed stress, mixed, and urge incontinence was found to be 18.7%, 12.0%, and 6.8%, respectively. Quality of life was found to significantly decrease with increasing urinary incontinence severity. Of the 234 chart-reviewed women, 5% were found to have physician-documented urinary incontinence. CONCLUSIONS These results suggest that a significant proportion of women in this managed care population are suffering from urinary incontinence that remains undiagnosed. Efforts should be made to encourage women and physicians to initiate conversations about urinary incontinence symptoms in order to decrease the unnecessary burden of this disease.

The effects of metabolic conditions on prostate cancer incidence over 15 years of follow-up: results from the Olmsted County Study

Study Type – Prognosis (population‐based cohort) Level of Evidence 2a

Medical and Psychosocial Complications Associated With Method of Bladder Management After Traumatic Spinal Cord Injury

OBJECTIVES To determine the relationships between bladder management method and medical complications (renal calculi or decubitus ulcers), number of hospital days, and psychosocial factors. We hypothesized that indwelling catheterization would be associated with more complications, more hospitalizations, and worse psychosocial outcomes compared with other bladder management methods. DESIGN Inception cohort study. SETTING Model spinal cord injury (SCI) centers funded by the National Institute on Disability and Rehabilitation Research from 1973 to 2005. PARTICIPANTS Persons with new traumatic SCI (N=24,762) enrolled in the National SCI Database entire data set forms I and II. Patients were stratified according to the bladder management method recorded at each time of data collection into 1 of 4 groups as follows: indwelling catheterization, spontaneous voiding, condom catheterization, and intermittent catheterization. Those who reported no management method or errors in reporting were excluded (n=1564). INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Medical complications, including pressure ulcer number and grade of worst ulcer, kidney stones, and hospitalizations, as well as psychosocial factors (satisfaction with life, perceived health status, societal participation), were stratified by bladder management method. Results were adjusted for level and completeness of neurologic injury and other confounding and modifying factors. RESULTS Compared with other forms of bladder management, use of an indwelling catheter was associated with more pressure ulcers and longer and more hospitalizations for all causes and urology-specific causes. Indwelling catheter use was associated with the lowest levels of participation, but similar satisfaction with life and perceived health status. CONCLUSIONS Indwelling catheterization was associated with more medical complications and lower levels of participation than other bladder management methods, but more research is required to ascertain the causality of these complications.

Psychosocial Factors Associated with an Increased Frequency of Prostate Cancer Screening in Men Ages 40 to 79 Years: The Olmsted County Study

Prostate cancer is the second leading cause of cancer deaths among U.S. men. Early detection is associated with drastically improved 5-year survival rates. It is unclear, however, what psychosocial factors motivate or discourage men from taking advantage of both prostate-specific antigen (PSA) testing and digital rectal examination (DRE). The goal of the current study was to identify psychosocial factors that influence screening behavior for prostate cancer in a cohort of 2,447 men. In 1990, a randomly selected cohort of Caucasian men, ages 40 to 79 years, from Olmsted County, Minnesota, were enrolled in the study. These men completed a questionnaire containing queries on family history of prostate cancer, concern about getting prostate cancer, and marital status. Medical and laboratory records were reviewed to determine the number DREs (1989-1996) and PSA tests (1989-1998). Frequent screening was defined as the upper 25th percentile for number of DREs (>4) or PSAs (>3). Men who have a family history and men who worry or have concern about prostate cancer were more likely [odds ratio (OR), 1.5; 95% confidence interval (95% CI), 1.2-2.0 and OR, 1.9; 95% CI, 1.4-2.5] to seek screening compared with those without a family history or worry. The association between family history and frequent screening was similar in men who were married or living with someone (OR, 1.7; 95% CI, 1.2-2.2); however, it was reduced among men who live alone (OR, 0.6; 95% CI, 0.2-1.8). These data suggest that psychosocial factors such as family history, worry, or concern about prostate cancer and marital status may play an important role in mens decisions about prostate cancer screening. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3588–92)

Prevalence of and risk factors for prostatitis in African American men: The Flint Men's Health Study

Prostatitis is a common, yet ill‐defined condition without clear diagnostic criteria and treatment strategies. Previous studies examining the prevalence and correlates of prostatitis are limited in their inclusion of primarily white populations. The objective of the current study was to identify prevalence of and risk factors for prostatitis in a population‐based sample of African‐American men.

Use of statins and prostate cancer recurrence among patients treated with radical prostatectomy.

Statins have shown broad spectrum anti‐cancer properties in laboratory studies. In epidemiological studies, use of statins has been associated with reduced risk of advanced prostate cancer. However, the effects of statins on prostate cancer disease progression following curative treatment have not been extensively studied, and previous studies reported conflicting results. This study found no clear association between overall statin use and risk of disease progression, as well as lack of a monotone dose–response relationship between the use of statins, whether it was use before or after prostatectomy, and prostate cancer disease progression.

Association of body mass index and prostate cancer mortality

OBJECTIVES Inconsistent evidence exists on whether obesity is associated with an increased risk of prostate cancer death post-radical prostatectomy. We examined data from three large health plans to evaluate if an increased body mass index (BMI) at prostate cancer diagnosis is related to prostate cancer mortality SUBJECTS AND METHODS This population-based case-control study included 751 men with prostate cancer who underwent radical prostatectomy. Cases were men who died due to prostate cancer (N=323) and matched controls (N=428). We used multivariable logistic regression models to assess the association between BMI at diagnosis and prostate cancer mortality, adjusted for Gleason score, PSA, tumour characteristics, and matching factors. RESULTS Study subjects were classified into the following BMI (kg/m2) categories: healthy (18.5-24.9), overweight (25-29.9) and obese (≥30). Nearly 43% of the participants had a BMI ≥25 at diagnosis. A higher fraction of cases (30%) were obese compared to controls (22%). Overall, obese men had more than a 50% increase in prostate cancer mortality (adjusted odds ratio=1.50 [95% CI, 1.03-2.19]) when compared to men with healthy BMI. After stratifying by Gleason score, the odds of mortality generally rose with increasing BMI. The strongest effect was observed in the Gleason score 8+ category (2.37, 95% CI: 1.11-5.09). These associations persisted after adjusting for PSA at diagnosis and other tumour characteristics. CONCLUSIONS These results suggest that BMI at diagnosis is strongly correlated with prostate cancer mortality, and that men with aggressive disease have a markedly greater odds of death if they are overweight or obese.