Faculty Bibliography

BACKGROUND:While tamoxifen activity is mainly due to endoxifen and the concentration of this active metabolite is, in part, controlled by CYP2D6 metabolic status, clinical correlative studies have produced mixed results. FINDINGS/RESULTS:In an exploratory study, we determined the CYP2D6 metabolic status and plasma concentrations of endoxifen among 224 Filipino and Vietnamese women participating in a clinical trial of adjuvant hormonal therapy for operable breast cancer. We further conducted a nested-case-control study among 48 women (half with recurrent disease, half without) investigating the relationship of endoxifen concentrations and recurrence of disease. We found a significant association of reduced endoxifen plasma concentrations with functionally important CYP2D6 genotypes. High endoxifen concentrations were associated with higher risk of recurrence; with a quadratic trend fitted to a stratified Cox proportional hazards regression model, the likelihood ratio p-value was 0.002. The trend also showed that in 8 out of 9 pairs with low endoxifen concentrations, the recurrent case had lower endoxifen levels than the matched control. CONCLUSIONS:This exploratory analysis suggests that there is an optimal range for endoxifen concentrations to achieve favorable effects as adjuvant therapy. In particular, at higher concentrations (>70 ng.ml), endoxifen may promote recurrence.

OBJECTIVES/OBJECTIVE:To examine prestroke lifestyle factors associated with poststroke mortality and recovery in older women. DESIGN/METHODS:Longitudinal prospective cohort study. SETTING/METHODS:The Women's Health Initiative (WHI, clinical trials and observational study), 40 clinical centers in the United States. PARTICIPANTS/METHODS:WHI participants, women aged 50 to 79, who were stroke-free at baseline (1993/98), with incident stroke before 2005. MEASUREMENTS/METHODS:Participants were followed for mortality through 2010. Prestroke characteristics were from the last examination before the stroke event. Annual follow-up for clinical events ascertained hospitalization for stroke that was subsequently physician adjudicated with medical records. Multivariable regression models were used to analyze factors associated with poststroke mortality and poststroke recovery at hospital discharge (poststroke Glasgow score), adjusting for stroke type. RESULTS:Of 3,173 women with incident stroke, 1,111 (35%) died. Individuals who were overweight or obese before stroke had lower poststroke mortality than those who were normal weight (obese: hazard ratio (HR) = 0.69, 95% confidence interval (CI) = 0.53-0.88; overweight: HR = 0.72, 95% CI = 0.58-0.90); individuals who were underweight before stroke had nonsignificantly greater poststroke mortality (HR = 2.02, 95% CI = 0.98-4.16, P = .06). Other prestroke factors associated with poststroke mortality included diabetes mellitus (HR = 1.28, 95% CI = 1.01-1.64), current smoking (vs nonsmoker, HR = 2.13, 95% CI = 1.53-3.00), physical inactivity (vs >150 min of exercise per week, HR = 1.39, 95% CI = 1.09-1.78), and lowest physical function quartile (vs highest, HR = 1.54, 95% CI = 1.18-2.02). Prestroke diabetes mellitus was associated with lower odds of good recovery after stroke (odds ratio (OR) = 0.60, 95% CI = 0.44-0.82). Current hormone use before stroke was associated with greater odds of moderate than of severe disability after stroke (OR = 1.29, 95% CI = 1.00-1.66). CONCLUSION/CONCLUSIONS:Potentially modifiable factors before stroke, including smoking, diabetes mellitus, and being underweight, were associated with greater poststroke mortality in older women. Being overweight or obese and physical activity before stroke were associated with lower poststroke mortality in older women.

Substantial variation across states in the prevalence and trends in childhood overweight and obesity indicate a need for state-specific surveillance to make state comparisons to national estimates and identify high-risk populations. The purpose of this study was to examine body mass index (BMI) trends among third-grade children in Ohio between the 2004-2005 and 2009-2010 school years and examine changes in prevalence of obesity by specific demographic subgroups. Third-grade children (n=33,672) were directly weighed and measured throughout the school years by trained health care professionals. Trends in overweight/obesity (≥85th percentile of BMI by age/sex), obesity (≥95th percentile), and obesity level 2 (≥97th percentile) over five time periods (2004-2005, 2006-2007, 2007-2008, 2008-2009, 2009-2010) were modeled using logistic regression, accounting for the survey design and adjusting for sex, race/ethnicity, National School Lunch Program (NSLP) participation, and age. Differences in these BMI categories were also examined by these subgroups. BMI estimates did not demonstrate a statistically significant trend over the five time periods for overweight/obesity (34% to 36%), obesity (18% to 20%), or obesity level 2 (12% to 14%). However, increases in overweight/obesity prevalence were found in Hispanic children (37.8% vs 53.1%; P<0.01). Decreases in obesity (16.6% vs 14.1%; P=0.02) and obesity level 2 (11.3% vs 9.3%; P=0.02) were found among children not participating in NSLP and residing in suburban counties (obesity [17.3% vs 14.7%; P=0.03] and obesity level 2 [11.8% vs 9.8%; P=0.05]). Finally, decreases in overweight/obesity and obesity level 2 among boys were observed (15% vs 12.9%; P=0.02). Despite no significant overall trends in overweight/obesity, obesity, or obesity level 2 between 2004 and 2010, prevalence changed among specific subgroups. Obesity prevention efforts should be widespread and include special emphasis on groups experiencing increases or no change in prevalence.

BACKGROUND:Cervical cancer incidence and mortality rates are high among women from Appalachia, yet data do not exist on human papillomavirus (HPV) prevalence among these women. We examined the prevalence of genital HPV among Appalachian women and identified correlates of HPV detection. METHODS:We report data from a case-control study conducted between January 2006 and December 2008 as part of the Community Awareness, Resources, and Education (CARE) Project. We examined HPV prevalence among 1116 women (278 women with abnormal Pap tests at study entry [cases], 838 women with normal Pap tests [controls]) from Appalachian Ohio. Analyses used multivariable logistic regression to identify correlates of HPV detection. RESULTS:The prevalence of HPV was 43.1% for any HPV type, 33.5% for high-risk HPV types, 23.4% for low-risk HPV types, and 12.5% for vaccine-preventable HPV types. Detection of any HPV type was more common among women who were ages 18-26 (OR = 2.09, 95% CI: 1.26-3.50), current smokers (OR = 1.86, 95% CI: 1.26-2.73), had at least five male sexual partners during their lifetime (OR = 2.28, 95% CI: 1.56-3.33), or had multiple male sexual partners during the last year (OR = 1.98, 95% CI: 1.25-3.14). Similar correlates were identified for detection of a high-risk HPV type. CONCLUSIONS:HPV was prevalent among Appalachian women, with many women having a high-risk HPV type detected. Results may help explain the high cervical cancer rates observed among Appalachian women and can help inform future cervical cancer prevention efforts in this geographic region.

There is a need for time-efficient, valid measures of distal paretic upper extremity (UE) movement. The purposes of this study were to (1) determine the psychometric properties of the wrist stability and mobility and wrist/hand scale of the upper extremity Fugl-Meyer (w/h UE FM) as a "stand-alone" measure of distal UE movement; and (2) provide detailed instructions on w/h UE FM administration and scoring. The upper extremity Fugl Meyer (UE FM) and Action Research Arm Test (ARAT) were administered on 2 separate occasions to each of 29 subjects exhibiting stable, mild UE hemiparesis (23 men; mean age ± SD, 60.8±12.3 y; mean time since stroke onset for subjects in the sample, 36.0 mo). Fifty-eight observations were collected on each measure. w/h UE FM internal consistency levels (measured by Cronbach α) were high (.90 and .88 for first and second testing sessions, respectively). The intraclass correlation coefficient for the UE FM was .98, while the intraclass correlation coefficient for the w/h UE FM was .97. Concurrent validity measured by Spearman correlation was moderately high between the w/h UE FM and ARAT (.72, P<.001). From these data, it appears that the w/h UE FM is a promising tool to measure distal UE movement in minimally impaired stroke, although more research with a larger sample is needed. A standardized approach to UE test administration is critical to accurate score interpretation across patients and trials. Thus, the article also provides instructions and pictures for w/h UE FM administration and scoring.

Measurement of height and weight in large studies may force the use of multiple measurers. The purpose of this study was to evaluate the reliability of height, weight, and body mass index (BMI) measures collected by multiple measurers in a large, statewide BMI surveillance program. A random subsample of schools (n=30) was selected from schools that participated in the 2009 to 2010 Ohio third-grade Oral Health/BMI surveillance program. Children (n=1,189) were measured by multiple volunteer health professional measurers and again by a trained researcher, who was standard across all schools. Mean differences for height, weight, and BMI percentiles were calculated for BMI category classifications. Agreement was estimated by the reliability coefficient, McNemar's test, and Kappa statistic. Sensitivity, specificity, and positive and negative predictive values were estimated using the trained researcher measures as the reference. Overall mean differences (95% confidence interval) were 0.45 (0.41-0.48) cm for height, 0.07 (-0.01-0.15) kg for weight, and 1.37 (1.20-1.53) for BMI. The correlation coefficient for all three measures was over 0.9 (P<0.01), indicating a strong positive association between measures. BMI category classifications showed substantial reliability (Kappa range: 0.94-0.96). Percentage agreement ranged from 98% to 99% for all BMI categories, as did sensitivities and specificities. Positive predictive values for all BMI categories were approximately 97%, and close to 100% for negative predictive values. Reliability for height, weight, BMI percentile, and BMI classification was very high, supporting the use of multiple trained measurers in a statewide BMI surveillance program. Similar methods can be applied to other public health and clinical settings to improve anthropometric measurement reliability.

OBJECTIVE:To assess hypothetical acceptance of the human papillomavirus (HPV) vaccine for themselves and a daughter age 9-12 years among Appalachia Ohio women. METHODS:Women with an abnormal Pap smear and randomly selected women with a normal Pap smear from 17 clinics completed an interview in 2006-2008. RESULTS:From 1131 original study participants, 807 (71%) completed a survey about the HPV vaccine for their daughters and themselves. Nearly half, 380 (47%), of the participants had heard of a vaccine to prevent cancer, and 362 (95%) of respondents had heard of HPV. The participants were then told that the FDA had approved a vaccine to prevent HPV. Only 379 (38%) participants identified girls ages 9-12 years as a group who should get the vaccine. After being given the official HPV vaccine recommendation statement, 252 (31%) wanted the vaccine; 198 (25%) were "not sure"; and 353 (44%) did not want the vaccine for themselves. With respect to giving the HPV vaccine to a daughter ages 9-12 years, participants responded "yes" 445 (55%); "not sure" 163 (20%); or "no" 185 (23%). Numerous reasons were provided supporting and opposing vaccine acceptance for themselves and for a daughter. Their physician's recommendation for the HPV vaccine increased vaccine acceptance to 86% for themselves and 90% for a daughter. CONCLUSION/CONCLUSIONS:Knowledge, acceptance, and barriers about the HPV vaccine vary among women living in Appalachia Ohio. Physician recommendation is a key facilitator for vaccine diffusion in this region.

BACKGROUND:Obesity is a known risk factor and poor prognostic factor for many comorbidities including cancer. However, the influence of body mass index (BMI) on ovarian cancer outcomes is inconclusive. Therefore, the objective of this study was to evaluate the impact of BMI and weight changes on survival in patients with advanced ovarian cancer after primary treatment. METHODS:All patients with a diagnosis of advanced epithelial ovarian cancer from January 2000 to December 2007 undergoing primary cytoreductive surgery and adjuvant chemotherapy were identified. Patients were divided into 3 categories: underweight/normal weight (BMI, <25 kg/m), overweight (BMI, 25-30 kg/m), and obese (BMI, >30 kg/m). Adjusted hazard ratios for progression-free survival (PFS) and overall survival (OS) were calculated via Cox proportional hazards models. RESULTS:One hundred ninety-eight patients met the inclusion criteria. For all patients, the mean BMI was 26 kg/m (range, 16.4-49.1 kg/m), with 43% of patients being classified as normal weight, 29% overweight, and 28% as obese. Median 5-year OS was 48.2 months (95% confidence interval, 16.4-49.1 months), and no differences in OS were noted between BMI groups. Unadjusted median PFS for patients with normal weight was 13.7 months, compared with 15.5 and 17.9 months for the overweight and obese groups. Adjusted analysis of BMI over time indicates a trend of increased risk for patients who gain weight in the 6 months after primary therapy on disease progression (hazard ratio, 1.68; 95% confidence interval, 0.87-3.26). CONCLUSIONS:After adjustment for confounders, such as stage, grade, histology, age, and debulking status, data suggest a trend toward a shorter PFS in patients with a normal BMI. However, OS was not significantly related to BMI, and weight change in the 6 months after completion of treatment had no effect on PFS or OS. Further research should be directed at elucidating relationships between weight and cancer biology.

OBJECTIVES/OBJECTIVE:Multiple baseline designs (MBDs) have been suggested as alternatives to group-randomized trials (GRT). We reviewed structural features of MBDs and considered their potential effectiveness in public health research. We also reviewed the effect of staggered starts on statistical power. METHODS:We reviewed the MBD literature to identify key structural features, recent suggestions that MBDs be adopted in public health research, and the literature on power in GRTs with staggered starts. We also computed power for MBDs and GRTs. RESULTS:The features that have contributed to the success of small MBDs in some fields are not likely to translate well to public health research. MBDs can be more powerful than GRTs under some conditions, but those conditions involve assumptions that require careful evaluation in practice. CONCLUSIONS:MBDs will often serve better as a complement of rather than as an alternative to GRTs. GRTs may employ staggered starts for logistical or ethical reasons, but this will always increase their duration and will often increase their cost.

PURPOSE/OBJECTIVE:Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM. PATIENTS AND METHODS/METHODS:A phase I clinical trial was initiated for patients with relapsed myeloma with administration of oral lenalidomide on days 1 to 21 and CCI-779 intravenously once per week during a 28-day cycle. Pharmacokinetic data for both agents were obtained, and in vitro transport and uptake studies were conducted to evaluate potential drug-drug interactions. RESULTS:Twenty-one patients were treated with 15 to 25 mg lenalidomide and 15 to 20 mg CCI-779. The maximum-tolerated dose (MTD) was determined to be 25 mg lenalidomide with 15 mg CCI-779. Pharmacokinetic analysis indicated increased doses of CCI-779 resulted in statistically significant changes in clearance, maximum concentrations, and areas under the concentration-time curves, with constant doses of lenalidomide. Similar and significant changes for CCI-779 pharmacokinetics were also observed with increased lenalidomide doses. Detailed mechanistic interrogation of this pharmacokinetic interaction demonstrated that lenalidomide was an ABCB1 (P-glycoprotein [P-gp]) substrate. CONCLUSION/CONCLUSIONS:The MTD of this combination regimen was 25 mg lenalidomide with 15 mg CCI-779, with toxicities of fatigue, neutropenia, and electrolyte wasting. Pharmacokinetic and clinical interactions between lenalidomide and CCI-779 seemed to occur, with in vitro data indicating lenalidomide was an ABCB1 (P-gp) substrate. To our knowledge, this is the first report of a clinically significant P-gp-based drug-drug interaction with lenalidomide.