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1.  Psychological reactivity to laboratory stress is associated with hormonal responses in postmenopausal women 
The present study examined associations between psychological reactivity and hormonal responses to a standardized laboratory stressor (the Trier Social Stress Test [TSST]) in postmenopausal women.
Forty postmenopausal women ages 50–74 completed anxiety and mood assessments prior to and following the TSST. Blood samples were drawn across multiple time points for assessment of cortisol, adrenocorticotropic hormone (ACTH), and DHEA.
As expected, significant increases in anxiety and negative affect and decreases in positive affect were observed from pre- to post-TSST; however, the magnitude of change in anxiety and mood varied considerably across individuals. Analyses indicated that greater increases in anxiety and negative affect from pre- to post-TSST were associated with higher levels of cortisol, ACTH, and DHEA, controlling for race, age, body mass index, and smoking status. Changes in positive affect were not associated with cortisol, ACTH, or DHEA.
These findings suggest that enhanced reactivity to stress is associated with higher hormone levels among postmenopausal women, which could have potential implications for health.
PMCID: PMC4046251  PMID: 24595153
Trier Social Stress Test; anxiety; negative affect; cortisol; DHEA; ACTH
2.  Depressive Symptoms and Serum Lipid Levels in Young Adult Women 
Journal of behavioral medicine  2012;36(2):143-152.
Accumulating data suggest that depression is associated with risk factors for cardiovascular disease, but few studies have investigated potential behavioral mediators of such associations, particularly among women. In this study of healthy young adult women (n = 225), we examined associations among depressive symptoms, health behaviors, and serum lipid levels. Depressive symptoms were assessed with the 20-item Center for Epidemiologic Studies – Depression (CES-D) scale, and a fasting blood sample was obtained for serum lipid levels, including total cholesterol, high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C). Diet was measured using 24-hour recalls, and other health behaviors (physical activity, smoking) were assessed via self-report questionnaire. Results indicated a modest negative association between depressive symptoms and LDL-C levels. Higher levels of depressive symptoms were also associated with lower total and insoluble dietary fiber intake, both of which were associated with HDL-C and LDL-C. Mediational analyses indicated a significant indirect effect of depressive symptoms on LDL-C via total and insoluble dietary fiber in unadjusted analyses, but not in adjusted analyses. The present findings suggest that depressive symptoms are inversely associated with serum LDL-C levels in young adult women, but that these associations are not likely mediated by adverse lifestyle behaviors.
PMCID: PMC3376669  PMID: 22382824
Depression; cholesterol; health behaviors; diet
3.  A Web-Based Communication Aid for Patients with Cancer: The CONNECT™ Study 
Cancer  2013;119(7):1437-1445.
Cancer patients and their oncologists often report differing perceptions of consultation discussions and discordant expectations regarding treatment outcomes. CONNECT™, a computer-based communication aid, was developed to improve communication between patients and oncologists.
CONNECT includes assessment of patient values, goals, and communication preferences; patient communication skills training; and a pre-consult physician summary report. CONNECT was tested in a three-arm, prospective, randomized clinical trial. Prior to the initial medical oncology consultation, adult patients with advanced cancer were randomized to (a) control; (b) CONNECT with physician summary, or (c) CONNECT without physician summary. Outcomes were assessed with post-consultation surveys.
Of 743 patients randomized, 629 completed post-consultation surveys. Patients in the intervention arms (versus control) felt that the CONNECT program made treatment decisions easier to reach (p=0.003) and helped them to be more satisfied with these decisions (p<0.001). In addition, patients in the intervention arms reported higher levels of satisfaction with physician communication format (p=0.026) and discussion regarding support services (p=0.029) and quality of life concerns (p=0.042). The physician summary did not impact outcomes. Patients with higher levels of education and poorer physical functioning experienced greater benefit from CONNECT.
This prospective randomized clinical trial demonstrates that computer-based communication skills training can positively affect patient satisfaction with communication and decision making. Measureable patient characteristics may be used to identify subgroups most likely to benefit from an intervention such as CONNECT.
PMCID: PMC3604078  PMID: 23335150
Cancer communication; health communication; physician-patient communication; decision making; computer assisted; cancer
4.  Establishment and validation of circulating tumor cell-based prognostic nomograms in first-line metastatic breast cancer patients 
Circulating tumor cells (CTC) represent a new outcome-associated biomarker independently from known prognostic factors in metastatic breast cancer (MBC). The objective here was to develop and validate nomograms that combined baseline CTC counts and the other prognostic factors to assess the outcome of individual patients starting first-line treatment for MBC.
Experimental Design
We used a training set of 236 MBC patients starting a first-line treatment from the MD Anderson Cancer Center to establish nomograms that calculated the predicted probability of survival at different time points: 1, 2, and 5 years for overall survival (OS) and 6 months and 1 and 2 years for progression-free survival (PFS). The covariates computed in the model were: age, disease subtype, visceral metastases, performance status, and CTC counts by CellSearch. Nomograms were independently validated with 210 MBC patients from the Institut Curie who underwent first-line chemotherapy. The discriminatory ability and accuracy of the models were assessed using Harrell’s c-statistic and calibration plots at different time points in both training and validation datasets.
Median follow-up was of 23 and 29 months in the MD Anderson and Institut Curie cohorts, respectively. Nomograms demonstrated good C-statistics: 0.74 for OS and 0.65 for PFS and discriminated OS prediction at 1, 2, and 5 years, and PFS prediction at 6 months and 1 and 2 years.
Nomograms, which relied on CTC counts as a continuous covariate, easily facilitated the use of a web-based tool for estimating survival, supporting treatment-decisions and clinical trial stratification in first-line MBC.
PMCID: PMC3662240  PMID: 23340302
circulating tumor cells; first-line; metastatic breast cancer; nomogram; survival
5.  Advanced Imaging Modalities in Early Stage Breast Cancer: Preoperative Use in the United States Medicare Population 
Annals of surgical oncology  2012;20(1):102-110.
Guidelines for breast cancer staging exist, but adherence remains unknown. This study evaluates patterns of imaging in early-stage breast cancer usually reserved for advanced disease.
Surveillance Epidemiology and End Results data linked to Medicare claims from 1992–2005 were reviewed for stage I/II breast cancer patients. Claims were searched for preoperative performance of CT, PET, and bone scans, and brain MRIs (“advanced imaging”).
There were 67,874 stage I/II breast cancer patients; 18.8% (n=12,740) had preoperative advanced imaging. The proportion of patients having CTs, PET scans and brain MRIs increased from 5.7% to 12.4% (p<0.0001), 0.8% to 3.4% (p<0.0001) and 0.2% to 1.1% (p=0.008), respectively, from 1992–2005. Bone scans declined from 20.1% to 10.7% (p<0.0001). “Breast cancer” (174.x) was the only diagnosis code associated with 62.1% of PET scans, 37.7% of bone scans, 24.2% of CTs, and 5.1% of brain MRIs. ≥1 symptom or metastatic site was suggested for 19.6% of bone scans, 13.0% of CTs, 13.0% of PET scans and 6.2% of brain MRIs. Factors associated (p<0.05) with use of all modalities were urban setting, breast MRI and ultrasound. Breast MRI was the strongest predictor (p<0.0001) of bone scan (OR1.63, 95%CI 1.44–1.86), Brain MRI (OR1.74, 95%CI 1.15–2.63), CT (OR2.42, 95%CI 2.12–2.76), and PET (OR5.71, 95%CI 4.52–7.22).
Aside from bone scans, performance of advanced imaging is increasing in early-stage Medicare breast cancer patients, with limited rationale provided by coded diagnoses. In light of existing guidelines and increasing scrutiny about healthcare costs, greater reinforcement of current indications is warranted.
PMCID: PMC3923372  PMID: 22878617
6.  Targeting C4-demethylating genes in the cholesterol pathway sensitizes cancer cells to EGFR inhibitors via increased EGFR degradation 
Cancer discovery  2012;3(1):96-111.
Persistent signaling by the oncogenic epidermal growth factor receptor (EGFR) is a major source of cancer resistance to EGFR targeting. We established that inactivation of two sterol biosynthesis pathway genes, SC4MOL (sterol C4-methyl oxidase-like) and its partner NSDHL (NADP-dependent steroid dehydrogenase-like), sensitized tumor cells to EGFR inhibitors. Bioinformatics modeling of interactions for the sterol pathway genes in eukaryotes allowed us to hypothesize, and then extensively validate an unexpected role for SC4MOL and NSDHL in controlling the signaling, vesicular trafficking and degradation of EGFR and its dimerization partners, ERBB2 and ERBB3. Metabolic block upstream of SC4MOL with ketoconazole or CYP51A1 siRNA rescued cancer cell viability and EGFR degradation. Inactivation of SC4MOL markedly sensitized A431 xenografts to cetuximab, a therapeutic anti-EGFR antibody. Analysis of Nsdhl-deficient Bpa1H/+ mice confirmed dramatic and selective loss of internalized PDGFR in fibroblasts, and reduced activation of EGFR and its effectors in regions of skin lacking NSDHL.
PMCID: PMC3546138  PMID: 23125191
7.  Preoperative Delays in the US Medicare Population With Breast Cancer 
Journal of Clinical Oncology  2012;30(36):4485-4492.
Although no specific delay threshold after diagnosis of breast cancer has been demonstrated to affect outcome, delays can cause anxiety, and surgical waiting time has been suggested as a quality measure. This study was performed to determine the interval from presentation to surgery in Medicare patients with nonmetastatic invasive breast cancer who did not receive neoadjuvant chemotherapy and factors associated with a longer time to surgery.
Medicare claims linked to Surveillance, Epidemiology, and End Results data were reviewed for factors associated with delay between the first physician claim for a breast problem and first therapeutic surgery.
Between 1992 and 2005, 72,586 Medicare patients with breast cancer had a median interval (delay) between first physician visit and surgery of 29 days, increasing from 21 days in 1992 to 32 days in 2005. Women (29 days v 24 days for men; P < .001), younger patients (29 days; P < .001), blacks and Hispanics (each 37 days; P < .001), patients in the northeast (33 days; P < .001), and patients in large metropolitan areas (32 days; P < .001) had longer delays. Patients having breast conservation and mastectomies had adjusted median delays of 28 and 30 days, respectively, with simultaneous reconstruction adding 12 days. Preoperative components, including imaging modalities, biopsy type, and clinician visits, were also each associated with a specific additional delay.
Waiting times for breast cancer surgery have increased in Medicare patients, and measurable delays are associated with demographics and preoperative evaluation components. If such increases continue, periodic assessment may be required to rule out detrimental effects on outcomes.
PMCID: PMC3518727  PMID: 23169513
8.  Knowledge and perceptions of familial and genetic risks for breast cancer risk in adolescent girls 
Evidence suggests early events might modify adult breast cancer risk and many adolescents learn of familial and genetic risks for breast cancer. Little is known about how adolescent girls understand and respond to breast cancer risk.
Semi-structured interviews with 11-19 year-old girls at high-risk and population-risk for breast cancer evaluated knowledge and perceptions of breast cancer risk and risk modification. Framework analysis and descriptive statistics were utilized to analyze open-ended responses. Risk group and age differences were evaluated by Fisher’s exact and McNemar’s tests.
54 girls (86% of invited), 35 high-risk (65%) and 19 population-risk (35%) completed interviews. The most frequently reported risk for breast cancer was family history/hereditary predisposition (66%). Only 17% of girls were aware of BRCA1/2 genes. The majority (76%) of high-risk girls perceive themselves to be at increased risk for breast cancer, compared to 22% of population-risk girls (p=0.001). Half of girls reported that women can get breast cancer before 20 years old. The majority believe there are things women (70%) and girls (67%) can do to prevent breast cancer. Mother was the most frequently reported source of information for breast cancer among both high-risk (97%) and population-risk (89%) girls.
In this study, many high-risk girls perceive themselves to be at increased risk for breast cancer, and many girls believe that breast cancer can occur in teens. Yet, most girls believe there are things women and girls can do to prevent breast cancer. Research evaluating the impact of awareness and perceptions of breast cancer risk on psychosocial, health and risk behaviors is needed to develop strategies to optimize responses to cancer risk.
PMCID: PMC3513641  PMID: 23065030
Adolescents; Breast cancer; Breast cancer prevention; Cancer Risk Assessment; Perceived risk of cancer
9.  When parents disclose BRCA1/2 test results: Their communication and perceptions of offspring response 
Cancer  2012;118(13):3417-3425.
BRCA1/2 testing is not recommended for children, as risk reduction measures and screening are not generally recommended before 25 years old (YO). Little is known about the prevalence and predictors of parent communication to offspring and how offspring respond to this communication.
Semi-structured interviews were conducted with parents who had BRCA1/2 testing and at least one child <25 YO. Logistic regressions were utilized to evaluate associations with communication. Framework analysis was utilized to analyze open-ended responses.
253 parents completed interviews (61% response rate), reporting on 505 offspring. 29% of parents were BRCA1/2 mutation carriers. 334 (66%) offspring learned of their parent’s test result. Older offspring age (p<=0.01), offspring gender (female, p=0.05), parents’ negative test result (p=0.03) and parents’ education (high-school only, p=0.02) were associated with communication to offspring. The most frequently reported initial offspring responses were neutral (41%) or relief (28%). 13% of offspring were reported to experience concern or distress (11%) in response to parental communication of their test results. Distress was more frequently perceived among offspring learning of their parent’s BRCA1/2 positive or variant of uncertain significance result.
Many parents communicate their BRCA1/2 test results to young offspring. Parents’ perceptions of offspring responses appear to vary by offspring age and parent test result. A better understanding of how young offspring respond to information about hereditary risk for adult cancer could provide opportunities to optimize adaptive psychosocial responses to risk information and performance of health behaviors, in adolescence and throughout an at-risk lifespan.
PMCID: PMC3326182  PMID: 22231763
10.  A tutorial on principal stratification-based sensitivity analysis: Application to smoking cessation studies 
One problem with assessing effects of smoking cessation interventions on withdrawal symptoms is that symptoms are affected by whether participants abstain from smoking during trials. Those who enter a randomized trial but do not change smoking behavior might not experience withdrawal related symptoms.
We present a tutorial of how one can use a principal stratification sensitivity analysis to account for abstinence in the estimation of smoking cessation intervention effects. The paper is intended to introduce researchers to principal stratification and describe how they might implement the methods.
We provide a hypothetical example that demonstrates why estimating effects within observed abstention groups is problematic. We demonstrate how estimation of effects within groups defined by potential abstention that an individual would have in either arm of a study can provide meaningful inferences. We describe a sensitivity analysis method to estimate such effects, and use it to investigate effects of a combined behavioral and nicotine replacement therapy intervention on withdrawal symptoms in a female prisoner population.
Overall, the intervention was found to reduce withdrawal symptoms but the effect was not statistically significant in the group that was observed to abstain. More importantly, the intervention was found to be highly effective in the group that would abstain regardless of intervention assignment. The effectiveness of the intervention in other potential abstinence strata depends on the sensitivity analysis assumptions.
We make assumptions to narrow the range of our sensitivity parameter estimates. While appropriate in this situation, such assumptions might not be plausible in all situations.
A principal stratification sensitivity analysis provides a meaningful method of accounting for abstinence effects in the evaluation of smoking cessation interventions on withdrawal symptoms. Smoking researchers have previously recommended analyses in subgroups defined by observed abstention status in the evaluation of smoking cessation interventions. We believe that principal stratification analyses should replace such analyses as the preferred means of accounting for post-randomization abstinence effects in the evaluation of smoking cessation programs.
PMCID: PMC2874094  PMID: 20423924
12.  Functional Status In Older Women Following Gynecological Cancer Surgery: Can Choice of Measure Influence Evidence for Clinical Practice? 
Although functional status serves as a major predictor of morbidity, researchers and clinicians use different terms and measures, limiting comparisons across studies. To demonstrate how differing measures may generate varied findings, we compared and contrasted data from the SF-12 Health Survey Physical Component Summary Scale (SF-12 PCS) and the Enforced Social Dependency Scale (ESDS). The sample consisted of 49 women ages 65 and over recovering from gynecological cancer surgery with data collection at baseline (postoperative period) then 3 and 6 months. Analysis of the relationship between SF-12 PCS and ESDS over time using Generalized Estimating Equations (GEE) demonstrated the relationship was less than 1.0, signaling less than perfect agreement between measures (Beta=0.16, p=0.002). These findings suggest that that the two measures are not interchangeable and may produce conflicting evidence. This highlights the importance of researchers' and clinicians' careful conceptualization and operationalization of functional status prior to measure selection.
PMCID: PMC3549266  PMID: 22387192
13.  Academic Ranking Score: A Publication-Based Reproducible Metric of Thought Leadership in Urology 
European Urology  2011;61(3):435-439.
Hospital rankings have become integral to the marketing strategies of many health care systems. Methodology used in compiling these lists appears highly flawed.
Improve on current hospital ranking systems and to develop a more meaningful measure of a urology department’s contribution to the field, we developed an academic ranking score (ARS) based on publicly available data.
Design, setting, and participants
An active faculty list was assembled for each department. A list of all publications from each department from 2005 to 2010 was then compiled. Only publications with faculty members as first or last author were considered. The ARS was then derived by identifying the number of publications within an institution, normalized by the impact factor of the peer-reviewed journal in which the publication appeared.
The 2010 U.S. News and World Report (USNWR) urology list was reranked based on ARS and compared with the USNWR rank list. ARS was also calculated for several leading European urologic centers.
Results and limitations
A total of 6437 urologic publications were indexed to calculate the ARS. Two of the top three programs in the USNWR rankings dropped out of the top 10. The top 10 academically ranked programs increased or decreased an average of >5 positions (range: 0–17). No correlation was seen between programs ranked in the top 10 by USNWR and our objective ARS method (Spearman ρ: −0.1; p = 0.75). Because ARS only includes first- or last-author publications for faculty with clinical duties, ARS likely excludes basic science contributions and contributions from nonclinical faculty.
Ranking of urology departments through quantification of each program’s recent academic contribution, as captured by the ARS, differs substantially from rankings developed by USNWR. Integration of such objective measures into an overall urology program ranking system would replace current subjective opinions marred by historical biases with up-to-date merit-based assessments.
PMCID: PMC3269521  PMID: 22036644
14.  The impact of misclassification due to survey response fatigue on estimation and identifiability of treatment effects 
Statistics in medicine  2011;30(30):3560-3572.
Response fatigue can cause measurement error and misclassification problems in survey research. Questions asked later in a long survey are often prone to more measurement error or misclassification. The response given is a function of both the true response and participant response fatigue. We investigate the identifiability of survey order effects and their impact on estimators of treatment effects. The focus is on fatigue that affects a given answer to a question rather than fatigue that causes non-response and missing data. We consider linear, Gamma, and logistic models of response that incorporate both the true underlying response and the effect of question order. For continuous data, survey order effects have no impact on study power under a Gamma model. However, under a linear model that allows for convergence of responses to a common mean, the impact of fatigue on power will depend on how fatigue affects both the rate of mean convergence and the variance of responses. For binary data and for less than a 50% chance of a positive response, order effects cause study power to increase under a linear probability (risk difference) model, but decrease under a logistic model. The results suggest that measures designed to reduce survey order effects might have unintended consequences. We present a data example that demonstrates the problem of survey order effects.
PMCID: PMC3552436  PMID: 21953305
15.  Trends in Radical Prostatectomy: Centralization, Robotics, and Access to Urologic Cancer Care 
Cancer  2011;118(1):54-62.
Robotic surgery has been widely adopted for radical prostatectomy. We hypothesize that this change is rapidly shifting procedures away from hospitals that do not offer robotics and consequently increasing patient travel.
A population-based observational study of all prostatectomies for cancer in NY, NJ, and PA from 2000–2009 was performed using hospital discharge data. Hospital procedure volume was defined as the number of prostatectomies performed for cancer in a given year. Straight-line travel distance to treating hospital was calculated for each case. Hospitals were contacted to determine year of acquisition of first robot.
From 2000–2009, the total number of prostatectomies performed annually increased substantially. The increase occurred almost entirely at the very high volume centers (≥106 prostatectomies/year). The number of hospitals performing prostatectomy fell 37% from 2000–2009. By 2009, the 9% (21/244) of hospitals that had very high volume performed 57% of all prostatectomies, and the 35% (86/244) of hospitals with a robot performed 85% of all prostatectomies. Median travel increased 54% from 2000–2009, p<0.001. The proportion of patients traveling ≥15 miles increased from 24% to 40%, p<0.001.
Over the past decade, the number of radical prostatectomies performed has risen substantially. These procedures have been increasingly centralized at high volume centers, leading to longer patient travel distances. Few prostatectomies are now performed at hospitals that do not offer robotic surgery. Future work should focus on the impact of these trends on cancer control, functional outcomes, access to care and cost.
PMCID: PMC3184375  PMID: 21717436
16.  Serum Amino Acid Levels as a Biomarker for Renal Cell Carcinoma 
The Journal of urology  2011;186(4):1206-1212.
Prognosis in renal cell carcinoma (RCC) is dependent on tumor stage at presentation, with significant differences in survival between early and late stage disease. Currently, there are no screening tests or biomarkers identified for the early detection of kidney cancer. Here, we investigate if serum amino acid profiles are a potentially useful biomarker in patients with RCC.
Materials and Methods
The concentrations of 26 different amino acids were determined in serum taken pre-operatively from 189 RCC patients and 104 age and sex matched controls.
Statistically significant changes were observed in patient levels of 15 different amino acids, with 13 being decreased and two being elevated. A logistic regression model utilizing eight amino acids including cysteine, ornithine, histidine, leucine, tyrosine, proline, valine and lysine was created to distinguish cases from controls. A receiver operator curve based on this model had an area under the curve of 0.81. This same model also had predictive value in predicting overall survival and tumor recurrence in RCC patients.
Our findings suggest that serum amino acid levels may be useful as a screening tool for the identification of individuals with RCC and predicting patient outcomes.
PMCID: PMC3180900  PMID: 21849193
Kidney Cancer; biomarker; serum; amino acids
17.  Anatomic Features of Enhancing Renal Masses Predict Malignant and High-Grade Pathology: A Preoperative Nomogram Using the RENAL Nephrometry Score 
European urology  2011;60(2):241-248.
Counseling patients with enhancing renal mass currently occurs in the context of significant uncertainty regarding tumor pathology.
We evaluated whether radiographic features of renal masses could predict tumor pathology and developed a comprehensive nomogram to quantitate the likelihood of malignancy and high-grade pathology based on these features.
Design, setting, and participants
We retrospectively queried Fox Chase Cancer Center’s prospectively maintained database for consecutive renal masses where a Nephrometry score was available.
All patients in the cohort underwent either partial or radical nephrectomy.
The individual components of Nephrometry were compared with histology and grade of resected tumors. We used multiple logistic regression to develop nomograms predicting the malignancy of tumors and likelihood of high-grade disease among malignant tumors.
Results and limitations
Nephrometry score was available for 525 of 1750 renal masses. Nephrometry score correlated with both tumor grade (p < 0.0001) and histology (p < 0.0001), such that small endophytic nonhilar tumors were more likely to represent benign pathology. Conversely, large interpolar and hilar tumors more often represented high-grade cancers. The resulting nomogram from these data offers a useful tool for the preoperative prediction of tumor histology (area under the curve [AUC]: 0.76) and grade (AUC: 0.73). The model was subjected to out-of-sample cross-validation; however, lack of external validation is a limitation of the study.
The current study is the first to objectify the relationship between tumor anatomy and pathology. Using the Nephrometry score, we developed a tool to quantitate the preoperative likelihood of malignant and high-grade pathology of an enhancing renal mass.
PMCID: PMC3124570  PMID: 21458155
Kidney; Carcinoma; Renal cell; Nomograms; Nephrometry; Anatomy
18.  Height, adiposity and body fat distribution and breast density in young women 
Breast Cancer Research : BCR  2012;14(4):R107.
Breast density is one of the strongest risk factors for breast cancer, but determinants of breast density in young women remain largely unknown.
Associations of height, adiposity and body fat distribution with percentage dense breast volume (%DBV) and absolute dense breast volume (ADBV) were evaluated in a cross-sectional study of 174 healthy women, 25 to 29 years old. Adiposity and body fat distribution were measured by anthropometry and dual-energy X-ray absorptiometry (DXA), while %DBV and ADBV were measured by magnetic resonance imaging. Associations were evaluated using linear mixed-effects models. All tests of statistical significance are two-sided.
Height was significantly positively associated with %DBV but not ADBV; for each standard deviation (SD) increase in height, %DBV increased by 18.7% in adjusted models. In contrast, all measures of adiposity and body fat distribution were significantly inversely associated with %DBV; a SD increase in body mass index (BMI), percentage fat mass, waist circumference and the android:gynoid fat mass ratio (A:G ratio) was each associated significantly with a 44.4 to 47.0% decrease in %DBV after adjustment for childhood BMI and other covariates. Although associations were weaker than for %DBV, all measures of adiposity and body fat distribution also were significantly inversely associated with ADBV before adjustment for childhood BMI. After adjustment for childhood BMI, however, only the DXA measures of percentage fat mass and A:G ratio remained significant; a SD increase in each was associated with a 13.8 to 19.6% decrease in ADBV. In mutually adjusted analysis, the percentage fat mass and the A:G ratio remained significantly inversely associated with %DBV, but only the A:G ratio was significantly associated with ADBV; a SD increase in the A:G ratio was associated with an 18.5% decrease in ADBV.
Total adiposity and body fat distribution are independently inversely associated with %DBV, whereas in mutually adjusted analysis only body fat distribution (A:G ratio) remained significantly inversely associated with ADBV in young women. Research is needed to identify biological mechanisms underlying these associations.
PMCID: PMC3680938  PMID: 22800711
19.  Serum antimüllerian hormone in healthy premenopausal women 
Fertility and sterility  2011;95(8):2718-2721.
Antimüllerian hormone (AMH) is extensively studied in ovarian aging and pathology; however, little is known about correlates in healthy premenopausal women. We found that AMH levels are strongly inversely associated with age and differed significantly between oral contraceptive pill users and nonusers, whereas no significant associations were seen between AMH and other clinical, behavioral, and anthropometric characteristics and laboratory variables, making it an attractive hormone for clinical applications.
PMCID: PMC3163405  PMID: 21704216
Müllerian-inhibiting substance (MIS); antimüllerian hormone (AMH); ovary; premenopausal; healthy
20.  Response to Pearl's Comments on Principal Stratification 
Dr. Pearl invites researchers to justify their use of principal stratification. This comment explains how the use of principal stratification simplified a complex mediational problem encountered when evaluating a smoking cessation intervention's effect on reducing smoking withdrawal symptoms.
PMCID: PMC3114954  PMID: 21686084
causal inference; principal stratification; mediation; smoking cessation interventions
21.  Combining Extant Datasets with Differing Outcome Measures Across Studies of Older Adults after Cancer Surgery 
Combining extant datasets with differing outcome measures, an economical method to generate evidence guiding older adults’ cancer care, may introduce heterogeneity leading to invalid study results. We recently conducted a study combining extant datasets from five oncology nurse-directed clinical trials (parent studies) using norm-based scoring to standardize the differing outcome measures. The purpose of this article is to describe and analyze our methods in the recently completed study. Despite addressing and controlling for heterogeneity, our analysis found statistically significant heterogeneity (p<0.0001) in temporal trends among the five parent studies. We concluded that assessing heterogeneity in combined extant datasets with differing outcome measures is important to ensure similar magnitude and direction of findings across parent studies. Future research should include investigating reasons for heterogeneity to generate hypotheses about subgroup differences or differing measurement domains that may have an impact on outcomes.
PMCID: PMC3263316  PMID: 21210576
Combining data; Older Adults; Cancer
22.  Factors Affecting Recovery of Functional Status in Older Adults After Cancer Surgery 
To explore factors influencing functional status over time after cancer surgery in adults aged 65 and older.
Secondary data analysis of combined data subsets.
Five prospective, longitudinal oncology nurse-directed clinical studies conducted at three academic centers in the northwest and northeast United States.
Three hundred sixteen community-residing patients diagnosed with digestive system, thoracic, genitourinary, and gynecological cancers treated primarily with surgery.
Functional status, defined as performance of current life roles, was measured using the Enforced Social Dependency Scale and the Medical Outcomes Study 36-item Short-Form Survey (using physical component summary measures) after surgery (baseline) and again at 3 and 6 months. Number of symptoms, measured using the Symptom Distress Scale, quantified the effect of each additional common cancer symptom on functional status.
After controlling for cancer site and stage, comorbidities, symptoms, psychological status, treatment, and demographic variables, functional status was found to be significantly better at 3 and 6 months after surgery than at baseline. Factors associated with better functional status included higher income and better mental health. Factors associated with poorer average functional status were a greater number of symptoms and comorbidities. Persons reporting three or more symptoms experienced statistically significant and clinically meaningful poorer functional status than those without symptoms. Persons reporting three or more comorbidities were also found to have poorer functional status than those without comorbidities. No significant relationship existed between age and functional status in patients aged 65 and older.
Factors other than age affect recovery of functional status in older adults after cancer surgery.
PMCID: PMC3176326  PMID: 21226675
functional status; older adult; cancer surgery
23.  Enhanced genetic instability and dasatinib sensitivity in mammary tumor cells lacking Nedd9 
Cancer research  2010;70(21):8907-8916.
Elevated expression of the Nedd9/HEF1/Cas-L scaffolding protein promotes tumor cell invasion and metastasis in multiple cancer cell types. Conversely, generation of mammary tumors in the MMTV-polyoma virus middle T (PyVT) genetic model is delayed by a Nedd9−/− genotype. These activities arise from the role of Nedd9 in assembling complexes and supporting activity of cancer signaling proteins including FAK, SRC, SHC, and AKT, and would support evaluation of Nedd9 expression as an unambiguous biomarker for tumor aggressiveness. However, we here show that despite the initial delay in tumor growth, cells derived from MMTV-PyVT;Nedd9−/− tumors are characteristically hyperaggressive versus MMTV-PyVT;Nedd9+/+ cells in anchorage-independent growth, growth on 3D matrix produced by tumor-associated fibroblasts, and in formation of tumors after mammary orthotopic reinjection, and of lung metastases after tail vein injection. This reversal suggests the specific selection of MMTV-PyVT;Nedd9−/− cells for growth in an in vivo microenvironment. Indeed, MMTV-PyVT;Nedd9−/− cells have increased cell cycle, centrosomal, and mitotic defects, phenotypes compatible with the increased selection of these cells for aggressive growth. Intriguingly, in spite of their aggressive phenotype, MMTV-PyVT;Nedd9−/− cells persistently have low levels of SRC activation and are hypersensitive to the SRC kinase inhibitor dasatinib. These studies identify Nedd9 as a complex modulator of different aspects of mammary tumor growth.
PMCID: PMC2970659  PMID: 20940402
24.  Efficacy of Motivational Interviewing for Smoking Cessation: A Systematic Review and Meta-Analysis 
Tobacco control  2010;19(5):410-416.
A systematic review and meta-analysis to investigate the efficacy of interventions incorporating motivational interviewing for smoking cessation and identify correlates of treatment effects.
Data Sources
MEDLINE/PubMed, PsycInfo, and other sources including grey literature.
Study Selection
Title/abstract search terms were motivational interview* OR motivational enhancement AND smok*, cigarette*, tobacco, OR nicotine. Randomized trials reporting number of smokers abstinent at follow up were eligible.
Data Extraction
Data were independently coded by the first and third authors. We coded for a variety of study, participant, and intervention related variables.
Data Synthesis
A random effects logistic regression with both a random intercept and a random slope for the treatment effect.
Thirty-one smoking cessation research trials were selected for the study: 8 comprised adolescent samples, 8 comprised adults with chronic physical or mental illness, 5 comprised pregnant/postpartum women, and 10 comprised other adult samples. Analysis of the trials (9,485 individual participants) showed an overall odds ratio comparing likelihood of abstinence in the MI versus control condition of OR=1.45, 95% Confidence Interval or CI = 1.14-1.83). Additional potential correlates of treatment effects such as study, sample, and intervention characteristics were examined.
This is the most comprehensive review of MI for smoking cessation conducted to-date. These findings suggest that current MI smoking cessation approaches can be effective for adolescents and adults. However, comparative efficacy trials could be useful.
PMCID: PMC2947553  PMID: 20675688
Motivational Interviewing; Smoking Cessation; Systematic Review; Meta-Analysis
25.  Utilization of Systemic Therapy and Factors Impacting Survival for Patients Undergoing Cytoreductive Nephrectomy 
BJU international  2009;106(2):218-223.
Prospective randomized trials have demonstrated a survival benefit for nephrectomy in patients with metastatic renal cell carcinoma treated with immunotherapy. These data have been extrapolated to support cytoreductive nephrectomy in the targeted therapy era as well. However, the likelihood that patients with metastatic kidney cancer who undergo nephrectomy will receive systemic treatment postoperatively remains poorly defined. We present a multi-institutional experience evaluating the utilization of systemic therapy in patients undergoing cytoreductive nephrectomy.
141 patients who underwent cytoreductive nephrectomy between 1990 and 2008 were identified from our Institutional Kidney Cancer Registries. Kaplan Meier analyses and Cox regression models were used to assess the impact of clinicopathological and perioperative variables on patients’ subsequent receipt of systemic therapy and postoperative survival.
Overall, 98/141 patients (69.5%) received postoperative systemic treatment, at a median of 2.5 months (range 0.1–61.5) after nephrectomy. In this group, 52 (53%) patients received immunotherapy, 34 (35%) targeted agents, and 12 (12%) other regimens. By contrast, 43 patients (30.5%) did not receive systemic therapy, because of rapid disease progression (n=13, 30%), decision for surveillance by medical oncology (n=9, 21%), patient refusal (n=10, 23%), perioperative mortality (n=8, 19%), and unknown reasons in three patients (7.0%). Median survival following cytoreductive nephrectomy was 16.7 months (range 0–120). The risk of death after surgery correlated with the number of metastatic sites (p=0.012) and symptoms (p=0.001) at presentation, poor performance status (p=0.001), high tumor grade (p=0.006), and presence of sarcomatoid features (p<0.024).
Nearly one-third of patients undergoing cytoreductive nephrectomy did not receive systemic treatment. While some were electively observed or declined therapy, others did not receive treatment due to rapidly progressive disease. Further investigation is warranted to identify those patients at highest risk for rapid post-operative disease progression who might benefit instead from an initial approach to treatment with systemic therapy.
PMCID: PMC2906619  PMID: 19922542
renal cell carcinoma; metastases; nephrectomy; systemic therapy; targeted therapy

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