Faculty Bibliography

PURPOSE: Short-term reactions to BRCA1 and BRCA2 (BRCA1/2) genetic test results have been described in several reports, but the long-terms effects of testing have not been examined extensively. METHODS: We conducted an observational study to characterize the long-term impact of genetic testing for BRCA1/2 mutations in 167 women who had received genetic test results at least 4 years ago. We also evaluated the relationship between genetic testing-specific reactions and breast and ovarian cancer screening to determine the behavioral significance of adverse reactions. RESULTS: Seventy-four percent of women were not experiencing any distress regarding their test result, 41% were not experiencing any uncertainty, and 51% had a score for positive experiences that was suggestive of low levels of adverse reactions in terms of family support and communication. Mutation carriers (odds ratio, 3.96; 95% CI, 1.44 to 10.89; P = .01) were most likely to experience distress. Only less time since disclosure was related significantly to experiencing uncertainty (odds ratio, 0.62; 95% CI, 0.44 to 0.88; P = .008). In terms of cancer screening, 81% of women had a mammogram during the year before study enrollment, 25% had magnetic resonance imaging (MRI), 20% had a transvaginal ultrasound, and 20% had a CA-125. Experiencing distress was associated significantly with having a CA-125 (chi(2) = 3.89, P = .05), and uncertainty was associated with having an MRI (chi(2) = 8.90, P = .003). CONCLUSION: Our findings show that women are not likely to experience genetic testing concerns several years after receiving BRCA1/2 test results; distress and uncertainty are not likely to have adverse effects on screening among women at risk for hereditary disease.

BACKGROUND: Although colorectal cancer (CRC) is the second leading cause of cancer death among adults in the US and colonoscopy is efficacious in reducing morbidity and mortality from CRC, screening rates are sub-optimal. Understanding the socioeconomic, cultural, and health care context within which decisions about colonoscopy are made allows physicians to address patients' most salient beliefs and values and other constraints when making screening recommendations. OBJECTIVE: To evaluate the direct and interactive effects of socioeconomics, health care variables, psychological characteristics, and cultural values on colonoscopy use. DESIGN, SETTING, PARTICIPANTS: National survey completed between January-August 2009 in a random sample of African American, white, and Hispanic adults ages 50-75 without cancer (n = 582). MAIN MEASURE: Self-reported colonoscopy use. KEY RESULTS: Only 59% of respondents reported having a colonoscopy. The likelihood of colonoscopy increased with having health insurance (OR = 2.82, 95% CI = 1.24, 6.43, p = 0.004), and increasing age (OR = 1.40, 95% CI = 1.11, 1.77, p = 0.001). In addition, respondents with greater self-efficacy were more likely to have a colonoscopy (OR = 2.41, 95% CI = 1.35, 4.29, p = 0.003). CONCLUSIONS: Programs that help patients to overcome access and psychological barriers to screening are needed.

PURPOSE: To correlate the parenchymal texture features at digital breast tomosynthesis (DBT) and digital mammography with breast percent density (PD), an established breast cancer risk factor, in a screening population of women. MATERIALS AND METHODS: This HIPAA-compliant study was approved by the institutional review board. Bilateral DBT images and digital mammograms from 71 women (mean age, 54 years; age range, 34-75 years) with negative or benign findings at screening mammography were retrospectively collected from a separate institutional review board-approved DBT screening trial (performed from July 2007 to March 2008) in which all women had given written informed consent. Parenchymal texture features of skewness, coarseness, contrast, energy, homogeneity, and fractal dimension were computed from the retroareolar region. Principal component analysis (PCA) was applied to obtain orthogonal texture components. Mammographic PD was estimated with software. Correlation analysis and multiple linear regression with generalized estimating equations were performed to determine the association between texture features and breast PD. Regression was adjusted for age to determine the independent association of texture to breast PD when age was also considered as a predictor variable. RESULTS: Texture feature correlations to breast PD were stronger with DBT than with digital mammography. Statistically significant correlations (P < .001) were observed for contrast (r = 0.48), energy (r = -0.47), and homogeneity (r = -0.56) at DBT and for contrast (r = 0.26), energy (r = -0.26), and homogeneity (r = -0.33) at digital mammography. Multiple linear regression analysis of PCA texture components as predictors of PD also demonstrated significantly stronger associations with DBT. The association was strongest when age was also considered as a predictor of PD (R(2) = 0.41 for DBT and 0.28 for digital mammography; P < .001). CONCLUSION: Parenchymal texture features are more strongly correlated to breast PD in DBT than in digital mammography. The authors' long-term hypothesis is that parenchymal texture analysis with DBT will result in quantitative imaging biomarkers that can improve the estimation of breast cancer risk.

Cutaneous T-cell lymphoma (CTCL) is responsive at all stages to immunotherapy. We determined whether a novel agonist for Toll-like receptor (TLR) 7/8 (3M-007) combined with either interferon-gamma (IFN-gamma) or interleukin-15 (IL-15) would enhance patients' immune responses in vitro. Our data demonstrate that IFN-gamma or IL-15 in combination with 007 significantly increases patients' natural killer (NK) cytolytic activity against CTCL tumor cell lines and synergistically induces dendritic cell cytokines, compared to 007 alone. Microarray studies of gene expression of patients' peripheral blood mononuclear cells (PBMCs) primed with IFN-gamma followed by stimulation with 007 identified significant up-regulation of the expression of IL-12 p35 (alpha-chain), IL-12 p40 (beta-chain), and nine IFN-alpha genes. Importantly, the underlying mechanism of increased levels of IFN-alpha and IL-12 from combined treatment appears to involve IFN regulatory factor 8 (IRF-8). These results further support our hypothesis that combinations of biological modifiers activating different arms of the immune system may provide significant therapeutic benefits for patients with advanced CTCL.

For analyzing longitudinal binary data with nonignorable and nonmonotone missing responses, a full likelihood method is complicated algebraically, and often requires intensive computation, especially when there are many follow-up times. As an alternative, a pseudolikelihood approach has been proposed in the literature under minimal parametric assumptions. This formulation only requires specification of the marginal distributions of the responses and missing data mechanism, and uses an independence working assumption. However, this estimator can be inefficient for estimating both time-varying and time-stationary effects under moderate to strong within-subject associations among repeated responses. In this article, we propose an alternative estimator, based on a bivariate pseudolikelihood, and demonstrate in simulations that the proposed method can be much more efficient than the previous pseudolikelihood obtained under the assumption of independence. We illustrate the method using longitudinal data on CD4 counts from two clinical trials of HIV-infected patients.

BACKGROUND: Recent studies suggest that psoriasis, particularly if severe, may be a risk factor for major adverse cardiac events, such as myocardial infarction, stroke, and mortality from cardiovascular disease. We compared the risk of major adverse cardiac events between patients with psoriasis and the general population and estimated the attributable risk of severe psoriasis. METHODS: We performed a cohort study in the General Practice Research Database. Severe psoriasis was defined as receiving a psoriasis diagnosis and systemic therapy (N=3603). Up to 4 patients without psoriasis were selected from the same practices and start dates for each patient with psoriasis (N=14,330). RESULTS: Severe psoriasis was a risk factor for major adverse cardiac events (hazard ratio 1.53; 95% confidence interval, 1.26-1.85) after adjusting for age, gender, diabetes, hypertension, tobacco use, and hyperlipidemia. After fully adjusted analysis, severe psoriasis conferred an additional 6.2% absolute risk of 10-year major adverse cardiac events. CONCLUSION: Severe psoriasis confers an additional 6.2% absolute risk of a 10-year rate of major adverse cardiac events compared with the general population. This potentially has important therapeutic implications for cardiovascular risk stratification and prevention in patients with severe psoriasis. Future prospective studies are needed to validate these findings.

BACKGROUND: There is a need to better understand the safety of tumor necrosis factor (TNF) inhibitors in patients with psoriatic disease in whom TNF inhibitors are frequently used as monotherapy. OBJECTIVE: We sought to examine the risks of infection and malignancy with the use of TNF antagonists in adult patients with psoriatic disease. METHODS: We conducted a systematic search for trials of TNF antagonists for adults with plaque psoriasis and psoriatic arthritis. We included randomized, placebo-controlled trials of etanercept, infliximab, adalimumab, golimumab, and certolizumab for the treatment of plaque psoriasis and psoriatic arthritis. Twenty of 820 identified studies with a total of 6810 patients were included. Results were calculated using fixed effects models and reported as pooled odds ratios. RESULTS: Odds ratios for overall infection and serious infection over a mean of 17.8 weeks were 1.18 (95% confidence interval [CI] 1.05-1.33) and 0.70 (95% CI 0.40-1.21), respectively. When adjusting for patient-years, the incidence rate ratio for overall infection was 1.01 (95% CI 0.92-1.11). The odds ratio for malignancy was 1.48 (95% CI 0.71-3.09) and 1.26 (95% CI 0.39-4.15) when nonmelanoma skin cancer was excluded. LIMITATIONS: Short duration of follow-up and rarity of malignancies and serious infections are limitations. CONCLUSIONS: There is a small increased risk of overall infection with the short-term use of TNF antagonists for psoriasis that may be attributable to differences in follow-up time between treatment and placebo groups. There was no evidence of an increased risk of serious infection and a statistically significant increased risk in cancer was not observed with short-term use of TNF inhibitors.

BACKGROUND: Previous efforts to use incentives for weight loss have resulted in substantial weight regain after 16 weeks. OBJECTIVE: To evaluate a longer term weight loss intervention using financial incentives. DESIGN: A 32-week, three-arm randomized controlled trial of financial incentives for weight loss consisting of a 24-week weight loss phase during which all participants were given a weight loss goal of 1 pound per week, followed by an 8-week maintenance phase. PARTICIPANTS: Veterans who were patients at the Philadelphia Veterans Affairs Medical Center with BMIs of 30-40. INTERVENTION: Participants were randomly assigned to participate in either a weight-monitoring program involving a consultation with a dietician and monthly weigh-ins (control condition), or the same program with one of two financial incentive plans. Both incentive arms used deposit contracts (DC) in which participants put their own money at risk (matched 1:1), which they lost if they failed to lose weight. In one incentive arm participants were told that the period after 24 weeks was for weight-loss maintenance; in the other, no such distinction was made. MAIN MEASURE: Weight loss after 32 weeks. KEY RESULTS: Results were analyzed using intention-to-treat. There was no difference in weight loss between the incentive arms (P = 0.80). Incentive participants lost more weight than control participants [mean DC = 8.70 pounds, mean control = 1.17, P = 0.04, 95% CI of the difference in means (0.56, 14.50)]. Follow-up data 36 weeks after the 32-week intervention had ended indicated weight regain; the net weight loss between the incentive and control groups was no longer significant (mean DC = 1.2 pounds, 95% CI, -2.58-5.00; mean control = 0.27, 95% CI, -3.77-4.30, P = 0.76). CONCLUSIONS: Financial incentives produced significant weight loss over an 8-month intervention; however, participants regained weight post-intervention.

BACKGROUND: There is a need for standardized quantitative disease assessment measures in mycosis fungoides/Sezary syndrome. In 2005, a cutaneous T-cell lymphoma (CTCL)-severity index (SI) that not only measures disease extent (on a scale of 0-75) independent of the classic TNM(B) staging system but can also be used to estimate individual 5-year survival (SR5) was reported. OBJECTIVE: We sought to assess the generalizability of the CTCL-SI/SR5 equation (SR5 equation) to predict prognosis in our cohort of patients with advanced mycosis fungoides/Sezary syndrome (n = 50, photopheresis service, 1984-2001). METHODS: TNM(B) staging, CTCL-SI score (based on skin involvement, presence of tumors, lymph node/visceral/blood involvement), and SR5 (SR5 equation = 124 - 2 x [CTCL-SI]%) at initial diagnosis were calculated retrospectively and compared with overall survival by the Kaplan-Meier method. The prognostic significance of TNM(B) staging versus the CTCL-SI was determined by Cox proportional hazards models and Brier scores. RESULTS: Patients had stage IIA to IVA disease with a median actuarial overall survival of 58 months. By disease stage, the overall 5-year survival was 70% (stage IIA), 48% (stage IIB-IIIB), and 36% (stage IVA). In our cohort, the CTCL-SI itself was predictive of overall survival (P = .028) but the SR5 equation was not predictive of survival (Brier score of 0.29). LIMITATIONS: Small sample size, single academic center population, and retrospective design are limitations. CONCLUSIONS: The CTCL-SI is a relatively simple-to-use quantitative tool that measures disease activity in all compartments (skin, nodes, blood, viscera) and has prognostic significance in multivariate analysis. The CTCL-SI may be a useful adjunct to the TNM(B) staging for tracking disease activity quantitatively in all disease compartments (skin, nodes, blood, viscera) in clinical practice and trials, but the predictive ability of the SR5 equation needs further validation at other centers in larger groups of patients.

BACKGROUND: Psoriasis is a common disease frequently studied in large databases. To date the validity of psoriasis information has not been established in The Health Improvement Network (THIN). OBJECTIVES: To investigate the validity of THIN for identifying patients with psoriasis and to determine if the database can be used to determine the natural history of the disease. METHODS: First, we conducted a cross-sectional study to determine if psoriasis prevalence in THIN is similar to expected. Second, we created a cohort of 4900 patients, aged 45-64 years, with a psoriasis diagnostic Read Code and surveyed their general practitioners (GPs) to confirm the diagnosis clinically. Third, we created models to determine if psoriasis descriptors (extent, severity, duration and dermatologist confirmation) could be accurately captured from database records. RESULTS: Psoriasis prevalence was 1.9%, and showed the characteristic age distribution expected. GP questionnaires were received for 4634 of 4900 cohort patients (95% response rate), and psoriasis diagnoses were confirmed in 90% of patients. Duration of disease in the database showed substantial agreement with physician query (kappa = 0.69). GPs confirmed that the psoriasis diagnosis was corroborated by a dermatologist in 91% of patients whose database records contained a dermatology referral code associated with a psoriasis code. We achieved good discrimination between patients with and without extensive disease based on the number of psoriasis codes received per year (area under curve = 0.8). CONCLUSIONS: THIN is a valid data resource for studying psoriasis and can be used to identify characteristics of the disease such as duration and confirmation by a dermatologist.