Faculty Bibliography

CONTEXT: Rap1 GTPase-activating protein (GAP) regulates the activity of Rap1, a putative oncogene. We previously reported Rap1GAP was highly expressed in normal human thyroid cells and decreased in five papillary thyroid carcinomas (PTCs). OBJECTIVES: To confirm the significance of these findings, we analyzed Rap1GAP expression in a larger set of benign tumors (adenomas and hyperplastic nodules) and PTCs. We determined whether the presence of the BRAF(V600E) mutation or allelic loss of Rap1GAP related to changes in Rap1GAP protein expression. To determine the consequences of Rap1GAP loss, we targeted Rap1GAP in culture using small interfering RNA. DESIGN, PATIENTS, AND METHODS: A highly specific Rap1GAP antibody was applied to sections of 55 human thyroid tissues. Genomic DNA was analyzed for the presence of the BRAF(V600E) mutation, and loss of Rap1GAP. Rap1GAP expression in rat thyroid cells was abolished using small interfering RNA. RESULTS: We observed that down-regulation of Rap1GAP in benign lesions and PTCs was common. Rap1GAP expression was more severely decreased in PTCs. Loss of Rap1GAP expression was observed in multiple histological variants of PTCs. Approximately 20% of PTCs and adenomas exhibited allelic loss of Rap1GAP. Loss of Rap1GAP was not associated with the presence of the BRAF(V600E) mutation. In vitro, loss of Rap1GAP was sufficient to increase Rap1 activity in thyroid cells. CONCLUSIONS: These data indicate that loss of Rap1GAP is a frequent event in PTC. The more frequent and greater down-regulation of Rap1GAP in PTCs compared with adenomas suggests a role for Rap1GAP depletion in the progression of human thyroid tumors, possibly through unrestrained Rap activity.

BACKGROUND: Smoking is the leading preventable cause of premature death in the United States. Previous studies of financial incentives for smoking cessation in work settings have not shown that such incentives have significant effects on cessation rates, but these studies have had limited power, and the incentives used may have been insufficient. METHODS: We randomly assigned 878 employees of a multinational company based in the United States to receive information about smoking-cessation programs (442 employees) or to receive information about programs plus financial incentives (436 employees). The financial incentives were $100 for completion of a smoking-cessation program, $250 for cessation of smoking within 6 months after study enrollment, as confirmed by a biochemical test, and $400 for abstinence for an additional 6 months after the initial cessation, as confirmed by a biochemical test. Individual participants were stratified according to work site, heavy or nonheavy smoking, and income. The primary end point was smoking cessation 9 or 12 months after enrollment, depending on whether initial cessation was reported at 3 or 6 months. Secondary end points were smoking cessation within the first 6 months after enrollment and rates of participation in and completion of smoking-cessation programs. RESULTS: The incentive group had significantly higher rates of smoking cessation than did the information-only group 9 or 12 months after enrollment (14.7% vs. 5.0%, P<0.001) and 15 or 18 months after enrollment (9.4% vs. 3.6%, P<0.001). Incentive-group participants also had significantly higher rates of enrollment in a smoking-cessation program (15.4% vs. 5.4%, P<0.001), completion of a smoking-cessation program (10.8% vs. 2.5%, P<0.001), and smoking cessation within the first 6 months after enrollment (20.9% vs. 11.8%, P<0.001). CONCLUSIONS: In this study of employees of one large company, financial incentives for smoking cessation significantly increased the rates of smoking cessation. (ClinicalTrials.gov number, NCT00128375.)

FGFR2 and MAP3K1 are members of the RAS/RAF/MEK/ERK-signaling pathway and have been identified from genome-wide association studies to be breast cancer susceptibility genes. Potential interactions of these genes and their role with respect to tumor markers, hormonal factors and race on breast cancer risk have not been explored. We examined FGFR2 and MAP3K1 variants, breast tumor characteristics and hormone exposures in a population-based case-control sample of 1225 European-American (EA) and 584 African-American (AA) women. FGFR2 rs1219648 and rs2981582 genotypes were significantly associated with breast cancer in EA only in estrogen receptor-positive (ER+), progesterone receptor-positive (PR+) and HER2/Neu-negative (HER2-) tumors. MAP3K1 was not associated with breast cancer in EA women, but it was associated with breast cancer in AA women, again limited to ER+, PR+ and HER2- tumors. An interaction was observed between combined hormone replacement therapy use and FGFR2 rs1219648 genotypes on breast cancer risk in EA women (P = 0.010). Finally, we observed a significant interaction between MAP3K1 rs889312 and FGFR2 rs2981582 (P = 0.022) in AA but not EA women. These results confirm that FGFR2 and MAP3K1 are involved in breast cancer susceptibility and confer their effects primarily in ER+ and PR+ tumors. We further report that these genes confer their effects in HER2- tumors, interact with one another to confer breast cancer susceptibility in AA women and interact with hormone exposures in AA and EA women.

BACKGROUND: Sub-optimal adherence to warfarin places millions of patients at risk for stroke and bleeding complications each year. Novel methods are needed to improve adherence for warfarin. We conducted two pilot studies to determine whether a lottery-based daily financial incentive is feasible and improves warfarin adherence and anticoagulation control. METHODS: Volunteers from the University of Pennsylvania Anticoagulation Management Center who had taken warfarin for at least 3 months participated in either a pilot study with a lottery with a daily expected value of $5 (N = 10) or a daily expected value of $3 (N = 10). All subjects received use of an Informedix Med-eMonitor System with a daily reminder feature. If subjects opened up their pill compartments appropriately, they were entered into a daily lottery with a 1 in 5 chance of winning $10 and a 1 in 100 chance of winning $100 (pilot 1) or a 1 in 10 chance of winning $10 and a 1 in 100 chance of winning $100 (pilot 2). The primary study outcome was proportion of incorrect warfarin doses. The secondary outcome was proportion of INR measurements not within therapeutic range. Within-subject pre-post comparisons were done of INR measurements with comparisons with either historic means or within-subject comparisons of incorrect warfarin doses. RESULTS: In the first pilot, the percent of out-of-range INRs decreased from 35.0% to 12.2% during the intervention, before increasing to 42% post-intervention. The mean proportion of incorrect pills taken during the intervention was 2.3% incorrect pills, compared with a historic mean of 22% incorrect pill taking in this clinic population. Among the five subjects who also had MEMS cap adherence data from warfarin use in our prior study, mean incorrect pill taking decreased from 26% pre-pilot to 2.8% in the pilot. In the second pilot, the time out of INR range decreased from 65.0% to 40.4%, with the proportion of mean incorrect pill taking dropping to 1.6%. CONCLUSION: A daily lottery-based financial incentive demonstrated the potential for significant improvements in missed doses of warfarin and time out of INR range. Further testing should be done of this approach to determine its effectiveness and potential application to both warfarin and other chronic medications.

CONTEXT: Identifying effective obesity treatment is both a clinical challenge and a public health priority due to the health consequences of obesity. OBJECTIVE: To determine whether common decision errors identified by behavioral economists such as prospect theory, loss aversion, and regret could be used to design an effective weight loss intervention. DESIGN, SETTING, AND PARTICIPANTS: Fifty-seven healthy participants aged 30-70 years with a body mass index of 30-40 were randomized to 3 weight loss plans: monthly weigh-ins, a lottery incentive program, or a deposit contract that allowed for participant matching, with a weight loss goal of 1 lb (0.45 kg) a week for 16 weeks. Participants were recruited May-August 2007 at the Philadelphia VA Medical Center in Pennsylvania and were followed up through June 2008. MAIN OUTCOME MEASURES: Weight loss after 16 weeks. RESULTS: The incentive groups lost significantly more weight than the control group (mean, 3.9 lb). Compared with the control group, the lottery group lost a mean of 13.1 lb (95% confidence interval [CI] of the difference in means, 1.95-16.40; P = .02) and the deposit contract group lost a mean of 14.0 lb (95% CI of the difference in means, 3.69-16.43; P = .006). About half of those in both incentive groups met the 16-lb target weight loss: 47.4% (95% CI, 24.5%-71.1%) in the deposit contract group and 52.6% (95% CI, 28.9%-75.6%) in the lottery group, whereas 10.5% (95% CI, 1.3%-33.1%; P = .01) in the control group met the 16-lb target. Although the net weight loss between enrollment in the study and at the end of 7 months was larger in the incentive groups (9.2 lb; t = 1.21; 95% CI, -3.20 to 12.66; P = .23, in the lottery group and 6.2 lb; t = 0.52; 95% CI, -5.17 to 8.75; P = .61 in the deposit contract group) than in the control group (4.4 lb), these differences were not statistically significant. However, incentive participants weighed significantly less at 7 months than at the study start (P = .01 for the lottery group; P = .03 for the deposit contract group) whereas controls did not. CONCLUSIONS: The use of economic incentives produced significant weight loss during the 16 weeks of intervention that was not fully sustained. The longer-term use of incentives should be evaluated. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00520611.

PURPOSE: Given the molecular pathophysiology of thyroid cancer and the spectrum of kinases inhibited by sorafenib, including Raf kinase, vascular endothelial growth factor receptors, platelet-derived growth factor receptor, and RET tyrosine kinases, we conducted an open-label phase II trial to determine the efficacy of sorafenib in patients with advanced thyroid carcinoma. PATIENTS AND METHODS: Eligible patients with metastatic, iodine-refractory thyroid carcinoma received sorafenib 400 mg orally twice daily. Responses were measured radiographically every 2 to 3 months. The study end points included response rate, progression-free survival (PFS), and best response by Response Evaluation Criteria in Solid Tumors. RESULTS: Thirty patients were entered onto the study and treated for a minimum of 16 weeks. Seven patients (23%; 95% CI, 0.10 to 0.42) had a partial response lasting 18+ to 84 weeks. Sixteen patients (53%; 95% CI, 0.34 to 0.72) had stable disease lasting 14 to 89+ weeks. Seventeen (95%) of 19 patients for whom serial thyroglobulin levels were available showed a marked and rapid response in thyroglobulin levels with a mean decrease of 70%. The median PFS was 79 weeks. Toxicity was consistent with other sorafenib trials, although a single patient died of liver failure that was likely treatment related. CONCLUSION: Sorafenib has clinically relevant antitumor activity in patients with metastatic, iodine-refractory thyroid carcinoma, with an overall clinical benefit rate (partial response + stable disease) of 77%, median PFS of 79 weeks, and an overall acceptable safety profile. These results represent a significant advance over chemotherapy in both response rate and PFS and support further investigation of this agent in these patients.

PURPOSE: Raloxifene reduces breast cancer risk in women with osteoporosis, and both tamoxifen and raloxifene prevent breast cancer in high-risk women. However, in vitro, raloxifene does not share the pro-estrogenic effects of tamoxifen on the endometrium. Randomized trials of these agents have provided limited information about endometrial cancer risk in the general population. We sought to compare endometrial cancer risks associated with raloxifene, tamoxifen, and nonusers of a selective estrogen receptor modulator (SERM) in the general population and characterize the endometrial tumors occurring in these groups. METHODS: We performed a case-control study of white and African American women age 50 to 79 years in the Philadelphia area. Patients were diagnosed with endometrial cancer between July 1999 and June 2002. Controls were identified through random-digit dialing. RESULTS: We analyzed 547 cases and 1,410 controls. Among cases, 3.3% had taken raloxifene; 6.2% had taken tamoxifen. Among controls, 6.6% had taken raloxifene; 2.4% had taken tamoxifen. After adjustment for other risk factors, the odds of endometrial cancer among raloxifene users was 50% that of nonusers (odds ratio [OR] = 0.50; 95% CI, 0.29 to 0.85), whereas tamoxifen users had three times the odds of developing endometrial cancer compared with raloxifene users (OR = 3.0; 95% CI, 1.3 to 6.9). Endometrial tumors in raloxifene users had a more favorable histologic profile and were predominantly International Federation of Gynecology and Obstetrics stage I and low grade. CONCLUSION: Raloxifene users had significantly lower odds of endometrial cancer compared with both tamoxifen users and SERM nonusers, suggesting a role for raloxifene in endometrial cancer prevention and individualization of SERM therapy.

BACKGROUND: Reliable and validated measures of skin disease severity are needed for cutaneous dermatomyositis (DM). Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Dermatomyositis Skin Severity Index (DSSI) and Cutaneous Assessment Tool (CAT) skin indices have been developed as outcome instruments. OBJECTIVES: We sought to demonstrate reliability and validity of the CDASI, and to compare the CDASI with other potential tools for use in measuring disease severity in cutaneous dermatomyositis. PATIENTS AND METHODS: CDASI has four activity and two damage measures, with scores from 0 to 148. DSSI assesses activity based on body surface area and severity on a scale of 0-72. CAT uses 21 activity and damage items, for a range of 0-175 for activity and 0-33 for damage. Ten dermatologists used the instruments to score the same 12-16 patients in one session. Global validation measures were administered to physicians and patients. RESULTS: Global validation measures correlated with the three outcome instruments (P < 0.0001). CAT displayed lower inter- and intrarater reliability relative to the CDASI. All scales correlate better with physician than patient global skin measures. CONCLUSIONS: It appears that the CDASI may be a useful outcome measure for studies of cutaneous DM. Further testing to compare responsiveness of all three measures is necessary.