Andrea B. Troxel

Phase II Trial of Sorafenib in Advanced Thyroid Cancer

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.

Financial Incentive Based Approaches for Weight Loss: A Randomized Trial

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.

Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the General Practice Research Database

AIMS Psoriasis is a common chronic inflammatory T-helper cell-1/17 mediated skin disease. Recent studies suggest that psoriasis, particularly if severe, may be an independent risk factor for atherosclerosis, myocardial infarction (MI), and stroke. We conducted a cohort study using the General Practice Research Database to determine if severe psoriasis patients have an increased risk of cardiovascular (CV) mortality. METHODS AND RESULTS Severe psoriasis was defined as patients who received a psoriasis diagnosis and systemic therapy consistent with severe psoriasis (n = 3603). Up to four unexposed patients without psoriasis were selected from the same practices and start dates for each psoriasis patient (n = 14 330). For every death, the cause was determined by review of the electronic medical record. Severe psoriasis was an independent risk factor for CV mortality (HR 1.57; 95% CI 1.26, 1.96) when adjusting for age, sex, smoking, diabetes, hypertension, and hyperlipidaemia. Overall, severe psoriasis patients experienced one extra CV death per 283 patients per year, even when adjusting for major CV risk factors. The relative risk of CV mortality was modified by age. For example, the RR of CV death for a 40-year-old and 60-year-old with severe psoriasis was 2.69 (1.45, 4.99) and 1.92 (1.41, 2.62), respectively. The findings were robust to multiple sensitivity analyses. CONCLUSION Patients with severe psoriasis have an increased risk of CV mortality that is independent of traditional CV risk factors. Additional studies are needed to determine the mechanism of this association and the impact that control of psoriasis has on CV risk.

Weight Gain in the First Week of Life and Overweight in Adulthood A Cohort Study of European American Subjects Fed Infant Formula

Background—Successful prevention of obesity and related cardiovascular risk factors requires a clear understanding of its determinants over the life course. Rapid infancy weight gain is associated with childhood obesity, whereas low infancy weight is associated with coronary heart disease. Our aim was to identify during which periods in infancy weight gain is associated with adult obesity. Methods and Results—A cohort of European American formula-fed subjects, measured on 7 occasions during infancy as part of several infant formula studies, were contacted at age 20 to 32 years, when they reported usual adult weight and height. A life-course plot was used to identify critical periods of weight gain associated with adulthood overweight (body mass index ≥25 kg/m2). These associations were tested with logistic regressions. Data were available for 653 subjects (72% of eligible subjects). Approximately 32% of them were overweight adults. The period between birth and age 8 days was identified as potentially critical. After adjustment for important confounding factors, weight gain during the first week of life was associated with adulthood overweight status (OR for each 100-g increase 1.28, 95% CI 1.08 to 1.52), as was weight gain during the first 112 days of life (OR 1.04, 95% CI 1.01 to 1.08). Similar results were obtained after standardization with z scores from a reference population. Conclusions—In formula-fed infants, weight gain during the first week of life may be a critical determinant for the development of obesity several decades later. These results contribute to the understanding of chronic disease programming and suggest new approaches to obesity prevention.

Weight Lifting in Women with Breast-Cancer–Related Lymphedema

BACKGROUND Weight lifting has generally been proscribed for women with breast-cancer-related lymphedema, preventing them from obtaining the well-established health benefits of weight lifting, including increases in bone density. METHODS We performed a randomized, controlled trial of twice-weekly progressive weight lifting involving 141 breast-cancer survivors with stable lymphedema of the arm. The primary outcome was the change in arm and hand swelling at 1 year, as measured through displaced water volume of the affected and unaffected limbs. Secondary outcomes included the incidence of exacerbations of lymphedema, number and severity of lymphedema symptoms, and muscle strength. Participants were required to wear a well-fitted compression garment while weight lifting. RESULTS The proportion of women who had an increase of 5% or more in limb swelling was similar in the weight-lifting group (11%) and the control group (12%) (cumulative incidence ratio, 1.00; 95% confidence interval, 0.88 to 1.13). As compared with the control group, the weight-lifting group had greater improvements in self-reported severity of lymphedema symptoms (P=0.03) and upper- and lower-body strength (P<0.001 for both comparisons) and a lower incidence of lymphedema exacerbations as assessed by a certified lymphedema specialist (14% vs. 29%, P=0.04). There were no serious adverse events related to the intervention. CONCLUSIONS In breast-cancer survivors with lymphedema, slowly progressive weight lifting had no significant effect on limb swelling and resulted in a decreased incidence of exacerbations of lymphedema, reduced symptoms, and increased strength. (ClinicalTrials.gov number, NCT00194363.)

The risk of depression, anxiety and suicidality in patients with psoriasis: A population-based cohort study

OBJECTIVE To determine the incidence of depression, anxiety, and suicidality in patients with psoriasis compared with the general population. DESIGN A population-based cohort study using data collected as part of patients electronic medical record from 1987 to 2002. SETTING General Practice Research Database. PATIENTS Analyses included 146 042 patients with mild psoriasis, 3956 patients with severe psoriasis, and 766 950 patients without psoriasis. Five controls without psoriasis were selected from the same practices and similar cohort entry dates as patients with psoriasis. MAIN OUTCOME MEASURE Clinical diagnoses of depression, anxiety, and suicidality among patients. RESULTS The adjusted hazard ratios (HRs) for receiving a diagnosis of depression, anxiety, and suicidality in patients with psoriasis compared with controls were 1.39 (95% confidence interval [CI], 1.37-1.41), 1.31 (95% CI, 1.29-1.34), and 1.44 (95% CI, 1.32-1.57), respectively. The adjusted HR of depression was higher in severe (HR, 1.72; 95% CI, 1.57-1.88) compared with mild psoriasis (HR, 1.38; 95% CI, 1.35-1.40). Younger patients with psoriasis had elevated HRs of outcomes compared with older patients with psoriasis. CONCLUSIONS Patients with psoriasis have an increased risk of depression, anxiety, and suicidality. We estimate that in the United Kingdom, in excess of 10 400 diagnoses of depression, 7100 diagnoses of anxiety, and 350 diagnoses of suicidality are attributable to psoriasis annually. It is important for clinicians to evaluate patients with psoriasis for these conditions to improve outcomes. Future investigation should determine the mechanisms by which psoriasis is associated with psychiatric outcomes as well as approaches for prevention.

Randomized Trial of Black Cohosh for the Treatment of Hot Flashes Among Women With a History of Breast Cancer

PURPOSE Most breast cancer survivors experience hot flashes; many use complementary or alternative remedies for these symptoms. We undertook a randomized clinical trial of black cohosh, a widely used herbal remedy for menopausal symptoms, among breast cancer patients. PATIENTS AND METHODS Patients diagnosed with breast cancer who had completed their primary treatment were randomly assigned to black cohosh or placebo, stratified on tamoxifen use. At enrollment, patients completed a questionnaire about demographic factors and menopausal symptoms. Before starting to take the pills and at 30 and 60 days, they completed a 4-day hot flash diary. At the final visit, they completed another menopausal symptom questionnaire. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured in a subset of patients at the first and final visits. RESULTS Of 85 patients (59 on tamoxifen, 26 not on tamoxifen) enrolled in the study, 42 were assigned to treatment and 43 were assigned to placebo; 69 completed all three hot flash diaries. Both treatment and placebo groups reported declines in number and intensity of hot flashes; the differences between the groups were not statistically significant. Both groups also reported improvements in menopausal symptoms that were, for the most part, not significantly different. Changes in blood levels of FSH and LH also did not differ in the two groups. CONCLUSION Black cohosh was not significantly more efficacious than placebo against most menopausal symptoms, including number and intensity of hot flashes. Our study illustrates the feasibility and value of standard clinical trial methodology in assessing the efficacy and safety of herbal agents.

The risk of stroke in patients with psoriasis.

Psoriasis is a chronic Th-1 and Th-17 inflammatory disease. Chronic inflammation has also been associated with atherosclerosis and thrombosis. The purpose of this study was to determine the risk of stroke in patients with psoriasis. We conducted a population-based cohort study of patients seen by general practitioners participating in the General Practice Research Database in the United Kingdom, 1987-2002. Mild psoriasis was defined as any patient with a diagnostic code of psoriasis, but no history of systemic therapy. Severe psoriasis was defined as any patient with a diagnostic code of psoriasis and a history of systemic therapy consistent with severe psoriasis. The unexposed (control) population was composed of patients with no history of a psoriasis diagnostic code. When adjusting for major risk factors for stroke, both mild (hazard ratio (HR) 1.06, 95% confidence interval (CI) 1.0-1.1) and severe (1.43, 95% CI 1.1-1.9) psoriasis were independent risk factors for stroke. The excess risk of stroke attributable to psoriasis in patients with mild and severe disease was 1 in 4,115 per year and 1 in 530 per year, respectively. Patients with psoriasis, particularly if severe, have an increased risk of stroke that is not explained by major stroke risk factors identified in routine medical care.

Weight Lifting for Women at Risk for Breast Cancer–Related Lymphedema: A Randomized Trial

CONTEXT Clinical guidelines for breast cancer survivors without lymphedema advise against upper body exercise, preventing them from obtaining established health benefits of weight lifting. OBJECTIVE To evaluate lymphedema onset after a 1-year weight lifting intervention vs no exercise (control) among survivors at risk for breast cancer-related lymphedema (BCRL). DESIGN, SETTING, AND PARTICIPANTS A randomized controlled equivalence trial (Physical Activity and Lymphedema trial) in the Philadelphia metropolitan area of 154 breast cancer survivors 1 to 5 years postunilateral breast cancer, with at least 2 lymph nodes removed and without clinical signs of BCRL at study entry. Participants were recruited between October 1, 2005, and February 2007, with data collection ending in August 2008. INTERVENTION Weight lifting intervention included a gym membership and 13 weeks of supervised instruction, with the remaining 9 months unsupervised, vs no exercise. MAIN OUTCOME MEASURES Incident BCRL determined by increased arm swelling during 12 months (≥5% increase in interlimb difference). Clinician-defined BCRL onset was also evaluated. Equivalence margin was defined as doubling of lymphedema incidence. RESULTS A total of 134 participants completed follow-up measures at 1 year. The proportion of women who experienced incident BCRL onset was 11% (8 of 72) in the weight lifting intervention group and 17% (13 of 75) in the control group (cumulative incidence difference [CID], -6.0%; 95% confidence interval [CI], -17.2% to 5.2%; P for equivalence = .04). Among women with 5 or more lymph nodes removed, the proportion who experienced incident BCRL onset was 7% (3 of 45) in the weight lifting intervention group and 22% (11 of 49) in the control group (CID, -15.0%; 95% CI, -18.6% to -11.4%; P for equivalence = .003). Clinician-defined BCRL onset occurred in 1 woman in the weight lifting intervention group and 3 women in the control group (1.5% vs 4.4%, P for equivalence = .12). CONCLUSION In breast cancer survivors at risk for lymphedema, a program of slowly progressive weight lifting compared with no exercise did not result in increased incidence of lymphedema. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00194363.

Cause-specific mortality in patients with severe psoriasis: a population-based cohort study in the U.K.

Background  Severe psoriasis is associated with excess mortality and increased risk of cardiovascular death. Population‐based data evaluating cause‐specific mortality in patients with psoriasis are limited.