A real-world, community-based cohort study comparing the effectiveness of topical fluorouracil versus topical imiquimod for the treatment of actinic keratosis.

BACKGROUND: The most widely used topical agents for the field-based treatment of multiple actinic keratoses (AKs) are 5-fluorouracil and imiquimod, but their comparative effectiveness has not been assessed in a real-world setting. OBJECTIVE: We compared the effectiveness of 5-fluorouracil and imiquimod in reducing risk for subsequent AKs in a large, integrated health care delivery system in northern California. METHODS: In this cohort study, we identified adult health plan members who had an AK diagnosed in 2007 and who subsequently filled a prescription for 5-fluorouracil or imiquimod (N = 5700). We followed subjects for subsequent AKs identified by the International Classification of Diseases codes and estimated the 2-year (short-term) and 5-year (long-term) differences in cumulative risk while controlling for potential confounding by pretreatment variables. RESULTS: 5-Fluorouracil reduced the short-term incidence of subsequent AKs (cumulative risk difference -4.54% [95% confidence interval, -7.91% to -1.17%]), but there was no statistically significant evidence of a long-term decreased risk (cumulative risk difference -1.43% [95% confidence interval, -3.43% to 0.05%]) compared with that with imiquimod. LIMITATIONS: This is a retrospective study with limited ascertainment of all relevant potential confounding variables. CONCLUSION: We found that 5-fluorouracil appeared to be significantly more effective than imiquimod in the short-term, but not long-term, prevention of subsequent AKs.

The promotion of in vitro vessel-like organization of endothelial cells in magnetically responsive alginate scaffolds.

One of the major challenges in engineering thick, complex tissues such as cardiac muscle, is the need to pre-vascularize the engineered tissue in vitro to enable its efficient integration with host tissue upon implantation. Herein, we explored new magnetic alginate composite scaffolds to provide means of physical stimulation to cells. Magnetite-impregnated alginate scaffolds seeded with aortic endothelial cells stimulated during the first 7 days out of a total 14 day experimental course showed significantly elevated metabolic activity during the stimulation period. Expression of proliferating cell nuclear antigen (PCNA) indicated that magnetically stimulated cells had a lower proliferation index as compared to the non-stimulated cells. This suggests that the elevated metabolic activity could instead be related to cell migration and re-organization. Immunostaining and confocal microscopy analyses supported this observation showing that on day 14 in magnetically stimulated scaffolds without supplementation of any growth factors, cellular vessel-like (loop) structures, known as indicators of vasculogenesis and angiogenesis were formed as compared to cell sheets or aggregates observed in the non-stimulated (control) scaffolds. This work is the first step in our understanding of how to accurately control cellular organization to form tissue engineered constructs, which together with additional molecular signals could lead to a creation of an efficient pre-vascularized tissue construct with potential applicability for transplantation.

Supplement use and risk of cutaneous squamous cell carcinoma.

BACKGROUND: Laboratory and epidemiologic studies suggest that certain dietary supplements may alter risk of cutaneous squamous cell carcinoma (SCC). OBJECTIVE: We sought to examine the association between supplement use and SCC risk. METHODS: Cases (n = 415) were defined as Kaiser Permanente Northern California members with a pathology-verified SCC in 2004 and control subjects (n = 415) were age-, sex-, and race-matched members with no history of skin cancer. Supplement use and SCC risk factors were ascertained by questionnaire. Associations of SCC with use of multivitamins; vitamins A, C, D, and E; and grape seed extract were estimated as odds ratios and 95% confidence intervals using conditional logistic regression. Models were adjusted for SCC risk factors and other supplement use. RESULTS: Grape seed extract users had a significantly decreased risk of cutaneous SCC (adjusted odds ratio 0.26, confidence interval 0.08-0.89, P = .031). Multivitamin use was associated with a borderline significant reduction in SCC risk (adjusted odds ratio 0.71, confidence interval 0.51-1.00, P = .049). Use of vitamins A, C, D, and E was not associated with SCC risk. LIMITATIONS: The data may be prone to recall and selection bias because of the case-control design. No information was obtained on dose or duration of supplement use. CONCLUSIONS: Use of grape seed extract may be associated with a decreased risk of cutaneous SCC. The other supplements included in our study did not reveal clear associations with SCC risk.

Association of tea consumption and cutaneous squamous cell carcinoma.

Laboratory and epidemiologic studies suggest a protective effect of tea consumption on risk of cutaneous squamous cell carcinoma (SCC). We designed a case-control study to examine the association between putative protective exposures, including tea consumption, and SCC risk using a large health maintenance organization population. Cases (n=415) were defined as Kaiser Permanente Northern California (KPNC) members with a pathology-verified SCC in 2004 and controls (n=415) were age-, gender-, and race-matched members with no previous history of skin cancer. Tea consumption and SCC risk factors were ascertained by questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression to estimate the association of SCC with regular use, as well as dose and duration of tea consumption. Risk factor adjusted models included education, smoking, hair and eye color, skin type, family history of skin cancer, and history of freckling, sunburns, sun exposure, and tanning bed use. Adjusted analyses showed no reduction in SCC risk with regular consumption of tea (OR=1.11, 95% CI: 0.81-1.54). Examining duration, dose, and combined duration and dose exposure variables did not alter findings. We found no evidence that tea consumption was associated with cutaneous SCC risk.

Screening pharmaceuticals for possible carcinogenic effects: initial positive results for drugs not previously screened.

OBJECTIVE: To screen commonly used prescription drugs for possible carcinogenic effects. METHODS: In a large health care program we identified 105 commonly used drugs, not previously screened. Recipients were followed for up to 12½ years for incident cancer. Nested case-control analyses of 55 cancer sites and all combined included up to ten matched controls per case, with lag of at least 2 years between drug dispensing and cancer. Positive associations entailed a relative risk of 1.50, with p ≤ 0.01 and higher risk for three or more, than for one prescription. Evaluation included further analyses, searches of the literature, and clinical judgment. RESULTS: There were 101 associations of interest for 61 drugs. Sixty-six associations were judged to have involved substantial confounding. We found evidence that of the remaining 35, the following associations may not be due to chance: sulindac with gallbladder cancer and leukemia, hyoscyamine with nonHodgkin lymphoma, nortriptyline with esophageal and hepatic cancer, oxazepam with lung cancer, both fluoxetine and paroxetine with testicular cancer, hydrochlorothiazide with renal and lip cancer, and nifedipine with lip cancer. CONCLUSIONS: These preliminary findings suggest that further studies are indicated regarding sulindac, hyoscyamine, nortriptyline, oxazepam, fluoxetine, paroxetine, hydrochlorothiazide, and nifedipine.

Statin use and risk of basal cell carcinoma.

OBJECTIVE: We examined the association between statin use and basal cell carcinoma (BCC) risk. METHODS: We identified all members of a large integrated health care delivery system with a diagnosis of a histologically proven BCC in 1997. Subsequent BCCs were identified through 2006 from health plan electronic pathology records. Longitudinal exposure to statins and other lipid-lowering agents was determined from automated pharmacy records. We used extended Cox regression to examine the independent association between receipt of statin therapy (ever vs never, cumulative duration) and risk of subsequent BCC. To minimize confounding by indication, we conducted sensitivity analyses in the subset of individuals considered eligible for lipid-lowering therapy based on national guidelines. RESULTS: Among 12,123 members given a diagnosis of BCC who had no prior statin exposure, 6381 developed a subsequent BCC during follow-up. Neither "ever use of statins" (adjusted hazard ratio 1.02, 95% confidence interval: 0.92-1.12) or cumulative duration of statin (adjusted hazard ratio 1.02/year, 95% confidence interval: 0.99-1.11) was associated with subsequent BCC after adjustment for age, sex, and health care use. Risk estimates did not change appreciably when the analysis was limited to the subset of individuals who met eligibility criteria for initiating statin therapy. There was also no significant association between use of non-statin antilipemics and subsequent BCC (adjusted hazard ratio 1.10, 95% confidence interval: 0.76-1.58). LIMITATIONS: No information was available for BCC risk factors, such as sun sensitivity and sun exposure. CONCLUSIONS: Among a large cohort of individuals with BCC, statin therapy was not significantly associated with risk of subsequent BCC.

The confounded relation of coffee drinking to coronary artery disease.

After decades of conflicting studies, the relation of coffee drinking to coronary artery disease (CAD) risk remains unresolved. Using Cox proportional-hazards models with 5 covariates, 127,212 subjects who supplied baseline data at voluntary health examinations from 1978 to 1985 were studied. Subsequently, 8,357 subjects were hospitalized for CAD. Coffee drinking was unrelated to CAD risk in 58,888 never smokers, but in ex-smokers and current baseline smokers, daily coffee intake was associated with higher CAD risk. This disparity was generally consistent in stratified subgroups. In conclusion, this relation of coffee consumption to increased CAD risk only in smokers could be explained by incomplete control for smoking, by other traits of smokers, or by an adverse biologic interaction of a coffee ingredient with smoking effect on CAD.

Validation of high gradient magnetic field based drug delivery to magnetizable implants under flow.

The drug-eluting stent's increasingly frequent occurrence late stage thrombosis have created a need for new strategies for intervention in coronary artery disease. This paper demonstrates further development of our minimally invasive, targeted drug delivery system that uses induced magnetism to administer repeatable and patient specific dosages of therapeutic agents to specific sites in the human body. Our first aim is the use of magnetizable stents for the prevention and treatment of coronary restenosis; however, future applications include the targeting of tumors, vascular defects, and other localized pathologies. Future doses can be administered to the same site by intravenous injection. This implant-based drug delivery system functions by placement of a weakly magnetizable stent or implant at precise locations in the cardiovascular system, followed by the delivery of magnetically susceptible drug carriers. The stents are capable of applying high local magnetic field gradients within the body, while only exposing the body to a modest external field. The local gradients created within the blood vessel create the forces needed to attract and hold drug-containing magnetic nanoparticles at the implant site. Once these particles are captured, they are capable of delivering therapeutic agents such as antineoplastics, radioactivity, or biological cells.

Screening statins for possible carcinogenic risk: up to 9 years of follow-up of 361,859 recipients.

PURPOSE: Determine the risk of cancer in statin users. METHODS: Risk of cancer in up to 9.4 years after first recorded receipt of statins was evaluated in subscribers of an integrated health care program in northern California. Statin use and cancer development were ascertained from the program's pharmacy records and cancer registry from August 1994 to December 2003. RESULTS: Most of the 361,859 statin users received lovastatin, simvastatin or both. Results are presented from analyses with 2-year lag and use for over 5 years. Most of the observed associations were likely due to chance or confounding. The few associations that seemed less readily explainable were increased risk of cancers of the thyroid, esophagus and urinary tract and decreased risk of colon cancer in men. Increased risk of lung cancer was the only nominally statistically significant positive association in women and could be partially attributable to their smoking habits. CONCLUSIONS: Overall this study provided no strong evidence of either causation or prevention of cancer by statins.

Coffee, cirrhosis, and transaminase enzymes.

BACKGROUND: A minority of persons at risk develop liver cirrhosis, but knowledge of risk modulators is sparse. Several reports suggest that coffee drinking is associated with lower cirrhosis risk. METHODS: We studied 125,580 multiethnic members of a comprehensive prepaid health care plan without known liver disease who supplied baseline data at voluntary health examinations from 1978 to 1985. Subsequently, through 2001, 330 of them were diagnosed with liver cirrhosis. Review of medical records confirmed the diagnosis of cirrhosis and ascertained probable etiology. The association of coffee drinking with cirrhosis was estimated by Cox proportional hazards models with 7 covariates. We also did a cross-sectional analysis of baseline aspartate aminotransferase and alanine aminotransferase levels, studied by logistic regression. RESULTS: In the cohort study, relative risks of alcoholic cirrhosis (199 subjects) for coffee drinking (vs none) were less than 1 cup per day, 0.7 (95% confidence interval [CI], 0.4-1.1); 1 to 3 cups, 0.6 (95% CI, 0.4-0.8; P<.001); and 4 or more cups, 0.2 (95% CI, 0.1-0.4; P<.001). For 131 subjects with nonalcoholic cirrhosis, relative risks were less than 1 cup, 1.2 (95% CI, 0.6-2.2); 1 to 3 cups, 1.3 (95% CI, 0.8-2.1); and 4 or more cups, 0.7 (95% CI, 0.4-1.3). These relative risks for coffee drinking were consistent in subsets. Tea drinking was unrelated to alcoholic or nonalcoholic cirrhosis. In the cross-sectional analyses, coffee drinking was related to lower prevalence of high aspartate aminotransferase and alanine aminotransferase levels; for example, the odds ratio of 4 or more cups per day (vs none) for a high aspartate aminotransferase level was 0.5 (95% CI, 0.4-0.6; P<.001) and for a high alanine aminotransferase level, 0.6 (95% CI, 0.6-0.7; P<.001), with stronger inverse relations in those who drink large quantities of alcohol. CONCLUSION: These data support the hypothesis that there is an ingredient in coffee that protects against cirrhosis, especially alcoholic cirrhosis.

Early symptoms of ovarian cancer: a case-control study without recall bias.

BACKGROUND: Ovarian cancer is usually diagnosed after it has spread and is difficult to cure. Previous attempts to identify early symptoms have either lacked a control group or have been based on interviews of cases, with possible recall bias. OBJECTIVE: The purpose of this study was to identify early symptoms of ovarian cancer by reviewing prediagnostic medical records, free of recall bias, and comparing women with and without ovarian cancer. METHODS: In an integrated health care delivery system, symptoms recorded in medical records of 102 women with ovarian cancer during the two years before diagnosis were compared with those of 102 matched control women. RESULTS: More cases than controls complained of several symptoms up to one year before diagnosis. Most of these symptoms were abdominal or gastrointestinal in nature and were more prevalent in the advanced stage cases. Other symptom sites included pelvic, urinary, back, and systemic. Because case-control differences were not large and prevalence is low, positive predictive values were generally quite low. CONCLUSION: Previous reports of early symptoms of ovarian cancer were confirmed in a study with a control group and free of recall bias. It is not clear that these symptoms occurred while the disease was still localized. Because hundreds of women would have to be investigated to detect one case of ovarian cancer, the clinical utility of these symptoms is uncertain. Nevertheless, health care providers should keep ovarian cancer in mind, when women present with symptoms such as abdominal pain and bloating.

Cryptococcosis: the 1981-2000 epidemic.

The annual incidence of cryptococcosis during 1981-2000 was determined in subscribers of a large integrated health care program in Northern California and in those among them who were HIV positive. The incidence of cryptococcosis had been measured in this setting in the previous decade. The 20-year incidence per million person-years was 19.0 in males and 2.6 in females. In males, annual incidence rose sharply but irregularly from 1981 to 1992, then decreased irregularly. In females, trends were less marked, with maximum incidence in 1997. In HIV-positive patients cryptococcosis incidence was highest in 1981-85 and decreased thereafter in men. In women, maximum incidence occurred in 1986-90 and was followed by a decrease. Cryptococcosis was rare in the non-predisposed. Thus, cryptococcosis incidence increased markedly in men early in the AIDS epidemic, and began to decrease in both male and female HIV-positive patients well before highly active antiretroviral therapy became available.

Helicobacter pylori infection and the risk of development of esophageal adenocarcinoma.

BACKGROUND: An increase in the incidence of esophageal adenocarcinoma has coincided with a decrease in the prevalence of Helicobacter pylori infection. Whether these 2 phenomena are associated is unknown. METHODS: We conducted a nested case-control study of 128,992 members of an integrated health care system who had participated in a multiphasic health checkup (MHC) during 1964-1969. During follow-up, 52 patients developed esophageal adenocarcinoma. Three randomly chosen control subjects from the MHC cohort were matched to each case subject, on the basis of age at the MHC, sex, race, and the date and site of the MHC. Data on cigarette smoking, alcohol consumption, body mass index (BMI), and education level were obtained at the MHC. Serum samples collected at the MHC were tested for IgG antibodies to H. pylori and to the H. pylori CagA protein. RESULTS: Subjects with H. pylori infections were less likely than uninfected subjects to develop esophageal adenocarcinoma (odds ratio [OR], 0.37 [95% confidence interval (CI), 0.16-0.88]). This significant association was restricted to case subjects and control subjects <50 years old at the MHC (OR, 0.20 [95% CI, 0.06-0.68]). In patients with H. pylori infections, the OR for those who tested positive for IgG antibodies to the CagA protein was similar to that for those who tested negative for it. BMI >/=25 and cigarette smoking were strong independent risk factors for development of esophageal adenocarcinoma. CONCLUSION: The absence of H. pylori infection, independent of cigarette smoking and BMI, is associated with a markedly increased risk of development of esophageal adenocarcinoma.