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1.  Association of Tea Consumption and Cutaneous Squamous Cell Carcinoma 
Nutrition and cancer  2011;63(2):314-318.
Background
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.
Patient/Methods
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.
RESULTS
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.
CONCLUSIONS
We found no evidence that tea consumption was associated with cutaneous SCC risk.
doi:10.1080/01635581.2011.523496
PMCID: PMC3058800  PMID: 21240832
2.  Predictors of Patient Satisfaction With Mohs Surgery 
Archives of dermatology  2011;147(12):1387-1394.
Objective
To identify preoperative, intraoperative, and postoperative variables that predict higher short- and long-term patient satisfaction with Mohs surgery.
Design
Prospective cohort study.
Setting
A university-based dermatology practice and the affiliated Veterans Affairs medical center dermatology clinic.
Patients
A total of 339 consecutive patients treated with Mohs surgery in 1999 and 2000.
Main Outcome Measures
Short-term satisfaction at 1 week and long-term satisfaction at 1 year. We used directed acyclic graphs to determine appropriate confounding adjustment for preoperative, intraoperative, and postoperative variables that influence satisfaction with Mohs surgery in logistic regression models.
Results
Better preoperative skin-related quality of life (measured using Skindex) and more intraoperative Mohs stages were the most salient predictors of higher short- and long-term satisfaction; these odds ratios (ORs) were 2.33 (95% CI, 1.01–5.35) and 5.19 (1.66–16.29), respectively, for preoperative skin-related quality of life and 7.06 (2.02–24.67) and 5.30 (1.24–22.64), respectively, for more intraoperative Mohs stages. Patients not bothered by postoperative bleeding were more likely to be satisfied short term (OR, 2.25; 95% CI, 1.25–4.05), as were those who considered themselves involved in decision making about their treatment (3.05; 1.52–6.10). Higher long-term satisfaction with Mohs surgery was observed among patients who were married (2.36; 1.10–5.09).
Conclusions
Higher short- and long-term satisfaction with Mohs surgery is predicted by better preoperative skin-related quality of life and by more intraoperative Mohs stages. The effect of postoperative variables wanes over time, suggesting that factors influencing satisfaction can vary depending on the time frame when satisfaction is measured. Our results may help clinicians identify patients who are at higher risk of dissatisfaction following Mohs surgery.
doi:10.1001/archdermatol.2011.319
PMCID: PMC3620041  PMID: 22184760
3.  Needs Assessment for Mohs Micrographic Surgery 
Dermatologic clinics  2012;30(1):167-175.
doi:10.1016/j.det.2011.08.010
PMCID: PMC3225895  PMID: 22117877
4.  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
To examine the association between supplement use and SCC risk.
METHODS
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. 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 (OR) and 95% confidence intervals (CI) 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 OR = 0.26, CI: 0.08-0.89, p=0.031). Multivitamin use was associated with a borderline significant reduction in SCC risk (adjusted OR = 0.71, CI: 0.51-1.00, p= 0.049). 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 due to 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.
doi:10.1016/j.jaad.2010.09.009
PMCID: PMC3184340  PMID: 21664718
Antioxidant; Skin cancer; Squamous Cell Carcinoma; Supplement; Vitamin; Epidemiology
5.  Effect of Host, Tumor, Diagnostic, and Treatment Variables on Outcomes in a Large Cohort With Merkel Cell Carcinoma 
JAMA dermatology  2014;150(7):716-723.
IMPORTANCE
Merkel cell carcinoma (MCC) is a rare, aggressive, neuroendocrine-derived skin cancer with high rates of recurrence and associated mortality. Few published studies have used comprehensive patient data and long-term follow-up to examine factors that predict MCC outcomes.
OBJECTIVE
To characterize MCC in a large defined-population cohort and analyze predictors of disease recurrence and survival.
SETTING, DESIGN, AND PARTICIPANTS
Retrospective cohort study of 218 patients with MCC from the cancer registry of Kaiser Permanente Northern California, a large integrated health care delivery system. Patients were diagnosed as having MCC and followed up from January 1, 1995, through December 31, 2009. We examined host (age, sex, race, and immunosuppression), tumor (anatomic site, size, and extent), diagnostic (results of imaging and pathologic nodal evaluation), and treatment (surgery, radiation therapy, and chemotherapy) variables for their association with MCC outcomes.
EXPOSURE
Host, tumor, diagnostic, and treatment factors.
MAIN OUTCOMES AND MEASURES
Recurrence (locoregional and distant) of MCC and patient survival (overall and MCC specific).
RESULTS
We estimated adjusted hazard ratios (AHRs) and 95% CIs for outcomes using Cox proportional hazards regression models. After adjustment for host, tumor, diagnostic, and treatment variables, tumor extent (categorized as local, regional, and distant) remained significantly associated with all outcomes. Immunosuppression was associated with higher MCC-specific mortality (AHR, 4.9 [95% CI, 1.7–14.4]), and an unknown primary site was associated with a lower risk for distant metastasis (0.1 [0.0–0.7]) and improved survival (0.4 [0.2–0.9]). Pathological nodal evaluation was associated with a lower risk for metastasis (AHR, 0.2 [95% CI, 0.0–1.0]) and improved survival. Radiation treatment was associated with a decreased risk for locoregional recurrence (AHR, 0.3 [95% CI, 0.1–0.6]), whereas chemotherapy was not associated with any alteration in outcomes.
CONCLUSIONS AND RELEVANCE
Tumor site and extent, results of pathologic nodal evaluation, and the presence of radiation treatment were associated with MCC recurrence. Immunosuppression, tumor extent, and results of pathologic nodal evaluation were associated with MCC-specific survival, whereas chemotherapy was not associated with any outcomes. Our findings may help to inform diagnostic and therapeutic management of MCCs.
doi:10.1001/jamadermatol.2013.8116
PMCID: PMC4141075  PMID: 24807619
6.  Detection of Human Papillomavirus DNA in Cutaneous Squamous Cell Carcinoma among Immunocompetent Individuals 
The presence of certain types of human papillomavirus (HPV) is a known risk factor for the development of anogenital squamous cell carcinomas (SCCs). A similar association has been hypothesized for cutaneous SCCs, although, to our knowledge, no studies to date have combined sensitive HPV DNA detection techniques with epidemiologic data controlling for known risk factors to explore the association. We designed a case–control study examining HPV prevalence using highly sensitive PCR-detection assays in tissue samples from 85 immunocompetent patients with histologically confirmed SCCs and 95 age-matched individuals without a prior history of skin cancer. A standardized interview was administered to all study subjects to collect information pertaining to potential confounding variables. The overall detection rate of HPV DNA was high in case lesions (54%) and perilesions (50%) and in both sun-exposed normal tissue (59%) and non-sun-exposed normal tissue (49%) from controls. In comparing case tissue to control tissue, there was no differential detection of HPV DNA across various HPV species. However, HPV DNA from β-papillomavirus species 2 was more likely to be identified in tumors than in adjacent healthy tissue among cases (paired analysis, odds ratio = 4.0, confidence interval = 1.3–12.0). The high prevalence of HPV DNA detected among controls suggests that HPV DNA is widely distributed among the general population. However, the differential detection of HPV β-papillomavirus species in tumors among cases suggests that certain HPV types may be involved in the progression of cutaneous SCCs.
doi:10.1038/sj.jid.5701227
PMCID: PMC3268673  PMID: 18185530
7.  Association of Use of Nonsteroidal Anti-inflammatory Drugs and Cutaneous Squamous Cell Carcinoma 
Archives of dermatology  2010;146(4):388-395.
OBJECTIVE
To examine the association between non-steroidal anti-inflammatory drug (NSAID) use and cutaneous squamous cell carcinoma (SCC).
DESIGN
Retrospective case-control.
SETTING
Kaiser Permanente Northern California (KPNC), a large population based-health maintenance organization.
PATIENTS
Random sample of 415 KPNC members diagnosed with a pathology-verified SCC in 2004 and 415 age-, sex, and race-matched controls with no history of skin cancer.
MAIN EXPOSURE MEASURE
Self-reported NSAID use in the 10 years prior to baseline. NSAID use was categorized based on type (any NSAIDs, aspirin, ibuprofen, non-aspirin NSAIDs). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression to estimate the association of SCC with regular use, dose and duration of exposure to the different NSAID types. Information on pharmacy-dispensed NSAIDs was also examined to assess its association with SCC risk. Models were adjusted for all ascertained SCC risk factors (fully adjusted model) and only those variables associated with both SCC risk and NSAID use (parsimonious model).
RESULTS
Fully adjusted analyses showed no statistically significant reduction in SCC risk with self-reported regular use of any NSAID (OR=1.32, 95% CI: 0.92–1.89), aspirin (OR=1.38, 95% CI: 0.96–1.97), ibuprofen (OR=0.74, 95% CI: 0.46–1.19), or non-aspirin NSAIDs (OR=0.84, 95% CI: 0.56–1.26). Analyses examining duration, dose, and variables combining duration and dose of NSAID exposure did not appreciably change results. Analysis using the parsimonious model showed similar results. The data on pharmacy dispensed NSAIDs also showed no association with SCC risk.
CONCLUSIONS
Neither self-reported, nor pharmacy-dispensed NSAID exposure was associated with cutaneous SCC risk.
doi:10.1001/archdermatol.2009.374
PMCID: PMC2857681  PMID: 20157019
8.  A Large Cohort Study of Nonsteroidal Anti-inflammatory Drug Use and Melanoma Incidence 
Results of laboratory studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) may have chemopreventive activity and therapeutic efficacy against melanoma. However, few published epidemiological studies have examined the association between NSAID use and melanoma risk. We examined whether NSAID use was associated with melanoma risk among 63 809 men and women in the Vitamins and Lifestyle (VITAL) cohort study. Participants self-reported NSAID use (low-dose aspirin, regular or extra-strength aspirin, and nonaspirin NSAIDs) during the previous 10 years and data related to their melanoma risk factors on a baseline questionnaire. After linkage of the VITAL database to the NCI Surveillance, Epidemiology, and End Results cancer registry, 349 patients with incident melanoma were identified through December 31, 2005. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma by NSAID use as categorized by overall use, duration of use, and dose (expressed as average number of days of use during the past 10 years). All statistical tests were two-sided. After adjusting for melanoma risk factors and indications for NSAID use, no association between NSAID use and melanoma risk was found. When use of at least 4 d/wk was compared with nonuse, no melanoma risk reduction was detected for any NSAID dose (HR = 1.12, 95% CI = 0.84 to 1.48), for any NSAID excluding low-dose aspirin (HR = 1.03, 95% CI = 0.74 to 1.43), for regular- or extra-strength aspirin (HR = 1.10, 95% CI = 0.76 to 1.58), or for nonaspirin NSAIDs (HR = 1.22, 95% CI = 0.75 to 1.99). Moreover, NSAID use was not associated with tumor invasion (Pinteraction = .38), tumor thickness (Ptrend = .98), or risk of metastasis (HR = 1.09, 95% CI = 0.32 to 3.62). NSAIDs do not appear to be good candidates for the chemoprevention of melanoma.
doi:10.1093/jnci/djn154
PMCID: PMC2561247  PMID: 18577752
9.  A Cohort Study of Vitamin D Intake and Melanoma Risk 
Data suggest that vitamin D intake may have chemopreventive efficacy against melanoma, but there have been no published epidemiologic studies examining the association between vitamin D intake and melanoma risk in a large prospective cohort. We examined whether dietary and supplemental vitamin D intake was associated with melanoma risk among 68,611 men and women who were participants of the Vitamins and Lifestyle cohort study. Participants reported dietary vitamin D intake over the past year and 10-year use of multivitamin and individual vitamin D supplements on a baseline questionnaire. After follow-up through 2006, 455 incident melanomas were identified through linkage to the Surveillance, Epidemiology, and End Results cancer registry. Cox proportional hazards regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for vitamin D intake after adjustment for melanoma risk factors. Compared with the lowest quartile, we did not detect a risk reduction of melanoma in the highest quartiles of dietary vitamin D intake (RR = 1.31, CI = 0.94–1.82), 10-year average supplemental vitamin D intake (RR = 1.13, CI = 0.89–1.43), or combined dietary and supplemental intake (1.05, CI = 0.79–1.40). In this large prospective cohort, we did not find an association between vitamin D intake and melanoma risk.
doi:10.1038/jid.2008.451
PMCID: PMC2695831  PMID: 19194478
10.  A Large Cohort Study of Nonsteroidal Anti-inflammatory Drug Use and Melanoma Incidence 
Results of laboratory studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) may have chemopreventive activity and therapeutic efficacy against melanoma. However, few published epidemiological studies have examined the association between NSAID use and melanoma risk. We examined whether NSAID use was associated with melanoma risk among 63 809 men and women in the Vitamins and Lifestyle (VITAL) cohort study. Participants self-reported NSAID use (low-dose aspirin, regular or extra-strength aspirin, and nonaspirin NSAIDs) during the previous 10 years and data related to their melanoma risk factors on a baseline questionnaire. After linkage of the VITAL database to the NCI Surveillance, Epidemiology, and End Results cancer registry, 349 patients with incident melanoma were identified through December 31, 2005. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma by NSAID use as categorized by overall use, duration of use, and dose (expressed as average number of days of use during the past 10 years). All statistical tests were two-sided. After adjusting for melanoma risk factors and indications for NSAID use, no association between NSAID use and melanoma risk was found. When use of at least 4 d/wk was compared with nonuse, no melanoma risk reduction was detected for any NSAID dose (HR = 1.12, 95% CI = 0.84 to 1.48), for any NSAID excluding low-dose aspirin (HR = 1.03, 95% CI = 0.74 to 1.43), for regular- or extra-strength aspirin (HR = 1.10, 95% CI = 0.76 to 1.58), or for nonaspirin NSAIDs (HR = 1.22, 95% CI = 0.75 to 1.99). Moreover, NSAID use was not associated with tumor invasion (Pinteraction = .38), tumor thickness (Ptrend = .98), or risk of metastasis (HR = 1.09, 95% CI = 0.32 to 3.62). NSAIDs do not appear to be good candidates for the chemoprevention of melanoma.
doi:10.1093/jnci/djn154
PMCID: PMC2561247  PMID: 18577752
11.  Imputation of the Rare HOXB13 G84E Mutation and Cancer Risk in a Large Population-Based Cohort 
PLoS Genetics  2015;11(1):e1004930.
An efficient approach to characterizing the disease burden of rare genetic variants is to impute them into large well-phenotyped cohorts with existing genome-wide genotype data using large sequenced referenced panels. The success of this approach hinges on the accuracy of rare variant imputation, which remains controversial. For example, a recent study suggested that one cannot adequately impute the HOXB13 G84E mutation associated with prostate cancer risk (carrier frequency of 0.0034 in European ancestry participants in the 1000 Genomes Project). We show here that—by utilizing the 1000 Genomes Project data plus an enriched reference panel of mutation carriers—we were able to accurately impute the G84E mutation into a large cohort of 83,285 non-Hispanic White participants from the Kaiser Permanente Research Program on Genes, Environment and Health Genetic Epidemiology Research on Adult Health and Aging cohort. Imputation authenticity was confirmed via a novel classification and regression tree method, and then empirically validated analyzing a subset of these subjects plus an additional 1,789 men from the California Men’s Health Study specifically genotyped for the G84E mutation (r2 = 0.57, 95% CI = 0.37–0.77). We then show the value of this approach by using the imputed data to investigate the impact of the G84E mutation on age-specific prostate cancer risk and on risk of fourteen other cancers in the cohort. The age-specific risk of prostate cancer among G84E mutation carriers was higher than among non-carriers, and this difference increased with age. Risk estimates from Kaplan-Meier curves were 36.7% versus 13.6% by age 72, and 64.2% versus 24.2% by age 80, for G84E mutation carriers and non-carriers, respectively (p = 3.4×10−12). The G84E mutation was also suggestively associated with an increase in risk for the following cancer sites by approximately 50% in a pleiotropic manner: breast, non-Hodgkin’s lymphoma, kidney, bladder, melanoma, endometrium, and pancreas (p = 0.042).
Author Summary
An efficient approach to characterizing the disease burden of rare genetic variants is to impute them into existing well-phenotyped cohorts with genome-wide data by using large sequenced reference panels; however, the efficacy of this approach remains controversial. A recent study suggested that it is not possible to impute the rare HOXB13 G84E variant using neighboring SNP markers. We show that by using an enriched reference sequenced sample of 22 mutation carriers, we were able to impute this mutation into a large cohort of 83,285 non-Hispanic White individuals from the Kaiser Permanente Research Program on Genes, Environment, and Health Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. The imputation was confirmed via a novel classification and regression tree method, and then empirically validated by direct mutation genotyping of a subset of 1,673 of these individuals in addition to 1,789 other men from Kaiser. Using the same GERA cohort, we then confirmed that the G84E mutation is associated with increased risk of prostate cancer, and estimated the age-specific risk for carriers of the mutation. Finally, we obtained evidence that the mutation is associated with additional types of cancer in the GERA cohort.
doi:10.1371/journal.pgen.1004930
PMCID: PMC4309593  PMID: 25629170
12.  Variation in vitamin D supplementation among adults in a multi-race/ethnic health plan population, 2008 
Nutrition Journal  2012;11:104.
Background
Vitamin D may have a role in many chronic conditions in addition to bone health. Nutritional surveys among Americans have reported high levels of vitamin D insufficiency, especially among Blacks and Latinos. Our study examined variation in vitamin D supplementation practices in an adult health plan population by age, gender, and race-ethnicity.
Methods
Self-report data from a 2008 general health survey in a large Northern California health plan were used to characterize number and types of sources of vitamin D supplementation (multivitamin, calcium with D, singular D) among women and men aged 25-85, overall, by race-ethnicity, and for obese, diabetic, and hypertensive subgroups.
Results
In this population, 40% of women and 54% of men ≤ 50, and 24% of women and 53% of men aged 51-85 get no vitamin D from dietary supplements. Higher vitamin D supplementation among women > 50 is associated with higher reported intake of calcium with D. Black and Latina women aged 25-85 and Filipinas in the ≤ 50 age group were significantly less likely than non-Hispanic Whites to get vitamin D from supplements, whereas vitamin D supplementation practices among Chinese women did not significantly differ from non-Hispanic Whites. Among men, Latinos aged 25-85 and Black and Chinese ≤ 50 were significantly less likely than non-Hispanic Whites to get vitamin D from supplements. Similar race-ethnic differences in vitamin D supplementation patterns were observed for people in the obese, diabetic, and hypertensive groups.
Conclusions
Our survey results suggest that in 2008, a large percentage of women and an even larger percentage of men in a large Northern California health plan get no vitamin D from dietary supplements, and that Blacks and Latinos and obese adults, who are at higher risk of vitamin D deficiency, are also the least likely to get any vitamin D from dietary supplements.
doi:10.1186/1475-2891-11-104
PMCID: PMC3567957  PMID: 23231734
Vitamin D supplementation; Multivitamin supplementation; calcium supplementation; differences in vitamin D supplementation; gender differences in vitamin D supplementation
13.  Association of Vitamin A and Carotenoid Intake with Melanoma Risk in a Large Prospective Cohort 
Laboratory data suggest that intake of vitamin A and carotenoids, may have chemopreventive benefits against melanoma, but epidemiologic studies examining the association have yielded conflicting results. We examined whether dietary and supplemental vitamin A and carotenoid intake was associated with melanoma risk among 69,635 men and women who were participants of the Vitamins and Lifestyle (VITAL) cohort study in Western Washington. After an average of 5.84 years of follow-up, 566 incident melanomas were identified. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for risk of melanoma associated with dietary, supplement and total vitamin A and carotenoid intake after adjusting for melanoma risk factors. Baseline use of individual retinol supplements was associated with a significant reduction in melanoma risk (HR: 0.60, 95% CI: 0.41–0.89). High-dose (>1200 ug/day) supplemental retinol was also associated with reduced melanoma risk (HR: 0.74, 95% CI: 0.55–1.00), as compared to non-users. The reduction in melanoma risk was stronger in sun-exposed anatomic sites. There was no association of melanoma risk with dietary or total intake of vitamin A or carotenoids. Retinol supplementation may have a preventative role in melanoma among women.
doi:10.1038/jid.2012.21
PMCID: PMC3352977  PMID: 22377763
14.  Antihypertensive drugs and lip cancer in non-Hispanic whites 
Archives of internal medicine  2012;172(16):10.1001/archinternmed.2012.2754.
Background
In screening pharmaceuticals for possible carcinogenic effects we noted an association between lip cancer risk and the photosensitizing antihypertensive drugs hydrochlorothiazide (HCTZ) and nifedipine. Here we further characterized risk of lip cancer associated with these and other commonly used antihypertensive drugs.
Methods
In a comprehensive medical care program we ascertained prescriptions dispensed and cancer occurence from August 1994 to February 2008. We identified 712 patients with lip cancer (cases) and 22,904 age, sex, and cohort year of entry-matched comparison subjects (controls) in the susceptible group, non-Hispanic whites. We determined their use at least two years before diagnosis or control index date of the commonly prescribed diuretics, HCTZ and HCTZ combined with triamterene (HCTZ/TR), the angiotensin-converting-enzyme inhibitor lisinopril, the calcium channel blocker nifedipine, and the beta adrenergic blocker atenolol, the only non-photosensitizer studied. We analyzed use of each drug both exclusively and regardless of use of others, and focused on duration of use. Analysis employed conditional logistic regression for matched case-control sets with control for cigarette smoking.
Results
At least a five-year supply yielded the following odds ratios, respectively, compared to no use: HCTZ: 4.22 (2.82–6.31); HCTZ/TR: 2.82 (1.74–4.55); lisinopril: 1.42(0.95–2.13); nifedipine 2.50 (1.29–4.84); atenolol: 1.93 (1.29–2.91). When the other drugs were excluded the odds ratios for atenolol were reduced to 0.54 (0.07–4.08).
Conclusions
These data support an increased risk of lip cancer in non-Hispanic whites treated for hypertension with long term use of photosensitizing drugs.
doi:10.1001/archinternmed.2012.2754
PMCID: PMC3809130  PMID: 22869299
15.  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 healthcare delivery system diagnosed with 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 diagnosed with BCC who had no prior statin exposure, 6381 developed a subsequent BCC during follow-up. Neither ever use of statins (adjusted hazard ratio [aHR] 1.02, 95% CI: 0.92-1.12) or cumulative duration of statin (aHR 1.02 per year, 95% CI: 0.99-1.11) was associated with subsequent BCC after adjustment for age, sex, and healthcare utilization. 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 (aHR 1.10, 95% CI: 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.
doi:10.1016/j.jaad.2009.02.011
PMCID: PMC2700205  PMID: 19464071
16.  Association of Prediagnostic Serum Vitamin D levels with the Development of Basal Cell Carcinoma 
We investigated the association between serum 25-hydroxyvitamin D (25(OH)D) levels and basal cell carcinoma (BCC) risk in a nested case-control study at Kaiser Permanente Northern California (KPNC). 220 case patients with BCC diagnosed after serum collection were matched to 220 control subjects. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression. Fully adjusted models included body mass index (BMI), smoking, education, sun-exposure variables, x-ray exposure, and personal history of cancer. For each measure of serum 25(OH)D (continuous, clinically relevant tertiles, quintiles), we found an increased risk of BCC in unadjusted models (OR=1.03, 95% CI 1.00–1.05, p<0.05; OR= 3.98, 95% CI: 1.31–12.31, deficient vs. sufficient, test for trend p value <0.01; OR=2.32, 95% CI: 1.20–4.50, 1st vs. 5th quintile, test for trend p value 0.03). In fully adjusted models, the values attenuated slightly (OR=1.02, 95% CI 1.00–1.05, p<0.05; OR= 3.61, 95% CI: 1.00–13.10, deficient vs. sufficient, t-trend p=0.03; OR=2.09 1st vs. 5th quintile, 95% CI: 0.95–4.58, t-trend p=0.11). Our findings suggest that higher pre-diagnostic serum 25(OH)D levels may be associated with increased risk of subsequent BCC. Further studies to evaluate the effect of sun exposure on BCC and serum 25(OH)D levels may be warranted.
doi:10.1038/jid.2009.402
PMCID: PMC2855394  PMID: 20043012
17.  Potential Risk Factors for Cutaneous Squamous Cell Carcinoma include Oral Contraceptives: Results of a Nested Case-Control Study 
Recently, a population-based case-control study observed a 60% increased odds ratio (OR) for cutaneous squamous cell carcinoma (SCC) among women who had ever used oral contraceptives (OCs) compared with non users (95% confidence interval (CI) = 1.0–2.5). To further characterize the putative association between OC use and SCC risk, we conducted a nested case-control study using a large retrospective cohort of 111,521 Kaiser Permanente Northern California members. Multivariable conditional logistic regression was used to estimate ORs and CIs adjusting for known and hypothesized SCC risk factors. Pre-diagnostic OC use was associated with a statistically significant increased OR for SCC in univariate analysis (OR = 2.4, CI = 1.2–4.8), with borderline statistical significance in multivariable analysis (CI = 2.0, CI = 0.91–4.5). Given the high incidence of SCC in the general population and the prevalent use of OCs among women in the United States, there is a need for more large, carefully designed epidemiologic studies to determine whether the observed association between OC use and SCC can be replicated and to better understand the etiologic basis of an association if one exists.
doi:10.3390/ijerph7020427
PMCID: PMC2872290  PMID: 20616983
squamous cell carcinoma; oral contraceptives; risk factors; epidemiology
18.  Validity of Diagnostic Codes and Prevalence of Psoriasis and Psoriatic Arthritis in a Managed Care Population, 1996–2009 
Background
Few population-based studies have reported the prevalence of psoriatic disease.
Objective
We validated computerized diagnoses to estimate the prevalence of psoriasis and psoriatic arthritis.
Method
We identified adults with ≥1 ICD-9 diagnosis codes of 696.0 (psoriatic arthritis) or 696.1 (psoriasis) in clinical encounter data during 1996–2009, and used chart review to confirm the diagnoses in random samples of patients. We then used the best performing case-finding algorithms to estimate the point prevalence of psoriasis and psoriatic arthritis.
Results
The number of persons with a diagnosis for psoriasis (ICD-9 code 696.1) was 87,827. Chart review of a random sample of 101 cases with at least one dermatologist-rendered psoriasis code revealed a positive predictive value (PPV) of 90% (95% CI, 83–95) with sensitivity 88% (95% CI, 80–93). Psoriatic arthritis (code 696.0) was recorded for 5,187 patients, with the best performing algorithm requiring ≥2 diagnoses recorded by a rheumatologist or ≥1 diagnosis recorded by a rheumatologist together with ≥1 psoriasis diagnoses recorded by a dermatologist; the PPV was 80% (95% CI, 70–88) with sensitivity 73% (95% CI, 63–82). Among KPNC adults, the point prevalence of psoriasis, with or without psoriatic arthritis, was 939 (95% CI, 765–1142) per 100,000, and the overall prevalence of psoriatic arthritis, with or without psoriasis, was 68 (95% CI, 54–84) per 100,000.
Conclusion
Within an integrated health care delivery system, the use of computerized diagnoses rendered by relevant disease specialists is a valid method for identifying individuals with psoriatic disease.
doi:10.1002/pds.3447
PMCID: PMC3720770  PMID: 23637091
Psoriasis; Psoriatic Arthritis; Epidemiology; Incidence; Prevalence; Health Maintenance Organizations; Computerized Medical Information
19.  Antioxidant Supplementation and Risk of Incident Melanomas: Results from a Large Prospective Cohort Study 
Archives of dermatology  2009;145(8):879-882.
Objective
To examine whether antioxidant supplement use is associated with melanoma risk in light of recently published data from the Supplementation in Vitamins and Mineral Antioxidant (SUVIMAX) study which reported a four-fold higher melanoma risk among women who were randomized to a supplement with nutritionally appropriate doses of antioxidants.
Design
Prospective study (VITamins And Lifestyle (VITAL) cohort).
Setting
Population-based study targeting supplement users recruited from Western Washington State.
Participants
69,671 men and women who self-reported intake of multivitamins and supplemental antioxidants including selenium and beta-carotene over the past 10 years as well as melanoma risk factors on a baseline questionnaire.
Main Outcome Measure
incident melanoma identified through linkage to the Surveillance, Epidemiology, and End Results (SEER) cancer registry.
Results
Cox regression models were used to estimate multivariate relative risks (RR) and 95% confidence intervals (CI) for multivitamins, supplemental selenium and supplemental beta-carotene use. After adjusting for melanoma risk factors, we did not detect a significant association between multivitamins and melanoma risk for women (RR=1.14, CI = 0.78–1.66) or men (RR=1.09, CI =0.83–1.43). Moreover, we did not observe increased melanoma risk for supplemental beta-carotene (RR=0.87, CI=0.48, 1.56) or selenium (RR=0.98, CI=0.69–1.41) at doses comparable to the SUVIMAX study.
Conclusion
Antioxidants in nutritional doses do not appear to increase the melanoma risk.
doi:10.1001/archdermatol.2009.176
PMCID: PMC2729504  PMID: 19687417
20.  Aspirin is associated with lower melanoma risk among postmenopausal Caucasian women: the Women’s Health Initiative 
Cancer  2013;119(8):10.1002/cncr.27817.
Background
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with decreased risk of gastric, colorectal, and breast cancer. However, the impact of NSAIDs on risk of melanoma has been inconsistent. We evaluated the association between NSAID use and cutaneous melanoma risk in the WHI Observational Study (WHI OS).
Methods
At study entry, use of aspirin (ASA) and non-aspirin NSAIDs was assessed among 59,806 postmenopausal Caucasian women aged 50 to 79. We used Cox proportional hazards models after adjusting for participant skin type, sun exposure history, and medical indications for NSAID use among other confounders.
Results
During a median follow-up of 12 years, 548 incident melanomas were confirmed by medical review. Women who used ASA had a 21% lower risk of melanoma (HR: 0.79, 95% CI: 0.63-0.98) relative to non-users. Increased duration of ASA use (<1 year, 1-4 years, and ≥5 years) was associated with an 11% lower risk of melanoma for each categorical increase (ptrend=0.01), and women with ≥5 years use had a 30% lower melanoma risk (HR 0.70, 95% CI: 0.55-0.94). In contrast, use of non-ASA NSAIDs and acetaminophen were not associated with melanoma risk.
Conclusions
Postmenopausal women who used ASA had a significantly lower risk of melanoma, with longer duration of ASA use associated with greater protection. Although this study is limited by the observational design and self-report of NSAID use, these findings suggest that ASA may have a chemopreventive effect against the development of melanoma and warrant further clinical investigation.
doi:10.1002/cncr.27817
PMCID: PMC3880825  PMID: 23483536
Aspirin; anti-inflammatory agents, non-steroidal; melanoma; female; incidence
21.  HIV Infection Status, Immunodeficiency, and the Incidence of Non-Melanoma Skin Cancer 
Background
The incidence of non-melanoma skin cancers (NMSCs), including basal cell (BCC) or squamous cell carcinoma (SCC), is not well documented among HIV-positive (HIV+) individuals.
Methods
We identified 6560 HIV+ and 36 821 HIV-negative (HIV−) non-Hispanic white adults who were enrolled and followed up in Kaiser Permanente Northern California from 1996 to 2008. The first biopsy-proven NMSCs diagnosed during follow-up were identified from pathology records. Poisson models estimated rate ratios that compared HIV+ (overall and stratified by recent CD4 T-cell counts and serum HIV RNA levels) with HIV− subjects and were adjusted for age, sex, smoking history, obesity diagnosis history, and census-based household income. Sensitivity analyses were adjusted for outpatient visits (ie, a proxy for screening). All statistical tests were two-sided.
Results
The NMSC incidence rate was 1426 and 766 per 100 000 person-years for HIV+ and HIV− individuals, respectively, which corresponds with an adjusted rate ratio of 2.1 (95% confidence interval [CI] = 1.9 to 2.3). Similarly, the adjusted rate ratio for HIV+ vs HIV− subjects was 2.6 (95% CI = 2.1 to 3.2) for SCCs, and it was 2.1 (95% CI = 1.8 to 2.3) for BCCs. There was a statistically significant trend of higher rate ratios with lower recent CD4 counts among HIV+ subjects compared with HIV− subjects for SCCs (P trend < .001). Adjustment for number of outpatient visits did not affect the results.
Conclusion
HIV+ subjects had a twofold higher incidence rate of NMSCs compared with HIV− subjects. SCCs but not BCCs were associated with immunodeficiency.
doi:10.1093/jnci/djs529
PMCID: PMC3589255  PMID: 23291375
22.  High Prevalence of Vitamin D Deficiency in Patients With Basal Cell Nevus Syndrome 
Archives of dermatology  2010;146(10):1105-1110.
Objectives
To evaluate vitamin D status in patients with basal cell nevus syndrome (BCNS) who practice photo-protection because of their genetic predisposition to skin cancer and to determine risk factors for deficiency.
Design
Retrospective cohort study.
Setting
Academic medical centers.
Patients
Forty-one ambulatory patients with BCNS who participated in a 2-year chemoprevention clinical trial. Population-based controls (n=360) were selected and matched by age, sex, Fitzpatrick skin type, and season/geography.
Main Outcome Measures
Levels of 25-hydroxy-vitamin D (25[OH]D) and vitamin D deficiency (defined as a 25[OH]D level of ≤20 ng/mL).
Results
Twenty-three patients with BCNS (56%) were vitamin D deficient. Patients with BCNS had mean 25(OH)D levels below those of the general population (−3 ng/mL; P=.02) and were 3 times more likely to be vitamin D deficient (56% vs 18%; P<.001). Levels of 25(OH)D were lower in patients who were overweight (−3.0 ng/mL; P=.04) and who had blood collected in the winter compared with the summer (−7.1 ng/mL; P<.001).
Conclusion
Patients with BCNS may be at increased risk for vitamin D deficiency, depending on their adherence to photoprotection practices.
doi:10.1001/archdermatol.2010.247
PMCID: PMC3775573  PMID: 20956641
23.  Systemic immune suppression as a stage-independent predictor of diminished Merkel cell carcinoma-specific survival 
Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy linked to a contributory virus (Merkel cell polyomavirus/MCPyV). Multiple epidemiologic studies have established an increased incidence of MCC among persons with systemic immune suppression. Several forms of immune suppression are associated with increased MCC incidence, including hematologic malignancies, HIV/AIDS, and immunosuppressive medications for autoimmune disease or transplant. Indeed, immune suppressed persons represent approximately 10% of the MCC patients, a significant over-representation relative to the general population. We hypothesized that immune suppressed patients may have a poorer MCC-specific prognosis and examined a cohort of 471 patients with a combined follow-up of 1427 years (median 2.1 years). Immune suppressed persons (n=41) demonstrated reduced MCC-specific survival (40% at 3 years) compared to persons with no known systemic immune suppression (n=430; 74% MCC-specific survival at 3 years). By competing risk regression analysis, immune suppression was a stage-independent predictor of worsened MCC-specific survival (hazard ratio 3.8, p < 0.01). Immune-suppressed persons thus have both an increased chance of developing MCC and poorer MCC-specific survival. It may be appropriate to follow these higher-risk individuals more closely, and, when clinically feasible, there may be benefit of diminishing iatrogenic systemic immune suppression.
doi:10.1038/jid.2012.388
PMCID: PMC3570636  PMID: 23190897
24.  Vitamin D in cutaneous carcinogenesis Part II 
The role of vitamin D in health maintenance and disease prevention in fields ranging from bone metabolism to cancer is currently under intensive investigation. A number of epidemiologic studies have suggested that vitamin D may have a protective effect on cancer risk and cancer-associated mortality. With regard to skin cancer, epidemiologic and laboratory studies suggest that vitamin D and its metabolites may have a similar risk reducing effect. Potential mechanisms of action include inhibition of the hedgehog signaling pathway and upregulation of nucleotide excision repair enzymes. The key factor complicating the association between vitamin D and skin cancer is ultraviolet B radiation. The same spectrum of ultraviolet B radiation that catalyzes the production of vitamin D in the skin also causes DNA damage that can lead to epidermal malignancies. Part II of this continuing medical education article will summarize the literature on vitamin D and skin cancer to identify evidence-based optimal serum levels of vitamin D and to recommend ways of achieving those levels while minimizing the risk of skin cancer.
doi:10.1016/j.jaad.2012.07.022
PMCID: PMC3706259  PMID: 23062904
25(OH)D levels; basal cell carcinoma; melanoma; nonmelanoma skin cancer; vitamin D; vitamin D receptor; squamous cell carcinoma; sunlight
25.  Vitamin D in cutaneous carcinogenesis: Part I 
Skin cancer is the most common cancer in the United States. Exposure to ultraviolet radiation is a known risk factor for skin cancer but is also the principal means by which the body obtains vitamin D. Several studies have suggested that vitamin D plays a protective role in a variety of internal malignancies. With regard to skin cancer, epidemiologic and laboratory studies suggest that vitamin D and its metabolites may have a similar protective effect. These noncalcemic actions of vitamin D have called into question whether the current recommended intake of vitamin D is too low for optimal health and cancer prevention. Part I will review the role of vitamin D in the epidermis; part II will review the role of vitamin D in keratinocyte-derived tumors to help frame the discussion on the possible role of vitamin D in the prevention of skin cancer.
doi:10.1016/j.jaad.2012.05.044
PMCID: PMC3688468  PMID: 23062903
25(OH)D levels; cholecalciferol; supplements; vitamin D; ultraviolet radiation

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