Urinary mutagenicity and bladder cancer risk in northern New England.

The etiology of bladder cancer among never smokers without occupational or environmental exposure to established urothelial carcinogens remains unclear. Urinary mutagenicity is an integrative measure that reflects recent exposure to genotoxic agents. Here, we investigated its potential association with bladder cancer in rural northern New England. We analyzed 156 bladder cancer cases and 247 cancer-free controls from a large population-based case-control study conducted in Maine, New Hampshire, and Vermont. Overnight urine samples were deconjugated enzymatically and the extracted organics were assessed for mutagenicity using the plate-incorporation Ames assay with the Salmonella frameshift strain YG1041 + S9. Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer in relation to having mutagenic versus nonmutagenic urine, adjusted for age, sex, and state, and stratified by smoking status (never, former, and current). We found evidence for an association between having mutagenic urine and increased bladder cancer risk among never smokers (OR = 3.8, 95% CI: 1.3-11.2) but not among former or current smokers. Risk could not be estimated among current smokers because nearly all cases and controls had mutagenic urine. Urinary mutagenicity among never-smoking controls could not be explained by recent exposure to established occupational and environmental mutagenic bladder carcinogens evaluated in our study. Our findings suggest that among never smokers, urinary mutagenicity potentially reflects genotoxic exposure profiles relevant to bladder carcinogenesis. Future studies are needed to replicate our findings and identify compounds and their sources that influence bladder cancer risk.

Urine pH and Risk of Bladder Cancer in Northern New England.

BACKGROUND: Acidic urine pH is associated with rapid hydrolysis of N-glucuronide conjugates of aromatic amines into metabolites that may undergo metabolism in the bladder lumen to form mutagenic DNA adducts. We previously reported that consistently acidic urine was associated with increased bladder cancer risk in a hospital-based case-control study in Spain. Here, we conducted a separate study in northern New England to replicate these findings. METHODS: In a large, population-based case-control study conducted in Maine, New Hampshire, and Vermont, we examined bladder cancer risk in relation to consistent urine pH, measured twice daily by participants over 4 consecutive days using dipsticks. In parallel, we collected spot urine samples and conducted laboratory measurements of urinary acidity using a pH meter. Unconditional logistic regression was used to estimate associations, adjusting for age, gender, race, Hispanic status, and state. Analyses were further stratified by smoking status. RESULTS: Among 616 urothelial carcinoma cases and 897 controls, urine pH consistently ≤ 6.0 was associated with increased bladder cancer risk (OR = 1.27; 95% confidence interval, 1.02-1.57), with the effect limited to ever-smokers. These findings were supported by analyses of a spot urine, with statistically significant exposure-response relationships for bladder cancer risk overall (Ptrend = 5.1×10-3) and among ever-smokers (Ptrend = 1.2×10-3). CONCLUSIONS: Consistent with a previous study in Spain, our findings suggest that acidic urine pH is associated with increased bladder cancer risk. IMPACT: Our findings align with experimental results showing that acidic urine pH, which is partly modifiable by lifestyle factors, is linked to hydrolysis of acid-labile conjugates of carcinogenic aromatic amines.

Spectrum of diseases associated with pyoderma gangrenosum and correlation with effectiveness of therapy: New insights on the diagnosis and therapy of comorbid hidradenitis suppurativa.

Pyoderma gangrenosum (PG) has been linked to various underlying systemic diseases; many associations are based on case reports or small case series, including hidradenitis suppurativa. Literature examining systemic therapies according to underlying comorbid condition is limited. The study objective was to investigate comorbid diseases of PG and correlate disease associations with effectiveness of therapeutic interventions. Using Johns Hopkins Medical Institutions medical records, 220 patients had an ICD-9 code of 686.01 for PG between 1 January 2006 and 30 June 2015, of whom 130 patients met rigorous inclusion/exclusion criteria for PG (non-peristomal). The 130 PG patients in our study were 69% female, 58% Caucasian, and 35% African American. Documented comorbid conditions included inflammatory bowel disease (IBD; 35%), rheumatoid arthritis (RA; 12%), hidradenitis suppurativa (HS; 14%), and monoclonal gammopathy (12%). PG patients with HS versus without HS were more likely to be African-American (83% vs. 28%; P < 0.001) and had an earlier mean age of PG onset (38 vs. 48 years; P = 0.02). Strikingly, 53% of female African-American patients with PG onset prior to age 40 had comorbid HS. Comorbid inflammatory bowel disease was observed in 38% of PG patients with RA, 28% of PG patients with HS, and 27% of PG patients with monoclonal gammopathy. Of the 32 patients who received infliximab for active PG, complete ulcer healing was observed in 83% (5/6) of patients with comorbid HS versus 31% (8/26) of patients without HS (Fisher exact P = 0.03). Screening patients for associated systemic disease for multiple related illnesses is essential. Effectiveness of systemic therapy may depend upon the underlying systemic disease; hidradenitis suppurativa may be a specific example.

Periocular Dark Circles: Correlates of Severity.

BACKGROUND: Periocular dark circles (PDCs) are a common cosmetic complaint. Grading systems based on objective measures have been used but no standard system is in place. OBJECTIVE: To determine factors associated with subjective and objective PDC severity. METHODS: Enrolled patients (n=100) completed a questionnaire comprised of demographic variables, medical history, and self-perception of PDC. Those perceiving PDC graded dissatisfaction on a 10-point scale. Clinical severity (grades 0~4) and subtype (constitutional, post-inflammatory, vascular, shadow effects, or others) were determined. A Konica Minolta CR-400 chromameter was used to obtain colorimetry measurements (L*a*b* values). The objective average difference in darkness (ΔL*) between the periocular region and the cheek was determined. Comparisons were made using Spearman correlation coefficients (r). RESULTS: Patient dissatisfaction correlated with both clinical severity (r=0.46, p<0.001) and the ΔL* by colorimetry (r=0.35, p=0.004). Factors associated with subjective dissatisfaction were female sex (r=0.38, p=0.002), higher Fitzpatrick skin type (r=0.42, p=0.001), fewer hours of sleep (r=-0.28, p=0.03), and use of concealer (r=0.35, p=0.004). Factors associated with objective measures were higher Fitzpatrick skin type (r=0.36, p=0.0007 and r=0.28, p=0.009, respectively), family history of PDC (r=0.34, p<0.001 and r=0.20, p=0.05), and history of eczema (r=0.45, p<0.001 and r=0.20, p=0.0504). Clinical severity grading correlated with colorimetric severity (r=0.36, p=0.0003). CONCLUSION: Overall, subjective dissatisfaction was associated with clinical severity. However, factors associated with subjective severity did not necessarily overlap with factors associated with objective severity. These findings highlight the importance of patient-reported grading. There may be added value in incorporating a component of subjective grading into the traditionally objective PDC grading scales.

Characterization and Analysis of the Skin Microbiota in Rosacea: A Case-Control Study.

BACKGROUND: The efficacy of antibiotics in rosacea treatment suggests a role for microorganisms in its pathophysiology. Growing concern over the adverse effects of antibiotic use presents a need for targeted antimicrobial treatment in rosacea. OBJECTIVE: We performed a case-control study to investigate the skin microbiota in patients with rosacea compared to controls matched by age, sex, and race. METHODS: Nineteen participants with rosacea, erythematotelangiectatic, papulopustular, or both, were matched to 19 rosacea-free controls. DNA was extracted from skin swabs of the nose and bilateral cheeks of participants. Sequencing of the V3V4 region of the bacterial 16S ribosomal RNA gene was performed using Illumina MiSeq and analyzed using QIIME/MetaStats 2.0 software. RESULTS: Compared with controls, skin microbiota in erythematotelangiectatic rosacea was depleted in Roseomonas mucosa (p = 0.004). Papulopustular rosacea was enriched in Campylobacter ureolyticus (p = 0.001), Corynebacterium kroppenstedtii (p = 0.008), and the oral flora Prevotella intermedia (p = 0.001). The highest relative abundance of C. kroppenstedtii was observed in patients with both erythematotelangiectatic and papulopustular rosacea (19.2%), followed by papulopustular (5.06%) and erythematotelangiectatic (1.21%) rosacea. C. kroppenstedtii was also associated with more extensive disease, with the highest relative abundance in rosacea affecting both the cheeks and nose (2.82%), followed by rosacea sparing the nose (1.93%), and controls (0.19%). CONCLUSIONS: The skin microbiota in individuals with rosacea displays changes from that of healthy skin, suggesting that further studies examining a potential role for the skin microbiota in the pathophysiology of rosacea may be warranted.

Adapalene 0.3% Gel Shows Efficacy for the Treatment of Atrophic Acne Scars.

INTRODUCTION: Scarring is an unfortunate clinical outcome of acne. Current treatment options for atrophic acne scars are dominated by non-pharmacological, invasive procedures which may not be suitable or affordable to all patients. This phase II, single-center, open-label, exploratory study assessed the efficacy, safety and subject-reported outcomes of adapalene 0.3% gel in the treatment of atrophic acne scars. METHODS: The study included subjects aged 18-50 years with past history of acne and moderate to severe facial atrophic acne scars. Subjects received adapalene 0.3% gel once daily for the first 4 weeks and twice daily for the following 20 weeks. Assessments were performed at baseline, day 10 and weeks 4, 8, 16 and 24, and at post-treatment follow-ups (weeks 36 and 48-72). RESULTS: At week 24, investigator and subject assessments reported improvement in skin texture/atrophic scars in 50% and > 80% of subjects, respectively. Subjects were satisfied with the treatment and reported improvements in quality of life. CONCLUSION: Daily use of adapalene 0.3% gel for the treatment of atrophic acne scars showed promising clinical efficacy, a favorable tolerability profile, and improvement in quality of life. FUNDING: Nestlé Skin Health-Galderma R&D. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01213199.

Racial and ethnic differences in health care utilization for childhood eczema: An analysis of the 2001-2013 Medical Expenditure Panel Surveys.

BACKGROUND: Eczema is a common chronic inflammatory disease of the skin. Studies suggest differences in disease prevalence and severity by race/ethnicity. Our knowledge of health care utilization for eczema among different racial/ethnic groups remains limited. OBJECTIVE: To evaluate health care utilization for childhood eczema among different racial/ethnic groups in the United States. METHODS: We performed a cohort study of non-Hispanic white (reference), non-Hispanic black, and Hispanic white individuals under the age of 18 years with caregiver-reported eczema (N = 2043) pooled from the 2-year longitudinal cohorts of the 2001-2013 Medical Expenditure Panel Surveys. Health care utilization outcomes were evaluated over the 2-year follow-up period by race/ethnicity using multivariable regression. RESULTS: Among all children with eczema, non-Hispanic blacks were less likely than whites to report an ambulatory visit for eczema (adjusted odds ratio [ORadj] 0.69; 95% confidence interval [CI] 0.51-0.92). Among those with ≥1 ambulatory visit for eczema, non-Hispanic blacks reported more visits (adjusted incidence rate ratio [IRRadj] 1.68; 95% CI 1.10-2.55) and prescriptions (IRRadj 1.22; 95% CI 1.01-1.46) than whites and were more likely than whites to report a dermatology visit (ORadj 1.82; 95% CI 1.06-3.14) for eczema. LIMITATIONS: We used caregiver- or self-reported data. CONCLUSION: Our findings suggest disparities in health care utilization for eczema among non-Hispanic black children despite utilization patterns suggestive of more severe disease.

Research Techniques Made Simple: Choosing Appropriate Statistical Methods for Clinical Research.

The statistical significance of results is an important component to drawing appropriate conclusions in a study. Choosing the correct statistical test to analyze results is essential in interpreting the validity of the study and centers on defining the study variables and purpose of the analysis. The complexity of statistical modeling makes this a daunting task, so we propose a basic algorithmic approach as an initial step in determining what statistical method will be appropriate for a particular clinical study.

Melanoma subtypes demonstrate distinct PD-L1 expression profiles.

PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-γ-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n=16), mucosal (n=36), uveal (n=103), and chronic sun-damaged (CSD) (n=45) melanomas (24 lentigo maligna, 13 'mixed' desmoplastic, and 8 'pure' desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P<0.0001). Compared to our previously characterized cohort of cutaneous melanomas, the proportion of PD-L1(+) tumors was lower in uveal (P=0.0002) and higher in CSD (P=0.0073) melanomas, while PD-L1 expression in the acral and mucosal subtypes was on par. PD-L1 expression in all subtypes correlated with a moderate-severe grade of CD8+ TIL (all, P<0.003), supporting an adaptive mechanism of expression induced during the host antitumor response. The tumor microenvironments observed in CSD melanomas segregated by whether they were the pure desmoplastic subtype, which showed lower levels of PD-L1 expression when compared to other CSD melanomas (P=0.047). The presence of lymphoid aggregates was not associated with the level of PD-L1 expression, while PD-L1(+) cases with spindle cell morphology demonstrated higher levels of PD-L1 than those with a nested phenotype (P<0.0001). Our findings may underpin the reported clinical response rates for anti-PD-1 monotherapy, which vary by subtype.

Patterns of antimicrobial resistance in lesions of hidradenitis suppurativa.

BACKGROUND: Antibiotic therapy is commonly used to treat hidradenitis suppurativa (HS). Although concern for antibiotic resistance exists, data examining the association between antibiotics and antimicrobial resistance in HS lesions are limited. OBJECTIVE: We sought to determine the frequency of antimicrobial resistance in HS lesions from patients on antibiotic therapy. METHODOLOGY: A cross-sectional analysis was conducted on 239 patients with HS seen at the Johns Hopkins Medical Institutions from 2010 through 2015. RESULTS: Patients using topical clindamycin were more likely to grow clindamycin-resistant Staphylococcus aureus compared with patients using no antibiotics (63% vs 17%; P = .03). Patients taking ciprofloxacin were more likely to grow ciprofloxacin-resistant methicillin-resistant S aureus compared with patients using no antibiotics (100% vs 10%; P = .045). Patients taking trimethoprim/sulfamethoxazole were more likely to grow trimethoprim/sulfamethoxazole-resistant Proteus species compared with patients using no antibiotics (88% vs 0%; P < .001). No significant antimicrobial resistance was observed with tetracyclines or oral clindamycin. LIMITATIONS: Data on disease characteristics and antimicrobial susceptibilities for certain bacteria were limited. CONCLUSIONS: Antibiotic therapy for HS treatment may be inducing antibiotic resistance. These findings highlight the importance of stewardship in antibiotic therapy for HS and raise questions regarding the balance of antibiotic use versus potential harms associated with antibiotic resistance.

Association of Indoor Tanning Frequency With Risky Sun Protection Practices and Skin Cancer Screening.

IMPORTANCE: Indoor tanning is prevalent among young adults and women and is associated with increased risk of melanoma. Evidence suggests that indoor tanners may be more inclined to adopt poor photoprotective practices that further increase their risk of skin cancer; however, gaps in the literature exist in young adults and by indoor tanning frequency. OBJECTIVE: To examine the association between indoor tanning frequency and behaviors related to skin cancer prevention and to investigate whether these associations vary by age group or sex. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional population-based study of US 2015 National Health Interview Survey data including 10 262 non-Hispanic white adults aged 18 to 60 years without a history of skin cancer. MAIN OUTCOMES AND MEASURES: Rare/never use of sunscreen, protective clothing, shade; multiple sunburns within the past year; previous full-body skin examination. RESULTS: Of the 10 262 individuals in our study population (49% female; median age, 39 y), 787 (7.0%) reported having tanned indoors in the past year. Among individuals aged 18 to 34 years, frequent indoor tanners (≥10 times in the past year) were more likely to report never/rare use of protective clothing (adjusted prevalence ratio [aPR], 1.28; 95% CI, 1.10-1.49) and shade (aPR, 1.32; 95% CI, 1.03-1.70), compared with individuals who did not tan indoors. Among women aged 18 to 60 years, those who frequently tanned indoors were more likely to rarely/never use sunscreen (aPR, 1.34; 95% CI, 1.11-1.62), protective clothing (aPR, 1.27; 95% CI, 1.15-1.42), and shade (aPR, 1.54; 95% CI, 1.25-1.90) on a warm sunny day, as well as more likely to report multiple sunburns in the past year (aPR, 1.21; 95% CI, 1.00-1.45) compared with those who did not tan indoors. Individuals who tanned indoors in the past year were not significantly more likely to have undergone a previous full-body skin examination in any subpopulation examined. CONCLUSIONS AND RELEVANCE: Individuals who tan indoors often exhibited a concurrent tendency to sunburn, avoid sun protection, and avoid skin cancer screening. Thus, the findings highlight that in addition to tanning bed avoidance, it is critical to emphasize sun protection and skin cancer screening in individuals who tan indoors.

Squamous cell carcinoma complicating a chronic lesion of hidradenitis suppurativa: a case report and review of the literature.

Squamous cell carcinoma (SCC) arising from chronic hidradenitis suppurativa (HS) is rare; however, the morbidity associated with this presentation is high and management has not been standardised or optimised. We present a case of HS of the perineum and buttocks complicated by SCC, requiring multiple extensive surgical resections. Adjuvant radiotherapy was withheld initially because of concern for poor healing of the surgical wound but was eventually initiated after a second recurrence was identified. The patient ultimately expired 4 years after the initial diagnosis of SCC. We also review 80 cases of SCC complicating HS found in the English literature. Case reports and mechanistic studies suggest the possibility that human papilloma virus and smoking may be risk factors associated with SCC in HS. Despite the majority of SCC cases being well-differentiated tumours in HS, the highly aggressive nature of SCC in HS and its high likelihood for rapid progression, recurrence, metastasis and high mortality suggests the need to advocate for aggressive treatment. We recommend an aggressive approach to management at the time of SCC diagnosis in HS, which includes appropriate imaging to establish the extent of the tumour, large and deep surgical excision, sentinel lymph node evaluation, consultation with radiation oncology for potential adjuvant radiation therapy and close surveillance.

Pigmentation in African American skin decreases with skin aging.

BACKGROUND: Tristimulus colorimetry, which uses the Commission Internationale de l'Eclairage L*a*b* model to quantify color, has previously been used to analyze pigmentation and erythema in human skin; however, colorimetry of African American skin is not well characterized. OBJECTIVE: We sought to analyze skin color patterns in African Americans and compare them with those of Caucasians. METHODS: Colorimetry readings of the sun-protected buttock and sun-exposed back of forearm were taken from 40 Caucasian and 43 African American participants from March 2011 through August 2015. African American participants also completed a lifestyle questionnaire. Correlation coefficients, paired t tests, and multivariable linear regression analyses were used for statistical comparisons. RESULTS: Forearm skin was lighter in African Americans ages 65 years and older versus 18 to 30 years (P = .02) but darker in Caucasians ages 65 years or older versus 18 to 30 years (P = .03). In African Americans ages 18 to 30 years, the buttock was darker than the forearm (P < .001), whereas in Caucasians the buttock was lighter than the forearm (P < .001). A lighter forearm than buttock was correlated with supplement use, smoking (ages 18-30 years), and less recreational sun exposure (ages ≥65 years) in African Americans. LIMITATIONS: Our study was limited by the sample size and focal geographic source. CONCLUSIONS: Pigmentation patterns regarding sun-protected and sun-exposed areas in African Americans may differ from that of Caucasians, suggesting that other factors may contribute to skin pigmentation in African Americans.

Sunburn and sun-protective behaviors among adults with and without previous nonmelanoma skin cancer (NMSC): A population-based study.

BACKGROUND: Individuals with previous nonmelanoma skin cancer (NMSC) are at increased risk for subsequent skin cancer, and should therefore limit ultraviolet exposure. OBJECTIVE: We sought to determine whether individuals with previous NMSC engage in better sun protection than those with no skin cancer history. METHODS: We pooled self-reported data (2005 and 2010 National Health Interview Surveys) from US non-Hispanic white adults (758 with and 34,161 without previous NMSC). We calculated adjusted prevalence odds ratios (aPOR) and 95% confidence intervals (CI), taking into account the complex survey design. RESULTS: Individuals with previous NMSC versus no history of NMSC had higher rates of frequent use of shade (44.3% vs 27.0%; aPOR 1.41; 95% CI 1.16-1.71), long sleeves (20.5% vs 7.7%; aPOR 1.55; 95% CI 1.21-1.98), a wide-brimmed hat (26.1% vs 10.5%; aPOR 1.52; 95% CI 1.24-1.87), and sunscreen (53.7% vs 33.1%; aPOR 2.11; 95% CI 1.73-2.59), but did not have significantly lower odds of recent sunburn (29.7% vs 40.7%; aPOR 0.95; 95% CI 0.77-1.17). Among those with previous NMSC, recent sunburn was inversely associated with age, sun avoidance, and shade but not sunscreen. LIMITATIONS: Self-reported cross-sectional data and unavailable information quantifying regular sun exposure are limitations. CONCLUSION: Physicians should emphasize sunburn prevention when counseling patients with previous NMSC, especially younger adults, focusing on shade and sun avoidance over sunscreen.

Rosacea is associated with chronic systemic diseases in a skin severity-dependent manner: results of a case-control study.

BACKGROUND: Rosacea is a common chronic inflammatory dermatosis of unclear origin. It has been associated with systemic comorbidities, but methodical studies addressing this association are lacking. OBJECTIVE: We evaluated: (1) the association between rosacea and systemic comorbidities; and (2) if the severity of rosacea is impacted by comorbidities. METHODS: This was a case-control study: patients with rosacea were matched (1:1) to rosacea-free control subjects by age, sex, and race. Relative risk estimates were calculated using logistic regression as odds ratios with 95% confidence intervals. RESULTS: Among 130 participants (65 patients/65 control subjects), we observed a significant association between rosacea and allergies (airborne, food), respiratory diseases, gastroesophageal reflux disease, other gastrointestinal diseases, hypertension, metabolic and urogenital diseases, and female hormone imbalance. Compared with mild rosacea, moderate to severe rosacea was significantly associated with hyperlipidemia, hypertension, metabolic diseases, cardiovascular diseases, and gastroesophageal reflux disease. LIMITATIONS: This was a case-control study with moderate sample size. Associated medical conditions were self-reported and could not always be confirmed by medication use and medical records. CONCLUSIONS: Rosacea is associated with numerous systemic comorbid diseases in a skin severity-dependent manner. Physicians should be aware of these associations to provide comprehensive care to patients with rosacea, especially to those with more severe disease.

Is a personal history of nonmelanoma skin cancer associated with increased or decreased risk of other cancers?

Two conflicting hypotheses have been tested concerning the association between a personal history of nonmelanoma skin cancer (NMSC) and risk of other malignancies. One hypothesis is that as a marker of extensive sunlight exposure and hence vitamin D status, NMSC should be inversely associated with risk of other cancers. Alternatively, under the multiple primary cancer model, NMSC is postulated to be an informative first cancer to study as a marker of increased risk of subsequent primary cancer diagnoses. In this journal issue, Ong and colleagues report the results of a large-scale study in the United Kingdom with findings that NMSC was significantly associated with increased risk of a broad spectrum of other malignancies, with the associations stronger the younger the age of onset of NMSC. These results are consistent with the larger body of evidence on this topic, which is highly asymmetrical in favor of the multiple primary cancer hypothesis. Two divergent hypotheses have been tested, with the empirical evidence unequivocally indicating that NMSC is a marker of a high cancer risk phenotype. Future research is warranted to better characterize this association, to understand why NMSC is a marker of excess risk of other cancers, and to determine whether this association is clinically relevant.

Nonsteroidal anti-inflammatory drugs and other analgesic use and bladder cancer in northern New England.

A few epidemiologic studies have found that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of bladder cancer. However, the effects of specific NSAID use and individual variability in risk have not been well studied. We examined the association between NSAIDs use and bladder cancer risk, and its modification by 39 candidate genes related to NSAID metabolism. A population-based case-control study was conducted in northern New England, enrolling 1,171 newly diagnosed cases and 1,418 controls. Regular use of nonaspirin, nonselective NSAIDs was associated with reduced bladder cancer risk, with a statistically significant inverse trend in risk with duration of use (ORs of 1.0, 0.8, 0.6 and 0.6 for <5, 5-9, 10-19 and 20+ years, respectively; p(trend) = 0.015). This association was driven mainly by ibuprofen; significant inverse trends in risk with increasing duration and dose of ibuprofen were observed (p(trend) = 0.009 and 0.054, respectively). The reduced risk from ibuprofen use was limited to individuals carrying the T allele of a single nucleotide polymorphism (rs4646450) compared to those who did not use ibuprofen and did not carry the T allele in the CYP3A locus, providing new evidence that this association might be modified by polymorphisms in genes that metabolize ibuprofen. Significant positive trends in risk with increasing duration and cumulative dose of selective cyclooxygenase (COX-2) inhibitors were observed. Our results are consistent with those from previous studies linking use of NSAIDs, particularly ibuprofen, with reduced risk. We observed a previously unrecognized risk associated with use of COX-2 inhibitors, which merits further evaluation.