Mitochondrial DNA sequence variation and risk of glioma.

BACKGROUND: Malignant gliomas are the most common primary adult brain tumors, with a poor prognosis and ill-defined etiology. Mitochondrial DNA (mtDNA) sequence variation has been linked with certain cancers; however, research on glioma is lacking. METHODS: We examined the association of common (minor allele frequency ≥ 5%) germline mtDNA variants and haplogroups with glioma risk in 1,566 glioma cases and 1,017 controls from a US case-control study, and 425 glioma cases and 1,534 matched controls from the UK Biobank cohort (UKB). DNA samples were genotyped using the UK Biobank array that included a set of common and rare mtDNA variants. Risk associations were examined separately for glioblastoma (GBM) and lower grade tumors (non-GBM). RESULTS: In the US study, haplogroup W was inversely associated with glioma when compared with haplogroup H (OR = 0.43, 95%CI: 0.23-0.79); this association was not demonstrated in the UKB (OR = 1.07, 95%CI: 0.47-2.43). In the UKB, the variant m.3010G > A was significantly associated with GBM (OR = 1.32; 95%CI: 1.01-1.73; p = 0.04), but not non-GBM (1.23; 95%CI: 0.78-1.95; p = 0.38); no similar association was observed in the US study. In the US study, the variant m.14798 T > C, was significantly associated with non-GBM (OR = 0.72; 95%CI: 0.53-0.99), but not GBM (OR = 0.86; 95%CI: 0.66-1.11), whereas in the UKB, a positive association was observed between this variant and GBM (OR = 1.46; 95%CI: 1.06-2.02) but not non-GBM (OR = 0.92; 95%CI: 0.52-1.63). None of these associations were significant after adjustment for multiple testing. CONCLUSION: The association of inherited mtDNA variation, including rare and singleton variants, with glioma risk merits further study.

A prospective study of pre-diagnostic circulating tryptophan and kynurenine, and the kynurenine/tryptophan ratio and risk of glioma.

BACKGROUND: Conversion of tryptophan to kynurenine may promote glioma growth and suppress antitumor immune response through activation of the aryl hydrocarbon receptor. Expression of the enzymes indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase-2 in the glioma microenvironment has been shown to mediate tryptophan catabolism, and the ratio between kynurenine and tryptophan is considered an indirect measure of this enzyme activity. METHODS: We explored whether tryptophan, kynurenine, and the ratio of kynurenine to tryptophan (KTR) in pre-diagnostic blood samples was related to risk of glioma in a nested case-control study of 84 cases and 168 matched controls from two cohort studies - the Nurses' Health Study, and the Health Professionals Follow-Up Study. Tryptophan and kynurenine were measured by liquid chromatography-tandem mass spectrometry. Conditional logistic regression models were used to estimate risk ratios (RRs) and 95% confidence intervals (95%CI) for the associations between tertiles of these analytes and glioma risk. RESULTS: We observed no significant associations for either analyte or the ratio for risk of glioma overall. The RR for the highest KTR tertile compared to the lowest for all gliomas was 0.74 (95% CI: 0.34-1.59). All results were essentially unchanged in lagged analyses excluding the first two or four years of follow up, though data were sparse. CONCLUSION: Our findings do not provide support for an association between pre-diagnostic circulating KTR and risk of glioma.

Mitochondrial DNA sequence variation and risk of meningioma.

BACKGROUND: Risk factors for meningioma include female gender, African American race, high body mass index (BMI), and exposure to ionizing radiation. Although genome-wide association studies (GWAS) have identified two nuclear genome risk loci for meningioma (rs12770228 and rs2686876), the relation between mitochondrial DNA (mtDNA) sequence variants and meningioma is unknown. METHODS: We examined the association of 42 common germline mtDNA variants (minor allele frequency ≥ 5%), haplogroups, and genes with meningioma in 1080 controls and 478 meningioma cases from a case-control study conducted at medical centers in the southeastern United States. Associations were examined separately for meningioma overall and by WHO grade (n = 409 grade I and n = 69 grade II/III). RESULTS: Overall, meningioma was significantly associated with being female (OR 2.85; 95% CI 2.21-3.69), self-reported African American race (OR 2.38, 95% CI 1.41-3.99), and being overweight (OR 1.48; 95% CI 1.11-1.97) or obese (OR 1.70; 95% CI 1.25-2.31). The variant m.16362T > C (rs62581341) in the mitochondrial control region was positively associated with grade II/III meningiomas (OR 2.33; 95% CI 1.14-4.77), but not grade I tumors (OR 0.99; 95% CI 0.64-1.53). Haplogroup L, a marker for African ancestry, was associated with meningioma overall (OR 2.92; 95% CI 1.01-8.44). However, after stratifying by self-reported race, this association was only apparent among the few self-reported Caucasians with this haplogroup (OR 6.35; 95% CI 1.56-25.9). No other mtDNA variant, haplogroup, or gene was associated with meningioma. CONCLUSION: Common mtDNA variants and major mtDNA haplogroups do not appear to have associations with the odds of developing meningioma.

A prospective study of inflammatory biomarkers and growth factors and risk of glioma in the UK Biobank.

PURPOSE: The role of growth factors and inflammation in the onset of glioma is poorly understood, and conflicting reports of associations of circulating IGF-1 and inflammatory biomarkers with glioma risk exist in the literature. We examined associations between C-reactive protein (CRP), white blood cell count (WBC), neutrophil-to-lymphocyte ratio (NLR), and insulin-like growth factor-1 (IGF-1) and glioma risk in the UK Biobank cohort. METHODS: Hazard ratios (HR) and 95% confidence intervals (CI) for glioma according to circulating biomarkers concentrations were calculated using Cox proportional hazards regression, adjusted for age, sex, race, and education. Analyses were conducted separately for glioma overall and by glioma subtype. RESULTS: We identified 417 incident glioma cases among 428,537 participants with 3,255,815 person-years of follow up. Weak, non-significant associations were observed with increasing levels of these biomarkers for risk of glioma overall or by glioma subtype. Among women only, IGF-1 in the highest quartile was positively associated with glioma risk compared to the lowest quartile (HR=1.64, 95%CI: 1.03-2.60, p-trend=0.08), as was NLR (HR=1.54, 95%CI: 1.00-2.39, p-trend=0.05). CONCLUSION: In this prospective cohort, we found no significant associations between the inflammatory biomarkers CRP and WBC and the development of glioma. NLR and IGF-1 were associated with risk in women, but not men. When considered with previous studies, further investigation of NLR and IGF-1 as markers of glioma risk appears warranted, particularly in women.

Alcohol intake and risk of glioma: results from three prospective cohort studies.

PURPOSE: The association between alcohol intake and glioma remains unclear. We evaluated the association between alcohol intake and incidence of glioma in three large, prospective cohort studies with repeated alcohol assessments. METHODS: We harnessed data from three studies with repeat alcohol assessment to compute hazard ratios (HR) and 95% confidence intervals (CI) for glioma by overall alcohol intake and intake from specific beverages using Cox proportional hazards regression, adjusted for age, cohort, body mass index, smoking status, and caloric intake. Analyses were conducted separately for glioma overall and for glioblastoma (GBM). RESULTS: We confirmed 554 incident glioma cases (362 GBM) among 237,505 participants with 6,216,378 person-years of follow up. Cumulative average alcohol intake was associated with reduced risk of glioma (HR = 0.75, 95%CI:0.56-0.99 comparing > 8-15 to ≤ 0.5 g/d; HR = 0.71, 95%CI:0.53-0.96 comparing > 15 g/d to ≤ 0.5 g/d). When stratified by sex, for the same comparisons, the HRs for men were 0.57 (95%CI:0.36-0.89) and 0.79 (0.53-1.16), and for women 0.90 (95%CI:0.62-1.30) and 0.62, 95%CI:0.39-0.97. Results were consistent when examining cumulative average, baseline, and recent intake, and with a 4 year lag. CONCLUSION: These results provide evidence against a positive association between alcohol intake and glioma risk. Alcohol intake was associated with reduced risk of glioma in both men and women.

Prospective study of sleep duration and glioma risk.

PURPOSE: Both long and short sleep duration have been linked with risk of some cancers, but evidence for glioma is lacking. METHODS: Using prospective data from the UK Biobank (UKB), the Nurses' Health Study (NHS), and the Health Professionals Follow-Up Study (HPFS), we examined the association between self-reported hours of sleep and incident glioma in multivariable-adjusted Cox proportional hazards models. RESULTS: In the UKB, compared to 7 h, sleep durations of < 7 h (HR = 0.90; 95% CI 0.70-1.16) or > 7 h (HR = 1.05; 95% CI 0.85-1.30) were not significantly associated with glioma risk. Likewise, no significant associations were found between sleep duration and glioma risk in the NHS/HPFS for either < 7 h (HR = 0.93; 95% CI 0.69-1.26) or > 7 h (HR = 1.22; 95% CI 0.94-1.57), compared to 7 h. Results were similar for low-grade and high-grade glioma, did not materially change after lagging 2 years, or after accounting for factors known to disrupt sleep. CONCLUSION: Sleep duration was not associated with incident glioma in either the UKB or the NHS/HPFS cohorts.

Prevalence of Self-Reported Hypertension and Antihypertensive Medication Use by County and Rural-Urban Classification - United States, 2017.

In 2017, approximately one in three U.S. adults reported having been told by a health care professional that they had high blood pressure (hypertension) (1). Although hypertension prevalence is well documented at national and state levels, less is known about rural-urban variation and county-level prevalence. To examine prevalence of self-reported hypertension and antihypertensive medication use by rural-urban classification and county, CDC analyzed data reported by 442,641 adults aged ≥18 years who participated in the 2017 Behavioral Risk Factor Surveillance System (BRFSS). In rural (noncore) areas, 40.0% (unadjusted prevalence) of adults reported having hypertension, whereas in the most urban (large central metro) areas, 29.4% reported having hypertension. Age-standardized hypertension prevalence was significantly higher in the most rural areas, compared with the most urban areas within nearly all categories of age, sex, and other demographic characteristics. Model-based hypertension prevalence across counties ranged from 18.0% to 55.0% and was highest in Southeastern* and Appalachian† counties. Model-based county-level prevalence of antihypertensive medication use among adults with hypertension ranged from 54.3% to 84.7%. Medication use also was higher in rural areas compared with use in most urban areas, with prevalence highest in Southeastern and Appalachian counties as well as counties in the Dakotas and Nebraska. CDC is working with states to enhance hypertension awareness and management through a strategy of team-based care that involves physicians, nurses, pharmacists, dietitians, and community health workers. The increased use of telemedicine to support this strategy might improve access to care among underserved populations.

Prevalence of Self-Reported Hypertension and Antihypertensive Medication Use Among Adults - United States, 2017.

Hypertension, or high blood pressure, is a major risk factor for heart disease and stroke (1). The prevalence of hypertension is higher among men than among women, increases with age, is highest among non-Hispanic blacks (blacks) (2), and has been consistently highest in the Southeastern region of the United States (1). To update prevalence estimates for self-reported hypertension and use of antihypertensive medication, CDC analyzed data from the 2017 Behavioral Risk Factor Surveillance System (BRFSS). The overall (unadjusted) prevalence of self-reported hypertension was 32.4% (95% confidence interval [CI] = 32.1%-32.7%). The age-standardized, median state-specific prevalence of self-reported hypertension was 29.7% (range = 24.3%-38.6%). Overall age-standardized hypertension prevalence was higher among men (32.9%) than among women (27.0%), highest among blacks (40.0%), decreased with increasing levels of education and household income, and was generally highest in the Southeastern and Appalachian states.* Among persons reporting hypertension, the overall unadjusted prevalence of self-reported antihypertensive medication use was 76.0% (95% CI = 75.5%-76.4%). The age-standardized, median state-specific prevalence of antihypertensive medication use among persons with reported hypertension was 59.4% (range = 50.2%-71.2%). Prevalence was higher among women than men, highest among blacks compared with other racial/ethnic groups, and highest among states in the Southeast, Appalachia, and the Dakotas. These findings can help inform CDC's initiatives to enhance hypertension awareness, treatment, and control across all states.

Patient Characteristics and Product Use Behaviors Among Persons with E-cigarette, or Vaping, Product Use-Associated Lung Injury - Indiana, June ̶ October 2019.

As of December 4, 2019, a total of 2,291 cases of hospitalized e-cigarette, or vaping, product use-associated lung injury (EVALI) have been reported from 50 states, the District of Columbia, and two U.S. territories (Puerto Rico and the U.S. Virgin Islands) (1). State health departments, including the Indiana State Department of Health (ISDH), are working with their local health departments and with CDC, the Food and Drug Administration, and other clinical and public health partners in investigating this outbreak of EVALI. On August 7, 2019, ISDH issued an advisory regarding patients hospitalized in Wisconsin with severe acute lung injury who reported the use of e-cigarette, or vaping, products (2); health care providers were requested to notify ISDH of similar cases. On August 8, 2019, ISDH received reports of five similar cases among Indiana residents. Suspected cases EVALI reported to ISDH were investigated further only among patients who required hospitalization. Established case definitions were used to classify cases.* Medical record abstractions and patient interviews were completed using nationally standardized forms to ascertain patient characteristics, medical care received, and product-use behaviors.

Elevated Bladder Cancer in Northern New England: The Role of Drinking Water and Arsenic.

BACKGROUND: Bladder cancer mortality rates have been elevated in northern New England for at least five decades. Incidence rates in Maine, New Hampshire, and Vermont are about 20% higher than the United States overall. We explored reasons for this excess, focusing on arsenic in drinking water from private wells, which are particularly prevalent in the region. METHODS: In a population-based case-control study in these three states, 1213 bladder cancer case patients and 1418 control subjects provided information on suspected risk factors. Log transformed arsenic concentrations were estimated by linear regression based on measurements in water samples from current and past homes. All statistical tests were two-sided. RESULTS: Bladder cancer risk increased with increasing water intake (Ptrend = .003). This trend was statistically significant among participants with a history of private well use (Ptrend = .01). Among private well users, this trend was apparent if well water was derived exclusively from shallow dug wells (which are vulnerable to contamination from manmade sources, Ptrend = .002) but not if well water was supplied only by deeper drilled wells (Ptrend = .48). If dug wells were used pre-1960, when arsenical pesticides were widely used in the region, heavier water consumers (>2.2 L/day) had double the risk of light users (<1.1 L/day, Ptrend = .01). Among all participants, cumulative arsenic exposure from all water sources, lagged 40 years, yielded a positive risk gradient (Ptrend = .004); among the highest-exposed participants (97.5th percentile), risk was twice that of the lowest-exposure quartile (odds ratio = 2.24, 95% confidence interval = 1.29 to 3.89). CONCLUSIONS: Our findings support an association between low-to-moderate levels of arsenic in drinking water and bladder cancer risk in New England. In addition, historical consumption of water from private wells, particularly dug wells in an era when arsenical pesticides were widely used, was associated with increased bladder cancer risk and may have contributed to the New England excess.

Occupational exposure to chlorinated solvents and risks of glioma and meningioma in adults.

OBJECTIVES: Chlorinated solvents are classified as probable or possible carcinogens. It is unknown whether exposure to these agents increases the risk of malignant or benign brain tumours. Our objective was to evaluate associations of brain tumour risk with occupational exposure to six chlorinated solvents (i.e., dichloromethane, chloroform, carbon tetrachloride, 1,1,1-trichloroethane, trichloroethylene and perchloroethylene). METHODS: 489 glioma cases, 197 meningioma cases and 799 controls were enrolled in a hospital-based case-control study conducted at three U.S.A. hospitals in Arizona, Massachusetts and Pennsylvania. Information about occupational history was obtained through a detailed inperson interview that included job-specific modules of questions such that the interview was tailored to each individual's particular work history. An industrial hygienist assessed potential solvent exposure based on this information and an exhaustive review of the relevant industrial hygiene literature. Unconditional logistic regression models were used to calculate OR and 95% CI for each solvent for ever/never, duration, cumulative, average weekly and highest exposure. RESULTS: Overall, we found no consistent evidence of an increased risk of glioma or meningioma related to occupational exposure to the six chlorinated solvents evaluated. There was some suggestion of an association between carbon tetrachloride and glioma in analyses restricted to exposed subjects, with average weekly exposure above the median associated with increased risk compared with below the median exposure (OR = 7.1, 95% CI 1.1 to 45.2). CONCLUSIONS: We found no consistent evidence for increased brain tumour risk related to chlorinated solvents.

The Diesel Exhaust in Miners study: a nested case-control study of lung cancer and diesel exhaust.

BACKGROUND: Most studies of the association between diesel exhaust exposure and lung cancer suggest a modest, but consistent, increased risk. However, to our knowledge, no study to date has had quantitative data on historical diesel exposure coupled with adequate sample size to evaluate the exposure-response relationship between diesel exhaust and lung cancer. Our purpose was to evaluate the relationship between quantitative estimates of exposure to diesel exhaust and lung cancer mortality after adjustment for smoking and other potential confounders. METHODS: We conducted a nested case-control study in a cohort of 12 315 workers in eight non-metal mining facilities, which included 198 lung cancer deaths and 562 incidence density-sampled control subjects. For each case subject, we selected up to four control subjects, individually matched on mining facility, sex, race/ethnicity, and birth year (within 5 years), from all workers who were alive before the day the case subject died. We estimated diesel exhaust exposure, represented by respirable elemental carbon (REC), by job and year, for each subject, based on an extensive retrospective exposure assessment at each mining facility. We conducted both categorical and continuous regression analyses adjusted for cigarette smoking and other potential confounding variables (eg, history of employment in high-risk occupations for lung cancer and a history of respiratory disease) to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Analyses were both unlagged and lagged to exclude recent exposure such as that occurring in the 15 years directly before the date of death (case subjects)/reference date (control subjects). All statistical tests were two-sided. RESULTS: We observed statistically significant increasing trends in lung cancer risk with increasing cumulative REC and average REC intensity. Cumulative REC, lagged 15 years, yielded a statistically significant positive gradient in lung cancer risk overall (P (trend) = .001); among heavily exposed workers (ie, above the median of the top quartile [REC ≥ 1005 µg/m(3)-y]), risk was approximately three times greater (OR = 3.20, 95% CI = 1.33 to 7.69) than that among workers in the lowest quartile of exposure. Among never smokers, odd ratios were 1.0, 1.47 (95% CI = 0.29 to 7.50), and 7.30 (95% CI = 1.46 to 36.57) for workers with 15-year lagged cumulative REC tertiles of less than 8, 8 to less than 304, and 304 µg/m(3)-y or more, respectively. We also observed an interaction between smoking and 15-year lagged cumulative REC (P (interaction) = .086) such that the effect of each of these exposures was attenuated in the presence of high levels of the other. CONCLUSION: Our findings provide further evidence that diesel exhaust exposure may cause lung cancer in humans and may represent a potential public health burden.

Urinary pH, cigarette smoking and bladder cancer risk.

Glucuronide conjugates of 4-aminobiphenyl and its N-hydroxy metabolite can be rapidly hydrolyzed in acidic urine to undergo further metabolic activation and form DNA adducts in the urothelium. We conducted a large multicenter case-control study in Spain to explore the etiology of bladder cancer and evaluated the association between urine pH and bladder cancer risk, alone and in combination with cigarette smoking. In total, 712 incident urothelial cell carcinoma cases and 611 hospital controls directly measured their urine pH with dipsticks twice a day (first void in the morning and early in the evening) during four consecutive days 2 weeks after hospital discharge. We found that a consistently acidic urine pH ≤6.0 was associated with an increased risk of bladder cancer [odds ratio (OR) = 1.5, 95% confidence interval (CI): 1.2-1.9] compared with all other subjects. Furthermore, risk estimates for smoking intensity and risk of bladder cancer among current smokers tended to be higher for those with a consistently acidic urine (OR = 8.8, 11.5 and 23.8) compared with those without (OR = 4.3, 7.7 and 5.8, respectively, for 1-19, 20-29 and 30+ cigarettes per day; P(interaction) for 30+ cigarettes per day = 0.024). These results suggest that urine pH, which is determined primarily by diet and body surface area, may be an important modifier of smoking and risk of bladder cancer.

Occupation and bladder cancer in a population-based case-control study in Northern New England.

OBJECTIVES: We used data from a large, population-based case-control study in Maine, New Hampshire, and Vermont to examine relationships between occupation, industry and bladder cancer risk. METHODS: Lifetime occupational histories were obtained by personal interview from 1158 patients newly diagnosed with urothelial carcinoma of the bladder in 2001-2004, and from 1402 population controls. Unconditional logistic regression was used to calculate ORs and 95% CIs, adjusted for demographic factors, smoking and employment in other high-risk occupations. RESULTS: Male precision metalworkers and metalworking/plasticworking machine operators had significantly elevated risks and significant trends in risk with duration of employment (precision metalworkers: OR 2.2, 95% CI 1.4 to 3.4, p(trend) = 0.0065; metalworking/plasticworking machine operators: OR 1.6, 95% CI 1.01 to 2.6, p(trend) = 0.047). Other occupations/industries for which risk increased significantly with duration of employment included: for men, textile machine operators, mechanics/repairers, automobile mechanics, plumbers, computer systems analysts, information clerks, and landscape industry workers; for women, service occupations, health services, cleaning and building services, management-related occupations, electronic components manufacturing and transportation equipment manufacturing. Men reporting use of metalworking fluids (MWF) had a significantly elevated bladder cancer risk (OR 1.7, 95% CI 1.1 to 2.5). CONCLUSIONS: Our findings support the hypothesis that some component(s) of MWF may be carcinogenic to the bladder. Our results also corroborate many other previously reported associations between bladder cancer risk and various occupations. More detailed analyses using information from the study's job-specific questionnaires may help to identify MWF components that may be carcinogenic, and other bladder carcinogens associated with a variety of occupations.

Polymorphisms in GSTT1, GSTZ1, and CYP2E1, disinfection by-products, and risk of bladder cancer in Spain.

BACKGROUND: Bladder cancer has been linked with long-term exposure to disinfection by-products (DBPs) in drinking water. OBJECTIVES: In this study we investigated the combined influence of DBP exposure and polymorphisms in glutathione S-transferase (GSTT1, GSTZ1) and cytochrome P450 (CYP2E1) genes in the metabolic pathways of selected by-products on bladder cancer in a hospital-based case-control study in Spain. METHODS: Average exposures to trihalomethanes (THMs; a surrogate for DBPs) from 15 years of age were estimated for each subject based on residential history and information on municipal water sources among 680 cases and 714 controls. We estimated effects of THMs and GSTT1, GSTZ1, and CYP2E1 polymorphisms on bladder cancer using adjusted logistic regression models with and without interaction terms. RESULTS: THM exposure was positively associated with bladder cancer: adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were 1.2 (0.8-1.8), 1.8 (1.1-2.9), and 1.8 (0.9-3.5) for THM quartiles 2, 3, and 4, respectively, relative to quartile 1. Associations between THMs and bladder cancer were stronger among subjects who were GSTT1 +/+ or +/- versus GSTT1 null (P(interaction) = 0.021), GSTZ1 rs1046428 CT/TT versus CC (P(interaction) = 0.018), or CYP2E1 rs2031920 CC versus CT/TT (P(interaction) = 0.035). Among the 195 cases and 192 controls with high-risk forms of GSTT1 and GSTZ1, the ORs for quartiles 2, 3, and 4 of THMs were 1.5 (0.7-3.5), 3.4 (1.4-8.2), and 5.9 (1.8-19.0), respectively. CONCLUSIONS: Polymorphisms in key metabolizing enzymes modified DBP-associated bladder cancer risk. The consistency of these findings with experimental observations of GSTT1, GSTZ1, and CYP2E1 activity strengthens the hypothesis that DBPs cause bladder cancer and suggests possible mechanisms as well as the classes of compounds likely to be implicated.

A case-control study of smoking and bladder cancer risk: emergent patterns over time.

BACKGROUND: Cigarette smoking is a well-established risk factor for bladder cancer. The effects of smoking duration, intensity (cigarettes per day), and total exposure (pack-years); smoking cessation; exposure to environmental tobacco smoke; and changes in the composition of tobacco and cigarette design over time on risk of bladder cancer are unclear. METHODS: We examined bladder cancer risk in relation to smoking practices based on interview data from a large, population-based case-control study conducted in Maine, New Hampshire, and Vermont from 2001 to 2004 (N = 1170 urothelial carcinoma case patients and 1413 control subjects). We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression. To examine changes in smoking-induced bladder cancer risk over time, we compared odds ratios from New Hampshire residents in this study (305 case patients and 335 control subjects) with those from two case-control studies conducted in New Hampshire in 1994-1998 and in 1998-2001 (843 case patients and 1183 control subjects). RESULTS: Regular and current cigarette smokers had higher risks of bladder cancer than never-smokers (for regular smokers, OR = 3.0, 95% CI = 2.4 to 3.6; for current smokers, OR = 5.2, 95% CI = 4.0 to 6.6). In New Hampshire, there was a statistically significant increasing trend in smoking-related bladder cancer risk over three consecutive periods (1994-1998, 1998-2001, and 2002-2004) among former smokers (OR = 1.4, 95% CI = 1.0 to 2.0; OR = 2.0, 95% CI = 1.4 to 2.9; and OR = 2.6, 95% CI = 1.7 to 4.0, respectively) and current smokers (OR = 2.9, 95% CI = 2.0 to 4.2; OR = 4.2, 95% CI = 2.8 to 6.3; OR = 5.5, 95% CI = 3.5 to 8.9, respectively) (P for homogeneity of trends over time periods = .04). We also observed that within categories of intensity, odds ratios increased approximately linearly with increasing pack-years smoked, but the slope of the increasing trend declined with increasing intensity. CONCLUSIONS: Smoking-related risks of bladder cancer appear to have increased in New Hampshire since the mid-1990s. Based on our modeling of pack-years and intensity, smoking fewer cigarettes over a long time appears more harmful than smoking more cigarettes over a shorter time, for equal total pack-years of cigarettes smoked.

Does increased urination frequency protect against bladder cancer?

Experimental studies suggest that increased urination frequency may reduce bladder cancer risk if carcinogens are present in the urine. Only 2 small studies of the effect of increased urination frequency on bladder cancer risk in humans have been conducted with conflicting results. Our purpose was to evaluate the effect of urination frequency on risk of bladder cancer in a large, multicenter case-control study. We analyzed data based on interviews conducted with 884 patients with newly diagnosed, bladder cancer and 996 controls from 1998 to 2001 in Spain. We observed a consistent, inverse trend in risk with increasing nighttime voiding frequency in both men (p = 0.0003) and women (p = 0.07); voiding at least 2 times per night was associated with a significant, 40-50% risk reduction. The protective effect of nocturia was apparent among study participants with low, moderate and high water consumption. The risk associated with cigarette smoking was reduced by nocturia. Compared with nonsmokers who did not urinate at night, current smokers who did not urinate at night had an OR of 7.0 (95% CI = 4.7-10.2), whereas those who voided at least twice per night had an OR of 3.3 (95% CI = 1.9-5.8) (p value for trend = 0.0005). Our findings suggest a strong protective effect of nocturia on bladder cancer risk, providing evidence in humans that bladder cancer risk is related to the contact time of the urothelium with carcinogens in urine. Increased urination frequency, coupled with possible dilution of the urine from increased water intake, may diminish the effect of urinary carcinogens on bladder cancer risk.

Occupational exposure to pesticides and risk of adult brain tumors.

The authors examined incident glioma and meningioma risk associated with occupational exposure to insecticides and herbicides in a hospital-based, case-control study of brain cancer. Cases were 462 glioma and 195 meningioma patients diagnosed between 1994 and 1998 in three US hospitals. Controls were 765 patients admitted to the same hospitals for nonmalignant conditions. Occupational histories were collected during personal interviews. Exposure to pesticides was estimated by use of a questionnaire, combined with pesticide measurement data abstracted from published sources. Using logistic regression models, the authors found no association between insecticide and herbicide exposures and risk for glioma and meningioma. There was no association between glioma and exposure to insecticides or herbicides, in men or women. Women who reported ever using herbicides had a significantly increased risk for meningioma compared with women who never used herbicides (odds ratio = 2.4, 95% confidence interval: 1.4, 4.3), and there were significant trends of increasing risk with increasing years of herbicide exposure (p = 0.01) and increasing cumulative exposure (p = 0.01). There was no association between meningioma and herbicide or insecticide exposure among men. These findings highlight the need to go beyond job title to elucidate potential carcinogenic exposures within different occupations.