Analyzing data from over 650,000 individuals, Dr. Steven Moore and colleagues report that greater amounts of leisure-time physical activity were associated with higher life expectancy across a wide range of activity levels and body mass index groups.

Background

Leisure time physical activity reduces the risk of premature mortality, but the years of life expectancy gained at different levels remains unclear. Our objective was to determine the years of life gained after age 40 associated with various levels of physical activity, both overall and according to body mass index (BMI) groups, in a large pooled analysis.

Methods and Findings

We examined the association of leisure time physical activity with mortality during follow-up in pooled data from six prospective cohort studies in the National Cancer Institute Cohort Consortium, comprising 654,827 individuals, 21–90 y of age. Physical activity was categorized by metabolic equivalent hours per week (MET-h/wk). Life expectancies and years of life gained/lost were calculated using direct adjusted survival curves (for participants 40+ years of age), with 95% confidence intervals (CIs) derived by bootstrap. The study includes a median 10 y of follow-up and 82,465 deaths. A physical activity level of 0.1–3.74 MET-h/wk, equivalent to brisk walking for up to 75 min/wk, was associated with a gain of 1.8 (95% CI: 1.6–2.0) y in life expectancy relative to no leisure time activity (0 MET-h/wk). Higher levels of physical activity were associated with greater gains in life expectancy, with a gain of 4.5 (95% CI: 4.3–4.7) y at the highest level (22.5+ MET-h/wk, equivalent to brisk walking for 450+ min/wk). Substantial gains were also observed in each BMI group. In joint analyses, being active (7.5+ MET-h/wk) and normal weight (BMI 18.5–24.9) was associated with a gain of 7.2 (95% CI: 6.5–7.9) y of life compared to being inactive (0 MET-h/wk) and obese (BMI 35.0+). A limitation was that physical activity and BMI were ascertained by self report.

Conclusions

More leisure time physical activity was associated with longer life expectancy across a range of activity levels and BMI groups.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

Regular physical activity is essential for human health. It helps to maintain a healthy body weight and prevents or delays heart disease, type 2 diabetes, and some cancers. It also makes people feel better and increases life expectancy. The World Health Organization (WHO) currently recommends that adults do at least 150 minutes of moderate- to vigorous-intensity physical activity every week. Moderate-intensity physical activities (for example, brisk walking and gardening) require a moderate amount of effort and noticeably increase the heart rate; vigorous-intensity physical activities (for example, running or fast swimming) require a large amount of effort and cause rapid breathing and a substantial heart rate increase. Worryingly, people in both developed and developing countries are becoming increasingly physically inactive. People are sitting at desks all day instead of doing manual labor; they are driving to work in cars instead of walking or cycling; and they are participating in fewer leisure time physical activities.

Why Was This Study Done?

Although various studies suggest that physical activity increases life expectancy, few have quantified the years of life gained at distinct levels of physical activity. Moreover, the difference in life expectancy between active, overweight individuals and inactive, normal weight individuals has not been quantified. Thus, it is hard to develop a simple public health message to maximize the population benefits of physical activity. In this pooled prospective cohort analysis, the researchers determine the association between levels of leisure time physical activities, such as recreational walking, and years of life gained after age 40, both overall and within body mass index (BMI) groups. A pooled prospective cohort analysis analyzes the combined data from multiple studies that have followed groups of people to investigate associations between baseline characteristics and outcomes such as death. BMI is a ratio of weight to height, calculated by dividing a person's weight by their height squared; normal weight is defined as a BMI of 18.5–24.9 kg/m2, obesity (excessive body fat) is defined as a BMI of more than 30 kg/m2.

What Did the Researchers Do and Find?

The researchers pooled self-reported data on leisure time physical activities and BMIs from nearly 650,000 individuals over the age of 40 years enrolled in one Swedish and five US prospective cohort studies, most of which were investigating associations between lifestyle factors and disease risk. They used these and other data to calculate the gain in life expectancy associated with specific levels of physical activity. A physical activity level equivalent to brisk walking for up to 75 minutes per week was associated with a gain of 1.8 years in life expectancy relative to no leisure time activity. Being active—having a physical activity level at or above the WHO-recommended minimum of 150 minutes of brisk walking per week—was associated with an overall gain of life expectancy of 3.4–4.5 years. Gains in life expectancy were seen also for black individuals and former smokers, groups for whom relatively few data had been previously available. The physical activity and life expectancy association was also evident at all BMI levels. Being active and normal weight was associated with a gain of 7.2 years of life compared to being inactive and class II+ obese (having a BMI of more than 35.0 kg/m2). However, being inactive but normal weight was associated with 3.1 fewer years of life compared to being active but class I obese (having a BMI of 30–34.9 kg/m2).

What Do These Findings Mean?

These findings suggest that participation in leisure time physical activity, even below the recommended level, is associated with a reduced risk of mortality compared to participation in no leisure time physical activity. This result may help convince currently inactive people that a modest physical activity program may have health benefits, even if it does not result in weight loss. The findings also suggest that physical activity at recommended levels or higher may increase longevity further, and that a lack of leisure time physical activity may markedly reduce life expectancy when combined with obesity. Although the accuracy and generalizability of these findings may be limited by certain aspects of the study's design (for example, some study participants may have overestimated their leisure time physical activity), these findings reinforce the public health message that both a physically active lifestyle and a normal body weight are important for increasing longevity.

Additional Information

Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001335.

The World Health Organization provides information about physical activity and health (in several languages); its 2010 Global Recommendations on Physical Activity for Health is available in several languages

The US Centers for Disease Control and Prevention provides information on physical activity for different age groups; its Physical Activity for Everyone webpages include guidelines, instructional videos, and personal success stories

The UK National Health Service information source NHS Choices also explains the benefits of regular physical activity and includes physical activity guidelines, tips for exercising, and some personal stories

MedlinePlus has links to other resources about exercise and physical fitness (in English and Spanish)

Background

Inflammation and pulmonary diseases, including interstitial lung diseases, are associated with increased lung cancer risk. Circulating levels of surfactant protein-D (SP-D) and Krebs von Lungren-6 (KL-6) are elevated in interstitial lung disease patients, and may be useful markers of processes contributing to lung cancer.

Methods

We conducted a nested case-control study, including 532 lung cancer cases, 582 matched controls and 150 additional controls with chest x-ray (CXR) evidence of pulmonary scarring, in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Serum SP-D and KL-6 levels were measured using enzyme immunoassay. Logistic regression was used to estimate the associations of SP-D and KL-6 with lung cancer and CXR scarring.

Results

Cases had higher levels than controls for SP-D (median 118.7 vs. 105.4 ng/ml, p-value=0.008) and KL-6 (372.0 vs. 325.8 μg/ml, p-value=0.001). Lung cancer risk increased with SP-D (p-trend=0.0003) and KL-6 levels (p-trend=0.005). Compared to the lowest quartile, lung cancer risk was elevated among those with the highest quartiles of SP-D (odds ratio [OR]=1.87; 95% confidence interval [CI] 1.32–2.64), or KL-6 (OR=1.58; 95% CI 1.11–2.25). Among controls, participants with CXR scarring were more likely than those without scarring to have elevated levels of SP-D (quartile 4 vs. quartile 1: OR=1.67; 95% CI: 1.04–2.70; p-trend=0.05) but not of KL-6 (OR=1.04; 95% CI: 0.64–1.68; p-trend=0.99).

Conclusion

Circulating levels of SP-D and KL-6 are associated with subsequent lung cancer risk.

Impact

Our findings support a potential role for interstitial lung disease in lung cancer etiology or early detection, but additional research is needed.

Background

The incidence of breast cancer increased in the United States until circa 2000 then decreased, mostly among women with estrogen receptor (ER)–positive cancers. Time trends provide important clues for cancer etiology and prevention; however, the observed trends of ER-positive and ER-negative breast cancers can be biased by missing ER data.

Methods

We developed a simple imputation method to correct invasive female breast cancer incidence for missing or unknown ER expression, using nationally representative data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program during 1980–2008, including 588 720 invasive female breast cancer patients with 471 336 233 woman-years of follow-up. Corrected rates of ER-positive and ER-negative breast cancers were used to calculate age-standardized incidence rates, estimated annual percentage changes, and projections derived from age–period–cohort models.

Results

The recent decrease in the incidence of breast cancer overall stabilized near 200 per 100 000 woman-years by 2007–2008, reflecting a transient decrease in ER-positive cancers and a steady decrease in ER-negative cancers. The projected incidence rate for breast cancer overall through the year 2016 was similar to the incidence rate during 2007–2008. In contrast, rates of ER-positive breast cancers were projected to increase 5.3% (95% confidence interval = 5.2% to 5.4%), whereas rates of ER-negative breast cancers were projected to decrease 11.4% (95% confidence interval = 11.3% to 11.6%) during 2009–2016.

Conclusion

Recent changes in breast cancer incidence overall reflect the superimposition of divergent trends in ER-positive and ER-negative cancers. If current trends continue, the incidence of ER-positive breast cancers will increase, the incidence of ER-negative breast cancers will continue to decrease, and the incidence of breast cancer overall will remain similar to its current level.

Background

Previous studies that were based primarily on small numbers of patients suggested that certain circulating proinflammatory cytokines may be associated with lung cancer; however, large independent studies are lacking.

Methods

Associations between serum interleukin 6 (IL-6) and interleukin 8 (IL-8) levels and lung cancer were analyzed among 270 case patients and 296 control subjects participating in the National Cancer Institute-Maryland (NCI-MD) case–control study. Results were validated in 532 case patients and 595 control subjects in a nested case–control study within the prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Association with C-reactive protein (CRP), a systemic inflammation biomarker, was also analyzed. Associations between biomarkers and lung cancer were estimated using logistic regression models adjusted for smoking, stage, histology, age, and sex. The 10-year standardized absolute risks of lung cancer were estimated using a weighted Cox regression model.

Results

Serum IL-6 and IL-8 levels in the highest quartile were associated with lung cancer in the NCI-MD study (IL-6, odds ratio [OR] = 3.29, 95% confidence interval [CI] = 1.88 to 5.77; IL-8, OR = 2.06, 95% CI = 1.19 to 3.57) and with lung cancer risk in the PLCO study (IL-6, OR = 1.48, 95% CI = 1.04 to 2.10; IL-8, OR = 1.57, 95% CI = 1.10 to 2.24), compared with the lowest quartile. In the PLCO study, increased IL-6 levels were only associated with lung cancer diagnosed within 2 years of blood collection, whereas increased IL-8 levels were associated with lung cancer diagnosed more than 2 years after blood collection (OR = 1.57, 95% CI = 1.15 to 2.13). The 10-year standardized absolute risks of lung cancer in the PLCO study were highest among current smokers with high IL-8 and CRP levels (absolute risk = 8.01%, 95% CI = 5.77% to 11.05%).

Conclusions

Although increased levels of both serum IL-6 and IL-8 are associated with lung cancer, only IL-8 levels are associated with lung cancer risk several years before diagnosis. Combination of IL-8 and CRP are more robust biomarkers than either marker alone in predicting subsequent lung cancer.

Background: In epidemiologic studies that rely on professional judgment to assess occupational exposures, the raters’ accurate assessment is vital to detect associations. We examined the influence of the type of questionnaire, type of industry, and type of rater on the raters’ ability to reliably and validly assess within-industry differences in exposure. Our aim was to identify areas where improvements in exposure assessment may be possible.

Methods: Subjects from three foundries (n = 72) and three textile plants (n = 74) in Shanghai, China, completed an occupational history (OH) and an industry-specific questionnaire (IQ). Six total dust measurements were collected per subject and were used to calculate a subject-specific measurement mean, which was used as the gold standard. Six raters independently ranked the intensity of each subject’s current job on an ordinal scale (1–4) based on the OH alone and on the OH and IQ together. Aggregate ratings were calculated for the group, for industrial hygienists, and for occupational physicians. We calculated intra-class correlation coefficients (ICCs) to evaluate the reliability of the raters. We calculated the correlation between the subject-specific measurement means and the ratings to evaluate the raters’ validity. Analyses were stratified by industry, type of questionnaire, and type of rater. We also examined the agreement between the ratings by exposure category, where the subject-specific measurement means were categorized into two and four categories.

Results: The reliability and validity measures were higher for the aggregate ratings than for the ratings from the individual raters. The group’s performance was maximized with three raters. Both the reliability and validity measures were higher for the foundry industry than for the textile industry. The ICCs were consistently lower in the OH/IQ round than in the OH round in both industries. In contrast, the correlations with the measurement means were higher in the OH/IQ round than in the OH round for the foundry industry (group rating, OH/IQ: Spearman rho = 0.77; OH: rho = 0.64). No pattern by questionnaire type was observed for the textile industry (group rating, Spearman rho = 0.50, both assessment rounds). For both industries, the agreement by exposure category was higher when the task was reduced to discriminating between two versus four exposure categories.

Conclusions: Assessments based on professional judgment may reduce misclassification by using two or three raters, by using questionnaires that systematically collect task information, and by defining intensity categories that are distinguishable by the raters. However, few studies have the resources to use multiple raters and these additional efforts may not be adequate for obtaining valid subjective ratings. Thus, improving exposure assessment approaches for studies that rely on professional judgment remain an important research need.

Background

Anal cancer remains rare (incidence of ∼1.5 per 100,000 women annually) but rates are increasing in many countries. Human papillomavirus-16 (HPV16) infection causes most cases. We evaluated vaccine efficacy (VE) of an ASO4-adjuvanted HPV16/18 vaccine against anal HPV16/18 infection.

Methods

In a randomized double-blind controlled trial designed to evaluate VE against persistent cervical HPV16/18 infections and associated precancerous lesions in Costa Rica, 4210 healthy women underwent anal specimen collection (4224 of 5968= 70.8% of eligible women) at the final blinded study visit 4 years after vaccination to evaluate anal HPV16/18 VE. Cervical HPV16/18 VE among the same women at the same visit was calculated as a comparator. For this ancillary work, analyses were conducted in a restricted cohort of women both cervical HPV16/18 DNA negative and HPV 16/18 seronegative prior at enrollment (N=1989), and in the full cohort (all women with an anal specimen).

Findings

In the restricted cohort, VE against prevalent HPV16/18 anal infection measured one-time, four-years post-vaccination was 83.6% (95%CI 66.7% to 92.8%), which was comparable to cervical HPV16/18 VE (87.9%, 95%CI 77.4% to 94.0%). In the full cohort, HPV16/18 VE was statistically lower at the anus (62.0%, 95%CI 47.1% to 73.1%) compared to the cervix (76.4%, 95%CI 67.0% to 83.5%) (p for anatomic-site interaction =0.03). Significant and comparable VE estimates against a composite endpoint of HPV31/33/45 (i.e.: cross-protection) was observed at the anus and cervix.

Interpretation

The ASO4-adjuvanted vaccine affords strong protection against anal HPV, particularly among women more likely to be HPV naïve at vaccination. Funding. The Costa Rica HPV Vaccine Trial is sponsored and funded by the NCI (contract N01-CP-11005), with funding support from the National Institutes of Health Office of Research on Women's Health, and conducted with support from the Ministry of Health of Costa Rica. Vaccine was provided for our trial by GlaxoSmithKline Biologicals (GSK), under a Clinical Trials Agreement with the NCI.

Objective

To increase participation in cervical cancer screening of under-served women living in the Mississippi Delta, a U.S. population at high risk for cervical cancer

Methods

We conducted a door-to-door feasibility study of women living in the Mississippi Delta to increase participation in cervical cancer screening in 2009-10. Women (n=119) aged 26-65 years who had not been screened in last 3 years or more, were not pregnant, and had a cervix were offered a choice: clinic-based Pap testing or home self-collection with HPV DNA testing.

Results

Seventy-seven women (64.7%) chose self-collection with HPV testing, of which 62 (80.5%) returned their self-collected specimen. By comparison, 42 women (35.3%) chose Pap testing, of which 17 (40.5%) attended their clinic appointment. Thus there was an almost 4-fold greater participation of under-screened women in self-collection with HPV testing than in free Pap testing (78.4% vs. 21.5%).

Conclusions

We found that offering self-collection will increase participation in cervical cancer screening among under-screened populations living in the Mississippi Delta. Based on these preliminary results, we suggest that self-collection with HPV DNA testing might complement current Pap testing programs to reach under-screened populations of women, such as those living in the Mississippi Delta.

Background

Human papillomavirus (HPV) infection of the genital mucosa is thought to require trauma to the cervicovaginal epithelium. Therefore, we determined whether a cytology specimen collection procedure (Pap smear), which disrupts the epithelium by design, renders the cervix more susceptible to HPV infection in a primate model.

Methods

In a series of female rhesus macaques, a speculum examination was performed with (n = 8) or without (n = 4) a cytology specimen collection procedure as it is commonly practiced in a gynecology clinic. An internal digital examination was performed after specimen collection using Surgilube (n = 4) or 1% iota-carrageenan, a previously indentified HPV inhibitor (n = 4) as the lubricant. The cervix was then inoculated with HPV16 pseudovirions expressing red fluorescent protein. After 3 days, the reproductive tracts were excised and the cervix was cryosectioned. Sections were analyzed by fluorescent confocal microscopy for the number of red fluorescent protein–positive keratinocytes.

Results

Substantial infection of the ectocervix, the transformation zone, and the endocervix was detected, but only in conjunction with the cytology specimen collection procedure (cytology using Surgilube vs without cytology using Surgilube, mean = 84 infectious events per section vs mean = 0.05 infectious events per section, difference = 84 infectious events per section, 95% confidence interval = 19 to 384 infectious events per section). When the carrageenan gel was substituted for Surgilube for an internal digital examination, the mean number of infectious events decreased (carrageenan gel vs Surgilube, mean = 3.5 events per section vs mean = 84 infectious events per section difference = 81 events per section, 95% confidence interval = 33 to 213 events per section).

Conclusions

These findings indicate that cytology screening in women might lead to a transient enhancement of susceptibility to HPV infection and that use of a carrageenan-based gel during the examination might mitigate this enhancement.

Background

Cervical cancer prevention programs are being reconfigured to incorporate human papillomavirus (HPV) testing and vaccination. To define priority areas for prevention efforts, we examined the geographic distribution of cervical cancer screening, incidence, stage, and mortality in the United States prior to the introduction of HPV-based prevention technologies.

Methods

County-level cervical cancer incidence data from 37 central registries were obtained from Surveillance, Epidemiology, and End Results (SEER) and North American Association of Central Cancer Registries (NAACCR) registries. A spatial- temporal model that accounted for demographic and behavioral attributes was used to generate a complete view of county-level incidence from 1995–2004, including counties with missing data. Distribution of stage at diagnosis was examined by registry. Counties with high mortality and infrequent screening were identified using vital statistics and newly available county level screening estimates.

Results

Compared to non-Hispanic whites and Asian and Pacific Islanders, incidence rates were higher among non-Hispanic black, American Indian and Alaska Native, and Hispanic women. Counties with infrequent screening often experienced elevated incidence and mortality rates and were located in states with suboptimal stage-at-diagnosis profiles. Affected areas included Appalachia, the southeastern Atlantic states, and the lower Mississippi Valley. Elevated death rates were experienced in central counties of large metropolitan areas.

Conclusions

Geographic and racial/ethnic variability were evident in cervical cancer incidence and mortality. Women living in areas with endemic poverty would benefit from access to HPV-based prevention technologies.

Impact

These findings provide a baseline for monitoring progress in cervical cancer control in the era of HPV-based prevention.

Objective. We investigated coinfection patterns for 25 human papillomavirus (HPV) types and assessed the risk conferred by multiple HPV types toward cervical disease.

Methods. Sexually active women (n=5,871) in the NCI-sponsored Costa Rica HPV Vaccine Trial's prevaccination enrollment visit were analyzed. Genotyping for 25 HPVs was performed using SPF10/LiPA25. We calculated odds ratios (ORs) to assess coinfection patterns for each genotype with 24 other genotypes. These ORs were pooled and compared with pair-specific ORs to identify genotype combinations that deviated from the pooled OR. We compared risk of CIN2+/HSIL+between multiple and single infections and assessed additive statistical interactions.

Results. Of the 2478 HPV-positive women, 1070 (43.2%) were infected with multiple types. Multiple infections occurred significantly more frequently than predicted by chance. However, this affinity to be involved in a coinfection (pooled OR for 300 type-type combinations=2.2; 95% confidence interval [CI]=2.1-2.4) was not different across HPV type-type combinations. Compared with single infections, coinfection with multiple α9 species was associated with significantly increased risk of CIN2+(OR=2.2; 95% CI=1.1–4.6) and HSIL+(OR=1.6; 95% CI=1.1–2.4). However, disease risk was similar to the sum of estimated risk from individual types, with little evidence for synergistic interactions.

Conclusions. Coinfecting HPV genotypes occur at random and lead to cervical disease independently.

The presence of more than one human papillomavirus (HPV) genotype may influence the duration of prevalently detected infections. This analysis included 1,646 infections detected at enrollment in 980 women from the Guanacaste, Costa Rica, cohort who were actively followed up every 6–12 months for up to 8 years. We categorized HPV infections as single or multiple types. Persistence of infections was estimated using discrete-time survival analysis. The difference between the duration of single and that of concurrent multiple type-specific prevalent HPV infections was not significant (P = .9; log-rank test). Concurrent, prevalent detection of additional HPV types did not change the likelihood of viral persistence.

Background

Concurrent HPV testing and cervical cytology (co-testing) is an approved and promising alternative to cytology alone in women aged 30 and older. However, broad acceptance of co-testing is being hindered by a lack of evidence about its performance in routine clinical practice. We evaluated the safety of three-year screening intervals for women testing HPV-negative with normal cytology (Pap-negative) and assessed the ability of co-testing to identify women at high risk of CIN3+ or cervical cancer over five years.

Methods

We analyzed five-year cumulative incidence of cervical cancer and cervical intraepithelial neoplasia grade 3 or worse (CIN3+) for 331,818 women aged 30 and older who enrolled in co-testing at Kaiser Permanente Northern California starting 2003-2005 (and had adequate enrollment co-test results) and were followed through December 31, 2009.

Findings

Five-year cumulative incidence of cancer for all 315,061 HPV-negative women was extremely low (3.8 per 100,000 women per year), only slightly higher than for the 306,969 women who were both HPV-negative and Pap-negative (3.2 per 100,000 women per year), and half the cancer risk of all 319,177 women who were Pap-negative (7.5 per 100,000 women per year). Almost all (99.5%; 313,465) HPV-negative women had either normal cytology or minor abnormalities. Abnormal cytology greatly increased cumulative incidence of CIN3+ over five years for the 16,757 HPV-positive women (12% vs. 5.9%, p<0.0001). In contrast, although statistically significant, abnormal cytology did not increase 5-year CIN3+ risk for HPV-negative women to a substantial level (0.86% vs. 0.16%). 73% of HPV-positive women had no cytologic abnormality (12,208 women). HPV-positive women with no cytologic abnormality experienced 34% of the CIN3+, 29% of the cancers, and 63% of the adenocarcinomas.

Interpretation

For women aged 30 and older in routine clinical practice, a single negative HPV test sufficed to provide strong reassurance against cervical cancer over five years, demonstrating the safety of 3-year screening intervals for HPV-negative/Pap-negative women and suggesting that five-year intervals may also be safe. Concurrent HPV testing resulted in earlier identification of the women at high risk of cervical cancer, especially adenocarcinoma. HPV testing without adjunctive cytology may be sufficiently sensitive for primary cervical cancer screening.

This study represents a multiplex cytokine analysis of serum from a 10-month randomized, controlled trial of 238 subjects that investigated the effects of selenomethionine and/or celecoxib in subjects with mild or moderate esophageal squamous dysplasia. The original chemoprevention study found that among those with mild dysplasia, selenomethionine treatment favorably altered dysplasia grade. The current analysis found that selenomethionine down-regulated IL-2 by 9% (p=0.04), while celecoxib down-regulated IL-7 by 11% (p=0.006) and up-regulated IL-13 by 17% (p=0.008). In addition, an increase in IL-7 tertile from baseline to t10 was significantly associated with an increase in dysplasia grade, both overall (OR=1.47, p=0.03) and among those with mild dysplasia at t0 (OR=2.53 p=0.001). An increase in IL-2 tertile from baseline to t10 was also non-significantly associated with worsening dysplasia for all participants (OR=1.32 p=0.098), and significantly associated with worsening dysplasia among those with mild dysplasia at baseline (OR=2.0 p=0.01). The association of increased IL-2 with worsening dysplasia remained significant in those on selenomethionine treatment who began the trial with mild dysplasia (OR=2.52 p=0.03). The current study shows that selenomethionine supplementation decreased serum IL-2 levels, while celecoxib treatment decreased IL-7 levels and increased IL-13 levels during a 10 month randomized chemoprevention trial. An increase in IL-2 or IL-7 was associated with increased severity of dysplasia over the course of the trial, especially in those who began the trial with mild dysplasia. The favorable effect of selenomethionine on esophageal dysplasia in the original trial may have been mediated in part by its effect on reducing levels of IL-2.

Purpose

Chronic inflammation could play a role in lung carcinogenesis, underscoring the potential for lung cancer prevention and screening. We investigated the association of circulating high-sensitivity C-reactive protein (CRP, an inflammation biomarker) and CRP single nucleotide polymorphisms (SNPs) with prospective lung cancer risk.

Patients and Methods

We conducted a nested case-control study of 592 lung cancer patients and 670 controls with available prediagnostic serum and 378 patients and 447 controls with DNA within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N = 77,464). Controls were matched to patients on age, sex, entry year, follow-up time, and smoking. We measured CRP levels in baseline serum samples and genotyped five common CRP SNPs.

Results

Elevated CRP levels were associated with increased lung cancer risk (odds ratio [OR], 1.98; 95% CI, 1.35 to 2.89; P-trend < .001 for fourth quartile [Q4, ≥ 5.6 mg/L] v Q1 [< 1.0 mg/L]). The CRP association did not differ significantly by histology, follow-up time, or smoking status, but was most apparent for squamous cell carcinomas (OR, 2.92; 95% CI, 1.30 to 6.54), 2 to 5 years before lung cancer diagnosis (OR, 2.33; 95% CI, 1.24 to 4.39), and among former smokers (OR, 2.48; 95% CI, 1.53 to 4.03) and current smokers (OR, 1.90; 95% CI, 1.06 to 3.41). Although CRP SNPs and haplotypes were associated with CRP levels, they were not associated with lung cancer risk. Ten-year standardized absolute risks of lung cancer were higher with elevated CRP levels among former smokers (Q4: 2.55%; 95% CI, 1.98% to 3.27% v Q1: 1.39%; 95% CI, 1.07% to 1.81%) and current smokers (Q4: 7.37%; 95% CI, 5.81% to 9.33% v Q1: 4.03%; 95% CI, 3.01% to 5.40%).

Conclusion

Elevated CRP levels are associated with subsequently increased lung cancer risk, suggesting an etiologic role for chronic pulmonary inflammation in lung carcinogenesis.

Background

The natural history of human papillomavirus (HPV) infections in older women is critical for preventive strategies, including vaccination and screening intervals, but is poorly understood. In a 7-year population-based cohort study in Guanacaste, Costa Rica, we examined whether women’s age and the duration of carcinogenic HPV infections influenced subsequent persistence of infection and risk of cervical intraepithelial neoplasia grade 2 (CIN 2) or worse disease.

Methods

At enrollment, of the 9466 participants eligible for pelvic examination, 9175 were screened for cervical neoplasia using multiple methods; those with CIN 2 or worse disease were censored and treated. Participants at low risk of CIN 2 or worse (n = 6029) were rescreened at 5–7 years (passively followed), whereas higher-risk participants (n = 2115) and subsets of low-risk women (n = 540) and initially sexually inactive women (n = 410) were rescreened annually or semiannually (actively followed) for up to 7 years. HPV testing was done using a polymerase chain reaction–based method. We determined, by four age groups (18–25, 26–33, 34–41, and ≥42 years), the proportion of prevalent infections (found at baseline) and newly detected infections (first found during follow-up) that persisted at successive 1-year time points and calculated absolute risks of CIN 2 and CIN grade 3 (CIN 3) or worse during follow-up. P values are two-sided.

Results

Regardless of the woman's age, newly detected infections were associated with very low absolute risks of persistence, CIN 2, or worse disease. For newly detected infections, the rate of progression to CIN 2+ (or CIN 3+), after 3 years of follow-up, was not higher for women aged 34 years and older than for younger women. Moreover, rates of newly detected infections declined sharply with age (in the actively followed group, at ages 18–25, 26–33, 34–41, and ≥42 years, rates were 35.9%, 30.6%, 18.1%, and 13.5%, respectively; P < .001). Among prevalent infections, persistent infections among older women (≥42 years) was higher than that among younger age groups or new infections at any age (P < .01 for comparison of eight groups). Most (66 of 85) CIN 2 or worse detected during follow-up was associated with prevalent infections. Only a small subset (25 of 1128) of prevalent infections persisted throughout follow-up without apparent CIN 2 or worse.

Conclusions

The rate of new infections declines with age, and new infections typically do not progress to CIN 2 or worse disease in older women; thus, overall potential benefit of prophylactic vaccination or frequent HPV screening to prevent or detect new carcinogenic HPV infections at older ages is low.

Chronic inflammation may play an etiologic role in endometrial cancer. Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce inflammatory activity by inhibiting the pro-inflammatory cyclooxygenase enzymes and therefore may decrease cancer risk. However, few studies have examined the association between NSAID use and endometrial cancer. We conducted a prospective study among 72,524 women in the NIH-AARP Diet and Health Study. Women completed a questionnaire in 1996–97 on lifestyle and health-related factors, including type and frequency of NSAID use within the past year, and were followed through 2003 by linkages to cancer registries and vital status databases. During 488,261 person-years of follow-up, there were 732 incident endometrial cancers. NSAID use, compared with non-use of NSAIDs, was not significantly associated with endometrial cancer risk (relative risk (RR) = 0.90, 95% CI: 0.74–1.09). Null associations also were observed by type of NSAID use (aspirin only, RR = 0.88, 95% CI: 0.70–1.11; non-aspirin NSAID [NA-NSAID] only, RR= 1.01, 95% CI: 0.79–1.29; both aspirin and NA-NSAIDs, RR=0.85, 95% CI: 0.68–1.06). Generally, results were not statistically significant by frequency of use for aspirin or non-aspirin NSAIDs. Results did not change when women with a history of heart disease, hypertension, or diabetes were excluded to minimize the potential for confounding by indication. Overall, our data do not support an association between aspirin or NA-NSAID use and endometrial cancer risk.

Background

While many studies have compared the efficacy of Pap cytology, visual inspection with acetic acid (VIA) and human papillomavirus (HPV) DNA assays for the detection cervical intraepithelial neoplasia and cancer, few have evaluated the program effectiveness.

Methods and Findings

A population-based sample of 5603 women from Medchal Mandal in Andhra Pradesh, India were invited to participate in a study comparing Pap cytology, VIA, and HPV DNA screening for the detection of CIN3+. Participation in primary screening and all subsequent follow-up visits was rigorously tracked. A 20% random sample of all women screened, in addition to all women with a positive screening test result underwent colposcopy with directed biopsy for final diagnosis. Sensitivity, specificity, positive and negative predictive values were adjusted for verification bias. HPV testing had a higher sensitivity (100%) and specificity (90.6%) compared to Pap cytology (sensitivity  =  78.2%; specificity = 86.0%) and VIA (sensitivity = 31.6%; specificity = 87.5%). Since 58% of the sample refused involvement and another 28% refused colposcopy or biopsy, we estimated that potentially 87.6% of the total underlying cases of CIN3 and cancer may have been missed due to program failures.

Conclusions

We conclude that despite our use of available resources, infrastructure, and guidelines for cervical cancer screening implementation in resource limited areas, community participation and non-compliance remain the major obstacles to successful reduction in cervical cancer mortality in this Indian population. HPV DNA testing was both more sensitive and specific than Pap cytology and VIA. The use of a less invasive and more user-friendly primary screening strategy (such as self-collected swabs for HPV DNA testing) may be required to achieve the coverage necessary for effective reduction in cervical cancer mortality.

Objective

To relate aspects of online colposcopic image assessment to the diagnosis of grades 2 and 3 cervical intraepithelial neoplasia (CIN2+).

Methods

To simulate colposcopic assessment, digitized cervical images were obtained at enrollment after acetic acid application from 919 women referred for equivocal or minor cytologic abnormalities into the ASCUS-LSIL Triage Study. For each, two randomly assigned evaluators from a pool of 20 colposcopists assessed images using a standardized tool on-line. We calculated the accuracy of these assessments for predicting histologic CIN2+ over the two years of study. For validation, a subset of on-line results was compared to same-day enrollment colposcopic assessments.

Results

Identifying any acetowhite lesion in images yielded high sensitivity: 93% of women with CIN2+ had at least one acetowhite lesion. However, 74% of women without CIN2+ also had acetowhitening, regardless of human papillomavirus (HPV) status. The sensitivity for CIN2+ of an on-line colpophotographic assessment of high grade disease was 39%. The sensitivity for CIN2+ of a high grade diagnosis by Reid Index scoring was 30%, and individual Reid Index component scores had similar levels of sensitivity and specificity. The performance of on-line assessment was not meaningfully different from that of same-day enrollment colposcopy, suggesting that these approaches have similar utility.

Conclusion

Finding acetowhite lesions identifies women with CIN2+, but using subtler colposcopic characteristics to grade lesions is insensitive. All acetowhite lesions should be assessed with biopsy to maximize sensitivity of colposcopic diagnosis with good specificity.

Developing, targeting, and evaluating genomic strategies for population-based disease prevention require population-based data. In response to this urgent need, genotyping has been conducted within the Third National Health and Nutrition Examination (NHANES III), the nationally-representative household-interview health survey in the U.S. However, before these genetic analyses can occur, family relationships within households must be accurately ascertained. Unfortunately, reported family relationships within NHANES III households based on questionnaire data are incomplete and inconclusive with regards to actual biological relatedness of family members. We inferred family relationships within households using DNA fingerprints (Identifiler®) that contain the DNA loci used by law enforcement agencies for forensic identification of individuals. However, performance of these loci for relationship inference is not well understood. We evaluated two competing statistical methods for relationship inference on pairs of household members: an exact likelihood ratio relying on allele frequencies to an Identical By State (IBS) likelihood ratio that only requires matching alleles. We modified these methods to account for genotyping errors and population substructure. The two methods usually agree on the rankings of the most likely relationships. However, the IBS method underestimates the likelihood ratio by not accounting for the informativeness of matching rare alleles. The likelihood ratio is sensitive to estimates of population substructure, and parent-child relationships are sensitive to the specified genotyping error rate. These loci were unable to distinguish second-degree relationships and cousins from being unrelated. The genetic data is also useful for verifying reported relationships and identifying data quality issues. An important by-product is the first explicitly nationally-representative estimates of allele frequencies at these ubiquitous forensic loci.

Objectives

To estimate efficacy of a visual triage of human papillomavirus (HPV)– positive women to either immediate cryotherapy or referral if not treatable (eg, invasive cancer, large precancers).

Methods

We evaluated visual triage in the HPV-positive women aged 25 to 55 years from the 10,000-woman Guanacaste Cohort Study (n = 552). Twelve Peruvian midwives and 5 international gynecologists assessed treatability by cryotherapy using digitized high-resolution cervical images taken at enrollment. The reference standard of treatability was determined by 2 lead gynecologists from the entire 7-year follow-up of the women. Women diagnosed with histologic cervical intraepithelial neoplasia grade 2 or worse or 5-year persistence of carcinogenic HPV infection were defined as needing treatment.

Results

Midwives and gynecologists judged 30.8% and 41.2% of women not treatable by cryotherapy, respectively (P < 0.01). Among 149 women needing treatment, midwives and gynecologists correctly identified 57.5% and 63.8% (P = 0.07 for difference) of 71 women judged not treatable by the lead gynecologists and 77.6% and 59.7% (P < 0.01 for difference) of 78 women judged treatable by cryotherapy. The proportion of women judged not treatable by a reviewer varied widely and ranged from 18.6%to 61.1%. Interrater agreement was poor with mean pairwise overall agreement of 71.4% and 66.3% and κ ’s of 0.33 and 0.30 for midwives and gynecologists, respectively.

Conclusions

In future “screen-and-treat” cervical cancer prevention programs using HPV testing and cryotherapy, practitioners will visually triage HPV-positive women. The suboptimal performance of visual triage suggests that screen-and-treat programs using cryotherapy might be insufficient for treating precancerous lesions. Improved, low-technology triage methods and/or improved safe and low-technology treatment options are needed.