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1.  Associations Between Anthropometry, Cigarette Smoking, Alcohol Consumption, and Non-Hodgkin Lymphoma in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 
American Journal of Epidemiology  2010;171(12):1270-1281.
Prospective studies of lifestyle and non-Hodgkin lymphoma (NHL) are conflicting, and some are inconsistent with case-control studies. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was used to evaluate risk of NHL and its subtypes in association with anthropometric factors, smoking, and alcohol consumption in a prospective cohort study. Lifestyle was assessed via questionnaire among 142,982 male and female participants aged 55–74 years enrolled in the PLCO Trial during 1993–2001. Hazard ratios and 95% confidence intervals were calculated using Cox proportional hazards regression. During 1,201,074 person-years of follow-up through 2006, 1,264 histologically confirmed NHL cases were identified. Higher body mass index (BMI; weight (kg)/height (m)2) at ages 20 and 50 years and at baseline was associated with increased NHL risk (Ptrend < 0.01 for all; e.g., for baseline BMI ≥30 vs. 18.5–24.9, hazard ratio = 1.32, 95% confidence interval: 1.13, 1.54). Smoking was not associated with NHL overall but was inversely associated with follicular lymphoma (ever smoking vs. never: hazard ratio = 0.62, 95% confidence interval: 0.45, 0.85). Alcohol consumption was unrelated to NHL (drinks/week: Ptrend = 0.187). These data support previous studies suggesting that BMI is positively associated with NHL, show an inverse association between smoking and follicular lymphoma (perhaps due to residual confounding), and do not support a causal association between alcohol and NHL.
doi:10.1093/aje/kwq085
PMCID: PMC2915494  PMID: 20494998
alcoholic beverages; anthropometry; body height; body mass index; body weight; life style; lymphoma; non-Hodgkin; smoking
2.  Race and Colorectal Cancer Disparities: Health-Care Utilization vs Different Cancer Susceptibilities 
Background
It is unclear whether the disproportionately higher incidence and mortality from colorectal cancer among blacks compared with whites reflect differences in health-care utilization or colorectal cancer susceptibility.
Methods
A total of 60 572 non-Hispanic white and black participants in the ongoing Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial underwent trial-sponsored screening flexible sigmoidoscopy (FSG) without biopsy at baseline in 10 geographically dispersed centers from November 1993 to July 2001. Subjects with polyps or mass lesions detected by FSG were referred to their physicians for diagnostic workup, the cost of which was not covered by PLCO. The records of follow-up evaluations were collected and reviewed. We used log binomial modeling with adjustment for age, education, sex, body mass index, smoking, family history of colorectal cancer, colon examination within previous 3 years, personal history of polyps, and screening center to examine whether utilization of diagnostic colonoscopy and yield of neoplasia differed by race.
Results
Among 57 561 whites and 3011 blacks who underwent FSG, 13 743 (23.9%) and 767 (25.5%) had abnormal examinations, respectively. A total of 9944 (72.4%) whites and 480 (62.6%) blacks had diagnostic colonoscopy within 1 year following the abnormal FSG screening. When compared with whites, blacks were less likely to undergo diagnostic evaluation (adjusted risk ratio = 0.88, 95% confidence interval = 0.83 to 0.93). Overall, among subjects with diagnostic colonoscopy (n = 10 424), there was no statistically significant difference by race in the prevalence of adenoma, advanced adenoma, advanced pathology in small adenomas (high-grade dysplasia or villous histology in adenomas <10 mm), or colorectal cancer.
Conclusions
We observed a lower follow-up for screen-detected abnormalities among blacks when compared with whites but little difference in the yield of colorectal neoplasia. Health-care utilization may be playing more of a role in colorectal cancer racial disparity than biology.
doi:10.1093/jnci/djq068
PMCID: PMC2857802  PMID: 20357245
3.  Lung Cancer Risk Prediction: Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial Models and Validation 
Introduction
Identification of individuals at high risk for lung cancer should be of value to individuals, patients, clinicians, and researchers. Existing prediction models have only modest capabilities to classify persons at risk accurately.
Methods
Prospective data from 70 962 control subjects in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) were used in models for the general population (model 1) and for a subcohort of ever-smokers (N = 38 254) (model 2). Both models included age, socioeconomic status (education), body mass index, family history of lung cancer, chronic obstructive pulmonary disease, recent chest x-ray, smoking status (never, former, or current), pack-years smoked, and smoking duration. Model 2 also included smoking quit-time (time in years since ever-smokers permanently quit smoking). External validation was performed with 44 223 PLCO intervention arm participants who completed a supplemental questionnaire and were subsequently followed. Known available risk factors were included in logistic regression models. Bootstrap optimism-corrected estimates of predictive performance were calculated (internal validation). Nonlinear relationships for age, pack-years smoked, smoking duration, and quit-time were modeled using restricted cubic splines. All reported P values are two-sided.
Results
During follow-up (median 9.2 years) of the control arm subjects, 1040 lung cancers occurred. During follow-up of the external validation sample (median 3.0 years), 213 lung cancers occurred. For models 1 and 2, bootstrap optimism-corrected receiver operator characteristic area under the curves were 0.857 and 0.805, and calibration slopes (model-predicted probabilities vs observed probabilities) were 0.987 and 0.979, respectively. In the external validation sample, models 1 and 2 had area under the curves of 0.841 and 0.784, respectively. These models had high discrimination in women, men, whites, and nonwhites.
Conclusion
The PLCO lung cancer risk models demonstrate high discrimination and calibration.
doi:10.1093/jnci/djr173
PMCID: PMC3131220  PMID: 21606442
4.  Lung Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial 
Background
The 5-year overall survival rate of lung cancer patients is approximately 15%. Most patients are diagnosed with advanced-stage disease and have shorter survival rates than patients with early-stage disease. Although screening for lung cancer has the potential to increase early diagnosis, it has not been shown to reduce lung cancer mortality rates. In 1993, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was initiated specifically to determine whether screening would reduce mortality rates from PLCO cancers.
Methods
A total of 77 464 participants, aged 55–74 years, were randomly assigned to the intervention arm of the PLCO Cancer Screening Trial between November 8, 1993, and July 2, 2001. Participants received a baseline chest radiograph (CXR), followed by three annual single-view CXRs at the 10 US screening centers. Cancers were classified as screen detected and nonscreen detected (interval or never screened) and according to tumor histology. The positivity rates of screen-detected cancers and positive predictive values (PPVs) were calculated. Because 51.6% of the participants were current or former smokers, logistic regression analysis was performed to control for smoking status. All statistical tests were two-sided.
Results
Compliance with screening decreased from 86.6% at baseline to 78.9% at the last screening. Overall positivity rates were 8.9% at baseline and 6.6%–7.1% at subsequent screenings; positivity rates increased modestly with smoking risk categories (Ptrend < .001). The PPVs for all participants were 2.0% at baseline and 1.1%, 1.5%, and 2.4% at years 1, 2, and 3, respectively; PPVs in current smokers were 5.9% at baseline and 3.3%, 4.2%, and 5.6% at years 1, 2, and 3, respectively. A total of 564 lung cancers were diagnosed, of which 306 (54%) were screen-detected cancers and 87% were non–small cell lung cancers. Among non–small cell lung cancers, 59.6% of screen-detected cancers and 33.3% of interval cancers were early (I–II) stage.
Conclusions
The PLCO Cancer Screening Trial demonstrated the ability to recruit, retain, and screen a large population over multiple years at multiple centers. A higher proportion of screen-detected lung cancers were early stage, but a conclusion on the effectiveness of CXR screening must await final PLCO results, which are anticipated at the end of 2015.
doi:10.1093/jnci/djq126
PMCID: PMC2873186  PMID: 20442215
5.  Prostate cancer specific survival in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial 
Cancer epidemiology  2012;36(6):e401-e406.
Background
The prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized screening trial demonstrated no mortality effect of screening. Here we analyze prostate cancer specific survival in PLCO and its relation to screening.
Methods
76,693 men aged 55–74 were randomized to usual care (n = 38,350) or intervention (n = 38,343). Intervention arm men received annual prostate-specific antigen (6 years) and digital rectal exam (4 years). Men were followed for cancer diagnosis and mortality through 13 years. Medical record abstractors confirmed prostate cancer diagnoses, stage and grade. Prostate-specific survival in PLCO cases was analyzed using Kaplan–Meier analysis and proportional hazards modeling. We utilized data from the Surveillance, Epidemiology and End Results (SEER) program to compute expected survival in PLCO and compared this to observed.
Results
There was no significant difference in prostate-specific survival rates between arms; 10 year survival rates were 94.7% (intervention, n = 4250 cases) versus 93.5% (usual care, n = 3815 cases). Within the intervention arm, cases never screened in PLCO had lower 10 year survival rates (82%) than screen detected or interval (following a negative screen) cases, both around 95.5%. The ratio of observed to expected 10 year prostate-specific death (1-survival) rates was 0.59 (95% CI: 0.51–0.68) for all PLCO cases, 0.66 (95% CI: 0.51–0.81) for Gleason 5–7 cases and 1.07 (95% CI: 0.87–1.3) for Gleason 8–10 cases.
Conclusion
Prostate cancer specific survival in PLCO was comparable across arms and significantly better than expected based on nationwide population data. How much of the better survival is due to a healthy volunteer effect and to lead-time and overdiagnosis biases is not readily determinable.
doi:10.1016/j.canep.2012.08.008
PMCID: PMC3582194  PMID: 23000116
Prostate cancer; Screening; PSA; Survival; Gleason grade
6.  LOW VITAMIN D STATUS IS ASSOCIATED WITH PHYSICAL INACTIVITY, OBESITY AND LOW VITAMIN D INTAKE IN A LARGE US SAMPLE OF HEALTHY MIDDLE-AGED MEN AND WOMEN 
The aim of this study was to investigate modifiable predictors of vitamin D status in healthy individuals, aged 55-74, and living across the USA. Vitamin D status [serum 25-hydroxyvitamin D (25(OH)D)] was measured along with age and season at blood collection, demographics, anthropometry, physical activity (PA), diet, and other lifestyle factors in 1357 male and 1264 female controls selected from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort. Multivariate linear and logistic regression analyses were used to identify associations with vitamin D status. Three, 29 and 79% of the population had serum 25(OH)D levels <25, <50 and <80 nmol/L, respectively. The major modifiable predictors of low vitamin D status were low vitamin D dietary and supplement intake, body mass index (BMI) >30 kg/m2, physical inactivity (PA) and low milk and calcium supplement intake. In men, 25(OH)D was determined more by milk intake on cereal and in women, by vitamin D and calcium supplement and menopausal hormone therapy (MHT) use. Thus targeting an increase in vigorous activity and vitamin D and calcium intake and decreasing obesity could be public health interventions independent of sun exposure to improve vitamin D status in middle-aged Americans.
doi:10.1016/j.jsbmb.2010.03.091
PMCID: PMC2906665  PMID: 20399270
Vitamin D status; 25(OH)D; vitamin D deficiency; exercise; physical activity; obesity; body mass index(BMI); vitamin D dietary and supplement intake; calcium supplement intake; menopausal hormone therapy (MHT); milk intake
7.  Limitations of basing screening policies on screening trials: The US Preventive Services Task Force and prostate cancer screening 
Medical care  2013;51(4):295-300.
Background
The US Preventive Services Task Force recently recommended against prostate-specific antigen (PSA) screening for prostate cancer based primarily on evidence from the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial.
Objective
To examine limitations of basing screening policy on evidence from screening trials.
Methods
We review published modeling studies that examine population and trial data. The studies (1) project the roles of screening and changes in primary treatment in the US mortality decline, (2) extrapolate the ERSPC mortality reduction to the long-term US setting, (3) estimate overdiagnosis based on US incidence trends, and (4) quantify the impact of control arm screening on PLCO mortality results.
Results
Screening plausibly explains 45% and changes in primary treatment can explain 33% of the US prostate cancer mortality decline. Extrapolating the ERSPC results to the long-term US setting implies an absolute mortality reduction at least 5 times greater than that observed in the trial. Approximately 28% screen-detected cases are overdiagnosed in the US versus 58% of screen-detected cases suggested by the ERSPC results. Control arm screening can explain the null result in the PLCO trial.
Conclusions
Modeling studies indicate that population trends and trial results extended to the long-term population setting are consistent with greater benefit of PSA screening—and more favorable harm-benefit tradeoffs—than has been suggested by empirical trial evidence.
doi:10.1097/MLR.0b013e31827da979
PMCID: PMC3604989  PMID: 23269114
Mass screening; policy development; prostatic neoplasms; simulation modeling
8.  Genetic variants in frizzled-related protein (FRZB) and the risk of colorectal neoplasia 
Cancer causes & control : CCC  2008;20(4):487-490.
Objective
The Wnt/APC/β-catenin signaling pathway, which includes frizzled-related protein (FRZB), plays a critical role in the development of colorectal cancer, and recent evidence suggests that the functional polymorphism, FRZB Arg324Gly, may be associated with risk for this disease. To determine if this finding could be replicated, we investigated the association between two FRZB polymorphisms (Arg324Gly and Arg200Trp) and the risk of colorectal adenoma and cancer in nested case-control studies.
Methods
Participants consisted of 1709 adenoma cases, 620 cancer cases, and 1849 controls within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI) for the associations with colorectal neoplasia.
Results
No association was observed for either polymorphism or any haplotypes with colorectal adenoma or colorectal cancer (P > 0.05 for all).
Conclusion
Our study does not support the previously observed association between the FRZB 324Gly variant and colorectal cancer risk. However, further study of additional genetic variants within this pathway is still warranted, given the important role of the Wnt signaling pathway in colorectal carcinogenesis.
doi:10.1007/s10552-008-9274-y
PMCID: PMC2667207  PMID: 19067193
Colorectal adenoma; colorectal cancer; polymorphism; Wnt signaling pathway
9.  The impact of PLCO control arm contamination on perceived PSA screening efficacy 
Cancer causes & control : CCC  2012;23(6):827-835.
Purpose
To quantify the extent to which a clinically significant prostate cancer mortality reduction due screening could have been masked by control arm screening (contamination) in the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial.
Methods
We used three independently developed models of prostate cancer natural history to conduct a virtual PLCO trial. Simulated participants underwent pre-trial screening based on population patterns. The intervention arm followed observed compliance during the trial then resumed population screening. A contaminated control arm followed observed contamination during the trial then resumed population screening, while an uncontaminated control arm discontinued screening upon entry. We assumed a clinically significant screening benefit, applied population treatments and survival patterns, and calculated mortality rate ratios relative to the contaminated and uncontaminated control arms.
Results
The virtual trial reproduced observed incidence, including stage and grade distributions, and control arm mortality after 10 years of complete follow-up. Under the assumed screening benefit, the three models found that contamination increased the mortality rate ratio from 0.68–0.77 to 0.86–0.91, increased the chance of excess mortality in the intervention arm from 0–4% to 15–28%, and decreased the power of the trial to detect a mortality difference from 40–70% to 9–25%.
Conclusions
Our computer simulation models indicate that contamination substantially limited the ability of the PLCO to identify a clinically significant screening benefit. While the trial shows annual screening doesn’t reduce mortality relative to population screening, contamination prevents concluding whether screening reduces mortality relative to no screening.
doi:10.1007/s10552-012-9951-8
PMCID: PMC3556907  PMID: 22488488
Computer simulation; early detection of cancer; mortality; prostate-specific antigen; prostatic neoplasms; randomized controlled trial
10.  Genetic Variation on 9p22 Is Associated with Abnormal Ovarian Ultrasound Results in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 
PLoS ONE  2011;6(7):e21731.
Background
A recent ovarian cancer genome-wide association study (GWAS) identified a locus on 9p22 associated with reduced ovarian cancer risk. The single nucleotide polymorphism (SNP) markers localize to the BNC2 gene, which has been associated with ovarian development.
Methods
We analyzed the association of 9p22 SNPs with transvaginal ultrasound (TVU) screening results and CA-125 blood levels from participants without ovarian cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO); 1,106 women with adequate ultrasound screening results and available genotyping information were included in the study.
Results
We observed a significantly increased risk of abnormal suspicious TVU results for seven SNPs on 9p22, with odds ratios between 1.68 (95% CI: 1.04–2.72) for rs4961501 and 2.10 (95% CI: 1.31–3.38) for rs12379183. Associations were restricted to abnormal suspicious findings at the first TVU screen. We did not observe an association between 9p22 SNPs and CA-125 levels.
Conclusions
Our findings suggest that 9p22 SNPs, which were found to be associated with decreased risk of ovarian cancer in a recent GWAS, are associated with sonographically detectable ovarian abnormalities. Our results corroborate the relevance of the 9p22 locus for ovarian biology. Further studies are required to understand the complex relationship between screening abnormalities and ovarian carcinogenesis and to evaluate whether this locus can influence the risk stratification of ovarian cancer screening.
doi:10.1371/journal.pone.0021731
PMCID: PMC3131287  PMID: 21750727
11.  Allellic variants in regulatory regions of cyclooxygenase-2: association with advanced colorectal adenoma 
British journal of cancer  2005;93(8):953-959.
Cyclooxygenase 2 (Cox-2) is upregulated in colorectal adenomas and carcinomas. Polymorphisms in the Cox-2 gene may influence its function and/or its expression and may modify the protective effect of nonsteroidal anti-inflammatory drugs (NSAIDs), thereby impacting individuals’ risk of developing colorectal cancer and response to prevention/intervention strategies. In a nested case–control study, four polymorphisms in the Cox-2 gene (two in the promoter, −663 insertion/deletion, GT/(GT) and −798 A/G; one in intron 5-5229, T/G; one in 3′ untranslated region (UTR)-8494, T/C) were genotyped in 726 cases of colorectal adenomas and 729 age- and gender-matched controls in the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial. There was no significant association between the Cox-2 polymorphisms and adenoma development in the overall population. However, in males, the relatively rare heterozygous genotype GT/(GT) at −663 in the promoter and the variant homozygous genotype G/G at intron 5-5229 appeared to have inverse associations (odds ratio (OR) = 0.59, confidence interval (CI): 0.34–1.02 and OR = 0.48, CI: 0.24–0.99, respectively), whereas the heterozygous genotype T/C at 3′UTR-8494 had a positive association (OR = 1.31, CI: 1.01–1.71) with adenoma development. Furthermore, the haplotype carrying the risk-conferring 3′UTR-8494 variant was associated with a 35% increase in the odds for adenoma incidence in males (OR = 1.35, CI: 1.07–1.70), but the one with a risk allele at 3′UTR-8494 and a protective allele at intron 5-5229 had no effect on adenoma development (OR = 0.85, CI: 0.66–1.09). Gender-related differences in adenoma risk were also noted with tobacco usage and protective effects of NSAIDs. Our analysis underscores the significance of the overall allelic architecture of Cox-2 as an important determinant for risk assessment.
doi:10.1038/sj.bjc.6602806
PMCID: PMC1369968  PMID: 16205694
cyclooxygenase-2; colorectal adenomas; polymorphisms; haplotypes
12.  Allellic variants in regulatory regions of cyclooxygenase-2: association with advanced colorectal adenoma 
British Journal of Cancer  2005;93(8):953-959.
Cyclooxygenase 2 (Cox-2) is upregulated in colorectal adenomas and carcinomas. Polymorphisms in the Cox-2 gene may influence its function and/or its expression and may modify the protective effect of nonsteroidal anti-inflammatory drugs (NSAIDs), thereby impacting individuals' risk of developing colorectal cancer and response to prevention/intervention strategies. In a nested case–control study, four polymorphisms in the Cox-2 gene (two in the promoter, −663 insertion/deletion, GT/(GT) and −798 A/G; one in intron 5-5229, T/G; one in 3′untranslated region (UTR)-8494, T/C) were genotyped in 726 cases of colorectal adenomas and 729 age- and gender-matched controls in the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial. There was no significant association between the Cox-2 polymorphisms and adenoma development in the overall population. However, in males, the relatively rare heterozygous genotype GT/(GT) at −663 in the promoter and the variant homozygous genotype G/G at intron 5-5229 appeared to have inverse associations (odds ratio (OR)=0.59, confidence interval (CI): 0.34–1.02 and OR=0.48, CI: 0.24–0.99, respectively), whereas the heterozygous genotype T/C at 3′UTR-8494 had a positive association (OR=1.31, CI: 1.01–1.71) with adenoma development. Furthermore, the haplotype carrying the risk-conferring 3′UTR-8494 variant was associated with a 35% increase in the odds for adenoma incidence in males (OR=1.35, CI: 1.07–1.70), but the one with a risk allele at 3′UTR-8494 and a protective allele at intron 5-5229 had no effect on adenoma development (OR=0.85, CI: 0.66–1.09). Gender-related differences in adenoma risk were also noted with tobacco usage and protective effects of NSAIDs. Our analysis underscores the significance of the overall allelic architecture of Cox-2 as an important determinant for risk assessment.
doi:10.1038/sj.bjc.6602806
PMCID: PMC1369968  PMID: 16205694
cyclooxygenase-2; colorectal adenomas; polymorphisms; haplotypes
13.  Serum C-Reactive Protein and Risk of Pancreatic Cancer in Two Nested, Case-Control Studies 
Background
Many epidemiologic studies have examined the association between CRP and risk of cancer with inconsistent results.
Methods
We conducted two nested, case-control studies in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial to test whether pre-diagnostic circulating CRP concentrations were associated with pancreatic adenocarcinoma. Between 1985 and 2004, 311 cases occurred in ATBC and between 1994 and 2006, 182 cases occurred in PLCO. Controls (n=510 in ATBC, n=374 in PLCO) were alive at the time the case was diagnosed and were matched by age, date of blood draw, sex, and race. We used conditional logistic regression adjusted for smoking to calculate odds ratios (OR) and 95% confidence intervals (CI) for pancreatic cancer.
Results
CRP concentrations (ng/ml) tended to be inversely or not associated with pancreatic cancer risk in ATBC, PLCO, and combined analyses (per standardized quintile increase in CRP, continuous OR= 0.94, 95% CI 0.89, 0.99; OR=0.99, 95% CI 0.95, 1.04; OR=0.98, 95% CI 0.95, 1.01, respectively). In combined analyses, we observed a significant interaction (p-interaction=0.02) such that inverse associations were suggestive in younger (OR=0.95; 95% CI, 0.90–1.01), but not older participants.
Conclusion
Our results do not support the hypothesis that higher CRP concentrations are associated with incident pancreatic cancer.
Impact
Our results highlight the importance of investigating more specific biomarkers for inflammation that may reflect the biological mechanisms underlying pancreatic cancer in prospective cohort studies.
doi:10.1158/1055-9965.EPI-10-1024
PMCID: PMC3495286  PMID: 21173171
CRP; ATBC; PLCO; Pancreatic; Case-Control
14.  Selection Criteria for Lung-Cancer Screening 
The New England journal of medicine  2013;368(8):728-736.
BACKGROUND
The National Lung Screening Trial (NLST) used risk factors for lung cancer (e.g., ≥30 pack-years of smoking and <15 years since quitting) as selection criteria for lung-cancer screening. Use of an accurate model that incorporates additional risk factors to select persons for screening may identify more persons who have lung cancer or in whom lung cancer will develop.
METHODS
We modified the 2011 lung-cancer risk-prediction model from our Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to ensure applicability to NLST data; risk was the probability of a diagnosis of lung cancer during the 6-year study period. We developed and validated the model (PLCOM2012) with data from the 80,375 persons in the PLCO control and intervention groups who had ever smoked. Discrimination (area under the receiver-operating-characteristic curve [AUC]) and calibration were assessed. In the validation data set, 14,144 of 37,332 persons (37.9%) met NLST criteria. For comparison, 14,144 highest-risk persons were considered positive (eligible for screening) according to PLCOM2012 criteria. We compared the accuracy of PLCOM2012 criteria with NLST criteria to detect lung cancer. Cox models were used to evaluate whether the reduction in mortality among 53,202 persons undergoing low-dose computed tomographic screening in the NLST differed according to risk.
RESULTS
The AUC was 0.803 in the development data set and 0.797 in the validation data set. As compared with NLST criteria, PLCOM2012 criteria had improved sensitivity (83.0% vs. 71.1%, P<0.001) and positive predictive value (4.0% vs. 3.4%, P = 0.01), without loss of specificity (62.9% and. 62.7%, respectively; P = 0.54); 41.3% fewer lung cancers were missed. The NLST screening effect did not vary according to PLCOM2012 risk (P = 0.61 for interaction).
CONCLUSIONS
The use of the PLCOM2012 model was more sensitive than the NLST criteria for lung-cancer detection.
doi:10.1056/NEJMoa1211776
PMCID: PMC3929969  PMID: 23425165
15.  Pathologic Findings Following False-Positive Screening Tests for Ovarian Cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial 
Gynecologic oncology  2010;120(3):474-479.
Objective
In the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), ovarian cancer screening with transvaginal ultrasound (TVU) and CA-125 produced a large number of false-positive tests. We examined relationships between histopathologic diagnoses, false-positive test group, and participant and screening test characteristics.
Methods
The PLCO ovarian cancer screening arm included 39,105 women aged 55-74 years assigned to annual CA-125 and TVU. Histopathologic diagnoses from women with false-positive tests and subsequent surgery were reviewed in this analysis: all CA125+ (n=121); all CA125+/TVU+ (n=46); and a random sample of TVU+ (n=373). Demographic and ovarian cancer risk factor data were self-reported. Pathologic diagnoses were abstracted from surgical pathology reports. We compared participant characteristics and pathologic diagnoses by category of false-positive using Pearson χ2, Fisher's exact, or Wilcoxon-Mann-Whitney tests.
Results
Women with a false-positive TVU were younger (P < 0.001), heavier (P < 0.001), and reported a higher frequency of prior hysterectomy (P < 0.001). Serous cystadenoma, the most common benign ovarian diagnosis, was more frequent among women with TVU+ compared to CA-125+ and CA-125+/TVU+ (P < 0.001). Benign non-ovarian findings were commonly associated with all false-positives, although more frequently with CA-125+ than TVU+ or CA-125+/TVU+ groups (P=0.019). Non-ovarian cancers were diagnosed most frequently among CA-125+ (P < 0.001).
Conclusions
False-positive ovarian cancer screening tests were associated with a range of histopathologic diagnoses, some of which may be related to patient and screening test characteristics. Further research into the predictors of false-positive ovarian cancer screening tests may aid efforts to reduce false-positive results.
doi:10.1016/j.ygyno.2010.11.015
PMCID: PMC3040283  PMID: 21144559
16.  Flexible Sigmoidoscopy in the Randomized Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial: Added Yield from a Second Screening Examination 
Background
Among randomized trials evaluating flexible sigmoidoscopy (FSG) for its effect on colorectal cancer mortality, only the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial screened its participants more than one time. We report outcomes from the PLCO screening FSG program and evaluate the increased yield produced by a second FSG.
Methods
Participants were screened by 60-cm FSG in 10 regional screening centers at study entry and 3 or 5 years later, depending on the time of random assignment. Results from subsequent diagnostic intervention were tracked and recorded in a standardized fashion, and outcomes were compared according to sex and age. The protocol discouraged repeat FSG in persons with colorectal cancer or adenoma diagnosed after the initial FSG.
Results
Of 77 447 enrollees, 67 073 (86.6%) had at least one FSG and 39 443 (50.9%) had two FSGs. Diagnostic intervention occurred in 74.9% after a positive first FSG and in 78.7% after a positive repeat FSG. The second FSG increased the screening yield by 32%: Colorectal cancer or advanced adenoma was detected in 37.8 per 1000 persons after first screening and in 49.8 per 1000 persons after all screenings. The second FSG increased the yield of cancer or advanced adenoma by 26% in women and by 34% in men. Of 223 subjects who received a diagnosis of colorectal carcinoma within 1 year of a positive FSG, 64.6% had stage I and 17.5% had stage II disease.
Conclusions
Repeat FSG increased the detection of colorectal cancer or advanced adenoma in women by one-fourth and in men by one-third. Screen-detected carcinomas were early stage (stage I or II) in greater than 80% of screened persons. Colorectal cancer mortality data from the PLCO, as the definitive endpoint, will follow in later publications.
doi:10.1093/jnci/djr549
PMCID: PMC3283538  PMID: 22298838
17.  Relationship between Detection of Adenomas by Flexible Sigmoidoscopy and Interval Distal Colorectal Cancer 
Background & Aims
Low rates of adenoma detection by colonoscopy have been associated with increased rates of interval colorectal cancer. We evaluated the relationship between the rate of adenoma detection by flexible sigmoidoscopy and interval, distal colorectal cancer.
Methods
We analyzed data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer screening trial, which used flexible sigmoidoscopy as a colorectal cancer screening modality (46,835 subjects, 66,711 examinations by 93 examiners). An adenoma detection rate was defined for each examiner as the number of exams that identified adenomas (confirmed by pathology analysis) divided by the total number of screening exams. Interval cancers were defined as cancers presumed detectable but not detected, based on the stage at diagnosis and the elapsed time from screening to diagnosis.
Results
The PLCO study identified 32 distal interval cancers. The incidence of interval cancer for individuals screened by examiners in the lowest quartile of distal adenoma detection (2.0%–7.2%) was 9.0/10,000 examinations, whereas the incidence of interval cancers was lower among individuals whose examiners were in higher quartiles of adenoma detection, ranging from 3.0-5.4/10,000 exams. The odds of distal interval cancer were significantly increased for patients of examiners in the lowest quartile of distal adenoma detection (<7.2%) with an adjusted odds ratio of 2.4 (95% confidence interval [CI], 1.1–5.0; P=.02).
Conclusions
Lower levels of adenoma detection by flexible sigmoidoscopy increase the risk for distal, interval cancer. Detection of distal adenomas is a marker of the performance quality of flexible sigmoidoscopy. The parent study is registered under ClinicalTrials.gov, number NCT00002540.
doi:10.1016/j.cgh.2012.08.002
PMCID: PMC3525787  PMID: 22902761
sigmoidoscopy quality; adenoma detection rate; colorectal cancer prevention; epidemiology
18.  Ovarian Cancer Biomarker Performance in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Specimens 
Establishing a cancer screening biomarker’s intended performance requires “phase III” specimens obtained in asymptomatic individuals before clinical diagnosis rather than “phase II” specimens obtained from symptomatic individuals at diagnosis. We used specimens from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial to evaluate ovarian cancer biomarkers previously assessed in phase II sets.
Phase II specimens from 180 ovarian cancer cases and 660 benign disease or general population controls were assembled from four Early Detection Research Network (EDRN) or Ovarian Cancer Specialized Program of Research Excellence (SPORE) sites and used to rank 49 biomarkers. Thirty-five markers, including 6 additional markers from a fifth site, were then evaluated in PLCO proximate specimens from 118 women with ovarian cancer and 474 matched controls.
Top markers in phase II specimens included CA125, HE4, transthyretin, CA15.3, and CA72.4 with sensitivity at 95% specificity ranging from 0.73 to 0.40. Except for transthyretin, these markers had similar or better sensitivity when moving to phase III specimens that had been drawn within six months of the clinical diagnosis. Performance of all markers declined in phase III specimens more remote than 6 months from diagnosis.
Despite many promising new markers for ovarian cancer, CA125 remains the single-best biomarker in the phase II and phase III specimens tested in this study.
doi:10.1158/1940-6207.CAPR-10-0195
PMCID: PMC3085251  PMID: 21372036
Ovarian neoplasms; CA125; HE4; Screening tests; CA72.4
19.  Xenobiotic Metabolizing Gene Variants, Dietary Heterocyclic Amine Intake and Risk of Prostate Cancer 
Cancer research  2009;69(5):1877-1884.
We recently reported that heterocyclic amines (HCAs) are associated with prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We now employ extensive genetic data from this resource to determine if risks associated with dietary HCAs (PhIP, MeIQx, DiMeIQx) from cooked meat are modified by single nucleotide polymorphisms (SNPs) in genes involved in HCA metabolism (CYP1A1, CYP1A2, CYP1B1, GSTA1, GSTM1, GSTM3, GSTP1, NAT1, NAT2, SULT1A1, SULT1A2, and UGT1A locus). We conducted a nested case-control study that included 1,126 prostate cancer cases and 1,127 controls selected for a genome-wide association study for prostate cancer. Unconditional logistic regression was used to estimate odds ratios (ORs), 95% confidence intervals (CIs) and p-values for the interaction between SNPs, HCA intake and risk of prostate cancer. The strongest evidence for an interaction was noted between DiMeIQx and MeIQx and the polymorphism rs11102001 downstream of the GSTM3 locus (p-interaction 0.001 for both HCAs; statistically significant after correction for multiple testing). Among men carrying the A variant, the risk of prostate cancer associated with high DiMeIQx intake was two-fold greater than those with low intake (OR=2.3, 95% CI: 1.2-4.7). The SNP, rs11102001, which encodes a nonsynonymous amino acid change P356S in EPS8L3, is a potential candidate modifier of the effect of HCAs on prostate cancer risk. The observed effect provides evidence to support the hypothesis that HCAs may act as promoters of malignant transformation by altering mitogenic signaling.
doi:10.1158/0008-5472.CAN-08-2447
PMCID: PMC2662592  PMID: 19223546
heterocyclic amines; prostate cancer; single nucleotide polymorphisms; xenobiotic metabolizing enzymes
20.  Genetic variation in innate immunity and inflammation pathways associated with lung cancer risk 
Cancer  2012;118(22):5630-5636.
Background
Pulmonary inflammation may contribute to lung cancer etiology. We conducted a broad evaluation of the association of single nucleotide polymorphisms (SNPs) in innate immunity and inflammation pathways with lung cancer risk, and conducted comparisons with a lung cancer genome wide association study (GWAS).
Methods
We included 378 lung cancer cases and 450 controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. An Illumina GoldenGate oligonucleotide pool assay was used to genotype 1,429 SNPs. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for each SNP, and p-values for trend were calculated. For statistically significant SNPs (p-trend<0.05), we replicated our results with genotyped or imputed SNPs in the GWAS, and adjusted p-values for multiple testing.
Results
In our PLCO analysis, we observed a significant association between 81 SNPs located in 44 genes and lung cancer (p-trend<0.05). Of these 81 SNPS, there was evidence for confirmation in the GWAS for 10 SNPs. However, after adjusting for multiple comparisons, the only SNP that remained significantly associated with lung cancer in the replication phase was rs4648127 (NFKB1; multiple testing adjusted p-trend=0.02). The CT/TT genotype of NFKB1 was associated with reduced odds of lung cancer in the PLCO study (OR=0.56; 95% CI 0.37–0.86) and the GWAS (OR=0.79; 95% CI 0.69–0.90).
Conclusions
We found a significant association between a variant in the NFKB1 gene and lung cancer risk. Our findings add to evidence implicating inflammation and immunity in lung cancer etiology.
doi:10.1002/cncr.27605
PMCID: PMC3485420  PMID: 23044494
lung cancer; genetics; inflammation; immunity; epidemiology
21.  Genome-Wide Association Study of Serum Selenium Concentrations 
Nutrients  2013;5(5):1706-1718.
Selenium is an essential trace element and circulating selenium concentrations have been associated with a wide range of diseases. Candidate gene studies suggest that circulating selenium concentrations may be impacted by genetic variation; however, no study has comprehensively investigated this hypothesis. Therefore, we conducted a two-stage genome-wide association study to identify genetic variants associated with serum selenium concentrations in 1203 European descents from two cohorts: the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening and the Women’s Health Initiative (WHI). We tested association between 2,474,333 single nucleotide polymorphisms (SNPs) and serum selenium concentrations using linear regression models. In the first stage (PLCO) 41 SNPs clustered in 15 regions had p < 1 × 10−5. None of these 41 SNPs reached the significant threshold (p = 0.05/15 regions = 0.003) in the second stage (WHI). Three SNPs had p < 0.05 in the second stage (rs1395479 and rs1506807 in 4q34.3/AGA-NEIL3; and rs891684 in 17q24.3/SLC39A11) and had p between 2.62 × 10−7 and 4.04 × 10−7 in the combined analysis (PLCO + WHI). Additional studies are needed to replicate these findings. Identification of genetic variation that impacts selenium concentrations may contribute to a better understanding of which genes regulate circulating selenium concentrations.
doi:10.3390/nu5051706
PMCID: PMC3708345  PMID: 23698163
selenium; serum; selenoprotein; genome-wide association study; AGA; NEIL3; SLC39A11
22.  Association between genetic variants in the 8q24 cancer risk regions and circulating levels of androgens and sex-hormone binding globulin 
Background
Genome-wide association studies have identified multiple independent regions on chromosome 8q24 that are associated with cancers of the prostate, breast, colon, and bladder.
Methods
To investigate their biological basis, we examined the possible association between 164 single nucleotide polymorphism (SNPs) in the 8q24 risk regions, spanning 128,101,433–128,828,043 bp, and serum androgen (testosterone, androstenedione, 3αdiol G, and bioavailable testosterone) and sex hormone-binding globulin levels in 563 healthy, non-Hispanic, Caucasian men (55–74 years old) from a prospective cohort study, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Age-adjusted linear regression models were used to determine the association between the SNPs in an additive genetic model and log transformed biomarker levels.
Results
Three adjacent SNPs centromeric to prostate cancer risk-region 2 (rs12334903, rs1456310, and rs980171) were associated with testosterone (P<1.1×10−3) and bioavailable testosterone (P<6.3×10−4). Suggestive associations were seen for a cluster of 9 SNPs in prostate cancer risk region 1 and androstenedione (P<0.05).
Conclusions
These preliminary findings require confirmation in larger studies, but raise the intriguing hypothesis that genetic variations in the 8q24 cancer risk regions may correlate with androgen levels.
Impact
These results may provide some clues for the strong link between 8q24 and prostate cancer risk.
doi:10.1158/1055-9965.EPI-10-0101
PMCID: PMC2901401  PMID: 20551303
8q24; genetic polymorphisms; serum androgens
23.  Prospective study of genomic hypomethylation of leukocyte DNA and colorectal cancer risk 
Background
Systematic genome-wide reductions of methylated cytosine (5-mC) levels have been observed in colorectal cancer tissue and are suspected to play a role in carcinogenesis, possibly as a consequence of inadequate folate intake. Reduced 5-mC levels in peripheral blood leukocytes have been associated with increased risk of colorectal cancer and adenoma in cross-sectional studies.
Methods
To minimize disease- and/or treatment-related effects, we studied leukocyte 5-mC levels in prospectively collected blood specimens of 370 cases and 493 controls who were cancer-free at blood collection from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial., Leukocyte 5-mC level was determined by an HPLC/Tandem Mass Spectrometry method and expressed as the relative amount of methyl- to total cytosine residues, or %5-mC. We estimated the association between colorectal cancer risk and %5-mC categories by computing odds ratios (ORs) and 95% confidence intervals (CIs) through logistic regression modeling.
Results
We observed no dose-dependent association between colorectal cancer and %5-mC categories (lowest tertile vs. highest: OR=1.14, 95% CI=0.80–1.63; P trend=0.51). However, among subjects whose 5-mC levels were at the highest tertile, we observed an inverse association between natural folate intake and colorectal cancer (highest tertile of natural folate vs. lowest: OR=0.35, 95% CI=0.17–0.71; P trend=0.003; P interaction=0.003).
Conclusions
This prospective investigation show no clear association between leukocyte 5-mC level and subsequent colorectal cancer risk, but a suggestive risk modification between 5-mC level and natural folate intake.
Impact
Adequate folate status may protect against colorectal carcinogenesis through mechanisms involving adequate DNA methylation in the genome.
doi:10.1158/1055-9965.EPI-12-0700-T
PMCID: PMC3493855  PMID: 23001241
5-mC; PLCO; folate; colorectal
24.  Genome-wide association study of circulating retinol levels 
Human Molecular Genetics  2011;20(23):4724-4731.
Retinol is one of the most biologically active forms of vitamin A and is hypothesized to influence a wide range of human diseases including asthma, cardiovascular disease, infectious diseases and cancer. We conducted a genome-wide association study of 5006 Caucasian individuals drawn from two cohorts of men: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We identified two independent single-nucleotide polymorphisms associated with circulating retinol levels, which are located near the transthyretin (TTR) and retinol binding protein 4 (RBP4) genes which encode major carrier proteins of retinol: rs1667255 (P =2.30× 10−17) and rs10882272 (P =6.04× 10−12). We replicated the association with rs10882272 in RBP4 in independent samples from the Nurses’ Health Study and the Invecchiare in Chianti Study (InCHIANTI) that included 3792 women and 504 men (P =9.49× 10−5), but found no association for retinol with rs1667255 in TTR among women, thus suggesting evidence for gender dimorphism (P-interaction=1.31× 10−5). Discovery of common genetic variants associated with serum retinol levels may provide further insight into the contribution of retinol and other vitamin A compounds to the development of cancer and other complex diseases.
doi:10.1093/hmg/ddr387
PMCID: PMC3209826  PMID: 21878437
25.  Intra-individual variability over time in serum cytokine levels among participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial 
Cytokine  2011;56(2):145-148.
Background
Serum measurements of cytokines, mediators of various B cell and T cell activities, are important markers of inflammation and immune dysregulation. We assessed the reproducibility of serum cytokine measurements over a five-year period among participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO).
Methods
Levels of 13 cytokines [interleukin (IL) 1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, interferon-gamma (IFNγ), granulocyte macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-α (TNFα)] in stored sera from three collections (study baseline, +1 yr, and +5 yr) among 28 randomly selected PLCO participants were measured using a high-sensitivity Luminex xMap-based multiplex panel. Within- and between-subject components of variance were estimated from random effects models and were used to calculate the coefficient of variation (CV) and intraclass correlation coefficient (ICC) for analytes with <30% of samples below the limit of detection (LOD). Spearman correlation coefficients between measurements of the same analyte over time and between analytes were also calculated.
Results
Among the six cytokines with <30% of samples below the LOD, we observed excellent reproducibility for IL-6, IL-7, IL-13, and TNFα (ICC ≥ 0.73), and fair to good reproducibility for IL-8 (ICC = 0.55) and IL-10 (ICC = 0.60). Spearman correlation coefficients comparing paired measurements of each cytokine at baseline and at +5 yr were high (ρ ≥ 0.74) with the exception of IL-10 (ρ = 0.44).
Conclusions
These results suggest that measurements of most of the cytokines evaluated in this study were highly reproducible over a five-year period.
doi:10.1016/j.cyto.2011.06.012
PMCID: PMC3185107  PMID: 21764327
cytokines; inflammation; variability; serum; cancer

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