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1.  Expression of EGFR, VEGF, and NOTCH1 Suggest Differences in Tumor Angiogenesis in HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinoma 
Head and Neck Pathology  2013;7(4):344-355.
There is current interest in anti-angiogenesis therapies for head and neck squamous cell carcinomas (HNSCC), although the utility of these therapies in human papillomavirus (HPV) positive and HPV-negative HNSCC is unclear. Therefore, we explored heterogeneity in expression of a distal factor in angiogenesis (EGFR, the epidermal growth factor receptor), a proximal factor in angiogenesis (VEGF, the vascular endothelial growth factor) and a putative factor in angiogenesis (NOTCH1) in a HNSCC case series using immunohistochemistry in N = 67 cases (27 HPV-positive, 40 HPV-negative, by in situ hybridization). Box plots and the Wilcoxon rank sum or Kruskal–Wallis tests were used to compare staining scores (intensity × percent of cells staining) by HPV status and lifestyle factors. Associations between EGFR, VEGF, and NOTCH1 were assessed using box plots and Spearman correlation (ρ) in all cases, and stratified by HPV status. HPV-negative HNSCC over-expressed EGFR [median (range): 30 (0–300)] relative to HPV-positive HNSCC [7.5 (0–200)] (P = 0.006). VEGF and NOTCH1 were unrelated to HPV status (P > 0.05). EGFR was associated with VEGF in HPV-negative (ρ = 0.40, P = 0.01) but not HPV-positive HNSCC (ρ = 0.25, P = 0.20). NOTCH1 and VEGF were associated in HPV-negative (ρ = 0.40, P = 0.01) but not HPV-positive tumors (ρ = −0.12, P = 0.57). NOTCH1 was not associated with EGFR (P > 0.05). Our results are suggestive of heterogeneity in HNSCC angiogenesis. Future studies should explore angiogenesis mechanisms in HPV-positive and HPV-negative HNSCC.
Electronic supplementary material
The online version of this article (doi:10.1007/s12105-013-0447-y) contains supplementary material, which is available to authorized users.
PMCID: PMC3824798  PMID: 23645351
Head and neck neoplasms; Receptor, epidermal growth factor; Receptor, NOTCH1; Vascular endothelial growth factors; Angiogenic proteins
2.  Erythrocyte Omega-6 and Omega-3 Fatty Acids and Mammographic Breast Density 
Nutrition and cancer  2013;65(3):410-416.
Diets low in omega-6 (n-6) polyunsaturated fatty acids (PUFAs) and high in omega-3 (n-3) PUFAs may protect against breast cancer development. Associations of PUFA intake with mammographic density, an intermediate marker of breast cancer risk, have been inconsistent; however, prior studies have relied on self-reported dietary PUFA intake. We examined the association between circulating erythrocyte n-6 and n-3 PUFAs with mammographic density in 248 postmenopausal women who were not taking exogenous hormones. PUFAs in erythrocytes were measured by gas-liquid chromatography, and mammographic density was assessed quantitatively by planimetry. Spearman’s correlation coefficients and generalized linear models were used to evaluate the relationships between PUFA measures and mammographic density. None of the erythrocyte n-6 or n-3 PUFA measures were associated with percent density or dense breast area.
PMCID: PMC3657737  PMID: 23530640
3.  Comparison of Survival Outcomes Between Patients With Malignant Mixed Mullerian Tumors and High-Grade Endometrioid, Clear Cell, and Papillary Serous Endometrial Cancers 
Malignant mixed mullerian tumors (MMMTs) are an aggressive subtype of endometrial cancer (EC). Previous studies compare survival between high-grade endometrioid (EM), clear cell (CC), and papillary serous (PS) ECs; yet few studies compare MMMTs to these aggressive subtypes. The goal of this study was to compare recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) among EC subtypes.
We conducted a retrospective cohort study of EC cases treated at Magee-Women’s Hospital between 1996 and 2008. Kaplan-Meier estimates of RFS, DSS, and OS as well as and log-rank tests were used to compare survival distributions between histologic subtypes. Cox regression was used to estimate hazard ratios for histologic subtypes, adjusted for other significant prognostic factors. Interactions between histologic subtype and prognostic factors were examined to assess effect modification.
This cohort included 81 MMMT (15%), 254 high-grade EM (46%), 73 CC (13%), and 147 PS (26%) cases. Compared to high-grade EM (6%) and CC (7%) cases, relatively more MMMT (12%) and PS (12%) cases were nonwhite. Stage differed significantly among the subtypes, with 36%, 34%, 37%, and 51% of MMMT, high-grade EM, CC, and PS cases, respectively, diagnosed at advanced late stage (P < 0.001). Kaplan-Meier curves and log-rank tests showed similar RFS, DSS, and OS between MMMT, high-grade EM, CC, and PS cases stratified by stage. In adjusted Cox regression models, RFS and DSS were not significantly different between MMMT and other subtypes. High-grade EM cases had a significantly better OS compared to MMMT cases (HR, 0.63; 95% confidence interval [CI], 0.41–0.98).
This is the first retrospective study to suggest that certain survival outcomes are similar among MMMT, high-grade EM, CC, and PS subtypes. Other large-scale studies are needed to confirm these findings.
PMCID: PMC3827731  PMID: 21666484
Mortality; Aggressive endometrial cancers; Carcinosarcoma
4.  Longitudinal multistage model for lung cancer incidence, mortality, and CT detected indolent and aggressive cancers 
Mathematical biosciences  2012;240(1):20-34.
It is currently not known whether most lung cancers detected by computerized tomography (CT) screening are aggressive and likely to be fatal if left untreated, or if a sizable fraction are indolent and unlikely to cause death during the natural lifetime of the individual. We developed a longitudinal biologically-based model of the relationship between individual smoking histories and the probability for lung cancer incidence, CT screen detection, lung cancer mortality, and other-cause mortality. The longitudinal model relates these different outcomes to an underlying lung cancer disease pathway and an effective other-cause mortality pathway, which are both influenced by the individual smoking history. The longitudinal analysis provides additional information over that available if these outcomes were analyzed separately, including testing if the number of CT detected and histologically-confirmed lung cancers is consistent with the expected number of lung cancers “in the pipeline”. We assume indolent nodules undergo Gompertz growth and are detectable by CT, but do not grow large enough to contribute significantly to symptom-based lung cancer incidence or mortality. Likelihood-based model calibration was done jointly to data from 6,878 heavy smokers without asbestos exposure in the control (placebo) arm of the Carotene and Retinol Efficacy Trial (CARET); and to 3,642 heavy smokers with comparable smoking histories in the Pittsburgh Lung Screening Study (PLuSS), a single-arm prospective trial of low-dose spiral CT screening for diagnosis of lung cancer. Model calibration was checked using data from two other single-arm prospective CT screening trials, the New York University Lung Cancer Biomarker Center (NYU) (n=1,021), and Moffitt Cancer Center (Moffitt) cohorts (n=677). In the PLuSS cohort, we estimate that at the end of year 2, after the baseline and first annual CT exam, that 33.0 (26.9, 36.9)% of diagnosed lung cancers among females and 7.0 (4.9, 11.7)% among males were overdiagnosed due to being indolent cancers. At the end of the PLuSS study, with maximum follow-up of 5.8 years, we estimate that due to early detection by CT and limited follow-up, an additional 2.2 (2.0, 2.4) % of all diagnosed cancers among females and 7.1 (6.7, 8.0) % among males would not have been diagnosed in the absence of CT screening. We also find a higher apparent cure rate for lung cancer among CARET females than males, consistent with the larger indolent fraction of CT detected and histologically confirmed lung cancers among PLuSS females. This suggests that there are significant gender differences in the aggressiveness of lung cancer. Females may have an inherently higher proportion of indolent lung cancers than males, or aggressive lung cancers may be brought into check by the immune system more frequently among females than males.
PMCID: PMC3412888  PMID: 22705252
CT screening; multistage; longitudinal model; lung cancer
5.  Prospective study of genomic hypomethylation of leukocyte DNA and colorectal cancer risk 
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.
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.
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).
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.
Adequate folate status may protect against colorectal carcinogenesis through mechanisms involving adequate DNA methylation in the genome.
PMCID: PMC3493855  PMID: 23001241
5-mC; PLCO; folate; colorectal
6.  CYP2A6 Genotype and Smoking Behavior in Current Smokers Screened for Lung Cancer 
Substance use & misuse  2013;48(7):490-494.
Functional CYP2A6 genetic variation partially determines nicotine metabolism. In 2005, we examined functional CYP2A6 variants associated with reduced metabolism (CYP2A6*2, CYP2A6*9, CYP2A6*4), smoking history, and change in smoking in 878 adult smokers undergoing lung cancer screening in an urban setting. At one year, 216 quit smoking for more than 30 days while 662 continued smoking. Compared to subjects who smoked 30 cigarettes per day at baseline, the odds of a reduced metabolism genotype was 52% higher in subjects smoking 20–29 cigarettes per day and 86% higher in subjects smoking less than 20 cigarettes per day (p-trend = 0.016). Reduced metabolism genotypes appeared unrelated to quitting. Though related to smoking dose, CYP2A6 may not influence cessation.
PMCID: PMC3788637  PMID: 23528144
smoking cessation; smoking initiation; cigarette smoking; genetics; cytochrome P450; nicotine metabolism
7.  Genetic variability in DNA repair and cell cycle control pathway genes and risk of smoking-related lung cancer 
Molecular carcinogenesis  2011;51(Suppl 1):E11-E20.
DNA repair and cell cycle control play an important role in the repair of DNA damage caused by cigarette smoking. Given this role, functionally relevant single nucleotide polymorphisms (SNPs) in genes in these pathways may well affect the risk of smoking-related lung cancer. We examined the relationship between 240 SNPs in DNA repair and cell cycle control pathway genes and lung cancer risk in a case-control study of white current and ex-cigarette smokers (722 cases and 929 controls). Additive, dominant and recessive genetic models were evaluated for each SNP. A genetic risk summary score was also constructed. Odds ratios (OR) for lung cancer risk and 95% confidence intervals (95% CI) were estimated using logistic regression models. Thirty-eight SNPs were associated with lung cancer risk in our study population at P<0.05. The strongest associations were observed for rs2074508 in GTF2H4 (Padditive=0.003), rs10500298 in LIG1 (Precessive=2.7×10−4), rs747658 and rs3219073 in PARP1 (rs747658: Padditive=5.8×10−5; rs3219073: Padditive=4.6×10−5), and rs1799782 and rs3213255 in XRCC1 (rs1799782: Pdominant=0.006; rs3213255: Precessive=0.004). Compared to individuals with first quartile (lowest) risk summary scores, individuals with third and fourth quartile summary score results were at increased risk for lung cancer (OR: 2.21, 95% CI: 1.66–2.95 and OR: 3.44, 95% CI: 2.58–4.59, respectively; Ptrend<0.0001). Our data suggests that variation in DNA repair and cell cycle control pathway genes is associated with smoking-related lung cancer risk. Additionally, combining genotype information for SNPs in these pathways may assist in classifying current and ex-cigarette smokers according to lung cancer risk.
PMCID: PMC3289753  PMID: 21976407
SNP; case-control; lung cancer
8.  Use of fertility drugs and risk of ovarian cancer: results from a US-based case-control study 
Previous studies examining associations between use of fertility drugs and ovarian cancer risk have provided conflicting results. We used data from a large case-control study to determine whether fertility drug use significantly impacts ovarian cancer risk when taking into account parity, gravidity, and cause of infertility.
Data from the Hormones and Ovarian Cancer Prediction (HOPE) study were used (902 cases, 1802 controls). Medical and reproductive histories were collected via in-person interviews. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Models were adjusted for age, race, education, age at menarche, parity, oral contraceptive use, breastfeeding, talc use, tubal ligation, and family history of breast/ovarian cancer.
Ever use of fertility drugs was not significantly associated with ovarian cancer within the total HOPE population (OR: 0.93, 95%CI: 0.65–1.35) or among women who reported seeking medical attention for infertility (OR: 0.87, 95%CI 0.54–1.40). We did observe a statistically significant increased risk of ovarian cancer for ever use of fertility drugs among women who, despite seeking medical attention for problems getting pregnant, remained nulligravid (OR: 3.13, 95%CI 1.01–9.67).
These results provide further evidence that fertility drug use does not significantly contribute to ovarian cancer risk among the majority of women; however, women who despite infertility evaluation and fertility drug use remain nulligravid, may have an elevated risk for ovarian cancer.
Our results suggest that fertility drug use does not significantly contribute to overall risk of ovarian cancer when adjusting for known confounding factors.
PMCID: PMC3415595  PMID: 22707710
ovarian cancer; fertility drugs; infertility; case-control
9.  Survival outcomes in endometrial cancer patients are associated with CXCL12 and estrogen receptor expression 
CXCL12 is a chemotactic cytokine that has pro-metastatic functions in several malignancies through interactions with its receptor, CXCR4. CXCL12 is an estrogen-regulated gene, and notably, estrogen is a major risk factor for endometrial cancer (EC) development. As few studies examine concurrent CXCL12, CXCR4, and estrogen receptor (ER) expression in EC patients, we examined this pathway in 199 EC patients with data from the University of Pittsburgh Medical Center Cancer Registry. Immunohistochemistry (IHC) was used to detect CXCR4, CXCL12, and ER protein expression. As CXCR4 expression was positive in all cases, this investigation focused on associations between CXCL12 and ER expression, clinicopathologic factors, and survival outcomes using chi-square tests, Kaplan-Meier graphs, and log-rank tests. CXCL12 expression was negative in 63 cases (32%) and positive in 136 cases (68%). Negative CXCL12 expression was borderline significantly associated with metastasis (χ2 p=0.07). ER expression was negative in 75 cases (38%) and positive in 124 cases (62%). Positive ER expression was significantly associated with low grade and early stage tumors (χ2 p<0.001). CXCL12 and ER were not significantly associated (χ2 p=0.11). Positive CXCL12 expression was associated with longer overall survival (OS) (log-rank p=0.006) and longer recurrence-free survival (RFS) (log-rank p=0.01) in ER negative patients, but not in ER positive patients. We identified a unique molecular signature associated with better OS and RFS in EC patients. In addition to pathological characteristics of the tumor, expression of CXCL12 and ER may be clinically useful for assigning adjuvant treatment to EC cases.
PMCID: PMC3291748  PMID: 22025313
clear cell; papillary serous; prognostic biomarkers; chemokines; metastasis
10.  Meat-related mutagen exposure, xenobiotic metabolizing gene polymorphisms and the risk of advanced colorectal adenoma and cancer 
Carcinogenesis  2012;33(7):1332-1339.
Meat mutagens, including heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs) and N-nitroso compounds (NOCs), may be involved in colorectal carcinogenesis depending on their activation or detoxification by phase I and II xenobiotic metabolizing enzymes (XME). Using unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), we examined the intake of five meat mutagens and >300 single nucleotide polymorphisms (SNPs) in 18 XME genes in relation to advanced colorectal adenoma (1205 cases and 1387 controls) and colorectal cancer (370 cases and 401 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Dietary intake of meat mutagens was assessed using a food frequency questionnaire with a detailed meat-cooking module. An interaction was observed between 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) intake and the NAT1 polymorphism rs6586714 in the adenoma study (P interaction = 0.001). Among individuals carrying a GG genotype, high MeIQx intake was associated with a 43% increased risk of adenoma (95% CI 1.11–1.85, P trend = 0.07), whereas the reverse was observed among carriers of the A variant (OR = 0.50, 95% CI 0.30–0.84, P trend = 0.01). In addition, we observed some suggestive (P < 0.05) modifying effects for SNPs in other XME genes (UGT1A, CYP2E1, EPHX1, AHR and GSTM3), but these were not significant after adjustment for multiple testing. This large and comprehensive study of XME genes, meat mutagens and the risk of colorectal tumours found that a NAT1 polymorphism modified the association between MeIQx intake and colorectal adenoma risk.
PMCID: PMC3499048  PMID: 22552404
Head & neck  2008;30(9):1139-1147.
Genetic variation in xenobiotic metabolizing enzymes may explain differing susceptibilities to the cancer causing effects of tobacco and alcohol.
We compared 203 oral squamous cell carcinoma cases and 416 controls for single nucleotide polymorphisms (SNPs) in 8 genes (CYP1A1, CYP2E1, MPO, mEH, GSTM1, GSTT1, GSTP1, and NAT2). Except for NAT2, genotype frequencies were similar in the 2 groups. We classified subjects as fast or slow NAT2 acetylators genotyping 13 NAT2 SNPs.
Fast acetylators were overrepresented in cases (53.7%) compared with controls (43.9%; odds ratio (OR) 1.55, 95% confidence interval (CI) 1.08–2.20; p value = .03). Gene–gene interaction testing suggested several cancer-NAT2 associations, with association strongest among persons without a CYP1A1 variant (*2C or *4) allele (OR 1.77, 95% CI 1.20–2.60, p value = .03) or with a variant MPO (463A) allele (OR 2.38, 95% CI 1.34–4.21, p value = .05).
These results implicate fast NAT2 acetylation as a risk factor for oral cancer.
PMCID: PMC3627181  PMID: 18642288
tobacco; oral cancer; polymorphism; metabolizing enzymes; susceptibility
12.  A Multiplexed Serum Biomarker Immunoassay Panel Discriminates Clinical Lung Cancer Patients from High-Risk Individuals Found to be Cancer-Free by CT Screening 
Journal of Thoracic Oncology  2012;7(4):698-708.
Clinical decision-making in the setting of CT screening could benefit from accessible biomarkers that help predict the level of lung cancer risk in high-risk individuals with indeterminate pulmonary nodules.
To identify candidate serum biomarkers, we measured 70 cancer-related proteins by Luminex xMAP® multiplexed immunoassays in a training set of sera from 56 patients with biopsy-proven primary non small cell lung cancer and 56 age-, sex- and smoking-matched CT-screened controls.
We identified a panel of 10 serum biomarkers – prolactin, transthyretin, thrombospondin-1, E-selectin, C-C motif chemokine 5, macrophage migration inhibitory factor, plasminogen activator inhibitor, receptor tyrosine-protein kinase, Cyfra 21.1, and serum amyloid A – that distinguished lung cancer from controls with an estimated balanced accuracy (average of sensitivity and specificity) of 76.0%±3.8% from 20-fold internal cross-validation. We then iteratively evaluated this model in independent test and verification case/control studies confirming the initial classification performance of the panel. The classification performance of the 10-biomarker panel was also analytically validated using ELISAs in a second independent case/control population further validating the robustness of the panel.
The performance of this 10-biomarker panel based model was 77.1% sensitivity/76.2% specificity in cross-validation in the expanded training set, 73.3% sensitivity/93.3% specificity (balanced accuracy 83.3%) in the blinded verification set with the best discriminative performance in Stage I/II cases: 85% sensitivity (balanced accuracy 89.2%). Importantly, the rate of misclassification of CT-screened controls was not different in most control subgroups with or without airflow obstruction or emphysema or pulmonary nodules. These biomarkers have potential to aid in the early detection of lung cancer and more accurate interpretation of indeterminate pulmonary nodules detected by screening CT.
PMCID: PMC3308353  PMID: 22425918
Lung cancer; serum protein biomarkers; CT screening; Luminex xMAP® immunoassays; pulmonary nodules
13.  Flexible Sigmoidoscopy in the Randomized Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial: Added Yield from a Second Screening Examination 
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.
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.
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.
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.
PMCID: PMC3283538  PMID: 22298838
Cancer causes & control : CCC  2008;20(3):375-386.
Vascular endothelial growth factor (VEGF) is a key factor in angiogenesis and is important to carcinogenesis. Previous studies relating circulating levels of VEGF to breast cancer have been limited by small numbers of participants and lack of adjustment for confounders. We studied the association between serum VEGF and breast cancer in an unmatched case-control study of 407 pre- and postmenopausal women (N=203 cases, N=204 controls). Logistic regression was used to model breast cancer risk as a function of natural log transformed VEGF levels adjusted for age, Gail score, education, physical activity, history of breastfeeding, serum testosterone, and hormone therapy use. The majority of the population was postmenopausal (67.6%) and the average age was 56 years; age and menopausal status were similar among cases and controls. Geometric mean VEGF levels were non-significantly higher in cases (321.4 pg/mL) than controls (291.4 pg/mL; p=0.21). In a multivariable model the odds of breast cancer was 37% higher for women with VEGF levels ≥314.2 pg/mL compared to those with levels below 314.2 pg/mL, albeit not significantly (p=0.16). There was no interaction between VEGF and menopausal status (p=0.52). In this case-control study VEGF was not significantly associated with breast cancer risk in pre- and postmenopausal women.
PMCID: PMC3575594  PMID: 18987982
Angiogenesis; breast neoplasms; premenopausal; postmenopausal
15.  Prostate Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: Mortality Results after 13 Years of Follow-up 
The prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was undertaken to determine whether there is a reduction in prostate cancer mortality from screening using serum prostate-specific antigen (PSA) testing and digital rectal examination (DRE). Mortality after 7–10 years of follow-up has been reported previously. We report extended follow-up to 13 years after the trial.
A total of 76 685 men, aged 55–74 years, were enrolled at 10 screening centers between November 1993 and July 2001 and randomly assigned to the intervention (organized screening of annual PSA testing for 6 years and annual DRE for 4 years; 38 340 men) and control (usual care, which sometimes included opportunistic screening; 38 345 men) arms. Screening was completed in October 2006. All incident prostate cancers and deaths from prostate cancer through 13 years of follow-up or through December 31, 2009, were ascertained. Relative risks (RRs) were estimated as the ratio of observed rates in the intervention and control arms, and 95% confidence intervals (CIs) were calculated assuming a Poisson distribution for the number of events. Poisson regression modeling was used to examine the interactions with respect to prostate cancer mortality between trial arm and age, comorbidity status, and pretrial PSA testing. All statistical tests were two-sided.
Approximately 92% of the study participants were followed to 10 years and 57% to 13 years. At 13 years, 4250 participants had been diagnosed with prostate cancer in the intervention arm compared with 3815 in the control arm. Cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10 000 person-years, respectively, resulting in a relative increase of 12% in the intervention arm (RR = 1.12, 95% CI = 1.07 to 1.17). After 13 years of follow-up, the cumulative mortality rates from prostate cancer in the intervention and control arms were 3.7 and 3.4 deaths per 10 000 person-years, respectively, resulting in a non-statistically significant difference between the two arms (RR = 1.09, 95% CI = 0.87 to 1.36). No statistically significant interactions with respect to prostate cancer mortality were observed between trial arm and age (Pinteraction = .81), pretrial PSA testing (Pinteraction = .52), and comorbidity (Pinteraction = .68).
After 13 years of follow-up, there was no evidence of a mortality benefit for organized annual screening in the PLCO trial compared with opportunistic screening, which forms part of usual care, and there was no apparent interaction with age, baseline comorbidity, or pretrial PSA testing.
PMCID: PMC3260132  PMID: 22228146
16.  Effects of ERCC2 Lys751Gln (A35931C) and CCND1 (G870A) polymorphism on outcome of advanced-stage squamous cell carcinoma of the head and neck are treatment dependent 
Germline variation in DNA damage response may explain variable treatment outcomes from squamous cell carcinoma of the head and neck (SCCHN). Grouping patients according to stage and radiation treatment, we compared SCCHN survival according to ERCC2 A35931C (Lys751Gln, rs13181) and CCND1 G870A (Pro241Pro, rs9344) genotypes.
Recruiting a hospital-based SCCHN case series (all white, 24.7% female, mean age 58.4 years), this treatment outcome cohort study genotyped n=275 stage III-IV cases initially treated with radiation (with or without chemotherapy) and n=80 stage III-IV and n=130 stage I-II cases initially treated without radiation or chemotherapy and used Kaplan-Meier and Cox regression analysis to compare genotype groups according to overall, disease-specific, progression-free, and recurrence-free survival.
ERCC2-35931 AA predicted worse survival in stage III-IV treated with radiation (multiply adjusted hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.15-2.40; HR over the first three follow-up years 1.92, 95% CI 1.28-2.88) and better survival in stage III-IV not treated with radiation (HR 0.26, 95% CI 0.11-0.62). Unassociated with survival in stage III-IV treated with radiation (HR 1.00, 95% CI 0.67-1.51), CCND1-870 GG predicted better survival in stage III-IV not treated with radiation (HR 0.14, 95% CI 0.04-0.50). Survival in stage I-II did not depend on ERCC2 A35931C or CCND1 G870A genotype.
Promoting tumor progression in untreated patients, germline differences in DNA repair or cell cycle control may improve treatment outcome in patients treated with DNA damaging agents.
ERCC2 A35931C may help distinguish advanced stage SCCHN with better outcomes from radiation treatment.
PMCID: PMC3210907  PMID: 21890746
17.  Circulating levels of inflammatory markers and mammographic density among postmenopausal women 
Mammographic density is strongly associated with breast cancer risk. Inflammation is involved in breast carcinogenesis, perhaps through effects on mammographic density. We evaluated associations between inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) and mammographic density among postmenopausal women.
Plasma IL-6, TNF-α, and CRP levels were measured in 145 women with benign breast disease (benign controls) and 397 women with a negative screening mammogram (well controls) enrolled in the Mammograms and Masses Study. Associations between the inflammatory markers and mammographic density were evaluated separately for benign and well controls through correlation analyses and linear regressions.
Age-adjusted mean CRP levels were higher among benign controls (2.07 μg/mL) compared to well controls (1.63 μg/mL; p=0.02), while IL-6 and TNF-α levels were similar between groups. Using linear regression, IL-6, TNF-α, and CRP were not statistically significantly associated with dense breast area within either group. Statistically significant positive associations were observed between all three markers and nondense breast area in both groups; statistically significant negative associations were observed between IL-6 and percent density among benign controls, and between all three markers and percent density among well controls. These associations were all attenuated and non-significant upon adjustment for body mass index.
IL-6, TNF-α, and CRP levels were not independently associated with dense breast area, nondense breast area, or percent density in this study population. Our results suggest that these inflammatory factors do not impact breast carcinogenesis through independent effects on mammographic density.
PMCID: PMC3431555  PMID: 21069450
Interleukin-6 (IL-6); Tumor necrosis factor-α (TNF-α); C-reactive protein (CRP); Mammographic density; Postmenopausal
18.  Cost-Identification Analysis of Total Laryngectomy: An Itemized Approach to Hospital Costs 
To understand the contribution of intraoperative and postoperative hospital costs to total hospital costs, examine the costs associated with specific hospital services in the postoperative period, and recognize the impact of patient factors on hospital costs.
Study Design
Case series with chart review.
Large tertiary care teaching hospital system.
Subjects and Methods
Using the Pittsburgh Head and Neck Organ-Specific Database, 119 patients were identified as having total laryngectomy with bilateral selective neck dissection and primary closure from 1999 to 2009. Cost data were obtained for 112 patients. Costs include fixed and variable costs, adjusted to 2010 US dollars using the Consumer Price Index.
Mean total hospital costs were $29 563 (range, $10 915 to $120 345). Operating room costs averaged 24% of total hospital costs, whereas room charges, respiratory therapy, laboratory, pharmacy, and radiology accounted for 38%, 14%, 8%, 7%, and 3%, respectively. Median length of stay was 9 days (range, 6–43), and median Charlson comorbidity index score was 8 (2–16). Patients with ≥1 day in the intensive care unit had significantly higher hospital costs ($46 831 vs $24 601, P < .01). The authors found no significant cost differences with stratification based on previous radiation therapy ($27 598 vs $29 915 with no prior radiation, P = .62) or hospital readmission within 30 days ($29 483 vs $29 609 without readmission, P = .97).
This is one of few studies in surgery and the first in otolaryngology to analyze hospital costs for a relatively standardized procedure. Further work will include cost analysis from multiple centers with investigation of global cost drivers.
PMCID: PMC3419369  PMID: 21493420
cost-effectiveness analysis; laryngeal cancer; health economics; hospital finance
To study the relationship between emphysema, airflow obstruction and lung cancer in a high risk population we performed quantitative analysis of screening computed tomography (CT) scans.
Subjects completed questionnaires, spirometry and low-dose helical chest CT. Analyses compared cases and controls according to automated quantitative analysis of lung parenchyma and airways measures.
Our case-control study of 117 matched pairs of lung cancer cases and controls did not reveal any airway or lung parenchymal findings on quantitative analysis of screening CT scans that were associated with increased lung cancer risk. Airway measures including wall area %, lumen perimeter, lumen area and average wall HU, and parenchymal measures including lung fraction < −910 Hounsfield Units (HU), were not statistically different between cases and controls.
The relationship between visual assessment of emphysema and increased lung cancer risk could not be verified by quantitative analysis of low-dose screening CT scans in a high risk tobacco exposed population.
PMCID: PMC3157578  PMID: 21610523
20.  ADRB2 gene variants, DEXA body composition, and hypertension in Tobago men of African descent 
Classic tissue effects of β2 adrenergic receptor activation include skeletal muscle glycogenolysis and vascular smooth muscle relaxation, factors relevant to obesity and hypertension, respectively. In a population-based study, we examined two common amino acid substitutions in the β2 adrenergic receptor gene (ADRB2) in relation to body composition and blood pressure.
Design and subjects
Cross-sectional analysis of 1893 African-descent men living in Tobago and participating in a prostate cancer screening study.
Body mass index (BMI), waist circumference, blood pressure, dual energy X-ray absorptiometry (DEXA) body composition, and ADRB2 (Arg16Gly; Gln27Glu) genotype.
Twenty-six percent were obese (BMI ≥ 30 kg/m2) and 50% hypertensive. ADRB2 Arg16Gly and Gln27Glu alleles were in linkage disequilibrium (D′=0.96, r2=0.15). ADRB2 16Gly-containing and 27Glu-containing genotypes were equally frequent in low, medium, and high tertiles of percentage body fat mass (16Gly-containing genotypes: 73.4%, 74.4%, 74.5%, ptrend=0.66; 27Glu-containing genotypes: 27.6%, 23.8%, 25.4%, ptrend=0.39) and in normal blood pressure, pre-hypertensive, and hypertensive men (16Gly-containing genotypes: 73.4%, 72.8%, 74.4%, ptrend=0.61; 27Glu-containing genotypes: 25.6%, 24.1%, 26.7%, ptrend=0.50).
In a high obesity and high hypertension risk population with ancestry in common with African-Americans, genetic variation defined by two common ADRB2 amino acid substitutions was not associated with body composition or hypertension.
PMCID: PMC2992095  PMID: 20727557
African ancestry; adrenergic β2 receptor; genetic polymorphism; body composition blood pressure; hypertension
21.  A Method to Estimate Off-Schedule Observations in a Longitudinal Study 
Annals of epidemiology  2011;21(4):297-303.
Data in epidemiological studies sometimes are collected off-schedule from planned study visits. In an ancillary study to the Study of Women's Health Across the Nation (SWAN), longitudinal breast density data were collected retrospectively from mammograms that were not acquired at the study visits. We propose a method to estimate the off-schedule breast density measurements at the time of study visits.
This method uses local linear interpolation, withmultiply imputed error terms drawn from assumed subject-specific normal distributions based on the within-subject standard deviations of mammographic density measurements. We evaluate the validity and implications of this approach.
Coefficients of random intercept models assessing the association between annual changes in body mass index and dense breast area estimated with this approach (β=-0.17, P=0.46) differed from those obtained when each mammogram was matched to the nearest study visit (β=-0.30, P=0.04). The proposed estimation approach had a small average prediction error (0.11 cm2).
Because matching does not incorporatebreast density changes over time, ourlocal linear interpolation with multiple imputation approach may provide more accurate results. The proposed approach is applicable to other epidemiologic studies with off-schedule data where the missing variable changes linearly over relatively short periods of time.
PMCID: PMC3073647  PMID: 21376277
Epidemiologic Methods; Missing Data; Multiple Imputation; Linear Interpolation; Mammography
22.  Radiographic Emphysema Predicts Low Bone Mineral Density in a Tobacco-exposed Cohort 
Rationale: Studies demonstrating an association between chronic obstructive pulmonary disease and low bone mineral density (BMD) implicate factors distinct from treatments and severity of lung disease in the pathogenesis of osteoporosis. Whereas emphysema has been independently associated with vascular disease and other comorbidities, its association with BMD has not been well studied.
Objectives: We explored the associations of BMD with computed tomography (CT) measures of emphysema and other risk factors in current and former smokers.
Methods: One hundred ninety subjects completed a CT scan, pulmonary function testing, questionnaires, and dual x-ray absorptiometry measurements of hip and lumbar spine BMD. Subjects were classified as having normal BMD, osteopenia, or osteoporosis. Demographic, physiologic, and radiographic characteristics were compared and the association of BMD with radiographic emphysema, airflow obstruction, and osteoporosis risk factors was assessed.
Measurements and Main Results: No difference existed in age, tobacco exposure, oral steroid use, or physical activity across BMD categories. Both osteopenia and osteoporosis were associated with the presence of airflow obstruction, inhaled corticosteroid use, and female sex, and demonstrated a significant relationship with the presence of visual emphysema (P = 0.0003). Quantitative emphysema, but not CT-measured indices of airway wall thickness, was inversely associated with BMD. Visual emphysema alone was a significant predictor of osteopenia/osteoporosis (odds ratio = 2.55; 95% confidence interval, 1.24–5.25) in a model including obstruction severity, age, sex, and inhaled and oral steroid use.
Conclusions: Radiographic emphysema is a strong, independent predictor of low BMD in current and former smokers. This relationship suggests a common mechanistic link between emphysema and osteopenia/osteoporosis.
PMCID: PMC3086755  PMID: 20935108
pulmonary disease, chronic obstructive; emphysema; osteoporosis
23.  Lung Cancer Serum Biomarker Discovery Using Label Free LC-MS/MS 
Lung cancer remains the leading cause of cancer-related death with poor survival due to the late stage at which lung cancer is typically diagnosed. Given the clinical burden from lung cancer, and the relatively favorable survival associated with early stage lung cancer, biomarkers for early detection of lung cancer are of important potential clinical benefit.
We performed a global lung cancer serum biomarker discovery study using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in a set of pooled non-small cell lung cancer (NSCLC) case sera and matched controls. Immunoaffinity subtraction was used to deplete the top most abundant serum proteins; the remaining serum proteins were subjected to trypsin digestion and analyzed in triplicate by LC-MS/MS. The tandem mass spectrum data were searched against the human proteome database and the resultant spectral counting data were used to estimate the relative abundance of proteins across the case/control serum pools. The spectral counting derived abundances of some candidate biomarker proteins were confirmed with multiple reaction monitoring MS assays.
A list of 49 differentially abundant candidate proteins was compiled by applying a negative binomial regression model to the spectral counting data (p<0.01). Functional analysis with Ingenuity Pathway Analysis tools showed significant enrichment of inflammatory response proteins, key molecules in cell-cell signaling and interaction network and differential physiological responses for the two common NSCLC subtypes.
We identified a set of candidate serum biomarkers with statistically significant differential abundance across the lung cancer case/control pools which, when validated, could improve lung cancer early detection.
PMCID: PMC3104087  PMID: 21304412
Lung cancer; serum biomarkers; LC-MS/MS
24.  Nuclear Vitamin D Receptor Expression is Associated with Improved Survival in Non-Small Cell Lung Cancer 
Vitamin D has been shown to have anti-proliferative effects in a wide variety of cancers including lung cancer. The anticancer effects of Vitamin D are mediated primarily by its active metabolite, 1,25-dihydroxyvitamin D (calcitriol), through vitamin D receptor (VDR) signaling. However, thus far there have been no studies evaluating the association between VDR expression and survival outcome in lung cancer. Using immunohistochemical analysis, we evaluated VDR expression, separately in the nucleus and cytoplasm, in lung cancer samples from 73 non-small cell lung carcinoma (NSCLC) patients with no prior therapy, and investigated the association between VDR expression and overall survival (OS). Cox proportional hazard models were used for our primary analyses. There were 44 deaths during a median follow-up of 51 months (range 13-93 months). High nuclear VDR expression was associated with improved OS after adjusting for age, gender, stage, smoking status, and histology (adjusted hazard ratio, 0.36; 95% confidence interval, 0.17-0.79). There was no association between cytoplasmic VDR expression and OS. Our results suggest that nuclear VDR status may be a prognostic marker in NSCLC. Future large studies to replicate our findings and to assess the impact of VDR gene polymorphisms on VDR expression are required as therapies targeting the vitamin D signaling pathway may be influenced by VDR status in the target lung cancer tissue.
PMCID: PMC3010457  PMID: 20955794
Vitamin D receptor; Non-small cell lung cancer; Biomarker; Survival; Prognosis
25.  A case-cohort study of human herpesvirus 8 seropositivity and incident prostate cancer in Tobago 
We previously reported a cross-sectional association between the presence of human herpesvirus 8 (HHV-8) serum antibodies and screen-detected prostate cancer in men living in Tobago. In the same study population, we examined the association between HHV-8 seropositivity and incident prostate cancer discovered at later screenings.
In 40-81 year-old men without prostate cancer discovered at initial digital rectal examination (DRE) and prostate-specific antigen (PSA) screening, a case-cohort design measured the association between baseline HHV-8 seropositivity (modified immunofluorescence assay for antibodies against HHV-8 lytic antigens) and incident prostate cancer detected at DRE and PSA screenings three or five years later.
Analyses included 486 unique individuals, 96 incident prostate cancer cases, and 415 randomly selected subjects representing an at-risk cohort. By design, the random sub-cohort contained 25 incident prostate cancer cases. In the sub-cohort, the frequency of HHV-8 seropositivity increased across age groupings (40-49 years: 3.5%, 50-59 years: 13.6%, and ≥ 60 years: 22.9%). HHV-8 seropositivity was higher in men with elevated (≥ 4.0 ng/mL) than men with non-elevated PSA at initial screening (30.4% vs. 9.9% seropositive; crude odds ratio (OR) 3.96, 95% confidence interval (CI) 1.53-10.2; age-adjusted OR 2.42, 95% CI 0.91-6.47). HHV-8 seropositivity did not increase incident prostate cancer risk (age-adjusted hazard ratio (HR) 0.88, 95% CI 0.46-1.69).
Case-cohort analysis did not identify association between HHV-8 seropositivity and incident prostate cancer. However, analyses uncovered possible association between HHV-8 and PSA (a marker of prostate inflammation). Co-occurrence of HHV-8 seropositivity and PSA elevation may explain cross-sectional association between HHV-8 and PSA screen-detected prostate cancer.
PMCID: PMC3248833  PMID: 22151996
human herpesvirus 8; prostate cancer; case-cohort design

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