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1.  Absolute Risk Prediction of Second Primary Thyroid Cancer Among 5-Year Survivors of Childhood Cancer 
Journal of Clinical Oncology  2012;31(1):119-127.
Purpose
We developed three absolute risk models for second primary thyroid cancer to assist with long-term clinical monitoring of childhood cancer survivors.
Patients and Methods
We used data from the Childhood Cancer Survivor Study (CCSS) and two nested case-control studies (Nordic CCSS; Late Effects Study Group). Model M1 included self-reported risk factors, model M2 added basic radiation and chemotherapy treatment information abstracted from medical records, and model M3 refined M2 by incorporating reconstructed radiation absorbed dose to the thyroid. All models were validated in an independent cohort of French childhood cancer survivors.
Results
M1 included birth year, initial cancer type, age at diagnosis, sex, and past thyroid nodule diagnosis. M2 added radiation (yes/no), radiation to the neck (yes/no), and alkylating agent (yes/no). Past thyroid nodule was consistently the strongest risk factor (M1 relative risk [RR], 10.8; M2 RR, 6.8; M3 RR, 8.2). In the validation cohort, 20-year absolute risk predictions for second primary thyroid cancer ranged from 0.04% to 7.4% for M2. Expected events agreed well with observed events for each model, indicating good calibration. All models had good discriminatory ability (M1 area under the receiver operating characteristics curve [AUC], 0.71; 95% CI, 0.64 to 0.77; M2 AUC, 0.80; 95% CI, 0.73 to 0.86; M3 AUC, 0.75; 95% CI, 0.69 to 0.82).
Conclusion
We developed and validated three absolute risk models for second primary thyroid cancer. Model M2, with basic prior treatment information, could be useful for monitoring thyroid cancer risk in childhood cancer survivors.
doi:10.1200/JCO.2012.41.8996
PMCID: PMC3530689  PMID: 23169509
2.  Blood transfusions and the subsequent risk of cancers in the U.S. elderly 
Transfusion  2013;53(10):2198-2206.
BACKGROUND
Blood transfusions are common in older adults, and also may modulate the immune system. However, the impact of transfusion on cancer risk in the elderly has not been studied.
STUDY DESIGN AND METHODS
Cancer risk after blood transfusion was evaluated in a U.S. population-based case-control study using 552,951 elderly cases identified from cancer registries and 100,000 frequency-matched controls. Transfusions received 0–12 months, 13–30 months and 31–48 months prior to cancer diagnosis or selection date were identified using Medicare claims. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regressions. A Bonferroni correction adjusted for multiple testing.
RESULTS
Transfusions received 0–12 months before cancer diagnosis/selection were associated with significantly elevated risk of cancer overall (OR=2.05; 95% CI: 1.95–2.16), and cancers of the stomach, colon, liver, kidney/renal pelvis/ureter, lymphoma, myeloma and leukemia. No significant associations for cancer overall were observed for the two earlier intervals. No site was associated with transfusions received 13–30 or 31–48 months before diagnosis/selection. Nonetheless, overall cancer risk increased with the number of transfused periods (p-trend < 0.0001).
CONCLUSION
Risk of overall cancer and specific sites was elevated 0–12 months after blood transfusion and associated with multiple transfusions, possibly due to reverse causation, i.e. incipient cancers or cancer precursors causing anemia.
doi:10.1111/trf.12071
PMCID: PMC3633614  PMID: 23320915
Surveillance; Epidemiology and End Results (SEER) registries; SEER-Medicare database; latency periods; transfusion-transmissible infections; transfusion-related immunomodulation (TRIM); reverse causation
3.  Declining Second Primary Ovarian Cancer After First Primary Breast Cancer 
Journal of Clinical Oncology  2013;31(6):738-743.
Purpose
Although ovarian cancer incidence rates have declined in the United States, less is known of ovarian cancer trends among survivors of breast cancer. Therefore, we examined second primary ovarian cancers after first primary breast cancer.
Methods
Data were obtained from the Surveillance, Epidemiology, and End Results program (1973 to 2008). Standardized incidence ratios (SIRs) were calculated as the observed numbers of ovarian cancers among survivors of breast cancer compared with the expected numbers in the general population. Absolute rates were measured as the incidence rates for second primary ovarian cancer by year of diagnosis of the first primary breast cancer adjusted for age of breast cancer diagnosis and years since diagnosis.
Results
SIRs for second primary ovarian cancer were elevated over the entire study period (SIR, 1.24; 95% CI, 1.2 to 1.3), whereas the absolute rates declined with an estimated annual percentage change near 1% (−1.34% to −0.09% per year). Secular trends for second ovarian cancers were similar after estrogen receptor (ER) –positive and ER-negative breast cancers, whereas the age-specific patterns varied significantly by ER expression (P for interaction < .001). The largest SIR was among women age less than 50 years with ER-negative breast cancer (SIR, 4.35; 95% CI, 3.5 to 5.4).
Conclusion
Persistently elevated SIRs along with decreasing absolute rates over the entire study period suggest that ovarian cancers in both the general population and survivors of breast cancer are declining in parallel, possibly because of common risk factor exposures. Analytic studies are needed to further assess the parallel overall trends and the age-specific interaction by ER expression.
doi:10.1200/JCO.2012.43.2757
PMCID: PMC3574269  PMID: 23284037
4.  Human Papillomavirus and Rising Oropharyngeal Cancer Incidence in the United States 
Journal of Clinical Oncology  2011;29(32):4294-4301.
Purpose
Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking.
Patients and Methods
HPV status was determined for all 271 oropharyngeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping (Inno-LiPA), HPV16 viral load, and HPV16 mRNA expression. Trends in HPV prevalence across four calendar periods were estimated by using logistic regression. Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer registries to account for nonrandom selection and to calculate incidence trends. Survival of HPV-positive and HPV-negative patients was compared by using Kaplan-Meier and multivariable Cox regression analyses.
Results
HPV prevalence in oropharyngeal cancers significantly increased over calendar time regardless of HPV detection assay (P trend < .05). For example, HPV prevalence by Inno-LiPA increased from 16.3% during 1984 to 1989 to 71.7% during 2000 to 2004. Median survival was significantly longer for HPV-positive than for HPV-negative patients (131 v 20 months; log-rank P < .001; adjusted hazard ratio, 0.31; 95% CI, 0.21 to 0.46). Survival significantly increased across calendar periods for HPV-positive (P = .003) but not for HPV-negative patients (P = .18). Population-level incidence of HPV-positive oropharyngeal cancers increased by 225% (95% CI, 208% to 242%) from 1988 to 2004 (from 0.8 per 100,000 to 2.6 per 100,000), and incidence for HPV-negative cancers declined by 50% (95% CI, 47% to 53%; from 2.0 per 100,000 to 1.0 per 100,000). If recent incidence trends continue, the annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020.
Conclusion
Increases in the population-level incidence and survival of oropharyngeal cancers in the United States since 1984 are caused by HPV infection.
doi:10.1200/JCO.2011.36.4596
PMCID: PMC3221528  PMID: 21969503
5.  Epstein - Barr virus Serology as a Potential Screening Marker for Nasopharyngeal Carcinoma among High-risk Individuals from Multiplex Families in Taiwan 
Background
Nasopharyngeal carcinoma (NPC) is an EBV associated cancer that is highly treatable when diagnosed early, with 5-year disease-free survival of ~90%. However, NPC is typically diagnosed at advanced stages, where disease-free survival is <50%. There is therefore a need for clinical tools to assist in early NPC detection, particularly in high-risk individuals.
Methods
We evaluated the ability of anti-EBV IgA antibodies to detect incident NPC among high-risk Taiwanese individuals. NPC cases (N=21) and age and sex-matched controls (N=84) were selected. Serum collected prior to NPC diagnosis was tested for ELISA-based IgA markers against the following EBV peptides: EBNA1, VCAp18, EAp138, Ead_p47, and VCAp18 + EBNA1 peptide mixture. The sensitivity, specificity, and screening program parameters were calculated.
Results
EBNA1 IgA had the best performance characteristics. At an optimized threshold value, EBNA1 IgA measured at baseline identified 80% of the high-risk individuals who developed NPC during follow-up (80% sensitivity). However, approximately 40% of high-risk individuals who did not develop NPC also tested positive (false positives). Application of EBNA1 IgA as a biomarker to detect incident NPC in a previously unscreened, high-risk population revealed that 164 individuals needed to be screened to detect 1 NPC and that 69 individuals tested positive per case detected.
Conclusions
EBNA1 IgA proved to be a sensitive biomarker for identifying incident NPC, but future work is warranted to develop more specific screening tools to decrease the number of false positives.
Impact
Results from this study could inform decisions regarding screening biomarkers and referral thresholds for future NPC early-detection program evaluations.
doi:10.1158/1055-9965.EPI-13-1262
PMCID: PMC4082438  PMID: 24769890
Epstein-Barr virus; EBV serology; familial NPC; cancer screening
7.  Long-term Overall and Disease-specific Mortality Associated with Benign Gynecologic Surgery Performed at Different Ages 
Menopause (New York, N.Y.)  2014;21(6):592-601.
Objective
As bilateral salpingo-oophorectomy is frequently performed with hysterectomy for nonmalignant conditions, defining health outcomes associated with benign bilateral salpingo-oophorectomy performed at different ages is critical.
Methods
We assessed mortality risk associated with benign total abdominal hysterectomy or bilateral salpingo-oophorectomy among 52,846 Breast Cancer Detection and Demonstration Project Follow-up Study participants. Surgery and risk factor data were ascertained via baseline interview (1979-1986) and three questionnaires (1987-1998). During follow-up through December 2005 (mean=22.1 years), 13,734 deaths were identified. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and disease-specific mortality following total abdominal hysterectomy or bilateral salpingo-oophorectomy performed by ages 35, 40, 45, 50, or 55 years compared to not having surgery using landmark analyses and multivariable Cox regression.
Results
Undergoing bilateral salpingo-oophorectomy by age 35 was associated with increased mortality risk (HR35 years=1.20, 95% CI: 1.08, 1.34), which decreased with age (HR40 years=1.12, 95% CI: 1.04, 1.21; HR45 years=1.10, 95% CI: 1.03, 1.17). Total abdominal hysterectomy alone performed by age 40 was associated with increased mortality risk to a lesser extent (HR40 years=1.08, 95% CI: 1.01, 1.15). Analyses based on matched propensity scores related to having gynecological surgery yielded similar results. Elevated mortality risks were largely attributable to non-cancer causes.
Conclusions
Benign gynecologic surgeries among young women are associated with increased mortality risk, which attenuates with age.
doi:10.1097/GME.0000000000000118
PMCID: PMC4113222  PMID: 24253486
Bilateral oophorectomy; cohort studies; hysterectomy; mortality
8.  Pre-diagnostic lifestyle factors and survival after colon and rectal cancer diagnosis in the NIH-AARP Diet and Health Study 
Cancer  2014;120(10):1540-1547.
Background
Few studies have examined the relationship of lifestyle factors with mortality among colorectal cancer patients.
Methods
Among NIH-AARP Diet and Health study participants we identified 4,213 colon and 1,514 rectal cancer cases through linkage to state cancer registries and determined date and cause of death using the National Death Index. Lifestyle factors were assessed at baseline and included: healthy diet (measured by Healthy Eating Index 2005; HEI-2005), body mass index (BMI), physical activity, alcohol consumption and smoking. We examined the association of factors individually and combined into a lifestyle score with five-year mortality from all-causes, colorectal cancer, and cardiovascular disease (CVD). We estimated relative risks (RRs) and 95% confidence intervals (CIs) using Cox proportional hazards models.
Results
Among colon cancer survivors, smokers had increased risk of total mortality (RR 1.74; 95% CI 1.45–2.08) and colorectal cancer mortality (1.46; 1.17–1.82), compared to never smokers. Obese (BMI ≥30) individuals had increased risk of all death (1.19; 1.02–1.39) and CVD death (1.84; 1.05–3.23), compared to normal weight (BMI 18.5 to <25) individuals. Compared to those with the lowest lifestyle score, those with the highest score had a 34% lower risk of all-cause mortality (0.66; 0.50–0.87).
Among rectal cancer survivors, individuals in the highest quintile of HEI-2005 scores had reduced all-cause mortality (0.60; 0.42–0.86) compared to those in the lowest. Higher combined lifestyle scores were associated with a 46% lower risk of total mortality (0.54; 0.32–0.91).
Conclusion
Healthier lifestyle before cancer diagnosis was associated with improved overall survival after diagnosis with colorectal cancer.
doi:10.1002/cncr.28573
PMCID: PMC4151292  PMID: 24591061
Colorectal cancer; survivors; diet; body mass index; smoking; lifestyle
9.  Breast Cancer Risk in Older Women: Results from the NIH-AARP Diet and Health Study 
Cancer causes & control : CCC  2014;25(7):843-857.
Background
Divergent risk factors exist for premenopausal and postmenopausal breast cancers, but it is unclear whether differences by age exist among postmenopausal women.
Methods
We examined relationships among 190,872 postmenopausal women, ages 50-71 years recruited during 1995-1996 for the NIH-AARP Diet and Health Study, in whom 7,384 incident invasive breast carcinomas were identified through 2010. Multivariable Cox regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs) associated with breast cancer risk factors by age (50-59, 60-69, ≥70 years).
Results
The only factor showing significant statistical heterogeneity by age (phet=0.001) was menopausal hormone therapy (MHT) duration, but trends were apparent across all ages and the strongest association prevailed among women 60-69 years. Although other risk factors did not show statistically significant heterogeneity by age, we did observe attenuated relations for parity and late age at first birth among older women [e.g., HR for age at first birth ≥30 vs. 20-24=1.62, (95% CI 1.23-2.14) for women 50-59 years vs. 1.12 (0.96-1.31) for ≥70 years]. In contrast, risk estimates associated with alcohol consumption and BMI tended to be slightly stronger among the oldest subjects [e.g., HR for BMI ≥35 vs. 18.5-24.9=1.24 (95% CI 0.97-1.58) for 50-59 years vs. 1.46 (1.26-1.70) for ≥70 years]. These differences were somewhat more pronounced for estrogen receptor positive (ER+) and ductal cancers, tumors predominating among older women. Breast cancer family history, physical activity, and previous breast biopsies did not show divergent associations by age.
Conclusion
Although breast cancer risk factor differences among older women were not large, they may merit further consideration with respect to individualized risk prediction.
doi:10.1007/s10552-014-0385-3
PMCID: PMC4426978  PMID: 24810653
10.  Constitutional promoter methylation and risk of familial melanoma 
Epigenetics  2014;9(5):685-692.
Constitutional epigenetic changes detected in blood or non-disease involving tissues have been associated with disease susceptibility. We measured promoter methylation of CDKN2A (p16 and p14ARF) and 13 melanoma-related genes using bisulfite pyrosequencing of blood DNA from 114 cases and 122 controls in 64 melanoma-prone families (26 segregating CDKN2A germline mutations). We also obtained gene expression data for these genes using microarrays from the same blood samples. We observed that CDKN2A epimutation is rare in melanoma families, and therefore is unlikely to cause major susceptibility in families without CDKN2A mutations. Although methylation levels for most gene promoters were very low (<5%), we observed a significantly reduced promoter methylation (odds ratio = 0.63, 95% confidence interval = 0.50, 0.80, P < 0.001) and increased expression (fold change = 1.27, P = 0.048) for TNFRSF10C in melanoma cases. Future research in large prospective studies using both normal and melanoma tissues is required to assess the significance of TNFRSF10C methylation and expression changes in melanoma susceptibility.
doi:10.4161/epi.28151
PMCID: PMC4063827  PMID: 24762620
familial melanoma; CDKN2A; promoter methylation; peripheral blood mononuclear cells; TNFRSF10C
11.  Effect of Changing Breast Cancer Incidence Rates on the Calibration of the Gail Model 
Journal of Clinical Oncology  2010;28(14):2411-2417.
Purpose
The Gail model combines relative risks (RRs) for five breast cancer risk factors with age-specific breast cancer incidence rates and competing mortality rates from the Surveillance, Epidemiology, and End Results (SEER) program from 1983 to 1987 to predict risk of invasive breast cancer over a given time period. Motivated by changes in breast cancer incidence during the 1990s, we evaluated the model's calibration in two recent cohorts.
Methods
We included white, postmenopausal women from the National Institutes of Health (NIH) –AARP Diet and Health Study (NIH-AARP, 1995 to 2003), and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO, 1993 to 2006). Calibration was assessed by comparing the number of breast cancers expected from the Gail model with that observed. We then evaluated calibration by using an updated model that combined Gail model RRs with 1995 to 2003 SEER invasive breast cancer incidence rates.
Results
Overall, the Gail model significantly underpredicted the number of invasive breast cancers in NIH-AARP, with an expected-to-observed ratio of 0.87 (95% CI, 0.85 to 0.89), and in PLCO, with an expected-to-observed ratio of 0.86 (95% CI, 0.82 to 0.90). The updated model was well-calibrated overall, with an expected-to-observed ratio of 1.03 (95% CI, 1.00 to 1.05) in NIH-AARP and an expected-to-observed ratio of 1.01 (95% CI: 0.97 to 1.06) in PLCO. Of women age 50 to 55 years at baseline, 13% to 14% had a projected Gail model 5-year risk lower than the recommended threshold of 1.66% for use of tamoxifen or raloxifene but ≥ 1.66% when using the updated model. The Gail model was well calibrated in PLCO when the prediction period was restricted to 2003 to 2006.
Conclusion
This study highlights that model calibration is important to ensure the usefulness of risk prediction models for clinical decision making.
doi:10.1200/JCO.2009.25.2767
PMCID: PMC2881722  PMID: 20368565
12.  Age at cancer diagnosis among people with AIDS in the United States 
Annals of internal medicine  2010;153(7):452-460.
Background
Studies have reported young ages at cancer diagnosis in HIV-infected people, suggesting that HIV accelerates carcinogenesis. However, these comparisons did not account for differences in population age structures.
Objective
To compare ages at diagnosis for non-AIDS-defining cancers arising in the AIDS and general populations, after adjusting for differences between these populations in age and other demographic characteristics.
Design
Registry linkage study
Setting
15 U.S. HIV/AIDS and cancer registry databases.
Participants
People with AIDS in the HIV/AIDS Cancer Match Study (N=212,055, 1996–2007).
Measurements
We compared the age-at-diagnosis distributions of cancers in the AIDS and general populations, after adjusting for age and other demographics.
Results
The proportion of person-time contributed by older persons (65+ years) was far smaller in the AIDS (1.5%) than the general population (12.5%). Reflecting this difference, the ages at diagnosis for most cancers were ~20 years younger among people with AIDS. However, after adjustment for differences in the populations at risk, the ages at diagnosis in the AIDS and general populations did not differ for most cancers (e.g., no difference in the median ages of colon, prostate or breast cancers; all p>0.1). In contrast, ages at lung (median 50 vs. 54 years) and anal cancer (42 vs. 45 years) were significantly younger in people with AIDS than expected in the general population (p<0.001), and the age at Hodgkin lymphoma was significantly older (42 vs. 40 years, p<0.001).
Limitations
We lacked information on other cancer risk factors, including cigarette smoking. Further, our analysis was restricted to non-Hispanic whites and non-Hispanic blacks who had AIDS, perhaps limiting the generalizability of our findings to other racial and ethnic groups and to people with HIV, but without AIDS.
Conclusions
For most cancers, the age of diagnosis is similar in the AIDS and general populations, after accounting for the ages of the populations at risk. Modest age differences remained for a few cancers, perhaps reflecting acceleration of carcinogenesis by HIV or earlier exposure to cancer risk factors.
doi:10.1059/0003-4819-153-7-201010050-00008
PMCID: PMC3071616  PMID: 20921544
13.  LINE1 methylation levels associated with increased bladder cancer risk in pre-diagnostic blood DNA among US (PLCO) and European (ATBC) cohort study participants 
Epigenetics  2013;9(3):404-415.
Global methylation in blood DNA has been associated with bladder cancer risk in case-control studies, but has not been examined prospectively. We examined the association between LINE1 total percent 5-methylcytosine and bladder cancer risk using pre-diagnostic blood DNA from the United States-based, Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial (PLCO) (299 cases/676 controls), and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) cohort of Finnish male smokers (391 cases/778 controls). Logistic regression adjusted for age at blood draw, study center, pack-years of smoking, and sex was used to estimate odd ratios (ORs) and 95% confidence intervals (CIs) using study- and sex-specific methylation quartiles. In PLCO, higher, although non-significant, bladder cancer risks were observed for participants in the highest three quartiles (Q2–Q4) compared with the lowest quartile (Q1) (OR = 1.36, 95% CI: 0.96 -1.92). The association was stronger in males (Q2–Q4 vs. Q1 OR = 1.48, 95% CI: 1.00–2.20) and statistically significant among male smokers (Q2–Q4 vs. Q1 OR = 1.83, 95% CI: 1.14–2.95). No association was found among females or female smokers. Findings for male smokers were validated in ATBC (Q2–Q4 vs. Q1: OR = 2.31, 95% CI: 1.62–3.30) and a highly significant trend was observed (P = 8.7 × 10−7). After determining that study data could be combined, pooled analysis of PLCO and ATBC male smokers (580 cases/1119 controls), ORs were significantly higher in Q2-Q4 compared with Q1 (OR = 2.03, 95% CI: 1.52–2.72), and a trend across quartiles was observed (P = 0.0001). These findings suggest that higher global methylation levels prior to diagnosis may increase bladder cancer risk, particularly among male smokers.
doi:10.4161/epi.27386
PMCID: PMC4053459  PMID: 24316677
global methylation; bladder cancer; nested case-control; pre-diagnostic blood DNA; PLCO; ATBC
14.  Validation of a Colorectal Cancer Risk Prediction Model Among White Patients Age 50 Years and Older 
Journal of Clinical Oncology  2008;27(5):694-698.
Purpose
Validation of an absolute risk prediction model for colorectal cancer (CRC) by using a large, population-based cohort.
Patients and Methods
The National Institutes of Health (NIH) –American Association of Retired Persons (AARP) diet and health study, a prospective cohort study, was used to validate the model. Men and women age 50 to 71 years at baseline answered self-administered questionnaires that asked about demographic characteristics, diet, lifestyle, and medical histories. We compared expected numbers of CRC patient cases predicted by the model to the observed numbers of CRC patient cases identified in the NIH-AARP study overall and in subgroups defined by risk factor combinations. The discriminatory power was measured by the area under the receiver-operating characteristic curve (AUC).
Results
During an average of 6.9 years of follow-up, we identified 2,092 and 832 incident CRC patient cases in men and women, respectively. The overall expected/observed ratio was 0.99 (95% CI, 0.95 to 1.04) in men and 1.05 (95% CI, 0.98 to 1.11) in women. Agreement between the expected and the observed number of cases was good in most risk factor categories, except for in subgroups defined by CRC screening and polyp history. This discrepancy may be caused by differences in the question on screening and polyp history between two studies. The AUC was 0.61 (95% CI, 0.60 to 0.62) for men and 0.61 (95% CI, 0.59 to 0.62) for women, which was similar to other risk prediction models.
Conclusion
The absolute risk model for CRC was well calibrated in a large prospective cohort study. This prediction model, which estimates an individual's risk of CRC given age and risk factors, may be a useful tool for physicians, researchers, and policy makers.
doi:10.1200/JCO.2008.17.4813
PMCID: PMC2645089  PMID: 19114700
15.  Endometrial thickness and risk of breast and endometrial carcinomas in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 
Postmenopausal women with higher circulating estrogen levels are at increased risk of developing breast and endometrial carcinomas. In the endometrium, excess estrogen relative to progesterone produces a net proliferative stimulus, which may result in endometrial thickening. Therefore, we tested the hypothesis that endometrial thickness is a biological marker of excess estrogen stimulation that is associated with risk of breast and endometrial carcinomas. Endometrial thickness was measured in 1,272 postmenopausal women, aged 55–74, who underwent transvaginal ultrasound (TVU) screening as part of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Serial endometrial thickness measurements were available for a subset of women at one (n=1,018), two (n=869) and three years (n=641) after baseline. We evaluated associations between endometrial thickness and breast (n=91) and endometrial (n=14) carcinoma by estimating relative risks (RRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression with age as the time metric. Models incorporating baseline endometrial thickness and as a time-varying covariate using all measurements were examined. Median follow-up among study participants was 12.5 years (range: 0.3–13.8 years). Compared to baseline endometrial thickness of 1.0 – 2.99 mm, women with baseline endometrial thickness greater than or equal to 5.0 mm had an increased risk of breast (RR: 2.00, 95% CI 1.15, 3.48) and endometrial (RR: 5.02, 95% CI 0.96, 26.36) carcinomas in models adjusted for menopausal hormone use and BMI. Our data suggest that increased endometrial thickness as assessed by TVU was associated with increased risk of breast and endometrial carcinomas.
doi:10.1002/ijc.28404
PMCID: PMC3858514  PMID: 23907658
transvaginal ultrasound; screening; etiology
16.  Constitutive mitochondrial DNA copy number in peripheral blood of melanoma families with and without CDKN2A mutations 
Journal of carcinogenesis & mutagenesis  2014;2014(Suppl 4):006.
Quantitative changes in mitochondrial DNA (mtDNA) have been associated with the risk of a number of human cancers; however, the relationship between constitutive mtDNA copy number in blood and the risk of familial cutaneous malignant melanoma (CMM) has not been reported. We measured mtDNA copy number using quantitative PCR in blood-derived DNA from 136 CMM cases and 302 controls in 53 melanoma-prone families (23 segregating CDKN2A germline mutations). MtDNA copy number did not vary by age, sex, pigmentation characteristics, or CMM status. However, germline CDKN2A mutation carriers had significantly higher mean mtDNA copy number compared to non-carriers, particularly among CMM cases (geometric mean mtDNA copy number of 144 and 111 for carrier versus non-carrier, respectively; P= 0.02). When adjusting for age, sex, and familial correlation, having increasing mtDNA copy number was significantly associated with CDKN2A mutation status among CMM cases (OR=1.47, Ptrend=0.024). In particular, individuals with specific CDKN2A mutations with the potential to inactivate or reduce the level of the p16-INK4 reactive oxygen species (ROS) protective function had significantly increased mtDNA copy number levels (P=0.035). Future research in prospective studies is required to validate these findings and to further investigate mtDNA copy number in both blood and melanoma tissues in relation to CMM risk and CDKN2A mutation status.
doi:10.4172/2157-2518.S4-006
PMCID: PMC4326067  PMID: 25685612
Familial melanoma; CDKN2A; mtDNA copy number; peripheral blood
17.  Evaluation of a multiplex panel of immune-related markers in cervical secretions: a methodologic study 
While persistent carcinogenic human papillomvirus (HPV) infection is necessary for cervical carcinogenesis, the co-factors involved in HPV persistence and disease progression are poorly understood. Chronic cervical inflammation may increase risk, but few studies have measured immune markers (cytokines/chemokines/soluble receptors) in cervical secretions. We evaluated the performance of 74 multiplexed, bead-based immune markers in cervical secretions from three groups of women with biopsy evaluation of cervical intraepithelial neoplasia (CIN): 1) 25% detectability and >80% interclass correlation coefficients (ICC) acceptable for epidemiologic studies. Within-batch coefficients of variation (CV) of ≥25% indicated room for assay improvement. Secondarily, we explored associations between marker levels and CIN/HPV status adjusted for matching variables, assay batch, age, and number of sexual partners. Sixty-two markers (84%) had >25% detectability and ICCs>80%. Of those, 53 (85%) had CVs<25%. Using these preliminary data, we found that HPV-positivity was associated with increased eotaxin-1 (OR: 15.63, 95% CI: 1.26–200.00) and G-CSF (OR: 12.99, 95% CI: 1.10–142.86) among CIN-negative women. There was suggestive evidence that higher chemoattractant marker levels were associated with CIN2/3 (e.g., MIP-1delta, OR: 4.48, 95% CI: 0.87–23.04 versus
doi:10.1002/ijc.28354
PMCID: PMC3872247  PMID: 23824624
Background
Despite growing recognition of an etiologic role for inflammation in lung carcinogenesis, few prospective epidemiologic studies have comprehensively investigated the association of circulating inflammation markers with lung cancer.
Methods
We conducted a nested case–control study (n = 526 lung cancer patients and n = 592 control subjects) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Control subjects were matched to lung cancer case patients on age, sex, follow-up time (median = 2.9 years), randomization year, and smoking (pack-years and time since quitting). Serum levels of 77 inflammation markers were measured using a Luminex bead-based assay. Conditional logistic regression and weighted Cox models were used to estimate odds ratios (ORs) and cumulative risks, respectively.
Results
Of 68 evaluable markers, 11 were statistically significantly associated with lung cancer risk (P trend across marker categories < .05), including acute-phase proteins (C-reactive protein [CRP], serum amyloid A [SAA]), proinflammatory cytokines (soluble tumor necrosis factor receptor 2 [sTNFRII]), anti-inflammatory cytokines (interleukin 1 receptor antagonist [IL-1RA]), lymphoid differentiation cytokines (interleukin 7 [IL-7]), growth factors (transforming growth factor alpha [TGF-A]), and chemokines (epithelial neutrophil-activating peptide 78 [ENA 78/CXCL5], monokine induced by gamma interferon [MIG/CXCL9], B cell–attracting chemokine 1 [BCA-1/CXCL13], thymus activation regulated chemokine [TARC/CCL17], macrophage-derived chemokine [MDC/CCL22]). Elevated marker levels were associated with increased lung cancer risk, with odds ratios comparing the highest vs the lowest group ranging from 1.47 (IL-7) to 2.27 (CRP). For IL-1RA, elevated levels were associated with decreased lung cancer risk (OR = 0.71; 95% confidence interval = 0.51 to 1.00). Associations did not differ by smoking, lung cancer histology, or latency. A cross-validated inflammation score using four independent markers (CRP, BCA-1/CXCL13, MDC/CCL22, and IL-1RA) provided good separation in 10-year lung cancer cumulative risks among former smokers (quartile [Q] 1 = 1.1% vs Q4 = 3.1%) and current smokers (Q1 = 2.3% vs Q4 = 7.9%) even after adjustment for smoking.
Conclusions
Some circulating inflammation marker levels are associated with prospective lung cancer risk.
doi:10.1093/jnci/djt309
PMCID: PMC3888091  PMID: 24249745
Open Forum Infectious Diseases  2014;1(3):ofu110.
Treatment of hepatitis C virus (HCV) infection with ledipasvir/sofosbuvir promises tremendous benefits, but high cost may impede implementation of this regimen. Subgroups with excellent response to 8 weeks of treatment might respond to a shorter course. In ION-3, 423 previously untreated HCV genotype 1-infected patients without cirrhosis had outcome data after receiving ledipasvir/sofosbuvir for 8 weeks. After reanalyzing published ION-3 data, we found that sustained virologic response (SVR) rates varied significantly by gender (P = .002) and rs12979860 genotype (Ptrend = .03), exceeding 98% in women and rs12979860-CC individuals. The very high SVR rates in these subgroups suggest that these factors might be considered in selecting patients to receive 8 weeks of ledipasvir/sofosbuvir and support shorter trials of this regimen in selected patients.
doi:10.1093/ofid/ofu110
PMCID: PMC4324232  PMID: 25734178
clinical trial; cost-effectiveness; direct-acting antiviral agents; gender; hepatitis C virus; IFNL4
Cancer  2013;119(12):2300-2308.
BACKGROUND
Solid organ transplantation recipients have elevated cancer incidence. Estimates of absolute cancer risk after transplantation can inform prevention and screening.
METHODS
The Transplant Cancer Match Study links the US transplantation registry with 14 state/regional cancer registries. The authors used nonparametric competing risk methods to estimate the cumulative incidence of cancer after transplantation for 2 periods (1987–1999 and 2000–2008). For recipients from 2000 to 2008, the 5-year cumulative incidence, stratified by organ, sex, and age at transplantation, was estimated for 6 preventable or screen-detectable cancers. For comparison, the 5-year cumulative incidence was calculated for the same cancers in the general population at representative ages using Surveillance, Epidemiology, and End Results data.
RESULTS
Among 164,156 recipients, 8520 incident cancers were identified. The absolute cancer risk was slightly higher for recipients during the period from 2000 to 2008 than during the period from 1987 to 1999 (5-year cumulative incidence: 4.4% vs 4.2%; P =.006); this difference arose from the decreasing risk of competing events (5-year cumulative incidence of death, graft failure, or retransplantation: 26.6% vs 31.9%; P <.001). From 2000 to 2008, the 5-year cumulative incidence of non-Hodgkin lymphoma was highest at extremes of age, especially in thoracic organ recipients (ages 0–34 years: range, 1.74%–3.28%; aged >50 years; range, 0.36%–2.22%). For recipients aged >50 years, the 5-year cumulative incidence was higher for colorectal cancer (range, 0.33%–1.94%) than for the general population at the recommended screening age (aged 50 years: range, 0.25%–0.33%). For recipients aged >50 years, the 5-year cumulative incidence was high for lung cancer among thoracic organ recipients (range, 1.16%–3.87%) and for kidney cancer among kidney recipients (range, 0.53%–0.84%). The 5-year cumulative incidence for prostate cancer and breast cancer was similar or lower in transplantation recipients than at the recommended ages of screening in the general population.
CONCLUSIONS
Subgroups of transplantation recipients have a high absolute risk of some cancers and may benefit from targeted prevention or screening.
doi:10.1002/cncr.28043
PMCID: PMC4241498  PMID: 23559438
transplantation; screening; non-Hodgkin lymphoma; absolute risk
The transforming growth factor beta (TGF-β) pathway can play either a tumor-suppressing or a tumor-promoting role in human breast carcinogenesis. In order to determine whether expression of TGF-β signaling factors varies by age at onset and breast tumor characteristics that have prognostic significance, we undertook a study of 623 women with invasive breast carcinoma enrolled in a population-based case–control study conducted in Poland from 2000 to 2003. TGF-β signaling factors were analyzed by immunohistochemistry in tumor tissue microarrays. We found that most tumors expressed extracellular-TGF-β1 (78%), TGF-β2 (91%), TGF-β3 (93%), TGF-βR2 (72%), and phospho-SMAD2 (61%), whereas intracellular-TGF-β1 was expressed in 32% of tumors. Expression of TGF-β ligands (β1, β2, and β3) was associated with prognostically favorable pathological features including small size, and low grade, and these associations were similar for ER-positive and negative tumors. On the contrary, expression of the receptor TGF-βR2 was primarily associated with small tumor size among ER-negative tumors, while expression of the transcription factor phospho-SMAD2 was associated with positive nodal status among ER-negative tumors. The greater frequency of expression of phospho-SMAD2 in cancers associated with lymph node metastases is consistent with a pro-progression role for TGF-β. In addition, expression of extracellular-TGF-β1 (P = 0.005), TGF-βR2 (P = 8.2E-11), and phospho-SMAD2 (P = 1.3E-8) was strongly associated with earlier age at onset, independent of ER status. Our data provide evidence that TGF-β signaling patterns vary by age and pathologic features of prognostic significance including ER expression. These results warrant analysis in studies of clinical outcomes accounting for age, ER status and treatment.
doi:10.1007/s10549-009-0590-z
PMCID: PMC4159718  PMID: 19937272
Transforming growth factor beta; Breast cancer; Estrogen receptor
Introduction
Molecular and morphological alterations related to carcinogenesis have been found in terminal duct lobular units (TDLUs), the microscopic structures from which most breast cancer precursors and cancers develop, and therefore, analysis of these structures may reveal early changes in breast carcinogenesis and etiologic heterogeneity. Accordingly, we evaluated relationships of breast cancer risk factors and tumor pathology to estrogen receptor (ER) and progesterone receptor (PR) expression in TDLUs surrounding breast cancers.
Methods
We analyzed 270 breast cancer cases included in a population-based breast cancer case-control study conducted in Poland. TDLUs were mapped in relation to breast cancer: within the same block as the tumor (TDLU-T), proximal to tumor (TDLU-PT), or distant from (TDLU-DT). ER/PR was quantitated using image analysis of immunohistochemically stained TDLUs prepared as tissue microarrays.
Results
In surgical specimens containing ER-positive breast cancers, ER and PR levels were significantly higher in breast cancer cells than in normal TDLUs, and higher in TDLU-T than in TDLU-DT or TDLU-PT, which showed similar results. Analyses combining DT-/PT TDLUs within subjects demonstrated that ER levels were significantly lower in premenopausal women vs. postmenopausal women (odds ratio [OR]=0.38, 95% confidence interval [CI]=0.19, 0.76, P=0.0064) and among recent or current menopausal hormone therapy users compared with never users (OR=0.14, 95% CI=0.046–0.43, Ptrend=0.0006). Compared with premenopausal women, TDLUs of postmenopausal women showed lower levels of PR (OR=0.90, 95% CI=0.83–0.97, Ptrend=0.007). ER and PR expression in TDLUs was associated with epidermal growth factor receptor (EGFR) expression in invasive tumors (P=0.019 for ER and P=0.03 for PR), but not with other tumor features.
Conclusions
Our data suggest that TDLUs near breast cancers reflect field effects, whereas those at a distance demonstrate influences of breast cancer risk factors on at-risk breast tissue. Analyses of mapped TDLUs may provide information about the sequence of molecular changes occurring in breast carcinogenesis.
doi:10.1007/s10549-012-2380-2
PMCID: PMC4154606  PMID: 23271326
terminal duct lobular units (TDLUs); estrogen receptor; progesterone receptor; breast cancer; risk factors; tumor characteristics
Journal of medical virology  2013;85(9):1602-1610.
Risk of Kaposi sarcoma (KS) is linked to detection of Kaposi sarcoma-associated herpesvirus (KSHV) DNA in plasma, but little is known about the prevalence and risk factors for plasma KSHV DNA detection among the general population where KS is endemic. Correlates of KSHV plasma detection were investigated in a population-based sample of adult Ugandans (15–59 years) who participated in an HIV/AIDS serobehavioral survey in 2004/2005. KSHV DNA was measured in plasma of 1,080 KSHV seropositive and 356 KSHV seronegative persons using polymerase chain reaction (PCR). KSHV DNA in plasma was detected in 157 (8.7%) persons; of these 149 (95%) were KSHV seropositive and 8 (5%) were seronegative. Detection of KSHV DNA in plasma was significantly associated with male sex (P<0.001), older age (P=0.003), residence in a rural versus urban area (P=0.002), geographic region (P=0.02), and being KSHV seropositive (13.8% seropositive versus 2.3% seronegative, P<0.001). In a multivariable model, KSHV DNA plasma quantity was significantly higher in men (P=0.002), inversely associated with age (P=0.05), and residing in an urban area (P=0.01). In Uganda, KSHV is detected more frequently in the plasma of adult males and residents of rural regions, potentially explaining the increased risk of KS in these subsets of the Ugandan population.
doi:10.1002/jmv.23613
PMCID: PMC3755768  PMID: 23852686
Kaposi Sarcoma-Associated Herpesvirus; Kaposi Sarcoma; Plasma; Epidemiology; Uganda
Dysplastic nevi (DN) is a strong risk factor for cutaneous malignant melanoma (CMM), and it frequently occurs in melanoma-prone families. To identify genetic variants for DN, we genotyped 677 tagSNPs in 38 melanoma candidate genes that are involved in pigmentation, DNA repair, cell cycle control, and melanocyte proliferation pathways in a total of 504 individuals (310 with DN, 194 without DN) from 53 melanoma-prone families (23 CDKN2A mutation positive and 30 negative). Conditional logistic regression, conditioning on families, was used to estimate the association between DN and each SNP separately, adjusted for age, sex, CMM and CDKN2A status. P-values for SNPs in the same gene were combined to yield gene-specific p-values. Two genes, CDK6 and XRCC1, were significantly associated with DN after Bonferroni correction for multiple testing (P=0.0001 and 0.00025, respectively), whereas neither gene was significantly associated with CMM. Associations for CDK6 SNPs were stronger in CDKN2A mutation positive families (rs2079147, Pinteraction=0.0033), whereas XRCC1 SNPs had similar effects in mutation-positive and negative families. The association for one of the associated SNPs in XRCC1 (rs25487) was replicated in two independent datasets (random effect meta-analysis: P<0.0001). Our findings suggest that some genetic variants may contribute to DN risk independently of their association with CMM in melanoma-prone families.
doi:10.1038/jid.2013.316
PMCID: PMC3873368  PMID: 23892592
The incidence of bladder cancer among women is at least one third to one fourth that observed among men in many countries. Even after accounting for known risk factors, the reason for this gender disparity remains unexplained. We conducted a comprehensive evaluation of reproductive factors and exogenous hormone use with a primary focus on menopausal hormone therapy use and risk of bladder cancer in women in the NIH-AARP Diet and Health Study. Reproductive and hormonal factors were ascertained on the baseline questionnaire in 1995–1996 among 201,492 females who were followed until December 31, 2006. During follow-up, 651 cases of bladder cancer were diagnosed. A subset of women provided detailed information on use of MHT in a second questionnaire in 1996–1997. In this analysis, 127,361 females were followed through June 30, 2002 and 198 incident bladder cancer cases were identified. Cox proportional hazard models, adjusted for smoking status, cigarettes per day, and body mass index using age as the time metric, were used to obtain hazard ratios (HRs). A reduced risk was observed among parous women (HR=0.76; 95% CI 0.62–0.93) and women who reported late age at menarche (≥15 years) (HR=0.57; 95% CI 0.39–0.84). Women who reported ever using estrogen and progestin therapy had a decreased risk (HR=0.53; 95% CI: 0.34–0.83) compared to women who did not report MHT use. No association was observed for estrogen only users (HR=0.82; 95% CI: 0.58–1.15). Our results suggest a putative role for sex hormones in the etiology of bladder cancer among women.
doi:10.1002/ijc.28022
PMCID: PMC3646919  PMID: 23319449
reproductive factors; estrogen; progestin; parity; bladder cancer

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