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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.  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
4.  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
Familial melanoma; CDKN2A; mtDNA copy number; peripheral blood
5.  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
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
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
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
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
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
Clinical endocrinology  2013;79(1):10.1111/cen.12107.
SUMMARY
Objective
Serum thyroglobulin (Tg) has been associated with a number of thyroid disorders and has been proposed as an indicator of iodine deficiency in a population. However, few studies have addressed the epidemiology of Tg in a population-based setting or in the context of exposure to radioactive iodine-131 (I-131). Our objective was to evaluate baseline levels of Tg in relation to socio-demographic characteristics, iodine status, and thyroid function for individuals exposed to I-131.
Design
A population-based cohort assembled in Belarus following the Chornobyl accident provided demographic factors, clinical data, and physiological measurements.
Participants
Our analytic sample included 10,344 subjects of whom 7,890 had no thyroid disease and 2,454 had evidence of structural or functional thyroid abnormality.
Measurements
Standardized assays were used to measure serum Tg, urinary iodine, TSH, and antibodies to Tg and thyroid peroxidase. Ultrasound was used to assess the presence of nodules and estimate thyroid volume.
Results
In the fully adjusted model, percent change in Tg was significantly increased among females, smokers, and subjects of older age and Tg increased with decreasing urinary iodine concentration, increasing serum TSH and increasing thyroid volume (p-values for trend < 0.0001), and presence of thyroid nodules (p < 0.05). We found a complex interaction between region of residence, rural/urban living, presence/absence of thyroid abnormalities, and serum Tg (p < 0.0001).
Conclusions
In residents of Belarus, serum Tg is significantly related to presence of thyroid abnormalities as well as indicators of thyroid function and iodine deficiency and, therefore, could be used to characterize the iodine status and thyroid function of individuals in the context of epidemiological study.
doi:10.1111/cen.12107
PMCID: PMC3870891  PMID: 23190420
Thyroglobulin; Iodine; Thyroid; Chernobyl Nuclear Accident; Republic of Belarus
Transplant recipients have elevated risk for plasma cell neoplasms (PCNs, comprising multiple myeloma and plasmacytoma), but little is known about risk factors in the transplant setting. Through linkage of the U.S. solid organ transplant registry with 15 state/regional cancer registries, we identified 140 PCNs in 202,600 recipients (1987–2009). PCN risk was 1.8-fold increased relative to the general population (standardized incidence ratio [SIR] 1.80, 95%CI 1.51–2.12). Among cases, 102 were multiple myeloma (SIR 1.41) and 38 were plasmacytoma (SIR 7.06). PCN incidence increased with age, but due to the rarity of PCNs in younger people in the general population, SIRs were highest in younger transplant recipients (p=0.03). PCN risk was especially high in recipients who were Epstein-Barr virus (EBV) seronegative at transplantation (SIR 3.93). EBV status was known for 18 tumors, of which 7 (39%) were EBV positive. Following liver transplantation, PCN risk was higher in recipients with cholestatic liver disease (SIR 2.78); 5 of these cases had primary biliary cirrhosis (PBC). A role for primary EBV infection after transplantation is supported by the increased PCN risk in young EBV seronegative recipients and the presence of EBV in tumors. PBC may be another risk factor, perhaps by causing chronic immune activation.
doi:10.1111/ajt.12234
PMCID: PMC3676887  PMID: 23635036
multiple myeloma; plasmacytoma; post-transplant lymphoproliferative disorder; Epstein-Barr virus; immunosuppression; primary biliary cirrhosis
Lifetime data analysis  2013;20(2):252-275.
Absolute risk is the probability that a cause-specific event occurs in a given time interval in the presence of competing events. We present methods to estimate population-based absolute risk from a complex survey cohort that can accommodate multiple exposure-specific competing risks. The hazard function for each event type consists of an individualized relative risk multiplied by a baseline hazard function, which is modeled nonparametrically or parametrically with a piecewise exponential model. An influence method is used to derive a Taylor-linearized variance estimate for the absolute risk estimates. We introduce novel measures of the cause-specific influences that can guide modeling choices for the competing event components of the model. To illustrate our methodology, we build and validate cause-specific absolute risk models for cardiovascular and cancer deaths using data from the National Health and Nutrition Examination Survey. Our applications demonstrate the usefulness of survey-based risk prediction models for predicting health outcomes and quantifying the potential impact of disease prevention programs at the population level.
doi:10.1007/s10985-013-9258-4
PMCID: PMC3883938  PMID: 23686614
Absolute risk; Censored data; Crude risk; Cumulative incidence; NHANES; Survey cohort
Cancer causes & control : CCC  2013;24(4):749-757.
Background
Emerging data suggest that ovarian cancers differ by tumor grade. However, the reliability of microscopic grade as assigned in the general medical community and reflected in cancer registries is unknown.
Methods
We examined grade agreement between two gynecologic pathologists and the Surveillance Epidemiology and End Results (SEER) program. Grade agreement was assessed with percent observer agreement and kappa coefficients for 664 invasive ovarian carcinomas from SEER’s Residual Tissue Repository. We used three-tier and two-tier grading schemes. A random subset of ovarian carcinomas was selected to compare intra- and inter-pathologist agreement.
Results
Five hundred and eighty-six of SEER’s 664 tumors were confirmed invasive. Percent agreement was 49% with fair kappa coefficient = 0.25 (95% CI: 0.20 to 0.30) for the 664 tumors. Agreement improved slightly when restricted to the 586 confirmed invasive cancers; was better for high than low grade tumors, two-tier than three-tier grading systems, and within (66%) than between study pathologists (43%). Tumor grade was not a robust independent predictor of ovarian cancer-specific survival.
Conclusions
Grade agreement was fair irrespective of grading system between SEER and study pathologists. Recorded grade in SEER should be used with caution and is probably not a reliable metric for ovarian cancer epidemiology.
doi:10.1007/s10552-013-0157-5
PMCID: PMC4000689  PMID: 23378140
epidemiology; ovarian cancer; tumor grade; SEER; kappa coefficient
PLoS ONE  2014;9(4):e93219.
Background
Barrett's esophagus (BE) is a metaplastic precursor lesion of esophageal adenocarcinoma (EA), the most rapidly increasing cancer in western societies. While the prevalence of BE is increasing, the vast majority of EA occurs in patients with undiagnosed BE. Thus, we sought to identify genes that are altered in BE compared to the normal mucosa of the esophagus, and which may be potential biomarkers for the development or diagnosis of BE.
Design
We performed gene expression analysis using HG-U133A Affymetrix chips on fresh frozen tissue samples of Barrett's metaplasia and matched normal mucosa from squamous esophagus (NE) and gastric cardia (NC) in 40 BE patients.
Results
Using a cut off of 2-fold and P<1.12E-06 (0.05 with Bonferroni correction), we identified 1324 differentially-expressed genes comparing BE vs NE and 649 differentially-expressed genes comparing BE vs NC. Except for individual genes such as the SOXs and PROM1 that were dysregulated only in BE vs NE, we found a subset of genes (n = 205) whose expression was significantly altered in both BE vs NE and BE vs NC. These genes were overrepresented in different pathways, including TGF-β and Notch.
Conclusion
Our findings provide additional data on the global transcriptome in BE tissues compared to matched NE and NC tissues which should promote further understanding of the functions and regulatory mechanisms of genes involved in BE development, as well as insight into novel genes that may be useful as potential biomarkers for the diagnosis of BE in the future.
doi:10.1371/journal.pone.0093219
PMCID: PMC3979678  PMID: 24714516
Biostatistics (Oxford, England)  2012;14(2):366-381.
We recently proposed two novel criteria to assess the usefulness of risk prediction models for public health applications. The proportion of cases followed, PCF(p), is the proportion of individuals who will develop disease who are included in the proportion p of individuals in the population at highest risk. The proportion needed to follow-up, PNF(q), is the proportion of the general population at highest risk that one needs to follow in order that a proportion q of those destined to become cases will be followed (Pfeiffer, R.M. and Gail, M.H., 2011. Two criteria for evaluating risk prediction models. Biometrics 67, 1057–1065). Here, we extend these criteria in two ways. First, we introduce two new criteria by integrating PCF and PNF over a range of values of q or p to obtain iPCF, the integrated PCF, and iPNF, the integrated PNF. A key assumption in the previous work was that the risk model is well calibrated. This assumption also underlies novel estimates of iPCF and iPNF based on observed risks in a population alone. The second extension is to propose and study estimates of PCF, PNF, iPCF, and iPNF that are consistent even if the risk models are not well calibrated. These new estimates are obtained from case–control data when the outcome prevalence in the population is known, and from cohort data, with baseline covariates and observed health outcomes. We study the efficiency of the various estimates and propose and compare tests for comparing two risk models, both of which were evaluated in the same validation data.
doi:10.1093/biostatistics/kxs037
PMCID: PMC3695651  PMID: 23087412
Area under the receiver operator characteristics curve (ROC); AUC; Discrimination; Discriminatory accuracy; Risk models; Study design
Cancer  2012;119(7):1393-1401.
Background
Nulliparity is associated with an increased risk of endometrial cancer. Less clear is whether nulliparity modifies the association between other established hormone-related risk factors. The proportion of nulliparous women has increased since the mid-1970s, but most individual studies are too small to test the hypothesis that endometrial cancer risk factors may be more strongly associated with risk among nulliparous women compared with parous women.
Methods
We aggregated data on 26,936 postmenopausal, Caucasian nulliparous women (360 endometrial cancers) and 146,583 postmenopausal Caucasian parous women (1,378 endometrial cancers) from four U.S. prospective studies (1979–2006). We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) in stratified analyses.
Results
As expected, endometrial cancer risk was higher among nulliparous women than among parous women (HR, nulliparous vs. parous = 1.42, 95% CI 1.26 to 1.60). Stratified associations between endometrial cancer and hormone-related risk factors did not differ among nulliparous vs. parous women: among both groups, oral contraceptives and earlier menopause were associated with reduced risk. The highest HRs were for obesity; body mass index ≥30 kg/m2 (vs. <25 kg/m2) increased endometrial cancer risk three-fold among nulliparous (HR= 3.04, 95% CI 2.34 to 3.94) and parous (HR= 2.88, 95% CI 2.52 to 3.29) women.
Conclusions
The results from this large, pooled analysis of data from four large prospective studies suggest that nulliparity does not modify endometrial cancer risks associated with established hormone-related risk factors.
doi:10.1002/cncr.27909
PMCID: PMC3744666  PMID: 23280123
endometrial cancer; nulliparity; reproductive history; oral contraceptives; hormonal; obesity
AIDS (London, England)  2010;24(7):1025-1033.
Cytokine stimulation of B-cell proliferation may be an important etiologic mechanism for acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). The Epstein-Barr virus may be a co-factor, particularly for primary central nervous system (CNS) tumors, which are uniformly EBV-positive in the setting of AIDS. Thus, we examined associations of genetic variation in IL10 and related cytokine signaling molecules (IL10RA, CXCL12, IL13, IL4, IL4R, CCL5 and BCL6) with AIDS-related NHL risk and evaluated differences between primary CNS and systemic tumors. We compared 160 Multicenter AIDS Cohort Study (MACS) participants with incident lymphomas, of which 90 followed another AIDS diagnosis, to HIV-1-seropositive controls matched on duration of lymphoma-free survival post-HIV-1 infection (N=160) or post-AIDS diagnosis (N=90). We fit conditional logistic regression models to estimate odds ratios (ORs) and 95 percent confidence intervals (95%CIs). Carriage of at least one copy of the T allele for the IL10 rs1800871 (as compared to no copies) was associated with decreased AIDS-NHL risk specific to lymphomas arising from the CNS (CC vs. CT/TT: OR=0.3; 95%CI: 0.1, 0.7) but not systemically (CC vs. CT/TT: OR=1.0; 95%CI: 0.5, 1.9) (Pheterogeneity=0.03). Carriage of two copies of the “low IL10” haplotype rs1800896_A/rs1800871_T/rs1800872_A was associated with decreased lymphoma risk that varied by number of copies (Ptrend=0.02). None of the ORs for the other studied polymorphisms was significantly different from 1.0. Excessive IL10 response to HIV-1 infection may be associated with increased risk of NHL, particularly in the CNS. IL10 dysregulation may be an important etiologic pathway for EBV-related lymphomagenesis.
doi:10.1097/QAD.0b013e328332d5b1
PMCID: PMC3950937  PMID: 20299965
cytokine; SNPs; AIDS-related lymphoma
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
Background
Higher body mass index (BMI) and inactivity have been associated with a higher risk of developing endometrial cancer, but the impact on endometrial cancer survival is unclear.
Methods
Among incident endometrial cancer case subjects in the National Institutes of Health–AARP Diet and Health Study, we examined associations of prediagnosis BMI (n = 1400) and physical activity (n = 875) with overall and disease-specific 5- and 10-year mortality. Using Cox proportional hazards regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for tumor characteristics, treatment, and other risk factors. All statistical tests were two-sided.
Results
Compared with women with a BMI in the range of 18.5 to less than 25kg/m2, the hazard ratios for 5-year all-cause mortality were 1.74 (95% CI = 1.13 to 2.66) for BMI in the range of 25 to less than 30kg/m2, 1.84 (95% CI = 1.17 to 2.88) for BMI in the range of 30 to less than 35kg/m2, and 2.35 (95% CI = 1.48 to 3.73) for BMI greater than or equal to 35kg/m2 (P trend < .001). Higher BMI was also statistically significantly associated with poorer endometrial cancer–specific but not cardiovascular disease 5-year mortality. Hazard ratio estimates for 10-year all-cause and endometrial cancer–specific mortality as related to BMI were similar to 5-year hazard ratio estimates, whereas 10-year cardiovascular disease mortality became statistically significant (HR = 4.08; 95% CI = 1.56 to 10.71 comparing extreme BMI groups). More physical activity was related to lower all-cause 5-year mortality (HR = 0.57, 95% CI = 0.33 to 0.98 for >7 hours/week vs never/rarely), but the association was attenuated after adjustment for BMI (HR = 0.64, 95% CI = 0.37 to 1.12). No association was observed between physical activity and disease-specific mortality.
Conclusions
Our findings suggest that higher prediagnosis BMI increases risk of overall and disease-specific mortality among women diagnosed with endometrial cancer, whereas physical activity lowers risk. Intervention studies of the effect of these modifiable lifestyle factors on mortality are needed.
doi:10.1093/jnci/djs530
PMCID: PMC3589256  PMID: 23297041
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

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