Risk factors and early prevention of skin cancer in rural older outdoor workers: A scoping review.

Skin cancer risk increases with age and prolonged exposure to ultraviolet radiation (UVR), particularly in rural geographical locations and for individuals with light skin complexions. However, the impact of UVR-induced skin cancer risk and sun-protective behaviors in rural older populations working outdoors has yet to be explored. A scoping review was conducted to fill this gap, with 12 articles meeting the inclusion criteria of aged 50 years and older among rural outdoor workers. Skin cancer risk factors, prevention strategies, and barriers to sun-protective behaviors were summarized for each study. The scoping review addressed some key differences in age-related effects of UVR among rural older outdoor workers compared to studies among adults in general. Findings have policy and research implications that highlight the need to design feasible preventive strategies to reduce rural disparities in cancer care and enhance access to preventive services for this high-risk population.

Prediagnostic Leukocyte Telomere Length and Pancreatic Cancer Survival.

BACKGROUND: Leukocyte telomere length has been associated with risk of subsequent pancreatic cancer. Few prospective studies have evaluated the association of prediagnostic leukocyte telomere length with pancreatic cancer survival. METHODS: We prospectively examined the association of prediagnostic leukocyte telomere length with overall survival (OS) time among 423 participants diagnosed with pancreatic adenocarcinoma between 1984 and 2008 within the Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study, and Women's Health Initiative. We measured prediagnostic leukocyte telomere length in banked blood samples using quantitative PCR. Cox proportional hazards models were used to estimate HRs for OS with adjustment for potential confounders. We also evaluated 10 SNPs at the telomerase reverse transcriptase locus. RESULTS: Shorter prediagnostic leukocyte telomere length was associated with reduced OS among patients with pancreatic cancer (P trend = 0.04). The multivariable-adjusted HR for OS comparing the lowest with highest quintiles of leukocyte telomere length was 1.39 (95% confidence interval, 1.01-1.93), corresponding to a 3-month difference in median OS time. In an analysis excluding cases with blood collected within 2 years of cancer diagnosis, the association was moderately stronger (HR, 1.55; 95% confidence interval, 1.09-2.21; comparing the lowest with highest quintiles; P trend = 0.01). No prognostic association or effect modification for the prognostic association of prediagnostic leukocyte telomere length was noted in relation to the studied SNPs. CONCLUSIONS: Prediagnostic leukocyte telomere length was associated with pancreatic cancer survival. IMPACT: Prediagnostic leukocyte telomere length can be a prognostic biomarker in pancreatic cancer.

Regular Use of Aspirin or Non-Aspirin Nonsteroidal Anti-Inflammatory Drugs Is Not Associated With Risk of Incident Pancreatic Cancer in Two Large Cohort Studies.

BACKGROUND & AIMS: Use of aspirin and/or non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of several cancers, but it is not clear if use of these drugs is associated with risk of pancreatic cancer. METHODS: We evaluated aspirin and non-aspirin NSAID use and risk of pancreatic adenocarcinoma in 141,940 participants from the Health Professionals Follow-up Study and Nurses' Health Study using multivariable-adjusted Cox proportional hazards regression. We considered several exposure classifications to model differing lag times between NSAID exposure and cancer development. We also conducted a nested case-control study of participants from 3 prospective cohorts using conditional logistic regression to evaluate pre-diagnosis levels of plasma salicylurate, a major metabolite of aspirin, in 396 pancreatic cancer cases and 784 matched individuals without pancreatic cancer (controls). RESULTS: In the prospective cohort study, 1122 participants developed pancreatic adenocarcinoma over 4.2 million person-years. Use of aspirin or non-aspirin NSAIDs was not associated with pancreatic cancer risk, even after considering several latency exposure classifications. In a pre-planned subgroup analysis, regular aspirin use was associated with reduced pancreatic cancer risk among participants with diabetes (relative risk, 0.71; 95% CI, 0.54-0.94). In the nested case-control study, pre-diagnosis levels of salicylurate were not associated with pancreatic cancer risk (odds ratio, 1.08; 95% CI, 0.72-1.61; Ptrend 0.81; comparing participants in the highest quintile with those in the lowest quintile of plasma salicylurate). CONCLUSIONS: Regular aspirin or non-aspirin NSAID use was not associated with future risk of pancreatic cancer in participants from several large prospective cohort studies. A possible reduction in risk for pancreatic cancer among people with diabetes who regularly use aspirin should be further examined in preclinical and human studies.

Cigarette Smoking and Pancreatic Cancer Survival.

Purpose Cigarette smoking is associated with increased incidence of pancreatic cancer. However, few studies have prospectively evaluated the association of smoking with patient survival. Patients and Methods We analyzed survival by smoking status among 1,037 patients from two large US prospective cohort studies diagnosed from 1986 to 2013. Among 485 patients from four prospective US cohorts, we also evaluated survival by prediagnostic circulating levels of cotinine, a metabolite of nicotine that is proportional to tobacco smoke exposure. On the basis of prediagnosis cotinine levels, we classified patients as nonsmokers (< 3.1 ng/mL), light smokers (3.1-20.9 ng/mL), or heavy smokers (≥ 21.0 ng/mL). We estimated hazard ratios (HRs) for death by using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, body mass index, diabetes status, diagnosis year, and cancer stage. Results The multivariable-adjusted HR for death was 1.37 (95% CI, 1.11 to 1.69) comparing current smokers with never smokers ( P = .003). A statistically significant negative trend in survival was observed for increasing pack-years of smoking ( Ptrend = .008), with HR for death of 1.49 (95% CI, 1.05 to 2.10) for > 60 pack-years of smoking versus never smoking. Survival among former smokers was similar to that for never smokers, regardless of time since quitting. Heavy smokers defined by prediagnostic circulating cotinine levels had a multivariable-adjusted HR for death of 1.76 (95% CI, 1.23 to 2.51) compared with nonsmokers. Among patients with circulating cotinine levels measured within 5 years before diagnosis, heavy smokers had a multivariable-adjusted HR for death of 2.47 (95% CI, 1.24 to 4.92) compared with nonsmokers. Conclusion Cigarette smoking was associated with a reduction in survival among patients with pancreatic cancer.

Leucocyte telomere length, genetic variants at the TERT gene region and risk of pancreatic cancer.

OBJECTIVE: Telomere shortening occurs as an early event in pancreatic tumorigenesis, and genetic variants at the telomerase reverse transcriptase (TERT) gene region have been associated with pancreatic cancer risk. However, it is unknown whether prediagnostic leucocyte telomere length is associated with subsequent risk of pancreatic cancer. DESIGN: We measured prediagnostic leucocyte telomere length in 386 pancreatic cancer cases and 896 matched controls from five prospective US cohorts. ORs and 95% CIs were calculated using conditional logistic regression. Matching factors included year of birth, cohort (which also matches on sex), smoking status, fasting status and month/year of blood collection. We additionally examined single-nucleotide polymorphisms (SNPs) at the TERT region in relation to pancreatic cancer risk and leucocyte telomere length using logistic and linear regression, respectively. RESULTS: Shorter prediagnostic leucocyte telomere length was associated with higher risk of pancreatic cancer (comparing extreme quintiles of telomere length, OR 1.72; 95% CI 1.07 to 2.78; ptrend=0.048). Results remained unchanged after adjustment for diabetes, body mass index and physical activity. Three SNPs at TERT (linkage disequilibrium r2<0.25) were associated with pancreatic cancer risk, including rs401681 (per minor allele OR 1.33; 95% CI 1.12 to 1.59; p=0.002), rs2736100 (per minor allele OR 1.36; 95% CI 1.13 to 1.63; p=0.001) and rs2736098 (per minor allele OR 0.75; 95% CI 0.63 to 0.90; p=0.002). The minor allele for rs401681 was associated with shorter telomere length (p=0.023). CONCLUSIONS: Prediagnostic leucocyte telomere length and genetic variants at the TERT gene region were associated with risk of pancreatic cancer.

Pancreatic Cancer Risk Associated with Prediagnostic Plasma Levels of Leptin and Leptin Receptor Genetic Polymorphisms.

Leptin is an adipokine involved in regulating energy balance, which has been identified as a potential biologic link in the development of obesity-associated cancers, such as pancreatic cancer. In this prospective, nested case-control study of 470 cases and 1,094 controls from five U.S. cohorts, we used conditional logistic regression to evaluate pancreatic cancer risk by prediagnostic plasma leptin, adjusting for race/ethnicity, diabetes, body mass index, physical activity, plasma C-peptide, adiponectin, and 25-hydroxyvitamin D. Because of known differences in leptin levels by gender, analyses were conducted separately for men and women. We also evaluated associations between 32 tagging SNPs in the leptin receptor (LEPR) gene and pancreatic cancer risk. Leptin levels were higher in female versus male control participants (median, 20.8 vs. 6.7 ng/mL; P < 0.0001). Among men, plasma leptin was positively associated with pancreatic cancer risk and those in the top quintile had a multivariable-adjusted OR of 3.02 [95% confidence interval (CI), 1.27-7.16; Ptrend = 0.02] compared with men in the bottom quintile. Among women, circulating leptin was not associated with pancreatic cancer risk (Ptrend = 0.21). Results were similar across cohorts (Pheterogeneity = 0.88 for two male cohorts and 0.35 for three female cohorts). In genetic analyses, rs10493380 in LEPR was associated with increased pancreatic cancer risk among women, with an OR per minor allele of 1.54 (95% CI, 1.18-2.02; multiple hypothesis-corrected P = 0.03). No SNPs were significantly associated with risk in men. In conclusion, higher prediagnostic levels of plasma leptin were associated with an elevated risk of pancreatic cancer among men, but not among women. Cancer Res; 76(24); 7160-7. ©2016 AACR.

Prediagnostic Plasma 25-Hydroxyvitamin D and Pancreatic Cancer Survival.

PURPOSE: Although vitamin D inhibits pancreatic cancer proliferation in laboratory models, the association of plasma 25-hydroxyvitamin D [25(OH)D] with patient survival is largely unexplored. PATIENTS AND METHODS: We analyzed survival among 493 patients from five prospective US cohorts who were diagnosed with pancreatic cancer from 1984 to 2008. We estimated hazard ratios (HRs) for death by plasma level of 25(OH)D (insufficient, < 20 ng/mL; relative insufficiency, 20 to < 30 ng/mL; sufficient ≥ 30 ng/mL) by using Cox proportional hazards regression models adjusted for age, cohort, race and ethnicity, smoking, diagnosis year, stage, and blood collection month. We also evaluated 30 tagging single-nucleotide polymorphisms in the vitamin D receptor gene, requiring P < .002 (0.05 divided by 30 genotyped variants) for statistical significance. RESULTS: Mean prediagnostic plasma level of 25(OH)D was 24.6 ng/mL, and 165 patients (33%) were vitamin D insufficient. Compared with patients with insufficient levels, multivariable-adjusted HRs for death were 0.79 (95% CI, 0.48 to 1.29) for patients with relative insufficiency and 0.66 (95% CI, 0.49 to 0.90) for patients with sufficient levels (P trend = .01). These results were unchanged after further adjustment for body mass index and history of diabetes (P trend = .02). The association was strongest among patients with blood collected within 5 years of diagnosis, with an HR of 0.58 (95% CI, 0.35 to 0.98) comparing patients with sufficient to patients with insufficient 25(OH)D levels. No single-nucleotide polymorphism at the vitamin D receptor gene met our corrected significance threshold of P < .002; rs7299460 was most strongly associated with survival (HR per minor allele, 0.80; 95% CI, 0.68 to 0.95; P = .01). CONCLUSION: We observed longer overall survival in patients with pancreatic cancer who had sufficient prediagnostic plasma levels of 25(OH)D.

Identification of Risk Factors for Mortality and Poor-Quality-of-Life Survival in Frail Older Women Participating in the Women's Health Initiative Observational Study.

OBJECTIVES: To identify potentially modifiable factors associated with overall and poor-quality-of-life (QoL) survival in physically frail older women. DESIGN: Prospective study with 7 years of follow-up to examine mortality and, in survivors with a QoL measurement within the next 3 years, to examine poor- versus good-QoL patterns of survival. SETTING: Women's Health Initiative Observational Study (WHI OS). PARTICIPANTS: Frail older women (N = 11,070; average age 72.6, range 65-82). MEASUREMENTS: Frailty was defined using the modified Fried criteria. Study outcomes were overall survival and global QoL. Risk factors were measured at the first follow-up clinic visit for WHI OS participants between 1997 and 2001. RESULTS: Of 11,070 frail women, 1,487 (13%) died. After 2,677 survivors with poor or unknown QoL were excluded at study baseline, 3,153 (46%) reported good QoL, and 1,263 (18%) reported poor QoL at the end of study follow-up; QoL measures for 2,490 (38%) were unavailable. Older age, history of cardiovascular disease, diabetes mellitus, poor self-rated health, body mass index less than 25.0 kg/m(2) , waist circumference greater than 88 cm, systolic blood pressure greater than 140 mmHg, high number and severity of somatic symptoms, smoking, and low education were associated with greater likelihood of poor-QoL survival. Cumulative baseline risk scores demonstrated an approximately linear increase in probability of poor-QoL survival with an increase in risk factors. The probability of poor-QoL survival was 0.19 (95% confidence interval (CI) = 0.15-0.22) in those with zero to two risk factors and 0.40 (95% CI = 0.35-0.44) in those with six or more risk factors. CONCLUSION: Several potentially important risk factors for aging well that can be monitored in clinical and research settings, some of which are modifiable, were identified in a large group of frail old women.

Circulating Metabolites and Survival Among Patients With Pancreatic Cancer.

BACKGROUND: Pancreatic tumors cause changes in whole-body metabolism, but whether prediagnostic circulating metabolites predict survival is unknown. METHODS: We measured 82 metabolites by liquid chromatography-mass spectrometry in prediagnostic plasma from 484 pancreatic cancer case patients enrolled in four prospective cohort studies. Association of metabolites with survival was evaluated using Cox proportional hazards models adjusted for age, cohort, race/ethnicity, cancer stage, fasting time, and diagnosis year. After multiple-hypothesis testing correction, a P value of .0006 or less (.05/82) was considered statistically significant. Based on the results, we evaluated 33 tagging single-nucleotide polymorphisms (SNPs) in the ACO1 gene, requiring a P value of less than .002 (.05/33) for statistical significance. All statistical tests were two-sided. RESULTS: Two metabolites in the tricarboxylic acid (TCA) cycle--isocitrate and aconitate--were statistically significantly associated with survival. Participants in the highest vs lowest quintile had hazard ratios (HRs) for death of 1.89 (95% confidence interval [CI] = 1.06 to 3.35, Ptrend < .001) for isocitrate and 2.54 (95% CI = 1.42 to 4.54, Ptrend < .001) for aconitate. Isocitrate is interconverted with citrate via the intermediate aconitate in a reaction catalyzed by the enzyme aconitase 1 (ACO1). Therefore, we investigated the citrate to aconitate plus isocitrate ratio and SNPs in the ACO1 gene. The ratio was strongly associated with survival (P trend < .001) as was the SNP rs7874815 in the ACO1 gene (hazard ratio for death per minor allele = 1.37, 95% CI = 1.16 to 1.61, P < .001). Patients had an approximately three-fold hazard for death when possessing one or more minor alleles at rs7874851 and high aconitate or isocitrate. CONCLUSIONS: Prediagnostic circulating levels of TCA cycle intermediates and inherited ACO1 genotypes were associated with survival among patients with pancreatic cancer.

Longitudinal Cognitive Trajectories of Women Veterans from the Women's Health Initiative Memory Study.

PURPOSE OF THE STUDY: A comparison of longitudinal global cognitive functioning in women Veteran and non-Veteran participants in the Women's Health Initiative (WHI). DESIGN AND METHODS: We studied 7,330 women aged 65-79 at baseline who participated in the WHI Hormone Therapy Trial and its ancillary Memory Study (WHIMS). Global cognitive functioning (Modified Mini-Mental State Examination [3MSE]) in Veterans (n = 279) and non-Veterans (n = 7,051) was compared at baseline and annually for 8 years using generalized linear modeling methods. RESULTS: Compared with non-Veterans, Veteran women were older, more likely to be Caucasian, unmarried, and had higher rates of educational and occupational attainment. Results of unadjusted baseline analyses suggest 3MSE scores were similar between groups. Longitudinal analyses, adjusted for age, education, ethnicity, and WHI trial assignment revealed differences in the rate of cognitive decline between groups over time, such that scores decreased more in Veterans relative to non-Veterans. This relative difference was more pronounced among Veterans who were older, had higher educational/occupational attainment and greater baseline prevalence of cardiovascular risk factors (e.g., smoking) and cardiovascular disease (e.g., angina, stroke). IMPLICATIONS: Veteran status was associated with higher prevalence of protective factors that may have helped initially preserve cognitive functioning. However, findings ultimately revealed more pronounced cognitive decline among Veteran relative to non-Veteran participants, likely suggesting the presence of risks that may impact neuropathology and the effects of which were initially masked by Veterans' greater cognitive reserve.

The Enhancing Connections Program: a six-state randomized clinical trial of a cancer parenting program.

OBJECTIVE: The purpose of this study was to test the efficacy of a cancer parenting program for child rearing mothers with breast cancer, the Enhancing Connections Program. Primary goals were to decrease maternal depressed mood and anxiety, improve parenting quality, parenting skills and confidence, and enhance the child's behavioral-emotional adjustment to maternal breast cancer. METHOD: A total of 176 mothers diagnosed within 6 months with Stage 0 to Stage III breast cancer and their 8- to 12-year-old child were recruited from medical providers in 6 states: Washington, California, Pennsylvania, Minnesota, Arizona, and Indiana. After consenting and obtaining baseline measures, study participants were randomized into experimental or control groups. Experimental mothers received 5, 1-hr educational counseling sessions at 2-week intervals; controls received a booklet and phone call on communicating and supporting their child about the mother's cancer. Outcomes were assessed at 2 and 12 months. RESULTS: Compared to controls, at 2 months experimental mothers significantly improved on depressed mood and parenting skills; experimental children improved on behavioral-emotional adjustment: total behavior problems, externalizing problems, and anxiety/depressed mood significantly declined. At 1 year, experimental children remained significantly less depressed than controls on both mother- and child-reported measures. The intervention failed to significantly affect parenting self-efficacy or maternal anxiety. CONCLUSIONS: The Enhancing Connections Program benefitted mothers and children in specific areas and warrants refinement and further testing.

Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development.

Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.

Effects of tailored message education about breast cancer risk appraisal for obese Korean women.

PURPOSE/OBJECTIVES: To examine the effects of tailored message education about breast cancer risk in obese Korean women. DESIGN: Pretest/post-test with two comparison treatments. SETTING: Rural community settings in South Korea. SAMPLE: Non-random sample of 64 obese women. METHODS: Based on the Health Belief Model, tailored message education involved a one-session individual approach addressing cognitive, emotional, and behavioral domains. The comparison group received a one-time standard education group session. Data on breast cancer risk factors and mammography findings were recorded. MAIN RESEARCH VARIABLES: Knowledge, awareness, emotional barriers, self-efficacy, and intent to screen and prevent breast cancer. FINDINGS: Compared to standard education, tailored message education showed significantly higher score changes on awareness of personal risk (F = 5.21, p < 0.05), self-efficacy for breast self-examination (BSE) (F = 5.16, p < 0.001), intent to perform BSE (F = 6.24, p < 0.05), intent to have mammography (F = 5.45, p < 0.05), and intent to prevent breast cancer with eating habits (F = 7.28, p < 0.05) and exercising (F = 12.51, p < 0.001). CONCLUSIONS: Individually tailored education effectively enhanced awareness of personal risk for breast cancer, self-efficacy for BSE, and intent to screen and prevent breast cancer. IMPLICATIONS FOR NURSING: Tailored message education targeting breast cancer and risk associated with obesity is useful in breast cancer screening education. Future studies should incorporate individualized messages on nutrition, exercise, and cultural barriers to reduce breast cancer risk in obese women. KNOWLEDGE TRANSLATION: Individual educational strategies can effectively enhance breast cancer prevention and early screening. Public and preventive education should include a focus on cultural, cognitive, and emotional domains. For obese women, a heightened awareness and self-efficacy may influence screening behaviors.

Hyperglycemia, insulin resistance, impaired pancreatic ß-cell function, and risk of pancreatic cancer.

BACKGROUND: Obesity and diabetes mellitus are associated with an increased risk of pancreatic cancer. These associations may be secondary to consequences of peripheral insulin resistance, pancreatic ß-cell dysfunction, or hyperglycemia itself. Hemoglobin A1c (HbA1c) is a measure of hyperglycemia, whereas plasma insulin and proinsulin are markers of peripheral insulin resistance, and the proinsulin to insulin ratio marks pancreatic ß-cell dysfunction. METHODS: This was a prospective, nested case-control study of 449 case patients and 982 control subjects with prediagnostic blood samples and no diabetes history from five prospective US cohorts followed through 2008. Two or three control subjects were matched to each case patient by year of birth, cohort, smoking, and fasting status. Pancreatic cancer risk was assessed by prediagnostic HbA1c, insulin, proinsulin, and proinsulin to insulin ratio with multivariable-adjusted logistic regression. All P values were two-sided. RESULTS: The highest vs lowest quintiles of HbA1c, insulin, and proinsulin were associated with with an increased risk for pancreatic cancer (odds ratio [OR] = 1.79; 95% confidence interval [CI] = 1.17 to 2.72, P trend = .04 for HbA1c; OR = 1.57; 95% CI = 1.08 to 2.30; Ptrend = .002 for insulin; and OR = 2.22; 95% CI = 1.50 to 3.29; P trend < .001 for proinsulin). Proinsulin to insulin ratio was not associated with pancreatic cancer risk. Results were similar across studies (all P heterogeneity > .29). In cancers developing 10 or more years after blood collection, the associations with insulin and proinsulin became stronger (highest vs lowest quintile, OR = 2.77; 95% CI = 1.28 to 5.99 for insulin and OR = 3.60; 95% CI = 1.68 to 7.72 for proinsulin). In mutually adjusted models including HbA1c, insulin, and proinsulin, only proinsulin remained statistically significant ( highest vs lowest quintile, OR = 2.55; 95% CI = 1.54 to 4.21; Ptrend < .001). CONCLUSIONS: Among participants from five large prospective cohorts, circulating markers of peripheral insulin resistance, rather than hyperglycemia or pancreatic ß-cell dysfunction, were independently associated with pancreatic cancer risk.

Inflammatory plasma markers and pancreatic cancer risk: a prospective study of five U.S. cohorts.

Chronic inflammation may play a role in the development of pancreatic cancer. However, few prospective studies have examined the association between plasma inflammatory markers and pancreatic cancer risk. Therefore, we investigated the association of prediagnostic circulating C-reactive protein (CRP), interleukin-6 (IL-6), and TNF-α receptor II (TNF-αR2) with subsequent pancreatic cancer risk in a prospective, nested case-control study of 470 cases and 1,094 controls from Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study, Women's Health Initiative, and Women's Health Study. The median follow-up time of cases was 7.2 years (range 1-26 years). No association was observed between plasma CRP, IL-6, and TNF-αR2 and the risk of pancreatic cancer. Comparing extreme quintiles, the multivariate ORs were 1.10 [95% confidence interval (CI), 0.74-1.63; Ptrend = 0.81] for CRP, 1.19 (95% CI, 0.81-1.76; Ptrend = 0.08) for IL-6, and 0.88 (95% CI, 0.58-1.33; Ptrend = 0.57) for TNF-αR2. In conclusion, prediagnostic levels of circulating CRP, IL-6, and TNF-αR2 were not associated with the risk of pancreatic cancer, suggesting that systemic inflammation as measured by circulating inflammatory factors is unlikely to play a major role in the development of pancreatic cancer.

Effects of menopausal hormone therapy on ductal carcinoma in situ of the breast.

Post-menopausal hormone therapy with estrogen plus progestin is consistently reported to be associated with an increased risk of invasive breast cancer. However, findings on an association between hormone use and ductal carcinoma in situ of the breast (DCIS), a possible precursor lesion of invasive breast cancer, are sparse and inconsistent. Women's Health Initiative data were used to assess the effects of hormone therapy on the risk of DCIS in two clinical trials of hormone therapy (16,276 women enrolled in the trial of daily conjugated equine estrogens plus medroxyprogesterone acetate (CEE + MPA) vs placebo; 10,187 women enrolled in the trial of CEE-alone vs placebo). The effects of hormone therapy on DCIS in clinical trial participants were assessed during the intervention, post-intervention, and entire followup periods, and in the observational study (OS; 30,421 CEE + MPA users and non-users and 18,657 CEE-alone users and non-users who met eligibility criteria similar to the clinical trial). Compared to placebo, CEE + MPA was non-significantly associated with higher risk of DCIS over approximate average of 11 years of follow-up (HR = 1.23; 95 % CI: 0.91-1.64). No statistical difference was detected between intervention and post-intervention phases (p = 0.32). Corresponding OS results supported an increased risk for DCIS in CEE + MPA users compared to women who were non-users (HR = 1.65; 95 % CI: 1.25-2.19) after adjusting for potential confounders. There was no clear association between CEE-alone use and risk of DCIS. CEE-alone trial data showed that the risk of DCIS was non-significantly lower in the treatment than in the placebo group, while analysis of the corresponding OS showed a non-significantly higher risk of DCIS in the CEE-alone users than non-users. Our analysis suggests that combined estrogen plus progestin use in post-menopausal women may increase risk of DCIS. Whether estrogen-alone use is associated with DCIS requires further investigation.

A prospective study of plasma adiponectin and pancreatic cancer risk in five US cohorts.

BACKGROUND: The adipocyte-secreted hormone adiponectin has insulin-sensitizing and anti-inflammatory properties. Although development of pancreatic cancer is associated with states of insulin resistance and chronic inflammation, the mechanistic basis of the associations is poorly understood. METHODS: To determine whether prediagnostic plasma levels of adiponectin are associated with risk of pancreatic cancer, we conducted a nested case-control study of 468 pancreatic cancer case subjects and 1080 matched control subjects from five prospective US cohorts: Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study, Women's Health Initiative, and Women's Health Study. Control subjects were matched to case subjects by prospective cohort, year of birth, smoking status, fasting status, and month of blood draw. All samples for plasma adiponectin were handled identically in a single batch. Odds ratios were calculated with conditional logistic regression, and linearity of the association between adiponectin and pancreatic cancer was modeled with restricted cubic spline regression. All statistical tests were two-sided. RESULTS: Median plasma adiponectin was lower in case subjects versus control subjects (6.2 vs 6.8 µg/mL, P = .009). Plasma adiponectin was inversely associated with pancreatic cancer risk, which was consistent across the five prospective cohorts (P (heterogeneity) = .49) and independent of other markers of insulin resistance (eg, diabetes, body mass index, physical activity, plasma C-peptide). Compared with the lowest quintile of adiponectin, individuals in quintiles 2 to 5 had multivariable odds ratios ([ORs] 95% confidence intervals [CIs]) of OR = 0.61 (95% CI = 0.43 to 0.86), OR = 0.58 (95% CI = 0.41 to 0.84), OR = 0.59 (95% CI = 0.40 to 0.87), and OR = 0.66 (95% CI = 0.44 to 0.97), respectively (P (trend) = .04). Restricted cubic spline regression confirmed a nonlinear association (P (nonlinearity) < .01). The association was not modified by sex, smoking, body mass index, physical activity, or C-peptide (all P (interaction) > .10). CONCLUSIONS: In this pooled analysis, low prediagnostic levels of circulating adiponectin were associated with an elevated risk of pancreatic cancer.

The aromatase gene (CYP19A1) variants and circulating hepatocyte growth factor in postmenopausal women.

BACKGROUND: Estrogen and androgen have been linked to the regulation of circulating hepatocyte growth factor (HGF), an adipose tissue-derived cytokine. It is possible that the CYP19A1 gene which alters sex hormones production may influence HGF levels. We examined the association between the CYP19A1 gene variants and plasma HGF concentrations. DESIGN: We evaluated 45 common and putative functional variants of CYP19A1 and circulating levels of HGF among 260 postmenopausal women who later developed colorectal cancer from the Women's Health Initiative Observational Cohort. As the distribution of HGF levels was highly skewed, we transformed HGF concentrations for all women into a log-, ranked-, or normal score-scale value. Multiple linear regression with adjustment for age was used to evaluate the associations. RESULTS: We observed an association between the rs7172156, rs1008805, rs6493494, rs749292, and rs11636639 variants and HGF levels in ranked and normal score scales (corrected p values ≤0.02), although the association of these 5 SNPs with log-scale HGF was not significant (corrected p values ≥0.16). The associations remained unchanged after additional adjustment for hormone therapy use and estradiol levels. These 5 SNPs, which were in linkage disequilibrium (pairwise D'≥97%, r(2)≥56%), constituted a block with 2 common haplotypes accounting for 82% frequency. The most common haplotype, TCCCA, was associated with lower ranked- or normal score-transformed HGF levels (corrected p values ≤0.001), whereas the second most common haplotype, CTTCA, was associated with higher ranked- or normal score-transformed HGF levels (corrected p values ≤0.02). CONCLUSION: Our findings of a potential association between the CYP19A1 variants and circulating HGF levels warrant confirmation in studies with larger sample size.

Migraine history, nonsteroidal anti-inflammatory drug use, and risk of postmenopausal endometrial cancer.

Endometrial cancer is primarily a hormonally mediated disease. As such, factors that mediate or reflect exposure to estrogens, or that mediate response to such exposure, may plausibly be associated with endometrial cancer risk. History of migraines, another hormonally mediated condition, has recently been associated with a reduced risk of hormone receptor-positive breast cancer; however, the relationship between migraines and endometrial cancer has not previously been explored. We evaluated the relationship between migraine history and endometrial cancer risk in postmenopausal women, considering also the potential impact of nonsteroidal anti-inflammatory drug (NSAID) use, given the relationship of NSAIDs to hormones and to migraine history. We identified 93,384 women participating in the Women's Health Initiative prospective cohort who had an intact uterus at the time of study entry. Using Cox proportional hazards regression, we assessed risk of endometrial cancer during study follow-up according to history of migraines and according to current NSAID use at the time of study entry, adjusting for age, study arm, race, and hormone therapy use. We also evaluated interaction in these associations by body mass index. Having a history of migraines was not associated with endometrial cancer risk [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.75-1.11], regardless of body mass index (BMI) or NSAID use status. Similarly, current NSAID use was not associated with endometrial cancer risk (HR = 1.01, 95% CI = 0.88-1.16), regardless of BMI. Migraine history and NSAID use do not appear to be associated with risk of endometrial cancer.

Plasma 25-hydroxyvitamin D and risk of pancreatic cancer.

BACKGROUND: Laboratory studies suggest that vitamin D may inhibit pancreatic cancer cell growth. However, epidemiologic studies of vitamin D and pancreatic cancer risk have been conflicting. METHODS: To determine whether prediagnostic levels of plasma 25-hydroxyvitamin D (25[OH]D; IDS Inc.; enzyme immunoassay) were associated with risk of pancreatic cancer, we conducted a pooled analysis of nested case-control studies with 451 cases and 1,167 controls from five cohorts through 2008. Median follow-up among controls was 14.1 years in Health Professionals Follow-Up Study (HPFS), 18.3 years in Nurses' Health Study (NHS), 25.3 years in Physicians' Health Study (PHS), 12.2 years in Women's Health Initiative-Observational Study (WHI), and 14.4 years in Women's Health Study (WHS). Logistic regression was used to compare the odds of pancreatic cancer by plasma level of 25(OH)D. RESULTS: Mean plasma 25(OH)D was lower in cases versus controls (61.3 vs. 64.5 nmol/L, P = 0.005). In logistic regression models, plasma 25(OH)D was inversely associated with odds of pancreatic cancer. Participants in quintiles two through five had multivariable-adjusted ORs (95% confidence intervals) of 0.79 (0.56-1.10), 0.75 (0.53-1.06), 0.68 (0.48-0.97), and 0.67 (0.46-0.97; P(trend) = 0.03), respectively, compared with the bottom quintile. Compared with those with insufficient levels [25[OH]D, <50 nmol/L], ORs were 0.75 (0.58-0.98) for subjects with relative insufficiency [25[OH]D, 50 to <75 nmol/L] and 0.71 (0.52-0.97) for those with sufficient levels [25[OH]D, ≥ 75 nmol/L]. No increased risk was noted in subjects with 25(OH)D ≥100 nmol/L, as suggested in a prior study. In subgroup analyses, ORs for the top versus bottom quartile of 25(OH)D were 0.72 (0.48-1.08) for women, 0.73 (0.40-1.31) for men, and 0.73 (0.51-1.03) for Whites. CONCLUSIONS: Among participants in five large prospective cohorts, higher plasma levels of 25(OH)D were associated with a lower risk for pancreatic cancer. IMPACT: Low circulating 25(OH)D may predispose individuals to the development of pancreatic cancer.