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Background: Genetic variation in one-carbon metabolism may affect nutrient concentrations and biological functions. However, data on genetic variants associated with blood biomarkers of one-carbon metabolism in US postmenopausal women are limited, and whether these associations were affected by the nationwide folic acid (FA) fortification program is unclear.Objectives: We investigated associations between genetic variants and biomarkers of one-carbon metabolism using data from the Women's Health Initiative Observational Study.Methods: In 1573 non-Hispanic White (NHW) and 282 Black/African American, American Indian/Alaska Native, Asian/Pacific Islander, and Hispanic/Latino women aged 50-79 y, 288 nonsynonymous and tagging single-nucleotide variants (SNVs) were genotyped. RBC folate, plasma folate, pyridoxal-5'-phosphate (PLP), vitamin B-12, homocysteine, and cysteine concentrations were determined in 12-h fasting blood. Multivariable linear regression tested associations per variant allele and for an aggregated genetic risk score. Effect modifications before, during, and after nationwide FA fortification were examined.Results: After correction for multiple comparisons, among NHW women, 5,10-methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C→T) variant T was associated with lower plasma folate (-13.0%; 95% CI: -17.3%, -8.6%) and higher plasma homocysteine (3.5%; 95% CI: 1.7%, 5.3%) concentrations. Other associations for nonsynonymous SNVs included DNMT3A rs11695471 (T→A) with plasma PLP; EHMT2 rs535586 (G→A), TCN2 rs1131603 (L349S A→G), and TCN2 rs35838082 (R188W G→A) with plasma vitamin B-12; CBS rs2851391 (G→A) with plasma homocysteine; and MTHFD1 rs2236224 (G→A) and rs2236225 (R653Q G→A) with plasma cysteine. The influence of FA fortification on the associations was limited. Highest compared with lowest quartiles of aggregated genetic risk scores from SNVs in MTHFR and MTRR were associated with 14.8% to 18.9% lower RBC folate concentrations. Gene-biomarker associations were similar in women of other races/ethnicities.Conclusions: Our findings on genetic variants associated with several one-carbon metabolism biomarkers may help elucidate mechanisms of maintaining B vitamin status in postmenopausal women. [ABSTRACT FROM AUTHOR]

Background: Choline plays an integral role in one-carbon metabolism in the body, but it is unclear whether genetic polymorphisms are associated with variations in plasma choline and its metabolites.Objectives: This study aimed to evaluate the association of genetic variants in choline and one-carbon metabolism with plasma choline and its metabolites.Methods: We analyzed data from 1423 postmenopausal women in a case-control study nested within the Women's Health Initiative Observational Study. Plasma concentrations of choline, betaine, dimethylglycine (DMG), and trimethylamine N-oxide were determined in 12-h fasting blood samples collected at baseline (1993-1998). Candidate and tagging single-nucleotide polymorphisms (SNPs) were genotyped in betaine-homocysteine S-methyltransferase (BHMT), BHMT2, 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (NADP+ dependent 1) (MTHFD1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). Linear regression was used to derive percentage difference in plasma concentrations per variant allele, adjusting for confounders, including B-vitamin biomarkers. Potential effect modification by plasma vitamin B-12, vitamin B-6, and folate concentrations and folic-acid fortification periods was examined.Results: The candidate SNP BHMT R239Q (rs3733890) was associated with lower concentrations of plasma betaine and DMG concentrations (-4.00% and -6.75% per variant allele, respectively; both nominal P < 0.05). Another candidate SNP, BHMT2 rs626105 A>G, was associated with higher plasma DMG concentration (13.0%; P < 0.0001). Several tagSNPs in these 2 genes were associated with plasma concentrations after correction for multiple comparisons. Vitamin B-12 status was a significant effect modifier of the association between the genetic variant BHMT2 rs626105 A>G and plasma DMG concentration.Conclusions: Genetic variations in metabolic enzymes were associated with plasma concentrations of choline and its metabolites. Our findings contribute to the knowledge on the variation in blood nutrient concentrations in postmenopausal women. [ABSTRACT FROM AUTHOR]

Background: Prior research suggests that vitamin D protects against lung cancer only among certain subgroups. objectives: We investigated whether vitamin D intake was associated with lung cancer and explored whether vitamin A intake modified the association. Design: Prospective cohort data from 128,779 postmenopausal women, including 1771 incident lung cancers in the Women's Health Initiative (Clinical Trials and Observational Study) 1993-2010, were analyzed. Twelve percent of women received active intervention (1 g C a+4 00 IU vitamin D3/d) in the Calcium/Vitamin D Trial. Baseline total intake included both dietary intake (from food-frequency questionnaires) and supplement intake (from bottle labels). HRs were estimated by Cox proportional hazard models. Results: No significant association was observed overall. Among never smokers, a total vitamin D intake ≥400 IU/d was significantly associated with lower risks of lung cancer (HR: 0.37; 95% CI: 0.18, 0.77 for ≥ compared with,100 IU/d; P-trend = 0.01). No significant effect modification of total vitamin A intake on the association between total vitamin D intake and lung cancer was found. However, the Calcium/Vitamin D Trial active intervention was significantly associated with a lower lung cancer risk only among women with a vitamin A intake < 1000 μg/d retinol activity equivalents (HR: 0.69; 95% CI: 0.50, 0.96; P-interaction = 0.09). Conclusions: Vitamin D intake was associated with a lower lung cancer risk in never-smoking, postmenopausal women. Lower vitamin A intake may be important for a beneficial association of 1 g Ca + 400 IU vitamin D3 supplementation with lung cancer. This trial was registered at clinicaltrials.gov as NCT00000611. [ABSTRACT FROM AUTHOR]

Abstract: Objective: We examined the risk of colorectal polyps in relation to body size factors and candidate polymorphisms in selected genes of insulin-like growth factor (IGF1) (rs5742612), IGF1 receptor (IGF1R) (rs2229765), IGF binding protein 3 (IGFBP3) (rs2854746) and growth hormone (GH1) (rs2665802). Design: Cases with colorectal adenomas (n =519), hyperplastic polyps (n =691), or both lesions (n=227), and controls (n =772), aged 20–74years, were recruited from patients who underwent colonoscopy between December 2004 and September 2007 at a large integrated-health plan in Washington state. Subjects participated in a 45-minute telephone interview to ascertain body size and physical activity, and provided a buccal DNA sample for genetic analysis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable polytomous regression. Results: Compared to those of normal weight, higher body mass index (BMI) was associated with elevated risk of colorectal adenomas (OR=1.65, 95% CI 1.22-2.25 BMI≥30kg/m2, p-trend=0.002) and both lesions (OR=2.15, 95% CI 1.43-3.22 BMI≥30kg/m2, p-trend=0.003), but there was no relationship with hyperplastic polyps. Obesity at age 18 and a weight gain of ≥21kg since age 18 were also significantly associated with an increased risk of colorectal adenomas and both lesions, but not hyperplastic polyps. There was a reduced risk of colorectal adenomas (OR=0.63, 95% CI 0.42-0.94) and hyperplastic polyps (OR=0.7, 95% CI 0.5–0.9) associated with the homozygous variant genotype for GH1. Few meaningful results were evident for the other polymorphisms. Conclusions: There is an increased risk of colorectal adenomas and presence of both adenomas and hyperplastic polyps in relation to increasing body size. Some genetic variation in GH1 might contribute to a reduced risk of colorectal adenomas and hyperplastic polyps. [ABSTRACT FROM AUTHOR]

Introduction: The purpose of this study was to test the hypothesis that patients with Medicaid insurance or Medicaid-like coverage would have longer times to follow-up and be less likely to complete colonoscopy compared with patients with commercial insurance within the same healthcare systems.Methods: A total of 35,009 patients aged 50-64years with a positive fecal immunochemical test were evaluated in Northern and Southern California Kaiser Permanente systems and in a North Texas safety-net system between 2011 and 2012. Kaplan-Meier estimation was used between 2016 and 2017 to calculate the probability of having follow-up colonoscopy by coverage type. Among Kaiser Permanente patients, Cox regression was used to estimate hazard ratios and 95% CIs for the association between coverage type and receipt of follow-up, adjusting for sociodemographics and health status.Results: Even within the same integrated system with organized follow-up, patients with Medicaid were 24% less likely to complete follow-up as those with commercial insurance. Percentage receiving colonoscopy within 3 months after a positive fecal immunochemical test was 74.6% for commercial insurance, 63.10% for Medicaid only, and 37.5% for patients served by the integrated safety-net system.Conclusions: This study found that patients with Medicaid were less likely than those with commercial insurance to complete follow-up colonoscopy after a positive fecal immunochemical test and had longer average times to follow-up. With the future of coverage mechanisms uncertain, it is important and timely to assess influences of health insurance coverage on likelihood of follow-up colonoscopy and identify potential disparities in screening completion. [ABSTRACT FROM AUTHOR]

Introduction: Expert recommendations differ for colorectal cancer screening in the elderly. Recent studies suggest that healthy adults aged >75 years may benefit from screening. This study examined screening use and follow-up, and how they varied by health status within age strata, among a large cohort of elderly individuals in community settings.Methods: A population-based, longitudinal cohort study was conducted among health plan members aged 65-89 years enrolled during 2011-2012 in three integrated healthcare systems participating in the Population-Based Research Optimizing Screening through Personalized Regimens consortium. Comorbidity measurements used the Charlson index. Analyses, conducted in 2015, comprised descriptive statistics and multivariable modeling that estimated age by comorbidity-specific percentages of patients for two outcomes: colorectal cancer screening uptake and follow-up of abnormal fecal blood tests.Results: Among 846,267 patients, 72% were up-to-date with colorectal cancer screening. Of patients with a positive fecal blood test, 65% received follow-up colonoscopy within 3 months. Likelihood of being up-to-date and receiving timely follow-up was significantly lower for patients aged ≥76 years than their younger counterparts (p<0.001). Comorbidity was less influential than age and more strongly related to timely follow-up than being up-to-date. In all age groups, considerable numbers of patients with no/low comorbidity were not up-to-date or did not receive timely follow-up.Conclusions: In three integrated healthcare systems, many older, relatively healthy patients were not screening up-to-date, and some relatively young, healthy patients did not receive timely follow-up. Findings suggest a need for re-evaluating age-based screening guidelines and improving screening completion among the elderly. [ABSTRACT FROM AUTHOR]

Background For men on active surveillance for prostate cancer, utility of prostate-specific antigen (PSA) kinetics (PSAk) in predicting pathologic reclassification remains controversial. Objective To develop prediction methods for utilizing serial PSA and evaluate frequency of collection. Design, setting, and participants Data were collected from men enrolled in the multicenter Canary Prostate Active Surveillance Study, for whom PSA data were measured and biopsies performed on prespecified schedules. We developed a PSAk parameter based on a linear mixed-effect model (LMEM) that accounted for serial PSA levels. Outcome measurements and statistical analysis The association of diagnostic PSA and/or PSAk with time to reclassification (increase in cancer grade and/or volume) was evaluated using multivariable Cox proportional hazards models. Results and limitations A total of 851 men met the study criteria; 255 (30%) had a reclassification event within 5 yr. Median follow-up was 3.7 yr. After adjusting for prostate size, time since diagnosis, biopsy parameters, and diagnostic PSA, PSAk was a significant predictor of reclassification (hazard ratio for each 0.10 increase in PSAk = 1.6 [95% confidence interval 1.2–2.1, p < 0.001]). The PSAk model improved stratification of risk prediction for the top and bottom deciles of risk over a model without PSAk. Model performance was essentially identical using PSA data measured every 6 mo to those measured every 3 mo. The major limitation is the reliability of reclassification as an end point, although it drives most treatment decisions. Conclusions PSAk calculated using an LMEM statistically significantly predicts biopsy reclassification. Models that use repeat PSA measurements outperform a model incorporating only diagnostic PSA. Model performance is similar using PSA assessed every 3 or 6 mo. If validated, these results should inform optimal incorporation of PSA trends into active surveillance protocols and risk calculators. Patient summary In this report, we looked at whether repeat prostate-specific antigen (PSA) measurements, or PSA kinetics, improve prediction of biopsy outcomes in men using active surveillance to manage localized prostate cancer. We found that in a large multicenter active surveillance cohort, PSA kinetics improves the prediction of surveillance biopsy outcome. [ABSTRACT FROM AUTHOR]

Background Many patients who are on active surveillance (AS) for prostate cancer will have surveillance prostate needle biopsies (PNBs) without any cancer evident. Objective To define the association between negative surveillance PNBs and risk of reclassification on AS. Design, setting, and participants All men were enrolled in the Canary Prostate Active Surveillance Study (PASS) between 2008 and 2016. Men were included if they had Gleason ≤3 + 4 prostate cancer and <34% core involvement ratio at diagnosis. Men were prescribed surveillance PNBs at 12 and 24 mo after diagnosis and then every 24 mo. Outcome measurements and statistical analysis Reclassification was defined as an increase in Gleason grade and/or an increase in the ratio of biopsy cores to cancer to ≥34%. PNB outcomes were defined as follows: (1) no cancer on biopsy, (2) cancer without reclassification, or (3) reclassification. Kaplan–Meier and Cox proportional hazard models were performed to assess the risk of reclassification. Results and limitations A total of 657 men met inclusion criteria. On first surveillance PNB, 214 (32%) had no cancer, 282 (43%) had cancer but no reclassification, and 161 (25%) reclassified. Among those who did not reclassify, 313 had a second PNB. On second PNB, 120 (38%) had no cancer, 139 (44%) had cancer but no reclassification, and 54 (17%) reclassified. In a multivariable analysis, significant predictors of decreased future reclassification after the first PNB were no cancer on PNB (hazard ratio [HR] = 0.50, p = 0.008), lower serum prostate-specific antigen, larger prostate size, and lower body mass index. A finding of no cancer on the second PNB was also associated with significantly decreased future reclassification in a multivariable analysis (HR = 0.15, p = 0.003), regardless of the first PNB result. The major limitation of this study is a relatively small number of patients with long-term follow-up. Conclusions Men who have a surveillance PNB with no evidence of cancer are significantly less likely to reclassify on AS in the PASS cohort. These findings have implications for tailoring AS protocols. Patient summary Men on active surveillance for prostate cancer who have a biopsy showing no cancer are at a decreased risk of having worse disease in the future. This may have an impact on how frequently biopsies are required to be performed in the future. [ABSTRACT FROM AUTHOR]

Introduction: Racial/ethnic disparities in colorectal cancer (CRC) screening and diagnostic testing present challenges to CRC prevention programs. Thus, it is important to understand how differences in CRC screening approaches between healthcare systems are associated with racial/ethnic disparities.Methods: This was a retrospective cohort study of patients aged 50-75 years who were members of the Population-based Research Optimizing Screening Through Personalized Regimens cohort from 2010 to 2012. Data on race/ethnicity, CRC screening, and diagnostic testing came from medical records. Data collection occurred in 2014 and analysis in 2015. Logistic regression models were used to calculate AORs and 95% CIs comparing completion of CRC screening between racial/ethnic groups. Analyses were stratified by healthcare system to assess differences between systems.Results: There were 1,746,714 participants across four healthcare systems. Compared with non-Hispanic whites (whites), odds of completing CRC screening were lower for non-Hispanic blacks (blacks) in healthcare systems with high screening rates (AOR=0.86, 95% CI=0.84, 0.88) but similar between blacks and whites in systems with lower screening rates (AOR=1.01, 95% CI=0.93, 1.09). Compared with whites, American Indian/Alaskan Natives had lower odds of completing CRC screening across all healthcare systems (AOR=0.76, 95% CI=0.72, 0.81). Hispanics had similar odds of CRC screening (AOR=0.99, 95% CI=0.98, 1.00) and Asian/Pacific Islanders had higher odds of CRC screening (AOR=1.16, 95% CI=1.15, 1.18) versus whites.Conclusions: Racial/ethnic differences in CRC screening vary across healthcare systems, particularly for blacks, and may be more pronounced in systems with intensive CRC screening approaches. [ABSTRACT FROM AUTHOR]

Introduction: Timely follow-up of abnormal tests is critical to the effectiveness of cancer screening, but may vary by screening test, healthcare system, and sociodemographic group.Methods: Timely follow-up of abnormal mammogram and fecal occult blood testing or fecal immunochemical tests (FOBT/FIT) were compared by race/ethnicity using Population-Based Research Optimizing Screening through Personalized Regimens consortium data. Participants were women with an abnormal mammogram (aged 40-75 years) or FOBT/FIT (aged 50-75 years) in 2010-2012. Analyses were performed in 2015. Timely follow-up was defined as colonoscopy ≤3 months following positive FOBT/FIT; additional imaging or biopsy ≤3 months following Breast Imaging Reporting and Data System Category 0, 4, or 5 mammograms; or ≤9 months following Category 3 mammograms. Logistic regression was used to model receipt of timely follow-up adjusting for study site, age, year, insurance, and income.Results: Among 166,602 mammograms, 10.7% were abnormal; among 566,781 FOBT/FITs, 4.3% were abnormal. Nearly 96% of patients with abnormal mammograms received timely follow-up versus 68% with abnormal FOBT/FIT. There was greater variability in receipt of follow-up across healthcare systems for positive FOBT/FIT than for abnormal mammograms. For mammography, black women were less likely than whites to receive timely follow-up (91.8% vs 96.0%, OR=0.71, 95% CI=0.51, 0.97). For FOBT/FIT, Hispanics were more likely than whites to receive timely follow-up than whites (70.0% vs 67.6%, OR=1.12, 95% CI=1.04, 1.21).Conclusions: Timely follow-up among women was more likely for abnormal mammograms than FOBT/FITs, with small variations in follow-up rates by race/ethnicity and larger variation across healthcare systems. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: : New ovarian cancer biomarkers suitable for early disease diagnosis, prognosis or monitoring could improve patient management and outcomes. Design and Methods: : Nidogen-2 was measured by immunoassay in serum of 100 healthy women, 100 women with benign gynecological conditions and 100 women with ovarian carcinoma. Results: : Serum nidogen-2 concentration between normal and benign disease patients was not different (median, 13.2 and 12.1 mg/L, respectively). However, nidogen-2 concentration in serum of ovarian cancer patients was elevated (median, 18.6 mg/L; p <0.0001). Both nidogen-2 and CA125 were elevated more in serous histotypes of ovarian cancer and late state disease. Nidogen-2 and CA125 concentrations were strongly correlated. ROC curve analysis for nidogen-2 had an area under the curve (AUC) ranging from 0.73 to 0.83 but CA125 was superior (AUC ranging from 0.87 to 0.99). There was no complementarity between the two markers. Conclusions: : Nidogen-2 is a new biomarker for ovarian cancer which correlates closely with CA125. [Copyright &y& Elsevier]

Summary: Detection of lung cancer at early stages could potentially increase survival rates. One promising approach is the application of suitable lung cancer-specific biomarkers to specimens obtained by non-invasive methods. Thus far, clinically useful biomarkers that have high sensitivity have proven elusive. Certain genes, which are involved in cellular pathways such as signal transduction, apoptosis, cell to cell communication, cell cycles and cytokine signaling are down-regulated in cancers and may be considered as potential tumor suppressor genes. Aberrant promoter hypermethylation is a major mechanism for silencing tumor suppressor genes in many kinds of human cancers. Using quantitative real time PCR, we tested 11 genes (3-OST-2, RASSF1A, DcR1, DcR2, P16, DAPK, APC, ECAD, HCAD, SOCS1, SOCS3) for levels of methylation within their promoter sequences in non-small cell lung cancers (NSCLC), adjacent non-malignant lung tissues, in peripheral blood mononuclear cells (PBMC) from cancer free patients, in sputum of cancer patients and controls. Of all the 11 genes tested 3-OST-2 showed the highest levels of promoter methylation in tumors combined with lowest levels of promoter methylation in control tissues. 3-OST-2 followed by, RASSF1A showed increased levels of methylation with advanced tumor stage (P<0.05). Thus, quantitative analysis of 3-OST-2 and RASSF1A methylation appears to be a promising biomarker assay for NSCLC and should be further explored in a clinical study. Our preliminary data on the analysis of sputum DNA specimens from cancer patients further support these observations. [Copyright &y& Elsevier]