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Hypoglycemia, defined as a blood glucose < 2.2 mmol/L, is associated with death in pediatric cerebral malaria (CM). The optimal duration of glucose monitoring in CM is unknown. We collected data from 1,674 hospitalized Malawian children with CM to evaluate the association between hypoglycemia and death or neurologic disability in survivors. We assessed the optimal duration of routine periodic measurements of blood glucose. Children with hypoglycemia at admission had a 2.87-fold higher odds (95% CI: 1.35–6.09) of death and, if they survived, a 3.21-fold greater odds (95% CI: 1.51–6.86) of sequelae at hospital discharge. If hypoglycemia was detected at 6 hours but not at admission, there was a 7.27-fold higher odds of death (95% CI: 1.85–8.56). The presence of newly developed hypoglycemia after admission was not independently associated with neurological sequelae in CM survivors. Among all new episodes of blood sugar below a treatment threshold of 3.0 mmol/L, 94.7% occurred within 24 hours of admission. In those with blood sugar below 3.0 mmol/L in the first 24 hours, low blood sugar persisted or recurred for up to 42 hours. Hypoglycemia at admission or 6 hours afterward is strongly associated with mortality in CM. Children with CM should have 24 hours of post-admission blood glucose measurements. If a blood glucose less than the treatment threshold of 3.0 mmol/L is not detected, routine assessments may cease. Children who have blood sugar values below the treatment threshold detected within the first 24 hours should continue to have periodic glucose measurements for 48 hours post-admission.

The association between hyperglycemia and prostate cancer risk is inconsistent, and its association with prostate cancer mortality is understudied. Thus, we investigated the association between hyperglycemia and prostate cancer risk and mortality using multiple biomarkers simultaneously to classify hyper- and normoglycemia. We conducted a prospective analysis of 5,162 cancer-free men attending visit 2 (1990–1992) of the Atherosclerosis Risk in Communities (ARIC) study followed for total (N = 671) and lethal (N = 69) prostate cancer incidence and prostate cancer mortality (N = 64) through 2012. Men without diagnosed diabetes were classified as normo- or hyperglycemic using joint categories of fasting glucose, glycated hemoglobin, and glycated albumin (or fructosamine) defined by clinical or research cutpoints. We evaluated the multivariable-adjusted association of hyperglycemia with prostate cancer incidence and mortality using Cox proportional hazards regression; men with diagnosed diabetes were included as a separate exposure category. Among 4,753 men without diagnosed diabetes, 61.5% were classified as having hyperglycemia (high on ≥1 biomarker). HbA1c and glycated albumin together classified 61.9% of 1,736 men with normal fasting glucose as normoglycemic. Compared with men who were normal on all three biomarkers, men who were high on ≥1 biomarker had an increased risk of lethal [HR, 2.50; 95% confidence interval (CI), 1.12–5.58] and fatal (HR, 3.20; 95% CI, 1.26–8.48) disease, but not total prostate cancer incidence (HR, 0.98; 95% CI, 0.81–1.20); associations were similar including fructosamine instead of glycated albumin. Our findings indicate hyperglycemia is associated with an increased risk of lethal and fatal prostate cancer, but not total prostate cancer incidence.

Odds ratios (OR) and 95% confidence intervals (CI) for the association between body mass index (BMI) category and telomere variability* in prostate cancer cells overall and stratified by prostate cancer aggressiveness at surgery among men surgically treated for prostate cancer at Johns Hopkins Hospital, 1992 to 2016.

Supplemental Table 1: Association between lipid-lowering medication use and incident prostate cancer by frequency of routine physical examinations, and among participants who had health insurance or had private health insurance and/or Medicare, men in ARIC (1990-2012). Supplemental Table 2: Association between lipid-lowering medication use and fatal prostate cancer stratified by routine physical examination, and among participants who had health insurance or had private health insurance and/or Medicare, men in ARIC (1990-2012)

Supplemental methods, results from sensitivity analyses, and restricted cubic splines.

In our prior studies, obesity was associated with shorter telomeres in prostate cancer-associated stromal (CAS) cells, and shorter CAS telomeres were associated with an increased risk of prostate cancer death. To determine whether the association between obesity and shorter CAS telomeres is replicable, we conducted a pooled analysis of 790 men who were surgically treated for prostate cancer, whose tissue samples were arrayed on five tissue microarray (TMA) sets. Telomere signal was measured using a quantitative telomere-specific FISH assay and normalized to 4′,6-diamidino-2-phenylindole for 351 CAS cells (mean) per man; men were assigned their median value. Weight and height at surgery, collected via questionnaire or medical record, were used to calculate body mass index (BMI; kg/m2) and categorize men as normal (T2), obese men had a 3-fold increased odds of short CAS telomeres (OR: 3.06; 95% confidence interval: 1.07–8.75; Ptrend = 0.045) when compared with normal weight men. Telomere shortening in prostate stromal cells may be one mechanism through which lifestyle influences lethal prostate carcinogenesis.Prevention Relevance:This study investigates a potential mechanism underlying the association between obesity and prostate cancer death. Among men with aggressive prostate cancer, obesity was associated with shorter telomeres prostate cancer associated stromal cells, and shorter CAS telomeres have been associated with an increased risk of prostate cancer death.

PurposeCurrent biomarkers are inadequate prognostic predictors in localized prostate cancer making treatment decision-making challenging. Previously, we observed that the combination of more variable telomere length among prostate cancer cells and shorter telomere length in prostate cancer-associated stromal cells – the telomere biomarker – is strongly associated with progression to metastasis and prostate cancer death after prostatectomy independent of currently used pathologic indicators.Experimental DesignWe optimized our method allowing for semi-automated telomere length determination in single cells in fixed tissue, and tested the telomere biomarker in tissue microarrays from five cohort studies of men surgically treated for clinically localized disease (N=2,255). We estimated the relative risk (RR) of progression to metastasis (N=311) and prostate cancer death (N=85) using models appropriate to each study’s design adjusting for age, prostatectomy stage, and tumor grade, which then we meta-analyzed using inverse variance weights.ResultsCompared with men who had less variable telomere length among prostate cancer cells and longer telomere length in prostate cancer-associated stromal cells, men with the combination of more variable and shorter telomere length, had 3.76-times the risk of prostate cancer death (95% CI 1.37-10.3; p=0.01) and had 2.23-times the risk of progression to metastasis (95% CI 0.99-5.02, P=0.05). The telomere biomarker was associated with prostate cancer death in men with intermediate risk disease (Grade Groups 2/3: RR=9.18, 95% CI 1.14- 74.0, p=0.037) and with PTEN intact tumors (RR=6.74, 95% CI 1.46-37.6, p=0.015).ConclusionsThe telomere biomarker is robust and associated with poor outcome independent of current pathologic indicators in surgically-treated men.Translational RelevanceCurrent prognostic biomarkers in localized prostate cancer are inadequate imperfect predictors; therefore, new biomarkers are needed to improve the prognostic classification and management of these patients. In a five-cohort study, we confirmed that the tissue-based telomere biomarker – the combination of more variable telomere length among prostate cancer cells and shorter telomere length in prostate cancer-associated stromal cells – was associated with progression to metastasis and prostate cancer death independent of currently used prognostic indicators after prostatectomy for clinically-localized disease. Importantly, the telomere biomarker was associated with poor outcome in men with intermediate risk disease, as well as in men with intact PTEN tumors. Thus, this tissue-based telomere biomarker has the translational potential to improve treatment and surveillance decision-making.

Background Intraprostatic inflammation is an emerging prostate cancer risk factor. Estrogens are pro-inflammatory while androgens are anti-inflammatory. Thus, we investigated whether serum sex steroid hormone concentrations are associated with intraprostatic inflammation to inform mechanistic links among hormones, inflammation, and prostate cancer. Methods We conducted a cross-sectional study among 247 men in the placebo arm of the Prostate Cancer Prevention Trial who had a negative end-of-study biopsy, most (92.7%) performed without clinical indication per trial protocol. Serum estradiol, estrone, and testosterone were previously measured by immunoassay in pooled baseline and Year 3 serum. Free estradiol and free testosterone were calculated. Inflammation was visually assessed (median of three prostate biopsy cores per man). Polytomous or logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of some or all cores inflamed (both vs none) or any core inflamed (vs none) by hormone tertile, adjusting for age, race, and family history. We evaluated effect modification by waist circumference and body mass index (BMI). Results In all, 51.4% had some and 26.3% had all cores inflamed. Free (P-trend = .11) but not total estradiol was suggestively inversely associated with all cores inflamed. In men with waist circumference greater than or equal to 102 cm (P-trend = .021) and BMI ≥ 27.09 kg/m2 (P-trend = .0037) free estradiol was inversely associated with any core inflamed. Estrone was inversely associated with all cores inflamed (T3: OR = 0.36, 95% CI 0.14-0.95, P-trend = .036). Total (T3: OR = 1.91, 95% CI 0.91-4.02, P-trend = .11) and free (T3: OR = 2.19, 95% CI 1.01-4.74, P-trend = .05) testosterone were positively associated with any core inflamed, especially free testosterone in men with waist circumference less than 102 cm (T3: OR = 3.51, 95% CI 1.03-12.11, P-trend = .05). Conclusions In this first study in men without prostate cancer and irrespective of clinical indication for biopsy, contrary to the hypothesis, circulating estrogens appeared to be inversely associated, especially in heavy men, whereas androgens appeared to be positively associated with intraprostatic inflammation.

Background: Given our previous findings that low intratumoral and high extratumoral mast cell numbers are associated with higher risk of biochemical recurrence after radical prostatectomy, we now assessed this relationship with race and the development of metastases. Methods: We stained for mast cell tryptase via IHC and fluorescent immunolabeling in 885 men across multiple tissue microarray sets designed to assess biomarkers in association with race and prostate cancer outcomes (median follow-up, 7.0 years). Results: Intratumoral and extratumoral mast cell counts were significantly lower in tissues from African-American compared with European-American men, but not within strata of cancer grade. There was no association between mast cell counts and ERG positivity, PTEN loss, or TP53 missense mutation. Higher minimum extratumoral mast cells were associated with an increased risk of biochemical recurrence [comparing highest with lowest tertiles: HR, 1.61; 95% confidence interval (CI), 1.12–2.29; P trend = 0.01]; this pattern was similar among European-American and African-American men and by grade of disease. There was no significant association between minimum intratumoral mast cell count and biochemical recurrence, overall or within strata of race and grade. Finally, high minimum number of extratumoral mast cells was associated with prostate cancer metastases (comparing highest with lowest tertiles: HR, 2.12; 95% CI, 1.24–3.63; P trend = 0.01). Conclusions: High extratumoral mast cell numbers are associated with biochemical recurrence and the development of metastases after radical prostatectomy. Impact: Higher numbers of benign tissue mast cells are associated with a higher risk of adverse outcomes after radical prostatectomy, including metastatic prostate cancer.

Telomeres, the repetitive DNA elements at chromosome ends, are pivotal for maintenance of genome integrity. Previous studies from our group and others have highlighted the translational potential of tissue-based telomere length measurements to address the clinical challenge of improving diagnosis, individualized risk stratification, and accurate prognostication of different diseases. Here, we describe a high-throughput method that quantitates cell type-specific telomere lengths at a single cell level in archival tissues from patient cohorts for research on prognosis. This approach is based on telomere-specific fluorescence in situ hybridization (FISH) combined with multiplex immunostaining for cell type-specific antibodies, followed by semi-automated slide scanning and multi-channel acquisition of fluorescent images using the TissueFAXS Plus microscopy workstation and TissueQuest software (TissueGnostics). Here, we demonstrate that this method is sufficiently robust and reproducible to detect biologically significant differences in telomere lengths in archived tissues either on whole slides or sampled across tissue microarrays, which is essential when assessing prognosis in large patient cohorts.

OBJECTIVE Despite the emotional challenges of parental adjustment to a child’s type 1 diabetes diagnosis and the unique complexities of early childhood, there are few programs designed to meet the needs of parents of young children at new onset. This study evaluated First STEPS (Study of Type 1 in Early childhood and Parenting Support), a stepped-care behavioral intervention designed to support parents’ psychosocial functioning and promote children’s glycemic outcomes. RESEARCH DESIGN AND METHODS Using a two-site randomized clinical trial design, parents (n = 157) of children aged 1–6 years completed baseline data within 2 months of diabetes diagnosis and were randomly assigned to intervention (n = 115) or usual care (n = 42) for 9 months. Intervention steps included: 1) peer parent coaching, with step-ups to 2) structured behavioral counseling and 3) professional consultations with a diabetes educator and psychologist, based on parent mood and child HbA1c. Participants completed follow-ups at 9 and 15 months postrandomization. Primary outcomes were parent depressive symptoms and child HbA1c. RESULTS Depressive symptoms improved in both groups, and intervention parents had significantly lower depressive symptoms at the 9- and 15-month follow-ups compared with usual care. HbA1c decreased in both groups, but there were no between-group differences at 9 or 15 months. CONCLUSIONS First STEPS improved parents’ mood following young children’s type 1 diabetes diagnosis. Results indicate likely benefits of parent coach support, supplemented by intervention intensifications, including behavioral intervention and diabetes education. This model has high potential for patient engagement. The absence of a medical intervention component may explain null findings for HbA1c; incorporating targeted behavioral support for intensive diabetes treatment may maximize intervention impact.

Background Lipid-lowering drugs, particularly statins, are associated with reduced incidence of certain cancers in some studies. Associations with cancer mortality are not well studied, and whether associations are similar across race is unknown. Methods We conducted a prospective analysis of 12 997 cancer-free participants in the Atherosclerosis Risk in Communities Study who were never users at visit 1 (1987-1989). Ever use, duration of use, and age at first use were modeled as time-dependent variables using Cox regression to estimate associations with total, obesity- and smoking-associated, bladder, breast, colorectal, lung, and prostate cancer incidence and mortality. Results We ascertained 3869 cancer cases and 1661 cancer deaths in 237 999 or more person-years. At 6 years of follow-up, 70.8% of lipid-lowering drug use was a statin. Compared with never use, ever use was associated with lower total, obesity- and smoking-associated cancer mortality and with colorectal cancer mortality (hazard ratio [HR] = 0.50, 95% confidence interval [CI] = 0.32 to 0.79) and incidence (HR = 0.69, 95% CI = 0.53 to 0.92). Inverse associations were consistent by sex and race. Shorter-term use was associated with bladder cancer incidence in men ( Conclusions This study provides additional evidence for inverse associations between lipid-lowering drug use and cancer incidence and mortality but a positive association with bladder cancer incidence in men. Evaluation of the impact of chemoprevention strategies that include lipid-lowering drugs on population-level cancer burden is needed.

OBJECTIVE: To describe sociodemographic and parent psychosocial characteristics associated with patterns of continuous glucose monitor (CGM) use across the first 18 months post-type 1 diabetes (T1D) diagnosis among young children. METHODS: One hundred fifty-seven parent–child dyads enrolled in a behavioral intervention for parents of young children (1–6 years) newly diagnosed with T1D. Parents reported on baseline sociodemographic characteristics and psychosocial functioning; child CGM use was assessed at five time points during the first 18 months post-diagnosis. RESULTS: Most participants (81.8%) used CGM at least once. Four CGM trajectories emerged (always, later/stable, inconsistent, and never). Participants with private insurance were more likely to be in the always, later/stable, or inconsistent groups versus the never group. Youth in the always and later/stable groups had lower mean HbA1c at 18 months than those in the never group. CONCLUSIONS: Given the health benefits of CGM, further exploration of barriers to CGM use in families with public health insurance is needed. ClinicalTrials.gov identifier: NCT02527525

Purpose Severe periodontal disease and edentulism have been previously reported to be significantly associated with cancer risk and mortality, including in the Atherosclerosis Risk in Communities study (2018); however, complex sources of confounding by socioeconomic status (SES), and characteristics correlated with SES, could have been present in earlier analyses. Methods To capture life course SES and its correlates, we generated a propensity score and included it, along with other potential confounders such as smoking and obesity, into a Cox regression model to examine the association between periodontal disease and cancer risk. In addition, we stratified the model with the propensity score by low and high SES. All statistical tests were two-sided. Results Compared with our previous study, the associations for severe periodontitis and cancer incidence remained comparable after weighting by the propensity score (e.g., for total cancer: before weighting, hazard ratio = 1.24, 95% confidence interval = 1.07–1.42 vs. after weighting, hazard ratio = 1.23, 95% confidence interval = 1.05–1.44 when comparing severe periodontitis to no or mild periodontitis). Associations were comparable in low and high SES strata and statistically significant among participants with high SES. Conclusions Complex sources of confounding by SES and its correlates are unlikely to fully account for the positive associations observed for periodontal disease and edentulism and cancer risk.

Purpose To report age-specific serum estradiol concentration in nonsmoking, lean US men without comorbidities. We provide concentrations from 30 and 15 to 20 years ago given previously described declines in serum estradiol in US men over time. Methods We used data from the Third National Health and Nutrition Examination Survey (NHANES III; 1988 to 1991) and continuous NHANES (1999 to 2004). Serum estradiol and SHBG were previously measured by competitive electrochemiluminescence immunoassays. Free estradiol was estimated from estradiol, SHBG, and albumin. By age, we calculated median concentrations overall and for nonsmoking, lean (body mass index Results Overall, respective total estradiol medians for men ages 20 to 39, 40 to 59, and ≥60 years old were 37.0, 33.9, and 33.5 pg/mL in NHANES III and 31.3, 30.5, and 27.0 pg/mL in continuous NHANES. In nonsmoking, lean men without comorbidities, respective total estradiol medians were 32.0, 32.1, and 32.0 pg/mL in NHANES III and 29.1, 22.7, and 26.1 pg/mL in continuous NHANES. Overall, respective free estradiol medians were 0.82, 0.72, and 0.64 pg/mL in NHANES III and 0.67, 0.61, and 0.47 pg/mL in continuous NHANES. In nonsmoking, lean men without comorbidities, respective free estradiol medians were 0.64, 0.67, and 0.62 pg/mL in NHANES III and 0.58, 0.42, and 0.40 pg/mL continuous NHANES. Conclusion We report US nationally representative serum estradiol concentrations in healthy men, which could be used for targeting estradiol during testosterone supplementation and for general good health.

Summary The makeup of the tumor immune microenvironment may be associated with tumor somatic genomic alterations and plays a key role in tumor progression and response to immunotherapy. We examined the association of tumor-infiltrating T-cell density with TP53 status in surgically treated primary prostate cancer using 3 independent tissue microarray sets, including one set of tumors from grade-matched patients of European American or African American ancestry (n = 391), a retrospective case-cohort of intermediate- and high-risk patients enriched for adverse outcomes (n = 267), and a set of tumors with primary Gleason pattern 5 (n = 77). The presence of TP53 missense mutation, indicated by p53 nuclear accumulation using a genetically validated assay, was significantly associated with increased CD3+ T-cell density (median, 341 versus 231 CD3+ T cells/mm2; P = .004) in the matched European American and African American ancestry patient sets. The same association was present in patients of both ancestries when analyzed separately, despite the fact that p53 nuclear accumulation was less frequent among African American compared with European American tumors (7% versus 3%, P = .2). The validation cohorts of intermediate/high-risk and primary Gleason pattern 5 patients corroborated the association of increased CD3+ T-cell density with presence of p53 nuclear accumulation. In a pooled analysis of all sets, adjusting for clinicopathological variables, CD3+ and CD8+, but not FOXP3+, T-cell densities remained significantly higher in tumors with p53 nuclear accumulation compared with those without. TP53 mutation is associated with higher tumor-infiltrating T-cell density, which may be relevant in future clinical trials of immunotherapy in prostate cancer.

PURPOSE: Two prior cohort studies suggested that choline, but not betaine intake is associated with an increased risk of advanced prostate cancer (PCa). Given that evidence remains limited, we evaluated whether intakes of choline and derivative betaine are associated with total and lethal PCa risk and PCa death in men with PCa. METHODS: We included 6,528 men (24.4% African American) without a cancer diagnosis at baseline (1987–1989) followed through 2012. Dietary intake was assessed using a food frequency questionnaire coupled with a nutrient database. We used Cox proportional hazards regression to estimate hazards ratios (HRs) and 95% confidence intervals (CIs) of total and lethal PCa risk overall and by race. RESULTS: Choline intake was not associated with total (N=811) or lethal (N=95) PCa risk overall or by race. Betaine intake was inversely associated with lethal (tertile 3 versus 1, HR: 0.59, 95% CI: 0.35–1.00, p-trend=0.04), but not total PCa risk; patterns for lethal PCa were similar by race. Neither nutrient was associated with PCa death in men with PCa. CONCLUSIONS: Choline intake was not associated with total or lethal PCa or with PCa death in men with PCa. Betaine intake was inversely associated with lethal, but not total PCa risk or with PCa death in men with PCa. Our results do not support the hypothesis that higher choline intake increases lethal PCa risk, but do suggest that higher betaine intake may be associated with lower lethal PCa risk. Further investigation with a larger number of lethal cases is needed.

The association between hyperglycemia and prostate cancer risk is inconsistent, and its association with prostate cancer mortality is understudied. Thus, we investigated the association between hyperglycemia and prostate cancer risk and mortality using multiple biomarkers simultaneously to classify hyper- and normoglycemia. We conducted a prospective analysis of 5,162 cancer-free men attending visit 2 (1990–1992) of the Atherosclerosis Risk in Communities (ARIC) study followed for total (N = 671) and lethal (N = 69) prostate cancer incidence and prostate cancer mortality (N = 64) through 2012. Men without diagnosed diabetes were classified as normo- or hyperglycemic using joint categories of fasting glucose, glycated hemoglobin, and glycated albumin (or fructosamine) defined by clinical or research cutpoints. We evaluated the multivariable-adjusted association of hyperglycemia with prostate cancer incidence and mortality using Cox proportional hazards regression; men with diagnosed diabetes were included as a separate exposure category. Among 4,753 men without diagnosed diabetes, 61.5% were classified as having hyperglycemia (high on ≥1 biomarker). HbA1c and glycated albumin together classified 61.9% of 1,736 men with normal fasting glucose as normoglycemic. Compared with men who were normal on all three biomarkers, men who were high on ≥1 biomarker had an increased risk of lethal [HR, 2.50; 95% confidence interval (CI), 1.12–5.58] and fatal (HR, 3.20; 95% CI, 1.26–8.48) disease, but not total prostate cancer incidence (HR, 0.98; 95% CI, 0.81–1.20); associations were similar including fructosamine instead of glycated albumin. Our findings indicate hyperglycemia is associated with an increased risk of lethal and fatal prostate cancer, but not total prostate cancer incidence.

Objective To investigate whether bipolar androgen therapy (BAT), involving rapid cyclic administration of high-dose testosterone, as a novel treatment for metastatic castration-resistant prostate cancer (mCRPC) promotes improvements in body composition and associated improvements in lipid profiles and quality of life. Patients and methods Men from two completed trials with computed tomography imaging at baseline and after three cycles of BAT were included. Cross-sectional areas of psoas muscle, visceral and subcutaneous fat were measured at the L3 vertebral level. Functional Assessment of Chronic Illness Therapy - Fatigue questionnaire and 36-item short-form health survey were used to assess quality of life. Results The 60 included patients lost a mean (sd) of 7.8 (8.2)% of subcutaneous fat, 9.8 (18.2)% of visceral fat, and gained 12.2 (6.7)% muscle mass. Changes in subcutaneous and visceral fat were positively correlated with each other (Spearman's correlation coefficient 0.58, 95% confidence interval 0.35-0.71) independent of the effects of age, body mass index, and duration of androgen-deprivation therapy. Energy, physical function, and measures of limitations due to physical health were all significantly improved at 3 months. The improvements in body composition were not correlated with decreases in lipid levels or observed improvements in quality of life. Conclusions In the present study, BAT was associated with significant improvements in body composition, lipid parameters, and quality of life. This has promising implications for the long-term health of men with mCRPC.

In our prior studies, obesity was associated with shorter telomeres in prostate cancer-associated stromal (CAS) cells, and shorter CAS telomeres were associated with an increased risk of prostate cancer death. To determine whether the association between obesity and shorter CAS telomeres is replicable, we conducted a pooled analysis of 790 men who were surgically treated for prostate cancer, whose tissue samples were arrayed on five tissue microarray (TMA) sets. Telomere signal was measured using a quantitative telomere-specific FISH assay and normalized to 4′,6-diamidino-2-phenylindole for 351 CAS cells (mean) per man; men were assigned their median value. Weight and height at surgery, collected via questionnaire or medical record, were used to calculate body mass index (BMI; kg/m2) and categorize men as normal (T2), obese men had a 3-fold increased odds of short CAS telomeres (OR: 3.06; 95% confidence interval: 1.07–8.75; Ptrend = 0.045) when compared with normal weight men. Telomere shortening in prostate stromal cells may be one mechanism through which lifestyle influences lethal prostate carcinogenesis. Prevention Relevance: This study investigates a potential mechanism underlying the association between obesity and prostate cancer death. Among men with aggressive prostate cancer, obesity was associated with shorter telomeres prostate cancer associated stromal cells, and shorter CAS telomeres have been associated with an increased risk of prostate cancer death.

Anaplasia may be identified in a subset of tumors with a presumed pilocytic astrocytoma (PA) component or piloid features, which may be associated with aggressive behavior, but the biologic basis of this change remains unclear. Fifty-seven resections from 36 patients (23 M, 13 F, mean age 32 years, range 3–75) were included. A clinical diagnosis of NF1 was present in 8 (22%). Alternative lengthening of telomeres (ALT) was assessed by telomere-specific FISH and/or CISH. A combination of immunohistochemistry, DNA sequencing and FISH were used to study BRAF, ATRX, CDKN2A/p16, mutant IDH1 p.R132H and H3-K27M proteins. ALT was present in 25 (69%) cases and ATRX loss in 20 (57%), mostly in the expected association of ALT+/ATRX- (20/24, 83%) or ALT-/ATRX+ (11/11, 100%). BRAF duplication was present in 8 (of 26) (31%). H3-K27M was present in 5 of 32 (16%) cases, all with concurrent ATRX loss and ALT. ALT was also present in 9 (of 11) cases in the benign PA precursor, 7 of which also had ATRX loss in both the precursor and the anaplastic tumor. In a single pediatric case, ALT and ATRX loss developed in the anaplastic component only, and in another adult case, ALT was present in the PA-A component only, but ATRX was not tested. Features associated with worse prognosis included subtotal resection, adult vs. pediatric, presence of a PA precursor preceding a diagnosis of anaplasia, necrosis, presence of ALT and ATRX expression loss. ALT and ATRX loss, as well as alterations involving the MAPK pathway, are frequent in PA with anaplasia at the time of development of anaplasia or in their precursors. Additionally, a small subset of PA with anaplasia have H3-K27M mutations. These findings further support the concept that PA with anaplasia is a neoplasm with heterogeneous genetic features and alterations typical of both PA and diffuse gliomas.

Background: We describe the expansion of the Atherosclerosis Risk in Communities (ARIC) Study into a cancer cohort. In 1987 to 1989, ARIC recruited 15,792 participants 45 to 64 years old to be sex (55% female), race (27% black), and geographically diverse. ARIC has exceptional data collected during 6 clinical visits and calls every 6 months, repeated biospecimens, and linkage to Medicare claims data. Methods: We established a Cancer Coordinating Center to implement infrastructure activities, convened a Working Group for data use, leveraged ARIC staff and procedures, and developed protocols. We initiated a cancer-specific participant contact, added questions to existing contacts, obtained permission to collect medical records and tissue, abstracted records, linked with state cancer registries, and adjudicated cases and characterizing data. Results: Through 2012, we ascertained and characterized 4,743 incident invasive, first, and subsequent primary cancers among 4,107 participants and 1,660 cancer-related deaths. We generated a total cancer incidence and mortality analytic case file, and analytic case files for bladder, breast, colorectal, liver, lung, pancreas, and prostate cancer incidence, mortality, and case fatality. Adjudication of multiple data sources improved case records and identified cancers not identified via registries. From 2013 onward, we ascertain cases from self-report coupled with medical records. Additional cancer registry linkages are planned. Conclusions: Compared with starting a new cohort, expanding a cardiovascular cohort into ARIC Cancer was an efficient strategy. Our efforts yielded enhanced case files with 25 years of follow-up. Impact: Now that the cancer infrastructure is established, ARIC is contributing its unique features to modern cancer epidemiology research. Cancer Epidemiol Biomarkers Prev; 27(3); 295–305. ©2017 AACR.

The inflammatory microenvironment plays an important role in the pathogenesis and progression of tumors and may be associated with somatic genomic alterations. We examined the association of tumor-infiltrating T-cell density with clinical-pathologic variables, tumor molecular subtype, and oncologic outcomes in surgically treated primary prostate cancer occurring in patients of European-American or African-American ancestry. We evaluated 312 primary prostate tumors, enriched for patients with African-American ancestry and high grade disease. Tissue microarrays were immunostained for CD3, CD8, and FOXP3 and were previously immunostained for ERG and PTEN using genetically validated protocols. Image analysis for quantification of T-cell density in tissue microarray tumor spots was performed. Automated quantification of T-cell densities in tumor-containing regions of tissue microarray spots and standard histologic sections were correlated (r = 0.73, p

Background: We leveraged two trials to test the hypothesis of an inflammation–prostate cancer link prospectively in men without indication for biopsy. Methods: Prostate Cancer Prevention Trial (PCPT) participants who had an end-of-study biopsy performed per protocol that was negative for cancer and who subsequently enrolled in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) were eligible. We selected all 100 cases and sampled 200 frequency-matched controls and used PCPT end-of-study biopsies as “baseline.” Five men with PSA > 4 ng/mL at end-of-study biopsy were excluded. Tissue was located for 92 cases and 193 controls. We visually assessed inflammation in benign tissue. We estimated ORs and 95% confidence intervals (CI) using logistic regression adjusting for age and race. Results: Mean time between biopsy and diagnosis was 5.9 years. In men previously in the PCPT placebo arm, 78.1% of cases (N = 41) and 68.2% of controls (N = 85) had at least one baseline biopsy core (∼5 evaluated per man) with inflammation. The odds of prostate cancer (N = 41 cases) appeared to increase with increasing mean percentage of tissue area with inflammation, a trend that was statistically significant for Gleason sum 0– Conclusions: Benign tissue inflammation was positively associated with prostate cancer. Impact: This first prospective study of men without biopsy indication supports the hypothesis that inflammation influences prostate cancer development. Cancer Epidemiol Biomarkers Prev; 26(10); 1549–57. ©2017 AACR.

Background: Black men have worse prostate cancer outcomes following treatment than White men even when accounting for prognostic factors. However, biological explanations for this racial disparity have not been fully identified. We previously showed that more variable telomere lengths among cancer cells and shorter telomere lengths in cancer-associated stromal (CAS) cells individually and together (“telomere biomarker”) are associated with prostate cancer–related death in surgically treated men independent of currently used prognostic indicators. Here, we hypothesize that Black–White differences in the telomere biomarker and/or in its components may help explain the racial disparity in prostate cancer outcomes. Methods: Black [higher grade (Gleason ≥4+3) = 34 and lower grade = 93] and White (higher grade = 34 and lower grade = 89) surgically treated men were frequency matched on age, pathologic stage, and grade. We measured telomere lengths in cancer and CAS cells using a robust telomere-specific FISH assay. Tissue microarray and grade-specific distributional cutoff points without regard to race were evaluated. Results: Among men with higher grade disease, the proportion of Black men (47.1%) with more variable cancer cell telomere lengths was 2.3-times higher (P = 0.02) than that in White men (20.6%). In contrast, among men with lower grade disease, cancer cell telomere length variability did not differ by race. The proportion of men with shorter CAS cell telomeres did not differ by race for either higher or lower grade disease. Conclusions: A greater proportion of Black men with higher grade disease have an adverse prostate cancer cell telomere phenotype than White men with higher grade disease. Impact: Our findings suggest a possible explanation for the racial disparity in prostate cancer outcomes.

BackgroundPathological and clinical stage are associated with prostate cancer-specific survival after prostatectomy. With PSA screening, the post-surgery prognostic utility of clinical stage is debatable in studies seeking to identify new biomarkers. Few studies have investigated clinical stage and lethal prostate cancer association after accounting for pathological stage. We hypothesize that clinical stage provides prognostic information beyond pathological stage in the PSA era.MethodsCox regression models tested associations between clinical and pathological stage and lethal prostate cancer among 3,064 participants from the Health Professionals Follow-Up Study and Physicians' Health Study (HPFS/PHS) who underwent prostatectomy. Likelihood ratio tests and c-statistics were used to assess the models' prognostic utility. Equivalent analyses were performed in 16,134 men who underwent prostatectomy at Johns Hopkins.ResultsIndependently, clinical and pathological stage were associated (pConclusionsDespite stage migration resulting from widespread PSA screening, clinical stage remains associated with progression to lethal prostate cancer independent of pathological stage. Future studies evaluating associations between new factors and poor outcome following prostatectomy should consider including both clinical and pathological stages since the data is already available.

The presence of Alternative lengthening of telomeres (ALT) and/or ATRX loss, as well as the role of other telomere abnormalities, have not been formally studied across the spectrum of NF1-associated solid tumors. Utilizing a telomere-specific FISH assay, we classified tumors as either ALT-positive or having long (without ALT), short, or normal telomere lengths. A total of 426 tumors from 256 NF1 patients were evaluated, as well as 99 MPNST tumor samples that were sporadic or of unknown NF1 status. In the NF1-glioma dataset, ALT was present in the majority of high-grade gliomas: 14 (of 23; 60%) in contrast to only 9 (of 47; 19%) low-grade gliomas (p = 0.0009). In the subset of ALT-negative glioma cases, telomere lengths were estimated and we observed 17 (57%) cases with normal, 12 (40%) cases with abnormally long, and only 1 (3%) case with short telomeres. In the NF1-associated malignant nerve sheath tumor (NF1-MPNST) set (n = 75), ALT was present in 9 (12%). In the subset of ALT-negative NF1-MPNST cases, telomeres were short in 9 (38%), normal in 14 (58%) and long in 1 (3%). In the glioma set, overall survival was significantly decreased for patients with ALT-positive tumors (p

Context Testosterone deficiency prevalence increases with age, comorbidities, and obesity. Objective To inform clinical guidelines for testosterone deficiency management and development of targets for nonpharmacologic intervention trials for these men, we determined serum testosterone in never-smoking, lean men without select comorbidities in nationally representative surveys. Design, Setting, Participants We used cross-sectional data for never-smoking, lean men ≥20 years without diabetes, myocardial infarction, congestive heart failure, stroke, or cancer, without use of hormone-influencing medications, and participated in morning sessions of National Health and Nutrition Examination Survey (NHANES) III (phase I 1988–1991) or continuous NHANES (1999–2004). By age, we determined median total testosterone (ng/mL) measured previously by a Food and Drug Administration-approved immunoassay and median estimated free testosterone concentration. Results In NHANES III, in never-smoking, lean men without comorbidities, median (25th, 75th percentile) testosterone was 4% to 9% higher than all men—20 to 39 years: 6.24 (5.16, 7.51), 40 to 59: 5.37 (3.83, 6.49), and ≥60: 4.61 (4.01, 5.18). In continuous NHANES, in never-smoking, lean men without comorbidities, levels were 13% to 24% higher than all men—20 to 39 years: 6.26 (5.32, 7.27), 40 to 59: 5.86 (4.91, 6.55), and ≥60: 4.22 (3.74, 5.73). In never-smoking, lean men without comorbidities, median estimated free testosterone was similar to (NHANES III) or slightly higher than (continuous NHANES) in all men. Conclusions These nationally representative data document testosterone levels (immunoassay) in never-smoking, lean men without select comorbidities 30 and 15 to 20 years ago. This information can be incorporated into guidelines for testosterone deficiency management and used to develop targets for nonpharmacologic intervention trials for testosterone deficiency.

Background: Evidence is mounting that intraprostatic inflammation influences prostate cancer development. Uric acid crystals depositing in the prostate could result in injury and inflammation, increasing prostate cancer risk. Methods: Included were 6,574 men ages 45–64 years who enrolled in the Atherosclerosis Risk in Communities study in 1987 to 1989. We used Cox proportional hazards regression to estimate the association of serum urate concentration alone and to improve accuracy, jointly with a genetic risk score (GRS, N = 4,983) derived from variants predictive of urate concentration, with prostate cancer (N = 813) risk. Results: Serum urate concentration or joint categories of urate concentration and GRS were not associated with prostate cancer risk (Ptrend for quartiles = 0.3). Results were generally similar by race and after excluding users of medications that influence uric acid. Conclusions: Serum urate alone and with a urate-associated GRS were not associated with prostate cancer risk. Impact: It is unlikely that circulating urate concentration influences prostate cancer development.

BACKGROUND Mast cells are of interest in prostate cancer because they possess both pro- and anti-tumorigenic properties and are present in the tumor microenvironment. We studied the association of mast cell count and densities with prostate cancer recurrence using tissue microarrays (TMAs) for 462 men who recurred (cases) and 462 controls that were matched to the cases nested in a cohort of radical prostatectomy patients. METHODS Dual-immunostaining for mast cell tryptase and epithelial cytokeratin-8 and whole slide image analysis were used to assess total mast cell number, mast cell density (mast cell number/tissue area), and mast cell number per epithelial or stromal area in TMA spots containing tumor (up to 4 per man). We used conditional logistic regression to estimate the odds ratio (OR) and 95% confidence interval of recurrence for the mean, minimum, and maximum mast cell parameters in tumor tissue among each man's TMA spots. RESULTS After taking into account matching factors of age, race, Gleason sum, and pathologic stage, higher minimum mast cell density in the tumor (comparing highest to lowest quartiles: OR = 0.58, 95% CI 0.40–0.86; P-trend = 0.004) was associated with a lower risk of recurrence. Patterns for mast cell number and ratio of mast cell number to epithelial or stromal area were similar to those for mast cell density. CONCLUSIONS Our results suggest that intratumoral mast cells may be protective against prostate cancer recurrence and could potentially serve as a prognostic biomarker after prostatectomy. Prostate © 2016 Wiley Periodicals, Inc.

Background: A previous analysis of the placebo arm of the Prostate Cancer Prevention Trial (PCPT) reported 82% overall prevalence of intraprostatic inflammation and identified a link between inflammation and higher-grade prostate cancer and serum PSA. Here, we studied these associations in the PCPT finasteride arm. Methods: Prostate cancer cases (N = 197) detected either on a clinically indicated biopsy or on protocol-directed end-of-study biopsy, and frequency-matched controls (N = 248) with no cancer on an end-of-study biopsy were sampled from the finasteride arm. Inflammation in benign prostate tissue was visually assessed using digital images of hematoxylin and eosin–stained sections. Logistic regression was used for statistical analysis. Results: In the finasteride arm, 91.6% of prostate cancer cases and 92.4% of controls had at least one biopsy core with inflammation in benign areas (P < 0.001 for difference compared with placebo arm). Overall, the odds of prostate cancer did not differ by prevalence [OR, 0.90; 95% confidence interval (CI), 0.44–1.84] or extent (P trend = 0.68) of inflammation. Inflammation was not associated with higher-grade disease (prevalence: OR, 1.07; 95% CI, 0.43–2.69). Furthermore, mean PSA concentration did not differ by the prevalence or extent of inflammation in either cases or controls. Conclusion: The prevalence of intraprostatic inflammation was higher in the finasteride than placebo arm of the PCPT, with no association with higher-grade prostate cancer. Impact: Finasteride may attenuate the association between inflammation and higher-grade prostate cancer. Moreover, the missing link between intraprostatic inflammation and PSA suggests that finasteride may reduce inflammation-associated PSA elevation. Cancer Epidemiol Biomarkers Prev; 25(3); 463–9. ©2015 AACR.

Background: While lipid-lowering drugs, particularly statins, are associated with a modestly reduced risk of developing colorectal cancer (CRC), the association of lipid-lowering drug use, duration of use, and age at first use with CRC mortality in men and women without the diagnosis at baseline, has not been well studied. Further, whether associations are similar across race is unknown. Thus, we aimed to characterize the association between lipid-lowering drug use and CRC mortality in men and women and by race. We classified lipid-lowering drug use in a time-dependent manner as current use, duration of use, and age at first use. Methods: We conducted a prospective cohort study of 14,428 cancer-free men and women attending visit 2 (1990-1992) of the Atherosclerosis Risk in Communities (ARIC) Study. Death from CRC was ascertained from the underlying cause on death certificates. Follow-up began at visit 2 and ended at date of death or 12/31/2015, whichever came first. There were 384 incident CRC cases and 144 deaths in 290,249 person-years. Cox regression was used to estimate relative hazards (HR) and 95% confidence intervals (CI) for CRC incidence and death adjusting for age, sex, education, race and field center, BMI, smoking status and pack years, alcohol use, red and processed meat consumption, aspirin use, and family history of any cancer and family history of CRC overall and by gender and race. Current lipid-lowering medication use, duration of use ( Results: Mean age was 57 years and mean BMI was 28.1 kg/m2; 54.9% were women and 27.9% were Black. By visit 4 (1996-98), after an average of 6 years of follow-up, 22% of participants were using lipid-lowering drugs. Compared to never users, current use was associated with 53% lower risk of CRC death (HR 0.47; 95%CI 0.32-0.71). Inverse associations were present in both men (HR 0.59; 95%CI 0.35-0.99) and women (HR 0.37; 95%CI 0.20-0.69) and in Black (HR 0.44; 95%CI 0.19-1.00) and White (HR 0.49; 95%CI 0.31-0.77) participants. Inverse associations were consistent across different patterns of duration of use and was inverse irrespective of age at first use. Current use was also associated with a lower risk of CRC incidence (HR: 0.72; 95%CI 0.57-0.92). Conclusions: Current use of lipid-lowering drugs was associated with a statistically significant lower risk of dying from CRC in participants without cancer at baseline, including men and women and in Black and white participants, irrespective of the duration (15 year intervals) or age at first use. Support: NHLBI contracts, NCI grants, NPCR Citation Format: Michael T. Marrone, John R. Barber, Alison M. Mondul, Anna E. Prizment, David Couper, Corinne E. Joshu, Elizabeth A. Platz. Lipid-lowering drug use, duration of use, and age at first use is associated with a lower risk of colorectal cancer mortality in men and women in the Atherosclerosis Risk in Communities (ARIC) Study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2357.

Background: Non-Hispanic Blacks (NHBs) experience a markedly higher cancer burden and cancer mortality compared to non-Hispanic Whites (NHWs). Several factors account for this disparity, including suboptimal or deficient vitamin D status. Vitamin D has an important role in cancer risk, disease/cancer progression and telomere biology. Given the documented cancer disparities between these groups, it is important to examine vitamin D concentrations and leukocyte telomere length in utero, a window of susceptibility for disease and cancer risk later in life. We investigated racial differences in neonate umbilical cord blood vitamin D concentrations, and whether differences in vitamin D concentrations are associated with umbilical cord blood telomere length by race and gender. Methods: In 2006-2007, pregnant women were recruited for the Expanded Hormones in Umbilical Cord Blood Study (EHUB) and followed to postpartum. Venous umbilical cord blood samples, along with maternal and birth characteristics, were collected in 39 NHB and 65 NHW full-term neonates. 25(OH)D and 1,25(OH)2D levels were assayed using an equilibrium radioimmunoassay procedure, and relative telomere length was measured by qPCR in leukocyte DNA. Geometric mean plasma concentrations of 25(OH)D and 1,25(OH)2D were calculated. Linear regression analysis was used to examine associations between neonatal cord blood 25(OH)D and 1,25(OH)2D concentrations and leukocyte telomere length by race and gender. Results: Compared to NHW mothers, NHBs were younger, had higher parity, were more likely to be overweight and obese prepregnancy, and more likely to be exposed to secondhand smoke. NHB neonates had lower birth lengths (19.4 versus 20.2 inches; p Conclusion: We did not find an association between umbilical cord blood vitamin D concentrations and telomere length. Instead, our findings suggest an interaction between race and umbilical cord blood vitamin D on telomere length. Further research is warranted to understand whether the effect of in utero exposure to vitamin D concentration on telomere length can inform the underlying mechanisms that are associated with cancer disparities in adulthood. Citation Format: Tanya Agurs-Collins, John Barber, Jessica Bienstock, Paige Green, Christopher Heaphy, Jiayun Lu, Alan Meeker, Anthony Rizzo, Sabine Rohrmann, Elizabeth Platz. Racial variation in umbilical cord blood vitamin D concentrations and telomere length: Implications for cancer risk [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C027.

Lipid-lowering medications, particularly statins, may protect against aggressive prostate cancer. Fatal prostate cancer, the most clinically relevant outcome, remains understudied for this association. We prospectively studied lipid-lowering medication use and both incident and fatal prostate cancer in black and white men in the Atherosclerosis Risk in Communities (ARIC) study. A total of 6,518 men without cancer at visit 2 (1990–1992), the start of the statin era, were followed for prostate cancer incidence and death through 2012. Medication use was collected during study visits and telephone calls at up to nine time points during follow-up. Cox regression was used to estimate HR and 95% confidence intervals (CI) of total (white N = 541, black N = 259) and fatal (white N = 56, black N = 34) prostate cancer overall and by race. Lipid-lowering medication use was modeled as time-dependent current use or duration (never

Background: NSAIDs appear to moderately reduce prostate cancer risk. However, evidence is limited on whether NSAIDs protect against prostate cancer mortality (death from prostate cancer among men without a cancer history) and case fatality (death from prostate cancer among men with prostate cancer), and whether benefits are consistent in white and black men. This study investigated associations of aspirin and non-aspirin (NA) NSAID use with prostate cancer incidence, mortality, and case fatality in a population-based cohort of white and black men. Methods: We included 6,594 men (5,060 white and 1,534 black) from the Atherosclerosis Risk in Communities study without a cancer history at enrollment from 1987 to 1989. NSAID use was assessed at four study visits (1987–1998). Cancer outcomes were ascertained through 2012. Cox proportional hazards regression was used to estimate adjusted HRs, overall and by race. Results: Aspirin use was not associated with prostate cancer incidence. However, aspirin use was inversely associated with prostate cancer mortality [HR, 0.59; 95% confidence interval (CI), 0.36–0.96]. This association was consistent among white and black men and appeared restricted to men using aspirin daily and/or for cardiovascular disease prevention. Aspirin use was inversely associated with case fatality (HR, 0.45; 95% CI, 0.22–0.94). NA-NSAID use was not associated with these endpoints. Conclusions: Aspirin use was inversely associated with prostate cancer mortality and case fatality among white and black men. Impact: If confirmed by additional studies, benefits of aspirin for preventing prostate cancer mortality may need to be factored into risk–benefit calculations of men considering an aspirin regimen.

We have identified a discrete, focal telomere DNA expansion phenotype in the photoreceptor cell layer of normal, non-neoplastic human retinas. This phenotype is similar to that observed in a subset of human cancers, including a large fraction of tumors of the central nervous system, which maintain their telomeres via the non-telomerase-mediated alternative lengthening of telomeres (ALT) mechanism. We observed that these large, ultra-bright telomere DNA foci are restricted to the rod photoreceptors and are not observed in other cell types. Additionally, focus-positive rod cells are dispersed homogeneously throughout the posterior retinal photoreceptor cell layer and appear to be human-specific. We examined 108 normal human retinas obtained at autopsy from a wide range of ages. These large, ultra-bright telomere DNA foci were not observed in infants before 6 months of age; however, the prevalence of focus-positive rod cells dramatically increased throughout life. To investigate associations between this phenotype and retinal pathology, we assessed adult glaucoma (N = 29) and diabetic retinopathy (N = 38) cases. Focus-positive rod cells were prominent in these diseases. When compared to the normal group, after adjusting for age, logistic regression modeling revealed significantly increased odds of falling in the high category of focus-positive rod cells for glaucoma and diabetic retinopathy. In summary, we have identified a dramatic telomere alteration associated with aging and diseases affecting the retina.

Background While evidence is increasingly consistent with a positive association between periodontitis and cancer risk, most studies have relied on self-reported periodontitis. In this study, we prospectively evaluated the association of periodontal disease severity with cancer risk in black and white older adults in a cohort study that included a dental examination. Methods Included were 7466 participants in the Atherosclerosis Risk in Communities study cohort who at visit 4 (1996-1998) reported being edentulous or underwent the dental examination. Probing depth and gingival recession were measured at six sites on all teeth; these measurements were used to define periodontal disease severity. Incident cancers (n = 1648) and cancer deaths (n = 547) were ascertained during a median of 14.7 years of follow-up. All statistical tests were two-sided. Results An increased risk of total cancer (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 1.07 to 1.44, Ptrend = .004) was observed for severe periodontitis (>30% of sites with attachment loss >3 mm) compared with no/mild periodontitis ( 3 mm), adjusting for smoking and other factors. Strong associations were observed for lung cancer (HR = 2.33, 95% CI = 1.51 to 3.60, Ptrend < .001), and elevated risks were noted for colorectal cancer for severe periodontitis, which were significant among never smokers (HR = 2.12, 95% CI = 1.00 to 4.47). Associations were generally weaker, or not apparent among black participants, except for lung and colorectal cancers, where associations were similar by race. No associations were observed for breast, prostate, or hematopoietic and lymphatic cancer risk. Conclusions This study provides additional evidence that cancer risk, especially for lung and colorectal cancer, is elevated in individuals with periodontitis. Additional research is needed to understand cancer site-specific and racial differences in findings.

Mast cells are of interest in prostate cancer because they possess both pro- and anti-tumorigenic properties and are present in the tumor microenvironment. We studied the association of mast cell count and densities with prostate cancer recurrence using tissue microarrays (TMAs) for 462 men who recurred (cases) and 462 controls that were matched to the cases nested in a cohort of radical prostatectomy patients.Dual-immunostaining for mast cell tryptase and epithelial cytokeratin-8 and whole slide image analysis were used to assess total mast cell number, mast cell density (mast cell number/tissue area), and mast cell number per epithelial or stromal area in TMA spots containing tumor (up to 4 per man). We used conditional logistic regression to estimate the odds ratio (OR) and 95% confidence interval of recurrence for the mean, minimum, and maximum mast cell parameters in tumor tissue among each man's TMA spots.After taking into account matching factors of age, race, Gleason sum, and pathologic stage, higher minimum mast cell density in the tumor (comparing highest to lowest quartiles: OR = 0.58, 95% CI 0.40-0.86; P-trend = 0.004) was associated with a lower risk of recurrence. Patterns for mast cell number and ratio of mast cell number to epithelial or stromal area were similar to those for mast cell density.Our results suggest that intratumoral mast cells may be protective against prostate cancer recurrence and could potentially serve as a prognostic biomarker after prostatectomy. Prostate 77: 412-424, 2017. © 2016 Wiley Periodicals, Inc.

Background: Aspirin is commonly used to treat pain and inflammation, and is recommended for some individuals for prevention of cardiovascular disease (CVD) and colorectal cancer. Observational studies suggest that aspirin use may also lower risk of prostate cancer. However, there is limited evidence on whether aspirin may protect against lethal prostate cancer in particular, and on whether benefits are consistent in black and white men. This study sought to determine the association between aspirin use and risk of total and lethal prostate cancer, overall and by race, among men in the Atherosclerosis Risk in Communities (ARIC) cohort. Methods: The ARIC study enrolled individuals from four U.S. communities in 1987-89. This analysis was restricted to white and black men from this cohort who had non-missing data on aspirin use and were cancer-free at baseline. Aspirin use was assessed at four study visits (V1: 1987-89, V2: 1990-92, V3: 1993-95, V4: 1996-98). Indication for aspirin use was reported at V4. Cancer outcomes were ascertained through 2012. Cox proportional hazards regression was used to estimate cause-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for total incident prostate cancer and lethal prostate cancer, defined as cancer that was advanced at diagnosis or fatal during follow-up. Models were adjusted for race, study center, year of birth, education, and family history of prostate cancer (time-fixed), and smoking status, body mass index, use of statins, diabetes, and coronary heart disease (time-varying). Stratified models and likelihood ratio tests were used to test for effect modification by race. Results: There were 6,594 men (5,060 white, 1,534 black) included in this analysis. Aspirin use was reported by 29%, 33%, 37% and 44% of men at V1, V2, V3, and V4, respectively. Through the end of 2012, 817 total incident prostate cancers, including 97 lethal prostate cancers, were diagnosed. Aspirin use was not associated with risk of total prostate cancer (HR 1.06, 95% CI 0.91-1.23). However, aspirin use was inversely associated with risk of lethal prostate cancer (HR 0.58, 95% CI 0.35-0.95). This association was consistent among both white men (HR 0.64, 95% CI 0.36-1.13) and black men (HR 0.47, 95% CI 0.16-1.35, p-interaction=0.45). When looked at by indication for use, the inverse association with lethal prostate cancer appeared to be only among men who reported using aspirin regularly for CVD prevention (HR 0.63, 95% CI 0.27-1.50). Conclusions: Aspirin use was inversely associated with lethal prostate cancer, but not total prostate cancer, in this study population. The association was not modified by race and was possibly restricted to men who used aspirin regularly for CVD prevention. Support: NHLBI, NCI, NPCR Citation Format: Lauren M. Hurwitz, Corinne E. Joshu, John R. Barber, Anna E. Prizment, Mara Z. Vitolins, Miranda R. Jones, Aaron R. Folsom, Misop Han, Elizabeth A. Platz. Aspirin use and risk of lethal prostate cancer in the Atherosclerosis Risk in Communities cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4947.

Recent studies have suggested that testosterone levels are lower in men with Alzheimer's disease and that testosterone treatment improves cognition in older men. Since testosterone can be aromatized to estrogen, testosterone's effects could be due to conversion into estrogen. We treated aged male rats with either testosterone or dihydrotestosterone (DHT), the latter of which is not aromatized to estrogen, in order to determine whether these treatments improve spatial working and reference memory as assessed in the water radial arm maze. We also tested whether such effects are related to beta-amyloid levels in the hippocampus or neurotrophin levels in the hippocampus, entorhinal cortex, frontal cortex, or striatum. Aged rats made more errors than young rats on all memory measures. Testosterone, but not DHT, improved working memory and decreased hippocampal NGF protein in aged rats, while having no effect on beta-amyloid. However, higher beta-amyloid levels were correlated with poorer working memory performance in young rats. Neurotrophin levels in entorhinal cortex were positively correlated with errors for all memory measures in androgen-treated rats. Similar to findings in human studies, in our study androgen treatment lowered circulating estradiol levels in aged rats, suggesting that androgen treatment exerts feedback to the hypothalamic pituitary axis and that conversion to estrogen may not be the underlying biological mechanism of testosterone's effects on memory and growth factor levels. The ratio of estradiol to testosterone, or the actions of the aromatase enzyme itself, may be responsible for the observed effects. These data support the hypothesis that testosterone therapy in aging men may provide positive effects on cognition and that neural regions that are linked to cognition, such as the hippocampus and/or entorhinal cortex, may be involved in such effects.

Background: Obesity and weight gain are associated with poor prostate cancer outcome; underlying mechanisms are unknown. Obesity has been more strongly associated with lethal disease in men positive for the TMPRSS2:ERG gene fusion than negative for this fusion. PTEN loss is associated with increased risk of lethal progression; its association with obesity has not been explored. We evaluated whether prevalence of ERG expression and PTEN loss in prostate tumors differs by BMI and weight change. Methods: From a retrospective cohort study of 1,337 men with clinically-localized prostate cancer who underwent prostatectomy at Johns Hopkins (1993-2006), we sampled 291 men by combination of BMI at 1 year after surgery (normal, overweight, obese) and weight change from 5 years before to 1 year after surgery (loss, maintenance, gain). Within each category, men were frequency-matched on age, Gleason sum, organ confinement, and surgery year. We used genetically validated immunohistochemistry assays to assess ERG positivity and heterogeneous PTEN loss. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of BMI and weight change (adjusted for height, starting weight) with ERG positivity and heterogeneous PTEN loss. Results: Mean age was 56.1 years and mean Gleason sum was 6.2; 73% had organ-confined disease. Prevalence of ERG positivity did not statistically significantly differ by BMI or weight change. However, when jointly categorized by BMI and weight change, overweight/obese men who maintained (OR=2.5; 95%CI 1.1-5.7) or gained weight (OR=2.5; 95%CI 1.1-5.8), and normal weight men who gained weight (OR=4.7; 95%CI 1.4-15.2) were significantly more likely to have ERG positive tumors compared with normal weight men who maintained weight. Overweight/obese men were also significantly more likely (OR=2.4; 95%CI 1.3-4.7) to have PTEN loss compared with normal weight men. When stratified by ERG status, this association appeared to be stronger for men with ERG positive tumors (OR=2.9; 95%CI 1.3-6.8) than for men with ERG negative tumors (OR=1.6; 95%CI 0.6-4.9). Prevalence of PTEN loss did not differ by weight change. When jointly categorized by BMI and weight change, overweight/obese men who maintained (OR=2.0; 95%CI 0.8-5.3) or gained weight (OR=1.9; 95%CI 0.7-5.1) appeared to be more likely to have PTEN loss compared with normal weight men who maintained weight. Conclusions: Overweight/obese men who maintained or gained weight circa diagnosis and normal weight men who gained weight were more likely to have ERG positive tumors. Overweight/obese men were more likely to have tumors with PTEN loss; this association was stronger among overweight/obese men who also had ERG positive tumors. The TMPRSS2:ERG gene fusion and PTEN loss may contribute to the increased risk of poor prostate cancer outcomes among overweight/obese men. Funding: Prostate Cancer Foundation Citation Format: Janelle S. Ho, Ibrahim Kulac, Tamara L. Lotan, John R. Barber, Patrick C. Walsh, Misop Han, Angelo M. De Marzo, Elizabeth A. Platz, Corinne E. Joshu. ERG expression and PTEN loss by BMI and weight change in men with prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5324. doi:10.1158/1538-7445.AM2017-5324

Background: Studies show that lipid-lowering medications, particularly statins, may be protective for more aggressive prostate cancer. Lethal prostate cancer is often considered an optimal outcome in epidemiologic studies when the aim is to identify modifiable risk factors with the potential to reduce morbidity and mortality from this disease, yet this outcome remains understudied. Further, lipid drug use and prostate cancer risk is understudied in black men, whose risk of fatal prostate cancer is 2-3 times higher than that of white men. Thus, we studied lipid medication use and fatal prostate cancer risk in the ARIC Study, which includes ~25% black participants. Methods: The ARIC Study is a prospective cohort that included 15,792 participants (7,082 men) recruited from four US communities. We conducted a prospective cohort analysis of 6,547 men who attended visit 2 (1990-1992, the start of the statin era) and were followed for cancer death through 12/31/2012. Death from prostate cancer (n=90) as the underlying cause was obtained from death certificates supplemented with medical records. Updated information on medication use was collected throughout the study follow-up during study visits and annual telephone calls. Lipid medication use was modeled as a time-dependent variable in two ways: 1) current use (yes/no), and 2) duration of use ( Results: The prevalence of lipid medication use was 17% by visit 4, partway into the statin drug era, and 76% of those medications were statins. After adjustment for age, race, and study center, men who used lipid medications were statistically significantly less likely to die from prostate cancer than men who did not use lipid medications (HR=0.56, 95% CI=0.33-0.95). This finding was slightly attenuated after further mutlivariable adjustment (HR=0.62, 0.36-1.08). The statistically significant inverse association appeared to be restricted to men who used lipid medications for ≥10 years (vs. never use: HR=0.39, 95% CI=0.19-0.82, p-trend=0.02). Lipid medication use was inversely associated with a reduced risk of prostate cancer death in both white and black men. Conclusions: Use of lipid medications was associated with a lower risk of fatal prostate cancer in both black and white men. Whether the fact that black men are less likely to receive/take lipid medications could partly explain the black-white disparity in prostate cancer in the US requires further study. Support: NHLBI contracts, NCI grant, NPCR Citation Format: Alison M. Mondul, Corinne E. Joshu, John Barber, Anna Prizment, Nrupen Bahvsar, Josef Coresh, Elizabeth Selvin, Aaron Folsom, Elizabeth A. Platz. Lipid-lowering drug use and risk of fatal prostate cancer in the Atherosclerosis Risk in Communities (ARIC) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3009. doi:10.1158/1538-7445.AM2017-3009