PC Risk Research Articles

Does prostate inflammation on a negative prostate biopsy vary by race? Results from the REDUCE study.

116 Background: Prostateinflammation is linked with prostate cancer. However, whether prostate inflammation varies by race is unclear. Methods: We analyzed baseline acute and chronic prostate inflammation by race in REDUCE. REDUCE was a 4-year, multicenter, placebo-controlled study where all men received a single, negative prostate biopsy within 6 months prior to enrollment. Among 8,046 men who met the inclusion criteria, we included those with data on baseline biopsy prostate inflammation, acute/chronic or none, determined by central pathology. Logistic regression was used to compare prostate inflammation by race, and models were adjusted for demographic and clinical features. Results: Of the 8,046 men, 7,326 were white (91.1%), 184 (2.3%) black, 132 (1.6%) Asian, 323 (4.0%) Hispanic, and 81(1%) unknown. Seventy eight percent of men had chronic and 15% had acute prostate inflammation. Men with chronic inflammation were older (p<0.001), while men with acute inflammation were younger (p<0.001) compared to men with none prostate inflammation. Both acute and chronic inflammation was associated with lower PSA (all p≤0.0001), smaller prostate volume (all p≤0.0001) and geographic region (all p≤0.006). On crude analysis, compared to whites, Asian men were two times more likely to have acute prostate inflammation (OR=1.92, 95%CI: 1.29-2.85, p=0.001), whereas the associations with Hispanic and black race were not significant (all p≥0.39). However, on multivariable analysis, black men were 36% less likely to have acute prostate inflammation (OR=0.64, 95%CI: 0.41-0.99, p=0.04), whereas the likelihood of having acute prostate inflammation remained high in Asians (OR=1.85, 95%CI: 1.25-2.85, p=0.004). No associations by race were found with chronic prostate inflammation. Conclusions: Given that at the population level, black race is a high risk factor for PC and Asian men have lower risk of PC, these data indicate that the presence of acute inflammation in a negative prostate biopsy could be an indication of future PC risk. Further studies to confirm these findings are needed. Clinical trial information: NCT00056407.

Abstract B89: The significance of Vitamin D deficiency and anaerobes in prostate cancer

Abstract Objective: Long-term sun exposure estimates correlate with risk of PC possibly due to long-term Vitamin D deficiency diminishing macrophage function allowing persistence of low grade pathogens causing chronic inflammation leading to Proliferative Inflammatory Atrophy and then cancer. Recently infection with two low grade pathogenic organisms, teenage acne associated Vitamin D sensitive anaerobic bacterium Propionibacterium.acnes (PA) and protozoan Trichomonas vaginalis (TA), have been notable exceptions. This presentation reports a systematic review of reports on anaerobes, circumcision and the association of sun exposure in causation of PC and considers how these observations could contributing to increased PC in Africa Methods: Pubmed searches using terms prostate or prostatic, sunshine or UVB or Vitamin D and acne or PA or TA were performed Results: Two systematic reviews of PC and Vitamin D failed to produce a consistent association. 4/4 studies of index of long-term sun exposure involving 1568 patients and 9/12 geographic studies demonstrated that high UVB exposure reduced PC risk. 4/5 publications on PA and PC and 2/3 publications on TV and PC showed consistent increase risk of PC associated with infection. Ten studies involving 5681 patients demonstrated significant reduction of PC in circumcised individuals (OR 0.87), including one in African American Men showing lower incidence of circumcision possibly contributing to their higher frequency Conclusion: Reduced long-term Vitamin D mediated non-specific macrophage surveillance against low-grade pathogenic anaerobes could explain these associations with PC and increasing urbanisation could be a factor in the health inequality as measured by prostate cancer incidence in African-American men. Citation Format: Tim Oliver, Lucy Blackburn, Frank Chinegwundoh. The significance of Vitamin D deficiency and anaerobes in prostate cancer. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B89.

Investigating the Incidence of Prostate Cancer in Iran 2005 -2008 using Bayesian Spatial Ecological Regression Models.

Prostate cancer is the most commonly diagnosed form of cancer and the sixth leading cause of cancer-related deaths among men in the entire world. Reported standardized incidence rates are 12.6, 61.7, 11.9 and 27.9 in Iran, developed countries, developing countries and the entire world, respectively. The present study investigated the relative risk of PC in Iran at the province level and also explored the impact of some factors by the use of Bayesian models. Our study population was all men with PC in Iran from 2005 to 2008. Considered risk factors were smoking, fruit and vegetable intake, physical activity, obesity and human development index. We used empirical and full Bayesian models to study the relative risk in Iran at province level to estimate the risk of PC more accurately. In Iran from 2005 to 2008 the total number of known PC cases was 10,361 with most cases found in Fars and Tehran and the least in Ilam. In all models just human development index was found to be significantly related to PC risk Conclusions: In the unadjusted model, Fars, Semnam, Isfahan and Tehran provinces have the highest and Sistan-and-Baluchestan has the least risk of PC. In general, central provinces have high risk. After adjusting for covariates, Fars and Zanjan provinces have the highest relative risk and Kerman, Northern Khorasan, Kohgiluyeh Boyer Ahmad, Ghazvin and Kermanshah have the lowest relative risk. According to the results, the incidence of PC in provinces with higher human development index is higher.

Sleep and use of electronic devices in adolescence: results from a large population-based study

ObjectivesAdolescents spend increasingly more time on electronic devices, and sleep deficiency rising in adolescents constitutes a major public health concern. The aim of the present study was to investigate daytime...

Quantitative assessment of the association between CYP17 rs743572 polymorphism and prostate cancer risk.

Published data on the association between CYP17 rs743572 polymorphism and risk of PC showed inconclusive results. The aim of this study was to further estimate the pooled effect size of rs743572 polymorphism and PC progression via large-scale meta-analysis. We searched the case-control studies of rs743572 polymorphism and PC risk in PubMed, Embase, and Web of Science databases up to February 2014. Odds ratios (ORs) along with 95 % confidence intervals (CIs) were pooled by means of both fixed effects model and random effects model. A total of 38 publications consisting of 42 studies with 15,735 cases and 17,825 controls were included in this meta-analysis. Overall, no significant association was found between rs743572 polymorphism and PC risk. Stratified analyses by control source and sample size did not provide significant results. However, there was a borderline association in African population under A2A2 versus A1A2 + A1A1 genetic model (OR = 1.39, 95 % CI: 1.01-1.92, P = 0.975, I (2) = 0.0 %). Results from the current meta-analysis suggested that CYP17 rs743572 polymorphism might modify the risk of PC in the subjects of African decent.

MP79-04 MEASUREMENT OF PROSTATE CANCER-ASSOCIATED ABERRANT GLYCOSYLATION OF PROSTATE SPECIFIC ANTIGEN CAN IMPROVE DIAGNOSTIC ACCURACY

6; and intermediate risk included biochemical recurrence and Gleason 7 disease. Logistic regression analysis was used to examine the association between allele counts and tumor aggressiveness. Separate analyses were performed by race (European ancestry and African American) and Gleason score. RESULTS: Case-case analyses of men of European ancestry with highor low-risk disease showed that 12 SNPs were over-represented in men with highcompared to low-risk disease in an unadjusted analysis. Only 3 SNPs were demonstrated similar associations in African American men. Multivariate models that corrected the presence of the other SNPs showed that only SNP rs2735839 on 19q13.3 remained significant in both races (p<0.0001). A separate case-case analysis comparing Gleason score 8 to low-grade disease demonstrated that 13 and 6 SNPs were associated with Gleason score in both Europeans and African Americans, respectively. Again, multivariate analysis revealed only SNP rs2735839 remained significantly associated with Gleason grade. CONCLUSIONS: Many validated PC risk SNPs, including rs2735839, demonstrate an association with disease aggressiveness in both men of European and African American ancestry. However, future genome wide association studies involving men with highand low-risk disease are required to identify novel SNPs that can also be used to identify men most at risk of life-threatening disease.

Abstract 2865: The significance of Vitamin D deficiency and low grade pathogens in etiology of prostate cancer.

Abstract Introduction. Estimations of sun exposure (but less so spot serum Vitamin D levels) correlate with risk of prostate cancer occurrence. This suggests that it is due to long term Vitamin D deficiency over 10-40 years as a possible explanation. This, via diminished macrophage function, could allow persistence of low grade pathogens to set up chronic inflammation that could lead to Proliferative Inflammatory Atrophy (PIA) of the prostate, now thought to be an important precursor of cancer. Despite multiple investigations of sexually transmitted infections, there has been no consistently associated organism. However recently infection with two low grade pathogenic organisms, teenage acne associated anaerobic bacterium Propionibacterium.acnes (PA) and protozoan Trichomonas vaginalis (TA), have shown a more consistent association with prostate cancer. This abstract reports the results of a systematic review of publications investigating the association of sun exposure and prostate cancer and of PA and T V with prostate cancer and considers how these observations could lead to improved specificity of PSA screening Methods. Pubmed searches using terms prostate or prostatic, sunshine or UVB or Vitamin D and acne or PA or TA were performed and the abstracts reviewed and appropriate papers selected for review and data extraction Results . Amongst 1134 abstracts investigating PC and Vitamin D were two systematic reviews that failed to produce a consistent association. In contrast four of four studies of an index of sun exposure involving 1568 patients (OR 0.75, 0.75, 0.59 &amp; 0.89) and 6 of 7 geographic studies (0.32, 0.38, 0.44, 0.16, 0.52, 1.63 &amp; 0.64) demonstrated an association of high UVB exposure with reduced PC risk. Four of five publications on PA and PC (1.7, 1.67, 2.17 &amp; 0.67) and 2 of 3 publications on TV and PC (1.23, 1.43 &amp; 0.83) from 205 papers reviewed showed consistent increase risk of PC associated with infection. Conclusion. Lack of association with spot Vitamin D but clear association with index of sun exposure suggest that the association is due to reduced long term Vitamin D mediated non-specific macrophage surveillance that is involved against lowly pathogenic agents of which PA and TV could be lead organisms. Impact on PSA of elimination of these organisms could become an important strategy in future efforts of to improve the specificity of PSA screening and chemoprevention of PC Citation Format: Tim R T D Oliver. The significance of Vitamin D deficiency and low grade pathogens in etiology of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2865. doi:10.1158/1538-7445.AM2013-2865

Detection of Polymorphisms of DNA Repair Genes (XRCC1 and XPC) in Prostate Cancer

Prostate cancer is a common disease with a multifactorial and complex etiology. It is the most common male malignancy and the second leading cause of death in many countries. The widespread use of PSA testing has increased the detection of this cancer at earlier stages, although this diagnostic method has proved to be insufficient to identify the disease. DNA in most cells is regularly damaged by endogenous and exogenous mutagens. At least four main partially overlapping damage repair pathways operate in mammals. Common polymorphisms in DNA repair genes may alter protein function and an individual’s capacity to repair damaged DNA; deficits in repair capacity may lead to genetic instability and carcinogenesis. In the present study, we investigated the genotypic distribution of XRCC1 and XPC polymorphisms and its association with prostate cancer risk, pathological staging and Gleason’s scoring. The present study was conducted in the departments of Clinical Pathology, Pathology, and Urology Faculty of Medicine, Alexandria University-Egypt. A total number of 50 patients with pathologically confirmed prostate cancer and 50 age-matched control subjects were enrolled in this study. The diagnosis was made on the basis of histopathological findings, following radical prostatectomy or transurethral resection of the prostate (TURP). Genomic DNA was extracted from peripheral blood using QIAamp blood DNA isolation kits. PCR followed by enzymatic digestion of the PCR products for (XRCC1, XPC) was used for the genotyping of these polymorphisms. Statistical analyses were performed using SPSS statistics version 20. The genotype frequencies of the studied polymorphisms in all the samples (n = 100), PC patients (n = 50) and healthy controls (n = 50) were consistent with the Hardy-Weinberg equilibrium distribution (p-value > 0.05). There was no statistical difference in the genotypes of the XRCC1 Arg399Gln and XPC Lys939Gln between cases and controls. The “Gln” allele frequency of XPC Lys939Gln as well as the “Gln” allele frequency of XRCC1 Arg399Gln tended to be lower in controls than in PC patients. Yet, these decreases were not statistically significant. We also examined the combined effect of XPC and XRCC1 and we found a decreased PC risk when XPC 939 Lys/Lys + Lys/Gln and XRCC1 399 Arg/Arg + Arg/Gln are combined (OR = 0.370, 95% CI = 0.142 - 0.962).

Meta-analysis of impact of circumcision and vitamin D on occurrence of prostate cancer: Could they act by suppressing anaerobes colonizing areas of prostatic proliferative inflammatory atrophy?

259 Background: There is evidence that some false positive PSA tests can reflect prostatic inflammation that leads to Proliferative Inflammatory atrophy (PIA) that promotes malignant change. Report from circumcision trials in Africa suggest that dominant bacterial flora in un-circumcised men was anaerobes. As circumcised men have a lower incidence of PC this presentation reviews the literature on lack of circumcision and that on Vitamin D deficiency and as a cause of diminished host surveillance that could have potential to synergise as causes of PC. Methods: Three papers reporting incidence of PC in Jewish and non-Jewish men undergoing prostate biopsy for prostate symptoms and 7 series reporting case controlled studies published between 1952 and 2001 have provided data on circumcision and PC risk. There were 10 papers referred to in the IARC 2008 report on plasma 25-hydroxyvitamin D and PC. These have been reviewed together with 8 more published from 2008-10 and 3 that have examined impact of an index of life-time sun exposure on PC risk. Results: The 2 of 3 series of prostate biopsy reported 1951-65 demonstrated significant excess and 1 a non-significant excess of PC in the non-Jewish population. Of the 7 case controlled reported from 1971-2001, only 1 reported significant (OR 1.38) and 1 non-significant (OR 1.15) excess of lack of circumcision in those with prostate cancer, the remaining 6 studies having an excess cancer in those who have been circumcised (OR 0.50 – 0.82 pooled risk 0.70). Only 1 of the 18 plasma 25-OH Vit D series showed significant reduction of PC overall (6 did have reduction in prognostic subsets though 2 had higher incidence in the same sub-groups. In contrast all 3 series that have examined an index of life-time sun exposure showed significant reduction of PC (OR 0.18, 0.32 and 0.52 n= 850). Conclusions: The inconsistencies in the circumcision data suggest that it is not the surgery alone but the confounding variable of the hygiene rules that at least contribute to the reduced PC in Jewish men, and mirrors the similar differences seen in the protective value against AIDS of circumcision in Xhosa African and Asian Muslim men.

6616 POSTER Impact of Progression on Resource Utilization in the Treatment of NET

restriction fragment size was identified by horizontal electrophoresis. The survival was determined using Kaplan–Meier method, and the log-rank test was used for evaluation of differences in survival. The association between genetic factors and cancer risk were analyzed by logistic regression, and the results were expressed as odds ratios (OR) and 95% confidence intervals (CI). Statistical analyses were performed using CRAN 2.4.0 statistical software, and the decision on significance was based on p < 0.05. Results: Comparison of allele distribution between PC patients and controls demonstrated that Val/Val genotype carriers in codon 432 CYP1B1 had lower PC risk of pancreatic cancer development compared wild type carriers (OR 0.59; 95%CI 0.36–0.96; p = 0.035). Heterozygotes also had lower risk (OR 0.69; 95%CI 0.49–0.97; p = 0.033). There was an even more signficant increase of risk in patients who had histologically verified PC. Variant allele in GSTP1 codone 105 was associated with a trend of higher PC risk (OR 1.38; 95%CI 0.96–1.97, p < 0.05). Increased PC risk was also observed for GSTT1deletion (OR 1.56; 95%CI 0.93–2.61, p < 0.05). The combination of GSTT1 mutation and GSTP1 deletion was associted with significantly increased PC risk (OR 2.5; 95%CI 1.20–5.20; p < 0.05). No significant association was observed between the polymorphism of other biotransforming genes and PC risk, and none of the gene polymorphisms investigated was associated with differences in PC survival. Conclusions: Gene polymorphism of biotransforming genes may be associated with the risk of PC.

Genetic variability of the forkhead box O3 and prostate cancer risk in the European Prospective Investigation on Cancer

Forkhead box O3 (FOXO3) has a wide range of functions: it promotes tumor suppression, cell cycle arrest, repair of damaged DNA, detoxification of reactive oxygen species, apoptosis and plays a pivotal role in promoting longevity. FOXO3 is a key downstream target of the PI3K-Akt pathway in response to cellular stimulation by growth factors or insulin and has been proposed as a bridge between ageing and tumor suppression. Three SNPs in the FOXO3 gene (rs3800231, rs9400239 and rs479744) that have been shown to be strongly and consistently associated with longevity, were examined in relation to PC risk in a case control study of 1571 incident PC cases and 1840 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). There was no statistically significant association between the SNPs and PC risk regardless of the model of inheritance (dominant, codominant and recessive). The associations were not modified by disease aggressiveness, circulating levels of steroid sex hormones, or IGFs or BMI. We conclude that polymorphisms in the FOXO3 gene that are associated with longevity are not major risk factors for PC risk, in this population of Caucasian men.

Catastrophe reinsurance and risk capital in the wake of the credit crisis

Purpose – Property and casualty (“PC and external risk capital provided by third parties. The paper also explores the distinctions between four types of external catastrophe risk capital: reinsurance, industry loss warranties, catastrophe derivatives, and insurance‐linked securities. Finally, how the credit crisis has impacted alternative sources of catastrophe risk capital in different ways is considered.Design/methodology/approach – The discussion is based on the conceptual framework for analyzing risk capital developed by Merton and Perold.Findings – In 2008, the P&C insurance industry was...

Abstract B24: Attitudes of pancreatic cancer family members toward cancer risk and screening

Abstract B24 Purpose Pancreatic cancer (PC) is the fourth leading cause of cancer death in the United States for which no recommended screening guidelines are available. An estimated 34,290 deaths related to PC is expected to occur in 2008 and the 5-year relative survival rate for this cancer is 5% for all stages combined. A person's chance of developing this cancer increases three-fold if a first-degree relative has pancreatic cancer. The purpose of this study was to assess attitudes of unaffected family members in the Mayo Clinic Pancreas Cancer Family study toward PC cancer risk and future screening options. This is the first study to report such attitudes of PC family members. Subjects and Methods At-risk family members with two or more relatives affected with pancreas cancer in the kindred and primary care controls completed a survey asking about: perceived PC risk, degree of PC worry/concern, attitude toward cancer screening in general, and intentions regarding PC screening if it were a blood test or endoscopic ultrasound. Results 386 family members in 109 PC kindreds and 1058 controls completed surveys. Forty-six percent of PC family members reported that it was likely they would develop PC during their lifetime compared to 6% of controls. Forty-one percent of family members reported having thoughts regarding the possibility of getting pancreatic cancer during the past month versus 4.6% of controls. Similarly, 74% of family members reported concern about getting PC as compared to 40.6% of controls. 94% of family members reported they would be likely to undergo a blood-based PC screening test compared to 89.7% of controls. For endoscopic ultrasound, 71% of family members would be likely to undergo screening as compared to 55% of controls. All comparisons were statistically significant. Conclusion Compared to controls, PC family members perceive their personal PC risk to be high and report a higher rate of PC-related cancer worry/concern. A high percentage of family members and controls indicate receptivity to PC screening, especially if it were a blood test. If the screening is more invasive (i.e. EUS), interest declines, particularly among controls. This information can help investigators to understand and address potential motivators and barriers to recruitment for future PC studies and indicates that there is a need to develop educational interventions among these families to reduce their actual and perceived pancreatic cancer risk. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B24.

PSA kinetics and surrogacy: ready for prime time?

The gold standard in cancer clinical trials has always been overall survival. Although this remains a lofty aim, the long natural history of prostate cancer, even for patients with recurrent disease, 1 Freedland SJ Humphreys EB Mangold LA Eisenberger M Dorey FJ Walsh PC Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA. 2005; 294: 433-439 Crossref PubMed Scopus (1073) Google Scholar begs for an intermediate endpoint. This intermediate endpoint should not only correlate with overall survival, but help screen for new treatments that are likely to affect overall survival. In other words, this intermediate endpoint should be a surrogate endpoint. Time to biochemical failure and prostate-specific antigen doubling time as surrogates for prostate cancer-specific mortality: evidence from the TROG 96.01 randomised controlled trialThis study provides proof of principle that TTBF and PSADT can be useful as surrogate endpoints for prostate cancer-specific mortality and offer potential to substantially reduce follow up in clinical trials. These endpoints now require assessment in multi-trial meta-analyses before use in clinical trials. Full-Text PDF

Association between estrogen and androgen receptor genes and prostate cancer risk

Prostate cancer (PC) is one of the principal causes of death among men. Steroid hormones are involved in normal prostate growth and carcinogenesis. The purpose of our study was to investigate the effects on PC risk of polymorphisms from three steroid hormone receptor genes: the androgen (AR), and the alpha (ESR1) and beta (ESR2) estrogen receptors. The study was performed on a Caucasian population of 1045 PC patients and 814 controls. Using a logistic regression model, the different alleles and genotypes from those polymorphisms were analyzed according to case/control status, the tumor aggressiveness, and the age at onset. A significant association between PC risk and the pooled 4/5, 5/6, and 6/6 genotypes of the GGGA repeat located in the first intron of ESR1 (odds ratio (OR)=3.00, 95% CI=1.32-6.82, P=0.008) was observed. When we stratified the cases, this association was confined to patients with a Gleason score of 2-4 (OR=8.34, 95% CI=2.91-23.91, P<0.0001) or late onset PC (OR=2.91, 95% CI=1.22-6.93, P=0.016). An association between a short AR CAG repeat (less than 17 repeats) was also observed among patients with late onset PC (OR=2.34, 95% CI=1.15-4.76, P=0.019). These findings suggest that the GGGA repeat from ESR1 and the CAG repeat from AR may be associated with risk of late onset PC.