identification of peri prostatic neurovascular fibers before and after radical prostatectomy by means of diffusion tensor imaging dti with clinical correlations initial experience

Aim: To evaluate if Diffusion Tensor Imaging (DTI) is able to detect morphological changes of peri-prostatic neurovascular fibers (PNF) before and after robot-assisted radical prostatectomy (RARP) and if these changes are related to urinary incontinence (UI) and erectile dysfunction (ED). Materials and methods: From October 2014 and August 2017 26 patients with biopsy-proven prostate cancer underwent prostatic multi-parametric magnetic resonance imaging (mp-MRI) including DTI sequencing before and six months after, RARP. Images were analyzed by placing six regions of interest (ROI) respectively at the base, mid-gland and apex, one for each side, to obtain tractography reconstruction of the PNF. Patients were asked to complete an International Consultation Incontinence Questionnaire – Short Form (ICIQ-SF) and International Index of Erectile Function (IIEF-5) questionnaires before RARP and 6 months postoperatively. Fractional anisotropy (FA), number (N) and length (L) of PNF before and after RARP were compared by means of Student's t-test; Spearman test was used to evaluate the correlation between DTI parameters and questionnaires scores. We observed a significant difference in N values before and after RARP (p<0.001) and a negative correlation between IIEF-5 score and post-operative FA values at both the right (rho=-0.42; p= 0.0456) and left (rho=- 0.66; p=0.0006) base of the prostate. DTI with tractography of PNF is able to detect quantitative changes in N, L and FA values in PNF after RARP. In particular we observed an inverse correlation between FA of PNF and ED at 6 months after RARP. Further investigations are needed to confirm this trend

Complete IRAC mapping of the CFHTLS-DEEP, MUSYC AND NMBS-II FIELDS

The IRAC mapping of the NMBS-II fields program is an imaging survey at 3.6 and 4.5$\mu$m with the Spitzer Infrared Array Camera (IRAC). The observations cover three Canada-France-Hawaii Telescope Legacy Survey Deep (CFHTLS-D) fields, including one also imaged by AEGIS, and two MUSYC fields. These are then combined with archival data from all previous programs into deep mosaics. The resulting imaging covers a combined area of about 3 $deg^2$, with at least $\sim$2 hr integration time for each field. In this work, we present our data reduction techniques and document the resulting coverage maps at 3.6 and 4.5$\mu$m. All of the images are W-registered to the reference image, which is either the z-band stack image of the 25\% best seeing images from the CFHTLS-D for CFHTLS-D1, CFHTLS-D3, and CFHTLS-D4, or the K-band images obtained at the Blanco 4-m telescope at CTIO for MUSYC1030 and MUSYC1255. We make all images and coverage maps described herein publicly available via the Spitzer Science Center.Comment: Accepted in PASP; released IRAC mosaics available upon publication of the pape

Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease

Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort.

BACKGROUND: Epidemiological studies have observed a positive association between an earlier age at sexual development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in adolescent boys in a Mendelian randomization (MR) approach. METHODS: We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (n = 2,927), and used the PRACTICAL consortium (n = 43,737) as a replication sample. RESULTS: In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR) of high- vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64-0.89). In an instrumental variable estimation of the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between pubertal boys of the same age) was associated with a 77 % (95 % CI, 43-91 %) reduced odds of high Gleason prostate cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs. localized cancer, per tertile: 0.95; 95 % CI, 0.91-1.00) and prostate cancer-specific mortality (hazard ratio amongst cases, per tertile: 0.94; 95 % CI, 0.90-0.98), but not with disease grade. CONCLUSIONS: Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease.This work was supported by the World Cancer Research Fund (2011/419) and Cancer Research UK (C18281/A19169). The Integrative Epidemiology Unit (IEU) is supported by the MRC and the University of Bristol (G0600705, MC_UU_12013/19), and the Integrative Cancer Epidemiology Programme is supported by Cancer Research UK programme grant C18281/A19169. The National Institute for Health Research (NIHR) Bristol Nutrition Biomedical Research Unit is funded by the NIHR and is a partnership between University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The ProtecT study is supported by the UK NIHR Health Technology Assessment (HTA) Programme (HTA 96/20/99; ISRCTN20141297). Funding for PRACTICAL and the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/ A16565), the National Institutes of Health (CA128978), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 – the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. We acknowledge support from the NIHR to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s12916-016-0602-

Blood lipids and prostate cancer: a Mendelian randomization analysis.

Genetic risk scores were used as unconfounded instruments for specific lipid traits (Mendelian randomization) to assess whether circulating lipids causally influence prostate cancer risk. Data from 22,249 prostate cancer cases and 22,133 controls from 22 studies within the international PRACTICAL consortium were analyzed. Allele scores based on single nucleotide polymorphisms (SNPs) previously reported to be uniquely associated with each of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels, were first validated in an independent dataset, and then entered into logistic regression models to estimate the presence (and direction) of any causal effect of each lipid trait on prostate cancer risk. There was weak evidence for an association between the LDL genetic score and cancer grade: the odds ratio (OR) per genetically instrumented standard deviation (SD) in LDL, comparing high- (≥7 Gleason score) versus low-grade (<7 Gleason score) cancers was 1.50 (95% CI: 0.92, 2.46; P = 0.11). A genetically instrumented SD increase in TGs was weakly associated with stage: the OR for advanced versus localized cancer per unit increase in genetic risk score was 1.68 (95% CI: 0.95, 3.00; P = 0.08). The rs12916-T variant in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was inversely associated with prostate cancer (OR: 0.97; 95% CI: 0.94, 1.00; P = 0.03). In conclusion, circulating lipids, instrumented by our genetic risk scores, did not appear to alter prostate cancer risk. We found weak evidence that higher LDL and TG levels increase aggressive prostate cancer risk, and that a variant in HMGCR (that mimics the LDL lowering effect of statin drugs) reduces risk. However, inferences are limited by sample size and evidence of pleiotropy.C. J. B. is funded by the Wellcome Trust 4-year studentship WT083431MA. The Integrative Cancer Epidemiology Programme is supported by Cancer Research UK programme grant C18281/A19169. The MRC IEU is supported by the Medical Research Council and the University of Bristol (MC_UU_12013/1-9). The NIHR Bristol Nutrition Biomedical Research Unit is funded by the National Institute for Health Research (NIHR) and is a partnership between University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The CRUK study and PRACTICAL consortium is supported by the Canadian Institutes of Health Research, European Commission’s Seventh Framework Programme grant agreement no. 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, and C16913/ A6135. The National Institutes of Health (NIH) Cancer Post-Cancer GWAS initiative grant no. 1 U19 CA 148537-01 (the GAME-ON initiative) and NIHR support to the Biomedical Research Centre and The Institute of Cancer Research and Royal Marsden NHS Foundation Trust.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/cam4.69

Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array.

BACKGROUND: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B. METHODS: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. RESULTS: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant. CONCLUSIONS: MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/bjc.2016.5

The effects of height and BMI on prostate cancer incidence and mortality:a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium

Background\ud \ud Epidemiological studies suggest a potential role for obesity and determinants of adult stature in prostate cancer risk and mortality, but the relationships described in the literature are complex. To address uncertainty over the causal nature of previous observational findings, we investigated associations of height- and adiposity-related genetic variants with prostate cancer risk and mortality.\ud \ud Methods\ud \ud We conducted a case–control study based on 20,848 prostate cancers and 20,214 controls of European ancestry from 22 studies in the PRACTICAL consortium. We constructed genetic risk scores that summed each man’s number of height and BMI increasing alleles across multiple single nucleotide polymorphisms robustly associated with each phenotype from published genome-wide association studies.\ud \ud Results\ud \ud The genetic risk scores explained 6.31 and 1.46 % of the variability in height and BMI, respectively. There was only weak evidence that genetic variants previously associated with increased BMI were associated with a lower prostate cancer risk (odds ratio per standard deviation increase in BMI genetic score 0.98; 95 % CI 0.96, 1.00; p = 0.07). Genetic variants associated with increased height were not associated with prostate cancer incidence (OR 0.99; 95 % CI 0.97, 1.01; p = 0.23), but were associated with an increase (OR 1.13; 95 % CI 1.08, 1.20) in prostate cancer mortality among low-grade disease (p heterogeneity, low vs. high grade <0.001). Genetic variants associated with increased BMI were associated with an increase (OR 1.08; 95 % CI 1.03, 1.14) in all-cause mortality among men with low-grade disease (p heterogeneity = 0.03).\ud \ud Conclusions\ud \ud We found little evidence of a substantial effect of genetically elevated height or BMI on prostate cancer risk, suggesting that previously reported observational associations may reflect common environmental determinants of height or BMI and prostate cancer risk. Genetically elevated height and BMI were associated with increased mortality (prostate cancer-specific and all-cause, respectively) in men with low-grade disease, a potentially informative but novel finding that requires replication

Polyunsaturated fatty acids and prostate cancer risk: a Mendelian randomisation analysis from the PRACTICAL consortium.

BACKGROUND: Prostate cancer is a common cancer worldwide with no established modifiable lifestyle factors to guide prevention. The associations between polyunsaturated fatty acids (PUFAs) and prostate cancer risk have been inconsistent. Using Mendelian randomisation, we evaluated associations between PUFAs and prostate cancer risk. METHODS: We used individual-level data from a consortium of 22 721 cases and 23 034 controls of European ancestry. Externally-weighted PUFA-specific polygenic risk scores (wPRSs), with explanatory variation ranging from 0.65 to 33.07%, were constructed and used to evaluate associations with prostate cancer risk per one standard deviation (s.d.) increase in genetically-predicted plasma PUFA levels using multivariable-adjusted unconditional logistic regression. RESULTS: No overall association was observed between the genetically-predicted PUFAs evaluated in this study and prostate cancer risk. However, risk reductions were observed for short-chain PUFAs, linoleic (ORLA=0.95, 95%CI=0.92, 0.98) and α-linolenic acids (ORALA=0.96, 95%CI=0.93, 0.98), among men <62 years; whereas increased risk was found among men ⩾62 years for LA (ORLA=1.04, 95%CI=1.01, 1.07). For long-chain PUFAs (i.e., arachidonic, eicosapentaenoic, and docosapentaenoic acids), increased risks were observed among men <62 years (ORAA=1.05, 95%CI=1.02, 1.08; OREPA=1.04, 95%CI=1.01, 1.06; ORDPA=1.05, 95%CI=1.02, 1.08). CONCLUSION: Results from this study suggest that circulating ω-3 and ω-6 PUFAs may have a different role in the aetiology of early- and late-onset prostate cancer