Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Health Information Management Reimagined: Assessing Current Professional Skills and Industry Demand

Martin Luther King, Jr., once said, "Change does not roll in on the wheels of inevitability, but comes through continuous struggle." This paper discusses the changes that are affecting the Health Information Management professional’s skill set and where these changes are leading these individuals. As the industry continues to experience changes, so will the responsibilities of the HIM professional. The problem with these changes is determining whether the HIM professional has the necessary skill set to adapt to the changing environment.Health Administratio

Identification of naturally-occurring fluoride and selected metals in northwest Wisconsin groundwater

Northwest Wisconsin, encompassing the 11 counties of Ashland, Barron, Bayfield, Burnett, Douglas, Iron, Polk, Price, Rusk, Sawyer, and Washburn, has a large proportion of the population who obtain their drinking water from groundwater. There are over 56,000 public and private wells within this region of the state, however, the region is under-studied in terms of groundwater quality relative to other areas in Wisconsin. Fluoride and the metals iron, manganese, aluminum, arsenic, and lead, if present at high enough concentrations in groundwater, could impact public health. Little is known regarding baseline concentrations of these potential contaminants in northwestern Wisconsin aquifers. The objectives of this study, known as the Northwest Wisconsin Groundwater Monitoring Project, were to monitor naturally-occurring fluoride concentrations in groundwater samples collected from 11 counties in northwestern Wisconsin, determine concentrations of iron, manganese, aluminum, arsenic, and lead in a subset of these samples, foster public awareness among residents of the region about the need for regular private well testing, and increase the publicly-available groundwater data within the region. This monitoring study used a random sample design, and targeted 704 fluoride samples and 115 metals samples total. All of the samples were collected by volunteers who were recruited to participate in the project through a combination of social media postings, press releases, and outreach events. Sample kits containing sample bottles, instructions for collection, sample collection form, and a pre-paid shipping label were assembled and delivered to each of 26 distribution sites located throughout the 11-county study area. The data from 450 of 704 fluoride and 80 of 115 metals samples were reported. Samples were collected from all 11 counties in the study area, and were largely collected from drilled wells constructed 26 – 50 years ago, with a depth of 51 – 100 feet. None of the samples collected and analyzed for fluoride exceeded the Wisconsin Groundwater Quality Enforcement Standard (ES) of 4.0 mg/L and less than 1% exceeded the Preventative Action Limit (PAL) of 0.8 mg/L (Wis. Adm. Code Ch. NR 140). Iron concentrations were high in a number of samples, with 20% of samples collected exceeding the 0.3 mg/L ES. In 5% of samples collected, the ES for manganese, 300 µg/L, was exceeded. Overall, aluminum concentrations were low throughout the study area, but one sample exceeded the ES of 200 µg/L. The maximum arsenic concentration measured in this study was 10.0 µg/L, which is the state ES. However, 38.8% of samples had an arsenic concentration at or above the PAL (1 µg/L). There was a single sample that exceeded the ES for lead (15 µg/L) and 11.3% of samples had a lead concentration at or above the 1.5 µg/L PAL. To the authors’ knowledge, this study represents the first baseline groundwater monitoring effort encompassing the northwest Wisconsin region. With the exception of fluoride and arsenic, the ES was exceeded for all parameters measured in this study in at least one sample collected within the study area. This study utilized a random sample design, and the next logical step is to conduct targeted sampling of areas with contaminant-level metals concentrations in groundwater samples.Funding for this work was provided by the Wisconsin Department of Natural Resources via the Wisconsin Groundwater Coordinating Council

Total Mercury Concentrations in Sea Lamprey Transformers Collected from Rivers in Wisconsin and Michigan during Fall 2013

Prepared for the Great Lakes Indian Fish and Wildlife Commission

Metals Concentrations in Muscle Tissue from Walleye, Smallmouth Bass, and a Sturgeon Collected from Lakes and Rivers within the 1854 Ceded Territory during Fall 2016

Whole fish samples of walleye (Sander vitreus) and smallmouth bass (Micropterus dolomieu), captured during the fall of 2016 from lakes within the 1854 Ceded Territory were analyzed for total mercury (Hg) content at the University of Wisconsin-Superior’s Lake Superior Research Institute (LSRI). Forty three whole walleye and twenty two whole smallmouth bass samples from a total of three lakes were processed and the muscle tissue was analyzed for mercury. A sturgeon (Acipenseridae) that was found near death in the St. Louis River was also collected and the muscle tissue analyzed for total mercury (Hg) content along with nine other metals including: arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), iron (Fe), lead (Pb), manganese (Mn), selenium (Se), and zinc (Zn).Prepared for the 1854 Treaty Authority, 4428 Haines Road, Duluth, MN 55811

Total Mercury Concentrations in Muscle Tissue from Walleye, Northern Pike, and Muskellunge Collected from Inland Lakes during Spring 2014

Prepared for the Great Lakes Indian Fish and Wildlife Commission

Total Mercury Concentrations in Eggs of Female Sea Lamprey Collected from Rivers in Wisconsin and Michigan during Summer 2014

Prepared for the Great Lakes Indian Fish and Wildlife Commission

Total Mercury Concentrations in Muscle Tissue from Fish Captured during the Spring – Fall 2013 in Michigan Waters of Lake Superior

Prepared for the Great Lakes Indian Fish and Wildlife Commission