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1.  Circulating Folate and Vitamin B12 and Risk of Prostate Cancer: A Collaborative Analysis of Individual Participant Data from Six Cohorts Including 6875 Cases and 8104 Controls 
European Urology  2016;70(6):941-951.
Background
Folate and vitamin B12 are essential for maintaining DNA integrity and may influence prostate cancer (PCa) risk, but the association with clinically relevant, advanced stage, and high-grade disease is unclear.
Objective
To investigate the associations between circulating folate and vitamin B12 concentrations and risk of PCa overall and by disease stage and grade.
Design, setting, and participants
A study was performed with a nested case–control design based on individual participant data from six cohort studies including 6875 cases and 8104 controls; blood collection from 1981 to 2008, and an average follow-up of 8.9 yr (standard deviation 7.3). Odds ratios (ORs) of incident PCa by study-specific fifths of circulating folate and vitamin B12 were calculated using multivariable adjusted conditional logistic regression.
Outcome measurements and statistical analysis
Incident PCa and subtype by stage and grade.
Results and limitations
Higher folate and vitamin B12 concentrations were associated with a small increase in risk of PCa (ORs for the top vs bottom fifths were 1.13 [95% confidence interval (CI), 1.02–1.26], ptrend = 0.018, for folate and 1.12 [95% CI, 1.01–1.25], ptrend = 0.017, for vitamin B12), with no evidence of heterogeneity between studies. The association with folate varied by tumour grade (pheterogeneity < 0.001); higher folate concentration was associated with an elevated risk of high-grade disease (OR for the top vs bottom fifth: 2.30 [95% CI, 1.28–4.12]; ptrend = 0.001), with no association for low-grade disease. There was no evidence of heterogeneity in the association of folate with risk by stage or of vitamin B12 with risk by stage or grade of disease (pheterogeneity > 0.05). Use of single blood-sample measurements of folate and B12 concentrations is a limitation.
Conclusions
The association between higher folate concentration and risk of high-grade disease, not evident for low-grade disease, suggests a possible role for folate in the progression of clinically relevant PCa and warrants further investigation.
Patient summary
Folate, a vitamin obtained from foods and supplements, is important for maintaining cell health. In this study, however, men with higher blood folate levels were at greater risk of high-grade (more aggressive) prostate cancer compared with men with lower folate levels. Further research is needed to investigate the possible role of folate in the progression of this disease.
Take Home Message
Higher folate concentration was associated with an increased risk of high-grade disease that was not evident for low-grade disease. This finding suggests a possible role for folate in the progression of clinically relevant prostate cancer and warrants further investigation.
doi:10.1016/j.eururo.2016.03.029
PMCID: PMC5094800  PMID: 27061263
Folate; Vitamin B12; Prostate cancer; High grade; Prospective cohort; Pooled data meta-analysis
2.  Patient‐reported outcomes in the ProtecT randomized trial of clinically localized prostate cancer treatments: study design, and baseline urinary, bowel and sexual function and quality of life 
Lane, Athene | Metcalfe, Chris | Young, Grace J. | Peters, Tim J. | Blazeby, Jane | Avery, Kerry N. L. | Dedman, Daniel | Down, Liz | Mason, Malcolm D. | Neal, David E. | Hamdy, Freddie C. | Donovan, Jenny L. | Bonnington, Sue | Bradshaw, Lynne | Cooper, Debbie | Elliott, Emma | Herbert, Pippa | Holding, Peter | Howson, Joanne | Jones, Mandy | Lennon, Teresa | Lyons, Norma | Moody, Hilary | Plumb, Claire | O'Sullivan, Tricia | Salter, Liz | Tidball, Sarah | Thompson, Pauline | Adam, Tonia | Askew, Sarah | Atkinson, Sharon | Baynes, Tim | Blaikie, Jan | Brain, Carole | Breen, Viv | Brunt, Sarah | Bryne, Sean | Bythem, Jo | Clarke, Jenny | Cloete, Jenny | Dark, Susan | Davis, Gill | De La Rue, Rachael | Denizot, Jane | Dewhurst, Elspeth | Dimes, Anna | Dixon, Nicola | Ebbs, Penny | Emmerson, Ingrid | Ferguson, Jill | Gadd, Ali | Geoghegan, Lisa | Grant, Alison | Grant, Collette | Gray, Catherine | Godfrey, Rosemary | Goodwin, Louise | Hall, Susie | Hart, Liz | Harvey, Andrew | Hoult, Chloe | Hawkins, Sarah | Holling, Sharon | Innes, Alastair | Kilner, Sue | Marshall, Fiona | Mellen, Louise | Moore, Andrea | Napier, Sally | Needham, Julie | Pearse, Kevin | Pisa, Anna | Rees, Mark | Richards, Elliw | Robson, Lindsay | Roxburgh, Janet | Samuel, Nikki | Sharkey, Irene | Slater, Michael | Smith, Donna | Taggart, Pippa | Taylor, Helen | Taylor, Vicky | Thomas, Ayesha | Tomkies, Briony | Trewick, Nicola | Ward, Claire | Walker, Christy | Williams, Ayesha | Woodhouse, Colin | Wyber, Elizabeth | Aning, Jonathan | Bollina, Prasad | Catto, Jim | Doble, Andrew | Doherty, Alan | Durkan, Garett | Gillatt, David | Hughes, Owen | Kocklebergh, Roger | Kouparis, Anthony | Kynaston, Howard | Leung, Hing | Mariappan, Param | McNeill, Alan | Paez, Edgar | Paul, Alan | Persad, Raj | Powell, Philip | Prescott, Stephen | Rosario, Derek | Rowe, Edward | Schwaibold, Hartwig | Tulloch, David | Wallace, Mike | Bahl, Amit | Benson, Richard | Beresford, Mark | Ferguson, Catherine | Graham, John | Herbert, Chris | Howard, Grahame | James, Nick | Law, Alastair | Loughrey, Carmel | McClaren, Duncan | Patterson, Helen | Pedley, Ian | Robinson, Angus | Russell, Simon | Staffurth, John | Symonds, Paul | Thanvi, Narottam | Vasanthan, Subramaniam | Wilson, Paula | Appleby, Helen | Ash, Dominic | Aston, Dean | Bolton, Steven | Chalmers, Graham | Conway, John | Early, Nick | Geater, Tony | Goddall, Lynda | Heymann, Claire | Hicks, Deborah | Jones, Liza | Lamb, Susan | Lambert, Geoff | Lawrence, Gill | Lewis, Geraint | Lilley, John | MacLeod, Aileen | Massey, Pauline | McQueen, Alison | Moore, Rollo | Penketh, Lynda | Potterton, Janet | Roberts, Neil | Showler, Helen | Slade, Stephen | Steele, Alasdair | Swinscoe, James | Tiffany, Marie | Townley, John | Treeby, Jo | Wilkinson, Joyce | Williams, Lorraine | Wills, Lucy | Woodley, Owain | Yarrow, Sue | Bhattarai, Selina | Deshmukh, Neeta | Dormer, John | Fernando, Malee | Goepel, John | Griffiths, David | Grigor, Ken | Mayer, Nick | Oxley, Jon | Robinson, Mary | Varma, Murali | Warren, Anne | Brindle, Lucy | Davis, Michael | Khazragui, Hanan | Noble, Sian | Taylor, Hilary | Tazewell, Marta | Turner, Emma | Wade, Julia | Walsh, Eleanor | Baker, Susan | Bellis‐Sheldon, Elizabeth | Bougard, Chantal | Bowtell, Joanne | Brewer, Catherine | Burton, Chris | Charlton, Jennie | Christoforou, Nicholas | Clark, Rebecca | Coull, Susan | Croker, Christine | Currer, Rosemary | Daisey, Claire | Delaney, Gill | Donohue, Rose | Drew, Jane | Farmer, Rebecca | Fry, Susan | Haddow, Jean | Hale, Alex | Halpin, Susan | Harris, Belle | Hattrick, Barbara | Holmes, Sharon | Hunt, Helen | Jackson, Vicky | Johnson, Donna | Le Butt, Mandy | Leworthy, Jo | Liddiatt, Tanya | Martin, Alex | Mauree, Jainee | Moore, Susan | Moulam, Gill | Mutch, Jackie | Nash, Alena | Parker, Kathleen | Pawsey, Christopher | Purdie, Michelle | Robson, Teresa | Smith, Lynne | Snoeck, Jo | Stenton, Carole | Steuart‐Feilding, Tom | Sully, Chris | Sutton, Caroline | Torrington, Carol | Wilkins, Zoe | Williams, Sharon | Wilson, Andrea | Grant, Adrian | Roberts, Ian | Ashby, Deborah | Cowan, Richard | Fayers, Peter | Mellon, Killian | N'Dow, James | O'Brien, Tim | Sokhal, Michael | Baum, Michael | Adolfson, Jan | Albertsen, Peter | Dearnaley, David | Schroeder, Fritz | Roberts, Tracy | Zietman, Anthony
Bju International  2016;118(6):869-879.
Objectives
To present the baseline patient‐reported outcome measures (PROMs) in the Prostate Testing for Cancer and Treatment (ProtecT) randomized trial comparing active monitoring, radical prostatectomy and external‐beam conformal radiotherapy for localized prostate cancer and to compare results with other populations.
Materials and Methods
A total of 1643 randomized men, aged 50–69 years and diagnosed with clinically localized disease identified by prostate‐specific antigen (PSA) testing, in nine UK cities in the period 1999–2009 were included. Validated PROMs for disease‐specific (urinary, bowel and sexual function) and condition‐specific impact on quality of life (Expanded Prostate Index Composite [EPIC], 2005 onwards; International Consultation on Incontinence Questionnaire‐Urinary Incontinence [ICIQ‐UI], 2001 onwards; the International Continence Society short‐form male survey [ICSmaleSF]; anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), generic mental and physical health (12‐item short‐form health survey [SF‐12]; EuroQol quality‐of‐life survey, the EQ‐5D‐3L) were assessed at prostate biopsy clinics before randomization. Descriptive statistics are presented by treatment allocation and by men's age at biopsy and PSA testing time points for selected measures.
Results
A total of 1438 participants completed biopsy questionnaires (88%) and 77–88% of these were analysed for individual PROMs. Fewer than 1% of participants were using pads daily (5/754). Storage lower urinary tract symptoms were frequent (e.g. nocturia 22%, 312/1423). Bowel symptoms were rare, except for loose stools (16%, 118/754). One third of participants reported erectile dysfunction (241/735) and for 16% (118/731) this was a moderate or large problem. Depression was infrequent (80/1399, 6%) but 20% of participants (278/1403) reported anxiety. Sexual function and bother were markedly worse in older men (65–70 years), whilst urinary bother and physical health were somewhat worse than in younger men (49–54 years, all P < 0.001). Bowel health, urinary function and depression were unaltered by age, whilst mental health and anxiety were better in older men (P < 0.001). Only minor differences existed in mental or physical health, anxiety and depression between PSA testing and biopsy assessments.
Conclusion
The ProtecT trial baseline PROMs response rates were high. Symptom frequencies and generic quality of life were similar to those observed in populations screened for prostate cancer and control subjects without cancer.
doi:10.1111/bju.13582
PMCID: PMC5113698  PMID: 27415448
prostate cancer; treatment; functional status; quality of life; protect trial; ISRCTN 20141297
3.  Investigating the prostate specific antigen, body mass index and age relationship: is an age–BMI-adjusted PSA model clinically useful? 
Cancer Causes & Control  2016;27(12):1465-1474.
Purpose
Previous studies indicate a possible inverse relationship between prostate-specific antigen (PSA) and body mass index (BMI), and a positive relationship between PSA and age. We investigated the associations between age, BMI, PSA, and screen-detected prostate cancer to determine whether an age–BMI-adjusted PSA model would be clinically useful for detecting prostate cancer.
Methods
Cross-sectional analysis nested within the UK ProtecT trial of treatments for localized cancer. Of 18,238 men aged 50–69 years, 9,457 men without screen-detected prostate cancer (controls) and 1,836 men with prostate cancer (cases) met inclusion criteria: no history of prostate cancer or diabetes; PSA < 10 ng/ml; BMI between 15 and 50 kg/m2. Multivariable linear regression models were used to investigate the relationship between log-PSA, age, and BMI in all men, controlling for prostate cancer status.
Results
In the 11,293 included men, the median PSA was 1.2 ng/ml (IQR: 0.7–2.6); mean age 61.7 years (SD 4.9); and mean BMI 26.8 kg/m2 (SD 3.7). There were a 5.1% decrease in PSA per 5 kg/m2 increase in BMI (95% CI 3.4–6.8) and a 13.6% increase in PSA per 5-year increase in age (95% CI 12.0–15.1). Interaction tests showed no evidence for different associations between age, BMI, and PSA in men above and below 3.0 ng/ml (all p for interaction >0.2). The age–BMI-adjusted PSA model performed as well as an age-adjusted model based on National Institute for Health and Care Excellence (NICE) guidelines at detecting prostate cancer.
Conclusions
Age and BMI were associated with small changes in PSA. An age–BMI-adjusted PSA model is no more clinically useful for detecting prostate cancer than current NICE guidelines. Future studies looking at the effect of different variables on PSA, independent of their effect on prostate cancer, may improve the discrimination of PSA for prostate cancer.
doi:10.1007/s10552-016-0827-1
PMCID: PMC5108825  PMID: 27830401
Prostate cancer; PSA; BMI; Age; Prostate cancer screening; PSA–BMI equation
4.  A meta-analysis of individual participant data reveals an association between circulating levels of IGF-I and prostate cancer risk 
Cancer research  2016;76(8):2288-2300.
The role of insulin-like growth factors (IGFs) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the odds ratios (ORs) for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (Ptrend all ≤ 0.005), and IGFBP-1 was weakly inversely associated with risk (Ptrend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (Pheterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, Pheterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval=1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development.
doi:10.1158/0008-5472.CAN-15-1551
PMCID: PMC4873385  PMID: 26921328
prostate cancer; insulin-like growth factor; insulin-like growth factor binding protein; pooled analysis
5.  Characteristics of men responding to an invitation to undergo testing for prostate cancer as part of a randomised trial 
Trials  2016;17:497.
Background
Sociodemographic characteristics are associated with participating in cancer screening and trials. We compared the characteristics of those responding with those not responding to a single invitation for prostate-specific antigen (PSA) testing for prostate cancer as part of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP).
Methods
Age, rurality and deprivation among 197,763 men from 271 cluster-randomised primary care centres in the UK were compared between those responding (n = 90,300) and those not responding (n = 100,953) to a prostate cancer testing invitation.
Results
There was little difference in age between responders and nonresponders. Responders were slightly more likely to come from urban rather than rural areas and were slightly less deprived than those who did not respond.
Conclusion
These data indicate similarities in age and only minor differences in deprivation and urban location between responders and nonresponders. These differences were smaller, but in the same direction as those observed in other screening trials.
Trial registration
ISRCTN92187251. Registered on 29 November 2004.
doi:10.1186/s13063-016-1624-6
PMCID: PMC5064919  PMID: 27737692
Prostate cancer; Screening; Randomised controlled trial; PSA testing; Prostate specific antigen testing
6.  The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer 
European Urology  2016;70(2):214-218.
The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy. We used mass spectrometry, immunohistochemistry, and gene expression array (validated by reverse transcription-polymerase chain reaction) to compare resected tumour with matched, controlled, untreated PCa tissue. All patients had levels of serum androgen, with reduced levels of intraprostatic androgen at prostatectomy. We observed differential expression of known androgen-regulated genes (TMPRSS2, KLK3, CAMKK2, FKBP5). We identified 749 genes downregulated and 908 genes upregulated following castration. AR regulation of α-methylacyl-CoA racemase expression and three other genes (FAM129A, RAB27A, and KIAA0101) was confirmed. Upregulation of oestrogen receptor 1 (ESR1) expression was observed in malignant epithelia and was associated with differential expression of ESR1-regulated genes and correlated with proliferation (Ki-67 expression).
Patient summary
This first-in-man study defines the rapid gene expression changes taking place in prostate cancer (PCa) following castration. Expression levels of the genes that the androgen receptor regulates are predictive of treatment outcome. Upregulation of oestrogen receptor 1 is a mechanism by which PCa cells may survive despite castration.
Take Home Message
This first-in-man study defines the rapid gene expression changes taking place in prostate cancer (PCa) following castration. Upregulation of ESR1 is a mechanism by which PCa cells may survive despite castration.
doi:10.1016/j.eururo.2015.10.042
PMCID: PMC4926724  PMID: 26572708
Prostate cancer; Androgen receptor; Castration; Clinical trial; Immunohistochemistry; Gene transcription
7.  Assessing the role of insulin‐like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels 
International Journal of Cancer  2016;139(7):1520-1533.
Circulating insulin‐like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome‐wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF‐I, IGF‐II, IGFBP‐2 and IGFBP‐3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF‐II and IGFBP‐3, less so for IGF‐I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF‐II/IGFBP‐3 level‐raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF‐II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.
What's New?
Circulating insulin‐like growth factors (IGF) and their binding proteins have been associated with prostate cancer risk in observational epidemiological studies but it is not clear whether there is a causal relationship with disease. To address this question, the authors used Mendelian randomization, a method that uses genetic variants as proxies for measured exposures. Their results implicate the IGF pathway in general in prostate cancer development but specific biomarkers remain to be determined.
doi:10.1002/ijc.30206
PMCID: PMC4957617  PMID: 27225428
insulin‐like growth factors; insulin‐like growth factor‐binding proteins; prostate cancer; Mendelian randomization; single nucleotide polymorphisms; IGFBP3; ProtecT; PRACTICAL; ALSPAC; UKHLS
8.  Response of Degarelix treatment in human prostate cancer monitored by HR-MAS 1H NMR spectroscopy 
Metabolomics  2016;12:120.
Introduction
The androgen receptor (AR) is the master regulator of prostate cancer cell metabolism. Degarelix is a novel gonadotrophin-releasing hormone blocker, used to decrease serum androgen levels in order to treat advanced human prostate cancer. Little is known of the rapid metabolic response of the human prostate cancer tissue samples to the decreased androgen levels.
Objectives
To investigate the metabolic responses in benign and cancerous tissue samples from patients after treatment with Degarelix by using HRMAS 1H NMR spectroscopy.
Methods
Using non-destructive HR-MAS 1H NMR spectroscopy we analysed the metabolic changes induced by decreased AR signalling in human prostate cancer tissue samples. Absolute concentrations of the metabolites alanine, lactate, glutamine, glutamate, citrate, choline compounds [t-choline = choline + phosphocholine (PC) + glycerophosphocholine (GPC)], creatine compounds [t-creatine = creatine (Cr) + phosphocreatine (PCr)], taurine, myo-inositol and polyamines were measured in benign prostate tissue samples (n = 10), in prostate cancer specimens from untreated patients (n = 7) and prostate cancer specimens from patients treated with Degarelix (n = 6).
Results
Lactate, alanine and t-choline concentrations were significantly elevated in high-grade prostate cancer samples when compared to benign samples in untreated patients. Decreased androgen levels resulted in significant decreases of lactate and t-choline concentrations in human prostate cancer biopsies.
Conclusions
The reduced concentrations of lactate and t-choline metabolites due to Degarelix could in principle be monitored by in vivo 1H MRS, which suggests that it would be possible to monitor the effects of physical or chemical castration in patients by that non-invasive method.
Electronic supplementary material
The online version of this article (doi:10.1007/s11306-016-1055-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s11306-016-1055-0
PMCID: PMC4927592  PMID: 27429605
Prostate; Cancer; Metabolomics; Degarelix; Metabolism; NMR; HR-MAS
9.  Contemporary accuracy of death certificates for coding prostate cancer as a cause of death: Is reliance on death certification good enough? A comparison with blinded review by an independent cause of death evaluation committee 
British Journal of Cancer  2016;115(1):90-94.
Background:
Accurate cause of death assignment is crucial for prostate cancer epidemiology and trials reporting prostate cancer-specific mortality outcomes.
Methods:
We compared death certificate information with independent cause of death evaluation by an expert committee within a prostate cancer trial (2002–2015).
Results:
Of 1236 deaths assessed, expert committee evaluation attributed 523 (42%) to prostate cancer, agreeing with death certificate cause of death in 1134 cases (92%, 95% CI: 90%, 93%). The sensitivity of death certificates in identifying prostate cancer deaths as classified by the committee was 91% (95% CI: 89%, 94%); specificity was 92% (95% CI: 90%, 94%). Sensitivity and specificity were lower where death occurred within 1 year of diagnosis, and where there was another primary cancer diagnosis.
Conclusions:
UK death certificates accurately identify cause of death in men with prostate cancer, supporting their use in routine statistics. Possible differential misattribution by trial arm supports independent evaluation in randomised trials.
doi:10.1038/bjc.2016.162
PMCID: PMC4931376  PMID: 27253172
cluster randomised controlled trial; screening; prostate cancer; prostate cancer mortality; cause of death; death certification; sensitivity; specificity
10.  Validating the use of Hospital Episode Statistics data and comparison of costing methodologies for economic evaluation: an end-of-life case study from the Cluster randomised triAl of PSA testing for Prostate cancer (CAP) 
BMJ Open  2016;6(4):e011063.
Objectives
To evaluate the accuracy of routine data for costing inpatient resource use in a large clinical trial and to investigate costing methodologies.
Design
Final-year inpatient cost profiles were derived using (1) data extracted from medical records mapped to the National Health Service (NHS) reference costs via service codes and (2) Hospital Episode Statistics (HES) data using NHS reference costs. Trust finance departments were consulted to obtain costs for comparison purposes.
Setting
7 UK secondary care centres.
Population
A subsample of 292 men identified as having died at least a year after being diagnosed with prostate cancer in Cluster randomised triAl of PSA testing for Prostate cancer (CAP), a long-running trial to evaluate the effectiveness and cost-effectiveness of prostate-specific antigen (PSA) testing.
Results
Both inpatient cost profiles showed a rise in costs in the months leading up to death, and were broadly similar. The difference in mean inpatient costs was £899, with HES data yielding ∼8% lower costs than medical record data (differences compatible with chance, p=0.3). Events were missing from both data sets. 11 men (3.8%) had events identified in HES that were all missing from medical record review, while 7 men (2.4%) had events identified in medical record review that were all missing from HES. The response from finance departments to requests for cost data was poor: only 3 of 7 departments returned adequate data sets within 6 months.
Conclusions
Using HES routine data coupled with NHS reference costs resulted in mean annual inpatient costs that were very similar to those derived via medical record review; therefore, routinely available data can be used as the primary method of costing resource use in large clinical trials. Neither HES nor medical record review represent gold standards of data collection. Requesting cost data from finance departments is impractical for large clinical trials.
Trial registration number
ISRCTN92187251; Pre-results.
doi:10.1136/bmjopen-2016-011063
PMCID: PMC4853970  PMID: 27130167
resource use; cost-effectiveness analysis; economic evaluation; costing methodology; hospital episode statistics; validation
11.  A genetic study and meta-analysis of the genetic predisposition of prostate cancer in a Chinese population 
Oncotarget  2016;7(16):21393-21403.
Prostate cancer predisposition has been extensively investigated in European populations, but there have been few studies of other ethnic groups. To investigate prostate cancer susceptibility in the under-investigated Chinese population, we performed single-nucleotide polymorphism (SNP) array analysis on a cohort of Chinese cases and controls and then meta-analysis with data from the existing Chinese prostate cancer genome-wide association study (GWAS). Genotyping 211,155 SNPs in 495 cases and 640 controls of Chinese ancestry identified several new suggestive Chinese prostate cancer predisposition loci. However, none of them reached genome-wide significance level either by meta-analysis or replication study. The meta-analysis with the Chinese GWAS data revealed that four 8q24 loci are the main contributors to Chinese prostate cancer risk and the risk alleles from three of them exist at much higher frequencies in Chinese than European populations. We also found that several predisposition loci reported in Western populations have different effect on Chinese men. Therefore, this first extensive single-nucleotide polymorphism study of Chinese prostate cancer in comparison with European population indicates that four loci on 8q24 contribute to a great risk of prostate cancer in a considerable large proportion of Chinese men. Based on those four loci, the top 10% of the population have six- or two-fold prostate cancer risk compared with men of the bottom 10% or median risk respectively, which may facilitate the design of prostate cancer genetic risk screening and prevention in Chinese men. These findings also provide additional insights into the etiology and pathogenesis of prostate cancer.
doi:10.18632/oncotarget.7250
PMCID: PMC5008293  PMID: 26881390
Chinese prostate cancer; genetic risk; single-nucleotide polymorphism; predisposition; population difference
12.  Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort 
BMC Medicine  2016;14:66.
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.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-016-0602-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-016-0602-x
PMCID: PMC4820939  PMID: 27044414
Boys; Mendelian randomization; Prostate cancer; Puberty; Tanner scale
13.  Implications of polygenic risk-stratified screening for prostate cancer on overdiagnosis 
Purpose
This study aims to quantify the probability of overdiagnosis of prostate cancer by polygenic risk.
Methods
We calculated the polygenic risk score based on 66 known prostate cancer susceptibility variants for 17,012 men aged 50-69 years (9,404 men identified with prostate cancer and 7,608 with no cancer) derived from three UK-based ongoing studies. We derived the probabilities of overdiagnosis by quartiles of polygenic risk considering that the observed prevalence of screen-detected prostate cancer is a combination of underlying incidence, mean sojourn time (MST), test sensitivity, and overdiagnosis.
Results
Polygenic risk quartiles one to four had 9%, 18%, 25% and 48% of the cases respectively. For a PSA test sensitivity of 80% and MST of nine years, 43%, 30%, 25% and 19% of the prevalent screen-detected cancers in quartiles one to four, respectively, were likely to be overdiagnosed cancers. Overdiagnosis decreased with increasing polygenic risk, with 56% drop between the lowest and the highest polygenic risk quartiles.
Conclusion
Targeting screening to men at higher polygenic risk could reduce the problem of overdiagnosis and lead to a better benefit to harm balance in screening for prostate cancer.
doi:10.1038/gim.2014.192
PMCID: PMC4430305  PMID: 25569441
Overdiagnosis; Polygenic risk; Prostate cancer; Risk-stratified screening
14.  Implications of polygenic risk-stratified screening for prostate cancer on overdiagnosis 
Genetics in Medicine  2015;17(10):789-795.
Purpose:
This study aimed to quantify the probability of overdiagnosis of prostate cancer by polygenic risk.
Genet Med 17 10, 789–795.
Methods:
We calculated the polygenic risk score based on 66 known prostate cancer susceptibility variants for 17,012 men aged 50–69 years (9,404 men identified with prostate cancer and 7,608 with no cancer) derived from three UK-based ongoing studies. We derived the probabilities of overdiagnosis by quartiles of polygenic risk considering that the observed prevalence of screen-detected prostate cancer is a combination of underlying incidence, mean sojourn time (MST), test sensitivity, and overdiagnosis.
Genet Med 17 10, 789–795.
Results:
Polygenic risk quartiles 1 to 4 comprised 9, 18, 25, and 48% of the cases, respectively. For a prostate-specific antigen test sensitivity of 80% and MST of 9 years, 43, 30, 25, and 19% of the prevalent screen-detected cancers in quartiles 1 to 4, respectively, were likely to be overdiagnosed cancers. Overdiagnosis decreased with increasing polygenic risk, with 56% decrease between the lowest and the highest polygenic risk quartiles.
Genet Med 17 10, 789–795.
Conclusion:
Targeting screening to men at higher polygenic risk could reduce the problem of overdiagnosis and lead to a better benefit-to-harm balance in screening for prostate cancer.
Genet Med 17 10, 789–795.
doi:10.1038/gim.2014.192
PMCID: PMC4430305  PMID: 25569441
overdiagnosis; polygenic risk; prostate cancer; risk-stratified screening
15.  Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer 
Human Molecular Genetics  2016;25(5):1008-1018.
Transcriptional and splicing anomalies have been observed in intron 8 of the CASP8 gene (encoding procaspase-8) in association with cutaneous basal-cell carcinoma (BCC) and linked to a germline SNP rs700635. Here, we show that the rs700635[C] allele, which is associated with increased risk of BCC and breast cancer, is protective against prostate cancer [odds ratio (OR) = 0.91, P = 1.0 × 10−6]. rs700635[C] is also associated with failures to correctly splice out CASP8 intron 8 in breast and prostate tumours and in corresponding normal tissues. Investigation of rs700635[C] carriers revealed that they have a human-specific short interspersed element-variable number of tandem repeat-Alu (SINE-VNTR-Alu), subfamily-E retrotransposon (SVA-E) inserted into CASP8 intron 8. The SVA-E shows evidence of prior activity, because it has transduced some CASP8 sequences during subsequent retrotransposition events. Whole-genome sequence (WGS) data were used to tag the SVA-E with a surrogate SNP rs1035142[T] (r2 = 0.999), which showed associations with both the splicing anomalies (P = 6.5 × 10−32) and with protection against prostate cancer (OR = 0.91, P = 3.8 × 10−7).
doi:10.1093/hmg/ddv622
PMCID: PMC4754045  PMID: 26740556
16.  Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci 
Background
Genome-wide association studies have identified multiple genetic variants associated with prostate cancer (PrCa) risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of PrCa.
Methods
We genotyped 25 PrCa susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical Odds Ratios for PrCa associated with different risk strata defined by PRS and derived age-specific absolute risks of developing PrCa by PRS stratum and family history.
Results
The PrCa risk for men in the top 1% of the PRS distribution was 30.6 (95% CI 16.4–57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI 3.2–5.5) fold compared with the median risk. The absolute risk of PrCa by age 85 was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation=0.09).
Conclusions
Risk profiling can identify men at substantially increased or reduced risk of PrCa. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of PrCa. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles.
Impact
We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.
doi:10.1158/1055-9965.EPI-14-0317
PMCID: PMC4491026  PMID: 25837820
Prostate Cancer risk; Genetic and Molecular Epidemiology; Genitourinary Cancers: Prostate; Risk Assessment; Methodology; Modelling and biostatistics; Methodology for SNP data analysis; Statistical methods in Genetics
17.  Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci 
Background
Genome-wide association studies have identified multiple genetic variants associated with prostate cancer (PrCa) risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of PrCa.
Methods
We genotyped 25 PrCa susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical Odds Ratios for PrCa associated with different risk strata defined by PRS and derived age-specific absolute risks of developing PrCa by PRS stratum and family history.
Results
The PrCa risk for men in the top 1% of the PRS distribution was 30.6 (95% CI 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI 3.2-5.5) fold compared with the median risk. The absolute risk of PrCa by age 85 was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation=0.09).
Conclusions
Risk profiling can identify men at substantially increased or reduced risk of PrCa. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of PrCa. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles.
Impact
We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.
doi:10.1158/1055-9965.EPI-14-0317
PMCID: PMC4491026  PMID: 25837820
Prostate Cancer risk; Genetic and Molecular Epidemiology; Genitourinary Cancers: Prostate; Risk Assessment; Methodology; Modelling and biostatistics; Methodology for SNP data analysis; Statistical methods in Genetics
18.  Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target 
Background:
The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling.
Methods:
Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ2 tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided.
Results:
CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts.
Conclusions:
CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa.
doi:10.1093/jnci/djv371
PMCID: PMC4849803  PMID: 26657335
19.  Physical activity, alcohol consumption, BMI and smoking status before and after prostate cancer diagnosis in the ProtecT trial: Opportunities for lifestyle modification 
Associations between certain lifestyle characteristics and prostate cancer risk have been reported, and continuation post-diagnosis can adversely affect prognosis. We explored whether men make spontaneous changes to their physical activity and alcohol intake, body mass index (BMI) and smoking status, following a diagnosis of localised prostate cancer. A detailed diet, health and lifestyle questionnaire was completed by 511 participants within the Prostate Testing for Cancer and Treatment (ProtecT) randomised controlled trial, both before and 9 months after a diagnosis of prostate cancer. Of 177 men who were insufficiently active before their diagnosis (median 0 activity units/week; IQR 0–9), 40.7% had increased their activity by a median of 22 U week−1 (IQR 15–35) 9 months later, and there was weak evidence that men were more active after diagnosis than before (p = 0.07). Men categorised as “working” occupational social class and who were insufficiently active before diagnosis were 2.03 (95%, CI = 1.03–3.99, p = 0.04) times more likely to have increased their physical activity levels compared to men classified as “managerial or professional.” Similarly, men who were insufficiently active pre-diagnosis and with T-stage 2 compared with T-stage 1 prostate cancer were 2.47 (95%, CI = 1.29–4.71, p = 0.006) times more likely to be sufficiently active post-diagnosis. Following diagnosis, there was an overall reduction in alcohol intake (p = 0.03) and the proportion of current smokers (p = 0.09), but no overall change in BMI. We conclude that some men spontaneously change certain lifestyle behaviours on receiving a diagnosis of prostate cancer. For many men, however, additional support through lifestyle interventions is probably required to facilitate and maintain these changes.
What’s new?
Does cancer diagnosis lead individuals to consider making healthy lifestyle changes? These authors studied men diagnosed with prostate cancer to find out whether they changed their activity level, alcohol consumption, body mass index, or smoking habits after being diagnosed with prostate cancer. They found that some men increased their activity level and/or decreased their alcohol consumption, but not all. As making positive lifestyle changes may improve prognosis, it’s worth looking for ways to encourage newly diagnosed patients to make healthy changes.
doi:10.1002/ijc.29514
PMCID: PMC4672695  PMID: 25761662
prostate cancer; behaviour change; randomised control trial
20.  The Evolutionary History of Lethal Metastatic Prostate Cancer 
Nature  2015;520(7547):353-357.
Cancers emerge from an on-going Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour1-4. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths5. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported6-8, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and inter-clonal cooperation between multiple subclones9,10. In this study, we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole genome sequencing, we characterised multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen deprivation therapy in prostate cancer.
doi:10.1038/nature14347
PMCID: PMC4413032  PMID: 25830880
21.  Incorporating Known Genetic Variants Does Not Improve the Accuracy of PSA Testing to Identify High Risk Prostate Cancer on Biopsy 
PLoS ONE  2015;10(10):e0136735.
Introduction
Prostate-specific antigen (PSA) testing is a widely accepted screening method for prostate cancer, but with low specificity at thresholds giving good sensitivity. Previous research identified four single nucleotide polymorphisms (SNPs) principally associated with circulating PSA levels rather than with prostate cancer risk (TERT rs2736098, FGFR2 rs10788160, TBX3 rs11067228, KLK3 rs17632542). Removing the genetic contribution to PSA levels may improve the ability of the remaining biologically-determined variation in PSA to discriminate between high and low risk of progression within men with identified prostate cancer. We investigate whether incorporating information on the PSA-SNPs improves the discrimination achieved by a single PSA threshold in men with raised PSA levels.
Materials and Methods
Men with PSA between 3-10ng/mL and histologically-confirmed prostate cancer were categorised as high or low risk of progression (Low risk: Gleason score≤6 and stage T1-T2a; High risk: Gleason score 7–10 or stage T2C). We used the combined genetic effect of the four PSA-SNPs to calculate a genetically corrected PSA risk score. We calculated the Area under the Curve (AUC) to determine how well genetically corrected PSA risk scores distinguished men at high risk of progression from low risk men.
Results
The analysis includes 868 men with prostate cancer (Low risk: 684 (78.8%); High risk: 184 (21.2%)). Receiver operating characteristic (ROC) curves indicate that including the 4 PSA-SNPs does not improve the performance of measured PSA as a screening tool for high/low risk prostate cancer (measured PSA level AU C = 59.5% (95% CI: 54.7,64.2) vs additionally including information from the 4 PSA-SNPs AUC = 59.8% (95% CI: 55.2,64.5) (p-value = 0.40)).
Conclusion
We demonstrate that genetically correcting PSA for the combined genetic effect of four PSA-SNPs, did not improve discrimination between high and low risk prostate cancer in men with raised PSA levels (3-10ng/mL). Replication and gaining more accurate estimates of the effects of the 4 PSA-SNPs and additional variants associated with PSA levels and not prostate cancer could be obtained from subsequent GWAS from larger prospective studies.
doi:10.1371/journal.pone.0136735
PMCID: PMC4592274  PMID: 26431041
22.  Prostatic relapse of an undifferentiated teratoma 24 years after orchidectomy 
BMC Research Notes  2015;8:524.
Background
Non-seminomatous germ cell tumours make up about 40 % of all germ cell tumours, which in turn are the most common tumours in men aged 15–44 years. Low risk stage I non-seminomatous germ cell tumours, which are confined to the testes, are commonly treated by orchiectomy and surveillance. Up to 20 % of patients with this diagnosis relapse, usually within 1–2 years of follow up, but very rarely after more than 5 years. The most common sites of relapse are the retroperitoneal lymph nodes, the mediastinum, and the lungs. We describe a case of relapse in the prostate over 20 years after initial diagnosis, which has not been described in the literature so far.
Case presentation
This report presents a 49-year-old white British man with relapsed testicular non-seminomatous germ cell tumour 22 years after initial treatment with orchidectomy only. He relapsed with a prostatic mass, haematospermia and back pain. His prostate specific antigen levels were within normal range. Alpha feto-protein and lactate dehydrogenase levels were elevated, and his human chorionic gonadotrophin levels were normal. A biopsy confirmed undifferentiated malignant tumour, shown immunohistochemically to be a yolk sac tumour. The patient was initially treated with bleomycin, etoposide and cisplatin chemotherapy, but developed bleomycin-related pulmonary side effects after two cycles. His treatment was changed and he completed four cycles of chemotherapy by receiving two cycles of etoposide, ifosfamide, and cisplatin. Post treatment blood tumour markers were normal, but a follow up computed tomography showed a mass in the base of the prostate, the trigone and the left distal ureter which was surgically resected. The histology from the surgical resection was of necrotic tissue. The patient is now in follow up at 3 years after treatment with no evidence of residual disease on computed tomography. His Alpha feto-protein, beta human chorionic gonadotrophin and lactate dehydrogenase levels are normal.
Conclusions
Very late relapse in stage I non-seminomatous germ cell tumours is extremely rare and the prostate is a highly unusual site of relapsed disease. For diagnosis of late relapse, this case confirms the value of serum biomarkers in germ cell tumours, in particular non-seminomatous germ cell tumours.
doi:10.1186/s13104-015-1445-9
PMCID: PMC4591709  PMID: 26428307
Germ cell tumour; Stage I teratoma; Late relapse; Prostatic metastasis; Tumour markers
23.  Analysis of the Genetic Phylogeny of Multifocal Prostate Cancer Identifies Multiple Independent Clonal Expansions in Neoplastic and Morphologically Normal Prostate Tissue 
Nature genetics  2015;47(4):367-372.
Whole genome DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of on-going abnormal mutational processes, consistent with field-effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissue or between different ERG-lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.
doi:10.1038/ng.3221
PMCID: PMC4380509  PMID: 25730763
24.  Salt-inducible Kinase 2 Regulates Mitotic Progression and Transcription in Prostate Cancer 
Molecular cancer research : MCR  2014;13(4):620-635.
SIK2 is a multifunctional kinase of the AMPK family which plays a role in CREB1-mediated gene transcription and was recently reported to have therapeutic potential in ovarian cancer. The expression of this kinase was investigated in prostate cancer clinical specimens. Interestingly, auto-antibodies against SIK2 were increased in the plasma of patients with aggressive disease. Examination of SIK2 in prostate cancer cells found that it functions both as a positive regulator of cell cycle progression and a negative regulator of CREB1 activity. Knockdown of SIK2 inhibited cell growth, delayed cell cycle progression, induced cell death and enhanced CREB1 activity. Expression of a kinase-dead mutant of SIK2 also inhibited cell growth, induced cell death and enhanced CREB1 activity. Treatment with a small molecule SIK2 inhibitor (ARN-3236), currently in preclinical development, also led to enhanced CREB1 activity in a dose- and time-dependent manner. Since CREB1 is a transcription factor and proto-oncogene, it was posited that the effects of SIK2 on cell proliferation and viability might be mediated by changes in gene expression. To test this, gene expression array profiling was performed and whilst SIK2 knockdown or over-expression of the kinase-dead mutant affected established CREB1 target genes; the overlap with transcripts regulated by forskolin (FSK), the adenylate cyclase/CREB1 pathway activator, was incomplete.
Implications
This study demonstrates that targeting SIK2 genetically or therapeutically will have pleiotropic effects on cell cycle progression and transcription factor activation, which should be accounted for when characterizing SIK2 inhibitors.
doi:10.1158/1541-7786.MCR-13-0182-T
PMCID: PMC4383640  PMID: 25548099
Prostate cancer; salt-inducible kinase 2; cell cycle; cAMP response element-binding protein; transducers of regulated CREB1 activity; endoplasmic reticulum stress response
25.  Establishing nurse-led active surveillance for men with localised prostate cancer: development and formative evaluation of a model of care in the ProtecT trial 
BMJ Open  2015;5(9):e008953.
Objectives
To develop a nurse-led, urologist-supported model of care for men managed by active surveillance or active monitoring (AS/AM) for localised prostate cancer and provide a formative evaluation of its acceptability to patients, clinicians and nurses. Nurse-led care, comprising an explicit nurse-led protocol with support from urologists, was developed as part of the AM arm of the Prostate testing for cancer and Treatment (ProtecT) trial.
Design
Interviews and questionnaire surveys of clinicians, nurses and patients assessed acceptability.
Setting
Nurse-led clinics were established in 9 centres in the ProtecT trial and compared with 3 non-ProtecT urology centres elsewhere in UK.
Participants
Within ProtecT, 22 men receiving AM nurse-led care were interviewed about experiences of care; 11 urologists and 23 research nurses delivering ProtecT trial care completed a questionnaire about its acceptability; 20 men managed in urology clinics elsewhere in the UK were interviewed about models of AS/AM care; 12 urologists and three specialist nurses working in these clinics were also interviewed about management of AS/AM.
Results
Nurse-led care was commended by ProtecT trial participants, who valued the flexibility, accessibility and continuity of the service and felt confident about the quality of care. ProtecT consultant urologists and nurses also rated it highly, identifying continuity of care and resource savings as key attributes. Clinicians and patients outside the ProtecT trial believed that nurse-led care could relieve pressure on urology clinics without compromising patient care.
Conclusions
The ProtecT AM nurse-led model of care was acceptable to men with localised prostate cancer and clinical specialists in urology. The protocol is available for implementation; we aim to evaluate its impact on routine clinical practice.
Trial registration numbers
NCT02044172; ISRCTN20141297.
doi:10.1136/bmjopen-2015-008953
PMCID: PMC4577970  PMID: 26384727
UROLOGY

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