Understanding of prognosis in non-metastatic prostate cancer: a randomised comparative study of clinician estimates measured against the PREDICT prostate prognostic model

Abstract: PREDICT Prostate is an individualised prognostic model that provides long-term survival estimates for men diagnosed with non-metastatic prostate cancer (www.prostate.predict.nhs.uk). In this study clinician estimates of survival were compared against model predictions and its potential value as a clinical tool was assessed. Prostate cancer (PCa) specialists were invited to participate in the study. 190 clinicians (63% urologists, 17% oncologists, 20% other) were randomised into two groups and shown 12 clinical vignettes through an online portal. Each group viewed opposing vignettes with clinical information alone, or alongside PREDICT Prostate estimates. 15-year clinician survival estimates were compared against model predictions and reported treatment recommendations with and without seeing PREDICT estimates were compared. 155 respondents (81.6%) reported counselling new PCa patients at least weekly. Clinician estimates of PCa-specific mortality exceeded PREDICT estimates in 10/12 vignettes. Their estimates for treatment survival benefit at 15 years were over-optimistic in every vignette, with mean clinician estimates more than 5-fold higher than PREDICT Prostate estimates. Concomitantly seeing PREDICT Prostate estimates led to significantly lower reported likelihoods of recommending radical treatment in 7/12 (58%) vignettes, particularly in older patients. These data suggest clinicians overestimate cancer-related mortality and radical treatment benefit. Using an individualised prognostic tool may help reduce overtreatment

General practitioner perception of prostate-specific antigen testing has improved, but more awareness of prostate cancer risk in younger patients is still awaited.

BACKGROUND: In 2006, a county-wide survey of general practitioners (GPs) in the United Kingdom (UK) identified a reluctance to refer younger men with abnormal prostate specific antigen (PSA) levels. Younger men have the most to gain from early-detection of prostate cancer (PCa), which remains a national government priority in the UK and around the world. We sought to assess changes in perception of abnormal PSA-values amongst UK GPs over the past 10 years. MATERIALS AND METHODS: A total of 500 self-administered paper questionnaires were distributed to individually named GPs. One hundred and forty two responded (28.4%), representing a patient population of ∼600,000. A series of visual analogue questions assessed referral thresholds and understanding of risk factors related to the development of PCa. RESULTS: GPs with a median of 23-years experience responded. Although mean PSA threshold for referral to urology did fall between 2006 and 2016 in both the 45-year (5.42 ng/mL vs. 4.61 ng/mL P = 0.0003) and 55-year (5.81 ng/mL vs. 5.30 ng/mL P = 0.0164) age groups, the median referral values were unchanged. Significantly, referral thresholds quoted for younger men (<65 years) were considerably higher than recommended UK maximum PSA-levels. Using case-based scenarios, practitioners appeared more likely to refer older men with abnormal PSA values, with GPs reporting an average 56.2% likelihood of referring an asymptomatic 55-year-old with elevated age-adjusted PSA of 4.6 ng/mL. A total of 95.1% recognised a family history of PCa to be a potential risk factor but other at-risk categories were not so clearly understood. CONCLUSION: Awareness of abnormal PSA values in UK primary care is improving, but continues to lag behind the evidence. Strategies to disseminate knowledge of maximum PSA-values to GPs should focus especially on those for younger patients

Individual prognosis at diagnosis in nonmetastatic prostate cancer: Development and external validation of the PREDICT Prostate multivariable model.

BACKGROUND: Prognostic stratification is the cornerstone of management in nonmetastatic prostate cancer (PCa). However, existing prognostic models are inadequate-often using treatment outcomes rather than survival, stratifying by broad heterogeneous groups and using heavily treated cohorts. To address this unmet need, we developed an individualised prognostic model that contextualises PCa-specific mortality (PCSM) against other cause mortality, and estimates the impact of treatment on survival. METHODS AND FINDINGS: Using records from the United Kingdom National Cancer Registration and Analysis Service (NCRAS), data were collated for 10,089 men diagnosed with nonmetastatic PCa between 2000 and 2010 in Eastern England. Median follow-up was 9.8 years with 3,829 deaths (1,202 PCa specific). Totals of 19.8%, 14.1%, 34.6%, and 31.5% of men underwent conservative management, prostatectomy, radiotherapy (RT), and androgen deprivation monotherapy, respectively. A total of 2,546 men diagnosed in Singapore over a similar time period represented an external validation cohort. Data were randomly split 70:30 into model development and validation cohorts. Fifteen-year PCSM and non-PCa mortality (NPCM) were explored using separate multivariable Cox models within a competing risks framework. Fractional polynomials (FPs) were utilised to fit continuous variables and baseline hazards. Model accuracy was assessed by discrimination and calibration using the Harrell C-index and chi-squared goodness of fit, respectively, within both validation cohorts. A multivariable model estimating individualised 10- and 15-year survival outcomes was constructed combining age, prostate-specific antigen (PSA), histological grade, biopsy core involvement, stage, and primary treatment, which were each independent prognostic factors for PCSM, and age and comorbidity, which were prognostic for NPCM. The model demonstrated good discrimination, with a C-index of 0.84 (95% CI: 0.82-0.86) and 0.84 (95% CI: 0.80-0.87) for 15-year PCSM in the UK and Singapore validation cohorts, respectively, comparing favourably to international risk-stratification criteria. Discrimination was maintained for overall mortality, with C-index 0.77 (95% CI: 0.75-0.78) and 0.76 (95% CI: 0.73-0.78). The model was well calibrated with no significant difference between predicted and observed PCa-specific (p = 0.19) or overall deaths (p = 0.43) in the UK cohort. Key study limitations were a relatively small external validation cohort, an inability to account for delayed changes to treatment beyond 12 months, and an absence of tumour-stage subclassifications. CONCLUSIONS: 'PREDICT Prostate' is an individualised multivariable PCa prognostic model built from baseline diagnostic information and the first to our knowledge that models potential treatment benefits on overall survival. Prognostic power is high despite using only routinely collected clinicopathological information.The Urology Foundatio

Improving the safety and tolerability of local anaesthetic out-patient transperineal prostate biopsies: a pilot study of the CAMbridge PROstate Biopsy (CAMPROBE) method

Objectives: The aim of this study was to pilot the use of a bespoke device (CAMPROBE, the CAMbridge PROstate Biopsy) to enable routine outpatient free-hand local anaesthetic (LA) transperineal prostate biopsies. Materials and methods: The CAMPROBE prototype was designed and built in our institution. Men on active surveillance due prostate resampling were invited to have a CAMPROBE biopsy as an alternative to repeat transrectal ultrasound-guided prostate biopsies (TRUSBx) as part of an approved trial (NCT02375035). Biopsies were performed using LA infiltration only, without sedation or additional analgesia. Patient-reported outcomes were recorded at day 0 and 7 using validated questionnaires and visual analogue scales (VAS). Complications were recorded prospectively. Results: Thirty men underwent biopsies with a median of 11 cores taken per procedure (interquartile range 10–12). There were no infections, sepsis or retention episodes. Haematuria and haematospermia occurred in 67% and 62% of patients, which are similar to rates reported for TRUSBx. Mean VAS for pain (0–10 scale) was less than 3 for every part of the procedure. All 30 men described the procedure as tolerable under LA. In total, 26/30 (86.7%) men expressed a preference for a CAMPROBE procedure over TRUSBx and a further 3 (10.0%) would have either. Conclusions: In this small pilot study, the CAMPROBE device and method appears to be a safe, simple and well-tolerated out-patient transperineal replacement for TRUSBx. A major new National Institute for Health Research grant will allow its further development from a prototype to a single use, low-cost disposable device ready for multi-centre testing.The work presented herewith has been made possible through funding support from Health Enterprise East, The Addenbrooke’s Charitable Trust and infrastructure support through the Cambridge Biomedical Campus

Evolution and oncological outcomes of a contemporary radical prostatectomy practice in a UK regional tertiary referral centre

Objective To investigate the clinical and pathological trends over a ten-year period for robotic-assisted laparoscopic prostatectomy (RALP) in a UK regional tertiary referral centre. Patients and Methods 1500 consecutive patients underwent RALP between October 2005 and January 2015. Prospective data was collected on clinic-pathological details at presentation as well as surgical outcomes and compared over time. Results The median(range) age of patients throughout the period was 62(35-78) years. The proportion of pre-operative high-grade cases (Gleason sum 8-10) rose from 4.6% in 2005-2008 to 18.2% in 2013-2015 (p<0.0001). In the same periods the proportion of clinical stage T3 cases operated on rose from 2.4% to 11.4% (p<0.0001). Median PSA at diagnosis did not alter significantly. Overall 11.6% of men in 2005-2008 were classified pre-operatively as high-risk by NICE criteria, compared to 33.6% in 2013-2015 (p<0.0001). The corresponding proportions for low-risk cases were 48.6% and 17.3% respectively. Final surgical pathology demonstrated an increase in tumour stage, Gleason grade and nodal status across time. The proportion of pT3 cases rose from 43.2% in 2005-2008 to 55.5% in 2013-15 (p=0.0007), Gleason grade 9-10 tumours increased from 1.8% to 9.1% (p=0.0002) and positive nodal status increased from 1.6% to 12.9% (p<0.0001) between the same periods. Despite this, positive surgical margin rates showed a downward trend in all pT groups across the different eras (p=0.72). Conclusion This study suggests that the patient profile for RALP in our unit is changing, with increasing proportions of higher-stage and more advanced disease being referred and operated on. Surgical margin outcomes however have remained good.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/bju.1351

Radical cystectomy in England from 2013 to 2019 on 12,644 patients : an analysis of national trends and comparison of surgical approaches using Hospital Episode Statistics data

Introduction We evaluate the data of 12,644 Radical Cystectomies in England (Open, Robotic and Laparoscopic) with trends in the adaption of techniques and post-operative complications. Methods This analysis utilised national Hospital Episode Statistics (HES) from NHS England. Results There was a statistically significant increase (P < .001) in the number of Robotic assisted radical cystectomies from 10.8% in 2013-2014 and 39.5% in 2018-2019.The average LOS reduced from 12.3 to 10.8 days for RARC from 2013 to 2019 similarly the LOS reduced from 16.2 to 14.3 for ORC. The rate of sepsis (0-90 days) did rise from 5% to 14.5% between 2013-2014 and 2017-2018 for the entire cohort (P < .001). Acute renal failure (ARF) increased over the years from 9.5% to 17% (P < .001). The rate for fever, UTI, critical care activity and ARF were higher for ORC than RARC (P < .001).The comparison of all episodes within 90 days for conduit versus non-conduit diversions showed significantly higher rates of sepsis, infections, UTI and fever in non-conduit group .Overall complications were significantly higher in non-conduit group throughout the duration except was year 2016-17(P < .001).The robotic approach has increased in last 5 years with nearly 40% of the cystectomies now being robotically in 2018-19 from the initial percentage of 10.8% in 2013-14. Conclusion This evaluation of the HES data from NHS England for 12,644 RC confirms an increase in the adoption of Robotic Cystectomy. Our data confirms the need to develop strategies with enhanced recovery protocols and post-operative close monitoring following Radical Cystectomy in order to reduce post-operative complications

Evolution and oncological outcomes of a contemporary radical prostatectomy practice in a UK regional tertiary referral centre.

OBJECTIVE: To investigate the clinical and pathological trends, over a 10-year period, in robot-assisted laparoscopic prostatectomy (RALP) in a UK regional tertiary referral centre. PATIENTS AND METHODS: In all, 1 500 consecutive patients underwent RALP between October 2005 and January 2015. Prospective data were collected on clinicopathological details at presentation as well as surgical outcomes and compared over time. RESULTS: The median (range) age of patients throughout the period was 62 (35-78) years. The proportion of preoperative high-grade cases (Gleason score 8-10) rose from 4.6% in 2005-2008 to 18.2% in 2013-2015 (P < 0.001). In the same periods the proportion of clinical stage T3 cases operated on rose from 2.4% to 11.4% (P < 0.001). The median prostate-specific antigen (PSA) level at diagnosis did not alter significantly. Overall, 11.6% of men in 2005-2008 were classified preoperatively as high-risk by National Institute for Health and Care Excellence criteria, compared with 33.6% in 2013-2015 (P < 0.001). The corresponding proportions for low-risk cases were 48.6% and 17.3%, respectively. Final surgical pathology showed an increase in tumour stage, Gleason grade, and nodal status over time. The proportion of pT3 cases rose from 43.2% in 2005-2008 to 55.5% in 2013-2015 (P < 0.001), Gleason score 9-10 tumours increased from 1.8% to 9.1% (P < 0.001) and positive nodal status increased from 1.6% to 12.9% (P < 0.001) between the same periods. Despite this, positive surgical margin rates showed a downward trend in all pT groups across the different eras (P = 0.72). CONCLUSION: This study suggests that the patient profile for RALP in our unit is changing, with increasing proportions of higher stage and more advanced disease being referred and operated on. However, surgical margin outcomes have remained good.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/bju.1351

Characterization of cis- and trans-acting elements in the imprinted human SNURF-SNRPN locus

The imprinted SNRPN locus is a complex transcriptional unit that encodes the SNURF and SmN polypeptides as well as multiple non-coding RNAs. SNRPN is located within the Prader-Willi and Angelman syndrome (PWS/AS) region that contains multiple imprinted genes, which are coordinately regulated by a bipartite imprinting center (IC). The SNRPN 5′ region co-localizes with the PWS-IC and contains two DNase I hypersensitive sites, DHS1 at the SNRPN promoter, and DHS2 within intron 1, exclusively on the paternally inherited chromosome. We have examined DHS1 and DHS2 to identify cis- and trans-acting regulatory elements within the endogenous SNRPN 5′ region. Analysis of DHS1 by in vivo footprinting and chromatin immunoprecipitation identified allele-specific interaction with multiple regulatory proteins, including NRF-1, which regulates genes involved in mitochondrial and metabolic functions. DHS2 acted as an enhancer of the SNRPN promoter and contained a highly conserved region that showed allele-specific interaction with unphosphorylated RNA polymerase II, YY1, Sp1 and NRF-1, further suggesting a key role for NRF-1 in regulation of the SNRPN locus. We propose that one or more of the regulatory elements identified in this study may also contribute to PWS-IC function

High resolution imaging reveals heterogeneity in chromatin states between cells that is not inherited through cell division

BACKGROUND: Genomes of eukaryotes exist as chromatin, and it is known that different chromatin states can influence gene regulation. Chromatin is not a static structure, but is known to be dynamic and vary between cells. In order to monitor the organisation of chromatin in live cells we have engineered fluorescent fusion proteins which recognize specific operator sequences to tag pairs of syntenic gene loci. The separation of these loci was then tracked in three dimensions over time using fluorescence microscopy. RESULTS: We established a work flow for measuring the distance between two fluorescently tagged, syntenic gene loci with a mean measurement error of 63 nm. In general, physical separation was observed to increase with increasing genomic separations. However, the extent to which chromatin is compressed varies for different genomic regions. No correlation was observed between compaction and the distribution of chromatin markers from genomic datasets or with contacts identified using capture based approaches. Variation in spatial separation was also observed within cells over time and between cells. Differences in the conformation of individual loci can persist for minutes in individual cells. Separation of reporter loci was found to be similar in related and unrelated daughter cell pairs. CONCLUSIONS: The directly observed physical separation of reporter loci in live cells is highly dynamic both over time and from cell to cell. However, consistent differences in separation are observed over some chromosomal regions that do not correlate with factors known to influence chromatin states. We conclude that as yet unidentified parameters influence chromatin configuration. We also find that while heterogeneity in chromatin states can be maintained for minutes between cells, it is not inherited through cell division. This may contribute to cell-to-cell transcriptional heterogeneity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12860-016-0111-y) contains supplementary material, which is available to authorized users

Genome-Wide Distribution of RNA-DNA Hybrids Identifies RNase H Targets in tRNA Genes, Retrotransposons and Mitochondria

During transcription, the nascent RNA can invade the DNA template, forming extended RNA-DNA duplexes (R-loops). Here we employ ChIP-seq in strains expressing or lacking RNase H to map targets of RNase H activity throughout the budding yeast genome. In wild-type strains, R-loops were readily detected over the 35S rDNA region, transcribed by Pol I, and over the 5S rDNA, transcribed by Pol III. In strains lacking RNase H activity, R-loops were elevated over other Pol III genes, notably tRNAs, SCR1 and U6 snRNA, and were also associated with the cDNAs of endogenous TY1 retrotransposons, which showed increased rates of mobility to the 5'-flanking regions of tRNA genes. Unexpectedly, R-loops were also associated with mitochondrial genes in the absence of RNase H1, but not of RNase H2. Finally, R-loops were detected on actively transcribed protein-coding genes in the wild-type, particularly over the second exon of spliced ribosomal protein genes