Risk of prostate cancer after isolated high-grade prostatic intraepithelial neoplasia (HGPIN) detected on extended core needle biopsy : a UK hospital experience.

Background High-grade prostatic intraepithelial neoplasia (HGPIN) is a precursor lesion to prostate cancer (CaP). UK-based studies examining the occurrence of isolated HGPIN and subsequent risk of CaP are lacking. Our aim was to assess the occurrence of HGPIN in a regional UK population and to determine whether in a retrievable cohort of such patients that had repeat extended core biopsies, there was an elevated risk of CaP. Methods A retrospective analysis of the pathology database was conducted at our institution (Lancashire Teaching Hospitals NHS Foundation Trust) for prostate biopsies recorded between January 2001 and December 2005 (all extended core biopsies). Those patients with isolated HGPIN on 1st set of biopsies were identified and, their clinical characteristics and pathological findings from subsequent biopsies (if any) were determined. The risk of CaP on subsequent biopsies based on presenting baseline PSA was stratified. Results Of 2,192 biopsied patients, there were 88 cases of isolated HGPIN of which 67 patients underwent one or more repeat biopsies. In this repeat-biopsy group, 28 CaP diagnoses were made. Age at first biopsy (P 20 ng/ml – 87.5%. Conclusion Based on our results, we recommend delaying the 1st repeat biopsy at low PSA range but to have a shorter interval to repeat biopsies at intermediate and higher PSA ranges

Prostate imaging features that indicate benign or malignant pathology on biopsy

Accurate diagnosis of clinically significant prostate cancer is essential in identifying patients who should be offered treatment with curative intent. Modifications to the Gleason grading system in recent years show that accurate grading and reporting at needle biopsy can improve identification of clinically significant prostate cancers. Extracapsular extension of prostate cancer has been demonstrated to be an adverse prognostic factor with greater risk of metastatic spread than organ-confined disease. Tumor volume may be an independent prognostic factor and should be considered in conjunction with other factors. Multiparametric magnetic resonance imaging (MP-MRI) has become an increasingly important tool in the diagnosis and characterization of prostate cancer. MP-MRI allows T2-weighted (T2W) anatomical imaging to be combined with functional and physiological assessment. Diffusion-weighted imaging (DWI) has shown greater sensitivity, specificity and negative predictive value compared to prostate specific antigen (PSA) testing and T2W imaging alone and has a more positive correlation with Gleason score and tumour volume. Dynamic gadolinium contrast-enhanced (DCE) imaging can exhibit difficulties in distinguishing prostatitis from Malignancy in the peripheral zone, and between benign prostatic hyperplasia (BPH) and Malignancies in the transition zone (TZ). Computer aided diagnosis utilizes software to aid radiologists in detecting and diagnosing Abnormalities from diagnostic imaging. New techniques of quantitative MRI, such as VERDICT MRI use tissue-specific factors to delineate different cellular and microstructural phenotypes, characterizing tissue properties with greater detail. Proton MR spectroscopic imaging (MRSI) is a more technically challenging imaging modality than DCE and DWI MRI. Over the last decade, choline and prostate-specific membrane antigen (PSMA) positron emission tomography (PET) have developed as better tools for staging than conventional imaging. While hyperpolarized MRI shows promise in improving the imaging and differentiation of benign and Malignant lesions there is further work required. Accurate reading and interpretation of diagnostic investigations is key to accurate identification of abnormal areas requiring biopsy, sparing those in whom benign or indolent disease can be managed by non-invasive means. Embracing and advancing existing technologies is essential in furthering this process

Elevated Oestrogen Receptor Splice Variant ERαΔ5 Expression in Tumour-adjacent Hormone-responsive Tissue

Susceptibility to prostate or endometrial cancer is linked with obesity, a state of oestrogen excess. Oestrogen receptor (ER) splice variants may be responsible for the tissue-level of ER activity. Such micro-environmental regulation may modulate cancer initiation and/or progression mechanisms. Real-time reverse transcriptase (RT) polymerase chain reaction (PCR) was used to quantitatively assess the levels of four ER splice variants (ERαΔ3, ERαΔ5, ERβ2 and ERβ5), plus the full-length parent isoforms ERα and ERβ1, in high-risk [tumour-adjacent prostate (n = 10) or endometrial cancer (n = 9)] vs. low-risk [benign prostate (n = 12) or endometrium (n = 9)], as well as a comparison of UK (n = 12) vs. Indian (n = 15) benign prostate. All three tissue groups expressed the ER splice variants at similar levels, apart from ERαΔ5. This splice variant was markedly raised in all of the tumour-adjacent prostate samples compared to benign tissues. Immunofluorescence analysis for ERβ2 in prostate tissue demonstrated that such splice variants are present in comparable, if not greater, amounts as the parent full-length isoform. This small pilot study demonstrates the ubiquitous nature of ER splice variants in these tissue sites and suggests that ERαΔ5 may be involved in progression of prostate adenocarcinoma

Factors associated with spontaneous stone passage in a contemporary cohort of patients presenting with acute ureteric colic. Results from the MIMIC Study (A Multi-centre cohort study evaluating the role of Inflammatory Markers in patients presenting with acute ureteric Colic)

Objectives There is conflicting data on the role of white blood cell count (WBC) and other inflammatory markers in spontaneous stone passage in patients with acute ureteric colic. The aim of the study was to assess the relationship of WBC and other routinely collected inflammatory and clinical markers including stone size, stone position and Medically Expulsive Therapy use (MET) with spontaneous stone passage (SSP) in a large contemporary cohort of patients with acute ureteric colic. Subjects and Methods Multi‐centre retrospective cohort study coordinated by the British Urology Researchers in Surgical Training (BURST) Research Collaborative at 71 secondary care hospitals across 4 countries (United Kingdom, Republic of Ireland, Australia and New Zealand). 4170 patients presented with acute ureteric colic and a computer tomography confirmed single ureteric stone. Our primary outcome measure was SSP as defined by the absence of need for intervention to assist stone passage. Multivariable mixed effects logistic regression was used to explore the relationship between key patient factors and SSP. Results 2518 patients were discharged with conservative management and had further follow up with a SSP rate of 74% (n = 1874/2518). Sepsis after discharge with conservative management was reported in 0.6% (n = 16/2518). On multivariable analysis neither WBC, Neutrophils or CRP were seen to predict SSP, with an adjusted OR of 0.97 [95% CI 0.91 to 1.04, p = 0.38], 1.06 [95% CI 0.99 to 1.13, p = 0.1] and 1.00 [95% CI 0.99 to 1.00, p = 0.17], respectively. Medical expulsive therapy (MET) also did not predict SSP [adjusted OR 1.11 [95% CI 0.76 to 1.61]). However, stone size and stone position were significant predictors. SSP for stones 7mm. For stones in the upper ureter the SSP rate was 52% [95% CI 48 to 56], middle ureter was 70% [95% CI 64 to 76], and lower ureter was 83% [95% CI 81 to 85]. Conclusion In contrast to the previously published literature, we found that in patients with acute ureteric colic who are discharged with initial conservative management, neither WBC, Neutrophil count or CRP help determine the likelihood of spontaneous stone passage. We also found no overall benefit from the use of MET. Stone size and position are important predictors and our findings represent the most comprehensive stone passage rates for each mm increase in stone size from a large contemporary cohort adjusting for key potential confounders. We anticipate that these data will aid clinicians managing patients with acute ureteric colic and help guide management decisions and the need for intervention

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

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

CYP1B1 expression is higher in the peripheral zone compared to the transition zone : a difference underlying zonal susceptibility to prostate adenocarcinoma?

Introduction The prostate is a composite organ divided into zones. Prostate adenocarcinoma (CaP) mostly occurs in the peripheral zone. Cytochrome P-450 (CYP) isoenzymes are constitutively expressed and inducible enzymes, many of which (e.g. CYP1A1, CYP1A2 and CYP1B1 isoforms) are involved in hormone and carcinogen hydroxylation. Aim To assess variations in CYP expression in the prostate on an intra-(peripheral zone Vs. transition zone) and inter-individual basis. Materials and Methods Human prostates (n=24) were obtained, with ethical approval, from radical retropubic prostatectomies. Study participants exhibited low PSA (< 20 μg/l serum) and low volume of disease (< two/eight core biopsies positive for CaP). Following resection, tissue sets consisting of peripheral zone and transition zone were isolated from a lobe pre-operatively identified as negative for CaP. A histopathologist always examined adjacent tissue. Real-time RT-PCR was employed to quantitatively examine CYP1A1, CYP1A2 and CYP1B1. Results CYP1A1 mRNA transcripts were detected in either or both zones of twenty tissue sets (in seven cases, in both zones) and were undetectable in four others. In eleven tissue sets, higher levels of CYP1A1 expression were observed in the peripheral zone compared to the transition zone (maximum six-fold difference) whereas in nine other tissue sets this relationship (maximum 2.5- fold difference) was reversed. CYP1A2, although detectable in twelve tissue sets, was not quantifiably expressed. CYP1B1 expression was detected in both zones of all tissue sets examined. Inter-individual variation in CYP1B1 expression levels in peripheral zone (five-fold differences) and transition zone (tenfold differences) were noted. In sixteen out of seventeen tissue sets found to be cancer free, CYP1B1 expression was found to be two- to fifty-fold higher in the peripheral zone compared to the transition zone; in the remaining tissue set an equal level of gene expression was detected in both zones. In the tissue sets containing CaP, CYP1B1 expression was higher in the cancerous zone (be it peripheral or transition) in five of six cases; in another tissue set containing PIN, an equal level of gene expression was again detected in both zones. Immunohistochemistry clearly demonstrated a nuclear staining pattern for CYP1B1 in epithelial and stromal cells of both zones; the staining density of this protein was markedly elevated in cancerous tissue. Discussion CYP1B1 preferentially catalyses the 4-hydroxylation of 17β- oestradiol, metabolically activates exogenous pro-carcinogens and inactivates anticancer agents. Future studies will investigate whether CYP1B1 may be employed as a target either for chemoprevention strategies or treatment of clinically invasive disease

Inter-and intra-individual variations in prostate CYP1B1 expression suggest a role in peripheral-zone susceptibility to adenocarcinoma.

The prostate is conventionally divided into zones. Prostate adenocarcinoma (CaP) is commonly confined to the peripheral zone. Cytochrome P-450 (CYP) isoenzymes are constitutively expressed and inducible enzymes, many of which are involved in hormone and carcinogen hydroxylation. These include the CYP1A1, CYP1A2 and CYP1B1 isoforms. Human prostates (n 5 12) were obtained, with ethical approval, from radical retropubic prostatectomies. Study participants exhibited low PSA (520 mg/l serum) and low volume of disease (5two/eight core biopsies positive for CaP). Following resection, tissue sets consisting of peripheral zone and transition zone were isolated from a lobe pre-operatively identified as negative for CaP. Real-time RT-PCR was employed to quantitatively examine CYP1A1, CYP1A2 and CYP1B1. CYP1A1 expression was quantifiable in either or both zones of nine tissue sets and was unquantifiable in three others. In six tissue sets, higher levels of CYP1A1 expression were observed in the transition zone compared to the peripheral zone. CYP1A2, although detectable, was not quantifiably expressed. CYP1B1 expression was detected in both zones of all tissue sets examined. Interindividual variation in CYP1B1 expression levels in peripheral zone (0.5--2-fold) and transition zone (0.5--5-fold) were noted. In ten tissue sets found to be cancer free, CYP1B1 expression was 2- to 6-fold higher in the peripheral zone compared to the transition zone. In the remaining two tissue sets, CYP1B1 expression was approximately equal in both zones; histopathology showed CaP in one of the zones. CYP1B1 preferentially catalyses the 4-hydroxylation of 17b-oestradiol, metabolically activates exogenous procarcinogens and inactivates anticancer agents. Our results suggest that CYP1B1 may influence susceptibility to CaP