Shyam S. Matanhelia

The economic consequences of prostate and bladder cancer in the UK.

To compare the costs of managing prostate and bladder cancer and relate them to current expenditure on research, as the increasing prevalence of both necessitates the adequate direction of resources.

A potential paradox in prostate adenocarcinoma progression: Oestrogen as the initiating driver

One in 10 men in the developed world will present with prostate cancer (CaP), and in an ageing population developing strategies for its chemoprevention or treatment is of significance. For decades, androgen ablation has remained the frontline treatment for CaP that is no longer organ-confined and thus deemed surgically inoperable. Orchidectomy or drug-induced reduction of serum testosterone levels with the consequent removal of growth-promoting effects in the prostate is the driving rationale for this regimen. However, resistance often develops within a few months to years and androgen-insensitive tumours develop. In recent years, there has been an increasing focus on chemoprevention with agents such as finasteride being employed to reduce the risk of developing CaP. Significantly, such chemoprevention strategies are also based on 5alpha-reductase inhibition thus reducing intraprostatic dihydrotestosterone levels. Although there may be an overall reduction in CaP incidence in cohorts using such chemoprevention, in a subset of users who do develop this pathology there results a more aggressive, higher-grade disease. There have also been suggestions regarding the protective role of androgens against high-grade CaP. This leads to the intriguing notion that 17beta-oestradiol (E2) may be an initiating driver of CaP; in fact, in old studies in which CaP was induced in rodents, E2 often accelerated the effect of the carcinogen. Might certain chemoprevention strategies or androgen ablation result in a systemic feedback loop in hormone synthesis or metabolism? If so, elevated serum E2 levels could result in its increased conversion to genotoxic catechol oestrogens in target tissues such as the prostate. Paradoxically, if E2 were to be an initiating factor in CaP, anti-oestrogens might be an overlooked treatment or chemoprevention strategy.

Quantification of phase I / II metabolizing enzyme gene expression and polycyclic aromatic hydrocarbon-DNA adduct levels in human prostate

Studies of migrant populations suggest that dietary and/or environmental factors play a crucial role in the etiology of prostatic adenocarcinoma (CaP). The human prostate consists of the peripheral zone (PZ), transition zone (TZ), and central zone (CZ); CaP occurs most often in the PZ.

Differential gene expression in the peripheral zone compared to the transition zone of the human prostate gland.

Gene expression profiles may lend insight into whether prostate adenocarcinoma (CaP) predominantly occurs in the peripheral zone (PZ) compared to the transition zone (TZ). From human prostates, tissue sets consisting of PZ and TZ were isolated to investigate whether there is a differential level of gene expression between these two regions of this gland. Gene expression profiling using Affymetrix Human Genome U133 plus 2.0 arrays coupled with quantitative real-time reverse transcriptase-PCR was employed. Genes associated with neurogenesis, signal transduction, embryo implantation and cell adhesion were found to be expressed at a higher level in the PZ. Those overexpressed in the TZ were associated with neurogenesis development, signal transduction, cell motility and development. Whether such differential gene expression profiles may identify molecular mechanisms responsible for susceptibility to CaP remains to be ascertained.

The Unusual History and the Urological Applications of Botulinum Neurotoxin

Introduction: Botulinum neurotoxin (BoNT) is probably the most potent biological toxin that can affect humans. Since its discovery by Justinus Kerner, BoNT has seen use in a wide range of cosmetic and non-cosmetic conditions such as cervical dystonia, cerebral palsy, migraines and hyperhidrosis. We tried to trace its history from its inception to its recent urological applications. Materials and Methods: Historical articles about botulinum toxin were reviewed and a Medline search was performed for its urological utility. We hereby present a brief review of historical aspects of BoNT and its applications in urology. Results: In 1793, the first known outbreak of botulism occurred due to ‘spoiled’ sausage in Wildebad, Germany. The German physician and poet Justinus Kerner published the first accurate description of the clinical symptoms of botulism (sausage poison). He was also the first to mention its potential therapeutic applications. In urology, BoNT has been used in bladder and urethral lesions with varying degree of success. Recently, BoNT applications were explained for prostatic disorders. BoNT applications in urology are in the treatment of detrusor external sphincter dyssynergia, detrusor overactivity, detrusor underactivity, spastic conditions of the urethral sphincter, chronic prostate pain, interstitial cystitis, non-fibrotic bladder outflow obstruction (including benign prostatic hyperplasia) and acute urinary retention in women. Conclusion: Justinus Kerner is the godfather of botulism research. The role of BoNT in urology has evolved exponentially and it is widely used as an adjuvant in voiding dysfunction. In the future, its utility will broaden and guide the urologist in managing various urological disorders.

Quantified gene expression levels for phase I/II metabolizing enzyme and estrogen receptor levels in benign prostate from cohorts designated as high-risk (UK) versus low-risk (India) for adenocarcinoma at this organ site: a preliminary study.

Risk of clinically significant prostate adenocarcinoma (CaP) varies worldwide, although there is a uniform prevalence of latent disease. A hormone-responsive tissue, the prostate possesses the metabolizing capacity to biotransform a variety of environmental procarcinogens or endogenous hormones. Whether such metabolizing capacity or estrogen receptor (ER) status underlies these demographic differences in susceptibility to CaP remains unclear. With appropriate ethical permission, verified-benign tissues were obtained following transurethral resection of the prostate from a high-risk region (n = 12 UK-resident Caucasians) and a typically low-risk region (n = 14 India-resident Asians). Quantitative gene expression analysis was employed for cytochrome P450 (CYP)1B1, N-acetyltransferase (NAT)1, NAT2, catechol-O-methyl transferase (COMT), sulfotransferase (SULT)1A1, ERalpha, ERbeta and aromatase (CYP19A1). To quantify the presence or absence of CYP1B1, ERalpha or ERbeta, and to identify their in situ localization, immunohistochemistry was carried out. The two cohorts had reasonably well-matched serum levels of prostate-specific antigen or hormones. Expression levels for the candidate genes investigated were similar. However, clear differences in protein levels for CYP1B1 and ERbeta were noted. Staining for CYP1B1 tended to be nuclear-associated in the basal glandular epithelial cells, and in UK-resident Caucasian tissues was present at a higher (P = 0.006) level compared with that from India-resident Asians. In contrast, a higher level of positive ERbeta staining was noted in prostates from India-resident Asians. These study findings point to differences in metabolizing capacity and ER status in benign prostate tissues that might modulate susceptibility to the emergence of clinically significant CaP in demographically distinct populations.

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

BackgroundHigh-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.MethodsA 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.ResultsOf 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 < 0.001), higher mean baseline prostate-specific antigen (PSA) (P < 0.005) and higher mean change in PSA (P < 0.05) were predictive of CaP detection on repeat biopsies. PSA ranges and their associated predictive values for cancer were: 0 to 5 ng/ml – 11%; 5 to 10 ng/ml – 34%; 10 to 20 ng/ml – 50%; and > 20 ng/ml – 87.5%.ConclusionBased 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.

Is DRE essential for the follow up of prostate cancer patients? A prospective audit of 194 patients.

BackgroundProstate cancer follow up forms a substantial part of the urology outpatient workload. Nurse led prostate cancer follow up clinics are becoming more common. Routine follow-up may involve performing DRE, which may require training.ObjectivesThe aim of this audit was to assess the factors that influenced the change in the management of prostate cancer patients during follow up. This would allow us to pave the way towards a protocol driven follow up clinic led by nurse specialists without formal training in DRE.Results194 prostate cancer patients were seen over a period of two months and all the patients had DRE performed on at least one occasion. The management was changed in 47 patients. The most common factor influencing this change was PSA trend. A change in DRE findings influenced advancement of the clinic visit in 2 patients.ConclusionsPSA is the most common factor influencing change in the management of these patients. Nurse specialists can run prostate cancer follow-up clinics in parallel to existing consultant clinics and reserve DRE only for those patients who have a PSA change or have onset of new symptoms. However larger studies are required involving all the subgroups of patients to identify the subgroups of patients who will require DRE routinely.

Use of tissue ink to maintain identification of individual cores on needle biopsies of the prostate

Background: There is an increasing necessity to extract the maximum amount of information, beyond even a cancer diagnosis, from prostate biopsies. Thus, maintaining site-specific information regarding individual biopsy cores might be critical. Aim: To evaluate the applicability of employing tissue ink to maintain the identity of individual prostatic biopsy cores. Method: In this ongoing study, 12 core prostate biopsy specimens are sent to the laboratory in individual pots labelled according to anatomical site. The specimens are placed in two separate multi-compartment cassettes. They are inked with different colours to identify the site of origin from each lobe. The cassettes are then processed with a single paraffin block for each side; the six cores from each side can be mounted on a single slide. Results: The different colours used adhere well to the biopsy cores, thus maintaining the identity of each core. Six cores from each side are embedded in a single paraffin block and examined on a single slide, making it cost-effective, while maintaining high quality, accurate histopathological information. Conclusion: Differential inking of prostate biopsy cores is an easily applicable method that is cost-effective and provides tumour location information. Prostate biopsy data archived to maintain individual core information might be used to determine applicability of such information to predict extra-capsular extension by correlating with imaging and radical prostatectomy findings, and for treatment planning.

The economic and workload impact of 'backdoor' prostate-specific antigen screening on the UK National Health Service: a single-centre experience.

To determine the economic burden and additional cost on one hospital within the UK National Health Service secondary to prostate‐specific antigen screening by a private recruitment company for a clinical drug trial.