Adaptation and performance of a mobile application for early detection of cutaneous leishmaniasis.

BACKGROUND: Detection and management of neglected tropical diseases such as cutaneous leishmaniasis present unmet challenges stemming from their prevalence in remote, rural, resource constrained areas having limited access to health services. These challenges are frequently compounded by armed conflict or illicit extractive industries. The use of mobile health technologies has shown promise in such settings, yet data on outcomes in the field remain scarce. METHODS: We adapted a validated prediction rule for the presumptive diagnosis of CL to create a mobile application for use by community health volunteers. We used human-centered design practices and agile development for app iteration. We tested the application in three rural areas where cutaneous leishmaniasis is endemic and an urban setting where patients seek medical attention in the municipality of Tumaco, Colombia. The application was assessed for usability, sensitivity and inter-rater reliability (kappa) when used by community health volunteers (CHV), health workers and a general practitioner, study physician. RESULTS: The application was readily used and understood. Among 122 screened cases with cutaneous ulcers, sensitivity to detect parasitologically proven CL was >95%. The proportion of participants with parasitologically confirmed CL was high (88%), precluding evaluation of specificity, and driving a high level of crude agreement between the app and parasitological diagnosis. The chance-adjusted agreement (kappa) varied across the components of the risk score. Time to diagnosis was reduced significantly, from 8 to 4 weeks on average when CHV conducted active case detection using the application, compared to passive case detection by health facility-based personnel. CONCLUSIONS: Translating a validated prediction rule to a mHealth technology has shown the potential to improve the capacity of community health workers and healthcare personnel to provide opportune care, and access to health services for underserved populations. These findings support the use of mHealth tools for NTD research and healthcare.

Men's experiences of radiotherapy treatment for localized prostate cancer and its long-term treatment side effects: a longitudinal qualitative study.

PURPOSE: To investigate men's experiences of receiving external-beam radiotherapy (EBRT) with neoadjuvant Androgen Deprivation Therapy (ADT) for localized prostate cancer (LPCa) in the ProtecT trial. METHODS: A longitudinal qualitative interview study was embedded in the ProtecT RCT. Sixteen men with clinically LPCa who underwent EBRT in ProtecT were purposively sampled to include a range of socio-demographic and clinical characteristics. They participated in serial in-depth qualitative interviews for up to 8 years post-treatment, exploring experiences of treatment and its side effects over time. RESULTS: Men experienced bowel, sexual, and urinary side effects, mostly in the short term but some persisted and were bothersome. Most men downplayed the impacts, voicing expectations of age-related decline, and normalizing these changes. There was some reticence to seek help, with men prioritizing their relationships and overall health and well-being over returning to pretreatment levels of function. Some unmet needs with regard to information about treatment schedules and side effects were reported, particularly among men with continuing functional symptoms. CONCLUSIONS: These findings reinforce the importance of providing universal clear, concise, and timely information and supportive resources in the short term, and more targeted and detailed information and care in the longer term to maintain and improve treatment experiences for men undergoing EBRT.

Association Of Plasma And Urinary Mutant DNA With Clinical Outcomes In Muscle Invasive Bladder Cancer.

Muscle Invasive Bladder Cancer (MIBC) has a poor prognosis. Whilst patients can achieve a 6% improvement in overall survival with Neo-Adjuvant Chemotherapy (NAC), many do not respond. Body fluid mutant DNA (mutDNA) may allow non-invasive identification of treatment failure. We collected 248 liquid biopsy samples including plasma, cell pellet (UCP) and supernatant (USN) from spun urine, from 17 patients undergoing NAC. We assessed single nucleotide variants and copy number alterations in mutDNA using Tagged-Amplicon- and shallow Whole Genome- Sequencing. MutDNA was detected in 35.3%, 47.1% and 52.9% of pre-NAC plasma, UCP and USN samples respectively, and urine samples contained higher levels of mutDNA (p = <0.001). Longitudinal mutDNA demonstrated tumour evolution under the selective pressure of NAC e.g. in one case, urine analysis tracked two distinct clones with contrasting treatment sensitivity. Of note, persistence of mutDNA detection during NAC predicted disease recurrence (p = 0.003), emphasising its potential as an early biomarker for chemotherapy response.

Prostate cancer risk related to foods, food groups, macronutrients and micronutrients derived from the UK Dietary Cohort Consortium food diaries.

BACKGROUND/OBJECTIVES: The influence of dietary factors remains controversial for screen-detected prostate cancer and inconclusive for clinically detected disease. We aimed to examine these associations using prospectively collected food diaries. SUBJECTS/METHODS: A total of 1,717 prostate cancer cases in middle-aged and older UK men were pooled from four prospective cohorts with clinically detected disease (n=663), with routine data follow-up (means 6.6-13.3 years) and a case-control study with screen-detected disease (n=1054), nested in a randomised trial of prostate cancer treatments (ISCTRN 20141297). Multiple-day food diaries (records) completed by men prior to diagnosis were used to estimate intakes of 37 selected nutrients, food groups and items, including carbohydrate, fat, protein, dairy products, fish, meat, fruit and vegetables, energy, fibre, alcohol, lycopene and selenium. Cases were matched on age and diary date to at least one control within study (n=3528). Prostate cancer risk was calculated, using conditional logistic regression (adjusted for baseline covariates) and expressed as odds ratios in each quintile of intake (±95% confidence intervals). Prostate cancer risk was also investigated by localised or advanced stage and by cancer detection method. RESULTS: There were no strong associations between prostate cancer risk and 37 dietary factors. CONCLUSIONS: Prostate cancer risk, including by disease stage, was not strongly associated with dietary factors measured by food diaries in middle-aged and older UK men.

Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer.

BACKGROUND: Robust data on patient-reported outcome measures comparing treatments for clinically localized prostate cancer are lacking. We investigated the effects of active monitoring, radical prostatectomy, and radical radiotherapy with hormones on patient-reported outcomes. METHODS: We compared patient-reported outcomes among 1643 men in the Prostate Testing for Cancer and Treatment (ProtecT) trial who completed questionnaires before diagnosis, at 6 and 12 months after randomization, and annually thereafter. Patients completed validated measures that assessed urinary, bowel, and sexual function and specific effects on quality of life, anxiety and depression, and general health. Cancer-related quality of life was assessed at 5 years. Complete 6-year data were analyzed according to the intention-to-treat principle. RESULTS: The rate of questionnaire completion during follow-up was higher than 85% for most measures. Of the three treatments, prostatectomy had the greatest negative effect on sexual function and urinary continence, and although there was some recovery, these outcomes remained worse in the prostatectomy group than in the other groups throughout the trial. The negative effect of radiotherapy on sexual function was greatest at 6 months, but sexual function then recovered somewhat and was stable thereafter; radiotherapy had little effect on urinary continence. Sexual and urinary function declined gradually in the active-monitoring group. Bowel function was worse in the radiotherapy group at 6 months than in the other groups but then recovered somewhat, except for the increasing frequency of bloody stools; bowel function was unchanged in the other groups. Urinary voiding and nocturia were worse in the radiotherapy group at 6 months but then mostly recovered and were similar to the other groups after 12 months. Effects on quality of life mirrored the reported changes in function. No significant differences were observed among the groups in measures of anxiety, depression, or general health-related or cancer-related quality of life. CONCLUSIONS: In this analysis of patient-reported outcomes after treatment for localized prostate cancer, patterns of severity, recovery, and decline in urinary, bowel, and sexual function and associated quality of life differed among the three groups. (Funded by the U.K. National Institute for Health Research Health Technology Assessment Program; ProtecT Current Controlled Trials number, ISRCTN20141297 ; ClinicalTrials.gov number, NCT02044172 .).

Radiotherapy for Prostate Cancer: is it 'what you do' or 'the way that you do it'? A UK Perspective on Technique and Quality Assurance.

AIMS: The treatment of prostate cancer has evolved markedly over the last 40 years, including radiotherapy, notably with escalated dose and targeting. However, the optimal treatment for localised disease has not been established in comparative randomised trials. The aim of this article is to describe the history of prostate radiotherapy trials, including their quality assurance processes, and to compare these with the ProtecT trial. MATERIALS AND METHODS: The UK ProtecT randomised trial compares external beam conformal radiotherapy, surgery and active monitoring for clinically localised prostate cancer and will report on the primary outcome (disease-specific mortality) in 2016 following recruitment between 1999 and 2009. The embedded quality assurance programme consists of on-site machine dosimetry at the nine trial centres, a retrospective review of outlining and adherence to dose constraints based on the trial protocol in 54 participants (randomly selected, around 10% of the total randomised to radiotherapy, n = 545). These quality assurance processes and results were compared with prostate radiotherapy trials of a comparable era. RESULTS: There has been an increasingly sophisticated quality assurance programme in UK prostate radiotherapy trials over the last 15 years, reflecting dose escalation and treatment complexity. In ProtecT, machine dosimetry results were comparable between trial centres and with the UK RT01 trial. The outlining review showed that most deviations were clinically acceptable, although three (1.4%) may have been of clinical significance and were related to outlining of the prostate. Seminal vesicle outlining varied, possibly due to several prostate trials running concurrently with different protocols. Adherence to dose constraints in ProtecT was considered acceptable, with 80% of randomised participants having two or less deviations and planning target volume coverage was excellent. CONCLUSION: The ProtecT trial quality assurance results were satisfactory and comparable with trials of its era. Future trials should aim to standardise treatment protocols and quality assurance programmes where possible to reduce complexities for centres involved in multiple trials.

Integration of copy number and transcriptomics provides risk stratification in prostate cancer: A discovery and validation cohort study.

BACKGROUND: Understanding the heterogeneous genotypes and phenotypes of prostate cancer is fundamental to improving the way we treat this disease. As yet, there are no validated descriptions of prostate cancer subgroups derived from integrated genomics linked with clinical outcome. METHODS: In a study of 482 tumour, benign and germline samples from 259 men with primary prostate cancer, we used integrative analysis of copy number alterations (CNA) and array transcriptomics to identify genomic loci that affect expression levels of mRNA in an expression quantitative trait loci (eQTL) approach, to stratify patients into subgroups that we then associated with future clinical behaviour, and compared with either CNA or transcriptomics alone. FINDINGS: We identified five separate patient subgroups with distinct genomic alterations and expression profiles based on 100 discriminating genes in our separate discovery and validation sets of 125 and 103 men. These subgroups were able to consistently predict biochemical relapse (p = 0.0017 and p = 0.016 respectively) and were further validated in a third cohort with long-term follow-up (p = 0.027). We show the relative contributions of gene expression and copy number data on phenotype, and demonstrate the improved power gained from integrative analyses. We confirm alterations in six genes previously associated with prostate cancer (MAP3K7, MELK, RCBTB2, ELAC2, TPD52, ZBTB4), and also identify 94 genes not previously linked to prostate cancer progression that would not have been detected using either transcript or copy number data alone. We confirm a number of previously published molecular changes associated with high risk disease, including MYC amplification, and NKX3-1, RB1 and PTEN deletions, as well as over-expression of PCA3 and AMACR, and loss of MSMB in tumour tissue. A subset of the 100 genes outperforms established clinical predictors of poor prognosis (PSA, Gleason score), as well as previously published gene signatures (p = 0.0001). We further show how our molecular profiles can be used for the early detection of aggressive cases in a clinical setting, and inform treatment decisions. INTERPRETATION: For the first time in prostate cancer this study demonstrates the importance of integrated genomic analyses incorporating both benign and tumour tissue data in identifying molecular alterations leading to the generation of robust gene sets that are predictive of clinical outcome in independent patient cohorts.

The genomic evolution of human prostate cancer.

Prostate cancers are highly prevalent in the developed world, with inheritable risk contributing appreciably to tumour development. Genomic heterogeneity within individual prostate glands and between patients derives predominantly from structural variants and copy-number aberrations. Subtypes of prostate cancers are being delineated through the increasing use of next-generation sequencing, but these subtypes are yet to be used to guide the prognosis or therapeutic strategy. Herein, we review our current knowledge of the mutational landscape of human prostate cancer, describing what is known of the common mutations underpinning its development. We evaluate recurrent prostate-specific mutations prior to discussing the mutational events that are shared both in prostate cancer and across multiple cancer types. From these data, we construct a putative overview of the genomic evolution of human prostate cancer.

Evaluation of models predicting insignificant prostate cancer to select men for active surveillance of prostate cancer.

BACKGROUND: In an era of personalized medicine, individualized risk assessment using easily available tools on the internet and the literature are appealing. However, uninformed use by clinicians and the public raises potential problems. Herein, we assess the performance of published models to predict insignificant prostate cancer (PCa), using a multi-national low-risk population that may be considered for active surveillance (AS) based on contemporary practice. METHODS: Data on men suitable for AS but undergoing upfront radical prostatectomy were pooled from three international academic institutions in Cambridge (UK), Toronto (Canada) and Melbourne (Australia). Four predictive models identified from literature review were assessed for their ability to predict the presence of four definitions of insignificant PCa. Evaluation was performed using area under the curve (AUC) of receiver operating characteristic curves and Brier scores for discrimination, calibration curves and decision curve analysis. RESULTS: A cohort of 460 men meeting the inclusion criteria of all four nomograms was identified. The highest AUCs calculated for any of the four models ranged from 0.618 to 0.664, suggesting weak positive discrimination at best. Models had best discriminative ability for a definition of insignificant disease characterized by organ-confined Gleason score ⩽6 with a total volume ⩽0.5 ml or 1.3 ml. Calibration plots showed moderate range of predictive ability for the Kattan model though this model did not perform well at decision curve analysis. CONCLUSIONS: External assessment of models predicting insignificant PCa showed moderate performance at best. Uninformed interpretation may cause undue anxiety or false reassurance and they should be used with caution.

Prevalence of the HOXB13 G84E germline mutation in British men and correlation with prostate cancer risk, tumour characteristics and clinical outcomes.

BACKGROUND: A rare recurrent missense variant in HOXB13 (rs138213197/G84E) was recently reported to be associated with hereditary prostate cancer. Population-based studies have established that, since the frequency of this single-nucleotide polymorphism (SNP) varies between geographic regions, the associated proportion of prostate cancer (PrCa) risk contribution is also highly variable by country. PATIENTS AND METHODS: This is the largest comprehensive case-control study assessing the prevalence of the HOXB13 G84E variant to date and is the first in the UK population. We genotyped 8652 men diagnosed with PrCa within the UK Genetic Prostate Cancer Study (UKGPCS) and 5252 healthy men from the UK ProtecT study. RESULTS: HOXB13 G84E was identified in 0.5% of the healthy controls and 1.5% of the PrCa cases, and it was associated with a 2.93-fold increased risk of PrCa [95% confidence interval (CI) 1.94-4.59; P = 6.27 × 10(-8)]. The risk was even higher among men with family history of PrCa [odds ratio (OR) = 4.53, 95% CI 2.86-7.34; P = 3.1 × 10(-8)] and in young-onset PrCa (diagnosed up to the age of 55 years; OR = 3.11, 95% CI 1.98-5.00; P = 6.1 × 10(-7)). There was no significant association between Gleason Score, presenting prostate specific antigen, tumour-node-metastasis (TNM) stage or NCCN risk group and carrier status. HOXB13 G84E was not associated with overall or cancer-specific survival. We found that the polygenic PrCa risk score (PR score), calculated using the 71 known single-nucleotide polymorphisms (SNPs) associated with PrCa and the HOXB13 G84E variant act multiplicatively on PrCa risk. Based on the estimated prevalence and risk, this rare variant explains ∼1% of the familial risk of PrCa in the UK population. CONCLUSIONS: The clinical importance of HOXB13 G84E in PrCa management has not been established. This variant was found to have no effect on prognostic implications but could be used for stratifying screening, by identifying men at high risk. CLINICAL TRIALS NUMBERS: Prostate Testing for Cancer and Treatment (ProtecT): NCT02044172. UK GENETIC PROSTATE CANCER STUDY: Epidemiology and Molecular Genetics Studies (UKGPCS): NCT01737242.

Design and preliminary recruitment results of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP).

BACKGROUND: Screening for prostate cancer continues to generate controversy because of concerns about over-diagnosis and unnecessary treatment. We describe the rationale, design and recruitment of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP) trial, a UK-wide cluster randomised controlled trial investigating the effectiveness and cost-effectiveness of prostate-specific antigen (PSA) testing. METHODS: Seven hundred and eighty-five general practitioner (GP) practices in England and Wales were randomised to a population-based PSA testing or standard care and then approached for consent to participate. In the intervention arm, men aged 50-69 years were invited to undergo PSA testing, and those diagnosed with localised prostate cancer were invited into a treatment trial. Control arm practices undertook standard UK management. All men were flagged with the Health and Social Care Information Centre for deaths and cancer registrations. The primary outcome is prostate cancer mortality at a median 10-year-follow-up. RESULTS: Among randomised practices, 271 (68%) in the intervention arm (198,114 men) and 302 (78%) in the control arm (221,929 men) consented to participate, meeting pre-specified power requirements. There was little evidence of differences between trial arms in measured baseline characteristics of the consenting GP practices (or men within those practices). CONCLUSIONS: The CAP trial successfully met its recruitment targets and will make an important contribution to international understanding of PSA-based prostate cancer screening.

Identification of pathologically insignificant prostate cancer is not accurate in unscreened men.

BACKGROUND: Identification of men harbouring insignificant prostate cancer (PC) is important in selecting patients for active surveillance. Tools have been developed in PSA-screened populations to identify such men based on clinical and biopsy parameters. METHODS: Prospectively collected case series of 848 patients was treated with radical prostatectomy between July 2007 and October 2011 at an English tertiary care centre. Tumour volume was assessed by pathological examination. For each tool, receiver operator characteristics were calculated for predicting insignificant disease by three different criteria and the area under each curve compared. Comparison of accuracy in screened and unscreened populations was performed. RESULTS: Of 848 patients, 415 had Gleason 3+3 disease on biopsy. Of these, 32.0% had extra-prostatic extension and 50.2% were upgraded. One had positive lymph nodes. Two hundred and six (24% of cohort) were D'Amico low risk. Of these, 143 had more than two biopsy cores involved. None of the tools evaluated has adequate discriminative power in predicting insignificant tumour burden. Accuracy is low in PSA-screened and -unscreened populations. CONCLUSIONS: In our unscreened population, tools designed to identify insignificant PC are inaccurate. Detection of a wider size range of prostate tumours in the unscreened may contribute to relative inaccuracy.

N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 is overexpressed in cancer and promotes a pro-migratory and pro-metastatic phenotype.

N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 (NAALADL2) is a member of the glutamate carboxypeptidase II family, best characterized by prostate-specific membrane antigen (PSMA/NAALAD1). Using immunohistochemistry (IHC), we have shown overexpression of NAALADL2 in colon and prostate tumours when compared with benign tissue. In prostate cancer, NAALADL2 expression was associated with stage and Grade, as well as circulating mRNA levels of the NAALADL2 gene. Overexpression of NAALADL2 was shown to predict poor survival following radical prostatectomy. In contrast to PSMA/NAALAD1, NAALADL2 was localized at the basal cell surface where it promotes adhesion to extracellular matrix proteins. Using stable knockdown and overexpression cell lines, we have demonstrated NAALADL2-dependent changes in cell migration, invasion and colony-forming potential. Expression arrays of the knockdown and overexpression cell lines have identified nine genes that co-expressed with NAALADL2, which included membrane proteins and genes known to be androgen regulated, including the prostate cancer biomarkers AGR2 and SPON2. Androgen regulation was confirmed in a number of these genes, although NAALADL2 itself was not found to be androgen regulated. NAALADL2 was also found to regulate levels of Ser133 phosphorylated C-AMP-binding protein (CREB), a master regulator of a number of cellular processes involved in cancer development and progression. In combination, these data suggest that changes in expression of NAALADL2 can impact upon a number of pro-oncogenic pathways and processes, making it a useful biomarker for both diagnosis and prognosis.

Elevated levels of FOXA1 facilitate androgen receptor chromatin binding resulting in a CRPC-like phenotype.

Castration-resistant prostate cancer (CRPC) continues to pose a significant clinical challenge with new generation second-line hormonal therapies affording limited improvement in disease outcome. As the androgen receptor (AR) remains a critical driver in CRPC, understanding the determinants of its transcriptional activity is important for developing new AR-targeted therapies. FOXA1 is a key component of the AR transcriptional complex yet its role in prostate cancer progression and the relationship between AR and FOXA1 are not completely resolved. It is well established that FOXA1 levels are elevated in advanced prostate cancer and metastases. We mimicked these conditions by overexpressing FOXA1 in the androgen-responsive LNCaP prostate cancer cell line and observed a significant increase in AR genomic binding at novel regions that possess increased chromatin accessibility. High levels of FOXA1 resulted in increased proliferation at both sub-optimal and high 5α-dihydrotestosterone (DHT) concentrations. Immunohistochemical staining for FOXA1 in a clinical prostate cancer cohort revealed that high FOXA1 expression is associated with shorter time to biochemical recurrence after radical prostatectomy (hazard ratio (HR) 5.0, 95% confidence interval (CI) 1.2-21.1, P=0.028), positive surgical margins and higher stage disease at diagnosis. The gene expression program that results from FOXA1 overexpression is enriched for PTEN, Wnt and other pathways typically represented in CRPC gene signatures. Together, these results suggest that in an androgen-depleted state, elevated levels of FOXA1 enhance AR binding at genomic regions not normally occupied by AR, which in turn facilitates prostate cancer cell growth.

Peroxiredoxin-3 is overexpressed in prostate cancer and promotes cancer cell survival by protecting cells from oxidative stress.

OBJECTIVE: We have previously identified peroxiredoxin-3 (PRDX-3) as a cell-surface protein that is androgen regulated in the LNCaP prostate cancer (PCa) cell line. PRDX-3 is a member of the peroxiredoxin family that are responsible for neutralising reactive oxygen species. EXPERIMENTAL DESIGN: PRDX-3 expression was examined in tissue from 32 patients using immunohistochemistry. Subcellular distribution was determined using confocal microscopy. PRDX-3 expression was determined in antiandrogen-resistant cell lines by western blotting and quantitative RT-PCR. The pathways of PRDX-3 overexpression and knockdown on apoptosis and response to oxidative stress were investigated using protein arrays. RESULTS: PRDX-3 is upregulated in a number of endocrine-regulated tumours; in particular in PCa and prostatic intraepithelial neoplasia. Although the majority of PRDX-3 is localised to the mitochondria, we have confirmed that PRDX-3 at the cell membrane is androgen regulated. In antiandrogen-resistant LNCaP cell lines, PRDX-3 is upregulated at the protein but not RNA level. Resistant cells also possess an upregulation of the tricarboxylic acid (TCA) pathway and resistance to H2O2-induced apoptosis through a failure to activate pro-apoptotic pathways. Knockdown of PRDX-3 restored H2O2 sensitivity. CONCLUSION: Our results suggest that PRDX-3 has an essential role in regulating oxidation-induced apoptosis in antiandrogen-resistant cells. PRDX-3 may have potential as a therapeutic target in castrate-independent PCa.

Systematic review and economic modelling of the relative clinical benefit and cost-effectiveness of laparoscopic surgery and robotic surgery for removal of the prostate in men with localised prostate cancer.

BACKGROUND: Complete surgical removal of the prostate, radical prostatectomy, is the most frequently used treatment option for men with localised prostate cancer. The use of laparoscopic (keyhole) and robot-assisted surgery has improved operative safety but the comparative effectiveness and cost-effectiveness of these options remains uncertain. OBJECTIVE: This study aimed to determine the relative clinical effectiveness and cost-effectiveness of robotic radical prostatectomy compared with laparoscopic radical prostatectomy in the treatment of localised prostate cancer within the UK NHS. DATA SOURCES: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, BIOSIS, Science Citation Index and Cochrane Central Register of Controlled Trials were searched from January 1995 until October 2010 for primary studies. Conference abstracts from meetings of the European, American and British Urological Associations were also searched. Costs were obtained from NHS sources and the manufacturer of the robotic system. Economic model parameters and distributions not obtained in the systematic review were derived from other literature sources and an advisory expert panel. REVIEW METHODS: Evidence was considered from randomised controlled trials (RCTs) and non-randomised comparative studies of men with clinically localised prostate cancer (cT1 or cT2); outcome measures included adverse events, cancer related, functional, patient driven and descriptors of care. Two reviewers abstracted data and assessed the risk of bias of the included studies. For meta-analyses, a Bayesian indirect mixed-treatment comparison was used. Cost-effectiveness was assessed using a discrete-event simulation model. RESULTS: The searches identified 2722 potentially relevant titles and abstracts, from which 914 reports were selected for full-text eligibility screening. Of these, data were included from 19,064 patients across one RCT and 57 non-randomised comparative studies, with very few studies considered at low risk of bias. The results of this study, although associated with some uncertainty, demonstrated that the outcomes were generally better for robotic than for laparoscopic surgery for major adverse events such as blood transfusion and organ injury rates and for rate of failure to remove the cancer (positive margin) (odds ratio 0.69; 95% credible interval 0.51 to 0.96; probability outcome favours robotic prostatectomy = 0.987). The predicted probability of a positive margin was 17.6% following robotic prostatectomy compared with 23.6% for laparoscopic prostatectomy. Restriction of the meta-analysis to studies at low risk of bias did not change the direction of effect but did decrease the precision of the effect size. There was no evidence of differences in cancer-related, patient-driven or dysfunction outcomes. The results of the economic evaluation suggested that when the difference in positive margins is equivalent to the estimates in the meta-analysis of all included studies, robotic radical prostatectomy was on average associated with an incremental cost per quality-adjusted life-year that is less than threshold values typically adopted by the NHS (£30,000) and becomes further reduced when the surgical capacity is high. LIMITATIONS: The main limitations were the quantity and quality of the data available on cancer-related outcomes and dysfunction. CONCLUSIONS: This study demonstrated that robotic prostatectomy had lower perioperative morbidity and a reduced risk of a positive surgical margin compared with laparoscopic prostatectomy although there was considerable uncertainty. Robotic prostatectomy will always be more costly to the NHS because of the fixed capital and maintenance charges for the robotic system. Our modelling showed that this excess cost can be reduced if capital costs of equipment are minimised and by maintaining a high case volume for each robotic system of at least 100-150 procedures per year. This finding was primarily driven by a difference in positive margin rate. There is a need for further research to establish how positive margin rates impact on long-term outcomes. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

International multicentre study examining selection criteria for active surveillance in men undergoing radical prostatectomy.

BACKGROUND: The controversies concerning possible overtreatment of prostate cancer, highlighted by debate over PSA screening, have highlighted active surveillance (AS) as an alternative management option for appropriate men. Regional differences in the underlying prevalence of PSA testing may alter the pre-test probability for high-risk disease, which can potentially interfere with the performance of selection criteria for AS. In a multicentre study from three different countries, we examine men who were initially suitable for AS according to the Toronto and Prostate Cancer Research International: Active Surveillance (PRIAS) criteria, that underwent radical prostatectomy (RP) in regards to:1.the proportion of pathological reclassification(Gleason score ≥7, ≥pT3 disease),2.predictors of high-risk disease,3.create a predictive model to assist with selection of men suitable for AS. METHODS: From three centres in the United Kingdom, Canada and Australia, data on men who underwent RP were retrospectively reviewed (n=2329). Multivariable logistic regression was performed to identify predictors of high-risk disease. A nomogram was generated by logistic regression analysis, and performance characterised by receiver operating characteristic curves. RESULTS: For men suitable for AS according to the Toronto (n=800) and PRIAS (410) criteria, the rates for upgrading were 50.6, 42.7%, and upstaging 17.6, 12.4%, respectively. Significant predictors of high-risk disease were:•Toronto criteria: increasing age, cT2 disease, centre of diagnosis and number of positive cores.•PRIAS criteria: increasing PSA and cT2 disease.Cambridge had a high pT3a rate (26 vs 12%). To assist selection of men in the United Kingdom for AS, from the Cambridge data, we generated a nomogram predicting high-risk features in patients who meet the Toronto criteria (AUC of 0.72). CONCLUSION: The proportion of pathological reclassification in our cohort was higher than previously reported. Care must be used when applying the AS criteria generated from one population to another. With more stringent selection criteria, there is less reclassification but also fewer men who may benefit from AS.

Diagnosis of bladder cancer by immunocytochemical detection of minichromosome maintenance protein-2 in cells retrieved from urine.

BACKGROUND: We tested the accuracy of immunocytochemistry (ICC) for minichromosome maintenance protein-2 (MCM-2) in diagnosing bladder cancer, using cells retrieved from urine. METHODS: Adequate samples were obtained from 497 patients, the majority presenting with gross haematuria (GH) or undergoing cystoscopic surveillance (CS) following previous bladder cancer. We performed an initial study of 313 patients, followed by a validation study of 184 patients. In all cases, presence/absence of bladder cancer was established by cystoscopy/biopsy. RESULTS: In the initial study, receiver operator characteristic analysis showed an area under the curve of 0.820 (P<0.0005) for the GH group and 0.821 (P<0.01) for the CS group. Optimal sensitivity/specificity were provided by threshold values of 50+ MCM-2-positive cells in GH samples and 200+ cells in CS samples, based on a minimum total cell number of 5000. Applying these thresholds to the validation data set gave 81.3% sensitivity, 76.0% specificity and 92.7% negative predictive value (NPV) in GH and 63.2% sensitivity, 89.9% specificity and 89.9% NPV in CS. Minichromosome maintenance protein-2 ICC provided clinically relevant improvements over urine cytology, with greater sensitivity in GH and greater specificity in CS (P=0.05). CONCLUSIONS: Minichromosome maintenance protein-2 ICC is a reproducible and accurate test that is suitable for both GH and CS patient groups.