James Catto

Epidemiology and Risk Factors of Urothelial Bladder Cancer

CONTEXT Urothelial bladder cancer (UBC) is a disease of significant morbidity and mortality. It is important to understand the risk factors of this disease. OBJECTIVE To describe the incidence, prevalence, and mortality of UBC and to review and interpret the current evidence on and impact of the related risk factors. EVIDENCE ACQUISITION A literature search in English was performed using PubMed. Relevant papers on the epidemiology of UBC were selected. EVIDENCE SYNTHESIS UBC is the 7th most common cancer worldwide in men and the 17th most common cancer worldwide in women. Approximately 75% of newly diagnosed UBCs are noninvasive. Each year, approximately 110 500 men and 70 000 women are diagnosed with new cases and 38 200 patients in the European Union and 17 000 US patients die from UBC. Smoking is the most common risk factor and accounts for approximately half of all UBCs. Occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons are other important risk factors. The impact of diet and environmental pollution is less evident. Increasing evidence suggests a significant influence of genetic predisposition on incidence. CONCLUSIONS UBC is a frequently occurring malignancy with a significant impact on public health and will remain so because of the high prevalence of smoking. The importance of primary prevention must be stressed, and smoking cessation programs need to be encouraged and supported.

10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer

BACKGROUND The comparative effectiveness of treatments for prostate cancer that is detected by prostate-specific antigen (PSA) testing remains uncertain. METHODS We compared active monitoring, radical prostatectomy, and external-beam radiotherapy for the treatment of clinically localized prostate cancer. Between 1999 and 2009, a total of 82,429 men 50 to 69 years of age received a PSA test; 2664 received a diagnosis of localized prostate cancer, and 1643 agreed to undergo randomization to active monitoring (545 men), surgery (553), or radiotherapy (545). The primary outcome was prostate-cancer mortality at a median of 10 years of follow-up. Secondary outcomes included the rates of disease progression, metastases, and all-cause deaths. RESULTS There were 17 prostate-cancer-specific deaths overall: 8 in the active-monitoring group (1.5 deaths per 1000 person-years; 95% confidence interval [CI], 0.7 to 3.0), 5 in the surgery group (0.9 per 1000 person-years; 95% CI, 0.4 to 2.2), and 4 in the radiotherapy group (0.7 per 1000 person-years; 95% CI, 0.3 to 2.0); the difference among the groups was not significant (P=0.48 for the overall comparison). In addition, no significant difference was seen among the groups in the number of deaths from any cause (169 deaths overall; P=0.87 for the comparison among the three groups). Metastases developed in more men in the active-monitoring group (33 men; 6.3 events per 1000 person-years; 95% CI, 4.5 to 8.8) than in the surgery group (13 men; 2.4 per 1000 person-years; 95% CI, 1.4 to 4.2) or the radiotherapy group (16 men; 3.0 per 1000 person-years; 95% CI, 1.9 to 4.9) (P=0.004 for the overall comparison). Higher rates of disease progression were seen in the active-monitoring group (112 men; 22.9 events per 1000 person-years; 95% CI, 19.0 to 27.5) than in the surgery group (46 men; 8.9 events per 1000 person-years; 95% CI, 6.7 to 11.9) or the radiotherapy group (46 men; 9.0 events per 1000 person-years; 95% CI, 6.7 to 12.0) (P<0.001 for the overall comparison). CONCLUSIONS At a median of 10 years, prostate-cancer-specific mortality was low irrespective of the treatment assigned, with no significant difference among treatments. Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring. (Funded by the National Institute for Health Research; ProtecT Current Controlled Trials number, ISRCTN20141297 ; ClinicalTrials.gov number, NCT02044172 .).

Changes in circulating microRNA levels associated with prostate cancer

Background:The aim of this study was to investigate the hypothesis that changes in circulating microRNAs (miRs) represent potentially useful biomarkers for the diagnosis, staging and prediction of outcome in prostate cancer.Methods:Real-time polymerase chain reaction analysis of 742 miRs was performed using plasma-derived circulating microvesicles of 78 prostate cancer patients and 28 normal control individuals to identify differentially quantified miRs.Results:A total of 12 miRs were differentially quantified in prostate cancer patients compared with controls, including 9 in patients without metastases. In all, 11 miRs were present in significantly greater amounts in prostate cancer patients with metastases compared with those without metastases. The association of miR-141 and miR-375 with metastatic prostate cancer was confirmed using serum-derived exosomes and microvesicles in a separate cohort of patients with recurrent or non-recurrent disease following radical prostatectomy. An analysis of five selected miRs in urine samples found that miR-107 and miR-574-3p were quantified at significantly higher concentrations in the urine of men with prostate cancer compared with controls.Conclusion:These observations suggest that changes in miR concentration in prostate cancer patients may be identified by analysing various body fluids. Moreover, circulating miRs may be used to diagnose and stage prostate cancer.

Systematic Review of Complications of Prostate Biopsy

CONTEXT Prostate biopsy is commonly performed for cancer detection and management. The benefits and risks of prostate biopsy are germane to ongoing debates about prostate cancer screening and treatment. OBJECTIVE To perform a systematic review of complications from prostate biopsy. EVIDENCE ACQUISITION A literature search was performed using PubMed and Embase, supplemented with additional references. Articles were reviewed for data on the following complications: hematuria, rectal bleeding, hematospermia, infection, pain, lower urinary tract symptoms (LUTS), urinary retention, erectile dysfunction, and mortality. EVIDENCE SYNTHESIS After biopsy, hematuria and hematospermia are common but typically mild and self-limiting. Severe rectal bleeding is uncommon. Despite antimicrobial prophylaxis, infectious complications are increasing over time and are the most common reason for hospitalization after biopsy. Pain may occur at several stages of prostate biopsy and can be mitigated by anesthetic agents and anxiety-reduction techniques. Up to 25% of men have transient LUTS after biopsy, and <2% have frank urinary retention, with slightly higher rates reported after transperineal template biopsy. Biopsy-related mortality is rare. CONCLUSIONS Preparation for biopsy should include antimicrobial prophylaxis and pain management. Prostate biopsy is frequently associated with minor bleeding and urinary symptoms that usually do not require intervention. Infectious complications can be serious, requiring prompt management and continued work into preventative strategies.

MicroRNA in prostate, bladder, and kidney cancer: A systematic review

CONTEXT MicroRNAs (miRNA) are noncoding RNAs that post-transcriptionally regulate gene expression. Their altered expression and function have been observed in most urologic cancers. MiRNAs represent potential disease biomarkers and novel therapeutic targets. OBJECTIVE To review and evaluate the evidence implicating miRNAs in the pathogenesis of prostate cancer (PCa), bladder cancer (BCa), and renal cancer. EVIDENCE ACQUISITION A systematic review was performed using PubMed and Embase to search for reports using strings for microRNA, non-coding RNA, cancer, prostate, bladder, and renal cancer. Identified manuscripts were retrieved and references searched. Selected studies were required to concentrate on the role of miRNA in these urologic cancers. EVIDENCE SYNTHESIS We reviewed articles that focus on this topic. More than 40 miRNAs have been implicated in urologic cancer and many target common carcinogenic pathways. In particular, apoptosis avoidance, cell proliferation, epithelial-to-mesenchymal transition, angiogenic signalling, and the generation of androgen independence are targeted or facilitated by more than one miRNA. Little work has been done to evaluate the translational applications for this knowledge to date. Novel therapeutic strategies have been developed and are under investigation to selectively modulate miRNAs; such work would potentially enable personalised tumour therapy. CONCLUSIONS MiRNAs appear to be important modulators of urologic cancer. Their expression is frequently altered in these tumours, and many are functionally implicated in their pathogenesis. They require evaluation to determine the translational role and therapeutic potential for this knowledge.

Promoter hypermethylation is associated with tumor location, stage, and subsequent progression in transitional cell carcinoma.

PURPOSE Transitional cell carcinoma (TCC) is a pan-urothelial disease characterized by multiplicity. Although little is known about the molecular events in upper-tract TCC, similar carcinogenic mechanisms are thought to occur throughout the urinary tract. However, we have previously shown that distinct patterns of microsatellite instability occur in upper and lower urinary tract TCC, suggesting biologic differences between these tumors. Here we investigate the extent of promoter hypermethylation in TCC throughout the urinary tract. PATIENTS AND METHODS Tissue was obtained from 280 patients (median follow-up, 56 months) whose tumors comprised 116 bladder and 164 upper-tract tumors (UTT). Analysis for hypermethylation at 11 CpG islands, using methylation-sensitive polymerase chain reaction and bisulfite sequencing, was performed for each sample and compared with the tumors clinicopathologic details, microsatellite instability status, and subsequent behavior. RESULTS Promoter methylation was present in 86% of TCC and occurred both more frequently and more extensively in UTT (94%) than in bladder tumors (76%; P < .0001). Methylation was associated with advanced tumor stage (P = .0001) and higher tumor progression (P = .03) and mortality rates (P = .04), when compared with tumors without methylation. Multivariate analysis revealed that methylation at the RASSF1A and DAPK loci, in addition to tumor stage and grade, were associated with disease progression (P < .04). CONCLUSION Despite morphologic similarities, there are genetic and epigenetic differences between TCC in the upper and lower urinary tracts. Methylation occurs commonly in urinary tract tumors, may affect carcinogenic mechanisms, and is a prognostic marker and a potential therapeutic target.

Distinct MicroRNA Alterations Characterize High- and Low-Grade Bladder Cancer

Urothelial carcinoma of the bladder (UCC) is a common disease that arises by at least two different molecular pathways. The biology of UCC is incompletely understood, making the management of this disease difficult. Recent evidence implicates a regulatory role for microRNA in cancer. We hypothesized that altered microRNA expression contributes to UCC carcinogenesis. To test this hypothesis, we examined the expression of 322 microRNAs and their processing machinery in 78 normal and malignant urothelial samples using real-time rtPCR. Genes targeted by differentially expressed microRNA were investigated using real-time quantification and microRNA knockdown. We also examined the role of aberrant DNA hypermethylation in microRNA downregulation. We found that altered microRNA expression is common in UCC and occurs early in tumorogenesis. In normal urothelium from patients with UCC, 11% of microRNAs had altered expression when compared with disease-free controls. This was associated with upregulation of Dicer, Drosha, and Exportin 5. In UCC, microRNA alterations occur in a tumor phenotype-specific manner and can predict disease progression. High-grade UCC were characterized by microRNA upregulation, including microRNA-21 that suppresses p53 function. In low-grade UCC, there was downregulation of many microRNA molecules. In particular, loss of microRNAs-99a/100 leads to upregulation of FGFR3 before its mutation. Promoter hypermethylation is partly responsible for microRNA downregulation. In conclusion, distinct microRNA alterations characterize UCC and target genes in a pathway-specific manner. These data reveal new insights into the disease biology and have implications regarding tumor diagnosis, prognosis and therapy.

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 .).

Short term outcomes of prostate biopsy in men tested for cancer by prostate specific antigen: prospective evaluation within ProtecT study.

Objectives To measure the effect of the adverse events within 35 days of transrectal ultrasound guided biopsy from the perspective of asymptomatic men having prostate specific antigen (PSA) testing; to assess early attitude to re-biopsy; to estimate healthcare resource use associated with adverse events due to biopsy; and to develop a classification scheme for reporting adverse events after prostate biopsy. Design Prospective cohort study (Prostate Biopsy Effects: ProBE) nested within Prostate Testing for Cancer and Treatment (ProtecT) study. Participants Between 1999 and 2008, 227 000 community dwelling men aged 5069 years were identified at 352 practices and invited to counselling about PSA testing. 111 148 attended a nurse led clinic in the community, and 10 297 with PSA concentrations of 3-20 ng/mL were offered biopsy within ProtecT. Between February 2006 and May 2008, 1147/1753 (65%) eligible men (mean age 62.1 years, mean PSA 5.4 ng/mL) having 10 core transrectal ultrasound guided biopsy under antibiotic cover in the context of ProtecT were recruited to the ProBE study. Outcome measures Purpose designed questionnaire administered at biopsy and 7 and 35 days after the procedure to measure frequency and effect of symptoms related to pain, infection, and bleeding; patients’ attitude to repeat biopsy assessed immediately after biopsy and 7 days later; participants’ healthcare resource use within 35 days of biopsy evaluated by questionnaire, telephone follow-up, and medical note review; each man’s adverse event profile graded according to symptoms and healthcare use. Results Pain was reported by 429/984 (43.6%), fever by 172/985 (17.5%), haematuria by 642/976 (65.8%), haematochezia by 356/967 (36.8%), and haemoejaculate by 605/653 (92.6%) men during the 35 days after biopsy. Fewer men rated these symptoms as a major/moderate problem—71/977 (7.3%) for pain, 54/981 (5.5%) for fever, 59/958 (6.2%) for haematuria, 24/951 (2.5%) for haematochezia, and 172/646 (26.6%) for haemoejaculate. Immediately after biopsy, 124/1142 (10.9%, 95% confidence interval 9.2 to 12.8) men reported that they would consider further biopsy a major or moderate problem: seven days after biopsy, this proportion had increased to 213/1085 (19.6%, 17.4% to 22.1%). A negative attitude to repeat biopsy was associated with unfavourable experience after the first biopsy, particularly pain at biopsy (odds ratio 8.2, P<0.001) and symptoms related to infection (7.9, P<0.001) and bleeding (4.2, P<0.001); differences were evident between centres (P<0.001). 119/1147 (10.4%, 8.7% to 12.3%) men reported consultation with a healthcare professional (usually their general practitioner), most commonly for infective symptoms. Complete data for all index symptoms at all time points were available in 851 participants. Symptoms and healthcare use could be used to grade these men as follows: grade 0 (no symptoms/contact) 18 (2.1%, 1.3% to 3.3%); grade 1 (minor problem/no contact) 550 (64.6%, 61.4% to 67.8%); grade 2 (moderate/major problem or contact) 271 (31.8%, 28.8% to 35.1%); grade 3 (hospital admission) 12 (1.4%, 0.8% to 2.4%); and grade 4 (death) 0. Grade of adverse event was associated with an unfavourable attitude to repeat biopsy (Kendall’s τ-b ordinal by ordinal 0.29, P<0.001). Conclusion This study with a high response rate of 89% at 35 days in men undergoing biopsy in the context of a randomised controlled trial has shown that although prostate biopsy is well tolerated by most men, it is associated with significant symptoms in a minority and affects attitudes to repeat biopsy and primary care resource use. These findings will inform men who seek PSA testing for detection of prostate cancer and assist their physicians during counselling about the potential risks and effect of biopsy. Variability in the adverse event profile between centres suggests that patients’ outcomes could be improved and healthcare use reduced with more effective administration of local anaesthetic and antibiotics. Trial registration Current Controlled Trials ISRCTN20141297.

Epigenetics in Prostate Cancer: Biologic and Clinical Relevance

CONTEXT Prostate cancer (PCa) is one of the most common human malignancies and arises through genetic and epigenetic alterations. Epigenetic modifications include DNA methylation, histone modifications, and microRNAs (miRNA) and produce heritable changes in gene expression without altering the DNA coding sequence. OBJECTIVE To review progress in the understanding of PCa epigenetics and to focus upon translational applications of this knowledge. EVIDENCE ACQUISITION PubMed was searched for publications regarding PCa and DNA methylation, histone modifications, and miRNAs. Reports were selected based on the detail of analysis, mechanistic support of data, novelty, and potential clinical applications. EVIDENCE SYNTHESIS Aberrant DNA methylation (hypo- and hypermethylation) is the best-characterized alteration in PCa and leads to genomic instability and inappropriate gene expression. Global and locus-specific changes in chromatin remodeling are implicated in PCa, with evidence suggesting a causative dysfunction of histone-modifying enzymes. MicroRNA deregulation also contributes to prostate carcinogenesis, including interference with androgen receptor signaling and apoptosis. There are important connections between common genetic alterations (eg, E twenty-six fusion genes) and the altered epigenetic landscape. Owing to the ubiquitous nature of epigenetic alterations, they provide potential biomarkers for PCa detection, diagnosis, assessment of prognosis, and post-treatment surveillance. CONCLUSIONS Altered epigenetic gene regulation is involved in the genesis and progression of PCa. Epigenetic alterations may provide valuable tools for the management of PCa patients and be targeted by pharmacologic compounds that reverse their nature. The potential for epigenetic changes in PCa requires further exploration and validation to enable translation to the clinic.