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ABSTRACT: PURPOSE: To determine the risk of disease specific mortality (DSM) in patients with primary low-risk non-invasive (G1pTa) bladder cancer. To compare this to DSM for age and gender matched general populations. PATIENTS AND METHODS: We identified all patients with primary low-risk cancer at our institution. We excluded those with adverse pathological features and matched histopathology, pharmacy, hospital episode and Cancer Registry records. We reviewed case notes for patients with subsequent muscle invasion (progression) or DSM. Patients underwent post-resection surveillance and treatment using standard regimens. The national and regional DSM rates were calculated from appropriate data. RESULTS: In total, 699 patients met our inclusion criteria (median follow up 61 months (IQ range 24-105)). Seventeen patients (2.4%) died from bladder cancer, including 13/14 that progressed to muscle invasion and 4/19 with grade-progression to high-grade non-muscle invasive disease. Low-grade dysplasia in the initial resection specimen and tumor weight were associated with DSM (Cox regression analyses p<0.003). DSM in these patients was 5 times the background rate for matched populations. Limitations to this study include its retrospective nature and the low frequency of adverse events. CONCLUSIONS: Patients with low risk bladder cancer rarely progress to muscle invasion but do have a higher risk of DSM than the general population. Current surveillance regimens appeared ineffective in detecting progression in time to alter prognosis.
The Journal of urology 09/2012; · 4.02 Impact Factor
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ABSTRACT: PURPOSE: Upper urinary tract urothelial carcinoma (UTUC) shares many similarities with bladder-UC, but there is strong evidence on a clinical, aetiological, epidemiological and genetic level that key differences exist. In this review, we aim to highlight how UTUC differs from bladder-UC and report on the utility of molecular markers in the diagnosis and management of UTUC. MATERIALS AND METHODS: A systematic literature search was conducted using the Medline and Embase databases and specific keyword combinations: 'urothelial carcinoma', 'bladder cancer', 'transitional cell carcinoma', 'upper tract', 'upper urinary tract', 'genetics', 'prognosis' and 'biomarkers'. RESULTS: UTUC has specific acquired (e.g. Balkans nephropathy, phenacetin abuse) and genetic hereditary non-polyposis colorectal cancer risk factors compared with bladder-UC. In general, the molecular biology of UC is broadly similar, irrespective of location in the urinary tract. However, there are distinct genetic (microsatellite instability) and epigenetic (hypermethylation) differences between some UTUC and bladder-UC. Clinical-pathological variables (e.g. hydronephrosis, tumour architecture, tumour location, stage and grade) have independent predictive power in UTUC, but tissue and urinary biomarkers can improve the clinical prediction of recurrence, invasion and survival in UTUC, though the evidence level is weak. CONCLUSIONS: UTUC shares many similarities with bladder-UC, but there is strong evidence that they should be considered as distinct urothelial entities. Prospective multi-institutional studies investigating molecular markers are urgently needed to augment clinic-pathological predictors in UTUC.
World Journal of Urology 09/2012; · 2.41 Impact Factor
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ABSTRACT: BACKGROUND: The treatment of high-risk non-muscle-invasive bladder cancer (BCa) is problematic given the variable natural history of the disease. Few reports have compared outcomes for primary high-risk tumours with those that develop following previous BCas (relapses). The latter represent a self-selected cohort, having failed previous treatments. OBJECTIVE: To compare outcomes in patients with primary, progressive, and recurrent high-risk non-muscle-invasive BCa. DESIGN, SETTING, AND PARTICIPANTS: We identified all patients with primary and relapsing high-risk BCa tumours at our institution since 1994. Relapses were divided into progressive (previous low- or intermediate-risk disease) and recurrent (previous high-risk disease) cancers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships with outcome analysed using multivariable Cox regression and log-rank analysis. RESULTS AND LIMITATIONS: We identified 699 primary, 110 progressive, and 494 recurrent high-risk BCa tumours in 809 patients (average follow-up: 59 mo [interquartile range: 6-190]). Muscle invasion occurred most commonly in recurrent (23%) tumours, when compared to progressive (20%) and primary (14.6%) cohorts (log rank p<0.001). Disease-specific mortality (DSM) occurred more frequently in patients with recurrent (25.5%) and progressive (24.6%) tumours compared to primary disease (19.2%; log rank p=0.006). Other-cause mortality was similar in all groups (log rank p=0.57), and overall mortality was highest in the progressive cohort (62%) compared with the recurrent (58%) and primary groups (54%; log rank p<0.001). In multivariable analysis, progression and DSM were predicted by tumour grouping (hazard ratio [HR]: >1.15; p<0.026), stage (HR: >1.30; p<0.001), and patient age and sex (HR: >1.03; p<0.037). Carcinoma in situ was only predictive of outcome in primary tumors. Limitations include retrospective design and limited details regarding bacillus Camille-Guérin use. CONCLUSIONS: Patients with relapsing, high-risk, BCa tumors have higher progression, DSM, and overall mortality rates than those with primary cancers. The use of bladder-sparing strategies in these patients should approached cautiously. Carcinoma in situ has little predicative role in relapsing, high-risk, BCa tumors.
European urology 09/2012; · 7.67 Impact Factor
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ABSTRACT: BACKGROUND: The treatment of high-risk nonmuscle-invasive bladder cancer (NMIBC) is difficult given its unpredictable natural history and patient comorbidities. Because current case series are mostly limited in size, the authors report the outcomes from a large, single-center series. METHODS: The authors reviewed all patients with primary, high-risk NMIBC at their institution from 1994 to 2010. Outcomes were matched with clinicopathologic data. Patients who had muscle invasion within 6 months or had insufficient follow-up (<6 months) were excluded. Correlations were analyzed using multivariable Cox regression and log-rank analysis (2-sided; P < .05). RESULTS: In total, 712 patients (median age, 73.7 years) were included. Progression to muscle invasion occurred in 110 patients (15.8%; 95% confidence interval [CI], 13%-18.3%) at a median of 17.2 months (interquartile range, 8.9-35.8 months), including 26.5% (95% CI, 22.2%-31.3%) of the 366 patients who had >5 years follow-up. Progression was associated with age (hazard ratio [HR], 1.04; P = .007), dysplastic urothelium (HR, 1.6; P = .003), urothelial cell carcinoma variants (HR, 3.2; P = .001), and recurrence (HR, 18.3; P < .001). Disease-specific mortality occurred in 134 patients (18.8%; 95% CI, 16.1%-21.9%) at a median of 28 months (interquartile range, 15-45 months), including 28.7% (95% CI, 24.5%-33.3%) of those who had 5 years of follow-up. Disease-specific mortality was associated with age (HR, 1.1; P < .001), stage (HR, 1.7; P = .003), dysplasia (HR, 1.3; P = .05), and progression (HR, 5.2; P < .001). Neither progression nor disease-specific mortality were associated with the receipt of bacillus Calmette-Guerin (P > .6). CONCLUSIONS: Within a program of conservative treatment, progression of high-risk NMIBC was associated with a poor prognosis. Surveillance and bacillus Calmette-Guerin were ineffective in altering the natural history of this disease. The authors concluded that the time has come to rethink the paradigm of management of this disease. Cancer 2012;. © 2012 American Cancer Society.
Cancer 04/2012; · 4.77 Impact Factor
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European urology 03/2012; 62(1):76-7. · 7.67 Impact Factor
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The Journal of urology 02/2012; 187(4):1155-6. · 4.02 Impact Factor
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Derek J Rosario,
J Athene Lane,
Chris Metcalfe,
Jenny L Donovan,
Andy Doble,
Louise Goodwin,
Michael Davis, James W F Catto,
Kerry Avery,
David E Neal,
Freddie C Hamdy
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ABSTRACT: 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.
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 50-69 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.
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.
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).
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.
BMJ (Clinical research ed.). 01/2012; 344:d7894.
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European urology 10/2011; 60(4):867. · 7.67 Impact Factor
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European urology 07/2011; 60(5):917-9. · 7.67 Impact Factor
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James W F Catto
European urology 07/2011; 60(1):37-8. · 7.67 Impact Factor
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James W F Catto
European urology 07/2011; 60(1):16-8; discussion 19-20. · 7.67 Impact Factor
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James W F Catto
European urology 02/2011; 59(5):719-20. · 7.67 Impact Factor
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James W F Catto,
Antonio Alcaraz,
Anders S Bjartell,
Ralph De Vere White,
Christopher P Evans,
Susanne Fussel,
Freddie C Hamdy,
Olli Kallioniemi,
Lourdes Mengual,
Thorsten Schlomm,
Tapio Visakorpi
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ABSTRACT: 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.
To review and evaluate the evidence implicating miRNAs in the pathogenesis of prostate cancer (PCa), bladder cancer (BCa), and renal cancer.
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.
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.
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.
European urology 02/2011; 59(5):671-81. · 7.67 Impact Factor
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ABSTRACT: Epigenetic gene regulation is important in human cancer. Both functional and observational data implicate alterations of histone modifications, DNA promoter methylation, and non-coding RNA expression in carcinogenic roles. We sought to explore the role of aberrant DNA hypermethylation in the regulation of microRNA (miR) expression in human cancer. From human genome databases we calculated that 13 and 28% of human miR genes are located within 3 and 10 kb of a CpG island, respectively. To identify miRs that are regulated by epigenetic mechanisms in cancer, we performed expression profiling prior to and following treatment of cell lines with 5-azacytidine. We used oligonucleotide microarrays to determine miR expression. For miRs whose expression changed following 5-azacytidine treatment, we sequenced the adjacent CpG island and promoter using bisulphite-treated DNA. Here, we describe these methods to enable other researchers to use this approach.
Methods in molecular biology (Clifton, N.J.) 01/2011; 676:165-84.
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BJU International 09/2010; 106(5):593-4. · 2.84 Impact Factor
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European urology 12/2009; · 7.67 Impact Factor
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James W F Catto,
Maysam F Abbod,
Peter J Wild,
Derek A Linkens,
Christian Pilarsky,
Ishtiaq Rehman,
Derek J Rosario,
Stefan Denzinger,
Maximilian Burger,
Robert Stoehr,
Ruth Knuechel,
Arndt Hartmann,
Freddie C Hamdy
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ABSTRACT: New methods for identifying bladder cancer (BCa) progression are required. Gene expression microarrays can reveal insights into disease biology and identify novel biomarkers. However, these experiments produce large datasets that are difficult to interpret.
To develop a novel method of microarray analysis combining two forms of artificial intelligence (AI): neurofuzzy modelling (NFM) and artificial neural networks (ANN) and validate it in a BCa cohort.
We used AI and statistical analyses to identify progression-related genes in a microarray dataset (n=66 tumours, n=2800 genes). The AI-selected genes were then investigated in a second cohort (n=262 tumours) using immunohistochemistry.
We compared the accuracy of AI and statistical approaches to identify tumour progression.
AI identified 11 progression-associated genes (odds ratio [OR]: 0.70; 95% confidence interval [CI], 0.56-0.87; p=0.0004), and these were more discriminate than genes chosen using statistical analyses (OR: 1.24; 95% CI, 0.96-1.60; p=0.09). The expression of six AI-selected genes (LIG3, FAS, KRT18, ICAM1, DSG2, and BRCA2) was determined using commercial antibodies and successfully identified tumour progression (concordance index: 0.66; log-rank test: p=0.01). AI-selected genes were more discriminate than pathologic criteria at determining progression (Cox multivariate analysis: p=0.01). Limitations include the use of statistical correlation to identify 200 genes for AI analysis and that we did not compare regression identified genes with immunohistochemistry.
AI and statistical analyses use different techniques of inference to determine gene-phenotype associations and identify distinct prognostic gene signatures that are equally valid. We have identified a prognostic gene signature whose members reflect a variety of carcinogenic pathways that could identify progression in non-muscle-invasive BCa.
European urology 11/2009; 57(3):398-406. · 7.67 Impact Factor
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James W F Catto,
Saiful Miah,
Helen C Owen,
Helen Bryant,
Katie Myers,
Ewa Dudziec,
Stéphane Larré,
Marta Milo,
Ishtiaq Rehman,
Derek J Rosario,
Erica Di Martino,
Margaret A Knowles,
Mark Meuth,
Adrian L Harris,
Freddie C Hamdy
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ABSTRACT: 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.
Cancer Research 11/2009; 69(21):8472-81. · 7.86 Impact Factor
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James W F Catto
European urology 07/2009; 55(6):1487-8. · 7.67 Impact Factor
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ABSTRACT: Bladder cancer recurrence occurs in 40% of patients following radical cystectomy (RC) and pelvic lymphadenectomy (PLND). Although recurrence can be reduced with adjuvant chemotherapy, the toxicity and low response rates of this treatment restrict its use to patients at highest risk. We developed a neurofuzzy model (NFM) to predict disease recurrence following RC and PLND in patients who are not usually administered adjuvant chemotherapy.
The study comprised 1,034 patients treated with RC and PLND for bladder urothelial carcinoma. Four hundred twenty-five patients were excluded due to lymph node metastases and/or administration of chemotherapy. For the remaining 609 patients, we obtained complete clinicopathologic data relating to their tumor. We trained, tested, and validated two NFMs that predicted risk (Classifier) and timing (Predictor) of post-RC recurrence. We measured the accuracy of our model at various postoperative time points.
Cancer recurrence occurred in 172 (28%) patients. With a median follow-up of 72.7 months, our Classifier NFM identified recurrence with an accuracy of 0.84 (concordance index 0.92, sensitivity 0.81, and specificity 0.85) and an excellent calibration. This was better than two predictive nomograms (0.72 and 0.74 accuracies). The Predictor NFMs identified the timing of tumor recurrence with a median error of 8.15 months.
We have developed an accurate and well-calibrated model to identify disease recurrence following RC and PLND in patients with nonmetastatic bladder urothelial carcinoma. It seems superior to other available predictive methods and could be used to identify patients who would potentially benefit from adjuvant chemotherapy.
Clinical Cancer Research 04/2009; 15(9):3150-5. · 7.74 Impact Factor
