• Reflections on attempted Anglo-Japanese collaboration on STAMPEDE: a randomized controlled trial for men with prostate cancer.

      Sydes, M R; Egawa, S; Sanders, K; Amos, C; Clarke, Noel W; Kimura, T; James, N D; Cancer Group, Medical Research Council Clinical Trials Unit, London (2011-08)
    • Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma.

      Morris, M R; Ricketts, C J; Gentle, D; McRonald, F; Carli, N; Khalili, H; Brown, Michael D; Kishida, T; Yao, M; Banks, R E; Clarke, Noel W; Latif, F; Maher, E R; Cancer Research UK Renal Molecular Oncology Group, University of Birmingham, Birmingham, UK. (2011-03-24)
      The detection of promoter region hypermethylation and transcriptional silencing has facilitated the identification of candidate renal cell carcinoma (RCC) tumour suppressor genes (TSGs). We have used a genome-wide strategy (methylated DNA immunoprecipitation (MeDIP) and whole-genome array analysis in combination with high-density expression array analysis) to identify genes that are frequently methylated and silenced in RCC. MeDIP analysis on 9 RCC tumours and 3 non-malignant normal kidney tissue samples was performed, and an initial shortlist of 56 candidate genes that were methylated by array analysis was further investigated; 9 genes were confirmed to show frequent promoter region methylation in primary RCC tumour samples (KLHL35 (39%), QPCT (19%), SCUBE3 (19%), ZSCAN18 (32%), CCDC8 (35%), FBN2 (34%), ATP5G2 (36%), PCDH8 (58%) and CORO6 (22%)). RNAi knockdown for KLHL35, QPCT, SCUBE3, ZSCAN18, CCDC8 and FBN2 resulted in an anchorage-independent growth advantage. Tumour methylation of SCUBE3 was associated with a significantly increased risk of cancer death or relapse (P=0.0046). The identification of candidate epigenetically inactivated RCC TSGs provides new insights into renal tumourigenesis.
    • Is Population Screening for Prostate Cancer Good or Bad?

      Clarke, Noel W; The Christie and Salford Royal Hospitals, Manchester University, Manchester, UK (2011)
    • Targeted Caval Cytoreduction: Solid Foundations or Shifting Sands?

      Bex, A; Clarke, Noel W; Department of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands (2011)
    • Integrating Surgery with Targeted Therapies for Renal Cell Carcinoma: Maximizing Benefits, Minimizing Risk.

      Clarke, Noel W; The Christie and Salford Royal Hospitals, Manchester University, Manchester, United Kingdom. (2010-09-26)
    • Imaging in primary penile cancer: current status and future directions.

      Kochhar, Rohit; Taylor, Benjamin; Sangar, Vijay K; Department of Radiology, The Christie, NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK. rohit.kochhar@christie.nhs.uk (2010-01)
      Penile cancer is a rare neoplasm in the developed world. Clinical assessment often results in inaccurate staging and radiological techniques have a key role in staging and postoperative assessment. Magnetic resonance imaging (MRI) depicts penile anatomy in detail and is the most accurate technique for local staging and postoperative follow-up. MRI and ultrasound (US), although helpful for assessment of lymph nodes, are not reliable enough for accurate nodal staging. US-guided fine needle aspiration cytology (FNAC), however, remains a valuable tool to confirm metastases in suspicious inguinal nodes. Lymphoscintigraphy with dynamic sentinel node biopsy (DSNB) is a promising technique used to predict occult lymph node metastases. Novel imaging techniques such as positron emission tomography/computed tomography (PET-CT) and nanoparticle enhanced MRI have high sensitivity and specificity for lymph node metastases but their availability is limited and clinical utility is not fully established. The radiologist needs to be familiar with the normal penile anatomy, imaging appearances of pre- and post-treatment penile cancer, and the advantages and limitations of the available imaging techniques. This review highlights the above points and presents a systematic approach to make the best use of imaging in the management of patients with penile cancer.
    • Cd133: a marker of transit amplification rather than stem cell phenotype in the prostate?

      Grey, Benjamin R; Oates, Jeremy E; Brown, Michael D; Clarke, Noel W; Genito-Urinary Cancer Research Group, University of Manchester Paterson Institute for Cancer Research, Manchester, UK. bengrey@doctors.org.uk (2009-04)
    • Testis cancer: the UK as a model.

      Maddineni, Satish B; Clarke, Noel W; Urological Oncology, The Christie Hospital NHS Foundation Trust, Wilmslow Road, M20 4BX, Manchester, England. (2009-04)
      Over the course of the past 30 years progress in identification of risk factors, improvements in therapy regimens and advances in treatment delivery have all served to render testis cancer a treatable and survivable malignancy. Institution of specialised oncology centres in the UK to address treatment options for urological cancers has proven to be an effective approach to managing testis cancer by drawing on interdisciplinary expertise and applying insights gained from ongoing R&D. This strategy could become a model for treating other cancers as well.
    • Systemic therapy for advancing or metastatic prostate cancer (STAMPEDE): a multi-arm, multistage randomized controlled trial.

      James, Nicholas D; Sydes, Matthew R; Clarke, Noel W; Mason, Malcolm D; Dearnaley, David P; Anderson, John; Popert, Richard J; Sanders, Karen; Morgan, Rachel C; Stansfeld, J; Dwyer, John; Masters, John; Parmar, Mahesh K B; CRUK Institute for Cancer Studies, University of Birmingham, UK. (2009-02)
      There is a need to improve the outcomes for men with high-risk localised, nodal or metastatic prostate cancer, or with aggressively relapsing disease after initial therapy for local disease. This group of men is currently managed with long-term hormone therapy. Thus we aim to evaluate the toxicity and efficacy of three different systemic therapies (docetaxel, zoledronic acid and celecoxib) used alone or combined at the initiation of hormone manipulation for high-risk prostate cancer. A novel statistical design (multi-arm, multistage method) simultaneously tests multiple distinct strategies in parallel against a single control arm. The trial has several 'stages', from initial confirmation of safety to a phase III assessment of survival, with a series of intervening activity stages. This method provides a means of assessing several agents more quickly and efficiently, and allows inactive treatments to be dropped from further study at an early stage. STAMPEDE has been designed to address in parallel the activity and efficacy of these agents for this patient group. It is a flagship randomized clinical trial for academic research into prostate cancer in the UK. More than 500 patients have been recruited on schedule, confirming the acceptability of this complex trial design to patients and clinicians. The trial targets a population of approximately 3000 patients. STAMPEDE is a major new trial with a novel design applicable to the synchronous testing of several agents. It is hoped that the results will improve outcomes for patients with high-risk prostate cancer. The design could be applicable to the study of new therapies in other cancer types. Continued efforts are required by the urological cancer community to maintain the excellent recruitment shown to date.
    • Investigating FTIR based histopathology for the diagnosis of prostate cancer.

      Baker, Matthew J; Gazi, Ehsan; Brown, Michael D; Shanks, Jonathan H; Clarke, Noel W; Gardner, Peter; Manchester Interdisciplinary Biocentre, Centre for Instrumentation and Analytical Science, School of Chemical Engineering and Analytical Science, The University of Manchester, 131 Princess Street, Manchester, UK. (2009-02)
      Prostate cancer is the most common gender specific cancer. The current gold standard for diagnosis, histopathology, is subjective and limited by variation between different pathologists. The diagnostic problems associated with the correct grading and staging of prostate cancer (CaP) has led to an interest in the development of spectroscopic based diagnostic techniques. FTIR microspectroscopy used in combination with a Principal Component Discriminant Function Analysis (PC-DFA) was applied to investigate FTIR based histopathology for the diagnosis of CaP. In this paper we report the results of a large patient study in which FTIR has been proven to grade CaP tissue specimens to a high degree of sensitivity and specificity.
    • Molecular mechanisms of metastasis in prostate cancer.

      Clarke, Noel W; Hart, Claire A; Brown, Michael D; 1Genito-Urinary Cancer Research Group, School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, Christie Hospital, University of Manchester, Manchester M20 4BX, UK. (2009-01)
      Prostate cancer (PCa) preferentially metastasizes to the bone marrow stroma of the axial skeleton. This activity is the principal cause of PCa morbidity and mortality. The exact mechanism of PCa metastasis is currently unknown, although considerable progress has been made in determining the key players in this process. In this review, we present the current understanding of the molecular processes driving PCa metastasis to the bone.Asian Journal of Andrology (2009) 11: 57-67. doi: 10.1038/aja.2008.29; published online 1 December 2008.
    • Use of classical and novel biomarkers as prognostic risk factors for localised prostate cancer: a systematic review.

      Sutcliffe, P; Hummel, S; Simpson, E; Young, T; Rees, A; Wilkinson, A; Hamdy, F; Clarke, Noel W; Staffurth, J; The University of Sheffield, School of Health and Related Research (ScHARR), UK. (2009-01)
      OBJECTIVES: To provide an evidence-based perspective on the prognostic value of novel markers in localised prostate cancer and to identify the best prognostic model including the three classical markers and investigate whether models incorporating novel markers are better. DATA SOURCES: Eight electronic bibliographic databases were searched during March-April 2007. The reference lists of relevant articles were checked and various health services research-related resources consulted via the internet. The search was restricted to publications from 1970 onwards in the English language. METHODS: Selected studies were assessed, data extracted using a standard template, and quality assessed using an adaptation of published criteria. Because of the heterogeneity regarding populations, outcomes and study type, meta-analyses were not undertaken and the results are presented in tabulated format with a narrative synthesis of the results. RESULTS: In total 30 papers met the inclusion criteria, of which 28 reported on prognostic novel markers and five on prognostic models. A total of 21 novel markers were identified from the 28 novel marker studies. There was considerable variability in the results reported, the quality of the studies was generally poor and there was a shortage of studies in some categories. The marker with the strongest evidence for its prognostic significance was prostate-specific antigen (PSA) velocity (or doubling time). There was a particularly strong association between PSA velocity and prostate cancer death in both clinical and pathological models. In the clinical model the hazard ratio for death from prostate cancer was 9.8 (95% CI 2.8-34.3, p < 0.001) in men with an annual PSA velocity of more than 2 ng/ml versus an annual PSA velocity of 2 ng/ml or less; similarly, the hazard ratio was 12.8 (95% CI 3.7-43.7, p < 0.001) in the pathological model. The quality of the prognostic model studies was adequate and overall better than the quality of the prognostic marker studies. Two issues were poorly dealt with in most or all of the prognostic model studies: inclusion of established markers and consideration of the possible biases from study attrition. Given the heterogeneity of the models, they cannot be considered comparable. Only two models did not include a novel marker, and one of these included several demographic and co-morbidity variables to predict all-cause mortality. Only two models reported a measure of model performance, the C-statistic, and for neither was it calculated in an external data set. It was not possible to assess whether the models that included novel markers performed better than those without. CONCLUSIONS: This review highlighted the poor quality and heterogeneity of studies, which render much of the results inconclusive. It also pinpointed the small proportion of models reported in the literature that are based on patient cohorts with a mean or median follow-up of at least 5 years, thus making long-term predictions unreliable. PSA velocity, however, stood out in terms of the strength of the evidence supporting its prognostic value and the relatively high hazard ratios. There is great interest in PSA velocity as a monitoring tool for active surveillance but there is as yet no consensus on how it should be used and, in particular, what threshold should indicate the need for radical treatment.
    • A FTIR microspectroscopic study of the uptake and metabolism of isotopically labelled fatty acids by metastatic prostate cancer.

      Gazi, Ehsan; Harvey, Tim J; Brown, Michael D; Lockyer, Nicholas P; Gardner, Peter; Clarke, Noel W; Genito Urinary Cancer research Group, School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK (2009)
    • Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial.

      Sydes, Matthew R; Parmar, Mahesh K B; James, Nicholas D; Clarke, Noel W; Dearnaley, David P; Mason, Malcolm D; Morgan, Rachel C; Sanders, Karen; Royston, Patrick; MRC Clinical Trials Unit, London, UK. matthew.sydes@ctu.mrc.ac.uk (2009)
      BACKGROUND: The multi-arm multi-stage (MAMS) trial is a new paradigm for conducting randomised controlled trials that allows the simultaneous assessment of a number of research treatments against a single control arm. MAMS trials provide earlier answers and are potentially more cost-effective than a series of traditionally designed trials. Prostate cancer is the most common tumour in men and there is a need to improve outcomes for men with hormone-sensitive, advanced disease as quickly as possible. The MAMS design will potentially facilitate evaluation and testing of new therapies in this and other diseases. METHODS: STAMPEDE is an open-label, 5-stage, 6-arm randomised controlled trial using MAMS methodology for men with prostate cancer. It is the first trial of this design to use multiple arms and stages synchronously. RESULTS: The practical and statistical issues faced by STAMPEDE in implementing MAMS methodology are discussed and contrasted with those for traditional trials. These issues include the choice of intermediate and final outcome measures, sample size calculations and the impact of varying the assumptions, the process for moving between trial stages, stopping accrual to each trial arm and overall, and issues around perceived trial complexity. CONCLUSION: It is possible to use the MAMS design to initiate and undertake large scale cancer trials. The results from STAMPEDE will not be known for some years but the lessons learned from running a MAMS trial are shared in the hope that other researchers will use this exciting and efficient method to perform further randomised controlled trials. TRIAL REGISTRATION: ISRCTN78818544, NCT00268476.
    • CpG methylation profiling in VHL related and VHL unrelated renal cell carcinoma.

      McRonald, Fiona E; Morris, Mark R; Gentle, Dean; Winchester, Laura; Baban, Dilair; Ragoussis, Jiannis; Clarke, Noel W; Brown, Michael D; Kishida, Takeshi; Yao, Masahiro; Latif, Farida; Maher, Eamonn R; Cancer Research UK Renal Molecular Oncology Group, University of Birmingham, Birmingham, UK. f.e.mcronald@bham.ac.uk (2009)
      BACKGROUND: Renal cell carcinoma (RCC) is histopathologically heterogeneous with clear cell and papillary the most common subtypes. The most frequent molecular abnormality in clear cell RCC is VHL inactivation but promoter methylation of tumour suppressor genes is common in both subtypes of RCC. To investigate whether RCC CpG methylation status was influenced by histopathology and VHL status we performed high-throughput epigenetic profiling using the Illumina Goldengate Methylation Array in 62 RCC (29 RCC from von Hippel-Lindau (VHL) disease patients, 20 sporadic clear cell RCC with wild type VHL and 13 sporadic papillary RCC). RESULTS: 43 genes were methylated in >20% of primary RCC (range 20-45%) and most (37/43) of these had not been reported previously to be methylated in RCC. The distribution of the number of methylated CpGs in individual tumours differed from the expected Poisson distribution (p < 0.00001; log-likelihood G test) suggesting that a subset of RCC displayed a CpG Island Methylator Phenotype. Comparison of RCC subtypes revealed that, on average, tumour specific CpG methylation was most prevalent in papillary RCC and least in VHL RCC. Many of the genes preferentially methylated in pRCC were linked to TGFbeta or ERK/Akt signalling. CONCLUSION: These findings demonstrate differing patterns of tumour-specific CpG methylation in VHL and non VHL clear cell RCC and papillary RCC, and identify multiple novel potential CpG methylation biomarkers for RCC.
    • FTIR-based spectroscopic analysis in the identification of clinically aggressive prostate cancer.

      Baker, Matthew J; Gazi, Ehsan; Brown, Michael D; Shanks, Jonathan H; Gardner, Peter; Clarke, Noel W; Manchester Interdisciplinary Biocentre, Centre for Instrumentation and Analytical Science, School of Chemical Engineering and Analytical Science, The University of Manchester, Manchester, M1 7DN, UK. M.J.Baker@manchester.ac.uk (2008-12-02)
      Fourier transform infrared (FTIR) spectroscopy is a vibrational spectroscopic technique that uses infrared radiation to vibrate molecular bonds within the sample that absorbs it. As different samples contain different molecular bonds or different configurations of molecular bonds, FTIR allows us to obtain chemical information on molecules within the sample. Fourier transform infrared microspectroscopy in conjunction with a principal component-discriminant function analysis (PC-DFA) algorithm was applied to the grading of prostate cancer (CaP) tissue specimens. The PC-DFA algorithm is used alongside the established diagnostic measures of Gleason grading and the tumour/node/metastasis system. Principal component-discriminant function analysis improved the sensitivity and specificity of a three-band Gleason score criterion diagnosis previously reported by attaining an overall sensitivity of 92.3% and specificity of 99.4%. For the first time, we present the use of a two-band criterion showing an association of FTIR-based spectral characteristics with clinically aggressive behaviour in CaP manifest as local and/or distal spread. This paper shows the potential for the use of spectroscopic analysis for the evaluation of the biopotential of CaP in an accurate and reproducible manner.
    • Aetiology, diagnosis and management of urothelial tumours of the renal pelvis and ureter.

      Maddineni, Satish B; Clarke, Noel W; Sutherland, Douglas E; Jarrett, Thomas W; Department of Urology, Christie Hospital NHS Foundation Trust, Manchester, UK. (2008-11)
    • STAMPEDE: Systemic Therapy for Advancing or Metastatic Prostate Cancer--a multi-arm multi-stage randomised controlled trial.

      James, Nicholas D; Sydes, Matthew R; Clarke, Noel W; Mason, Malcolm D; Dearnaley, David P; Anderson, John; Popert, Richard J; Sanders, Karen; Morgan, Rachel C; Stansfeld, J; Dwyer, John; Masters, John; Parmar, Mahesh K B (2008-10)
    • Survival from prostate cancer in England and Wales up to 2001.

      Clarke, Noel W; Department of Urological Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK. noel.clark@srft.nhs.uk (2008-09-23)