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The Nuffield Department of Surgical Sciences is the academic department of surgery at the University of Oxford, and hosts a multidisciplinary team of senior clinical academic surgeons, senior scientists, junior clinicians and scientists in training.
Prostate cancer: a systems approach overview
Systems thinking is a set of methodologies that facilitate analysis and predictions for a complex system in a holistic way. Prostate cancer has precursor stages that are difficult to detect and a number of different therapy options for different stages, so it is a complex disease to manage within healthcare systems. In this review we show how systems thinking, especially causal loop diagrams, can be a very valuable tool for gaining greater insight into the pathogenesis and diagnosis of prostate cancer and to predict the consequences in major changes in the pattern of healthcare for this disease, e.g. introduction of national screening programmes using serum prostate specific antigen. The systems thinking approach can be used to predict changes in histopathology workflow when other parts of the system are changed. © 2008 Elsevier Ltd. All rights reserved.
Current vaccination strategies for prostate cancer.
CONTEXT: The first therapeutic cancer vaccine demonstrating effectiveness in a phase 3 study was approved by the US Food and Drug Administration on 29 April 2010. The pivotal trial demonstrated overall survival (OS) benefit in patients treated with antigen-loaded leukapheresis cells compared with a control infusion. Results of other prostate cancer (PCa) vaccination strategies are awaited, as this approach may herald a new era in the care for patients with advanced PCa. OBJECTIVE: Consider effectiveness and safety of vaccination strategies in the treatment of PCa. EVIDENCE ACQUISITION: We searched three bibliographic databases (January 1995 through October 2010) for randomised phase 2 and 3 studies of vaccination strategies for PCa based on predetermined relevant Medical Subject Heading terms and free text terms. EVIDENCE SYNTHESIS: Data from 3 randomised phase 3 and 10 randomised phase 2 vaccination trials are discussed with respect to clinical outcome in terms of progression-free survival and OS, toxicity, prostate-specific antigen (PSA) response, and immunologic response. Three phase 3 trials (D9901, D9902A, and D9902B) that enrolled a total of 737 patients, all controlled and double-blinded, tested the efficacy of sipuleucel-T. The largest of these three trials, called Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT), has demonstrated safety and effectiveness of sipuleucel-T (now marketed as Provenge) as measured by prolonged survival of 512 asymptomatic patients with metastatic castration-resistant PCa (mCRPC). The study showed a 4.1-mo median survival benefit in the sipuleucel-T vaccine-treated group compared with the control group (25.8 vs 21.7 mo; hazard ratio [HR]: 0.78; 95% confidence interval [CI], 0.62-0.98; p=0.032) and extended 3-yr survival (31.7% vs 23.0%). In contrast, two phase 3 vaccination trials with a whole-tumour-cell mixture of two PCa cell lines (GVAX) and testing GVAX either alone or in combination with chemotherapy versus chemotherapy alone (VITAL1 and 2) were terminated prematurely based on futility and increased deaths. Other phase 2 vaccination trials testing different types of vaccines in castration-resistant PCa patients have been reported with variable outcomes. Notably, a controlled, double-blind, randomised phase 2 vaccine trial of PROSTVAC-VF, a recombinant viral vector containing complementary DNA encoding PSA, in 125 patients with chemotherapy-naïve, minimally symptomatic mCRPC also demonstrated safety but no significant effect on the time to disease progression. In comparison with controls (n=40), PROSTVAC-VF-treated patients (n=82) experienced longer median survival of 8.5 mo (25.1 vs 16.6 mo; HR: 0.56; 95% CI, 0.37-0.85; p=0.0061) and extended 3-yr survival (30% vs 17%). In general, PCa vaccines are perceived to have less toxicity compared with current cytotoxic or targeted therapies. Evaluation of clinical efficacy of different vaccination strategies (eg, protein-, peptide- and DNA-based vaccines) in the context of properly designed and controlled phase 3 studies is warranted. CONCLUSIONS: Cancer vaccines represent a new paradigm in the treatment of PCa. The IMPACT trial showed improved survival but no difference in time to disease progression in mCRPC patients with minimal tumour burden. Observations in phase 2 and 3 trials pave the way for other vaccination approaches for this disease, raise questions regarding the most appropriate clinical trial designs, and underscore the importance of identifying biomarkers for antitumour effect to better implement such therapies.
The future of randomised controlled trials in urology.
Randomised controlled trials in urology are challenging yet essential for generating high-quality, practice-changing evidence. Future trials should focus on high-priority questions, be conducted by multidisciplinary investigative teams with patient and public stakeholder involvement, and be grounded in successful feasibility studies.
Use of classical and novel biomarkers as prognostic risk factors for localised prostate cancer: a systematic review.
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.
[Promoter methylation and microsatellite mutation reveals the clonal relationship of multiple urothelial carcinomas with mutator phenotype].
AIMS: The clonality of multiple urothelial carcinomas (UC) is subject to debate and affects treatment. Evidence derived from X-chromosome mosaicism and patterns of molecular alterations supports both a mono- and polyclonal relationship. In contrast to most UC, tumours with the mutator phenotype have frequent mutations in repetitive sequences (MSI) and promoter methylation. The aim of this study was to investigate the clonality of multifocal UC with MSI. METHODS: We have screened 400 UC for MSI and found it to occur in 1% of bladder and 15% of upper tract UC. Of these, 9 patients, whose tumours had MSI, developed or presented with multiple UC. A total of 32 UC (occurring over 0-6 years, 2-12 TCC per patient), 2 cases of CIS and 9 normal urothelial samples were screened for MSI at 17 loci and aberrant promoter methylation at 7 genes. RESULTS: In 8 of 9 patients, the pattern of microsatellite mutation and promoter methylation suggested that the multiple tumours had a clonal origin. Patterns of aberrant methylation in multiple tumours were more similar than microsatellite mutations, suggesting an earlier carcinogenic timing. MSI and promoter methylation were present in macroscopically normal urothelium from these patients. CONCLUSIONS: Aberrant promoter methylation occurs before microsatellite alteration in UC with mutator phenotype. The majority of recurrent UC with MSI are monoclonal in origin and macroscopically normal urothelium harbours multiple molecular abnormalities. Thus, at the time of apparently successful treatment, there is molecular evidence of residual tumour that subsequently develops into recurrent disease.
Prostate specific antigen: biology, biochemistry and available commercial assays.
Prostate specific antigen (PSA) is the marker of choice in the management of prostate cancer. However, PSA is not a simple molecule, existing in the serum in five isoforms and a number of molecular configurations and complexes. The elucidation of the biochemistry of PSA has increased the potential use of the marker in the diagnosis of prostate malignancy. This review summarizes the clinical use of PSA in the management of prostate disease and the assays available in the UK. Assay calibration in relation to the World Health Organization 1st International Standard for Prostate Specific Antigen (90:10) has increased conformity between the various commercial assay kits, and the non-equimolar kits have largely been superseded or withdrawn. Special reference is made to evaluations performed on behalf of the Medical Devices Agency of the Department of Health.
Prognostic and predictive factors in prostate cancer.
Prostate cancer is a major public health problem in the Western world, and the second most common male malignancies in the European Union. Detection of the disease is possible at an early stage, using serum prostate specific antigen measurement and prostatic biopsies. To date, however, screening for prostate cancer has not been shown to be of benefit to patients in improving outcome. This is compounded by uncertainties surrounding treatment efficacy, as more men appear to die with prostate cancer than from it. Studies addressing these issues are underway in Europe and the U.S.A. Clinicians are currently unable to advise their patients with any degree of certainty as to the appropriateness of treatment for prostate cancer, because of their inability to differentiate tumours that will progress from those that will remain quiescent. This article reviews the various clinical, pathological and experimental markers available, and their value in providing prognostic information, which may assist clinicians and patients in making management decisions. Further research is still required to understand the biological behaviour of prostate cancer and to assess the value of screening and treatment efficacy in order to advise patients, clinicians and health care systems accordingly.
Artificial neural networks and prognosis in prostate cancer
I. INTRODUCTION When a patient is found to have cancer, there are three main concerns which are translated into crucial questions for the clinician. He/she wants to know how (1) serious the disease is, i.e., how life threatening it is; (2) what the best treatment is with its potential deleterious effects; and (3) the prognosis with or without treatment. Whilst with many cancers there is a first choice treatment and the ideal course of action is clear, for other malignancies, particularly in urology - e.g., certain grades and stages of prostate and bladder cancer - treatment decisions are more difficult. Decisions are made usually on the basis of conventional information such as tumour grade, stage, age and co-morbidity, statistical probabilities of disease progression, and an informed discussion between the treating clinician and the patient. For instance, if a man is diagnosed with low-grade and low-stage prostate cancer and he is told that he has a 10-15% risk of progression over a period of 10 years, the clinician is unable to predict exactly which side of the risk fence the patient will fall into. The consequence of such uncertainties could therefore be either overtreatment or undertreatment with their sequelae. Patients with such cancers would benefit greatly from any new methods of predicting outcome that will help them in selecting their treatment, which would be offered with a greater degree of confidence by the physician.
The use of prostate-specific antigen testing in the detection of localized prostate cancer: Current opinion and urological practice in the United Kingdom
Background: The prostate-specific antigen (PSA) test and its interpretation plays a crucial role in the detection of early localized prostate cancer. However, inaccuracy of the test, inability to predict the aggressiveness of the disease and the lack of evidence about the comparative effectiveness of treatments have led to major dilemmas in considering whether to employ the PSA test and which cut-off points to use in interpreting its results. The aim of this study was to evaluate current urological practice in the UK regarding the use of PSA testing. Methods: A postal questionnaire survey of all consultant urologist members of the British Association of Urological Surgeons was conducted. Statistical analysis included proportional odds regression models to examine factors associated with urologists' preferences for different definitions of 'normal' PSA cut-off levels. Results: The survey response rate was 60%. The majority of consultant urologists applied the PSA test routinely. There was a high level of agreement amongst UK urologists on normal PSA cut-off points (<4.0 ng/ml) for asymptomatic men under 60 years of age. There was very wide variation in the definition of normal PSA cut-offs for older (≥60 years) asymptomatic men. A preference for lower cut-off points, leading to investigation with ultrasound and biopsy, was significantly associated with larger urology department size, the presence of a prostate cancer subspecialist in the department and relatively short length of specialization in urology. Conclusions: Prostate cancer screening and early detection practices and reported incidence rates of the disease are likely to be influenced by variation in urologists' interpretations of PSA. Despite increasing evidence in favour of lower PSA cut-off levels, particularly for younger men (<60 years), urologists in the UK are divided over their interpretation. Men, particularly over age 60 years, have varying chances of further investigation following PSA testing. Any trial of prostate cancer screening or treatment should take this potential variation into account. Standard protocols for PSA interpretation should be implemented.
Bone morphogenetic protein-6: potential mediator of osteoblastic metastases in prostate cancer.
The mechanisms by which prostate cancer metastasizes to bone with a strong osteoblastic reaction remain poorly understood. Several factors have been previously implicated, including transforming growth factor-beta, fibroblast growth factors, endothelin-1 and bone morphogenetic proteins (BMPs). BMP-6 expression has been shown exclusively in the malignant epithelial cells of prostate cancers that have metastasized, but not in organ confined disease. Expression of BMP-6 in radical prostatectomy specimens has been shown to correlate with increased recurrence rates and decreased survival. This article presents the results of work by the authors' group in this field and a current literature review. Prostate Cancer and Prostatic Diseases (2000) 3, 283-285
Localization and quantification of mRNA for matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) in human benign and malignant prostatic tissue.
BACKGROUND: The family of matrix metalloproteinases (MMPs) has been shown to be involved in proteolytic degradation of the extracellular matrix, which is an essential step in tumor invasion and metastasis. MMPs are tightly regulated by the levels of active enzymes and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). MMP-2 and its ratio to TIMP-2 have been associated with tumor recurrence and progression in a number of human malignancies. METHODS: We examined the relationship between MMP-2 and TIMP-2 mRNA expression in 42 men with malignant (n = 32) and benign (n = 10) prostates using nonisotopic in situ hybridization and Northern blot analysis. RESULTS: mRNA for MMP-2 and TIMP-2 was localized to the malignant epithelial cells of both high- and low-grade tumors in the periphery of the glands and in areas of extracapsular involvement, and to the glandular epithelium in the benign prostates. Using Northern blot analysis, the mean MMP-2 to TIMP-2 ratio was approximately one in the benign prostates and low-grade and -stage cancers. The MMP-2 to TIMP-2 ratio increased to 3.3 in the high-grade and 2.8 in the high-stage tumors. CONCLUSIONS: The results suggest a close association between MMP-2/TIMP-2 expression and local tumor invasion, with a disruption in expression of the two genes leading to disease progression. Future studies should focus on the activity of these enzymes and on the ratio of enzyme/inhibitor expression, which may become a useful prognostic marker in prostate cancer.
Staging of prostate cancer using 3-dimensional transrectal ultrasound images: a pilot study.
PURPOSE: We used conventional transrectal ultrasound images for 3-dimensional (D) reconstruction of the prostate, and determined its value in staging clinically localized prostate cancer. MATERIALS AND METHODS: A total of 36 patients with newly diagnosed clinically localized prostate cancer were studied. All patients underwent conventional transrectal ultrasonography with 3-D reconstruction. Images were examined and analyzed blindly, and findings were compared to histopathological staging following radical prostatectomy. RESULTS: Pathological staging of specimens revealed 15 sites of extracapsular extension in 10 patients, of whom 8 had positive margins and 2 had seminal vesicle invasion. The 3-D imaging identified 12 sites of extracapsular extension in 9 patients with 80% sensitivity, 96% specificity and 90% positive predictive value. Of the 2 patients with seminal vesicle invasion 1 was identified correctly on 3-D images. Overall staging accuracy of 3-D imaging was 94%. CONCLUSIONS: The 3-D reconstruction of conventional transrectal ultrasonography imaging is superior to 2-D imaging for staging localized prostate cancer. However, this advantage relies entirely on the visibility of prostate cancer lesions on conventional ultrasonography. Further studies are warranted to evaluate this technology for the management of prostate cancer.
Apoptosis regulating genes in prostate cancer (review).
Prostatic adenocarcinoma is emerging as a major cause of morbidity and mortality in the male population in the western world. Programmed cell death (apoptosis) in the prostate is activated by hormone ablation and is under the control of several regulating genes including the tumour suppressor gene p53 and the proto-oncogene bcl-2. Bcl-2 belongs to a rapidly expanding family of genes which form two functionally antagonistic groups controlling cell death and survival. Apoptosis regulating genes appear to play an important role in the development and progression of prostatic adenocarcinoma and offer a potential target for future therapeutic strategies.
Detection of circulating prostate-specific antigen-positive cells in patients with prostate cancer by flow cytometry and reverse transcription polymerase chain reaction.
The presence of prostate-specific antigen (PSA)-positive cells has previously been demonstrated in the peripheral blood of prostate cancer patients by flow cytometry (FC), but the identity of these cells has not been established. In this study, the reverse transcriptase polymerase chain reaction (RT-PCR) was compared with analytical FC in an attempt to detect and characterise these cells. Peripheral blood was obtained from 12 patients with newly diagnosed and untreated prostate cancer and five controls. Nine of the 12 patients with prostate cancer (75%) had circulating PSA-positive cells as shown by FC. Only one of those patients (11.1%) was found to express PSA mRNA by RT-PCR. The absence of PSA mRNA in the majority of samples showing PSA-positive cells suggests that they do not represent haematogenous micrometastases. PSA-positive cells in the blood could represent monocytes that express PSA, either following binding/phagocytosis of free serum PSA or phagocytosis of tumour cells.
Use of dexamethasone for ureteric obstruction in advanced prostate cancer: percutaneous nephrostomies can be avoided.
OBJECTIVE: To evaluate the effectiveness of dexamethasone in relieving bilateral lower ureteric obstruction in the acute phase of renal failure secondary to locally advanced prostate cancer. PATIENTS AND METHODS: This study comprised 11 patients (median age 72 years, range 52-84) presenting with advanced prostate cancer, bilateral ureteric obstruction and gross renal failure. Their response to immediate administration of intravenous followed by oral dexamethasone for 4 weeks, in conjunction with definitive treatment and final outcome, was evaluated. RESULTS: Renal function improved in 10 patients within 72 h. avoiding the need for insertion of percutaneous nephrostomies. However, four of 10 patients whose renal failure initially improved, failed to respond to definitive therapy, and died 3 to 4 weeks after cessation of the steroids. CONCLUSION: When administered in the acute phase of renal failure from prostate cancer, dexamethasone may obviate the need for urinary diversion in patients with bilateral ureteric obstruction, particularly in men who will not respond favourably to available forms of therapy for advanced and aggressive disease.