Ethics of clinical trials from bayesian perspective: randomisation to clinical trials may solve dilemma of treatment choice in prostate cancer.
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Clinical Trials as Topic↗
Biomedical subjects
David E Neal
Publications and source records attributed to David E Neal.
Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development.
Prostate cancer (CaP) is initially androgen sensitive and responsive to hormone ablation therapy. However, cancer growth recurs despite androgen deprivation in the majority of cases of advanced disease. The molecular basis of this progression still remains unknown. The significance of androgen receptor (AR) coactivator proteins in this androgen-dependent malignancy is only beginning to emerge. In the present study, we examined the role of Tat interactive protein, 60 kDa (Tip60), an AR coactivator, in CaP progression. In hormone refractory CaP biopsies, we observed a nuclear accumulation of Tip60 expression in contrast to a more diffuse distribution pattern observed in benign prostate hyperplasia and primary CaP. Furthermore, in both the prostate xenograft model CWR22 and the LNCaP CaP cell line, we observed that androgen withdrawal promoted upregulation of Tip60 as well as nuclear accumulation. In contrast, androgen exposure resulted in decreased Tip60 expression that was more closely linked to a cytoplasmic presence. Chromatin immunoprecipitation analysis revealed Tip60's recruitment to the PSA gene promoter in both androgen-dependent and -independent cell lines. Thus, in vitro and in vivo data support a possible role for Tip60 in the molecular pathway leading to the development of androgen-independent CaP following long-term androgen deprivation therapy.
Acetyltransferases↗
Perceptions of equipoise are crucial to trial participation: a qualitative study of men in the ProtecT study.
Recruitment to trials is known to be difficult. Previous research suggests that a crucial factor may be participants' difficulty with the concept of randomization. This study explored patients' perceptions of randomization and reasons for consent or refusal to participate in the ProtecT study (a randomized trial of surgery, radiotherapy, and monitoring for localized prostate cancer). In-depth interviews were conducted with 21 men diagnosed with localized prostate cancer who were invited to participate in the ProtecT treatment trial. Interviewees were selected purposefully from three U.K. clinical centers to ensure the inclusion of similar proportions of those agreeing or refusing random treatment allocation in each of the treatment groups. Interviews explored men's recall and understanding of chance, comparison, and equipoise, and reasons for consent/refusal of randomization and acceptance/rejection of treatment allocation. Data were analyzed methodically using the techniques of constant comparison. Checking of coding and interpretation was assured by four experienced qualitative researchers. Recall and understanding of the major principles of the randomized design were good and were similar for "chance" and "comparison" between those who consented to and refused randomization. Clinical equipoise, however, caused difficulty. Almost all recalled and understood it, but those who found it acceptable tended to consent to randomization and those who could not accept it tended to refuse to participate. Belief in clinical equipoise was key to participants' consent to randomization. Ensuring patients understand and accept equipoise may thus increase their readiness to consent to participate in trials. A priority for future research is to focus on the provision and presentation of suitable and effective trial information, concentrating in particular on the neglected concept of clinical equipoise.
Aged↗
Who can best recruit to randomized trials? Randomized trial comparing surgeons and nurses recruiting patients to a trial of treatments for localized prostate cancer (the ProtecT study).
BACKGROUND AND OBJECTIVE: Recruitment to randomized trials is often difficult, but few studies have investigated interventions to improve recruitment. In a randomized trial nested within a trial of treatments for localized prostate cancer, we investigated the comparative effectiveness and cost-effectiveness of nurses and surgeons in recruiting patients. METHODS: Men with localized prostate cancer were randomized to see a nurse or urologic surgeon for an "information appointment" in which they were asked to consent to the ProtecT treatment trial comparing surgery, radiotherapy, and active monitoring. Analysis was conducted by intention to treat using chi-square with 95% confidence intervals for proportions and differences between groups. An economic evaluation was performed using the duration of appointments and grade of recruitment staff. RESULTS: Case-finding identified 167 men with localized prostate cancer. One hundred fifty (90%) took part in the recruitment trial. There was a 4.0% difference between nurses and surgeons in recruitment rates (67% nurses, 71% urologists, 95% CI -10.8% to +18.8%, P=.60). Cost-minimization analysis showed that nurses spent longer times with patients but surgeon costs were higher and nurses often supported surgeon-led clinics. CONCLUSION: Nurses were as effective and more cost-effective recruiters than urologic surgeons. This suggests an increased role for nurses in recruiting patients to randomized trials.
Aged↗
Alteration in urinary matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 ratio predicts recurrence in nonmuscle-invasive bladder cancer.
PURPOSE: The purpose is to assess the prognostic significance of matrix metalloproteinase (MMP)-9 in patients with bladder cancer using a combination of ELISA (to measure MMP-9 in voided urine) and immunohistochemistry (to study MMP-9 in bladder tumors). The relationship between MMP-9 and its principal inhibitor, tissue inhibitor of metalloproteinase (TIMP)-1 (in voided urine samples) was also studied. EXPERIMENTAL DESIGN: A total of 134 patients with bladder tumors (7 cis, 76 T(a), 27 T(1), 24 T(2)-T(4); 40 G1, 43 G2, and 44 G3), 33 patients with benign urological conditions, and 36 healthy volunteers was studied. Samples from 106 patients with bladder cancer and 12 controls were stained for MMP-9. Clinical follow-up data were available on 116 patients (median: 25 months; range: 4-36 months). RESULTS: MMP-9 was present in all urine samples analyzed. There were no differences between patients with cancer and patients with benign disorders. However, patients had significantly higher urinary MMP-9 than normal volunteers (P = 0.0167). Urinary MMP-9 was associated with bladder tumors of advanced stage (P = 0.0065) and large size (P < 0.0001) but not with grade (P = 0.14), multiplicity (P = 0.31), recurrence (P = 0.55), progression (P = 0.83), or survival (P = 0.55). Low MMP-9:TIMP-1 ratios in patients with nonmuscle-invasive tumors were associated with higher recurrence rates (P = 0.0035). Sixty percent (64 of 106) of bladder tumor specimens expressed MMP-9 compared with none of 12 normal urothelial biopsies (P < 0.0001). MMP-9 staining was associated with tumor size (P = 0.014), disease progression (P = 0.005), and poor disease-specific survival (P = 0.022) but was unrelated to tumor stage (P = 0.46), grade (P = 0.26), multiplicity (P = 0.85), or recurrence rate (P = 0.62). CONCLUSIONS: High urinary MMP-9 levels are associated with large bladder tumors. A low urinary MMP-9:TIMP-1 ratio may indicate a higher risk of intraluminal nonmuscle-invasive tumor recurrence and may assist in planning follow-up surveillance protocols.
Adult↗
Key questions in benign prostatic hyperplasia.
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Family Practice↗
Adhesion of lymphocytes to bladder cancer cells: the role of the alpha(E)beta(7) integrin.
The alpha(E)beta(7)integrin (defined by CD103) is expressed by most intra-epithelial lymphocytes (IEL) but by fewer than 2% peripheral blood lymphocytes (PBL). An important ligand for this molecule is the epithelial cell adhesion molecule E-cadherin. Loss of E-cadherin is associated with increased invasion and metastasis in bladder cancer. This study examines the role of the alpha(E)beta(7)-E-cadherin interaction in lymphocyte targeting of bladder cancer cells. Lymphocytes were activated in vitro by mixed lymphocyte reaction (MLR) and CD103 was upregulated by treatment with transforming growth factor beta (TGFbeta). The CD103(+) lymphocytes were used in a flow cytometric adhesion assay with bladder cancer cell lines, differing in expression of E-cadherin and intercellular adhesion molecule-1 (ICAM-1). Antibody blockade was used to confirm the relative importance of CD103 and ICAM-1 to intercellular adhesion. Lymphocytes with upregulated CD103 compared to control lymphocytes showed enhanced adhesion to an E-cadherin expressing bladder cancer cell line ( P=0.0003). This increased adhesion could be abrogated by anti-CD103 adhesion blockade. For ICAM-1 expressing bladder cells, adhesion of lymphocytes could be markedly reduced using anti-ICAM-1 blockade. In conclusion, the upregulation of CD103 by lymphocytes increases adhesion to E-cadherin expressing bladder cancer targets. Loss of E-cadherin in bladder cancer progression may provide a mechanism both for increased invasion and effective immune evasion.
Antigens, CD↗
Regulation of FGF8 expression by the androgen receptor in human prostate cancer.
Fibroblast growth factor 8 (FGF8) has been shown to play a key role in prostate carcinogenesis. It was initially cloned as an androgen induced protein in mouse mammary cancer SC3 cells. In this study, we examined if FGF8 was also regulated by the androgen receptor in human prostate cancer. FGF8b protein expression in resected clinical prostate cancer correlated closely with expression of the androgen receptor (AR). In the androgen sensitive CWR22 prostate xenograft, we observed up-regulation of FGF8b immunoreactivity in testosterone supplemented mice while castration markedly reduced its signal. Furthermore, FGF8b protein expression in AR positive LNCaP cells was similarly enhanced by androgens. The proximal promoter of the human FGF8 gene was cloned into a luciferase reporter construct (FGF8.luc). FGF8.luc activity in AR positive LNCaP and SC3 cells was increased 2.5-fold by androgens. In AR negative DU145 cells, maximal induction of FGF8.luc required both co-transfection of the AR and the presence of androgens. The anti-androgen bicalutamide completely abolished AR mediated FGF8.luc induction. Deletion constructs from FGF8.luc have further defined an active promoter region and an androgen responsive region. Nucleotide analysis of this androgen responsive region has revealed putative androgen response elements. Finally, using ChIP assays we confirmed in vivo interaction between the AR and the androgen responsive region of the FGF8 promoter. Taken together these data provide first evidence that expression of the mitogen FGF8 in prostate cancer is, at least in part, regulated by the androgen receptor at the transcriptional level.
Androgen Antagonists↗
Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor.
The androgen receptor (AR), a member of the nuclear hormone receptor superfamily, is thought to play an important role in the development of prostate cancer. The AR is a hormone-dependent transcription factor that activates expression of numerous androgen-responsive genes. Histone acetyltransferase-containing proteins have been shown to increase activity of several transcription factors, including nuclear hormone receptors, by eliciting histone acetylation, which facilitates promoter access to the transcriptional machinery. Conversely, histone deacetylases (HDACs) have been identified which reduce levels of histone acetylation and are associated with transcriptional repression by various transcription factors. We have previously shown that Tip60 (Tat-interactive protein, 60 kDa) is a bona fide co-activator protein for the AR. Here we show that Tip60 directly acetylates the AR, which we demonstrate is a requisite for Tip60-mediated transcription. To define a mechanism for repression of AR function, we demonstrate that AR activity is specifically down-regulated by the histone deacetylase activity of HDAC1. Furthermore, using both mammalian two-hybrid and immunoprecipitation experiments, we show that AR and HDAC1 interact, suggestive of a direct role for down-regulation of AR activity by HDAC1. In chromatin immunoprecipitation assays, we provide evidence that AR, Tip60, and HDAC1 form a trimeric complex upon the endogenous AR-responsive PSA promoter, suggesting that acetylation and deacetylation of the AR is an important mechanism for regulating transcriptional activity.
Acetylation↗
Sexual dysfunction in men after treatment for lower urinary tract symptoms: evidence from randomised controlled trial.
OBJECTIVE: To examine the impact on sexual function of treatments for lower urinary tract symptoms in men. DESIGN: Multicentre pragmatic randomised controlled trial of standard surgery (transurethral resection of the prostate), non-contact laser therapy, and conservative management (no active intervention). SETTING: Three clinical centres in the United Kingdom. PARTICIPANTS: 340 men aged between 48 and 90 years with lower urinary tract symptoms related to benign prostatic enlargement. MAIN OUTCOME MEASURES: ICSsex questionnaire items concerned with erectile stiffness, ejaculatory volume, pain or discomfort on ejaculation, whether sex life was spoilt by urinary symptoms. RESULTS: Erectile and ejaculatory dysfunction were common (70%) and problematic at baseline and showed the expected trends with ageing. After treatment, reduced ejaculation was reported in all groups but was not significantly worse after standard surgery than after laser therapy. Erectile function was significantly improved after standard surgery; no significant difference was found between standard surgery and laser therapy (odds ratio 0.70, 95% confidence interval 0.36 to 1.38). Standard surgery was significantly better at relieving pain or discomfort on ejaculation than either conservative management (0.06, 0.007 to 0.49) or laser therapy (0.09, 0.01 to 0.73). CONCLUSIONS: Compared with laser therapy standard surgery for lower urinary tract symptoms has a beneficial effect on aspects of sexual function-particularly in improving erectile function and reducing reported pain or discomfort on ejaculation. Older men who need treatment and want to retain or improve sexual function may thus want to consider standard surgery rather than non-contact laser therapy.
Aged↗
Expression of S100A4 protein is associated with metastasis and reduced survival in human bladder cancer.
The calcium-binding protein S100A4 induces the metastatic phenotype in rodent models of breast cancer and its expression correlates strongly with reduced survival in human breast cancer. The expression of S100A4 in normal bladders and 101 bladder tumours has been studied using immunocytochemistry. Moderate or strong expression of S100A4 was found in 28% of the tumours, whilst the remaining tumours and normal urothelium either failed to stain or showed weak staining. S100A4 staining was more frequently observed in invasive bladder tumours than in non-invasive tumours (p<0.05). In invasive tumours, S100A4 staining was usually strongest in invasive regions and single infiltrating cells. Statistically significant associations were found between S100A4 expression and metastasis (p=0.0003) and reduced survival (p<0.0001). It is concluded that S100A4 expression may play an important role in bladder cancer and may identify a subgroup of patients at increased risk of metastasis who should be considered for adjuvant systemic therapy.
Aged↗
Transfection of S100A4 produces metastatic variants of an orthotopic model of bladder cancer.
The calcium-binding protein S100A4 induces the metastatic phenotype in rodent models of breast cancer, and its expression strongly correlates with reduced survival in human breast and bladder cancer. We have established an orthotopic model of bladder cancer by injecting a cell line derived from a carcinogen-induced rat bladder tumor into the muscular wall of syngeneic rats. MYU-3L cells produce rapidly growing, invasive tumors in the bladder wall but they fail to metastasize. Transfection of MYU-3L cells with a plasmid vector directing overexpression of the S100A4 gene generates variants in which S100A4 expression is elevated by up to sevenfold in comparison with the untransfected cells. Variants overexpressing S100A4 produce primary tumors at similar frequencies and latencies to the parental cell line, a significant number of which metastasize to the para-aortic lymph nodes or lungs. Expression of S100A4 protein in the primary tumors was heterogeneous, but was stronger and more consistent in the metastases, suggesting that transfectants overexpressing S100A4 possess an enhanced ability to form metastatic lesions. We conclude that overexpression of S100A4 can induce the metastatic phenotype in this rodent model of bladder cancer. Taken together with the results from our parallel studies of human bladder cancer, these data suggest a significant role for S100A4 in bladder cancer metastasis and identify a potential new target for systemic therapy in patients with this disease.
Animals↗
Transurethral prostate resection, noncontact laser therapy or conservative management in men with symptoms of benign prostatic enlargement? An economic evaluation.
PURPOSE: We evaluated the cost-effectiveness of noncontact laser therapy compared with transurethral prostate resection and conservative treatment in men with symptoms associated with benign prostatic enlargement. MATERIALS AND METHODS: A total of 340 men with uncomplicated lower urinary tract symptoms participated in a large multicenter pragmatic randomized trial called the CLasP (Conservative management, Laser therapy, transurethral resection of the Prostate) study. Costs to the United Kingdom National Health Service and patients were determined from the time of randomization to the 7.5-month followup. Incremental cost-effectiveness ratios using conservative management as the base case were calculated for certain trial outcomes, including International Prostate Symptom Score (I-PSS), I-PSS quality of life score, maximum urinary flow, post-void residual urine volume, quality adjusted life-years and a composite measure of success based on I-PSS and maximum urinary flow. One-way sensitivity analysis of the basic costs and incremental cost-effectiveness ratios were done from the NHS viewpoint. RESULTS: Mean costs per patient were greatest for noncontact laser therapy and least for conservative management. The incremental cost-effectiveness ratios showed that transurethral prostate resection was more cost-effective than noncontact laser treatment for all primary trial outcomes. The incremental cost-effectiveness ratios of transurethral prostate resection compared with conservative management were pound 81 per unit decrease in the I-PSS score and pound 1,338 per additional successful case per 100 patients. Sensitivity analysis showed that the initial results were robust. CONCLUSIONS: Noncontact laser was the mostly costly treatment option. Transurethral prostate resection was more cost-effective than noncontact laser therapy in terms of symptomatic improvement. In men wishing to delay treatment conservative treatment appears to provide a cost-effective alternative in the short term.
Adult↗
Vitamin B12 malabsorption following bladder reconstruction or diversion with bowel segments.
BACKGROUND: Vitamin B12 is absorbed exclusively in the terminal ileum the resection of which may produce malabsorption of B12. The present study aimed to determine whether the length or specific segment of the intestine used in bladder reconstruction affects the overall incidence of B12 malabsorption. It was also aimed at the reasonable way of following these patients. METHODS: Seventy patients who underwent urinary reconstruction between 1988 and 1997 were studied: 28 had undergone orthotopic reconstruction, 14 had ileal conduit diversion, 8 had continent diversion and 20 had undergone enterocystoplasty. The median follow up was 65 months (10-137 months). Indications for operation included carcinoma of the bladder, neurogenic bladder dysfunction, idiopathic detrusor instability and interstitial cystitis. Schilling tests were performed, and serum B12 level and haematological indices were measured. RESULTS: Patients were classified depending on whether the ileocaecal junction was used. Group 1 included ileal conduit and entero-cystoplasty where 15-20 cm of ileum, 15-20 cm from ileocaecal junction was used. Group 2 consisted of orthotopic reconstruction and continent diversions where the ileocaecal segment was used. Group 3 comprised patients in whom long ileal segments (50-60 cm) had been used for reconstruction. Five patients in group 1 and one in group 2 had low B12 levels, but none had developed neuropathy or megaloblastic anaemia. One patient in group 1, and six patients in group 2 had low Schilling tests indicating intestinal malabsorption of B12. No patient in group 3 had a low B12 or an abnormal Schilling test. CONCLUSION: This study showed that use of ileocaecal segments results in intestinal malabsorption of B12. The length of ileum alone does not seem to be the determinant factor in causing B12 deficiency or B12 malabsorption.
Body Weights and Measures↗
Evaluation of dendritic cell immunogenicity after activation and chemical fixation: a mixed lymphocyte reaction model.
Dendritic cells (DC) are central to the control of adaptive immunity. Their ability to activate antigen-specific T cells depends on their maturation state. Many microbial and inflammatory products have stimulated DC maturation. This in vitro study used assays of phenotype and function to examine the potential of bacillus Calmette-Guerin, muramyl dipeptide, and CpG-rich oligodeoxynucleotides to stimulate DC maturation. A chemical fixation method was developed to reliably assess the functional potential of stimulated DC within a mixed lymphocyte reaction model. Using this method, it was shown that bacillus Calmette-Guerin provides a maturation signal as effective as the prototype DC stimulant interleukin-1beta. Furthermore, weaker stimuli such as muramyl dipeptide and CpG-rich oligodeoxynucleotides also are able to induce functional maturation of DC. Using chemical fixation, it was possible to generate stable DC in an immature or a mature state. These observations have importance for our understanding of the regulation of adaptive immunity and for the design of DC-based immunotherapeutic strategies.
Acetylmuramyl-Alanyl-Isoglutamine↗