Statistical problems with 'optimal' thresholds in studies of new prognostic factors in urology.
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Biomarkers, Tumor↗
Biomedical subjects
D E Neal
Publications and source records attributed to D E Neal.
Current status of linkage studies in hereditary prostate cancer.
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Chromosome Mapping↗
Insulin-like growth factor II and androgen receptor expression in the prostate.
OBJECTIVE: To determine the effect of insulin-like growth factor (IGF)-II on androgen receptor (AR) expression in prostate tissue, as IGFs may be important in re-activating androgen-regulated genes in advanced prostate cancer because they can trans-activate the AR in the absence of ligand. Materials and methods Primary BPH stromal cells, LNCaP and U2OS cells were grown in full medium, medium devoid of growth factors and devoid medium supplemented with IGF-II. The relationship between IGF-II and AR expression was then investigated using the reverse-transcription polymerase chain reaction, and the effects of anti-androgens on IGF-II expression assessed using northern blot analysis. RESULTS: IGF-II had no effect in benign tissue, but the AR expression doubled in LNCaP and U2OS cells after culture with IGF-II. Androgens had a minimal effect on IGF-II mRNA levels, but anti-androgens reduced IGF-II mRNA levels by more than half. CONCLUSION: These findings support the idea of a complementary paracrine (IGF) and autocrine (androgen) growth loop in prostate tissue. The study suggests that IGF-II has a role in regulating AR expression in prostate cancer cells, and that the action of anti-androgens is mediated partly by an ability to suppress IGF-II expression.
Blotting, Northern↗
Fibroblast growth factor receptor-2 mutation analysis in human prostate cancer.
OBJECTIVE: To assess whether mutations in the hot-spots of the fibroblast growth factor (FGF) receptor-2 gene (FGFR2, exons encoding the IIIa, IIIb, IIIc and transmembrane domain, TMD) are associated with the development of prostate cancer, as the IIIb variant is the specific receptor for FGF7/KGF, an androgen-inducible paracrine factor regulating prostatic growth. Materials and methods Single-strand conformational polymorphism-polymerase chain reaction (SSCP-PCR) and cycle-sequencing analysis were used to screen FGFR2 mutations in 30 patients with prostate cancer; corresponding blood samples were analysed from 11 of the patients. The human prostate cell lines, LNCaP, PC3, DU145, PNT1A and PNT1B were also examined. In addition, 10 foci of invasive cancer from three patients who underwent radical prostatectomy were also assessed. RESULTS: Positive controls containing FGFR2 mutations (Crouzon disease and Pfieffer syndrome) were confirmed by SSCP-PCR and sequencing. Analysis of all prostate tumour samples and prostate-derived cell lines revealed no polymorphisms or mutations in the IIIa, IIIb, IIIc and TMD regions of FGFR2. CONCLUSION: FGFR2 mutations in the-FGF binding domain and the TMD are not frequent events in human prostate cancer.
Cohort Studies↗
Androgen receptor signalling in the prostate.
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Cell Communication↗
Androgen receptor nuclear translocation is facilitated by the f-actin cross-linking protein filamin.
The human androgen receptor (hAR) is a ligand-dependent transcription factor responsible for the development of the male phenotype. The mechanism whereby nuclear translocation of the hAR is induced by its natural ligand 5alpha-dihydrotestosterone is a phenomenon not fully understood. The two-hybrid interaction trap assay has been used to isolate proteins that interact with the hAR in an attempt to identify molecules involved in hAR transactivation and movement. We have identified the actin-binding protein filamin, a 280-kDa component of the cytoskeleton, as an hAR interacting protein. This interaction is ligand independent but is enhanced in its presence. The functional significance of this interaction was analyzed using a cell line deficient in filamin via transient expression of a green fluorescent protein-hAR chimera. In filamin-deficient cells this revealed that hAR remained cytoplasmic even after prolonged exposure to synthetic ligand. Nuclear shuttling was restored when this cell line regained wild-type expression of filamin. These data suggest a novel role for filamin, implicating it as an important molecule in AR movement from the cytoplasm to the nucleus.
Actins↗
A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice.
PURPOSE: The commonly accepted diagnostic algorithm for hematuria includes excretory urography (IVP) and cystoscopy. Some have suggested that ultrasound of the upper urinary tract is adequate and that cystoscopy is not necessary in younger patients with microscopic hematuria. We ascertain whether a less intensive algorithm could be adopted while retaining diagnostic efficacy. MATERIALS AND METHODS: A total of 1,930 patients were enrolled prospectively in the study at a hematuria clinic between October 1994 and March 1997. Evaluation consisted of basic demographics, history and examination, routine blood tests, urinalysis and cytology. All patients underwent plain abdominal radiography, renal ultrasound, IVP and flexible cystoscopy. RESULTS: A total of 1,194 males and 736 females with a mean age of 58 years (range 17 to 96) were included in the study. Overall, 61% of patients had no basis found for hematuria, 12% had bladder cancer, 13% had urinary tract infection and 2% had stones. Kidney and upper tract tumors were noted in 14 patients (0.7%), including 4 who presented with microscopic hematuria. If only ultrasound or IVP had been performed 4 of these cases would have been missed. Of 982 patients presenting with microscopic hematuria 51 had cancer. Bladder cancer was found in 7 patients younger than 40 years. CONCLUSIONS: Our findings suggest that cystoscopy cannot be safely avoided even in younger patients with microscopic hematuria. Only a combination of ultrasound and IVP detected all upper tract tumors.
Adolescent↗
Neural network analysis of clinicopathological and molecular markers in bladder cancer.
PURPOSE: To evaluate retrospectively the ability of an artificial neural network (ANN) to predict bladder cancer recurrence within 6 months of diagnosis and stage progression in patients with Ta/T1 bladder cancer, and 12-month cancer-specific survival in patients with T2-T4 bladder cancer. MATERIALS AND METHODS: Data were analyzed using a NeuralWorks Professional II/Plus software package. The input neural data consisted of clinicopathological and molecular characteristics. Distinct patient groups were used for the prediction of stage progression and tumor recurrence in Ta/T1 bladder cancers, and 12-month cancer-specific survival for patients with T2-T4 tumors. ANN predictions were compared with those of four consultant urologists. RESULTS: The accuracy of the neural network in predicting stage progression and recurrence within 6 months for Ta/T1 tumors and 12-month cancer-specific survival for T2-T4 cancers was 80%, 75% and 82% respectively; with corresponding figures for clinicians being 74%, 79% and 65%. On restricting the validation subset to patients with T1G3 tumors in relation to stage progression, the sensitivity of the ANN analysis increased to 100% with a specificity of 78% and an overall accuracy of 82%. The performance of the ANN in predicting stage progression in T1G3 tumors was significantly higher than that of clinicians (p = 0.25 for the ANN and p = 0.008 for clinicians, McNemar test). CONCLUSIONS: Data analysis using an ANN has been shown to be a useful adjunct in predicting outcomes in patients with bladder cancer and out-performs clinicians' predictions of stage progression in the high risk group of patients with T1G3 disease.
Biomarkers, Tumor↗
A prospective randomized trial comparing transurethral resection of the prostate and laser therapy in men with chronic urinary retention: The CLasP study.
PURPOSE: We assessed the effectiveness of laser therapy versus transurethral prostatic resection in men with symptomatic chronic urinary retention secondary to benign prostatic enlargement. MATERIALS AND METHODS: This trial was multicenter, pragmatic and randomized. Analysis was done by intent to treat. Laser therapy involved neodymium:YAG noncontact visual prostate ablation, while transurethral prostatic resection was performed by standard electroresection. Patients were included in our study if they reported moderate to severe lower urinary tract symptoms with an International Prostate Symptom Score (I-PSS) of 8 or more, benign prostatic enlargement and a persistent post-void residual urine volume of more than 300 ml. Followup was 7.5 months. Primary outcome measures included the I-PSS, I-PSS quality of life score, maximum urinary flow and post-void residual urine volume. Secondary outcome measures included treatment failure, complications, hospital stay and catheterization time. RESULTS: A total of 82 patients agreed to be randomized to receive laser therapy (38) or transurethral prostatic resection (44). There were significant improvements in all primary outcomes in each group from randomization to followup. Transurethral prostatic resection was significantly better than laser therapy for I-PSS and maximum urinary flow values (p = 0.035 and 0.029, respectively) but there were no differences in post-void residual urine volume and I-PSS quality of life score between the groups. We noted significantly more treatment failures with laser therapy than resection (8 versus 0, p = 0.0014), although only 3 patients required resection after laser therapy because of persistent symptoms. In addition, hospital stay after resection was 2-fold that after laser therapy (ratio of geometric means 2.01, 95% confidence interval 1.54 to 2.61, p <0.0001). However, time to catheter removal was 9 times longer in the laser therapy group (p <0. 0001). Complication rates were significantly higher for transurethral prostatic resection (chi-square 5.05, 1 df, p = 0.025). CONCLUSIONS: Transurethral prostatic resection is more effective than laser ablation in men with chronic urinary retention in terms of symptom score, maximum urinary flow and failure. However, men who underwent resection had significantly more treatment complications and were hospitalized longer than those who received laser therapy. This finding implies that laser ablation therapy may have a role in patients at higher risk who are willing to accept a lower level of effectiveness in exchange for decreased complication rates and hospital stay.
Humans↗
A randomized trial comparing transurethral resection of the prostate, laser therapy and conservative treatment of men with symptoms associated with benign prostatic enlargement: The CLasP study.
PURPOSE: We evaluated the effectiveness of a new technology (noncontact laser therapy) versus that of standard surgery (transurethral prostatic resection) and conservative management for lower urinary tract symptoms associated with benign prostatic enlargement. MATERIALS AND METHODS: Men with uncomplicated lower urinary tract symptoms, that is no acute or chronic urinary retention, were randomized to receive laser therapy with a noncontact, side firing neodymium:YAG probe, standard transurethral prostatic resection or conservative management, including monitoring without active intervention, in a large multicenter pragmatic randomized controlled trial called the CLasP study. Primary outcomes were International Prostate Symptom Score (I-PSS), maximum urinary flow rate, a composite measure of success based on I-PSS and maximum urinary flow rate categories, I-PSS quality of life score and post-void residual urine volume. Secondary outcomes included treatment failure, hospital stay and major complications. Followup was 7.5 months after randomization. Intent to treat analysis was done using analysis of covariance, proportional odds models and the Newman-Keuls multiple comparisons procedure. RESULTS: Of symptomatic patients 117, 117 and 106 were randomized to receive laser therapy, transurethral prostatic resection and conservative management, respectively. Baseline characteristics were similar. All primary outcomes indicated that transurethral prostatic resection and laser therapy were superior to conservative management, and resection was superior to laser therapy. As measured by combined improved symptoms and maximum urinary flow, a successful outcome was achieved in 81%, 67% and 15% of men who underwent transurethral prostatic resection, laser therapy and conservative management, respectively. Hospital stay was significantly shorter and complications fewer for laser therapy than for resection but catheters were in place significantly longer. Men treated conservatively did not have deterioration or treatment failure. CONCLUSIONS: Laser therapy and transurethral prostatic resection are effective for decreasing lower urinary tract symptoms and post-void residual urine volume as well as improving quality of life and maximum urinary flow in the short term in men presenting with moderate to severe symptoms. Transurethral prostatic resection is superior to laser therapy in terms of effectiveness but some patients may elect laser therapy due to the shorter hospital stay and lower risk of complications. Conservative management may be acceptable and safe in men with lower urinary tract symptoms since we observed no marked deterioration in the short term.
Aged↗
Peroxisome proliferator-activated receptor alpha is an androgen-responsive gene in human prostate and is highly expressed in prostatic adenocarcinoma.
Peroxisome proliferator-activated receptor (PPAR) alpha is a member of the nuclear receptor superfamily of ligand-activated transcription factors. PPARalpha is activated by peroxisome proliferators and fatty acids and has been shown to be involved in the transcriptional regulation of genes involved in fatty acid metabolism. In rodents, the PPARalpha-mediated change in such genes results in peroxisome proliferation and can lead to the induction of hepatocarcinogenesis. Using the mRNA differential display technique and Northern blot analysis, we have shown that chronic exposure of the prostate cancer epithelial cell line LNCaP to the synthetic androgen mibolerone results in the down-regulation of PPARalpha mRNA. Levels of PPARalpha mRNA are reduced to approximately 40% of control levels in LNCaP cells exposed to 10 nM mibolerone for 96 h. PPARalpha-responsive reporter plasmids derived from human ApoA-II and muscle carnitine palmitoyl-transferase I genes were stimulated by the PPARalpha-activating ligand Wy-14,643 in LNCaP cells. In situ hybridization and immunohistochemical analyses showed that PPARalpha expression in prostate is confined to epithelial cells. In benign prostatic tissue, PPARalpha mRNA was either absent or only weakly expressed in the basal epithelial cells. In 11 of 18 (61%) poorly differentiated (Gleason score, 8-10) prostatic carcinoma specimens, there was strong expression of PPARalpha compared with 4 of 12 Gleason score 7 tumors and 2 of 11 Gleason score 3-6 tumors (P < 0.01). These results suggest that PPARalpha is found and functional in human prostate and is down-regulated by androgens. The role of PPARalpha may be to integrate dietary fatty acid and steroid hormone signaling pathways, and its overexpression in advanced prostate cancer may indicate a role in tumor progression with the potential involvement of dietary factors.
Adenocarcinoma↗
Mucin gene expression in human urothelium and in intestinal segments transposed into the urinary tract.
PURPOSE: The repertoire of mucin (MUC) gene expression in the normal human urothelium is poorly defined and the alterations in MUC gene expression following transposition of intestinal segments into the urinary tract has not previously been studied. The aims of this study were to define MUC gene expression in the normal human urothelium; and in transposed intestinal segments. MATERIALS AND METHODS: Non-isotopic in-situ hybridization was carried out using eight digoxigenin labeled oligonucleotide mucin gene probes (MUC 1 - 7). Immunohistochemistry using NCL-MUC1 and NCL-MUC2 monoclonal antibodies was performed on sections of paraffin-embedded tissues. Twenty-seven patients were investigated (normal human urothelium, n = 6; transposed ileal segments, n = 14 and normal ileal controls, n = 7). RESULTS: MUC1 and MUC4 were the predominant mucin genes expressed in the normal urothelium with MUC3 being expressed in a third of cases studied; MUC2, 5AC, 5B, 6 and 7 were not expressed. Despite the morphological changes seen in transposed ileal segments, MUC2 and MUC3 continued to be expressed in these segments albeit in a disorganised fashion. Both MUC1 and MUC4 were up-regulated in transposed ileal segments, genes expressed by the normal human urothelium. All eight mucin genes were expressed in an area of pyloric-type metaplasia found in one transposed ileal segment. In patients with clam enterocystoplasty there was evidence of increasing up-regulation of MUC2, 3, 4 and 5AC expression in the urothelium toward the anastomotic site. CONCLUSION: Transposition of ileal segments into the urinary tract results in up-regulation of MUC1 and MUC4, the predominant MUC genes expressed in the human bladder. The clinical implication of the up-regulation of some MUC genes toward the anastomotic site in patients with an enteroplasty and the aberrant expression of MUC5AC - MUC7 by transposed segments is at present unclear.
Adult↗
Serum keratinocyte growth factor measurement in patients with prostate cancer.
PURPOSE: Keratinocyte growth factor (KGF) is a stromally derived growth factor important in mediating androgen induced activities in benign prostatic hyperplasia (BPH) and prostate cancer. We assessed whether serum KGF could be used as a molecular marker in patients with prostate cancer. MATERIALS AND METHODS: Using a modified double sandwich enzyme-linked immunosorbent assay, we measured serum KGF in 56 men with prostate cancer and 81 men with BPH. Comparative analyses were made with total serum prostate specific antigen (PSA), disease stage and clinical grade. RESULTS: Following optimization, a sensitive and reproducible assay for serum KGF measurement was developed. Serum KGF levels tend to be higher in men with BPH compared to those with prostate cancer (1,242 and 828 pg./ml., respectively). A weak but significant linear relationship between PSA and KGF (p = 0.034) was found in patients with BPH. There was no association between KGF and tumor grade or stage but there was a strong positive linear relationship between PSA and KGF (p = 0.006, R(2) = 68.3%) in low grade tumors. In those men with serum PSA less than 10 ng./ml. KGF levels were significantly higher in BPH compared to prostate cancer cases (965 +/- 245 and 133 +/- 61.3 pg./ml., respectively, p = 0.0058). Using a KGF threshold range of 500 to 900 pg./ml., specificity for detecting BPH was 88% to 100% and the positive predictive value was 92% to 100%. CONCLUSIONS: We have optimized a reproducible and sensitive enzyme-linked immunosorbent assay system for the measurement of serum KGF. Overall KGF levels tend to be lower in patients with prostate cancer than with BPH. In patients with serum PSA less than 10 ng./ml. serum KGF levels were significantly higher in the BPH compared to the prostate cancer group. A large prospective study is indicated to assess the role of serum KGF measurement in patients with prostate cancer.
Aged↗
Tip60 is a nuclear hormone receptor coactivator.
The androgen receptor (AR) is a member of the nuclear hormone receptor superfamily. Recent work in this field has been focused upon defining the mechanisms of transcriptional control exacted by members of this superfamily. Using a COOH-terminal region of the human AR in a yeast two-hybrid screen, we have identified Tip60 as an AR-interacting protein. In this report, we show that Tip60, which was originally identified as a coactivator for the human immunodeficiency virus TAT protein, can enhance AR-mediated transactivation in a ligand-dependent manner in LNCaP and COS-1 cell lines. In addition, our experiments show that Tip60 can also enhance transactivation through the estrogen receptor and progesterone receptor in a ligand-dependent manner; thus identifying Tip60 as a nuclear hormone receptor coactivator. Our studies also demonstrate that Tip60 co-immunoprecipitates with the full-length AR in vitro and that, in our system, Tip60 enhances transactivation to levels observed with the coactivators steroid receptor coactivator 1, p300, and CREB-binding protein. The importance of such proteins in enhancing nuclear hormone receptor-mediated transcriptional activation is widely accepted, and this work suggests that Tip60 may have an equally important role to play.
Acetyltransferases↗
FGF8 over-expression in prostate cancer is associated with decreased patient survival and persists in androgen independent disease.
Identification of prostate cancers at high risk of progression is difficult and a better understanding of how peptide growth factors influence cellular function might be useful. Fibroblast growth factors (FGFs) have been implicated in prostate cancer development. FGF8 was identified in the Shionogi mouse mammary carcinoma SC-3 cell line as an androgen-induced mitogen. We tested if FGF8 was over-expressed in human prostate cancer and if its expression correlated with clinical data and outcome. One hundred and six cases of prostate cancer and ten cases of BPH were examined. In situ hybridization was employed to detect FGF8 mRNA expression, which was identified within the malignant prostatic epithelium in 85/106 (80.2%) cases. Increased expression of FGF8 correlated significantly with higher Gleason scores (P=0.0004) and advanced tumour stage (P=0.0016). Using immunohistochemistry, we confirmed over-expression of the FGF8b isoform. Men with tumours which expressed high levels of FGF8 had worse survival (P=0.034), although FGF8 mRNA was not able to provide additional prognostic information in a multivariate analysis. Additionally, FGF8 expression was shown to persist in androgen independent prostate cancer. Using a range of normal adult tissues, FGF8 expression was restricted to neurones and the germinal epithelium in addition to the prostate. In vitro studies demonstrated that in the presence of neutralizing antibody to FGF8b there was significant inhibition of prostate cancer cell growth, confirming the biological significance of FGF8 in prostate carcinogenesis.
Adult↗
Laser ablation of urethral hair.
BACKGROUND AND OBJECTIVE: Two separate cases involving laser ablation of hair follicles in the neourethra are described. STUDY DESIGN/MATERIALS AND METHODS: Urethral hair developed secondarily to free-flap urethroplasty for congenital urethral defects. In both cases, cystoscopic depilation with electrocautery fulguration was attempted on multiple occasions. RESULTS: No improvement was seen; therefore, laser ablation was employed. Both patients remain free of regrowth at greater than one year of follow-up.
Adult↗
aFGF immunoreactivity in prostate cancer and its co-localization with bFGF and FGF8.
Fibroblast growth factors (FGFs) have been implicated in the development of numerous malignancies including prostate cancer. In a pilot study it has been shown that FGF8 mRNA is up-regulated in prostate cancer. The aim of the present study was to determine whether aFGF and bFGF were co-expressed with FGF8 in human prostate cancer. Twenty-nine cases of prostate cancer of different histological grades were examined. Immunohistochemical analysis was employed to study aFGF and bFGF expression. In the light of the results, aFGF immunoreactivity was studied in a further 43 cases. aFGF and bFGF immunoreactivity was identified in the cytoplasm of the malignant prostatic epithelium. aFGF was overexpressed in 62/72 (86.1 per cent) cases and bFGF in 19/29 (65.5 per cent). High levels of aFGF immunoreactivity were noted in areas of high-grade prostatic intraepithelial neoplasia (PIN). In this series, aFGF immunoreactivity was most commonly observed and correlated closely with Gleason score and tumour stage ( p=0.007 and 0.007, respectively). Co-localization of aFGF, bFGF, and FGF8 was detected in 9/29 (31.0 per cent) cases. There was a significant correlation between aFGF and FGF8 expression. In conclusion, aFGF, bFGF, and FGF8 are co-localized in human prostate cancer; they may have a synergistic effect in prostate cancer growth and progression.
Aged↗
Host defense mechanisms in urinary tract infections.
The host response to urinary tract infections is directed against both bacterial surface antigens, as well as bacterial products. The local response is perhaps the most important, with prevention of binding and tissue invasion as the hallmarks. Once an infection is established, the humoral immune system is most active in curtailing the damage and clearing the infecting organism. The prostate has a specialized complex of defenses that serves to reduce the incidence of infections in males.
Antibody Formation↗