Urologist led one-stop testicular clinic: the UK 'gold standard'.

Prompt diagnosis and early treatment for testicular cancer is vital. To help with this a one-stop, urologist run, testicular clinic with testicular ultrasound scanning as an integral part of the clinic format was introduced to investigate patients in an efficient and timely manner. The aim of this study was to assess the feasibility and efficiency of running a one-stop testicular clinic. A prospectively collected electronic database of all patients attending a one-stop testicular clinic at a busy university hospital was interrogated over a 6-year period. Only new referral males, above the age of 15 years old were included. Case notes were reviewed retrospectively. A total of 1757 patients were found with a median age of 36. 6.3 % had a suspicious ultrasound scan and overall 5.6 % were found to have malignancy histologically. In addition a significant proportion of men with a history of testicular maldescent went on to develop testicular cancer (p < 0.01). Median time from referral to clinic and clinic to orchidectomy for suspected testicular cancers was 9 and 5 days respectively (95 % CI). Some of the benefits of a urologist run one-stop testicular clinic include: timely diagnosis and treatment, early reassurance with normal investigations, the discovery of clinically unsuspecting malignancy and the increase in teaching opportunities. These collective benefits must improve patient experience and benefit the department as a whole. A urologist led one-stop testicular clinic should be regarded as the gold standard.

Cadherin switching dictates the biology of transitional cell carcinoma of the bladder: ex vivo and in vitro studies.

Bladder cancer is the fifth most common malignancy in the UK. Clinically, the most important process in determining prognosis is the development of invasion, initially of the lamina propria and then beyond as these transitional cell carcinomas (TCCs) progress from stage pT1 to stages T2+. Cadherins and catenins are the main mediators of cell-cell interactions in epithelial tissues, and loss of membranous E-cadherin immunoreactivity is strongly correlated with high grade, advanced stage and poor prognosis in bladder cancer and other malignancies. However, the role of P-cadherin is yet to be fully elucidated in bladder TCC. The objectives of this study were to establish how the expression of cadherins and catenins determines clinical and in vitro behaviour in bladder TCC. Utilizing immunohistochemistry, immunofluorescence and western blotting, we demonstrated a significant reduction in the expression of E-cadherin and beta-catenin as grade and stage of bladder TCC progress, accompanied by a significant increase in P-cadherin expression (all p < 0.05, Pearson's chi2 test). Increased P-cadherin expression was also associated with a significantly worse bladder cancer-specific survival (log rank p = 0.008), with Cox regression showing P-cadherin to be an independent prognostic factor. Utilizing a variety of tissue culture models in a range of functional studies, we demonstrated that P-cadherin mediates defective cell-cell adhesion and enhances anchorage-independent growth. The results provide evidence that increased P-cadherin expression promotes a more malignant and invasive phenotype of bladder cancer, and appears to have a novel role late in the disease.

Bicalutamide (Casodex) 150 mg plus standard care in early non-metastatic prostate cancer: results from Early Prostate Cancer Trial 24 at a median 7 years' follow-up.

Trial 24, one of three ongoing trials in the Early Prostate Cancer programme, is evaluating the efficacy and tolerability of bicalutamide (Casodex) 150 mg following standard care (radiotherapy, radical prostatectomy or watchful waiting) in patients with early, non-metastatic prostate cancer. At 7 years' median follow-up, addition of bicalutamide significantly improved objective progression-free survival (PFS) for patients with locally advanced disease, reducing the risk of progression by 34% versus standard care alone (hazard ratio 0.66; 95% confidence interval 0.55, 0.79; P<0.001). In localized disease, a significant difference in objective PFS was not found. There was no significant difference in overall survival.

Bicalutamide ('Casodex') 150 mg in addition to standard care in patients with nonmetastatic prostate cancer: updated results from a randomised double-blind phase III study (median follow-up 5.1 y) in the early prostate cancer programme.

Trial 24 is one of three placebo-controlled trials within the ongoing bicalutamide ('Casodex') Early Prostate Cancer (EPC) programme evaluating bicalutamide 150 mg/day in addition to radical prostatectomy, radiotherapy or watchful waiting for T1b-4, any N, M0 prostate cancer. In Trial 24, at 5.1 y median follow-up, the addition of bicalutamide significantly (P < 0.0001) improved objective progression-free survival (PFS) and prostate-specific antigen PFS compared with standard care alone. There was no significant difference in overall survival (P = 0.746). In the context of the whole EPC programme, long-term bicalutamide is not appropriate for localised disease, yet provides advantages in delaying disease progression in patients with locally advanced prostate cancer.

CD40 expression in prostate cancer: a potential diagnostic and therapeutic molecule.

CD40, a member of the TNF receptor superfamily, is widely expressed on human immune cells. It is also frequently expressed on epithelial malignancies, suggesting that CD40 may contribute to the pathogenesis of some cancers. Activation of CD40 in cancer cells induces growth inhibition and sensitization to apoptotic stimuli. This study investigates CD40 expression in archival tissue from patients with prostate cancer. In all cases, normal prostatic acini expressed CD40, however, in 56 of 57 cases of prostate cancer no CD40 expression was detected. In the one other case, patchy CD40 expression was associated with prostatic in situ neoplasia. In conclusion, invasive prostate cancer is a CD40-negative tumour. These data may be relevant as a diagnostic tool; in providing insight into progression of cancer from normal epithelium; and in identifying novel therapeutic strategies for prostate cancer.

An antagonist of retinoic acid receptors more effectively inhibits growth of human prostate cancer cells than normal prostate epithelium.

Screening of synthetic retinoids for activity against prostate carcinoma cell lines has identified antagonists of retinoic acid receptors (RARs) as potent growth inhibitors (Hammond et al, 2001, Br J Cancer 85, 453-462). Here we report that 5 days of exposure to a high-affinity pan-RAR antagonist (AGN194310) abolished growth of prostate carcinoma cells from 14 out of 14 patients, with half-maximal inhibition between 200 and 800 nM. It had similar effects (at approximately 250 nM) on the prostate carcinoma lines LNCaP, DU-145 and PC-3. AGN194310 inhibited the growth of normal prostate epithelium cells less potently, by 50% at approximately 1 microM. The growth of tumour cells was also inhibited more than that of normal cells when RARbeta together with RARgamma, but not RARalpha alone, were antagonised. Treatment of LNCaP cells with AGN194310 arrested them in G1 of cell cycle within 12 h, with an accompanying rise in the level of p21(waf1). The cells underwent apoptosis within 3 days, as indicated by mitochondrial depolarisation, Annexin V binding and DNA fragmentation. Apoptosis was caspase-independent: caspases were neither cleaved nor activated, and DNA fragmentation was unaffected by the pan-caspase inhibitor Z-VAD-FMK. The ability of AGN 194310 to induce apoptosis of prostate cancer cells and its differential effect on malignant and normal prostate epithelial cells suggests that this compound may be useful in the treatment of prostate cancer.

Is the efficacy of hormonal therapy affected by lymph node status? data from the bicalutamide (Casodex) Early Prostate Cancer program.

OBJECTIVES: To report an exploratory subgroup analysis assessing the extent to which the overall benefit found in the Early Prostate Cancer program is dependent on lymph node status at randomization. The program is ongoing, and the overall survival data are immature. The first combined analysis of the bicalutamide (Casodex) Early Prostate Cancer program at 3 years' median follow-up showed that bicalutamide, 150 mg once daily, plus standard care (radical prostatectomy, radiotherapy, or watchful waiting), significantly reduced the risk of objective progression and prostate-specific antigen (PSA) doubling in patients with localized/locally advanced prostate cancer. METHODS: Men (n = 8113) with localized/locally advanced disease received bicalutamide 150 mg or placebo once daily, plus standard care. The time to event data (objective progression, PSA doubling) was analyzed by lymph node status at randomization. RESULTS: Compared with standard care alone, bicalutamide significantly reduced the risk of objective progression, irrespective of lymph node status, with the most pronounced reduction in patients with N+ (hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.15 to 0.56) compared with those with N0 (HR 0.59; 95% CI 0.48 to 0.73) and Nx (HR 0.60; 95% CI 0.50 to 0.72) disease. The largest decrease in risk of PSA doubling with bicalutamide was observed in N+ disease (HR 0.16; 95% CI 0.09 to 0.29), with significantly reduced risks seen in N0 (HR 0.45; 95% CI 0.40 to 0.51) and Nx (HR 0.38; 95% CI 0.33 to 0.44) disease. CONCLUSIONS: The greatest reduction in the risk of objective progression and PSA doubling with bicalutamide was seen in patients with N+ disease. However, bicalutamide also provided a statistically significant benefit in those with N0 and Nx disease.

Long-term results of a phase II study of synchronous chemoradiotherapy in advanced muscle invasive bladder cancer.

We conducted a phase I/II study investigating synchronous chemoradiotherapy with mitomycin C and infusional 5-fluorouracil (5-FU) in muscle invasive bladder cancer. Early dose escalation results were previously published. We report the long-term toxicity and efficacy results with the optimised regimen. Patients with muscle invasive bladder cancer with glomerular filtration rate >25 ml min(-1) were eligible. Mitomycin (12 mg m(-2) on day 1 only) and infusional 5-FU (500 mg m(-2) day(-1)) for 5 days were administered during weeks 1 and 4 of radiotherapy of 55 Gy in 20 fractions. A total of 41 patients were enrolled, median age was 68 years, 33 were male and eight female patients. Out of the 41 patients, 20 (49%) had hydronephrosis at presentation and 25 (62%) had T3b or T4 disease. Four patients experienced Grade III thrombocytopenia and three patients had Grade III neutropenia. There were no episodes of febrile neutropenia. Four patients experienced Grade III diarrhoea and 1 Grade III urgency and dysuria. Six patients did not undergo cystoscopic evaluation due to early metastatic spread although there was no clinical suggestion of bladder failure. In all, out of 35 evaluable patients, 25 (71%) had macroscopic complete response at 3-month cystoscopy, and biopsy confirmed in 24 out of 25. A total of 16 (39%) patients remain alive with a median follow-up of 50.7 (range 23.5-68.8) months, 14 with a functioning bladder with no reported long-term treatment-related bladder or bowel toxicity. Five out of 41 patients have undergone salvage cystectomy: two for persistent CIS, two T1 and one muscle invasive recurrence. Four patients have received intravesical chemotherapy, of whom two remain alive with a functioning bladder. Overall 12-, 24- and 60-month (m) survival rates were 68, 49 and 36%. Local and distant progression free rates were 82 and 86% at 12-m and 79 and 75% at 24-m. Organ preservation using multimodality therapy is feasible and safe, even in patients with poor renal reserve, and does not compromise salvage therapies. A national phase III trial BC2001 (www.bc2001.org.uk) exploring the effects of synchronous chemoradiotherapy with this regimen is currently recruiting.

The role of beta-catenin signaling in the malignant potential of cystitis glandularis.

PURPOSE: Chronic inflammation is a risk factor for malignant transformation in the bladder. The pro-inflammatory cytokine tumor necrosis factor-alpha (TNFalpha) is a mediator of such inflammation that induces nuclear localization of the adherens junction component beta-catenin. This mechanism has a key role in the initiation and progression of the premalignant lesion Barrett's metaplasia of the esophagus. Cystitis glandularis is a metaplastic lesion of the bladder urothelium occurring in the presence of chronic inflammation and in up to 13% of asymptomatic bladders. Two subtypes are described (typical and intestinal/colonic) with uncertain malignant potential. Etiologically and histologically cystitis glandularis mimics Barrett's metaplasia. We investigated the roles of beta-catenin and TNFalpha in cystitis glandularis. MATERIALS AND METHODS: Immunohistochemistry and immunofluorescence were used to demonstrate the expression and localization of E-cadherin, beta-catenin and TNFalpha in 9 sections of typical cystitis glandularis and 4 of intestinal/colonic cystitis glandularis. Appropriate controls were used for all experiments. RESULTS: Immunohistochemistry demonstrated normal membranous expression of E-cadherin and beta-catenin in all cystitis glandularis sections with increased TNFalpha expression. Immunofluorescence showed nuclear localization of beta-catenin in the intestinal/colonic subtype only, which was not observed in typical cystitis glandularis. CONCLUSIONS: The presence of nuclear beta-catenin suggests that intestinal/colonic cystitis glandularis shares the same signaling pathway with the premalignant lesion Barrett's metaplasia of the esophagus and the intestinal/colonic subtype of cystitis glandularis may have the potential to progress to malignancy. This finding has important implications for the management of this lesion.

Management of renal angiomyolipoma in patients with tuberous sclerosis complex.

Renal angiomyolipomas are common in patients with tuberous sclerosis complex (TSC), and the risk of severe haemorrhage from these angiomyolipomas can become substantial. This case illustrates a potentially life-threatening condition due to the development of a large aneurysm within an angiomyolipoma, which was discovered within 14 months of her screening renal ultrasound scan. Renal arterial embolisation and renal sparing surgery resulted in good recovery. Clear guidelines for the screening, surveillance, and treatment of angiomyolipomas in patients with TSC are required. This includes the appropriate frequency of surveillance for patients in different age groups and at different stages of angiomyolipoma development, based on a growing knowledge of the natural history of this condition, since growth of renal angiomyolipomas can be rapid and asymptomatic. Computed tomography or magnetic resonance imaging may be required to demonstrate complications in large lesions, as three ultrasound examinations in this patient failed to detect the large aneurysm which had developed. Angiogenesis inhibitors could potentially play a role in preventing the development of angiomyolipomas, which could improve the prognosis for patients with TSC and therefore warrants investigation through phase II/III clinical trials.

Luteinising hormone releasing hormone analogues in the treatment of prostate cancer.

The use of the luteinising hormone releasing hormone (LHRH) analogues--goserelin (Zoladex, AstraZeneca) and leuprorelin (Prostap, Wyeth)--is well established and forms the backbone of the treatment of locally advanced and metastatic prostate cancer. Comparable efficacy with orchidectomy and, historically, diethylstilbestrol (DES) is accepted, with the advantages of reversibility and limited thromboembolic and cardiovascular toxicity, respectively. Side effects such as hot flushes, loss of libido, lethargy and decreased bone mineral density have recently stimulated more interest in the use of non-steroidal anti-androgens such as bicalutamide (Casodex, AstraZeneca) in locally advanced disease. Although better tolerated, bicalutamide has significant problems with gynaecomastia and breast pain. Maximal androgen blockade using LHRH analogues and their adjuvant use with radiotherapy are discussed, as well as their experimental application in intermittent androgen suppression therapy. Similar side effect profiles are reported for the LHRH analogues but injection tolerability differs with the smaller 23G needle for Prostap 3 compared to the 16G needle for Zoladex LA. There is no evidence to suggest a difference in the efficacy between the LHRH analogues goserelin and leuprorelin, although no direct comparison has yet been undertaken.

Haematospermia: in the context of a genitourinary medicine setting.

Haematospermia should be taken more seriously. Although it is usually benign and self-limiting, it provokes great anxiety in patients. Malignancy is generally rare, but it should particularly be considered in older patients (40 years old or above). Recent investigative modalities, especially non-invasive, have made diagnosis feasible in most cases. What will constitute a reasonable approach to the problem of haematospermia in the context of a genitourinary medicine setting? A detailed history and physical examination, including genital and rectal examination, would be necessary. Initial investigations could include screening for STIs, urine examination and full blood count. Few patients will need further investigations, which will depend on the findings in patients' history and examination as well as the nature of the bleeding. Patients should be given a detailed explanation of their condition, and a plan of management and follow up should be made clear to them. Treatment depends on the underlying cause but often simply involves reassurance. Referral to a urologist may include patients with recurrent or persistent haematospermia, those with associated symptoms and patients who are 40 years old or above.

Does smoking status influence the prognosis of bladder cancer? A systematic review.

OBJECTIVE: To summarize, in a systematic review, the evidence for the effect of stopping smoking on recurrence, cancer-specific and all cause-mortality among smokers with newly diagnosed bladder cancer. MATERIALS AND METHODS: Two electronic databases and the reference lists of identified primary studies and reviews were searched. Studies were included if a hazard ratio and its confidence intervals could be extracted. A predefined set of study characteristics was extracted which defined whether studies were giving valid prognostic data on the effects of smoking in reasonably homogenous cohorts. The results of studies were synthesized qualitatively. RESULTS: Fifteen relevant studies were identified; former and current smokers were combined in many studies. Many studies produced information on prognosis that was confounded by the mixing of incident and prevalent cases. Only three studies examined the influence of smoking on prognosis in only incident cases, most of whom had superficial disease. Of these, only one was of high quality. These three studies and the other 12 showed suggestive evidence that continued smoking or a lifetime of smoking constitutes a moderate risk factor for recurrence and death, and that stopping smoking could favourably change this. However, the evidence base for this is weak because of the methodological shortcomings and because most studies' results were not statistically significant. A life-table model showed that if stopping smoking altered the prognosis, the size of the benefit would be clinically worthwhile. CONCLUSION: There is suggestive evidence that stopping smoking might favourably alter the course of bladder cancer, but this is insufficient for clinicians to inform patients that doing so will improve their prognosis, and for providing specialized services to assist in stopping smoking to patients with bladder cancer.

Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program.

PURPOSE: We determine the efficacy and tolerability of bicalutamide as immediate therapy, either alone or as adjuvant to treatment of curative intent, in patients with clinically localized or locally advanced prostate cancer. MATERIALS AND METHODS: This international program consists of 3 ongoing, randomized, double-blind, placebo controlled clinical trials (trials 23, 24, and 25). Men with localized or locally advanced (T1-T4, Nx/N0, M0) prostate cancer were randomized to receive 150 mg. bicalutamide daily or placebo, in addition to standard care with radical prostatectomy, radiotherapy or watchful waiting. Primary end points are time to objective progression and overall survival. In this first analysis data from the trials were combined in a single overview analysis according to protocol. RESULTS: Data are available for 8,113 patients (4,052 randomized to bicalutamide, 4,061 to standard care alone) at a median followup of 3.0 years. Treatment with bicalutamide provided a highly significant reduction of 42% in the risk of objective progression compared with standard care alone (9.0% versus 13.8%, hazards ratio 0.58; 95% confidence interval 0.51, 0.66; p <<0.0001). The overall result was reflected in 2 of the 3 trials (trials 24 and 25) with trial 3 (trial 23) showing a nonsignificant difference at this time. Reductions in the risk of disease progression were seen across the entire patient population, irrespective of primary treatment or disease stage. Overall survival data are currently immature and longer followup will determine if there is also a survival benefit with bicalutamide. The most frequently reported side effects of bicalutamide were gynecomastia and breast pain. CONCLUSIONS: Immediate treatment with 150 mg. bicalutamide daily, either alone or as adjuvant to treatment of curative intent, significantly reduces the risk of disease progression in patients with localized or locally advanced prostate cancer. This benefit must be balanced with the morbidity associated with long-term hormonal therapy. Followup is ongoing to determine potential survival benefits of this treatment approach.

Delay and survival in bladder cancer.

OBJECTIVE: To assess in detail and evaluate the effect on survival of delays in the diagnosis and treatment of cancer (which might lead to a worse prognosis), dividing the delay from onset of symptoms to first treatment into several components, comprising patient delay, general practitioner (GP) delay, and two or more periods of hospital delay. PATIENTS AND METHODS: Data were prospectively collected on 1537 new cases of urothelial cancer in the West Midlands from 1 January 1991 to 30 June 1992. Death information was obtained from the West Midlands Cancer Intelligence Unit and censored at 31 July 2000. The influence of delay times on survival was explored. RESULTS: The median delay from onset of symptoms to GP referral was 14 days (Delay 1), from GP referral to first hospital attendance was 28 days (Delay 2), and from first hospital attendance to first transurethral resection of bladder tumour was 20 days (Delay 3). The median hospital delay (Delay 2 + 3) was 68 days and the median total delay (Delay 1 + 2 + 3) was 110 days. Patients with a shorter Delay 1 had a lower tumour stage and a 5% better 5-year survival. Patients with a shorter hospital delay had worse survival; total delay had no effect on survival. CONCLUSIONS: There was significantly better survival for patients referred to hospital within 14 days of the onset of symptoms. The relationship between delay and survival in bladder cancer is complex. Hospital delays may be influenced more by comorbidity than by the characteristics of the tumour. However, the adverse effects of delay seem to be most pronounced for patients with pT1 tumours.