Current perspectives in bladder cancer management.

More than 350,000 new cases of bladder cancer are diagnosed worldwide each year; the vast majority (> 90%) of these are transitional cell carcinomas (TCC). The most important risk factors for the development of bladder cancer are smoking and occupational exposure to toxic chemicals. Painless visible haematuria is the most common presenting symptom of bladder cancer; significant haematuria requires referral to a specialist urology service. Cystoscopy and urine cytology are currently the recommended tools for diagnosis of bladder cancer. Excluding muscle invasion is an important diagnostic step, as outcomes for patients with muscle invasive TCC are less favourable. For non-muscle invasive bladder cancer, transurethral resection followed by intravesical chemotherapy (typically Mitomycin C or epirubicin) or immunotherapy [bacillus Calmette-Guérin (BCG)] is the current standard of care. For patients failing BCG therapy, cystectomy is recommended; for patients unsuitable for surgery, the choice of treatment options is currently limited. However, novel interventions, such as chemohyperthermia and electromotive drug administration, enhance the effects of conventional chemotherapeutic agents and are being evaluated in Phase III trials. Radical cystectomy (with pelvic lymphadenectomy and urinary diversion) or radical radiotherapy are the current established treatments for muscle invasive TCC. Neoadjuvant chemotherapy is recommended before definitive treatment of muscle invasive TCC; cisplatin-containing combination chemotherapy is the recommended regimen. Palliative chemotherapy is the first-choice treatment in metastatic TCC.

Developing Healthcare Team Observations for Patient Safety (HTOPS): senior medical students capture everyday clinical moments.

BACKGROUND: Aviation has used a real-time observation method to advance anonymised feedback to the front-line and improve safe practice. Using an experiential learning method, this pilot study aimed to develop an observation-based real-time learning tool for final-year medical students with potential wider use in clinical practice. METHODS: Using participatory action research, we collected data on medical students' observations of real-time clinical practice. The observation data was analysed thematically and shared with a steering group of experts to agree a framework for recording observations. A sample of students (observers) and front-line clinical staff (observed) completed one-to-one interviews on their experiences. The interviews were analysed using thematic analysis. RESULTS: Thirty-seven medical students identified 917 issues in wards, theatres and clinics in an acute hospital trust. These issues were grouped into the themes of human influences, work environment and systems. Aviation approaches were adapted to develop an app capable of recording real-time positive and negative clinical incidents. Five students and eleven clinical staff were interviewed and shared their views on the value of a process that helped them learn and has the potential to advance the quality of practice. Concerns were shared about how the observational process is managed. CONCLUSION: The study developed an app (Healthcare Team Observations for Patient Safety-HTOPS), for recording good and poor clinical individual and team behaviour in acute-care practice. The process advanced medical student learning about patient safety. The tool can identify the totality of patient safety practice and illuminate strength and weakness. HTOPS offers the opportunity for collective ownership of safety concerns without blame and has been positively received by all stakeholders. The next steps will further refine the app for use in all clinical areas for capturing light noise.

Epidermal growth factor receptor status predicts local response to radical radiotherapy in muscle-invasive bladder cancer.

AIMS: Epidermal growth factor receptor (EGFR) is expressed by over 70% of muscle-invasive bladder tumours and is associated with diminished overall survival. In model tumour systems, ionising radiation has been shown to activate EGFR, leading to cellular proliferation and is therefore a possible mechanism of underlying radioresistance. We carried out an immunohistochemical study relating the clinical outcome of patients receiving radical radiotherapy for muscle-invasive bladder cancer to tumour EGFR status. MATERIALS AND METHODS: Archived paraffin-embedded tumours from 110 consecutive patients receiving radical radiotherapy for muscle-invasive bladder cancer between 1991 and 1997 were immunohistochemically stained for EGFR. Data were collected concerning the tumour stage and grade, the presence of ureteric obstruction, the response to radiotherapy at 3 months, local recurrence rates, metastatic spread and survival. Multivariate analysis of potential independent prognostic factors of impaired bladder cancer-specific survival was carried out using Cox's regression. RESULTS: Of 110 tumours, 79 (72%) stained positively for EGFR. Of 87 patients undergoing the 3-month check cystoscopy, 60 (69%) had a positive response to radiotherapy. A positive response to radiotherapy correlated significantly with a negative EGFR status (chi(2) test, P = 0.05). Kaplan-Meier survival analysis revealed a trend towards improved bladder cancer-specific survival in EGFR-negative patients (Log-rank, P = 0.10). A lack of response to radiotherapy at 3 months, local recurrence, metastatic spread and the presence of ureteric obstruction were all independent prognostic factors for diminished bladder cancer-specific survival (Cox's regression: P = 0.009, P = 0.001, P = 0.04 and P = 0.005, respectively). CONCLUSIONS: EGFR status predicts the local response to radiotherapy but does not provide prognostic utility in relation to overall or bladder cancer-specific survival. As EGFR status seems to be linked to the initial response to radiotherapy, its inhibition may be a means of enhancing the radio-responsiveness of these poor prognosis tumours. Colquhoun, A. J.

Oxidative stress and cyclooxygenase activity in prostate carcinogenesis: targets for chemopreventive strategies.

Over the last decade, epidemiological, experimental and clinical studies have implicated oxidative stress in the development and progression of prostate cancer. Oxidative stress may be linked to the effects of androgens, anti-oxidant systems and the pre-malignant condition, high-grade prostatic intraepithelial neoplasia. Cyclooxygenase-2 activity has been linked with prostate carcinogenesis. Evidence suggests that oxidative stress and cyclo-oxygenase-2 activity may be mechanistically linked. Agents such as anti-oxidants and cyclo-oxgenase-2 inhibitors may be of value in the chemoprevention of prostate cancer. The feasibility of intervention with such agents will depend on the development and validation of biomarkers for clinical trials, particularly markers of oxidative damage caused by reactive oxygen species (ROS). A greater understanding of the molecular events associated with oxidative stress will enhance the development of such biomarkers and should result in better strategies for the chemoprevention of prostate cancer.

A prospective audit of hypospadias correction in a regional paediatric surgery centre.

AIM: To prospectively review the management and treatment of hypospadias in a single regional centre, and in particular, to assess the spectrum of cases treated, techniques used and to determine the nature of the complications. METHODS: One hundred and fifty-three consecutive boys undergoing hypospadias repair during a 36-month period were included in the study. Information was collected prospectively and included the site of the urethral meatus, presence of chordee, surgical technique employed, use of urinary diversion, and the prescription of postoperative antibiotics and analgesics. Patients were assessed in the clinic following surgery at which time information on outcome and complications was obtained. RESULTS: One hundred and fifty-seven procedures for hypospadias were performed. Single-stage reconstruction was performed in 145 boys. GRAP (glanular reconstruction and preputioplasty) repair was the most common operation employed (n=112). The overall fistula rate was 11.7 % with the majority of patients having a satisfactory functional and cosmetic outcome following surgery. CONCLUSION: A variety of techniques can be employed to provide satisfactory correction of hypospadias with an increasing emphasis on single-stage day case procedures. GRAP repair is the favoured option for distal hypospadias and incorporates preservation of the prepuce.

Systematic review of the clinical effectiveness and cost-effectiveness of photodynamic diagnosis and urine biomarkers (FISH, ImmunoCyt, NMP22) and cytology for the detection and follow-up of bladder cancer.

OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of photodynamic diagnosis (PDD) compared with white light cystoscopy (WLC), and urine biomarkers [fluorescence in situ hybridisation (FISH), ImmunoCyt, NMP22] and cytology for the detection and follow-up of bladder cancer. DATA SOURCES: Major electronic databases including MEDLINE, MEDLINE In-Process, EMBASE, BIOSIS, Science Citation Index, Health Management Information Consortium and the Cochrane Controlled Trials Register were searched until April 2008. REVIEW METHODS: A systematic review of the literature was carried out according to standard methods. An economic model was constructed to assess the cost-effectiveness of alternative diagnostic and follow-up strategies for the diagnosis and management of patients with bladder cancer. RESULTS: In total, 27 studies reported PDD test performance. In pooled estimates [95% confidence interval (CI)] for patient-level analysis, PDD had higher sensitivity than WLC [92% (80% to 100%) versus 71% (49% to 93%)] but lower specificity [57% (36% to 79%) versus 72% (47% to 96%)]. Similar results were found for biopsy-level analysis. The median sensitivities (range) of PDD and WLC for detecting lower risk, less aggressive tumours were similar for patient-level detection [92% (20% to 95%) versus 95% (8% to 100%)], but sensitivity was higher for PDD than for WLC for biopsy-level detection [96% (88% to 100%) versus 88% (74% to 100%)]. For more aggressive, higher-risk tumours the median sensitivity of PDD for both patient-level [89% (6% to 100%)] and biopsy-level [99% (54% to 100%)] detection was higher than those of WLC [56% (0% to 100%) and 67% (0% to 100%) respectively]. Four RCTs comparing PDD with WLC reported effectiveness outcomes. PDD use at transurethral resection of bladder tumour resulted in fewer residual tumours at check cystoscopy [relative risk, RR, 0.37 (95% CI 0.20 to 0.69)] and longer recurrence-free survival [RR 1.37 (95% CI 1.18 to 1.59)] compared with WLC. In 71 studies reporting the performance of biomarkers and cytology in detecting bladder cancer, sensitivity (95% CI) was highest for ImmunoCyt [84% (77% to 91%)] and lowest for cytology [44% (38% to 51%)], whereas specificity was highest for cytology [96% (94% to 98%)] and lowest for ImmunoCyt [75% (68% to 83%)]. In the cost-effectiveness analysis the most effective strategy in terms of true positive cases (44) and life-years (11.66) [flexible cystoscopy (CSC) and ImmunoCyt followed by PDD in initial diagnosis and CSC followed by WLC in follow-up] had an incremental cost per life-year of over 270,000 pounds. The least effective strategy [cytology followed by WLC in initial diagnosis (average cost over 20 years 1403 pounds, average life expectancy 11.59)] was most likely to be considered cost-effective when society's willingness to pay was less than 20,000 pounds per life-year. No strategy was cost-effective more than 50% of the time, but four of the eight strategies in the probabilistic sensitivity analysis (three involving a biomarker or PDD) were each associated with a 20% chance of being considered cost-effective. In sensitivity analyses the results were most sensitive to the pretest probability of disease (5% in the base case). CONCLUSIONS: The advantages of PDD's higher sensitivity in detecting bladder cancer have to be weighed against the disadvantages of a higher false-positive rate. Taking into account the assumptions made in the model, strategies involving biomarkers and/or PDD provide additional benefits at a cost that society might be willing to pay. Strategies replacing WLC with PDD provide more life-years but it is unclear whether they are worth the extra cost.

Metastasis-associated protein S100A4: spotlight on its role in cell migration.

S100A4 (also known as Mts1, metastasin, p9Ka, pEL98, CAPL, calvasculin, Fsp-1, placental calcium-binding protein) belongs to the family of EF-hand calcium-binding proteins, whose expression is elevated in a number of pathological conditions. Although it is well documented that S100A4 is expressed in cancer cells and contributes to tumor cell motility and metastatic progression, the exact underlying mechanisms remain elusive. An important characteristic feature of S100 proteins is their dual function, inside and outside the cell. In this review, we focus on the intracellular function of S100A4. The review contains structural analysis of S1004 in comparison with other members of S100 proteins. Possible modes of the interaction of S100 proteins with targets are described. Several examples of best-studied molecular interactions involving S100A4 with heavy chain of nonmuscle myosin IIA, LAR-interacting protein liprin beta1 and tumor suppressor protein p53 are provided. We suggest that the binding of S100A4 to these molecules is critical for the S100A4 function. Further studies of the implications of these interactions in different molecular pathways may shed additional light on the role of S100A4 protein in the control of tumor cell motility and migration. We discuss the approaches for down-regulation of S100A4 expression and their potential for application in the clinics.

Evolving immunotherapeutic strategies in bladder and renal cancer.

For patients with urological cancers, immunotherapy is currently a treatment option for metastatic renal cell carcinoma, and those with "high risk" superficial bladder cancers. In this review, our current understanding of tumour immune escape is discussed. The principles and role of current immunotherapies for these tumours are described, and new areas of immunotherapeutic promise are highlighted.

Treatment of carcinoma in situ with intravesical bacillus Calmette-Guerin without maintenance.

PURPOSE: Data concerning the relative efficacy of intravesical bacillus Calmette-Guerin (BCG) on subgroups of carcinoma in situ of the bladder are limited. We report the outcome of primary carcinoma in situ and carcinoma in situ associated with Ta or T1 transitional cell carcinoma of the bladder treated with BCG. MATERIALS AND METHODS: Between 1987 and 1997, 135 patients (median age 70 years) with biopsy proven bladder carcinoma in situ underwent a standard course of 6 BCG instillations. Patients were divided into group 1-23 patients with primary carcinoma in situ, group 2-37 with carcinoma in situ associated with Ta transitional cell carcinoma and group 3-75 with carcinoma in situ associated with T1 transitional cell carcinoma. RESULTS: Median followup was 41 months. For groups 1 to 3, complete response rates at 3 months were 74% (17 of 23 cases), 70% (26 of 37) and 75% (56 of 75), respectively. The overall progression rates at 5 years were 20% (3 of 15 cases), 18% (4 of 22) and 49% (25 of 51). Cancer specific survival rates were 83% (10 of 12 patients), 86% (12 of 14) and 59% (17 of 29), and the numbers of patients alive with the bladder intact were 60% (9 of 15), 58% (11 of 19) and 30% (12 of 40). Patients in group 3 treated with BCG had progression significantly earlier than those in groups 1 and 2 (log-rank test p = 0.013). A complete response to BCG in group 3 patients significantly delayed time to progression (Cox regression p = 0.001) but did not reduce death from transitional cell carcinoma. Indeed, only 38% (8 of 21) of complete responders were alive with the bladder intact at 5 years. CONCLUSIONS: A single course of BCG is remarkably effective for primary carcinoma in situ and carcinoma in situ associated with Ta transitional cell carcinoma but is suboptimal in patients with carcinoma in situ associated with T1 transitional cell carcinoma. Better outcomes in each of the 3 groups may have occurred with maintenance BCG.

Cytologic analysis of ureteral washings is informative in patients with grade 2 upper tract TCC considering endoscopic treatment.

OBJECTIVES: To determine the diagnostic accuracy of ureteroscopic biopsy and whether exfoliated cell cytology can improve diagnostic accuracy. METHODS: Sixty-two cases of upper tract transitional cell carcinoma were diagnosed by ureteroscopic biopsy and treated by nephroureterectomy. Stage and grade evaluation was possible in 51 cases. Cytology for exfoliated cells from the ureter/pelvis was available in 48 cases. RESULTS: Biopsies were staged as Tis in 3, Ta in 35, and T1 in 13 and graded as G1 in 6, G2 in 32, and G3 in 13. Cytology was positive/suspicious in 40% (19 of 48). The biopsy grade accurately predicted the pathologic grade (P <0.0001) and stage (P = 0.001). The biopsy stage was not associated with the final stage (P = 0.112, Fisher's exact test). Biopsy G3 accurately predicted high-grade (G3) transitional cell carcinoma in 92% (12 of 13) of cases. The remaining 1 case was G2 by final histologic examination. No case of high-grade (G3) disease was found in the 6 G1 biopsies (100%). Of 32 G2 biopsies, 9 were upgraded to G3. Cytology was available for 8 of the 9 and 5 (63%) were positive. For patients with G2 biopsies, combining cytology and biopsy grade improved the sensitivity and specificity of high-grade tumor detection from 43% to 55% and 23% to 85%, respectively. CONCLUSIONS: The results of this study have shown that biopsy grade reflects the pathologic stage and grade. Combining exfoliated cell cytology improved the predictive power of biopsy G2 disease for high-risk specimen grade. Exfoliated cell cytology in combination with biopsy grade is recommended as part of the evaluation of upper tract transitional cell carcinoma selected for endoscopic management.