Objectives: To evaluate the effect of adjuvant chemotherapy in invasive bladder cancer.Methods: We conducted a systematic review and meta-analysis of updated individual patient data from all available randomised controlled trials comparing local treatment plus adjuvant chemotherapy versus the same local treatment alone.Results: Analyses were based on 491 patients from six trials, representing 90% of all patients randomised in cisplatin-based combination chemotherapy trials and 66% of patients from all eligible trials. The power of this meta-analysis is clearly limited. The overall hazard ratio for survival of 0.75 (95% CI 0.60-0.96, p = 0.019) suggests a 25% relative reduction in the risk of death for chemotherapy compared to that on control. Cox regression suggests that small imbalances in patient characteristics do not bias the results in favour of chemotherapy. However, the impact of trials that stopped early, of patients not receiving allocated treatments or not receiving salvage chemotherapy is less clear.Conclusions: This IPD meta-analysis provides the best evidence currently available on the role of adjuvant chemotherapy for invasive bladder cancer. However, at present there is insufficient evidence on which to reliably base treatment decisions. These results highlight the urgent need for further research into the use of adjuvant chemotherapy. The results of appropriately sized randomised trials, such as the ongoing EORTC-30994 trial are needed before any definitive conclusions can be drawn. (c) 2005 Elsevier B.V. All rights reserved.

BJU InternationalVolume 95, Issue 4 p. 491-496 Molecular pathways in bladder cancer: Part 2 Richard T. Bryan, Corresponding Author Richard T. Bryan The Epithelial Laboratory, The Division of Medical Sciences Department of Urology, The Queen Elizabeth HospitalRichard T. Bryan, Department of Urology, The Queen Elizabeth Hospital, Birmingham B15 2TH, UK. e-mail: rtb@dsl.pipex.comSearch for more papers by this authorSyed A. Hussain, Syed A. Hussain Cancer Research UK, Institute for Cancer Studies, The University of Birmingham, BirminghamSearch for more papers by this authorNicholas D. James, Nicholas D. James Cancer Research UK, Institute for Cancer Studies, The University of Birmingham, BirminghamSearch for more papers by this authorJanusz A. Jankowski, Janusz A. Jankowski University Departments of Medicine and Oncology, The University of Leicester, Leicester, UKSearch for more papers by this authorD. Michael A. Wallace, D. Michael A. Wallace Department of Urology, The Queen Elizabeth HospitalSearch for more papers by this author Richard T. Bryan, Corresponding Author Richard T. Bryan The Epithelial Laboratory, The Division of Medical Sciences Department of Urology, The Queen Elizabeth HospitalRichard T. Bryan, Department of Urology, The Queen Elizabeth Hospital, Birmingham B15 2TH, UK. e-mail: rtb@dsl.pipex.comSearch for more papers by this authorSyed A. Hussain, Syed A. Hussain Cancer Research UK, Institute for Cancer Studies, The University of Birmingham, BirminghamSearch for more papers by this authorNicholas D. James, Nicholas D. James Cancer Research UK, Institute for Cancer Studies, The University of Birmingham, BirminghamSearch for more papers by this authorJanusz A. Jankowski, Janusz A. Jankowski University Departments of Medicine and Oncology, The University of Leicester, Leicester, UKSearch for more papers by this authorD. Michael A. Wallace, D. Michael A. Wallace Department of Urology, The Queen Elizabeth HospitalSearch for more papers by this author First published: 10 February 2005 https://doi.org/10.1111/j.1464-410X.2005.05326.xCitations: 18Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume95, Issue4March 2005Pages 491-496 RelatedInformation

You have accessJournal of UrologyDiscussed Poster, Monday, May 23, 2005, 8:00am - 12:00 pm1 Apr 2005663: Suicide Gene Therapy Using Adenovirus Encoded Nitroreductase (NTR) and CB1954 in Patients with Localized Prostate Cancer Prashant Patel, Vivien Mautner, James G. Young, Daniel Jackson, Diana Hull, Anjna Badhan, Peter F. Searle, Andrew Mountain, John Ellis, Elizabeth Peers, Alan P. Doherty, D.M.A. Wallace, Hing Y. Leung, Lawrence S Young, and Nicholas D. James Prashant PatelPrashant Patel More articles by this author , Vivien MautnerVivien Mautner More articles by this author , James G. YoungJames G. Young More articles by this author , Daniel JacksonDaniel Jackson More articles by this author , Diana HullDiana Hull More articles by this author , Anjna BadhanAnjna Badhan More articles by this author , Peter F. SearlePeter F. Searle More articles by this author , Andrew MountainAndrew Mountain More articles by this author , John EllisJohn Ellis More articles by this author , Elizabeth PeersElizabeth Peers More articles by this author , Alan P. DohertyAlan P. Doherty More articles by this author , D.M.A. WallaceD.M.A. Wallace More articles by this author , Hing Y. LeungHing Y. Leung More articles by this author , Lawrence S YoungLawrence S Young More articles by this author , and Nicholas D. JamesNicholas D. James More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)34903-6AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "663: Suicide Gene Therapy Using Adenovirus Encoded Nitroreductase (NTR) and CB1954 in Patients with Localized Prostate Cancer." The Journal of Urology, 173(4S), p. 181 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 173Issue 4SApril 2005Page: 181 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Prashant Patel More articles by this author Vivien Mautner More articles by this author James G. Young More articles by this author Daniel Jackson More articles by this author Diana Hull More articles by this author Anjna Badhan More articles by this author Peter F. Searle More articles by this author Andrew Mountain More articles by this author John Ellis More articles by this author Elizabeth Peers More articles by this author Alan P. Doherty More articles by this author D.M.A. Wallace More articles by this author Hing Y. Leung More articles by this author Lawrence S Young More articles by this author Nicholas D. James More articles by this author Expand All Advertisement PDF DownloadLoading ...

3091 Background: Bacterial nitroreductase (ntr) converts the weak monofunctional alkylating agent CB1954 into a highly cytotoxic bifunctional alkylating agent effective in replicating and quiescent cells. We have previously reported phase I safety and biodistribution studies using intraprostatic injection of a replication defective adenovirus encoding ntr (CTL102). Immunohistochemistry of resected prostate demonstrated dose-related ntr staining in tumour, glandular epithelium and stroma. Increasing the injection volume achieved more widespread ntr expression. We now report a phase I clinical trial in prostate cancer using direct intraprostatic injection of CTL102 + intravenous prodrug CB1954. Methods: Patients with biopsy-confirmed local disease and rising PSA underwent 4 TRUS-guided intraprostatic injection of CTL102 in escalating total doses, from 5x1010 to 1x1012 particles with iv CB1954 24mg/m2 48 hours post injection. Primary endpoints were safety and tolerability; secondary endpoints were efficacy by PSA & biopsy. Results: 11 patients with biopsy-confirmed locally relapsed PCa have been treated with virus and prodrug combination (virus particle dose 5x1010 n=3, 1011n=3, 5x1011 n=3, 1012n=2). Both virus and prodrug injections were well tolerated with no significant toxicity apart from a transient transaminitis at day 8 in 7 patients and mild lymphopenia at day 1 in 9 patients. 10 patients had flu-like symptoms at week one. At month 3, 3/8 patients had stable disease and a further 2/8 patients had a PSA reduction of >10% without any additional treatment from baseline. Mean time to PSA progression (>10% rise in PSA from baseline) was 20.6 weeks (95%CI 13.4, 27.8). Two-thirds of patients remain PSA progression free at 6 months. Conclusions: Direct intraprostatic injection of CTL102 followed by iv CB1954 is feasible and safe. Dose limiting toxicity has not been observed; although efficacy has been a secondary endpoint, there are some encouraging initial results and a further study is underway. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ML Laboratories PLC ML Laboratories PLC ML Laboratories PLC

To investigate the relationship between deprivation, delay and survival from bladder cancer in the West Midlands, as socio-economic deprivation is associated with worse survival in many malignancies, and it has been suggested that treatment differences and delay in seeking care are major contributing causes.Data were prospectively collected on 1537 newly diagnosed cases of urothelial cancer presenting in the West Midlands between January 1991 and June 1992. Survival was censored at 31 July 2000, when 785 (51%) patients had died. The influence of deprivation on survival was explored using cause-specific and all-cause mortality.Patients in less affluent groups had significantly worse survival than patients in more affluent groups when considering deaths from all causes (P = 0.02), which held true when adjusting for independent prognostic factors (age, smoking history, and tumour grade, stage, type and size). Bladder cancer-specific mortality showed no significant difference between socio-economic groups (P = 0.30).Socio-economic deprivation is a significant predictor of survival when death from all causes is considered. However, this does not hold true for bladder cancer-specific death. The perceived differences in treatment and delay between socio-economic groups do not seem to occur for bladder cancer in the West Midlands.

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.

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.

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.

Background Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment 06 survival in patients with this disease.Methods We analysed updated data for 2688 individual patients from ten available randomised trials.Findings Platinum-based combination chemotherapy showed a significant benefit to overall survival (combined hazard ratio [HR] 0.87 [95% Cl 0.78-0.98, p=0.016]; 13% reduction in risk of death; 5% absolute benefit at 5 years [1-7]; overall survival increased from 45% to 50%). This effect was observed irrespective of the type of local treatment, and did not vary between subgroups of patients. The HR for all trials, including those using single-agent cisplatin, tended to favour neoadjuvant chemotherapy (HR=0.91, 95% Cl 0.83-1.01) although this tendency was not significant (p=0.084). Although platinum based combination chemotherapy was beneficial, there was no evidence to support the use of single-agent platinum; indeed, there was a significant difference in the effect between these groups of trials (p=0.044).Interpretation This improvement in survival encourages the use of platinum-based combination chemotherapy for patients with invasive 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.

BACKGROUND:The management of locally advanced bladder cancer remains controversial with poor local control with radiotherapy alone. Synchronous chemotherapy regimens have yielded encouraging results in other primary sites.PATIENTS AND METHODS:Patients with T2-T4a N0/NX M0 bladder cancer were entered into this single centre phase I-II study. Patients received radiotherapy to 55 Gy in 20 fractions over four weeks. Concurrent chemotherapy was given with Mitomycin C 12 mg/m2 day 1 and 5-fluorouracil 500 mg/m2/24 hours weeks one and four of radiotherapy for five or seven days on each occasion.RESULTS:Thirty-one patients entered the trial from March 1998 to December 1999 (22: 5-day; 9: 7-day schedule). Median age was 68 (range 58-79) years, 23 males and 8 females. T2: 9 (29%); T3a: 4 (12%); T3b: 9 (29%); T4: 9 (29%); TCC grade 2: 8 (26%) and grade 3: 23 (74%); 14 of 31 had hydronephrosis. Ten of thirty-one had a GFR < 50 ml/min. Toxicity was mild to moderate with the five-day schedule. More severe toxicity was seen with the seven-day schedule: five of nine patients failed to complete planned therapy. Pathological complete response rate at three months was 74% (5-day regimen) and 50% (7-day regimen). Overall 12-month survival was 65%.CONCLUSION:Chemoradiotherapy with the five-day schedule is feasible with acceptable toxicity in poor prognosis patients. A randomised trial is being launched.

OBJECTIVE:To assess the prognostic significance of Bcl-2 expression on the clinical outcome after radiotherapy for muscle-invasive bladder cancer, and to determine if it is possible to identify a subgroup of patients to whom neoadjuvant chemotherapy can be targeted to improve survival. PATIENTS AND METHODS:Immunohistochemical staining for Bcl-2 and p53 was performed on the tumours of 51 patients with stage T2-T4a NXM0 transitional cell carcinoma of the bladder who had been included in a randomized clinical trial of radiotherapy with or without neoadjuvant cisplatin. The association between positive staining and salvage cystectomy rate and overall survival was examined, with a median follow-up of 12 years. RESULTS:Bcl-2 and p53 expression was positive in 31 (61%) and 39 (76%) of the tumours, with no association between either, or with tumour stage or grade. There was no difference according to Bcl-2 positivity in the salvage cystectomy rate (P = 0.83) or survival (P = 0.68) for the 51 patients as a whole, but Bcl-2-negative patients receiving neoadjuvant cisplatin had a significantly better prognosis, with a median survival of 72 months compared to 17 months in Bcl-2-positive patients, and a 5-year survival rate of 55% (P = 0.03). CONCLUSIONS:Quantifying Bcl-2 in patients undergoing radiotherapy for advanced bladder cancer identifies those who may benefit from neoadjuvant chemotherapy. Further studies of other members of the Bcl-2 family and other proteins controlling both cell proliferation and apoptosis are warranted, to define the roles and the interactions between them that may contribute to oncogenesis and resistance to standard treatments. This may allow the targeting of specific treatments to patients known to be sensitive to them, and aid the future development of novel therapies for bladder cancer.

Objectives: To establish the long–term outcome for muscle–invasive transitional cell carcinoma of the bladder treated by radiotherapy with or without neoadjuvant cisplatin.Methods: 159 patients with T2–T4a NX M0 bladder cancer were entered into a prospective randomized trial between June 1984 and June 1988. Follow–up was by 3–monthly cystoscopy in the first year, 6–monthly the next 2 years and yearly thereafter. Salvage surgery was performed at the discretion of the participating clinician.Results: Minimum follow–up was 9 (median 11) years, at which time 29 patients (18%) remain alive. Median survival was 24 months with no difference between the treatment groups (χ2 = 0.08, p = 0.77). Overall cystectomy rate was 24% (radiotherapy alone 20%, combined therapy 28%; p = 0.24). Median time to cystectomy from primary treatment was 12 months; range 56 days to 10 years. The risk of cystectomy was 11, 10 and 7% for the first, second and third years after radiotherapy respectively, and 8% in total after the third year. The proportion of patients alive in each successive year who had required a cystectomy was between 20 and 30% for 5 of the first 8 years after treatment.Conclusions: Salvage cystectomy is necessary in a quarter of patients after radiotherapy and this can be needed up to 10 years after treatment. During this time, multiple invasive procedures are likely to be performed, resulting in significant patient morbidity and cost. Patients should be fully counselled about the need for prolonged surveillance and the persisting risk of salvage surgery when deciding between primary cystectomy and radiotherapy.