Nicholas P. Munro

Urinary biomarker profiling in transitional cell carcinoma

Urinary biomarkers or profiles that allow noninvasive detection of recurrent transitional cell carcinoma (TCC) of the bladder are urgently needed. We obtained duplicate proteomic (SELDI) profiles from 227 subjects (118 TCC, 77 healthy controls and 32 controls with benign urological conditions) and used linear mixed effects models to identify peaks that are differentially expressed between TCC and controls and within TCC subgroups. A Random Forest classifier was trained on 130 profiles to develop an algorithm to predict the presence of TCC in a randomly selected initial test set (n = 54) and an independent validation set (n = 43) several months later. Twenty two peaks were differentially expressed between all TCC and controls (p < 10−7). However potential confounding effects of age, sex and analytical run were identified. In an age‐matched sub‐set, 23 peaks were differentially expressed between TCC and combined benign and healthy controls at the 0.005 significance level. Using the Random Forest classifier, TCC was predicted with 71.7% sensitivity and 62.5% specificity in the initial set and with 78.3% sensitivity and 65.0% specificity in the validation set after 6 months, compared with controls. Several peaks of importance were also identified in the linear mixed effects model. We conclude that SELDI profiling of urine samples can identify patients with TCC with comparable sensitivities and specificities to current tumor marker tests. This is the first time that reproducibility has been demonstrated on an independent test set analyzed several months later. Identification of the relevant peaks may facilitate multiplex marker assay development for detection of recurrent disease.

A 10-YEAR RETROSPECTIVE REVIEW OF A NONRANDOMIZED COHORT OF 458 PATIENTS UNDERGOING RADICAL RADIOTHERAPY OR CYSTECTOMY IN YORKSHIRE, UK

PURPOSE We have previously reported on the mortality, morbidity, and 5-year survival of 458 patients who underwent radical radiotherapy or surgery for invasive bladder cancer in Yorkshire from 1993 to 1996. We aim to present the 10-year outcomes of these patients and to reassess factors predicting survival. METHODS AND MATERIALS The Northern and Yorkshire Cancer Registry identified 458 patients whose cases were subjected to Kaplan-Meier all-cause survival analyses, and a retrospective casenote analysis was undertaken on 398 (87%) for univariate and multivariate Cox proportional hazards modeling. Additional proportional hazards regression modeling was used to assess the statistical significance of variables on overall survival. RESULTS The ratio of radiotherapy to cystectomy was 3:1. There was no significant difference in overall 10-year survival between those who underwent radiotherapy (22%) and radical cystectomy (24%). Univariate analyses suggested that female sex, performance status, hydronephrosis and clinical T stage, were associated with an inferior outcome at 10 years. Patient age, tumor grade, treatment delay, and caseload factors were not significant. Multivariate analysis models were created for 0-2 and 2-10 years after treatment. There were no significant differences in treatment for 0-2 years; however, after 2 years follow-up there was some evidence of increased survival for patients receiving surgery compared with radiotherapy (hazard ratio 0.66, 95% confidence interval: 0.44-1.01, p = 0.06). CONCLUSIONS a 10-year minimum follow-up has rarely been reported after radical treatment for invasive bladder cancer. At 10 years, there was no statistical difference in all-cause survival between surgery and radiotherapy treatment modalities.

Outcomes from Gleason 7, intermediate risk, localized prostate cancer treated with Iodine-125 monotherapy over 10 years

BACKGROUND AND PURPOSE The effect of predominating Gleason grade (3+4 versus 4+3) in Gleason sum score (GS) 7 prostate cancer (PCa) on brachytherapy outcomes is unclear. The 10 year experience of permanent brachytherapy monotherapy at a single UK centre for GS 7, intermediate risk (Memorial Sloan-Kettering model), PSA < or = 10 ng/ml, localised PCa is reported. MATERIALS AND METHODS Between 1995 and 2004, the outcomes of 187 patients with GS 7 PCa (PSA < or = 10 ng/ml) were analysed from a cohort of 1298 men treated with permanent Iodine-125 prostate brachytherapy, including PSA relapse-free survival (PSA-RFS). RESULTS Median follow-up was 5.0 years (range 2.0-10.1 years). One patient has died of PCa. At 10 years, PSA-RFS was 82.4%/78% (ASTRO consensus and nadir +2 definitions). For GS 3+4, 5 year PSA-RFS was 86.7%/87.9% and for GS 4+3: 85.2%/96.6% respectively, with no significant difference between groups. Five year PSA-RFS (ASTRO) of 92.6% was seen for D(90) > or = 140 Gy (50% total), compared with 77.0% below 140 Gy (p=0.08). CONCLUSIONS Iodine-125 brachytherapy monotherapy achieved good rates of medium term biochemical control in GS 7, intermediate risk localised PCa patients. There was a trend to improved outcomes in men with a D90 in excess of 140 Gy.

Accelerated Methotrexate, Vinblastine, Doxorubicin, and Cisplatin (AMVAC) as Neoadjuvant Chemotherapy for Patients With Muscle-Invasive Transitional Cell Carcinoma of the Bladder

Meta‐analysis data demonstrate a 5% absolute survival benefit for neoadjuvant chemotherapy (NAC) using cisplatin‐based combination regimens in the radical treatment of muscle‐invasive bladder cancer (MIBC). However, there are no randomized, controlled trial data on the optimum regimen. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) is a dose‐intense regimen that has the potential to minimize delays to definitive, potentially curative therapy. A retrospective analysis is presented of the efficacy and toxicity of AMVAC as NAC in patients with MIBC and its impact on the patient pathway.

Fibroblast growth factors and their receptors in transitional cell carcinoma

PURPOSE The recent identification in transitional cell carcinoma of mutations in a fibroblast growth factor (FGF) receptor, namely FGF receptor-3, has provoked great interest in the potential usefulness of FGF receptors and their ligands as molecular markers and as targets for bladder cancer therapy. We examined these possibilities in light of the published literature. MATERIALS AND METHODS We reviewed the world literature on FGFs and their receptors from 1966 to January 2002 using PubMed. RESULTS The recent identification in transitional cell carcinoma of a high frequency of mutations in FGF receptor-3 predicted to activate kinase activity of the receptor indicate a likely role as an oncogene in the urothelium. The finding of FGF receptor-3 mutations only rarely in other tumor types to date indicates surprising urothelial specificity that requires tissue specific approaches for evaluation and exploitation. In contrast, FGF receptor-2 expression is down-regulated in bladder tumors, suggesting a possible tumor suppressor role. Information is available on the expression of FGF receptors-1 and 2 in normal bladder and urine, and in bladder tumors. These angiogenic factors represent potential urine markers of bladder neoplasia, although as single markers they lack sufficient sensitivity and specificity. Some interesting insights into the potential role of these factors have come from studies using in vitro model systems. However, there is little information on the numerous other members of this family of growth factors in the bladder and, therefore, much scope for future studies. CONCLUSIONS It is clear that the FGFs and their receptors have important roles in the development of transitional cell carcinoma. Undoubtedly it will be a focus for much future research. It can be anticipated that members of these protein families would represent useful clinical markers and potential targets for bladder cancer therapy.

Radiotherapy in localized bladder cancer: what is the evidence?

Purpose of review Bladder-sparing bladder treatments have recently been rejuvenated with the introduction of concomitant chemotherapy usually as part of multimodality therapy including endoscopic resection and radiotherapy. This article reviews recent evidence for the role of radiotherapy in the treatment of localized bladder cancer. Recent findings Several single institution series of multimodality radiochemotherapy have shown consistently fair disease-specific survival and local control in those who show a complete response after endoscopic resection. Developments in radiotherapy fractionation, adaptive planning and chemotherapy delivery are clearly in progress. Summary Much of the evidence is retrospective and involves treating locally advanced poor-risk patients. It would seem right to attempt to prospectively evaluate these treatments for truly localized (T1/2) bladder cancer.

Fulguration of the lumen does not improve vasectomy sterilization rates

To assess the effect of adding lumen diathermy fulguration to our standard technique of vas ligation with polyglactin 910 (VicrylTM, Ethicon, Sommerville, NJ, USA) excision and fascial interposition, in an attempt to improve our sterilization rates. We previously reported the effect of changing suture material on vasectomy success rates; 3005 post‐vasectomy semen analyses (PVSA) revealed a decrease in sterilization rates after surgery on changing from chromic catgut to polyglactin 910.