Search

What's known on the subject? and What does the study add? Insulin-like growth factor mRNA-binding protein 3 (IMP3) is an oncofetal protein found to be re-expressed in a series of human cancers including bladder cancer. In vitro analyses showed an invasion and proliferation promoting effect for IMP3. Further in vitro studies suggested that IMP3 is able to bind to the mRNAs of CD44 and insulin-like growth factor 2 (IGF2), enhancing their stability and expression. However, this molecular interaction has not yet been analysed in tumour samples. In the present study, we identified for the first time high IMP3 tissue protein expression as an independent predictor of poor patients' survival in muscle-invasive bladder cancer. Furthermore, there was no correlation between IMP3 and its molecular targets in bladder carcinoma specimens and concluded that the tumour-promoting effect of IMP3 is not related to its regulatory action on IGF2 and CD44. OBJECTIVE To assess the prognostic value and molecular actions of the oncofetal protein insulin-like growth factor mRNA-binding protein 3 (IMP3) in muscle-invasive bladder cancer (BC)., PATIENTS AND METHODS IMP3 expression was analysed by immunohistochemistry, real-time polymerase chain reaction and Western blot analysis in 224 patients with BC., The molecular targets of IMP3; CD44, insulin-like growth factor 2 (IGF2) and its receptor the IGF1 receptor (IGF1-R) were also investigated., Expression levels were correlated with clinical follow-up data by using both univariate and multivariate Cox regression analyses., RESULTS IMP3 mRNA and protein levels were significantly elevated in high-stage and high-grade muscle-invasive BC., In muscle-invasive BC IMP3 protein but not gene expression proved to be an independent predictor of disease-specific (hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.28-4.56, P = 0.004) and overall survival (HR 2.07, 95% CI 1.12-3.82, P = 0.020)., The expression levels of IGF2 and CD44 showed no correlation with that of IMP3., CONCLUSIONS High IMP3 protein levels may identify patients with BC at high risk of disease progression and may therefore select patients for a more intensive therapy or for a strict follow-up., Its high expression in high-grade bladder carcinoma cells makes IMP3 for an attractive target for therapy., The tumour promoting effect of IMP3 is independent from its regulatory action on IGF2 and CD44 expression. [ABSTRACT FROM AUTHOR]

Endostatin, the proteolytic fragment of collagen XVIII, is an inhibitor of angiogenesis and tumor growth. Interestingly, elevated circulating endostatin levels have been found to correlate with poor patients' prognosis in several cancers. The aim of this study was to assess the prognostic value of endostatin in bladder cancer (BC) and to gain insight into the mechanisms involved in its production. This retrospective study included a total of 337 patients with BC and 103 controls. Collagen XVIII gene expression was analyzed using real-time PCR ( n = 82). Endostatin tissue localization was assessed by immunohistochemistry ( n = 27). Endostatin serum ( n = 87) and urine ( n = 153) levels were determined by ELISA. In 12 cases, both serum and paraffinized tissue samples from the same patients were available. We found decreased collagen XVIII tissue expression and increased endostatin urine and serum concentration in samples of patients with BC compared to controls. High serum endostatin levels correlated with the presence of lymph node metastases and MMP-7 concentrations and were independently associated with poor metastasis-free and disease-specific survival. Immunohistochemical analysis revealed a strong endostatin staining in the wall of tumor associated blood vessels in superficial but not in muscle-invasive BCs. Based on these, we concluded that elevated endostatin levels in patients with BC are the consequence of enhanced extracellular matrix degradation and are independent from collagen XVIII expression. Furthermore, serum endostatin levels may provide prognostic information independent from histopathological parameters and may therefore help to optimize therapy decisions. Loss of endostatin expression in tumor associated blood vessels might represent an important step supporting tumor-induced angiogenesis. [ABSTRACT FROM AUTHOR]

OBJECTIVE To assess the presence of matrix metalloproteinase (MMP)-7 in urine samples of patients with bladder cancer and to investigate the correlation between MMP-7 urine concentration and clinicopathological variables. PATIENTS AND METHODS The presence of MMP-7 in the urine of patients with bladder cancer was tested in 32 representative cases using immunoprecipitation followed by western blot analysis. Urinary MMP-7 concentration levels were analyzed in 132 patients with bladder cancer and 96 controls using an enzyme-linked immunosorbent assay.RESULTS MMP-7 levels did not differ significantly between patients with localized bladder cancer and controls ( P = 0.174). On the other hand, we detected a fourfold, significantly elevated MMP-7 concentration in urine samples of patients with bladder cancer with regional or distant metastasis ( P = 0.003). Using a threshold value of 6.88 ng/ml, determined by receiver-operating characteristic curve analysis, a specificity of 82% and a sensitivity of 78% were observed. Western blot analysis revealed that the 55-kDa tissue inhibitor of metalloproteinase 1 complexed MMP-7 is the dominant form of urinary matrilysin. CONCLUSIONS MMP-7 is present in detectable amounts in the urine of patients with bladder cancer. Its concentrations are significantly elevated in patients with metastatic disease. Determination of urinary matrilysin level could help to detect bladder cancer metastasis, and may therefore provide a more reliable prognosis and influence therapy decisions. [ABSTRACT FROM AUTHOR]

Introduction: While adjuvant immunotherapy with Bacille Calmette Guérin (BCG) is effective in non-muscle-invasive bladder cancer (BC), adverse events (AEs) are considerable. Monocyte-derived activated killer cells (MAK) are discussed as essential in antitumoural immunoresponse, but their application may imply risks. The present trial compared autologous intravesical macrophage cell therapy (BEXIDEM®) to BCG in patients after transurethral resection (TURB) of BC. Materials and methods: This open-label trial included 137 eligible patients with TaG1-3, T1G1-2 plurifocal or unifocal tumours and = 2 occurrences within 24 months and was conducted from June 2004 to March 2007. Median follow-up for patients without recurrence was 12 months. Patients were randomized to BCG or mononuclear cells collected by apheresis after ex vivo cell processing and activation (BEXIDEM). Either arm treatment consisted of 6 weekly instillations and 2 cycles of 3 weekly instillations at months 3 and 6. Toxicity profile (primary endpoint) and prophylactic effects (secondary endpoint) were assessed. Results: Patient characteristics were evenly distributed. Of 73 treated with BCG and 64 with BEXIDEM, 85% vs. 45% experienced AEs and 26% vs. 14% serious AEs (SAE), respectively (p < 0.001). Recurrence occurred significantly less frequent with BCG than with BEXIDEM (12% vs. 38%; p < 0.001). Discussion: This initial report of autologous intravesical macrophage cell therapy in BC demonstrates BEXIDEM treatment to be safe. Recurrence rates were significantly lower with BCG however. As the efficacy of BEXIDEM remains uncertain, further data, e.g. marker lesions studies, are warranted. Trial registration: The trial has been registered in the ISRCTN registry http://isrctn.org under the registration number ISRCTN35881130. [ABSTRACT FROM AUTHOR]

Objective: To assess the role and prognostic significance of angiostatin, basic fibroblast growth factor (bFGF), and tyrosine endothelial kinase (TEK/Tie2) in transitional cell bladder carcinoma. Materials and Methods: Angiostatin, bFGF, and TEK serum concentrations were measured in 82 bladder cancer patients and 20 age-matched healthy controls using enzyme-linked immunosorbent assay. Results were compared with clinicopathologic and follow-up data with the Mann-Whitney U test and Kaplan-Meier, univariate and multivariate Cox regression analyses. Results: We found significantly decreased angiostatin and TEK serum levels and mildly elevated bFGF concentrations in samples of bladder cancer patients compared with controls (P < .001, P < .001, and P = .083, respectively). Furthermore, high TEK serum levels were correlated with poor disease-specific and metastasis-free survival in muscle-invasive bladder cancer (P = .013, P = .018), whereas angiostatin and bFGF concentrations did not show any correlation with patients'' prognosis. Multivariate analysis revealed high TEK levels (<1.60 ng/mL) as borderline significant independent risk-factor of disease-specific survival (HR 1.83, 95% CI 0.97-3.44, P = .061) and metastasis-free survival (HR 2.65, 95% CI 0.93-7.55, P = .069). Conclusion: The characteristic differences in the circulating levels of angiostatin, TEK, and bFGF between patients and controls, suggest the presence of a tumor-induced proangiogenic milieu in bladder cancer. Serum TEK levels may contribute to a more reliable preoperative risk stratification in muscle-invasive bladder cancer and therefore may help to optimize therapeutic decisions. [Copyright &y& Elsevier]