Progression Of Superficial Bladder Cancer Research Articles

Significance of muscularis mucosae on the risk of recurrence and progression in patients with superficial bladder cancer

Background. Due to the currently accepted operative technique of the transurethral resection (TUR) of bladder, during the surgery we obtain a histological material that is multiple pieces of the tissueof exophytic area of tumor, the bladder base and the bladder wall, in which a specialist histologist can be guided only with careful labeling, and the correct pathologic diagnosis is possible only in case of the presence of all layers of the bladder wall in the preparation. The performanceof TUR of bladderen blochas allowed visualizing an additional morphological feature in the preparation – its own muscularis mucosa. Objective. The evaluation of effectiveness of the transurethral surgical treatment of thepatients with superficial bladder cancer by comparing the immediate and long-term results of the standard TUR and the TUR of bladder wall tumor en bloc. The assessment of the role of the tumor invasion of propermuscularis mucosa in the prediction of recurrence and progression of superficial bladder cancer. Materials and methods. We analyzed the results of the examination and treatment of 270 patients with newly diagnosed «bladder cancer» who were treated between 2003 and 2012. All patients were divided into 2 groups: the main group (n = 94) who underwent the transurethral resection of the wall bladder tumor en bloc, and the compared group (n = 176) who underwent the standard transurethral resection. As a result wehave evaluated the role of the tumor invasion of propermuscularis mucosa in the prediction of recurrence and progression of superficial bladder cancer. Results and conclusions. The technique of the operation affects the recurrence rate by reducing it from 47.7 % in cases of the standard TUR to 34 % in cases of the TUR en bloc (p 0.05). The application of the TUR en bloc reduces the frequency of progressionby 4 times (p < 0.001) and increases the termsbeforethe progression by almost 2 times (p < 0.05). It allows to reduce the recurrences in the area of the resection to a minimum and to increase the periods before the occurrence of relapse. The presence of the damage ofproper muscularis mucosa (the in-growth or invasion, the categories T1b and T1c) increases the frequency of relapses for more than 2 times, and the way out of the tumor outside the layer of proper muscularis mucosareduces the term of relapse by 2.5 times, the progression rate increases from 2 % to 22.7 % and 18.5 %, and the average time before progression reduces from 41.5 to 26.0 and 17.1 with increase of the depth of tumor invasion with categories T1a, T1b and T1c respectively.

Abstract 51: Elevated levels of E2F1, EZH2 and SUZ12 lead to invasive progression of superficial bladder cancers

Abstract Bladder cancer is increasing a rate of occurrence in aging societies. A superficial bladder cancer is noninvasive that is presented as a good prognosis after receiving treatment. However, about 20∼50% of superficial bladder cancer patients progressed to invasive tumor which represent the poor survival rates within 5 years. In previous study, we addressed if the transcriptional characteristics of the superficial bladder cancer could be used as predictive biomarkers for the progression of superficial tumors to invasive ones. Using gene expression data from 165 bladder cancer patients, we identified a gene expression signature that could predict the likelihood of progression to invasive tumors. Gene network analyses of the signature revealed that E2F1 and its downstream effectors EZH2 and SUZ12 could be important mediators for the invasive and metastatic progression of superficial tumors. In this study, we investigated how these genes may affect the invasive and metastatic progression of superficial tumors. For confirmation of the expression of E2F1, EZH2 and SUZ12 in two groups of bladder cancer cells, we performed quantitative RT-PCR and western blot assay. Both of mRNA and protein expression of E2F1, EZH2 and SUZ12 in superficial bladder cancer were significantly lower than invasive bladder cancer cells (p&amp;lt; 0.0001). Next, we performed an invasion and migration assay. The overexpression of E2F1, EZH2 and SUZ12 presented an increase of invasiveness and migratory in UC9 superficial bladder cancer. On the other hand, the silencing of gene expression in EJ invasive cell was shown a significantly decreasing of invasiveness and migratory ability. Also, we determine the effect of proliferation and colony formation in superficial and invasive bladder cancer. The depletion of E2F1, EZH2 and SUZ12 in EJ and 5637 invasive bladder cancer cells that significantly decreasing of forming colonies on soft agar. Furthermore, we founded the reduction of tumor size when injected cells depleted E2F1, EZH2 and SUZ12 than control by xenograft assay. Together, our findings reveal that the estimating the roles of E2F1, EZH2 and SUZ12 for the invasive and metastatic progression in superficial bladder cancer. Citation Format: Se-Ra Lee, Yun-Gil Roh, Won-Tae Kim, Seon-Kyu Kim, Jeonghoon Heo, In-Sun Chu, Sun-Hee Leem. Elevated levels of E2F1, EZH2 and SUZ12 lead to invasive progression of superficial bladder cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 51. doi:10.1158/1538-7445.AM2014-51

Loss of nuclear prothymosin-α expression is associated with disease progression in human superficial bladder cancer.

In this paper, we report a study on the clinical relevance of prothymosin-α expression and its correlation with intratumoral Foxp3(+) and CD8(+) lymphocytes (Foxp3(+)TIL and CD8(+)TIL) in bladder cancer patients. We used immunohistochemical staining for prothymosin-α, Foxp3, and CD8 on 101 tumor specimens harvested by endoscopic resection. The results were correlated with clinicopathological variables and clinical outcome in bladder cancer patients, particularly in 73 patients with superficial disease, using the log-rank test and Cox proportional hazard model. Overall, of the tumors, 30% were negative, 34% showed nuclear, and 37% showed cytoplasmic prothymosin-α expression. Foxp3(+)TILs were detected in 11% of patients (nonnuclear vs. nuclear, p = 0.096). Patients with a history of urothelial carcinoma have a higher frequency of nonnuclear prothymosin-α expression than those without (p = 0.016, chi-square test). By univariate and multivariate analyses of cases with superficial disease, grade and stage were identified as independent predictors for recurrence-free survival (p = 0.016 and 0.016, respectively). Higher stage and nonnuclear prothymosin-α expression independently predict shorter progression-free survival (p = 0.006 and 0.043, respectively). The presence of Foxp3(+)TILs was significantly associated with disease progression by univariate analysis (p = 0.022), but not by multivariate analysis (p = 0.147). In vitro assays showed that J82 cells which express ectopically nuclear prothymosin-α exhibit higher growth rate and secrete less TGF-β1 than those with cytoplasmic expression or control cells. Altogether, prothymosin-α expression is a determinant of disease progression in superficial bladder cancer. Foxp3(+)TILs tend to be found more often in bladder cancer with nonnuclear prothymosin-α expression. Future study is required to unravel their interaction.

The Inhibitory Effect of Intravesical Fisetin against Bladder Cancer by Induction of p53 and Down‐Regulation of NF‐kappa B Pathways in a Rat Bladder Carcinogenesis Model

Intravesical chemotherapy after transurethral resection has been widely used as an adjuvant therapy to prevent recurrence and progression of superficial bladder cancer. Due to the insufficiency of the current chemotherapeutics, there is an urgent need to search for more novel, effective and safe intravesical agents. Previously, we have proved the in vitro apoptotic effects of fisetin, a dietary flavonoid, on bladder carcinoma cells. In the present study, we have further explored its intravesical efficacy and investigated the underlying mechanisms of its inhibitory effect of bladder cancer through an autochthonous rat model of bladder cancer induced by intravesical N-methyl-N-nitrosourea (MNU). We found that fisetin-induced apoptosis in bladder cancer is mediated via modulation of two related pathways: up-regulation of p53 and down-regulation of NF-κB pathway activity, causing changes in the ratio of pro- and antiapoptotic proteins. Meanwhile, administration of fisetin significantly reduced the incidence of MNU-induced bladder tumours by suppressing NF-κB activation and modulating the expression of NF-κB target genes that regulate cell proliferation and cell apoptosis. Our study suggests that the activation of p53 and inhibition of the NF-κB pathway may play important roles in the fisetin-induced apoptosis in bladder cancer. Furthermore, intravesical fisetin effectively inhibited, without any toxicity, the carcinogenesis of bladder cancer in MNU-initiated rats. These findings identify the in vivo chemopreventive efficacy of fisetin and suggest that fisetin could be used as a novel, effective and safe intravesical agent for bladder cancer.

The Effect of Restaging Transurethral Resection on Recurrence and Progression Rates in Patients with Nonmuscle Invasive Bladder Cancer Treated with Intravesical Bacillus Calmette-Guérin

We determined whether restaging resection before initiating induction intravesical bacillus Calmette-Guérin improves the recurrence-free rate in patients with high risk nonmuscle invasive bladder cancer. We retrospectively analyzed data on 1,021 patients treated at our institution with intravesical bacillus Calmette-Guérin for nonmuscle invasive high risk bladder cancer. All patients underwent a second resection except those already receiving bacillus Calmette-Guérin at the time of initial consultation and those who refused restaging resection. All patients were assessed every 3 to 12 months for a minimum of 5 years. Univariate and multivariate regression was used to identify predictors of 5-year recurrence. Restaging transurethral resection was performed in 894 patients (87.5%). At restaging resection viable tumor was found in 496 patients (55.5%). At 3 months patients with a single resection had a 44.3% recurrence rate compared to 9.6% in those with restaging resection (p <0.01). On multivariate analysis a single transurethral resection was the only predictor of recurrence at 5 years (OR 2.1, 95% CI 1.3-3.3, p = 0.01). Time to recurrence in patients with a single resection was significantly shorter than in those with restaging resection (median 22 vs 36 months, p <0.001). Failure to repeat resection before initiating intravesical bacillus Calmette-Guérin therapy for high risk nonmuscle invasive bladder cancer significantly increases the risk of recurrence. Therefore, we believe that restaging resection should be performed before initiating bacillus Calmette-Guérin therapy in all patients with high risk nonmuscle invasive bladder cancer.

Abstract 896: Enhancing mTOR targeted therapy in bladder cancer

Abstract Bladder cancer is the 4th most commonly diagnosed cancer in the United States. Because superficial bladder cancer (SBC) recurs in about 60% of cases, standard treatment involves tumor resection followed by intravesical therapies to prevent recurrence, as well as lifelong periodic cystoscopy. There is an urgent need for better intravesical therapies to prevent both the recurrence and progression of SBC. The Mammalian Target Of Rapamycin (mTOR) complex is upregulated in many bladder cancer tumors. We have targeted both the mTORc1 and mTORc2 complexes with drugs that inhibit both complexes. We used PP242 and a second inhibitor, OSI-027, which is currently in a phase I clinical trial for solid tumors (NCT00698243). Our in vitro model targets cell proliferation in three bladder cancer cell line (HT1376, T24 and UM-UC-3). Both drugs are effective in inhibiting the growth of bladder cancer cell lines with IC50 values between 0.6 and 18µM. In comparison with rapamycin, both drugs demonstrate effects on downstream targets of both the mTORc1 and mTORc2 pathways including 4EBP1 and pAkt. Receptor tyrosine kinases are another therapeutic target for bladder cancer. Lapatinib which targets EGFR and Her3, in combination with OSI-027 forms a highly synergistic treatment that inhibits bladder cancer cell line growth. Downstream molecular targets of the combination therapy, including the apoptosis markers PARP and caspase 3, were evaluated by Western blots. Our in vitro data suggests that a combination of dual mTOR inhibitors with RTK inhibitors may provide a novel effective therapeutic treatment for bladder cancer. Future studies of the in vivo efficacy of these drug combinations in a mouse model are planned. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 896. doi:1538-7445.AM2012-896

Abstract 1671: GSK3-beta as a therapeutic target in bladder cancer

Abstract Bladder cancer is the 5th most commonly diagnosed cancer in the United States. Because superficial bladder cancer (SBC) recurs in about 60% of cases, standard treatment involves tumor resection followed by intravesical therapies to prevent recurrence, as well as lifelong periodic cystoscopy. There is an urgent need for better intravesical therapies to prevent both the recurrence and progression of SBC. Recent evidence has demonstrated that glycogen synthase kinase – 3 beta (GSK3β) plays an important role in pancreatic, ovarian and colon cancers; however, to date the possible role of this important kinase has not been examined in bladder cancer. We propose that GSK3β plays a cancer promoting role in bladder cancer and that inhibition of GSK3β will reduce bladder cancer growth. The GSK3β inhibitor, AR-A014418, has been demonstrated to reduce tumor growth in the previously cited cancers. AR-A014418 reduced cell proliferation of three bladder cancer cell lines (HT1376, T24 and UM-UC-3) with EC50 values of 17.5μM for HT1376, 8μM for T24, and 10μM for UM-UC-3 cells. The effect of AR-A014418 on downstream targets in these cell lines was evaluated by Western blots which indicated an increase in apoptosis in these cells in response to drug treatment as demonstrated by the presence by both PARP and caspase 3 cleavage. The NFkB downstream target XIAP also exhibited reduced protein levels after drug treatment. The HT1376 cell line was transduced with luciferase containing lentivirus particles to generate a luciferase expressing cell line, HT1376-LUC to use for both ectopic and orthotopic models of bladder cancer growth. The efficacy of AR-A014418 in reducing bladder cancer tumor growth was tested in an ectopic mouse model. HT1376-LUC cells mixed with matrigel were transplanted into the right flank of 50 female nude mice. After one week, mice containing tumors with an average volume of 52 mm3 were randomized into four treatment groups of 10 mice each. Mice were treated twice weekly via IP injection with placebo, 1, 5 or 7mg/kg AR-A014418. Tumor sizes were measured and imaged for luciferase activity once weekly. Tumor growth was inhibited by both 5mg/kg and 7mg/kg doses by 19 days of treatment (p &amp;lt; 0.05, Student's T test). Together, the in vitro and in vivo data suggest that GSK3β is a novel target for bladder cancer treatment. Future studies using an orthotopic model of bladder cancer are planned. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1671. doi:10.1158/1538-7445.AM2011-1671

Amount of tobacco consumption is associated with superficial bladder cancer progression.

To evaluate the association between smoking habits and outcome of patients with superficial bladder cancer. A retrospective study was performed evaluating 99 patients (67.0 ± 13.2 years, ranging from 31.4-93.4 years, 72.7% males and 27.3% females) treated at our institution with non muscle-invasive bladder cancer, between 1994 and 2000, with a mean follow-up of 49.3 months (range 4.0-177.9 months). Patients were divided according to smoking status, and the main measured outcome was progression to invasive disease. Additional cohort analysis was performed dividing patients according to previous tobacco exposure: smokers and non-smokers. Smokers were stratified into former smokers, early-quitters, late quitters and continued smokers. Smoking habit was significantly more common in males (p = 0.03). Cancer also occurred at an earlier age among smokers (70.8 versus 64.8 years, p = 0.030). Tobacco consumption was present in 62.7% of the patients with bladder cancer. There was a significant higher progression rate to muscle-invasive disease in patients that had more than 60 pack-years of exposure (52.9 versus 26.2%, p = 0.037). These patients had a mean progression time of 59.3 months, whereas patients who had smoked less than 60 pack-years progressed after a mean time of 131.8 months. A direct association between the amount of tobacco consumed and disease progression is observed in patients with bladder cancer, as suggested by the present study. Tobacco consumption has a direct association with progression of superficial bladder cancer to invasive disease and also shortens the period of time for muscle invasion. Larger and prospective studies are still necessary to bring further definitive conclusions about reproducibility of our data and to better understand how smoking cessation affects progression of superficial bladder cancer.

Clinical Outcomes of Primary Bladder Carcinoma In Situ in a Contemporary Series

The natural history of primary bladder carcinoma in situ has not been well described. We describe patterns of disease recurrence and progression, and identify clinical outcome predictors of primary carcinoma in situ after bacillus Calmette-Guerin therapy. We performed a retrospective analysis of 155 patients diagnosed with isolated primary high grade carcinoma in situ at a tertiary center from 1990 to 2008 who underwent transurethral resection followed by intravesical bacillus Calmette-Guerin therapy. The end points included time to disease recurrence, time to progression to invasive disease (cT1 or higher) or to muscle invasive disease (cT2 or higher), or early radical cystectomy. Predictors included gender, age, race, smoking history, presenting symptoms, carcinoma in situ pattern (focal, multiple or diffuse) and response to bacillus Calmette-Guerin. A total of 155 patients received bacillus Calmette-Guerin therapy within 6 months. The 5-year cumulative incidence of progression to cT1 or higher was 45% (95% CI 37-55) and to cT2 or higher was 17% (95% CI 12-25) adjusting for the competing risk of radical cystectomy. Of 130 patients evaluated for response to bacillus Calmette-Guerin 81 (62%) were considered responders. Response to bacillus Calmette-Guerin was significantly associated with progression to cT1 or higher/radical cystectomy (HR 0.59, 95% CI 0.36-0.95, p = 0.029) and to cT2 or higher/radical cystectomy (HR 0.53, 95% CI 0.32-0.88, p = 0.015). This association was largely driven by the higher rate of early radical cystectomy among nonresponders. Despite bacillus Calmette-Guerin therapy and early radical cystectomy, patients with primary carcinoma in situ had a high rate of disease progression. Response to bacillus Calmette-Guerin was significantly associated with a lower rate of disease progression or early radical cystectomy.

The Role of Tumor-Free Status in Repeat Resection Before Intravesical Bacillus Calmette-Guerin for High Grade Ta, T1 and CIS Bladder Cancer

We evaluated the outcome of repeat transurethral bladder tumor resection for high risk nonmuscle invasive bladder cancer before induction and maintenance bacillus Calmette-Guerin. Included in the study were 151 consecutive patients with a mean age of 68.6 years (range 32 to 86) with primary high grade, nonmuscle invasive (Ta, T1 or CIS) bladder cancer. All patients underwent repeat transurethral bladder tumor resection and were shown by repeat resection to be tumor-free or have residual tumor before bacillus Calmette-Guerin. The bacillus Calmette-Guerin response was evaluated by disease recurrence and progression. A total of 70 tumor-free patients and 47 with residual tumor received bacillus Calmette-Guerin induction and maintenance therapy after repeat transurethral bladder tumor resection, of whom 84 (71.8%) were disease-free during followup. In the tumor-free group 11.4% of tumors recurred compared with 27.7% in the residual tumor group (p <0.05). Progression was noted in 5.7% of tumor-free cases vs 17.0% of residual tumor cases (p <0.05). Time to recurrence was significantly less in the residual tumor group than in the tumor-free group (17.8 vs 23.9 months, p <0.001). Tumor-free status at repeat transurethral bladder tumor resection improves the bacillus Calmette-Guerin response rate and delays tumor recurrence. During followup recurrence in residual tumor-free patients develop more likely as low grade lesions than in patients with residual tumor at repeat transurethral bladder tumor resection.

MP-19.13: CYP3A mediated dapsone recovery ratio may predict tumour progression in superficial bladder cancer

MP-19.13: CYP3A mediated dapsone recovery ratio may predict tumour progression in superficial bladder cancer

A re‐staging transurethral resection predicts early progression of superficial bladder cancer

To determine whether pathology on a re-staging transurethral resection (TUR) predicts the early progression of superficial bladder cancer. In all, 710 patients presenting with multiple superficial bladder cancers were evaluated by re-staging TUR and followed for 5 years. Tumours were classified by stage as confined to mucosa (Ta) or invading submucosa (T1), and by grade (low- or high-grade). Pathology on re-staging TUR was correlated with the endpoints of tumour recurrence and stage progression. Of the 710 patients, 490 (69%) had a recurrence and 149 (21%) progressed over 5 years. Eighty patients had high-grade invasive (T1G3) cancer on re-staging TUR and 61 (76%) progressed to muscle invasion (median time to progression 15 months), compared with 88 of 630 (14%) who had no evidence of tumour (T0) or other than T1 tumours detected on re-staging TUR. A re-staging TUR identifies patients with superficial bladder cancer who are at high risk of early tumour progression.

829: A Restaging Transurethral Resection Predicts Early Progression of Superficial Bladder Cancer

829: A Restaging Transurethral Resection Predicts Early Progression of Superficial Bladder Cancer

Natural History, Recurrence and Progression in Superficial Bladder Cancer

Natural History, Recurrence and Progression in Superficial Bladder Cancer

Natural History, Recurrence, and Progression in Superficial Bladder Cancer

Superficial bladder cancer encompasses patients with stage Ta T1 tumors and patients with carcinoma in situ (CIS). The natural history or treatment-related prognosis of these patients varies considerably from one patient to the next based on the patients clinical and the tumor's pathological characteristics. Based on a review of the literature, the most important prognostic factors for recurrence are the prior recurrence rate, number of tumors, and tumor size; whereas for progression, the most important prognostic factors are the T category, grade, and presence of CIS. Treatment with intravesical bacillus Calmette-Guerin reduces both the risk of recurrence and the risk of progression, and is the treatment of choice in high-risk papillary tumors and in patients with CIS. Assessment of a patient's prognostic factors and his or her risk of recurrence and progression is a prerequisite for determining the most appropriate treatment and frequency of follow-up for a given patient.

Prognostic Significance of E2F3 Expression in Bladder Cancer

Purpose: E2F3 is important for cell cycle regulation and DNA replication. Recent studies have reported that members of the E2F family can play specific and diverse roles in the tumorigenesis of human malignancies, and the E2F3 expression appears to provide a growth advantage to tumor cells by activating cell proliferation in bladder tumors. We studied the prognostic significance of E2F3 expression in bladder cancer. Materials and Methods: We examined the expression of E2F3 with using immunohistochemical staining in the tumor samples from 109 patients suffering with bladder cancer, and we analyzed the prognostic significance of E2F3 according to the grade, stage, recurrence and progression of bladder cancer. Results: We found positive staining for E2F3 in 23 cases (21.1%). The E2F3 expression was correlated with the tumor stage (superficial vs. invasive, p<0.001) and the tumor grade (p=0.001). The E2F3 expression was not correlated with the recurrence and progression of superficial bladder cancer. Conclusions: In this study, our results showed that the E2F3 expression was observed in a portion of the bladder cancer specimens. These results suggest that E2F3 may contribute to the development of bladder cancer, but it may not play a role as a prognostic factor of bladder cancer. (Korean J Urol 2006;47:75-79) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

A Second Look at the pT1 G3 Bladder Tumour

People with pT1 G3 bladder cancer are at high risk of tumour progression and death. Induction and maintenance intravesical Bacillus Calmette-Guerin (BCG) has been proven to reduce tumour progression in superficial bladder cancer at moderate risk of progression. By extrapolation, this treatment is often now given for pT1 G3 bladder cancer. Phase II studies published over the past 10 years on the use of adjuvant intravesical BCG following transurethral resection (TUR) of the tumour(s) suggest an important effect on the number of patients progressing. The data are mixed, however. A randomised study of the use of adjuvant radiotherapy in pT1 G3 bladder cancer has shown that it is not of benefit and that, overall, the progression rate remains high. Early cystectomy for high-risk cases is not commonly used, and its results are often disappointing, presumably a consequence of negative selection. Identification of patients at extra high risk of progression is desirable. Tumour size, the co-existence of carcinoma in situ and early tumour recurrence may be prognostic indicators, but the data are at present insufficient.

Can nomograms using urinary NMP22 predict recurrence and progression of superficial bladder cancer?

Can nomograms using urinary NMP22 predict recurrence and progression of superficial bladder cancer?

Prognostic significance of angiogenesis in superficial bladder cancer.

To assess the prognostic significance of angiogenesis parameters such as microvessel density (MVD) and vascular endothelial growth factor (VEGF) in superficial bladder cancer. We studied 127 superficial bladder cancer samples immunohistochemically for the above factors. We compared them with standard clinicopathological features (grade, stage, concurrent in situ, multifocality, primary or recurrent status) as well as with p53 expression, recurrence and progression to muscle infiltrating disease. During a 36 months median follow up of 109 patients with superficial primary tumors (min. 3, max. 69 months), 80 of them recurred (73.4%), while 8 patients (7.3%) progressed to muscle invading disease. A significant correlation was noted between MVD and VEGF in all 127 samples (p = 0.019). No association was noted between MVD or VEGF with the other clinicopathological features, recurrence or progression. Although progression free survival rates of categorized microvessel density (up to and higher than median value) differed significantly only in grade 3 patients, no independent prognostic significance could be attributed to MVD. No correlation was observed between MVD or VEGF with p53 protein. Based on our data we suggest that VEGF is not useful for predicting recurrence or progression in superficial bladder cancer. Microvessel density determination may help to predict progression of grade 3 patients to muscle invasive disease but not as an independent prognostic factor.

Expression and prognostic significance of LIVIN, SURVIVINand other apoptosis-related genes in the progression of superficial bladder cancer

It has been suggested that progression of superficial bladder cancer may be regulated at the molecular level by a typical pattern of expression of genes involved in apoptosis. Recently LIVIN, belonging to the inhibitors of apoptosis (IAP) family, has been found to be expressed in most solid tumors, where its expression is suggested to have prognostic significance. No data are available concerning the significance of LIVIN in the progression of bladder tumors. In the present paper we used RT-PCR to investigate the expression of LIVIN isoforms alpha and beta, SURVIVIN, BCL-X and BCL-2/BAX expression ratio both in normal and tumoral bladder tissues, and correlated their expression with the emergence of early relapses in a follow-up of 4 years. This study shows that only the alpha isoform of LIVIN, which is not expressed in normal bladder tissue, is expressed in a proportion of tumors with a high risk of relapse. LIVIN was found in 7/30 patients (23%), SURVIVIN in 9/30 (30%), BCL-2/BAX ratio >1 in 16/30 (53%), BCL-2/BAX expression ratio <1 in 14/30 (46.6%) and BCL-X, only in isoform BCL-X(L), in 11/30 (36.6%). When we evaluated the dependence between each gene expression and relapse free time of patients, we found that LIVIN, high BCL-2/BAX ratio and BCL-X(L), but not SURVIVIN, reached statistical significance in order to predict relapses. Our findings suggest that LIVIN may be involved in the progression of superficial bladder cancer and used as a marker of early recurrence; while the expression of SURVIVIN cannot be used to identify patients with high risk of relapse.