High Risk Superficial Bladder Tumors Research Articles

Miliary Pulmonary Tuberculosis After Intravesical BCG Instillation in a Patient with High-Grade Bladder Cancer

Intravesical administration of Bacillus Calmette-Guerin (BCG) vaccine is used in the treatment of superficial bladder cancer. In clinical practice, intravesical BCG immunotherapy after transurethral tumor resection is a highly effective treatment option in preventing tumor recurrence and progression in medium and high risk superficial bladder tumors. Since patients are given live tuberculosis (TB) bacillus, serious side effects such as pneumonia, sepsis and even death can be seen. Lung involvement occurs in less than 1% of patients and most commonly presents as interstitial pneumonia or miliary TB. Miliary TB is difficult to diagnose and is usually based on high clinical suspicion, as Mycobacterium bovis is not isolated in most cases. Treatment is not completely standardized. However, in severe cases, a combination of antituberculosis drugs and corticosteroids is recommended. In this report, a case of miliary tuberculosis, a very rare complication after instillation of BCG into the bladder in a patient with a diagnosis of superficial bladder cancer, was presented. A 73-year-old male patient diagnosed with bladder tumor underwent transurethral resection of bladder tumor, and then weekly intravesical injection of BCG-MEDAC for six weeks had no adverse effects. Three weeks of intravesical BCG supplementation was planned for the patient who had no signs of recurrence when checked three months later by cystoscopy. Two hours after the first dose, the patient, who applied to the emergency department with the complaint of chills and shivering, was hospitalized for further follow-up and treatment. Afterwards, repeat cultures were taken from the patient whose fever continued on the seventh day of treatment with broad-spectrum antibiotics (meropenem and teicoplanin). In addition, when abdominal and thorax computed tomography (CT) were performed, multiple miliary nodular lesions were detected in both lungs and were evaluated in favor of miliary TB. With these findings, the patient was started on miliary TB therapy [isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and streptomycin (STM)] targeting Mycobacterium bovis, since it was an infection that developed after BCG injection. In the third week of the treatment, the patient's fever was under control, and he was discharged on the 25th day of his hospitalization because of significant improvement in infection markers [C-reactive protein(CRP)-procalcitonin]. At the end of two months, there was clear regression of pulmonary abnormalities on control thorax CT. In conclusion, miliary TB developing after intravesical BCG instillation is a very rare condition, the cause of which is not fully understood, the etiology of fever can be easily missed, and the diagnosis is difficult. In addition, this case is presented to draw attention to a critical disease that requires long treatment and follow-up and requires attention.

TURBT for Treatment of Recurrent High Risk Superficial or Muscle-Invasive Bladder Tumours: Factors Contributing to T0 Radical Cystectomy Specimens

TURBT for Treatment of Recurrent High Risk Superficial or Muscle-Invasive Bladder Tumours: Factors Contributing to T0 Radical Cystectomy Specimens

S104 TURBT for treatment of high risk superficial or muscle-invasive bladder tumours: Factors contributing to T0 radical cystectomy specimens

S104 TURBT for treatment of high risk superficial or muscle-invasive bladder tumours: Factors contributing to T0 radical cystectomy specimens

Use of Fluorescence In Situ Hybridization to Predict Response to Bacillus Calmette-Guérin Therapy for Bladder Cancer: Results of a Prospective Trial

No reliable methods currently exist to predict patient response to intravesical immunotherapy with bacillus Calmette-Guérin given after transurethral resection for high risk nonmuscle invasive bladder cancer. We initiated a prospective clinical trial to determine whether fluorescence in situ hybridization results during bacillus Calmette-Guérin immunotherapy can predict therapy failure. Candidates for standard of care bacillus Calmette-Guérin were offered participation in a clinical trial. Fluorescence in situ hybridization was performed before bacillus Calmette-Guérin, and at 6 weeks, 3 months and 6 months during bacillus Calmette-Guérin therapy with maintenance. Cox proportional hazards regression was used to assess the relationship between fluorescence in situ hybridization results and tumor recurrence or progression. The Kaplan-Meier product limit method was used to estimate recurrence-free and progression-free survival. A total of 126 patients participated in the study. At a median followup of 24 months 31% of patients had recurrent tumors and 14% experienced disease progression. Patients who had positive fluorescence in situ hybridization results during bacillus Calmette-Guérin therapy were 3 to 5 times more likely than those who had negative fluorescence in situ hybridization results to experience recurrent tumors and 5 to 13 times more likely to have disease progression (p <0.01). The timing of positive fluorescence in situ hybridization results also affected outcomes. For example, patients with a negative fluorescence in situ hybridization result at baseline, 6 weeks and 3 months demonstrated an 8.3% recurrence rate compared to 48.1% for those with a positive result at all 3 points. Fluorescence in situ hybridization results can identify patients at risk for tumor recurrence and progression during bacillus Calmette-Guérin immunotherapy. This information may be used to counsel patients about alternative treatment strategies.

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.

Loss of Heterozygosis on IFN-α Locus is a Prognostic Indicator of Bacillus Calmette-Guerin Response for Nonmuscle Invasive Bladder Cancer

We evaluated the role of loss of heterozygosity on the interferon-alpha locus to predict the response to bacillus Calmette-Guerin therapy in patients with nonmuscle invasive bladder cancer. A total of 117 consecutive patients were selected, including 77 with nonmuscle invasive bladder cancer and 40 controls. Loss of heterozygosity on the interferon-alpha locus (chromosome 9p21) was assessed in blood and urine samples before transurethral resection. All patients underwent transurethral resection and then 6 weekly bacillus Calmette-Guerin instillations. Those with nonmuscle invasive bladder cancer were assigned to groups 1 and 2 with and without loss of heterozygosity on the interferon-alpha locus, respectively. Of the 77 patients with nonmuscle invasive bladder cancer 39 (50.6%) had loss of heterozygosity on the interferon-alpha locus (group 1) and 38 (49.4%) had no alteration (group 2). Only 1 of 40 controls showed loss of heterozygosity on the interferon-alpha locus. At the end of followup 13 patients in group 1 and 27 in group 2 were alive without recurrence. We noted a significant difference between loss of heterozygosity on interferon-alpha and followup status (dF 01, LR 11.252, p = 0.003). Kaplan-Meier analysis revealed a significant difference in recurrence probability (response to bacillus Calmette-Guerin) and loss of heterozygosity on interferon-alpha (p <0.0001). On multivariate analysis loss of heterozygosity (HR 4.09, 95% CI 2.59-6.28, p = 0.002), grade (grade 3 HR 3.31, 95% CI 1.38-3.35, p = 0.03) and the number of lesions (3 or greater HR 2.31, 95% CI 1.38-3.25, p = 0.03) were independent predictors of the bacillus Calmette-Guerin response. This study highlights the predictive value of loss of heterozygosity analysis on interferon-alpha in patients with nonmuscle invasive bladder cancer treated with bacillus Calmette-Guerin.

Urovysion™ testing can lead to early identification of intravesical therapy failure in patients with high risk non-muscle invasive bladder cancer

In this study, we investigated the ability of UroVysion to assess response to intravesical therapy in patients with high risk superficial bladder tumors. We performed a retrospective review of patients undergoing intravesical therapy for high risk superficial bladder tumors. Urine specimens were collected for UroVysion analysis before and immediately after a course of intravesical therapy. Cytology and cystoscopy were performed six weeks after treatment, using either a positive cytology or visible abnormality on cystoscopy as a prompt for biopsy. The operating characteristics of the UroVysion test were then determined. 41 patients were identified in whom 47 cycles of induction and 41 cycles of maintenance intravesical therapy were given during the study period. This yielded a total of 88 treatment and evaluation cycles. Median follow-up was 9 months per induction (range 1-21 months) and 13 months per patient (range 1-25 months). A total of 133 urine samples were collected for UroVysionTM of which 40 were positive. Based upon standard clinical evaluation, 41 biopsies were performed which detected 20 recurrences. UroVysionTM testing performed immediately upon completion of therapy for the 41 patients undergoing biopsy yielded a sensitivity, specificity, and accuracy of 85%, 61%, and 71%. The use of UroVysionTM following intravesical therapy for high-risk superficial bladder tumors helps to identify patients at high risk of refractory or recurrent disease who should undergo immediate biopsy under anesthesia.

A multicolour fluorescence in situ hybridization test predicts recurrence in patients with high‐risk superficial bladder tumours undergoing intravesical therapy

To determine whether a multicolour fluorescence in situ hybridization test (UroVysion, Abbott Molecular Inc., Des Plaines, IL, USA) in patients with high-risk superficial bladder tumours maintains its predictive ability in a multivariate model for recurrence and progression, incorporating clinical and pathological predictors of outcome. The charts of patients with superficial bladder cancer treated with induction or maintenance intravesical therapy (IVT) were reviewed retrospectively. UroVysion testing was used at the beginning and end of each IVT cycle, and cytology and cystoscopy 6 weeks after completing each cycle. Kaplan-Meier actuarial survival was analysed, stratified by the UroVysion result after IVT. Univariate and multivariate Cox regression analyses were used to identify significant predictors of recurrence. In all, 42 patients had induction IVT with bacille Calmette-Guérin (BCG), BCG + interferon, or mitomycin. The median follow-up was 21 months. Recurrent disease was detected in 18 patients. In a univariate analysis, chronic renal insufficiency (hazard ratio 12.1, P = 0.03), positive cytology after IVT (2.7, P = 0.05), and a positive UroVysion test after IVT (8.3, P < 0.01) were predictive of failure. In the multivariate analysis, high grade disease (5.3, P = 0.05), a risk score of >6 (4.7, P = 0.02) and a positive UroVysion test after IVT (6.7, P < 0.01) were significant predictors of recurrence. In patients with high-risk superficial bladder tumours undergoing IVT, a positive UroVysion test after treatment is highly predictive of recurrence, even in a multivariate model. Additional adjuvant therapy might be necessary in these patients to improve the outcome.

Radical Cystectomy for Carcinoma of the Bladder: 2,720 Consecutive Cases 5 Years Later

We performed a critical analysis of the results of radical cystectomy for invasive bladder carcinoma treated at 1 center. Between 1970 and 2000, 2,090 men and 630 women with invasive bladder cancer were treated with 1-stage radical cystectomy and urinary diversion. Followup ranged from 0 to 34.2 years with a mean of 5.5 +/- 5.7. Survival data were correlated to patient and tumor characteristics using univariate and multivariate analysis. Postoperative mortality was 2.6%. Squamous tumors accounted for 49.4% of cases, transitional cell carcinoma for 36.4% and adenocarcinoma for 9.6%. Regional lymph nodes were involved in 20.4% of cases. The 5 and 10-year disease-free survival rates were 55.5% and 50.03%, respectively. Evidence was provided that tumor stage, histological grade and lymph node status are the only independent variables which affect survival probability. Contemporary cystectomy can be performed with minimal mortality. Radical cystectomy for organ confined disease is followed by good therapeutic results and enhances the possibilities for functional restoration. With stage progression there is a stepwise reduction in survival probability. The radical operation can provide disease-free survival for an important subgroup of node positive cases (27.3%). Additional therapy is needed to improve the oncological outcome for advanced locoregional disease.

835: Prophylactic Ofloxacin to Improve Tolerance of BCG Intravesical Instillations: A Randomised Prospective, Double Blind, Placebo-Controlled, Multicentre Study in Patients with Mid to High Risk Superficial Bladder Tumors

You have accessJournal of UrologyModerated Poster, Monday, May 22, 2006, 1:00 - 3:00 pm1 Apr 2006835: Prophylactic Ofloxacin to Improve Tolerance of BCG Intravesical Instillations: A Randomised Prospective, Double Blind, Placebo-Controlled, Multicentre Study in Patients with Mid to High Risk Superficial Bladder Tumors Pascal Rischmann, Marc Colombel, Dominique K. Chopin, Ludovic Nicolas, and Bernard Malavaud Pascal RischmannPascal Rischmann More articles by this author , Marc ColombelMarc Colombel More articles by this author , Dominique K. ChopinDominique K. Chopin More articles by this author , Ludovic NicolasLudovic Nicolas More articles by this author , and Bernard MalavaudBernard Malavaud More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)33071-4AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "835: Prophylactic Ofloxacin to Improve Tolerance of BCG Intravesical Instillations: A Randomised Prospective, Double Blind, Placebo-Controlled, Multicentre Study in Patients with Mid to High Risk Superficial Bladder Tumors." The Journal of Urology, 175(4S), p. 269 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 175Issue 4SApril 2006Page: 269 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Pascal Rischmann More articles by this author Marc Colombel More articles by this author Dominique K. Chopin More articles by this author Ludovic Nicolas More articles by this author Bernard Malavaud More articles by this author Expand All Advertisement PDF DownloadLoading ...

Cystectomy in Patients with High Risk Superficial Bladder Tumors Who Fail Intravesical BCG Therapy:: Pre-Cystectomy Prostate Involvement as a Prognostic Factor

Purpose: To review understaging and outcome of patients who underwent radical cystectomy (RC) for high risk superficial bladder cancer after bacillus Calmette-Guérin (BCG) failure. Patients and methods: We carried out a retrospective study of 62 cases in which RC was indicated for clinical stage Tis, Ta, T1 transitional cell bladder tumors that failed transurethral resection (TUR) and BCG treatment. We used BCG (81 mg/Connaught BCG) in patients with superficial grade 3 tumors and CIS. We considered BCG failure a high-grade recurrence at 3 months of the first BCG course or after 2 courses. RC indications, correlation between their clinical and pathological stage and the ensuing progress were analyzed. We assessed the existence of any pre-cystectomy clinical or pathological factor related to understaging and survival. Results: RC was performed in 22 patients with carcinoma in situ (CIS) (35%), 7 with Ta (11,2%), 31 with T1 (50%), and 2 with Tx tumors (3%). All 62 but one were high-grade tumors (grade 3 and/or CIS). Tumor was clinically understaged with stages pT2 or greater on the RC specimen in 17 patients (27%). The presence of tumor in the prostatic urethra at the moment of endoscopic staging before RC was the only factor associated with clinical understaging ( p = 0.003) and shorter survival ( p < 0.0002). Five-year disease-specific survival rate was significantly lower in understaged (38%) as compared with not-understaged patients (90%) after a median follow-up of 40-months (range 1–142) ( p = 0.006). Overall five-year disease-specific survival was 79%. Conclusions: RC should be performed prior to progression in high risk superficial tumors that fail after TUR and BCG. In patients with clinical and pathological nonmuscle invasive disease, RC provides an excellent disease-free survival. One third of patients with HRSBT who underwent RC after BCG failure were understaged and had a shorter survival. Tumor in the prostatic urethra at endoscopic staging was the only factor associated to understaging and shorter survival.

868Prophylactic ofloxacine to improve tolerance of BCG intravesical instillations: A randomised prospective, double-blind, placebo-controlled, multicentre study in patients with mid to high risk superficial bladder tumours

868Prophylactic ofloxacine to improve tolerance of BCG intravesical instillations: A randomised prospective, double-blind, placebo-controlled, multicentre study in patients with mid to high risk superficial bladder tumours

The optimum timing of radical cystectomy for patients with recurrent high‐risk superficial bladder tumour

To establish the optimum time of radical cystectomy (RC) for patients with recurrent high-risk superficial bladder tumours after the failure of intravesical therapy. Among 318 patients with transitional cell carcinoma treated with RC and with no neoadjuvant therapy, there were 46 with clinical stage Ta, T1 or Tis refractory to transurethral resection associated with intravesical therapy. These patients had at least one of: (i) high-risk superficial bladder tumours after failure of two consecutive induction courses of intravesical therapy; (ii) superficial bladder tumours with prostatic stromal invasion; (iii) superficial bladder tumours with mucosa/ducts involvement after failure of one course of intravesical therapy; (iv) uncontrolled superficial tumours with transurethral resection associated or not with intravesical therapy. Progression and cause-specific survival of these patients were compared to those with muscle-invasive tumours. Univariate and multivariate analyses of predictive factors for cause-specific survival were also used in patients with superficial tumours. The incidence of significant prognostic factors was compared in both superficial and muscle-invasive tumours, as were the progression pattern and survival. The progression-free and cause-specific survival of patients with superficial tumours was 54% and 67%, respectively, with no significant difference from those with muscle-invasive tumours. In multivariate analysis, positive lymph-nodes and prostatic stromal invasion were significant and independent variables for survival. The incidence of positive lymph nodes was 15% vs 30% (P < 0.05) and of stromal invasion was 32% vs 1.5% (P < 0.001) in patients with superficial and muscle-invasive tumours, respectively. Accounting for the progression pattern in patients with superficial tumours, extravesical urothelial recurrence prevailed over local or distant recurrences (30% vs 15%), whereas in patients with muscle-invasive tumours the opposite occurred (5% vs 33%, respectively). The cause-specific survival of patients with superficial tumour and prostatic stromal invasion was one of three, and in those who developed extravesical urothelial recurrence was 28.5%. In patients with recurrent high-risk superficial bladder cancer after intravesical therapy, our criteria for RC were inappropriate, and patients had a survival rate similar to those with muscle-invasive tumours. RC might have been used too late, as there was a high incidence of prostatic stromal invasion and extravesical urothelial recurrence after RC. Both events seem to be responsible of the low cause-specific survival. Predictive factors for progression are needed to indicate early RC in patients with recurrent high-risk superficial tumours. From a previous analysis the pathological pattern of the clinical lack of response (T1, G3, bladder carcinoma in situ and prostate involvement) to intravesical therapy evaluated at 3 months might be important for predicting progression, and an early RC at that time might be useful.

High Risk Superficial Bladder Tumours: Is a Second Transurethral Resection after Intravesical Bcg Necessary?

According to some authors, residual tumour rate after superficial bladder cancer transurethral resection varies from 4–78%; among high risk superficial tumours (TaG3, T1G3, Tis) managed by transurethral resection of the bladder (TURB) and adjuvant immunotherapy, residual tumour rate varies from 57–76%. This study was aimed to evaluate residual tumour and/or tumour recurrence in 56 patients diagnosed with high risk superficial bladder tumour, who underwent transurethral resection, adjuvant 6-weekly course of intravesical bacille Calmette-Guérin (BCG) and second TURB on the first resection sites, and in other sites suspicious for recurrence. Overall, 7/56 patients (12.5%) had residual tumour and/or recurrent disease at second TURB; no histological progression was recorded. Disease persistence or recurrence was not related to tumour multifocality at first diagnosis. Our results appear to be consistent with other recent experiences, reporting low rates of residual tumour and disease progression in superficial bladder tumours after a first adequate resection and adjuvant immunotherapy. Thus, our current practice in management of high risk superficial bladder tumour is oriented towards routine cystoscopy within 3 months after first bladder tumour resection, completed by cold biopsies on previous resection sites. To our opinion, this approach provides adequate diagnostic reliability besides sparing the costs of a new resection and improving patients quality of life.

Clinical Panurothelial Disease in Patients with Superficial Bladder Tumors: Therapeutic Implications

We established the prognostic and therapeutic implications of panurothelial involvement in patients with superficial bladder tumors for optimizing therapeutic approaches in those at risk for panurothelial involvement. We studied the records of 35 patients with clinical panurothelial disease. Since all of these patients presented with high risk superficial bladder cancer during followup, they were included in specific therapeutic and followup regimens. Radical procedures or conservative therapies were indicated mainly according to pathological examination and the recurrence pattern. Panurothelial involvement was a late stage of a recurrent and diffuse process that essentially developed in sequences, in which all patients presented with high risk superficial bladder tumors. This process involved continued relapse after panurothelial involvement developed. Notably 19 patients (79.1%) at risk for recurrence had repeat relapse in the urothelium. In the upper urinary tract 12 patients (34.3%) had bilateral involvement, including 7 (41.2%) of 17 patients after cystectomy. We identified 2 subgroups of patients. The subgroup with a better prognosis included 27 patients in whom late panurothelial disease developed step by step after a complete response to intravesical therapy, including 14 (51.8%) who were free of disease. The other subgroup with a poor prognosis included 8 patients with concurrent bladder carcinoma in situ and prostate involvement as well as early panurothelial disease, of whom only 2 (25%) were disease-free. All patients underwent many therapeutic approaches. A mean of 7.5 surgical procedures per patient were done, including a mean of 5.5 transurethral resections, a mean of 1 conservative approach to the upper urinary tract and a mean of 1.1 radical procedures. At a median followup of 111 months 10 patients (28.5%) were disease-free but only 7 (20%) retained the bladder, while 19 (54.3%) died of tumor. Patients with high risk superficial bladder multifocal tumors and associated bladder carcinoma in situ are at high risk for panurothelial involvement. Radical cystectomy may be recommended in these patients when initially or during followup, concurrent high risk superficial bladder tumors and prostate involvement develop or prostate involvement recurs. For the upper urinary tract conservative therapies may be advisable when noninfiltrating tumors are diagnosed even after cystectomy due to the high rate of bilateral new onset disease. When cystectomy is performed, extended excision of the upper urinary tract and pyelo-intestinal anastomosis may be considered.

Classification, facteurs favorisants, prévention et traitement des effets indésirables (EI) associés au bacille de Calmette-Guérin (BCG) dans le traitement des tumeurs superficielles de vessie

The efficacy of Bacillus Calmette-Guérin (BCG) in the treatment of superficial bladder cancer was first reported by Morales in 1976. Several authors have since demonstrated the efficacy of BCG in the prophylaxis and treatment of high-risk superficial bladder tumors (pT1G3, CIS). Although BCG is now recommended as an adjunctive treatment for superficial bladder tumors, the optimal treatment schedule remains to be defined. Results reported by Lamm suggest that an initial induction cycle of six weekly intravesical BCG instillations is suboptimal unless maintenance therapy (three consecutive weekly instillations) is given 3, 6, 12, 18, 24, 30 and 36 months later. However, the use of maintenance therapy is hindered by troublesome adverse reactions. This article reviews adverse reactions associated with BCG treatment, proposed a classification and discusses their prevention and treatment.

DOES EARLY CYSTECTOMY IMPROVE THE SURVIVAL OF PATIENTS WITH HIGH RISK SUPERFICIAL BLADDER TUMORS?

We compared survival after early versus delayed cystectomy in patients with high risk superficial bladder tumors. Of 307 patients with high risk superficial bladder tumors who were treated initially with transurethral resection and bacillus Calmette-Guerin (BCG) therapy 90 (29%) underwent cystectomy for recurrent tumor during a followup of 15 to 20 years. Disease specific survival distribution of these 90 patients was determined relative to the indications for and time of cystectomy. Of the 90 patients who underwent cystectomy 44 (49%) survived a median of 96 months. Of 35 patients with recurrent superficial bladder tumors 92% and 56% survived who underwent cystectomy less than 2 years after initial BCG therapy and after 2 years of followup, respectively. Of 55 patients with recurrent muscle invasive bladder disease 41% and 18% survived when cystectomy was performed within and after 2 years, respectively. Multivariate analysis showed that survival was improved in patients who underwent earlier rather than delayed cystectomy for nonmuscle invasive tumor relapse. Earlier cystectomy improves the long-term survival of patients with high risk superficial bladder tumors in whom BCG therapy fails.

CD44 standard form expression as a predictor of progression in high risk superficial bladder tumors.

The purpose of this study was to assess the significance of the standard CD44 adhesion molecule expression in predicting progression of high risk superficial bladder carcinoma in the short term. Sixty-six patients (51 males and 15 females, aged 27 to 89 years (mean 64.75 years) with primary superficial transitional cell bladder cancer initially treated with transurethral resection (TURBT) were enrolled in the study. Only pTa/pT1 grade 2 multiple tumors as well as all grade 3 tumors were included in this study. All tumor samples obtained after the resection were immunohistochemically evaluated for the expression of the CD44 standard molecule. Fifty eight patients remained during the follow up period which ranged from 3 to 36 months (mean 11.8 months). Tumor progression in the short term was considered as the critical end point of interest in this study. The prognostic significance of tumor stage, grade, presence of carcinoma-in-situ (CIS) and expression of CD44 in determining the risk for progression, was studied with both univariate (log rank test) and multivariate (Cox proportional hazards) methods of analysis. Kaplan-Meier survival curves indicated that a shorter median progression-free survival is expected for those patients with G3 bladder tumors (p = 0.0055), concomitant CIS (p = 0.0051), and loss of expression of CD44 (p = 0.0015), whereas a similar association with stage was not detected (p = 0.5793). The cox regression multivariate analysis did not yield a significant result for any of the studied parameters therefore no one of the factors taken into account can serve as an independent predictor of progression in superficial bladder cancer in the short term. The immunohistochemically detectable loss of the expression of CD44 standard form from superficial bladder tumor samples may be, complementary to the established prognostic factors, a useful predictor of tumor progression in the short term.

Intravesical liposome-mediated interleukin-2 gene therapy in orthotopic murine bladder cancer model.

Using a novel orthotopic MBT-2 murine bladder tumor model, we evaluated the feasibility of intravesical gene therapy utilizing a cationic liposome, DMRIE/DOPE. Superficial bladder tumors were consistently established by intravesical instillation of 5x10(5) MBT-2 cells in syngeneic C3H female mice. In situ gene transfer to bladder tumors was accomplished via intravesical instillation of plasmid DNA/DMRIE/DOPE lipoplex. Beta-Galactosidase (beta-gal) gene expression was preferentially evident in bladder tumors and was present for at least 7 days after a single 30 min in situ transfection. Murine interleukin-2 (IL-2) gene was used for treatment of 3-day-old pre-established bladder tumors. Forty percent of animals treated with IL-2 gene were completely free of tumors by 60 days following the initial tumor implantation, while all control groups treated with beta-gal gene died. Those animals initially cured of pre-established tumors were completely resistant to a subsequent tumor re-challenge and their splenocyte-derived cytotoxic T lymphocytes were shown to be specific to MBT-2 cells, indicating that immunological memory against MBT-2 tumors was elicited by the treatment. These results demonstrate the possibility of an effective clinical application of this in situ intravesical IL-2 gene delivery system to high-risk superficial bladder tumors, obviating a need for tumor procurement and ex vivo gene transfer.

Can p53 nuclear over-expression, Bcl-2 accumulation and PCNA status be of prognostic significance in high-risk superficial and invasive bladder tumours?

AimsTo evaluate p53 and Bcl-2 expression and proliferating status (PCNA) in subgroups of patients with high-risk superficial and invasive bladder cancer, with relation to cancer progression and death, and to correlate the results with established clinical prognostic factors.MethodsParaffin-embedded sections from 42 high-risk superficial (T1G2,T1G3) and 33 invasive (T2–T4aG3N0M0) tumours were investigated immunohistochemically for p53, Bcl-2 and PCNA. The median follow-up was 52 months.ResultsIn the cohort of superficial tumours, statistical analysis showed that p53 and PCNA positivity were significant prognostic factors (P-values: 0.008 and 0.006, respectively) for disease-specific death (DSD). When life expectancy was evaluated (log-rank test), p53(+) (P=0.015) and PCNA(+) (P=0.017) offered the most accurate prognosis compared to grade, tumour size and multiplicity. Bcl-2 status had no significant effect on patient survival. In the subset of muscle-invasive tumours we failed to demonstrate any important role of p53, Bcl-2 or PCNA positivity.Conclusionsp53 and PCNA over-expression may offer valuable additional prognostic information in high-risk subgroups of superficial bladder tumours. From our results, Bcl-2 does not appear to contribute significantly to the prognosis of these patients. None of the studied markers offered prognostic information in muscle-invading disease.