Superficial Transitional Cell Bladder Cancer Research Articles

Nuclear Matrix Protein 22 as Adjunct to Urine Cytology and Cystoscopy in Follow-up of Superficial TCC of Urinary Bladder

To assess the efficacy of nuclear matrix protein 22 (NMP-22) in the diagnosis of recurrent, superficial bladder cancer and whether it can predict for future recurrence. Patients with diagnosed and treated superficial transitional cell carcinoma urinary bladder (Stage Ta, T1, Tis, Nx, and M0) presenting for surveillance follow-up were prospectively enrolled in this study from February 2004 to August 2005. These patients underwent urine cytology, NMP-22 testing, and cystopanendoscopy on enrollment in the study. For the next year, these patients underwent cystopanendoscopy and cytology at 3-month intervals. The ability of NMP-22 to predict for recurrence was determined using the cystoscopy findings as the reference standard. A total of 145 patients were included in the study. Of these, 56 had recurrence at enrollment. Of the 56 patients, 48 had positive NMP-22 findings and 22 had positive urine cytology findings. The sensitivity, specificity, positive predictive value, and negative predictive value was 85.7%, 77.5%, 70.6%, and 89.6%, respectively, for NMP-22 alone and 92.9%, 75.3%, 70.3%, and 94.4%, respectively, when the cytology and NMP-22 findings were combined. During the subsequent follow-up of 1 year, 61 recurrences developed in 47 patients. Cox regression analysis showed that those with positive NMP-22 had a 9.57 times greater risk of recurrence during 1 year compared with those with negative NMP-22. The results of our study have shown that the addition of NMP-22 testing to cytology increases the sensitivity for recurrence detection in patients with superficial transitional cell bladder cancer. Patients with positive NMP-22 findings developed significantly more recurrences compared with those with negative NMP-22 findings.

The role of repeat transurethral resection in the management of high‐risk superficial transitional cell bladder cancer

The role of repeat transurethral resection in the management of high‐risk superficial transitional cell bladder cancer

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.

Chromosomal aberrations in transitional cell carcinoma that are predictive of disease outcome are independent of polyploidy.

To determine whether aneusomy for chromosomes 7, 9 and 17 (reported to predict recurrence in up to 65% of patients with superficial transitional cell bladder cancer and thus providing the opportunity for early and effective treatment) reflects specific genetic events on these chromosomes or merely wider unspecific genetic damage to the cell, e.g. that increased copy numbers for 7 and 17 reflect tumour polyploidy. The study comprised 25 primary tumours; 6 microm thick sections from formalin-fixed and paraffin-embedded tumours were analysed. Chromosome copy numbers were determined by fluorescence in situ hybridization (FISH) using pericentromeric probes for chromosomes 7, 8, 9, 10, 11 and 17. A minimum of 200 nuclei per tumour area were scored by two independent observers. Eight of the 25 tumours examined (32%) showed no evidence of chromosomal abnormalities as detected by FISH for any chromosomes analysed. Twelve tumours (48%) showed abnormalities for one or two chromosomes, five tumours (20%) showed abnormalities for multiple chromosomes and one tumour showed abnormalities for all chromosomes analysed, suggestive of polyploidy. Chromosomal abnormalities predictive of recurrence occur largely in the absence of other gross chromosomal lesions. In a small proportion of cases other chromosomes are affected, but this is almost always distinct from tumour polyploidy.

Evaluation of overexpression of p53 tumor suppressor protein in superficial and invasive transitional cell bladder cancer: Comparison with dna ploidy

Objectives p53 tumor suppressor gene is considered to play a significant role in carcinogenesis. Mutations in the p53 are the most frequent genetic abnormalities encountered in human malignancies. Our aim was to investigate the expression of p53 oncoprotein in superficial and invasive transitional cell bladder cancer (TCC) as well as its correlation with established prognostic factors, such as histologic grade, tumor stage, DNA content, and survival. Methods Forty-five patients with superficial TCC (Ta-T1) and 42 with invasive TCC (T2-T4) were included in our study. Material from transurethral biopsy was examined using an immunohistochemical method and the monoclonal antibody Pab 1801. Results p53 tumor suppressor protein was overexpressed in 48.3% of TCC cases and more frequently in invasive than superficial TCCs ( P = 0.03) and undetectable in the tumor adjacent to normal tissue. p53 positivity was related to the degree of differentiation and with the stage of the disease of invasive TCCs ( P = 0.03 and P = 0.004, respectively), whereas no statistical significance was documented for superficial TCCs. Moreover, p53 overexpression demonstrated a statistical significance with DNA ploidy in superficial Ta-T1 tumors ( P = 0.04) and was suggestive in invasive T2-T4 tumors ( P = 0.08). There was no correlation of recurrence related to p53-positive superficial tumors ( P = 0.29). Patients with p53-positive invasive TCCs showed statistically significant worse survival ( P = 0.007), but in multivariate analysis, p53 positivity is not independently related to poor overall survival ( P = 0.30). When we combined ploidy and p53 status, we realized that the subset of patients with aneuploidy and p53 positivity had the worst prognosis ( P = 0.008). Conclusions The results suggest the involvement of p53 protein as a late event in bladder carcinogenesis. p53 does not seem to be a prognostic marker for recurrences of superficial tumors and is not independently related to survival. The aneuploidy of tumors correlates with the p53 positivity in bladder cancer. The combined expression of aneuploidy and p53 positivity in invasive tumors has strong association with the survival of patients.

Bacillus Calmette-Guerin Versus Doxorubicin Versus Thiotepa: A Randomized Prospective Study in 202 Patients with Superficial Bladder Cancer

We report the second interim analysis of data from a randomized prospective trial comparing the prophylactic effect of 15 courses of 50mg. doxorubicin, 50mg. thiotepa or 150mg. bacillus Calmette-Guerin instilled intravesically against recurrences and progression of superficial transitional cell bladder cancer. Of 202 enrolled patients 176 currently are evaluable with a mean followup of 3 years (range 3 to 97 months).The number of patients with recurrences was significantly lower in the bacillus Calmette-Guerin arm (9 of 67) compared to the doxorubicin (23 of 53, p equals 0.002) and thiotepa (20 of 56, p equals003) arms. The over-all recurrence index per 100 patient-months also was lower for the bacillus Calmette-Guerin versus the thiotepa and doxorubicin groups (0.53 versus 1.55 and 1.7, respectively). Bacillus Calmette-Guerin also was superior in preventing recurrences and progression of high risk tumors, that is stage Tl, grade 3 or multiple growths, associated or not with carcinoma in situ. In the stage Tl category 19 of 32 (60%) tumors recurred under treatment with doxorubicin, 11 of 33 (33%) with thiotepa and 6 of 49 (12%) with bacillus Calmette-Guerin.Toxicity to intravesical bacillus Calmette-Guerin was higher compared to the other drugs but it was not limiting: bladder irritability and malaise occurred in 42% of the patients, granulomatous cystitis in 16.4% and bladder contraction in 1.4% (1 of 64). The latter complication occurred in a patient whose stage Tim grade 2 tumors had recurred 3 times, who underwent 3 transurethral bladder resections within 15 months and who had received thiotepa for 4 months after having been removed from the study 11 months after entry.Three patients in the doxorubicin group (5.6%) underwent radical cystectomy for local urothelial progression. One patient (1.8%) in the same group died of distant progression.Our preliminary results suggest that at the dose, periodicity and duration used in the study bacillus Calmette-Guerin is significantly superior to the chemotherapeutic agents doxorubicin and thiotepa for the prophylaxis of recurrence and retardation of progression in superficial transitional cell bladder tumors.

Long-Term versus Short-Term Doxorubicin Hydrochloride Instillation after Transurethral Resection of Superficial Bladder Cancer

In a prospective randomized study the influence of short-term instillation therapy versus long-term instillation therapy after transurethral resection of superficial transitional cell bladder cancer on tumor recurrence, tumor progression and patient survival were evaluated. The data of 146 patients of 160 who entered the study were evaluable. After transurethral resection of the initial tumor and random biopsies of the bladder, patients were divided into two groups at random: group 1--doxorubicin weekly for 6 weeks and afterwards no further treatment (short-term regimen) and group 2--doxorubicin weekly for 6 weeks and afterwards monthly instillation for 2 years (long-term regimen). The follow-up was 5 years. Neither frequency of recurrences, nor tumor progression nor survival rate was improved significantly by the long-term instillation regimen.

Biologic response modifiers in genitourinary neoplasia

With the exception of testis cancer, the variety of genitourinary cancers have not been found to be consistently responsive to chemotherapeutic agents or regimens for other than anecdotal short duration. This has generated keen interest in the possibility that biologic response modifiers might either directly or through manipulation of immune response mechanisms successfully prevent tumor progression in these systems. In recent years, those substances that have attracted the greatest attention have included interferon (and, more recently, recombinant gamma interferon), bacillus Calmette-Guerin (BCG), tumor necrosis factor, prostaglandin synthetase inhibitors, and interleukin-2. Results with each of these agents in the variety of genitourinary cancers have been both promising and disappointing. A number of mechanisms have been suggested to underlie the actions of each of these substances, and the successful or unsuccessful recruitment of these mechanisms, in the context of the particular intrinsic behavior of the cancers being treated, have been suggested as reasons for the treatment results that have been seen. Therapeutic efficacy has been described in the treatment of renal cell cancer by both systemic interferon and interleukin-2. Successful treatments have been reported in approximately 20% of patients treated with each substance, but generally, these results have been of short duration. Topical BCG has been used with great success to treat superficial transitional cell bladder cancer. In these instances, the generation of tumor necrosis factor has been suggested as possibly accounting for the 70% success rate both in therapy and prophylaxis that has been seen. Leukocyte-derived interferon and, more recently, recombinant gamma interferon, were found in initial trials to generate a 20% response rate in renal cell carcinoma patients. Enthusiasm for these agents, however, has been tempered more recently both by a failure to reproduce these results with any substantial duration as well as by the significant side effects that have been seen. Clearly, these agents continue to be intriguing both because of their intellectual appeal through the mechanisms by which they may be effective, as well as by the absence of any definitive therapy for the cancers they are being used to treat. An understanding of the complex host/tumor cell interaction that may ultimately determine therapeutic efficacy for each of these agents is undoubtedly critical if the role of these substances in the treatment of genitourinary cancer is to be successfully implemented, either alone or in combination with other treatment modalities.

Intensive Intravesical Cheiviotherapy in the Treatment of Flat Carcinoma in Situ: Is it Safe?

Recent enthusiasm for the use of intensive regimens of intravesical chemotherapy in the management of various forms of superficial transitional cell carcinoma of the bladder prompted us to examine retrospectively a group of patients with carcinoma in situ treated by such regimens who failed with progressive and metastatic cancer. Of 8 patients with flat carcinoma in situ treated with thiotepa 5 presented initially with concomitant solitary stage Tl papillary tumors that were resected successfully at initial presentation. Six patients had diffuse or multifocal carcinoma in situ, while 2 others had only a solitary focus of in situ disease. All patients had persistently positive urinary cytology studies during treatment, prompting 3 of them to receive intravesical mitomycin C following their course of thiotepa. Involvement of the prostatic urethra developed during therapy in 3 patients and 3 had muscle-infiltrative disease. At cystectomy 3 of 7 patients had positive pelvic lymph nodes and 4 died of distant metastases at an average of 8 months after cystectomy. These results suggest that despite the apparent advances that have been made in the control of recurrent superficial transitional cell bladder cancer, the intrinsic behavior of some forms of the disease may determine cancer progression. Identification of such patients is indicated for the institution of early aggressive treatment, which in the end may actually be the more conservative therapeutic approach.