Superficial Transitional Cell Carcinoma Research Articles

Serum Th1 and Th2 cytokine balance in patients of superficial transitional cell carcinoma of bladder pre- and post-intravesical combination immunotherapy

Combination therapy with intravesical bacillus Calmette-Guerin (BCG) plus interferon-α2b (IFN-α2b) for superficial transitional cell carcinoma (TCC) seems to be immune-dependent and activation of Th1 immune response is required for clinical efficacy. The present study evaluates circulating serum cytokine profiles (Th1/Th2 cytokines IFN-γ, IL-2 TNF-α, IL-4, IL-6 and IL-10) in 41 bladder cancer patients prior to transurethral resection of tumor (TURBT) (pre-therapy), and following intravesical combination immunotherapy (post-therapy) and their association with recurrence. Mean levels of IL-2 and TNF-α were significantly reduced while IL-4, IL-6 and IL-10 were significantly enhanced in pre-therapy samples as compared to controls. Mean levels of IFN-γ, IL-2 and TNF-α were significantly increased while IL-4 and IL-10 were significantly reduced in patients after instillation of combination immunotherapy. These findings suggest that bladder cancer patients develop Th2 dominant status with deficient type 1 immune response that shows tendency to reversal following therapy.

Insertion/Deletion Polymorphism in the Promoter Region ofNFKB1Gene Increases Susceptibility for Superficial Bladder Cancer in Chinese

Recently, a functional insertion/deletion polymorphism (-94 insertion/deletion ATTG) in the promoter of NFKB1 gene, which encodes the p50 subunit of nuclear factor-kappaB protein complex, was identified. The aim of this study was to explore the association between this polymorphism and bladder cancer in a Chinese population. The NFKB1 polymorphism was assessed in 207 patients with superficial transitional cell carcinomas in bladder and in 228 age-, sex-, and smoking-matched healthy volunteers. The polymerase chain reaction assay was used to determine the NFKB1 genotypes. Genomic DNA used for the assay was extracted from peripheral blood lymphocytes. This study found that the frequency of ATTG(2) allele in bladder cancer patients was significantly higher than that in control subjects (65.2% vs. 56.1%, p = 0.006, odds ratio = 1.465), suggesting that the functional NFKB1 promoter polymorphism is associated with increased risk for superficial transitional cell carcinoma of the bladder.

The Use of NMP22 and Urine Cytology for the Surveilance of Patients with Superficial Bladder Cancer

Aim To see if NMP22 combined with urine cytology can safely increase the interval between cystoscopies in the surveillance of superficial bladder cancers. Methods Thirty four patients with low grade superficial bladder transitional cell carcinomas were prospectively recruited and followed up with regular flexible cystoscopies over 2 years. Freshly voided urine was collected for urine cytology and NMP22 test prior to cystoscopy. Patients with suspicious cystoscopy findings or suspicious cytology underwent biopsies and/or resection of the suspicious lesions. Results 172 urine samples were collected and analyzed. The NMP 22 results were compared with voided urine cytology, cystoscopy and histological findings. Using the 10U/ml cutoff for quantitative measurement, the sensitivity, specificity, positive and negative predictive values of urinary NMP22 were 50%, 90.7%, 21.0%, and 97.3% respectively. When combined with voided urine cytology, the sensitivity, specificity, positive and negative predictive values were 71.4%, 88.5%, 25.0%, and 98.3% respectively. In comparison, the sensitivity, specificity, positive and negative predictive value of cystoscopy were 85.7%, 97.6%, 66.7%, and 99.2% respectively. Analysis with a receiver operating characteristic(ROC) curve found the ideal threshold of determinance of NMP22 for the detection of recurrences is 8.5U/ml with 100% sensitivity and 73.9% specificity. In our center, replacing alternate cystoscopy examination at 3,9,18 and 30 months with NMP22, results in a cost saving USD$740 or 37% per patient over 5 years. In the event of false positives, the patient will revert to the current surveillance schedule, with no increased costs incurred. Conclusion We propose that the optimal cutoff value for NMP22 is 8.5U/ml. At this level. the combination of the NMP22 BladderChek test and voided urine cytology is a sensitive non-invasive alternative to cystoscopy in the surveillance of patients who have had superficial low grade bladder cancer.

The Molecular, the Bad, and the Ugly: Preventing Bladder Cancer via mTOR Inhibition

This perspective on Seager et al. (beginning on p. 1008) considers an important advance in the effort to control bladder cancer. Frontline therapy for superficial transitional cell carcinoma of the bladder involves instillation of the crude immunomodulatory bacterial extract Bacillus Calmette-Guérin directly into the organ. Seager et al. now show that local administration of a chemical inhibitor of mammalian target of rapamycin strongly suppressed growth in a novel preclinical mouse model that develops carcinoma in situ, a particularly problematic form of transitional cell carcinoma of the bladder. The results not only support the clinical evaluation of mammalian target of rapamycin inhibitors in this setting, they open the door for the evaluation of additional molecular local therapies as well.

Outcome of Simultaneous Transurethral Resection of Bladder Tumor and Transurethral Resection of the Prostate in Comparison with the Procedures in Two Separate Sittings in Patients with Bladder Tumor and Urodynamically Proven Bladder Outflow Obstruction

A prospective randomized study was undertaken wherein transurethral resection of bladder tumor (TURBT) was performed along with transurethral resection of the prostate (TURP) in the same sitting (group A) in patients with bladder tumor and urodynamically proven bladder outflow obstruction. The outcome (recurrence and progression of superficial transitional cell carcinoma) was compared with patients who underwent TURBT and TURP in two separate sittings (group B) approximately 6 months apart. Between January 2002 and December 2007, 48 patients were randomized for this study. The inclusion and exclusion criteria are described below. The patients were followed up according to standard protocols. The two groups were compared for the recurrence and progression of the bladder tumor. Mean age in both the groups were similar (group A = 56.06 +/- 4.45 years, group B = 57.36 +/- 3.65 years). The mean duration of follow-up was also similar between the two groups (group A, 35.71 +/- 12.8 months; group B, 37.55 +/- 14.12 months; P > 0.05). In group A, 12 (50%) patients had recurrence, while in group B, 11 (42.85%) patients had recurrence. The differences in recurrence, mean elapsed time to recurrence, and progression of tumor between the two groups were statistically insignificant. TURBT and TURP can be performed simultaneously without any increased risk of recurrence and progression of tumor, if performed in a properly selected group of patients.

Dysfunction of natural killer cells in patients with transitional cell carcinoma

Previous studies had established that transforming growth factor-β1 (TGF-β1) is highly expressed in bladder tumor, facilitating progression and spreading of the cancerous cells. Here, we report that both the number and the cytotoxic function of natural killer (NK) cells are decreased in patients with superficial transitional cell carcinoma (TCC). In consistent with previously reported findings, the plasma TGF-β1 concentration is also elevated in patients with superficial TCC. In vitro, the cytotoxic function of NK cells was impaired by the presence of TGF-β1. Hence, our data suggested elevated concentration of serum TGF-β1 in loss of NK cytotoxicity in superficial TCC patients, implicating altered innate immunity may correlate with the incidence of TCC.

Intravesical Gemcitabine in High-Risk Superficial Transitional Cell Carcinoma of the Bladder

Intravesical Gemcitabine in High-Risk Superficial Transitional Cell Carcinoma of the Bladder

Genoproteomic Mining of Urothelial Cancer Suggests γ-Glutamyl Hydrolase and Diazepam-Binding Inhibitor as Putative Urinary Markers of Outcome after Chemotherapy

Urinary biomarkers for the detection of bladder cancer have been developed, but no similar markers exist for prediction of clinical outcomes after receiving chemotherapy. Here we evaluate an approach that combines genomic, proteomic, and therapeutic outcome datasets to identify novel putative urinary biomarkers of clinical outcome after neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). Using this method, we identified gamma-glutamyl hydrolase (GGH), emmprin, survivin, and diazepam-binding inhibitor (DBI). Interestingly, GGH is a protein associated with methotrexate resistance, whereas emmprin, survivin, and DBI had been previously identified as predictors of outcome after platinum-containing chemotherapeutic regimens when assessed on tumor tissue. Using disease-free survival as a marker for clinical outcome, we evaluated the ability of GGH, emmprin, survivin, and DBI expression in tumor tissue to stratify 27 patients treated with neoadjuvant MVAC. DBI (P = 0.046) but not GGH (P = 0.190), emmprin (P = 0.066), or survivin (P = 0.393) successfully stratified patients. When GGH was used with DBI the significance of stratification improved (P = 0.024), whereas the addition of survivin or emmprin to this latter two-gene model reduced its significance (P = 0.036 and P = 0.040, respectively). Although these predictive results were obtained on tumor tissues, the presence of GGH and DBI in urine serves as a rationale for developing them as urinary markers of clinical outcomes for patients treated with neoadjuvant MVAC.

Reply

Absorption through the bladder wall is dependent on 2 variables, the molecular weight of the agent, and the integrity of the asymmetric unit membrane (AUM) of the epithelial lining. 1 Waltz T. Haner M. Wu X.R. et al. Towards the molecular architecture of the asymmetric unit membrane of the mammalian urinary bladder epithelium: a closed “twisted ribbon” structure. J Mol Biol. 1995; 248: 887-900 Crossref PubMed Scopus (93) Google Scholar With regard to gemcitabine, what we observe in systemic toxicity, namely, the side effects referred to in the above comment, is dependent also on the expression of cytidine deaminase (CDA), which is known to be affected by variation. In previous studies, we observed occasional systemic toxicity also with the drug administered to intact bladders, 2 Maffezzini M. Campodonico F. Canepa G. et al. Short-schedule intravesical gemcitabine with ablative intent in recurrent Ta-T1, G1-2, low- or intermediate Risk transitional cell carcinoma of the bladder. Eur Urol. 2007; 51: 956-961 Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar and enhancement of absorption through tumor tissue, as compared with normal urothelium, was observed by others. 3 Paroni R. Salonia A. Lev A. et al. Effect of local hyperthermia to the bladder on mitomycin C pharmacokinetics during intravesical chemotherapy for the treatment of superficial transitional cell carcinoma. Br J Clin Pharmacol. 2001; 52: 273-278 Crossref PubMed Scopus (74) Google Scholar Systemic Absorption and Pharmacokinetics of Single-dose Intravesical Gemcitabine After Transurethral Resection of the Bladder in Non-muscle-invasive Bladder CancerUrologyVol. 74Issue 5PreviewTo evaluate the systemic quantitative absorption, pharmacokinetics, and toxicities of gemcitabine administered intravesically at the recommended, high-concentration dose of 40 mg/mL, immediately after transurethral resection. Full-Text PDF Editorial CommentUrologyVol. 74Issue 5PreviewThe authors demonstrate the limited absorption of gemcitabine in the post-TURB setting, and confirm that it is safe to use not only immediately after TURB, but also after a large resection. The toxicities of gemcitabine are dose-dependent and are primarily related to marrow suppression, with myelosuppression, anemia, and thrombocytopenia being the most common. At the low systemic doses absorbed and with rapid clearance, none of the patients studied reached an exposure near intravenous administration levels. Full-Text PDF

Analysis of the prognostic factors affecting postoperative recurrence and progression in patients with superficial bladder transitional cell carcinoma

Objective To evaluate the prognostic factors affecting postoperative recurrence and progression in patients with superficial bladder transitional cell carcinoma(SBTCC). Methods From 2000 to 2004,150 patients with SBTCC were treated, of which 120 patients were followed up. The possible prognostic factors including clinical and pathological figures were analyzed by Cox's proportional hazard model in these patients. Results The mean fol-low-up period was 84.7 months. The recurrence rates at 3-year,5-year were 27.5% and 36.7% respectively. The main variables affecting recurrence were histological grades,tumor stage,tumor number and recurring tumor,and the first three were the independent risk factors. The progression rotes at 3-year,5-year were 9. 2% and 17.5%. The main variables affecting progression were histological grade,tumor stage, tumor number and recurring tumor, and the first one was the independent risk factor. Conclusion The main variables affecting progression were histological grade, tumor stage,tumor number and recurring tumor,and the first one were the independent risk factor. Key words: Urinary bladder neoplasms; Neoplasms recurrence, local; Prognosis

MP-20.08: Evaluation of P53 and CD44 as Markers of Tumor Recurrence in Low Risk Superficial Transitional Cell Carcinoma of the Bladder

MP-20.08: Evaluation of P53 and CD44 as Markers of Tumor Recurrence in Low Risk Superficial Transitional Cell Carcinoma of the Bladder

Multidrug Resistance in a Urothelial Cancer Cell Line After 1-Hour Mitomycin C Exposure

A factor pertinent to the design of cancer chemotherapy is multidrug resistance. Research in this area conventionally involves in vitro models using resistant cell lines generated by continuous low dose drug exposure for many months, unlike the exposure experienced by residual superficial bladder cancer cells during chemotherapy adjuvant to resection. Recently we noted a measure of multidrug resistance induced by 3 short exposures to mitomycin C during 10 weeks. We currently report detectable functional resistance after a single 1-hour insult. RT112 bladder cancer cells (Catalog No. ACC 418, Deutsche Sammlung von Mikroorganismen und Zellkulturen, Braunschweig, Germany) were exposed to a range of mitomycin C concentrations for 1 hour. Cells regrew in 3 of 24 cultures at 15.6, 3.91 and 0.98 mg/ml exposure. These cells were subjected to 3 functional tests of cross resistance to epirubicin, including MTT cytotoxicity assay, quantitative accumulation by flow cytometry and nuclear uptake or exclusion by live cell fluorescence microscopy. MTT assay and flow cytometry revealed clear indications of resistance. Intracellular distribution, in which nuclear exclusion indicates resistance, was distinctively resistant in 1 subline and another 2 were equivocal. Results indicate that some multidrug resistance potential exists even in a cloned cell line that is capable of surviving 1 short drug exposure and expanding after that insult. The exposures used are consistent with those probably experienced by many superficial transitional cell carcinoma cells during an intravesical chemotherapy application. The result gives added weight to considering multidrug resistance induction in dose scheduling or drug combinations for topical chemotherapy.

Clusterin as a Diagnostic and Prognostic Marker for Transitional Cell Carcinoma of the Bladder

We investigated the feasibility of profiling and measuring the concentration of clusterin in urine and serum for individuals with transitional cell carcinoma (TCC) of the bladder and comparing it with nontumor controls. In addition, we analyzed the correlation of expression of clusterin in specimens of TCC to various clinicopathologic parameters and prognosis of bladder cancer. Blood and urine samples were used from 68 patients with TCC of the bladder and from 61 patients with benign urological diseases. Enzyme-linked immunosorbent assays (ELISA) were performed for clusterin from serum and urine. Quantitation of clusterin mRNA was carried out in 68 bladder tumor specimens from radical cystectomy or transurethral resection and 26 normal bladder specimens from BPH patients by using RT-PCR method. Correlation for the expression of clusterin mRNA with clinicopathologic parameters was analyzed. Serum and urine clusterin was significantly higher in individuals with bladder cancer than control (p = 0.001). Sensitivity and specificity of serum and urine clusterin as a tumor marker for TCC of the bladder was found to be 80%, 91%, 87.1% and 96.7% respectively. Clusterin expression was significantly higher in TCC specimens than normal tissue specimens (P < 0.001). Expression of clusterin was significantly higher in patients with invasive TCC of the bladder than that in patients with superficial TCC and control (P < 0.001). Overexpression of clusterin mRNA was significantly associated with tumor recurrence and overall survival (p < 0.001). The recurrence-free survival time of patients with overexpression of clusterin was significantly shorter than that of patients with weak expression of clusterin (9.8 months vs. 35.2 months). Clusterin may be considered as a potential diagnostic and prognostic biomarker for bladder cancer using urine, serum and/or molecular biology techniques.

Enhancing the efficacy of cancer vaccines in urologic oncology: new directions

Immunotherapeutic interventions have long been utilized in urologic oncology for the treatment of metastatic renal cell or superficial transitional cell carcinoma. Most recently, the first active specific immunotherapeutic approach, a cancer vaccine, has passed the final phase of human testing and its approval by the FDA is pending. However, evidence suggests that the full protective and therapeutic potential of cancer vaccines has not yet been achieved. Through multiple mechanisms, tumors promote conditions in the tumor-bearing host that mitigate or even eliminate the vaccine-induced antitumor response. Restoration of the impaired immune function is, therefore, imperative for achieving optimum vaccine efficacy. Targeted pharmacological interventions are capable of overcoming tumor-mediated immunosuppression, and thereby enable cancer vaccination to reach its full therapeutic potential.

Failure of Bacillus Calmette Guerin (BCG) therapy for the treatment of bladder cancer: Al-Azhar experience

To determine the failure rate of intravesical Bacillus Calmette Guerin (BCG) instillation following complete transurethral resection of superficial transitional cell carcinoma (TCC) of the urinary bladder at the Urology Department, Al-Azhar University, Cairo, Egypt. A prospective analysis of 160 patients with superficial TCC of the urinary bladder treated by transurethral resection of the bladder tumor (TURT) and adjuvant intravesical BCG instillation was performed at the Urology Department, Al-Azhar University, Cairo, between 2002 and 2008. The mean follow-up was 37 ± 4 (range 3 to 64) months. After the initiation of BCG treatment 12 patients (7.5%) were lost to follow-up, 6 (3.8%) stopped BCG due to side-effects and were subsequently treated with intravesical chemotherapy, while another 5 (3.1%) died during BCG therapy due to tumor-unrelated causes. The overall survival rate at 3 years was 90.4%. At a mean follow-up period of 37 ± 4 months, 70.4% of the patients showed no tumor recurrence and 82% no tumor progression. BCG failure was significantly observed in cases with stage T1, or grade-3 tumors or in cases associated with carcinoma in situ. TURT with adjuvant intravesical BCG therapy is considered the first treatment option in high and intermediate risk patients with superficial TCC. Failure of BCG treatment is mainly observed in stage T1 or grade-3 tumors. Different treatment modalities can be used after a second tumor recurrence or progression according to the tumor aggressiveness and the patient’s preference.

S2 Evaluation of the clinical value of urinary NMP22 as a marker in the surveillance of superficial transitional cell carcinoma of the urinary bladder

S2 Evaluation of the clinical value of urinary NMP22 as a marker in the surveillance of superficial transitional cell carcinoma of the urinary bladder

Shotgun proteome expression profile of microdissected superficial transitional cell carcinoma and biomarker discovery from urine

The aim of this study was to globally characterize the expression profile of superficial transitional cell carcinoma using shotgun proteome strategy and to discuss the biomarker panel identified from urine. We identified 440 commonly expressed proteins from four samples of superficial transitional cell carcinoma using laser capture microdissection coupled with two-dimensional liquid chromatography tandem mass spectrometry. The identified proteins were further analyzed using bioinformatics tools and compared with the published literature. Compared with the entire list of the International Protein Index, there were 41/22 Gene ontology (GO) terms found to be enriched/depleted within the biological process annotation. GO biological process enrichment/depletion analysis was consistent with the results of urine proteome analysis. Proteins classified under the terms cell adhesion, cell proliferation and cell differentiation are good candidate biomarkers for cancer detection from urine. In conclusion, the present study identified an extensive expression profile in superficial transitional cell carcinoma of the bladder, providing information for the understanding of cancer cell biology and the discovery of a biomarker panel from urine.

Results at 5 years of intra vesical gemcitabine (G) single agent as adjuvant chemotheray in superficial transitional cell carcinoma (TCC) of the bladder

e16087 Background: Systemic intravenous gemcitabine is usually used in advanced bladder carcinoma, intravesical G is a novel treatment approach for TCC. In this study we evaluate the efficacy of intravesical Gemcitabine in patients (pts) with superficial bladder carcinoma. Methods: From February 2003 to June 2004, 60 pts (57M/3F) were enrolled in the study (M/F = 57/3). The median age was 59,5 years old (24–84). Nine pts had a carcinoma in situ (Cis) and 51 had pT1 lesions. Three weeks after a total transurethral resection (TUR), patients receive intravesical instillation of 2000 mg G every week for 6 weeks, than every month for six months. They received a total of 720 instillations, Follow up was with cystoscopy and urine cytology every six months. Results: At a median follow-up time 60 months, all patients were evaluable for tumor response: 23(38, 3%) patient had a persistant complete remission after treatment, 26 patients (43,3%) had a superficial relapse of TCC, six patients (10%) had progressive disease: four with muscle invasion and two with distant metastasis. Conclusions: Intravesical therapy with gemcitabine is active and well tolerated treatment in patients with superficial TCC carcinoma of the bladder. A phase III trial comparing GEM with intravesical BCG or MMC is warranted No significant financial relationships to disclose.

Cigarette Smoking and Drinking Water Source: Correlation with Clinical Features and Pathology of Superficial Bladder Carcinoma

Objective: Water source and cigarette smoking are related to clinical characteristics and pathology of superficial transitional cell carcinoma of the bladder. Methods: Tumor number, dimension, G-grade, T-stage, recurrences, cigarette smoking and water supply were recorded in patients harboring Ta–T1 G1–3 transitional cell carcinoma of the bladder. Results: Of 577 patients, 61% had multiple and 36% recurrent tumors. Two hundred and forty-one patients (42%) were current smokers and 188 (33%) were former smokers. Bottled water was the only drinkable source for 249 (45%) patients, municipal water supply for 177 (32%), artesian wells for 38 (7%), spring water for 7 (1%) and mixed source for 89 (16%). By adopting a cut-off of 30 years of smoking, patients affected by recurrent tumors varied from 22 to 43% (p = 0.0001). T1 tumors were more frequent in patients drinking nonbottled water (p = 0.03). Nonbottled supply was more frequent in never smokers (p = 0.015) and could represent a weak risk factor not detectable in smokers. Conclusions: Cigarette smoking correlates with the number of recurrences. T1 tumors were statistically more frequent in patients taking nonbottled drinking water. Chlorinated water supply was more frequent among patients who did not present cigarette smoking as a risk factor.

Clinical effects of second biopsy and resection in patients with high risk superficial transitional cell carcinoma of the bladder

Objective To explore the effects of second biopsy and resection on tumor recurrence and progression in patients with high risk non-muscle invasive bladder cancer. Methods The second biopsy and resections were performed 4-6 weeks after the first transurethral resection in 52 patients. Routine follow-up was done in another 71 patients. The tumor recurrence and progression rates were compared. Results Residual tumors were found in 54%(28/52) of patients underwent second biop-sy and resection, including muscle-invasive tumors in 5 patients. Two patients underwent radical cys-tectomy due to resection findings. During same period, 71 patients were routinely followed. After a median observation of 27 months, patients underwent second biopsy and resection showed lower recur-rence rate (P<0.05). The progression rate was no difference between the 2 groups(P0.05). Conclusion Second biopsy and resection may reduce recurrence rate in high risk non-muscle invasive bladder cancers, but may not change the tumor progression rate. Key words: Bladder neoplasms; Carcinoma; Reoperation