EXPRESSION OF BCL-2 AND BCL-X IN BLADDER CANCER

Purpose

TP53 and RB1 gene mutations in bladder transitional cell carcinoma (TCC) are correlated with grade, stage, recurrence, and survival and may correlate with tumor cell apoptotic potential. Overexpression of the bcl-2 and bcl-X anti-apoptotic genes has been correlated with poor prognosis and chemotherapy resistance in other systems. Similar studies have not been performed in TCC. We thus sought to determine expression of bcl-2 and bcl-X in TCC and correlate these with stage, survival and abnormal pRb or p53 expression.

Materials and Methods

Forty-two TCC samples (19 Ta and 23 locally advanced tumors) and normal urothelial controls were examined. Immunohistochemistry for p53, pRb, bcl-2 and bcl-X was performed on an automated system using indirect streptavidin biotin/horseradish peroxidase staining. Western immunoblot analysis was performed on bladder cancer cell lines to further characterize bcl-X expression. Recurrence-free and disease-specific survival were retrospectively determined. Kaplan-Meier survival curves were compared using the log rank test, and correlation of abnormal staining with stage and p53 or pRb status was determined using Fisher's exact test.

Results

Bcl-2 was expressed in less than 1% of normal urothelial cells, but moderate expression of bcl-x was found in all normal urothelial samples. Only 7.0% of TCC samples (1/19 Ta and 2/23 locally advanced tumors) demonstrated bcl-2 overexpression. Bcl-X overexpression was observed in 45.2% of TCC (8/19 Ta and 11/23 locally advanced tumors). Western blot analysis also revealed that both the long (29 kDa) anti-apoptotic form and short (19 kDa) pro-apoptotic form were overexpressed in bladder cancer cell lines and normal human urothelial cells. Bcl-X overexpression was weakly correlated with normal p53 expression (p = 0.06). There were no correlations of bcl-2 and bcl-X overexpression with abnormal p53, pRb, or tumor stage. There were no differences in recurrence-free or overall survival in patients with abnormal bcl-X staining.

Conclusions

Bcl-2 overexpression is rare in TCC. Bcl-X overexpression is common, likely reflecting its expression pattern in normal urothelium, but is not correlated with stage or abnormal p53 or pRb staining. Within the power limitations of this small study, bcl-X overexpression is not correlated with recurrence or survival.     

Relationship of p53 and bcl-2 to Prognosis in Muscle-Invasive Transitional Cell Carcinoma of the Bladder

Purpose

We examined the presence of the p53 and Bcl-2 oncoproteins, as detected by immunohistochemistry, in muscle-invasive bladder cancer and correlated this with survival.

Materials and Methods

Formalin-fixed cystectomy specimens from 41 consecutive patients with mean follow-up of 52 months were used. Five patients were either lost to follow-up or died of other diseases and were not included in the survival evaluation.

Results

Eighteen of 36 patients died of metastatic transitional cell carcinoma. p53 immunostaining was found in 61 percent of patients. In 21 of 23 this staining was homogeneous, with more than 75 percent of cancer cells staining using a DO-1/DO-7 antibody cocktail. p53 staining was not correlated with stage (p greater than 0.25) or grade (p less than 0.10) in these invasive cancer specimens. Contrary to recent studies p53 immunostaining was not correlated with disease-specific survival. Bcl-2 immunostaining was found in 28 percent of patients and was not correlated with grade (p greater than 0.25) or disease-specific survival. No combination of p53 and Bcl-2 staining gave added predictive information.

Conclusions

Cytoplasmic Bcl-2 is found in a small percentage of these cancers and does not correlate with prognosis. Further, p53 molecular overexpression is detected in the majority of muscle-invasive bladder tumors as a field defect. However, in patients undergoing cystectomy, it does not correlate with prognosis.     

METHOTREXATE RESISTANCE IN HUMAN UROEPITHELIAL CELLS WITH p53 ALTERATIONS

Purpose

Bladder cancers are frequently treated with combination chemotherapy that includes methotrexate (MTX). The development of drug resistance is a common problem in treatment of bladder cancers. We tested if the status of p53 and/or pRb affects the development of MTX resistance in bladder epithelial cell lines.

Materials and Methods

We used two isogeneic sets of cell lines in which we manipulated the status of p53 and/or pRb by transformation with Human Papillomavirus (HPV) E6 and/or E7 or with a transdominant TP53 mutant (TP53 sup 143). One series of isogeneic origin was derived from normal human uroepithelial cells (HUC), and the other was derived from a human transitional cell carcinoma (TCC). Cell lines with p53 and/or pRb alterations were cultured for six months while increasing the MTX concentration in each line, as resistance developed.

Results

Two cell lines with both pRb and p53 alterations, alpha E6/E7-HUC and alpha E7-HUC^p53mu, acquired the greatest resistance (750 nM) to MTX. One line with p53 loss, E6-TCC#10, acquired intermediate resistance (500 nM), while two lines, alpha E7-HUC and E7-TCC#10, with altered pRb but wildtype p53, showed low levels of MTX resistance (125 nM and 80 nM, respectively). Two clear mechanisms of MTX resistance were identified. All five MTX resistant cell lines showed altered uptake of MTX. In addition, two of five MTX resistant cell lines, both with altered p53, showed dihydrofolate reductase (DHFR) amplification.

Conclusions

p53 alteration increases the risk for development of drug resistance by both DHFR amplification and altered MTX transport in transformed human bladder epithelial cell lines.     

Methotrexate, Vinblastine, Doxorubicin and Cisplatin Chemotherapy and Cystectomy for Unresectable Bladder Cancer

Purpose

We combined chemotherapy and surgery to improve local control and survival of patients with unresectable bladder cancer.

Materials and Methods

A total of 41 patients with unresectable bladder cancer (T4bnX/N+M0) received methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) chemotherapy followed by radical cystectomy when possible. End points were response to M-VAC, local control and survival.

Results

Minimum followup was 4 years (range 4 to 7). Of the 41 patients 14 (34 percent) achieved a complete (T0) and 27 (66 percent) achieved an incomplete (T+) clinical response to M-VAC, including 29 who underwent exploration and 24 who underwent cystectomy. Definitive surgery was not done in 17 patients due to lack of response to M-VAC with local or systemic tumor progression, or refusal. Nine patients (22 percent) are alive, including all but 1 after cystectomy for T0 disease, and 2 had T+ tumor confined to the bladder for longer than 5 years. None of the patients with no response or tumor progression on M-VAC survived. Resection of extravesical disease after M-VAC in 16 patients did not prolong survival or improve local tumor control. Six patients required laparotomy for palliation of tumor related complications.

Conclusions

Our results suggest that patients who present with unresectable bladder cancer may benefit from M-VAC and definitive surgery, especially when disease is T0 and P0 status. Surgery may salvage select cases of advanced pelvic tumor down staged by chemotherapy to tumors pathologically confined to the bladder. Alternative treatment strategies are needed for the majority of patients with locally advanced bladder cancer.     

Primary Cisplatin, Methotrexate and Vinblastine Aiming at Bladder Preservation in Invasive Bladder Cancer: Multivariate Analysis on Prognostic Factors

Purpose

Although radical cystectomy is the standard therapy for invasive bladder cancer, cisplatin based multi-drug chemotherapy has proved to be effective for advanced transitional cell urothelial carcinoma. The potential for bladder preservation with neoadjuvant chemotherapy is currently under investigation.

Materials and Methods

A phase 2 protocol is presented for conservative treatment of muscle invasive transitional cell carcinoma of the bladder consisting of primary cisplatin, methotrexate and vinblastine chemotherapy followed by reevaluation for bladder sparing surgery and surveillance. A total of 61 patients completed the protocol with a mean followup of 41.4 months.

Results

Initial complete response to chemotherapy associated with tumor stage, size and configuration was noted in 20 patients (33 percent). Bladder preservation, intended only for the complete response group, was achieved in 16 patients (26 percent) but only 11 (18 percent) were alive with the bladder intact at study closure. Disease-free 5-year survival rate was 47 percent (95 percent confidence interval 65 to 26 percent). Tumor stage (p = 0.0007), size (p = 0.0003), response to chemotherapy (p = 0.002), patient age (p = 0.039) and tumor grade (p = 0.048) influenced survival. Multivariate analysis revealed response to chemotherapy (beta = 0.988, p = 0.034) and tumor size (beta = 0.978, p = 0.042) to be the only independent predictors.

Conclusions

Induction of cisplatin, methotrexate and vinblastine chemotherapy is helpful in identifying patients with a greater chance for survival among those with locally advanced bladder cancer. However, a bladder preservation strategy based on this therapy is only of limited success.     

Five-year Followup of a Prospective Trial of Radical Cystectomy and Neoadjuvant Chemotherapy: Nordic Cystectomy Trial 1

Purpose

Chemotherapy is widely used in patients with locally advanced bladder cancer but until now there has been no conclusive evidence that this therapy improves survival. The Nordic Cooperative Bladder Cancer Study Group conducted a randomized phase III study to assess the possible benefit of neoadjuvant chemotherapy in patients with bladder cancer undergoing radical cystectomy after short-term radiotherapy.

Materials and Methods

Our trial included 325 patients with locally advanced stage T1 grade 3 or stages T2 to T4aNXMO bladder cancer allocated randomly into a chemotherapy or no chemotherapy group (control). The chemotherapy schedule consisted of 2 cycles of 70 mg./m.² cisplatin and 30 mg./m.² doxorubicin with a 3-week interval between the cycles.

Results

After 5 years the overall survival rate was 59 percent in the chemotherapy group and 51 percent in the control group (p = 0.1). The corresponding cancer specific survival rate was 64 and 54 percent, respectively. In regard to treatment, no difference was observed for stages T1 and T2 disease, while there was a 15 percent difference in overall survival for patients with stages T3 to T4a disease (p = 0.03). In a multivariate analysis only chemotherapy and T category emerged as independent prognostic factors. The relative death risk for patients who received chemotherapy was 0.69 (95 percent confidence interval 0.49 to 0.98) compared to the control group after adjustment for the other tested factors.

Conclusions

Neoadjuvant chemotherapy seems to improve long-term survival after cystectomy in patients with stages T3 to T4a bladder carcinoma, while no survival benefit was found for stages T1 to T2 disease.     

Association of tumor-associated trypsin inhibitor (TATI) expression with molecular markers, pathologic features and clinical outcomes of urothelial carcinoma of the urinary bladder

Purposes

To describe the differential tissue expression of tumor-associated trypsin inhibitor (TATI) in normal bladder urothelium, primary urothelial carcinoma of the bladder (UCB) and metastatic UCB and to assess the association of TATI expression with molecular markers commonly altered in UCB and clinical outcomes after radical cystectomy.

Methods

Slides from eight cystectomy patients without cancer, 191 radical cystectomy patients, 20 lymph nodes without metastasis and 40 lymph nodes with UCB were stained. Tissue expression of TATI, cyclin E1, cyclin D1, p53, p21, p27, pRB, Ki-67, Bcl-2, Caspase-3, Survivin and Cyclooxigenase-2 was measured in a tissue microarray. Cancer-specific and recurrence-free survival after radical cystectomy was recorded.

Results

TATI was expressed in 100% of patients without cancer, while 71% of radical cystectomy specimens and 90% of lymph node metastases exhibited decreased or no TATI expression. In radical cystectomy specimens, TATI expression decreased with advancing pathologic stage (P?P?=?0.055). In univariate analyses, but not in multivariable Cox proportional hazard regression analyses, decreased TATI expression was associated with increased probability of tumor recurrence and cancer-specific mortality. Decreased TATI expression was correlated with altered expression of Cyclooxigenase-2 (P?=?0.005), p21 (P?=?0.035) and Ki-67 (P?=?0.004).

Conclusions

We found that normal urothelium expresses TATI and that TATI expression decreases with advancing tumor stage. While there was no prognostic benefit to TATI when adjusted for standard clinicopathologic features, it seems to play an important biologic role in UCB pathogenesis and invasion. Its association with markers involved in the cell cycle, proliferation and inflammation serves as hypothesis for molecular interactions.     

p53, p21/WAF1, pRb的表达与T1G3膀胱癌预后的关系

目的　探讨p5 3,p2 1/WAF1和pRb的异常表达在T1G3 膀胱癌预后判断中的价值。　方法　对 4 7例T1G3 膀胱癌患者进行术后随访 ,采用p5 3,p2 1/WAF1和pRb单克隆抗体对手术标本行免疫组化染色。将肿瘤进展情况与染色结果和与预后相关的临床指标进行分析。　结果　 39例手术保留膀胱的患者总进展率为 5 9% ,其中 9例发生远处转移。 8例行膀胱全切术的患者 1例于术后 2年发现肺转移。肿瘤细胞核p5 3,p2 1/WAF1和pRb蛋白的异常表达率分别为 6 6 .7%、5 1.4 %和 71.8%。多因素分析显示 ,p5 3、pRb同时异常表达 (P <0 .0 5 )和p5 3、p2 1/WAF1、pRb三者同时异常表达(P <0 .0 1)与肿瘤进展显著相关。　结论　p5 3,p2 1/WAF1和pRb的表达与T1G3 膀胱癌患者的预后密切相关     

Prevalence and Clinical Significance of Her-2/neu, p53 and Rb Expression in Primary Superficial Bladder Cancer

Purpose

The usefulness of the expression of HER2/neu oncoprotein and of p53 and Rb suppressor gene product as predictors of tumor recurrence was evaluated by using a bank of prospectively collected primary papillary bladder tumors treated initially only by transurethral resection.

Materials and Methods

The expression of HER-2/neu oncoprotein and of p53 and Rb suppressor genes was evaluated by immunohistochemistry in 256, 265 and 74 specimens of primary Ta/T1 superficial bladder tumors obtained from patients enrolled in a prospective study from 1990 to 1992. Survival analysis was used to evaluate the association between time to first recurrence and expression of each marker, the follow-up period extending to March 1994. Immunostaining for p53 and HER-2/neu was performed on paraffin-embedded tissue and, for Rb, on frozen tissue only.

Results

Her-2/neu was expressed in 21 (8.2 percent) cases and p53 in 39 cases (14.7 percent); Rb expression was altered in 12 (16.2 percent). In this study, p53 expression was only related to earlier recurrence in a univariate analysis. Multivariate analysis, however, failed to recognize p53 expression as an independent predictor of recurrence.

Conclusions

Our study demonstrate the low prevalence of HER2/neu, p53 and altered Rb expression in superficial TCC at initial resection. Only p53 expression was significantly associated with an earlier first tumor recurrence, but this association was not independent of other prognostic factors.     

Neoadjuvant and adjuvant chemotherapy in muscle-invasive bladder cancer

Context

The use of neoadjuvant and adjuvant chemotherapy in the treatment of muscle-invasive bladder cancer is still controversial.

Objective

To determine the optimal use of chemotherapy in the neoadjuvant and adjuvant settings in patients with advanced urothelial cell carcinoma. Bladder preservation is also discussed.

Evidence acquisition

A critical review of the published literature on chemotherapy for patients with locally advanced bladder cancer was performed.

Evidence synthesis

The presence of occult micrometastases at the time of radical cystectomy leads to both distant and local failure in patients with locally advanced transitional cell carcinoma of the bladder. Both neoadjuvant and adjuvant therapies have been evaluated in patients with locally advanced bladder cancer. Studies evaluating adjuvant chemotherapy have been limited by inadequate statistical power to detect meaningful clinical answers as well as by experimental arms utilizing inadequate chemotherapy.

Conclusions

The aggregate of available evidence suggests that neoadjuvant cisplatin-based combination chemotherapy should be considered as a standard of care for patients with muscle-invasive or locally advanced operable bladder cancer. In patients who are either unfit for or refuse radical cystectomy, neoadjuvant chemotherapy with or without radiation can render bladder preservation possible for patients who attain an excellent clinical response. With the introduction of new cytotoxic drugs, there is a need for well-designed studies to address the optimal utility of perioperative therapy in high-risk patients with bladder cancer.     

THE MOLECULAR CHARACTERISTICS OF BLADDER CANCER IN YOUNG PATIENTS

Purpose

The molecular characteristics of bladder cancer in children and young adults remain largely undefined. We sought to identify common molecular changes in bladder tumors in young patients using standard immunohistochemical and interphase cytogenetic methods.

Materials and Methods

We retrospectively evaluated 73 bladder tumors removed from patients younger than 30 years for the p53 tumor suppressor gene product using immunohitochemical techniques and numerical aberrations of chromosomes 9, 17, X and Y.

Results

Regardless of stage, immunohistochemical evidence of p53 gene product over expression was found in the majority of tumors studied. Numerical abberations (mosomy) of chromosome 9 were rare. Aneuploidy of chromosome 17 was common, particularly in carcinoma in situ and invasive bladder cancer.

Conclusions

These data suggest that immunohistochemical evidence of p53 gene product over expression is common in bladder cancer in young patients. Further prospective analysis of lesions in this population may help to establish a comprehensive molecular progression model for urothelial neoplasms.     

Epidermal growth factor receptor expression: predictive value for the outcome after cystectomy for bladder cancer?

OBJECTIVE: To determine whether epidermal growth factor receptor (EGFR) immunostaining of tumour cells is associated with cancer-specific death after cystectomy for locally advanced bladder cancer. PATIENTS AND METHODS: The hospital records of all patients treated with cystectomy for urothelial cancer of the urinary bladder between 1967 and 1992 were reviewed retrospectively. The paraffin-embedded specimens obtained before treatment from 173 patients were processed for immunohistochemical staining, using the monoclonal antibody NCL-EGFR (Novocastra, UK). EGFR immunostaining was considered positive if membrane staining was found in at > or = 20% of tumour cells in one or more fields at > or = 200 (area 0.59 mm2). RESULTS: Most patients (149) received preoperative irradiation and one had neoadjuvant chemotherapy. The mean observation time was 81.3 months; 63 patients (36%) had tumour recurrence within 1-80 months (mean 18.3). Positive EGFR immunostaining was found in 100 patients (58%). The proportion of T2-4 tumours was higher in those EGFR-positive than in those EGFR-negative. Proportional-hazards analysis revealed that clinical stage was significantly associated with cancer-specific death, but EGFR expression was not. CONCLUSION: Although positive immunostaining for EGFR was more frequent in higher stages of locally advanced bladder cancer, this variable was not an independent predictor of outcome after cystectomy.     

RELATIONSHIP AMONG CYSTECTOMY, MICROVESSEL DENSITY AND PROGNOSIS IN STAGE T1 TRANSITIONAL CELL CARCINOMA OF THE BLADDER

Purpose

The selection of therapy for stage T1 bladder cancer is controversial, and reliable biomarkers that identify patients likely to require cystectomy for local disease control have not been established. We evaluated our experience with T1 bladder cancer to determine whether early cystectomy improves prognosis, and whether microvessel density has prognostic value for T1 lesions and could be used for patient selection.

Materials and Methods

We retrospectively reviewed the records of 88 patients with T1 transitional cell carcinoma of the bladder. Patient outcome was correlated with therapeutic intervention. Paraffin embedded tissue from 54 patients was available for factor VIII immunohistochemical staining for microvessel density quantification.

Results

Median followup was 48 months (range 12 to 239). Of the patients 34% had no tumor recurrence. The rates of recurrence only and progression to higher stage disease were 41 and 25%, respectively. The survival of patients in whom disease progressed was diminished (p = 0.0002). Grade did not predict recurrence or progression nor did cystectomy provide a survival advantage. Microvessel density did not correlate with recurrence or progression.

Conclusions

Patients with T1 bladder cancer have a high risk of recurrence and progression. Tumor progression has a significant negative impact on survival. Neither grade nor early tumor recurrence predicted disease progression. Because early cystectomy did not improve patient outcome, we suggest reserving cystectomy for patients with progression or disease refractory to local therapy. Microvessel density is not a prognostic marker for T1 bladder cancer and has no value in selecting patients with T1 disease for cystectomy.     

Prospective Evaluation of a Molecular Marker Panel for Prediction of Recurrence and Cancer-specific Survival After Radical Cystectomy

Background

Retrospective studies demonstrated that cell cycle–related and proliferation biomarkers add information to standard pathologic tumor features after radical cystectomy (RC). There are no prospective studies validating the clinical utility of markers in bladder cancer.

Objective

To prospectively determine whether a panel of biomarkers could identify patients with urothelial carcinoma of the bladder (UCB) who were likely to experience disease recurrence or mortality.

Design, setting, and participants

Between January 2007 and January 2012, every patient with high-grade bladder cancer, including 216 patients treated with RC and lymphadenectomy, underwent immunohistochemical staining for tumor protein p53 (Tp53); cyclin-dependent kinase inhibitor 1A (p21, Cip1) (CDKN1A); cyclin-dependent kinase inhibitor 1B (p27, Kip1); antigen identified by monoclonal antibody Ki-67 (MKI67); and cyclin E1.

Intervention

Every patient underwent RC and lymphadenectomy, and marker staining.

Outcome measurements and statistical analysis

Cox regression analyses tested the ability of the number of altered biomarkers to predict recurrence or cancer-specific mortality (CSM).

Results and limitations

Pathologic stage among the study population was pT0 (5%), pT1 (35%), pT2 (19%), pT3 (29%), and pT4 (13%); lymphovascular invasion (LVI) was seen in 34%. The median number of removed lymph nodes was 23, and 60 patients had lymph node involvement (LNI). Median follow-up was 20 mo. Expression of p53, p21, p27, cyclin E1, and Ki-67 were altered in 54%, 26%, 46%, 15%, and 75% patients, respectively. In univariable analyses, pT stage, LNI, LVI, perioperative chemotherapy (CTx), margin status, and number of altered biomarkers predicted disease recurrence. In a multivariable model adjusting for pathologic stage, margins, LNI, and adjuvant CTx, only LVI and number of altered biomarkers were independent predictors of recurrence and CSM. The concordance index of a baseline model predicting CSM (including pathologic stage, margins, LVI, LNI, and adjuvant CTx) was 80% and improved to 83% with addition of the number of altered markers.

Conclusions

Molecular markers improve the prediction of recurrence and CSM after RC. They may identify patients who might benefit from additional treatments and closer surveillance after cystectomy.     

Cyclophosphamide Associated Bladder Cancer--A Highly Aggressive Disease: Analysis of 12 Cases

Purpose

We gained knowledge of the etiology, treatment and prevention of cyclophosphamide associated urothelial cancer.

Materials and Methods

The medical records of 6 men and 6 women (mean age 55 years) with cyclophosphamide associated bladder cancer were reviewed.

Results

All tumors were grade 3 or 4 transitional cell carcinoma. Of the 5 patients initially treated with endoscopic resection alone only 1 is alive without disease. Of The 6 patients who underwent early cystectomy 4 were alive at 24 to 111 months. The remaining patient with extensive cancer underwent partial cystectomy for palliation and died 3 months later.

Conclusions

Cyclophosphamide associated bladder tumor is an aggressive disease. However, long-term survival is possible when radical cystectomy is performed for bladder tumors with any sign of invasion and for recurrent high grade disease, even when noninvasive.     

p53 Protein and Gene Alterations in Pathological Stage C Prostate Carcinoma

Purpose

We determined the extent of p53 immunoreactivity in pathological stage C prostate cancer as well as its correlation to tumor grade, substage, recurrence and proliferation rate. To define better the temporal relationship of p53 nuclear reactivity in prostate cancer p53 immunoreactivity was evaluated in all associated prostatic intraepithelial neoplasia lesions.

Materials and Methods

Using immunohistochemistry p53 status and proliferation rate were determined in 96 tumors from patients with pathological stage C prostate cancer. Single strand conformational polymorphism in exons 5 to 8 was used in a subset of specimens to assess the association of p53 nuclear accumulation with mutations in the p53 gene.

Results

p53 Nuclear reactivity was demonstrated in 10 tumors (10.4%), including 6 with high and 4 with low level nuclear reactivity. Of the tumors 86 (89.6%) had no evidence of p53 immunoreactivity. Each of the 6 tumors with high level p53 reactivity had associated areas of prostatic intraepithelial neoplasia that also showed p53 nuclear reactivity. Furthermore, pathological stage C substage (C1, 2 or 3) was significantly associated with p53 nuclear reactivity (p = 0.04). Proliferation rates were correlated with p53 nuclear reactivity (p = 0.09), while there was no association with tumor grade or recurrence. p53 Gene alterations were noted in 2 of the 3 p53 positive tumors versus no alterations in the p53 gene of 3 p53 negative tumors.

Conclusions

p53 Nuclear accumulation is uncommon in pathological stage C prostate cancer and its presence in premalignant prostatic intraepithelial neoplasia lesions suggests that it may be an early event in a subset of prostate cancers.     

Maximizing cure for muscle-invasive bladder cancer: integration of surgery and chemotherapy

Context

The optimal treatment strategy for muscle-invasive bladder cancer remains controversial.

Objective

To determine optimal combination of chemotherapy and surgery aimed at preserving survival of patients with locally advanced bladder cancer.

Evidence acquisition

We performed a critical review of the published abstract and presentation literature on combined modality therapy for muscle-invasive bladder cancer. We emphasized articles of the highest scientific level, combining radical cystectomy and perioperative chemotherapy with curative intent to affect overall and disease-specific survival.

Evidence synthesis

Locally invasive, regional, and occult micrometastases at the time of radical cystectomy lead to both distant and local failure, causing bladder cancer deaths. Neoadjuvant and adjuvant chemotherapy regimens have been evaluated, as well as the quality of cystectomy and pelvic lymph node dissection.

Conclusions

Prospective, randomized clinical trials argue strongly for neoadjuvant cisplatin-based chemotherapy followed by high-quality cystectomy performed by an experienced surgeon operating in a high-volume center. Adjuvant chemotherapy after surgery is also effective when therapeutic doses can be given in a timely fashion. Both contribute to improved overall survival; however, many patients receive only one or none of these options, and the barriers to receiving optimal, combined, systemic therapy and surgery remain to be defined. An aging, comorbid, and often unfit population increasingly affected by bladder cancer poses significant challenges in management of individual patients.     

Epidermal growth factor expression as a predictor of chemotherapeutic resistance in muscle-invasive bladder cancer

Background

Epidermal growth factor receptor (EGFR) overexpression is believed to be associated with bladder cancer (BC) progression and poor clinical outcomes. In vivo studies have linked EGFR subcellular trafficking and chemo-resistance to cisplatin-based chemotherapies. This has not been studied in the clinical adjuvant setting. We aimed to investigate the prognostic significance of EGFR expression in patients receiving cisplatin-based adjuvant chemotherapy following radical cystectomy for advanced BC.

Methods

The database from the Urology and Nephrology Center at Mansoura University was reviewed. BC patients who were treated with radical cystectomy and adjuvant chemotherapy for adverse pathological features or node positive disease were identified. Patients who underwent palliative cystectomy, had histological diagnoses other than pure urothelial carcinoma, or received adjuvant radiotherapy were excluded from the study. Immunohistochemical staining for EGFR expression was performed on archived bladder specimens. The following in vitro functional analyses were performed to study the relationship of EGFR expression and chemoresponse.

Results

The study included 58 patients, among which the mean age was 57 years old. Majority of patients had node positive disease (n?=?53, 91%). Mean follow up was 26.61 months. EGFR was overexpressed in 25 cystectomy specimens (43%). Kaplan-Meier analysis revealed that EGFR over-expression significantly correlated with disease recurrence (p?=?0.021). Cox proportional hazard modeling identified EGFR overexpression as an independent predictor for disease recurrence (p?=?0.04). Furthermore, in vitro experiments demonstrated that inhibition of EGFR may sensitize cellular responses to cisplatin.

Conclusions

Our findings suggest that EGFR overexpression is associated with disease recurrence following adjuvant chemotherapy for advanced BC. This may aid in patient prognostication and selection prior to chemotherapeutic treatment for BC.

     

SNAI1 Protein Expression is an Independent Negative Prognosticator in Muscle-Invasive Bladder Cancer

Background

The prognosis of muscle-invasive bladder cancer is poor. Molecular prognosticators have gained increasing attention for individualized therapeutic options because they can identify patients with different prognoses.

Methods

Tissue microarrays of formalin-fixed and paraffin-embedded tumor samples from 206 bladder cancer patients treated with cystectomy and chemotherapy were studied for SNAI1 protein expression by immunohistochemistry. SNAI1 expression was evaluated using an immunoreactive score (IRS). For statistical analysis, the patients were separated into two groups: those with tumor specimens negative for SNAI1 expression (IRS = 0), and the other positive for SNAI1 expression (IRS ≥1).

Results

Tumor samples from 42 patients showed negative SNAI1 expression, whereas the nuclei of tumor cells from 164 patients showed detectable nuclear staining of SNAI1. A Kaplan–Meier analysis of the bladder cancer patients with negative SNAI1 expression showed significantly reduced disease-specific survival (DSS) and progression-free survival (PFS) compared to the patients with positive expression (p = 0.010 and 0.013). A multivariate Cox regression analysis (adjusted for gender, age, tumor stage, tumor grade, lymph node metastasis, chemotherapy, and histologic subtype) again showed a significant correlation between patients lacking SNAI1 expression and DSS (p = 0.005; relative risk 2.31; 95 % confidence interval 1.28–4.17) or PFS (p = 0.004; relative risk 2.20; 95 % confidence interval 1.29–3.78) compared to patients with positive SNAI1 staining.

Conclusions

Loss of SNAI1 protein expression is an independent prognosticator for PFS and DSS in bladder cancer patients treated by radical cystectomy and adjuvant chemotherapy. Its prognostic value for neoadjuvant or adjuvant chemotherapy must be evaluated in further prospective randomized controlled trials.     

Radical Cystectomy Using Endoscopic Stapling Devices: Preliminary Experience With a Simple and Reliable Technique

Purpose

We introduce a new technique to decrease operative time and blood loss during radical cystectomy.

Materials and Methods

We used endoscopic stapling devices for secure hemostasis, as well as rapid division of the bladder and prostatic lateral ligaments, and the deep dorsal vein complex during radical cystectomy in 16 patients with bladder or urethral cancer compared to 11 who underwent cystectomy via a conventional method, consisting of incision and ligation with sutures.

Results

In most cases the endoscopic staplers were useful for sufficient hemostasis and rapid division of the ligaments and/or venous plexus. Mean total operative time with the stapling technique was significantly shorter than that with the standard technique (p = 0.003), and mean total blood loss was less than with the standard technique but the difference was not statistically significant.

Conclusions

Although our study was not designed in a randomized manner, we believe that endoscopic stapling devices facilitate radical cystectomy.