Significance of lymphovascular invasion in organ-confined, node-negative urothelial cancer of the bladder: data from the prospective p53-MVAC trial.

OBJECTIVES: To investigate the association between lymphovascular invasion (LVI) and clinical outcome in organ-confined, node-negative urothelial cancer of the bladder (UCB) in a post hoc analysis of a prospective clinical trial. To explore the effect of adjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) on outcome in the subset of patients whose tumours exhibited LVI. PATIENTS AND METHODS: Surgical and tumour factors were extracted from the operative and pathology reports of 499 patients who had undergone radical cystectomy (RC) for pT1-T2 N0 UCB in the p53-MVAC trial (Southwest Oncology Group 4B951/NCT00005047). The presence or absence of LVI was determined by pathological examination of transurethral resection or RC specimens. Variables were examined in univariate and multivariate Cox proportional hazards models for associations with time to recurrence (TTR) and overall survival (OS). RESULTS: Among 499 patients with a median follow-up of 4.9 years, a subset of 102 (20%) had LVI-positive tumours. Of these, 34 patients had pT1 and 68 had pT2 disease. LVI was significantly associated with TTR with a hazard ratio (HR) of 1.78 [95% confidence interval (CI) 1.15-2.77; number of events (EV) 95; P = 0.01) and with OS with a HR of 2.02 (95% CI 1.31-3.11; EV 98; P = 0.001) after adjustment for pathological stage. Among 27 patients with LVI-positive tumours who were randomised to receive adjuvant chemotherapy, receiving MVAC was not significantly associated with TTR (HR 0.70, 95% CI 0.16-3.17; EV 7; P = 0.65) or with OS (HR 0.45, 95% CI 0.11-1.83; EV 9; P = 0.26). CONCLUSIONS: Our post hoc analysis of the p53-MVAC trial revealed an association between LVI and shorter TTR and OS in patients with pT1-T2N0 disease. The analysis did not show a statistically significant benefit of adjuvant MVAC chemotherapy in patients with LVI, although a possible benefit was not excluded.

Variability in surgical quality in a phase III clinical trial of radical cystectomy in patients with organ-confined, node-negative urothelial carcinoma of the bladder.

BACKGROUND AND OBJECTIVES: Previous studies have shown that variability in surgical technique can affect the outcomes of cooperative group trials. We analyzed measures of surgical quality and clinical outcomes in patients enrolled in the p53-MVAC trial. METHODS: We performed a post-hoc analysis of patients with pT1-T2N0M0 urothelial carcinoma of the bladder following radical cystectomy (RC) and bilateral pelvic and iliac lymphadenectomy (LND). Measures of surgical quality were examined for associations with time to recurrence (TTR) and overall survival (OS). RESULTS: We reviewed operative and/or pathology reports for 440 patients from 35 sites. We found that only 31% of patients met all suggested trial eligibility criteria of having ≥15 lymph nodes identified in the pathologic specimen (LN#) and having undergone both extended and presacral LND. There was no association between extent of LND, LN#, or presacral LND and TTR or OS after adjustment for confounders and multiple testing. CONCLUSIONS: We demonstrated that there was substantial variability in surgical technique within a cooperative group trial. Despite explicit entry criteria, many patients did not undergo per-protocol LNDs. While outcomes were not apparently affected, it is nonetheless evident that careful attention to study design and quality monitoring will be critical to successful future trials.

Combination of molecular alterations and smoking intensity predicts bladder cancer outcome: a report from the Los Angeles Cancer Surveillance Program.

BACKGROUND: Traditional single-marker and multimarker molecular profiling approaches in bladder cancer do not account for major risk factors and their influence on clinical outcome. This study examined the prognostic value of molecular alterations across all disease stages after accounting for clinicopathological factors and smoking, the most common risk factor for bladder cancer in the developed world, in a population-based cohort. METHODS: Primary bladder tumors from 212 cancer registry patients (median follow-up, 13.2 years) were immunohistochemically profiled for Bax, caspase-3, apoptotic protease-activating factor 1 (Apaf-1), Bcl-2, p53, p21, cyclooxygenase-2, vascular endothelial growth factor, and E-cadherin alterations. "Smoking intensity" quantified the impact of duration and daily frequency of smoking. RESULTS: Age, pathological stage, surgical modality, and adjuvant therapy administration were significantly associated with survival. Increasing smoking intensity was independently associated with worse outcome (P < .001). Apaf-1, E-cadherin, and p53 were prognostic for outcome (P = .005, .014, and .032, respectively); E-cadherin remained prognostic following multivariable analysis (P = .040). Combined alterations in all 9 biomarkers were prognostic by univariable (P < .001) and multivariable (P = .006) analysis. A multivariable model that included all 9 biomarkers and smoking intensity had greater accuracy in predicting prognosis than models composed of standard clinicopathological covariates without or with smoking intensity (P < .001 and P = .018, respectively). CONCLUSIONS: Apaf-1, E-cadherin, and p53 alterations individually predicted survival in bladder cancer patients. Increasing number of biomarker alterations was significantly associated with worsening survival, although markers comprising the panel were not necessarily prognostic individually. Predictive value of the 9-biomarker panel with smoking intensity was significantly higher than that of routine clinicopathological parameters alone.

Radical Cystectomy in the Treatment of Invasive Bladder Cancer: Long-Term Results in 1,054 Patients.

PURPOSE: To evaluate our long-term experience with patients treated uniformly with radical cystectomy and pelvic lymph node dissection for invasive bladder cancer and to describe the association of the primary bladder tumor stage and regional lymph node status with clinical outcomes. PATIENTS AND METHODS: All patients undergoing radical cystectomy with bilateral pelvic iliac lymphadenectomy, with the intent to cure, for transitional-cell carcinoma of the bladder between July 1971 and December 1997, with or without adjuvant radiation or chemotherapy, were evaluated. The clinical course, pathologic characteristics, and long-term clinical outcomes were evaluated in this group of patients. RESULTS: A total of 1,054 patients (843 men [80%] and 211 women) with a median age of 66 years (range, 22 to 93 years) were uniformly treated. Median follow-up was 10.2 years (range, 0 to 28 years). There were 27 (2.5%) perioperative deaths, with a total of 292 (28%) early complications. Overall recurrence-free survival at 5 and 10 years for the entire cohort was 68% and 66%, respectively. The 5- and 10-year recurrence-free survival for patients with organ-confined, lymph node-negative tumors was 92% and 86% for P0 disease, 91% and 89% for Pis, 79% and 74% for Pa, and 83% and 78% for P1 tumors, respectively. Patients with muscle invasive (P2 and P3a), lymph node-negative tumors had 89% and 87% and 78% and 76% 5- and 10-year recurrence-free survival, respectively. Patients with nonorgan-confined (P3b, P4), lymph node-negative tumors demonstrated a significantly higher probability of recurrence compared with those with organ-confined bladder cancers (P < .001). The 5- and 10-year recurrence-free survival for P3b tumors was 62% and 61%, and for P4 tumors was 50% and 45% , respectively. A total of 246 patients (24%) had lymph node tumor involvement. The 5- and 10-year recurrence-free survival for these patients was 35%, and 34%, respectively, which was significantly lower than for patients without lymph node involvement (P < .001). Patients could also be stratified by the number of lymph nodes involved and by the extent of the primary bladder tumor (p stage). Patients with fewer than five positive lymph nodes, and whose p stage was organ-confined had significantly improved survival rates. Bladder cancer recurred in 311 patients (30%) . The median time to recurrence among those patients in whom the cancer recurred was 12 months (range, 0.04 to 11.1 years). In 234 patients (22%) there was a distant recurrence, and in 77 patients (7%) there was a local (pelvic) recurrence. CONCLUSION: These data from a large group of patients support the aggressive surgical management of invasive bladder cancer. Excellent long-term survival can be achieved with a low incidence of pelvic recurrence.

Long-term outcome in patients with a Gleason score ≤ 6 prostate cancer treated by radical prostatectomy.

OBJECTIVE: • To determine the actual recurrence risk of patients with a Gleason score (GS) ≤ 6 treated with radical retropubic prostatectomy (RRP) and bilateral lymphadenectomy in a cohort with long-term follow-up. PATIENTS AND METHODS: • The USC/Norris Comprehensive Cancer Center database included 3235 consecutive patients who underwent RRP for prostate cancer between January 1972 and December 2005. We identified 1383 patients with a GS ≤ 6 in prostatectomy specimens. Median follow-up was 8.3 years. Data on pathological and clinical characteristics and outcome were prospectively recorded. • Statistical analysis was performed using the stratified log-rank test and stepwise Cox regression analysis. RESULTS: • A GS of 6 was present in 66%, 5 in 27%, 4 in 5% and 3 or 2 in 3% of cases. Tumour classification was pT2N0 (83%), pT3N0 (14%), pT4N0 (0.1%) and any TN1 (2%). • Positive margins were seen in 18%. Estimated PSA and clinical recurrence rate were 14% and 4% after 10 years and 18% and 6% after 15 years, respectively. In multivariate analysis, N-stage (P < 0.001), T-stage (P= 0.02) and margin status (P < 0.001) were associated with PSA recurrence. • N-stage (P < 0.001) and T-stage (P= 0.01) were associated with clinical recurrence. • Overall, patients with a GS ≤ 6 accounted for 26% of all PSA recurrences and for 20% of all patients with clinical recurrences in the database. CONCLUSION: • A relatively small proportion of patients with a GS ≤ 6 cancer developed PSA recurrence and/or overt metastasis. However, these patients account for a substantial minority of those who experienced recurrence and metastasis.

Long-term oncological outcomes in women undergoing radical cystectomy and orthotopic diversion for bladder cancer.

PURPOSE: We compared oncological outcomes in women undergoing radical cystectomy and orthotopic diversion for bladder transitional cell carcinoma. MATERIALS AND METHODS: From 1990 to 2005, 201 women underwent radical cystectomy, including 120 with an orthotopic neobladder. Median followup was 8.6 years. The clinical course, and pathological and oncological outcomes in these 120 women were analyzed and compared to those in 81 women undergoing radical cystectomy and cutaneous diversion during the same period. RESULTS: Overall 3 of 120 women (2.5%) who received a neobladder died perioperatively. In this group the tumor was pathologically organ confined in 73 patients (61%), extravesical in 18 (15%) and lymph node positive in 29 (24%). Overall 5 and 10-year recurrence-free survival was 62% and 55%, respectively. Five and 10-year recurrence-free survival in patients with organ confined and extravesical disease was similar at 75% and 67%, and 71% and 71%, respectively. Patients with lymph node positive disease had significantly worse 5 and 10-year recurrence-free survival (24% and 19%, respectively). One woman had recurrence in the urethra and 2 (1.7%) had local recurrence. As stratified by pathological subgroups, similar outcomes were observed when comparing women with an orthotopic neobladder to the 81 who underwent cutaneous diversion. CONCLUSIONS: Orthotopic diversion does not compromise the oncological outcome in women after radical cystectomy for bladder transitional cell carcinoma. Excellent local and urethral control may be expected. Women with node positive disease are at highest risk for recurrence. Similar outcomes were observed in women undergoing cutaneous diversion.

Clinical outcomes and recurrence predictors of lymph node positive urothelial cancer after cystectomy.

PURPOSE: Lymph node metastasis in patients who undergo radical cystectomy for bladder transitional cell carcinoma is considered a poor prognostic factor. However, patients with minimal lymph node involvement likely have a better outcome than those with extensive disease. We examined outcomes in patients with low volume lymph node metastasis and identified variables associated with disease recurrence. MATERIALS AND METHODS: Our institution maintains a database of 1,600 patients with bladder transitional carcinoma who underwent radical cystectomy from 1971 to 2005 with intent to cure. All patients with low volume lymph node metastasis, defined as 1 or 2 positive lymph nodes, without concomitant distant metastasis were included in study. RESULTS: A total of 181 patients were identified. Median followup was 12.8 years, during which 96 patients experienced recurrence. Estimated 5 and 10-year recurrence-free survival was 43.8% and 40.9%, respectively. Multivariate analysis indicated that pathological stage/subgroup (RR 1.733, p = 0.015), lymph node density (RR 1.935, p = 0.014) and adjuvant chemotherapy (RR 0.538, p = 0.004) were significant independent predictors of recurrence-free survival. CONCLUSIONS: A considerable proportion of patients with low volume lymph node metastasis in our cohort remained free of recurrence during followup. Extravesical tumor extension and lymph node density greater than 4% were associated with a higher recurrence risk and adjuvant chemotherapy was associated with a lower risk. Although some patients with low volume lymph node metastasis may be cured by surgery alone, these data support adjuvant chemotherapy in these patients.

The impact of positive soft tissue surgical margins following radical cystectomy for high-grade, invasive bladder cancer.

INTRODUCTION: We evaluate the incidence and risk factors associated with positive soft tissue surgical margins (STSM) and determine the association with various surgical and pathological characteristics and clinical outcomes in patients undergoing radical cystectomy (RC) for bladder cancer. PATIENTS AND METHODS: From November 1971 to December 2005, 1,591 patients with primary transitional cell carcinoma (TCC) of the bladder underwent RC, with an extended bilateral pelvic lymphadenectomy and urinary diversion. A positive STSM was defined as tumor identified at the inked perivesical soft tissue surrounding the cystectomy specimen. Data were analyzed according to various clinical and pathologic variables, and survival analysis was performed. RESULTS: A total of 18 patients (1%) demonstrated pathologic evidence of a positive STSM following RC. Positive STSM were significantly associated with lymphovascular invasion, advanced pathologic stage, lymph node involvement, extent of nodal involvement and lymph node density. No patient with an organ-confined primary bladder tumor had a positive STSM, while 3% with extravesical tumor extension demonstrated a positive STSM. Recurrence-free and overall survival at 5 and 10 years for patients with a positive STSM was 29 and 22%, and 29 and 11%, respectively (p < 0.001). A positive STSM increased the risk of recurrence by threefold and the overall risk of death by 2.6 times. Only nine patients (1%) without evidence of nodal involvement had a positive STSM with a worse survival compared to those same pathologic subgroup and negative STSM. Nine patients (2%) with lymph node tumor involvement had positive STSM and also demonstrated significantly worse survival. CONCLUSION: Although a positive STSM was present in only 1% of patients undergoing a RC for TCC of the bladder, it was found to be an independent risk factor for advanced disease, lymph node involvement and tumor progression with worse survival. A dedicated effort should be made to avoid a positive STSM at the time of RC.

Outcomes of patients with clinical CIS-only disease treated with radical cystectomy.

OBJECTIVES: To report the long-term oncological efficacy of radical cystectomy for patients with presumed clinical CIS only disease, to characterize the likelihood of clinical understaging, and to characterize the pattern of recurrence. METHODS: One thousand six hundred patients have undergone radical cystectomy and pelvic lymph node dissection with intent to cure from August 1971 to December 2005 at the University of Southern California; 27 patients from this cohort who satisfied both the inclusion and exclusion criteria were identified. Relevant clinical and pathological data at time of cystectomy and during follow-up were reported. Overall and recurrence-free survival was estimated using the Kaplan-Meier method. RESULTS: At time of cystectomy, 33% of patients were found to be clinically understaged. Median follow-up was 94 months. Estimated 5- and 10-year overall survival was 87 and 56%, respectively. Estimated 5- and 10-year recurrence-free survival was 100 and 83%, respectively. CONCLUSIONS: Excellent long-term survival outcomes can be achieved with radical cystectomy. Radical cystectomy should be strongly considered for patients who have failed prior intravesical therapy. Long-term surveillance of the retained urethra and of the upper tract is essential, as recurrence can occur years following cystectomy. Patients who recur are at high risk of dying from disease.

Adjuvant chemotherapy for locally advanced urothelial carcinoma: an overview of the USC experience.

OBJECTIVES: To describe the tolerability of two chemotherapy regimens, gemcitabine and cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) for adjuvant treatment of patients with locally advanced urothelial cancer after radical cystectomy. METHODS: The USC Department of Urology bladder cancer database was searched for subjects who received adjuvant chemotherapy following cystectomy for transitional cell carcinoma with extravesical and/or lymph node involvement, yielding 187 cases. Clinical details regarding toxicity, number of cycles administered, and cancer outcome were analyzed. RESULTS: The majority of subjects had lymph node involvement (70%). Sixty-eight percent of subjects received MVAC and 32% received GC, the latter regimen was predominant after 2000. Fifty-six percent of subjects received all four planned cycles (51% GC and 58% MVAC). With a median follow-up of 11.2 years (range 1.9-19.6), 96 patients (51%) have suffered a relapse, with no significant difference between chemotherapy regimens. Median time to recurrence for the population was 3.7 years and median overall survival is 4.6 years (3.0-9.3). The median time from recurrence to death was 6.7 months and was not significantly different between MVAC and GC. CONCLUSIONS: Both MVAC and GC are tolerated after cystectomy for advanced urothelial carcinoma. A significant proportion of high-risk patients survive, free of disease, beyond 10 years. At recurrence, patients previously treated with adjuvant chemotherapy have a survival that appears much shorter than patients who develop metastases in the absence of this exposure, suggesting resistance to salvage chemotherapy.

Comparison of extraperitoneal and intraperitoneal augmentation enterocystoplasty for neurogenic bladder in spinal cord injury patients.

OBJECTIVES: Augmentation enterocystoplasty is the standard treatment for patients with neurogenic bladder who have failed medical management. Our "extraperitoneal" approach involves a small peritoneotomy to obtain the segment of bowel for augmentation, and a standard "clam" enterocystoplasty. We compared operative and postoperative parameters and clinical outcomes of this technique with the standard intraperitoneal technique. METHODS: We retrospectively reviewed charts of 73 patients with neurogenic voiding dysfunction refractory to medical management who underwent augmentation enterocystoplasty alone or in conjunction with additional procedures. A total of 49 patients underwent extraperitoneal augmentation and 24 patients underwent intraperitoneal augmentation. Operative and postoperative parameters including time of surgery, estimated blood loss, need for blood transfusion, time for return of bowel function, and length of hospital stay were examined. Clinical outcomes including early and late postoperative complications, and continence status were also analyzed. RESULTS: Median follow-up was 2.5 years. Patients in the extraperitoneal group had significantly shorter operative time (3.9 vs. 5.6 h, P < 0.0001); shorter hospital stay (8.0 vs. 10.5 days, P = 0.009); and shorter time to return of bowel function (3.5 vs. 4.9 days, P = 0.0005). There was no significant difference in complication rates. Postoperative continence was equally improved in both groups. When only patients with no prior abdominal surgery were compared, the findings were analogous: shorter operative time, shorter length of stay, sooner return of bowel function, and no difference in complication rate. CONCLUSIONS: The extraperitoneal technique provides an equally effective method of bladder augmentation to the standard technique with easier early postoperative recovery.

Training the urologic oncologist of the future: where are the challenges?

OBJECTIVE: Training the new generation of urologic oncologist from a surgical perspective poses unique challenges. The advent of minimally invasive surgical procedures coupled with the need to perform open surgical procedures has significantly increased the demands upon both the trainer and trainee. The learning and practice of complex procedures demand continuous improvements in surgical training programs. This review discusses some theoretical and practical issues to be considered for the successful and safe transmission of surgical skills in an era of increasing regulations. FINDINGS: Few systematic studies address this topic, leaving ample margin for research and improvement in this endeavor. It is the authors' opinion that mentorship remains the most significant and important component to successful surgical training today. The advent of simulation, virtual reality, and modular teaching represent (novel and important) advances in the field of surgical education. While some residency programs have incorporated these changes into their surgical training curriculum, this has not become widespread and the available literature remains at best sporadic. CONCLUSIONS: Mentorship remains an integral if not the most critical component to surgical training today. Other novel approaches to surgical training have developed and should be incorporated into the traditional concepts of mentorship training. This may become even more important with the advent of minimally invasive approaches to surgery. The vast majority of the studies published concur that the traditional model of "see one, do one, teach one" is not an optimal approach for training surgical skills. Socioeconomic changes are forcing the surgical community to rethink how they train residents and absorb new technologies. Adapting to the new demands posed on surgical educators represents a great challenge for the upcoming years.

Predictors of intravesical therapy for nonmuscle invasive bladder cancer: results from the surveillance, epidemiology and end results program 2003 patterns of care project.

PURPOSE: In response to variations in cancer care organizations have developed clinical guidelines. In the case of nonmuscle invasive bladder cancer, also known as superficial bladder cancer, 2 similar sets of guidelines were released in the late 1990s that provide care recommendations. We examined patterns of intravesical therapy use in nonmuscle invasive bladder cancer in 2003 to determine whether disparities remained in the quality of cancer care. MATERIALS AND METHODS: Data from the SEER (Surveillance, Epidemiology and End Results) Program 2003 Bladder Cancer Patterns of Care project were used. Subjects newly diagnosed with nonmuscle invasive bladder cancer in 2003 were included. Clinical and sociodemographic data were obtained from the SEER Program and a detailed medical record review. Statistical analysis was performed to identify independent predictors of intravesical therapy in the entire cohort and in a subset of patients at high risk. RESULTS: A total of 685 patients were included in the study, of whom 216 (31.5%) received intravesical therapy. In addition to higher tumor stage and grade, intravesical therapy was independently associated with race/ethnicity and geographic region. Of the subset of 350 patients at high risk 42% received intravesical therapy. Stage, grade, race/ethnicity and geographic region were independently associated with intravesical therapy in this subcohort. CONCLUSIONS: These data suggest the underuse of intravesical therapy even in patients with high risk nonmuscle invasive bladder cancer as well as disparities in the quality of care. Barriers to using this cancer treatment must be identified, particularly in individuals at higher risk, and providers must become more aware of existing clinical guidelines.

Invasive T1 bladder cancer: indications and rationale for radical cystectomy.

Invasive T1 bladder cancers are potentially lethal tumours with varying degrees of aggressiveness and progression. The management of invasive tumours can be very difficult and includes bladder-sparing with transurethral resection and intravesical therapy, or a more aggressive approach with radical cystectomy. Certain clinical and pathological factors might provide some risk stratification for invasive T1 tumours, and might better direct the physician towards an earlier cystectomy for some patients. This review provides a rationale for a radical cystectomy in patients with high-risk, invasive T1 bladder cancer.

Surgical benchmarks for the treatment of invasive bladder cancer.

Radical cystectomy is the gold standard for treatment of localized invasive bladder cancer in the United States. In recent years, there has been increasing focus on the importance of surgical technique as a factor that may influence the clinical and oncologic outcome of the operation, beyond the classically recognized patient and tumor-related factors. There is still insufficient high-quality evidence to support the absolute standardization of the surgical technique or the establishment of firm benchmarks by which the individual surgeon can measure performance. However, there is considerable evidence suggesting that 3 aspects of surgical technique have an impact on outcome: (1) Positive surgical margins nearly always result in ultimate cancer death. The rate of positive margins varies with surgeon experience as well as with cancer-specific variables. (2) The extent of lymphadenectomy has a significant impact on recurrence rates of the cancer, regardless of whether the lymph nodes are pathologically positive or not. (3) Higher volume surgeons have lower operative mortality and fewer positive surgical margins than low-volume surgeons. Higher volume hospitals also have lower operative mortalities and shorter hospital stays for patients who have undergone radical cystectomy. In this review, the authors evaluate the evidence supporting each of these statements and suggest potential areas of standardization of surgical technique that could translate into improved patient outcomes.

Lymphadenectomy in bladder cancer: a review.

BACKGROUND: Radical cystectomy is the standard treatment for muscle invasive bladder cancer, however the role and appropriate extent of an associated lymphadenectomy continues to change. METHODS: We performed a detailed review of the medical literature pertaining to the development and rationale for an extended lymphadenectomy in patients undergoing radical cystectomy. RESULTS: A perspective of lymphadenectomy and an anatomic account of bladder lymphatic drainage are presented. The technique of an extended lymphadenectomy is also highlighted. Autoptic contemporary clinical data are presented to suggest that a more extensive lymphadenectomy has both prognostic and therapeutic utility. Furthermore, the stage of the primary bladder tumor, total number of lymph nodes removed, and the lymph node tumor burden are shown to be important prognostic variables in patients undergoing cystectomy with pathologic evidence of lymph node metastasis. CONCLUSIONS: Radical cystectomy provides excellent local cancer control with the Lowe's pelvic recurrence rates and the best long-term survival. Radical cystectomy with an appropriate extended lymphadenectomy, while surgically more challenging, does not significantly increase the morbidity or mortality of the procedure. The limits of lymph node dissection are still subject to debate and there is growing evidence that an extended lymphadenectomy provides further diagnostic and therapeutic benefit.

EphB4 expression and biological significance in prostate cancer.

Prostate cancer is the most common cancer in men. Advanced prostate cancer spreading beyond the gland is incurable. Identifying factors that regulate the spread of tumor into the regional nodes and distant sites would guide the development of novel diagnostic, prognostic, and therapeutic targets. The aim of our study was to examine the expression and biological role of EphB4 in prostate cancer. EphB4 mRNA is expressed in 64 of 72 (89%) prostate tumor tissues assessed. EphB4 protein expression is found in the majority (41 of 62, 66%) of tumors, and 3 of 20 (15%) normal prostate tissues. Little or no expression was observed in benign prostate epithelial cell line, but EphB4 was expressed in all prostate cancer cell lines to varying degrees. EphB4 protein levels are high in the PC3 prostate cancer cell line and several folds higher in a metastatic clone of PC3 (PC3M) where overexpression was accompanied by EphB4 gene amplification. EphB4 expression is induced by loss of PTEN, p53, and induced by epidermal growth factor/epidermal growth factor receptor and insulin-like growth factor-I/insulin-like growth factor-IR. Knockdown of the EphB4 protein using EphB4 short interfering RNA or antisense oligodeoxynucleotide significantly inhibits cell growth/viability, migration, and invasion, and induces apoptosis in prostate cancer cell lines. Antisense oligodeoxynucleotide targeting EphB4 in vivo showed antitumor activity in murine human tumor xenograft model. These data show a role for EphB4 in prostate cancer and provide a rationale to study EphB4 for diagnostic, prognostic, and therapeutic applications.

Lymphadenectomy in bladder cancer: how high is "high enough"?

PURPOSE: The role of a regional lymphadenectomy in the surgical treatment of high-grade, invasive transitional cell carcinoma of the bladder has evolved over the last several decades. Although the application of a lymphadenectomy for bladder cancer is not significantly debated, the absolute extent or level of proximal dissection of the lymphadenectomy remains a controversial issue. MATERIAL AND METHODS: A review of the literature should help elucidate the rationale and extent of an appropriate lymphadenectomy in patients undergoing radical cystectomy for bladder cancer. Various surgical issues of lymphadenectomy as well as prognostic factors in patients undergoing radical cystectomy for bladder cancer are examined. RESULTS: A growing body of evidence, spanning from early autopsy and cadaveric studies to recent retrospective series and multicenter prospective trials, suggests that an extended lymph node dissection (cephalad extent to include the common iliac arteries) may provide not only prognostic information but also provide a therapeutic benefit for both patients with lymph node-positive and lymph node-negative disease undergoing radical cystectomy for bladder cancer. Although the absolute boundaries of the lymphadenectomy remain a subject of controversy, historical reports confirmed by recent lymphatic mapping studies suggest the inclusion of the common iliac as well as possibly presacral nodes in the routine lymphadenectomy for transitional cell carcinoma of the bladder. The need to extend the dissection higher to include the distal para-aortic and paracaval lymph nodes may be important in select individuals but remains more controversial. The extent of the primary bladder tumor (p-stage), number of lymph nodes removed, the lymph node tumor burden (tumor volume), and lymph node density (number of lymph nodes involved/number of lymph nodes removed) are all important prognostic variables in patients undergoing cystectomy with pathologic evidence of lymph node metastases. Systemic adjuvant chemotherapy remains a mainstay of treatment of patients with lymph node metastases. CONCLUSIONS: Radical cystectomy with an appropriately performed lymphadenectomy provides the best survival outcomes and lowest local recurrence rates. Although the absolute limits of the lymph node dissection remain to be determined, evidence supports a more extended lymphadenectomy to include the common iliac vessels and presacral lymph nodes at cystectomy in patients who are appropriate surgical candidates. When feasible, adjuvant chemotherapy is warranted in patients with positive nodal metastasis.

Combined effects of p53, p21, and pRb expression in the progression of bladder transitional cell carcinoma.

PURPOSE: To determine the combined effects of p53, p21, and pRb alterations in predicting the progression of bladder transitional cell carcinoma. PATIENTS AND METHODS: p53, p21, and pRb expression was examined immunohistochemically on archival radical cystectomy samples from 164 patients with invasive or high-grade recurrent superficial transitional cell carcinoma (TCC; lymph node-negative, 117 patients; lymph node-positive, 47 patients). Median follow-up was 8.6 years. Based on percentage of nuclear reactivity, p53 was considered as wild-type (0% to 10%) or altered (>10%); p21 was scored as wild-type (>10%) or altered (<10%); and pRb status was considered wild-type (1% to 50%) or altered (0% or >50%). RESULTS: As individual determinants, the p53, p21, and pRb status were independent predictors of time to recurrence (P<.001, P<.001, and P<.001, respectively), and overall survival (P<.001, P=.002, and P=.001, respectively). By examining these determinants in combination, patients were categorized as group I (no alteration in any determinant, 47 patients), group II (any one determinant altered, 51 patients), group III (any two determinants altered, 42 patients), and group IV (all three determinants altered, 24 patients). The 5-year recurrence rates in these groups were 23%, 32%, 57%, and 93%, respectively (log-rank P<.001), and the 5-year survival rates were 70%, 58%, 33%, and 8%, respectively (log-rank P<.001). After stratifying by stage, the number of altered proteins remained significantly associated with time to recurrence and overall survival. CONCLUSION: This study suggests that alterations in p53, p21, and pRb act in cooperative or synergistic ways to promote bladder cancer progression. Examining these determinants in combination provides additional information above the use of a single determinant alone.

Retroperitoneal lymph node dissection in the treatment of low-stage nonseminomatous germ cell tumors of the testicle: an update.

Nonseminomatous germ cell tumors (NSGCT) of the testicle are highly treatable and curable. The evolution of cancer control for this disease has shown an effective integration of medical and surgical approaches over the last 3 decades. Current emphasis in the therapy of NSGCT focuses on minimizing treatment-related morbidity while maintaining consistently high cure rates as previously seen. Retroperitoneal lymph node dissection (RPLND) in experienced hands is a critical component of the treatment armamentarium in this disease. RPLND is an accurate staging tool providing important information to determine the need for chemotherapy. When performed properly, RPLND eliminates the retroperitoneum as a site for relapse, which in turn provides emotional and psychological relief to the patient, and simplifies the follow-up protocol. RPLND alone can also provide high cure rates in patients with low clinical stage disease and high risk factors, such as lymphovascular invasion or predominance of embryonal histology in the primary tumor. Teratoma is chemoresistant and, when present in the primary tumor of patients with low stage, may be best treated with primary RPLND. Primary chemotherapy in the treatment of low stage NSGCT deserves continual investigation as long-term toxicities become more apparent. Observation is an option for the highly motivated patient but requires a rigorous follow-up schedule to avoid relapse. Laparoscopic RPLND is a viable staging tool; however, oncologic control of the retroperitoneum has not been reliably determined.