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Purpose: We compared clinical and pathological staging in a contemporary, consecutive series of patients treated with partial or radical nephrectomy for renal cell carcinoma and we determined the effect of clinical and pathological stage discrepancy on outcomes., Materials and Methods: We collected retrospective clinical, pathological and survival data on 264 consecutive patients with clinical T1-3 renal cell carcinoma who were treated with laparoscopic or open partial or radical nephrectomy at a single institution from 1994 to 2003., Results: Pathological up staging occurred in 44 of 264 patients (17%) patients. Of 135 clinical T1 tumors 25 (18.5%) and 18 of 85 (21.2%) clinical T2 tumors were pathologically up staged. Patients with clinical T1 and T2 tumors were stratified into 2 groups, including those with the same clinical and pathological stage, and those with pathological up staging. Mean 5-year recurrence-free survival +/- SD for same stage vs pathologically up staged clinical T1 (84.3% +/- 4.4% vs 47.4% +/- 11.5%) and clinical T2 (80.0% +/- 6.8% vs 40.7% +/- 13.4%) tumors was significantly different (p < 0.0002). Five-year cancer specific survival for same stage vs pathologically up staged clinical T1 tumors was significantly different (98.5% +/- 1.5% vs 69.7% +/- 11.3%, p = 0.0005), while that for clinical T2 tumors approached clinical significance (90.9% +/- 5.0% vs 72.7% +/- 13.4%, p = 0.0501)., Conclusions: Stage discrepancy is common in surgically treated patients diagnosed with renal masses and it has a significant impact on clinical outcome. Implications of such clinical and pathological stage discrepancy should be considered when counseling patients and determining therapeutic approaches.

Objectives: To describe the cancer-specific outcomes of patients with pathologic carcinoma in situ (CIS) only at radical cystectomy., Methods: The records of 812 consecutive patients who underwent radical cystectomy and pelvic lymphadenectomy for bladder transitional cell carcinoma at three U.S. academic centers were reviewed. Of the 812 patients, 99 (12%) had CIS only at radical cystectomy., Results: The distribution of clinical stage for the 99 patients with CIS only at radical cystectomy was as follows: 47% of patients had CIS only, 8% had cT1, 15% had cT1 plus CIS, 10% had cT2, 13% had cT2 plus CIS, 6% had cTa, and 1% had Ta plus CIS. Two patients had lymphovascular invasion in the radical cystectomy specimen, and three had metastases to the lymph nodes. The actuarial recurrence-free survival estimates were 89.8% (95% confidence interval [CI] 83.0% to 96.6%) at 3 years and 83.0% (95% CI 73.2% to 92.8%) at 5 and 7 years after radical cystectomy. Six patients (6%) had died of bladder cancer at analysis and 13 (13%) had died of other causes without evidence of disease recurrence. The actuarial disease-specific survival estimates were 95.8% (95% CI 91.2% to 99.9%) at 3 years, 90.7% (95% CI 82.4% to 98.9%) at 5 years, and 87.2% (95% CI 76.8% to 97.5%) at 7 years after surgery. On univariate Cox regression analyses, only metastasis to lymph nodes was associated with bladder cancer recurrence and death (P <0.001)., Conclusions: Disease control seemed durable for patients with pathologic CIS only at radical cystectomy in the absence of metastases to the lymph nodes, even in the case of failure after intravesical therapy.

Background: The U.S. Food and Drug Administration recently approved screening high-risk patients for bladder cancer using urine-based markers. The cost and life-years saved associated with bladder cancer screening were evaluated., Methods: A Markov model was created to estimate cumulative cancer-related costs and efficacy of screening (vs. no screening) of a high-risk population for bladder cancer using a urine-based tumor marker over a 5-year period. Assumptions were based on literature review of survival and progression rates for patients with bladder cancer and costs associated with different bladder cancer disease states., Results: Screening for bladder cancer in a population with a 4% incidence of bladder cancer resulted in a gain of 3.0 life years per 1000 subjects at a cost savings of $101,000 for the population, assuming a 50% downstaging in the screened population from muscle-invasive to nonmuscle-invasive disease. One-way sensitivity analyses found that screening is the most cost-effective strategy if cancer incidence is >1.6%, tumor marker costs <$126, marker sensitivity is >26%, marker specificity is >54%, downstaging with screening is >20%, and office cystoscopy costs <$694. Varying costs of cystectomy, transurethral resection of bladder tumor (TURBT), chemotherapy, end-of-life care, costs of metastatic disease, and a computed tomography scan over a wide range did not affect the superiority of screening., Conclusions: The model found that urine-based markers are cost-effective in a high-risk population. Prospective randomized trials in a completely asymptomatic high-risk cohort are indicated before bladder cancer screening can be recommended.

Background and Purpose: Laparoscopic retroperitoneal lymph node dissection (L-RPLND) has been reported as efficacious for staging of the retroperitoneum in patients with stage I nonseminomatous germ-cell testis tumors (NSGCT). However, reports are limited to a few centers, and this procedure has yet to be widely accepted as an alternative to open retroperitoneal lymph node dissection (O-RPLND). Thus, we compared our contemporary open and laparoscopic experience with RPLND., Patients and Methods: A retrospective chart review identified 28 patients who underwent either open (N = 6) or laparoscopic (N = 22) RPLND for clinical stage I NSGCT since 2000. Each patient received the appropriate modified template dissection. Perioperative demographic data, histologic nodal status, and recurrence data were evaluated. The mean follow-up was similar in the two groups., Results: The mean operative time was not significantly different (313 minutes for L-RPLND v 284 minutes for O-RPLND). However, L-RPLND did have a significantly shorter hospitalization (1.2 v 8.5 days). Significantly more lymph nodes were removed with O-LPLND than with L-RPLND (mean 33 v 17). There was a single recurrence outside the modified template after both L-RPLND and O-RPLND and one within-the-template recurrence in the O-RPLND group., Conclusions: The L-RPLND is associated with less blood loss and a shorter hospital stay than O-RPLND, whereas the lymph-node yield of O-RPLND is greater. However, during the critical early follow-up period, the oncologic effectiveness and morbidity of L-RPLND for clinical stage I NSGCT appears similar to that of O-RPLND.

Purpose: We assessed variability in the diagnostic performance of NMP22 for detecting recurrence and progression in patients with Ta, T1, and/or CIS transitional cell carcinoma of the bladder in a large international cohort., Materials and Methods: NMP22 voided urine levels were measured in 2,871 patients who underwent office cystoscopy for monitoring previous stage Ta, T1 and/or CIS transitional cell carcinoma at 12 participating institutions., Results: Patient characteristics varied considerably among institutions. Overall 1,045 patients (36.4%) had recurrent transitional cell carcinoma (range across institutions 13.6% to 54.3%). Median NMP22 was 5.5 U/ml (range across institutions 2.5 to 18.8). Of the patients 33.5% had grade III tumors (range across institutions 20.6% to 54.0%) and 22.4% had muscle invasive tumors (range across institutions 3.2% to 38.2%). Area under the ROC curve for bladder TCC detection was 0.735 (95% CI 0.715 to 0.755, range across institutions 0.676 to 0.889). The manufacturer recommended cutoff of 10 U/ml detected 57% of cases with a 19% false-positive rate. AUC for grade III and stage T2 or greater disease was 0.806 (95% CI 0.780 to 831) and 0.864 (95% CI 0.839 to 0.890), respectively. For each NMP22 cutoff NMP22 had higher sensitivity for detecting grade III and stage T2 or greater bladder transitional cell carcinoma than for detecting any cancer. No optimal cutoffs for detecting any or aggressive bladder transitional cell carcinoma could be derived based on NMP22 values., Conclusions: There is a substantial degree of heterogeneity in the diagnostic performance of NMP22 applied to populations from different institutions. There is no clearly defined NMP22 cutoff but there is a continuum of risk for recurrence and progression.

Objective: To illustrate the problem of urethral recurrence of transitional cell carcinoma (TCC) after radical cystectomy, and define surveillance and treatment algorithms., Methods: There are 6 unique cases of urethral tumor recurrence presented, and current relevant literature is reviewed. Three risk groups are defined based on the likelihood of urethral recurrence. Surveillance and treatment options are delineated., Results: Although the incidence of recurrent tumor in the urethra is low, the prevalence is increasing because of improvements in bladder cancer survival and the fact that the urethra is retained more often for orthotopic urinary diversion. Patients can be categorized as low, intermediate, and high risk based on the pathologic finding of degree of prostatic involvement by the initial tumor., Conclusion: Based on limited available literature, it appears that surveillance strategies range from observation alone to more invasive monitoring that includes urethral wash cytology and urethroscopy. Treatment options include local resection, intraurethral agents, and complete urethrectomy. A surveillance algorithm based on risk for recurrence and a treatment algorithm based on histopathologic risk factors of the recurrent tumor are proposed. This problem will assume increasing importance in the future.

Purpose: The Food and Drug Administration recently approved the use of bladder markers such as BladderChek (NMP22; Matritech, Inc., Newton, MA) and UroVysion (Abbott Laboratories, Abbott Park, IL) for use in screening for bladder cancer. The purpose of this analysis was to assess the cost associated with implementing a widespread screening program using a noninvasive bladder tumor marker., Methods: Data for the accuracy of NMP22 in detecting bladder cancer was gathered from a comprehensive literature review. A decision tree analysis was constructed to evaluate the total cost of screening a low and high-risk population for bladder cancer using NMP22. Sensitivity analyses were conducted to evaluate the effect of relaxing the various assumptions in the model., Results: Application of the model to all men, regardless of the degree of risk, rendered a cost per cancer detected of $783,913, $269,028, and $139,305 for ages 50-59, 60-69, and 70-79 years, respectively. Screening only patients at high-risk for bladder cancer (annual incidence 6%) would yield a cost per cancer detected of $3,310. Incidence of cancer and marker specificity had the highest influence on cost per cancer detected., Conclusions: Application of NMP22 to the entire population would render an extremely high cost per cancer detected. However, application to an appropriate high-risk target population could achieve cost per cancer detected comparable to currently used screening programs for prostate, colon, and breast cancer. Further studies are needed to assess the accuracy of bladder tumor markers in detecting bladder cancer in a completely asymptomatic cohort.

Objective: Renal cell carcinomas often form venous thrombi that extend into the vena cava. Frequently, cardiovascular consultation is necessary for complete surgical excision. We sought to investigate the risk factors, surgical techniques, and outcomes of patients treated for renal cell carcinoma with venous extension., Methods: We reviewed the records of 46 consecutive patients who underwent surgical management of renal cell carcinoma with venous extension between 1991 and 2005. Data on patient history, staging, surgical techniques, morbidity, and survival were analyzed., Results: There were 29 men and 17 women with a mean age of 60.2 +/- 12.0 years. Twenty-five (54%) procedures were completed with cardiovascular assistance. Nephrectomy was performed in 44 (96%) cases. Three (7%) patients underwent right heart venovenous bypass, and 2 (5%) patients underwent cardiopulmonary bypass with circulatory arrest. Fourteen (32%) patients had perioperative complications, including 1 (2%) perioperative death. Patients who required cardiovascular procedures (inferior vena cava clamping, right heart venovenous bypass, and cardiopulmonary bypass with circulatory arrest) had higher risks of perioperative complications (P < .02). The 1-, 2-, and 5-year overall survival rates were 78%, 69%, and 56%., Conclusions: This large series demonstrates that aggressive treatment of renal cell carcinoma with venous thrombus provides favorable outcomes. Our 5-year survival is among the highest of recent reviews, and our perioperative morbidity and mortality rates are comparable with those of other series. Tumors that require cardiovascular procedures are associated with increased complications when compared with radical nephrectomy and thrombectomy alone. Nevertheless, this aggressive treatment approach offers encouraging patient survival.

Purpose: The effect of bladder cancer histological subtypes other than transitional cell carcinoma (nonTCC) on clinical outcomes remains uncertain. We conducted a multi-institutional retrospective study of patients with bladder cancer treated with radical cystectomy to assess the impact of nonTCC histology on bladder cancer specific outcomes., Materials and Methods: A total of 955 consecutive patients underwent radical cystectomy with bilateral pelvic lymphadenectomy for bladder cancer at 3 academic institutions. TCC was present in the radical cystectomy specimen in 888 patients (93%). NonTCC histology was present in 67 patients (7%), including squamous cell carcinoma in 26, adenocarcinoma in 13, small cell carcinoma in 10 and other nonTCC subtypes (ie spindle cell carcinoma, carcinosarcoma and undifferentiated carcinoma) in 18. For patients alive at last followup median followup was 39 and 23 months for patients with TCC and nonTCC histologies, respectively. Bladder cancer specific progression and survival were assessed using Kaplan-Meier and multivariate Cox proportional hazards analyses., Results: Bladder cancer specific progression and mortality did not differ significantly between patients with SCC and TCC histologies. Patients with nonTCC and nonSCC bladder cancer were at significantly increased risk for progression and death compared to patients with TCC or SCC (p <0.001). This association remained statistically significant in patients with organ confined disease (stage pT2 or lower) and patients with nonorgan confined disease (stage pT3 or higher) (p <0.001). In a multivariate analysis nonTCC and nonSCC histology was associated with an increased risk of bladder cancer progression and death (OR 2.272 and 2.585, respectively, p <0.001), even after adjusting for final pathological stage, lymph node status, lymphovascular invasion and neoadjuvant or adjuvant treatments., Conclusions: NonTCC and nonSCC histological subtype is an independent predictor of bladder cancer progression and mortality in patients undergoing radical cystectomy for bladder cancer. Patients with bladder TCC and SCC share similar stage specific clinical outcomes.

Purpose: We assessed clinical outcomes in patients found to have no evidence of disease, ie pT0, in the cystectomy specimen following radical cystectomy for transitional cell carcinoma., Materials and Methods: Between 1984 and 2003, 955 consecutive patients underwent bilateral pelvic lymphadenectomy and radical cystectomy for bladder cancer at 3 institutions, namely The Johns Hopkins Hospital, University of Texas Southwestern Medical Center and Baylor College of Medicine. Excluding nonTCC histology and patients with missing data resulted in 888 evaluable cases. Primary end points were recurrence-free survival and bladder cancer specific survival., Results: Final pathological evaluation revealed absent transitional cell carcinoma in the cystectomy specimen, ie pT0, in 59 patients (7%), of whom 2 (3%) had pathologically positive lymph nodes. Transurethral resection stage or clinical stage data were available on 56 patients (95%), including Tis in 5 (9%), Ta in 2 (4%), T1 in 18 (32%), T2 in 29 (52%) and T3 in 2 (4%). Overall 6 recurrences (10%) were noted, including cTis in 1 case, cT1 in 1, cT2 in 3 and cT3 in 1. Median followup in patients with pT0 disease was 56 months (range 3 to 183). Three patients (5%) died of bladder cancer and another 4 (7%) died of other causes. Five and 10-year bladder cancer progression-free and cancer specific survival estimates in patients with pT0 disease were 90% and 81%, and 95% and 85%, respectively., Conclusions: Despite excellent clinical outcomes in the majority of patients with no evidence of tumor on final pathological evaluation not all patients with pT0 disease in the cystectomy specimen are cured of bladder cancer. These events may even occur in patients with nonmuscle invasive or muscle invasive organ confined pathology at staging transurethral resection. Further study is needed to identify prognostic factors in this population.

Objective: To assess the contemporary inter-institutional accuracy of urinary cytology in predicting the recurrence of transitional cell carcinoma (TCC) of the bladder, in a large multi-institutional cohort from four continents, as cystoscopy and urinary cytology represent the 'gold standards' for surveillance of TCC recurrences, but the ability of cytology to predict recurrence varies., Patients and Methods: Ten institutions contributed 2542 patients with a history of superficial TCC, of whom 898 had TCC recurrence. Age- and gender-adjusted logistic regression models were used to evaluate the association between urine cytology and TCC recurrence. The predictive accuracy derived from the logistic regression model was tested using the area under the receiver operating characteristic curve. The resulting predictive accuracy estimates were internally validated with 200 bootstrap re-samples., Results: The mean (range across institutions) age of the patients was 65 (48-69) years and 75 (67-87)% were men. Cytology was positive in 19 (10-38)% of patients; recurrence was identified in 35 (27-54)% of patients. The sensitivity was 38-65% across institutions. Urinary cytology varied significantly in its ability to predict recurrence of bladder cancer. Institution-specific predictive accuracy adjusted for gender and age was 0.627-0.893. Stratifying by grade and stage only partly attenuated the discrepancies between centres., Conclusions: The variability of urinary cytology results was very appreciable among the 10 centres and ranged from poor (63%) to excellent (89%).

Background: The objective of this study was to test the hypothesis that elevated urinary levels of soluble Fas (sFas) would aid in the surveillance of patients with a past history of nonmuscle-invasive transitional cell carcinoma (TCC) of the urinary bladder., Methods: sFas levels were determined in cell lysates and supernatants from 2 human bladder cancer cell lines (T24 and TCC-SUP) and in voided urine from 188 consecutive patients who were at risk for TCC recurrence, 31 patients who had noncancerous urologic conditions, and 10 healthy individuals. The authors also obtained barbotage cytology and voided nuclear matrix protein 22 (NMP22) levels. sFas was analyzed continuously and categorically on the basis of its quintile distribution., Results: sFas was present in cell lysates and conditioned media from both cell lines. sFas levels were found to be higher in the TCC group (n = 122 patients) compared with the control group (P < .001). Higher levels of sFas were associated with positive cytology assay results (P < .001), higher NMP22 levels (P < .001), NMP22 levels > 10 U/mL (P < .001), and tumor stage > or = T1 (P < .001). The areas under the receiver operating characteristics (ROC) curves of sFas and NMP22 for bladder cancer detection were 0.757 (95% confidence interval, 0.694-0.819) and 0.704 (95% confidence interval, 0.637-0.772), respectively. In the > 75% sensitivity region of the ROC curves, sFas was consistently more specific than NMP22. In multivariate analyses, sFas, NMP22, and cytology all were found to be associated with the presence of bladder cancer (P values < or = .009), but only sFas and cytology were associated with tumor stage > or = T1 (P values < or = .026)., Conclusions: sFas was produced and released by bladder TCC cells. Urine sFas was an independent predictor of bladder cancer recurrence and invasiveness in patients who had a past history of nonmuscle invasive bladder TCC, and it outperformed NMP22., (2006 American Cancer Society)

Background and Purpose: The acute and long-term effects of radiofrequency ablation (RFA) on kidney function have not been well studied. The functional change when RFA is used in combination with renal ischemia is likewise unknown. Our goal was to determine the change in renal function caused by various volumes of RFA on a porcine kidney model and the effect cold ischemia had on the results., Materials and Methods: Twenty-two female pigs with solitary kidneys underwent various volumes of RFA both with and without cold ischemia. Animals were divided into control, 10%, 15%, and 20% ablation of the total kidney volume. Measurements of creatinine were obtained for 2 weeks., Results: In the nonischemic group, the mean acute (day 1-3) creatinine changes in control, 10%, 15%, and 20% ablations were 0.6, 2.4, 1.7, and 2.6 mg/dL, respectively. In the cold-ischemia group, the mean acute creatinine changes were 0.85, 2.33, 3.3, and 3.75 mg/dL, respectively. Regression line analysis demonstrated a positive linear relationship in both groups. Fourteen-day mean creatinine changes for the nonischemic group were similar to those in the control animals and did not show a correlation with ablation volume. The mean creatinine changes at 14 days in the cold-ischemia group showed a positive linear correlation with ablation volume., Conclusions: The volume of RFA correlates with an acute change in renal function in the porcine model for both nonischemic and cold-ischemia groups. This study may help predict the extent of acute renal dysfunction in patients undergoing RFA for large or multiple renal masses. These results also suggest renal function may recover after nonischemic RFA.

Purpose: We hypothesized that bladder cancer patients with associated lymphovascular invasion (LVI) are at increased risk of occult metastases., Methods: A multi-institutional group (University of Texas Southwestern [Dallas, TX], Baylor College of Medicine [Houston, TX], Johns Hopkins University [Baltimore, MD]) carried out a retrospective study of 958 patients who underwent cystectomy for bladder cancer between 1984 and 2003. Of patients with transitional-cell carcinoma (n = 776), LVI status was available for 750. LVI was defined as the presence of tumor cells within an endothelium-lined space., Results: LVI was present in 36.4% (273 of 750) overall, involving 26% (151 of 581) and 72% (122 of 169) of node-negative and node-positive patients, respectively. Prevalence of LVI increased with higher pathologic stage (9.0%, 23%, 60%, and 78%, for T1, T2, T3, and T4, respectively; P < .001). Using multivariate Cox regression analyses including age, stage, grade, and number of pelvic lymph nodes removed, LVI was an independent predictor of local (HR = 2.03, P = .049), distant (HR = 2.60, P = .0011), and overall (HR = 2.02, P = .0003) recurrence in node-negative patients. LVI was an independent predictor of overall (HR = 1.84, P = .0002) and cause-specific (HR = 2.07, P = .0012) survival in node-negative patients. LVI maintained its independent predictor status in competing risks regression models (P = .013), where other-cause mortality was considered as a competing risk. LVI was not a predictor of recurrence or survival in node-positive patients., Conclusion: LVI is an independent predictor of recurrence and decreased cause-specific and overall survival in patients who undergo cystectomy for invasive bladder cancer and are node-negative. These patients represent a high risk group that may benefit from integrated therapy with cystectomy and perioperative systemic chemotherapy.

Purpose: We developed and validated nomograms that accurately predict disease recurrence and progression in patients with Ta, T1, or CIS transitional cell carcinoma (TCC) of the bladder using a large international cohort., Methods: Univariate and multivariate logistic regression models targeted histologically confirmed disease recurrence, and focused on 2,542 patients with bladder TCC from 10 participating centers. Variables consisted of pre-cystoscopy voided urine Nuclear Matrix Protein 22 (NMP22) assay, urine cytology, age and gender. Resulting nomograms were internally validated with bootstrapping. Nomogram performance was explored graphically with Loess smoothing plots., Results: Overall 957 patients had recurrent TCC. Tumor grade and stage was available for 898 patients, including 24% grade I, 43% grade II, and 33% grade III; 45% stage Ta, 32% T1 and/or CIS, and 23% T2 or greater. Bootstrap corrected predictive accuracy for any TCC recurrence was 0.842; grade III Ta/T1 or CIS was 0.869; and T2 or higher stage TCC of any grade was 0.858. Virtually perfect performance characteristics were observed for the nomograms predicting any TCC recurrence or grade III Ta/T1 or CIS. The nomogram predicting T2 or higher stage TCC overestimated the observed probability for predicted values greater than 45%., Conclusions: We developed and internally validated nomograms that incorporate urinary NMP22, cytology, age and gender to predict with high accuracy the probability of disease recurrence and progression in patients with Ta, T1, and/or CIS bladder TCC. These nomograms could provide a means for individualizing followup in patients with Ta, T1, CIS bladder TCC.

Objectives: To describe the histopathologic changes and evaluate the interpretability of human renal tumor specimens obtained after temperature-based radiofrequency ablation (RFA)., Methods: RFA of 119 solid kidney tumors was performed percutaneously under computed tomography guidance, laparoscopically or during open surgery, using a temperature-based system. Of the 119 tumors, 70 were biopsied (two or more samples) after RFA, 39 immediately before ablation, and 10 were not biopsied. All specimens were pathologically classified, and for those specimens obtained after RFA, analysis of the acute histologic changes secondary to RFA was performed by a single pathologist using standard hematoxylin-eosin staining., Results: Ablated tumor specimens maintained their tissue architecture and had predictable changes (cytoplasmic eosinophilia, nuclear elongation, cytoplasmic dissolution) easily recognizable by our pathologists. The diagnostic rate of renal cell carcinoma after RFA (72%) was comparable to the diagnostic rate reported for tumors less than 4 cm in other non-RFA biopsy series. Only 2.6% of specimens obtained before and 5.7% obtained after RFA were nondiagnostic secondary to the paucity of tissue obtained. In 8.3% of all tumors (regardless of RFA treatment), the distinction between oncocytoma and low-grade oncocytic renal cell carcinoma could not be made because of insufficient tissue., Conclusions: Acutely, RFA of renal tumors causes predictable histologic changes and preserves the tissue architecture. Obtaining two or more incisional biopsies after RFA provided sufficient tissue for reliable pathologic diagnosis.

Objective: To examine whether Gleason score (GS) 3 + 4 and 4 + 3 cancers at radical prostatectomy behave differently and whether this behaviour is independently associated with prostate cancer outcome., Patients and Methods: From July 1994 to December 2002 309 consecutive men who had a radical retropubic prostatectomy for clinically localized disease had final GS 7 tumours in their prostatectomy specimen. Statistical analyses, including multivariate logistic regression, were used to evaluate the association between variables, i.e. standard preoperative features, stage, PSA progression, standard pathological variables, metastasis and death., Results: In all, 215 patients (70%) had a final GS of 3 + 4 and 94 (30%) of 4 + 3. A final GS of 4 + 3 was associated with clinical stage T2 disease (P = 0.024), a higher biopsy GS (P < 0.001), seminal vesicle involvement (P < 0.001), positive surgical margins (P = 0.036), lymphovascular invasion (P = 0.018), metastases to regional lymph nodes (P = 0.008), higher preoperative serum prostate-specific antigen (PSA) (P = 0.042), and percentage positive biopsy cores (P = 0.006). In univariate analysis, patients with GS 4 + 3 had a significantly higher risk of biochemical progression than those with GS 3 + 4 (P = 0.002). The 5-year actuarial risk of biochemical progression was 17% and 35% for GS 3 + 4 and 4 + 3, respectively (P = 0.0016). In a standard postoperative multivariate analysis, only preoperative PSA and metastases to regional lymph nodes were associated with PSA progression (P < 0.001 and 0.002, respectively). However, patients with final GS 4 + 3 had a shorter PSA doubling time after progression than those with GS 3 + 4 (P = 0.009)., Conclusions: Tumours with a final GS of 4 + 3 are more aggressive than GS 3 + 4 tumours. Recognising the distinction in GS 7 between predominant 4 vs 3 scores after radical prostatectomy should improve the ability of clinicians to counsel patients. The GS 4 pattern deserves further molecular study.

Purpose: We examined if the percent of positive biopsies is associated with features of biologically aggressive prostate cancer, biochemical progression and development of distant metastases in patients undergoing radical prostatectomy (RP)., Materials and Methods: Multivariate analyses of preoperative features in 605 consecutive patients who underwent RP for clinically localized disease were evaluated to determine the association between the percent positive biopsy cores (PosBx), pathological stage and grade, and biochemical progression following RP. The percent of PosBx cores was defined using the formula, (number of positive biopsy cores/total number of biopsy cores) x 100., Results: The mean number of biopsy cores and percent PosBx cores +/- SE was 8.8 +/- 6.0 and 31.4 +/-21.1, respectively. Higher percent PosBx was significantly associated with higher preoperative prostate specific antigen (PSA), extracapsular extension, seminal vesicle invasion, positive surgical margins, higher final Gleason sum, lymphovascular invasion, perineural invasion and metastases to regional lymph nodes. On multivariate analyses adjusted for the effects of standard preoperative features percent PosBx was associated with nonorgan confined disease, seminal vesicle invasion and biochemical progression after surgery (p = 0.049, 0.050 and 0.006, respectively). Percent PosBx retained its independent association with PSA progression after adjustment for the effects of postoperative pathological features (p = 0.015). Higher percent PosBx was associated with shorter PSA doubling time after PSA progression, and an increased risk of distant metastases and overall mortality (p = 0.039, 0.001 and 0.018, respectively)., Conclusions: Percent PosBx is associated with established pathological features, biochemical progression, distant metastases and overall death in patients who undergo RP for clinically localized disease. Percent PosBx should be included in preoperative predictive models for prognosticating outcomes after primary treatment and it may assist in selecting patients for inclusion in neoadjuvant and/or adjuvant therapy trials.

Background and Purpose: Rapid evolution of laparoscopic and ablative techniques is changing the approach to renal masses. We evaluated our approach to managing renal masses in light of newly available technology., Patients and Methods: The records for all patients who underwent treatment for a renal mass between January 2000 and July 2002 at UT Southwestern Medical Center were reviewed for patient demographics, operative details, and pathology results. There were 180 patients with 190 masses. Of the 190 masses, 97 were <4 cm, 47 were between 4 and 7 cm, and 46 were >7 cm., Results: Most tumors >7 cm were managed with open radical nephrectomy (RN). For patients with masses between 4 and 7 cm, the majority were treated with laparoscopic RN, while 21% were treated by open partial nephrectomy (PN). Tumors <4 cm were treated with the widest variety of approaches. Open PN was the most commonly utilized, followed by laparoscopic RN and percutaneous ablation. The number of laparoscopic and percutaneous ablative procedures increased significantly with time, from none in the first year to 13% (7/55) and 29% (16/55) in the last year, respectively. Benign pathology was found in 20%, 17%, and none of lesions <4, 4 to 7, and >7 cm, respectively., Conclusions: The addition of laparoscopy and ablative technologies has increased the treatment options for patients with renal masses. We propose a treatment algorithm that incorporates ablative technologies and favors parenchyma-sparing approaches for small lesions.

Unlabelled: We examined whether invasion of lymphatic and/or vascular vessels (LVI), or perineural spaces (PNI) is associated with prostate cancer features and outcome., Materials and Methods: A total of 630 consecutive men underwent radical retropubic prostatectomy for clinically localized disease. LVI and PNI examination was part of the routine specimen evaluation., Results: Foci of LVI were identified in 32 patients (5%) and 381 (60.5%) had PNI. LVI and PNI were associated with clinical stage T2 disease, higher biopsy and final Gleason sum, extraprostatic extension, seminal vesicle involvement, positive surgical margins and a higher percent of positive biopsy cores (p <0.001). LVI was associated with metastases to regional lymph nodes and higher preoperative serum prostate specific antigen (p <0.001 and 0.004, respectively). PNI and LVI were associated with an increased risk of rapid biochemical progression after radical prostatectomy on univariate (p <0.001 and 0.001, respectively) but not on multivariate analysis. LVI was associated with shorter prostate specific antigen doubling time after biochemical progression (p = 0.012) and higher probabilities of failed local salvage radiation therapy (p = 0.0169), distant metastases (p <0.001) and death (p <0.001)., Conclusions: Only LVI is associated with metastases to regional and distant sites, and most importantly with overall survival. LVI and PNI are associated with established markers of biologically aggressive disease and rapid biochemical progression in patients who underwent radical prostatectomy. Our findings support the routine evaluation of LVI status in radical prostatectomy specimens and its inclusion in predictive models for clinical outcomes, since it appears to be a pathological marker of the lethal phenotype of prostate cancer.

Purpose: To test the hypothesis that voided urinary levels of nuclear matrix protein 22 (NMP22) would add to the predictive ability of urine cytology in the diagnosis, staging and grading of bladder transitional cell carcinoma (TCC), and to evaluate the diagnostic performance of different NMP22 cut-points., Materials: NMP22 level and barbotage cytology were evaluated in voided urine specimens collected before cystoscopy from 302 subjects with a history of TCC, 32 subjects with benign urologic pathologies, and 10 healthy volunteers., Results: 180 patients (52%) had bladder TCC. Higher levels of NMP22 and positive cytology were independently associated with an increased risk of TCC, invasive stage, and high grade. The NMP22 value with equal sensitivity and specificity for prediction of bladder cancer was 6.5U/ml; for prediction of grade 3 TCC it was 13.5U/ml; and for prediction of invasive tumor stage it was 17.4U/ml. The NMP22 cut-point of 6.5U/ml outperformed the 10U/ml cut-point in all pathologic stages and grades. The diagnostic sensitivity of the cytology and NMP22 combined was superior across all pathologic stages and grades to that of either marker alone. NMP22 and cytology stratified patients into groups with significantly different risk for TCC presence, invasive stage, and high grade., Conclusions: 6.5U/ml is a robust NMP22 cut-point for bladder cancer surveillance. The diagnostic sensitivities of the combined NMP22 and cytology for TCC presence, stage, and grade were significantly higher than those of single marker alone. The combination of urine cytology and NMP22 could be used to tailor the frequency of cystoscopic follow up.

Purpose: Radio frequency ablation (RFA) is evolving as a nephron sparing treatment alternative for select patents with small renal tumors. The impact of ablated tissue on the remaining kidney parenchyma is unknown. To assess this impact we evaluated pretreatment and posttreatment serum creatinine (sCr), and blood pressure of patients treated with RFA with at least 6 months of followup., Materials and Methods: From our series of 69 tumors treated with RFA 25 patients with a total of 26 tumors and a minimum 6-month followup were identified. RFA was delivered percutaneously or laparoscopically depending on tumor location and patient preference. Blood pressure measurements and sCr levels were obtained at preoperative and postoperative office visits. Values for preoperative and postoperative systolic blood pressure, diastolic pressure and sCr were each compared. Estimated creatinine clearance was calculated for each patient before and after treatment, and compared., Results: No patient experienced new onset hypertension or worsening of existing hypertension. Likewise no changes in mean sCr and estimated creatinine clearance were observed., Conclusions: Treatment with RFA does not appear to have an effect on renal function or blood pressure. RFA appears to be a medically safe therapy for patients with small renal tumors.

Background: The 1997 TNM staging classification for renal cell carcinoma (RCC) defined Stage I tumors as organ-confined tumors measuring up to 7 cm in size. The authors evaluated the validity of this cutoff size by assessing the survival of patients with Stage I RCC according to a series of alternative size cutoff values. In addition, the authors determined how these size cutoffs affected the risk of having nonorgan-confined tumors, regional lymph node involvement, and metastatic disease., Methods: A database containing the records of 1324 patients with RCC who underwent open radical nephrectomy between 1960 and 1991 was evaluated. Patients with Stage I disease were stratified by size cutoffs ranging from 2.5 to 7.0 cm in 0.5-cm increments. Five-year disease-specific survival (DSS) rates were estimated using the Kaplan-Meier method. The log-rank test was used to compare survival curves. The survival of patients with tumors smaller than a specified size cutoff was compared with the survival of patients with tumors larger than that cutoff and the most discriminating cutoff was identified. The same size cutoffs were used to compare the incidence of local nonorgan-confined, lymph node-positive, and metastatic disease for all patients with tumors 7.0 cm or smaller., Results: Of 544 evaluable patients, 351 patients had tumors 7.0 cm or smaller and 233 of these patients had 1997 Stage I (T1N0M0) disease. When patients with 1997 Stage I tumors were separated using the various size cutoffs, survivals were most different using a 5.0-cm cutoff. The 5-year DSS rates for patients with Stage I tumors 5 cm or smaller versus those with tumors measuring 5.1-7 cm were 94.6% versus 79.2% (P = 0.003). Furthermore, the survival of patients with Stage I RCC lesions measuring 5.1-7.0 cm was the same as for patients with 1997 Stage II (T2N0M0) RCC. The difference in probability of having local nonorgan-confined disease was also greatest with a 5.0 cm cutoff value. Nonorgan- confined disease was reported to be present in 16.2% of the patients with tumors smaller than 5.0 cm compared with 36.8% of the patients with tumors measuring 5.1-7.0 cm in size. The difference in the probabilities of having lymph node-positive or metastatic disease did not change significantly using any of the cutoffs, although the probability of both of these increased with increasing tumor size., Conclusions: Survival and disease recurrence analysis in a large group of patients with RCC who underwent radical nephrectomy showed that the 1997 TNM cutoff of 7.0 cm used to separate Stage I from Stage II disease was too high. A size-related survival difference was found among patients with organ-confined 1997 Stage I disease and a 5.0-cm cutoff best stratified this difference. This finding was in general agreement with the changes made in the 6th edition of the American Joint Committee on Cancer cancer staging manual. Patients with tumors measuring between 5.1 cm and 7.0 cm were found to have the same survival as patients with Stage II disease. Thus, subclassification of T1 into T1a and T1b, as in the 6th edition of the AJCC cancer staging manual, may not be optimal. The 5-cm cutoff also best stratified the risk of developing nonorgan-confined disease. This finding may have an impact on nephron-sparing surgery in selected patients. The findings of the current study, as well as those of others, supported an upper size cutoff of 4-5 cm for patients with Stage I RCC., (Copyright 2003 American Cancer Society.)

Objectives: To review the pathologic findings of a contemporary series of surgically treated renal tumors suspicious for malignancy to assess the frequency of benign disease in the modern era. The extensive application of modern imaging techniques has led to an increase in the number of incidentally discovered solid renal masses, many of which are small. A significant proportion of small renal tumors are benign or are low-grade malignancies., Methods: The records of all patients at our institution who underwent treatment for a renal mass suspicious for malignancy between November 1999 and July 2002 were retrospectively reviewed., Results: A total of 173 patients with 186 renal tumors had pathologic information available for analysis. Of the 186 tumors, 48% were discovered incidentally. For masses 4 cm or less, the percentage of incidentally discovered tumors increased to 58%. The pathologic evaluation demonstrated malignancy in 160 (86%) and benignity in 26 (14%) overall. For tumors 4 cm or less, 18 (20%) of 90 were benign; for tumors between 4 and 7 cm, 8 (17%) of 47 benign. No tumors greater than 7 cm were benign. All renal cell carcinomas less than 2 cm in size were Fuhrman grade 1 or 2., Conclusions: Small renal tumors, many of which are incidentally discovered, are often benign or are low-grade malignancies. For tumors 4 cm or less, the frequency of benign pathologic findings is greater than previously quoted in published reports. As a result, we recommend parenchymal-sparing approaches whenever possible.

Purpose: Concern has been raised about possible increased morbidity associated with laparoscopic donor nephrectomy (LDN) during the learning curve of the procedure and at centers with a low volume of living donors. We evaluated the safety and success of LDN at a low volume living donor transplant center with a skilled laparoscopic urologist and experienced renal transplant team., Materials and Methods: We reviewed the records of all patients who underwent LDN at our institution. A single surgeon skilled in laparoscopy (JAC) performed all LDNs. Patient demographics, operative reports, complications and recipient outcomes were evaluated., Results: A total of 17 LDNs were performed between January 2000 and September 2002. There was 1 elective conversion to an open procedure for kidney harvest due to complex hilar anatomy. Only 1 minor complication occurred (wound seroma) and 1 donor had creatinine persistently elevated to 1.9 mg/dl (normal 0.6 to 1.2). Mean operating room time, estimated blood loss and hospital stay were 250 minutes, 188 ml and 2.5 days, respectively. Recipient creatinine had a nadir mean of 1.2 mg/dl and a 90-day postoperative mean of 1.6 mg/dl. One recipient eventually lost the graft due to recurrent disease., Conclusions: LDN can be performed safely and efficiently at low volume transplant centers with a skilled laparoscopist and experienced renal transplant team. Laparoscopic skills developed during similar procedures, such as laparoscopic radical and partial nephrectomy, minimize the learning curve and morbidity of LDN to produce results consistent with those in the published literature.

Purpose: We assessed the risk of tissue cobalamin (vitamin B12) deficiency in patients after various types of urinary diversion., Materials and Methods: Serum vitamin B12, methylmalonic acid and homocysteine were measured in 41 patients with urinary diversion, including an ileal neobladder in 12, ileal reservoir in 2, ileocecal reservoir in 10 and ileal conduit in 17. Followup was 0 to 10 years., Results: The complete cobalamin profiles revealed a much higher incidence of tissue cobalamin deficiency in patients with each type of urinary diversion than measuring the vitamin B12 level alone., Conclusions: The risk of chronic tissue cobalamin deficiency after urinary diversion is higher than previously reported based on measuring serum vitamin B12 alone. Long-term patient monitoring for cobalamin deficiency or empirical supplemental therapy is indicated to prevent clinical cobalamin deficiency and irreversible sequelae.

Background: Mismatch repair (MMR) genes are responsible for coordinated correction of misincorporated nucleotides formed during DNA replication. Inactivating mutations in MMR genes have been described in sporadic cancers and a hereditary cancer predisposition syndrome. Mismatch repair deficiency causes instability at microsatellites and increased mutation rates. Although microsatellite instability (MSI) has been described in high-grade and lymph node positive prostate carcinoma specimens, an analysis comparing hMSH2 expression, MSI, and outcome in clinically organ confined prostate carcinoma has not been reported., Methods: Immunohistochemical analysis of benign and malignant prostate tissue from 101 patients was performed using a monoclonal antibody specific for the hMSH2 protein. Expression was correlated with MSI using dinucleotide repeat markers and laser-captured microdissected DNA from normal and tumor cells. hMSH2 protein expression and MSI were assessed with respect to pathologic stage, Gleason score, and time to detectable serum prostate specific antigen (PSA) after prostatectomy in patients with clinically localized prostate carcinoma., Results: In normal glands, hMSH2 staining was minimal to low and confined to the basal cell layer. In 32% of benign prostatic hyperplasia cases, hMSH2 staining was increased in the basal and luminal cell layers whereas 71% of cancer specimens had uniform moderate to high staining. Microsatellite instability was detected in 60% of absent to low staining and 26% of moderate to high staining prostate carcinoma specimens. Differential staining in benign versus malignant prostate tissues was statistically significant (P < 0.001) as was the correlation between absent to low hMSH2 staining and presence of MSI (P = 0.028). Decreased risk for PSA recurrence after radical prostatectomy correlated with absent to low hMSH2 staining in malignant prostate tissue but was only marginally significant (P = 0.05 for 24 month recurrence and P = 0.08 for overall time to PSA recurrence)., Conclusions: The results of the current study demonstrate differential hMSH2 expression in benign and malignant prostate tissue. Moreover, hMSH2 expression is altered in a subset of clinically localized prostate carcinoma specimens independent of pathologic stage and Gleason pattern. A statistically significant correlation between hMSH2 immunohistochemical staining intensity and MSI also was identified in prostate carcinoma specimens. Furthermore, the time to cancer recurrence as determined by detectable serum PSA after prostatectomy was associated with hMSH2 staining intensity. Taken together, our results suggest that hMSH2 gene expression in prostate carcinoma may be a useful prognostic marker for outcome in men with clinically organ confined prostate carcinoma., (Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10247)

The coxsackie and adenovirus receptor (CAR) is identified as a high-affinity receptor for adenovirus type 5. We observed that invasive bladder cancer specimens had significantly reduced CAR mRNA levels compared with superficial bladder cancer specimens, which suggests that CAR may play a role in the progression of bladder cancer. Elevated CAR expression in the T24 cell line (CAR-negative cells) increased its sensitivity to adenovirus infection and significantly inhibited its in vitro growth, accompanied by p21 and hypophosphorylated retinoblastoma accumulation. Conversely, decreased CAR levels in both RT4 and 253J cell lines (CAR-positive cells) promoted their in vitro growth. To unveil the mechanism of action of CAR, we showed that the extracellular domain of CAR facilitated intercellular adhesion. Furthermore, interrupting intercellular adhesion of CAR by a specific antibody alleviates the growth-inhibitory effect of CAR. We also demonstrated that both the transmembrane and intracellular domains of CAR were critical for its growth-inhibitory activity. These data indicate that the cell-cell contact initiated by membrane-bound CAR can elicit a negative signal cascade to modulate cell cycle regulators inside the nucleus of bladder cancer cells. Therefore, the presence of CAR cannot only facilitate viral uptake of adenovirus but also inhibit cell growth. These results can be integrated to formulate a new strategy for bladder cancer therapy.

Purpose: Mismatch repair genes are responsible for the coordinated correction of misincorporated nucleotides formed during DNA replication. Inactivating and inherited mutations in the prototypic mismatch repair gene hMSH2 have been described in a cancer predisposition syndrome known as hereditary nonpolyposis colon cancer. Patients with hereditary nonpolyposis colon cancer are at increased risk for colon cancer and extracolonic cancers such as upper tract transitional cell carcinoma but not prostate cancer. We investigated expression of hMSH2 in prostate cancer cell lines using genetic and molecular analysis., Materials and Methods: We used the 3 well described prostate cancer cell lines, DU145, LNCaP and PC3. Western blot analysis with monoclonal antibody to hMSH2 was used to assess expression. Southern blot and polymerase chain reaction of genomic DNA were used to identify genetic alterations in the hMSH2 gene. Single cell cloning, dinucleotide repeats and BAT-26 were used to assess the cell lines for microsatellite instability., Results: The prostate cancer cell line LNCaP did not express hMSH2 and was found to have a homozygous deletion of hMSH2 exons 9 to 16, resulting in truncation of the protein. While microsatellite analysis did not reveal alterations at the BAT-26 locus, single cell cloning produced several LNCaP subclones with alteration at 1 dinucleotide repeat., Conclusions: The well described prostate cancer cell line LNCaP has a mutation in the hMSH2 gene, resulting in loss of expression and possible evidence of microsatellite instability. To our knowledge our finding is the first demonstration of a genetic alteration in hMSH2 in a prostate cancer cell line.

To our knowledge, peritoneovaginal fistula is a complication of cystectomy that has not been reported before. We describe 2 patients in whom a transvaginal approach using a Martius flap was utilized to repair persistent vaginal leakage after cystectomy. At a mean follow-up of 20 months, both patients are free from vaginal leakage and have no evidence of recurrent fistula. This approach offers a safe and effective way to repair a peritoneovaginal fistula in a cystectomy patient.

Purpose: The purpose of this article was to report an unusual presentation of abdominal actinomycosis masquerading as a tumor., Methods: The patient was a 54-year-old male who presented with vague abdominal discomfort and a palpable left lower quadrant mass defined on CT scan. Multiple intraoperative core biopsies were nondiagnostic, and he underwent en bloc resection of the mass and adjacent organs for a presumed tumor., Results: Examination of tissue from deep within the excised specimen revealed sulfur granules diagnostic for actinomycosis., Conclusion: Abdominal actinomycosis is an extremely rare infection that can mimic multiple disease processes and requires accurate diagnosis for successful therapy. This novel presentation and a review of the literature are reported.

Background: The human mismatch repair (MMR) gene hMSH2 (human mutS homolog-2) is a DNA repair gene that has been reported to be mutated in 40% of hereditary nonpolyposis colon cancer (HNPCC) kindreds and a small percentage of sporadic tumors. HNPCC is a cancer predisposition syndrome with an increased risk of carcinoma of the colon, endometrium, stomach, small intestine, ovary, ureter, and renal pelvis. Immunohistochemical analysis demonstrated increased hMSH2 expression in sporadic colon carcinoma and in the replicative compartment of normal epithelium. A recent immunohistochemical analysis of hMSH2 in bladder tumors correlated reduced hMSH2 expression with recurrence and higher tumor grade. In the current study, we examined hMSH2 expression in urothelial malignancy using immunohistochemical analysis and developed a molecular assay for the detection of hMSH2 expression in bladder washes., Methods: Immunohistochemical analysis of 17 tumors from the genitourinary tract and reverse transcription coupled with polymerase chain reaction (RT-PCR) of 40 bladder washes were used to investigate hMSH2 expression in noninvasive and invasive urothelial malignancies., Results: Increased expression of hMSH2 was detected in all tumors examined using immunohistochemical analysis independent of grade or stage. Reverse transcription-PCR of hMSH2 mRNA from bladder washes detected 17 of 21 patients with primary or recurrent urothelial neoplasms or tumors involving the urothelial system. Four patients with urothelial malignancies without detectable hMSH2 expression from their bladder washes had high grade lesions. Ten of 13 patients without pathologic or cystoscopic evidence of bladder tumors were negative for hMSH2 expression in bladder washes. Two patients with bladder tumors and bladder washes that were positive for hMSH2 subsequently were found to be negative for hMSH2 after treatment of their tumors and at last follow-up had remained recurrence free for at least 1 year., Conclusions: The results of the current study suggest that hMSH2 expression is increased in low and high grade urothelial neoplasms, similar to the expression pattern in sporadic colon carcinoma. However, a fraction of high grade lesions may not express hMSH2 as detected by RT-PCR from bladder washes. The ability to detect hMSH2 expression in bladder washes may allow the use of hMSH2 expression as a marker for urothelial malignancy. In addition, the ability to define hMSH2 deficient tumors using bladder washes may have prognostic significance in the treatment of patients with urothelial carcinoma.

Objectives: An intergroup study (SWOG 8795) comparing two forms of adjunctive therapy (immuno and chemo), bacillus Calmette-Guerin (BCG) and mitomycin C (MMC), furnished preregistration index tumors for 244 patients with superficial, papillary stage Ta/T1 TCC. These were examined by flow cytometry to learn whether DNA ploidy or proliferation (low vs high S-phase fraction (SPF) helped to predict disease recurrence or progression., Methods: Cell cycle analysis using commercially available (Multicycle) programs was performed on 249 Ta/T1 bladder cancers. Tumor grade, available for 223 cases, was assigned by a single study pathologist. The SWOG statistical office reviewed follow-up information and other data and performed statistical analysis., Results: Disease recurrence occurred in half the cases studied. The most parsimonious model predictive of recurrence included only treatment arm and tumor grade, with the MMC arm and tumor grade greater than I indicating worse prognosis (p = 0. 014). Neither ploidy nor SPF predicted recurrence-free survival or contributed prognostic information that was additive to tumor grade. Within 5 years of follow-up, disease progression or death from bladder cancer occurred for 29/223 (13%) of patients. The most parsimonious model for progression-free survival included only grade greater than I (p<0.001) and high SPF (p = 0.029) (relative risk: tumor grade, 4.3, high SPF, 1.9)., Conclusions: Knowledge of tumor proliferation (low versus high SPF) contributes prognostic information about tumor progression that is additive to tumor grade.

Purpose: To evaluate whether p21 (WAF-1/CIP1) should be considered a potential candidate for human bladder cancer gene therapy, we determined: (1) the basal level of p21 expression in bladder cancer cell lines, (2) the response of bladder cancer cells to increased p21 expression following p21 adenovirus infection, and (3) the mechanism of growth inhibition produced by p21 overexpression., Materials and Methods: Five established human bladder cancer cell lines and one primary culture derived from an invasive transitional cell carcinoma were used in this study. To examine the effect of p21 protein on the growth of human bladder cancer cells, a recombinant adenovirus vector system containing p21 cDNA, under the control of cytomegalovirus promoter, was constructed. A control virus containing p21 in an antisense orientation was used to eliminate potential artifacts caused by viral toxicity., Results: Human bladder cancer cell lines exhibit variable endogenous p21 levels which correlate with the in vitro growth status. Significant, but highly variable increases in the steady-state level of p21 were detected in p21 adenovirus infected cells. Human bladder cancer cell lines responded heterogeneously to p21 adenovirus infection. Growth of the WH cell line was substantially inhibited in a dose and time-course dependent fashion. The mechanism of p21 growth inhibition was found to be due to G0/G1 arrest and not the induction of apoptosis. In contrast, p21 adenovirus failed to inhibit the growth of T24 bladder cancer cells because T24 cells were resistant to viral infection. The 253J bladder cancer cells exhibited marked sensitivity to adenovirus; substantial growth inhibition was seen with both sense and antisense p21 very early in the time course of infection., Conclusions: We found significant variation in the basal level of p21 protein expression in several human bladder cancer cell lines. Increased p21 expression as a result of adenoviral infection may be a potent growth suppressor in some human bladder cancer because it elicits cell cycle arrest in G0/G1 stage, but not the induction of apoptosis. Bladder cancer cells exhibit a wide spectrum of sensitivity to adenoviral infection that may be caused by the presence of viral receptor heterogeneity. This wide spectrum of sensitivity has significant basic scientific and clinical implications and warrants further study.

A case of solitary metastasis to the contralateral adrenal 22 years after radical nephrectomy for renal cell carcinoma (RCC) is described. This case highlights the variable behavior of RCC, the tendency for adrenal metastasis, and the potential for prolonged survival after resection of late solitary metastases.

Objectives: To determine the hormonal (luteinizing hormone [LH] and testosterone) and biochemical (serum prostate-specific antigen [PSA]) response to withdrawal of luteinizing hormone-releasing hormone (LHRH) agonists in patients who received more than 2 years of LHRH therapy for advanced prostate cancer., Methods: Fourteen patients with clinical Stage T3 or higher prostate cancer and no evidence of clinical or biochemical progression, who had received 2 years or more of LHRH therapy, were enrolled at the time of their scheduled 3-month depot injection. Patients underwent history, physical examination, and measurement of serum PSA, LH, and testosterone at baseline, monthly for 3 months, and then every 3 months for 1 year following LHRH withdrawal., Results: The mean age of patients was 70.3 years (range 56 to 84). Patients previously received LHRH agonist for a mean of 38.6 months (range 25 to 82). All patients had castrate levels of testosterone (median 10.0 ng/dL) and suppressed LH levels (median 0.1 mIU/mL) at baseline. Median baseline PSA was 0.15 ng/mL. On multiple groupwise comparison, there was no significant change (compared with baseline) in LH or testosterone until 6 months after withdrawal and no change in PSA throughout the duration of the study (median PSA at 1 2 months 0.30 ng/mL). Despite significant increases in LH and testosterone when compared with baseline beginning at 6 months, both LH and testosterone remained markedly suppressed, with median testosterone remaining in the castrate range at both 6 and 9 months and significantly below the lower limit of normal at 12 months (median 111.0 ng/dL). Despite no statistically significant change for the entire cohort in serum PSA, a rising PSA was noted in 4 patients between 3 and 9 months, and LHRH therapy was reinitiated. The remaining patients continued to have suppressed LH and testosterone, with 4 patients remaining in the castrate range at 12 months., Conclusions: The recovery of function of the hypothalamic-pituitary-testicular axis after prolonged LHRH administration is variable. Castrate levels of testosterone and suppressed LH may persist even up to 1 year after discontinuing LHRH. These results have significant implications regarding the interpretation of clinical trials incorporating neoadjuvant and adjuvant hormonal therapy. Further studies are needed to expand on these preliminary observations and should also address the feasibility of incorporating LHRH withdrawal into clinical practice.

There is great interest in the development of gene therapeutic strategies for the treatment of benign and malignant diseases. Recombinant adenovirus has a wide spectrum of tissue specificity and is an efficient vector delivery system. Successful gene delivery, however, requires viral entry into the target cells via specific receptor-mediated uptake. Recently, a cDNA clone (the coxsackie and adenovirus receptor [CAR]) encoding a 46-kDa protein was identified as the receptor for group C adenovirus (e.g., adenovirus type 2 and 5). Currently, little is known regarding the expression of adenoviral receptor in normal tissue and cancer. In this paper, we have documented a significant difference in viral receptor levels that may be due to transcriptional regulation of the CAR gene in several human bladder cancer cell lines. The differences in viral receptor levels in these cells correlated with their sensitivity to viral infection. Transfection of receptor-negative cell line with CAR cDNA led to increased virus binding and increased susceptibility to adenovirus-mediated gene delivery. Our results demonstrate that the expression of adenoviral receptor is variable among human bladder cancer cells. This variability may have a significant impact on the outcome of adenovirus-based gene therapy.

Objectives: To review a large single-center experience of patients treated for upper tract transitional cell carcinoma (TCC) with extended follow-up in order to identify patterns of recurrence, assess patient outcomes, and determine the impact of traditional prognostic factors., Methods: We reviewed 252 patients treated surgically for upper tract TCC with a median follow-up of 64 months. Most patients (77%) underwent nephroureterectomy, whereas 17% were treated with a parenchymal sparing approach. Traditional prognostic factors including age, sex, tumor stage, grade, location, and type of surgical treatment were analyzed with respect to disease recurrence and survival., Results: Disease relapse occurred in 67 patients (27%) at a median time of 12.0 months. Recurrences were local in the retroperitoneum (9%), the bladder (51%), remaining upper tract (18%), or distant in the lung, bone, or liver (22%). The 6 patients with local relapse were among the 73 patients with pT3 or pT4 tumors, and all died of TCC at a median time from diagnosis of 37 months. Significant prognostic factors for recurrence by univariate analysis were tumor grade (P = 0.0014) and stage (P = 0.0001). On multivariate analysis, only tumor stage (P = 0.017) and treatment modality (P = 0.020) were predictors of recurrence. Actuarial 5-year disease-specific survival rates by primary tumor stage were 100% for Ta/cis, 91.7% for T1, 72.6% for T2, and 40.5% for T3. Patients with primary Stage T4 tumors had a median survival of 6 months. Although tumor stage and grade correlated with disease-specific survival on univariate analysis, only patient age (P = 0.042) and stage (P = 0.0001) were significant on multivariate analysis with the type of surgical procedure performed approaching significance (P = 0.0504)., Conclusions: Primary tumor stage and surgical procedure performed (radical versus parenchymal sparing) are important predictors of disease recurrence. Patient age and tumor stage were the only predictors of disease-specific survival on multivariate analysis with the type of surgical procedure approaching significance. Radical nephroureterectomy achieves excellent local control even in the setting of locally advanced (pT3 or T4) disease. The major clinical feature in this setting is distant failure, and the development of effective systemic therapy is needed to improve the outcome in these patients.

Purpose: We review the outcome of patients with advanced stage III or IV transitional cell carcinoma of the upper urinary tract and the impact of postoperative radiotherapy., Materials and Methods: We identified 74 patients who were treated surgically with curative intent for stage III (49) or IV (25) transitional cell carcinoma of the upper urinary tract. Median followup was 21 months (range 1 to 236) for all patients and 60 months (range 29 to 172) for those alive at last contact. A median dose of 40 Gy. adjuvant radiotherapy was delivered to the tumor bed and regional nodes of 15 patients (30%) with stage III and 13 (52%) with stage IV disease., Results: The actuarial 5-year overall and disease specific survival for patients with stage III disease was 28 and 40%, respectively. Median disease specific survival was 37 months. Median overall and disease specific survival for patients with stage IV disease was 7 months. Isolated local recurrence was identified in 5 of 49 patients with stage III and only 1 of 25 with stage IV disease. The 5-year actuarial disease specific survival rate in patients with stage III disease whether or not they were treated with postoperative radiotherapy was 45 versus 40%, respectively. For patients with stage IV disease median survival was 7 and 9 months for those who were and those who were not treated with postoperative radiotherapy, respectively., Conclusions: Patients with stages III and IV transitional cell carcinoma of the upper urinary tract have a high risk of disease relapse and cancer mortality. The major clinical feature is distant failure with isolated local relapse uncommon following initial aggressive surgical therapy. There is no survival benefit with postoperative adjuvant radiotherapy. More effective systemic adjuvant therapy is necessary to improve the outcome of these patients.

Purpose: The intermediate followup results with split-cuff nipple ureteral reimplantation in larger numbers of urinary diversion patients are reviewed., Materials and Methods: Split-cuff nipple ureteroenteric anastomosis was performed in 98 ureters of 51 adult patients. Mean duration of followup was 23 months (range 3 to 62). Two minor variations in technique compared to the original report are presented., Results: Urinary reflux was prevented in 97.6 and 96.8% of cases at 1 and 2-year followup, respectively. Ureteroenteric anastomotic obstruction occurred in 3.1% of ureters by 3 months postoperatively. No cases of anastomotic leak or later obstruction occurred. Four episodes of acute pyelonephritis occurred in the early postoperative period., Conclusions: The split-cuff nipple ureteral reimplant technique in urinary diversion continues to provide excellent results with low rates of reflux or obstruction. The 2 described minor technical modifications further simplify the procedure.

Objectives: Bropirimine is an oral immunomodulator that has demonstrated anticancer activity in transitional cell carcinoma in situ (CIS) in both the bladder and upper urinary tract. Activity also has been documented in patients after prior therapy with bacille Calmette-Guérin (BCG). To more accurately estimate bropirimine's efficacy in BCG-resistant bladder CIS, a Phase II trial was performed. A separate analysis was performed in additional patients intolerant of BCG toxicity., Methods: Patients received bropirimine 3.0 g/day by mouth for 3 consecutive days, weekly, for up to 1 year. Bladder biopsies and cytologic examination were performed quarterly. Complete response (CR) required negative biopsy and cytology results., Results: Twenty-one of 86 patients entered were not evaluable. CR was seen in 21 (32%; 95th percentile confidence interval [CI], 21% to 44%) of 65 evaluable patients, including 14 (30%, CI 17% to 43%) of 47 BCG-resistant, and 7 (39%, CI 16% to 61%) of 18 BCG-intolerant patients. Overall, by intent-to-treat analysis, CR was thus seen in 21 (24%) of 86 subjects. Most BCG-resistant patients were failures to BCG without relapse, and had received 12 to 36 (median 12) BCG treatments; intolerant patients had received 4 to 11 treatments (median 6). Response duration ranged from 65 to 810 days, with median not yet reached (but greater than 12 months). Thirteen (15%) of 86 stopped bropirimine due to toxicity. Progression to invasive or metastatic disease during or immediately after therapy was documented in only 4 patients (6%), all nonresponders., Conclusions: Bropirimine may be an alternative to cystectomy for some patients with bladder CIS who have failed or have not tolerated BCG. Further evaluation to improve responses and durability is warranted.

Objectives: To assess the relationship of prostatic intraepithelial neoplasia (PIN) with both incidental and clinical carcinoma of the prostate., Methods: We retrospectively reviewed prostate histology in 48 men (group 1) who underwent surgical removal of the prostate for diagnoses other than prostate cancer, as well as in 64 men (group 2) who underwent radical prostatectomies. Both groups were assessed for the presence and extent of high-grade (HG-) PIN and compared with respect to patient age, Gleason score, and volume of prostate cancer., Results: HG-PIN was present in 40 of 48 (83%) group 1 cases. Forty-six percent of these cases (22 of 48) had incidental prostate cancer. Twenty-nine of 48 (60%) group 1 patients with HG-PIN had multifocal or extensive disease. Twenty of 22 (91%) incidental prostate cancers were present in 29 prostates with multifocal or extensive HG-PIN. In contrast, only 2 of 19 (11%) cases with absent to focal HG-PIN had prostate cancer. The association of multifocal or extensive HG-PIN with incidental prostate cancer was significant (P = 0.001); the relationships of extent of HG-PIN and cancer volume (P = 0.06) or high Gleason score (P = 0.017) were not significant. HG-PIN was present in 61 of 64 (95%) group 2 cases. The associations of extent of HG-PIN and cancer volume (P = 0.169) or high Gleason score (P = 0.156) were not significant., Conclusions: Both the low rate of incidental prostate cancer in specimens with absent to focal HG-PIN and the high rate of cancer in specimens with multifocal or extensive HG-PIN suggest that HG-PIN is a marker for concurrent prostate cancer and that the risk of concurrent prostate cancer is related to the volume of HG-PIN in the prostate gland.

Objectives: To determine the statistical performance of three different assays for prostate specific antigen (PSA) and the percentage of free PSA with respect to the differentiation of histologic benign prostatic hyperplasia (BPH) and prostate cancer in men who underwent surgical removal of prostate tissue., Methods: Serum of 86 men scheduled for prostate surgery (transurethral resection of the prostate [TURP], simple open prostatectomy, radical prostatectomy, cystoprostatectomy) was frozen and subjected to measurement in batches using three different assays for total PSA (Hybritech Tandem-E, Abbott IMx, Tosoh AIA-600) and free PSA by the Hybritech method after a single freeze-thaw cycle. The histologic diagnosis of the removed tissue (35 BPH and 51 cancer) was used as a "gold standard" for classification of disease status. Sensitivity, specificity, positive and negative predictive values, and diagnostic efficiency were calculated for the three total PSA assays and the free/total PSA ratios for the entire cohort and subsets. Receiver-operating characteristic (ROC) curve analysis was used to compare the performance of the assays and ratios., Results: Mean and median total PSA values differed slightly between the three assays for all patients, and for those with BPH and cancer, but this difference was not significant. Because of a considerable overlap, the differences between the mean PSA values for men with BPH and prostate cancer were not significant. At a cutpoint of 4.0 ng/mL, sensitivity with respect to the differentiation between BPH and prostate cancer was 68.6% for all three total PSA assays; the respective AUCs (0.613-0.625) were not significantly different. While the performance of the free/total PSA ratios was superior, the differences were only significant when subsets of patients were considered with a total PSA between 4 and 10 ng/mL or 4 and 15 ng/mL (AUCs 0.789-0.816). Likewise, sensitivity, specificity, and diagnostic efficiency was better in these subsets of patients., Conclusions: In this study in which a "gold standard" based on histologic analysis of the entire (or large part of) the prostate gland was used to classify disease status, the three assays for total serum PSA (Hybritech Tandem-E, Abbott IMx, and Tosoh AIA-600) performed very similarly with identical sensitivities (at a cutpoint of 4.0 ng/mL) and comparable AUCs with respect to the differentiation of men with histologic BPH and prostate cancer. The ratios of free/total PSA calculated as free PSA by the Hybritech manual immunoradiometric assay (IRMA) method over all three total PSA assays, performed marginally better in the entire patient population. However, in the subsets of patients with a PSA of 4-10 ng/mL and 4-15 ng/mL, all three ratios performed significantly better than the three total PSA assays. The proper choice of a cutpoint for the ratio (15%, 17%, 19%, or 21%) depends on the desirability of maximizing either sensitivity or specificity while optimizing diagnostic efficiency.

While 80% of transitional cell carcinomas (TCC) present as Ta Tl lesions, they account for only 15% of deaths caused by TCC. We have evaluated the ability of DNA ploidy analysis to predict outcome in 228 patients with Ta Tl TCC. All patients were judged to be at increased risk for tumor recurrence due to having two occurrences of Stage TI tumor within 56 weeks, or three or more tumors presenting simultaneously within 16 weeks of registration. Concurrent carcinoma in situ was acceptable. All patients were treated with either bacillus Calmette Guerin (BCG) immunotherapy or mitomycin-C (MMC) intravesical chemotherapy. Patients with nondiploid tumors had higher hazard rates for both tumor progression and death (p = 0.007 and p = 0.016, respectively); however, the prognostic information of DNA ploidy was not additive to tumor grade.

Purpose: A split-cuff nipple technique was developed for ureteral reimplantation in urinary diversion., Materials and Methods: Ureteroenteric anastomosis was performed with a uniform split-cuff nipple technique in 46 ureters of 24 adult patients undergoing various forms of conduit or continent urinary diversion. The outcome of 42 reimplants in 22 patients (mean followup 22.5 months, minimum 10) was analyzed. The technique is described in detail., Results: Reflux was prevented in 97.6% and 95% of cases at initial and 2-year followup, respectively. Neither anastomotic leakage nor obstruction occurred. There were 2 episodes of pyelonephritis in the early postoperative period. Results are compared with those in the literature of ureteroenteric anastomoses in general and of various split-cuff nipple techniques., Conclusions: The technique is easy to perform. Favorable early results warrant continued use of the procedure. Long-term followup in a larger number of patients is indicated.