Ganesh S. Palapattu

Lymphovascular Invasion Is Independently Associated With Overall Survival, Cause-Specific Survival, and Local and Distant Recurrence in Patients With Negative Lymph Nodes at Radical Cystectomy

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 i...

Preoperative Serum DNA GSTP1 CpG Island Hypermethylation and the Risk of Early Prostate-Specific Antigen Recurrence Following Radical Prostatectomy

Purpose: Hypermethylation of the CpG island at the promoter region of the π-class glutathione S-transferase gene (GSTP1) is the most common somatic genome abnormality in human prostate cancer. We evaluated circulating cell-free DNA GSTP1 CpG island hypermethylation as a prognostic biomarker in the serum of men with prostate cancer. Experimental Design: Prostate cancer DNA GSTP1 CpG island hypermethylation was detected using a restriction endonuclease quantitative PCR technique. We analyzed preoperative serum from 85 men with clinically localized prostate cancer treated with radical prostatectomy and from 35 men with a negative prostate biopsy. We then assayed preoperative serum from a data set of 55 pairs of men with clinically localized prostate cancer treated with radical prostatectomy, matched for Gleason score, comprising 55 men suffering prostate-specific antigen (PSA) recurrence (median, 2 years) and 55 men who were free of disease at last follow-up (median, 3 years). The association of serum GSTP1 CpG island hypermethylation and PSA recurrence was determined. Results: Circulating cell-free DNA with GSTP1 CpG island hypermethylation was not detected in the serum of men with a negative prostate biopsy but was detected in 12% of men with clinically localized disease and 28% of men with metastatic cancer (P = 0.003). In the matched data set, eight men (15%) who developed PSA recurrence were positive for DNA with GSTP1 CpG hypermethylation, whereas no patient who was free of disease was positive for GSTP1 CpG island hypermethylation (McNemar test, χ2 = 6.1, P = 0.01). In a multivariable analysis that accounted for recognized prognostic factors, the presence of serum DNA with GTSP1 CpG island hypermethylation was the most significant predictor of PSA recurrence (hazard ratio, 4.4; 95% confidence interval, 2.2, 8.8; P < 0.001). Conclusion: Our study suggests that GSTP1 CpG island hypermethylation may be an important DNA-based prognostic serum biomarker for prostate cancer.

Nomograms provide improved accuracy for predicting survival after radical cystectomy

Aims: To develop multivariate nomograms that determine the probabilities of all-cause and bladder cancer–specific survival after radical cystectomy and to compare their predictive accuracy to that of American Joint Committee on Cancer (AJCC) staging. Methods: We used Cox proportional hazards regression analyses to model variables of 731 consecutive patients treated with radical cystectomy and bilateral pelvic lymphadenectomy for bladder transitional cell carcinoma. Variables included age of patient, gender, pathologic stage (pT), pathologic grade, carcinoma in situ, lymphovascular invasion (LVI), lymph node status (pN), neoadjuvant chemotherapy (NACH), adjuvant chemotherapy (ACH), and adjuvant external beam radiotherapy (AXRT). Two hundred bootstrap resamples were used to reduce overfit bias and for internal validation. Results: During a mean follow-up of 36.4 months, 290 of 731 (39.7%) patients died; 196 of 290 patients (67.6%) died of bladder cancer. Actuarial all-cause survival estimates were 56.3% [95% confidence interval (95% CI), 51.8-60.6%] and 42.9% (95% CI, 37.3-48.4%) at 5 and 8 years after cystectomy, respectively. Actuarial cancer-specific survival estimates were 67.3% (62.9-71.3%) and 58.7% (52.7-64.2%) at 5 and 8 years, respectively. The accuracy of a nomogram for prediction of all-cause survival (0.732) that included patient age, pT, pN, LVI, NACH, ACH, and AXRT was significantly superior (P = 0.001) to that of AJCC staging–based risk grouping (0.615). Similarly, the accuracy of a nomogram for prediction of cancer-specific survival that included pT, pN, LVI, NACH, and AXRT (0.791) was significantly superior (P = 0.001) to that of AJCC staging–based risk grouping (0.663). Conclusions: Multivariate nomograms provide a more accurate and relevant individualized prediction of survival after cystectomy compared with conventional prediction models, thereby allowing for improved patient counseling and treatment selection.

Multiple biomarkers improve prediction of bladder cancer recurrence and mortality in patients undergoing cystectomy

Tested was whether the assessment of 5 established bladder cancer biomarkers (p53, pRB, p21, p27, and cyclin E1) could improve the ability to predict disease recurrence and cancer‐specific survival after radical cystectomy in patients with pTa‐3N0M0 urothelial carcinoma of the bladder (UCB).

Clinical Outcomes Following Radical Cystectomy for Primary Nontransitional Cell Carcinoma of the Bladder Compared to Transitional Cell Carcinoma of the Bladder

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.

Selective expression of CD44, a putative prostate cancer stem cell marker, in neuroendocrine tumor cells of human prostate cancer.

Hormonal therapy is effective for advanced prostate cancer (PC) but the disease often recurs and becomes hormone‐refractory. It is hypothesized that a subpopulation of cancer cells, that is, cancer stem cells (CSCs), survives hormonal therapy and leads to tumor recurrence. CD44 expression was shown to identify tumor cells with CSC features. PC contains secretory type epithelial cells and a minor population of neuroendocrine cells. Neuroendocrine cells do not express androgen receptor and are quiescent, features associated with CSCs. The purpose of the study was to determine the expression of CD44 in human PC and its relationship to neuroendocrine tumor cells.

Prognostic value of preoperative serum cell-free circulating DNA in men with prostate cancer undergoing radical prostatectomy

Purpose: We evaluated the association of preoperative serum cell-free circulating DNA concentration in men with clinically localized prostate cancer who underwent radical prostatectomy with prostate-specific antigen (PSA) recurrence. Experimental Design: One hundred and ninety-two men with clinically localized prostate cancer, who underwent radical prostatectomy at the Johns Hopkins Hospital and had preoperative serum available for analyses constituted our study population. All serum samples were collected before prostate biopsy or at least 4 months after prostate biopsy. The total amount of serum cell-free circulating DNA from each sample was calculated using a standard curve generated via quantitative real-time PCR. PSA recurrence was defined as a single postoperative PSA level of ≥0.2. The natural logarithm (ln) of the DNA concentration was used for statistical analyses. Results: Of the 192 men in our study, 56 (29%) experienced PSA recurrence within the study period (median time to PSA recurrence 2 years). The median follow-up time for men free of disease at last follow-up was 3 years. The median serum cell-free DNA concentration of all men in the study was 5.3 ng/mL (mean 18.05 ng/mL; range 0.2-320 ng/mL). The mean serum DNA concentration for men who recurred and for those who did not was 3.8 ± 34.1 and 13.7 ± 33.6 ng/mL, respectively (P = 0.001). In a univariate analysis, ln DNA concentration was significantly associated with PSA recurrence (hazard ratio, 1.49; 95% confidence interval, 1.3-1.8; P < 0.001). In the multivariate model, ln DNA concentration was significantly associated with PSA recurrence (hazard ratio, 2.56; 95% confidence interval, 1.1-1.6; P = 0.003). Using bootstrap analyses, serum cell-free DNA concentrations ≥5.75 ng/mL were associated with an increased risk of PSA recurrence within 2 years of radical prostatectomy. Conclusion: Our study suggests that preoperative serum cell-free DNA concentration may be a useful prognostic biomarker for men with clinically localized prostate cancer treated with radical prostatectomy.

A delay in radical cystectomy of >3 months is not associated with a worse clinical outcome

The first three papers in this section relate to the use of radical cystectomy in bladder cancer, and each study describes issues which are uncommonly written about, but which are relevant and important to any urologist who manages such patients.

Assessing the minimum number of lymph nodes needed at radical cystectomy in patients with bladder cancer

To identify the likelihood of finding one or more positive lymph nodes (LNs) according to the number of LNs removed at radical cystectomy (RC), as the number of LNs removed affects disease progression and survival after RC.

Outcomes of Patients with Clinical T1 Grade 3 Urothelial Cell Bladder Carcinoma Treated with Radical Cystectomy

OBJECTIVES Urothelial tumors that invade the lamina propria but not the muscularis propria are a particularly problematic clinical entity. The aim of the present study was to assess the pathologic features and clinical outcomes of patients with clinical T1 grade 3 urothelial cell bladder carcinoma (UCBC) treated with radical cystectomy. METHODS We reviewed the records of 958 consecutive patients who underwent radical cystectomy and pelvic lymphadenectomy for bladder cancer at three U.S. academic centers. Of these patients, 167 (median age, 66.7 years) underwent radical cystectomy for clinical stage T1 grade 3 UCBC. RESULTS The median follow-up was 33.8 months (mean +/- standard deviation: 45.9 +/- 39.2 months, range, 0.4 to 177.1) for patients alive at last follow-up. Disease recurred in 48 of 167 of patients (29.4%) and 30 of 162 patients (18.5%) died from bladder cancer. A total of 29 of 166 patients (17.5%) had lymph nodal metastases. Of 167 patients, 84 (50%) were pathologically upstaged and 167 (27.5%) had extravesical disease. Patients with disease upstaging had poorer survival (P <0.001). A greater than 3-month delay between cystectomy and last transurethral resection showed a trend toward upstaging (P = 0.06). Presence of carcinoma in situ (CIS) was the only precystecomy factor that predicted disease recurrence (hazard ratio [HR]: 2.13, 95% confidence interval [CI]: 1.14 to 3.98) and mortality (HR: 2.75, 95% CI: 1.17 to 6.46). CONCLUSIONS A large proportion of patients undergoing cystectomy for clinical T1 grade 3 disease have adverse pathological features. The recurrence and survival outcomes in this group are suboptimal. Presence of CIS precystectomy predicts outcomes. Better markers are needed to identify patients at high risk for adverse outcomes.