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Purpose The importance of primary Gleason grade among men with Gleason score 7 disease has been well-defined. However, this dichotomization may oversimplify the continuous spectrum of absolute percent Gleason grade 4 disease (G4%). In this study we report the prognostic value of G4% in cancer related outcomes of men undergoing radical prostatectomy. Materials and Methods Patients who underwent radical prostatectomy for clinically localized Gleason 6-8 prostate cancer from 2005 to 2013 were included in the study. G4% was determined as biopsy tumor length containing Gleason pattern 4/total tumor length, which performed better than alternative quantifications of pattern 4 involvement. G4% was correlated with time to biochemical recurrence and presence of adverse radical prostatectomy pathology, defined as primary Gleason 4 or pT3 or greater, by multivariable Cox and logistic regressions. Results Of 1,691 patients 517 (30.6%) had adverse pathological features and 86 (5.6%) experienced biochemical recurrence. On multivariable analyses G4% was a significant predictor of adverse pathology (OR 1.04, 95% CI 1.03–1.05) and time to biochemical recurrence (HR 1.02, CI 1.01–1.03). G4% was also a significant independent predictor of adverse pathology in subsets of patients with Gleason score 7 (OR 1.05, 95% CI 1.03–1.06), 3+4 (OR 1.06, 95% CI 1.04–1.08) and 4+3 cancer (OR 1.05, 95% CI 1.03–1.06). We found a significantly increased risk of adverse pathology at potentially meaningful G4% thresholds (1% to 10% vs 20% to 30%). Conclusions The incremental percentage of Gleason grade 4 disease in biopsy specimens is an important predictor of adverse pathology and biochemical recurrence across the entire range of G4% disease. Accounting for G4% can improve risk assessment even among those patients with Gleason 3+4 or 4+3 cancer and may help inform patient counseling. [ABSTRACT FROM AUTHOR]

Purpose A previously published risk stratification algorithm based on renal mass biopsy and radiographic mass size was useful to designate surveillance vs the need for immediate treatment of small renal masses. Nonetheless, there were some incorrect assignments, most notably when renal mass biopsy indicated low risk malignancy but final pathology revealed high risk malignancy. We studied other factors that might improve the accuracy of this algorithm. Materials and Methods For 202 clinically localized small renal masses in a total of 200 patients with available R.E.N.A.L. (radius, exophytic/endophytic, nearness of tumor to collecting system or sinus, anterior/posterior, hilar tumor touching main renal artery or vein and location relative to polar lines) nephrometry score, preoperative renal mass biopsy and final pathology we assessed the accuracy of management assignment (surveillance vs treatment) based on the previously published risk stratification algorithm as confirmed by final pathology. Logistic regression was used to determine whether other factors (age, gender, R.E.N.A.L. score, R.E.N.A.L. score components and nomograms based on R.E.N.A.L. score) could improve assignment. Results Of the 202 small renal masses 53 (26%) were assigned to surveillance and 149 (74%) were assigned to treatment by the risk stratification algorithm. Of the 53 lesions assigned to surveillance 25 (47%) had benign/favorable renal mass biopsy histology while in 28 (53%) intermediate renal mass biopsy histology showed a mass size less than 2 cm. Nine of these 53 masses (17%) were incorrectly assigned to surveillance in that final pathology indicated the need for treatment (ie intermediate histology and a mass greater than 2 cm or unfavorable histology). Final pathology confirmed a correct assignment in all 149 masses assigned to treatment. None of the additional parameters assessed improved assignment with statistical significance. Conclusions Age, gender, R.E.N.A.L. nephrometry score, R.E.N.A.L. score components and nomograms or combinations of these factors do not improve the predictive performance of a small renal mass management risk stratification algorithm based on renal mass biopsy and radiographic mass size. [ABSTRACT FROM AUTHOR]

Purpose: Certificate of need programs are a primary mechanism to regulate the use and cost of health care services at the state level. The effect of certificate of need programs on the use of intensity modulated radiation therapy and the increasing costs of prostate cancer care is unknown. We compared the use of intensity modulated radiation therapy and change in prostate cancer health care costs in regions with vs without active certificate of need programs. Materials and Methods: This population based, observational study using SEER (Surveillance, Epidemiology, and End Results)-Medicare linked data from 2002 through 2009 was comprised of 13,814 men treated for prostate cancer in 3 regions with active certificate of need programs (CON Yes) vs 44,541 men treated for prostate cancer in 9 regions without active certificate of need programs (CON No). We assessed intensity modulated radiation therapy use relative to other prostate cancer definitive therapies and overall prostate cancer health care costs with respect to certificate of need status. Results: In propensity score adjusted analyses, intensity modulated radiation therapy use increased from 2.3% to 46.4% of prostate cancer definitive therapies in CON Yes regions vs 11.3% to 41.7% in CON No regions from 2002 to 2009. Furthermore, we observed greater intensity modulated radiation therapy use with time in CON Yes vs No regions (p <0.001). Annual cost growth did not differ between CON Yes vs No regions (p = 0.396). Conclusions: Certificate of need programs were not effective in limiting intensity modulated radiation therapy use or attenuating prostate cancer health care costs. There remains an unmet need to control the rapid adoption of new, more expensive therapies for prostate cancer that have limited cost and comparative effectiveness data. [ABSTRACT FROM AUTHOR]

Purpose: Minimally invasive radical prostatectomy has supplanted radical retropubic prostatectomy in popularity despite the absence of strong comparative effectiveness data demonstrating its superiority. We examined the influence of patient, surgeon and hospital characteristics on the use of minimally invasive radical prostatectomy vs radical retropubic prostatectomy. Materials and Methods: Using SEER (Surveillance, Epidemiology and End Results)-Medicare linked data we identified 11,732 men who underwent radical prostatectomy from 2003 to 2007. We assessed the contribution of patient, surgeon and hospital characteristics to the likelihood of undergoing minimally invasive radical prostatectomy vs radical retropubic prostatectomy using multilevel logistic regression mixed models. Results: Patient factors (36.7%) contributed most to the use of minimally invasive radical prostatectomy vs radical retropubic prostatectomy, followed by surgeon (19.1%) and hospital (11.8%) factors. Among patient specific factors Asian race (OR 1.86, 95% CI 1.27–2.72, p = 0.001), clinically organ confined tumors (OR 2.71, 95% CI 1.60–4.57, p <0.001) and obtaining a second opinion from a urologist (OR 3.41, 95% CI 2.67–4.37, p <0.001) were associated with the highest use of minimally invasive radical prostatectomy while lower income was associated with decreased use of minimally invasive radical prostatectomy. Among surgeon and hospital specific factors, higher surgeon volume (OR 1.022, 95% CI 1.015–1.028, p <0.001), surgeon age younger than 50 years (OR 2.68, 95% CI 1.69–4.24, p <0.001) and greater hospital bed size (OR 1.001, 95% CI 1.001–1.002, p <0.001) were associated with increased use of minimally invasive radical prostatectomy, while solo or 2 urologist practices were associated with decreased use of minimally invasive radical prostatectomy (OR 0.48, 95% CI 0.27–0.86, p = 0.013). Conclusions: The adoption of minimally invasive radical prostatectomy vs radical retropubic prostatectomy is multifactorial, and associated with specific patient, surgeon and hospital related factors. Obtaining a second opinion from another urologist was the strongest factor associated with opting for minimally invasive radical prostatectomy. [Copyright &y& Elsevier]

Purpose: We hypothesized that in patients with T2N0 stage disease at transurethral bladder tumor resection a lower residual cancer stage (P1N0 or less) at radical cystectomy may correlate with improved outcomes relative to those with residual P2N0 disease. Materials and Methods: We analyzed 208 patients with T2N0 stage disease at transurethral bladder tumor resection whose tumors were organ confined at radical cystectomy (P2 or lower, pN0). None received perioperative chemotherapy. Kaplan-Meier as well as univariable and multivariable Cox regression models addressed the effect of residual pT stage at radical cystectomy on recurrence and cancer specific mortality rates. Covariates consisted of age, gender, grade, lymphovascular invasion, carcinoma in situ, number of lymph nodes removed and year of surgery. Results: Residual pT stage at radical cystectomy was P0 in 24 (11.5%) patients, Pa in 9 (4.3%), PCIS in 22 (10.6%), P1 in 35 (16.8%) and P2 in 118 (56.7%). Median followup of censored patients was 55.7 months for recurrence and 52.1 months for cancer specific mortality analyses. The 5-year recurrence-free survival rates of patients with P0/Pa/PCIS, P1 and P2 stage disease were 100%, 85% and 75%, respectively. The 5-year cancer specific survival rates for the same cohorts were 100%, 93% and 81%, respectively. On multivariable analysis the effect of residual stage P1 or lower at radical cystectomy achieved independent predictor status for recurrence (adjusted HR 0.20, p = 0.002) and cancer specific mortality (adjusted HR 0.24, p = 0.02). Conclusions: Down staging from initial T2N0 bladder cancer at transurethral bladder tumor resection to lower stage at radical cystectomy significantly reduces recurrence and cancer specific mortality. Further validation of this finding is warranted. [Copyright &y& Elsevier]

Purpose: We have noted that hypermethylation at GSTP1 in the preoperative serum of men with localized prostate cancer predicts early prostate specific antigen failure following surgical treatment. In this study we investigated the hypermethylation profile of several genes in the serum of men with localized and hormone refractory prostate cancer. Materials and Methods: We assayed the serum of 192 men with clinically localized prostate cancer and 18 with hormone refractory metastatic disease. A total of 35 serum samples from patients with negative prostate biopsy served as a negative control. CpG Island hypermethylation status of certain genes was assessed, including MDR1, EDNRB, CD44, NEP, PTGS2, RASSF1A, RAR-β and ESR1. The results of hypermethylation at GSTP1 were included from a previous study. Results: CpG island hypermethylation at MDR1 was positive in 38.2% of cases without PSA recurrence and in 16.1% of those with biochemical recurrence after radical prostatectomy. DNA hypermethylation at the remaining 7 gene loci was not detected in the serum of patients with localized prostate cancer. In serum from metastatic prostate cancer cases CpG island hypermethylation was detected at MDR1 in 15 (83.3%), EDNRB in 9 (50%), RAR-β in 7 (38.9%), GTSP1 in 5 (27.8%) and NEP or RASSF1A in 3 (16.7%). CpG island hypermethylation at CD44, PTGS2 or ESR was not detected in any samples. All histologically normal cases were negative for CpG island hypermethylation. Conclusions: DNA hypermethylation at MDR1 was detected in cases of localized prostate cancer. CpG island hypermethylation at several gene loci was detected in men with advanced disease. No single gene was consistently observed to be hypermethylated in men with hormone refractory disease. These results suggest that the CpG island hypermethylation status of a defined panel of genes may be a useful biomarker in men with hormone refractory prostate cancer. [Copyright &y& Elsevier]

Purpose: We present the characteristics and outcomes of a large, contemporary, consecutive series of patients treated with radical cystectomy and pelvic lymphadenectomy for transitional cell carcinoma of the bladder. Materials and Methods: We developed a multi-institutional database and collected retrospective and prospective data on 888 consecutive patients with bladder transitional cell carcinoma who were treated with radical cystectomy and pelvic lymphadenectomy at 3 academic centers in the United States between 1984 and 2003. Results: Of the patients 25% had extravesical tumor extension with negative lymph nodes and 23% had lymph node metastasis. The rate of lymph node involvement increased with advancing pathological stage. Mean recurrence-free and bladder cancer specific survival ± SE was 58% ± 2% and 66% ± 2% at 5 years, respectively. On preoperative multivariate analysis clinical tumor stage and neoadjuvant systemic chemotherapy were associated with cancer recurrence, while more advanced age, clinical tumor stage and preoperative carcinoma in situ were associated with bladder cancer specific mortality. On postoperative multivariate analysis pathological tumor stage, lymph node metastasis, lymphovascular invasion, adjuvant radiotherapy and adjuvant chemotherapy were associated with cancer recurrence, while higher pathological tumor stage, more advanced age, lymph node metastasis, lymphovascular invasion and adjuvant radiotherapy were associated with disease specific survival. Patients with metastasis to regional lymph nodes (pT any N1-3) were at significantly higher risk for bladder cancer recurrence and death than patients with extravesical tumor extension (pT3N0), who in turn were at significantly higher risk than patients with organ confined disease (pT2 N0 or less). Conclusions: The results of this large, contemporary, multi-institutional series show that radical cystectomy and pelvic lymphadenectomy provide durable local control and disease specific survival in patients with localized invasive transitional cell carcinoma. [Copyright &y& Elsevier]

Purpose: American Joint Committee on Cancer staging represents the gold standard for prediction of recurrence after radical cystectomy in patients with invasive bladder cancer. We tested the hypothesis that American Joint Committee on Cancer stage based predictions may be improved when pathological tumor and node stage information is combined with additional clinical and pathological variables within a prognostic nomogram. Materials and Methods: We used Cox proportional hazards regression analysis to model variables of 728 patients with transitional cell carcinoma of the bladder treated with radical cystectomy and bilateral pelvic lymphadenectomy at 1 of 3 participating institutions. Standard predictors, pT and pN, were complemented by age, gender, tumor grade at cystectomy, presence of lymphovascular invasion, presence of carcinoma in situ in the cystectomy specimen, neoadjuvant chemotherapy, adjuvant chemotherapy and adjuvant radiotherapy. The concordance index was used to quantify the accuracy of regression coefficient based nomograms. A total of 200 bootstrap resamples were used to reduce overfit bias and for internal validation. Calibration plots were used to graphically explore the performance characteristics of the multivariate nomogram. Results: Followup ranged from 0.1 to 183.4 months (median 24.9, mean 36.4). Recurrence was recorded in 249 (34.2%) patients with a median time to recurrence of 108 months (range 0.8 to 131.9). Actuarial recurrence-free probabilities were 69.6% (95% CI 65.8%–73.0%), 60.2% (55.8%–64.3%) and 52.9% (47.3%–58.1%) at 2, 5 and 8 years after cystectomy, respectively. Two-hundred bootstrap corrected predictive accuracy of American Joint Committee on Cancer stage based predictions was 0.748. Accuracy increased by 3.2% (0.780) when age, lymphovascular invasion, carcinoma in situ, neoadjuvant chemotherapy, adjuvant chemotherapy and adjuvant radiotherapy were added to pathological stage information and used within a nomogram. Conclusions: A nomogram predicting bladder cancer recurrence after cystectomy is 3.2% more accurate than American Joint Committee on Cancer stage based predictions. Moreover, a nomogram approach combines several advantages such as easy and precise estimation of individual recurrence probability at key points after cystectomy, which all patients deserve to know and all treating physicians need to know. [Copyright &y& Elsevier]

Purpose: Using various nonphysiological tissue injury/repair models numerous studies have demonstrated the capacity of bone marrow derived cells to contribute to the repopulation of epithelial tissues following damage. To investigate whether this phenomenon might also occur during periods of physiological tissue degeneration/regeneration we compared the ability of bone marrow derived cells to rejuvenate the prostate gland in mice that were castrated and then later treated with dihydrotestosterone vs mice with prostate epithelium that had been damaged by lytic virus infection. Materials and Methods: Using allogenic bone marrow grafts from female donor transgenic mice expressing green fluorescent protein transplanted into lethally irradiated males we were able to assess the contributions of bone marrow derived cells to recovery of the prostatic epithelium in 2 distinct systems, including 1) surgical castration followed 1 week later by dihydrotestosterone replacement and 2) intraprostatic viral injection. Eight to 10-week-old male C57/Bl6 mice were distributed among bone marrow donor→recipient/prostate injury groups, including 5 with C57/Bl6→C57/Bl6/no injury, 3 with green fluorescent protein→C57/Bl6/no injury, 3 with green fluorescent protein→C57/Bl6/vehicle injection, 4 with green fluorescent protein→C57/Bl6/virus injection and 3 each with green fluorescent protein→C57/Bl6/castration without and with dihydrotestosterone, respectively. Prostate tissues were harvested 3 weeks after dihydrotestosterone replacement or 14 days following intraprostatic viral injection. Prostate tissue immunofluorescence was performed with antibodies against the epithelial marker cytokeratin 5/8, the hematopoietic marker CD45 and green fluorescent protein. Results: Mice that sustained prostate injury from vaccinia virus infection with concomitant severe inflammation and glandular disruption showed evidence of bone marrow derived cell reconstitution of prostate epithelium, that is approximately 4% of all green fluorescent protein positive cells in the epithelial compartment 14 days after injury expressed cytokeratin 5/8, similar to the proportion of green fluorescent protein positive cells in the prostate that no longer expressed the hematopoietic marker CD45. When prostatic degeneration/regeneration was triggered by androgen deprivation and reintroduction, no green fluorescent protein positive prostate epithelial cells were detected. Conclusions: These findings are consistent with a requirement for inflammation associated architectural destruction for the bone marrow derived cell contribution to the regeneration of prostate epithelium. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]