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Abstract: Background: To provide an updated review of adverse events associated with sunitinib, pazopanib, bevacizumab, temsirolimus, axitinib, everolimus and sorafenib and their management. Materials and methods: We performed a PubMed and Cochrane-based review of side effects associated with the seven agents including product monographs to provide an outline of treatment measures aiming to reduce their toxicities. Subject and outcome of interest, design type, sample size, pertinence and quality, and detail of reporting were the indicators of manuscript quality. Results: All targeted therapies cause adverse events. Most adverse events may be prevented or tested before they escalate to severe levels. Conclusion: Prevention, early recognition, and prompt management of side effects are of key importance and avoid unnecessary dose reductions, which may undermine treatment efficacy. [Copyright &y& Elsevier]

Purpose: The use of robot-assisted radical prostatectomy has increased rapidly despite the absence of randomized, controlled trials showing the superiority of this approach. While recent studies suggest an advantage for perioperative complication rates, they fail to account for the volume-outcome relationship. We compared perioperative outcomes after robot-assisted and open radical prostatectomy, while considering the impact of this established relationship. Materials and Methods: Using the NIS (Nationwide Inpatient Sample), we abstracted data on patients treated with radical prostatectomy in 2009. Univariable and multivariable logistic regression analyses were done to compare the rates of blood transfusion, intraoperative and postoperative complications, prolonged length of stay, increased hospital charges and mortality between robot-assisted and open radical prostatectomy overall and across volume quartiles. Results: An estimated 77,616 men underwent radical prostatectomy, including a robot-assisted and an open procedure in 63.9% and 36.1%, respectively. Low volume centers averaged 26.2 robot-assisted and 5.2 open cases, while very high volume centers averaged 578.8 robot-assisted and 150.2 open cases. Overall, patients treated with the robot-assisted procedure experienced a lower rate of adverse outcomes than those treated with the open procedure for all measured categories. Across equivalent volume quartiles robot-assisted radical prostatectomy outcomes were generally favorable. However, the open procedure at high volume centers resulted in a lower postoperative complication rate (OR 0.59, 95% CI 0.46–0.75), elevated hospital charges (OR 0.75, 95% CI 0.64–0.87) and a comparable blood transfusion rate (OR 1.38, 95% CI 0.93–2.02) relative to the robot-assisted procedure at low volume centers. Conclusions: Regionalization has occurred to a greater extent for robot-assisted than for open radical prostatectomy with an associated benefit in overall outcomes. Nonetheless, low volume institutions experienced inferior outcomes relative to the highest volume centers irrespective of approach. These findings demonstrate the importance of accounting for hospital volume when examining the benefit of a surgical technique. [Copyright &y& Elsevier]

Purpose: The benefit of active treatment for prostate cancer is a subject of continuous debate. We assessed the relationship between treatment type (radical prostatectomy vs observation) and cancer specific mortality in a large, population based cohort. Materials and Methods: We examined the records of 44,694 patients treated with radical prostatectomy or observation between 1992 and 2005 in the SEER (Surveillance, Epidemiology and End Results)-Medicare linked database. Patients were matched by propensity score. Competing risks analysis was done to test the effect of treatment type on cancer specific mortality after accounting for other cause mortality. The number needed to treat was calculated. All analysis was stratified by prostate cancer risk group, baseline Charlson comorbidity index and patient age. Results: For patients treated with radical prostatectomy vs observation the 10-year cancer specific mortality rate was 5.2% vs 12.8% for high risk prostate cancer, 1.4% vs 3.8% for low-intermediate risk prostate cancer, 2.4% vs 5.8% for a Charlson comorbidity index of 0, 2.3% vs 6.4% for a comorbidity index of 1, 2.5% vs 5.4% for a comorbidity index of 2 or greater, 2.0% vs 4.6% at ages 65 to 69, 2.6% vs 5.6% at ages 70 to 74 and 2.7% vs 8.1% at ages 75 to 80 years (each p <0.001). The corresponding number need to treat was 13, 42, 29, 24, 34, 38, 33 and 19, respectively. On multivariable analysis radical prostatectomy was an independent predictor of more favorable cancer specific mortality in all categories (each p <0.001). Conclusions: Patients with high risk prostate cancer benefit the most from radical prostatectomy. The lowest benefit was observed in patients with low-intermediate risk prostate cancer. An intermediate benefit was observed when patients were classified by Charlson comorbidity index and age category. [ABSTRACT FROM AUTHOR]

Purpose: Discharge patterns, including rates of prolonged length of stay and transfer to a facility, were evaluated in the context of radical cystectomy. Materials and Methods: Within the Nationwide Inpatient Sample we focused on radical cystectomy performed between 1998 and 2007. Multivariable logistic regression analyses predicting the likelihood of prolonged length of stay or transfer to a facility were performed. Results: Overall 11,876 eligible radical cystectomy cases were identified. The rates of prolonged length of stay decreased from 59% in the early period (1998 to 2001) to 50% in the late period (2005 to 2007, p <0.001) while the rates of transfer to a facility remained stable (14%). On multivariable analyses adjusted for clustering, prolonged length of stay was more frequently recorded in patients from low annual caseload hospitals (OR 1.42, p <0.001), as well as in Medicaid and Medicare patients (OR 1.66 and 1.17, respectively, all p <0.01). Similarly rates of transfer to a facility were significantly higher for patients from low annual caseload hospitals (OR 1.81, p <0.001) and for those with Medicaid or Medicare (OR 2.18 and 1.54, respectively, all p <0.001), as well as for patients treated at nonacademic institutions (OR 1.31, p <0.001). Conclusions: It is encouraging that the rates of prolonged length of stay have decreased while the rates of transfer to a facility remained stable. However, it is worrisome that individuals treated at low annual caseload centers as well as those with Medicare and Medicaid insurance experience less favorable discharge patterns. [ABSTRACT FROM AUTHOR]

Purpose: We examined the impact of hospital volume on short-term outcomes after nephrectomy for nonmetastatic renal cell carcinoma. Materials and Methods: Using the Nationwide Inpatient Sample we identified 48,172 patients with nonmetastatic renal cell carcinoma treated with nephrectomy (1998 to 2007). Postoperative complications, blood transfusions, prolonged length of stay and in-hospital mortality were examined. Stratification was performed according to teaching status, nephrectomy type (partial vs radical nephrectomy) and surgical approach (open vs laparoscopic). Multivariable logistic regression models were fitted. Results: Patients treated at high volume centers were younger and healthier at nephrectomy. High hospital volume predicted lower blood transfusion rates (8.5% vs 9.7% vs 11.8%), postoperative complications (14.4% vs 16.6% vs 17.2%) and shorter length of stay (43.1% vs 49.8% vs 54.0%, all p <0.001). In multivariable analyses stratified according to teaching status, nephrectomy type and surgical approach, high hospital volume was an independent predictor of lower rates of postoperative complications (OR 0.73–0.88), blood transfusions (OR 0.71–0.78) and prolonged length of stay (OR 0.76–0.89, all p <0.001). Exceptions were postoperative complications at nonteaching centers (OR 0.94, p >0.05) and blood transfusions in nephrectomies performed laparoscopically (OR 0.68, p >0.05). Conclusions: On average, high hospital volume results in more favorable outcomes during hospitalization after nephrectomy. [ABSTRACT FROM AUTHOR]

Purpose: Radical prostatectomy outcomes may be better at academic institutions than at nonacademic centers. We examined the effect of academic status on 5 short-term radical prostatectomy outcomes. Materials and Methods: In the Health Care Utilization Project Nationwide Inpatient Sample we focused on radical prostatectomy performed within the 7 most contemporary years (2001 to 2007). We tested the rates of homologous blood transfusions and extended length of stay, as well as intraoperative and postoperative complications stratified according to institutional academic status. Multivariable logistic regression analyses further adjusted for confounding variables. Results: Overall 89,965 radical prostatectomies were identified, yielding a weighted national estimate of 442,811. Of those procedures 58.2% were recorded at academic institutions. Patients at academic institutions had a lower Charlson comorbidity index and more frequently had private insurance (p <0.001). Radical prostatectomy at academic institutions was associated with fewer blood transfusions (5.4% vs 7.4%), fewer postoperative complications (10.1% vs 12.9%) and lower rates of hospital stay above the median (18.0% vs 28.2%). On multivariable analyses institutional academic status exerted a protective effect on postoperative complication rates (OR 0.93, p = 0.02) and on rates of hospital stay in excess of the median (OR 0.91, p <0.001). Similarly radical prostatectomy performed at hospitals with a high annual caseload were less frequently associated with intraoperative (OR 0.8, p = 0.01) and postoperative (OR 0.63, p <0.001) complications, length of stay beyond the median (OR 0.19, p <0.001) and homologous blood transfusions (OR 0.35, p <0.001). Conclusions: Even after adjusting for annual hospital caseload, radical prostatectomy performed at academic institutions is associated with better outcomes than radical prostatectomy performed at nonacademic institutions. This relationship illustrates averages and does not imply that academic institutions invariably offer better care. [Copyright &y& Elsevier]

Purpose: In patients with nonmetastatic muscle invasive bladder cancer, radical cystectomy and pelvic lymph node dissection represent a comprehensive surgical treatment. We tested the hypothesis that radical cystectomy performed at a high caseload hospital and/or by a high caseload surgeon is more likely to include pelvic lymph node dissection. Materials and Methods: We identified 12,274 patients with bladder cancer treated with radical cystectomy between 1998 and 2007 within the Nationwide Inpatient Sample. Univariable and multivariable analyses tested the relationship between hospital and surgical caseload at radical cystectomy, and the pelvic lymph node dissection rate. Generalized estimating equation models were used to adjust for clustering among hospitals and surgeons. Results: Overall 70% of patients received comprehensive surgical treatment defined as radical cystectomy and pelvic lymph node dissection. The pelvic lymph node dissection rate was 63% vs 67% vs 80% for low vs intermediate vs high annual hospital caseload tertiles, respectively (p <0.001). The pelvic lymph node dissection rate was 64% vs 68% vs 80% for low vs intermediate vs high annual surgical caseload tertiles, respectively (p <0.001). On multivariable analyses and after adjusting for clustering, annual hospital caseload and annual surgical caseload were independent predictors of the pelvic lymph node dissection rate. Conclusions: Our findings indicate that a potentially comprehensive surgical treatment, defined as radical cystectomy with pelvic lymph node dissection, is only offered to a subset of patients. Annual hospital caseload and annual surgical caseload represent important determinants of potentially comprehensive bladder cancer surgery. Efforts should be made to ensure that virtually all patients with bladder cancer receive comprehensive surgical treatment. [ABSTRACT FROM AUTHOR]

Purpose: We tested the relationship between caseload and total hospital charges after stratifying by minimally invasive and open radical prostatectomy. Materials and Methods: We evaluated 1,188 vs 3,354 men treated with minimally invasive vs open radical prostatectomy in the Florida Hospital Inpatients data file in 2008. Caseload was defined as the count of procedures performed by each surgeon between the study start on January 1, 2008 and the date of each procedure. Patients were divided into tertiles based on their procedure specific caseload. Univariate and multivariate analysis was done to address the relation between caseload and total hospital charges for the minimally invasive and open procedures. Covariates were patient age, race, comorbidity, and length of stay. Results: Median total hospital charges for minimally invasive and open radical prostatectomy were $33,234 and $33,674, respectively (p = 0.03). Median total hospital charges in the low, intermediate and high minimally invasive vs open procedure caseload tertiles were $41,765, $34,799 and $28,780 vs $35,642, $34,726 and $32,726, respectively. On multivariate analysis with the high minimally invasive caseload tertile as the reference category the increments of the probability of charges in excess of the 2008 median of $33,588 were 3.9 and 8.1-fold for the intermediate and low caseload minimally invasive procedures, and 2.5, 3.6 and 2.8-fold for the high, intermediate and low caseload open procedures, respectively (each p <0.001). Conclusions: Overall median total hospital charges are virtually the same for minimally invasive and open radical prostatectomy. However, total hospital charges for the minimally invasive procedure have a more sensitive caseload effect, as evidenced by the wider distribution of the median of minimally invasive caseload specific total hospital charges vs that of open radical prostatectomy. The high caseload minimally invasive procedure resulted in the lowest total hospital charges relative to all other minimally invasive and open radical prostatectomy categories. [Copyright &y& Elsevier]

Purpose: Penile cancer is rare. Thus, predicting cancer specific mortality may be difficult. We devised an accurate and yet easily applicable predictive rule that compares favorably with 2 previous models (73.8% and 74.7% accuracy, respectively). Materials and Methods: We identified patients treated with primary tumor excision for all stages of penile squamous cell carcinoma between 1998 and 2006. Disease stage definitions using Surveillance, Epidemiology and End Results stage, American Joint Committee on Cancer stage and TNM classification, and tumor grade were used to predict cancer specific mortality. Predictive accuracy estimates were compared using the DeLong method for related AUCs. Results: Surveillance, Epidemiology and End Results stage alone (1 predictor variable) was least accurate (74.5%). American Joint Committee on Cancer stage with tumor grade (2 predictor variables) was the most simple and most accurate (80.9%, p <0.001). A benefit similar to that of American Joint Committee on Cancer stage with tumor grade was seen for TNM classification and TG (80.7%, p = 0.8). However, this rule (4 predictor variables) was more complex than American Joint Committee on Cancer stage and tumor grade. Conclusions: American Joint Committee on Cancer stage combined with tumor grade is the simplest, most accurate cancer specific mortality prediction rule after primary tumor excision for penile squamous cell carcinoma. This method is also more accurate than 2 previous cancer specific mortality prediction rules. [ABSTRACT FROM AUTHOR]

Purpose: Radical prostatectomy is the standard of care for localized prostate cancer. Numerous previous reports show the relationship between surgical experience and various outcomes. We examined the effect of surgical experience on complications and transfusion rates, and determined individual surgeon annual caseload trends in a contemporary radical prostatectomy cohort. Materials and Methods: We analyzed annual caseload temporal trends in 34,803 patients who underwent surgery between 1999 and 2008 in Florida. Logistic regression models controlled for clustering among surgeons addressed the relationship of surgical experience, defined as the number of radical prostatectomies done since January 1, 1999 until each radical prostatectomy, with complications and transfusions. Results: During the study period the proportion of surgeons in the high annual caseload tertile (24 radical prostatectomies or greater yearly) and the proportion of patients treated by those surgeons increased from 5% to 10% and from 20% to 55%, respectively. Conversely complication and transfusion rates decreased from 14.3% to 9.2% and 12.6% to 6.9%, respectively. Radical prostatectomies done by surgeons in the high surgical experience tertile (86 or greater radical prostatectomies) decreased the risk of any complication by 33% and of any transfusion by 30% vs those in patients operated on by surgeons in the low surgical experience tertile (27 or fewer radical prostatectomies). Conclusions: The proportion of surgeons in the high annual caseload tertile and the proportion of patients treated by these surgeons steadily increased during the last decade. Complication and transfusion rates decreased with time. The implications of these encouraging findings may result in improved outcomes in patients with surgically managed prostate cancer. [Copyright &y& Elsevier]

Purpose: A positive surgical margin after radical prostatectomy is considered an adverse prognostic feature. However, few groups have explored the potential interaction between surgical margin status and other cancer characteristics, specifically pathological stage. We addressed the first degree of interaction between positive surgical margins and other established adverse predictors of biochemical recurrence after radical prostatectomy. Materials and Methods: We used univariate and multivariate analysis to test the effect of surgical margin status on biochemical recurrence in 4,490 patients treated at a single institution between 1992 and 2008. We systematically tested all first-degree interactions between surgical margin status, and pretreatment prostate specific antigen, pT and pN stage, and radical prostatectomy Gleason sum. If interactions were significant, we quantified the effect on the biochemical recurrence rate. Results: Overall 850 patients (18.9%) had positive surgical margins. In those with negative vs positive surgical margins the 5-year biochemical recurrence-free survival rate was 95% vs 83%, 74% vs 62% and 47% vs 29% for pT2, pT3a and pT3b disease, respectively. In multivariate models only the pT stage-surgical margin status interaction achieved independent predictor status (p = 0.003). Negative vs positive surgical margin multivariate HRs were 1 vs 2.9, 2.3 vs 4.3 and 4.1 vs 5.6 in pT2, pT3a and pT3b cases, respectively. Conclusions: Compared to negative surgical margins, positive surgical margins increase the absolute biochemical recurrence 5-year rate by 12% to 18%. More importantly, positive surgical margins may substantially worsen the prognosis beyond that of the original pathological disease stage. [Copyright &y& Elsevier]

Purpose: To date no study to our knowledge has compared cancer control outcomes of segmental ureterectomy relative to nephroureterectomy, which represents the standard of care for ureteral transitional cell carcinoma. We compared cancer specific mortality rates according to surgery type (nephroureterectomy vs segmental ureterectomy) in a large population based cohort of patients with ureteral transitional cell carcinoma. Materials and Methods: Our analyses involved 2,044 patients with pathological T1–T4 N0M0 ureteral transitional cell carcinoma from the Surveillance, Epidemiology and End Results database. Survival plots and Cox regression models compared cancer specific mortality after segmental ureterectomy, or nephroureterectomy with or without bladder cuff removal. Covariates consisted of pathological stage and grade, age, race, gender and year of surgery. Results: Median followup of censored patients was 30.0 months. Overall 569 (27.8%) patients underwent segmental ureterectomy vs 1,222 (59.8%) nephroureterectomy with bladder cuff removal and 253 (12.4%) nephroureterectomy without bladder cuff removal. At 5 years cancer specific mortality-free rates for segmental ureterectomy vs nephroureterectomy with bladder cuff removal vs nephroureterectomy without bladder cuff removal were 86.6% vs 82.2% vs 80.5%, respectively (all pairwise log rank comparisons p ≥0.05). On univariable and multivariable analyses of the entire cohort, as well as after stratification according to pT1–2 vs pT3–4 stage, the type of surgery (segmental ureterectomy vs nephroureterectomy with bladder cuff removal vs nephroureterectomy without bladder cuff removal) failed to affect cancer specific mortality rates (p ≥0.2). Conclusions: In patients with ureteral transitional cell carcinoma segmental ureterectomy does not undermine cancer control outcomes relative to nephroureterectomy (with or without bladder cuff removal). Therefore, segmental ureterectomy may be offered to virtually all patients with ureteral transitional cell carcinoma when it is technically feasible, which also includes carefully selected patients with T3 or even T4 lesions. [Copyright &y& Elsevier]

Purpose: Inguinal hernia is considered one of the major morbidities after radical prostatectomy. We compared inguinal hernia repair rates in patients treated with radical prostatectomy for localized prostate cancer relative to those of 2 nonsurgically treated groups of patients, namely individuals who underwent prostate biopsy or transurethral resection of the prostate, and a surgically treated group of patients who underwent pelvic lymph node dissection, within a large North American database. Materials and Methods: Using the Quebec Health Plan database we identified 5,478 men treated with radical prostatectomy vs 6,933, 7,697 and 532 who underwent prostate biopsy, transurethral resection of the prostate or pelvic lymph node dissection, respectively, between 1990 and 2000. Kaplan-Meier plots graphically explored inguinal hernia repair rates. Univariable and multivariable Cox regression analyses examined variables associated with inguinal hernia repair after either group. Covariates consisted of age, year of treatment and the Charlson comorbidity index. Results: The 1, 2, 5 and 10-year inguinal hernia repair rates after radical prostatectomy were 4.4%, 6.7%, 11.7% and 17.1%, respectively. For the same points after prostate biopsy the rates were 1.7%, 2.9%, 6.1% and 9.8% vs 1.7%, 2.6%, 5.5% and 9.2%, respectively, after transurethral resection of the prostate, and 0.8%, 2.4%, 4.9% and 9.3% after pelvic lymph node dissection (pairwise log rank tests p <0.001). On multivariable Cox regression analyses the rate of inguinal hernia repair was 1.9, 2.1 and 1.7-fold higher for patients who underwent radical prostatectomy vs prostate biopsy, transurethral resection of the prostate and pelvic lymph node dissection, respectively (all p <0.001). Conclusions: Radical prostatectomy predisposes to higher inguinal hernia repair rates than in the 3 examined control groups. A higher rate of inguinal hernia repair after radical prostatectomy warrants consideration in the discussion of radical prostatectomy perioperative complications. [Copyright &y& Elsevier]

Purpose: The polyamines spermine and spermidine are ubiquitous polycationic structures which are essential for cell proliferation and differentiation. Circulating polyamines, spermine and spermidine, represent valuable prognostic markers in prostate cancer, acute leukemia and supratentorial malignant glioma. We tested whether spermine and spermidine could improve the prognostic ability of several established predictors of cancer specific mortality after partial or radical nephrectomy for renal cell carcinoma. Materials and Methods: Testing was performed on 399 patients with stages T1–4, N0–2, M0–1 renal cell carcinoma who were treated with radical or partial nephrectomy at a single institution between 1990 and 2007. Univariable and multivariable Cox regression models tested the prognostic ability of spermine and spermidine levels in cancer specific mortality predictions. Covariates consisted of TNM stage, Fuhrman grade, tumor size and symptom classification. Harrell''s concordance index (c-index) quantified accuracy and 200 bootstrap resamples were used to correct for overfit bias. Results: The 5-year cancer specific mortality-free survival of patients with spermine levels 3 or less, 3.1 to 8, 8.1 to 13 and greater than 13 nmol/8×109 erythrocytes was 88.8%, 75.8%, 40.2% and 21.8%, respectively. Similarly the 5-year cancer specific mortality-free survival of patients with spermidine levels 12 or less, 12.1 to 15, 15.1 to 21 and greater than 21 nmol/8×109 erythrocytes was 79.0%, 56.6%, 53.2% and 27.4%, respectively. On multivariable analyses addressing cancer specific mortality after surgery spermine (p = 0.007) and spermidine (p = 0.04) achieved independent predictor status. Consideration of spermine and spermidine also improved the accuracy of established cancer specific mortality predictors by 2.2% (p <0.001). Conclusions: Spermine and spermidine may significantly improve the prognostic value of established cancer specific mortality predictors after partial or radical nephrectomy for all stages of renal cell carcinoma. Independent external validation of our findings is required. [Copyright &y& Elsevier]

Purpose: Fuhrman grade represents a key determinant of the natural history of small renal masses that represent renal cell carcinoma. We tested whether renal mass biopsy prediction of Fuhrman grade in the nephrectomy specimen could be safely substituted for by an accurate statistical model. To date the best available model has shown poor accuracy (55.6%), which is close to flipping a coin (50%) and clearly inadequate for use in clinical practice. Materials and Methods: We identified 1,139 patients with T1aN0M0 renal cell carcinoma treated with partial or radical nephrectomy at 11 participating institutions from 1989 to 2004. This cohort was used in univariate and multivariate logistic regression models predicting high Fuhrman grade (III–IV) at nephrectomy. Predictors included age at diagnosis, gender, tumor size and symptom classification. Multivariate logistic regression coefficients were used to generate a nomogram. Results: The rate of Fuhrman grade III–IV in patients with T1aN0M0 renal cell carcinoma was 12.3%. Stratifying patients with Fuhrman grade III–IV by age, gender, histological subtypes and sample size failed to reveal statistically significant differences. On univariate analysis predicting Fuhrman grade III–IV at nephrectomy only tumor size was a statistically significant predictor (p = 0.05). The most accurate multivariate nomogram for Fuhrman grade III–IV prediction was 58.3% (95% CI 57.8–58.9) accurate. Of all tested predictors only tumor size achieved independent predictor status (p = 0.009). Conclusions: Our analysis derived in European patients shows that statistical models cannot safely replace renal mass biopsy based prediction of Fuhrman grade III–IV at nephrectomy. Our findings corroborate a report from the United States in which a similar model had 55.6% accuracy. Jointly the studies indicate that statistical models are unreliable and cannot safely be substituted for renal mass biopsy in North American or European patients. [Copyright &y& Elsevier]

Purpose: Conditional survival implies that on average long-term cancer survivors have a better prognosis than do newly diagnosed individuals. We explored the effect of conditional survival in renal cell carcinoma. Materials and Methods: We studied 3,560 patients with renal cell carcinoma of all stages treated with nephrectomy. We applied conditional survival methodology to a previously reported posttreatment nomogram predicting survival after nephrectomy for patients with renal cell carcinoma stage I to IV. We used the same predictor variables that were integrated in the original multivariable Cox regression models, namely TNM stage, Fuhrman grade, tumor size and symptom classification. To validate the conditional survival nomogram we used an independent cohort of 3,560 patients from 15 institutions. Results: The 5-year survival of patients immediately after nephrectomy was 74.2%, which increased to 80.4%, 85.1%, 90.6% and 89.6% at 1, 2, 5 and 10 years after nephrectomy, respectively. The predicted probabilities varied by as much as 50% when, for example, predictions of renal cell carcinoma specific mortality at 10 years were made after nephrectomy vs 5 years later. Within the external validation cohort the accuracy of the conditional nomogram was 89.5%, 90.5%, 88.5% and 86.7% at 1, 2, 5 and 10 years after nephrectomy. Conclusions: We developed (2,530) and externally validated (3,560) a conditional nomogram for predicting renal cell carcinoma specific mortality that allows consideration of the length of survivorship. Our tool provides the most realistic prognosis estimates with high accuracy. [Copyright &y& Elsevier]

Purpose: The prognostic significance of renal pelvis vs ureteral upper urinary tract urothelial carcinoma tumor location is controversial. We assessed the prognostic significance of upper urinary tract urothelial carcinoma tumor location in a large, population based data set. Materials and Methods: Our analyses relied on 2,824 patients treated with nephroureterectomy for upper urinary tract urothelial carcinoma within 9 SEER registries between 1988 and 2004. Univariable and multivariable models tested the effect of tumor location on cancer specific mortality rates. Covariates consisted of age, race, SEER registry, gender, type of surgery (nephroureterectomy with vs without bladder cuff removal), pT stage, pN stage, grade and year of surgery. Results: Relative to ureteral tumors renal pelvis tumors were of higher stage (T3/T4 disease 38.4% vs 57.9%, p <0.001) and had a higher rate of lymph node metastases (6.0% vs 9.8%, p = 0.003) at nephroureterectomy. The respective 5-year cancer specific mortality-free survival estimates were 81.0% vs 75.5% (p = 0.007). However, after multivariable adjustment tumor location failed to reach independent predictor status of cancer specific mortality (p = 0.8). Conclusions: To our knowledge this is the largest cohort in which the impact of upper urinary tract urothelial carcinoma tumor location on cancer specific mortality was examined. At nephroureterectomy renal pelvis tumors had significantly more advanced T and N stages compared to ureteral tumors. However, after adjustment for stage, grade and other covariates tumor location did not independently predict cancer specific mortality. Thus, the biological behavior of renal pelvis vs ureteral tumors is the same after nephroureterectomy as long as stage, grade, and other patient and tumor characteristics are accounted for. [Copyright &y& Elsevier]

Purpose: A recent multi-institutional analysis of 995 patients treated for renal cell cancer questioned the relationship between tumor size and the synchronous metastasis rate. We revisited the hypothesis that metastatic potential is unrelated to tumor size. Materials and Methods: We tested the relationship between tumor size and synchronous metastasis in 22,204 patients with T1a and T1b renal cell cancer diagnosed and/or treated with nephrectomy for clear cell, papillary or chromophobe histological subtypes in 1 of 9 Surveillance, Epidemiology and End Results registries between 1988 and 2004. Results: In the study population the synchronous metastasis rate was 9.6%, including 5.6% vs 14.2% for T1a vs T1b. Stratification by 1 cm tumor size intervals revealed that the rate increased with increasing tumor size, that is 4.8% at 1.0 cm or less, 4.2% at 1.1 to 2.0 cm, 4.9% at 2.1 to 3.0 cm, 7.1% at 3.1 to 4.0 cm, 12.1% at 4.1 to 5.0 cm, 13.3% at 5.1 to 6.0 cm and 18.4% 6.1 to 7.0 cm (chi-square trend p <0.001). Cubic spline analysis showed that tumor size was virtually linearly related to the synchronous metastasis rate. Stratification by histological subtype in patients treated with nephrectomy revealed that clear cell renal cell cancer was most frequently associated with synchronous metastasis. Finally, tumor size was an independent predictor of synchronous metastasis in multivariate regression models adjusted for age, gender, histological subtype and year of diagnosis quartiles. Conclusions: Our study confirms that tumor size is an important determinant of the likelihood of synchronous metastasis in patients with T1a and T1b renal cell cancer. The synchronous metastasis rate directly increases with increasing tumor size. Even patients with small renal masses are at risk for synchronous metastasis and patients with clear cell renal cell cancer are at highest risk. [Copyright &y& Elsevier]

Purpose: Benign prostatic hyperplasia affects 60% of men at the age of 60 years. Transurethral resection of the prostate is the gold standard of therapy. We assessed the 30-day mortality rate after transurethral resection of the prostate for benign prostatic hyperplasia, identified risk factors related to 30-day mortality and developed a model that discriminates among individual 30-day mortality risk levels. Materials and Methods: We performed development (7,362) and external validation (7,362) of a multivariable logistic regression model predicting the individual probability of 30-day mortality after transurethral resection of the prostate based on an administrative data set (Quebec Health Plan) of 14,724 patients 43 to 99 years old treated between January 1, 1989 and December 31, 2000. Results: Overall 30-day mortality occurred in 58 patients (0.4%) undergoing transurethral resection of the prostate. On univariable analyses increasing age (p <0.001) and increasing Charlson comorbidity index (p <0.001) were statistically significant predictors of 30-day mortality after transurethral resection of the prostate. Conversely annual surgical volume was not. On multivariable analyses age (p <0.001) and Charlson comorbidity index (p <0.001) reached independent predictor status. The accuracy of the age and Charlson comorbidity index based nomogram that predicts the individual probability of 30-day mortality after transurethral resection of the prostate was 83% in the external validation cohort. Conclusions: Age and Charlson comorbidity index are important determinants of 30-day mortality after transurethral resection of the prostate. The combination of these parameters allows an 83% accurate prediction of individual 30-day mortality risk after transurethral resection of the prostate. Despite limitations such as the need for additional external validations and possibly the need for inclusion of clinical parameters, the use of the current model is warranted for the purpose of informed consent before transurethral resection of the prostate and/or for patient counseling. [Copyright &y& Elsevier]

Purpose: Large variability exists in the rates of perioperative mortality after cystectomy. Contemporary estimates range from 0.7% to 5.6%. We tested several predictors of perioperative mortality and devised a model for individual perioperative mortality prediction. Materials and Methods: We relied on life tables to quantify 30, 60 and 90-day mortality rates according to age, gender, stage (localized vs regional), grade, type of surgery (partial vs radical cystectomy), year of cystectomy and histological bladder cancer subtype. We fitted univariable and multivariable logistic regression models using 5,510 patients diagnosed with bladder cancer and treated with partial or radical cystectomy within 4 SEER (Surveillance, Epidemiology, and End Results) registries between 1984 and 2004. We then externally validated the model on 5,471 similar patients from 5 other SEER registries. Results: At 30, 60 and 90 days the perioperative mortality rates were 1.1%, 2.4% and 3.9%, respectively. Age, stage and histological subtype represented statistically significant and independent predictors of 90-day mortality. The combined use of these 3 variables and of tumor grade resulted in the most accurate model (70.1%) for prediction of individual probability of 90-day mortality after cystectomy. Conclusions: The accuracy of our model could potentially be improved with the consideration of additional parameters such as surgical and hospital volume or comorbidity. While better models are being developed and tested we suggest the use of the current model in individual decision making and in informed consent considerations because it provides accurate predictions in 7 of 10 patients. [Copyright &y& Elsevier]

Purpose: The Partin tables were updated in 2007. However, to our knowledge their accuracy and performance characteristics have not been confirmed in an external validation cohort. Materials and Methods: We examined the discrimination and calibration properties of the 2007 Partin tables in 1,838 men treated with radical prostatectomy between 2001 and 2005 at Cleveland Clinic Foundation. The ROC derived AUC and the Brier score were used to quantify the discriminant properties of the predictions of the 2007 Partin tables for extraprostatic extension, seminal vesical invasion and lymph node invasion. Loess based calibration plots were used to examine the relationship between the predicted and observed rates of extraprostatic extension, seminal vesical invasion and lymph node invasion. Results: The rates of extraprostatic extension, seminal vesical invasion and lymph node invasion were 26.9%, 5.5% and 1.8%. The accuracy of extraprostatic extension, seminal vesical invasion and lymph node invasion prediction was 71%, 80% and 75% according to the AUC method, and 0.176, 0.051 and 0.037 according to the Brier score, respectively. Extraprostatic extension predictions between 0% and 25%, and lymph node invasion predictions between 0% and 5% correlated well with observed extraprostatic extension and lymph node invasion rates, respectively. Conversely a suboptimal correlation was recorded between predicted and observed seminal vesical invasion rates as well as between predicted and observed rates of extraprostatic extension and lymph node invasion for predicted extraprostatic extension and lymph node invasion values above 25% and 5%, respectively. Conclusions: In this examined validation cohort the overall accuracy (AUC) of the Partin tables was comparable to results reported in the original 2007 development cohort. However, performance characteristics indicate that predictions within specific probability ranges should be interpreted with caution. [Copyright &y& Elsevier]

Purpose: Ejaculatory disorders will be experienced in most men who are treated for localized prostate cancer. Baseline rates of ejaculatory disorders are unknown in men at risk for prostate cancer. Therefore, we explored the prevalence of those disorders and associated bother in men without evidence of prostate cancer who participated in an annual prostate cancer screening event. Materials and Methods: A cohort of 1,273 men without clinical evidence of prostate cancer completed the self-administered Danish Prostate Symptom Score for sexual dysfunction. This questionnaire quantifies the rate of reduced ejaculatory volume, ejaculatory pain and the rate of coexistent erectile dysfunction. Results: Mean age was 57.6 years (range 40 to 89). Of all men 46% (563) had reduced ejaculatory volume and 66% (356) of affected men were bothered by this condition. Ejaculatory pain was reported in 11% (134) and 89% (118) of these men reported associated bother. Finally, 45% (554) reported erectile dysfunction and 73% (403) reported associated bother. Reduced ejaculatory volume was associated with erectile dysfunction (p <0.001) and advanced age (p <0.001). Ejaculatory pain was not associated with one of these variables. Conclusions: Virtually all men will be affected by ejaculatory disorders after definitive treatment for localized prostate cancer. Therefore, it is important to observe that half of these individuals already have underlying reduced ejaculatory volume before treatment. Moreover, 1 of 10 men will be affected by ejaculatory pain. Both disorders are a significant source of bother and should be considered when treatment related quality of life is assessed. [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: We report on 25-year cancer control and survival outcomes after radical prostatectomy in a single center series of patients treated during a 40-year period. Materials and Methods: Between 1954 and 1994, 787 consecutive patients underwent radical prostatectomy at Virginia Mason Medical Center in Seattle, Washington. Kaplan-Meier 25-year probabilities of prostate cancer specific, overall, prostate specific antigen progression-free, local and distant progression-free survival were determined. Multivariate Cox regression models addressed prostate cancer specific mortality. Results: Prostate cancer specific survival, overall survival, prostate specific antigen progression-free survival, local and distant progression-free survival ranged from 99.0% to 81.5%, 93.5% to 19.3%, 84.8% to 54.5%, 95.3% to 87.8% and 95.9% to 78.2%, respectively. In univariate analyses pathological stage, surgical margin status, pathological Gleason sum, delivery of hormonal therapy and radiotherapy represented statistically significant predictors of prostate cancer specific mortality (all p ≤0.001). In multivariate analyses only Gleason sum (p = 0.03) and delivery of hormonal therapy (p <0.001) remained significant. Conclusions: This is one of the most mature radical prostatectomy series. It demonstrates that long-term biochemical cancer control outcomes after radical prostatectomy might be suboptimal. However, local and distant control outcomes are excellent, and cancer specific mortality is minimal even 25 years after surgery. [Copyright &y& Elsevier]

Purpose: We have previously have reported a tree structured regression model for predicting SS-ECE. Others recently reported a logistic regression based SS-ECE nomogram. We developed a nomogram and compared the performance and discriminant properties of the tree regression and the nomogram in a contemporary cohort of European patients treated with radical retropubic prostatectomy. Materials and Methods: The cohort consisted of 1,118 patients with pretreatment prostate specific antigen 0.1 to 73.2 ng/ml (median 6.6). Each of the 2,236 prostate lobes was considered separately. Clinical stage, pretreatment PSA, biopsy Gleason sum, percent positive cores and percent cancer in the biopsy specimen were used as predictors in a logistic regression model predicting SS-ECE. Regression coefficients were then used to generate an SS-ECE nomogram. Performance characteristics and discriminant properties of the previously published tree regression were also tested in the same cohort. For internal validation and to decrease overfit bias 200 bootstrap re-samples were applied to accuracy estimates for each method. Results: ECE was present in 303 of 1,118 radical retropubic prostatectomy specimens (27%) and in 385 lobes (17%). In logistic regression models all variables were statistically significant multivariate predictors of SS-ECE except the percent of positive biopsy cores (p = 0.7). Bootstrap corrected predictive accuracy of the SS-ECE nomogram was 0.840 vs 0.700 for the tree regression model. Conclusions: Logistic regression based nomogram predictions of SS-ECE are highly accurate and represent a valuable aid for assessing the risk of ECE prior to surgery. [Copyright &y& Elsevier]