Urologic Oncology: Seminars and Original Investigations - Articles in Press

The prognostic value of transrectal ultrasound guided biopsy in patients over 70 years old with a prostate specific Antigen (PSA) level ≤15 ng/ml and normal digital rectal examination: A 10-year prospective follow-up study of 427 consecutive patients - Corrected Proof

2012-05-17

Abstract: Introduction: As a urologist, it is common to review a patient above the age of 70 being referred to a prostate assessments clinic with an elevated PSA. We evaluate the prognosis of these patients clinically as there is no international consensus on the exact PSA cutoff level or a single international guideline as to when these patients should be offered a prostate biopsy. Patients and methods: On receiving ethic committee approval, we recruited 427 consecutive patients aged 70 years and above referred with a PSA of ≥4 ng/ml, from January 1996 to December 2000, into our study. All patients were assessed, examined with a digital rectal examination (DRE) of the prostate, and a subsequent prostate biopsy. We followed up on their histologic diagnosis for up to 10 years and analyzed their outcome. The main outcome measures were disease-free survival and overall survival, stratified according to the PSA level (≤15 vs. >15 ng/ml) and DRE findings (normal vs. sbnormal). Results: There was a statistically significant difference in the overall survival (P value < 0.011) and disease specific survival (P value < 0.0001) of cancer patients with a PSA was >15 ng/ml and an abnormal DRE. However, in patients with a PSA ≤15 ng/ml and normal DRE, the incidence of cancer was low and they had no disease-specific or overall survival benefit. Conclusions: A policy of deferring prostate biopsy in patients with a PSA ≤15 ng/ml and normal DRE (Group A) would significantly decrease the need of unnecessary prostate biopsies. Within this group, patients did not have any survival advantage compared with those without cancer. We conclude that up to 20% of the prostate biopsies performed in this age group could have been avoided.

Fas expression in nephrectomized, non-cancerous specimens predicts post-nephrectomy chronic kidney disease progression in patients with renal and upper urinary tract malignancies - Corrected Proof

2012-05-17

Abstract: Objectives: Despite the surgical curability of renal cell carcinoma (RCC) and upper urinary tract urothelial carcinoma (UUT-UC), post-nephrectomy chronic kidney disease (CKD) continues to be a cause of concern. We investigated the correlation between the expression of apoptotic regulatory molecules in the nephrectomized, noncancerous cortex, as well as CKD progression and CKD-related mortality. Materials and methods: Fas and Bcl-2 mRNA and protein expression in surgically resected specimens from 100 patients with RCC and UUT-UC were determined. The estimated glomerular filtration rates (eGFR) were determined sequentially before surgery and up to 5 years after surgery. The relationships between CKD progression, the expression of these molecules in the renal cortex, and the clinical characteristics were analyzed. Results: The mean 1-year postoperative percent eGFR decrease was 30.2 (Standard deviation [SD]: 15.2). The 1-year postoperative percent eGFR decrease greater than the approximate value of mean ± SD (45) was categorized as severe renal functional deterioration (SRFD). Glomerular Fas protein expression and a Fas/β-actin mRNA ratio >0.3 were independent predictors for SRFD. Significantly increased mortality rates due to cardiovascular events were indicated by glomerular Fas protein expression, Fas mRNA levels >0.3, and SRFD. No significant change in Bcl-2 levels was observed. Conclusions: This study is the first report to demonstrate the significance of Fas expression in the nephrectomized normal cortex as a predictor of post-nephrectomy CKD progression. The results from nephrectomized kidney showed that the natural course of renal function in the remaining kidney may be affected not only by Fas-induced glomerular cell apoptosis but also by the total amount of Fas mRNA in cortical cells.

Simultaneous progression of oxidative stress, angiogenesis, and cell proliferation in prostate carcinoma - Corrected Proof

2012-05-17

Abstract: Aim: To understand the association between markers of oxidative stress, levels of vascular endothelial growth factor (VEGF), and cell proliferation index in relation to disease progression, clinical stage, and cytologic grade in pathophysiology of prostate carcinoma. Patients and methods: Case control study comprised of 40 prostate carcinoma patients along with 40 age- and sex-matched healthy subjects as controls. Levels of 8-hydroxy-2-deoxy guanosine, protein carbonyl, and malondialdehyde along with total antioxidant status were measured to study the oxidative stress status in the study subjects. Angiogenesis was evaluated by studying the VEGF level and cell proliferation index. Results: The levels of markers of oxidative stress along with VEGF and cell proliferation index were found to be significantly higher with significantly decreased levels of antioxidant activity in the study subjects in comparison with healthy controls. The results indicate oxidative stress, angiogenesis, and cell proliferation activity increase progressively with the increase in staging and progression of disease. Conclusions: Oxidative stress parameters, angiogenesis, and cell proliferation activity point clearly that with the progression of oxidative stress there is a simultaneous progression of angiogenesis, regulation and control of endothelial cell proliferation in relation to disease progression, clinical stage, and cytologic grade in the pathophysiology of prostate carcinoma.

Presence of positive surgical margin in patients with organ-confined prostate cancer equals to extracapsular extension negative surgical margin. A plea for TNM staging system reclassification - Corrected Proof

2012-05-17

Abstract: Background: To test the hypothesis that patients with pT2 and positive surgical margins (SM) have a similar biochemical-recurrence (BCR) risk to patients with pT3a, and negative SM. Moreover, we examined the effect of incorporating positive SM as a higher stage on the discrimination accuracy of the current TNM staging system. Materials and methods: We evaluated 1,503 prostate cancer patients treated with radical prostatectomy, between 1998 and 2010. Only individuals with pT2N0 or pT3aN0, without neoadjuvant and/or adjuvant therapy, were included. Cox regression analyses tested the relationship between SM status (negative [R0] vs. positive [R1]) and BCR rate, after stratification according to T stage. Predictive accuracy of the current T stage and of a novel T stage, which consider positive SM as a higher stage, was quantified with Harrell's concordance index. Results: Positive SM rate was 20.3%. The 5-year BCR rates were 96%, 82%, 78%, and 62% for patients with, respectively, pT2R0, pT2R1, pT3aR0, and pT3a1 (all P ≤ 0.03). In multivariable analyses, the BCR rate was 3.6-, 2.5-, and 6.0-fold higher (all P < 0.001) in patients with, respectively, pT2R1, pT3aR0, and pT3aR1 stage relative to patients with pT2R0 stage. The maximum univariable (14.1%) and multivariable (6.9%) discrimination accuracy gains were observed, when tumor stage was stratified into pT2R0 vs. pT2R1/pT3R0 vs. pT3R1. Conclusions: The presence of positive SM at radical prostatectomy (RP) specimen substantially increases the BCR risk. Patients with pT2R1 have similar BCR risk to patients with pT3aR0. Considering these patients as 1 category substantially improves the discrimination accuracy of the current TNM staging system.

Muscle-invasive bladder cancer developing after nephroureterectomy for upper urinary tract urothelial carcinoma - Corrected Proof

2012-05-17

Abstract: Objectives: To evaluate the risk factors and prognosis of muscle-invasive bladder cancer (MIBC) developing after nephroureterectomy for upper urinary tract urothelial cell carcinoma (UUT-UC). Materials and methods: We reviewed the medical records of 422 patients who underwent nephroureterectomy for UUT-UC between 1990 and 2010, and identified 173 (40.9%) with intravesical recurrence and 28 (6.6%) with MIBC. We evaluated the clinicopathologic features, risk factors, and cancer-specific survival (CSS) using the Kaplan-Meier method and the Cox proportional hazards regression models. Results: The median intervals from nephroureterectomy to intravesical recurrence and the development of MIBC were 8 and 17 months, respectively. On multivariate analysis, the pathologic stage (≥pT3 vs. Ta/T1, HR 5.03, P = 0.001) and ureteral tumor location (HR 2.79, P = 0.011) were independent risk factors for the development of MIBC, whereas a history of previous or concomitant bladder tumor was the only significant risk factor for intravesical recurrence. The probability of developing MIBC 5 years after nephroureterectomy was 12.6% in patients with 1 risk factor and 20.6% in patients with both risk factors. Patients with MIBC had significantly worse CSS than those without MIBC (P = 0.004), whereas CSS rates were similar in patients with and without intravesical recurrence (P = 0.593). However, stratification analysis for matching pathology revealed that CSS rates were not significantly different in patients with pT2 or higher stage of UUT-UC. Conclusions: Approximately 5% of the patients developed MIBC after nephroureterectomy with a median interval of 17 months. Patients with advanced pathologic stage (≥pT3) and a ureteral tumor location are at increased risk of developing MIBC after nephroureterectomy.

Preoperative estimated glomerular filtration rate predicts overall mortality in patients undergoing radical prostatectomy - Corrected Proof

2012-05-14

Abstract: Background: Assessment of overall health is a critical component in the evaluation of patients presenting with clinically localized prostate cancer. Estimated glomerular filtration rate (eGFR) has been associated with increased risk of cardiovascular and overall mortality. Therefore, the objective of our study was to evaluate the impact of baseline renal function on oncologic outcomes and overall survival following radical prostatectomy. Materials and methods: We identified 10,099 patients who underwent radical prostatectomy at our institution from 1990 to 2004 with a preoperative serum creatinine available for analysis. eGFR was calculated by the chronic kidney disease-epidemiology formula (CKD-EPI) and reported as ml/min per 1.73 m2. Patients were then classified according to their eGFR: <30, 30–59, 60–89, 90–119, and 120–150 ml/min/1.73 m2. Multivariate Cox proportional hazard regression models were used to analyze the impact of eGFR on postoperative outcomes. Results: At the time of surgery, 25 patients (0.1%) had an eGFR <30 ml/min/1.73 m2, 2,398 (23.7%) between 30 and 60, 7,097 (70.3%) between 60 and 90, and 605 (6.0%) patients had an eGFR >90. eGFR was not associated with oncologic outcomes, including biochemical recurrence, systemic progression or cancer-specific survival (P > 0.05 for all). However, eGFR was strongly associated with all-cause mortality and non-prostate cancer death. On multivariate analysis, after controlling for age, BMI, prostate-specific antigen doubling time (PSA), Gleason score, and clinical stage, eGFR remains a statistically significant predictor of all-cause mortality. Conclusions: Assessment of eGFR is an important metric in the overall evaluation of patient health and should be considered in combination with patient age and other medical comorbidities when selecting the initial treatment of prostate cancer. While prostate cancer-specific outcomes do not appear to be impacted by renal function, overall survival is decreased in those with lower and higher than normal eGFR.

Morbidity and costs of salvage vs. primary radical prostatectomy in older men - Corrected Proof

2012-05-11

Abstract: Objectives: Salvage radical prostatectomy (RP) is performed with curative intent following post-radiotherapy recurrence for prostate cancer. While single-center salvage RP outcomes appear promising, little is known about outcomes in the community setting in elderly men. We sought to evaluate utilization, outcomes, and costs of salvage RP vs. primary RP in older men. Materials and methods: Surveillance, Epidemiology and End Results-Medicare linked data from 1992 to 2007 was used to identify 18,317 men aged 65 years or older who underwent RP from 2002 to 2007. Propensity score analyses were used to compare outcomes and costs for primary vs. salvage RP. Results: Salvage RP was rare, accounting for 0.5% of RP. Men undergoing salvage vs. primary RP were older, white, and less likely to undergo CT, bone scan and prostate biopsy preoperatively (P < 0.05 for all). In adjusted analyses, salvage vs. primary RP was associated with increased 30-day complications (60.1% vs. 22.7%, P < 0.01), lengths of stay (mean 7 vs. 3 days, P < 0.01), and hospital readmissions within 30 days (30.4% vs. 5.7%, P < 0.01). The odds of death within 90 days were higher for salvage vs. primary RP (OR 26.7, 95% CI 12.9–55.1, P < 0.01). The median expenditure for salvage RP within 6 months postoperatively was almost twice that for primary RP (US$30,881 vs. US$12,431, P < 0.01). Conclusions: Metastatic workup was performed less frequently before salvage vs. primary RP, and morbidity and mortality for salvage RP was high relative to primary RP. Given the morbidity and high cost of salvage RP, guidelines for patient selection and selective referral may optimize outcomes, especially in older men.

The characteristics of bladder cancer after radiotherapy for prostate cancer - Corrected Proof

Michael R. Abern, Annie M. Dude, Matvey Tsivian, Christopher L. Coogan — 2012-05-11

Abstract: Objectives: Prostate radiotherapy (RT) has been associated with an increased risk of bladder cancer (CaB). However it is unknown how prior RT affects the stage, grade, and histology of secondary CaB. While irradiated patients have adverse surgical outcomes, how RT affects survival is also unknown. We sought to determine how RT for prostate cancer (CaP) affects the characteristics and outcomes of secondary CaB. Materials and methods: A retrospective review of 275,200 cases of clinically localized CaP submitted to the Surveillance, Epidemiology, and End Results (SEER) database between 1988 and 2007 was performed. CaP treatment was stratified by radical prostatectomy (RP) alone, RT, or RP + RT. Diagnosis of CaB at least 1 year after CaP, and CaB death were the primary outcomes. The stage, grade, and histology of CaB of patients exposed to RT or RP were compared. A competing risks multivariable survival analysis was performed to determine the effect of RT on CaB-specific mortality. Results: CaP patients treated with any RT were 1.70 times as likely to develop CaB (95% CI 1.57–1.86, P < 0.001) compared with RP alone. CaB in men who had RT were more likely non-urothelial (6.4% vs. 3.8%, P = 0.004), trigonal (6.9% vs. 5.4%, P = 0.012), and carcinoma in-situ (CIS) (9.2% vs. 7.0%, P < 0.001) compared with RP. RT increased CaB-specific mortality (HR = 1.30, P = 0.02), which remained significant when adjusted for CaB features (HR = 1.28, P = 0.05). Conclusions: Patients with localized CaP treated with RT have a higher risk of CaB. CaB after RT is more likely to be located at the trigone and contain CIS. Patients with CaB after RT have decreased cancer-specific survival compared with those undergoing RP alone.

Intravesical valrubicin in patients with bladder carcinoma in situ and contraindication to or failure after cacillus Calmette-Guérin - Corrected Proof

Colin P.N. Dinney, Richard E. Greenberg, Gary D. Steinberg — 2012-05-11

Abstract: Objectives: Evaluate the efficacy and safety of valrubicin for bacillus Calmette-Guérin (BCG)–refractory carcinoma in situ (CIS) of the bladder based on updated phase III pivotal trial efficacy data together with efficacy and safety data from a supportive phase II/III study. Materials and Methods: In a phase II/III open-label study (A9303), BCG refractory/intolerant adults with CIS (≥1 previous course of BCG or could not complete a BCG course owing to toxicity or contraindication) were randomized to receive 6 or 9 weekly intravesical valrubicin (800 mg) instillations. In the pivotal phase III open-label study, BCG-refractory/recurrent adults with CIS (≥2 previous courses of intravesical therapy, including ≥1 BCG course) received 6 weekly intravesical valrubicin (800 mg) instillations. Patients with muscle-invasive disease were excluded. Patients underwent a primary disease evaluation (PDE) at 3 months (∼6 weeks after last dose) that included cytoscopy, biopsy, and cytology. Disease recurrence was monitored at 3-month intervals. Complete response (CR) was defined as no evidence of disease at the PDE (month 3) and follow-up (month 6). Efficacy data from the pivotal trial reflect updated information based on US Food and Drug Administration review. Safety assessments in A9303 included local bladder adverse events (LBAEs) and other adverse events (AEs). Results: Eighty patients enrolled and 78 completed treatment and underwent the PDE in study A9303; in the pivotal trial, the respective numbers were 90 and 87 patients. In study A9303, 39% of patients had received ≥2 previous courses of BCG and 11% had received ≥3 courses vs. 70% and 28%, respectively, in the pivotal trial. In both studies, the CR rate was 18%. In A9303, LBAEs were the most common AEs, reported by 86% of patients during treatment and 45% during follow-up; most treatment-related LBAEs were mild to moderate. 2 serious AEs in 1 patient (azotemia/reflux nephropathy) were judged as definitely or possibly treatment related; none of the patient deaths were judged to be related to valrubicin. Conclusions: Two trials of valrubicin in patients with CIS demonstrate a consistent degree of efficacy in highly pretreated patients (pivotal trial; BCG-refractory patients) and those with fewer previous therapies (A9303; BCG-refractory/intolerant patients).

8q24 and 17q Prostate cancer susceptibility loci in a multiethnic Asian cohort☆ - Corrected Proof

2012-05-07

Abstract: Objectives: Recently, several genome-wide association studies have demonstrated a cumulative association of 5 polymorphic variants in chromosomes 8q24 and 17q with prostate cancer (CaP) risk in Caucasians, particularly those harboring aggressive clinicopathologic characteristics. The purpose of this study was to evaluate the influence of these variants on CaP susceptibility in Singaporean Asian men. Materials and methods: We performed a case-control study in 289 Chinese CaP patients and 412 healthy subjects (144 Chinese, 134 Malays, and 134 Indians), and examined the association of the 5 single nucleotide polymorphisms (SNPs) with CaP. Results: In the healthy subjects, rs16901979 A-allele frequency was highest amongst Chinese (0.32) compared with Malays (0.13; P < 0.0001) or Indians (0.09; P < 0.0001); rs6983267 G-allele was highest in Indians (0.51) compared with Chinese (0.42; P = 0.041) or Malays (0.43; P = 0.077); whereas rs1859962 G-allele frequency was highest amongst Indians (0.56) compared with Chinese (0.40; P = 0.0002) or Malays (0.38; P < 0.0001). Individuals with the rs4430796 TT genotype were at increased CaP risk in the Chinese via a recessive model (odds ratios (OR) = 1.56, 95% CI = 1.04–2.33). Significant associations were observed for rs4430796 TT with Gleason scores of ≥7 (OR = 1.76, 95% CI = 1.14–2.73) and prostate-specific antigen (PSA) levels of ≥10 ng/ml at diagnosis (OR = 1.63, 95% CI = 1.01–2.63), as well as for rs6983267 GG with stage 3–4 CaPs (OR = 1.91, 95% CI = 1.01–3.61). A cumulative gene interaction influence on disease risk, which approximately doubled for individuals with at least 2 susceptibility genotypes, was also identified (OR = 2.18, 95% CI = 1.10–4.32). Conclusions: This exploratory analysis suggests that the 5 genetic variants previously described may contribute to prostate cancer risk in Singaporean men.

Efficacy of docetaxel-based chemotherapy following ketoconazole in metastatic castration-resistant prostate cancer: Implications for prior therapy in clinical trials - Corrected Proof

2012-05-03

Abstract: Objectives: Abiraterone acetate (AA) is a CYP17 inhibitor of androgen synthesis approved for use following docetaxel for metastatic castration-resistant prostate cancer (mCRPC); evaluation in the pre-docetaxel setting is ongoing. Given that the reported efficacy of AA is lower following docetaxel vs. pre-docetaxel, the potential exists for cross resistance given docetaxel's partly androgen receptor targeting activity. The efficacy of docetaxel following ketoconazole (KC), a weaker and nonspecific inhibitor of CYP17, may provide some insights into this potential interaction. We retrospectively evaluated the efficacy of every 3-week docetaxel with prednisone (DP) in mCRPC previously exposed to KC compared to KC-naive patients. Materials and methods: A randomized phase II trial of men with mCRPC treated with DP + AT-101 (bcl-2 inhibitor) vs. DP plus placebo was analyzed. Both arms were combined for analysis as no significant differences were seen. Overall survival (OS), progression-free survival (PFS), objective response (ORR), pain, and prostate-specific antigen (PSA) response rates were estimated with and without prior KC. Cox proportional hazards regression models were used to estimate the effect of covariates on OS. Results: Of 220 evaluable men, 40 (18.2%) received prior KC. The median OS with DP-based therapy of KC-naive patients (18.3 months, 95% CI: 15.0, 24.5) and post-KC patients (17.0 months, 95% CI: 9.9, 20.4) was not statistically different (P = 0.20). After controlling for prognostic classifications, analyses demonstrated consistent trends for worsening of OS after KC, with (hazard ratios (HRs) 1.33–1.46. Similar unfavorable trends were observed for ORR, PSA declines, and PFS. Conclusions: In this hypothesis-generating analysis, patients treated with docetaxel-based chemotherapy following prior KC had numerically and consistently worse outcomes than patients not exposed to prior KC. Although the estimated differences did not attain statistical significance, evaluation of outcomes with docetaxel in particular, and all classes of novel and emerging agents following AA, is of clinical importance, given its more potent androgen synthesis inhibition compared with KC. Drug development should take into account the potential impact of previous therapy.

The risk of biopsy-detectable prostate cancer using the prostate cancer prevention Trial Risk Calculator in a community setting - Corrected Proof

2012-05-03

Abstract: Materials and methods: Risks of prostate cancer (CaP) and high-grade CaP were evaluated using the Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) in an age-stratified random sample of 1,021 Caucasian and African-American men with no previous diagnosis of CaP, aged 55–74 years, residing in King County, WA, USA. Results: Median PCPTRC risks of CaP (high-grade CaP) were 15.6% (1.2%), 18.7% (2.0%), 18.5% (2.2%), and 26.4% (5.1%) for 55–59, 60–64, 65–69, and 70–74-year-old men, respectively; 25.2% of men aged 55–59 had a 25% or greater PCPTRC risk of CaP; this increased to 53.1% in men aged 70–74; 9.4% of men aged 55–59 had a 6% or greater PCPTRC risk of high-grade CaP, increasing to 44.1% in men aged 70–74. Conclusions: PCPTRC risk of CaP in a community of US males is high and confounded with overdetected cancers. In contrast, average community PCPTRC risk of high-grade disease is low and increases gradually by age and may better serve for counseling purposes.

Long-term outcomes of radiotherapy for stage II testicular seminoma–the Mayo Clinic experience - Corrected Proof

Christopher L. Hallemeier, Thomas M. Pisansky, Brian J. Davis, Richard Choo — 2012-04-27

Abstract: Objectives: To report long-term outcomes of patients with stage II testicular seminoma treated with radiotherapy (RT). Materials and methods: A retrospective review was performed of 52 patients who received megavoltage RT for stage II testicular seminoma at Mayo Clinic between 1974 and 2007. Forty-eight patients (92%) had computed tomography staging. Overall survival (OS), relapse-free survival (RFS), and cause-specific survival (CSS) were determined using the Kaplan-Meier method. Major cardiac event (MCE) was defined as myocardial infarction, coronary artery bypass grafting or stenting, or valve replacement. Second malignancy (SM) was defined as biopsy-confirmed malignancy occurring in the RT field. Results: The median patient age at diagnosis was 36 years. Stage was IIA (n = 24), IIB (n = 7), IIC (n = 17), and II not otherwise specified (NOS, n = 4). The median infradiaphragmatic RT dose was 30.7 Gy. Twenty-six patients (50%) received prophylactic mediastinal/supraclavicular (MSCV) RT. The median follow-up was 19 years. Estimates of OS, RFS, and CSS were 94%, 80%, and 96% at 10 years, and 83%, 72%, and 96% at 20 years, respectively. RFS at 10 years for stage IIA, IIB, IIC, and II NOS were 83%, 54%, 81%, and 100%, respectively (log-rank P = 0.21). Ten patients (19%) experienced disease relapse in the MSCV region (n = 7), para-aortic lymph nodes (n = 1), lung (n = 1), or peritoneal cavity (n = 1). Eight patients were successfully salvaged with chemotherapy and/or surgery, while 2 died of seminoma. Risk of MSCV relapse was significantly lower in patients who received MSCV RT vs. those who did not (10-year estimates: 4% vs. 21%, respectively, log-rank P = 0.01). MCE occurred in 10 patients (19%) at a median of 18 years (range 7–30) after RT. SM occurred in 5 patients (10%) at a median of 27 years (range 20–34) after RT. Conclusions: In patients with stage II testicular seminoma treated with RT, relapse in the irradiated site was uncommon. Infradiaphragmatic RT alone was associated with a significant risk of MSCV failure. Most MCE and SM events occurred more than 20 years after RT, highlighting the importance of vigilant long-term follow-up.

The Role of Hypoxia-Inducible Factor-1α and -2α in Androgen Insensitive Prostate Cancer Cells☆ - Corrected Proof

2012-04-27

Abstract: Objectives: The aim of this study was to investigate the effects of induction and knocking down of hypoxia-inducible factor (HIF)-1α and/or -2α on tumor biology in androgen insensitive prostate cancer cell lines. Materials and methods: The induction patterns of HIF-1α and -2α after treatment with ZnSO4 were evaluated in PC3 and DU145 cells. Both cell lines were transfected with siRNA targeted against HIF-1α and/or -2α, and the expression patterns of these 2 HIF isoforms were examined. We next performed cell counting Kit-8 (CCK-8) assays and matrigel invasion assays. Potential additive effects of HIF blockade to chemotherapy (docetaxel) or target agents (sunitinib and sorafenib) were examined. In addition, gene expression changes were determined in ZnSO4-treated DU145 cells using Western blotting. Results: ZnSO4 affected the expression of HIF in a dose-dependent manner. HIF expression was increased within the first 3 hours but then decreased. Cells in which HIF-1α and/or -2α had been knocked down using siRNA showed decreased cell viability. Invasion abilities were increased by ZnSO4 treatment in both cell lines overexpressing HIF. However, invasion potencies were decreased in response to treatment with HIF siRNAs. Blocking HIF prominently augmented the antitumor effects of target agents. The underlying mechanism could be associated with p21, cMET, IGF-1, and GLUT-1. Conclusions: Our results demonstrate that HIF-1α and -2α are important for cell proliferation and invasion ability in prostate cancer. Together, our results indicate that combinations of target agents with HIF knockdown may represent a promising strategy for the treatment of prostate cancer.

Retrospective analysis of survival outcomes and the role of cisplatin-based chemotherapy in patients with urethral carcinomas referred to medical oncologists☆ - Corrected Proof

2012-04-26

Abstract: Objectives: Primary carcinomas of the urethra (PCU) are rare and often advanced when diagnosed. Treatment standards are lacking. We studied treatment response and survival in a cohort of patients with PCU, with emphasis on modern platinum-containing chemotherapy regimens plus surgery for advanced disease. Materials and methods: This was a retrospective chart review of consecutive patients with PCU seen by medical oncologists at our institution over a recent 5-year period. Outcome was measured as best response to chemotherapy. Kaplan-Meier estimates were generated for survival and Cox proportional hazard was used for prognostic factors for survival. Results: The 44 patients (64% women) included had a median age at diagnosis of 66.5 years. The most prevalent histologic subtypes of PCU were squamous cell carcinoma and adenocarcinoma. At diagnosis, 43% already had lymph node-positive [lymph node (LN)+] disease, and 16% had distant metastases. The entire cohort's overall survival (OS) was 31.7 months. The response rate to platinum-containing neoadjuvant chemotherapy was 72%. Twenty-one patients with locally advanced or LN+ PCU underwent chemotherapy plus surgery. Their median OS from chemotherapy initiation was 25.6 months. Four of 9 patients (44%) with LN+ PCU at diagnosis were alive at our review, with a minimum follow-up of more than 3 years. Conclusions: Modern platinum-containing regimens appear to be effective in advanced PCU. Preoperative chemotherapy is associated with prolonged disease-free survival in a subgroup of LN+ cases.

Oncologic outcomes for lymph node-positive urothelial carcinoma patients treated with robot assisted radical cystectomy: With mean follow-up of 3.5 years - Corrected Proof

2012-04-26

Abstract: Purpose: Previous studies have shown robot assisted radical cystectomy (RARC) to have comparable perioperative outcomes to open radical cystectomy. There are few reports that have examined the oncologic results of RARC, specifically with respect to lymph node-positive patients. We report the outcomes of pathologic node-positive patients who have undergone RARC with medium-term follow-up. Materials and methods: A total of 275 patients underwent RARC at 2 institutions for invasive bladder cancer between April 2005 and June 2009. We examined the 50 patients with lymph node-positive disease. Oncologic outcomes, overall, and recurrence-free survival were analyzed and compared with the open literature. Results: Mean (median) clinical follow-up in this cohort was 42 (39.5) months (range 16–75 months). The mean (median) number of lymph nodes (LN) removed was 18 (17.5) (range 5–35), and mean (median) number of positive LN was 3 (2) (range 1–12). Mean lymph node density was 18%. Seventeen (34%) patients had ≤ pT2 disease and 33 (66%) pT3/T4 disease. At this follow-up, 29 patients have recurred, and 22 patients have died of disease. Mean (median) time to recurrence was 10 (9) months. The estimated overall survival at 36 and 60 months was 55%, and 45%, respectively. The recurrence-free survival at 36 and 60 months was 43%, and 39%, respectively. Thirty-three (66%) patients had an LN density <20%. The estimated overall survival at 36 months of patients with a lymph node density of <20% was higher than those with a lymph node density >20%, though the difference was not statistically significant. A total of 58% of patients received chemotherapy in this cohort. The use of chemotherapy was associated with a statistically significant (P = 0.033) improvement in overall survival, with an overall survival of 68% at 36 months compared with 36% for the patients who did not receive any chemotherapy. Conclusions: The oncologic outcomes of patients with lymph node-positive bladder cancer treated with robot assisted radical cystectomy (RARC) compare favorably to previous published studies of open radical cystectomy at medium-term (mean follow-up of 42 months). As our follow-up increases, we expect to continue to accurately define the long-term clinical suitability and oncologic success of this procedure in this high-risk population.

Risk factors for biochemical recurrence following radical perineal prostatectomy in a large contemporary series: A detailed assessment of margin extent and location - Corrected Proof

2012-04-26

Abstract: Objectives: The implications of positive surgical margin (PSM) extent and location during radical perineal prostatectomy (RPP) have not been assessed in a contemporary series. We aimed to examine the incidence, location, and extent of PSM as well as their impact on biochemical recurrence (BCR) following RPP. Materials and methods: A total of 794 patients underwent RPP by a single surgeon between June 1993 and August 2010. Covariates included age, pathologic T stage, pathologic Gleason sum, preoperative PSA, prostate volume, PSM extent, and location. Life table, Kaplan-Meier, and Cox regression analyses assessed predictors of BCR following RPP. Results: PSM were recorded in 162 patients (20.4%); of these, 83 (51.2%) were focal (≤1 mm) whereas 79 (48.8%) were broad (>1 mm). Location of PSM was anterior 10.5%, posterior or lateral 14.8%, bladder neck 23.5%, apical 32.1%, and multifocal 19.1%. At a median follow-up of 54 months, the 5-year BCR-free probability was 90.8% in patients with negative margins, 77.5% in patients with focal PSM, and 47.5% in patients with broad PSM. On multivariable analyses adjusted for age, pathologic T stage, pathologic Gleason sum, preoperative PSA, and prostate volume, broad PSM, (HR = 3.49, P < 0.001) as well as anterior (HR = 3.77, P = 0.003), bladder neck (HR = 2.25, P = 0.01) and multifocal (HR = 3.55, P < 0.001) PSM were independent predictors of BCR. Conclusions: In this study, we present oncologic outcomes following RPP in a large contemporary cohort of patients undergoing RPP. In adjusted analyses, broad and anterior PSM carried the highest risk of recurrence after RPP.

Paraneoplastic symptoms: Cachexia, polycythemia, and hypercalcemia are, respectively, related to vascular endothelial growth factor (VEGF) expression in renal clear cell carcinoma - Corrected Proof

2012-04-26

Abstract: Aims: To evaluate whether there is a relation between expression of vascular endothelial growth factor (VEGF) and any of the paraneoplastic syndromes (PNS) in clear cell renal cell carcinoma (ccRCC) patients. Materials and methods: A total of 667 patients with ccRCC and at least one PNS were included. Thorough history taking, physical examinations, and laboratory tests were used to diagnose PNS. Immunohistochemistry was performed for VEGF evaluation. Results: There were 10 different PNS identified in the population. Sixty patients had a single paraneoplastic presentation. In all patients, presence of cachexia (n = 267, P < 0.0001), polycythemia (n = 40, P = 0.0014), and hypercalcemia (n = 48, P = 0.0006) was correlated to VEGF expression. Correlation was neither acquired in Stauffer's syndrome, pyrexia, elevated erythrocyte sedimentation rate (ESR), anemia, thrombocytosis, hypertension, neuromyopathy nor obtained within patients with single PNS. Conclusions: Relations between PNS and VEGF expression in renal cell carcinoma (RCC) has not been studied yet. The results we gained hereby can help us further understand the mechanistic of PNS in RCC.

Thermal ablation of the small renal mass: Case selection using the R.E.N.A.L-Nephrometry Score - Corrected Proof

2012-04-23

Abstract: Objectives: Treatment decision-making for localized renal lesions remains overly subjective. While the AUA Guidelines list thermal ablation (TA) as a treatment option for the clinical T1 renal mass, few data exist regarding the relationship between TA and tumor complexity. The R.E.N.A.L.-Nephrometry Scoring System (NS) was introduced to objectify salient renal mass anatomy and standardize academic reporting. Here we correlate the salient anatomical attributes of renal masses undergoing TA with technical and oncologic outcomes. Materials and methods: We queried our prospectively maintained kidney cancer database of 2,312 patients and identified 39 patients who underwent TA with available nephrometry scores. Patient clinical, technical, functional, and oncologic characteristics were reviewed. Results: Median patient age, serum creatinine, estimated glomerular filtration rate, and Charlson Comorbidity Index were 71 (range = 57–86) years, 1.37 (range = 0.7–3.5) mg/dl, 57.1 (range = 23.3–93.8) ml/min, and 2 (range = 0–5), respectively. Median Nephrometry Score for patients undergoing tumor ablation was 6 (4–10). Low (NS = 4–6), moderate (NS = 7–9), and high (NS = 10–12) complexity tumors were identified in 20 (51.3%), 17 (43.6%), and 2 (5.1%) patients. Six (15%) patients experienced a tumor recurrence. Of those with a recurrence, 5/6 (83.3%) had moderate complexity tumors with the remaining tumor being low complexity. Minor and major Clavien complications occurred in 4 (10%) and 1 (3%) patients, all of whom had moderate complexity tumors. Conclusions: At our institution, 95% of tumors undergoing TA were anatomically low or moderate complexity lesions as measured by the R.E.N.A.L-Nephrometry Scoring System. Nephrometry may help predict disease recurrence and peri-procedural complications, yet multi-institutional analysis is needed to further validate these findings.

Prognostic significance of non-muscle-invasive bladder tumor history in patients with upper urinary tract urothelial carcinoma - Corrected Proof

2012-04-23

Abstract: Objective: To evaluate the prognostic factors for survival and disease recurrence in patients treated surgically for upper tract urothelial carcinoma (UTUC), focusing especially on the impact of history of non-muscle-invasive bladder cancer. Patients and methods: A single-center series of 221 consecutive patients who were treated surgically for UTUC between January 1999 and December 2010 was evaluated. Patients who had a history of bladder tumor at a higher stage than the upper tract disease, preoperative chemotherapy, or previous contralateral UTUC were excluded. None of the patients included in this study had distant metastasis at diagnosis of UTUC. In total, 183 patients (mean age 66 years, range 36–88) were then available for evaluation. Tumor multifocality was defined as the synchronous presence of 2 or more pathologically confirmed tumors in any upper urinary tract location (renal pelvis or ureter). All patients were treated with either open radical nephroureterectomy (RNU) or open conservative surgery. Recurrence-free probabilities and cancer-specific survival were estimated using the Kaplan-Meier method and Cox regression analyses. Results and limitations: Fifty-one patients (28%) had previous carcinoma not invading bladder muscle. Previous history of non-muscle-invasive bladder cancer was significantly associated with tumor multifocality (P < 0.001), concomitant bladder cancer (P < 0.001), higher tumor stage (P = 0.020), and lymphovascular invasion (P = 0.026). Using univariate analyses, history of non-muscle-invasive bladder cancer was significantly associated with an increased risk of both any recurrence (HR = 2.17; P = 0.003) and bladder-only recurrence (HR = 3.17; P = 0.001). Previous carcinoma not invading bladder muscle (HR = 2.58; P = 0.042) was an independent predictor of bladder-only recurrence. Overall 5-year disease recurrence-free (any recurrence and bladder-only recurrence) survival rates were 66.7% and 77%, respectively. Previous history of non-muscle-invasive bladder cancer was not associated with cancer-specific survival. Our results are subject to the inherent biases associated with high-volume tertiary care centers. Conclusions: Patients with previous history of non-muscle-invasive bladder cancer had a higher risk of having multifocal and UTUC with higher tumor stages (pT3 or greater). History of bladder tumor was an independent predictor of bladder cancer recurrence but had no effect on non-bladder recurrence, and cancer-specific survival in patients who underwent surgical treatment of UTUC.

Inverted papilloma of the bladder: A review and an analysis of the recent literature of 365 patients - Corrected Proof

2012-04-23

Abstract: Objectives: Until the 1970s, inverted urothelial papilloma (IUP) of the bladder was generally regarded as a benign neoplasm. However, in the 1980s, several reported cases suggested the malignant potential of these papillomas, including cases with features indicative of malignancy, recurrent cases, and cases of IUP synchronous or metachronous with transitional cell carcinoma. The aim of this systematic review and analysis of the literature since 1990 to date is to contribute to unresolved issues regarding the biological behavior and prognosis of these neoplasms to establish some key points in the clinical and surgical management of IUP. Materials and methods: Database searches yielded 109 references. Exclusion of irrelevant references left 10 references describing studies that fulfilled the predefined inclusion criteria. Results: One problem regarding these neoplasms is the difficulty of obtaining a correct histopathologic diagnosis. The main differential diagnosis is endophytic urothelial neoplasia, including papillary urothelial neoplasia of low malignant potential or urothelial carcinoma of low or high grade, while other considerably rare differential diagnoses include nephrogenic adenoma, paraganglioma, carcinoid tumor, cystitis cystica, cystitis glandularis, and Brunn's cell nests. The size of the lesions ranged from 1 to 50 mm (mean 12.8 mm). Most cases occurred in the fifth and sixth decade of life. The mean age of affected patients was 59.3 years (range 20–88 years). Analysis of the literature revealed a strong male predominance with a male/female ratio of 5.8:1. The most commonly reported sites of IUP were the bladder neck region and trigone. Of 285 cases included in 8 studies, 12 cases (4.2%) were multiple. Out of the total of 348 patients, 6 patients (1.72%) had a previous history of transitional cell carcinoma of the urinary bladder, 5 patients (1.43%) had synchronous transitional cell carcinoma of the urinary bladder, and 4 patients (1.15%) had subsequent transitional cell carcinoma of the urinary tract. The time before recurrence was <45 months (range 5–45 months, mean 27.7 months) after surgery. Conclusions: Inverted papilloma could be considered a risk factor for transitional cell carcinoma, and it is clinically prudent to exclude transitional cell cancer when it is diagnosed. Follow-up is needed if the histologic diagnosis is definitive or doubtful. We recommend 4-monthly flexible cystoscopy for the first year and then every 6 months for the subsequent 3 years. Routine surveillance of the upper urinary tract in cases of inverted papilloma of the lower part of the urinary tract is not deemed necessary.

Outcomes after radical prostatectomy for patients with clinical stages T1-T2 prostate cancer with pathologically positive lymph nodes in the prostate-specific antigen era☆ - Corrected Proof

Ryan P. Dorin, Gary Lieskovsky, Adrian S. Fairey, Jie Cai, Siamak Daneshmand — 2012-04-20

Abstract: Objectives: To evaluate the outcomes of radical prostatectomy (RP) and pelvic lymph node dissection (PLND) for clinically organ confined prostate cancer (CaP) with regional lymph node metastases (pN1) treated in the era of prostate-specific antigen (PSA) screening. Materials and methods: A single institution cohort of 2,487 men with cT1-T2 CaP treated with open radical prostatectomy and pelvic lymph node dissection between 1988 and 2008 were analyzed. Kaplan-Meier and Cox proportional regression models were used to analyze overall survival (OS), clinical recurrence-free survival (cRFS), and biochemical recurrence-free survival (bRFS). Results: Overall, 150 out of 2,487 patients (6%) had pN1 disease, with a median follow-up of 10.4 years. The predicted 10-year OS, cRFS, and bRFS rates for patients with pN0 and pN1 were 86% and 74% (Log rank P < 0.001), 97% and 84% (Log rank P < 0.001), and 88% and 57% (Log rank P < 0.001), respectively. In the subset of pN1 patients treated with surgery only (n = 49), the predicted 10-year OS, cRFS, and bRFS rates were 81%, 80%, and 59%, respectively. Exploratory univariate regression analysis showed that age (P = 0.003), total number of lymph nodes identified (P = 0.040), and total number of positive lymph nodes identified (P = 0.004) were associated with OS. Total number of positive lymph nodes (LNs) identified was also significantly associated with cRFS (P = 0.05). Conclusions: The incidence of pN1 in patients with cT1-T2 CaP treated with surgery in the era of PSA screening was low. RP and PLND demonstrated therapeutic efficacy in a subset of pN1 patients treated with surgery alone.

The follicle-stimulating hormone receptor: A novel target in genitourinary malignancies - Corrected Proof

Benjamin A. Gartrell, Che-kai Tsao, Matthew D. Galsky — 2012-04-19

Abstract: Follicle-stimulating hormone (FSH) is a central hormone in mammalian reproductive biology. The FSH receptor (FSHR), which was previously believed to be expressed primarily in the ovary and testis, was recently found to be expressed in the tumor blood vessels of many solid tumor types, including prostate adenocarcinoma, urothelial carcinoma, and renal cell carcinoma. While the biologic significance of FSHR in tumor blood vessels has yet to be elucidated, FSHR may contribute to neoangiogenesis. FSHR has been reported to be expressed by prostate cancer cells and, thus, targeting FSHR in prostate cancer may be of particular utility. In this report, we discuss the finding of FSHR in tumor blood vessels and review the literature concerning FSHR in genitourinary malignancy. We also discuss the features that make FSHR an appealing target for therapeutic and imaging purposes and the potential utility of FSHR as a prognostic and/or predictive biomarker in genitourinary cancers.

The lymphatic system in clinically localized urothelial carcinoma of the bladder: Morphologic characteristics and predictive value - Corrected Proof

2012-04-16

Abstract: Objective: To assess the lymphatic vessel density (LVD) and lymphangiogenesis in urothelial carcinoma of the bladder (UCB) and to identify predictors of progression in patients treated by transurethral resection (TUR). Materials and methods: One hundred eleven patients who underwent TUR for UCB were retrospectively included. Lymphatic endothelial cells were stained immunohistochemically [D2-40 (podoplanin) antibody in all samples; Prox-1, LYVE-1, and VEGFR-3 (Flt-4) in subgroups]. LVD was measured in representative intratumoral (ITLVD), peritumoral (PTLVD), and nontumoral (NTLVD) areas using standardized criteria. Double-immunostainings with D2-40/CD-34 were performed to distinguish between blood and lymphatic vessels, and D2-40/Ki-67 stainings were done to detect lymphangiogenesis. Lymph-specific parameters were correlated with pathologic and clinical characteristics. In patients with non-muscle-invasive UCB (n = 76) univariable and multivariable analyses were performed to identify predictors of progression. Results: The PTLVD was significantly higher than ITLVD and NTLVD (P < 0.001). Proliferating lymphatic vessels were observed in all specimens assessed with D2-40/Ki-67. Characteristic suburothelial D2-40 positivity was observed in noninvasive pTa tumors. LYVE-1-stainings revealed the existence of tumor-associated macrophages. The presence of intratumoral lymphatic vessels was significantly associated with higher tumor stage, high grade, and sessile growth (all P < 0.001). Muscle-invasive tumors (P = 0.020), higher grade (P = 0.026), the presence of lymphovascular invasion (P < 0.001), and concomitant carcinoma in situ (CIS) (P = 0.020), sessile growth (P = 0.004), and loss of suburothelial D2-40 positivity (P = 0.031) were associated with disease progression in univariable analysis. LVD values in any area were not significantly associated with progression despite detection of proliferating lymphatic vessels. The presence of concomitant CIS was identified as an independent predictor of progression on multivariable analysis (P = 0.041; hazard ratio 4.620). Conclusions: A high peritumoral LVD is present in clinically localized UCB. The presence of intratumoral lymphatic vessels correlates with characteristics of aggressive disease. Lymphangiogenesis occurs; however, the lymph-specific parameters tested in this study cannot be used to predict progression following TUR. The presence of concomitant CIS is an important risk factor for later disease progression in patients with non-muscle-invasive UCB. Our results contribute to the understanding of metastatic tumor spread in UCB.

Comparison of prostate volume measured by transrectal ultrasound and magnetic resonance imaging: Is transrectal ultrasound suitable to determine which patients should undergo active surveillance? - Corrected Proof

Brian E. Weiss, Alan J. Wein, S. Bruce Malkowicz, Thomas J. Guzzo — 2012-04-16

Abstract: Objectives: To compare prostate volume obtained by transrectal ultrasound (TRUS) and endorectal MRI (eMRI) to assess the reliability of TRUS in determining prostate-specific antigen (PSA) density. Materials and methods: Data for 2,410 patients diagnosed with localized prostate cancer (CaP) and treated with radical retropubic prostatectomy (RRP) at the University of Pennsylvania Health System between 1991 and 2005 was reviewed. Of these patients, 756 had both a preoperative TRUS and eMRI of the prostate performed. Prostate size was estimated using the prolate ellipsoid formula (height × width × length × π/6); maximal height or antero-posterior (A-P) diameter was determined using a midsagittal view for TRUS and an axial view for eMRI. Pearson's correlation, linear regression, and paired t-test were performed to compare prostate volumes estimated via both imaging modalities. Results: Average prostate size measured with TRUS and eMRI correlated significantly with one another (R = 0.801; P < 0.0001), demonstrating a strong linear relationship (y = 0.891x + 2.622, R2 = 0.642). Comparison of PSA density also demonstrated a strong linear relationship (y = 0.811x + 0.053, R2 = 0.765). Average prostate volume differed by 1.7 ml (TRUS relative to eMRI), which was statistically significant based on a paired t-test (P < 0.001). Upon stratification of patients into three groups based on average TRUS volume (≤30, >30–60, and >60 ml), significant correlation (0.318, 0.564, 0.650) and difference between volumes (−2.1, 4.0, 5.1 ml; P < 0.0001, P < 0.0001, P < 0.05 TRUS relative to eMRI) was maintained. Conclusions: Prostate volume estimations with TRUS and eMRI are highly correlated. It is therefore, reasonable to conclude that in the hands of an experienced sonographer, TRUS is not only an efficient and economical examination, but also an accurate and reproducible modality to estimate prostate size.

LASP-1, a Novel Urinary Marker for Detection of Bladder Cancer - Corrected Proof

2012-04-05

Abstract: The LIM and SH3 (LASP)-1 protein is a focal adhesion protein that has been linked to oncogenesis. The aim of this study was to evaluate the diagnostic use of the detection of LASP-1 in tumor specimens and in urine for noninvasive detection of transitional cell carcinoma (TCC). Immunohistochemical staining for LASP-1 was performed on 72 archived bladder tumor specimens, and LASP-1 content was measured in 132 spontaneous urine sample sediments by Western blot analysis. In the histologic specimens, immunohistochemical staining for LASP-1 showed abundant expression throughout the urothelium of the bladder and ureter. However, modest overexpression of LASP-1 was observed in the TCC specimens. Measurement of the LASP-1 protein concentrations in urinary cell pellets from healthy donors and bladder cancer patients was highly sensitive for the presence of TCC. The cut-off value was determined by receiver operating characteristic (ROC) analysis. When a cut-off value of 1 ng LASP-1/500 μl of urine was used, the sensitivity, specificity, and positive and negative predictive values of the assay were 83.1%, 85.3%, 83.1%, and 80.6%, respectively. The increased urinary LASP-1 content in TCC patients was attributable in part to a specific increase in cell shedding presumably caused by changes in cell adhesion, as confirmed by LASP-1 knockdown. Contamination with erythrocytes above 250 cells/μl and urinary infection gave false positive results and are therefore sample exclusion criteria. In conclusion, in the absence of urinary infection or gross hematuria, urinary LASP-1 level is a promising marker for transitional cell carcinoma.

Modified orthotopic spiral ileal bladder substitution: Surgical technique and long-term results - Corrected Proof

Wei-Gao Wang, Huan Zhong, Bin Yu, Jian-Er Tang, Yu Chen, Min Cao, Xiao-Dong Jin — 2012-04-05

Abstract: Objectives: The objectives of this study are to introduce the surgical technique of a modified spiral orthotopic ileal neobladder and to assess the long-term outcomes. Patients and methods: Between January 1998 and January 2006, 44 male and 7 female patients with bladder cancer received radical cystectomy (RC) and pelvic lymphadenectomy. An ileal segment 40 cm to 45 cm long was isolated to create a spiral orthotopic ileal neobladder, and the ureters were implanted into the reservoir using a non-refluxing split-cuff nipple technique. Preoperative, perioperative, and postoperative data were collected. Complications were classified as early (less than 3 months after surgery) or late (more than 3 months after surgery). Continence incidence and urodynamic studies were evaluated 5 years after surgery. Duration of follow-up was an average of 95 months (range 60–156 months). Results: There were no perioperative deaths. The mean operative time was 315 ± 34 minutes. The mean blood loss was 783 ± 316 ml. There were 31 early complications in 21 patients (41%) and 42 late complications in 30 patients (59%). Urodynamic studies showed the maximum neobladder capacity to be 500 ± 71 ml, maximum flow rate to be 16 ± 5 ml/s and post-voiding residual (PVR) to be 50 ± 44 ml. Postoperative continence was excellent with a daytime continence rate of 90% and a nocturnal continence rate of 78% 5 years after surgery. Conclusions: The modified spiral neobladder is easy to perform and allows for excellent long-term results with regard to complications and continence.

Does the medical evidence justify robotic assisted laparoscopic radical prostatectomy as the new gold standard for radical prostatectomy? - Corrected Proof

Herbert Lepor — 2012-04-05

Abstract: Today, over 70% of radical prostatectomies (RP) are performed using the daVinci robot. The robot has been heavily promoted and marketed to both the urologic community and the lay public as a minimally invasive and superior alternative to open radical prostatectomy. The robot has also been heavily promoted to hospitals as a means to increase market share by advertising “cutting edge” technology. Web sites promoting this new technology have consistently failed to legitimize claims of superiority with credible medical evidence. The time has come to critically examine whose interests have been best served by the robot: the patients, the surgeons, or the health care delivery system? As physicians who have taken the Hippocratic oath, it is the interest of the patient we must pursue and defend.

3.0 T multiparametric prostate MRI using pelvic phased-array coil: Utility for tumor detection prior to biopsy - Corrected Proof

2012-04-05

Abstract: Objective: To evaluate the role of multiparametric magnetic resonance imaging (MRI) performed in men without a biopsy-proven diagnosis of prostate cancer using follow-up biopsy as the reference standard. Materials and methods: Forty-two patients without biopsy-proven cancer and who underwent MRI were included. In all patients, MRI was performed at 3T using a pelvic phased-array coil and included T2-weighted imaging, diffusion-weighted imaging, and dynamic contrast-enhanced imaging. Thirteen had undergone no previous biopsy, and 29 had undergone at least 1 previous negative biopsy. All patients underwent prostate biopsy following MRI. Two fellowship-trained radiologists in consensus reviewed all cases and categorized each lobe as positive or negative for tumor. These interpretations were correlated with findings on post-MRI biopsy. Results: Follow-up biopsy was positive in 23 lobes in 15 patients (36% of study cohort). On a per-patient basis, MRI had a sensitivity of 100%, specificity of 74%, positive predictive value (PPV) of 68%, and negative predictive value (NPV) of 100%. On a per-lobe basis, MRI had a sensitivity of 65%, specificity of 84%, PPV of 60%, and NPV of 86%. There was a nearly significant association between Gleason score and tumor detection on MRI (P = 0.072). Conclusions: In our sample, MRI had 100% sensitivity in predicting the presence of tumor on subsequent biopsy on a per-patient basis, suggesting a possible role for MRI in selecting patients with an elevated prostatic specific antigen (PSA) to undergo prostate biopsy. However, MRI had weaker specificity for prediction of a subsequent positive biopsy, as well as weaker sensitivity for tumor on a per-lobe basis, indicating that in patients with a positive MRI result, tissue sampling remains necessary for confirmation of the diagnosis as well as for treatment planning.

Thirty years of research on infection and prostate cancer: No conclusive evidence for a link. A systematic review - Corrected Proof

Jan Hrbacek, Michael Urban, Eva Hamsikova, Ruth Tachezy, Jiri Heracek — 2012-03-29

Abstract: Background: The potential role of genitourinary infection in the etiology of prostate cancer (CaP) has been extensively investigated for 30 years. Two basic approaches have been used: tissue-based methods (polymerase chain reaction, immunohistochemistry, and in situ hybridization) and serologic assays (enzyme-linked immunosorbent assay, immunofluorescence, etc.). The objective of this review was to answer the question of whether infection of the male genitourinary tract may have a role in the etiology of CaP. Materials and methods: We have carried out a systematic review of the evidence that was published in the MEDLINE/PubMed database until December 2011. The search terms included “prostate cancer,” “infection,” and the explicit names of the various infectious agents. Additional studies were identified using a reference search. A total of 74 papers were included in the review, which cover the following infectious agents: human papillomavirus, cytomegalovirus, herpes simplex virus, Epstein-Barr virus, human herpesvirus, BK virus, JC virus, chlamydia, mycoplasma, ureaplasma, trichomonas, neisseria, treponema, Propionibacterium acnes, xenotropic murine leukemia virus-related virus and Candida albicans. Results: Despite the variable study designs and methodological approaches that were used, most of the pathogens that were studied were unlikely to be directly involved in prostate carcinogenesis. Conclusions: The role of infection in the etiology of CaP has yet to be determined despite 30 years of research efforts. A discovery of an infectious agent that is associated with CaP would be of great medical importance; however, such a link would have to be firmly established before impacting on patient care.

Clinical applications of multiparametric MRI within the prostate cancer diagnostic pathway - Corrected Proof

2012-03-29

Interest in integrating MRI into the prostate (CaP) cancer diagnostic pathway seems to be gaining ground []. Multiparametric (mp)MRI combines diffusion-weighted, dynamic contrast enhanced sequences or MR spectroscopy with conventional T2-weighted sequences. This has resulted in accuracy rates for the detection of clinically important CaP that compare favorably with established tests, such as X-ray mammography, for the detection of breast cancer []. However, its exact clinical utility remains the subject of legitimate professional disagreement. In this commentary, we attempt to highlight the areas in which mpMRI may have a role in improving the diagnosis and management of CaP.

Photodynamic Therapy of Bladder Cancer – A Phase I Study Using Hexaminolevulinate (HAL) - Corrected Proof

2012-03-23

Abstract: Objectives: To assess the safety and feasibility of hexaminolevulinate (HAL) based photodynamic therapy (PDT) as adjuvant treatment after transurethral resection of the bladder (TURB) in patients with intermediate or high-risk urothelial cell carcinoma (UCC) of the bladder. Materials and methods: Seventeen patients received 50 ml of either a 16 mM (4 patients) or 8 mM HAL (13 patients) solution instilled intravesically. Bladder wall irradiation was performed using an incoherent white light source coupled via a quartz fiber assembled into a flexible transurethral irrigation catheter. Each patient received 3 treatments with HAL-PDT 6 weeks apart. After PDT, patients were followed by regular cystoscopy for up to 21 months to assess time to recurrence. Reported adverse events (AEs) were coded according the World Health Organization Adverse Reaction Terminology (WHO-ART). Efficacy was assessed by cystoscopy, cytology, and histology, and was defined as the number of patients who were tumor-free at 6 or 21 months after initial PDT treatment. Transient bladder irritability was reported by 15 of the 17 patients and resolved completely in all patients. No evidence of a cumulative effect of treatment on the incidence of AEs could be detected. PDT treatment was performed without any technical complications. Furthermore preliminary assessment of efficacy showed that of the 17 patients included, 9 (52.9%; 95% CI: 27.8–77.0) were tumor-free at 6 months, 4 (23.5%; 95% CI: 6.8–49.9) were tumor-free at 9 months, and 2 (11.8%, 95% CI: 1.5–36.4) were tumor-free after 21 months. Conclusions: PDT using hexaminolevulinate and an incoherent white light system with the special flexible irradiation catheter system is technically feasible and safe and may offer an alternative in the treatment of non-muscle-invasive intermediate and high-risk bladder cancer.

Clear-Cell differentiation and lymphatic invasion, but not the revised TNM classification, predict lymph node metastases in pT1 penile cancer: A clinicopathologic study of 76 patients from a low incidence area - Corrected Proof

2012-03-16

Abstract: Objective: Prediction of lymph node (LN) metastases in penile invasive cancer relies on clinical features and histologic characteristics of the primary tumor. Correct prediction, however, is difficult, as only 50% patients undergoing lymphadenectomies will have LN metastases. In 2009, the tumor, nodes, metastases (TNM) classification for staging of early penile cancers was revised. We tested the predictive accuracy of the revised TNM classification in a low incidence area for penile carcinoma. Materials and methods: The presence of LN metastases in 76 men with pT1 penile cancers was correlated with the 2009 TNM subclassification, which is based on a combined evaluation of tumor grade and lymphatic invasion, but also with individual parameters, such as histologic grade, lymphatic invasion, perineural invasion, invasion depth, growth pattern and human papilloma virus (HPV) status. Results: 76pT1 penile cancers were reclassified into 31pT1a squamous cell carcinomas (SCC) and 45pT1b (41 SCC; 4 clear-cell carcinomas); 12/22 men (55%; 8 SCC, 4 clear-cell carcinomas) undergoing lymphadenectomy for enlarged inguinal lymph nodes had metastases, 54 patients without enlarged LN and lymphadenectomies had no LN metastases during follow-up of median 47 months. Statistically, clear cell differentiation of the primary carcinoma was highly associated with metastases (100% clear-cell carcinomas vs. 11% SCC) and poor survival (50% vs. 5.5%). Among conventional SCC, only lymphatic invasion showed a highly significant association with metastases with 100% specificity. The 2009 TNM classification, tumor grade alone, perineural invasion, growth pattern, invasion depth or HPV status could not predict LN status. Lymphadenectomy for enlarged LN resulted in 100% sensitivity and 42% predictive probability for identifying metastases and a 16% false positive rate. Statistically, survival correlated significantly with clear-cell differentiation and with lymphatic invasion in both clear-cell carcinomas and conventional SCC. Conclusions: Penile clear-cell carcinomas are more aggressive cancers than SCC. Our observation suggests a benefit of a prophylactic lymphadenectomy for patients with clear-cell carcinomas. Among conventional SCC, only lymphatic invasion predicted LN metastases. Neither tumor grade alone nor perineural invasion, growth pattern, depth of invasion, and subgrouping according to the revised TNM classification correlated with metastases. Clinical evaluation of the LN status was superior to histologic risk stratification.

Slug contributes to cadherin switch and malignant progression in muscle-invasive bladder cancer development - Corrected Proof

2012-03-16

Abstract: Objectives: The Snail family of zinc finger transcription factors (i.e., Snail and Slug) predicts the tumor recurrence in superficial bladder cancers, while their roles in the development of muscle-invasion, metastasis, and chemoresistance in muscle-invasive bladder cancers with poor prognosis have not been investigated. This study evaluates the clinical significance of Slug in aggressive bladder cancer. Materials and methods: A pair of sublines (i.e., T24-P and T24-L) from a unique orthotropic metastatic model of bladder cancer was firstly utilized to identify the potential precursors contributing to those aggressive phenotypes. The coexpression of Slug, E-cadherin, and N-cadherin in bladder cancer cell lines (i.e., 5637, RT4, 253 J, J82, and T24) and tissues was evaluated by reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemistry staining analysis. The function of Slug expression on E- to N-cadherin switch, cell invasion, and chemoresistance to proapoptotic treatment was validated by gain-in-function and knockdown strategy in vitro. Results: Slug was identified as one of the novel targets contributed to the aggressive phenotypes of T24-L cells, which showed enhanced cell invasive, metastatic, and chemoresistant potentials in vitro and in vivo as previously described. Up-regulation of Slug was significantly correlated with a higher tumor stage and the E- to N-cadherin switch in bladder cancer cells and tissues, whereas ectopic expression of Slug in bladder cancer 5637 and RT-4 cell lines promoted epithelial-to-mesenchymal transition (EMT), increased cell invasiveness and chemoresistance. By contrast, knocking down Slug using siRNA in T24-L cell lines reversed these changes. Conclusions: Slug elevates in invasive or metastatic bladder cancer and plays a critical role in EMT via control of cadherin switch. Slug may be a potential marker or target for improving the diagnosis and treatment of muscle-invasive bladder cancers.

αB-Crystallin in clear cell renal cell carcinoma: Tumor progression and prognostic significance - Corrected Proof

2012-03-15

Abstract: Objectives: AlphaB-crystallin (αB-crystallin), a small heat shock protein, has been reported to be involved in the growth, antiapoptosis, migration, and chemoresistance of human malignancies. Materials and methods: αB-crystallin expression in normal renal and clear cell renal cell carcinoma (ccRCC) tissues was examined with two-dimensional (2D) gel electrophoresis assays. Immunohistochemistry was conducted to determine the presence of αB-crystallin-positive tumor cells and staining intensity in 50 cases of ccRCC tissue samples. The association of αB-crystallin protein expression, clinicopathogic parameters and prognosis of ccRCC patients was also analyzed with Student's t-test and Kaplan-Meier analysis. Moreover, Western blot assays were performed to detect the protein expression of αB-crystallin in normal and tumor tissues and the alteration of cell cycle regulators in αB-crystallin-overexpressing cells. MTT (3-[4,5-dimethythiazol-2-yl]-2,5-diphenyltetrazolium bromide), BrdU, and transwell assays were performed to demonstrate the effects of αB-crystallin overexpression on cell growth, DNA synthesis and cell migration of ccRCC cells, respectively. Results: The results showed the up-regulation of αB-crystallin expression in ccRCC tissues. Overall survival of ccRCC patients was significantly correlated with αB-crystallin expression in tumor tissues. We found that αB-crystallin overexpression increased the expression of cyclin A and the incorporation of BrdU, which may be related to the enhancement of cell growth. Transwell analyses demonstrated that presence of αB-crystallin overexpression enhanced cell migration in ccRCC cells. Furthermore, rapamycin-resistance of tumor cells was induced when αB-crystallin was overexpressed. Conclusions: Our experimental findings highlight the importance of αB-crystallin in the tumor growth, migration, and target therapy-resistance of ccRCC cells.

Sensitivity to chemoradiation predicts development of metastasis in muscle-invasive bladder cancer patients - Corrected Proof

2012-03-05

Abstract: Objectives: In bladder-sparing approaches for muscle-invasive bladder cancer (MIBC) involving transurethral resection of the bladder tumor (TURBT) and chemoradiation, survival outcomes are excellent for patients who achieve tumor-free state after TURBT and chemoradiation but poor for those with persistent disease. Since metastatic disease accounts for most bladder cancer deaths, we hypothesized that tumor sensitivity to chemoradiation may reflect metastatic potential in MIBC. Materials and methods: From 1997 to 2010, 179 cT2-4aN0M0 bladder cancer patients underwent TURBT and induction chemoradiation (40 Gy with cisplatin 20 mg/d for 5 days × 2). Study subjects were 73 patients who had had macroscopic disease after TURBT and were evaluated for tumor sensitivity to the induction chemoradiation; of the 73 patients, chemoradiation response was evaluated pathologically in partial and radical cystectomy specimens for 8 and 44 patients, respectively, and clinically for the remaining 21 who did not undergo cystectomy. Tumors were defined as chemoradiation-sensitive when they regressed to T0 pathologically for the 52 patients undergoing cystectomy or clinically for the 21 undergoing no cystectomy; otherwise, they were defined as chemoradiation-resistant. Primary and secondary endpoints were metastasis-free and cancer-specific survival, respectively. The association between chemoradiation sensitivity and development of metastasis was investigated in MIBC patients. Results: Of the 73 patients, 21 (29%: 13 pathologic and 8 clinical T0) had chemoradiation-sensitive tumors while 52 (71%) had chemoradiation-resistant tumors. Median follow-up was 53 months. Multivariate analysis identified chemoradiation resistance as the strongest independent predictor for the development of metastasis (hazard ratio (HR) 18.9, P < 0.0001). When stratified by chemoradiation sensitivity, 5-year metastasis-free and cancer-specific survival rates were 94.7% and 100%, respectively, for patients with chemoradiation-sensitive tumors, and 45.7% (P = 0.0005) and 41.0% (P < 0.0001), respectively, for patients with chemoradiation-resistant tumors. Conclusions: Chemoradiation sensitivity predicts the development of metastasis in bladder cancer. Clinical and translational research results indicate that chemoradiation sensitivity is likely to reflect metastatic potential.

Two decades' experience with a prospective biobank for urologic oncology: research, clinical care, and the patients' view - Corrected Proof

2012-03-05

Abstract: Objectives: Collection of clinical data and associated tissue samples has become an essential tool for oncologic research. Since 1990, efforts have been ongoing to implement prospective documentation of all oncologic cases in our department accompanied by a special aftercare program ensuring regular visits and reliable data acquisition. Materials and methods: Our prospective database comprises a total of 6,567 cases covering all types of urologic malignancies: prostate (40.7%), renal (30.5%), urothelial (21.8%), testicular (5.8%), penile (0.8%), and other (0.4%). A specialized full-time documentalist supported by 3 student assistants entered 38,135 aftercare visits characterized by approximately 100 partly disease-specific items. The Institute of Pathology's general collection contains more than 6 million paraffin-embedded samples, and since 2005 the interdisciplinary Tissue Bank at the National Center for Tumor Diseases in Heidelberg has collected about 21,000 cryo-samples. Furthermore, we asked the opinion of 158 patients who attended our clinic for cancer surgery using a self-designed questionnaire. Results: Of 158 patients asked to be included in the biobank, from 09/07 through 02/08, none refused. Their additional questionnaire had a return rate of 81% (n = 128). Moral obligation for supporting medical research was realized by 95%, and circumstantial pressure to participate was not a relevant factor for 87%. Whereas only 68% were hoping for personal benefit, altruism seemed to be a much stronger motive: 96% believe others could be healed because of further medical progress; 93% wanted to be actively informed about recommended aftercare visits. Consequently, response rates in the “Heidelberg Cancer Maintenance Program” are constantly above 93%. Regarding research, a total of 144 scientific inquiries have been answered using our database since 1995. Within the last 5 years, 37 manuscripts originated from biobank data: herein, molecular markers and risk factors have been correlated with clinical outcome. Additionally, TNM-validation studies were conducted. Conclusions: Prospective collection of clinical data and corresponding tissue has become an indispensable research tool in oncology. In general, patients do not object tissue banking and embrace special aftercare programs.

Cost comparison of nephron-sparing treatments for cT1a renal masses - Corrected Proof

2012-02-23

Abstract: Objectives: Treatment options for small renal tumors have evolved from radical nephrectomy (RN) to partial nephrectomy (PN), thermal ablation, or active surveillance. With the advancement of techniques, costs differences are unclear. The objective of this study is to compare the 6-month costs associated with nephron-sparing procedures for cT1a renal tumors. Materials and methods: We performed a review of patients diagnosed with a solitary cT1a renal mass who underwent surgical treatment from June 2008 to May 2011. Open partial nephrectomy (OPN), robot-assisted partial nephrectomy (RLPN), laparoscopic radio-frequency ablation (LRFA), or computed tomography guided radio frequency ablation (CTRFA) was performed on 173 patients. Cost data were collected for surgical costs, associated hospital stay, and the 6-month postoperative period. Results: Patients underwent surgery, including 52 OPN, 48 RLPN, 44 LRFA, and 29 CTRFA. Median total costs associated were $17,018, $20,314, $13,965, and $6,475, for OPN, RLPN, LRFA, and CTRFA, respectively. When stratified by approach differences were noted for total cost (P < 0.001), operating room (OR) time (P < 0.001), surgical supply (P < 0.001), and room and board (P < 0.001) in univariable analysis. Multivariable linear regression (R2 = 0.966) showed surgical approach (P = 0.007), length of stay (P < 0.001), and OR time (P < 0.001) to be significant predictors of total cost. However, tumor size (P = 0.175), and Charlson comorbidity index (P = 0.078) were not statistically significant. Conclusions: Six-month cost of nephron-sparing surgery is lowest with radio frequency ablation (RFA) by either laparoscopic or computed tomography (CT)-guided approach compared to RLPN and OPN. As oncologic and safety outcomes improve and become comparable in all nephron-sparing surgery (NSS) approaches, cost of each procedure will start to play a stronger role in the clinical and healthcare policy setting.

Bother problems in prostate cancer patients after curative treatment - Corrected Proof

2012-02-20

Abstract: Background: Most previous studies of prostate cancer (CaP) patients have focused on functional side effects. In the decision about treatment, the patients' subjective experience of function (bother) should also be considered. In this prospective study of CaP patients, we used both categorical and dimensional methods to examine changes of sexual, urinary, and bowel bother after robot-assisted prostatectomy (RALP), after high dose radiotherapy alone (RAD), or with adjuvant androgen deprivation therapy (RAD + ADT). We also studied the associations between psychosocial factors and post-treatment bother and the correlations between bother and function at the follow-up time points. Methods: A total of 462 patients (n = 150 RALP, n = 104 RAD, and n = 208 RAD + ADT) completed questionnaires at all time points (baseline, 3, 6, 12, and 24 months post-treatment). Our outcome measures were the proportion of patients who regained their baseline bother core (PBS-100) and the mean group scores on sexual, urinary, and bowel bother based on the UCLA-PCI questionnaire. Generalized estimating equation (GEE) identified the time points at which various variables were significantly associated with bother at 2 years. The time points at which the proportions of bothered patients became stable were defined. Results: The different treatment modalities provided distinctive patterns over time regarding urinary, sexual, and bowel bothers. RALP gave sexual and urinary bother, RAD + ADT patients reported bowel and sexual bother, while RAD patient suffered mainly from bowel bother. According to GEE, the bother scores at 3 or 6 months were significantly associated with the bother scores at 24 months for all groups. PBS-100 and stability of the recovered bother domains was reached at 3 to 6 months. Strong correlations were observed between function and bother for the urinary and bowel domains but not for the sexual domain. The associations between psychosocial factors and bother were weak. Conclusions: Two years after treatment, RALP patients mainly reported sexual and urinary bother, while irradiated patients were bothered by bowel dysfunction. Sexual, urinary, and bowel bother reached stable proportions at 3 to 6 months post-treatment. Based on GEE, bother at 6 months was in general significantly associated with bother at 24 months.

Overexpression of Reptin in renal cell carcinoma contributes to tumor malignancies and its inhibition triggers senescence of cancer cells - Corrected Proof

2012-02-20

Abstract: Objectives: Reptin is an AAA+ ATPase associated with several complexes involved in chromatin remodeling, transcriptional regulation, DNA damage repair, and telomerase activity. Functional studies have implicated reptin in many cellular processes highly relevant to cancer. In this study, we investigated reptin expression in renal cell carcinoma (RCC) and its biologic functions in RCC cells. Materials and methods: A total of 81 RCC patients were involved in the study. Cancerous and adjacent normal renal tissues were analyzed for reptin expression using immunohistochemistry. Univariate association with survival was evaluated using Kaplan-Meier curves. Gene expression was depleted with specific small interference RNA. Clonogenesis, cellular senescence, and cell cycle distribution were examined by foci formation, β-galactosidase staining, and flow cytometry, respectively. Cell migration and invasion capability were determined by scratch migration assay and Matrigel invasion assay. Results: Reptin is overexpressed in cancerous tissues compared with tumor adjacent renal tissues. Cytoplasmic expression of reptin positively correlates with the poor differentiation of RCC, and predicts an unfavorable outcome for patients. Depleting reptin expression substantially inhibited clonogenic potential of cancer cells and induced senescence of RCC cells. Moreover, reptin depletion attenuated migration and invasion ability of RCC cells in vitro. Conclusions: Reptin is overexpressed and aberrantly distributed in RCC. It is required for sustained proliferation of cancer cells by preventing cell growth arrest and senescence. Furthermore, reptin promotes cell migration and invasion, which may contribute to the progression of RCC. Therefore, reptin may prove to be a valuable target for prevention and treatment of renal cell carcinoma.

Paclitaxel-hyaluronan hydrosoluble bioconjugate: Mechanism of action in human bladder cancer cell lines - Corrected Proof

2012-02-20

Abstract: Objectives: A previously described hydrosoluble paclitaxel-hyaluronan bioconjugate appears particularly well suited for treatment of superficial bladder cancer because of its in vitro cytotoxic profile against urothelial carcinoma (UC) cell lines and in vivo biocompatibility. The aim of this work was to assess the mechanism of action of the bioconjugate in UC cells. Materials and methods: Expression of CD44 and RHAMM hyaluronan-binding receptors in RT-4 and RT-112/84 UC cell lines, interaction of fluorochrome-labeled bioconjugate with tumor cells, CD44 modulation upon incubation with the compound or free hyaluronan, and caspase activation were assessed by flow cytometry. Cytotoxicity was studied by the MTT assay. Analysis of bioconjugate intracellular localization and effects on β-tubulin organization was carried out by confocal microscopy. Results: The paclitaxel-hyaluronan bioconjugate bound to UC tumor cells entered intracellular compartments through a saturable and energy-dependent mechanism that involved CD44, as assessed by blocking with specific antibody. Upon internalization, the bioconjugate accumulated into lysosomes where the esteric bond between paclitaxel and the hyaluronan moiety was cleaved, leading to cytoplasmic diffusion of the free drug, caspase activation, and disruption of the β-tubulin microtubular mesh with subsequent cell death. Conclusions: Conjugation of paclitaxel to hyaluronan results in a new chemical entity, characterized by selective targeting to polymer receptors on plasma membrane and cell entry through receptor-mediated endocytosis, followed by lysosomal accumulation. Ultimately, the active molecule is released, fully preserving the cytotoxic potential and profile of clinically used free paclitaxel.

Roles of HIF-1α in a novel optical orthotopic spontaneous metastatic bladder cancer animal model - Corrected Proof

2012-02-16

Abstract: Although metastatic disease is lethal in the majority of bladder cancer cases, study on the molecular mechanism(s) of this process suffers from the limited source of distant metastatic tumor tissues and very few suitable animal models. To address this need, we generated an orthotopic animal model by instilling human bladder cancer T24-tumorigenic (T24-t) cells into mouse bladder, and sublines were subsequently derived as primary (T24-parental, T24-P) and lung metastatic (T24-L) sites. Data from invasion, migration, and adhesion assays suggested higher metastatic potential of T24-L cells than T24-P cells in vitro. Using two metastatic models to assess the metastatic ability in vivo, T24-L cells exhibited higher incidence of tumor metastasis. Mechanistically, the up-regulation of MMP-1 and HIF-1α was observed in T24-L cells. Knocking down HIF-1α can significantly down-regulate the expression of MMP-1, accompanied by the decreased invasion ability in vitro. Using immunohistochemical staining, we further observed HIF-1α elevation in the metastatic lymphomatic tissues compared with the primary bladder cancer tissues from the same patients. Taken together, our study provides the evident of the function of HIF-1α/MMP-1 in regulating metastasis of bladder cancer and HIF-1α as a potential target for controlling bladder cancer metastasis.

Rationing in urologic oncology: Lessons from sipuleucel-T for advanced prostate cancer☆ - Corrected Proof

Jeffrey Peppercorn, Andrew Armstrong, David W. Zaas, Daniel George — 2012-02-10

Abstract: Objectives: As complex novel cancer drugs are developed, supply may transiently fail to meet demand as production capacity established for research purposes is scaled up to meet anticipated clinical volume. There are no clear guidelines for how clinicians and medical centers should allocate scarce cancer care resources among patients who may benefit from the intervention. Materials and methods: We describe a recent scenario in which demand exceeded supply for a novel immunotherapy, sipuleucel-T, that was newly approved by the FDA for castration-resistant prostate cancer. Production of this autologous cellular therapy was initially limited to one facility with supply projected to serve only 2,000 out of approximately 30,000 potentially eligible patients in the United States. Results and conclusions: We propose basic guidelines that should be followed when allocating scarce cancer therapies and highlight ongoing challenges that must be resolved both with regard to rationing cancer care and with regard to access to high cost novel interventions in oncology in general.

Optimizing outcomes for octogenarians with invasive bladder cancer: One size does not fit all - Corrected Proof

Matthew J. Resnick, Sam S. Chang — 2012-02-10

Management of the elderly patient with invasive bladder cancer remains a clinical challenge for the treating urologist. The decision to perform radical surgery complex and must take into account the individual patient's life expectancy, risk of perioperative morbidity and/or mortality, treatment goals, attitudes towards quality of life, and social support structure. As surgeons, we strive to provide patients with the necessary information upon which they can make informed treatment decisions. Unfortunately, there are few high quality data upon which to base these decisions and, as such, both patients and physicians are left with a considerable degree of uncertainty surrounding optimal individualized treatment strategies.

Transperineal template-guided prostate biopsy for patients with persistently elevated PSA and multiple prior negative biopsies - Corrected Proof

Boris Gershman, Anthony L. Zietman, Adam S. Feldman, W. Scott McDougal — 2012-02-10

Abstract: Objective: To evaluate the use of transperineal template-guided prostate biopsy for patients with persistently elevated PSA despite multiple negative prior biopsies. Materials and methods: A retrospective review was performed of patients with at least two prior prostate biopsies who underwent transperineal template-guided biopsy. Electronic medical records were reviewed to obtain relevant clinical, laboratory, and pathologic data. Results: A total of 34 patients underwent transperineal template-guided biopsy. Patients had a mean of 3.7 ± 1.6 (range 2–8) prior biopsies, including prior negative transurethral resection (TUR) biopsy in 6 (17.6%) patients. Prostate cancer was detected in 17 (50%) of the 34 patients. Of these, 14 (82.4%) patients had cancer in the anterior prostate, 9 (52.9%) patients had cancer in the apical prostate, and 16 (94.1%) patients had cancer in either the anterior or apical prostate. Gleason score was 3+3 in 9 (52.9%) patients and 3+4 or greater in 7 (47.1%) patients. The mean number of positive cores was 4.5 ± 3.0 (range 1–11). Of the 17 patients with a diagnosis of cancer, 7 underwent radical prostatectomy, 7 underwent radiation therapy, 1 elected active surveillance, and 1 was deciding between surgery and radiation therapy; 1 patient received palliative chemotherapy for synchronous metastatic pancreatic carcinoma. Patients in whom cancer was detected had significantly smaller prostate volume, higher PSA, higher PSA density, and greater PSA velocity. Conclusions: Transperineal template-guided prostate biopsy is an effective technique for detecting cancer in patients with persistently elevated PSA despite multiple negative biopsies. It improves sampling of the anterior and apical prostate, and should be included as part of the diagnostic algorithm to reduce extensive repeat biopsy.

Effects of the T-786C, G894T, and Intron 4 VNTR (4a/b) polymorphisms of the endothelial nitric oxide synthase gene on the risk of prostate cancer - Corrected Proof

Mohammad Reza Safarinejad, Shiva Safarinejad, Nayyer Shafiei, Saba Safarinejad — 2012-02-10

Abstract: Several studies have shown that nitric oxide (NO) and nitric oxide synthase (NOS) system plays an important role in carcinogenesis. Endothelial nitric oxide synthase (eNOS) gene polymorphisms significantly affects serum NO concentrations. Studies addressing the relationship between eNOS gene polymorphisms and prostate cancer (CaP) are very scarce. We examined the association between the 3 eNOS gene polymorphisms (T-786C, G894T, and 4a/b) with risk and clinical features of CaP. One hundred seventy patients with CaP (mean age 63.6 ± 12.4 years) and 340 age-matched healthy controls (mean age 64.9 ± 12.9 years) were recruited in this case-control study. Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique. For T-786C polymorphism, we found that CC genotype was associated to CaP risk [odds ratio (OR) = 3.62, 95% confidence interval (CI): 1.89–7.74, P = 0.002), high grade tumor (OR = 2.46, 95% CI:1.78–4.72; P = 0.006), and advanced disease (OR = 4.67, 95% CI: 2.64−8.61; P = 0.002). Neither the CaP risk nor clinical features of CaP were associated with the G894T polymorphism. It was found that, compared with 4a/b bb genotype, the 4a/b “a” variant genotypes were associated with an increased risk of CaP in an allele dose dependent manner (OR = 2.12, 95% CI: 1.68–3.44; P = 0.031 for 4a/b ab genotype, and OR = 4.32, 95% CI: 2.21–6.08; P = 0.001 for 4a/b aa genotype). In addition, genotypes with the “a” allele of the eNOS 4a/b polymorphism predispose the patients to high grade (OR = 4.76, 95% CI: 2.74–8.62; P = 0.001) and advanced CaP (OR = 5.28, 95% CI: 3.64–8.72; P = 0.001). Furthermore, the T-Asp-b and C-Asp-b haplotypes were associated with a significantly decreased risk of CaP (OR = 0.44, 95% CI: 0.33–0.77; P = 0.004, and OR = 0.39, 95% CI: 0.26–0.61; P = 0.001, respectively). We found significant differences in genotype distribution and allelic frequencies between CaP patients and controls for the T-786C, and 4a/b eNOS polymorphisms.

Prostate cancer risk prediction in a urology clinic in Mexico - Corrected Proof

2012-02-06

Abstract: Objectives: To evaluate factors affecting the risk of prostate cancer (CaP) and high-grade disease (HGCaP, Gleason score ≥ 7) in a Mexican referral population, with comparison to the Prostate Cancer Prevention Trial Prostate Cancer Risk Calculator (PCPTRC). Methods and materials: From a retrospective study of 826 patients who underwent prostate biopsy between January 2005 and December 2009 at the Instituto Nacional de Cancerología, Mexico, logistic regression was used to assess the effects of age, prostate-specific antigen (PSA), digital rectal exam (DRE), first-degree family history of CaP, and history of a prior prostate biopsy on CaP and HGCaP, separately. Internal discrimination, goodness-of-fit, and clinical utility of the resulting models were assessed with comparison to the PCPTRC. Results: Rates of both CaP (73.2%) and HGCaP (33.3%) were high among referral patients in this Mexican urology clinic. The PCPTRC generally underestimated the risk of CaP but overestimated the risk of HGCaP. Four factors influencing CaP on biopsy were logPSA, DRE, family history and a prior biopsy history (all P < 0.001). The internal AUC of the logistic model was 0.823 compared with 0.785 of the PCPTRC for CaP (P < 0.001). The same 4 factors were significantly associated with HGCaP as well and the AUC was 0.779 compared with 0.766 of the PCPTRC for HGCaP (P = 0.13). Conclusions: Lack of screening programs or regular urologic checkups in Mexico imply that men typically first reach specialized clinics with a high cancer risk. This renders diagnostic tools developed on comparatively healthy populations, such as the PCPTRC, of lesser utility. Continued efforts are needed to develop and externally validate new clinical diagnostic tools specific to high-risk referral populations incorporating new biomarkers and more clinical characteristics.

Summary of the 6th annual bladder cancer think tank: New directions in urologic research - Corrected Proof

2012-02-02

Abstract: The 6th Annual Bladder Cancer Think Tank brought together a multidisciplinary group of clinicians, researchers, and representatives from the National Cancer Institute and Industry in an effort to advance bladder cancer research efforts. This year's meeting comprised panel discussions and research involving 5 separate working groups, including the Survivorship, Clinical Trials, Standardization of Care, Data Mining, and Translational Science working groups. In this manuscript, the accomplishments and objectives of the working groups are summarized. Notable efforts include: (1) the development of a survivorship care plan for early and late-stage bladder cancer; (2) the development of consensus criteria for eligibility and endpoints for bladder cancer clinical trials; (3) an improved understanding of current practice patterns regarding the use of perioperative chemotherapy in an effort to standardize care; (4) creation of a comprehensive handbook to assist researchers with developing bladder cancer databases; and (5) identification of response to therapy of high-grade non muscle invasive disease through a collaborative exchange of expertise and resources.

Detailed biopsy pathologic features as predictive factors for initial reclassification in prostate cancer patients eligible for active surveillance - Corrected Proof

2012-02-02

Abstract: Objective: To evaluate the impact of detailed biopsy characteristics such as positive cores location or multifocality on the risk of initial reclassification in prostate cancer (CaP) patients eligible for active surveillance (AS). Materials and methods: We reviewed data from 300 consecutive men eligible for AS (PSA ≤ 10 ng/ml, clinical stage T1c, Gleason score ≤6, <3 positive cores, extent of cancer in any core < 50%) who have undergone a radical prostatectomy (RP). Reclassification was defined as upstaged disease and/or upgraded disease in RP specimens. Results: Biopsy features showed 36% of CaP involving 2 cores and a mean total tumor length of 2.63 mm. The 2 most frequently positive sites were base and apex. Mean total tumor length was significantly associated with upgraded disease (P = 0.025). In a multivariate model taking into account PSA, PSAD, number of positive cores and total tumor length, a total tumor length > 5 mm were independently predictor for a upgraded disease (OR 1.93, P = 0.046). The number, the multifocality and the bilaterality of positive cores were not associated with reclassification. Upgraded disease was significantly less reported in case of positivity at midline zone compared with positivity at base, apex, or transition zone (P = 0.013). Conclusions: Detailed biopsy data provide additional information on the initial risk of reclassification in AS patients. Patients having a total tumor length < 5 mm and positive cores at midline zone are more likely to have favorable pathologic characteristics at diagnosis. These variables can be used for selection and monitoring improvement in AS programs.

Ureterorenoscopic biopsy and urinary cytology according to the 2004 WHO classification underestimate tumor grading in upper urinary tract urothelial carcinoma - Corrected Proof

2012-02-02

Abstract: Objectives: To determine accuracy of upper tract cytology and ureteroscopic biopsy according to the 2004 World Health Organization (WHO) classification in predicting the correct tumor grade in patients with urothelial cancer of the upper urinary tract (UUT-UC). Methods: Pathology reports of 77 nephroureterectomy specimens were retrospectively analyzed for tumor grade and compared with preoperatively gained cytology and ureteroscopic biopsy results. For analysis, the 2004 WHO classification was used. Results: Overall sensitivity of cytology and biopsy in diagnosis of UUT-UC was 64% and 74%, respectively. Accuracy of cytology and biopsy in predicting high grade cancer was 53% and 58%, respectively. Combination of cytology and biopsy could improve sensitivity (84%) and accuracy (68%), but even for this combination, 15% of high grade tumors were misinterpreted as low grade cancer. Conclusion: Our results show only limited accuracy for preoperative cytology and ureterorenoscopically performed biopsies in the prediction of the correct tumor grading of an UUT-UC. Therefore, we suggest the use of additional diagnostic procedures before the decision for definitive surgical treatment in patients with UUT-UC is made.