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Background & Objective: Asymptomatic microhematuria (aMh) remains a diagnostic challenge in urological practice: while aMh is a risk factor of urothelial carcinoma (UC), prevalence of aMh is high. Guidelines were developed to permit risk stratification and reduce diagnostic workload. This study investigates the efficacy of several recommendations., Material & Methods: Sixty hundred eight patients with newly diagnosed aMh without previous UC from an academic referral center (A; n = 320) and a private outpatient clinic (B; n = 288) were included. All patients underwent clinical workup including medical history, urine cytology, upper tract imaging and cystoscopy. Eleven former and current guidelines were applied to each patient individually; every patient was classified as either low risk (no further workup recommended) or high risk. Furthermore, a recently developed nomogram for hematuria assessment was included., Results: The cohort comprised 142 females and 466 males (mean age 62 [range 18-92] years). Sixty-one patients (10.0%) were diagnosed with UC. Excluding the Swedish and recent NICE guideline generally advising against urologic workup, application of 9 other recommendations would have diagnosed all UCs and saved 1.6% to 16.1% of patients from workup. For the 2020 US guideline, solely applied to cohort B, 10.6% of patients were classified as low risk. The use of the nomogram would have saved 17.1% to 25% of patients from workup., Conclusions: Practical relevance of current guidelines is limited as they do not sufficiently identify patients not requiring clinical work up. Thus, guideline adherence may trigger overdiagnosis and even overtreatment. New ways of risk stratification are needed to improve aMh assessment., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest within the context of this study, (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Due to possible synergistic effects, the combination of radiation therapy (RT) and immune checkpoint inhibitors (ICI) represents an interesting therapeutic option. An increasing number of clinical trials are ongoing to investigate this combination in genitourinary malignancies and the first results are available., Objectives: To review and summarize available data on the combination of RT and ICI in genitourinary malignancies and update the evidence for this potential therapeutic approach., Evidence Acquisition: A study protocol was registered in the PROSPERO-Database. Terms of search were prostate cancer, bladder cancer, renal cell carcinoma, penile cancer, testicular cancer, radiotherapy, and immunotherapy in multiple literature databases and study registers. Clinical studies reporting on the combination treatment of RT and ICI were included. A systematic review of ongoing trials according to the PRISMA statement and a meta-analysis of available trials were performed., Evidence Synthesis: Overall, 43 studies met the inclusion criteria examining the therapeutic effect of combined RT and ICI. For bladder cancer, renal cell carcinoma, prostate cancer, and penile cancer 28, 9, 5, and 1 trial could be identified, respectively. No study was found for testicular cancer. Three phases III trials were identified, all other trials were phase I or II. Twelve studies have been completed so far. The meta-analysis of available data indicates comparable toxicity of RT plus ICI vs. ICI alone for grade 3/4 AEs. Mature efficacy data is limited with interesting early results., Conclusion: This article reviews the clinical trial landscape investigating RT and ICI in genitourinary malignancies. It provides an overview of ongoing trials and discusses available results. Actual data regarding efficacy is limited, while toxicities seem comparable to ICI alone. Especially in bladder and kidney cancer, further trial results might impact on the clinical use of the combination therapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: Polymerase I and transcript release factor (PTRF) has been implicated in cancer biology but its role in upper tract urothelial carcinoma (UTUC) is unknown. From a pilot transcriptome, we identified PTRF was significantly upregulated in high stage UTUC. Bladder cancer transcriptome from The Cancer Genome Atlas (TCGA) supported our finding and high PTRF level also predicted poor survival. We, therefore, investigated the correlation of PTRF with patients' clinicopathologic characteristics and outcomes in a multiracial UTUC cohort., Materials and Methods: By immunohistochemical staining, PTRF expression was determined using H-score. PTRF expression of 575 UTUCs from 8 institutions, including 118 Asians and 457 Caucasians, was compared with various clinicopathologic parameters. Human urothelial cancer cell lines were used to evaluate the level of PTRF protein and mRNA expression, and PTRF transcript level was assessed in fresh samples from 12 cases of the cohort. The impact of PTRF expression on disease progression, cancer-specific death and overall mortality was also examined., Results: High PTRF expression was significantly associated with multifocality (P = 0.023), high pathologic tumor stage (P < 0.00001), nonurothelial differentiation (P = 0.035), lymphovascular invasion (P = 0.003) and lymph node metastasis (P = 0.031). PTRF mRNA expression was also markedly increased in advanced stage UTUC (P = 0.0003). High PTRF expressing patients had consistently worse outcomes than patients with low PTRF expression regardless of demographic variation (all P < 0.005). In multivariate analysis, high PTRF expression was an independent predictor for progression-free survival (hazard ratio [HR] 1.70, 95% confidence interval [CI] 1.07-2.69, P = 0.025), cancer-specific survival (HR 2.09, 95% CI 1.28-3.42, P = 0.003), and overall survival (HR 2.04, 95% CI 1.33-3.14, P = 0.001)., Conclusions: Results indicate that PTRF is a predictive biomarker for progression and survival and an independent prognosticator of UTUC. Elevated PTRF could probably propel clinically aggressive disease and serve as a potential therapeutic target for UTUC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To evaluate patient-reported health-related quality of life (HRQOL) and decision regret (DR surgery or DR radiation therapy) after radiation therapy to the prostatic bed (PBRT) with or without whole pelvic radiation therapy (WPRT)., Methods and Materials: Patients received 79.29 Gy (n = 78; R1/detectable tumors) or 71.43 Gy (n = 56; R0/undetectable tumors) equivalent dose in 2-Gy fractions (EQD-2). Out of 134 patients, 51 had received additional WPRT with 44 Gy. Decision regret was reported using a 5-item instrument (best/worst scores: 0-100); European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-PR25 questionnaires were used for HRQOL evaluation., Results: At a median follow-up of 53 months, 134 valid questionnaires were returned. Most patients had locally advanced, node-positive (T3-4/N0 = 54.5%; N1 = 17.2%) or high-risk tumors (27.6%). Mean DR surgery was 17.61 and not associated with positive margins, salvage strategy, or radiation therapy regimen. Mean DR radiation therapy was 18.64 and better in patients who had PBRT compared with WPRT (P = .034; 24.39 vs. 15.24). Patient-reported bowel and urinary symptoms were worse after WPRT compared with PBRT (both P < .05); general HRQOL was numerically but not significantly better after PBRT without WPRT (P = .055). Subset analyses identified increased bowel and urinary symptom scores after WPRT irrespective of higher or lower dose cohorts (all P < .05)., Conclusions: WPRT was associated with increased symptom burden and decision regret compared with PBRT. It is uncertain if the results can be extrapolated to lower-dose (<70 Gy) regimens. Further research is required to evaluate if specific decision support tools or treatment modifications according to the individual risk situation may be beneficial in this setting., (Copyright © 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the mRNA expression of lymphangiogenesis and proliferation markers and to examine its association with histopathological characteristics and clinical outcome in patients with urothelial carcinoma of the bladder (UCB) after radical cystectomy (RC)., Patients and Methods: Gene expression analysis of the vascular endothelial growth -C and -D (VEGF-C/-D), its receptor VEGF receptor-3 (VEGFR-3), MKI67, and RACGAP1 was performed in 108 patients after radical cystectomy and their correlation with clinical-pathological parameters was investigated. Uni- and multivariate regression analyses were used to identify predictors for cancer-specific survival (CSS), recurrence-free survival (RFS) and overall survival (OS) after RC., Results: The expression of RACGAP1 and VEGFR-3 showed an association with a higher pT stage (P = 0.049; P = 0.009). MKI67 showed an association with a high-grade urothelial carcinoma of the bladder (P = 0.021). VEGFR-3 expression was significantly associated with the presence of lymphovascular invasion (LVI) (P = 0.016) and lymph node metastases (pN+) (P = 0.028). With the univariate analysis, overexpression of VEGFR-3 (P = 0.029) and the clinical-pathological parameters pT stage (P < 0.0001), pN+ (P = 0.0004), LVI (P < 0.0001) and female gender (P = 0.021) were significantly associated with a reduced CSS. Multivariate analysis identified a higher pT stage (P = 0.017) and LVI (P = 0.008) as independent predictors for reduced CSS. Independent predictors for reduced OS were a higher pT stage (P = 0.0007) and LVI (P = 0.0021), while overexpression of VEGF-D was associated with better OS (P < 0.0001)., Conclusions: The mRNA expression of the investigated markers showed associations with common histopathological parameters. Increased expression of VEGF-D is independently associated with better overall survival., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Enhancer of zeste homolog 2 is a methyltransferase encoded by the EZH2 gene, whose role in upper tract urothelial carcinoma (UTUC) is poorly understood. We sought to evaluate the prognostic value of EZH2 expression in UTUC., Methods: We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy for high-grade UTUC from 1990 to 2008. Immunohistochemistry for EZH2 was performed on tissue microarrays. Percentage of staining was evaluated, and the discriminative value of EZH2 was tested, with EZH2 positivity defined as>20% staining present. Clinicopathologic characteristics and oncologic outcomes (recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS)) were compared, stratified by EZH2 positivity. The prognostic role of EZH2 was assessed using Kaplan-Meier, univariate (UVA), and multivariate (MVA) Cox regression analyses. Significance was defined for P<0.05., Results: A total of 376 patients were included for analysis, with median follow-up 36.0 months. Overall, 78 (20.7%) were EZH2-positive. EZH2 expression was more often associated with ureteral location, lymphovascular invasion, sessile architecture, necrosis, and concomitant carcinoma in situ. On UVA, increased EZH2 expression was a significant predictor for inferior RFS (HR 1.63, P = 0.033), CSS (HR 2.03, P = 0.003), and OS (HR 2.11, P<0.001). On MVA EZH2 remained a significant predictor of worse CSS (HR 1.99 [95% CI: 1.21-3.27], P = 0.007) and OS (HR 1.54 [95% CI: 1.06-2.24], P = 0.024), while significance was lost for RFS., Conclusion: Increased EZH2 expression is associated with adverse pathologic features and inferior oncologic outcomes in patients with high-grade UTUC. The role of EZH2 biology in UTUC pathogenesis remains to be further elucidated., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Case volume has been suggested to affect surgical outcomes in different arrays of procedures. We aimed to delineate the relationship between case volume and surgical outcomes and quality of care criteria of radical cystectomy (RC) in a prospectively collected multicenter cohort., Patients and Methods: This was a retrospective analysis of a prospectively collected European cohort of patients with bladder cancer treated with RC in 2011. We relied on 479 and 459 eligible patients with available information on hospital case volume and surgeon case volume, respectively. Hospital case volume was divided into tertiles, and surgeon volume was dichotomized according to the median annual number of surgeries performed. Binomial generalized estimating equations controlling for potential known confounders and inter-hospital clustering assessed the independent association of case volume with short-term complications and mortality, as well as the fulfillment of quality of care criteria., Results: The high-volume threshold for hospitals was 45 RCs and, for high-volume surgeons, was > 15 cases annually. In adjusted analyses, high hospital volume remained an independent predictor of fewer 30-day (odds ratio, 0.34; P = .002) and 60- to 90-day (odds ratio, 0.41; P = .03) major complications but not of fulfilling quality of care criteria or mortality. No difference between surgeon volume groups was noted for complications, quality of care criteria, or mortality after adjustments., Conclusion: The coordination of care at high-volume hospitals might confer a similar important factor in postoperative outcomes as surgeon case volume in RC. This points to organizational elements in high-volume hospitals that enable them to react more appropriately to adverse events after surgery., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Tumor progression is associated with aberrant hemostasis, and patients with malignant diseases have an elevated risk of developing thrombosis. A crosstalk among the vascular endothelium, components of the coagulation cascade, and cancer cells transforms the intravascular milieu to a prothrombotic, proinflammatory, and cell-adhesive state. We review the existing evidence on activation of the coagulation system and its implication in genitourinary malignancies and discuss the potential therapeutic benefit of antithrombotic agents. A literature review was performed searching the Medline database and the Cochrane Library for original articles and reviews. A second search identified studies reporting on oncological benefit of anticoagulants in genitourinary cancer. An elevated expression of procoagulatory tissue factor on tumor cells and tumor-derived microparticles seems to stimulate cancer development and progression. Several components of the hemostatic system, including D-dimers, von Willebrand Factor, thrombin, fibrin-/ogen, soluble P-selectin, and prothrombin fragments 1 + 2 were either overexpressed or overactive in genitourinary cancers. Hypercoagulation was in general associated with a poorer prognosis. Experimental models and small trials in humans showed reduced cancer progression after treatment with anticoagulants. Main limitations of these studies were heterogeneous experimental methodology, small patient numbers, and a lack of prospective validation. In conclusion, experimental and clinical evidence suggests procoagulatory activity of genitourinary neoplasms, particularly in prostate, bladder and kidney cancer. This may promote the risk of vascular thrombosis but also metastatic progression. Clinical studies linked elevated biomarkers of hemostasis with poor prognosis in patients with genitourinary cancers. Thus, anticoagulation may have a therapeutic role beyond prevention of thromboembolism., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Guidelines recommend neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) in patients with urothelial carcinoma of the bladder in clinical stages T2-T4a, cN0M0. We examined the frequency and current practice of NAC and sought to identify predictors for the use of NAC in a prospective contemporary cohort., Materials and Methods: We analyzed prospective data from 679 patients in the PROMETRICS (PROspective MulticEnTer RadIcal Cystectomy Series 2011) database. All patients underwent RC in 2011. Uni- and multivariable regression analyses identified predictors of NAC application. Furthermore, a questionnaire was used to evaluate the practice patterns of NAC at the PROMETRICS centers., Results: A total of 235 patients (35%) were included in the analysis. Only 15 patients (2.2%) received NAC before RC. Younger age (< 70 years; P = .035), lower case volume of the center (< 30 RC/year; P < .001), and advanced tumor stage (≥ cT3; P = .038) were identified as predictors for NAC. Of the 200 urologists who replied to the questionnaire, 69% (n = 125) declared tumor stage cT3-4 a/o N1M0 to be the best indication for NAC application, although 45% of the urologists stated that they would not perform NAC despite recommendations. The decision for NAC was made by the individual urologist in 69% of cases, and only 29% reported that all cases were discussed in an interdisciplinary tumor board., Conclusion: NAC was rarely applied in the present cohort. We observed a discrepancy between guideline recommendations and practice patterns, despite medical indication and pre-therapeutic interdisciplinary discussion. The potential benefit of NAC within a multimodal approach seems to be neglected by many urologists., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Mammalian kidneys are rich in sulfatides. Papillary sulfatides, especially, contribute to renal adaptation to chronic metabolic acidosis. Due to differences in their cer-amide (Cer) anchors, the structural diversity of renal sulfatides is large. However, the underling biological function of this complexity is not understood. As a compound's function and its tissue location are intimately connected, we analyzed individual renal sulfatide distributions of control and Cer synthase 2 (CerS)2-deficient mice by imaging MS (IMS) and by LC-MS(2) (in controls for the cortex, medulla, and papillae separately). To explain locally different structures, we compared our lipid data with regional mRNA levels of corresponding anabolic enzymes. The combination of IMS and in source decay-LC-MS(2) analyses revealed exclusive expression of C20-sphingosine-containing sulfatides within the renal papillae, whereas conventional C18-sphingosine-containing compounds were predominant in the medulla, and sulfatides with a C18-phytosphingosine were restricted to special cortical structures. CerS2 deletion resulted in bulk loss of sulfatides with C23/C24-acyl chains, but did not lead to decreased urinary pH, as previously observed in sulfatide-depleted kidneys. The reasons may be the almost unchanged C22-sulfatide levels and constant total renal sulfatide levels due to compensation with C16- to C20-acyl chain-containing compounds. Intriguingly, CerS2-deficient kidneys were completely depleted of phytosphingosine-containing cortical sulfatides without any compensation., (Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)

Objectives: To evaluate the role of lymph vessel density (LVD) and lymphangiogenesis in nonseminomatous testicular germ cell tumors (NSGCT) using the specific lymphatic endothelial cell (LEC) marker LYVE-1., Materials and Methods: NSGCT specimens of 77 patients (32 with and 45 without metastases) were stained immunohistochemically using a LYVE-1 antibody. LVD was measured in different representative areas by the standardized "hot spot" method. Fluorescence double stainings for LYVE-1 and Ki-67 were performed. The median follow-up period was 46 (range 3-170) months., Results: The mean peritumoral (2.16 ± 2.17) and nontumoral LVD (3.17 ± 3.24) were significantly higher than intratumoral LVD (0.16 ± 0.73) (both: P = < 0.001). In 5 patients proliferating LECs were observed. The peritumoral LVD was 2.66 (± 2.31) and 1.80 (± 2.02) in metastatic and nonmetastatic NSGCT, respectively. A higher peritumoral LVD was associated with the presence of metastases at the time of diagnosis (P = 0.087). The mean peritumoral LVD in tumors with and without lymphovascular invasion (LVI) was 3.33 (± 2.20) and 1.62 (± 1.95), respectively (P < 0.001). The presence of LVI detected by LYVE-1 (LVI-LYVE-1) was independently associated with metastatic disease (logistic regression; P = 0.045)., Conclusions: The presence of a high peritumoral LVD and LVI-LYVE-1 are both associated with metastatic disease in NSGCT. LVI-LYVE-1 was independently associated with the presence of metastases at the time of diagnosis. Proliferating LECs are present, suggesting that lymphangiogenesis may promote metastatic dissemination of tumor cells in NSGCT., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To evaluate the expression of multiple lymph-specific markers and to test its association with histopathological characteristics and clinical outcomes in patients with urothelial carcinoma of the bladder (UCB) treated by radical cystectomy (RC)., Patients and Methods: Vascular endothelial growth factor-C and -D (VEGF-C/-D), its receptor VEGF receptor-3 (VEGFR-3), and chemokine receptor type 7 (CCR7) expressions were assessed by immunohistochemistry in RC specimens of 119 patients. Semiquantitative analyses of marker expressions were correlated with clinical and pathological characteristics. Univariable and multivariable analyses were performed to identify predictors of disease-specific survival (DSS) and recurrence free survival (RFS)., Results: VEGF-C, VEGF-D, VEGFR-3, and CCR7 were overexpressed in 37.8%, 26.2%, 50.4%, and 23.5% of UCB samples, respectively. VEGF-D overexpression was significantly associated with a positive lymph node status (pN+). On univariable analysis, a higher pT stage, pN+, the presence of lymphovascular invasion (LVI) and vascular invasion (VI) (all P<0.001), and overexpressions of VEGF-D (P = 0.049) and VEGFR-3 (P = 0.032) were significantly associated with reduced DSS. On multivariable analysis, pT stage (P = 0.002) and pN+status (P = 0.009) were identified as independent predictors of reduced DSS. In a subgroup of patients without lymph node metastasis (pN0; n = 75), pT stage (P = 0.043) and VEGFR-3 overexpression (P = 0.008) were independent predictors of reduced DSS., Conclusion: Lymph-specific markers are frequently overexpressed in UCB. VEGF-D overexpression is associated with the presence of lymphatic metastasis. In patients without lymph node metastasis at the time of RC, an assessment of VEGFR-3 expression may improve the identification of high-risk patients. These findings require prospective validation to determine the potential benefit of more aggressive adjuvant treatment., (© 2013 Published by Elsevier Inc.)

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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the role of lymph vessel density (LVD) and lymphangiogenesis in seminomatous testicular cancer (STC) by using the lymphatic endothelial cell (LEC) markers LYVE-1 and D2-40., Methods and Materials: Paraffin embedded tumor specimens from 40 patients with STC were stained by specific D2-40 and Lyve-1 antibodies. LVD was measured in different representative and standardized areas. Fluorescence double immunostaining for Lyve-1 and Ki-67 was performed and results were correlated with clinicopathologic data. The median follow-up period was 55 (range 10-135) months., Results: Mean intratumoral LVD (D2-40: 1.30 ± 1.99; Lyve-1: 1.82 ± 2.34) was significantly lower than peritumoral LVD (D2-40: 4.94 ± 2.58; Lyve-1: 4.62 ± 2.73) and LVD in nontumoral areas (D2-40: 4.81 ± 3.79; Lyve-1: 4.22 ± 3.19). There was no significant difference between LVD measures when using D2-40 or LYVE-1. Detection rates of lymphatic vascular invasion (LVI) were significantly higher than in conventional HE-stained sections (77.5% vs. 52.5%). No proliferating lymphatic vessels were found., Conclusions: We found that LVD is decreased within tumor areas of STC. Despite a higher peritumoral LVD, no signs of proliferating endothelial cells were observed, suggesting a lack of lymphangiogenesis in STC. Detection of LVI can be optimized by specific D2-40 or LYVE-1 staining., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Bladder cancer (UCB) staged pT4a show heterogeneous outcome after radical cystectomy (RC). No risk model has been established to date. Despite gender-specific differences, no comparative studies exist for this tumor stage., Materials and Methods: Cancer-specific survival (CSS) of 245 UCB patients without neoadjuvant chemotherapy staged pT4a, pN0-2, M0 after RC were analyzed in a retrospective multi-center study. Seventeen patients were excluded from further analysis due to carcinoma in situ (CIS) of the prostatic urethra and/or positive surgical margins. Average follow-up period was 30 months (IQR: 14-45). The influence of different clinical and histopathologic variables on CSS was determined through uni- and multivariate Cox regression analyses. Two risk groups were generated using factors with independent effect in multivariate models. Internal validity of the prediction model was evaluated by bootstrapping., Results: Eighty-four percent of the patients (n = 192) were male; 72% (n = 165) showed lymphovascular invasion (LVI). The 5-year CSS rate was 31%, and significantly different between male and female (35% vs. 15%, P = 0.003). Multivariate Cox regression modeling, female gender (HR = 1.83, P = 0.008), LVI (HR = 1.92, P = 0.005), and absence of adjuvant chemotherapy (HR = 0.61, P = 0.020) significantly worsened CSS. Two risk groups were generated using these 3 criteria, which differed significantly between each other in CSS (5-year-CSS: 46% vs. 12%, P < 0.001). The c-index value of the risk model was 0.61 (95% CI: 0.53-0.68, P < 0.001)., Conclusions: Prognosis in UCB staged pT4a is heterogeneous. Female gender and LVI are adverse factors. Adjuvant chemotherapy seems to improve outcome. The present analysis establishes the first risk model for this demanding tumor stage., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: The natural history of urothelial carcinoma arising at the uretero-enteric junction (UEJ) is poorly defined, and the data guiding clinical management of these patients is limited. Therefore, we evaluated oncologic outcomes of patients treated for urothelial carcinoma at the UEJ., Methods: Utilizing a multi-institutional database of patients treated with radical nephroureterectomy (RNU), we assessed the clinicopathologic parameters and oncologic outcomes of UEJ tumors compared with other upper tract urothelial carcinomas (UTUC). Survival analyses were performed to determine independent predictors of disease recurrence and cancer-specific mortality after RNU., Results: The study included 1,363 patients, 921 men and 442 women with 36 months median follow-up after RNU. Compared with UTUC in the kidney or ureter, UEJ tumors (n = 22) were more likely to demonstrate features of advanced disease, which were proved to be independent predictors of disease recurrence and cancer-specific mortality after RNU. The 5 year disease-free survival (DFS) and cancer-specific survival (CSS) rates were 25% and 39% in those with UEJ tumors vs. 69% and 73% in those with UTUC in the kidney or ureter (P = 0.001 and P = 0.008, respectively)., Conclusions: UEJ tumors harbor features of locally advanced disease associated with high risk of systemic recurrence and death from cancer after RNU. Our findings suggest the need for integration of systemic therapy into the management paradigm of these patients., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: To test the sensitivity of urinary cytology at a tertiary academic institution and to assess the impact of pathologist' experience on detection of urothelial carcinoma of the bladder (UCB)., Materials and Methods: Between April 1999 and September 2008, 8,574 cytology specimens were evaluated. There were 882 consecutive patients (612 males, 270 females) who underwent bladder biopsy or transurethral resection of bladder tumor for UCB. Sensitivity rates of prior urinary cytology were determined. We tested the influence of experience of pathologist on sensitivity., Results: Urinary cytology detected 237 out of 503 UCB (overall sensitivity 47.1%). Cytology after bladder washing resulted in higher sensitivity than in voided urine (50.4% vs. 36.2%; P = 0.008). Sensitivity rates significantly increased by UCB stage; 30.6% in pTa (n = 245), 60.5% in patients with any form of CIS (n = 119), 62.9% in pT1 (n = 89), and 69.6% in ≥pT2 (n = 46; P < 0.001). Similarly, higher sensitivity was observed with increasing grade, ranging from 16.7% in low (n = 108) to 62.2% in high grade tumors (n = 283; P < 0.001). No statistically significant difference between more and less experienced investigators was observed., Conclusions: Sensitivity rates of urinary cytology at our institution are not superior to those reported in the literature. Cytology missed many high grade cancers, pointing to inherent methodological limitations of urinary cytology. A higher experience level of the pathologist was not significantly associated with higher sensitivity rates. Urinary cytology represents a flawed adjunct to cystoscopy with limited potential of improvement even in the hands of experienced pathologists., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aim: The outcome of patients with urothelial carcinoma of the bladder (UCB) after radical cystectomy (RC) shows remarkable variability. We evaluated the ability of artificial neural networks (ANN) to perform risk stratification in UCB patients based on common parameters available at the time of RC., Methods: Data from 2111 UCB patients that underwent RC in eight centers were analysed; the median follow-up was 30 months (IQR: 12-60). Age, gender, tumour stage and grade (TURB/RC), carcinoma in situ (TURB/RC), lymph node status, and lymphovascular invasion were used as input data for the ANN. Endpoints were tumour recurrence, cancer-specific mortality (CSM) and all-cause death (ACD). Additionally, the predictive accuracies (PA) of the ANNs were compared with the PA of Cox proportional hazards regression models., Results: The recurrence-, CSM-, and ACD- rates after 5 years were 36%, 33%, and 46%, respectively. The best ANN had 74%, 76% and 69% accuracy for tumour recurrence, CSM and ACD, respectively. Lymph node status was one of the most important factors for the network's decision. The PA of the ANNs for recurrence, CSM and ACD were improved by 1.6% (p = 0.247), 4.7% (p < 0.001) and 3.5% (p = 0.007), respectively, in comparison to the Cox models., Conclusions: ANN predicted tumour recurrence, CSM, and ACD in UCB patients after RC with reasonable accuracy. In this study, ANN significantly outperformed the Cox models regarding prediction of CSM and ACD using the same patients and variables. ANNs are a promising approach for individual risk stratification and may optimize individual treatment planning., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: To perform the first external validation of a recently identified association between disease-free survival at two years (DFS2) or three years (DFS3) and overall survival at five years (OS5) in patients after radical cystectomy (RC) for muscle-invasive urothelial carcinoma of the bladder (UCB)., Methods and Methods: Records of 2483 patients who underwent RC for UCB at eight European centers between 1989 and 2008 were reviewed. The cohort included 1738 patients with pT2-4a tumors and negative soft tissue surgical margins (STSM) according to the selection criteria of the previous study (study group (SG)). In addition, 745 patients with positive STSM or other tumor stages (pT0-T1, pT4b) that were excluded from the previous study (excluded patient group (EPG)) were evaluated. Kappa statistic was used to measure the agreement between DFS2 or DFS3 and OS5., Results: The overall agreement between DFS2 and OS5 was 86.5% (EPG: 88.7%) and 90.1% (EPG: 92.1%) between DFS3 and OS5. The kappa values for comparison of DFS2 or DFS3 with OS5 were 0.73 (SE: 0.016) and 0.80 (SE: 0.014) respectively for the SG, and 0.67 (SE: 0.033) and 0.78 (SE: 0.027) for the EPG (all p-values <0.001)., Conclusions: We externally validated a correlation between DFS2 or DFS3 and OS5 for patients with pT2-4a UCB with negative STSM that underwent RC. Furthermore, this correlation was found in patients with other tumor stages regardless of STSM status. These findings indicate DFS2 and DFS3 as valid surrogate markers for survival outcome with RC., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Carcinoma in situ (CIS) is associated with increased risk of progression when found with high-grade non-muscle-invasive bladder cancer, yet its impact is less clear in the upper urinary tract. In the current study, we evaluated the impact of concomitant CIS on recurrence-free survival and cancer-specific survival following radical nephroureterectomy for upper tract urothelial carcinoma (UTUC)., Materials and Methods: A multi-institutional retrospective cohort of 1,387 patients undergoing radical nephroureterectomy was identified. Concomitant CIS was defined as the presence of CIS in association with another pathologic stage; patients with CIS alone were excluded from the analysis. The presence of concomitant CIS served as the exposure variable with disease recurrence and cancer-specific mortality as the outcomes. Organ-confined disease was defined as AJCC/UICC stage II or lower., Results: Concomitant CIS was identified in 371 of 1,387 (26.7%) patients and was significantly more common in patients with a previous bladder cancer history, high grade, and high stage tumors. In a multivariable analysis, concomitant CIS was a predictor of disease recurrence (HR = 1.25, P = 0.04) and cancer specific mortality (HR = 1.34, P = 0.05) for patients with organ-confined UTUC, but not in the entire cohort. Other prognostic variables, such as grade, stage, lymphovascular invasion, and lymph node status, were associated with poorer overall and recurrence-free survival for all patients., Conclusion: The presence of concomitant CIS in patients with organ-confined UTUC is associated with a higher risk of recurrent disease and cancer-specific mortality. This information may be useful in refining surveillance protocols and in more appropriate selection of patients for adjuvant chemotherapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To examine the potential effect of tumor-induced angiogenesis in squamous cell carcinoma of the penis as a possible prognostic factor., Patients and Methods: Immunohistochemistry was preformed to detect microvessels in tumor samples of 64 patients with squamous cell carcinoma of the penis. We used a monoclonal mouse antibody directed against CD34 antigen. Only 61 (30 with and 31 without metastasis) patients had good staining properties and were included. After immunostaining, the entire tumor section was scanned microscopically at low power (× 40) to identify hot spots within the tumor and at its periphery. Individual tumor microvessels were then counted under high power (× 200) to obtain a vessel count in a defined area, and the mean of the 3 highest microvessel counts was taken as the microvessel density (MVD). Microvessel counting was performed using a computer-aided image analysis system. The nodal status was based on histopathologic examination or an uneventful follow-up ≥ 2 years., Results: The 5-year overall survival (OAS) was 75% and 30 % for those with high and low peritumoral MVD, respectively (log rank P = 0.01). No difference was noticed within the tumor with regard to high (5-year OAS of 65.03%) and low (5-year OAS of 60.56%) intratumoral MVD (log rank P = 0.99). The mean intratumoral MVD was 32.35 (3.16), 37.94 (3.35), and 62.66 (5.47) in T1, T2, and T3 respectively (ANOVA P = 0.0006), with increasing tendency. The mean peritumoral MVD was 55.91 (5.60), 56.8 (4.00), and 78.86 (8.71), respectively (P = 0.06). No correlation between MVD lymph node status and tumor grade was seen (P > 0.05)., Conclusion: In our group of patients, a high peritumoral MVD was associated with a better 5-year OAS. However, for a reliable and reproducible assessment of tumor angiogenesis in penile squamous cell carcinoma, validation procedures and quality control protocols are mandatory., (Copyright © 2012. Published by Elsevier Inc.)

With a diagnosis of squamous cell carcinoma of the penis, there is still a significant need to define the tumor criteria that allow the disease to be stratified according to the risk of developing lymph node metastases. The histopathology of the primary tumor in 72 consecutive patients with resected squamous cell carcinoma of the penis was reviewed for this study. Tumor tissue was reviewed for (1) histologic grade, (2) invasion pattern, (3) tumor stage, (4) proportion of poorly differentiated tumor cells, (5) invasion depth, (6) proportion of tumor necrosis, (7) angioinvasion, (8) histologic classification, (9) number of lesions, (10) growth pattern, (11) number of mitoses, (12) degree of keratinization, and (13) clinical groin status. It was found that the presence of inguinal lymph node metastases correlated in descending order of frequency with grade G2/G3, clinically positive groin status, reticular invasion, stage pT2/T3, >50% poorly differentiated tumor cells, depth of invasion, and comedolike tumor necrosis. These results revealed that the risk of inguinal lymph node metastasis in penile carcinoma can be predicted on the basis of 3 major factors: histologic grade, pattern of invasion, and clinical groin status., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: To evaluate if preoperative symptom classification could refine prediction of outcomes for patients with clinically localized upper-tract urothelial carcinoma (UTUC) managed by radical nephroureterectomy (RNU)., Methods: Data on 654 patients with localized UTUC who underwent RNU were reviewed. Preoperative symptoms were classified as incidental (S1), local (S2), and systemic (S3). Clinical and pathologic data were compared between the cohorts. Kaplan-Meier analyses and Cox proportional hazard modeling were used to determine recurrence-free and cancer-specific survival amongst the symptom cohorts., Results: Symptom classification was S1 in 213 (33%) patients, S2 in 402 (61%), and S3 in 39 (6%). S3 symptoms were associated with advanced pathology, including higher stage, grade, and lymph node (LN) positivity. Five and 10-year recurrence-free and cancer-specific survival estimates were similar for patients with S1 and S2 symptoms (P = 0.75 and 0.58, respectively), but was worse for patients with S3 symptoms (P < 0.001 for both). On multivariate analysis adjusting for final pathologic stage, grade, and LN status, S3 symptoms were not an independent predictor of recurrence (HR 1.44, P = 0.19) or death due to disease (HR 1.66, P = 0.07). Addition of symptom classification, however, increased the accuracy of a model consisting of stage, grade, and LNs for prediction of recurrence-free and cancer-specific survival by 1.4% and 1.3%, respectively (P < 0.001 for both)., Conclusions: Local symptoms do not confer worse prognosis compared with patients with incidentally detected UTUC. However, systemic symptoms are associated with worse outcomes despite apparently effective RNU. Patients with systemic symptoms may harbor micrometastatic disease and could potentially benefit from a more rigorous metastatic evaluation or perioperative chemotherapy regimens., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: Information on the association of perioperative parameters with costs for robotic-assisted laparoscopic radical prostatectomy (RALP) is lacking. Understanding factors that impact cost may allow reduction in cost of prostate cancer care. We identified factors associated with higher costs in a contemporary series of RALP., Materials and Methods: Total direct cost and clinicopathologic data were available for 264 patients who underwent RALP at our institution between May 2005 and April 2008. We performed linear regression analyses to identify predictors of direct cost using preoperative, intraoperative, and postoperative variables., Results: On univariable analyses, operating room (OR) time, placement of a pelvic drain (both P<0.001), complications during surgery (P=0.002) or hospitalization, blood transfusion, and length of stay (all P<0.001) were associated with higher direct costs. On multivariable analysis, none of the preoperative features were found to predict direct costs. Of the intraoperative factors, OR time (P<0.001) and pelvic drain placement (P=0.006) were associated with higher direct costs. A longer OR time, length of stay, and usage of transfusions (all P<0.001) during the postoperative course were independently associated with higher direct costs., Conclusions: Of factors that are available preoperatively, none seems to be useful to predict added costs for individual patients undergoing RALP. Higher costs for RALP are driven by events occurring during the procedure or postoperative hospital stay., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Therapy failure after intravesical and systemic chemotherapy for transitional cell carcinoma (TCC) is still high. Antiapoptotic proteins such as Bcl-2 and Bcl-xL have been reported to promote chemoresistance in TCC. Targeting bcl-2 and bcl-xL messenger ribonucleic acid with antisense oligodeoxynucleotides (AS-ODNs) may enhance the cytotoxic effects of chemotherapeutic agents. Therefore, we investigated the effects of bcl-2 and bcl-xL AS-ODNs in combined treatment with conventional and new chemotherapeutic agents to evaluate the cytotoxic effects in comparison to monotreatment., Methods and Materials: Western blot analysis or immunohistochemistry verified Bcl-2 and Bcl-xL expression in a panel of human TCC cell lines that had been monotreated with cisplatin, gemcitabine, mitomycin C, and paclitaxel. In addition, bcl-2 or bcl-xL AS-ODNs were applied in combination with each chemotherapeutic agent. Cell viability was determined using a standard MTT assay and Neubauer hemocytometry., Results: All cell lines responded to chemotherapeutic monotreatment in a dose-dependent manner. Maximum cell death rates after monotreatment were 47.4% (cisplatin), 39.0% (gemcitabine), 83.4% (mitomycin C), and 54.8% (paclitaxel). After combined treatment with chemotherapy and bcl-2 or bcl-xL AS-ODNs, cell death rates were significantly higher (e.g., 30.3% vs. 87.2% in HT 1197 cells for monotreatment vs. the combination of paclitaxel and bcl-xL AS-ODNs). Three-way analysis of variance revealed that combined treatment had a significant effect on all cell lines., Conclusions: Our study confirms that the addition of bcl-2 and bcl-xL AS-ODNs enhances the cytotoxic potential of chemotherapeutic agents in TCC cell lines as a result of combined effects. Further trials in ex vivo and in vivo models have to be performed to promote clinical application in patients.

Background: Pulmonary artery stenosis remains the most frequent late complication and cause of reintervention after the arterial switch operation for transposition of the great arteries. We investigated the influence of an extended pericardial patch augmentation of the neopulmonary root and pulmonary artery on late pulmonary artery stenosis development., Methods: Augmentation of the neopulmonary root and pulmonary artery was achieved by reconstructing the posterior wall using a large glutaraldehyde-treated autologous pericardial patch. Reviewed were regular follow-up echocardiograms from 58 out of 87 patients undergoing the arterial switch operation who presented a follow-up period of at least 5 years. An actual follow-up echocardiographic evaluation focusing on the maximal instantaneous transpulmonary continuous-wave (cw)-Doppler gradient was performed, followed by cardiac catheterization when indicated (peak cw-Doppler gradient > 40 mm Hg)., Results: Follow-up was 8.9 [5 to 15] years. There was no reintervention due to residual pulmonary artery stenosis. Actual Doppler examination revealed a transpulmonary peak gradient of 19.5 [0 to 56] mm Hg, compared with 20 [0 to 60] mm Hg at discharge. Forty-three patients (74.1%) had no or only trivial pulmonary artery stenosis (pressure gradient < 25 mm Hg), 14 patients (24.2%) had mild stenosis (25 to 49 mm Hg), and 1 patient (1.7%) had moderate stenosis (50 to 79 mm Hg)., Conclusions: Compared with the majority of literature data, we could demonstrate a low incidence of late pulmonary artery stenosis after the arterial switch operation by employing an extended pericardial patch reconstruction technique with augmentation of the neopulmonary root and pulmonary artery.