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The initial substrate inhibiting island growth and the formation of an interfacial layer with uncontrollable characteristics are the two main drawbacks of the Atomic Layer Deposition (ALD) of high-k metal-oxide gate dielectrics on silicon (Si). In this paper, we investigate the ALD of Al2O3 films from trimethyl aluminum and H2O, on fluorhydric acid (HF) cleaned, as well as on HF-cleaned and in situ N2-NH3 plasma pretreated Si between 0 and 75 cycles. The films and their interface were characterized via Scanning Transmission Electron Microscopy coupled to Energy-Dispersive X-ray spectroscopy. The initial deposition is clearly increased on the pretreated surfaces, obtaining a linear ALD regime even after 5 ALD cycles, compared to several tens of cycles needed on HF-cleaned Si. Furthermore, a SixNy layer is formed by the N2-NH3 plasma pretreatment, which acts as a barrier layer, reducing the oxidation of the Si substrate beneath it. This analysis provides a general framework for the understanding and determination of adequate surface pretreatments, able to combat the substrate inhibited initial growth and the Si oxidation during metal-oxide ALD on Si. [ABSTRACT FROM AUTHOR]

We assessed the accuracy of frozen section analysis (FSA) for detecting malignant urethral margins during radical cystectomy for bladder cancer. FSA for detecting malignant urethral margins is high on initial examination but drops considerably in case of re-resection. A positive urethral FSA was the only independent risk for a positive final margin. Conversion of a positive FSA finding to a negative final margin was associated with a lower risk of urethral recurrence. Objective: To assess the accuracy of frozen section analysis (FSA) for detecting and eliminating malignant urethral margins during radical cystectomy (RC) for bladder cancer (BC) and its impact on urethral recurrence. Methods: Urethral margins were initially examined by FSA in 217 patients at RC. When positive, additional resections were performed. Subsequently, all specimens were re-examined on formalin-fixed, paraffin-embedded sections (FFPE). Malignancy was defined as either the presence of carcinoma in situ, high-grade or invasive tumor cells at the urethral margin. Kaplan-Meier analysis was used to assess the impact of the final urethral margin status on urethral recurrence. Multinomial logistic regression addressed independent risk factors for a positive final urethral margin. Results: At initial examination, urethral margins were positive on FSA and FFPE in 21 (9.7%) and 17 (7.8) patients, respectively. The corresponding sensitivit y, specificit y, positive and negative predictive values were 88.2%, 97.0%, 71.4% and 99.0% (overall accuracy: 96.3%). After initial FSA, 23 patients (including 2 with equivocal histological findings) received re-resections (median: 1, total range: 1-3). Persistent positive margins were detected on FSA in 10 (43.5%) while none of these margins were positive on FFPE (overall accuracy: 52.2%). A positive urethral FSA at initial assessment was the only independent risk for a positive final urethral margin. The 3-year urethral recurrence-free survival was 99.1% for patients with negative margins on initial assessment (I), 100% for those with negative final margins after re-resection (II) and 83.3% for patients with positive final margins (III; P = .013 for I/II vs. III). Conclusions: The accuracy of FSA for detecting malignant urethral margins is high on initial examination but drops considerably in case of re-resection while most positive margins at initial FSA are converted to negative final ones on FFPE. Conversion of a positive to a negative margin was associated with a lower risk of urethral recurrence. [ABSTRACT FROM AUTHOR]

This retrospective analysis investigated the predictive and prognostic value of serum gammaglutamyltransferase (GGT) in 324 patients undergoing RC for invasive bladder cancer (BC). Elevated preoperative serum GGT levels was associated with increased risk of locally advanced BC and mortality after RC. The data suggest that GGT levels may be a useful for improved prognostication in invasive BC. Introduction: The aim of the study was to elucidate the predictive and prognostic value of serum gammaglutamyltransferase (GGT) in patients with invasive bladder cancer (BC). Patients and Methods: Preoperative serum GGT concentrations were assessed in 324 patients treated with RC for cM0 BC between 2002 and 2013. Laboratory values were obtained 1 to 3 days prior to RC. Uni- and multivariable analyses were carried out to evaluate clinicopathologic risk factors for survival. The median follow-up was 36 months (IQR: 10-55). Results: Elevated preoperative GGT levels were diagnosed in 77 patients (23.8%). Elevated GGT was significantly associated with higher ECOG PS and tumor stage (both P = .001), lymph-node tumor involvement (P < .001), positive surgical margins (P = .018), lymphovascular invasion (P = .024), muscle-invasive disease at primary diagnosis (P = .033), increased tumor size (P = .035), hydronephrosis at RC (P = .049) and increased preoperative CRP, GPT and GOT levels (both P < .001). Patients with elevated GGT had decreased 3-year overall (49.2% vs. 69.6%; P = .005) and cancer-specific survival (71.1% vs. 80.9%; P = .042) compared with patients with normal levels. On multivariable analysis, advanced tumor stage (P = .032), lymph node positive disease (P = .030), positive soft tissue surgical margins (P = .014), hydronephrosis at RC (both P = .010), higher ECOG performance status and elevated GGT (P = .043) levels were independent predictors of all-cause mortality. Conclusion: Elevated preoperative serum GGT levels are associated with increased risk of locally advanced BC and mortality after RC. These data suggest that GGT levels may be useful for improved prognostication in invasive BC. [ABSTRACT FROM AUTHOR]

To assess whether single-nucleotide polymorphisms (SNPs) of the 8q24 chromosome region are associated with recurrence-free survival (RFS) after radical cystoprostatectomy (RC) in patients with concomitant bladder (BC) and prostate cancer (PC). A cohort of thirty-six patients treated with RC and pelvic lymph node dissection and histologically exhibited invasive BC and incidental PC. Using Sanger sequencing, a total of seven SNPs in the androgen-responsive element of the promoter region of the following genes were assessed in tumor-free lymph nodes and correlated with oncological outcomes: PSCA (rs2294008, rs2978974, rs1045531, rs3736001), MYC (rs6983267), FXBO32 (rs7830622), and MIR151A (rs14974929). The median follow-up was 26 months (range: 4–68). In a dominant model, patients exhibiting rs2978974 as a minor allelic variant of the PSCA gene had worse RFS (32 vs. 75%, p = 0.015). No associations were found for the other SNPs. These data suggest that the rs2978974 of the PSCA gene correlates with inferior BC-specific RFS after RC and should be further evaluated in larger studies. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that affects nearly 2.8 million people each year. MS distinguishes three main types: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS). RRMS is the most common type, with the majority of patients eventually progressing to SPMS, in which neurological development is constant, whereas PPMS is characterized by a progressive course from disease onset. New or additional insights into the role of effector and regulatory cells of the immune and CNS systems, Epstein-Barr virus (EBV) infection, and the microbiome in the pathophysiology of MS have emerged, which may lead to the development of more targeted therapies that can halt or reverse neurodegeneration. Depending on the type and severity of the disease, various disease-modifying therapies (DMTs) are currently used for RRMS/SPMS and PPMS. As a last resort, and especially in highly active RRMS that does not respond to DMTs, autologous hematopoietic stem cell transplantation (AHSCT) is performed and has shown good results in reducing neuroinflammation. Nevertheless, the question of its potential role in preventing disability progression remains open. The aim of this review is to provide a comprehensive update on MS pathophysiology, assessment of MS disability progression and current treatments, and to examine the potential role of AHSCT in preventing disability progression. • New insights into MS pathophysiology hold promise for improving MS treatment. • DMT options for MS treatment continue to expand. • So far, no DMT has proven useful in halting MS disability progression. • AHSCT appears to be a promising alternative, especially in very aggressive RRMS. • AHSCT may play a role in halting progression of MS disability in carefully selected patients. [ABSTRACT FROM AUTHOR]

Objective: To determine whether transurethral en bloc submucosal hydrodissection of bladder tumours (TUEB) improves the quality of the resection compared to conventional transurethral resection of bladder tumour (TURBT) in patients with non‐muscle‐invasive bladder cancer (NMIBC). Patients and Methods: A randomised, multicentre trial (HYBRIDBLUE) was conducted with a superiority design. Six German academic centres participated between September 2012 and August 2015. Based on literature analysis, a sample size for accurate histopathological assessment concerning muscle invasion was assumed to be feasible in 50% (P0 = 0.5) of TURBT and 80% of TUEB cases. After pre‐screening of a total of 305 patients, participants were allocated to two study arms: Group I: hexaminolevulinate (HAL)‐guided TUEB; Group II: conventional HAL‐guided TURBT. The primary endpoint was the proportion of specimens that could be reliably evaluated pathologically concerning muscle invasiveness. Secondary endpoints included rates of histopathological completeness of the resection, muscularis propria content, recurrence, and complication rates. Results: A total of 115 patients (TUEB 56; TURBT 59) were eligible for final analysis. Adequate histopathological assessment, which included muscularis propria content and tumour margins (R0 vs R1), was present in 48/56 (86%) TUEB patients compared to 37/59 (63%; P = 0.006) in the TURBT group. R0 was confirmed in 30/56 TUEB patients (57%) and five of 59 TURBT patients (9%; P < 0.001). No complications of Grade ≥III were observed in both arms. At 3 and 12 months, three and 19 patients recurred in the TUEB group vs seven and 11 patients in the TURBT group, respectively (P = 0.33 and P = 0.08). Conclusions: In this randomised study, TUEB was shown to be clinically safe regarding perioperative endpoints. An adequate histopathological assessment concerning muscle invasion was significantly better assessable in the TUEB arm compared to standard TURBT. This finding indicates the clinical potential for reducing the rate of early re‐resections. Yet, a larger study with recurrence‐free survival as the primary endpoint is needed to assess the oncological efficacy between both techniques. [ABSTRACT FROM AUTHOR]

Introduction: To examine whether previous tonsillectomy (TE) impacts on survival after radical cystectomy (RC) for bladder cancer (BC). Patients and Methods: A total of 320 patients were staged cM0 and underwent RC for BC between 2002 and 2013. We retrospectively investigated whether patients had undergone TE prior to RC. Chi-square/Fisher-Exact test was carried out to compare clinicopathological features between the TE- and non-TE-group. Kaplan–Meier analysis with log-rank test was used to estimate recurrence-free survival (RFS) and multivariable Cox-regression analysis of risk factors of recurrence. The median follow-up was 31 months (interquartile range: 9–54). Results: A history of TE was present in 18 of the 320 patients (5.6%). All TEs were performed for benign conditions. TE prior to RC was associated with a history of appendectomy (p = 0.045), lower age at RC (p = 0.029), tumor unifocality (p < 0.001), advanced histopathological tumor stage (p = 0.015), non-pure urothelial carcinoma (p = 0.025), lymphovascular invasion (p = 0.035) and receipt of palliative chemotherapy (p = 0.004). The 3-year RFS was 39.2% for patients with previous TE and 62.4% for those without (p = 0.008). In multivariable analysis, adjusted for all significant parameters of univariable analysis, lymph-node tumor involvement (p = 0.017), positive surgical margins (p = 0.047), tumor grade (p = 0.032), advanced tumor stage (≥pT3a; p = 0.049) and a history of TE (p = 0.021) remained independent prognosticators of recurrence. Conclusion: In this series, previous TE was an independent predictor of recurrence after RC for BC. Further studies are needed to assess whether TE induces immunological alterations that might exert adverse effects on cancer progression of patients with invasive BC. [ABSTRACT FROM AUTHOR]

During the first stages of Atomic Layer Deposition (ALD) of Al 2 O 3 on silicon (Si), the substrate nature affects the surface chemistry, leading to an initial island growth mode. Furthermore, an interfacial zone develops between the Si surface and the dielectric, thus damaging the physical properties of the deposited structure. In this work, these two main shortcomings are investigated for the ALD of Al 2 O 3 films on Si from TMA and H 2 O. The film and the interfacial zone are characterized by a complete range of techniques, including XRR, TEM, XPS, EDX and ToF-SIMS. In parallel, a computational model is developed to study the initial nucleation and growth steps of the film. An induction period is experimentally evidenced and numerically reproduced, together with the island growth and coalescence phenomena. The chemical composition of the (Al, O, Si) interfacial layer is precisely analyzed to get insight in the mechanisms of its formation. We show that Si oxidation occurs during the island growth, catalyzed by the presence of Al, while it is also fed by species interdiffusion through the ALD film. Unlabelled Image • The initial steps of Al 2 O 3 ALD on Si are studied, experimentally and theoretically. • An induction period is evidenced leading to island growth. • An interface oxide layer is formed between the Al 2 O 3 film and the Si substrate. • The interface consists of SiO x , with possible presence of SiOAl. • The interface is formed during the island growth and through species interdiffusion. [ABSTRACT FROM AUTHOR]

Highlights • Surface mechanisms of alumina ALD are studied using a novel surface kinetic model. • The GPC behavior within the ALD temperature window is investigated. • Competition between desorption and reactions of adsorbed reactants is revealed. • The effect of temperature on the surface kinetics is studied. • The effect of transport phenomena on the uniformity of the film is revealed. Abstract The surface mechanisms involved in the Atomic Layer Deposition of Al 2 O 3 from TMA and H 2 O are investigated by means of combined experimental and computational analyses. Reactant adsorption, desorption and surface reaction are taken into account by a surface chemistry model, coupled to a CFD model for an industrial reactor treating 200 mm substrates. Once the model validated by comparison with experimental deposition rates, the relative contribution of each surface phenomenon is quantitatively determined between 100 and 300 °C through original reaction probability calculations. It is revealed that the competition between surface reactions and desorption of adsorbed H 2 O plays a crucial role in the ALD growth of alumina. The H 2 O desorption is the limiting factor for the growth at low process temperature whereas it is the OH group surface concentration at higher temperature. This integrated (surface chemistry/kinetics and CFD) model shows a direct link between transport phenomena, such as gas flow recirculation and low temperature zones in the reactor, and film uniformity. [ABSTRACT FROM AUTHOR]

Context Urothelial carcinoma is considered a pan-urothelial disease. As such, the remnant urothelium in the upper urinary tract and urethra following radical cystectomy (RC) remains at risk for secondary urothelial tumors (SUTs). Objective To describe the incidence, diagnosis, treatment, and outcomes of patients with SUTs after RC. Evidence acquisition A systematic search was conducted using PubMed database according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to identify studies between 1970 and 2016 reporting on malignant diseases of the urothelium after RC for bladder cancer. The search strategy separated between upper and lower tract urothelial tumors. Evidence synthesis Of a total of 1069 studies, 57 were considered for evidence synthesis. SUTs occured in approximately 4–10% of patients after RC. Carcinoma in situ of the bladder, a history of nonmuscle invasive bladder cancer, and tumor involvement of the distal ureter are the strongest risk factors for secondary upper tract tumors. Risk factors for secondary urethral tumors represent urothelial malignancy in the prostatic urethra/prostate and bladder neck (in women), nonorthotopic diversions, and positive findings on permanent sections. The majority of patients (84%) with SUTs, presented with urothelial recurrence without evidence of metastasis. Of those, 84.0% were treated with surgery, 10.5% with systemic chemotherapy and/or radiotherapy, and 5.6% with topical chemotherapy and/or immunotherapy. After a median follow-up of 91 mo (range: 26–155), 65.9% of patients died of disease and 21.5% died of other causes. Detection and treatment of SUTs at an asymptomatic stage can reduce the risks of cancer-specfific and overall mortality by 30%. A limitation of the study is that the available data were retrospective. Conclusions SUTs are rare oncological events and most patients have an adverse prognosis despite absence of distant disease at diagnosis. Therefore, surveillance of the remnant urothelium should be implemented for patients with histological features of panurothelial disease as it may improve timely detection and treatment. Patient summary Secondary tumors of the renal pelvis, ureters, and urethra occur in approximately 4–10% of patients after radical removal of the bladder for bladder cancer. These patients’ prognoses are reduced, likely due to delayed diagnosis. Therefore, routine surveillance might be important to detect tumors at an early stage. [ABSTRACT FROM AUTHOR]

Purpose: To provide a comprehensive overview and update of the joint consultation of the International Consultation on Urological Diseases (ICUD) and Société Internationale d'Urologie for the treatment of localized high-risk upper tract urothelial carcinoma (UTUC). Methods: A detailed analysis of the literature was conducted reporting on treatment modalities and outcomes in localized high-risk UTUC. An international, multidisciplinary expert committee evaluated and graded the data according to the Oxford System of Evidence-based Medicine modified by the ICUD. Results: Radical nephroureterectomy (RNU) is the standard of treatment for high-grade or clinically infiltrating UTUC and includes the removal of the entire kidney, ureter and ipsilateral bladder cuff. The distal ureter can be managed either by extravesical or transvesical approach, whereas endoscopically assisted procedures are associated with decreased intravesical recurrence-free survival. Post-operative intravesical chemotherapy decreases the risk of subsequent bladder tumour recurrence. Regional lymph node dissection is of prognostic importance in infiltrative UTUC, but its extent has not been standardized. Renal-sparing surgery is an option for manageable, high-grade tumours of any part of the upper tract, especially of the distal ureter, as an alternative to RNU. Endoscopy-based renal-sparing procedures are associated with a higher risk of recurrence and progression. Conclusions: A multimodal approach should be considered in localized high-risk UTUC to improve outcomes. RNU is the standard of treatment in high-risk disease. Renal-sparing approaches may be oncologically equivalent alternatives to RNU in well-selected patients, especially in those with distal ureteric tumours. [ABSTRACT FROM AUTHOR]

Introduction: The study aimed to investigate oncological outcomes of patients with concomitant bladder cancer (BC) and urethral carcinoma. Methods: This is a multicenter series of 110 patients (74 men, 36 women) diagnosed with urethral carcinoma at 10 referral centers between 1993 and 2012. Kaplan- Meier analysis was used to investigate the impact of BC on survival, and Cox regression multivariable analysis was performed to identify predictors of recurrence. Results: Syn-chronous BC was diagnosed in 13 (12%) patients, and the median follow-up was 21 months (interquartile range 4-48). Urethral cancers were of higher grade in patients with synchronous BC compared to patients with non-synchronous BC (p = 0.020). Patients with synchronous BC exhibited significantly inferior 3-year recurrence-free survival (RFS) compared to patients with non-synchronous BC (63.2 vs. 34.4%; p = 0.026). In multivariable analysis, inferior RFS was associated with clinically advanced nodal stage (p < 0.001), proximal tumor location (p < 0.001) and synchronous BC (p = 0.020). Conclusion: The synchronous presence of BC in patients diagnosed with urethral carcinoma has a significant adverse impact on RFS and should be an impetus for a multimodal approach. [ABSTRACT FROM AUTHOR]

[Display omitted] • A new growth mechanism is proposed for the CVD of CNTs. • Model predictions are in good agreement with experimental measurements. • Up to 750 °C, the process is limited by the carbon diffusion through the catalyst. • Above 750 °C, the gas-phase acetylene reaction results in catalyst deactivation. • The catalyst lifetime is investigated for the first time computationally. The mechanisms of carbon nanotube (CNT) growth by chemical vapor deposition of acetylene on Fe/SiO 2 :Al 2 O 3 (zeolite Y) catalyst are unraveled through a combined computational and experimental study. CNTs are synthesized in a horizontal reactor under atmospheric pressure within the temperature range 650 °C–850 °C and characterized by SEM, TEM and Raman spectroscopy. A macroscopic computational fluid dynamics (CFD) model accounting for fluid flow, heat transfer and species transport is developed for the process, incorporating also kinetic expressions for acetylene surface decomposition, acetylene gas-phase reactions, carbon diffusion through the bulk of the catalyst, carbon surface accumulation on the catalyst surface and eventually, CNTs growth. The experimental behavior of the CNTs growth can be accurately described by the proposed macroscopic model. Most importantly, theoretical predictions suggest that there are two distinct temperature regimes for CNTs formation: at the low temperature regime, the process is dominated by the competition between carbon diffusion through the catalyst and carbon impurity layer formation on the catalyst surface, while at higher temperature, the gas-phase reactions of acetylene prevails, releasing byproducts that deposit on the catalyst surface in the form of carbon impurities. Finally, using the developed computational approach, the catalyst lifetime, which is directly affected by these mechanisms, is correlated with the CNTs growth process. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to evaluate the impact of the clinical significance of incidental prostate cancer (PC) on overall survival (OS) after radical cystoprostatectomy (RC) for bladder cancer (BC). Methods: A total of 822 consecutive men underwent RC in 3 academic centers between 1996 and 2011. The clinical significance of incidental PC was determined according to the Epstein criteria. The Kaplan-Meier analysis with log-rank was used to investigate the impact of PC on OS and univariate and multivariate Cox regression analyses for risk factors of OS. The median follow-up was 36 months (interquartile range 10-49). Results: Of the 822 men, 117 (14.2%) had clinically significant, 243 (29.6%) insignificant and 462 (56.2) no PC at RC. Men with PC were at higher risk for lymphovascular invasion (LVI) of BC compared to men without PC (p < 0.001). The 5-year OS for men with clinically significant, insignificant and no PC was 33.3, 51.3 and 51.5%, respectively (p = 0.050). In the subgroup of pN0 patients (n = 601), clinically significant PC was significantly associated with inferior OS (p = 0.044) but not in multivariable analysis (p = 0.46). Conclusions: We did not find the clinical significance of incidental PC to be an independent predictor. However, the positive correlation between incidental PC and LVI of BC deserves further investigation. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate risk factors for survival in a large international cohort of patients with primary urethral cancer (PUC). Methods: A series of 154 patients (109 men, 45 women) were diagnosed with PUC in ten referral centers between 1993 and 2012. Kaplan-Meier analysis with log-rank test was used to investigate various potential prognostic factors for recurrence-free (RFS) and overall survival (OS). Multivariate models were constructed to evaluate independent risk factors for recurrence and death. Results: Median age at definitive treatment was 66 years (IQR 58-76). Histology was urothelial carcinoma in 72 (47 %), squamous cell carcinoma in 46 (30 %), adenocarcinoma in 17 (11 %), and mixed and other histology in 11 (7 %) and nine (6 %), respectively. A high degree of concordance between clinical and pathologic nodal staging (cN+/cN0 vs. pN+/pN0; p < 0.001) was noted. For clinical nodal staging, the corresponding sensitivity, specificity, and overall accuracy for predicting pathologic nodal stage were 92.8, 92.3, and 92.4 %, respectively. In multivariable Cox-regression analysis for patients staged cM0 at initial diagnosis, RFS was significantly associated with clinical nodal stage ( p < 0.001), tumor location ( p < 0.001), and age ( p = 0.001), whereas clinical nodal stage was the only independent predictor for OS ( p = 0.026). Conclusions: These data suggest that clinical nodal stage is a critical parameter for outcomes in PUC. [ABSTRACT FROM AUTHOR]

Objective. The aim of this study was to investigate perioperative, oncological and functional outcomes of the "I-Pouch" neobladder. Materials and methods. From 2002 to 2011, 97 patients (72 men, 25 women, median age 65, range 42-84 years) underwent radical cystectomy with I-Pouch neobladder reconstruction. Complications were graded according to the Clavien-Dindo classification. Oncological and functional outcomes were assessed. The median oncological and functional follow-up was 41 months (range 3-107 months) and 18 months (3-111 months), respectively. Results. In the total cohort, the 5 year cancer-specific survival was 67.9%. The major 30 and 90 day complication rates were 14.4% and 17.5%, respectively. Open reimplantation for ureterointestinal stricture was necessary in two (2.1%). Of the 95 functionally evaluable patients postoperatively, 93 urinated spontaneously (97.9%) and two patients (2.1%) required clean intermittent catheterization to empty their neobladder. The median postvoid residual urine volume (PVR) was 0 ml (range 0-200 ml). One patient had postoperative reflux (1%), as evidenced by voiding cystography. The median number of urinary tract infections per year was 0 (range 0-2) and showed no association with increased PVR (p = 0.18). Conclusions. The perioperative, oncological and functional outcomes of the I-Pouch are comparable to those of other types of ileal neobladder. An advantage of the I-Pouch is that the implantation of the ureters lies on the neobladder floor, which facilitates later instrumentation of the upper tract. [ABSTRACT FROM AUTHOR]

Objective. The aim of this study was evaluate the incidence and significance of immunohistochemically assessed lymphatic (LVI) and blood vessel invasion (BVI) in primary T1 urothelial carcinoma of the bladder (UCB) treated with radical cystectomy (RC). Materials and methods. Thirty-two patients with T1 UCB at primary diagnosis were identified who underwent radical cystectomy (RC) subsequently. Of these, 16 (50%) had pTINOMO (group I) and 16 (50%) ≥ pT2aN0-3M0 UCB (group II) at RC. The presence of LVI and BVI in transurethral resection of bladder tumor (TURBT) and corresponding RC specimens was assessed using hematoxylin & eosin (H&E) and immunohistochemical (IHC) staining against the lymphatic (D2-40) and vascular endothelium (CD31). Results. At TURBT and RC, none of the patients in group I showed LVI or BVI on H&E and IHC sections. In group II, at TURBT, LVI and BVI were negative on H&E staining in all patients, but detectable by IHC in two patients (13%) and one patient (6%), respectively (p = 0.48 and p = 0.99 compared to group I). At RC, LVI and BVI were detected by IHC in eight (50%) and five (31%) of the 16 patients, respectively (p = 0.002 and p = 0.021 compared to group I). Of these eight and five patients, detection of LVI and BVI was only possible with IHC in six (75%) and three (60%), respectively. Conclusions. Although this hypothesis-generating study did not show a high degree of concordance between TURBT and RC specimens, IHC assessment on a regular basis may increase the detection rates of LVI and BVI at initial diagnosis and improve the selection of those T1 patients who should be offered early radical treatment. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether photodynamic diagnosis (PDD)-guided bladder tumour resection (TUR-BT) is of prognostic value in patients undergoing subsequent radical cystectomy (RC) for bladder cancer (BC). Methods: In 224 consecutive patients who underwent RC and bilateral pelvic lymphadenectomy for BC between 2002 and 2010 (median follow-up 29 months [IQR 8-59]), we retrospectively investigated whether patients had previously undergone PDD-guided (hexaminolevulinate [HAL] vs. 5-aminolevulinate [ALA]) versus white light (WL)-TUR-BT. Kaplan-Meier analysis was used to estimate recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS) using log-rank and Cox regression model for uni- and multivariable analysis. Results: Of the 224 patients, 66 (29.5 %) underwent HAL-, 23 (10.3 %) ALA- and 135 (60.2 %) WL-TUR-BT before RC. The 3-year RFS/CSS/OS was 77.8/83.9/74.0 % for HAL-, 53.6/74.5/60.9 % for ALA- and 52.4/59.7/56.5 % for WL-TUR-BT ( p = 0.002/0.023/0.037 for HAL vs. WL/ALA). PDD-TUR-BT was associated with a higher number of TUR-BTs before RC ( p < 0.001) and re-resections ( p = 0.015), a longer time between the first TUR-BT and RC ( p = 0.044) and a lower rate of post-operative systemic chemotherapy ( p = 0.001). In multivariable analysis, performance of HAL-TUR-BT, pathologic tumour and nodal stage as well as soft tissue surgical margin status were independent predictors for RFS, CSS and OS. Conclusions: This series indicates for the first time that HAL-guided TUR-BT is an independent predictor for improved survival after RC. [ABSTRACT FROM AUTHOR]

Purpose: To test the hypothesis whether the number of the C(ytosine)-A(denine)-G(uanine) triplets in the androgen receptor (AR-) gene and further single-nucleotide polymorphisms in the androgen-responsive element of the promoter region of genes regulating the androgen pathway influence oncologic outcomes in patients with concomitant bladder (BC) and prostate cancer (PC) at a predisposing level.Material and Methods: A cohort of 36 patients was treated with radical cystectomy and histologically exhibited invasive BC and incidental PC. The number of cytosine-adenine-guanine (CAG)-triplets (rs4045402) in the AR gene was assessed in tumor-free lymph nodes as well as rs743572 in the CYP17A1 gene and rs676033, rs523349, rs9282858 in the SRD5A2. In addition, the clinical significance of incidental PC based on the Epstein-criteria was assessed with regard to BC-specific recurrence-free survival (RFS). The median follow-up was 26 months (range: 4-68).Results: Patients with clinically significant PC had worse BC-specific RFS compared with patients with insignificant PC (P = 0.016). Patients with a PC volume of >0.2 cm3 had shorter 3-year BC-specific RFS compared with patients with a PC volume ≤0.2 cm3 (P = 0.025). The median number of CAG-triplets was 24 (mean ± SEM: 23 ± 2, interquartile range: 22-25, total range 18-29). Patients with a CAG-triplet number <23 exhibited significantly decreased 3-year BC specific RFS compared with patients with ≥23 repeats (27% vs. 65%; P = 0.026). No further significance were noted for the other tested SNPs and survival.Conclusions: A detailed description of incidental PC at radical cystoprostatectomy (RC) may be of greater prognostic importance than previously assumed in the literature. The CAG-repeat in the AR gene may predispose to worse oncologic outcomes after RC and should be further evaluated in larger studies. [ABSTRACT FROM AUTHOR]

Aim of the study To assess the impact of perioperative platelet count (PLT) kinetics on recurrence-free survival (RFS) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Methods From three prospectively maintained databases of three tertiary care centres a total of 269 patients undergoing RNU without perioperative treatment between 1996 and 2011 were considered for this analysis. Pre- and postoperatively elevated PLT count was defined as >400 × 10 9 /L. PLT levels were measured 1–3 days preoperatively and 7–10 days postoperatively. The median follow-up was 24 months (Interquartile range (IQR): 10–52). A new weighted scoring model was developed to predict recurrence after RNU based on significant parameters of multivariable analysis. Results The 5-year RFS in patients with preoperatively normal and elevated PLT count was 58.3% and 29.3%, respectively ( p < 0.001). The 5-year-RFS was 57.6% in patients with normal postoperative PLT count and 29.7% in those with elevated PLT levels ( p < 0.001). In multivariable analysis, pT-stage, lymphovascular invasion, ureteral margin status and postoperative thrombocytosis remained independent predictors for RFS. The 5-year RFS in patients with a score of 0 (low-risk), 1 (intermediate-risk) and 2–4 (high-risk) was 77.7%, 47.5% and 12.3%, respectively ( p < 0.001). Consideration of the variable postoperative thrombocytosis in the final model increased its predictive accuracy by 1.9% with a concordance index of 0.758 ( p = 0.015). Conclusion PLT kinetics is significantly associated with RFS after RNU for UTUC. We constructed a simple, PLT-based prognostic model for recurrence after RNU. [ABSTRACT FROM AUTHOR]

Context: Because pelvic lymph node (LN)-positive prostate cancer (PCa) is generally considered a regionally metastatic disease, surgery needs to be better defined. Objective: To review the impact of radical prostatectomy (RP) and pelvic lymph node dissection (PLND), possibly in conjunction with a multimodal approach using local radiotherapy and/or androgen-deprivation therapy (ADT), in LN-positive PCa. Evidence acquisition: A systematic Medline search for studies reporting on treatment regimens and outcomes in patients with LN-positive PCa undergoing RP between 1993 and 2012 was performed. Evidence synthesis: RP can improve progression-free and overall survival in LN-positive PCa, although there is a lack of high-level evidence. Therefore, the former practice of aborting surgery in the presence of positive nodes might no longer be supported by current evidence, especially in those patients with a limited LN tumor burden. Current data demonstrate that the lymphatic spread takes an ascending pathway from the pelvis to the retroperitoneum, in which the internal and the common iliac nodes represent critical landmarks in the metastatic distribution. Sophisticated imaging technologies are still under investigation to improve the prediction of LN-positive PCa. Nonetheless, extended PLND including the common iliac arteries should be offered to intermediate- and high-risk patients to improve nodal staging with a possible benefit in prostate-specific antigen progression-free survival by removing significant metastatic load. Adjuvant ADT has the potential to improve overall survival after RP; the therapeutic role of a trimodal approach with adjuvant local radiotherapy awaits further elucidation. Age is a critical parameter for survival because cancer-specific mortality exceeds overall mortality in younger patients (<60 yr) with high-risk PCa and should be an impetus to treat as thoroughly as possible. Conclusions: Increasing evidence suggests that RP and extended PLND improve survival in LN-positive PCa. Our understanding of surgery of the primary tumor in LN-positive PCa needs a conceptual change from a palliative option to the first step in a multimodal approach with a significant improvement of long-term survival and cure in selected patients. Take Home Message: Our understanding of radical prostatectomy in lymph node-positive prostate cancer needs a conceptual change from a palliative option to an effective instrument for significant improvement of long-term survival. [ABSTRACT FROM AUTHOR]

Abstract: Context: The European Association of Urology (EAU) Guidelines Group on Muscle-Invasive and Metastatic Bladder Cancer prepared these guidelines to deliver current evidence-based information on the diagnosis and treatment of patients with primary urethral carcinoma (UC). Objective: To review the current literature on the diagnosis and treatment of patients with primary UC and assess its level of scientific evidence. Evidence acquisition: A systematic literature search was performed to identify studies reporting urethral malignancies. Medline was searched using the controlled vocabulary of the Medical Subject Headings database, along with a free-text protocol. Evidence synthesis: Primary UC is considered a rare cancer, accounting for <1% of all malignancies. Risk factors for survival include age, tumour stage and grade, nodal stage, presence of distant metastasis, histologic type, tumour size, tumour location, and modality of treatment. Pelvic magnetic resonance imaging is the preferred method to assess the local extent of urethral tumour; computed tomography of the thorax and abdomen should be used to assess distant metastasis. In localised anterior UC, urethra-sparing surgery is an alternative to primary urethrectomy in both sexes, provided negative surgical margins can be achieved. Patients with locally advanced UC should be discussed by a multidisciplinary team of urologists, radiation oncologists, and oncologists. Patients with noninvasive UC or carcinoma in situ of the prostatic urethra and prostatic ducts can be treated with a urethra-sparing approach with transurethral resection and bacillus Calmette-Guérin (BCG). Cystoprostatectomy with extended pelvic lymphadenectomy should be reserved for patients not responding to BCG or as a primary treatment option in patients with extensive ductal or stromal involvement. Conclusions: The 2013 guidelines document on primary UC is the first publication on this topic by the EAU. It aims to increase awareness in the urologic community and provide scientific transparency to improve outcomes of this rare urogenital malignancy. [Copyright &y& Elsevier]

Prostate-sparing techniques have been advocated to improved functional outcomes after radical cystoprostatectomy (RCP) for invasive bladder cancer, but this may endanger the oncological outcome. This review addresses the current status of risk factors of prostate cancer (PCa) recurrence in patients with incidental PCa after RCP. The overall 7-year risk of PCa recurrence after RCP is approximately 9%. Increased risk has been suggested in the presence of clinically significant PCa as: ≥pT3a stage, presence of lymph-node metastasis, positive surgical margins, Gleason pattern ≥4, tumour multifocality (three or more foci) and tumour volume >0.5 cm3. However, the prognostic significance of these parameters has not been evaluated within multivariable analyses so far. Preoperatively elevated prostate-specific antigen (PSA) values correlate weakly with the clinical significance of incidental PCa, while prostate biopsy has a limited accuracy for detecting incidental PCa in the preoperative setting. Genetic markers, e.g. the prostate stem cell antigen (PSCA) gene, have recently been associated with risk of recurrence in patients with incidental PCa. Incidental PCa at RCP is usually clinically insignificant. Yet, clinicopathological parameters for clinical significant cancers have not been investigated independently in the literature so far. Consequently, lifelong PSA surveillance should be conducted in all patients with incidental PCa after RCP. In the presence of clinically significant PCa treatment decisions should be based not only on histological criteria but also on patient-centred parameters (e.g. patient age and comorbidities). Assessment of PSCA expression in RCP specimens may enable improved risk assessment for PCa recurrence after RCP. [ABSTRACT FROM AUTHOR]

Purpose: To describe the role of sex steroid-dependent growth of muscle-invasive bladder cancer (MIBC) and the role of single-nucleotide polymorphisms (SNP) located on chromosome 8q24 as a molecular explanation for gender-specific differences in the incidence and outcome of MIBC. Methods: A detailed, non-systematic analysis was performed for articles and reviews investigating the role of sex steroids in the development and progression of MIBC between 2000 and 2012. Results: Localized MIBCs overexpress the androgen receptor (AR), whereas in lymph node-positive stages, loss of AR expression has been found. High-risk SNPs of genes on chromosome 8q24, that is, the rs2294008 of prostate stem cell antigen (PSCA) gene, have been linked with increased susceptibility for MIBC. The PSCA gene possesses an androgen-responsive element (ARE) in its promoter region. Recent studies suggest that loss of AR responsiveness to the PSCA promoter may result in the induction of an androgen-independent mechanism, that is, the insulin-like growth factor-binding protein 2 signalling pathway-a key event in the development of hormone-independent prostate cancer-and this may increase the metastatic potential. In females, it can be hypothesized that due to the altered androgen levels, these mechanisms may be initiated earlier during tumor progression in females and result in inferior survival compared to males. Conclusion: Muscle-invasive bladder cancer (MIBC) is a sex steroid-dependent tumor. AREs in the promoter region of high-risk genes may drive tumor progression and result in loss of androgen responsiveness, which eventually leads to the activation of androgen-independent processes forming the metastatic potential. The determination of the AR status in cystectomy specimens additionally offers new adjuvant approaches after cystectomy. [ABSTRACT FROM AUTHOR]

This reviews describes the concept of androgen-dependent growth of bladder cancer and the role of single-nucleotide polymorphisms (SNPs) located on chromosome 8q24 as a common carcinogenetic pathway for the development of concomitant prostate and bladder cancer. Recent genome-wide association studies have identified high-risk SNPs on chromosome 8q24 that have been linked with increased susceptibility for bladder and prostate cancer and alterations in the androgen receptor (AR) pathway. Muscle-invasive bladder cancers overexpress the AR, whereas in locally advanced or lymph-node positive stages loss of AR expression has been found. The prostate stem cell antigen (PSCA) gene possesses an androgen-responsive element (ARE) in its promoter region. Heterozymous and homozygous carriers of the SNP rs22940008 in the first exon of the PSCA gene are at increased risk for invasive bladder cancers. They exhibit significantly lower PSCA messenger RNA expression than patients with the wild-type genotype. Loss of the AR responsivity of the PSCA promoter may be a result of an altered affinity of the AR to the ARE mediated by the rs2294008 SNP or reduced expression of AR coactivators. Thereafter, induction of an androgen-independent mechanism, i.e. the insulin-like growth factor binding protein-2 signalling pathway- a key event in the development of hormone-independent prostate cancer- may increase tumour aggressiveness and metastatic potential of invasive bladder cancer cells. Loss of PSCA expression may represent an important step for androgen-independent growth, linked with the presence of the rs2294008 SNP. Determination of the AR status in cystectomy specimens offers new therapeutic approaches in locally advanced bladder cancer. [ABSTRACT FROM AUTHOR]

Abstract: Context: New guidelines of the International Consultation on Urological Diseases for the treatment of muscle-invasive bladder cancer (MIBC) have recently been published. Objective: To provide a comprehensive overview of the current role of radical cystectomy (RC) in MIBC. Evidence acquisition: A detailed Medline analysis was performed for original articles addressing the role of RC with regard to indication, timing, surgical extent, perioperative morbidity, oncologic outcome, and follow-up. The analysis also included radiation-based bladder-preserving strategies. Evidence synthesis: The major findings are presented in an evidence-based fashion and are based on large retrospective unicenter and multicenter series with some prospective data. Conclusions: Open RC is the standard treatment for locoregional control of MIBC. Delay of RC is associated with reduced cancer-specific survival. In males, standard RC includes the removal of the bladder, prostate, seminal vesicles, and distal ureters; in females, RC includes an anterior pelvic exenteration including the bladder, entire urethra and adjacent vagina, uterus, and distal ureters. A procedure sparing the urethra and the urethra-supplying autonomous nerves can be performed in case of a planned orthotopic neobladder. Further technical variations (ie, seminal-sparing or vaginal-sparing techniques) aimed at improving functional outcomes must be weighed against the risk of a positive margin. Laparoscopic surgery is promising, but long-term data are required prior to accepting it as an option equivalent to the open procedure. Lymphadenectomy should remove all lymphatic tissue around the common iliac, external iliac, internal iliac, and obturator region bilaterally. Complications after RC should be reported according to the modified Clavien grading system. In selected patients with MIBC, bladder-preserving therapy with cystectomy reserved for tumor recurrence represents a safe and effective alternative to immediate RC. [Copyright &y& Elsevier]

What's known on the subject? and What does the study add? Currently, prognostication of patients with invasive BC is hampered owing to the inadequacy of standard clinicopathological risk factors to predict accurately individual treatment outcomes. This review provides a comprehensive albeit brief overview on current studies elucidating the potential role of different molecular markers to close this gap of evidence. It focusses on biostatistical considerations in the interpretation of study results which are essential to provide meaningful clinical conclusions for an individual patient. OBJECTIVE To improve prognostication and the management of patients with invasive bladder cancer (BC)., METHODS Standard clinicopathological risk factors are not reliably enough to accurately predict outcomes in patients after radical treatment and guide clinicians for recommending selectively the use of adjuvant therapies., With detailed insights into the molecular pathology of BC, biomarkers have come to the fore of researchers as a potential tool to close this gap of evidence., However, their definitive role in the diagnostic and therapeutic management of patients with invasive BC has not clearly been addressed so far., RESULTS Invasive BC are an extremely heterogenenous group of malignancies which are characterized by multiple genetic alterations involved in the carcinogenesis and development of metastatic spread. Thus, it is questionable whether any single marker will provide superior prognostication compared with a combination of markers., Current studies evaluating the predictive value of a multitude of markers have used high-throughput technologies and investigated the gain in predictive accuracy within new nomograms which encompass well-established clinicopathological and novel putative molecular parameters. p53 overexpression was found to be associated with increased risk of recurrence in urothelial and non-urothelial cancer. In pT1 disease, the combination of p53, p21 and p16 as well as epigenetic alterations of myopodin expression has been shown to provide improved prognostication, and this might help to advocate more selectively the use of early radical treatment., After the bladder-sparing approach, p53 and p21 overexpression indicate decreased probability of long-term bladder preservation. Additionally, altered retinoblastoma expression is associated with improved survival after adjuvant chemotherapy., To provide meaningful conclusions for individual prognosis and the need of adjuvant treatment, biostatistical pitfalls in the analysis and interpretation of results have to be taken into account., CONCLUSIONS Different molecular markers have the potential to improve prognostication of patients with invasive BC and provide improved evidence for targeted therapy in the neoadjuvant, adjuvant and metastatic setting., However, in order to advocate their routine clinical use on a sound scientific basis prospective data are still necessary. [ABSTRACT FROM AUTHOR]

Management of prostate cancer is recognized as one of the most important medical problems. Latest findings concerning the role of circulating (CTC) and disseminated tumor cells (DTC) have provided new insights into the biology of metastasis with important implications for the clinical management of prostate cancer patients. Most of the established methods of circulating/disseminated tumor cell enrichment use density-gradient centrifugation and immunomagnetic procedures. Reverse transcriptase polymerase chain reaction is another used detection technique. Novel methods, the CTC-chip and the epithelial immunospot assay already showed promising results. For localized and metastatic prostate cancer, significant correlations between spreading tumor cells and well-established indicators of disease activity have been demonstrated. Careful randomized prospective trials will be required to justify the routine use of CTCs/DTCs for therapy decision making. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to compare a novice surgeon with an expert surgeon independently performing minimally invasive percutaneous neprolitholapaxy (PCNL) excluding the influence of the expert in the learning curve. Methods: Clinical records of 84 patients (novice: n = 35; expert: n = 49) undergoing minimally invasive PCNL between 04/2007 and 04/2008 were retrospectively reviewed for the following parameters: drop in hemoglobin, operative and fluoroscopy time, length of hospital stay, stone-free rate and complication rate. Complications were graded according to the Clavien classification. Statistical analysis was carried out by student's t test (Chi-square test) with p < 0.05 considered significant. Results: The novice surgeon experienced longer median operative and fluoroscopy time, lower stone-free rate and higher re-treatment rate (all p < 0.005) but no longer length of hospital stay ( p = 0.19) compared to the experienced surgeon. The novice showed a notable improvement in operating time ( p = 0.0208). Altogether, 16 complications occurred in 84 minimally invasive PCNL (19.1%) with five patients (6.0%) encountering grade III complications. Four patients (8.2%) treated by the expert surgeon developed complications (all grade I/II) compared to 12 of the patients (34.3%) treated by the novice surgeon ( p = 0.0265). All grade III complications occurred in the first 20 patients of the novice surgeon group. Conclusions: Despite longer operating time and a lower initial stone-free rate, the novice showed a significant improvement with growing experience and a low rate of higher grade (≥IIIa) complications. This demonstrates that the concept of minimally invasive PCNL can also be learned by urologists who do not have the support of an experienced colleague without endangering patient safety. [ABSTRACT FROM AUTHOR]

Purpose: Recent lung cancer data have shown an association of XPA-210, a key peptide of thymidine kinase, with advanced disease. We thus assessed its proliferation status in primary (M0) and metastatic (M1) renal cell carcinoma (RCC). Methods: Paraffin slides from 30 patients (mean age: 61.2 years; range: 42-84) with clear-cell RCC (M0 in 10; non-osseous M1 in 10; osseous M1 in 10) were T-matched for pT1/pT3. Corresponding malignant and benign renal parenchyma were immunohistochemically stained against XPA-210. Staining density was determined by a semi-quantitative score of positive cell shares. Staining intensity included the precise cellular location. Results: XPA-210 occurred predominantly in the nucleus, with a minor cytoplasmatic component. RCC tissue showed higher density and stronger intensity than did benign renal tissue in both nucleus ( P = 0.005) and cytoplasm ( P = 0.01). Density and intensity were positively associated with tumor diameters ≤7 cm, whereas they tended to correlate inversely in tumors >7 cm ( P = 0.07). Density of stained cells was significantly higher in metastatic than in localized RCC in both nucleus and cytoplasm ( P < 0.04). Non-osseous M1 tissue showed significantly higher nuclear and cytoplasmatic expression than did M0 tissue ( P < 0.05), whereas osseous M1 tissue did not. Conclusions: In all RCC tissues, XPA-210 staining was significantly higher in the nucleus than in cytoplasm, potentially owing to large cytoplasmatic spaces as a characteristic histologic feature of clear-cell component. XPA-210 expression gradually increased from localized to metastatic disease, peaking in patients without bone involvement. Therefore, XPA-210 might aid the selection of appropriate adjuvant treatment in high-risk patients. [ABSTRACT FROM AUTHOR]

Study Type - Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? There is increasing evidence for a prognostic significance of pretherapeutically elevated serum C-reactive protein levels in various cancers. However, little is known about its significance in patients with invasive bladder cancer. This study shows that serum CRP is an independent predictor for cancer-specific survival in bladder cancer, and its incorporation into a new outcome model (TNR-C Score) encompassing major pathological determinants for survival, increases significantly its predictive accuracy. OBJECTIVE • To assess the predictive value of preoperative C-reactive protein (CRP) in patients undergoing radical cystectomy (RC) for carcinoma invading the bladder in light of recent data showing it to be an independent indicator of adverse oncological outcome in other malignancies. PATIENTS AND METHODS • A contemporary, consecutive series of 246 patients undergoing RC and bilateral pelvic lymphadenectomy for bladder cancer between 1999 and 2009. • Elevated CRP was defined as >0.5 mg/dL and was consistent during the study period. The median (range) follow-up was 30 (6-116) months. • Kaplan-Meier analysis was used to estimate cancer-specific survival (CSS) using a log-rank test and Cox regression analysis for multivariate analysis of risk factors. • Based on regression estimates of significant parameters in multivariate analysis, a new CRP-based scoring model was developed to predict cancer-specific outcomes. The predictive accuracy of the model was evaluated using the concordance index. RESULTS • The 3-year CSS was 74.0% in patients with normal and 44.0% with elevated CRP ( P < 0.001). • In multivariate analysis, CRP ( P < 0.001; used as a continuous variable), tumour stage ( P= 0.001), lymph-node density ≥0.09 ( P= 0.02) and resection margin status ( P < 0.001) were independent predictors of CSS. • The 3-year CSS in patients with a score in the ranges 0-2, 3-6 and 7-10 was 80.5%, 44.9% and 7.1%, respectively ( P < 0.001). Consideration of CRP in the final model increased its predictive accuracy by 4.9% with a concordance index of 0.788 ( P= 0.01). CONCLUSIONS • This is the largest, contemporary series to date indicating that preoperative serum CRP is an independent risk factor for CSS. • CRP may be a useful parameter to include in predictive bladder cancer nomograms. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To evaluate characteristic imaging findings of tumor attenuation in multiphase computed tomography (CT) between renal oncocytomas and clear-cell renal cell carcinoma (ccRCC) of small tumor size (≤5cm). Methods: We retrospectively identified 20 patients with complete four-phase CT with either histologically confirmed small renal oncocytoma (N =10) or ccRCC (N =10) who underwent subsequent total or partial nephrectomy. Exclusion criteria for RCC were non-clear-cell components in histology and a tumor diameter >5cm. The relative attenuation of solid renal lesions and normal renal cortex was determined in the unenhanced, corticomedullary, nephrographic and excretory phase. Statistical comparison was carried out by Wilcoxon Rank Sum Test. Results: Mean tumor size of renal oncocytomas was 2.8±0.4cm (1.2–5) and of ccRCC 2.5±0.2cm (1.7–4.4; p =0.57). All lesions were homogenous without extended areas of necroses. In the nephrographic phase, the difference of attenuation between renal cortex and tumor lesion was highest in both entities (oncocytoma, 48.1±5.2HU; ccRCC, 67.5±12.1) but not between entities (p =0.30). In the corticomedullary phase, renal oncocytomas showed greater isodensity to the normal renal cortex (13.9±4.3HU) compared to clear-cell RCC (51.5±5.0HU; p =0.003). No further significant differences were found for the unenhanced and excretory phase. Conclusions: In this study, the maximum tumor-to-kidney contrast coincided with the nephrographic phase which was thus the most reliable for the detection of a renal lesion <5cm. For lesion characterization, the corticomedullary phase was most useful for differentiating both entities. This finding is particularly important for the preoperative planning of a partial nephrectomy. [Copyright &y& Elsevier]

Purpose: The aim of this study was to evaluate the accuracy of frozen section analysis (FSA) for detecting and eliminating malignant ureteral margins at radical cystectomy (RC) and to determine the impact of final margin status obtained by a sequential resectioning strategy on the risk of upper urinary tract recurrence (UUT-R). Methods: A total of 425 ureteral margins obtained from 218 patients undergoing RC for invasive bladder cancer between 1999 and 2009 were initially examined by FSA. When positive, additional resections were performed. Subsequently, all specimens were reexamined on formalin-fixed, paraffin-embedded (FFPE) sections. Fisher-Exact test/logistic regression were used for uni-/multivariate analysis and log-rank test for the impact of margin status on UUT-R. Results: Of 425 specimens, malignant ureteral margins were found on initial FSA in 17, on FFPE in 23 (sensitivity: 73.9%). FSA results were false-positive in 1/402 margins (specificity: 99.8%) resulting in an overall accuracy of 98.3%. On multivariate analysis (95%-CI), correlations were found between distal ureteral malignancy and FSA ( p < 0.0001) and tumor multifocality ( p = 0.04). In 10/17 positive initial margins it was not possible to obtain a negative final margin despite multiple reresections, of which one resulted in a UUT recurrence, which was more frequent than in patients with a negative margin (4/208, p = 0.03). Moreover, three of these five recurrences were proximally to the anastomosis. All patients had multifocal disease at RC. Conclusions: FSA has a high accuracy for detecting malignant ureteral margins. Patients with positive final margins are at increased risk of UUT-R. With sequential resection, however, positive margins cannot reliably be converted to negative ones. [ABSTRACT FROM AUTHOR]

OBJECTIVE • To determine whether there is a difference in survival in patients with node-negative pT2a vs pT2b urothelial carcinoma of the bladder (UBC), as recent studies suggest that the new American Joint Committee on Cancer substratification may not have prognostic significance. PATIENTS AND METHODS • Of 252 patients undergoing radical cystectomy (RC) and extended bilateral pelvic lymphadenectomy (ePLND) between 1999 and 2009, 72 (28.6%), with a mean (range) age of 66 (44-83) years (50 men, 22 women), had pathologically confirmed pT2 UCB. • Fisher's exact test and Cox regression analysis were used for uni- and multivariate analysis of risk factors of recurrence at a median (range) follow-up of 28 (2.2-115.7) months. • Kaplan-Meier plots were used to estimate the impact of pT2 substratification in lymph node (LN)-negative disease on recurrencefree (RFS) and cancer-specific (CSS) survival using log-rank test. RESULTS • Of the 72 patients, 39 had pT2a (54.2%) and 33 pT2b UCB (45.8%) on definitivehistological examination. The median (range) number of LNs removed was 19 (6-38) in pT2a and 22 (4-36) in pT2b ( P = 0.31) UCB. • At RC, there was LN-positive disease in one patient with pT2a UCB, whereas seven patients with pT2b UCB had LN-positive disease ( P = 0.02). • The median (range) number of LNs removed in LN-positive disease was 18 (11-30) and in LN-negative disease was 20 (4-38) ( P = 0.52). • In LN-negative disease, actuarial 5-year RFS was 85.9% in patients with pT2a UCB vs 37.5% in those with pT2b UCB ( P < 0.001). Actuarial 5-year CSS was 84.8% in patients with LN-negative pT2a UCB vs 59.6% in patients with LN-negative pT2b UCB ( P = 0.01). • In Cox regression analysis, pT2 substratification was the only independent risk factor of recurrence and cancer-specific death ( P < 0.001 and P = 0.008). CONCLUSIONS • In this contemporary series of patients undergoing RC with ePLND, there was a significant difference in RFS and CSS between LN-negative pT2a and pT2b UCB, and pT2 substratification was the only risk factor of recurrence and cancer-specific death. • These data are supportive of the current concept of substratification in LN-negative pT2 UCB. [ABSTRACT FROM AUTHOR]

Abstract: Orthotopic neobladder substitution represents an important step in the evolution of urinary diversion. It is now considered the diversion of choice for the majority of patients, both male and female, who undergo cystectomy and is the procedure with which other types of diversion must be compared. Nevertheless, in the preoperative setting, all options for urinary diversion should be explained comprehensibly to the patient, along with the potential short- and long-term risks and the beneficial effects of each type of diversion. With regard to the risk of urethral recurrence, the decision to perform a neobladder ultimately depends on the intraoperative frozen section analysis of the distal urethral margin. Neobladder construction is based on the concept of detubularization and folding to construct a low-pressure reservoir. All parts of the small and large intestine as well as the stomach have been intensely studied for the construction of neobladders. In this respect, there is substantial agreement in the literature that the terminal ileum possesses superior anatomic and functional characteristics. Given the lack of prospective randomized trials, controversies still exist with regard to the technique for preventing reflux in orthotopic substitutes and the superiority of one neobladder technique over others, provided the detubularized intestinal segment is reconfigured to an adequate-sized spherical reservoir. [Copyright &y& Elsevier]

Study Type – Therapy (case series) Level of Evidence 4 OBJECTIVE To analyse retrospectively the clinicopathological features of incidental prostate cancer in patients undergoing radical cystoprostatovesiculectomy (RCP) for invasive bladder cancer, as recent studies suggest that prostatic apex-sparing surgery in patients undergoing RCP improves urinary continence and erectile function after surgery, but in those with incidental prostate cancer, leaving the apical region endangers the oncological outcome. PATIENTS AND METHODS From 2004 to 2007, at our institution, 95 men had RCP for invasive bladder cancer. We reviewed their clinicopathological variables, especially apical involvement, and the course of prostate-specific antigen (PSA) levels before and after surgery. We compared clinically significant and insignificant prostate cancers. RESULTS Of the 95 patients, 26 had incidental prostate cancer (mean age 68 years, range 53–80) on definitive histological examination. The mean (sd, range) preoperative PSA level in all 26 men was 3.6 (0.8, 0.2–14) ng/mL, but six of the 26 patients had preoperative PSA levels of >4 ng/mL and one other had suspicious findings on a digital rectal examination. Involvement of the apex was histologically confirmed in seven of the 26 patients (27%), including four with significant prostate cancer ( P = 0.039). Preoperative PSA levels did not differ significantly between the seven patients with significant and 19 with insignificant prostate cancer, but seven patients with apical involvement had significantly higher PSA levels before RCP than the 19 who did not ( P < 0.04). PSA levels after RCP remained below the limit of detection in all patients over a mean (range) follow-up 14.3 (3–32) months. CONCLUSION In our series, preserving the apex of the prostate to decrease morbidity after RCP carried a 7.3% risk (seven of 95 patients) of leaving significant cancer in the residual prostatic tissue. No preoperative clinical value could exclude apical involvement. Therefore, our findings stress the oncological need for a careful and complete excision of the prostate during RCP. [ABSTRACT FROM AUTHOR]

We report on the very rare case of a patient with a malignant melanoma in the right ureter initially hospitalized for colic pains. Ureterorenoscopy revealed a pigmented solid mass adherent to the mid-ureteral wall. Histomorphological and immunohistochemical examination of the biopsy specimen demonstrated a malignant neoplasia with HMB45, Melan A and S100 positivity establishing the diagnosis of metastatic malignant melanoma. Hence, partial ureterectomy was performed with no further evidence of disease at the time of surgical intervention. Subsequently, multiple metastases in the renal pelvis and ureter led to secondary nephroureterectomy and retroperitoneal lymphadenectomy with complete excision of the ureteral orifice. Secondary metastatic lesions of the urinary bladder wall were completely resected followed by dacarbazine-based chemotherapy and resection of retroperitoneal recurrences. Based on this case as well as on recent published reports, we propose a possible algorithm for the treatment of metastatic melanoma of the upper urinary tract. [ABSTRACT FROM AUTHOR]

Simple Summary: Among the various options for urinary diversion following radical cystectomy, the orthotopic neobladder most closely resembles the original bladder both in location and function. However, a significant number of patients with these reservoirs have dysfunctional voiding. Our objective here is to provide the first systematic review focusing on the urodynamic and continence outcomes of ileal orthotopic neobladders. By summarising these important outcomes, the current paper may represent the reference manuscript for outcome comparison in future papers. The manuscript also describes the methodology of the urodynamic evaluation of the neobladders, highlighting the frequent lack of precise indications, accurate guidelines (at the state of the art, the same parameters used for the native bladder are also used for the ileal neobladders), standardised definitions, and standard values for outcome comparison. By underlining these gaps, our systematic review may aid future studies in having more adequate designs and will allow for a more accurate functional evaluation of the patients harbouring an ileal neobladder. Introduction: The orthotopic neobladder is the type of urinary diversion (UD) that most closely resembles the original bladder. However, in the literature the urodynamic aspects are scarcely analysed. Objective: To provide the first systematic review (SR) on the urodynamic (UDS) outcomes of the ileal orthotopic neobladders (ONB). Continence outcomes are also presented. Methods: A PubMed, Embase and Cochrane CENTRAL search for peer-reviewed studies on ONB published between January 2001–December 2022 was performed according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Results and Conclusion: Fifty-nine manuscripts were eligible for inclusion in this SR. A great heterogeneity of data was encountered. Concerning UDS parameters, the pooled mean was 406.2 mL (95% CI: 378.9–433.4 mL) for maximal (entero)cystometric capacity (MCC) and 21.4 cmH2O (95% CI: 17.5–25.4 cmH2O) for Pressure ONB at MCC. Postvoid-residual ranged between 4.9 and 101.6 mL. The 12-mo rates of day and night-time continence were 84.2% (95% CI: 78.7–89.1%) and 61.7% (95% CI: 51.9–71.1%), respectively.Despite data heterogeneity, the ileal ONB seems to guarantee UDS parameters that resemble those of the native bladder. Although acceptable rates of daytime continence are reported the issue of high rates of night-time incontinence remains unsolved. Adequately designed prospective trials adopting standardised postoperative care, terminology and methods of outcome evaluation as well as of conduction of the UDS in the setting of ONB are necessary to obtain homogeneous follow-up data and to establish UDS guidelines for this setting. [ABSTRACT FROM AUTHOR]

Bladder cancer (BC) is the 10th most common cancer in the world. The therapeutic spectrum of BC is broad and is constantly expanding. Despite the wide clinical use of photodynamic diagnosis (PTD) for BC, PDT has not been sufficiently investigated in the treatment landscape of BC. We performed an online search of the PubMed database using these keywords: photodynamic therapy, bladder cancer, urothelial carcinoma, in vivo, in vitro, cell line, animal model. Reviews, case reports, and articles devoted to photodynamic diagnostics and the photodynamic therapy of tumors other than urothelial carcinoma were excluded. Of a total of 695 publications, we selected 20 articles with clinical data, 34 articles on in vivo PDT, and 106 articles on in vitro data. The results presented in animal models highlight the potential use of PDT in the neoadjuvant or adjuvant setting to reduce local recurrence in the bladder and upper urinary tracts. Possible regimens include the combination of PDT with intravesical chemotherapy for improved local tumor control or the integration of vascular-targeted PDT in combination with modern systemic drugs in order to boost local response. We summarize available evidence on the preclinical and clinical application of PDT for urothelial carcinoma in order to explain the current trends and future perspectives. [ABSTRACT FROM AUTHOR]

The objective of the European Association of Urology guidelines is to provide practical evidence-based recommendations and consensus statements on the clinical management of urological conditions, with a focus on diagnosis and treatment. In this context the summary of the 2023 guideline on muscle-invasive and metastatic bladder cancer provides updated information on the diagnosis and treatment of this disease for incorporation in clinical practice. We present an overview of the updated 2023 European Association of Urology (EAU) guidelines for muscle-invasive and metastatic bladder cancer (MMIBC). To provide practical evidence-based recommendations and consensus statements on the clinical management of MMIBC with a focus on diagnosis and treatment. A broad and comprehensive scoping exercise covering all areas of the MMIBC guidelines has been performed annually since 2017. Searches cover the Medline, EMBASE, and Cochrane Libraries databases for yearly guideline updates. A level of evidence and strength of recommendation are assigned. The evidence cutoff date for the 2023 MIBC guidelines was May 4, 2022. Patients should be counselled regarding risk factors for bladder cancer. Pathologists should describe tumour and lymph nodes in detail, including the presence of histological subtypes. The importance of the presence or absence of urothelial carcinoma (UC) in the prostatic urethra is emphasised. Magnetic resonance imaging (MRI) of the bladder is superior to computed tomography (CT) for disease staging, specifically in differentiating T1 from T2 disease, and may lead to a change in treatment approach in patients at high risk of an invasive tumour. Imaging of the upper urinary tract, lymph nodes, and distant metastasis is performed with CT or MRI; the additional value of flurodeoxyglucose positron emission tomography/CT still needs to be determined. Frail and comorbid patients should be evaluated by a multidisciplinary team. Postoperative histology remains the most important prognostic variable, while circulating tumour DNA appears to be an interesting predictive marker. Neoadjuvant systemic therapy remains cisplatin-based. In motivated and selected women and men, sexual organ–preserving cystectomy results in better functional outcomes without compromising oncological outcomes. Robotic and open cystectomy have comparable outcomes and should be combined with (extended) lymph node dissection. The diversion type is an individual choice after taking patient and tumour characteristics into account. Radical cystectomy remains a highly complex procedure with considerable morbidity and risk of mortality, although lower rates are observed for higher hospital volumes (>20 cases/yr). With proper patient selection, trimodal therapy (chemoradiation) has comparable outcomes to radical cystectomy. Adjuvant chemotherapy after surgery improves disease-specific survival and overall survival (OS) in patients with high-risk disease who did not receive neoadjuvant treatment, and is strongly recommended. There is a weak recommendation for adjuvant nivolumab, as OS data are not yet available. Health-related quality of life should be assessed using validated questionnaires at baseline and after treatment. Surveillance is needed to monitor for recurrent cancer and functional outcomes. Recurrences detected on follow-up seem to have better prognosis than symptomatic recurrences. This summary of the 2023 EAU guidelines provides updated information on the diagnosis and treatment of MMIBC for incorporation into clinical practice. The European Association of Urology guidelines panel on muscle-invasive and metastatic bladder cancer has released an updated version of the guideline containing information on diagnosis and treatment of this disease. Recommendations are based on studies published up to May 4, 2022. Surgical removal of the bladder and bladder preservation are discussed, as well as updates on the use of chemotherapy and immunotherapy in localised and metastatic disease. [ABSTRACT FROM AUTHOR]

Background: To evaluate the impact of salvage therapy (ST) on overall survival (OS) in recurrent primary urethral cancer (PUC).Patients: A series of 139 patients (96 men, 43 women; median age = 66, interquartile range: 57-77) were diagnosed with PUC at 10 referral centers between 1993 and 2012. The modality of ST of recurrence (salvage surgery vs. radiotherapy) was recorded. Kaplan-Meier analysis with log-rank was used to estimate the impact of ST on OS (median follow-up = 21, interquartile range: 5-48).Results: The 3-year OS for patients free of any recurrence (I), with solitary or concomitant urethral recurrence (II), and nonurethral recurrence (III) was 86.5%, 74.5%, and 48.2%, respectively (P = 0.002 for I vs. III and II vs. III; P = 0.55 for I vs. II). In the 80 patients with recurrences, the modality of primary treatment of recurrence was salvage surgery in 30 (37.5%), salvage radiotherapy (RT) in 8 (10.0%), and salvage surgery plus RT in 5 (6.3%) whereas 37 patients did not receive ST for recurrence (46.3%). In patients with recurrences, those who underwent salvage surgery or RT-based ST had similar 3-year OS (84.9%, 71.6%) compared to patients without recurrence (86.7%, P = 0.65), and exhibited superior 3-year OS compared to patients who did not undergo ST (38.0%, P<0.001 compared to surgery, P = 0.045 to RT-based ST, P = 0.29 for surgery vs. RT-based ST).Conclusions: In this study, patients who underwent ST for recurrent PUC demonstrated improved OS compared to those who did not receive ST and exhibited similar survival to those who never developed recurrence after primary treatment. [ABSTRACT FROM AUTHOR]

The article offers information on a study which examines lymphovascular invasion (LVI) as basis for the need of adjuvant chemotherapy for bladder cancer patient. Topics discussed include the benefit of early detection of LVI and adjuvant chemotherapy in the patient, the influence of LVI in postoperative outcome, improvement in survival of patient.

The author discusses the study on cluster of differentiation 74 (CD74) expression in bladder cancer tissues. The author says that CD74 is a histocompatibility complex class II protein on immune cells which serves as macrophage migration inhibitor factor receptor. He mentions the prognostic significance of immunological serum-based parameters as predictors of survival, thrombocytosis, and serum-C-reactive protein.

The article discusses the prognostic benefit of pre-cystectomy decision-tree model in pathological upstaging and predicting outcomes in cT2 bladder cancer. The clinical and pathological parameters have compared the effectiveness of the prediction model to neoadjuvant chemotherapy in patients with advances cancer stages. It reveals that incorporating the serum C-reactive protein and thrombocytosis into basic prognostic models after cystectomy can significantly improve predictive accuracy.

Objectives To evaluate risk factors for urethral recurrence (UR) in women with neobladder. Material and methods From 1994 to 2011, 297 women (median age = 54 y; interquartile range: 47–57) underwent radical cystectomy with ileal neobladder for bladder cancer in 4 centers. None of the patients had bladder neck involvement at preoperative assessment. Univariable and multivariable analyses were used to estimate recurrence-free survival and overall survival. The median follow-up was 64 months (interquartile range: 25–116). Results Of the 297 patients, 81 developed recurrence (27%). The 10- and 15-year recurrence-free survival rates were 66% and 66%, respectively. The 10- and 15-year overall survival rates were 57% and 55%, respectively. UR occurred in 2 patients (0.6%) with solitary urethral, 4 (1.2%) with concomitant urethral and distant recurrence, and 1 with concomitant urethral and local recurrence (0.3%). Bladder tumors were located at the trigone in 27 patients (9.1%). None of these patients developed UR. Lymph node tumor involvement was present in 60 patients (20.2%). On univariable and multivariable analyses, pathologic tumor and nodal stage were independent predictors for the overall risk of recurrence. UR was associated with a positive final urethral margin status ( P <0.001) whereas no significant associations were found for carcinoma in situ, pathologic tumor and nodal stage, and bladder trigone involvement. Conclusions In this series, only 0.6% of women developed solitary UR. A positive final urethral margin was associated with an increased risk of UR. Women with involvement of the bladder trigone were not at higher risk of UR. [ABSTRACT FROM AUTHOR]