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Renal cell carcinoma (RCC) is a common malignancy frequently diagnosed at the metastatic stage. We performed a comprehensive analysis of the tumor immune microenvironment (TIME) in RCC patients, including the peritumoral tissue microenvironment, to characterize the phenotypic patterns and functional characteristics of infiltrating immune cells. T cells from various compartments (peripheral blood, tumor, peritumoral area, and adjacent healthy renal tissue) were assessed using flow cytometry and Luminex analyses, both before and after T cell-specific stimulation, to evaluate activation status and migratory potential. Our findings demonstrated that tumor-infiltrating lymphocytes (TILs) exhibited heightened cytokine production compared to peritumoral T cells (pTILs), acting as the primary source of cytotoxic markers (IFN-γ, granzyme B, and FasL). CD8 + T cells primarily employed Fas Ligand for cytotoxicity, while CD4 + T cells relied on CD107a. In addition, a statistically significant negative correlation between patient mortality and the presence of CD4 + CD107 + pTILs was demonstrated. The engagement with the PD-1/PD-L1 pathway was also more evident in CD4 + and CD8 + pTILs as opposed to TILs. PD-L1 expression in the non-leukocyte fraction of the tumor tissue was relatively lower than in their leukocytic counterparts and upon stimulation, peripheral blood T cells displayed much stronger responses to stimulation than TILs and pTILs. Our results suggest that tumor and peritumoral T cells exhibit limited responsiveness to additional activation signals, while peripheral T cells retain their capacity to respond to stimulatory signals., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. Jirina Bartunkova reports a relationship with Sotio Biotech as that includes: employment., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: There is a significant unmet need for new and efficacious therapies in urothelial cancer (UC). To provide recommendations on appropriate clinical trial designs across disease settings in UC, the Society for Immunotherapy of Cancer (SITC) and the International Bladder Cancer Group (IBCG) convened a multidisciplinary, international consensus panel., Methods: Through open communication and scientific debate in small- and whole-group settings, surveying, and responses to clinical questionnaires, the consensus panel developed recommendations on optimal definitions of the disease state, end points, trial design, evaluations, sample size calculations, and pathology considerations for definitive studies in low- and intermediate-risk nonmuscle-invasive bladder cancer (NMIBC), high-risk NMIBC, muscle-invasive bladder cancer in the neoadjuvant and adjuvant settings, and metastatic UC. The expert panel also solicited input on the recommendations through presentations and public discussion during an open session at the 2021 Bladder Cancer Advocacy Network (BCAN) Think Tank (held virtually)., Results: The consensus panel developed a set of stage-specific bladder cancer clinical trial design recommendations, which are summarized in the table that accompanies this text., Conclusion: These recommendations developed by the SITC-IBCG Bladder Cancer Clinical Trial Design consensus panel will encourage uniformity among studies and facilitate drug development in this disease.

Purpose: To learn about the history and development of en bloc resection of bladder tumour (ERBT), and to discuss its future directions in managing bladder cancer., Methods: In this narrative review, we summarised the history and early development of ERBT, previous attempts in overcoming the tumour size limitation, consolidative effort in standardising the ERBT procedure, emerging evidence in ERBT, evolving concepts in treating large bladder tumours, and the future directions of ERBT., Results: Since the first report on ERBT in 1980, there has been tremendous advancement in terms of its technique, energy modalities and tumour retrieval methods. In 2020, the international consensus statement on ERBT has been developed and it serves as a standard reference for urologists to practise ERBT. Recently, high-quality evidence on ERBT has been emerging. Of note, the EB-StaR study showed that ERBT led to a reduction in 1-year recurrence rate from 38.1 to 28.5%. An individual patient data meta-analysis is currently underway, and it will be instrumental in defining the true value of ERBT in treating non-muscle-invasive bladder cancer. For large bladder tumours, modified approaches of ERBT should be accepted, as the quality of resection is more important than a mere removal of tumour in one piece. The global ERBT registry has been launched to study the value of ERBT in a real-world setting., Conclusion: ERBT is a promising surgical technique in treating bladder cancer and it has gained increasing interest globally. It is about time for us to embrace this technique in our clinical practice., (© 2023. The Author(s).)

Bladder cancer is common and one of the most costly cancer forms, due to a lack of curative therapies. Recently, clinical safety and efficacy of the alpha1-oleate complex was demonstrated in a placebo-controlled study of nonmuscle invasive bladder cancer. Our study investigated if long-term therapeutic efficacy is improved by repeated treatment cycles and by combining alpha1-oleate with low-dose chemotherapy. Rapidly growing bladder tumors were treated by intravesical instillation of alpha1-oleate, Epirubicin or Mitomycin C alone or in combination. One treatment cycle arrested tumor growth, with a protective effect lasting at least 4 weeks in mice receiving 8.5 mM of alpha1-oleate alone or 1.7 mM of alpha-oleate combined with Epirubicin or Mitomycin C. Repeated treatment cycles extended protection, defined by a lack of bladder pathology and a virtual absence of bladder cancer-specific gene expression. Synergy with Epirubicin was detected at the lower alpha1-oleate concentration and in vitro, alpha1-oleate was shown to enhance the uptake and nuclear translocation of Epirubicin, by tumor cells. Effects at the chromatin level affecting cell proliferation were further suggested by reduced BrdU incorporation. In addition, alpha1-oleate triggered DNA fragmentation, defined by the TUNEL assay. The results suggest that bladder cancer development may be prevented long-term in the murine model, by alpha1-oleate alone or in combination with low-dose Epirubicin. In addition, the combination of alpha1-oleate and Epirubicin reduced the size of established tumors. Exploring these potent preventive and therapeutic effects will be of immediate interest in patients with bladder cancer., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

An updated Council of the EU recommendation on cancer screening was adopted in December 2022 during the Czech EU presidency. The recommendation included prostate cancer as a suitable target disease for organised screening, and invited countries to proceed with piloting and further research. To support further discussions and actions to promote early detection of prostate cancer, an international conference in November 2022 (Prostaforum 2022) resulted in a joint declaration. Here we describe the EU policy background, summarise the preparation of the declaration and the key underlying evidence and expert recommendations, and report the text of the declaration. The declaration summarises the striking inequalities in prostate cancer burden in Europe and calls on all stakeholders to consider and support concrete steps for advancement of organised early detection of prostate cancer. Our aim is to request endorsement of the text and potential initiation of practical actions by all stakeholders to support the aims of the declaration., Patient Summary: Prostate cancer is among the most frequent cancers and is one of the most common causes of cancer death among men. The European Union has recommended new pilot programmes for prostate cancer screening. The Prostaforum 2022 declaration invites all stakeholders to support this new recommendation with specific steps., (© 2023 The Author(s).)

Purpose of Review: Transurethral resection of bladder cancer (TURBT) is in its standard form an inherently imperfect technique. Fluorescence-guided photodynamic diagnosis (PDD) represents one way to improve the outcome by enhancing tumour detection. Fluorescence has been used in connection with bladder cancer since the 1970s, with a number of studies being published since then. However, the method is still not recommended as a standard part of TURBT mainly because of the limited level of evidence of concerned studies, questionable cost-effectiveness and even contradictory results. The review lists the latest articles covering this topic., Recent Findings: Several recently published meta-analyses reviewed a series of randomized controlled trials (RCTs) concerning PDD assisted TURBT. Results were generally supporting the positive effect on reduction of recurrence rate. However, the mentioned meta-analyses are overlapping in terms of reviewed RCT that provide only a low level of evidence according to a recent Cochrane review. Supposed limitations of PDD (timing of the procedure, low specificity) and possible solutions are also covered., Summary: Most of the published data confirmed reduced early recurrence rate after PDD assisted TURBT comparing to standard TURBT. Its impact on late recurrence rate, progression rate or cost-effectiveness has not been sufficiently demonstrated., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

This case-based discussion describes the management of a 66-yr-old man who presented to the emergency department with gross hematuria. His urine cytology was benign, and computed tomography (CT) with nephrographic phase revealed a 2.5 cm filling defect within the left renal pelvis and luminal narrowing in the right proximal ureter with hydronephrosis. CT showed no lymphadenopathy and no sign of metastatic disease. Cystoscopy was normal. In a progressive case-based discussion fashion, we will discuss the diagnostic and treatment options with two different perspectives: (1) guidelines-based current standard of care and (2) an outlook on future perspectives using the latest scientific advances that may soon become the standard of care. PATIENT SUMMARY: This presentation of a real-life clinical scenario will be useful in describing the current standard of care and future perspectives regarding the diagnosis and treatment of upper urinary tract tumors., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Non-muscle-invasive bladder cancer (NMIBC) is an early-stage cancer without invasion into the detrusor muscle layer. Transurethral resection of bladder tumour (TURBT) is a diagnostic and potentially curative procedure for NMIBC, but has some limitations, including difficulties in ascertaining complete tumour removal upon piecemeal resection and the possibility of tumour re-implantation after the procedure. The oncological control of NMIBC is far from satisfactory, with a 1-year recurrence rate of 15-61%, and a 5-year recurrence rate of 31-78%. Various recurrence mechanisms have been described for NMIBC, such as undetected tumours upon cystoscopy, incomplete resection during TURBT, tumour re-implantation after TURBT, drop metastasis from upper tract urothelial carcinoma and field change cancerization. Understanding the recurrence mechanisms from a clinical perspective has strong implications for the optimization of NMIBC oncological outcomes, as a cure for patients with NMIBC can only be achieved by tackling all possible recurrence mechanisms in a comprehensive manner., (© 2022. Springer Nature Limited.)

Introduction: It has been hypothesized that transurethral en bloc (TUEB) of bladder tumor offers benefits over conventional transurethral resection of bladder tumor (cTURBT). This study aimed to compare disease outcomes of TUEB and cTURBT with focus on the different energy sources. Methods: A systematic search was performed using PubMed and Web of Science databases in June 2021. Studies that compared the pathological (detrusor muscle presence), oncological (recurrence rates) efficacy, and safety (serious adverse events [SAEs]) of TUEB and cTURBT were included. Random- and fixed-effects meta-analytic models and Bayesian approach in the network meta-analysis was used. Results: Seven randomized clinical trials (RCTs) and seven non-RCTs (NRCT), with a total of 2092 patients. The pooled 3- and 12-month recurrence risk ratios (RR) of five and four NRCTs were 0.46 (95% CI 0.29-0.73) and 0.56 (95% CI 0.33-0.96), respectively. The pooled 3- and 12-month recurrence RRs of four and seven RCTs were 0.57 (95% CI 0.25-1.27) and 0.89 (95% CI 0.69-1.15), respectively. The pooled RR for SAEs such as prolonged hematuria and bladder perforation of seven RCTs was 0.16 (95% CI 0.06-0.41) in benefit of TUEB. Seven RCTs ( n  = 1077) met our eligibility criteria for network meta-analysis. There was no difference in 12-month recurrence rates between hybridknife, laser, and bipolar TUEB compared with cTURBT. Contrary, laser TUEB was significantly associated with lower SAEs compared with cTURBT. Surface under the cumulative ranking curve ranking analyses showed with high certainty that laser TUEB was the best treatment option to access all endpoints. Conclusion: While NRCTs suggested a recurrence-free benefit to TUEB compared with cTURBT, RCTs failed to confirm this. Conversely, SAEs were consistently and clinically significantly better for TUEB. Network meta-analyses suggested laser TUEB has the best performance compared with other energy sources. These early findings need to be confirmed and expanded upon.

Background: Radical cystectomy (RC) is indicated in primary or secondary muscle-invasive bladder cancer (primMIBC, secMIBC) and in primary or recurrent high- or very high-risk non-muscle-invasive bladder cancer (primHR-NMIBC, recHR-NMIBC). The optimal timing for RC along the disease spectrum of nonmetastatic urothelial carcinoma remains unclear., Objective: To compare outcomes after RC between patients with primHR-NMIBC, recHR-NMIBC, primMIBC, and secMIBC., Design Setting and Participants: This retrospective, multicenter study included patients with clinically nonmetastatic bladder cancer (BC) treated with RC., Outcome Measurements and Statistical Analysis: We assessed oncological outcomes for patients who underwent RC according to the natural history of their BC. primHR-NMIBC and primMIBC were defined as no prior history of BC, and recHR-NMIBC and secMIBC as previously treated NMIBC that recurred or progressed to MIBC, respectively. Log-rank analysis was used to compare survival outcomes, and univariable and multivariable Cox and logistic regression analyses were used to identify predictors for survival., Results and Limitations: Among the 908 patients included, 211 (23%) had primHR-NMIBC, 125 (14%) had recHR-NMIBC, 404 (44%) had primMIBC, and 168 (19%) had secMIBC. Lymph node involvement and pathological upstaging were more frequent in the secMIBC group than in the other groups ( p  < 0.001). The median follow-up was 37 mo. The 5-year recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were 77.9%, 83.2%, and 72.7% in primHR-NMIBC, 60.0%, 59%, and 48.9% in recHR-NMIBC, 60.9%, 64.5%, and 54.8% in primMIBC, and 41.3%, 46.5%, and 39% in secMIBC, respectively, with statistically significant differences across all survival outcomes except between recHR-NMIBC and primMIBC. On multivariable Cox regression, recHR-NMIBC was independently associated with shorter RFS (hazard ratio [HR] 1.64; p  = 0.03), CSS (HR 1.79; p  = 0.01), and OS (HR 1.45; p  = 0.03), and secMIBC was associated with shorter CSS (HR 1.77; p  = 0.01) and OS (HR 1.57; p  = 0.006). Limitations include the biases inherent to the retrospective study design., Conclusions: Patients with recHR-NMIBC and primHR-MIBC had similar survival outcomes, while those with sec-MIBC had the worst outcomes. Therefore, early radical intervention may be indicated in selected patients, and potentially neoadjuvant systemic therapies in some patients with recHR-NMIBC., Patient Summary: We compared cancer outcomes in different bladder cancer scenarios in a large, multinational series of patients who underwent removal of the bladder with curative intent. We found that patients who experienced recurrence of non-muscle-invasive bladder cancer (NMIBC) had similar survival outcomes to those with initial muscle-invasive bladder cancer (MIBC), while patients who experienced progression of NMIBC to MIBC had the worst outcomes. Selected patients with non-muscle-invasive disease may benefit from early radical surgery or from perioperative chemotherapy or immunotherapy., (© 2022 The Author(s).)

Background and Aim: Placental Growth Factor (PlGF) plays a crucial role in angiogenesis and was identified as a potential prognostic biomarker in various types of cancer. Therefore, we evaluated the diagnostic accuracy and prognostic value of PlGF serum concentration in patients with clear cell renal cell carcinoma (ccRCC)., Patients and Methods: A total of 49 patients subjected to partial or radical nephrectomy for ccRCC [localized without relapse (lccRCC; n=31), localized with later relapse (rccRCC; n=8), primary metastatic cancer (mccRCC; n=10); median of follow-up 4.4 years] were enrolled in a prospective study to assess the significance of PlGF serum concentration. PlGF was measured prior to surgery and 3 months postoperatively. Our control group consisted of 38 healthy subjects., Results: PlGF serum concentration was significantly higher in ccRCC compared to controls (P=0.002). The cut-off value of PlGF concentration for the risk of ccRCC was determined at 12.71 pg/mL (AUC=0.729; P=0.0001). Prior to surgery, among ccRCC subgroups, significantly higher PlGF concentration was detected in mccRCC compared to lccRCC (P=0.002). Postoperatively, we observed a tendency to higher PlGF serum concentration in rccRCC compared to lccRCC subgroup, however without significance (P=0.17). The cut-off value for the risk of relapse was 11.41 pg/mL (AUC=0.792; P=0.0003). In subjects with localized ccRCC with PlGF concentration below 11.41 pg/mL 3-years cancer specific survival was 93% compared to 61% in subject with concentration above the cut-off value (P=0.018)., Conclusion: Based on our findings, PlGF serum concentration seems to be a useful biomarker in diagnostics and prediction of prognosis in ccRCC.

Purpose: To investigate the association of patients' sex with recurrence and disease progression in patients treated with intravesical bacillus Calmette-Guérin (BCG) for T1G3/HG urinary bladder cancer (UBC)., Materials and Methods: We analyzed the data of 2635 patients treated with adjuvant intravesical BCG for T1 UBC between 1984 and 2019. We accounted for missing data using multiple imputations and adjusted for covariate imbalance between males and females using inverse probability weighting (IPW). Crude and IPW-adjusted Cox regression analyses were used to estimate the hazard ratios (HR) with their 95% confidence intervals (CI) for the association of patients' sex with HG-recurrence and disease progression., Results: A total of 2170 (82%) males and 465 (18%) females were available for analysis. Overall, 1090 (50%) males and 244 (52%) females experienced recurrence, and 391 (18%) males and 104 (22%) females experienced disease progression. On IPW-adjusted Cox regression analyses, female sex was associated with disease progression (HR 1.25, 95%CI 1.01-1.56, p = 0.04) but not with recurrence (HR 1.06, 95%CI 0.92-1.22, p = 0.41). A total of 1056 patients were treated with adequate BCG. In these patients, on IPW-adjusted Cox regression analyses, patients' sex was not associated with recurrence (HR 0.99, 95%CI 0.80-1.24, p = 0.96), HG-recurrence (HR 1.00, 95%CI 0.78-1.29, p = 0.99) or disease progression (HR 1.12, 95%CI 0.78-1.60, p = 0.55)., Conclusion: Our analysis generates the hypothesis of a differential response to BCG between males and females if not adequately treated. Further studies should focus on sex-based differences in innate and adaptive immune system and their association with BCG response., (© 2021. The Author(s).)

Open radical cystectomy (ORC) remains the gold standard for the treatment of muscle-invasive and high-risk non-muscle invasive bladder cancer unsuitable for bladder preservation techniques. Despite improvements in operative technique and perioperative care, it continues to be associated with significant complications. We analyzed our series of prospectively collected data of patients who underwent ORC at a tertiary referral academic center and evaluated early and late postoperative complications and mortality. The records of 391 ORCs with ileal diversion performed at our institution between January 2008 and July 2018 for non-metastatic transitional bladder carcinoma and other distinct pathological types were analyzed. Perioperative mortality was determined and 30-day and 90-day complications were reported according to the Martin Criteria and the European Association of Urology and graded according to the five-grade Clavien-Dindo classification. Univariate and multivariate analyses were used to evaluate predictors of complications and mortality. Gastrointestinal and infectious complications represented 41% and 43% of the total complications observed at 30 and 90 days after the surgery, respectively. The strongest predictor of infectious complications was the choice of ileal neobladder as the urinary diversion (p≤0.0001). Diabetes was a predictor of the overall, major and major infectious complications (p<0.05). The 30-day mortality rate was 1% while the 90-day mortality rate was 1.5%. Age ≥75 was the single predictor of mortality at both 30-days (p-value 0.003) and 90-days (p-value 0.01) in univariate and multivariate analyses. ORC is a morbid procedure, associated with a high mortality rate. Elderly patients should have proper counseling before the indication of this procedure. Gastrointestinal and infectious complications represent the most common and serious complications, and the study of their predictors is of the utmost importance.

Partially unfolded alpha-lactalbumin forms the oleic acid complex HAMLET, with potent tumoricidal activity. Here we define a peptide-based molecular approach for targeting and killing tumor cells, and evidence of its clinical potential (ClinicalTrials.gov NCT03560479). A 39-residue alpha-helical peptide from alpha-lactalbumin is shown to gain lethality for tumor cells by forming oleic acid complexes (alpha1-oleate). Nuclear magnetic resonance measurements and computational simulations reveal a lipid core surrounded by conformationally fluid, alpha-helical peptide motifs. In a single center, placebo controlled, double blinded Phase I/II interventional clinical trial of non-muscle invasive bladder cancer, all primary end points of safety and efficacy of alpha1-oleate treatment are reached, as evaluated in an interim analysis. Intra-vesical instillations of alpha1-oleate triggers massive shedding of tumor cells and the tumor size is reduced but no drug-related side effects are detected (primary endpoints). Shed cells contain alpha1-oleate, treated tumors show evidence of apoptosis and the expression of cancer-related genes is inhibited (secondary endpoints). The results are especially encouraging for bladder cancer, where therapeutic failures and high recurrence rates create a great, unmet medical need.

Background: Bladder cancer is a major urological disease, with approximately 550 000 new cases diagnosed in 2018., Objective: We examined gender-specific incidence and mortality patterns, and trends of bladder cancer from a global perspective. We further investigated their associations with tobacco use and gross domestic product (GDP) per capita., Design, Setting, and Participants: We retrieved data on the incidence and mortality of bladder cancer from the GLOBOCAN database, Cancer Incidence in Five Continents, and the WHO mortality database. Data on the rate of tobacco use were retrieved from the WHO Global Health Observatory. Data on GDP per capita was retrieved from the United Nations Human Development Report., Outcome Measurements and Statistical Analysis: We performed two sets of analyses. The first set of analysis is based on bladder cancer incidence and mortality data in 2018. The gender-specific age-standardised rates (ASRs) of incidence and mortality, and their correlations with the rate of tobacco use and GDP per capita were investigated. A multivariable linear regression analysis was also performed. In the second set of analysis, we examined the 10-yr temporal trends of bladder cancer incidence and mortality by average annual percent change using joinpoint regression analysis. A further exploratory analysis on GDP per capita in countries with decreasing trends of tobacco use was also performed., Results and Limitations: Wide variations in bladder cancer incidence and mortality were observed globally. There were positive correlations between the rate of tobacco use and the ASRs of bladder cancer incidence (r=0.20) and mortality (r=0.38) in men, and between the rate of tobacco use and the ASRs of bladder cancer incidence (r=0.67) and mortality (r=0.22) in women. There were positive correlations between GDP per capita, and the ASRs of bladder cancer incidence in men (r=0.48) and women (r=0.44). There was a weak positive correlation between GDP per capita and bladder cancer mortality in men (r=0.19), but no correlation with bladder cancer mortality in women (r=0.06). Upon multivariable linear regression analysis, tobacco use was significantly associated with bladder cancer incidence and mortality in men, and bladder cancer incidence in women. Regarding the 10-yr temporal trends of bladder cancer, Europe has an increasing incidence but decreasing mortality, and Asia has a decreasing incidence but increasing male mortality. Among countries with decreasing trends of tobacco use, the mean GDP per capita was higher in countries with decreasing trends of bladder cancer mortality than in those with increasing trends of bladder cancer mortality. A major limitation of the study is that cancer incidence might be underdetected and under-reported in less developed nations., Conclusions: There were observable trends of bladder cancer incidence and mortality globally. Tobacco use was significantly associated with both bladder cancer incidence and mortality. A certain level of economic capacity might be needed to further reduce bladder cancer mortality in countries with a decreasing trend of tobacco use., Patient Summary: There are different trends of bladder cancer incidence and mortality globally. Smoking is significantly associated with the incidence and mortality of bladder cancer. A higher financial capacity may be needed to further improve the disease outcomes., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: This systematic review assessed compliance to guidelines for the management of nonmuscle-invasive bladder carcinoma (NMIBC)., Methods: The PUBMED, Web of Science, Cochrane Library, and Scopus databases were searched in November 2019 in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis statement., Results: Fifteen studies incorporating a collective total of 10,575 NMIBC patients were eligible for inclusion in this systematic review. We found that the rates of compliance were 53.0% with a single immediate intravesical instillation in patients with presumed low or intermediate risk, 37.1% with intravesical bacillus Calmette-Guerin or chemotherapy in those with intermediate risk, 43.4% with performance of a second transurethral resection in high-risk patients, 32.5% with administration of adjuvant intravesical bacillus Calmette-Guerin in high-risk patients, 36.1% with radical cystectomy in highest-risk patients, and 82.2% with cystoscopy for follow-up., Conclusions: Compliance with NMIBC guidelines remains low. Better guideline education and understanding holds the key to achieving high compliance. Strategies to improve guideline compliance at the physician level are urgently required., (Copyright © 2020. Published by Elsevier Inc.)

Background: There has been increasing interest in en bloc resection of bladder tumour (ERBT) as an oncologically noninferior alternative to transurethral resection of bladder tumour (TURBT) with fewer complications and better histology specimens. However, there is a lack of robust randomised controlled trial (RCT) data for making recommendations., Objective: We aimed to develop a consensus statement to standardise various aspects of ERBT for clinical practice and to guide future research., Design, Setting, and Participants: We developed the consensus statement on ERBT using a modified Delphi method. First, two systematic reviews were performed to investigate the clinical effectiveness of ERBT versus TURBT (effectiveness review) and to identify areas of uncertainty in ERBT (uncertainties review). Next, 200 health care professionals (urologists, oncologists, and pathologists) with experience in ERBT were invited to complete a two-round Delphi survey. Finally, a 16-member consensus panel meeting was held to review, discuss, and re-vote on the statements as appropriate., Outcome Measurements and Statistical Analysis: Meta-analyses were performed for RCT data in the effectiveness review. Consensus statements were developed from the uncertainties review. Consensus was defined as follows: (1) ≥70% scoring a statement 7-9 and ≤15% scoring the statement 1-3 (consensus agree), or (2) ≥70% scoring a statement 1-3 and ≤15% scoring the statement 7-9 (consensus disagree)., Results and Limitations: A total of 10 RCTs were identified upon systematic review. ERBT had a shorter irrigation time (mean difference -7.24 h, 95% confidence interval [CI] -9.29 to -5.20, I 2  = 85%, p < 0.001) and a lower rate of bladder perforation (risk ratio 0.30, 95% CI 0.11-0.83, I 2  = 1%, p = 0.02) than TURBT, both with moderate certainty of evidence. There were no significant differences in recurrences at 0-12, 13-24, or 25-36 mo (all very low certainty of evidence). A total of 103 statements were developed, of which 99 reached a consensus. A summary of statements is as follows: ERBT should always be considered for treating non-muscle-invasive bladder cancer; ERBT should be considered feasible even for bladder tumours larger than 3 cm; number and location of bladder tumours are not major limitations in performing ERBT; the planned circumferential margin should be at least 5 mm from any visible bladder tumour; after ERBT, additional biopsy of the tumour edge or tumour base should not be performed routinely; for the ERBT specimen, T1 substage, and circumferential and deep resection margins must be assessed; it is safe to give a single dose of immediate intravesical chemotherapy, perform second-look transurethral resection, and give intravesical bacillus Calmette-Guérin (BCG) therapy after ERBT; and in studies of ERBT, both per-patient and -tumour analysis should be performed for different outcomes as appropriate. Important outcomes for future ERBT studies were also identified. A limitation is that as consensus statements are brief, concise and binary in nature, areas of uncertainty that are complex in nature may not be addressed adequately., Conclusions: We have provided the most comprehensive review of the evidence base to date using a meta-analysis where appropriate and applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and mobilised the international urology community to develop a consensus statement on ERBT using transparent and robust methods. The consensus statement will provide interim guidance for health care professionals who practice ERBT and inform researchers regarding ERBT-related studies in the future., Patient Summary: En bloc resection of bladder tumour (ERBT) is a surgical technique aiming to resect a bladder tumour in one piece. We included an international panel of experts to agree on the best practice of ERBT, and this will provide guidance to clinicians and researchers in the future., (Copyright © 2020 European Association of Urology. All rights reserved.)

Introduction and Objectives: To evaluate the prognostic role of modified Glasgow prognostic score (mGPS) for the prediction of oncological outcomes in a retrospective large multicenter cohort of upper tract urothelial carcinoma (UTUC) patients treated with radical nephroureterectomy (RNU)., Materials and Methods: We retrospectively analyzed a multicenter cohort of patients treated with RNU for clinically nonmetastatic UTUC. Multivariable logistic regression analyses were performed to evaluate the ability of mGPS to predict nonorgan confined (NOC) disease and lymph-node involvement (LNI) at RNU. Multivariable Cox-regression models were performed to evaluate the preoperative and postoperative prognostic effect of mGPS on survival outcomes., Results: Overall, 2,492 patients were included in the study. Of these, 1,929 (77%), 530 (21%), and 33 (1%) had a mGPS of 0, 1, and 2, respectively. mGPS was associated with characteristics of tumor aggressiveness and independently predicted LNI and NOC at RNU (both P < 0.05). On univariable and multivariable Cox-regression analyses, higher mGPS was independently associated with recurrence-free, cancer-specific, and overall survival, both in a preoperative and in a postoperative setting. The inclusion of mGPS significantly improved the discrimination of a preoperative model for the prediction of oncologic outcomes compared to standard prognosticators., Conclusions: We found that mGPS is independently associated with clinicopathologic features and survival outcomes after RNU. Future studies should investigate the role of mGPS in a panel of preoperative markers for the prediction of NOC and LNI in UTUC patients, thus possibly improving the selection for perioperative systemic therapy., Competing Interests: Conflicts of interest I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript are the following: Shahrokh Shariat owns or co-owns the following patents: Methods to determine prognosis after therapy for prostate cancer. Granted 2002-09-06. Methods to determine prognosis after therapy for bladder cancer. Granted 2003-06-19. Prognostic methods for patients with prostatic disease. Granted 2004-08-05. Soluble Fas: urinary marker for the detection of bladder transitional cell carcinoma. Granted 2010-07-20. He is advisory board member of Astellas, Cepheid, Ipsen, Jansen, Lilly, Olympus, Pfizer, Pierre Fabre, Sanofi, and Wolff. He is speaker for Astellas, Ipsen, Jansen, Lilly, Olympus, Pfizer, Pierre Fabre, Sanochemia, Sanofi, and Wolff. The other authors made no disclosures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To validate the predictive and prognostic role of the De Ritis ratio in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy in a large multi-institutional cohort., Materials and Methods: The preoperative De Ritis ratio was assessed in a multi-institutional cohort of 2,492 patients. An altered De Ritis ratio was defined as a ratio >1.35. Logistic regression analyses were performed to assess the association of the De Ritis ratio with advanced disease. The association of the De Ritis ratio with survival outcomes was evaluated using Cox proportional hazards regression models., Results: An altered De Ritis ratio was observed in 985 (41.5%) patients; it was associated with a more advanced pathological features. In a preoperative model, the De Ritis ratio was an independent predictive factor for the presence of lymph node metastasis and muscle-invasive and nonorgan-confined disease (P < 0.05). Compared to patients with a normal De Ritis ratio, those with an altered De Ritis ratio had worse recurrence free (P <0.0001), cancer specific (P = 0.0003), and overall survival (P = 0.0014) in the Kaplan-Meier analyses. In the multivariable analyses that was adjusted for the effects of standard clinicopathologic features, the De Ritis ratio did not retain its independent prognostic value., Conclusions: In UTUC, the preoperative De Ritis ratio is associated with adverse clinicopathologic features and independently predicts features of biologically and clinically aggressive UTUC. Therefore, it might be useful to incorporate the De Ritis ratio into prognostic tools in selecting appropriate treatment strategies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial., Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management., Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference., Setting: Online Delphi survey and consensus conference., Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management., Outcome Measurements and Statistical Analysis: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), and 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus)., Results and Limitations: Overall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease., Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach., Patient Summary: This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available., (Copyright © 2019 European Society of Medical Oncology and European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The European Association of Urology (EAU) non-muscle-invasive bladder cancer (NMIBC) guidelines are meant to help minimise morbidity and improve the care of patients with NMIBC. However, there may be underuse of guideline-recommended care in this potentially curable cohort., Objective: To assess European physicians' current practice in the management of NMIBC and evaluate its concordance with the EAU 2013 guidelines., Design, Setting, and Participants: Initial 45-min telephone interviews were conducted with 20 urologists to develop a 26-item questionnaire for a 30-min online quantitative interview. A total of 498 physicians with predefined experience in treatment of NMIBC patients, from nine European countries, completed the online interviews., Outcome Measurements and Statistical Analysis: Descriptive statistics of absolute numbers and percentages of the use of diagnostic tools, risk group stratification, treatment options chosen, and follow-up regimens were used., Results and Limitations: Guidelines are used by ≥87% of physicians, with the EAU guidelines being the most used ones (71-100%). Cystoscopy (60-97%) and ultrasonography (42-95%) are the most used diagnostic techniques. Using EAU risk classification, 40-69% and 88-100% of physicians correctly identify all the prognostic factors for low- and high-risk tumours, respectively. Re-transurethral resection of the bladder tumour (re-TURB) is performed in 25-75% of low-risk and 55-98% of high-risk patients. Between 21% and 88% of patients received a single instillation of chemotherapy within 24h after TURB. Adjuvant intravesical treatment is not given to 6-62%, 2-33%, and 1-20% of the patients with low-, intermediate-, and high-risk NMIBC, respectively. Patients with low-risk NMIBC are likely to be overmonitored and those with high-risk NMIBC undermonitored. Our study is limited by the possible recall bias of the selected physicians., Conclusions: Although most European physicians claim to apply the EAU guidelines, adherence to them is low in daily practice., Patient Summary: Our survey among European physicians investigated discrepancies between guidelines and daily practice in the management of non-muscle-invasive bladder cancer (NMIBC). We conclude that the use of the recommended diagnostic tools, risk-stratification of NMIBC, and performance of re-TURB have been adopted, but adjuvant intravesical treatment and follow-up are not uniformly applied., (Copyright © 2017. Published by Elsevier B.V.)

Many changes have been made during these last years and concepts for understanding bladder cancer have evolved. We make an update with the latest findings of the WHO (World Health Organistaion) 2016, ICCR (International Collaboration on Cancer Reporting) and other official organisms and try to show the latest developments. In this document we provide new consensus guidelines and insights. We kept this document short and concise providing consensus guidelines to clinicians for the best patient care, it should be easy to understand for a non pathologists. We focussed on several burning issues, such as the anatomical and histological understanding of the bladder wall, the prognostic significance of grading and the most challenging problems in staging, we underline our needs from the clinicians such as clinical information, we further discuss the histological subtypes of bladder cancer, which is an extremely important issue in the light of molecular classifications and give prognostic insights. Furthermore, we discuss the ICCR worldwide consensus reporting, urinary cytology with the Paris system and several issues such as frozen section specimen.

Objectives: With the advent of novel genomic and transcriptomic technologies, new urinary biomarkers have been identified and tested for bladder cancer (BCa) surveillance. To summarize the current status of urinary biomarkers for the detection of recurrence and/or progression in the follow-up of non-muscle invasive BCa patients, and to assess the value of urinary biomarkers in predicting response to intravesical Bacillus Calmette-Guerin (BCG) therapy., Methods and Materials: A medline/pubmed© literature search was performed. The performance of commercially available and investigational biomarkers has been reviewed. End points were cancer detection (recurrence), cancer progression, and response to BCG therapy., Results: The performance requirements for biomarkers are variable according to the clinical scenario. The clinical role of urinary biomarkers in the follow-up of non-muscle invasive BCa patients remains undefined. The FDA-approved tests provide unsatisfactory sensitivity and specificity levels and their use is limited. Fluorescence in situ hybridization (FISH) has been shown to be useful in specific scenarios, mostly as a reflex test and in the setting of equivocal urinary cytology. FISH and immunocytology could conceivably be used to assess BCG response. Recently developed biomarkers have shown promising results; upcoming large trials will test their utility in specific clinical scenarios in a manner similar to a phased drug development strategy., Conclusions: Current commercially available urinary biomarker-based tests are not sufficiently validated to be widely used in clinical practice. Several novel biomarkers are currently under investigation. Prospective multicenter analyses will be needed to establish their clinical relevance and value.

Purpose of Review: Over the last decade, the world has experienced health-threatening supply shortages of Bacillus Calmette-Guérin (BCG) immunotherapy for nonmuscle-invasive bladder cancer (NMIBC). We summarize the current literature to assist in treatment decisions in light of suboptimal supply., Recent Findings: Currently available data do not support a superiority of one BCG strain over the other. Intravesical chemotherapy seems to provide similar results in term of disease progression but not recurrence in intermediate-risk patients. One trial has shown that a 3-year maintenance course of BCG in high-risk NMIBC has no advantage in term of progression or overall survival in comparison with 1-year maintenance. Synergo radiofrequency-induced hyperthermia is a reliable alternative in intermediate or high-risk NMIBC with at least similar recurrence rates compared with BCG., Summary: Patients with intermediate-risk NMIBC can be offered multiple instillations of intravesical chemotherapy for up to 12 months. In high-risk patients and in case of BCG shortage, BCG instillations can be terminated when the patient has completed 1 year of maintenance. Mitomycin C is an alternative in lowest risk high-risk (G3Ta) NMIBC, whereas patients with pT1/carcinoma in situ can be offered Synergo with mitomycin C when radical cystectomy is not feasible. Immediate radical cystectomy should always be considered in highest risk NMIBC after weighing up benefit to risk.

Background: Insufficient specificity and invasiveness of currently used diagnostic methods raises the need for new markers of urological tumors. The aim of this study was to find a link between the urinary excretion of amino acids and the presence of urological tumors., Materials and Methods: Using ion-exchange chromatography, we tested urine samples of patients with prostate cancer (n=30), urinary bladder cancer (n=28), renal cell carcinoma (n=16) and healthy volunteers (control group; n=21)., Results: In each category, we found a group of amino acids which differed in concentration compared to the control group. These differences were most significant in sarcosine in patients with prostate cancer; leucine, phenylalanine and arginine in those with bladder cancer; and sarcosine, glutamic acid, glycine, tyrosine and arginine in the those with renal cell carcinoma., Conclusion: Results of our research imply a possible connection between the occurrence of specific types of amino acids in the urine and the presence of urological tumors., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: To characterize outcomes of patients with TaT1 urothelial carcinoma of the bladder stratified by the European Association of Urology (EAU) categories and to compare them with European Organization for Research and Treatment of Cancer (EORTC) risk groups to assess the rate and effect of reclassification., Patients and Methods: A multi-institutional database of 5,122 patients with TaT1 urothelial carcinoma of the bladder who underwent transurethral resection of the bladder with or without adjuvant therapy at 8 institutions between 1996 and 2007. Multivariable Cox-regression analyses addressed factors associated with disease recurrence and progression. The net reclassification index was used to compare the performance of the EAU categories with the EORTC scoring system., Results: Of 5,122 patients, 632 (12.3%), 2,302 (45.0%), and 2,188 (42.7%) were assigned to the low-, intermediate-, and high-risk EAU category, respectively. Within a median follow-up of 62 months (interquartile range: 27-97), 2,365 (46.2%) and 516 (10.1%) patients experienced disease recurrence and progression, respectively. In multivariable Cox-regression analyses, EAU intermediate- and high-risk categories were associated with a higher risk of disease recurrence (P<0.001) and progression (P<0.001) compared to low-risk patients. Application of the EAU categories reclassified 1,940 (37.9%) patients into a higher risk group for recurrence. Likewise, 602 (11.8%) patients were reclassified to a higher and 278 (5.4%) to a lower risk group for progression. The net reclassification index of the EAU risk stratification was 0.1% (95% CI: -3.1% to 3.2%) for recurrence and 10.1% (95% CI: -8.0% to 12.0%) for progression, respectively., Conclusions: Compared to EORTC risk stratification, the EAU categories reclassifies 37.9% patients into a higher risk group of recurrence and 11.8% into a higher risk of progression. However, the novel risk stratification assigns most patients to the same treatment as the more complex EORTC tables and can be regarded as an alternative tool for treatment decision-making., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Context: Tumour grade is an important prognostic indicator in non-muscle-invasive bladder cancer (NMIBC). Histopathological classifications are limited by interobserver variability (reproducibility), which may have prognostic implications. European Association of Urology NMIBC guidelines suggest concurrent use of both 1973 and 2004/2016 World Health Organization (WHO) classifications., Objective: To compare the prognostic performance and reproducibility of the 1973 and 2004/2016 WHO grading systems for NMIBC., Evidence Acquisition: A systematic literature search was undertaken incorporating Medline, Embase, and the Cochrane Library. Studies were critically appraised for risk of bias (QUIPS). For prognosis, the primary outcome was progression to muscle-invasive or metastatic disease. Secondary outcomes were disease recurrence, and overall and cancer-specific survival. For reproducibility, the primary outcome was interobserver variability between pathologists. Secondary outcome was intraobserver variability (repeatability) by the same pathologist., Evidence Synthesis: Of 3593 articles identified, 20 were included in the prognostic review; three were eligible for the reproducibility review. Increasing tumour grade in both classifications was associated with higher disease progression and recurrence rates. Progression rates in grade 1 patients were similar to those in low-grade patients; progression rates in grade 3 patients were higher than those in high-grade patients. Survival data were limited. Reproducibility of the 2004/2016 system was marginally better than that of the 1973 system. Two studies on repeatability showed conflicting results. Most studies had a moderate to high risk of bias., Conclusions: Current grading classifications in NMIBC are suboptimal. The 1973 system identifies more aggressive tumours. Intra- and interobserver variability was slightly less in the 2004/2016 classification. We could not confirm that the 2004/2016 classification outperforms the 1973 classification in prediction of recurrence and progression., Patient Summary: This article summarises the utility of two different grading systems for non-muscle-invasive bladder cancer. Both systems predict progression and recurrence, although pathologists vary in their reporting; suggestions for further improvements are made., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: To assess the role of N-cadherin as a prognostic biomarker in patients with non-muscle-invasive bladder cancer (NMIBC) treated with transurethral resection with or without adjuvant intravesical therapy., Patients and Methods: Immunohistochemistry using monoclonal mouse antibody was used to evaluate the expression status of N-cadherin in 827 patients with NMIBC. N-cadherin was considered positive if any immunoreactivity with membranous staining was detected. Multivariable Cox regression models were performed to evaluate the prognostic effect of N-cadherin on survival outcomes., Results: N-cadherin expression was observed in 333 patients (40.3%); it was associated with pT1 stage and high tumor grade (both were P<0.001). Median follow-up was 55 months (interquartile range: 18-106). On multivariable Cox regression analyses that adjusted for the effect of the standard clinicopathologic features, N-cadherin expression remained associated with recurrence-free survival (P = 0.007) but not progression-free survival (P = 0.3), cancer-specific survival (P = 0.2), or overall survival (P = 0.9). Adding N-cadherin to a model for prediction of disease recurrence modestly improved its discrimination from 72.8% to 73.4%., Conclusion: N-cadherin is expressed in approximately 2/5 patients with NMIBC. Its expression is associated with adverse pathological features and higher risk of disease recurrence but not progression. N-cadherin could be incorporated in predictive tools to assist in recurrence prediction helping thereby in patient selection regarding adjuvant therapies and follow-up planning., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Potential differences in efficacy of different bacillus Calmette-Guérin (BCG) strains are of importance for daily practice, especially in the era of BCG shortage., Objective: To retrospectively compare the outcome with BCG Connaught and BCG TICE in a large study cohort of pT1 high-grade non-muscle-invasive bladder cancer patients., Design, Setting, and Participants: Individual patient data were collected for 2,451 patients with primary T1G3 tumors from 23 centers who were treated with BCG for the first time between 1990 and 2011., Outcome Measurements and Statistical Analysis: Using Cox multivariable regression and adjusting for the most important prognostic factors in this nonrandomized comparison, BCG Connaught and TICE were compared for time to recurrence, progression, and the duration of cancer specific survival and overall survival., Results and Limitations: Information on the BCG strain was available for 2,099 patients: 957 on Connaught and 1,142 on TICE. Overall, 765 (36%) patients received some form of maintenance BCG, 560 (59%) on Connaught and 205 (18%) on TICE. Without maintenance, Connaught was more effective than TICE only for the time to first recurrence (hazard ratio [HR] = 1.48; 95% CI: 1.20-1.82; P<0.001). With maintenance, TICE was more effective than Connaught for the time to first recurrence (HR = 0.66; 95% CI: 0.47-0.93; P = 0.019) with a trend for cancer specific survival (HR = 0.36; 95% CI: 0.14-0.92; P = 0.033). For time to progression and overall survival, Connaught and TICE had a similar efficacy. Compared to no maintenance therapy, maintenance BCG significantly reduced the risk of recurrence, progression and death, both overall, and disease specific, for TICE, but not for Connaught., Conclusions: We found that BCG Connaught results in a lower recurrence rate as compared with BCG TICE when no maintenance is used. However, the opposite is true when maintenance is given., Patient Summary: As there is currently a BCG shortage, information on the efficacy of different BCG strains is important. In this nonrandomized retrospective comparison in over 2,000 patients, we found that BCG Connaught reduces the recurrence rate compared to BCG TICE when no maintenance is used, but the opposite is true when maintenance is given., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To determine if a re-transurethral resection (TUR), in the presence or absence of muscle at the first TUR in patients with T1-high grade (HG)/Grade 3 (G3) bladder cancer, makes a difference in recurrence, progression, cancer specific (CSS) and overall survival (OS)., Patients and Methods: In a large retrospective multicentre cohort of 2451 patients with T1-HG/G3 initially treated with bacille Calmette-Guérin, 935 (38%) had a re-TUR. According to the presence or absence of muscle in the specimen of the primary TUR, patients were divided in four groups: group 1 (no muscle, no re-TUR), group 2 (no muscle, re-TUR), group 3 (muscle, no re-TUR) and group 4 (muscle, re-TUR). Clinical outcomes were compared across the four groups., Results: Re-TUR had a positive impact on recurrence, progression, CSS and OS only if muscle was not present in the primary TUR specimen. Adjusting for the most important prognostic factors, re-TUR in the absence of muscle had a borderline significant effect on time to recurrence [hazard ratio (HR) 0.67, P = 0.08], progression (HR 0.46, P = 0.06), CSS (HR 0.31, P = 0.07) and OS (HR 0.48, P = 0.05). Re-TUR in the presence of muscle in the primary TUR specimen did not improve the outcome for any of the endpoints., Conclusions: Our retrospective analysis suggests that re-TUR may not be necessary in patients with T1-HG/G3, if muscle is present in the specimen of the primary TUR., (© 2015 The Authors BJU International © 2015 BJU International Published by John Wiley & Sons Ltd.)

MicroRNAs (miRNAs) in urine are examined as potential biomarkers. We examined the urine samples from 70 individuals (45 males, 25 females, mean age 65 years, range 20-84 years). Of the urine donors, 15 were healthy volunteers, 5 were patients with non-cancer diseases, 50 were patients with different stages of bladder cancer. To examine the spectrum of miRNAs in the cell-free fraction of urine, TaqMan Human miRNA Array Card A v.2.1 was used. A set of 30 miRNAs were found that are constantly present in urine supernatants independently of sex, age and health status of the subjects. We compared this set with miRNAs found in plasma, expressed in kidney and genito-urinary tract. Our results indicate that some miRNA could be transferred from the circulation into urine.

Introduction: Extended transrectal ultrasound-guided prostate biopsy is a state-of-the-art tool for prostate cancer detection. Nevertheless, approximately 1/3 of cancers are missed when using this method and repeat biopsy sessions are often required. The aim of this study was to investigate how sampling density (a compound variable reflecting the number of biopsy cores and prostate volume) impacts on detection rate in multiple repeat TRUS-biopsies., Material and Methods: A total of 1007 consecutive patients undergoing their 1 st , 2 nd , 3 rd and any further repeat prostate biopsies were included. The relationship between sampling density and other clinical variables (age, prostate-specific antigen level, free/total PSA ratio, digital rectal examination, number of previous biopsies) and cancer detection rate were assessed by interaction analysis., Results: There were 562 primary re-biopsies, 267 second re-biopsies and 178 third and further re-biopsies included in the study. Detection rate was 25.4%, 25.8% and 25.3%, respectively. Interaction of sampling density with age was demonstrated in patients undergoing their first repeat biopsy (but not further re-biopsies). No interaction was observed with other variables investigated., Conclusions: A more extensive prostate sampling leads to a higher cancer detection rate on repeat prostate biopsies, as shown previously. However, this effect seems to be particularly pronounced in men younger than 65 years undergoing their first repeat prostate biopsy., Competing Interests: The authors declare no conflicts of interest.

We evaluated dendritic cells (DC), regulatory T lymphocytes (Treg) and neutrophils in 37 patients with newly diagnosed renal cell carcinoma (RCC) in the tumor and peripheral blood (PB) and correlated these parameters with tumor staging (early-T1, 2, late-T3, 4 and metastatic disease). The number of myeloid and plasmacytoid DC in blood of RCC patients was higher than in healthy controls. The percentage of myeloid dendritic cells (mDC) from CD45+ cells in tumors was higher in comparison with peripheral blood irrespective of disease stage. Higher percentage of these cells expressed a maturation marker in the periphery in the early stage (CD83 expressing cells). The number of plasmacytoid dendritic cells (pDC) in PB was similar in both early and late stage groups, but the early group displayed a significantly higher percentage of pDC in tumor cell suspension. Neutrophil counts in the peripheral blood of RCC patients were higher than in healthy controls, but the counts in both tumor stage groups were similar. The proportion of neutrophils from CD45+ cells was higher in late stage tumors. Higher percentage of Treg from CD4+ cells was detected in renal carcinoma tissue in comparison to PB with no difference between stages of the disease. Our results reflect the complex interplay between various cells of the immune system and the tumor microenvironment. Activation of dendritic cell subpopulations at early stages of the disease course is counterbalanced by the early appearance of T regulatory cells both in the periphery and tumor tissue. Later stages are characterized by the accumulation of neutrophils in the tumor. Appropriate timing of anticancer strategies, especially immunotherapy, should take these dynamics of the immune response in RCC patients into account., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To investigate the impact of variant histologies of urothelial carcinoma of the bladder (UCB) on oncologic outcomes after radical cystectomy (RC)., Materials and Methods: Data from 1984 UCB patients treated by RC without preoperative chemo- or radiotherapy were reviewed for histological differentiation and variants. We analysed the differences between pure UCB and UCB with variant histology, and those between the different histological variants using various stratifications., Results: Overall, 488 (24.6%) patients had UCB variants with squamous cell (11.4%) and glandular differentiation (3.8%) being the most common. Histological UCB variants were associated with advanced tumour stage, lymphovascular invasion and lymph node metastasis (all p-values<0.01) when compared to pure UCB. In univariable analyses, patients with non-squamous UCB variants were at significantly higher risk for disease recurrence and cancer-specific mortality than those with pure UCB patients (p-values=0.001) and those with squamous cell differentiated UCB (p-values=0.04); the latter two had the same risk. In multivariable analyses that adjusted for the effects of standard clinicopathologic characteristics, variant UCB histology was not associated with both survival end-points. In patients treated with adjuvant chemotherapy (n=492) there was no difference in cancer-specific survival between pure UCB, squamous cell differentiated UCB and other histological UCB variants., Conclusions: A quarter of UCB patients treated with RC harboured histological UCB variants. Variant UCB histologies were associated with features of biologically aggressive disease. While variant UCB histology was associated with worse outcomes in univariable analyses, this effect did not remain significant in multivariable analyses., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The presence of positive soft tissue surgical margins (STSM) at radical cystectomy (RC) is rare. Although some patients with STSM experience disease recurrence rapidly, some have long-term local disease control. We sought to describe the oncologic outcomes, identify predictors, and assess the impact of location and multifocality in patients with positive STSMs at RC., Methods: We retrospectively collected the data of 4,335 patients treated with RC and pelvic lymphadenectomy at 11 academic centers from 1981 to 2008. STSM was defined as the presence of tumor at inked areas of soft tissue on the RC specimen. Univariate and multivariate Cox regression models addressed recurrence-free survival and cancer-specific survival after surgery., Results: STSM were identified in 231 patients (5%). Actuarial recurrence-free survival estimates at 2 and 5 years after RC were 26 ± 3 and 21 ± 3%, respectively. Actuarial cancer-specific survival estimates at 2 and 5 years after RC were 33 ± 3 and 25 ± 4%, respectively. Higher body mass index (p = 0.050), higher tumor stage (p = 0.017), presence of grade 3 disease (p = 0.046), lymphovascular invasion (p = 0.003), and lymph node involvement (p = 0.003) were all independently associated with disease recurrence. Furthermore, higher tumor stage (p = 0.015), lymphovascular invasion (p = 0.006), and lymph node involvement (p = 0.006) were independently associated with cancer specific mortality. Location and multifocality of STSM were not associated with outcomes., Conclusions: Although most patients with STSM at RC had poor outcomes, more than one-fifth had durable cancer control. Pathologic features associated with disease recurrence in the general RC population also stratify patients with STSM into differential risk groups.