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Treatment of muscle invasive bladder cancer can be challenging since treatment is associated with significant side effects and complication rates-especially in patients who often present with relevant comorbidities. In the metastatic stage, the purpose of treatment is palliation, although the oligometastatic stage takes a distinct role. At this stage, treatment of the primary tumor can play a role, if metastasis can be treated locally in addition to systemic treatment, especially the evolving drug treatment landscape could also change long holding paradigms in the near future.This review focuses on the influence of definitive treatment of the primary tumor in patients with oligometastatic urothelial bladder cancer.Based on a literature search, the aim was to summarize data and give an overview on treatment of oligo-metastatic bladder cancer with focus on treatment of the primary tumor. Presented data derived mostly from retrospective studies and meta-analyses.Local treatment of the primary tumor in context of a multimodal therapy of lymph node metastatic or oligometastatic bladder cancer can have a positive influence on survival, quality of life and prevention of local complications in selected patients. The choice of local treatment should follow the same criteria as in non-metastatic bladder cancer.HINTERGRUND: Das muskelinvasive Blasenkarzinom stellt in seiner Behandlung eine besondere Herausforderung dar, da die Therapie mit signifikanten Nebenwirkungen und Komplikationsraten einhergeht, insbesondere bei Patienten mit relevanten Begleiterkrankungen. Im metastasierten Stadium besteht der Therapiezweck in der Palliation, wobei das Vorliegen einer Oligometastasierung eine gesonderte Rolle einnimmt. In diesem Stadium kann auch die Therapie des Primärtumors relevant sein, wenn die Metastasen neben einer systemischen Therapie ebenso lokal behandelt werden können – insbesondere auch in Hinblick auf die über die letzten Jahre die Therapielandschaft erweiternden neuen medikamentösen Möglichkeiten.In diesem Reviewartikel sollen die Einflüsse einer definitiven Therapie des Primärtumors bei Patienten mit oligometastasiertem Urothelkarzinom der Harnblase dargelegt werden.Basierend auf einer nicht-systemischen Literaturrecherche soll ein Überblick über bestehende Ergebnisse zur Therapie des oligometastasierten Blasenkarzinoms in Hinblick auf den Einfluss der Therapie des Primärtumors geben, wobei die Daten meist auf retrospektiven Studien und Metaanalysen bestehen.Eine Lokaltherapie des Primärtumors im Rahmen eines multimodalen Therapiekonzepts kann bei selektionierten Patienten mit lymphogen metastasiertem und oligometastasiertem Blasenkarzinom einen positiven Einfluss auf Überleben, Lebensqualität und Vermeidung von Lokalkomplikationen nehmen, wobei für die Wahl der lokalen Therapie dieselben Kriterien angewendet werden sollten wie im nicht-metastasierten Stadium.

Context Immune-checkpoint inhibitors (ICIs) are a mainstay treatment of metastatic renal cell carcinoma (mRCC). As not all patients benefit from ICIs, a biomarker-driven clinical decision-making strategy is desirable. Objective To assess the predictive value of programmed death ligand 1 (PD-L1) in mRCC patients treated with ICIs. Evidence acquisition Multiple databases were searched for articles published up to April 2020 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Studies comparing objective response rate (ORR), complete response rate (CRR), progressive disease rate (PDR), or progression-free survival (PFS) based on tumor PD-L1 status in mRCC patients were eligible. Evidence synthesis Six studies matched our eligibility criteria. Treatment with ICIs was associated with significantly higher ORRs and CRRs, and lower PDRs in patients with PD-L1–positive tumors than in those with PD-L1–negative status (odds ratio [OR] 1.84, 95% confidence interval [CI] 1.48–2.28; OR 3.11, 95% CI 2.04–4.75; and OR 0.43, 95% CI 0.31–0.60, respectively). ICI treatment was associated with significantly better PFS in PD-L1–positive patients than in sunitinib-treated patients (hazard ratio 0.65, 95% CI 0.57–0.74), whereas this was not found in patients with PD-L1–negative tumors. Compared with sunitinib, ICI combination therapy improved ORRs and PFS significantly in PD-L1–positive patients of all examined ICIs. Nivolumab plus ipilimumab had the highest likelihood of providing the highest ORR and longest PFS in PD-L1–positive patients. Conclusions PD-L1 positivity of the tumor is associated with improved ORRs and prolonged PFS in mRCC patients receiving ICI treatment and thus helps identify mRCC patients most likely to benefit from ICI treatment. Patient summary The use of an immune-checkpoint inhibitor for the treatment of metastatic renal cell carcinoma (mRCC) improved oncological outcomes, and the status of programmed death ligand 1 could contribute to guiding patients and clinicians when determining personalized treatment strategies for mRCC.

Purpose of review Indications for chemotherapy have increased in prostate cancer (PCA), many of which are shared with new hormonal agents (NHA). With no head to head comparison available, defining the optimal sequence and identifying biomarkers to predict response, has been a focus of intense research in PCA. We aim to summarize the best currently available evidence in all stages of disease to help guide therapy. Recent findings In metastatic castration-resistant prostate cancer, Cabazitaxel has shown improved radiographic progression-free survival over another NHA after Docetaxel and one NHA. For hormone sensitive PCA (mHSPC) multiple meta-analyses have shown combination therapy with Docetaxel or an NHA to be superior to androgen deprivation therapy alone, yet no clear benefit over each other. For peri-interventional chemotherapy with local therapy, there is currently only one positive prospective trial, for very high-risk disease. Summary Cabazitaxel is underutilized and should be used earlier. NHAs should not be used in succession as there is significant cross resistance. Combination therapy should be used in mHSPC, yet there is no clear benefit for any combination. Peri-interventional chemotherapy might have a benefit for a small group of patients with very high-risk disease, yet this must be carefully evaluated, and side effects must be taken into account.

Objectives: To evaluate cancer-specific (CSS) and overall survival (OS) in a group of frail patients who were treated with RT without chemotherapy and to compare them with a matched cohort of patients treated with RC. Methods: This study identified 71 patients treated with RT only for high-risk bladder cancer. Patients with metastatic (cN + or cM+) or non-resectable tumors (cT4) and those who received any form of chemotherapy were excluded. Patients where matched 1:1 using propensity scores which adjusted for the effects of age, clinical stage and age-adjusted Charlson comorbidity index (CCI). OS and CSS were evaluated using the Cox proportional hazards regression model and the Fine and Gray competing risk model. Results: In the overall population, RT was associated with worse OS (HR = 1.78, 95% CI = 1.15–2.77, p = 0.01) compared to RC, but not with CSS (HR 1.1, p = 0.74). In the matched cohort, RT was neither associated with OS nor CSS (p > 0.05) compared to RC. In the competing risk analyses no statistically significant association of any of the treatments was observed in the total or in the matched data set (p > 0.05). Conclusion: The use of RT may be an alternative option in well selected patients with limited disease who are considered unfit for systemic chemotherapy and RC. Future research should focus on improving patient selection and assess the quality-of-life as well as the need for reintervention in patients treated with RT.

Summary Neoadjuvant cisplatin-based chemotherapy is standard treatment for muscle-invasive bladder cancer before radical cystectomy (RC). Despite level 1 evidence demonstrating an overall survival benefit for patients undergoing RC after neoadjuvant chemotherapy (NAC), acceptance rates are still low. In high-risk upper tract urothelial cancer (UTUC), cumulative evidence suggests that NAC for locally advanced UTUC can improve oncological outcome. Ongoing phase 3 trials will finally prove the benefit or futility of NAC in this tumor entity. Since urothelial cancer (UC) is a heterogeneous disease, predictive biomarkers are needed to select specific patient populations and potentially increase response rates to NAC. Novel targeting therapies, including immune checkpoint inhibitors, have been approved for metastatic UC. In combination with predictive biomarkers, these might have the potential to change systemic therapy for UC from a “one-fits-all” principle to a more individualized approach.

BACKGROUND Testicular germ cell tumor (TGCT) is one the most common solid tumors in men between the age of 15 and 35 with an overall incidence rate of 1-1.5 %. Epidemiologic studies have demonstrated different incidence patterns in western civilized countries with overall rising incidence trends. OBJECTIVE To analyze differences in regional tumor incidence rates for TGCT and perform a trend analysis for TGCT between 2003 and 2014 in Germany. MATERIAL AND METHODS TGCT cases in Germany which were diagnosed between 2003 and 2014 were provided by the Robert-Koch-Institute, Berlin. For statistical analysis, cluster and spatial scan tests according to Kulldorff were used for cases with seminoma and non-seminoma. Results are presented in administrative districts and graphically illustrated. We performed a trend-analysis in order to evaluate age-adjusted incidence trends in Germany. Tests were two-sided with a level of significance of α=0.05. RESULTS In total we included 35,066 patients. Overall, 22,634 cases had newly diagnosed seminoma and 12,432 were diagnosed as non-seminoma. Maximum incidence of seminoma and non-seminoma was observed for age-group 38-40 years and 26-28 years, respectively. No second peak for the incidences of seminoma and non-seminoma with respect to age were observed. Cluster analysis revealed areas with high and low incidence rates as well as slightly different spatial distribution in Germany between seminoma and nonseminoma. Furthermore, there was no significant increase in age-adjusted incidence rates over the reviewed time period in both cohorts. DISCUSSION In this study differences in reginal tumor incidence rates for seminoma and non-seminoma are reported with both tumor entities revealing distinct clusters. Furthermore, tumor incidence trends for seminoma and nonseminoma between 2003 and 2014 were stable which might indicate the beginning of a plateau phase for TGCT incidence rates in Germany. CONCLUSION In this analysis we were able to identify regions with significantly higher tumor incidence rates for both seminoma and non-seminoma which were specific for these two subtypes. Furthermore, trend analysis revealed a steady incidence rate for testicular cancer in Germany.

Purpose We performed a retrospective analysis of patients treated with radical cystectomy and lymphadenectomy (LAD) for bladder cancer to assess the differential association of the extent of LAD with perioperative complications and re-hospitalization. Materials and methods LAD templates were defined as limited (lLAD = external, internal iliac and obturator), extended (eLAD = up to crossing of ureter and presacral lymph nodes), and super-extended (sLAD = up to the inferior mesenteric artery). Logistic regression models investigated the association of LAD templates with intraoperative, 30- and 30–90-day postoperative complications, as well as re-hospitalizations within 30 and 30–90 days. Results A total of 284 patients were available for analysis. sLAD led to a higher lymph-node yield (median 39 vs 13 for lLAD and 31 for eLAD, p 500 ml (OR 1.3, 95% CI 1.08–1.49, p = 0.003) but not with intraoperative transfusion, operation time, or length of hospital stay (p > 0.05). Overall, 11 (4%) patients were readmitted within 30 days and 50 (17.6%) within 30–90 days. The 30- and 30–90-day mortality rates were 2.8% and 1.4%, respectively. On logistic regression, LAD template was not associated with postoperative complications or re-hospitalization rates. Conclusions sLAD leads to higher lymph-node yield and N2/N3 rate but not to higher complication rate compared to lLAD and eLAD. With the advent of novel adjuvant systemic therapies, precise nodal staging will have a crucial role in patients counseling and clinical decision making. Electronic supplementary material The online version of this article (10.1007/s00345-019-02769-9) contains supplementary material, which is available to authorized users.

OBJECTIVES To investigate prospectively the clinical utility and influence on decision-making of Bladder EpiCheck™, a non-invasive urine test, in the surveillance of non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS Urine samples from 440 patients undergoing surveillance for NMIBC were prospectively collected at five centres and evaluated using the Bladder EpiCheck test (NCT02647112). A multivariable nomogram and decision-curve analysis (DCA) were used to evaluate the impact of Bladder EpiCheck on decision-making when used in routine clinical practice. The test was designed to exclude recurrent disease. RESULTS Data from 357 patients were available for analysis. The test had a specificity of 88% (95% confidence interval [CI] 84-91), a negative predictive value (NPV) of 94.4% (95% CI 91-97) for the detection of any cancer and an NPV of 99.3% for the detection of high-grade cancer. In multivariable analysis, positive Bladder EpiCheck results were independently associated with any and high-grade disease recurrence (odds ratio [OR] 18.1, 95% CI 8.7-40.2; P < 0.001 and OR 78.3, 95% CI 19.2-547; P < 0.001). The addition of Bladder EpiCheck to standard variables improved its predictive ability for any and high-grade disease recurrence by a difference of 16% and 22%, respectively (area under the curve 85.9% and 96.1% for any and high-grade cancer, respectively). DCA showed an improvement in the net benefit relative to cystoscopy over a large threshold of probability, resulting in a significant reduction in unnecessary investigations. These results were similar in subgroups assessing the impact of specific clinical features. CONCLUSIONS Bladder EpiCheck is a robust high-performing diagnostic test in patients with NMIBC undergoing surveillance that can potentially reduce the number of unnecessary investigations.

There is an urgent need to provide a risk-stratification tool for intermediate-risk non-muscle-invasive bladder cancer (NMIBC), especially at the time of bacillus Calmette-Guerin (BCG) shortage.To assess whether patients with intermediate-risk NMIBC can be stratified into different risk groups, thereby providing a practical tool for the selection of the optimal adjuvant therapy, based on the individualized risk of disease progression.This was a retrospective analysis of 636 patients with intermediate-risk NMIBC.A multivariable Cox-regression model was built to evaluate the impact of each variable on recurrence and progression to muscle-invasive disease. A Cox-based nomogram to predict patient-specific probability of disease progression was performed, and the decision curve analysis (DCA) was used to evaluate its clinical benefit.Within a median follow-up of 92 mo (interquartile range 56-118), disease recurrence and progression occurred in 346 (54%) and 91 (14%) patients, respectively. On multivariable analysis, age, early recurrence (12 mo), and tumor size≥3cm were found to be independent predictors of progression. The Harrell C-index of the model for the prediction of progression was 0.75 and exceeded that of the model proposed by the International Bladder Consultation Group. DCA showed superior net benefits for the nomogram compared with the strategies of treating all/none and previous predictive models. Limitations are inherent to the retrospective design.We provided a risk-stratification tool that helps identify individual risk of disease progression in patients with intermediate-risk NMIBC. This tool outperforms standard strategies in the threshold probability range of interest and could help select the optimal intravesical therapy regimen based on the individual risk of disease progression.In this study, we provided a practical tool for risk stratification in patients with intermediate-risk non-muscle-invasive bladder cancer. This tool may help select the most appropriate adjuvant therapy (either bacillus Calmette-Guerin [BCG] or chemotherapy) based on patient and tumor characteristics, thus making a step forward toward the era of personalized medicine.

International audience; Median age at bladder cancer (BC) diagnosis is older than for other major tumours. Age should not determine treatment, and patients should be fully involved in decisions. Patients should be screened with Mini-Cog™ for cognitive impairment and the G8 to ascertain need for comprehensive geriatric assessment. In non-muscle invasive disease, older adult patients should have standard therapy. Age does not contraindicate intravesical therapy. Independent of age and fitness, patients with muscle-invasive BC should have at least cross-sectional imaging. Data suggest extensive undertreatment in older adult patients, leading to poor outcomes. Standard treatment for a fit patient differs between countries. Radical cystectomy and trimodality therapy are first-line options. Radical cystectomy patients should be referred to an experienced centre and prehabilitation is mandatory. Older adult patients should be considered for neoadjuvant and adjuvant therapy, according to guidelines. In urinary diversion, avoiding bowel surgery for reconstruction of the lower urinary tract significantly reduces complications. If a patient is unfit for or refuses standard treatment, RT alone, or TURBT in selected cases should be considered. In metastatic BC, older adult patients should receive standard systemic therapy, depending on fitness for cisplatin and prognosis. Efficacy and tolerability of immunotherapy (IO) appears similar to younger patients. Second line IO is standard in platinum pre-treated patients, with benefit and tolerability in the older adult similar to younger patients. The toxicity profile seems to favour IO in the older adult but more data are needed. Patients progressing on IO may respond to further systemic treatment. In metastatic disease, palliative care should begin early.

Purpose of review Immune-checkpoint inhibitors (CPIs) have been implemented in the treatment algorithm of metastatic urothelial cancer as they have shown higher and more sustained responses compared with conventional second-line chemotherapy. Recently, several clinical trials have reported on CPIs in earlier disease stages such as muscle-invasive bladder cancer (MIBC). This review summarizes ongoing clinical trials and results from early phase clinical trials in muscle invasive and locally advanced bladder cancer. Recent findings In phase II clinical trials, neoadjuvant use of CPIs as mono and combination therapy, in patients with MIBC planned for radical cystectomy, has shown promising pathological complete response rates. Whether this will translate in survival benefit remains to be assessed. Combination of CPIs and conventional chemotherapy or other targeted agents promises to increase the efficacy of perioperative systemic therapy with potentially additive toxicities. Recently, preclinical models of combined trimodal therapy with CPIs delivered the proof of principle leading to several ongoing trials in this setting. Summary First results of clinical trials evaluating CPIs in MIBC demonstrate very promising results that warrant further investigation as they could revolutionize management of MIBC in the near future. The trend and hope are toward higher rates of safe and sustained bladder preservation.

Use of molecular markers in urine, tissue or blood offers potential opportunities to improve understanding of bladder cancer biology which may help identify disease earlier, risk stratify patients, improve prediction of outcomes or help target therapy. A review of the published literature was performed, without restriction of time. Despite the fast-growing literature about the topic and the approval of several urinary biomarkers for use in clinical practice, they have not reached the level of evidence for widespread utilization. Biomarkers could be used in different clinical scenarios, mainly to overcome the limitations of current diagnostic, predictive, and prognostic tools. They have been evaluated to detect bladder cancer in asymptomatic populations or those with hematuria and in surveillance of disease as adjuncts to cystoscopy. There is also a potential role as prognosticators of disease recurrence, progression and survival both in patients with non-invasive cancers and in those with advanced disease. Finally, they promise to be helpful in predicting the response to local and/or systemic chemotherapy and/or immunotherapy. To date, due to the lack of high-quality prospective trials, the level of evidence provided by the current literature remains low and, therefore, the potential of biomarkers exceeds utilization in clinical practice.

Background: We assessed the role of N-cadherin as a prognostic biomarker in patients with invasive bladder cancer (BCa) who had undergone radical cystectomy (RC). Patients and Methods: The present retrospective single-center study included 433 BCa patients who had undergone RC and bilateral lymph node dissection. Formalin-fixed paraffin tissue microarrays were stained with an anti-N-cadherin monoclonal mouse antibody. N-cadherin expression was considered positive if any immunoreactivity was detected. Multivariable Cox regression models were created to evaluate the prognostic effect of N-cadherin on survival. Results: N-cadherin expression was observed in 189 patients (43.7%). It was associated with advanced pathologic stage (P = .001) and lymph node metastasis (P < .001). During a median follow-up period of 10.6 years, N-cadherin expression was associated with worse recurrence-free survival, overall survival, and cancer-specific survival (P < .001, P = .001, and P < .001, respectively). On multivariable analysis adjusted for the effects of standard clinicopathologic features, N-cadherin expression retained its association with worse recurrence-free survival (hazard ratio, 1.41; 95% confidence interval, 1.02-1.92; P = .032) but not cancer-specific survival (P = .07) and overall survival (P = .3). Conclusion: N-cadherin was expressed in approximately 40% of patients with invasive BCa. Its expression was associated with features of biologically and pathologically adverse disease and worse recurrence-free survival. N-cadherin could be a part of a marker panel to help clinical decision-making and therapy for BCa.

Simple Summary Seasonal variations in cancer diagnosis could already be demonstrated in prostate and breast cancer. The reasons for this observed seasonal pattern are still unclear. The health care system or other determinants such as the protective function of vitamin D3 in carcinogenesis could be assumed as one explanation. Testicular germ cell tumors are the most common developed malignancy among young men. The aim of our study was to investigate, for the first time, the seasonal variations in the clinical diagnosis of testicular germ cell tumors. We have been able to confirm that the frequency of monthly newly diagnosed cases of testicular cell tumors in Austria has a strong seasonality, with a significant reduction in the tumor incidence during the summer months and an increase during the winter months. Abstract We conducted a retrospective National Cancer Registry study in Austria to assess a possible seasonal variation in the clinical diagnosis of testicular germ cell tumors (TGCT). In total, 3615 testicular cancer diagnoses were identified during an 11-year period from 2008 to 2018. Rate ratios for the monthly number of TGCT diagnoses, as well as of seasons and half-years, were assessed using a quasi-Poisson model. We identified, for the first time, a statistically significant seasonal trend (p < 0.001) in the frequency of monthly newly diagnosed cases of TGCT. In detail, clear seasonal variations with a reduction in the tumor incidence during the summer months (Apr–Sep) and an increase during the winter months (Oct–Mar) were observed (p < 0.001). Focusing on seasonality, the incidence during the months of Oct–Dec (p = 0.008) and Jan–Mar (p < 0.001) was significantly higher compared to the months of Jul–Sep, respectively. Regarding histopathological features, there is a predominating incidence in the winter months compared to summer months, mainly concerning pure seminomas (p < 0.001), but not the non-seminoma or mixed TGCT groups. In conclusion, the incidence of TGCT diagnoses in Austria has a strong seasonal pattern, with the highest rate during the winter months. These findings may be explained by a delay of self-referral during the summer months. However, the hypothetical influence of vitamin D3 in testicular carcinogenesis underlying seasonal changes in TGCT diagnosis should be the focus of further research.

Objective To investigate the characteristics and outcomes of late recurrence (LR) in patients with bladder cancer (BCa) treated with radical cystectomy (RC) and to identify clinicopathologic predictors of LR and postrecurrence survival. Materials and Methods This multicenter study included 1652 BCa patients. LR was defined as occurring more than 5 years after RC. Differences in postrecurrence overall survival according to the timing of disease recurrence and the location of recurrence were calculated using the log-rank test. A logistic regression model was used to identify predictors of LR, and Cox regression models were used to evaluate variables associated with postrecurrence overall survival (OS). Results Overall, 548 patients experienced disease recurrence. Of these, 67 patients (12.2%) experienced LR, with a median time to recurrence of 86 months (interquartile range 70.5-107.2). LR was more likely to be located in the urothelium (P =.005). On multivariable analysis, younger age (P =.008) and non–organ confined disease (P =.03) were found to be predictors of LR. Postrecurrence 5-year OS was worse in patients who experienced early recurrence compared with those with LR (12% vs 25%, P =.02) and in those with nonurothelial recurrence compared to those with disease recurrence in the remaining urothelium (12% vs 51%, P

Purpose Overexpression of Caveolin-1 has been associated with cancer growth, migration, and metastases in several malignancies, but only few data are available on its role in bladder cancer (BCa). The aim of this study is to validate Caveolin-1 as a prognosticator of recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS) in a large cohort of patients treated with radical cystectomy (RC) for BCa. Methods Caveolin-1 expression was evaluated by immunochemistry on a tissue microarray from 424 patients treated with RC for UCB at a single institution. Caveolin-1 was considered overexpressed when at least 50% of the tumor cells stained positively. Univariable and multivariable Cox proportional hazards regression models were used to assess the association of Caveolin-1 expression with RFS, OS, and CSS. Results Overexpression of Caveolin-1 was observed in 116 (27.4%) patients and was associated with lymph node metastasis ( P = 0.003). Median follow-up for patients alive at last follow-up was 129 months (interquartile range [IQR]: 82–178). Patients with overexpression of Caveolin-1 had significant worse RFS, OS, and CSS compared to those with normal expression (log-rank test, P = 0.008, P = 0.001, and P = 0.005, respectively). At multivariable analyses that adjusted for the effects of standard clinicopathologic features, Caveolin-1 remained associated with OS (hazard ratio = 1.47, P = 0.002) and CSS (hazard ratio = 1.42, P = 0.03). Conversely, no association with RFS was found ( P = 0.1). Addition of Caveolin-1 in a model for prediction of survival did not improve the accuracy of the prognostic model. Actually, C-index did not differ among models with or without Caveolin-1 (0.72 for a model predicting RFS, 0.65 for OS, and 0.71 for CSS). Conclusions Caveolin-1 is overexpressed in one-third of patients with BCa treated with RC. Overexpression of Caveolin-1 is significantly associated with OS and CSS, but not with RFS, in patients with BCa treated with RC. However, it is not clinically useful as it does not improve upon the predictive accuracy of survival achieved by pathologic variables alone.

Objectives To evaluate the impact of an eight-item surgical checklist (SC) on the recurrence-free survival (RFS) of patients with non-muscle-invasive bladder cancer (NMIBC) undergoing transurethral resection of bladder tumour (TURBT). Patients and methods A group of urologists at two tertiary referral centres, with expertise in bladder cancer, identified eight critical items that should be performed in every high-quality TURBT. An eight-item SC was prospectively implemented into clinical practice and the operative reports of TURBTs performed before and after implementation were reviewed. Results from both institutions were combined to estimate the impact of introducing the SC on oncological outcomes. Multivariable logistic and Cox hazards regression analyses were performed to evaluate the impact of the SC on the presence of detrusor muscle in the TURBT specimen and on RFS, respectively. Results The operative reports of 266 TURBTs performed after the SC implementation were reviewed and compared to those of 281 TURBTs performed prior to the SC introduction. The SC was independently associated with a significant improvement in RFS (P = 0.02). However, the introduction of the SC was not significantly associated with the presence of detrusor muscle in the surgical specimen (P = 0.4). Conclusion The use of an eight-item SC during TURBT in clinical practice increases the quality of operative reports thereby potentially improving individualised risk-stratification and care resulting in lower disease recurrence rates. Therefore, the introduction of a SC can be recommended to enhance oncological outcomes by improving surgical standardisation and operative reporting.

Urothelial cancer (UC) is devastating disease, once it reaches muscle invasive (MIBC) and metastatic stage. Even when performing radical cystectomy (RC) with pelvic lymphadenectomy in patients with MIBC, approximately half of the patients will develop metastasis and still no long-term cure for metastatic urothelial cancer (mUC) has been found (1).

Purpose: Recent molecular analyses of bladder cancer open the door to significant advances in targeted therapies. NOTCH has been identified as a tumor suppressor in bladder cancer, but prior reports have focused on NOTCH1. Here we hypothesized that NOTCH2 is an oncogene suitable for therapeutic targeting in bladder cancer. Experimental design: We studied genomic aberrations of NOTCH, compared survival and tumor progression according to NOTCH2 expression levels, and studied NOTCH2 function in vitro and vivo. Results: We report a high rate of NOTCH2 copy number gain in bladder cancer. High NOTCH2 expression was identified especially in the basal subtype and in mesenchymal tumors. NOTCH2 activation correlated with adverse disease parameters and worse prognosis by immunohistochemistry. Forced overexpression of the intracellular domain of NOTCH2 (N2ICD) induced cell growth and invasion by cell-cycle progression, maintenance of stemness and epithelial-to-mesenchymal transition (EMT). These effects were abrogated by silencing of CSL, indicating that the effects were mediated through the canonical NOTCH signaling pathway. In an orthotopic xenograft model, forced overexpression of N2ICD increased growth, invasion, and metastasis. To explore the potential for therapeutic targeting of NOTCH2, we first silenced the receptor with shRNA and subsequently treated with a specific inhibitory antibody. Both interventions decreased cell growth, invasion, and metastasis in vitro and in the orthotopic xenograft model. Conclusions: We have demonstrated that NOTCH2 acts as an oncogene that promotes bladder cancer growth and metastasis through EMT, cell-cycle progression, and maintenance of stemness. Inhibition of NOTCH2 is a rational novel treatment strategy for invasive bladder cancer. Clin Cancer Res; 22(12); 2981–92. ©2016 AACR.

Recent meta-analyses on checkpoint inhibitors in cancer report conflicting data regarding the association of patient gender with inhibitor efficacy. In advanced kidney cancer, checkpoint inhibitors have shown improved outcomes in first- and second-line settings compared with standard of care, but the role of patient gender on treatment outcome is unclear. We aimed to assess the efficacy of immunotherapy according to patient gender in advanced kidney cancer. We performed a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search was performed using PubMed, Scopus, Web of Science, and The Cochrane Library to identify eligible studies published through February 16, 2019. Studies were included if they reported on the differential outcomes of male and female patients with metastatic kidney cancer receiving immunotherapy. Our outcomes of interest were overall survival (OS) or progression-free survival (PFS). Four randomized controlled trials comprising a total of 3664 patients (2715 males and 949 females) met our inclusion criteria. Both men and women with metastatic kidney cancer had an OS and PFS advantage with immunotherapy compared with standard-of-care, but no statistically significant difference between the genders was observed (OS hazard ratio [HR] for men, 0.69; 95% confidence interval [CI], 0.59-0.8; P = .40; HR for women, 0.62; 95% CI, 0.48-0.81; P = .13; PFS HR for men, 0.7; 95% CI, 0.59-0.82; P = .24; HR for women, 0.68; 95% CI, 0.52-0.90; P = .105). In patients with advanced kidney cancer receiving checkpoint inhibitors, there seems to be no association of patient gender with treatment outcome.

Serum cholinesterase (ChE) has been reported to be a prognostic factor in several cancers, but its relationship with oncologic outcomes of non-muscle-invasive bladder cancer (NMIBC) has not yet been well-studied.We retrospectively assessed 1117 patients with NMIBC undergoing transurethral resection of the bladder. Cox regression analyses were performed to elucidate the association between preoperative ChE and oncologic outcomes such as recurrence-free survival (RFS) and progression-free survival.The median preoperative ChE level was 5.51 kU/L (interquartile range, 4.95-7.01), and the optimal cut-off value of ChE obtained from receiver operator characteristic analysis was 5.55 kU/L. The 5-year RFS in patients with low and normal ChE levels were 41.1% and 70.0%, respectively (P .001). The 5-year progression-free survival in patients with low and normal ChE levels were 93.2% and 91.4%, respectively (P = .053). On multivariable analysis, ChE was significantly associated with shorter RFS (P .001). ChE as a continuous variable and low ChE levels improved the C-index for prediction of disease recurrence by 4.0% and 2.7% to 72.4% and 71.1%, respectively. In patients stratified into the European Association of Urology high-risk category, serum ChE was also a strong predictor of disease recurrence (hazard ratio, 4.14; 95% confidence interval, 2.90-5.89). Moreover, in the European Association of Urology high-risk patients treated with bacillus Calmette-Guérin immunotherapy, serum ChE was still strongly correlated with worse RFS (hazard ratio, 5.46; 95% confidence interval, 2.91-10.2).Decreased ChE is associated with shorter RFS in patients with NMIBC undergoing transurethral resection of the bladder. Preoperative ChE could improve patients' risk stratification and selection for adjuvant therapy. The mechanisms underlying this association needs further elucidation to design potential targets for intervention.

Testicular germ cell cancer in a metastatic state is curable with a cisplatin‑based first line chemotherapy. However, 10‑15% of these patients are resistant to first line chemotherapy and are thus left with only palliative options. Immunotherapies and inhibition of angiogenesis used in multiple types of cancer; however, the molecular context of angiogenesis and immune checkpoints in the development and progression of testicular cancers is still unknown. Therefore, the present study performed tissue micro array based analysis of 84 patients with immunohistochemistry of programmed cell death protein 1 (PD‑1), programmed cell death ligand 1 (PD‑L1) and vascular endothelial growth factor receptor 2 (VEGFR2) of testicular cancer and corresponding normal appearing testis tissue, matching the results with clinical data. The results demonstrated that PD‑L1 was significantly upregulated in testicular tumors and that PD‑1 positive cells significantly infiltrated the testicular tumor when compared with normal testicular tissue. VEGFR2 was significantly upregulated in testicular cancer. It was indicated that PD‑1 expressing cytotoxic cells may require pathologic tumor vessels to pass the blood‑testis‑barrier in order to migrate into the tumor. Notably, when matching the clinical data for PD‑1, PD‑L1 and VEGFR2 there were no differences in expression in the different International Germ Cell Cancer Collaborative Group stages of non‑seminoma. These data suggested that the anti‑PD‑1/PD‑L1 immunotherapy and the anti‑angiogenic therapy, sequentially or in combination, may be a promising option in the treatment of testicular cancer.

Purpose Lymphovascular invasion (LVI) is an important step in bladder cancer cell dissemination. We aimed to perform a systematic review and meta-analysis of the literature to assess the prognostic value of LVI in radical cystectomy (RC) specimens. Patients and methods A systematic review and meta-analysis of the last 10 years was performed using the MEDLINE, EMBASE, and the Cochrane libraries in July 2017. The analyses were performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Results We retrieved 65 studies (including 78,107 patients) evaluating the effect of LVI on oncologic outcomes in patients treated with RC. LVI was reported in 35.4% of patients. LVI was associated with disease recurrence (pooled hazard ratio [HR] = 1.57; 95% CI: 1.45–1.70) and cancer-specific mortality (CSM) (pooled HR = 1.59; 95% CI: 1.48–1.73) in all studies regardless of tumor stage and node status (pT1–4 pN0–2). LVI was associated with recurrence and CSM in patients with node-negative bladder cancer (BC). In patients with node-negative BC, LVI rate increased and was associated with worse oncologic outcome. LVI had a lower but still significant association with disease recurrence and CSM in node-positive BC. Conclusions LVI is a strong prognostic factor of worse prognosis in patients treated with RC for bladder cancer. This association is strongest in node-negative BC, but it is also in node-positive BC. LVI should be part of all pathological reporting and could provide additional information for treatment-decision making regarding adjuvant therapy after RC.

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.

Objectives A small subset of patients treated with immune checkpoint inhibitors manifest atypical patterns of response, the so-called pseudoprogression (PP) and hyperprogression (HP). Their prevalence in urothelial (UC) and renal cancer (RCC) remains, to date, mostly uninvestigated. Therefore, we aimed to provide a summary of the current knowledge about PP and HP during immune checkpoint inhibitor therapy in UC and RCC patients. Methods and materials A systematic medline/pubmed© literature search was performed. The atypical patterns of response to systemic immunotherapy were reviewed. Endpoints were PP and HP in UC and RCC. Results Tumors respond differently to immunotherapy compared to systemic chemotherapy. To evaluate response to immunotherapy, new guidelines (iRECIST) have been developed. To date, no studies focused on PP in UC and RCC, and the only way to evaluate its role is to take patients who respond to treatment beyond progression as surrogate for pseudoprogressors. PP seems to occur in a non-negligible rate of UC and RCC (from 1.5 to 17% and from 5 to 15%, respectively). The concept of HP, defined as a rapid progression after treatment, just took the first steps, and therefore, data from ongoing trials are awaited to elucidate its impact in genitourinary cancers. Conclusions PP and HP are not uncommon entities in UC and RCC patients, treated with PD-1/PD-L1 inhibitors. Further investigation is warranted to define which patients are likely to experience PP and could benefit from treatment beyond progression and which ones will instead rapidly experience progression despite treatment and should, therefore, avoid systemic immunotherapy.

Overactive bladder (OAB) is a symptom complex which is present in approximately 17% of the European population. It is observed in the presence or absence of incontinence (wet or dry) and is associated with a high degree of psychological stress as well as high costs for the healthcare system. Myogenic, urothelial and neurogenic factors lead to frequently unknown changes of muscular, neural and connective tissue. The diagnosis of OAB is empirical and can be used as a basis for initial treatment, while lower urinary tract symptoms have to be evaluated up front. As there are no established biomarkers for OAB, a definitive diagnosis is problematic. It is important to carry out routine diagnostics including a detailed medical history and if needed urodynamic evaluation of the patient. Therapy of OAB will be the topic of a further continuing medical education (CME) article entitled "Therapy of overactive bladder (OAB)".

To our knowledge the frequency and prognostic significance of PTEN protein expression in upper tract urothelial carcinoma have not yet been investigated in large studies. We analyzed PTEN protein status and its association with disease recurrence and survival outcomes in a large, multi-institutional upper tract urothelial carcinoma cohort.We retrospectively analyzed the records of 611 patients with upper tract urothelial carcinoma treated with radical nephroureterectomy between 1991 and 2008 at a total of 7 institutions. Median followup was 23 months. Tissue microarrays and immunohistochemical PTEN staining (monoclonal antibody) were performed. Univariable and multivariable Cox regression models were created to address the association of PTEN protein expression with disease recurrence, and cancer specific and overall mortality.PTEN staining was absent in 45 cases (7.4%). Patients with PTEN loss had significantly advanced pathological tumor stage and grade (p0.001), and higher rates of lymph node metastasis (p0.01) and lymphovascular invasion (p 0.001) compared to patients with PTEN expression. PTEN loss was associated with disease recurrence, and cancer specific and overall mortality on univariable Cox regression analyses. However, on multivariable Cox regression analyses adjusted for the effect of standard clinicopathological features PTEN loss was only associated with overall mortality (HR 1.69, 95% CI 1.09-2.61, p = 0.02).In patients undergoing radical nephroureterectomy for upper tract urothelial carcinoma loss of PTEN protein expression is rare but associated with features of biologically aggressive disease such as higher grade and stage as well as lymph node metastasis. Loss of PTEN expression was associated with overall mortality. PTEN loss seemed to promote worse outcomes in this relatively small group of patients.

Background: Neutrophil–lymphocyte ratio (NLR) is a widely used, representative marker of systemic inflammatory response within the body. NLR can be calculated from simple, inexpensive peripheral blood samples. High NLR is a negative prognostic factor in a variety of malignancies including urological tumors. In this study, we aim to assess the prognostic value of preoperative neutrophil- lymphocyte ratio (NLR) in patients treated with radical prostatectomy (RP) for localized prostate cancer (PCa). Materials and methods: Records of 7426 patients were retrospectively analyzed from prospectively collected datasets. A cut-off point of 3 was taken for NLR based on ROC analyses and previous literature. Results: 23% (n = 1707) of patients had an NLR of ≥3. Patients with NLR ≥3 were more likely to harbor unfavorable pathological features such as higher biopsy Gleason score (GS), higher RP GS, higher rates of extra capsular extension, nodal involvement (all p < 0.001) and positive surgical margins (p = 0.002). On multivariable analyses, NLR ≥ 3 was associated with higher RP GS (OR 2.32; p < 0.001), seminal vesicle invasion (OR 1.60; p < 0.001) and nodal involvement (OR 1.43; p < 0.001). On multivariable analyses, NLR ≥ 3 was significantly associated with GS upgrading at RP (OR 1.39 p < 0.001). During a median follow up of 45 months, NLR ≥ 3 was associated with higher risk of BCR (p = 0.001). However, on multivariable Cox regression analysis such association was not shown (HR 0.86; p = 0.4). Conclusion: Preoperative NLR ≥ 3 was associated with aggressive PCa, such as upgrading at RP. Even though its effect on clinical-decision making seems to be limited when all clinical and pathological confounders are taken into account, preoperative NLR may still be useful in selected patients to identify aggressive PCa helping patient selection for active surveillance protocols. Conversely, it does not predict BCR when adjusted for the effect of pathological features.

Objectives To analyze the frequency of incidental prostate cancer (PC) at radical cystoprostatectomy (RC) for urothelial carcinoma of the bladder (UCB) and its association with survival outcomes in an international cohort. Patients and methods In this retrospective study, we included 2114 who underwent RC and lymphadenectomy for UCB between 1976 and 2012 male patients from seven institutions. Univariable and multivariable Cox regression models addressed the association of incidental PC with cancer-specific mortality and overall mortality after RC. Results Overall, incidental PC was found in 513 (24.3%) patients with the lowest frequency in a Japanese center (23/164, 11.2%) and the highest frequency in a North American center (122/325, 37.5%), respectively (p < 0.001). Within a median follow up of 27 months (IQR: 50 months), 20 patients (3.9%) were diagnosed with biochemical recurrence (BCR) and none of the patients died of PC. PC pathological tumor stage was more advanced in patients experiencing BCR (p < 0.001). In multivariable Cox regression analyses adjusted for standard clinicopathologic features, incidental PC was not associated with cancer-specific (HR: 1.11, 95% CI: 0.91–1.35, p = 0.30) or overall mortality (HR: 1.06, 95% CI: 0.83–1.35, p = 0.65). Conclusions Incidental PC at RC for UCB is a frequent event. However, the majority of PC cases are well-differentiated and organ-confined. Presence of incidental PC shows significant geographic differences. The risk of BCR after incidental PC is low and incidental PC is not associated with survival in UCB patients treated with RC.

Background: Measurement of prostate-specific antigen (PSA) advanced the diagnostic and prognostic potential for prostate cancer (PCa). However, due to PSA’s lack of specificity, novel biomarkers are needed to improve risk assessment and ensure optimal personalized therapy. A set of protein molecules as potential biomarkers was therefore evaluated in serum of PCa patients. Methods: Serum samples from patients undergoing radical prostatectomy (RPE) for biopsy-proven PCa without neoadjuvant treatment were compared to serum samples from healthy subjects. Preliminary screening of 119 proteins in 10 PCa patients and 10 controls was carried out by the Proteome Profiler Antibody Array. Those markers showing distinct differences between patients and controls were then further evaluated by ELISA in the serum of 165 PCa patients and 19 controls. Uni- and multivariate as well as correlation analysis were performed to test the capability of these molecules to detect disease and predict pathological outcome. Results: Screening showed that soluble (s)E-cadherin, E-selectin, MMP2, MMP9, TIMP1, TIMP2, Galectin and Clusterin warranted further evaluation. sE-Cadherin, TIMP1, Galectin and Clusterin were significantly over- and MMP9 under-expressed in PCa compared to controls. The concentration of sE-cadherin, MMP2 and Clusterin correlated negatively and that of MMP9 and TIMP1 positively with the Gleason Sum at prostatectomy. Only sE-cadherin significantly correlated with the highest Gleason pattern. Compared to serum PSA, sE-cadherin provided an independent and better matching predictive ability for discriminating PCas with an upgrade at RPE and aggressive tumors with a Gleason Sum ≥7. Conclusions: sE-cadherin performed most favorably from a large panel of serum proteins in terms of diagnostic and predictive potential in curatively treatable PCa. sE-cadherin merits further investigation as a biomarker for PCa.

To investigate the learning curve of a novice in MRI/TRUS software fusion biopsy and to compare his results with the expert standard at our institution. Overall 126 MRI/TRUS fusion-guided transrectal biopsies were performed using an electromagnetic tracking ultrasonography platform. The learning progress of the novice was evaluated comparing his initial 42 procedures (group A) with his following 42 (group B). The institution’s expert standard (group C), which was compared to the novice’s groups, was defined by the expert’s experience of 42 MRI/TRUS fusion biopsies. Primary learning curve parameters were targeted biopsy detection quotient and biopsy time. Overall detection of prostate cancer was 64% (27/42), 62% (26/42) and 62% (26/42) in groups A, B and C, respectively. The median target biopsy detection quotient significantly increased (p = 0.04) in group B (0.75, interquartile range (IQR) 0.25–1.0) compared to group A. (0.33, IQR 0.2–0.5). Group C revealed a median detection quotient of 0.5 (IQR 0.25–0.76) that did not differ significantly from the novice’s groups (p = 0.2). Median biopsy time was significantly higher in group A (45 min, IQR 33–50 min) compared to groups B (25 min, IQR 23–29 min) and C (24 min, IQR 16–46 min) (p

Nanoparticle albumin?bound (nab)-paclitaxel appears to exhibit better response rates in patients with metastatic urothelial cancer of the bladder whom are pretreated with nab-paclitaxel compared with conventional paclitaxel. Paclitaxel may induce multidrug resistance in patients with cancer, while the mechanisms of resistance against paclitaxel are manifold. These include reduced function of pro?apoptotic proteins, mutations of tubulin and overexpression of the drug transporter adenosine 5'?triphosphate?binding cassette transporter subfamily B, member 1 (ABCB1). To evaluate the role of ABCB1 in nab?paclitaxel resistance in urothelial cancer cells, the bladder cancer cell lines T24 and TCC?SUP, as well as sub?lines with acquired resistance against gemcitabine (T24rGEMCI20 and TCC?SUPrGEMCI20) and vinblastine (T24rVBL20 and TCC?SUPrVBL20) were examined. For the functional inhibition of ABCB1, multi-tyrosine kinase inhibitors with ABCB1?inhibiting properties, including cabozantinib and crizotinib, were used. Additional functional assessment was performed with cell lines stably transduced with a lentiviral vector encoding for ABCB1, and protein expression was determined by western blotting. It was indicated that cell lines overexpressing ABCB1 exhibited similar resistance profiles to nab?paclitaxel and paclitaxel. Cabozantinib and crizotinib sensitized tumor cells to nab?paclitaxel and paclitaxel in the same dose?dependent manner in cell lines overexpressing ABCB1, without altering the downstream signaling of tyrosine kinases. These results suggest that the overexpression of ABCB1 confers resistance to nab?paclitaxel in urothelial cancer cells. Additionally, small molecules may overcome resistance to anticancer drugs that are substrates of ABCB1.

Micro-Abstract We evaluated the predictive and prognostic role of preoperative thrombocytosis (TC) in upper tract urothelial carcinoma. Records of 2492 patients undergoing radical nephroureterectomy between 1990 and 2008 were retrospectively analyzed. Preoperative TC predicts non–organ-confined disease (P 400 × 109/L, irrespective of gender type. Logistic regression analyses were performed to evaluate its association with pathologic features. Cox proportional hazards regression was used for estimation of recurrence-free survival, cancer-specific survival, and overall survival. Results Preoperative TC was found in 309 (12.4%) patients and was associated with advanced tumor stage and grade, lymph node metastasis, lymphovascular invasion, tumor architecture, necrosis, and concomitant carcinoma in situ (P-values ≤.027). Preoperative TC independently predicted ≥ pT2 (P

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

Aim: To investigate the role of ABO blood group and Rhesus factor as a predictor of outcome in patients undergoing radical cystectomy (RC) for non-metastatic urothelial carcinoma of the bladder. Materials and Methods: Data of 463 consecutive patients treated with RC between 1988 and 2003 were retrospectively analyzed. The effect on recurrence-free survival, and cancer-specific and overall mortality were assessed using the Kaplan-Meier and multivariable Cox regression methods. Results: Overall, 185 (41.3%), 190 (42.4%), 46 (10.3%) and 27 (6%) patients expressed O, A, B and AB phenotypes, respectively; 65 (14.5%) were Rhesus-negative. Median follow-up was 14.2 years (interquartile range=10.2-17.1 years). No individual blood group was associated with any clinicopathological characteristics whereas Rhesus-positive patients had a higher rate of pT4 disease (11% vs. 22%; p=0.02). ABO blood groups were not associated with outcomes. Rhesuspositive patients had an increased risk of shorter recurrencefree survival, and of cancer-specific and overall mortality compared to Rhesus-negative patients (all p

Purpose To evaluate the effect of preoperative anemia (PA) on oncological outcomes in a multicenter cohort of patients with non–muscle-invasive bladder cancer (NMIBC) treated with transurethral resection of the bladder (TURB) and adjuvant intravesical therapies. We hypothesize that PA represents a marker of disease aggressiveness and could be used to improve the discrimination of prognostic tools for the prediction of disease recurrence and progression. Methods This multicenter retrospective study included 1,117 patients from 4 different centers. The presence of PA was assessed according to the World Health Organization classification as a preoperative hemoglobin level of≤13 g/dl in men and≤12 g/dl in women. PA evaluation was done at each institution, generally 1 to 3 days before surgery. Multivariable Cox regression models were performed to evaluate the prognostic effect of PA on survival outcomes. Results Overall, 381 (34%) patients with NMIBC treated with TURB, had PA. Median follow-up for patients alive at last follow-up was 62.7 months (interquartile range: 25–110.7). On multivariable Cox regression analyses that accounted for the effect of standard clinicopathologic prognosticators, PA was independently associated with recurrence-free survival ( P = 0.045) and progression-free survival ( P = 0.01). Adding PA to a model for the prediction of disease recurrence and progression improved the discrimination of the prognostic models marginally from 69.8% to 70.3% and from 71.6% to 73.1%, respectively. Conclusions PA was found in more than one-third of patients with NMIBC treated with TURB. PA was associated with poor oncological outcomes and was an independent predictor of intravesical disease recurrence and progression. However, the additional prognostic information provided by PA remains limited.

Purpose To evaluate the role of lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio (NLR) as pre-operative markers for predicting extravesical disease and survival outcomes in patients undergoing radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). Materials and methods Data from 4335 patients undergoing RC for clinically non-metastatic UCB were analyzed. Multivariable logistic regression models were used to predict lymph node involvement and extravesical disease (defined as ≥pT3 and N0). Recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS) were evaluated using multivariable Cox models. The accuracy of the models was assessed with receiver operating characteristics (ROC) curves and concordance-index. Results Median LMR was 3.5 and median NLR was 2.7. Addition of LMR and NLR to a standard preoperative model improved its discrimination for prediction of lymph node metastasis by 4.5%. On multivariable analysis LMR and NLR independently predicted RFS, CSS, and OS. The discrimination of this model increased by adding LMR and NLR but was not significant. Conclusions LMR and NLR independently improved the preoperative prediction of lymph node metastasis and survival outcomes. As they are readily available, they could be integrated in a panel of preoperative markers helping selecting patients who have extravesical lymph node involvement and more aggressive disease.

The neutrophil-to-lymphocyte ratio is associated with poor outcomes in patients with muscle-invasive bladder cancer. We found that the neutrophil-to-lymphocyte ratio is independently associated with disease recurrence and progression in patients with non–muscle-invasive bladder cancer. Introduction The purpose of this study was to assess the role of pretreatment neutrophil-to-lymphocyte ratio (NLR) as a predictor of clinical outcomes in patients treated with transurethral resection (TURB) for primary non–muscle-invasive bladder cancer (NMIBC). Patients and Methods Data from 918 patients treated with TURB for primary NMIBC were retrospectively collected. NLR was evaluated as binary variable with the cut-point of 3 based on the visual best correlation of the receiver operating curve analyses focusing on disease recurrence. The median follow-up was 62 months. Cox regression analyses were used to evaluate associations with recurrence (RFS) and progression-free survival (PFS). Subgroup analyses were done according to risk groups and receipt of intravesical bacillus Calmette-Guérin therapy. Results Overall, 293 patients had a NLR ≥ 3. High NLR was associated with pathologic T stage and smoking status. The 5-year RFS and PFS for NLR < 3 and NLR ≥ 3 were, respectively, 55.5% versus 45.9% (P = .01) and 94.9% versus 89.9% (P = .004). On multivariable analyses, NLR ≥ 3 remained significantly associated with RFS and PFS. The addition of NLR increased the discrimination of a multivariable model by 0.6% and 2.3% for RFS and PFS, respectively. Moreover, NLR showed a trend in the association with outcomes in patients treated with intravesical bacillus Calmette-Guérin therapy. Conclusions Integration of NLR in a prediction model could be helpful in predicting RFS and PFS in patients with primary NMIBC and identifying those who are likely to fail therapy and may benefit from an early radical cystectomy. Limitations are associated to the retrospective design.

Purpose To investigate the prognostic value of preoperative modified Glasgow Prognostic Score (mGPS) in patients with non–muscle-invasive bladder cancer (NMIBC) treated with transurethral resection of bladder with or without intravesical therapy. Material and Methods We retrospectively reviewed our medical records to identify 1,096 consecutive patients with NMIBC treated with transurethral resection of bladder. The mGPS of each patient was calculated on the basis of preoperative serum C-reactive protein and albumin. Univariable and multivariable Cox regression analyses were performed to investigate the association of mGPS with recurrence-free survival (RFS) and progression-free survival (PFS). Results The mGPS of 0, 1, and 2 was observed in 764 (69.7%), 299 (27.3%), and 33 (3.0%) patients, respectively. On univariable analysis, mGPS 2 was associated with worse RFS (Hazard Ratio [HR]: 1.60, 95%; CI: 1.01–2.54). However, on multivariable analyses, which adjusted for the effects of established clinicopathologic features, mGPS 2 did not maintain its independent association with RFS (HR: 1.41, 95% CI: 0.88–2.26). On multivariable analysis, mGPS 1 and 2 were both independently associated with worse PFS compared to mGPS 0 (HR: 2.06, 95% CI: 1.37–3.12 and HR: 3.31, 95% CI: 1.40–7.87, respectively). The inclusion of mGPS improved the discrimination of a standard prognostic model for PFS from 71.6% to 73.8%. In subgroup analyses, mGPS 1 was associated with PFS (HR 2.09, 95% CI: 1.24–3.52) on multivariable analysis in patients with the European Association of Urology high-risk group. Additionally, in patients treated with bacillus Calmette-Guerin, mGPS 2 was associated with disease PFS (HR10.1, 95% CI: 2.61–38.8). Conclusions The mGPS independently predicts PFS in patients with NMIBC. Inclusion of mGPS in prognostic models might help identify patients who are more likely to fail standard therapy and experience disease progression and, therefore, may benefit from intensified therapy such as radical cystectomy or inclusion in clinical trials of novel immunotherapeutics.

Purpose: To evaluate the predictive and prognostic role as well as the clinical impact on decision-making of serum cholinesterase (ChoE) levels in patients treated with radical prostatectomy for clinically nonmetastatic prostate cancer. Materials and methods: We conducted a retrospective analysis of our multi institutional database. Preoperative ChoE was evaluated as continuous and dichotomized variable using a visual assessment of the functional form of the association of ChoE with biochemical recurrence (BCR)-free survival. We assessed its association with perioperative clinicopathologic characteristics and outcomes. Multivariable models established its independent prognostic value for BCR. Cox proportional hazard coefficients were used to build nomograms for the prediction of early and late BCR. Decision curve analysis was used to assess the clinical impact on decision making of preoperative ChoE. Results: In all, 6,041 patients were available for the analysis. Decreased ChoE was associated with higher biopsy Gleason score, preoperative PSA levels, pathologic Gleason score, pathological stage, lymph node metastasis, positive surgical margin, and lymphovascular invasion at radical prostatectomy (all P < 0.01). Preoperative ChoE ≤ 6.52 U/ml was associated with higher probability of BCR (HR 1.72, 95% CI 1.48–1.99, P < 0.001). Preoperative and postoperative multivariable models that adjusted for the effects of established clinicopathologic features confirmed its independent association with BCR. In decision curve analysis inclusion of preoperative ChoE did not improve the net benefit of preoperative and postoperative models for the prediction of BCR. Conclusions: Despite independent association with clinicopathologic features and BCR, preoperative serum ChoE has no impact on clinical decision making. Future studies should investigate the possible relationship between ChoE activity and neoplastic cell transformation with a rational for targeting.

Locally advanced (T3b, T4 and N1-N3) and metastatic urothelial bladder cancer (BCa) is a lethal disease with poor survival outcomes. Combination chemotherapy remains the treatment of choice in patients with metastatic disease and an important part of treatment in addition to radical cystectomy (RC) in patients with locally advanced tumour. Approximately half of patients who underwent RC for muscle invasive BCa relapse after surgery with either local recurrence or distant metastasis. This review focuses on the management of muscle invasive, locally advanced and metastatic BCa with emphasis on the role of surgery; to summarize the current knowledge in order to enhance clinical decision-making and counselling process.

Background: Systemic chemotherapy with gemcitabine and cisplatin is standard of care for patients with metastatic urothelial bladder cancer. However, resistance formation is common after initial response. The protein Src is known as a proto-oncogene, which is overexpressed in various human cancers. Since there are controversial reports about the role of Src in bladder cancer, we evaluated the efficacy of the Src kinase inhibitor dasatinib in the urothelial bladder cancer cell line RT112 and its gemcitabine-resistant sub-line RT112rGEMCI20 in vitro and in vivo. Methods: RT112 urothelial cancer cells were adapted to growth in the presence of 20 ng/ml gemcitabine (RT112rGEMCI20) by continuous cultivation at increasing drug concentrations. Cell viability was determined by MTT assay, cell growth kinetics were determined by cell count, protein levels were measured by western blot, and cell migration was evaluated by scratch assays. In vivo tumor growth was tested in a murine orthotopic xenograft model using bioluminescent imaging. Results: Dasatinib exerted similar effects on Src signaling in RT112 and RT112rGEMCI20 cells but RT112rGEMCI20 cells were less sensitive to dasatinib-induced anti-cancer effects (half maximal inhibitory concentration (IC50) of dasatinib in RT112 cells: 349.2 ± 67.2 nM; IC50 of dasatinib in RT112rGEMCI20 cells: 1081.1 ± 239.2 nM). Dasatinib inhibited migration of chemo-naive and gemcitabine-resistant cells. Most strikingly, dasatinib treatment reduced RT112 tumor growth and muscle invasion in orthotopic xenografts, while it was associated with increased size and muscle-invasive growth in RT112rGEMCI20 tumors. Conclusion: Dasatinib should be considered with care for the treatment of urothelial cancer, in particular for therapy-refractory cases.