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NOTCH2-inactivating antibody inhibited tumor progression in vitro and in vivo.

NOTCH2 silencing inhibited tumor progression through decreased cell proliferation and invasion.

NOTCH2-induced cell invasion was blocked by downstream inhibition of canonical NOTCH2 signaling.

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.

NOTCH2 overexpression promoted bladder cancer progression through increased proliferation and invasion.

The lists of antibodies, primers and patients characteristics and detailed information of methods were described in Supplementary Material and Methods.

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.

Urothelial cancer (UC) is most commonly found in the urinary bladder, but can also appear in the upper urinary tract, where it is associated with several disease-specific challenges affecting its diagnosis, clinical staging, surgical management, and systemic therapy. A significant number of patients experience extra-vesical disease recurrence despite radical nephroureterectomy (RNU), leading to inevitable demise. Over the last years, the therapeutic armamentarium of UC has expanded with several systemic treatment options entering clinical care and deliver the potential to support a more individualized treatment in the near future. Currently, novel targeted therapies are emerging, accompanied with extensive biomarker research, which leads to a better understanding of the disease and therefore, reshaping the treatment landscape continuously and decisively. Though, systemic treatment of UTUC comes along with certain challenges that are specific to the disease, e.g., loss of renal function after RNU, which might result in ineligibility for a cisplatin-based chemotherapy. In this narrative review, the current standard of systemic treatment of UC in the perioperative and metastatic treatment setting are reported, with focus on UTUC. In addition, molecular aspects of UTUC, as well as future directions and specific implications for treatment of patients diagnosed with UTUC are discussed.

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.

BACKGROUND To investigate the predictive and prognostic value of the preoperative modified Glasgow Prognostic Score (mGPS) in patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy (RC). METHODS We conducted a retrospective analysis of an established multicenter database consisting of 4,335 patients who were treated with RC +/- adjuvant chemotherapy for UCB between 1979 and 2012. The mGPS of each patient was calculated on the basis of preoperative serum C-reactive protein and albumin. Uni- and multivariable logistic and Cox regression analyses were performed. The discriminatory ability of the models was assessed by calculating the area under receiver operating characteristics curves (AUC) and concordance-indices (C-Index). The additional clinical net-benefit was assessed using the decision curve analysis (DCA). RESULTS A mGPS of 0, 1, and 2 was observed in 3,158 (72.8%), 1,020 (23.5%), and 157 (3.6%) patients, respectively. On multivariable logistic regression analyses, mGPS of 1 or 2 were associated with an increased risk of pT3/4 disease at RC (OR 1.25, p=0.004 and OR 2.58, p

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.

Purpose of review This review provides an overview of currently ongoing clinical trials evaluating the combination of immune checkpoint inhibitors (CPI) with other therapies in locally advanced or metastatic urothelial cancer and the rationale for this combination approach. We discuss the preliminary results from early data presented at recent meetings regarding the efficacy and safety of novel combination therapies including a CPI for metastatic urothelial cancer. Recent findings CPI emerged as novel first-line or second-line treatment options in advanced and metastatic urothelial cancer (mUC). Although the response rates and their sustainability are promising, it is far from a home run. Combination therapies have already shown improved efficacy in several other tumor entities. Summary Numerous clinical trials currently investigate combinations of CPI with other CPI, previously established systemic chemotherapy, targeted therapies, vaccines, or accompanied with radiotherapy. Preliminary data shows promising results. These results suggest that targeting pathways of immune response combined with established or novel oncological therapies may lead to a synergistic antitumor effect.

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.

This review provides an overview of currently ongoing clinical trials evaluating the combination of immune checkpoint inhibitors (CPI) with other therapies in locally advanced or metastatic urothelial cancer and the rationale for this combination approach. We discuss the preliminary results from early data presented at recent meetings regarding the efficacy and safety of novel combination therapies including a CPI for metastatic urothelial cancer.CPI emerged as novel first-line or second-line treatment options in advanced and metastatic urothelial cancer (mUC). Although the response rates and their sustainability are promising, it is far from a home run. Combination therapies have already shown improved efficacy in several other tumor entities.Numerous clinical trials currently investigate combinations of CPI with other CPI, previously established systemic chemotherapy, targeted therapies, vaccines, or accompanied with radiotherapy. Preliminary data shows promising results. These results suggest that targeting pathways of immune response combined with established or novel oncological therapies may lead to a synergistic antitumor effect.

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.

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.

Summary Until recently, there were no true innovations in the management of locally advanced (aUC) and metastatic urothelial cancer (mUC) in the last three decades. Vinflunine has been approved by the EMA (European Medicines Agency) with only limited improvement compared to best supportive care in second line treatment. In addition, gemcitabine/cisplatin has been established as an alternative to methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). The advent of checkpoint inhibitors (CPI) revolutionized the care of these patients, transforming a unanimously deadly disease into one with hope through sustained disease control. Five immune CPI have recently been approved for aUC/mUC by the US Food and Drug Administration (FDA) including atezolizumab, nivolumab, pembrolizumab, durvalumab and avelumab. All five CPI are FDA-approved as second-line therapy with atezolizumab and pembrolizumab also being approved for first-line therapy in cisplatin-ineligible patients. The rapid acceptance in the treatment algorithm of UC is based on the impressive clinical efficacy of these agents in some patients, combined with their excellent safety profile. These new agents are indeed the most important advancement in UC care. However, the challenge in the age of precision medicine is to identify the patients who are most likely to benefit from CPIs, as the majority of patients do not respond to CPI. Toward this goal, validation of clinical, molecular and imaging biomarkers that serve for prediction and monitoring of treatment response are of central necessity.

Various ischemia type during partial nephrectomy for renal cell cancer (RCC) resulted in different postoperative functional outcomes. Our objective was to systematically review the contemporary literature on robot-assisted partial nephrectomy (RPN) and investigate the association of ischemia type and tumor complexity with postoperative functional outcomes of the operated kidney and overall.Forty-five of the 99 reports identified were selected for qualitative analysis. All included studies were observational and nonrandomized. Overall, we found that patients undergoing RPN with zero ischemia and selective artery clamping had a lower decrease in glomerular filtration rates of the operated kidney in comparison to both warm and cold ischemia. This association seems also to play a role in patients with bilateral kidneys harboring complex tumors.Zero ischemia and selective artery clamping provide the best functional outcomes following robotic partial nephrectomy. This seems to be of particular relevance in patients with single kidney or tumors of high complexity. Whether these changes are statistically or clinically significant cannot be determined within this systematic review.

Incidence rates for urothelial carcinoma (UC) have been reported to differ between countries within the European Union (EU). Besides occupational exposure to chemicals, other substances such as tobacco and nitrite in groundwater have been identified as risk factors for UC. We investigated if regional differences in UC incidence rates are associated with agricultural, industrial and residential land use.Newly diagnosed cases of UC between 2003 and 2010 were included. Information within 364 administrative districts of Germany from 2004 for land use factors were obtained and calculated as a proportion of the total area of the respective administrative district and as a smoothed proportion. Furthermore, information on smoking habits was included in our analysis. Kulldorff spatial clustering was used to detect different clusters. A negative binomial model was used to test the spatial association between UC incidence as a ratio of observed versus expected incidence rates, land use and smoking habits.We identified 437,847,834 person years with 171,086 cases of UC. Cluster analysis revealed areas with higher incidence of UC than others (p=0.0002). Multivariate analysis including significant pairwise interactions showed that the environmental factors were independently associated with UC (p0.001). The RR was 1.066 (95% CI 1.052-1.080), 1.066 (95% CI 1.042-1.089) and 1.067 (95% CI 1.045-1.093) for agricultural, industrial and residential areas, respectively, and 0.996 (95% CI 0.869-0.999) for the proportion of never smokers.This study displays regional differences in incidence of UC in Germany. Additionally, results suggest that socioeconomic factors based on agricultural, industrial and residential land use may be associated with UC incidence rates.

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.

Purpose of review Immunotherapies for urological malignancies have made tremendous progress by targeting immune checkpoints and have been implemented in clinical practice nowadays. Though siginifcant number of patients does not respond to immunotherapy. Biomarkers could help to predict response to treatment, but are still under investigation. We reviewed the literature to identify relevant biomarkers in patient treated with immunotherapy. Recent findings A comprehensive search of PubMed through has been performed to identify important relevant publications from 2016 to 2017 on biomarkers for immunotherapies in urological cancers including reported clinical trials. In addition, abstracts of relevant oncological scientific meetings from 2017 have been implemented. Summary Checkpoint inhibitors have shown substantial improvement in the treatment of metastatic RCC and metastatic and locally advanced urothelial cancer. There is an unmet need for the development of predictive biomarkers in order to identify patients who are more likely to respond to therapy.

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.

The efficacy of RARC in oncologic outcomes compared ORC is controversial. We assess potential differences in oncologic outcomes between robot-assisted radical cystectomy (RARC) and open radical cystectomy (ORC).We performed the literature search systematically according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. A pooled meta-analysis was performed to assess the difference in oncologic outcomes between RARC and ORC, separately in randomized controlled trials (RCTs) and non-randomized studies (NRCTs).Five RCTs and 28 NRCTs were included in this systematic review and meta-analysis. There was no difference in the rate of overall positive surgical margin (PSM) in RCTs, while NRCTs showed a lower rate for RARC. There was no difference in the soft tissue PSM rate between RARC and ORC in both RCTs and NRCTs. There was no difference in the lymph node yield by standard and extended lymph node dissection between RARC and ORC in both RCTs and NRCTs. There was no significant difference in survival outcomes between RARC and ORC in both RCTs and NRCTs.Based on the current evidence, there is no difference in the rate of PSMs, lymph node yield, recurrence rate and location as well as short-term survival outcomes between RARC and ORC in RCTs. In NRCTs, only PSM rates were better for RARC compared to ORC, but this was likely due to selection and reporting bias which are inherent to retrospective study designs.

Purpose: The efficacy of RARC in oncologic outcomes compared ORC is controversial. We assess potential differences in oncologic outcomes between robot-assisted radical cystectomy (RARC) and open radical cystectomy (ORC). Methods: We performed the literature search systematically according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. A pooled meta-analysis was performed to assess the difference in oncologic outcomes between RARC and ORC, separately in randomized controlled trials (RCTs) and non-randomized studies (NRCTs). Results: Five RCTs and 28 NRCTs were included in this systematic review and meta-analysis. There was no difference in the rate of overall positive surgical margin (PSM) in RCTs, while NRCTs showed a lower rate for RARC. There was no difference in the soft tissue PSM rate between RARC and ORC in both RCTs and NRCTs. There was no difference in the lymph node yield by standard and extended lymph node dissection between RARC and ORC in both RCTs and NRCTs. There was no significant difference in survival outcomes between RARC and ORC in both RCTs and NRCTs. Conclusions: Based on the current evidence, there is no difference in the rate of PSMs, lymph node yield, recurrence rate and location as well as short-term survival outcomes between RARC and ORC in RCTs. In NRCTs, only PSM rates were better for RARC compared to ORC, but this was likely due to selection and reporting bias which are inherent to retrospective study designs.

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.