Nivolumab + Ipilimumab as Immunotherapeutic Boost in Metastatic Urothelial Carcinoma: A Nonrandomized Clinical Trial.

Importance: Studies with nivolumab, an approved therapy for metastatic urothelial carcinoma (mUC) after platinum-based chemotherapy, demonstrate improved outcomes with added high-dose ipilimumab. Objective: To assess efficacy and safety of a tailored approach using nivolumab + ipilimumab as an immunotherapeutic boost for mUC. Design, Setting, and Participants: In this phase 2 nonrandomized trial, patients with mUC composed 2 cohorts. Cohort 1 received first-line or second-/third-line nivolumab with escalating doses of ipilimumab, and cohort 2 received second-/third-line nivolumab with high-dose ipilimumab. Recruitment spanned 26 sites in Germany and Austria from August 8, 2017, to February 18, 2021. All patients had a 70% or higher Karnofsky Performance Score and measurable disease per Response Evaluation Criteria in Solid Tumours, version 1.1. Interventions: All patients initiated 4 doses of 240-mg nivolumab (1× every 2 wk). Week 8 nonresponders received nivolumab + ipilimumab (1× every 3 wk). Cohort 1 received 2 doses of 3-mg/kg nivolumab + 1-mg/kg ipilimumab followed by 2 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab if no response. Due to safety concerns, cohort 1 treatment was halted, and first-line cohort 2 treatment was not pursued. Cohort 2 received 2 to 4 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab. Responders continued with nivolumab maintenance but could receive nivolumab + ipilimumab for later progression. Main Outcomes and Measures: The primary end point was objective response rate. Results: The study comprised 169 patients (118 [69.8%] men; median [range] age, 68 [37-84] years): 86 in cohort 1 (42 first-line; 44 second-/third-line) and 83 in cohort 2. The median (IQR) follow-up times were 10.4 (4.2-23.5) months (first-line cohort 1), 7.5 (3.1-23.8) months (second-/third-line cohort 1), and 6.2 (3.2-22.7) months (cohort 2). Response rates to nivolumab induction were 12/42 (29%, first-line cohort 1), 10/44 (23%, second-/third-line cohort 1), and 17/83 (20%, cohort 2). Response rates to a tailored approach were 20/42 (48% [90% CI, 34%-61%], first-line cohort 1), 12/44 (27% [90% CI, 17%-40%], second-/third-line cohort 1), and 27/83 (33% [90% CI, 23%-42%], cohort 2). Three-year overall survival rates for first-line cohort 1, second-/third-line cohort 1, and cohort 2 using the Kaplan-Meier method were 32% (95% CI, 17%-49%), 19% (95% CI, 8%-33%), and 34% (95% CI, 23%-44%), respectively. Conclusions and Relevance: In this nonrandomized trial, although first-line cohort 1 treatment improved objective response rates, considerable progression events urge caution with this as a first-line therapy. Second-/third-line cohort 1 treatment did not improve response rates compared with nivolumab monotherapy. However, added high-dose ipilimumab may improve tumor response and survival in patients with mUC. Trial Registration: ClinicalTrials.gov Identifier: NCT03219775.

Simulation of the effects of molecular urine markers in follow-up of patients with high-risk non-muscle invasive bladder cancer.

A plethora of urine markers for the management of patients with bladder cancer has been developed and studied in the past. However, the clinical impact of urine testing on patient management remains obscure. The goal of this manuscript is to identify scenarios for the potential use of molecular urine markers in the follow-up of patients with high-risk non-muscle-invasive BC (NMIBC) and estimate potential risks and benefits. Information on the course of disease of patients with high-risk NMIBC and performance data of a point-of-care test (UBC rapid™), an MCM-5 directed ELISA (ADXBLADDER™), and 2 additional novel assays targeting alterations of mRNA expression and DNA methylation (Xpert bladder cancer monitor™, Epicheck™) were retrieved from high-quality trials and/or meta-analyses. In addition, the sensitivity of white light cystoscopy (WLC) and the impact of a urine marker result on the performance of WLC were estimated based on fluorescence cystoscopy data and information from the CeFub trial. This information was applied to different scenarios in patient follow-up and sensitivity, estimated number of cystoscopies, and the numbers needed to diagnose were calculated. The sensitivity of guideline-based regular follow-up (SOC) at 1 year was calculated at 96%. For different marker-supported strategies sensitivities ranging from 77% to 97.9% were estimated. Calculations suggest that several strategies are effective for the SOC. While for the SOC 24.6 WLCs were required to diagnose 1 tumor recurrence (NND), this NND dropped below 5 in some marker-supported strategies. Based on the results of this simulation, a marker-supported follow-up of patients with HR NMIBC is safe and offers the option to significantly reduce the number of WLCs. Further research focusing on prospective randomized trials is needed to finally find a way to implement urine markers into clinical decision-making.

Considering the Effects of Modern Point-of-Care Urine Biomarker Assays in Follow-Up of Patients with High-Risk Non-muscle-Invasive Bladder Cancer.

BACKGROUND: Although a plethora of urine markers for diagnosis and follow-up of patients with bladder cancer (BC) has been developed and studied, the clinical impact of urine testing on patient management remains unclear. The goal of this manuscript is to identify scenarios for a potential use of modern point-of-care (POC) urine marker assays in the follow-up of patients with high-risk non-muscle-invasive BC (NMIBC) and estimate potential risks and benefits. METHODS: To permit comparison between different assays, the results of 5 different POC assays studied in a recent prospective multicenter study including 127 patients with suspicious cystoscopy undergoing TURB were used for this simulation. For the current standard of care (SOC), a "marker-enforced" procedure, and a combined strategy sensitivity (Se), estimated number of cystoscopies, and the numbers needed to diagnose (NND) over a 1-year follow-up period were calculated. RESULTS: For regular cystoscopy (SOC), a Se of 91.7% and a NND of 42.2 repetitive office cystoscopies (WLCs) for 1 recurrent tumor at 1 year were calculated. For the "marker-enforced" strategy, marker sensitivities between 94.7% and 97.1% were observed. The "combined" strategy yielded for markers with a Se exceeding 50% an overall Se at 1 year similar or superior to the current SOC. Savings regarding the number of cystoscopies in the "marker-enforced" strategy vs. the SOC were small, while, depending on the marker, up to 45% of all cystoscopies may be saved using the "combined" strategy. CONCLUSIONS: Based on the results of this simulation, a marker-supported follow-up of patients with high-risk (HR) NMIBC is safe and offers options to significantly reduce the number of cystoscopies without compromising the Se. Further research focusing on prospective randomized trials is needed to finally find a way to include marker results into clinical decision-making.

Tailored immunotherapy approach with nivolumab with or without ipilimumab in patients with advanced transitional cell carcinoma after platinum-based chemotherapy (TITAN-TCC): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Nivolumab is used after platinum-based chemotherapy in patients with metastatic urothelial carcinoma. Studies suggest improved outcomes for dual checkpoint inhibition with high ipilimumab doses. We aimed to examine the safety and activity of nivolumab induction and high-dose ipilimumab as an immunotherapeutic boost as a second-line treatment for patients with metastatic urothelial carcinoma. METHODS: TITAN-TCC is a multicentre, single-arm, phase 2 trial done at 19 hospitals and cancer centres in Germany and Austria. Adults aged 18 years or older with histologically confirmed metastatic or surgically unresectable urothelial cancer of the bladder, urethra, ureter, or renal pelvis were eligible. Patients had to have progression during or after first-line platinum-based chemotherapy and up to one more second-line or third-line treatment, a Karnofsky Performance Score of 70 or higher, and measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1. After four doses of intravenous nivolumab 240 mg induction monotherapy every 2 weeks, patients with a partial or complete response at week 8 continued maintenance nivolumab, whereas those with stable or progressive disease (non-responders) at week 8 received a boost of two or four doses of intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks. Patients who subsequently had progressive disease during nivolumab maintenance also received a boost, using this schedule. The primary endpoint was the confirmed investigator-assessed objective response rate in the intention-to-treat population and had to exceed 20% for the null hypothesis to be rejected (based on the objective response rate with nivolumab monotherapy in the CheckMate-275 phase 2 trial). This study is registered with ClinicalTrials.gov, NCT03219775, and is ongoing. FINDINGS: Between April 8, 2019, and Feb 15, 2021, 83 patients with metastatic urothelial carcinoma were enrolled and all received nivolumab induction treatment (intention-to-treat population). The median age of enrolled patients was 68 years (IQR 61-76), and 57 (69%) were male and 26 (31%) were female. 50 (60%) patients received at least one boost dose. A confirmed investigator-assessed objective response was recorded in 27 (33%) of 83 patients in the intention-to-treat population, including six (7%) patients who had a complete response. This objective response rate was significantly higher than the prespecified threshold of 20% or less (33% [90% CI 24-42]; p=0·0049). The most common grade 3-4 treatment-related adverse events were immune-mediated enterocolitis (nine [11%] patients) and diarrhoea (five [6%] patients). Two (2%) treatment-related deaths were reported, both due to immune-mediated enterocolitis. INTERPRETATION: Treatment with nivolumab and nivolumab plus ipilimumab boosts in early non-responders and patients who progress late significantly improved objective response rate after previous platinum-based chemotherapy compared with the rate reported with nivolumab in the CheckMate-275 trial. Our study provides evidence for the added value of high-dose ipilimumab 3 mg/kg and suggests a potential role for the combination as a rescue strategy in platinum-pretreated patients with metastatic urothelial carcinoma. FUNDING: Bristol Myers Squibb.

Bladder preservation after neoadjuvant therapy - 2021 IBCN updates part 1.

The morbidity associated with radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) has fueled investigations into the feasibility of bladder preservation strategies after a favorable clinical response to neoadjuvant therapy (NAT). Identifying optimal candidates for bladder preservation is predicated on our ability to identify tumors with inherent cisplatin sensitivity and accurately stage patients before and after NAT. In the present review, we evaluate the accuracy and limitations of contemporary staging modalities and investigate clinical outcomes in patients with MIBC who were managed with bladder preservation after NAT. Lastly, we discuss the predictive role of cisplatin-sensitizing DNA damage response (DDR) gene alterations as a foundational component to current prospective clinical trials evaluating bladder preservation in the setting of MIBC.

25 years International Bladder Cancer Network (IBCN): The past, the present, and the future.

In 1997 an international group of scientists organized a meeting in Barcelona, Spain, to discuss the use of biomarkers in the management of patients with bladder cancer. This meeting was the offspring of an - initially informal - group that finally resulted in the foundation and incorporation of the International Bladder Cancer Network (IBCN) e.V. in 2005. Over the years the group has supported several research initiatives and generated several recommendations on the use of biomarkers in the diagnosis and treatment of bladder cancer. Meeting quality was generated by inviting experts presenting state-of-the-art lectures or work in progress reports, interdisciplinarity and the limited number of participants supporting an open and personal exchange resulted in a format increasingly attracting participants from all over the world. The recent limitations caused by the Covid-19 pandemic were partially met by organizing several well attended webinars. The future challenge is to maintain the IBCN meeting spirit despite an increasing interest of the scientific community and industrial partners to participate. However, the integration of and interaction between increasingly more specialized disciplines is a challenge that can be better catalyzed by an international multidisciplinary network than mostly national professional associations.

Discriminative capacity of guideline recommendations in the assessment of patients with asymptomatic microhematuria.

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

Lifestyle aspects in a contemporary middle-European cohort of patients undergoing androgen deprivation therapy for advanced prostate cancer: data from the non-interventional LEAN study.

Androgen deprivation therapy (ADT) in men with prostate cancer (PCa) is associated with significant side effects. With the transition of PCa from a foudroyant course to a chronic disease, managing these side effects has become increasingly important. There is growing evidence that nutritional changes and physical activity are beneficial in these patients. Here we examine the impact of written patient information on the physical activity and dietary habits of PCa patients receiving ADT and behaviour changes between baseline and 1 year, in the open-label, non-interventional LEAN study. In total, 959 patients with advanced hormone-sensitive PCa requiring ADT with the Leuprorelin Sandoz® implant were included from January 2014 to July 2015 and followed for ≥ 12 months. At the start of the study, urologists received a questionnaire concerning the written information provided to patients regarding their disease, patient advocacy groups, diet and physical activity. Patients received a questionnaire on their dietary habits and physical activity at the start and end of the study. Urologists from 147 study centres and 540 patients responded to the questionnaires. While 69 % of these patients received disease-specific information, only 30 % and 17 % received information regarding nutrition and physical activity, respectively. The majority of urologists estimate that their patients rarely or never follow guidance on nutrition or physical activity, yet > 90 % of patients indicate they would make use of this information, if provided. Few patients showed behavioural changes between baseline and 1 year without evident differences between patients that received information and those that did not.

Tailored Immunotherapy Approach With Nivolumab in Advanced Transitional Cell Carcinoma.

PURPOSE: Several anti-programmed cell death (ligand)-1 (PD-[L]1) immune checkpoint inhibitors are approved in advanced/metastatic urothelial carcinoma (mUC). Recently, improved activity of an anti-PD-1/anticytotoxic T-cell lymphocyte-4 (CTLA-4) combination versus anti-PD-1 monotherapy has been reported. We report a response-based approach starting treatment with nivolumab monotherapy with nivolumab/ipilimumab as immunotherapeutic boost. METHODS: After four doses of nivolumab induction, responders continued with nivolumab maintenance therapy. Patients with stable/progressive disease received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks for 2 doses followed by nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 2 doses, if not responding to the initial boost. Responders to boosts continued with nivolumab maintenance. Between July 2017 and April 2019, 86 patients were enrolled. The median follow-up is 7.7 months. The primary end point is objective response rate (ORR) per RECIST1.1. Secondary end points include efficacy of nivolumab induction, remission rate with nivolumab/ipilimumab boosts, overall survival, and safety. RESULTS: Of all patients, 42, 39, and five were first- (1L), second- (2L), and third-line (3L), respectively. The median age was 68 years. The ORR with nivolumab monotherapy (assessed at week 8) was 29% in 1L and 23% in 2/3L, respectively. Forty-one patients received early (week 8) and 11 received later nivolumab/ipilimumab boosts. ORRs with nivolumab with or without nivolumab/ipilimumab (best overall response) were 45% and 27% in 1L and 2/3L, respectively. In 1L, 7 of 17 patients receiving boosts at week 8 improved, compared with 2 of 24 in 2/3L. CONCLUSION: The tailored approach of TITAN-TCC shows meaningful clinical activity supporting dual checkpoint inhibition in 1L mUC. However, starting therapy with nivolumab exclusively appears inadequate given the aggressive nature of mUC. In 2/3L, nivolumab/ipilimumab boosts with escalating ipilimumab dose did not improve efficacy outcomes versus nivolumab monotherapy. An independent 2L cohort of TITAN-TCC receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 4 doses is ongoing.

Effectiveness and Distribution of Testosterone Levels within First Year of Androgen Deprivation Therapy in a Real-World Setting: Results from the Non-Interventional German Cohort LEAN Study.

BACKGROUND: Observational studies generate information on real-world therapy and complement data from prospective randomized trials. LEAN is an open-label, non-interventional, multi-centre, German cohort study on leuprorelin in routine clinical practice. OBJECTIVES: To extend knowledge on the use, effectiveness, and tolerability of HEXAL/Sandoz leuprorelin (in this article, the term Leuprone® HEXAL® covers Leuprorelin Sandoz® as well) solid implant in patients with prostate cancer (PCa) in a real-world setting. METHODS: 959 PCa patients scheduled for androgen deprivation therapy (ADT) received leuprorelin acetate implant. Metabolism, serum prostate-specific antigen (PSA), and testosterone data, if available, were collected at baseline and follow-up visits for ≥12 months. RESULTS: Of 694 patients in the modified full analysis set, 26.4% received GnRH analogues ≤6 months before enrolment. Fifty-one percent of patients were treated for locally advanced or metastatic PCa. In 19.6% of patients, ADT was used in neoadjuvant or adjuvant settings and in 28.5% with rising PSA after definite therapy. Testosterone levels <0.5 ng/mL were achieved in >90% of patients. Safety profile was in line with the summary of product characteristics. Therapy was well tolerated, with patient-triggered therapy discontinuation in 3.6%. CONCLUSIONS: This interim analysis confirmed previous efficacy findings for leuprorelin implant in a real-world setting. This contemporary cohort showed a shift in the use of ADT to non-metastatic PCa stages.

Prognostic markers in pT3 bladder cancer: A study from the international bladder cancer tissue microarray project.

PURPOSE: We evaluated the prognostic value of 10 putative tumor markers by immunohistochemistry in a large multi-institutional cohort of patients with locally advanced urothelial cancer of the bladder (UCB) with the aim to validate their clinical value and to harmonize protocols for their evaluation. MATERIALS AND METHODS: Primary tumor specimens from 576 patients with pathologic (p)T3 UCB were collected from 24 institutions in North America and Europe. Three replicate 0.6-mm core diameter samples were collected for the construction of a tissue microarray (TMA). Immunohistochemistry (IHC) for 10 previously described tumor markers was performed and scored at 3 laboratories independently according to a standardized protocol. Associations between marker positivity and freedom from recurrence (FFR) or overall survival (OS) were analyzed separately for each individual laboratory using Cox regression analysis. RESULTS: The overall agreement of the IHC scoring among laboratories was poor. Correlation among the 3 laboratories varied across the 10 markers. There was generally a lack of association between the individual markers and FFR or OS. The number of altered cell cycle regulators (p53, Rb, and p21) was associated with increased risk of cancer recurrence (P < 0.032). There was no clear pattern in the relationship between the percentage of markers altered in an 8-marker panel and FFR or OS. CONCLUSIONS: This large international TMA of locally advanced (pT3) UCB suggests that altered expression of p53, Rb, and p21 is associated with worse outcome. However this study also highlights limitations in the reproducibility of IHC even in the most expert hands.

Eosinophilic cystitis mimicking bladder cancer-considerations on the management based upon a case report and a review of the literature.

The hypereosinophilic syndrome (HES) is a rare disorder characterized by hypereosinophilia and infiltration of various organs with eosinophils. Eosinophilic cystitis (EC), mimicking bladder cancer clinically but also in ultrasound and in radiographic imaging, is one potential manifestation of the HES occurring in adults as well as in children. This case report describes the course of disease in a 57-year-old male presenting with severe gait disorders and symptoms of a low compliance bladder caused by a large retropubic tumor. After extensive urine and serologic examination and histologic confirmation of EC the patient was subjected to medical treatment with cetirizine and prednisolone for 5 weeks. While gait disorders rapidly resolved, micturition normalized only 10 months after initiation of therapy. Based upon this course the authors recommend patience and reluctance concerning radical surgical intervention in EC. Key Points • Eosinophilic cystitis is a rare condition with app. 200 cases reported, so far. • Etiology of eosinophilic cystitis is obscure, but allergies and parasitic infections may trigger the disease. • Genetic alterations (e.g., BRAF mutations) may predispose for the disease • Corticosteroids and antihistamines are the backbone of therapy and may be complemented by antibiotics and non-steroidal anti-inflammatory drugs in case of concomitant (underlying) infections. • As recovery can occur even after a long time, radical surgery should be restricted to highly selected cases.

Toward noninvasive follow-up of low-risk bladder cancer - Rationale and concept of the UroFollow trial.

BACKGROUND: Follow-up recommendations for patients with nonmuscle invasive bladder cancer (NMIBC) are largely based upon expert opinion. A growing body of evidence suggests that current follow-up strategies for bladder cancer patients with low and intermediate risk represent overdiagnosis and may lead to overtreatment. The goal of this study is to explore the options of a noninvasive follow-up in patients with pTa G1-2/low-grade NMIBC. METHODS: The risks and options for a urine marker-guided, noninvasive follow-up of patients with pTa G1-2/low-grade NMIBC were defined and the study design for a prospective randomized trial (UroFollow) was developed based upon the current literature. RESULTS: The investigators postulated that follow-up of patients with pTa G1-2/low-grade NMIBC requires a high sensitivity of urinary tumor markers. However, data from prospective studies with prediagnostic urine samples are scarce, even for approved markers, and cross-sectional studies with symptomatic patients overestimate the sensitivity. So far, cell-based markers (e.g., uCyt+ and UroVysion) in urine appeared to have higher sensitivities and specificities in low-grade NMIBC than urine cytology and markers analyzing soluble tumor-associated antigens. Marker panels are more sensitive than single-marker approaches at the expense of a lower specificity. Given a prospective randomized comparison with a marker sensitivity of 80% compared to usual care with cystoscopy, the sample size calculation yielded that 62 to 185 patients under study per arm are needed depending on different recurrence rates. CONCLUSIONS: Based upon these findings the UroFollow trial has been designed as a prospective randomized study comparing a noninvasive marker-based (UroVysion, NMP22, urine cytology, and ultrasound) follow-up with the current standard of care over a period of 3 years.

Editorial: Basic research in bladder cancer - refining the tools. 3rd IBCN seminars series1.

This editorial highlights submissions to part II of the 3rd IBCN Seminars Series particularly focusing on the tools required for conduction of translational research in bladder cancer. One of the submissions describe the ex vivo culture of primary tumor cells from N-methyl-N-nitrosourea-induced bladder tumors in rats and subsequent establishment of an immortalized cell line. In a next step the authors thoroughly characterize this cell line. They conclude that differentiation marker expression patterns observed in the original tumors are largely retained in the spheroids. Although new cancer models, such as organoid tissue cultures, hold great promise for studying cancer progression and might have a potential for development and selection of an optimal treatment, their limitations must be kept in mind. The second submission, therefore, critically questions the current role of organoid tissue culture as a predictive tool in urothelial cancer patients. The third manuscript of this series provides a broader overview of post-translational modification in bladder cancer is presented and how PTMs can be exploited as potential therapeutic targets. The 3 manuscripts featured in this issue demonstrate especially how basic research is being channeled to inform clinically actionable discoveries.

New horizons in bladder cancer research.

The 16th Meeting of the International Bladder Cancer Network (IBCN) took place from October 11 to 13, 2018 in Rotterdam, the Netherlands. As in the previous year, muscle-invasive bladder cancer (MIBC) was the main topic of the congress based upon the rapid evolution in this field over the last several years. This year´s meeting was dominated by presentations focusing on genomic subtyping in MIBC and identification of novel therapeutic targets. These topics were complemented by submissions on immunotherapy, a variety of clinical topics, and biomarker research. Based upon the presentations, it may be concluded that the IBCN increasingly serves as an interdisciplinary forum not only for the presentation of work-in-progress covering all facets of bladder cancer research, but also for catalyzing the discussion of discrepant research findings in an effort to find consensus. The 16th Meeting of the IBCN took place from October 11 to 13th, 2018 in Rotterdam, the Netherlands, hosted by Ellen Zwarthoff and Joost Boormans. Approximately 120 participants gathered for another fully packed program displaying recent achievements in basic and clinical research covering the entire spectrum of bladder cancer. This year's meeting was dominated by presentations focusing on genomic subtyping and identification of novel therapeutic targets. These topics were complemented by submissions on immunotherapy, clinical topics, and biomarker research. Keynote lectures were delivered by G. Robertson (Canada) on MIBC genomics and the organizational challenges of the PanCancerAtlas project. Comprehensive information was provided on the Cancer Genome Atlas (TCGA) project including the structure of the consortium and the development and validation of molecular classification of MIBC. Results from the project suggest that regulons (groups of genes controlled by a common regulator) appear to be correlated with prognosis and may replace gene expression analysis in the future. M. Thelen (Switzerland) discussed the role of chemokines in cancer metastasization reporting on his research on the atypical chemokine receptor 3. The inaugural IBCN lecture was presented by M. Ingersoll (France) discussing gender disparities in development of adaptive immunity following Bacillus Calmette-Guerin therapy. In addition to the traditional "Industry meets IBCN" sessions, a format for discussion between industry representatives, researchers, and physicians in break-out groups, new formats were introduced-in the Oxford style of debate, P.J. Goebell (Germany) and W. Stadler (USA) delivered animated discussion on the appropriateness of urologists administering systemic immune checkpoint inhibitors. There was consensus that practice may differ between different health systems and countries, and educational/training background. In a second interesting discussion, D. McConkey (USA) and H. Al-Ahmadie (USA) debated if traditional histology will be replaced by molecular classification of bladder tumors. It was concluded that molecular classification offers valuable additional information but cannot yet replace traditional histology. Furthermore, the growing evidence of tumor heterogeneity in bladder cancer was discussed in a separate topic session. L. Dyrskjot discussed genomic and transcriptomic heterogeneity and their impact on clinical decision making. G. Sjödahl presented data on heterogeneity of molecular subtypes within the primary tumor and between the primary tumor and metastases, that is surprisingly limited. Y. Allory discussed spatial and temporal heterogeneity of bladder cancers particularly focusing on the basal-like phenotype. Due to the continued increase in the number of participants and abstract submissions, a poster session was implemented at this year´s meeting for the first time. Posters were briefly presented in the forum. Two travel awards were presented to H. Yamashita (USA) for his submission on peroxisome proliferator-activated receptor gamma-mediated repression of transcription factor activating protein 2 alfa expression identifying a transcriptional circuit in basal-squamous bladder cancer in a cell line model. S.B. Williams (USA) received his award for his registry-based analysis of outcome and costs in patients with localized MIBC undergoing either bladder sparing trimodal therapy or radical cystectomy. The latter was found to generate improved survival outcomes at lower costs as compared with trimodal therapy. The best presentation awards were presented to A. Kamoun (France) who discussed a consensus molecular classification for MIBC. The international demand for a consensus classification, already raised at previous meetings, has resonated with important players in this field. A potential consensus comprising 6 classes was proposed based upon a thorough analysis of the existing classifications. As an extension of the IBCN meeting a consensus conference on genomic classification of MIBC was held that included all major groups in this field. M. Garige (USA) received his award for a detailed examination of inhibitors of metabolic processes in bladder cancer cells before and after therapy. A take home message of the meeting was that the IBCN increasingly serves as an interdisciplinary forum not for the presentation of work-in-progress covering all facets of bladder cancer research, but also for catalyzing the discussion of discrepant research findings in an effort to find consensus. Exemplified may this also be by the fact that the efforts to unify the subclassification of MIBC had its nidus on the preceding meetings of the IBCN on this topic and brought together the various disciplines which ultimately were able to finalize their consensus work in a last concluding meeting directly following the IBCN. Thus, the IBCN meetings and the close cooperation of IBCN with its official journal, Urological Oncology, continue to provide a unique platform for exchange, discussing and intensifying multidimensional collaborations, thus finally satisfying the increasing need for answers regarding the management of bladder cancer patients. The 17th meeting of the IBCN will take place in Aarhus, Denmark, October 3 to 5, 2019.

Systematic Review of Factors Associated with the Utilization of Radical Cystectomy for Bladder Cancer.

CONTEXT: Despite established guidelines for the treatment of muscle-invasive bladder cancer, it has been reported that radical cystectomy (RC) is markedly underused, especially among patients of advanced age and those with higher comorbidity burden and lower access to care. Understanding the interactions between patient, provider, and hospital factors may inform targeted interventions to optimize RC utilization. OBJECTIVE: To systematically review the literature regarding factors associated with RC utilization. EVIDENCE ACQUISITION: A systematic search was conducted using Ovid and Medline according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to identify studies between 1970 and 2017 reporting on RC utilization. Prospective and retrospective studies were included. EVIDENCE SYNTHESIS: There are no published randomized control trials on RC utilization. Variations in study quality and design precluded a formal statistical meta-analysis. RC receipt significantly depended on patient, provider, and hospital factors. Patient factors associated with lower RC use included advanced age, African American and Hispanic race/ethnicity, higher comorbidity burden, unmarried marital status, higher tumor stage and grade, and lower socioeconomic status. Provider factors associated with underutilization included lower surgeon volume and a metropolitan location. Finally, hospital factors associated with lower RC use included low hospital volume, nonacademic affiliation, and hospital location in the Midwest. CONCLUSIONS: RC is reportedly underutilized. We found that age, race, marital status, socioeconomic factors, cancer severity, comorbidity burden, surgeon volume, and facility type and location significantly determined RC receipt. Improved understanding of the varying contributions of the risk factors according to patient, provider, and hospital determinants may assist in developing targeted interventions to improve RC utilization. PATIENT SUMMARY: In this review we explored the clinical evidence for factors predicting the utilization of radical cystectomy for muscle-invasive bladder cancer. Many factors related to the patient, provider, and hospital determine whether patients receive this guideline-recommended treatment. However, there remains a lack of understanding on characterization and targeted interventions according to these levels, which may improve use.