Frontiers in combining immune checkpoint inhibitors for advanced urothelial cancer management.

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.

Immune checkpoint inhibition in muscle-invasive and locally advanced bladder cancer.

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.

Diagnostic accuracy, clinical utility and influence on decision-making of a methylation urine biomarker test in the surveillance of non-muscle-invasive bladder cancer.

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.

Surgical checklist impact on recurrence-free survival of patients with non-muscle-invasive bladder cancer undergoing transurethral resection of bladder tumour.

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.

Oncologic outcomes after robot-assisted versus open radical cystectomy: a systematic review and meta-analysis.

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.

Molecular markers in bladder cancer.

PURPOSE: 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. METHODS: A review of the published literature was performed, without restriction of time. RESULTS: 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. CONCLUSIONS: 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.

Pseudoprogression and hyperprogression during immune checkpoint inhibitor therapy for urothelial and kidney cancer.

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.

Molecularly-driven precision medicine for advanced bladder cancer.

Urothelial carcinoma of the bladder is a heterogeneous disease with many challenges for clinicians and patients alike. However, for the most part of the last three decades, treatment and outcomes for patients with this disease have not changed a lot. With recent advances in immunooncology leading to the approval of multiple agents for the metastatic setting, the treatment landscape started to change. With the emergent data from landmark multi-institutional sequencing projects as well as molecular data from recent trials, our understanding of the underlying disease biology, response patterns as well as definition of molecular subtypes has evolved tremendously. This review aims to summarize the currently available concepts of mutational profiles and molecular subtypes as well as their implications for management of urothelial carcinoma.

An up-to-date catalog of available urinary biomarkers for the surveillance of non-muscle invasive bladder cancer.

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.

Biomarkers for immunotherapy in urological cancers.

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.

HER2 overexpression is associated with worse outcomes in patients with upper tract urothelial carcinoma (UTUC).

PURPOSE: The aim of our study was to evaluate the expression pattern of HER2 overexpression in patients with upper tract urothelial carcinoma (UTUC) and to evaluate its association with clinical outcomes. METHODS: This multicenter retrospective study included 732 patients treated with radical nephroureterectomy for UTUC. HER2 expression was assessed using immunohistochemistry and scored according to the HercepTest: Scores of 0 or 1 were considered negative and 2 or 3 as positive. To qualify for 2 scoring, complete membrane staining of more than 10 % of tumor cells at a moderate intensity had to be observed. RESULTS: HER2 was overexpressed in 262 (35.8 %) patients. It was associated with pathologic characteristics such as more advanced T stage (p < 0.001), presence of lymph node metastasis (p = 0.006), high-grade tumor (p < 0.001), tumor necrosis (p = 0.01) and lymphovascular invasion (p = 0.02). Patients with HER2 overexpression had a 1.66-fold increased risk of experiencing disease recurrence (95 % CI 1.24-2.24, p = 0.001), 1.55-fold increased risk of death (95 % CI 1.21-1.99, p = 0.001) and 1.81-fold increased risk of cancer-specific death (95 % CI 1.33-2.48, p < 0.001). On multivariable analysis that adjusted for the effects of standard clinicopathologic variables, HER2 overexpression remained associated with disease recurrence (p = 0.04), overall (p = 0.02) and cancer-specific mortality (p = 0.02). CONCLUSIONS: Approximately, one-third of UTUC patients overexpressed HER2. HER2 overexpression was associated with features of clinically and biologically aggressive disease as well as prognosis. HER2 may represent a good marker for therapeutic risk stratification and potentially a target for therapy in some UTUC tumors.

Lymphocyte-to-monocyte ratio and neutrophil-to-lymphocyte ratio as biomarkers for predicting lymph node metastasis and survival in patients treated with radical cystectomy.

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.

Intensified antineoplastic effect by combining an HDAC-inhibitor, an mTOR-inhibitor and low dosed interferon alpha in prostate cancer cells.

A significant proportion of men diagnosed with prostate cancer (PCa) eventually develop metastatic disease, which progresses to castration resistance, despite initial response to androgen deprivation. As anticancer therapy has become increasingly effective, acquired drug resistance has emerged, limiting efficacy. Combination treatment, utilizing different drug classes, exemplifies a possible strategy to foil resistance development. The effects of the triple application of the histone deacetylase (HDAC) inhibitor valproic acid (VPA), the mammalian target of rapamycin inhibitor everolimus and low dosed interferon alpha (IFNα) on PCa cell growth and dissemination capacity were investigated. For that purpose, the human PCa cell lines, PC-3, DU-145 and LNCaP were treated with the combined regimen or separate single agents. Cell growth was investigated by the MTT dye reduction assay. Flow cytometry served to analyse cell cycle progression. Adhesion to vascular endothelium or immobilized collagen, fibronectin and laminin was quantified. Migration and invasion characteristics were determined by the modified Boyden chamber assay. Integrin α and ß subtypes were investigated by flow cytometry, western blotting and RT-PCR. Integrin related signalling, Epidermal Growth Factor Receptor (EGFr), Akt, p70S6kinase and extracellular signal-regulated kinases (ERK)1/2 activation were also assessed. The triple application of VPA, everolimus and low dosed IFNα blocked tumour cell growth and dissemination significantly better than any agent alone. Antitumour effects were associated with pronounced alteration in the cell cycle machinery, intracellular signalling and integrin expression profile. Combining VPA, everolimus and low dosed IFNα might be a promising option to counteract resistance development and improve outcome in PCa patients.

CCL2 promotes integrin-mediated adhesion of prostate cancer cells in vitro.

PURPOSE: Chemokines undergo alterations during neoplasia. However, knowledge about their functional significance in prostate cancer (PCa) progression is still sparse. Since chemokine (C-C motif) ligand 2 (CCL2) is significantly up-regulated in patients with PCa, aim of the current study was to assess whether CCL2 contributes to invasive behavior of prostate cancer cells in vitro. METHODS: The human PCa cell line PC3 was stimulated with CCL2. Cell growth was investigated by MTT dye reduction assay. Cell adhesion was analyzed by measuring attachment to a human endothelial cell (HUVEC) monolayer and immobilized collagen. Cell migration was assessed by a chemotactic assay. Integrin expression on the cell surface was evaluated by Western blot. Blocking studies were performed with anti-integrin α3, anti-integrin α6 and anti-integrin ß4 monoclonal antibodies. RESULTS: PC3 cell growth 72 h after CCL2 exposure was significantly increased, compared to controls. Activation of tumor cells by CCL2 significantly enhanced tumor cell adhesion to HUVEC and immobilized collagen. CCL2, added for 4 or 24 h, elevated α6 and ß4 (4 > 24 h) integrin expression. α3 was enhanced after 4 h, but reduced after 24 h. Blocking either α3, α6 or ß4 led to significant suppression of tumor cell binding to immobilized collagen. CONCLUSIONS: CCL2 stimulates PCa cell adhesion and induces alterations in α3-, α6- and ß4-integrin expression on the cell surface. Blocking these integrins leads to a significant reduction in cell adhesion.

DHH is an independent prognosticator of oncologic outcome of clear cell renal cell carcinoma.

PURPOSE: Aberrant HH signaling has proved important in the pathogenesis of several solid cancers. Limited in vitro analyses suggested an oncogenic role for HH in renal cell carcinoma. In this explorative study we sought to validate aberrant HH expression in patients with renal cell carcinoma. MATERIALS AND METHODS: A tissue microarray was constructed from 140 radical nephrectomy specimens of patients with clear cell renal cell carcinoma. We performed immunohistochemistry for Ki67 and HH pathway biomarkers, including PTCH1, Smo, SHH, IHH, DHH, Gli1, Gli2 and Gli3. Staining intensity was measured by automated image processing and related to tumor stage and grade. The impact of biomarker expression on cancer specific survival was determined by univariate and multivariate Cox regression analysis. RESULTS: Gli3, PTCH1, DHH and SHH demonstrated markedly higher expression in high than in low grade tumors. Tumor stage was not associated with marker expression. On univariate analysis DHH expression, and tumor grade and stage were associated with cancer specific survival. Multivariate analysis revealed that DHH, grade and stage were independent predictors of cancer specific survival. CONCLUSIONS: To our knowledge we report for the first time that a biomarker of the HH pathway is associated with adverse pathological features and poor disease outcomes in patients with clear cell renal cell carcinoma. DHH may serve as an independent predictor of cancer specific survival in clear cell renal cell carcinoma cases. This supports further evaluation of HH signaling to validate the pathway as a target for novel therapy.

The feasibility of ureteral tissue engineering using autologous veins: an orthotopic animal model with long term results.

BACKGROUND: In an earlier study we demonstrated the feasibility to create tissue engineered venous scaffolds in vitro and in vivo. In this study we investigated the use of tissue engineered constructs for ureteral replacement in a long term orthotopic minipig model. In many different projects well functional ureretal tissue was established using tissue engineering in animals with short-time follow up (12 weeks). Therefore urothelial cells were harvested from the bladder, cultured, expanded in vitro, labelled with fluorescence and seeded onto the autologous veins, which were harvested from animals during a second surgery. Three days after cell seeding the right ureter was replaced with the cell-seeded matrices in six animals, while further 6 animals received an unseeded vein for ureteral replacement. The animals were sacrificed 12, 24, and 48 weeks after implantation. Gross examination, intravenous pyelogram (IVP), H&E staining, Trichrome Masson's Staining, and immunohistochemistry with pancytokeratin AE1/AE3, smooth muscle alpha actin, and von Willebrand factor were performed in retrieved specimens. RESULTS: The IVP and gross examination demonstrated that no animals with tissue engineered ureters and all animals of the control group presented with hydronephrosis after 12 weeks. In the 24-week group, one tissue engineered and one unseeded vein revealed hydronephrosis. After 48 weeks all tissue engineered animals and none of the control group showed hydronephrosis on the treated side. Histochemistry and immunohistochemistry revealed a multilayer of urothelial cells attached to the seeded venous grafts. CONCLUSIONS: Venous grafts may be a potential source for ureteral reconstruction. The results of so far published ureteral tissue engineering projects reveal data up to 12 weeks after implantation. Even if the animal numbers of this study are small, there is an increasing rate of hydronephrosis revealing failure of ureteral tissue engineering with autologous matrices in time points longer than 3 months after implantation. Further investigations have to prove adequate clinical outcome and appropriate functional long-term results.

Hiding in plain view: genetic profiling reveals decades old cross contamination of bladder cancer cell line KU7 with HeLa.

PURPOSE: KU7 is a popular urothelial carcinoma cell line that was isolated from the bladder of a patient at Keio University in 1980. It has subsequently been widely used in laboratories around the world. We describe how routine cell line authentication revealed that KU7 was cross contaminated almost 30 years ago with HeLa, a cervical carcinoma cell line. MATERIALS AND METHODS: Presumed KU7 clones dating from 1984 to 1999 were provided by M.D. Anderson Cancer Center, Vancouver Prostate Centre, Kyoto University, Tokyo Medical University and Keio University. HeLa was obtained from ATCC. Genomic DNA was isolated and short tandem repeat analysis was performed at the M.D. Anderson Cancer Center Characterized Cell Line Core Facility, Johns Hopkins University Fragment Analysis Facility and RIKEN BioResource Center, Ibaraki, Japan. Comparative genomic hybridization was performed on a platform (Agilent Technologies, Santa Clara, California) at Vancouver Prostate Centre. RESULTS: The short tandem repeat profile of all KU7 clones was an exact match with that of HeLa. Comparative genomic hybridization of all samples revealed an abundance of shared chromosomal aberrations. Slight differences in some genomic areas were explained by genomic drift in different KU7 clones separated by many years. CONCLUSIONS: Our analysis identified that cross contamination of KU7 with HeLa occurred before 1984 at the source institution. All KU7 clones in the urological literature should be considered HeLa and experimental results should be viewed in this light. Our results emphasize the need to authenticate cell lines in oncological research.

Sarcopenia Predicts Disease Progression in Patients with T1 High-grade Non-muscle-invasive Bladder Cancer Treated with Adjuvant Intravesical Bacillus Calmette-Guérin: Implications for Decision-making?

Background: Skeletal muscle loss (sarcopenia) has been linked to cancer cachexia and can predict survival in several tumors, including advanced genitourinary malignancies. Objective: To investigate the predictive and prognostic role of sarcopenia in patients with T1 high grade (HG) non-muscle invasive bladder cancer (NMIBC) treated with adjuvant intravesical Bacillus Calmette-Guerin (BCG). Design setting and participants: Oncological outcomes were evaluated for 185 patients with T1 HG NMIBC treated with BCG at two European referral centers. Sarcopenia, identified from computed tomography scans performed within 2 mo after surgery, was defined as a skeletal muscle index of <39 cm2/m2 for women and <55 cm2/m2 for men. Outcome measurements and statistical analysis: The main endpoint was the association between sarcopenia and disease recurrence and progression. Kaplan-Meier curves and multivariable Cox models were built, and the clinical value of any association was assessed using Harrell's C index and decision curve analysis (DCA). Results and limitations: Sarcopenia was present in 130 patients (70%). On multivariable Cox regression analyses that accounted for the effect of standard clinicopathological prognosticators, sarcopenia was independently associated with disease progression (hazard ratio 3.41; p = 0.02). Addition of sarcopenia to a standard model for prediction of disease progression improved the discrimination of the model from 62% to 70%. DCA revealed superior net benefits for the proposed model in comparison to the strategies of treating all or no patients with radical cystectomy, and in comparison to the existing predictive model. Limitations are inherent to the retrospective design. Conclusions: We demonstrated the prognostic role of sarcopenia in T1 HG NMIBC. Pending external validation, this tool could be easily incorporated into existing nomograms for prediction of disease progression to improve clinical decision-making and patient counseling. Patient summary: We looked at the role of loss of skeletal muscle (sarcopenia) as a factor in predicting prognosis for stage T1 high-grade non-muscle-invasive bladder cancer. We found that sarcopenia is a ready-to-use, cost-free marker that could be used to guide treatment and follow-up in this disease, although the results need to be confirmed in other studies.

[Locally advanced or oligometastatic bladder cancer-role of local treatment of the primary tumor and metastases]. / Lokal fortgeschrittene oder oligometastasierte Blasenkarzinome ­ Stellenwert der Lokaltherapie von Primärtumor und Metastasen.

BACKGROUND: 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. OBJECTIVES: This review focuses on the influence of definitive treatment of the primary tumor in patients with oligometastatic urothelial bladder cancer. MATERIALS AND METHODS: 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. CONCLUSION: 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.