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Objectives: To report pre-, postoperative and oncological outcomes in patients treated with spot-specific sLND for patients with exclusive nodal recurrence after PCa primary treatment., Materials and Methods: With regard to salvage treatment failure (sTF), 46 consecutive patients, undergoing 52 sLND for nodal recurrence detected by PET/CT scan were stratified in 3 groups (group A: post-sLND PSA nadir < 0.01 ng/ml and in follow-up reaching a value > 0.2 ng/ml, group B: post-sLND PSA nadir > 0.01 ng/ml and in follow-up reaching a value equal to pre-sLND PSA; group C: additional salvage treatment administration). Surgical outcome of patients was analyzed by descriptive statistics (Student's t test for continuous variables, Chi-square and Fisher's test for categorial ones). Time to sTF of each group was analyzed and compared by Kaplan-Meier method and correlations regarding sTF and pre-sLND PSA, time from PCa primary treatment to PET/CT scan, time from PCa primary treatment to sLND and number of positive PET/CT scan spots were assessed., Results: Median PSA at PET/CT scan was 2.9 ng/ml (IQR 1.2-6.1). Open and laparoscopic sLND were performed in 40/52 (77%) and 12/52 (23%), respectively. Median number of removed lymph nodes was 6 (IQR 4-13). Histological report was positive for PCa in 39/52 sLND (75%). Median blood loss was 50 ml (IQR 0-50, range 0-600). Median length of hospital stay was 5 days (IQR 4-6). 4 and 7 patients had low-grade (I/II) and high-grade (≥ III) Clavien-Dindo complications, respectively. Readmission rates at 30 and 90 days were 5/52 (9.6%) and 1/52 (2%), respectively. sTF was observed in 2/7 (group A), 12/12 (group B) and 22/22 patients (group C). Median time to sTF in group B and C was 3.5 (IQR 1.7-13.2) and 4 months (IQR 2.0-10), respectively., Conclusion: Even spot-specific PET/CT sLND harbors a measurable (CD > III) morbidity in 1 out of 7 patients. Only patients with positive histological report and a PSA nadir < 0.01 ng/ml after sLND seem to experience a long-term benefit. Patients with a PSA nadir > 0.01 ng/ml have a delay of systemic treatment of up to 4 months. sLND remains an experimental approach and long-term oncological benefit needs an improved selection of patients.

Available treatment options and outcomes for patients suffering from urothelial bladder cancer, especially in the metastatic stage, have hardly improved over decades. However, the increasing use of high-throughput analyses and the concept of immune surveillance against tumours have recently changed our understanding of tumour biology in terms of tumour development and progression. Our knowledge of genetic mutations and molecular subtypes provides the possibility of tailor-made therapeutic approaches for patients suffering from bladder cancer. For example, changes in DNA repair signalling pathways are possible predictors of chemotherapy response, and targeted therapies using FGFR or PARP inhibitors are currently being tested in clinical trials. The extent to which molecular subtypes will find their way into clinical practice depends on the prospective evaluation of their prognostic and predictive value. The introduction of immune checkpoint inhibitors is probably the most significant expansion of available treatment options in bladder cancer. Despite their promising results, however, a lot of questions remain to be answered, as only 25 % of patients respond. Again, this highlights the need for predictive biomarkers. The large inter- and intratumoural heterogeneity represents a particular challenge for the clinical implementation of personalised treatment options in bladder cancer. All in all, some important steps towards personalised medicine in urothelial bladder cancer have been taken in the past few years, but, for the most part, their prospective evaluation is still pending., Competing Interests: C.M. Grunewald: keine Interessenkonflikte G. Niegisch: Referententätigkeit: Pfizer Pharma GmbH (seit 2016), Pierre Fabre Pharma GmbH (2016), Roche Pharma AG (seit 2016), medac GmbH (seit 2017), Advisory Boards/beratende Tätigkeit: Roche Parma AG (seit 2015), IMS Health AG (seit 2016), BMS AG (2016), (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Several ongoing phase 2 trials are evaluating new neoadjuvant therapy regimens in patients with muscle-invasive bladder cancer (MIBC). The 1-yr recurrence-free survival (RFS) after radical cystectomy (RC), with or without perioperative chemotherapy, can be used to model statistical assumptions and interpret outcomes from these studies., Objective: To provide a benchmark for predicting 1-yr RFS in patients with cT2-4N0 MIBC., Design, Setting, and Participants: We identified 950 patients with clinical stage T2-4N0 MIBC undergoing RC at 27 centers between 1990 and 2016. We assessed 1-yr RFS rates for patients managed with no perioperative chemotherapy, neoadjuvant chemotherapy (NAC), adjuvant chemotherapy (AC), or NAC followed by AC. Cox regression analyses tested for 1-yr postsurgical RFS predictors. A Cox-based nomogram was developed to estimate 1-yr RFS and its accuracy was assessed in terms of Harrell's c-index, a calibration plot, and decision curve analysis. We report 1-yr RFS rates across the nomogram tertiles., Results and Limitations: The 1-yr RFS rates were 67.9% (95% confidence interval [CI] 64-72) after no perioperative chemotherapy, 76.9% (95% CI 72-83%) after NAC, 77.8% (95% CI 71-85%) after AC, and 57% (95% CI 37-87) after NAC+AC. On multivariable analysis, positive surgical margins (p=0.002), pT stage (p<0.0001), and pN stage (p<.0001) were significantly associated with RFS, while NAC was not (p=0.6). The model including all these factors yielded a c-index of 0.76 (95% CI 0.72-0.79), good calibration, and a high net benefit. The 1-yr RFS rates across nomogram tertiles were 90.5% (95% CI 87-94%), 73.4% (95% CI 68-79%), and 51.1% (95% CI 45-58%), respectively. The results lack external validation., Conclusions: Benchmark 1-yr RFS estimates for phase 2 design of new neoadjuvant trials are proposed and can be used for statistical assumptions, pending external validation., Patient Summary: Our prognostic model predicting 1-yr survival free from recurrence of bladder cancer after radical cystectomy, with or without standard chemotherapy, could provide an improvement to the quality of phase 2 clinical trial designs and interpretation of their results., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Mutations, dysregulation, and dysbalance of epigenetic regulators are especially frequent in urothelial carcinoma (UC) compared to other malignancies. Accordingly, targeting epigenetic regulators may provide a window of opportunity particularly in anticancer therapy of UC. In general, these epigenetic regulators comprise DNA methyltransferases and DNA demethylases (for DNA methylation), histone methyltransferases, and histone demethylases (for histone methylation) as well as acetyl transferases and histone deacetylases (for histone and non-histone acetylation).As epigenetic regulators target a plethora of cellular functions and available inhibitors often inhibit enzymatic activity of more than one isoenzyme or may have further off-target effects, analysis of their functions in UC pathogenesis as well as of the antineoplastic capacity of according inhibitors should follow a multidimensional approach.Here, we present our standard approach for the analysis of the cellular and molecular functions of individual HDAC enzymes, their suitability as treatment targets and for the evaluation of isoenzyme-specific HDAC inhibitors regarding their antineoplastic efficacy. This approach may also serve as prototype for the preclinical evaluation of other epigenetic treatment approaches.

Perioperative chemotherapy is likely to improve survival in both the neoadjuvant and the adjuvant setting. Therefore, it is an integral part of the modern treatment of patients with muscle-invasive urothelial bladder cancer. All patients who are suitable for cisplatin-based chemotherapy should be involved in a corresponding concept.Cisplatin-based combinations are standard regimens in the perioperative and palliative systemic treatment of urothelial cancer. Carboplatin is only an inferior substitute for "unfit" patients in the palliative treatment situation. Vinflunine may be used as a second-line agent in case of recurrence after palliative first-line treatment or in patients presenting with rapid progression after perioperative treatment. Alternatively, taxane or taxane-based combinations can be used in these situations.New therapeutic options may include the use of immune checkpoint inhibitors, which have shown promising results in early studies. Two substances have already been approved by the FDA for the treatment of advanced/metastatic urothelial cancer following platin-based upfront treatment. Other future options may be "tailored" treatment concepts based on the molecular pathogenesis of the individual patient. However, extensive pre-clinical work is still required for this approach., Competing Interests: Interessenkonflikt: Forschungsunterstützung: 4SC AG (seit 2015)Vortragsstätigkeit: Pfizer Pharma GmbH (2016), Pierre Fabre Pharma GmbH (2016), Roche Pharma AG (2016)Beratertätigkeit: Roche Parma AG (seit 2015), IMS Health AG (seit 2016), Bristol-Myers Squibb GmbH & Co. KGaA (seit 2016), medac GmbH (2012 – 2014)Fortbildungsunterstützung: Pfizer Pharma GmbH (2015 & 2016), Roche Pharma AG (2016), Bristol-Myers Squibb GmbH & Co. KGaA (2017), (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Targeting of class I histone deacetylases (HDACs) exerts antineoplastic actions in various cancer types by modulation of transcription, upregulation of tumor suppressors, induction of cell cycle arrest, replication stress and promotion of apoptosis. Class I HDACs are often deregulated in urothelial cancer. 4SC-202, a novel oral benzamide type HDAC inhibitor (HDACi) specific for class I HDACs HDAC1, HDAC2 and HDAC3 and the histone demethylase LSD1, shows substantial anti-tumor activity in a broad range of cancer cell lines and xenograft tumor models., Aim: The aim of this study was to investigate the therapeutic potential of 4SC-202 in urothelial carcinoma (UC) cell lines., Methods: We determined dose response curves of 4SC-202 by MTT assay in seven UC cell lines with distinct HDAC1, HDAC2 and HDAC3 expression profiles. Cellular effects were further analyzed in VM-CUB1 and UM-UC-3 cells by colony forming assay, caspase-3/7 assay, flow cytometry, senescence assay, LDH release assay, and immunofluorescence staining. Response markers were followed by quantitative real-time PCR and western blotting. Treatment with the class I HDAC specific inhibitor SAHA (vorinostat) served as a general control., Results: 4SC-202 significantly reduced proliferation of all epithelial and mesenchymal UC cell lines (IC 50 0.15-0.51 μM), inhibited clonogenic growth and induced caspase activity. Flow cytometry revealed increased G2/M and subG1 fractions in VM-CUB1 and UM-UC-3 cells. Both effects were stronger than with SAHA treatment., Conclusion: Specific pharmacological inhibition of class I HDACs by 4SC-202 impairs UC cell viability, inducing cell cycle disturbances and cell death. Combined inhibition of HDAC1, HDAC2 and HDAC3 seems to be a promising treatment strategy for UC., Competing Interests: Compliance with Ethical Standards Authors’ Contributions GN, WAS, MJH, HK and MP conceived and designed the study. HK provided 4SC-202 inhibitor from 4SC AG. MP performed most experiments, MJH carried out additional experiments. MP, WAS and GN carried out data analysis. MP and GN prepared the initial manuscript. WAS, MJH and HK contributed to the manuscript. GN supervised the project with the support of WAS. All authors read and approved the final manuscript. Funding The work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG) to GN (Grant-No.: NI 1398/1-1). Conflicts of Interest WAS has received a grant for preclinical investigation of 4SC-201 from 4SC AG in the past. 4SC-202 was provided by 4SC AG to GN. 4SC AG paid fees for open access publication; further funding was not granted for this study. HK is an employee of 4SC AG. MP and MJH declare no further conflicts of interest.

Urothelial carcinoma is the most frequent type of bladder cancer. Improvements in diagnostics and therapy of this common tumor are urgently required and need to be based on a better understanding of its biology. Epigenetic aberrations are crucial to urothelial carcinoma development and progression. They affect DNA methylation, histone modifications, chromatin remodeling, long noncoding RNAs, and microRNAs. Compared to other cancers, DNA hypomethylation, especially at LINE-1 retrotransposons, and mutations in enzymes establishing or removing histone acetylation or methylation are particularly prominent. Accumulating evidence suggests that disturbances in DNA methylation, histone modifications and noncoding RNAs may contribute especially to altered differentiation and metastatic potential. With proper selection, histone-modifying enzymes may constitute good targets for therapy. For diagnostics, DNA methylation and miRNA biomarkers are well suited because of their relatively high stability. There are indeed excellent biomarker candidates for DNA-methylation-based diagnostics of urothelial carcinoma, whereas miRNAs are well investigated, but there are still many discrepancies between studies published to date.

Objectives: To assess the surgical and oncological outcome of robot-assisted radical cystectomy (RARC) compared with open radical cystectomy (ORC)., Patients and Methods: Clinical data of 64 patients undergoing RARC between August 2010 and August 2013 were prospectively documented and retrospectively compared with 79 patients undergoing ORC between August 2008 and August 2013 at a single academic institution. Perioperative results, surgical margins status, and nodal yield after RARC and ORC were compared using Mann-Whitney U test (continuous variables) and chi-square test (categorical variables). Additional age-stratified analysis was performed in elderly patients (≥75 y). To avoid inference errors by multiple testing, P-values were adjusted using Bonferroni׳s correction., Results: Baseline characteristics of both cohorts were balanced. RARC patients had significantly less blood loss (RARC: 300 [interquartile range {IQR}: 200-500]ml; perioperative transfusion rate: 0 [IQR: 0-2] red packed blood cells [RPBCs]; ORC: 800 [IQR: 500-1200]ml, P<0.01; transfusion rate: 3 [IQR: 2-4] RPBCs, P<0.01), and hospital stay of RARC patients was reduced by 20% (RARC: 13 [IQR: 9-17]d, ORC: 16 [IQR: 13-21]d, P< 0.01). A total of 55 patients who underwent RARC and 59 patients who underwent ORC were eligible for analysis of oncological surrogates "surgical margin status" and "lymph-node yield" as well as for survival data. No differences between patients undergoing RARC or ORC were observed. In elderly patients (≥75 y; RARC: 17 patients, ORC: 28 patients), decreased intraoperative blood loss (RARC: 300 [IQR: 100-475]ml; ORC: 800 [IQR: 400-1300]ml, P<0.01) and lower transfusion rate (RARC: 0 [IQR: 0-1] RPBCs; ORC: 4 [IQR: 2-5] RPBCs, P<0.01) were observed in the robotic group. Major limitations of this study are the retrospective study design and a potential selection bias., Conclusions: RARC provides significant advantages compared with ORC regarding blood loss and postoperative recovery, whereas surgical and oncological outcomes are not different., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: Carcinoma of the bladder is the fifth most common cancer whose incidence continues to rise. MTDH/AEG-1 is associated with the initiation and progression of many cancers including breast, hepatocellular, ovarian, and colorectal carcinomas. However, the expression and functional importance of MTDH/AEG-1 in bladder cancer remains unknown. The present study was aimed at exploring the functional role of MTDH/AEG-1 in selected bladder cancer cell lines., Methods and Materials: The relative expression of MTDH/AEG-1 was assessed by real-time quantitative reverse transcription-polymerase chain reaction in several human bladder cancer cell lines as well as cancerous and benign bladder tissues. Then, expression of MTDH/AEG-1 in RT112 and 647V bladder cancer cell lines was knocked down by an RNA interference strategy. Cell viability and apoptosis were determined after treatment with specific interfering RNA. Potential effects of MTDG/AEG-1 specific interfering RNA on the cell cycle were investigated by flow cytometry. We also performed anchorage-independent growth and wound-healing assays to study MTDH/AEG-1 function., Results: Down-regulation of MTDH/AEG-1 did not significantly affect the cell cycle distribution but rather reduced cell viability via apoptosis, as evidenced by increased annexin V staining and caspase 3/7 activities as well as mitochondrial potential disruption. Of note, serum starvation did not exacerbate the effects of MTDH/AEG-1 knockdown. Furthermore, MTDH/AEG-1 down-regulation significantly decreased anchorage-independent growth and migration of bladder carcinoma cells., Conclusion: Overexpression of MTDH/AEG-1 contributes to the neoplastic phenotype of bladder cancer cells by promoting survival, clonogenicity, and migration., (© 2013 Published by Elsevier Inc.)

Background: Urothelial carcinoma (UC) is characterized by multiple recurrent chromosomal changes on a background of increasing genomic instability. To define target genes of recurrent deletions and amplifications, we explored which gene alterations are common in UC, in two recently established cell lines, BC44 and BC61., Materials and Methods: Genes located in regions of gain or deletion in the cell lines were identified by array comparative genomic hybridization (aCGH). Six published microarray datasets were analyzed for genes differentially expressed between urothelial tumor vs. normal tissues. Gene expression and chromosomal changes were compared in BC61 cells., Results: The cell lines share homozygous deletions at 9p21 around CDKN2A and amplifications at 11q13.2 around CCND1. In both cell lines 11 genes were commonly lost and 115 gained. Across UC in general, 230 genes were expressed stronger and 349 weaker; a subset displaying corresponding genetic changes in the cell lines. The commonly affected subset contains well-investigated genes like E2F1 and CCNE1, but also several genes not yet sufficiently investigated in UC., Discussion: Our approach highlights genes involved in cell cycle regulation, apoptosis and signal transduction as commonly deregulated across UC. Nevertheless, many chromosomal regions undergoing recurrent changes harbor several commonly deregulated genes that may act jointly in UC development and progression., (Copyright© 2014, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.)