[New therapeutic approaches for non-muscle invasive bladder cancer-is organ preservation also possible after BCG (Bacillus Calmette Guérin)?] / Neue Therapieansätze beim nicht-muskelinvasiven Urothelkarzinom der Harnblase ­ Ist der Organerhalt auch nach BCG (Bacillus Calmette-Guérin) möglich?

Bacillus Calmette-Guérin (BCG) therapy is the standard of care in the treatment of high-risk non-muscle invasive bladder cancer (NMIBC). In the absence of a response to BCG and persistent high-grade disease, cystectomy is recommended depending on the clinical risk. A variety of targeted therapy approaches, which aim at immune- and gene-based molecular targets, such as PD-(L)1 and FGFR, are currently being investigated in randomized studies for BCG-unresponsive NMIBC. Furthermore, novel forms of application for instillation therapy, such as the TAR device, in combination with gemcitabine or erdafitinib are being investigated in clinical trials in order to extend the duration of action of the active substance on the urothelium. Thus, there are now many developments that could make bladder-preserving therapy with comparable survival data possible as an alternative to BCG or in the event of BCG failure. In the future, it will be necessary to clarify how BCG response can be predicted by using molecular markers and how to define risk groups that should primarily be given an alternative therapy to BCG.

Real-world performance of Uromonitor® in urothelial bladder cancer detection: a multicentric trial.

OBJECTIVES: To compare Uromonitor® (U-Monitor Lda, Porto, Portugal), a multitarget DNA assay that detects mutated proto-oncogenes (telomerase reverse transcriptase [TERT], fibroblast growth factor receptor 3 [FGFR-3], Kirsten rat sarcoma viral oncogene homologue [KRAS]), with urine cytology in the urine-based diagnosis of urothelial carcinoma of the bladder (UCB) within a multicentre real-world setting. PATIENTS AND METHODS: This multicentre, prospective, double-blind study was conducted across four German urological centres from 2019 to 2024. We evaluated the diagnostic performance of Uromonitor compared to urine cytology in a cohort of patients with UCB and in healthy controls within a real-world setting. Sensitivity, specificity, positive-predictive value (PPV), negative-predictive value (NPV), and accuracy of the tests were measured, in addition to multivariate analyses to assess the ability of individual proto-oncogene mutations in detecting UCB. The biometric sample size was designed to achieve a 10% difference in sensitivity. RESULTS: Patients with UCB comprised 63.7% (339/532) of the study group. Uromonitor showed a sensitivity, specificity, PPV, NPV, accuracy, and an area-under-the-curve of 49.3%, 93.3%, 92.8%, 51.1%, 65.2%, and 0.713%, respectively. These metrics did not demonstrate statistical superiority over urine cytology in terms of sensitivity (44.6%; P = 0.316). Moreover, the comparison of additional test parameters, as well as the comparison within various sensitivity analyses, yielded no significant disparity between the two urinary tests. Multivariate logistic regression underscored the significant predictive value of a positive Uromonitor for detecting UCB (odds ratio [OR] 9.03; P < 0.001). Furthermore, mutations in TERT and FGFR-3 were independently associated with high odds of UCB detection (OR 13.30 and 7.04, respectively), while KRAS mutations did not exhibit predictive capability. CONCLUSION: Despite its innovative approach, Uromonitor fell short of confirming the superior results anticipated from previous studies in this real-world setting. The search for an optimal urine-based biomarker for detecting and monitoring UCB remains ongoing. Results from this study highlight the complexity of developing non-invasive diagnostic tools and emphasise the importance of continued research efforts to refine these technologies.

Prognostic Impact and Spatial Interplay of Immune Cells in Urothelial Cancer.

BACKGROUND AND OBJECTIVE: Quantity and the spatial relationship of specific immune cell types can provide prognostic information in bladder cancer. The objective of the study was to characterize the spatial interplay and prognostic role of different immune cell subpopulations in bladder cancer. METHODS: A total of 2463 urothelial bladder carcinomas were immunostained with 21 antibodies using BLEACH&STAIN multiplex fluorescence immunohistochemistry in a tissue microarray format and analyzed using a framework of neuronal networks for an image analysis. Spatial immune parameters were compared with histopathological parameters and overall survival data. KEY FINDINGS AND LIMITATIONS: The identification of > 300 different immune cell subpopulations and the characterization of their spatial relationship resulted in numerous spatial interaction patterns. Thirty-nine immune parameters showed prognostic significance in univariate analyses, of which 16 were independent from pT, pN, and histological grade in muscle-invasive bladder cancer. Among all these parameters, the strongest association with prolonged overall survival was identified for intraepithelial CD8+ cytotoxic T cells (time-dependent area under receiver operating characteristic curve [AUC]: 0.70), while stromal CD8+ T cells were less relevant (AUC: 0.65). A favorable prognosis of inflamed cancers with high levels of "exhaustion markers" suggests that TIM3, PD-L1, PD-1, and CTLA-4 on immune cells do not hinder antitumoral immune response in tumors rich of tumor infiltrating immune cells. CONCLUSIONS AND CLINICAL IMPLICATIONS: The density of intraepithelial CD8+ T cells was the strongest prognostic feature in muscle-invasive bladder cancer. Given that tumor cell killing by CD8+ cytotoxic T lymphocytes through direct cell-to-cell-contacts represents the "terminal end route" of antitumor immunity, the quantity of "tumor cell adjacent CD8+ T cells" may constitute a surrogate for the efficiency of cancer recognition by the immune system that can be measured straightaway in routine pathology as the CD8 labeling index. PATIENT SUMMARY: Quantification of intraepithelial CD8+ T cells, the strongest prognosticfeature identified in muscle-invasive bladder cancer, can easily be assessed by brightfield immunohistochemistry and is therefore "ready to use" for routine pathology.

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.

BTA stat®, NMP22® BladderChek®, UBC® Rapid Test, and CancerCheck® UBC® rapid VISUAL as urinary marker for bladder cancer: Final results of a German multicenter study.

INTRODUCTION AND OBJECTIVE: BTA stat®, NMP22® BladderChek®, UBC® Rapid Test, and CancerCheck® UBC® rapid VISUAL are urinary-based rapid tests. This multicenter study is the first study comparing all available rapid tests on a large cohort of bladder cancer patients and healthy controls in one setting. METHODS: In total 732 urine samples (second morning urine) in a real-world assessment have been analyzed. We evaluated clinical samples from 464 patients with histologically confirmed urothelial tumors of the urinary bladder (17 solitary CIS, 189 low-grade, 187 high-grade nonmuscle invasive, 71 high-grade muscle invasive), 77 patients with No Evidence of Disease (NED), and from 191 healthy controls. Urine samples were analyzed by the BTA stat®, NMP22® BladderChek®, UBC® Rapid Test point-of-care (POC) system using the concile Omega 100 POC reader, and CancerCheck® UBC® rapid VISUAL. Sensitivities and specificities were calculated by contingency analyses. RESULTS: All investigated urinary markers detected more pathological concentrations in urine of bladder cancer patients compared to tumor-free patients. The calculated diagnostic sensitivities for BTA stat®, NMP22® BladderChek®, UBC® Rapid Test, CancerCheck® UBC® rapid VISUAL, and cytology were 62.4%, 13.4%, 58.2%, 28.6%, 36.2% for low-grade, 83.4%, 49.5%, 84.5%, 63.1%, 71.2% for high-grade nonmuscle invasive, and 95.8%, 35.2%, 76.1%, 50.7%, 67.7% for high-grade muscle-invasive bladder cancer. The specificity was 67.9%, 95.5%, 79.4%, 94.4%, and 83.7%, respectively. The area under the curve (AUC) after receiver operating characteristics (ROC) analysis for high-grade non-muscle-invasive tumors was 0.757, 0.725, 0.819, 0.787, and 0.774, respectively. CONCLUSIONS: The analysis of more than 700 urine samples offers an objective view on urine-based rapid diagnostics. Elevated pathological concentrations of markers in urine of bladder cancer patients were detected in all investigated tests. The highest sensitivities for high-grade non-muscle-invasive tumors were calculated for BTA stat® and UBC® Rapid Test, whereas NMP22® BladderChek®, and cytology showed the highest specificities. BTA stat® and UBC® Rapid Test have the potential to be used as a clinical valuable urinary protein biomarker for the detection of high-grade non-muscle-invasive bladder cancer patients and could be included in the management of these tumors.

Luminophore Chemistry for Detection of Urinary Bladder Cancer - Comparison to Cytology and Urinary Rapid Tests (BTA stat®, NMP22® BladderChek® and UBC® Rapid Test).

BACKGROUND/AIM: New luminometric chelates were developed for the detection of urinary bladder cancer and compared to cytology and urinary rapid tests BTA stat®, NMP22® BladderChek® and UBC® Rapid Test. MATERIALS AND METHODS: This single-center study analyzed urine from two different cohorts: Firstly, a retrospective pilot cohort (n=27) and secondly a prospective validation cohort (n=60) including patients with bladder cancer and healthy controls. The samples were studied with nine different terbium and europium chelates to detect cancer cases. After identification of an efficient luminophore in the first cohort, the second validation cohort was run with the selected chelates to re-evaluate the results and compare them with urinary rapid tests and cytology. RESULTS: The compared methods showed area under the curve (AUC) values ranging from 0.567 to 0.767. Tb3+-chelate-based assay detected high-grade cancer cases (p=0.035) with an AUC of 0.663. The Eu-probe signal level was higher in cancer cases of any grade than in healthy controls (p=0.001) with an AUC of 0.759. The Eu-probe had a sensitivity of 46.7% and a specificity of 100% in cancer detection. CONCLUSION: Evaluation of terbium and europium chelates for the detection of urinary bladder cancer showed highest specificity among all methods and improved overall performance (characterized by AUC) compared to commercial urine-based rapid tests and cytology. The Eu-probe has the potential to be clinically valuable in urine-based detection of bladder cancer, especially for high-grade cancer.

Prediction of Response to Cisplatin-Based Neoadjuvant Chemotherapy of Muscle-Invasive Bladder Cancer Patients by Molecular Subtyping including KRT and FGFR Target Gene Assessment.

Patients with muscle-invasive urothelial carcinoma achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NAC) have improved prognosis. Molecular subtypes of bladder cancer differ markedly regarding sensitivity to cisplatin-based chemotherapy and harbor FGFR treatment targets to various content. The objective of the present study was to evaluate whether preoperative assessment of molecular subtype as well as FGFR target gene expression is predictive for therapeutic outcome­rate of ypT0 status­to justify subsequent prospective validation within the "BladderBRIDGister". Formalin-fixed paraffin-embedded (FFPE) tissue specimens from transurethral bladder tumor resections (TUR) prior to neoadjuvant chemotherapy and corresponding radical cystectomy samples after chemotherapy of 36 patients were retrospectively collected. RNA from FFPE tissues were extracted by commercial kits, Relative gene expression of subtyping markers (e.g., KRT5, KRT20) and target genes (FGFR1, FGFR3) was analyzed by standardized RT-qPCR systems (STRATIFYER Molecular Pathology GmbH, Cologne). Spearman correlation, Kruskal−Wallis, Mann−Whitney and sensitivity/specificity tests were performed by JMP 9.0.0 (SAS software). The neoadjuvant cohort consisted of 36 patients (median age: 69, male 83% vs. female 17%) with 92% of patients being node-negative during radical cystectomy after 1 to 4 cycles of NAC. When comparing pretreatment with post-treatment samples, the median expression of KRT20 dropped most significantly from DCT 37.38 to 30.65, which compares with a 128-fold decrease. The reduction in gene expression was modest for other luminal marker genes (GATA3 6.8-fold, ERBB2 6.3-fold). In contrast, FGFR1 mRNA expression increased from 33.28 to 35.88 (~6.8-fold increase). Spearman correlation revealed positive association of pretreatment KRT20 mRNA levels with achieving pCR (r = 0.3072: p = 0.0684), whereas pretreatment FGFR1 mRNA was associated with resistance to chemotherapy (r = −0.6418: p < 0.0001). Hierarchical clustering identified luminal tumors of high KRT20 mRNA expression being associated with high pCR rate (10/16; 63%), while the double-negative subgroup with high FGFR1 expression did not respond with pCR (0/9; 0%). Molecular subtyping distinguishes patients with high probability of response from tumors as resistant to neoadjuvant chemotherapy. Targeting FGFR1 in less-differentiated bladder cancer subgroups may sensitize tumors for adopted treatments or subsequent chemotherapy.

Molecular Diagnostic and Prognostication Assays for the Subtyping of Urinary Bladder Cancer Are on the Way to Illuminating Our Vision.

After the successful publication of three Special Issues devoted to highlighting novel scientific research results in the field of bladder cancer and their clinical implications, we are now directing our efforts towards a fourth edition which will aim at compiling innovative research strategies that will ultimately guide and support clinicians in the decision-making process for targeted bladder cancer therapies [...].

Nomograms including the UBC® Rapid test to detect primary bladder cancer based on a multicentre dataset.

OBJECTIVES: To evaluate the clinical utility of the urinary bladder cancer antigen test UBC® Rapid for the diagnosis of bladder cancer (BC) and to develop and validate nomograms to identify patients at high risk of primary BC. PATIENTS AND METHODS: Data from 1787 patients from 13 participating centres, who were tested between 2012 and 2020, including 763 patients with BC, were analysed. Urine samples were analysed with the UBC® Rapid test. The nomograms were developed using data from 320 patients and externally validated using data from 274 patients. The diagnostic accuracy of the UBC® Rapid test was evaluated using receiver-operating characteristic curve analysis. Brier scores and calibration curves were chosen for the validation. Biopsy-proven BC was predicted using multivariate logistic regression. RESULTS: The sensitivity, specificity, and area under the curve for the UBC® Rapid test were 46.4%, 75.5% and 0.61 (95% confidence interval [CI] 0.58-0.64) for low-grade (LG) BC, and 70.5%, 75.5% and 0.73 (95% CI 0.70-0.76) for high-grade (HG) BC, respectively. Age, UBC® Rapid test results, smoking status and haematuria were identified as independent predictors of primary BC. After external validation, nomograms based on these predictors resulted in areas under the curve of 0.79 (95% CI 0.72-0.87) and 0.95 (95% CI: 0.92-0.98) for predicting LG-BC and HG-BC, respectively, showing excellent calibration associated with a higher net benefit than the UBC® Rapid test alone for low and medium risk levels in decision curve analysis. The R Shiny app allows the results to be explored interactively and can be accessed at www.blucab-index.net. CONCLUSION: The UBC® Rapid test alone has limited clinical utility for predicting the presence of BC. However, its combined use with BC risk factors including age, smoking status and haematuria provides a fast, highly accurate and non-invasive tool for screening patients for primary LG-BC and especially primary HG-BC.

Evaluation of Therapeutic Targets in Histological Subtypes of Bladder Cancer.

Histologically, bladder cancer is a heterogeneous group comprising urothelial carcinoma (UC), squamous cell carcinoma, adenocarcinomas (ACs), urachal carcinomas (UrCs), and small cell neuroendocrine carcinomas (SCCs). However, all bladder cancers have been treated so far uniformly, and targeted therapy options are still limited. Thus, we aimed to determine the protein expression/molecular status of commonly used cancer targets (programmed cell death 1 ligand 1 (PD-L1), mismatch repair (MMR), androgen and estrogen receptors (AR/ER), Nectin-4, tumor-associated calcium signal transducer 2 (Tacstd2, Trop-2), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and fibroblast growth factor receptor 3 (FGFR3)) to give first insights into whether patients with SCC, AC/UrCs, and squamous-differentiated carcinomas (Sq-BLCA) of the bladder could be eligible for targeted therapies. In addition, for MMR-deficient tumors, microsatellite instability was analyzed. We completed our own data with molecular data from The Cancer Genome Atlas (TCGA). We present ratios for each drug and cumulative ratios for multiple therapeutic options for each nonurothelial subtype. For example, 58.9% of SCC patients, 33.5% of AC/UrCs patients, and 79.3% of Sq-BLCA patients would be eligible for at least one of the analyzed targets. In conclusion, our findings hold promise for targeted therapeutic approaches in selected patients in the future, as various drugs could be applied according to the biomarker status.

Identifying the Molecular Mechanisms Contributing to Progression, Metastasis, and Death in Low-grade Non-muscle-invasive Bladder Cancer: A Case Report.

Transitional cell carcinoma of the bladder is a common malignancy with an estimated 549 393 new cases occurring in 2018 alone. Both non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) show high recurrence and progression rates, and therefore impose a great burden on patients and health care systems. Current risk stratification and therapy strategies are predominantly based on clinical and histopathological findings for tumor stage and grade. The chemoresistance and metastasis of low-grade tumors suggest an incomplete understanding of disease mechanisms, despite numerous studies on differentiating molecular subtypes of bladder cancer to identify tumor drivers and potential therapeutic targets. We present a highly unusual course for a low-grade bladder tumor leading to metastasis and death, for which we used postmortem histopathological and molecular analyses to evaluate targetable alterations in key signaling pathways driving the underlying tumor biology.

Comparison of initial and second opinion reads of multiparametric magnetic resonance imaging of the prostate for transperineal template-guided biopsies with MRI-Ultrasound fusion.

PURPOSE: To investigate the value of second-opinion evaluation of multiparametric prostate magnetic resonance imaging (MRI) by subspecialised uroradiologists for the detection of significant cancer in transperineal fusion prostate biopsy. METHODS: The evaluated data included age, PSA (ng/ml), PSA density, Gleason score, digital rectal examination (DRE), prostate volume of 149 patients. Twenty-seven patients (18%) had no previous prostate biopsy, 114 patients (77%) had a previous negative biopsy, and 8 patients (5%) were on active surveillance. Using PI-RADS v2 scores for mpMRI a second report was performed by a specialist uroradiologist. In all cases a subsequent transperineal biopsy was performed with at least 2 cores per target and additional background systemic cores. Initial and second-opinion radiology reports were evaluated for detection of any cancer and Gleason score (GS) 7-10 cancer, including positive predictive value and negative (NPV) and compared by Fisher's exact test. RESULTS: At transperineal biopsy, 51 % (76/149) of patients had a GS 6-10 prostate cancer (PCa), 27 % (40/149) of patients had a GS 3 + 3 PCa and 12 % (18/149) a GS 3 + 4 and 12 % (18/149) had a GS ≥4 + 3 PCa. Agreement between initial and second-opinion reads was observed in 57.7% (86/149; kappa value = 0.32). The detection of clinically significant cancers with second-opinion reads was significantly higher (0.61; 17/28) compared to initial reads (0.35; 17/49); P = 0.034. CONCLUSIONS: Second reading of prostate mpMRIs by subspecialised uroradiologists significantly improved the positive predictive value for detection of clinically significant prostate cancer and showed a trend towards improved NPV for MRI-negative cases where biopsy could be safely avoided. Urologists should be aware that the experience of the reporter will affect the report when making decisions if and how to obtain biopsies. Reporter experience may help to reduce overcalling and avoid over-targeting of lesions.

Evaluating the Utility of Combined Bladder Cancer Biomarkers, the Molecular Prognostication of Tumor Subtypes, or What Else Is Needed to Illuminate Our Vision?

In the last few years, we published two special issues devoted to highlighting important scientific results in the field of bladder cancer research and clinical implications [...].

SWI/SNF Alterations in Squamous Bladder Cancers.

Dysfunction of the SWI/SNF complex has been observed in various cancers including urothelial carcinomas. However, the clinical impact of the SWI/SNF complex in squamous-differentiated bladder cancers (sq-BLCA) remains unclear. Therefore, we aimed to analyze potential expression loss and genetic alterations of (putative) key components of the SWI/SNF complex considering the co-occurrence of genetic driver mutations and PD-L1 expression as indicators for therapeutic implications. Assessment of ARID1A, SMARCA2, SMARCA4, SMARCB1/INI1, SMARCC1, SMARCC2 and PBRM1 mutations in a TCGA data set of sq-BLCA (n = 45) revealed that ARID1A was the most frequently altered SWI/SNF gene (15%) while being associated with protein downregulation. Genetic alterations and loss of ARID1A were confirmed by Targeted Next Generation Sequencing (NGS) (3/6) and immunohistochemistry (6/116). Correlation with further mutational data and PD-L1 expression revealed co-occurrence of ARID1A loss and TP53 mutations, while positive correlations with other driver mutations such as PIK3CA were not observed. Finally, a rare number of sq-BLCA samples were characterized by both ARID1A protein loss and strong PD-L1 expression suggesting a putative benefit upon immune checkpoint inhibitor therapy. Hence, for the first time, our data revealed expression loss of SWI/SNF subunits in sq-BLCA, highlighting ARID1A as a putative target of a small subgroup of patients eligible for novel therapeutic strategies.

Prognostic Role of Survivin and Macrophage Infiltration Quantified on Protein and mRNA Level in Molecular Subtypes Determined by RT-qPCR of KRT5, KRT20, and ERBB2 in Muscle-Invasive Bladder Cancer Treated by Adjuvant Chemotherapy.

OBJECTIVES: Bladder cancer is a heterogeneous malignancy. Therefore, it is difficult to find single predictive markers. Moreover, most studies focus on either the immunohistochemical or molecular assessment of tumor tissues by next-generation sequencing (NGS) or PCR, while a combination of immunohistochemistry (IHC) and PCR for tumor marker assessment might have the strongest impact to predict outcome and select optimal therapies in real-world application. We investigated the role of proliferation survivin/BIRC5 and macrophage infiltration (CD68, MAC387, CLEVER-1) on the basis of molecular subtypes of bladder cancer (KRT5, KRT20, ERBB2) to predict outcomes of adjuvant treated muscle-invasive bladder cancer patients with regard to progression-free survival (PFS) and disease-specific survival (DSS). MATERIALS AND METHODS: We used tissue microarrays (TMA) from n = 50 patients (38 males, 12 female) with muscle-invasive bladder cancer. All patients had been treated with radical cystectomy followed by adjuvant triple chemotherapy. Median follow-up time was 60.5 months. CD68, CLEVER-1, MAC387, and survivin protein were detected by immunostaining and subsequent visual inspection. BIRC5, KRT5, KRT20, ERBB2, and CD68 mRNAs were detected by standardized RT-qPCR after tissue dot RNA extraction using a novel stamp technology. All these markers were evaluated in three different centers of excellence. RESULTS: Nuclear staining rather than cytoplasmic staining of survivin predicted DSS as a single marker with high levels of survivin being associated with better PFS and DSS upon adjuvant chemotherapy (p = 0.0138 and p = 0.001, respectively). These results were validated by the quantitation of BIRC5 mRNA by PCR (p = 0.0004 and p = 0.0508, respectively). Interestingly, nuclear staining of survivin protein was positively associated with BIRC5 mRNA, while cytoplasmic staining was inversely related, indicating that the translocation of survivin protein into the nucleus occurred at a discrete, higher level of its mRNA. Combining survivin/BIRC5 levels based on molecular subtype being assessed by KRT20 expression improved the predictive value, with tumors having low survivin/BIRC5 and KRT20 mRNA levels having the best survival (75% vs. 20% vs. 10% 5-year DSS, p = 0.0005), and these values were independent of grading, node status, and tumor stage in multivariate analysis (p = 0.0167). Macrophage infiltration dominated in basal tumors and was inversely related with the luminal subtype marker gene expression. The presence of macrophages in survivin-positive or ERBB2-positive tumors was associated with worse DSS. CONCLUSIONS: For muscle-invasive bladder cancer patients, the proliferative activity as determined by the nuclear staining of survivin or RT-qPCR on the basis of molecular subtype characteristics outperforms single marker detections and single technology approaches. Infiltration by macrophages detected by IHC or PCR is associated with worse outcome in defined subsets of tumors. The limitations of this study are the retrospective nature and the limited number of patients. However, the number of molecular markers has been restricted and based on predefined assumptions, which resulted in the dissection of muscle-invasive disease into tumor-biological axes of high prognostic relevance, which warrant further investigation and validation.

Health-related quality of life and rates of toxicity after high-dose-rate brachytherapy in combination with external beam radiation therapy for high-risk prostate cancer.

Purpose: High-dose-rate brachytherapy (HDR-BT) with external beam radiation therapy (EBRT) is a common treatment option for locally advanced prostate cancer. Quality of life is an important factor when discussing therapy options for high-risk prostate cancer. This study evaluated adverse effects and health-related quality of life (HRQOL). Materials and Methods: Ninety male patients (median age, 71 years; range, 50 to 79 years) with high-risk prostate cancer underwent HDR-BT after EBRT between December 2009 and January 2017 with a median follow-up of 43 months. A total of 57 patients (69.5%) answered the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life of Cancer Patients questionnaire (QLQ-C30; ver. 3.0), and 8 patients died during follow-up. In order to put the results of this study in context, we compared the results with reference data from the EORTC QLQ-C30 Scoring Manual. Correlations of prostate-specific antigen (PSA) values, International Prostate Symptom Score, and HRQOL measures were calculated. Results: The study participants reported better physical functioning and better global health compared with the reference data, but worse social, role, and cognitive functioning. We found negative statistically significant correlations between the last-measured PSA value and social functioning (p>0.01), cognitive functioning, pain, and constipation (all p<0.05). Toxicity rates were 10.0% for gastrointestinal and 12.2% for genitourinary adverse effects. All reported complications for toxicity were Grade I. Conclusions: The described therapy results in high biochemical control rates with minimal adverse effects. Compared with reference groups, the HRQOL of this study cohort was acceptable. PSA values during follow-up seem to be a possible indicator to influence HRQOL.

Illumination of a Vision 2020-Urinary Based Biomarkers for Bladder Cancer on the Way to Clinical Decisions-Dream or Nightmare?

Bladder cancer is one of the most frequent malignancies worldwide [...].