Robotic radical cystectomy - more precision needed?

PURPOSE OF REVIEW: Recently, several trials as well as registry-data analyses investigating the role of robot-assisted radical cystectomy with extra or intracorporal urinary diversion were completed and follow up matured. This review aims to comment on the current evidence-based findings and interpret the future role of the robotic approach as a part of the treatment of bladder cancer. RECENT FINDINGS: Numerous trials and registry-data analyses revealed no significant differences in progression-free and overall survival after open radical cystectomy or robot-assisted radical cystectomy irrespective of urinary diversion. Perioperative parameters, especially intraoperative blood loss, transfusions, thromboembolic events, wound infections and hospitalization were significantly increased in open radical cystectomy. Patients' convalescence, and especially early postsurgical quality of life, was improved by the robotic approach. The highly demanding surgery itself displayed by a flat learning curve required more than 130 surgeries per institution to reach a stable plateau of complications. The performance of high-quality radical cystectomy irrespective of the approach was significantly increased in high-volume centres. Local recurrence occurs in 11% after radical cystectomy. Current research focuses on intraoperatively usable detection methods and instruments to minimize the risk of residual tumour cells. SUMMARY: Taken together, the total intracorporal approach in radical cystectomy holds the potential to improve perioperative parameters and reduces hospitalization without impairing oncological performance of the procedure. To provide best results for the patient radical cystectomy and especially the technically challenging total intracorporal procedure will gain importance in bladder cancer treatment but should be limited to high-volume centres.

Differential Expression and Clinical Relevance of C-X-C Motif Chemokine Receptor 4 (CXCR4) in Renal Cell Carcinomas, Benign Renal Tumors, and Metastases.

C-X-C Motif Chemokine Receptor 4 (CXCR4) is part of the human chemokine system and involved in progression and metastasis in renal cell carcinoma (RCC). However, the role of CXCR4 protein expression in RCC remains controversial. In particular, data regarding the subcellular distribution of CXCR4 in RCC and RCC metastasis as well as CXCR4 expression in renal tumors of variant histology are limited. The aim of the present study was the evaluation of the differential CXCR4 expression in RCC primary tumor and metastatic tissue as well as in variant renal histologies. In addition, the prognostic capacity of CXCR4 expression in organ-confined clear cell RCC (ccRCC) was evaluated. Three independent renal tumor cohorts (primary ccRCC cohort n1 = 64; cohort of various histological entities n2 = 146; metastatic RCC tissue cohort n3 = 92) were evaluated using tissue microarrays (TMA). After immunohistochemical staining for CXCR4, nuclear and cytoplasmic expression patterns were evaluated. CXCR4 expression was correlated with validated pathologic prognosticators, clinical data, and overall and cancer-specific survival. Positive cytoplasmic staining was observed in 98% of the benign and 38.9% of the malignant samples. Nuclear staining was positive for 94.1% of the benign samples and 83% of the malignant samples. The median cytoplasmic expression score was found to be higher in benign tissue than in ccRCC (130.00 vs. 0.00); median nuclear expression score analysis indicated the opposite (56.0 vs. 71.0). Within malignant subtypes, the highest expression score was seen in papillary renal cell carcinomas (cytoplasmic: 117.50, nuclear: 41.50). Within benign renal tumors, high cytoplasmic and nuclear CXCR4 expression scores were seen for oncocytomas (cytoplasmic: 100.00, nuclear: 31.00). Expression scores in RCC metastasis ranked between benign renal tissue and ccRCC in cytoplasmic and nuclear expression. Cytoplasmic CXCR4 expression was identified as a prognostic factor for OS and CSS (p = 0.042; p = 0.019). Multivariate analysis including clinicopathological parameters did not reveal an independent prognostic character of CXCR4 expression. CXCR4 expression differs significantly within benign lesions and renal neoplasms. Cytoplasmic and nuclear expression of CXCR4 could be detected across all RCC subtypes. The prognostic value of CXCR4 in ccRCC was confirmed in univariate analysis.

Prognostic impact of complete metastasectomy in metastatic renal cell carcinoma in the era of immuno-oncology-based combination therapies.

PURPOSE: Complete metastasectomy of renal cell carcinoma (RCC) is receding into the past due to the progress of immuno-oncology-based combinations (IO) in systemic therapy. The prognostic impact of curative intended complete metastasectomy vs. immediate IO-based therapy or tyrosine kinase inhibition (TKI) on progression-free survival (PFS) and cancer-specific survival (CSS) was investigated in the first-line setting. METHODS: 205 patients with synchronous or metachronous metastasis received complete metastasectomy (n = 80) or systemic therapy (n = 125, TKI: 87, TKI-IO: 13, IO-IO: 25) as first-line therapy. The prognostic impact of these therapies was assessed using Cox regression and Kaplan-Meier analyses. RESULTS: First-line complete metastasectomy significantly improved CSS compared to both TKI monotherapy (6.1 vs. 2.6 years, HR 0.45, p < 0.001) and IO-based combination therapy (IO-IO/TKI-IO, 6.1 vs. 3.5 years, HR 0.28, p = 0.007). Repetitive complete metastasectomy without ever receiving systemic therapy vs. systemic therapy in first-line significantly prolonged CSS (11.3 vs. 3.1 years, HR 0.34, p = 0.002). First-line complete metastasectomy and subsequent systemic therapy at tumor progression was associated with a significant CSS benefit vs. systemic therapy (5.8 vs. 3.1 years, HR 0.53, p = 0.003), also compared to IO-based combinations (5.8 vs. 3.5 years, HR 0.30, p = 0.017). Median PFS was improved by IO-based therapy compared to TKI monotherapy in the first-line setting (HR 0.61, p = 0.05), with maximal benefit of the TKI-IO combination vs. TKI monotherapy (HR 0.27, p = 0.01), as well as compared to PFS of complete metastasectomy (HR 0.34, p = 0.035). CONCLUSION: Despite the progress of IO-based combination therapies in first line, complete metastasectomy remains an integral part of the multimodality treatment of metastatic RCC.

Expression of tumour progression-associated genes in circulating tumour cells of patients at different stages of prostate cancer.

OBJECTIVE: To evaluate the presence of circulating tumour cells (CTCs) at different stages of prostate cancer using the AdnaTest® ProstateCancerDetect kit (Qiagen). Moreover, we aimed to assess the expression of transcripts that are specific for cancer stem cells (AdnaTest StemCell) and epithelial-mesenchymal transition (EMT) in CTCs (AdnaTest EMT), as well as additional genes that are known to promote prostate cancer progression. PATIENTS AND METHODS: In this prospective study, we included 81 patients who underwent treatment for prostate cancer between 07/2014 and 02/2015, including: Group A, 18 patients (22.2%) with low-risk clinically localised prostate cancer; Group B, 25 patients (30.9%) with high-risk clinically localised prostate cancer; Group C, 11 patients (13.6%) with metastatic castration-sensitive prostate cancer (mCSPC); and Group D, 27 patients (33.3%) with metastatic castration-resistant prostate cancer (mCRPC). AdnaTest ProstateCancer and AdnaTest StemCell/EMT were performed in all cases. In addition, expression of the androgen receptor (AR), c-met, c-kit and thymidylate synthase (TYMS) in CTCs was assessed using specific polymerase chain reaction assays. RESULTS: A positive AdnaTest ProstateCancer was present in three (16.7%), two (8.0%), six (54.5%) and 19 (70.5%) patients in groups A, B, C and D, respectively (P < 0.01, chi-squared test). The AdnaTest EMT and AdnaTest StemCell were positive in zero (0.0%), zero (0.0%), one (9.1%), and two (7.4%); and in five (27.8%), four (16.0%), three (27.3%), and 11 (40.7%) patients in groups A, B, C and D, respectively, with no significant differences noted between groups. CTCs expressing TYMS (44.4% and 50.0% vs 13.9%) or AR (18.2% and 25.9% vs 0.0%) were seen more commonly in patients in groups C and D vs patients with non-metastatic disease (all P < 0.05). Expression of c-kit and c-met were rare events, with only two patients positive for either marker. CONCLUSIONS: AdnaTest ProstateCancerDetect exhibits positive results mainly in patients with metastatic disease. Expression of AR and TYMS are frequent events in CTCs of patients with advanced disease, whereas c-met and c-kit gene expression is seen in only a small proportion of patients. The implications of these results for the use of CTC analysis as a decision factor for personalised treatment strategies in advanced prostate cancer remain to be determined.

The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell-based immunotherapy.

Direct analysis of HLA-presented antigens by mass spectrometry provides a comprehensive view on the antigenic landscape of different tissues/malignancies and enables the identification of novel, pathophysiologically relevant T-cell epitopes. Here, we present a systematic and comparative study of the HLA class I and II presented, nonmutant antigenome of multiple myeloma (MM). Quantification of HLA surface expression revealed elevated HLA molecule counts on malignant plasma cells compared with normal B cells, excluding relevant HLA downregulation in MM. Analyzing the presentation of established myeloma-associated T-cell antigens on the HLA ligandome level, we found a substantial proportion of antigens to be only infrequently presented on primary myelomas or to display suboptimal degrees of myeloma specificity. However, unsupervised analysis of our extensive HLA ligand data set delineated a panel of 58 highly specific myeloma-associated antigens (including multiple myeloma SET domain containing protein) which are characterized by frequent and exclusive presentation on myeloma samples. Functional characterization of these target antigens revealed peptide-specific, preexisting CD8(+) T-cell responses exclusively in myeloma patients, which is indicative of pathophysiological relevance. Furthermore, in vitro priming experiments revealed that peptide-specific T-cell responses can be induced in response-naive myeloma patients. Together, our results serve to guide antigen selection for T-cell-based immunotherapy of MM.

Differentiation of bladder cancer with water flow elastography (WaFE).

Cancer affects the mechanical properties of tissue. Therefore, elastography techniques can be used to differentiate cancerous from healthy tissue. Due to probe size and restricted handling, most elastography techniques are not applicable in minimally invasive surgery (MIS). Established techniques such as endoscopic ultrasound elastography measure under undefined boundary conditions, making the determination of quantitative mechanical properties challenging. Water flow elastography (WaFE) has recently been introduced for application in MIS. Here, we present an improved WaFE measurement method in which the probe attaches itself to the sample with a small suction pressure. This leads to defined boundary conditions, allowing for a quantitative determination of the Young's modulus of tissue. To facilitate fast measurements, we developed a correction model for the hydrodynamic resistance and the fluid inertia of the tubing. We used WaFE for ex vivo measurements on human bladders and found a significantly larger Young's modulus for cancerous vs. healthy tissue. We determined the optimal classification threshold for the Young's modulus to be 8 kPa and found that WaFE can differentiate between cancerous and healthy tissue with a sensitivity of 0.96 and a specificity of 1. Our results underline that WaFE can be a helpful differentiating tool in MIS.

PD-L1 Expression in High-Risk Non-Muscle-Invasive Bladder Cancer Is Influenced by Intravesical Bacillus Calmette-Guérin (BCG) Therapy.

In the expanding landscape of immune checkpoint inhibitors (CPI) in high-risk (HR) non-muscle-invasive bladder cancer (NMIBC), the role of programmed death ligand 1 (PD-L1) as prognostic and predictive is increasingly significant. However, data evaluating its variability and susceptibility to Bacillus Calmette-Guérin (BCG) therapy in HR NMIBC patients is scarce. This retrospective study analyzed 126 HR NMIBC tissue samples from 63 patients (38× BCG-treated, 25× BCG-naïve) at two time points to assess PD-L1 expression using the 'combined positivity score' (CPS) with the 22C3 DAKO antibody method and correlated it with clinicopathological parameters. A CPS > 10 defined PD-L1 positivity. The impact of initial PD-L1 status and its change over time on time-to-recurrence, progression-free survival, and overall survival (TTR, PFS, OS) was analyzed using Kaplan-Meier and Cox proportional hazard models. BCG treatment significantly increased PD-L1 expression (5.31 vs. 0.22, p = 0.0423), with PD-L1 positive cases rising post-treatment in the BCG group and remaining unchanged in BCG-naïve patients. Multivariate analysis including T-stage, CIS, grading, tumor size, multifocality, age, and sex revealed a significant correlation between PD-L1 status change to positivity and improved TTR (p = 0.03). Our findings demonstrate a potential modulation of the PD-L1 status by an intravesical BCG therapy. However, its prognostic value appears limited.

Effects of Scaffolds on Urine- and Urothelial Carcinoma Tissue-Derived Organoids from Bladder Cancer Patients.

Organoids are three-dimensional constructs generated by placing cells in scaffolds to facilitate the growth of cultures with cell-cell and cell-matrix interactions close to the in vivo situation. Organoids may contain different types of cells, including cancer cells, progenitor cells, or differentiated cells. As distinct culture conditions have significant effects on cell metabolism, we explored the expansion of cells and expression of marker genes in bladder cancer cells expanded in two different common scaffolds. The cells were seeded in basement membrane extract (BME; s.c., Matrigel®) or in a cellulose-derived hydrogel (GrowDex®, GD) and cultured. The size of organoids and expression of marker genes were studied. We discovered that BME facilitated the growth of significantly larger organoids of cancer cell line RT112 (p < 0.05), cells from a solid tumor (p < 0.001), and a voiding urine sample (p < 0.001). Expression of proliferation marker Ki76, transcription factor TP63, cytokeratin CK20, and cell surface marker CD24 clearly differed in these different tumor cells upon expansion in BME when compared to cells in GD. We conclude that the choice of scaffold utilized for the generation of organoids has an impact not only on cell growth and organoid size but also on protein expression. The disadvantages of batch-to-batch-variations of BME must be balanced with the phenotypic bias observed with GD scaffolds when standardizing organoid cultures for clinical diagnoses.

Enhancing Tissue Impedance Measurements Through Modeling of Fluid Flow During Viscoelastic Relaxation.

OBJECTIVE: Bladder cancer recurrence is an important issue after endoscopic urological surgeries. Additional sensor information such as electrical impedance measurements aim to support surgeons to ensure that the entirety of the tumor is removed. The foundation for differentiating lies in the altered sodium contents and cell structures within tumors that change their conductivity and permittivity. Mechanical deformations in the tissue expel fluid from the compressed area and pose a great difficulty, as they also lead to impedance changes. It is crucial to determine if this effect outweighs the alterations due to the tumorous tissue properties. METHODS: Impedance measurements under ongoing viscoelastic relaxation are taken on healthy and tumorous tissue samples from human bladders and breasts. A fluid model to account for extra- and intracellular fluid flow under compression is derived. It is based on the fluid content within the individual tissue compartments and their outflow via diffusion. RESULTS: After an initial deformation, the tissue relaxes and the impedance increases. The proposed model accurately represents these effects and validates the link between fluid flow under mechanical deformation and its impact on tissue impedance. A method to compensate for these undesired effects of fluid flow is proposed and the measurements are assessed in terms of differentiability between tumorous and healthy tissue samples. CONCLUSION: The electrical parameters are found to be promising for differentiation even under varying mechanical deformation, and the distinction is additionally improved by the proposed compensation approach. SIGNIFICANCE: Electrical impedance measurements show great potential to support urologist during endoscopic surgeries.

Stress Urinary Incontinence: An Unsolved Clinical Challenge.

Stress urinary incontinence is still a frequent problem for women and men, which leads to pronounced impairment of the quality of life and withdrawal from the social environment. Modern diagnostics and therapy improved the situation for individuals affected. But there are still limits, including the correct diagnosis of incontinence and its pathophysiology, as well as the therapeutic algorithms. In most cases, patients are treated with a first-line regimen of drugs, possibly in combination with specific exercises and electrophysiological stimulation. When conservative options are exhausted, minimally invasive surgical therapies are indicated. However, standard surgeries, especially the application of implants, do not pursue any causal therapy. Non-absorbable meshes and ligaments have fallen into disrepute due to complications. In numerous countries, classic techniques such as colposuspension have been revived to avoid implants. Except for tapes in the treatment of stress urinary incontinence in women, the literature on randomized controlled studies is insufficient. This review provides an update on pharmacological and surgical treatment options for stress urinary incontinence; it highlights limitations and formulates wishes for the future from a clinical perspective.

A Protocol for Organoids from the Urine of Bladder Cancer Patients.

This study investigates the feasibility of establishing urine-derived tumor organoids from bladder cancer (BC) patients as an alternative to tissue-derived organoids. BC is one of the most common cancers worldwide and current diagnostic methods involve invasive procedures. Here, we investigated the potential of using urine samples, which contain exfoliated tumor cells, to generate urine-derived BC organoids (uBCOs). Urine samples from 29 BC patients were collected and cells were isolated and cultured in a three-dimensional matrix. The establishment and primary expansion of uBCOs were successful in 83% of the specimens investigated. The culturing efficiency of uBCOs was comparable to cancer tissue-derived organoids. Immunohistochemistry and immunofluorescence to characterize the uBCOs exhibited similar expressions of BC markers compared to the parental tumor. These findings suggest that urine-derived BC organoids hold promise as a non-invasive tool for studying BC and evaluating therapeutic responses. This approach could potentially minimize the need for invasive procedures and provide a platform for personalized drug screening. Further research in this area may lead to improved diagnostic and treatment strategies for BC patients.

Cystoscopic depth estimation using gated adversarial domain adaptation.

Monocular depth estimation from camera images is very important for surrounding scene evaluation in many technical fields from automotive to medicine. However, traditional triangulation methods using stereo cameras or multiple views with the assumption of a rigid environment are not applicable for endoscopic domains. Particularly in cystoscopies it is not possible to produce ground truth depth information to directly train machine learning algorithms for using a monocular image directly for depth prediction. This work considers first creating a synthetic cystoscopic environment for initial encoding of depth information from synthetically rendered images. Next, the task of predicting pixel-wise depth values for real images is constrained to a domain adaption between the synthetic and real image domains. This adaptation is done through added gated residual blocks in order to simplify the network task and maintain training stability during adversarial training. Training is done on an internally collected cystoscopy dataset from human patients. The results after training demonstrate the ability to predict reasonable depth estimations from actual cystoscopic videos and added stability from using gated residual blocks is shown to prevent mode collapse during adversarial training.

Enfortumab vedotin - next game-changer in urothelial cancer.

Introduction: The therapeutic landscape of metastatic urothelial carcinoma (mUC) becomes increasingly dense: standard therapy remains cisplatin-based chemotherapy, followed by immunotherapy with checkpoint inhibitors as maintenance or second-line. New directions include erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor in patients with corresponding mutations in FGFR2/3 receptor. Enfortumab vedotin (EV) is an antibody-drug conjugate targeting nectin-4 and is conjugated with monomethyl auristatin E (MMAE). It received FDA approval based on phase I/II data recently and thus represents an alternative to established third-line chemotherapies with vinflunine, paclitaxel, or docetaxel.Areas covered: The aim of this review was to evaluate the added value of Enfortumab vedotin in the therapeutic landscape of mUC. Current therapeutic options and alternatives for the affected patients are described, followed by a detailed description of the characteristics and available results of EV. Ongoing studies are explained, the present significance of the substance is assessed and its further future potential is outlined.Expert opinion Enfortumab vedotin has shown encouraging efficacy and a good tolerability in phase I/II trials, especially in heavily pretreated patients and patients with liver metastases. It appears to outperform third-line chemotherapies; ongoing studies will show the future potential of EV in treatment sequence.

Comparison of the metabolome in urine prior and eight weeks after radical prostatectomy uncovers pathologic and molecular features of prostate cancer.

Prostate cancer (PCa) is associated with cellular metabolism alterations leading to changes of the metabolome. So far, studies investigating these alterations mainly focused on comparisons of metabolite profiles of PCa patients and healthy controls. In the present study we compared for the first time metabolite profiles in a significant number of paired urine samples collected before and eight weeks after radical prostatectomy (rPX) in 34 patients with PCa. Our comprehensive non-targeted liquid chromatographic-mass spectrometric metabolomics approach covered > 3000 metabolite ion masses. We annotated 23 metabolites showing significant changes eight weeks after rPX. While the levels of uridine and six acylcarnitines in urine were increased before surgery, lower levels were detected for 16 metabolites, like e.g. citrate, phenyl-lactic acid, choline, myo-inositol, emphasizing a relevant pathophysiological role of these biomarkers and the associated metabolic pathways. These results have important implications for potential use of metabolome analyses for detection of prostate cancer and related pathologic and molecular features.

Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer.

Molecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion of treatment options and its high genomic heterogeneity. We profile minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compare to same-patient tumor tissue obtained during invasive surgery. Patient ctDNA abundance is independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduces the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue is 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations are identified across serial ctDNA samples, concordance for serial tumor tissue is significantly lower. Overall, our exploratory analysis demonstrates that genomic profiling of ctDNA in mUC is reliable and practical, and mitigates against disease undersampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC.

Bone Health Issues in Patients with Prostate Cancer: An Evidence-Based Review.

Bone health in prostate cancer patients represents a prerequisite for acceptable quality of life and optimal outcome of this disease. The major threat for bone health in prostate cancer displays cancer treatment induced bone loss as well as the development of bone metastases. In recent years, several new pharmaceuticals targeting bone metabolism such as denosumab or androgen pathway targeting drugs (abiraterone acetate and enzalutamide) have been approved for the treatment of progressive disease aiming to interrupt the vicious circle of bone metastasis and aberrant bone resorption. This development raised the awareness of the pivotal role of bone health in prostate cancer and introduced (symptomatic) skeletal related events as an important end point in recent clinical trials. Bone targeted drugs have become standard of care in patients with metastatic castration resistant prostate cancer, their role in metastatic hormone sensitive prostate cancer has been discussed controversely. In oligometastatic prostate cancer patients several promising approaches in metastasis directed therapy, including conventional surgery, stereotactic ablative radiation and image-guided single-fraction robotic stereotactic radiosurgery (CyberKnife®) were launched but are not in routine clinical use until now caused by sparse clinical evidence.

An evaluation of avelumab for the treatment of genitourinary tumors.

INTRODUCTION: The immune checkpoint inhibitors (ICI) programmed cell death protein and ligands 1 (PD1- and PD-L1) as well as cytotoxic T-lymphocyte-associated protein 4 have demonstrated clinical efficacy in genitourinary cancer. While different ICI exist, focus of the current study work was to evaluate the PD-L1 antibody avelumab within this framework of ICI. AREAS COVERED: The manuscript reviews the pharmacological characteristics and preclinical and clinical data of avelumab in the treatment for advanced or metastatic genitourinary cancers. It highlights its respective clinical relevance and special features in the context of the other available ICI. EXPERT OPINION: Avelumab has shown promising antitumor activity and a manageable safety profile in patients with mRCC and mUC as mono- and combination therapy. The approach of an avelumab maintenance therapy in mUC is promising and could become part of future clinical practice. Results of ICI used in the neoadjuvant or adjuvant setting are eagerly awaited. Avelumab's uniqueness is its capacity to enhance antibody-dependent cell-mediated cytotoxicity. Because of this, currently ongoing clinical trials investigate the combination of avelumab with other immune modulating agents like IL-12 and IL-15. Thereby, it can be assumed that avelumab will have an ongoing role in the treatment of patients with genitourinary tumors.

Prognostic impact of somatostatin receptor expression in advanced bladder cancer.

INTRODUCTION AND OBJECTIVES: Somatostatin receptors (SSTR) recently have been identified as potential targets for treatment of solid tumors. Furthermore, they have been shown to be of high relevance for tumor biology and prognosis in various types of cancer. However, there is a lack of clinical data for SSTR in bladder cancer (BC). Aim of this study was to determine the expression of all relevant somatostatin receptor subtypes in benign urothelium and tumor tissue of patients with muscle invasive BC. Furthermore, their potential role as prognostic factor for cancer-specific survival (CSS) and overall survival (OS) was evaluated. METHODS: The collective included BC and benign urothelium tissue of 103 patients (Median age 69; range 32-84, 79 male, 24 female) who underwent a radical cystectomy. A tissue microarray with subsequent immunohistochemical staining was used to assess membranous expression of SSTR1-5. Results were correlated to clinical and histopathological data as well as CSS and OS. RESULTS: Expressions of SSTR1-4 were significantly decreased in BC compared to benign urothelium (P < 0.002 each), whereas SSTR5 expression was increased (P = 0.0017). Expression of SSTR1 was associated with organ-confined disease (≤pT2) (P = 0.0477). No correlation between SSTR1-5 expression and N- and M-stage was observed. Univariate analyses showed a significantly longer CSS and OS in patients with high expression of SSTR3 (P = 0.0316 and 0.0044). Multivariate analyses confirmed SSTR3 expression as independent marker of improved CSS and OS (P = 0.0324 and 0.0076). CONCLUSIONS: The majority of somatostatin receptor subtypes exhibit decreased expression in BC compared to benign bladder tissue. Expression of SSTR3 is an indicator for favorable prognosis in patients with muscle-invasive BC. These results support preclinical investigations using somatostatin receptor analogues such as octreotide to influence BC growth.

Mass spectrometry-based identification of a B-cell maturation antigen-derived T-cell epitope for antigen-specific immunotherapy of multiple myeloma.

The B-cell maturation antigen (BCMA) is currently being evaluated as promising tumor-associated surface antigen for T-cell-based immunotherapy approaches, such as CAR T cells and bispecific antibodies, in multiple myeloma (MM). Cytotoxic T cells bearing BCMA-specific T-cell receptors might further allow targeting HLA-presented antigens derived from the intracellular domain of BCMA. By analyzing a mass spectrometry-acquired immunopeptidome dataset of primary MM samples and MM cell lines for BCMA-derived HLA ligands, we identified the naturally presented HLA-B*18-restricted ligand P(BCMA)B*18. Additionally, P(BCMA)B*18 was identified on primary CLL samples, thereby expanding the range for possible applications. P(BCMA)B*18 induced multifunctional BCMA-specific cells de novo from naïve CD8+ T cells of healthy volunteers. These T cells exhibited antigen-specific lysis of autologous peptide-loaded cells. Even in the immunosuppressive context of MM, we detected spontaneous memory T-cell responses against P(BCMA)B*18 in patients. By applying CTLA-4 and PD-1 inhibition in vitro we induced multifunctional P(BCMA)B*18-specific CD8+ T cells in MM patients lacking preexisting BCMA-directed immune responses. Finally, we could show antigen-specific lysis of autologous peptide-loaded target cells and even MM.1S cells naturally presenting P(BCMA)B*18 using patient-derived P(BCMA)B*18-specific T cells. Hence, this BCMA-derived T-cell epitope represents a promising target for T-cell-based immunotherapy and monitoring following immunotherapy in B-cell malignancy patients.

Molecular markers in disease detection and follow-up of patients with non-muscle invasive bladder cancer.

INTRODUCTION: Diagnosis and surveillance of non-muscle invasive bladder cancer (NMIBC) is mainly based on endoscopic bladder evaluation and urine cytology. Several assays for determining additional molecular markers (urine-, tissue- or blood-based) have been developed in recent years but have not been included in clinical guidelines so far. Areas covered: This review gives an update on different molecular markers in the urine and evaluates their role in patients with NMIBC in disease detection and surveillance. Moreover, the potential of recent approaches such as DNA methylation assays, multi-panel RNA gene expression assays and cell-free DNA analysis is assessed. Expert commentary: Most studies on various molecular urine markers have mainly focused on a potential replacement of cystoscopy. New developments in high throughput technologies and urine markers may offer further advantages as they may represent a non-invasive approach for molecular characterization of the disease. This opens new options for individualized surveillance strategies and may help to choose the best therapeutic option. The implementation of these technologies in well-designed clinical trials is essential to further promote the use of urine diagnostics in the management of patients with NMIBC.