Molecular predictors of response to PD-1/PD-L1 inhibition in urothelial cancer.

INTRODUCTION: The survival of patients with metastatic urothelial cancer (mUC) is poor. During the last 40 years, chemotherapy was the predominant treatment modality for mUC. The discovery of the immune checkpoint inhibitors (ICI), especially the inhibitors of the programmed cell death 1 and its ligand (PD-1/PD-L1), has revolutionized cancer immunotherapy. The PD-1 and PD-L1 inhibitors provide a new and effective treatment option for patients with UC, particularly for patients with recurrence after platinum-based therapy and those who are ineligible for cisplatin. METHODS: A literature search on PubMed, ClinicalTrials.gov and selected annual congress abstracts was conducted in May 2018, using a combination of keywords, medical subject headings (MeSH) terms and free text incorporating urothelial bladder cancer; immunotherapy; immune checkpoint inhibition, biomarkers, PD1/PD-L1. RESULTS: Although some patients demonstrate complete and/or durable responses under ICI, the reliable prediction of response to ICI is not possible. In the clinical setting, physicians are not able to predict response to ICI in mUC and to adequately select patients who will benefit. Exploratory analysis of clinical trial data revealed that PD-L1 expression, tumor mutation burden, tumor-infiltrating lymphocytes and gene expression profiles might have some predictive and/or prognostic value in different patient populations. CONCLUSION: Validated robust biomarkers are still needed to overcome this hurdle to forecast response of ICI in UC patients.

Single-use versus reusable ureterorenoscopes for retrograde intrarenal surgery (RIRS): systematic comparative analysis of physical and optical properties in three different devices.

INTRODUCTION: Retrograde intrarenal surgery (RIRS) represents a standard option for kidney stone removal. However, RIRS is considered a cost-intensive procedure. Single-use flexible ureterorenoscopes have been introduced to improve budget predictability in RIRS. We assessed differences in physical and optical properties of single-use devices compared to standard reusable endoscopes. METHODS: In two single-use (LithoVue™, Boston Scientific; Pusen Uscope UE3011™), and one reusable ureterorenoscope (Flex-Xc™, Karl Storz), we investigated flow rates, deflection, illuminance, and intrapelvic pressure in a porcine kidney model. Subjective image quality was assessed using a standardized questionnaire. Common insertable devices were applied to investigate additional influence on physical properties. RESULTS: Significant variability in maximum flow rates was observed (Flex-Xc™: 25.8 ml/min, LithoVue™: 30.3 ml/min, Pusen™: 33.4 ml/min, p < 0.05). Insertion of a guide wire resulted in the highest reduction of flow rates in all endoscopes. Flection led to a reduction of absolute flow rates up to 9.4% (Flex-Xc™). Light intensity at 20/50 mm distance was 9090 lx/1857 lx (Flex-Xc™) and 5733 lx/1032 lx (LithoVue™) and 2160 lx/428 lx (Pusen™), respectively (p < 0.05). Subjective image quality score was highest using the Flex-Xc™ endoscope. During manipulation, maximum intrarenal pressure up to 66 mmHg (Pusen™) was measured. CONCLUSIONS: Significant differences in physical and optical properties of single-use or reusable flexible ureterorenoscopes are present, with putative influence on surgical efficacy and complications. Further comparative evaluation of single-use and reusable endoscopes in a clinical scenario is useful. Moreover, utilization of ureteral access sheaths may be considered to avoid renal damage.

Transurethral Resection of Bladder Tumors: Next-generation Virtual Reality Training for Surgeons.

BACKGROUND: The number of virtual reality (VR) simulators is increasing. The aim of this prospective trial was to determine the benefit of VR cystoscopy (UC) and transurethral bladder tumor resection (TURBT) training in students. DESIGN, SETTING, AND PARTICIPANTS: Medical students without endoscopic experience (n=51, median age=25 yr, median 4th academic year) were prospectively randomized into groups A and B. After an initial VR-UC and VR-TURBT task, group A (n=25) underwent a video-based tutorial by a skilled expert. Group B (n=26) was trained using a VR training program (Uro-Trainer). Following the training, every participant performed a final VR-UC and VR-TURBT task. Performance indicators were recorded via the simulator. Data was analyzed by Mann-Whitney U test. INTERVENTION: VR cystoscopy and TURBT. RESULTS AND LIMITATIONS: No baseline and post-training differences were found for VR-UC between groups. During baseline, VR-TURBT group A showed higher inspected bladder surface than group B (56% vs 73%, p=0.03). Subgroup analysis detected differences related to sex before training (male: 31.2% decreased procedure time; 38.1% decreased resectoscope movement; p=0.02). After training, significant differences in procedure time (3.9min vs 2.7min, p=0.007), resectoscope movement (857mm vs 529mm, p=0.005), and accidental bladder injury (n=3.0 vs n=0.88, p=0.003) were found. Male participants showed reduced blood loss (males: 3.92ml vs females: 10.12ml; p=0.03) after training. CONCLUSIONS: Measuring endoscopic skills within a virtual environment can be done easily. Short training improved efficacy and safety of VR-TURBT. Nevertheless, transfer of improved VR performance into real world surgery needs further clarification. PATIENT SUMMARY: We investigated how students without endoscopic experience profit from simulation-based training. The safe environment and repeated simulations can improve the surgical training. It may be possible to enhance patient's safety and the training of surgeons in long term.

Transketolase like 1 (TKTL1) expression alterations in prostate cancer tumorigenesis.

BACKGROUND: Prostate cancer (CaP) is the most common nonepidermal cancer in elderly males. Due to its heterogeneity and high variability in regards to clinical outcome and therapeutic response, urologists' handling of this disease remains a challenge. The objective of this study was to assess Transketolase like 1 (TKTL1) expression in benign prostatic tissue, peritumoral tissue and in CaP (in different stages of disease), and its correlation with clinicopathological findings, in order to detect if TKTL1 expression is associated with CaP tumorigenesis. METHODS: In total, 100 tissue samples were included: (i) 22 benign specimens, (ii) 46 specimens with nonmetastatic CaP, and (iii) 32 specimens from patients with metastatic CaP. From the tissue microarray slides, we evaluated immunohistochemically the expression of the TKTL1 protein, using the H-score. RESULTS: The TKTL1 protein expression pattern ranges from a low level in benign prostatic tissue (100 [57.5-105]), moderately low in peritumoral tissue (135.42 [100-195.16]), moderate expression in nonmetastatic CaP (200 [172.19-254.38]) to high in metastatic CaP (300 [222.50-300]). A significant rise of TKTL1 mean expression was seen throughout disease progression. A significant difference was also found in TKTL1 expression between peritumoral tissue and benign tissue. CONCLUSION: The results obtained in this study suggest that pentose phosphate pathway and its key enzyme TKTL1 is altered throughout the CaP tumorigenesis, and this pathway merits further investigation.