Alteration of Cadherin 3 Expression and DNA Methylation in Association with Aggressive Renal Cell Carcinoma.

Cadherins (calcium-dependent adhesion proteins) are important in cellular adhesion and may play a role in the development and progression of renal cell carcinoma (RCC). This study investigated changes in cadherin 3 (CDH3; P-cadherin) mRNA expression, DNA methylation, and protein expression in RCC and compared the results with the histopathological and clinical characteristics of patients. The possible contribution of CDH3 to tumor cell invasiveness was tested in a functional assay using siRNA-based suppression of CDH3 expression and subsequent real-time impedance analysis using a Matrigel invasion model. Our analyses revealed a tumor-specific loss of CDH3 mRNA expression, CDH3 DNA hypermethylation, and loss of distal tubular and collecting duct CDH3 protein expression in RCC. A relatively higher methylation level in tumors was associated with a loss of cell differentiation and higher clinical stage. siRNA-induced suppression of CDH3 expression modulated the invasion characteristics of tumor cells in the impedance-based real-time cellular analysis. Our results indicate that loss of CDH3 expression is common in RCC and may contribute to the pathogenesis of a subset of RCC. Further studies to reveal the mechanisms of loss of expression and its effects on the invasive behavior of renal tumor cells are required.

ShinyLUTS-A Shiny web application for structured data management and analysis for patients with lower urinary tract symptoms (LUTS).

OBJECTIVES: Clinical, time-dependent, therapeutic and diagnostic data of patients with LUTS are highly complex. To better manage these data for therapists' and researchers' we developed the application ShinyLUTS. MATERIAL AND METHODS: The statistical programming language R and the framework Shiny were used to develop a platform for data entry, monitoring of therapy and scientific data analysis. As part of a use case, ShinyLUTS was evaluated for patients with non-neurogenic LUTS who were receiving Rezum™ therapy. RESULTS: The final database on patients with LUTS comprised a total of 8.118 time-dependent parameters in 11 data tables. Data entry, monitoring of therapy as well as data retrieval for scientific use, was deemed feasible, intuitive and well accepted. CONCLUSION: The ShinyLUTs application presented here is suitable for collecting, archiving, and managing complex data on patients with LUTS. Aside from the implementation in a scientific workflow, it is suited for monitoring treatment of patients and functional results over time.

First experiences using transurethral ultrasound ablation (TULSA) as a promising focal approach to treat localized prostate cancer: a monocentric study.

PURPOSE: To share our experience using transurethral ultrasound ablation (TULSA) treatment for focal therapy of localized prostate cancer (PCa). MATERIALS AND METHODS: Between 10/2019 and 06/2021 TULSA treatment for localized PCa was performed in 22 men (mean age: 67 ± 7 years, mean initial PSA: 6.8 ± 2.1 ng/ml, ISUP 1 in n = 6, ISUP 2 in n = 14 and 2 patients with recurrence after previous radiotherapy). Patients were selected by an interdisciplinary team, taking clinical parameters, histopathology from targeted or systematic biopsies, mpMRI and patients preferences into consideration. Patients were thoroughly informed about alternative treatment options and that TULSA is an individual treatment approach. High-intensity ultrasound was applied using an ablation device placed in the prostatic urethra. Heat-development within the prostatic tissue was monitored using MR-thermometry. Challenges during the ablation procedure and follow-up of oncologic and functional outcome of at least 12 months after TULSA treatment were documented. RESULTS: No major adverse events were documented. In the 12 month follow-up period, no significant changes of urinary continence, irritative/obstructive voiding symptoms, bowel irritation or hormonal symptoms were reported according to the Expanded Prostate Cancer Index Composite (EPIC) score. Erectile function was significantly impaired 3-6 months (p < 0.01) and 9-12 months (p < 0.05) after TULSA. PSA values significantly decreased after therapy (2.1 ± 1.8 vs. 6.8 ± 2.1 ng/ml, p < 0.001). PCa recurrence rate was 23% (5/22 patients). CONCLUSION: Establishment of TULSA in clinical routine was unproblematic, short-term outcome seems to be encouraging. The risk of erectile function impairment requires elaborate information of the patient.

Transurethral water vapor ablation of the prostate with the Rezum system: Urodynamic findings.

AIMS: The efficacy of the transurethral convective interstitial radiofrequency water vapor thermal ablation of the prostate with the Rezum system for the treatment of male lower urinary tract symptom due to benign prostatic hyperplasia is well proven. The improvement of urodynamic parameters obtained from a simple uroflowmetry cannot measure the effect of water vapor injection on the bladder outlet obstruction. METHODS: This monocentric retrospective pilot study analyzes the data of pressure-flow studies performed before and after 17 Rezum procedures to answer the question whether thus obtained ablation of prostate tissue has a disobstructive effect on the bladder outlet. RESULTS: All the functional outcomes were consistently improved after the procedure, with a median flowrate increase of 5.1 ml/s (p = 0.0022) and a median postvoid residual urine (PVR) reduction of 100 ml (p = 0.0042). The prostate volume was reduced by 40% (p < 0.0001) and the median Bladder Outlet Obstruction Index (BOOI) reduction was 53.8 (p < 0.0001). CONCLUSIONS: These data show that the possibility to significantly reduce the obstruction grade with even a single Rezum procedure is concrete and seems to be independent from the degree of the obstruction grade.

Age-Related DNA Methylation in Normal Kidney Tissue Identifies Epigenetic Cancer Risk Susceptibility Loci in the ANKRD34B and ZIC1 Genes.

Both age-dependent and age-independent alteration of DNA methylation in human tissues are functionally associated with the development of many malignant and non-malignant human diseases. TCGA-KIRC data were biometrically analyzed to identify new loci with age-dependent DNA methylation that may contribute to tumor risk in normal kidney tissue. ANKRD34B and ZIC1 were evaluated as candidate genes by pyrosequencing of 539 tissues, including 239 normal autopsy, 157 histopathologically tumor-adjacent normal, and 143 paired tumor kidney samples. All candidate CpG loci demonstrated a strong correlation between relative methylation levels and age (R = 0.70−0.88, p < 2 × 10−16) and seven out of 10 loci were capable of predicting chronological age in normal kidney tissues, explaining 84% of the variance (R = 0.92). Moreover, significantly increased age-independent methylation was found for 9 out of 10 CpG loci in tumor-adjacent tissues, compared to normal autopsy tissues (p = 0.001−0.028). Comparing tumor and paired tumor-adjacent tissues revealed two patient clusters showing hypermethylation, one cluster without significant changes in methylation, and a smaller cluster demonstrating hypomethylation in the tumors (p < 1 × 10−10). Taken together, our results show the presence of additional methylation risk factors besides age for renal cancer in normal kidney tissue. Concurrent tumor-specific hypermethylation suggests a subset of these loci are candidates for epigenetic renal cancer susceptibility.

Re-evaluation of the immunohistochemical distribution of isoforms of nitric oxide synthase in the human prostate: A light and electron microscopical study.

Up until today, there are still uncertainties regarding the occurrence of isoforms of the nitric oxide synthase (eNOS, nNOS) in the human prostate. While nNOS was exclusively seen in slender nerve fibres branching within the transition zone, eNOS was reported in glandular structures and also in small vessels interspersing the tissue. This study aimed to re-evaluate by means of light and electron microscopy (LM, EM), the distribution of eNOS and nNOS in the transition zone of the human prostate. Tissue specimens were obtained from 16 patients who underwent surgery for pelvic malignancies. Using specific antibodies in conjunction with advanced fixation and staining procedures, the occurrence of eNOS and nNOS was investigated. nNOS was detected in nerve fibres interspersing the tissue and was also seen in glandular structures. EM revealed that in glandular epithelial cells immunoreaction for nNOS was limited to the cytoplasmic compartment. Vascular endothelial cells of small vessels transversing glandular structures significantly stained for eNOS, while epithelial layers of prostatic glandules appeared free of eNOS. The results implicate that, in the prostate, nNOS is a mediator of stromal and glandular tissue function, and counteract the assumption of eNOS activity in glandular epithelial cells as a source of NO synthesis.

Comparison of PD-L1 Scores in Primary Kidney Tumors Versus Accompanying Venous Tumor Thrombi: Retrospective, Comparative, Monocentric Study in Treatment-Naive Patients.

INTRODUCTION: Renal cell carcinoma (RCC), an immunogenic tumor, is the most common form of kidney cancer worldwide. Immune checkpoint inhibitors (ICIs) play an important role in the treatment of metastatic RCC. Programmed death-ligand (PD-L1) has already been proposed as a possible prognosticator for ICIs effectiveness. To elucidate the feasible role of ICIs in neoadjuvant settings, we have assessed the most common PD-L1 expression modalities [tumor proportion score (TPS), combined positivity score (CPS) and inflammatory cell (IC) score] in primary tumors (PTs) and venous tumor thrombi (VTT) in first diagnosed, previously untreated RCC patients with accompanying VTT. METHODS: Between January 1999 and December 2016, 71 patients with a first diagnosed, untreated, locally advanced RCC (aRCC) (≥ pT3a) underwent surgery in Hanover Medical School (MHH). PD-L1 expression was examined separately in PTs and VTT using the CPS, IC score and TPS. We also considered the age at the time of the initial surgery and gender as probable influencing factors. By using a cutoff value of 1 (1%), PD-L1 expression levels in PTs and VTT were assessed to enable the determination of any frequency differences. RESULTS: Positive scores for PTs were shown by 54 (CPS), 53 (IC score) and 34 (TPS) patients, whereas in VTT, positive scores were evaluated for a total of 50 (CPS), 47 (IC-score) and 36 (TPS) patients. No statistically significant differences were obtained between the PD-L1 expression immunoscores for PTs and VTT. The covariates age at the time of the initial surgery and gender could not be statistically proven to influence the differences in PD-L1 expression between the VTT and PTs. CONCLUSION: To the best of our knowledge, this research is the largest study to investigate PD-L1 expression in PTs and VTT in 71 cases. It could have relevance for the future development of neoadjuvant immunotherapy options, particularly in aRCC with VTT.

Cancer-Specific Loss of Urocortin 3 in Human Renal Cancer.

INTRODUCTION: The corticotropin-releasing hormone (CRH) system, its receptors corticotropin-releasing hormone receptor 1 (CRHR1) and 2 (CRHR2), and its corresponding binding protein corticotropin-releasing hormone-binding protein (CRHBP) as well as the urocortin proteins-structural homologues to CRH, which are included in this peptide family-have become interesting oncological targets recently. Carcinogenesis of various human tumors has been reported with an altered presence of members of this system. The aim of the present study was to examine the role of urocortin 3 (UCN3) in renal cell carcinoma (RCC). METHODS: Therefore, tumoral tissues of 106 patients with RCC and available corresponding normal tissues were analyzed using qPCR for quantitative mRNA expression analysis. Tissue localization and protein signals of UCN3 in normal and tumoral renal specimens were evaluated using western blot and immunohistochemistry. In addition, correlation studies of UCN3 mRNA expression with clinicopathological parameters of patients with RCC and different histological subtypes were evaluated. RESULTS: UCN3 mRNA was significantly downregulated in nearly all tumoral tissues (p = 7.92 × 10-13). The same effect was observed at protein level using immunohistochemistry. Level of UCN3 mRNA expression was not directly correlated with clinicopathological parameters. CONCLUSION: We report for the first time the significant downregulation of UCN3 in RCC. These results demonstrate a possible involvement of the CRH system and its significance in carcinogenesis of RCC.

Expert System for Bone Scan Interpretation Improves Progression Assessment in Bone Metastatic Prostate Cancer.

INTRODUCTION: The bone scan index (BSI) was introduced as a quantitative tool for tumor involvement in bone of patients with metastatic prostate cancer (mPCa). The computer-aided diagnosis device for BSI analysis EXINIboneBSI seems to represent technical progress for the quantitative assessment of bone involvement. But it is not yet clear if the automated BSI (aBSI) could contribute to improved evaluation of progression in patients under antiandrogens or chemotherapy in contrast to the visual interpretation and/or conventional biomarkers such as the prostate-specific antigen (PSA). METHODS: In 49 mPCa patients, bone scans were performed initially and during different therapy courses. Scans were evaluated visually and by the artificial-neural-network-based expert system EXINIboneBSI. Progression of metastatic bone involvement was defined according to the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria in the visual interpretation. The computer-assisted interpretation was based on different cutoff values in relative changes of the aBSI. Additionally, assessments according to bone scanning were compared to changes in the PSA value as a potential surrogate for treatment response. RESULTS: Using a sensitive cutoff value (5% or 10%) for the relative aBSI increase led to significantly increased progression determination compared to the visual interpretation of bone scans (49% and 43% vs. 27%, p < 0.001). In 63% of the cases PSA and BSI changes matched, whereas in 18% progression was only indicated by the aBSI. A relative cutoff of 5% for the aBSI decrease could reclassify 47 serial scan pairs which were visually interpreted as stable into 22 progressive and 25 remissive scans. CONCLUSION: Distinct thresholds of the relative aBSI could help to better assess disease progression in mPCa patients. Manual corrections of the BSI values are not required in most cases. The aBSI could serve as a useful additional parameter for therapy monitoring in mPCa patients in the future.

Granular cell tumour of the urinary bladder.

With only 16 cases reported in the literature, the mostly benign granular cell tumour of the urinary bladder is exceptionally rare. We present the case of a 68-year old patient with one of these lesions demonstrating our histological findings including several immunohistochemical stainings used to differentiate between other more common entities.

Decreased galectin-8 is a strong marker for recurrence in urothelial carcinoma of the bladder.

OBJECTIVE: To investigate galectin-8 expression patterns in normal urothelium and bladder cancer specimens and to elucidate its prognostic value. MATERIALS AND METHODS: 162 samples of non-muscle-invasive transitional cell carcinoma, 25 samples of muscle-invasive transitional cell carcinoma and 10 samples of normal urothelium were investigated by immunohistochemistry using tissue microarrays. Complete patient and tumor characteristics were compared with galectin-8 staining patterns. The likelihood of tumor recurrence and progression was analyzed based on a 3-year follow-up. RESULTS: Loss of galectin-8 was associated with the likelihood of tumor recurrence in univariate (p < 0.05) and multivariate analyses (p < 0.01). No significance was observed for tumor progression. Patients whose specimens showed weak galectin-8 expression had a shorter recurrence-free interval (42 vs. 12 months; p < 0.01, log-rank test). All of the 10 normal urothelium samples showed high galectin-8 expression. Decreased staining was found to be associated with higher tumor stages and grades (p < 0.0001, one-way ANOVA). A significant difference was found comparing normal urothelium with any tumor stage (p < 0.01), pTa vs. pT1 tumors (p < 0.05) and non-muscle-invasive vs. muscle-invasive tumors (p < 0.0001). CONCLUSIONS: Loss of galectin-8 might be an early step in the development of malignant lesions of the bladder and is a significant independent predictor of recurrence.

Decreased expression of galectin-3 predicts tumour recurrence in pTa bladder cancer.

Galectin-3 (gal-3) is a glycoprotein involved in various physiological cellular processes. Altered expression/loss of function of gal-3 is suggested to be involved in the pathogenesis and further progression of various human cancer entities. The aim of the present investigation was to elucidate the role of galectin-3 in the development and/or progression of non-muscle invasive (pTa, pT1) transitional cell carcinoma (TCC) of the urinary bladder. Gal-3 was analyzed by immunohistochemistry in 162 randomly selected non-muscle invasive bladder cancer specimens (pTa, 91; pT1, 71) using tissue microarray technique. It was compared with various patient and tumour characteristics (t-test). In addition, the role of gal-3 in association with tumour recurrence and progression was investigated (Log-rank test, Cox regression analysis). Gal-3 was found to be negatively correlated with tumour grade (p<0.02). Within the group of non-muscle invasive TCC, gal-3 could not differentiate between pTa and pT1 tumours (p=0.50), and within the subgroup of pTa tumours, loss of gal-3 determined the likelihood for the development of recurrent disease (p<0.03; Student's t-test). Furthermore, as demonstrated by Kaplan-Meier analysis, the expression level of gal-3 was identified to predict the duration of recurrence-free survival (p=0.01). In the multivariate analysis, gal-3 was found as an independent prognostic marker for predicting recurrence among the cohort of bladder tumours classified as pTa. In conclusion, loss of galectin-3 appears to be involved in the carcinogenesis of TCC and to serve as a valuable biological variable to identify a subgroup of Ta bladder cancer patients at high risk for the development of recurrent disease.

Intracranial aspergillosis in a non-immunocompromised patient treated for muscle-invasive bladder cancer.

We report a case of intracerebral Aspergillosis in a patient undergoing radical cystectomy for the treatment of muscle-invasive bladder cancer who did not reveal any deterioration of the immune system. Aspergillus fumigatus is an ubiquitously present, airborne fungus that tends to infect the upper respiratory tract. However, the latter was not observed in the patient presented. Complications in the form of an involvement of the central nervous system are very rarely recognized as a result of an Aspergillus infection and primarily occur in patients who are not immunologically competent. To our knowledge, we present the first case of intracerebral invasive Aspergillosis in an otherwise healthy patient diagnosed with an urological malignancy.