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Background: Water vapor thermal therapy (Rezum) is a minimally invasive treatment for benign prostatic enlargement (BPE). Studies reporting urodynamic results regarding the procedure are rare. Our study aimed to assess the effectiveness of Rezum on urinary outcome parameters in a consecutive series of patients and compare urodynamic data before and after treatment., Methods: We retrospectively evaluated all the patients treated with Rezum between 07/2017 and 12/2023 at our institution. Patients who had more than one Rezum intervention, those who were unable to void (i.e., catheter-dependent patients), and those with insufficient data were excluded from the data analysis. Descriptive outcomes, such as symptom scores (IPSS, IPSS-QoL), peak flow in uroflowmetry (Qmax), post-micturition residual urine volume (PVR), and prostate volume (PVol), were analyzed. If available, preoperative and postoperative urodynamic results were evaluated., Results: In total, 250 Rezum procedures were performed during the observational period. After applying the exclusion criteria, the data from 193 patients were included in the analysis. Patients achieved significant symptom relief as measured using the IPSS (46% reduction) and IPSS-QoL scores (41% reduction). Qmax improved by 4.8 ml/s, as the mean PVR significantly decreased by 50%. PVol and PSA values decreased by 30% and 27.5%, respectively. In 19/193 patients with a urodynamic evaluation, pre- and postoperative data analysis showed a significant reduction in the bladder outlet obstruction index (BOOI) by approximately 70%., Conclusions: Rezum is effective and can improve urinary symptoms. In appropriate patients, Rezum can significantly reduce the bladder outlet obstruction (BOO)., (© 2024. The Author(s).)

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.

Purpose: To investigate the safety and feasibility of spider silk interposition for erectile nerve reconstruction in patients undergoing robotic radical prostatectomy (RARP)., Methods: The major-ampullate-dragline from Nephila edulis was used for spider silk nerve reconstruction (SSNR). After removal of the prostate with either uni- or bilateral nerve-sparing, the spider silk was laid out on the site of the neurovascular bundles. Data analysis included inflammatory markers and patient reported outcomes., Results: Six patients underwent RARP with SSNR. In 50% of the cases, only a unilateral nerve-sparing was performed, bilateral nerve-sparing could be performed in three patients. Placement of the spider silk conduit was uneventful, contact of the spider silk with the surrounding tissue was mostly sufficient for a stable connection with the proximal and distal ends of the dissected bundles. Inflammatory markers peaked until postoperative day 1 but stabilized until discharge without any need for antibiotic treatment throughout the hospital stay. One patient was readmitted due to a urinary tract infection. Three patients reported about erections sufficient for penetration after three months with a continuous improvement of erectile function both after bi- and unilateral nerve-sparing with SSNR up to the last follow-up after 18 months., Conclusion: In this analysis of the first RARP with SSNR, a simple intraoperative handling without major complications was demonstrated. While the series provides evidence that SSNR is safe and feasible, a prospective randomized trial with long-term follow-up is needed to identify further improvement in postoperative erectile function due to the spider silk-directed nerve regeneration., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Macrophages and monocytes are main players in innate immunity. The relevance of mononuclear phagocyte infiltrates on clinical outcomes remains to be determined in native kidney diseases., Methods: Our cross-sectional study included 324 patients with diagnostic renal biopsies comprising 17 disease entities and normal renal tissues for comparison. All samples were stained for CD68 + macrophages. Selected groups were further subtyped for CD14 + monocytes and CD163 + alternatively activated macrophages. Using precise pixel-based digital measurements, we quantified cell densities as positively stained areas in renal cortex and medulla as well as whole renal tissue. Laboratory and clinical data of all cases at the time of biopsy and additional follow-up data in 158 cases were accessible., Results: Biopsies with renal disease consistently revealed higher CD68 + -macrophage densities and CD163 + -macrophage densities in cortex and medulla compared to controls. High macrophage densities correlated with impaired renal function at biopsy and at follow-up in all diseases and in diseases analyzed separately. High cortical CD68 + -macrophage densities preceded shorter renal survival, defined as requirement of permanent dialysis. CD14 + monocyte densities showed no difference compared to controls and did not correlate with renal function., Conclusion: Precise quantification of macrophage densities in renal biopsies may contribute to risk stratification to identify patients with high risk for end-stage renal disease (ESRD) and might be a promising therapeutic target in renal disease., (© 2022 Published by Elsevier Inc. on behalf of the International Society of Nephrology.)

Approximately 21% of patients with renal cell cancer (RCC) present with synchronous metastatic disease at the time of diagnosis, and metachronous metastatic disease occurs in 20-50% of cases within 5 years. Recent advances in adjuvant treatment of aggressive RCC following surgery suggest that biomarker-based prediction of risk for distant metastasis could improve patient selection. Biometrical analysis of TCGA-KIRC data identified candidate loci in the NK6 homeobox 2 gene ( NKX6-2 ) that are hypermethylated in primary metastatic RCC. Analyses of NKX6-2 DNA methylation in three gene regions including a total of 16 CpG sites in 154 tumor-adjacent normal tissue, 189 RCC, and 194 metastatic tissue samples from 95 metastasized RCC patients revealed highly significant tumor-specific, primary metastatic-specific, and metastatic tissue-specific hypermethylation of NKX6-2 . Combined CpG site methylation data for NKX6-2 and metastasis-associated genes ( INA , NHLH2 , and THBS4 ) demonstrated similarity between metastatic tissues and metastatic primary RCC tissues. The random forest method and evaluation of an unknown test cohort of tissues using receiver operator characteristic curve analysis revealed that metastatic tissues can be differentiated by a median area under the curve of 0.86 ( p = 1.7 × 10 -8 -7.5 × 10 -3 ) in 1000 random runs. Analysis of variable importance demonstrated an above median contribution for decision-making of at least one CpG site in each of the genes, suggesting superior informativity for sites annotated to NHLH2 and NKX6 -2. Thus, DNA methylation of NKX6-2 is associated with the metastatic state of RCC tissues and contributes to a four-gene-based statistical predictor of tumoral and metastatic renal tissues.

Available tests to detect clinically significant prostate cancer frequently lead to overdiagnosis and overtreatment. Our study assessed the feasibility of combining a urinary biomarker-based risk score (SelectMDx®) and multiparametric MRI outcomes in order to identify patients with prostate cancer on prostate biopsy with increased accuracy and reliability. Samples of 74 men with suspicion of prostate cancer and available multiparametric MRI were analysed in a prospective cross-sectional study design. First-voided urine for determination of HOXC6 and DLX1 mRNA levels was collected after digital rectal examination and prior to MRI/ultrasound fusion-guided prostate biopsy. All multiparametric MRI images were centrally reviewed by two experienced radiologists blinded for urine test results and biopsy outcome. The PI-RADS v2 was used. SelectMDx® score, PI-RADS and Gleason Sore were obtained. Associations between Gleason Score, PI-RADS scores and SelectMDx® were assessed using ANOVA and t-test. Sensitivity and specificity were assessed and evaluated as area-under-the-curve of the receiver operating characteristic. Upon biopsy, 59.5% of patients were diagnosed with prostate cancer, whereby 40.6% had high-grade prostate cancer (GS ≥ 7a). SelectMDx® scores were significantly higher for patients with positive biopsy findings (49.07 ± 25.99% vs. 22.00 ± 26.43%; p < 0.001). SelectMDx® scores increased with higher PI-RADS scores. Combining SelectMDx®, history of prior biopsy with benign histology and PI-RADS scores into a novel scoring system led to significant prostate cancer detection rates with tiered detection rate of 39%, 58%, 81% and 100% for Gleason grade group II, III, IV, and V, respectively. The area-under-the-curve for our novel sum score in receiver operating characteristic analysis was 0.84. The synergistic combination of two non-invasive tests into a sum score with increased sensitivity may help avoiding unnecessary biopsies for initial prostate cancer diagnosis. For confirmation, further prospective studies with larger sample sizes and univariate and multivariate regression analyses and decision curve analyses are required., Competing Interests: The authors received no specific funding for this work. The authors thank the “Fritz und Gertrud Stegmeier Stiftung” for the general financial support. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The detection of DNA methylation in primary tumor tissues could be relevant for early stratification of aggressive renal cell carcinomas (RCCs) as a basis for future personalized adjuvant therapy. Methylated TCGA KIRC based candidate CpG loci in INA, NHLH2 , and THBS4 that are possibly associated with RCC metastasis were evaluated by pyrosequencing in 154 paired normal adjacent and primary tumor tissues, as well as in 202 metastatic tissues. Statistical analysis was carried out by bivariate logistic regression for group comparisons, log rank survival analysis, and unsupervised and supervised analysis for the classification of tumors. Increased methylation of INA, NHLH2 , and THBS4 loci were significantly associated with distant metastasis in primary tumors ( p < 0.05), tissue-specific hypermethylation in metastatic ( p = 7.88 × 10 -8 , 5.57 × 10 -10 , 2.06 × 10 -7 ) and tumor tissues ( p = 3.72 × 10 -24 , 3.17 × 10 -13 , 1.58 × 10 -19 ), and shortened progression free survival in patients ( p = 0.03). Combined use of CpG site-specific methylation permits the discrimination of tissues with metastatic disease and reveals a significant contribution of CpG sites in all genes to the statistical classification model. Thus, metastasis in RCC is significantly associated with methylation alterations in INA, NHLH2 , and THBS4 loci, providing independent information for the potential early detection of aggressive renal cancers as a rationale for stratifying patients to adjuvant therapies.

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.

Background: DNA methylation is frequently observed in the development and progression of many human tumors as well as renal cell cancer (RCC). Tumor Associated Calcium Signal Transducer 2 (TACSTD2) participates in cell cycle progression through MAPK signalling pathway activation. Moreover, tumor-specific hypermethylation and association with aggressive cancer characteristics has been found for lung adenocarcinoma, hepatocellular carcinoma and cholangiocarcinoma. Whether TACSTD2 is tumor specifically hypermethylated in RCC or shows association of methylation with adverse clinicopathological parameters and survival of patients has not been investigated at yet., Methods: Quantitative methylation-specific PCR (qMSP) analysis of a locus in the intron 1 region of TACSTD2 gene was carried out in a cross-sectional study of 127 paired RCC and normal samples. In silico analysis of TACSTD2 methylation in the TCGA Kidney Renal Clear Cell Carcinoma (KIRC) dataset of 280 patients served as validation cohort. Statistical analyses were carried out using the two-sided paired t-test for matched tumor and normal sample comparisons, logistic regression for subgroup comparisons, Cox regression for analysis of recurrence free survival (RFS) and Pearson correlation analysis for correlation of TACSTD2 methylation and TACSTD2 mRNA in KIRC data., Results: Higher methylation levels in RCC were significantly associated with advanced disease (p < 0.001), high tumor stage (p = 0.003), tumor differentiation (p = 0.033) and presence of lymph node (p = 0.021) or distant metastases (p = 0.008). TACSTD2 hypermethylation was associated with a shorter RFS of patients and demonstrate statistical independency from clinical parameters as state of metastasis, tumor stage, grade and state of advanced disease. In silico validation using TCGA KIRC data also demonstrated association of TACSTD2 loci with adverse clinicopathology and shortened RFS of patients. In addition, in silico analyses of TCGA KIRC data showed an inverse correlation between DNA methylation levels of TACSTD2 and mRNA expression., Conclusions: Our results suggest an association between TACSTD2 methylation and disease progression and clinical course of RCC.

Background: While a considerable number of tumor-specific hypermethylated loci have been identified in renal cell cancer (RCC), DNA methylation of loci showing successive increases in normal, tumoral, and metastatic tissues could point to genes with high relevance both for the process of tumor development and progression. Here, we report that DNA methylation of a locus in a genomic region corresponding to the 3'UTR of the transcription factor T-box brain 1 (TBR1) mRNA accumulates in normal renal tissues with age and possibly increased body mass index. Moreover, a further tissue-specific increase of methylation was observed for tumor and metastatic tissue samples., Results: Biometric analyses of the TCGA KIRC methylation data revealed candidate loci for age-dependent and tumor-specific DNA methylation within the last exon and in a genomic region corresponding to the 3'UTR TBR1 mRNA. To evaluate whether methylation of TBR1 shows association with RCC carcinogenesis, we measured 15 tumor cell lines and 907 renal tissue samples including 355 normal tissues, 175 tissue pairs of normal tumor adjacent and corresponding tumor tissue as well 202 metastatic tissues samples of lung, bone, and brain metastases by the use of pyrosequencing. Statistical evaluation demonstrated age-dependent methylation in normal tissue (R = 0.72, p < 2 × 10 -16 ), association with adiposity (P = 0.019) and tumor-specific hypermethylation (P = 6.1 × 10 -19 ) for RCC tissues. Comparison of tumor and metastatic tissues revealed higher methylation in renal cancer metastases (P = 2.65 × 10 -6 )., Conclusions: Our analyses provide statistical evidence of association between methylation of TBR1 and RCC development and disease progression.

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.

DNA methylation plays an important role in the genesis and progression of tumor diseases. To identify new DNA methylation markers possibly associated with the clinical characteristics of renal cell carcinoma (RCC), we investigated loci in the sarcosine dehydrogenase (SARDH) gene. SARDH is involved in the metabolism of the glycine‑derivative sarcosine and is closely linked through a functional control loop. Statistical evaluation of methylation data and clinical characteristics of patients showed that kidney tumors with clinically aggressive features such as a high tumor stage, positive lymph nodes, distant metastases or a previously advanced tumor status exhibited significantly lower methylation of a locus in the SARDH gene. Moreover, SARDH methylation was found to be a significant prognostic factor for recurrence‑free survival in RCC patients showing statistical independence from the clinical prognosticators, grade, stage and state of metastasis. In conclusion, the methylation status of the SARDH‑CGI was identified as an independent prognostic candidate marker for RCC.

Recent studies have shown that NELL1 expression is silenced epigenetically in human renal cell cancer (RCC) tissues and in RCC cell lines. However, it remains unknown whether NELL1 promoter methylation observed in clinical specimens might be associated with the clinicopathology or survival of patients with RCC. We analyzed NELL1 DNA methylation in tissues from patients with RCC and in adjacent normal renal tissues. In addition, we evaluated NELL1 methylation in cell lines derived from different urogenital tumors (prostate cancer, urothelial cancer and RCC). We performed regression analyses to determine whether NELL1 methylation is associated with clinicopathological parameters and recurrence‑free survival (RFS). This cross‑sectional study included 98 patients with RCC and 63 paired tumor and adjacent normal tissue samples. We analyzed a locus in the intron 1 region of NELL1 with pyrosequencing. We performed in silico analysis of NELL1 methylation in the TCGA Kidney Renal Clear Cell Carcinoma (KIRC) data set (n=284 patients), which served as a validation study. Statistical analyses were performed with the two‑sided paired t‑test for paired tumor and adjacent normal samples. We used logistic regression for subgroup comparisons and Cox regression for RFS comparisons. The mean methylation level was 6.8% higher in RCC tissues compared to paired adjacent normal tissues (paired t‑test, P<0.001). Methylation levels in RCC were associated with advanced disease (P=0.002), the presence of distant metastases (P=0.004), and shorter RFS (P=0.035, HR: 4.15). In silico validation with TCGA KIRC data for adjacent loci also demonstrated that high relative methylation levels were associated with adverse clinicopathology and shortened RFS. Our results suggest that NELL1 methylation contributes to RCC disease progression. This finding could provide a clinical marker to complement recent functional analyses in tumor models.

Objectives: We had previously demonstrated changes in defecation after radical cystectomy (RC). Reports addressing long-term bowel disorders following RC are rare. This cross-sectional study evaluates long-term bowel issues in a large cohort., Material and Methods: A questionnaire assessing changes in bowel function (diarrhea, constipation, urge to defecate, sensation of incomplete defecation, and flatulence) and its effect on quality of life was developed based on the gastrointestinal quality of life index and distributed in collaboration with the German bladder cancer support group. There were 431 evaluable questionnaires. For the analyses, we focused on patients that had the RC>1 year ago (n = 324)., Results: Current bowel problems were reported by 42.6% of patients. The most frequent bowel problems were flatulence (48.8%), diarrhea (29.6%), and sensation of incomplete defecation (22.5%). In cases of bowel problems, 39.7% and 59.8% of the patients indicated life restriction and dissatisfaction, respectively. Prevalence of diarrhea and flatulence were significantly higher>12 (vs. ≤12) months following RC. Both symptoms significantly correlated with younger age at RC, life restriction, lower quality of life, lower health state, and lower energy level. Additionally, diarrhea significantly correlated with pouches as urinary diversion (vs. ileal conduit or ureterocutaneostomy) and higher dissatisfaction level., Conclusions: To our knowledge this is the largest cohort evaluating long-term bowel symptoms after RC. Diarrhea is a prominent symptom after RC with a high impact on daily life that leads to dissatisfaction. A better understanding of long-term bowel symptoms could be translated into optimized surgical procedures, postoperative medication/nutrition, and patient education., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Massive bleeding of the urogenital tract is, in the same way as acute bleeding from all other organs, a medical emergency and necessitates precise diagnostics and treatment. In this article the topic is addressed in four main categories: first the inflammatory causes are discussed, followed by surgical, traumatic and neoplastic causes of massive bleeding. Subsequently, the rare but clinically relevant causes of acute and massive bleeding are described.

A range of new treatment options has recently become available for patients with advanced metastatic castration-resistant prostate cancer (mCRPC). Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone is continued when performing chemotherapy or androgen deprivation with new second-generation therapeutic agents such as enzalutamide or abiraterone acetate. Despite the fact that free testosterone (FT) is the biologically active form, it is common practice that androgen suppression is monitored via total testosterone levels only. The aim of the present study was to evaluate the role of FT as a prognostic biomarker for cancer-specific survival (CSS) and its feasibility as an ADT monitoring biomarker in patients with mCRPC for the first time. The requirement for continued ADT in mCRPC patients is discussed within the basis of the current literature. A total of 34 patients with continuous measurements of FT levels and mCRPC status underwent therapy with docetaxel, abiraterone acetate, enzalutamide, cabozantinib, carboplatin or cabazitaxel. Data were obtained from the Departments of Urology and Urological Oncology, Hannover Medical School (Hannover, Germany) between March 2009 and April 2014. A cutoff point of 0.5 pg/ml was used to discriminate between patients according to FT levels. Statistical evaluation of CSS was performed by applying Kaplan Meier survival estimates, multivariate Cox regression analyses and log-rank tests. The median age of all 34 patients was 72 years (range, 51-86 years). The mean follow-up interval was 16.1 months (range, 0.7-55.6 months). Despite the fact that all patients were undergoing androgen deprivation, the mean serum FT levels for each patient varied; the mean FT concentration in the cohort was 0.328 pg/ml, ranging from 0.01-9.1 pg/ml. A notable difference with regard to CSS was observed for patients with regard to serum FT concentration; CSS was significantly longer for patients with a serum FT level below the cutoff level (43.6 vs. 17.3 months, respectively, P=0.0063). Upon multivariate Cox regression analysis, the mean FT concentration during treatment remained a significant prognostic factor for CSS (hazard ratio, 1.22; 95% confidence interval, 1.03-1.43; P=0.0182). In conclusion, in patients with mCRPC, the serum FT level is a strong predictor of CSS in patients under therapy with second-line anti-hormonal therapeutic medication and chemotherapy. It may be concluded that FT levels should be included into the routine control of androgen suppression while under treatment with ADT and second-generation hormonal therapy.

The relevance of Corticotropin Releasing Hormone (CRH)-system in human malignancies is a question of growing interest. Here we investigated hypermethylation and epigenetic silencing of the CRH-Binding Protein (CRHBP) gene in clear cell renal cell cancer (ccRCC). Relative methylation of the CRHBP CpG island (CGI) was determined in 17 tumor cell lines as well as 86 ccRCC samples and 66 paired normal tissues using pyrosequencing and quantitative methylation specific PCR of bisulfite converted DNA. Results were statistically compared with relative mRNA expression levels of CRHBP and clinicopathological parameters of patients. Re-expression of CRHBP following 5-aza-2´-deoxycytidine treatment was investigated by quantitative mRNA expression analysis. Real-time impedance analysis was applied for analysis of invasiveness of renal tumor cells following si-RNA knockdown of CRHBP expression or ectopic expression of CRHBP. We found the CRHBP CGI to be frequently methylated in tumor cell lines of renal, prostatic, and bladder cancer. Comparison of methylation in normal and paired renal cancer tissue specimens revealed hypermethylation of the CRHBP CGI in tumors (p<1*10-12). DNA methylation and decreased mRNA expression were correlated (R = 0.83, p<1*10-12). Tumor cell lines showed 5-aza-2´-deoxycytidine dependent reduction of methylation and re-expression of CRHBP was associated with altered cellular invasiveness of renal cancer cells in real-time impedance invasion assays. Hypermethylation and inverse relationship with mRNA expression were validated in silico using the TCGA network data. We describe for the first time tumor specific epigenetic silencing of CRHBP and statistical association with aggressive tumors thus suggesting the CRH system to contribute to the development of kidney cancer., Competing Interests: The authors have declared that no competing interests exist.

The era of cytokines, given to patients with metastatic renal cell carcinoma (mRCC) as part of an unspecific immunomodulatory treatment concept, seems to have ended with the introduction of targeted therapies. However, preliminary data from studies on treatment with checkpoint inhibitors (e. g. anti-PD-1 and anti-PD-L1) may point the way to second-generation immunotherapy. The rationale of such immunomodulatory treatment is to stop or interrupt the tumour from "escaping" the body's immune defence. Thompson et al. report that increased protein expression of PD-L1 (CD274/ B7-H1) in tumour cells and tumour-infiltrating immune cells (TILs; lymphocytes and histiocytes) is associated with unfavourable clinical pathological parameters as well as poor survival. In small pilot groups of mRCC patients it was found that increased PD-L1 protein expression in tumours and TILs may be correlated with the objective response to anti-PD-1 treatment. Sometimes, however, a very wide variety of response rates was observed, which raises the question if this can be explained by individual expression levels of PD-L1 (CD 274) or PD-1 (PDCD1).Recently published data from the Cancer Genome Atlas (TCGA) Kidney Renal Clear Cell Carcinoma (KIRC) Network now provide a genome-wide data base that allows us to review or validate the molecular results obtained in clear cell renal cell carcinomas (ccRCC) to date.In this study, we analysed the TCGA KIRC mRNA expression data for PD-L1 and PD-1 for a possible association with clinical pathological parameters and the survival of 417 ccRCC patients.The mRNA expression of PD-L1 in primary nephrectomy specimens revealed no significant association with unfavourable clinical parameters. Interestingly, though, a positive correlation with patient survival was found (HR=0,59, p=0,006).These results, which partly contradict the concept applied to date, point out the necessity to ascertain the characteristics of PD-L1 and PD-1 expression at mRNA and protein level in an appropriately sized patient population and evaluate the clinical significance., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Patients after radical cystectomy (RC) frequently complain about bowel disorders (BDs). Reports addressing related long-term complications are sparse. This cross-sectional study assessed changes in bowel habits (BH) after RC., Methods: A total of 89 patients with a minimum follow-up ≥1 year after surgery were evaluated with a questionnaire. Patients with BD prior to surgery were excluded. Symptoms such as diarrhea, constipation, bloating/flatulence, incomplete defecation, uncontrolled stool loss, and impact on quality of life (QoL) were assessed., Results: A total of 46.1 % of patients reported changes in BH; however, only 25.8 % reported experiencing related dissatisfaction. Primary causes of dissatisfaction were diarrhea and uncontrolled stool loss. The most common complaints were bloating/flatulence and the feeling of incomplete defecation, but these symptoms did not necessarily lead to dissatisfaction or impairment in quality of life. No difference was identified between an orthotopic neobladder and ileal conduit, and even patients without bowel surgery were affected. QoL, health status, and energy level were significantly decreased in unsatisfied patients., Conclusions: About 25 % of patients complain about BDs after RC. More prospective studies assessing symptoms, comorbidities, and dietary habits are necessary to address this issue and to identify strategies for follow-up recommendations.

GATA-binding proteins 1 (GATA1) and 2 (GATA2) are zinc-finger transcription factors and belong to the GATA family proteins 1-6. GATA1 interacts with the TP53 tumor suppressor gene, and both GATAs have been shown to be involved in cell growth, apoptosis, and tumorigenesis of several solid tumors. GATA1 and GATA2 expression alterations are associated with poor survival and adverse clinicopathology in prostate and colorectal cancer, while the significance and prognostic value in clear cell renal cell carcinoma (ccRCC) has not been investigated as yet. We investigated relative messenger RNA (mRNA) expression levels of GATA1 and GATA2 in 77 ccRCC and 58 paired adjacent noncancerous renal tissues by quantitative real-time reverse-transcribed PCR. Relative mRNA expression levels were determined using the ΔΔCt method. GATA1 and GATA2 expression levels were significantly decreased in tumor tissues compared with normal tissues (p < 0.001, paired t test). In univariate logistic regression analysis, decreased GATA1 and GATA2 expression levels were associated with advanced tumor disease (p = 0.005 and 0.008), positive distant metastasis (p = 0.03 and 0.001), and lymph node metastasis status (p = 0.011 and 0.038). Reduced expression levels of GATA1 and GATA2 were associated with an increased risk of disease recurrence (p = 0.005 and 0.006; hazard ratio = 0.05 and 0.21). Pairwise bivariate analysis after adjusting for clinicopathological parameters revealed relative mRNA expression of GATA1, but not GATA2, as an independent candidate prognosticator for ccRCC. Our results support that GATA1 and GATA2 are involved in ccRCC tumor biology possibly affecting tumor development and aggressiveness.

Objective: To provide first insights into the potential role of iNOS expressed by skull base chordoma, which causes brainstem compression in and around Barrington's nucleus, and its effect on the micturition center., Methods: Urodynamic testing of 22 symptomatic patients was performed. All women and men with skull base chordoma treated in two hospitals in Germany between 1986 and 2007 were studied. Lower urinary tract symptoms (LUTS) were documented in patients with acute brainstem compression due to local chordoma growth positive for iNOS expression. Brain magnetic resonance (MRI) images of the lesions of the symptomatic patients were performed., Results: Of 74 treated patients, 22 (7 women, 15 men) with a median age of 37 years were evaluated with voiding diaries and computer urodynamic investigation. Urodynamic testing of 22 symptomatic patients with positive iNOS expression of skull base chordoma revealed detrusor overactivity in 55 %, low-compliance bladder in 14 %, detrusor sphincter dyssynergia in 45 % and uninhibited sphincter relaxation in 27 %. There was a significant correlation between strong iNOS expression (score 3-6) in skull base chordoma and severe urinary symptoms (p = 0.003, Spearman ρ = 0.526)., Conclusions: The expression of iNOS in skull base chordoma compressing the dorsolateral pons, in and around Barrington's nucleus, may influence the pontine micturition center (PMC) and be responsible for lower urinary tract symptoms. Nitric oxide may possibly act as a neurotransmitter. We assume that the high infiltration of chordoma with monocyte/macrophages enhances the release of nitric oxide, as monocyte/macrophages are the main source of iNOS.

Neurofilament Heavy polypeptid (NEFH) belongs to the group of type IV intermediate filament proteins. DNA methylation of the NEFH promoter and loss of expression have previously been shown to activate the AKT/β-catenin pathway in tumor cells. When identifying hypermethylation of the NEFH CpG island (CGI) in renal cell cancer (RCC) we asked whether methylation could provide clinical or prognostic information for RCC and/or predict therapy response in patients with metastatic RCC (mRCC) undergoing antiangiogenic therapy. Relative methylation of the NEFH CGI was analyzed in 132 RCC samples and 83 paired normal tissues using quantitative methylation-specific PCR. Results were statistically compared with tumor histology, clinicopathological parameters, progression-free survival (PFS) as well as with overall survival (OS) in a subset of 18 mRCC patients following antiangiogenic therapy regimens. The NEFH CGI methylation demonstrated a tumor-specific increase (P < 0.001), association with advanced disease (P < 0.001), and distant metastasis (P = 0.005). Higher relative methylation was also significantly associated with a poor PFS (HR = 8.6, P < 0.001) independent from the covariates age, gender, diameter of tumors, state of advanced disease, and local and distant metastasis. Median OS following targeted therapy was 29.8 months for patients with low methylation versus 9.8 months for the group with high methylation (P = 0.028). We identified NEFH methylation as a candidate epigenetic marker for prognosis of RCC patients as well as prediction of anti-vascular endothelial growth factor-based therapy response., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To provide the first insights into the potential role of skull base chordoma, which causes brainstem compression in and around Barrington's nucleus and its effect on the micturition center. Chordoma is a rare malignant bone tumor that originates from the remnants of the embryonic notochord, which normally forms and dissolves during early fetal development. Although it is a slowly growing tumor, it displays local invasive growth., Methods: Urodynamic testing of 22 symptomatic patients was performed. All women and men with skull base chordoma treated in 2 hospitals in Germany between 1986 and 2007 were studied. Follow-up periods ranged from 6 months to 10 years. Lower urinary tract symptoms were documented in patients with acute brainstem compression because of local chordoma growth., Results: Of 74 patients treated, 22 (7 women, 15 men) with a median age of 37 years were evaluated with voiding diaries and computer urodynamic investigation. Urodynamic testing of 22 symptomatic patients revealed detrusor overactivity in 55%, low compliance bladder in 14%, detrusor-sphincter dyssynergia in 45%, and uninhibited sphincter relaxation in 27%. Despite the description of incomplete emptying and urgency, 4 patients had normal urodynamic findings (18%). Brain magnetic resonance images of the lesions of the symptomatic patients were obtained to determine the side of lesions., Conclusion: The dorsolateral pons, including pontine reticular nucleus and the reticular formation and the locus coeruleus, seems to be mainly responsible for lower urinary tract symptoms in our patients with skull base chordoma and brainstem compression., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Transcriptional inactivation and CpG island (CGI) methylation of GATA transcription factor family members GATA3 and GATA5 have been reported for a few types of human cancer. Whether high-density CGI methylation of GATA3 or GATA5 is associated with the clinical course of patients with renal cell cancer (RCC) has not been clarified. Quantitative methylation-specific PCR assays were carried out to analyze 25 tumor cell lines including 6 RCC lines and 119 RCC and 87 adjacent normal tissues for the presence of densely methylated sequences. Methylation values were statistically compared with clinicopathological and recurrence-free survival (RFS) data for patients. Comparison of GATA3 and GATA5 methylation in different tumor cell lines revealed a marker-specific methylation characteristic with high and frequent signals for both methylation marks in RCC lines. GATA3 and GATA5 CGI relative methylation levels were found to be strongly associated with the state of metastasis (P=0.003 and P<0.001, respectively) and advanced disease (P=0.024 and P<0.001, respectively). Moreover, an independent decrease in RFS in Cox proportional hazard analysis was found for tumors exhibiting high GATA5 methylation (P<0.001, hazard ratio, 19.3; 95% confidence interval, 4.58-81.6). Epigenetic alterations in GATA family members may be associated with aggressive tumor phenotypes in RCC, and in the case of GATA5, may serve as a new independent molecular marker for aggressiveness and disease progression.

Background: Numerous studies have shown a positive correlation between elevated C-reactive protein (CRP) and systemic spread of malignancies. The goal of the current study was to assess the predictive significance of preoperative CRP in patients undergoing radical cystectomy (RC)., Material and Methods: Preoperative CRP values were measured in 194 patients undergoing RC because of urothelial carcinoma between 1996 and 2005. Elevated CRP level was defined as ≥ 5 mg/l., Results: Preoperative increased CRP values were detected in 89 (45.9%) patients and these patients were more likely to have advanced tumor stages (pT3-4), positive resection margins and positive lymph nodes. Advanced urinary diversions were more common in patients with normal CRP values. In multivariate analysis, CRP was identified as an independent prognostic indicator for poor cancer-specific survival., Conclusion: The results confirm previous reports that showed a prognostic significance of preoperative CRP elevation.

Chordomas are locally invasive tumors that have a tendency to relapse despite optimal treatment. Specific biological markers might be used to describe their behavior. There is currently no agreement regarding the best way to manage intracranial chordomas. We studied the expression of vascular endothelial growth factor receptor 2 (VEGFR-2), inducible nitric oxide synthase (iNOS), and Ki-M1P in 145 paraffin-embedded tumors. The purpose of our study was to determine: (a) the role of potent angiogenic factors VEGFR-2 and iNOS and their relationship to each other in skull base chordoma and (b) the role of monocytes/macrophages as a potential iNOS source in the angiogenic process. A series of 74 chordoma patients for a total of 145 lesions (including 71 recurrent lesions) and 10 specimens from embryonic notochord were investigated for the expression of iNOS, VEGFR-2, Ki-M1P, and CD-34 using immunohistochemistry. In the majority of the chordomas, correlations were found between iNOS and the immunoreactivity of Ki-M1P (r = 0.5303, P < 0.0001). Furthermore, the expressions of Ki-M1P was correlated with VEGFR-2 (r = 0.4181, P < 0.0001). Our results indicate that chordomas may respond to receptor tyrosine kinase inhibitors such as VEGFR-2 or modulators of other downstream signaling molecules. The future of VEGFR-2 and iNOS inhibitors as therapeutic agents in the treatment of chordoma will be clearer over the next years as results of the current clinical trials become available and as the factors regulating angiogenesis and the interactions between these factors are elucidated. However, appropriate functional experiments remain to be conducted to prove such a hypothesis.