[Urinary diversion with or without simple cystectomy as a salvage option for benign diseases of the lower urinary tract]. / Harnableitungen mit oder ohne simple Zystektomie in der Salvage-Therapie benigner Erkrankungen des unteren Harntraktes.

Benign diseases of the lower urinary tract can occur as a result of oncological or neurological diseases or their respective therapies (e.g., surgery or radiation treatment) and can significantly reduce the quality of life for affected patients. Urinary diversion serves as a salvage option when all other therapeutic regimens have been carried out and proven unsuccessful. When selecting the suitable urinary diversion, a comprehensive clinical assessment of the patients is required in order to ensure long-term success. In some cases, a cutaneous, catheterizable pouch offers the last and only option for a long-term and definitive treatment of a patient's condition. Overall, a decreasing trend in the establishment of a continent urinary diversion is observed in Germany. Current data on benign indications for urinary diversion are limited. Therefore, further data collection and research are needed.

Management of Medium and Long Term Complications Following Prostate Cancer Treatment Resulting in Urinary Diversion - A Narrative Review.

The purpose of this narrative review is to discuss and highlight recently published studies regarding the surgical management of patients suffering from prostate cancer treatment complications. Focus will be put on the recalcitrant and more complex cases which might lead to urinary diversion as a definite, last resort treatment. It is in the nature of every treatment, that complications will occur and be bothersome for both patients and physicians. A small percentage of patients following prostate cancer treatment (radical prostatectomy, radiation therapy, or other focal therapies) will suffer side effects and thus, will experience a loss of quality of life. These side effects can persist for months and even years. Often, conservative management strategies fail resulting in recalcitrant recurrences. Prostate cancer patients with "end-stage bladder," "devastated outlet," or a history of multiple failed interventions, are fortunately rare, but can be highly challenging for both patients and Urologists. In a state of multiple previous surgical procedures and an immense psychological strain for the patient, urinary diversion can offer a definite, last resort surgical solution for this small group of patients. Ideally, they should be transferred to centers with experience in this field and a careful patient selection is needed. As these cases are highly complex, a multidisciplinary approach is often necessary in order to guarantee an improvement of quality of life.

The contrasting roles of Dysferlin during tumor progression in renal cell carcinoma.

BACKGROUND: The vesicle fusion protein Dysferlin (DYSF) is mainly known as a membrane repair protein in muscle cells. Mutations of DYSF lead to muscular dystrophies and cardiomyopathies. In contrast to other members of the Ferlin protein family, few is known about its role in cancer. Our study was designed to investigate the expression and functional properties of DYSF in ccRCC and its association with clinicopathological parameters and survival. MATERIAL AND METHODS: TCGA cohort: mRNA expression data of DYSF were extracted from TCGA for patients with ccRCC (n = 603; ccRCC n = 522, benign n = 81). Study cohort: mRNA expression of DYSF in ccRCC was determined using qPCR (n = 126; ccRCC n = 82, benign n = 44). Immunohistochemical staining against DYSF was performed on tissue microarrays to validate protein expression (n = 172; ccRCC n = 142, benign n = 30). Correlations between mRNA/protein expression and clinicopathological data were statistically tested. Following siRNA-mediated knockdown of DYSF in ccRCC cell line ACHN, cell migration, invasion and proliferation were investigated. RESULTS: Both DYSF mRNA and protein expression are significantly up-regulated in ccRCC tissue. DYSF mRNA expression decreased during tumor progression: lower expression levels were measured in higher stage/grade and metastatic ccRCC with independent prognostic significance for overall and cancer-specific survival. In contrast, protein expression correlated positively with pathological parameters. Overexpression showed tendency toward poor survival. Accordingly, knockdown of DYSF suppressed migration and invasion of ccRCC cells. CONCLUSION: DYSF mRNA and protein expression are opposingly involved in tumor progression of ccRCC. DYSF could be used as a prognostic biomarker to predict survival of patients with ccRCC.

A matched-pair analysis on survival and response rates between German and non-German cancer patients treated at a Comprehensive Cancer Center.

BACKGROUND: Research shows disparities in cancer outcomes by ethnicity or socio-economic status. Therefore, it is the aim of our study to perform a matched-pair analysis which compares the outcome of German and non-German (in the following described as 'foreign') cancer patients being treated at the Center for Integrated Oncology (CIO) Köln Bonn at the University Hospital of Bonn between January 2010 and June 2016. METHODS: During this time, 6314 well-documented patients received a diagnosis of cancer. Out of these patients, 219 patients with foreign nationality could be matched to German patients based on diagnostic and demographic criteria and were included in the study. All of these 438 patients were well characterized concerning survival data (Overall survival, Progression-free survival and Time to progression) and response to treatment. RESULTS: No significant differences regarding the patients' survival and response rates were seen when all German and foreign patients were compared. A subgroup analysis of German and foreign patients with head and neck cancer revealed a significantly longer progression-free survival for the German patients. Differences in response to treatment could not be found in this subgroup analysis. CONCLUSIONS: In summary, no major differences in survival and response rates of German and foreign cancer patients were revealed in this study. Nevertheless, the differences in progression-free survival, which could be found in the subgroup analysis of patients with head and neck cancer, should lead to further research, especially evaluating the role of infectious diseases like human papillomavirus (HPV) and Epstein-Barr virus (EBV) on carcinogenesis and disease progression.

Evaluation of Serum Biomarkers (FGF-2, HGF, MIF and PTN) in Patients With Testicular Germ Cell Cancer.

BACKGROUND/AIM: FGF-2, HGF, MIF and PTN have been suggested as biomarkers for testicular germ cell cancer patients in earlier studies. Our study was designed to validate these potential novel tumor markers. MATERIALS AND METHODS: Serum FGF-2, HGF, MIF and PTN levels were analysed using an ELISA technique in a screening cohort of 20 testicular germ cell cancer patients and 10 healthy men. MIF levels were measured in a validation cohort of 84 patients with testicular cancer, 24 with non-malignant testicular tumors and 64 healthy men. RESULTS: Serum FGF-2, HGF and PTN levels did not differ in cancer patients and healthy males within the screening cohort, whereas MIF was significantly increased among cancer patients. Within the validation cohort, a modest but insignificant increase of serum MIF was observed in TGCT patients compared to healthy men. MIF levels were not correlated with adverse clinical-pathological parameters. CONCLUSION: FGF-2, HGF, MIF and PTN are not suitable as non-invasive biomarkers for testicular germ cell cancer patients.

Systematic expression analysis of the mitochondrial respiratory chain protein subunits identifies COX5B as a prognostic marker in clear cell renal cell carcinoma.

OBJECTIVE: To analyze the expression of mitochondrial respiratory chain protein subunits in clear cell renal cell carcinoma. METHODS: Possible prognostic candidates were determined using The Cancer Genome Atlas database (n = 605). The database provided valid messenger ribonucleic acid expression data for 93 genes encoding for the subunits. Selected subunits were further investigated at the messenger ribonucleic acid and protein level by real-time polymerase chain reaction, western blot and immunohistochemistry with the cohorts of the University Hospital Bonn. RESULTS: The Cancer Genome Atlas messenger ribonucleic acid expression data indicated univariate and multivariate prognostic impact for seven subunits (NDUFS8, NDUFS7, COX5B, COX6B1, SDHD, COX15 and COX19). Using real-time polymerase chain reaction, significant downregulation (P < 0.05, n = 74) could be shown for COX5B, COX6B1, NDUFS7 and NDUF8 in clear cell renal cell carcinoma tissue. Survival analysis of polymerase chain reaction data showed a non-significant relationship (P = 0.067) of high COX5B expression and poor overall survival. Western blot (n = 8) and immunohistochemistry analysis (n = 167) confirmed significant COX5B downregulation on the protein level. Immunohistochemistry analysis identified COX5B as a prognostic marker for overall (P = 0.017) and cancer-specific survival (P = 0.042). CONCLUSIONS: The present study findings suggest downregulation of additional subunits of mitochondrial respiratory chain proteins in clear cell renal cell carcinoma. Remarkably, COX5B, a subunit of the respiratory chain complex IV, can be identified as a novel prognostic marker.

The European Prostate Cancer Centres of Excellence: A Novel Proposal from the European Association of Urology Prostate Cancer Centre Consensus Meeting.

BACKGROUND: High-quality management of prostate cancer is needed in the fields of clinics, research, and education. OBJECTIVE: The objective of this project was to develop the concept of "European Prostate Cancer Centres of Excellence" (EPCCE), with the specific aim of identifying European centres characterised by high-quality cancer care, research, and education. DESIGN, SETTING, AND PARTICIPANTS: A task force of experts aimed at identifying the general criteria to define the EPCCE. Discussion took place in conference calls and by e-mail from March 2017 to November 2017, and the final consensus meeting named "European Association of Urology (EAU) Prostate Cancer Centre Consensus Meeting" was held in Barcelona on November 16, 2017. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The required criteria were grouped into three main steps: (1) clinics, (2) research, and (3) education. A quality control approach for the three steps was defined. RESULTS AND LIMITATIONS: The definition of EPCCE consisted of the following steps: (1) clinical step-five items were identified and classified as core team, associated services, multidisciplinary approach, diagnostic pathway, and therapeutic pathway; (2) research step-internal monitoring of outcomes was required; clinical data had to be collected through a prespecified database, clinical outcomes had to be periodically assessed, and prospective trials had to be conducted; (3) educational step-it consists of structured fellowship programmes of 1yr, including 6mo of research and 6mo of clinics; and (4) quality assurance and quality control procedures, related to the quality assessment of the previous three steps. A limitation of this project was that the definition of standards and items was mainly based on a consensus among experts rather than being an evidence-based process. CONCLUSIONS: The EAU Prostate Cancer Centre Consensus Meeting defined the criteria for the identification of the EPCCE in the fields of clinics, research, and education. The inclusion of a quality control approach represents the novelty that supports the excellence of these centres. PATIENT SUMMARY: A task force of experts defined the criteria for the identification of European Prostate Cancer Centres of Excellence, in order to certify the high-quality centres for prostate cancer management.

Apelin and apelin receptor expression in renal cell carcinoma.

BACKGROUND: The APLNR (apelin receptor) has been shown to be an essential gene for cancer immunotherapy, with deficiency in APLNR leading to immunotherapy failure. The aim of this study is to investigate the expression of APLN (apelin) and APLNR in patients with renal cell carcinoma (RCC), and its association with clinicopathological parameters and survival. METHODS: Three well-characterised patient cohorts with RCC were used: Study cohort 1 (clear-cell RCC; APLN/APLNR mRNA expression; n = 166); TCGA validation cohort (clear-cell RCC; APLN/APLNR mRNA expression; n = 481); Study cohort 2 (all RCC subtypes; APLNR protein expression/immunohistochemistry; n = 300). Associations between mRNA/protein expression and clinicopathological variables/patients' survival were tested statistically. RESULTS: While APLN showed only very weak association with tumour histological grade (TCGA cohort), APLNR/mRNA protein expression correlate significantly with ccRCC aggressiveness. APLNR is expressed in tumour vasculature and tumour cells at different levels, and these expression levels associate with tumour aggressiveness in opposing directions. APLNR expression was negatively correlated with PD-L1 expression by tumour cells in a subset of patients with ccRCC. APLNR expression in either compartment is an independent prognostic factor for survival of patients with ccRCC. CONCLUSION: The APLNR/APLN-system appears to play an important role in ccRCC, warranting further clinical investigation.

Mitochondrial PIWI-interacting RNAs are novel biomarkers for clear cell renal cell carcinoma.

PURPOSE: PIWI-interacting RNAs (piRNAs) have been suggested to serve as biomarkers in cancer. In this study, we validated the expression profile of two piRNAs derived from mitochondria, piR-34536 and piR-51810, in tissue and serum of a cohort of clear cell renal cell carcinoma (ccRCC) patients. METHODS: Tissue and serum samples of patients with ccRCC were collected prospectively in our biobank. Total RNA was isolated from 118 ccRCC tissues, 75 normal renal tissues as well as 30 serum samples from patients with ccRCC, and 15 serum samples from patients with non-malignant diseases. The expression of piRNAs was determined using quantitative real-time PCR. RESULTS: Both piR-34536 and piR-51810 were downregulated in ccRCC compared to non-malignant renal tissue. Decreased tissue piRNA levels were significant and independent predictors of shortened progression-free, cancer-specific and overall survival of ccRCC patients. The piRNA levels in serum did not differ in ccRCC patients and control subjects. CONCLUSIONS: The expression of piR-34536 and piR-51810 in ccRCC tissues may be used as prognostic biomarkers in ccRCC.

tRNA-halves are prognostic biomarkers for patients with prostate cancer.

OBJECTIVE: Noncoding RNAs play an important role in carcinogenesis; a number of tRNA-halves are expressed in response to androgen stimulation and are involved in prostate cancer (CaP) initiation and progression. In this study, we evaluated the expression profile of androgen-dependent tRNA-halves in CaP. MATERIALS AND METHODS: Total RNA was isolated from formalin-fixed paraffin-embedded 58 CaP, and 25 benign prostate hyperplasia tissues. We also studied the expression in serum from 49 localized and 21 metastatic castration-resistant CaP samples. The ligation of a RNA adaptor molecule to the tRNA-halves allowed the specific amplification of 3'/5'-tRNA-halves using quantitative TaqMan reverse transcription polymerase chain reaction. The expression levels were correlated with clinicopathological parameters as well as prostate-specific antigen recurrence free survival. RESULTS: 5'-tRNA-Asp-GUC-half and 3'-tRNA-Asp-GUC-half were up-regulated in CaP tissues compared with benign prostate hyperplasia tissues. An increased expression level of all the 5 candidate tRNA-halves was associated with adverse clinicopathological parameters (pT-stage, pN-stage, prostate-specific antigen, International Society of Urological Pathology /ISUP grade) and a shorter time to biochemical relapse. In serum, 5'-tRNA-Glu-CUC-half was circulating at a higher level in metastatic castration-resistant CaP patients compared to patients with localized CaP. CONCLUSIONS: The androgen-dependent tRNA-halves can potentially act as biomarkers to monitor and predict the progression of CaP.

The knockdown of the Mediator complex subunit MED15 restrains urothelial bladder cancer cells' malignancy.

The Mediator complex, a multi-subunit protein complex, plays an integral role in regulating transcription. Genetic alterations of the mediator subunit 15 (MED15) in separate tumor entities have been described previously. However, till now, not much is known about the role of MED15 in urothelial bladder cancer (BCa). Using cBioPortal, database analysis was executed for the mRNA expression and survival analysis of MED15 in BCa. Immunohistochemistry (IHC) analysis against MED15 was performed on tissue microarrays with 18 benign, 126 BCa, and 38 metastases samples. The intensity evaluation was performed using a staining intensity score from 0 to 3 and associated with clinicopathological data. The BCa cell lines T24 and TCCSUP were used for the functional investigation. After the MED15 knockdown by small interfering (si)RNA, cell proliferation, migration and invasion were investigated. On the mRNA level, only a low number of alterations (2%) was found for MED15 in BCa. Due to the small count of events, there were no significant differences or tendencies in survival. For IHC, MED15 was found to have a higher expression in non-muscle invasive BCa compared with benign and muscle invasive BCa. For survival analysis, no significant differences between samples with or without overexpression of MED15 were found. In the functional analysis, proliferation, migration, and invasion were significantly reduced in BCa-cells following the transient siRNA-mediated MED15 knockdown. In summary, MED15 appears to play a role in the tumor parameters proliferation, migration, and invasion in BCa, but further investigations are necessary.

The knockdown of the mediator complex subunit MED30 suppresses the proliferation and migration of renal cell carcinoma cells.

BACKGROUND: The mediator complex consists of 33 subunits and plays a central role in transcription. Studies have already described the involvement of individual subunits, especially in carcinogenesis. With regard to the subunit MED30, this has, so far, only been confirmed in gastric and breast carcinoma. The role of MED30 in urological tumours is unknown. MATERIALS AND METHODS: First, a database analysis using cBioPortal was performed for the mRNA expression and survival analysis of MED30 in clear cell renal cell carcinoma (ccRCC) and papillary RCC (pRCC). The immunohistochemical analysis (IHC) against MED30 was performed on tissue microarrays (TMA), with benign, ccRCC, pRCC samples, and ccRCC-metastases. Intensity evaluation was performed using the IRS (Immunoreactive Score). The ccRCC cell lines ACHN and A-498 were used for the functional investigation of proliferation, migration, and invasion after the knockdown of MED30 by siRNA. RESULTS: In a database analysis by cBioPortal, it was shown that mRNA overexpression of MED30 in the pRCC was significantly associated with a poorer overall survival and progression-free survival. In the IHC, pRCC showed the highest level of MED30 expression, unfortunately without significant results in the survival analysis. The knockdown of MED30 resulted in a significant decrease in proliferation, migration, and invasion in ccRCC. CONCLUSION: In summary, MED30 seems to be involved in the progression of the RCC.

YRNA expression in prostate cancer patients: diagnostic and prognostic implications.

OBJECTIVE: To study the expression of YRNAs (Ro-associated Y), a novel class of non-coding RNAs, in prostate cancer (PCA) patients. METHODS: The expression of all four YRNAs (RNY1, RNY3, RNY4, RNY5) was determined in archival PCA (prostate adenocarcinoma, n = 56), normal (n = 36) and benign prostatic hyperplasia (BPH; n = 28) tissues using quantitative real-time PCR. Associations with clinicopathological parameters and prognostic role for biochemical recurrence-free survival were analysed. RESULTS: All YRNAs were significantly downregulated in PCA tissue compared to normal tissue (all YRNAs) and to BPH tissue (RNY4 and RNY5; RNY1 and RNY3 as trend). Among tumor ISUP grade groups, the most prominent differences in the expression were evident between groups 1 and 2 (RNY1, RNY3 und RNY4; all p < 0.05). Discrimination ability for normal/BPH tissue versus tumor tissue in ROC analysis (area under curve) was ranging from 0.658 (RNY1) to 0.739 (RNY4). Higher RNY5 expression was associated with poor prognosis (biochemical recurrence-free survival). CONCLUSION: The expression of YRNAs is altered in PCA and associated with poor prognosis (RNY5). Possible diagnostic role of YRNAs in prostate cancer should be investigated in further studies.

The Mediator complex subunit MED15, a promoter of tumour progression and metastatic spread in renal cell carcinoma.

BACKGROUND/OBJECTIVE: MED15 is a part of the multiprotein Mediator complex which is involved in the transcription of polymerase (Pol) II-dependent genes. Several studies in this field have reported altered expressions of distinct subunits in human malignancy. However, the role of MED15 in renal cell carcinoma (RCC) has not be investigated yet. METHODS: First, we performed an RNA expression and survival analysis of MED15 in RCC by using the database cBioPortal. To confirm these data on the protein level, we executed immunohistochemical (IHC) staining against MED15 on a tissue microarray containing 184 samples of the most common subtypes of the tumour at the various stages. Further, we performed functional analysis including proliferation, migration, and invasion assays on the RCC cell lines A-498 and ACHN following the siRNA-mediated MED15 knockdown. RESULTS: On the mRNA level, higher expression of MED15 was associated with worse patient survival rates. IHC staining validated this tendency, unfortunately the results were not significant. However, supporting this tendency, in vitro-assays showed a significant decrease in proliferation, migration, and invasion after knockdown of MED15. CONCLUSION: The research concludes that MED15 does seem to play a tumour promoting role in the progression and metastatic spread of renal cell carcinoma.

Serum miR-122-5p and miR-206 expression: non-invasive prognostic biomarkers for renal cell carcinoma.

Background: MicroRNAs (miRNA) play a relevant role in carcinogenesis, cancer progression, invasion, and metastasis. Thus, they can serve as diagnostic/prognostic biomarkers. The knowledge on circulating miRNAs for clear cell renal cell carcinomas (ccRCC) is limited. Our study was designed to identify novel biomarkers for ccRCC patients. Results: The serum small RNA expression profile was determined in 18 ccRCC and 8 patients with benign renal tumors (BRT) using small RNA sequencing. We detected 29 differentially expressed miRNAs (17 upregulated and 12 downregulated in ccRCC) in the expression profiling cohort. Based on the expression levels, we next validated serum miR-122-5p, miR-193a-5p, and miR-206 levels in an independent cohort (68 ccRCC, 47 BRT, and 28 healthy individuals) using quantitative real-time PCR. Serum expression levels of miR-122-5p and miR-206 were significantly decreased in ccRCC compared to healthy individuals. Both miRNAs were circulating at similar levels in ccRCC and BRT patients. miR-193a-5p expression levels were not different within the study cohort. High serum miR-122-5p and miR-206 levels were associated with adverse clinicopathological parameters: miR-122-5p levels were correlated with metastatic RCC and grade, and miR-206 with pT-stage and metastasis. Furthermore, high miR-122-5p and miR-206 serum levels were associated with a shorter period of progression-free, cancer-specific, and overall survival in patients with ccRCC. Conclusion: We identified serum miR-122-5p and miR-206 as novel non-invasive prognostic biomarkers for patients with ccRCC.

YRNA Expression Profiles are Altered in Clear Cell Renal Cell Carcinoma.

BACKGROUND: Noncoding RNAs play an important role in human carcinogenesis. YRNAs, a novel class of noncoding RNAs, have been identified as biomarkers in breast cancer patients. OBJECTIVE: To test the hypothesis that YRNA expression is dysregulated in clear cell renal cell carcinoma (ccRCC). DESIGN, SETTING, AND PARTICIPANTS: We first measured the expression of all known YRNAs (hY1, hY3, hY4, and hY5) in a screening cohort (30 ccRCC and 15 normal renal tissues). Subsequently, hY3 and hY4 were validated in an independent cohort (88 ccRCC and 59 normal renal tissues). Finally, hY3 and hY4 levels in serum samples from 30 ccRCC and 15 control individuals were measured. YRNAs were detected using quantitative real-time polymerase chain reaction. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relative expression values were analyzed using the Mann-Whitney-U test and Kaplan Meier estimates. RESULTS AND LIMITATIONS: Expression of hY3 and hY4 was increased in ccRCC samples compared with normal renal tissue, whereas hY1 and hY5 levels were similar. Expression levels of hY4 correlated with ccRCC stage and the presence of lymph node metastases. Neither hY3 nor hY4 were circulating at different levels in ccRCC patients and control individuals. CONCLUSIONS: The expression of hY3 and hY4 is altered in ccRCC and associated with advanced disease. PATIENT SUMMARY: In this report we studied the expression of noncoding YRNA in clear cell renal cell carcinoma tissue. We observed increased hY3 and hY4 expression levels in cancer tissues. However, expression levels were not different in the serum of patients with cancer or benign disease.

5'-tRNA Halves are Dysregulated in Clear Cell Renal Cell Carcinoma.

PURPOSE: In various malignancies RNA fragments are dysregulated. Our study was designed to determine the expression of 4, 5'-tRNA halves in the tissue and serum of patients with clear cell renal cell carcinoma. MATERIALS AND METHODS: Tissue and serum samples of patients with clear cell renal cell carcinoma and nonmalignant disease were collected prospectively in our biobank. We isolated total RNA from 95 clear cell renal cell carcinomas and 50 normal renal tissues as well as serum RNA from 27 patients with clear cell renal cell carcinoma and 13 with nonmalignant urological disease. To specifically determine the expression of 5'-tRNA halves we dephosphorylated and ligated an adaptor nucleotide to the 3' end of the tRNA halves. The expression levels of 4, 5'-tRNA halves (5'-tRNA-Arg-CCT, 5'-tRNA-Glu-CTC, 5'-tRNA-Leu-CAG and 5'-tRNA-Lys-TTT) were then measured by TaqMan® based quantitative reverse transcription-polymerase chain reaction. RESULTS: All studied 5'-tRNA halves were down-regulated in clear cell renal cell carcinoma tissues, indicating a potential role as a tumor suppressor. Furthermore, we noted decreased expression of 5'-tRNA halves in patients with adverse clinicopathological parameters. All 5'-tRNA halves were expressed at lower levels in nonorgan confined clear cell renal cell carcinoma. The 5'-tRNA-Lys-TTT halves inversely correlated with ISUP (International Society of Urological Pathology) grade. In patients with clear cell renal cell carcinoma 5'-tRNA-Arg-CCT, 5'-tRNA-Glu-CTC and 5'-tRNA-Lys-TTT halves circulated at lower levels than in control subjects, indicating relevance as noninvasive biomarkers. CONCLUSIONS: In patients with clear cell renal cell carcinoma 5'-tRNA halves have potential as diagnostic and prognostic biomarkers. The 5'-tRNA halves may act in a tumor suppressive manner, which requires further research to confirm.

Comprehensive Evaluation of Prostate Specific Membrane Antigen Expression in the Vasculature of Renal Tumors: Implications for Imaging Studies and Prognostic Role.

PURPOSE: Prostate specific membrane antigen is expressed by the endothelium of many tumors. The aim of the study was to find a rationale for prostate specific membrane antigen based imaging and investigate the prognostic role of vascular prostate specific membrane antigen expression in patients with renal cell carcinoma. MATERIALS AND METHODS: A total of 257 patients with renal cell carcinoma were included in study with a median followup exceeding 10.0 years. Prostate specific membrane antigen expression on tumor vessels was detected by immunohistochemistry. Vascular expression of FOLH1 gene (prostate specific membrane antigen) mRNA was investigated in clear cell carcinoma and papillary renal cell carcinoma using TCGA (The Cancer Genome Atlas) data. RESULTS: Endothelial prostate specific membrane antigen protein expression was higher in clear cell than in papillary and chromophobe renal cell carcinoma. Higher grade and stage, metastatic and lethal clear cell renal cell carcinoma showed higher prostate specific membrane antigen expression in tumor vessels. On univariate and multivariate analysis the intensity of positive vs negative endothelial prostate specific membrane antigen protein expression was significantly associated with overall survival. TCGA based analyses confirmed the prognostic role of vascular expression of FOLH1 mRNA. The analyses also supported the usefulness of prostate specific membrane antigen based imaging in cases of clear cell but not papillary renal cell carcinoma. CONCLUSIONS: We provide a rationale for further development of prostate specific membrane antigen targeted imaging in patients with clear cell renal cell carcinoma. The prognostic role of prostate specific membrane antigen was determined at the protein level in clear cell renal cell carcinoma and at the mRNA level in clear cell and papillary renal cell carcinoma.

The Contrasting Role of the Mediator Subunit MED30 in the Progression of Bladder Cancer.

BACKGROUND/AIM: The Mediator complex is a key regulator of gene transcription, and several studies have demonstrated altered expression of particular subunits in diverse human diseases, especially cancer. To date, nothing is known about the role of MED30 in bladder cancer. MATERIALS AND METHODS: We, therefore, performed an RNA expression and survival analysis of the subunit MED30 in 537 samples of bladder cancer by using the database cBioPortal. To validate these data on the protein level, we practiced immunohistochemical staining against MED30 on a tissue microarray containing 210 samples of all tumour stages and performed survival analyses. For functional analysis, the siRNA-mediated knockdown of MED30 was performed in the cell lines T24 and TCCSUP followed by proliferation, migration, and invasion assays. RESULTS: On the mRNA and protein levels, higher expression of MED30 is associated with better patient survival. In accordance with this, advanced T- and N-stages showed lower expression of MED30. In contrast, knockdown of MED30 led to reduction of the tumour parameters proliferation, migration, and invasion in the BCa cell lines. CONCLUSION: MED30 appears to be integrated in the progression of the urothelial tumour in the bladder.

Systematic Analysis of the Expression of the Mitochondrial ATP Synthase (Complex V) Subunits in Clear Cell Renal Cell Carcinoma.

Mitochondrial dysfunction is common in cancer and the mitochondrial electron transport chain is often affected in carcinogenesis. To date, little is known about the expression of the ATP synthase subunits in clear cell renal cell carcinoma (ccRCC). The NextBio database was used to determine an expression profile of the ATP synthase subunits based on published microarray studies. We observed down-regulation of 23 out of 29 subunits of the ATP synthase. Differential expression was validated exemplarily for 12 genes (ATP5A1, ATP5B, ATPAF1, ATP5C1, ATP5D, ATP5O, ATP5F1, ATP5G1, ATP5G2, ATP5G3, ATP5I, ATP5S; screening cohort ccRCC n=18 and normal renal tissue n=10) using real-time PCR. Additional eight genes (ATP5A1, ATP5B, ATPAF1, ATP5F1, ATP5G1, ATP5G2, ATP5G3, ATP5S) were internally validated within an enlarged cohort (ccRCC n=74; normal renal tissue n=36). Furthermore, down-regulation of ATP5A1, ATPAF1, ATP5G1/G2/G3 was confirmed on the protein level using Western Blot and immunohistochemistry. We observed that altered expression of ATPAF1 and ATP5G1/G2/G3 was correlated with overall survival in patients with ccRCC. In conclusion, down-regulation of many ATP Synthase subunits occurs in ccRCC and is the basis for the reduced activity of the mitochondrial electron chain. Alteration of the expression of ATP5A1, ATPAF1, and ATP5G1/G2/G3 is characteristic for ccRCC and may be prognostic for ccRCC patients' outcome.