Dimitrios Volanis

Environmental factors and genetic susceptibility promote urinary bladder cancer.

Cancer of the urinary bladder is the second most common malignancy of the genitourinary tract, currently accounting for up to 5% of all newly diagnosed tumours in the western world. Urinary bladder carcinogenesis seems to develop from the interaction of environmental exposure and genetic susceptibility. Smoking, specific industrial chemicals, dietary nitrates and arsenic represent the most important exogenous risk factors. Chromosomal abnormalities, silencing of certain genes by abnormal methylation of their promoter region, alterations in tumour suppressor genes and proto-oncogenes that induce uncontrolled cell proliferation and reduced apoptosis, are molecular mechanisms that have been reported in bladder carcinogenesis. In this article, we discuss the environmental risk factors of bladder cancer and we review the genetic and epigenetic alterations, including aberrant DNA methylation and deregulation of microRNAs expression. We also discuss the role of p53 and retinoblastoma suppressor genes in disease progression. Finally, we present recent reports on the use of molecular profiling to predict disease stage and grade and direct targeted therapy.

Expression of miRNAs involved in angiogenesis, tumor cell proliferation, tumor suppressor inhibition, epithelial-mesenchymal transition and activation of metastasis in bladder cancer.

PURPOSE miRNAs are noncoding RNAs that posttranscriptionally regulate gene expression. Altered expression and function have been observed in bladder cancer. We analyzed the expression profile of a group of miRNAs involved in bladder cancer angiogenesis, tumor cell proliferation, tumor suppressor inhibition, epithelial-mesenchymal transition and metastasis activation. Prognostic and diagnostic value, and validated targets were further examined. MATERIALS AND METHODS Using quantitative real-time polymerase chain reaction 77 bladder cancer cases and 77 matched tumor associated normal samples were investigated to determine the expression of miR-10b, 19a, 19b, 21, 126, 145, 205, 210, 221, 296-5p and 378. The relationship between miRNA expression, patient survival and tumor pathological features was also examined. RESULTS miR-10b, 19a, 126, 145, 221, 296-5p and 378 were significantly down-regulated in bladder cancer compared to adjacent normal urothelium. miR-145 was the most down-regulated microRNA of this group. miR-19b, 21, 205 and 210 showed no significant difference between the 2 tissue types. High miR-21 expression correlated with worse overall patient survival (p = 0.0099). Multivariate analysis revealed that miR-21, 210 and 378 may serve as independent prognostic factors for overall patient survival (p = 0.005, 0.033 and 0.012, respectively). miR-21 and 378 may serve as independent prognostic factors for recurrence (p = 0.030 and 0.031, respectively). miR-145, 221, 296-5p and 378 showed the best combined ROC curves for specificity and sensitivity. miRWalk analysis was used to identify validated miRNA target genes. Further Gene Ontology enrichment revealed the main classes of biological functions of these validated targets. CONCLUSIONS Most miRNAs analyzed are down-regulated in bladder cancer. They may serve as candidate biomarkers for diagnostic and prognostic purposes in the future.

Spotlight on Differentially Expressed Genes in Urinary Bladder Cancer

Introduction We previously identified common differentially expressed (DE) genes in bladder cancer (BC). In the present study we analyzed in depth, the expression of several groups of these DE genes. Materials and Methods Samples from 30 human BCs and their adjacent normal tissues were analyzed by whole genome cDNA microarrays, qRT-PCR and Western blotting. Our attention was focused on cell-cycle control and DNA damage repair genes, genes related to apoptosis, signal transduction, angiogenesis, as well as cellular proliferation, invasion and metastasis. Four publicly available GEO Datasets were further analyzed, and the expression data of the genes of interest (GOIs) were compared to those of the present study. The relationship among the GOI was also investigated. GO and KEGG molecular pathway analysis was performed to identify possible enrichment of genes with specific biological themes. Results Unsupervised cluster analysis of DNA microarray data revealed a clear distinction in BC vs. control samples and low vs. high grade tumors. Genes with at least 2-fold differential expression in BC vs. controls, as well as in non-muscle invasive vs. muscle invasive tumors and in low vs. high grade tumors, were identified and ranked. Specific attention was paid to the changes in osteopontin (OPN, SPP1) expression, due to its multiple biological functions. Similarly, genes exhibiting equal or low expression in BC vs. the controls were scored. Significant pair-wise correlations in gene expression were scored. GO analysis revealed the multi-facet character of the GOIs, since they participate in a variety of mechanisms, including cell proliferation, cell death, metabolism, cell shape, and cytoskeletal re-organization. KEGG analysis revealed that the most significant pathway was that of Bladder Cancer (p = 1.5×10−31). Conclusions The present work adds to the current knowledge on molecular signature identification of BC. Such works should progress in order to gain more insight into disease molecular mechanisms.

Role of the angiogenic components, VEGFA, FGF2, OPN and RHOC, in urothelial cell carcinoma of the urinary bladder

The objective of this study was to analyze the expression profile of the angiogenic components, vascular endothelial growth factor-A (VEGFA), basic fibroblast growth factor-2 (FGF2), osteopontin (OPN) and ras homolog gene family, member C (RHOC), in urothelial cell carcinoma (UCC) of the urinary bladder and to examine their role as candidate diagnostic biomarkers. Using qPCR, 77 samples of UCC of the urinary bladder and 77 matched tumor-associated normal samples were investigated to determine the expression of the four angiogenic components. The correlation between gene expression, patient survival and pathological features of the tumors was also examined. The VEGFA and OPN transcript levels were greater in the bladder cancer tissue than in the normal urothelium (P<0.001). Patients with higher VEGFA mRNA levels showed a tendency towards shorter cancer-specific survival. OPN levels showed a gradual increase, the lowest levels being found in non-invasive carcinoma and the highest in muscle invasive tumors. Elevated OPN levels indicated poor prognosis in connection with advanced disease stage (P<0.001). Both superficially invasive and muscle invasive tumors had significantly higher FGF2 levels compared to the control tissues (P=0.018 and P=0.050, respectively). Moreover, FGF2 was significantly higher in the metastatic vs. the non-metastatic tumors (P=0.0097). FGF2 levels exhibited a trend towards a correlation with worse patient survival. RHOC mRNA levels were higher in muscle invasive compared to superficially invasive tumors, as well as in grade III vs. grade I/II tumors. Furthermore, we detected worse overall survival for patients with high RHOC expression levels. VEGFA and FGF2 exhibited the best linear combination in the ROC curves for specificity and sensitivity. Thus, VEGFA and FGF2 may serve as candidate biomarkers for diagnostic purposes. Higher OPN expression may be used as a potential biomarker to predict patient survival relative to advanced tumor stage. However, further studies are required to investigate its role in urinary bladder carcinogenesis.

Incidence of needle-tract seeding following prostate biopsy for suspected cancer: a review of the literature

With the widespread clinical use of prostate‐specific antigen (PSA), biopsy of the prostate has become one of the most commonly performed urological procedures. In general it is well tolerated, although there is some morbidity and risk of infection. In recent years, there have been increasing concerns that prostate biopsy may lead to tumour seeding along the needle tract. The aim of the present paper was to review the evidence on the prevalence of tumour seeding after prostate biopsy and to define the risk of this event in the context of current clinical practice. A PubMed literature search was conducted in January 2014 according to the Preferred Reporting Items for Systematic Reviews and Meta‐analysis (PRISMA) statement. Literature was examined with emphasis on the incidence of seeding, clinical presentation and on risk factors including type of needle used, transrectal vs transperineal approach, as well as tumour grade and stage. In all, 26 publications were identified reporting needle‐tract seeding after prostate biopsy. In all, 42 patients with needle‐tract seeding were identified. In most cases, seeding was reported after transperineal biopsy of the prostate, while nine cases occurred after transrectal biopsy. Based on the reviewed series the incidence of seeding appears to be <1%. The increase in the number of biopsies and cores taken at each biopsy over the years has not resulted in an increase in the reported cases of seeding. In conclusion, seeding along the needle track is a rare complication after prostate biopsy. Its actual incidence is presently difficult to quantify. It is reasonable to advise appropriate counselling and take measures to reduce this event where possible; however, we do not advocate avoidance of biopsies as the benefits of appropriate cancer diagnosis and management outweigh any potential risks from seeding.

Platinum Priority – Review – Prostatic DiseaseComparative Oncologic and Toxicity Outcomes of Salvage Radical Prostatectomy Versus Nonsurgical Therapies for Radiorecurrent Prostate Cancer: A Meta–Regression Analysis

CONTEXT In the absence of randomised controlled trials comparing the oncologic, toxicity, and functional outcomes of salvage radical prostatectomy (SRP), salvage high-intensity focused ultrasound (SHIFU), salvage brachytherapy (SBT), and salvage cryotherapy (SCT), controversy exists as to the optimal salvage modality in radiorecurrent prostate cancer. OBJECTIVE We carried out a meta-regression analysis to determine whether there is a difference in oncologic, toxicity, and functional outcomes using data from original publications of salvage modalities in the postradiation setting. EVIDENCE ACQUISITION We performed a systematic review of PubMed/Medline citations according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. We included 63 articles in the analysis (25 on SRP, 8 on SHIFU, 16 on SCT, 14 on SBT). EVIDENCE SYNTHESIS Median values of the following variables were extracted from each study: patient age, length of follow-up, prostate-specific antigen (PSA) before radiotherapy (RT), PSA before salvage therapy, Gleason score before RT, and time interval between RT and salvage therapy. Functional, toxicity, and oncologic outcomes were measured according to rates of impotence, incontinence, fistula formation, urethral strictures, and biochemical recurrence. Meta-regression adjusting for confounders found no significant difference in oncologic outcomes between SRP and nonsurgical salvage modalities. SBT, SCT, and SHIFU appeared to have better continence outcomes than SRP. No significant difference in toxicity outcomes between modalities was found, although limitations such as reporting, selection, and publication bias and between-study heterogeneity must also be considered with these conclusions. CONCLUSIONS Oncologic outcomes are comparable for SRP and all three nonsurgical salvage modalities. We found no significant differences in toxicity outcomes among modalities; however, SRP appears to be associated with worse rates of urinary incontinence than SBT, SCT, and SHIFU. PATIENT SUMMARY We performed a meta-regression analysis to compare oncologic, functional, and toxicity outcomes between salvage radical prostatectomy and nonsurgical salvage modalities. Oncologic and toxicity outcomes appear to be similar; however, all nonsurgical salvage modalities may be associated with better continence outcomes.

Comparative Oncologic and Toxicity Outcomes of Salvage Radical Prostatectomy Versus Nonsurgical Therapies for Radiorecurrent Prostate Cancer: A Meta–Regression Analysis

CONTEXT In the absence of randomised controlled trials comparing the oncologic, toxicity, and functional outcomes of salvage radical prostatectomy (SRP), salvage high-intensity focused ultrasound (SHIFU), salvage brachytherapy (SBT), and salvage cryotherapy (SCT), controversy exists as to the optimal salvage modality in radiorecurrent prostate cancer. OBJECTIVE We carried out a meta-regression analysis to determine whether there is a difference in oncologic, toxicity, and functional outcomes using data from original publications of salvage modalities in the postradiation setting. EVIDENCE ACQUISITION We performed a systematic review of PubMed/Medline citations according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. We included 63 articles in the analysis (25 on SRP, 8 on SHIFU, 16 on SCT, 14 on SBT). EVIDENCE SYNTHESIS Median values of the following variables were extracted from each study: patient age, length of follow-up, prostate-specific antigen (PSA) before radiotherapy (RT), PSA before salvage therapy, Gleason score before RT, and time interval between RT and salvage therapy. Functional, toxicity, and oncologic outcomes were measured according to rates of impotence, incontinence, fistula formation, urethral strictures, and biochemical recurrence. Meta-regression adjusting for confounders found no significant difference in oncologic outcomes between SRP and nonsurgical salvage modalities. SBT, SCT, and SHIFU appeared to have better continence outcomes than SRP. No significant difference in toxicity outcomes between modalities was found, although limitations such as reporting, selection, and publication bias and between-study heterogeneity must also be considered with these conclusions. CONCLUSIONS Oncologic outcomes are comparable for SRP and all three nonsurgical salvage modalities. We found no significant differences in toxicity outcomes among modalities; however, SRP appears to be associated with worse rates of urinary incontinence than SBT, SCT, and SHIFU. PATIENT SUMMARY We performed a meta-regression analysis to compare oncologic, functional, and toxicity outcomes between salvage radical prostatectomy and nonsurgical salvage modalities. Oncologic and toxicity outcomes appear to be similar; however, all nonsurgical salvage modalities may be associated with better continence outcomes.