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.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.euf.2015.09.00

Mixed adenoneuroendocrine carcinoma of the urethra

Mixed adenoneuroendocrine carcinoma (MANEC) is a rare tumour found predominantly in the gastrointestinal tract. Comprising adenocarcinomatous and neuroendocrine components, MANEC have been reported in the bladder. We report the first case to our knowledge of a MANEC arising in the urethra. A 62-year-old woman presented with a suburethral mass. Initial excision of the mass revealed it to be a MANEC. Immunohistochemistry staining was positive for CK20 and synaptophysin associated with neuroendocrine tumours. Cross-sectional imaging ruled out metastases and the patient underwent radical urethrectomy, vaginal reconstruction and Mitrofanoff urinary diversion. The patient declined adjuvant chemotherapy and remained under regular surveillance. MANECs are uncommon tumours and treatment was therefore guided by expert opinion. A multidisciplinary approach is essential with the early involvement of surgeons, oncologists, histopathologist, radiologist and neuroendocrine specialists.</p

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

Comparative study of the expression of RHO kinases in urinary bladder cancer

Urinary bladder cancer (BC) is the most common malignancy of the urinary tract, responsible for significant mortality and morbidity worldwide. In Europe, an estimate of 105.000 new cases of bladder cancer are diagnosed annually, while approximately 20.000 patients die from bladder cancer each year. Nearly all bladder cancers are carcinomas, arising from the urothelium. At presentation, 75-85% of tumours are restricted to the mucosa, or invade the lamina propria mucosae. The remainder present with invasion of the muscular layer of the bladder wall or extend to perivesical tissue, adjacent organs and even the pelvic wall. The behaviour of urothelial cell carcinoma (UCC) is highly diverse and defined by two separate, but related processes: tumour recurrence and progression. In specific, more than 60% of the superficial tumours will recur at least once and progress to less differentiated or invasive neoplasms in a significant percentage of patients. In current clinical practice the most useful prognostic parameters are tumour grade, stage, size, prior recurrence rate and the synchronous presence of carcinoma in situ (CIS). However, neither recurrence nor progression can be predicted accurately and a better understanding of the natural history of UCC is expected upon the elucidation its molecular mechanisms. Rho kinases comprise a major subgroup of the Ras superfamily that mediate housekeeping aspects of cell biology. In particular, Rho kinases play a fundamental role in the reorganization of actin and microtubule cytoskeleton. Therefore, Rho proteins govern a variety of cytoskeletondependent processes including alterations in cell shape, polarity, adhesion, cell motility, as well as cell to cell and cell to matrix interactions. Furthermore, Rho proteins appear to be involved in gene transcription by activating Serum Response Factor (SRF) and in the regulation of cell cycle progression, growth and apoptosis. Rho members affect the process of tumourigenesis either by over-expression of some members of the family with oncogenic activity or by down-modulation of other members with suggested tumour suppressor activity. Moreover, since Rho GTPases regulate actomyosin-based contractility and extracellular matrix remodelling, they may be involved in the transmigration of cells, thereby facilitating local invasiveness and metastasis. In the present study we investigated the expression of RhoA, RhoB, RhoC, Rac1 and Cdc42 kinases in UCC of the urinary bladder. Additionally, we determined the expression profile of 107 Rho-associated genes, including GTPases, GDIs, GAPs and GEFs. The expression was investigated using microarrays, qPCR and Western blotting in 77 UCC specimens compared to paired normal urothelium. Computational analysis was also performed on Gene Expression Omnibus datasets in order to further elucidate whether differences in the expression of Rho kinases occur among xviii superficial and invasive tumours. Further microarray analysis was carried out for the expression profiling of the Rho-associated genes. Finally, the correlation of the mRNA and protein levels of the genes of interest was also examined in UCC and normal tissue, using the Spearman rank correlation test According to our results RhoB RNA and protein levels were significantly lower in UCC, suggesting a tumour-suppressor role. On the contrary, RNA of RhoC and protein levels of RhoA, RhoC and Cdc42, respectively, were significantly higher in UCC compared to normal urothelium. High Cdc42 RNA levels correlated with worse overall survival, whereas high RhoB RNA levels correlated both with better overall and cancer-specific survival. Computational analysis verified the expression profile of Rho kinases among superficial UCC, muscle-invasive UCC and normal urothelium. Our findings in conjunction with the results of other investigators indicate that overexpression of either RhoA and/or RhoC is involved in tumourigenesis irrespective of its origin. In addition, over-expression of RhoA appears to be one of the events leading to more aggressive UCCs, characterized by higher histological grade and more extensive local invasion. RhoB in BC plays a tumour suppressor role, opposing the positive functions of RhoA and RhoC. Regarding its role in other malignancies a review of literature yielded contradictory results. These data suggest different Rho kinases play different roles in tumourigenesis and one Rho kinase may have different roles in different tumour development. Rac1 and Cdc42 seem to cross activate RhoA and/or RhoC in UCC and may contribute to tumour formation and progression. More importantly, preliminary evidence suggests that Cdc42 silencing leads to growth suppression in human bladder-cancer cells. In conclusion, the present study showed that the RNA and protein levels of RhoC and the protein levels of RhoA and Cdc42 were significantly higher in UCC compared to normal tissue. RhoB RNA and protein levels exhibited an inverse expression profile, supporting its role as a tumour suppressor gene. Elucidating the regulatory mechanisms that modulate Rho-mediated signaling pathways in tumours may therefore provide novel targets for small molecule therapeutic agents against cance

Mixed adenoneuroendocrine carcinoma of the urethra

Mixed adenoneuroendocrine carcinoma (MANEC) is a rare tumour found predominantly in the gastrointestinal tract. Comprising adenocarcinomatous and neuroendocrine components, MANEC have been reported in the bladder. We report the first case to our knowledge of a MANEC arising in the urethra. A 62-year-old woman presented with a suburethral mass. Initial excision of the mass revealed it to be a MANEC. Immunohistochemistry staining was positive for CK20 and synaptophysin associated with neuroendocrine tumours. Cross-sectional imaging ruled out metastases and the patient underwent radical urethrectomy, vaginal reconstruction and Mitrofanoff urinary diversion. The patient declined adjuvant chemotherapy and remained under regular surveillance. MANECs are uncommon tumours and treatment was therefore guided by expert opinion. A multidisciplinary approach is essential with the early involvement of surgeons, oncologists, histopathologist, radiologist and neuroendocrine specialists.</jats:p