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OBJECTIVE - LithoVue™ is a novel, single-use, digital flexible ureteroscope that was released to the US market in January 2016. There are scant data regarding its performance in humans. Procedural outcomes comparing LithoVue with reusable ureteroscopes are presented in patients undergoing ureteroscopy for upper urinary tract pathology.
PATIENTS AND METHODS - Clinical outcomes between two groups of patients undergoing flexible ureteroscopy for upper urinary tract pathology were analyzed. The first group underwent surgery utilizing LithoVue, and the second group used reusable fiber-optic flexible ureteroscopes. Differences in procedural outcomes, operative times, and time spent in hospital were analyzed using two-tailed t-tests and chi-squared and Fisher's exact tests.
RESULTS - One hundred fifteen cases utilizing LithoVue and 65 cases utilizing reusable ureteroscopes were included in this study. Demographics, surgical indications, stone size, location, total stone burden, composition, procedural outcomes, and complications were comparable between groups. For all cases, LithoVue procedures lasted 54.1 ± 25.7 minutes compared with 64.5 ± 37.0 minutes for reusable scope procedures (p < 0.05) and for stone removal cases, 57.3 ± 25.1 vs 70.3 ± 36.9 minutes, respectively (p < 0.05). Scope failure occurred in 4.4% of LithoVue cases and 7.7% of reusable cases (p = 0.27).
CONCLUSIONS - LithoVue represents a feasible alternative to reusable ureteroscopes with a low rate of scope failure comparable with reusable ureteroscopes. Its use shortens procedure duration, a finding that warrants further investigation.
We previously found loss of forkhead box A1 (FOXA1) expression to be associated with aggressive urothelial carcinoma of the bladder, as well as increased tumor proliferation and invasion. These initial findings were substantiated by The Cancer Genome Atlas, which identified FOXA1 mutations in a subset of bladder cancers. However, the prognostic significance of FOXA1 inactivation and the effect of FOXA1 loss on urothelial differentiation remain unknown. Application of a univariate analysis (log-rank) and a multivariate Cox proportional hazards regression model revealed that loss of FOXA1 expression is an independent predictor of decreased overall survival. An ubiquitin Cre-driven system ablating Foxa1 expression in urothelium of adult mice resulted in sex-specific histologic alterations, with male mice developing urothelial hyperplasia and female mice developing keratinizing squamous metaplasia. Microarray analysis confirmed these findings and revealed a significant increase in cytokeratin 14 expression in the urothelium of the female Foxa1 knockout mouse and an increase in the expression of a number of genes normally associated with keratinocyte differentiation. IHC confirmed increased cytokeratin 14 expression in female bladders and additionally revealed enrichment of cytokeratin 14-positive basal cells in the hyperplastic urothelial mucosa in male Foxa1 knockout mice. Analysis of human tumor specimens confirmed a significant relationship between loss of FOXA1 and increased cytokeratin 14 expression.
Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Bladder cancer is the fourth most common cancer in the United States. Urothelial carcinoma that originates from the urinary bladder is the most common subtype. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) provide recommendations on the diagnosis and management of non-muscle-invasive and muscle-invasive urothelial carcinoma of the bladder. This version of the guidelines provides extensive reorganization and updates on the principles of chemotherapy management.
Hindgut-derived endoderm can differentiate into rectal, prostatic, and bladder phenotypes. Stromal-epithelial interactions are crucial for this development; however, the precise mechanisms by which epithelium responds to stromal cues remain unknown. We have previously reported ectopic expression of peroxisome proliferator-activated receptor-γ2 (PPARγ2) increased androgen receptor expression and promoted differentiation of mouse prostate epithelium. PPARγ is also implicated in urothelial differentiation. Herein we demonstrate that knockdown of PPARγ2 in benign human prostate epithelial cells (BHPrEs) promotes urothelial transdifferentiation. Furthermore, in vitro and in vivo heterotypic tissue regeneration models with embryonic bladder mesenchyme promoted urothelial differentiation of PPARγ2-deficient BHPrE cells, and deficiency of both PPARγ isoforms 1 and 2 arrested differentiation. Because PTEN deficiency is cooperative in urothelial pathogenesis, we engineered BHPrE cells with combined knockdown of PPARγ and PTEN and performed heterotypic recombination experiments using embryonic bladder mesenchyme. Whereas PTEN deficiency alone induced latent squamous differentiation in BHPrE cells, combined PPARγ and PTEN deficiency accelerated the development of keratinizing squamous metaplasia (KSM). We further confirmed via immunohistochemistry that gene expression changes in metaplastic recombinants reflected human urothelium undergoing KSM. In summary, these data suggest that PPARγ isoform expression provides a molecular basis for observations that adult human epithelium can be transdifferentiated on the basis of heterotypic mesenchymal induction. These data also implicate PPARγ and PTEN inactivation in the development of KSM.
Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Approximately 50% of patients with muscle-invasive bladder cancer (MIBC) develop metastatic disease, which is almost invariably lethal. However, our understanding of pathways that drive aggressive behavior of MIBC is incomplete. Members of the FOXA subfamily of transcription factors are implicated in normal urogenital development and urologic malignancies. FOXA proteins are implicated in normal urothelial differentiation, but their role in bladder cancer is unknown. We examined FOXA expression in commonly used in vitro models of bladder cancer and in human bladder cancer specimens, and used a novel in vivo tissue recombination system to determine the functional significance of FOXA1 expression in bladder cancer. Logistic regression analysis showed decreased FOXA1 expression is associated with increasing tumor stage (p<0.001), and loss of FOXA1 is associated with high histologic grade (p<0.001). Also, we found that bladder urothelium that has undergone keratinizing squamous metaplasia, a precursor to the development of squamous cell carcinoma (SCC) exhibited loss of FOXA1 expression. Furthermore, 81% of cases of SCC of the bladder were negative for FOXA1 staining compared to only 40% of urothelial cell carcinomas. In addition, we showed that a subpopulation of FOXA1 negative urothelial tumor cells are highly proliferative. Knockdown of FOXA1 in RT4 bladder cancer cells resulted in increased expression of UPK1B, UPK2, UPK3A, and UPK3B, decreased E-cadherin expression and significantly increased cell proliferation, while overexpression of FOXA1 in T24 cells increased E-cadherin expression and significantly decreased cell growth and invasion. In vivo recombination of bladder cancer cells engineered to exhibit reduced FOXA1 expression with embryonic rat bladder mesenchyme and subsequent renal capsule engraftment resulted in enhanced tumor proliferation. These findings provide the first evidence linking loss of FOXA1 expression with histological subtypes of MIBC and urothelial cell proliferation, and suggest an important role for FOXA1 in the malignant phenotype of MIBC.
Differentiation is defined as the ability of a cell to acquire full functional behavior. For instance, the function of bladder urothelium is to act as a barrier to the diffusion of solutes into or out of the urine after excretion by the kidney. The urothelium also serves to protect the detrusor muscle from toxins present in stored urine. A major event in the initiation and progression of bladder cancer is loss of urothelial differentiation. This is important because less differentiated urothelial tumors (higher histologic tumor grade) are typically associated with increased biologic and clinical aggressiveness. The differentiation status of urothelial carcinomas can be assessed by histopathologic examination and is reflected in the assignment of a histologic grade (low-grade or high-grade). Although typically limited to morphologic evaluation in most routine diagnostic practices, tumor grade can also be assessed using biochemical markers. Indeed, current pathological analysis of tumor specimens is increasingly reliant on molecular phenotyping. Thus, high priorities for bladder cancer research include identification of (1) biomarkers that will enable the identification of high grade T1 tumors that pose the most threat and require the most aggressive treatment; (2) biomarkers that predict the likelihood that a low grade, American Joint Committee on Cancer stage pTa bladder tumor will progress into an invasive carcinoma with metastatic potential; (3) biomarkers that indicate which pTa tumors are most likely to recur, thus enabling clinicians to prospectively identify patients who require aggressive treatment; and (4) how these markers might contribute to biological processes that underlie tumor progression and metastasis, potentially through loss of terminal differentiation. This review will discuss the proteins associated with urothelial cell differentiation, with a focus on those implicated in bladder cancer, and other proteins that may be involved in neoplastic progression. It is hoped that ongoing discoveries associated with the study of these differentiation-promoting proteins can be translated into the clinic to positively impact patient care.
Copyright © 2013 Elsevier Inc. All rights reserved.
A replacement material for autologous grafts for urinary tract reconstruction would dramatically reduce the complications of surgery for these procedures. However, acellular materials have not proven to work sufficiently well, and cell-seeded materials are technically challenging and time consuming to generate. An important function of the urinary tract is to prevent urine leakage into the surrounding tissue--a function usually performed by the urothelium. We hypothesize that by providing an impermeable barrier in the acellular graft material, urine leakage would be minimized, as the urothelium forms in vivo. However, since urothelial cells require access to nutrients from the supporting vasculature, the impermeable barrier must degrade over time. Here we present the development of a novel biomaterial composed of the common degradable polymers, poly(ε-caprolactone) and poly(L-lactic acid) and generated by electrospinning directly onto spin-coated thin films. The composite scaffolds with thin films on the luminal surface were compared to their electrospun counterparts and commercially available small intestinal submucosa by surface analysis using scanning electron microscopy and by analysis of permeability to small molecules. In addition, the materials were examined for their ability to support urothelial cell adhesion, proliferation, and multilayered urothelium formation. We provide evidence that these unique composite scaffolds provide significant benefit over commonly used acellular materials in vitro and suggest that they be further examined in vivo.
© 2010 Wiley Periodicals, Inc.
The neuronal adhesion protein Dragon acts as a bone morphogenetic protein (BMP) coreceptor that enhances BMP signaling. Given the importance of BMP signaling in nephrogenesis and its putative role in the response to injury in the adult kidney, we studied the localization and function of Dragon in the kidney. We observed that Dragon localized predominantly to the apical surfaces of tubular epithelial cells in the thick ascending limbs, distal convoluted tubules, and collecting ducts of mice. Dragon expression was weak in the proximal tubules and glomeruli. In mouse inner medullary collecting duct (mIMCD3) cells, Dragon generated BMP signals in a ligand-dependent manner, and BMP4 is the predominant endogenous ligand for the Dragon coreceptor. In mIMCD3 cells, BMP4 normally signaled through BMPRII, but Dragon enhanced its signaling through the BMP type II receptor ActRIIA. Dragon and BMP4 increased transepithelial resistance (TER) through the Smad1/5/8 pathway. In epithelial cells isolated from the proximal tubule and intercalated cells of collecting ducts, we observed coexpression of ActRIIA, Dragon, and BMP4 but not BMPRII. Taken together, these results suggest that Dragon may enhance BMP signaling in renal tubular epithelial cells and maintain normal renal physiology.
Current bioengineered bladder wall substitutes include acellular scaffolds and grafts seeded with autologous cells. The transplanted cells on a seeded graft may regenerate and/or be replaced by cells of the patient's bladder. This may or may not be advantageous depending upon the underlying pathology. A theoretically perfect bioengineered graft would be intact bladder wall. To determine if such a graft is feasible and to study the cellular changes, we transplanted full-thickness bladder grafts from male inbred rats onto bladders of female syngeneic rats. Bladders were harvested at 1, 3, 6, 12, and 16 months after surgery and evaluated for histologic changes. Cell origin (male donor vs. female host) was determined with fluorescent in situ hybridization with unique probes for rat X and Y chromosomes. Urothelial hyperplasia, inflammation, and increased stromal thickness subsided down to control values by 6 months after surgery. At 16 months, graft muscle demonstrated persistence of male cells. On the other hand, graft urothelium was partially replaced by female host cells with a pattern suggestive of a hematogenous route rather than ingrowth from the host bladder. Bladder wall transplantation is feasible. The slow replacement of the transplanted urothelium and persistence of muscle may imply the same fate for engineered grafts.
PURPOSE - In the classic view of bladder development the trigone originates from the mesoderm derived wolffian ducts while the remainder of the bladder originates from the endoderm derived urogenital sinus. Recent molecular developmental studies have questioned the veracity of this received wisdom, suggesting an endodermal origin for the trigone. To shed further light on this issue we observed mesenchymal-epithelial interactions between trigone epithelium and fetal urogenital sinus mesenchyma to infer the trigonal germ layer of origin.
MATERIALS AND METHODS - Mouse trigone epithelium was recombined with fetal rat urogenital sinus mesenchyma in tissue recombinant grafts that were placed beneath the renal capsule of athymic mouse hosts. Grafts were harvested at 4 weeks. Control grafts with bladder dome and ureteral epithelium were also examined. Tissues were evaluated with hematoxylin and eosin, and Hoechst dye 33258 to confirm cell species origin. Immunohistochemistry was done with androgen receptor, broad spectrum uroplakin, dorsolateral prostate secretions and seminal vesicle secretions to differentiate prostatic and seminal vesicle differentiation.
RESULTS - Grafts of mouse trigone epithelium with fetal rat urogenital sinus mesenchyma yielded epithelial tissue that stained for dorsolateral prostate secretions but not for seminal vesicle secretions. Control grafts of bladder dome epithelium yielded the expected endodermal prostate differentiation. Control grafts of ureteral epithelium yielded the expected mesodermal seminal vesicle differentiation.
CONCLUSIONS - The consistent finding of prostatic epithelium in tissue recombinants of trigone epithelium and fetal urogenital sinus mesenchyma reinforces the hypothesis that the trigone is derived from the endoderm and not from the mesoderm, as commonly accepted.