Prognostic significance of epidermal growth factor receptor (EGFR) over expression in urothelial carcinoma of urinary bladder.

PubMed

Hashmi, Atif Ali; Hussain, Zubaida Fida; Irfan, Muhammad; Khan, Erum Yousuf; Faridi, Naveen; Naqvi, Hanna; Khan, Amir; Edhi, Muhammad Muzzammil

2018-06-07

Epidermal growth factor receptor (EGFR) has been shown to have abnormal expression in many human cancers and is considered as a marker of poor prognosis. Frequency of over expression in bladder cancer has not been studied in our population; therefore we aimed to evaluate the frequency and prognostic significance of EGFR immunohistochemical expression in locoregional population. We performed EGFR immunohistochemistry on 126 cases of bladder cancer and association of EGFR expression with tumor grade, lamina propria invasion, deep muscle invasion and recurrence of disease was evaluated. High EGFR expression was noted in 26.2% (33 cases), 15.1% (19 cases) and 58.7% (74 cases) revealed low and no EGFR expression respectively. Significant association of EGFR expression was noted with tumor grade, lamina propria invasion, deep muscle invasion and recurrence status while no significant association was seen with age, gender and overall survival. Kaplan- Meier curves revealed significant association of EGFR expression with recurrence while no significant association was seen with overall survival. Significant association of EGFR overexpression with tumor grade, muscularis propria invasion and recurrence signifies its prognostic value; therefore EGFR can be used as a prognostic biomarker in Urothelial bladder carcinoma.

The progression from a lower to a higher invasive stage of bladder cancer is associated with severe alterations in glucose and pyruvate metabolism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Conde, Vanessa R.; Oliveira, Pedro F.; Department of Microscopy, Laboratory of Cell Biology and Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Institute of Biomedical Sciences, University of Porto – UMIB/ICBAS/UP

Cancer cells present a particular metabolic behavior. We hypothesized that the progression of bladder cancer could be accompanied by changes in cells glycolytic profile. We studied two human bladder cancer cells, RT4 and TCCSUP, in which the latter represents a more invasive stage. The levels of glucose, pyruvate, alanine and lactate in the extracellular media were measured by Proton Nuclear Magnetic Resonance. The protein expression levels of glucose transporters 1 (GLUT1) and 3 (GLUT3), monocarboxylate transporter 4 (MCT4), phosphofructokinase-1 (PFK1), glutamic-pyruvate transaminase (GPT) and lactate dehydrogenase (LDH) were determined. Our data showed that glucose consumption and GLUT3 levels were similarmore » in both cell lines, but TCCSUP cells displayed lower levels of GLUT1 and PFK expression. An increase in pyruvate consumption, concordant with the higher levels of lactate and alanine production, was also detected in TCCSUP cells. Moreover, TCCSUP cells presented lower protein expression levels of GPT and LDH. These results illustrate that bladder cancer progression is associated with alterations in cells glycolytic profile, namely the switch from glucose to pyruvate consumption in the more aggressive stage. This may be useful to develop new therapies and to identify biomarkers for cancer progression. - Highlights: • Metabolic phenotype of less and high invasive bladder cancer cells was studied. • Bladder cancer progression involves alterations in cells glycolytic profile. • More invasive bladder cancer cells switch from glucose to pyruvate consumption. • Our results may help to identify metabolic biomarkers of bladder cancer progression.« less

Amaranthus caudatus extract inhibits the invasion of E. coli into uroepithelial cells.

PubMed

Mohanty, Soumitra; Zambrana, Silvia; Dieulouard, Soizic; Kamolvit, Witchuda; Nilsén, Vera; Gonzales, Eduardo; Östenson, Claes-Göran; Brauner, Annelie

2018-06-28

Amaranthus caudatus is traditionally used to treat infections. Based on its traditional usage, we investigated the effect of A. caudatus on the bladder epithelial cells in the protection of E. coli infection. The direct antimicrobial effects of A. caudatus on uropathogenic bacteria were investigated using minimum inhibitory concentration (MIC) assay. Bladder epithelial cell lines T24 and 5637 and uropathogenic E. coli strain #12 were used to investigate the effect of A. caudatus. Bacterial adhesion and invasion into bladder cells treated with A. caudatus was analyzed. Expression of uroplakin-1a (UPK1A), β1 integrin (ITGB1), caveolin-1 (CAV1) and the antimicrobial peptides human β defensin-2 (DEFB4A) and LL-37 (CAMP) was evaluated using RT-PCR. No direct antibacterial effect on E. coli or any of the tested uropathogenic strains was observed by A. caudatus. However, we demonstrated reduced mRNA expression of uroplakin-1a and caveolin-1, but not β1 integrin after treatment of uroepithelial cells, mirrored by the decreased adhesion and invasion of E. coli. A. caudatus treatment did not induce increased gene expression of the antimicrobial peptides, LL-37 and human β-defensin-2. Our results showed that A. caudatus has a protective role on bladder epithelial cells against uropathogenic E. coli infection by decreasing the bacterial adhesion and invasion, thereby preventing infection. Copyright © 2018 Elsevier B.V. All rights reserved.

Effects of increased Kindlin-2 expression in bladder cancer stromal fibroblasts.

PubMed

Wu, Jitao; Yu, Cuicui; Cai, Li; Lu, Youyi; Jiang, Lei; Liu, Chu; Li, Yongwei; Feng, Fan; Gao, Zhenli; Zhu, Zhe; Yu, Shengqiang; Yuan, Hejia; Cui, Yuanshan

2017-08-01

Kindlin-2 is a focal adhesion protein highly expressed in bladder cancer stromal fibroblasts. We investigated the prognostic significance of Kindlin-2 in bladder cancer stromal fibroblasts and evaluated the effects of Kindlin-2 on the malignant behaviors of tumor cells. Immunohistochemical staining of 203 paraffin-embedded bladder cancer tissues showed that Kindlin-2 expression correlated with advanced stage, high grade, and relapse of bladder cancer. Kaplan-Meier survival analysis demonstrated that patients exhibiting high Kindlin-2 expression had shorter survival times than those with low Kindlin-2 expression ( p < 0.01). Multivariate analysis revealed that high Kindlin-2 expression leads to poor prognosis in bladder cancer. Using cancer-associated fibroblasts (CAFs) isolated from human bladder cancer tissue, we observed that Kindlin-2 knockdown decreased CAFs activation, resulting in decreased expression of α-smooth muscle actin (α-SMA) and the extracellular matrix protein fibronectin. Kindlin-2 suppression also reduced CAF-induced bladder cancer cell migration and invasion. Moreover, we found that Kindlin-2 activates CAFs and promotes the invasiveness of bladder cancer cells by stimulating TGF-β-induced epithelial-mesenchymal transition. These results support targeting Kindlin-2 and the corresponding activated CAFs in bladder cancer therapy.

Enhanced inhibition of urinary bladder cancer growth and muscle invasion by allyl isothiocyanate and celecoxib in combination

PubMed Central

Zhang, Yuesheng

2013-01-01

Allyl isothiocyanate (AITC) occurs in cruciferous vegetables that are commonly consumed by humans and has been shown to inhibit urinary bladder cancer growth and progression in previous preclinical studies. However, AITC does not significantly modulate cyclooxygenase-2 (Cox-2), whose oncogenic activity has been well documented in bladder cancer and other cancers. Celecoxib is a selective Cox-2 inhibitor and has been widely used for treatment of several diseases. Celecoxib has also been evaluated in bladder cancer patients, but its efficacy against bladder cancer as a single agent remains unclear. In a syngeneic rat model of orthotopic bladder cancer, treatment of the animals with the combination of AITC and celecoxib at low dose levels (AITC at 1mg/kg and celecoxib at 10mg/kg) led to increased or perhaps synergistic inhibition of bladder cancer growth and muscle invasion, compared with each agent used alone. The combination regime was also more effective than each single agent in inhibiting microvessel formation and stimulating microvessel maturation in the tumor tissues. The anticancer efficacy of the combination regime was associated with depletion of prostaglandin E2, a key downstream signaling molecule of Cox-2, caspase activation and downregulation of vascular endothelial growth factor in the tumor tissues. These data show that AITC and celecoxib complement each other for inhibition of bladder cancer and provide a novel combination approach for potential use for prevention or treatment of human bladder cancer. PMID:23946495

The Long Non-Coding RNA XIST Interacted with MiR-124 to Modulate Bladder Cancer Growth, Invasion and Migration by Targeting Androgen Receptor (AR).

PubMed

Xiong, Yaoyao; Wang, Long; Li, Yuan; Chen, Minfeng; He, Wei; Qi, Lin

2017-01-01

Long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) is involved in the progression of several tumors. The interaction between lncRNA and miRNA or miRNA's target genes is reported to play crucial roles in malignancy. In addition, Androgen receptor (AR) is considered to be involved in bladder cancer progression. In this study, we investigated the role of XIST in human bladder cancer and its interaction with miR-124 and AR. XIST and AR expression was detected in bladder tumor samples and cell lines. Effects of XIST and AR on bladder cancer cells growth, invasion and migration were analyzed. Bioinformatic analysis and luciferase assays were used to identify the interaction among XIST, AR and miR-124. The correlations of miR-124 with XIST and AR in bladder cancer samples were statistically analyzed. XIST and AR were upregulated in bladder cancer tissues and positively correlated. Higher XIST and AR expression were related to poorer TNM stage of bladder cancer. XIST knockdown reduced bladder cancer cells' proliferation, invasion and migration. While this inhibitory effect could be partially restored by AR overexpression. XIST inhibited miR-124 expression by directly targeting. Moreover, miR-124 could bind to the 3'UTR of AR to regulate its expression. MiR-124 inhibition partially restored the XIST knockdown-induced reduction of AR, c-myc, p27, MMP13 and MMP9 expression. In bladder cancer tissues, miR-124 level was inversely correlated with the expression of XIST and AR, respectively. These findings indicated that XIST might be an oncogenic lncRNA that promoted the bladder cancer growth, invasion and migration via miR-124 dependent AR regulation. © 2017 The Author(s). Published by S. Karger AG, Basel.

NOTCH pathway inactivation promotes bladder cancer progression

PubMed Central

Maraver, Antonio; Fernandez-Marcos, Pablo J.; Cash, Timothy P.; Mendez-Pertuz, Marinela; Dueñas, Marta; Maietta, Paolo; Martinelli, Paola; Muñoz-Martin, Maribel; Martínez-Fernández, Mónica; Cañamero, Marta; Roncador, Giovanna; Martinez-Torrecuadrada, Jorge L.; Grivas, Dimitrios; de la Pompa, Jose Luis; Valencia, Alfonso; Paramio, Jesús M.; Real, Francisco X.; Serrano, Manuel

2015-01-01

NOTCH signaling suppresses tumor growth and proliferation in several types of stratified epithelia. Here, we show that missense mutations in NOTCH1 and NOTCH2 found in human bladder cancers result in loss of function. In murine models, genetic ablation of the NOTCH pathway accelerated bladder tumorigenesis and promoted the formation of squamous cell carcinomas, with areas of mesenchymal features. Using bladder cancer cells, we determined that the NOTCH pathway stabilizes the epithelial phenotype through its effector HES1 and, consequently, loss of NOTCH activity favors the process of epithelial-mesenchymal transition. Evaluation of human bladder cancer samples revealed that tumors with low levels of HES1 present mesenchymal features and are more aggressive. Together, our results indicate that NOTCH serves as a tumor suppressor in the bladder and that loss of this pathway promotes mesenchymal and invasive features. PMID:25574842

Prostate stem cell antigen is overexpressed in human transitional cell carcinoma.

PubMed

Amara, N; Palapattu, G S; Schrage, M; Gu, Z; Thomas, G V; Dorey, F; Said, J; Reiter, R E

2001-06-15

Prostate stem cell antigen (PSCA), a homologue of the Ly-6/Thy-1 family of cell surface antigens, is expressed by a majority of human prostate cancers and is a promising target for prostate cancer immunotherapy. In addition to its expression in normal and malignant prostate, we recently reported that PSCA is expressed at low levels in the transitional epithelium of normal bladder. In the present study, we compared the expression of PSCA in normal and malignant urothelial tissues to assess its potential as an immunotherapeutic target in transitional cell carcinoma (TCC). Immunohistochemical analysis of PSCA protein expression was performed on tissue sections from 32 normal bladder specimens, as well as 11 cases of low-grade transitional cell dysplasia, 21 cases of carcinoma in situ (CIS), 38 superficial transitional cell tumors (STCC, stages T(a)-T(1)), 65 muscle-invasive TCCs (ITCCs, stages T(2)-T(4)), and 7 bladder cancer metastases. The level of PSCA protein expression was scored semiquantitatively by assessing both the intensity and frequency (i.e., percentage of positive tumor cells) of staining. We also examined PSCA mRNA expression in a representative sample of normal and malignant human transitional cell tissues. In normal bladder, PSCA immunostaining was weak and confined almost exclusively to the superficial umbrella cell layer. Staining in CIS and STCC was more intense and uniform than that seen in normal bladder epithelium (P < 0.001), with staining detected in 21 (100%) of 21 cases of CIS and 37 (97%) of 38 superficial tumors. PSCA protein was also detected in 42 (65%) of 65 of muscle-invasive and 4 (57%) of 7 metastatic cancers, with the highest levels of PSCA expression (i.e., moderate-strong staining in >50% of tumor cells) seen in 32% of invasive and 43% of metastatic samples. Higher levels of PSCA expression correlated with increasing tumor grade for both STCCs and ITCCs (P < 0.001). Northern blot analysis confirmed the immunohistochemical data, showing a dramatic increase in PSCA mRNA expression in two of five muscle-invasive transitional cell tumors when compared with normal samples. Confocal microscopy demonstrated that PSCA expression in TCC is confined to the cell surface. These data demonstrate that PSCA is overexpressed in a majority of human TCCs, particularly CIS and superficial tumors, and may be a useful target for bladder cancer diagnosis and therapy.

Naturally Occurring Canine Invasive Urinary Bladder Cancer: A Complementary Animal Model to Improve the Success Rate in Human Clinical Trials of New Cancer Drugs.

PubMed

Fulkerson, Christopher M; Dhawan, Deepika; Ratliff, Timothy L; Hahn, Noah M; Knapp, Deborah W

2017-01-01

Genomic analyses are defining numerous new targets for cancer therapy. Therapies aimed at specific genetic and epigenetic targets in cancer cells as well as expanded development of immunotherapies are placing increased demands on animal models. Traditional experimental models do not possess the collective features (cancer heterogeneity, molecular complexity, invasion, metastasis, and immune cell response) critical to predict success or failure of emerging therapies in humans. There is growing evidence, however, that dogs with specific forms of naturally occurring cancer can serve as highly relevant animal models to complement traditional models. Invasive urinary bladder cancer (invasive urothelial carcinoma (InvUC)) in dogs, for example, closely mimics the cancer in humans in pathology, molecular features, biological behavior including sites and frequency of distant metastasis, and response to chemotherapy. Genomic analyses are defining further intriguing similarities between InvUC in dogs and that in humans. Multiple canine clinical trials have been completed, and others are in progress with the aim of translating important findings into humans to increase the success rate of human trials, as well as helping pet dogs. Examples of successful targeted therapy studies and the challenges to be met to fully utilize naturally occurring dog models of cancer will be reviewed.

Naturally Occurring Canine Invasive Urinary Bladder Cancer: A Complementary Animal Model to Improve the Success Rate in Human Clinical Trials of New Cancer Drugs

PubMed Central

Fulkerson, Christopher M.; Ratliff, Timothy L.; Hahn, Noah M.

2017-01-01

Genomic analyses are defining numerous new targets for cancer therapy. Therapies aimed at specific genetic and epigenetic targets in cancer cells as well as expanded development of immunotherapies are placing increased demands on animal models. Traditional experimental models do not possess the collective features (cancer heterogeneity, molecular complexity, invasion, metastasis, and immune cell response) critical to predict success or failure of emerging therapies in humans. There is growing evidence, however, that dogs with specific forms of naturally occurring cancer can serve as highly relevant animal models to complement traditional models. Invasive urinary bladder cancer (invasive urothelial carcinoma (InvUC)) in dogs, for example, closely mimics the cancer in humans in pathology, molecular features, biological behavior including sites and frequency of distant metastasis, and response to chemotherapy. Genomic analyses are defining further intriguing similarities between InvUC in dogs and that in humans. Multiple canine clinical trials have been completed, and others are in progress with the aim of translating important findings into humans to increase the success rate of human trials, as well as helping pet dogs. Examples of successful targeted therapy studies and the challenges to be met to fully utilize naturally occurring dog models of cancer will be reviewed. PMID:28487862

Epithelial-mesenchymal transition, a novel target of sulforaphane via COX-2/MMP2, 9/Snail, ZEB1 and miR-200c/ZEB1 pathways in human bladder cancer cells.

PubMed

Shan, Yujuan; Zhang, Lanwei; Bao, Yongping; Li, Baolong; He, Canxia; Gao, Mingming; Feng, Xue; Xu, Weili; Zhang, Xiaohong; Wang, Shuran

2013-06-01

Metastasis and recurrence of bladder cancer are the main reasons for its poor prognosis and high mortality rates. Because of its biological activity and high metabolic accumulation in urine, sulforaphane, a phytochemical exclusively occurring in cruciferous vegetables, has a powerful and specific potential for preventing bladder cancer. In this paper, sulforaphane is shown to significantly suppress a variety of biochemical pathways including the attachment, invasion, migration and chemotaxis motion in malignant transitional bladder cancer T24 cells. Transfection with cyclooxygenase-2 (COX-2) overexpression plasmid largely abolished inhibition of MMP2/9 expression as well as cell invasive capability by sulforaphane. Moreover, sulforaphane inhibited the epithelial-to-mesenchymal transition (EMT) process which underlies tumor cell invasion and migration mediated by E-cadherin induction through reducing transcriptional repressors, such as ZEB1 and Snail. Under conditions of over-expression of COX-2 and/or MMP2/9, sulforaphane was still able to induce E-cadherin or reduce Snail/ZEB1 expression, suggesting that additional pathways might be involved. Further studies indicated that miR-200c played a role in the regulation of E-cadherin via the ZEB1 repressor but not by the Snail repressor. In conclusion, the EMT and two recognized signaling pathways (COX-2/MMP2,9/ ZEB1, Snail and miR-200c/ZEB1) are all targets for sulforaphane. This study indicated that sulforaphane may possess therapeutic potential in preventing recurrence of human bladder cancer. Copyright © 2013 Elsevier Inc. All rights reserved.

Bladder Cancer—Health Professional Version

Cancer.gov

Transitional cell carcinoma of the bladder can be low-grade or high-grade. Bladder cancer is also divided into muscle-invasive and nonmuscle-invasive disease. Find evidence-based information on bladder cancer including treatment, screening, research, and statistics.

Infiltrating T Cells Promote Bladder Cancer Progression via Increasing IL1→Androgen Receptor→HIF1α→VEGFa Signals.

PubMed

Tao, Le; Qiu, Jianxin; Jiang, Ming; Song, Wenbin; Yeh, Shuyuan; Yu, Hong; Zang, Lijuan; Xia, Shujie; Chang, Chawnshang

2016-08-01

The tumor microenvironment impacts tumor progression and individual cells, including CD4(+) T cells, which have been detected in bladder cancer tissues. The detailed mechanism of how these T cells were recruited to the bladder cancer tumor and their impact on bladder cancer progression, however, remains unclear. Using a human clinical bladder cancer sample survey and in vitro coculture system, we found that bladder cancer has a greater capacity to recruit T cells than surrounding normal bladder tissues. The consequences of higher levels of recruited T cells in bladder cancer included increased bladder cancer metastasis. Mechanism dissection revealed that infiltrating T cells might function through secreting the cytokine IL1, which increases the recruitment of T cells to bladder cancer and enhances the bladder cancer androgen receptor (AR) signaling that results in increased bladder cancer cell invasion via upregulation of hypoxia-inducible factor-1α (HIF1α)/VEGFa expression. Interruption of the IL1→AR→HIF1α→VEGFa signals with inhibitors of HIF1α or VEGFa partially reversed the enhanced bladder cancer cell invasion. Finally, in vivo mouse models of xenografted bladder cancer T24 cells with CD4(+) T cells confirmed in vitro coculture studies and concluded that infiltrating CD4(+) T cells can promote bladder cancer metastasis via modulation of the IL1→AR→HIF1α→VEGFa signaling. Future clinical trials using small molecules to target this newly identified signaling pathway may facilitate the development of new therapeutic approaches to better suppress bladder cancer metastasis. Mol Cancer Ther; 15(8); 1943-51. ©2016 AACR. ©2016 American Association for Cancer Research.

Systemic Immunotherapy of Non–Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti–PD-L1 Immune Checkpoint Inhibitor

PubMed Central

Vandeveer, Amanda J.; Fallon, Jonathan K.; Tighe, Robert; Sabzevari, Helen; Schlom, Jeffrey; Greiner, John W.

2016-01-01

Bacillus Calmette-Guerin (BCG) is the standard of care for intravesical therapy for carcinoma in situ and non–muscle invasive, nonmetastatic human urothelial carcinoma. While the responsiveness to this immunotherapeutic is believed to be linked with (i) a high number of somatic mutations and (ii) a large number of tumor-infiltrating lymphocytes, recent findings of the roles that inhibitory immune receptors and their ligands play in tumor evasion may provide insights into the limitations of the effectiveness of BCG and offer new targets for immune-based therapy. In this study, an aggressive, bioluminescent orthotopic bladder cancer model, MB49 tumor cells transfected with luciferase (MB49luc), was used to study the antitumor effects of avelumab, an antibody to PD-L1. MB49luc murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non–muscle invasive, nonmetastatic urothelial carcinomas. MB49luc bladder tumors are highly positive for the expression of PD-L1 and avelumab administration induced significant (P<0.05) antitumor effects. These antitumor effects were more dependent on the presence of CD4 than CD8 T cells, as determined by in vivo immune cell depletions. The findings suggest that in this bladder tumor model, interruption of the immune suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth. This bladder tumor model can be used to further identify host antitumor immune mechanisms and evaluate combinations of immune-based therapies for carcinoma in situ and non–muscle invasive, nonmetastatic urothelial carcinoma, to provide the rationale for subsequent clinical studies. PMID:26921031

Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti-PD-L1 Immune Checkpoint Inhibitor.

PubMed

Vandeveer, Amanda J; Fallon, Jonathan K; Tighe, Robert; Sabzevari, Helen; Schlom, Jeffrey; Greiner, John W

2016-05-01

Bacillus Calmette-Guerin (BCG) is the standard of care for intravesical therapy for carcinoma in situ and non-muscle invasive, nonmetastatic human urothelial carcinoma. Although the responsiveness to this immunotherapeutic is believed to be linked with (i) a high number of somatic mutations and (ii) a large number of tumor-infiltrating lymphocytes, recent findings of the roles that inhibitory immune receptors and their ligands play in tumor evasion may provide insights into the limitations of the effectiveness of BCG and offer new targets for immune-based therapy. In this study, an aggressive, bioluminescent orthotopic bladder cancer model, MB49 tumor cells transfected with luciferase (MB49(luc)), was used to study the antitumor effects of avelumab, an antibody to PD-L1. MB49(luc) murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non-muscle invasive, nonmetastatic urothelial carcinomas. MB49(luc) bladder tumors are highly positive for the expression of PD-L1, and avelumab administration induced significant (P < 0.05) antitumor effects. These antitumor effects were more dependent on the presence of CD4 than CD8 T cells, as determined by in vivo immune cell depletions. The findings suggest that in this bladder tumor model, interruption of the immune-suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth. This bladder tumor model can be used to further identify host antitumor immune mechanisms and evaluate combinations of immune-based therapies for carcinoma in situ and non-muscle invasive, nonmetastatic urothelial carcinoma, to provide the rationale for subsequent clinical studies. Cancer Immunol Res; 4(5); 452-62. ©2016 AACR. ©2016 American Association for Cancer Research.

Role of androgen receptor and associated lysine-demethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer.

PubMed

Kauffman, Eric C; Robinson, Brian D; Downes, Martin J; Powell, Leagh G; Lee, Ming Ming; Scherr, Douglas S; Gudas, Lorraine J; Mongan, Nigel P

2011-12-01

Bladder cancer is approximately three times more common in men as compared to women. We and others have previously investigated the contribution of androgens and the androgen receptor (AR) to bladder cancer. JMJD2A and LSD1 are recently discovered AR coregulator proteins that mediate AR-dependent transcription via recently described histone lysine-demethylation (KDM) mechanisms. We used immunohistochemistry to examine JMJD2A, LSD1, and AR expression in 72 radical cystectomy specimens, resulting in evaluation of 129 tissue samples (59 urothelial carcinoma, 70 benign). We tested levels of these proteins for statistical association with clinicopathologic variables and patient survival. Expression of these markers was also assessed in human bladder cancer cell lines. The effects of pharmacological inhibition of LSD1 on the proliferation of these bladder cancer cells was determined. JMJD2A and AR levels were significantly lower in malignant versus benign urothelium, while increased LSD1 levels were observed in malignant urothelium relative to benign. A significant reduction in all three proteins occurred with cancer stage progression, including muscle invasion (JMJD2A/LSD1/AR), extravesical extension (JMJD2A/LSD1), and lymph node metastasis (JMJD2A/AR). Lower JMJD2A intensity correlated with additional poor prognostic features, including lymphovascular invasion, concomitant carcinoma in situ and tobacco usage, and predicted significantly worse overall survival. Pharmacological inhibition of LSD1 suppressed bladder cancer cell proliferation and androgen-induced transcription. Our results support a novel role for the AR-KDM complex in bladder cancer initiation and progression, identify JMJD2A as a promising prognostic biomarker, and demonstrate targeting of the KDM activity as an effective potential approach for bladder cancer growth inhibition. Copyright © 2011 Wiley Periodicals, Inc.

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

PubMed Central

McGarvey, Terry; Wang, Huiyi; Lal, Priti; Puthiyaveettil, Raghunath; Tomaszewski, John; Sepulveda, Jorge; Labelle, Ed; Weiss, Jayne S.; Nickerson, Michael L.; Kruth, Howard S.; Brandt, Wolfgang; Wessjohann, Ludger A.; Malkowicz, S. Bruce

2011-01-01

Convergent evidence implicates the TERE1 protein in human bladder tumor progression and lipid metabolism. Previously, reduced TERE1 expression was found in invasive urologic cancers and inhibited cell growth upon re-expression. A role in lipid metabolism was suggested by TERE1 binding to APOE, a cholesterol carrier, and to TBL2, a candidate protein in triglyceride disorders. Natural TERE1 mutations associate with Schnyder's corneal dystrophy, characterized by lipid accumulation. TERE1 catalyzes menaquinone synthesis, known to affect cholesterol homeostasis. To explore this relationship, we altered TERE1 and TBL2 dosage via ectopic expression and interfering RNA and measured cholesterol by Amplex red. Protein interactions of wild-type and mutant TERE1 with GST-APOE were evaluated by binding assays and molecular modeling. We conducted a bladder tumor microarray TERE1 expression analysis and assayed tumorigenicity of J82 cells ectopically expressing TERE1. TERE1 expression was reduced in a third of invasive specimens. Ectopic TERE1 expression in J82 bladder cancer cells dramatically inhibited nude mouse tumorigenesis. TERE1 and TBL2 proteins inversely modulated cellular cholesterol in HEK293 and bladder cancer cells from 20% to 50%. TERE1 point mutations affected APOE interactions, and resulted in cholesterol levels that differed from wild type. Elevated tumor cell cholesterol is known to affect apoptosis and growth signaling; thus, loss of TERE1 in invasive bladder cancer may represent a defect in menaquinone-mediated cholesterol homeostasis that contributes to progression. PMID:21740188

MicroRNA-137 Upregulation Increases Bladder Cancer Cell Proliferation and Invasion by Targeting PAQR3

PubMed Central

Xia, Shunyao; Jin, Chengjun; Yin, Huaifu; Zhao, Weiming; Wu, Qiong

2014-01-01

There is increasing evidence suggesting that dysregulation of some microRNAs (miRNAs) may contribute to tumor progression and metastasis and have been proposed to be key regulators of diverse biological processes such as transcriptional regulation, cell growth and tumorigenesis. Previous studies have shown that miR-137 is dysregulated in some malignancies, but its role in bladder cancer is still unknown. In our study, we find that miR-137 is up-regulated in human bladder cancer tissues and cell lines. Moreover, the higher level of miR-137 was associated with pM or pTNM stage in clinical bladder cancer patients. Enforced expression of miR-137 in bladder cancer cells significantly enhanced their proliferation, migration and invasion. Bioinformatics analysis identified the tumor suppressor gene PAQR3 as a potential miR-137 target gene. Further studies indicated that miR-137 suppressed the expression of PAQR3 by binding to its 3′-untranslated region. Silencing of PAQR3 by small interfering RNAs phenocopied the effects of miR-137 overexpression, whereas restoration of PAQR3 in bladder cancer cells bladder cancer cells overexpressing miR-137, partially reversed the suppressive effects of miR-137. These findings indicate that miR-137 could be a potential oncogene in bladder cancer. PMID:25330156

Superficial and muscle-invasive bladder cancer: principles of management for outcomes assessments.

PubMed

Parekh, Dipen J; Bochner, Bernard H; Dalbagni, Guido

2006-12-10

Bladder cancer is a heterogeneous disease. Non-muscle-invasive bladder cancer embraces a spectrum of tumors with varying degrees of clinical behavior. Transurethral resection remains the surgical mainstay for the treatment of non-muscle-invasive bladder cancer. In an attempt to decrease the recurrence or progression rate, intravesical chemotherapy or immunotherapy is also used. Radical cystectomy with bilateral pelvic lymph node dissection remains the gold standard for treating muscle-invasive bladder cancer. Over the last decade, the orthotopic neobladder has gained widespread popularity as the preferred mode of urinary diversion in both males and females with similar oncologic and functional outcomes. Well-designed trials with effective chemotherapy have shown a beneficial role for neoadjuvant chemotherapy.

Interleukin-4 receptor alpha overexpression in human bladder cancer correlates with the pathological grade and stage of the disease.

PubMed

Joshi, Bharat H; Leland, Pamela; Lababidi, Samir; Varrichio, Frederick; Puri, Raj K

2014-12-01

Previously, we have demonstrated that interleukin-4 receptor α (IL-4Rα) is overexpressed on a variety of human cancers and can serve as target for IL-4 immunotoxin comprised of IL-4 and a mutated Pseudomonas exotoxin. However, its expression and association with grade and clinical stage of bladder cancer has not been studied. IL-4Rα expression was examined in human bladder cancer cell lines, mouse xenografts, and biopsy specimens at mRNA and protein levels by real-time RT-PCR and IHC/ISH techniques. We also examined the effect of IL-4 on proliferation and invasion of bladder carcinoma cell lines. For tissue microarray (TMA) results, we analyzed the precision data using exact binomial proportion with exact two-sided P-values. We used Cochran-Armitage Statistics with exact two-sided P-values to examine the trend analysis of IL-4Rα over grade or stage of the bladder cancer specimens. The influence of age and gender covariates was also analyzed using multiple logistic regression models. IL-4Rα is overexpressed in five bladder cancer cell lines, while normal bladder and human umbilical vein cell lines (HUVEC) expressed at low levels. Two other chains of IL-4 receptor complex, IL-2RγC and IL-13Rα1, were absent or weakly expressed. IL-4 modestly inhibited the cell proliferation, but enhanced cell invasion of bladder cancer cell lines in a concentration-dependent manner. Bladder cancer xenografts in immunodeficient mice also maintained IL-4Rα overexpression in vivo. Analysis of tumor biopsy specimens in TMAs revealed significantly higher IL-4Rα immunostaining (≥ 2+) in Grade 2 (85%) and Grade 3 (97%) compared to Grade 1 tumors (0%) (P ≤ 0.0001). Similarly, 9% stage I tumors were positive for IL-4Rα (≥ 2+) compared to 84% stage II (P ≤ 0.0001) and 100% stages III-IV tumors (P ≤ 0.0001). IL-13Rα1 was also expressed in tumor tissues but at low levels and it did not show any correlation with the grade and stage of disease. However, the IL-2RγC was not expressed. Ten normal bladder specimens demonstrated ≤ 1+ staining for IL-4Rα and IL-13Rα1 and no staining for IL-2RγC. These results demonstrate that IL-4Rα is overexpressed in human bladder cancer, which correlates with advanced grade and stage of the disease. Thus, IL-4Rα may be a bladder tumor-associated protein and a prognostic biomarker. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. Cancer Medicine published by John Wiley & Sons Ltd.

Surgical technique for en bloc transurethral resection of bladder tumour with a Hybrid Knife(®).

PubMed

Islas-García, J J O; Campos-Salcedo, J G; López-Benjume, B I; Torres-Gómez, J J; Aguilar-Colmenero, J; Martínez-Alonso, I A; Gil-Villa, S A

2016-05-01

Bladder cancer is the second most common malignancy of the urinary tract and the 9th worldwide. Latin American has an incidence of 5.6 per 100,000 inhabitants per year. Seventy-five percent of newly diagnosed cases are nonmuscle invasive bladder cancer, and 25% of cases present as muscle invasive. The mainstay of treatment for nonmuscle invasive bladder cancer is loop transurethral resection. In 2013, the group led by Dr Mundhenk of the University Hospital of Tübingen, Germany, was the first to describe the Hybrid Knife(®) equipment for performing en bloc bladder tumour resection, with favourable functional and oncological results. To describe the surgical technique of en bloc bladder tumour resection with a Hybrid Knife(®) as an alternative treatment for nonmuscle invasive bladder tumours. A male patient was diagnosed by urotomography and urethrocystoscopy with a bladder tumour measuring 2×1cm on the floor. En bloc transurethral resection of the bladder tumour was performed with a Hybrid Knife(®). Surgery was performed for 35min, with 70 watts for cutting and 50 watts for coagulation, resecting and evacuating en bloc the bladder tumour, which macroscopically included the muscle layer of the bladder. There were no complications. The technique of en bloc bladder tumour resection with Hybrid Knife(®) is an effective alternative to bipolar loop transurethral resection. Resection with a Hybrid Knife(®) is a procedure with little bleeding and good surgical vision and minimises the risk of bladder perforation and tumour implants. The procedure facilitates determining the positivity of the neoplastic process, vascular infiltration and bladder muscle invasion in the histopathology study. Copyright © 2015 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

Adenoviral mediated interferon-alpha 2b gene therapy suppresses the pro-angiogenic effect of vascular endothelial growth factor in superficial bladder cancer.

PubMed

Adam, Liana; Black, Peter C; Kassouf, Wassim; Eve, Beryl; McConkey, David; Munsell, Mark F; Benedict, William F; Dinney, Colin P N

2007-05-01

Intravesical adenovirus mediated interferon-alpha gene transfer has a potent therapeutic effect against superficial human bladder carcinoma xenografts growing in the bladder of athymic nude mice. We determined whether the inhibition of angiogenesis might contribute to the antitumor effect. We treated several human urothelial carcinoma cells with adenovirus mediated interferon-alpha 2b and monitored its effects on the production of angiogenic factors using real-time reverse-transcription polymerase chain reaction, Western blotting, and immunohistochemical analysis and a gel shift based transcription factor array. To assess the role of adenovirus mediated interferon 2b in angiogenic activity we used in vitro invasion assays and evaluated the anti-angiogenic effects of adenovirus mediated interferon gene therapy in an orthotopic murine model of human superficial bladder cancer. In adenovirus mediated interferon-alpha infected 253J B-V cells vascular endothelial growth factor was decreased and anti-angiogenic interferon-gamma inducible protein 10 was up-regulated. In contrast, the addition of as much as 100,000 IU recombinant interferon had no apparent effect on vascular endothelial growth factor production. Conditioned medium derived from adenovirus mediated interferon 2b infected 253J B-V cells greatly decreased the invasive potential of human endothelial cells and down-regulated their matrix metalloproteinase 2 expression compared to controls. Furthermore, adenovirus mediated interferon 2b blocked pro-angiogenic nuclear signals, such as the transcription factors activating protein-1 and 2, stimulating protein-1, nuclear factor kappaB and c-myb. In vivo experiments revealed significant vascular endothelial growth factor down-regulation and decreased tumor vessel density in the adenovirus mediated interferon 2b treated group compared to controls. Treatment with adenovirus mediated interferon 2b increases the angiostatic activity of the bladder cancer microenvironment. This inhibition may prove beneficial for treating superficial bladder cancer with adenovirus mediated interferon-alpha and hopefully contribute to a decreased recurrence rate of this neoplasm.

Bladder Smooth Muscle Cells Differentiation from Dental Pulp Stem Cells: Future Potential for Bladder Tissue Engineering

PubMed Central

Song, Bing; Jiang, Wenkai; Alraies, Amr; Liu, Qian; Gudla, Vijay; Oni, Julia; Wei, Xiaoqing; Sloan, Alastair; Ni, Longxing; Agarwal, Meena

2016-01-01

Dental pulp stem cells (DPSCs) are multipotent cells capable of differentiating into multiple cell lines, thus providing an alternative source of cell for tissue engineering. Smooth muscle cell (SMC) regeneration is a crucial step in tissue engineering of the urinary bladder. It is known that DPSCs have the potential to differentiate into a smooth muscle phenotype in vitro with differentiation agents. However, most of these studies are focused on the vascular SMCs. The optimal approaches to induce human DPSCs to differentiate into bladder SMCs are still under investigation. We demonstrate in this study the ability of human DPSCs to differentiate into bladder SMCs in a growth environment containing bladder SMCs-conditioned medium with the addition of the transforming growth factor beta 1 (TGF-β1). After 14 days of exposure to this medium, the gene and protein expression of SMC-specific marker (α-SMA, desmin, and calponin) increased over time. In particular, myosin was present in differentiated cells after 11 days of induction, which indicated that the cells differentiated into the mature SMCs. These data suggested that human DPSCs could be used as an alternative and less invasive source of stem cells for smooth muscle regeneration, a technology that has applications for bladder tissue engineering. PMID:26880982

New clinical trial open for patients with muscle-invasive bladder cancer | Center for Cancer Research

Cancer.gov

Muscle-invasive bladder cancer is an aggressive form of bladder cancer in which the tumor invades deep into the musculature of the bladder wall, making it more likely to spread to other parts of the body. Standard treatment involves cisplatin-based chemotherapy followed by radical cystectomy, which is surgery to remove the bladder and nearby organs. However, many patients

An analysis of suppressing migratory effect on human urinary bladder cancer cell line by silencing of snail-1.

PubMed

Salehi, Shima; Mansoori, Behzad; Mohammadi, Ali; Davoudian, Sadaf; Musavi Shenas, Seyed Mohammad Hossein; Shajari, Neda; Majidi, Jafar; Baradaran, Behzad

2017-12-01

Snail-1 actively participates in tumor progression, invasion, and migration. Targeting snail-1 expression can suppress the EMT process in cancer. The aim of this study was to investigate the effect of snail1 silencing on urinary bladder cancer. Quantitative RT-PCR was used to detect snail-1 and other related metastatic genes expression following siRNA knockdown in urinary bladder cancer EJ-138 cells. The protein level of snail1 was assessed by Western blot. MTT and TUNEL assays were assessed to understand if snail-1 had survival effects on EJ-138 cells. Scratch wound healing assay measured cell motility effects after snail1 suppression. The significant silencing of snail-1 reached 60pmol siRNA in a 48-h post-transfection. The result of scratch assay showed that snail-1 silencing significantly decreased Vimentin, MMPs, and CXCR4 expression; however, expression of E-cadherin was induced. The cell death assay indicated that snail-1 played the crucial role in bladder cancer survival rate. These results propose that snail-1 plays a major role in the progression and migration of urinary bladder cancer, and can be a potential therapeutic target for target therapy of invasive urinary bladder cancer. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

[Can MRI be used to distinguish between superficial and invasive transitional cell bladder cancer?].

PubMed

Tillou, X; Grardel, E; Fourmarier, M; Bernasconi, T; Demailly, M; Hakami, F; Saint, F; Petit, J

2008-07-01

To determine the sensitivity and specificity of MRI to distinguish between superficial and invasive transitional cell bladder cancer. Sixty patients (52 men and eight women) with a mean age of 66.8 years were assessed by bladder MRI between May 2002 and November 2005 for a primary bladder cancer diagnosed by endoscopy, followed by transurethral resection and histological examination of the bladder cancer. Patients presenting a discordance between MRI findings and histological examination were analysed. Imaging and pathology staging was concordant for 49 bladder cancers (40 superficial and nine invasive). Ten tumours considered to be invasive on MRI were superficial on histological examination and six of them relapsed at the resection scar at one or three months. The sensitivity of MRI was 80% for a specificity of 90% and a positive predictive value of 97.5%. MRI is a reliable examination to confirm the superficial nature of bladder cancer. When MRI and histological examination of a bladder cancer resection specimen are discordant, second look surgery is recommended to treat residual disease, which was present in 60% of cases in the present series.

Nano-BCG: A Promising Delivery System for Treatment of Human Bladder Cancer.

PubMed

Buss, Julieti Huch; Begnini, Karine Rech; Bender, Camila Bonemann; Pohlmann, Adriana R; Guterres, Silvia S; Collares, Tiago; Seixas, Fabiana Kömmling

2017-01-01

Mycobacterium bovis bacillus Calmette-Guerin (BCG) remains at the forefront of immunotherapy for treating bladder cancer patients. However, the incidence of recurrence and progression to invasive cancer is commonly observed. There are no established effective intravesical therapies available for patients, whose tumors recur following BCG treatment, representing an important unmet clinical need. In addition, there are very limited options for patients who do not respond to or tolerate chemotherapy due to toxicities, resulting in poor overall treatment outcomes. Within this context, nanotechnology is an emergent and promising tool for: (1) controlling drug release for extended time frames, (2) combination therapies due to the ability to encapsulate multiple drugs simultaneously, (3) reducing systemic side effects, (4) increasing bioavailability, (5) and increasing the viability of various routes of administration. Moreover, bladder cancer is often characterized by high mutation rates and over expression of tumor antigens on the tumor cell surface. Therapeutic targeting of these biomolecules may be improved by nanotechnology strategies. In this mini-review, we discuss how nanotechnology can help overcome current obstacles in bladder cancer treatment, and how nanotechnology can facilitate combination chemotherapeutic and BCG immunotherapies for the treatment of non-muscle invasive urothelial bladder cancer.

Nano-BCG: A Promising Delivery System for Treatment of Human Bladder Cancer

PubMed Central

Buss, Julieti Huch; Begnini, Karine Rech; Bender, Camila Bonemann; Pohlmann, Adriana R.; Guterres, Silvia S.; Collares, Tiago; Seixas, Fabiana Kömmling

2018-01-01

Mycobacterium bovis bacillus Calmette–Guerin (BCG) remains at the forefront of immunotherapy for treating bladder cancer patients. However, the incidence of recurrence and progression to invasive cancer is commonly observed. There are no established effective intravesical therapies available for patients, whose tumors recur following BCG treatment, representing an important unmet clinical need. In addition, there are very limited options for patients who do not respond to or tolerate chemotherapy due to toxicities, resulting in poor overall treatment outcomes. Within this context, nanotechnology is an emergent and promising tool for: (1) controlling drug release for extended time frames, (2) combination therapies due to the ability to encapsulate multiple drugs simultaneously, (3) reducing systemic side effects, (4) increasing bioavailability, (5) and increasing the viability of various routes of administration. Moreover, bladder cancer is often characterized by high mutation rates and over expression of tumor antigens on the tumor cell surface. Therapeutic targeting of these biomolecules may be improved by nanotechnology strategies. In this mini-review, we discuss how nanotechnology can help overcome current obstacles in bladder cancer treatment, and how nanotechnology can facilitate combination chemotherapeutic and BCG immunotherapies for the treatment of non-muscle invasive urothelial bladder cancer. PMID:29379438

Cruciferous vegetables, isothiocyanates, and prevention of bladder cancer

PubMed Central

Veeranki, Omkara L.; Bhattacharya, Arup; Tang, Li; Marshall, James R.; Zhang, Yuesheng

2015-01-01

Approximately 80% of human bladder cancers (BC) are non-muscle invasive when first diagnosed and are usually treated by transurethral tumor resection. But 50–80% of patients experience cancer recurrence. Agents for prevention of primary BC have yet to be identified. Existing prophylactics against BC recurrence, e.g., Bacillus Calmette-Guerin (BCG), have limited efficacy and utility; they engender significant side effects and require urethral catheterization. Many cruciferous vegetables, rich sources of isothiocyanates (ITCs), are commonly consumed by humans. Many ITCs possess promising chemopreventive activities against BC and its recurrence. Moreover, orally ingested ITCs are selectively delivered to bladder via urinary excretion. This review is focused on urinary delivery of ITCs to the bladder, their cellular uptake, their chemopreventive activities in preclinical and epidemiological studies that are particularly relevant to prevention of BC recurrence and progression, and their chemopreventive mechanisms in BC cells and tissues. PMID:26273545

Gamma-Klotho exhibits multiple roles in tumor growth of human bladder cancer.

PubMed

Hori, Shunta; Miyake, Makito; Tatsumi, Yoshihiro; Morizawa, Yosuke; Nakai, Yasushi; Onishi, Sayuri; Onishi, Kenta; Iida, Kota; Gotoh, Daisuke; Tanaka, Nobumichi; Fujimoto, Kiyohide

2018-04-13

Alpha-Klotho (KLα) and beta-Klotho (KLβ) have recently been reported to correlate with cancer prognosis in some malignancies and we previously reported the association between KLα, KLβ, and urothelial carcinoma of the bladder (UCB), indicating that KLβ acts as a tumor promoter. However, the association between gamma-Klotho (KLγ) and cancer prognosis remains unclear. In the present study, we evaluated the association between KLγ and UCB. To evaluate the effect of KLγ on human bladder cancer cell lines in vitro assays were performed. Exogenous KLγ increased the ability of human bladder cancer cells to proliferate, migrate, invade, form colonies, and provide anchorage-independent growth potential. In in vivo assays, eighteen mice bearing xenografts inoculated using UM-UC-3, were randomly divided into three groups and treated with a small interfering RNA (siRNA) by intratumoral administration once a week for four weeks. Knockdown of KLγ with siRNA led to a dramatic change in tumor growth and suggested that KLγ had effects on tumor growth, including promotion of cell proliferation, inhibition of apoptosis, and enhancement of the epithelial-mesenchymal transition. To confirm the study, human tissue samples were used and patients were divided into two groups according to KLγ expression level. High expression of KLγ was significantly associated with higher stage and grade cancer and the presence of lymphovascular invasion compared to patients with lower expression of KLγ. Our results suggest that KLγ plays an important role in tumor invasion and progression and these results may lead to the development of new therapies and diagnostic methods for UCB.

Gamma-Klotho exhibits multiple roles in tumor growth of human bladder cancer

PubMed Central

Hori, Shunta; Miyake, Makito; Tatsumi, Yoshihiro; Morizawa, Yosuke; Nakai, Yasushi; Onishi, Sayuri; Onishi, Kenta; Iida, Kota; Gotoh, Daisuke; Tanaka, Nobumichi; Fujimoto, Kiyohide

2018-01-01

Alpha-Klotho (KLα) and beta-Klotho (KLβ) have recently been reported to correlate with cancer prognosis in some malignancies and we previously reported the association between KLα, KLβ, and urothelial carcinoma of the bladder (UCB), indicating that KLβ acts as a tumor promoter. However, the association between gamma-Klotho (KLγ) and cancer prognosis remains unclear. In the present study, we evaluated the association between KLγ and UCB. To evaluate the effect of KLγ on human bladder cancer cell lines in vitro assays were performed. Exogenous KLγ increased the ability of human bladder cancer cells to proliferate, migrate, invade, form colonies, and provide anchorage-independent growth potential. In in vivo assays, eighteen mice bearing xenografts inoculated using UM-UC-3, were randomly divided into three groups and treated with a small interfering RNA (siRNA) by intratumoral administration once a week for four weeks. Knockdown of KLγ with siRNA led to a dramatic change in tumor growth and suggested that KLγ had effects on tumor growth, including promotion of cell proliferation, inhibition of apoptosis, and enhancement of the epithelial-mesenchymal transition. To confirm the study, human tissue samples were used and patients were divided into two groups according to KLγ expression level. High expression of KLγ was significantly associated with higher stage and grade cancer and the presence of lymphovascular invasion compared to patients with lower expression of KLγ. Our results suggest that KLγ plays an important role in tumor invasion and progression and these results may lead to the development of new therapies and diagnostic methods for UCB. PMID:29731962

Metastasis of Non-Muscle-Invasive Bladder Cancer Into the Thyroid Gland: A Literature Review Accompanied by a Rare Case

PubMed Central

Tuncer, Murat; Faydaci, Gokhan; Altin, Gokhan; Kibar, Sermin; Sanli, Arif; Bilgici, Dilek

2014-01-01

Bladder cancer is the most prevalent malignancy of the urinary tract. About 90% of bladder cancers are urothelial carcinomas. Seventy percent of cases newly diagnosed are superficial diseases; roughly 30% of newly diagnosed cases are muscle-invasive metastatic diseases. Bladder urothelial carcinoma primarily metastasizes into regional lymph nodes and then into liver, lung, mediastinum, bone, and adrenal gland. In our case, non-muscle-invasive bladder cancer metastasized into the bone, mediastinum, iliac lymph node, and adrenal and thyroid glands. This is the first reported case in the current literature in which urothelial carcinoma metastasized into the thyroid gland. PMID:24648880

Innovation in Bladder Cancer Immunotherapy.

PubMed

Grossman, H Barton; Lamm, Donald L; Kamat, Ashish M; Keefe, Stephen; Taylor, John A; Ingersoll, Molly A

2016-10-01

Bladder cancer is understudied despite its high prevalence and its remarkable response to immunotherapy. Indeed, funding for studies to explore mechanisms of tumor immunity and novel new therapeutics is disproportionately lower for bladder cancer in comparison with malignancies of the breast, prostate, or lung. However, the recent successes of checkpoint blockade therapy suggest that new therapeutic strategies are on the horizon for bladder cancer. Here, we give a perspective into the evolution of bladder cancer therapy, focusing on strategies to treat high-risk nonmuscle invasive disease, followed by a discussion of recent advances in the treatment of muscle invasive bladder cancer and their potential applicability to lower stage disease. Finally, we explore immunotherapeutic strategies, which have been demonstrated to be successful in the treatment of other malignancies, for their potential to treat and cure patients with nonmuscle and muscle invasive bladder cancer.

CIP2A is a predictor of survival and a novel therapeutic target in bladder urothelial cell carcinoma.

PubMed

Xue, Yijun; Wu, Gengqing; Wang, Xiaoning; Zou, Xiaofeng; Zhang, Guoxi; Xiao, Rihai; Yuan, Yuanhu; Long, Dazhi; Yang, Jun; Wu, Yuting; Xu, Hui; Liu, Folin; Liu, Min

2013-03-01

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified human oncoprotein that stabilizes the c-MYC protein. Herein, we aimed to investigate its expression pattern, clinical significance, and biological function in urothelial cell carcinoma (UCC) of the bladder. CIP2A expression was examined in 20 fresh bladder UCC tissues and paired adjacent normal bladder tissues by RT-PCR and Western blot. Immunohistochemistry for CIP2A was performed on additional 117 bladder UCC tissues. The clinical significance of CIP2A expression was analyzed. CIP2A downregulation was performed in bladder UCC cell line T24 with high abundance of CIP2A, and the effects of CIP2A silencing on cell proliferation, migration, invasion in vitro, and tumor growth in vivo were evaluated. We found that CIP2A expression was upregulated in bladder UCC tissues relative to adjacent normal bladder tissues. Clinicopathological analysis showed that CIP2A expression was significantly associated with tumor stage (P = 0.004), histological grade (P = 0.007), and lymph node status (P = 0.001). The Kaplan-Meier survival curves revealed that CIP2A expression was associated with poor prognosis in bladder UCC patients (log-rank value = 14.704, P < 0.001). CIP2A expression was an independent prognostic marker of overall patient survival in a multivariate analysis (P = 0.015). Knockdown of the CIP2A expression reduced cell proliferation, anchorage-independent growth, migration, invasion, and tumor growth in xenograft model mice. Our findings suggest that CIP2A is an independent predictor of poor prognosis of bladder UCC patients, and inhibition of its expression might be of therapeutic significance.

Review of invasive urodynamics and progress towards non-invasive measurements in the assessment of bladder outlet obstruction

PubMed Central

Griffiths, C. J.; Pickard, R. S.

2009-01-01

Objective: This article defines the need for objective measurements to help diagnose the cause of lower urinary tract symptoms (LUTS). It describes the conventional techniques available, mainly invasive, and then summarizes the emerging range of non-invasive measurement techniques. Methods: This is a narrative review derived form the clinical and scientific knowledge of the authors together with consideration of selected literature. Results: Consideration of measured bladder pressure urinary flow rate during voiding in an invasive pressure flow study is considered the gold standard for categorization of bladder outlet obstruction (BOO). The diagnosis is currently made by plotting the detrusor pressure at maximum flow (pdetQmax) and maximum flow rate (Qmax) on the nomogram approved by the International Continence Society. This plot will categorize the void as obstructed, equivocal or unobstructed. The invasive and relatively complex nature of this investigation has led to a number of inventive techniques to categorize BOO either by measuring bladder pressure non-invasively or by providing a proxy measure such as bladder weight. Conclusion: Non-invasive methods of diagnosing BOO show great promise and a few have reached the stage of being commercially available. Further studies are however needed to validate the measurement technique and assess their worth in the assessment of men with LUTS. PMID:19468436

Downregulation of feline sarcoma-related protein inhibits cell migration, invasion and epithelial-mesenchymal transition via the ERK/AP-1 pathway in bladder urothelial cell carcinoma.

PubMed

Hu, Xudong; Zhang, Zhiqiang; Liang, Zhaofeng; Xie, Dongdong; Zhang, Tao; Yu, Dexin; Zhong, Caiyun

2017-02-01

Feline sarcoma-related protein (Fer) is a nuclear and cytoplasmic non-receptor protein tyrosine kinase and Fer overexpression is associated with various biological processes. However, the clinicopathological characteristics and molecular mechanisms of Fer expression in bladder urothelial cell carcinoma (UCC) have yet to be elucidated. The present study demonstrated that Fer was significantly upregulated in bladder UCC tissues and cell lines. A clinicopathological analysis suggested that Fer expression was significantly associated with tumor stage, histological grade and lymph node status, and Fer expression was a prognostic factor for overall survival in a multivariate analysis. Furthermore, small interfering RNA (siRNA) was used to silence the expression of the Fer gene in human bladder UCC T24 cells, and was shown to significantly reduce the migration and invasion of the cells. It was also observed that Fer-siRNA caused the T24 cells to acquire an epithelial cobblestone phenotype, and was able to reverse the epithelial-mesenchymal transition of the cells. Subsequently, Fer-knockdown was shown to deactivate the extracellular signal-regulated kinase/activator protein-1 signaling pathway in T24 cells. These results indicated, for the first time, that Fer has a critical role in bladder UCC progression and may be a potential therapeutic target for bladder UCC metastasis.

Thermal dosimetry for bladder hyperthermia treatment. An overview.

PubMed

Schooneveldt, Gerben; Bakker, Akke; Balidemaj, Edmond; Chopra, Rajiv; Crezee, Johannes; Geijsen, Elisabeth D; Hartmann, Josefin; Hulshof, Maarten C C M; Kok, H Petra; Paulides, Margarethus M; Sousa-Escandon, Alejandro; Stauffer, Paul R; Maccarini, Paolo F

2016-06-01

The urinary bladder is a fluid-filled organ. This makes, on the one hand, the internal surface of the bladder wall relatively easy to heat and ensures in most cases a relatively homogeneous temperature distribution; on the other hand the variable volume, organ motion, and moving fluid cause artefacts for most non-invasive thermometry methods, and require additional efforts in planning accurate thermal treatment of bladder cancer. We give an overview of the thermometry methods currently used and investigated for hyperthermia treatments of bladder cancer, and discuss their advantages and disadvantages within the context of the specific disease (muscle-invasive or non-muscle-invasive bladder cancer) and the heating technique used. The role of treatment simulation to determine the thermal dose delivered is also discussed. Generally speaking, invasive measurement methods are more accurate than non-invasive methods, but provide more limited spatial information; therefore, a combination of both is desirable, preferably supplemented by simulations. Current efforts at research and clinical centres continue to improve non-invasive thermometry methods and the reliability of treatment planning and control software. Due to the challenges in measuring temperature across the non-stationary bladder wall and surrounding tissues, more research is needed to increase our knowledge about the penetration depth and typical heating pattern of the various hyperthermia devices, in order to further improve treatments. The ability to better determine the delivered thermal dose will enable clinicians to investigate the optimal treatment parameters, and consequentially, to give better controlled, thus even more reliable and effective, thermal treatments.

Bladder cancer biomarker discovery using global metabolomic profiling of urine.

PubMed

Wittmann, Bryan M; Stirdivant, Steven M; Mitchell, Matthew W; Wulff, Jacob E; McDunn, Jonathan E; Li, Zhen; Dennis-Barrie, Aphrihl; Neri, Bruce P; Milburn, Michael V; Lotan, Yair; Wolfert, Robert L

2014-01-01

Bladder cancer (BCa) is a common malignancy worldwide and has a high probability of recurrence after initial diagnosis and treatment. As a result, recurrent surveillance, primarily involving repeated cystoscopies, is a critical component of post diagnosis patient management. Since cystoscopy is invasive, expensive and a possible deterrent to patient compliance with regular follow-up screening, new non-invasive technologies to aid in the detection of recurrent and/or primary bladder cancer are strongly needed. In this study, mass spectrometry based metabolomics was employed to identify biochemical signatures in human urine that differentiate bladder cancer from non-cancer controls. Over 1000 distinct compounds were measured including 587 named compounds of known chemical identity. Initial biomarker identification was conducted using a 332 subject sample set of retrospective urine samples (cohort 1), which included 66 BCa positive samples. A set of 25 candidate biomarkers was selected based on statistical significance, fold difference and metabolic pathway coverage. The 25 candidate biomarkers were tested against an independent urine sample set (cohort 2) using random forest analysis, with palmitoyl sphingomyelin, lactate, adenosine and succinate providing the strongest predictive power for differentiating cohort 2 cancer from non-cancer urines. Cohort 2 metabolite profiling revealed additional metabolites, including arachidonate, that were higher in cohort 2 cancer vs. non-cancer controls, but were below quantitation limits in the cohort 1 profiling. Metabolites related to lipid metabolism may be especially interesting biomarkers. The results suggest that urine metabolites may provide a much needed non-invasive adjunct diagnostic to cystoscopy for detection of bladder cancer and recurrent disease management.

Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNA-UCA1.

PubMed

Xue, Mei; Chen, Wei; Xiang, An; Wang, Ruiqi; Chen, He; Pan, Jingjing; Pang, Huan; An, Hongli; Wang, Xiang; Hou, Huilian; Li, Xu

2017-08-25

To overcome the hostile hypoxic microenvironment of solid tumors, tumor cells secrete a large number of non-coding RNA-containing exosomes that facilitate tumor development and metastasis. However, the precise mechanisms of tumor cell-derived exosomes during hypoxia are unknown. Here, we aim to clarify whether hypoxia affects tumor growth and progression by transferring long non-coding RNA-urothelial cancer-associated 1 (lncRNA-UCA1) enriched exosomes secreted from bladder cancer cells. We used bladder cancer 5637 cells with high expression of lncRNA-UCA1 as exosome-generating cells and bladder cancer UMUC2 cells with low expression of lncRNA-UCA1 as recipient cells. Exosomes derived from 5637 cells cultured under normoxic or hypoxic conditions were isolated and identified by transmission electron microscopy, nanoparticle tracking analysis and western blotting analysis. These exosomes were co-cultured with UMUC2 cells to evaluate cell proliferation, migration and invasion. We further investigated the roles of exosomal lncRNA-UCA1 derived from hypoxic 5637 cells by xenograft models. The availability of lncRNA-UCA1 in serum-derived exosomes as a biomarker for bladder cancer was also assessed. We found that hypoxic exosomes derived from 5637 cells promoted cell proliferation, migration and invasion, and hypoxic exosomal RNAs could be internalized by three bladder cancer cell lines. Importantly, lncRNA-UCA1 was secreted in hypoxic 5637 cell-derived exosomes. Compared with normoxic exosomes, hypoxic exosomes derived from 5637 cells showed the higher expression levels of lncRNA-UCA1. Moreover, Hypoxic exosomal lncRNA-UCA1 could promote tumor growth and progression though epithelial-mesenchymal transition, in vitro and in vivo. In addition, the expression levels of lncRNA-UCA1 in the human serum-derived exosomes of bladder cancer patients were higher than that in the healthy controls. Together, our results demonstrate that hypoxic bladder cancer cells remodel tumor microenvironment to facilitate tumor growth and development though secreting the oncogenic lncRNA-UCA1-enriched exosomes and exosomal lncRNA-UCA1 in human serum has the possibility as a diagnostic biomarker for bladder cancer.

Whole-Pelvis or Bladder-Only Chemoradiation for Lymph Node-Negative Invasive Bladder Cancer: Single-Institution Experience

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tunio, Mutahir A., E-mail: drmutahirtonio@hotmail.com; Hashmi, Altaf; Qayyum, Abdul

2012-03-01

Purpose: Whole-pelvis (WP) concurrent chemoradiation (CCRT) is the standard bladder preserving option for patients with invasive bladder cancer. The standard practice is to treat elective pelvic lymph nodes, so our aim was to evaluate whether bladder-only (BO) CCRT leads to results similar to those obtained by standard WP-CCRT. Methods and Materials: Patient eligibility included histopathologically proven muscle-invasive bladder cancer, lymph nodes negative (T2-T4, N-) by radiology, and maximal transurethral resection of bladder tumor with normal hematologic, renal, and liver functions. Between March 2005 and May 2006, 230 patients were accrued. Patients were randomly assigned to WP-CCRT (120 patients) and BO-CCRTmore » (110 patients). Data regarding the toxicity profile, compliance, initial complete response rates at 3 months, and occurrence of locoregional or distant failure were recorded. Results: With a median follow-up time of 5 years (range, 3-6), WP-CCRT was associated with a 5-year disease-free survival of 47.1% compared with 46.9% in patients treated with BO-CCRT (p = 0.5). The bladder preservation rates were 58.9% and 57.1% in WP-CCRT and BO-CCRT, respectively (p = 0.8), and the 5-year overall survival rates were 52.9% for WP-CCRT and 51% for BO-CCRT (p = 0.8). Conclusion: BO-CCRT showed similar rates of bladder preservation, disease-free survival, and overall survival rates as those of WP-CCRT. Smaller field sizes including bladder with 2-cm margins can be used as bladder preservation protocol for patients with muscle-invasive lymph node-negative bladder cancer to minimize the side effects of CCRT.« less

Effect of TRPV2 cation channels on the proliferation, migration and invasion of 5637 bladder cancer cells.

PubMed

Liu, Quanliang; Wang, Xinghuan

2013-11-01

Transient receptor potential vanilloid 2 (TRPV2), a nonselective cation channel, has become an attractive target gene for tumor studies due to its wide range of physiological and pathological functions. However, its specific role in bladder cancer development and progression remains unclear. The aim of the present study was to investigate the effects of TRPV2 on the proliferation, migration and invasion of 5637 bladder cancer cells in vitro . Rat TRPV2 cDNA was transfected into 5637 bladder cancer cells and changes in the behavior of the cells were detected. It was observed that TRPV2 enhanced bladder cancer cell migration and invasion; however, it did not affect cell proliferation in vitro . TRPV2 activity, which may be mediated by direct matrix metalloproteinase 2 (MMP2) regulation, is important in bladder tumor development and progression. The results of this study suggest that TRPV2 channels are a potential therapeutic target for bladder carcinoma.

Effect of TRPV2 cation channels on the proliferation, migration and invasion of 5637 bladder cancer cells

PubMed Central

LIU, QUANLIANG; WANG, XINGHUAN

2013-01-01

Transient receptor potential vanilloid 2 (TRPV2), a nonselective cation channel, has become an attractive target gene for tumor studies due to its wide range of physiological and pathological functions. However, its specific role in bladder cancer development and progression remains unclear. The aim of the present study was to investigate the effects of TRPV2 on the proliferation, migration and invasion of 5637 bladder cancer cells in vitro. Rat TRPV2 cDNA was transfected into 5637 bladder cancer cells and changes in the behavior of the cells were detected. It was observed that TRPV2 enhanced bladder cancer cell migration and invasion; however, it did not affect cell proliferation in vitro. TRPV2 activity, which may be mediated by direct matrix metalloproteinase 2 (MMP2) regulation, is important in bladder tumor development and progression. The results of this study suggest that TRPV2 channels are a potential therapeutic target for bladder carcinoma. PMID:24223658

Formononetin inhibits human bladder cancer cell proliferation and invasiveness via regulation of miR-21 and PTEN.

PubMed

Wu, Yiying; Zhang, Xing; Li, Zhengzhao; Yan, Haibiao; Qin, Jian; Li, Tianyu

2017-03-22

The isoflavone formononetin is the main active component of Astragalus membranaceus and possesses anti-tumorigenic properties. However, the role of formononetin in human bladder cancer (BCa) has not been fully elucidated. The aim of the present study was to investigate the anti-tumor effects of formononetin on BCa cells and its potential molecular mechanism. T24 cells were treated with different concentrations of formononetin, and then the cell proliferation was assessed by MTT assay, cell apoptosis by Hoechst 33258 stain assay, cell invasiveness by transwell invasion assay, microRNA-21 (miR-21) expression by real-time PCR and the protein level of phosphatase and tensin homolog (PTEN) and phosphorylated homolog of Akt (p-Akt) by western blotting. The results showed that formononetin significantly inhibited the proliferation of T24 cells in a time- and dose-dependent manner. T24 cells treated with formononetin displayed obvious morphological changes of apoptosis and lower invasiveness. In addition, miR-21 expression was significantly decreased in formononetin-treated T24 cells, followed by increase of PTEN, and down-regulation of p-Akt. Collectively, these results suggest that formononetin exerts an anti-carcinogenic effect on BCa in vitro, which might be due to miR-21-mediated regulation of the PTEN/Akt pathway.

Phase II Pazopanib in Combination With Weekly Paclitaxel in Refractory Urothelial Cancer

ClinicalTrials.gov

2017-05-08

Bladder Cancer; Bladder (Urothelial, Transitional Cell) Cancer; Bladder (Urothelial, Transitional Cell) Cancer Superficial (Non-Invasive); Bladder (Urothelial, Transitional Cell) Cancer Resectable (Pre-Cystectomy); Bladder (Urothelial, Transitional Cell) Cancer Metastatic or Unresectable

Bacillus Calmette-Guérin enhances production and secretion of type IV collagenases in peripheral blood mononuclear cells.

PubMed

Kageyama, Y; Kawakami, S; Fujii, Y; Kihara, K; Oshima, H

1997-03-01

Intravesical administration of bacillus Calmette-Guérin (BCG) is an effective and widely accepted treatment for superficial bladder cancer. Rapid progression of the disease after BCG therapy, however, has been reported in some cases refractory to the treatment. We examined whether BCG treatment and coexistence of peripheral blood mononuclear cells (PBMCs) alter the invasive potential of bladder cancer cells. Production and secretion of two type IV collagenases, matrix metalloproteinase (MMP) 2 and MMP 9, by PBMCs from five healthy donors or bladder cancer cells (T24, JTC 30, and JTC 32) were evaluated by gelatin zymography, western blot analysis, and northern blot analysis. Invasion of bladder cancer cells was also examined using reconstituted basement membrane (Matrigel). BCG (5, 50, and 500 micrograms/ml) had no effect on secretion of MMP 2 and MMP 9 by bladder cancer cells, but increased the production and secretion of MMP 9 by PBMCs in a dose-dependent manner. The coexistence of PBMCs increased invasion of T24 cells and BCG further enhanced the invasion. Thus, BCG promotes invasion of bladder cancer cells under certain conditions. An increase in the secretion of MMP 9 by PBMCs may account in part for the effect.

Mitomycin C Intravesical Chemotherapy in Conjunction With Synergo® Radiofrequency-Induced Hyperthermia for Treatment of Carcinoma in Situ Non-Muscle Invasive Bladder Cancer Patients Unresponsive to Bacillus Calmette-Guérin, With or Without Papillary Tumors.

ClinicalTrials.gov

2018-03-20

Bladder Cancer; Bladder Neoplasm; Bladder Tumors; Cancer of Bladder; Cancer of the Bladder; Malignant Tumor of Urinary Bladder; Neoplasms, Bladder; Urinary Bladder Cancer; Carcinoma in Situ of Bladder; Papillary Carcinoma of Bladder (Diagnosis); BCG-Unresponsive Bladder Cancer

Comprehensive gene expression analysis of canine invasive urothelial bladder carcinoma by RNA-Seq.

PubMed

Maeda, Shingo; Tomiyasu, Hirotaka; Tsuboi, Masaya; Inoue, Akiko; Ishihara, Genki; Uchikai, Takao; Chambers, James K; Uchida, Kazuyuki; Yonezawa, Tomohiro; Matsuki, Naoaki

2018-04-27

Invasive urothelial carcinoma (iUC) is a major cause of death in humans, and approximately 165,000 individuals succumb to this cancer annually worldwide. Comparative oncology using relevant animal models is necessary to improve our understanding of progression, diagnosis, and treatment of iUC. Companion canines are a preferred animal model of iUC due to spontaneous tumor development and similarity to human disease in terms of histopathology, metastatic behavior, and treatment response. However, the comprehensive molecular characterization of canine iUC is not well documented. In this study, we performed transcriptome analysis of tissue samples from canine iUC and normal bladders using an RNA sequencing (RNA-Seq) approach to identify key molecular pathways in canine iUC. Total RNA was extracted from bladder tissues of 11 dogs with iUC and five healthy dogs, and RNA-Seq was conducted. Ingenuity Pathway Analysis (IPA) was used to assign differentially expressed genes to known upstream regulators and functional networks. Differential gene expression analysis of the RNA-Seq data revealed 2531 differentially expressed genes, comprising 1007 upregulated and 1524 downregulated genes, in canine iUC. IPA revealed that the most activated upstream regulator was PTGER2 (encoding the prostaglandin E 2 receptor EP2), which is consistent with the therapeutic efficiency of cyclooxygenase inhibitors in canine iUC. Similar to human iUC, canine iUC exhibited upregulated ERBB2 and downregulated TP53 pathways. Biological functions associated with cancer, cell proliferation, and leukocyte migration were predicted to be activated, while muscle functions were predicted to be inhibited, indicating muscle-invasive tumor property. Our data confirmed similarities in gene expression patterns between canine and human iUC and identified potential therapeutic targets (PTGER2, ERBB2, CCND1, Vegf, and EGFR), suggesting the value of naturally occurring canine iUC as a relevant animal model for human iUC.

Elective bladder-sparing treatment for muscle invasive bladder cancer.

PubMed

Lendínez-Cano, G; Rico-López, J; Moreno, S; Fernández Parra, E; González-Almeida, C; Camacho Martínez, E

2014-01-01

Radical cystectomy is the standard treatment for localised muscle invasive bladder cancer (MIBC). We offer a bladder-sparing treatment with TURB +/- Chemotherapy+Radiotherapy to selected patients as an alternative. We analyze, retrospectively, 30 patients diagnosed with MIBC from March 1991 to October 2010. The mean age was 62.7 years (51-74). All patients were candidates for a curative treatment, and underwent strict selection criteria: T2 stage, primary tumor, solitary lesion smaller than 5cm with a macroscopic disease-free status after TURB, negative random biopsy without hydronephrosis. Staging CT evaluation was normal. Restaging TURB or tumor bed biopsy showed a disease-free status or microscopic muscle invasion. 14 patients underwent TURB alone, 13 TURB+Chemotherapy and 3 TURB+Chemotherapy+Radiotherapy. The mean follow up was 88.7 months (19-220). 14 patients remained disease free (46.6%), 10 had recurrent non-muscle invasive bladder cancer (33%). 81.3% complete clinical response. 71% bladder preserved at 5-years. Overall, 5-years survival rate was 79% and 85% cancer-specific survival rate. Although radical cystectomy is the standard treatment for localised MIBC, in strictly selected cases, bladder-sparing treatment offers an alternative with good long term results. Copyright © 2013 AEU. Published by Elsevier Espana. All rights reserved.

Inhibition of Bladder Cancer by Broccoli Isothiocyanates Sulforaphane and Erucin: Characterization, Metabolism and Interconversion

PubMed Central

Abbaoui, Besma; Riedl, Kenneth M; Ralston, Robin A; Thomas-Ahner, Jennifer M; Schwartz, Steven J; Clinton, Steven K; Mortazavi, Amir

2013-01-01

Epidemiologic evidence suggests diets rich in cruciferous vegetables, particularly broccoli, are associated with lower bladder cancer risk. Our objectives are to investigate these observations and determine the role of isothiocyanates in primary or secondary bladder cancer prevention. We initially investigate the mechanisms whereby broccoli and broccoli sprout extracts and pure isothiocyanates inhibit normal, non-invasive (RT4) and invasive (J82, UMUC3) human urothelial cell viability. Sulforaphane (IC50= 5.66±1.2μM) and erucin (IC50= 8.79±1.3μM) are found to be the most potent inhibitors and normal cells are least sensitive. This observation is associated with downregulation of survivin, EGFR and HER2/neu, G2/M cell cycle accumulation and apoptosis. In a murine UMUC3 xenograft model, we fed semipurified diets containing 4% broccoli sprouts, or 2% broccoli sprout isothiocyanate extract; or gavaged pure sulforaphane or erucin (each at 295 μmol/kg, similar to dietary exposure); and report tumor weight reduction of 42% (p=0.02), 42% (p=0.04), 33% (p=0.04) and 58% (p<0.0001), respectively. Sulforaphane and erucin metabolites are present in mouse plasma (micromolar range) and tumor tissue, with N-acetyl cysteine conjugates as the most abundant. Interconversion of sulforaphane and erucin metabolites was observed. This work supports development of fully characterized, novel food products for phase I/II human studies targeting bladder cancer prevention. PMID:23038615

Bladder Carcinoma Data with Clinical Risk Factors and Molecular Markers: A Cluster Analysis

PubMed Central

Redondo-Gonzalez, Enrique; de Castro, Leandro Nunes; Moreno-Sierra, Jesús; Maestro de las Casas, María Luisa; Vera-Gonzalez, Vicente; Ferrari, Daniel Gomes; Corchado, Juan Manuel

2015-01-01

Bladder cancer occurs in the epithelial lining of the urinary bladder and is amongst the most common types of cancer in humans, killing thousands of people a year. This paper is based on the hypothesis that the use of clinical and histopathological data together with information about the concentration of various molecular markers in patients is useful for the prediction of outcomes and the design of treatments of nonmuscle invasive bladder carcinoma (NMIBC). A population of 45 patients with a new diagnosis of NMIBC was selected. Patients with benign prostatic hyperplasia (BPH), muscle invasive bladder carcinoma (MIBC), carcinoma in situ (CIS), and NMIBC recurrent tumors were not included due to their different clinical behavior. Clinical history was obtained by means of anamnesis and physical examination, and preoperative imaging and urine cytology were carried out for all patients. Then, patients underwent conventional transurethral resection (TURBT) and some proteomic analyses quantified the biomarkers (p53, neu, and EGFR). A postoperative follow-up was performed to detect relapse and progression. Clusterings were performed to find groups with clinical, molecular markers, histopathological prognostic factors, and statistics about recurrence, progression, and overall survival of patients with NMIBC. Four groups were found according to tumor sizes, risk of relapse or progression, and biological behavior. Outlier patients were also detected and categorized according to their clinical characters and biological behavior. PMID:25866762

Effect of quantum dots on the biological behavior of the EJ human bladder urothelial carcinoma cell line.

PubMed

Yuan, Run; Yu, Wei-Min; Cheng, Fan; Zhang, Xiao-Bin; Ruan, Yuan; Cao, Zhi-Xiu; Larré, Stéphane

2015-10-01

Quantum dots (QDs) are a type of fluorescent label with applications in biological molecules, cells and in vivo imaging. The current study investigated the effect of QDs on the toxicity, proliferation, migration and invasion of the EJ human bladder cancer cell line in vitro. The cell counting kit‑8 test was used to measure the survival rate of EJ cells following incubation with varying concentrations of QDs. Additionally, the effect of QDs on tumor cell migration and invasion was evaluated using the Transwell chamber assay, and cell proliferation rate was assessed using a hemocytometer. Data from the current study demonstrated no significant differences in survival rate between the experimental and control groups with the conventionally used concentrations (5, 10 and 20 nM) of QD605 (P>0.05). However, with high concentrations of QD605 (40 and 80 nM), significant differences were observed (P<0.001). The survival rate of EJ cells, however, remained at 92.6%. In addition, no significant differences were observed between the EJ cells labeled with transactivator of transcription (TAT)‑QD605 and the unlabeled EJ cells with regard to proliferation, migration and invasion (P>0.05). Thus, the results of the current study indicate that QDs exhibit a certain degree of influence on the activity of the EJ bladder cancer cell line at high concentrations. However, at the concentrations that QDs are conventionally used, there was little impact on the survival of the EJ cells. In addition, the proliferation, migration and invasion abilities of the EJ cells were not affected by TAT‑QDs. Therefore, the peptide‑conjugated QDs have potential to be applied in the imaging and tracking of live cells in vitro and of animals in vivo. Notably, QDs may provide the foundation for a novel, non‑invasive imaging strategy for the early diagnosis of tumors.

A Real-Time Non-invasive Auto-bioluminescent Urinary Bladder Cancer Xenograft Model.

PubMed

John, Bincy Anu; Xu, Tingting; Ripp, Steven; Wang, Hwa-Chain Robert

2017-02-01

The study was to develop an auto-bioluminescent urinary bladder cancer (UBC) xenograft animal model for pre-clinical research. The study used a humanized, bacteria-originated lux reporter system consisting of six (luxCDABEfrp) genes to express components required for producing bioluminescent signals in human UBC J82, J82-Ras, and SW780 cells without exogenous substrates. Immune-deficient nude mice were inoculated with Lux-expressing UBC cells to develop auto-bioluminescent xenograft tumors that were monitored by imaging and physical examination. Lux-expressing auto-bioluminescent J82-Lux, J82-Ras-Lux, and SW780-Lux cell lines were established. Xenograft tumors derived from tumorigenic Lux-expressing auto-bioluminescent J82-Ras-Lux cells allowed a serial, non-invasive, real-time monitoring by imaging of tumor development prior to the presence of palpable tumors in animals. Using Lux-expressing auto-bioluminescent tumorigenic cells enabled us to monitor the entire course of xenograft tumor development through tumor cell implantation, adaptation, and growth to visible/palpable tumors in animals.

MicroRNA-320c inhibits tumorous behaviors of bladder cancer by targeting Cyclin-dependent kinase 6

PubMed Central

2014-01-01

Background Increasing evidence has suggested that dysregulation of microRNAs (miRNAs) could contribute to human disease including cancer. Previous miRNA microarray analysis illustrated that miR-320c is down-regulated in various cancers. However, the roles of miR-320c in human bladder cancer have not been well elucidated. Therefore, this study was performed to investigate the biological functions and molecular mechanisms of miR-320c in human bladder cancer cell lines, discussing whether it could be a therapeutic biomarker of bladder cancer in the future. Methods Two human bladder cancer cell lines and samples from thirteen patients with bladder cancer were analyzed for the expression of miR-320c by quantitative RT-PCR. Over-expression of miR-320c was established by transfecting mimics into T24 and UM-UC-3. Cell proliferation and cell cycle were assessed by cell viability assay, flow cytometry and colony formation assay. Cell motility ability was evaluated by transwell assay. The target gene of miR-320c was determined by luciferase assay, quantitative RT-PCR and western blot. The regulation of cell cycle and mobility by miR-320c was analyzed by western blot. Results We observed that miR-320c was down-regulated in human bladder cancer tissues and bladder cancer cell lines T24 and UM-UC-3. Over-expression of miR-320c could induce G1 phase arrest in UM-UC-3 and T24 cells, and subsequently inhibited cell growth. We also indentified miR-320c could impair UM-UC-3 and T24 cell motility. In addition, we identified CDK6, a cell cycle regulator, as a novel target of miR-320c. Moreover, we demonstrated miR-320c could induce bladder cancer cell cycle arrest and mobility via regulating CDK6. We also observed that inhibition of miR-320c or restoration of CDK6 in miR-320c-over-expressed bladder cancer cells partly reversed the suppressive effects of miR-320c. Conclusions miR-320c could inhibit the proliferation, migration and invasion of bladder cancer cells via regulating CDK6. Our study revealed that miR-320c could be a therapeutic biomarker of bladder cancer in the future. PMID:25178497

Fluorescent imaging of high-grade bladder cancer using a specific antagonist for chemokine receptor CXCR4.

PubMed

Nishizawa, Koji; Nishiyama, Hiroyuki; Oishi, Shinya; Tanahara, Noriko; Kotani, Hirokazu; Mikami, Yoshiki; Toda, Yoshinobu; Evans, Barry J; Peiper, Stephen C; Saito, Ryoichi; Watanabe, Jun; Fujii, Nobutaka; Ogawa, Osamu

2010-09-01

We previously reported that the expression of CXC chemokine receptor-4 (CXCR4) was upregulated in invasive bladder cancers and that the small peptide T140 was a highly sensitive antagonist for CXCR4. In this study, we identified that CXCR4 expression was induced in high-grade superficial bladder tumors, including carcinoma in situ and invasive bladder tumors. To visualize the bladder cancer cells using urinary sediments from the patients and chemically induced mouse bladder cancer model, a novel fluorescent CXCR4 antagonist TY14003 was developed, that is a T140 derivative. TY14003 could label bladder cancer cell lines expressing CXCR4, whereas negative-control fluorescent peptides did not label them. When labeling urinary sediments from patients with invasive bladder cancer, positive-stained cells were identified in all patients with bladder cancer and positive urine cytology but not in controls. Although white blood cells in urine were also labeled with TY14003, they could be easily discriminated from urothelial cells by their shape and size. Finally, intravesical instillation of TY14003 into mouse bladder, using N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder cancer model, demonstrated that fluorescent signals were detected in the focal areas of bladder of all mice examined at 12 weeks of BBN drinking by confocal microscopy and fluorescent endoscopy. On the contrary, all the normal bladders were found to be negative for TY14003 staining. In conclusion, these results indicate that TY14003 is a promising diagnostic tool to visualize small or flat high-grade superficial bladder cancer.

[The diagnostic value of microsatellite LOH analysis and the prognostic relevance of angiogenic gene expression in urinary bladder cancer].

PubMed

Szarvas, Tibor

2009-12-01

Bladder cancer is the second most common malignancy affecting the urinary system. Currently, histology is the only tool that determines therapy and patients' prognosis. As the treatment of non-invasive (Ta/T1) and muscle invasive (T2-T4) bladder tumors are completely different, correct staging is important, although it is often hampered by disturbing factors. Molecular methods offer new prospects for early disease detection, confirmation of unclear histological findings and prognostication. Applying molecular biological methods, the present study is searching for answers to current diagnostic and prognostic problems in bladder carcinoma. We analyzed tumor, blood and/or urine samples of 334 bladder cancer patients and 117 control individuals. Genetic alterations were analyzed in urine samples of patients and controls, both by PCR-based microsatellite loss of heterozigosity (LOH) analysis using 12 fluorescently labeled primers and by DNA hybridization based UroVysion FISH technique using 4 probes, to assess the diagnostic values of these methods. Whole genome microsatellite analysis (with 400 markers) was performed in tumor and blood specimens of bladder cancer patients to find chromosomal regions, the loss of which may be associated with tumor stage. Furthermore, we assessed the prognostic value of Tie2, VEGF, Angiopoietin-1 and -2. We concluded that DNA analysis of voided urine samples by microsatellite analysis and FISH are sensitive and non-invasive methods to detect bladder cancer. Furthermore, we established a panel of microsatellite markers that could differentiate between non-invasive and invasive bladder cancer. However, further analyses in a larger cohort of patients are needed to assess their specificity and sensitivity. Finally, we identified high Ang-2 and low Tie2 gene expression as significant and independent risk factors of tumor recurrence and cancer related survival.

Effects of tumor necrosis factor-alpha and interferon-gamma on expressions of matrix metalloproteinase-2 and -9 in human bladder cancer cells.

PubMed

Shin, K Y; Moon, H S; Park, H Y; Lee, T Y; Woo, Y N; Kim, H J; Lee, S J; Kong, G

2000-10-31

We have investigated the effects of tumor necrosis factor-alpha (TNF-alpha) and interferon (INF-gamma), the potent Bacillus Calmette-Guerin (BCG)-induced cytokines on the production of MMP-2, MMP-9, TIMP-1, TIMP-2 and MT1-MMP in high grade human bladder cancer cell lines, T-24, J-82 and HT-1376 cell lines. MMP-2 expression and activity were decreased in T-24 cells treated with both cytokines in a dose dependent manner. However, J-82 cells treated with TNF-alpha and INF-gamma revealed dose dependent increases of MMP-9 expression and activity with similar baseline expression and activity of MMP-2. HT-1376 cells after exposure to TNF-alpha only enhanced the expression and activity of MMP-9. These results indicate that TNF-alpha and INF-gamma could regulate the production of MMP-2 or MMP-9 on bladder cancer cells and their patterns of regulation are cell specific. Furthermore, this diverse response of bladder cancer cells to TNF-alpha and INF-gamma suggests that BCG immunotherapy may enhance the invasiveness of bladder cancer in certain conditions with induction of MMPs.

Minimally invasive percutaneous cystostomy with ureteroscopic pneumatic lithotripsy for calculus in bladder diverticula

PubMed Central

GU, SI-PING; YOU, ZHI-YUAN; HUANG, YUNTENG; LU, YI-JIN; HE, CAOHUI; CAI, XIAO-DONG; ZHOU, XIAO-MING

2013-01-01

The aim of this study was to investigate the effectiveness of minimally invasive percutaneous cystostomy with ureteroscopic pneumatic lithotripsy for treating calculus in bladder diverticula. Percutaneous cystostomy with ureteroscopic pneumatic lithotripsy was performed on six elderly male patients with calculi in bladder diverticula, who could not be treated with transurethral ureteroscopic lithotripsy. The stones were successfully removed from all patients, with no complications such as bladder perforation, rupture, urethritis or cystitis. The surgery time was 15–60 min, with an average time of 32 min. Postoperative ultrasound or X-ray examination showed no stone residues and the bladder stoma healed well. No recurrent stones were detected in the follow-up of 3–24 months (average, 16 months). Minimally invasive percutaneous cystostomy with ureteroscopic pneumatic lithotripsy is a safe, efficient and easy treatment for calculus in bladder diverticula. This method provides a new clinical approach for lithotripsy and we suggest that it is worthy of wider use. PMID:23837044

Activation of RAS family genes in urothelial carcinoma.

PubMed

Boulalas, I; Zaravinos, A; Karyotis, I; Delakas, D; Spandidos, D A

2009-05-01

Bladder cancer is the fifth most common malignancy in men in Western society. We determined RAS codon 12 and 13 point mutations and evaluated mRNA expression levels in transitional cell carcinoma cases. Samples from 30 human bladder cancers and 30 normal tissues were analyzed by polymerase chain reaction/restriction fragment length polymorphism and direct sequencing to determine the occurrence of mutations in codons 12 and 13 of RAS family genes. Moreover, we used real-time reverse transcriptase-polymerase chain reaction to evaluate the expression profile of RAS genes in bladder cancer specimens compared to that in adjacent normal tissues. Overall H-RAS mutations in codon 12 were observed in 9 tumor samples (30%). Two of the 9 patients (22%) had invasive bladder cancer and 7 (77%) had noninvasive bladder cancer. One H-RAS mutation (11%) was homozygous and the remaining 89% were heterozygous. All samples were WT for K and N-RAS oncogenes. Moreover, 23 of 30 samples (77%) showed over expression in at least 1 RAS family gene compared to adjacent normal tissue. K and N-RAS had the highest levels of over expression in bladder cancer specimens (50%), whereas 27% of transitional cell carcinomas demonstrated H-RAS over expression relative to paired normal tissues. Our results underline the importance of H-RAS activation in human bladder cancer by codon 12 mutations. Moreover, they provide evidence that increased expression of all 3 RAS genes is a common event in bladder cancer that is associated with disease development.

Abnormal Protein Glycosylation and Activated PI3K/Akt/mTOR Pathway: Role in Bladder Cancer Prognosis and Targeted Therapeutics.

PubMed

Costa, Céu; Pereira, Sofia; Lima, Luís; Peixoto, Andreia; Fernandes, Elisabete; Neves, Diogo; Neves, Manuel; Gaiteiro, Cristiana; Tavares, Ana; Gil da Costa, Rui M; Cruz, Ricardo; Amaro, Teresina; Oliveira, Paula A; Ferreira, José Alexandre; Santos, Lúcio L

2015-01-01

Muscle invasive bladder cancer (MIBC, stage ≥T2) is generally associated with poor prognosis, constituting the second most common cause of death among genitourinary tumours. Due to high molecular heterogeneity significant variations in the natural history and disease outcome have been observed. This has also delayed the introduction of personalized therapeutics, making advanced stage bladder cancer almost an orphan disease in terms of treatment. Altered protein glycosylation translated by the expression of the sialyl-Tn antigen (STn) and its precursor Tn as well as the activation of the PI3K/Akt/mTOR pathway are cancer-associated events that may hold potential for patient stratification and guided therapy. Therefore, a retrospective design, 96 bladder tumours of different stages (Ta, T1-T4) was screened for STn and phosphorylated forms of Akt (pAkt), mTOR (pmTOR), S6 (pS6) and PTEN, related with the activation of the PI3K/Akt/mTOR pathway. In our series the expression of Tn was residual and was not linked to stage or outcome, while STn was statically higher in MIBC when compared to non-muscle invasive tumours (p = 0.001) and associated decreased cancer-specific survival (log rank p = 0.024). Conversely, PI3K/Akt/mTOR pathway intermediates showed an equal distribution between non-muscle invasive bladder cancer (NMIBC) and MIBC and did not associate with cancer-specif survival (CSS) in any of these groups. However, the overexpression of pAKT, pmTOR and/or pS6 allowed discriminating STn-positive advanced stage bladder tumours facing worst CSS (p = 0.027). Furthermore, multivariate Cox regression analysis revealed that overexpression of PI3K/Akt/mTOR pathway proteins in STn+ MIBC was independently associated with approximately 6-fold risk of death by cancer (p = 0.039). Mice bearing advanced stage chemically-induced bladder tumours mimicking the histological and molecular nature of human tumours were then administrated with mTOR-pathway inhibitor sirolimus (rapamycin). This decreased the number of invasive lesions and, concomitantly, the expression of STn and also pS6, the downstream effector of the PI3K/Akt/mTOR pathway. In conclusion, STn was found to be marker of poor prognosis in bladder cancer and, in combination with PI3K/Akt/mTOR pathway evaluation, holds potential to improve the stratification of stage disease. Animal experiments suggest that mTOR pathway inhibition could be a potential therapeutic approach for this specific subtype of MIBC.

Protein Interactome of Muscle Invasive Bladder Cancer

PubMed Central

Bhat, Akshay; Heinzel, Andreas; Mayer, Bernd; Perco, Paul; Mühlberger, Irmgard; Husi, Holger; Merseburger, Axel S.; Zoidakis, Jerome; Vlahou, Antonia; Schanstra, Joost P.; Mischak, Harald; Jankowski, Vera

2015-01-01

Muscle invasive bladder carcinoma is a complex, multifactorial disease caused by disruptions and alterations of several molecular pathways that result in heterogeneous phenotypes and variable disease outcome. Combining this disparate knowledge may offer insights for deciphering relevant molecular processes regarding targeted therapeutic approaches guided by molecular signatures allowing improved phenotype profiling. The aim of the study is to characterize muscle invasive bladder carcinoma on a molecular level by incorporating scientific literature screening and signatures from omics profiling. Public domain omics signatures together with molecular features associated with muscle invasive bladder cancer were derived from literature mining to provide 286 unique protein-coding genes. These were integrated in a protein-interaction network to obtain a molecular functional map of the phenotype. This feature map educated on three novel disease-associated pathways with plausible involvement in bladder cancer, namely Regulation of actin cytoskeleton, Neurotrophin signalling pathway and Endocytosis. Systematic integration approaches allow to study the molecular context of individual features reported as associated with a clinical phenotype and could potentially help to improve the molecular mechanistic description of the disorder. PMID:25569276

Dietary flavonoid luteolin attenuates uropathogenic Escherichia. Coli invasion of the urinary bladder.

PubMed

Shen, Xiao-Fei; Teng, Yan; Sha, Kai-Hui; Wang, Xin-Yuan; Yang, Xiao-Long; Guo, Xiao-Juan; Ren, Lai-Bin; Wang, Xiao-Ying; Li, Jingyu; Huang, Ning

2016-11-12

Uropathogenic Escherichia coli (UPEC), the primary uropathogen, adhere to and invade bladder epithelial cells (BECs) to establish a successful urinary tract infection (UTI). Emerging antibiotic resistance requires novel nonantibiotic strategies. Our previous study indicated that luteolin attenuated adhesive and invasive abilities as well as cytotoxicity of UPEC on T24 BECs through down-regulating UPEC virulence factors. The aims of this study were to investigate the possible function of the flavonoid luteolin and the mechanisms by which luteolin functions in UPEC-induced bladder infection. Firstly, obvious reduction of UPEC invasion but not adhesion were observed in luteolin-pretreated 5637 and T24 BECs sa well as mice bladder via colony counting. The luteolin-mediated suppression of UPEC invasion was linked to elevated levels of intracellular cAMP induced by inhibiting the activity of cAMP-phosphodiesterases (cAMP-PDEs), which resulting activation of protein kinase A, thereby negatively regulating Rac1-GTPase-mediated actin polymerization. Furthermore, p38 MAPK was primarily and ERK1/2 was partially involved in luteolin-mediated suppression of UPEC invasion and actin polymerization, as confirmed with chemical activators of p38 MAPK and ERK1/2. These data suggest that luteolin can protect bladder epithelial cells against UPEC invasion. Therefore, luteolin or luteolin-rich products as dietary supplement may be beneficial to control the UPEC-related bladder infections, and cAMP-PDEs may be a therapy target for UTIs treatment. © 2016 BioFactors, 42(6):674-685, 2016. © 2016 International Union of Biochemistry and Molecular Biology.

Atezolizumab in Treating Patients With Recurrent BCG-Unresponsive Non-muscle Invasive Bladder Cancer

ClinicalTrials.gov

2018-06-25

Recurrent Bladder Urothelial Carcinoma; Stage 0a Bladder Urothelial Carcinoma AJCC v6 and v7; Stage 0is Bladder Urothelial Carcinoma AJCC v6 and v7; Stage I Bladder Cancer With Carcinoma In Situ; Stage I Bladder Urothelial Carcinoma AJCC v6 and v7

Correlation between messenger RNA expression and protein expression of immune checkpoint-associated molecules in bladder urothelial carcinoma: A retrospective study.

PubMed

Le Goux, Constance; Damotte, Diane; Vacher, Sophie; Sibony, Mathilde; Delongchamps, Nicolas Barry; Schnitzler, Anne; Terris, Benoit; Zerbib, Marc; Bieche, Ivan; Pignot, Géraldine

2017-05-01

Immunotherapy for bladder cancer seems to have promising results. Here, we evaluated the association between messenger RNA (mRNA) and protein levels and possible prognostic value of the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) immune checkpoint pathways during bladder carcinogenesis. Tumor samples were obtained from 155 patients (84 with muscle-invasive bladder cancer [MIBC], and 71 non-muscle-invasive bladder cancer [NMIBC]) and normal bladder tissue from 15 patients. We evaluated the mRNA expression of 3 genes in the PD-1 pathway (PD-1, PD-L1, and PD-L2) and 4 in the CTLA4 pathway (CTLA4, CD28, CD80, and CD86) in normal and tumoral human bladder samples by quantitative real-time reverse transcription polymerase chain reaction, with immunohistochemistry used to evaluate the protein expression of PD-1 and PD-L1 in tumor and immune cells. Results of molecular analyses were compared with survival analyses. As compared with normal bladder tissue, MIBC tissue showed PD-1, PD-L1, CTLA4, and CD80 overexpression (59.5%, 60.7%, 84.5%, and 92.9%, respectively), whereas overexpression was lower in NMIBC tissue (22.5%, 4.2%, 35.2%, and 46.5%, respectively). The results of reverse transcription polymerase chain reaction analysis were confirmed by immunohistochemistry, with a high correlation between mRNA and protein expression. On multivariate analyses, overexpression of the studied genes was not associated with prognosis in relapse or progression of NMIBC or in recurrence-free and overall survival of MIBC. The CTLA4 pathway appears to be deregulated along with the PD-1/PD-L1 pathway in bladder carcinogenesis, with good correlation between mRNA and protein expression endorsing the useful role of immune checkpoints, especially for a large subgroup of MIBC. Copyright © 2017 Elsevier Inc. All rights reserved.

[Bladder-conserving treatment for bladder cancer: potential of and developments in radiotherapy].

PubMed

Hulshof, Maarten C C M; Pieters, Bradley R; Koning, Caro C E

2013-01-01

The standard treatment for muscle-invasive bladder cancer is surgical removal of the bladder and construction of a neobladder. Recently, important improvements have been made in the potential for bladder-conserving treatment using radiotherapy. External beam radiotherapy has undergone technological improvements, as a result of which it is possible to radiate the tumour more precisely while decreasing radiation to healthy tissue. Radiochemotherapy improves local recurrence-free and overall survival compared with radiotherapy alone. The results of this combined treatment are comparable with those of surgery. Additionally, Dutch radiotherapy departments have collected data in a national database of 1040 selected patients with confined bladder cancer. These patients were treated with external beam radiation, limited surgery and brachytherapy. The 5-year local recurrence-free survival was 75%. Bladder conserving treatment options for muscle-invasive bladder cancer should be discussed during the multidisciplinary meeting.

Vitamin D-deficient mice have more invasive urinary tract infection.

PubMed

Hertting, Olof; Lüthje, Petra; Sullivan, Devin; Aspenström, Pontus; Brauner, Annelie

2017-01-01

Vitamin D deficiency is a common health problem with consequences not limited to bone and calcium hemostasis. Low levels have also been linked to tuberculosis and other respiratory infections as well as autoimmune diseases. We have previously shown that supplementation with vitamin D can induce the antimicrobial peptide cathelicidin during ex vivo infection of human urinary bladder. In rodents, however, cathelicidin expression is not linked to vitamin D and therefore this vitamin D-related effect fighting bacterial invasion is not relevant. To determine if vitamin D had further protective mechanisms during urinary tract infections, we therefore used a mouse model. In vitamin D-deficient mice, we detected more intracellular bacterial communities in the urinary bladder, higher degree of bacterial spread to the upper urinary tract and a skewed cytokine response. Furthermore, we show that the vitamin D receptor was upregulated in the urinary bladder and translocated into the cell nucleus after E. coli infection. This study supports a more general role for vitamin D as a local immune response mediator in the urinary tract.

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

PubMed

Syring, Isabella; Weiten, Richard; Müller, Tim; Schmidt, Doris; Steiner, Susanne; Kristiansen, Glen; Müller, Stefan C; Ellinger, Jörg

2017-12-01

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. 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. 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. MED30 appears to be integrated in the progression of the urothelial tumour in the bladder. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

[Recurrent urological cancer--diagnose and treatment].

PubMed

Takeshima, H; Akaza, H

1998-02-01

Clinical efforts to spare bladder function even in the case of muscle invasive recurrent bladder cancer is taking. Early detection of recurrence is essential for bladder sparing, and both urinary NMP22 and BTA are thought to have potency to detect recurrence of bladder cancer earlier than urinary cytology. Intravesical administration of BCG for superficial bladder cancer and intraarterial injection of chemoagents (Methotrexate and Cisplatin) with radiation for muscle invasive bladder cancer are thought to play important roles in sparing the bladder. Early detection of recurrent prostate cancer is becoming easier by ultrasensitive PSA assay. Though the value of early detection of recurrence is not proven since the benefits of early hormonal treatment have not yet been established, that should be a good indicator to evaluate new and coming treatments and play a important role to develop an effective treatment for recurrent prostate cancer.

Pazopanib in Treating Patients With Metastatic Urothelial Cancer

ClinicalTrials.gov

2014-05-22

Distal Urethral Cancer; Proximal Urethral Cancer; Recurrent Bladder Cancer; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Urethral Cancer; Stage IV Bladder Cancer; Transitional Cell Carcinoma of the Bladder; Urethral Cancer Associated With Invasive Bladder Cancer

Talimogene Laherparepvec in Treating Patients With Non-Muscle Invasive Bladder Transitional Cell Carcinoma

ClinicalTrials.gov

2018-05-15

Stage 0 Bladder Urothelial Carcinoma AJCC v6 and v7; Stage 0a Bladder Urothelial Carcinoma AJCC v6 and v7; Stage 0is Bladder Urothelial Carcinoma AJCC v6 and v7; Stage I Bladder Urothelial Carcinoma AJCC v6 and v7

Management of transitional cell carcinoma of the urinary bladder in dogs: a review.

PubMed

Fulkerson, Christopher M; Knapp, Deborah W

2015-08-01

Transitional cell carcinoma (TCC), also referred to as urothelial carcinoma, is the most common form of urinary bladder cancer in dogs, affecting tens of thousands of dogs worldwide each year. Canine TCC is usually a high grade invasive cancer. Problems associated with TCC include urinary tract obstruction, distant metastases in >50% of affected dogs, and clinical signs that are troubling both to the dogs and to their owners. Risk factors for TCC include exposure to older types of flea control products and lawn chemicals, obesity, female sex, and a very strong breed-associated risk. This knowledge is allowing pet owners to take steps to reduce the risk of TCC in their dog. The diagnosis of TCC is made by histopathology of tissue biopsies obtained by cystoscopy, surgery, or catheter. Percutaneous aspirates and biopsies should be avoided due to the risk of tumor seeding. TCC is most commonly located in the trigone region of the bladder precluding complete surgical resection. Medical treatment is the mainstay for TCC therapy in dogs. Although TCC is not usually curable in dogs, multiple drugs have activity against it. Approximately 75% of dogs respond favorably to TCC treatment and can enjoy several months to a year or more of good quality life. Many promising new therapies for TCC are emerging and with the close similarity between TCC in dogs and high grade invasive bladder cancer in humans, new treatment strategies found to be successful in canine studies are expected to help dogs and to be subsequently translated to humans. Copyright © 2015 Elsevier Ltd. All rights reserved.

Suppression of progranulin expression inhibits bladder cancer growth and sensitizes cancer cells to cisplatin.

PubMed

Buraschi, Simone; Xu, Shi-Qiong; Stefanello, Manuela; Moskalev, Igor; Morcavallo, Alaide; Genua, Marco; Tanimoto, Ryuta; Birbe, Ruth; Peiper, Stephen C; Gomella, Leonard G; Belfiore, Antonino; Black, Peter C; Iozzo, Renato V; Morrione, Andrea

2016-06-28

We have recently demonstrated a critical role for progranulin in bladder cancer. Progranulin contributes, as an autocrine growth factor, to the transformed phenotype by modulating Akt-and MAPK-driven motility, invasion and anchorage-independent growth. Progranulin also induces F-actin remodeling by interacting with the F-actin binding protein drebrin. In addition, progranulin is overexpressed in invasive bladder cancer compared to normal tissue controls, suggesting that progranulin might play a key role in driving the transition to the invasive phenotype of urothelial cancer. However, it is not established whether targeting progranulin could have therapeutic effects on bladder cancer. In this study, we stably depleted urothelial cancer cells of endogenous progranulin by shRNA approaches and determined that progranulin depletion severely inhibited the ability of tumorigenic urothelial cancer cells to migrate, invade and grow in anchorage-independency. We further demonstrate that progranulin expression is critical for tumor growth in vivo, in both xenograft and orthotopic tumor models. Notably, progranulin levels correlated with response to cisplatin treatment and were upregulated in bladder tumors. Our data indicate that progranulin may constitute a novel target for therapeutic intervention in bladder tumors. In addition, progranulin may serve as a novel biomarker for bladder cancer.

A novel role for drebrin in regulating progranulin bioactivity in bladder cancer.

PubMed

Xu, Shi-Qiong; Buraschi, Simone; Morcavallo, Alaide; Genua, Marco; Shirao, Tomoaki; Peiper, Stephen C; Gomella, Leonard G; Birbe, Ruth; Belfiore, Antonino; Iozzo, Renato V; Morrione, Andrea

2015-05-10

We recently established a critical role for the growth factor progranulin in bladder cancer insofar as progranulin promotes urothelial cancer cell motility and contributes, as an autocrine growth factor, to the transformed phenotype by modulating invasion and anchorage-independent growth. In addition, progranulin expression is upregulated in invasive bladder cancer tissues compared to normal controls. However, the molecular mechanisms of progranulin action in bladder cancer have not been fully elucidated. In this study, we searched for novel progranulin-interacting proteins using pull-down assays with recombinant progranulin and proteomics. We discovered that drebrin, an F-actin binding protein, bound progranulin in urothelial cancer cells. We characterized drebrin function in urothelial cancer cell lines and showed that drebrin is critical for progranulin-dependent activation of the Akt and MAPK pathways and modulates motility, invasion and anchorage-independent growth. In addition, drebrin regulates tumor formation in vivo and its expression is upregulated in bladder cancer tissues compared to normal tissue controls. Our data are translationally relevant as indicate that drebrin exerts an essential functional role in the regulation of progranulin action and may constitute a novel target for therapeutic intervention in bladder tumors. In addition, drebrin may serve as novel biomarker for bladder cancer.

Suppression of progranulin expression inhibits bladder cancer growth and sensitizes cancer cells to cisplatin

PubMed Central

Stefanello, Manuela; Moskalev, Igor; Morcavallo, Alaide; Genua, Marco; Tanimoto, Ryuta; Birbe, Ruth; Peiper, Stephen C.; Gomella, Leonard G.; Belfiore, Antonino; Black, Peter C.; Iozzo, Renato V.; Morrione, Andrea

2016-01-01

We have recently demonstrated a critical role for progranulin in bladder cancer. Progranulin contributes, as an autocrine growth factor, to the transformed phenotype by modulating Akt-and MAPK-driven motility, invasion and anchorage-independent growth. Progranulin also induces F-actin remodeling by interacting with the F-actin binding protein drebrin. In addition, progranulin is overexpressed in invasive bladder cancer compared to normal tissue controls, suggesting that progranulin might play a key role in driving the transition to the invasive phenotype of urothelial cancer. However, it is not established whether targeting progranulin could have therapeutic effects on bladder cancer. In this study, we stably depleted urothelial cancer cells of endogenous progranulin by shRNA approaches and determined that progranulin depletion severely inhibited the ability of tumorigenic urothelial cancer cells to migrate, invade and grow in anchorage-independency. We further demonstrate that progranulin expression is critical for tumor growth in vivo, in both xenograft and orthotopic tumor models. Notably, progranulin levels correlated with response to cisplatin treatment and were upregulated in bladder tumors. Our data indicate that progranulin may constitute a novel target for therapeutic intervention in bladder tumors. In addition, progranulin may serve as a novel biomarker for bladder cancer. PMID:27220888

Bladder cancer: overview and disease management. Part 1: non-muscle-invasive bladder cancer.

PubMed

Anderson, Beverley

2018-05-10

Part 1 of this two-part article provides an overview of bladder cancer and discusses its management. Since publication of a previous article entitled 'Understanding the role of smoking in the aetiology of bladder cancer' ( Anderson, 2009 ), the author has received many requests for an update. This article provides an overview of bladder cancer and its current management practices, underlining the continued role of smoking as the predominant risk factor in the disease's development. The management of bladder cancer is governed by specific guidelines. Management of non-muscle-invasive cancers, including surgical intervention with transurethral resection, and intravesical therapy using chemotherapy and immunotherapy agents, is discussed. Cystectomy (removal of the bladder), is sometimes necessary. Treatments are effective in reducing tumour recurrence, but the effects of the risks and side-effects on the individual's quality of life can be significant. The prevalence of bladder cancer, and the nature of its management make this cancer one of the most expensive for the NHS to treat. The effectiveness of health promotional strategies in increasing peoples' awareness of their risk of developing the disease, and in enabling them to change long-term health behaviours is discussed. The role of the multidisciplinary team is explored, along with that of the uro-oncology cancer nurse specialist. Part 2 will consider the management of muscle-invasive and metastatic bladder cancer.

A Novel Intraurethral Device Diagnostic Index to Classify Bladder Outlet Obstruction in Men with Lower Urinary Tract Symptoms

PubMed Central

Reis, Leonardo O.; Barreiro, Guilherme C.; Prudente, Alessandro; Silva, Cleide M.; Bassani, José W. M.; D'Ancona, Carlos A. L.

2009-01-01

Objectives. Using a urethral device at the fossa navicularis, bladder pressure during voiding can be estimated by a minimal invasive technique. This study purposes a new diagnostic index for patients with lower urinary tract symptoms (LUTSs). Methods. Fifty one patients presenting with LUTSs were submitted to a conventional urodynamic and a minimal invasive study. The results obtained through the urethral device and invasive classic urodynamics were compared. The existing bladder outlet obstruction index (BOOI) equation that classifies men with LUTSs was modified to allow minimal invasive measurement of isovolumetric bladder pressure in place of detrusor pressure at maximum urine flow. Accuracy of the new equation for classifying obstruction was then tested in this group of men. Results. The modified equation identified men with obstruction with a positive predictive value of 68% and a negative predictive value of 70%, with an overall accuracy of 70%. Conclusions. The proposed equation can accurately classify over 70% of men without resorting to invasive pressure flow studies. We must now evaluate the usefulness of this classification for the surgical treatment of men with LUTSs. PMID:19125194

New clinical trial open for patients with muscle-invasive bladder cancer | Center for Cancer Research

Cancer.gov

Muscle-invasive bladder cancer is an aggressive form of bladder cancer in which the tumor invades deep into the musculature of the bladder wall, making it more likely to spread to other parts of the body. Standard treatment involves cisplatin-based chemotherapy followed by radical cystectomy, which is surgery to remove the bladder and nearby organs. However, many patients don’t receive chemotherapy before surgery or may not respond to it. Other patients are ineligible for cisplatin treatment due to poor kidney function. CCR investigators are leading a phase III trial to determine whether an immunotherapy drug given shortly after cystectomy can help these patients. Read more…

A place for precision medicine in bladder cancer: targeting the FGFRs.

PubMed

di Martino, Erica; Tomlinson, Darren C; Williams, Sarah V; Knowles, Margaret A

2016-10-01

Bladder tumors show diverse molecular features and clinical outcome. Muscle-invasive bladder cancer has poor prognosis and novel approaches to systemic therapy are urgently required. Non-muscle-invasive bladder cancer has good prognosis, but high recurrence rate and the requirement for life-long disease monitoring places a major burden on patients and healthcare providers. Studies of tumor tissues from both disease groups have identified frequent alterations of FGFRs, including mutations of FGFR3 and dysregulated expression of FGFR1 and FGFR3 that suggest that these may be valid therapeutic targets. We summarize current understanding of the molecular alterations affecting these receptors in bladder tumors, preclinical studies validating them as therapeutic targets, available FGFR-targeted agents and results from early clinical trials in bladder cancer patients.

A place for precision medicine in bladder cancer: targeting the FGFRs

PubMed Central

di Martino, Erica; Tomlinson, Darren C; Williams, Sarah V; Knowles, Margaret A

2016-01-01

Bladder tumors show diverse molecular features and clinical outcome. Muscle-invasive bladder cancer has poor prognosis and novel approaches to systemic therapy are urgently required. Non-muscle-invasive bladder cancer has good prognosis, but high recurrence rate and the requirement for life-long disease monitoring places a major burden on patients and healthcare providers. Studies of tumor tissues from both disease groups have identified frequent alterations of FGFRs, including mutations of FGFR3 and dysregulated expression of FGFR1 and FGFR3 that suggest that these may be valid therapeutic targets. We summarize current understanding of the molecular alterations affecting these receptors in bladder tumors, preclinical studies validating them as therapeutic targets, available FGFR-targeted agents and results from early clinical trials in bladder cancer patients. PMID:27381494

Nomograms Predicting Response to Therapy and Outcomes After Bladder-Preserving Trimodality Therapy for Muscle-Invasive Bladder Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coen, John J., E-mail: jcoen@harthosp.org; Paly, Jonathan J.; Niemierko, Andrzej

2013-06-01

Purpose: Selective bladder preservation by use of trimodality therapy is an established management strategy for muscle-invasive bladder cancer. Individual disease features have been associated with response to therapy, likelihood of bladder preservation, and disease-free survival. We developed prognostic nomograms to predict the complete response rate, disease-specific survival, and likelihood of remaining free of recurrent bladder cancer or cystectomy. Methods and Materials: From 1986 to 2009, 325 patients were managed with selective bladder preservation at Massachusetts General Hospital (MGH) and had complete data adequate for nomogram development. Treatment consisted of a transurethral resection of bladder tumor followed by split-course chemoradiation. Patientsmore » with a complete response at midtreatment cystoscopic assessment completed radiation, whereas those with a lesser response underwent a prompt cystectomy. Prognostic nomograms were constructed predicting complete response (CR), disease-specific survival (DSS), and bladder-intact disease-free survival (BI-DFS). BI-DFS was defined as the absence of local invasive or regional recurrence, distant metastasis, bladder cancer-related death, or radical cystectomy. Results: The final nomograms included information on clinical T stage, presence of hydronephrosis, whether a visibly complete transurethral resection of bladder tumor was performed, age, sex, and tumor grade. The predictive accuracy of these nomograms was assessed. For complete response, the area under the receiving operating characteristic curve was 0.69. The Harrell concordance index was 0.61 for both DSS and BI-DFS. Conclusions: Our nomograms allow individualized estimates of complete response, DSS, and BI-DFS. They may assist patients and clinicians making important treatment decisions.« less

Nuclear Factor-κB Promotes Urothelial Tumorigenesis and Cancer Progression via Cooperation with Androgen Receptor Signaling.

PubMed

Inoue, Satoshi; Ide, Hiroki; Mizushima, Taichi; Jiang, Guiyang; Netto, George J; Gotoh, Momokazu; Miyamoto, Hiroshi

2018-06-01

We investigated the role of NF-κB in the development and progression of urothelial cancer as well as cross-talk between NF-κB and androgen receptor (AR) signals in urothelial cells. Immunohistochemistry in surgical specimens showed that the expression levels of NF-κB/p65 ( P = 0.015)/phospho-NF-κB/p65 ( P < 0.001) were significantly elevated in bladder tumors, compared with those in nonneoplastic urothelial tissues. The rates of phospho-NF-κB/p65 positivity were also significantly higher in high-grade ( P = 0.015)/muscle-invasive ( P = 0.033) tumors than in lower grade/non-muscle-invasive tumors. Additionally, patients with phospho-NF-κB/p65-positive muscle-invasive bladder cancer had significantly higher risks of disease progression ( P < 0.001) and cancer-specific mortality ( P = 0.002). In immortalized human normal urothelial SVHUC cells stably expressing AR, NF-κB activators and inhibitors accelerated and prevented, respectively, their neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene. Bladder tumors were identified in 56% (mock), 89% (betulinic acid), and 22% (parthenolide) of N -butyl- N -(4-hydroxybutyl)nitrosamine-treated male C57BL/6 mice at 22 weeks of age. NF-κB activators and inhibitors also significantly induced and reduced, respectively, cell proliferation/migration/invasion of AR-positive bladder cancer lines, but not AR-knockdown or AR-negative lines, and their growth in xenograft-bearing mice. In both nonneoplastic and neoplastic urothelial cells, NF-κB activators/inhibitors upregulated/downregulated, respectively, AR expression, whereas AR overexpression was associated with increases in the expression levels of NF-κB/p65 and phospho-NF-κB/p65. Thus, NF-κB appeared to be activated in bladder cancer, which was associated with tumor progression. NF-κB activators/inhibitors were also found to modulate tumorigenesis and tumor outgrowth in AR-activated urothelial cells. Accordingly, NF-κB inhibition, together with AR inactivation, has the potential of being an effective chemopreventive and/or therapeutic approach for urothelial carcinoma. Mol Cancer Ther; 17(6); 1303-14. ©2018 AACR . ©2018 American Association for Cancer Research.

The management of non-invasive bladder tumours with Doxorubicin intravesical instillation after transurethral resection.

PubMed

Al-Gallab, Musa I; Naddaf, Louai A; Kanan, Mohamad R

2009-04-01

Evaluation of the intravesical instillation of doxorubicin for its effect on disease recurrence for patients with non-invasive bladder tumour. The study was performed at Al Assad University Hospital in Lattakia, Syria and included patients with non-invasive bladder tumours who were managed with transurethral resection and induction and maintenance therapy with intravesical doxorubicin. They were followed up by cystoscopy every 3 months for 2 years and every 6 months thereafter with special emphasis on recurrence rates. The study included 85 patients with non-invasive bladder tumours: 23 with non-invasive papillary carcinoma (Stage Ta), 62 with tumour invading subepithelial connective tissue (Stage T1). Twelve patients had well differentiated tumours (Grade 1), 48 had moderately differentiated (Grade 2), 25 had poorly differentiated (Grade 3) tumours. The total recurrence rate was 23%. The rates of recurrence were 56% in Grade 3 and 0% in Grade 1. The recurrence rate was 41% in patients with large tumours versus 17% in those with small tumours; 44% in those with multiple tumours compared to 18% in those with solitary tumours; 30% of Stage Ta tumours recurred and 21% of Stage T1 tumours. In short term follow-up, our rate of recurrence was 23%. Adjuvant intravesical doxorubicin was shown to reduce the recurrence of superficial bladder cancer. Tumour grade, size and number were shown to be prognostic factors for recurrence.

Nanotechnology in bladder cancer: current state of development and clinical practice

PubMed Central

Tomlinson, Ben; Lin, Tzu-yin; Dall'Era, Marc; Pan, Chong-Xian

2015-01-01

Nanotechnology is being developed for the diagnosis and treatment of both nonmyoinvasive bladder cancer (NMIBC) and invasive bladder cancer. The diagnostic applications of nanotechnology in NMIBC mainly focus on tumor identification during endoscopy to increase complete resection of bladder cancer while nanotechnology to capture malignant cells or their components continues to be developed. The therapeutic applications of nanotechnology in NMIBC are to reformulate biological and cytotoxic agents for intravesical instillation, combine both diagnostic and therapeutic application in one nanoformulation. In invasive and advanced bladder cancer, magnetic resonance imaging with supraparamagnetic iron oxide nanoparticles can improve the sensitivity and specificity in detecting small metastasis to lymph nodes. Nanoformulation of cytotoxic agents can potentially decrease the toxicity while increasing efficacy. PMID:25929573

Adenoviral receptor expression of normal bladder and transitional cell carcinoma of the bladder.

PubMed

Buscarini, Maurizio; Quek, Marcus L; Gilliam-Hegarich, Susan; Kasahara, Nori; Bochner, Bernard

2007-01-01

The insertion of absent or underexpressed genes into cancer cells to alter their malignant phenotype is an important potential application of available gene therapy technology. One of the more common viral vector systems that has been extensively studied for this purpose are the replication-deficient adenoviruses (Ad). Adenoviral infection of cells is mediated through a complex pathway, initiated following viral-cell attachment. Adenoviral-cell attachment occurs following interactions with a 46-kDa transmembrane protein with high affinity for both the Coxsackie and adenovirus, designated the CAR (Coxsackie and adenoviral receptor). Additional important cell-viral interactions that occur involve the alpha(v)-based integrins, specifically alpha(v)beta3 and alpha(v)beta5. The purpose of the present study was to determine the extent of expression and localization of the known Ad receptor proteins (CAR, alpha(v)beta3, and alpha(v)beta5) in normal and cancerous human bladders. Frozen tissue samples of normal bladder and invasive transitional cell cancers of the bladder were evaluated. Tissue blocks containing muscle-invasive transitional cell carcinoma (TCC) were obtained following radical cystectomy, which were performed at our institution. Thirty-two invasive transitional cell bladder tumors were evaluated, each with a matched sample of histologically normal-appearing bladder used as a control. Four additional samples of normal bladder were obtained from patients with no evidence of disease of the bladder and served as further controls. Three additional cases of invasive bladder cancer with no matching normal tissue were also evaluated. Identification of the CAR receptor was performed using the anti-CAR mouse monoclonal antibody designated RmBC. The integrins alpha(v)beta3 and alpha(v)beta5 were identified using the mouse monoclonal antibodies designated LM609 and P1F6 respectively. All slides were evaluated by two of the authors (M.B., B.B.) without knowledge of the clinical and pathological data. Normal bladder: Normal bladder mucosa demonstrated a marked positivity for CAR in 29/35 (82.8%) cases. In contrast, normal transitional epithelial cells were uniformly negative when tested for the integrins alpha(v)beta3 and alpha(v)beta5. Subepithelial tissues, specifically the connective tissue components of the lamina propria and deep muscle wall of the bladder, were positive for alpha(v)beta3 and for alpha(v)beta5 in 61 and 75% of samples, respectively. Endothelial cells associated with the various layers throughout the bladder uniformly expressed both integrins and served as a consistent internal control for both antibodies. An almost identical staining pattern of the endothelium was observed using LM609 and P1F6 in all samples tested. Bladder transitional cell carcinoma: CAR immunoreactivity against TCC cells was uniformly decreased compared to normal transitional cells. Nine tumors exhibited a weak positivity for CAR while the remaining samples were negative. In some cases, the absence of CAR positivity was associated with histological evidence of carcinoma in situ. In 6 cases, it led to the identification of small regions of carcinoma in situ that were not noted on primary pathological evaluation. Peritumoral connective tissue expressed both integrins in the majority of cases, similar to the pattern described above for normal bladder. Transitional cell cancers demonstrated a similar pattern of expression of alpha(v)beta5, in which all tumor cells exhibited minimal or no staining. The success of all viral-mediated gene therapy strategies relies on the ability of the vector to efficiently deliver its genetic material to a target cell population. In the current study, we demonstrate that the bladder epithelial layer consistently expresses high levels of CAR. Deeper layers of the epithelium also express CAR, including the basal layer cells. A decrease in the expression of CAR appears as an early event in bladder carcinogenesis. We observed that both alpha(v)beta3 and alpha(v)beta5 are strongly expressed in muscle cells surrounding the neoplastic cells, as well as within the peritumoral connective tissue. In cases of invasive bladder cancer that have lost CAR expression, an adenoviral vector may still be utilized through the less efficient interactions with the integrins. Bladder tumor tissue may be less susceptible to an adenoviral-mediated gene therapy approach in which a significant percentage of tumor cells require transduction. Adenoviral uptake by tumor or peritumoral cells with subsequent gene transfer could be predicted by the level of CAR and alpha(v)-based integrin expression. This would enhance our ability to identify those patients whose tumors would be more susceptible to Ad-mediated gene delivery as part of an antitumor treatment. 2007 S. Karger AG, Basel

Urinary long noncoding RNAs in nonmuscle-invasive bladder cancer: new architects in cancer prognostic biomarkers.

PubMed

Terracciano, Daniela; Ferro, Matteo; Terreri, Sara; Lucarelli, Giuseppe; D'Elia, Carolina; Musi, Gennaro; de Cobelli, Ottavio; Mirone, Vincenzo; Cimmino, Amelia

2017-06-01

Several reports over the last 10 years provided evidence that long noncoding RNAs (lncRNAs) are often altered in bladder cancers. lncRNAs are longer than 200 nucleotides and function as important regulators of gene expression, interacting with the major pathways of cell growth, proliferation, differentiation, and survival. A large number of lncRNAs has oncogenic function and is more expressed in tumor compared with normal tissues. Their overexpression may be associated with tumor formation, progression, and metastasis in a variety of tumors including bladder cancer. Although lncRNAs have been shown to have critical regulatory roles in cancer biology, the biological functions and prognostic values in nonmuscle-invasive bladder cancer remain largely unknown. Nevertheless, a growing body of evidence suggests that several lncRNAs expression profiles in bladder malignancies are associated with poor prognosis, and they can be detected in biological fluids, such as urines. Here, we review current progress in the biology and the implication of lncRNAs associated with bladder cancer, and we discuss their potential use as diagnosis and prognosis biomarkers in bladder malignancies with a focus on their role in high-risk nonmuscle-invasive tumors. Copyright © 2017 Elsevier Inc. All rights reserved.

A novel role for drebrin in regulating progranulin bioactivity in bladder cancer

PubMed Central

Morcavallo, Alaide; Genua, Marco; Shirao, Tomoaki; Peiper, Stephen C.; Gomella, Leonard G.; Birbe, Ruth; Belfiore, Antonino; Iozzo, Renato V.; Morrione, Andrea

2015-01-01

We recently established a critical role for the growth factor progranulin in bladder cancer insofar as progranulin promotes urothelial cancer cell motility and contributes, as an autocrine growth factor, to the transformed phenotype by modulating invasion and anchorage-independent growth. In addition, progranulin expression is upregulated in invasive bladder cancer tissues compared to normal controls. However, the molecular mechanisms of progranulin action in bladder cancer have not been fully elucidated. In this study, we searched for novel progranulin-interacting proteins using pull-down assays with recombinant progranulin and proteomics. We discovered that drebrin, an F-actin binding protein, bound progranulin in urothelial cancer cells. We characterized drebrin function in urothelial cancer cell lines and showed that drebrin is critical for progranulin-dependent activation of the Akt and MAPK pathways and modulates motility, invasion and anchorage-independent growth. In addition, drebrin regulates tumor formation in vivo and its expression is upregulated in bladder cancer tissues compared to normal tissue controls. Our data are translationally relevant as indicate that drebrin exerts an essential functional role in the regulation of progranulin action and may constitute a novel target for therapeutic intervention in bladder tumors. In addition, drebrin may serve as novel biomarker for bladder cancer. PMID:25839164

Differentiation‐associated urothelial cytochrome P450 oxidoreductase predicates the xenobiotic‐metabolizing activity of “luminal” muscle‐invasive bladder cancers

PubMed Central

Arlt, Volker M.; Indra, Radek; Joel, Madeleine; Stiborová, Marie; Eardley, Ian; Ahmad, Niaz; Otto, Wolfgang; Burger, Maximilian; Rubenwolf, Peter; Phillips, David H.; Southgate, Jennifer

2018-01-01

Extra‐hepatic metabolism of xenobiotics by epithelial tissues has evolved as a self‐defence mechanism but has potential to contribute to the local activation of carcinogens. Bladder epithelium (urothelium) is bathed in excreted urinary toxicants and pro‐carcinogens. This study reveals how differentiation affects cytochrome P450 (CYP) activity and the role of NADPH:P450 oxidoreductase (POR). CYP1A1 and CYP1B1 transcripts were inducible in normal human urothelial (NHU) cells maintained in both undifferentiated and functional barrier‐forming differentiated states in vitro. However, ethoxyresorufin O‐deethylation (EROD) activity, the generation of reactive BaP metabolites and BaP‐DNA adducts, were predominantly detected in differentiated NHU cell cultures. This gain‐of‐function was attributable to the expression of POR, an essential electron donor for all CYPs, which was significantly upregulated as part of urothelial differentiation. Immunohistology of muscle‐invasive bladder cancer (MIBC) revealed significant overall suppression of POR expression. Stratification of MIBC biopsies into “luminal” and “basal” groups, based on GATA3 and cytokeratin 5/6 labeling, showed POR over‐expression by a subgroup of the differentiated luminal tumors. In bladder cancer cell lines, CYP1‐activity was undetectable/low in basal PORlo T24 and SCaBER cells and higher in the luminal POR over‐expressing RT4 and RT112 cells than in differentiated NHU cells, indicating that CYP‐function is related to differentiation status in bladder cancers. This study establishes POR as a predictive biomarker of metabolic potential. This has implications in bladder carcinogenesis for the hepatic versus local activation of carcinogens and as a functional predictor of the potential for MIBC to respond to prodrug therapies. PMID:29323757

VEGF Trap in Treating Patients With Recurrent, Locally Advanced, or Metastatic Cancer of the Urothelium

ClinicalTrials.gov

2014-10-10

Adenocarcinoma of the Bladder; Distal Urethral Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Proximal Urethral Cancer; Recurrent Bladder Cancer; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Urethral Cancer; Squamous Cell Carcinoma of the Bladder; Stage III Bladder Cancer; Stage III Urethral Cancer; Stage IV Bladder Cancer; Transitional Cell Carcinoma of the Bladder; Urethral Cancer Associated With Invasive Bladder Cancer

Safety and Tolerability of TAR-200 and Nivolumab in Subjects With Muscle-Invasive Bladder Cancer

ClinicalTrials.gov

2018-05-04

Bladder Cancer TNM Staging Primary Tumor (T) T2; Bladder Cancer TNM Staging Primary Tumor (T) T2A; Bladder Cancer TNM Staging Primary Tumor (T) T2B; Bladder Cancer TNM Staging Primary Tumor (T) T3; Bladder Cancer TNM Staging Primary Tumor (T) T3A; Bladder Cancer TNM Staging Primary Tumor (T) T3B; Bladder Cancer TNM Staging Regional Lymph Node (N) N0; Bladder Cancer TNM Staging Regional Lymph Node (N) N1; Bladder Cancer TNM Staging Distant Metastasis (M) M0

Comparative analysis of the effect of prostatic invasion patterns on cancer-specific mortality after radical cystectomy in pT4a urothelial carcinoma of the bladder.

PubMed

Vallo, Stefan; Gilfrich, Christian; Burger, Maximilian; Volkmer, Björn; Boehm, Katharina; Rink, Michael; Chun, Felix K; Roghmann, Florian; Novotny, Vladimir; Mani, Jens; Brisuda, Antonin; Mayr, Roman; Stredele, Regina; Noldus, Joachim; Schnabel, Marco; May, Matthias; Fritsche, Hans-Martin; Pycha, Armin; Martini, Thomas; Wirth, Manfred; Roigas, Jan; Bastian, Patrick J; Nuhn, Philipp; Dahlem, Roland; Haferkamp, Axel; Fisch, Margit; Aziz, Atiqullah

2016-10-01

To evaluate the prognostic relevance of different prostatic invasion patterns in pT4a urothelial carcinoma of the bladder (UCB) after radical cystectomy. Our study comprised a total of 358 men with pT4a UCB. Patients were divided in 2 groups-group A with stromal infiltration of the prostate via the prostatic urethra with additional muscle-invasive UCB (n = 121, 33.8%) and group B with continuous infiltration of the prostate through the entire bladder wall (n = 237, 66.2%). The effect of age, tumor grade, carcinoma in situ, lymphovascular invasion, soft tissue surgical margin, lymph node metastases, administration of adjuvant chemotherapy, and prostatic invasion patterns on cancer-specific mortality (CSM) was evaluated using competing-risk regression analysis. Decision curve analysis was used to evaluate the net benefit of including the variable invasion pattern within our model. The estimated 5-year CSM-rates for group A and B were 50.1% and 66.0%, respectively. In multivariable competing-risk analysis, lymph node metastases (hazard ratio [HR] = 1.73, P<0.001), lymphovascular invasion (HR = 1.62, P = 0.0023), soft tissue surgical margin (HR = 1.49, P = 0.026), absence of adjuvant chemotherapy (HR = 2.11, P<0.001), and tumor infiltration of the prostate by continuous infiltration of the entire bladder wall (HR = 1.37, P = 0.044) were significantly associated with a higher risk for CSM. Decision curve analysis showed a net benefit of our model including the variable invasion pattern. Continuous infiltration of the prostate through the entire bladder wall showed an adverse effect on CSM. Besides including these patients into clinical trials for an adjuvant therapy, we recommend including prostatic invasion patterns in predictive models in pT4a UCB in men. Copyright © 2016 Elsevier Inc. All rights reserved.

Gene Discovery in Bladder Cancer Progression using cDNA Microarrays

PubMed Central

Sanchez-Carbayo, Marta; Socci, Nicholas D.; Lozano, Juan Jose; Li, Wentian; Charytonowicz, Elizabeth; Belbin, Thomas J.; Prystowsky, Michael B.; Ortiz, Angel R.; Childs, Geoffrey; Cordon-Cardo, Carlos

2003-01-01

To identify gene expression changes along progression of bladder cancer, we compared the expression profiles of early-stage and advanced bladder tumors using cDNA microarrays containing 17,842 known genes and expressed sequence tags. The application of bootstrapping techniques to hierarchical clustering segregated early-stage and invasive transitional carcinomas into two main clusters. Multidimensional analysis confirmed these clusters and more importantly, it separated carcinoma in situ from papillary superficial lesions and subgroups within early-stage and invasive tumors displaying different overall survival. Additionally, it recognized early-stage tumors showing gene profiles similar to invasive disease. Different techniques including standard t-test, single-gene logistic regression, and support vector machine algorithms were applied to identify relevant genes involved in bladder cancer progression. Cytokeratin 20, neuropilin-2, p21, and p33ING1 were selected among the top ranked molecular targets differentially expressed and validated by immunohistochemistry using tissue microarrays (n = 173). Their expression patterns were significantly associated with pathological stage, tumor grade, and altered retinoblastoma (RB) expression. Moreover, p33ING1 expression levels were significantly associated with overall survival. Analysis of the annotation of the most significant genes revealed the relevance of critical genes and pathways during bladder cancer progression, including the overexpression of oncogenic genes such as DEK in superficial tumors or immune response genes such as Cd86 antigen in invasive disease. Gene profiling successfully classified bladder tumors based on their progression and clinical outcome. The present study has identified molecular biomarkers of potential clinical significance and critical molecular targets associated with bladder cancer progression. PMID:12875971

Updated results of bladder-sparing trimodality approach for invasive bladder cancer.

PubMed

Zapatero, Almudena; Martin de Vidales, Carmen; Arellano, Ramón; Bocardo, Gloria; Pérez, Mar; Ríos, Patricia

2010-01-01

To update long-term results with selective organ preservation in invasive bladder cancer using aggressive transurethral resection of bladder tumor (TURBT) and radiochemotherapy (RCT) and to identify treatment factors that may predict overall survival (OS). Between 1990 and 2007, a total of 74 patients with T2-T4 bladder cancer were enrolled in 2 sequential bladder-sparing protocols including aggressive TURB and RCT. From 1990 to 1999, 41 patients were included in protocol no. 1 (P1) that consisted of three cycles of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy prior to re-evaluation and followed by radiotherapy (RT) 60 Gy in complete responders. Between 2000 and 2007, 33 patients were entered in protocol no. 2 (P2) that consisted of concurrent RCT 64, 8 Gy with weekly cisplatin. In case of invasive residual tumor or recurrence, salvage cystectomy was recommended. Primary endpoints were OS, overall survival with bladder preservation (OSB), and late toxicity. The mean follow-up for the whole series was 54 months (range 9-156), 69 months for patients in P1 and 36 months for patients in P2. The actuarial 5-year OS and OSB for all series were 72% and 60%, respectively. Distant metastases were diagnosed in 11 (15%) patients. Grade 3 late genitourinary (GU) and intestinal (GI) complications were 5% and 1.3%, respectively. There were no significant differences in the incidence of superficial recurrences (P = 0.080), muscle-invasive relapses (P = 0.722), distant metastasis (P = 0.744), grade >/=2 late complications (P = 0.217 for GU and P = 0.400 for GI), and death among the 2 protocols (P value for OS = 0.643; P value for OSB = 0.532). These data confirm that trimodality therapy with bladder preservation represents a real alternative to radical cystectomy in selected patients, resulting in an acceptable rate of the long-term survivors retaining functional bladders. Copyright 2010 Elsevier Inc. All rights reserved.

Microwave radiometry for non-invasive detection of vesicoureteral reflux (VUR) following bladder warming

NASA Astrophysics Data System (ADS)

Stauffer, Paul R.; Maccarini, Paolo F.; Arunachalam, Kavitha; De Luca, Valeria; Salahi, Sara; Boico, Alina; Klemetsen, Oystein; Birkelund, Yngve; Jacobsen, Svein K.; Bardati, Fernando; Tognolotti, Piero; Snow, Brent

2011-03-01

Background: Vesicoureteral reflux (VUR) is a serious health problem leading to renal scarring in children. Current VUR detection involves traumatic x-ray imaging of kidneys following injection of contrast agent into bladder via invasive Foley catheter. We present an alternative non-invasive approach for detecting VUR by radiometric monitoring of kidney temperature while gently warming the bladder. Methods: We report the design and testing of: i) 915MHz square slot antenna array for heating bladder, ii) EMI-shielded log spiral microstrip receive antenna, iii) high-sensitivity 1.375GHz total power radiometer, iv) power modulation approach to increase urine temperature relative to overlying perfused tissues, and v) invivo porcine experiments characterizing bladder heating and radiometric temperature of aaline filled 30mL balloon "kidney" implanted 3-4cm deep in thorax and varied 2-6°C from core temperature. Results: SAR distributions are presented for two novel antennas designed to heat bladder and monitor deep kidney temperatures radiometrically. We demonstrate the ability to heat 180mL saline in in vivo porcine bladder to 40-44°C while maintaining overlying tissues <38°C using time-modulated square slot antennas coupled to the abdomen with room temperature water pad. Pathologic evaluations confirmed lack of acute thermal damage in pelvic tissues for up to three 20min bladder heat exposures. The radiometer clearly recorded 2-6°C changes of 30mL "kidney" targets at depth in 34°C invivo pig thorax. Conclusion: A 915MHz antenna array can gently warm in vivo pig bladder without toxicity while a 1.375GHz radiometer with log spiral receive antenna detects >=2°C rise in 30mL "urine" located 3-4cm deep in thorax, demonstrating more than sufficient sensitivity to detect Grade 4-5 reflux of warmed urine for non-invasive detection of VUR.

Microwave Radiometry for Non-Invasive Detection of Vesicoureteral Reflux (VUR) Following Bladder Warming.

PubMed

Stauffer, Paul R; Maccarini, Paolo F; Arunachalam, Kavitha; De Luca, Valeria; Salahi, Sara; Boico, Alina; Klemetsen, Oystein; Birkelund, Yngve; Jacobsen, Svein K; Bardati, Fernando; Tognolatti, Piero; Snow, Brent

2011-01-01

BACKGROUND: Vesicoureteral reflux (VUR) is a serious health problem leading to renal scarring in children. Current VUR detection involves traumatic x-ray imaging of kidneys following injection of contrast agent into bladder via invasive Foley catheter. We present an alternative non-invasive approach for detecting VUR by radiometric monitoring of kidney temperature while gently warming the bladder. METHODS: We report the design and testing of: i) 915MHz square slot antenna array for heating bladder, ii) EMI-shielded log spiral microstrip receive antenna, iii) high-sensitivity 1.375GHz total power radiometer, iv) power modulation approach to increase urine temperature relative to overlying perfused tissues, and v) invivo porcine experiments characterizing bladder heating and radiometric temperature of aaline filled 30mL balloon "kidney" implanted 3-4cm deep in thorax and varied 2-6°C from core temperature. RESULTS: SAR distributions are presented for two novel antennas designed to heat bladder and monitor deep kidney temperatures radiometrically. We demonstrate the ability to heat 180mL saline in in vivo porcine bladder to 40-44°C while maintaining overlying tissues <38°C using time-modulated square slot antennas coupled to the abdomen with room temperature water pad. Pathologic evaluations confirmed lack of acute thermal damage in pelvic tissues for up to three 20min bladder heat exposures. The radiometer clearly recorded 2-6°C changes of 30mL "kidney" targets at depth in 34°C invivo pig thorax. CONCLUSION: A 915MHz antenna array can gently warm in vivo pig bladder without toxicity while a 1.375GHz radiometer with log spiral receive antenna detects ≥2°C rise in 30mL "urine" located 3-4cm deep in thorax, demonstrating more than sufficient sensitivity to detect Grade 4-5 reflux of warmed urine for non-invasive detection of VUR.

Enzalutamide inhibits androgen receptor-positive bladder cancer cell growth.

PubMed

Kawahara, Takashi; Ide, Hiroki; Kashiwagi, Eiji; El-Shishtawy, Kareem A; Li, Yi; Reis, Leonardo O; Zheng, Yichun; Miyamoto, Hiroshi

2016-10-01

Emerging preclinical evidence suggests that androgen-mediated androgen receptor (AR) signals promote bladder cancer progression. However, little is known about the efficacy of an AR signaling inhibitor, enzalutamide, in the growth of bladder cancer cells. In this study, we compared the effects of enzalutamide and 2 other classic antiandrogens, flutamide and bicalutamide, on androgen-induced bladder cancer cell proliferation, migration, and invasion as well as tumor growth in vivo. Thiazolyl blue cell viability assay, flow cytometry, scratch wound-healing assay, transwell invasion assay, real-time polymerase chain reaction, and reporter gene assay were performed in AR-positive (e.g., UMUC3, TCCSUP, and 647V-AR) and AR-negative (e.g., UMUC3-AR-short hairpin RNA [shRNA], TCCSUP-AR-shRNA, 647V) bladder cancer lines treated with dihydrotestosterone and each AR antagonist. We also used a mouse xenograft model for bladder cancer. Dihydrotestosterone increased bladder cancer cell proliferation, migration, and invasion indicating that endogenous or exogenous AR was functional. Enzalutamide, hydroxyflutamide, and bicalutamide showed similar inhibitory effects, without significant agonist activity, on androgen-mediated cell viability/apoptosis, cell migration, and cell invasion in AR-positive lines. No significant effects of dihydrotestosterone as well as AR antagonists on the growth of AR-negative cells were seen. Correspondingly, in UMUC3 cells, these AR antagonists down-regulated androgen-induced expression of AR, matrix metalloproteinase-2, and interleukin-6. Androgen-enhanced AR-mediated transcriptional activity was also blocked by each AR antagonist exhibiting insignificant agonist activity. In UMUC3 xenograft-bearing mice, oral gavage treatment with each antiandrogen retarded tumor growth, and only enzalutamide demonstrated a statistically significant suppression compared with mock treatment. Our current data support recent observations indicating the involvement of the AR pathway in bladder cancer growth and further suggest that AR antagonists, including enzalutamide, are of therapeutic benefit in AR-positive bladder cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Optimal Timing of Chemotherapy and Surgery in Patients with Muscle-Invasive Bladder Cancer and Upper Urinary Tract Urothelial Carcinoma.

PubMed

Tabayoyong, William; Li, Roger; Gao, Jianjun; Kamat, Ashish

2018-05-01

Radical cystectomy with bilateral pelvic lymph node dissection is the standard of care for patients with clinically localized muscle-invasive bladder cancer. Survival after radical cystectomy is associated with final pathologic staging. Survival decreases with increasing pT stage because of the presence of occult micrometastases, indicating the need for systemic chemotherapy. Systemic chemotherapy is delivered as either neoadjuvant therapy preoperatively, or as adjuvant therapy postoperatively. This article reviews the evidence for neoadjuvant and adjuvant chemotherapy for the treatment of muscle-invasive bladder and upper tract urothelial cancer and offers recommendations based on these data and recently updated clinical guidelines. Copyright © 2018 Elsevier Inc. All rights reserved.

Sorafenib in Treating Patients With Regional or Metastatic Cancer of the Urothelium

ClinicalTrials.gov

2014-05-20

Adenocarcinoma of the Bladder; Distal Urethral Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Proximal Urethral Cancer; Recurrent Bladder Cancer; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Urethral Cancer; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Squamous Cell Carcinoma of the Bladder; Stage III Bladder Cancer; Stage IV Bladder Cancer; Transitional Cell Carcinoma of the Bladder; Urethral Cancer Associated With Invasive Bladder Cancer

A Non-Invasive Bladder Sensory Test Supports a Role for Dysmenorrhea Increasing Bladder Noxious Mechanosensitivity

PubMed Central

TU, Frank F.; EPSTEIN, Aliza E.; POZOLO, Kristen E.; SEXTON, Debra L.; MELNYK, Alexandra I.; HELLMAN, Kevin M.

2012-01-01

Objective Catheterization to measure bladder sensitivity is aversive and hinders human participation in visceral sensory research. Therefore, we sought to characterize the reliability of sonographically-estimated female bladder sensory thresholds. To demonstrate this technique’s usefulness, we examined the effects of self-reported dysmenorrhea on bladder pain thresholds. Methods Bladder sensory threshold volumes were determined during provoked natural diuresis in 49 healthy women (mean age 24 ± 8) using three-dimensional ultrasound. Cystometric thresholds (Vfs – first sensation, Vfu – first urge, Vmt – maximum tolerance) were quantified and related to bladder urgency and pain. We estimated reliability (one-week retest and interrater). Self-reported menstrual pain was examined in relationship to bladder pain, urgency and volume thresholds. Results Average bladder sensory thresholds (mLs) were Vfs (160±100), Vfu (310±130), and Vmt (500±180). Interrater reliability ranged from 0.97–0.99. One-week retest reliability was Vmt = 0.76 (95% CI 0.64–0.88), Vfs = 0.62 (95% CI 0.44–0.80), and Vfu = 0.63, (95% CI 0.47–0.80). Bladder filling rate correlated with all thresholds (r = 0.53–0.64, p < 0.0001). Women with moderate to severe dysmenorrhea pain had increased bladder pain and urgency at Vfs and increased pain at Vfu (p’s < 0.05). In contrast, dysmenorrhea pain was unrelated to bladder capacity. Discussion Sonographic estimates of bladder sensory thresholds were reproducible and reliable. In these healthy volunteers, dysmenorrhea was associated with increased bladder pain and urgency during filling but unrelated to capacity. Plausibly, dysmenorrhea sufferers may exhibit enhanced visceral mechanosensitivity, increasing their risk to develop chronic bladder pain syndromes. PMID:23370073

Role of imaging techniques in the diagnosis and follow-up of muscle-invasive bladder carcinoma.

PubMed

Mesa, A; Nava, E; Fernández Del Valle, A; Argüelles, B; Menéndez-Del Llano, R; Sal de Rellán, S

2017-10-10

Muscle-invasive bladder malignancies represent 20-30% of all bladder cancers. These patients require imaging tests to determine the regional and distant staging. To describe the role of various imaging tests in the diagnosis, staging and follow-up of muscle-invasive bladder cancer. To assess recent developments in radiology aimed at improving the sensitivity and specificity of local staging and treatment response. We conducted an updated literature review. Computed tomography and magnetic resonance imaging (MRI) are the tests of choice for performing proper staging prior to surgery. Computed tomography urography is currently the most widely used technique, although it has limitations in local staging. Ultrasonography still has a limited role. Recent developments in MRI have improved its capacity for local staging. MRI has been suggested as the test of choice for the follow-up, with promising results in assessing treatment response. Positron emission tomography could improve the detection of adenopathies and extrapelvic metastatic disease. Imaging tests are essential for the diagnosis, staging and follow-up of muscle-invasive bladder cancer. Recent technical developments represent important improvements in local staging and have opened the possibility of assessing treatment response. Copyright © 2017 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

New insights into the influence of cigarette smoking on urothelial carcinogenesis: smoking-induced gene expression in tumor-free urothelium might discriminate muscle-invasive from nonmuscle-invasive urothelial bladder cancer.

PubMed

Gabriel, Ute; Li, Li; Bolenz, Christian; Steidler, Annette; Kränzlin, Bettina; Saile, Maria; Gretz, Norbert; Trojan, Lutz; Michel, Maurice Stephan

2012-11-01

Smoking is the main risk factor for urothelial bladder cancer. In former smokers the risk decreases but does not reach the low level of never smokers. This indicates reversible and permanent smoking-derived genetic alterations. Transcriptional changes may point to mechanisms, how smoking promotes urothelial bladder cancer. To identify smoking-derived transcriptional changes we performed gene expression profiling in current, former, and never smokers, using tumor and tumor-free urothelium from patients with nonmuscle-invasive urothelial bladder cancer (NMIBC) or muscle-invasive urothelial bladder cancer (MIBC). Smoking turned out to influence gene expression much less than tumor stage (NMIBC or MIBC) and tumor transformation (tumor-free or tumor). Smoking seemed to influence gene expression in patients with MIBC more strongly compared to those with NMIBC. The least irreversible changes after smoking cessation were proposed in tumor-free urothelium from patients with NMIBC. Growth factors and oncogenes were up-regulated in tumor-free urothelium from smokers with MIBC but not from smokers with NMIBC. A panel of genes up-regulated in smokers have potential for early detection and distinction of MIBC from NMIBC using tumor-free tissue. Copyright © 2011 Wiley Periodicals, Inc.

Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. | Office of Cancer Genomics

Cancer.gov

We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival.

CD147 as a novel biomarker for predicting the prognosis and clinicopathological features of bladder cancer: a meta-analysis

PubMed Central

Li, Hongru; Xu, Yadong; Li, Hui

2017-01-01

Objective To assess the prognostic and clinicopathological characteristics of CD147 in human bladder cancer. Methods Studies on CD147 expression in bladder cancer were retrieved from PubMed, EMBASE, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, and the WanFang databases. Outcomes were pooled with meta-analyzing softwares RevMan 5.3 and STATA 14.0. Results Twenty-four studies with 25 datasets demonstrated that CD147 expression was higher in bladder cancer than in non-cancer tissues (OR=43.64, P<0.00001). Moreover, this increase was associated with more advanced clinical stages (OR=73.89, P<0.0001), deeper invasion (OR=3.22, P<0.00001), lower histological differentiation (OR=4.54, P=0.0005), poorer overall survival (univariate analysis, HR=2.63, P<0.00001; multivariate analysis, HR=1.86, P=0.00036), disease specific survival (univariate analysis, HR=1.65, P=0.002), disease recurrence-free survival (univariate analysis, HR=2.78, P=0.001; multivariate analysis, HR=5.51, P=0.017), rate of recurrence (OR=1.91, P=0.0006), invasive depth (pT2∼T4 vs. pTa∼T1; OR=3.22, P<0.00001), and histological differentiation (low versus moderate-to-high; OR=4.54, P=0.0005). No difference was found among disease specific survival in multivariate analysis (P=0.067), lymph node metastasis (P=0.12), and sex (P=0.15). Conclusion CD147 could be a biomarker for early diagnosis, treatment, and prognosis of bladder cancer. PMID:28977970

What are the currently available and in development molecular markers for bladder cancer? Will they prove to be useful in the future?

PubMed

Abdulmajed, Mohamed Ismat; Sancak, Eyüp Burak; Reşorlu, Berkan; Al-Chalaby, Gydhia Zuhair

2014-12-01

Urothelial carcinoma is the 9(th) most common cancer worldwide. Most urothelial tumors are non-muscle invasive on presentation. However, two-thirds of non-invasive bladder cancers will eventually recur with a 25% risk of progression to muscle-invasive bladder cancer. Tumor stage, histological grade and pathological invasion of blood vessels and lymphatic tissue are the main indicators for urothelial cancer prognosis. The gold standard for diagnosing bladder cancer is conventional white-light cystoscopy and biopsy. Urine cytology is a highly specific, sensitive test for high-grade tumors or carcinoma in situ (CIS). Urinary NMP22 has an overall sensitivity and specificity for detecting bladder cancer of 49% and 87%, respectively. However, there are false-positive results in the presence of urinary tract infection or hematuria. The detection of specific gene mutations related to urothelial cancers has been studied and employed to reproduce markers helpful for diagnosis. According to current studies, molecular markers can be used to predict tumor recurrence. From a prognostic point of view, new molecular markers have yet to be established as reliable indicators of tumor aggressiveness. We aimed to review the molecular markers with possible prognostic significance that have been discussed in the literature. This review examined the literature for various molecular markers under development for bladder cancer in an attempt to optimize patient care and reduce the costs of treating these patients.

Quality of life in patients with muscle invasive and non-muscle invasive bladder cancer.

PubMed

Singer, S; Ziegler, C; Schwalenberg, T; Hinz, A; Götze, H; Schulte, T

2013-05-01

Compared to the literature on other malignancies, data on quality of life (QoL) in bladder cancer are sparse. This study sought answers to the following questions: In what QoL domains do patients with bladder cancer differ from the general population? Do patients with radical cystectomy differ in QoL compared to those who received conservative treatment? Do patients with neobladder generally have better QoL compared to patients with other diversion methods? At the beginning of inpatient rehabilitation, N = 823 patients with bladder cancer were assessed. Data of a representative community sample (N = 2037) were used for comparison. The questionnaire EORTC QLQ-C30 was used to measure QoL. Multivariate linear regression models were computed to investigate differences between groups. Patients with both non-muscle invasive and muscle invasive bladder cancer reported significantly more problems and worse functioning than the general population. Radiotherapy is associated with clinically relevant more pain, dyspnoea, constipation, appetite loss and decreased social functioning while chemotherapy is associated more with dyspnoea. Cystectomy patients reported more fatigue, appetite loss and decreased role functioning. Male patients ≥70 years with conduit experienced more sleep and emotional problems. These effects of urinary diversion were not observed in women and younger patients. Patients with bladder cancer experience various QoL concerns at the beginning of inpatient rehabilitation. These problems can partly be explained by the type of treatment the patients receive. Type of urinary diversion is relevant for QoL in subgroups of patients.

Proton beam therapy for invasive bladder cancer: A prospective study of bladder-preserving therapy with combined radiotherapy and intra-arterial chemotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hata, Masaharu; Miyanaga, Naoto; Tokuuye, Koichi

Purpose: To present outcomes of bladder-preserving therapy with proton beam irradiation in patients with invasive bladder cancer. Methods and Materials: Twenty-five patients with transitional cell carcinoma of the urinary bladder, cT2-3N0M0, underwent transurethral resection of bladder tumor(s), followed by pelvic X-ray irradiation combined with intra-arterial chemotherapy with methotrexate and cisplatin. Upon completion of these treatments, patients were evaluated by transurethral resection biopsy. Patients with no residual tumor received proton irradiation boost to the primary sites, whereas patients demonstrating residual tumors underwent radical cystectomy. Results: Of 25 patients, 23 (92%) were free of residual tumor at the time of re-evaluation; consequently,more » proton beam therapy was applied. The remaining 2 patients presenting with residual tumors underwent radical cystectomy. Of the 23 patients treated with proton beam therapy, 9 experienced recurrence at the median follow-up time of 4.8 years: local recurrences and distant metastases in 6 and 2 patients, respectively, and both situations in 1. The 5-year overall, disease-free, and cause-specific survival rates were 60%, 50%, and 80%, respectively. The 5-year local control and bladder-preservation rates were 73% and 96%, respectively, in the patients treated with proton beam therapy. Therapy-related toxicities of Grade 3-4 were observed in 9 patients: hematologic toxicities in 6, pulmonary thrombosis in 1, and hemorrhagic cystitis in 2. Conclusions: The present bladder-preserving regimen for invasive bladder cancer was feasible and effective. Proton beam therapy might improve local control and facilitate bladder preservation.« less

Curcumin inhibits bladder cancer progression via regulation of β-catenin expression.

PubMed

Shi, Jing; Wang, Yunpeng; Jia, Zhuomin; Gao, Yu; Zhao, Chaofei; Yao, Yuanxin

2017-07-01

Bladder cancer has a considerable morbidity and mortality impact with particularly poor prognosis. Curcumin has been recently noticed as a polyphenolic compound separated from turmeric to regulate tumor progression. However, the precise molecular mechanism by which curcumin inhibits the invasion and metastasis of bladder cancer cells is not fully elucidated. In this study, we investigate the effect of curcumin on the bladder cancer as well as possible mechanisms of curcumin. The expression of β-catenin was detected by quantitative real-time polymerase chain reaction and immunohistochemical analysis in a series of bladder cancer tissues. In addition, bladder cancer cell lines T24 and 5637 cells were treated with different concentrations of curcumin. The cytotoxic effect of curcumin on cell proliferation of T24 and 5637 cells was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The migration and invasion capacity of T24 and 5637 cells were measured by transwell assay. The effects of curcumin on expression levels of β-catenin and epithelial-mesenchymal transition marker were determined by western blotting. The β-catenin expression was significantly upregulated in bladder cancer tissues when compared with corresponding peri-tumor tissues. Furthermore, curcumin inhibited the cell proliferation of T24 and 5637 cells, and curcumin reduced the migration and invasive ability of T24 and 5637 cells via regulating β-catenin expression and reversing epithelial-mesenchymal transition. Curcumin may be a new drug for bladder cancer.

Evaluation of transforming growth factor-β1 suppress Pokemon/epithelial-mesenchymal transition expression in human bladder cancer cells.

PubMed

Li, Wei; Kidiyoor, Amritha; Hu, Yangyang; Guo, Changcheng; Liu, Min; Yao, Xudong; Zhang, Yuanyuan; Peng, Bo; Zheng, Junhua

2015-02-01

Transforming growth factor-β1 (TGF-β1) plays a dual role in apoptosis and in proapoptotic responses in the support of survival in a variety of cells. The aim of this study was to determine the function of TGF-β1 in bladder cancer cells and the relationship with POK erythroid myeloid ontogenic factor (Pokemon). TGF-β1 and its receptors mediate several tumorigenic cascades that regulate cell proliferation, migration, and survival of bladder cancer cells. Bladder cancer cells T24 were treated with different levels of TGF-β1. Levels of Pokemon, E-cadherin, Snail, MMP2, MMP9, Twist, VEGF, and β-catenin messenger RNA (mRNA) and protein were examined by real-time quantitative fluorescent PCR and Western blot analysis, respectively. The effects of TGF-β1 on epithelial-mesenchymal transition of T24 cells were evaluated with wound-healing assay, proliferation of T24 was evaluated with reference to growth curves with MTT assay, and cell invasive ability was investigated by Transwell assay. Data show that Pokemon was inhibited by TGF-β1 treatment; the gene and protein of E-cadherin and β-catenin expression level showed decreased markedly after TGF-β1 treatment (P < 0.05). While the bladder cancer cell after TGF-β1 treatment showed a significantly reduced wound-closing efficiency at 6, 12, and 24 h, mechanistic analyses demonstrated that different levels of TGF-β1 promotes tumor cell growth, migration, and invasion in bladder cancer cells (P < 0.01, P < 0.05, respectively). In summary, our findings suggest that TGF-β1 may inhibit the expression of Pokemon, β-catenin, and E-cadherin. The high expression of TGF-β1 leads to an increase in the phenotype and apical-base polarity of epithelial cells. These changes of cells may result in the recurrence and progression of bladder cancer at last. Related mechanism is worthy of further investigation.

Current trends in the management of bladder cancer.

PubMed

Patel, Amit R; Campbell, Steven C

2009-01-01

This article provides a review of bladder cancer etiology, diagnosis, and management for WOC nurses. Bladder cancer incidence continues to rise yearly in the United States, and patients with bladder cancer comprise some of the most challenging cases in urologic oncology. Nurses are involved with all aspects of the processes of care for the patient with bladder cancer, from initial diagnosis and treatment to postsurgical care and follow-up. For nonmuscle invasive bladder cancer, treatment includes transurethral resection followed by intravesical chemotherapy or immunotherapy to prevent recurrence or progression. Radical cystectomy along with chemotherapy protocols provides a survival advantage for muscle invasive bladder cancer, although the timing of chemotherapy remains controversial. Numerous factors are considered when determining the type of urinary diversion used at the time of radical cystectomy, but patient, family, surgeon, and nursing input are essential for preserving an optimal health-related quality of life and reducing morbidity. Patients with metastatic bladder cancer are generally treated with a cisplatin-based chemotherapy but continue to have a poor prognosis. Newer therapies involving novel molecular-targeted agents provide hope for the future for patients with metastatic disease.

Jarid2 is essential for the maintenance of tumor initiating cells in bladder cancer.

PubMed

Zhu, Xin-Xing; Yan, Ya-Wei; Ai, Chun-Zhi; Jiang, Shan; Xu, Shan-Shan; Niu, Min; Wang, Xiang-Zhen; Zhong, Gen-Shen; Lu, Xi-Feng; Xue, Yu; Tian, Shaoqi; Li, Guangyao; Tang, Shaojun; Jiang, Yi-Zhou

2017-04-11

Bladder cancer is the most common urologic malignancy in China, with an increase of the incidence and mortality rates over past decades. Recent studies suggest that bladder tumors are maintained by a rare fraction of cells with stem cell proprieties. Targeting these bladder tumor initiating cell (TICs) population can overcome the drug-resistance of bladder cancer. However, the molecular and genetic mechanisms regulating TICs in bladder cancer remain poorly defined. Jarid2 is implicated in signaling pathways regulating cancer cell epithelial-mesenchymal transition, and stem cell maintenance. The goal of our study was to examine whether Jarid2 plays a role in the regulation of TICs in bladder cancer. We found that knockdown of Jarid2 was able to inhibit the invasive ability and sphere-forming capacity in bladder cancer cells. Moreover, knockdown of Jarid2 reduced the proportion of TICs and impaired the tumorigenicity of bladder cancer TICs in vivo. Conversely, ectopic overexpression of Jarid2 promoted the invasive ability and sphere-forming capacity in bladder cancer cells. Mechanistically, reduced Jarid2 expression led to the upregulation of p16 and H3K27me3 level at p16 promoter region. Collectively, we provided evidence that Jarid2 via modulation of p16 is a putative novel therapeutic target for treating malignant bladder cancer.

Ixabepilone in Treating Patients With Advanced Urinary Tract Cancer

ClinicalTrials.gov

2013-01-23

Distal Urethral Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Proximal Urethral Cancer; Recurrent Bladder Cancer; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Urethral Cancer; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Stage III Bladder Cancer; Stage IV Bladder Cancer; Transitional Cell Carcinoma of the Bladder; Urethral Cancer Associated With Invasive Bladder Cancer

Researchers studying alternative to bladder removal for bladder cancer patients | Center for Cancer Research

Cancer.gov

A new phase I clinical trial conducted by researchers at the Center for Cancer Research (CCR) is evaluating the safety and tolerability, or the degree to which any side effects can be tolerated by patients, of a two-drug combination as a potential alternative to bladder removal for bladder cancer patients. The trial targets patients with non-muscle invasive bladder cancer

Drug-induced keratin 9 interaction with Hsp70 in bladder cancer cells.

PubMed

Andolino, C; Hess, C; Prince, T; Williams, H; Chernin, M

2018-05-25

A pull-down experiment (co-immunoprecipitation) was performed on a T24 human bladder cancer cell lysate treated with the Hsp inhibitor VER155008 using an Hsp70 antibody attached to Dynabeads. Keratin 9, a cytoskeleton intermediate filament protein, was identified by LC MS/MS analysis. This novel finding was confirmed by Western blotting, RT-PCR, and immunocytochemistry. Other members of the keratin family of proteins have been shown to be involved in cancer progression, most recently identified to be associated with cell invasion and metastasis. The specific role of keratin 9 expression in these cells is yet to be determined.

Randomized Noninferiority Trial of Reduced High-Dose Volume Versus Standard Volume Radiation Therapy for Muscle-Invasive Bladder Cancer: Results of the BC2001 Trial (CRUK/01/004)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huddart, Robert A., E-mail: robert.huddart@icr.ac.uk; Hall, Emma; Hussain, Syed A.

2013-10-01

Purpose: To test whether reducing radiation dose to uninvolved bladder while maintaining dose to the tumor would reduce side effects without impairing local control in the treatment of muscle-invasive bladder cancer. Methods and Materials: In this phase III multicenter trial, 219 patients were randomized to standard whole-bladder radiation therapy (sRT) or reduced high-dose volume radiation therapy (RHDVRT) that aimed to deliver full radiation dose to the tumor and 80% of maximum dose to the uninvolved bladder. Participants were also randomly assigned to receive radiation therapy alone or radiation therapy plus chemotherapy in a partial 2 × 2 factorial design. Themore » primary endpoints for the radiation therapy volume comparison were late toxicity and time to locoregional recurrence (with a noninferiority margin of 10% at 2 years). Results: Overall incidence of late toxicity was less than predicted, with a cumulative 2-year Radiation Therapy Oncology Group grade 3/4 toxicity rate of 13% (95% confidence interval 8%, 20%) and no statistically significant differences between groups. The difference in 2-year locoregional recurrence free rate (RHDVRT − sRT) was 6.4% (95% confidence interval −7.3%, 16.8%) under an intention to treat analysis and 2.6% (−12.8%, 14.6%) in the “per-protocol” population. Conclusions: In this study RHDVRT did not result in a statistically significant reduction in late side effects compared with sRT, and noninferiority of locoregional control could not be concluded formally. However, overall low rates of clinically significant toxicity combined with low rates of invasive bladder cancer relapse confirm that (chemo)radiation therapy is a valid option for the treatment of muscle-invasive bladder cancer.« less

A Randomized Pilot Trial of Dietary Modification for the Chemoprevention of Non-invasive Bladder Cancer: The Dietary Intervention in Bladder Cancer Study (DIBS)

PubMed Central

Parsons, J. Kellogg; Pierce, John P.; Natarajan, Loki; Newman, Vicky A.; Barbier, Leslie; Mohler, James; Rock, Cheryl L.; Heath, Dennis D.; Guru, Khurshid; Jameson, Michael B.; Li, Hongying; Mirheydar, Hossein; Holmes, Michael A.; Marshall, James

2013-01-01

Epidemiological data suggest robust associations of high vegetable intake with decreased risks of bladder cancer incidence and mortality, but translational prevention studies have yet to be performed. We designed and tested a novel intervention to increase vegetable intake in patients with non-invasive bladder cancer. We randomized 48 patients aged 50 to 80 years with biopsy-proven non-invasive (Ta, T1, or carcinoma in situ) urothelial cell carcinoma to telephone- and Skype-based dietary counseling or a control condition that provided print materials only. The intervention behavioral goals promoted 7 daily vegetable servings, with at least 2 of these as cruciferous vegetables. Outcome variables were self-reported diet and plasma carotenoid and 24-hour urinary isothiocyanate (ITC) concentrations. We used 2-sample t-tests to assess between-group differences at 6-month follow-up. After 6 months, intervention patients had higher daily intakes of vegetable juice (p=0.02), total vegetables (p=0.02), and cruciferous vegetables (p=0.07); lower daily intakes of energy (p=0.007), (p=0.002) and energy from fat (p=0.06); and higher plasma alpha-carotene concentrations (p=0.03). Self-reported cruciferous vegetable intake correlated with urinary ITC concentrations at baseline (p<0.001) and at 6 months (p=0.03). Although urinary ITC concentrations increased in the intervention group and decreased in the control group, these changes did not attain between-group significance (p=0.32). In patients with non-invasive bladder cancer, our novel intervention induced diet changes associated with protective effects against bladder cancer. These data demonstrate the feasibility of implementing therapeutic dietary modifications to prevent recurrent and progressive bladder cancer. PMID:23867158

Gynaecomastia: an unusual presenting symptom of bladder cancer.

PubMed

Ahmed, Mashrafi; Kanji, Aleem; Begum, Tahmina

2015-06-25

A 74-year-old man presented to the outpatient clinic with painful gynaecomastia. A detailed physical examination to sort out possible causes of the gynaecomastia, including intracranial tumour, liver cirrhosis, hyperthyroidism, and adrenal and testicular tumour, was negative. No offending agent was found in his medication list. A CT scan of the head and ultrasound of the scrotum did not show any mass lesion. His serum β-human chorionic gonadotropin (β-hCG) and oestradiol levels were elevated. A CT scan of the abdomen and pelvis revealed bladder wall thickening with soft tissue mass. A cystoscopic biopsy confirmed transitional cell carcinoma with muscle invasion. The patient was started on chemotherapy but responded poorly. This case report describes the β-hCG and oestradiol-secreting transitional cell carcinoma of the bladder presenting as gynaecomastia in an older man. 2015 BMJ Publishing Group Ltd.

Fibroblast growth factor receptor 1 and cytokeratin 20 expressions and their relation to prognostic variables in bladder cancer.

PubMed

Abdul-Maksoud, Rehab S; Shalaby, Sally M; Elsayed, Walid S H; Elkady, Saad

2016-10-15

Tumor grade and stage are currently the most important prognostic variables in bladder cancer but establishing additional criteria is still needed for effective treatment. The aim of the study was to assess the expression of fibroblast growth factor receptor 1 (FGFR1) and cytokeratin 20 (CK20) in cancer bladder (CB) and to evaluate their association with the clinicopathological features of the disease. The study included 80 patients diagnosed as bladder cancer of different stages and grades and 80 patients with nonmalignant urothelial diseases of matched age and sex to the malignant group. The expressions of FGFR1 and CK20 in tissue samples were determined by RT-PCR and immunohistochemistry. The expression levels of FGFR1 and CK20 were increased in the malignant group when compared to the control group (P<0.001 for each). Analysis of their expression showed that levels of FGFR1 and CK20 were significantly higher in invasive tumor stages (pT2-pT4) than in non-invasive stages (pTis, pTa, pT1) (P<0.001). Interestingly, the sensitivity and specificity of combined detection with CK20 and FGFR1 for the differentiation between invasive and non-invasive stages of bladder cancer reached 97.5% and 92.5%, respectively. Our results determined overexpression of both FGFR1 and CK20 in CB specimens. The alterations in the expression of FGFR1 and CK20 were associated with disease stage and grade. Lastly, combined detection of FGFR1 and CK20 had a high predictive prognostic value in differentiating invasive from non-invasive carcinoma. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of Angiotensin Inhibitor Valsartan on the Expression of the Angiotensin II 1 Receptor, Matrix Metalloproteinases -2 and -9 in Human Bladder Cancer Cell Lines.

PubMed

Yang, Delin; Huo, Qian; Luan, Ting; Wang, Jiansong; Tang, Zhaoran; Wang, Haifeng

2016-08-01

In order to investigate how valsartan-the angiotensin II 1 receptor (AT1R) antagonist-affects the expressions of AT1R antigen, matrix metalloproteinases (MMPs) -2 and -9 in carcinoma of urinary bladder (CUB) cell lines with different invasive abilities. Three cell lines, EJ-M3, EJ, and BIU-87, with different invasive abilities were cultured and treated with valsartan. Cell proliferation states were determined by the methyl thiazolyl tetrazolium (MTT) method. The expressions at protein level and gene level were determined by Western blot and real-time fluorescence reverse transcription polymerase chain reaction (RT-PCR), respectively. The invasive abilities and migratory abilities of the three cell lines were determined by Transwell in vitro cell invasion assay and wound healing assay, respectively. MTT results show that valsartan can inhibit the proliferation of CUB cells, and the inhibition effect is enhanced with the increase of concentration. AngII promotes the MMP2 and MMP9 expressions (both protein and gene levels) in CUB cells through AT1R, but their expressions can be effectively inhibited by valsartan, the AngII inhibitor. AngII inhibitor may become a novel drug that can inhibit CUB metastasis and prolong the survival of CUB patients.

Trastuzumab in Treating Patients With Previously Treated, Locally Advanced, or Metastatic Cancer of the Urothelium

ClinicalTrials.gov

2013-05-01

Distal Urethral Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Proximal Urethral Cancer; Recurrent Bladder Cancer; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Urethral Cancer; Stage IV Bladder Cancer; Transitional Cell Carcinoma of the Bladder; Urethral Cancer Associated With Invasive Bladder Cancer

Hypofractionated Intensity Modulated Radiation Therapy in Combined Modality Treatment for Bladder Preservation in Elderly Patients With Invasive Bladder Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Turgeon, Guy-Anne; Souhami, Luis, E-mail: luis.souhami@muhc.mcgill.ca; Cury, Fabio L.

2014-02-01

Purpose/Objective(s): To review our experience with bladder-preserving trimodality treatment (TMT) using hypofractionated intensity modulated radiation therapy (IMRT) for the treatment of elderly patients with muscle-invasive bladder cancer. Methods and Materials: Retrospective study of elderly patients treated with TMT using hypofractionated IMRT (50 Gy in 20 fractions) with concomitant weekly radiosensitizing chemotherapy. Eligibility criteria were as follows: age ≥70 years, a proven diagnosis of muscle-invasive transitional cell bladder carcinoma, stage T2-T3N0M0 disease, and receipt of TMT with curative intent. Response rate was assessed by cystoscopic evaluation and bladder biopsy. Results: 24 patients with a median age of 79 years were eligible.more » A complete response was confirmed in 83% of the patients. Of the remaining patients, 1 of them underwent salvage cystectomy, and no disease was found in the bladder on histopathologic assessment. After a median follow-up time of 28 months, of the patients with a complete response, 2 patients had muscle-invasive recurrence, 1 experienced locoregional failure, and 3 experienced distant metastasis. The overall and cancer-specific survival rates at 3 years were 61% and 71%, respectively. Of the surviving patients, 75% have a disease-free and functioning bladder. All patients completed hypofractionated IMRT, and 19 patients tolerated all 4 cycles of chemotherapy. Acute grade 3 gastrointestinal or genitourinary toxicities occurred in only 4% of the patients, and acute grade 3 or 4 hematologic toxicities, liver toxicities, or both were experienced by 17% of the cohort. No patient experienced grade 4 gastrointestinal or genitourinary toxicity. Conclusions: Hypofractionated IMRT with concurrent radiosensitizing chemotherapy appears to be an effective and well-tolerated curative treatment strategy in the elderly population and should be considered for patients who are not candidates for cystectomy or who wish to avoid cystectomy.« less

Progression of urothelial carcinoma in situ of the urinary bladder: a switch from luminal to basal phenotype and related therapeutic implications.

PubMed

Barth, Isabella; Schneider, Ursula; Grimm, Tobias; Karl, Alexander; Horst, David; Gaisa, Nadine T; Knüchel, Ruth; Garczyk, Stefan

2018-05-01

The stratification of bladder cancer into luminal and basal tumors has recently been introduced as a novel prognostic system in patient cohorts of muscle-invasive bladder cancer or high-grade papillary carcinomas. Using a representative immunohistochemistry panel, we analyzed luminal and basal marker expression in a large case series (n = 156) of urothelial carcinoma in situ (CIS), a precancerous lesion that frequently progresses to muscle-invasive disease. The majority of CIS cases was characterized by a positivity for luminal markers (aberrant cytokeratin (CK) 20 85% (132/156), GATA3 median Remmele score (score of staining intensity (0-3) multiplied with percentage of positive cells (0-4)): 12, estrogen receptor (ER) β Remmele score > 2: 88% (138/156), human epidermal growth factor receptor 2 (Her2) Dako score 3+ 32% (50/156), Her2 Dako score 2+ 33% (51/156)), and marginal expression of basal markers (CK5/6+ 2% (3/156), CK14+ 1% (2/156)). To further investigate phenotypic stability during disease progression, we compared 48 pairs of CIS and invasive tumors from the same biopsy. A highly significant loss of luminal marker expression (p < 0.001) was observed in the course of progression whereas an increase of basal marker expression (p < 0.01) was noted in the invasive compartment. Importantly, 91% of CIS cases demonstrated a positivity for at least one of the two predictive markers Her2 and ERβ, indicating that the analysis of Her2 and ERβ may help to identify CIS-patient subgroups prone to more efficient targeted treatment strategies. Larger prospective and biomarker-embedded clinical trials are needed to confirm and validate our preliminary findings.

Bladder Cancer Treatment (PDQ®)—Health Professional Version

Cancer.gov

Bladder cancer treatment options depend on if it is nonmuscle or muscle invasive and may include surgery, BCG, chemotherapy, and targeted therapy. Get detailed information about the diagnosis and treatment of newly diagnosed and recurrent bladder cancer in this summary for clinicians.

Long-Term Outcomes Among Patients Who Achieve Complete or Near-Complete Responses After the Induction Phase of Bladder-Preserving Combined-Modality Therapy for Muscle-Invasive Bladder Cancer: A Pooled Analysis of NRG Oncology/RTOG 9906 and 0233

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mitin, Timur, E-mail: mitin@ohsu.edu; George, Asha; Zietman, Anthony L.

Purpose: To investigate the differences in outcomes among patients with muscle-invasive bladder cancer on NRG Oncology Radiation Therapy Oncology Group protocols 9906 and 0233 who achieved complete response and near-complete response after induction chemoradiation and then completed bladder-preserving therapy with chemoradiation therapy (chemo-RT) to full dose (60-64 Gy). Patients and Methods: A pooled analysis was performed on 119 eligible patients with muscle-invasive bladder cancer enrolled on NRG Oncology Radiation Therapy Oncology Group trials 9906 and 0233, who were classified as having a complete (T0) or near-complete (Ta or Tis) response after induction chemo-RT and completed consolidation with a total RT dose ofmore » at least 60 Gy. Bladder recurrence, salvage cystectomy rates, and disease-specific survival were estimated by the cumulative incidence method and bladder-intact and overall survivals by the Kaplan-Meier method. Results: Among the 119 eligible patients, 101 (85%) achieved T0, and 18 (15%) achieved Ta or Tis after induction chemo-RT and proceeded to consolidation. After a median follow-up of 5.9 years, 36 of 101 T0 patients (36%) versus 5 of 18 Ta or Tis patients (28%) experienced bladder recurrence (P=.52). Thirteen patients among complete responders eventually required late salvage cystectomy for tumor recurrence, compared with 1 patient among near-complete responders (P=.63). Disease-specific, bladder-intact, and overall survivals were not significantly different between T0 and Ta/Tis cases. Conclusions: The bladder recurrence and salvage cystectomy rates of the complete and the near-complete responders were similar. Therefore it is reasonable to recommend that patients with Ta or Tis after induction chemo-RT continue with bladder-sparing therapy with consolidation chemo-RT to full dose (60-64 Gy).« less

Tunneling nanotubes promote intercellular mitochondria transfer followed by increased invasiveness in bladder cancer cells

PubMed Central

Lu, Jinjin; Zheng, Xiufen; Li, Fan; Yu, Yang; Chen, Zhong; Liu, Zheng; Wang, Zhihua; Xu, Hua; Yang, Weimin

2017-01-01

Intercellular transfer of organelles via tunneling nanotubes (TNTs) is a novel means of cell-to-cell communication. Here we demonstrate the existence of TNTs between co-cultured RT4 and T24 bladder cancer cells using light microscopy, fluorescence imaging, and scanning electron microscopy (SEM). Spontaneous unidirectional transfer of mitochondria from T24 to RT4 cells was detected using fluorescence imaging and flow cytometry. The distribution of mitochondria migrated from T24 cells was in good agreement with the original mitochondria in RT4 cells, which may imply mitochondrial fusion. We detected cytoskeleton reconstruction in RT4-Mito-T24 cells by observing F-actin redistribution. Akt, mTOR, and their downstream mediators were activated and increased. The resultant increase in the invasiveness of bladder cancer cells was detected in vitro and in vivo. These data indicate that TNTs promote intercellular mitochondrial transfer between heterogeneous cells, followed by an increase in the invasiveness of bladder cancer cells. PMID:28107184

Molecular Landscape of Non-Muscle Invasive Bladder Cancer.

PubMed

Meeks, Joshua J; Lerner, Seth P

2017-11-13

In this issue of Cancer Cell, Hurst et al. report an integrated analysis of non-invasive (stage Ta) bladder cancer. Two genomic subtypes are distinguished by chromosome 9q loss, resulting in increased AKT/PI3K/mTOR signaling. Tumors from female patients have a higher frequency of KDM6A mutations. Copyright © 2017 Elsevier Inc. All rights reserved.

The use of water-soluble mucoadhesive gels for the intravesical delivery of epirubicin to the bladder for the treatment of non-muscle-invasive bladder cancer.

PubMed

Chatta, Dani; Cottrell, Lewis; Burnett, Bruce; Laverty, Garry; McConville, Christopher

2015-10-01

To develop an epirubicin-loaded, water-soluble mucoadhesive gels that have the correct rheological properties to facilitate their delivery into the bladder via a catheter, while allowing for their spread across the bladder wall with limited expansion of the bladder and increasing the retention of epirubicin in the bladder and flushing with urine. Epirubicin-loaded hydroxyl ethyl cellulose (HEC) and hydroxy propyl methyl cellulose (HPMC) gels were manufactured and tested for their rheological properties. Their ability to be pushed through a catheter was also assessed as was their in-vitro drug release, spreading in a bladder and retention of epirubicin after flushing with simulated urine. Epirubicin drug release was viscosity-dependent. The 1 and 1.5% HEC gels and the 1, 1.5 and 2% HPMC gels had the correct viscosity to be administered through a model catheter and spread evenly across the bladder wall under the pressure of the detrusor muscle. The epirubicin-loaded gels had an increased retention time in the bladder when compared with a standard intravesical solution of epirubicin, even after successive flushes with simulated urine. The increased retention of epirubicin in the bladder by the HEC and HPMC gels warrant further investigation, using an in-vivo model, to assess their potential for use as treatment for non-muscle-invasive bladder cancer. © 2015 Royal Pharmaceutical Society.

[Therapeutic effect of mitomycin C in the immediate postoperative period in patients with intermediate-risk non-muscle-invasive bladder tumors].

PubMed

Jalón Monzón, A; Fernández Gómez, J M; Escaf Barmadah, S; Alvarez Múgica, M; Martín Benito, J L; Regadera Sejas, F J

2008-10-01

Approximately 70-85% of transitional bladder cell carcinomas are non-muscle-invasive. After an initial surgery, around 60-90% will have a recurrence, being the highest risk period the first two years. Urothelium instability could be the main reason for recurrence in mid grade tumours, reason why a single dose of a chemotherapy after transurethral resection of the bladder (TURB) might be insufficient. That is why a deferred therapy in occasions associated with maintenance is recommended. A prospective, controlled and randomized study was performed. We included non-muscle-invasive mid risk bladder tumours. All patients had initially a TURB performed and were randomized to receive a single dose of mitomycin C (MMC), in the immediate postoperative period. A total of 105 patients were included. Mean follow-up was 22, 70 +/- 8, 15 months. MMC was administered to 53 patients. Of these 66, 0% had no recurrence and 34.0% had a non-muscle-invasive recurrence. Of the 52 patients in the non MMC group, 53.8% had no recurrence and 44.2% had a non-muscle-invasive recurrence and only 1 patient had a muscle-invasive progression. We did not find significantly differences in time to recurrence in mid risk tumours when using immediate postoperative single dose of MMC or deferred therapy. There was only one case of myelosuppression. In mid risk non-muscle-invasive tumors, some studies suggest that early intravesical instillation of chemotherapy reduces the risk of recurrence after TURB. We could not show significantly differences when comparing postoperatorive MMC versus traditional deferred instillations.

Inhibition of long non-coding RNA UCA1 by CRISPR/Cas9 attenuated malignant phenotypes of bladder cancer.

PubMed

Zhen, Shuai; Hua, Ling; Liu, Yun-Hui; Sun, Xiao-Min; Jiang, Meng-Meng; Chen, Wei; Zhao, Le; Li, Xu

2017-02-07

CRISPR/Cas9 is a novel and effective genome editing technique, but its application is not widely expanded to manipulate long non-coding RNA (lncRNA) expression. The lncRNA urothelial carcinoma-associated 1 (UCA1) is upregulated in bladder cancer and promotes the progression of bladder cancer. Here, we design gRNAs specific to UCA1 and construct CRISPR/Cas9 systems targeting UCA1. Single CRISPR/Cas9-UCA1 can effectively inhibit UCA1 expression when transfected into 5637 and T24 bladder cancer cells, while the combined transfection of the two most effective CRISPR/Cas9-UCA1s can generate more satisfied inhibitory effect. CRISPR/Cas9-UCA1s attenuate UCA1 expression via targeted genome-specific DNA cleavage, resulting in the significant inhibition of cell proliferation, migration and invasion in vitro and in vivo. The mechanisms associated with the inhibitory effect of CRISPR/Cas9-UCA1 on malignant phenotypes of bladder cancer are attributed to the induction of cell cycle arrest at G1 phase, a substantial increase of apoptosis, and an enhanced activity of MMPs. Additionally, urinary UCA1 can be used as a non-invasive diagnostic marker for bladder cancer as revealed by a meta-analysis. Collectively, our data suggest that CRISPR/Cas9 technique can be used to down-modulate lncRNA expression, and urinary UCA1 may be used as a non-invasive marker for diagnosis of bladder cancer.

Gemcitabine Hydrochloride and Cisplatin or High-Dose Methotrexate, Vinblastine, Doxorubicin Hydrochloride, and Cisplatin in Treating Patients With Urothelial Cancer

ClinicalTrials.gov

2014-01-27

Anterior Urethral Cancer; Localized Transitional Cell Cancer of the Renal Pelvis and Ureter; Posterior Urethral Cancer; Recurrent Bladder Cancer; Recurrent Urethral Cancer; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Stage III Bladder Cancer; Transitional Cell Carcinoma of the Bladder; Ureter Cancer; Urethral Cancer Associated With Invasive Bladder Cancer

In vivo electric conductivity of cervical cancer patients based on B₁⁺ maps at 3T MRI.

PubMed

Balidemaj, E; de Boer, P; van Lier, A L H M W; Remis, R F; Stalpers, L J A; Westerveld, G H; Nederveen, A J; van den Berg, C A T; Crezee, J

2016-02-21

The in vivo electric conductivity (σ) values of tissue are essential for accurate electromagnetic simulations and specific absorption rate (SAR) assessment for applications such as thermal dose computations in hyperthermia. Currently used σ-values are mostly based on ex vivo measurements. In this study the conductivity of human muscle, bladder content and cervical tumors is acquired non-invasively in vivo using MRI. The conductivity of 20 cervical cancer patients was measured with the MR-based electric properties tomography method on a standard 3T MRI system. The average in vivo σ-value of muscle is 14% higher than currently used in human simulation models. The σ-value of bladder content is an order of magnitude higher than the value for bladder wall tissue that is used for the complete bladder in many models. Our findings are confirmed by various in vivo animal studies from the literature. In cervical tumors, the observed average conductivity was 13% higher than the literature value reported for cervical tissue. Considerable deviations were found for the electrical conductivity observed in this study and the commonly used values for SAR assessment, emphasizing the importance of acquiring in vivo conductivity for more accurate SAR assessment in various applications.

Recombinant Mycobacterium bovis BCG for immunotherapy in nonmuscle invasive bladder cancer.

PubMed

Begnini, K R; Buss, J H; Collares, T; Seixas, F K

2015-05-01

In the past three decades, intravesical instillation of Mycobacterium bovis bacille Calmette-Guérin (BCG) has been used for treating bladder cancer and it still remains at the forefront of immunotherapy for cancer patients. Although BCG-based therapy is the most effective intravesical therapy for this kind of tumor and represents the only agent known to reduce progression into muscle invasive bladder cancer, BCG is ineffective in approximately 30-40 % of cases and disease recurs in up to 50 % of patients. Since that BCG is considered an effective vehicle for delivery of antigens due to its unique characteristics, the genetic manipulation of these mycobacteria has been appealing in the search for less toxic and more potent therapeutic agents for bladder cancer immunotherapy. Herein, we discuss current advances in recombinant BCG construction, research, concerns, and future directions to promote the development of this promising immunotherapeutic approach for bladder cancer.

Noninvasive Electromagnetic Detection of Bladder Cancer

PubMed Central

Cormio, Luigi; Vedruccio, Clarbruno; Leucci, Giorgio; Massenio, Paolo; Di Fino, Giuseppe; Cavaliere, Vincenzo; Carrieri, Giuseppe

2014-01-01

Objectives. Normal and neoplastic human tissues have different electromagnetic properties. This study aimed to determine the diagnostic accuracy of noninvasive electromagnetic detection of bladder cancer (BC) by the tissue-resonance interaction method (TRIM-prob). Patients and Methods. Consecutive patients were referred for cystoscopy because of (i) microscopic or gross hematuria and/or irritative voiding symptoms and (ii) bladder ultrasounds and urinary cytology findings negative or just suspicious of malignancy. Patients were first submitted to TRIM-prob bladder scanning by a single investigator and then to cystoscopy by another investigator blind to TRIM-prob data. Results. In 125 evaluated patients cystoscopy was positive for BC in 47 and negative in the remaining 78; conversely, TRIM-prob bladder scanning was positive for BC in 53 and negative in 72. In particular, TRIM-prob scanning yielded 7 false positives and only one false negative; therefore, its overall sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 97.9%, 89.9%, 86.8%, 98.6%, and 93.6%, respectively. Conclusions. TRIM-prob bladder scanning was a simple and quite accurate method for non-invasive electromagnetic detection of BC. If the elevated positive and negative predictive values will be replicated in further well-designed studies, it could be used to screen asymptomatic patients at high risk of BC. PMID:24563795

Downregulation of glutathione S-transferase M1 protein in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced mouse bladder carcinogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chuang, Jing-Jing; Dai, Yuan-Chang; Lin, Yung-Lun

2014-09-15

Bladder cancer is highly recurrent following specific transurethral resection and intravesical chemotherapy, which has prompted continuing efforts to develop novel therapeutic agents and early-stage diagnostic tools. Specific changes in protein expression can provide a diagnostic marker. In our present study, we investigated changes in protein expression during urothelial carcinogenesis. The carcinogen BBN was used to induce mouse bladder tumor formation. Mouse bladder mucosa proteins were collected and analyzed by 2D electrophoresis from 6 to 20 weeks after commencing continuous BBN treatment. By histological examination, the connective layer of the submucosa showed gradual thickening and the number of submucosal capillaries graduallymore » increased after BBN treatment. At 12-weeks after the start of BBN treatment, the urothelia became moderately dysplastic and tumors arose after 20-weeks of treatment. These induced bladder lesions included carcinoma in situ and connective tissue invasive cancer. In protein 2D analysis, the sequentially downregulated proteins from 6 to 20 weeks included GSTM1, L-lactate dehydrogenase B chain, keratin 8, keratin 18 and major urinary proteins 2 and 11/8. In contrast, the sequentially upregulated proteins identified were GSTO1, keratin 15 and myosin light polypeptide 6. Western blotting confirmed that GSTM1 and NQO-1 were decreased, while GSTO1 and Sp1 were increased, after BBN treatment. In human bladder cancer cells, 5-aza-2′-deoxycytidine increased the GSTM1 mRNA and protein expression. These data suggest that the downregulation of GSTM1 in the urothelia is a biomarker of bladder carcinogenesis and that this may be mediated by DNA CpG methylation. - Highlights: • GSTM1 and NQO-1 proteins decreased in the mouse bladder mucosa after BBN treatment. • BBN induced GSTO1 and Sp1 protein expression in the mouse bladder mucosa. • 5-Aza-2′-deoxycytidine increased GSTM1 mRNA and protein in human bladder cancer cell. • GSTM1 downregulation in the urothelia may be a biomarker of bladder carcinogenesis.« less

[Urodynamics foundations: contractile potency and urethral doppler].

PubMed

Benítez Navío, Julio; Caballero Gómez, Pilar; Delgado Elipe, Ildefonso

2002-12-01

To calculate the bladder softening factor, elastic constant and contractile potency. For the analysis we considered bladder behavior like that of a spring. See articles 1 and 2 published in this issue. Using flowmetry, Doppler ultrasound and abdominal pressure (Transrectal pressure register catheter) an analytical solution that permits calculation of factors defining bladder behavior was looked for. Doppler ultrasound allows us to know urine velocity through the prostatic urethra and, therefore, to calculate bladder contractile potency. Equations are solved reaching an analytical solution that allows calculating those factors that define bladder behavior: Bladder contractile potency, detrusor elastic constant, considering it behaves like a spring, and calculation of muscle resistance to movement. All thanks to Doppler ultrasound that allows to know urine speed. The bladder voiding phase is defined with the aforementioned factors; storage phase behavior can be indirectly inferred. Only uroflowmetry curves, Doppler ultrasound and abdominal pressure value are used. We comply with the so called non invasive urodynamics although for us it is just another phase in the biomechanical study of the detrusor muscle. Main conclusion is the addition of Doppler ultrasound to the urodynamist armamentarium as an essential instrument for the comprehension of bladder dynamics and calculation of bladder behavior defining factors. It is not a change in the focus but in the methods, gaining knowledge and diminishing invasion.

Decreased microbiota diversity associated with urinary tract infection in a trial of bacterial interference.

PubMed

Horwitz, Deborah; McCue, Tyler; Mapes, Abigail C; Ajami, Nadim J; Petrosino, Joseph F; Ramig, Robert F; Trautner, Barbara W

2015-09-01

Patients with long-term indwelling catheters are at high risk of catheter-associated urinary tract infection (CAUTI). We hypothesized that colonizing the bladder with a benign Escherichia coli strain (E. coli HU2117, a derivative of E. coli 83972) would prevent CAUTI in older, catheterized adults. Adults with chronic, indwelling urinary catheters received study catheters that had been pre-coated with E. coli HU2117. We monitored the cultivatable organisms in the bladder for 28 days or until loss of E. coli HU2117. Urine from 4 subjects was collected longitudinally for 16S rRNA gene profiling. Eight of the ten subjects (average age 70.9 years) became colonized with E. coli HU2117, with a mean duration of 57.7 days (median: 28.5, range 0-266). All subjects also remained colonized by uropathogens. Five subjects suffered invasive UTI, 3 febrile UTI and 2 urosepsis/bacteremia, all associated with overgrowth of a urinary pathogen. Colonization with E. coli HU2117 did not impact bacterial bladder diversity, but subjects who developed infections had less diverse bladder microbiota. Colonization with E. coli HU2117 did not prevent bladder colonization or subsequent invasive disease by uropathogens. Microbial diversity may play a protective role against invasive infection of the catheterized bladder. ClinicalTrials.gov, NCT00554996 http://clinicaltrials.gov/ct2/show/NCT00554996. Published by Elsevier Ltd.

Discordance Between Preoperative and Postoperative Bladder Cancer Location: Implications for Partial-Bladder Radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goldsmith, Benjamin; Tucker, Kai; Conway, Robert Greg

2013-03-01

Purpose: There is strong interest in partial-bladder radiation whether as a boost or definitive therapy to limit long-term toxicity. It is unclear that a standard preoperative examination can accurately identify all sites of disease within the bladder. The purpose of this study was to determine the correlation between preoperative localization of bladder tumors with postoperative findings to facilitate partial-bladder radiation techniques when appropriate. Methods and Materials: We examined patients with clinically staged T1-T4 invasive transitional cell carcinoma (TCC) or TCC with variant histology with no history of radiation or partial cystectomy undergoing radical cystectomy. Patients were scored as “under-detected” ifmore » a bladder site was involved with invasive disease (≥T1) at the time of cystectomy, but not identified preoperatively. Patients were additionally scored as “widely under-detected” if they had postoperative lesions that were not identified preoperatively in a given site, nor in any adjacent site. Rates of under-detected and widely under-detected lesions, as well as univariate and multivariate association between clinical variables and under-detection, were evaluated using logistic regression. Results: Among 222 patients, 96% (213/222) had at least 1 area of discordance. Fifty-eight percent of patients were under-detected in at least 1 location, whereas 12% were widely under-detected. Among 24 patients with a single site of disease on preoperative evaluation, 21/24 (88%) had at least 1 under-detected lesion and 14/24 (58%) were widely under-detected. On multivariate analysis, only solitary site of preoperative disease was associated with increased levels of under-detection of invasive disease (OR = 4.161, 95% CI, 1.368-12.657). Conclusion: Our study shows a stark discordance between preoperative and postoperative localization of bladder tumors. From a clinical perspective, incomplete localization of all sites of disease within the bladder may lead to marginal misses when a partial-bladder technique is used.« less

Researchers studying alternative to bladder removal for bladder cancer patients | Center for Cancer Research

Cancer.gov

A new phase I clinical trial conducted by researchers at the Center for Cancer Research (CCR) is evaluating the safety and tolerability, or the degree to which any side effects can be tolerated by patients, of a two-drug combination as a potential alternative to bladder removal for bladder cancer patients. The trial targets patients with non-muscle invasive bladder cancer (NMIBC) whose cancers have stopped responding to traditional therapies. Read more...

Do patients with OAB experience bladder sensations in the same way as healthy volunteers? A focus group investigation.

PubMed

Heeringa, R; van Koeveringe, G A; Winkens, B; van Kerrebroeck, P E V; de Wachter, S G G

2012-04-01

To describe the terminology and pattern of bladder sensations experienced during non-invasive rapid bladder filling in a controlled setting in patients with OAB and to compare these results with a previous study conducted in healthy volunteers. Three groups of patients with OAB, in total 10 patients, participated in three consecutive focus group sessions. Before each session a strict water loading protocol was given. During the first two sessions, participants described how they experienced their bladder sensations in daily life and during a non-invasive bladder filling with constant focus on their bladder. The third session focused on verifying the interpretation of the data gathered and describing the pattern of sensations. Patients describe their bladder sensations as a pressure or a tingling sensation and the pattern can be described by terms ranging from no sensation to an absolute need to void. The absolute need to void may develop suddenly or more slowly progressive. The mean development of bladder sensation is significantly different between patients and healthy volunteers as well as their average diuresis. Patients with OAB describe their bladder sensations as a pressure or a tingling sensation. There appear to be two types of urgency: a sudden absolute need to void and a slowly developing absolute need to void. Furthermore bladder sensation develops significantly different in volunteers than in OAB patients. Copyright © 2012 Wiley Periodicals, Inc.

Non-invasive characterization of real-time bladder sensation using accelerated hydration and a novel sensation meter: An initial experience

PubMed Central

Nagle, Anna S.; Speich, John E.; De Wachter, Stefan G.; Ghamarian, Peter P.; Le, David M.; Colhoun, Andrew F.; Ratz, Paul H.; Barbee, Robert W.; Klausner, Adam P.

2016-01-01

AIMS The purpose of this investigation was to develop a non-invasive, objective, and unprompted method to characterize real-time bladder sensation. METHODS Volunteers with and without overactive bladder (OAB) were prospectively enrolled in a preliminary accelerated hydration study. Participants drank 2L Gatorade-G2® and recorded real-time sensation (0–100% scale) and standardized verbal sensory thresholds using a novel, touch-screen “sensation meter.” 3D bladder ultrasound images were recorded throughout fillings for a subset of participants. Sensation data were recorded for two consecutive complete fill-void cycles. RESULTS Data from 14 normal and 12 OAB participants were obtained (ICIq-OAB-5a = 0 vs. ≥3). Filling duration decreased in fill2 compared to fill1, but volume did not significantly change. In normals, adjacent verbal sensory thresholds (within fill) showed no overlap, and identical thresholds (between fill) were similar, demonstrating effective differentiation between degrees of %bladder capacity. In OAB, within-fill overlaps and between-fill differences were identified. Real-time %capacity-sensation curves left shifted from fill1 to fill2 in normals, consistent with expected viscoelastic behavior, but unexpectedly right shifted in OAB. 3D ultrasound volume data showed that fill rates started slowly and ramped up with variable end points. CONCLUSIONS This study establishes a non-invasive means to evaluate real-time bladder sensation using a two-fill accelerated hydration protocol and a sensation meter. Verbal thresholds were inconsistent in OAB, and the right shift in OAB %capacity–sensation curve suggests potential biomechanical and/or sensitization changes. This methodology could be used to gain valuable information on different forms of OAB in a completely non-invasive way. PMID:27654469

Non-invasive characterization of real-time bladder sensation using accelerated hydration and a novel sensation meter: An initial experience.

PubMed

Nagle, Anna S; Speich, John E; De Wachter, Stefan G; Ghamarian, Peter P; Le, David M; Colhoun, Andrew F; Ratz, Paul H; Barbee, Robert W; Klausner, Adam P

2017-06-01

The purpose of this investigation was to develop a non-invasive, objective, and unprompted method to characterize real-time bladder sensation. Volunteers with and without overactive bladder (OAB) were prospectively enrolled in a preliminary accelerated hydration study. Participants drank 2L Gatorade-G2® and recorded real-time sensation (0-100% scale) and standardized verbal sensory thresholds using a novel, touch-screen "sensation meter." 3D bladder ultrasound images were recorded throughout fillings for a subset of participants. Sensation data were recorded for two consecutive complete fill-void cycles. Data from 14 normal and 12 OAB participants were obtained (ICIq-OAB-5a = 0 vs. ≥3). Filling duration decreased in fill2 compared to fill1, but volume did not significantly change. In normals, adjacent verbal sensory thresholds (within fill) showed no overlap, and identical thresholds (between fill) were similar, demonstrating effective differentiation between degrees of %bladder capacity. In OAB, within-fill overlaps and between-fill differences were identified. Real-time %capacity-sensation curves left shifted from fill1 to fill2 in normals, consistent with expected viscoelastic behavior, but unexpectedly right shifted in OAB. 3D ultrasound volume data showed that fill rates started slowly and ramped up with variable end points. This study establishes a non-invasive means to evaluate real-time bladder sensation using a two-fill accelerated hydration protocol and a sensation meter. Verbal thresholds were inconsistent in OAB, and the right shift in OAB %capacity-sensation curve suggests potential biomechanical and/or sensitization changes. This methodology could be used to gain valuable information on different forms of OAB in a completely non-invasive way. © 2016 Wiley Periodicals, Inc.

Modeling bladder cancer in mice: opportunities and challenges

PubMed Central

Kobayashi, Takashi; Owczarek, Tomasz B.; McKiernan, James M.; Abate-Shen, Cory

2015-01-01

The prognosis and treatment of bladder cancer have hardly improved in the last 20 years. Bladder cancer remains a debilitating and often fatal disease, and among the most costly cancers to treat. The generation of informative mouse models has the potential to improve our understanding of bladder cancer progression, as well as impact its diagnosis and treatment. However, relatively few mouse models of bladder cancer have been described and particularly few that develop invasive cancer phenotypes. This review focuses on opportunities for improving the landscape of mouse models of bladder cancer. PMID:25533675

Fruit and Vegetable Intakes Are Associated with Lower Risk of Bladder Cancer among Women in the Multiethnic Cohort Study12

PubMed Central

Park, Song-Yi; Ollberding, Nicholas J.; Woolcott, Christy G.; Wilkens, Lynne R.; Henderson, Brian E.; Kolonel, Laurence N.

2013-01-01

Fruits and vegetables have been examined for their possible effects on the risk of bladder cancer, as they contain numerous nutrients, phytochemicals, and antioxidants with potentially anticarcinogenic properties. In a prospective analysis of 185,885 older adults participating in the Multiethnic Cohort Study, we examined whether the consumption of fruits and vegetables, or of nutrients concentrated in fruits and vegetables, was associated with bladder cancer risk. Cox proportional hazards models were used to calculate HRs and 95% CIs for bladder cancer in relation to dietary intakes. A total of 581 invasive bladder cancer cases (429 men and 152 women) were diagnosed over a mean follow-up period of 12.5 y. In women, total fruits and vegetables [HR = 0.35 (95% CI: 0.22, 0.56); highest vs. lowest quartile], total vegetables [HR = 0.49 (95% CI: 0.29, 0.83)], yellow-orange vegetables [HR = 0.48 (95% CI: 0.30, 0.77)], total fruits [HR = 0.54 (95% CI: 0.34, 0.85)], and citrus fruits [HR = 0.56 (95% CI: 0.34, 0.90)] were inversely associated with the risk of invasive bladder cancer in risk factor-adjusted models. In addition, women with the highest intakes of vitamins A, C, and E; the carotenoids α-carotene, β-carotene, and β-cryptoxanthin; and folate had a lower risk of bladder cancer. For men, no associations for fruits, vegetables, or nutrients were found overall, although inverse associations were observed for vegetable intake among current smokers, and in ethnic-specific analyses, for fruit and vegetable intake among Latinos specifically. Our findings suggest that greater consumption of fruits and vegetables may lower the risk of invasive bladder cancer among women and highlight the need for specific subgroup analyses in future studies. PMID:23739308

Lymphovascular invasion, ureteral reimplantation and prior history of urothelial carcinoma are associated with poor prognosis after partial cystectomy for muscle-invasive bladder cancer with negative pelvic lymph nodes.

PubMed

Ma, B; Li, H; Zhang, C; Yang, K; Qiao, B; Zhang, Z; Xu, Y

2013-10-01

To identify predictive factors underlying recurrence and survival after partial cystectomy for pelvic lymph node-negative muscle-invasive bladder cancer (MIBC) (urothelial carcinoma) and to report the results of partial cystectomy among select patients. We retrospectively reviewed 101 cases that received partial cystectomy for MIBC (pT2-3N0M0) between 2000 and 2010. The log-rank test and a Cox regression analyses were performed to identify factors that were predictive of recurrence and survival. With a median follow-up of 53.0 months (range 9-120), the 5-year overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS) rates were 58%, 65% and 50%, respectively. A total of 33 patients died of bladder cancer and 52 patients survived with intact bladder. Of the 101 patients included, 55 had no recurrence, 12 had non-muscle-invasive recurrence in the bladder that was treated successfully, and 34 had recurrence with advanced disease. The multivariate analysis showed that prior history of urothelial carcinoma (PH.UC) was associated with both CSS and RFS and weakly associated with OS; lymphovascular invasion (LVI) and ureteral reimplantation (UR) were associated with OS, CSS and RFS. Among patients with pelvic lymph node-negative MIBC, PH.UC and UR should be considered as contraindications for partial cystectomy, and LVI is predictive of poor outcomes after partial cystectomy. Highly selective partial cystectomy is a rational alternative to radical cystectomy for the treatment of MIBC with negative pelvic lymph nodes. Copyright © 2013 Elsevier Ltd. All rights reserved.

Bladder Preservation for Localized Muscle-Invasive Bladder Cancer: The Survival Impact of Local Utilization Rates of Definitive Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kozak, Kevin R.; Hamidi, Maryam; Manning, Matthew

2012-06-01

Purpose: This study examines the management and outcomes of muscle-invasive bladder cancer in the United States. Methods and Materials: Patients with muscle-invasive bladder cancer diagnosed between 1988 and 2006 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Patients were classified according to three mutually exclusive treatment categories based on the primary initial treatment: no local management, radiotherapy, or surgery. Overall survival was assessed with Kaplan-Meier analysis and Cox models based on multiple factors including treatment utilization patterns. Results: The study population consisted of 26,851 patients. Age, sex, race, tumor grade, histology, and geographic location were associated withmore » differences in treatment (all p < 0.01). Patients receiving definitive radiotherapy tended to be older and have less differentiated tumors than patients undergoing surgery (RT, median age 78 years old and 90.6% grade 3/4 tumors; surgery, median age 71 years old and 77.1% grade 3/4 tumors). No large shifts in treatment were seen over time, with most patients managed with surgical resection (86.3% for overall study population). Significant survival differences were observed according to initial treatment: median survival, 14 months with no definitive local treatment; 17 months with radiotherapy; and 43 months for surgery. On multivariate analysis, differences in local utilization rates of definitive radiotherapy did not demonstrate a significant effect on overall survival (hazard ratio, 1.002; 95% confidence interval, 0.999-1.005). Conclusions: Multiple factors influence the initial treatment strategy for muscle-invasive bladder cancer, but definitive radiotherapy continues to be used infrequently. Although patients who undergo surgery fare better, a multivariable model that accounted for patient and tumor characteristics found no survival detriment to the utilization of definitive radiotherapy. These results support continued research into bladder preservation strategies and suggest that definitive radiotherapy represents a viable initial treatment strategy for those who wish to attempt to preserve their native bladder.« less

Non-contrast magnetic resonance imaging for bladder cancer: fused high b value diffusion-weighted imaging and T2-weighted imaging helps evaluate depth of invasion.

PubMed

Lee, Minsu; Shin, Su-Jin; Oh, Young Taik; Jung, Dae Chul; Cho, Nam Hoon; Choi, Young Deuk; Park, Sung Yoon

2017-09-01

To investigate the utility of fused high b value diffusion-weighted imaging (DWI) and T2-weighted imaging (T2WI) for evaluating depth of invasion in bladder cancer. We included 62 patients with magnetic resonance imaging (MRI) and surgically confirmed urothelial carcinoma in the urinary bladder. An experienced genitourinary radiologist analysed the depth of invasion (T stage <2 or ≥2) using T2WI, DWI, T2WI plus DWI, and fused DWI and T2WI (fusion MRI). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were investigated. Area under the curve (AUC) was analysed to identify T stage ≥2. The rate of patients with surgically confirmed T stage ≥2 was 41.9% (26/62). Sensitivity, specificity, PPV, NPV and accuracy were 50.0%, 55.6%, 44.8%, 60.6% and 53.2%, respectively, with T2WI; 57.7%, 77.8%, 65.2%, 71.8% and 69.4%, respectively, with DWI; 65.4%, 80.6%, 70.8%, 76.3% and 74.2%, respectively, with T2WI plus DWI and 80.8%, 77.8%, 72.4%, 84.9% and 79.0%, respectively, with fusion MRI. AUC was 0.528 with T2WI, 0.677 with DWI, 0.730 with T2WI plus DWI and 0.793 with fusion MRI for T stage ≥2. Fused high b value DWI and T2WI may be a promising non-contrast MRI technique for assessing depth of invasion in bladder cancer. • Accuracy of fusion MRI was 79.0% for T stage ≥2 in bladder cancer. • AUC of fusion MRI was 0.793 for T stage ≥2 in bladder cancer. • Diagnostic performance of fusion MRI was comparable with T2WI plus DWI. • As a non-contrast MRI technique, fusion MRI is useful for bladder cancer.

Artificial intelligence and bladder cancer arrays.

PubMed

Wild, P J; Catto, J W F; Abbod, M F; Linkens, D A; Herr, A; Pilarsky, C; Wissmann, C; Stoehr, R; Denzinger, S; Knuechel, R; Hamdy, F C; Hartmann, A

2007-01-01

Non-muscle invasive bladder cancer is a heterogenous disease whose management is dependent upon the risk of progression to muscle invasion. Although the recurrence rate is high, the majority of tumors are indolent and can be managed by endoscopic means alone. The prognosis of muscle invasion is poor and radical treatment is required if cure is to be obtained. Progression risk in non-invasive tumors is hard to determine at tumor diagnosis using current clinicopathological means. To improve the accuracy of progression prediction various biomarkers have been evaluated. To discover novel biomarkers several authors have used gene expression microarrays. Various statistical methods have been described to interpret array data, but to date no biomarkers have entered clinical practice. Here, we describe a new method of microarray analysis using neurofuzzy modeling (NFM), a form of artificial intelligence, and integrate it with artificial neural networks (ANN) to investigate non-muscle invasive bladder cancer array data (n=66 tumors). We develop a predictive panel of 11 genes, from 2800 expressed genes, that can significantly identify tumor progression (average Logrank p = 0.0288) in the analyzed cancers. In comparison, this panel appears superior to those genes chosen using traditional analyses (average Logrank p = 0.3455) and tumor grade (Logrank, p = 0.2475) in this non-muscle invasive cohort. We then analyze panel members in a new non-muscle invasive bladder cancer cohort (n=199) using immunohistochemistry with six commercially available antibodies. The combination of 6 genes (LIG3, TNFRSF6, KRT18, ICAM1, DSG2 and BRCA2) significantly stratifies tumor progression (Logrank p = 0.0096) in the new cohort. We discuss the benefits of the transparent NFM approach with respect to other reported methods.

[Immunotherapy : a revolution in the management of urothelial bladder cancer ?

PubMed

Adam, Sophie Mc; Derré, Laurent; Jichlinski, Patrice; Lucca, Ilaria

2017-11-29

The treatment of urothelial bladder cancer has changed very little in recent years, with high rates of disease recurrence and progression, even in low aggressive urothelial bladder cancer. Immunotherapy has already proven its effectiveness as a treatment for several types of cancer and has been used in high-grade non-muscle-invasive bladder cancer for decades. Recent findings on immune checkpoints inhibitors have opened up a new chapter for treatment of bladder cancer, offering interesting therapeutic perspectives that could revolutionize the management.

Bladder preservation in non-metastatic muscle-invasive bladder cancer (MIBC): a single-institution experience

PubMed Central

Gerardi, Marianna A.; Jereczek-Fossa, Barbara A.; Zerini, Dario; Surgo, Alessia; Dicuonzo, Samantha; Spoto, Ruggero; Fodor, Cristiana; Verri, Elena; Rocca, Maria Cossu; Nolè, Franco; Muto, Matteo; Ferro, Matteo; Musi, Gennaro; Bottero, Danilo; Matei, Deliu V.; De Cobelli, Ottavio; Orecchia, Roberto

2016-01-01

The aim of this study is to access the feasibility, toxicity profile, and tumour outcome of an organ preservation curative approach in non-metastatic muscle-invasive bladder cancer. A retrospective analysis was conducted on patients affected by M0 bladder cancer, who refused cystectomy and were treated with a curative approach. The standard bladder preservation scheme included maximal transurethral resection of bladder tumour (TURBT) and combination of radiotherapy and platin-based chemotherapy, followed by endoscopic evaluation, urine cytology, and instrumental evaluation. Thirteen patients fulfilled the inclusion criteria. TNM stage was cT2cN0M0 and cT2cNxM0, in 12 and one patients, respectively. All patients had transitional cell cancer. Twelve patients completed the whole therapeutic programme (a bimodal treatment without chemotherapy for one patient). Median follow-up is 36 months. None of the patients developed severe urinary or intestinal acute toxicity. In 10 patients with a follow-up > 6 months, no cases of severe late toxicity were observed. Response evaluated in 12 patients included complete response and stable disease in 11 patients (92%), and one patient (8%), respectively. At the time of data analysis (March 2016), 10 patients (77%) are alive with no evidence of disease, two patients (15%) died for other reasons, and one patient has suspicious persistent local disease. The trimodality approach, including maximal TURBT, radiotherapy, and chemotherapy for muscle-invasive bladder cancer, is well-tolerated and might be considered a valid and feasible option in fit patients who refuse radical cystectomy. PMID:27563352

Bladder preservation in non-metastatic muscle-invasive bladder cancer (MIBC): a single-institution experience.

PubMed

Gerardi, Marianna A; Jereczek-Fossa, Barbara A; Zerini, Dario; Surgo, Alessia; Dicuonzo, Samantha; Spoto, Ruggero; Fodor, Cristiana; Verri, Elena; Rocca, Maria Cossu; Nolè, Franco; Muto, Matteo; Ferro, Matteo; Musi, Gennaro; Bottero, Danilo; Matei, Deliu V; De Cobelli, Ottavio; Orecchia, Roberto

2016-01-01

The aim of this study is to access the feasibility, toxicity profile, and tumour outcome of an organ preservation curative approach in non-metastatic muscle-invasive bladder cancer. A retrospective analysis was conducted on patients affected by M0 bladder cancer, who refused cystectomy and were treated with a curative approach. The standard bladder preservation scheme included maximal transurethral resection of bladder tumour (TURBT) and combination of radiotherapy and platin-based chemotherapy, followed by endoscopic evaluation, urine cytology, and instrumental evaluation. Thirteen patients fulfilled the inclusion criteria. TNM stage was cT2cN0M0 and cT2cNxM0, in 12 and one patients, respectively. All patients had transitional cell cancer. Twelve patients completed the whole therapeutic programme (a bimodal treatment without chemotherapy for one patient). Median follow-up is 36 months. None of the patients developed severe urinary or intestinal acute toxicity. In 10 patients with a follow-up > 6 months, no cases of severe late toxicity were observed. Response evaluated in 12 patients included complete response and stable disease in 11 patients (92%), and one patient (8%), respectively. At the time of data analysis (March 2016), 10 patients (77%) are alive with no evidence of disease, two patients (15%) died for other reasons, and one patient has suspicious persistent local disease. The trimodality approach, including maximal TURBT, radiotherapy, and chemotherapy for muscle-invasive bladder cancer, is well-tolerated and might be considered a valid and feasible option in fit patients who refuse radical cystectomy.

Hypoxia enhances the malignant nature of bladder cancer cells and concomitantly antagonizes protein O-glycosylation extension

PubMed Central

Lima, Luís; Azevedo, Rita; Soares, Janine; Cotton, Sofia; Parreira, Beatriz; Neves, Manuel; Amaro, Teresina; Tavares, Ana; Teixeira, Filipe; Palmeira, Carlos; Rangel, Maria; Silva, André M.N.; Reis, Celso A.; Santos, Lúcio Lara; Oliveira, Maria José; Ferreira, José Alexandre

2016-01-01

Invasive bladder tumours express the cell-surface Sialyl-Tn (STn) antigen, which stems from a premature stop in protein O-glycosylation. The STn antigen favours invasion, immune escape, and possibly chemotherapy resistance, making it attractive for target therapeutics. However, the events leading to such deregulation in protein glycosylation are mostly unknown. Since hypoxia is a salient feature of advanced stage tumours, we searched into how it influences bladder cancer cells glycophenotype, with emphasis on STn expression. Therefore, three bladder cancer cell lines with distinct genetic and molecular backgrounds (T24, 5637 and HT1376) were submitted to hypoxia. To disclose HIF-1α-mediated events, experiments were also conducted in the presence of Deferoxamine Mesilate (Dfx), an inhibitor of HIF-1α proteasomal degradation. In both conditions all cell lines overexpressed HIF-1α and its transcriptionally-regulated protein CA-IX. This was accompanied by increased lactate biosynthesis, denoting a shift toward anaerobic metabolism. Concomitantly, T24 and 5637 cells acquired a more motile phenotype, consistent with their more mesenchymal characteristics. Moreover, hypoxia promoted STn antigen overexpression in all cell lines and enhanced the migration and invasion of those presenting more mesenchymal characteristics, in an HIF-1α-dependent manner. These effects were reversed by reoxygenation, demonstrating that oxygen affects O-glycan extension. Glycoproteomics studies highlighted that STn was mainly present in integrins and cadherins, suggesting a possible role for this glycan in adhesion, cell motility and invasion. The association between HIF-1α and STn overexpressions and tumour invasion was further confirmed in bladder cancer patient samples. In conclusion, STn overexpression may, in part, result from a HIF-1α mediated cell-survival strategy to adapt to the hypoxic challenge, favouring cell invasion. In addition, targeting STn-expressing glycoproteins may offer potential to treat tumour hypoxic niches harbouring more malignant cells. PMID:27542232

Treatment of Muscle-Invasive Bladder Cancer in Older Patients.

PubMed

Skinner, Eila C

2016-01-01

Treatment of muscle-invasive bladder cancer in older patients is challenging. Definitive therapy of localized disease requires either surgery or radiation therapy, ideally combined with systemic chemotherapy. However, current population data suggest that less than half of patients older than age 70 are offered such treatments. We will review tools available to assess the fitness of older patients for surgery, alternatives, and tips for perioperative patient treatment.

Muscle Invasive Bladder Cancer: From Diagnosis to Survivorship

PubMed Central

Mohamed, N. E.; Diefenbach, M. A.; Goltz, H. H.; Lee, C. T.; Latini, D.; Kowalkowski, M.; Philips, C.; Hassan, W.; Hall, S. J.

2012-01-01

Bladder cancer is the fifth most commonly diagnosed cancer and the most expensive adult cancer in average healthcare costs incurred per patient in the USA. However, little is known about factors influencing patients' treatment decisions, quality of life, and responses to treatment impairments. The main focus of this paper is to better understand the impact of muscle invasive bladder cancer on patient quality of life and its added implications for primary caregivers and healthcare providers. In this paper, we discuss treatment options, side effects, and challenges that patients and family caregivers face in different phases along the disease trajectory and further identify crucial areas of needed research. PMID:22924038

Oncogenic role of fibroblast growth factor receptor 3 in tumorigenesis of urinary bladder cancer.

PubMed

Pandith, Arshad A; Shah, Zafar A; Siddiqi, Mushtaq A

2013-05-01

Bladder cancer is the second most common genitourinary tumor and constitutes a very heterogeneous disease. Molecular and pathologic studies suggest that low-grade noninvasive and high-grade invasive urothelial cell carcinoma (UCC) arise via distinct pathways. Low-grade noninvasive UCC represent the majority of tumors at presentation. A high proportion of patients with low-grade UCC develop recurrences but usually with no progression to invasive disease. At presentation, a majority of the bladder tumors (70%-80%) are low-grade noninvasive (pTa). Several genetic changes may occur in bladder cancer, but activating mutations in the fibroblast growth factor receptor 3 (FGFR3) genes are the most common and most specific genetic abnormality in bladder cancer. Interestingly, these mutations are associated with bladder tumors of low stage and grade, which makes the FGFR3 mutation the first marker that can be used for diagnosis of noninvasive bladder tumors. Since the first report of FGFR3 involvement in bladder tumors, numerous studies have been conducted to understand its function and thereby confirm the oncogenic role of this receptor particularly in noninvasive groups. Efforts are on to exploit this receptor as a therapeutic target, which holds much promise in the treatment of bladder cancer, particularly low-grade noninvasive tumors. Further studies need to explore the potential use of FGFR3 mutations in bladder cancer diagnosis, prognosis, and in surveillance of patients with bladder cancer. This review focuses on the role of FGFR3 in bladder tumors in the backdrop of various studies published. Copyright © 2013 Elsevier Inc. All rights reserved.

A Methylation Panel for Bladder Cancer — EDRN Public Portal

Cancer.gov

Participate in a prevalidation study for methylation based detection of bladder cancer. In addition, a panel of three markers identified will be evaluated for their ability to a) identify bladder cancer patients from those with benign urologic disease; b) identify patients with superficial (papillary) cancers from those with high grade invasive cancers

Monoclonal antibody Zt/g4 targeting RON receptor tyrosine kinase enhances chemosensitivity of bladder cancer cells to Epirubicin by promoting G1/S arrest and apoptosis.

PubMed

Chen, Jun-Feng; Yu, Bi-Xia; Yu, Rui; Ma, Liang; Lv, Xiu-Yi; Cheng, Yue; Ma, Qi

2017-02-01

Epirubicin (EPI) is one of the most used intravesical chemotherapy agents after transurethral resection to non-muscle invasive bladder tumors (NMIBC) to prevent cancer recurrence and progression. However, even after resection of bladder tumors and intravesical chemotherapy, half of them will recur and progress. RON is a membrane tyrosine kinase receptor usually overexpressed in bladder cancer cells and associated with poor pathological features. This study aims to investigate the effects of anti-RON monoclonal antibody Zt/g4 on the chemosensitivity of bladder cells to EPI. After Zt/g4 treatment, cell cytotoxicity was significantly increased and cell invasion was markedly suppressed in EPI-treated bladder cancer cells. Further investigation indicated that combing Zt/g4 with EPI promoted cell G1/S-phase arrest and apoptosis, which are the potential mechanisms that RON signaling inhibition enhances chemosensitivity of EPI. Thus, combing antibody-based RON targeted therapy enhances the therapeutic effects of intravesical chemotherapy, which provides new strategy for further improvement of NMIBC patient outcomes.

[Steroid and xenobiotic receptor (SXR), multidrug resistance gene (MDR1) and GSTs, SULTs and CYP polymorphism expression in invasive bladder cancer, analysis of their expression and correlation with other prognostic factors].

PubMed

Rioja Zuazu, J; Bandrés Elizalde, E; Rosell Costa, D; Rincón Mayans, A; Zudaire Bergera, J; Gil Sanz, M J; Rioja Sanz, L A; García Foncillas, J; Berián Polo, J M

2007-01-01

Steroid and Xenobiotic Receptor (SXR) has demonstrated its activation by numerous drugs, including cytochrome P450 potent inducers like rifampicina or cotrimazol. The role of SXR is well known, and lies regulating in a positive manner cytochrome P450 3A4 (CYP3A4) transcription and the multidrug resistance gene (MDR1), it's considered a key in the xenobiotic detoxification mechanism, being involved in all phases of the detoxification process. Enzymes involved in Policyclic Aromatic hidrocarbures (PAH) metabolism and degradation are polymorphic in humans, including glutation S-transferases (GSTs), N-acetiltransferases (NATs), sulfotransferases (SULTs)1A1 and cytochrome p450 (CYP)1B1. The objectives we've planned are: 1. Analyze the expression of the transcription factor SXR and MDR1 in bladder by means of RT-PCR real time, both in normal bladder and in tumoral bladder. 2. Analyze the relation between clinical and pathological factors with the expression of SXR and MDR1. 3. Analyze the expression of the polymorphims CYP1B1, GSTM1 GSTT1 and SULT1A1 and their correlation with different clinic-pathological and molecular factors. In a prospective way the size of the sample was estimated. In 67 patients from two institutions (Hospital Universitario Miguel Servet (49 HUMS) and Clinica Universitaria de Navarra (18 CUN)), diagnosed of invasive bladder cancer and treated by means of radical cystectomy, were determined the expression of both SXR and MDR1 by means of real time PCR, as well as the polymorphisms CYP1B1, GSTM1 GSTT1 y SULT1A1 by means of RFLP (Restriction fragment length polymorphism). Correlations with other prognostic factors by contingency tables were performed. Average follow up was 23.7 months with a median of 28.26 months. Of the 67 patients studied, 31 patients (46.3) presented disease progression, in form of local recurrence or in distant metastasis or both. With a average time to progression of 12.4 months and a median of 10 months, with a range of 1.1 month to 31.9 month. 36 patients (53.7%) did not have any evidence of disease progression during follow up. The Steroid and Xenobiotic Receptor as well as the Multidrug Resistance Gene (MDR1) are expressed in both normal bladder (0.94DeltaCt y 0.94DeltaCt) and tumoral bladder in the cystectomy specimen (1.09 DeltaCt y 0.45 DeltaCt). We've analyzed their expression in a quantitative manner and in a qualitative manner. The expression of SXR correlates with the presence of ca. in situ (p=0.024), vasculo-lymphatic invasion (p=0.05) mean while MDR1 correlates with presence of vasculo-lymphatic invasion (p=0.05) Both factors are correlate between each others (p=0.011). Polymorphisms: CYP1B1, GSTM1, GSTT1 and SULT1A1, are expressed in these patients but their expression doesn't correlates with any prognostic factor Both SXR and MDR1 are expressed in normal bladder as well as in tumoral bladder. And their expression correlates with different prognostic factors with influence in the survival described in the literature.

TRPV2 mediates adrenomedullin stimulation of prostate and urothelial cancer cell adhesion, migration and invasion.

PubMed

Oulidi, Agathe; Bokhobza, Alexandre; Gkika, Dimitra; Vanden Abeele, Fabien; Lehen'kyi, V'yacheslav; Ouafik, L'houcine; Mauroy, Brigitte; Prevarskaya, Natalia

2013-01-01

Adrenomedullin (AM) is a 52-amino acid peptide initially isolated from human pheochromocytoma. AM is expressed in a variety of malignant tissues and cancer cell lines and was shown to be a mitogenic factor capable of stimulating growth of several cancer cell types. In addition, AM is a survival factor for certain cancer cells. Some data suggest that AM might be involved in the progression cancer metastasis via angiogenesis and cell migration and invasion control. The Transient Receptor Potential channel TRPV2 is known to promote in prostate cancer cell migration and invasive phenotype and is correlated with the stage and grade of bladder cancer. In this work we show that AM induces prostate and urothelial cancer cell migration and invasion through TRPV2 translocation to plasma membrane and the subsequent increase in resting calcium level.

Proteomics Analysis of Bladder Cancer Exosomes*

PubMed Central

Welton, Joanne L.; Khanna, Sanjay; Giles, Peter J.; Brennan, Paul; Brewis, Ian A.; Staffurth, John; Mason, Malcolm D.; Clayton, Aled

2010-01-01

Exosomes are nanometer-sized vesicles, secreted by various cell types, present in biological fluids that are particularly rich in membrane proteins. Ex vivo analysis of exosomes may provide biomarker discovery platforms and form non-invasive tools for disease diagnosis and monitoring. These vesicles have never before been studied in the context of bladder cancer, a major malignancy of the urological tract. We present the first proteomics analysis of bladder cancer cell exosomes. Using ultracentrifugation on a sucrose cushion, exosomes were highly purified from cultured HT1376 bladder cancer cells and verified as low in contaminants by Western blotting and flow cytometry of exosome-coated beads. Solubilization in a buffer containing SDS and DTT was essential for achieving proteomics analysis using an LC-MALDI-TOF/TOF MS approach. We report 353 high quality identifications with 72 proteins not previously identified by other human exosome proteomics studies. Overrepresentation analysis to compare this data set with previous exosome proteomics studies (using the ExoCarta database) revealed that the proteome was consistent with that of various exosomes with particular overlap with exosomes of carcinoma origin. Interrogating the Gene Ontology database highlighted a strong association of this proteome with carcinoma of bladder and other sites. The data also highlighted how homology among human leukocyte antigen haplotypes may confound MASCOT designation of major histocompatability complex Class I nomenclature, requiring data from PCR-based human leukocyte antigen haplotyping to clarify anomalous identifications. Validation of 18 MS protein identifications (including basigin, galectin-3, trophoblast glycoprotein (5T4), and others) was performed by a combination of Western blotting, flotation on linear sucrose gradients, and flow cytometry, confirming their exosomal expression. Some were confirmed positive on urinary exosomes from a bladder cancer patient. In summary, the exosome proteomics data set presented is of unrivaled quality. The data will aid in the development of urine exosome-based clinical tools for monitoring disease and will inform follow-up studies into varied aspects of exosome manufacture and function. PMID:20224111

Self-inflicted long complex urethro-vesical foreign body: is open surgery always needed?

PubMed Central

Garg, Manish; Kumar, Manoj; Sankhwar, Satyanarayan; Singh, Vishwajeet

2013-01-01

In this case report, we describe our experience of a self-inflicted long complex urethrovesical foreign body managed suprapubically through the minimally invasive technique. A 21-year-old man with antipsychotic treatment for the past 10 years presented with a long electric cable wire in his bladder with the distal end in the penile urethra. He presented with symptoms of voiding difficulty and gross haematuria. An attempt of gentle retrieval of wire through the cystoscopic forceps was not successful due to a very complex knot of cable in the bladder. To avoid open surgery such as suprapubic cystotomy, the percutaneous minimally invasive approach was planned. Access to the bladder was achieved by the suprapubic puncture of the bladder, placement of a guide-wire and serial dilation of supra-pubic tract. With the help of nephroscope, through suprapubic tract, the cable wire was retrieved antegradely without causing undue trauma to the bladder or urethra. PMID:23749820

PLK-1 Silencing in Bladder Cancer by siRNA Delivered With Exosomes.

PubMed

Greco, Kristin A; Franzen, Carrie A; Foreman, Kimberly E; Flanigan, Robert C; Kuo, Paul C; Gupta, Gopal N

2016-05-01

To use exosomes as a vector to deliver small interfering ribonucleic acid (siRNA) to silence the polo-like kinase 1 (PLK-1) gene in bladder cancer cells. Exosomes were isolated from both human embryonic kidney 293 (HEK293) cell and mesenchymal stem cell (MSC) conditioned media. Fluorescently labeled exosomes were co-cultured with bladder cancer and normal epithelial cells and uptake was quantified by image cytometry. PLK-1 siRNA and negative control siRNA were loaded into HEK293 and MSC exosomes using electroporation. An invasive bladder cancer cell line (UMUC3) was co-cultured with the electroporated exosomes. Quantitative reverse transcriptase polymerase chain reaction was performed. Protein analysis was performed by Western blot. Annexin V staining and MTT assays were used to investigate effects on apoptosis and viability. Bladder cancer cell lines internalize an increased percentage of HEK293 exosomes when compared to normal bladder epithelial cells. Treatment of UMUC3 cells with exosomes electroporated with PLK-1 siRNA achieved successful knockdown of PLK-1 mRNA and protein when compared to cells treated with negative control exosomes. HEK293 and MSC exosomes were effectively used as a delivery vector to transport PLK-1 siRNA to bladder cancer cells in vitro, resulting in selective gene silencing of PLK-1. The use of exosomes as a delivery vector for potential intravesical therapy is attractive. Copyright © 2016 Elsevier Inc. All rights reserved.

Bladder cancers respond to intravesical instillation of HAMLET (human alpha-lactalbumin made lethal to tumor cells).

PubMed

Mossberg, Ann-Kristin; Wullt, Björn; Gustafsson, Lotta; Månsson, Wiking; Ljunggren, Eva; Svanborg, Catharina

2007-09-15

We studied if bladder cancers respond to HAMLET (human alpha-lactalbumin made lethal to tumor cells) to establish if intravesical HAMLET application might be used to selectively remove cancer cells in vivo. Patients with nonmuscle invasive transitional cell carcinomas were included. Nine patients received 5 daily intravesical instillations of HAMLET (25 mg/ml) during the week before scheduled surgery. HAMLET stimulated a rapid increase in the shedding of tumor cells into the urine, daily, during the 5 days of instillation. The effect was specific for HAMLET, as intravesical instillation of NaCl, PBS or native alpha-lactalbumin did not increase cell shedding. Most of the shed cells were dead and an apoptotic response was detected in 6 of 9 patients, using the TUNEL assay. At surgery, morphological changes in the exophytic tumors were documented by endoscopic photography and a reduction in tumor size or change in tumor character was detected in 8 of 9 patients. TUNEL staining was positive in biopsies from the remaining tumor in 4 patients but adjacent healthy tissue showed no evidence of apoptosis and no toxic response. The results suggest that HAMLET exerts a direct and selective effect on bladder cancer tissue in vivo and that local HAMLET administration might be of value in the future treatment of bladder cancers. (c) 2007 Wiley-Liss, Inc.

The mechanism of the growth-inhibitory effect of coxsackie and adenovirus receptor (CAR) on human bladder cancer: a functional analysis of car protein structure.

PubMed

Okegawa, T; Pong, R C; Li, Y; Bergelson, J M; Sagalowsky, A I; Hsieh, J T

2001-09-01

The coxsackie and adenovirus receptor (CAR) is identified as a high-affinity receptor for adenovirus type 5. We observed that invasive bladder cancer specimens had significantly reduced CAR mRNA levels compared with superficial bladder cancer specimens, which suggests that CAR may play a role in the progression of bladder cancer. Elevated CAR expression in the T24 cell line (CAR-negative cells) increased its sensitivity to adenovirus infection and significantly inhibited its in vitro growth, accompanied by p21 and hypophosphorylated retinoblastoma accumulation. Conversely, decreased CAR levels in both RT4 and 253J cell lines (CAR-positive cells) promoted their in vitro growth. To unveil the mechanism of action of CAR, we showed that the extracellular domain of CAR facilitated intercellular adhesion. Furthermore, interrupting intercellular adhesion of CAR by a specific antibody alleviates the growth-inhibitory effect of CAR. We also demonstrated that both the transmembrane and intracellular domains of CAR were critical for its growth-inhibitory activity. These data indicate that the cell-cell contact initiated by membrane-bound CAR can elicit a negative signal cascade to modulate cell cycle regulators inside the nucleus of bladder cancer cells. Therefore, the presence of CAR cannot only facilitate viral uptake of adenovirus but also inhibit cell growth. These results can be integrated to formulate a new strategy for bladder cancer therapy.

Quality of Life in Non-Muscle-Invasive Bladder Cancer Survivors: A Systematic Review.

PubMed

Jung, Ahrang; Nielsen, Matthew E; Crandell, Jamie L; Palmer, Mary H; Bryant, Ashley Leak; Smith, Sophia K; Mayer, Deborah K

2018-06-01

Non-muscle-invasive bladder cancer (NMIBC) represents approximately 75% of newly diagnosed patients with bladder cancer. Non-muscle-invasive bladder cancer survivors have unique chronic burdens including frequent recurrences, repeated surveillance cystoscopies and treatments, and the highest lifetime medical cost per person among all cancers. The purpose of this study was to summarize studies assessing quality of life (QOL) in NMIBC survivors. The literature from January 2005 to March 2017 found in PubMed, CINAHL, and PsycINFO databases was reviewed systematically. Inclusion criteria were as follows: (1) research about NMIBC survivors, (2) outcomes included QOL, (3) original research article published in peer-reviewed journals, and (4) published in English. A total of 15 studies were included: 14 quantitative studies and 1 mixed-methods study. Non-muscle-invasive bladder cancer survivors had significantly lower QOL compared with the general population, especially in fatigue, physical and role functioning, and mental health. Repeated transurethral resections and intravesical treatments were associated with impaired physical function and mental health. Most NMIBC survivors had concerns of urinary and bowel problems and sexual function. Despite a good prognosis, NMIBC and its treatment have a significant impact on QOL in survivors. The findings showed large burdens in NMIBC survivors and suggest that further research is needed to better understand potential opportunities to improve QOL in this population. Oncology nurses are in the critical position for assessing symptoms and concerns. Oncology nurses should pay special attention to NMIBC survivors who have unique symptoms and burden with the aim of improving survivors' QOL.

Development of a Natural Language Processing Engine to Generate Bladder Cancer Pathology Data for Health Services Research.

PubMed

Schroeck, Florian R; Patterson, Olga V; Alba, Patrick R; Pattison, Erik A; Seigne, John D; DuVall, Scott L; Robertson, Douglas J; Sirovich, Brenda; Goodney, Philip P

2017-12-01

To take the first step toward assembling population-based cohorts of patients with bladder cancer with longitudinal pathology data, we developed and validated a natural language processing (NLP) engine that abstracts pathology data from full-text pathology reports. Using 600 bladder pathology reports randomly selected from the Department of Veterans Affairs, we developed and validated an NLP engine to abstract data on histology, invasion (presence vs absence and depth), grade, the presence of muscularis propria, and the presence of carcinoma in situ. Our gold standard was based on an independent review of reports by 2 urologists, followed by adjudication. We assessed the NLP performance by calculating the accuracy, the positive predictive value, and the sensitivity. We subsequently applied the NLP engine to pathology reports from 10,725 patients with bladder cancer. When comparing the NLP output to the gold standard, NLP achieved the highest accuracy (0.98) for the presence vs the absence of carcinoma in situ. Accuracy for histology, invasion (presence vs absence), grade, and the presence of muscularis propria ranged from 0.83 to 0.96. The most challenging variable was depth of invasion (accuracy 0.68), with an acceptable positive predictive value for lamina propria (0.82) and for muscularis propria (0.87) invasion. The validated engine was capable of abstracting pathologic characteristics for 99% of the patients with bladder cancer. NLP had high accuracy for 5 of 6 variables and abstracted data for the vast majority of the patients. This now allows for the assembly of population-based cohorts with longitudinal pathology data. Published by Elsevier Inc.

Clinical characteristics of bladder cancer in patients with spinal cord injury: the experience from a single centre.

PubMed

Böthig, Ralf; Kurze, Ines; Fiebag, Kai; Kaufmann, Albert; Schöps, Wolfgang; Kadhum, Thura; Zellner, Michael; Golka, Klaus

2017-06-01

Life expectancy for people with spinal cord injury has shown a marked increase due to modern advances in treatment methods and in neuro-urology. However, since life expectancy of people with paralysis increases, the risk of developing of urinary bladder cancer is gaining importance. Single-centre retrospective evaluation of patient data with spinal cord injuries and proven urinary bladder cancer and summary of the literature. Between 1998 and 2014, 24 (3 female, 21 male) out of a total of 6599 patients with spinal cord injury were diagnosed with bladder cancer. The average age at bladder cancer diagnosis was 57.67 years, which is well below the average for bladder cancer cases in the general population (male: 73, female: 77). All but one patient had a latency period between the onset of the spinal paralysis and tumour diagnosis of more than 10 years. The median latency was 29.83 years. The median survival for these patients was 11.5 months. Of the 24 patients, 19 (79%) had muscle invasive bladder cancer at ≥T2 at the time of diagnosis. The type of neurogenic bladder (neurogenic detrusor overactivity or acontractility) and the form of bladder drainage do not appear to influence the risk. Long-term indwelling catheter drainage played only a minor role in the investigated patients. The significantly younger age at onset and the frequency of invasive tumours at diagnosis indicate that spinal cord injury influences bladder cancer risk and prognosis as well. Early detection of bladder cancer in patients with spinal cord injury remains a challenge.

Molecular biology of bladder cancer.

PubMed

Martin-Doyle, William; Kwiatkowski, David J

2015-04-01

Classic as well as more recent large-scale genomic analyses have uncovered multiple genes and pathways important for bladder cancer development. Genes involved in cell-cycle control, chromatin regulation, and receptor tyrosine and PI3 kinase-mammalian target of rapamycin signaling pathways are commonly mutated in muscle-invasive bladder cancer. Expression-based analyses have identified distinct types of bladder cancer that are similar to subsets of breast cancer, and have prognostic and therapeutic significance. These observations are leading to novel therapeutic approaches in bladder cancer, providing optimism for therapeutic progress. Copyright © 2015 Elsevier Inc. All rights reserved.

Renin-Angiotensin Inhibitors Decrease Recurrence after Transurethral Resection of Bladder Tumor in Patients with Nonmuscle Invasive Bladder Cancer.

PubMed

Blute, Michael L; Rushmer, Timothy J; Shi, Fangfang; Fuller, Benjamin J; Abel, E Jason; Jarrard, David F; Downs, Tracy M

2015-11-01

Prior reports suggest that renin-angiotensin system inhibition may decrease nonmuscle invasive bladder cancer recurrence. We evaluated whether angiotensin converting enzyme inhibitor or angiotensin receptor blocker treatment at initial surgery was associated with decreased recurrence or progression in patients with nonmuscle invasive bladder cancer. Using an institutional bladder cancer database we identified 340 patients with data available on initial transurethral resection of bladder tumor. Progression was defined as an increase to stage T2. Cox proportional hazards models were used to evaluate associations with recurrence-free and progression-free survival. Median patient age was 69.6 years. During a median followup of 3 years (IQR 1.3-6.1) 200 patients (59%) had recurrence and 14 (4.1%) had stage progression. Of those patients 143 were receiving angiotensin converting enzyme inhibitor/angiotensin receptor blockers at the time of the first transurethral resection. On univariate analysis factors associated with improved recurrence-free survival included carcinoma in situ (p = 0.040), bacillus Calmette-Guérin therapy (p = 0.003) and angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapy (p = 0.009). Multivariate analysis demonstrated that patients treated with bacillus Calmette-Guérin therapy (HR 0.68, 95% CI 0.47-0.87, p = 0.002) or angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapy (HR 0.61, 95% CI 0.45-0.84, p = 0.005) were less likely to experience tumor recurrence. The 5-year recurrence-free survival rate was 45.6% for patients treated with angiotensin converting enzyme inhibitor/angiotensin receptor blockers and 28.1% in those not treated with angiotensin converting enzyme inhibitor/angiotensin receptor blockers (p = 0.009). Subgroup analysis was performed to evaluate nonmuscle invasive bladder cancer pathology (Ta, T1 and carcinoma in situ) in 85 patients on bacillus Calmette-Guérin therapy alone and in 52 in whom it was combined with angiotensin converting enzyme inhibitor/angiotensin receptor blocker. Multivariate analysis revealed that patients treated with bacillus Calmette-Guérin alone (HR 2.19, 95% CI 1.01-4.77, p = 0.04) showed worse recurrence-free survival compared to patients treated with bacillus Calmette-Guérin and angiotensin converting enzyme inhibitor/angiotensin receptor blocker (stage Ta HR 0.45, 95% CI 0.21-0.98, p = 0.04). Pharmacological inhibition of the renin-angiotensin system is associated with improved outcomes in patients with bladder cancer. Renin-angiotensin system inhibitor administration in nonmuscle invasive bladder cancer cases should be studied in a prospective randomized trial. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Human Urine Decreases Function and Expression of Type 1 Pili in Uropathogenic Escherichia coli

PubMed Central

Greene, Sarah E.; Hibbing, Michael E.; Janetka, James; Chen, Swaine L.

2015-01-01

ABSTRACT Uropathogenic Escherichia coli (UPEC) is the primary cause of community-acquired urinary tract infections (UTIs). UPEC bind the bladder using type 1 pili, encoded by the fim operon in nearly all E. coli. Assembled type 1 pili terminate in the FimH adhesin, which specifically binds to mannosylated glycoproteins on the bladder epithelium. Expression of type 1 pili is regulated in part by phase-variable inversion of the genomic element containing the fimS promoter, resulting in phase ON (expressing) and OFF (nonexpressing) orientations. Type 1 pili are essential for virulence in murine models of UTI; however, studies of urine samples from human UTI patients demonstrate variable expression of type 1 pili. We provide insight into this paradox by showing that human urine specifically inhibits both expression and function of type 1 pili. Growth in urine induces the fimS phase OFF orientation, preventing fim expression. Urine also contains inhibitors of FimH function, and this inhibition leads to a further bias in fimS orientation toward the phase OFF state. The dual effect of urine on fimS regulation and FimH binding presents a potential barrier to type 1 pilus-mediated colonization and invasion of the bladder epithelium. However, FimH-mediated attachment to human bladder cells during growth in urine reverses these effects such that fim expression remains ON and/or turns ON. Interestingly, FimH inhibitors called mannosides also induce the fimS phase OFF orientation. Thus, the transduction of FimH protein attachment or inhibition into epigenetic regulation of type 1 pilus expression has important implications for the development of therapeutics targeting FimH function. PMID:26126855

Use of Artificial Intelligence and Machine Learning Algorithms with Gene Expression Profiling to Predict Recurrent Nonmuscle Invasive Urothelial Carcinoma of the Bladder.

PubMed

Bartsch, Georg; Mitra, Anirban P; Mitra, Sheetal A; Almal, Arpit A; Steven, Kenneth E; Skinner, Donald G; Fry, David W; Lenehan, Peter F; Worzel, William P; Cote, Richard J

2016-02-01

Due to the high recurrence risk of nonmuscle invasive urothelial carcinoma it is crucial to distinguish patients at high risk from those with indolent disease. In this study we used a machine learning algorithm to identify the genes in patients with nonmuscle invasive urothelial carcinoma at initial presentation that were most predictive of recurrence. We used the genes in a molecular signature to predict recurrence risk within 5 years after transurethral resection of bladder tumor. Whole genome profiling was performed on 112 frozen nonmuscle invasive urothelial carcinoma specimens obtained at first presentation on Human WG-6 BeadChips (Illumina®). A genetic programming algorithm was applied to evolve classifier mathematical models for outcome prediction. Cross-validation based resampling and gene use frequencies were used to identify the most prognostic genes, which were combined into rules used in a voting algorithm to predict the sample target class. Key genes were validated by quantitative polymerase chain reaction. The classifier set included 21 genes that predicted recurrence. Quantitative polymerase chain reaction was done for these genes in a subset of 100 patients. A 5-gene combined rule incorporating a voting algorithm yielded 77% sensitivity and 85% specificity to predict recurrence in the training set, and 69% and 62%, respectively, in the test set. A singular 3-gene rule was constructed that predicted recurrence with 80% sensitivity and 90% specificity in the training set, and 71% and 67%, respectively, in the test set. Using primary nonmuscle invasive urothelial carcinoma from initial occurrences genetic programming identified transcripts in reproducible fashion, which were predictive of recurrence. These findings could potentially impact nonmuscle invasive urothelial carcinoma management. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

The trophoblast cell surface antigen 2 and miR-125b axis in urothelial bladder cancer

PubMed Central

Lazzarini, Raffaella; Gesuita, Rosaria; Guerra, Emanuela; Tossetta, Giovanni; Castellucci, Clara; Giannubilo, Stefano Raffaele; Procopio, Antonio; Alberti, Saverio; Mazzucchelli, Roberta

2017-01-01

Human trophoblast cell surface antigen 2 (Trop-2) is a 40-kDa transmembrane glycoprotein that was first identified as a marker of human trophoblast cells. Trop-2 acts on cell proliferation, adhesion, and migration by activating a number of intracellular signalling pathways. Elevated Trop-2 expression has been demonstrated in several types of cancer and correlated with aggressiveness and poor prognosis. Since no data are available on Trop-2 in bladder cancer (BC), the purpose of the study was to determine its levels in tissue specimens from normal individuals and patients with BC at different stages. Moreover, since according to recent evidence Trop-2 is a miR-125b target, miR-125b expression was also assessed in tissue specimens. Finally, the effect of the Trop-2/miR-125b axis on the proliferation and migration of BC cells was evaluated in vitro. The Trop-2/miR-125b axis was seen to be differentially expressed in normal urothelium, non-invasive BC and invasive BC tissue. Significant miR-125b down-regulation was associated with a significant increase in Trop-2 protein levels in BC tissue and correlated with disease severity. In vitro analysis confirmed the role of miR-125b in down-modulation of Trop-2 protein levels and showed that Trop-2/miR-125b axis affects cellular proliferation in bladder tissue. In conclusion, our findings highlight a role for the Trop-2/miR-125b axis in BC progression and suggest Trop-2 and miR-125b as diagnostic/prognostic marker candidates as well as druggable targets for innovative therapeutic approaches. PMID:28938585

Invasive micropapillary carcinoma of urinary bladder: a clinicopathological study.

PubMed

Chatterjee, Debajyoti; Das, Ashim; Radotra, Bishan D

2015-01-01

Micropapillary variant of urothelial carcinoma (MPUC) is a rare but well-recognized tumor of the urinary bladder. Tumors with micropapillary areas accompanying conventional urothelial carcinoma are more aggressive compared to conventional urothelial carcinoma and show variable keratin 7, keratin 20 and human epidermal growth factor receptor 2 (Her 2)neu expression. The aim of the study was to analyze the clinical, morphological and immunohistochemical profile of MPUC. Transurethral resection of bladder tumor (TURBT) chips of seven cases of invasive MPUC with subsequent cystoprostatectomy specimens of five patients was reviewed. Epithelial membrane antigen (EMA), Keratin 7, Keratin 20, and Her 2 immunohistochemistry were performed in all cases. Follow-up information was available for all patients (2-36 months). All seven patients were male, and their ages ranged from 50 to 62 years. All cases presented with hematuria. The micropapillary pattern was seen in 20-95% of the tumor. All cases showed extensive lymphatic emboli with detrusor muscle invasion. Lymph node metastasis was present in all cases undergoing cystoprostatectomy except one. Keratin 7 and abluminal pattern of EMA positivity were seen in all cases. Keratin 20 was positive in five cases (71%), and Her 2neu positivity was seen in four cases. Three patients died 2, 3, and 6 months after initial diagnosis, among which two were Her 2 positive and one was Her 2 negative. There was no clear prognostic significance of Her 2 positivity. (1) MPUC is a rare but highly aggressive tumor. (2) Micropapillary is usually the predominant pattern. (3) Keratin 7 is expressed universally, whereas Keratin 20 expression is variable. (4) Her 2 expression has no clear influence on the survival.

PIK3CA gene alterations in bladder cancer are frequent and associate with reduced recurrence in non-muscle invasive tumors.

PubMed

Dueñas, Marta; Martínez-Fernández, Mónica; García-Escudero, Ramón; Villacampa, Felipe; Marqués, Miriam; Saiz-Ladera, Cristina; Duarte, José; Martínez, Victor; Gómez, M José; Martín, M Luisa; Fernández, Manoli; Castellano, Daniel; Real, Francisco X; Rodriguez-Peralto, Jose L; De La Rosa, Federico; Paramio, Jesús M

2015-07-01

Bladder cancer (BC) is the fifth most common cancer in the world, being the non-muscle invasive tumors (NMIBC) the most frequent. NMIBC shows a very high frequency of recurrence and, in certain cases, tumor progression. The phosphatidylinositol 3-kinase (PI3K) pathway, which controls cell growth, tumorigenesis, cell invasion and drug response, is frequently activated in numerous human cancers, including BC, in part through alterations of PIK3CA gene. However, the significance of PIK3CA gene alterations with respect to clinicopathological characteristics, and in particular tumor recurrence and progression, remains elusive. Here, we analyzed the presence of mutations in FGFR3 and PIK3CA genes and copy number alterations of PIK3CA gene in bladder tumor and their correspondent paired normal samples from 87 patients. We observed an extremely high frequency of PIK3CA gene alterations (mutations, copy gains, or both) in tumor samples, affecting primarily T1 and T2 tumors. A significant number of normal tissues also showed mutations and copy gains, being coincident with those found in the corresponding tumor sample. In low-grade tumors PIK3CA mutations associated with FGFR3 mutations. Alterations in PIK3CA gene resulted in increased Akt activity in tumors. Interestingly, the presence of PIK3CA gene alterations, and in particular gene mutations, is significantly associated with reduced recurrence of NMIBC patients. Importantly, the presence of FGFR3 mutations may influence the clinical outcome of patients bearing alterations in PIK3CA gene, and increased recurrence was associated to FGFR3 mutated, PIK3CA wt tumors. These findings may have high relevance in terms of using PI3K-targeted therapies for BC treatment. © 2013 Wiley Periodicals, Inc.

Lipid Profiles of Canine Invasive Transitional Cell Carcinoma of the Urinary Bladder and Adjacent Normal Tissue by Desorption Electrospray Ionization Imaging Mass Spectrometry

PubMed Central

Dill, Allison L.; Ifa, Demian R.; Manicke, Nicholas E.; Costa, Anthony B.; Ramos-Vara, José A.; Knapp, Deborah W.; Cooks, R. Graham

2009-01-01

Desorption electrospray ionization (DESI) mass spectrometry (MS) was used in an imaging mode to interrogate the lipid profiles of thin tissue sections of canine spontaneous invasive transitional cell carcinoma (TCC) of the urinary bladder (a model of human invasive bladder cancer) as well as adjacent normal tissue from four different dogs. The glycerophospholipids and sphingolipids that appear as intense signals in both the negative ion and positive ion modes were identified by tandem mass spectrometry (MS/MS) product ion scans using collision-induced dissociation. Differences in the relative distributions of the lipid species were present between the tumor and adjacent normal tissue in both the negative and positive ion modes. DESI-MS images showing the spatial distributions of particular glycerophospholipids, sphinoglipids and free fatty acids in both the negative and positive ion modes were compared to serial tissue sections that were stained with hematoxylin and eosin (H&E). Increased absolute and relative intensities for at least five different glycerophospholipids and three free fatty acids in the negative ion mode and at least four different lipid species in the positive ion mode were seen in the tumor region of the samples in all four dogs. In addition, one sphingolipid species exhibited increased signal intensity in the positive ion mode in normal tissue relative to the diseased tissue. Principal component analysis (PCA) was also used to generate unsupervised statistical images from the negative ion mode data and these images are in excellent agreement with the DESI images obtained from the selected ions and also the H&E stained tissue PMID:19810710

Investigating Genetic Alterations in Bladder Cancer | Center for Cancer Research

Cancer.gov

Bladder cancer (BC) is the fifth most common cancer worldwide and the sixth most common cancer in the U.S. Mutations in a number of oncogenes and tumor suppressor genes were previously associated with invasive or noninvasive forms of the disease. More recently, next generation sequencing (NGS) of bladder tumors from over 100 Chinese patients revealed alterations in additional

TRPV2 Mediates Adrenomedullin Stimulation of Prostate and Urothelial Cancer Cell Adhesion, Migration and Invasion

PubMed Central

Vanden Abeele, Fabien; Lehen’kyi, V’yacheslav; Ouafik, L’Houcine; Mauroy, Brigitte; Prevarskaya, Natalia

2013-01-01

Adrenomedullin (AM) is a 52-amino acid peptide initially isolated from human pheochromocytoma. AM is expressed in a variety of malignant tissues and cancer cell lines and was shown to be a mitogenic factor capable of stimulating growth of several cancer cell types. In addition, AM is a survival factor for certain cancer cells. Some data suggest that AM might be involved in the progression cancer metastasis via angiogenesis and cell migration and invasion control. The Transient Receptor Potential channel TRPV2 is known to promote in prostate cancer cell migration and invasive phenotype and is correlated with the stage and grade of bladder cancer. In this work we show that AM induces prostate and urothelial cancer cell migration and invasion through TRPV2 translocation to plasma membrane and the subsequent increase in resting calcium level. PMID:23741410

Interstitial lung disease secondary to Cetuximab in bladder cancer: an Oncologist's perspective.

PubMed

Price, Louise; Glynn, Patricia; Zarkar, Anjali

2017-12-20

A wide variety of cytotoxic medications cause interstitial lung disease (ILD). For the first time, we describe ILD in an 82-year-old woman with muscle invasive bladder cancer 10 days after receiving cetuximab as part of a novel trial. She had no significant medical history or drug allergies, had good exercise tolerance and a 5 pack-year smoking history. She received neoadjuvant chemotherapy (gemcitabine, cisplatin) with a good response on MRI. She was eligible for a phase 2 trial of cetuximab with chemotherapy and radiotherapy for muscle invasive bladder cancer (TUXEDO), in which the trial arm used cetuximab plus standard chemoradiotherapy to the bladder (64 grey in 32 fractions plus mitomycinandfluorouracil). Ten days after her third infusion of cetuximab, she was presented with type 1 respiratory failure. Thoracic CT scan demonstrated new widespread ground glass change in the lungs. She received high-dose steroids (prednisolone 1 mg/kg), broad spectrum antibacterial cover and non-invasive ventilation. She survived to be discharged with residual respiratory failure. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Previous Bladder Cancer History in Patients with High-Risk, Non-muscle-invasive Bladder Cancer Correlates with Recurrence and Progression: Implications of Natural History.

PubMed

Mitrakas, Lampros P; Zachos, Ioannis V; Tzortzis, Vassileios P; Gravas, Stavros A; Rouka, Erasmia C; Dimitropoulos, Konstantinos I; Vandoros, Gerasimos P; Karatzas, Anastasios D; Melekos, Michael D; Papavassiliou, Athanasios G

2015-07-01

The purpose of this study was to assess the correlation of previous bladder cancer history with the recurrence and progression of patients with high-risk non-muscle-invasive bladder cancer treated with adjuvant Bacillus Calmette-Guérin (BCG) and to evaluate their natural history. Patients were divided into two groups based on the existence of previous bladder cancer (primary, non-primary). A logistic regression analysis was used to identify the possible differences in the probabilities of recurrence and progression with respect to tumor history, while potential differences due to gender, tumor size (> 3 cm, < 3 cm), stage (pTa, T1), concomitant carcinoma in situ (pTis) and number of tumors (single, multiple) were also assessed. Univariate and multivariate models were employed. In addition, Kaplan-Meier survival analysis was used to compare recurrence- and progression-free survival between the groups. A total of 192 patients were included (144 with primary and 48 with non-primary tumors). The rates of recurrence and progression for patients with primary tumors were 27.8% and 12.5%, respectively. The corresponding percentages for patients with non-primary tumors were 77.1% and 33.3%, respectively. The latter group of patients displayed significantly higher probabilities of recurrence (p=0.000; 95% confidence interval [CI], 4.067 to 18.804) and progression (p=0.002; 95% CI, 1.609 to 7.614) in a univariate logistic regression analysis. Previous bladder cancer history remained significant in the multivariate model accounting for history, age, gender, tumor size , number of tumors, stage and concomitant pTis (p=0.000; 95% CI, 4.367 to 21.924 and p=0.002; 95% CI, 1.611 to 8.182 for recurrence and progression respectively). Kaplan-Meier curves revealed that the non-primary group hadreduced progression- and recurrence-free survival. Previous non-muscle-invasive bladder cancer history correlates significantly with recurrence and progression in patients with high-risk non-muscle-invasive disease treated with adjuvant BCG.

Expression analysis and clinical significance of CXCL16/CXCR6 in patients with bladder cancer.

PubMed

Lee, Jun Taik; Lee, Sang Don; Lee, Jeong Zoo; Chung, Moon Kee; Ha, Hong Koo

2013-01-01

The interactions between chemokines and their receptors are closely involved in the progression and metastasis of cancer. We hypothesized that the CXCL16-CXCR6 ligand-receptor system plays an important role in bladder cancer progression. To evaluate this hypothesis, the expression levels of CXCL16 and CXCR6 were evaluated in 160 patients, including 155 patients with bladder cancer and 5 patients with benign bladder disease. The tissues were analyzed by immunohistochemical (IHC) staining and real-time reverse-transcription polymerase chain reaction. We compared the expression of CXCL16/CXCR6 in bladder cancer and benign bladder disease. The expression of CXCR6 was increased in patients with bladder cancer compared with benign bladder disease in RT-PCR. The mRNA expression levels of CXCL16 and CXCR6 were 1.75×10(-2) and 1.99×10(-2) in benign bladder tissue and 1.39×10(-2) and 2.32×10(-2) in bladder cancer tissue, respectively. In IHC staining, the expression of CXCL16/CXCR6 in bladder cancer tissues was higher compared with benign bladder tissues. On multivariate analysis, the IHC staining of CXCL16 was correlated with the 2004 WHO grade and lymphovascular invasion (P=0.021 and P=0.011, respectively). CXCR6 was correlated with the 1973 WHO grade (P=0.001), 2004 WHO grade (P<0.001), pathological T stage (P=0.002) and perineural invasion (P=0.031). However, Cox regression analysis revealed that the expression of CXCL16 and CXCR6 was not correlated with cancer recurrence and cancer-specific survival (P=0.142 and P=0.324, respectively). The expression of CXCL16/CXCR6 was higher in bladder cancer compared to benign disease and correlated with aggressive cancer behavior. Based on our results, the CXCL16/CXCR6 axis appears to be important in the progression of bladder cancer. Thus, CXCL16 and CXCR6 serve as potential therapeutic targets.

Inhibition of bladder overactivity by a combination of tibial neuromodulation and tramadol treatment in cats

PubMed Central

Zhang, Fan; Mally, Abhijith D.; Ogagan, P. Dafe; Shen, Bing; Wang, Jicheng; Roppolo, James R.; de Groat, William C.

2012-01-01

Our recent study in cats revealed that inhibition of bladder overactivity by tibial nerve stimulation (TNS) depends on the activation of opioid receptors. TNS is a minimally invasive treatment for overactive bladder (OAB), but its efficacy is low. Tramadol (an opioid receptor agonist) is effective in treating OAB but elicits significant adverse effects. This study was to determine if a low dose of tramadol (expected to produce fewer adverse effects) can enhance the TNS inhibition of bladder overactivity. Bladder overactivity was induced in α-chloralose-anesthetized cats by an intravesical infusion of 0.25% acetic acid (AA) during repeated cystometrograms (CMGs). TNS (5 Hz) at two to four times the threshold intensity for inducing toe movement was applied during CMGs before and after tramadol (0.3–7 mg/kg iv) to examine the interaction between the two treatments. AA irritation significantly reduced bladder capacity to 24.8 ± 3.3% of the capacity measured during saline infusion. TNS alone reversibly inhibited bladder overactivity and significantly increased bladder capacity to 50–60% of the saline control capacity. Tramadol administered alone in low doses (0.3–1 mg/kg) did not significantly change bladder capacity, whereas larger doses (3–7 mg/kg) increased bladder capacity (50–60%). TNS in combination with tramadol (3–7 mg/kg) completely reversed the effect of AA. Tramadol also unmasked a prolonged (>2 h) TNS inhibition of bladder overactivity that persisted after termination of the stimulation. The results suggest a novel treatment strategy for OAB by combining tibial neuromodulation with a low dose of tramadol, which is minimally invasive with a potentially high efficacy and fewer adverse effects. PMID:22496406

The Involvement of Hepatocyte Growth Factor-MET-Matrix Metalloproteinase 1 Signaling in Bladder Cancer Invasiveness and Proliferation. Effect of the MET Inhibitor, Cabozantinib (XL184), on Bladder Cancer Cells.

PubMed

Shintani, Terumichi; Kusuhara, Yoshito; Daizumoto, Kei; Dondoo, Tsogt-Ochir; Yamamoto, Hiroki; Mori, Hidehisa; Fukawa, Tomoya; Nakatsuji, Hiroyoshi; Fukumori, Tomoharu; Takahashi, Masayuki; Kanayama, Hiroomi

2017-03-01

To clarify the invasive mechanisms of muscle-invasive bladder cancer (BCa) would be useful for the determination of appropriate treatment strategies. We previously showed that hepatocyte growth factor (HGF)-MET signaling is correlated with invasiveness of BCa cells. Here, we investigated the effects of the MET inhibitor, cabozantinib (XL184), on BCa cells. We first conducted Western blot analysis to investigate MET expression in BCa cell lines. Next, we examined the effect of cabozantinib on their proliferation and invasive abilities using MTT and Matrigel invasion assays, respectively. Invasion assays were performed using the xCELLigence system. Additionally, to investigate the biological function of HGF-MET signaling, we analyzed gene expression profiles and performed real-time polymerase chain reaction analyses of 5637 cells that were cultivated with or without HGF stimulation, with or without cabozantinib. MET was highly expressed in 4 of 5 BCa cell lines, and 5637 and T24 cells showed especially high protein expression of MET. Cabozantinib suppressed cell proliferation and invasion (cell index; mock, 1.49 vs HGF, 2.26 vs HGF + XL184, 1.47, P < .05). Gene expression profile analysis indicated that matrix metalloproteinase 1 (MMP1) was significantly elevated at the mRNA level with addition of HGF. Moreover, cabozantinib suppressed HGF-induced MMP1 expression in 5637 T24 cells. These data indicate that cabozantinib suppressed MMP1 expression by blocking HGF-MET signaling and that HGF-MET-MMP1 signaling is involved in the invasiveness and proliferation of BCa cells. These results suggest that cabozantinib might prove useful for future treatment of muscle-invasive BCa. Copyright © 2016 Elsevier Inc. All rights reserved.

Clinical utility of three-dimensional contrast-enhanced ultrasound in the differentiation between noninvasive and invasive neoplasms of urinary bladder.

PubMed

Li, Qiu-yang; Tang, Jie; He, En-hui; Li, Yan-mi; Zhou, Yun; Zhang, Xu; Chen, Guangfu

2012-11-01

The purpose of this study was to evaluate the effectiveness of three-dimensional contrast-enhanced ultrasound in differentiating invasive and noninvasive neoplasms of urinary bladder. A total of 60 lesions in 60 consecutive patients with bladder tumors received three dimensional ultrasonography, low acoustic power contrast enhanced ultrasonography and low acoustic power three-dimensional contrast-enhanced ultrasound examination. The IU22 ultrasound scanner and a volume transducer were used and the ultrasound contrast agent was SonoVue. The contrast-specific sonographic imaging modes were PI (pulse inversion) and PM (power modulation). The three dimensional ultrasonography, contrast enhanced ultrasonography, and three-dimensional contrast-enhanced ultrasound images were independently reviewed by two readers who were not in the images acquisition. Images were analyzed off-site. A level of confidence in the diagnosis of tumor invasion of the muscle layer was assigned on a 5° scale. Receiver operating characteristic analysis was used to assess overall confidence in the diagnosis of muscle invasion by tumor. Kappa values were used to assess inter-readers agreement. Histologic diagnosis was obtained for all patients. Final pathologic staging revealed 44 noninvasive tumors and 16 invasive tumors. Three-dimensional contrast-enhanced ultrasound depicted all 16 muscle-invasive tumors. The diagnostic performance of three-dimensional contrast-enhanced ultrasound was better than those of three dimensional ultrasonography and contrast enhanced ultrasonography. The receiver operating characteristic curves were 0.976 and 0.967 for three-dimensional contrast-enhanced ultrasound, those for three dimensional ultrasonography were 0.881 and 0.869, those for contrast enhanced ultrasonography were 0.927 and 0.929. The kappa values in the three dimensional ultrasonography, contrast enhanced ultrasonography and three-dimensional contrast-enhanced ultrasound for inter-reader agreements were 0.717, 0.794 and 0.914. Three-dimensional contrast-enhanced ultrasound imaging, with contrast-enhanced spatial visualization is clinical useful for differentiating invasive and noninvasive neoplasms of urinary bladder objectively. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Interstitial cystitis/bladder pain syndrome: diagnosis and management.

PubMed

Offiah, I; McMahon, S B; O'Reilly, B A

2013-08-01

The bladder pain syndrome (BPS) is a spectrum of urological symptoms characterised by bladder pain with typical cystoscopic features. Diagnosis and management of this syndrome may be difficult. There is no evidence-based management approach for the diagnosis or treatment of BPS. The objective of this study was to critically review and summarise the evidence relating to the diagnosis and treatment of the bladder pain syndrome. A review of published data on the diagnosis and treatment of the BPS was performed. Our search was limited to English-language articles, on the "diagnosis", and "management" or "treatment" of "interstitial cystitis" and the "bladder pain syndrome" in "humans." Frequency, urgency and pain on bladder filling are the most common symptoms of BPS. All urodynamic volumes are reduced in patients with BPS. Associated conditions include psychological distress, depression, history of sexual assault, irritable bowel syndrome and fibromyalgia. Cystoscopy remains the test for definitive diagnosis, with visualisation of haemorrhage on cystoreduction. A multidisciplinary treatment approach is essential in the management of this condition. Orally administered amitriptyline is an efficacious medical treatment for BPS. Intravesical hyaluronic acid and local anaesthetic, with/without hydrodistension are among new treatment strategies. Sacral or pudendal neuromodulation is effective, minimally invasive and safe. Surgery is reserved for refractory cases. There remains a paucity of evidence for the diagnosis and treatment of BPS. We encountered significant heterogeneity in the assessment of symptoms, duration of treatment and follow up of patients in our literature review.

Advancements in optical techniques and imaging in the diagnosis and management of bladder cancer.

PubMed

Rose, Tracy L; Lotan, Yair

2018-03-01

Accurate detection and staging is critical to the appropriate management of urothelial cancer (UC). The use of advanced optical techniques during cystoscopy is becoming more widespread to prevent recurrent nonmuscle invasive bladder cancer. Standard of care for muscle-invasive UC includes the use of computed tomography and/or magnetic resonance imaging, but staging accuracy of these tests remains imperfect. Novel imaging modalities are being developed to improve current test performance. Positron emission tomography/computed tomography has a role in the initial evaluation of select patients with muscle-invasive bladder cancer and in disease recurrence in some cases. Several novel immuno-positron emission tomography tracers are currently in development to address the inadequacy of current imaging modalities for monitoring of tumor response to newer immune-based treatments. This review summaries the current standards and recent advances in optical techniques and imaging modalities in localized and metastatic UC. Copyright © 2018 Elsevier Inc. All rights reserved.

N-acetyltransferase 2 gene polymorphism as a biomarker for susceptibility to bladder cancer in Bangladeshi population.

PubMed

Hosen, Md Bayejid; Islam, Jahidul; Salam, Md Abdus; Islam, Md Fakhrul; Hawlader, M Zakir Hossain; Kabir, Yearul

2015-03-01

To investigate the association between the three most common single nucleotide polymorphisms of the N-acetyltransferase 2 gene together with cigarette smoking and the risk of developing bladder cancer and its aggressiveness. A case-control study on 102 bladder cancer patients and 140 control subjects was conducted. The genomic DNA was extracted from peripheral white blood cells and N-acetyltransferase 2 alleles were differentiated by polymerase chain reaction-based restriction fragment length polymorphism methods. Bladder cancer risk was estimated as odds ratio and 95% confidence interval using binary logistic regression models adjusting for age and gender. Overall, N-acetyltransferase 2 slow genotypes were associated with bladder cancer risk (odds ratio=4.45; 95% confidence interval=2.26-8.77). The cigarette smokers with slow genotypes were found to have a sixfold increased risk to develop bladder cancer (odds ratio=6.05; 95% confidence interval=2.23-15.82). Patients with slow acetylating genotypes were more prone to develop high-grade (odds ratio=6.63; 95% confidence interval=1.15-38.13; P<0.05) and invasive (odds ratio=10.6; 95% confidence interval=1.00-111.5; P=0.05) tumor. N-acetyltransferase 2 slow genotype together with tobacco smoking increases bladder cancer risk. Patients with N-acetyltransferase 2 slow genotypes were more likely to develop a high-grade and invasive tumor. N-acetyltransferase 2 slow genotype is an important genetic determinant for bladder cancer in Bangladesh population. © 2014 Wiley Publishing Asia Pty Ltd.

Chromium in urothelial carcinoma of the bladder.

PubMed

Golabek, Tomasz; Socha, Katarzyna; Kudelski, Jacek; Darewicz, Barbara; Markiewicz-Zukowska, Renata; Chlosta, Piotr; Borawska, Maria

2017-12-23

Many epidemiological and experimental studies report a strong role of chemical carcinogens in the etiology of bladder cancer. However, the involvement of heavy metals in tumourigenesis of urothelial carcinoma of the bladder has been poorly investigated. Therefore, the aim of this study was to examine the relationship between chromium (Cr) and bladder cancer. Chromium concentration in two 36-sample series of bladder cancer tissue and sera from patients with this neoplasm were matched with those of a control group. The amount of trace elements in every tissue sample was determined using atomic absorption spectrometry. This was correlated with tumour stage. While the median chromium concentration levels reached statistically higher values in the bladder cancer tissue, compared with the non-cancer tissue (99.632ng/g and 33.144ng/g, respectively; p<0.001), the median Cr levels in the sera of the patients with this carcinoma showed no statistical difference when compared to those of the control group (0.511μg/l and 0.710μg/l, respectively; p=0.408). The median levels of Cr in the bladder tissue, depending on the stage of the tumour, compared with the tissue without the neoplasm, observed the same relationship for both non-muscle invasive and muscle-invasive tumours (p<0.001 and p<0.01, respectively). This study shows that patients with urothelial carcinoma of the bladder had higher tissue Cr levels than people without tumour, while no difference was found in the Cr serum levels between the two groups of patients under investigation.

Safety of three sequential whole bladder photodynamic therapy (WBPDT) treatments in the management of resistant bladder cancer

NASA Astrophysics Data System (ADS)

Mejia, Maria C.; Nseyo, Unyime O.

2009-02-01

INTRODUCTION: WBPDT has been used to treat resistant superficial bladder cancer, with clinical benefits and associated dose-dependent side effects. OBJECTIVE: The objective of this study was to assess the safety of three sequential WBPDT treatments in patients with resistant non-muscle invasive (NMI) bladder cancer. MATERIALS AND METHODS: 12 males and one female provided written informed consent in this Phase II study. Each patient received intravenous injection of Photofrin® (AXCAN Parma Inc, Canada) at 1.5 mg/kg two days prior to whole bladder laser (630nm) treatment. Assessment of safety and efficacy included weekly urinary symptoms; cystoscopy, biopsy and cytology; and measurement of bladder volume quarterly after each treatment at baseline, six and 12 months. Treatment #2 and/or #3 occurred only in the absence of bladder contracture, and/or disease progression. RESULTS: 13 patients: 12 males and one female have been enrolled and average age of enrollees is 67.1(52 - 87) years. Four patients had Ta-T1/Grade I-III tumors; two patients had CIS associated with T1/GI-III; and seven patients had carcinoma in situ (CIS) only. Three patients received 3/3 treatments, and are evaluable for toxicity; three patients received two treatments only; and seven patients received one treatment only. There was no bladder contracture; transient mild to moderate bladder irritative voiding symptoms of dysuria, urinary frequency, nocturia and urgency occurred in all patients. The three evaluable patients were without evidence of disease at average of 13.1 (7-20) months. CONCLUSION: Three sequential WBPDT treatments might have a favorable toxicity profile in the management of recurrent/ refractory non-muscle invasive bladder cancer.

Reduced glucocorticoid receptor expression predicts bladder tumor recurrence and progression.

PubMed

Ishiguro, Hitoshi; Kawahara, Takashi; Zheng, Yichun; Netto, George J; Miyamoto, Hiroshi

2014-08-01

To assess the levels of glucocorticoid receptor (GR) expression in bladder tumors because the status and its prognostic value remain largely unknown. We immunohistochemically stained for GR in bladder tumor and matched non-neoplastic bladder tissue specimens. Overall, GR was positive in 129 (87%) of 149 urothelial tumors, which was significantly (P=.026) lower than in non-neoplastic urothelium (90 [96%] of 94). Forty-two (79%) of 53 low-grade tumors vs 45 (47%) of 96 high-grade carcinomas (P<.001) and 61 (73%) of 84 non-muscle-invasive (NMI) tumors vs 26 (40%) of 65 muscle-invasive (MI) carcinomas (P<.001) were moderately to strongly immunoreactive for GR. Kaplan-Meier and log-rank tests revealed that loss or weak positivity of GR significantly or marginally correlated with recurrence of NMI tumors (P=.025), progression of MI tumors (P=.082), and cancer-specific survival of MI tumors (P=.067). Multivariate analysis identified low GR expression as a strong predictor for recurrence of NMI tumors (P=.034). GR expression was downregulated in bladder tumors compared with nonneoplastic bladder tumors and in high-grade/MI tumors compared with low-grade/NMI tumors. Decreased expression of GR, as an independent prognosticator, predicted recurrence of NMI tumors. These results support experimental evidence suggesting an inhibitory role of GR signals in bladder cancer outgrowth. Copyright© by the American Society for Clinical Pathology.

Prognostic value of cell cycle regulatory proteins in muscle-infiltrating bladder cancer.

PubMed

Galmozzi, Fabia; Rubagotti, Alessandra; Romagnoli, Andrea; Carmignani, Giorgio; Perdelli, Luisa; Gatteschi, Beatrice; Boccardo, Francesco

2006-12-01

The aims of this study were to investigate the expression levels of proteins involved in cell cycle regulation in specimens of bladder cancer and to correlate them with the clinicopathological characteristics, proliferative activity and survival. Eighty-two specimens obtained from patients affected by muscle-invasive bladder cancer were evaluated immunohistochemically for p53, p21 and cyclin D1 expression, as well as for the tumour proliferation index, Ki-67. The statistical analysis included Kaplan-Meier curves with log-rank test and Cox proportional hazards models. In univariate analyses, low Ki-67 proliferation index (P = 0.045) and negative p21 immunoreactivity (P = 0.04) were associated to patient's overall survival (OS), but in multivariate models p21 did not reach statistical significance. When the combinations of the variables were assessed in two separate multivariate models that included tumour stage, grading, lymph node status, vascular invasion and perineural invasion, the combined variables p21/Ki-67 or p21/cyclin D1 expression were independent predictors for OS; in particular, patients with positive p21/high Ki-67 (P = 0.015) or positive p21/negative cyclin D1 (P = 0.04) showed the worst survival outcome. Important alterations in the cell cycle regulatory pathways occur in muscle-invasive bladder cancer and the combined use of cell cycle regulators appears to provide significant prognostic information that could be used to select the patients most suitable for multimodal therapeutic approaches.

Spatial and temporal profile of cisplatin delivery by ultrasound-assisted intravesical chemotherapy in a bladder cancer model.

PubMed

Sasaki, Noboru; Ishi, Kazuhiro; Kudo, Nobuki; Nakayama, Shouta M M; Nakamura, Kensuke; Morishita, Keitaro; Ohta, Hiroshi; Ishizuka, Mayumi; Takiguchi, Mitsuyoshi

2017-01-01

Non-muscle invasive bladder cancer is one of the most common tumors of the urinary tract. Despite the current multimodal therapy, recurrence and progression of disease have been challenging problems. We hereby introduced a new approach, ultrasound-assisted intravesical chemotherapy, intravesical instillation of chemotherapeutic agents and microbubbles followed by ultrasound exposure. We investigated the feasibility of the treatment for non-muscle invasive bladder cancer. In order to evaluate intracellular delivery and cytotoxic effect as a function to the thickness, we performed all experiments using a bladder cancer mimicking 3D culture model. Ultrasound-triggered microbubble cavitation increased both the intracellular platinum concentration and the cytotoxic effect of cisplatin at the thickness of 70 and 122 μm of the culture model. The duration of enhanced cytotoxic effect of cisplatin by ultrasound-triggered microbubble cavitation was approximately 1 hr. Based on the distance and duration of delivery, we further tested the feasibility of repetition of the treatment. Triple treatment increased the effective distance by 1.6-fold. Our results clearly showed spatial and temporal profile of delivery by ultrasound-triggered microbubble cavitation in a tumor-mimicking structure. Furthermore, we demonstrated that the increase in intracellular concentration results in the enhancement of the cytotoxic effect in a structure with the certain thickness. Repetition of ultrasound exposure would be treatment of choice in future clinical application. Our results suggest ultrasound-triggered microbubble cavitation can be repeatable and is promising for the local control of non-muscle invasive bladder cancer.

Molecular subtypes of bladder cancer: Jekyll and Hyde or chalk and cheese?

PubMed

Knowles, Margaret A

2006-03-01

Cancer of the bladder shows divergent clinical behaviour following diagnosis and it has been proposed that two major groups of tumours exist that develop via different molecular pathways. Low-grade, non-invasive papillary tumours recur frequently, but patients with these tumours do not often suffer progression of disease to muscle invasion. In contrast, tumours that are invading muscle at diagnosis are aggressive and associated with significant mortality. Molecular studies have identified distinct genetic, epigenetic and expression changes in these groups. However, it is not yet clear whether there is direct progression of low-grade superficial tumours to become invasive (a Jeckell and Hyde scenario) or whether in those patients who apparently progress from one form of the disease to the other, different tumour clones are involved and that the two tumour groups are mutually exclusive ('chalk and cheese'). If the latter is true, then attempts to identify molecular markers to predict progression of low-grade superficial bladder tumours may be fruitless. Similarly, it is not clear whether other subgroups of tumours exist that arise via different molecular pathways. There is now a large amount of molecular information about bladder cancer that facilitates examination of these possibilities. Some recent studies provide evidence for the existence of at least one further group of tumours, high-grade superficial papillary tumours, which may develop via a distinct molecular pathway. Patients with such tumours do show increased risk of disease progression and for these there may exist a real progression continuum from non-invasive to invasive. If this is the case, definition of the molecular signature of this pathway and improved understanding of the biological consequences of the events involved will be pivotal in disease management.

Cigarette smoke induced urocystic epithelial mesenchymal transition via MAPK pathways.

PubMed

Yu, Dexin; Geng, Hao; Liu, Zhiqi; Zhao, Li; Liang, Zhaofeng; Zhang, Zhiqiang; Xie, Dongdong; Wang, Yi; Zhang, Tao; Min, Jie; Zhong, Caiyun

2017-01-31

Cigarette smoke has been shown to be a major risk factor for bladder cancer. Epithelial-mesenchymal transition (EMT) is a crucial process in cancer development. The role of MAPK pathways in regulating cigarette smoke-triggered urocystic EMT remains to be elucidated. Human normal urothelial cells and BALB/c mice were used as in vitro and in vivo cigarette smoke exposure models. Exposure of human normal urothelial cells to cigarette smoke induced morphological change, enhanced migratory and invasive capacities, reduced epithelial marker expression and increased mesenchymal marker expression, along with the activation of MAPK pathways. Moreover, we revealed that ERK1/2 and p38 inhibitors, but rather JNK inhibitor, effectively attenuated cigarette smoke-induced urocystic EMT. Importantly, the regulatory function of ERK1/2 and p38 pathways in cigarette smoke-triggered urocystic EMT was further confirmed in mice exposed to CS for 12 weeks. These findings could provide new insight into the molecular mechanisms of cigarette smoke-associated bladder cancer development as well as its potential intervention.

Sniffer mice discriminate urine odours of patients with bladder cancer: A proof-of-principle study for non-invasive diagnosis of cancer-induced odours.

PubMed

Sato, Takaaki; Katsuoka, Yoji; Yoneda, Kimihiko; Nonomura, Mitsuo; Uchimoto, Shinya; Kobayakawa, Reiko; Kobayakawa, Ko; Mizutani, Yoichi

2017-11-07

Similar to fingerprints, humans have unique, genetically determined body odours. In case of urine, the odour can change due to variations in diet as well as upon infection or tumour formation. We investigated the use of mice in a manner similar to "sniffer dogs" to detect changes in urine odour in patients with bladder cancer. We measured the odour discrimination thresholds of mice in a Y-maze, using urine mixtures from patients with bladder cancer (Stage I) and healthy volunteers (dietary variations) as well as occult blood- or antibiotic drug metabolite-modulated samples. Threshold difference indicated that intensities of urinary olfactory cues increase in the following order: dietary variation < bladder cancer < occult blood < antibiotic drug metabolites. After training with patient urine mixtures, sniffer mice discriminated between urine odours of pre- and post-transurethral resection in individual patients with bladder cancer in an equal-occult blood diluted condition below the detection level of dietary variations, achieving a success rate of 100% (11/11). Furthermore, genetic ablation of all dorsal olfactory receptors elevated the discrimination thresholds of mice by ≥ 10 5 -fold. The marked reduction in discrimination sensitivity indicates an essential role of the dorsal olfactory receptors in the recognition of urinary body odours in mice.

Androgen receptor activation: a prospective therapeutic target for bladder cancer?

PubMed

Mizushima, Taichi; Tirador, Kathleen A; Miyamoto, Hiroshi

2017-03-01

Patients with non-muscle-invasive or muscle-invasive bladder cancer undergoing surgery and currently available conventional therapy remain having a high risk of tumor recurrence or progression, respectively. Novel targeted molecular therapy is therefore expected to improve patient outcomes. Meanwhile, substantially higher incidence of bladder cancer in men has prompted research on androgen-mediated androgen receptor (AR) signaling in this malignancy. Indeed, preclinical evidence has suggested that AR signaling plays an important role in urothelial carcinogenesis and tumor outgrowth as well as resistance to some of the currently available conventional non-surgical therapies. Areas covered: We summarize and discuss available data suggesting the involvement of AR and its potential downstream targets in the development and progression of bladder cancer. Associations between AR signaling and sensitivity to cisplatin/doxorubicin or bacillus Calmette-Guérin treatment are also reviewed. Expert opinion: AR activation is likely to correlate with the promotion of urothelial carcinogenesis and cancer outgrowth as well as resistance to conventional therapies. Molecular therapy targeting the AR may thus provide effective chemopreventive and therapeutic approaches for urothelial cancer. Accordingly, bladder cancer can now be considered as an endocrine-related neoplasm. Clinical application of various anti-AR therapies available for AR-dependent prostate cancer to bladder cancer patients is anticipated.

LYMPHOEPITHELIOMA-LIKE CARCINOMA OF THE URINARY BLADDER ASSOCIATED WITH SCHISTOSOMIASIS: A CASE REPORT AND REVIEW OF LITERATURE.

PubMed

Mina, Samir N; Antonios, Sanaa N

2015-08-01

Lymphoepithelioma-like carcinoma is an undifferentiated carcinoma with histological features similar to undifferentiated, non-keratinizing carcinoma of the nasopharynx. Lymphoepithelioma-like carcinoma of the urinary bladder is uncommon with a reported. incidence of 0.4% -1.3% of all bladder cancers. This case describes an 80 years old Egyptian male patient presented with recurrent hematuria and necroturia. Cystoscopy revealed a tumor involving the left lateral and the posterior wall of the urinary bladder. The patient underwent transurethral resection of the bladder tumor. Pathological examination showed muscle invasive lymphoepithelioma-like carcinoma associated with schistosomiasis of the urinary bladder. To the best of our knowledge the association of schistosomiasis with lymphoepithelioma-like bladder cancer was not described in the literature before this case report.

Using microRNA profiling in urine samples to develop a non-invasive test for bladder cancer.

PubMed

Mengual, Lourdes; Lozano, Juan José; Ingelmo-Torres, Mercedes; Gazquez, Cristina; Ribal, María José; Alcaraz, Antonio

2013-12-01

Current standard methods used to detect and monitor bladder urothelial cell carcinoma (UCC) are invasive or have low sensitivity. The incorporation into clinical practice of a non-invasive tool for UCC assessment would enormously improve patients' quality of life and outcome. This study aimed to examine the microRNA (miRNA) expression profiles in urines of UCC patients in order to develop a non-invasive accurate and reliable tool to diagnose and provide information on the aggressiveness of the tumor. We performed a global miRNA expression profiling analysis of the urinary cells from 40 UCC patients and controls using TaqMan Human MicroRNA Array followed by validation of 22 selected potentially diagnostic and prognostic miRNAs in a separate cohort of 277 samples using a miRCURY LNA qPCR system. miRNA-based signatures were developed by multivariate logistic regression analysis and internally cross-validated. In the initial cohort of patients, we identified 40 and 30 aberrantly expressed miRNA in UCC compared with control urines and in high compared with low grade tumors, respectively. Quantification of 22 key miRNAs in an independent cohort resulted in the identification of a six miRNA diagnostic signature with a sensitivity of 84.8% and specificity of 86.5% (AUC = 0.92) and a two miRNA prognostic model with a sensitivity of 84.95% and a specificity of 74.14% (AUC = 0.83). Internal cross-validation analysis confirmed the accuracy rates of both models, reinforcing the strength of our findings. Although the data needs to be externally validated, miRNA analysis in urine appears to be a valuable tool for the non-invasive assessment of UCC. Copyright © 2013 UICC.

Future directions in bladder cancer immunotherapy: towards adaptive immunity

PubMed Central

Smith, Sean G; Zaharoff, David A

2016-01-01

The clinical management of bladder cancer has not changed significantly in several decades. In particular, intravesical bacillus Calmette–Guérin (BCG) immunotherapy has been a mainstay for high-risk nonmuscle invasive bladder cancer since the late 1970s/early 1980s. This is despite the fact that bladder cancer has the highest recurrence rates of any cancer and BCG immunotherapy has not been shown to induce a tumor-specific immune response. We and others have hypothesized that immunotherapies capable of inducing tumor-specific adaptive immunity are needed to impact bladder cancer morbidity and mortality. This article summarizes the preclinical and clinical development of bladder cancer immunotherapies with an emphasis on the last 5 years. Expected progress in the near future is also discussed. PMID:26860539

Future directions in bladder cancer immunotherapy: towards adaptive immunity.

PubMed

Smith, Sean G; Zaharoff, David A

2016-01-01

The clinical management of bladder cancer has not changed significantly in several decades. In particular, intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been a mainstay for high-risk nonmuscle invasive bladder cancer since the late 1970s/early 1980s. This is despite the fact that bladder cancer has the highest recurrence rates of any cancer and BCG immunotherapy has not been shown to induce a tumor-specific immune response. We and others have hypothesized that immunotherapies capable of inducing tumor-specific adaptive immunity are needed to impact bladder cancer morbidity and mortality. This article summarizes the preclinical and clinical development of bladder cancer immunotherapies with an emphasis on the last 5 years. Expected progress in the near future is also discussed.

Expression analysis and clinical significance of CXCL16/CXCR6 in patients with bladder cancer

PubMed Central

LEE, JUN TAIK; LEE, SANG DON; LEE, JEONG ZOO; CHUNG, MOON KEE; HA, HONG KOO

2013-01-01

The interactions between chemokines and their receptors are closely involved in the progression and metastasis of cancer. We hypothesized that the CXCL16-CXCR6 ligand-receptor system plays an important role in bladder cancer progression. To evaluate this hypothesis, the expression levels of CXCL16 and CXCR6 were evaluated in 160 patients, including 155 patients with bladder cancer and 5 patients with benign bladder disease. The tissues were analyzed by immunohistochemical (IHC) staining and real-time reverse-transcription polymerase chain reaction. We compared the expression of CXCL16/CXCR6 in bladder cancer and benign bladder disease. The expression of CXCR6 was increased in patients with bladder cancer compared with benign bladder disease in RT-PCR. The mRNA expression levels of CXCL16 and CXCR6 were 1.75×10−2 and 1.99×10−2 in benign bladder tissue and 1.39×10−2 and 2.32×10−2 in bladder cancer tissue, respectively. In IHC staining, the expression of CXCL16/CXCR6 in bladder cancer tissues was higher compared with benign bladder tissues. On multivariate analysis, the IHC staining of CXCL16 was correlated with the 2004 WHO grade and lymphovascular invasion (P=0.021 and P=0.011, respectively). CXCR6 was correlated with the 1973 WHO grade (P=0.001), 2004 WHO grade (P<0.001), pathological T stage (P=0.002) and perineural invasion (P=0.031). However, Cox regression analysis revealed that the expression of CXCL16 and CXCR6 was not correlated with cancer recurrence and cancer-specific survival (P=0.142 and P=0.324, respectively). The expression of CXCL16/CXCR6 was higher in bladder cancer compared to benign disease and correlated with aggressive cancer behavior. Based on our results, the CXCL16/CXCR6 axis appears to be important in the progression of bladder cancer. Thus, CXCL16 and CXCR6 serve as potential therapeutic targets. PMID:23255926

Can re-cTURBT be useful in pT1HG disease as a risk indicator of recurrence and progression? A single centre experience.

PubMed

Giulianelli, Roberto; Gentile, Barbara Cristina; Mirabile, Gabriella; Albanesi, Luca; Tariciotti, Paola; Rizzo, Giorgio; Buscarini, Maurizio; Vermiglio, Mauro

2017-12-31

Understaging after initial transurethral resection is common in patients with high-risk non muscle infiltrating bladder cancer (NMIBC) and can delay accurate diagnosis and definitive treatment. The rate of upstaging from T1 to T2 disease after repeated transurethral resection ranges from 0 to 28%, although the rate of upstaging may be even higher up to 49% when muscularis propria is absent in the first specimen. A restaging classic transurethral resection of bladder tumour (re-cTURBT) is the better predictor of early stage progression. According to some reports, the rate of positivity for tumor in re-cTURBT performed within eight weeks after initial cTURBT was as high as 18-77%, and in about 40% of the patients a change in tumor stage was reported. We aimed to investigate, in high risk group, the presence of residual tumor following white light classical transurethral resection of bladder tumor (WLre-cTURBT) and the different recurrence and progression rate between patients with persistent or negative (pT0) oncological disease after WLre-cTURBT. A cohort of 285 patients presenting with primitive bladder cancer underwent to WLcTURBT from January 2011 to December 2015; out of them 92 (32.28%) were T1HG. In according to EAU guidelines 2011, after 4-6 weeks all HG bladder cancer patients underwent a WL recTURBT . All patients were submitted to a subsequent followup including cystoscopy every 3 months with multiple biopsies, randomly and in the previous zone of resection; urinary citology on 3 specimens and kidney/bladder ultrasound every 6 months. The average follow-up was 48 months. Following WLre-cTURBT we observed a persistent disease in 18 (15.2%) patients: 14 (77.7%) with a HG-NMIBC and 4 (22.2%) with a high grade (HG) muscle invasive bladder cancer (pT2HG). After follow up of all 92 patients according to the guidelines EAU, we observed recurrence in 36/92 (39.1%) and progression in 14/92 (15.2%). Of 14 NMIBC with persistent disease, 10 patients (71.4%) showed recurrence: 4 patients (40%) were pT1HG with concomitant carcinoma in situ (CIS), 3 patients (30%) multifocal pTaHG, 2 (20%) patients CIS and one patient (10%) a muscle invasive neoplasm (pT2HG). Instead of the group of 48 patients pT0 following WL recTURBT, we observed recurrence in 26 patients (54.1%) and in two patients (4.1%) progressions, who presented after 3 months in association with CIS. The remaining 22 patients (45.9%) with initial pT1HG are still progression free. Multivariate analysis showed that the most important variable of early progression were persistent neoplasm and histopathological findings at WLre-cTURBt (p = 0.01), followed by the Summary No conflict of interest declared. INTRODUCTION Bladder cancer is a common genito-urinary malignancy, with transitional cell carcinoma comprising nearly 90% of all primary bladder tumours. At the first diagnosis 70% to 80% of urothelial tumours are confined to the epithelium, the remainder is characterized by muscle invasion. A significant number of patients with high risk non-muscle invasive bladder tumours (HG-NMIBT) treated with white light classic transurethral resection of bladder tumours (WLcTURBT) and intravesical BCG will progress to invasive disease (1-3). Progression to muscle invasion (pT2) mandates immediate radical cystectomy (4). WLcTURBT is the standard initial therapy for NMIBT, but the high percentage of recurrence after surgery is still an unresolved problem (5). High grade pT1 bladder neoplasm (pT1HG) really represents a therapeutic challenge due to the high risk of progression (about 15-30%) to muscle-invasive disease, usually within 5 years (6). However, no consensus exists regarding the treatment of patients with recurrent bladder tumours that invade the lamina propria (pT1) (7-9). Recent studies suggested that the first cTURBT may be incomplete in a significant number of cases (10). Understaging at the time of the initial transurethral resection is common for patients with high-risk NMIBC and can delay accurate diagnosis and definitive treatment. It is therefore recommended for patients with high-risk disease and in those with large or multiple tumors or when the initial transurethral resection is incomplete, to repeat WLre-cTURBT within 2-6 DOI: 10.4081/aiua.2017.4.272 result of the first cystoscopy (p = 0.002) and presence of CIS (p = 0.02). Following WLre-cTURBt in HG-NMIBC patients we identified in 15% of cases a persistent disease with a 4.3% of MIBC. In the high risk persistent bladder neoplasms group we observed recurrent and progression rate higher than in T0 bladder tumours group (Δ = + 17.3% and = Δ + 62.5%, p < 0.05.

Significance of Random Bladder Biopsies in Non-Muscle Invasive Bladder Cancer

PubMed Central

Kumano, Masafumi; Miyake, Hideaki; Nakano, Yuzo; Fujisawa, Masato

2013-01-01

Background/Aims To evaluate retrospectively the clinical outcome of random bladder biopsies in patients with non-muscle invasive bladder cancer (NMIBC) undergoing transurethral resection (TUR). Patients and Method This study included 234 consecutive patients with NMIBC who underwent random biopsies from normal-appearing urothelium of the bladder, including the anterior wall, posterior wall, right wall, left wall, dome, trigone and/or prostatic urethra, during TUR. Result Thirty-seven patients (15.8%) were diagnosed by random biopsies as having urothelial cancer. Among several factors available prior to TUR, preoperative urinary cytology appeared to be independently related to the detection of urothelial cancer in random biopsies on multivariate analysis. Urinary cytology prior to TUR gave 50.0% sensitivity, 91.7% specificity, 56.8% positive predictive value and 89.3% negative predictive value for predicting the findings of the random biopsies. Conclusion Biopsies of normal-appearing urothelium resulted in the additional detection of urothelial cancer in a definite proportion of NMIBC patients, and it remains difficult to find a reliable alternative to random biopsies. Collectively, these findings suggest that it would be beneficial to perform random biopsies as part of the routine management of NMIBC. PMID:24917759

Platelet-derived growth factor receptor beta: a novel urinary biomarker for recurrence of non-muscle-invasive bladder cancer.

PubMed

Feng, Jiayu; He, Weifeng; Song, Yajun; Wang, Ying; Simpson, Richard J; Zhang, Xiaorong; Luo, Gaoxing; Wu, Jun; Huang, Chibing

2014-01-01

Non-muscle-invasive bladder cancer (NMIBC) is one of the most common malignant tumors in the urological system with a high risk of recurrence, and effective non-invasive biomarkers for NMIBC relapse are still needed. The human urinary proteome can reflect the status of the microenvironment of the urinary system and is an ideal source for clinical diagnosis of urinary system diseases. Our previous work used proteomics to identify 1643 high-confidence urinary proteins in the urine from a healthy population. Here, we used bioinformatics to construct a cancer-associated protein-protein interaction (PPI) network comprising 16 high-abundance urinary proteins based on the urinary proteome database. As a result, platelet-derived growth factor receptor beta (PDGFRB) was selected for further validation as a candidate biomarker for NMIBC diagnosis and prognosis. Although the levels of urinary PDGFRB showed no significant difference between patients pre- and post-surgery (n = 185, P>0.05), over 3 years of follow-up, urinary PDGFRB was shown to be significantly higher in relapsed patients (n = 68) than in relapse-free patients (n = 117, P<0.001). The levels of urinary PDGFRB were significantly correlated with the risk of 3-year recurrence of NMIBC, and these levels improved the accuracy of a NMIBC recurrence risk prediction model that included age, tumor size, and tumor number (area under the curve, 0.862; 95% CI, 0.809 to 0.914) compared to PDGFR alone. Therefore, we surmise that urinary PDGFRB could serve as a non-invasive biomarker for predicting NMIBC recurrence.

Nanodiamonds facilitate killing of intracellular uropathogenic E. coli in an in vitro model of urinary tract infection pathogenesis.

PubMed

Iyer, Janaki Kannan; Dickey, Alexia; Rouhani, Parvaneh; Kaul, Anil; Govindaraju, Nirmal; Singh, Raj Narain; Kaul, Rashmi

2018-01-01

About 25-44% of women will experience at least one episode of recurrent UTI and the causative agent in over 70% of UTI cases is uropathogenic Escherichia coli (UPEC). UPEC cause recurrent UTI by evading the bladder's innate immune system through internalization into the bladder epithelium where antibiotics cannot reach or be effective. Thus, it is important to develop novel therapeutics to eliminate these intracellular pathogens. Nanodiamonds (NDs) are biocompatible nanomaterials that serve as promising candidates for targeted therapeutic applications. The objective of the current study was to investigate if 6 or 25 nm NDs can kill extracellular and intracellular UPEC in infected bladder cells. We utilized the human bladder epithelial cell line, T24, and an invasive strain of UPEC that causes recurrent UTI. We found that acid-purified 6 nm NDs displayed greater antibacterial properties towards UPEC than 25 nm NDs (11.5% vs 94.2% CFU/mL at 100 μg/mL of 6 and 25 nm, respectively; P<0.001). Furthermore, 6 nm NDs were better than 25 nm NDs in reducing the number of UPEC internalized in T24 bladder cells (46.1% vs 81.1% CFU/mL at 100 μg/mL of 6 and 25 nm, respectively; P<0.01). Our studies demonstrate that 6 nm NDs interacted with T24 bladder cells in a dose-dependent manner and were internalized in 2 hours through an actin-dependent mechanism. Finally, internalization of NDs was required for reducing the number of intracellular UPEC in T24 bladder cells. These findings suggest that 6 nm NDs are promising candidates to treat recurrent UTIs.

Treatment of non-muscle invasive bladder cancer with Bacillus Calmette–Guerin (BCG): Biological markers and simulation studies

PubMed Central

Kiselyov, Alex; Bunimovich-Mendrazitsky, Svetlana; Startsev, Vladimir

2015-01-01

Intravesical Bacillus Calmette–Guerin (BCG) vaccine is the preferred first line treatment for non-muscle invasive bladder carcinoma (NMIBC) in order to prevent recurrence and progression of cancer. There is ongoing need for the rational selection of i) BCG dose, ii) frequency of BCG administration along with iii) synergistic adjuvant therapy and iv) a reliable set of biochemical markers relevant to tumor response. In this review we evaluate cellular and molecular markers pertinent to the immunological response triggered by the BCG instillation and respective mathematical models of the treatment. Specific examples of markers include diverse immune cells, genetic polymorphisms, miRNAs, epigenetics, immunohistochemistry and molecular biology ‘beacons’ as exemplified by cell surface proteins, cytokines, signaling proteins and enzymes. We identified tumor associated macrophages (TAMs), human leukocyte antigen (HLA) class I, a combination of Ki-67/CK20, IL-2, IL-8 and IL-6/IL-10 ratio as the most promising markers for both pre-BCG and post-BCG treatment suitable for the simulation studies. The intricate and patient-specific nature of these data warrants the use of powerful multi-parametral mathematical methods in combination with molecular/cellular biology insight and clinical input. PMID:26673853

Silibinin inhibits β-catenin/ZEB1 signaling and suppresses bladder cancer metastasis via dual-blocking epithelial-mesenchymal transition and stemness.

PubMed

Wu, Kaijie; Ning, Zhongyun; Zeng, Jin; Fan, Jinhai; Zhou, Jiancheng; Zhang, Tingting; Zhang, Linlin; Chen, Yule; Gao, Yang; Wang, Bin; Guo, Peng; Li, Lei; Wang, Xinyang; He, Dalin

2013-12-01

Muscle-invasive bladder cancer is associated with a high frequency of metastasis, and fewer therapies substantially prolong survival. Silibinin, a nontoxic natural flavonoid, has been shown to exhibit pleiotropic anticancer effects in many cancer types, including bladder cancer. Our and other previous studies have demonstrated that silibinin induced apoptosis and inhibited proliferation of bladder cancer cells, whether silibinin could suppress bladder cancer metastasis has not been elucidated. In the present study, we utilized a novel highly metastatic T24-L cell model, and found that silibinin treatment not only resulted in the suppression of cell migration and invasion in vitro, but also decreased bladder cancer lung metastasis and prolonged animal survival in vivo. Mechanistically, silibinin could inhibit glycogen synthase kinase-3β (GSK3β) phosphorylation, β-catenin nuclear translocation and transactivation, and ZEB1 gene transcription that subsequently regulated the expression of cytokeratins, vimentin and matrix metalloproteinase-2 (MMP2) to reverse epithelial-mesenchymal transition (EMT). On the other hand, silibinin inhibited ZEB1 expression and then suppressed the properties of cancer stem cells (CSCs), which were evidenced as decreased spheroid colony formation, side population, and the expression of stem cell factor CD44. Overall, this study reveals a novel mechanism for silibinin targeting bladder cancer metastasis, in which inactivation of β-catenin/ZEB1 signaling by silibinin leads to dual-block of EMT and stemness. © 2013.

Use of Ulex europaeus agglutinin I (UEAI) to distinguish vascular and "pseudovascular" invasion in transitional cell carcinoma of bladder with lamina propria invasion.

PubMed

Larsen, M P; Steinberg, G D; Brendler, C B; Epstein, J I

1990-01-01

We used Ulex europaeus agglutinin I (UEAI)-immunoperoxidase staining of endothelium to study the accuracy of hematoxylin and eosin (H&E) diagnosis, occurrence, and significance of lymphvascular invasion in transitional cell carcinoma (TCC) of the bladder invading the lamina propria (Stage T1). Original histologic slides from cases (1967 to 1985) with and without vascular invasion were destained and restained with UEAI-immunoperoxidase. Only 5 of 36 biopsies originally diagnosed with lymphvascular invasion had tumor nests within endothelium-lined spaces. The 31 negative biopsies had extensive retraction artifacts lined by connective tissue and fibroblasts around tumor nests. Thirty-five control biopsies remained negative for lymphvascular invasion. Clinical follow-up of the five patients with proven lymphvascular invasion found three without progression of disease 3 to 10 yr postbiopsy, one dead of a local recurrence of TCC 1.67 yr postbiopsy, and one lost to follow-up. Based on this study, we feel that lymphvascular invasion by TCC in Stage T1 tumors is unusual, is frequently misdiagnosed on H&E stain, and does not necessarily portend a poor prognosis.

Trimodality therapy in bladder cancer: Who, what and when?

PubMed Central

Premo, Christopher; Apolo, Andrea B.; Agarwal, Piyush K.

2015-01-01

Summary Radical cystectomy is a standard treatment for non-metastatic, muscle-invasive bladder cancer. Treatment with trimodality therapy consisting of maximal transurethral resection of the bladder tumor (TURBT) followed by concurrent chemotherapy and radiation has emerged as a method to preserve the native bladder in highly motivated patients. A number of factors can impact the likelihood of long term bladder preservation after trimodality therapy, and therefore should be taken into account when selecting patients. New radiation techniques such as intensity modulated radiation therapy and image guided radiation therapy may decrease the toxicity of radiotherapy in this setting, but remain an area of active study. Novel chemotherapy regimens may improve response rates and minimize toxicity. PMID:25882559

Rare complication of needleless mini-sling procedure: Case report.

PubMed

Karalar, Mustafa; Keles, Ibrahim; Unlu, Serdar; Sarici, Hasmet; Kose, Mesut; Ay, Cemil

2017-01-01

The mini-sling procedure is a widely used, minimally invasive treatment for stress urinary incontinence. While bladder perforation and stone formation over the mesh is not an expected complication of the mini-sling procedure, in this case, we report on the management of bladder calculi formed over the mesh, which was passed through the bladder while applying the mini-sling procedure, and was eventually removed using holmium laser. Performing cystoscopy in patients with irritative and obstructive symptoms after the sling procedure will help confirm bladder perforation, and an endoscopic approach using holmium laser is an effective treatment.

Naturally-Occurring Canine Invasive Urothelial Carcinoma: A Model for Emerging Therapies

PubMed Central

Sommer, Breann C.; Dhawan, Deepika; Ratliff, Timothy L.; Knapp, Deborah W.

2018-01-01

The development of targeted therapies and the resurgence of immunotherapy offer enormous potential to dramatically improve the outlook for patients with invasive urothelial carcinoma (InvUC). Optimization of these therapies, however, is crucial as only a minority of patients achieve dramatic remission, and toxicities are common. With the complexities of the therapies, and the growing list of possible drug combinations to test, highly relevant animal models are needed to assess and select the most promising approaches to carry forward into human trials. The animal model(s) should possess key features that dictate success or failure of cancer drugs in humans including tumor heterogeneity, genetic-epigenetic crosstalk, immune cell responsiveness, invasive and metastatic behavior, and molecular subtypes (e.g., luminal, basal). While it may not be possible to create these collective features in experimental models, these features are present in naturally-occurring InvUC in pet dogs. Naturally occurring canine InvUC closely mimics muscle-invasive bladder cancer in humans in regards to cellular and molecular features, molecular subtypes, biological behavior (sites and frequency of metastasis), and response to therapy. Clinical treatment trials in pet dogs with InvUC are considered a win-win scenario; the individual dog benefits from effective treatment, the results are expected to help other dogs, and the findings are expected to translate to better treatment outcomes in humans. This review will provide an overview of canine InvUC, the similarities to the human condition, and the potential for dogs with InvUC to serve as a model to predict the outcomes of targeted therapy and immunotherapy in humans. PMID:29732386

Naturally-Occurring Canine Invasive Urothelial Carcinoma: A Model for Emerging Therapies.

PubMed

Sommer, Breann C; Dhawan, Deepika; Ratliff, Timothy L; Knapp, Deborah W

2018-04-26

The development of targeted therapies and the resurgence of immunotherapy offer enormous potential to dramatically improve the outlook for patients with invasive urothelial carcinoma (InvUC). Optimization of these therapies, however, is crucial as only a minority of patients achieve dramatic remission, and toxicities are common. With the complexities of the therapies, and the growing list of possible drug combinations to test, highly relevant animal models are needed to assess and select the most promising approaches to carry forward into human trials. The animal model(s) should possess key features that dictate success or failure of cancer drugs in humans including tumor heterogeneity, genetic-epigenetic crosstalk, immune cell responsiveness, invasive and metastatic behavior, and molecular subtypes (e.g., luminal, basal). While it may not be possible to create these collective features in experimental models, these features are present in naturally-occurring InvUC in pet dogs. Naturally occurring canine InvUC closely mimics muscle-invasive bladder cancer in humans in regards to cellular and molecular features, molecular subtypes, biological behavior (sites and frequency of metastasis), and response to therapy. Clinical treatment trials in pet dogs with InvUC are considered a win-win scenario; the individual dog benefits from effective treatment, the results are expected to help other dogs, and the findings are expected to translate to better treatment outcomes in humans. This review will provide an overview of canine InvUC, the similarities to the human condition, and the potential for dogs with InvUC to serve as a model to predict the outcomes of targeted therapy and immunotherapy in humans.

Tumour front inflammation and necrosis are independent prognostic predictors in high-grade urothelial carcinoma of the bladder.

PubMed

Hodgson, Anjelica; Xu, Bin; Satkunasivam, Raj; Downes, Michelle R

2018-02-01

Inflammation and necrosis have been associated with prognosis in multiple epithelial malignancies. Our objective was to evaluate inflammation and necrosis in a cohort of patients with high-grade urothelial carcinomas of the bladder to determine their association with pathological parameters and their prognostic effect on relapse-free and disease-specific survival. A retrospective cohort that underwent radical cystectomy for urothelial carcinomas (n=235) was evaluated for invasive front and central inflammation using the Klintrup-Makinen assessment method. Necrosis was scored using a four-point scale. The relationship of inflammation and necrosis with stage, nodal status, carcinoma in situ, tumour size, margin status and vascular space invasion and the impact on relapse-free and disease-specific survival were calculated using appropriate statistical tests. On multivariate analysis, invasive front inflammation (p=0.003) and necrosis (p=0.000) were independent predictors of relapse-free survival. Both invasive front inflammation (p=0.009) and necrosis (p=0.002) again were independent predictors of disease-specific survival. For pathological features, low invasive front inflammation was associated with lymphovascular space invasion (p=0.008), a positive soft tissue margin (p=0.028) and carcinoma in situ (p=0.042). Necrosis was statistically associated with tumours >3 cm in size (p=0.013) and carcinoma in situ (p<0.001). Necrosis and invasive front inflammation are additional histological variables with independent prognostic relevance in high-grade urothelial carcinoma of the bladder. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Competing mortality in patients diagnosed with bladder cancer: evidence of undertreatment in the elderly and female patients.

PubMed

Noon, A P; Albertsen, P C; Thomas, F; Rosario, D J; Catto, J W F

2013-04-16

Bladder cancer (BC) predominantly affects the elderly and is often the cause of death among patients with muscle-invasive disease. Clinicians lack quantitative estimates of competing mortality risks when considering treatments for BC. Our aim was to determine the bladder cancer-specific mortality (CSM) rate and other-cause mortality (OCM) rate for patients with newly diagnosed BC. Patients (n=3281) identified from a population-based cancer registry diagnosed between 1994 and 2009. Median follow-up was 48.15 months (IQ range 18.1-98.7). Competing risk analysis was performed within patient groups and outcomes compared using Gray's test. At 5 years after diagnosis, 1246 (40%) patients were dead: 617 (19%) from BC and 629 (19%) from other causes. The 5-year BC mortality rate varied between 1 and 59%, and OCM rate between 6 and 90%, depending primarily on the tumour type and patient age. Cancer-specific mortality was highest in the oldest patient groups. Few elderly patients received radical treatment for invasive cancer (52% vs 12% for patients <60 vs >80 years, respectively). Female patients with high-risk non-muscle-invasive BC had worse CSM than equivalent males (Gray's P<0.01). Bladder CSM is highest among the elderly. Female patients with high-risk tumours are more likely to die of their disease compared with male patients. Clinicians should consider offering more aggressive treatment interventions among older patients.

Prostaglandin receptors EP1-4 as a potential marker for clinical outcome in urothelial bladder cancer.

PubMed

von der Emde, Laura; Goltz, Diane; Latz, Stefan; Müller, Stefan C; Kristiansen, Glen; Ellinger, Jörg; Syring, Isabella

2014-01-01

Prostaglandins, especially prostaglandin E2 (PGE2), and COX-2 play an important role in carcinogenesis of many tumors including bladder cancer (BCA). The PGE2 receptors EP1-4 regulate tumor cell growth, invasion and migration in different tumor entities but EP expression in BCA remains to be determined. In the present study we examined the expression of EP1-4 in non-muscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC) and normal urothelial tissue (NU) using immunohistochemistry. Nuclear and cytoplasmic EP1-4 expression was correlated with clinicopathological parameters and survival of BCA patients. EP1, EP2 and EP3 were significantly less expressed in the cytoplasm und nucleus of NMIBC and MIBC than in NU; EP4 cytoplasmic staining in MIBC was significantly higher compared to NU. The cytoplasmic staining was significantly more abundant in MIBC than in NMIBC in all investigated receptors except EP2. The level of EP staining in NMIBC was correlated with staging and grading, especially cytoplasmic EP1. Nuclear staining of EP1 was an independent predictor of BCA recurrence-free survival in NMIBC patients. EP receptors are dysregulated in BCA. The increase of EP1 may be used as prognostic parameter in NMIBC patients and its dysregulation could be targeted by specific EP1 inhibitors.

Prostaglandin receptors EP1-4 as a potential marker for clinical outcome in urothelial bladder cancer

PubMed Central

von der Emde, Laura; Goltz, Diane; Latz, Stefan; Müller, Stefan C; Kristiansen, Glen; Ellinger, Jörg; Syring, Isabella

2014-01-01

Prostaglandins, especially prostaglandin E2 (PGE2), and COX-2 play an important role in carcinogenesis of many tumors including bladder cancer (BCA). The PGE2 receptors EP1-4 regulate tumor cell growth, invasion and migration in different tumor entities but EP expression in BCA remains to be determined. In the present study we examined the expression of EP1-4 in non-muscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC) and normal urothelial tissue (NU) using immunohistochemistry. Nuclear and cytoplasmic EP1-4 expression was correlated with clinicopathological parameters and survival of BCA patients. EP1, EP2 and EP3 were significantly less expressed in the cytoplasm und nucleus of NMIBC and MIBC than in NU; EP4 cytoplasmic staining in MIBC was significantly higher compared to NU. The cytoplasmic staining was significantly more abundant in MIBC than in NMIBC in all investigated receptors except EP2. The level of EP staining in NMIBC was correlated with staging and grading, especially cytoplasmic EP1. Nuclear staining of EP1 was an independent predictor of BCA recurrence-free survival in NMIBC patients. EP receptors are dysregulated in BCA. The increase of EP1 may be used as prognostic parameter in NMIBC patients and its dysregulation could be targeted by specific EP1 inhibitors. PMID:25520883

[Photodynamic therapy of urinary bladder cancer using a chlorin based photosensitizer].

PubMed

Iagudaev, D M; Martov, A G; Sorokatyĭ, A E; Geĭnits, A V

2006-01-01

Photodynamic therapy (PDT) is a modem, low-invasive method of urinary bladder (UB) cancer treatment. PDT can induce complete or partial destruction of the tumor, reduce recurrence rate, provide assistance to elderly patients with compromised somatic status who are not radically operable. A combined technique improves the results of photodynamic therapy in patients with surface and invasive UB cancer of stage T2 because photodynamic impact affects not only the tumor but also all UB mucosa by light fiber with cylindric diffusor introduced in a silicon balloon with water. This leads to tumor destruction and a recurrence rate decrease.

Fruit and vegetable intake and the risk of recurrence in patients with non-muscle invasive bladder cancer: a prospective cohort study.

PubMed

Jochems, Sylvia H J; van Osch, Frits H M; Reulen, Raoul C; van Hensbergen, Mitch; Nekeman, Duncan; Pirrie, Sarah; Wesselius, Anke; van Schooten, Frederik-Jan; James, Nicholas D; Wallace, D Michael A; Bryan, Richard T; Cheng, K K; Zeegers, Maurice P

2018-06-01

There is some evidence that greater consumption of fruit and vegetables decreases the risk of bladder cancer. The role of fruit and vegetables in bladder cancer recurrence is still unknown. The role of total fruit and vegetable intake in relation to the risk of developing bladder cancer recurrence in a prospective cohort study. 728 patients with non-muscle invasive bladder cancer (NMIBC), who completed self-administrated questionnaires on fruit and vegetable intake at time of diagnosis (over the year before diagnosis) and 1 year after diagnosis, were included. Hazard ratios and 95% confidence intervals were calculated by multivariable Cox regression for developing recurrent bladder cancer in relation to fruit and vegetable intake. During 2,051 person-years of follow-up [mean (SD) follow-up 3.7 (1.5) years], 241 (33.1%) of the included 728 NMIBC patients developed a recurrence of bladder cancer. The sum of total fruit and vegetables before diagnosis was not related to a first bladder cancer recurrence (HR 1.07; 95% CI 0.78-1.47, p = 0.66). No association was found between greater consumption of fruit and vegetables over the year before diagnosis and the risk of developing multiple recurrences of bladder cancer (HR 1.02; 95% CI 0.90-1.15, p = 0.78). Among the remaining 389 NMIBC patients who reported on fruit and vegetable intake 1 year after diagnosis, no association was found between greater consumption of fruit and vegetables and a first recurrence of bladder cancer (HR 0.65; 95% CI 0.42-1.01, p = 0.06) nor with multiple recurrences of bladder cancer (HR 1.00, 95% CI 0.85-1.18, p = 1.00). Similar results were obtained when investigating the association between total intakes of fruit and vegetables separately and bladder cancer recurrence. Results from this study did not indicate a protective role for total fruit and vegetables in the development of a recurrence of NMIBC.

The Patient Burden of Bladder Outlet Obstruction after Prostate Cancer Treatment.

PubMed

Liberman, Daniel; Jarosek, Stephanie; Virnig, Beth A; Chu, Haitao; Elliott, Sean P

2016-05-01

Bladder outlet obstruction after prostate cancer therapy imposes a significant burden on health and quality of life in men. Our objective was to describe the burden of bladder outlet obstruction after prostate cancer therapy by detailing the type of procedures performed and how often those procedures were repeated in men with recurrent bladder outlet obstruction. Using SEER (Surveillance, Epidemiology and End Results)-Medicare linked data from 1992 to 2007 with followup through 2009 we identified 12,676 men who underwent at least 1 bladder outlet obstruction procedure after prostate cancer therapy, including external beam radiotherapy in 3,994, brachytherapy in 1,485, brachytherapy plus external beam radiotherapy in 1,847, radical prostatectomy in 4,736, radical prostatectomy plus external beam radiotherapy in 369 and cryotherapy in 245. Histogram, incidence rates and Cox proportional hazards models with repeat events analysis were done to describe the burden of repeat bladder outlet obstruction treatments stratified by prostate cancer therapy type. We describe the type of bladder outlet obstruction surgery grouped by level of invasiveness. At a median followup of 8.8 years 44.6% of men underwent 2 or more bladder outlet obstruction procedures. Compared to men who underwent radical prostatectomy those treated with brachytherapy and brachytherapy plus external beam radiotherapy were at increased adjusted risk for repeat bladder outlet obstruction treatment (HR 1.2 and 1.32, respectively, each p <0.05). After stricture incision the men treated with radical prostatectomy or radical prostatectomy plus external beam radiotherapy were most likely to undergo dilation at a rate of 34.7% to 35.0%. Stricture resection/ablation was more common after brachytherapy, external beam radiotherapy or brachytherapy plus external beam radiotherapy at a rate of 28.9% to 41.2%. Almost half of the men with bladder outlet obstruction after prostate cancer therapy undergo more than 1 procedure. Furthermore men with bladder outlet obstruction after radiotherapy undergo more invasive endoscopic therapies and are at higher risk for multiple treatments than men with bladder outlet obstruction after radical prostatectomy. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Correlation of the cell surface antigens with stage and grade in cancer of the bladder.

PubMed

Emmott, R C; Javadpour, N; Bergman, S M; Soares, T

1979-01-01

We examined 76 bladder tumors of various stages and grades for the presence of the ABO (H) cell surface antigen, using the specific red cell adherence technique. Of the grade I lesions studied 70 per cent were positive for the cell surface antigen and none of the 26 grade III tumors retained the antigens. When correlated with clinical stage the tumors showed no antigens for those of stages B1 to D, while 12 of 16 stage A lesions were positive for the antigen. When stage A lesions were studied and the findings were correlated with recurrence and metastasis/invasion rates the cell surface antigen was present on the initial tumor in only 1 lesion that recurred at an invasive stage. The findings of this study show that the specific red cell adherence technique may be valuable for predicting malignant potential in low grade, low stage cancer of the bladder. If supported by further investigation this technique may offer the capability of selecting low grade, low stage bladder tumors that are destined to invade or metastasize while they are at curable stages.

Flavonoid silybin improves the response to radiotherapy in invasive bladder cancer.

PubMed

Prack Mc Cormick, Barbara; Langle, Yanina; Belgorosky, Denise; Vanzulli, Silvia; Balarino, Natalia; Sandes, Eduardo; Eiján, Ana M

2018-01-24

Conservative treatment for invasive bladder cancer (BC) involves a complete transurethral tumor resection combined with chemotherapy (CT) and radiotherapy (RT). The major obstacles of chemo-radiotherapy are the addition of the toxicities of RT and CT, and the recurrence due to RT and CT resistances. The flavonoid Silybin (Sb) inhibits pathways involved in cell survival and resistance mechanisms, therefore the purpose of this paper was to study in vitro and in vivo, the ability of Sb to improve the response to RT, in two murine BC cell lines, with different levels of invasiveness, placing emphasis on radio-sensitivity, and pathways involved in radio-resistance and survival. In vitro, Sb radio-sensitized murine invasive cells through the inhibition of RT-induced NF-κB and PI3K pathways, and the increase of oxidative stress, while non-invasive cells did not show to be sensitized. In vivo, Sb improved RT-response and overall survival in invasive murine tumors. As Sb is already being tested in clinical trials for other urological cancers and it improves RT-response in invasive BC, these results could have translational relevance, supporting further research. © 2018 Wiley Periodicals, Inc.

Diagnostic ultrasound and telemedicine utilization in the international space station

NASA Astrophysics Data System (ADS)

Carter, Stephen J.; Stewart, Brent K.; Kushmerick, Martin J.; Langer, Steve G.; Schmiedl, Udo P.; Winter, Thomas C.; Conley, Kevin E.; Jubrias, Sharon A.

1999-01-01

Clinical diagnostic ultrasound (US) is experiencing an expanding role that is well suited to application on the International Space Station (ISS). Diagnostic US can be used to reduce the risks associated with long duration human space flight by providing a non-invasive tool with head-to-toe diagnostic capability in both biomedical research and crew health care. General health care of the astronauts will be diagnosed with US, e.g., kidney stones, gall bladder disease, appendicitis, etc. Initial studies will focus on detection of ``ureteral jets'' in the bladder. This is a non-invasive test to rule out obstructive uropathy from kidney stones with minimal requirements for crew training. Biomedical research experiments, focusing on the effects of the microgravity environment, will be performed using both the HHU and the HDI 5000. US will be used to evaluate bone density and muscle mass in this environment. Prolonged or emergency EVAs may occur with the ISS. The hand-held ultrasound unit (HHU) and its telemedicine capability will be used in EVA settings to monitor events such as decompression sickness (DCS) microbubble formation in the cardiovascular system. There will be telemetry links between the HHU and the ATL/Lockheed Martin rack mounted HDI 5000 in the ISS Human Research Facility (HRF), as well as between the HRF and medical expertise on the ground. These links will provide the ISS with both real-time and store-and-forward telemedicine capabilities. The HHU can also be used with the existing telemedicine instrument pack (TIP).

Monitoring of lower urinary tract function in patients with spinal cord injury using near infrared spectroscopy

NASA Astrophysics Data System (ADS)

Shadgan, Babak; Macnab, Andrew; Nigro, Mark; Stothers, Lynn

2012-02-01

Background: One of the most important conditions where there is loss of normal bladder function is spinal cord injury (SCI). Currently, evaluation of bladder function is limited to periodic invasive urodynamic testing (UDS). The purpose of this study was to assess the feasibility and usefulness of near-infrared spectroscopy (NIRS) in monitoring bladder function in patients with SCI during bladder filling and emptying and to investigate the correlations of NIRS measures with simultaneous UDS parameters. NIRS is a non-invasive optical method to study tissue oxygenation, hemodynamics and function by monitoring changes in the chromophore concentrations of oxygenated (O2Hb), deoxygenated (HHb) and total hemoglobin (tHb). Methods: 10 adult paraplegic patients with neurogenic bladder dysfunction who were referred for regular urodynamic evaluation were recruited. Changes in O2Hb, HHb and tHb, and tissue saturation index (TSI%) in the detrusor were monitored and recorded by a wireless NIRS system during the urodynamic evaluation. Time points of urgency and urinary leakage were marked and patterns of change in NIRS parameters were compared to standard urodynamic pressure tracings. Results: Strong consistency between changes in NIRS-derived tHb and changes in intravesical pressure were observed during filling across the subjects. During bladder filling a gradual increase in O2Hb and tHb with minimal changes in HHb was observed. Interestingly, a drop in TSI% was detected seconds before strong urgency and urinary leakage. Conclusions: Our preliminary data suggest a relationship between noninvasive NIRS measures and UDS parameters during bladder filling in SCI patients.

Identification of Methylated Genes Associated with Aggressive Bladder Cancer

PubMed Central

Marsit, Carmen J.; Houseman, E. Andres; Christensen, Brock C.; Gagne, Luc; Wrensch, Margaret R.; Nelson, Heather H.; Wiemels, Joseph; Zheng, Shichun; Wiencke, John K.; Andrew, Angeline S.; Schned, Alan R.; Karagas, Margaret R.; Kelsey, Karl T.

2010-01-01

Approximately 500,000 individuals diagnosed with bladder cancer in the U.S. require routine cystoscopic follow-up to monitor for disease recurrences or progression, resulting in over $2 billion in annual expenditures. Identification of new diagnostic and monitoring strategies are clearly needed, and markers related to DNA methylation alterations hold great promise due to their stability, objective measurement, and known associations with the disease and with its clinical features. To identify novel epigenetic markers of aggressive bladder cancer, we utilized a high-throughput DNA methylation bead-array in two distinct population-based series of incident bladder cancer (n = 73 and n = 264, respectively). We then validated the association between methylation of these candidate loci with tumor grade in a third population (n = 245) through bisulfite pyrosequencing of candidate loci. Array based analyses identified 5 loci for further confirmation with bisulfite pyrosequencing. We identified and confirmed that increased promoter methylation of HOXB2 is significantly and independently associated with invasive bladder cancer and methylation of HOXB2, KRT13 and FRZB together significantly predict high-grade non-invasive disease. Methylation of these genes may be useful as clinical markers of the disease and may point to genes and pathways worthy of additional examination as novel targets for therapeutic treatment. PMID:20808801

Identification of methylated genes associated with aggressive bladder cancer.

PubMed

Marsit, Carmen J; Houseman, E Andres; Christensen, Brock C; Gagne, Luc; Wrensch, Margaret R; Nelson, Heather H; Wiemels, Joseph; Zheng, Shichun; Wiencke, John K; Andrew, Angeline S; Schned, Alan R; Karagas, Margaret R; Kelsey, Karl T

2010-08-23

Approximately 500,000 individuals diagnosed with bladder cancer in the U.S. require routine cystoscopic follow-up to monitor for disease recurrences or progression, resulting in over $2 billion in annual expenditures. Identification of new diagnostic and monitoring strategies are clearly needed, and markers related to DNA methylation alterations hold great promise due to their stability, objective measurement, and known associations with the disease and with its clinical features. To identify novel epigenetic markers of aggressive bladder cancer, we utilized a high-throughput DNA methylation bead-array in two distinct population-based series of incident bladder cancer (n = 73 and n = 264, respectively). We then validated the association between methylation of these candidate loci with tumor grade in a third population (n = 245) through bisulfite pyrosequencing of candidate loci. Array based analyses identified 5 loci for further confirmation with bisulfite pyrosequencing. We identified and confirmed that increased promoter methylation of HOXB2 is significantly and independently associated with invasive bladder cancer and methylation of HOXB2, KRT13 and FRZB together significantly predict high-grade non-invasive disease. Methylation of these genes may be useful as clinical markers of the disease and may point to genes and pathways worthy of additional examination as novel targets for therapeutic treatment.

The association between smoking cessation before and after diagnosis and non-muscle-invasive bladder cancer recurrence: a prospective cohort study.

PubMed

van Osch, Frits H M; Jochems, Sylvia H J; Reulen, Raoul C; Pirrie, Sarah J; Nekeman, Duncan; Wesselius, Anke; James, Nicholas D; Wallace, D Michael A; Cheng, K K; van Schooten, Frederik J; Bryan, Richard T; Zeegers, Maurice P

2018-07-01

Smoking is a major risk factor for bladder cancer, but the relationship between smoking cessation after initial treatment and bladder cancer recurrence has been investigated less frequently and not prospectively yet. 722 non-muscle-invasive bladder cancer (NMIBC) patients (pTa, pT1, and CIS) from the prospective Bladder Cancer Prognosis Programme (BCPP) cohort, selected in the UK between 2005 and 2011, provided complete data on smoking behavior before and up to 5 years after diagnosis. The impact of smoking behavior on NMIBC recurrence was explored by multivariable Cox regression models investigating time-to-first NMIBC recurrence. Over a median follow-up period of 4.21 years, 403 pathologically confirmed NMIBC recurrences occurred in 210 patients. Only 25 current smokers at diagnosis quit smoking (14%) during follow-up and smoking cessation after diagnosis did not decrease risk of recurrence compared to continuing smokers (p = 0.352). Although quitting smoking after diagnosis might reduce the risk of recurrence based on retrospective evidence, this is not confirmed in this prospective study because the number of NMIBC patients quitting smoking before their first recurrence was too low. Nevertheless, this indicates an important role for urologists and other health care professionals in promoting smoking cessation in NMIBC.

Prognostic value of sex-hormone receptor expression in non-muscle-invasive bladder cancer.

PubMed

Nam, Jong Kil; Park, Sung Woo; Lee, Sang Don; Chung, Moon Kee

2014-09-01

We investigated sex-hormone receptor expression as predicting factor of recurrence and progression in patients with non-muscle invasive bladder cancer. We retrospectively evaluated tumor specimens from patients treated for transitional cell carcinoma of the bladder at our institution between January 2006 and January 2011. Performing immunohistochemistry using a monoclonal androgen receptor antibody and monoclonal estrogen receptor-beta antibody on paraffin-embedded tissue sections, we assessed the relationship of immunohistochemistry results and prognostic factors such as recurrence and progression. A total of 169 patients with bladder cancer were evaluated in this study. Sixty-threepatients had expressed androgen receptors and 52 patients had estrogen receptor beta. On univariable analysis, androgen receptor expression was significant lower in recurrence rates (p=0.001), and estrogen receptor beta expression was significant higher in progression rates (p=0.004). On multivariable analysis, significant association was found between androgen receptor expression and lower recurrence rates (hazard ratio=0.500; 95% confidence interval, 0.294 to 0.852; p=0.011), but estrogen receptor beta expression was not significantly associated with progression rates. We concluded that the possibility of recurrence was low when the androgen receptor was expressed in the bladder cancer specimen and it could be the predicting factor of the stage, number of tumors, carcinoma in situ lesion and recurrence.

KITENIN is associated with tumor progression in human gastric cancer.

PubMed

Ryu, Ho-Seong; Park, Young-Lan; Park, Su-Jin; Lee, Ji-Hee; Cho, Sung-Bum; Lee, Wan-Sik; Chung, Ik-Joo; Kim, Kyung-Keun; Lee, Kyung-Hwa; Kweon, Sun-Seog; Joo, Young-Eun

2010-09-01

KAI1 COOH-terminal interacting tetraspanin (KITENIN) promotes tumor cell migration, invasion and metastasis in colon, bladder, head and neck cancer. The aims of current study were to evaluate whether KITENIN affects tumor cell behavior in human gastric cancer cell line and to document the expression of KITENIN in a well-defined series of gastric tumors, including complete long-term follow-up, with special reference to patient prognosis. To evaluate the impact of KITENIN knockdown on behavior of a human gastric cancer cell line, AGS, migration, invasion and proliferation assays using small-interfering RNA were performed. The expression of activator protein-1 (AP-1) target genes and AP-1 transcriptional activity were evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and luciferase reporter assay. The expression of KITENIN and AP-1 target genes by RT-PCR and Western blotting or immunohistochemistry was also investigated in human gastric cancer tissues. The knockdown of KITENIN suppressed tumor cell migration, invasion and proliferation in AGS cells. The mRNA expression of matrix metalloproteinase-1 (MMP-1), MMP-3, cyclooxygenase-2 (COX-2), and CD44 was reduced by knockdown of KITENIN in AGS. AP-1 transcriptional activity was significantly decreased by knockdown of KITENIN in AGS cells. KITENIN expression was significantly increased in human cancer tissues at RNA and protein levels. Expression of MMP-1, MMP-3, COX-2 and CD44 were significantly increased in human gastric cancer tissues. Immunostaining of KITENIN was predominantly identified in the cytoplasm of cancer cells. Expression of KITENIN was significantly associated with tumor size, Lauren classification, depth of invasion, lymph node metastasis, tumor stage and poor survival. These results indicate that KITENIN plays an important role in human gastric cancer progression by AP-1 activation.

Systemic therapy in muscle-invasive and metastatic bladder cancer: current trends and future promises.

PubMed

Aragon-Ching, Jeanny B; Trump, Donald L

2016-09-01

Bladder urothelial cancers remain an important urologic cancer with limited treatment options in the locally advanced and metastatic setting. While neoadjuvant chemotherapy for locally advanced muscle-invasive cancers has shown overall survival benefit, clinical uptake in practice have lagged behind. Controversies surrounding adjuvant chemotherapy use are also ongoing. Systemic therapies for metastatic bladder cancer have largely used platinum-based therapies without effective standard second-line therapy options for those who fail, although vinflunine is approved in Europe as a second-line therapy based on a Phase III trial, and most recently, atezolizumab, a checkpoint inhibitor, was approved by the US FDA. Given increasing recognition of mutational signatures expressed in urothelial carcinomas, several promising agents with use of VEGF-targeted therapies, HER2-directed agents and immunotherapies with PD-1/PD-L1 antibodies in various settings are discussed herein.

OK-432 Suppresses Proliferation and Metastasis by Tumor Associated Macrophages in Bladder Cancer.

PubMed

Tian, Yuan-Feng; Tang, Kun; Guan, Wei; Yang, Tao; Xu, Hua; Zhuang, Qian-Yuan; Ye, Zhang-Qun

2015-01-01

OK-432, a Streptococcus-derived anticancer immunotherapeutic agent, has been applied in clinic for many years and achieved great progress in various cancers. In the present study, we investigated its anticancer effect on bladder cancer through tumor associated macrophages (TAMs). MTS assay validated OK-432 could inhibit proliferation in both T24 and EJ bladder cell lines. OK-432 also induced apoptosis of bladder cancer cells in vitro. Consequently, we demonstrated that OK-432 could suppress the bladder cancer cells migration and invasion by altering the EMT-related factors. Furthermore, using SD rat model, we revealed that OK-432 inhibited tumor growth, suppressed PCNA expression and inhibited metastasis in vivo. Taken together, these findings strongly suggest that OK-432 inhibits cell proliferation and metastasis through inducing macrophages to secret cytokines in bladder cancer.

Natural killer cell-based adoptive immunotherapy eradicates and drives differentiation of chemoresistant bladder cancer stem-like cells.

PubMed

Ferreira-Teixeira, Margarida; Paiva-Oliveira, Daniela; Parada, Belmiro; Alves, Vera; Sousa, Vitor; Chijioke, Obinna; Münz, Christian; Reis, Flávio; Rodrigues-Santos, Paulo; Gomes, Célia

2016-10-21

High-grade non-muscle invasive bladder cancer (NMIBC) has a high risk of recurrence and progression to muscle-invasive forms, which seems to be largely related to the presence of tumorigenic stem-like cell populations that are refractory to conventional therapies. Here, we evaluated the therapeutic potential of Natural Killer (NK) cell-based adoptive immunotherapy against chemoresistant bladder cancer stem-like cells (CSCs) in a pre-clinical relevant model, using NK cells from healthy donors and NMIBC patients. Cytokine-activated NK cells from healthy donors and from high-grade NMIBC patients were phenotypically characterized and assayed in vitro against stem-like and bulk differentiated bladder cancer cells. Stem-like cells were isolated from two bladder cancer cell lines using the sphere-forming assay. The in vivo therapeutic efficacy was evaluated in mice bearing a CSC-induced orthotopic bladder cancer. Animals were treated by intravesical instillation of interleukin-activated NK cells. Tumor response was evaluated longitudinally by non-invasive bioluminescence imaging. NK cells from healthy donors upon activation with IL-2 and IL-15 kills indiscriminately both stem-like and differentiated tumor cells via stress ligand recognition. In addition to cell killing, NK cells shifted CSCs towards a more differentiated phenotype, rendering them more susceptible to cisplatin, highlighting the benefits of a possible combined therapy. On the contrary, NK cells from NMIBC patients displayed a low density on NK cytotoxicity receptors, adhesion molecules and a more immature phenotype, losing their ability to kill and drive differentiation of CSCs. The local administration, via the transurethral route, of activated NK cells from healthy donors provides an efficient tumor infiltration and a subsequent robust tumoricidal activity against bladder cancer with high selective cytolytic activity against CSCs, leading to a dramatic reduction in tumor burden from 80 % to complete remission. Although pre-clinical, our results strongly suggest that an immunotherapeutic strategy using allogeneic activated NK cells from healthy donors is effective and should be exploited as a complementary therapeutic strategy in high-risk NMIBC patients to prevent tumor recurrence and progression.

Preconditioning methods influence tumor property in an orthotopic bladder urothelial carcinoma rat model

PubMed Central

MIYAZAKI, KOZO; MORIMOTO, YUJI; NISHIYAMA, NOBUHIRO; SATOH, HIROYUKI; TANAKA, MASAMITSU; SHINOMIYA, NARIYOSHI; ITO, KEIICHI

2014-01-01

Urothelial carcinoma (UC) is an extremely common type of cancer that occurs in the bladder. It has a particularly high rate of recurrence. Therefore, preclinical studies using animal models are essential to determine effective forms of treatment. In the present study, in order to establish an orthotopic bladder UC animal model with clinical relevance, the effects of preconditioning methods on properties of the developed tumor were evaluated. The bladder cavity was pretreated with phosphate-buffered saline (PBS), acid-base, trypsin (TRY) or poly (L-lysine) (PLL) and then rat UC cells (AY-27) (4×106 cells) were inoculated. The results demonstrated that, two weeks later, the tumorigenic rate (88%) and tumor count (2.3 per rat) were not significantly different among the preconditioning methods, whereas tumor volume and invasion depth into bladder tissue were significantly different. Average tumor volumes were >50 mm3 in the PBS and acid-base-treated groups and <10 mm3 in the TRY- and PLL-treated groups. The percentage of invasive tumors (T2 or more advanced stage) was ∼75% of total tumors in the PBS- and acid-base-treated groups, whereas the percentages were reduced in the TRY- and PLL-treated groups (58 and 32%, respectively). Non-invasive tumors (Ta or T1) accounted for 54% of tumors in the PLL-treated group, which was 2-5-fold higher than the percentages in the remaining groups. Properties of the developed tumor in the rat orthotopic UC model were different depending on preconditioning methods. Therefore, different animal models suitable for a discrete preclinical examination may be established by using the appropriate preconditioning condition. PMID:24649309

Quality-of-life survey for patients diagnosed with nonmuscle-invasive bladder cancer.

PubMed

Abáigar-Pedraza, I; Megías-Garrigós, J; Sánchez-Payá, J

2016-05-01

To determine the reliability and validity of a quality-of-life survey for patients with nonmuscle-invasive bladder cancer. A total of 180 patients were included in the study. We developed a survey with 21 questions grouped into 5 areas. The patients filled in this survey and the Functional Assessment of Cancer Therapy - Bladder Cancer (FACT-BL) survey. To assess reliability, we calculated Cronbach's alpha coefficient and the kappa index. To determine criterion validity, we studied the association between the scores obtained from our survey and those from the FACT-BL survey using the Pearson correlation coefficient. To determine the construct validity (factorial and discriminatory), we performed a factor analysis, comparing it with Student's t-test for the scores obtained according to the tumour characteristics of reduced quality of life (e.g., malignancies located at the trigone of the bladder). Cronbach's alpha reliability coefficient was .83, and the kappa index varied between .7 and 1. For the association study between the new survey and the FACT-BL survey, we measured an r=.82 for the overall score and between r=.68 (disease) and r=.97 (sex life) in the various measures. In the factor analysis, we measured a Kaiser-Meyer-Olkin index of .77 and performed the Barlett test (P<.001). The comparison between the scores, in the presence or absence of certain tumour characteristics, has shown a reduced quality of life when those characteristics are present, which was statistically significant (P<.05) in the majority of cases. Our survey to measure the quality of life of patients with nonmuscle-invasive bladder cancer is reliable and valid. Copyright © 2015 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

History of Non-Muscle-Invasive Bladder Cancer May Have a Worse Prognostic Impact in cT2-4aN0M0 Bladder Cancer Patients Treated With Radical Cystectomy.

PubMed

Kayama, Emina; Kikuchi, Eiji; Fukumoto, Keishiro; Shirotake, Suguru; Miyazaki, Yasumasa; Hakozaki, Kyohei; Kaneko, Gou; Yoshimine, Shunsuke; Tanaka, Nobuyuki; Takahiro, Maeda; Kanai, Kunimitsu; Oyama, Masafumi; Nakajima, Yosuke; Hara, Satoshi; Monma, Tetsuo; Oya, Mototsugu

2018-04-28

To investigate whether a history of non-muscle-invasive bladder cancer (NMIBC) plays a prognostic role in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy in the era when neoadjuvant chemotherapy was established as standard therapy for MIBC. A total of 282 patients who were diagnosed with cT2-T4aN0M0 bladder cancer treated with open radical cystectomy at our institutions were included. Initially diagnosed MIBC without a history of NMIBC was defined as primary MIBC group (n = 231), and MIBC that progressed from NMIBC was defined as progressive MIBC (n = 51). The rate of cT3/4a tumors was significantly higher in the primary MIBC group than in the progressive MIBC group (P = .004). Five-year recurrence-free survival and cancer-specific survival (CSS) rates for the primary MIBC group versus progressive MIBC group were 68.2% versus 55.9% (P = .039) and 76.1% versus 61.6% (P = .005), respectively. Progressive MIBC (hazard ratio, 2.170; P = .008) was independently associated with cancer death. In the primary MIBC group, the 5-year CSS rate in patients treated with neoadjuvant chemotherapy was 85.4%, which was significantly higher than that in patients without (71.5%, P = .023). In the progressive MIBC group, no significant differences were observed in CSS between patients treated with and without neoadjuvant chemotherapy. MIBC that progressed from NMIBC had a significantly worse clinical outcome than MIBC without a history of NMIBC and may not respond as well to neoadjuvant chemotherapy. These results are informative, even for NMIBC patients treated with conservative intravesical therapy. Copyright © 2018 Elsevier Inc. All rights reserved.

Non-invasive quantification of tumour heterogeneity in water diffusivity to differentiate malignant from benign tissues of urinary bladder: a phase I study.

PubMed

Nguyen, Huyen T; Shah, Zarine K; Mortazavi, Amir; Pohar, Kamal S; Wei, Lai; Jia, Guang; Zynger, Debra L; Knopp, Michael V

2017-05-01

To quantify the heterogeneity of the tumour apparent diffusion coefficient (ADC) using voxel-based analysis to differentiate malignancy from benign wall thickening of the urinary bladder. Nineteen patients with histopathological findings of their cystectomy specimen were included. A data set of voxel-based ADC values was acquired for each patient's lesion. Histogram analysis was performed on each data set to calculate uniformity (U) and entropy (E). The k-means clustering of the voxel-wised ADC data set was implemented to measure mean intra-cluster distance (MICD) and largest inter-cluster distance (LICD). Subsequently, U, E, MICD, and LICD for malignant tumours were compared with those for benign lesions using a two-sample t-test. Eleven patients had pathological confirmation of malignancy and eight with benign wall thickening. Histogram analysis showed that malignant tumours had a significantly higher degree of ADC heterogeneity with lower U (P = 0.016) and higher E (P = 0.005) than benign lesions. In agreement with these findings, k-means clustering of voxel-wise ADC indicated that bladder malignancy presented with significantly higher MICD (P < 0.001) and higher LICD (P = 0.002) than benign wall thickening. The quantitative assessment of tumour diffusion heterogeneity using voxel-based ADC analysis has the potential to become a non-invasive tool to distinguish malignant from benign tissues of urinary bladder cancer. • Heterogeneity is an intrinsic characteristic of tumoral tissue. • Non-invasive quantification of tumour heterogeneity can provide adjunctive information to improve cancer diagnosis accuracy. • Histogram analysis and k-means clustering can quantify tumour diffusion heterogeneity. • The quantification helps differentiate malignant from benign urinary bladder tissue.

Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer

PubMed Central

Kitchen, Mark O.; Bryan, Richard T.; Emes, Richard D.; Glossop, John R.; Luscombe, Christopher; Cheng, K. K.; Zeegers, Maurice P.; James, Nicholas D.; Devall, Adam J.; Mein, Charles A.; Gommersall, Lyndon; Fryer, Anthony A.; Farrell, William E.

2016-01-01

ABSTRACT High-grade non-muscle invasive bladder cancer (HG-NMIBC) is a clinically unpredictable disease with greater risks of recurrence and progression relative to their low-intermediate-grade counterparts. The molecular events, including those affecting the epigenome, that characterize this disease entity in the context of tumor development, recurrence, and progression, are incompletely understood. We therefore interrogated genome-wide DNA methylation using HumanMethylation450 BeadChip arrays in 21 primary HG-NMIBC tumors relative to normal bladder controls. Using strict inclusion-exclusion criteria we identified 1,057 hypermethylated CpGs within gene promoter-associated CpG islands, representing 256 genes. We validated the array data by bisulphite pyrosequencing and examined 25 array-identified candidate genes in an independent cohort of 30 HG-NMIBC and 18 low-intermediate-grade NMIBC. These analyses revealed significantly higher methylation frequencies in high-grade tumors relative to low-intermediate-grade tumors for the ATP5G2, IRX1 and VAX2 genes (P<0.05), and similarly significant increases in mean levels of methylation in high-grade tumors for the ATP5G2, VAX2, INSRR, PRDM14, VSX1, TFAP2b, PRRX1, and HIST1H4F genes (P<0.05). Although inappropriate promoter methylation was not invariantly associated with reduced transcript expression, a significant association was apparent for the ARHGEF4, PON3, STAT5a, and VAX2 gene transcripts (P<0.05). Herein, we present the first genome-wide DNA methylation analysis in a unique HG-NMIBC cohort, showing extensive and discrete methylation changes relative to normal bladder and low-intermediate-grade tumors. The genes we identified hold significant potential as targets for novel therapeutic intervention either alone, or in combination, with more conventional therapeutic options in the treatment of this clinically unpredictable disease. PMID:26929985

Nanodiamonds facilitate killing of intracellular uropathogenic E. coli in an in vitro model of urinary tract infection pathogenesis

PubMed Central

Iyer, Janaki Kannan; Dickey, Alexia; Rouhani, Parvaneh; Kaul, Anil; Govindaraju, Nirmal; Singh, Raj Narain

2018-01-01

About 25–44% of women will experience at least one episode of recurrent UTI and the causative agent in over 70% of UTI cases is uropathogenic Escherichia coli (UPEC). UPEC cause recurrent UTI by evading the bladder’s innate immune system through internalization into the bladder epithelium where antibiotics cannot reach or be effective. Thus, it is important to develop novel therapeutics to eliminate these intracellular pathogens. Nanodiamonds (NDs) are biocompatible nanomaterials that serve as promising candidates for targeted therapeutic applications. The objective of the current study was to investigate if 6 or 25 nm NDs can kill extracellular and intracellular UPEC in infected bladder cells. We utilized the human bladder epithelial cell line, T24, and an invasive strain of UPEC that causes recurrent UTI. We found that acid-purified 6 nm NDs displayed greater antibacterial properties towards UPEC than 25 nm NDs (11.5% vs 94.2% CFU/mL at 100 μg/mL of 6 and 25 nm, respectively; P<0.001). Furthermore, 6 nm NDs were better than 25 nm NDs in reducing the number of UPEC internalized in T24 bladder cells (46.1% vs 81.1% CFU/mL at 100 μg/mL of 6 and 25 nm, respectively; P<0.01). Our studies demonstrate that 6 nm NDs interacted with T24 bladder cells in a dose-dependent manner and were internalized in 2 hours through an actin-dependent mechanism. Finally, internalization of NDs was required for reducing the number of intracellular UPEC in T24 bladder cells. These findings suggest that 6 nm NDs are promising candidates to treat recurrent UTIs. PMID:29324795

Occupational Bladder Cancer in a 4,4′-Methylenebis(2-chloroaniline) (MBOCA)-Exposed Worker

PubMed Central

Liu, Chiu-Shong; Liou, Saou-Hsing; Loh, Ching-Hui; Yu, Yi-Chun; Uang, Shi-Nian; Shih, Tung-Sheng; Chen, Hong-I

2005-01-01

A 52-year-old male chemical worker was admitted to the hospital with a history of paroxysmal microscopic hematuria for about 2 years and nocturia with gross hematuria about five times per night for 2 months. He was a nonsmoker and denied a history of any other bladder carcinogen exposure except for occasional pesticide application during agricultural work. Intravenous urogram imaging showed a mass occupying half of the bladder capacity. Cystoscopy revealed a mass over the left dome of the bladder. Cystoscopic biopsy revealed a grade 3 invasive transitional cell carcinoma with marked necrosis. From 1987 until hospital admission in 2001, the patient had worked in a company that produced the 4,4′-methylenebis(2-chloroaniline) (MBOCA) curing agent. He did not wear any personal protective equipment during work. Ambient air MBOCA levels in the purification process area (0.23–0.41 mg/m3) exceeded the U.S. Occupational Safety and Health Administration’s permissible exposure level. Urinary MBOCA levels (267.9–15701.1 μg/g creatinine) far exceeded the California Occupational Safety and Health Administration’s reference value of 100 μg/L. This patient worked in the purification process with occupational exposure to MBOCA for 14 years. According to the environmental and biologic monitoring data and latency period, and excluding other potential bladder carcinogen exposure, this worker was diagnosed as having occupational bladder cancer due to high exposure to MBOCA through inhalation or dermal absorption in the purification area. This case finding supports that MBOCA is a potential human carcinogen. Safe use of skin-protective equipment and respirators is required to prevent workers from MBOCA exposure. PMID:15929884

[A case of eosinophilic cystitis mimicking an invasive bladder cancer].

PubMed

Okazaki, Satoshi; Hori, Jun-Ichi; Kita, Masafumi; Yamaguchi, Satoshi; Kawakami, Norihiro; Kakizaki, Hidehiro

2014-12-01

A 60-year-old woman was referred to our hospital because of gross hematuria, right lumbar pain and lower abdominal pain. Computed tomography (CT) scan revealed hydronephrosis of the right kidney, irregular bladder wall thickening at the right lateral and posterior portion and external iliac lymph node swelling of the right side. Laboratory data revealed disseminated intravascular coagulation syndrome (DIC) and eosinophilia. Because she developed a high fever that was caused by acute obstructive pyelonephritis of the right kidney, percutaneous nephrostomy was placed and the therapy for DIC was initiated. Pathological examination of transurethral resection of bladder tumor performed twice showed no malignancy but inflammatory infiltration of many eosinocytes, leading to the diagnosis of eosinophilic cystitis (EC). We considered the possibility of allergic reaction to the drugs she was taking as the etiology of EC and discontinued all drugs. Although eosinophilia was resolved afterward, she then developed brain infarction, followed by cerebral hemorrhage. She was transferred to a rehabilitation hospital for long-term care. CT scan that was performed 4 months after the initial presentation showed the resolution of hydronephrosis of the right kidney and external iliac lymph node swelling and the improvement of bladder wall thickness. Hydronephrosis of the right kidney has not recurred after removing the nephrostomy catheter. EC is a rare condition that could mimic an invasive bladder cancer. EC should be considered if bladder tumor is associated with eosinophilia. Therapeutic consideration for thromboembolic events should be made in patients with EC.

Wnt7a activates canonical Wnt signaling, promotes bladder cancer cell invasion, and is suppressed by miR-370-3p.

PubMed

Huang, Xiaojing; Zhu, Hongwen; Gao, Zemin; Li, Junzun; Zhuang, Junlong; Dong, Yu; Shen, Bing; Li, Meiqian; Zhou, Hu; Guo, Hongqian; Huang, Ruimin; Yan, Jun

2018-05-04

Once urinary bladder cancer (UBC) develops into muscle-invasive bladder cancer, its mortality rate increases dramatically. However, the molecular mechanisms of UBC invasion and metastasis remain largely unknown. Herein, using 5637 UBC cells, we generated two sublines with low (5637 NMI) and high (5637 HMI) invasive capabilities. Mass spectrum analyses revealed that the Wnt family protein Wnt7a is more highly expressed in 5637 HMI cells than in 5637 NMI cells. We also found that increased Wnt7a expression is associated with UBC metastasis and predicted worse clinical outcome in UBC patients. Wnt7a depletion in 5637 HMI and T24 cells reduced UBC cell invasion and decreased levels of active β-catenin and its downstream target genes involved in the epithelial-to-mesenchymal transition (EMT) and extracellular matrix (ECM) degradation. Consistently, treating 5637 NMI and J82 cells with recombinant Wnt7a induced cell invasion, EMT, and expression of ECM degradation-associated genes. Moreover, TOP/FOPflash luciferase assays indicated that Wnt7a activated canonical β-catenin signaling in UBC cells, and increased Wnt7a expression was associated with nuclear β-catenin in UBC samples. Wnt7a ablation suppressed matrix metalloproteinase 10 (MMP10) expression, and Wnt7a overexpression increased MMP10 promoter activity through two TCF/LEF promoter sites, confirming that Wnt7a-mediated MMP10 activation is mediated by the canonical Wnt/β-catenin pathway. Of note, the microRNA miR-370-3p directly repressed Wnt7a expression and thereby suppressed UBC cell invasion, which was partially restored by Wnt7a overexpression. Our results have identified an miR-370-3p/Wnt7a axis that controls UBC invasion through canonical Wnt/β-catenin signaling, which may offer prognostic and therapeutic opportunities. © 2018 Huang et al.

Trends in the survival of patients diagnosed with kidney or urinary bladder cancer in the Nordic countries 1964-2003 followed up to the end of 2006.

PubMed

Engholm, Gerda; Hakulinen, Timo; Gislum, Mette; Tryggvadóttir, Laufey; Klint, Asa; Bray, Freddie; Storm, Hans H

2010-06-01

Previous studies have shown systematic differences between the Nordic Countries in population-based relative survival following a kidney or urinary bladder cancer diagnosis. Comparison of bladder cancer over time and between Nordic registries is complicated by variable coding practices with respect to the inclusion of in situ cases with invasive tumours. Five-year relative survival of patients with urinary cancer diagnosed in the Nordic countries 1964-2003 and followed up for death through 2006 was studied and contrasted with developments in incidence and mortality. The survival following bladder cancer was higher than for kidney cancer and highest for men. Survival increased over the years in all countries, more for kidney cancer than bladder cancer. For Danish kidney cancer patients, the rate of increase over all the years has been lower than in the other countries, especially among women, resulting in a survival in Denmark some 10-20% points lower than elsewhere in 1999-2003. Danish bladder cancer patient survival was in the last period 4% points lower among men and 10% points lower among women than in the other Nordic countries. The differences were mainly found in the first year following diagnosis, where a higher excess mortality in Denmark was observed. Survival decreased with higher age at diagnosis. The increasing 5-year relative survival in all the Nordic countries for both kidney and bladder cancer are promising, but for kidney cancer a higher percentage detected coincidentally during an imaging investigation for other diseases could play a role. Denmark had the lowest survival, despite their known practice of including benign conditions with invasive bladder cancers. The lower Danish survival after kidney and bladder cancer in the first year after diagnosis could be due to later diagnosis on average, a higher co-morbidity from smoking-related diseases, and perhaps, less adequate cancer treatment and management in Denmark.

Summary and Recommendations from the National Cancer Institute’s Clinical Trials Planning Meeting on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer

PubMed Central

Lerner, Seth P.; Bajorin, Dean F.; Dinney, Colin P.; Efstathiou, Jason A.; Groshen, Susan; Hahn, Noah M.; Hansel, Donna; Kwiatkowski, David; O’Donnell, Michael; Rosenberg, Jonathan; Svatek, Robert; Abrams, Jeffrey S.; Al-Ahmadie, Hikmat; Apolo, Andrea B.; Bellmunt, Joaquim; Callahan, Margaret; Cha, Eugene K.; Drake, Charles; Jarow, Jonathan; Kamat, Ashish; Kim, William; Knowles, Margaret; Mann, Bhupinder; Marchionni, Luigi; McConkey, David; McShane, Lisa; Ramirez, Nilsa; Sharabi, Andrew; Sharpe, Arlene H.; Solit, David; Tangen, Catherine M.; Amiri, Abdul Tawab; Van Allen, Eliezer; West, Pamela J.; Witjes, J. A.; Quale, Diane Zipursky

2016-01-01

The NCI Bladder Cancer Task Force convened a Clinical Trials Planning Meeting (CTPM) Workshop focused on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer (NMIBC). Meeting attendees included a broad and multi-disciplinary group of clinical and research stakeholders and included leaders from NCI, FDA, National Clinical Trials Network (NCTN), advocacy and the pharmaceutical and biotech industry. The meeting goals and objectives were to: 1) create a collaborative environment in which the greater bladder research community can pursue future optimally designed novel clinical trials focused on the theme of molecular targeted and immune-based therapies in NMIBC; 2) frame the clinical and translational questions that are of highest priority; and 3) develop two clinical trial designs focusing on immunotherapy and molecular targeted therapy. Despite successful development and implementation of large Phase II and Phase III trials in bladder and upper urinary tract cancers, there are no active and accruing trials in the NMIBC space within the NCTN. Disappointingly, there has been only one new FDA approved drug (Valrubicin) in any bladder cancer disease state since 1998. Although genomic-based data for bladder cancer are increasingly available, translating these discoveries into practice changing treatment is still to come. Recently, major efforts in defining the genomic characteristics of NMIBC have been achieved. Aligned with these data is the growing number of targeted therapy agents approved and/or in development in other organ site cancers and the multiple similarities of bladder cancer with molecular subtypes in these other cancers. Additionally, although bladder cancer is one of the more immunogenic tumors, some tumors have the ability to attenuate or eliminate host immune responses. Two trial concepts emerged from the meeting including a window of opportunity trial (Phase 0) testing an FGFR3 inhibitor and a second multi-arm multi-stage trial testing combinations of BCG or radiotherapy and immunomodulatory agents in patients who recur after induction BCG (BCG failure). PMID:27376138

Expression of cyclooxygenase-2 in normal urothelium, and superficial and advanced transitional cell carcinoma of bladder.

PubMed

Margulis, Vitaly; Shariat, Shahrokh F; Ashfaq, Raheela; Thompson, Melissa; Sagalowsky, Arthur I; Hsieh, Jer-Tsong; Lotan, Yair

2007-03-01

We compared the differential expression of cyclooxygenase-2 in normal bladder tissue, primary bladder transitional cell carcinoma and transitional cell carcinoma metastases to lymph nodes, and determined whether cyclooxygenase-2 expression is associated with molecular alterations commonly found in bladder transitional cell carcinoma and clinical outcomes after radical cystectomy. Immunohistochemical staining for cyclooxygenase-2, survivin (Novus Biologicals, Littleton, Colorado), p21, p27, pRB, p53, MIB-1, Bax, Bcl-2, cyclin D(1) (Dakotrade mark), cyclin E (Oncogene, Cambridge, Massachusetts) and caspase-3 (Cell Signaling, Beverley, Massachusetts) was performed on archival bladder specimens from 9 subjects who underwent cystectomy for benign causes, 21 patients who underwent transurethral resection and 157 consecutive patients after radical cystectomy, and on 41 positive lymph nodes. Cyclooxygenase-2 was expressed in none of the 9 normal bladder specimens (0%), 52% of transurethral resection specimens, 62% of cystectomy specimens and 80% of lymph nodes involved with transitional cell carcinoma. Cyclooxygenase-2 expression was associated with higher pathological stage, lymphovascular invasion and metastases to lymph nodes (p=0.001, 0.045 and 0.002, respectively). Cyclooxygenase-2 expression was associated with altered expression of p53 (p=0.039), pRB (p=0.025), cyclin D1 (p=0.034) and caspase-3 (p=0.014). On univariate analysis cyclooxygenase-2 expression was associated with an increased risk of disease recurrence and bladder cancer specific mortality (p=0.0189 and 0.0472, respectively). However, on multivariate analysis only pathological stage and metastases to lymph nodes were associated with disease recurrence (p<0.001 and <0.001) and survival (p<0.001 and 0.015, respectively). Cyclooxygenase-2 is not expressed in normal bladder urothelium. Cyclooxygenase-2 over expression is associated with pathological and molecular features of biologically aggressive disease, suggesting a role for cyclooxygenase-2 in bladder cancer development and invasion.

[Nitric oxide pathway and female lower urinary tract. Physiological and pathophysiological role].

PubMed

Gamé, X; Rischmann, P; Arnal, J-F; Malavaud, B

2013-09-01

The aim was to review the literature on nitric oxide and female lower urinary tract. A literature review through the PubMed library until December, 31 2012 was carried out using the following keywords: lower urinary tract, bladder, urethra, nervous central system, innervation, female, women, nitric oxide, phosphodiesterase, bladder outlet obstruction, urinary incontinence, overactive bladder, urinary tract infection. Two nitric oxide synthase isoforms, the neuronal (nNOS) and the endothelial (eNOS), are constitutively expressed in the lower urinary tract. Nevertheless, nNOS is mainly expressed in the bladder neck and the urethra. In the bladder, NO modulates the afferent neurons activity. In pathological condition, inducible NOS expression induces an increase in detrusor contractility and bladder wall thickness and eNOS facilitates Escherichia coli bladder wall invasion inducing recurrent urinary tract infections. In the urethra, NO play a major role in smooth muscle cells relaxation. The NO pathway plays a major role in the female lower urinary tract physiology and physiopathology. While it acts mainly on bladder outlet, in pathological condition, it is involved in bladder dysfunction occurrence. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Molecular markers in disease detection and follow-up of patients with non-muscle invasive bladder cancer.

PubMed

Maas, Moritz; Walz, Simon; Stühler, Viktoria; Aufderklamm, Stefan; Rausch, Steffen; Bedke, Jens; Stenzl, Arnulf; Todenhöfer, Tilman

2018-05-01

Diagnosis and surveillance of non-muscle invasive bladder cancer (NMIBC) is mainly based on endoscopic bladder evaluation and urine cytology. Several assays for determining additional molecular markers (urine-, tissue- or blood-based) have been developed in recent years but have not been included in clinical guidelines so far. Areas covered: This review gives an update on different molecular markers in the urine and evaluates their role in patients with NMIBC in disease detection and surveillance. Moreover, the potential of recent approaches such as DNA methylation assays, multi-panel RNA gene expression assays and cell-free DNA analysis is assessed. Expert commentary: Most studies on various molecular urine markers have mainly focused on a potential replacement of cystoscopy. New developments in high throughput technologies and urine markers may offer further advantages as they may represent a non-invasive approach for molecular characterization of the disease. This opens new options for individualized surveillance strategies and may help to choose the best therapeutic option. The implementation of these technologies in well-designed clinical trials is essential to further promote the use of urine diagnostics in the management of patients with NMIBC.

[Negative prognostic impact of female gender on oncological outcomes following radical cystectomy].

PubMed

Dabi, Y; Rouscoff, Y; Delongchamps, N B; Sibony, M; Saighi, D; Zerbib, M; Peyraumore, M; Xylinas, E

2016-02-01

To confirm gender specific differences in pathologic factors and survival rates of urothelial bladder cancer patients treated with radical cystectomy. We conducted a retrospective monocentric study on 701 patients treated with radical cystectomy and pelvic lymphadenectomy for muscle invasive bladder cancer. Impact of gender on recurrence rate, specific and non-specific mortality rate were evaluated using Cox regression models in univariate and multivariate analysis. We collected data on 553 males (78.9%) and 148 females (21.1%) between 1998 and 2011. Both groups were comparable at inclusion regarding age, pathologic stage, nodal status and lymphovascular invasion. Mean follow-up time was 45 months (interquartile 23-73) and by that time, 163 patients (23.3%) had recurrence of their tumor and 127 (18.1%) died from their disease. In multivariable Cox regression analyses, female gender was independently associated with disease recurrence (RR: 1.73; 95% CI 1.22-2.47; P=0.02) and cancer-specific mortality (RR=2.50, 95% CI=1.71-3.68; P<0.001). We confirmed female gender to be an independent negative prognosis factor for patients following a radical cystectomy and lymphadenectomy for an invasive muscle bladder cancer. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Methylation status as a predictor of intravesical Bacillus Calmette-Guérin (BCG) immunotherapy response of high grade non-muscle invasive bladder tumor.

PubMed

Husek, Petr; Pacovsky, Jaroslav; Chmelarova, Marcela; Podhola, Miroslav; Brodak, Milos

2017-06-01

Genetic and epigenetic alterations play an important role in urothelial cancer pathogenesis. Deeper understanding of these processes could help us achieve better diagnosis and management of this life-threatening disease. The aim of this research was to evaluate the methylation status of selected tumor suppressor genes for predicting BCG response in patients with high grade non-muscle-invasive bladder tumor (NMIBC). We retrospectively evaluated 82 patients with high grade non-muscle-invasive bladder tumor (stage Ta, T1, CIS) who had undergone BCG instillation therapy. We compared epigenetic methylation status in BCG-responsive and BCG-failure groups. We used the MS-MLPA (Methylation-Specific Multiplex Ligation-Dependent Probe Amplification probe sets ME001 and ME004. The control group was 13 specimens of normal urotel (bladder tissue)). Newly identified methylations in high grade NMIBC were found in MUS81a, NTRK1 and PCCA. The methylation status of CDKN2B (P=0.00312 ** ) and MUS81a (P=0.0191 * ) is associated with clinical outcomes of BCG instillation therapy response. CDKN2B and MUS81a unmethylation was found in BCG failure patients. The results show that the methylation status of selected tumor suppressor genes (TSGs) has the potential for predicting BCG response in patients with NMIBC high grade tumors. Tumor suppressor genes such as CDKN2b, MUS81a, PFM-1, MSH6 and THBS1 are very promising for future research.

Clinical results of conformal versus intensity-modulated radiotherapy using a focal simultaneous boost for muscle-invasive bladder cancer in elderly or medically unfit patients.

PubMed

Lutkenhaus, Lotte J; van Os, Rob M; Bel, Arjan; Hulshof, Maarten C C M

2016-03-18

For elderly or medically unfit patients with muscle-invasive bladder cancer, cystectomy or chemotherapy are contraindicated. This leaves radical radiotherapy as the only treatment option. It was the aim of this study to retrospectively analyze the treatment outcome and associated toxicity of conformal versus intensity-modulated radiotherapy (IMRT) using a focal simultaneous tumor boost for muscle-invasive bladder cancer in patients not suitable for cystectomy. One hundred eighteen patients with T2-4 N0-1 M0 bladder cancer were analyzed retrospectively. Median age was 80 years. Treatment consisted of either a conformal box technique or IMRT and included a simultaneous boost to the tumor. To enable an accurate boost delivery, fiducial markers were placed around the tumor. Patients were treated with 40 Gy in 20 fractions to the elective treatment volumes, and a daily tumor boost up to 55-60 Gy. Clinical complete response was seen in 87 % of patients. Three-year overall survival was 44 %, with a locoregional control rate of 73 % at 3 years. Toxicity was low, with late urinary and intestinal toxicity rates grade ≥ 2 of 14 and 5 %, respectively. The use of IMRT reduced late intestinal toxicity, whereas fiducial markers reduced acute urinary toxicity. Radical radiotherapy using a focal boost is feasible and effective for elderly or unfit patients, with a 3-year locoregional control of 73 %. Toxicity rates were low, and were reduced by the use of IMRT and fiducial markers.

The Role of Structural Extracellular Matrix Proteins in Urothelial Bladder Cancer (Review)

PubMed Central

Brunner, Andrea; Tzankov, Alexandar

2007-01-01

The extracellular matrix (ECM) plays a key role in the modulation of cancer cell invasion. In urothelial carcinoma of the bladder (UC) the role of ECM proteins has been widely studied. The mechanisms, which are involved in the development of invasion, progression and generalization, are complex, depending on the interaction of ECM proteins with each other as well as with cancer cells. The following review will focus on the pathogenetic role and prognostic value of structural proteins, such as laminins, collagens, fibronectin (FN), tenascin (Tn-C) and thrombospondin 1 (TSP1) in UC. In addition, the role of integrins mediating the interaction of ECM molecules and cancer cells will be addressed, since integrin-mediated FN, Tn-C and TSP1 interactions seem to play an important role during tumor cell invasion and angiogenesis. PMID:19662222

Gene Expression, DNA Methylation and Prognostic Significance of DNA Repair Genes in Human Bladder Cancer.

PubMed

Wojtczyk-Miaskowska, Anita; Presler, Malgorzata; Michajlowski, Jerzy; Matuszewski, Marcin; Schlichtholz, Beata

2017-01-01

This study investigated the gene expression and DNA methylation of selected DNA repair genes (MBD4, TDG, MLH1, MLH3) and DNMT1 in human bladder cancer in the context of pathophysiological and prognostic significance. To determine the relationship between the gene expression pattern, global methylation and promoter methylation status, we performed real-time PCR to quantify the mRNA of selected genes in 50 samples of bladder cancer and adjacent non-cancerous tissue. The methylation status was analyzed by methylation-specific polymerase chain reaction (MSP) or digestion of genomic DNA with a methylation-sensitive restriction enzyme and PCR with gene-specific primers (MSRE-PCR). The global DNA methylation level was measured using the antibody-based 5-mC detection method. The relative levels of mRNA for MBD4, MLH3, and MLH1 were decreased in 28% (14/50), 34% (17/50) and 36% (18/50) of tumor samples, respectively. The MBD4 mRNA expression was decreased in 46% of non-muscle invasive tumors (Ta/T1) compared with 11% found in muscle invasive tumors (T2-T4) (P<0.003). Analysis of mRNA expression for TDG did not show any significant differences between Ta/T1 and T2-T4 tumors. The frequency of increased DNMT1 mRNA expression was higher in T2-T4 (52%) comparing to Ta/T1 (16%). The overall methylation rates in tumor tissue were 18% for MBD4, 25% for MLH1 and there was no evidence of MLH3 promoter methylation. High grade tumors had significantly lower levels of global DNA methylation (P=0.04). There was a significant association between shorter survival and increased expression of DNMT1 mRNA (P=0.002), decreased expression of MLH1 mRNA (P=0.032) and the presence of MLH1 promoter methylation (P=0.006). This study highlights the importance of DNA repair pathways and provides the first evidence of the role of MBD4 and MLH3 in bladder cancer. In addition, our findings suggest that DNMT1 mRNA and MLH1 mRNA expression, as well as the status of MLH1 promoter methylation, are attractive prognostic markers in this pathology. © 2017 The Author(s). Published by S. Karger AG, Basel.

Combined inhibition of heat shock proteins 90 and 70 leads to simultaneous degradation of the oncogenic signaling proteins involved in muscle invasive bladder cancer

PubMed Central

Cavanaugh, Alice; Juengst, Brendon; Sheridan, Kathleen; Danella, John F.; Williams, Heinric

2015-01-01

Heat shock protein 90 (HSP90) plays a critical role in the survival of cancer cells including muscle invasive bladder cancer (MIBC). The addiction of tumor cells to HSP90 has promoted the development of numerous HSP90 inhibitors and their use in clinical trials. This study evaluated the role of inhibiting HSP90 using STA9090 (STA) alone or in combination with the HSP70 inhibitor VER155008 (VER) in several human MIBC cell lines. While both STA and VER inhibited MIBC cell growth and migration and promoted apoptosis, combination therapy was more effective. Therefore, the signaling pathways involved in MIBC were systematically interrogated following STA and/or VER treatments. STA and not VER reduced the expression of proteins in the p53/Rb, PI3K and SWI/SWF pathways. Interestingly, STA was not as effective as VER or combination therapy in degrading proteins involved in the histone modification pathway such as KDM6A (demethylase) and EP300 (acetyltransferase) as predicted by The Cancer Genome Atlas (TCGA) data. This data suggests that dual HSP90 and HSP70 inhibition can simultaneously disrupt the key signaling pathways in MIBC. PMID:26556859

Characterization of a human anti-tumoral NK cell population expanded after BCG treatment of leukocytes

PubMed Central

García-Cuesta, Eva M.; Esteso, Gloria; Ashiru, Omodele; López-Cobo, Sheila; Álvarez-Maestro, Mario; Linares, Ana; Ho, Mei M.; Martínez-Piñeiro, Luis; T. Reyburn, Hugh; Valés-Gómez, Mar

2017-01-01

ABSTRACT Immunotherapy, via intra-vesical instillations of BCG, is the therapy of choice for patients with high-risk non-muscle invasive bladder cancer. The subsequent recruitment of lymphocytes and myeloid cells, as well as the release of cytokines and chemokines, is believed to induce a local immune response that eliminates these tumors, but the detailed mechanisms of action of this therapy are not well understood. Here, we have studied the phenotype and function of the responding lymphocyte populations as well as the spectrum of cytokines and chemokines produced in an in vitro model of human peripheral blood mononuclear cells (PBMCs) co-cultured with BCG. Natural killer (NK) cell activation was a prominent feature of this immune response and we have studied the expansion of this lymphocyte population in detail. We show that, after BCG stimulation, CD56dim NK cells proliferate, upregulate CD56, but maintain the expression of CD16 and the ability to mediate ADCC. CD56bright NK cells also contribute to this expansion by increasing CD16 and KIR expression. These unconventional CD56bright cells efficiently degranulated against bladder cancer cells and the expansion of this population required the release of soluble factors by other immune cells in the context of BCG. Consistent with these in vitro data, a small, but significant increase in the intensity of CD16 expression was noted in peripheral blood CD56bright cells from bladder cancer patients undergoing BCG therapy, that was not observed in patients treated with mitomycin-C instillations. These observations suggest that activation of NK cells may be an important component of the anti-tumoral immune response triggered by BCG therapy in bladder cancer. PMID:28507799

miR-1182 inhibits growth and mediates the chemosensitivity of bladder cancer by targeting hTERT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Jun; Dai, Wenbin, E-mail: daiwenbin271@163.com; Song, Jianming

2016-02-05

microRNAs (miRNAs) have been demonstrated to contribute to tumor progression and metastasis and proposed to be key regulators of diverse biological processes. In this study, we report that miR-1182 is deregulated in bladder cancer tissues and cell lines. To characterize the role of miR-1182 in bladder cancer cells, we performed functional assays. The overexpression of miR-1182 significantly inhibits bladder cancer cell proliferation, colony formation, and invasion. Moreover, its up-regulation induced cell cycle arrest and apoptosis and mediated chemosensitivity to cisplatin in bladder cancer. Furthermore, a luciferase reporter assay and a rescue experiment indicated that miR-1182 directly targets hTERT by bindingmore » its 3′UTR. In conclusion, these results demonstrate that miR-1182 acts as a tumor suppressor and may be a potential biomarker for bladder cancer diagnosis and treatment.« less

The use of alteplase for the resolution of an intravesical clot in a neonate receiving extracorporeal membrane oxygenation.

PubMed

Olarte, J L; Glover, M L; Totapally, B R

2001-01-01

We present a case of the use of alteplase for the lysis of a large urinary bladder clot. A neonate presented with respiratory failure, secondary to a left diaphragmatic hernia necessitating the need for extracorporeal membrane oxygenation (ECMO) support. On day 3 of ECMO support, hematuria was noted, and a subsequent urinary bladder ultrasound revealed a significant urinary bladder clot. Alteplase (0.5-1 mg) was instilled into the urinary bladder via a 10 French Foley catheter (Sherwood Medical, St. Louis, MO). The catheter was clamped for 1 hour, followed by irrigation with normal saline. Multiple doses of alteplase were administered, resulting in complete resolution of the bladder clot. No adverse effects were attributed to the use of the intravesical alteplase. Alteplase seems to be safe and effective for the resolution of bladder clots, thereby potentially avoiding more invasive surgical procedures.

Production of the Escherichia coli Common Pilus by Uropathogenic E. coli Is Associated with Adherence to HeLa and HTB-4 Cells and Invasion of Mouse Bladder Urothelium

PubMed Central

Carrillo-Casas, Erika Margarita; Durán, Laura; Zhang, Yushan; Hernández-Castro, Rigoberto; Puente, José L.; Daaka, Yehia; Girón, Jorge A.

2014-01-01

Uropathogenic Escherichia coli (UPEC) strains cause urinary tract infections and employ type 1 and P pili in colonization of the bladder and kidney, respectively. Most intestinal and extra-intestinal E. coli strains produce a pilus called E. coli common pilus (ECP) involved in cell adherence and biofilm formation. However, the contribution of ECP to the interaction of UPEC with uroepithelial cells remains to be elucidated. Here, we report that prototypic UPEC strains CFT073 and F11 mutated in the major pilin structural gene ecpA are significantly deficient in adherence to cultured HeLa (cervix) and HTB-4 (bladder) epithelial cells in vitro as compared to their parental strains. Complementation of the ecpA mutant restored adherence to wild-type levels. UPEC strains produce ECP upon growth in Luria-Bertani broth or DMEM tissue culture medium preferentially at 26°C, during incubation with cultured epithelial cells in vitro at 37°C, and upon colonization of mouse bladder urothelium ex vivo. ECP was demonstrated on and inside exfoliated bladder epithelial cells present in the urine of urinary tract infection patients. The ability of the CFT073 ecpA mutant to invade the mouse tissue was significantly reduced. The presence of ECP correlated with the architecture of the biofilms produced by UPEC strains on inert surfaces. These data suggest that ECP can potentially be produced in the bladder environment and contribute to the adhesive and invasive capabilities of UPEC during its interaction with the host bladder. We propose that along with other known adhesins, ECP plays a synergistic role in the multi-step infection of the urinary tract. PMID:25036370

Production of the Escherichia coli common pilus by uropathogenic E. coli is associated with adherence to HeLa and HTB-4 cells and invasion of mouse bladder urothelium.

PubMed

Saldaña, Zeus; De la Cruz, Miguel A; Carrillo-Casas, Erika Margarita; Durán, Laura; Zhang, Yushan; Hernández-Castro, Rigoberto; Puente, José L; Daaka, Yehia; Girón, Jorge A

2014-01-01

Uropathogenic Escherichia coli (UPEC) strains cause urinary tract infections and employ type 1 and P pili in colonization of the bladder and kidney, respectively. Most intestinal and extra-intestinal E. coli strains produce a pilus called E. coli common pilus (ECP) involved in cell adherence and biofilm formation. However, the contribution of ECP to the interaction of UPEC with uroepithelial cells remains to be elucidated. Here, we report that prototypic UPEC strains CFT073 and F11 mutated in the major pilin structural gene ecpA are significantly deficient in adherence to cultured HeLa (cervix) and HTB-4 (bladder) epithelial cells in vitro as compared to their parental strains. Complementation of the ecpA mutant restored adherence to wild-type levels. UPEC strains produce ECP upon growth in Luria-Bertani broth or DMEM tissue culture medium preferentially at 26°C, during incubation with cultured epithelial cells in vitro at 37°C, and upon colonization of mouse bladder urothelium ex vivo. ECP was demonstrated on and inside exfoliated bladder epithelial cells present in the urine of urinary tract infection patients. The ability of the CFT073 ecpA mutant to invade the mouse tissue was significantly reduced. The presence of ECP correlated with the architecture of the biofilms produced by UPEC strains on inert surfaces. These data suggest that ECP can potentially be produced in the bladder environment and contribute to the adhesive and invasive capabilities of UPEC during its interaction with the host bladder. We propose that along with other known adhesins, ECP plays a synergistic role in the multi-step infection of the urinary tract.

Non-invasive prediction of recurrence in bladder cancer by detecting somatic TERT promoter mutations in urine.

PubMed

Descotes, Françoise; Kara, Norelyakin; Decaussin-Petrucci, Myriam; Piaton, Eric; Geiguer, Florence; Rodriguez-Lafrasse, Claire; Terrier, Jean E; Lopez, Jonathan; Ruffion, Alain

2017-08-08

Urothelial bladder cancer (UBC) is characterised by a high risk of recurrence. Patient monitoring is currently based on iterative cystoscopy and on urine cytology with low sensitivity in non-muscle-invasive bladder cancer (NMIBC). Telomerase reverse transcriptase (TERT) is frequently reactivated in UBC by promoter mutations. We studied whether detection of TERT mutation in urine could be a predictor of UBC recurrence and compared this to cytology/cystoscopy for patient follow-up. A total of 348 patients treated by transurethral bladder resection for UBC were included together with 167 control patients. Overall sensitivity was 80.5% and specificity 89.8%, and was not greatly impacted by inflammation or infection. TERT remaining positive after initial surgery was associated with residual carcinoma in situ. TERT in urine was a reliable and dynamic predictor of recurrence in NMIBC (P<0.0001). In univariate analysis, TERT positive-status after initial surgery increased risk of recurrence by 5.34-fold (P=0.0004). TERT positive-status was still associated with recurrence in the subset of patients with negative cystoscopy (P=0.034). TERT mutations in urine might be helpful for early detection of recurrence in UBC, especially in NMIBC.

Comparison of the safety and efficacy of conventional monopolar and 2-micron laser transurethral resection in the management of multiple nonmuscle-invasive bladder cancer.

PubMed

Liu, H; Wu, J; Xue, S; Zhang, Q; Ruan, Y; Sun, X; Xia, S

2013-08-01

To compare the safety and efficacy of conventional monopolar transurethral resection of bladder tumour (TURBT) and 2-micron continuous-wave laser resection (2-µm laser) techniques in the management of multiple nonmuscle-invasive bladder cancer (NMIBC), and to investigate long-term effects on tumour recurrence. Patients with multiple NMIBC were randomized to receive TURBT or 2-µm laser in a nonblinded manner. All patients received intravesical chemotherapy with epirubicin (40 mg/40 ml) for 8 weeks, beginning 1 week after surgery, followed with monthly maintenance therapy for 12 months. Three-year follow-up data of preoperative, operative and postoperative management were recorded. In total, 120 patients were included: 56 in the TURBT group and 64 in the 2-µm laser group. Intra- and postoperative complications (including bladder perforation, bleeding and irritation) were less frequently observed in the 2-µm laser group compared with the TURBT group. There were no significant differences in first time to recurrence, overall recurrence or occurrence of urethral strictures. The 2-µm laser resection method was more effective than TURBT in reducing rates of intra- and postoperative complications, but offered no additional benefit regarding tumour recurrence.

Disseminated Mycobacterium bovis infection post-kidney transplant following remote intravesical BCG therapy for bladder cancer.

PubMed

Ziegler, Jennifer; Ho, Julie; Gibson, Ian W; Nayak, Jasmir G; Stein, Markus; Walkty, Andrew; Orr, Pamela

2018-05-29

Intravesical Bacillus Camlette-Guérin (BCG) is the treatment of choice for non-muscle invasive bladder cancer, and has been used successfully for over 40 years. A rare and potentially fatal complication of intravesical BCG therapy is BCG-induced sepsis. We report a rare case in which a patient with end-stage renal disease secondary to chronic granulomatous interstitial nephritis underwent remote, pre-transplant intravesical BCG treatment for high-grade non-invasive papillary bladder carcinoma. The patient subsequently received a deceased donor kidney transplant 5 years after BCG therapy, with thymoglobulin induction therapy and standard triple maintenance immunosuppression. Two years post-transplant, he developed BCG-induced sepsis confirmed by cultures from urine, blood and left native kidney biopsy. He died from disseminated BCG-induced sepsis and failure of his renal allograft. This case highlights the potential adverse reactions associated with intravesical BCG therapy that may occur years after bladder cancer therapy is completed, and should heighten physician awareness for BCG-related infections during pre-transplant assessment and post-transplant care of solid organ transplants recipients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Cytoplasmatic and Nuclear YAP1 and pYAP1 Staining in Urothelial Bladder Cancer.

PubMed

Latz, Stefan; Umbach, Tine; Goltz, Diane; Kristiansen, Glen; Müller, Stephan C; Ellinger, Jörg

2016-01-01

Yes-associated protein 1 (YAP1), the nuclear effector of the Hippo pathway, plays an important role in many tumor entities. We evaluated staining and clinical significance of YAP1 and phosphorylated YAP1 (pYAP1) in urothelial bladder cancer (BCA). We used a tissue micorarray with samples of patients with muscle-invasive bladder cancer (MIBC, n = 192), non-muscle-invasive bladder cancer (NMIBC, n = 192) and normal urothelial bladder tissue (CTRL, n = 38) to determine the immunhistochemical staining of YAP1 and pYAP1. Cytoplasmatic and nuclear levels were evaluated. The t test was used for comparative analysis. Overall survival and progression-free survival were evaluated by Kaplan-Meier estimates and the Cox proportional hazard regression model. Nuclear YAP1 as well as cytoplasmatic pYAP1 levels were higher in CTRL than in BCA, whereby both--NMIBC and MIBC--had lower levels than CTRL. Among patients with MIBC, cytoplasmatic YAP1 and pYAP1 staining decreased with advanced stage. YAP1 and pYAP1 staining did not correlate with the recurrence rate, progression-free, cancer-specific or overall survival. Immunhistochemical staining and subcellular localization of YAP1 and pYAP1 are different for BCA, NMIBC, MIBC and CTRL, indicating that the Hippo pathway is involved in urothelial carcinogenesis. © 2015 S. Karger AG, Basel.

Significance of ERBB2 Overexpression in Therapeutic Resistance and Cancer-Specific Survival in Muscle-Invasive Bladder Cancer Patients Treated With Chemoradiation-Based Selective Bladder-Sparing Approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Inoue, Masaharu; Koga, Fumitaka, E-mail: f-koga@cick.jp; Yoshida, Soichiro

2014-10-01

Purpose: To investigate the associations of ERBB 2 overexpression with chemoradiation therapy (CRT) resistance and cancer-specific survival (CSS) in muscle-invasive bladder cancer (MIBC) patients treated with the CRT-based bladder-sparing protocol. Methods and Materials: From 1997 to 2012, 201 patients with cT2-4aN0M0 bladder cancer were treated with CRT (40 Gy with concurrent cisplatin) following transurethral resection of bladder tumor (TURBT). Basically, patients with tumors that showed good CRT response and were amenable to segmental resection underwent partial cystectomy (PC) with pelvic lymph node dissection for bladder preservation; otherwise, radical cystectomy (RC) was recommended. Included in this study were 119 patients in whom TURBTmore » specimens were available for immunohistochemical analysis of ERBB 2 expression. Following CRT, 30 and 65 patients underwent PC or RC, respectively; the remaining 24 patients did not undergo cystectomy. Tumors were defined as CRT-resistant when patients did not achieve complete response after CRT. Associations of ERBB 2 overexpression with CRT resistance and CSS were evaluated. Results: CRT resistance was observed clinically in 56% (67 of 119 patients) and pathologically (in cystectomy specimens) in 55% (52 of 95 patients). ERBB 2 overexpression was observed in 45 patients (38%). On multivariate analysis, ERBB 2 overexpression was an independent predictor for CRT resistance clinically (odds ratio, 3.6; P=.002) and pathologically (odds ratio, 2.9; P=.031). ERBB 2 overexpression was associated with shorter CSS (5-year CSS rates, 56% vs 87% for the ERBB 2 overexpression group vs the others; P=.001). ERBB 2 overexpression was also an independent risk factor for bladder cancer death at all time points of our bladder-sparing protocol (pre-CRT, post-CRT, and post-cystectomy). Conclusions: ERBB 2 overexpression appears relevant to CRT resistance and unfavorable CSS in MIBC patients treated with the CRT-based bladder-sparing protocol. ERBB 2-targeting treatment may improve the outcomes of such patients.« less

Significance of ERBB2 overexpression in therapeutic resistance and cancer-specific survival in muscle-invasive bladder cancer patients treated with chemoradiation-based selective bladder-sparing approach.

PubMed

Inoue, Masaharu; Koga, Fumitaka; Yoshida, Soichiro; Tamura, Tomoki; Fujii, Yasuhisa; Ito, Eisaku; Kihara, Kazunori

2014-10-01

To investigate the associations of ERBB 2 overexpression with chemoradiation therapy (CRT) resistance and cancer-specific survival (CSS) in muscle-invasive bladder cancer (MIBC) patients treated with the CRT-based bladder-sparing protocol. From 1997 to 2012, 201 patients with cT2-4aN0M0 bladder cancer were treated with CRT (40 Gy with concurrent cisplatin) following transurethral resection of bladder tumor (TURBT). Basically, patients with tumors that showed good CRT response and were amenable to segmental resection underwent partial cystectomy (PC) with pelvic lymph node dissection for bladder preservation; otherwise, radical cystectomy (RC) was recommended. Included in this study were 119 patients in whom TURBT specimens were available for immunohistochemical analysis of ERBB 2 expression. Following CRT, 30 and 65 patients underwent PC or RC, respectively; the remaining 24 patients did not undergo cystectomy. Tumors were defined as CRT-resistant when patients did not achieve complete response after CRT. Associations of ERBB 2 overexpression with CRT resistance and CSS were evaluated. CRT resistance was observed clinically in 56% (67 of 119 patients) and pathologically (in cystectomy specimens) in 55% (52 of 95 patients). ERBB 2 overexpression was observed in 45 patients (38%). On multivariate analysis, ERBB 2 overexpression was an independent predictor for CRT resistance clinically (odds ratio, 3.6; P=.002) and pathologically (odds ratio, 2.9; P=.031). ERBB 2 overexpression was associated with shorter CSS (5-year CSS rates, 56% vs 87% for the ERBB 2 overexpression group vs the others; P=.001). ERBB 2 overexpression was also an independent risk factor for bladder cancer death at all time points of our bladder-sparing protocol (pre-CRT, post-CRT, and post-cystectomy). ERBB 2 overexpression appears relevant to CRT resistance and unfavorable CSS in MIBC patients treated with the CRT-based bladder-sparing protocol. ERBB 2-targeting treatment may improve the outcomes of such patients. Copyright © 2014 Elsevier Inc. All rights reserved.

Neurogenic bladder in spinal cord injury patients

PubMed Central

Taweel, Waleed Al; Seyam, Raouf

2015-01-01

Neurogenic bladder dysfunction due to spinal cord injury poses a significant threat to the well-being of patients. Incontinence, renal impairment, urinary tract infection, stones, and poor quality of life are some complications of this condition. The majority of patients will require management to ensure low pressure reservoir function of the bladder, complete emptying, and dryness. Management typically begins with anticholinergic medications and clean intermittent catheterization. Patients who fail this treatment because of inefficacy or intolerability are candidates for a spectrum of more invasive procedures. Endoscopic managements to relieve the bladder outlet resistance include sphincterotomy, botulinum toxin injection, and stent insertion. In contrast, patients with incompetent sphincters are candidates for transobturator tape insertion, sling surgery, or artificial sphincter implantation. Coordinated bladder emptying is possible with neuromodulation in selected patients. Bladder augmentation, usually with an intestinal segment, and urinary diversion are the last resort. Tissue engineering is promising in experimental settings; however, its role in clinical bladder management is still evolving. In this review, we summarize the current literature pertaining to the pathology and management of neurogenic bladder dysfunction in patients with spinal cord injury. PMID:26090342

Spontaneous Urinary Bladder Leiomyoma in a Rhesus Macaque (Macaca mulatta).

PubMed

Scott, Kathleen E; Frydman, Galit; Fox, James G; Bakthavatchalu, Vasudevan

2018-06-01

Here we report the case of a urinary bladder leiomyoma in a rhesus macaque. The animal was clinically normal and had a lipoma localized to the stifle. Endovesicular leiomyomas are the most common form of urinary bladder leiomyoma in humans. In contrast, this macaque's tumor exhibited extravesicular localization in the bladder. Urinary bladder leiomyomas account for less than 0.5% of all bladder tumors in humans, with only 250 cases reported in total.

Traces: making sense of urodynamics testing--Part 8: Evaluating sensations of bladder filling.

PubMed

Gray, Mikel

2011-01-01

The "Traces" series discusses how the urodynamic clinician generates usable data from a filling cystometrogram (CMG). Part 8 focuses on the question, "What are the sensations of bladder filling?" Recent research suggests that sensations of bladder filling wax and wane from consciousness in healthy persons free of bothersome lower urinary tract symptoms. Because of its invasive and atypical nature when compared to daily life, multichannel urodynamics testing cannot reproduce the numerous and complex variables that influence bladder sensation in the healthy individual, making the evaluation of sensations of bladder filling a particularly challenging component of the filling CMG. Routine assessment of bladder sensations focuses on identification of three landmarks--first sensation of bladder filling, first desire to void, and a strong desire to void. A fourth sensation, bladder fullness or a compelling desire to void, is recommended. In addition to assessing these sensations, the urodynamic clinician must assess sensations indicating associated disease or disorders affecting lower urinary tract function, including urgency, pain, and atypical sensations. This assessment should be completed in the context of the results of one or more validated instruments used to measure bladder sensations.

Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer.

PubMed

Liu, David; Abbosh, Philip; Keliher, Daniel; Reardon, Brendan; Miao, Diana; Mouw, Kent; Weiner-Taylor, Amaro; Wankowicz, Stephanie; Han, Garam; Teo, Min Yuen; Cipolla, Catharine; Kim, Jaegil; Iyer, Gopa; Al-Ahmadie, Hikmat; Dulaimi, Essel; Chen, David Y T; Alpaugh, R Katherine; Hoffman-Censits, Jean; Garraway, Levi A; Getz, Gad; Carter, Scott L; Bellmunt, Joaquim; Plimack, Elizabeth R; Rosenberg, Jonathan E; Van Allen, Eliezer M

2017-12-19

Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. Here, we analyze whole exome sequencing of matched pre- and post-neoadjuvant cisplatin-based chemotherapy primary bladder tumor samples from 30 muscle-invasive bladder cancer patients. We observe no overall increase in tumor mutational burden post-chemotherapy, though a significant proportion of subclonal mutations are unique to the matched pre- or post-treatment tumor, suggesting chemotherapy-induced and/or spatial heterogeneity. We subsequently identify and validate a novel mutational signature in post-treatment tumors consistent with known characteristics of cisplatin damage and repair. We find that post-treatment tumor heterogeneity predicts worse overall survival, and further observe alterations in cell-cycle and immune checkpoint regulation genes in post-treatment tumors. These results provide insight into the clinical and genomic dynamics of tumor evolution with cisplatin-based chemotherapy, suggest mechanisms of clinical resistance, and inform development of clinically relevant biomarkers and trials of combination therapies.

Diagnostic and Prognostic Significance of Serum and Tissue Galectin 3 Expression in Patients with Carcinoma of the Bladder

PubMed Central

Gendy, Hoda El; Madkour, Bothina; Abdelaty, Sara; Essawy, Fayza; Khattab, Dina; Hammam, Olfat; Nour, Hani H.

2014-01-01

Background Galectins are group of proteins found in the cytoplasm, nucleus, cell surface and extracellular matrix. Galectin 3 (Gal-3) displays pathological expression in a variety of processes such as tumorigenesis. Patients and Method 70 patients classified into the control group, cystitis group, transitional cell carcinoma group, and squamous cell carcinoma group were enrolled in this study which aimed to detect the serum level and the intensity of tissue expression of Gal-3. Results Both serum level and tissue expression of Gal-3 were statistically higher in bladder cancer patients compared to the other groups. Gal-3 level expression increased from low to high grade urothelial tumors, with a statistically significant increase of its level and expression between muscle invasive and non-muscle invasive Ta urothelial tumors. Conclusion The serum Gal-3 level is sensitive and specific for the diagnosis of bladder cancer. The prognostic significance of tissue expression is to be confirmed. PMID:26195948

Minimally invasive management with holmium laser in total urinary tract calculi.

PubMed

Zhang, Xiao; Yu, Jianjun; Yang, Ranxing

2013-05-01

The purpose of this article was to study the management of total urinary tract calculi using holmium laser minimally invasive techniques. It is rare for patients to present kidney stones, ureteral stones, and bladder stones simultaneously, and their treatment is considered to be complicated and difficult, specifically by minimally invasive techniques. We collected seven cases of total urinary tract calculi from May 2007 to September 2012. Three cases were unilateral, and the others were bilateral. All of the cases presented calculus in the bladder, ureter, and kidney, which were secondary to the long-term indwelling double J stent or lower urinary obstruction. Extracorporeal shock-wave lithotripsy (SWL) was administered first, followed by the operation. For patients with bilateral calculi, at one stage, ureteroscopic lithotripsy (URL) with holmium laser was performed in all four cases to remove the bladder and bilateral ureter stones. Then, all patients underwent percutaneous nephrolithotomy (PCNL) with holmium procedures to address the bilateral kidney and upper ureter stones at the second stage. The indwelling double J stents were removed at the same time. For the patients with unilateral calculi, we performed a single operation, but it was conducted using the same treatment sequence as the bilateral procedure. The related symptoms in all cases disappeared after the operation. Re-examination showed that the stones were nearly dissolved and that renal function was recovered. URL with holmium laser for the bladder and ureters combined with PCNL to dissolve kidney and upper ureteral stones could be the ideal choice for the treatment of total urinary tract calculi.

Muscle invasive bladder cancer: examining survivor burden and unmet needs.

PubMed

Mohamed, Nihal E; Chaoprang Herrera, Phapichaya; Hudson, Shawna; Revenson, Tracey A; Lee, Cheryl T; Quale, Diane Z; Zarcadoolas, Christina; Hall, Simon J; Diefenbach, Michael A

2014-01-01

Although improvements in perioperative care have decreased surgical morbidity after radical cystectomy for muscle invasive bladder cancer, treatment side effects still have a negative impact on patient quality of life. We examined unmet patient needs along the illness trajectory. A total of 30 patients (26.7% women) treated with cystectomy and urinary diversion for muscle invasive bladder cancer participated in the study. Patients were recruited from the Department of Urology at Mount Sinai and through advertisements on the Bladder Cancer Advocacy Network (BCAN) website between December 2011 and September 2012. Data were collected at individual interviews, which were audiotaped and transcribed. Transcribed data were quantitatively analyzed to explore key unmet needs. At diagnosis unmet informational needs were predominant, consisting of insufficient discussion of certain topics, including urinary diversion options and their side effects, self-care, the recovery process and medical insurance. Unmet psychological needs related to depression, and worries about changes in body image and sexual function were reported. Postoperative unmet needs revolved around medical needs (eg pain and bowel dysfunction) and instrumental needs (eg need of support for stomal appliances, catheters and incontinence). During survivorship (ie 6 to 72 months postoperatively) unmet needs centered around psychological support (ie depression, poor body image and sexual dysfunction) and instrumental support (eg difficulty adjusting to changes in daily living). Meeting patient needs is imperative to ensure adequate patient involvement in health care and enhance postoperative quality of life. An effective support provision plan should follow changes in patient needs. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer.

PubMed

James, Nicholas D; Hussain, Syed A; Hall, Emma; Jenkins, Peter; Tremlett, Jean; Rawlings, Christine; Crundwell, Malcolm; Sizer, Bruce; Sreenivasan, Thiagarajan; Hendron, Carey; Lewis, Rebecca; Waters, Rachel; Huddart, Robert A

2012-04-19

Radiotherapy is an alternative to cystectomy in patients with muscle-invasive bladder cancer. In other disease sites, synchronous chemoradiotherapy has been associated with increased local control and improved survival, as compared with radiotherapy alone. In this multicenter, phase 3 trial, we randomly assigned 360 patients with muscle-invasive bladder cancer to undergo radiotherapy with or without synchronous chemotherapy. The regimen consisted of fluorouracil (500 mg per square meter of body-surface area per day) during fractions 1 to 5 and 16 to 20 of radiotherapy and mitomycin C (12 mg per square meter) on day 1. Patients were also randomly assigned to undergo either whole-bladder radiotherapy or modified-volume radiotherapy (in which the volume of bladder receiving full-dose radiotherapy was reduced) in a partial 2-by-2 factorial design (results not reported here). The primary end point was survival free of locoregional disease. Secondary end points included overall survival and toxic effects. At 2 years, rates of locoregional disease-free survival were 67% (95% confidence interval [CI], 59 to 74) in the chemoradiotherapy group and 54% (95% CI, 46 to 62) in the radiotherapy group. With a median follow-up of 69.9 months, the hazard ratio in the chemoradiotherapy group was 0.68 (95% CI, 0.48 to 0.96; P=0.03). Five-year rates of overall survival were 48% (95% CI, 40 to 55) in the chemoradiotherapy group and 35% (95% CI, 28 to 43) in the radiotherapy group (hazard ratio, 0.82; 95% CI, 0.63 to 1.09; P=0.16). Grade 3 or 4 adverse events were slightly more common in the chemoradiotherapy group than in the radiotherapy group during treatment (36.0% vs. 27.5%, P=0.07) but not during follow-up (8.3% vs. 15.7%, P=0.07). Synchronous chemotherapy with fluorouracil and mitomycin C combined with radiotherapy significantly improved locoregional control of bladder cancer, as compared with radiotherapy alone, with no significant increase in adverse events. (Funded by Cancer Research U.K.; BC2001 Current Controlled Trials number, ISRCTN68324339.).

Prognostic Performance and Reproducibility of the 1973 and 2004/2016 World Health Organization Grading Classification Systems in Non-muscle-invasive Bladder Cancer: A European Association of Urology Non-muscle Invasive Bladder Cancer Guidelines Panel Systematic Review.

PubMed

Soukup, Viktor; Čapoun, Otakar; Cohen, Daniel; Hernández, Virginia; Babjuk, Marek; Burger, Max; Compérat, Eva; Gontero, Paolo; Lam, Thomas; MacLennan, Steven; Mostafid, A Hugh; Palou, Joan; van Rhijn, Bas W G; Rouprêt, Morgan; Shariat, Shahrokh F; Sylvester, Richard; Yuan, Yuhong; Zigeuner, Richard

2017-11-01

Tumour grade is an important prognostic indicator in non-muscle-invasive bladder cancer (NMIBC). Histopathological classifications are limited by interobserver variability (reproducibility), which may have prognostic implications. European Association of Urology NMIBC guidelines suggest concurrent use of both 1973 and 2004/2016 World Health Organization (WHO) classifications. To compare the prognostic performance and reproducibility of the 1973 and 2004/2016 WHO grading systems for NMIBC. A systematic literature search was undertaken incorporating Medline, Embase, and the Cochrane Library. Studies were critically appraised for risk of bias (QUIPS). For prognosis, the primary outcome was progression to muscle-invasive or metastatic disease. Secondary outcomes were disease recurrence, and overall and cancer-specific survival. For reproducibility, the primary outcome was interobserver variability between pathologists. Secondary outcome was intraobserver variability (repeatability) by the same pathologist. Of 3593 articles identified, 20 were included in the prognostic review; three were eligible for the reproducibility review. Increasing tumour grade in both classifications was associated with higher disease progression and recurrence rates. Progression rates in grade 1 patients were similar to those in low-grade patients; progression rates in grade 3 patients were higher than those in high-grade patients. Survival data were limited. Reproducibility of the 2004/2016 system was marginally better than that of the 1973 system. Two studies on repeatability showed conflicting results. Most studies had a moderate to high risk of bias. Current grading classifications in NMIBC are suboptimal. The 1973 system identifies more aggressive tumours. Intra- and interobserver variability was slightly less in the 2004/2016 classification. We could not confirm that the 2004/2016 classification outperforms the 1973 classification in prediction of recurrence and progression. This article summarises the utility of two different grading systems for non-muscle-invasive bladder cancer. Both systems predict progression and recurrence, although pathologists vary in their reporting; suggestions for further improvements are made. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Do we have biomarkers to predict response to neoadjuvant and adjuvant chemotherapy and immunotherapy in bladder cancer?

PubMed Central

Wezel, Felix; Vallo, Stefan

2017-01-01

Radical cystectomy (RC) is the standard of care treatment of localized muscle-invasive bladder cancer (BC). However, about 50% of patients develop metastases within 2 years after cystectomy. Neoadjuvant cisplatin-based chemotherapy before cystectomy improves the overall survival (OS) in patients with muscle-invasive BC. Pathological response to neoadjuvant treatment is a strong predictor of better disease-specific survival. Nevertheless, some patients do not benefit from chemotherapy. The identification of reliable biomarkers enabling clinicians to identify patients who might benefit from chemotherapy is a very important clinical task. An identification tool could lead to individualized therapy, optimizing response rates. In addition, unnecessary treatment with chemotherapy which potentially leads to a loss of quality of life and which might also might cause a delay of cystectomy in a neoadjuvant setting could be avoided. The present review aims to summarize and discuss the current literature on biomarkers for the prediction of response to systemic therapy in muscle-invasive BC. Tremendous efforts in genetic and molecular characterization have led to the identification of predictive candidate biomarkers in urothelial carcinoma (UC), although prospective validation is pending. Ongoing clinical trials examining the benefit of individual therapies in UC of the bladder (UCB) by molecular patient selection hold promise to shed light on this question. PMID:29354494

Predicting the failure of retrograde ureteral stent insertion for managing malignant ureteral obstruction in outpatients

PubMed Central

WANG, JIN-YOU; ZHANG, HAI-LIANG; ZHU, YAO; QIN, XIAO-JIAN; DAI, BO; YE, DING-WEI

2016-01-01

Malignant ureteral obstruction (MUO) is an unpropitious sign that is commonly observed in patients with advanced incurable cancer. The present study aimed to evaluate predictive factors for the failure of retrograde ureteral stent insertion in the management of MUO in outpatients. A total of 164 patients with MUO were retrospectively assessed in this study. Clinical factors, including age, gender, type of malignancy, level of obstruction, cause of obstruction, pre-operative creatinine level, degree of hydronephrosis, condition of the contralateral ureter, prior radiotherapy, Eastern Cooperative Oncology Group performance status (ECOG PS), bladder wall invasion and technical failure, were recorded for each case. Univariate and multivariate logistic regression analyses were used to investigate the risk factors for predicting the failure of retrograde ureteral stent insertion. In total, 38 out of 164 patients experienced bilateral obstruction, therefore, a total of 202 ureteral units were available for data analysis. The rate of insertion failure in MUO was 34.65%. Multivariate analyses identified ECOG PS, degree of hydronephrosis and bladder wall invasion as independent predictors for insertion failure. Overall, the present study found that rate of retrograde ureteral stent insertion failure is high in outpatients with MUO, and that ECOG PS, degree of hydronephrosis and bladder invasion are potential independent predictors of insertion failure. PMID:26870299

[Transitional tumours of urinary bladder (author's transl)].

PubMed

Laumonier, R

1979-01-01

An overall survey of the transitional epithelium of the bladder and its carcinomas. This study is based upon the recent literature, in particular the considerable contribution of scanner electron microscopy. a) The transitional epithelium has the reputation of having a simple structure and even behaviour. In fact, it is complex with highly specialised surface cells. It has marked powers of regeneration after aggressions of various types. b) Tumours of the transitional epithelium are defined in relation to rupture of the basal lamina. Invasive carcinomas are classified according to their histological stage of penetration, their pure or partially metaplasic type and their degree defined according to the criteria of Broders. There exists a correlation between these three types of evaluation. Non-invasive carcinomas are either papillary--putting into question the reality of benign bladder papilloma--or flat mucosal and then often associated closely or at a distance with an invasive carcinoma. c) Abnormal regeneration, dysplasia or hyperplasia as a result of aggressions of different types or developing in isolation represent a high risk histologically, implying the need for careful follow-up and surveillance. d) Histopathological study of urothelial or transitional tumours is simple in operative specimens but difficult in biopsies. It requires close cooperation between surgeons and pathologists to ensure correct orientation of the fragments.

Overexpression of caldesmon is associated with tumor progression in patients with primary non-muscle-invasive bladder cancer

PubMed Central

Lee, Myung-Shin; Lee, Jisu; Kim, Joo Heon; Kim, Won Tae; Kim, Wun-Jae; Ahn, Hanjong; Park, Jinsung

2015-01-01

The expression and function of caldesmon (CAD) in urothelial bladder carcinoma (BC) have not been reported. Here, we investigated the expression, prognostic value, and potential functional mechanism of CAD in primary non-muscle-invasive bladder cancer (NMIBC). Protein profiling of tissue samples using antibody microarrays showed significantly higher CAD expression in muscle-invasive BC tissues compared with NMIBC tissues. We then validated the CAD expression in BC cells by immunohistochemistry analysis using paraffin-embedded tissue blocks and western blots using BC cell lines. In addition, we examined the expression of CAD variants by reverse transcription-polymerase chain reaction, and confirmed the expression of low-molecular-weight isoforms (L-CAD), specifically encoded by WI-38 L-CAD II (transcript variant 2), in BC cells. Survival analysis in an independent primary NMIBC cohort comprising 132 patients showed that positive CAD expression was significantly associated with poorer prognosis than no CAD expression with regard to recurrence- and progression-free survival (p = 0.001 and 0.014, respectively). Multivariate analyses further indicated that positive CAD expression was an independent predictor of progression-free survival (p = 0.032; HR = 5.983). Data obtained from in vitro silencing and overexpression studies indicated that L-CAD promotes migration and invasiveness of BC cells. Immunofluorescence assays showed dramatic structural changes in the actin cytoskeleton of BC cells after L-CAD overexpression. Our findings collectively suggest that L-CAD overexpression in primary NMIBC is significantly associated with tumor progression and that a possible mechanism for L-CAD's activity is implicated in increased cell motility and invasive characteristics through morphological changes in BC cells. PMID:26430961

EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016.

PubMed

Babjuk, Marko; Böhle, Andreas; Burger, Maximilian; Capoun, Otakar; Cohen, Daniel; Compérat, Eva M; Hernández, Virginia; Kaasinen, Eero; Palou, Joan; Rouprêt, Morgan; van Rhijn, Bas W G; Shariat, Shahrokh F; Soukup, Viktor; Sylvester, Richard J; Zigeuner, Richard

2017-03-01

The European Association of Urology (EAU) panel on Non-muscle-invasive Bladder Cancer (NMIBC) released an updated version of the guidelines on Non-muscle-invasive Bladder Cancer. To present the 2016 EAU guidelines on NMIBC. A broad and comprehensive scoping exercise covering all areas of the NMIBC guidelines published between April 1, 2014, and May 31, 2015, was performed. Databases covered by the search included Medline, Embase, and the Cochrane Libraries. Previous guidelines were updated, and levels of evidence and grades of recommendation were assigned. Tumours staged as TaT1 or carcinoma in situ (CIS) are grouped as NMIBC. Diagnosis depends on cystoscopy and histologic evaluation of the tissue obtained by transurethral resection of the bladder (TURB) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TURB is essential for the patient's prognosis. If the initial resection is incomplete, there is no muscle in the specimen, or a high-grade or T1 tumour is detected, a second TURB should be performed within 2-6 wk. The risks of both recurrence and progression may be estimated for individual patients using the European Organisation for Research and Treatment of Cancer (EORTC) scoring system and risk tables. The stratification of patients into low-, intermediate-, and high-risk groups is pivotal to recommending adjuvant treatment. For patients with a low-risk tumour and intermediate-risk patients at a lower risk of recurrence, one immediate instillation of chemotherapy is recommended. Patients with an intermediate-risk tumour should receive 1 yr of full-dose bacillus Calmette-Guérin (BCG) intravesical immunotherapy or instillations of chemotherapy for a maximum of 1 yr. In patients with high-risk tumours, full-dose intravesical BCG for 1-3 yr is indicated. In patients at highest risk of tumour progression, immediate radical cystectomy (RC) should be considered. RC is recommended in BCG-refractory tumours. The long version of the guidelines is available at the EAU Web site (www.uroweb.org/guidelines). These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice. The European Association of Urology has released updated guidelines on Non-muscle-invasive Bladder Cancer (NMIBC). Stratification of patients into low-, intermediate-, and high-risk groups is essential for decisions about adjuvant intravesical instillations. Risk tables can be used to estimate risks of recurrence and progression. Radical cystectomy should be considered only in case of failure of instillations or in NMIBC with the highest risk of progression. Copyright © 2016. Published by Elsevier B.V.

Effectiveness of platinum-based adjuvant chemotherapy for muscle-invasive bladder cancer: A weighted propensity score analysis.

PubMed

Shimizu, Fumitaka; Muto, Satoru; Taguri, Masataka; Ieda, Takeshi; Tsujimura, Akira; Sakamoto, Yoshiro; Fujita, Kazuhiko; Okegawa, Takatsugu; Yamaguchi, Raizo; Horie, Shigeo

2017-05-01

To evaluate the clinical benefit of adjuvant platinum-based chemotherapy after radical cystectomy for muscle-invasive bladder cancer in routine clinical practice. The present observational study was carried out to compare the effectiveness of adjuvant chemotherapy versus observation post-radical cystectomy in patients with clinically muscle-invasive bladder cancer. Cancer-specific survival and overall survival between the adjuvant chemotherapy group and radical cystectomy alone group were compared using Kaplan-Meier method and log-rank test. After adjusting for background factors using propensity score weighting, differences in cancer-specific survival and overall survival between these two groups were compared. Subgroup analyses by the pathological characteristics were carried out. In total, 322 patients were included in the present study. Of these, 23% received adjuvant chemotherapy post-radical cystectomy. Clinicopathological characteristics showed that patients in the adjuvant chemotherapy group were pathologically more advanced and were at higher risk than the radical cystectomy alone group. In the unadjusted population, although it is not significant, the adjuvant chemotherapy group had lower overall survival (3-year overall survival; 61.5% vs 73.6%, HR 1.33, P = 0.243, log-rank test, adjuvant chemotherapy vs radical cystectomy alone). In the weighted propensity score analysis, although it is not significant, the adjuvant chemotherapy group were superior to radical cystectomy alone groups (overall survival: HR 0.65, 95% CI 0.39-1.09, P = 0.099, log-rank test, adjuvant chemotherapy vs radical cystectomy alone). Subgroup analyses showed that adjuvant chemotherapy significantly reduced the hazard ratio of overall survival and cancer-specific survival in the ≥pT3, pN+, ly+ and v+ subgroups. Platinum-based adjuvant chemotherapy might be associated with increased cancer-specific survival and overall survival in patients with high-risk invasive bladder cancer. © 2017 The Japanese Urological Association.

Oncogene miR-187-5p is associated with cellular proliferation, migration, invasion, apoptosis and an increased risk of recurrence in bladder cancer.

PubMed

Li, Zuwei; Lin, Canbin; Zhao, Liwen; Zhou, Liang; Pan, Xiang; Quan, Jing; Peng, Xiqi; Li, Weiqing; Li, Hang; Xu, Jinling; Xu, Weijie; Guan, Xin; Chen, Yun; Lai, Yongqing

2018-06-05

Bladder cancer, the ninth-most-common malignancy worldwide with an estimated 356,000 new cases and 145,000 deaths annually, has a propensity to relapse, requiring lifelong monitoring after diagnosis. 75% patients diagnosed with BC are non-muscle invasive BC and over 50% of them experience recurrences within 6-12 years of initial diagnosis. miRNA are small, noncoding RNA and shown to be oncogenes or anti-oncogenes in bladder cancer, contributing to numerous BC cell processes, including cell proliferation, differentiation, migration and apoptosis. RT-qPCR were performed to detect the expression of miR-187-5p in tissues and cell lines, After which, clinicopathological variables and the prognostic value of altered miR-187-5p expression in BC was analyzed with the 48 formalin-fixed paraffin-embedded BC samples. Moreover, Cell functional assays (wound healing assay, CCK-8 assay, transwell assay and flow cytometry assay) were performed to explore the relationship between miR-187-5p expression and cell proliferation, migration, invasion and apoptosis in BC. Up-regulation of miR-187-5p was observed in BC tissues and BC cell lines. Cox proportional hazard regression analysis demonstrated that the patients with low expression of miR-187-5p experience lower risks of recurrence in the univariate and multivariate analysis. The Kaplan-Meier recurrence-free curves suggested that the patients with low expression of miR-187-5p experience lower risks of recurrence. Up-regulation of miR-187-5p promotes cell proliferation and mobility and inhibits the apoptosis of 5637 and UM-UC-3 cell, while down-regulation of miR-187-5p reverses these effects. The results of our study demonstrated that oncogene miR-187-5p is associated with cellular proliferation, migration, invasion, apoptosis and an increased risk of recurrence in bladder cancer. Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Occult Pelvic Lymph Node Involvement in Bladder Cancer: Implications for Definitive Radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goldsmith, Benjamin; Baumann, Brian C.; He, Jiwei

2014-03-01

Purpose: To inform radiation treatment planning for clinically staged, node-negative bladder cancer patients by identifying clinical factors associated with the presence and location of occult pathologic pelvic lymph nodes. Methods and Materials: The records of patients with clinically staged T1-T4N0 urothelial carcinoma of the bladder undergoing radical cystectomy and pelvic lymphadenectomy at a single institution were reviewed. Logistic regression was used to evaluate associations between preoperative clinical variables and occult pathologic pelvic or common iliac lymph nodes. Percentages of patient with involved lymph node regions entirely encompassed within whole bladder (perivesicular nodal region), small pelvic (perivesicular, obturator, internal iliac, andmore » external iliac nodal regions), and extended pelvic clinical target volume (CTV) (small pelvic CTV plus common iliac regions) were calculated. Results: Among 315 eligible patients, 81 (26%) were found to have involved pelvic lymph nodes at the time of surgery, with 38 (12%) having involved common iliac lymph nodes. Risk of occult pathologically involved lymph nodes did not vary with clinical T stage. On multivariate analysis, the presence of lymphovascular invasion (LVI) on preoperative biopsy was significantly associated with occult pelvic nodal involvement (odds ratio 3.740, 95% confidence interval 1.865-7.499, P<.001) and marginally associated with occult common iliac nodal involvement (odds ratio 2.307, 95% confidence interval 0.978-5.441, P=.056). The percentages of patients with involved lymph node regions entirely encompassed by whole bladder, small pelvic, and extended pelvic CTVs varied with clinical risk factors, ranging from 85.4%, 95.1%, and 100% in non-muscle-invasive patients to 44.7%, 71.1%, and 94.8% in patients with muscle-invasive disease and biopsy LVI. Conclusions: Occult pelvic lymph node rates are substantial for all clinical subgroups, especially patients with LVI on biopsy. Extended coverage of pelvic lymph nodes up to the level of the common iliac nodes may be warranted in subsets of patients.« less

Exploration of risk factors predicting outcomes for primary T1 high-grade bladder cancer and validation of the Spanish Urological Club for Oncological Treatment scoring model: Long-term follow-up experience at a single institute.

PubMed

Miyake, Makito; Gotoh, Daisuke; Shimada, Keiji; Tatsumi, Yoshihiro; Nakai, Yasushi; Anai, Satoshi; Torimoto, Kazumasa; Aoki, Katsuya; Tanaka, Nobumichi; Konishi, Noboru; Fujimoto, Kiyohide

2015-06-01

To determine the prognostic factors of primary T1 high-grade bladder cancer and to validate the Spanish Urological Club for Oncological Treatment model in Japanese patients with T1 high-grade bladder cancer treated at a single institution. Records of 106 patients with T1 high-grade bladder cancer treated from 1998 to 2013 were retrospectively reviewed. Variables included various clinicopathological parameters, including lymphovascular invasion and tumor growth pattern at the invasion front. Recurrence-free survival and progression-free survival were analyzed. Multivariate Cox proportional regression analysis was used to verify the prognostic significance of the variables. Scores for recurrence and progression were calculated using the Spanish Urological Club for Oncological Treatment model. Of 106 patients, 44 (42%) had recurrence and 16 (15%) developed progression after a median (interquartile range) follow-up period of 54 months (range 32-81 months). Non-papillary shape was the only independent predictor for recurrence, while broad-based tumor stalk and infiltrative tumor growth pattern at the invasion front were determined to be independent predictors for progression. Stratification of patients according to the number of progression risk factors yielded hazard ratios of 10.1 and 13.1 in patients having one and two risks, respectively, compared with those without any risks. The Spanish Urological Club for Oncological Treatment model successfully stratified our patients with a trend toward different probabilities of recurrence and progression. The results of the present study might be helpful for counseling certain patients towards intensive treatment, such as radical cystectomy and/or platinum-based systemic chemotherapy. In addition, the Spanish Urological Club for Oncological Treatment model might be applicable to Japanese patients with T1 high-grade bladder cancer. © 2015 The Japanese Urological Association.

Scientific basis for learning transfer from movements to urinary bladder functions for bladder repair in human patients with CNS injury.

PubMed

Schalow, G

2010-01-01

Coordination Dynamics Therapy (CDT) has been shown to be able to partly repair CNS injury. The repair is based on a movement-based re-learning theory which requires at least three levels of description: the movement or pattern (and anamnesis) level, the collective variable level, and the neuron level. Upon CDT not only the actually performed movement pattern itself is repaired, but the entire dynamics of CNS organization is improved, which is the theoretical basis for (re-) learning transfer. The transfer of learning for repair from jumping on springboard and exercising on a special CDT and recording device to urinary bladder functions is investigated at the neuron level. At the movement or pattern level, the improvement of central nervous system (CNS) functioning in human patients can be seen (or partly measured) by the improvement of the performance of the pattern. At the collective variable level, coordination tendencies can be measured by the so-called 'coordination dynamics' before, during and after treatment. At the neuron level, re-learning can additionally be assessed by surface electromyography (sEMG) as alterations of single motor unit firings and motor programs. But to express the ongoing interaction between the numerous neural, muscular, and metabolic elements involved in perception and action, it is relevant to inquire how the individual afferent and efferent neurons adjust their phase and frequency coordination to other neurons to satisfy learning task requirements. With the single-nerve fibre action potential recording method it was possible to measure that distributed single neurons communicate by phase and frequency coordination. It is shown that this timed firing of neurons is getting impaired upon injury and has to be improved by learning The stability of phase and frequency coordination among afferent and efferent neuron firings can be related to pattern stability. The stability of phase and frequency coordination at the neuron level can therefore be assessed integratively at the (non-invasive) collective variable level by the arrhythmicity of turning (coordination dynamics) when a patient is exercising on a special CDT device. Upon jumping on springboard and exercising on the special CDT device, the intertwined neuronal networks, subserving movements (somatic) and urinary bladder functions (autonomic and somatic) in the sacral spinal cord, are synchronously activated and entrained to give rise to learning transfer from movements to bladder functions. Jumping on springboard and other movements primarily repair the pattern dynamics, whereas the exactly coordinated performed movements, performed on the special CDT device for turning, primarily improve the preciseness of the timed firing of neurons. The synchronous learning of perceptuomotor and perceptuobladder functioning from a dynamical perspective (giving rise to learning transfer) can be understood at the neuron level. Especially the activated phase and frequency coordination upon natural stimulation under physiologic and pathophysiologic conditions among a and gamma-motoneurons, muscle spindle afferents, touch and pain afferents, and urinary bladder stretch and tension receptor afferents in the human sacral spinal cord make understandable that somatic and parasympathetic functions are integrated in their functioning and give rise to learning transfer from movements to bladder functions. The power of this human treatment research project lies in the unit of theory, diagnostic/measurement, and praxis, namely that CNS injury can partly be repaired, including urinary bladder functions, and the repair can partly be understood even at the neuron level of description in human.

The Epigenetics of Kidney Cancer and Bladder Cancer

PubMed Central

Hoffman, Amanda M.; Cairns, Paul

2012-01-01

Summary This review focuses on the epigenetic alterations of aberrant promoter hypermethylation of genes, histone modifications or RNA interference in cancer cells. The current knowledge of hypermethylation of allele(s) in classical tumor suppressor genes in inherited and sporadic cancer, candidate tumor suppressor and other cancer genes is summarized gene by gene. Global and array-based studies of tumor cell hypermethylation are discussed. The importance of standardization of scoring of the methylation status of a gene is highlighted. The histone marks associated with hypermethylated genes, and the microRNAs with dysregulated expression, in kidney or bladder tumor cells are also discussed. Kidney cancer has the highest mortality rate of the genitourinary cancers. There are management issues with the high recurrence rate of superficial bladder cancer while muscle invasive bladder cancer has a poor prognosis. These clinical problems are the basis for translational application of gene hypermethylation to the diagnosis and prognosis of kidney and bladder cancer. PMID:22126150

Identification of novel potential genetic predictors of urothelial bladder carcinoma susceptibility in Pakistani population.

PubMed

Ali, Syeda Hafiza Benish; Bangash, Kashif Sardar; Rauf, Abdur; Younis, Muhammad; Anwar, Khursheed; Khurram, Raja; Khawaja, Muhammad Athar; Azam, Maleeha; Qureshi, Abid Ali; Akhter, Saeed; Kiemeney, Lambertus A; Qamar, Raheel

2017-10-01

Urothelial bladder carcinoma (UBC) is the most common among urinary bladder neoplasms. We carried out a preliminary study to determine the genetic etiology of UBC in Pakistani population, for this 25 sequence variants from 17 candidate genes were studied in 400 individuals by using polymerase chain reaction-based techniques. Multivariate logistic regression analysis was performed for association analysis of the overall data as well as the data stratified by smoking status, tumor grade and tumor stage. Variants of GSTM1, IGFBP3, LEPR and ACE were found to be associated with altered UBC risk in the overall comparison. CYP1B1 and CDKN1A variants displayed a risk modulation among smokers; IGFBP3 and LEPR variants among non-smokers while GSTM1 polymorphism exhibited association with both. GSTM1 and LEPR variants conferred an altered susceptibility to low grade UBC; GSTT1, IGFBP3 and PPARG variants to high grade UBC while ACE polymorphism to both grades. GSTM1 and LEPR variants exhibited risk modulation for non-muscle-invasive bladder cancer (NMIBC); GSTT1 and PPARG variants for muscle-invasive bladder cancer (MIBC), and ACE variant for NMIBC as well as MIBC. In general, the susceptibility markers were common for low grade and NMIBC; and distinct from those for high grade and MIBC indicating the distinct pathologies of both groups. In brief, our results conform to reports of previously associated variants in addition to identifying novel potential genetic predictors of UBC susceptibility.

Case report of metastatic invasive breast lobular carcinoma to the urinary bladder.

PubMed

Al Ibraheemi, Ahmed A

2016-01-01

Breast cancer is the most common cancer in women except skin cancer. The common metastatic sites include lymph node, lung, liver and bone. However, metastasis to the bladder is extremely rare. To our knowledge, this is the first case of breast cancer metastasis to urinary bladder in Jordan which is reported. Nine years after the initial diagnosis of lobular breast carcinoma, the patient suffered from left side leg edema; Ultrasonography and Computed tomography scanning showed thickening of posterior bladder wall and bilateral hydronephrosis. The biopsy of the bladder confirmed metastatic lesion from the breast. In contrast to the primary tumor, bladder metastasis showed negative expression of estrogen (ER) and progesterone (PR) receptors. However, Her2neu test was negative in both. The reported case confirms that bladder metastasis from breast cancer tend to occur late after the diagnosis of the primary tumor. Furthermore, bladder metastasis can be asymptomatic and heterogeneous in ER and PR expression in comparison with the primary tumor. This report supports the need for careful follow-up and early intervention whenever such clinical situation is suspected. This report supports further evaluation of receptor status at time of metastasis.

Topical and systemic immunoreaction triggered by intravesical chemotherapy in an N-butyl-N-(4-hydroxybutyl) nitorosamine induced bladder cancer mouse model

PubMed Central

Nakai, Yasushi; Tanaka, Nobumichi; Fujimoto, Kiyohide

2017-01-01

Intravesical bacillus Calmette-Guerin (BCG) treatment is the most common therapy to prevent progression and recurrence of non-muscle invasive bladder cancer (NMIBC). Although the immunoreaction elicited by BCG treatment is well documented, those induced by intravesical treatment with chemotherapeutic agents are much less known. We investigated the immunological profiles caused by mitomycin C, gemcitabine, adriamycin and docetaxel in the N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced orthotopic bladder cancer mouse model. Ninety mice bearing orthotopic bladder cancer induced by BBN were randomly divided into six groups and treated with chemotherapeutic agents once a week for four weeks. After last treatment, bladder and serum samples were analyzed for cell surface and immunological markers (CD4, CD8, CD56, CD204, Foxp3, and PD-L1) using immunohistochemistry staining. Serum and urine cytokine levels were evaluated by ELISA. All chemotherapeutic agents presented anti-tumor properties similar to those of BCG. These included changes in immune cells that resulted in fewer M2 macrophages and regulatory T cells around tumors. This result was compatible with those in human samples. Intravesical chemotherapy also induced systemic changes in cytokines, especially urinary interleukin (IL)-17A and granulocyte colony stimulating factor (G-CSF), as well as in the distribution of blood neutrophils, lymphocytes, and monocytes. Our findings suggest that intravesical treatment with mitomycin C and adriamycin suppresses protumoral immunity while enhancing anti-tumor immunity, possibly through the action of specific cytokines. A better understanding of the immunoreaction induced by chemotherapeutic agents can lead to improved outcomes and fewer side effects in intravesical chemotherapy against NMIBC. PMID:28406993

High-Grade Hydronephrosis Predicts Poor Outcomes After Radical Cystectomy in Patients with Bladder Cancer

PubMed Central

Kim, Dong Suk; Cho, Kang Su; Lee, Young Hoon; Cho, Nam Hoon; Oh, Young Taek

2010-01-01

We examined whether the presence and severity of preoperative hydronephrosis have prognostic significance in patients who underwent radical cystectomy for transitional cell carcinoma of the bladder. The medical records of 457 patients who underwent radical cystectomy for bladder cancer between 1986 and 2005 were retrospectively reviewed. Following the Society for Fetal Urology grading system, patients were divided into low-, and high-grade hydronephrosis groups. Clinicopathologic factors associated with preoperative hydronephrosis and survival were evaluated. Of a total of 406 patients, unilateral hydronephrosis was found in 74 (18.2%), bilateral hydronephrosis in 11 (2.7%), and no hydronephoris in 321 (79.1%). Low-grade hydronephrosis was found in 57 (12.2%) patients and high-grade hydronephrosis in 28 (6%). Preoperative hydronephrosis was related to higher pT stage and lymph node invasion. In univariate analysis, the presence of hydronephrosis, hydronephrosis grade, age, pT and pN stage, tumor grade, surgical margin, number of retrieved nodes, carcinoma in situ, and lymphovascular invasion were significant prognostic factors for cancer-specific survival. In multivariate analysis, bilateral hydronephrosis and high-grade hydronephrosis remained significant predictors for decreased survival. The presence of preoperative hydronephrosis, and high-grade hydronephrosis are significant prognostic factors in patients with bladder cancer after radical cystectomy. PMID:20191034

In vivo optical coherence tomography in endoscopic diagnostics of bladder disease

NASA Astrophysics Data System (ADS)

Daniltchenko, Dmitri; Lankenau, Eva; Konig, Frank; Shay, Brian; Huettmann, Gereon; Sachs, Markus D.; Schnorr, Dietmar; Loening, Stefan A.

2004-07-01

Purpose: OCT is a new imaging method which produces a 3 mm wide x 2.5 mm deep 2D picture with a resolution of 15 μm. Materials and Methods: We utilised the Tomograph Sirius 713, developed at the Medical Laser Centre in cooperation with 4-Optics AG, Lubeck, Germany. This apparatus uses a special Super-Luminescence-Diode (SLD) that produces light within the near infrared wavelength, with a central wavelength of 1300 nm and spectral width of 45 nm. The coherence length is reduced to 15 μm. The light is introduced into a fibreglass optic which is a couple of meters long and is easy to handle. To measure the depth of invasion and position of urothelial bladder tumours, the fibreglass optic is attached to a regular endoscope (Wolf, Knittlingen, Germany) via a OCT adapter. That way, in parallel to the regular endoscopic view of the bladder mucosa with or without pathologic findings, an OCT picture of the superficial as well as the deeper muscle layers is visible online. OCT was used to obtaine 275 images from the bladder of 30 patients. Results: OCT of normal bladder mucosa produces an image with a cross section of up to 2.5 mm. It is possible to distinguish transitional epithelium, lamina propria, smooth muscles and capillaries. In cystitis the thickness of the mucosa is constant, but the distinction between the different layers is blurred. In squamous metaplasia there is thickening of the epithelial layer, with preservation of lamination of the lower layers. In transitional cell carcinoma there is a complete loss of the regular layered structure. Thus, the border between tumour and normal bladder tissue can be easily distinguished. Conclusions: This method can provide valuable information on tumour invasion and extension in real time and therefore influence therapeutic strategies

LeuX tRNA-dependent and -independent mechanisms of Escherichia coli pathogenesis in acute cystitis

PubMed Central

Hannan, Thomas J.; Mysorekar, Indira U.; Chen, Swaine L.; Walker, Jennifer N.; Jones, Jennifer M.; Pinkner, Jerome S.; Hultgren, Scott J.; Seed, Patrick C.

2013-01-01

Summary Uropathogenic Escherichia coli (UPEC) contain multiple horizontally acquired pathogenicity-associated islands (PAI) implicated in the pathogenesis of urinary tract infection. In a murine model of cystitis, type 1 pili-mediated bladder epithelial invasion and intracellular proliferation are key events associated with UPEC virulence. In this study, we examined the mechanisms by which a conserved PAI contributes to UPEC pathogenesis in acute cystitis. In the human UPEC strain UTI89, spontaneous excision of PAI IIUTI89 disrupts the adjacent leuX tRNA locus. Loss of wild-type leuX-encoded tRNA5Leu significantly delayed, but did not eliminate, FimB recombinase-mediated phase variation of type 1 pili. FimX, an additional FimB-like, leuX-independent recombinase, was also found to mediate type 1 pili phase variation. However, whereas FimX activity is relatively slow in vitro, it is rapid in vivo as a non-piliated strain lacking the other fim recombinases rapidly expressed type 1 pili upon experimental infection. Finally, we found that disruption of leuX, but not loss of PAI IIUTI89 genes, reduced bladder epithelial invasion and intracellular proliferation, independent of type 1 piliation. These findings indicate that the predominant mechanism for preservation of PAI IIUTI89 during the establishment of acute cystitis is maintenance of wild-type leuX, and not PAI IIUTI89 gene content. PMID:18036139

Functional Assay of Cancer Cell Invasion Potential Based on Mechanotransduction of Focused Ultrasound.

PubMed

Weitz, Andrew C; Lee, Nan Sook; Yoon, Chi Woo; Bonyad, Adrineh; Goo, Kyo Suk; Kim, Seaok; Moon, Sunho; Jung, Hayong; Zhou, Qifa; Chow, Robert H; Shung, K Kirk

2017-01-01

Cancer cells undergo a number of biophysical changes as they transform from an indolent to an aggressive state. These changes, which include altered mechanical and electrical properties, can reveal important diagnostic information about disease status. Here, we introduce a high-throughput, functional technique for assessing cancer cell invasion potential, which works by probing for the mechanically excitable phenotype exhibited by invasive cancer cells. Cells are labeled with fluorescent calcium dye and imaged during stimulation with low-intensity focused ultrasound, a non-contact mechanical stimulus. We show that cells located at the focus of the stimulus exhibit calcium elevation for invasive prostate (PC-3 and DU-145) and bladder (T24/83) cancer cell lines, but not for non-invasive cell lines (BPH-1, PNT1A, and RT112/84). In invasive cells, ultrasound stimulation initiates a calcium wave that propagates from the cells at the transducer focus to other cells, over distances greater than 1 mm. We demonstrate that this wave is mediated by extracellular signaling molecules and can be abolished through inhibition of transient receptor potential channels and inositol trisphosphate receptors, implicating these proteins in the mechanotransduction process. If validated clinically, our technology could provide a means to assess tumor invasion potential in cytology specimens, which is not currently possible. It may therefore have applications in diseases such as bladder cancer, where cytologic diagnosis of tumor invasion could improve clinical decision-making.

Functional Assay of Cancer Cell Invasion Potential Based on Mechanotransduction of Focused Ultrasound

PubMed Central

Weitz, Andrew C.; Lee, Nan Sook; Yoon, Chi Woo; Bonyad, Adrineh; Goo, Kyo Suk; Kim, Seaok; Moon, Sunho; Jung, Hayong; Zhou, Qifa; Chow, Robert H.; Shung, K. Kirk

2017-01-01

Cancer cells undergo a number of biophysical changes as they transform from an indolent to an aggressive state. These changes, which include altered mechanical and electrical properties, can reveal important diagnostic information about disease status. Here, we introduce a high-throughput, functional technique for assessing cancer cell invasion potential, which works by probing for the mechanically excitable phenotype exhibited by invasive cancer cells. Cells are labeled with fluorescent calcium dye and imaged during stimulation with low-intensity focused ultrasound, a non-contact mechanical stimulus. We show that cells located at the focus of the stimulus exhibit calcium elevation for invasive prostate (PC-3 and DU-145) and bladder (T24/83) cancer cell lines, but not for non-invasive cell lines (BPH-1, PNT1A, and RT112/84). In invasive cells, ultrasound stimulation initiates a calcium wave that propagates from the cells at the transducer focus to other cells, over distances greater than 1 mm. We demonstrate that this wave is mediated by extracellular signaling molecules and can be abolished through inhibition of transient receptor potential channels and inositol trisphosphate receptors, implicating these proteins in the mechanotransduction process. If validated clinically, our technology could provide a means to assess tumor invasion potential in cytology specimens, which is not currently possible. It may therefore have applications in diseases such as bladder cancer, where cytologic diagnosis of tumor invasion could improve clinical decision-making. PMID:28824873

Methylation of HOXA9 and ISL1 Predicts Patient Outcome in High-Grade Non-Invasive Bladder Cancer

PubMed Central

Kitchen, Mark O.; Bryan, Richard T.; Haworth, Kim E.; Emes, Richard D.; Luscombe, Christopher; Gommersall, Lyndon; Cheng, K. K.; Zeegers, Maurice P.; James, Nicholas D.; Devall, Adam J.; Fryer, Anthony A.; Farrell, William E.

2015-01-01

Introduction Inappropriate DNA methylation is frequently associated with human tumour development, and in specific cases, is associated with clinical outcomes. Previous reports of DNA methylation in low/intermediate grade non-muscle invasive bladder cancer (NMIBC) have suggested that specific patterns of DNA methylation may have a role as diagnostic or prognostic biomarkers. In view of the aggressive and clinically unpredictable nature of high-grade (HG) NMIBC, and the current shortage of the preferred treatment option (Bacillus:Calmette-Guerin), novel methylation analyses may similarly reveal biomarkers of disease outcome that could risk-stratify patients and guide clinical management at initial diagnosis. Methods Promoter-associated CpG island methylation was determined in primary tumour tissue of 36 initial presentation high-grade NMIBCs, 12 low/intermediate-grade NMIBCs and 3 normal bladder controls. The genes HOXA9, ISL1, NKX6-2, SPAG6, ZIC1 and ZNF154 were selected for investigation on the basis of previous reports and/or prognostic utility in low/intermediate-grade NMIBC. Methylation was determined by Pyrosequencing of sodium-bisulphite converted DNA, and then correlated with gene expression using RT-qPCR. Methylation was additionally correlated with tumour behaviour, including tumour recurrence and progression to muscle invasive bladder cancer or metastases. Results The ISL1 genes’ promoter-associated island was more frequently methylated in recurrent and progressive high-grade tumours than their non-recurrent counterparts (60.0% vs. 18.2%, p = 0.008). ISL1 and HOXA9 showed significantly higher mean methylation in recurrent and progressive tumours compared to non-recurrent tumours (43.3% vs. 20.9%, p = 0.016 and 34.5% vs 17.6%, p = 0.017, respectively). Concurrent ISL1/HOXA9 methylation in HG-NMIBC reliably predicted tumour recurrence and progression within one year (Positive Predictive Value 91.7%), and was associated with disease-specific mortality (DSM). Conclusions In this study we report methylation differences and similarities between clinical sub-types of high-grade NMIBC. We report the potential ability of methylation biomarkers, at initial diagnosis, to predict tumour recurrence and progression within one year of diagnosis. We found that specific biomarkers reliably predict disease outcome and therefore may help guide patient treatment despite the unpredictable clinical course and heterogeneity of high-grade NMIBC. Further investigation is required, including validation in a larger patient cohort, to confirm the clinical utility of methylation biomarkers in high-grade NMIBC. PMID:26332997

Endoscopic Optical Coherence Tomography in Urology

NASA Astrophysics Data System (ADS)

Pan, Yingtian; Waltzer, Wayne; Ye, Zhangqun

Clinical statistics has shown a stable prevalence of bladder cancer in recent years, which by far remains among the most common types of malignancy in the USA. With smoking as the most well-established risk factor, bladder cancer is the fourth most common cancer occurrences in male population [1]. In the year of 2014, an estimated 74,690 new cases are expected to occur with estimated 15,580 deaths. Bladder cancer often refers to transitional cell carcinoma (TCC) as it originates primarily from the epithelial cell layer (i.e., urothelium) of the bladder. Unlike prostate-specific antigen (PSA) for prostate cancer screening, there is currently no effective screening technique approved or recommended for the population at average risk [2-5]. As a result, hematuria (i.e., blood in the urine) is often the first clinical symptom of bladder cancer. Fortunately, urinary bladder is more accessible than prostate glands endoscopically; thus cytology following white-light cystoscopy has been the gold standard for current clinical detection of bladder cancer. This is important because bladder cancer if diagnosed prior to muscle invasion (e.g., superficial or at

Comparative study of the organisation and phenotypes of bladder interstitial cells in human, mouse and rat.

PubMed

Gevaert, Thomas; Neuhaus, Jochen; Vanstreels, Els; Daelemans, Dirk; Everaerts, Wouter; Der Aa, Frank Van; Timmermans, Jean-Pierre; Roskams, Tania; Steiner, Clara; Pintelon, Isabel; De Ridder, Dirk

2017-12-01

With most research on interstitial cells (IC) in the bladder being conducted on animal models, it remains unclear whether all structural and functional data on IC from animal models can be translated to the human context. This prompted us to compare the structural and immunohistochemical properties of IC in bladders from mouse, rat and human. Tissue samples were obtained from the bladder dome and subsequently processed for immunohistochemistry and electron microscopy. The ultrastructural properties of IC were compared by means of electron microscopy and IC were additionally characterized with single/double immunohistochemistry/immunofluorescence. Our results reveal a similar organization of the IC network in the upper lamina propria (ULP), the deep lamina propria (DLP) and the detrusor muscle in human, rat and mouse bladders. Furthermore, despite several similarities in IC phenotypes, we also found several obvious inter-species differences in IC, especially in the ULP. Most remarkably in this respect, ULP IC in human bladder predominantly displayed a myoid phenotype with abundant presence of contractile micro-filaments, while those in rat and mouse bladders showed a fibroblast phenotype. In conclusion, the organization of ULP IC, DLP IC and detrusor IC is comparable in human, rat and mouse bladders, although several obvious inter-species differences in IC phenotypes were found. The present data show that translating research data on IC in laboratory animals to the human setting should be carried out with caution.

Nanotechnology and cancer: improving real-time monitoring and staging of bladder cancer with multimodal mesoporous silica nanoparticles.

PubMed

Sweeney, Sean K; Luo, Yi; O'Donnell, Michael A; Assouline, Jose

Despite being one of the most common cancers, bladder cancer is largely inefficiently and inaccurately staged and monitored. Current imaging methods detect cancer only when it has reached "visible" size and has significantly disrupted the structure of the organ. By that time, thousands of cells will have proliferated and perhaps metastasized. Repeated biopsies and scans are necessary to determine the effect of therapy on cancer growth. In this report, we describe a novel approach based on multimodal nanoparticle contrast agent technology and its application to a preclinical animal model of bladder cancer. The innovation relies on the engineering core of mesoporous silica with specific scanning contrast properties and surface modification that include fluorescence and magnetic resonance imaging (MRI) contrast. The overall dimensions of the nano-device are preset at 80-180 nm, depending on composition with a pore size of 2 nm. To facilitate and expedite discoveries, we combined a well-known model of bladder cancer and our novel technology. We exposed nanoparticles to MB49 murine bladder cancer cells in vitro and found that 70 % of the cells were labeled by nanoparticles as measured by flow cytometry. The in vivo mouse model for bladder cancer is particularly well suited for T1- and T2-weighted MRI. Under our experimental conditions, we demonstrate that the nanoparticles considerably improve tumor definition in terms of volumetric, intensity and structural characteristics. Important bladder tumor parameters can be ascertained, non-invasively, repetitively, and with great accuracy. Furthermore, since the particles are not biodegradable, repetitive injection is not required. This feature allows follow-up diagnostic evaluations during cancer treatment. Changes in MRI signals show that in situ uptake of free particles has predilection to tumor cells relative to normal bladder epithelium. The particle distribution within the tumors was corroborated by fluorescent microscopy of sections of excised bladders. In addition, MRI imaging revealed fibrous finger-like projections into the tumors where particles insinuated themselves deeply. This morphological characteristic was confirmed by fluorescence microscopy. These findings may present new options for therapeutic intervention. Ultimately, the combination of real-time and repeated MRI evaluation of the tumors enhanced by nanoparticle contrast may have the potential for translation into human clinical studies for tumor staging, therapeutic monitoring, and drug delivery.

Urothelial bladder cancer with cavitary lung metastases

PubMed Central

Kurian, Anil; Lee, Jason; Born, Abraham

2011-01-01

Transitional cell carcinoma (TCC) of the bladder tends to remain superficial; however, in 5% to 20% of cases, it progresses to muscle invasion and, more rarely, can metastasize. TCC of the bladder primarily spreads via regional lymphatics. The most common sites of distant metastases of TCC are the liver, lung, mediastinum and bone. Long-term survival of patients with metastatic bladder cancer is rare. Patterns of pulmonary metastasis include multiple nodules, a solitary mass or interstitial micronodule. When multiple nodules are present, they are round and well-circumscribed, without calcification or cavitation. An unusual case of rapidly metastatic TCC to the lung causing large cavitary masses and nodules is presented. Imaging performed after the patient began chemotherapy revealed widespread necrosis of the metastatic cavitary masses causing moderate volume hemoptysis. PMID:21766082

Insulin-like growth factor-1 receptor overexpression is associated with outcome in invasive urothelial carcinoma of urinary bladder: a retrospective study of patients treated using radical cystectomy.

PubMed

Gonzalez-Roibon, Nilda; Kim, Jenny J; Faraj, Sheila F; Chaux, Alcides; Bezerra, Stephania M; Munari, Enrico; Ellis, Carla; Sharma, Rajni; Keizman, Daniel; Bivalacqua, Trinity J; Schoenberg, Mark; Eisenberger, Mario; Carducci, Michael; Netto, George J

2014-06-01

To assess the insulin-like growth factor-1 receptor (IGF1R) expression in urothelial carcinoma (UC) and its prognostic role in relation to clinicopathologic parameters. A total of 100 cases of invasive UC were evaluated using tissue microarrays. Membranous IGF1R staining was evaluated using immunohistochemistry. A scoring method analogous to that of HER2 expression in breast carcinoma was used, and the highest score was assigned in each tumor. IGF1R was considered overexpressed in cases with score≥1. We found IGF1R overexpression in 62% of invasive UC. IGF1R overexpression was associated with race (P=.04) and pT category (P=.03). Median follow-up was 29 months (range, 0.5-212). Progression rate was 60%, and overall mortality and cancer-specific mortality rates were 69% and 51%, respectively. In invasive UC, IGF1R overexpression was significantly associated with overall mortality and cancer-specific mortality (Mantel Cox P=.0002 and P=.006, respectively). IGF1R overexpression was associated with increased hazard ratios (HRs) for overall mortality (HR=2.63, P=.001) and cancer-specific mortality (HR=2.45, P=.01), independently and after adjusting for clinicopathologic features and treatment modalities. We found IGF1R overexpression in 62% of bladder UC. More importantly, IGF1R overexpression was a significant predictor of overall mortality and cancer-specific mortality, suggesting its potential role as a prognosticator in UC of bladder. Copyright © 2014 Elsevier Inc. All rights reserved.

Pathology of carcinoma in situ of the urinary bladder and related lesions.

PubMed

Farrow, G M

1992-01-01

In the United States, nearly all cases of bladder cancer are of the transitional cell type, and epidemiological evidence indicates that among these, approximately 80% present initially as more or less well-differentiated, superficial papillary neoplasms with a tendency for multifocal or diffuse involvement of the urothelial surface and/or recurrent tumor episodes, but with limited potential for invasive growth or a lethal outcome. Bladder tumors with lethal potential generally begin as poorly differentiated, sessile growths that are usually invasive at first diagnosis. Carcinoma in situ is a change that must be elicited among intact surface cells before progressive proliferation results in a tumor mass. Evidence for such an association is both temporal and spatial. Since most transitional cell carcinomas begin as well-differentiated tumors, i.e., resembling normal urothelium, recognition of early neoplastic alteration before a papillary structure forms is unlikely and most of the evidence is spatial based upon urothelial changes adjacent to papillary tumors. The morphologic definition of carcinoma in situ is arbitrary and generally defined as a total replacement of the urothelial surface by cells which bear morphologic features of carcinoma, but which lack architectural alteration other than an increase in the number of cell layers, i.e., a flat lesion. The Union Internationále Contra Cancer/American Joint Committee on Cancer (UICC/AJCC) staging scheme for bladder cancer distinguishes non-invasive papillary growths as Ta and carcinoma in situ as Tis. Because detection of carcinoma in situ, either by cytology or biopsy, depends upon recognizable malignant morphologic characteristics, studies of the lesion tend to be limited to the higher grade or more anaplastic examples.(ABSTRACT TRUNCATED AT 250 WORDS)

The management of invasive transitional cell carcinoma of the bladder. Results of definitive and preoperative radiation therapy in 390 patients treated at the Prince of Wales Hospital, Sydney, Australia.

PubMed

Mameghan, H; Fisher, R J; Watt, W H; Meagher, M J; Rosen, I M; Mameghan, J; Brook, S; Tynan, A P; Korbel, E I; Millard, R J

1992-06-01

The treatment results for invasive transitional cell carcinoma (TCC) of the bladder were assessed in a series of 390 patients referred to the Department of Radiation Oncology at the Prince of Wales Hospital, Sydney, Australia, during the period 1977 to 1988. These patients were managed by one of two strategies: cystectomy (87 patients) and radiation therapy (303 patients). Actuarial survival rates (death from any cause) were determined and comparisons were made using log-rank tests and Cox regression analyses. The mean follow-up time was 7.6 years. Independent prognostic factors for shorter survival were: the presence of a ureteric obstruction (P less than 0.001), increasing clinical stage (P less than 0.001), increasing patient age (P = 0.003), and earlier year of presentation (P = 0.008). Comparison of the two strategies indicated no significant difference in overall survival after adjusting for imbalances in prognostic factors (P = 0.007 unadjusted; P = 0.29 adjusted). The slightly longer survival of 46 patients from 1983 onward who received primary systemic chemotherapy (compared with 149 patients not given chemotherapy) was not statistically significant (P = 0.12 unadjusted; P = 0.56 adjusted for prognostic factors). The 5-year actuarial rates of severe complications were 8.0% after cystectomy and 5.3% after radiation therapy. In 303 patients treated by definitive radiation therapy, the 5-year actuarial rate of freedom from bladder failure for all clinical tumor stages was 44% (Tx, 67%; T1, 45%; T2, 56%; T3, 39%; and T4, 39%). These results suggest that definitive radiation therapy is a viable alternative to radical cystectomy for patients with invasive TCC of the bladder.

Chemoprevention of urothelial cell carcinoma growth and invasion by the dual COX-LOX inhibitor licofelone in UPII-SV40T transgenic mice.

PubMed

Madka, Venkateshwar; Mohammed, Altaf; Li, Qian; Zhang, Yuting; Patlolla, Jagan M R; Biddick, Laura; Lightfoot, Stan; Wu, Xue-Ru; Steele, Vernon; Kopelovich, Levy; Rao, Chinthalapally V

2014-07-01

Epidemiologic and clinical data suggest that use of anti-inflammatory agents is associated with reduced risk for bladder cancer. We determined the chemopreventive efficacy of licofelone, a dual COX-lipoxygenase (LOX) inhibitor, in a transgenic UPII-SV40T mouse model of urothelial transitional cell carcinoma (TCC). After genotyping, six-week-old UPII-SV40T mice (n = 30/group) were fed control (AIN-76A) or experimental diets containing 150 or 300 ppm licofelone for 34 weeks. At 40 weeks of age, all mice were euthanized, and urinary bladders were collected to determine urothelial tumor weights and to evaluate histopathology. Results showed that bladders of the transgenic mice fed control diet weighed 3 to 5-fold more than did those of the wild-type mice due to urothelial tumor growth. However, treatment of transgenic mice with licofelone led to a significant, dose-dependent inhibition of the urothelial tumor growth (by 68.6%-80.2%, P < 0.0001 in males; by 36.9%-55.3%, P < 0.0001 in females) compared with the control group. The licofelone diet led to the development of significantly fewer invasive tumors in these transgenic mice. Urothelial tumor progression to invasive TCC was inhibited in both male (up to 50%; P < 0.01) and female mice (41%-44%; P < 0.003). Urothelial tumors of the licofelone-fed mice showed an increase in apoptosis (p53, p21, Bax, and caspase3) with a decrease in proliferation, inflammation, and angiogenesis markers (proliferating cell nuclear antigen, COX-2, 5-LOX, prostaglandin E synthase 1, FLAP, and VEGF). These results suggest that licofelone can serve as potential chemopreventive for bladder TCC. ©2014 American Association for Cancer Research.

Clinical significance of serum and urinary HER2/neu protein levels in primary non-muscle invasive bladder cancer.

PubMed

Arikan, Ozgur; Yýldýrým, Asýf; Ýsbilen, Banu; Canakci, Cengiz; Atýs, Gokhan; Gurbuz, Cenk; Erol, Bulent; Ýsman, Ferruh Kemal; Ozkanli, Seyma; Caskurlu, Turhan

2015-01-01

We aimed to compare serum and urinary HER2/neu levels between healthy control group and patients with non-muscle invasive bladder cancer. Additionally, we evaluated relationship of HER2/neu levels with tumor stage, grade, recurrence and progression. Fourty-four patients with primary non-muscle invasive bladder tumors (Group 2) and 40 healthy control group (Group 1) were included the study. Blood and urinary samples were collected from all patients and HER2/neu levels were measured by ELISA method. Blood and urinary HER2/neu levels and additionally, ratio of urinary HER2/neu levels to urinary creatinine levels were recorded. Demographic data and tumor characteristics were recorded. Mean serum HER2/neu levels were similar between two groups and statistically significant difference wasn't observed. Urinary HER2/neu levels were significantly higher in group 2 than group 1. Ratio of urinary HER2/neu to urinary creatinine was significantly higher in group 2 than group 1, (p=0,021). Serum and urinary HER2/ neu levels were not associated with tumor stage, grade, recurrence and progression while ratio of urinary HER2/neu to urinary creatinin levels were significantly higher in high-grade tumors. HER2/neu, the sensitivity of the test was found to be 20.5%, and the specificity was 97.5%, also for the urinary HER2/neu/urinary creatinine ratio, the sensitivity and specificity of the test were found to be 31.8% and 87.5%, respectively. Urinary HER2/neu and ratio of urinary creatinine urine were significantly higher in patients with bladder cancer compared to healthy subjects. Large series and controlled studies are needed for use as a tumor marker.

Do neural tube defects lead to structural alterations in the human bladder?

PubMed

Pazos, Helena M F; Lobo, Márcio Luiz de P; Costa, Waldemar S; Sampaio, Francisco J B; Cardoso, Luis Eduardo M; Favorito, Luciano Alves

2011-05-01

Anencephaly is the most severe neural tube defect in human fetuses. The objective of this paper is to analyze the structure of the bladder in anencephalic human fetuses. We studied 40 bladders of normal human fetuses (20 male and 20 female, aged 14 to 23 WPC) and 12 bladders of anencephalic fetuses (5 male and 7 female, aged 18 to 22 WPC). The bladders were removed and processed by routine histological techniques. Stereological analysis of collagen, elastic system fibers and smooth muscle was performed in sections. Data were expressed as volumetric density (Vv-%). The images were captured with Olympus BX51 microscopy and Olympus DP70 camera. The stereological analysis was done using the software Image Pro and Image J. For biochemical analysis, samples were fixed in acetone, and collagen concentrations were expressed as micrograms of hydroxyproline per mg of dry tissue. Means were statistically compared using the unpaired t-test (p<0.05). We observed a significant increase (p<0.0001) in the Vv of collagen in the bladders of anencephalic fetuses (69.71%) when compared to normal fetuses (52.74%), and a significant decrease (p<0.0001) in the Vv of smooth muscle cells in the bladders of anencephalic fetuses (23.96%) when compared to normal fetuses (38.35%). The biochemical analyses showed a higher concentration of total collagen in the bladders of anencephalic fetuses (37354 µg/mg) when compared to normal fetuses (48117 µg/mg, p<0.02). The structural alterations of the bladder found in this study may suggest the existence of functional alterations in the bladder of anencephalic human fetuses.

Single-cell Sequencing Reveals Variants in ARID1A, GPRC5A and MLL2 Driving Self-renewal of Human Bladder Cancer Stem Cells.

PubMed

Yang, Zhao; Li, Chong; Fan, Zusen; Liu, Hongjie; Zhang, Xiaolong; Cai, Zhiming; Xu, Liqin; Luo, Jian; Huang, Yi; He, Luyun; Liu, Chunxiao; Wu, Song

2017-01-01

Cancer stem cells are considered responsible for many important aspects of tumors such as their self-renewal, tumor-initiating, drug-resistance and metastasis. However, the genetic basis and origination of human bladder cancer stem cells (BCSCs) remains unknown. Here, we conducted single-cell sequencing on 59 cells including BCSCs, bladder cancer non-stem cells (BCNSCs), bladder epithelial stem cells (BESCs) and bladder epithelial non-stem cells (BENSCs) from three bladder cancer (BC) specimens. Specifically, BCSCs demonstrate clonal homogeneity and suggest their origin from BESCs or BCNSCs through phylogenetic analysis. Moreover, 21 key altered genes were identified in BCSCs including six genes not previously described in BC (ETS1, GPRC5A, MKL1, PAWR, PITX2 and RGS9BP). Co-mutations of ARID1A, GPRC5A and MLL2 introduced by CRISPR/Cas9 significantly enhance the capabilities of self-renewal and tumor-initiating of BCNSCs. To our knowledge, our study first provides an overview of the genetic basis of human BCSCs with single-cell sequencing and demonstrates the biclonal origin of human BCSCs via evolution analysis. Human bladder cancer stem cells show the high level of consistency and may derived from bladder epithelial stem cells or bladder cancer non-stem cells. Mutations of ARID1A, GPRC5A and MLL2 grant bladder cancer non-stem cells the capability of self-renewal. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Human urinary bladder regeneration through tissue engineering - an analysis of 131 clinical cases.

PubMed

Pokrywczynska, Marta; Adamowicz, Jan; Sharma, Arun K; Drewa, Tomasz

2014-03-01

Replacement of urinary bladder tissue with functional equivalents remains one of the most challenging problems of reconstructive urology over the last several decades. The gold standard treatment for urinary diversion after radical cystectomy is the ileal conduit or neobladder; however, this technique is associated with numerous complications including electrolyte imbalances, mucus production, and the potential for malignant transformation. Tissue engineering techniques provide the impetus to construct functional bladder substitutes de novo. Within this review, we have thoroughly perused the literature utilizing PubMed in order to identify clinical studies involving bladder reconstruction utilizing tissue engineering methodologies. The idea of urinary bladder regeneration through tissue engineering dates back to the 1950s. Many natural and synthetic biomaterials such as plastic mold, gelatin sponge, Japanese paper, preserved dog bladder, lyophilized human dura, bovine pericardium, small intestinal submucosa, bladder acellular matrix, or composite of collagen and polyglycolic acid were used for urinary bladder regeneration with a wide range of outcomes. Recent progress in the tissue engineering field suggest that in vitro engineered bladder wall substitutes may have expanded clinical applicability in near future but preclinical investigations on large animal models with defective bladders are necessary to optimize the methods of bladder reconstruction by tissue engineering in humans.

ZIP8 expression in human proximal tubule cells, human urothelial cells transformed by Cd+2 and As+3 and in specimens of normal human urothelium and urothelial cancer

PubMed Central

2012-01-01

Background ZIP8 functions endogenously as a Zn+2/HCO3- symporter that can also bring cadmium (Cd+2) into the cell. It has also been proposed that ZIP8 participates in Cd-induced testicular necrosis and renal disease. In this study real-time PCR, western analysis, immunostaining and fluorescent localization were used to define the expression of ZIP8 in human kidney, cultured human proximal tubule (HPT) cells, normal and malignant human urothelium and Cd+2 and arsenite (As+3) transformed urothelial cells. Results It was shown that in the renal system both the non-glycosylated and glycosylated form of ZIP8 was expressed in the proximal tubule cells with localization of ZIP8 to the cytoplasm and cell membrane; findings in line with previous studies on ZIP8. The studies in the bladder were the first to show that ZIP8 was expressed in normal urothelium and that ZIP8 could be localized to the paranuclear region. Studies in the UROtsa cell line confirmed a paranuclear localization of ZIP8, however addition of growth medium to the cells increased the expression of the protein in the UROtsa cells. In archival human samples of the normal urothelium, the expression of ZIP8 was variable in intensity whereas in urothelial cancers ZIP8 was expressed in 13 of 14 samples, with one high grade invasive urothelial cancer showing no expression. The expression of ZIP8 was similar in the Cd+2 and As+3 transformed UROtsa cell lines and their tumor transplants. Conclusion This is the first study which shows that ZIP8 is expressed in the normal urothelium and in bladder cancer. In addition the normal UROtsa cell line and its transformed counterparts show similar expression of ZIP8 compared to the normal urothelium and the urothelial cancers suggesting that the UROtsa cell line could serve as a model system to study the expression of ZIP8 in bladder disease. PMID:22550998

HumanMethylation450K Array–Identified Biomarkers Predict Tumour Recurrence/Progression at Initial Diagnosis of High-risk Non-muscle Invasive Bladder Cancer

PubMed Central

Kitchen, Mark O; Bryan, Richard T; Emes, Richard D; Luscombe, Christopher J; Cheng, KK; Zeegers, Maurice P; James, Nicholas D; Gommersall, Lyndon M; Fryer, Anthony A

2018-01-01

Background: High-risk non-muscle invasive bladder cancer (HR-NMIBC) is a clinically unpredictable disease. Despite clinical risk estimation tools, many patients are undertreated with intra-vesical therapies alone, whereas others may be over-treated with early radical surgery. Molecular biomarkers, particularly DNA methylation, have been reported as predictive of tumour/patient outcomes in numerous solid organ and haematologic malignancies; however, there are few reports in HR-NMIBC and none using genome-wide array assessment. We therefore sought to identify novel DNA methylation markers of HR-NMIBC clinical outcomes that might predict tumour behaviour at initial diagnosis and help guide patient management. Patients and methods: A total of 21 primary initial diagnosis HR-NMIBC tumours were analysed by Illumina HumanMethylation450 BeadChip arrays and subsequently bisulphite Pyrosequencing. In all, 7 had not recurred at 1 year after resection and 14 had recurred and/or progressed despite intra-vesical BCG. A further independent cohort of 32 HR-NMIBC tumours (17 no recurrence and 15 recurrence and/or progression despite BCG) were also assessed by bisulphite Pyrosequencing. Results: Array analyses identified 206 CpG loci that segregated non-recurrent HR-NMIBC tumours from clinically more aggressive recurrence/progression tumours. Hypermethylation of CpG cg11850659 and hypomethylation of CpG cg01149192 in combination predicted HR-NMIBC recurrence and/or progression within 1 year of diagnosis with 83% sensitivity, 79% specificity, and 83% positive and 79% negative predictive values. Conclusions: This is the first genome-wide DNA methylation analysis of a unique HR-NMIBC tumour cohort encompassing known 1-year clinical outcomes. Our analyses identified potential novel epigenetic markers that could help guide individual patient management in this clinically unpredictable disease. PMID:29343995

Fibroblast growth factor receptors-1 and -3 play distinct roles in the regulation of bladder cancer growth and metastasis: implications for therapeutic targeting.

PubMed

Cheng, Tiewei; Roth, Beat; Choi, Woonyoung; Black, Peter C; Dinney, Colin; McConkey, David J

2013-01-01

Fibroblast growth factor receptors (FGFRs) are activated by mutation and overexpressed in bladder cancers (BCs), and FGFR inhibitors are currently being evaluated in clinical trials in BC patients. However, BC cells display marked heterogeneity in their responses to FGFR inhibitors, and the biological mechanisms underlying this heterogeneity are not well defined. Here we used a novel inhibitor of FGFRs 1-3 and RNAi to determine the effects of inhibiting FGFR1 or FGFR3 in a panel of human BC cell lines. We observed that FGFR1 was expressed in BC cells that also expressed the "mesenchymal" markers ZEB1 and vimentin, whereas FGFR3 expression was restricted to the E-cadherin- and p63-positive "epithelial" subset. Sensitivity to the growth-inhibitory effects of BGJ-398 was also restricted to the "epithelial" BC cells and it correlated directly with FGFR3 mRNA levels but not with the presence of activating FGFR3 mutations. In contrast, BGJ-398 did not strongly inhibit proliferation but did block invasion in the "mesenchymal" BC cells in vitro. Similarly, BGJ-398 did not inhibit primary tumor growth but blocked the production of circulating tumor cells (CTCs) and the formation of lymph node and distant metastases in mice bearing orthotopically implanted "mesenchymal" UM-UC3 cells. Together, our data demonstrate that FGFR1 and FGFR3 have largely non-overlapping roles in regulating invasion/metastasis and proliferation in distinct "mesenchymal" and "epithelial" subsets of human BC cells. The results suggest that the tumor EMT phenotype will be an important determinant of the biological effects of FGFR inhibitors in patients.

Suppression of ERβ signaling via ERβ knockout or antagonist protects against bladder cancer development.

PubMed

Hsu, Iawen; Chuang, Kun-Lung; Slavin, Spencer; Da, Jun; Lim, Wei-Xun; Pang, See-Tong; O'Brien, Jeanne H; Yeh, Shuyuan

2014-03-01

Epidemiological studies showed that women have a lower bladder cancer (BCa) incidence, yet higher muscle-invasive rates than men, suggesting that estrogen and the estrogen receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), may play critical roles in BCa progression. Using in vitro cell lines and an in vivo carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced mouse BCa model, we found that ERβ plays a positive role in promoting BCa progression. Knockdown of ERβ with ERβ-shRNA in ERβ-positive human BCa J82, 647v and T24 cell lines led to suppressed cell growth and invasion. Mice lacking ERβ have less cancer incidence with reduced expression of the proliferation marker Ki67 in BBN-induced BCa. Consistently, our results show that non-malignant urothelial cells with ERβ knockdown are more resistant to carcinogen-induced malignant transformation. Mechanism dissection found that targeting ERβ suppressed the expression of minichromosome maintenance complex component 5 (MCM5), a DNA replication licensing factor that is involved in tumor cell growth. Restoring MCM5 expression can partially reverse ERβ knockdown-mediated growth reduction. Supportively, treating cells with the ERβ-specific antagonist, 4-[2-Phenyl-5,7-bis(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP), reduced BCa cell growth and invasion, as well as MCM5 expression. Furthermore, we provide the first evidence that BCa burden and mortality can be controlled by PHTPP treatment in the carcinogen-induced BCa model. Together, these results demonstrate that ERβ could play positive roles in promoting BCa progression via MCM5 regulation. Targeting ERβ through ERβ-shRNA, PHTPP or via downstream targets, such as MCM5, could serve as potential therapeutic approaches to battle BCa.

Minimal Intervention Dentistry – A New Frontier in Clinical Dentistry

PubMed Central

NK., Bajwa; A, Pathak

2014-01-01

Minimally invasive procedures are the new paradigm in health care. Everything from heart bypasses to gall bladder, surgeries are being performed with these dynamic new techniques. Dentistry is joining this exciting revolution as well. Minimally invasive dentistry adopts a philosophy that integrates prevention, remineralisation and minimal intervention for the placement and replacement of restorations. Minimally invasive dentistry reaches the treatment objective using the least invasive surgical approach, with the removal of the minimal amount of healthy tissues. This paper reviews in brief the concept of minimal intervention in dentistry. PMID:25177659

Minimal intervention dentistry - a new frontier in clinical dentistry.

PubMed

Mm, Jingarwar; Nk, Bajwa; A, Pathak

2014-07-01

Minimally invasive procedures are the new paradigm in health care. Everything from heart bypasses to gall bladder, surgeries are being performed with these dynamic new techniques. Dentistry is joining this exciting revolution as well. Minimally invasive dentistry adopts a philosophy that integrates prevention, remineralisation and minimal intervention for the placement and replacement of restorations. Minimally invasive dentistry reaches the treatment objective using the least invasive surgical approach, with the removal of the minimal amount of healthy tissues. This paper reviews in brief the concept of minimal intervention in dentistry.

Ten Years of Complete Remission of Pulmonary Metastasis after Post-Cystectomy Palliative Cisplatin-Gemcitabine Chemotherapy with Gefitinib for Muscle Invasive Bladder Cancer: A Case Report.

PubMed

Fahmy, Omar; Scharpf, Marcus; Schubert, Tina; Feyerabend, Susan; Stenzl, Arnulf; Schwentner, Christian; Fend, Falko; Gakis, Georgios

2016-01-01

Muscle-invasive bladder cancer (MIBC) is considered one of the most lethal malignancies with high metastatic potential. Usually, metastatic bladder cancer carries worse prognosis with a median survival rate of approximately 6 months, which can be prolonged for up to 14 months with palliative systemic chemotherapy. We present the case of a 61-year-old male patient diagnosed with localized MIBC 10 years ago. He underwent nerve-sparing radical cystectomy with ileal neobladder, but developed pulmonary metastatic disease 7 months postoperatively. Six cycles of gemcitabine/cisplatin combination chemotherapy with an addition of gefitinib as daily oral medication were administered within a randomized phase II clinical trial; this resulted in complete remission of the pulmonary metastases. Until now, the patient is still on gefitinib daily without any side effects. Although, the addition of gefitinib to standard systemic chemotherapy has not been shown to improve the survival in metastatic urothelial cancer, this case represents a very pleasant albeit uncommon long-term outcome. © 2016 S. Karger AG, Basel.

Active surveillance for nonmuscle invasive bladder cancer.

PubMed

Miyake, Makito; Fujimoto, Kiyohide; Hirao, Yoshihiko

2016-06-01

Nonmuscle invasive bladder cancer (NMIBC) is known to be a heterogeneous malignancy that requires varying treatment modalities and follow-up schedules. Low-grade Ta papillary tumors are categorized as low-risk NMIBC because of their favorable prognosis. There is an expanding movement that overdiagnosis and overtreatment should be avoided considering the economic impact and the patients' quality of life. It has been over 10 years since the initial assessment of active surveillance for low-risk NMIBC suggested its feasibility and safety. However, urologists are still unfamiliar with this treatment option, which can be ideal in appropriately selected patients. In this review article, we focus on active surveillance for low-risk NMIBC and discuss the evidence and rationale for this treatment option. There are several issues to resolve in order to advocate active surveillance as a standard option in selected patients. A specific follow-up protocol including intervals of cystoscopy, urine cytology, urine markers, and other radiographic examinations need to be optimized and validated. Finally, we integrate the available data into the follow-up strategy and propose a new surveillance protocol for active surveillance of recurrent low-risk bladder cancer.

Contemporary management of patients with high-risk non-muscle-invasive bladder cancer who fail intravesical BCG therapy.

PubMed

Yates, D R; Rouprêt, M

2011-08-01

It is advocated that patients with high-risk non-muscle-invasive bladder cancer (NMIBC) receive an adjuvant course of intravesical Bacille Calmette-Guerin (BCG) as first-line treatment. However, a substantial proportion of patients will 'fail' BCG, either early with persistent (refractory) disease or recur late after a long disease-free interval (relapsing). Guideline recommendation in the 'refractory' setting is radical cystectomy, but there are situations when extirpative surgery is not feasible due to competing co-morbidity, a patient's desire for bladder preservation or reluctance to undergo surgery. In this review, we discuss the contemporary management of NMIBC in patients who have failed prior BCG and are not suitable for radical surgery and highlight the potential options available. These options can be categorised as immunotherapy, chemotherapy, device-assisted therapy and combination therapy. However, the current data are still inadequate to formulate definitive recommendations, and data from ongoing trials and maturing studies will give us an insight into whether there is a realistic efficacious second-line treatment for patients who fail intravesical BCG but are not candidates for definitive surgery.

Future robotic platforms in urologic surgery: Recent Developments

PubMed Central

Herrell, S. Duke; Webster, Robert; Simaan, Nabil

2014-01-01

Purpose of review To review recent developments at Vanderbilt University of new robotic technologies and platforms designed for minimally invasive urologic surgery and their design rationale and potential roles in advancing current urologic surgical practice. Recent findings Emerging robotic platforms are being developed to improve performance of a wider variety of urologic interventions beyond the standard minimally invasive robotic urologic surgeries conducted presently with the da Vinci platform. These newer platforms are designed to incorporate significant advantages of robotics to improve the safety and outcomes of transurethral bladder surgery and surveillance, further decrease the invasiveness of interventions by advancing LESS surgery, and allow for previously impossible needle access and ablation delivery. Summary Three new robotic surgical technologies that have been developed at Vanderbilt University are reviewed, including a robotic transurethral system to enhance bladder surveillance and TURBT, a purpose-specific robotic system for LESS, and a needle sized robot that can be used as either a steerable needle or small surgeon-controlled micro-laparoscopic manipulator. PMID:24253803

[A novel technique for distal ureterectomy and bladder cuff excision].

PubMed

Sotelo, R; Ramírez, D; Carmona, O; di Grazia, E; de Andrade, R; Giedelman, C; Pascal, Z; Gill, I; Desai, M

2011-03-01

We describe a novel endoscopic approach and provide a literature review for the "en bloc" dissection of the distal ureter and bladder cuff during laparoscopic radical nephroureterectomy using a transvesical single port approach under pneumovesicum. The procedure was performed in an 80-year old male with a history of gross hematuria due to left renal pelvic TCC and no history of prior bladder TCC. Laparoscopic radical nephroureterectomy was performed and the ureter was dissected down to the bladder and clipped. A single-port device was inserted transvesically and pneumovesicum established. A full thickness incision of the bladder around the ureter was performed with progressive intravesical mobilization of the distal ureter. Subsequently, a water-tight closure of the bladder defect was achieved. The distal ureter, together with the bladder cuff, was then delivered en bloc laparoscopically with the specimen. The operating time (LESS radical nephroureterectomy, RPLND, and bladder cuff excision) was 6hours and 15minutes. The bladder cuff time was 45minutes. There were no intra or postoperative complications and the catheter was removed after 6 days. Histopathological analysis showed kidney-invasive papillary urothelial cancer, pT3 pN0 (0/7) G3. The distal ureter and bladder cuff techniques have not yet been standardized. Management of the bladder cuff with a single port is feasible. Additional studies are needed to identify the best approach for management of the distal ureter at the time of laparoscopic nephroureterectomy. Copyright © 2010 AEU. Published by Elsevier Espana. All rights reserved.

Rhabdomyosarcoma of the urinary bladder in adults: predilection for alveolar morphology with anaplasia and significant morphologic overlap with small cell carcinoma.

PubMed

Paner, Gladell P; McKenney, Jesse K; Epstein, Jonathan I; Amin, Mahul B

2008-07-01

Rhabdomyosarcoma (RMS) represents the most common malignant soft tissue tumor in children and adolescents with the urinary bladder representing a frequent site. Most of these urinary bladder tumors are embryonal RMS, predominantly the botryoid subtype. RMSs of the urinary bladder in adults are distinctively rare and the subject of only case reports. We report the clinicopathologic features of 5 bladder neoplasms with rhabdomyosarcomatous differentiation in adults and emphasize the differential diagnosis in the adult setting. The patients, 4 men and 1 woman, ranged in age from 23 to 85 years (mean 65.4 y). Gross hematuria was the most common initial symptom, although 2 patients had metastatic disease at presentation. Four cases were pure primary RMSs of the bladder and 1 case was a sarcomatoid urothelial carcinoma with RMS representing the extensive heterologous component. All 5 cases demonstrated a diffuse growth pattern (ie, non-nested), of which 4 cases had nuclear anaplasia (Wilms criteria without the atypical mitotic figure requirement); only 1 case (the sarcomatoid carcinoma) showed obvious rhabdomyoblastic differentiation (ie, strap cells). Three cases were of the alveolar subtype (1 admixed with embryonal histology) and 2 were RMS, not further classified. Microscopically, all tumors had a primitive undifferentiated morphology with cells containing scant cytoplasm, varying round to fusiform nuclei with even chromatin distribution, and frequent mitoses. The degree of morphologic overlap with small cell carcinoma of the bladder, a relatively more common round cell tumor in adults, was striking. The epithelial component of the sarcomatoid carcinoma was high-grade invasive urothelial carcinoma with glandular differentiation. No other case had previous history of bladder cancer or concurrent carcinoma in situ or invasive urothelial carcinoma. All tumors showed immunohistochemical expression for desmin, myogenin, and/or MyoD1. Synaptophysin was performed in 4 cases, and 3 showed weak cytoplasmic immunoreactivity. Two patients received chemotherapy, 2 underwent cystectomy, and 1 had transurethral resection alone. Outcome data were available in 4 cases, and all 4 died of disease (1, 4, 8, and 8 mo). In conclusion, (1) RMS of the urinary bladder in adults more commonly presents as a primitive round blue cell neoplasm that has significant morphologic and immunohistochemical overlap with small cell carcinoma of the bladder. (2) Although RMS in children generally have a botryoid embryonal histology with favorable outcome, bladder RMS in adults frequently demonstrates alveolar or unclassified histology, commonly with anaplasia, and have a uniformly aggressive clinical course.

[Spinal cord injury with neurogenic lower urinary tract dysfunction as a potential risk factor for bladder carcinoma].

PubMed

Böthig, Ralf; Fiebag, Kai; Kowald, Birgitt; Hirschfeld, Sven; Thietje, Roland; Kurze, Ines; Schöps, Wolfgang; Böhme, Holger; Kaufmann, Albert; Zellner, Michael; Kadhum, Thura; Golka, Klaus

2018-05-29

 Life expectancy for people with spinal cord injury/disease (SCI/D) is increasing, due to modern advances in treatment methods and in neuro-urology. However, with the increased life expectancy the risk of developing urinary bladder cancer is gaining importance. How is this patient group different from the general population?  Single-centre retrospective evaluation of consecutive patient data with spinal cord injury and proven urinary bladder cancer.  Between January 1st 1998 and March 31st 2017, 32 (3 female, 29 male) out of a total of 6432 patients with SCI/D were diagnosed with bladder cancer.The average age at bladder cancer diagnosis was 54.5 years, which is well below the average for bladder cancer cases in the general population (male: 74, female: 75).Twenty-seven patients suffered from urodynamically confirmed neurogenic detrusor overactivity, while five patients (all male) had detrusor acontractility.The median latency period between the onset of SCI/D and tumor diagnosis was 29.5 years. Temporary indwelling catheterisation was found in four patients for only 1.61 % of the overall latency period of all patients.The majority of the patients (n = 27) had transitional cell carcinoma, while five had squamous cell carcinoma. Of the 32 patients, 25 (78 %) had muscle invasive bladder cancer at ≥ T2 at the time of diagnosis. Regarding tumour grading, 23 out of 32 patients showed a histologically poorly differentiated G3 carcinoma; two patients each had G2 and G1 tumours repectively (no information on tumour grading was available in five patients).The median survival for all patients was 11.5 months. The prognosis of patients with squamous cell carcinoma was even worse; 4 out of 5 died within 7 months (median 4 months).  The significantly younger age at onset and the frequency of invasive, poorly differentiated tumour at diagnosis indicate that SCI/D influences both bladder cancer risk and prognosis significantly. The latency period between paralysis and tumour disease seems to be a decisive risk parameter.The type of neurogenic bladder dysfunction and the form of bladder drainage do not appear to influence the risk. Long-term indwelling catheter drainage played only a minor role in the investigated patients.Early detection of bladder cancer in patients with spinal cord injury remains a challenge. © Georg Thieme Verlag KG Stuttgart · New York.

Biomarkers in patients treated with BCG: an update.

PubMed

Klap, Julia; Schmid, Marianne; Loughlin, Kevin R

2014-08-01

Bacillus Calmette-Guerin (BCG) instillations are the recommended treatment for non-muscle invasive bladder cancer but high recurrence and progression rates remain after treatment. Despite patients risk stratification, BCG effectiveness remains unpredictable. A close, invasive and expensive follow up is mandatory. To improve or even replace this heavy surveillance in this high risk population, validated biomarkers were developed. To identify the useful tools for the urologist in monitoring bladder cancer patients, we reviewed the literature focusing on plasma and urinary biomarkers of BCG-therapy outcome. Articles dated from 1988 to 2013 including specific keywords (urinary bladder neoplasm, biological markers, intravesical administration, recurrence) were examined and relevant papers were selected. Before treatment initiation, genetic polymorphisms of multiple agents (cytokines, matrix-metalloproteinases) were found to become very useful to tailor therapy and monitoring. Those biomarkers belong to personalized medicine which is a topic of great interest today, but still need to be validated in cohorts from different ethnicities. During instillations, cytokines (IL-2, IL-8, IL-6/IL-10) were reported to be reliable to determine treatment response and efficacy. Further studies are needed to confirm results and standardize thresholds. After treatment, UroVysion, the FDA-approved fluorescence in situ hybridization (FISH), appeared to be the most robust marker of all the clinical parameters reviewed; but is not yet validated for BCG-treated patients. No recommendations for everyday practice can be established today, but a combination of several markers and clinicopathological characteristics may be the future. As bladder cancer diagnosis and management are evolving, practicing urologists should be aware of and utilize bladder cancer markers in clinical practice.

Urinary ATP May Be a Dynamic Biomarker of Detrusor Overactivity in Women with Overactive Bladder Syndrome

PubMed Central

Oliveira, Olga; Ferreira, Sónia; Reis, Maria Júlia; Oliveira, José Carlos; Correia-de-Sá, Paulo

2013-01-01

Background Nowadays, there is a considerable bulk of evidence showing that ATP has a prominent role in the regulation of human urinary bladder function and in the pathophysiology of detrusor overactivity. ATP mediates nonadrenergic-noncholinergic detrusor contractions in overactive bladders. In vitro studies have demonstrated that uroepithelial cells and cholinergic nerves from overactive human bladder samples (OAB) release more ATP than controls. Here, we compared the urinary ATP concentration in samples collected non-invasively from OAB women with detrusor overactivity and age-matched controls. Methods Patients with neurologic diseases, history of malignancy, urinary tract infections or renal impairment (creatinine clearance <70 ml/min) were excluded. All patients completed a 3-day voiding diary, a 24 h urine collection and blood sampling to evaluate creatinine clearance. Urine samples collected during voluntary voids were immediately freeze-preserved for ATP determination by the luciferin-luciferase bioluminescence assay; for comparison purposes, samples were also tested for urinary nerve growth factor (NGF) by ELISA. Results The urinary content of ATP, but not of NGF, normalized to patients’ urine creatinine levels (ATP/Cr) or urinary volume (ATP.Vol) were significantly (P<0.05) higher in OAB women with detrusor overactivity (n = 34) than in healthy controls (n = 30). Significant differences between the two groups were still observed by boosting urinary ATP/Cr content after water intake, but these were not detected for NGF/Cr. In OAB patients, urinary ATP/Cr levels correlated inversely with mean voided volumes determined in a 3-day voiding diary. Conclusion A high area under the receiver operator characteristics (ROC) curve (0.741; 95% CI 0.62–0.86; P<0.001) is consistent with urinary ATP/Cr being a highly sensitive dynamic biomarker for assessing detrusor overactivity in women with OAB syndrome. PMID:23741373

Image-guided photo-therapeutic nanoporphyrin synergized HSP90 inhibitor in patient-derived xenograft bladder cancer model.

PubMed

Long, Qilai; Lin, Tzu-Yin; Huang, Yee; Li, Xiaocen; Ma, Ai-Hong; Zhang, Hongyong; Carney, Randy; Airhart, Susan; Lam, Kit S; deVere White, Ralph W; Pan, Chong-Xian; Li, Yuanpei

2018-04-01

Photodynamic therapy is a promising and effective non-invasive therapeutic approach for the treatment of bladder cancers. Therapies targeting HSP90 have the advantage of tumor cell selectivity and have shown great preclinical efficacy. In this study, we evaluated a novel multifunctional nanoporphyrin platform loaded with an HSP90 inhibitor 17AAG (NP-AAG) for use as a multi-modality therapy against bladder cancer. NP-AAG was efficiently accumulated and retained at bladder cancer patient-derived xenograft (PDX) over 7 days. PDX tumors could be synergistically eradicated with a single intravenous injection of NP-AAG followed by multiple light treatments within 7 days. NP-AAG mediated treatment could not only specifically deliver 17AAG and produce heat and reactive oxygen species, but also more effectively inhibit essential bladder cancer essential signaling molecules like Akt, Src, and Erk, as well as HIF-1α induced by photo-therapy. This multifunctional nanoplatform has high clinical relevance and could dramatically improve management for bladder cancers with minimal toxicity. Copyright © 2018 Elsevier Inc. All rights reserved.

An Inexpensive, Point-of-Care Urine Test for Bladder Cancer in Patients Undergoing Hematuria Evaluation.

PubMed

Acharya, Abhinav P; Theisen, Kathryn M; Correa, Andres; Meyyappan, Thiagarajan; Apfel, Abraham; Sun, Tao; Tarin, Tatum V; Little, Steven R

2017-11-01

Although hematuria (blood in urine) is the most common symptom of bladder cancer, 70-98% of hematuria cases are benign. These hematuria patients unnecessarily undergo costly, invasive, and expensive evaluation for bladder cancer. Therefore, there remains a need for noninvasive office-based tests that can rapidly and reliably rule out bladder cancer in patients undergoing hematuria evaluation. Herein, a clinical assay for matrix metalloproteinases ("Ammps") is presented, which generates a visual signal based on the collagenase activity (in urine of patients) on the Ammps substrates. Ammps substrates are generated by crosslinking gelatin with Fe(II) chelated alginate nanoparticles, which precipitate in urine samples. The cleavage of gelatin-conjugated alginate (Fe(II)) nanoparticles by collagenases generates free-floating alginate (Fe(II)) nanoparticles that participate in Fenton's reaction to generate a visual signal. In a pilot study of 88 patients, Ammps had 100% sensitivity, 85% specificity, and a negative predictive value (NPV) of 100% for diagnosing bladder cancer. This high NPV can be useful in ruling out bladder cancer in patients referred for hematuria evaluation. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Ultrasound-guided urinary bladder biopsy through a urinary catheter in a bitch.

PubMed

Lopez, Julio; Norman, Brian C

2014-01-01

A 34.4 kg 5 yr old spayed female mixed-breed dog was presented for evaluation of a urinary bladder mass. The dog had a recent onset of hematuria and stranguria but otherwise appeared to be healthy. Abdominal ultrasound revealed a mass in the urinary bladder. The dog was sedated and a 10-French rubber catheter that had the blunt end removed was passed from the urethra to the urinary bladder. Using ultrasound guidance, ellipsoid cup biopsy forceps were advanced through the rubber catheter to the urinary bladder mass and biopsies were successfully obtained. The dog was discharged from the hospital a few hours after the procedure. Histopathology of the mass was consistent with polypoid cystitis. Follow-up surgical removal of the polyp was uneventful, and histopathology confirmed the presurgical biopsy diagnosis. Procurement of urinary bladder biopsies through a urinary catheter with ultrasound guidance was used as a minimally invasive alternative to either cystoscopy or surgery in a bitch. Use of this technique achieved a diagnosis without the need for specialized endoscopic equipment, anesthesia, or surgery.

Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer.

PubMed

Robertson, A Gordon; Kim, Jaegil; Al-Ahmadie, Hikmat; Bellmunt, Joaquim; Guo, Guangwu; Cherniack, Andrew D; Hinoue, Toshinori; Laird, Peter W; Hoadley, Katherine A; Akbani, Rehan; Castro, Mauro A A; Gibb, Ewan A; Kanchi, Rupa S; Gordenin, Dmitry A; Shukla, Sachet A; Sanchez-Vega, Francisco; Hansel, Donna E; Czerniak, Bogdan A; Reuter, Victor E; Su, Xiaoping; de Sa Carvalho, Benilton; Chagas, Vinicius S; Mungall, Karen L; Sadeghi, Sara; Pedamallu, Chandra Sekhar; Lu, Yiling; Klimczak, Leszek J; Zhang, Jiexin; Choo, Caleb; Ojesina, Akinyemi I; Bullman, Susan; Leraas, Kristen M; Lichtenberg, Tara M; Wu, Catherine J; Schultz, Nicholaus; Getz, Gad; Meyerson, Matthew; Mills, Gordon B; McConkey, David J; Weinstein, John N; Kwiatkowski, David J; Lerner, Seth P

2017-10-19

We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments. Copyright © 2017 Elsevier Inc. All rights reserved.

Photodynamic diagnosis of bladder cancer in ex vivo urine cytology

NASA Astrophysics Data System (ADS)

Fu, C. Y.; Ng, B. K.; Razul, S. Gulam; Olivo, Malini C.; Lau, Weber K. O.; Tan, P. H.; Chin, William

2006-02-01

Bladder cancer is the fourth common malignant disease worldwide, accounting for 4% of all cancer cases. In Singapore, it is the ninth most common form of cancer. The high mortality rate can be reduced by early treatment following precancerous screening. Currently, the gold standard for screening bladder tumors is histological examination of biopsy specimen, which is both invasive and time-consuming. In this study ex vivo urine fluorescence cytology is investigated to offer a timely and biopsy-free means for detecting bladder cancers. Sediments in patients' urine samples were extracted and incubated with a novel photosensitizer, hypericin. Laser confocal microscopy was used to capture the fluorescence images at an excitation wavelength of 488 nm. Images were subsequently processed to single out the exfoliated bladder cells from the other cells based on the cellular size. Intensity histogram of each targeted cell was plotted and feature vectors, derived from the histogram moments, were used to represent each sample. A difference in the distribution of the feature vectors of normal and low-grade cancerous bladder cells was observed. Diagnostic algorithm for discriminating between normal and low-grade cancerous cells is elucidated in this paper. This study suggests that the fluorescence intensity profiles of hypericin in bladder cells can potentially provide an automated quantitative means of early bladder cancer diagnosis.

Bladder perforation during sling procedures: diagnosis and management of injury.

PubMed

Israfil-Bayli, F; Bulchandani, S; Parsons, M; Jackson, S; Toozs-Hobson, P

2014-05-01

Midurethral slings are an effective and minimally invasive treatment for stress urinary incontinence. One of the most common intraoperative complications is bladder perforation, complicating between 2 and 10% of all operations, and on average 4.7%. It is usually corrected during surgery, with repositioning of the trocars. The purpose of this video is to demonstrate a method of replacing the trocars under direct vision. This video exhibits a bladder perforation during insertion of a retropubic midurethral sling (Advantage Fit; Boston Scientific) and gives a step-by step guide to the removal and repositioning of the sling under direct visualisation. Repositioning of the trocars under direct vision in cases of bladder perforation may have numerous advantages. It may prevent damage to the urethra, possibly reduce the risk of postoperative infection and may be beneficial for trainees.

Primary prostatic haemangiosarcoma causing severe haematuria in a dog.

PubMed

Della Santa, D; Dandrieux, J; Psalla, D; Gorgas, D; Lang, J; Geissbuehler, U; Howard, J

2008-05-01

A 10-year-old, entire, male, mixed-breed dog was presented for severe haematuria and stranguria. Ultrasound revealed a large intraluminal urinary bladder blood clot and a prostatic space-occupying lesion. Invasion of the lesion into the prostatic urethra was detected ultrasonographically during compression of the urinary bladder. Post-mortem examination revealed primary prostatic haemangiosarcoma infiltrating the urethra. Haemangiosarcoma should be considered as a rare cause of prostatic mass lesions, haematuria or lower urinary tract signs in dogs.

Ablative Intravesical Chemotherapy for Small Recurrent Non-Muscle-Invasive Bladder Cancer: A Prospective Study.

PubMed

Decaestecker, Karel; Lumen, Nicolaas; Ringoir, Annelies; Oosterlinck, Willem

2016-01-01

The efficacy of intravesical chemotherapy in abolishing small papillary recurrences of non-muscle-invasive bladder cancer (NMIBC), the disease-free interval in responders and patients' preferences were explored. When a small (≤1 cm) papillary recurrence of a NMIBC was diagnosed, the patient could choose between immediate transurethral resection of the bladder (TURB) or four weekly intravesical instillations with mitomycin C (MMC) or epirubicin (ERC). Control cystoscopy was scheduled 2-3 weeks after the last instillation. Complete remission was defined as total disappearance of all papillary tumours and negative cytology. 25 patients with 47 recurrence episodes were recruited from February 2003 until August 2011. The median follow-up was 35 months. After exclusion of 2 patients with intolerance to the instillations, 45 study episodes could be analysed. All patients to whom this was proposed preferred the instillations over immediate TURB. Complete, partial and no response was seen in 23 (51%), 6 (13%) and 16 (36%) out of 45 episodes, respectively. The median disease-free interval after complete remission was 16 months (95% confidence interval 9-24). Small papillary recurrences of NMIBC completely disappear in about half of the cases receiving four weekly bladder instillations with MMC or ERC. This is followed by a disease-free interval. Intravesical chemotherapy was preferred by all patients over immediate TURB. © 2015 S. Karger AG, Basel.

Telomerase reverse transcriptase (TERT) promoter mutation analysis of benign, malignant and reactive urothelial lesions reveals a subpopulation of inverted papilloma with immortalizing genetic change.

PubMed

Cheng, Liang; Davidson, Darrell D; Wang, Mingsheng; Lopez-Beltran, Antonio; Montironi, Rodolfo; Wang, Lisha; Tan, Puay-Hoon; MacLennan, Gregory T; Williamson, Sean R; Zhang, Shaobo

2016-07-01

To understand more clearly the genetic ontogeny of inverted papilloma of urinary bladder, we analysed telomerase reverse transcriptase (TERT) promoter mutation status in a group of 26 inverted papillomas in comparison with the mutation status of urothelial carcinoma with inverted growth (26 cases), conventional urothelial carcinoma (36 Ta non-invasive urothelial carcinoma, 35 T2 invasive urothelial carcinoma) and cystitis glandularis (25 cases). TERT promoter mutations in inverted papilloma, urothelial carcinoma with inverted growth, urothelial carcinoma and cystitis glandularis were found in 15% (four of 26), 58% (15 of 26), 63% (45 of 71) and 0% (none of 25), respectively. C228T mutations were the predominant mutations (97%) found in bladder tumours, while C250T aberrations occurred in approximately 3% of bladder tumours. In the inverted papilloma group, TERT mutation occurred predominantly in female patients (P = 0.006). Among urothelial carcinomas, TERT promoter mutation status did not correlate with gender, histological grade or pathological stage. TERT promoter mutations were found in 15% of inverted papillomas. Our data suggest that there is a subpopulation of inverted papilloma that shares a carcinogenetic pathway with urothelial carcinoma with inverted growth and conventional urothelial carcinomas. Caution is warranted in exploring TERT promoter mutation status as a screening or adjunct diagnostic test for bladder cancer. © 2015 John Wiley & Sons Ltd.

Endometrial stromal sarcoma involving the urinary bladder: a study of 6 cases.

PubMed

Tian, Wei; Latour, Mathieu; Epstein, Jonathan I

2014-07-01

Endometrial stromal sarcoma (ESS) involving the urinary bladder is very rare, with no prior series reported. We identified 6 cases of low-grade ESS involving the bladder at our institution (1998 to 2013), 5 of them consults. The median age at bladder involvement was 60 years (range, 44 to 77 y). One patient presented with bladder involvement at initial diagnosis of ESS. The remaining 5 cases with bladder involvement presented 7 to 30 years (mean 18 y) after a known diagnosis of ESS (n=2) or after a remote history of hysterectomy with an uncertain diagnosis (n=3). The location of bladder involvement included dome (n=1), trigone (n=2), diffuse (n=1), and unknown (n=2). Two cases demonstrated worm-like infiltrating tumor nests classic of low-grade ESS with little stromal reaction with retraction artifact mimicking vascular invasion. One case originating from the ovary showed focal glandular differentiation in the bladder, resembling endometriosis. Two cases had abundant keloidal collagen formation, arranged haphazardly or in a sunburst pattern. One case showed primitive cells infiltrating entirely hyalinized stroma, after chemotherapy given for a misdiagnosis of urothelial carcinoma. CD31 was negative in all cases, except for 1 case with obvious large vessel invasion. The differential diagnosis included a large nested variant of urothelial carcinoma, carcinoid tumor, synovial sarcoma, solitary fibrous tumor, Ewing sarcoma/primitive neuroectodermal tumors, and endometriosis. CD10 was strongly positive in 5 cases, and 1 case had very focal, moderate staining. Estrogen receptor showed strong and diffuse staining in all 6 cases. Progesterone receptor showed moderate to strong staining in 5 cases and focal staining in 1 case. One case showed PAX8 expression, and 2 cases showed p16 nuclear and cytoplasmic expression. CD56 showed weak to strong staining in 4 cases. Two cases had diffuse synaptophysin, and 1 case had focal p63 positivity. GATA-3, CD34, and CD99 were negative in all cases. The Ki-67 index was 1% to 10% (mean 4%). The mitotic count was 0 to 3/10 HPF (mean <1/10 HPF). Two patients had metastases to pelvic lymph nodes, and 1 had possible lung metastasis. Three patients were treated with Megace and 1 with Arimidex after surgery. Follow-up averaged 19 years (0 to 33 y) after the initial diagnosis of ESS or hysterectomy and 3.5 years (0 to 11 y) after bladder surgery. ESS involving the bladder is extremely rare with a very long interval from onset to bladder involvement. In female patients, low-grade spindle cell lesions involving the bladder should include ESS in the differential diagnosis.

Hexavalent chromium induces chromosome instability in human urothelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wise, Sandra S.; Holmes, Amie L.; Department of Radiation Oncology, Dana Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215

Numerous metals are well-known human bladder carcinogens. Despite the significant occupational and public health concern of metals and bladder cancer, the carcinogenic mechanisms remain largely unknown. Chromium, in particular, is a metal of concern as incidences of bladder cancer have been found elevated in chromate workers, and there is an increasing concern for patients with metal hip implants. However, the impact of hexavalent chromium (Cr(VI)) on bladder cells has not been studied. We compared chromate toxicity in two bladder cell lines; primary human urothelial cells and hTERT-immortalized human urothelial cells. Cr(VI) induced a concentration- and time-dependent increase in chromosome damagemore » in both cell lines, with the hTERT-immortalized cells exhibiting more chromosome damage than the primary cells. Chronic exposure to Cr(VI) also induced a concentration-dependent increase in aneuploid metaphases in both cell lines which was not observed after a 24 h exposure. Aneuploidy induction was higher in the hTERT-immortalized cells. When we correct for uptake, Cr(VI) induces a similar amount of chromosome damage and aneuploidy suggesting that the differences in Cr(VI) sensitivity between the two cells lines were due to differences in uptake. The increase in chromosome instability after chronic chromate treatment suggests this may be a mechanism for chromate-induced bladder cancer, specifically, and may be a mechanism for metal-induced bladder cancer, in general. - Highlights: • Hexavalent chromium is genotoxic to human urothelial cells. • Hexavalent chromium induces aneuploidy in human urothelial cells. • hTERT-immortalized human urothelial cells model the effects seen in primary urothelial cells. • Hexavalent chromium has a strong likelihood of being carcinogenic for bladder tissue.« less

Surgical correction of bladder neck contracture following prostate cancer treatment.

PubMed

Bugeja, Simon; Andrich, Daniela E; Mundy, Anthony R

2014-01-01

The surgical and non-surgical treatment of localised prostate cancer may be complicated by bladder neck contractures, prostatic urethral stenoses and bulbomembranous urethral strictures. In general, such complications following radical prostatectomy are less extensive, easier to treat and associated with a better outcome and more rapid recovery than the same complications following radiotherapy, high-intensity focussed ultrasound and cryotherapy. Treatment options range from minimally invasive endoscopic procedures to more complex and specialised open surgical reconstruction.In this chapter the surgical management of bladder neck contractures following the treatment of prostate cancer is described together with the management of prostatic urethral stenoses and bulbomembranous urethral strictures, given the difficulty in distinguishing them from one another clinically.

GENE EXPRESSION DOSE-RESPONSE IN THE MOUSE BLADDER FOLLOWING EXPOSURE TO ARSENATE IN DRINKING WATER

EPA Science Inventory

The association between drinking water exposures to inorganic arsenic and life-threatening tumors in the human is strongest for bladder cancer. Moreover, a working model for the pathogenesis of human bladder cancer has been developed. To investigate the mode of action for inorgan...

Targeting IL-5Rα with antibody-conjugates reveals a strategy for imaging and therapy for invasive bladder cancer.

PubMed

Paquette, Michel; Vilera-Perez, Luis-Guillermo; Beaudoin, Simon; Ekindi-Ndongo, Nadia; Boudreaut, Pierre-Luc; Bonin, Marc-Andre; Battista, Marie-Claude; Bentourkia, M'hamed; Lopez, Angel F; Lecomte, Roger; Marsault, Eric; Guérin, Brigitte; Sabbagh, Robert; Leyton, Jeffrey V

2017-01-01

Despite the high interest and concern due to an increasing incidence and death rate, patients who develop muscle invasive bladder cancer (MIBC) have few options available. However, the past decade has produced many candidate bladder tumor-specific markers but further development of these markers is still needed for creating effective targeted medications to solve this urgent need. Interleukin-5 receptor α-subunit (IL-5Rα) has recently been reported to be involved in MIBC progression. Thus, we aimed to validate IL-5Rα as a target for antibody-conjugates to better manage patients with MIBC. Patients were recruited and their tumors were processed for IL-5Rα immunohistochemical analysis. NOD/SCID mice were also heterotopically implanted with the human MIBC HT-1376 and HT-B9 cell lines and established xenografts immunohistochemically evaluated for IL-5Rα and compared against patient tumors. Using the mAb A14, an antibody-drug conjugate (ADC) and a radiolabeled immunoconjugate (RIC) were developed by conjugating to vinblastine and to the positron emitter copper-64 ( 64 Cu), respectively. As a proof-of-concept for ADC and RIC efficacy, in vitro cytotoxicity and in vivo positron emission tomography (PET) imaging in tumor-bearing mice were performed, respectively. In addition, as rapid internalization and accumulation are important components for effective antibody-conjugates, we evaluated these aspects in response to IL-5 and 64 Cu-A14 treatments. Our findings suggest that although IL-5Rα protein expression is preferentially increased in MIBC, it is rapid IL-5Rα-mediated internalization allowing vinblastine-A14 to have cytotoxic activity and 64 Cu-A14 to detect MIBC tumors in vivo . This is the first report to elucidate the potential of IL-5Rα as an attractive MIBC target for antibody-conjugate applications.

Targeting IL-5Rα with antibody-conjugates reveals a strategy for imaging and therapy for invasive bladder cancer

PubMed Central

Vilera-Perez, Luis-Guillermo; Beaudoin, Simon; Ekindi-Ndongo, Nadia; Boudreaut, Pierre-Luc; Bonin, Marc-Andre; Battista, Marie-Claude; Bentourkia, M'hamed; Lopez, Angel F.; Lecomte, Roger; Marsault, Eric; Sabbagh, Robert; Leyton, Jeffrey V.

2017-01-01

ABSTRACT Despite the high interest and concern due to an increasing incidence and death rate, patients who develop muscle invasive bladder cancer (MIBC) have few options available. However, the past decade has produced many candidate bladder tumor-specific markers but further development of these markers is still needed for creating effective targeted medications to solve this urgent need. Interleukin-5 receptor α-subunit (IL-5Rα) has recently been reported to be involved in MIBC progression. Thus, we aimed to validate IL-5Rα as a target for antibody-conjugates to better manage patients with MIBC. Patients were recruited and their tumors were processed for IL-5Rα immunohistochemical analysis. NOD/SCID mice were also heterotopically implanted with the human MIBC HT-1376 and HT-B9 cell lines and established xenografts immunohistochemically evaluated for IL-5Rα and compared against patient tumors. Using the mAb A14, an antibody-drug conjugate (ADC) and a radiolabeled immunoconjugate (RIC) were developed by conjugating to vinblastine and to the positron emitter copper-64 (64Cu), respectively. As a proof-of-concept for ADC and RIC efficacy, in vitro cytotoxicity and in vivo positron emission tomography (PET) imaging in tumor-bearing mice were performed, respectively. In addition, as rapid internalization and accumulation are important components for effective antibody-conjugates, we evaluated these aspects in response to IL-5 and 64Cu-A14 treatments. Our findings suggest that although IL-5Rα protein expression is preferentially increased in MIBC, it is rapid IL-5Rα-mediated internalization allowing vinblastine-A14 to have cytotoxic activity and 64Cu-A14 to detect MIBC tumors in vivo. This is the first report to elucidate the potential of IL-5Rα as an attractive MIBC target for antibody-conjugate applications. PMID:29123949

Development of a near-infrared spectroscopy instrument for applications in urology.

PubMed

Macnab, Andrew J; Stothers, Lynn

2008-10-01

Near infrared spectroscopy (NIRS) is an established technology using photons of light in the near infrared spectrum to monitor changes in tissue of naturally occurring chromophores, including oxygenated and deoxygenated hemoglobin. Technology and methodology have been validated for measurement of a range of physiologic parameters. NIRS has been applied successfully in urology research; however current instruments are designed principally for brain and muscle study. To describe development of a NIRS instrument specifically designed for monitoring changes in chromophore concentration in the bladder detrusor in real time, to facilitate research to establish the role of this non-invasive technology in the evaluation of patients with voiding dysfunction The portable continuous wave NIRS instrument has a 3 laser diode light source (785, 808 and 830 nanometers), fiber optic cables for light transmission, a self adhesive patient interface patch with an emitter and sensor, and software to detect the difference between the light transmitted and received by the instrument. Software incorporated auto-attenuates the optical signals and converts raw optical data into chromophore concentrations displayed graphically. The prototype was designed, tested, and iteratively developed to achieve optimal suprapubic transcutaneous monitoring of the detrusor in human subjects during bladder filling and emptying. Evaluation with simultaneous invasive urodynamic measurement in men and women indicates good specificity and sensitivity of NIRS chromophore concentration changes by receiver operator curve analysis, and correlation between NIRS data and urodynamic pressures. Urological monitoring with this NIRS instrument is feasible and generates data of potential diagnostic value.

Comparison of the efficacy and feasibility of laser enucleation of bladder tumor versus transurethral resection of bladder tumor: a meta-analysis.

PubMed

Yang, Huan; Wang, Ning; Han, Shanfu; Male, Musa; Zhao, Chenming; Yao, Daqiang; Chen, Zhiqiang

2017-12-01

The transurethral resection of bladder tumor (TURBT) remains the most widely used method in the surgical treatment of the non-muscle invasive bladder tumor (NMIBT). Despite its popularity, the laser technique has been widely used in urology as an alternative, via the application of transurethral laser enucleation of bladder tumor. The aim of the present study was to compare the efficacy and feasibility between transurethral laser enucleation and transurethral resection of bladder tumor. A systematic search of the following databases was conducted: PubMed, Wed of Science, Cochrane Library, EMBASE, Google scholar, and Medline. The search included studies up to the 1st of January 2017. The outcomes of interest that were used in order to assess the two techniques included operation time, catheterization time, hospitalization time, obturator nerve reflex, bladder perforation, bladder irritation, 24-month-recurrence rate, and the postoperative adjuvant intravesical chemotherapy. A total of 13 trials with 2012 participants were included, of which 975 and 1037 underwent transurethral laser enucleation and transurethral resection of bladder tumor, respectively. No significant difference was noted in the operation time between the two groups, although significant differences were reported for the variables catheterization time, hospitalization time, obturator nerve reflex, bladder perforation, bladder irritation, and 24-month-recurrence rate. In the mitomycin and epirubicin subgroups, no significant differences were observed in the laser enucleation and TURBT methods with regard to the 24-month-recurrence rate. The laser enucleation was superior to TURBT with regard to the parameters obturator nerve reflex, bladder perforation, catheterization time, hospitalization time, and 24-month-recurrence rate. Moreover, laser enucleation can offer a more accurate result of the tumor's pathological stage and grade.

A pilot study on bladder wall thickness at different filling stages

NASA Astrophysics Data System (ADS)

Zhang, Xi; Liu, Yang; Li, Baojuan; Zhang, Guopeng; Liang, Zhengrong; Lu, Hongbing

2015-03-01

The ever-growing death rate and the high recurrence of bladder cancer make the early detection and appropriate followup procedure of bladder cancer attract more attention. Compare to optical cystoscopy, image-based studies have revealed its potentials in non-invasive observations of the abnormities of bladder recently, in which MR imaging turns out to be a better choice for bladder evaluation due to its non-ionizing and high contrast between urine and wall tissue. Recent studies indicate that bladder wall thickness tends to be a good indicator for detecting bladder wall abnormalities. However, it is difficult to quantitatively compare wall thickness of the same subject at different filling stages or among different subjects. In order to explore thickness variations at different bladder filling stages, in this study, we preliminarily investigate the relationship between bladder wall thickness and bladder volume based on a MRI database composed of 40 datasets acquired from 10 subjects at different filling stages, using a pipeline for thickness measurement and analysis proposed in our previous work. The Student's t-test indicated that there was no significant different on wall thickness between the male group and the female group. The Pearson correlation analysis result indicated that negative correlation with a correlation coefficient of -0.8517 existed between the wall thickness and bladder volume, and the correlation was significant(p <0.01). The corresponding linear regression equation was then estimated by the unary linear regression. Compared to the absolute value of wall thickness, the z-score of wall thickness would be more appropriate to reflect the thickness variations. For possible abnormality detection of a bladder based on wall thickness, the intra-subject and inter-subject thickness variation should be considered.

Rapidly quantifying the relative distention of a human bladder

NASA Technical Reports Server (NTRS)

Companion, John A. (Inventor); Heyman, Joseph S. (Inventor); Mineo, Beth A. (Inventor); Cavalier, Albert R. (Inventor); Blalock, Travis N. (Inventor)

1991-01-01

A device and method was developed to rapidly quantify the relative distention of the bladder of a human subject. An ultrasonic transducer is positioned on the human subject near the bladder. A microprocessor controlled pulser excites the transducer by sending an acoustic wave into the human subject. This wave interacts with the bladder walls and is reflected back to the ultrasonic transducer where it is received, amplified, and processed by the receiver. The resulting signal is digitized by an analog to digital converter, controlled by the microprocessor again, and is stored in data memory. The software in the microprocessor determines the relative distention of the bladder as a function of the propagated ultrasonic energy. Based on programmed scientific measurements and the human subject's past history as contained in program memory, the microprocessor sends out a signal to turn on any or all of the available alarms. The alarm system includes and audible alarm, the visible alarm, the tactile alarm, and the remote wireless alarm.

Incidence and location of lymph node metastases in patients undergoing radical cystectomy for clinical non-muscle invasive bladder cancer: results from a prospective lymph node mapping study.

PubMed

Bruins, Harman M; Skinner, Eila C; Dorin, Ryan P; Ahmadi, Hamed; Djaladat, Hooman; Miranda, Gus; Cai, Jie; Daneshmand, Siamak

2014-01-01

The objective of this study is to investigate the incidence and location of lymph node metastases (LNMs) in patients undergoing radical cystectomy (RC) and lymph node dissection (LND) for clinical non-muscle invasive bladder cancer (NMIBC). Prospectively collected data of 637 patients who underwent RC and 'superextended' LND with intent-to-cure for urothelial carcinoma of the bladder between 2002 and 2008 were examined. Inclusion criteria were (a) clinical stage Ta, Tis-only, or T1, (b) muscle presence at diagnostic transurethral resection in clinical T1 patients, (c) no prior diagnosis of ≥ T2 disease, (d) no neoadjuvant therapy, and (e) lymphatic tissue sample submitted from all 13 predesignated locations. Lymph node mapping was performed in all patients to determine the location of metastatic lymph nodes. Median follow-up time was 4.7 years. Recurrence-free survival and overall survival were reported. A total of 114 patients were included of whom 9 patients (7.9%) had LNM. Stratified by clinical stage, LNM was present in 6/67 (9.0%) patients with cT1, 3/25 (12.0%) patients with cTis-only, and none of the 22 patients with cTa. Of the 9 node-positive patients (33.3%), 3 had LNM proximal to the aortic bifurcation. No skip metastases were found. After RC, 27 patients (23.7%) were upstaged to muscle invasive disease; of whom 16.7% had cT1, 2.6% had cTa, and 4.4% had cTis-only. Of the remaining 87 patients with pathologic NMIBC, 1 patient (1.1%) had LNM, limited to the true pelvis. Five-year RFS was 82.3%, 81.5%, and 62.0% in patients with pathologic NMIBC, clinical NMIBC, and pathologic muscle invasive bladder cancer, respectively. Routine LND is important in patients with cT1 and cTis-only bladder cancer, but may have limited value in patients with cTa. LNM beyond the boundaries of a standard LND occurred in up to one-third of node-positive patients. In the absence of skip metastases, however, performing a standard LND would correctly identify all node-positive patients. Whether removal of LNM proximal to the common iliac vessels provides a survival benefit remains to be evaluated in future prospective studies. Copyright © 2014 Elsevier Ltd. All rights reserved.

Pseudocarcinomatous epithelial hyperplasia in the bladder unassociated with prior irradiation or chemotherapy.

PubMed

Lane, Zhaoli; Epstein, Jonathan I

2008-01-01

Pseudocarcinomatous epithelial hyperplasia in the bladder is a little known phenomenon, recognized to be associated with prior irradiation and/or chemotherapy. Whether this process can occur outside of this setting has not been studied. We identified 8 of these cases mimicking invasive urothelial carcinoma from our consultation files from 07/04 to 07/06 with no prior history of radiation or chemotherapy. The mean age at diagnosis was 65 years (range, 42 to 81 y), with 5 of the 8 males. Seven patients had a potential etiology for these changes that could either have resulted in localized ischemia or injury to the urothelium. These included case 1: atrial fibrillation, hypertension, congestive heart failure, gastrointestinal bleeding, and coronary artery vascular disease; case 2: coronary angioplasty, atrial fibrillation, hyperlipidemia, and amputation of arm for ischemia; case 3: hypertension, uncontrolled diabetes, hyperlipidemia, and atrial fibrillation; case 4: underlying arteriovenous malformation of the bladder; cases 5 to 6: history of indwelling Foley catheter; and case 7: history of radical prostatectomy for prostate cancer but no radiation. One patient had no potential contributing factors. All 8 patients presented with gross hematuria. At cystoscopy, 7 patients had polypoid lesions with 1 appearing nonpolypoid. Histologically, all cases showed epithelial proliferation of urothelium with cells having prominent eosinophilic cytoplasm. This process that mimicked invasive cancer within the lamina propria was marked in 3 cases (38%). Moderate nuclear pleomorphism was seen in 6 cases (75%). Only 1 case revealed mitotic figures. Ulceration was seen in 1 case. All cases showed some degree of hemorrhage with hemosiderin deposition identified in 3 cases (38%). Fibrin deposition was present in 1 case within the stroma, 3 cases in the vessels, and 4 cases in both. Five cases show stromal fibrosis. Edema and vascular congestion were common features (90% and 100%, respectively). Six out of 8 cases were accompanied by moderate to marked acute and chronic inflammation. The original diagnosis included nested variant urothelial carcinoma (1 case), atypical suspicious for invasive carcinoma (5 cases), hemangioma (1 case), and eosinophilic cystitis (1 case). Patients were followed for a mean of 16.5 months (range, 10 to 34 mo), and none developed bladder cancer. As a rare response to ischemia and chronic irritation, pseudocarcinomatous epithelial proliferations in the bladder may be confused with invasive urothelial carcinoma. Pathologists must be aware of the histologic changes mimicking cancer, and recognize that it can occur outside of the setting of prior irradiation or chemotherapy.

Alterations to the protein profile of bladder carcinoma cell lines induced by plant extract MINA-05 in vitro.

PubMed

Nguyen-Khuong, Terry; White, Melanie Y; Hung, Tzong-Tyng; Seeto, Shona; Thomas, Melissa L; Fitzgerald, Anna M; Martucci, Carlos E; Luk, Sharon; Pang, Shiu-Fu; Russell, Pamela J; Walsh, Bradley J

2009-04-01

Bladder cancer (BLCa) is a severe urological cancer of both men and women that commonly recurs and once invasive, is difficult to treat. MINA-05 (CK Life Sciences Int'l, Hong Kong) is a derivative of complex botanical extracts, shown to reduce cellular proliferation of bladder and prostate carcinomas. We tested the effects of MINA-05 against human BLCa cell sublines, B8, B8-RSP-GCK, B8-RSP-LN and C3, from a transitional cell carcinoma, grade IV, to determine the molecular targets of treatment by observing the cellular protein profile. Cells were acclimatised for 48 h then treated for 72 h with concentrations of MINA-05 reflecting 1/2 IC(50), IC(50) and 2 x IC(50) (n = 3) or with vehicle, (0.5% DMSO). Dose-dependant changes in protein abundance were detected and characterised using 2-dimensional electrophoresis and MS. We identified 10 proteins that underwent changes in abundance, pI and/or molecular mass in response to treatment. MINA-05 was shown to influence proteins across numerous functional classes including cytoskeletal proteins, energy metabolism proteins, protein degradation proteins and tumour suppressors, suggesting a global impact on these cell lines. This study implies that the ability of MINA-05 to retard cellular proliferation is attributed to its ability to alter cell cycling, metabolism, protein degradation and the cancer cell environment.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schooneveldt, G.; Kok, H.P.; Bakker, A.

Purpose: Hyperthermia combined with Mitomycin C is used for the treatment of non-muscle invasive bladder cancer (NMIBC), using a phased array system of microwave antennas for bladder heating. Often some air is present in the bladder, which effectively blocks the microwave radiation, potentially preventing proper treatment of that part of the bladder. Air can be a relevant fraction of the bladder content and large air pockets are expected to have a noticeable influence on achieved temperatures. Methods: We analysed 14 NMIBC patients treated at our institute with our AMC-4 hyperthermia device with four 70MHz antennas around the pelvis. A CTmore » scan was made after treatment and a physician delineated the bladder on the CT scan. On the same scan, the amount of air present in the bladder was delineated. Using our in-house developed hyperthermia treatment planning system, we simulated the treatment using the clinically applied device settings. We did this once with the air pocket delineated on the CT scan, and once with the same volume filled with bladder tissue. Results: The patients had on average 4.2ml (range 0.8–10.1ml) air in the bladder. The bladder volume was delineated by the physician, that is including air pocket and bladder wall, was on average 253ml (range 93–452ml). The average volume in which changes exceeded 0.25°C was 22ml (range 0–108 ml), with the bladder being up to 2°C cooler when an air pocket was present. Except for extreme cases, there was no evident relation between the quantity of air and the difference in temperature. Conclusion: The effect of an air pocket in the bladder during bladder hyperthermia treatment varies strongly between patients. Generally, this leads to lower temperatures in the bladder, potentially affecting treatment quality, and suggesting that care need be taken to minimise the size of air pockets during hyperthermia treatments. The KWF Dutch Cancer Society financially supported this work, grant UVA 2012-5539.« less

Molecular Targeted Fluorescence-Guided Intraoperative Imaging of Bladder Cancer Nodal Drainage Using Indocyanine Green During Radical and Partial Cystectomy.

PubMed

Patel, Manish N; Hemal, Ashok K

2016-10-01

Optical imaging is a relatively inexpensive, fast, and sensitive addition to a surgeon's arsenal for the non-invasive detection of malignant dissemination. Optical cameras in the near infrared spectrum are able to successfully identify injected indocyanine green in lymphatic channels and sentinel lymph nodes. The use of this technology is now being used in the operating room to help with lymph node dissection and improve the prognosis of patients diagnosed with muscle invasive bladder cancer. Indocyanine green has the potential for many more applications due to its versatility. In the future, there is a potential to use it for lymphangiography during nephroureterctomy for upper tract urothelial carcinoma, adrenal surgery for partial or radical adrenalectomy. Further investigations at multiple centers will validate this technique and its efficiency.

Bladder cancer screening in aluminum smelter workers.

PubMed

Taiwo, Oyebode A; Slade, Martin D; Cantley, Linda F; Tessier-Sherman, Baylah; Galusha, Deron; Kirsche, Sharon R; Donoghue, A Michael; Cullen, Mark R

2015-04-01

To present results of a bladder cancer screening program conducted in 18 aluminum smelters in the United States from January 2000 to December 2010. Data were collected on a cohort of workers with a history of working in coal tar pitch volatile exposed areas including urine analysis for conventional cytology and ImmunoCyt/uCyt+ assay. ImmunoCyt/uCyt+ and cytology in combination showed a sensitivity of 62.30%, a specificity of 92.60%, a negative predictive value of 99.90%, and a positive predictive value of 2.96%. Fourteen cases of bladder cancer were detected, and the standardized incidence ratio of bladder cancer was 1.18 (95% confidence interval, 0.65 to 1.99). Individuals who tested positive on either test who were later determined to be cancer free had undergone expensive and invasive tests. Evidence to support continued surveillance of this cohort has not been demonstrated.

Bladder Cancer Screening in Aluminum Smelter Workers

PubMed Central

Taiwo, Oyebode A.; Slade, Martin D.; Cantley, Linda F.; Tessier-Sherman, Baylah; Galusha, Deron; Kirsche, Sharon R.; Donoghue, A. Michael

2015-01-01

Objective: To present results of a bladder cancer screening program conducted in 18 aluminum smelters in the United States from January 2000 to December 2010. Methods: Data were collected on a cohort of workers with a history of working in coal tar pitch volatile exposed areas including urine analysis for conventional cytology and ImmunoCyt/uCyt+ assay. Results: ImmunoCyt/uCyt+ and cytology in combination showed a sensitivity of 62.30%, a specificity of 92.60%, a negative predictive value of 99.90%, and a positive predictive value of 2.96%. Fourteen cases of bladder cancer were detected, and the standardized incidence ratio of bladder cancer was 1.18 (95% confidence interval, 0.65 to 1.99). Individuals who tested positive on either test who were later determined to be cancer free had undergone expensive and invasive tests. Conclusions: Evidence to support continued surveillance of this cohort has not been demonstrated. PMID:25525927

Percutaneous treatment of calculi in reconstructed bladder.

PubMed

Paez, Edgar; Reay, Emma; Murthy, L N S; Pickard, Robert S; Thomas, David J

2007-03-01

To report our results with percutaneous removal of calculi from reconstructed bladders. Twelve patients with reconstructed bladders who underwent endoscopic cystolithotomy were identified from our departmental database, and retrospective review of case notes and imaging was performed. Access was gained via an ultrasound-guided new tract in 9 patients (75%). An old suprapubic tract site was used in two patients, and the Mitrofanoff stoma was the route of access in one patient. The procedure was successful, with stone clearance achieved in all 12 cases. No major complications were observed. At a median follow up of 24 months, stone recurrence was observed in 5 patients (42%), 4 of whom underwent repeat procedures. Follow-up showed no change in continence in the patient with a Mitroffanoff stoma. Percutaneous cystolithotomy is a safe and effective minimally invasive option for removal of stones in a reconstructed bladder. We recommend endoscopic removal as the treatment of choice in these patients.

Xanthogranulomatous cystitis: a challenging imitator of bladder cancer.

PubMed

Ekici, Sinan; Dogan Ekici, Isin; Ruacan, Sevket; Midi, Ahmet

2010-06-29

Xanthogranulomatous cystitis is a rare, benign, chronic inflammatory disease of the bladder, mimicking malignancy with unknown etiology. Herein, we report a 57-year-old man who presented with pollakiuria, nocturia, dysuria, left flank pain, and a palpable mass on the right lower abdomen. Computerized tomography demonstrated an obstructing 10-mm stone in the lower third of the left ureter and a 6-cm solid mass on the right at the anterolateral wall of the bladder. The mass presented local perivesical invasion at the anterolateral side. Cystouretroscopy revealed a mass protruding into the bladder cavity with edematous smooth surface. Frozen section analysis of the partial cystectomy specimen could not rule out malignancy. Therefore, radical cystoprostatectomy and ureterolithotomy were performed. Histologically, fibrosis, numerous plasma cells, eosinophils, and, immunohistochemically, CD68-positive epithelioid and foamy macrophages were detected. Localized prostatic adenocarcinoma was also found. The present case of xanthogranulomatous cystitis is the 23rd to be reported in the world literature.

Defining Priorities to Improve Patient Experience in Non-Muscle Invasive Bladder Cancer.

PubMed

Garg, Tullika; Connors, Jill Nault; Ladd, Ilene G; Bogaczyk, Tyler L; Larson, Sharon L

2018-01-20

Although approximately 75% of bladder cancers are non-muscle invasive (NMIBC) at diagnosis, most research tends to focus on invasive disease (e.g., experiences related to radical cystectomy and urinary diversion). There is a lack of studies on quality of life, and especially qualitative research, in bladder cancer generally. As a result, relatively little is known about the experiences and needs of NMIBC patients. To understand patient experience, define care priorities, and identify targets for care improvement in NMIBC across the cancer continuum. Through focus groups, patients treated for NMIBC (stage

Prognostic and therapeutic impact of argininosuccinate synthetase 1 control in bladder cancer as monitored longitudinally by PET imaging.

PubMed

Allen, Michael D; Luong, Phuong; Hudson, Chantelle; Leyton, Julius; Delage, Barbara; Ghazaly, Essam; Cutts, Rosalind; Yuan, Ming; Syed, Nelofer; Lo Nigro, Cristiana; Lattanzio, Laura; Chmielewska-Kassassir, Malgorzata; Tomlinson, Ian; Roylance, Rebecca; Whitaker, Hayley C; Warren, Anne Y; Neal, David; Frezza, Christian; Beltran, Luis; Jones, Louise J; Chelala, Claude; Wu, Bor-Wen; Bomalaski, John S; Jackson, Robert C; Lu, Yong-Jie; Crook, Tim; Lemoine, Nicholas R; Mather, Stephen; Foster, Julie; Sosabowski, Jane; Avril, Norbert; Li, Chien-Feng; Szlosarek, Peter W

2014-02-01

Targeted therapies have yet to have significant impact on the survival of patients with bladder cancer. In this study, we focused on the urea cycle enzyme argininosuccinate synthetase 1 (ASS1) as a therapeutic target in bladder cancer, based on our discovery of the prognostic and functional import of ASS1 in this setting. ASS1 expression status in bladder tumors from 183 Caucasian and 295 Asian patients was analyzed, along with its hypothesized prognostic impact and association with clinicopathologic features, including tumor size and invasion. Furthermore, the genetics, biology, and therapeutic implications of ASS1 loss were investigated in urothelial cancer cells. We detected ASS1 negativity in 40% of bladder cancers, in which multivariate analysis indicated worse disease-specific and metastasis-free survival. ASS1 loss secondary to epigenetic silencing was accompanied by increased tumor cell proliferation and invasion, consistent with a tumor-suppressor role for ASS1. In developing a treatment approach, we identified a novel targeted antimetabolite strategy to exploit arginine deprivation with pegylated arginine deiminase (ADI-PEG20) as a therapeutic. ADI-PEG20 was synthetically lethal in ASS1-methylated bladder cells and its exposure was associated with a marked reduction in intracellular levels of thymidine, due to suppression of both uptake and de novo synthesis. We found that thymidine uptake correlated with thymidine kinase-1 protein levels and that thymidine levels were imageable with [(18)F]-fluoro-L-thymidine (FLT)-positron emission tomography (PET). In contrast, inhibition of de novo synthesis was linked to decreased expression of thymidylate synthase and dihydrofolate reductase. Notably, inhibition of de novo synthesis was associated with potentiation of ADI-PEG20 activity by the antifolate drug pemetrexed. Taken together, our findings argue that arginine deprivation combined with antifolates warrants clinical investigation in ASS1-negative urothelial and related cancers, using FLT-PET as an early surrogate marker of response.

[Guidelines for good practice of intravesical instillations of BCG and mitomycin C from the French national cancer committee (CC-AFU) for non-muscle invasive bladder cancer].

PubMed

Rouprêt, M; Neuzillet, Y; Larré, S; Pignot, G; Coloby, P; Rébillard, X; Mongiat-Artus, P; Chartier-Kastler, E; Soulié, M; Pfister, C

2012-11-01

Intravesical BCG immunotherapy and mitomycin C are considered as the standard treatment for non-muscle invasive bladder cancer. These guidelines aim to describe the optimal condition to perform intravesical instillation of BCG or mitomycin C in order to increase its oncologic efficiency and to decrease its morbidity. Online systematic literature search was performed on PubMed(®) until April 2010. Regulation texts, published guidelines and results of recent urologists practice study were taken into consideration. Level of evidence was assigned to each recommendation. A bibliographic research in French and English using Medline(®) and Embase(®) with the keywords "BCG", "mitomycin C", "bladder", "complication", "toxicity", "adverse reaction", "prevention" and "treatment" was performed. Patient information must be prior to the first intravesical instillation and should be given through a medical exam by the physician performing the procedure. The check for formal contra-indication to BCG is systematically mandatory by the physician during the medical exam. Intravesical instillation must be realized in a health center where urologic endoscopic procedures are made frequently. A recent urine culture has to be checked systematically before any instillation done either by the urologist or a specialized nurse. Contingent upon a bladder catheter has been inserted in the bladder without any injury of the lower urinary tract, the instillation can be done. The pharmaceutical agent needs to be kept two hours in the bladder. After instillation, the patient must be seated to void and also has to keep in mind that he needs to drink at least 2 liters of water per day for 2 days. To improve the oncologic performance and to reduce the risk of complication and adverse event, achievement of intravesical instillations of BCG and/or mitomycin C should follow a standardized procedure. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Combined Chemoradiation Therapy With Twice-Weekly Gemcitabine and Cisplatin for Organ Preservation in Muscle-Invasive Bladder Cancer: Long-Term Results of a Phase 1 Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Azria, David, E-mail: david.azria@icm.unicancer.fr; INSERM, U896, IRCM, Montpellier; Riou, Olivier

2014-03-15

Purpose: Concomitant treatment with radiation therapy and cisplatin (CDDP) remains the gold standard for bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC). We present the long-term results of a phase 1 clinical trial to assess the association of twice-weekly gemcitabine with CDDP and radiation therapy in this setting. Methods and Materials: Patients with pT2-pT4N0M0 MIBC without hydronephrosis or diffuse carcinoma in situ were enrolled in this study. After maximal transurethral resection of the bladder tumor, patients received concomitant radiation therapy (63 Gy in 1.8 fractions) and chemotherapy (CDDP 20 mg/m²/day over 4 days every 21 days and gemcitabinemore » twice a week). The starting dose of gemcitabine was 15 mg/m² with dose escalation to 20, 25, and 30 mg/m². The primary endpoint was the maximum tolerated dose (MTD). Secondary endpoints included toxicity and tumor control. Results: Fourteen patients were enrolled. Dose-limiting toxicity occurred in 2 patients treated with 30 mg/m² gemcitabine (grade 4 thrombocytopenia and severe impairment of World Health Organization performance status, respectively). Nine patients received the complete chemoradiation therapy protocol. The recommended dose of gemcitabine was 25 mg/m². The median follow-up time was 53 months, and the overall and disease-specific 5-year survival rates were 62% and 77%, respectively. Among the patients who received the complete treatment, bladder-intact survival was 76% at 5 years, and the median overall survival was 69.6 months. Conclusions: This regimen was well tolerated. The gemcitabine MTD was 25 mg/m². Bladder preservation and disease control were promising. A multicenter phase 2 randomized trial is ongoing.« less

Assessment of the quality of life and sexual functions of patients followed-up for non-muscle invasive bladder cancer: preliminary results of the prospective-descriptive study.

PubMed

Bolat, Deniz; Çelik, Serdar; Aydın, Mehmet Erhan; Aydoğdu, Özgü; Günlüsoy, Bülent; Değirmenci, Tansu; Dinçel, Çetin

2018-03-09

The aim of this study is to evaluate sexual functions and quality life of patients who are followed- up for non-muscle invasive bladder cancer (NMIBC). Between March 2015-June 2016, 50 patients underwent cystoscopy for NMIBC. At the end of the 1 st year follow-up patients were assessed for sexual functions using 5-item version of the International Sexual Function Index (IIEF-5) for male and the Female Sexual Function Index(FSFI) for female; for quality of life (QoL) by the European Organisation for Research and Treatment of Cancer-Non-Muscle Invasiv Bladder Cancer Quality of Life Questionnaire (EORTC QLQ-NMIBC24) and for emotional status by Beck depression inventory. There were 44 male and 6 female patients with the mean age of 57.6±11.5 years. Twenty patients received intravesical treatment after transurethral resection of bladder tumour (TURBT). The mean Beck (10.7±9.5) IIEF-5 (15.6±5.9), FSFI (19.2±10.9), and the EORTC-QLQ NMBIC 24 (38.2±7.7) scores of the patients were determined as indicated. Among the patients, 42 (84%) of them were not feeling bad about their bladder tumors and 37 (74%) were not worrying about their daily lives. Moreover, 12 (24%) patients were not interested with sexuality, while 27 (54%) of them did not feel comfortable about sexual sincerity. Interestingly, 27 patients receiving intravesical treatment were concerned that the treatment they received for prevention of recurrence and progression of bladder tumor infect their partners during sexual intercourse. NMIBC affects patients' sexual functions and QoL negatively. Therefore during the follow-up of these patients, it is important to inform these patients accurately about their treatments to be applied and predicted complications in the follow up period.

[The necessary perseverance of surgery for the treatment of locally advanced colorectal cancer].

PubMed

Gu, Jin

2018-03-25

Colorectal cancer, a malignant tumor arising from the colon or rectum, is a common cancer in China, with most patients diagnosed at the advanced stage or locally advanced stage. Large tumor size results in the invasion of adjacent organs and the multiple organ involvement, which poses certain challenges for clinical treatment. When facing advanced stage colorectal cancer, some surgeons do not consider surgery, a reasonable option. However, in fact, multi-disciplinary treatment can achieve relatively good treatment outcomes in patients with advanced stage or locally advanced stage colorectal cancer. Therefore, reasonable surgery should not be hastily abandoned. For patients with large tumors without distant metastases but with multiple organ involvement, directly surgical resection is difficult, therefore, preoperative adjuvant therapy can be considered. The basic principle of surgical treatment is to accomplish maximum protection of organ functions and to perform reasonable regional lymph node dissection on the basis of achieving R0 resection. Common surgical procedures for locally advanced colorectal cancer are as follows: (1)Right-sided colon cancer with duodenal invasion: first, the colon must be freed from three directions, namely the right posterior surface of the colon, the left side of the tumor, and the upper side of the tumor inferior to the pylorus, so as to expose and assess the spatial relationship between the tumor and the duodenum; the actual tumor invasion depth in the duodenum may be shallow. (2) Splenic flexure colon cancer with invasion of the cauda pancreatis and hilum lienis: multivisceral resection must be performed without separating the attachment between the tumor and spleen. The tumor border can be found more easily through manipulations starting from the descending colon. (3) Giant sigmoid colorectal cancer with bladder invasion: invasion usually occurs at the bladder fundus. Therefore, during surgery, the attachment between the rectum and the bladder must not be separated first, but instead, an assessment must be made to determine if the bladder trigone is involved. (4) Rectal cancer with invasion of the sacrum: sacral invasion below S3 can be resected. The proximal end of the rectum to the point where it joins the sacrum is freed, and the rectum is severed. A permanent colostomy is made at the proximal end, while a h-shaped incision is made in the sacrum. The sacrum is then resected along pre-determined resection lines. (5) Rectal cancer with invasion of the uterus, adnexa, vagina, or prostate and seminal vesicles: it is usually observed in low rectal cancer. For unilateral ovarian involvement, combined resection of the bilateral adnexa should be performed. For vaginal involvement, combined resection of the vagina should be performed. For prostatic involvement, partial resection of the prostate can be performed. In general, when facing relatively complicated advanced or locally advanced colorectal cancer, clinical surgeons must adopt a positive attitude and strive zealously against the odds. With the support of multi-disciplinary treatment, the option of surgery must not be hastily abandoned in order to increase the survival chances of patients.

Effectivity of intravescical thermo-chemotherapy prophylaxis for patients with high recurrence and progression risk for non-muscle invasive bladder cancer.

PubMed

Gözen, Ali Serdar; Umari, Paolo; Scheitlin, Walter; Su, Fuat Ernis; Akin, Yigit; Rassweiler, Jens

2017-06-30

Background&Aim: High grade non-muscle invasive bladder cancer (NMIBC) is common in urological practice. Most of these cancers are or become refractory to intravesical immunotherapy and chemotherapy. Here we evaluated the efficacy of combined local bladder hyperthermia and intravesical mitomycin-C (MMC) instillation in patients with high-risk recurrent NMIBC. Between February 2014 and December 2015, 18 patients with high risk NMIBC were enrolled. Patients were treated in an outpatient basis with 6 weekly induction sessions followed by monthly maintenance sessions with intravesical MMC in local hyperthermia with bladder wall thermo-chemotherapy (BWT) system (PelvixTT system, Elmedical Ltd., Hod Hasharon, Israel). The follow-up regimen included cystoscopy after the induction cycle and thereafter with regular intervals. Time to disease recurrence was defined as time from the first intravesical treatment to endoscopic or histological documentation of a new bladder tumour. Adverse events were recorded according to CTC 4.0 (Common Toxicity Criteria) score system. Mean age was 72 (32-87) years. 10 patients had multifocal disease, 9 had CIS, 6 had recurrent disease and 2 had highly recurrent disease (> 3 recurrences in a 24 months period). 6 patients underwent previous intravesical chemotherapy with MMC. The average number of maintenance sessions per patient was 7.6. After a mean follow-up of 433 days, 15 patients (83.3%) were recurrence-free. 3 patients had tumour recurrence after a mean period of 248 days without progression. Side effects were limited to grade 1 in 2 patients and grade 2 in 1 patient. BWT seems to be feasible and safe in high grade NMIBC. More studies are needed to identify the subgroup of patients who may benefit more from this treatment.

Prognostic Relevance of Urinary Bladder Cancer Susceptibility Loci

PubMed Central

Grotenhuis, Anne J.; Dudek, Aleksandra M.; Verhaegh, Gerald W.; Witjes, J. Alfred; Aben, Katja K.; van der Marel, Saskia L.; Vermeulen, Sita H.; Kiemeney, Lambertus A.

2014-01-01

In the last few years, susceptibility loci have been identified for urinary bladder cancer (UBC) through candidate-gene and genome-wide association studies. Prognostic relevance of most of these loci is yet unknown. In this study, we used data of the Nijmegen Bladder Cancer Study (NBCS) to perform a comprehensive evaluation of the prognostic relevance of all confirmed UBC susceptibility loci. Detailed clinical data concerning diagnosis, stage, treatment, and disease course of a population-based series of 1,602 UBC patients were collected retrospectively based on a medical file survey. Kaplan-Meier survival analyses and Cox proportional hazard regression were performed, and log-rank tests calculated, to evaluate the association between 12 confirmed UBC susceptibility variants and recurrence and progression in non-muscle invasive bladder cancer (NMIBC) patients. Among muscle-invasive or metastatic bladder cancer (MIBC) patients, association of these variants with overall survival was tested. Subgroup analyses by tumor aggressiveness and smoking status were performed in NMIBC patients. In the overall NMIBC group (n = 1,269), a statistically significant association between rs9642880 at 8q24 and risk of progression was observed (GT vs. TT: HR = 1.08 (95% CI: 0.76–1.54), GG vs. TT: HR = 1.81 (95% CI: 1.23–2.66), P for trend = 2.6×10−3). In subgroup analyses, several other variants showed suggestive, though non-significant, prognostic relevance for recurrence and progression in NMIBC and survival in MIBC. This study provides suggestive evidence that genetic loci involved in UBC etiology may influence disease prognosis. Elucidation of the causal variant(s) could further our understanding of the mechanism of disease, could point to new therapeutic targets, and might aid in improvement of prognostic tools. PMID:24586564

LINC00857 expression predicts and mediates the response to platinum-based chemotherapy in muscle-invasive bladder cancer.

PubMed

Dudek, Aleksandra M; van Kampen, Jasmijn G M; Witjes, J Alfred; Kiemeney, Lambertus A L M; Verhaegh, Gerald W

2018-06-01

Approximately 20% of patients with bladder cancer are diagnosed with muscle-invasive disease (MIBC). The treatment involves radical cystectomy, but almost 50% of patients with MIBC eventually relapse and develop metastasis. The use of platinum-based chemotherapy in the neoadjuvant setting or for metastatic patients has been shown to improve the overall survival in a subset of patients. Unfortunately, no biomarkers are available to select patients with MIBC who will benefit from chemotherapy or to monitor the efficacy of the treatment. Recently, long noncoding RNAs (lncRNAs) were shown to regulate a variety of processes involved in the development and progression of cancer, including bladder cancer. Moreover, several lncRNAs have been shown to play a role in chemotherapy resistance. Here, we analyzed lncRNA expression associated with response to platinum-based chemotherapy in metastatic MIBC using data from the MiTranscriptome lncRNA expression database. Expression of the lncRNA, LINC00857, was found to be upregulated in tumors from patients that did not respond to platinum-based chemotherapy. Moreover, high expression of LINC00857 is correlated with shorter recurrence-free and overall survival of patients with MIBC. Knockdown of LINC00857 significantly decreased cell viability of bladder cancer cell lines through the induction of apoptosis. Furthermore, LINC00857 knockdown sensitized UM-UC-3 and T24 bladder cancer cells to cisplatin, via the negative regulation of the LMAN1 gene. Our data indicate that LINC00857 plays an important role in the regulation of response to platinum-based chemotherapy. LINC00857 potentially could serve as a novel prognostic and predictive biomarker and might be a therapeutic target to overcome cisplatin resistance in patients with MIBC. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Relevance of prostate cancer in patients with synchronous invasive bladder urothelial carcinoma: a monocentric retrospective analysis.

PubMed

Dell'Atti, Lucio

2015-03-31

We retrospectively reviewed data of patients with incidental prostate cancer (PCa) who underwent radical cystoprostatectomy (RCP) for invasive bladder cancer and we analyzed their features with regard to incidence, pathologic characteristics, clinical significance, and implications for management. Clinical data and pathological features of 64 patients who underwent standard RCP for bladder cancer were included in this study. Besides the urothelial carcinoma of the urinary bladder, the location and tumor volume of the PCa, prostate apex involvement, Gleason score, pathological staging and surgical margins were evaluated. Clinically significant PCa was defined as a tumor with a Gleason 4 or 5 pattern, stage ≥ pT3, lymph node involvement, positive surgical margin or multifocality of three or more lesions. Postoperative follow-up was scheduled every 3 months in the first year, every 6 months in the second and third year, annually thereafter. 11 out of 64 patients (17.2%) who underwent RCP had incidentally diagnosed PCa. 3 cases (27.3%) were diagnosed as significant PCa, while 8 cases (72.7%) were clinically insignificant. The positive surgical margin of PCa was detected in 1 patient with significant disease. The prostate apex involvement was present in 1 patient of the significant PCa group. Median follow-up period was 47.8 ± 29.2 (range 4-79). During the follow-up, biochemical recurrence occurred in 1 patient (9%). Concerning the cancer specific survival there was no statistical significance (P = 0.326) between the clinically significant and clinical insignificant cancer group. In line with published studies, incidental PCa does not impact on the prognosis of bladder cancer of patients undergoing RCP.

Panel of Urinary Diagnostic Markers for Non-Invasive Detection of Primary and Recurrent Urothelial Urinary Bladder Carcinoma.

PubMed

Soukup, Viktor; Kalousová, Marta; Capoun, Otakar; Sobotka, Roman; Breyl, Zuzana; Pešl, Michael; Zima, Tomas; Hanuš, Tomáš

2015-01-01

To determine the combination of urinary protein markers for noninvasive detection of primary and recurrent urothelial bladder carcinomas. Urinary concentrations of 27 biomarkers (NSE, ATT, AFABP, Resistin, Midkine, Clusterin, Uromodulin, ZAG2, HSP27, HSP 60, NCAM1/CD56, Angiogenin, Calreticulin, Chromogranin A, CEACAM1, CXCL1, IL13Ra2, Progranulin, VEGFA, CarbAnhydIX, Annexin-V, TIM4, Galectin1, Cystatin B, Synuclein G, ApoA1 and ApoA2) were assessed by enzyme-linked immunosorbent assay or by electrochemiluminiscence immunoassay. During the primary diagnostics, a group of 70 patients with primary occurrence of bladder cancer and 49 healthy control subjects were compared. For this clinical situation, the most accurate combination proved to be the combination of cytology with markers Midkine and Synuclein G (sensitivity 91.8%, specificity 97.5%). During the monitoring of patients with non-muscle invasive bladder cancer (NMIBC), a group of 44 patients with cancer recurrence was compared with the group of 61 patients with a history of NMIBC without current disease. For this clinical situation, the most accurate combination proved to be the combination of cytology and erythrocytes count in urine sediment with markers Midkine, ZAG2, CEACAM1, and Synuclein G (sensitivity 92.68%, specificity 90.16%). A lower accuracy of the diagnostic panel and the necessity to use more markers in the case of recurrence was connected with a different structure of patients. Multi-marker test can significantly improve the bladder cancer detection both during the primary diagnostics and monitoring of patients with NMIBC. This outcome should result in other, larger studies. © 2015 S. Karger AG, Basel.

Patient-centered prioritization of bladder cancer research.

PubMed

Smith, Angela B; Chisolm, Stephanie; Deal, Allison; Spangler, Alejandra; Quale, Diane Z; Bangs, Rick; Jones, J Michael; Gore, John L

2018-05-04

Patient-centered research requires the meaningful involvement of patients and caregivers throughout the research process. The objective of this study was to create a process for sustainable engagement for research prioritization within oncology. From December 2014 to 2016, a network of engaged patients for research prioritization was created in partnership with the Bladder Cancer Advocacy Network (BCAN): the BCAN Patient Survey Network (PSN). The PSN leveraged an online bladder cancer community with additional recruitment through print advertisements and social media campaigns. Prioritized research questions were developed through a modified Delphi process and were iterated through multidisciplinary working groups and a repeat survey. In year 1 of the PSN, 354 patients and caregivers responded to the research prioritization survey; the number of responses increased to 1034 in year 2. The majority of respondents had non-muscle-invasive bladder cancer (NMIBC), and the mean time since diagnosis was 5 years. Stakeholder-identified questions for noninvasive, invasive, and metastatic disease were prioritized by the PSN. Free-text questions were sorted with thematic mapping. Several questions submitted by respondents were among the prioritized research questions. A final prioritized list of research questions was disseminated to various funding agencies, and a highly ranked NMIBC research question was included as a priority area in the 2017 Patient-Centered Outcomes Research Institute announcement of pragmatic trial funding. Patient engagement is needed to identify high-priority research questions in oncology. The BCAN PSN provides a successful example of an engagement infrastructure for annual research prioritization in bladder cancer. The creation of an engagement network sets the groundwork for additional phases of engagement, including design, conduct, and dissemination. Cancer 2018. © 2018 American Cancer Society. © 2018 American Cancer Society.

Biodistribution and radiation dosimetry of the hypoxia marker 18F-HX4 in monkeys and humans determined by using whole-body PET/CT.

PubMed

Doss, Mohan; Zhang, James J; Bélanger, Marie-José; Stubbs, James B; Hostetler, Eric D; Alpaugh, Katherine; Kolb, Hartmuth C; Yu, Jian Q

2010-12-01

F-HX4 is a novel positron emission tomography (PET) tracer for imaging hypoxia. The purpose of this study was to determine the biodistribution and estimate the radiation dose of F-HX4 using whole-body PET/computed tomography (CT) scans in monkeys and humans. Successive whole-body PET/CT scans were done after the injection of F-HX4 in four healthy humans (422±142 MBq) and in three rhesus monkeys (189±3 MBq). Biodistribution was determined from PET images and organ doses were estimated using OLINDA/EXM software. The bladder, liver, and kidneys showed the highest percentage of the injected radioactivity for humans and monkeys. For humans, approximately 45% of the activity is eliminated by bladder voiding in 3.6 h, and for monkeys 60% is in the bladder content after 3 h. The critical organ is the urinary bladder wall with the highest absorbed radiation dose of 415±18 (monkeys) and 299±38 μGy/MBq (humans), in the 4.8-h bladder voiding interval model. The average value of effective dose for the adult male was estimated at 42±4.2 μSv/MBq from monkey data and 27±2 μSv/MBq from human data. Bladder, kidneys, and liver have the highest uptake of injected F-HX4 activity for both monkeys and humans. The urinary bladder wall receives the highest dose of F-HX4 and is the critical organ. Thus, patients should be encouraged to maintain adequate hydration and void frequently. The effective dose of F-HX4 is comparable with that of other F-based imaging agents.

Serratia marcescens internalization and replication in human bladder epithelial cells

PubMed Central

Hertle, Ralf; Schwarz, Heinz

2004-01-01

Background Serratia marcescens, a frequent agent of catheterization-associated bacteriuria, strongly adheres to human bladder epithelial cells in culture. The epithelium normally provides a barrier between lumal organisms and the interstitium; the tight adhesion of bacteria to the epithelial cells can lead to internalization and subsequent lysis. However, internalisation was not shown yet for S. marcescens strains. Methods Elektronmicroscopy and the common gentamycin protection assay was used to assess intracellular bacteria. Via site directed mutagenesis, an hemolytic negative isogenic Serratia strain was generated to point out the importance of hemolysin production. Results We identified an important bacterial factor mediating the internalization of S. marcescens, and lysis of epithelial cells, as the secreted cytolysin ShlA. Microtubule filaments and actin filaments were shown to be involved in internalization. However, cytolysis of eukaryotic cells by ShlA was an interfering factor, and therefore hemolytic-negative mutants were used in subsequent experiments. Isogenic hemolysin-negative mutant strains were still adhesive, but were no longer cytotoxic, did not disrupt the cell culture monolayer, and were no longer internalized by HEp-2 and RT112 bladder epithelial cells under the conditions used for the wild-type strain. After wild-type S. marcescens became intracellular, the infected epithelial cells were lysed by extended vacuolation induced by ShlA. In late stages of vacuolation, highly motile S. marcescens cells were observed in the vacuoles. S. marcescens was also able to replicate in cultured HEp-2 cells, and replication was not dependent on hemolysin production. Conclusion The results reported here showed that the pore-forming toxin ShlA triggers microtubule-dependent invasion and is the main factor inducing lysis of the epithelial cells to release the bacteria, and therefore plays a major role in the development of S. marcescens infections. PMID:15189566

Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells

PubMed Central

Celià-Terrassa, Toni; Meca-Cortés, Óscar; Mateo, Francesca; Martínez de Paz, Alexia; Rubio, Nuria; Arnal-Estapé, Anna; Ell, Brian J.; Bermudo, Raquel; Díaz, Alba; Guerra-Rebollo, Marta; Lozano, Juan José; Estarás, Conchi; Ulloa, Catalina; ρlvarez-Simón, Daniel; Milà, Jordi; Vilella, Ramón; Paciucci, Rosanna; Martínez-Balbás, Marian; García de Herreros, Antonio; Gomis, Roger R.; Kang, Yibin; Blanco, Jerónimo; Fernández, Pedro L.; Thomson, Timothy M.

2012-01-01

Malignant progression in cancer requires populations of tumor-initiating cells (TICs) endowed with unlimited self renewal, survival under stress, and establishment of distant metastases. Additionally, the acquisition of invasive properties driven by epithelial-mesenchymal transition (EMT) is critical for the evolution of neoplastic cells into fully metastatic populations. Here, we characterize 2 human cellular models derived from prostate and bladder cancer cell lines to better understand the relationship between TIC and EMT programs in local invasiveness and distant metastasis. The model tumor subpopulations that expressed a strong epithelial gene program were enriched in highly metastatic TICs, while a second subpopulation with stable mesenchymal traits was impoverished in TICs. Constitutive overexpression of the transcription factor Snai1 in the epithelial/TIC-enriched populations engaged a mesenchymal gene program and suppressed their self renewal and metastatic phenotypes. Conversely, knockdown of EMT factors in the mesenchymal-like prostate cancer cell subpopulation caused a gain in epithelial features and properties of TICs. Both tumor cell subpopulations cooperated so that the nonmetastatic mesenchymal-like prostate cancer subpopulation enhanced the in vitro invasiveness of the metastatic epithelial subpopulation and, in vivo, promoted the escape of the latter from primary implantation sites and accelerated their metastatic colonization. Our models provide new insights into how dynamic interactions among epithelial, self-renewal, and mesenchymal gene programs determine the plasticity of epithelial TICs. PMID:22505459

The expression of pigment epithelium-derived factor in bladder transitional cell carcinoma.

PubMed

Jang, Tae Jung; Kim, Sung Woo; Lee, Kyung Seop

2012-06-01

Pigment epithelium-derived factor (PEDF) is an anti-angiogenic factor. The purpose of this study is to examine the involvement of PEDF in the angiogenesis and biological behavior of bladder transitional cell carcinoma (TCC). We examined the expression of PEDF in 99 bladder TCCs and ten non-neoplastic tissues, and evaluated microvessel density (MVD). The positive immunoreactivity for PEDF was seen in normal urothelium in 60% (6/10) and TCC in 13% (13/99). The PEDF expression had a significant correlation with MVD, i.e., a low MVD in 42% (5/12), a middle MVD in 11% (8/76) and a high MVD 0% (0/11) of tumors. The PEDF expression was not significantly correlated with the differentiation and invasion of TCC, but the degree of MVD was significantly higher in both high grade TCC and the pT2 tumors. The degree of PEDF expression is significantly higher in normal bladder urothelium than bladder TCC; it is inversely correlated with the angiogenesis; and it is not related to the differentiation and progression of TCC. It can therefore be concluded that bladder TCC would initially occur if there is a lack of the PEDF expression.

The Expression of Pigment Epithelium-Derived Factor in Bladder Transitional Cell Carcinoma

PubMed Central

Kim, Sung Woo; Lee, Kyung Seop

2012-01-01

Background Pigment epithelium-derived factor (PEDF) is an anti-angiogenic factor. The purpose of this study is to examine the involvement of PEDF in the angiogenesis and biological behavior of bladder transitional cell carcinoma (TCC). Methods We examined the expression of PEDF in 99 bladder TCCs and ten non-neoplastic tissues, and evaluated microvessel density (MVD). Results The positive immunoreactivity for PEDF was seen in normal urothelium in 60% (6/10) and TCC in 13% (13/99). The PEDF expression had a significant correlation with MVD, i.e., a low MVD in 42% (5/12), a middle MVD in 11% (8/76) and a high MVD 0% (0/11) of tumors. The PEDF expression was not significantly correlated with the differentiation and invasion of TCC, but the degree of MVD was significantly higher in both high grade TCC and the pT2 tumors. Conclusions The degree of PEDF expression is significantly higher in normal bladder urothelium than bladder TCC; it is inversely correlated with the angiogenesis; and it is not related to the differentiation and progression of TCC. It can therefore be concluded that bladder TCC would initially occur if there is a lack of the PEDF expression. PMID:23110012

Sixteen-slice multidetector computed tomographic virtual cystoscopy in the evaluation of a patient with suspected bladder tumor and history of bladder carcinoma operation.

PubMed

Basak, Muzaffer; Ozkurt, Huseyin; Tanriverdi, Orhan; Cay, Esra; Aydin, Mustafa; Miroglu, Cengiz

2009-01-01

The purpose of this study was to evaluate the use of virtual cystoscopy performed with multidetector computed tomography (CT) in patients with suspected bladder tumors and histories of bladder carcinoma operation. Thirty-six patients (29 men and 7 women) with a mean age of 66 years (range, 24-88 years) with suspected bladder tumors and histories of bladder carcinoma operation were included in this prospective study. Virtual cystoscopy was performed by 16-slice multidetector CT scanner. The bladder was filled with diluted contrast material solution through a Foley catheter. Then, all patients underwent conventional cystoscopy examination. Two reviewers found 18 lesions detected by virtual cystoscopy by consensus, whereas 19 lesions were depicted by conventional cystoscopy. At virtual and conventional cystoscopies, the conditions of 3 patients, 2 with chronic inflammations and 1 with foreign body reaction, were wrongly diagnosed as tumors. At conventional cystoscopy, one patient's result was wrongly interpreted as normal. In pathologic evaluation, all tumors were diagnosed as transitional cell carcinoma. Bladder tumor can be noninvasively diagnosed using virtual cystoscopy. Use of virtual cystoscopy should be considered inpatients who present with hematuria or have histories of bladder carcinoma operation and are for follow-up because of its lesser complication risk and its being a less invasive, easily applied procedure without need of anesthesia. In the future, owing to the development of the CT technology and image processing technique, virtual cystoscopy may have a part in the detection of bladder cancer.

The evolution of bladder cancer genomics: What have we learned and how can we use it?

PubMed

Audenet, François; Attalla, Kyrollis; Sfakianos, John P

2018-03-21

With advancements in molecular biology techniques, great progress has been made in the understanding of urothelial carcinoma pathogenesis. To examine the historic description of molecular alterations in bladder cancer and their evolution towards our current comprehension of the biology of the disease. Historically, a two-pathway model was described from histological and cytogenetic studies: low-grade papillary non-muscle invasive bladder cancers (NMIBC) were described to arise from epithelial hyperplasia with loss of chromosome 9 as an early event, whereas muscle-invasive bladder cancers (MIBC) were considered to develop from dysplasia, associated with genetic instability. Although there could be connections between the 2 pathways, NMIBC and MIBC were largely believed to develop secondary to different molecular alterations. Next-generation sequencing has allowed important insights into cancer biology and a better understanding of the pathways involved in bladder cancer pathogenesis and heterogeneity. Urothelial carcinoma has been found to have a high frequency of somatic mutations compared to other solid tumors, including several mutations in multiple signaling pathways, such as cell cycle regulators (TP53, RB1), RTK/RAS/RAF pathway, PI3K/AKT/mTOR pathway and TERT gene promoter. Epigenetic changes and mutations in chromatin remodeling genes are especially frequent in bladder cancer. Mutations in FGFR3 and KDM6A are more common in NMIBC than in MIBC, whereas mutations in TP53 and KMT2D are more common in MIBC, suggesting the previously hypothesized 2 different pathways, with a subset of tumors progressing from NMIBC to MIBC. Using comprehensive RNA expression profiling studies, at least 5 subtypes of bladder cancer have been identified, the most fundamental division being Basal/Squamous-like and Luminal. These subtypes have different prognoses, natural histories and responses to systemic treatments: Luminal subtypes are enriched with papillary histology and have a better prognosis, while Basal/Squamous-like subtypes are enriched with squamous features, are associated with advanced stage at presentation, and portend a worse prognosis. This new understanding of bladder cancer will optimistically translate into better understanding of this heterogeneous disease and lead to improvement in patient outcome and quality of life through better tailored treatments. Copyright © 2018 Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Paul-Yann; Lin, Yung-Lun; Huang, Chin-Chin

Epidemiological studies have revealed that exposure to an arsenic-contaminated environment correlates with the incidence of bladder cancer. Bladder cancer is highly recurrent after intravesical therapy, and most of the deaths from this disease are due to invasive metastasis. In our present study, the role of inorganic arsenic in bladder carcinogenesis is characterized in a mouse model. This work provides the first evidence that inorganic arsenic in drinking water promotes N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced bladder tissue damage, including the urothelium and submucosal layer. This damage to the bladder epithelium induced by BBN includes thickening of the submucosal layer, the loss of the glycosaminoglycanmore » layer and an increase in both the deoxyguanosine oxidation and cytosine methylation levels in the DNA. Further, when 10 ppm inorganic arsenic is combined with BBN, the number of bladder submucosal capillaries is increased. In addition, inorganic arsenic also increases the deoxyguanosine oxidation level, alters the cytosine methylation state, decreases the activities of glutathione reductase and glucose-6-phosphate dehydrogenase, decreases the protein expression of NAD(P)H quinone oxidoreductase-1 (NQO-1) and increases the protein expression of specific protein 1 (Sp1) in bladder tissues. In summary, our data reveal that inorganic arsenic in drinking water promotes the BBN-induced pre-neoplastic damage of bladder tissue in mice, and that the 8-hydroxy-2′-deoxyguanosine, 5-methylcytosine, NQO-1 protein and Sp1 protein levels may be pre-neoplastic markers of bladder tumors. -- Highlights: ► The role of inorganic arsenic in bladder carcinogenesis is characterized in mice. ► We examine the changes in the histology and biochemistry of bladder tissues. ► Inorganic arsenic enhances BBN-induced DNA oxidation while decreases BBN-induced DNA methylation in the mouse bladder. ► Inorganic arsenic alters the activities of the anti-oxidant enzymes in the mouse bladder. ► Inorganic arsenic increases Sp1 while decreases NQO-1 protein expression in the mouse whole bladder.« less

METABOLISM AND DNA ADDUCT FORMATION OF 2-ACETYLAMINOFLUORENE BY BLADDER EXPLANTS FROM HUMAN, DOG, MONKEY, HAMSTER AND RAT

EPA Science Inventory

It is concluded that bladder explants of the human, dog, monkey, hamster, and rat metabolize AAF mainly to ring-hydroxylated products, but also form small amounts of the proximate carcinogenic metabolite N-hydroxy-AAF. Neither the overall binding of AAF to bladder DNA, nor the fo...

Acute and Chronic Deficits in the Urinary Bladder after Spinal Contusion Injury in the Adult Rat

PubMed Central

Herrera, Juan J.; Haywood-Watson, Ricky J.L.

2010-01-01

Abstract Traumatic spinal cord injury (SCI) permanently alters bladder function in humans. Hematuria and cystitis occur in both human SCI as well as in rodent models of SCI. Others have reported early SCI-dependent disruption to bladder uroepithelial integrity that results in increased permeability to urine and urine-borne substances. This can result in cystitis, or inflammation of the bladder, an ongoing pathological condition present throughout the chronic phase of SCI in humans. The goals of our study were twofold: (1) to begin to examine the inflammatory and molecular changes that occur within the bladder uroepithelium using a clinically-relevant spinal contusion model of injury, and (2) to assess whether these alterations continue into the chronic phase of SCI. Rats received either moderate SCI or sham surgery. Urine was collected from SCI and sham subjects over 7 days or at 7 months to assess levels of excreted proteins. Inflammation in the bladder wall was assessed via biochemical and immunohistochemical methods. Bladder tight junction proteins, mediators of uroepithelial integrity, were also measured in both the acute and chronic phases of SCI. Urine protein and hemoglobin levels rapidly increase following SCI. An SCI-dependent elevation in numbers of neutrophils within the bladder wall peaked at 48 h. Bladder tight junction proteins demonstrate a rapid but transient decrease as early as 2 h post-SCI. Surprisingly, elevated levels of urine proteins and significant deficits in bladder tight junction proteins could be detected in chronic SCI, suggesting that early pathological changes to the bladder may continue throughout the chronic phase of injury. PMID:19891526

Increased expression of GGN promotes tumorigenesis in bladder cancer and is correlated with poor prognosis.

PubMed

Wang, Wentao; Li, Changfu; Chen, Yongsheng; Teng, Lichen; Cao, Yan; Xu, Yongpeng; Pan, Hongxin; An, Ruihua

2018-04-30

Bladder cancer has shown great challenge for people's life. Traditional therapeutics against bladder cancer including surgery could not bring much benefit for patients, particularly for the late stage patients. So it is necessary to keep in mind why and how bladder cancer cells survive in our body. In this study, we explored the function and the molecular mechanism of GGN gene in bladder cancer. GGN was shown to be expressed at a high level in bladder cancer tissues compared to the control and was associated with the unsatisfactory survival rate of patients. GGN was also expressed abundantly in bladder cancer cell lines such as T24, 5637 and BIU87. Then GGN was knocked down in 5637 cells and T24 cells at both RNA and protein level. In accordance, aberrant growth and proliferation were demonstrated in bladder cancer cells. The ability of migration and invasion of bladder cancer cells was also inhibited. The in vivo data further proved that the xenograft tumor growth was dramatically suppressed by GGN knockdown. Then we demonstrated that the level of IκB, bax and truncated caspase3 was upregulated after GGN was knocked down in 5637 cells. In contrast, expression level of NFκB, IKK, c-Myc, cyclin D1 and Bcl-2 was reduced. Further, the phosphorylation level of IκB was also downregulated. These data suggest that NFκB/caspase3-mediated apoptosis signaling was regulated by GGN. Conclusively, GGN played a tumor-promoting role in bladder cancer through regulation of NFκB/caspase3-mediated apoptosis signaling. This study provides a new clue for the treatment of patients with bladder cancer. Copyright © 2018 Elsevier B.V. All rights reserved.

Assessing the clinical benefit of nuclear matrix protein 22 in the surveillance of patients with nonmuscle-invasive bladder cancer and negative cytology: a decision-curve analysis.

PubMed

Shariat, Shahrokh F; Savage, Caroline; Chromecki, Thomas F; Sun, Maxine; Scherr, Douglas S; Lee, Richard K; Lughezzani, Giovanni; Remzi, Mesut; Marberger, Michael J; Karakiewicz, Pierre I; Vickers, Andrew J

2011-07-01

Several studies have demonstrated that abnormal levels of nuclear matrix protein 22 (NMP22) are associated with bladder cancer and have led to the approval of NMP22 as a urinary biomarker by the US Food and Drug Administration. Nonetheless, the clinical significance of NMP22 remains unclear. The objective of this study was to use decision analysis to determine whether NMP22 improves medical decision-making. The current study included 2222 patients who had a history of nonmuscle-invasive bladder cancer and current negative cytology. The authors developed models to predict cancer recurrence or progression to muscle-invasive disease using voided NMP22 levels, cystoscopy, age, and sex. Clinical net benefit was calculated by summing the benefits (true-positives), subtracting the harms (false-positives), and weighting these values by the threshold probability at which a patient or clinician would opt for cytoscopy. After cystoscopy, 581 patients (26%) had cancer identified. The NMP22 level was associated significantly with bladder cancer recurrence and progression (P < .001 for both). The use of NMP22 in a model with age and sex was associated with better patient outcomes than performing cystoscopy on everyone and produced threshold probabilities > 8% for recurrence and > 3% for progression. Only offering cystoscopy to those who had a risk > 15% reduced the number of cystoscopies by 229 while missing only 25 cancer recurrences per 1000 men with negative cytology. The current study was limited by its multicenter design. For clinicians who would perform a cystoscopy at a threshold of 5% for recurrence or 1% for progression, NMP22 did not aid clinical decision-making. For less risk-averse clinicians who would only perform a cystoscopy at a threshold probability >thinsp;8% for recurrence or > 3% for progression, NMP22 helped to indicate which patients required cystoscopy and which could be spared this procedure. Copyright © 2011 American Cancer Society.

Gender-specific Differences in Recurrence of Non-muscle-invasive Bladder Cancer: A Systematic Review and Meta-analysis.

PubMed

Uhlig, Annemarie; Strauss, Arne; Seif Amir Hosseini, Ali; Lotz, Joachim; Trojan, Lutz; Schmid, Marianne; Uhlig, Johannes

2017-09-06

The incidence of urothelial carcinoma of the bladder (UCB) is lower in women; however, women tend to present with more advanced disease. To date, there is no quantitative synthesis of studies reporting gender-specific outcomes in non-muscle-invasive UCB. To conduct a meta-analysis evaluating gender-specific differences in recurrence of non-muscle-invasive urinary bladder cancer (NMIBC). An unrestricted systematic literature search of the MEDLINE, EMBASE, and Cochrane libraries was conducted. Studies evaluating the impact of gender on disease recurrence after local treatment of NMIBC using multivariable Cox proportional hazard models were included. Random effect meta-analysis, subgroup analyses, meta-influence, and cumulative meta-analyses were conducted. Publication bias was assessed via a funnel plot and Eggeŕs test. Of 609 studies screened, 27 comprising 23 754 patients were included. Random effect meta-analyses indicated women at increased risk for UCB recurrence compared with men (hazard ratio [HR]=1.11, 95% confidence interval [CI]: 1.01-1.23, p=0.03). Subgroup analyses yielded estimates between HR=0.99 and HR=1.68. Gender-specific differences in UCB recurrence were most pronounced in studies administering exclusively bacillus Calmette-Guerin (BCG; HR=1.64, 95% CI: 1.13-2.39, p=0.01), especially in a long-term treatment regimen (HR=1.68, 95% CI: 1.32-2.15, p<0.001). Sensitivity analyses confirmed female patients at increased risk for UCB recurrence. Women are at increased risk for disease recurrence after local treatment of NMIBC compared with male patients. Reduced effectiveness of BCG treatment might underlie this observation. Gender-specific differences were evident across various subgroups and proved robust upon sensitivity analyses. In this report, we combined several studies on gender-specific differences in relapse of superficial bladder cancer. Women were more likely to experience cancer relapse than men. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Genetic instability in urinary bladder cancer: An evolving hallmark.

PubMed

Wadhwa, N; Mathew, B B; Jatawa, S K; Tiwari, A

2013-01-01

Bladder cancer is a major health-care concern. A successful treatment of bladder cancer depends on its early diagnosis at the initial stage. Genetic instability is an essential early step toward the development of bladder cancer. This instability is found more often at the chromosomal level than at the nucleotide level. Microsatellite and chromosomal instability markers can be used as a prognostic marker for screening bladder cancer. Bladder cancer can be distinguished in two different categories according to genetic instability: Cancers with chromosomal level instability and cancers with nucleotide level instability. Deoxyribonucleic acid (DNA) mismatch repair (MMR) system and its correlation with other biologic pathway, both are essential to understand the basic mechanisms of cancer development. Microsatellite instability occurs due to defects in DNA MMR genes, including human mutL homolog 1 and human mutL homolog 2. Chromosomal alterations including deletions on chromosome 3, 8, 9, 11, 13, 17 have been detected in bladder cancer. In the current review, the most recent literature of genetic instability in urinary bladder cancer has been summarized.

A case of large cell neuroendocrine carcinoma of the bladder with prolonged spontaneous remission

PubMed Central

Chong, Vincent; Zwi, Jonathan; Hanning, Fritha; Lim, Remy; Cadwallader, Jon

2017-01-01

Abstract Large cell neuroendocrine carcinoma (LCNEC) of the urinary bladder are rare. We present a case of a 72-year-old man who presented with back pain and acute renal failure. Ultrasound showed a soft tissue mass in the base of the bladder causing bilateral ureteric obstruction. Subsequent biopsy of this mass demonstrated neuroendocrine carcinoma. He was commenced on neoadjuvant chemotherapy (carboplatin/etoposide) and proceeded to a radical cysto-prostatectomy. Histology revealed a LCNEC involving the bladder, T4a with invasion through to adipose tissue and posteriorly at perivesical resection margins. In addition, there was a Gleason score 9 prostatic adenocarcinoma, distinct from the neuroendocrine carcinoma. Following surgery, the patient developed gross local-regional recurrence and refused further systemic therapy. However, 1 year following referral to palliative care, a further CT-PET showed complete spontaneous remission of his disease. There are only few case reports of LCNEC of the urinary bladder therefore the pathogenesis and treatment protocol are still unclear. This case report highlights the unpredictable nature of this disease. PMID:28560016

A case of large cell neuroendocrine carcinoma of the bladder with prolonged spontaneous remission.

PubMed

Chong, Vincent; Zwi, Jonathan; Hanning, Fritha; Lim, Remy; Williams, Andrew; Cadwallader, Jon

2017-05-01

Large cell neuroendocrine carcinoma (LCNEC) of the urinary bladder are rare. We present a case of a 72-year-old man who presented with back pain and acute renal failure. Ultrasound showed a soft tissue mass in the base of the bladder causing bilateral ureteric obstruction. Subsequent biopsy of this mass demonstrated neuroendocrine carcinoma. He was commenced on neoadjuvant chemotherapy (carboplatin/etoposide) and proceeded to a radical cysto-prostatectomy. Histology revealed a LCNEC involving the bladder, T4a with invasion through to adipose tissue and posteriorly at perivesical resection margins. In addition, there was a Gleason score 9 prostatic adenocarcinoma, distinct from the neuroendocrine carcinoma. Following surgery, the patient developed gross local-regional recurrence and refused further systemic therapy. However, 1 year following referral to palliative care, a further CT-PET showed complete spontaneous remission of his disease. There are only few case reports of LCNEC of the urinary bladder therefore the pathogenesis and treatment protocol are still unclear. This case report highlights the unpredictable nature of this disease.

Fibroblast growth factors and their receptors in cancer.

PubMed

Wesche, Jørgen; Haglund, Kaisa; Haugsten, Ellen Margrethe

2011-07-15

FGFs (fibroblast growth factors) and their receptors (FGFRs) play essential roles in tightly regulating cell proliferation, survival, migration and differentiation during development and adult life. Deregulation of FGFR signalling, on the other hand, has been associated with many developmental syndromes, and with human cancer. In cancer, FGFRs have been found to become overactivated by several mechanisms, including gene amplification, chromosomal translocation and mutations. FGFR alterations are detected in a variety of human cancers, such as breast, bladder, prostate, endometrial and lung cancers, as well as haematological malignancies. Accumulating evidence indicates that FGFs and FGFRs may act in an oncogenic fashion to promote multiple steps of cancer progression by inducing mitogenic and survival signals, as well as promoting epithelial-mesenchymal transition, invasion and tumour angiogenesis. Therapeutic strategies targeting FGFs and FGFRs in human cancer are therefore currently being explored. In the present review we will give an overview of FGF signalling, the main FGFR alterations found in human cancer to date, how they may contribute to specific cancer types and strategies for therapeutic intervention.

Evaluation of associations between lifetime exposure to drinking water disinfection by-products and bladder cancer in dogs.

PubMed

Backer, Lorraine C; Coss, Angela M; Wolkin, Amy F; Flanders, W Dana; Reif, John S

2008-06-01

To assess the risk of bladder cancer in dogs from exposure to drinking water disinfection by-products and determine whether dogs could serve as sentinels for human bladder cancer associated with such exposures. Case-control study. 100 dogs with cancer of the urinary bladder and 100 control dogs. Case and control dogs were frequency-matched by age (within 2 years) and sex. Owners of dogs enrolled provided verbal informed consent and were interviewed by telephone. The telephone questionnaire included a complete residence history for each dog. Each dog's total exposure history to trihalomethanes was reconstructed from its residence history and corresponding drinking water utility company data. No association was detected between increasing years of exposure to chlorinated drinking water and risk of bladder cancer. Dogs with bladder cancer were exposed to higher total trihalomethanes concentrations than control dogs; however, the difference was not significant. Although humans and their dogs live in the same household, the activity patterns of dogs may lead to lower exposures to household tap water. Thus, although exposure to disinfection by-products in tap water may be a risk factor for human bladder cancer, this may not be true for canine bladder cancer at the concentrations at which dogs are exposed.

Vitamin D Induction of the Human Antimicrobial Peptide Cathelicidin in the Urinary Bladder

PubMed Central

Hertting, Olof; Holm, Åsa; Lüthje, Petra; Brauner, Hanna; Dyrdak, Robert; Jonasson, Aino Fianu; Wiklund, Peter; Chromek, Milan; Brauner, Annelie

2010-01-01

The urinary tract is frequently being exposed to potential pathogens and rapid defence mechanisms are therefore needed. Cathelicidin, a human antimicrobial peptide is expressed and secreted by bladder epithelial cells and protects the urinary tract from infection. Here we show that vitamin D can induce cathelicidin in the urinary bladder. We analyzed bladder tissue from postmenopausal women for expression of cathelicidin, before and after a three-month period of supplementation with 25-hydroxyvitamin D3 (25D3). Cell culture experiments were performed to elucidate the mechanisms for cathelicidin induction. We observed that, vitamin D per se did not up-regulate cathelicidin in serum or in bladder tissue of the women in this study. However, when the bladder biopsies were infected with uropathogenic E. coli (UPEC), a significant increase in cathelicidin expression was observed after 25D3 supplementation. This observation was confirmed in human bladder cell lines, even though here, cathelicidin induction occurred irrespectively of infection. Vitamin D treated bladder cells exerted an increased antibacterial effect against UPEC and colocalization to cathelicidin indicated the relevance of this peptide. In the light of the rapidly growing problem of resistance to common urinary tract antibiotics, we suggest that vitamin D may be a potential complement in the prevention of UTI. PMID:21179490

Urinary metabotyping of bladder cancer using two-dimensional gas chromatography time-of-flight mass spectrometry.

PubMed

Pasikanti, Kishore Kumar; Esuvaranathan, Kesavan; Hong, Yanjun; Ho, Paul C; Mahendran, Ratha; Raman Nee Mani, Lata; Chiong, Edmund; Chan, Eric Chun Yong

2013-09-06

Cystoscopy is the gold standard clinical diagnosis of human bladder cancer (BC). As cystoscopy is expensive and invasive, it compromises patients' compliance toward surveillance screening and challenges the detection of recurrent BC. Therefore, the development of a noninvasive method for the diagnosis and surveillance of BC and the elucidation of BC progression become pertinent. In this study, urine samples from 38 BC patients and 61 non-BC controls were subjected to urinary metabotyping using two-dimensional gas chromatography time-of-flight mass spectrometry (GC×GC-TOFMS). Subsequent to data preprocessing and chemometric analysis, the orthogonal partial least-squares discriminant analysis (OPLS-DA, R2X=0.278, R2Y=0.904 and Q2Y (cumulative)=0.398) model was validated using permutation tests and receiver operating characteristic (ROC) analysis. Marker metabolites were further screened from the OPLS-DA model using statistical tests. GC×GC-TOFMS urinary metabotyping demonstrated 100% specificity and 71% sensitivity in detecting BC, while 100% specificity and 46% sensitivity were observed via cytology. In addition, the model revealed 46 metabolites that characterize human BC. Among the perturbed metabolic pathways, our clinical finding on the alteration of the tryptophan-quinolinic metabolic axis in BC suggested the potential roles of kynurenine in the malignancy and therapy of BC. In conclusion, global urinary metabotyping holds potential for the noninvasive diagnosis and surveillance of BC in clinics. In addition, perturbed metabolic pathways gleaned from urinary metabotyping shed new and established insights on the biology of human BC.

[Inhibitory effects of 11 coumarin compounds against growth of human bladder carcinoma cell line E-J in vitro].

PubMed

Yang, Xiu-wei; Xu, Bo; Ran, Fu-xiang; Wang, Rui-qing; Wu, Jun; Cui, Jing-rong

2007-01-01

To screen antitumor active compounds, drug-like or leading compounds from Chinese traditional and herbal drugs. Eleven coumarin compounds isolated from the Chinese traditional and herbal drugs were studied for their antitumor activities in vitro by determining the inhibition rates against growth of human bladder carcinoma cell line E-J. It showed that umbelliferone, scoparone, demethylfuropinarine, isopimpinellin, forbesoside, columbianadin, decursin and glycycoumarin inhibited the growth of human bladder carcinoma cell line E-J in vitro and their activities showed a concentration-effect relationship. The inhibitory effects of forbesoside, columbianadin, decursin and umbelliferone, with IC50 values of 7.50x10(-7), 2.30x10(-6), 6.00x10(-6) and 1.30x10(-6) mol/L, respectively, were stronger than those of the other tested compounds. However, xanthotoxin, esculin and sphondin did not inhibit the growth of human bladder carcinoma cell line E-J in this assay condition. These findings indicate that forbesoside, columbianadin, esculin, decursin and umbelliferone would be effective or regarded as potent drug-like or leading compounds against human bladder carcinoma.

Use of donor bladder tissues for in vitro research.

PubMed

Garthwaite, Mary; Hinley, Jennifer; Cross, William; Warwick, Ruth M; Ambrose, Anita; Hardaker, Henry; Eardley, Ian; Southgate, Jennifer

2014-01-01

To evaluate deceased non-heart beating (DNHB) donors and deceased heart beating (DHB) brain-stem dead donors, as sources of viable urological tissue for use in biomedical research. To identify sources of viable human bladder tissue as an essential resource for cell biological research aimed at understanding human diseases of the bladder and for developing new tissue engineering and regenerative medicine strategies for bladder reconstruction. Typically, normal human urinary tract tissue is obtained from adult or paediatric surgical patients with benign urological conditions, but few surgical procedures yield useful quantities of healthy bladder tissue for research. Research ethics committee approval was obtained for collection of donor bladder tissue. Consent for DHB donors was undertaken by the Donor Transplant Coordinators. Tissue Donor Coordinators were responsible for consent for DNHB donors and the retrieval of bladders was coordinated through the National Blood Service Tissue Banking Service. All retrievals were performed by practicing urologists and care was taken to maintain sterility and to minimise bacterial contamination. Two bladders were retrieved from DNHB donors and four were retrieved from DHB donors. By histology, DNHB donor bladder tissue exhibited marked urothelial tissue damage and necrosis, with major loss or absence of urothelium. No cell cultures could be established from these specimens, as the urothelial cells were not viable in primary culture. Bladder urothelium from DHB donors was intact, but showed some damage, including loss of superficial cells and variable separation from the basement membrane. All four DHB bladder specimens yielded viable urothelial cells that attached in primary culture, but cell growth was slow to establish and cultures showed a limited capacity to form a functional barrier epithelium and a propensity to senesce early. We have shown that normal human bladder urothelial cell cultures can be established and serially propagated from DHB donor bladders. However, our study suggests that rapid post-mortem changes to the bladder affect the quality and viability of the urothelium, rendering tissue from DNHB donors an inadequate source for urothelial cell culture. Our experience is that whereas patients are willing to donate surgical tissue for research, there is a barrier to obtaining consent from next of kin for retrieved tissues to be used for research purposes. © 2013 The Authors. BJU International © 2013 BJU International.

Comparative immunohistochemical characterization of interstitial cells in the urinary bladder of human, guinea pig and pig.

PubMed

Steiner, Clara; Gevaert, Thomas; Ganzer, Roman; De Ridder, Dirk; Neuhaus, Jochen

2018-05-01

Interstitial cells (ICs) are thought to play a functional role in urinary bladder. Animal models are commonly used to elucidate bladder physiology and pathophysiology. However, inter-species comparative studies on ICs are rare. We therefore analyzed ICs and their distribution in the upper lamina propria (ULP), the deeper lamina propria (DLP) and the detrusor muscular layer (DET) of human, guinea pig (GP) and pig. Paraffin slices were examined by immunohistochemistry and 3D confocal immunofluorescence of the mesenchymal intermediate filament vimentin (VIM), alpha-smooth muscle actin (αSMA), platelet-derived growth factor receptor alpha (PDGFRα) and transient receptor potential cation channel A1 (TRPA1). Image stacks were processed for analysis using Huygens software; quantitative analysis was performed with Fiji macros. ICs were identified by immunoreactivity for VIM (excluding blood vessels). In all species ≥ 75% of ULP ICs were VIM + /PDGFRα + and ≥ 90% were VIM + /TRPA1 + . In human and pig ≥ 74% of ULP ICs were VIM + /αSMA + , while in GP the percentage differed significantly with only 37% VIM + /αSMA + ICs. Additionally, over 90% of αSMA + ICs were also TRPA1 + and PDGFRα + in human, GP and pig. In all three species, TRPA1 + and PDGFRα + ICs point to an active role for these cells in bladder physiology, regarding afferent signaling processes and signal modification. We hypothesize that decline in αSMA-positivity in GP reflects adaptation of bladder histology to smaller bladder size. In our experiments, pig bladder proved to be highly comparable to human urinary bladder and seems to provide safer interpretation of experimental findings than GP.

Primary fibrosarcoma of the urinary bladder in a cat: follow-up after incomplete surgical excision.

PubMed

Greci, Valentina; Rocchi, Paola M; Sontuoso, Antonio F; Olivero, Daniela; Capasso, Angelo; Raiano, Vera

2017-01-01

An 11-year-old female spayed domestic shorthair cat was presented with haematuria of 2 months' duration followed by pollakiuria and stranguria. A firm, non-painful mass in the urinary bladder was palpated. Abdominal radiographs and ultrasound were suggestive of a urinary neoplasia. During explorative laparotomy, a partial cystectomy and surgical debulking were performed. Histopathology and immunostaining were consistent with a fibrosarcoma. The cat was discharged 10 days after surgery with a residual mass of about 1.8 cm on ultrasound re-examination. The cat was not given adjuvant therapy. The cat was euthanased 8 months after surgery because of tumour invasion of the urinary trigone and subsequent ureter dilation, hydronephrosis and severe azotaemia. Malignant urinary fibrosarcoma in this cat appeared to be only locally invasive. Palliative surgery without adjuvant postoperative chemotherapy in this cat resulted in an 8 month period of good quality of life.

Cohort profile: The Swedish National Register of Urinary Bladder Cancer (SNRUBC) and the Bladder Cancer Data Base Sweden (BladderBaSe).

PubMed

Häggström, Christel; Liedberg, Fredrik; Hagberg, Oskar; Aljabery, Firas; Ströck, Viveka; Hosseini, Abolfazl; Gårdmark, Truls; Sherif, Amir; Malmström, Per-Uno; Garmo, Hans; Jahnson, Staffan; Holmberg, Lars

2017-09-27

To monitor the quality of bladder cancer care, the Swedish National Register of Urinary Bladder Cancer (SNRUBC) was initiated in 1997. During 2015, in order to study trends in incidence, effects of treatment and survival of men and women with bladder cancer, we linked the SNRUBC to other national healthcare and demographic registers and constructed the Bladder Cancer Data Base Sweden (BladderBaSe). The SNRUBC is a nationwide register with detailed information on 97% of bladder cancer cases in Sweden as compared with the Swedish Cancer Register. Participants in the SNRUBC have registered data on tumour characteristics at diagnosis, and for 98% of these treatment data have been captured. From 2009, the SNRUBC holds data on 88% of eligible participants for follow-up 5 years after diagnosis of non-muscle invasive bladder cancer, and from 2011, data on surgery details and complications for 85% of participants treated with radical cystectomy. The BladderBaSe includes all data in the SNRUBC from 1997 to 2014, and additional covariates and follow-up data from linked national register sources on comorbidity, socioeconomic factors, detailed information on readmissions and treatment side effects, and causes of death. Studies based on data in the SNRUBC have shown inequalities in survival and treatment indication by gender, regions and hospital volume. The BladderBaSe includes 38 658 participants registered in SNRUBC with bladder cancer diagnosed from 1 January 1997 to 31 December 2014. The BladderBaSe initiators are currently in collaboration with researchers from the SNRUBC investigating different aspects of bladder cancer survival. The SNRUBC and the BladderBaSe project are open for collaborations with national and international research teams. Collaborators can submit proposals for studies and study files can be uploaded to servers for remote access and analysis. For more information, please contact the corresponding author. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Fenoterol functionally activates the β₃-adrenoceptor in human urinary bladder, comparison with rat and mouse: implications for drug discovery.

PubMed

Palea, Stefano; Rekik, Moèz; Rouget, Céline; Camparo, Philippe; Botto, Henri; Rischmann, Pascal; Lluel, Philippe; Westfall, Timothy D

2012-09-05

Fenoterol has been reported to be a potent and selective β(2)-adrenoceptor agonist and is currently used clinically to treat asthma. Electrical field stimulation (EFS) of isolated urinary bladder mimics the voiding contraction by stimulating parasympathetic nerves, resulting in neurogenic contractions. To determine if stimulation of β(2)-adrenoceptors can inhibit this response, fenoterol was tested against EFS-induced contractions in human isolated urinary bladder and compared with mouse and rat. Bladder strips were mounted in organ baths and reproducible contractions induced by EFS. Fenoterol was added cumulatively in the presence of the β(2)-adrenoceptor antagonist ICI118551 or the β(3)-adrenoceptor antagonist L-748337. Fenoterol inhibited neurogenic contractions in all three species in a concentration-dependent manner with pEC(50) values of 6.66 ± 0.11, 6.86 ± 0.06 and 5.71 ± 0.1 in human, mouse and rat respectively. In human bladder strips ICI118551 (100 nM) did not affect responses to fenoterol, while L-748337 (0.3-3 μM) produced rightward shifts of the concentration-response curves with a pA(2) value of 8.10. In mouse bladder strips ICI118551 (30 nM) blocked the inhibitory effect of fenoterol (pA(2)=8.80), while L-748337 (10 μM) inhibited the response with a pA(2) of 5.79. In rat bladder ICI118551 (30 nM) was without effect, while L-748,337 (10 μM) inhibited the response to fenoterol with a pA(2) of 5.40. From these results it is clear that fenoterol potently activates β(3)-adrenoceptors in human isolated urinary bladder to inhibit EFS-induced contractions. Fenoterol also activates β(3)-adrenoceptors in rat, but β(2)-adrenoceptors in mouse bladder to inhibit EFS-induced contractions. Copyright © 2012 Elsevier B.V. All rights reserved.

Validation of the urostomy education scale: the European experience.

PubMed

Jensen, Bente Thoft; de Blok, W; Kiesbye, Berit; Kristensen, Susanne A

2013-01-01

Bladder cancer is the fourth most common cancer among European males. Once diagnosed with muscle invasive bladder cancer, a radical cystectomy is the first line treatment, which results in a urostomy. The placement of a urostomy and the care required impacts the patient's life. Previous research validated the Urostomy Education Scale as the first standardized tool capable of documenting the patients' level of stoma self-care skills and useful to guide patient education interventions. A Danish-Dutch Fellowship was established to support and provide further evidence of applicability of the Urostomy Education Scale.

Hexavalent Chromium Induces Chromosome Instability in Human Urothelial Cells

PubMed Central

Wise, Sandra S.; Holmes, Amie L.; Liou, Louis; Adam, Rosalyn M.; Wise, John Pierce

2016-01-01

Numerous metals are well-known human bladder carcinogens. Despite the significant occupational and public health concern of metals and bladder cancer, the carcinogenic mechanisms remain largely unknown. Chromium, in particular, is a metal of concern as incidences of bladder cancer have been found elevated in chromate workers, and there is an increasing concern for patients with metal hip implants. However, the impact of Cr(VI) on bladder cells has not been studied. We compared chromate toxicity in two bladder cell lines; primary human urothelial cells and hTERT-immortalized human urothelial cells. Hexavalent chromium (Cr(VI)) induced a concentration- and time-dependent increase in chromosome damage in both cell lines, with the hTERT-immortalized cells exhibiting more chromosome damage than the primary cells. Chronic exposure to Cr(VI) also induced a concentration-dependent increase in aneuploid metaphases in both cell lines which was not observed after a 24 h exposure. Aneuploidy induction was higher in the hTERT-immortalized cells. When we correct for uptake, Cr(VI) induces a similar amount of chromosome damage and aneuploidy suggesting that the differences in Cr(VI) sensitivity between the two cells lines were due to differences in uptake. The increase in chromosome instability after chronic chromate treatment suggests this may be a mechanism for chromate-induced bladder cancer specifically and may be a mechanism for metal-induced bladder cancer in general. PMID:26908176

Protoporphyrin IX induced by 5-aminolevulinic acid in bladder cancer cells in voided urine can be extracorporeally quantified using a spectrophotometer.

PubMed

Nakai, Yasushi; Anai, Satoshi; Onishi, Sayuri; Masaomi, Kuwada; Tatsumi, Yoshihiro; Miyake, Makito; Chihara, Yoshitomo; Tanaka, Nobumichi; Hirao, Yoshihiko; Fujimoto, Kiyohide

2015-06-01

We evaluated the feasibility of photodynamic diagnosis of bladder cancer by spectrophotometric analysis of voided urine samples after extracorporeal treatment with 5-aminolevulinic acid (ALA). Sixty-one patients with bladder cancer, confirmed histologically after the transurethral resection of a bladder tumor, were recruited as the bladder cancer group, and 50 outpatients without history of urothelial carcinoma or cancer-related findings were recruited as the control group. Half of the voided urine sample was incubated with ALA (ALA-treated sample), and the rest was incubated without treatment (ALA-untreated sample). For detecting cellular protoporphyrin IX levels, intensity of the samples at the excitation wavelength of 405 nm was measured using a spectrophotometer. The difference between the intensity of the ALA-treated and ALA-untreated samples at 635 nm was calculated. The differences in the bladder cancer group were significantly greater than those in the control group (p < 0.001). These differences were also significantly greater in patients with high-grade tumors than in those with low-grade tumors (p = 0.004), and also in patients with invasive bladder cancer than in those with noninvasive bladder cancer (p = 0.007). The area under the curve was 0.84. Sensitivity and specificity of the method were 82% and 80%, respectively. We demonstrated that protoporphyrin IX levels in urinary cells treated with ALA could be quantitatively detected by spectrophotometer in patients with bladder cancer. Therefore, this cancer detection system has a potential for clinical use. Copyright © 2015 Elsevier B.V. All rights reserved.

High VEGF-D and Low MMP-2 Serum Levels Predict Nodal-Positive Disease in Invasive Bladder Cancer

PubMed Central

Benoit, Tobias; Keller, Etienne X.; Wolfsgruber, Pirmin; Hermanns, Thomas; Günthart, Michele; Banzola, Irina; Sulser, Tullio; Provenzano, Maurizio; Poyet, Cédric

2015-01-01

Background To investigate stromal variables including angiogenesis, lymphangiogenesis, and matrix metalloproteinase (MMP) in the serum of patients with urothelial carcinoma of the bladder (UCB) and to evaluate their association with histopathological characteristics and clinical outcome. Material/Methods Protein levels of vascular endothelial growth factors-A, -C, -D (VEGF-A/-C/-D), their receptors- VEGF-R2 and -R3 (VEGF-R2/-R3), and matrix metalloproteinases 2, -3, and -7 (MMP-2, MMP-3, MMP-7) were quantified in the blood serum samples of 71 patients with UCB before radical cystectomy (RC). Samples of patients with non-invasive UCB or no history of UCB were investigated as controls (n=20). Protein levels in the serum were measured using a flow cytometric cytokine assay. Results A positive association for VEGF-D (p<0.001) and an inverse association for MMP-2 (p=0.017) were observed in patients with positive lymph node (LN) status at the time of RC. VEGF-A (p<0.001), VEGF-C (p<0.001), MMP-2 (p<0.001), and MMP-7 (p=0.005) serum levels were different in serum of patients with invasive UCB compared with non-invasive UCB or healthy individuals. None of the serum markers were associated with disease progression. Conclusions High VEGF-D and low MMP-2 serum levels predict LN metastasis in patients with UCB at the time of RC. VEGF-A, VEGF-C, MMP-2, and MMP-7 serum levels varied significantly between invasive and non-invasive disease as well as in comparison with healthy individuals. Clinical implementation of these marker serum measurements may be valuable to select high-risk patients with more invasive or nodal-positive disease. PMID:26241709

Altered RECQL5 expression in urothelial bladder carcinoma increases cellular proliferation and makes RECQL5 helicase activity a novel target for chemotherapy

PubMed Central

Patterson, Karl; Arya, Lovleen; Bottomley, Sarah; Morgan, Susan; Cox, Angela; Catto, James; Bryant, Helen E.

2016-01-01

RECQ helicases are a family of enzymes with both over lapping and unique functions. Functional autosomal recessive loss of three members of the family BLM, WRN and RECQL4, results in hereditary human syndromes characterized by cancer predisposition and premature aging, but despite the finding that RECQL5 deficient mice are cancer prone, no such link has been made to human RECQL5. Here we demonstrate that human urothelial carcinoma of the bladder (UCC) has increased expression of RECQL5 compared to normal bladder tissue and that increasing RECQL5 expression can drive proliferation of normal bladder cells and is associated with poor prognosis. Further, by expressing a helicase dead RECQL5 and by depleting bladder cancer cells of RECQL5 we show that inhibition of RECQL5 activity has potential as a new target for treatment of UCC. PMID:27764811

Stricture of the afferent isoperistaltic tubular segment: a late and rare cause of bilateral dilation of the upper urinary tract after ileal bladder substitution.

PubMed

Kiss, Bernhard; Schöndorf, Daniel; Studer, Urs E; Roth, Beat

2013-08-01

To evaluate the etiology and treatment of bilateral hydronephrosis not responding to bladder substitute drainage after ileal bladder substitution using an afferent isoperistaltic tubular segment. A retrospective analysis was performed of a consecutive series of 739 patients who had undergone bladder substitution from April 1985 to August 2012. Of the 739 ileal bladder substitute patients, 10 (1.4%) developed bilateral hydronephrosis unresponsive to complete bladder substitute drainage. The etiology was stenosis of the afferent isoperistaltic tubular segment. The median interval to presentation was 131 months (range 45-192). The incidence of afferent tubular segment stenosis was significantly higher in the 61 ileal bladder substitute patients with recurrent urinary tract infection (9 [15%]) than in the 678 without recurrent urinary tract infection (1 [0.15%]; P <.001). Urine cultures revealed mixed infections (34%), Escherichia coli (18%), Staphylococcus aureus (13%), enterococci (11%), Candida (8%), Klebsiella (8%), and others (8%). Seven patients underwent 10 endourologic interventions, only 1 of which was successful (10%). After failed endourologic treatment, 7 open surgical revisions with resection of the stricture were performed, with all 7 (100%) successful. Bilateral dilation of the upper urinary tract after ileal orthotopic bladder substitution unresponsive to complete bladder substitute drainage is likely to be caused by stenosis of the afferent isoperistaltic tubular segment. The stenosis occurs almost exclusively in patients with long-lasting, recurrent urinary tract infection and can develop many years after the ileal bladder substitution. Minimally invasive endourologic treatment is usually unsuccessful; however, open surgical revision offers excellent results. Copyright © 2013 Elsevier Inc. All rights reserved.

Assessment of the Radiation-Equivalent of Chemotherapy Contributions in 1-Phase Radio-chemotherapy Treatment of Muscle-Invasive Bladder Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Plataniotis, George A., E-mail: george.plataniotis@nhs.net; Dale, Roger G.

2014-03-15

Purpose: To estimate the radiation equivalent of the chemotherapy contribution to observed complete response rates in published results of 1-phase radio-chemotherapy of muscle-invasive bladder cancer. Methods and Materials: A standard logistic dose–response curve was fitted to data from radiation therapy-alone trials and then used as the platform from which to quantify the chemotherapy contribution in 1-phase radio-chemotherapy trials. Two possible mechanisms of chemotherapy effect were assumed (1) a fixed radiation-independent contribution to local control; or (2) a fixed degree of chemotherapy-induced radiosensitization. A combination of both mechanisms was also considered. Results: The respective best-fit values of the independent chemotherapy-induced completemore » response (CCR) and radiosensitization (s) coefficients were 0.40 (95% confidence interval −0.07 to 0.87) and 1.30 (95% confidence interval 0.86-1.70). Independent chemotherapy effect was slightly favored by the analysis, and the derived CCR value was consistent with reports of pathologic complete response rates seen in neoadjuvant chemotherapy-alone treatments of muscle-invasive bladder cancer. The radiation equivalent of the CCR was 36.3 Gy. Conclusion: Although the data points in the analyzed radio-chemotherapy studies are widely dispersed (largely on account of the diverse range of chemotherapy schedules used), it is nonetheless possible to fit plausible-looking response curves. The methodology used here is based on a standard technique for analyzing dose-response in radiation therapy-alone studies and is capable of application to other mixed-modality treatment combinations involving radiation therapy.« less

Enhanced Application of 18F-FDG PET/CT in Bladder Cancer by Adding Early Dynamic Acquisition to a Standard Delayed PET Protocol.

PubMed

Yoon, Hai-Jeon; Yoo, Jang; Kim, Yemi; Lee, Dong Hyeon; Kim, Bom Sahn

2017-10-01

We investigated the value of early dynamic (ED) PET for the detection and characterization of bladder cancer. Fifty-two bladder cancer patients were prospectively enrolled. The study protocol was composed of ED, whole-body (WB, 60 minutes after injection), and additional delayed (AD, 120 minutes after injection) PET acquisition. Early dynamic PET was acquired for 10 minutes and reconstructed as 5 frames at 2-minute intervals. A focal radiotracer accumulation confined to the bladder wall was considered as PET positive and referred for further quantitative measurement. SUVmax on ED (SUVmax, SUVmax, SUVmax, SUVmax, and SUVmax for 5 frames), WB (SUVmax), and AD PET (SUVmax) were measured. PET results were correlated with bladder cancer pathology variables. The sensitivities of ED, WB, and AD PET for bladder cancer were 84.6%, 57.7%, and 61.2%, respectively. The sensitivity of ED PET was significantly higher than that of WB (P = 0.002) and AD PET (P = 0.008). On ED PET, SUVmax was significantly correlated with muscle invasiveness, histological grade, and pathological tumor size (P = 0.018, P = 0.030, and P = 0.030). On WB and AD PET, only pathological tumor size showed significant positive correlation with SUVmax and SUVmax (P = 0.043 and P = 0.007). Early dynamic PET can help to detect and characterize bladder cancer.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Canyilmaz, Emine, E-mail: dremocan@yahoo.com; Yavuz, Melek Nur; Serdar, Lasif

Purpose: The aim of this study was to evaluate the long-term clinical efficacy and toxicity of concomitant boost and accelerated hyperfractionated radiation therapy (CBAHRT) in patients with invasive bladder cancer. Methods and Materials: Between October 1997 and September 2012, 334 patients with diagnoses of invasive bladder cancer were selected. These patients received CBAHRT as a bladder-conserving approach. The treatment consisted of a dose of 45 Gy/1.8 Gy to the whole pelvis with a daily concomitant boost of 1.5 Gy to the tumor. Total dose was 67.5 Gy in 5 weeks. A total of 32 patients (10.3%) had a diagnosis of stage T1, 202 (64.3%) weremore » at stage T2, 46 (14.6%) were at stage T3a, 22 (7%) were at stage T3b, and 12 (3.8%) were at stage T4a. Results: The follow-up period was 33.1 months (range, 4.3-223.3 months). Grade 3 late intestinal toxicity was observed in 9 patients (2.9%), whereas grade 3 late urinary toxicity was observed in 8 patients (2.5%). The median overall survival (OS) was 26.3 months (95% confidence interval [CI]: 21.4-31.2). The 5-, 10, and 15-year OS rates were 32.1% (standard error [SE], ± 0.027), 17.9% (SE, ± 0.025) and 12.5% (SE, ± 0.028), respectively. The median cause-specific survival (CSS) was 42.1 months (95% CI: 28.7-55.5). The 5-, 10-, and 15-year CSS rates were 43.2% (SE, ± 0.03), 30.3% (SE, ± 0.03), and 28% (SE, ± 0.04), respectively. The median relapse-free survival (RFS) was 111.8 months (95% CI: 99.6-124). The 5-, 10-, and 15-year RFS rates were 61.9% (SE, ± 0.03), 57.6% (SE, ± 0.04), and 48.2% (SE, ± 0.07), respectively. Conclusions: The CBAHRT technique demonstrated acceptable toxicity and local control rates in patients with invasive bladder cancer, and this therapy facilitated bladder conservation. In selected patients, the CBAHRT technique is a practical alternative treatment option with acceptable 5-, 10-, and 15-year results in patients undergoing cystectomy as well as concurrent chemoradiation therapy.« less

Unique Case Report of Pineal Gland Metastasis From Bladder Carcinoma.

PubMed

Li, Jun; Wang, Ping; Wang, Bin

2016-05-01

Pineal metastasis is uncommon and most metastatic pineal lesions are asymptomatic. To our knowledge the herein reported case is the first in which the pineal gland was confirmed as the metastatic site of a bladder carcinoma.The patient reported in this case is a 59-year-old man who suffered from headache and delirium for 4 days after surgical treatment for removal of a bladder carcinoma 1 year ago. Magnetic resonance imaging (MRI) revealed a solid tumor involving the pineal gland with significant enhancement.The patient underwent surgical treatment for removal of the neoplastic lesion in the pineal gland. Histopathological examination confirmed invasion of the pineal gland by metastatic urothelial carcinoma.This case highlighted that the presence of pineal lesions in patient with known malignancy should raise suspicion of metastatic involvement.

Photodynamic therapy in the prophylactic management of bladder cancer

NASA Astrophysics Data System (ADS)

Nseyo, Unyime O.; Lundahl, Scott L.; Merrill, Daniel C.

1991-06-01

Nine patients were treated with red light whole bladder photodynamic therapy (WBPDT): five had mucosal involvement (Ta) and four submucosal invasion (T1). Patients received slow intravenous injection with 2mg/kg body weight of photofrin 48-72 hours before undergoing global light treatment via a 22-French cystoscope with a 400-micron quartz fiber bulb (isotropic) tip fiber. Three months after PDT, eight of the patients had normal cystoscopy, and negative biopsy and urine cytology. Two patients who had recurrences at six and twelve months were retreated with a higher dose (20 J/cm2). They had no increased morbidity and no evidence of recurrent disease six months later. WBPDT should be considered as an important alternative treatment for patients who have recurrent or refractory superficial bladder cancer.

Primary adenocarcinoma of bladder.

PubMed

Wilson, T G; Pritchett, T R; Lieskovsky, G; Warner, N E; Skinner, D G

1991-09-01

Between April 1983 and December 1987, we have treated and followed 16 patients at the University of Southern California for adenocarcinoma of the bladder. In 10 patients, the cancer originated from a nonurachal source; all underwent radical cystectomy, bilateral pelvic lymph node dissection, and urinary diversion. The other 6 patients had an apparent urachal origin of their cancer. Half of these patients were treated with radical cystectomy and urinary diversion and half were treated initially with segmental cystectomy. Presenting characteristics (age, sex ratio, and symptoms) were similar for both groups. Three-year adjusted acturial tumor-free survival rates for the two groups were 48 percent and 31 percent, respectively. We advocate an aggressive approach of radical cystectomy, bilateral pelvic lymph node dissection, and urinary diversion for all invasive adenocarcinoma of the bladder, regardless of location.

Characterization and zoonotic potential of uropathogenic Escherichia coli isolated from dogs.

PubMed

Nam, Eui-Hwa; Ko, Sungjin; Chae, Joon-Seok; Hwang, Cheol-Yong

2013-03-01

The aim of this study was to investigate the characteristics of canine uropathogenic Escherichia coli (UPEC) and the interaction between canine UPEC and human bladder epithelial cells. Ten E. coli isolates collected from dogs with cystitis were analyzed for antimicrobial resistance patterns, the presence of virulence factors, and biofilm formation. The ability of these isolates to induce cytotoxicity, invade human bladder epithelial cells, and stimulate an immune response was also determined. We observed a high rate of antimicrobial resistance among canine UPEC isolates. All virulence genes tested (including adhesins, iron acquisition, and protectin), except toxin genes, were detected among the canine UPEC isolates. We found that all isolates showed varying degrees of biofilm formation (mean, 0.26; range, 0.07 to 0.82), using a microtiter plate assay to evaluate biofilm formation by the isolates. Cytotoxicity to human bladder epithelial cells by the canine UPEC isolates increased in a time-dependent manner, with a 56.9% and 36.1% reduction in cell viability compared with the control at 6 and 9 h of incubation, respectively. We found that most canine UPEC isolates were able to invade human bladder epithelial cells. The interaction between these isolates and human bladder epithelial cells strongly induced the production of proinflammatory cytokines such as IL-6 and IL-8. We demonstrated that canine UPEC isolates can interact with human bladder epithelial cells, although the detailed mechanisms remain unknown. The results suggest that canine UPEC isolates, rather than dogspecific pathogens, have zoonotic potential.

Acrolein- and 4-Aminobiphenyl-DNA adducts in human bladder mucosa and tumor tissue and their mutagenicity in human urothelial cells

PubMed Central

Weng, Mao-wen; Hu, Yu; Chen, Wei-sheng; Chou, David; Liu, Yan; Donin, Nicholas; Huang, William C.; Lepor, Herbert; Wu, Xue-Ru; Wang, Hailin; Beland, Frederick A.; Tang, Moon-shong

2014-01-01

Tobacco smoke (TS) is a major cause of human bladder cancer (BC). Two components in TS, 4-aminobiphenyl (4-ABP) and acrolein, which also are environmental contaminants, can cause bladder tumor in rat models. Their role in TS related BC has not been forthcoming. To establish the relationship between acrolein and 4-ABP exposure and BC, we analyzed acrolein-deoxyguanosine (dG) and 4-ABP-DNA adducts in normal human urothelial mucosa (NHUM) and bladder tumor tissues (BTT), and measured their mutagenicity in human urothelial cells. We found that the acrolein-dG levels in NHUM and BTT are 10-30 fold higher than 4-ABP-DNA adduct levels and that the acrolein-dG levels in BTT are 2 fold higher than in NHUM. Both acrolein-dG and 4-ABP-DNA adducts are mutagenic; however, the former are 5 fold more mutagenic than the latter. These two types of DNA adducts induce different mutational signatures and spectra. We found that acrolein inhibits nucleotide excision and base excision repair and induces repair protein degradation in urothelial cells. Since acrolein is abundant in TS, inhaled acrolein is excreted into urine and accumulates in the bladder and because acrolein inhibits DNA repair and acrolein-dG DNA adducts are mutagenic, we propose that acrolein is a major bladder carcinogen in TS. PMID:24939871

Suprapubic Bladder Catheterization of Male Spinal-Cord–Injured Sprague–Dawley Rats

PubMed Central

Robinson, Mary A; Herron, Alan J; Goodwin, Bradford S; Grill, Raymond J

2012-01-01

The rat spinal-cord–injury (SCI) model is widely used to study the pathologic mechanisms that contribute to sensory and motor dysfunction in humans. This model is thought to mimic many of the negative outcomes experienced by humans after spinal contusion injury. We theorized that manual bladder expression contributed to the kidney and bladder lesions reported in previous studies using the rat SCI model. In the present study, rats were surgically implanted with bladder catheters after spinal contusion injury to provide continuous drainage of urine. After 72 h, the rats were euthanized and their kidneys and bladders examined histologically. BUN, serum creatinine, and urine protein were compared at 0 and 72 h after surgery. Kidney and bladder lesions were similar in SCI rats with and without implanted bladder catheters. BUN at 72 h was higher than baseline values in both groups, whereas serum creatinine was higher at 72 h compared with baseline values only in the catheterized rats. These findings indicate that suprapubic bladder catheterization does not reduce hydronephrosis in SCI rats and that the standard of care for bladder evacuation should continue to be manual expression of urine. PMID:22330872

CXCL5 knockdown expression inhibits human bladder cancer T24 cells proliferation and migration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng, Jiajia; Zhu, Xi; Zhang, Jie, E-mail: zhangjiebjmu@163.com

2014-03-28

Highlights: • We first demonstrated CXCL5 is highly expressed in human bladder tumor tissues and cells. • CXCL5 knockdown inhibits proliferation, migration and promotes apoptosis in T24 cells. • CXCL5 knockdown inhibits Snail, PI3K-AKT and ERK1/2 signaling pathways in T24 cells. • CXCL5 is critical for bladder tumor growth and progression. - Abstract: CXCL5 (epithelial neutrophil activating peptide-78) which acts as a potent chemoattractant and activator of neutrophil function was reported to play a multifaceted role in tumorigenesis. To investigate the role of CXCL5 in bladder cancer progression, we examined the CXCL5 expression in bladder cancer tissues by real-time PCRmore » and Western blot, additionally, we used shRNA-mediated silencing to generate stable CXCL5 silenced bladder cancer T24 cells and defined its biological functions. Our results demonstrated that mRNA and protein of CXCL5 is increased in human bladder tumor tissues and cell lines, down-regulation of CXCL5 in T24 cells resulted in significantly decreased cell proliferation, migration and increased cell apoptosis in vitro through Snail, PI3K-AKT and ERK1/2 signaling pathways. These data suggest that CXCL5 is critical for bladder tumor growth and progression, it may represent a potential application in cancer diagnosis and therapy.« less

Understanding the Role of Non-Coding RNAs in Bladder Cancer: From Dark Matter to Valuable Therapeutic Targets

PubMed Central

Pop-Bica, Cecilia; Gulei, Diana; Cojocneanu-Petric, Roxana; Braicu, Cornelia; Petrut, Bogdan; Berindan-Neagoe, Ioana

2017-01-01

The mortality and morbidity that characterize bladder cancer compel this malignancy into the category of hot topics in terms of biomolecular research. Therefore, a better knowledge of the specific molecular mechanisms that underlie the development and progression of bladder cancer is demanded. Tumor heterogeneity among patients with similar diagnosis, as well as intratumor heterogeneity, generates difficulties in terms of targeted therapy. Furthermore, late diagnosis represents an ongoing issue, significantly reducing the response to therapy and, inevitably, the overall survival. The role of non-coding RNAs in bladder cancer emerged in the last decade, revealing that microRNAs (miRNAs) may act as tumor suppressor genes, respectively oncogenes, but also as biomarkers for early diagnosis. Regarding other types of non-coding RNAs, especially long non-coding RNAs (lncRNAs) which are extensively reviewed in this article, their exact roles in tumorigenesis are—for the time being—not as evident as in the case of miRNAs, but, still, clearly suggested. Therefore, this review covers the non-coding RNA expression profile of bladder cancer patients and their validated target genes in bladder cancer cell lines, with repercussions on processes such as proliferation, invasiveness, apoptosis, cell cycle arrest, and other molecular pathways which are specific for the malignant transformation of cells. PMID:28703782

Understanding the Role of Non-Coding RNAs in Bladder Cancer: From Dark Matter to Valuable Therapeutic Targets.

PubMed

Pop-Bica, Cecilia; Gulei, Diana; Cojocneanu-Petric, Roxana; Braicu, Cornelia; Petrut, Bogdan; Berindan-Neagoe, Ioana

2017-07-13

The mortality and morbidity that characterize bladder cancer compel this malignancy into the category of hot topics in terms of biomolecular research. Therefore, a better knowledge of the specific molecular mechanisms that underlie the development and progression of bladder cancer is demanded. Tumor heterogeneity among patients with similar diagnosis, as well as intratumor heterogeneity, generates difficulties in terms of targeted therapy. Furthermore, late diagnosis represents an ongoing issue, significantly reducing the response to therapy and, inevitably, the overall survival. The role of non-coding RNAs in bladder cancer emerged in the last decade, revealing that microRNAs (miRNAs) may act as tumor suppressor genes, respectively oncogenes, but also as biomarkers for early diagnosis. Regarding other types of non-coding RNAs, especially long non-coding RNAs (lncRNAs) which are extensively reviewed in this article, their exact roles in tumorigenesis are-for the time being-not as evident as in the case of miRNAs, but, still, clearly suggested. Therefore, this review covers the non-coding RNA expression profile of bladder cancer patients and their validated target genes in bladder cancer cell lines, with repercussions on processes such as proliferation, invasiveness, apoptosis, cell cycle arrest, and other molecular pathways which are specific for the malignant transformation of cells.

Incidental gall bladder carcinoma in laparoscopic cholecystectomy: a report of 6 cases and a review of the literature.

PubMed

Sujata, Jetley; S, Rana; Sabina, Khan; Mj, Hassan; Jairajpuri, Zeeba Shamim

2013-01-01

Gall bladder carcinoma accounts for 98% of all the gall bladder malignancies and it is the sixth most common malignancy of the gastrointestinal tract worldwide. The incidence of incidental gall bladder carcinoma which is diagnosed during or after a laparoscopic cholecystectomy is reported to be around 0.19-3.3% in the literature. This study was aimed at detecting the incidence of gall bladder carcinomas which were diagnosed incidentally during or after laparoscopic cholecystectomies which were done for gall stone disease and cholecystitis. We analyzed the medical records of patients with symptomatic gallstone disease and acute or chronic cholecystitis, who underwent laparoscopic cholecystectomies at the Hakeem Abdul Hameed Centenary Hospital during the period from January 2007 to June 2012. A total of 622 laparoscopic cholecystectomies were performed at our institute during the study period of five and a half years. In 6 (0.96%) cases, incidental carcinomas of the gallbladder were discovered. A laparoscopic cholecystectomy which is performed for benign gall bladder disease rarely results in a diagnosis of unexpected gallbladder cancer. The microscopic examination of the specimens, with special attention to the depth of invasion, range of the mucosal spread and the lymphovascular involvement, is critical in diagnosing the incidental malignancies as well as for the subsequent management of the cases.

The inverse relationship between bladder and liver in 4-aminobiphenyl-induced DNA damage

PubMed Central

Stablewski, Aimee B.; Vouros, Paul; Zhang, Yuesheng

2015-01-01

Bladder cancer risk is significantly higher in men than in women. 4-Aminobiphenyl (ABP) is a major human bladder carcinogen from tobacco smoke and other sources. In mice, male bladder is more susceptible to ABP-induced carcinogenesis than female bladder, but ABP is more carcinogenic in the livers of female mice than of male mice. Here, we show that castration causes male mice to acquire female phenotype regarding susceptibility of bladder and liver to ABP. However, spaying has little impact on organ susceptibility to ABP. Liver UDP-glucuronosyltransferases (UGTs) are believed to protect liver against but sensitize bladder to ABP, as glucuronidation of ABP and its metabolites generally reduces their toxicity and promotes their elimination via urine, but the metabolites are labile in urine, delivering carcinogenic species to the bladder. Indeed, liver expression of ABP-metabolizing human UGT1A3 transgene in mice increases bladder susceptibility to ABP. However, ABP-specific liver UGT activity is significantly higher in wild-type female mice than in their male counterparts, and castration also significantly increases ABP-specific UGT activity in the liver. Taken together, our data suggest that androgen increases bladder susceptibility to ABP via liver, likely by modulating an ABP-metabolizing liver enzyme, but exclude UGT as an important mediator. PMID:25596734

'Cutting for the stone': the ancient art of lithotomy.

PubMed

Herr, Harry W

2008-05-01

Bladder stone was a common ailment plaguing mankind from antiquity to the 20th century. Largely forgotten today, lithotomy relieved the anguish of bladder stones and identified urology as a medical specialty nearly 2500 years ago. The historical literature pertaining to lithotomy was reviewed. Translated and original documents describing operative techniques and developments pertaining to the history of lithotomy were obtained through the internet and library sources. The ancient art of lithotomy was first recorded by the Greeks and evolved through five phases: the Celsian method, or 'lesser operation'; the Marian, or 'greater operation'; the lateral operation; suprapubic cystotomy, or 'high operation', and proctocystotomy. The practice of open lithotomy ceased to exist owing to better minimally invasive alternative methods and most notably by the virtual disappearance of bladder stones in modern man. The history of lithotomy is a fascinating story of how early surgeons forced by the culture and customs of the time dealt with common but devastating bladder stones. Out of their efforts, urology was born.

Xanthogranulomatous Cystitis: A Challenging Imitator of Bladder Cancer

PubMed Central

Ekici, Sinan; Dogan Ekici, Isin; Ruacan, Sevket; Midi, Ahmet

2010-01-01

Xanthogranulomatous cystitis is a rare, benign, chronic inflammatory disease of the bladder, mimicking malignancy with unknown etiology. Herein, we report a 57-year-old man who presented with pollakiuria, nocturia, dysuria, left flank pain, and a palpable mass on the right lower abdomen. Computerized tomography demonstrated an obstructing 10-mm stone in the lower third of the left ureter and a 6-cm solid mass on the right at the anterolateral wall of the bladder. The mass presented local perivesical invasion at the anterolateral side. Cystouretroscopy revealed a mass protruding into the bladder cavity with edematous smooth surface. Frozen section analysis of the partial cystectomy specimen could not rule out malignancy. Therefore, radical cystoprostatectomy and ureterolithotomy were performed. Histologically, fibrosis, numerous plasma cells, eosinophils, and, immunohistochemically, CD68-positive epithelioid and foamy macrophages were detected. Localized prostatic adenocarcinoma was also found. The present case of xanthogranulomatous cystitis is the 23rd to be reported in the world literature. PMID:20602075

Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer.

PubMed

Korpal, Manav; Puyang, Xiaoling; Jeremy Wu, Zhenhua; Seiler, Roland; Furman, Craig; Oo, Htoo Z; Seiler, Michael; Irwin, Sean; Subramanian, Vanitha; Julie Joshi, Jaya; Wang, Chris K; Rimkunas, Victoria; Tortora, Davide; Yang, Hua; Kumar, Namita; Kuznetsov, Galina; Matijevic, Mark; Chow, Jesse; Kumar, Pavan; Zou, Jian; Feala, Jacob; Corson, Laura; Henry, Ryan; Selvaraj, Anand; Davis, Allison; Bloudoff, Kristjan; Douglas, James; Kiss, Bernhard; Roberts, Morgan; Fazli, Ladan; Black, Peter C; Fekkes, Peter; Smith, Peter G; Warmuth, Markus; Yu, Lihua; Hao, Ming-Hong; Larsen, Nicholas; Daugaard, Mads; Zhu, Ping

2017-07-24

Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. Although immunotherapies are approved for MIBC, the majority of patients fail to respond, suggesting existence of complementary immune evasion mechanisms. Here, we report that the PPARγ/RXRα pathway constitutes a tumor-intrinsic mechanism underlying immune evasion in MIBC. Recurrent mutations in RXRα at serine 427 (S427F/Y), through conformational activation of the PPARγ/RXRα heterodimer, and focal amplification/overexpression of PPARγ converge to modulate PPARγ/RXRα-dependent transcription programs. Immune cell-infiltration is controlled by activated PPARγ/RXRα that inhibits expression/secretion of inflammatory cytokines. Clinical data sets and an in vivo tumor model indicate that PPARγ High /RXRα S427F/Y impairs CD8 + T-cell infiltration and confers partial resistance to immunotherapies. Knockdown of PPARγ or RXRα and pharmacological inhibition of PPARγ significantly increase cytokine expression suggesting therapeutic approaches to reviving immunosurveillance and sensitivity to immunotherapies. Our study reveals a class of tumor cell-intrinsic "immuno-oncogenes" that modulate the immune microenvironment of cancer.Muscle-invasive bladder cancer (MIBC) is a potentially lethal disease. Here the authors characterize diverse genetic alterations in MIBC that convergently lead to constitutive activation of PPARgamma/RXRalpha and result in immunosurveillance escape by inhibiting CD8+ T-cell recruitment.

Extended lymphadenectomy in bladder cancer.

PubMed

Dorin, Ryan P; Skinner, Eila C

2010-09-01

Radical cystectomy with pelvic lymph node dissection (PLND) is the preferred treatment for invasive bladder cancer. It not only results in the best disease-free term survival rates, but also provides the most accurate disease staging and most effective local symptom control. Recent investigations have demonstrated a clinical benefit to performance of an extended PLND, including all lymphatic tissue to the level of the aortic bifurcation. This review will summarize recent findings regarding the clinical benefits of radical cystectomy with extended lymphadenectomy, and will also examine the latest surgical techniques for optimizing the performance of this technically demanding procedure. Recent studies have demonstrated increased recurrence-free survival and overall survival rates in patients undergoing radical cystectomy with extended PLND, even in cases of pathologically lymph node negative disease. The growing use of minimally invasive techniques has prompted interest in robotic radical cystectomy and extended PLND, and recent reports have demonstrated the feasibility of this technique. The standardization of extended PLND templates has also been a focus of contemporary research. Contemporary research strongly suggests that all patients undergoing radical cystectomy for bladder cancer should undergo concomitant extended PLND. Randomized trials are still needed to confirm the benefits of extended over 'standard' PLND, and to clarify which patients may receive the greatest benefit from this procedure.

Proteomic Identification of the Galectin-1-Involved Molecular Pathways in Urinary Bladder Urothelial Carcinoma.

PubMed

Li, Chien-Feng; Shen, Kun-Hung; Chien, Lan-Hsiang; Huang, Cheng-Hao; Wu, Ting-Feng; He, Hong-Lin

2018-04-19

Among various heterogeneous types of bladder tumors, urothelial carcinoma is the most prevalent lesion. Some of the urinary bladder urothelial carcinomas (UBUCs) develop local recurrence and may cause distal invasion. Galectin-1 de-regulation significantly affects cell transformation, cell proliferation, angiogenesis, and cell invasiveness. In continuation of our previous investigation on the role of galectin-1 in UBUC tumorigenesis, in this study, proteomics strategies were implemented in order to find more galectin-1-associated signaling pathways. The results of this study showed that galectin-1 knockdown could induce 15 down-regulated proteins and two up-regulated proteins in T24 cells. These de-regulated proteins might participate in lipid/amino acid/energy metabolism, cytoskeleton, cell proliferation, cell-cell interaction, cell apoptosis, metastasis, and protein degradation. The aforementioned dys-regulated proteins were confirmed by western immunoblotting. Proteomics results were further translated to prognostic markers by analyses of biopsy samples. Results of cohort studies demonstrated that over-expressions of glutamine synthetase, alcohol dehydrogenase (NADP⁺), fatty acid binding protein 4, and toll interacting protein in clinical specimens were all significantly associated with galectin-1 up-regulation. Univariate analyses showed that de-regulations of glutamine synthetase and fatty acid binding protein 4 in clinical samples were respectively linked to disease-specific survival and metastasis-free survival.

Sex differences in the MB49 syngeneic, murine model of bladder cancer

PubMed Central

White-Gilbertson, Shai; Davis, Megan; Voelkel-Johnson, Christina; Kasman, Laura M.

2016-01-01

OBJECTIVE The MB49 syngeneic, murine model of bladder cancer has been widely used for more than 35 years. In humans, bladder cancer is one third as prevalent in women as in men, with a trend toward lower prevalence in parous compared to nulliparous women. Our objective was to determine if the MB49 bladder cancer model reproduces the sex differences observed in humans, and to determine its sensitivity to testosterone and the pregnancy hormone, human chorionic gonadotropin (hCG). METHODS Male and female C57BL/6 mice were implanted with MB49 murine bladder cancer cells, and observed for tumor growth. MB49 dose responses to hCG and dihydrotestosterone were determined in vitro. RESULTS MB49 tumor growth was significantly greater in male mice than female mice. Pregnancy did not affect MB49 tumor growth in female mice. MB49 cells did not proliferate in response to hCG in vitro and the functional receptor for gonadotropins was absent. Dihydrotestosterone strongly stimulated growth of MB49 cells in vitro. CONCLUSIONS The MB49 murine model of bladder cancer reproduced some aspects of the sex differences observed in humans. Our results suggest that testosterone may stimulate MB49 cell proliferation, which may explain the more rapid MB49 tumor growth observed in male mice. PMID:26998503

Sex differences in the MB49 syngeneic, murine model of bladder cancer.

PubMed

White-Gilbertson, Shai; Davis, Megan; Voelkel-Johnson, Christina; Kasman, Laura M

The MB49 syngeneic, murine model of bladder cancer has been widely used for more than 35 years. In humans, bladder cancer is one third as prevalent in women as in men, with a trend toward lower prevalence in parous compared to nulliparous women. Our objective was to determine if the MB49 bladder cancer model reproduces the sex differences observed in humans, and to determine its sensitivity to testosterone and the pregnancy hormone, human chorionic gonadotropin (hCG). Male and female C57BL/6 mice were implanted with MB49 murine bladder cancer cells, and observed for tumor growth. MB49 dose responses to hCG and dihydrotestosterone were determined in vitro . MB49 tumor growth was significantly greater in male mice than female mice. Pregnancy did not affect MB49 tumor growth in female mice. MB49 cells did not proliferate in response to hCG in vitro and the functional receptor for gonadotropins was absent. Dihydrotestosterone strongly stimulated growth of MB49 cells in vitro . The MB49 murine model of bladder cancer reproduced some aspects of the sex differences observed in humans. Our results suggest that testosterone may stimulate MB49 cell proliferation, which may explain the more rapid MB49 tumor growth observed in male mice.

Understanding bladder management on a palliative care unit: a grounded theory study.

PubMed

Gutmanis, Iris; Hay, Melissa; Shadd, Joshua; Byrne, Janette; McCallum, Sarah; Bishop, Kristen; Whitfield, Patricia; Faulds, Cathy

2017-03-16

Research regarding factors associated with nursing-initiated changes to bladder management at end-of-life is sparse. To explore the process of Palliative Care Unit (PCU) nurses' approach to bladder management changes. Nursing staff from one PCU in London, Canada were interviewed regarding bladder management care practices. A constructivist grounded theory was generated. Four interconnected themes emerged: humanity (compassionate support of patients); journey (making the most of a finite timeline); health condition (illness, functional decline); and context (orders, policies, supplies). These overlapping themes must be considered in light of ongoing changes which prompt recycling through the framework. While bladder management necessitates shared decision-making and individualised care, nurses' phronetic experience may serve to detect the presence of change and the need to consider other alternatives. End-of-life bladder management requires nurses to continually reconsider the significance of humanity, journey, health condition and context in light of ongoing changes.

The role of muscarinic receptor subtypes on carbachol-induced contraction of normal human detrusor and overactive detrusor associated with benign prostatic hyperplasia.

PubMed

Yamanishi, Tomonori; Kaga, Kanya; Fuse, Miki; Shibata, Chiharu; Kamai, Takao; Uchiyama, Tomoyuki

2015-06-01

The aim of this study was to compare the effect of antimuscarinic antagonists on carbachol-induced contraction of normal human bladder and detrusor overactivity associated with benign prostatic hyperplasia (DO/BPH). Samples of human bladder muscle were obtained from patients undergoing total cystectomy for bladder cancer (normal bladder), and those undergoing retropubic prostatectomy for BPH. All of the patients with DO/BPH had detrusor overactivity according to urodynamic studies. Detrusor muscle strips were mounted in 10-ml organ baths containing Krebs solution, and concentration-response curves for carbachol were obtained in the presence of antimuscarinic antagonists (4-DAMP, methoctramine, pirenzepine, tolterodine, solifenacin, trospium, propiverine, oxybutynin, and imidafenacin) or vehicle. All antagonists competitively antagonized concentration-response curves to carbachol with high affinities in normal bladder. The rank order of mean pA2 values was as follows: trospium (10.1) > 4-DAMP (9.87), imidafenacin (9.3) > solifenacin (8.8) > tolterodine (8.6) > oxybutynin (8.3) > propiverine (7.7) > pirenzepine (7.4) > methoctramine (6.6). The effects of these antimuscarinic antagonists did not change when tested with DO/BPH bladder, suggesting that each antimuscarinic antagonist has a similar effect in this condition. Schild plots showed a slope corresponding to unity, except for propiverine with DO/BPH detrusor. In conclusion, M3-receptors mainly mediate contractions in human bladder strips with normal state and DO/BPH. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Analyses of publicly available genomics resources define FGF-2-expressing bladder carcinomas as EMT-prone, proliferative tumors with low mutation rates and high expression of CTLA-4, PD-1 and PD-L1.

PubMed

McNiel, Elizabeth A; Tsichlis, Philip N

2017-01-01

FGF-2 is overexpressed in a subset of invasive bladder carcinomas and its overexpression correlates with poor prognosis. Analyses of publicly available databases addressing the molecular mechanisms that may be responsible for the poor prognosis of these tumors, revealed that FGF-2 expression correlates positively with the expression of EMT-promoting transcription factors and with changes in gene expression that are characteristic of EMT. The same analyses also revealed that FGF-2 correlates negatively with the expression, mutation and copy number variations of FGFR-3, all of which are associated with non-invasive bladder carcinomas. Finally, they showed that FGF-2 expression correlates with the expression of FGFR-1, the expression of the IIIc variant of FGFR-2 and with the expression of Akt3. The latter observation is significant because our earlier studies had shown that Akt3 regulates FGFR-2 alternative splicing, shifting the balance toward the IIIc relative to the IIIb FGFR-2 splice variant. Since the IIIc variant is recognized by FGF-2, while the IIIb variant is not, we conclude that Akt3 may facilitate the FGF-2 response. FGF-2 is known to promote the expression of KDM2B, which functions in concert with EZH2 to repress the EZH2-targeting microRNA miR-101, activating a switch, which stably upregulates EZH2. TCGA data showing a correlation between KDM2B and EZH2 expression and Oncomine data, showing a correlation between KDM2B and tumor progression, strongly support the role of the FGF-2/KDM2B/miR-101/EZH2 pathway in bladder cancer. These observations combined, suggest a model according to which FGF-2 induces EMT, cell proliferation and cancer stem cell self-renewal by coupling the Akt3 and KDM2B-controlled pathways outlined above, in bladder carcinomas. Further analyses of publicly-available databases, revealed that FGF-2-expressing bladder carcinomas carry fewer genetic alterations and they tend to express high levels of CTLA-4, PD-1 and PD-L1, which suggests immune blockade by checkpoint activation. EMT, enhanced proliferation and immune checkpoint activation combined, may be responsible for the poor prognosis of FGF-2-expressing bladder carcinomas.

Bacteria and cancer: cause, coincidence or cure? A review

PubMed Central

Mager, DL

2006-01-01

Research has found that certain bacteria are associated with human cancers. Their role, however, is still unclear. Convincing evidence links some species to carcinogenesis while others appear promising in the diagnosis, prevention or treatment of cancers. The complex relationship between bacteria and humans is demonstrated by Helicobacter pylori and Salmonella typhi infections. Research has shown that H. pylori can cause gastric cancer or MALT lymphoma in some individuals. In contrast, exposure to H. pylori appears to reduce the risk of esophageal cancer in others. Salmonella typhi infection has been associated with the development of gallbladder cancer; however S. typhi is a promising carrier of therapeutic agents for melanoma, colon and bladder cancers. Thus bacterial species and their roles in particular cancers appear to differ among different individuals. Many species, however, share an important characteristic: highly site-specific colonization. This critical factor may lead to the development of non-invasive diagnostic tests, innovative treatments and cancer vaccines. PMID:16566840

Bladder Cancer in HIV-infected Adults: An Emerging Issue? Case-Reports and Systematic Review.

PubMed

Chawki, Sylvain; Ploussard, Guillaume; Montlahuc, Claire; Verine, Jérome; Mongiat-Artus, Pierre; Desgrandchamps, François; Molina, Jean-Michel

2015-01-01

Non-AIDS-related malignancies now represent a frequent cause of death among HIV-infected patients. Albeit bladder cancer is one of the most common malignancies worldwide, it has been rarely reported among HIV-infected patients. We wished to assess the prevalence and characteristics of bladder cancer in HIV-infected patients. We conducted a single center retrospective study from 1998 to 2013 in a university hospital in Paris. Cases of bladder cancer among HIV-infected patients were identified using the electronic records of the hospital database and of the HIV-infected cohort. Patient characteristics and outcomes were retrieved from patients charts. A systematic review of published cases of bladder cancers in patients with HIV-infection was also performed. During the study period we identified 15 HIV-infected patients (0.2% of the cohort) with a bladder cancer. Patients were mostly men (73%) and smokers (67%), with a median age of 56 years at cancer diagnosis. Bladder cancer was diagnosed a median of 14 years after HIV-infection. Most patients were on ART (86%) with median current and nadir CD4 cell counts of 506 and 195 cells/mm3, respectively. Haematuria (73%) was the most frequent presenting symptom and HPV-associated lesions were seen in 6/10 (60%) patients. Histopathology showed transitional cell carcinoma in 80% and a high proportion of tumors with muscle invasion (47%) and high histologic grade (73%). One-year survival rate was 74.6%. The systematic review identified 13 additional cases of urothelial bladder cancers which shared similar features. Bladder cancers in HIV-infected patients remain rare but may occur in relatively young patients with a low nadir CD4 cell count, have aggressive pathological features and can be fatal.

Bladder outlet obstruction in women: definition and characteristics.

PubMed

Groutz, A; Blaivas, J G; Chaikin, D C

2000-01-01

The prevalence of bladder outlet obstruction in women is unknown and most probably has been underestimated. Moreover, there are no standard definitions for the diagnosis of bladder outlet obstruction in women. Our study was conducted to define as well as to examine the clinical and urodynamic characteristics of bladder outlet obstruction among women referred for evaluation of voiding symptoms. Bladder outlet obstruction was defined as a persistent, low, maximum "free" flow rate of <12 mL/s in repeated non-invasive uroflow studies, combined with high detrusor pressure at a maximum flow (p(det.Q)(max) >20 cm H(2)O) during detrusor pressure-uroflow studies. A urodynamic database of 587 consecutive women identified 38 (6.5%) women with bladder outlet obstruction. The mean age of the patients was 63.9 +/- 17.5 years. The mean maximum "free" flow, voided volume, and residual urinary volume were 9.4 +/-3.9 mL/s, 144. 9 +/- 72.7 mL, and 86.1 +/- 98.8 mL, respectively. The mean p(det. Q)(max) was 37.2 +/- 19.2 cm H(2)O. Previous anti-incontinence surgery and severe genital prolapse were the most common etiologies, accounting for half of the cases. Other, less common, etiologies included urethral stricture (13%), primary bladder neck obstruction (8%), learned voiding dysfunction (5%), and detrusor external sphincter dyssynergia (5%). Symptomatology was defined as mixed obstructive and irritative in 63% of the patients, isolated irritative in 29%, and isolated obstructive in other 8%. In conclusion, bladder outlet obstruction in women appears to be more common than was previously recognized, occurring in 6.5% of our patients. Micturition symptoms relevant to bladder outlet obstruction are non-specific, and a full urodynamic evaluation is essential in making the correct diagnosis and formulating a treatment plan.

Functional and Molecular Evidence for Kv7 Channel Subtypes in Human Detrusor from Patients with and without Bladder Outflow Obstruction

PubMed Central

Svalø, Julie; Sheykhzade, Majid; Nordling, Jørgen; Matras, Christina; Bouchelouche, Pierre

2015-01-01

The aim of the study was to investigate whether Kv7 channels and their ancillary β-subunits, KCNE, are functionally expressed in the human urinary bladder. Kv7 channels were examined at the molecular level and by functional studies using RT-qPCR and myography, respectively. We found mRNA expression of KCNQ1, KCNQ3-KCNQ5 and KCNE1-5 in the human urinary bladder from patients with normal bladder function (n = 7) and in patients with bladder outflow obstruction (n = 3). Interestingly, a 3.4-fold up-regulation of KCNQ1 was observed in the latter. The Kv7 channel subtype selective modulators, ML277 (activator of Kv7.1 channels, 10 μM) and ML213 (activator of Kv7.2, Kv7.4, Kv7.4/7.5 and Kv7.5 channels, 10 μM), reduced the tone of 1 μM carbachol pre-constricted bladder strips. XE991 (blocker of Kv7.1–7.5 channels, 10 μM) had opposing effects as it increased contractions achieved with 20 mM KPSS. Furthermore, we investigated if there is interplay between Kv7 channels and β-adrenoceptors. Using cumulative additions of isoprenaline (β-adrenoceptor agonist) and forskolin (adenylyl cyclase activator) in combination with the Kv7 channel activator and blocker, retigabine and XE991, we did not find interplay between Kv7 channels and β-adrenoceptors in the human urinary bladder. The performed gene expression analysis combined with the organ bath studies imply that compounds that activate Kv7 channels could be useful for treatment of overactive bladder syndrome. PMID:25692982

Functional and molecular evidence for Kv7 channel subtypes in human detrusor from patients with and without bladder outflow obstruction.

PubMed

Svalø, Julie; Sheykhzade, Majid; Nordling, Jørgen; Matras, Christina; Bouchelouche, Pierre

2015-01-01

The aim of the study was to investigate whether Kv7 channels and their ancillary β-subunits, KCNE, are functionally expressed in the human urinary bladder. Kv7 channels were examined at the molecular level and by functional studies using RT-qPCR and myography, respectively. We found mRNA expression of KCNQ1, KCNQ3-KCNQ5 and KCNE1-5 in the human urinary bladder from patients with normal bladder function (n = 7) and in patients with bladder outflow obstruction (n = 3). Interestingly, a 3.4-fold up-regulation of KCNQ1 was observed in the latter. The Kv7 channel subtype selective modulators, ML277 (activator of Kv7.1 channels, 10 μM) and ML213 (activator of Kv7.2, Kv7.4, Kv7.4/7.5 and Kv7.5 channels, 10 μM), reduced the tone of 1 μM carbachol pre-constricted bladder strips. XE991 (blocker of Kv7.1-7.5 channels, 10 μM) had opposing effects as it increased contractions achieved with 20 mM KPSS. Furthermore, we investigated if there is interplay between Kv7 channels and β-adrenoceptors. Using cumulative additions of isoprenaline (β-adrenoceptor agonist) and forskolin (adenylyl cyclase activator) in combination with the Kv7 channel activator and blocker, retigabine and XE991, we did not find interplay between Kv7 channels and β-adrenoceptors in the human urinary bladder. The performed gene expression analysis combined with the organ bath studies imply that compounds that activate Kv7 channels could be useful for treatment of overactive bladder syndrome.

Characterization and noninvasive diagnosis of bladder cancer with serum surface enhanced Raman spectroscopy and genetic algorithms

NASA Astrophysics Data System (ADS)

Li, Shaoxin; Li, Linfang; Zeng, Qiuyao; Zhang, Yanjiao; Guo, Zhouyi; Liu, Zhiming; Jin, Mei; Su, Chengkang; Lin, Lin; Xu, Junfa; Liu, Songhao

2015-05-01

This study aims to characterize and classify serum surface-enhanced Raman spectroscopy (SERS) spectra between bladder cancer patients and normal volunteers by genetic algorithms (GAs) combined with linear discriminate analysis (LDA). Two group serum SERS spectra excited with nanoparticles are collected from healthy volunteers (n = 36) and bladder cancer patients (n = 55). Six diagnostic Raman bands in the regions of 481-486, 682-687, 1018-1034, 1313-1323, 1450-1459 and 1582-1587 cm-1 related to proteins, nucleic acids and lipids are picked out with the GAs and LDA. By the diagnostic models built with the identified six Raman bands, the improved diagnostic sensitivity of 90.9% and specificity of 100% were acquired for classifying bladder cancer patients from normal serum SERS spectra. The results are superior to the sensitivity of 74.6% and specificity of 97.2% obtained with principal component analysis by the same serum SERS spectra dataset. Receiver operating characteristic (ROC) curves further confirmed the efficiency of diagnostic algorithm based on GA-LDA technique. This exploratory work demonstrates that the serum SERS associated with GA-LDA technique has enormous potential to characterize and non-invasively detect bladder cancer through peripheral blood.

Voided urine versus bladder washing cytology for detection of urothelial carcinoma: which is better?

PubMed

Keller, Anna Krarup; Jensen, Jørgen Bjerggaard

2017-08-01

Cytology is recommended as part of the follow-up of high-grade non-muscle-invasive bladder cancer (NMIBC). However, currently there are no solid guideline recommendations regarding the use of voided urine versus bladder washing for cytology as part of the diagnosis or follow-up of NMIBC. The aim of this study was to investigate whether the cytological outcome was equal regarding the two techniques. The authors reviewed all outpatient flexible cystoscopies carried out in their department in 2013. Patient records in the registry of pathology were examined and those with simultaneous urine and bladder washing cytology were included. Previous urothelial disease and positive histology within 3 months after the cystoscopy were registered. A total of 1458 patients had both voided urine and bladder washing cytology and were included in the study, of whom 643 (44%) had a history of urothelial disease. An equal outcome of urine and bladder washing cytology was found in 1447 patients (99.2%). For the remaining 11 patients, only four patients underwent further examinations based on cytology findings in addition to what had already been planned after cystoscopy. Of the included patients, 100 (6.9%) had a positive histological outcome within 3 months. In most patients, no relevant difference between voided urine and bladder washing cytology was observed. Therefore, if cytology is indicated, it is recommended to use the test that is most readily available locally. The additional gain in using both urine and bladder wash is minimal, and can therefore be discarded.

Inverse expression of estrogen receptor-beta and nuclear factor-kappaB in urinary bladder carcinogenesis.

PubMed

Kontos, Stylianos; Kominea, Athina; Melachrinou, Maria; Balampani, Eleni; Sotiropoulou-Bonikou, Georgia

2010-09-01

To investigate the expression of nuclear factor-kappaB (NF-kappaB) and estrogen receptor-beta (ER-beta) signalling pathways in bladder urothelial carcinoma according to clinicopathological features, in order to elucidate their role during carcinogenesis. Immunohistochemical methodology was carried out on formalin-fixed, paraffin-embedded sections from urinary bladder carcinomas of 140 patients (94 males and 46 females) who underwent transurethral resection of bladder neoplasms. Correlations between ER-beta and NF-kappaB, and tumor grade and T-stage were evaluated, along with demographic data, sex and age. A significant decrease in ER-beta expression in the nucleus of bladder cells during loss of cell differentiation (r(s) = -0.61, P-value < 0.001, test of trend P-value = 0.003) and in muscle invasive carcinomas (T2-T4; test of trend P-value < 0.001) was found. p65 Subunit of NF-kappaB was expressed in the nucleus and in the cytoplasm of bladder epithelial cells. A strong positive association between tumor grade and nuclear expression of NF-kappaB was shown. No correlation between NF-kappaB, nuclear or cytoplasmic staining, with T-stage was observed. An inverse correlation between ER-beta and nuclear p65 immunoreactivity was observed (r(s) = -0.45, P-value < 0.001). There was no correlation with demographic data. Our immunohistochemical study suggests the possible inverse regulation of NF-kappaB and ER-beta transcription factor during bladder carcinogenesis. Selective ER-beta agonists and agents, inhibitors of NF-kappaB, might represent a possible new treatment strategy for bladder urothelial tumors.

The stem cell growth factor receptor KIT is not expressed on interstitial cells in bladder.

PubMed

Gevaert, Thomas; Ridder, Dirk De; Vanstreels, Els; Daelemans, Dirk; Everaerts, Wouter; Aa, Frank Van Der; Pintelon, Isabel; Timmermans, Jean-Pierre; Roskams, Tania; Steiner, Clara; Neuhaus, Jochen

2017-06-01

The mast/stem cell growth factor receptor KIT has long been assumed to be a specific marker for interstitial cells of Cajal (ICC) in the bladder, with possible druggable perspectives. However, several authors have challenged the presence of KIT + ICC in recent years. The aim of this study was therefore to attempt to clarify the conflicting reports on KIT expression in the bladder of human beings, rat, mouse and guinea pig and to elucidate the possible role of antibody-related issues and interspecies differences in this matter. Fresh samples were obtained from human, rat, mouse and guinea pig cystectomies and processed for single/double immunohistochemistry/immunofluorescence. Specific antibodies against KIT, mast cell tryptase (MCT), anoctamin-1 (ANO1) and vimentin were used to characterize the cell types expressing KIT. Gut (jejunum) tissue was used as an external antibody control. Our results revealed KIT expression on mast cells but not on ICC in human, rat, mouse and guinea pig bladder. Parallel immunohistochemistry showed KIT expression on ICC in human, rat, mouse and guinea pig gut, which confirmed the selectivity of the KIT antibody clones. In conclusion, we have shown that KIT + cells in human, rat, mouse and guinea pig bladder are mast cells and not ICC. The present report is important as it opposes the idea that KIT + ICC are present in bladder. In this perspective, functional concepts of KIT + ICC being involved in sensory and/or motor aspects of bladder physiology should be revised. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Population-based assessment of racial/ethnic differences in utilization of radical cystectomy for patients diagnosed with bladder cancer.

PubMed

Williams, Stephen B; Huo, Jinhai; Kosarek, Christopher D; Chamie, Karim; Rogers, Selwyn O; Williams, Michele A; Giordano, Sharon H; Kim, Simon P; Kamat, Ashish M

2017-07-01

Radical cystectomy is a surgical treatment for recurrent non-muscle-invasive and muscle-invasive bladder cancer; however, many patients may not receive this treatment. A total of 27,578 patients diagnosed with clinical stage I-IV bladder cancer from 1 January 2007 to 31 December 2013 were identified from the Surveillance, Epidemiology, and End Results (SEER) registry database. We used multivariable regression analyses to identify factors predicting the use of radical cystectomy and pelvic lymph node dissection. Cox proportional hazards models were used to analyze survival outcomes. A total of 1,693 (6.1%) patients with bladder cancer underwent radical cystectomy. Most patients (92.4%) who underwent radical cystectomy also underwent pelvic lymph node dissection. When compared with white patients, non-Hispanic blacks were less likely to undergo a radical cystectomy [odds ratio (OR) 0.79, 95% confidence interval (CI) 0.64-0.96, p = 0.019]. Moreover, recent year of surgery 2013 versus 2007 (OR 2.32, 95% CI 1.90-2.83, p < 0.001), greater percentage of college education ≥36.3 versus <21.3% (OR 1.23, 95% CI 1.04-1.44, p = 0.013), Midwest versus West (OR 1.64, 95% CI 1.39-1.94, p < 0.001), and more advanced clinical stage III versus I (OR 29.1, 95% CI 23.9-35.3, p < 0.001) were associated with increased use of radical cystectomy. Overall survival was improved for patients who underwent radical cystectomy compared with those who did not undergo a radical cystectomy (hazard ratio 0.88, 95% CI 0.80-0.97, p = 0.008). There is significant underutilization of radical cystectomy in patients across all age groups diagnosed with bladder cancer, especially among older, non-Hispanic black patients.

Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry

PubMed Central

Figueroa, Jonine D.; Middlebrooks, Candace D.; Banday, A. Rouf; Ye, Yuanqing; Garcia-Closas, Montserrat; Chatterjee, Nilanjan; Koutros, Stella; Kiemeney, Lambertus A.; Rafnar, Thorunn; Bishop, Timothy; Furberg, Helena; Matullo, Giuseppe; Golka, Klaus; Gago-Dominguez, Manuela; Taylor, Jack A.; Fletcher, Tony; Siddiq, Afshan; Cortessis, Victoria K.; Kooperberg, Charles; Cussenot, Olivier; Benhamou, Simone; Prescott, Jennifer; Porru, Stefano; Dinney, Colin P.; Malats, Núria; Baris, Dalsu; Purdue, Mark P.; Jacobs, Eric J.; Albanes, Demetrius; Wang, Zhaoming; Chung, Charles C.; Vermeulen, Sita H.; Aben, Katja K.; Galesloot, Tessel E.; Thorleifsson, Gudmar; Sulem, Patrick; Stefansson, Kari; Kiltie, Anne E.; Harland, Mark; Teo, Mark; Offit, Kenneth; Vijai, Joseph; Bajorin, Dean; Kopp, Ryan; Fiorito, Giovanni; Guarrera, Simonetta; Sacerdote, Carlotta; Selinski, Silvia; Hengstler, Jan G.; Gerullis, Holger; Ovsiannikov, Daniel; Blaszkewicz, Meinolf; Castelao, Jose Esteban; Calaza, Manuel; Martinez, Maria Elena; Cordeiro, Patricia; Xu, Zongli; Panduri, Vijayalakshmi; Kumar, Rajiv; Gurzau, Eugene; Koppova, Kvetoslava; Bueno-De-Mesquita, H. Bas; Ljungberg, Börje; Clavel-Chapelon, Françoise; Weiderpass, Elisabete; Krogh, Vittorio; Dorronsoro, Miren; Travis, Ruth C.; Tjønneland, Anne; Brennan, Paul; Chang-Claude, Jenny; Riboli, Elio; Conti, David; Stern, Marianna C.; Pike, Malcolm C.; Van Den Berg, David; Yuan, Jian-Min; Hohensee, Chancellor; Jeppson, Rebecca P.; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva; Turman, Constance; De Vivo, Immaculata; Giovannucci, Edward; Hunter, David J.; Kraft, Peter; Lindstrom, Sara; Carta, Angela; Pavanello, Sofia; Arici, Cecilia; Mastrangelo, Giuseppe; Kamat, Ashish M.; Zhang, Liren; Gong, Yilei; Pu, Xia; Hutchinson, Amy; Burdett, Laurie; Wheeler, William A.; Karagas, Margaret R.; Johnson, Alison; Schned, Alan; Monawar Hosain, G. M.; Schwenn, Molly; Kogevinas, Manolis; Tardón, Adonina; Serra, Consol; Carrato, Alfredo; García-Closas, Reina; Lloreta, Josep; Andriole, Gerald; Grubb, Robert; Black, Amanda; Diver, W. Ryan; Gapstur, Susan M.; Weinstein, Stephanie; Virtamo, Jarmo; Haiman, Christopher A.; Landi, Maria Teresa; Caporaso, Neil E.; Fraumeni, Joseph F.; Vineis, Paolo; Wu, Xifeng; Chanock, Stephen J.; Silverman, Debra T.; Prokunina-Olsson, Ludmila; Rothman, Nathaniel

2016-01-01

Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10−6), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10−11) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10−10). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region—the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r2 = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case–case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer. PMID:26732427

Identification of differentially expressed proteins during human urinary bladder cancer progression.

PubMed

Memon, Ashfaque A; Chang, Jong W; Oh, Bong R; Yoo, Yung J

2005-01-01

Comparative proteome analysis was performed between RT4 (grade-1) and T24 (grade-3) bladder cancer cell lines, in an attempt to identify differentially expressed proteins during bladder cancer progression. Among those relatively abundant proteins, seven spots changed more than two-fold reproducibly and identified by peptide mass fingerprinting using mass spectrometry and database search. We found most extensive and reproducible down-regulation of NADP dependent isocitrate dehydrogenase cytoplasmic (IDPc) and peroxiredoxin-II (Prx-II), in poorly differentiated T24 compared to well-differentiated RT4 bladder cancer cell line. Subsequent Western blotting analysis of human biopsy samples from bladder cancer patient revealed significant loss of IDPc and Prx-II in more advance tumor samples, in agreement with data on cell lines. These results suggest that loss of IDPc and Prx-II during tumor development may involve in tumor progression and metastasis. However, additional investigations are needed on large number of human samples to further verify these findings.

Effect of (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective beta3-adrenoceptor agonist, on bladder function.

PubMed

Takasu, Toshiyuki; Ukai, Masashi; Sato, Shuichi; Matsui, Tetsuo; Nagase, Itsuro; Maruyama, Tatsuya; Sasamata, Masao; Miyata, Keiji; Uchida, Hisashi; Yamaguchi, Osamu

2007-05-01

We evaluated the pharmacological characteristics of (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenylethyl)amino]-ethyl} acetanilide (YM178). YM178 increased cyclic AMP accumulation in Chinese hamster ovary (CHO) cells expressing human beta3-adrenoceptor (AR). The half-maximal effective concentration (EC50) value was 22.4 nM. EC50 values of YM178 for human beta1- and beta2-ARs were 10,000 nM or more, respectively. The ratio of intrinsic activities of YM178 versus maximal response induced by isoproterenol (nonselective beta-AR agonist) was 0.8 for human beta3-ARs, 0.1 for human beta1-ARs, and 0.1 for human beta2-ARs. The relaxant effects of YM178 were evaluated in rats and humans bladder strips precontracted with carbachol (CCh) and compared with those of isoproterenol and 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (CGP-12177A) (beta3-AR agonist). EC50 values of YM178 and isoproterenol in rat bladder strips precontracted with 10(-6) M CCh were 5.1 and 1.4 microM, respectively, whereas those in human bladder strips precontracted with 10(-7) M CCh were 0.78 and 0.28 microM, respectively. In in vivo study, YM178 at a dose of 3 mg/kg i.v. decreased the frequency of rhythmic bladder contraction induced by intravesical filling with saline without suppressing its amplitude in anesthetized rats. These findings suggest the suitability of YM178 as a therapeutic drug for the treatment of symptoms of overactive bladder such as urinary frequency, urgency, and urge incontinence.

Mechanisms of Progranulin Action and Regulation in Genitourinary Cancers.

PubMed

Tanimoto, Ryuta; Lu, Kuojung G; Xu, Shi-Qiong; Buraschi, Simone; Belfiore, Antonino; Iozzo, Renato V; Morrione, Andrea

2016-01-01

The growth factor progranulin has emerged in recent years as a critical regulator of transformation in several cancer models, including breast cancer, glioblastomas, leukemias, and hepatocellular carcinomas. Several laboratories, including ours, have also demonstrated an important role of progranulin in several genitourinary cancers, including ovarian, endometrial, cervical, prostate, and bladder tumors, where progranulin acts as an autocrine growth factor thereby modulating motility and invasion of transformed cells. In this review, we will focus on the mechanisms of action and regulation of progranulin signaling in genitourinary cancers with a special emphasis on prostate and bladder tumors.

Mechanisms of Progranulin Action and Regulation in Genitourinary Cancers

PubMed Central

Tanimoto, Ryuta; Lu, Kuojung G.; Xu, Shi-Qiong; Buraschi, Simone; Belfiore, Antonino; Iozzo, Renato V.; Morrione, Andrea

2016-01-01

The growth factor progranulin has emerged in recent years as a critical regulator of transformation in several cancer models, including breast cancer, glioblastomas, leukemias, and hepatocellular carcinomas. Several laboratories, including ours, have also demonstrated an important role of progranulin in several genitourinary cancers, including ovarian, endometrial, cervical, prostate, and bladder tumors, where progranulin acts as an autocrine growth factor thereby modulating motility and invasion of transformed cells. In this review, we will focus on the mechanisms of action and regulation of progranulin signaling in genitourinary cancers with a special emphasis on prostate and bladder tumors. PMID:27512385

The Urinary Bladder Transcriptome and Proteome Defined by Transcriptomics and Antibody-Based Profiling

PubMed Central

Habuka, Masato; Fagerberg, Linn; Hallström, Björn M.; Pontén, Fredrik; Yamamoto, Tadashi; Uhlen, Mathias

2015-01-01

To understand functions and diseases of urinary bladder, it is important to define its molecular constituents and their roles in urinary bladder biology. Here, we performed genome-wide deep RNA sequencing analysis of human urinary bladder samples and identified genes up-regulated in the urinary bladder by comparing the transcriptome data to those of all other major human tissue types. 90 protein-coding genes were elevated in the urinary bladder, either with enhanced expression uniquely in the urinary bladder or elevated expression together with at least one other tissue (group enriched). We further examined the localization of these proteins by immunohistochemistry and tissue microarrays and 20 of these 90 proteins were localized to the whole urothelium with a majority not yet described in the context of the urinary bladder. Four additional proteins were found specifically in the umbrella cells (Uroplakin 1a, 2, 3a, and 3b), and three in the intermediate/basal cells (KRT17, PCP4L1 and ATP1A4). 61 of the 90 elevated genes have not been previously described in the context of urinary bladder and the corresponding proteins are interesting targets for more in-depth studies. In summary, an integrated omics approach using transcriptomics and antibody-based profiling has been used to define a comprehensive list of proteins elevated in the urinary bladder. PMID:26694548

Clinical utility of urinary soluble Fas in screening for bladder cancer.

PubMed

Srivastava, Anupam Kumar; Singh, Pankaj Kumar; Singh, Dhramveer; Dalela, Divakar; Rath, Srikanta Kumar; Bhatt, Madan Lal Brahma

2016-06-01

Early diagnosis of carcinoma of urinary bladder remains a challenge. Urine cytology, as an adjunct to cystoscopy, is less sensitive for low-grade tumors. Soluble Fas (sFas), a cell-surface receptor and member of the tumor necrosis factor superfamily, is frequently expressed in urinary bladder carcinoma. The objective of this study was to investigate the urinary sFas for diagnosis of transitional cell carcinoma (TCC) of urinary bladder. We examined urinary sFas concentration in 74 controls and 117 cases of TCC, both primary and recurrent disease, by using enzyme-linked immunosorbent assay and compared it with urinary cytology. Urinary sFas concentration was found to be significantly higher in the patient as compared to control group (P < 0.05). An optimal cutoff value of 174.0 pg/mL was proposed. The urinary sFas level was found to have an approximate sensitivity and specificity of 88.03% and 89.19% (P < 0.001), whereas urine cytology had sensitivity of 66.67% and specificity of 95.95%. sFas had better sensitivity in higher grade and both primary and recurrent cases of urinary bladder cancer in comparison with cytology. Out of 15 node positive bladder cancer cases, 13 had high urinary sFas levels, whereas 12 were urinary cytology positive for malignancy. Urinary sFas can be used as a non-invasive diagnostic biomarker for TCC of urinary bladder, both for primary and recurrent disease. © 2014 Wiley Publishing Asia Pty Ltd.

Effect of routine repeat transurethral resection for superficial bladder cancer: a long-term observational study.

PubMed

Grimm, Marc-Oliver; Steinhoff, Christine; Simon, Xenia; Spiegelhalder, Philipp; Ackermann, Rolf; Vogeli, Thomas Alexander

2003-08-01

We determined the long-term outcome in patients with superficial bladder cancer (Ta and T1) undergoing routine second transurethral bladder tumor resection (ReTURB) in regard to recurrence and progression. We performed an inception cohort study of 124 consecutive patients with superficial bladder cancer undergoing transurethral resection and routine ReTURB (83) between November 1993 and October 1995 at a German university hospital. Immediately after transurethral resection all lesions were documented on a designed bladder map. ReTURB of the scar from initial resection and other suspicious lesions was performed at a mean of 7 weeks. Patients were followed until recurrence or death, or a minimum of 5 years. Residual tumor was found in 33% of all ReTURB cases, including 27% of Ta and 53% of T1 disease, and in 81% at the initial resection site. Five of the 83 patients underwent radical cystectomy due to ReTURB findings. The estimated risk of recurrence after years 1 to 3 was 18%, 29% and 32%, respectively. After 5 years 63% of the patients undergoing ReTURB were still disease-free (mean recurrence-free survival 62 months, median 87). Progression to muscle invasive disease was observed in only 2 patients (3%) after a mean observation of 61 months. These data suggest a favorable outcome regarding recurrence and progression in patients with superficial bladder cancer who undergo ReTURB. ReTURB is suggested at least in those at high risk when bladder preservation is intended.

Prompt diagnosis key in bladder cancer.

PubMed

DeSouza, Karen; Chowdhury, Simon; Hughes, Simon

2014-01-01

Bladder cancer is the most frequently diagnosed cancer involving the urinary tract and is the seventh most common cancer in the UK. Delayed diagnosis is associated with high-grade muscle invasive disease which has the potential to progress rapidly, metastasise and is often fatal. Urothelial cancer (transitional cell carcinoma) is the predominant histological subtype in Europe, where it accounts for 90% of all bladder cancers. Haematuria, which is typically intermittent, frank, painless and at times present throughout micturition, is the classical and most common presentation of bladder cancer. However, irritative symptoms such as dysuria, urgency, urge incontinence and frequency as well as obstructive symptoms can also be experienced. Fatigue; weight loss; anorexia; renal failure; respiratory symptoms and a suprapubic palpable mass are usually signs of advanced or metastatic malignancy. Cigarette smokers have up to four times the risk of bladder cancer compared with non-smokers. Other risk factors include: exposure to aniline dyes; use of cyclophosphamide; history of pelvic radiation; exposure to chemical carcinogens associated with certain industries; spinal cord injuries requiring long-term indwelling catheters; type 2 diabetes treated with pioglitazone and condylomata acuminata. Frank haematuria has a high diagnostic yield for malignancies involving the urinary tract and initial routine tests should be directed towards identifying a variety of potential non-malignant causes. A thorough physical examination should be undertaken to identify evidence of bleeding diathesis and metastatic malignancy. Suggested laboratory investigations include FBC, coagulation, creatinine and PSA. The diagnosis of bladder cancer is based on urine cytology, cystoscopy and pathological assessment of the bladder biopsy.

MX-INDUCED URINARY BLADDER EPITHELIAL HYPERPLASIA IN EKER RATS

EPA Science Inventory

MX-INDUCED URINARY BLADDER EPITHELIAL HYPERPLASIA IN EKER RATS

Epidemiological studies have shown a positive association between chronic exposure to chlorinated drinking water and human cancer, particularly of the urinary bladder. MX (3- chloro-4-(dichloromethyl)-5-hydrox...

Intrafraction Bladder Motion in Radiation Therapy Estimated From Pretreatment and Posttreatment Volumetric Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Foroudi, Farshad, E-mail: farshad.foroudi@petermac.org; Pham, Daniel; Bressel, Mathias

2013-05-01

Purpose: The use of image guidance protocols using soft tissue anatomy identification before treatment can reduce interfractional variation. This makes intrafraction clinical target volume (CTV) to planning target volume (PTV) changes more important, including those resulting from intrafraction bladder filling and motion. The purpose of this study was to investigate the required intrafraction margins for soft tissue image guidance from pretreatment and posttreatment volumetric imaging. Methods and Materials: Fifty patients with muscle-invasive bladder cancer (T2-T4) underwent an adaptive radiation therapy protocol using daily pretreatment cone beam computed tomography (CBCT) with weekly posttreatment CBCT. A total of 235 pairs of pretreatmentmore » and posttreatment CBCT images were retrospectively contoured by a single radiation oncologist (CBCT-CTV). The maximum bladder displacement was measured according to the patient's bony pelvis movement during treatment, intrafraction bladder filling, and bladder centroid motion. Results: The mean time between pretreatment and posttreatment CBCT was 13 minutes, 52 seconds (range, 7 min 52 sec to 30 min 56 sec). Taking into account patient motion, bladder centroid motion, and bladder filling, the required margins to cover intrafraction changes from pretreatment to posttreatment in the superior, inferior, right, left, anterior, and posterior were 1.25 cm (range, 1.19-1.50 cm), 0.67 cm (range, 0.58-1.12 cm), 0.74 cm (range, 0.59-0.94 cm), 0.73 cm (range, 0.51-1.00 cm), 1.20 cm (range, 0.85-1.32 cm), and 0.86 cm (range, 0.73-0.99), respectively. Small bladders on pretreatment imaging had relatively the largest increase in pretreatment to posttreatment volume. Conclusion: Intrafraction motion of the bladder based on pretreatment and posttreatment bladder imaging can be significant particularly in the anterior and superior directions. Patient motion, bladder centroid motion, and bladder filling all contribute to changes between pretreatment and posttreatment imaging. Asymmetric expansion of CTV to PTV should be considered. Care is required in using image-guided radiation therapy protocols that reduce CTV to PTV margins based only on daily pretreatment soft tissue position.« less

Tibial nerve stimulation for overactive bladder syndrome unresponsive to medical therapy.

PubMed

Ridout, A E; Yoong, W

2010-02-01

Overactive bladder syndrome is defined as a symptom syndrome which includes urinary urgency, with or without urge incontinence, usually accompanied by frequency (>8 micturitions/24 h) and nocturia. Conservative treatment usually comprises behavioural techniques, bladder retraining, pelvic floor re-education and pharmacotherapy but up to 30% of patients will remain refractory to treatment. Although second-line treatment options such as sacral nerve stimulation and intravesical botulinum A injections are valuable additions to the therapeutic arsenal, they are relatively invasive and can have serious side-effects. Inhibition of detrusor activity by peripheral neuromodulation of the posterior tibial nerve was first described in 1983, with recent authors further confirming a 60-80% positive response rate. This review was undertaken to examine published literature on percutaneous tibial nerve stimulation and to discuss outcome measures, maintenance therapy and prognostic factors of this technique.

Bladder exstrophy-epispadias complex and triple-X syndrome: incidental finding or causality?

PubMed

Ramaekers, Paul; Loeys, Bart; von Lowtzow, Catharina; Reutter, Heiko; Leroy, Yves; Colpaert, Cécile; Blaumeiser, Bettina; Janssens, Katrien; Parizel, Maxim; Jacquemyn, Yves

2014-10-01

Bladder exstrophy is a rare malformation. Prenatal diagnosis is usually an incidental finding on routine ultrasound examination. Triple-X syndrome (karyotype 47,XXX) is the most frequent sex chromosome aneuploidy in live-born females (approximately 1 in 1000). The diagnosis is often not made because women with 47,XXX karyotype have no or hardly any clinical symptoms during life. Prenatal diagnosis of triple X karyotype is usually an incidental finding when an invasive prenatal diagnosis is performed for other reasons. Here, we report on two cases with bladder exstrophy and triple-X syndrome, one in a fetus and one in an adult. In view of two previous reports of this association in literature, causality of these two conditions should be considered. A gene dosage effect as possible underlying mechanisms will be discussed. © 2014 Wiley Periodicals, Inc.

Recommended oral sodium bicarbonate administration for urine alkalinization did not affect the concentration of mitomycin-C in non-muscle invasive bladder cancer patients.

PubMed

Seo, Ho Kyung; Kim, Sung Han; Ahn, Kyung-Ohk; Lee, Sang-Jin; Park, Weon Seo; Kim, Sohee; Hwang, Sang-Hyun; Lee, Do Hoon; Joung, Jae Young; Chung, Jinsoo; Joo, Jungnam; Jeong, Kyung-Chae

2017-11-10

Sodium bicarbonate has been reported to maximize the efficacy of intravesical instillation of mitomycin-C (IVI-MMC) therapy by urine alkalinization in non-muscle-invasive bladder cancer (NMIBC). This study aimed to analyze the changes in MMC concentration according to urinary pH and evaluate the efficacy of sodium bicarbonate to maintain the concentration of active form of MMC during IVI-MMC. We prospectively enrolled 26 patients with NMIBC after transurethral resection of bladder tumor. Patients with very high-risk and low-risk NMIBC were excluded. Urinary creatinine, volume, pH, and concentrations of MMC and its degraded form were measured immediately before and after IVI-MMC. The patients were administered 1.5 g of oral sodium bicarbonate during the preceding evening, in the morning, and immediately before the fourth cycle of the six-cycle IVI-MMC. The correlation between MMC concentration and urinary pH changes was explored with or without oral bicarbonate therapy. Recurrence without progression to muscle-invasive disease was noted in 4 of 26 patients in a 23.7-month follow-up. The mean urinary pH before and after the therapy increased from 6.03 to 6.50, and 6.46 to 7.24, without or with oral SB therapy, respectively. Despite this increase, the concentration of active form of MMC did not change significantly. No correlation was found between urinary pH and MMC concentration. Urine alkalinization by SB administration did not maintain the high concentration of urinary MMC. Urine alkalinization by sodium bicarbonate administration for IVI-MMC did not maintain the high concentration of active urinary MMC in NMIBC.

Upper Tract Urothelial Carcinomas Accompanied by Previous or Synchronous Nonmuscle-Invasive Bladder Cancer and Preoperative Hydronephrosis Might Have Worse Oncologic Outcomes After Radical Nephroureterectomy.

PubMed

Liang, Chengcai; Chi, Runmin; Huang, Liqun; Wang, Jinliang; Liu, Hailong; Xu, Ding; Qian, Subo; Qian, Xiaoqiang; Qi, Jun

2016-10-01

The purpose of the study was to identify predictors of clinicopathologic features and oncologic outcomes in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy (RNU). The medical records of 172 patients treated with RNU from January 2001 to September 2014 were retrospectively reviewed. Logistic regression and survival analysis methodology were respectively used to evaluate predictors of clinicopathologic features and oncologic outcomes. Of the enrolled 172 patients, 80 (46.5%) had renal pelvic tumors, 67 (39%) had ureteral tumors, and the remaining 25 (14.5%) patients had multifocal tumors. Compared with patients with renal pelvic tumors, those with ureteral and multifocal tumors were more likely to have previous or synchronous nonmuscle-invasive bladder cancer (NMIBC) and severe hydronephrosis (P = .001 and P < .001, respectively). Logistic regression analysis showed that previous or synchronous NMIBC was significantly associated with worse renal function and high grade (P = .034 and P = .014, respectively), and severe hydronephrosis independently predicted worse renal function and positive lymph node or lymphovascular invasion status (P = .001 and P = .007, respectively). Moreover, severe hydronephrosis was an independent risk factor for overall survival and cancer-specific survival in multivariate analysis (P = .025 and P = .045, respectively). Multifocality and previous or synchronous NMIBC were significantly associated with bladder-recurrence-free survival (P = .023 and P = .001, respectively). Upper tract urothelial carcinoma accompanied by previous or synchronous NMIBC and preoperative severe hydronephrosis could have worse oncologic outcomes after RNU. These common accompanied diagnoses could be valuable for guiding preoperative planning and postoperative adjuvant therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

Anti-inflammatory use may not negatively impact oncologic outcomes following intravesical BCG for high-grade non-muscle-invasive bladder cancer.

PubMed

Singla, Nirmish; Haddad, Ahmed Q; Passoni, Niccolo M; Meissner, Matthew; Lotan, Yair

2017-01-01

To evaluate whether anti-inflammatory agents affect outcomes in patients receiving intravesical BCG therapy for high-grade (HG) non-muscle-invasive bladder cancer (NMIBC). We reviewed the records of 203 patients in a prospective database of HG NMIBC from 2006 to 2012 at a single institution. Patients who had muscle-invasive disease (n = 32), low-grade pathology (n = 4), underwent early cystectomy within 3 months (n = 25), had <3 months of follow-up (n = 11), or did not receive an induction course of intravesical BCG (n = 32) were excluded. Clinicopathologic data were tabulated including demographics, comorbidities, pathologic stage and grades, intravesical therapy, and concomitant use of aspirin, NSAIDs, COX inhibitors, and statins. Multivariate Cox regression analysis explored predictive factors for recurrence, progression (stage progression or progression to cystectomy), cancer-specific survival (CSS), and overall survival (OS). Ninety-nine patients with HG NMIBC who received at least one induction course of intravesical BCG were identified, with median follow-up of 31.4 months. There were 20 (20.2 %) deaths, including 6 (6.1 %) patients with bladder cancer-related mortality. 13 % patients experienced tumor progression and 27 % underwent cystectomy following failure of intravesical therapy. Anti-inflammatory use included statins (65 %), aspirin (63 %), or non-aspirin NSAIDs/COX inhibitors (26 %). Anti-inflammatory use was not significantly predictive of recurrence, progression, or mortality outcomes on Cox regression. CIS stage was associated with higher progression, while age, BMI, and Charlson score were independent predictors of overall mortality. Despite speculation of inhibitory effects on BCG immunomodulation there was no evidence that anti-inflammatory agents impacted oncologic outcomes in patients receiving BCG for HG NMIBC.

Clinical course of a cohort of children with non-neurogenic daytime urinary incontinence symptoms followed at a tertiary center.

PubMed

Lebl, Adrienne; Fagundes, Simone Nascimento; Koch, Vera Hermina Kalika

2016-01-01

To characterize a cohort of children with non-neurogenic daytime urinary incontinence followed-up in a tertiary center. Retrospective analysis of 50 medical records of children who had attained bladder control or minimum age of 5 years, using a structured protocol that included lower urinary tract dysfunction symptoms, comorbidities, associated manifestations, physical examination, voiding diary, complementary tests, therapeutic options, and clinical outcome, in accordance with the 2006 and 2014 International Children's Continence Society standardizations. Female patients represented 86.0% of this sample. Mean age was 7.9 years and mean follow-up was 4.7 years. Urgency (56.0%), urgency incontinence (56.0%), urinary retention (8.0%), nocturnal enuresis (70.0%), urinary tract infections (62.0%), constipation (62.0%), and fecal incontinence (16.0%) were the most prevalent symptoms and comorbidities. Ultrasound examinations showed alterations in 53.0% of the cases; the urodynamic study showed alterations in 94.7%. At the last follow-up, 32.0% of patients persisted with urinary incontinence. When assessing the diagnostic methods, 85% concordance was observed between the predictive diagnosis of overactive bladder attained through medical history plus non-invasive exams and the diagnosis of detrusor overactivity achieved through the invasive urodynamic study. This subgroup of patients with clinical characteristics of an overactive bladder, with no history of urinary tract infection, and normal urinary tract ultrasound and uroflowmetry, could start treatment without invasive studies even at a tertiary center. Approximately one-third of the patients treated at the tertiary level remained refractory to treatment. Copyright © 2015 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Chloroquine and hydroxychloroquine inhibit bladder cancer cell growth by targeting basal autophagy and enhancing apoptosis.

PubMed

Lin, Yi-Chia; Lin, Ji-Fan; Wen, Sheng-I; Yang, Shan-Che; Tsai, Te-Fu; Chen, Hung-En; Chou, Kuang-Yu; Hwang, Thomas I-Sheng

2017-05-01

Chloroquine (CQ) and hydroxychloroquine (HCQ), two antimalarial drugs, are suggested to have potential anticancer properties. in the present study, we investigated the effects of CQ and HCQ on cell growth of bladder cancer with emphasis on autophagy inhibition and apoptosis induction in vitro. The results showed that CQ and HCQ inhibited the proliferation of multiple human bladder cell lines (including RT4, 5637, and T24) in a time- and dose-dependent fashion, especially in advanced bladder cancer cell lines (5637 and T24) compared to immortalized uroepithelial cells (SV-Huc-1) or other reference cancer cell lines (PC3 and MCF-7). We found that 24-hour treatment of CQ or HCQ significantly decreased the clonogenic formation in 5637 and T24 cells compared to SV-Huc-1. As human bladder cancer tumor exhibits high basal level of autophagic activities, we detected the autophagic flux in cells treated with CQ and HCQ, showing an alternation in LC3 flux in CQ- or HCQ-treated cells. Moreover, bladder cancer cells treated with CQ and HCQ underwent apoptosis, resulting in increased caspase 3/7 activities, increased level of cleaved poly(ADP-ribose) polymerase (PARP), caspase 3, and DNA fragmentation. Given these results, targeting autophagy with CQ and HCQ represents an effective cancer therapeutic strategy against human bladder cancer. Copyright © 2017. Published by Elsevier Taiwan.

Current status of tissue engineering applied to bladder reconstruction in humans.

PubMed

Gasanz, C; Raventós, C; Morote, J

2018-01-11

Bladder reconstruction is performed to replace or expand the bladder. The intestine is used in standard clinical practice for tissue in this procedure. The complications of bladder reconstruction range from those of intestinal resection to those resulting from the continuous contact of urine with tissue not prepared for this contact. In this article, we describe and classify the various biomaterials and cell cultures used in bladder tissue engineering and reviews the studies performed with humans. We conducted a review of literature published in the PubMed database between 1950 and 2017, following the principles of the PRISM declaration. Numerous in vitro and animal model studies have been conducted, but only 18 experiments have been performed with humans, with a total of 169 patients. The current evidence suggests that an acellular matrix, a synthetic polymer with urothelial and autologous smooth muscle cells attached in vitro or stem cells would be the most practical approach for experimental bladder reconstruction. Bladder replacement or expansion without using intestinal tissue is still a challenge, despite progress in the manufacture of biomaterials and the development of cell therapy. Well-designed studies with large numbers of patients and long follow-up times are needed to establish an effective clinical translation and standardisation of the check-up functional tests. Copyright © 2017 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

[Virtual CT-pneumocystoscopy: indications, advantages and limitations. Our experience].

PubMed

Regine, Giovanni; Atzori, Maurizio; Buffa, Vitaliano; Miele, Vittorio; Ialongo, Pasquale; Adami, Loredana

2003-09-01

The use of CT volume-rendering techniques allows the evaluation of visceral organs without the need for endoscopy. Conventional endoscopic evaluation of the bladder is limited by the invasiveness of the technique and the difficulty exploring the entire bladder. Virtual evaluation of the bladder by three-dimensional CT reconstruction offers potential advantages and can be used in place of endoscopy. This study investigates the sensitivity of virtual CT in assessing lesion of the bladder wall to compare it with that of conventional endoscopy, and outlines the indications, advantages and disadvantages of virtual CT-pneumocystography. Between September 2001 and May 2002, 21 patients with haematuria and positive cystoscopic findings were studied. After an initial assessment by ultrasound, the patients underwent pelvic CT as a single volumetric scan after preliminary air distension of the bladder by means of 12 F Foley catheter. The images were processed on an independent workstation (Advantage 3.0 GE) running dedicated software for endoluminal navigation. The lesions detected by endoscopy were classified as sessile or pedunculated, and according to size (more or less than 5 mm). Finally, the results obtained at virtual cystoscopy were evaluated by two radiologists blinded to the conventional cystoscopy results. Thirty lesions (24 pedunculated, 6 sessile) were detected at conventional cystoscopy in 16 patients (multiple polyposis in 3 cases). Virtual cystoscopy identified 23 lesions (19 pedunculated and 4 sessile). The undetected lesions were pedunculated <5 mm (5 cases) and sessile (2 cases). One correctly identified pedunculated lesion was associated with a bladder stone. Good quality virtual images were obtained in all of the patients. In only one patient with multiple polyposis the quality of the virtual endoscopic evaluation was limited by the patient's intolerance to bladder distension, although identification of the lesions was not compromised. The overall sensitivity was 77%; this was higher for pedunculated lesions (79%) than for sessile lesions (50%). The virtual technique is less invasive and tends to be associated with fewer complications than is conventional cystoscopy. It also demonstrated a good sensitivity for evaluating pedunculated lesions, allowing evaluation of the bladder base and anterior wall, sites that are commonly poorly accessible at conventional cystoscopy. Further advantages of the virtual technique include the possibility of accurately measuring the extent of the lesion and obtaining virtual images even in patients with severe urethral obstruction and active bleeding. The limitations include the inability to obtain tissue for histologic examination or to perform endoscopic resection of pedunculated lesions. The technique is less sensitive than conventional cystoscopy in the detection of sessile lesions or very small polyps (<5 mm). Furthermore, diffuse wall thickening reduces bladder distension thereby preventing optimal evaluation. The most valuable indication appears to be the follow-up of treated wall lesions. Virtual CT-pneumocystoscopy can replace conventional cystoscopy in cases with pedunculated lesions when there is no need for biopsy, when the lesions are located at the bladder base or when cystoscopic instrumentation cannot be introduced into the bladder due to stenosis. Virtual pneumocystoscopy can also be used in the follow-up of treated polypoid lesions in association with pelvic CT-angiography.

Incidental Gall Bladder Carcinoma in Laparoscopic Cholecystectomy: A Report of 6 Cases and a Review of the Literature

PubMed Central

Sujata, Jetley; S, Rana; Sabina, Khan; MJ, Hassan; Jairajpuri, Zeeba Shamim

2013-01-01

Background: Gall bladder carcinoma accounts for 98% of all the gall bladder malignancies and it is the sixth most common malignancy of the gastrointestinal tract worldwide. The incidence of incidental gall bladder carcinoma which is diagnosed during or after a laparoscopic cholecystectomy is reported to be around 0.19-3.3% in the literature. Aim: This study was aimed at detecting the incidence of gall bladder carcinomas which were diagnosed incidentally during or after laparoscopic cholecystectomies which were done for gall stone disease and cholecystitis. Materials and Methods: We analyzed the medical records of patients with symptomatic gallstone disease and acute or chronic cholecystitis, who underwent laparoscopic cholecystectomies at the Hakeem Abdul Hameed Centenary Hospital during the period from January 2007 to June 2012. Results: A total of 622 laparoscopic cholecystectomies were performed at our institute during the study period of five and a half years. In 6 (0.96%) cases, incidental carcinomas of the gallbladder were discovered. Conclusion: A laparoscopic cholecystectomy which is performed for benign gall bladder disease rarely results in a diagnosis of unexpected gallbladder cancer. The microscopic examination of the specimens, with special attention to the depth of invasion, range of the mucosal spread and the lymphovascular involvement, is critical in diagnosing the incidental malignancies as well as for the subsequent management of the cases. PMID:23449518

The relation between Ring Box-1 protein overexpression and tumor grade and stage in bladder urothelial cell carcinoma.

PubMed

Celik, Zeliha Esin; Kaynar, Mehmet; Karabagli, Pinar; Gergerlioglu, Nursadan; Goktas, Serdar

2017-12-06

Ring Box Protein-1 (RBX-1), a component of SCF E3 ubiquitin ligases, has a crucial role in bladder urothelial cell carcinoma (UCC) carcinogenesis and progression. In the present study, it is aimed to determine the expression of RBX-1 protein in bladder UCC and the association between tumor grade, stage and RBX-1 expression. Ninety UCC samples and 20 samples containing foci of normal bladder urothelium were recruited and analyzed immunohistochemically in terms of RBX-1 expression. Immuno-reactivity scoring system (IRS) was used to determine RBX-1 expression levels. RBX-1 overexpression was associated with high tumor grade (p= 0.001) and advanced stage (p= 0.001). pT1 tumors showed higher RBX-1 expression than pTa tumors. pT2 tumors showed not only higher expression than pTa tumors but also higher expression than the total of pTa and pT1 groups combined. There was no statistically significant relation between RBX-1 expression and patient gender (p= 0.116) or age (p= 0.191). In bladder UCC, RBX-1 overexpression is associated with high tumor grade and advanced stage and represents biological potential of invasiveness and aggressive disease. Results of the present study have to be supported with further studies to reveal clinical and therapeutic implications of RBX-1 overexpression in bladder UCC.

Analgesic and anti-inflammatory drug use and risk of bladder cancer: a population based case control study

PubMed Central

Fortuny, Joan; Kogevinas, Manolis; Zens, Michael S; Schned, Alan; Andrew, Angeline S; Heaney, John; Kelsey, Karl T; Karagas, Margaret R

2007-01-01

Background Use of phenacetin and other analgesic and non-steroidal anti-inflammatory drugs (NSAIDs) potentially influences bladder cancer incidence, but epidemiologic evidence is limited. Methods We analyzed data from 376 incident bladder cancer cases and 463 controls from a population-based case-control study in New Hampshire on whom regular use of analgesic drugs and NSAIDs was obtained. Odds ratios and 95% confidence intervals were computed using logistic regression with adjustment for potentially confounding factors. Separate models by tumor stage, grade and TP53 status were conducted. Results We found an elevated odds ratio (OR) associated with reported use of phenacetin-containing medications, especially with longer duration of use (OR >8 years = 3.00, 95% confidence interval (CI) = 1.4–6.5). In contrast, use of paracetamol did not relate overall to risk of bladder cancer. We also found that regular use of any NSAID was associated with a statistically significant decrease in bladder cancer risk (OR = 0.6, 95% CI = 0.4–0.9), and specifically use of aspirin. Further, the association with NSAID use was largely among invasive, high grade and TP53 positive tumors. Conclusion While these agents have been investigated in several studies, a number of questions remain regarding the effects of analgesic and NSAID use on risk of bladder cancer. PMID:17692123

Expression of gap junction protein connexin 43 in bovine urinary bladder tumours.

PubMed

Corteggio, A; Florio, J; Roperto, F; Borzacchiello, G

2011-01-01

The aetiopathogenesis of urinary bladder tumours in cattle involves prolonged ingestion of bracken fern and infection by bovine papillomavirus types 1 or 2 (BPV-1/2). The oncogenic activity of BPV is largely associated with the major oncoprotein E5. Gap junctions are the only communicating junctions found in animal tissues and are composed of proteins known as connexins. Alterations in connexin expression have been associated with oncogenesis. The present study investigated biochemically and immunohistochemically the expression of connexin 43 in samples of normal (n=2), dysplastic (n=3) and neoplastic (n=23) bovine urothelium. The tumours included 10 carcinomas in situ, five papillary urothelial carcinomas and eight invasive urothelial carcinomas. Normal and dysplastic urothelium had membrane expression of connexin 43, but this was reduced in samples of carcinoma in situ. Papillary urothelial carcinomas showed moderate cytoplasmic and membrane labelling, while invasive carcinoma showed loss of connexin 43 expression. Copyright © 2010 Elsevier Ltd. All rights reserved.

[The Predictive Factors of Stent Failure in the Treatment of Malignant Extrinsc Ureteral Obstruction Using Internal Ureteral Stents].

PubMed

Matsuura, Hiroshi; Arase, Shigeki; Hori, Yasuhide; Tochigi, Hiromi

2017-12-01

In this study, we retrospectively reviewed the experiences at our single institute in the treatment of malignant extrinsic ureteral obstruction (MUO) using ureteral stents to investigate the clinical outcomes and the predictive factors of stent failure. In 52 ureters of 38 patients who had radiologically significant hydronephrosis due to MUO, internal ureteral stents (The BARD(R) INLAY(TM) ureteral stent set) were inserted. The median follow-up interval after the initial stent insertion was 124.5 days (4-1,120). Stent failure occurred in 8 ureters (15.4%) of the 7 patients. The median interval from the first stent insertion to stent failure was 88 days (1-468). A Cox regression multivariate analysis showed that the significant predictors of stent failure were bladder invasion. Based on the possibility of stent failure, the adaptation of the internal ureteral stent placement should be considered especially in a patient with MUO combined with bladder invasion.

Primary fibrosarcoma of the urinary bladder in a cat: follow-up after incomplete surgical excision

PubMed Central

Greci, Valentina; Rocchi, Paola M; Sontuoso, Antonio F; Olivero, Daniela; Capasso, Angelo; Raiano, Vera

2017-01-01

Case summary An 11-year-old female spayed domestic shorthair cat was presented with haematuria of 2 months’ duration followed by pollakiuria and stranguria. A firm, non-painful mass in the urinary bladder was palpated. Abdominal radiographs and ultrasound were suggestive of a urinary neoplasia. During explorative laparotomy, a partial cystectomy and surgical debulking were performed. Histopathology and immunostaining were consistent with a fibrosarcoma. The cat was discharged 10 days after surgery with a residual mass of about 1.8 cm on ultrasound re-examination. The cat was not given adjuvant therapy. The cat was euthanased 8 months after surgery because of tumour invasion of the urinary trigone and subsequent ureter dilation, hydronephrosis and severe azotaemia. Relevance and novel information Malignant urinary fibrosarcoma in this cat appeared to be only locally invasive. Palliative surgery without adjuvant postoperative chemotherapy in this cat resulted in an 8 month period of good quality of life. PMID:28680699

Targeting Hsp90 in urothelial carcinoma

PubMed Central

Skotnicki, Kamil; Landas, Steve; Bratslavsky, Gennady; Bourboulia, Dimitra

2015-01-01

Urothelial carcinoma, or transitional cell carcinoma, is the most common urologic malignancy that carries significant morbidity, mortality, recurrence risk and associated health care costs. Despite use of current chemotherapies and immunotherapies, long-term remission in patients with muscle-invasive or metastatic disease remains low, and disease recurrence is common. The molecular chaperone Heat Shock Protein-90 (Hsp90) may offer an ideal treatment target, as it is a critical signaling hub in urothelial carcinoma pathogenesis and potentiates chemoradiation. Preclinical testing with Hsp90 inhibitors has demonstrated reduced proliferation, enhanced apoptosis and synergism with chemotherapies and radiation. Despite promising preclinical data, clinical trials utilizing Hsp90 inhibitors for other malignancies had modest efficacy. Therefore, we propose that Hsp90 inhibition would best serve as an adjuvant treatment in advanced muscle-invasive or metastatic bladder cancers to potentiate other therapies. An overview of bladder cancer biology, current treatments, molecular targeted therapies, and the role for Hsp90 inhibitors in the treatment of urothelial carcinoma is the focus of this review. PMID:25909217

Current status of adjuvant chemotherapy after radical cystectomy for deeply invasive bladder cancer.

PubMed

Skinner, D G; Daniels, J R; Lieskovsky, G

1984-07-01

Between March, 1976, and December, 1982, 70 of 157 patients (45%) undergoing single-stage radical cystectomy with pelvic lymphadenectomy and urinary diversion with the intent to cure invasive bladder cancer were found to have pathologic Stage P3B, P4 and/or N + disease. Thirty-four of the 70 patients received adjuvant prophylactic chemotherapy after cystectomy and 36 patients were followed expectantly. From 1976 through 1977 adjuvant chemotherapy consisted of cyclophosphamide 1 Gm/M2 each month for six months; from 1978 through June, 1980, adjuvant chemotherapy consisted of cis-platinum 100 mg/M2 each month for four months with the exception of 1 patient treated more aggressively with combination chemotherapy (CISCA). Since July, 1980, a prospective study has been utilized in which patients were randomized into two groups, Group A receiving combination chemotherapy and Group B followed up expectantly; adjuvant chemotherapy appears to result in a slight delay in time to relapse but no influence in overall survival was observed.

Asthma status is associated with decreased risk of aggressive urothelial bladder cancer.

PubMed

Rava, Marta; Czachorowski, Maciej J; Silverman, Debra; Márquez, Mirari; Kishore, Sirish; Tardón, Adonina; Serra, Consol; García-Closas, Montse; Garcia-Closas, Reina; Carrato, Alfredo; Rothman, Nathaniel; Real, Francisco X; Kogevinas, Manolis; Malats, Núria

2018-02-01

Previous studies suggested an association between atopic conditions and specific cancers. The results on the association with urothelial bladder cancer (UBC) are scarce and inconsistent. To evaluate the association between asthma and risk of UBC, we considered 936 cases and 1,022 controls from the Spanish Bladder Cancer/EPICURO Study (86% males, mean age 65.4 years), a multicenter and hospital-based case-control study conducted during 1998-2001. Participants were asked whether they had asthma and detailed information about occupational exposures, smoking habits, dietary factors, medical conditions and history of medication was collected through face-to-face questionnaires performed by trained interviewers. Since asthma and UBC might share risk factors, association between patients' characteristics and asthma was studied in UBC controls. Association between UBC and asthma was assessed using logistic regression unadjusted and adjusted for potential confounders. The complex interrelationships, direct and mediating effect of asthma on UBC, were appraised using counterfactual mediation models. Asthma was associated with a reduced risk of UBC (odds ratio (OR) = 0.54, 95% confidence interval (CI) 0.37, 0.79) after adjusting for a wide range of confounders. No mediating effect was identified. The reduced risk associated with asthma was restricted to patients with high-risk non-muscle invasive (OR = 0.25, 95%CI 0.10, 0.62) and muscle invasive UBC (OR = 0.32, 95%CI 0.15, 0.69). Our results support that asthma is associated with a decreased risk of UBC, especially among aggressive tumors. Further work on the relationship between asthma and other atopic conditions and cancer risk should shed light on the relationship between immune response mechanisms and bladder carcinogenesis. © 2017 UICC.

Potential therapeutic strategies for non - muscle invasive bladder cancer based on association of intravesical immunotherapy with P-MAPA and systemic administration of cisplatin and doxorubicin

PubMed Central

Dias, Queila Cristina; Nunes, Iseu da Silva; Garcia, Patrick Vianna; Fávaro, Wagner José

2016-01-01

ABSTRACT The present study describes the histopathological and molecular effects of P-MAPA (Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride) intravesical immunotherapy combined with systemic doxorubicin or cisplatin for treatment of non-muscle invasive bladder cancer (NMIBC) in an appropriate animal model. Our results showed an undifferentiated tumor, characterizing a tumor invading mucosa or submucosa of the bladder wall (pT1) and papillary carcinoma in situ (pTa) in the Cancer group. The histopathological changes were similar between the combined treatment with intravesical P-MAPA plus systemic Cisplatin and P-MAPA immunotherapy alone, showing decrease of urothelial neoplastic lesions progression and histopathological recovery in 80% of the animals. The animals treated systemically with cisplatin or doxorubicin singly, showed 100% of malignant lesions in the urinary bladder. Furthemore, the combined treatment with P-MAPA and Doxorubicin showed no decrease of urothelial neoplastic lesions progression and histopathological recovery. Furthermore, Akt, PI3K, NF-kB and VEGF protein levels were significantly lower in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments than other groups. In contrast, PTEN protein levels were significantly higher in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments. Thus, it could be concluded that combination of intravesical P-MAPA immunotherapy and systemic cisplatin in the NMIBC animal model was effective, well tolerated and showed no apparent signs of antagonism between the drugs. In addition, intravesical P-MAPA immunotherapy may be considered as a valuable option for treatment of BCG unresponsive patients that unmet the criteria for early cystectomy. PMID:24893914

Potential therapeutic strategies for non - muscle invasive bladder cancer based on association of intravesical immunotherapy with p - mapa and systemic administration of cisplatin and doxorubicin.

PubMed

Dias, Queila Cristina; Nunes, Iseu da Silva; Garcia, Patrick Vianna; Favaro, Wagner Jose

2016-01-01

The present study describes the histopathological and molecular effects of P-MAPA (Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride) intravesical immunotherapy combined with systemic doxorubicin or cisplatin for treatment of non-muscle invasive bladder cancer (NMIBC) in an appropriate animal model. Our results showed an undifferentiated tumor, characterizing a tumor invading mucosa or submucosa of the bladder wall (pT1) and papillary carcinoma in situ (pTa) in the Cancer group. The histopathological changes were similar between the combined treatment with intravesical P-MAPA plus systemic Cisplatin and P-MAPA immunotherapy alone, showing decrease of urothelial neoplastic lesions progression and histopathological recovery in 80% of the animals. The animals treated systemically with cisplatin or doxorubicin singly, showed 100% of malignant lesions in the urinary bladder. Furthemore, the combined treatment with P-MAPA and Doxorubicin showed no decrease of urothelial neoplastic lesions progression and histopathological recovery. Furthermore, Akt, PI3K, NF-kB and VEGF protein levels were significantly lower in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments than other groups. In contrast, PTEN protein levels were significantly higher in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments. Thus, it could be concluded that combination of intravesical P-MAPA immunotherapy and systemic cisplatin in the NMIBC animal model was effective, well tolerated and showed no apparent signs of antagonism between the drugs. In addition, intravesical P-MAPA immunotherapy may be considered as a valuable option for treatment of BCG unresponsive patients that unmet the criteria for early cystectomy. Copyright® by the International Brazilian Journal of Urology.

The prognostic value of family history among patients with urinary bladder cancer.

PubMed

Egbers, Lieke; Grotenhuis, Anne J; Aben, Katja K; Alfred Witjes, J; Kiemeney, Lambertus A; Vermeulen, Sita H

2015-03-01

A history of urinary bladder cancer (UBC) in first-degree relatives increases UBC risk by twofold. The influence of positive family history on UBC prognosis is unknown. Here, we investigated association of first-degree UBC family history with clinicopathological characteristics and prognosis of UBC patients. Detailed clinical data of 1,465 non-muscle-invasive bladder cancer (NMIBC) and 250 muscle-invasive or metastatic bladder cancer (MIBC) patients, diagnosed from 1995 to 2010, were collected through medical file review. Competing risk analyses were used to compare recurrence-free survival (RFS) and progression-free survival (PFS) of NMIBC patients according to self-reported UBC family history. Overall survival in MIBC patients was estimated using Kaplan-Meier analysis. The added value of family history in prediction of NMIBC prognosis was quantified with Harrell's concordance-index. Hundred (6.8%) NMIBC and 14 (5.6%) MIBC patients reported UBC in first-degree relatives. Positive family history was statistically significantly associated with smaller tumor size and non-significantly with more favorable distribution of other tumor characteristics. In univariable analyses, positive family history correlated with longer RFS (p = 0.11) and PFS (p = 0.04). Hazard ratios for positive vs. negative family history after adjustment for clinicopathological characteristics were 0.75 (95% CI = 0.53-1.07) and 0.45 (95% CI = 0.18-1.12) for RFS and PFS, respectively. Five familial and 48 sporadic MIBC patients (Kaplan-Meier 10-year risk: 41% and 25%) died within 10 years. Family history did not improve the c-index of prediction models. This study shows that a first-degree family history of UBC is not clearly associated with NMIBC prognosis. Family history does not aid in prediction of NMIBC recurrence or progression. © 2014 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.

RUNX3 methylation in normal surrounding urothelium of patients with non-muscle-invasive bladder cancer: potential role in the prediction of tumor progression.

PubMed

Jeong, P; Min, B D; Ha, Y S; Song, P H; Kim, I Y; Ryu, K H; Kim, J H; Yun, S J; Kim, W J

2012-11-01

Previously, we reported a causal relationship between RUNX3 methylation and bladder tumor development. Thus, in order to clarify its role in tumorigenesis, this study aims to identify the function of RUNX3 methylation in normal adjacent urothelium of patients with non-muscle invasive bladder cancer (NMIBC). Tumor tissue and donor-matched normal adjacent tissue from 55 patients who underwent transurethral resection (TUR) were selected for the study, and RUNX3 promoter methylation was assessed using methylation-specific polymerase chain reaction (MS-PCR). RUNX3 promoter methylation occurred more frequently in tumor samples than in histologically normal urothelium in patients with NMIBC (P = 0.02). The methylation rates for the RUNX3 promoter in normal adjacent urothelium and tumor tissue were 47% and 69%, respectively. Interestingly, RUNX3 methylation in normal adjacent urothelium was associated with tumor number (P = 0.022) and progression (P = 0.035). Kaplan-Meier estimates revealed that RUNX3 methylation in normal urothelium showed a significant association with time to progression (P = 0.017) in NMIBC patients. Stratifying the patients into 'both methylation', 'one methylation' and 'no methylation' groups for tumors and normal urothelium revealed that no progression occurred in the 'no methylation' group during follow-up. Multivariate Cox regression analysis demonstrated that RUNX3 methylation in normal urothelium [hazards ratio (HR): 5.692, P = 0.042] was an independent predictor of progression. RUNX3 methylation was associated with transition from normal urothelium to bladder tumor. More importantly, RUNX3 methylation in normal adjacent urothelium may predict progression in NMIBC patients who have undergone TUR. Copyright © 2012 Elsevier Ltd. All rights reserved.

Effectiveness of transurethral resection (TUR) plus systemic chemotherapy as definitive treatment for muscle-invasive bladder cancer (MIBC) in population-level data.

PubMed

Audenet, François; Waingankar, Nikhil; Ferket, Bart S; Niglio, Scot A; Marqueen, Kathryn E; Sfakianos, John P; Galsky, Matthew D

2018-06-04

To investigate the characteristics and outcomes of patients with muscle-invasive bladder cancer (MIBC) treated with transurethral resection (TUR) plus chemotherapy alone in a large observational cohort reflecting the continuum of practice settings in the United States. Within the National Cancer Database (2004-2015), we identified 1,538 patients treated with TUR plus multi-agent chemotherapy as definitive treatment for cT2-T4aN0M0 urothelial carcinoma of the bladder. For comparison purposes, we included 17,866 patients treated with radical cystectomy ± perioperative chemotherapy. Baseline characteristics were compared between the 2 groups using multivariable logistic regression. Treatment outcomes were assessed using Kaplan-Meier analysis and Cox regression model. In multivariate analysis, several variables, including patients' demography (older age, African-American race, prior malignancy, lack of insurance), tumor characteristics (higher cT stage) and facility types (non-academic facilities, lower volume of radical cystectomy) were associated with a higher probability of receiving TUR plus chemotherapy for MIBC, compared to the standard of care. The 2-year and 5-year survival rates for all patients treated with TUR plus chemotherapy were 49.0% and 32.9% and limited to patients with cT2 disease were 52.6% and 36.2%, respectively. This large population-level cohort of unselected patients shows that long-term survival can be achieved in a subset of patients treated with TUR plus chemotherapy alone for MIBC. However, the best candidates for this approach remain to be defined. Ongoing clinical trials are now being launched to evaluate the ability of biomarkers to accurately select patients who could be treated with this bladder-sparing strategy. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Apparent diffusion coefficient on magnetic resonance imaging (MRI) in bladder cancer: relations with recurrence/progression risk

PubMed Central

Kikuchi, Ken; Shigihara, Takeshi; Hashimoto, Yuko; Miyajima, Masayuki; Haga, Nobuhiro; Kojima, Yoshiyuki; Shishido, Fumio

2017-01-01

Abstract AIMS: To evaluate the relationship between the apparent diffusion coefficient (ADC) value for bladder cancer and the recurrence/progression risk of post-transurethral resection (TUR). METHODS: Forty-one patients with initial and non-muscle-invasive bladder cancer underwent MRI from 2009 to 2012. Two radiologists measured ADC values. A pathologist calculated the recurrence/progression scores, and risk was classified based on the scores. Pearson’s correlation was used to analyze the correlations of ADC value with each score and with each risk group, and the optimal cut-off value was established based on receiver operating characteristic (ROC) curve analysis. Furthermore, the relationship between actual recurrence / progression of cases and ADC values was examined by Unpaird U test. RESULTS: There were significant correlations between ADC value and the recurrence score as well as the progression score (P<0.01, P<0.01, respectively). There were also significant correlations between ADC value and the recurrence risk group as well as progression risk group (P=0.042, P<0.01, respectively). The ADC cut-off value on ROC analysis was 1.365 (sensitivity 100%; specificity 97.4%) for the low and intermediate recurrence risk groups, 1.024 (sensitivity 47.4%; specificity 100%) for the intermediate and high recurrence risk groups, 1.252 (sensitivity 83.3%; specificity 81.3%) for the low and intermediate progression risk groups, and 0.955 (sensitivity 87.5%; specificity 63.2%) between the intermediate and high progression risk groups. The difference between the ADC values of the recurrence and nonrecurrence group in Unpaired t test was significant (P<0.05). CONCLUSION: ADC on MRI in bladder cancer could potentially be useful, non-invasive measurement for estimating the risks of recurrence and progression. PMID:28680010

Evaluation of an Epigenetic Profile for the Detection of Bladder Cancer in Patients with Hematuria.

PubMed

van Kessel, Kim E M; Van Neste, Leander; Lurkin, Irene; Zwarthoff, Ellen C; Van Criekinge, Wim

2016-03-01

Many patients enter the care cycle with gross or microscopic hematuria and undergo cystoscopy to rule out bladder cancer. Sensitivity of this invasive examination is limited, leaving many patients at risk for undetected cancer. To improve current clinical practice more sensitive and noninvasive screening methods should be applied. A total of 154 urine samples were collected from patients with hematuria, including 80 without and 74 with bladder cancer. DNA from cells in the urine was epigenetically profiled using 2 independent assays. Methylation specific polymerase chain reaction was performed on TWIST1. SNaPshot™ methylation analysis was done for different loci of OTX1 and ONECUT2. Additionally all samples were analyzed for mutation status of TERT (telomerase reverse transcriptase), PIK3CA, FGFR3 (fibroblast growth factor receptor 3), HRAS, KRAS and NRAS. The combination of TWIST1, ONECUT2 (2 loci) and OTX1 resulted in the best overall performing panel. Logistic regression analysis on these methylation markers, mutation status of FGFR3, TERT and HRAS, and patient age resulted in an accurate model with 97% sensitivity, 83% specificity and an AUC of 0.93 (95% CI 0.88-0.98). Internal validation led to an optimism corrected AUC of 0.92. With an estimated bladder cancer prevalence of 5% to 10% in a hematuria cohort the assay resulted in a 99.6% to 99.9% negative predictive value. Epigenetic profiling using TWIST1, ONECUT2 and OTX1 results in a high sensitivity and specificity. Accurate risk prediction might result in less extensive and invasive examination of patients at low risk, thereby reducing unnecessary patient burden and health care costs. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

The Impact of Blue Light Cystoscopy with Hexaminolevulinate (HAL) on Progression of Bladder Cancer - A New Analysis.

PubMed

Kamat, Ashish M; Cookson, Michael; Witjes, J Alfred; Stenzl, Arnulf; Grossman, H Barton

2016-04-27

Background: The International Bladder Cancer Group (IBCG) recently proposed a new definition of disease progression in non-muscle invasive bladder cancer (NMIBC), including change in T-stage, change to T2 or higher or change from low to high grade. Objective: To establish whether blue light cystoscopy with hexaminolevulinate (HAL) impacts the rate of progression and time to progression using the revised definition. Methods: An earlier long-term follow-up of a controlled Phase III study reported outcomes following blue light cystoscopy with HAL (255 patients) or white light (WL) cystoscopy (261 patients) in NMIBC patients. The data was re-analysed according to the new definition. Results: In the original analysis, after 4.5 years (median), eight HAL and 16 WL patients were deemed to have progressed (transition from NMIBC to muscle invasive bladder cancer, (T2-4)). According to the new definition, additional patients in both groups were found to have progressed: 31 (12.2%) HAL vs 46 (17.6%) WL ( p  = 0.085) with four (1.6%) HAL and 11 (4.2%) WL patients progressing from Ta to CIS. Time to progression was longer in the HAL group ( p  = 0.05). Conclusions: Applying the new IBCG definition there was a trend towards a lower rate of progression in HAL patients, particularly in those progressing from Ta to CIS. Time to progression was significantly prolonged. This suggests that patients should receive blue light cystoscopy with HAL rather than WL at resection. Adoption of the new definition could allow more patients at risk of progression to be treated appropriately earlier.

Comparison of the short-term efficacy of sequential treatment with intravesical single-port laparoscopic partial cystectomy with bladder preservation or open partial cystectomy in combination with cisplatin plus gemcitabine chemotherapy

PubMed Central

MAI, HAI-XING; LIU, JUN-LE; PEI, SHU-JUN; ZHAO, LI; QU, NAN; DONG, JIN-KAI; CHEN, BIAO; WANG, YA-LIN; HUANG, CHENG; CHEN, LI-JUN

2015-01-01

This study aimed to assess the short-term efficacy of sequential therapy for T2/T3a bladder cancer with intravesical single-port laparoscopic partial cystectomy or open partial cystectomy combined with cisplatin plus gemcitabine (GC) chemotherapy in a prospective randomized controlled study. Thirty patients with bladder cancer who underwent open partial cystectomy (group A) or single-port laparoscopic partial cystectomy (group B) and received standard GC chemotherapy were analyzed. Perioperative functional indicators and tumor recurrence during a 1-year postoperative follow-up were compared between the two groups. The baseline characteristics were comparable between the two groups. The mean operative time, amount of blood loss and duration of hospital stay were 90.3 min, 182.0 ml and 7.3 days, respectively, for group A, and 105.3 min, 49.3 ml and 5.8 days, respectively, for group B. No secondary postoperative bleeding, urine leakage, wound infection or other complications were observed in the two groups. Postoperative scarring was not evident in group B. The overall incidence of surgical complications, tumor recurrence rate and complications during chemotherapy in the postoperative follow-up period of 12 months were similar between the two groups. Single-port laparoscopic partial cystectomy surgery is an idea surgical method for the treatment of invasive bladder cancer, with good surgical effect, minimal invasiveness, rapid recovery and short hospital stay. The data from 1-year postoperative follow-up showed that laparoscopic surgery was superior with regard to perioperative bleeding, postoperative recovery and duration of indwelling urinary catheter use. However, regarding the tumor recurrence rate, long-term comparative details are required to determine the effect of laparoscopic surgery. PMID:26170915

Characterization of the tachykinin neurokinin-2 receptor in the human urinary bladder by means of selective receptor antagonists and peptidase inhibitors.

PubMed

Giuliani, S; Patacchini, R; Barbanti, G; Turini, D; Rovero, P; Quartara, L; Giachetti, A; Maggi, C A

1993-11-01

The tachykinin (NK2) receptor-mediating contraction of the human isolated bladder to NKA was investigated by studying the affinities of eight structurally different receptor-selective antagonists (linear peptides, cyclic peptides and pseudopeptides, nonpeptide NK2 receptor antagonists). The affinities of the antagonists were compared to those measured for the same ligands at the NK2 receptors previously characterized in the rabbit pulmonary artery and hamster trachea. In the presence of a cocktail of peptidase inhibitors (bestatin captopril and thiorphan, 1 microM each) no significant correlation was found between pA2 values measured in the human bladder vs. those measured in the other two NK2 receptor-bearing preparation. In the presence of the aminopeptidase inhibitor amastatin, however, pA2 values of linear antagonists bearing an N-terminal Asp residue MEN 10,207 and MEN 10,376 were significantly enhanced and these pA2 values were used for analysis; a significant correlation was found between pA2 values measured in the human urinary bladder and rabbit pulmonary artery. The pseudopeptide analog of NKA (4-10), MDL 28,564 which also bears a N-terminal Asp residue behaved as an agonist and its action was enhanced by amastatin. We conclude that the NK2 receptor-mediating contraction of the human urinary bladder smooth muscle is similar to that previously characterized in the rabbit pulmonary artery (NK2A receptor category); in the human bladder smooth muscle an amastatin-sensitive peptidase (possibly aminopeptidase A) limits biological activity of linear peptide derivatives of NKA bearing a N-terminal Asp residue.

Cancer Cells Regulate Biomechanical Properties of Human Microvascular Endothelial Cells*

PubMed Central

Mierke, Claudia Tanja

2011-01-01

Metastasis is a key event of malignant tumor progression. The capability to metastasize depends on the ability of the cancer cell to migrate into connective tissue, adhere, and possibly transmigrate through the endothelium. Previously we reported that the endothelium does not generally act as barrier for cancer cells to migrate in three-dimensional extracellular matrices (3D-ECMs). Instead, the endothelium acts as an enhancer or a promoter for the invasiveness of certain cancer cells. How invasive cancer cells diminish the endothelial barrier function still remains elusive. Therefore, this study investigates whether invasive cancer cells can decrease the endothelial barrier function through alterations of endothelial biomechanical properties. To address this, MDA-MB-231 breast cancer cells were used that invade deeper and more numerous into 3D-ECMs when co-cultured with microvascular endothelial cells. Using magnetic tweezer measurements, MDA-MB-231 cells were found to alter the mechanical properties of endothelial cells by reducing endothelial cell stiffness. Using spontaneous bead diffusion, actin cytoskeletal remodeling dynamics were shown to be increased in endothelial cells co-cultured with MDA-MB-231 cells compared with mono-cultured endothelial cells. In addition, knockdown of the α5 integrin subunit in highly transmigrating α5β1high cells derived from breast, bladder, and kidney cancer cells abolished the endothelial invasion-enhancing effect comparable with the inhibition of myosin light chain kinase. These results indicate that the endothelial invasion-enhancing effect is α5β1 integrin-dependent. Moreover, inhibition of Rac-1, Rho kinase, MEK kinase, and PI3K reduced the endothelial invasion-enhancing effect, indicating that signaling via small GTPases may play a role in the endothelial facilitated increased invasiveness of cancer cells. In conclusion, decreased stiffness and increased cytoskeletal remodeling dynamics of endothelial cells may account for the breakdown of endothelial barrier function, suggesting that biomechanical alterations are sufficient to facilitate the transmigration and invasion of invasive cancer cells into 3D-ECMs. PMID:21940631

DIFFERENTIAL MODULATION OF CANCER-RELATED MOLECULAR NETWORKS IN HUMAN AND RAT URINARY BLADDER CELLS EXPOSED TO TRIVALENT ARSENICALS

EPA Science Inventory

Arsenic (As) is classified as a known human carcinogen with primary targets of urinary bladder (UB), skin and lung. The most prevalent source of As exposure in humans is drinking water contaminated with inorganic As (iAs), and millions of people worldwide are exposed to drinking ...

SESN2/sestrin 2 induction-mediated autophagy and inhibitory effect of isorhapontigenin (ISO) on human bladder cancers.

PubMed

Liang, Yuguang; Zhu, Junlan; Huang, Haishan; Xiang, Daimin; Li, Yang; Zhang, Dongyun; Li, Jingxia; Wang, Yulei; Jin, Honglei; Jiang, Guosong; Liu, Zeyuan; Huang, Chuanshu

2016-08-02

Isorhapontigenin (ISO) is a new derivative of stilbene isolated from the Chinese herb Gnetum cleistostachyum. Our recent studies have revealed that ISO treatment at doses ranging from 20 to 80 μM triggers apoptosis in multiple human cancer cell lines. In the present study, we evaluated the potential effect of ISO on autophagy induction. We found that ISO treatment at sublethal doses induced autophagy effectively in human bladder cancer cells, which contributed to the inhibition of anchorage-independent growth of cancer cells. In addition, our studies revealed that ISO-mediated autophagy induction occurred in a SESN2 (sestrin 2)-dependent and BECN1 (Beclin 1, autophagy related)-independent manner. Furthermore, we identified that ISO treatment induced SESN2 expression via a MAPK8/JNK1 (mitogen-activated protein kinase 8)/JUN-dependent mechanism, in which ISO triggered MAPK8-dependent JUN activation and facilitated the binding of JUN to a consensus AP-1 binding site in the SESN2 promoter region, thereby led to a significant transcriptional induction of SESN2. Importantly, we found that SESN2 expression was dramatically downregulated or even lost in human bladder cancer tissues as compared to their paired adjacent normal tissues. Collectively, our results demonstrate that ISO treatment induces autophagy and inhibits bladder cancer growth through MAPK8-JUN-dependent transcriptional induction of SESN2, which provides a novel mechanistic insight into understanding the inhibitory effect of ISO on bladder cancers and suggests that ISO might act as a promising preventive and/or therapeutic drug against human bladder cancer.

[Mechanisms for effect of osthole on inhibiting the growth and invasion of bladder cancer cells].

PubMed

Liu, Jun; Xu, Ran; Zhao, Xiaokun

2016-04-01

To investigate the effect of osthole on epidermal growth factor receptor tyrosine kinase (EGFR-TPK), matrix-metalloproteinase-2 (MMP-2), aminopeptidase N (APN) in bladder cancer cell and the underlying mechanism.
 The T24 cell lines were cultured. The inhibitory effects of osthole on EGFR-TPK, APN and MMP-2 were evaluated by spectrophotometric and MTT assay. The caspase-3 activity and the expression COX-2 and VEGF in T24 were examined. The activity of NF-κB was determined by electrophoretic mobility shift assay.
 The half inhibition concentrations (IC50) of osthole on EGFR-TPK, APN and MMP-2 were (45.33±3.98), (28.21±3.23) and (8.11±0.54) µmol/L, respectively. The growth inhibitory rates for T24 cells were increased in a dose-dependent manner (P<0.05). The caspase-3 activities were significantly increased in T24 cells in the osthole group compared with control group, while the expression of angiogenesis related-protein COX-2, VEGF, and NF-κB in T24 cells were decreased.
 Through the inhibitory effect on EGFR-TPK, APN and MMP-2, osthole can decrease COX-2, VEGF and NF-κB expression while increase the activity of caspase-3, eventually blocking the growth and invasion of bladder cancer cell.

Clinicopathological Profiling of LC3B, an Autophagy Marker, and ESRRA (Estrogen-related Receptor-alpha) in Muscle-invasive Bladder Cancer.

PubMed

Kim, Sup; Lee, Adam Jaehyeok; Yeo, Min-Kyung; Na, Yong Gil; Kim, Ji-Yeon; Cho, Moon-June; Kim, Jun-Sang; Jo, Eun-Kyeong; Kim, Jin-Man

2018-04-01

Microtubule-associated protein 1 light chain 3B (LC3B), an autophagy marker, has been used as a promising marker in various cancer types. However, the expression of LC3B in muscle-invasive bladder cancer (MIBC) and its prognostic significance have not been investigated. Recent studies pointed to the involvement of ESRRA in regulating autophagy via both transcriptional and post-translational control. In the current study, prognostic importance of LC3B and ESRRA in MIBC was investigated. We immunohistochemically studied the expression of LC3B and ESRRA in 56 MIBC samples. LC3B was stained high in 16 patients (28.6%) and low or negative in 40 patients (71.4%). ESRRA expression was high for 20 patients (35.7%) and low for 36 patients (64.3%). Both LC3B (p=0.003) and ESRRA (p=0.026) expression correlated significantly with disease-free survival rates. Double-positive LC3B and ESRRA correlated with poor overall survival (p=0.007) and disease-free survival (p=0.001) in MIBC patients. LC3B and ESRRA might be a useful prognostic factor in patients with MIBC. The co-expression of LC3B and ESRRA might be a prognostic and therapeutic target for patients with bladder cancer. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

The role of lasers in modern urology.

PubMed

Dołowy, Łukasz; Krajewski, Wojciech; Dembowski, Janusz; Zdrojowy, Romuald; Kołodziej, Anna

2015-01-01

The functioning of modern urological departments and the high level of service they provide is possible through, among other things, the use of modern laser techniques. Open operations have been replaced by minimally invasive procedures, and classical surgical tools by advanced lasers. The search for new applications with lasers began as technology developed. Among many devices available, holmium, diode and thulium lasers are currently the most popular. Depending on the wavelength, the absorption by water and hemoglobin and the depth of penetration, lasers can be used for coagulation, vaporization and enucleation. In many centres, after all the possibilities of pharmacological treatment have been exhausted, lasers are used as the primary treatment for patients with benign prostatic hyperplasia, with therapeutic results that are better than those obtained through open or endoscopic operations. The use of lasers in the treatment of urolithiasis, urinary strictures and bladder tumours has made treatment of older patients with multiple comorbidities safe, without further necessity to modify the anticoagulant drug treatment. Laser procedures are additionally less invasive, reduce hospitalization time and enable a shorter bladder catheterization time, sometimes even eliminating the need for bladder catherterization completely. Such procedures are also characterized by more stable outcomes and a lower number of reoperations. There are also indications that with the increased competition among laser manufacturers, decreased purchase and maintenance costs, and increased operational safety, laser equipment will become mandatory and indispensable asset in all urology wards.

Carcinomas of the urinary bladder simulating malignant lymphoma. A report of five cases.

PubMed

Zukerberg, L R; Harris, N L; Young, R H

1991-06-01

We report five carcinomas of the urinary bladder, four of them transitional cell carcinomas and one undifferentiated carcinoma, with unusual features that have received little or no comment in the literature and may be the cause of diagnostic difficulty because of their possible confusion with malignant lymphoma. Four patients were male and one female. They ranged from 61 to 76 years of age. Three tumors from these patients had a prominent (2 cases) or massive (1 case) lymphoid infiltrate that partially obscured the invasive carcinoma in two cases and largely obscured it in the third case, which closely resembled a lymphoepithelioma. The diagnosis of malignant lymphoma was only excluded with confidence in the last case after thorough immunohistochemical study. The lymphoid infiltrate was composed of numerous T-cells (UCHL-1 and Leu 22 positive) and polytypic plasma cells with admixed eosinophils; occasional germinal centers were present in one case. The tumors were deeply invasive in two patients, one of whom is alive with no evidence of disease 4 years after treatment with chemotherapy and radiation therapy; the other two cases are too recent for meaningful follow-up. Two other transitional cell carcinomas had diffuse patterns that simulated lymphoma or plasmacytoma. Recognition of these patterns of vesical carcinoma is important in order to avoid the misdiagnosis of the very rare malignant lymphoma of the urinary bladder.

Bladder Function Preservation With Brachytherapy, External Beam Radiation Therapy, and Limited Surger in Bladder Cancer Patients: Long-Term Results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aluwini, Shafak, E-mail: s.aluwini@erasmusmc.nl; Rooij, Peter H.E. van; Kirkels, Wim J.

2014-03-01

Purpose: To report long-term results of a bladder preservation strategy for muscle-invasive bladder cancer (MIBC) using external beam radiation therapy and brachytherapy/interstitial radiation therapy (IRT). Methods and Materials: Between May 1989 and October 2011, 192 selected patients with MIBC were treated with a combined regimen of preoperative external beam radiation therapy and subsequent surgical exploration with or without partial cystectomy and insertion of source carrier tubes for afterloading IRT using low dose rate and pulsed dose rate. Data for oncologic and functional outcomes were prospectively collected. The primary endpoints were local recurrence-free survival (LRFS), bladder function preservation survival, and salvage cystectomy-freemore » survival. The endpoints were constructed according to the Kaplan-Meier method. Results: The mean follow-up period was 105.5 months. The LRFS rate was 80% and 73% at 5 and 10 years, respectively. Salvage cystectomy-free survival at 5 and 10 years was 93% and 85%. The 5- and 10-year overall survival rates were 65% and 46%, whereas cancer-specific survival at 5 and 10 years was 75% and 67%. The distant metastases-free survival rate was 76% and 69% at 5 and 10 years. Multivariate analysis revealed no independent predictors of LRFS. Radiation Therapy Oncology Group grade ≥3 late bladder and rectum toxicity were recorded in 11 patients (5.7%) and 2 patients (1%), respectively. Conclusions: A multimodality bladder-sparing regimen using IRT offers excellent long-term oncologic outcome in selected patients with MIBC. The late toxicity rate is low, and the majority of patients preserve their functional bladder.« less

Detecting DNA methylation of the BCL2, CDKN2A and NID2 genes in urine using a nested methylation specific polymerase chain reaction assay to predict bladder cancer.

PubMed

Scher, Michael B; Elbaum, Michael B; Mogilevkin, Yakov; Hilbert, David W; Mydlo, Jack H; Sidi, A Ami; Adelson, Martin E; Mordechai, Eli; Trama, Jason P

2012-12-01

Detection of methylated DNA has been shown to be a good biomarker for bladder cancer. Bladder cancer has the highest recurrence rate of any cancer and, as such, patients are regularly monitored using invasive diagnostic techniques. As urine is easily attainable, bladder cancer is an optimal cancer to detect using DNA methylation. DNA methylation is highly specific in cancer detection. However, it is difficult to detect because of the limited amount of DNA present in the urine of patients with bladder cancer. Therefore, an improved, sensitive and noninvasive diagnostic test is needed. We developed a highly specific and sensitive nested methylation specific polymerase chain reaction assay to detect the presence of bladder cancer in small volumes of patient urine. The genes assayed for DNA methylation are BCL2, CDKN2A and NID2. The regions surrounding the DNA methylation sites were amplified in a methylation independent first round polymerase chain reaction and the amplification product from the first polymerase chain reaction was used in a real-time methylation specific polymerase chain reaction. Urine samples were collected from patients receiving treatment at Wolfson Medical Center in Holon, Israel. In a pilot clinical study using patient urine samples we were able to differentiate bladder cancer from other urogenital malignancies and nonmalignant conditions with a sensitivity of 80.9% and a specificity of 86.4%. We developed a novel methylation specific polymerase chain reaction assay for the detection and monitoring of bladder cancer using DNA extracted from patient urine. The assay may also be combined with other diagnostic tests to improve accuracy. Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Cheliensisin A (Chel A) induces apoptosis in human bladder cancer cells by promoting PHLPP2 protein degradation.

PubMed

Zhang, Ruowen; Che, Xun; Zhang, Jingjie; Li, Yang; Li, Jingxia; Deng, Xu; Zhu, Junlan; Jin, Honglei; Zhao, Qinshi; Huang, Chuanshu

2016-10-11

Cheliensisin A (Chel A), a styryl-lactone compound extracted from Goniothalamus cheliensis, is reported to have significant anti-cancer effects in various cancer cells. Here we demonstrated that Chel A treatment resulted in apoptosis and an inhibition of anchorage-independent growth in human bladder cancer T24, T24T and U5637 cells. Mechanistic studies showed that such effect is mediated by PH domain and Leucine rich repeat Protein Phosphatases (PHLPP2) protein. Chel A treatment led to PHLPP2 degradation and subsequently increased in c-Jun phosphorylation. Moreover PHLPP2 degradation could be attenuated by inhibition of autophagy, which was mediated by Beclin 1. Collectively, we discover that Chel A treatment induces Beclin-dependent autophagy, consequently mediates PHLPP2 degradation and JNK/C-Jun phosphorylation and activation, further in turn contributing to apoptosis in human bladder cancer cells. Current studies provide a significant insight into understanding of anticancer effect of Chel A in treatment of human bladder cancer.

Cheliensisin A (Chel A) induces apoptosis in human bladder cancer cells by promoting PHLPP2 protein degradation

PubMed Central

Li, Yang; Li, Jingxia; Deng, Xu; Zhu, Junlan; Jin, Honglei; Zhao, Qinshi; Huang, Chuanshu

2016-01-01

Cheliensisin A (Chel A), a styryl-lactone compound extracted from Goniothalamus cheliensis, is reported to have significant anti-cancer effects in various cancer cells. Here we demonstrated that Chel A treatment resulted in apoptosis and an inhibition of anchorage-independent growth in human bladder cancer T24, T24T and U5637 cells. Mechanistic studies showed that such effect is mediated by PH domain and Leucine rich repeat Protein Phosphatases (PHLPP2) protein. Chel A treatment led to PHLPP2 degradation and subsequently increased in c-Jun phosphorylation. Moreover PHLPP2 degradation could be attenuated by inhibition of autophagy, which was mediated by Beclin 1. Collectively, we discover that Chel A treatment induces Beclin-dependent autophagy, consequently mediates PHLPP2 degradation and JNK/C-Jun phosphorylation and activation, further in turn contributing to apoptosis in human bladder cancer cells. Current studies provide a significant insight into understanding of anticancer effect of Chel A in treatment of human bladder cancer. PMID:27556506

Robotic-assisted versus open radical cystectomy in bladder cancer: A meta-analysis of four randomized controlled trails.

PubMed

Tang, Jin-Qiu; Zhao, Zhihong; Liang, Yiwen; Liao, Guixiang

2018-02-01

Robot-assisted radical cystectomy (RARC) is increasing annually for treatment of bladder cancer. The objective of this meta-analysis was to compare the safety and efficacy of RARC and open radical cystectomy (ORC) for bladder cancer. Our meta-analysis searches were conducted using PubMed, Web of Science, and Cochrane Library databases to identify randomized controlled trials (RCT) assessing the two techniques. Four RCT studies were identified, including 239 cases. Our studies indicated that RARC was associated with longer operative time (WMD: 69.69, 95% CI:17.25 to122.12; P= 0.009), lower estimated blood loss (WMD: -299.83, 95% CI:-414.66to -184.99; P<0.00001). The two groups had no significant difference in overall perioperative complications, length of hospital stay, lymph node yield and positive surgical margins. RARC is mini-invasive alternative to ORC for bladder cancer. The advantage of RARC was reduced estimated blood loss. More studies are needed to compare the two techniques. Copyright © 2017 John Wiley & Sons, Ltd.

Severity of hydronephrosis correlates with tumour invasiveness and urinary bladder recurrence of ureteric cancer.

PubMed

Luo, Hao Lun; Kang, Chih Hsiung; Chen, Yen Ta; Chuang, Yao Chi; Lee, Wei Ching; Cheng, Yuan Tso; Chiang, Po Hui

2013-08-01

To explore the prognostic role of hydronephrosis grade in patients with pure ureteric cancer. The study included 162 patients with pure ureteric cancer who were treated between January 2005 and December 2010 at a single tertiary referral centre. The association between hydronephrosis grade with pathological findings and oncological outcomes was assessed using multivariate Cox regression analysis. Hydronephrosis grade >2 was independently associated with non-organ-confined ureteric cancer (P = 0.003). Hydronephrosis grade <2 was highly prevalent in organ-confined disease. Hydronephrosis grade >2 and bladder cancer history independently predict bladder cancer recurrence (P = 0.021 and P = 0.002, respectively) Hydronephrosis of grade >2 was found to be associated with local and distant recurrence only in univariate analysis; non-organ-confined pathology independently predicted local and distant oncological failure (P ≤ 0.001 and P = 0.002, respectively). Hydronephrosis grade >2 is associated with non-organ-confined ureteric cancer and with bladder cancer recurrence. Non-organ-confined pathology is still the most important predictor for local and distant oncological failure. © 2013 BJU International.

[DAB2IP expression in bladder transitional cell carcinoma and its correlation with clinical outcome].

PubMed

Zhu, Jian-Ning; Wu, Kai-Jie; Guan, Zhen-Feng; Liu, Li-Xia; Ning, Zhong-Yun; Zhou, Jian-Cheng; Wang, Xin-Yang; Fan, Jin-Hai

2014-07-01

To investigate the expression of DAB2IP in bladder transitional cell carcinoma (BTCC) and its correlation with clinical characteristics and prognosis of BTCC patients. Immunohistochemical staining was applied to detect DAB2IP protein level in 79 cases of TCCB tissues and 11 cases of normal bladder tissues, and the relationships of the staining results with pathological grade, stage, lymph node metastasis, gender, age and the 3-year survival rate of the patients were analyzed. The expression of DAB2IP in BTCC tissues was significantly lower than that in normal bladder epithelium, and the expression score and rate of DAB2IP in the high-grade, invasive and metastatic BTCC were significantly lower than those in low-grade, superficial and non-metastatic BTCC (P < 0.05). The 3-year survival rate of the patients with high DAB2IP expression was significantly higher than that of the patients with low DAB2IP expression. DAB2IP may be one of the important inhibitory factors during the occurrence and progression of BTCC.

Urinary retinoic acid receptor-β2 gene promoter methylation and hyaluronidase activity as noninvasive tests for diagnosis of bladder cancer.

PubMed

Eissa, Sanaa; Zohny, Samir F; Shehata, Hanan Hussien; Hegazy, Marwa G A; Salem, Ahmed M; Esmat, Mohamed

2012-04-01

We evaluated the significance of urinary retinoic acid receptor-β2 (RAR-β2) gene promoter methylation and hyaluronidase activity in comparison with voided urine cytology (VUC) in diagnosis of bladder cancer. This study included 100 patients diagnosed with bladder cancer, 65 patients with benign urological disorders and 51 healthy volunteers. Urine supernatant was used for determining hyaluronidase activity by zymography while urine sediment was used for cytology and detection of methylated RAR-β2 gene promoter by methylation specific nested PCR. The sensitivity and specificity were 53% and 90.5% for VUC, 65% and 89.7% for percent methylation fraction of RAR-β2 gene promoter, and 89% and 90.5% for hyaluronidase activity; combination of the three parameters increased sensitivity to 95%. A significant association was observed between investigated markers and advanced grade tumor. Combined use of RAR-β2 gene promoter methylation, hyaluronidase activity and VUC is promising non-invasive tool for bladder cancer detection. Copyright © 2012. Published by Elsevier Inc.

A rare case of metastatic squamous urachal carcinoma.

PubMed

Andrei, S; Andrei, A; Rusu Muntean, G; Ungureanu, M; Herlea, V; Becheanu, G; Popescu, I

2013-01-01

Squamous cell carcinoma is a very rare type of urachal malignancy, only a few cases being reported in the medical literature. We present the case of a 49-year-old male patient diagnosed with infected squamous cell urachal carcinoma with multiple pulmonary metastases, after complaints of lower abdominal pain, abdominal mass and fever, without respiratory symptoms. The abdominal ultrasonography and the CT scan revealed a tumoral mass in the lower abdomen in contact with the abdominal wall and the urinary bladder dome, displacing the small bowel. Pulmonary nodular lesions were described in the left lobe pyramid. The intraoperative diagnosis was necrotic urachal tumor with urinary bladder dome invasion and suspected pulmonary metastases, and tumor ablation with bladder dome resection and suture of the bladder were performed. The histopathological result was poorly differentiated squamous cell carcinoma (G3), with negative resection margins. The patient recovered well after surgery, but the prognosis is very poor due to the metastatic stage in which the tumor was diagnosed, no standard chemotherapy regimen for the treatment of metastatic urachal carcinoma being known as effective until now. Celsius.

Transcriptional and post-transcriptional upregulation of p27 mediates growth inhibition of isorhapontigenin (ISO) on human bladder cancer cells.

PubMed

Jiang, Guosong; Huang, Chao; Li, Jingxia; Huang, Haishan; Wang, Jingjing; Li, Yawei; Xie, Fei; Jin, Honglei; Zhu, Junlan; Huang, Chuanshu

2018-03-08

There are few approved drugs available for the treatment of muscle-invasive bladder cancer (MIBC). Recently, we have demonstrated that isorhapontigenin (ISO), a new derivative isolated from the Chinese herb Gnetum cleistostachyum, effectively induces cell-cycle arrest at the G0/G1 phase and inhibits anchorage-independent cell growth through the miR-137/Sp1/cyclin D1 axis in human MIBC cells. Herein, we found that treatment of bladder cancer (BC) cells with ISO resulted in a significant upregulation of p27, which was also observed in ISO-treated mouse BCs that were induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Importantly, knockdown of p27 caused a decline in the ISO-induced G0-G1 growth arrest and reversed ISO suppression of anchorage-independent growth in BC cells. Mechanistic studies revealed that ISO promoted p27 expression at mRNA transcription level through increasing direct binding of forkhead box class O1 (FOXO1) to its promoter, while knockdown of FOXO1 attenuated ISO inhibition of BC cell growth. On the other hand, ISO upregulated the 3'-untranslated region (3'-UTR) activity of p27, which was accompanied by a reduction of miR-182 expression. In line with these observations, ectopic expression of miR-182 significantly blocked p27 3'-UTR activity, whereas mutation of the miR-182-binding site at p27 mRNA 3'-UTR effectively reversed this inhibition. Accordingly, ectopic expression of miR-182 also attenuated ISO upregulation of p27 expression and impaired ISO inhibition of BC cell growth. Our results not only provide novel insight into understanding of the underlying mechanism related to regulation of MIBC cell growth but also identify new roles and mechanisms underlying ISO inhibition of BC cell growth.

Research progress on bladder cancer molecular genetics.

PubMed

Kang, Zhengjun; Li, Yuhui; Yu, Yang; Guo, Zhan

2014-11-01

Bladder cancer is a common malignant urinary tumor with a high rate of recurrence and quick progression, which threats human health. With the research on bladder cancer molecular genetics, the knowledge of gene modification and the development of molecular detection methods, more tumor markers have been discovered, which may have potential for early diagnosis, clinical examination and prognosis. This article reviews the research progress on bladder cancer molecular genetics.

The Chinese approach to complementary and alternative medicine treatment for interstitial cystitis/bladder pain syndrome.

PubMed

Pang, Ran; Ali, Abdullah

2015-12-01

Management of interstitial cystitis/bladder pain syndrome (IC/BPS) remains a challenge due to poor understanding on its etiology. Complementary and alternative medicine (CAM), as an optional treatment, has been widely used, because no definitive conventional therapy is available. The different domain of CAM provides miscellaneous treatments for IC/BPS, which mainly include dietary modification, nutraceuticals, bladder training, biofeedback, yoga, massage, physical therapy, Qigong, traditional Chinese medicine and acupuncture. Clinical evidence has shown that each therapy can certainly benefit a portion of IC/BPS patients. However, the target patient group of each therapy has not been well studied and randomized, controlled trials are needed to further confirm the efficacy and reliability of CAM on managing IC/BPS. Despite these limitations, CAM therapeutic characteristics including non-invasive and effectiveness for specific patients allow clinicians and patients to realize multimodal and individualized therapy for IC/BPS.

The Chinese approach to complementary and alternative medicine treatment for interstitial cystitis/bladder pain syndrome

PubMed Central

Ali, Abdullah

2015-01-01

Management of interstitial cystitis/bladder pain syndrome (IC/BPS) remains a challenge due to poor understanding on its etiology. Complementary and alternative medicine (CAM), as an optional treatment, has been widely used, because no definitive conventional therapy is available. The different domain of CAM provides miscellaneous treatments for IC/BPS, which mainly include dietary modification, nutraceuticals, bladder training, biofeedback, yoga, massage, physical therapy, Qigong, traditional Chinese medicine and acupuncture. Clinical evidence has shown that each therapy can certainly benefit a portion of IC/BPS patients. However, the target patient group of each therapy has not been well studied and randomized, controlled trials are needed to further confirm the efficacy and reliability of CAM on managing IC/BPS. Despite these limitations, CAM therapeutic characteristics including non-invasive and effectiveness for specific patients allow clinicians and patients to realize multimodal and individualized therapy for IC/BPS. PMID:26816867

IDENTIFICATION OF INTERSPECIES CONCORDANCE OF MECHANISMS OF ARSENIC INDUCED BLADDER CANCER BY GENE EXPRESSION.

EPA Science Inventory

Arsenic is a human carcinogen that induces urinary bladder cancer. Several mechanisms have been proposed for arsenic-induced cancer. Although inorganic arsenic (iAs) does not induce tumors in adult rodents, dimethylarsinic acid (DMA), a major metabolite of iAs, is a rat bladder c...

Transient receptor potential vanilloid type 2 (TRPV2) expression in normal urothelium and in urothelial carcinoma of human bladder: correlation with the pathologic stage.

PubMed

Caprodossi, Sara; Lucciarini, Roberta; Amantini, Consuelo; Nabissi, Massimo; Canesin, Giacomo; Ballarini, Patrizia; Di Spilimbergo, Adriana; Cardarelli, Marco Andrea; Servi, Lucilla; Mammana, Gabriele; Santoni, Giorgio

2008-09-01

To evaluate the expression of transient receptor potential vanilloid type 2 (TRPV2) in normal human bladder and urothelial carcinoma (UC) tissues. Bladder specimens were obtained by transurethral resection or radical cystectomy. TRPV2 mRNA expression in normal human urothelial cells (NHUCs), UC cell lines, and formalin-fixed paraffin-embedded normal (n=6) and cancer bladder tissues (n=58) was evaluated by polymerase chain reaction (PCR) and quantitative real-time PCR (RT-PCR). TRPV2 protein expression was assessed by cytofluorimetric and confocal microscopy analyses in NHUCs and UC cells and by Western blotting and immunohistochemistry in normal and UC tissues. Enhanced TRPV2 mRNA and protein expression was found in high-grade and -stage UC specimens and UC cell lines. Both the full-length TRPV2 (hTRPV2) and a short splice-variant (s-TRPV2) were detected in NHUC and normal bladder specimens, whereas a progressive decline of s-TRPV2 in pTa, pT1, and pT2 stages was observed, up to a complete loss in pT3 and pT4 UC specimens. Normal human urothelial cells and bladder tissue specimens express TRPV2 at both the mRNA and protein levels. A progressive loss of s-TRPV2 accompanied by a marked increase of hTRPV2 expression was found in high-grade and -stage UC tissues.