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Sample records for predict urothelial carcinoma

  1. Predictive value of topoisomerase IIα immunostaining in urothelial bladder carcinoma

    PubMed Central

    Nakopoulou, L; Zervas, A; Lazaris, A; Constantinides, C; Stravodimos, C; Davaris, P; Dimopoulos, C

    2001-01-01

    Aims—The nuclear enzyme DNA topoisomerase II has been shown to be required for chromatin condensation and chromosomal segregation during mitosis; its isoform topo IIα is linked with active cell proliferation in mammalian cells. The aim of this study was to examine the relation of the expression of topo IIα to the biological behaviour of conventional urinary bladder cancer. Methods—Formalin fixed, paraffin wax embedded tissue from 94 specimens of bladder urothelial cancer were immunohistochemically stained for topo IIα. For each case, a topo IIα index was determined. A similar index had been determined for Ki-67, a known cell proliferation marker. Each case had also been graded, staged, and evaluated for DNA ploidy as well as for p53 and bcl-2 immunoreactivity. Results—Raised topo IIα expression (in ≥ 10% of malignant nuclei) correlated with two adverse prognosticators—high grade (p = 0.027) and invasion of the muscularis propria (p = 0.013), but with no other evaluated parameter. By multivariate survival analysis using Cox's proportional hazard model, high expression of topo IIα was found to be predictive for worse survival (p = 0.0047). Patients' age, tumour stage, and grade were also retained as independent prognostic factors (p = 0.0349, p = 0.00005, and p = 0.0130, respectively). The negative influence of increased topo IIα immunopositivity on patients' survival was also seen in the subgroup of patients with non-muscle invasive carcinomas (p = 0.0004), in patients with a bcl-2 negative phenotype (p = 0.0330), and in those with low Ki-67 indices (p = 0.0341). Conclusions—Because topo IIα and Ki-67 failed to demonstrate a significant inter-relation, they appear to be different molecules that both function at separate phases in the complex process of cellular proliferation. The assessment of increased topo IIα immunoreactivity in specimens from urothelial carcinomas might help to select patients (particularly among those with superficial

  2. Immunoprofile-based subgrouping of urothelial bladder carcinomas for survival prediction.

    PubMed

    Kim, Kyungeun; Sung, Chang Ohk; Park, Bong-Hee; Ku, Ja Yoon; Go, Heounjeong; Ro, Jae Y; Kim, Jiyoon; Cho, Yong Mee

    2015-10-01

    One of the major challenges in bladder cancer management is in distinguishing aggressive from indolent tumors with similar clinicopathological factors, especially in cases of high-grade T1 stage tumors. To define a set of prognostic factors that can be easily assessed in clinical practice with a high cost-effectiveness, the expressions of 11 proteins were examined immunohistochemically in 403 cases of transurethral resection of bladder tumors, then correlated to clinical outcomes. Based on the protein immunoprofiles, urothelial carcinomas were divided into 4 intrinsic molecular subgroups with different clinical outcomes: subgroups 1 and 4 with the poorest survival, subgroup 2 with the best survival, and subgroup 3 with the intermediate survival outcome. The protein expression patterns of the 4 subgroups were mutually exclusive: overexpression of p53, EZH2, E2F1, and IMP3 and high Ki-67 proliferation index in subgroup 1; overexpression of cytoplasmic survivin in subgroup 4; overexpression of membranous TSP1 and cytoplasmic p27 in subgroup 2; and no representative protein overexpression in subgroup 3. Using these protein immunoprofiles, 3 risk groups were generated, which predicted disease-specific survival not only in total bladder carcinoma cases with 0.737 of predictive accuracy but also in high-grade stage T1 tumors with 0.658 of predictive accuracy. These results showed that urothelial carcinomas were composed of 4 clinically relevant molecular subgroups based on protein expression and that overall survival of those patients could be predicted using a set of a small number of protein expressions not only in total cases but also in high-grade stage T1 tumors. PMID:26232864

  3. Concurrent Preoperative Presence of Hydronephrosis and Flank Pain Independently Predicts Worse Outcome of Upper Tract Urothelial Carcinoma

    PubMed Central

    Yeh, Hsin-Chih; Jan, Hau-Chern; Wu, Wen-Jeng; Li, Ching-Chia; Li, Wei-Ming; Ke, Hung-Lung; Huang, Shu-Pin; Liu, Chia-Chu; Lee, Yung-Chin; Yang, Sheau-Fang; Liang, Peir-In; Huang, Chun-Nung

    2015-01-01

    Objectives To investigate the impact of preoperative hydronephrosis and flank pain on prognosis of patients with upper tract urothelial carcinoma. Methods In total, 472 patients with upper tract urothelial carcinoma managed by radical nephroureterectomy were included from Kaohsiung Medical University Hospital Healthcare System. Clinicopathological data were collected retrospectively for analysis. The significance of hydronephrosis, especially when combined with flank pain, and other relevant factors on overall and cancer-specific survival were evaluated. Results Of the 472 patients, 292 (62%) had preoperative hydronephrosis and 121 (26%) presented with flank pain. Preoperative hydronephrosis was significantly associated with age, hematuria, flank pain, tumor location, and pathological tumor stage. Concurrent presence of hydronephrosis and flank pain was a significant predictor of non-organ-confined disease (multivariate-adjusted hazard ratio = 2.10, P = 0.025). Kaplan-Meier analysis showed significantly poorer overall and cancer-specific survival in patients with preoperative hydronephrosis (P = 0.005 and P = 0.026, respectively) and in patients with flank pain (P < 0.001 and P = 0.001, respectively) than those without. However, only simultaneous hydronephrosis and flank pain independently predicted adverse outcome (hazard ratio = 1.98, P = 0.016 for overall survival and hazard ratio = 1.87, P = 0.036 for and cancer-specific survival, respectively) in multivariate Cox proportional hazards models. In addition, concurrent presence of hydronephrosis and flank pain was also significantly predictive of worse survival in patient with high grade or muscle-invasive disease. Notably, there was no difference in survival between patients with hydronephrosis but devoid of flank pain and those without hydronephrosis. Conclusion Concurrent preoperative presence of hydronephrosis and flank pain predicted non-organ-confined status of upper tract urothelial carcinoma. When

  4. ARID1A immunohistochemistry improves outcome prediction in invasive urothelial carcinoma of urinary bladder.

    PubMed

    Faraj, Sheila F; Chaux, Alcides; Gonzalez-Roibon, Nilda; Munari, Enrico; Ellis, Carla; Driscoll, Tina; Schoenberg, Mark P; Bivalacqua, Trinity J; Shih, Ie-Ming; Netto, George J

    2014-11-01

    AT-rich interactive domain 1A (ARID1A) is tumor suppressor gene that interacts with BRG1 adenosine triphosphatase to form a SWI/SNF chromatin remodeling protein complex. Inactivation of ARID1A has been described in several neoplasms, including epithelial ovarian and endometrial carcinomas, and has been correlated with prognosis. In the current study, ARID1A expression in urothelial carcinoma (UC) of the bladder and its association with clinicopathological parameters and outcome are addressed. Five tissue microarrays were constructed from 136 cystectomy specimens performed for UC at our institution. Nuclear ARID1A staining was evaluated using immunohistochemistry. An H-score was calculated as the sum of the products of intensity (0-3) multiplied by extent of expression (0%-100%). Average H-score per case was used for statistical analysis. ARID1A expression was categorized in low and high using Youden index to define the cut point. ARID1A expression significantly increased from normal to noninvasive UC to invasive UC. For both tumor progression and cancer death, Youden index yielded an H-score of 288 as the optimal cut point for ARID1A expression. Low ARID1A expression showed a tendency for lower risk of tumor progression and cancer mortality. Adding ARID1A expression to pathologic features offers a better model for predicting outcome than pathologic features alone. Low ARID1A expression was more frequently seen in earlier stage disease. There was a tendency for low ARID1A expression to predict better outcome. More importantly, the findings indicate that adding ARID1A expression to pathologic features increases the goodness of fit of the predictive model. PMID:25175170

  5. Nested Variant of Urothelial Carcinoma

    PubMed Central

    Venyo, Anthony Kodzo-Grey

    2014-01-01

    Background. Nested variant of urothelial carcinoma was added to the WHO's classification in 2004. Aims. To review the literature on nested variant of urothelial carcinoma. Results. About 200 cases of the tumour have been reported so far and it has the ensuing morphological features: large numbers of small confluent irregular nests of bland-appearing, closely packed, haphazardly arranged, and poorly defined urothelial cells infiltrating the lamina propria and the muscularis propria. The tumour has a bland histomorphologic appearance, has an aggressive biological behaviour, and has at times been misdiagnosed as a benign lesion which had led to a significant delay in the establishment of the correct diagnosis and contributing to the advanced stage of the disease. Immunohistochemically, the tumour shares some characteristic features with high-risk conventional urothelial carcinomas such as high proliferation index and loss of p27 expression. However, p53, bcl-2, or EGF-r immunoreactivity is not frequently seen. The tumour must be differentiated from a number of proliferative lesions of the urothelium. Conclusions. Correct and early diagnosis of this tumour is essential to provide early curative treatment to avoid diagnosis at an advanced stage. A multicentre trial is required to identify treatment options that would improve the outcome of this tumour. PMID:24587796

  6. Prognostic genetic signatures in upper tract urothelial carcinoma

    PubMed Central

    Li, Qiang; Bagrodia, Aditya; Cha, Eugene K.; Coleman, Jonathan A.

    2016-01-01

    Urothelial carcinoma is a highly heterogeneous disease that can arise throughout the entire urothelial lining from the renal pelvis to the proximal urethra. Upper tract urothelial carcinoma (UTUC) is rare and while it shares many similarities with urothelial carcinoma of bladder (UCB), there are also significant differences between UTUC and UCB regarding clinical management and outcomes. No major advances have been made recently in the development of new systemic therapies for urothelial carcinoma, partly due to the lack of understanding of underlying molecular pathogenetic mechanisms. In the past decade, the emergence of next-generation sequencing has greatly enabled genomic characterization of tumor samples. Researchers are currently exploring a personalized approach to augment traditional clinical decision-making based on genetic alterations. In the present review, we summarize current genomic advances in UTUC and discuss the potential implications of these developments for developing prognostic and predictive biomarkers. PMID:26757906

  7. Prognostic Genetic Signatures in Upper Tract Urothelial Carcinoma.

    PubMed

    Li, Qiang; Bagrodia, Aditya; Cha, Eugene K; Coleman, Jonathan A

    2016-02-01

    Urothelial carcinoma is a highly heterogeneous disease that can arise throughout the entire urothelial lining from the renal pelvis to the proximal urethra. Upper tract urothelial carcinoma (UTUC) is rare, and while it shares many similarities with urothelial carcinoma of bladder (UCB), there are also significant differences between UTUC and UCB regarding clinical management and outcomes. No major advances have been made recently in the development of new systemic therapies for urothelial carcinoma, partly due to the lack of understanding of underlying molecular pathogenetic mechanisms. In the past decade, the emergence of next-generation sequencing has greatly enabled genomic characterization of tumor samples. Researchers are currently exploring a personalized approach to augment traditional clinical decision-making based on genetic alterations. In the present review, we summarize current genomic advances in UTUC and discuss the potential implications of these developments for developing prognostic and predictive biomarkers. PMID:26757906

  8. Persistent Uroplakin Expression in Advanced Urothelial Carcinomas: Implications in Urothelial Tumor Progression and Clinical Outcome

    PubMed Central

    Huang, Hong-Ying; Shariat, Shahrokh F.; Sun, Tung-Tien; Lepor, Herbert; Shapiro, Ellen; Hsieh, Jer-Tsong; Ashfaq, Raheela; Lotan, Yair; Wu, Xue-Ru

    2007-01-01

    As the terminal differentiation products of human urothelium, uroplakins (UPs) would be expected to diminish during urothelial tumorigenesis. Surprisingly, recent studies found UPs to be retained even by well-advanced urothelial carcinomas, suggesting that the loss of UPs does not strictly parallel urothelial transformation. Little is known, however, about whether the status of UPs is associated with a particular pathological parameter, tumor’s biological behavior or patient outcome. Here we assessed UP expression by immunohistochemistry on tissue arrays from 285 patients with bladder urothelial carcinomas or non-tumor conditions. UPs were expressed in all 9 normal urothelial specimens, 63/74 (85%) patients with non-muscle-invasive urothelial carcinomas on transurethral resection, 104/202 (51.5%) patients who underwent radical cystectomy for advanced urothelial carcinomas, and 33/50 (66%) lymph node metastases. Normally associated with urothelial apical surface, UPs were localized aberrantly in tumors, including micro-luminal, basal-laminal, cytoplasmic or uniform patterns. In non-muscle-invasive diseases, there was no association between UP expression and disease recurrence, progression or mortality. In contrast, in invasive diseases, absent UP expression was significantly associated with advanced pathologic stage, lymph node metastases, disease recurrence and bladder cancer-specific mortality (p=0.042, p=0.035, p=0.023 and p=0.022, respectively) in univariate analyses. Furthermore, UP status was independent of key cell-cycle regulators, including p53, pRb, p27 and cyclin D1, thus excluding a functional link between these two groups of proteins. Our data demonstrate for the first time that persistent UP expression is associated with a favorable clinical outcome and that UPs may be used as adjunct markers for predicting the prognoses of patients with invasive and metastatic bladder carcinomas. Our results also suggest that UP-positive and –negative carcinomas

  9. Necdin Overexpression Predicts Poor Prognosis in Patients with Urothelial Carcinomas of the Upper Urinary Tract and Urinary Bladder

    PubMed Central

    Chang, I-Wei; Wang, Yu-Hui; Wu, Wen-Jeng; Liang, Peir-In; Li, Wei-Ming; Yeh, Bi-Wen; Wu, Ting-Feng; He, Hong-Lin; Huang, Steven Kuan-Hua; Li, Chien-Feng

    2016-01-01

    Background and Aims: Oncogenesis is a multistep process, resulting from the accumulations of multiple mutations. Of these mutations, self-sufficiency in growth signals, i.e., disruption of cell growth regulation, is the first episode. Nonetheless, the genes associated with cell growth dysregulation have seldom been systematically evaluated in either urothelial carcinomas of upper urinary tract (UTUC) or urothelial carcinomas of urinary baldder (UBUC). By data mining a published transcriptomic dataset of UBUCs (GSE31684), we identified the NDN gene as one of the most significant of those associated with the regulation of cell growth and found this gene is associated with advanced tumor status and metastatic disease (GO:0001558). Accordingly, we analyzed NDN transcript and protein expression with their clinicopathological significance. Materials and Methods: We used real time RT-PCR to detect NDN transcript levels in 27 UTUCs and 27 UBUCs, respectively. Immunohistochemical study was performed to determine NDN protein (a.k.a. Necdin) expression evaluated by H-score method in 340 UTUCs and 295 UBUCs. NDN expression was further correlated with clinicopathological features and disease-specific survival (DSS) and metastasis-free survival (MeFS). Results: NDN transcriptional level was significantly higher in UCs of both sites with stepwise more advanced pT statuses. Through immunohistochemistry, we found NDN protein expression was significantly associated with adverse clinicopathological parameters, e.g., advanced pT status, nodal metastasis, high grade histological patterns, and frequent mitotses (all P<0.05). In univariate analysis, NDN overexpression not only predicted worse DSS and MeFS in both the UTUC and UBUC groups, it also served as an independent prognostic factor for DSS and MeFS in multivariate analysis (all P<0.05). Conclusions: NDN may play an important role in tumor progression in UC and could serve as a prognostic biomarker and a potential novel therapeutic

  10. Ureterocele urothelial carcinoma: managing a rare presentation

    PubMed Central

    Astigueta, Juan Carlos; Abad-Licham, Milagros; Silva, Eloy; Alvarez, Víctor; Piccone, Francis; Cruz, Enrique; Redorta, Joan Palou

    2016-01-01

    It is very uncommon for urothelial carcinoma to develop in an ureterocele. It is generally discovered in an imaging study or in connection with haematuria. We found very few reports in the literature. Here, we report on the case of a 71-year-old male who initially presented with haematuria and low back pain and who then underwent transurethral resection for an intraureterocele tumour. Pathology confirmed urothelial carcinoma. PMID:26913072

  11. Genomic Biomarkers for the Prediction of Stage and Prognosis of Upper Tract Urothelial Carcinoma

    PubMed Central

    Sfakianos, John P.; Zabor, Emily C.; Bochner, Bernard H.; Al-Ahmadie, Hikmat A.; Solit, David B.; Coleman, Jonathan A.; Iyer, Gopa; Scott, Sasinya N.; Shah, Ronak; Ostrovnaya, Irina; Lee, Byron; Desai, Neil B.; Ren, Qinghu; Rosenberg, Jonathan E.; Dalbagni, Guido; Bajorin, Dean F.; Reuter, Victor E.; Berger, Michael F.

    2016-01-01

    Purpose Genomic characterization of radical nephroureterectomy (RNU) specimens in patients with upper tract urothelial carcinoma (UTUC) may allow for thoughtful integration of systemic and targeted therapies. We sought to determine if genomic alterations in UTUC are associated with adverse pathologic and clinical outcomes. Materials and Methods Next-generation exon capture sequencing of 300 cancer-associated genes was performed in 83 patients with UTUC. Genomic alterations were assessed individually and also grouped into core signal transduction pathways or canonical cell functions for association with clinicopathologic outcomes. Binary outcomes, including grade (high vs. low), T stage (pTa/T1/T2 vs. pT3/T4), and organ-confined status (≤pT2 and N0/Nx vs. >pT2 or N+) were assessed with Kruskal-Wallis test and Fisher's exact test as appropriate. Associations between alterations and survival were estimated using the Kaplan-Meier method and Cox regression. Results Of the 24 most commonly altered genes within 9 pathways, TP53/MDM2 alterations and FGFR3 mutations were the only two alterations uniformly associated with high-grade, advanced stage, non-organ-confined disease, recurrence-free survival, and cancer-specific survival. TP53/MDM2 alterations were associated with adverse clinicopathologic outcomes whereas FGFR3 mutations were associated with favorable outcomes. We created a risk score using TP53/MDM2 and FGFR3 status that was able to discriminate between adverse pathologic and clinical outcomes, including in the subset of patients with high-grade disease. The study is limited by small numbers and lack of validation. Conclusions Our data indicate that specific genomic alterations in RNU specimens correlate with tumor grade, stage, and cancer-specific survival outcomes. PMID:26778714

  12. A Novel Risk Stratification to Predict Local-Regional Failures in Urothelial Carcinoma of the Bladder After Radical Cystectomy

    SciTech Connect

    Baumann, Brian C.; Guzzo, Thomas J.; He Jiwei; Keefe, Stephen M.; Tucker, Kai; Bekelman, Justin E.; Hwang, Wei-Ting; Vaughn, David J.; Malkowicz, S. Bruce; Christodouleas, John P.

    2013-01-01

    Purpose: Local-regional failures (LF) following radical cystectomy (RC) plus pelvic lymph node dissection (PLND) with or without chemotherapy for invasive urothelial bladder carcinoma are more common than previously reported. Adjuvant radiation therapy (RT) could reduce LF but currently has no defined role because of previously reported morbidity. Modern techniques with improved normal tissue sparing have rekindled interest in RT. We assessed the risk of LF and determined those factors that predict recurrence to facilitate patient selection for future adjuvant RT trials. Methods and Materials: From 1990-2008, 442 patients with urothelial bladder carcinoma at University of Pennsylvania were prospectively followed after RC plus PLND with or without chemotherapy with routine pelvic computed tomography (CT) or magnetic resonance imaging (MRI). One hundred thirty (29%) patients received chemotherapy. LF was any pelvic failure detected before or within 3 months of distant failure. Competing risk analyses identified factors predicting increased LF risk. Results: On univariate analysis, pathologic stage {>=}pT3, <10 nodes removed, positive margins, positive nodes, hydronephrosis, lymphovascular invasion, and mixed histology significantly predicted LF; node density was marginally predictive, but use of chemotherapy, number of positive nodes, type of surgical diversion, age, gender, race, smoking history, and body mass index were not. On multivariate analysis, only stage {>=}pT3 and <10 nodes removed were significant independent LF predictors with hazard ratios of 3.17 and 2.37, respectively (P<.01). Analysis identified 3 patient subgroups with significantly different LF risks: low-risk ({<=}pT2), intermediate-risk ({>=}pT3 and {>=}10 nodes removed), and high-risk ({>=}pT3 and <10 nodes) with 5-year LF rates of 8%, 23%, and 42%, respectively (P<.01). Conclusions: This series using routine CT and MRI surveillance to detect LF confirms that such failures are relatively common

  13. Metastatic brain tumor from urothelial carcinoma of the prostatic urethra

    PubMed Central

    Morita, Kohei; Oda, Masashi; Koyanagi, Masaomi; Saiki, Masaaki

    2016-01-01

    Background: Urothelial carcinoma occurs in the bladder, upper urinary tract, and lower urinary tract, including prostatic urethra. A majority of the reported cases of intracranial metastasis from urothelial carcinoma originates from the bladder and upper urinary tract. Brain metastasis from urothelial carcinoma of the prostatic urethra has not yet been reported in the literature. Case Description: A 72-year-old male presented with a metastatic brain tumor and a 3-year history of urothelial carcinoma of the prostatic urethra treated with cystourethrectomy and chemotherapy with gemcitabine-cisplatin. Pathological diagnosis for tumor removal was compatible with metastatic brain tumor from urothelial carcinoma. Conclusion: Brain metastasis from urothelial carcinoma of the prostatic urethra has not yet been reported in the literature. It is an extremely rare case, however, we should be careful of brain metastasis during follow-up for urothelial carcinoma in the lower urinary tract. PMID:27512612

  14. The Emerging Molecular Landscape of Urothelial Carcinoma.

    PubMed

    Solomon, James P; Hansel, Donna E

    2016-09-01

    Although there have been many recent discoveries in the molecular alterations associated with urothelial carcinoma, current understanding of this disease lags behind many other malignancies. Historically, a two-pathway model had been applied to distinguish low- and high-grade urothelial carcinoma, although significant overlap and increasing complexity of molecular alterations has been recently described. In many cases, mutations in HRAS and FGFR3 that affect the MAPK and PI3K pathways seem to be associated with noninvasive low-grade papillary tumors, whereas mutations in TP53 and RB that affect the G1-S transition of the cell cycle are associated with high-grade in situ and invasive carcinoma. However, recent large-scale analyses have identified overlap in these pathways relative to morphology, and in addition, many other variants in a wide variety of oncogenes and tumor-suppressor genes have been identified. New technologies including next-generation sequencing have enabled more detailed analysis of urothelial carcinoma, and several groups have proposed molecular classification systems based on these data, although consensus is elusive. This article reviews the current understanding of alterations affecting oncogenes and tumor-suppressor genes associated with urothelial carcinoma, and their application in the context of morphology and classification schema. PMID:27523968

  15. Mucinous Urothelial Carcinoma of the Renal Pelvis

    PubMed Central

    Behzatğlu, Kemal; Boyaci, Ceren; Okçu, Oğuzhan; Hacihasanoğlu, Ezgi; Çakir, Yasemin; Darakçi, Seher

    2014-01-01

    Urothelial carcinoma with abundant myxoid stroma is a newly-described and extremely rare entity. Since only very few cases have been reported, there is no consensus on its nomenclature. Microscopic examination revealed invasive urothelial carcinoma with widespread low-grade noninvasive areas. There were focal invasive areas in the neighborhood of the renal parenchyma. Malignant urothelial tumor/cell groups localized in the stroma had abundant myxoid/mucinous background in the invasive areas. The cytoplasm of the tumoral cells was more eosinophilic in these areas and the cells formed small groups and cords. Histochemically, PAS and Alcian Blue were positive in the cytoplasm of the tumoral cells and in the stroma while negative in the non-mucinous areas. Immunohistochemically, the tumoral cells of the mucinous invasive areas diffusely expressed MUC1 and MUC2. We discuss the origin of the mucinous/myxoid stroma, the tumor’s nature and its nomenclature with histochemical and immunohistochemical features. PMID:25568745

  16. Brain and Skin Metastasis From Urothelial Carcinoma of the Bladder

    PubMed Central

    Chung, Jae Hoon; Lee, Joo Yong; Pyo, Ju Yeon; Oh, Young Ha; Lee, Seung Wook; Moon, Hong Sang

    2013-01-01

    Brain and skin metastasis from urothelial carcinoma of the bladder is rare. There have been few case reports of the clinical course of patients with metastatic urothelial carcinoma of the brain and skin. In the present case, a 60-year-old man had undergone radical cystectomy with an ileal conduit owing to urothelial carcinoma (T1N0M0). The patient developed dizziness 9 years later and a solitary brain tumor was discovered in his left cerebellar hemisphere. The tumor was totally resected and the mass was verified to be metastatic urothelial carcinoma. One year after the metastasectomy of the brain lesion, multiple erythematous nodular lesions developed on his abdominal skin. The skin lesions were excised and verified to be metastatic urothelial carcinoma. This report describes this case of urothelial carcinoma of the bladder that metastasized to the brain and abdominal skin. PMID:23362451

  17. 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

  18. Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma

    PubMed Central

    2014-01-01

    Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. To date, no molecularly targeted agents have been approved for the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell cycle regulation, chromatin regulation, and kinase signaling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in miRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the PI3K/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any common cancer studied to date, suggesting the future possibility of targeted therapy for chromatin abnormalities. PMID:24476821

  19. Comprehensive molecular characterization of urothelial bladder carcinoma.

    PubMed

    2014-03-20

    Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities. PMID:24476821

  20. Cutaneous invasion from sarcomatoid urothelial carcinoma: clinical and dermatopathologic features*

    PubMed Central

    Bernardes Filho, Fred; de Melo, Alessandro Severo Alves; Pires, Andréa Rodriguez Cordovil; Lupi, Omar; Neves, Daniel Gama das; da Cruz, Margareth Fernandes; Kac, Bernard Kawa

    2016-01-01

    In Brazil, without considering the non-melanoma skin tumors, bladder cancer in men is the eighth most common, and the urothelial carcinoma or transitional cell carcinoma is the most common among these. Cutaneous metastases from urothelial neoplasms appear as single or multiple erythematous, infiltrated nodules or plaques, and like other cases of distant disease, it is indicative of poor prognosis. The invasive urothelial carcinoma is recognized for its ability to present divergent differentiation and morphological variants. The sarcomatoid urothelial carcinoma is a rare cancer that consists of two different components: one composed of epithelial tissue and the other with sarcomatoid features of mesenchymal origin. The authors describe a case of cutaneous metastasis of sarcomatoid urothelial carcinoma in a 63-year-old male patient. PMID:26982782

  1. Urothelial carcinoma: Stem cells on the edge

    PubMed Central

    Brandt, William D.; Matsui, William; Rosenberg, Jonathan E.; He, Xiaobing; Ling, Shizhang; Schaeffer, Edward M.

    2010-01-01

    Tumors are heterogeneous collections of cells with highly variable abilities to survive, grow, and metastasize. This variability likely stems from epigenetic and genetic influences, either stochastic or hardwired by cell type-specific lineage programs. That differentiation underlies tumor cell heterogeneity was elegantly demonstrated in hematopoietic tumors, in which rare primitive cells (cancer stem cells (CSCs)) resembling normal hematopoietic stem cells are ultimately responsible for tumor growth and viability. Because of the compelling clinical implications CSCs pose—across the entire spectrum of cancers—investigators applied the CSC model to cancers arising in tissues with crudely understood differentiation programs. Instead of relying on differentiation, these studies used empirically selected markers and statistical arguments to identify CSCs. The empirical approach has stimulated important questions about “stemness” in cancer cells as well as the validity and stoichiometry of CSC assays. The recent identification of urothelial differentiation programs in urothelial carcinomas (UroCas) supports the idea that solid epithelial cancers (carcinomas) develop and differentiate analogously to normal epithelia and provides new insights about the spatial localization and molecular makeup of carcinoma CSCs. Importantly, CSCs from invasive UroCas (UroCSCs) appear well situated to exchange important signals with adjacent stroma, to escape immune surveillance, and to survive cytotoxic therapy. These signals have potential roles in treatment resistance and many participate in druggable cellular pathways. In this review, we discuss the implications of these findings in understanding CSCs and in better understanding how UroCas form, progress, and should be treated. PMID:20012172

  2. Pericardial Metastasis Induced Tamponade from Urothelial Carcinoma: A Rare Entity

    PubMed Central

    Khan, Rafay; Jehangir, Waqas; Tulpule, Sunil; Osman, Mohamed; Singh, Shilpi; Sen, Shuvendu

    2016-01-01

    Urothelial carcinoma in a few cases may result in cardiac metastasis. A rare presentation of this condition is its diagnosis as a result of cardiac tamponade. Tamponade is an unusual entity as a result of urothelial carcinoma and has only been reported in four cases. There have also been only a total of fifteen cases of cardiac metastasis from this form of malignancy. It is through this discussion that we emphasize the importance of early detection and monitoring of cardiac symptoms with the implementation of echocardiogram imaging. Although not feasible in all patients it may be considered in those presenting with cardiac and pulmonary symptoms. In this case we discuss the presentation of a 71-year-old gentleman with a history of urothelial carcinoma after cystectomy and while on chemotherapy presented with new onset atrial fibrillation and later was diagnosed with cardiac tamponade as a result of malignant metastasis. PMID:27148366

  3. A Rare Cause of Testicular Metastasis: Upper Tract Urothelial Carcinoma

    PubMed Central

    Manav, Alper Nesip; Kazan, Ercan; Ertek, Mehmet Şirin; Amasyalı, Akın Soner; Çulhacı, Nil; Erol, Haluk

    2014-01-01

    Metastatic testicular cancers are rare. Primary tumor sources are prostate, lung, and gastrointestinal tract for metastatic testicular cancers. Metastasis of urothelial carcinoma (UC) to the testis is extremely rare. Two-thirds of upper tract urothelial carcinoma (UTUC) is of invasive stage at diagnosis and metastatic sites are the pelvic lymph nodes, liver, lung, and bone. We report a rare case of metastatic UTUC to the testis which has not been reported before, except one case in the literature. Testicular metastasis of UC should be considered in patients with hematuria and testicular swelling. PMID:25120937

  4. A rare cause of testicular metastasis: upper tract urothelial carcinoma.

    PubMed

    Manav, Alper Nesip; Kazan, Ercan; Ertek, Mehmet Şirin; Amasyalı, Akın Soner; Culhacı, Nil; Erol, Haluk

    2014-01-01

    Metastatic testicular cancers are rare. Primary tumor sources are prostate, lung, and gastrointestinal tract for metastatic testicular cancers. Metastasis of urothelial carcinoma (UC) to the testis is extremely rare. Two-thirds of upper tract urothelial carcinoma (UTUC) is of invasive stage at diagnosis and metastatic sites are the pelvic lymph nodes, liver, lung, and bone. We report a rare case of metastatic UTUC to the testis which has not been reported before, except one case in the literature. Testicular metastasis of UC should be considered in patients with hematuria and testicular swelling. PMID:25120937

  5. Expression of Estrogen Receptor Beta Predicts Oncologic Outcome of pT3 Upper Urinary Tract Urothelial Carcinoma Better Than Aggressive Pathological Features

    PubMed Central

    Luo, Hao Lun; Sung, Ming Tse; Tsai, Eing Mei; Lin, Chang Shen; Lee, Nai Lun; Chung, Yueh-Hua; Chiang, Po Hui

    2016-01-01

    Upper urinary tract urothelial carcinoma (UT-UC) is rare and treatment options or prognostic markers are limited. There is increasing evidence indicating that urothelial carcinoma may be an endocrine-related cancer. The aim of this study was to analyze the prognostic effect of estrogen receptor beta (ERβ) on the outcome of UT-UC. From 2005 to 2012, this study included 105 patients with pT3 UT-UC. Perioperative factors, pathological features, and ERβ immunostaining were reviewed and prognostic effects were examined by multivariate analysis. This study divided patients into either the ERβ-high (n = 52) or ERβ-low (n = 53) group and analyzed their oncologic outcomes. All pathological features except infiltrating tumor architecture (significantly higher incidence in ERβ-low group, p = 0.004) are symmetric in both groups. Low ERβ expression was significantly correlated with local recurrence and distant metastasis in univariate analysis (p = 0.035 and 0.004, respectively) and multivariate analysis (p = 0.05 and 0.008, respectively). Cell line study also proved that knock down of ERβ cause less UTUC proliferation and migration. In addition, ERβ agonist also enhanced the cytotoxic and migration inhibition effect of cisplatin and ERβ antagonist cause the UTUC cell more resistant to cisplatin. This result may help identify patients in need of adjuvant therapy or develop potential targeted therapy. PMID:27052470

  6. Novel immunotherapeutic approaches to the treatment of urothelial carcinoma.

    PubMed

    Muthigi, Akhil; George, Arvin K; Brancato, Sam J; Agarwal, Piyush K

    2016-06-01

    Immunotherapy has long played a role in urothelial cancers with the use of bacille Calmette Guérin (BCG) being a mainstay in the treatment of nonmuscle invasive bladder cancer. Novel therapeutic approaches have not significantly impacted mortality in this population and so a renaissance in immunotherapy has resulted. This includes recombinant BCG, oncolytic viruses, monoclonal antibodies, vaccines, and adoptive T-cell therapy. Herein, we provide a review of the current state of the art and future therapies regarding immunotherapeutic strategies for urothelial carcinoma. PMID:27247630

  7. Novel immunotherapeutic approaches to the treatment of urothelial carcinoma

    PubMed Central

    Muthigi, Akhil; George, Arvin K.; Brancato, Sam J.; Agarwal, Piyush K.

    2016-01-01

    Immunotherapy has long played a role in urothelial cancers with the use of bacille Calmette Guérin (BCG) being a mainstay in the treatment of nonmuscle invasive bladder cancer. Novel therapeutic approaches have not significantly impacted mortality in this population and so a renaissance in immunotherapy has resulted. This includes recombinant BCG, oncolytic viruses, monoclonal antibodies, vaccines, and adoptive T-cell therapy. Herein, we provide a review of the current state of the art and future therapies regarding immunotherapeutic strategies for urothelial carcinoma. PMID:27247630

  8. Optimizing oncologic outcomes in upper tract urothelial carcinoma.

    PubMed

    Hutchinson, Ryan C; Margulis, Vitaly

    2016-08-01

    Upper tract urothelial carcinoma is a disease with rapidly changing management. Though rare, recent multi-institutional collaborations have allowed for study of its biology and treatment outcomes in greater detail than ever before. In coming years physicians treating ureteral cancers will have an expanded armamentarium of treatment options and better data on which to base treatment decisions. Currently there is exciting work underway both in terms of developmental therapies, including neoadjuvant chemotherapy, as well as improved prognostics allowing for better utilization of nephron-sparing approaches where applicable. We present a review of current management techniques and the data on which to base management choices for surgeons treating upper tract urothelial carcinoma. The ultimate goal is improving outcomes for patients; with recent developments and current work in the field, there is reason to be optimistic for the future in this rare, challenging disease. PMID:26756501

  9. Risk Prediction Models of Locoregional Failure After Radical Cystectomy for Urothelial Carcinoma: External Validation in a Cohort of Korean Patients

    SciTech Connect

    Ku, Ja Hyeon; Kim, Myong; Jeong, Chang Wook; Kwak, Cheol; Kim, Hyeon Hoe

    2014-08-01

    Purpose: To evaluate the predictive accuracy and general applicability of the locoregional failure model in a different cohort of patients treated with radical cystectomy. Methods and Materials: A total of 398 patients were included in the analysis. Death and isolated distant metastasis were considered competing events, and patients without any events were censored at the time of last follow-up. The model included the 3 variables pT classification, the number of lymph nodes identified, and margin status, as follows: low risk (≤pT2), intermediate risk (≥pT3 with ≥10 nodes removed and negative margins), and high risk (≥pT3 with <10 nodes removed or positive margins). Results: The bootstrap-corrected concordance index of the model 5 years after radical cystectomy was 66.2%. When the risk stratification was applied to the validation cohort, the 5-year locoregional failure estimates were 8.3%, 21.2%, and 46.3% for the low-risk, intermediate-risk, and high-risk groups, respectively. The risk of locoregional failure differed significantly between the low-risk and intermediate-risk groups (subhazard ratio [SHR], 2.63; 95% confidence interval [CI], 1.35-5.11; P<.001) and between the low-risk and high-risk groups (SHR, 4.28; 95% CI, 2.17-8.45; P<.001). Although decision curves were appropriately affected by the incidence of the competing risk, decisions about the value of the models are not likely to be affected because the model remains of value over a wide range of threshold probabilities. Conclusions: The model is not completely accurate, but it demonstrates a modest level of discrimination, adequate calibration, and meaningful net benefit gain for prediction of locoregional failure after radical cystectomy.

  10. Conditional Survival in de novo Metastatic Urothelial Carcinoma

    PubMed Central

    Yuh, Bertram; DeWalt, Kara; Kazarian, Austin; Vogelzang, Nicholas; Nelson, Rebecca A.

    2015-01-01

    Background Second-line therapy is frequently utilized for metastatic urothelial carcinoma, but there are limited data to guide this approach. While an assessment of overall survival based on registry data may not capture the impact of second- and third-line therapies on clinical outcome, this may be reflected in relative conditional survival (RCS). Methods Patients with stage IV urothelial carcinoma diagnosed from 1990–2010 were identified from the Surveillance, Epidemiology and End Results (SEER) dataset. The association of clinicopathologic variables with disease specific survival (DSS) was explored through univariate and multivariate analyses. DSS in subgroups divided by time period (1990–2000 v 2001–2010) was compared using the Kaplan-Meier method and log-rank test. One-year RCS at annual landmarks up to 5 years was compared in subgroups divided by time period. Results Of 261,987 patients diagnosed with urothelial carcinoma from 1990–2010, 3,110 patients met criteria for the current analysis. Characteristics of patients diagnosed between 1990 and 2000 (n = 810) and 2001 to 2010 (n = 2,300) were similar and there was no significant difference in DSS between the two groups. On multivariate analysis, older age (age ≥ 80) was associated with shorter DSS (HR 1.79, 95%CI 1.48–2.15), but no association was found between time period of diagnosis and outcome. One-year RCS improved substantially through successive annual landmarks up to 5 years, but no differences were seen in subgroups divided by time of diagnosis. Conclusions No difference in RCS was observed amongst patients with stage IV urothelial carcinoma diagnosed from 1990–2000 and 2001–2010. A lack of difference in RCS (more so than cumulative DSS) may reflect a lack of progress in salvage therapies for the disease. PMID:26308952

  11. ARID1A alteration in aggressive urothelial carcinoma and variants of urothelial carcinoma.

    PubMed

    Li, Jianhong; Lu, Shaolei; Lombardo, Kara; Monahan, Rene; Amin, Ali

    2016-09-01

    ARID1A mutation leads to loss of the products of this tumor-suppressor gene. Studies demonstrated ARID1A mutation in 20% of stage IV urothelial carcinomas (UCs) with worse prognosis. The expression of ARID1A in aggressive variants of UC is not studied properly. From 2000 to 2015, 81 variants of UC (29 micropapillary, 33 sarcomatoid, 31 small cell, 2 nested, and 3 plasmacytoid variants) were identified in the archives of Rhode Island Hospital. Immunohistochemistry for anti-ARID1A antibody (Sigma-Aldrich, St Louis, MO) was performed. The staining pattern was semiquantitatively scored, and results were analyzed by Fisher exact test (2 tailed) on contingency tables, survival curve, and log-rank test. Patients were predominantly male (78%) with mean age of 67.9 years. The plasmacytoid variant group occurred in younger ages (mean: 54 years). Half of the specimens contained concurrent conventional UCs. Normal urothelium invariably exhibited strong ARID1A nuclear staining. There was no difference in expression between upper and lower tracts. ARID1A expression was lower in the variants compared with conventional UCs (P<.0001). In micropapillary UCs, an inverse correlation between stage and ARID1A expression was noted, with significant correlation between ARID1A expression and overall survival (P=.0221). Sarcomatoid UCs and small cell CCs showed lower ARID1A expression compared with UCs that was not statistically significant, and neither showed any significant correlation with stage or overall survival. ARID1A expression is significantly decreased in higher stages of UC and its aggressive variants; therefore, ARID1A mutation appears to play an important role in the prognosis of UC and its aggressive variants. This finding may have therapeutic implications. PMID:27137986

  12. Upper tract urothelial carcinoma: Paradigm shift towards nephron sparing management

    PubMed Central

    Fiuk, Julia V; Schwartz, Brad F

    2016-01-01

    Upper tract urothelial carcinoma (UTUC) is relatively rare compared to urothelial carcinoma of the lower tract, comprising only 5%-10% of all urothelial cancers. Although both entities share histologic properties, UTUC tends to be more invasive at diagnosis and portend a worse prognosis, with a 5 year overall mortality of 23%. To date, the gold standard management of UTUC has been radical nephroureterectomy (RNU), with nephron sparing techniques reserved for solitary kidneys or cases where the patient could not tolerate radical surgery. Limited data from these series, as well as select series where nephron-sparing endoscopic management has been offered to a broader patient base, suggest that minimally invasive, nephron sparing techniques can offer comparable oncologic and survival outcomes to RNU in appropriately selected patients. We review the current literature on the topic and discuss long term outcomes and sequelae of the gold standard treatment, RNU. We also discuss the oncologic outcomes of minimally invasive, endoscopic management of UTUC. Our goal is to provide the reader a comprehensive overview of the current state of the field in order to inform and guide their treatment decisions. PMID:26981440

  13. Epithelial plasticity in urothelial carcinoma: Current advancements and future challenges.

    PubMed

    Garg, Minal

    2016-08-26

    Urothelial carcinoma (UC) of the bladder is characterized by high recurrence rate where a subset of these cells undergoes transition to deadly muscle invasive disease and later metastasizes. Urothelial cancer stem cells (UroCSCs), a tumor subpopulation derived from transformation of urothelial stem cells, are responsible for heterogeneous tumor formation and resistance to systemic treatment in UC of the bladder. Although the precise reason for pathophysiologic spread of tumor is not clear, transcriptome analysis of microdissected cancer cells expressing multiple progenitor/stem cell markers validates the upregulation of genes that derive epithelial-to-mesenchymal transition. Experimental studies on human bladder cancer xenografts describe the mechanistic functions and regulation of epithelial plasticity for its cancer-restraining effects. It has been further examined to be associated with the recruitment of a pool of UroCSCs into cell division in response to damages induced by adjuvant therapies. This paper also discusses the various probable therapeutic approaches to attenuate the progressive manifestation of chemoresistance by co-administration of inhibitors of epithelial plasticity and chemotherapeutic drugs by abrogating the early tumor repopulation as well as killing differentiated cancer cells. PMID:27621760

  14. Epithelial plasticity in urothelial carcinoma: Current advancements and future challenges

    PubMed Central

    Garg, Minal

    2016-01-01

    Urothelial carcinoma (UC) of the bladder is characterized by high recurrence rate where a subset of these cells undergoes transition to deadly muscle invasive disease and later metastasizes. Urothelial cancer stem cells (UroCSCs), a tumor subpopulation derived from transformation of urothelial stem cells, are responsible for heterogeneous tumor formation and resistance to systemic treatment in UC of the bladder. Although the precise reason for pathophysiologic spread of tumor is not clear, transcriptome analysis of microdissected cancer cells expressing multiple progenitor/stem cell markers validates the upregulation of genes that derive epithelial-to-mesenchymal transition. Experimental studies on human bladder cancer xenografts describe the mechanistic functions and regulation of epithelial plasticity for its cancer-restraining effects. It has been further examined to be associated with the recruitment of a pool of UroCSCs into cell division in response to damages induced by adjuvant therapies. This paper also discusses the various probable therapeutic approaches to attenuate the progressive manifestation of chemoresistance by co-administration of inhibitors of epithelial plasticity and chemotherapeutic drugs by abrogating the early tumor repopulation as well as killing differentiated cancer cells. PMID:27621760

  15. SPOCK1 Overexpression Confers a Poor Prognosis in Urothelial Carcinoma

    PubMed Central

    Ma, Li-Jung; Wu, Wen-Jen; Wang, Yu-Hui; Wu, Ting-Feng; Liang, Peir-In; Chang, I-Wei; He, Hong-Lin; Li, Chien-Feng

    2016-01-01

    Purpose:The majority deaths of cancer patients are related to metastasis, thus genes associated with cell motility interest us. SPOCK1 was elected by data mining and serial evaluation. In addition, SPOCK1 has been reported to be highly expressed in different human cancers and been related to adverse outcomes. Therefore, we validate its prognostic significance in urothelial carcinoma (UC). Materials and Methods:Real-time RT-PCR assay was used to detect SPOCK1 transcript level in 27 urinary tract urothelial carcinoma (UTUC) and 27 urinary bladder urothelial carcinoma (UBUC) samples. Immunohistochemistry evaluated by H-score determined SPOCK1 expressions in 340 UTUCs and 295 UBUCs. The transcript and protein expression were correlated with clinicopathological features. Further evaluations of the prognostic significance of SPOCK1 for disease-specific survival (DSS) and metastasis-free survival (MeFS) were analyzed. Results:The expressions of SPOCK1 in UC were higher than those in normal urothelium by immunohistochemistry. The statistical analysis of clinicopathologic characteristics and immunohistochemistry showed that the higher expression of SPOCK1 was correlated to pT status (P<0.001), lymph node metastasis (UTUC, P=0.006; UBUC, P=0.033), higher histological grade (UTUC, P<0.001; UBUC, P<0.001), vascular invasion (UTUC, P<0.001; UBUC, P<0.001), perineurial invasion (UTUC, P<0.001; UBUC, P=0.001) and frequent mitosis (UTUC, P<0.001; UBUC, P=0.001). The prognosis of SPOCK1 of UC showed high SPOCK1 expression had significantly worse DSS and MeFS. Conclusions:The investigation demonstrated that the higher expression of SPOCK1 correlates with a poor prognosis in UC. PMID:26918061

  16. Upper tract urothelial carcinoma: epidemiology, high risk populations and detection.

    PubMed

    Redrow, Grant P; Matin, Surena F

    2016-08-01

    Upper tract urothelial carcinoma (UTUC) is a rare but highly morbid genitourinary malignancy. In 2014 approximately 15,000 new cases were diagnosed in the United States. It accounts for approximately 5-10% of all urothelial cell carcinomas, and 10% of renal tumors. Recent research has increased understanding of the epidemiology of this disease, including several high-risk populations. Environmental exposure to tobacco as well as aristolochic acid, and other carcinogens significantly increase the development of UTUC. Additionally, the genetic condition of hereditary nonpolyposis colorectal carcinoma (HNPCC), also known as Lynch Syndrome (LS) is linked to development of UTUC. Advances in imaging, ureteroscopy, cytological techniques and pathological recognition have allowed for improved detection of primary tumors and recurrent disease. Non-invasive imaging with computed tomography (CT) and magnetic resonance imaging (MRI) now represent the gold standard in imaging detection and surveillance, while technological advances in ureteroscopy allow for minimally invasive approaches to obtain pathologic diagnosis anywhere within the upper tracts. This review will highlight these recent improvements to allow better understanding of who is affected by this rare and morbid disease, as well as the latest developments in detection and surveillance. PMID:27008468

  17. Complement Component 1, s Subcomponent Overexpression is an Independent Poor Prognostic Indicator in Patients with Urothelial Carcinomas of the Upper Urinary Tract and Urinary Bladder

    PubMed Central

    Chang, I-Wei; Lin, Victor Chia-Hsiang; Wu, Wen-Jen; Liang, Peir-In; Li, Wei-Ming; Yeh, Bi-Wen; He, Hong-Lin; Liao, Alex Chien-Hwa; Chan, Ti-Chun; Li, Chien-Feng

    2016-01-01

    Purpose: Urothelial carcinoma of the urinary bladder and upper tract is prevalent. By subjecting a documented transcriptome data set of urothelial carcinoma of bladder (GSE31684) to data mining and focusing on genes linked to peptidase activity (GO:0008233), we recognized C1S as the most significantly upregulated gene related to an advanced tumor status and metastasis. We subsequently analyzed the association of both C1S mRNA and its encoded protein expression with the clinical and pathological significance. Materials and Methods: We used real-time reverse transcription polymerase chain reaction to detect C1S transcription levels in 20 cases each of urothelial carcinoma of bladder and upper tract. An immunohistochemical stain was conducted to determine C1s protein expression levels in patients with urothelial carcinoma of upper tract (n = 340) and urinary bladder (n = 295). Furthermore, we examined the correlation of C1s expression with clinicopathological characteristics, disease-specific survival, and metastasis-free survival. Results: C1S transcription levels were significantly high in patients with advanced-stage tumors of both groups (all P < .05). Immunohistochemical analysis revealed that C1s expression levels were significantly associated with adverse clinicopathological parameters in both groups of urothelial carcinoma (all P < .05). C1s overexpression predicted poor disease-specific and metastasis-free survival rates for both urothelial carcinoma groups in the univariate analysis, and it was also an independent prognostic factor in the multivariate analysis (all P < .05). Conclusions: C1s may play a pivotal role in urothelial carcinoma progress and can represent a vital prognostic marker and a promising new therapeutic target in urothelial carcinoma. PMID:27471555

  18. Canine urothelial carcinoma: genomically aberrant and comparatively relevant

    PubMed Central

    Shapiro, S. G.; Raghunath, S.; Williams, C.; Motsinger-Reif, A. A.; Cullen, J. M.; Liu, T.; Albertson, D.; Ruvolo, M.; Lucas, A. Bergstrom; Jin, J.; Knapp, D. W.; Schiffman, J. D.

    2015-01-01

    Urothelial carcinoma (UC), also referred to as transitional cell carcinoma (TCC), is the most common bladder malignancy in both human and canine populations. In human UC, numerous studies have demonstrated the prevalence of chromosomal imbalances. Although the histopathology of the disease is similar in both species, studies evaluating the genomic profile of canine UC are lacking, limiting the discovery of key comparative molecular markers associated with driving UC pathogenesis. In the present study, we evaluated 31 primary canine UC biopsies by oligonucleotide array comparative genomic hybridization (oaCGH). Results highlighted the presence of three highly recurrent numerical aberrations: gain of dog chromosome (CFA) 13 and 36 and loss of CFA 19. Regional gains of CFA 13 and 36 were present in 97% and 84% of cases, respectively, and losses on CFA 19 were present in 77% of cases. Fluorescence in situ hybridization (FISH), using targeted bacterial artificial chromosome (BAC) clones and custom Agilent SureFISH probes, was performed to detect and quantify these regions in paraffin-embedded biopsy sections and urine-derived urothelial cells. The data indicate that these three aberrations are potentially diagnostic of UC. Comparison of our canine oaCGH data with that of 285 human cases identified a series of shared copy number aberrations. Using an informatics approach to interrogate the frequency of copy number aberrations across both species, we identified those that had the highest joint probability of association with UC. The most significant joint region contained the gene PABPC1, which should be considered further for its role in UC progression. In addition, cross-species filtering of genome-wide copy number data highlighted several genes as high-profile candidates for further analysis, including CDKN2A, S100A8/9, and LRP1B. We propose that these common aberrations are indicative of an evolutionarily conserved mechanism of pathogenesis and harbor genes key to

  19. The role of WNT signalling in urothelial cell carcinoma.

    PubMed

    Ahmad, I

    2015-10-01

    Urothelial cell carcinoma (UCC) of the bladder is one of the most common malignancies, causing considerable morbidity and mortality worldwide. It is unique among the epithelial carcinomas as two distinct pathways to tumourigenesis appear to exist: low grade, recurring papillary tumours usually contain oncogenic mutations in FGFR3 or HRAS whereas high grade, muscle invasive tumours with metastatic potential generally have defects in the pathways controlled by the tumour suppressors p53 and retinoblastoma. Over the last two decades, a number of transgenic mouse models of UCC, containing deletions or mutations of key tumour suppressor genes or oncogenes, have helped us understand the mechanisms behind tumour development. In this summary, I present my work investigating the role of the WNT signalling cascade in UCC. PMID:26274747

  20. Autophagy and urothelial carcinoma of the bladder: A review

    PubMed Central

    Chandrasekar, Thenappan

    2016-01-01

    The incidence of urothelial carcinoma of the urinary bladder (bladder cancer) remains high. While other solid organ malignancies have seen significant improvement in morbidity and mortality, there has been little change in bladder cancer mortality in the past few decades. The mortality is mainly driven by muscle invasive bladder cancer, but the cancer burden remains high even in nonmuscle invasive bladder cancer due to high recurrence rates and risk of progression. While apoptosis deregulation has long been an established pathway for cancer progression, nonapoptotic pathways have gained prominence of late. Recent research in the role of autophagy in other malignancies, including its role in treatment resistance, has led to greater interest in the role of autophagy in bladder cancer. Herein, we summarize the literature regarding the role of autophagy in bladder cancer progression and treatment resistance. We address it by systematically reviewing treatment modalities for nonmuscle invasive and muscle invasive bladder cancer. PMID:27326411

  1. Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma.

    PubMed

    Hedegaard, Jakob; Lamy, Philippe; Nordentoft, Iver; Algaba, Ferran; Høyer, Søren; Ulhøi, Benedicte Parm; Vang, Søren; Reinert, Thomas; Hermann, Gregers G; Mogensen, Karin; Thomsen, Mathilde Borg Houlberg; Nielsen, Morten Muhlig; Marquez, Mirari; Segersten, Ulrika; Aine, Mattias; Höglund, Mattias; Birkenkamp-Demtröder, Karin; Fristrup, Niels; Borre, Michael; Hartmann, Arndt; Stöhr, Robert; Wach, Sven; Keck, Bastian; Seitz, Anna Katharina; Nawroth, Roman; Maurer, Tobias; Tulic, Cane; Simic, Tatjana; Junker, Kerstin; Horstmann, Marcus; Harving, Niels; Petersen, Astrid Christine; Calle, M Luz; Steyerberg, Ewout W; Beukers, Willemien; van Kessel, Kim E M; Jensen, Jørgen Bjerggaard; Pedersen, Jakob Skou; Malmström, Per-Uno; Malats, Núria; Real, Francisco X; Zwarthoff, Ellen C; Ørntoft, Torben Falck; Dyrskjøt, Lars

    2016-07-11

    Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal- and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment. PMID:27321955

  2. Urothelial Carcinoma With Villoglandular Differentiation: A Rare Entity.

    PubMed

    Mitra, Suvradeep; Sundaram, Archana K; Gupta, Kirti; Devana, Sudheer Kumar

    2016-06-01

    Urothelial neoplasms are the commonest neoplasms of the urinary bladder. Many variants of urothelial neoplasms have been described in the literature with diagnostic, therapeutic, and prognostic significance. We describe a rare case of urothelial neoplasm with villoglandular differentiation along with its immunohistochemical profile arising in an elderly male. Its poor prognosis signifies its need to be recognized. PMID:26721305

  3. Muscle-invasive urothelial carcinoma of the bladder.

    PubMed

    Malkowicz, S Bruce; van Poppel, Hendrik; Mickisch, Gerald; Pansadoro, Vito; Thüroff, Joachim; Soloway, Mark S; Chang, Sam; Benson, Mitchell; Fukui, Iwao

    2007-01-01

    Muscle-invasive urothelial (transitional cell) carcinoma is a potentially lethal condition for which an attempt at curative surgery is required. Clinical staging does not allow for accurate determination of eventual pathologic status. Muscle-invasive urothelial carcinoma is a highly progressive disease, and initiation of definitive therapy within 3 months of diagnosis is worthwhile. Age is not a contraindication for aggressive surgical care, and surgical candidates should be evaluated in the context of overall medical comorbidity. In those patients who undergo surgery, clinical pathways may streamline care. Radical cystectomy remains the "gold standard" of therapy, providing 5-year survival rates of 75% to 80% in patients with organ-confined disease, yet organ-sparing procedures demonstrate clinical effectiveness as well. Cystectomy should be undertaken with the intent of performing complete pelvic lymph node dissection and attaining surgically negative margins. In younger female patients, the preservation of reproductive organs may be achieved in many cases. Prostate- and seminal vesicle-preserving cystectomy has been performed, yet the long-term safety and efficacy of such a procedure remains to be determined. Laparoscopic and robotic cystectomy procedures continue to be explored by several investigators. The role of "radical transurethral resection" in muscle-invasive disease is limited to a small cohort of patients, and, when it is performed, cystectomy may be required to consolidate therapy. Postoperative follow-up after cystectomy should occur over short intervals during the first 2 years and can be extended, but not discontinued, beyond that time. Currently, no tumor markers have been prospectively validated to help guide clinical decision making, and prospective trials incorporating marker data should be encouraged. PMID:17280906

  4. Clinicopathological prognostic factors for upper tract urothelial carcinoma

    PubMed Central

    Timev, Alexander; Dimitrov, Plamen; Vasilev, Vasil; Krastanov, Alexander; Georgiev, Marincho; Yanev, Krasimir; Simeonov, Peter; Panchev, Peter

    2016-01-01

    Introduction The aim of the present study was to evaluate the influence of clinicopathological factors including age, gender, tumor grade, tumor stage, lymphovascular invasion (LVI), tumor necrosis and previous history of non-muscle invasive bladder cancer on outcomes of patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). Material and methods A total of 60 patients who underwent radical nephroureterectomy for upper tract urothelial carcinoma at our institute between 2005 to 2012 were included in our study. Univariate and multivariate analysis was performed using the Kaplan-Meier method, log rank statistics, the chi-square test and Cox regression models. Results The mean length of follow-up time was 33.3 months. There were 27 (45%) patients alive with the disease, whereas 33 (55%) were dead. In 19 cases (31.7%) the tumor grade was low, while in 41 cases (68.3%) it was high. Lymphovascular invasion was observed in 28 (46.7%) cases. Tumor necrosis was registered in 14 patients (23.3%). From the patients with LVI, 3 (9.6%) were alive, whereas from the patients negative for LVI, 75% were alive. Significant relationship was found between gender and grading and between positive LVI and low grading. Conclusions Day case Variables such as gender, grading, tumor stage, LVI and tumor necrosis were all demonstrated to be significant independent prognostic factors for the overall survival. On the multivariate analysis only LVI remained statistically significant, which may explain the different clinical course in patients and could be considered as a part of pathological reporting and treatment planning for the future. PMID:27123328

  5. Expression of MLH1 and MSH2 in urothelial carcinoma of the renal pelvis.

    PubMed

    Ehsani, Laleh; Osunkoya, Adeboye O

    2014-09-01

    In this study, we investigated microsatellite instability in urothelial carcinoma of the renal pelvis by lack of immunohistochemical staining for MLH1 and MSH2. The study included 44 cases of urothelial carcinoma of the renal pelvis obtained from radical nephroureterectomy specimens at our institution. We evaluated the loss of nuclear immunohistochemical staining of MLH1 and MSH2. Eight of 44 (18 %) patients had negative MLH1 expression and 25/44 (57 %) patients had negative MSH2 expression. Six of 8 (75 %) patients with negative MLH1 expression were male and 2/8 (25 %) patients were female. Nineteen of 25 (75 %) patients with negative MSH2 expression were male, and 6/25 (24 %) patients were female. Seven of 8 (88 %) cases with negative MLH1 expression were high-grade urothelial carcinoma, and 21/25 (84 %) cases with negative MSH2 expression were high-grade urothelial carcinoma. Twenty-one of 44 (48 %) cases had an inverted growth pattern, of which 3/21 (14 %) cases had negative MLH1 expression and 14/21 (67 %) cases had negative MSH2 expression. Our study showed that microsatellite instability based on negative expression of MLH1 and MSH2 was more common in male patients with high-grade urothelial carcinoma. There is a strong correlation between inverted growth pattern and negative MSH2 expression. Microsatellite instability testing should be performed in patients with upper urinary tract carcinoma and may have prognostic value. PMID:24874052

  6. Invasive urothelial carcinoma within a calyceal diverticulum associated with renal stones: A case report

    PubMed Central

    NAKANO, TAITO; KITAGAWA, YASUHIDE; IZUMI, KOUJI; IKEDA, HIROKO; NAMIKI, MIKIO

    2015-01-01

    Calyceal diverticula are rare outpouchings of the upper collecting system lying within the renal parenchyma. These often contain stones, however, carcinoma within a calyceal diverticulum is uncommon. The present study reports a case of invasive urothelial carcinoma within a calyceal diverticulum associated with renal stones. A 70-year-old male with a left renal mass identified by abdominal computed tomography was referred to the Department of Urology, Kanazawa University Hospital. Pre-operative diagnosis was difficult owing to an atypical imaging finding of a hypovascular renal mass with calcification. A laparoscopic nephroureterectomy was performed, and the surgical specimens showed invasive high-grade urothelial carcinoma within a calyceal diverticulum, and the calcifications were renal stones consisting of 97% calcium oxalate. Urothelial carcinoma in calyceal diverticula is a rare condition, however, a pre-operative definite diagnosis is difficult and a high potential for invasion of the renal parenchyma is suspected in this disease. PMID:26622866

  7. Confocal Laser Endomicroscopy of Bladder and Upper Tract Urothelial Carcinoma: A New Era of Optical Diagnosis?

    PubMed Central

    Chen, Stephanie P.; Liao, Joseph C.

    2014-01-01

    Urothelial carcinoma of the bladder and upper tract pose significant diagnostic and therapeutic challenges. White light endoscopy plays a central role in the management of urothelial carcinoma but has several well-recognized shortcomings. New optical imaging technologies may improve diagnostic accuracy, enhance local cancer control, and better stratify treatment options. Confocal laser endomicroscopy enables dynamic imaging of the cellular structures below the mucosal surface and holds promise in providing real time optical diagnosis and grading of urothelial carcinoma. A variety of imaging probes are available that are compatible with the full spectrum of cystoscopes and ureteroscopes. We review the underlying principles and technique of confocal laser endomicroscopy in the urinary tract, with emphasis on specific application towards urothelial carcinoma. While the available data are largely related to urothelial carcinoma of the bladder, the lessons learned are directly applicable to the upper tract, where the clinical needs are significant. Ongoing efforts to optimize this technology offer an exciting glimpse into future advances in optical imaging and intraoperative image guidance. PMID:25002073

  8. The Utility of GATA3 in the Diagnosis of Urothelial Carcinomas With Variant Morphologic Patterns.

    PubMed

    Verduin, Lindsey; Mentrikoski, Mark J; Heitz, Christopher T; Wick, Mark R

    2016-08-01

    The transcription factor GATA3 is a recently described biomarker that is highly expressed in bladder and breast carcinomas. Although it has shown sensitivity as a marker of primary bladder carcinomas with purely urothelial differentiation, the ability of GATA3 to label primary bladder carcinomas with variant morphologic patterns has been incompletely assessed to date. The current study was designed to determine whether GATA3 staining is retained in "unconventional" bladder carcinomas. Eighty-eight cases of primary bladder cancers were retrieved from the authors' institutional archive, and they included the following histomorphologic types: 6 small cell carcinomas, 12 sarcomatoid carcinomas, 17 adenocarcinomas (both primary and urothelial variants with glandular differentiation), 24 micropapillary carcinomas, and 27 squamous cell carcinomas (both primary and urothelial variants with squamous differentiation). A tissue microarray was constructed and automated immunostaining for GATA3 (Clone L50-823, Biocare Medical, Concord, CA) was performed using standard technique. Among the 5 variants of unconventional bladder carcinoma, only the micropapillary and sarcomatoid forms exhibited consistent and strong immunolabeling for GATA3. Hence, the sensitivity of this determinant is diminished in several histologic forms of primary bladder carcinoma. That fact will affect the interpretation of GATA3 stains in the context of possible metastasis from primary bladder carcinomas with variant morphologic patterns, as well as their distinction from secondary bladder involvement by tumors of nonurothelial origin. PMID:26317312

  9. Role of FGFR3 in Urothelial Cell Carcinoma: Biomarker and Potential Therapeutic Target

    PubMed Central

    Knowles, Margaret A.

    2016-01-01

    Although non-invasive bladder tumours (pTa) are the most common group of bladder tumours at presentation, there has until recently been relatively little information on their molecular biology. Thus it was of great interest when mutations in the FGF receptor 3 (FGFR3) were identified in bladder tumours and it became apparent that these were most common in tumours of low grade and stage. Since the initial description of activating mutations of FGFR3, there have been numerous studies confirming the frequency and spectrum of these mutations in bladder cancers of all grades and stages. Mutation screening techniques have evolved and improved. FGFR3 mutation has been assessed as a predictive biomarker in tumour tissues and as a diagnostic biomarker in urine. Efforts have been made to understand the function of FGFR3 in urothelial and other cells. Although our understanding of FGFR3 function is incomplete, it is already apparent that this may represent an important therapeutic target not only in non-invasive bladder cancer but also in a significant number of invasive tumours. This review summarises the current state of knowledge of this interesting receptor in urothelial carcinoma (UC). PMID:17912529

  10. High-grade urothelial carcinoma with squamous differentiation metastasizing to the tongue.

    PubMed

    Khurram, Syed A; Farthing, Paula M; Whitworth, Abigail; McKechnie, Alasdair J; Fernando, Malee

    2016-05-01

    Tumors metastasizing to the head and neck region are uncommon. Metastasis of urothelial carcinoma to the maxillofacial region is exceedingly rare and mostly involves the jaw. We present a case of urothelial carcinoma metastasizing to the tongue. Immunohistochemistry in conjunction with fluorescent in situ hybridization was used to confirm the relation between the primary and metastatic lesions, making it the first such reported case employing the UroVysion (Catalogue number 02 J27-025, Abbott Molecular Inc., Des Plaines, IL, USA) fluorescent in situ hybridization probe in a metastatic lesion in the head and neck region. PMID:26525101

  11. Plasmacytoid urothelial carcinoma of the bladder with extensive scrotal wall invasion

    PubMed Central

    Wang, Yong Gang; Perera, Marlon; Gleeson, Jacob

    2016-01-01

    Plasmacytoid urothelial carcinoma (PUC) is an extremely rare and aggressive variant of urothelial carcinoma. We report a case of a 62-year-old male who presented with a rapid spread of PUC to involve his entire scrotal wall after failed surgery and chemotherapy. The second course of chemotherapy was effective in providing symptom control. We believe this is the first case report of PUC causing such rapid and extensive scrotal invasion. This case highlights the important features of PUC including the pattern of tumor spread along fascial planes, the tendency for initial understaging, and the rapid recurrence after initially response to chemotherapy. PMID:27453668

  12. Association of urothelial carcinoma of the renal pelvis with papillary and medullary thyroid carcinomas. A new sporadic neoplastic syndrome?

    PubMed

    Albores-Saavedra, Jorge; Dorantes-Heredia, Rita; Chablé-Montero, Fredy; Córdova-Ramón, Juan Carlos; Henson, Donald E

    2014-10-01

    We describe 2 adult women (72 and 54 years), 1 with a low-grade noninvasive papillary urothelial carcinoma of the renal pelvis, who 14 years later developed a papillary carcinoma in 1 thyroid lobe and a medullary carcinoma in the contralateral lobe. Both neoplasms were similar in size and appeared symmetrical. Despite its small size, the medullary carcinoma metastasized in multiple cervical lymph nodes. The second patient had a high-grade invasive papillary urothelial carcinoma of the renal pelvis that infiltrated the renal parenchyma and metastasized in one of the lungs. Five months later, a papillary carcinoma was discovered in the thyroid gland. The 2 papillary thyroid carcinomas were of the follicular variant. Adjacent to 1 papillary carcinoma, there was a dominant nodule of a colloid and adenomatous goiter. The medullary carcinoma contained stromal amyloid and was immunoreactive for calcitonin and carcinoembryonic antigen. There was no C-cell hyperplasia (medullary carcinoma in situ). The 2 patients are alive, 1 is living with pulmonary metastasis from the high-grade urothelial carcinoma. Twelve cases of this neoplastic association were registered in the Survey, Epidemiology, and End Results Program from 1980 to 2009. We believe that the combination of these unusual neoplasms in the same patient may represent a new sporadic neoplastic syndrome. PMID:25175810

  13. Infiltration related miRNAs in bladder urothelial carcinoma.

    PubMed

    Xie, Peng; Xu, Feng; Cheng, Wen; Gao, Jianping; Zhang, Zhengyu; Ge, Jingping; Wei, Zhifeng; Xu, Xiaofeng; Liu, Youhuang

    2012-08-01

    This study aimed to investigate infiltration related microRNAs (miRNAs) in bladder urothelial carcinoma (BUC). Twenty patients with BUC were enrolled and divided into 2 groups according to infiltration or not: infiltrating BUC group (n=12) and non-infiltrating BUC group (n=8). Gene chip was used to detect infiltration related miRNAs in the BUC samples. In other recruited 17 patients with BUC who were divided into infiltrating BUC samples (n=14) and non-infiltrating BUC samples (n=3), and in 4 BUC cell lines (EJ, 5637, T24 and BIU-87), the expression of miRNAs was assayed by using reverse transcription-polymerase chain reaction (RT-PCR). In infiltrating BUC group, as compared with non-infiltrating BUC group, there were 7 differentially expressed miRNAs: hsa-miR-29c, hsa-miR-200a, hsa-miR-378, hsa-miR-429, hsa-miR-200c and hsa-miR-141 were up-regulated, while hsa-miR-451 was down-regulated. In the BUC samples, the results of RT-PCR were consistent with those by the miRNA array. In the cancer cell lines, RT-PCR in T24 only revealed the similar expression pattern of miRNAs to that by the miRNA array. It is suggested that infiltration of BUC is related with different expression of miRNAs, which may provide a novel platform for further study on function and action mechanism of miRNAs. PMID:22886973

  14. [Urothelial carcinoma related to exposure to aromatic amines].

    PubMed

    Naito, S; Kumazawa, J

    1989-12-01

    Clinical and statistical observations were made on a group of 438 persons who had worked with aromatic amines (benzidine, 2-naphthylamine, 1-naphthylamine and dianisidine) with reference to their carcinogenic properties in the urinary tract. Urinary tract tumors developed in 68 (15.5%), with an average latent period of 22 years and 11 months. In these 68 cases, upper urinary tract tumors were found in 16 cases, 8 of which had bilateral lesions. The average age of onset was 48.1 ranging from 24 to 79. The incidence of tumors increased with the length of exposure to the amines. There was no finding that smoking habit increased the incidence of tumors in this group. Of the 49 new patients with bladder tumor, urine cytology was positive in 24 (49.0%) and suspicious of malignancy in 10 (20.4%), respectively. This indicated that it could be a useful screening test. Transurethral surgery was most frequently performed as an initial treatment. Recurrence occurred in 50 cases (73.5%), but 5-, 10- and 20-year-survival rates were 89.0 79.3 and 64.7%, respectively, showing a good prognosis. Malignant tumors in other organs developed in 18 (4.1%) of the 438 workers. The incidence of such malignant tumors was significantly higher in the workers who had been exposed to 2-naphthylamine than in others. Our data indicate that close observation is still necessary for early detection of patient with new or recurrent urothelial carcinoma in this group. PMID:2618901

  15. Testicular Metastasis of a Upper Urinary Tract High-grade Papillary Urothelial Carcinoma, 2 Years After Nephroureterectomy

    PubMed Central

    Kubiak, M.; Klein, J.; de Perrot, T.; Tille, J.C.; Iselin, C.E.

    2015-01-01

    Urothelial carcinomas are the fourth most common tumors in men. Upper tract urinary carcinomas (UTUCs) are uncommon and represent only 5–10% of urothelial carcinomas.1 Metastatic testicular cancers are rare and primary tumor sources are the prostate, lung, and gastrointestinal tract. We report the first case of testicular metastasis 2 years after initial curative surgery for a high-grade UTUC, all other reported cases weren't proceed by curative surgery.3 PMID:26793571

  16. Recurrent TERT promoter mutations in urothelial carcinoma and potential clinical applications.

    PubMed

    Kurtis, Boaz; Zhuge, Jian; Ojaimi, Caroline; Ye, Fei; Cai, Dongming; Zhang, David; Fallon, John T; Zhong, Minghao

    2016-04-01

    Increased telomerase activity is associated with almost all types of advanced human cancers with unknown molecular mechanism(s). Two recurrent point mutations in the promoter region of telomerase reverse transcriptase (TERT)-the key subunit of telomerase-have recently been identified in melanoma as well as a small sample of bladder cancer cell lines. However, the incidence and clinical-pathological significance of these mutations in urothelial carcinoma have not been well established yet. We collected 86 specimens of urothelial carcinoma including upper and lower urinary tract: high grade and low grade, invasive and noninvasive, and primary and metastatic. We also included some matched benign urothelium and common benign bladder lesions: cystitis, nephrogenic adenoma, and inverted papilloma. In addition, we collected urine samples for urothelial carcinoma workup; blood samples from patients underwent cystectomy with extensive lymphovascular invasion. All specimens were subject to polymerase chain reaction amplification and bidirectional Sanger sequencing for the TERT promoter mutations: C228T and C250T. We found that 64 (74%) of 86 carcinoma samples harbored 1 of the 2 TERT promoter mutations (C228T, n = 54; C250T, n = 10); the incidences were roughly equal regardless of site of origin, histologic grade, and invasive status. All matched benign and benign lesion samples showed wild-type sequence. These TERT promoter mutations are the most common genetic alterations in urothelial carcinoma and are not associated with tumor locations, grade, or invasiveness. Importantly, the feasibility of detecting these mutations in urine samples may provide a novel method to detect urothelial carcinoma in urine. PMID:27040924

  17. Urothelial carcinoma of the allograft kidney developed in a renal transplant patient

    PubMed Central

    Gökçe, Mehmet İlker; Kocaay, Akın Fırat; Aktürk, Serkan; Tüzüner, Acar

    2016-01-01

    Renal transplantation is the best option in the treatment of end-stage renal disease However these patients are under the risk of developing malignancies particularly due to effects of immune supression. These malignancies tend to be more agressive compared to the general population. Here, we present a case of urothelial carcinoma develoing in the ureter of allograft kidney.

  18. Clinical Behavior of Bladder Urothelial Carcinoma in Young Patients: A Single Center Experience

    PubMed Central

    Bozkurt, Ozan; Demir, Omer; Esen, Ahmet Adil; Aslan, Guven; Kefi, Aykut; Celebi, Ilhan

    2016-01-01

    Background. There is not enough evidence about clinical behavior of bladder cancer in younger patients. Objective. We aimed to evaluate the clinical characteristics and prognosis of bladder urothelial carcinoma patients under the age of 40 years. Methods. Medical records of patients listed in our cancer database were retrospectively reviewed. A total of 40 patients who were initially diagnosed with bladder urothelial carcinoma at the age less than 40 years were included in the study. Patients' records were reviewed for recurrence and progression rates, demographic data, medical history, and treatment modalities. Results. Pathological results revealed 33 (82.5%) Ta low-grade, 6 (15%) T1 high-grade, and 1 (2.5%) T2 high-grade urothelial carcinomas. Recurrence was detected in 14/39 (35.9%) patients but progression was not observed in any patients. The mean age of recurrent patients was significantly higher than nonrecurrent patients (34.8 versus 28.5 years; p < 0.05). Besides, recurrence was detected in only 1 patient with the age under 30 years (6.2%) and 13 patients (54.1%) between 30 and 40 years old, respectively (p < 0.05). Conclusion. Bladder urothelial carcinoma diagnosed at young age tends to be a low pathologic stage, with relatively low rate of recurrence and progression.

  19. Role of computed tomography urography in the clinical evaluation of upper tract urothelial carcinoma.

    PubMed

    Jinzaki, Masahiro; Kikuchi, Eiji; Akita, Hirotaka; Sugiura, Hiroaki; Shinmoto, Hiroshi; Oya, Mototsugu

    2016-04-01

    Intravenous urography has been widely used for the evaluation of upper tract urothelial carcinoma. However, computed tomography urography presently has a higher diagnostic accuracy for upper tract urothelial carcinoma (94.2-99.6%) than intravenous urography (80.8-84.9%), and has replaced intravenous urography as the first-line imaging test for investigating patients with a high risk of upper tract urothelial carcinoma. Although the detection rate for bladder tumors using standard computed tomography urography is not yet high enough to replace cystoscopy, the addition of a 60- to 80-s delayed scan after the administration of contrast material for the whole pelvis improves the detection rate. A drawback to computed tomography urography is the higher radiation dose of 15-35 mSv, compared with a mean effective dose of 5-10 mSv for intravenous urography. Among several approaches to reducing the radiation dose, the use of an iterative reconstruction algorithm is most likely to become an effective solution because of its simplicity. One advantage of computed tomography urography over intravenous urography is its ability to reliably differentiate between upper tract urothelial carcinoma and calculi or blood clots. Computed tomography urography also shows characteristic findings of other benign conditions. These findings, in combination with negative cytology, are very important diagnostic clues for avoiding an unnecessary nephroureterectomy. For the clinical staging, a recent study has reported the high diagnostic accuracy of computed tomography urography with respect to ≥pT3 tumors. The present review shows the current status of computed tomography urography for the evaluation of upper tract urothelial carcinoma. PMID:26750188

  20. Polyomavirus large T antigen is prevalent in urothelial carcinoma post-kidney transplant.

    PubMed

    Yan, Ling; Salama, Mohamed E; Lanciault, Christian; Matsumura, Linh; Troxell, Megan L

    2016-02-01

    Viral pathogens have been associated with both infectious disease and neoplasia in transplant recipients. Polyomavirus is emerging as a potential causative agent for genitourinary tract cancer in post-kidney transplant patients. Human papillomavirus (HPV) has a proven role in squamous cancers, but has not been studied in genitourinary malignancies in transplantation. Of 2345 kidney transplants performed at our center over the past 20 years, we identified 16 patients with 20 genitourinary cancers (0.7%), including 13 bladder/ureter carcinomas, 5 renal cell carcinomas (RCCs), and 2 prostate carcinomas. We performed immunohistochemical staining for polyomavirus large T antigen and p16, followed by in situ hybridization for HPV in p16+ cases. Four cases of high-grade invasive urothelial bladder carcinomas were positive for large T. Large T+ urothelial carcinomas developed at least 8 years posttransplant in young men, 3 with history of BK polyoma viremia, 2 of whom had native kidney failure due to reflux/obstruction. In situ hybridization for high-risk HPV was negative in all tested cases. Overall, 3 patients died of carcinoma. All 5 RCCs were negative for both large T and p16; 2 prostate cancers were p16 negative and p16+/HPV negative, respectively. Thus, our study shows a relatively high prevalence of large T antigen in urothelial carcinoma in kidney transplant patients (31%), but not in RCC. Although sample size is small, young patients with obstructive disease may be at particular risk for developing large T-positive urothelial carcinoma. Overall, our data further support the necessities of long-term cancer surveillance for renal transplant patients. PMID:26615524

  1. Pembrolizumab and Docetaxel or Gemcitabine Hydrochloride in Treating Patients Urothelial Cancer

    ClinicalTrials.gov

    2015-08-26

    Metastatic Urothelial Carcinoma of the Renal Pelvis and Ureter; Recurrent Bladder Carcinoma; Recurrent Urothelial Carcinoma of the Renal Pelvis and Ureter; Regional Urothelial Carcinoma of the Renal Pelvis and Ureter; Stage III Bladder Urothelial Carcinoma; Stage III Urethral Cancer; Stage IV Bladder Urothelial Carcinoma; Stage IV Urethral Cancer; Urethral Urothelial Carcinoma

  2. Incidental Lymphoma Discovered During Surveillance for Low-Grade Upper Tract Urothelial Carcinoma Treated Ureteroscopically: A Case Report Series

    PubMed Central

    Healy, Kelly A.; Raval, Amar J.; Lallas, Costas D.; Filicko-O'Hara, Joanne; Bagley, Demetrius H.

    2016-01-01

    Abstract Two cases of incidentally found follicular lymphoma during surveillance for ureteroscopically treated upper tract urothelial carcinoma with cross-sectional imaging are described. Multiple independent primary malignancies should be considered in this population. PMID:27579404

  3. Incidental Lymphoma Discovered During Surveillance for Low-Grade Upper Tract Urothelial Carcinoma Treated Ureteroscopically: A Case Report Series.

    PubMed

    Hubosky, Scott G; Healy, Kelly A; Raval, Amar J; Lallas, Costas D; Filicko-O'Hara, Joanne; Bagley, Demetrius H

    2016-01-01

    Two cases of incidentally found follicular lymphoma during surveillance for ureteroscopically treated upper tract urothelial carcinoma with cross-sectional imaging are described. Multiple independent primary malignancies should be considered in this population. PMID:27579404

  4. Human epidermal growth factor receptor 2 expression in urothelial carcinoma of the renal pelvis: correlation with clinicopathologic parameters.

    PubMed

    Ehsani, Laleh; Osunkoya, Adeboye O

    2014-01-01

    The significance of human epidermal growth factor receptor 2 (HER2) overexpression in breast cancer is well established, and these patients are subsequently treated with Trastuzumab. Although HER2 expression in urothelial carcinoma of the urinary bladder has also been recently characterized, it has not been well studied in urothelial carcinoma of the renal pelvis. We investigated the relationship between HER2 overexpression in urothelial carcinoma of the renal pelvis and clinicopathologic parameters. Forty six cases were identified. HER2 overexpression was present in 34/46 (74%) cases. Mean patient age with HER2 overexpression was 68 years (range: 42-87 years). There was a male predominance with 28/34 (82%) patients. High grade urothelial carcinoma was present in 32/34 (94%) cases and 2/34 (6%) cases had low grade urothelial carcinoma. Pathologic staging was as follows; 9/34 (26%) cases were pTa, 10/34 (29%) cases were pT1, 2/34 (6%) cases were pT2, 12/34 (35%) cases were pT3, and 1/34 (3%) cases was pT4. An inverted growth pattern was present in 23/46 (50%) cases. HER2 overexpression was present in 15/23 (65%) cases of urothelial carcinoma with an inverted growth pattern. Our study showed that HER2 overexpression is more common in male patients with high grade urothelial carcinoma, especially those with an inverted growth pattern. It is highly conceivable that patients with urothelial carcinoma of the renal pelvis may be further stratified based on HER2 overexpression, and may also be potential candidates for Trastuzumab therapy in the neoadjuvant or adjuvant setting. PMID:24966967

  5. Simultaneous robot-assisted radical cystoprostatectomy and nephroureterectomy in a patient with multifocal invasive urothelial carcinoma and previous contralateral nephroureterectomy.

    PubMed

    Özveren, Bora; Türkeri, Levent

    2013-12-01

    We present a case of simultaneous robot-assisted radical cystoprostatectomy and nephroureterectomy with extended lymphadenectomy for multifocal invasive urothelial carcinoma in a patient with recurrent high-grade urothelial cancer and a previous right nephroureterectomy. The total urinary exenteration and extended lymphadenectomy was successfully performed with robot-assisted surgery in this unique case where the patient was rendered anephric at the end of the operation. We discuss the operative steps and the techniques performed to optimize the oncological results of robot-assisted surgery for invasive urothelial carcinoma, while attempting to preserve the renal function until the patient's urinary system was totally exenterated. PMID:27001880

  6. Impacts of CA9 Gene Polymorphisms on Urothelial Cell Carcinoma Susceptibility and Clinicopathologic Characteristics in Taiwan

    PubMed Central

    Ou, Yen-Chuan; Chen, Chuan-Shu; Li, Jian-Ri; Yang, Shun-Fa

    2013-01-01

    Background Carbonic anhydrase 9 (CA9) is reportedly overexpressed in several types of carcinomas and is generally considered a marker of malignancy. The current study explored the effect of CA9 gene polymorphisms on the susceptibility of developing urothelial cell carcinoma (UCC) and the clinicopathological status. Methodology and Principal Findings A total of 442 participants, including 221 healthy people and 221 patients with UCC, were recruited for this study. Four single-nucleotide polymorphisms (SNPs) of the CA9 gene were assessed by a real-time PCR with the TaqMan assay. After adjusting for other co-variants, the individuals carrying at least one A allele at CA9 rs1048638 had a 2.303-fold risk of developing UCC than did wild-type (CC) carriers. Furthermore, UCC patients who carried at least one A allele at rs1048638 had a higher invasive stage risk (p< 0.05) than did patients carrying the wild-type allele. Moreover, among the UCC patients with smoker, people with at least one A allele of CA9 polymorphisms (rs1048638) had a 4.75-fold (95% CI = 1.204–18.746) increased risk of invasive cancer. Conclusion The rs1048638 polymorphic genotypes of CA9 might contribute to the prediction of susceptibility to and pathological development of UCC. This is the first study to provide insight into risk factors associated with CA9 variants in carcinogenesis of UCC in Taiwan. PMID:24349364

  7. Post-operative urothelial recurrence in patients with upper urinary tract urothelial carcinoma managed by radical nephroureterectomy with an ipsilateral bladder cuff: Minimal prognostic impact in comparison with non-urothelial recurrence and other clinical indicators

    PubMed Central

    TAKAHARA, KIYOSHI; INAMOTO, TERUO; KOMURA, KAZUMASA; WATSUJI, TOSHIKAZU; AZUMA, HARUHITO

    2013-01-01

    Upper urinary tract urothelial carcinoma (UTUC) is a rare disease, and novel prognostic factors for patients who have undergone a radical nephroureterectomy (RNU) for UTUC have been studied intensely. To the best of our knowledge, the prognostic value of urothelial recurrence in patients with UTUC has not been previously described in studies. The present study compared the prognostic value of urothelial and non-urothelial recurrence in patients with UTUC of the kidney and ureter managed by surgery. The inclusion criteria consisted of a diagnosis of non-metastatic UTUC (any T stage, N0–1 and M0) and receipt of an RNU with an ipsilateral bladder cuff as the primary treatment. Of the 153 patients that were screened for the study, comprehensive clinical and pathological data was available for 103 patients, who were consequently included in the analysis. Overall survival (OS) and cancer-specific survival (CSS) times were estimated. A multivariate analysis was performed using the Cox regression model. The median follow-up period was 29 months (interquartile range, 14–63 months). The patient population was comprised of 71 males (68.9%) and 32 females (31.1%). A total of 32 patients (31.1%) showed non-urothelial recurrence, while 38 patients (36.9%) exhibited urothelial recurrence and 33 patients (32.0%) exhibited no recurrence. When comparing the risk parameters between the non-urothelial recurrence categories, the factors of pathological grade, microvascular invasion, lymphatic invasion and pT classification showed significant differences. However, there were no significant differences between the urothelial recurrence categories. No significant difference was observed between the OS and CSS times within the urothelial recurrence categories (P=0.3955 and P=0.05891, respectively), but significant differences were identified in the non-urothelial recurrence categories (P<0.0001 and P<0.0001, respectively). Among the other relevant descriptive pre

  8. Tailored Selection of First-Line Cisplatin-Based Chemotherapy in Patients with Metastatic Urothelial Carcinoma of Bladder

    PubMed Central

    Hsieh, Meng-Che; Huang, Cheng-Hua; Chiang, Po-Hui; Chen, Yen-Yang; Tang, Yeh; Su, Yu-Li

    2016-01-01

    Purpose: Methotrexate, vinblastine, doxorubicin plus cisplatin (MVAC) and gemcitabine plus cisplatin (GC) are both effective first-line chemotherapy. We explore the responsive variables of MVAC and GC for patients with metastatic urothelial carcinoma of bladder (mUCB). Materials and Methods: Patients who were initially diagnosed to have mUCB and received MVAC or GC as metastatic first-line chemotherapy between 2000 and 2014 at Kaohsiung Chang Gung Memorial Hospital were reviewed. Totally, 130 patients were enrolled into our study. Univariable Cox proportional hazard models were constructed for OS. Hazard ratio (HR) and 95% confidence intervals (CIs) was also presented. Results: There were 50 patients (38%) in the MVAC group and 80 patients (62%) in the GC group. The median OS was insignificantly different between MVAC and GC groups, accounting for 17.0 and 14.4 months (P = 0.214), respectively. OS of MVAC group was significantly longer with regard to age ≦ 60 years (HR: 0.38, 95% CI: 0.12-0.97, P = 0.036), pure urothelial carcinoma (HR: 0.56, 95% CI: 0.34-0.90, P = 0.015), > 1 metastatic sites (HR: 0.19, 95% CI: 0.08-0.44, P = < 0.001), and neutrophil to lymphocyte ratio > 3(HR: 0.45, 95% CI: 0.25-0.81, P = 0.006), while OS with GC group was significantly longer with regard to variant urothelial carcinoma (HR: 0.56, 95% CI: 0.34-0.90, P = 0.015). Conclusions: Our study disclosed the predictive factors of different regimen for mUCB. These results have clinical implication for physicians who treat patients with mUCB. PMID:27390610

  9. Obesity and Outcomes in Patients with Metastatic Urothelial Carcinoma1

    PubMed Central

    Leiter, Amanda; Doucette, John; Krege, Susan; Lin, Chia-Chia; Hahn, Noah; Ecke, Thorsten; Sonpavde, Guru; Bamias, Aristotle; Oh, William K.; Galsky, Matthew D.

    2016-01-01

    Background: Obesity has been associated with worse outcomes in patients with clinically localized urothelial cancer. However, this impact has not been evaluated in metastatic disease. Objective: To assess the impact of obesity on outcomes of patients with metastatic urothelial cancer. Methods: Data from 537 patients were aggregated from eight phase II and phase III clinical trials investigating first-line cisplatin-based combination therapy in metastatic urothelial cancer. Chemotherapy regimen, adverse events, treatment response, and survival outcomes were compared across body mass index (BMI) and body surface area (BSA) categories. Results: BMI was classified according to WHO criteria (<18.5 underweight, 18.5–24.99 normal weight, 25–29.99 overweight, >30 obese). BSA was classified as either below or greater than or equal to (average for this cohort (1.87 m2 for males and 1.66 m2 for females). There was no significant difference in number of chemotherapy cycles, adverse events, and response rate or survival outcomes (overall and progression-free) across BMI and BSA categories. There was no significant difference in adverse events across BMI categories, but the incidences of embolic events and renal failure were higher in patients with an average or higher BSA than those with a lower than average BSA (6.6% vs. 3.1% for renal failure p = 0.06; 5.9% vs. 2.7% for renal failure, p = 0.07). There was no significant difference in response rate or survival outcomes (overall and progression-free) amongst BMI and BSA categories. Conclusions: Obese patients with metastatic urothelial cancer on cisplatin-based therapies have similar response rates, survival outcomes, and tolerability of cisplatin-based therapy to non-obese patients. PMID:27500201

  10. A Case with Significant Proteinuria Caused by Secreted Protein from Urothelial Carcinoma

    PubMed Central

    Sakakima, Masanori; Fujigaki, Yoshihide; Yasuda, Hideo; Togawa, Akashi; Fujikura, Tomoyuki; Otsuka, Atsushi; Ozono, Seiichiro; Hishida, Akira

    2011-01-01

    58-year-old female was admitted to our hospital complaining isolated proteinuria of 1.7 g/day. Abdominal echography showed right-sided unilateral hydronephrosis, and computed tomography pointed out a tumor of the right renal pelvis, suggesting cancer of renal pelvis. The right nephroureterectomy was carried out. Pathological diagnosis was urothelial carcinoma. Renal tissue revealed no apparent glomerulopathy with tubular atrophy, interstitial fibrosis, and mildly-to-moderately interstitial mononuclear cell infiltration. Immunofluorescence study showed no deposition of immunoreactanct, and electron microscopy showed almost normal glomerulus without electron dense deposit. Proteinuria disappeared within 6 days after the operation. Moderate amount of proteinuria in our patient was probably caused by secreted protein from urothelial carcinoma. This condition is rare but should be taken into account in patients with even moderate amount of proteinuria. PMID:24533189

  11. Primary apocrine adenocarcinoma of scrotum suspected as urothelial carcinoma metastasis: A clinical and pathological dilemma.

    PubMed

    Huang, Sean; Frydenberg, Mark; Pham, Alan; Grummet, Jeremy P

    2015-01-01

    A 78-year-old man presented with an enlarging, tender mass in the scrotum separate to the testes. This was on the background of radical cystoprostatectomy, urethrectomy, and ileal conduit formation for high-grade urothelial carcinoma of the bladder invading submucosa 3 years prior. Examination revealed a 4 × 5 cm lesion, which was hard, fixed to the overlying skin and nodular to palpation. Ultrasound confirmed a solid mass in the scrotum extending into the perineum. Computerized tomography of the chest, abdomen, and pelvis revealed enlargement of inguinal lymph nodes but no other metastases. Complete resection of the scrotal lesion and selective removal of regional lymph nodes was performed. Rather than a cutaneous scrotal metastasis from the bladder urothelial carcinoma, histological examination suggested a primary apocrine adenocarcinoma of the scrotum. This case report explores the clinical and pathological features associated with both of these unusual differential diagnoses. PMID:25657556

  12. Coexistence of Malakoplakia and Papillary Urothelial Carcinoma of the Urinary Bladder.

    PubMed

    Lee, Song Liang Joshua; Teo, Jin Kiat; Lim, Sey Kiat Terence; Salkade, Hema Parag; Mancer, Kent

    2015-10-01

    Malakoplakia is a rare granulomatous disease that commonly involves the genitourinary tract, with the urinary bladder being the most frequently affected site. Grossly, malakoplakia can present as soft yellow plaques, nodules, bladder mass, or even without any visible lesion. In this article, we present a 74-year-old female with a background of hypertension, hyperlipidemia, and poorly controlled diabetes who presented with sepsis of unknown origin. During the course of the investigation of the source of her sepsis, an incidental bladder tumor was discovered. She subsequently underwent transurethral resection of the bladder tumor. Histology revealed ordinary low-grade papillary urothelial carcinoma that had small colonies of malakoplakia that appeared to have developed secondary to the tumor and presented concurrently. We seek to demonstrate the rare association of papillary urothelial carcinoma and malakoplakia. PMID:26194600

  13. Comparative gene expression profiling analysis of urothelial carcinoma of the renal pelvis and bladder

    PubMed Central

    2010-01-01

    Background Urothelial carcinoma (UC) can arise at any location along the urothelial tract, including the urethra, bladder, ureter, or renal pelvis. Although tumors arising in these various locations have similar morphology, it is unclear whether the gene expression profiles are similar between the upper-tract (ureter and renal pelvis) and lower-tract (bladder and urethra) carcinomas. Because differences may facilitate different screening and treatment modalities, we sought to examine the relationship between urothelial carcinoma of the renal pelvis (rUC) and urothelial carcinoma of the bladder (bUC). Methods Fresh tumor tissue was collected from patients with bUC (n = 10) and benign mucosa from the bladder of individuals undergoing resection for non-UC conditions (n = 7). Gene expression profiles from these samples were determined using high-throughput Affymetrix gene expression microarray chips. Bioinformatic approaches were used to compare the gene expression profiles of these samples with those of rUC samples and normal kidney samples that had been described previously. Results Using unsupervised analytic approaches, rUC and bUC were indistinguishable. Yet when a supervised analytic approach was used, a small number of differentially expressed genes were identified; these differences were most likely limited to a single pathway--the chloride ion binding activity pathway--which was more frequently activated in rUC than in bUC. Conclusions We found that the gene expression profiles of UCs from the upper and lower tract were extremely similar, suggesting that similar pathogenic mechanisms likely function in the development of these tumors. The differential expression of genes in the identified pathway may represent a new avenue for detection of upper-tract tumors. PMID:21159190

  14. [Renal urothelial carcinoma mainly composed of signet-ring cells].

    PubMed

    Povzun, S A; Guseva, E A; Konstantinova, A M; Shelekhova, K V

    2015-01-01

    Autopsy study of an 80-year-old man has identified his renal tumor metastasizing to the heart, lung, and liver as urothelial car- cinoma; at the same time some cells in the main tumor and all cells in the metastases had a signet-ring phenotype, but neither mucicarcimine nor alcian blue stained the cell cytoplasm. The paper provides the histological and immunohistochemical pattern of the tumor and emphasizes its exclusive rarity. Attention is drawn to the possibility of signet-ring cell transformation in the cells of different tumors, including nonepithelial ones. PMID:26841650

  15. Invasive urothelial carcinoma with chordoid features of the ureter: a rare entity and review of literature

    PubMed Central

    Wei, Jianguo; Yue, Zhenying; Song, Dianhang; Wang, Qiang; Teng, Xiaodong

    2015-01-01

    Invasive urothelial carcinoma (UC) is characterized by some histologic variants that can sometimes lead to diagnostic difficulty. In addition to those described by the World Health Organization. Recently invasive urothelial carcinoma with chordoid features (UCC) has been described as a distinct entity and there are relatively few reported cases in the English-language literature. To date 13 cases of UCC have been reported in 2 case series, respectively in 2009 and 2015. We report the 14th case in an 80-year-old female, and to the best of our knowledge this is the second case report of UCC in the ureter. She was admitted to our hospital with macroscopic haematuria and unspecific left lower abdominal pain. Computed tomography scan revealed a soft tissue nodule in the middle of the left ureter. The left nephroureterectomy was performed. Morphologically, 85% areas had acellular myxoid stroma was associated with the neoplastic cells. The neoplastic cells had scant eosinophilic cytoplasm and were arranged into cords closely mimicking chordoma or extraskeletal myxoid chondrosarcoma. 15% areas was typical invasive urothelial carcinoma, and focal areas had transition phenomenon between them. Immunohistochemically, the tumor cells were positive for CK, 34βE12 and p63, but were negative for S100, AFP, CD34, Syn and CgA. The final histopathological diagnosis was UCC of the ureter. PMID:26823892

  16. TERT promoter mutations in renal cell carcinomas and upper tract urothelial carcinomas.

    PubMed

    Wang, Kun; Liu, Tiantian; Liu, Li; Liu, Jikai; Liu, Cheng; Wang, Chang; Ge, Nan; Ren, Hongbo; Yan, Keqiang; Hu, Sanyuan; Björkholm, Magnus; Fan, Yidong; Xu, Dawei

    2014-04-15

    TERT promoter mutations are identified in many malignancies including bladder cancer (BC) and upper tract urothelial carcinoma (UTUC). In contrast, no mutations were found in renal cell carcinoma (RCC) as reported in a recent study. Because the mutant TERT promoter in urine DNA was recently tested as a marker for BC, it is important to ascertain whether these mutations are truly absent in RCCs. Here we determined TERT promoter mutations in 109 patients with RCC and 14 patients with UTUC. The mutations were found in 9/96 (9.3%) clear cell RCC (ccRCC) tumors and 1/8 (13%) chromophobe RCC tumors. Among ccRCC patients, the mutation was correlated with the advanced stages and metastasis, and higher TERT expression. Among UTUCs, the mutation was detected in tumors from 3/5 (60%) patients with renal pelvic cancer and 1/9 (11%) patients with ureter cancer. The mutation was also detected in 1 of 4 urine samples from patients with mutation+ UTUC. Collectively, TERT promoter mutations do occur in RCCs and are associated with aggressive disease. The mutation is more frequent in renal pelvic cancer. Thus, the mutant TERT promoter found in urine may come from not only BC, but also RCC or UTUC. PMID:24742867

  17. Lifetime risk of urothelial carcinoma and lung cancer in the arseniasis-endemic area of Northeastern Taiwan

    NASA Astrophysics Data System (ADS)

    Yang, Tse-Yen; Hsu, Ling-I.; Chen, Hui-Chi; Chiou, Hung-Yi; Hsueh, Yu-Mei; Wu, Meei-Maan; Chen, Chi-Ling; Wang, Yuan-Hung; Liao, Ya-Tang; Chen, Chien-Jen

    2013-11-01

    Arsenic in drinking water has been shown to increase the risk of urothelial carcinoma and lung cancer. However, the lifetime risk of developing urothelial carcinoma and lung cancer caused by exposure to arsenic in drinking water has not been reported. This study aimed to assess the lifetime risk of urothelial carcinoma and lung cancer caused by arsenic exposure from drinking water and cigarette smoking habit for residents living in the arseniasis-endemic area in Northeastern Taiwan. We recruited 8086 residents in 1991-1994 and monitored them for their newly developed types of cancers, identified by computerized linkage with the national cancer registry profile. There were 37 newly diagnosed urothelial carcinoma cases and 223 new lung cancer cases during the follow-up period (until 2007). The lifetime (35-85 years old) cumulative risk of developing urothelial carcinoma from an arsenic concentration in the drinking water of <10, 10-99, and 100+ μg/L was 0.29%, 1.07% and 3.43%, respectively. The corresponding probabilities were 7.42%, 8.99% and 17.09% for the lifetime risk of developing lung cancer. Cigarette smoking was associated with an increased risk of urothelial carcinoma and lung cancer, showing the hazard ratio (95% confidence interval) of 2.48 (1.27-4.82) and 3.44 (2.00-5.90) after adjusting for the arsenic concentration in drinking water. After adjusting for cigarette smoking, the hazard ratio (95% confidence interval) of developing urothelial carcinoma caused by the arsenic concentration in drinking water of <10, 10-99 and 100+ μg/L was 1.0 (the reference group), 2.18 (0.59-8.01), and 8.71 (2.49-30.48), respectively. The corresponding figures were 1.0 (the reference group), 1.14 (0.80-1.61), 1.84 (1.28-2.65) for lung cancer. Synergistic effects on the development of urothelial carcinoma and lung cancer existed between the arsenic exposure level and cigarette smoking. It is suggested that people who have had a high exposure to arsenic in drinking water

  18. MicroRNA Profiling in Patients with Upper Tract Urothelial Carcinoma Associated with Balkan Endemic Nephropathy.

    PubMed

    Popovska-Jankovic, Katerina; Noveski, Predrag; Jankovic-Velickovic, Ljubinka; Stojnev, Slavica; Cukuranovic, Rade; Stefanovic, Vladisav; Toncheva, Draga; Staneva, Rada; Polenakovic, Momir; Plaseska-Karanfilska, Dijana

    2016-01-01

    Balkan endemic nephropathy (BEN) is a disease that affects people that live in the alluvial plains along the tributaries of the Danube River in the Balkan region. BEN is a chronic tubulointerstitial disease with a slow progression to terminal renal failure and has strong association with upper tract urothelial carcinoma (UTUC). There are several hypotheses about the etiology of BEN, but only the toxic effect of aristolochic acid has been confirmed as a risk factor in the occurrence of the disease. Aberrantly expressed miRNAs have been shown to be associated with many types of cancers. A number of studies have investigated the expression of microRNAs in urothelial carcinoma, mainly on urothelial bladder cancer, and only a few have included patients with UTUC. Here we present the first study of microRNA profiling in UTUC tissues from patients with BEN (BEN-UTUC) and patients with UTUC from nonendemic Balkan regions (non-BEN-UTUC) in comparison to normal kidney tissues. We found 10 miRNAs that were differentially expressed in patients with BEN-UTUC and 15 miRNAs in patients with non-BEN-UTUC. miRNA signature determined in BEN-UTUC patients differs from the non-BEN-UTUC patients; only miR-205-5p was mutual in both groups. PMID:27218105

  19. MicroRNA Profiling in Patients with Upper Tract Urothelial Carcinoma Associated with Balkan Endemic Nephropathy

    PubMed Central

    Popovska-Jankovic, Katerina; Noveski, Predrag; Jankovic-Velickovic, Ljubinka; Stojnev, Slavica; Cukuranovic, Rade; Stefanovic, Vladisav; Toncheva, Draga; Staneva, Rada; Polenakovic, Momir; Plaseska-Karanfilska, Dijana

    2016-01-01

    Balkan endemic nephropathy (BEN) is a disease that affects people that live in the alluvial plains along the tributaries of the Danube River in the Balkan region. BEN is a chronic tubulointerstitial disease with a slow progression to terminal renal failure and has strong association with upper tract urothelial carcinoma (UTUC). There are several hypotheses about the etiology of BEN, but only the toxic effect of aristolochic acid has been confirmed as a risk factor in the occurrence of the disease. Aberrantly expressed miRNAs have been shown to be associated with many types of cancers. A number of studies have investigated the expression of microRNAs in urothelial carcinoma, mainly on urothelial bladder cancer, and only a few have included patients with UTUC. Here we present the first study of microRNA profiling in UTUC tissues from patients with BEN (BEN-UTUC) and patients with UTUC from nonendemic Balkan regions (non-BEN-UTUC) in comparison to normal kidney tissues. We found 10 miRNAs that were differentially expressed in patients with BEN-UTUC and 15 miRNAs in patients with non-BEN-UTUC. miRNA signature determined in BEN-UTUC patients differs from the non-BEN-UTUC patients; only miR-205-5p was mutual in both groups. PMID:27218105

  20. A case of brain and leptomeningeal metastases from urothelial carcinoma of the bladder.

    PubMed

    Erhamamcı, S; Reyhan, M; Altinkaya, N

    2014-01-01

    Brain metastases are unusual from urethelial carcinoma of bladder and particularly the occurrence of leptomeningeal metastases is extremely rare, with few cases described in the literature. We present a case of a 45-year-old man with a rare brain metastases as the first metastatic manifestation secondary to urethelial carcinoma of bladder followed by leptomeningeal metastases without any other organ involvement. Eleven months after the diagnosis of high-grade urethelial carcinoma of bladder (T2N0M0), the patient was detected having brain metastases by MRI. FDG PET/CT images for the metastatic evaluation showed no abnormal FDG uptake elsewhere in the body except the brain. Histopathology examination from brain lesion demonstrated the cerebral lesion to be a metastatic urothelial carcinoma. Two months later, the patient was diagnosed to have leptomeningeal metastases by MRI. Our patient's condition gradually worsened, and he died 3 months after the diagnosis of leptomeningeal metastases. PMID:25043771

  1. Unique Transcriptomic Profile of Collecting Duct Carcinomas Relative to Upper Tract Urothelial Carcinomas and other Kidney Carcinomas.

    PubMed

    Malouf, Gabriel G; Compérat, Eva; Yao, Hui; Mouawad, Roger; Lindner, Veronique; Rioux-Leclercq, Nathalie; Verkarre, Virginie; Leroy, Xavier; Dainese, Linda; Classe, Marion; Descotes, Jean-Luc; Barthelemy, Philippe; Yacoub, Mokrane; Rouprêt, Morgan; Bernhard, Jean-Christophe; Creighton, Chad J; Spano, Jean-Philippe; Su, Xiaoping; Khayat, David

    2016-01-01

    Collecting duct carcinoma (CDC) is a kidney cancer subtype that is thought to arise from principal cells in distal parts of the collecting ducts. Some studies suggested an overlap of CDC with upper tract urothelial carcinoma (UTUC), making the pathological diagnosis challenging. Herein, we performed for the first time transcriptome sequencing of CDC and compared them to UTUC and renal cell carcinoma subtypes. We discovered that CDC displays a unique transcriptomic signature among kidney cancer subtypes, with a putative cell of origin in the distal convoluted tubules. Hierarchical unsupervised clustering reveals that the CDC signature is closer to that of other RCC subtypes than to UTUC, which is similar to that of bladder carcinoma. CDC is characterized by a metabolic shift, with impairment of oxidoreductase activity, pyruvate metabolism and the tricarboxlyic acid cycle, as well as an immunogenic response consistent with increased tumor infiltrating lymphocytes, particularly within metastatic cases. In addition, pathways differentially altered between CDC and UTUC point to a basal-like phenotype of CDC in contrast to the luminal-like signature of UTUC. We conclude that CDC harbors a pathognomonic transcriptomic signature characterized by immunogenic and a metabolic aberrations, indicating that targeting these processes might provide therapeutic options for patients. PMID:27484008

  2. Unique Transcriptomic Profile of Collecting Duct Carcinomas Relative to Upper Tract Urothelial Carcinomas and other Kidney Carcinomas

    PubMed Central

    Malouf, Gabriel G.; Compérat, Eva; Yao, Hui; Mouawad, Roger; Lindner, Veronique; Rioux-leclercq, Nathalie; Verkarre, Virginie; Leroy, Xavier; Dainese, Linda; Classe, Marion; Descotes, Jean-Luc; Barthelemy, Philippe; Yacoub, Mokrane; Rouprêt, Morgan; Bernhard, Jean-Christophe; Creighton, Chad J.; Spano, Jean-Philippe; Su, Xiaoping; Khayat, David

    2016-01-01

    Collecting duct carcinoma (CDC) is a kidney cancer subtype that is thought to arise from principal cells in distal parts of the collecting ducts. Some studies suggested an overlap of CDC with upper tract urothelial carcinoma (UTUC), making the pathological diagnosis challenging. Herein, we performed for the first time transcriptome sequencing of CDC and compared them to UTUC and renal cell carcinoma subtypes. We discovered that CDC displays a unique transcriptomic signature among kidney cancer subtypes, with a putative cell of origin in the distal convoluted tubules. Hierarchical unsupervised clustering reveals that the CDC signature is closer to that of other RCC subtypes than to UTUC, which is similar to that of bladder carcinoma. CDC is characterized by a metabolic shift, with impairment of oxidoreductase activity, pyruvate metabolism and the tricarboxlyic acid cycle, as well as an immunogenic response consistent with increased tumor infiltrating lymphocytes, particularly within metastatic cases. In addition, pathways differentially altered between CDC and UTUC point to a basal-like phenotype of CDC in contrast to the luminal-like signature of UTUC. We conclude that CDC harbors a pathognomonic transcriptomic signature characterized by immunogenic and a metabolic aberrations, indicating that targeting these processes might provide therapeutic options for patients. PMID:27484008

  3. CD73 Predicts Favorable Prognosis in Patients with Nonmuscle-Invasive Urothelial Bladder Cancer

    PubMed Central

    Wettstein, Marian S.; Buser, Lorenz; Hermanns, Thomas; Roudnicky, Filip; Eberli, Daniel; Baumeister, Philipp; Sulser, Tullio; Wild, Peter; Poyet, Cédric

    2015-01-01

    Aims. CD73 is a membrane associated 5′-ectonucleotidase that has been proposed as prognostic biomarker in various solid tumors. The aim of this study is to evaluate CD73 expression in a cohort of patients with primary bladder cancer in regard to its association with clinicopathological features and disease course. Methods. Tissue samples from 174 patients with a primary urothelial carcinoma were immunohistochemically assessed on a tissue microarray. Associations between CD73 expression and retrospectively obtained clinicopathological data were evaluated by contingency analysis. Survival analysis was performed to investigate the predictive value of CD73 within the subgroup of pTa and pT1 tumors in regard to progression-free survival (PFS). Results. High CD73 expression was found in 46 (26.4%) patients and was significantly associated with lower stage, lower grade, less adjacent carcinoma in situ and with lower Ki-67 proliferation index. High CD73 immunoreactivity in the subgroup of pTa and pT1 tumors (n = 158) was significantly associated with longer PFS (HR: 0.228; p = 0.047) in univariable Cox regression analysis. Conclusion. High CD73 immunoreactivity was associated with favorable clinicopathological features. Furthermore, it predicts better outcome in the subgroup of pTa and pT1 tumors and may thus serve as additional tool for the selection of patients with favorable prognosis. PMID:26543299

  4. Prospective evaluation of FISH for detecting upper tract urothelial carcinoma in voided urine specimens

    PubMed Central

    YU, QIUBO; LI, YANAN; LI, GANG; LI, TINGHONG; ZENG, HAN; YANG, ZHU; WANG, DELING

    2016-01-01

    The aim of the present study was to estimate the diagnostic value of fluorescence in situ hybridization (FISH) analysis of tumor cells in voided urine specimens for detecting upper tract urothelial carcinoma (UTUC). Cytology and FISH analyses were conducted on voided urine collected in the morning from 125 patients with suspected UTUC. During follow-up, ureteroscopy with biopsy and histopathology were used to confirm the presence of tumors. The average follow-up time was 23.8 months (range, 6–36 months). A total of 8 patients who could not be contacted until the last follow-up were excluded from the study. Of the remaining 117 patients, 19 were histologically demonstrated to have UTUC, of whom, 3 patients had stage pTis disease, 6 had stage pTa disease, 5 had stage pT1 disease and 5 had stage pT2 disease (7 G1, 8 G2 and 4 G3). The overall sensitivity of FISH to detect UTUCs in voided urine specimens was 84.21% (16/19), whereas that of cytology was 42.11% (8/19) (P<0.05). The overall specificity of FISH to detect UTUCs in voided urine specimens was 89.80% (88/98), compared with 94.90% (93/98) of cytology (P>0.05). The positive predictive value (PPV) and negative predictive value of FISH were 80.00% (16/20) and 97.78% (88/90), respectively, whereas those of cytology were 100.00% (8/8) (P>0.05) and 90.29% (93/103) (P>0.05), respectively. The present data indicated that FISH was a method capable of detecting UTUCs in voided urine specimens with good sensitivity and specificity, although it exhibited a high rate of false positivity and low PPV. PMID:27347122

  5. Papillary urothelial carcinoma with squamous differentiation in association with human papilloma virus: case report and literature review

    PubMed Central

    Guma, Sergei; Maglantay, Remegio; Lau, Ryan; Wieczorek, Rosemary; Melamed, Jonathan; Deng, Fang-Ming; Zhou, Ming; Makarov, Danil; Lee, Peng; Pincus, Matthew R; Pei, Zhi-Heng

    2016-01-01

    Background: The human papilloma virus (HPV) is a carcinogen known for its strong association with cervical cancers and cervical lesions. It is also known to be associated with a variety of squamous cell carcinomas in other areas, such as the penis, vulva, anus and head and neck. However, the association with urothelial carcinoma remains controversial. Here, we report a case of urothelial carcinoma with squamous differentiation associated with HPV-6/HPV-11. Case presentation: This is a case of a 70 year old man who presented with nocturia and pressure during urination. During the TURP procedure for what was clinically thought to be benign prostate hyperplasia with pathologic diagnosis as prostate carcinoma, a 2 cm papillary mass was found in the distal penile urethra. The papillary mass was found to be a high grade urothelial carcinoma positive for GATA 3 expression, with focal areas of squamous differentiation. The areas with squamous differentiation demonstrated koilocytic differentiation, which were positive for strong p16 expression. The tumor was found to harbor low risk HPV 6/11 by in situ hybridization. Conclusions: This study case demonstrates HPV infection with a low risk subtype (HPV 6/11) associated with an urothelial carcinoma with squamous differentiation and condylomatous features. PMID:27069958

  6. Bladder cancer will grow anywhere: report of a urothelial carcinoma drop metastasis to the vagina and literature review.

    PubMed

    Uhlman, Matthew A; Bevill, Mark D; Goodheart, Michael J; Brown, James A; O'Donnell, Michael A

    2016-08-01

    Urothelial carcinoma is the 2nd most common cancer of the urinary tract and accounts for the majority of cases of bladder cancer. Metastases are not infrequently encountered, increasing with disease stage and are most commonly seen in the bones and lungs. Many other sites have been described including the omentum, liver, and ovaries. An extremely rare site of metastatic disease however is within the vagina. Here we present a case of a probable vaginal 'drop metastasis' from previously treated urothelial carcinoma in the ureter and bladder. PMID:27544563

  7. 18F-FDG PET/CT Findings of Metastasis to Spongy Body of Penis From Urothelial Carcinoma of Bladder.

    PubMed

    Wang, Yan-Li; Fang, Na; Zeng, Lei; Wu, Zeng-Jie; Cui, Xin-Jian

    2016-05-01

    The spongy body of the penis metastasis from other primary sites is a rare clinical entity. It is frequently associated with widespread metastatic disease and poor prognosis clinically. We report a case of a 61-year-old man with a previous history of cystectomy due to infiltrating urothelial carcinoma of the bladder 12 months ago and presented with penile shaft swelling pain and hematuria for 3 months. The restaging F-FDG PET/CT scan demonstrated a hypermetabolic mass at his penile shaft. This lesion was confirmed on phallectomy to be infiltrating urothelial carcinoma metastasis from the known primary bladder tumor. PMID:26359570

  8. Fluorescence spectroscopy incorporating a ratiometric approach for the diagnosis and classification of urothelial carcinoma

    NASA Astrophysics Data System (ADS)

    Anand, Suresh; Cicchi, Riccardo; Crisci, Alfonso; Nesi, Gabriella; Carini, Marco; Pavone, Francesco S.

    2016-02-01

    The current most popular clinical method for the screening of urothelial carcinoma is white light cystoscopy. This method has inherent disadvantages making a strong genesis towards developing more powerful diagnostic techniques. Laser induced intrinsic fluorescence spectroscopy has been studied as an adjunct to current methods for the detection of tumors. This technique allows real time results based on the changes in spectral profile between normal and tumor tissues. We conducted a pilot study based on fluorescence spectroscopy at two wavelengths 378 and 445 nm excitation for the differentiation of urothelial carcinoma. At both the excitation wavelengths, the measured fluorescence signal showed an increased intensity at wavelengths greater than 520 nm. In addition, the emission profile showed modulation at 580 nm which is due to the reabsorption of emitted fluo- rescence due to hemoglobin. Additionally, we developed a tissue characterizing algorithm, based on fluorescence intensity ratios, F510/F600 and F520/F580 at 378 and 445 nm excitation wavelengths respectively. Further, the results were correlated with the pathologists assessment of urothelial carcinoma. This ratiometric classification algorithm yielded 81% sensitivity and 83% specificity at 378 nm and while at 445 nm excitation we achieved a sensitivity and specificity of 85% and 86% for classifying normal and tumor bladder tissues. In this study we have demonstrated the potential of a simple ratiometric algorithm based on fluorescence spectroscopy could be an alternative tool to tissue biopsy. Furthermore, this technique based fiber-based fluorescence spectroscopy could be integrated into an endoscopy system for use in the operating room.

  9. Impact of EZH2 Polymorphisms on Urothelial Cell Carcinoma Susceptibility and Clinicopathologic Features

    PubMed Central

    Hsieh, Ming-Ju; Wang, Shian-Shiang; Wang, Po-Hui; Weng, Wei-Chun; Yang, Shun-Fa

    2014-01-01

    Background The gene EZH2, the polycomb group protein enhancer of zeste 2, encodes a transcriptional repressor that also serves as a histone methyltransferase that is associated with progression to more advanced disease in a variety of malignancies. EZH2 expression level in urothelial cell carcinoma (UCC) is highly correlated with tumor aggressiveness, but it has not been determined if specific EZH2 genetic variants are associated with UCC risk. This study investigated the potential associations of EZH2 single-nucleotide polymorphisms with UCC susceptibility and its clinicopathologic characteristics. Methodology/Principal Findings A total of 233 UCC patients and 552 cancer-free controls, all of whom were from Taiwan, were analyzed for four EZH2 single-nucleotide polymorphisms (rs6950683, rs2302427, rs3757441, and rs41277434) using real-time PCR genotyping. After adjusting for other co-variants, we found that individuals carrying at least one C allele at EZH2 rs6950683 had a lower risk of developing UCC than did major allele carriers. The CCCA or TGTA haplotype among the four EZH2 sites was also associated with a reduced risk of UCC. Furthermore, UCC patients who carried at least one G allele at rs2302427 had a lower invasive tumor stage than did patients carrying the major allele. Conclusions The rs6950683 SNPs of EZH2 might contribute to the prediction of UCC susceptibility. This is the first study to provide insight into risk factors associated with EZH2 variants in carcinogenesis of UCC in Taiwan. PMID:24691023

  10. Prognostic Significance of Preoperative Albumin-Globulin Ratio in Patients with Upper Tract Urothelial Carcinoma

    PubMed Central

    Zhou, Li-Qun; He, Zhi-Song; Shen, Cheng; He, Qun; Li, Jun; Liu, Li-Bo; Wang, Cong; Chen, Xiao-Yu; Fan, Yu; Hu, Shuai; Zhang, Lei; Han, Wen-Ke; Jin, Jie

    2015-01-01

    Background Preoperative albumin-globulin ratio (AGR) reflects both malnutrition and systemic inflammation in cancer patients. In particular, systemic inflammation has been reported to contribute to tumor progression and poor oncological outcome in various malignancies. However, the prognostic value of preoperative AGR in upper tract urothelial carcinoma (UTUC) has not been examined. Methods We retrospectively reviewed medical data of 187 operable UTUC patients in a Chinese cohort with a high incidence of chronic kidney disease (CKD). AGR was calculated as [AGR = albumin/(serum total protein—albumin)]. The associations of preoperative AGR with clinicopathologic characteristics and prognosis were assessed. Multivariate analyses using Cox regression models were performed to determine the independent prognostic factors. Results The median (IQR) preoperative AGR was 1.50 (1.30–1.70), and the optimal cutoff value was determined to be 1.45 according to the receiver operating curve analysis. Low AGR was significantly associated with female gender, high CKD stage and tumor grade (P < 0.05). Eighty-three patients died before the follow-up endpoint. Kaplan-Meier analysis showed that an AGR < 1.45 predicted significantly poorer overall and cancer-specific survivals compared to an AGR ≥ 1.45 (P < 0.001 and P = 0.008, respectively). Multivariate analyses showed that an AGR < 1.45 was an independent risk factor for poorer overall and cancer-specific survivals (P = 0.002 and P = 0.015, respectively). Conclusions Preoperative AGR can act as an effective biomarker with easy accessibility for evaluating the prognosis of patients with UTUC. AGR should be applied in UTUC patients for risk stratification and determination of optimal therapeutic regimens. PMID:26681341

  11. Mixed low- and high-grade papillary urothelial carcinoma: histopathogenetic and clinical significance.

    PubMed

    Mai, Kien T; Flood, Trevor A; Williams, Phillip; Kos, Zuzana; Belanger, Eric C

    2013-10-01

    There are two pathways of urothelial carcinogenesis: low-grade urothelial carcinoma (LGUC) with low rates of gene alterations and high-grade urothelial carcinoma (HGUC) with numerous gene alterations. HGUC often displays strong reactivity for cytokeratin 20 (CK20) and p16. Despite distinct molecular changes, urothelial carcinoma (UC) with both low- and high-grade features is not uncommon. We examined cases with patterns of mixed low- and high-grade UC (MLHGUC). Consecutive cases of UC at our institution were reviewed. There were 45 cases that showed a mixture of both LGUC and HGUC. IHC for CK5, CK20, CD44, p16, and Ki67 was performed. Areas of HGUC displayed strong and diffuse reactivity for p16, CK20, and Ki67 in 20-50 % of the tumor, while LGUC areas had negative or focal reactivity for CK20 and Ki67 in 10-30 %. There were two distinct cohorts of MLHGUC: patients with a history of LGUC (group A) and those without (group B). Group A patients (n = 8) had a history of LGUC for 1-10 years. The tumor specimens weighed 1.5 ± 1.7 g and had HGUC components of 25 ± 20 % of the tissue. Superficial invasion was present in one case. All tumors had BCG treatment with one recurrence. In group B (n = 37), tumor specimens weighed 3 ± 3.9 g and had HGUC components in 43 ± 21 % of the tissue. Superficial invasion was present in five cases, and muscle invasion with lung metastasis occurred in one case. Four cases were refractory to BCG with an increased proportion of HGUC, and one case requiring cystectomy. Differences in size and proportion of HGUC between groups A and B MLHGUC were significant (P < 0.05), with group B presenting with a higher tumor burden and proportion of HGUC. MLHGUC is diagnostically challenging and is commonly assigned high grade since this determines prognosis. Group A MLHGUC likely develops as a result of progression from LGUC, whereas group B MLHGUC likely develops de novo, is associated with larger tumors, shows a

  12. Comprehensive profiling and localisation of the matrix metalloproteinases in urothelial carcinoma

    PubMed Central

    Wallard, M J; Pennington, C J; Veerakumarasivam, A; Burtt, G; Mills, I G; Warren, A; Leung, H Y; Murphy, G; Edwards, D R; Neal, D E; Kelly, J D

    2006-01-01

    The matrix metalloproteinases (MMPs) are endopeptidases which break down the extracellular matrix and regulate cytokine and growth factor activity. Several MMPs have been implicated in the promotion of invasion and metastasis in a broad range of tumours including urothelial carcinoma. In this study, RNA from 132 normal bladder and urothelial carcinoma specimens was profiled for each of the 24 human MMPs, the four endogenous tissue inhibitors of MMPs (TIMPs) and several key growth factors and their receptors using quantitative real time RT–PCR. Laser capture microdissection (LCM) of RNA from 22 tumour and 11 normal frozen sections was performed allowing accurate RNA extraction from either stromal or epithelial compartments. This study confirms the over expression in bladder tumour tissue of well-documented MMPs and highlights a range of MMPs which have not previously been implicated in the development of urothelial cancer. In summary, MMP-2, MT1-MMP and the previously unreported MMP-28 were very highly expressed in tumour samples while MMPs 1, 7, 9, 11, 15, 19 and 23 were highly expressed. There was a significant positive correlation between transcript expression and tumour grade for MMPs 1, 2, 8, 10, 11, 12, 13, 14, 15 and 28 (P<0.001). At the same confidence interval, TIMP-1 and TIMP-3 also correlated with increasing tumour grade. LCM revealed that most highly expressed MMPs are located primarily within the stromal compartment except MMP-13 which localised to the epithelial compartment. This work forms the basis for further functional studies, which will help to confirm the MMPs as potential diagnostic and therapeutic targets in early bladder cancer. PMID:16465195

  13. Geographic Variation of Chronic Kidney Disease Prevalence: Correlation with the Incidence of Renal Cell Carcinoma or Urothelial Carcinoma?

    PubMed Central

    Yap, Yit-Sheung; Chuang, Kai-Wen; Chiang, Chun-Ju; Chuang, Hung-Yi; Lu, Sheng-Nan

    2015-01-01

    Background. The aim of this study is to evaluate whether geographic variations in the prevalence of late-stage chronic kidney disease (CKD) exist and are associated with incidence rates of renal cell carcinoma (RCC), upper tract urothelial carcinoma (UTUC), or lower tract urothelial carcinoma (LTUC). Methods. Prevalence rates of late-stage CKD for 366 townships (n > 30) in Taiwan were calculated for 1,518,241 and 1,645,151 subjects aged 40 years or older in years 2010 and 2009, respectively. Late-stage CKD prevalence in year 2010 was used as a training set and its age-adjusted standardized morbidity rates (ASMR) were divided into three groups as defined <1.76%, 1.76% ≤ ASMR < 2.64%, and ≥2.64%, respectively. Year 2009, defined as the validation set, was used to validate the results. Results. The ASMR of late-stage CKD in years 2010 and 2009 were 1.76%, and 2.09%, respectively. Geographic variations were observed, with notably higher rates of disease in areas of the central, southwestern mountainside, and southeastern seaboard. There were no significant differences among different combined risk groups of RCC, UTUC, and LTUC incidence. Conclusion. The substantial geographic variations in the prevalence of late-stage CKD exist, but are not correlated with RCC, UTUC, or LTUC incidence. PMID:26605329

  14. [Case of a Plasmacytoid Urothelial Carcinoma Identified Due to the Hardening of the Abdominal Wall].

    PubMed

    Yanagisawa, Masahiro; Kawakami, Toshifumi; Suzuki, Kotaro; Nakayama, Takashi

    2016-02-01

    The patient was a 75 year-old male. Noticing areas of hardening in the lower abdomen, and consequently feelings of systemic fatigue and difficulty in walking, the patient visited a clinic and was diagnosed with kidney failure prior to the visit to our clinic. Computed tomography and magnetic resonance imaging showed thickness of the rectus abdominis muscle and the bladder wall, and bilateral hydronephrosis was also identified. As no explicit tumor was identified in the bladder, the patient underwent biopsies of the abdominal wall and bladder membrane mucous, and was diagnosed with a plasmacytoid urothelial carcinoma primarily developed in the bladder. The patient displayed a poor general state of health and died five months after the diagnosis. It is known that plasmacytoid urothelial carcinomas progress rapidly and the prognosis is poorer than for the micropapillary variant. It is important to obtain a tissue specimen in the early stage of this disease because there are cases in which no explicit tumor can be identified. Furthermore, the value of carbohydrate antigen (CA) 19-9 of the patient was much higher than would be expected as normal at the first visit. It kept rising during the follow-up and was useful as a marker to indicate the progress of the disease. PMID:27018411

  15. Poor prognostic value of lymphovascular invasion for pT1 urothelial carcinoma with squamous differentiation in bladder cancer.

    PubMed

    Li, Gang; Song, Hualin; Wang, Jiaxin; Bao, Yali; Niu, Yuanjie

    2016-01-01

    Lymphovascular invasion (LVI) is the primary and essential step in the systemic dissemination of cancer cells. The aim of our study was to assess the independent prognostic role of LVI for pT1 urothelial carcinoma with squamous differentiation in bladder cancer. We retrospectively analyzed the clinical and pathological information of 206 patients diagnosed pT1 urothelial carcinoma with squamous differentiation. Of the 206 patients, LVI was detected in 57 (27.6%) patients. The 5 year cancer specific survival (CSS) rates were 87.2% in LVI (-) and 52.4% in LVI (+) (p < 0.001). According to univariate analysis, tumor multiplicity, tumor size, recurrence and LVI were the prognostic factors associated with CSS. Additionally, tumor size and LVI significantly influenced the CSS in multivariate analysis. TURBT had shorter median CSS than RC in recurred patients with LVI (+). Our study suggested that LVI is an important predictor for survival of pT1 urothelial carcinoma with squamous differentiation. LVI positive status and tumor size ≥3 cm led to a higher risk of death. RC should be routinely performed in recurred LVI (+) bladder cancer patients of pT1 urothelial carcinoma with squamous differentiation. PMID:27279531

  16. Poor prognostic value of lymphovascular invasion for pT1 urothelial carcinoma with squamous differentiation in bladder cancer

    PubMed Central

    Li, Gang; Song, Hualin; Wang, Jiaxin; Bao, Yali; Niu, Yuanjie

    2016-01-01

    Lymphovascular invasion (LVI) is the primary and essential step in the systemic dissemination of cancer cells. The aim of our study was to assess the independent prognostic role of LVI for pT1 urothelial carcinoma with squamous differentiation in bladder cancer. We retrospectively analyzed the clinical and pathological information of 206 patients diagnosed pT1 urothelial carcinoma with squamous differentiation. Of the 206 patients, LVI was detected in 57 (27.6%) patients. The 5 year cancer specific survival (CSS) rates were 87.2% in LVI (−) and 52.4% in LVI (+) (p < 0.001). According to univariate analysis, tumor multiplicity, tumor size, recurrence and LVI were the prognostic factors associated with CSS. Additionally, tumor size and LVI significantly influenced the CSS in multivariate analysis. TURBT had shorter median CSS than RC in recurred patients with LVI (+). Our study suggested that LVI is an important predictor for survival of pT1 urothelial carcinoma with squamous differentiation. LVI positive status and tumor size ≥3 cm led to a higher risk of death. RC should be routinely performed in recurred LVI (+) bladder cancer patients of pT1 urothelial carcinoma with squamous differentiation. PMID:27279531

  17. Pulmonary tumor thrombotic microangiopathy associated with urothelial carcinoma of the urinary bladder: antemortem diagnosis by pulmonary microvascular cytology

    PubMed Central

    Yamakawa, Hideaki; Yoshida, Masahiro; Yamada, Masami; Ishikawa, Takeo; Takagi, Masamichi; Katagi, Hiroaki; Yoshida, Jun; Kosuga, Tsuneharu; Kuwano, Kazuyoshi

    2015-01-01

    Key Clinical Message PTTM (Pulmonary tumor thrombotic microangiopathy) is very difficult to diagnose before death. We report a case of urothelial carcinoma of the urinary bladder associated with PTTM in which an antemortem diagnosis by PMC (pulmonary microvascular cytology). PMC may represent the only chance for diagnosis and achievement of remission in PTTM. PMID:26401277

  18. Diagnostic Value of Liquid-Based Cytology in Urothelial Carcinoma Diagnosis: A Systematic Review and Meta-Analysis

    PubMed Central

    Yang, Li; Fu, Sheng-Jun

    2015-01-01

    Objective To evaluate the value of liquid-based cytology (LBC) in the diagnosis of urothelial carcinoma. Method Diagnostic studies were searched for the diagnostic value of LBC in urothelial carcinoma in PubMed, Embase, Cochrane Library, Web of Science, CBM and CNKI. The latest retrieval date was September 2014. The data were extracted and the quality of the included studies was independently assessed by 2 reviewers. Stata 13 software was used to perform the statistical analysis. The research was conducted in compliance with the PRISMA statement. Result Nineteen studies, which included 8293 patients, were evaluated. The results of the meta-analysis showed that the pooled sensitivity and specificity of LBC were 0.58 (0.51–0.65) and 0.96 (0.93–0.98), respectively. The diagnostic odds ratio (DOR) was 31 (18–56) and the area under the curve (AUC) of summary receiver operating characteristic (SROC) was 0.83 (0.80–0.86). The post-test probability was 80% when a positive diagnosis was made. Compared with high grade urothelial carcinoma (HGUC), the sensitivity of detecting low-grade urothelial carcinoma (LGUC) was significantly lower, risk ratio of sensitivity was 0.54 (0.43–0.66), P<0.001. However, no significant sensitivity improvement was observed with LBC when compared with traditional cytospin cytology, risk ratio was 1.03 (0.94–1.14), P = 0.524. Conclusion Despite LBC having a pooled 58% positive rate for urothelial carcinoma diagnosis in our meta-analysis, no significant improvement in sensitivity was observed based on the studies evaluated. Further research is needed to validate these findings. PMID:26241896

  19. Renal pelvis urothelial carcinoma of the upper moiety in complete right renal duplex: a case report

    PubMed Central

    Zhang, Yiran; Yu, Quanfeng; Zhang, Zhihong; Liu, Ranlu; Xu, Yong

    2015-01-01

    Urothelial carcinoma (UC) originated from renal pelvis is the common tumor of the urinary system, however, neoplasia of the renal pelvis in duplex kidneys is extremely rare, especially in the complete renal and ureteral duplex cases. We present the first case of renal pelvis UC of the upper moiety in a complete right renal duplex. This male patient has bilateral complete renal and ureteral duplex. To the best of our knowledge, this is the first reported case of renal pelvis UC in a complete renal duplex system. After this experience we feel that the diagnosis of renal pelvis UC in duplex kidneys is not so easy, and once the diagnosis is determined, the whole renal duplex units and bladder cuff or ectopic orifice should be excised radically. PMID:26823906

  20. Metachronous urothelial carcinoma of whole urinary tract in a dialysis-dependent patient: A case report

    PubMed Central

    WANG, YIMIN; JIN, BAIYE; YAO, XIAOLIN

    2016-01-01

    Numerous studies have reported an association between end-stage renal disease (ESRD) and malignancy. The predominant malignant tumor that occurs in patients with ESRD in Asian countries is urothelial carcinoma (UC). According to recent research, cases of UC in dialysis-dependent patients are associated with higher recurrence rates and more aggressive biological behavior compared with patients without ESRD. The necessity of 1-step total urinary tract exenteration for dialysis-dependent patients with UC is advocated by certain studies. The current study reports a case of metachronous bladder cancer and bilateral upper urinary tract tumor in a dialysis-dependent patient. Three separate surgeries were performed to remove the bladder, and left and right urinary tract, respectively. The question of whether the stepwise strategy or the 1-step surgery should be selected for such special cases remains in debate. PMID:27313734

  1. Integrated Genomic and Gene Expression Profiling Identifies Two Major Genomic Circuits in Urothelial Carcinoma

    PubMed Central

    Lindgren, David; Sjödahl, Gottfrid; Lauss, Martin; Staaf, Johan; Chebil, Gunilla; Lövgren, Kristina; Gudjonsson, Sigurdur; Liedberg, Fredrik; Patschan, Oliver; Månsson, Wiking; Fernö, Mårten; Höglund, Mattias

    2012-01-01

    Similar to other malignancies, urothelial carcinoma (UC) is characterized by specific recurrent chromosomal aberrations and gene mutations. However, the interconnection between specific genomic alterations, and how patterns of chromosomal alterations adhere to different molecular subgroups of UC, is less clear. We applied tiling resolution array CGH to 146 cases of UC and identified a number of regions harboring recurrent focal genomic amplifications and deletions. Several potential oncogenes were included in the amplified regions, including known oncogenes like E2F3, CCND1, and CCNE1, as well as new candidate genes, such as SETDB1 (1q21), and BCL2L1 (20q11). We next combined genome profiling with global gene expression, gene mutation, and protein expression data and identified two major genomic circuits operating in urothelial carcinoma. The first circuit was characterized by FGFR3 alterations, overexpression of CCND1, and 9q and CDKN2A deletions. The second circuit was defined by E3F3 amplifications and RB1 deletions, as well as gains of 5p, deletions at PTEN and 2q36, 16q, 20q, and elevated CDKN2A levels. TP53/MDM2 alterations were common for advanced tumors within the two circuits. Our data also suggest a possible RAS/RAF circuit. The tumors with worst prognosis showed a gene expression profile that indicated a keratinized phenotype. Taken together, our integrative approach revealed at least two separate networks of genomic alterations linked to the molecular diversity seen in UC, and that these circuits may reflect distinct pathways of tumor development. PMID:22685613

  2. Differential diagnosis of urothelial carcinoma in situ from non-neoplastic urothelia: Analysis of CK20, CD44, P53 and Ki67

    PubMed Central

    Asgari, Mojgan; Nabi Maybodi, Mahtab; Abolhasani, Maryam

    2016-01-01

    Background: Flat urothelial lesions comprise a spectrum of morphologic changes ranging from reactive atypia to carcinoma in situ (CIS). Urothelial dysplasia and CIS are associated with the recurrence and progression of urothelial carcinoma. Distinguishing CIS and dysplasia from reactive atypia based on histolopathogical features alone is often difficult. Using different immunohistochemical markers such as Cytokeratin 20 (CK20), CD44, p53, and Ki-67 is recommended for differential diagnosis. The aim of this study was to evaluate the immunohistochemical pattern of these antibodies to differentiate different flat urothelial lesions. Methods: In this cross- sectional study, three groups of bladder biopsy specimens were evaluated: 20 samples with reactive urothelial lesions, 20 histologically diagnosed as CIS, and 20 morphologically normal samples. Immunohistochemical staining of CK20, p53, CD44 and Ki-67 markers was performed on paraffin-embedded blocks. The groups were compared using chi square test, and the diagnostic value of the markers were evaluated with sensitivity, specificity, positive and negative predictive values. Results: CK20 was full thickness positive in 15 (75%) CIS samples and negative in all samples of the normal and reactive groups (p<0.001); CD44 was positive in 2 (10%) cases of the CIS group and in 17 (85%) of the reactive group; this marker was negative in all the normal samples (p<0.001). P53 was positive in 12 (60%) samples of the CIS group and negative in all samples of the normal and reactive groups (p<0.001). Ki67 was positive in 13 (65%) samples of the CIS group and 1 (5%) sample of the reactive group. This marker was negative in all samples of the normal group (p<0.001). Conclusion: The results of this study revealed that CK20, CD44, P53 and Ki67 are useful in distinguishing CIS from reactive and normal samples. However, they should be used in a panel including at least three markers. Correlation with the morphologic features is necessary

  3. Effects of radiation and lifestyle factors on risks of urothelial carcinoma in the Life Span Study of atomic bomb survivors.

    PubMed

    Grant, E J; Ozasa, K; Preston, D L; Suyama, A; Shimizu, Y; Sakata, R; Sugiyama, H; Pham, T-M; Cologne, J; Yamada, M; De Roos, A J; Kopecky, K J; Porter, M P; Seixas, N; Davis, S

    2012-07-01

    Among the Life Span Study (LSS) of Atomic-bomb survivors, recent estimates showed that unspecified bladder cancer had high radiation sensitivity with a notably high female-to-male excess relative risk (ERR) per radiation dose ratio and were the only sites for which the ERR did not decrease with attained age. These findings, however, did not consider lifestyle factors, which could potentially confound or modify the risk estimates. This study estimated the radiation risks of the most prevalent subtype of urinary tract cancer, urothelial carcinoma, while accounting for smoking, consumption of fruit, vegetables, alcohol and level of education (a surrogate for socioeconomic status). Eligible study subjects included 105,402 (males = 42,890) LSS members who were cancer-free in 1958 and had estimated radiation doses. Members were censored due to loss of follow-up, incident cancer of another type, death, or the end of calendar year 2001. Surveys (by mail or clinical interview) gathered lifestyle data periodically for 1963-1991. There were 63,827 participants in one or more survey. Five hundred seventy-three incident urothelial carcinoma cases occurred, of which 364 occurred after lifestyle information was available. Analyses were performed using Poisson regression methods. The excess relative risk per weighted gray unit (the gamma component plus 10 times the neutron component, Gy(w)) was 1.00 (95% CI: 0.43-1.78) but the risks were not dependent upon age at exposure or attained age. Lifestyle factors other than smoking were not associated with urothelial carcinoma risk. Neither the magnitude of the radiation ERR estimate (1.00 compared to 0.96), nor the female-to-male (F:M) ERR/Gy(w) ratio (3.2 compared to 3.4) were greatly changed after accounting for all lifestyle factors. A multiplicative model of gender-specific radiation and smoking effects was the most revealing though there was no evidence of significant departures from either the additive or multiplicative joint

  4. Polyoma (BK) virus associated urothelial carcinoma originating within a renal allograft five years following resolution of polyoma virus nephropathy.

    PubMed

    Salvatore, Steven P; Myers-Gurevitch, Patricia M; Chu, Stacy; Robinson, Brian D; Dadhania, Darshana; Seshan, Surya V

    2016-03-01

    A direct role for BK polyomavirus infection in malignant tumors of renal allografts and urinary tract is emerging. Case reports suggest a link between BK virus (BKV) reactivation and development of malignancy in renal allograft recipients. Herein we describe the first case of BKV positive invasive urothelial carcinoma within the renal allograft, presenting with chronic diarrhea and weight loss 5 years following resolution of BK viremia/nephropathy (BKVN). Unique to our case was the remote history of BK viremia/BKVN, rising titer of anti-HLA antibody and presence of renal limited urothelial carcinoma with microinvasion of malignant cells staining positive for SV40 large T antigen (T-Ag). These findings suggest that persistence of subclinical BKV infection within the renal allograft may play a role in the malignant transformation of epithelial cells. Patients with history of BKVN may be at risk for kidney and urinary tract malignancy despite resolution of BK viremia/BKVN. PMID:26709521

  5. Expression of programmed cell death protein 4 (PDCD4) and miR-21 in urothelial carcinoma

    SciTech Connect

    Fischer, Nicolas; Goeke, Friederike; Splittstoesser, Vera; Lankat-Buttgereit, Brigitte; Mueller, Stefan C.; Ellinger, Joerg

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer The tumor suppressor gene PDCD4 is down-regulated in many tumorous entities. Black-Right-Pointing-Pointer We investigate the impact of PDCD4 and its regulating factor miR-21 in urothelial carcinoma. Black-Right-Pointing-Pointer We confirm PDCD4 as a tumor suppressor gene and it could be a diagnostic marker for this tumor. -- Abstract: Background: We investigated the role of the programmed cell death 4 (PDCD4) tumor suppressor gene in specimens of transitional cell carcinoma and of healthy individuals. Methods: PDCD4 immunohistochemical expression was investigated in 294 cases in histologically proven transitional cell carcinoma in different tumorous stages (28 controls, 122 non-muscle invasive urothelial carcinoma, stages Tis-T1, 119 invasive transitional cell carcinoma stages T2-T4 and 25 metastases). MiR-21 expression, an important PDCD4 regulator, was assessed with real-time PCR analysis and showed inverse correlation to tissue PDCD4 expression. Results: Nuclear and cytoplasmatic PDCD4 immunostaining decreased significantly with histopathological progression of the tumor (p < 0001). Controls showed strong nuclear and cytoplasmatic immunohistochemical staining. MiR-21 up regulation in tissue corresponded to PDCD4 suppression. Conclusions: These data support a decisive role for PDCD4 down regulation in transitional cell carcinoma and confirm miR-21 as a negative regulator for PDCD4. Additionally, PDCD4 immunohistochemical staining turns out to be a possible diagnostic marker for transitional cell carcinoma.

  6. Inhibition of Class I Histone Deacetylases 1 and 2 Promotes Urothelial Carcinoma Cell Death by Various Mechanisms.

    PubMed

    Pinkerneil, Maria; Hoffmann, Michèle J; Deenen, René; Köhrer, Karl; Arent, Tanja; Schulz, Wolfgang A; Niegisch, Günter

    2016-02-01

    Class I histone deacetylases HDAC1 and HDAC2 contribute to cell proliferation and are commonly upregulated in urothelial carcinoma. To evaluate whether specific inhibition of these enzymes might serve as an appropriate therapy for urothelial carcinoma, siRNA-mediated knockdown and specific pharmacologic inhibition of HDAC1 and HDAC2 were applied in urothelial carcinoma cell lines (UCC) with distinct HDAC1 and HDAC2 expression profiles. HDACs and response marker proteins were followed by Western blotting and qRT-PCR. Effects of class I HDAC suppression on UCCs were analyzed by viability, colony forming, and caspase-3/7 assays; flow cytometry, senescence and lactate dehydrogenase cytotoxicity assays; and immunofluorescence staining. Whereas single knockdowns of HDAC1 or HDAC2 were impeded by compensatory upregulation of the other isoenzyme, efficient double knockdown of HDAC1 and HDAC2 reduced proliferation by up to 80% and induced apoptosis-like cell death in all UCCs. Clonogenic growth was cell line- and HDAC-dependently reduced, with double knockdown of HDAC1 and HDAC2 being usually most efficient. Class I HDAC-specific inhibitors, especially the more specific HDAC1/2 inhibitors romidepsin and givinostat, significantly reduced proliferation of all UCCs (IC50, 3.36 nmol/L-4.59 μmol/L). Romidepsin and givinostat also significantly inhibited clonogenic growth of UCCs, with minor effects on nontumorigenic controls. Intriguingly, these compounds induced primarily S-phase disturbances and nonapoptotic cell death in UCCs. Thus, although both ways of inhibiting HDAC1/2 share mechanisms and efficaciously inhibit cell proliferation, their modes of action differ substantially. Regardless, combined inhibition of HDAC1/2 appears to represent a promising strategy for urothelial carcinoma therapy. Mol Cancer Ther; 15(2); 299-312. ©2016 AACR. PMID:26772204

  7. Identification of Nine Genomic Regions of Amplification in Urothelial Carcinoma, Correlation with Stage, and Potential Prognostic and Therapeutic Value

    PubMed Central

    Rosenberg, Jonathan; Riester, Markus; Dai, Qishan; Lin, Sharron; Guo, Yanan; McDougal, W. Scott; Kwiatkowski, David J.

    2013-01-01

    We performed a genome wide analysis of 164 urothelial carcinoma samples and 27 bladder cancer cell lines to identify copy number changes associated with disease characteristics, and examined the association of amplification events with stage and grade of disease. Multiplex inversion probe (MIP) analysis, a recently developed genomic technique, was used to study 80 urothelial carcinomas to identify mutations and copy number changes. Selected amplification events were then analyzed in a validation cohort of 84 bladder cancers by multiplex ligation-dependent probe assay (MLPA). In the MIP analysis, 44 regions of significant copy number change were identified using GISTIC. Nine gene-containing regions of amplification were selected for validation in the second cohort by MLPA. Amplification events at these 9 genomic regions were found to correlate strongly with stage, being seen in only 2 of 23 (9%) Ta grade 1 or 1–2 cancers, in contrast to 31 of 61 (51%) Ta grade 3 and T2 grade 2 cancers, p<0.001. These observations suggest that analysis of genomic amplification of these 9 regions might help distinguish non-invasive from invasive urothelial carcinoma, although further study is required. Both MIP and MLPA methods perform well on formalin-fixed paraffin-embedded DNA, enhancing their potential clinical use. Furthermore several of the amplified genes identified here (ERBB2, MDM2, CCND1) are potential therapeutic targets. PMID:23593348

  8. Ultrasound and Biomarker Tests in Predicting Cancer Aggressiveness in Tissue Samples of Patients With Bladder Cancer

    ClinicalTrials.gov

    2016-06-09

    Bladder Papillary Urothelial Carcinoma; Stage 0a Bladder Urothelial Carcinoma; Stage 0is Bladder Urothelial Carcinoma; Stage I Bladder Cancer With Carcinoma In Situ; Stage I Bladder Urothelial Carcinoma; Stage II Bladder Urothelial Carcinoma; Stage III Bladder Urothelial Carcinoma; Stage IV Bladder Urothelial Carcinoma

  9. A Modified Single Mini-Incision Complete Urinary Tract Exenteration for Urothelial Carcinoma in Dialysis Patients

    PubMed Central

    Chen, I-Hsuan; Lin, Jen-Tai; Tsai, Jeng-Yu; Wu, Tony; Yu, Chia-Cheng

    2014-01-01

    Objective. To present our experience with single mini-incision complete urinary tract exenteration (CUTE) for female dialysis patients suffering from urothelial carcinoma (UC). Patients and Methods. Institutional review board approval was obtained. From 2005 through 2012, 14 female dialysis patients with UC underwent single mini-incision CUTE, in combination with radical hysterectomy and bilateral salpingo-oophorectomy. All were placed in the modified dorsal lithotomy position without repositioning. An infraumbilical midline mini-incision was made. Bilateral nephroureterectomy was first performed entirely extraperitoneally, followed by radical cystectomy with removal of the uterus and ovaries transperitoneally. Results. All procedures were done successfully without major complications. The median operative time was 242.5 minutes, and estimated blood loss was 500 mL. The median time to oral intake was 2 postoperative days; the median hospital stay was 11 days. Ten patients remained cancer-free at a median follow-up of 46.5 months; six patients were confirmed as having preoperatively undetectable UC or renal cell carcinoma, even after reviewing preoperative computed tomography. Conclusions. This modified technique provides a time-saving complete urinary tract extirpation to eliminate preoperatively undetectable malignancy, reduce metachronous recurrences, and avert perioperative complications associated with pneumoperitoneum and repositioning. Good cancer control and early convalescence can mutually be achieved in experienced hands. PMID:25180189

  10. YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage.

    PubMed

    Ciamporcero, E; Shen, H; Ramakrishnan, S; Yu Ku, S; Chintala, S; Shen, L; Adelaiye, R; Miles, K M; Ullio, C; Pizzimenti, S; Daga, M; Azabdaftari, G; Attwood, K; Johnson, C; Zhang, J; Barrera, G; Pili, R

    2016-03-24

    Current standard of care for muscle-invasive urothelial cell carcinoma (UCC) is surgery along with perioperative platinum-based chemotherapy. UCC is sensitive to cisplatin-based regimens, but acquired resistance eventually occurs, and a subset of tumors is intrinsically resistant. Thus, there is an unmet need for new therapeutic approaches to target chemotherapy-resistant UCC. Yes-associated protein (YAP) is a transcriptional co-activator that has been associated with bladder cancer progression and cisplatin resistance in ovarian cancer. In contrast, YAP has been shown to induce DNA damage associated apoptosis in non-small cell lung carcinoma. However, no data have been reported on the YAP role in UCC chemo-resistance. Thus, we have investigated the potential dichotomous role of YAP in UCC response to chemotherapy utilizing two patient-derived xenograft models recently established. Constitutive expression and activation of YAP inversely correlated with in vitro and in vivo cisplatin sensitivity. YAP overexpression protected while YAP knockdown sensitized UCC cells to chemotherapy and radiation effects via increased accumulation of DNA damage and apoptosis. Furthermore, pharmacological YAP inhibition with verteporfin inhibited tumor cell proliferation and restored sensitivity to cisplatin. In addition, nuclear YAP expression was associated with poor outcome in UCC patients who received perioperative chemotherapy. In conclusion, these results suggest that YAP activation exerts a protective role and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of UCC. PMID:26119935

  11. YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage

    PubMed Central

    Ciamporcero, Eric; Shen, He; Ramakrishnan, Swathi; Ku, Sheng Yu; Chintala, Sreenivasulu; Shen, Li; Adelaiye, Remi; Miles, Kiersten Marie; Ullio, Chiara; Pizzimenti, Stefania; Daga, Martina; Azabdaftari, Gissou; Attwood, Kris; Johnson, Candace; Zhang, Jianmin; Barrera, Giuseppina; Pili, Roberto

    2015-01-01

    Current standard of care for muscle-invasive urothelial cell carcinoma (UCC) is surgery along with perioperative platinum-based chemotherapy. UCC is sensitive to cisplatin-based regimens, but acquired resistance eventually occurs, and a subset of tumors is intrinsically resistant. Thus, there is an unmet need for new therapeutic approaches to target chemotherapy-resistant UCC. Yes-associated protein (YAP) is a transcriptional co-activator that has been associated with bladder cancer progression and cisplatin resistance in ovarian cancer. In contrast, YAP has been shown to induce DNA damage associated apoptosis in non-small cell lung carcinoma. However, no data have been reported on the YAP role in UCC chemo-resistance. Thus, we have investigated the potential dichotomous role of YAP in UCC response to chemotherapy utilizing two patient-derived xenograft models recently established. Constitutive expression and activation of YAP inversely correlated with in vitro and in vivo cisplatin sensitivity. YAP overexpression protected while YAP knock-down sensitized UCC cells to chemotherapy and radiation effects via increased accumulation of DNA damage and apoptosis. Furthermore, pharmacological YAP inhibition with verteporfin inhibited tumor cell proliferation and restored sensitivity to cisplatin. In addition, nuclear YAP expression was associated with poor outcome in UCC patients who received perioperative chemotherapy. In conclusion, these results suggest that YAP activation exerts a protective role and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of UCC. PMID:26119935

  12. Characterization of HGF/Met Signaling in Cell Lines Derived From Urothelial Carcinoma of the Bladder

    PubMed Central

    Lee, Young H.; Apolo, Andrea B.; Agarwal, Piyush K.; Bottaro, Donald P.

    2014-01-01

    There is mounting evidence of oncogenic hepatocyte growth factor (HGF)/Met signaling in urothelial carcinoma (UC) of the bladder. The effects of three kinase inhibitors, cabozantinib, crizotinib and EMD1214063, on HGF-driven signaling and cell growth, invasion and tumorigenicity were analyzed in cultured UC cell lines. SW780 xenograft growth in SCID and human HGF knock-in SCID (hHGF/SCID) mice treated with cabozantinib or vehicle, as well as tumor levels of Met and pMet, were also determined. Met content was robust in most UC-derived cell lines. Basal pMet content and effector activation state in quiescent cells were low, but significantly enhanced by added HGF, as were cell invasion, proliferation and anchorage independent growth. These HGF-driven effects were reversed by Met inhibitor treatment. Tumor xenograft growth was significantly higher in hHGF/SCID mice vs. SCID mice and significantly inhibited by cabozantinib, as was tumor phospho-Met content. These studies indicate the prevalence and functionality of the HGF/Met signaling pathway in UC cells, suggest that paracrine HGF may contribute to UC tumor growth and progression, and that support further preclinical investigation of Met inhibitors for the treatment of UC is warranted. PMID:25534569

  13. Incidence and Predictors of Understaging in Patients with Clinical T1 Urothelial Carcinoma Undergoing Radical Cystectomy

    PubMed Central

    Ark, Jacob T.; Keegan, Kirk A.; Barocas, Daniel A.; Morgan, Todd M.; Resnick, Matthew J.; You, Chaochen; Cookson, Michael S.; Penson, David F.; Davis, Rodney; Clark, Peter E.; Smith, Joseph A.; Chang, Sam S.

    2013-01-01

    Summary Objective To evaluate predictors of understaging in patients with presumed non-muscle invasive bladder cancer (NMIBC) identified on transurethral resection of bladder tumor (TURBT) who underwent radical cystectomy (RC) with attention to the role of a restaging TURBT. Materials and Methods We retrospectively evaluated 279 consecutive patients with clinically staged T1 (cT1) disease following TURBT who underwent RC at our institution from April 2000 to July 2011. 60 of these cT1 patients had undergone a restaging TURBT prior to RC. The primary outcome measure was pathological staging of T2 or greater disease at the time of RC. Results 134 (48.0%) patients were understaged. Of the 60 patients who remained cT1 after a restaging TURBT, 28 (46.7%) were understaged. Solitary tumor (OR 0.43, 95% CI 0.25–0.76, p = 0.004) and fewer prior TURBTs (OR 0.84, 95% CI 0.71–1.00, p = 0.05) were independent risk factors for understaging. Conclusions Despite the overall improvement in staging accuracy linked to restaging TURBTs, the risk of clinical understaging remains high in restaged patients found to have persistent T1 urothelial carcinoma who undergo RC. Solitary tumor and fewer prior TURBTs are independent risk factors for being understaged. Incorporating these predictors into preoperative risk stratification may allow for augmented identification of those patients with clinical NMIBC who stand to benefit most from RC. PMID:24053444

  14. Urothelial carcinoma with oncocytic features: an extremely rare case presenting a diagnostic challenge in urine cytology.

    PubMed

    Tajima, Shogo

    2015-01-01

    Recognizing histological variants in urothelial carcinoma (UC) is important because some may be associated with different clinical outcomes and/or therapeutic approaches; being aware of unusual histological variants may also be crucial in preventing diagnostic misinterpretations. Histological variants based on cytoplasmic features, such as clear-cell, plasmacytoid, rhabdoid, and lipoid-rich variants, are described in invasive UC; however, these cytoplasmic features are not formally defined and not usually encountered in non-invasive UC. Oncocytic cytoplasm has not been well described in either invasive or non-invasive UC. Herein, we report an exceedingly rare case of UC with oncocytic features arising in the right renal pelvis, which presented a diagnostic challenge in urine cytology due to the relatively low nuclear-to-cytoplasmic ratio; however, it could definitively be diagnosed using histological specimens. UC diagnosis is based on the presence of papillary architecture and widespread p53 nuclear accumulation, suggesting malignancy. An oncocytic tumor is generally considered to be not actively dividing, as shown by the low Ki-67 labeling index in this case. In spite of the low proliferative activity, the possibility of intravesicle recurrence (IVR) should be considered since positive preoperative cytology of upper tract UC is a risk factor for IVR after nephroureterectomy. PMID:26339439

  15. Endemic nephropathy and upper urothelial carcinoma--new insights in molecular biology.

    PubMed

    Jankovic Velickovic, Ljubinka; Dolicanin, Zana; Stefanovic, Vladisav

    2014-01-01

    Upper Tract Urothelial Carcinoma (UTUC) is an uncommon disease which occurs more frequently in some regions of Balkan countries than in other areas in the world. Investigation of UTUC in the South Morava River basin and its tributaries where BEN is endemic revealed increased frequency not only of tumour of the renal pelvis and ureter but also of urinary bladder tumours. A comparative morphological and immunohistochemical study of UTUC in the BEN region and control rural and city populations free of BEN, identify growth pattern as the best morphological characteristic which differentiated BEN and control tumours, i.e. solid growth for BEN tumours and papillary for control tumours. Overexpression of tumour suppressor p53 as well as decreased expression of E-CD was detected in BEN tumours. Other cells cycle related molecular markers--Cyclin D1, p16, and HER-2 showed no difference in expression between groups, as well as the proliferative marker Ki-67. Investigation of apoptosis-related markers identifies Bax as a specific marker of BEN-associated UTUC. Decrease of the pro-apoptotic protein Bax together with alteration of Survivin may be indicative of specific disturbances of an intrinsic apoptotic pathway in UTUC arising in endemic areas. PMID:24802310

  16. Homozygous losses detected by array comparative genomic hybridization in multiplex urothelial carcinomas of the bladder.

    PubMed

    Beothe, Tamas; Zubakov, Dmitry; Kovacs, Gyula

    2015-09-01

    Urothelial carcinomas (UCs) may present at first as a solitary or multifocal neoplasm. We applied high resolution array comparative genomic hybridization to 24 solitary and 32 multiplex UCs and used the hidden Markov model algorithm to identify the copy number changes at the probe level. Copy number losses and homozygous deletions at the chromosome 9p region affecting the CDKN2A and MTAP genes were the most frequent alterations in both groups of tumors. We have delineated two new tumor suppressor gene regions at chromosome 9p that harbor the PTPRD and BNC2 genes. Copy number losses at chromosomal regions 2q, 8p, and 18p occurred preferentially in solitary UCs, whereas multiplex UCs displayed loss of large chromosomal regions at 9q, 10q, 11q, 18q, and 21q. Homozygous deletions harboring loci of cell adhesion genes such as claudins, desmocollins, and desmogleins were seen exclusively in multiplex UCs. Amplifications occurred only in invasive G3 UCs irrespective of staging. Our study suggests that solitary and multiplex UCs may have divergent genetic pathways. The biallelic inactivation of cellular adhesion genes by homozygous deletions in multiplex UCs may explain the frequent intravesical spreading of tumor cells. . PMID:26235493

  17. Chemotherapy for urothelial carcinoma in renal transplantation patients: Initial results from a single center

    PubMed Central

    ZHU, YICHEN; XIAO, JING; GUO, YUWEN; LIN, JUN; ZHANG, LEI; TIAN, YE

    2015-01-01

    The aim of this study was to assess the safety and efficacy of gemcitabine plus cisplatin/carboplatin (GC/GCa) chemotherapy in renal transplantation (RT) patients with urothelial carcinoma (UC). We reviewed the records of 12 RT patients with metastatic or locally advanced UC who received chemotherapy at our institution since January, 2013. All the patients received intravenous gemcitabine (800 mg/m2) on days 1, 8 and 15, plus cisplatin (70 mg/m2) or carboplatin (area under the curve = 5) on day 2, every 28 days. A total of 10 patients completed all the cycles, while 1 patient discontinued treatment due to disease progression and 1 patient discontinued due to non-medical reasons. In total, 12 patients received a median of four cycles of chemotherapy. The overall response rate was 50% (4/8 cases) in patients with measurable lesions. At the time of the study, 5 patients had succumbed to the disease (overall survival, 9.2 months), while 7 patients remained alive (follow-up time, 13.3 months). The most common toxicities were myelosuppression and gastrointestinal effects. Therefore, the GC/GCa regimen was found to be effective and tolerable in RT patients with UC. However, further studies involving more patients and control groups are required to confirm our results. PMID:26807252

  18. Angiogenesis in upper tract urothelial carcinoma associated with Balkan endemic nephropathy

    PubMed Central

    Velickovic, Ljubinka Jankovic; Petrovic, Ana Ristic; Stojnev, Slavica; Dolicanin, Zana; Hattori, Takanori; Sugihara, Hiroyuki; Mukaisho, Ken-ichi; Stojanovic, Mariola; Stefanovic, Vladisav

    2012-01-01

    Upper tract urothelial carcinoma (UTUC) associated with Balkan endemic nephropathy (BEN) is characterized by a number of aberrations in cell-cycle regulation and apoptosis. The aim of this study was to detect angiogenesis-related marker(s) specific for BEN UTUC, and to examine the influence of HIF 1α upon angiogenesis and apoptosis in UTUC. Present investigation included 110 patients with UTUC, 50 from BEN region and 60 control tumors. Altered expression of VEGFR1 was more often present in control UTUC than in BEN tumors (p<0.005). It was associated with high grade, low and high stage, solid growth, and metaplastic change of control UTUC. Microvessel density assessed by CD31 (MVD CD31) was significantly higher in UTUC with lymphovascular invasion (p<0.05), and in BEN tumors with papillary growth (p<0.05). Discriminant analysis indicated that BEN and control tumors do not differ significantly in expression of angiogenesis related markers. The most important discriminant variable that determined control UTUC was expression of VEGFR1 (p=0.002). HIF 1α in UTUC significantly correlated with the low stage, papillary growth and expression of Bcl-2, Caspase-3 index, and MVD CD34 (p<0.001; 0.0005; 0.01; 0.005; 0.01, respectively). HIF-1α may be helpful marker in evaluation of UTUC, especially when combined with angiogenesis and apoptosis. PMID:22977664

  19. Therapeutic role of template-based lymphadenectomy in urothelial carcinoma of the upper urinary tract

    PubMed Central

    Kondo, Tsunenori; Takagi, Toshio; Tanabe, Kazunari

    2015-01-01

    Lymphadenectomy for urothelial carcinoma of the upper urinary tract has attracted the attention of physicians. The mapping study of lymphatic spread has shown that a relatively wide area should comprise the regional nodes for tumors of the right renal pelvis or the right upper two-thirds of the ureter. A prospective study showed that an anatomical template-based lymphadenectomy significantly improved patient survival in tumors of the renal pelvis. This benefit was more evident for patients with pT2 stage tumors or higher. The risk of regional node recurrence is significant reduced by template-based lymphadenectomy, which is likely to be associated with improved patient survival. The removal of lymph node micrometastases is assumed to be the reason for therapeutic benefit following lymphadenectomy. The number of resected lymph nodes can be used to assess the quality of lymphadenectomy, but not to determine the extent of lymphadenectomy. The guidelines currently recommend lymphadenectomy for patients with muscle-invasive disease, even though the current recommendation grades are still low. The present limitation of lymphadenectomy is the lack of standardization of the extent of lymphadenectomy and the randomized trials. Further studies are warranted to collect the evidence to support lymphadenectomy. PMID:26677437

  20. Human bladder carcinoma cell lines as indicators of oncogenic change relevant to urothelial neoplastic progression.

    PubMed Central

    Rieger, K. M.; Little, A. F.; Swart, J. M.; Kastrinakis, W. V.; Fitzgerald, J. M.; Hess, D. T.; Libertino, J. A.; Summerhayes, I. C.

    1995-01-01

    Analysis of human tumour-derived cell lines has previously resulted in the identification of novel transformation-related elements and provided a useful tool for functional studies of different genes. To establish the utility of such cell lines as indicators of change relevant to urothelial cancer, we have characterised the expression of five genes (p53, MDM2, Rb, E-cadherin, APC) within a panel of human bladder carcinoma cell lines. Using single-strand conformation polymorphism (SSCP) and direct sequencing, p53 mutations were identified in 7/15 (47%) cell lines reflecting events reported in bladder tumours. Immunohistochemical analysis of p53 in cultured cells and in paraffin-embedded sections of xenografts from the cell line panel revealed discordant results. An absence of p53 nuclear staining was associated with an exon 5 mutation in EJ and with multiple p53 mutations found in J82. Two cell lines positive for p53 staining in the absence of detectable mutation displayed overexpression of MDM2 (PSI, HT1197) in Western blot analysis. Loss or aberrant Rb expression was recorded in 5/15 (TCCSUP, SCaBER, 5637, HT1376, J82) cell lines. Absence of E-cadherin was recorded in 5/15 cell lines (TCCSUP, EJ, KK47, UM-UC-3, J82) with loss of alpha-catenin in immunoprecipitated E-cadherin complexes of CUBIII. Western blot analysis of APC revealed a truncated protein in 1/15 (CUBIII) cell lines. The characterisation of oncogenic events within this panel of human bladder carcinoma cell lines establishes a representation of change observed in bladder tumours and better defines the genotypic background in these experimental human cell models of neoplastic progression. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:7669581

  1. Clinical, demographic and histopathological prognostic factors for urothelial carcinoma of the bladder

    PubMed Central

    Pala, Emel Ebru; Cakır, Ebru; Sezer, Ozlem; Bayol, Umit; Divrik, Rauf Taner; Cakmak, Ozgur

    2015-01-01

    Introduction Our aim is to evaluate the influence of clinical and histopathological parameters, including age, gender, tumor stage, grade, tumor differentiation, necrosis, lymphovascular/perineural invasion (LVI/PNI) and concomitant carcinoma in situ (CIS), on outcomes of patients with urothelial carcinoma of the bladder (UCB). Material and methods A total of 84 patients who underwent radical cystectomy (RC) (n = 11) and radical cystoprostatectomy (n = 73) for muscle-invasive bladder cancer at our hospital between 2007-2013, were included in the study. Results The mean age of patients at diagnosis was 66.1, of whom 75 were males and 9 were females. Of the 84 patients, 38 were ≤65 years and 46 were >65 years. Mean tumor diameter was 3.66 cm. There were 38 cases which showed divergent differentiations. Concomitant CIS was observed in 30 tumors, 41 cases showed tumor necrosis, 44 PNI and 61 LVI. The rate of overall survival (OS) in patients aged ≤65 years was statistically significantly higher than in those aged >65 years. A negative statistical relationship was found between OS with lymph node metastasis (LNM) and tumor differentiation. On the other hand, necrosis did not remain significant on multivariate analysis. No statistically significant relationship was found between smoking, tumor stage, PNI, LVI and concomitant CIS and OS. Conclusions In this study, advanced age, LNM, tumor differentiation were found to be independent prognostic risk factors associated with OS after RC. These additional factors, which may explain the different clinical course in patients with similar tumor stage and lymph node status, should be taken into consideration in treatment planning. PMID:25914835

  2. Impact of lymphovascular invasion on recurrence and progression rates in patients with pT1 urothelial carcinoma of bladder after transurethral resection

    PubMed Central

    Sha, Nan; Xie, Linguo; Chen, Tao; Xing, Chen; Liu, Xiaoteng; Zhang, Yu; Shen, Zhonghua; Xu, Hao; Wu, Zhouliang; Hu, Hailong; Wu, Changli

    2015-01-01

    Objective To evaluate the clinical significance of lymphovascular invasion (LVI) on recurrence and progression rates in patients with pT1 urothelial carcinoma of bladder after transurethral resection. Methods This retrospective study was performed with 155 patients with newly diagnosed pT1 urothelial carcinoma of bladder who were treated with transurethral resection of bladder tumor at our institution from January 2006 to January 2010. The presence or absence of LVI was examined by pathologists. Chi-square test was performed to identify the correlations between LVI and other clinical and pathological features. Kaplan–Meier method was used to estimate the recurrence-free survival (RFS) and progression-free survival curves and difference was determined by the log-rank test. Univariate and multivariate analyses were performed to determine the predictive factors through a Cox proportional hazards analysis model. Results LVI was detected in a total of 34 patients (21.9%). While LVI was associated with high-grade tumors (P<0.001) and intravesical therapy (P=0.009). Correlations with age (P=0.227), sex (P=0.376), tumor size (P=0.969), tumor multiplicity (P=0.196), carcinoma in situ (P=0.321), and smoking (P=0.438) were not statistically significant. There was a statistically significant tendency toward higher recurrence rate and shorter RFS time in LVI-positive patients. However, no statistically significant differences were observed in progression rate between the two groups. Moreover, multivariate Cox proportional hazards analysis revealed that LVI, tumor size, and smoking were independent prognostic predictors of recurrence. The hazard ratios (95% confidence interval) were 2.042 (1.113–3.746, P=0.021), 1.817 (1.014–3.256, P=0.045), and 2.079 (1.172–3.687, P=0.012), respectively. Conclusion The presence of LVI in transurethral resection of bladder tumor specimens is significantly associated with higher recurrence rate and shorter RFS time in patients with newly

  3. Collecting and Studying Blood and Tissue Samples From Patients With Locally Recurrent or Metastatic Prostate or Bladder/Urothelial Cancer

    ClinicalTrials.gov

    2016-06-06

    Healthy Control; Localized Urothelial Carcinoma of the Renal Pelvis and Ureter; Metastatic Malignant Neoplasm in the Bone; Metastatic Malignant Neoplasm in the Soft Tissues; Metastatic Urothelial Carcinoma of the Renal Pelvis and Ureter; Recurrent Bladder Carcinoma; Recurrent Prostate Carcinoma; Recurrent Urothelial Carcinoma of the Renal Pelvis and Ureter; Stage IV Bladder Cancer; Stage IV Bladder Urothelial Carcinoma; Stage IV Prostate Cancer

  4. Preoperative Plasma Fibrinogen Level Represents an Independent Prognostic Factor in a Chinese Cohort of Patients with Upper Tract Urothelial Carcinoma

    PubMed Central

    Jin, Jie; Zhou, Li-Qun; He, Zhi-Song; Shen, Cheng; He, Qun; Li, Jun; Liu, Li-Bo; Wang, Cong; Chen, Xiao-Yu; Fan, Yu; Hu, Shuai; Zhang, Lei; Yu, Wei; Han, Wen-Ke

    2016-01-01

    Background Increased plasma fibrinogen is thought to contribute to tumor progression and metastasis. The association of plasma fibrinogen with clinicopathological characteristics, and the optimal cutoff with an ideal predictive value has not been fully determined in patients with upper tract urothelial carcinoma (UTUC). We aimed to investigate the clinical significance of this parameter in a Chinese cohort of patients with UTUC. Methods A retrospective study was conducted to analyze the clinical data of 184 operable UTUC patients in a Chinese cohort with a high incidence of chronic kidney disease (CKD). An optimal cutoff was set for further analysis according to validated web-based software. The associations of plasma fibrinogen with clinicopathological characteristics and survival were assessed. Multivariate analyses were performed to determine the independent prognostic factors. Results Elevated plasma fibrinogen was significantly associated with tumor necrosis, lymph node involvement, and a higher preoperative CKD stage, pathological tumor stage and grade (all P < 0.05). Kaplan-Meier analysis showed that plasma fibrinogen ≥ 3.54 g/L predicted a poorer overall and cancer-specific survival than < 3.54 g/L (P < 0.001 for both). Multivariate analyses revealed that elevated preoperative plasma fibrinogen was an independent negative prognostic factor for overall survival (HR = 2.026; 95% CI: 1.226–3.349; P = 0.006) and cancer-specific survival (HR = 1.886; 95% CI: 1.019–3.490; P = 0.043). Conclusions Increased plasma fibrinogen was an independent prognostic risk factor for poor outcomes in UTUC. This parameter may serve as an effective biomarker with easy accessibility for evaluating prognosis for patients with UTUC. PMID:26930207

  5. AB051. Comparison of urine cytology and UroVysion FISH for upper tract urothelial carcinoma detection in Chinese patients

    PubMed Central

    Peng, Weibin; Jun, Lin; Zhao, Jimao; Xu, Xiuhong; Chi, Qiang; Wang, Zhiyong

    2016-01-01

    Objective UroVysion FISH has been used for screening bladder cancer in western countries, but still limited in China. This non-invasive assay is also practical for detecting upper tract urothelial carcinoma. The present study evaluates the effectiveness of UroVysion and urine cytology in detecting upper tract urothelial carcinoma (UTUC) in 216 urine samples from 75 Chinese patients. Methods A total of 75 cases from two centers (Chengde medical college affiliated hospital and Beijing Friendship hospital) were selected with the following criteria: valid results of both UroVysion and cytology from same urine sample; histological and/or cystoscopic follow up within at least one year. The results of the UroVysion and cytology were correlated with clinical outcome that was derived from combination of histological, cystoscopic and clinical follow up information. Results Overall sensitivity, specificity, PPV and NPV in detecting UTUC were 69.3%, 83.3%, 91.2% and 52.1%, respectively for UroVysion, and 50.7%, 86.7%, 86.4% and 41.3%, respectively for cytology. The performance of both UroVysion and cytology was generally better in the surveillance population and in samples with high grade UTUC, but UroVysion manifests more efficiently than cytology in samples with low grade UTUC. In 57 of 216 samples from patients treated by endoscope or partial resection of ureter, the sensitivity of UroVysion and cytology are 70.1% and 61.3%. Conclusions Comparing with urine cytology, UroVysion is an efficient assay for upper tract urothelial carcinoma (UTUC) diagnosis and monitoring, with excellent clinical performance and utility in Chinese patients.

  6. Multiple cytokeratin-negative malignant tumors composed only of rhabdoid cells in the renal pelvis: a sarcomatoid urothelial carcinoma?

    PubMed Central

    Terada, Tadashi

    2013-01-01

    The author presents a unique case of multiple cytokeratin-negative malignant tumors consisting only of rhabdoid cells in the renal pelvis. A 54-year-old man complained of hematuria. A transurethral endoscopic examination revealed multiple papillary tumors, and transurethral resection of the bladder tumors was performed. Pathologically, they were ordinary papillary urothelial transitional cell carcinomas. Imaging modalities revealed multiple tumors of the right renal pelvis, and nephrectomy was performed. Grossly, three polypoid tumors measuring 2-4 cm were present in the pelvis. Histologically, they were composed only of malignant cells with rhabdoid features. There were no elements of transitional cell carcinoma. Immunohistochemically, the pelvic tumors were positive for vimentin and Ki-67 antigen (labeling=40%). They were negative for pancytokeratins (AE1/3, CAM5.2, KL-1 and polyclonal wide), 34βE12, cytokeratin (CK) 5/6, CK7, CK8, CK14, CK18, CK19, CK20, melanosome, EMA, CEA, desmin, S100 protein, α-smooth muscle actin, myoglobin, myogenin, CD34, p53 protein, p63, CD3, CD20, CD30, CD45, CD45RO, chromograin, synaptophysin, CD56, CD68, and KIT. NSE and PDGFRA were focally present, but this appeared nonspecific. Namely, the pelvic tumors expressed only vimentin. The author speculates that the pelvic multiple malignant “rhabdoid” tumors are not sarcomas but urothelial “rhabdoid” carcinoma with complete loss of CKs. PMID:23573320

  7. Value of Preoperative Superselective Embolization of the Isthmus in a Patient with Upper Urinary Tract Urothelial Carcinoma and Horseshoe Kidney

    SciTech Connect

    Wilhelmsen, Skadi; Janitzky, Andreas; Porsch, Markus; Liehr, Uwe-Bernd; Dudeck, Oliver

    2011-02-15

    Standard treatment for upper urinary tract urothelial carcinoma (UUTUC) implies the radical removal of all urothelium-lined tissue, which requires nephroureterectomy with bladder cuff removal. We report on a patient with a rare coincidence of UUTUC and horseshoe kidney in whom a preoperative angiography helped to identify and subsequently embolize an abberant isthmic feeding artery, which was located in between both collecting systems. Ischemic discoloration of the isthmus area facilitated resection and no major blood loss occurred. Preoperative superselective embolization of the isthmus as the renal split area can be an effective tool to facilitate nephroureterectomy in the case of a horseshoe kidney.

  8. Phenotypic impact of deregulated expression of class I histone deacetylases in urothelial cell carcinoma of the bladder.

    PubMed

    Junqueira-Neto, Susana; Vieira, Filipa Q; Montezuma, Diana; Costa, Natália R; Antunes, Luís; Baptista, Tiago; Oliveira, Ana Isabel; Graça, Inês; Rodrigues, Ângelo; Magalhães, José S; Oliveira, Jorge; Henrique, Rui; Jerónimo, Carmen

    2015-07-01

    Deregulated expression of histone deacetylases (HDACs) has been implicated in tumorigenesis. Herein, we investigated class I HDACs expression in bladder urothelial cell carcinoma (BUCC), its prognostic value and biological significance. Significantly increased transcript levels of all HDACs were found in BUCC compared to 20 normal mucosas, and these were higher in lower grade and stage tumors. Increased HDAC3 levels were associated with improved patient survival. SiRNA experiments showed decrease cell viability and motility, and increased apoptosis. We concluded that class I HDACs play an important role in bladder carcinogenesis through deregulation of proliferation, migration and apoptosis, constituting putative therapeutic targets. PMID:24293253

  9. FGFR3b Extracellular Loop Mutation Lacks Tumorigenicity In Vivo but Collaborates with p53/pRB Deficiency to Induce High-grade Papillary Urothelial Carcinoma

    PubMed Central

    Zhou, Haiping; He, Feng; Mendelsohn, Cathy L.; Tang, Moon-shong; Huang, Chuanshu; Wu, Xue-Ru

    2016-01-01

    Missense mutations of fibroblast growth factor receptor 3 (FGFR3) occur in up to 80% of low-grade papillary urothelial carcinoma of the bladder (LGP-UCB) suggesting that these mutations are tumor drivers, although direct experimental evidence is lacking. Here we show that forced expression of FGFR3b-S249C, the most prevalent FGFR3 mutation in human LGP-UCB, in cultured urothelial cells resulted in slightly reduced surface translocation than wild-type FGFR3b, but nearly twice as much proliferation. When we expressed a mouse equivalent of this mutant (FGFR3b-S243C) in urothelia of adult transgenic mice in a tissue-specific and inducible manner, we observed significant activation of AKT and MAPK pathways. This was, however, not accompanied by urothelial proliferation or tumorigenesis over 12 months, due to compensatory tumor barriers in p16-pRB and p19-p53-p21 axes. Indeed, expressing FGFR3b-S249C in cultured human urothelial cells expressing SV40T, which functionally inactivates pRB/p53, markedly accelerated proliferation and cell-cycle progression. Furthermore, expressing FGFR3b-S243C in transgenic mouse urothelium expressing SV40T converted carcinoma-in-situ to high-grade papillary urothelial carcinoma. Together, our study provides new experimental evidence indicating that the FGFR3 mutations have very limited urothelial tumorigenicity and that these mutations must collaborate with other genetic events to drive urothelial tumorigenesis. PMID:27157475

  10. FGFR3b Extracellular Loop Mutation Lacks Tumorigenicity In Vivo but Collaborates with p53/pRB Deficiency to Induce High-grade Papillary Urothelial Carcinoma.

    PubMed

    Zhou, Haiping; He, Feng; Mendelsohn, Cathy L; Tang, Moon-Shong; Huang, Chuanshu; Wu, Xue-Ru

    2016-01-01

    Missense mutations of fibroblast growth factor receptor 3 (FGFR3) occur in up to 80% of low-grade papillary urothelial carcinoma of the bladder (LGP-UCB) suggesting that these mutations are tumor drivers, although direct experimental evidence is lacking. Here we show that forced expression of FGFR3b-S249C, the most prevalent FGFR3 mutation in human LGP-UCB, in cultured urothelial cells resulted in slightly reduced surface translocation than wild-type FGFR3b, but nearly twice as much proliferation. When we expressed a mouse equivalent of this mutant (FGFR3b-S243C) in urothelia of adult transgenic mice in a tissue-specific and inducible manner, we observed significant activation of AKT and MAPK pathways. This was, however, not accompanied by urothelial proliferation or tumorigenesis over 12 months, due to compensatory tumor barriers in p16-pRB and p19-p53-p21 axes. Indeed, expressing FGFR3b-S249C in cultured human urothelial cells expressing SV40T, which functionally inactivates pRB/p53, markedly accelerated proliferation and cell-cycle progression. Furthermore, expressing FGFR3b-S243C in transgenic mouse urothelium expressing SV40T converted carcinoma-in-situ to high-grade papillary urothelial carcinoma. Together, our study provides new experimental evidence indicating that the FGFR3 mutations have very limited urothelial tumorigenicity and that these mutations must collaborate with other genetic events to drive urothelial tumorigenesis. PMID:27157475

  11. Association between selected dietary scores and the risk of urothelial cell carcinoma: A prospective cohort study.

    PubMed

    Dugué, Pierre-Antoine; Hodge, Allison M; Brinkman, Maree T; Bassett, Julie K; Shivappa, Nitin; Hebert, James R; Hopper, John L; English, Dallas R; Milne, Roger L; Giles, Graham G

    2016-09-15

    Studies investigating the association of food and nutrient consumption with the risk of urothelial cell carcinoma (UCC) have produced mixed results. We used three common dietary scores, the Mediterranean Diet Score (MDS), the Alternate Healthy Eating Index 2010 (AHEI-2010) and the Dietary Inflammatory Index (DII) to assess the evidence of an association between diet and the risk of UCC. Over a median follow-up time of 21.3 years, 379 incident UCC cases were diagnosed. Dietary scores were calculated using data from a 121-item food frequency questionnaire administered at baseline. We used Cox models to compute hazard ratios (HR) for the association between dietary scores (per one standard deviation) and UCC risk. In order to reflect overall adherence to a healthy diet, a metascore was constructed by summing the quintiles of each of the three scores. None of the dietary scores was associated with the risk of UCC overall. A healthier diet was found to be inversely associated with the risk of invasive (MDS: HR = 0.86, 95% CI: 0.74-1.00, metascore: HR = 0.84, 95% CI: 0.71-0.98), but not superficial disease (heterogeneity between subtypes p = 0.04 and p = 0.03, respectively). Results were consistent but weaker for the DII and the AHEI-2010. We found some evidence of effect modification by smoking, in particular for the metascore (Current: HR = 0.77, 95% CI: 0.58-1.01, Former: HR = 0.77, 95% CI: 0.64-0.92, Never: HR = 1.01, 95% CI: 0.81-1.26, p for heterogeneity = 0.05). A healthy diet may be protective against the risk of invasive, but not superficial, UCC. Promoting healthy dietary habits may help lower the risk of invasive UCC, especially for current and former smokers. PMID:27149545

  12. Neoadjuvant chemotherapy improves survival of patients with upper tract urothelial carcinoma

    PubMed Central

    Porten, Sima; Siefker-Radtke, Arlene O.; Xiao, Lianchun; Margulis, Vitaly; Kamat, Ashish M.; Wood, Christopher G.; Jonasch, Eric; Dinney, Colin P. N.; Matin, Surena F.

    2015-01-01

    Background High-grade upper tract urothelial carcinoma (UTUC) is frequently upstaged after surgery and is associated with uniformly poor survival. Neoadjuvant chemotherapy may offer a way to improve clinical outcomes. We compare the survival rates of UTUC patients who received neoadjuvant chemotherapy prior to surgery with patients who did not. Methods Retrospective review of patients with high-risk UTUC who received neoadjuvant chemotherapy followed by surgery in 2004–2008 (study group), compared to a matched cohort who underwent initial surgery in 1993–2003 (control group). The Fisher exact, Wilcoxon rank-sum, and Kaplan-Meier methods were used. The log-rank test and Cox proportional hazards model were used to evaluate association of these two outcomes with patient, treatment, and tumor characteristics in univariate and multivariate models. Results Of 112 patients, 31 were in the study group and 81 in the control group. Patients who received neoadjuvant chemotherapy had improved OS and DSS with a 5-year DSS of 90.1% and 5-year OS rate 80.2%, versus a 5-year DSS and OS of 57.6% for those treated with initial surgery (p = 0.0204 and p = 0.0015, respectively). In multivariate analyses the neoadjuvant group had a lower risk of mortality (OS hazard ratio 0.42 [p = 0.035]; DSS hazard ratio 0.19 [p = 0.006]). Conclusions Neoadjuvant chemotherapy improves survival in patients with UTUC compared with a matched historical cohort of patients treated with initial surgery. Patients with high-risk UTUC should be considered for neoadjuvant chemotherapy, in view of the limited opportunity to administer effective cisplatin-based chemotherapy after nephroureterectomy. PMID:24633966

  13. Detection of Copy Number Imbalance in Canine Urothelial Carcinoma With Droplet Digital Polymerase Chain Reaction.

    PubMed

    Mochizuki, H; Shapiro, S G; Breen, M

    2016-07-01

    Urothelial carcinoma (UC) is the most common neoplasm of the canine urinary tract. Clinical presentation of UC is shared with several other, more common urinary tract disorders, and this often delays diagnosis of the UC. Definitive diagnosis of UC requires histopathologic examination of a biopsy specimen, but the cost and invasiveness for these diagnostic tests often result in most diagnoses being made on the basis of clinical findings, diagnostic imaging, and cytologic examination of urine sediment. Regardless of the diagnostic process used, most UCs currently are not diagnosed until they are at an advanced clinical stage and so are associated with poor prognosis. Improved methods for earlier and less invasive detection are needed. In a previous study, the authors demonstrated the presence of highly recurrent DNA copy number aberrations (CNAs) in canine UC and hypothesized that detection of these CNAs in tumor cells can be used as a molecular diagnostic for UC. In this study, a multiplexed droplet digital polymerase chain reaction (ddPCR) assay was detected to detect and quantify CNAs of specific regions of canine chromosomes 8, 13, 19, and 36. The assay was effective at differentiating 31 neoplastic and 25 nonneoplastic bladder tissues based on copy number, with 100% sensitivity and specificity in tissue samples. CNAs were also detected by ddPCR in 67% (12 of 18) of urine DNA specimens derived from UC patients. The findings show that ddPCR is a useful molecular technique to detect CNAs and may be used as a noninvasive molecular diagnostic test for canine UC. PMID:26574558

  14. Urinary arsenic profile affects the risk of urothelial carcinoma even at low arsenic exposure

    SciTech Connect

    Pu, Y.-S.; Yang, S.-M.; Huang, Y.-K.; Chung, C.-J.; Huang, Steven K.; Chiu, Allen Wen-Hsiang; Yang, M.-H.; Chen, C.-J.; Hsueh, Y.-M. . E-mail: ymhsueh@tmu.edu.tw

    2007-01-15

    Arsenic exposure is associated with an increased risk of urothelial carcinoma (UC). To explore the association between individual risk and urinary arsenic profile in subjects without evident exposure, 177 UC cases and 313 age-matched controls were recruited between September 2002 and May 2004 for a case-control study. Urinary arsenic species including the following three categories, inorganic arsenic (As{sup III} + As{sup V}), monomethylarsonic acid (MMA{sup V}) and dimethylarsinic acid (DMA{sup V}), were determined with high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Arsenic methylation profile was assessed by percentages of various arsenic species in the sum of the three categories measured. The primary methylation index (PMI) was defined as the ratio between MMA{sup V} and inorganic arsenic. Secondary methylation index (SMI) was determined as the ratio between DMA{sup V} and MMA{sup V}. Smoking is associated with a significant risk of UC in a dose-dependent manner. After multivariate adjustment, UC cases had a significantly higher sum of all the urinary species measured, higher percent MMA{sup V}, lower percent DMA{sup V}, higher PMI and lower SMI values compared with controls. Smoking interacts with the urinary arsenic profile in modifying the UC risk. Differential carcinogenic effects of the urinary arsenic profile, however, were seen more prominently in non-smokers than in smokers, suggesting that smoking is not the only major environmental source of arsenic contamination since the UC risk differs in non-smokers. Subjects who have an unfavorable urinary arsenic profile have an increased UC risk even at low exposure levels.

  15. Expression and significance of androgen receptor coactivators in urothelial carcinoma of the bladder.

    PubMed

    Boorjian, Stephen A; Heemers, Hannelore V; Frank, Igor; Farmer, Sara A; Schmidt, Lucy J; Sebo, Thomas J; Tindall, Donald J

    2009-03-01

    Urothelial carcinoma (UC) of the bladder is approximately three times more common in men than women. While the etiology for this gender difference in incidence remains unknown, a role for androgen receptor (AR) signaling has been suggested. The mechanisms by which AR activity is regulated in UC cells, however, are largely elusive. Here, we explore the significance of coregulators that are critical for the formation of a functional AR transcriptional complex, in UC cells. Using two AR-positive UC cell lines, TCC-SUP and UMUC3, we demonstrate the expression of the coactivators NCOA1, NCOA2, NCOA3, CREBBP, and EP300 in UC cells. small interfering RNA-mediated knockdown of the AR or any of these coactivators markedly impacted cell viability and abrogated androgen-dependent cell proliferation. Noteworthy, contrary to AR-positive prostate cancer cells, expression of these AR-associated coactivators was not androgen regulated in UC cells. To assess the clinical relevance of coactivator expression, we performed immunohistochemistry on paraffin-embedded sections from 55 patients with UC of the bladder. We found that while 24 out of 55 (44%) of tumors expressed the AR, each of the coactivators was expressed by 85-100% of the bladder cancers. Moreover, we noted a significant downregulation of NCOA1 expression in tumors versus adjacent, non-tumor bladder urothelium, with a mean of 68% (range 0-100) of tumor cells demonstrating NCOA1 staining versus a mean of 81% (range 0-90) of non-tumor cells (P=0.03). Taken together, our data suggest an important role for AR-associated coactivators in UC and point toward differences in the regulation of AR activity between bladder and prostate cancer cells. PMID:18845648

  16. XRCC1 Polymorphisms and Urinary 8-Hydroxydeoxyguanine Levels Are Associated with Urothelial Carcinoma

    PubMed Central

    Chiang, Chien-I; Huang, Ya-Li; Huang, Chao-Yuan; Shiue, Horng-Sheng; Chen, Wei-Jen; Pu, Yeong-Shiau; Lin, Ying-Chin; Hsueh, Yu-Mei

    2015-01-01

    The aim of this study was to examine the associations between the combined effects of urinary 8-Hydroxydeoxyguanine (8-OHdG) level and polymorphisms of XRCC1 Arg194Trp and XRCC1 Arg399Gln on the risk of urothelial carcinoma (UC). We conducted a hospital-based case-control study that included 168 cases of UC and 336 age- and gender-matched healthy controls. We used polymerase chain reaction and restriction fragment length polymorphism analyses to examine the genotypes of XRCC1 Arg194Trp and XRCC1 Arg399Gln. We used a competitive in vitro enzyme-linked immunosorbent assay to determine urinary 8-OHdG levels. The XRCC1 399 Gln/Gln genotype and the XRCC1 194 Arg/Arg genotype were positively correlated to UC (OR [95%CI] = 2.27 [1.20–4.27] and 1.59 [1.06–2.36], respectively). Urinary 8-OHdG levels were associated with UC in a dose-dependent manner. Participants with the XRCC1 (Arg399Gln) Gln/Gln genotype or the G-C/A-C haplotype of XRCC1 and a high urinary 8-OHdG level had a significantly higher risk of UC than those with the Arg/Arg + Arg/Gln genotype or the G-T haplotype and a low urinary 8-OHdG level. This is the first study to investigate the combined effect of urinary 8-OHdG level and XRCC1 polymorphisms on UC risk. The findings are especially meaningful for participants with XRCC1 399Gln or XRCC1 Arg194 genotypes and a high urinary 8-OHdG level, since these variables are associated with an increased risk of UC. PMID:25938407

  17. Therapeutic potential of sepantronium bromide YM155 in gemcitabine-resistant human urothelial carcinoma cells.

    PubMed

    Huang, Yen Ta; Cheng, Chuan Chu; Lin, Tzu Chun; Chiu, Ted H; Lai, Pei Chun

    2014-02-01

    Survivin is overexpressed in transitional cell carcinoma (TCC), the most common type of bladder cancer. Previous reports demonstrated that knockdown of survivin by siRNA induced apoptosis of TCC cells. The present study evaluated the therapeutic effects of sepantronium bromide (YM155), a novel small molecule survivin inhibitor under clinical trials, on TCC cells in vitro. BFTC905, a grade III TCC cell line derived from a patient of blackfoot disease in Taiwan, was the most gemcitabine-resistant cell line when compared to BFTC909, TSGH8301 and T24 in cytotoxicity assay, resulting from upregulation of securin and bcl-2 after gemcitabine treatment. YM155 caused potent concentration‑dependent cytotoxicity in 4 TCC cell lines (IC50s ≤20 nM), but exhibited no cytotoxicity in survivin-null primary human urothelial cells. For BFTC905 cells, addition of gemcitabine and/or cisplatin, the standard TCC chemotherapy regimen, to YM155 did not exert additive cytotoxic effects. Molecular analyses indicated that YM155 inhibited the proliferation of BFTC905 cells by increasing p27kip1, suppressing Ki-67, and inducing quiescence. In addition, YM155 elicited apoptosis manifested with DNA fragmentation through suppressing the expression of survivin, securin and bcl-2. Furthermore, YM155 induced autophagy in BFTC905 cells as autophagic inhibitor, 3-methyladenine, attenuated YM155-induced LC3B-II levels and reversed the cytotoxicity of YM155. mTOR inhibitors sirolimus and everolimus did not increase YM155-induced expression of LC3B-II nor augment YM155-induced cytotoxicity. These results indicate that YM155 exerts its lethal effect on BFTC905 cells via apoptotic and autophagic death pathways and suggest that YM155 may be a potential drug for the therapy of gemcitabine-resistant bladder cancer. PMID:24297644

  18. Polymorphisms in cell cycle regulatory genes, urinary arsenic profile and urothelial carcinoma

    SciTech Connect

    Chung, C.-J.; Huang, C.-J.; Pu, Y.-S.; Su, C.-T.; Huang, Y.-K.; Chen, Y.-T.; Hsueh, Y.-M.

    2008-10-15

    Introduction: Polymorphisms in p53, p21 and CCND1 could regulate the progression of the cell cycle and might increase the susceptibility to inorganic arsenic-related cancer risk. The goal of our study was to evaluate the roles of cell cycle regulatory gene polymorphisms in the carcinogenesis of arsenic-related urothelial carcinoma (UC). Methods: A hospital-based case-controlled study was conducted to explore the relationships among the urinary arsenic profile, 8-hydroxydeoxyguanosine (8-OHdG) levels, p53 codon 72, p21 codon 31 and CCND1 G870A polymorphisms and UC risk. The urinary arsenic profile was determined using high-performance liquid chromatography (HPLC) and hydride generator-atomic absorption spectrometry (HG-AAS). 8-OHdG levels were measured by high-sensitivity enzyme-linked immunosorbent assay (ELISA) kits. Genotyping was conducted using polymerase chain reaction-restriction fragment length polymerase (PCR-RFLP). Results: Subjects carrying the p21 Arg/Arg genotype had an increased UC risk (age and gender adjusted OR = 1.53; 95% CI, 1.02-2.29). However, there was no association of p53 or CCND1 polymorphisms with UC risk. Significant effects were observed in terms of a combination of the three gene polymorphisms and a cumulative exposure of cigarette smoking, along with the urinary arsenic profile on the UC risk. The higher total arsenic concentration, monomethylarsonic acid percentage (MMA%) and lower dimethylarsinic acid percentage (DMA%), possessed greater gene variant numbers, had a higher UC risk and revealed significant dose-response relationships. However, effects of urinary 8-OHdG levels combined with three gene polymorphisms did not seem to be important for UC risk. Conclusions: The results showed that the variant genotype of p21 might be a predictor of inorganic arsenic-related UC risk.

  19. Regional differences in practice patterns and associated outcomes for upper tract urothelial carcinoma in Canada

    PubMed Central

    Metcalfe, Michael; Kassouf, Wassim; Rendon, Ricardo; Bell, David; Izawa, Jonathan; Chin, Joseph; Kapoor, Anil; Matsumoto, Edward; Lattouf, Jean-Baptiste; Saad, Fred; Lacombe, Louis; Fradet, Yves; Fairey, Adrian; Jacobson, Niels-Eric; Drachenberg, Darryl; Cagiannos, Ilias; So, Alan; Black, Peter

    2012-01-01

    Introduction: We delineated Canadian regional differences in practice patterns in the management of upper tract urothelial carcinoma (UTUC) after nephroureterectomy and relate these to patient outcomes. Methods: A database was created with 1029 patients undergoing radical nephroureterectomy for UTUC between 1994 and 2009 at 10 Canadian centres. Demographic, clinical and pathological variables were collected from chart review. Practice pattern variables were defined as: open versus laparoscopic nephroureterectomy, management strategy for the distal ureter, performance of lymphadenectomy and administration of chemotherapy and/or radiation therapy. The outcome measures were overall (OS), disease-specific (DSS) and recurrence-free survival (RFS). The centres were divided into three regions (West, Central, East). Cox proportional multivariable linear regression analysis was used to determine the association between regional differences in practice patterns and clinical outcomes. Results: There was a significant difference in practice patterns between regions within Canada for: time from diagnosis to surgery (p = 0.001), type of surgery (open vs. laparoscopic, p < 0.01) and method of management of the distal ureter (p = 0.001). As well, there were significant differences in survival between regions across Canada: 5-year OS (West 70%, Central 81% and East 62%, p < 0.0001) and DSS (West=79%, Central=85%, East=75%, p = 0.007) were significantly different, but there was no difference in RFS (West 47%, Central 48%, East 46%, p = 0.88). Multivariable linear regression analysis demonstrated that the differences in survival were independent of region OS (p = 0.78), DSS (p = 0.30) or RFS (p = 0.43). Conclusion: There is significant disparity in practice patterns between regions within Canada, but these do not appear to have an effect on survival. We believe that the variability in practice is a reflection of the lack of standardized treatments for UTUC and underlines the need for

  20. Urinary 8-hydroxydeoxyguanosine and urothelial carcinoma risk in low arsenic exposure area

    SciTech Connect

    Chung, C.-J.; Huang, C.-J.; Pu, Y.-S.; Su, C.-T.; Huang, Y.-K.; Chen, Y.-T.; Hsueh, Y.-M.

    2008-01-01

    Arsenic is a well-documented human carcinogen and is known to cause oxidative stress in cultured cells and animals. A hospital-based case-control study was conducted to evaluate the relationship among the levels of urinary 8-hydroxydeoxyguanosine (8-OHdG), the arsenic profile, and urothelial carcinoma (UC). Urinary 8-OHdG was measured by using high-sensitivity enzyme-linked immunosorbent assay (ELISA) kits. The urinary species of inorganic arsenic and their metabolites were analyzed by high-performance liquid chromatography (HPLC) and hydride generator-atomic absorption spectrometry (HG-AAS). This study showed that the mean urinary concentration of total arsenics was significantly higher, at 37.67 {+-} 2.98 {mu}g/g creatinine, for UC patients than for healthy controls of 21.10 {+-} 0.79 {mu}g/g creatinine (p < 0.01). Urinary 8-OHdG levels correlated with urinary total arsenic concentrations (r = 0.19, p < 0.01). There were significantly higher 8-OHdG levels, of 7.48 {+-} 0.97 ng/mg creatinine in UC patients, compared to healthy controls of 5.95 {+-} 0.21 ng/mg creatinine. Furthermore, female UC patients had higher 8-OHdG levels of 9.22 {+-} 0.75 than those of males at 5.76 {+-} 0.25 ng/mg creatinine (p < 0.01). Multiple linear regression analyses revealed that high urinary 8-OHdG levels were associated with increased total arsenic concentrations, inorganic arsenite, monomethylarsonic acid (MMA), and dimethylarsenate (DMA) as well as the primary methylation index (PMI) even after adjusting for age, gender, and UC status. The results suggest that oxidative DNA damage was associated with arsenic exposure, even at low urinary level of arsenic.

  1. The Characteristics of Recurrent Upper Tract Urothelial Carcinoma after Radical Nephroureterectomy without Bladder Cuff Excision

    PubMed Central

    Kang, Minyong; Jeong, Chang Wook; Kwak, Cheol; Kim, Hyeon Hoe

    2015-01-01

    Purpose To investigate oncological outcomes based on bladder cuff excision (BCE) during radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) and to provide clinical evidence of tumor recurrence in patients without BCE. Materials and Methods We retrospectively collected data of 372 consecutive patients who underwent RNU at our institution from May 1989 through October 2010. After excluding some data, we reviewed 336 patients for the analysis. Results Of the patients who underwent RNU with BCE (n=279, 83.0%) and without BCE (n=57, 17.0%), patients without BCE had poorer cancer-specific and overall survival rates. Among 57 patients without BCE, 35 (61.4%) experienced tumor recurrence. Recurrence at the remnant ureter resulted in poor oncological outcomes compared to those in patients with bladder recurrence, but better outcomes were observed compared to recurrence at other sites. No significant predictors for tumor recurrence at the remnant ureter were identified. In patients without BCE, pathological T stage [hazard ratio (HR), 5.73] and lymphovascular invasion (HR, 3.65) were independent predictors of cancer-specific survival, whereas age (HR, 1.04), pathological T stage (HR, 5.11), and positive tumor margin (HR, 6.50) were independent predictors of overall survival. Conclusion Patients without BCE had poorer overall and cancer-specific survival after RNU than those with BCE. Most of these patients experienced tumor recurrence at the remnant ureter and other sites. Patients with non-organ confined UTUC after RNU without BCE may be considered for adjuvant chemotherapy with careful follow-up. PMID:25683984

  2. CEBPD amplification and overexpression in urothelial carcinoma: a driver of tumor metastasis indicating adverse prognosis

    PubMed Central

    Wang, Yu-Hui; Wu, Wen-Jeng; Wang, Wei-Jan; Huang, Hsuan-Ying; Li, Wei-Ming; Yeh, Bi-Wen; Wu, Ting-Feng; Shiue, Yow-Ling; Sheu, Jim Jinn-Chyuan; Wang, Ju-Ming; Li, Chien-Feng

    2015-01-01

    The molecular aberrations responsible for the progression of urothelial carcinoma (UC) remain largely obscure. To search candidate driver oncogenes in UC, we performed array-based genomic hybridization (aCGH) on 40 UBUC samples. Amplification of 8q11.21 was preferentially identified in patients who developed disease-specific death (53.8%) and distal metastasis (50.0%) but was barely detected in non-eventful cases (3.7% and 0%, respectively). In order to quantify the expression of candidate genes harbored in 8q11.21, laser-capture microdissection coupled with RT-PCR was performed on 32 of the 40 cases submitted to aCGH. With this, we identified CEBPD mRNA expression as most significantly associated with gains of 8q11.21, suggesting amplification-driven expression. By performing CEBPD-specific FISH and immunohistochemistry on 295 UBUCs, we confirmed CEBPD amplification (21.3%) and overexpression (29.8%) were strongly related to each other (p<0.001). Moreover, both were associated with adverse clinicopathologic features and worse outcomes. Furthermore, the clinical significance of CEBPD expression was also confirmed in an independent cohort comprised of 340 UCs from the upper urinary tract. Interestingly, CEBPD knockdown suppressed cell proliferation, migration and, most significantly, cell invasion ability in UC cells. The latter phenotype is attributed to downregulation of MMP2 as identified by RT2 Profiler PCR array. Moreover, expression of CEBPD significantly enhanced MMP2 expression and transcriptional activation by directly binding to its promoter region, as confirmed by promoter reporter assay and chromatin immunoprecipitation assay. Conclusively, CEBPD amplification is a mechanism driving increased mRNA and protein expression that confers aggressiveness in UC through MMP2-mediated cell invasiveness. PMID:26307680

  3. Sacituzumab Govitecan, a Novel Antibody--Drug Conjugate, in Patients With Metastatic Platinum-Resistant Urothelial Carcinoma.

    PubMed

    Faltas, Bishoy; Goldenberg, David M; Ocean, Allyson J; Govindan, Serengulam V; Wilhelm, Francois; Sharkey, Robert M; Hajdenberg, Julio; Hodes, Gillian; Nanus, David M; Tagawa, Scott T

    2016-02-01

    Patients with metastatic, platinum-resistant urothelial carcinoma (PRUC) have no Food and Drug Administration-approved therapies. The response rates to second-line chemotherapy have generally been < 20%, with a median overall survival of < 1 year. We report our experience with 6 heavily pretreated patients with advanced PRUC (ClinicalTrials.gov identifier NCT01631552) with the novel antibody-drug conjugate, sacituzumab govitecan (IMMU-132). This antibody-drug conjugate comprises the active metabolite of irinotecan, SN-38, conjugated to an anti-Trop-2 antibody. Trop-2 is widely expressed in ≤ 83% of urothelial carcinomas. Of the 6 patients, 3 had a clinically significant response (progression-free survival, 6.7 to 8.2 months; overall survival, 7.5+ to 11.4+ months). Sacituzumab govitecan was well tolerated. Because of these results, a phase II trial has been initiated. The present report highlights the promise of antibody-drug conjugates, such as sacituzumab govitecan, as a novel therapeutic strategy for the treatment of PRUC. PMID:26541586

  4. [A CASE OF UROTHELIAL CARCINOMA OF THE URINARY BLADDER WITH SQUAMOUS DIFFERENTIATION RESPONDING TO PACLITAXEL AND CARBOPLATIN NEOADJUVANT CHEMOTHERAPY].

    PubMed

    Banno, Eri; Nishino, Aki; Nagai, Yasuharu; Yasuda, Muneo; Tahara, Hideo; Kino, Shigeo; Kanno, Norihumi

    2015-07-01

    A 42-year-old man was referred to our hospital for macrohematuria. Computer tomography and magnetic resonance imaging revealed right hydronephrosis and a retroperitoneal mass, located next to right side of the bladder. Cystoscopy showed a protruded lesion covered with normal mucosa at the right lateral wall. The patient underwent transurethral resection of the bladder tumor and biopsies of the bladder wall. Histological examination showed squamous cell carcinoma. Neoadjuvant chemotherapy using paclitaxel and carboplatin (TC) was performed. A total cystectomy, right nephroureterectomy and construction of the ileal conduit were performed after one course of systemic chemotherapy. Histological examination showed urothelial carcinoma with squamous cell differentiation. Unexpectedly, a small amount of CIS was detected only in the vicinity of the TUR scar. The patient received 2 cycles of TC chemotherapy as adjuvant chemotherapy. Unfortunately, 11 months later, local recurrence and liver metastasis were detected. He died 17 months after the surgery. PMID:26419080

  5. TERT promoter mutations are associated with distant metastases in upper tract urothelial carcinomas and serve as urinary biomarkers detected by a sensitive castPCR.

    PubMed

    Wang, Kun; Liu, Tiantian; Ge, Nan; Liu, Li; Yuan, Xiaotian; Liu, Jikai; Kong, Feng; Wang, Chang; Ren, Hongbo; Yan, Keqiang; Hu, Sanyuan; Xu, Zhonghua; Björkholm, Magnus; Fan, Yidong; Zhao, Shengtian; Liu, Cheng; Xu, Dawei

    2014-12-15

    TERT promoter C228T and C250T mutations occur in various malignancies including bladder cancer (BC) and may serve as urinary tumor markers. However, the mutation association with clinical variables in upper tract urothelial carcinomas (UTUCs) is unclear. There is also a lack of sensitive tools to detect the minor mutant TERT promoter in bulk urinary DNA. Here we analyzed 220 UTUC patients [98 with renal pelvic carcinoma (RPC) and 122 with ureter carcinoma (UC)] and developed a Competitive Allele-Specific TaqMan PCR (castPCR) for urinary assay. We identified C228T or C250T mutations in 42 of 98 (43%) RPC and 23 of 122 (19%) UC tumors. Distant metastases were significantly correlated with UTUC patients harboring TERT promoter mutations (P = 0.001). C228T were detected in 6/10 and 9/10 of urine samples from patients with mutation-carrying tumors using Sanger sequencing and castPCR, respectively. When urine samples from 70 BC patients were analyzed together, the sensitivity of urinary C228T assay was 89% and 50% for castPCR and Sanger sequencing, respectively (P < 0.001). Collectively, TERT promoter mutations occur in UTUCs with a high frequency in RPCs and predict distant metastasis. castPCR assays of the mutation are a useful tool for urine-based diagnostics of urological malignancies. PMID:25474136

  6. Impact of Smoking on Oncologic Outcomes of Upper Tract Urothelial Carcinoma After Radical Nephroureterectomy

    PubMed Central

    Rink, Michael; Xylinas, Evanguelos; Margulis, Vitaly; Cha, Eugene K.; Ehdaie, Behfar; Raman, Jay D.; Chun, Felix K.; Matsumoto, Kazumasa; Lotan, Yair; Furberg, Helena; Babjuk, Marek; Pycha, Armin; Wood, Christopher G.; Karakiewicz, Pierre I.; Fisch, Margit; Scherr, Douglas S.; Shariat, Shahrokh F.

    2014-01-01

    Background Ci garette smoking is a common risk factor for developing upper tract urothelial carcinoma (UTUC). Objective To assess the impact of cigarette smoking status, cumulative smoking exposure, and time from cessation on oncologic UTUC outcomes in patients treated with radical nephroureterectomy (RNU). Design, setting, and participants A total of 864 patients underwent RNU at five institutions. The median follow-up in this retrospective study was 50 mo. Smoking history included smoking status, quantity of cigarettes per day (CPD), duration in years, and years from smoking cessation. The cumulative smoking exposure was categorized as light-short-term (≤19 CPD and ≤19.9 yr), moderate (all combinations except light-short-term and heavy-long-term), and heavy-long-term (≥ 20CPD and ≥ 20 yr). Interventions RNU with or without lymph node dissection. No patient received neoadjuvant chemotherapy. Outcome measurements and statistical analysis Univariable and multivariable logistic regression and competing risk regression analyses assessed the effects of smoking on oncologic outcomes. Results and limitations A total of 244 patients (28.2%) never smoked; 297 (34.4%) and 323 (37.4%) were former and current smokers, respectively. Among smokers, 87 (10.1%), 331 (38.3%), and 202 (23.4%) were light-short-term, moderate, and heavy-long-term smokers, respectively. Current smoking status, smoking ≥20CPD ≥20 yr, and heavy-long-term smoking were associated with advanced disease (p values ≤0.004), greater likelihood of disease recurrence (p values ≤0.01), and cancer-specific mortality (p values ≤0.05) on multivariable analyses that adjusted for standard features. Patients who quit smoking ≥10 yr prior to RNU did not differ from never smokers regarding advanced tumor stages, disease recurrence, and cancer-specific mortality, but they had better oncologic outcomes then current smokers and those patients who quit smoking <10 yr prior to RNU. The study is limited by

  7. Polymorphism of inflammatory genes and arsenic methylation capacity are associated with urothelial carcinoma

    SciTech Connect

    Wu, Chia-Chang; Huang, Yung-Kai; Chung, Chi-Jung; Huang, Chao-Yuan; Pu, Yeong-Shiau; Shiue, Horng-Sheng; Lai, Li-An; Lin, Ying-Chin; Su, Chien-Tien; Hsueh, Yu-Mei

    2013-10-01

    Chronic exposure to arsenic can generate reactive oxidative species, which can induce certain proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8). TNF-α, IL-6 and IL-8 have been shown to be involved in the development and progression of various cancers, including bladder cancer. This study aimed to investigate the joint effect of the polymorphism of TNF-α − 308 G/A, IL-6 − 174 G/C, IL-8 − 251 T/A and urinary arsenic profiles on urothelial carcinoma (UC) risk. This study evaluated 300 pathologically-confirmed cases of UC and 594 cancer-free controls. Urinary arsenic species were detected using high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. The polymorphism of TNF-α − 308 G/A, IL-6 − 174 G/C and IL-8 − 251 T/A was determined using polymerase chain reaction-restriction fragment length polymorphism. The joint effects on UC risk were estimated by odds ratios and 95% confidence intervals using unconditional logistic regression. We found that the TNF-α − 308 A/A and IL-8 − 251 T/T polymorphisms were significantly associated with UC. Moreover, significant dose–response joint effect of TNF-α − 308 A/A or IL-8 − 251 T/T genotypes and arsenic methylation indices were seen to affect UC risk. The present results also showed a significant increase in UC risk in subjects with the IL-8 − 251 T/T genotype for each SD increase in urinary total arsenic and MMA%. In contrast, a significant decrease in UC risk was found in subjects who carried the IL-8 − 251 T/T genotype for each SD increase in DMA%. - Highlights: • Joint effect of the TNF-α -308 A/A genotype and urinary total arsenic affected UC. • Joint effect of the IL-8 -251 T/T genotype and urinary total arsenic affected UC. • Urinary total arsenic level, TNF-α -308 A/A and IL-8 -251 T/T genotype affected UC.

  8. Detection of Urothelial Carcinoma: Comparison of Reduced-Dose Iterative Reconstruction with Standard-Dose Filtered Back Projection.

    PubMed

    Bahn, Young Eun; Kim, See Hyung; Kim, Mi Jeong; Kim, Chan Sun; Kim, Young Hwan; Cho, Seung Hyun

    2016-05-01

    Purpose To prospectively assess radiation dose, image quality, and diagnostic performance of computed tomography (CT) urography for detection of urothelial carcinomas by performing reduced-dose scanning with iterative reconstruction (IR) compared with standard-dose scanning with filtered back projection (FBP). Materials and Methods The institutional review board approved the study with written informed patient consent. In total, 2163 patients at high risk for urothelial carcinomas randomly underwent standard-dose scanning with FBP (protocol A, 120 kVp for >80 kg body weight; protocol B, 100 kVp for 50-80 kg body weight) or reduced-dose scanning with IR (protocol C, 100 kVp for >80 kg body weight; protocol D, 80 kVp for 50-80 kg body weight). Objective image quality (signal-to-noise ratio and contrast-to-noise ratio) between the two groups with same weight range was measured for various regions of interest. Subjective image quality (visual image noise, artifact, ureter depiction, and overall image quality) and diagnostic accuracy (per lesion and per patient) were assessed with three- and five-point scores, respectively. Results Size-specific dose estimate (protocol A vs protocol C, 24.2 mGy vs 19.2 mGy, respectively; protocol B vs protocol D,13.9 mGy vs 8.8 mGy, respectively) was significantly lower in reduced-dose scanning (P < .001 for both). There were significantly higher signal-to-noise and contrast-to-noise ratios in reduced-dose scanning, except for the abdominal aorta (P < .05 for all). There was no significant difference in subjective image quality, except for artifacts in protocols B and D (range, 4-5 vs 3-4; P < .05). Per-lesion diagnostic accuracy was 90.8% (89 of 98, protocol A), 91.3% (105 of 115, protocol B), 92.9% (79 of 85, protocol C), and 88.8% (111 of 125, protocol D). Conclusion Reduced-dose scanning with IR showed dose reduction and no significant difference of image quality in detection of urothelial carcinomas, except for some artifacts in 80

  9. The biological complexity of urothelial carcinoma: Insights into carcinogenesis, targets and biomarkers of response to therapeutic approaches.

    PubMed

    Grivas, Petros D; Melas, Marilena; Papavassiliou, Athanasios G

    2015-12-01

    Bladder cancer is a major cause of morbidity, mortality and health-related costs. Urothelial carcinoma is by far the most common histologic type of bladder cancer and may also arise from the upper urinary tract, e.g. renal pelvis and ureter, as well as from the proximal urethra. There have been no major advances in the development of new systemic therapies for urothelial carcinoma for over two decades, which may be related to prior lack of profound comprehension of biological pathogenetic mechanisms. However, in the last few years there has been a major shift in the development of new promising therapies that stem from improved molecular profiling of this malignancy. Developments in molecular biology, genomics, bioinformatics and immunology provide a solid foundation for therapeutic advances. A plethora of novel treatment targets and biomarkers are being evaluated, but there has been no molecular biomarker with established clinical utility so far. Genomic characterization of each patient's tumor has not been implemented due to the high cost, lack of validated standardized techniques that could be available in different laboratories, as well as absence of validated biomarkers and available therapeutic agents with clinically proven benefit. However, genomic characterization before treatment has now started to be implemented in novel clinical trial designs in order to contribute to proper patient selection based on biomarker-based enrichment strategies. Several "umbrella" or "basket" type, molecular biomarkers-based trials, in which patient eligibility and/or stratification is based on the presence of specific genetic alterations regardless of tissue of origin and/or histology, are being launched. Mathematical models and bioinformatics platforms that perform high level computational integrated pathway analysis may reveal clinical relevant signaling pathways amenable for targeting in individual patient tumors. Moreover, the high mutational burden of urothelial

  10. Benign and Malignant Brenner Tumors Show an Absence of TERT Promoter Mutations That Are Commonly Present in Urothelial Carcinoma.

    PubMed

    Khani, Francesca; Diolombi, Mairo L; Khattar, Pallavi; Huang, Weihua; Fallon, John T; Epstein, Jonathan I; Zhong, Minghao

    2016-09-01

    Brenner tumors are uncommon ovarian neoplasms, which have morphologic and immunophenotypical features of transitional cell (urothelial) differentiation. The origin of Brenner tumors is perplexing, but they are believed to arise from transitional cell metaplasia occurring within the ovary and/or fallopian tube, although it is controversial whether this metaplasia is truly along transitional cell lines. Recently, TERT promoter mutations have been identified in urothelial carcinoma (UC) with high frequency (approximately 70%), and the current literature suggests a potential diagnostic and/or prognostic role of these mutations in UC. Molecular evidence supporting that Brenner tumors represent neoplasms exhibiting transitional cell differentiation is scant. To explore this further, we investigated a series of 19 Brenner tumors of the ovary (15 benign and 4 malignant) for the presence of TERT promoter mutations after genomic DNA extraction from formalin-fixed paraffin-embedded tissue blocks and standard polymerase chain reaction sequencing. TERT promoter mutations were not identified in any of the cases (0/19). The absence of TERT promoter mutations in Brenner tumors suggests that despite the morphologic and some immunophenotypical resemblance to non-neoplastic and neoplastic transitional epithelium, Brenner tumors may exhibit a molecularly distinct pathogenesis. The findings also may portend diagnostic utility in rare cases wherein it is difficult to distinguish a primary malignant Brenner tumor of the ovary from metastatic UC. PMID:27299795

  11. Chinese Herbs Containing Aristolochic Acid Associated with Renal Failure and Urothelial Carcinoma: A Review from Epidemiologic Observations to Causal Inference

    PubMed Central

    Yang, Hsiao-Yu; Chen, Pau-Chung; Wang, Jung-Der

    2014-01-01

    Herbal remedies containing aristolochic acid (AA) have been designated to be a strong carcinogen. This review summarizes major epidemiologic evidence to argue for the causal association between AA exposure and urothelial carcinoma as well as nephropathy. The exposure scenarios include the following: Belgian women taking slimming pills containing single material Guang Fang Ji, consumptions of mixtures of Chinese herbal products in the general population and patients with chronic renal failure in Taiwan, occupational exposure in Chinese herbalists, and food contamination in farming villages in valleys of the Danube River. Such an association is corroborated by detecting specific DNA adducts in the tumor tissue removed from affected patients. Preventive actions of banning such use and education to the healthcare professionals and public are necessary for the safety of herbal remedies. PMID:25431765

  12. Massive renal urothelial carcinoma with renal vein tumor thrombus, pancreatic infiltration and adrenal metastasis: A case report

    PubMed Central

    Li, Tao; Gao, Liang; Wu, Weilu; Chen, Peng; Bu, Siyuan; Wei, Qiang; Yang, Lu

    2016-01-01

    A 49-year-old female patient presented with a massive left renal tumor, recurrent left flank pain and gross hematuria. The tumor was accompanied by a renal vein tumor thrombus, pancreatic infiltration and a solitary adrenal metastasis. Radical nephrectomy, distal pancreatectomy, ipsilateral adrenalectomy and splenectomy were performed. Histopathological examination suggested high-grade urothelial carcinoma (UC); however, tumor recurrence and multiple metastases were detected only 3 months after the surgery, and the patient succumbed during follow-up 1 month later. To the best of our knowledge, this is the first case of renal UC of such advanced stage with renal vein tumor thrombus, pancreatic infiltration and a solitary adrenal metastasis. PMID:27446406

  13. Androgen receptor expands the population of cancer stem cells in upper urinary tract urothelial cell carcinoma cells

    PubMed Central

    Chen, Chi-Cheng; Hsieh, Teng-Fu; Huang, Chi-Ping; Yu, Ai-Lin; Chang, Wen-Lin; Shyr, Chih-Rong

    2016-01-01

    Androgen receptor (AR) affects the development and progression of upper urinary tract urothelial cell carcinoma (UUTUC). However, the regulatory mechanism exerted by AR to affect UUTUC cells remains unclear. Here we investigated whether AR promotes UUTUC development and progression, possibly by expanding the population of cancer stem cells (CSCs), which are a particular population of cells within cancer cells responsible for tumor initiation, drug resistance and metastasis. We compared UUTUC cells with or without the addition of AR on their CSC population with flow cytometry, colony formation and sphere formation assay to determine the effect of AR on CSC activity, and real-time PCR was used to detect the expression stemness genes and miRNAs. In vivo tumor formation was evaluated with the implantation of cancer cells in nude mice. We found that the addition of AR in UUTUC cells, significantly increased the population of CSC, clonogenicity, sphere formation and the expression of stemness genes (Oct4, Bmi1 and Nanog), altered CSC-related miRNA profile, as well as promoted epithelial mesenchymal transition (EMT). And AR inhibitor, enzalutamide was shown to suppress AR’s effect on tumorsphere formation. Furthermore, in an immune-deficient mouse model, the addition of AR in UUTUC cells also increased the tumor formation capacity. This study will help us better understand the extent to which AR contributes to UUTUC progression by expanding their CSC population and capacity. Our findings could explain high incidence of UUTUC observed in males. And targeting AR may lead to novel therapeutic approaches for genetically diversified urothelial carcinomas in precision medicine era. PMID:27186399

  14. Prognostic significance of Bcl-xL expression and efficacy of Bcl-xL targeting therapy in urothelial carcinoma

    PubMed Central

    Yoshimine, S; Kikuchi, E; Kosaka, T; Mikami, S; Miyajima, A; Okada, Y; Oya, M

    2013-01-01

    Background: Bcl-xL has an important role in the control of cell death through its inhibition of apoptosis. The aim of this study was to investigate the clinicopathological significance of Bcl-xL in upper urinary tract urothelial carcinoma (UTUC) and the therapeutic effect of targeting Bcl-xL protein in urothelial carcinoma (UC) cells. Methods: We evaluated the immunohistochemical expression of Bcl-xL in 175 UTUC patients to determine the clinical role of Bcl-xL expression in clinical outcome. We used bafilomycin A1 (BMA) as a specific inhibitor of Bcl-xL to examine the biological effects in UC cells in vitro and in vivo. Results: Immunohistochemical analysis of Bcl-xL expression revealed that patients with a high Bcl-xL score had a significantly lower 5-year cancer-specific survival (CSS) rate (53.2%) than those with a low Bcl-xL score (77.2%) (P=0.0011). Multivariate analysis indicated that a high Bcl-xL score was an independent prognostic factor of CSS (P=0.023). BMA inhibited UMUC-3 cell proliferation in vitro by induction of apoptosis. Treatment with BMA significantly inhibited tumour growth in UMUC-3 tumours in this mouse xenograft model accompanied by an elevated apoptosis induction. Conclusion: Bcl-xL appears to be a significant molecular marker for the prognosis of UTUCs. Targeting Bcl-xL may be a promising therapeutic strategy for patients with UC. PMID:23674090

  15. High epidermal growth factor receptor immunohistochemical expression in urothelial carcinoma of the bladder is not associated with EGFR mutations in exons 19 and 21: a study using formalin-fixed, paraffin-embedded archival tissues☆

    PubMed Central

    Chaux, Alcides; Cohen, Julie S.; Schultz, Luciana; Albadine, Roula; Jadallah, Sana; Murphy, Kathleen M.; Sharma, Rajni; Schoenberg, Mark P.; Netto, George J.

    2012-01-01

    Summary Epidermal growth factor receptor (EGFR) is a member of the erbB tyrosine kinase family reported to be overexpressed in a variety of solid malignancies. Mutations in exons 19 to 21 of the tyrosine kinase domain have been detected in a subset of these tumors and its presence associated with a better response to EGFR inhibitors. Several clinical trials are currently underway to evaluate the performance of such drugs in patients with bladder cancer, but data on EGFR mutation status are limited. The current study assesses EGFR immunohistochemical expression and the presence of mutations in exons 19 and 21 by polymerase chain reaction in 19 bladder urothelial carcinomas from formalin-fixed, paraffin-embedded tissues. Representative paraffin sections were microdissected for DNA extraction using a pinpoint isolation system. Parallel sections were immunostained using a monoclonal anti-EGFR antibody. No mutations in exons 19 and 21 of EGFR were identified in any of the cases. Immunohistochemical EGFR positivity was observed in 14 of 19 cases. In summary, we found EGFR protein expression in 74% of urothelial carcinomas, but we failed to detect EGFR mutations at exons 19 to 21, suggesting that EGFR overexpression is not related to the presence of mutations in the tyrosine kinase domain of the gene. Mutation analysis of EGFR exons 19 and 21 is feasible in microdissected paraffin sections from archival tissues. Immunohistochemical expression of EGFR may not be useful to predict therapeutic response to EGFR inhibitors in patients with urothelial carcinomas. To explain EGFR immunohistochemical overexpression, other mechanisms besides mutations in the EGFR kinase domain should be investigated in future studies. PMID:22406363

  16. Gene Expression and DNA Methylation Status of Glutathione S-Transferase Mu1 and Mu5 in Urothelial Carcinoma

    PubMed Central

    Wang, Shou-Chieh; Huang, Chin-Chin; Shen, Cheng-Huang; Lin, Lei-Chen; Zhao, Pei-Wen; Chen, Shih-Ying; Deng, Yu-Chiao; Liu, Yi-Wen

    2016-01-01

    Bladder cancer is highly recurrent after therapy, which has an enormous impact on the health and financial condition of the patient. It is worth developing diagnostic tools for bladder cancer. In our previous study, we found that the bladder carcinogen BBN increased urothelial global DNA CpG methylation and decreased GSTM1 protein expression in mice. Here, the correlation of BBN-decreased GSTM1 and GSTM gene CpG methylation status was analyzed in mice bladders. BBN treatment decreased the protein and mRNA expression of GSTM1, and the CpG methylation ratio of GSTM1 gene promoter was slightly increased in mice bladders. Unlike mouse GSTM1, the human GSTM1 gene tends to be deleted in bladder cancers. Among 7 human bladder cancer cell lines, GSTM1 gene is really null in 6 cell lines except one, T24 cells. The CpG methylation level of GSTM1 was 9.9% and 5-aza-dC did not significantly increase GSTM1 protein and mRNA expression in T24 cells; however, the GSTM5 gene was CpG hypermethylated (65.4%) and 5-aza-dC also did not affect the methylation ratio and mRNA expression. However, in other cell lines without GSTM1, 5-aza-dC increased GSTM5 expression and decreased its CpG DNA methylation ratio from 84.6% to 61.5% in 5637, and from 97.4% to 75% in J82 cells. In summary, two biomarkers of bladder tumor were provided. One is the GSTM1 gene which is down-regulated in mice bladder carcinogenesis and is usually deleted in human urothelial carcinoma, while the other is the GSTM5 gene, which is inactivated by DNA CpG methylation. PMID:27404495

  17. Micropapillary morphology is an indicator of poor prognosis in patients with urothelial carcinoma treated with transurethral resection and radiochemotherapy.

    PubMed

    Bertz, Simone; Wach, S; Taubert, H; Merten, R; Krause, F S; Schick, S; Ott, O J; Weigert, E; Dworak, O; Rödel, C; Fietkau, R; Wullich, B; Keck, B; Hartmann, A

    2016-09-01

    Purpose of this study was to evaluate prognostic impact of rare variants of urothelial bladder cancer (BC) after treatment with combined radiochemotherapy (RCT). To this end tumour tissue of 238 patients with urothelial carcinoma (UC) treated with transurethral resection of the bladder (TUR-B) and RCT with curative intent was collected. Histomorphological analysis included re-evaluation and semi-quantitative assessment of rare UC subtypes. Additionally, human epidermal growth factor receptor 2 (HER2) chromogenic in situ hybridisation (CISH) was performed in tumours with a micropapillary component exceeding 30 %. Long-term follow-up was available for 200 patients (range 3-282 months). Variant UC histology was found in 45 of 238 tumours, most frequently micropapillary UC (N = 17) including cases with a small fraction of tumour with micropapillary morphology. The mere presence of micropapillary morphology did not affect prognosis. In tumours with extensive (≥30 %) micropapillary morphology (N = 8) Kaplan-Meier analysis revealed significantly worse cancer specific survival (CSS) (P = 0.002) compared to conventional UC (mean survival times 97 months and 229 months, respectively). Univariate Cox regression analysis of cases with ≥30 % micropapillary morphology revealed a hazard ratio of 4.726 (95 % CI 1.629-13.714) for CSS (P = 0.004). CISH revealed HER2 gene amplification in 3/10 tumours with ≥30 % micropapillary component. In conclusion, for BC treated with TUR-B and RCT, the presence of micropapillary morphology in more than 30 % of the tumour is an adverse prognostic factor. Further studies are needed to evaluate a potential benefit of different, especially multimodal treatment strategies for micropapillary UC and also other subtypes of UC. Her2 represents a promising therapeutic target in a subset of micropapillary UC. PMID:27392930

  18. AB058. Intravenous chemotherapy combined with intravesical chemotherapy to treat T1G3 bladder urothelial carcinoma after transurethral resection of bladder tumor: results of a retrospective study

    PubMed Central

    Zhang, Yu; Hu, Hailong; Tian, Dawei; Wu, Changli

    2016-01-01

    Objective The management of stage 1 and grade 3 (T1G3) bladder cancer continues to be controversial. Although the transurethral resection of bladder tumor (TURBT) followed by intravesical chemotherapy is a conservative strategy for treatment of T1G3 bladder cancer, a relatively high risk of tumor recurrence and progression remains regarding the therapy. This study aimed to compare the efficacy of intravenous chemotherapy combined with intravesical chemotherapy versus intravesical chemotherapy alone for T1G3 bladder cancer after TURBT surgery. Methods We retrospectively reviewed the cases of 457 patients who were newly diagnosed with T1G3 bladder urothelial carcinoma between January 2009 and March 2014. After TURBT, 281 patients received intravesical chemotherapy alone, whereas 176 patients underwent intravesical chemotherapy in combination with intravenous chemotherapy. Tumor recurrence and progression were monitored periodically by urine cytology and cystoscopy in follow-up. Recurrence-free survival and progression-free survival of the two chemotherapy strategies following TURBT were analyzed. Univariable and multivariable Cox hazards analyses were performed to predict the prognostic factors for tumor recurrence and progression. Results The tumor recurrence rate was 36.7% for patients who received intravesical chemotherapy alone after TURBT, compared with 19.9% for patients who received intravenous chemotherapy combined with intravesical chemotherapy after TURBT (P<0.001). The progression rate was 10.6% for patients who underwent intravesical chemotherapy alone and 2.3% for patients who underwent the combined chemotherapies (P=0.003). Kaplan-Meier curves showed significant differences in recurrence-free survival and progression-free survival between the two treatment strategies, with a log-rank P value of <0.001 and 0.003, respectively. Multivariable analyses revealed that intravenous chemotherapy was the independent prognostic factor for tumor recurrence and

  19. Intravenous chemotherapy combined with intravesical chemotherapy to treat T1G3 bladder urothelial carcinoma after transurethral resection of bladder tumor: results of a retrospective study

    PubMed Central

    Zhang, Yu; Xie, Linguo; Chen, Tao; Xie, Wanqin; Wu, Zhouliang; Xu, Hao; Xing, Chen; Sha, Nan; Shen, Zhonghua; Qie, Yunkai; Liu, Xiaoteng; Hu, Hailong; Wu, Changli

    2016-01-01

    Objective The management of stage 1 and grade 3 (T1G3) bladder cancer continues to be controversial. Although the transurethral resection of bladder tumor (TURBT) followed by intravesical chemotherapy is a conservative strategy for treatment of T1G3 bladder cancer, a relatively high risk of tumor recurrence and progression remains regarding the therapy. This study aimed to compare the efficacy of intravenous chemotherapy combined with intravesical chemotherapy versus intravesical chemotherapy alone for T1G3 bladder cancer after TURBT surgery. Methods We retrospectively reviewed the cases of 457 patients who were newly diagnosed with T1G3 bladder urothelial carcinoma between January 2009 and March 2014. After TURBT, 281 patients received intravesical chemotherapy alone, whereas 176 patients underwent intravesical chemotherapy in combination with intravenous chemotherapy. Tumor recurrence and progression were monitored periodically by urine cytology and cystoscopy in follow-up. Recurrence-free survival and progression-free survival of the two chemotherapy strategies following TURBT were analyzed. Univariable and multivariable Cox hazards analyses were performed to predict the prognostic factors for tumor recurrence and progression. Results The tumor recurrence rate was 36.7% for patients who received intravesical chemotherapy alone after TURBT, compared with 19.9% for patients who received intravenous chemotherapy combined with intravesical chemotherapy after TURBT (P<0.001). The progression rate was 10.6% for patients who underwent intravesical chemotherapy alone and 2.3% for patients who underwent the combined chemotherapies (P=0.003). Kaplan–Meier curves showed significant differences in recurrence-free survival and progression-free survival between the two treatment strategies, with a log-rank P-value of <0.001 and 0.003, respectively. Multivariable analyses revealed that intravenous chemotherapy was the independent prognostic factor for tumor recurrence and

  20. Connexin 43 expression predicts poor progression-free survival in patients with non-muscle invasive urothelial bladder cancer

    PubMed Central

    Poyet, Cédric; Buser, Lorenz; Roudnicky, Filip; Detmar, Michael; Hermanns, Thomas; Mannhard, Doris; Höhn, Andrej; Rüschoff, Jan; Zhong, Qing; Sulser, Tullio; Moch, Holger; Wild, Peter J

    2015-01-01

    Objectives To evaluate the protein expression of connexin 43 (Cx43) in primary urothelial bladder cancer and test its association with the histopathological characteristics and clinical outcome. Methods A tissue microarray containing 348 tissue samples from 174 patients with primary urothelial carcinomas of the bladder was immunohistochemically stained for Cx43. The intensity of staining was semiquantitatively evaluated (score 0, 1+, 2+), and the association with clinicopathological features was assessed. Univariable and multivariable analyses were performed to identify predictors for progression-free survival (PFS). Results Membranous Cx43 immunoreactivity was detected in 118 (67.8%) of 174 analysable urothelial carcinomas, of which 31 (17.8%) showed even a strong (score 2+) and mainly homogeneous staining. Strong expression levels of Cx43 (score 2+) were associated with higher tumour grade, multiplicity and increased proliferation (all p<0.05). In the subgroup of patients with stage pTa and pT1 bladder tumours (n=158), strong Cx43 expression (p<0.001), solid growth pattern (p<0.001) and increased Ki-67 proliferation fraction (p<0.05) were significantly associated with shorter PFS in an univariable Cox regression analysis. In multivariable Cox regression models, Cx43 immunoreactivity and histological growth pattern remained highly significant and adverse risk factors for PFS. Conclusions The expression levels of Cx43 are frequent in non-muscle invasive bladder cancer (NMIBC), with high expression levels being associated with poor prognosis. Routine assessment of Cx43 expression may improve the identification of high-risk NMIBC. PMID:26251520

  1. [Risk factors for urothelial carcinoma: drinking measures, smoking and other life style-related risk factors--results of the Berlin Urothelial Study (BUS)].

    PubMed

    Helmert, U; Bronder, E; Klimpel, A; Molzahn, M; Pommer, W

    2000-05-01

    With the exception of smoking and several occupational exposures there is little knowledge about risk factors for urothelial cancer. A case control study in the area of former West Berlin was performed from 1990-1995 to investigate the role of several lifestyle risk factors, such as smoking, drinking behaviour and regular intake of analgesics and laxatives. The study includes 647 hospital-based incident cases with bladder cancer (n = 571), renal pelvis cancer (n = 51), and ureter cancer (n = 25), and 647 population-based controls which were matched individually by sex and age. Data analyses were carried out using standard methods for case control studies (conditional multiple logistic regression analysis). Odds ratios (OR) and 95% confidence intervals (CI) were applied as effect parameter. Statistically significantly increased odds ratios were observed for current smoking (OR: 3.46, 95% CI: 2.50-4.78), previous but now abandoned smoking (OR: 1.51, 95% CI: 1.09-2.81), and for regular intake of laxatives (OR: 2.52, 95% CI: 1.56-4.09). Furthermore, an increased risk for urothelial cancer was observed for daily consumption of three and more litres of cold drinks (OR: 2.65 95% CI: 1.12-6.24). The results underline that lifestyle factors other than smoking may contribute to a higher risk of urothelial cancer. PMID:10893874

  2. Quantitative analysis of the association between sulfotransferase isoform 1A1 polymorphism and risk of urothelial carcinoma

    PubMed Central

    LIU, KANG; YE, JIAXIN; HUANG, YUAN; QIN, CHAO; LI, PU; LIU, BIANJIANG; LI, JIE; YIN, CHANGJUN

    2015-01-01

    Sulfotransferase isoform 1A1 (SULT1A1) is a member of the sulfotransferase family that plays an important role in the biotransformation of numerous carcinogenic and mutagenic compounds through sulfation. A number of case-control studies were conducted to investigate the association between the Arg213His polymorphism in SULT1A1 and the risk of urothelial carcinoma (UC) in humans. However, the results were inconsistent. A meta-analysis based on 10 case-control studies was performed to address this issue. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of this association. Between-study heterogeneity was assessed with the Chi-square-based Q test. Overall, a possibly decreased risk of UC was associated with the SULT1A1 A/A polymorphism for the heterozygote model (OR=0.86, 95% CI: 0.76–0.98, P=0.471). In the subgroup analysis by cancer type, the results indicated that individuals with the G/G genotype had a significantly higher bladder cancer (BC) risk (GA vs. GG: OR=0.88, 95% CI: 0.74–0.99, P=0.626; GA/AA vs. GG: OR=0.85, 95% CI: 0.74–0.97, P=0.504), which was contrary to the results of the upper urinary tract urothelial carcinoma (UTUC) group (AA vs. GG: OR=2.18, 95% CI: 1.28–3.69; AA vs. GA/GG: OR=2.05, 95% CI: 1.24–3.38). In addition, stratification by smoking status demonstrated that the Arg213His polymorphism was associated with a decreased risk of UC in non-smokers (OR=0.70, 95% CI: 0.53–0.92) but not in smokers (OR=0.85, 95% CI: 0.70–1.03) under the dominant model. In conclusion, this meta-analysis demonstrated a significant association between the SULT1A1 Arg213His polymorphism and BC. However, there was insufficient evidence to support a consistent association between this polymorphism and UC, partly due to the differences between BC and UTUC. PMID:25469277

  3. Intraoperative frozen section evaluation of ureteral and urethral margins: studies of 203 consecutive radical cystoprostatectomy for men with bladder urothelial carcinoma.

    PubMed

    Zhou, Haijun; Ro, Jae Y; Truong, Luan D; Ayala, Alberto G; Shen, Steven S

    2014-01-01

    Intraoperative frozen section (FS) evaluation of ureteral and urethral margins is frequently requested during radical cystoprostatectomy in patients with bladder urothelial carcinoma. However, it is still controversial whether intraoperative FSs of ureteral and urethral margins are necessary in all patients with cystoprostatectomy or a risk-based assessment with limited to the high risk patients is the best approach. A total of 203 radical cystoprostatectomy specimens with FS evaluation on margin status from men treated for bladder urothelial carcinoma from 2003 to 2010 in our institution were reviewed. Clinicopathologic features studied include: patients' age, pathologic tumor stage, presence of carcinoma in- situ (CIS), and intraoperative FS diagnosis. All 203 patients had intraoperative FS evaluation of ureter, and of these, 37 patients had additional urethra FS evaluation. Of the 203 ureteral FS cases, 17 (8.4%) had positive margin for CIS (16 cases) or CIS with invasive urothelial carcinoma (1 case). All 17 patients with positive ureteral margin on FS had concomitant CIS in the bladder (15.5%; 17 of 110 patients). In contrast, none of the patients without concomitant CIS (n=93) had positive ureteral margins on FS. Among 37 patients who also had FS evaluation on urethral resection margin, 3 patients (8.1%) had positive margins for CIS and all three of them had concomitant CIS in the bladder. Positive ureteral/urethral margin was not associated with patients' age or tumor stage, but was significantly associated with the presence of CIS in the bladder (p<0.001). Our study demonstrates that presence of concomitant CIS in bladder cancer was often associated with positive ureteral or urethral margin for CIS or invasive carcinoma; therefore, intraoperative FS evaluation may be indicated to these patients with concomitant bladder CIS. In contrast, in patients with no associated concomitant CIS in the bladder, FS of ureteral/urethral margins may not be necessary unless

  4. Perioperative Outcomes of Laparoscopic Radical Nephroureterectomy and Regional Lymphadenectomy in Patients with Upper Urinary Tract Urothelial Carcinoma After Neoadjuvant Chemotherapy

    PubMed Central

    Rajput, M. Zak; Kamat, Ashish M.; Clavell-Hernandez, Jonathan; Siefker-Radtke, Arlene O.; Grossman, H. Barton; Dinney, Colin P. N.; Matin, Surena F.

    2011-01-01

    Objectives To determine the effect of neoadjuvant chemotherapy on surgical outcomes in patients undergoing laparoscopic radical nephroureterectomy (LNUX) for upper urinary tract urothelial carcinoma (UTUC). Methods We performed a retrospective review of all UTUC patients who underwent LNUX performed at our institution between January 2003 and June 2010. We compared differences in demographic, clinicopathological, and operative parameters, including estimated blood loss, duration of surgery, length of postoperative hospitalization, and number of complications, between patients who underwent LNUX after neoadjuvant chemotherapy and patients who underwent LNUX without neoadjuvant chemotherapy. Logistic regression analysis was performed to identify predictors of complications. Results We identified 82 UTUC patients who underwent LNUX; 26 received neoadjuvant chemotherapy. Patients who underwent LNUX after neoadjuvant chemotherapy had a higher body mass index, higher biopsy tumor grade, and longer operative time than patients who underwent LNUX without neoadjuvant chemotherapy. Patients who received neoadjuvant chemotherapy underwent regional lymphadenectomy more often, with more lymph nodes and lymphoadipose tissue removed, than patients who did not receive neoadjuvant chemotherapy. Neoadjuvant chemotherapy resulted in a 15% complete remission rate. No differences in median estimated blood loss, intraoperative transfusions, and length of hospitalization between the two groups were found. Perioperative complication rates were similar in both groups. Conclusions We found no differences in surgical outcomes between patients who underwent LNUX after neoadjuvant chemotherapy and patients who underwent LNUX without neoadjuvant chemotherapy. Our findings support the use of LNUX in selected patients undergoing neoadjuvant chemotherapy for UTUC. PMID:21354598

  5. Detection of BRAF Mutation in Urine DNA as a Molecular Diagnostic for Canine Urothelial and Prostatic Carcinoma.

    PubMed

    Mochizuki, Hiroyuki; Shapiro, Susan G; Breen, Matthew

    2015-01-01

    Urothelial carcinoma (UC) of the lower urinary tract and prostatic carcinoma (PC) are aggressive genitourinary cancers in dogs, characterized by invasion to surrounding tissues and high metastatic potential. Current diagnosis of canine UC and PC requires histopathological examination of a biopsy. Such specimens require specialized medical equipment and are invasive procedures, limiting the availability of diagnosis by histopathology for many canine patients. Access to a non-invasive means to confirm diagnosis is currently an unmet need. Recently, the canine BRAF V595E mutation was detected in ~80% of canine UCs and PCs. In this study, we developed a droplet digital PCR (ddPCR) assay for detection of the canine BRAF V595E mutation in canine urogenital tumors. The assay was evaluated in DNA samples prepared from biopsy specimens of UC (n = 48) and PC (n = 27), as well and non-neoplastic bladder epithelium (n = 38). In addition the assay was assessed for use with DNA isolated from free catch urine samples derived from canine patients with UC (n = 23), PC (n = 3), as well as from dogs with cystitis and healthy controls (n = 37). In all cases the sensitivity to detect the mutant allele was compared with conventional Sanger sequencing. ddPCR had superior sensitivity for detection of the V595E mutation: 75% of UC, 85% of PC, and 0% of control samples were mutation positive, respectively, and the V595E mutation was detected at a level as low as just 1 in 10,000 alleles (~0.01%). Furthermore, the ddPCR assay identified the mutation in free catch urine samples from 83% of canine UC and PC patients, demonstrating its utility as a non-invasive means of diagnosis. We have shown that ddPCR is a sensitive molecular technique with the potential to facilitate accurate and non-invasive means of canine UC and PC diagnosis. PMID:26649430

  6. Detection of BRAF Mutation in Urine DNA as a Molecular Diagnostic for Canine Urothelial and Prostatic Carcinoma

    PubMed Central

    Mochizuki, Hiroyuki; Shapiro, Susan G.; Breen, Matthew

    2015-01-01

    Urothelial carcinoma (UC) of the lower urinary tract and prostatic carcinoma (PC) are aggressive genitourinary cancers in dogs, characterized by invasion to surrounding tissues and high metastatic potential. Current diagnosis of canine UC and PC requires histopathological examination of a biopsy. Such specimens require specialized medical equipment and are invasive procedures, limiting the availability of diagnosis by histopathology for many canine patients. Access to a non-invasive means to confirm diagnosis is currently an unmet need. Recently, the canine BRAF V595E mutation was detected in ~80% of canine UCs and PCs. In this study, we developed a droplet digital PCR (ddPCR) assay for detection of the canine BRAF V595E mutation in canine urogenital tumors. The assay was evaluated in DNA samples prepared from biopsy specimens of UC (n = 48) and PC (n = 27), as well and non-neoplastic bladder epithelium (n = 38). In addition the assay was assessed for use with DNA isolated from free catch urine samples derived from canine patients with UC (n = 23), PC (n = 3), as well as from dogs with cystitis and healthy controls (n = 37). In all cases the sensitivity to detect the mutant allele was compared with conventional Sanger sequencing. ddPCR had superior sensitivity for detection of the V595E mutation: 75% of UC, 85% of PC, and 0% of control samples were mutation positive, respectively, and the V595E mutation was detected at a level as low as just 1 in 10,000 alleles (~0.01%). Furthermore, the ddPCR assay identified the mutation in free catch urine samples from 83% of canine UC and PC patients, demonstrating its utility as a non-invasive means of diagnosis. We have shown that ddPCR is a sensitive molecular technique with the potential to facilitate accurate and non-invasive means of canine UC and PC diagnosis. PMID:26649430

  7. TREATMENT EFFECTS OF WST11 VASCULAR TARGETED PHOTODYNAMIC THERAPY IN UROTHELIAL CELL CARCINOMA AND FEASIBILITY, SAFETY, AND LONG TERM OUTCOMES IN THE UPPER URINARY TRACT OF SWINE

    PubMed Central

    Murray, Katie S; Winter, Ashley G; Corradi, Renato Beluco; LaRosa, Stephen; Jebiwott, Sylvia; Somma, Alexander; Takaki, Haruyuki; Srimathveeravalli, Govindarajan; Lepherd, Michelle; Monette, Sebastien; Kim, Kwanghee; Scherz, Avigdor; Coleman, Jonathan A

    2016-01-01

    Purpose Surgical management of upper tract urothelial carcinoma requires removal of kidney and ureter, compromising renal function. Non-surgical alternatives have potentially prohibitive safety concerns. We examine the feasibility and safety of ablation of the ureter and renal pelvis using endoluminal vascular-targeted photodynamic therapy in a porcine model and report efficacy of WST11 vascular-targeted photodynamic therapy in a murine model. Materials and Methods Following approval, we performed 28 endoluminal ablations in the ureters and renal pelvis of 18 swine. Intravenous infusion of WST11 (4mg/kg) followed by laser illumination (10 minutes) was performed via percutaneous access or retrograde ureteroscopic approach. Animals were followed clinically with laboratory testing, imaging and histology was evaluated at several post-ablation time points. A murine xenograft was created with the 5637 human urothelial cell carcinoma line to determine sensitivity to this therapy. Results At 24 hours, 50 mW/cm laser fluence produced superficial necrosis of the ureter and deeper necrosis (penetrating the muscularis propria or adventitia) was produced by treatment with 200 mW/cm in the ureter and renal pelvis. At 4 weeks, superficial urothelium had regenerated over the treatment site. No symptomatic obstruction, clinically relevant hydronephrosis, or abnormality of lab testing was noted up to 4 weeks. In mice, 80% had no evidence of tumor at 19 days after WST11 vascular-targeted photodynamic therapy. Conclusions Urothelial cell carcinoma appears to be sensitive to WST11 vascular-targeted photodynamic therapy. Depth of WST11 vascular-targeted photodynamic therapy treatment effects can be modulated in a dose-dependent manner by titration of light intensity. Moreover, this treatment modality, applied to the porcine upper urinary tract, is feasible via antegrade and retrograde access. PMID:26860792

  8. Fine needle aspiration biopsy of an osteoclast-rich undifferentiated urothelial carcinoma: A cytology case report and review of the literature

    PubMed Central

    Purohit, Chetna N.; Bui, Marilyn M.; Hakam, Ardeshir

    2010-01-01

    Osteoclast-rich undifferentiated carcinoma of urinary bladder (ORUCUB) is a very rare and an unusual variant of high-grade urothelial carcinoma. Here, we report an extraordinary case of metastatic ORUCUB, diagnosed by fine needle aspiration (FNA) biopsy, in a 74-year-old Hispanic male who presented with a palpable, tender left groin mass and a known previous history of high-grade carcinoma of urinary bladder and prostatic cancer. To the best of our knowledge, diagnosis of ORUCUB by FNA is the first case report in FNA cytology to be published to date. A review of the literature is emphasized on the cytological, histological and immunohistochemical features and differential diagnoses of giant cell tumor. PMID:20976205

  9. Metastasis in urothelial carcinoma mimicking prostate cancer metastasis in Ga-68 prostate-specific membrane antigen positron emission tomography-computed tomography in a case of synchronous malignancy.

    PubMed

    Gupta, Manoj; Choudhury, Partha Sarathi; Gupta, Gurudutt; Gandhi, Jatin

    2016-01-01

    Prostate cancer is the second most common cancer in man. It commonly presents with urinary symptoms, bone pain, or diagnosed with elevated prostate-specific antigen.(PSA) levels. Correct staging and early diagnosis of recurrence by a precise imaging tool are the keys for optimum management. Molecular imaging of prostate cancer with Ga-68 prostate-specific membrane antigen.(PSMA), positron emission tomography-computed tomography.(PET-CT) has recently received significant attention and frequently used with a signature to prostate cancer-specific remark. However, this case will highlight the more cautious use of it. A-72-year-old male treated earlier for synchronous double malignancy.(invasive papillary urothelial carcinoma right ureter and carcinoma prostate) presented with rising PSA.(0.51.ng/ml) and referred for Ga-68 PSMA PET-CT, which showed a positive enlarged left supraclavicular lymph node. Lymph node biopsy microscopic and immunohistochemistry examination revealed metastatic carcinoma favoring urothelial origin. Specificity of PSMA scan to prostate cancer has been seen to be compromised in a certain situation mostly due to neoangiogenesis, and false positives emerged in renal cell cancer, differentiated thyroid cancer, glioblastoma, breast cancer brain metastasis, and paravertebral schwannomas. Understanding the causes of false positive will further enhance the confidence of interpretating PSMA scans. PMID:27385897

  10. Metastasis in urothelial carcinoma mimicking prostate cancer metastasis in Ga-68 prostate-specific membrane antigen positron emission tomography-computed tomography in a case of synchronous malignancy

    PubMed Central

    Gupta, Manoj; Choudhury, Partha Sarathi; Gupta, Gurudutt; Gandhi, Jatin

    2016-01-01

    Prostate cancer is the second most common cancer in man. It commonly presents with urinary symptoms, bone pain, or diagnosed with elevated prostate-specific antigen.(PSA) levels. Correct staging and early diagnosis of recurrence by a precise imaging tool are the keys for optimum management. Molecular imaging of prostate cancer with Ga-68 prostate-specific membrane antigen.(PSMA), positron emission tomography-computed tomography.(PET-CT) has recently received significant attention and frequently used with a signature to prostate cancer-specific remark. However, this case will highlight the more cautious use of it. A-72-year-old male treated earlier for synchronous double malignancy.(invasive papillary urothelial carcinoma right ureter and carcinoma prostate) presented with rising PSA.(0.51.ng/ml) and referred for Ga-68 PSMA PET-CT, which showed a positive enlarged left supraclavicular lymph node. Lymph node biopsy microscopic and immunohistochemistry examination revealed metastatic carcinoma favoring urothelial origin. Specificity of PSMA scan to prostate cancer has been seen to be compromised in a certain situation mostly due to neoangiogenesis, and false positives emerged in renal cell cancer, differentiated thyroid cancer, glioblastoma, breast cancer brain metastasis, and paravertebral schwannomas. Understanding the causes of false positive will further enhance the confidence of interpretating PSMA scans. PMID:27385897

  11. Advanced small cell carcinoma of the bladder: clinical characteristics, treatment patterns and outcomes in 960 patients and comparison with urothelial carcinoma.

    PubMed

    Geynisman, Daniel M; Handorf, Elizabeth; Wong, Yu-Ning; Doyle, Jamie; Plimack, Elizabeth R; Horwitz, Eric M; Canter, Daniel J; Uzzo, Robert G; Kutikov, Alexander; Smaldone, Marc C

    2016-02-01

    To describe the clinical characteristics, treatment patterns and outcomes in advanced small cell bladder cancer (aSCBC) patients and compare to those with urothelial carcinoma (UC). Individuals in the National Cancer Data Base with a diagnosis of either nodal (TxN+M0) or distant metastatic (TxNxM1) disease were identified from 1998 to 2010. We assessed the relationships between stage, treatment modalities and survival in the aSCBC cohort and compared these to UC patients. In the 960 patient aSCBC cohort (62% M1), 50% received palliative therapy alone, 68% in M1 versus 21% in M0 groups (P < 0.0001). Single modality local therapy (15%) and surgical (21%) or radiation-based (14%) multimodal therapy (MMT) were used in the other 50%. Cystectomy-based MMT was utilized in 45% of N+M0 versus 6.4% of NxM1 patients (P < 0.0001). Median overall survival (OS) for aSCBC patients was 8.6 months; 13.0 months in N+M0 versus 5.3 months in NxM1 patients (P < 0.0001). Survival was similar between TxN1M0 and TxN2-3M0 patients (14.8 months vs. 12.1 months, P = 0.15). Urothelial carcinoma patients (n = 27,796, 45% M1) lived longer compared to aSCBC patients in the N+M0 group (17.3 months vs. 13.0 months, P = 0.0007). There were not clinically significant differences in OS between UC and aSCBC patients in the M1 group. Advanced SCBC is a rare disease with a poor survival and palliative therapy is common, especially in M1 patients. In comparison to UC, the outcomes for aSCBC patients are worse in those with lymph node only involvement but similar in those with distant disease. PMID:26679712

  12. Higher risk of urothelial carcinoma in the upper urinary tract than in the urinary bladder in hemodialysis patients.

    PubMed

    Hsiao, Po-Jen; Hsieh, Po-Fan; Chang, Chao-Hsiang; Wu, Hsi-Chin; Yang, Chi-Rei; Huang, Chi-Ping

    2016-06-01

    Purpose This study used the a nationwide population-based retrospective cohort study with the claims data from the Taiwan National Health Insurance Research Database to investigate the risk of urothelial carcinoma (UC) for hemodialysis (HD) patients. Methods The study population consisted of 2689 patients with end-stage renal disease (ESRD) newly diagnosed in 2000-2002 and underwent maintenance HD. Then, 21,449 reference patients were collected without HD randomly selected and matched with sex and age. The exclusion criteria were previous long-term analgesics and Chinese medication usage. Incidence density rates of UC in upper urinary tract (UTUC) and bladder (UBUC) were estimated for both cohorts by the end of 2012. Hazard ratios (HRs) of UC were measured in association with HD, covariates, and comorbidity. Results The incidence of UC was significantly higher in the HD cohort than in the reference cohort for both UT (21.8 vs. 0.65 per 10,000 person-years) and UB (17.7 vs. 3.55 per 10,000 person-years). The multivariate Cox proportional hazard regression analysis showed that the HRs of UTUC in HD cohort was 33.3 (95% CI = 15.9-69.5) and 5.14 for UBUC (95% CI = 3.24-8.15). The risk increased further for HD patients with comorbidity of hematuria, urinary tract infection (UTI) or hydronephrosis. Conclusion Patients with ESRD on HD are at a high risk of developing UC, especially UTUC in Taiwan. They will be paid more frequent to check urine analysis, urine cytology, and upper urinary tract survey. PMID:26956094

  13. AB064. Diagnostic ureteroscopy for upper tract urothelial carcinoma is independently associated with intravesical recurrence after radical nephroureterectomy

    PubMed Central

    Liu, Pei; Su, Xiao-Hong; Xiong, Geng-Yan; Li, Xue-Song; Zhou, Li-Qun

    2016-01-01

    Objective To determine the effect of diagnostic ureteroscopy on intravesical recurrence in patients with upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). Methods We conducted a retrospective analysis of 664 patients who were treated with RNU for UTUC from June 2000 to December 2011, excluding those who had concomitant/prior bladder tumors. Of the 664 patients, 81 underwent diagnostic ureteroscopy (URS). We analyzed the impact of diagnostic ureteroscopy on intravesical recurrence (IVR) using the Kaplan-Meier method. Univariate and multivariate analyses were used to determine the independent risk factors. Results The median follow-up time was 48 months [interquartile range (IQR): 31–77 months]. Patients who underwent ureteroscopy were more likely to have a small (P<0.01), early-staged (P=0.019), multifocality (p=0.035) and ureteral tumor (P<0.001). IVR occurred in 223 patients during follow-up within a median of 17 months (IQR: 7–33). Patients without preoperative ureteroscopy have a statistically significant better 2-year [(79.3±0.02)% vs. (71.4±0.02)%, P<0.001] and 5-year intravesical recurrence-free survival rates [(64.9±0.05)% vs. (44.3±0.06)%, P<0.001] than patients who underwent ureteroscopy. In multivariate analysis, the diagnostic ureteroscopy (P=0.006), multiple tumors (P=0.001), tumor size <3 cm (P=0.008), low-grade (P=0.022) and pN0 stage tumor (P=0.045) were independent predictors of IVR. Conclusions Diagnostic ureteroscopy is independently associated with intravesical recurrence after radical nephroureterectomy.

  14. Correlation of Apobec Mrna Expression with overall Survival and pd-l1 Expression in Urothelial Carcinoma.

    PubMed

    Mullane, Stephanie A; Werner, Lillian; Rosenberg, Jonathan; Signoretti, Sabina; Callea, Marcella; Choueiri, Toni K; Freeman, Gordon J; Bellmunt, Joaquim

    2016-01-01

    Metastatic urothelial carcinoma (mUC) has a very high mutational rate and is associated with an APOBEC mutation signature. We examined the correlation of APOBEC expression with overall survival (OS) and PD-L1 expression in a cohort of 73 mUC patients. mRNA expression of APOBEC3 family of genes (A3A, A3B, A3C, A3F_a, A3F_b, A3G, A3H) was measured using Nanostring. PD-L1 expression, evaluated by immunohistochemistry, on tumor infiltrating mononuclear cells (TIMCs) and tumor cells was scored from 0 to 4, with 2-4 being positive. Wilcoxon's non-parametric tests assessed the association of APOBEC and PD-L1. The Cox regression model assessed the association of APOBEC with OS. All APOBEC genes were expressed in mUC. Increased A3A, A3D, and A3H expression associates with PD-L1 positive TIMCs (p = 0.0009, 0.009, 0.06). Decreased A3B expression was marginally associated with PD-L1 positive TIMCs expression (p = 0.05). Increased A3F_a and A3F_b expression was associated with increased expression of PD-L1 on tumor cells (p = 0.05). Increased expression of A3D and A3H was associated with longer OS (p = 0.0009). Specific APOBEC genes have different effects on mUC in terms of survival and PD-L1 expression. A3D and A3H may have the most important role in mUC as they are associated with OS and PD-L1 TIMC expression. PMID:27283319

  15. A Nonselective Cyclooxygenase Inhibitor Enhances the Activity of Vinblastine in a Naturally-Occurring Canine Model of Invasive Urothelial Carcinoma

    PubMed Central

    Knapp, Deborah W.; Ruple-Czerniak, Audrey; Ramos-Vara, José A.; Naughton, James F.; Fulkerson, Christopher M.; Honkisz, Sonia I.

    2016-01-01

    Background: Chemotherapy is expected to remain an important part of invasive urothelial carcinoma (UC) treatment. Strategies to enhance chemotherapy efficacy are needed. Objective: To determine the chemotherapy-enhancing effects of a nonselective cyclooxygenase (COX) inhibitor on vinblastine in a naturally-occurring canine model of invasive UC. Methods: With IACUC approval, privately-owned dogs with naturally-occurring histologically-diagnosed invasive UC, expected survival ≥6 weeks, and informed owner consent were randomly allocated to receive vinblastine (2.5 mg/m2 intravenously every 2 weeks) plus piroxicam (0.3 mg/kg daily per os) or vinblastine alone (same dose) with the option to receive piroxicam alone when vinblastine failed. Scheduled evaluations included physical exam, standard laboratory analyses, thoracic radiography, abdominal ultrasonography, and standardized measurement of urinary tract tumors. Results: Dogs receiving vinblastine alone (n = 27) and vinblastine-piroxicam (n = 24) were similar in age, sex, breed, tumor stage, and grade. Remission occurred more frequently (P <  0.02) with vinblastine-piroxicam (58.3%) than with vinblastine alone (22.2%). The median progression free interval was 143 days with vinblastine alone and 199 days with the combination. Interestingly, the overall median survival time was significantly longer (P <  0.03) in dogs receiving vinblastine alone followed by piroxicam alone (n = 20, 531 days) than in dogs receiving the combination (299 days). Treatment was well tolerated in both arms. Conclusions: Piroxicam significantly enhanced the activity of vinblastine in dogs with UC where the cancer closely mimics the human condition, clearly justifying further study. The study suggest the potential importance of tracking COX inhibitor use in patients in clinical trials as COX inhibitors could affect treatment response. PMID:27376143

  16. Clinical and prognostic value of preoperative hydronephrosis in upper tract urothelial carcinoma: a systematic review and meta-analysis

    PubMed Central

    Wang, Zhiping

    2016-01-01

    Background. Epidemiological studies have reported various results relating preoperative hydronephrosis to upper tract urothelial carcinoma (UTUC). However, the clinical significance and prognostic value of preoperative hydronephrosis in UTUC remains controversial. The aim of this study was to provide a comprehensive meta-analysis of the extent of the possible association between preoperative hydronephrosis and the risk of UTUC. Methods. We searched PubMed, ISI Web of Knowledge, and Embase to identify eligible studies written in English. Summary odds ratios (ORs) or hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models. Results. Nineteen relevant studies, which had a total of 5,782 UTUC patients enrolled, were selected for statistical analysis. The clinicopathological and prognostic relevance of preoperative hydronephrosis was evaluated in the UTUC patients. The results showed that all tumor stages, lymph node status and tumor location, as well as the risk of cancer-specific survival (CSS), overall survival (OS), recurrence-free survival (RFS) and metastasis-free survival (MFS) were significantly different between UTUC patients with elevated preoperative hydronephrosis and those with low preoperative hydronephrosis. High preoperative hydronephrosis indicated a poor prognosis. Additionally, significant correlations between preoperative hydronephrosis and tumor grade (high grade vs. low grade) were observed in UTUC patients; however, no significant difference was observed for tumor grading (G1 vs. G2 + G3 and G1 + G2 vs. G3). In contrast, no such correlations were evident for recurrence status or gender in UTUC patients. Conclusions. The results of this meta-analysis suggest that preoperative hydronephrosis is associated with increased risk and poor survival in UTUC patients. The presence of preoperative hydronephrosis plays an important role in the carcinogenesis and prognosis of UTUC. PMID:27366646

  17. Prognostic Impact of Thrombospodin-2 (THBS2) Overexpression on Patients with Urothelial Carcinomas of Upper Urinary Tracts and Bladders

    PubMed Central

    Chang, I-Wei; Li, Chien-Feng; Lin, Victor Chia-Hsiang; He, Hong-Lin; Liang, Per-In; Wu, Wen-Jeng; Li, Ching-Chia; Huang, Chun-Nung

    2016-01-01

    Purpose: Urothelial carcinoma (UC) is a type of tumor, especially of the urinary bladder, that affects people worldwide. Clarification of its detailed tumor biology and discovery of potential targets for developing treatment strategies are imperative because of frequent recurrences and poor prognosis of advanced UCs. By data mining a published dataset of UC of bladder (UCB) transcriptome (GSE31684) from Gene Expression Omnibus, National Center of Biotechnology Information (GEO, NCBI), we identified that THBS2 was the most significantly upregulated gene among those related to structural molecule activity (GO:0005198). Therefore, we evaluated the clinical significance and prognostic impact of thrombospondin-2 (THBS2) protein, A.K.A. TSP2, which encoded by THBS2 gene. Materials and Methods: THBS2 immunostaining was performed in 340 UCs of upper urinary tract (UC-UUTs) and 295 UCBs; subsequently, both groups were dichotomized into high- and low-expression subgroups. Moreover, statistical analyses were performed to correlate the association between THBS2 expression and clinicopathological parameters with two survival indexes: disease-specific survival (DSS) and metastasis-free survival (MeFS). Results: High THBS2 immunoexpression was significantly associated with advanced primary tumor status, nodal metastasis, and vascular invasion in both UC-UUT and UCB groups (all P ≤ .001). In addition, THBS2 overexpression was linked to adverse DSS and MeFS in univariate analyses and served as an independent prognosticator indicating poor outcomes in both groups in multivariate analyses. Conclusion: THBS2 may play a crucial role in UC progression and may be a novel prognostic marker. Additional investigations to elucidate the molecular pathway are necessary for developing potential THBS2-targeted therapies for UCs. PMID:27471570

  18. Association of DNA Methyltransferases 3A and 3B Polymorphisms, and Plasma Folate Levels with the Risk of Urothelial Carcinoma

    PubMed Central

    Chung, Chi-Jung; Chang, Chao-Hsiang; Liu, Chiu-Shong; Huang, Chi-Ping; Chang, Yi-Huei; Chien, Ssu-Ning; Tsai, Ping-Huan; Hsieh, Hui-An

    2014-01-01

    Background Interindividual genetic variations of human DNA methyltransferases (DNMTs), which involve the methyl donor from the folate-related one-carbon metabolism pathway, are hypothesized as a risk factor for urothelial carcinoma (UC). Therefore, we evaluated the role of gene-environment interaction in UC carcinogenesis. Methods A hospital-based case-control study was conducted by recruiting 192 patients with UC and 381 controls. Their plasma folate levels were measured using a competitive immunoassay kit. In addition, DNMT3A −448A>G and DNMT3B −579G>T genotyping was evaluated using a polymerase chain reaction-restriction fragment length polymorphism technique. Multivariate logistic regression and 95% confidence intervals (CIs) were applied to estimate the UC risk. Results We observed that patients with UC exhibited a higher prevalence rate of folate insufficiency (folate levels ≤6 ng/mL) compared with the controls (35.94% and 18.37%, respectively). Furthermore, folate levels were higher in the prevalent UC patients than in the incident UC patients. However, folate insufficiency was similarly associated with a nearly two-fold increase in the risk of UC regardless of the UC patient group. In addition, the frequencies of the variant alleles for DNMT3A and DNMT3B were 0.80 and 0.92, respectively, and no association was observed with UC risk. However, participants with a variant homozygous genotype of DNMT3B −579G>T and folate insufficiency or with high cumulative cigarette smoking exhibited an increased risk of UC. Conclusion Overall, environmental factors may contribute more significantly to UC carcinogenesis compared with genetic susceptibility. Future studies should investigate other polymorphisms of DNMT3A and DNMT3B to determine genetic susceptibility. PMID:25126948

  19. Correlation of Apobec Mrna Expression with overall Survival and pd-l1 Expression in Urothelial Carcinoma

    PubMed Central

    Mullane, Stephanie A.; Werner, Lillian; Rosenberg, Jonathan; Signoretti, Sabina; Callea, Marcella; Choueiri, Toni K.; Freeman, Gordon J.; Bellmunt, Joaquim

    2016-01-01

    Metastatic urothelial carcinoma (mUC) has a very high mutational rate and is associated with an APOBEC mutation signature. We examined the correlation of APOBEC expression with overall survival (OS) and PD-L1 expression in a cohort of 73 mUC patients. mRNA expression of APOBEC3 family of genes (A3A, A3B, A3C, A3F_a, A3F_b, A3G, A3H) was measured using Nanostring. PD-L1 expression, evaluated by immunohistochemistry, on tumor infiltrating mononuclear cells (TIMCs) and tumor cells was scored from 0 to 4, with 2–4 being positive. Wilcoxon’s non-parametric tests assessed the association of APOBEC and PD-L1. The Cox regression model assessed the association of APOBEC with OS. All APOBEC genes were expressed in mUC. Increased A3A, A3D, and A3H expression associates with PD-L1 positive TIMCs (p = 0.0009, 0.009, 0.06). Decreased A3B expression was marginally associated with PD-L1 positive TIMCs expression (p = 0.05). Increased A3F_a and A3F_b expression was associated with increased expression of PD-L1 on tumor cells (p = 0.05). Increased expression of A3D and A3H was associated with longer OS (p = 0.0009). Specific APOBEC genes have different effects on mUC in terms of survival and PD-L1 expression. A3D and A3H may have the most important role in mUC as they are associated with OS and PD-L1 TIMC expression. PMID:27283319

  20. Upregulation of long non-coding RNA urothelial carcinoma associated 1 by CCAAT/enhancer binding protein α contributes to bladder cancer cell growth and reduced apoptosis

    PubMed Central

    XUE, MEI; LI, XU; WU, WENJING; ZHANG, SHUWAN; WU, SHOUZHEN; LI, ZHENGKUN; CHEN, WEI

    2014-01-01

    Long non-coding RNA urothelial carcinoma associated 1 (lncRNA-UCA1) is upregulated in bladder cancer and plays a pivotal role in bladder cancer progression and metastasis. Recent studies and our research found that lncRNA-UCA1 may be an important biomarker and therapeutic target for bladder cancer. However, the molecular mechanism involved in the upregulation of lncRNA-UCA1 in bladder cancer is largely unknown. In the present study, we showed that lncRNA-UCA1 expression in bladder cancer cells was upregulated by transcription factor CCAAT/enhancer binding protein α (C/EBPα), which was the only candidate transcription factor simultaneously predicted by a total of five bioinformatical software programs. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay indicated that C/EBPα bound to the lncRNA-UCA1 core promoter region in vitro and in vivo. The luciferase assays further showed that there was a point mutation (A231G) in the C/EBPα binding site of the lncRNA-UCA1 core promoter in various bladder cancer cell lines, which in turn significantly increased the transcriptional activity of lncRNA-UCA1. We also demonstrated that C/EBPα siRNA treatment contributed to the downregulation of lncRNA-UCA1 expression, whereas overexpression of C/EBPα enhanced lncRNA-UCA1 expression. Furthermore, lncRNA-UCA1 transcriptional repression by C/EBPα siRNA sharply reduced cell viability and induced cell apoptosis in vitro. Collectively, our results provide a novel therapeutic strategy for bladder cancer by effectively interrupting the binding of the lncRNA-UCA1 promoter and certain transcription factors, so as to reverse the upregulation of lncRNA-UCA1 and prevent bladder cancer progression. PMID:24648007

  1. Inverse p16 and p63 expression in small cell carcinoma and high-grade urothelial cell carcinoma of the urinary bladder.

    PubMed

    Buza, Natalia; Cohen, Paul J; Pei Hui; Parkash, Vinita

    2010-04-01

    Small cell carcinoma (SmCC) of the urinary bladder is a rare, highly aggressive neoplasm. The diagnosis is usually made on morphologic grounds, with the help of immunohistochemistry to document neuroendocrine differentiation. However, neuroendocrine markers generally have low sensitivity, ranging between 30-70%. Recent studies have reported p16 over-expression in SmCC of the lung, suggesting that p16 immunohistochemistry may be useful in the diagnosis of bladder SmCC. This is the first study to analyze the usefulness of p16 in the distinction of small cell and high grade urothelial cell carcinoma (HG-UCC). Fourteen cases of SmCCs and sixteen cases of HG-UCC of the bladder were stained with p16, p63, cytokeratin 20 (CK20), cytokeratin 7 (CK7), chromogranin (Chr), synaptophysin (Syn), and CD56. P16 expression was significantly higher in SmCCs (92.8%) when compared to HG-UCCs (43.7%). P63 and CK20, on the other hand, were positive in the majority of HG-UCCs (81.3% and 50%, respectively), while only 14.3% of SmCCs showed focal immunoreactivity with CK20. The sensitivity of the traditional neuroendocrine markers was low, ranging between 28.6% (Chr) and 71.4% (CD56) in SmCCs. P16 positivity in the absence of p63 and CK20 is highly characteristic of SmCC, while p63 and CK20 positivity with or without p16 expression is typical of HG-UCC. PMID:20164052

  2. Genetic polymorphisms in glutathione S-transferase (GST) superfamily and risk of arsenic-induced urothelial carcinoma in residents of southwestern Taiwan

    PubMed Central

    2011-01-01

    Background Arsenic exposure is an important public health issue worldwide. Dose-response relationship between arsenic exposure and risk of urothelial carcinoma (UC) is consistently observed. Inorganic arsenic is methylated to form the metabolites monomethylarsonic acid and dimethylarsinic acid while ingested. Variations in capacity of xenobiotic detoxification and arsenic methylation might explain individual variation in susceptibility to arsenic-induced cancers. Methods To estimate individual susceptibility to arsenic-induced UC, 764 DNA specimens from our long-term follow-up cohort in Southwestern Taiwan were used and the genetic polymorphisms in GSTM1, GSTT1, GSTP1 and arsenic methylation enzymes including GSTO1 and GSTO2 were genotyped. Results The GSTT1 null was marginally associated with increased urothelial carcinoma (UC) risk (HR, 1.91, 95% CI, 1.00-3.65), while the association was not observed for other GSTs. Among the subjects with cumulative arsenic exposure (CAE) ≥ 20 mg/L*year, the GSTT1 null genotype conferred a significantly increased cancer risk (RR, 3.25, 95% CI, 1.20-8.80). The gene-environment interaction between the GSTT1 and high arsenic exposure with respect to cancer risk was statistically significant (multiplicative model, p = 0.0151) and etiologic fraction was as high as 0.86 (95% CI, 0.51-1.22). The genetic effects of GSTO1/GSTO2 were largely confined to high arsenic level (CAE ≥ 20). Diplotype analysis showed that among subjects exposed to high levels of arsenic, the AGG/AGG variant of GSTO1 Ala140Asp, GSTO2 5'UTR (-183)A/G, and GSTO2 Asn142Asp was associated with an increased cancer risk (HRs, 4.91, 95% CI, 1.02-23.74) when compared to the all-wildtype reference, respectively. Conclusions The GSTs do not play a critical role in arsenic-induced urothelial carcinogenesis. The genetic effects of GSTT1 and GSTO1 on arsenic-induced urothelial carcinogenesis are largely confined to very high exposure level. PMID:21798077

  3. Suppression of urinary bladder urothelial carcinoma cell by the ethanol extract of pomegranate fruit through cell cycle arrest and apoptosis

    PubMed Central

    2013-01-01

    Background Pomegranate possesses many medicinal properties such as antioxidant, anti-inflammation and antitumor. It has been extensively used as a folk medicine by many cultures. Pomegranate fruit has been shown to have the inhibitory efficacy against prostate cancer and lung cancer in vitro and in vivo. It can be exploited in chemoprevention and chemotherapy of prostate cancer. In this study we examined the anti-cancer efficacy of pomegranate fruit grown in Taiwan against urinary bladder urothelial carcinoma (UBUC) and its mechanism of action. Methods Edible portion of Taiwanese pomegranate was extracted using ethanol and the anti-cancer effectiveness of ethanol extract was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry and western immunoblotting were exploited to uncover the molecular pathways underlying anti-UBUC activity of Taiwanese pomegranate ethanol extract. Results This study demonstrated that Taiwanese pomegranate fruit ethanol extract (PEE) could effectively restrict the proliferation of UBUC T24 and J82 cells. Cell cycle analyses indicated that the S phase arrest induced by PEE treatment might be caused by an increase in cyclin A protein level and a decrease in the expression of cyclin-dependent kinase 1. The results of western immunoblotting demonstrated that PEE treatment could not only evoke the activation of pro-caspase-3, -8,-9 but also increase Bax/Bcl-2 ratio in T24 cells. The above observations implicated that PEE administration might trigger the apoptosis in T24 cells through death receptor signaling and mitochondrial damage pathway. Besides we found that PEE exposure to T24 cells could provoke intensive activation of procaspase-12 and enhance the expressions of CHOP and Bip, endoplasmic reticulum (ER) stress marker, suggesting that ER stress might be the cardinal apoptotic mechanism of PEE-induced inhibition of bladder cancer cell. Conclusions The analytical results of this study help to provide

  4. XRCC1 Arg194Trp and Arg399Gln polymorphisms and arsenic methylation capacity are associated with urothelial carcinoma

    SciTech Connect

    Chiang, Chien-I; Huang, Ya-Li; Chen, Wei-Jen; Shiue, Horng-Sheng; Huang, Chao-Yuan; Pu, Yeong-Shiau; Lin, Ying-Chin; Hsueh, Yu-Mei

    2014-09-15

    The association between DNA repair gene polymorphisms and bladder cancer has been widely studied. However, few studies have examined the correlation between urothelial carcinoma (UC) and arsenic or its metabolites. The aim of this study was to examine the association between polymorphisms of the DNA repair genes, XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln, with urinary arsenic profiles and UC. To this end, we conducted a hospital-based case–control study with 324 UC patients and 647 age- and gender-matched non-cancer controls. Genomic DNA was used to examine the genotype of XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln by PCR-restriction fragment length polymorphism analysis (PCR-RFLP). Urinary arsenic profiles were measured by high performance liquid chromatography (HPLC) linked with hydride generator and atomic absorption spectrometry. The XRCC1 399 Gln/Gln and 194 Arg/Trp and Trp/Trp genotypes were significantly related to UC, and the odds ratio (OR) and 95% confidence interval (95%CI) were 1.68 (1.03–2.75) and 0.66 (0.48–0.90), respectively. Participants with higher total urinary arsenic levels, a higher percentage of inorganic arsenic (InAs%) and a lower percentage of dimethylarsinic acid (DMA%) had a higher OR of UC. Participants carrying XRCC1 risk diplotypes G-C/G-C, A-C/A-C, and A-T/G-T, and who had higher total arsenic levels, higher InAs%, or lower DMA% compared to those with other XRCC1 diplotypes had a higher OR of UC. Our results suggest that the XRCC1 399 Gln/Gln and 194 Arg/Arg DNA repair genes play an important role in poor arsenic methylation capacity, thereby increasing the risk of UC in non-obvious arsenic exposure areas. - Highlights: • The XRCC1 399Gln/Gln genotype was significantly associated with increased OR of UC. • The XRCC1 194 Arg/Trp and Trp/Trp genotype had a significantly decreased OR of UC. • Combined effect of the XRCC1 genotypes and poor arsenic methylation capacity on

  5. CSF2 Overexpression Is Associated with STAT5 Phosphorylation and Poor Prognosis in Patients with Urothelial Carcinoma

    PubMed Central

    Lee, Yi-Ying; Wu, Wen-Jeng; Huang, Chun-Nung; Li, Ching-Chia; Li, Wei-Ming; Yeh, Bi-Wen; Liang, Peir-In; Wu, Ting-Feng; Li, Chien-Feng

    2016-01-01

    Background: Urothelial carcinoma (UC) commonly occurs in the urinary bladder (UB) and rarely in upper the upper urinary tract (UT). Its molecular pathogenesis, however, remains obscure. Though the constitutive phosphorylation of Signal Transducer and Activator of Transcription 5 (STAT5) is an important part of carcinogenesis generally, researchers have not systematically investigated this process specifically in relation to UC. The present study addresses this gap. Through data mining a published transcriptomic database of UBUCs (GSE32894), it identified Colony Stimulating Factor 2 (CSF2) as the stepwise upregulated gene of much significance among those related to the positive regulation of tyrosine phosphorylation of STAT5 (GO:0042523). Since the phosphorylation of STAT5, a key process in the development of UC, is closely associated with CSF2, we then examine CSF2 transcript and protein expression, justifying their association with clinicopathological features and survival in our well-established cohort of patients with UC. Design: Laser capture microdissection in conjunction with real-time qRT-PCR are used to detect CSF2 transcript levels in 24 UBUCs and 6 non-tumor urothelium samples. We then used the H-score method to evaluate the immunohistochemistry in order to determine CSF2 protein expression in 296 UBUCs and 340 UTUCs, respectively. After correlating protein expression status with key clinicopathological features, the prognostic significance of CSF2 protein expression was determined for disease-specific survival (DSS) and metastasis-free survival (MeFS). Results: We exclusively detected the CSF2 transcript, which was stepwise upregulated in tumor lesions (p=0.010). In both groups of UC we found overexpression of CSF2 significantly related to incremental pT status (UTUC, p=0.011; UBUC, p<0.001), as well as with perineural invasion (UTUC, p=0.002; UBUC, p=0.001). Univariate analysis found a close correlation between CSF2 overexpression and unfavorable

  6. Fibroblast Growth Factor Receptor 1 Overexpression Is Associated with Poor Survival in Patients with Resected Muscle Invasive Urothelial Carcinoma

    PubMed Central

    Lim, Seungtaek; Koh, Myoung Ju; Jeong, Hyeon Joo; Cho, Nam Hoon; Choi, Young Deuk; Cho, Do Yeun; Lee, Hoi Young

    2016-01-01

    Purpose To examine the usefulness of various receptor tyrosine kinase expressions as prognostic markers and therapeutic targets in muscle invasive urothelial cancer (UC) patients. Materials and Methods We retrospectively analyzed the data of 98 patients with muscle invasive UC who underwent radical cystectomy between 2005 and 2010 in Yonsei Cancer Center. Using formalin fixed paraffin embedded tissues of primary tumors, immunohistochemical staining was done for human epidermal growth factor receptor 2 (HER2), fibroblast growth factor receptor 1 (FGFR1), and fibroblast growth factor receptor 3 (FGFR3). Results There were 41 (41.8%), 44 (44.9%), and 14 (14.2%) patients who have over-expressed HER2, FGFR1, and FGFR3, respectively. In univariate analysis, significantly shorter median time to recurrence (TTR) (12.9 months vs. 49.0 months; p=0.008) and overall survival (OS) (22.3 months vs. 52.7 months; p=0.006) was found in patients with FGFR1 overexpression. By contrast, there was no difference in TTR or OS according to the HER2 and FGFR3 expression status. FGFR1 remained as a significant prognostic factor for OS with hazard ratio of 2.23 (95% confidence interval: 1.27–3.90, p=0.006) in multivariate analysis. Conclusion Our result showed that FGFR1 expression, but not FGFR3, is an adverse prognostic factor in muscle invasive UC patients after radical cystectomy. FGFR1 might be feasible for prognosis prediction and a potential therapeutic target after thorough validation in muscle invasive UC. PMID:27189274

  7. The prognostic role of lymphovascular invasion in urothelial carcinoma of the bladder.

    PubMed

    Mathieu, Romain; Lucca, Ilaria; Rouprêt, Morgan; Briganti, Alberto; Shariat, Shahrokh F

    2016-08-01

    Outcome prediction in patients with bladder cancer has improved through the development of nomograms and predictive models. However, integration of further characteristics such as lymphovascular invasion (LVI) might increase the accuracy and clinical utility of these instruments. Assessment and reporting of LVI in specimens from transurethral resection of the bladder tumour (TURBT) or biopsy in patients with non-muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC) might enable improved staging, prognostication and clinical decision-making. In NMIBC, presence of LVI in TURBT and biopsy samples seems to be associated with understaging and increased risks of disease recurrence and progression. In MIBC, presence of LVI is associated with features of aggressive disease and predicts recurrence and survival. Integration of LVI status into predictive models might aid clinical decision-making regarding intravesical instillation schedules and regimens, early radical cystectomy in patients with high-grade T1 disease and perioperative chemotherapy. However, LVI assessment is hampered by insufficient reproducibility and reliability, lack of routine evaluation and limited concordance between findings in TURBT and radical cystectomy specimens. Standardization of the pathological criteria defining LVI is warranted to improve its reporting in routine clinical practice and its utility as a care-changing prognostic marker. PMID:27431340

  8. Complete Laparoscopic Nephroureterectomy for the Upper Urinary Tract Urothelial Carcinoma in a Female Patient with Severe Senile Kyphosis: An Initial Case Report

    PubMed Central

    Miyamoto, Tatsuya; Kira, Satoru; Sawada, Norifumi; Ootake, Yuko; Shimura, Hiroshi; Mitsui, Takahiko; Takeda, Masayuki

    2015-01-01

    Abstract Kyphosis is usually described as the deformity of the spine that results in an abnormally round back. Patients with kyphosis form a challenging group to laparoscopic surgeons because of difficulties in positioning and abdominal approach. The narrow abdomen causes difficulty with trocar insertion and some operative procedures. Here we report the transperitoneal complete laparoscopic nephroureterectomy in a case of kyphosis. An 81-year-old woman underwent this operation for urothelial carcinoma of the upper urinary tract. We took best care of the positioning and the trocar insertion; we could have accomplished utilizing four ports at semilateral position without any troubles and complications. This procedure is safe and feasible, and not thought to be a contraindication for the patients with senile kyphosis.

  9. Long-term oncologic outcomes of laparoscopic nephroureterectomy versus open nephroureterectomy for upper tract urothelial carcinoma: a systematic review and meta-analysis

    PubMed Central

    Zhang, Su; Luo, You; Wang, Cheng; Fu, Sheng-Jun

    2016-01-01

    Background. Several factors have been validated as predictors of disease recurrence in upper tract urothelial carcinoma. However, the oncological outcomes between different surgical approaches (open nephroureterectomy versus laparoscopic nephroureterectomy, ONU vs LNU) remain controversial. Therefore, we performed a meta-analysis to evaluate the oncological outcomes associated with different surgical approaches. Methods. We conducted an electronic search of the PubMed, Embase, ISI Web of Knowledge and Cochrane Library electronic databases through November 2015, screened the retrieved references, collected and evaluated the relevant information. We extracted and synthesized the corresponding hazard ratios (HRs) and 95% confidence intervals (95% CI) using Stata 13. Results. Twenty-one observational studies were eligible for inclusion in the meta-analysis. The results of the meta-analysis showed no differences in the intravesical recurrence-free survival (IRFS), unspecified recurrence-free survival (UnRFS) and overall survival (OS) between LNUandONU. However, improvements in the extravesical recurrence free survival (ExRFS) and cancer specific survival (CSS) were observed inLNU. The pooled hazard ratios were 1.05 (95% CI [0.92–1.18]) for IRFS, 0.80 (95% CI [0.64–0.96]) for ExRFS, 1.10 (95% CI [0.93–1.28]) for UnRFS, 0.91 (95% CI [0.66–1.17]) for OS and 0.79 (95% CI [0.68–0.91]) for CSS. Conclusion. Based on current evidence, LNU could provide equivalent prognostic effects for upper tract urothelial carcinoma, and had better oncological control of ExRFS and CSS compared to ONU. However, considering all eligible studies with the intrinsic bias of retrospective study design, the results should be interpreted with caution. Prospective randomized trials are needed to verify these results. PMID:27280069

  10. Long-term oncologic outcomes of laparoscopic nephroureterectomy versus open nephroureterectomy for upper tract urothelial carcinoma: a systematic review and meta-analysis.

    PubMed

    Zhang, Su; Luo, You; Wang, Cheng; Fu, Sheng-Jun; Yang, Li

    2016-01-01

    Background. Several factors have been validated as predictors of disease recurrence in upper tract urothelial carcinoma. However, the oncological outcomes between different surgical approaches (open nephroureterectomy versus laparoscopic nephroureterectomy, ONU vs LNU) remain controversial. Therefore, we performed a meta-analysis to evaluate the oncological outcomes associated with different surgical approaches. Methods. We conducted an electronic search of the PubMed, Embase, ISI Web of Knowledge and Cochrane Library electronic databases through November 2015, screened the retrieved references, collected and evaluated the relevant information. We extracted and synthesized the corresponding hazard ratios (HRs) and 95% confidence intervals (95% CI) using Stata 13. Results. Twenty-one observational studies were eligible for inclusion in the meta-analysis. The results of the meta-analysis showed no differences in the intravesical recurrence-free survival (IRFS), unspecified recurrence-free survival (UnRFS) and overall survival (OS) between LNUandONU. However, improvements in the extravesical recurrence free survival (ExRFS) and cancer specific survival (CSS) were observed inLNU. The pooled hazard ratios were 1.05 (95% CI [0.92-1.18]) for IRFS, 0.80 (95% CI [0.64-0.96]) for ExRFS, 1.10 (95% CI [0.93-1.28]) for UnRFS, 0.91 (95% CI [0.66-1.17]) for OS and 0.79 (95% CI [0.68-0.91]) for CSS. Conclusion. Based on current evidence, LNU could provide equivalent prognostic effects for upper tract urothelial carcinoma, and had better oncological control of ExRFS and CSS compared to ONU. However, considering all eligible studies with the intrinsic bias of retrospective study design, the results should be interpreted with caution. Prospective randomized trials are needed to verify these results. PMID:27280069

  11. Six-Month Progression-Free Survival as the Primary Endpoint to Evaluate the Activity of New Agents as Second-line Therapy for Advanced Urothelial Carcinoma

    PubMed Central

    Agarwal, Neeraj; Bellmunt, Joaquim; Maughan, Benjamin L.; Boucher, Kenneth M.; Choueiri, Toni K.; Qu, Angela Q.; Vogelzang, Nicholas J.; Fougeray, Ronan; Niegisch, Guenter; Albers, Peter; Wong, Yu-Ning; Ko, Yoo-Joung; Sridhar, Srikala S.; Tantravahi, Srinivas K.; Galsky, Matthew D.; Petrylak, Daniel P.; Vaishampayan, Ulka N.; Mehta, Amitkumar N.; Beer, Tomasz M.; Sternberg, Cora. N.; Rosenberg, Jonathan E.; Sonpavde, Guru

    2014-01-01

    This study examined the association of progression-free survival at 6 months with overall survival in the context of second-line therapy of advanced urothelial carcinoma in pooled patient-level data from 10 phase II trials and then externally validated in a large phase III trial. Progression-free survival at 6 months was significantly correlated with overall survival and is an innovative primary endpoint to evaluate new agents in this setting. Objective Second-line systemic therapy for advanced urothelial carcinoma (UC) has substantial unmet needs, and current agents show dismal activity. Second-line trials of metastatic UC have used response rate (RR) and median progression-free survival (PFS) as primary endpoints, which may not reflect durable benefits. A more robust endpoint to identify signals of durable benefits when investigating new agents in second-line trials may expedite drug development. PFS at 6 months (PFS6) is a candidate endpoint, which may correlate with overall survival (OS) at 12 months (OS12) and may be applicable across cytostatic and cytotoxic agents. Methods Ten second-line phase II trials with individual patient outcomes data evaluating chemotherapy or biologics were combined for discovery, followed by external validation in a phase III trial. The relationship between PFS6/RR and OS12 was assessed at the trial level using Pearson correlation and weighted linear regression, and at the individual level using Pearson chi-square test with Yates continuity correction. Results In the discovery dataset, a significant correlation was observed between PFS6 and OS12 at the trial (R2 = 0.55, Pearson correlation = 0.66) and individual levels (82%, Қ = 0.45). Response correlated with OS12 at the individual level less robustly (78%, Қ = 0.36), and the trial level association was not statistically significant (R2 = 0.16, Pearson correlation = 0.37). The correlation of PFS6 (81%, Қ = 0.44) appeared PMID:24220220

  12. Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted

    PubMed Central

    Langbein, S; Zerilli, M; zur Hausen, A; Staiger, W; Rensch-Boschert, K; Lukan, N; Popa, J; Ternullo, M P; Steidler, A; Weiss, C; Grobholz, R; Willeke, F; Alken, P; Stassi, G; Schubert, P; Coy, J F

    2006-01-01

    Tumours ferment glucose to lactate even in the presence of oxygen (aerobic glycolysis; Warburg effect). The pentose phosphate pathway (PPP) allows glucose conversion to ribose for nucleic acid synthesis and glucose degradation to lactate. The nonoxidative part of the PPP is controlled by transketolase enzyme reactions. We have detected upregulation of a mutated transketolase transcript (TKTL1) in human malignancies, whereas transketolase (TKT) and transketolase-like-2 (TKTL2) transcripts were not upregulated. Strong TKTL1 protein expression was correlated to invasive colon and urothelial tumours and to poor patients outcome. TKTL1 encodes a transketolase with unusual enzymatic properties, which are likely to be caused by the internal deletion of conserved residues. We propose that TKTL1 upregulation in tumours leads to enhanced, oxygen-independent glucose usage and a lactate-based matrix degradation. As inhibition of transketolase enzyme reactions suppresses tumour growth and metastasis, TKTL1 could be the relevant target for novel anti-transketolase cancer therapies. We suggest an individualised cancer therapy based on the determination of metabolic changes in tumours that might enable the targeted inhibition of invasion and metastasis. PMID:16465194

  13. Transthoracic fine-needle aspiration cytology of non-invasive, low-grade urothelial carcinoma with lung metastasis: A case report with review of the literature

    PubMed Central

    Vural, ÇiĞdem; Yildiz, Kürsat; Çabuk, Devrim; Akgül, Asli

    2015-01-01

    Radiological analyses in a 61-year-old patient being followed since 2005 for low-grade, non-invasive urothelial carcinoma (UC) (Ta) revealed a 5-cm pleural-based mass in the lower lobe of the right lung for which a subsequent transthoracic fine-needle aspiration cytology was performed. Upon observing the carcinoma cells consistent with UC metastasis, systemic chemotherapy was commenced. The patient underwent a metastatectomy based on the thoracic computerized tomography scan performed on the 4th month of treatment, which revealed notable regression. The resected tumor was morphologically similar to cells seen in the transthoracic fine-needle aspiration and was immunohistochemically positive for p63, uroplakin, thrombomodulin, CK7 and CK20 at varying degrees but was negative for TTF-1. We report a case of metastatic UC of the lung in a patient who had had a low-grade superficial UC of the urinary bladder and we discuss the cytopathological features of this rare entity in light of the literature. PMID:26229254

  14. The cAMP responsive element binding protein 1 transactivates epithelial membrane protein 2, a potential tumor suppressor in the urinary bladder urothelial carcinoma

    PubMed Central

    Wu, Wen-Ren; Liao, Yu-Jing; Chen, Lih-Ren; Huang, Chun-Nung; Li, Ching-Chia; Li, Wei-Ming; Huang, Hsuan-Ying; Chen, Yi-Ling; Liang, Shih-Shin; Chow, Nan-Haw; Shiue, Yow-Ling

    2015-01-01

    In this study, we report that EMP2 plays a tumor suppressor role by inducing G2/M cell cycle arrest, suppressing cell viability, proliferation, colony formation/anchorage-independent cell growth via regulation of G2/M checkpoints in distinct urinary bladder urothelial carcinoma (UBUC)-derived cell lines. Genistein treatment or exogenous expression of the cAMP responsive element binding protein 1 (CREB1) gene in different UBUC-derived cell lines induced EMP2 transcription and subsequent translation. Mutagenesis on either or both cAMP-responsive element(s) dramatically decreased the EMP2 promoter activity with, without genistein treatment or exogenous CREB1 expression, respectively. Significantly correlation between the EMP2 immunointensity and primary tumor, nodal status, histological grade, vascular invasion and mitotic activity was identified. Multivariate analysis further demonstrated that low EMP2 immunoexpression is an independent prognostic factor for poor disease-specific survival. Genistein treatments, knockdown of EMP2 gene and double knockdown of CREB1 and EMP2 genes significantly inhibited tumor growth and notably downregulated CREB1 and EMP2 protein levels in the mice xenograft models. Therefore, genistein induced CREB1 transcription, translation and upregulated pCREB1(S133) protein level. Afterward, pCREB1(S133) transactivated the tumor suppressor gene, EMP2, in vitro and in vivo. Our study identified a novel transcriptional target, which plays a tumor suppressor role, of CREB1. PMID:25940704

  15. Overexpression of RNF2 Is an Independent Predictor of Outcome in Patients with Urothelial Carcinoma of the Bladder Undergoing Radical Cystectomy

    PubMed Central

    Li, Xiang-Dong; Chen, Si-Liang; Dong, Pei; Chen, Jie-Wei; Wang, Feng-Wei; Guo, Sheng-Jie; Jiang, Li-Juan; Zhou, Fang-Jian; Xie, Dan; Liu, Zhuo-Wei

    2016-01-01

    RNF2 (ring finger protein 2) is frequently overexpressed in several types of human cancer, but the status of RNF2 amplification and expression in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance is unclear. In this study, immunohistochemical analysis and fluorescence in situ hybridization (FISH) were used to examine the expression and amplification of RNF2 in 184 UCB patients after radical cystectomy. Overexpression of RNF2 was observed in 44.0% of UCBs and was found to significantly associate with shortened overall and cancer-specific survival (P < 0.001). In different subsets of UCBs, RNF2 overexpression was also identified as a prognostic indicator in patients with pT1, pT2, pN(−), and/or negative surgical margins (P < 0.05). Importantly, RNF2 overexpression together with pT status and surgical margin status provided significant independent prognostic parameters in multivariate analysis (P < 0.01). FISH results showed amplification of RNF2 in 8/79 (10.1%) of informative UCB cases. Additionally, RNF2 overexpression was significantly associated with RNF2 gene amplification (P = 0.004) and cell proliferation (P = 0.003). These findings suggested that overexpression of RNF2, as examined by immunohistochemical analysis, might serve as a novel prognostic biomarker and potential therapeutic target for UCB patients who undergo radical cystectomy. PMID:26869491

  16. Cyproheptadine exhibits antitumor activity in urothelial carcinoma cells by targeting GSK3β to suppress mTOR and β-catenin signaling pathways.

    PubMed

    Hsieh, Hsiao-Yen; Shen, Cheng-Huang; Lin, Ru-Inn; Feng, Yu-Min; Huang, Shih-Yuan; Wang, Yuan-Hung; Wu, Shu-Fen; Hsu, Cheng-Da; Chan, Michael W Y

    2016-01-01

    Cyproheptadine, a serotonin antagonist, has recently been reported to function as a novel therapeutic agent by inhibiting PI3K/AKT signaling in several human cancers. However, the therapeutic effect of cyproheptadine in urothelial carcinoma (UC) has never been explored. In this study, we determined the effect of cyproheptadine on the growth of five human UC cell lines and an in vivo xenograft model. The results showed that cyproheptadine exerted an inhibitory effect on the proliferation of UC cells both in vitro and in vivo. Cyproheptadine also induced cell cycle arrest in the G1 phase, subsequently followed by apoptosis and necrosis. The underlying mechanisms of cell cycle arrest were associated with the reduction of c-Myc, induction of p21 and p27, and the stabilization of Rb expression. In addition, the suppression of the GSK3β/TSC2/mTOR pathway and deregulation of the GSK3β/β-catenin signaling were observed in cyproheptadine-treated UC cells. Furthermore, cyproheptadine-induced apoptosis was associated with ANGPTL4 expression followed by activation of caspase3 and PARP in UC cells. Our experimental results provide evidence that cyproheptadine is a suitable therapeutic agent for the treatment of UC. PMID:26454215

  17. The cAMP responsive element binding protein 1 transactivates epithelial membrane protein 2, a potential tumor suppressor in the urinary bladder urothelial carcinoma.

    PubMed

    Li, Chien-Feng; Wu, Wen-Jeng; Wu, Wen-Ren; Liao, Yu-Jing; Chen, Lih-Ren; Huang, Chun-Nung; Li, Ching-Chia; Li, Wei-Ming; Huang, Hsuan-Ying; Chen, Yi-Ling; Liang, Shih-Shin; Chow, Nan-Haw; Shiue, Yow-Ling

    2015-04-20

    In this study, we report that EMP2 plays a tumor suppressor role by inducing G2/M cell cycle arrest, suppressing cell viability, proliferation, colony formation/anchorage-independent cell growth via regulation of G2/M checkpoints in distinct urinary bladder urothelial carcinoma (UBUC)-derived cell lines. Genistein treatment or exogenous expression of the cAMP responsive element binding protein 1 (CREB1) gene in different UBUC-derived cell lines induced EMP2 transcription and subsequent translation. Mutagenesis on either or both cAMP-responsive element(s) dramatically decreased the EMP2 promoter activity with, without genistein treatment or exogenous CREB1 expression, respectively. Significantly correlation between the EMP2 immunointensity and primary tumor, nodal status, histological grade, vascular invasion and mitotic activity was identified. Multivariate analysis further demonstrated that low EMP2 immunoexpression is an independent prognostic factor for poor disease-specific survival. Genistein treatments, knockdown of EMP2 gene and double knockdown of CREB1 and EMP2 genes significantly inhibited tumor growth and notably downregulated CREB1 and EMP2 protein levels in the mice xenograft models. Therefore, genistein induced CREB1 transcription, translation and upregulated pCREB1(S133) protein level. Afterward, pCREB1(S133) transactivated the tumor suppressor gene, EMP2, in vitro and in vivo. Our study identified a novel transcriptional target, which plays a tumor suppressor role, of CREB1. PMID:25940704

  18. [A Case Report of Suspected Tuberculous Granuloma in the Kidney after BCG Perfusion Therapy for Urothelial Carcinoma of the Renal Pelvis].

    PubMed

    Kobayashi, Shin; Hori, Junichi; Okazaki, Satoshi; Hashizume, Kazumi; Watanabe, Masaki; Wada, Naoki; Kita, Masafumi; Azumi, Makoto; Iwata, Tatsuya; Matsumoto, Seiji; Kakizaki, Hidehiro

    2016-01-01

    A 66-year-old male patient was referred to our hospital for bilateral renal pelvic tumors. Ureteroscopic biopsy revealed urothelial carcinoma (UC) of low grade (G1) of the renal pelvis. Renal sparing treatment with systemic chemotherapy and percutaneous tumor resection was performed. However, during subsequent follow up, a recurrent tumor was found on the left ureter. After ureteroscopic laser ablation of the tumor, Bacillus Calmette-Guerin (BCG) perfusion therapy (once a week, total 6 weeks) was performed via a single J ureteral catheter with no adverse events. Later, another recurrent recurrence was found on the right ureter, and was managed by ureteroscopic laser ablation followed by BCG perfusion therapy via a single J ureteral catheter. However, the patient developed high fever with chill from the day after initial BCG perfusion therapy on the right side. Although we started antibiotics, high fever continued. Then antituberculous drugs were administered and his condition was improved. Computed tomographic scan revealed a right renal mass 57 mm in diameter, which was consistent with tuberculous granuloma. The tuberculous granuloma persisted despite the continuation of anti-tuberculous drugs. In exceptional cases of upper tract UC such as single kidney and bilateral tumor, BCG perfusion therapy has been used as adjunctive treatment to cure or prevent UC. However, dosages and administration methods of BCG perfusion therapy for upper tract UC still remain to be standardized. Serious adverse events after BCG perfusion therapy require prompt and proper management including the use of anti-tuberculous drugs. PMID:26932332

  19. A panel of tumor markers, calreticulin, annexin A2, and annexin A3 in upper tract urothelial carcinoma identified by proteomic and immunological analysis

    PubMed Central

    2014-01-01

    Background Upper tract urothelial carcinoma (UTUC) is a tumor with sizable metastases and local recurrence. It has a worse prognosis than bladder cancer. This study was designed to investigate the urinary potential tumor markers of UTUC. Methods Between January 2008 and January 2009, urine was sampled from 13 patients with UTUC and 20 healthy adults. The current study identified biomarkers for UTUC using non-fixed volume stepwise weak anion exchange chromatography for fractionation of urine protein prior to two-dimensional gel electrophoresis. Results Fifty five differential proteins have been determined by comparing with the 2-DE maps of the urine of UTUC patients and those of healthy people. Western blotting analysis and immunohistochemistry of tumor tissues and normal tissues from patients with UTUC were carried out to further verify five possible UTUC biomarkers, including zinc-alpha-2-glycoprotein, calreticulin, annexin A2, annexin A3 and haptoglobin. The data of western blot and immunohistochemical analysis are consistent with the 2-DE data. Combined the experimental data in the urine and in tumor tissues collected from patients with UTUC, the crucial over-expressed proteins are calreticulin, annexin A2, and annexin A3. Conclusions Calreticulin, annexin A2, and annexin A3 are very likely a panel of biomarkers with potential value for UTUC diagnosis. PMID:24884814

  20. Methylomics analysis identifies ZNF671 as an epigenetically repressed novel tumor suppressor and a potential non-invasive biomarker for the detection of urothelial carcinoma

    PubMed Central

    Hsieh, Hsiao-Yen; Jou, Yeong-Chin; Lin, Chang-Te; Tsai, Ming-Hsuan; Huang, Wen-Yu; Wang, Yi-Ting; Lin, Ru-Inn; Chen, Szu-Shan; Tung, Chun-Liang; Wu, Shu-Fen; Chang, De-Ching; Shen, Cheng-Huang; Hsu, Cheng-Da

    2015-01-01

    The molecular mechanism underlying the lethal phenomenon of urothelial carcinoma (UC) tumor recurrence remains unresolved. Here, by methylation microarray, we identified promoter methylation of the zinc-finger protein gene, ZNF671 in bladder UC tumor tissue samples, a finding that was independently validated by bisulphite pyrosequencing in cell lines and tissue samples. Subsequent assays including treatment with epigenetic depressive agents and in vitro methylation showed ZNF671 methylation to result in its transcriptional repression. ZNF671 re-expression in UC cell lines, via ectopic expression, inhibited tumor growth and invasion, in possible conjunction with downregulation of cancer stem cell markers (c-KIT, NANOG, OCT4). Clinically, high ZNF671 methylation in UC tumor tissues (n=96; 63 bladder, 33 upper urinary tract) associated with tumor grade and poor locoregional disease-free survival. Quantitative MSP analysis in a training (n=97) and test (n=61) sets of voided urine samples from bladder UC patients revealed a sensitivity and specificity of 42%-48% and 89%-92.8%, respectively, for UC cancer detection. Moreover, combining DNA methylation of ZNF671 and 2 other genes (IRF8 and sFRP1) further increased the sensitivity to 96.2%, suggesting a possible three-gene UC biomarker. In summary, ZNF671, an epigenetically silenced novel tumor suppressor, represents a potential predictor for UC relapse and non-invasive biomarker that could assist in UC clinical decision-making. PMID:26320192

  1. Evolving Immunotherapy Strategies in Urothelial Cancer

    PubMed Central

    Brancato, Sam J.; Lewi, Keidren; Agarwal, Piyush K.

    2016-01-01

    The treatment of nonmuscle-invasive urothelial carcinoma with bacillus Calmette-Guérin (BCG) represents the importance of immunotherapy in the treatment of cancer. Despite its clinical efficacy, up to 30% of patients will ultimately experience progression to muscle-invasive disease. This, along with an improved understanding of the biologic pathways involved, has led to efforts to improve, enhance, or alter the immune response in the treatment of urothelial carcinoma. A number of novel therapeutic approaches currently are being pursued, including recombinant BCG to induce T helper type 1 (Th1) immune responses, nonlive Mycobacterium agents, targeted agents toward cancer-associated antigens, immune-modulating vaccines, and adoptive T-cell therapies. Here, we review the current and future immunotherapy treatment options for patients with urothelial cancer. PMID:25993187

  2. Loss of expression of the SWI/SNF complex is a frequent event in undifferentiated/dedifferentiated urothelial carcinoma of the urinary tract.

    PubMed

    Agaimy, Abbas; Bertz, Simone; Cheng, Liang; Hes, Ondrej; Junker, Kerstin; Keck, Bastian; Lopez-Beltran, Antonio; Stöckle, Michael; Wullich, Bernd; Hartmann, Arndt

    2016-09-01

    Loss of the SWI/SNF chromatin remodeling complex has been recently implicated in the pathogenesis of dedifferentiated carcinomas from different organs, but its possible role in undifferentiated urothelial carcinoma (UC) has not been studied to date. In this study, we analyzed by immunohistochemistry 14 undifferentiated UCs (11 from bladder and 3 from renal pelvis) with a nondescript anaplastic or rhabdoid morphology, using commercially available antibodies against the SWI/SNF components SMARCB1 (INI1), SMARCA2, SMARCA4, SMARCC1, SMARCC2, and ARID1A. Patients were eight females and six males aged 40 to 84 years (median, 65). All tumors were muscle-invasive (9 were T3-4). A conventional UC component was seen in eight cases and varied from in situ to papillary. The undifferentiated component comprised 60-100 % of the tumors. Histologically, most tumors showed diffuse dyscohesive or pseudoalveolar growth of variably sized cells with frequent rhabdoid features. Transition from conventional to undifferentiated UC was abrupt, except in one case. The undifferentiated component almost always expressed pan-cytokeratin AE1/AE3 (13/14) and variably vimentin (8/14) and GATA3 (9/14). Complete loss of at least one SWI/SNF subunit limited to the undifferentiated component was detected in 10/14 cases (71 %). SMARCA2 was most frequently lost (six) followed by ARID1A (four), SMARCB1/INI1 (two), SMARCA4 (one), and SMARCC1 (one). This is the first study exploring SWI/SNF expression in undifferentiated UC of the urinary tract. Our results are in line with recent studies reporting involvement of the SWI/SNF complex in the dedifferentiation process of a variety of epithelial neoplasms in different organs, including the urinary tract, and association with aggressive clinical course. PMID:27339451

  3. Cyclosporine A and tacrolimus inhibit urothelial tumorigenesis.

    PubMed

    Kawahara, Takashi; Kashiwagi, Eiji; Li, Yi; Zheng, Yichun; Miyamoto, Yurina; Netto, George J; Ishiguro, Hitoshi; Miyamoto, Hiroshi

    2016-02-01

    The functional role of nuclear factor of activated T-cells (NFAT), while it has been extensively investigated in the immune system, remains uncertain in bladder cancer development. We here aim to assess the effects of cyclosporine A (CsA) and tacrolimus (FK506), immunosuppressants known to specifically inactivate the NFAT pathway in immune cells, on neoplastic transformation of urothelial cells. Immunohistochemistry revealed that the expression levels of NFATc1, a NFAT isoform shown to function as an oncogene in a sarcoma model, were elevated in urothelial neoplasms, compared with non-neoplastic urothelial tissues, and in low-grade and high-grade papillary urothelial carcinomas, compared with papillary urothelial neoplasms of low malignant potential. In an immortalized normal urothelial cell line SVHUC, CsA and FK506 reduced NFATc1 expression, NFAT transcriptional activity, and the expression of c-myc, a downstream target of NFATc1 signals. Treatment with CsA or FK506 in the SVHUC cells undergoing neoplastic transformation induced by exposure to a chemical carcinogen 3-methylcholanthrene resulted in strong inhibition in colony formation in vitro as well as tumor formation in NOD-SCID mice. CsA and FK506 were additionally found to up-regulate the expression of several molecules that play a protective role in bladder tumorigenesis, including p53, p21, and p27, and down-regulate that of oncogenic genes, such as cyclin D1, cyclin D3, and cyclin E, in SVHUC cells with the carcinogen challenge. Thus, CsA and FK506 likely inhibit urothelial tumorigenesis. These findings offer a potential chemopreventive approach for urothelial tumors using NFAT inhibitors. PMID:25594762

  4. The expression of ERCC1 and BRCA1 predicts prognosis of platinum-based chemotherapy in urothelial cancer

    PubMed Central

    Song, Wenhui; Ma, Hongshun

    2016-01-01

    Objective To investigate the expression and clinical significance of ERCC1 and BRCA1 genes in urothelial cancer patients. Methods Forty-two urothelial cancer patients who did not receive platinum-based chemotherapy during January 2009 to May 2013 were enrolled. The expression levels of ERCC1 and BRCA1 were determined by immunohistochemistry and the median survival time (MST) for these patients was calculated. Results ERCC1-positive patients who received oxaliplatin-based chemotherapy had a shorter MST than ERCC1-negative patients (P<0.05), whereas there is no difference of MST between BRCA1-positive and -negative patients. Furthermore, MST in ERCC1 and BRCA1 double-positive patients was shorter than ERCC1 and BRCA1 double-negative patients (P<0.05). The positive expression of ERCC1 had a significant positive correlation with BRCA1 (r=0.313, P=0.044). Conclusion The expression level of ERCC1 may be used as a prognostic marker for urothelial cancer patients who received postoperative adjuvant chemotherapy. PMID:27366083

  5. Factors predictive of survival in ampullary carcinoma.

    PubMed Central

    Howe, J R; Klimstra, D S; Moccia, R D; Conlon, K C; Brennan, M F

    1998-01-01

    OBJECTIVE: To review the recent Memorial Sloan-Kettering Cancer Center experience with adenocarcinoma of the ampulla of Vater and to identify clinicopathologic factors that have an impact on patient survival. SUMMARY BACKGROUND DATA: The prognosis for patients with tumors of the ampulla of Vater is improved relative to other periampullary neoplasms. Identification of independent prognostic factors in ampullary tumors has been limited by small numbers of tumors and a lack of pathologic review. METHODS: Data were collected prospectively for patients presenting with periampullary carcinomas to the Memorial Sloan-Kettering Cancer Center between October 15, 1983 and June 30, 1995. The correlation between clinicopathologic variables and survival of ampullary carcinoma was tested by the Kaplan-Meier method and log-rank test, and Cox proportional hazards regression. Survival of patients with periampullary adenocarcinomas was compared by the Kaplan-Meier method. RESULTS: In 123 patients presenting with ampullary carcinoma, 101 tumors (82.1%) were resected. Factors significantly correlated with improved survival were resection (p < 0.01), and in resected tumors, negative nodes (p = 0.04) and margins (p = 0.02) independently predicted for improved survival. In periampullary tumors, the highest rates of resection and overall survival (median, 43.6 months) were found in ampullary carcinomas. CONCLUSIONS: Factors predictive of improved survival in ampullary carcinoma include resection, negative margins, and negative nodes. Improved overall survival in ampullary relative to periampullary adenocarcinoma is due in part to a significantly higher rate of resection. Images Figure 1. PMID:9671071

  6. Protein expression and amplification of AIB1 in human urothelial carcinoma of the bladder and overexpression of AIB1 is a new independent prognostic marker of patient survival.

    PubMed

    Luo, Jun-Hang; Xie, Dan; Liu, Meng-Zhong; Chen, Wei; Liu, Yong-Dong; Wu, Guo-Qing; Kung, Hsiang-Fu; Zeng, Yi-Xin; Guan, Xin-Yuan

    2008-06-01

    AIB1, a candidate oncogene in human breast cancer, is frequently amplified and overexpressed in several types of human cancers, but the status of AIB1 amplification and expression in urothelial carcinoma of the bladder (UC) and its clinical/prognostic significance is unclear. In our study, the methods of immunohistochemistry and fluorescence in situ hybridization were utilized to examine protein expression and amplification of AIB1 in 163 primary UCs and in 30 samples of normal bladder mucosa. Overexpression of AIB1 and amplification of AIB1 was found in 32.5 and 7.0% of UCs, respectively. In univariate survival analysis of the UC cohorts, a highly significant association of overexpression of AIB1 with shortened patient survival (mean: 45.6 months vs. 59.0 months, p < 0.001, log rank test) was demonstrated. In different subsets of UC patients, overexpression of AIB1 was also a prognostic indicator in grade 1 (p = 0.007), grade 2 (p = 0.010) and grade 3 (p = 0.015) tumor patients, and in pTa (p = 0.025), pT2-4 (p = 0.004), pN0 (p < 0.001) and pT2-4/pN0 (p = 0.040) tumor patients. Importantly, AIB1 expression (p < 0.001) together with pT and pN status (p < 0.05) provided significant independent prognostic parameters in multivariate analysis. In addition, a significant correlation (p < 0.05) of overexpression of AIB1 with an increased UC labeling index of Ki-67 (a cell proliferation marker) was observed in these UCs. Thus, these findings provide evidence that an overexpression of AIB1, as detected by immunohistochemistry, is an independent molecular marker for poor prognosis (shortened survival time) of patients with UC. PMID:18246597

  7. The small conductance calcium-activated potassium channel 3 (SK3) is a molecular target for Edelfosine to reduce the invasive potential of urothelial carcinoma cells.

    PubMed

    Steinestel, Konrad; Eder, Stefan; Ehinger, Konstantin; Schneider, Juliane; Genze, Felicitas; Winkler, Eva; Wardelmann, Eva; Schrader, Andres J; Steinestel, Julie

    2016-05-01

    Metastasis is the survival-determining factor in urothelial carcinoma (UC) of the urinary bladder. The small conductance calcium-activated potassium channel 3 (SK3) enhances tumor cell invasion in breast cancer and malignant melanoma. Since Edelfosine, a glycerophospholipid with antitumoral properties, effectively inhibits SK3 channel activity, our goal was to evaluate SK3 as a potential molecular target to inhibit the gain of an invasive phenotype in UC. SK3 protein expression was analyzed in 208 tissue samples and UC cell lines. Effects of Edelfosine on SK3 expression and intracellular calcium levels as well as on cell morphology, cell survival and proliferation were assessed using immunoblotting, potentiometric fluorescence microscopy, and clonogenic/cell survival assay; furthermore, we analyzed the effect of Edelfosine and SK3 RNAi knockdown on tumor cell migration and invasion in vitro and in vivo. We found that SK3 is strongly expressed in muscle-invasive UC and in the RT112 cellular tumor model. Higher concentrations of Edelfosine have a strong antitumoral effect on UC cells, while 1 μM effectively inhibits migration/invasion of UC cells in vitro and in vivo comparable to the SK3 knockdown phenotype. Taken together, our results show strong expression of SK3 in muscle-invasive UC, consistent with the postulated role of the protein in tumor cell invasion. Edelfosine is able to effectively inhibit migration and invasion of UC cells in vitro and in vivo in an SK3-dependent way, pointing towards a possible role for Edelfosine as an antiinvasive drug to effectively inhibit UC cell invasion and metastasis. PMID:26619845

  8. The effect of cigarette smoke and arsenic exposure on urothelial carcinoma risk is modified by glutathione S-transferase M1 gene null genotype

    SciTech Connect

    Chung, Chi-Jung; Huang, Chao-Yuan; Pu, Yeong-Shiau; Shiue, Horng-Sheng; Su, Chien-Tien; Hsueh, Yu-Mei

    2013-01-15

    Inter-individual variation in the metabolism of xenobiotics, caused by factors such as cigarette smoking or inorganic arsenic exposure, is hypothesized to be a susceptibility factor for urothelial carcinoma (UC). Therefore, our study aimed to evaluate the role of gene–environment interaction in the carcinogenesis of UC. A hospital-based case–control study was conducted. Urinary arsenic profiles were measured using high-performance liquid chromatography–hydride generator-atomic absorption spectrometry. Genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism technique. Information about cigarette smoking exposure was acquired from a lifestyle questionnaire. Multivariate logistic regression was applied to estimate the UC risk associated with certain risk factors. We found that UC patients had higher urinary levels of total arsenic, higher percentages of inorganic arsenic (InAs%) and monomethylarsonic acid (MMA%) and lower percentages of dimethylarsinic acid (DMA%) compared to controls. Subjects carrying the GSTM1 null genotype had significantly increased UC risk. However, no association was observed between gene polymorphisms of CYP1A1, EPHX1, SULT1A1 and GSTT1 and UC risk after adjustment for age and sex. Significant gene–environment interactions among urinary arsenic profile, cigarette smoking, and GSTM1 wild/null polymorphism and UC risk were observed after adjustment for potential risk factors. Overall, gene–environment interactions simultaneously played an important role in UC carcinogenesis. In the future, large-scale studies should be conducted using tag-SNPs of xenobiotic-metabolism-related enzymes for gene determination. -- Highlights: ► Subjects with GSTM1 null genotype had significantly increased UC risk. ► UC patients had poor arsenic metabolic ability compared to controls. ► GSTM1 null genotype may modify arsenic related UC risk.

  9. Activity of CEP-9722, a poly (ADP-ribose) polymerase inhibitor, in urothelial carcinoma correlates inversely with homologous recombination repair response to DNA damage.

    PubMed

    Jian, Weiguo; Xu, Hua-Guo; Chen, Jianfeng; Xu, Zhi-Xiang; Levitt, Jonathan M; Stanley, Jennifer A; Yang, Eddy S; Lerner, Seth P; Sonpavde, Guru

    2014-09-01

    As loss of DNA-repair proteins is common in urothelial carcinoma (UC), a rationale can be made to evaluate the activity of poly (ADP-ribose) polymerase (PARP) inhibitors to exploit synthetic lethality. We aimed to preclinically evaluate a PARP inhibitor, CEP-9722, and its active metabolite, CEP-8983, in UC. The activity of CEP-8983 was evaluated using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay against human UC cell lines. Flow cytometry, COMET assay, and western blot were performed to assess apoptosis, DNA damage, and DNA-repair proteins, respectively. RT4 xenografts received placebo or CEP-9722 (100 or 200 mg/kg/day) orally. Xenografts were subjected to immunohistochemistry for apoptosis [cleaved caspase (cc)-3] and angiogenesis (CD31). CEP-8983 (1 μmol/l) reduced the viability of RT4 and T24 cells by 20%, but did not reduce the viability of 5637 and TCC-SUP cells. Apoptosis and necrosis occurred in 9.7 and 9.1% of RT4 and 5637 cells, respectively. RT4 cells showed greater DNA damage compared with 5637 cells. Increased DNA damage occurred with combination versus CEP-8983 or cisplatin alone in RT4 and 5637 cells. T24 and RT4 showed the least RAD51 foci 8 h following radiation, whereas TCC-SUP and 5637 robustly induced RAD51 foci. CEP-9722 showed dose-dependent antitumor activity in RT4 xenografts; 200 mg/kg daily was better than control (P=0.04) and 100 mg/kg was not (P=0.26). Immunohistochemistry of xenografts showed a significant increase in cc-3 and decrease in CD31 with both doses (P<0.05). Biomarker-driven evaluation of PARP inhibitors in UC is justified as the activity of CEP-9722 correlated inversely with homologous recombination repair response to DNA damage. PMID:24714082

  10. MLN4924, a novel protein neddylation inhibitor, suppresses proliferation and migration of human urothelial carcinoma: In vitro and in vivo studies.

    PubMed

    Kuo, Kuan Lin; Ho, I Lin; Shi, Chung Sheng; Wu, June Tai; Lin, Wei Chou; Tsai, Yu Chieh; Chang, Hong Chiang; Chou, Chien Tso; Hsu, Chen Hsun; Hsieh, Ju Ton; Chang, Shih Chen; Pu, Yeong Shiau; Huang, Kuo How

    2015-07-28

    MLN4924, a small molecule inhibitor of NEDD8 activating enzyme (NAE), has been reported to elicit an anti-tumor effect on various malignancies. In this study, we investigated the anti-tumor effect of MLN4924 in human urothelial carcinoma (UC) in vitro and in vivo by using three human UC cell lines of various grading (T24, NTUB1 and RT4). The impact of MLN4924 on UC cells was determined by measuring viability (MTT), proliferation (BrdU incorporation), cell cycle progression (flow cytometry with propidium iodide staining) and apoptosis (flow cytometry with annexin V-FITC labeling). The cell cycle regulatory molecules, apoptosis-related molecules, and cell stress-related proteins were examined by Western blotting. The influence of tumor cell migration and invasion was analyzed by Transwell and wound healing assays. We also evaluated the effects of MLN4924 on tumor growth by a SCID xenograft mouse model. The data show that MLN4924 induced dose-dependent cytotoxicity, anti-proliferation, anti-migration, anti-invasion and apoptosis in human UC cells, accompanied by activations of Bad, phospho-histone H2A.X, caspase-3, 7 and PARP, decreased level of phospho-Bcl2, and caused cell cycle retardation at the G2M phase. Moreover, MLN4924 activated endoplasmic reticulum stress-related molecules (caspase-4, phospho-eIF2α, ATF-4 and CHOP) and other stress responses (JNK and c-Jun activations). Finally, we confirmed MLN4924 inhibited tumor growth in a UC xenograft mouse model with minimal general toxicity. We concluded that MLN4924 induces apoptosis and cell cycle arrest, as well as activation of cell stress responses in human UC. These findings imply MLN4924 provides a novel strategy for the treatment of UC. PMID:25615422

  11. Maintenance monotherapy with Gemcitabine following cisplatin-based primary combination chemotherapy in surgically treated advanced urothelial carcinoma: A matched-pair single institution analysis

    PubMed Central

    KALOGIROU, CHARIS; SVISTUNOV, ANDREY; KREBS, MARKUS; LAUSENMEYER, EVA MARIA; VERGHO, DANIEL; RIEDMILLER, HUBERTUS; KOCOT, ARKADIUS

    2016-01-01

    The role of maintenance therapy with Gemcitabine (GEM) following cisplatin-based combination chemotherapy (CBCC) in patients with surgically treated advanced urothelial carcinoma (UC) remains to be fully elucidated. In the present case control study, a retrospective analysis was performed to evaluate the role of GEM monotherapy following surgical intervention for advanced UC. Between 1999 and 2013, 38 patients were identified with surgically treated advanced UC after having completed CBCC, who were additionally treated quarterly with two consecutive GEM (1,250 mg/m2) infusions as maintenance therapy. This collective was matched by propensity score matching to a control collective (n=38) that received primary CBCC alone, and the overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS) rates were determined for the two collectives using Kaplan-Meier estimates and the log-rank test. Regression analysis was performed using the Cox proportional hazards model. The median follow-up time was 37 months (interquartile range: 9–148). Interestingly, patients treated with GEM following primary chemotherapy had a significantly improved outcome with respect to the 5-year OS (46.2 vs. 26.4%, P=0.0314) and 5-year CSS (61.3 vs. 33.4%, P=0.0386) rates. Notably, the 5-year PFS rate did not differ between the two groups (10.3 vs. 16.1%, P=0.134). It is proposed that additional GEM maintenance monotherapy is able to improve survival rates following primary CBCC in surgically treated patients with advanced UC, suggesting a possible treatment option for patients with, e.g., unclear disease status, or those who would require an active maintenance therapy in the future. Prospective studies should further determine the impact of GEM monotherapy with respect to PFS rates in groups comprising larger numbers of patients. PMID:27073682

  12. Polymorphisms of human 8-oxoguanine DNA glycosylase 1 and 8-hydroxydeoxyguanosine increase susceptibility to arsenic methylation capacity-related urothelial carcinoma.

    PubMed

    Huang, Chao-Yuan; Pu, Yeong-Shiau; Shiue, Horng-Sheng; Chen, Wei-Jen; Lin, Ying-Chin; Hsueh, Yu-Mei

    2016-08-01

    Arsenic causes oxidative stress in cultured animal and human cells, and it is a well-documented human carcinogen. We conducted a hospital-based case-control study including 167 cases of urothelial carcinoma (UC) and 334 age- and gender-matched healthy controls to evaluate the relationships between urinary arsenic profiles, urinary 8-hydroxydeoxyguanosine (8-OHdG) levels, and human 8-oxoguanine DNA glycosylase (hOGG1) genotypes and UC. The urinary arsenic species were analyzed by high-performance liquid chromatography and hydride generator-atomic absorption spectrometry. Genotyping for hOGG1 (Ser326Cys) and hOGG1 (-15C>G) was performed using the Sequenom MassARRAY platform with iPLEX Gold chemistry. Urinary 8-OHdG was measured with high-sensitivity enzyme-linked immunosorbent assay kits. The results indicated that the hOGG1 326 Cys/Cys genotype and the hOGG1 -15C>G G/G genotype were associated with an increased risk of UC (OR [95 % CI] 1.57 [1.04-2.35] and 1.57 [1.04-2.35], respectively). Participants with high urinary total arsenic, regardless of the haplotype of hOGG1 Ser326Cys and the -15C>G polymorphism, had significantly higher urinary 8-OHdG compared to participants with low urinary total arsenic. This is the first study to investigate the joint effects of high urinary total arsenic or inefficient arsenic methylation capacity indices, and the high-risk G-G haplotype of hOGG1 on the risk of UC. The findings are especially meaningful for participants with risk factors such as high urinary total arsenic, inefficient arsenic methylation indices, high urinary 8-OHdG, and the high-risk G-G haplotype of hOGG1 which are all associated with an increased UC risk. PMID:26359225

  13. Radical cystectomy versus bladder preserving therapy for muscle-invasive urothelial carcinoma: examining confounding and misclassification bias in cancer observational comparative effectiveness research

    PubMed Central

    Bekelman, Justin E.; Handorf, Elizabeth A.; Guzzo, Thomas; Pollack, Craig Evan; Christodouleas, John; Resnick, Matthew J.; Swisher-McClure, Samuel; Vaughn, David; Have, Thomas Ten; Polsky, Daniel; Mitra, Nandita

    2013-01-01

    Objectives Radical cystectomy (RC) is the standard treatment for muscle-invasive Urothelial carcinoma of the bladder (UCB). Tri-modality bladder preserving therapy (BPT) is an alternative to RC, but randomized comparisons of RC versus BPT have proven infeasible. To compare RC versus BPT, we undertook an observational cohort study using registry and administrative claims data from the SEER-Medicare database. Methods We identified patients age 65 years or older diagnosed between 1995 and 2005 who received RC (n=1,426) or BPT (n=417). We examined confounding and stage misclassification in the comparison of RC and BPT using multivariable adjustment, propensity score-based adjustment, instrumental variable (IV) analysis and simulations. Results Patients who received BPT were older and more likely to have comorbid disease. After propensity score adjustment, BPT was associated with an increased hazard of death from any cause (HR 1.26; 95% CI, 1.05 – 1.53) and from bladder cancer (HR 1.31; 95% CI, 0.97 – 1.77). Using the local area cystectomy rate as an instrument, IV analysis demonstrated no differences in survival between BPT and RC (death from any cause HR 1.06; 95% CI, 0.78 – 1.31; death from bladder cancer HR 0.94; 95% CI, 0.55 – 1.18). Simulation studies for stage misclassification yielded results consistent with the IV analysis. Conclusions Survival estimates in an observational cohort of patients who underwent RC versus BPT differ by analytic method. Multivariable and propensity score adjustment revealed greater mortality associated with BPT relative to RC, while IV analysis and simulation studies suggest that the two treatments are associated with similar survival outcomes. PMID:23796296

  14. [Analgesics and laxatives as risk factors for cancer in the efferent urinary tract--results of the Berlin Urothelial Carcinoma Study].

    PubMed

    Bronder, E; Klimpel, A; Helmert, U; Greiser, E; Molzahn, M; Pommer, W

    1999-01-01

    A retrospective case-control study (1990-1995), the Berlin Urothelial Cancer Study (BUS), examined analgesics and laxatives as risks for the induction of urothelial cancer in renal pelvis, ureter and bladder. Especially for renal pelvis cancer could observe substance and dose specific risk of compound analgesics. The analgesic substances Phenacetin, Paracetamol, Acetylsalicylic acid (ASA) and Pyrazolones were assessed. Besides a risk of contact laxatives (chemical or anthranoide ingredients) for urothelial cancer was found, not yet described. The highest risk shows the anthranoide plant Senna. Thus this study confirms the risk of specific analgesic ingredients and found an evidence for a new risk of contact laxatives. As both, analgesics and contact laxatives, are typical OTC--("Over the counter") products, a severe controlling is demanded and for laxatives further studies are needed. PMID:10436491

  15. Comparative Gene Expression Analyses Identify Luminal and Basal Subtypes of Canine Invasive Urothelial Carcinoma That Mimic Patterns in Human Invasive Bladder Cancer.

    PubMed

    Dhawan, Deepika; Paoloni, Melissa; Shukradas, Shweta; Choudhury, Dipanwita Roy; Craig, Bruce A; Ramos-Vara, José A; Hahn, Noah; Bonney, Patty L; Khanna, Chand; Knapp, Deborah W

    2015-01-01

    More than 160,000 people are expected to die from invasive urothelial carcinoma (iUC) this year worldwide. Research in relevant animal models is essential to improving iUC management. Naturally-occurring canine iUC closely resembles human iUC in histopathology, metastatic behavior, and treatment response, and could provide a relevant model for human iUC. The molecular characterization of canine iUC, however, has been limited. Work was conducted to compare gene expression array results between tissue samples from iUC and normal bladder in dogs, with comparison to similar expression array data from human iUC and normal bladder in the literature. Considerable similarities between enrichment patterns of genes in canine and human iUC were observed. These included patterns mirroring basal and luminal subtypes initially observed in human breast cancer and more recently noted in human iUC. Canine iUC samples also exhibited enrichment for genes involved in P53 pathways, as has been reported in human iUC. This is particularly relevant as drugs targeting these genes/pathways in other cancers could be repurposed to treat iUC, with dogs providing a model to optimize therapy. As part of the validation of the results and proof of principal for evaluating individualized targeted therapy, the overexpression of EGFR in canine bladder iUC was confirmed. The similarities in gene expression patterns between dogs and humans add considerably to the value of naturally-occurring canine iUC as a relevant and much needed animal model for human iUC. Furthermore, the finding of expression patterns that cross different pathologically-defined cancers could allow studies of dogs with iUC to help optimize cancer management across multiple cancer types. The work is also expected to lead to a better understanding of the biological importance of the gene expression patterns, and the potential application of the cross-species comparisons approach to other cancer types as well. PMID:26352142

  16. Comparative Gene Expression Analyses Identify Luminal and Basal Subtypes of Canine Invasive Urothelial Carcinoma That Mimic Patterns in Human Invasive Bladder Cancer

    PubMed Central

    Dhawan, Deepika; Paoloni, Melissa; Shukradas, Shweta; Choudhury, Dipanwita Roy; Craig, Bruce A.; Ramos-Vara, José A.; Hahn, Noah; Bonney, Patty L.; Khanna, Chand; Knapp, Deborah W.

    2015-01-01

    More than 160,000 people are expected to die from invasive urothelial carcinoma (iUC) this year worldwide. Research in relevant animal models is essential to improving iUC management. Naturally-occurring canine iUC closely resembles human iUC in histopathology, metastatic behavior, and treatment response, and could provide a relevant model for human iUC. The molecular characterization of canine iUC, however, has been limited. Work was conducted to compare gene expression array results between tissue samples from iUC and normal bladder in dogs, with comparison to similar expression array data from human iUC and normal bladder in the literature. Considerable similarities between enrichment patterns of genes in canine and human iUC were observed. These included patterns mirroring basal and luminal subtypes initially observed in human breast cancer and more recently noted in human iUC. Canine iUC samples also exhibited enrichment for genes involved in P53 pathways, as has been reported in human iUC. This is particularly relevant as drugs targeting these genes/pathways in other cancers could be repurposed to treat iUC, with dogs providing a model to optimize therapy. As part of the validation of the results and proof of principal for evaluating individualized targeted therapy, the overexpression of EGFR in canine bladder iUC was confirmed. The similarities in gene expression patterns between dogs and humans add considerably to the value of naturally-occurring canine iUC as a relevant and much needed animal model for human iUC. Furthermore, the finding of expression patterns that cross different pathologically-defined cancers could allow studies of dogs with iUC to help optimize cancer management across multiple cancer types. The work is also expected to lead to a better understanding of the biological importance of the gene expression patterns, and the potential application of the cross-species comparisons approach to other cancer types as well. PMID:26352142

  17. Neoadjuvant Intravesical Vaccine Therapy in Treating Patients With Bladder Carcinoma Who Are Undergoing Cystectomy

    ClinicalTrials.gov

    2014-12-22

    Bladder Adenocarcinoma; Bladder Squamous Cell Carcinoma; Bladder Urothelial Carcinoma; Recurrent Bladder Carcinoma; Stage I Bladder Cancer; Stage II Bladder Cancer; Stage III Bladder Cancer; Stage IV Bladder Cancer

  18. Predictors of Intravesical Recurrence After Radical Nephroureterectomy for Upper Urinary Tract Urothelial Carcinoma: An Inflammation-Based Prognostic Score

    PubMed Central

    Cho, Yang Hyun; Seo, Young Ho; Chung, Seung Jun; Hwang, Insang; Yu, Ho Song; Kim, Sun-Ouck; Jung, Seung Il; Kang, Taek Won; Kwon, Dong Deuk; Park, Kwangsung; Hwang, Jun Eul; Heo, Suk Hee; Kim, Geun Soo

    2014-01-01

    Purpose Systemic inflammatory responses, which are defined in terms of the Glasgow prognostic score (GPS), have been reported to be independent predictors of unfavorable outcomes in various human cancers. We assessed the utility of the GPS as a predictor of intravesical recurrence after radical nephroureterectomy (RNU) in upper urinary tract carcinoma (UTUC). Materials and Methods We collected data for 147 UTUC patients with no previous history of bladder cancer who underwent RNU from 2004 to 2012. Associations between perioperative clinicopathological variables and intravesical recurrence were analyzed by using univariate and multivariate Cox regression models. Results Overall, 71 of 147 patients (48%) developed intravesical recurrence, including 21 patients (30%) diagnosed with synchronous bladder tumor. In the univariate analysis, performance status, diabetes mellitus (DM), serum albumin, C-reactive protein, GPS, and synchronous bladder tumor were associated with intravesical recurrence. In the multivariate analysis, performance status (hazard ratio [HR], 2.33; 95% confidence interval [CI], 1.41-3.85; p=0.001), DM (HR, 2.04; 95% CI, 1.21-3.41; p=0.007), cortical thinning (HR, 2.01; 95% CI, 1.08-3.71; p=0.026), and GPS (score of 1: HR, 6.86; 95% CI, 3.69-12.7; p=0.001; score of 2: HR, 5.96; 95% CI, 3.10-11.4; p=0.001) were independent predictors of intravesical recurrence. Conclusions Our results suggest that the GPS as well as performance status, DM, and cortical thinning are associated with intravesical recurrence after RNU. Thus, more careful follow-up, coupled with postoperative intravesical therapy to avoid bladder recurrence, should be considered in these patients. PMID:25045443

  19. SUCCINCT: An Open-label, Single-arm, Non-randomised, Phase 2 Trial of Gemcitabine and Cisplatin Chemotherapy in Combination with Sunitinib as First-line Treatment for Patients with Advanced Urothelial Carcinoma

    PubMed Central

    Geldart, Thomas; Chester, John; Casbard, Angela; Crabb, Simon; Elliott, Tony; Protheroe, Andrew; Huddart, Robert A.; Mead, Graham; Barber, Jim; Jones, Robert J.; Smith, Joanna; Cowles, Robert; Evans, Jessica; Griffiths, Gareth

    2015-01-01

    Gemcitabine and cisplatin chemotherapy (GC regimen) represents a standard treatment for advanced urothelial carcinoma. We performed an open-label, single-arm, non-randomised, phase 2 trial evaluating the addition of sunitinib to standard GC chemotherapy (SGC regimen). Overall, 63 treatment-naïve participants were recruited and received up to six 21-d cycles of cisplatin 70 mg/m2 (intravenously [IV], day 1) and gemcitabine 1000 mg/m2 (IV, days 1 and 8) combined with sunitinib 37.5 mg (orally, days 2–15). Following review of toxicity after the first six patients, the sunitinib dose was reduced to 25 mg for all patients. Overall response rate was 64%, with response noted in 37 of 58 patients. At 6 mo, 30 of 58 assessable patients (52%; 90% confidence interval [CI], 40–63%) were progression free. Median overall survival was 12 mo (95% CI, 9–15) and was heavily influenced by Bajorin prognostic group. Grade 3–4 toxicities were predominantly haematologic and limited the deliverability of the triple SGC regimen. The trial did not meet its prespecified primary end point of >60% patients progression free at 6 mo. Cumulative myelosuppression led to treatment delays of gemcitabine and cisplatin and dose reduction and/or withdrawal of sunitinib in the majority of cases. The triple-drug combination was not well tolerated. Phase 3 evaluation of the triple SGC regimen in advanced transitional cell carcinoma is not recommended. Patient summary The addition of sunitinib to standard cisplatin and gemcitabine chemotherapy was poorly tolerated and did not improve outcomes in advanced urothelial carcinoma. Treatment delivery was limited by myelotoxicity. PMID:25465968

  20. Mechanical characterization of benign and malignant urothelial cells from voided urine

    NASA Astrophysics Data System (ADS)

    Shojaei-Baghini, Ehsan; Zheng, Yi; Jewett, Michael A. S.; Geddie, William B.; Sun, Yu

    2013-03-01

    This study investigates whether mechanical differences exist between benign and malignant urothelial cells in voided urine. The Young's modulus of individual cells was measured using the micropipette aspiration technique. Malignant urothelial cells showed significantly lower Young's modulus values compared to benign urothelial cells. The results indicate that Young's modulus as a biomechanical marker could possibly provide additional information to conventional urinary cytology. We hope that these preliminary results could evoke attention to mechanical characterization of urine cells and spark interest in the development of biomechanical approaches to enhance non-invasive urothelial carcinoma detection.

  1. When Urothelial Differentiation Pathways Go Wrong: Implications for Bladder Cancer Development and Progression

    PubMed Central

    DeGraff, David J.; Cates, Justin M.; Mauney, Joshua R.; Clark, Peter E.; Matusik, Robert; Adam, Rosalyn M.

    2016-01-01

    Differentiation is defined as the ability of a cell to acquire full functional behavior. For instance, the function of bladder urothelium is to act as a barrier to the diffusion of solutes into or out of the urine after excretion by the kidney. The urothelium also serves to protect the detrusor muscle from toxins present in stored urine. A major event in the initiation and progression of bladder cancer is loss of urothelial differentiation. This is important because less differentiated urothelial tumors (higher histologic tumor grade) are typically associated with increased biologic and clinical aggressiveness. The differentiation status of urothelial carcinomas can be assessed by histopathologic examination and is reflected in the assignment of a histologic grade (low-grade or high-grade). Although typically limited to morphologic evaluation in most routine diagnostic practices, tumor grade can also be assessed using biochemical markers. Indeed, current pathological analysis of tumor specimens is increasingly reliant on molecular phenotyping. Thus, high priorities for bladder cancer research include identification of (1) biomarkers that will enable the identification of high grade T1 tumors that pose the most threat and require the most aggressive treatment; (2) biomarkers that predict the likelihood that a low grade, American Joint Committee on Cancer stage pTa bladder tumor will progress into an invasive carcinoma with metastatic potential; (3) biomarkers that indicate which pTa tumors are most likely to recur, thus enabling clinicians to prospectively identify patients who require aggressive treatment; and (4) how these markers might contribute to biological processes that underlie tumor progression and metastasis, potentially through loss of terminal differentiation. This review will discuss the proteins associated with urothelial cell differentiation, with a focus on those implicated in bladder cancer, and other proteins that may be involved in neoplastic

  2. [Evaluation of the complementary drug Factor AF2 as a supportive agent in management of advanced urothelial carcinoma. Prospective randomized multicenter study].

    PubMed

    Krege, S; Hinke, A; Otto, T; Rübben, H

    2002-03-01

    This is a prospective randomized multicenter trial for evaluation of the biological response modifier Factor AF2 in advanced urothelial cancer treated with chemotherapy. Main aim of the study was the analysis of supportive effects. Additionally patients were examined with regard to tumor response, time to progression and survival. 106 patients with advanced urothelial cancer received chemotherapy with cisplatin and methotrexate. They were randomized for additional Factor AF2 (500 mg i.v., given at days 0-3, 7-10 and 11-14). Myelotoxicity was more common and severe in the group without Factor AF2 reaching statistical significance. Gastrointestinal side effects occurred in both groups, though grade III to IV toxicity was more common without Factor AF2. Overall remission rate was 38%, median survival 33 weeks, mean time to progression 20 weeks. There was no significant difference between the two groups with or without Factor AF2. PMID:11993095

  3. Further characterization of the muscle layers and lamina propria of the urinary bladder by systematic histologic mapping: implications for pathologic staging of invasive urothelial carcinoma.

    PubMed

    Paner, Gladell P; Ro, Jae Y; Wojcik, Eva M; Venkataraman, Girish; Datta, Milton W; Amin, Mahul B

    2007-09-01

    bundles were noted in deep LP situated between the more typical slender MM layer and the MP. In conclusion, there are additional patterns of MM other than previously described. Awareness of the occasionally hyperplastic appearance of MM muscle is important to prevent overstaging of invasive urothelial carcinoma. In transurethral resection specimens, lack of orientation may preclude distinction of the hyperplastic MM from true MP in these rare situations. The number and orientation of muscle bundles, relationship to urothelium and vascular plexus, and comparison with more characteristic MP, if present, would be helpful; isolated bundles immediately adjacent to the urothelium with loose haphazard fiber orientation and irregular outlines favor MM over MP muscle. The hyperplastic MM mimicking MP may be more challenging; isolated muscle bundles immediately adjacent to the urothelium would favor hyperplastic pattern of MM over MP muscle. Topographical variations exist among the subsites, the more superficial location of the MP and the rarity of MM in the trigone, relative abundance of hyperplastic MM in dome, and presence of the more superficial ureteral MP at its insertion in the bladder complicate the traditional pT stage evaluation of invasion in these regions. The inconsistency of a distinct MM layer and variations in the LP vascular plexus indicate that substaging of pT1 would be problematic and thus provides further support to the World Health Organization/International Society of Urological Pathology 1998 and World Health Organization 2004 recommendation against its implementation at the current time. PMID:17721199

  4. Next-Generation Sequencing and In Silico Analysis Facilitate Prolonged Response to Pazopanib in a Patient With Metastatic Urothelial Carcinoma of the Renal Pelvis.

    PubMed

    Hahn, Andrew W; Giri, Smith; Patel, Dilan; Sluder, Heather; Vanderwalde, Ari; Martin, Mike G

    2015-10-01

    With the advent of widespread tumor genetic profiling, an increased number of mutations with unknown significance are being identified. Often, a glut of uninterpretable findings may confuse the clinician and provide little or inappropriate guidance in therapeutic decision-making. This report describes a method of protein modeling by in silico analysis (ie, using computer simulation) that is easily accessible to the practicing clinician without need for further laboratory analysis, which can potentially serve as a guide in therapeutic decisions based on poorly characterized tumor mutations. An example of this model is given wherein poorly characterized KIT, PDGFRB, and ERBB2 mutations were discovered in a patient with treatment-refractory metastatic transitional cell carcinoma of the renal pelvis. The KIT and PDGFRB mutations were predicted to be pathogenic using in silico analysis, whereas the ERBB2 mutation was predicted to be benign. Based on these findings, the patient was treated with pazopanib and achieved a partial response that lasted for 7.5 months. We propose that in silico analysis be explored as a potential means to further characterize genetic abnormalities found by tumor profiling assays, such as next-generation sequencing. PMID:26483058

  5. Urothelial Cancer With Occult Bone Marrow Metastases and Isolated Thrombocytopenia

    PubMed Central

    Alva, Ajjai; Davis, Elizabeth; Chinnaiyan, Arul M.; Dhanasekaran, Saravana; Mehra, Rohit

    2015-01-01

    Bladder cancer rarely presents clinically with a myelophthisic picture from diffuse bone marrow infiltration especially in the absence of detectable skeletal metastases. A 75-year old man presented with newly diagnosed urothelial cell carcinoma of the bladder. Pathology from transurethral resection of bladder tumor demonstrated muscle-invasive disease. Pre-therapy imaging including CT abdomen/pelvis, CXR and bone scan demonstrated liver lesions concerning for metastatic disease but no skeletal metastases. Labs were notable for isolated thrombocytopenia, hypercalcemia and acute kidney injury prompting hospitalization. Hematologic work-up including bone marrow aspiration and biopsy revealed diffuse infiltration of the bone marrow by urothelial cancer. The case illustrates the importance of fully investigating otherwise unexplained clinical findings in patients with clinically localized urothelial cancer prior to curative intent surgery. PMID:26793516

  6. [Monoclonal antibodies (MIB 1, PC 10, 486p and p53) as prognostic factors for recurrent urothelial carcinoma of the urinary bladder].

    PubMed

    Hake, R; Vorreuther, R; Borchmann, P; Lukowsky, S; Thiele, J; Fischer, R

    1993-01-01

    Using an immunohistochemical method expression of PCNA, Ki-67, 486p and p53 antigen was investigated in paraffin sections of 119 patients with primary transitional cell carcinoma of the bladder. The purpose of this study was to detect recurring G1 and G2 bladder tumours compared with non-recurrent tumours. A relative large fraction of labelled cells for PCNA and Ki-67 was found in recurring G1 and G2 carcinomas. Moreover, recurrent transitional cell carcinomas showed a more positive staining pattern for 486p and p53, in contrast to non-recurrent carcinomas. Immunohistochemistry of these four antigens seems to yield additional information about the possibility of recurrence in G1 and G2 bladder carcinomas, thus allowing early, i.e. more aggressive, therapy. PMID:7511288

  7. Pure Lymphoepithelioma-Like Carcinoma Originating from the Urinary Bladder

    PubMed Central

    Nagai, Takashi; Naiki, Taku; Kawai, Noriyasu; Iida, Keitaro; Etani, Toshiki; Ando, Ryosuke; Hamamoto, Shuzo; Sugiyama, Yosuke; Okada, Atsushi; Mizuno, Kentaro; Umemoto, Yukihiro; Yasui, Takahiro

    2016-01-01

    Lymphoepithelioma-like carcinoma of the urinary bladder (LELCB) is a rare variant of infiltrating urothelial carcinoma. We report a case of LELCB in a 43-year-old man. Ultrasonography and cystoscopy revealed two bladder tumors, one on the left side of the trigone and the other on the right side of the trigone. Transurethral resection of the bladder tumors was performed and pathological analysis revealed undifferentiated carcinoma. We therefore performed radical cystectomy and urinary diversion. Immunohistochemically the tumor cells were positive for cytokeratin, but negative for Epstein-Barr virus-encoded small RNA in situ hybridization as found for previous cases of LELCB. The final pathological diagnosis was a lymphoepithelioma-like variant of urothelial carcinoma with perivesical soft tissue invasion. For adjuvant systemic chemotherapy, three courses of cisplatin were administered. The patient subsequently became free of cancer 72 months postoperatively. Based on the literature, pure or predominant LELCB types show favorable prognoses due to their sensitivity to chemotherapy or radiotherapy. An analysis of the apparent diffusion coefficient (ADC) values of bladder tumors examined in our institution revealed that the ADC value measured for this LELCB was relatively low compared to conventional urothelial carcinomas. This suggests that measuring the ADC value of a lymphoepithelioma-like carcinoma prior to operation may be helpful in predicting LELCB. PMID:27099604

  8. Pure Lymphoepithelioma-Like Carcinoma Originating from the Urinary Bladder.

    PubMed

    Nagai, Takashi; Naiki, Taku; Kawai, Noriyasu; Iida, Keitaro; Etani, Toshiki; Ando, Ryosuke; Hamamoto, Shuzo; Sugiyama, Yosuke; Okada, Atsushi; Mizuno, Kentaro; Umemoto, Yukihiro; Yasui, Takahiro

    2016-01-01

    Lymphoepithelioma-like carcinoma of the urinary bladder (LELCB) is a rare variant of infiltrating urothelial carcinoma. We report a case of LELCB in a 43-year-old man. Ultrasonography and cystoscopy revealed two bladder tumors, one on the left side of the trigone and the other on the right side of the trigone. Transurethral resection of the bladder tumors was performed and pathological analysis revealed undifferentiated carcinoma. We therefore performed radical cystectomy and urinary diversion. Immunohistochemically the tumor cells were positive for cytokeratin, but negative for Epstein-Barr virus-encoded small RNA in situ hybridization as found for previous cases of LELCB. The final pathological diagnosis was a lymphoepithelioma-like variant of urothelial carcinoma with perivesical soft tissue invasion. For adjuvant systemic chemotherapy, three courses of cisplatin were administered. The patient subsequently became free of cancer 72 months postoperatively. Based on the literature, pure or predominant LELCB types show favorable prognoses due to their sensitivity to chemotherapy or radiotherapy. An analysis of the apparent diffusion coefficient (ADC) values of bladder tumors examined in our institution revealed that the ADC value measured for this LELCB was relatively low compared to conventional urothelial carcinomas. This suggests that measuring the ADC value of a lymphoepithelioma-like carcinoma prior to operation may be helpful in predicting LELCB. PMID:27099604

  9. From Clinical Trials to the Front Line: Vinflunine for Treatment of Urothelial Cell Carcinoma at the National Cancer Institute of Naples

    PubMed Central

    Facchini, Gaetano; Della Pepa, Chiara; Cavaliere, Carla; Cecere, Sabrina C.; Di Napoli, Marilena; D'Aniello, Carmine; Crispo, Anna; Iovane, Gelsomina; Maiolino, Piera; Tramontano, Teresa; Piscitelli, Raffaele; Pisconti, Salvatore; Montella, Maurizio; Berretta, Massimiliano; Sorrentino, Domenico; Perdonà, Sisto; Pignata, Sandro

    2016-01-01

    Background: The efficacy of Vinflunine, after failure of platinum-based chemotherapy in patients with metastatic or recurrent Transitional Cell Cancer of the Urothelial Tract, TCCU, has been demonstrated in an international, randomized, phase III trial comparing Vinflunine plus Best Supportive Care, BSC, with BSC alone. On the basis of that study vinflunine has been approved by the European Medicine Association, EMA, for treatment of TCCU patients after failure of a platinum treatment. However, since data in clinical trials often differ from routine clinical practice due to unselected population and less strict monitoring, “real life” experiences are very helpful to verify the efficacy of a new therapy. Methods: This was a spontaneous, observational, retrospective study involving 43 patients with metastatic TCCU treated with vinflunine at our cancer center, data about demographics, disease characteristics, and previous treatments were collected and outcome and toxicities of vinflunine were analyzed. Results: 41 of 43 patients were eligible for RR analysis, the Overall RR was 12%, the Disease Control Rate was 29%; when including only patients treated in II line the DCR rose to 33%; the median PFS and the median OS were 2.2 and 6.9 months, respectively. Conclusion: Our findings were consistent with the outcome data emerged in the phase III randomized trial and in the other observational studies conducted all around Europe in the last 2–3 years. This experience supports the use of vinflunine in patients with advanced TTCU as effective and manageable antineoplastic drug. PMID:27199753

  10. Increased Upper and Lower Tract Urothelial Carcinoma in Patients with End-Stage Renal Disease: A Nationwide Cohort Study in Taiwan during 1997–2008

    PubMed Central

    Wang, Shuo-Meng; Lai, Ming-Nan; Chen, Pau-Chung; Pu, Yeong-Shiau; Lai, Ming-Kuen; Hwang, Jing-Shiang; Wang, Jung-Der

    2014-01-01

    Background. Urothelial cancer (UC) is the leading cancer of patients with end-stage renal disease (ESRD) in Taiwan. The aims of this study were to explore the time trends of UC incidences and propose possible etiologic factors. Methods. Abstracting from the National Health Insurance Research Database (NHIRD), there were 90,477 newly diagnosed cases of ESRD between 1997 and 2008 covering the patients aged 40–85. Among them, 2,708 had developed UC after diagnosis of ESRD. The CIR40–85 (cumulative incidence rate) of upper tract UC (UTUC) and lower tract UC (LTUC) were calculated for ESRD patients and general population, as well as SIR40–85 (standardized incidence ratio) for comparison. Results. Female ESRD patients were found to have 9–18 times of elevated risks of UC, while those of males were increased up to 4–14 times. The time trends of CIR40–84 and SIR40–84 of UTUC in females appear to decline after calendar year 2000. These trends may be related to AA associated herbal products after 1998. Conclusions. Patients with ESRD are at increased risks for both LTUC and UTUC in Taiwan. We hypothesize that the time trends associate with the consumption of aristolochic acid in Chinese herbal products (female predominant). PMID:25025033

  11. A significantly joint effect between arsenic and occupational exposures and risk genotypes/diplotypes of CYP2E1, GSTO1 and GSTO2 on risk of urothelial carcinoma

    SciTech Connect

    Wang, Y.-H.; Yeh, S.-D.; Shen, K.-H.; Shen, Cheng-Huang; Juang, G.-D.; Hsu, L.-I; Chiou, H.-Y.; Chen, C.-J.

    2009-11-15

    Cigarette smoking, arsenic and occupational exposures are well-known risk factors for the development of urothelial carcinoma (UC). Therefore, the aim of this study is to investigate whether the effect of cigarette smoking, alcohol consumption, arsenic and occupational exposures on risk of UC could be modified by genetic polymorphisms of cytochrome P450 2E1 and glutathione S-transferase omega. A hospital-based case-control study consisted of 520 histologically confirmed UC cases, and 520 age- and gender-matched cancer-free controls were carried out from September 1998 to December 2007. Genotyping of CYP2E1, GSTO1 and GSTO2 was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Subjects with both of cigarette smoking and alcohol consumption have a significantly increased UC risk (odds ratio [OR] = 2.9; 95% confidence interval [CI] = 1.9-4.4). Significantly increased UC risks of 1.5 and 1.9 were found for study subjects with high arsenic exposure and those who have been exposed to two or more occupational exposures, respectively. A significantly increased UC risk of 3.9 was observed in study subjects with H2-H2 diplotype of GSTO1 and GSTO2. The significantly highest UC risk of 9.0 was found for those with all environmental risk factors of cigarette smoking, alcohol consumption, arsenic and occupational exposures and two or more risk genotypes/diplotypes of CYP2E1, GSTO1 and GSTO2. Our findings suggest that a significantly joint effect of cigarette smoking, alcohol consumption, arsenic and occupational exposures and risk genotypes/diplotypes of CYP2E1, GSTO1 and GSTO2 on risk of UC was found.

  12. A Model to Predict the Risk of Keratinocyte Carcinomas.

    PubMed

    Whiteman, David C; Thompson, Bridie S; Thrift, Aaron P; Hughes, Maria-Celia; Muranushi, Chiho; Neale, Rachel E; Green, Adele C; Olsen, Catherine M

    2016-06-01

    Basal cell and squamous cell carcinomas of the skin are the commonest cancers in humans, yet no validated tools exist to estimate future risks of developing keratinocyte carcinomas. To develop a prediction tool, we used baseline data from a prospective cohort study (n = 38,726) in Queensland, Australia, and used data linkage to capture all surgically excised keratinocyte carcinomas arising within the cohort. Predictive factors were identified through stepwise logistic regression models. In secondary analyses, we derived separate models within strata of prior skin cancer history, age, and sex. The primary model included terms for 10 items. Factors with the strongest effects were >20 prior skin cancers excised (odds ratio 8.57, 95% confidence interval [95% CI] 6.73-10.91), >50 skin lesions destroyed (odds ratio 3.37, 95% CI 2.85-3.99), age ≥ 70 years (odds ratio 3.47, 95% CI 2.53-4.77), and fair skin color (odds ratio 1.75, 95% CI 1.42-2.15). Discrimination in the validation dataset was high (area under the receiver operator characteristic curve 0.80, 95% CI 0.79-0.81) and the model appeared well calibrated. Among those reporting no prior history of skin cancer, a similar model with 10 factors predicted keratinocyte carcinoma events with reasonable discrimination (area under the receiver operator characteristic curve 0.72, 95% CI 0.70-0.75). Algorithms using self-reported patient data have high accuracy for predicting risks of keratinocyte carcinomas. PMID:26908057

  13. Muscle-invasive urothelial bladder cancer: an update on systemic therapy

    PubMed Central

    Knollman, Hayley; Godwin, J. Luke; Jain, Rishi; Wong, Yu-Ning; Plimack, Elizabeth R.; Geynisman, Daniel M.

    2015-01-01

    Urothelial carcinoma is a common malignancy that carries a poor prognosis when the disease includes muscle invasion. Metastatic urothelial carcinoma is almost uniformly fatal. The evidence behind treatment options in the neoadjuvant, adjuvant and metastatic settings are discussed in this manuscript, with a focused review of standard and investigational cytotoxic, targeted, and immunotherapy approaches. We have focused especially on neoadjuvant cisplatin-based therapy (supported by level one evidence) and on novel immunotherapy agents such as checkpoint inhibitors, which have shown great promise in early clinical studies. PMID:26622317

  14. Dysplasia and carcinoma in situ of the urinary bladder.

    PubMed

    Lopez-Beltran, Antonio; Marques, Rita C; Montironi, Rodolfo; Reymundo, Carlos; Fonseca, Jorge; Cheng, Liang

    2015-02-01

    Urothelial dysplasia (low-grade intraurothelial neoplasia) is recognized as a premalignant urothelial lesion in the 2004 World Health Organization (WHO) classification system. Although clarification of the diagnostic criteria of urothelial dysplasia has improved in recent years, there is still a lack of interobserver reproducibility. Active clinical follow-up is mandatory in patients with a diagnosis of urothelial dysplasia since it constitutes a marker of urothelial instability, and disease progression, in up to 19% of cases. The differential diagnosis of urothelial dysplasia is with other flat urothelial lesions with atypia, including flat urothelial hyperplasia, reactive urothelial atypia, urothelial atypia of unknown significance, and urothelial carcinoma in situ (high-grade intraurothelial neoplasia). In most cases, especially when small amounts of tissue are available, morphologic features alone may not be sufficient for diagnosis. Immunohistochemistry can be of help in selected cases, and a panel of cytokeratin 20, p53, and CD44 may help in the diagnosis. The use of HER2, p16, and Racemase remains as an option pending validation. Herein, we present the pathologic features and clinical significance of urothelial dysplasia and carcinoma in situ with emphasis on differential diagnosis from common flat lesions with atypia. PMID:26072632

  15. Pegylated liposomal doxorubicin as third-line chemotherapy in patients with metastatic transitional cell carcinoma of urothelial tract: results of a phase II study.

    PubMed

    Rozzi, Antonio; Santini, Daniele; Salerno, Margherita; Bordin, Francesca; Mancuso, Andrea; Minniti, Giuseppe; Nardoni, Chiara; Corona, Michela; Falbo, Pina Tiziana; Recine, Federica; Lanzetta, Gaetano

    2013-03-01

    Until the recent approval of vinflunine, no standard second-line chemotherapy existed for advanced transitional cell carcinoma (TCC). Few data exist about third-line chemotherapy for metastatic disease. Although administered in up-front regimens, anthracyclines were never evaluated beyond second-line treatment. This study assessed the activity of pegylated liposomal doxorubicin (PLD) in patients with advanced TCC previously treated with two chemotherapy regimens. From May 2005 to June 2009, 23 patients with metastatic TCC were recruited: median age was 62 years (49-76 years) with a median ECOG PS of 1. Patients received PLD 35 mg/m(2) every 21 days. All patients were evaluable for efficacy and toxicity. No patient showed complete response. Three patients (13 %) had partial response; seven patients (30 %) showed stable disease for a disease control rate of 43 %. The median time to progression (TTP) was 4.1 months with a median survival time (MST) of 6.3 months. Treatment was well tolerated: no patient developed grade 4 toxicities. This is the first study which evaluated the role of anthracyclines as third-line chemotherapy in metastatic TCC. Despite its manageable profile of toxicity, PLD showed modest activity. Beyond second-line chemotherapy, supportive care still represents the best therapeutic option for patients with metastatic TCC. PMID:23307245

  16. New and contemporary markers of prognosis in nonmuscle invasive urothelial cancer

    PubMed Central

    Nazim, Syed M

    2015-01-01

    Nonmuscle invasive (NMI) urothelial cancer (UC) is associated with varied biological potential. It is characterized by frequent recurrence and progression, which thus worsens the oncological outcome. Nearly three-quarters of NMI UCs recur within 5 years, whereas half can progress during follow-up. Progression is particularly seen in T1 and carcinoma in situ (CIS). Undoubtedly, NMI UC is one of the most expensive cancers to manage. The European Organisation for Research and Treatment of Cancer (EORTC) risk calculator is a commonly used tool for assessing the recurrence and progression potential of a newly diagnosed cancer. The parameters used in the assessment are tumor size and number, pathological stage and grade of the cancer, presence of CIS, and prior recurrence rate. The main advantages of the EORTC tool are its ease of use and the lack of need to run expensive molecular tests. However, reproducibility of pathologic stage and grade is modest, which is a concern to clinicians. Molecular markers have potential for predicting the clinical outcome of NMI UC, given that clinico-pathologic variables are not sufficient for prediction of prognosis in an individual. Significant work has been done in the past 2 decades in understanding the molecular biology of bladder cancer; however, the translational value of this knowledge remains poor. The role for molecular markers in predicting recurrence seems limited because multifocal disease and incomplete treatment are probably more important for recurrence than the molecular features of a resected tumor. Urinary markers have very limited value in prognostication of bladder cancer and are used (mainly as an adjunct to cytology) for detection and surveillance of urothelial cell cancer recurrence. Prediction of progression with molecular markers holds considerable promise. Nevertheless, the contemporary value of molecular markers over clinico-pathologic indexes is limited. PMID:26279824

  17. New and contemporary markers of prognosis in nonmuscle invasive urothelial cancer.

    PubMed

    Ather, M Hammad; Nazim, Syed M

    2015-08-01

    Nonmuscle invasive (NMI) urothelial cancer (UC) is associated with varied biological potential. It is characterized by frequent recurrence and progression, which thus worsens the oncological outcome. Nearly three-quarters of NMI UCs recur within 5 years, whereas half can progress during follow-up. Progression is particularly seen in T1 and carcinoma in situ (CIS). Undoubtedly, NMI UC is one of the most expensive cancers to manage. The European Organisation for Research and Treatment of Cancer (EORTC) risk calculator is a commonly used tool for assessing the recurrence and progression potential of a newly diagnosed cancer. The parameters used in the assessment are tumor size and number, pathological stage and grade of the cancer, presence of CIS, and prior recurrence rate. The main advantages of the EORTC tool are its ease of use and the lack of need to run expensive molecular tests. However, reproducibility of pathologic stage and grade is modest, which is a concern to clinicians. Molecular markers have potential for predicting the clinical outcome of NMI UC, given that clinico-pathologic variables are not sufficient for prediction of prognosis in an individual. Significant work has been done in the past 2 decades in understanding the molecular biology of bladder cancer; however, the translational value of this knowledge remains poor. The role for molecular markers in predicting recurrence seems limited because multifocal disease and incomplete treatment are probably more important for recurrence than the molecular features of a resected tumor. Urinary markers have very limited value in prognostication of bladder cancer and are used (mainly as an adjunct to cytology) for detection and surveillance of urothelial cell cancer recurrence. Prediction of progression with molecular markers holds considerable promise. Nevertheless, the contemporary value of molecular markers over clinico-pathologic indexes is limited. PMID:26279824

  18. Retroperitoneoscopic renal pelvis resection as treatment of the urothelial tumor in a solitary kidney

    PubMed Central

    Słojewski, Marcin; Gołąb, Adam; Petrasz, Piotr

    2013-01-01

    Urothelial carcinoma of the upper urinary tract is relatively rare. The standard treatment is invariably radical nephroureterectomy. In selected cases organ sparing surgery is justified. We present the case of the tumor of the kidney pelvis in a solitary organ where laparoscopic approach was successfully applied. PMID:24707368

  19. Risk prediction models for hepatocellular carcinoma in different populations.

    PubMed

    Ma, Xiao; Yang, Yang; Tu, Hong; Gao, Jing; Tan, Yu-Ting; Zheng, Jia-Li; Bray, Freddie; Xiang, Yong-Bing

    2016-04-01

    Hepatocellular carcinoma (HCC) is a malignant disease with limited therapeutic options due to its aggressive progression. It places heavy burden on most low and middle income countries to treat HCC patients. Nowadays accurate HCC risk predictions can help making decisions on the need for HCC surveillance and antiviral therapy. HCC risk prediction models based on major risk factors of HCC are useful and helpful in providing adequate surveillance strategies to individuals who have different risk levels. Several risk prediction models among cohorts of different populations for estimating HCC incidence have been presented recently by using simple, efficient, and ready-to-use parameters. Moreover, using predictive scoring systems to assess HCC development can provide suggestions to improve clinical and public health approaches, making them more cost-effective and effort-effective, for inducing personalized surveillance programs according to risk stratification. In this review, the features of risk prediction models of HCC across different populations were summarized, and the perspectives of HCC risk prediction models were discussed as well. PMID:27199512

  20. Risk prediction models for hepatocellular carcinoma in different populations

    PubMed Central

    Ma, Xiao; Yang, Yang; Tu, Hong; Gao, Jing; Tan, Yu-Ting; Zheng, Jia-Li; Bray, Freddie; Xiang, Yong-Bing

    2016-01-01

    Hepatocellular carcinoma (HCC) is a malignant disease with limited therapeutic options due to its aggressive progression. It places heavy burden on most low and middle income countries to treat HCC patients. Nowadays accurate HCC risk predictions can help making decisions on the need for HCC surveillance and antiviral therapy. HCC risk prediction models based on major risk factors of HCC are useful and helpful in providing adequate surveillance strategies to individuals who have different risk levels. Several risk prediction models among cohorts of different populations for estimating HCC incidence have been presented recently by using simple, efficient, and ready-to-use parameters. Moreover, using predictive scoring systems to assess HCC development can provide suggestions to improve clinical and public health approaches, making them more cost-effective and effort-effective, for inducing personalized surveillance programs according to risk stratification. In this review, the features of risk prediction models of HCC across different populations were summarized, and the perspectives of HCC risk prediction models were discussed as well. PMID:27199512

  1. Expression of the E-cadherin repressors Snail, Slug and Zeb1 in urothelial carcinoma of the urinary bladder: relation to stromal fibroblast activation and invasive behaviour of carcinoma cells.

    PubMed

    Schulte, Julia; Weidig, Michaela; Balzer, Philipp; Richter, Petra; Franz, Marcus; Junker, Kerstin; Gajda, Mieczyslaw; Friedrich, Karlheinz; Wunderlich, Heiko; Östman, Arne; Petersen, Iver; Berndt, Alexander

    2012-12-01

    Epithelial-mesenchymal transition (EMT) is regulated by interaction of carcinoma and stromal cells and crucial for progression of urinary bladder carcinoma (UBC). Therefore, the influence of activated fibroblasts on the expression of E-cadherin repressors as well as EMT and invasion in UBC was investigated. A correlative analysis of the immunohistochemical expression of fibroblast (ASMA, S100A4, FAP, SDF1, PDGFRβ) and EMT (Snail, Slug, Zeb1, E-cadherin) markers was performed on 49 UBC cases of different stages. The impact of distinguishable growth factor stimulated fibroblasts on invasion, EMT, and E-cadherin repressor expression was investigated in an invasion model. In situ, invasiveness was significantly correlated to the loss of membranous E-cadherin (E-cad_m) and increased Snail, Slug, Zeb1 in tumour cells, as well as to increased ASMA, S100A4, and PDGFRβ in stromal cells. A significant correlation to nodal metastasis could be evidenced for the loss of E-Cad_m, and for an increase in S100A4 and PDGFRβ. Comparison of stromal and EMT markers revealed significant correlations of ASMA to Snail and Slug; of S100A4 to the loss of E-cad_m and Zeb1; and of PDGFRβ to the loss of E-Cad_m, Slug and Zeb1. In vitro, TGFβ1 induced myofibroblasts were the strongest attractants, while aFGF or TGFβ1/aFGF stimulated fibroblasts were the most potent EMT inductors. As shown here for the first time, distinct sub-populations of fibroblasts are to various extents associated with EMT and tumour progression in UBC. These relevant findings might be the basis for the identification of new diagnostic markers and therapeutic targets selectively affecting tumour supporting CAF effects. PMID:22820858

  2. Negative predictive value of procalcitonin in medullary thyroid carcinoma.

    PubMed

    Lim, Soo Kyung; Guéchot, Jérôme; Vaubourdolle, Michel

    2016-01-01

    Calcitonin (CT), the major biochemical marker in medullary thyroid carcinoma (MTC) is prone to in vitro instability and suffers from scarcity of clinical laboratory platforms. Procalcitonin (PCT), the precursor of CT, free of these shortcomings, has been reported as a potential MTC marker. The aim of this study was to assess the negative predictive value (NPV) of PCT as a first-line marker in MTC. 476 serum samples referred to our laboratory for CT measurements were analyzed for PCT. NPVs of PCT were assessed at 3 cut-offs (0.05, 0.10 and 0.15 ng/mL) and the diagnosis of MTC was based on CT levels. PCT and CT levels were correlated (r=0.7554 for CT levels above 10 pg/mL, n=66). Accepting the CT cut-off based on the upper reference limit the NPV of PCT were 98.1% (0.05 ng/mL), 96.3% (0.10 ng/mL) and 95.4% (0.15 ng/mL) respectively. For a CT cut-off of 100 pg/mL the NPVs of PCT were 100% for all PCT thresholds. Serum PCT has a strong NPV and could be a good candidate for a first-line screening test to exclude MTC in patients with suspicious thyroid nodules or suggestive symptoms. Larger prospective studies are necessary to confirm our results. PMID:26806393

  3. The prophylaxis of nonindustrial urothelial tumours

    PubMed Central

    Mount, Balfour M.

    1973-01-01

    Present knowledge concerning carcinogenesis and the natural history of urothelial tumours precludes firm conclusions relative to nonindustrial prophylaxis. However, a number of measures are consistent with current data and may be instituted for those patients with a demonstrated propensity to urothelial tumours. Their acceptability is based on the lack of associated toxicity for the patient. These measures include the elimination of significant infection, cigarettes, artificial sweeteners, analgesic abuse and coffee, the administration of vitamins C and B6, and in selected cases, the use of thiotepa. It is emphasized that the merit of these steps in altering the natural history of urothelial tumours is uncertain. PMID:4197537

  4. [Occupation and urothelial cancer: the background and the clinical figure].

    PubMed

    Itatani, H

    1989-12-01

    Occupational urothelial carcinomas which were developed by benzidine and beta-naphthylamine have been diagnosed and treated in 60 workers. The number of cases of bladder tumor, ureteral tumor and bladder with upper urinary tract tumor was 49, 2 and 9, respectively. Death from urinary tract carcinoma was 5 (8.3%) and 12 out of 60 died from other diseases, 8 from other organ carcinomas and 4 from none cancer diseases. Organ preserving therapy for occupational urinary tract carcinoma should be selected because of high recurrence tendency, especially cisplatin-radiation or BCG instillation therapy. In future, new candidates will decrease but the fact of the patients becoming older will be important including other organ carcinomas, when we follow them up. Case control study was done by examining replies to questions answered by non-tumor-developing group and tumor developing group. Questions included alcohol, water and cigarette consumption, working duration and difference of chemical substance. A statistically significant result was obtained only in difference of production or messenger of the chemical substance (p = 0.001). PMID:2618899

  5. Highly Selective Anti-Cancer Activity of Cholesterol-Interacting Agents Methyl-β-Cyclodextrin and Ostreolysin A/Pleurotolysin B Protein Complex on Urothelial Cancer Cells.

    PubMed

    Resnik, Nataša; Repnik, Urška; Kreft, Mateja Erdani; Sepčić, Kristina; Maček, Peter; Turk, Boris; Veranič, Peter

    2015-01-01

    Cholesterol content can vary distinctly between normal and cancer cells, with elevated levels in cancer cells. Here, we investigated cholesterol sequestration with methyl-β-cyclodextrin (MCD), and pore-formation with the ostreolysin A/pleurotolysin B (OlyA/PlyB) protein complex that binds to cholesterol/sphingomyelin-rich membrane domains. We evaluated the effects on viability of T24 invasive and RT4 noninvasive human urothelial cancer cells and normal porcine urothelial (NPU) cells. Cholesterol content strongly correlated with cancerous transformation, as highest in the T24 high-grade invasive urothelial cancer cells, and lowest in NPU cells. MCD treatment induced prominent cell death of T24 cells, whereas OlyA/PlyB treatment resulted in greatly decreased viability of the RT4 low-grade noninvasive carcinoma cells. Biochemical and transmission electron microscopy analyses revealed that MCD and OlyA/PlyB induce necrotic cell death in these cancer cells, while viability of NPU cells was not significantly affected by either treatment. We conclude that MCD is more toxic for T24 high-grade invasive urothelial cancer cells, and OlyA/PlyB for RT4 low-grade noninvasive urothelial cancer cells, and neither is toxic for NPU cells. The cholesterol and cholesterol/sphingomyelin-rich membrane domains in urothelial cancer cells thus constitute a selective therapeutic target for elimination of urothelial cancer cells. PMID:26361392

  6. Highly Selective Anti-Cancer Activity of Cholesterol-Interacting Agents Methyl-β-Cyclodextrin and Ostreolysin A/Pleurotolysin B Protein Complex on Urothelial Cancer Cells

    PubMed Central

    Resnik, Nataša; Repnik, Urška; Kreft, Mateja Erdani; Sepčić, Kristina; Maček, Peter; Turk, Boris; Veranič, Peter

    2015-01-01

    Cholesterol content can vary distinctly between normal and cancer cells, with elevated levels in cancer cells. Here, we investigated cholesterol sequestration with methyl-β-cyclodextrin (MCD), and pore-formation with the ostreolysin A/pleurotolysin B (OlyA/PlyB) protein complex that binds to cholesterol/sphingomyelin-rich membrane domains. We evaluated the effects on viability of T24 invasive and RT4 noninvasive human urothelial cancer cells and normal porcine urothelial (NPU) cells. Cholesterol content strongly correlated with cancerous transformation, as highest in the T24 high-grade invasive urothelial cancer cells, and lowest in NPU cells. MCD treatment induced prominent cell death of T24 cells, whereas OlyA/PlyB treatment resulted in greatly decreased viability of the RT4 low-grade noninvasive carcinoma cells. Biochemical and transmission electron microscopy analyses revealed that MCD and OlyA/PlyB induce necrotic cell death in these cancer cells, while viability of NPU cells was not significantly affected by either treatment. We conclude that MCD is more toxic for T24 high-grade invasive urothelial cancer cells, and OlyA/PlyB for RT4 low-grade noninvasive urothelial cancer cells, and neither is toxic for NPU cells. The cholesterol and cholesterol/sphingomyelin-rich membrane domains in urothelial cancer cells thus constitute a selective therapeutic target for elimination of urothelial cancer cells. PMID:26361392

  7. Gender differences in incidence and outcomes of urothelial and kidney cancer.

    PubMed

    Lucca, Ilaria; Klatte, Tobias; Fajkovic, Harun; de Martino, Michela; Shariat, Shahrokh F

    2015-10-01

    A gender discrepancy exists in the incidence of both urothelial and kidney carcinomas, with more men presenting with these cancers than women. Men have a threefold greater risk of developing bladder cancer than women, but female gender has been identified as an independent adverse prognostic factor for both recurrence and progression of this disease. In particular, women with bladder cancer are often diagnosed with a higher tumour stage than men. Conclusive data on the influence of gender on outcomes of patients with upper tract urothelial carcinoma are currently lacking, although men seem to have a higher disease incidence, whereas survival outcomes might be independent of gender. Patients with renal cell carcinoma are more often men and they typically have larger tumours and higher stage and grade disease than women with this cancer. Smoking habits, tumour biology, occupational risk factors and sex steroid hormones and their receptors could have a role in these observed gender disparities. The majority of data support the theory that gender influences incidence and prognosis of urothelial and kidney cancers; men and women are different genetically and socially, making the consideration of gender a key factor in the clinical decision-making process. Thus, the inclusion of this variable in validated prognostic tables and nomograms should be discussed as a matter of importance. PMID:26436686

  8. Fluorescence photodetection of urothelial neoplastic foci in superficial bladder cancer

    NASA Astrophysics Data System (ADS)

    Jichlinski, Patrice; Forrer, Martin; Mizeret, Jerome C.; Braichotte, Daniel; Wagnieres, Georges A.; Zimmer, Georges; Guillou, Louis; Schmidlin, Franz R.; Graber, Peter; van den Bergh, Hubert; Leisinger, Hans-Juerg

    1997-05-01

    The prognosis of superficial bladder cancer in terms of recurrence and disease progression is related to the bladder tumor multiplicity and the presence of concomitant 'plane' tumors such as high grade dysplasia and carcinoma in situ (CIS). This study on 33 patients tries to demonstrate the interest of fluorescence cystoscopy in transurethral resection of superficial bladder cancer The method is based on the detection of the protoporphyrin IX (PpIX) induced fluorescence in urothelial cancer cells by topical administration of 5- aminolevulinic acid (ALA). The sensitivity and the specificity of this procedure on apparently normal mucosa in superficial bladder cancer is respectively estimated at 82.9% and 81.3%. Thus, fluorescence cystoscopy is a simple and reliable method in mapping the bladder mucosa, especially in case of multifocal bladder disease and it facilitates the screening of occult dysplasia.

  9. Increased risk of malignancy for non-atypical urothelial cell groups compared to negative cytology in voided urine. Morphological changes with LBC.

    PubMed

    Granados, Rosario; Butrón, Mercedes; Santonja, Carlos; Rodríguez, José-María; Martín, Ana; Duarte, Joanny; Camarmo, Encarnación; Corrales, Teresa; Aramburu, José-Antonio

    2016-07-01

    Liquid-based cytology (LBC) has recently become the preferred method for urine cytology analysis, but differences with conventional cytology (CC) have been observed. The purpose of this study is to analyze these differences and the clinical relevance of non-atypical urothelial cell groups (UCG) in voided urine specimens. Reporting terminology is discussed. Initially, diagnostic categories from 619 LBC and 474 CC samples, reviewed by five different pathologists, were compared (phase 1). Five years after LBC was implemented and applying strict cytologic criteria for UCG diagnosis, 760 samples were analyzed (phase 2) and compared to previous LBC specimens. Diagnostic differences, interobserver variability and clinicopathological correlation with a 6-month follow-up, were analyzed. UCG increased from 6.5% with CC to 20.7% (218%, 3.2 fold, P < 0.0001) with LBC. This difference was not related to interobserver variability. Five years later, the rate of UCG had decreased to 13 2%. While 6% of cases with a negative cytology had urothelial carcinoma (UC) within 6 months of diagnosis, this percentage increased to 15.7% with UCG. The sensitivity of the UCG category for UC was low (30.4%), but the specificity and the negative predictive value (NPV) were high (87.1% and 94%, respectively). LBC increases UCG when compared to CC. This can be corrected with observeŕs experience and using set cytological criteria. Due to its association with carcinoma, the presence of UCG in voided urine should be framed in a diagnostic category other than "negative for malignancy." Diagn. Cytopathol. 2016;44:582-590. © 2016 Wiley Periodicals, Inc. PMID:27089849

  10. A possible predictive marker of progression for hepatocellular carcinoma

    PubMed Central

    DI STASIO, MICHELE; VOLPE, MARIA GRAZIA; COLONNA, GIOVANNI; NAZZARO, MELISSA; POLIMENO, MIRIAM; SCALA, STEFANIA; CASTELLO, GIUSEPPE; COSTANTINI, SUSAN

    2011-01-01

    The correlation between decreased levels of selenium and increased DNA damage and oxidative stress shows the significance of this trace element. A number of studies have provided evidence for lower serum, plasma and tissue levels of selenium in patients with various diseases and types of cancer. In this study, liver selenium concentrations were measured in tissue samples of patients with hepatocellular carcinoma (HCC) by atomic absorption spectrometry. The results showed that the selenium concentrations decreased when the malignant grade increased. Furthermore, a significant correlation was found between selenium levels and human selenium binding protein-1 (SELENBP1) down-regulation in the liver. Therefore, we suggest that the evaluation of selenium and SELENBP1 concentrations can be used for improving the prognosis of HCC. PMID:22848296