Efeito protetivo do extrato de Echinodorus grandiflorus sobre o urotelio vesical de ratos com cistite induzida por ciclofosfamida / Extract of echinodorus grandiflorus presents renoprotetic effect on rats with acute nephrotoxicity induced by cyclophosphamid / Extracto de Echinodorus grandiflorus presenta efecto renoprotético en ratas con nefrotoxicidad aguda inducida por ciclofosfamida

cistite hemorrágica e a cistite intersticial expressam uma etiologia variável, desde idiopática à provocada por fármacos, dentre eles a ciclofosfamida. A cistite apresenta tratamento multifatorial, e o potencial efeito satisfatório do uso da medicina complementar, vem ganhando espaço na prática médica. Assim o objetivo do presente estudo foi avaliar o efeito protetivo do extrato bruto de Echinodorus grandiflorus sobre a bexiga de ratos induzidos a cistite por ciclofosfamida. Utilizou-se neste estudo, 35 ratos, machos, Wistar, com peso médio de 321g, que foram submetidos a indução de cistite com uso de ciclofosfamida por via intraperitoneal e tratados com diferentes doses de extrato de Echinodorus grandiflorus (30, 100, 300mg) e o grupo controle com o fármaco Mesna. Todos os animais foram mortos no décimo sétimo dia e suas bexigas urinarias foram ressecadas para avaliação macro e microscópica, além da análise de hemograma e leucograma. A análise do sangue mostrou leucopenia com diferença significativa em todos os animais que receberam a ciclofosfamida. Observou-se que a dose de 300mg/kg do extrato bruto da planta, apresentou efeito protetivo no urotélio vesical, porém, inferior ao uso de Mesna. Diante dos resultados apresentados neste estudo sugere-se que o extrato de Echinodorus grandiflorus apresenta efeito protetivo no urotélio vesical na dose de 300mg/kg, porém estudos futuros quanto a dose e também a uma possível associação terapêutica ao Mesna devam ser realizados. Por se tratar de uma patologia com prevalência importante e ser muitas vezes desagradável e limitante à vida, faz-se necessário o empenho em métodos terapêuticos alternativos aos atuais, afim de, diminuírem os custos e efeitos colaterais dos métodos já documentados.

Hemorrhagic cystitis and interstitial cystitis have a variable etiology, from idiopathic to drug-induced, including cyclophosphamide. Cystitis has a multifactorial treatment, and the potential satisfactory effect of the use of complementary medicine has been gaining ground in medical practice. Thus, the aim of the present study was to evaluate the protective effect of the crude extract of Echinodorus grandiflorus on the bladder of rats induced to cystitis by cyclophosphamide. In this study, 35 male Wistar rats, with an average weight of 321g, were submitted to cystitis induction with intraperitoneal use of cyclophosphamide and treated with different doses of Echinodorus grandiflorus extract (30, 100, 300mg) and the control group with the drug Mesna. All animals were killed on the seventeenth day and their urinary bladders were resected for macro and microscopic evaluation, in addition to the analysis of blood count and leukogram. Blood analysis showed leukopenia with a significant difference in all animals that received cyclophosphamide. It was observed that the dose of 300mg/kg of the crude extract of the plant had a protective effect on the vesical urothelium, however, it was inferior to the use of Mesna. In view of the results presented in this study, it is suggested that the Echinodorus grandiflorus extract has a protective effect on the vesical urothelium at a dose of 300mg/kg, but future studies regarding the dose and also a possible therapeutic association with Mesna should be carried out. Because it is a pathology with significant prevalence and is often unpleasant and life-limiting, it is necessary to commit to alternative therapeutic methods to the current ones, in order to reduce the costs and side effects of the methods already documented.

cistitis hemorrágica y la cistitis intersticial tienen una etiología variable, desde idiopática hasta inducida por fármacos, incluida la ciclofosfamida. La cistitis tiene un tratamiento multifactorial, y el potencial efecto satisfactorio del uso de la medicina complementaria ha ido ganando terreno en la práctica médica. Así, el objetivo del presente estudio fue evaluar el efecto protector del extracto crudo de Echinodorus grandiflorus sobre la vejiga de ratas inducidas a cistitis por ciclofosfamida. En este estudio, 35 ratas Wistar macho, con un peso promedio de 321g, fueron sometidas a inducción de cistitis con uso intraperitoneal de ciclofosfamida y tratadas con diferentes dosis de extracto de Echinodorus grandiflorus (30, 100, 300mg) y el grupo control con el fármaco Mesna. Todos los animales fueron sacrificados al decimoséptimo día y sus vejigas urinarias fueron resecadas para evaluación macro y microscópica, además del análisis de hemograma y leucograma. El análisis de sangre mostró leucopenia con una diferencia significativa en todos los animales que recibieron ciclofosfamida. Se observó que la dosis de 300 mg/kg del extracto crudo de la planta tuvo un efecto protector sobre el urotelio vesical, sin embargo, fue inferior al uso de Mesna. En vista de los resultados presentados en este estudio, se sugiere que el extracto de Echinodorus grandiflorus tiene un efecto protector sobre el urotelio vesical a una dosis de 300 mg/kg, pero se deben realizar estudios futuros sobre la dosis y también una posible asociación terapéutica con Mesna. llevado a cabo. Por tratarse de una patología con una prevalencia importante y muchas veces desagradable y

Carcinoma urotelial del tracto urinario superior: a propósito de un caso y revisión de la literatura / Upper urinary tract urothelial carcinoma: case report and review of the literature

El carcinoma urotelial (CU) del tracto urinario superior es infrecuente y representa solo del 5%-10% de todos los CU. Estas neoplasias crecen a partir del urotelio de los cálices renales hasta el tercio distal del uréter. Se reporta el caso de un paciente masculino de 68 años de edad quien presenta enfermedad actual de 3 meses de evolución caracterizada por dolor lumbar izquierdo, tipo cólico, de leve a moderada intensidad, el cual atenúa parcialmente con el uso de AINES, asociado a hematuria visible total de predominio nocturno. El uroanálisis mostró hematuria macroscópica y la citología urinaria evidenció atipias sugerentes de carcinoma. La TAC abdomino-pélvica contrastada evidenció un defecto de llenado en relación al cáliz inferior de riñón izquierdo y plastrón ganglionar paraaórtico izquierdo. Se practicó nefroureterectomía radical izquierda evidenciando tumor de 3 x 3 x 1 cm en relación a pelvis renal extensiva a cáliz inferior invadiendo parénquima renal. El estudio histopatológico mostró un carcinoma urotelial papilar infiltrativo de alto grado con márgenes sin lesiones y ganglios linfáticos con metástasis. El paciente evoluciona satisfactoriamente durante el período postoperatorio y actualmente recibe terapia adyuvante. A pesar de ser una patología poco frecuente, puede presentarse y el urólogo debe estar en capacidad para poder enfrentarla(AU)

Upper urinary tract urothelial carcinoma (UC) is infrequent and represents only 5%-10% of all UCs. These neoplasms grow from the urothelium of renal calyces to the distal third of the ureter. A case of UC of the upper urinary tract is reported in a 68-year-old male patient with a 3-month history of left lumbar mild to moderate pain, which partially mitigates with the use of NSAIDs associated with visible total predominantly nocturnal hematuria. Macroscopic hematuria was evident and urinary cytology reported carcinoma suggestive atypias. Contrasted CT of abdomen and pelvis showed filling defect in relation to lower calyx of the left kidney and left para-aortic ganglion plastron. Radical left nephroureterectomy was performed showing a 3 x 3 x 1 cm tumor in relation to the renal pelvis extending to the lower cavity and invading renal parenchyma. Histopathology showed high grade infiltrative papillary CU with margins without lesions and lymph nodes with metastasis. Patient evolves satisfactorily in the postoperative period and is currently in adjuvant therapy. Although this pathology is rare, it can occur and the urologist must be able to face it(AU)

Prognostic significance of inflammation-based prognostic scoring in patients with upper urinary tract urothelial carcinoma

ABSTRACT Objectives: To investigate whether Glasgow Prognostic Score has prognostic significance in patients with upper urinary urothelial carcinoma. Patients and methods: We retrospectively reviewed the clinical records of 74 patients with upper urinary urothelial carcinoma. We set the cut-off value for C-reactive protein as 1.0mg/dL, and 3.5mg/dL for albumin as Glasgow Prognostic Score. Their blood data including albumin and C-reactive protein for Glasgow Prognostic Score and cytokeratin 19 fragment 21-1 as a tumor marker were measured before starting treatment. The patients were stratified into three groups with Glasgow Prognostic Score: The Group-1, albumin ≥3.5g/dL and C-reactive protein < 1.0mg/dL; Group-2, albumin < 3.5g/dL or C-reactive protein ≥1.0mg/dL; Group-3, albumin < 3.5g/dL and C-reactive protein ≥1.0mg/dL. Results: The median follow-up for all patients was 26.9 months (range: 10.9-91.1 months), during which 37 (50%) patients died. There was a significant difference in the estimated survival rate among the 3 groups stratified by Glasgow Prognostic Score. The estimated survival rate in the Group-1 was significantly higher than those in Groups 2 and 3. In the univariate analysis C-reactive protein, serum cytokeratin 19 fragment 21-1 and Glasgow Prognostic Score were significant predictors of overall survival. On the multivariate analysis, serum cytokeratin 19 fragment 21-1 and Glasgow Prognostic Score were independently associated with shorter overall survival. Conclusion: Our review suggests Glasgow Prognostic Score may play as a prognostic predictor for upper urinary urothelial carcinoma.

Chorioallantoic urothelial tumor avatar. A clinical tool for phenotype-based therapy

Abstract In the muscle invasive bladder cancer (MIBC) standard of care treatment only patients presenting a major pathological tumor response are more likely to show the established modest 5% absolute survival benefit at 5 years after cisplatin-based neoadjuvant chemotherapy (NAC). To overcome the drawbacks of a blind NAC (i.e. late cystectomy with unnecessary NAC adverse events) with potential to survival improvements, preclinical models of urothelial carcinoma have arisen in this generation as a way to pre-determine drug resistance even before therapy is targeted. The implantation of tumor specimens in the chorioallantoic membrane (MCA) of the chicken embryo results in a high-efficiency graft, thus allowing large-scale studies of patient-derived "tumor avatar". This article discusses a novel approach that exploits cancer multidrug resistance to provide personalized phenotype-based therapy utilizing the MIBC NAC dilemma.

Time-Dependent Changes of Urethral Function in Diabetes Mellitus: A Review / 대한배뇨장애요실금학회지

This article reviewed the current knowledge on time-course manifestation of diabetic urethral dysfunction (DUD), and explored an early intervention target to prevent the contribution of DUD to the progression of diabetes-induced impairment of the lower urinary tract (LUT). In the literature search through PubMed, key words used included “diabetes mellitus,” “diabetic urethral dysfunction,” and “diabetic urethropathy.” Polyuria and hyperglycemia induced by diabetes mellitus (DM) can cause the time-dependent changes in functional and morphological manifestations of DUD. In the early stage, it promotes urethral dysfunction characterized by increased urethral pressure during micturition. However, the detrusor muscle of the bladder tries to compensate for inducing complete voiding by increasing the duration and amplitude of bladder contractions. As the disease progresses, it can induce an impairment of coordinated micturition due to dyssynergic activity of external urethra sphincter, leading to detrusor-sphincter dyssynergia. The impairment of relaxation mechanisms of urethral smooth muscles (USMs) may additionally be attributable to decreased responsiveness to nitric oxide, as well as increased USM responsiveness to α1-adrenergic receptor stimulation. In the late stage, diabetic neuropathy may play an important role in inducing LUT dysfunction, showing that the decompensation of the bladder and urethra, which can cause the decrease of voiding efficiency and the reduced thickness of the urothelium and the atrophy of striated muscle bundles, possibly leading to the vicious cycle of the LUT dysfunction. Further studies to increase our understandings of the functional and molecular mechanisms of DUD are warranted to explore potential targets for therapeutic intervention of DM-induced LUT dysfunction.

Urothelial Dysfunction and Chronic Inflammation are Associated With Increased Bladder Sensation in Patients With Chronic Renal Insufficiency / 대한배뇨장애요실금학회지

PURPOSE: Chronic kidney disease (CKD) or end-stage renal disease (ESRD) patients usually have lower urinary tract symptoms, such as frequency and urgency. Additionally, they frequently suffer from urinary tract infections. This study investigated dysfunction and chronic inflammation of the bladder urothelium in ESRD/CKD patients. METHODS: This study enrolled 27 patients with CKD (n=13) or ESRD (n=14) for urodynamic studies and bladder biopsies. Patients presented with detrusor underactivity (DU; n=8) or bladder oversensitivity (BO; n=19). Bladder biopsies were performed in these patients and in 20 controls. The bladder mucosa was examined for E-cadherin and zonula occludens-1 (ZO-1) expression, activated mast cell count (through tryptase staining), and urothelial apoptosis (through terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling [TUNEL]). The urodynamic parameters were also compared with variables regarding urothelial dysfunction. RESULTS: The bladder mucosa samples of ESRD and CKD patients revealed significantly higher mast cell counts, more urothelial apoptosis, and lower levels of ZO-1 expression than the control samples. E-cadherin expression was significantly reduced in ESRD/CKD patients with DU, but not in ESRD/CKD patients with BO. Increased mast cell and apoptotic cell counts were also associated with ESRD/CKD with BO. Less expression of ZO-1 and E-cadherin was significantly associated with increased bladder sensation and a small bladder capacity. CONCLUSIONS: Bladder urothelial dysfunction and chronic inflammation were present to a noteworthy extent in patients with ESRD or CKD. Increased inflammation and defective barrier function were more notable in ESRD/CKD bladders with BO than in those with DU. The clinical characteristics of these patients may involve urothelial pathophysiology.

Factores pronósticos de recurrencia y mortalidad en pacientes con tumor de urotelio superior tratados con cirugía / Prognostic Factors of Recurrence and Mortality in Patients with Upper Urothelial Tumor Treated with Surgery

Objetivos: Identificación de factores pronósticos de recurrencia y mortalidad cáncer-específica en pacientes con tumor de urotelio superior tratados con cirugía. Materiales y métodos: Análisis retrospectivo de pacientes con tumor de urotelio superior operados entre 1999 y 2011 en nuestro centro (139 pacientes). Se recogieron variables demográficas, clínicas, diagnósticas y patológicas, así como el tratamiento realizado, complicaciones y evolución. Análisis descriptivo mediante la prueba de chi cuadrado (X2 ) para variables categóricas y el test ANOVA (Analysis of Variance) para variables continuas. Análisis univariante y multivariante mediante modelo de riesgos proporcionales de Cox. La significación estadística se consideró con un valor de p<0,05. Todos los cálculos fueron realizados con el paquete estadístico IBM® SPSS® Statistics v-21. Resultados: En el análisis multivariante se identificaron como factores predictores independientes de recurrencia el crecimiento sólido tumoral (cociente de riesgo [hazard ratio, HR]=4,02; p<0,001) y el alto grado citológico (G3) (HR=3,42; p=0,01). La presencia de tumor vesical previo o concomitante (HR=1,84; p=0,07) presentó una tendencia a la significación. Se identificaron como factores predictores independientes de mortalidad cáncer-específica la presencia de tumor vesical previo o concomitante (HR=2,23; p=0,02), el crecimiento sólido tumoral (HR=2,73; p=0,008), la presencia de hidronefrosis (HR=2,46; p=0,02) y el estadío patológico avanzado pT3-pT4 (HR=2,74; p=0,01). Conclusiones: En nuestra serie, la existencia de tumor vesical previo o sincrónico, el crecimiento tumoral sólido y el alto grado citológico se comportaron como factores pronósticos de recurrencia. La hidronefrosis, el tumor vesical previo o sincrónico, el estadío pT3-4 y el crecimiento tumoral sólido se comportaron como factores pronósticos de mortalidad cáncer-específica. (AU)

Objectives: Identification of prognostic factors for recurrence and cancer-specific mortality in patients with upper urothelial tumor treated with surgery. Materials and methods: Retrospective analysis of patients with upper urothelial tumor operated between 1999 and 2011 in our center (139 patients). Demographic, clinical, diagnostic and pathological variables were collected, as well as the treatment performed, complications and evolution. Descriptive analysis using the chi-square test (X2 ) for categorical variables and the ANOVA (Analysis of Variance) test for continuous variables. Univariate and multivariate analysis using the Cox proportional hazards model. Statistical significance was considered with a value of p<0.05. All calculations were made with the statistical package IBM® SPSS® Statistics v-21. Results: In the multivariate analysis, solid tumor growth (hazard ratio, HR=4.02, p<0.001) and high cytological grade (G3) (HR=3, were identified as independent predictors of recurrence. 42, p=0.01). The presence of a previous or concomitant bladder tumor (HR=1.84, p= 0.07) presented a tendency towards significance. The presence of a previous or concomitant bladder tumor (HR=2.23, p=0.02), the solid tumor growth (HR=2.73, p=0.008), the presence of hydronephrosis (HR =2.46, p=0.02) and the advanced pathological stage pT3-pT4 (HR=2.74, p=0.01). Conclusions: In our series, the existence of previous or synchronic bladder tumor, solid tumor growth and high cytological grade behaved as prognostic factors of recurrence. Hydronephrosis, previous or synchronous bladder tumor, stage pT3-4 and solid tumor growth behaved as prognostic factors for cancer-specific mortality.(AU)

Factores Pronósticos de Recurrencia y Mortalidad en los Pacientes con Tumor de Urotelio Superior Tratados con Cirugía / Prognostic Factors for Recurrence and Mortality in Upper Urinary Tract Tumor

Objetivo Identificar factores pronósticos de recurrencia y mortalidad cáncer-específica en pacientes con tumor de urotelio superior tratados con cirugía. Material y Métodos Análisis retrospectivo de pacientes con tumor de urotelio superior operados entre 1999 y 2011 (139 pacientes). Se recogieron variables demográficas, clínicas, diagnósticas y patológicas así como el tratamiento, las complicaciones y la evolución. Análisis descriptivo mediante la prueba de la Chi cuadrado para variables categóricas y el test ANOVA para variables continuas. Análisis univariante y multivariante mediante modelo de riesgos proporcionales de Cox. Significación estadística si p < 0,05. Cálculos realizados con SPSS statistics v-21. Resultados En el análisis multivariante se identificaron como factores predictores independientes de recurrencia: crecimiento sólido tumoral (HR = 4,02; p < 0,001) y alto grado citológico (G3) (HR = 3,42; p = 0,01). La presencia de tumor vesical previo o concomitante (HR = 1,84; p = 0,07) presentó una tendencia a la significación. Se identificaron como factores predictores independientes de mortalidad cáncer-específica: presencia de tumor vesical previo o concomitante (HR = 2,23; p = 0,02), crecimiento sólido tumoral (HR = 2,73; p = 0,008), presencia de hidronefrosis (HR = 2,46; p = 0,02) y estadio patológico avanzado pT3-pT4 (HR = 2,74; p = 0,01). Conclusión En nuestra serie, la existencia de tumor vesical previo o sincrónico, el crecimiento tumoral sólido y el alto grado citológico se comportaron como factores pronósticos de recurrencia. La hidronefrosis, el tumor vesical previo o sincrónico, el estadio pT3­4 y el crecimiento tumoral sólido, se comportaron como factores pronósticos de mortalidad cáncer-específica.

Objective To identify predictors of recurrence and cancer-specific mortality in patients with upper urinary tract carcinoma treated with surgery. Material and Methods Retrospective analysis of patients with upper urinary tract urothelial carcinoma getting surgery between 1999 and 2011 in our institution (139 patients). We collected demographic, clinical, pathological and diagnostic variables as well as the treatment performed, the occurred complications and the evolution. A descriptive analysis was performed using the Chi square test for categorical variables and the ANOVA test for continuous variables. We performed an univariate and multivariate analysis using a proportional Cox risks model. Statistical significance was considered when p < 0.05. All calculcations were performed with SPSS statistics v-21. Results In the multivariate analysis, the solid tumor growth (HR = 4.02; p < 0.001) and a high cytological grade (G3) (HR = 3.42; p = 0.01) were identified as independent predictors; the presence of previous or concomitant bladder tumor (HR = 1.84; p = 0.07) showed a trend to statistical significance. In the multivariate analysis, the presence of previous or concomitant bladder tumor (HR = 2.23; p = 0.02), the solid tumor growth (HR = 2.73; p = 0.008), the presence of hydronephrosis (HR = 2.46; p = 0.02) and the advanced pathological stage pT3-pT4 (HR = 2.74; p = 0.01) were identified as independent predictors of cancer-specific mortality. Conclusion The existence of previous or concomitant bladder cancer at the diagnosis of upper urinary tract carcinoma, solid growth pattern and high cytological grade (G3) were identified as independent predictors of recurrence in our series. The existence of hydronephrosis at diagnosis, prior or concomitant bladder tumor, pathologic stage pT3­4 and the solid growth pattern were identified as independent predictors of cancerspecific mortality.

Feline Interstitial Cystitis Enhances Mucosa-Dependent Contractile Responses to Serotonin / 대한배뇨장애요실금학회지

PURPOSE: To determine whether responses to serotonin are altered in bladder strips from cats diagnosed with a naturally occurring form of bladder pain syndrome/interstitial cystitis termed feline interstitial cystitis (FIC). METHODS: Full thickness bladder strips were isolated from aged matched healthy control cats and cats with clinically verified FIC. Bladder strips were mounted in an organ bath and connected to a tension transducer to record contractile activity. A serotonin dose response (0.01–10μM) was determined for each strip with the mucosa intact or denuded. RESULTS: Bladder strips from control and FIC cats contracted in response to serotonin in a dose-dependent manner. The normalized force of serotonin-evoked contractions was significantly greater in bladder strips from cats with FIC (n=7) than from control cats (n=4). Removal of the mucosa significantly decreased serotonin-mediated responses in both control and FIC bladder preparations. Furthermore, the contractions in response to serotonin were abolished by 1μM atropine in both control and FIC bladder strips. CONCLUSIONS: The effect of serotonin on contractile force, but not sensitivity, was potentiated in bladder strips from cats with FIC, and was dependent upon the presence of the mucosa in control and FIC groups. As atropine inhibited these effects of serotonin, we hypothesize that, serotonin enhances acetylcholine release from the mucosa of FIC cat bladder strips, which could account for the increased force generated. In summary, FIC augments the responsiveness of bladder to serotonin, which may contribute to the symptoms associated with this chronic condition.

Which is best method for instillation of topical therapy to the upper urinary tract? An in vivo porcine study to evaluate three delivery methods

ABSTRACT Purpose: To compare the staining intensity of the upper urinary tract (UUT) urothelium among three UUT delivery methods in an in vivo porcine model. Materials and methods: A fluorescent dye solution (indigo carmine) was delivered to the UUT via three different methods: antegrade perfusion, vesico-ureteral reflux via in-dwelling ureteric stent and retrograde perfusion via a 5F open-ended ureteral catheter. Twelve renal units were tested with 4 in each method. After a 2-hour delivery time, the renal-ureter units were harvested en bloc. Time from harvesting to analysis was also standardised to be 2 hours in each arm. Three urothelium samples of the same weight and size were taken from each of the 6 pre-defined points (upper pole, mid pole, lower pole, renal pelvis, mid ureter and distal ureter) and the amount of fluorescence was measured with a spectrometer. Results: The mean fluorescence detected at all 6 predefined points of the UUT urothelium was the highest for the retrograde method. This was statistically significant with p-value less than <0.05 at all 6 points. Conclusions: Retrograde infusion of UUT by an open ended ureteral catheter resulted in highest mean fluorescence detected at all 6 pre-defined points of the UUT urothelium compared to antegrade infusion and vesico-ureteral reflux via indwelling ureteric stents indicating retrograde method ideal for topical therapy throughout the UUT urothelium. More clinical studies are needed to demonstrate if retrograde method could lead to better clinical outcomes compared to the other two methods.

Prognostic value of p53 expression intensity in urothelial cancers

Objective: To determine association of immunohistochemical expression intensity of p53 with grade and stage of urothelial cancers

Study Design: Descriptive cross-sectional analytical study

Place and Duration of Study: Pathology Department, King Edward Medical University, Lahore, from January to December 2016

Methodology: Data of transurethral resection/radical cystesctomy urinary bladder biopsies was collected. Clinical, radiological and cystoscopic findings of patients were noted from patients' charts in the Urology Ward. Biopsies were graded histologically according to WHO 2004 grading system. TNM system was used for pathological staging. On selected slides, immunoshistochemistry for p53 was applied. Nuclear immunoreactivity was considered positive if present in >10% of tumor cells and negative if <10% of tumor cells. Intensity was considered weak [less than 15% cells] and strong [more than 15% cells]. Data was analyzed by SPSS version 21. Linear-by-linear association was calculated between p53 expression and stage of urothelial tumors, Chi-Square test was used to see association between grade and intensity of p53. Qualitative variables, like grade and stage of carcinoma along with p53 expression, were calculated in terms of frequencies and percentages. P

Results: Out of the 70 patients, 61 [87%] were males and 9 [13%] females. Out of 25 low grade lesions, 4 [16%] cases were p53 positive; and out of 45 high grade lesions, 41 [91%] cases were p53 positive. There was 33% [2/6 cases] positivity in Tis, 55% [16/29 cases] in T1, 72% in T2 [21/29], and 100% in T3a [5/5 cases] and T3b [1/1 case]. Strong intensity of p53 staining was noted to be 5.4% [n=25] of low grade and 94.6% [n=45] of high grade tumors

Conclusion: p53 expression was greater and more frequently strong in higher grade and stage of urothelial carcinoma. It can be used as a prognostic marker in predicting higher grade and stage of bladder cancer

On the Site and Mechanism of Action of β₃-Adrenoceptor Agonists in the Bladder / 대한배뇨장애요실금학회지

The clinical success of mirabegron as the first β₃-adrenoceptor (AR) agonist for treatment of the overactive bladder (OAB) syndrome, has resulted in substantial interest in its site and mechanism of action. Even if the adrenergic innervation of the bladder and urethra has been well studied, the location(s) of β₃-ARs in different structures within the bladder wall and urethra, and the mode(s) of action of β₃-AR stimulation have still not been established. The recent demonstration of β₃-ARs on cholinergic nerve terminals with no immunoreactivity in urothelium or detrusor smooth muscle, is not in agreement with previous morphological studies, and functional data strongly suggest that β₃-ARs can be found these structures. However, recent studies suggest that the β₃-ARs on detrusor smooth muscle may not be the functionally most relevant. The assumption that β₃-AR activation during bladder filling inhibits acetylcholine release from parasympathetic neurons by a prejunctional mechanism and that this decreases bladder micromotions that generate afferent activity, is an attractive hypothesis. It does not exclude that other mechanisms may be contributing, and supports combined approaches to reduce afferent activity for treatment of the OAB syndrome.

Low grade urothelial carcinoma mimicking basal cell hyperplasia and transitional metaplasia in needle prostate biopsy

ABSTRACT Purpose The vast majority of urothelial carcinomas infiltrating the bladder are consistent with high-grade tumors that can be easily recognized as malignant in needle prostatic biopsies. In contrast, the histological changes of low-grade urothelial carcinomas in this kind of biopsy have not been studied. Materials and Methods We describe the clinicopathologic features of two patients with low-grade bladder carcinomas infiltrating the prostate. They reported dysuria and hematuria. Both had a slight elevation of the prostate specific antigen and induration of the prostatic lobes. Needle biopsies were performed. At endoscopy bladder tumors were found in both cases. Results Both biopsies showed nests of basophilic cells and cells with perinuclear clearing and slight atypia infiltrating acini and small prostatic ducts. The stroma exhibited extensive desmoplasia and chronic inflammation. The original diagnosis was basal cell hyperplasia and transitional metaplasia. The bladder tumors also showed low-grade urothelial carcinoma. In one case, the neoplasm infiltrated the lamina propria, and in another, the muscle layer. In both, a transurethral resection was performed for obstructive urinary symptoms. The neoplasms were positive for high molecular weight keratin (34BetaE12) and thrombomodulin. No metastases were found in either of the patients, and one of them has survived for five years. Conclusions The diagnosis of low-grade urothelial carcinoma in prostate needle biopsies is difficult and may simulate benign prostate lesions including basal cell hyperplasia and urothelial metaplasia. It is crucial to recognize low-grade urothelial carcinoma in needle biopsies because only an early diagnosis and aggressive treatment can improve the prognosis for these patients.

Urothelial neoplasm of the bladder in childhood and adolescence: a rare disease

ABSTRACT Purpose: Bladder tumors are rare in children and adolescents. For this reason, the diagnosis is sometimes delayed in pediatric patients. We aimed to describe the diagnosis, treatment, and follow-up methods of bladder urothelial neoplasms in children and adolescents. Materials and Methods: We carried out a retrospective multicenter study involving patients who were treated between 2008 and 2014. Eleven patients aged younger than 18 years were enrolled in the study. In all the patients, a bladder tumor was diagnosed using ultrasonography and was treated through transurethral resection of the bladder (TURBT). Results: Nine of the 11 patients (82%) were admitted with gross hematuria. The average delay in diagnosis was 3 months (range, 0–16 months) until the ultrasonographic diagnosis was performed from the first episodes of macroscopic hematuria. A single exophytic tumor (1–4cm) was present in each patient. The pathology of all patients was reported as superficial urothelial neoplasm: two with papilloma, one with papillary urothelial neoplasm of low malignant potential (PUNLMP), four with low grade pTa, and four with low grade pT1. No recurrence was observed during regular cystoscopic and ultrasonographic follow-up. Conclusions: Regardless of the presence of hematuria, bladder tumors in children are usually not considered because urothelial carcinoma in this population is extremely rare, which causes a delay in diagnosis. Fortunately, the disease has a good prognosis and recurrences are infrequent. Cystoscopy may be unnecessary in the follow-up of children with bladder tumors. We believe that ultrasonography is sufficient in follow-up.

Cutaneous invasion from sarcomatoid urothelial carcinoma: clinical and dermatopathologic features

Abstract 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.

Impaired Na+/K+-ATPase Function in Patients with Interstitial Cystitis/Painful Bladder Syndrome

Na+/K+-ATPase (NKA) is abundantly expressed in the basolateral membrane of epithelial cells, which is necessary for tight junction formation. The tight junction is an urothelial barrier between urine and the underlying bladder. Impairment of tight junctions allows migration of urinary solutes in patients with interstitial cystitis/painful bladder syndrome (IC/PBS). We evaluated NKA expression and activity in bladder samples from patients with IC/PBS. The study group consisted of 85 patients with IC/PBS, and the control group consisted of 20 volunteers. Bladder biopsies were taken from both groups. We determined the expression and distribution of NKA using NKA activity assays, immunoblotting, immunohistochemical staining, and immunofluorescent staining. The protein levels and activity of NKA in the study group were significantly lower than the control group (1.08 ± 0.06 vs. 2.39 ± 0.29 and 0.60 ± 0.04 vs. 1.81 ± 0.18 micromol ADP/mg protein/hour, respectively; P < 0.05). Additionally, immunofluorescent staining for detection of CK7, a marker of the bladder urothelium, predominantly colocalized with NKA in patients in the study group. Our results demonstrated the expression and activity of NKA were decreased in bladder biopsies of patients with IC/PBS. These findings suggest that NKA function is impaired in the bladders from patients with IC/PBS.

Expression of miRNA-630 in bladder urothelial carcinoma and its clinical significance / 华中科技大学学报（医学）（英德文版）

Many studies informed that microRNAs (miRNAs) could function as diagnostic and prognostic indicators in several cancers. The aims of this study were to explore the expression of miR-630 in bladder urothelial carcinoma and its clinical significance for the evaluation of cancer prognosis. A total of 116 patients with bladder urothelial carcinoma were obtained in this retrospective study between May, 2012 and Sep. 2015. Quantitative real-time PCR (qRT-PCR) was conducted to evaluate the expression level of miR-630. The chi-square test was used to examine the associations between miR-630 expression and the clinicopathological features. The Kaplan-Meier method was conducted to explore the survival status of urothelial carcinoma patients. The log-rank test was used to analyze differences in survival rate. The results showed an obvious increase in miR-630 expression from normal bladder to bladder urothelial carcinoma (P=0.027). Additionally, patients with higher miR-630 expression had significantly shorter disease-free survival (DFS) (P=0.043) and overall survival (OS) (P=0.038) than those with lower miR-630 expression. Furthermore, multivariate analysis revealed that up-regulation of miR-630 was an independent prognostic factor for both DFS (P=0.042) and OS (P=0.046). It was demonstrated that miR-630 may be a novel and valuable prognostic factor for bladder urothelial carcinoma.

A Case Report of Partial Nephrectomy of Mucinous Cystadenocarcinoma in Kidney and Its Literature Review / Journal of the Korean Cancer Association, 대한암학회지

Mucinous cystadenocarcinoma (MC) of the kidney is a rare epithelial tumor originating from the renal pelvic urothelium and few study cases have been reported. Because of the rarity of these tumors and their unknown histogenesis, its diagnosis is difficult until surgical exploration. We report here on a 55-year-old man referred to the urology department from the hepatology department because of a cystic renal mass measuring approximately 5 cm in size, which was detected incidentally under ultrasonography during the routine examination of liver. The renal mass was finally diagnosed as MC originating from kidney after partial nephrectomy and the patient still showed no evidence of recurrence until 12 months postoperatively. This is the first report on a case of renal MC in a patient who underwent partial nephrectomy. The aim of this report is to present our unusual case of MC and also review the previous literature on the pathological and radiological aspects of MC of kidney.

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

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.

Abnormal Sensory Protein Expression and Urothelial Dysfunction in Ketamine-Related Cystitis in Humans / 대한배뇨장애요실금학회지

PURPOSE: The aim of this study was to analyze patterns of sensory protein expression and urothelial dysfunction in ketamine-related cystitis (KC) in humans. METHODS: Biopsies of bladder mucosa were performed in 29 KC patients during cystoscopy. Then specimens were analyzed for tryptase, zonula occludens-1 (ZO-1), E-cadherin, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) with immunofluorescence staining and quantification. In addition, 10 healthy control bladder specimens were analyzed and compared with the KC specimens. Another 16 whole bladder specimens obtained from partial cystectomy were also analyzed for the muscarinic receptors M2 and M3, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), β-3 adrenergic receptors (β3-ARs), and the P2X₃ receptor by western blotting. In addition, 3 normal control bladder specimens were analyzed and compared with the KC specimens. RESULTS: The KC bladder mucosa revealed significantly less expression of ZO-1 and E-cadherin, and greater expression of TUNEL and tryptase activity than the control samples. The expression of M3 and β3-AR in the KC specimens was significantly greater than in the controls. The expression of iNOS, eNOS, M2, and P2X3 was not significantly different between the KC and control specimens. CONCLUSIONS: The bladder tissue of KC patients revealed significant urothelial dysfunction, which was associated with mast-cell mediated inflammation, increased urothelial cell apoptosis, and increased expression of the M3 and β3-AR.