Outcomes of an enhanced recovery after radical cystectomy program in a prospective multicenter study: compliance and key components for success.

OBJECTIVE: To investigate the effect of an Enhanced Recovery After Surgery (ERAS) program on complications and length of stay (LOS) after radical cystectomy (RC) and to assess if the number and type of components of ERAS play a key role on the decrease of surgical morbidity. MATERIALS AND METHODS: We analyzed the data of 277 patients prospectively recruited in 11 hospitals undergoing RC initially managed according to local practice (Group I) and later within an ERAS program (Group II). Two main outcomes were defined: 90-day complications rate and LOS. As secondary variables we studied 90-day mortality, 30-day readmission and transfusion rate. RESULTS: Patients in Group II had a higher use of ERAS measures (98.6%) than those in Group I (78.2%) (p < 0.05). Patients in Groups I and II experienced similar complications (70.5% vs. 66%, p = 0.42). LOS was not different between Groups I and II (12.5 and 14 days, respectively, p = 0.59). The risk of having any complication decreases for patients having more than 15 ERAS measures adopted [RR = 0.815; 95% confidence interval (CI) 0.667-0.996; p = 0.045]. Avoidance of transfusion and nasogastric tube, prevention of ileus, early ambulation and a fast uptake of a regular diet are independently associated with the absence of complications. CONCLUSIONS: Complications and LOS after RC were not modified by the introduction of an ERAS program. We hypothesize that at least 15 measures should be applied to maximize the benefit of ERAS.

Validación del índice de salud prostática en un modelo predictivo de cáncer de próstata / Validation of the prostate health index in a predictive model of prostate cancer

Objetivos: Validar y analizar la utilidad clínica de un modelo predictivo de cáncer de próstata que incorpora el biomarcador «[-2] proantígeno prostático específico» a través del índice de salud prostática (PHI) en la toma de decisión para realizar una biopsia de próstata. Material y métodos: Se aisló suero de 197 varones con indicación de biopsia de próstata para la determinación del antígeno prostático específico total (tPSA), fracción libre de PSA (fPSA) y [-2] proPSA (p2PSA); el PHI se calculó como p2PSA/fPSA × √tPSA. Se crearon 2 modelos predictivos que incorporaban variables clínicas junto a tPSA o a PHI. Se evaluó el rendimiento de PHI usando análisis de discriminación mediante curvas ROC, calibración interna y curvas de decisión. Resultados: Las áreas bajo la curva para el modelo tPSA y el modelo PHI fueron de 0,71 y 0,85, respectivamente. PHI mostró mejor capacidad de discriminación y mejor calibración para predecir cáncer de próstata, pero no para predecir un grado de Gleason en la biopsia ≥7. Las curvas de decisión mostraron un beneficio neto superior del modelo PHI para el diagnóstico de cáncer de próstata cuando el umbral de probabilidad está entre 15 y 35% y un mayor ahorro (20%) en el número de biopsias. Conclusiones: La incorporación de p2PSA a través de PHI a los modelos predictivos de cáncer de próstata mejora la exactitud en la estratificación del riesgo y ayuda en la toma de decisión sobre realizar una biopsia de próstata

Objectives: To validate and analyse the clinical usefulness of a predictive model of prostate cancer that incorporates the biomarker «[-2] pro prostate-specific antigen» using the prostate health index (PHI) in decision making for performing prostate biopsies. Material and methods: We isolated serum from 197 men with an indication for prostate biopsy to determine the total prostate-specific antigen (tPSA), the free PSA fraction (fPSA) and the [-2] proPSA (p2PSA). The PHI was calculated as p2PSA/fPSA × √tPSA. We created 2 predictive models that incorporated clinical variables along with tPSA or PHI. The performance of PHI was assessed with a discriminant analysis using receiver operating characteristic curves, internal calibration and decision curves. Results: The areas under the curve for the tPSA and PHI models were 0.71 and 0.85, respectively. The PHI model showed a better ability to discriminate and better calibration for predicting prostate cancer but not for predicting a Gleason score in the biopsy ≥7. The decision curves showed a greater net benefit with the PHI model for diagnosing prostate cancer when the probability threshold was 15-35% and greater savings (20%) in the number of biopsies. Conclusions: The incorporation of p2PSA through PHI in predictive models of prostate cancer improves the accuracy of the risk stratification and helps in the decision-making process for performing prostate biopsies

Validation of the prostate health index in a predictive model of prostate cancer. / Validación del índice de salud prostática en un modelo predictivo de cáncer de próstata.

OBJECTIVES: To validate and analyse the clinical usefulness of a predictive model of prostate cancer that incorporates the biomarker «[-2] pro prostate-specific antigen¼ using the prostate health index (PHI) in decision making for performing prostate biopsies. MATERIAL AND METHODS: We isolated serum from 197 men with an indication for prostate biopsy to determine the total prostate-specific antigen (tPSA), the free PSA fraction (fPSA) and the [-2] proPSA (p2PSA). The PHI was calculated as p2PSA/fPSA×√tPSA. We created 2 predictive models that incorporated clinical variables along with tPSA or PHI. The performance of PHI was assessed with a discriminant analysis using receiver operating characteristic curves, internal calibration and decision curves. RESULTS: The areas under the curve for the tPSA and PHI models were 0.71 and 0.85, respectively. The PHI model showed a better ability to discriminate and better calibration for predicting prostate cancer but not for predicting a Gleason score in the biopsy ≥7. The decision curves showed a greater net benefit with the PHI model for diagnosing prostate cancer when the probability threshold was 15-35% and greater savings (20%) in the number of biopsies. CONCLUSIONS: The incorporation of p2PSA through PHI in predictive models of prostate cancer improves the accuracy of the risk stratification and helps in the decision-making process for performing prostate biopsies.

Do we need new high-risk criteria for surgically treated renal cancer patients to improve the outcome of future clinical trials in the adjuvant setting? Results of a comprehensive analysis based on the multicenter CORONA database.

BACKGROUND: Since there is still an unmet need for potent adjuvant strategies for renal cancer patients with high progression risk after surgery, several targeted therapies are currently evaluated in this setting. We analyzed whether inclusion criteria of contemporary trials (ARISER, ASSURE, SORCE, EVEREST, PROTECT, S-TRAC, ATLAS) correctly identify high-risk patients. METHODS: The study group comprised 8873 patients of the international CORONA-database after surgery for non-metastatic renal cancer without any adjuvant treatment. Patients were divided into potentially eligible high-risk and assumable low-risk patients who didn't meet inclusion criteria of contemporary adjuvant clinical trials. The ability of various inclusion criteria for disease-free survival (DFS) prediction was evaluated by Harrell's c-index. RESULTS: During a median follow-up of 53 months 15.2% of patients experienced recurrence (5-year-DFS 84%). By application of trial inclusion criteria, 24% (S-TRAC) to 47% (SORCE) of patients would have been eligible for enrollment. Actual recurrence rates of eligible patients ranged between 29% (SORCE) and 37% (S-TRAC) opposed to <10% in excluded patients. Highest Hazard Ratio for selection criteria was proven for the SORCE-trial (HR 6.42; p < 0.001), while ASSURE and EVEREST reached the highest c-index for DFS prediction (both 0.73). In a separate multivariate Cox-model, two risk-groups were identified with a maximum difference in 5-year-DFS (94% vs. 61%). CONCLUSION: Results of contemporary adjuvant clinical trials will not be comparable as inclusion criteria differ significantly. Risk assessment according to our model might improve patient selection in clinical trials by defining a high-risk group (28% of all patients) with a 5-year-recurrence rate of almost 40%.

Asociación entre síndrome metabólico y cáncer de próstata: efecto sobre su agresividad y progresión / The association between metabolic syndrome and prostate cancer: Effect on its aggressiveness and progression

Objetivos: Evaluar el impacto del síndrome metabólico y de sus componentes individuales en los hallazgos en la biopsia de próstata, la pieza de prostatectomía radical y en la recidiva bioquímica. Material y métodos: Estudio observacional de 1.319 varones sometidos a biopsia de próstata entre enero de 2007 y diciembre de 2011. El impacto en los hallazgos en la biopsia, en la pieza de prostatectomía radical y en la recidiva bioquímica se ha evaluado mediante regresión logística y regresión de Cox. Resultados: De los 1.319 pacientes 275 (21%) presentaban Síndrome metabólico y se diagnosticaron 517 cánceres de próstata. Se encontró un mayor porcentaje de síndrome metabólico entre pacientes con cáncer de próstata que entre pacientes sin cáncer de próstata (25% frente a 18%; p = 0,002). Se encontraron peores hallazgos en la pieza de prostatectomía radical (grado de Gleason ≥ 7, p < 0,001; estadio ≥ T2c, p < 0,001; márgenes quirúrgicos positivos, p < 0,001) y un mayor porcentaje de recidivas bioquímicas en pacientes con síndrome metabólico que sin síndrome metabólico (24% frente a 13%; p = 0,003). El síndrome metabólico se comportó como factor predictivo independiente de encontrar un grado de Gleason de la pieza ≥ 7, así como de encontrar un estadio de la pieza ≥ T2c, y fue capaz de predecir de forma independiente una mayor tasa de recidivas bioquímicas (p < 0,001, OR: 3,6; p < 0,001 OR: 3,2; p = 0,03 HR: 1,7, respectivamente). Conclusiones: El síndrome metabólico se asocia a peores hallazgos en la pieza de prostatectomía radical y es un factor pronóstico independiente de recidiva bioquímica

Objectives: To evaluate the impact of metabolic syndrome and its individual components on prostate biopsy findings, the radical prostatectomy specimen and on biochemical recurrence. Material and methods: An observational study was conducted of 1319 men who underwent prostate biopsy between January 2007 and December 2011. The impact on the biopsy findings, the radical prostatectomy specimen and biochemical recurrence was evaluated using logistic regression and Cox regression.Results: Of the 1319 patients, 275 (21%) had metabolic syndrome, and 517 prostate cancers were diagnosed. A greater percentage of metabolic syndrome was found among patients with prostate cancer than among patients without prostate cancer (25% vs. 18%; P = .002). Poorer results were found in the radical prostatectomy specimens (Gleason score ≥ 7, P < .001; stage ≥ T2c, P < .001; positive surgical margins, P < .001), and there was a greater percentage of biochemical recurrence in patients with metabolic syndrome than in those without metabolic syndrome (24% vs. 13%; P = .003). Metabolic syndrome behaved as an independent predictive factor of finding a Gleason score ≥ 7 for the specimen, as well as for finding a specimen stage ≥ T2c. Metabolic syndrome was also able to independently predict a greater rate of biochemical recurrence (OR: 3.6, P < .001; OR: 3.2, P = .03; HR: 1.7; respectively). Conclusions: Metabolic syndrome is associated with poorer findings in the radical prostatectomy specimens and is an independent prognostic factor of biochemical recurrence

Evolución de las características del paciente candidato a prostatectomía radical y de los resultados obtenidos con la técnica / Evolution of the patient characteristics of candidates for radical prostatectomy and the results obtained with the technique

Objetivos: Evaluar el perfil oncológico y el riesgo de recidiva bioquímica de pacientes con cáncer de próstata sometidos a prostatectomía radical en función del periodo en el que fueron intervenidos. Evaluar las diferencias en el PSA al diagnóstico de los pacientes con o sin recidiva bioquímica en función de dichos periodos. Material y métodos: Diseño observacional hacia delante de una cohorte de 972 prostatectomías radicales realizadas en 3 periodos (1994-2000, 2001-2006, 2007-2011). La importancia del PSA al diagnóstico en los periodos y en la recidiva bioquímica se evaluó mediante modelo lineal generalizado. El comportamiento predictivo independiente de recidiva bioquímica se analizó mediante regresión de Cox. Resultados: La mediana de seguimiento fue de 38 (16-76) meses. El PSA diagnóstico fue más alto en el periodo 1994-2000 (12,97 ng/ml, p < 0,001). Un 72% de los pacientes del periodo 2007-2011 frente al 55% de los del periodo 1994-2000 se diagnosticaron con estadio clínico T1c (p < 0,001). El porcentaje de extensión extracapsular en la pieza disminuyó del 27 al 18% del periodo 1994-2000 al periodo 2007-2011 (p < 0,001). El porcentaje de pacientes con recidiva bioquímica pasó del 38 al 14% del primer al tercer periodo (p > 0,001). La diferencia entre el PSA al diagnóstico de los pacientes con o sin recidiva bioquímica fue independiente del periodo (p = 0,84). El periodo en que se realiza la cirugía no es un factor predictivo independiente de recidiva bioquímica (p = 0,09). Conclusiones: Los pacientes del periodo 2007-2011 presentan menos enfermedad extracapsular en la prostatectomía radical. El periodo no es un factor predictivo independiente de recidiva bioquímica

Objectives: To evaluate the oncological profile and risk of biochemical recurrence of patients with prostate cancer who underwent radical prostatectomy based on the time period in which the patients were operated. To evaluate the differences in prostate-specific antigen (PSA) at diagnosis of patients with or without biochemical recurrence based on these time periods. Material and methods: Observation carried forward study of a cohort of 972 radical prostatectomies performed during 3 time periods (1994-2000, 2001-2006, 2007-2011). The importance of PSA at diagnosis on the time periods and on biochemical recurrence was assessed using a generalized linear model. The independent predictive behavior of biochemical recurrence was analyzed using Cox regression. Results: The median follow-up was 38 (16-76) months. PSA levels at diagnosis were higher in the period 1994-2000 (12.97 ng/mL, P < .001). Seventy-two percent of the patients from the period 2007-2011 were diagnosed as clinical stage T1c (P < .001), compared with 55% from the period 1994-2000. The percentage of extracapsular extension in the specimen decreased from 27% to 18% from the period 1994-2000 to the period 2007-2011 (p<.001). The percentage of patients with biochemical recurrence went from 38% to 14% from the first to the third period (P > .001). The difference between PSA levels at diagnosis for the patients with or without biochemical recurrence was independent of the period (P = .84). The period during which surgery was performed was not an independent predictive factor for biochemical recurrence (P = .09). Conclusions: Patients from the 2007-2011 period had less extracapsular disease in the radical prostatectomy. The period was not an independent predictive factor for biochemical recurrence

Evolution of the patient characteristics of candidates for radical prostatectomy and the results obtained with the technique.

OBJECTIVES: To evaluate the oncological profile and risk of biochemical recurrence of patients with prostate cancer who underwent radical prostatectomy based on the time period in which the patients were operated. To evaluate the differences in prostate-specific antigen (PSA) at diagnosis of patients with or without biochemical recurrence based on these time periods. MATERIAL AND METHODS: Observation carried forward study of a cohort of 972 radical prostatectomies performed during 3 time periods (1994-2000, 2001-2006, 2007-2011). The importance of PSA at diagnosis on the time periods and on biochemical recurrence was assessed using a generalized linear model. The independent predictive behavior of biochemical recurrence was analyzed using Cox regression. RESULTS: The median follow-up was 38 (16-76) months. PSA levels at diagnosis were higher in the period 1994-2000 (12.97ng/mL, P<.001). Seventy-two percent of the patients from the period 2007-2011 were diagnosed as clinical stage T1c (P<.001), compared with 55% from the period 1994-2000. The percentage of extracapsular extension in the specimen decreased from 27% to 18% from the period 1994-2000 to the period 2007-2011 (p<.001). The percentage of patients with biochemical recurrence went from 38% to 14% from the first to the third period (P>.001). The difference between PSA levels at diagnosis for the patients with or without biochemical recurrence was independent of the period (P=.84). The period during which surgery was performed was not an independent predictive factor for biochemical recurrence (P=.09). CONCLUSIONS: Patients from the 2007-2011 period had less extracapsular disease in the radical prostatectomy. The period was not an independent predictive factor for biochemical recurrence.

The association between metabolic syndrome and prostate cancer: Effect on its aggressiveness and progression.

OBJECTIVES: To evaluate the impact of metabolic syndrome and its individual components on prostate biopsy findings, the radical prostatectomy specimen and on biochemical recurrence. MATERIAL AND METHODS: An observational study was conducted of 1319 men who underwent prostate biopsy between January 2007 and December 2011. The impact on the biopsy findings, the radical prostatectomy specimen and biochemical recurrence was evaluated using logistic regression and Cox regression. RESULTS: Of the 1319 patients, 275 (21%) had metabolic syndrome, and 517 prostate cancers were diagnosed. A greater percentage of metabolic syndrome was found among patients with prostate cancer than among patients without prostate cancer (25% vs. 18%; P=.002). Poorer results were found in the radical prostatectomy specimens (Gleason score ≥ 7, P<.001; stage ≥ T2c, P<.001; positive surgical margins, P<.001), and there was a greater percentage of biochemical recurrence in patients with metabolic syndrome than in those without metabolic syndrome (24% vs. 13%; P=.003). Metabolic syndrome behaved as an independent predictive factor of finding a Gleason score ≥ 7 for the specimen, as well as for finding a specimen stage ≥ T2c. Metabolic syndrome was also able to independently predict a greater rate of biochemical recurrence (OR: 3.6, P<.001; OR: 3.2, P=.03; HR: 1.7; respectively). CONCLUSIONS: Metabolic syndrome is associated with poorer findings in the radical prostatectomy specimens and is an independent prognostic factor of biochemical recurrence.

Impacto de la expresión de p53, MIB-1 y PECAM-1 en el pronóstico del carcinoma urotelial de la pelvis renal / Impact of p53, MIB-1 and PECAM-1 expression on the prognosis of urothelial carcinoma of the renal pelvis

Objetivo: Investigar si la sobreexpresión de los niveles proteicos de p53, MIB-1 y PECAM-1 ocupa un lugar de interés en la predicción de pronóstico del carcinoma de células transicionales del tracto urinario superior (CCT-TUS) de asiento primario en la pelvis renal. Material y método: Análisis uni y multivariante para la predicción de pronóstico en una serie de 82 pacientes con CCT-TUS de pelvis renal sin metástasis al diagnóstico (N0/Nx M0) tratados mediante nefroureterectomía exclusivamente. Se evalúan parámetros clínico-patológicos (edad, sexo, grado, extensión tumoral, variedad histológica, patrón de crecimiento, invasión vascular, infiltración del parénquima renal, necrosis tumoral) y expresión inmunohistoquímica (IHQ) de p53, MIB-1 (ki-67) y PECAM-1 (CD31) en secciones realizadas con microarray de tejido (TMA). Resultados: El 47,6% fueron lesiones de alto grado según la clasificación USIP-OMS. El patrón de crecimiento fue plano en 15,85%. La distribución por categoría T fue: 3,7% pTa, 51,2% pT1, 11% pT2, 29,3% pT3 y 4,9% pT4. El seguimiento medio fue 46,8 + 38,5 (rango: 4-172) meses. La mediana de supervivencia se alcanzó a los 57 (IC 95%: 44-63) meses. El análisis univariante reveló que la supervivencia en estos pacientes se asocia a tamaño tumoral (p = 0,028), variedad histológica (p < 0,0001), patrón de crecimiento (p < 0,0001), grado (p < 0,0001), pT (p = 0,01), invasión vascular (p = 0,025), necrosis (p = 0,004) y sobreexpresión de p53 (p = 0,0006), PECAM-1 (p = 0,0036) y MIB-1 (p = 0,0038). El modelo de regresión de Cox mostró que alto grado (HR = 4,2 [IC 95%: 1,28-13,79]; p = 0,018), patrón de crecimiento plano (HR = 2,52 [IC 95%: 1,05-6,03]; p = 0,038) y sobreexpresión de p53 (HR = 2,8 [IC 95%: 1,22-6,44]; p = 0,015) fueron variables predictivas independientes. Conclusión: El grado histológico, el patrón de crecimiento tumoral y la sobreexpresión de p53 se establecen como los principales factores predictivos de pronóstico en CCT-TUS primario de pelvis renal. No se reproduce el valor independiente de MIB-1 objetivado en otros estudios

Objective: Determining whether the overexpression of p53, MIB-1 and PECAM-1 of protein levels is of interest in predicting the prognosis of transitional cell carcinoma of the upper urinary tract (TCC-UUT) with the primary seat in the renal pelvis. Materials and methods: A univariate and multivariate analysis was conducted for prognosis prediction in a series of 82 patients with TCC-UUT of the renal pelvis who had no metastases at diagnosis (N0/Nx M0) and were treated exclusively with nephroureterectomy. We assessed clinicopathological parameters (age, gender, tumor grade and extent, histological variety, growth pattern, vascular invasion, infiltration of the renal parenchyma, and tumor necrosis) and the immunohistochemical expression of p53, MIB-1 (ki-67) and PECAM-1 (CD31) in sections performed with tissue microarray (TMA). Results: A total of 47.6% of the patients had high-grade lesions according to the USIP-WHO classification. The growth pattern was flat in 15.85%. The distribution by T category was: 3.7% pTa, 51.2% pT1, 11% pT2, 29.3% pT3 and 4.9% pT4. The mean follow-up was 46.8 ± 38.5 (range 4-172) months. The median survival was reached at 57 (95% CI 44-63) months. The univariate analysis revealed that survival in these patients is associated with tumor size (p = 0.028), histological variety (p < 0.0001), growth pattern (p < 0.0001), grade (p < 0.0001), pT (p = 0.01), vascular invasion (p = 0.025), necrosis (p = 0.004) and overexpression of p53 (p = 0.0006), PECAM-1 (p = 0.0036) and MIB-1 (p = 0.0038). The Cox regression model showed that high-grade (HR, 4.2; 95% CI 1.28-13.79; p = 0.018), flat-growth pattern (HR, 2.52; 95% CI 1.05-6.03; p = 0.038) and p53 overexpression (HR, 2.8; 95% CI 1.22-6.44; p = 0.015) were independent predictors. Conclusion: Histological grade, tumor growth pattern and p53 over expression were established as the primary predictors of prognosis for primary TCC-UUT of the renal pelvis. The independent value of MIB-1 observed in other studies was not reproduced in this study

Anatomía de la próstata en ratones motheaten viable (mev) con mutaciones en el gen de la proteína tirosina fosfatasa SHP-1 / Prostate anatomy in motheaten viable (me v) mice with mutations in the protein tyrosine phosphatase SHP-1

Objetivo: Estudiar la anatomía de la próstata y la vesícula seminal en ratones motheaten viable (mev) con mutaciones en el gen PTPN6 que conlleva una severa reducción en la actividad de la proteína tirosina fosfatasa SHP-1. Los ratones mev homocigotos muestran múltiples anomalías que incluyen inmunodeficiencias, aumento en la proliferación de macrófagos, neutrófilos y progenitores de eritrocitos, disminución de la densidad ósea y esterilidad. Material y método: Se analizó la anatomía macro y microscópica de la vesícula seminal y de la próstata, tanto a nivel macro como microscópico, de 5 ratones mev/mev (homocigotos mev) y 8 ratones wt/wt (tipo salvaje) adultos de 7 semanas. Se ha realizado análisis morfométrico computarizado para medir cambios relativos en el volumen epitelial de los diferentes lóbulos prostáticos. Resultados: Todos los ratones estudiados mostraron órganos genitales (pene, testículos, epidídimos, deferentes) y vejiga normales. La vesícula seminal se encontraba ausente en todos los ejemplares mev/mev analizados, siendo normal y muy llamativa en ratones wt/wt. Las diferentes glándulas que componen el complejo prostático (próstata anterior, ventral y dorsolateral) se encontraron atróficas en ratones mev/mev: próstata anterior 0,4 veces, ventral 0,19 veces, dorsal 0,35 veces y lateral 0,28 veces el tamaño de las respectivas regiones en ratones wt/wt. A nivel microscópico los ratones mev/mev mostraron ductos prostáticos mayores y escasos, acinos severamente atróficos con luces vacías y escaso y suelto componente epitelial formando penachos y pliegues, y cambios hiperplásicos en el estroma fibromuscular. Conclusiones: La próstata de ratones mev/mev muestra signos de diferenciación aberrante y el fenotipo resultante puede estar relacionado con la pérdida de función SHP-1. Las anomalías prostáticas en estos ratones influyen, junto con los defectos de la maduración espermática, en su esterilidad. Estos datos sugieren que SHP-1 desempeña un importante papel en la morfogénesis epitelial prostática

Objective: To study prostate and seminal vesicle anatomy in viable motheaten (mev) mice with mutations in the PTPN6 gene leading to a severe reduction in the activity of protein tyrosine phosphatase SHP-1. Homozygous mev mice exhibit multiple anomalies that include immunodeficiencies, increased proliferation of macrophage, neutrophil, and erythrocyte progenitors, decreased bone density and sterility. Materials and methods: We analyzed macro- and microscopic anatomy of the seminal vesicle and prostate macro- and microscopic anatomy of 5 mev/mev and 8 wt/wt adult 7-week-old mice. Computerized morphometric analysis was performed to measure the relative changes appearing in the epithelial volume of the different prostatic lobes. Results: All mice studied revealed normal genital organs (penis, testis, epididymis, vas deferens) and bladder. The seminal vesicle was absent in all mev/mev individuals analyzed, being normal and very noticeable in wt/wt mice. The different glands that compose the prostatic complex (anterior, ventral and dorso-lateral prostate) were atrophied in mev/mev mice: anterior prostate 0.4 times, ventral 0.19 times, dorsal 0.35 times and lateral 0.28 times those of the respective regions in wt/wt mice. Microscopically, mev/mev mice revealed scarce and large prostatic ducts, acini severely atrophic with empty lumen and scarce loose epithelial component forming tufts and infoldings, and hyperplastic changes in fibromuscular stroma. Conclusions: The prostate of mev/mev mice exhibits signs of aberrant differentiation and the resulting phenotype may be related to the loss of function of SHP-1. Prostatic anomalies in these mice affect, together with defects in sperm maturation, their sterility. These data suggest that SHP-1 plays an important role in prostate epithelial morphogenesis

Prostate anatomy in motheaten viable (me(v)) mice with mutations in the protein tyrosine phosphatase SHP-1.

OBJECTIVE: To study prostate and seminal vesicle anatomy in viable motheaten (mev) with mutations in PTPN6 gene leading to a severe reduction in the activity of protein tyrosine phosphatase SHP-1. Homozygous mev mice exhibit multiple anomalies that include immunodeficiencies, increased proliferation of macrophage, neutrophil, and erythrocyte progenitors, decreased bone density and sterility. MATERIAL AND METHOD: We analyzed macro- and microscopic anatomy of the seminal vesicle and prostate macro- and microscopic anatomy of 5 mev/mev and 8 wt/wt adult 7 week old mice. Computerized morphometric analysis was performed to measure the relative changes appearing in the epithelial volume of the different prostatic lobes. RESULTS: All mice studied revealed normal genital organs (penis, testis, epididymis, vas deferens) and bladder. The seminal vesicle was absent in all mev/mev individuals analyzed, being normal and very noticeable in wt/wt mice. The different glands that compose the prostatic complex (anterior, ventral and dorso-lateral prostate) were atrophied in mev/mev mice: anterior prostate 0.4 times, ventral 0.19 times, dorsal 0.35 times and lateral 0.28 times those of the respective regions in wt/wt mice. Microscopically, mev/mev mice revealed scarce and large prostatic ducts, acini severely atrophic with empty lumen and scarce loose epithelial component forming tufts and infoldings, and hyperplastic changes in fibromuscular stroma. CONCLUSIONS: The prostate of mev/mev mice exhibits signs of aberrant differentiation and the resulting phenotype may be related to the loss of function of SHP-1. Prostatic anomalies in these mice affect, together with defects in sperm maduration, for their sterility. These data suggest SHP-1 plays an important role in prostate epithelial morphogenesis.

Impact of p53, MIB-1 and PECAM-1 expression on the prognosis of urothelial carcinoma of the renal pelvis.

OBJECTIVE: Determine whether the overexpression p53, MIB-1 and PECAM-1 of protein levels is of interest in predicting the prognosis of transitional cell carcinoma of the upper urinary tract (TCC-UUT) with the primary seat in the renal pelvis. MATERIAL AND METHOD: A univariate and multivariate analysis was conducted for prognosis prediction in a series of 82 patients with TCC-UUT of the renal pelvis who had no metastases at diagnosis (N0/Nx M0) and were treated exclusively with nephroureterectomy. We assessed clinicopathological parameters (age, gender, tumor grade and extent, histological variety, growth pattern, vascular invasion, infiltration of the renal parenchyma, tumor necrosis) and the immunohistochemical expression of p53, MIB-1 (ki-67) and PECAM-1 (CD31) in sections performed with tissue microarray (TMA). RESULTS: A total of 47.6% of the patients had high-grade lesions according to the USIP-WHO classification. The growth pattern was flat in 15.85%. The distribution by T category was: 3.7% pTa, 51.2% pT1, 11% pT2, 29.3% pT3 and 4.9% pT4. The mean follow-up was 46.8+38.5 (range, 4-172) months. The median survival was reached at 57 (95% CI 44-63) months. The univariate analysis revealed that survival in these patients is associated with tumor size (P=.028), histological variety (P<.0001), growth pattern (P<.0001), grade (P<.0001), pT (P=.01), vascular invasion (P=.025), necrosis (P=.004) and overexpression of p53 (P=.0006), PECAM-1 (P=.0036) and MIB-1 (P=.0038). The Cox regression model showed that high-grade (HR, 4.2; 95% CI 1.28-13.79; P=.018), flat growth pattern (HR, 2.52; 95% CI 1.05-6.03; P=.038) and p53 overexpression (HR, 2.8; 95% CI 1.22-6.44; P=.015) were independent predictors. CONCLUSION: Histological grade, tumor growth pattern and p53 overexpression were established as the primary predictors of prognosis for primary TCC-UUT of the renal pelvis. The independent value of MIB-1 observed in other studies was not reproduced in this study.

[Postoperative prognosis of chromophobic renal cell carcinoma: comparative analysis of the multinational CORONA database]. / Die postoperative Prognose des chromophoben Nierenzellkarzinoms : Eine vergleichende Analyse anhand der multinationalen CORONA-Datenbank.

BACKGROUND: The chromophobe subtype represents the third most common histological subtype of renal cell carcinoma (chRCC). Due to the rarity of this subtype only one publication regarding the specific analysis of clinical and histopathological criteria as well as survival analysis of more than 200 patients with chRCC is known to date. MATERIALS AND METHODS: A total of 6,234 RCC patients from 11 centres who were treated by (partial) nephrectomy are contained in the database of this multinational study. Of the patients 259 were diagnosed with chRCC (4.2 %) and thus formed the study group for this retrospective investigation. These subjects were compared to 4,994 patients with a clear cell subtype (80.1 %) with respect to clinical and histopathological criteria. The independent influence of the chromophobe subtype regarding tumor-specific survival and overall survival was determined using analysis by Cox proportional hazards regression models. The median follow-up was 59 months (interquartile range 29-106 months). RESULTS: The chRCC patients were significantly younger (60 vs. 63.2 years, p < 0.001), more often female (50 vs. 41 %, p = 0.005) and showed simultaneous distant metastases to a lesser extent (3.5 vs. 7.1 %, p = 0.023) compared to patients with a clear cell subtype. Despite a comparable median tumor size a ≥ pT3 tumor stage was diagnosed in only 24.7 % of the patients compared to of 30.5 % in patients with a clear cell subtype (p = 0.047). In addition to the clinical criteria of age, sex and distant metastases, the histological variables pTN stage, grade and tumor size showed a significant influence on tumor-specific and overall survival. However, in the multivariable Cox regression analysis no independent effect on tumor-specific mortality (HR 0.88, p = 0.515) and overall mortality (HR 1.00, p = 0.998) due to the histological subtype was found (c-index 0.86 and 0.77, respectively). CONCLUSIONS: Patients with chRCC and clear cell RCC differ significantly concerning the distribution of clinical and histopathological criteria. Patients with chRCC present with less advanced tumors which leads to better tumor-specific survival rates in general; however, this advantage could not be verified after adjustment for the established risk factors.

El papel de la metaloproteinasa de la matriz MMP-9 y del inhibidor tisular de metaloproteinasa TIMP-2 como marcadores séricos de cáncer vesical / The role of matrix metalloproteinase MMP-9 and TIMP-2 tissue inhibitor of metalloproteinasas as serum markers of bladder cancer

Introducción: El diagnóstico y la estadificación molecular del cáncer vesical basados en la detección de ARNm de gelatinasas (MMP-2 y MMP-9) en células circulantes y mononucleares de sangre periférica han mostrado resultados prometedores. Analizamos si la determinación de los correspondientes productos de síntesis proteica permite diagnosticar y caracterizar pacientes con neoplasia vesical. Material y método: Se ha llevado a cabo la cuantificación de los niveles séricos de MMP-2, MMP-9 y TIMP-2 en una serie de 42 individuos (31 pacientes con cáncer vesical en diversos estadios y 11 controles sanos) mediante técnica de ELISA. Se compararon las determinaciones entre casos y controles (U Mann-Whitney), así como entre diferentes grupos de tumores (U Mann-Whitney o Kruskal-Wallis), según las características clínico-patológicas (edad, sexo, categoría T, categoría M o grado). Se evaluó el rendimiento diagnóstico de estos marcadores mediante análisis de curvas ROC Resultados: Existe correlación entre las determinaciones de MMP-2 y TIMP-2 (R = 0,699; p > 0,0001) y de MMP-9 y TIMP-2 (R = 0,305; p = 0,049). Los pacientes con cáncer de vejiga presentan niveles más elevados de MMP-9 (p < 0,0001) y TIMP-2 (p = 0,047) que los controles. Así mismo, el cociente MMP-9/TIMP-2 también es superior en pacientes con cáncer (p < 0,001). No se detectan diferencias entre cáncer y control respecto a edad (p = 0,64) o sexo (p = 0,64). Tampoco se detectan diferencias con respecto a MMP-2 (p = 0,35) ni al cociente MMP-2/TIMP-2 (p = 0,45). Dentro de la población de pacientes con cáncer los valores de MMP-2 y MMP-9 difieren según categoría T (p = 0,022 y p = 0,038, respectivamente) y los de TIMP-2 según categoría M (p = 0,036). El análisis de curvas ROC mostró que tanto MMP-9 como el cociente MMP-9/TIMP-2 discriminan pacientes con cáncer y controles, con equivalente exactitud diagnóstica (ABC 0,953) y unos puntos de corte de 3,93 ng/ml (S 90%; E 81%) y de 0,053 ng/ml (S 96%; E 84%), respectivamente. Conclusiones: Los resultados obtenidos sugieren que tanto MMP-9 como TIMP-2 séricos podrían tener una aplicación en la predicción del desarrollo y progresión del cáncer vesical, y potencial utilidad como marcadores clínicos de la enfermedad. Se requieren estudios multicéntricos prospectivos que confirmen estos resultados preliminares (AU)

Introduction: The diagnosis and molecular staging of bladder cancer based on the detection of gelatinases mRNA (MMP-2 and MMP-9) in peripheral blood circulating and mononuclear cells have shown promising results. We analyze if the determination of the corresponding protein synthesis products makes it possible to diagnose and characterize patients with bladder cancer. Material and method: Quantification of the serum levels of MMP-2, MMP-9 and TIMP-2 in a series of 42 individuals (31 patients with bladder cancer in different stages and 11 healthy controls) using the ELISA technique was carried out. The determinations were compared between cases and controls (Mann-Whitney U) and between different groups of tumors (Mann-Whitney U or Kruskal-Wallis), according to the clinical-pathological characteristics (age, gender, T category, M category or grade). Diagnostic yield of these markers was evaluated by analysis of the ROC curves. Results: There is a correlation between the determinations of MMP-2 and TIMP-2 (R = 0.699; P > 0.0001) and MMP-9 and TIMP-2 (R = 0.305; P = 0.049). Patients with bladder cancer have higher levels of MMP-9 (p < 0.0001) and TIMP-2 (P = 0.047) than the controls. Furthermore, the MMP-9/TIMP-2 ratio is also superior in cancer patients (P < 0.001). Differences were not detected between cancer and controls regarding age (P = 0.64) or gender (P = 0.64). Differences were also not detected regarding MMP-2 (P = 0.35) or MMP-2/TIMP-2 rate (P = 0.45). Within the cancer patient population, the MMP-2 and MMP-9 values differ according to T category (P =0 .022 and P = 0.038, respectively) and those of the TIMP-2 according to M category (P = 0.036). ROC curve analysis showed that both MMP-9 and the MMP-9/TIMP-2 ratio discriminate patients with cancer and controls, with equivalent diagnostic accuracy (ABC 0.953) and cut offs of 3.93 ng/mL (S 90%; Sp 81%) and 0.053 ng/mL (S 96%; Sp 84%), respectively. Conclusions: The results obtained suggest that both serum MMP-9 and TIMP-2 would have an application in the prediction of the development and progression of bladder cancer, and a potential utility as clinical markers of the disease. Multicenter, prospective studies that confirm their preliminary results are necessary (AU)

The role of matrix metalloproteinase MMP-9 and TIMP-2 tissue inhibitor of metalloproteinases as serum markers of bladder cancer.

INTRODUCTION: The diagnosis and molecular staging of bladder cancer based on the detection of gelatinases mRNA (MMP-2 and MMP-9) in peripheral blood circulating and mononuclear cells have shown promising results. We analyze if the determination of the corresponding protein synthesis products makes it possible to diagnose and characterize patients with bladder cancer. MATERIAL AND METHOD: Quantification of the serum levels of MMP-2, MMP-9 and TIMP-2 in a series of 42 individuals (31 patients with bladder cancer in different stages and 11 healthy controls) using the ELISA technique was carried out. The determinations were compared between cases and controls (Mann-Whitney U) and between different groups of tumors (Mann-Whitney U or Kruskal-Wallis), according to the clinical-pathological characteristics (age, gender, T category, M category or grade). Diagnostic yield of these markers was evaluated by analysis of the ROC curves. RESULTS: There is a correlation between the determinations of MMP-2 and TIMP-2 (R=.699; P>.0001) and MMP-9 and TIMP-2 (R=.305; P=.049). Patients with bladder cancer have higher levels of MMP-9 (p<0.0001) and TIMP-2 (P=.047) than the controls. Furthermore, the MMP-9/TIMP-2 ratio is also superior in cancer patients (P<.001). Differences were not detected between cancer and controls regarding age (P=.64) or gender (P=.64). Differences were also not detected regarding MMP-2 (P=.35) or MMP-2/TIMP-2 rate (P=.45). Within the cancer patient population, the MMP-2 and MMP-9 values differ according to T category (P=.022 and P=.038, respectively) and those of the TIMP-2 according to M category (P=.036). ROC curve analysis showed that both MMP-9 and the MMP-9/TIMP-2 ratio discriminate patients with cancer and controls, with equivalent diagnostic accuracy (ABC 0.953) and cut offs of 3.93 ng/mL (S 90%; Sp 81%) and 0.053 ng/mL (S 96%; Sp 84%), respectively. CONCLUSIONS: The results obtained suggest that both serum MMP-9 and TIMP-2 would have an application in the prediction of the development and progression of bladder cancer, and a potential utility as clinical markers of the disease. Multicenter, prospective studies that confirm their preliminary results are necessary.

El estudio de la metilación del ADN en el cáncer urológico: presente y futuro / The Study of DNA Methylation in Urological Cancer: Present and Future

Objetivos: Realizar una síntesis de los principales avances en el campo del estudio de la epigenética y concretamente la metilación de ADN respecto al diagnóstico de las neoplasias urológicas. Adquisición de evidencia: Revisión de la literatura (PubMed, Medline y Cochrane) sobre el estudio de la metilación del ADN en neoplasias urológicas (cáncer de próstata, cáncer de vejiga, cáncer renal y cáncer testicular) teniendo en cuenta todos los estudios publicados hasta enero de 2013. Síntesis de evidencia: Resulta posible determinar el estado de metilación de un gran número de genes en muestras de tumores, que al compararlo con muestras de tejido sano permite la definición de patrones de metilación aberrantes específicos para cada tipo de tumor. El estudio y la definición de patrones de metilación anómala específicos de cada tipo de tumor es una herramienta de potencial utilidad para el diagnóstico, evaluación, predicción de pronóstico y tratamiento de las diferentes formas de cáncer genitourinario. El análisis de la metilación de genes en la orina, tras la micción o masaje prostático, el semen, el plasma o el líquido de lavado de biopsias prostáticas puede permitir la detección precoz del cáncer vesical, prostático, renal y testicular. En cada una de las neoplasias se ha identificado una firma epigenética que puede detectarse en ADN obtenido de muestras muy escasamente o nada invasivas, con potencial en el diagnóstico y en la evaluación de pronóstico. La validación de estos estudios confirmará la precisión, efectividad y reproducibilidad de los resultados de los que se dispone hasta el momento. No están aún desarrollados criterios que determinen que un panel de genes sea lo suficientemente informativo en la práctica asistencial como para guiar un diagnóstico inequívoco o una conducta terapéutica. Se requiere un mayor número de estudios para contrastar en cada caso la sensibilidad, especificidad, el valor predictivo positivo y negativo de la prueba. Tampoco existen estudios multicéntricos que analicen la reproducibilidad real de estos resultados en un entorno clínico. Conclusiones: El estudio de la metilación aberrante del ADN en muestras biológicas de pacientes tiene enorme potencial para el diagnóstico precoz y cribado de las neoplasias genitourinarias. Se necesita un mayor número de estudios que permitan definir baterías de genes que supongan firmas inequívocas de malignidad. Esta metodología tiene también potencial a la hora de definir grupos pronóstico y potencial de respuesta a diferentes terapias (AU)

Objectives: We have synthesized the principal advances in the field of the study of epigenetics and specifically DNA methylation regarding the diagnosis of urological neoplasms. Acquisition of evidence: Review of the literature (PubMed, MEDLINE y COCHRANE) on the study of DNA methylation in urological neoplasms (prostate cancer, bladder cancer, renal cancer and testicular cancer), considering all the studies published up to January 2013. Synthesis of evidence: It was possible to determine the state of methylation of many genes in our tumor samples. When these were compared with healthy tissue samples, it was possible to define the specific aberrant methylation patterns for each type of tumor. The study and definition of specific abnormal methylation patterns of each type of tumor is a tool having potential utility for diagnosis, evaluation, prediction of prognosis and treatment of the different forms of genitourinary cancer. The analysis of gene methylation in urine after micturition or post-prostatic massage urine, semen, in the wash plasma or fluid from prostatic biopsies may allow early detection of bladder, prostate, renal and testicular cancer. In each one of the neoplasms, an epigenetic signature that may be detected in the DNA has been identified, obtained from very scarce or not at all invasive specimens, with potential in the diagnosis and evaluation of prognosis. Validation of these studies will confirm the accuracy, effectiveness and reproducibility of the results available up to now. Criteria have still not been developed that determine if a gene panel provides sufficient information in the health care practice to guide an unequivocal diagnosis or therapeutic conduct. More studies are needed to compare sensitivity, specificity, positive and negative predictive value of the test in each case. Multicenter studies analyzing the real reproducibility of these results in a clinical setting also do not exist. Conclusions: The study of aberrant DNA methylation in biological specimens of patients has an enormous potential for the early diagnosis and screening of genitourinary neoplasms. A larger number of studies is needed to be able to define the series of genes that would mean unequivocal signatures of malignancy. This methodology also has potential when defining prognostic groups and potential of response to different therapies (AU)

The study of DNA methylation in urological cancer: present and future.

OBJECTIVES: We have synthesized the principal advances in the field of the study of epigenetics and specifically DNA methylation regarding the diagnosis of urological neoplasms. ACQUISITION OF EVIDENCE: Review of the literature (PubMed, MEDLINE and Cochrane) on the study of DNA methylation in urological neoplasms (prostate cancer, bladder cancer, renal cancer and testicular cancer), considering all the studies published up to January 2013. SYNTHESIS OF EVIDENCE: It was possible to determine the state of methylation of many genes in our tumor samples. When these were compared with healthy tissue samples, it was possible to define the specific aberrant methylation patterns for each type of tumor. The study and definition of specific abnormal methylation patterns of each type of tumor is a tool having potential utility for diagnosis, evaluation, prediction of prognosis and treatment of the different forms of genitourinary cancer. The analysis of gene methylation in urine after micturition or post-prostatic massage urine, semen, in the wash plasma or fluid from prostatic biopsies may allow early detection of bladder, prostate, renal and testicular cancer. In each one of the neoplasms, an epigenetic signature that may be detected in the DNA has been identified, obtained from very scarce or not at all invasive specimens, with potential in the diagnosis and evaluation of prognosis. Validation of these studies will confirm the accuracy, effectiveness and reproducibility of the results available up to now. Criteria have still not been developed that determine if a gene panel provides sufficient information in the health care practice to guide an unequivocal diagnosis or therapeutic conduct. More studies are needed to compare sensitivity, specificity, positive and negative predictive value of the test in each case. Multicenter studies analyzing the real reproducibility of these results in a clinical setting also do not exist. CONCLUSIONS: The study of aberrant DNA methylation in biological specimens of patients has an enormous potential for the early diagnosis and screening of genitourinary neoplasms. A larger number of studies is needed to be able to define the series of genes that would mean unequivocal signatures of malignancy. This methodology also has potential when defining prognostic groups and potential of response to different therapies.

Variabilidad de la práctica clínica urológica en cáncer de próstata en España / Variability of the urological clinical practice in prostate cancer in Spain

Objetivos: Explorar la opinión de los urólogos españoles respecto a los principales puntos en el diagnóstico, prevención, calidad de vida y tratamiento del cáncer de próstata. Material y métodos: Se administró un cuestionario anónimo a 290 especialistas que representan el colectivo profesional urológico involucrado en el manejo del cáncer de próstata en España. En su definición se tuvo en cuenta el grado de experiencia profesional, el ámbito de trabajo, la relación contractual con el paciente y el carácter académico del centro. El análisis estadístico se basó en el estudio de frecuencias relativas para variables cualitativas. La interpretación de resultados se llevó a cabo en 2009-2010 y el informe de emisión final de los mismos en 2011. Resultados: La tasa de respuesta recogida y correctamente transcrita de los formularios fue del 96,9% (n=281), lo que supone un 10-15% del colectivo nacional. La mediana de edad fue 47,7 (29-69) años y el 92% fueron hombres. La mediana de experiencia profesional fue 19,1 (1-43) años. Se analizan las respuestas recogidas relativas a 153 cuestiones que tratan: a) cómo se lleva a cabo el diagnóstico de la enfermedad en el entorno de los encuestados; b) las opiniones vertidas acerca de la prevención de la enfermedad; c) el tratamiento de la enfermedad localizada; d) el tratamiento de la enfermedad avanzada; y e) la definición de campos de interés para el profesional. Conclusión: Esta encuesta demuestra una importante variabilidad en algunos puntos de la práctica clínica con respecto a las recomendaciones de expertos. Pone también en evidencia las principales preocupaciones del profesional, define oportunidades de mejora formativa y detecta necesidades en el colectivo urológico nacional (AU)

Objectives: Study the opinion of the Spanish urologists regarding the main points in the diagnosis, prevention, quality of life and treatment of prostate cancer. Material and methods: An anonymous questionnaire was administered to 290 specialists who represented the urological professional group involved in the management of prostate cancer in Spain. The following were considered in their definition: grade of professional experience, work setting, contractual relation with patient and academic character of the center. The statistical analysis was based on the study of relative frequencies for qualitative variables. The results were interpreted in 2009-10 and the final report of them was done in 2011. Results: Response rate collected and correctly transcribed from the forms was 96.9% (n=281). This accounts for 10-15% of the national group. Median age was 47.7 (29-69) years and 92% were men. Mean years of professional experience were 19.1 (1-43). Responses collected regarding 153 questions were analyzed. These dealt with: a) How the diagnosis of the disease was carried out in the setting of the surveyed; b) The opinions given on the disease prevention; c) Treatment of the localized treatment; d) Treatment of the advanced disease; and e) The definition of the fields of interest for the professional. Conclusion: This survey showed important variability in some points of clinical practice in regards to the recommendations of the experts. It also shows the principal concerns of the professional, defines opportunities for training improvements and detects needs in the national urological group (AU)

[Variability of the urological clinical practice in prostate cancer in Spain]. / Variabilidad de la práctica clínica urológica en cáncer de próstata en España.

OBJECTIVES: Study the opinion of the Spanish urologists regarding the main points in the diagnosis, prevention, quality of life and treatment of prostate cancer. MATERIAL AND METHODS: An anonymous questionnaire was administered to 290 specialists who represented the urological professional group involved in the management of prostate cancer in Spain. The following were considered in their definition: grade of professional experience, work setting, contractual relation with patient and academic character of the center. The statistical analysis was based on the study of relative frequencies for qualitative variables. The results were interpreted in 2009-10 and the final report of them was done in 2011. RESULTS: Response rate collected and correctly transcribed from the forms was 96.9% (n=281). This accounts for 10-15% of the national group. Median age was 47.7 (29-69) years and 92% were men. Mean years of professional experience were 19.1 (1-43). Responses collected regarding 153 questions were analyzed. These dealt with: a) How the diagnosis of the disease was carried out in the setting of the surveyed; b) The opinions given on the disease prevention; c) Treatment of the localized treatment; d) Treatment of the advanced disease; and e) The definition of the fields of interest for the professional. CONCLUSION: This survey showed important variability in some points of clinical practice in regards to the recommendations of the experts. It also shows the principal concerns of the professional, defines opportunities for training improvements and detects needs in the national urological group.

[Effectiveness and tolerability of zoledronic acid in the treatment of metastatic prostate cancer]. / Efectividad y tolerabilidad del acido zoledrónico en el tratamiento del cancer de próstata metastásico.

OBJECTIVES: To assess the effectiveness and tolerability of zoledronic acid in prostate cancer patients with bone metastases at the hormone-sensitive (HS) and hormone-independent (HI) stages. MATERIALS AND METHODS: A nationwide, observational, prospective, open and multi-centre trial was devised, with a total of 218 male patients diagnosed with prostate cancer at the HS stage (36%) or HI stage (64%) who were administered zoledronic acid (4 mg/IV/month for 6 months) in addition to their specific oncological treatment. Effectiveness was assessed by the following means: 1) Assessment of the improvement in pain and mobility; 2) Incidence and time to onset of skeletal-related events (SREs) and 3) Analysis of bone markers. Tolerability was assessed by means of registering the number and type of adverse effects. A satisfaction survey was carried out amongst the patients after the end of the trial. RESULTS: Out of the 218 patients, 170 (78%) were evaluable for effectiveness. A decrease in pain ratings at rest and during movement was observed in all patients, whether in the HS or HI groups (p < 0.0001). Improved mobility was observed likewise (p = 0.005), as was quality of life. The global incidence of skeletal events was 11.2%, with a time to onset of SREs of 10.7 months. There were no significant differences observed between HS vs. HI patients. Osteolysis markers (N-telopeptide) decreased significantly with the treatment across both the HS and HI groups. For safety reasons. 212 patients were evaluable (97.2%). The incidence of adverse drug reactions was 16% (34/212) and was found to be significantly higher in HS patients (22.4%) compared with HI patients (11.9%). Overall, the tolerability of zoledronic acid was good, with no significant morbidity in either group (HS and HI). 66% of the patients reported feeling satisfied or very satisfied. CONCLUSIONS: Zoledronic acid proved effective in the relief of pain, improving mobility and quality of life as well as reducing or delaying the occurrence of skeletal-related events in prostate cancer patients presenting metastatic bone disease, regardless of the phase, whether HS or HI, they found themselves in. Tolerability and patient satisfaction were rates as good.