What is the impact of post-radical prostatectomy urinary incontinence on everyday quality of life? Linking Pad usage and International Consultation on Incontinence Questionnaire Short-Form (ICIQ-SF) for a COMBined definition (PICOMB definition).

AIMS: To identify the definition for urinary continence (UC) after radical prostatectomy (RP) which reflects best patients' perception of quality of life (QoL). METHODS: Continence was prospectively assessed in 634 patients, 12 months after RP using the International Consultation on Incontinence Questionnaire Short-Form (ICIQ-SF) and the number of pads employed in a 24-hour period (pad usage). We used the one-way ANOVA technique with posthoc pairwise comparisons according to Scheffé's method (homogeneous subsets) for assessing the degree of QoL deficit related to urinary incontinence (UI). RESULTS: The continence prevalence is 64.4%, 74.1%, 88.3%, and 35.8% using "0 pads," "1 safety pad," "1 pad," and "ICIQ score 0" definitions, respectively. Pad usage is moderately strongly associated with ICIQ 1, 2, and 3 (ρ = 0.744, 0.677, and 0.711, respectively; p < 0.001). Concordance between classical UC definitions is acceptable between "0 pads-ICIQ score 0" (K = 0.466), but poor for "1 safety pad" and "1 pad" (K = 0.326 and 0.137, respectively). Patients with "0 pad usage" have better QoL related to urine leakage than patients with "1 safety pad" or "1 pad" (1.41 vs. 2.44 and 3.11, respectively; p < 0.05). There were no significant differences found regarding QoL between patients with ICIQ score 0 and ICIQ score 2 (1.01 vs. 1.63; p = 0.63). CONCLUSIONS: Pad usage and the ICIQ-SF's answers provide useful information. We propose a combined definition (0 pads and ICIQ score ≤2) as it is the definition with the least impact on daily QoL.

Characterization of the perioperative changes of exosomal immune-related cytokines induced by prostatectomy in early-stage prostate cancer patients.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are relevant in prostate cancer microenvironment collaborating in tumor development. The main tumor marker used in this disease, prostate-specific antigen (PSA), does not provide information related to this tumor microenvironment. Cancer cells secrete exosomes carrying bioactive molecules contributing to MDSCs recruitment and induction. The aim of this study was to characterize the perioperative changes of exosomal cytokines relevant in MDSCs recruitment induced by prostatectomy in prostate cancer patients. METHODS: Blood was drawn from 26 early-stage prostate cancer patients before and after radical prostatectomy and from 16 healthy volunteers. Serum exosomes were separated by precipitation. Cytokines related with MDSC cell recruitment and activation CCL2, CXCL2, CXCL5, CXCL8, CXCL12, MIF, S100A9 and TGF-ß were measured in serum and serum-derived exosomes using immunometric assays. RESULTS: All cytokines were detected both in serum and exosomes, except for CXCL12, which was detected only in serum. Exosomes were enriched specially in MIF, TGF-ß and CXCL2. Presurgical MIF levels in exosomes correlated negatively with serum PSA. Also, presurgical TGF-ß decreased both in serum and exosomes as Gleason score rises. Patients presurgical exosomes had increased CCL2, CXCL5 and TGF-ß levels than exosomes from healthy controls. These differences were not observed when cytokines were analyzed in serum, except for TGF-ß. Cytokine levels of CCL2, CXCL5 decreased in patients' postsurgical exosomes, while TGF-ß further increased. On the contrary, S100A9 levels were lower in patients presurgical exosomes but increased after radical prostatectomy. CONCLUSIONS: Blood exosomal content in cytokines constitute an attractive source to evaluate MDSCs immunomodulators providing additional information related to tumor microenvironment in prostate cancer.

[Prognostic factors and response predictors in castration resistant prostate cancer.] / Factores pronósticos y predictores de respuesta en cáncer de próstata resistente a la castración.

Prostate cancer is a health problem in many Countries worldwide. Understanding the essential function of androgens in the prostate physiology led to the development of hormonal blockade as a therapeutic option in advanced disease, with limited response with time and development of resistance. In this stage, where castration resistant prostate cancer (CRPC) is defined, it is associated with poor prognosis because survival varies between 18 and 24 months. Even with castration levels, tumors are dependent on the functional androgen receptor (AR). In this paper, we analyze pretreatment clinical parameters such as prognostic or progression-predictive biomarkers, castration resistance mechanisms, the development of new technologies for the use of the so called liquid biopsies from biological ayufluids and the identification of circulating tumor cells as CRPC response and progression biomarkers. Currently ongoing clinical trials are partially oriented to the search of new prognostic and predictive biomarkers, that will enable to open up precision medicine and so to improve oncological patient's quality of life with it.

[Immunotherapy in castration resistant prostate cancer.] / Inmunoterapia en cáncer de próstata resistente a la castración.

We review the role of immunotherapy in castration resistant prostate cancer. Two immunotherapeutic strategies have been applied, isolated or in combination, either with each other or with other agents with demonstrated efficacy in this scenario that would play a role as immunomodulators: vaccines or monoclonal antibodies aimed to block immune response checkpoint inhibitors. Although CRPC presents, a priori, characteristics suggesting that immunotherapy may play a relevant role as a therapeutic strategy, its clinical application has demonstrated a limited and heterogeneous activity, in terms of proportion of responders and response intensity. Generally, the objective response rate is very low, although, in patients who have response it is possible to detect a clear, long-lasting benefit. Only the autologous vaccine Sipuleucel T has demonstrated an overall survival increase in patients with good prognosis criteria. In these treatments, it is characteristic that no progression free survival increase is visible due to its action mechanism. PSA evolution may not be considered a surrogate variable of radiological response or clinical benefit in this environment either. It is necessary to identify what patient's or tumor's characteristics are able to maximize the response. An important limitation is the absence of response predictive biomarkers that serve for patient preselection. As a general rule, the best responses with isolated immunotherapeutic treatments have been observed in patients with low tumor load, which may suggest that their optimal application could be in earlier phases of the disease (high risk localized, biochemical failure, etc) Combination strategy, without doubt the one with best future, is based on additional treatments increasing cell lysis with the subsequent antigen exposure and/ or producing an immunomodulatory effect that can surmount tumor induced immunologic tolerance. The results obtained suggest that immunotherapy may be more effective in combined therapy with other active therapies (abiraterone, enzalutamide, Radium 223, docetaxel) in a fight to achieve disease chronification.

Inmunoterapia en cáncer de próstata resistente a la castración / Immunotherapy in castration resistant prostate cancer

Revisamos el papel de la inmunoterapia en el cáncer de próstata resistente a castración. Se han aplicado dos estrategias inmunoterápicas, de forma aislada o en combinación, bien entre ellas o bien con otros agentes de eficacia demostrada en este escenario y que ejercerían un papel inmunomodulador: vacunas o anticuerpos monoclonales destinados al bloqueo de puntos de control inhibidores de la respuesta inmune. Aunque a priori el CPRC presenta características que sugieren que la inmunoterapia podría jugar un papel relevante como estrategia terapéutica, su aplicación clínica ha demostrado una actividad limitada y heterogénea, en cuanto a la proporción de respondedores e intensidad de respuesta. En términos generales, la tasa de respuestas objetivas es muy baja, aunque, en los pacientes que responden, es posible detectar un beneficio claro y duradero. Sólo la vacuna autóloga Sipuleucel T ha demostrado un aumento de la supervivencia global en pacientes con criterios de buen pronóstico. Es característico en estos tratamientos que no se observe un incremento en la supervivencia libre de progresión debido a su propio mecanismo de acción. Tampoco la evolución del PSA puede considerarse una variante subrogada de respuesta radiológica o beneficio clínico en este entorno. Se hace necesario identificar qué características de los pacientes o del tumor son capaces de maximizar la respuesta. Una limitación importante es la ausencia de biomarcadores predictores de respuesta que sirvan para la preselección de pacientes. Como norma general, las mejores respuestas con tratamientos inmunoterápicos aislados se han observado en pacientes con baja carga tumoral, lo cual puede sugerir que su aplicación óptima podría ser en fases más precoces de la enfermedad (localizado de alto riesgo, fracaso bioquímico, etc.). La estrategia de combinación, sin lugar a dudas la de más futuro, se fundamenta en que los tratamientos adicionales incrementan la lisis celular con la consiguiente exposición antigénica y/o ejercen un efecto inmunomodulador capaz de vencer la tolerancia inmunológica inducida por el tumor. Los resultados obtenidos sugieren que la inmunoterapia puede ser más efectiva en modo tratamiento combinado con otros tratamientos activos (abiraterona, enzalutamida, Radio 223, docetaxel) en la lucha por lograr cronificar la enfermedad

We review the role of immunotherapy in castration resistant prostate cancer. Two immunotherapeutic strategies have been applied, isolated or in combination, either with each other or with other agents with demonstrated efficacy in this scenario that would play a role as immunomodulators: vaccines or monoclonal antibodies aimed to block immune response checkpoint inhibitors. Although CRPC presents, a priori, characteristics suggesting that immunotherapy may play a relevant role as a therapeutic strategy, its clinical application has demonstrated a limited and heterogeneous activity, in terms of proportion of responders and response intensity. Generally, the objective response rate is very low, although, in patients who have response it is possible to detect a clear, long-lasting benefit. Only the autologous vaccine Sipuleucel T has demonstrated an overall survival increase in patients with good prognosis criteria. In these treatments, it is characteristic that no progression free survival increase is visible due to its action mechanism. PSA evolution may not be considered a surrogate variable of radiological response or clinical benefit in this environment either. It is necessary to identify what patient`s or tumor's characteristics are able to maximize the response. An important limitation is the absence of response predictive biomarkers that serve for patient preselection. As a general rule, the best responses with isolated immunotherapeutic treatments have been observed in patients with low tumor load, which may suggest that their optimal application could be in earlier phases of the disease (high risk localized, biochemical failure, etc) Combination strategy, without doubt the one with best future, is based on additional treatments increasing cell lysis with the subsequent antigen exposure and/ or producing an immunomodulatory effect that can surmount tumor induced immunologic tolerance. The results obtained suggest that immunotherapy may be more effective in combined therapy with other active therapies (abiraterone, enzalutamide, Radium 223, docetaxel) in a fight to achieve disease chronification

Factores pronósticos y predictores de respuesta en cáncer de próstata resistente a la castración / Prognostic factors and response predictors in castration resistant prostate cancer

El cáncer de próstata es un problema de salud en muchos países a nivel mundial. La comprensión de la función esencial que los andrógenos tienen en la fisiología de la próstata condujo al desarrollo del bloqueo hormonal como opción de tratamiento en la enfermedad avanzada, con respuesta limitada en el tiempo y desarrollo de resistencia. Es en esta etapa donde se define el cáncer de próstata resistente a la castración (CPRC) y se asocia con mal pronóstico ya que la supervivencia oscila entre 18 y 24 meses a partir de ese momento. Aún con niveles de castración, los tumores son dependientes del receptor androgénico (RA) funcional. En el presente trabajo analizamos los parámetros clínicos pre-tratamiento como biomarcadores pronósticos o predictivos de progresión, los mecanismos de resistencia a la castración, el desarrollo de nuevas tecnologías para el uso de las denominadas biopsias líquidas a partir de fluidos biológicos y la identificación de células tumorales circulantes como biomarcadores de respuesta y progresión en CPRC. Los ensayos clínicos actualmente en marcha están en parte orientados hacia la búsqueda de nuevos biomarcadores pronósticos y predictivos, lo que permitirá abrir las puertas a la medicina de precisión y con ello mejorar la calidad de vida del paciente oncológico

Prostate cancer is a health problem in many Countries worldwide. Understanding the essential function of androgens in the prostate physiology led to the development of hormonal blockade as a therapeutic option in advanced disease, with limited response with time and development of resistance. In this stage, where castration resistant prostate cancer (CRPC) is defined, it is associated with poor prognosis because survival varies between 18 and 24 months. Even with castration levels, tumors are dependent on the functional androgen receptor (AR). In this paper, we analyze pretreatment clinical parameters such as prognostic or progression-predictive biomarkers, castration resistance mechanisms, the development of new technologies for the use of the so called liquid biopsies from biological ayufluids and the identification of circulating tumor cells as CRPC response and progression biomarkers. Currently ongoing clinical trials are partially oriented to the search of new prognostic and predictive biomarkers, that will enable to open up precision medicine and so to improve oncological patient's quality of life with it

Statistical evaluation of the geochemical variability in overbank sediments in Spain.

The overall objective of this study is to estimate, detect and specify the main sources of variance which affect the contents of the different elements in overbank sediments across Spain. These sources of variance were assessed and compared by means of a series of analyses of variance (ANOVAs), by regarding two parameters: their significance and their contribution to the total variance. Overbank sediments, sampled in erosion banks, were studied in several locations, in basins which drain different types of geological backgrounds and land uses (urban, mining, agricultural or pristine) across the Iberian Peninsula. Forty-eight elements (mostly in the < 63 µm fraction) were analysed by ICP-OES, ICP-MS and INAA. After an isometric log ratio (ilr) transformation of the data, three ANOVA analyses were performed considering three perspectives: (1) local scale, (2) regional scale: within-profile perspective and (3) regional scale: inter-profile perspective. On a local scale, it was observed that the variability of rare earth elements (REE) depends mostly on the grain size and that heavy metals are also influenced by depth. In the analysis carried out on a regional scale, from a within-profile perspective, depth and duplicates do not influence significantly the variability of the element contents. Finally, from an inter-profile perspective, the selected sources of variance were land use and provenance, whose significance is the highest. While grain size and the selection of depth are of crucial importance in the final results, on local studies, land use and provenance are the ones that influence the most the composition of sediments in regional studies.

[Robot-assisted and laparoscopic pyeloplasty.] / Pieloplastia robótica y laparoscópica.

OBJECTIVES: Uretero-pelvic junction (UPJ) obstruction has been classically treated by open dismembered pyeloplasty. Recently, laparoscopic (LP) and robotic pyeloplasty (RP) have become the techniques of choice for the treatment of UPJ stenosis in adult and pediatric population. Our objective in this paper is to review the results of minimally invasive surgery as the treatment of UPJ obstruction, the trend to use these approaches and the current limits of LP and RP. METHODS: A review of most relevant papers and meta-analysis about LP and RP in pediatric and adult population was performed using PubMed. RESULTS: In pediatric population, comparative studies and meta-analysis of relevant series show an overlap of results between LP, RP and open surgery in terms of success rate, rate of complications and hospital stay, being operating time shorter in open pyeloplasty compared to minimally invasive techniques. In infants and pre-school age open surgery remains as technique of choice for pediatric surgeons. In adults, comparative studies and meta-analysis of the most relevant series show also an overlap of results in terms of success rate and complication rate between LP and RP. Nonetheless, minimally invasive techniques seem to offer a significant shortening of hospital stay and need for analgesics compared to open surgery, reason why laparoscopic techniques are recommended over open pyeloplasty in adult population. CONCLUSIONS: In view of published literature, minimally invasive surgery has been postulated as the standard treatment in UPJ stenosis, with superimposable results to open surgery. The high cost of robotic approach limits its use in this type of pathology.

Application of lead isotopic methods to the study of the anthropogenic lead provenance in Spanish overbank floodplain deposits.

Changes in the principal sources of Pb in overbank sediment profiles have been documented for two Spanish areas by using Pb isotopes and Pb concentrations. These locations (Madrid and Tinto-Odiel basin) represent two of the most contaminated regions in Spain. The Community of Madrid is characterized by heavy industrial and urban activity, focused mainly in Madrid City. The Tinto-Odiel basin drains the Iberian Pyrite Belt, which hosts many polymetallic massive sulphides and is heavily affected by mining activities in their headwaters. It has been proven that the influence of anthropogenic activity is reflected in these overbank deposits by variations in Pb concentrations that, in general, correlate with shifts in the (206)Pb/(207)Pb ratio. Rivas profile (downstream of Madrid) was found to be the most anthropogenically influenced site. The sediments within this profile which were recently deposited (170 ± 40 years BP) have the least radiogenic signatures. (206)Pb/(207)Pb ratios ranged between 1.1763 and 1.1876 indicating significant contributions of anthropogenic Pb. In contrast, profiles upstream of Madrid possess an average (206)Pb/(207)Pb ratio of 1.2272. It is difficult to clearly identify the most prominent source as the sediments appear to be characterized by an input from several sources. The floodplain profiles in the Tinto-Odiel basin exhibit uniform (206)Pb/(207)Pb ratios ranging from 1.1627 (Odiel river) to 1.1665 (Tinto river). These ratios are similar to the ones possessed by sulphide ores in the area and differ from the ratios of other nonmineralized formations in the basin, indicating that mining activities are the primary, if not sole, source of Pb to the sediments.

A geochemical study of overbank sediments in an urban area (Madrid, Spain).

Overbank and stream sediments have been studied in the Community of Madrid. Four vertical profiles have been sampled corresponding to Guadarrama, Jarama, and finally Manzanares River, where two profiles have been studied upstream (El Pardo profile) and downstream (Rivas profile) Madrid city. Sieved samples (<63 µm) were subjected to total (ICP-MS/ICP-OES and INAA) and partial analysis (ICP-MS). AMS radiocarbon dating techniques revealed a young age (170 ± 40 years BP) at 2.40-2.65 m depth for Rivas profile. It has not been possible to detect pristine or pre-industrial overbank sediments, since in the rest of the studied profiles, anthropogenic wastes were found even in the lower levels. Three main sources of sediment have been detected in the area. Granitic and arkosic geology, located in the northern part of Madrid (U, Th, W, K, Na, or rare earth elements); clays located in the southeast of Madrid (Ni, Cr, or V), and finally an anthropogenic source has been identified (Au, Ag, Pb, Zn, or Sb) in Rivas profile. The influence of the anthropogenic activity has been established based on the contents distribution of contaminant elements in the profile. This can be associated to the growth of industrial activities and population in the city of Madrid during the last decades. The comparison of the profiles by a k-means cluster analysis showed some similarities for these samples that could have analogous sources (anthropogenic and geological).