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Prostate cancer (PCa) is one of the leading causes of cancer-related deaths among men. Consequently, the identification of novel molecular targets for treatment is urgently needed to improve patients' outcomes. Our group recently reported that some elements of the cellular machinery controlling alternative-splicing might be useful as potential novel therapeutic tools against advanced PCa. However, the presence and functional role of RBM22, a key spliceosome component, in PCa remains unknown. Therefore, RBM22 levels were firstly interrogated in 3 human cohorts and 2 preclinical mouse models (TRAMP/Pbsn-Myc). Results were validated in in silico using 2 additional cohorts. Then, functional effects in response to RBM22 overexpression (proliferation, migration, tumorspheres/colonies formation) were tested in PCa models in vitro (LNCaP, 22Rv1, and PC-3 cell-lines) and in vivo (xenograft). High throughput methods (ie, RNA-seq, nCounter PanCancer Pathways Panel) were performed in RBM22 overexpressing cells and xenograft tumors. We found that RBM22 levels were down-regulated (mRNA and protein) in PCa samples, and were inversely associated with key clinical aggressiveness features. Consistently, a gradual reduction of RBM22 from non-tumor to poorly differentiated PCa samples was observed in transgenic models (TRAMP/Pbsn-Myc). Notably, RBM22 overexpression decreased aggressiveness features in vitro, and in vivo. These actions were associated with the splicing dysregulation of numerous genes and to the downregulation of critical upstream regulators of cell-cycle (i.e., CDK1/CCND1/EPAS1). Altogether, our data demonstrate that RBM22 plays a critical pathophysiological role in PCa and invites to suggest that targeting negative regulators of RBM22 expression/activity could represent a novel therapeutic strategy to tackle this disease. This research was funded by the Spanish Ministry of Science, Innovation, and Universities (Research‐Grant: PID2019‐105564RB‐I00; Predoctoral contracts: FPU16/05059, FPU17/00263, FPU18/02485), Health Institute Carlos III (DTS20-00050), Junta de Andalucia [BIO-0139; Consejería de Transformación Económica, Industria, Conocimiento y Universidades (P20_00442); Consejería de Salud y Familias, co-funded by European Union (Programa Operativo FEDER de Andalucía 2014-2020, “Andalucía se mueve con Europa”: PEER-0048-2020)], and CIBERobn (CIBER is an initiative of Instituto de Salud Carlos III, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain). Funding for open access charge: University of Córdoba/CBUA. Some images were taken from Servier Medical Art (smart.servier.com) under the Creative Commons Attribution 3.0 Unported License. Special thanks to the staff of Biobank of the IMIBIC and of the experimental animal service (SAE) of the UCO/IMIBIC. We are gratefully indented to all the patients and their families for generously donating the samples and clinical data for research purposes. All authors have read the journal's authorship agreement.

Bladder cancer is the most common malignancy of the urinary tract worldwide. The therapeutic options to tackle this disease comprise surgery, intravesical or systemic chemotherapy, and immunotherapy. Unfortunately, a wide number of patients ultimately become resistant to these treatments and develop aggressive metastatic disease, presenting a poor prognosis. Therefore, the identification of novel therapeutic approaches to tackle this devastating pathology is urgently needed. However, a significant limitation is that the progression and drug response of bladder cancer is strongly associated with its intrinsic molecular heterogeneity. In this sense, RNA splicing is recently gaining importance as a critical hallmark of cancer since can have a significant clinical value. In fact, a profound dysregulation of the splicing process has been reported in bladder cancer, especially in the expression of certain key splicing variants and circular RNAs with a potential clinical value as diagnostic/prognostic biomarkers or therapeutic targets in this pathology. Indeed, some authors have already evidenced a profound antitumor effect by targeting some splicing factors (e.g., PTBP1), mRNA splicing variants (e.g., PKM2, HYAL4-v1), and circular RNAs (e.g., circITCH, circMYLK), which illustrates new possibilities to significantly improve the management of this pathology. This review represents the first detailed overview of the splicing process and its alterations in bladder cancer, and highlights opportunities for the development of novel diagnostic/prognostic biomarkers and their clinical potential for the treatment of this devastating cancer type. This article is categorized under: RNA ProcessingSplicing Regulation/Alternative Splicing RNA in Disease and DevelopmentRNA in Disease.

Focal therapy (FT) ablates areas of prostate cancer rather than treating the whole gland. We compared oncological outcomes of FT to radical prostatectomy (RP). Using prospective multicentre databases of 761 FT and 572 RP cases (November/2005-September/2018), patients with PSA

PSA is the most widely used diagnosticand prognostic biomarker in prostate cancer (PCa).However, its lack of specificity has generated the needto search for new complementary markers. In thisscenario, blood plasma constitutes one of the sourcesof search for new markers, which have been tried tobe combined with PSA and other clinical variables inorder to develop tests that increase their diagnosticspecificity.This narrative review of the literature provides anoverview of commercially available plasma biomarkers and tests for use in different clinical settingsfor PCa. The most studied markers to help select theappropriate patients for initial and / or repeat biopsyhave been: PHI, 4K, STHLM3. These markers havebeen oriented towards the diagnosis of the so-calledclinically signifi cant PCa, trying to validate and calibratetheir algorithms in different populations. Giventhe development and evolution in the diagnosis of PCa,there is still a lack of evidence of the impact of magneticresonance imaging (MRI) when used in combinationwith these new markers, as well as its possiblerole in the screening of the disease and not only in theearly diagnosis process. Furthermore, there are only asmall number of studies that have directly comparedthese tests with each other and with PSA, so there isnot enough evidence to know which test has the bestproperties in each clinical scenario. In order to clarifythe true diagnostic role of these new biomarkers, newprospective, comparative studies in different populationsare absolutely necessary to evaluate their clinicalutility in combination with MRI and fusion biopsy.El PSA es el biomarcador diagnóstico ypronóstico más ampliamente utilizado en cáncer deprostata (CaP). Sin embargo, su falta de especificidadha generado la necesidad de buscar nuevos marcadorescomplementarios. En este escenario, el plasmasanguíneo constituye una de las fuentes de búsquedade nuevos marcadores, los cuales han tratado decombinarse con el PSA y otras variables clínicas conel objeto de desarrollar tests que aumentaran su especificidaddiagnóstica.En esta revisión narrativa de la literatura se proporcionauna descripción general de los biomarcadoresplasmáticos y tests disponibles comercialmentepara ser utilizados en diferentes contextos clínicosdel CaP. Los test más estudiados para ayudar a seleccionarlos pacientes adecuados para la biopsia inicialy / o repetida han sido: PHI, 4K, STHLM3. Estos testse han orientado hacia el diagnóstico del denominadoCaP clínicamente significativo, intentando validary calibrar sus algoritmos en diferentes poblaciones.Dado el desarrollo y evolución en el diagnóstico deCaP, aún existe una falta de evidencia del impacto de la resonancia magnética (RM) al ser empleada encombinación con estos nuevos marcadores, así comosu posible papel en el screening de la enfermedad yno solo en el proceso de diagnóstico precoz. Además,solo se dispone de una pequeña cantidad de estudiosque hayan comparado directamente estos test entreellos y con el PSA, de modo que no existe evidenciasuficiente para saber qué test tiene mejores propiedadesen cada escenario clínico. En el escenarioactual, para poder aclarar el verdadero papel diagnósticode estos nuevos biomarcadores, son absolutamentenecesarios nuevos estudios prospectivos,comparativos y en diferentes poblaciones, que evalúensu utilidad clínica en combinación con la RM yla biopsia fusión.

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies worldwide and is associated with high mortality. Broad screening through prostate-specific antigen analysis, along with an...

Objectives Overall, 25% to 33% of patients on kidney transplant wait lists present with prior graft loss. In addition, the number of patients who require a retransplant seems to be increasing. Here, we describe our experience with patients who had a second kidney transplant after a previous pancreas-kidney transplant or a third or fourth kidney transplant. We focused specifically on the technical aspects and outcomes related to this patient group. Materials and methods A single-center retrospective study was performed. The cohortincluded 15 patients > 18 years old who had received a second kidney graft after pancreas-kidney transplant or a second or greater kidney graft between 2013 and 2019. Results Median age of recipients was 45 years (range, 20-58 y). In 10 patients, the transperitoneal approach was selected. In 5 patients, the retroperitoneal heterotopic kidney retransplant technique was used. Early surgical complications (≤ 30 days posttransplant) were reported in 4 patients. Three patients had late ureteral stenosis (> 90 days posttransplant). All grafts were functioning at time of patient discharge. Mean creatinine level was 2.69 mg/dL (range, 1.23-6.26 mg/dL). The 1-year and 2-year graft survivalrates were 85% and 75%, respectively. No grafts were lost because of surgical complications. Conclusions Retransplant of a second graft after pancreas-kidney transplant or retransplant of a third or fourth renal graft is challenging but feasible, with evidence of reasonably positive outcomes after retransplant.

Context Recent studies emphasize the importance of considering the metabolic status to develop personalized medicine approaches. This is especially relevant in prostate cancer (PCa), wherein the diagnostic capability of prostate-specific antigen (PSA) dramatically drops when considering patients with PSA levels ranging from 3 to 10 ng/mL, the so-called grey zone. Hence, additional noninvasive diagnostic and/or prognostic PCa biomarkers are urgently needed, especially in the metabolic-status context. Objective To assess the potential relation of urine In1-ghrelin (a ghrelin-splicing variant) levels with metabolic-related/pathological conditions (eg, obesity, diabetes, body mass index, insulin and glucose levels) and to define its potential clinical value in PCa (diagnostic/prognostic capacity) and relationship with PCa risk in patients with PSA in the grey zone. Methods Urine In1-ghrelin levels were measured by radioimmunoassay in a clinically, metabolically, pathologically well-characterized cohort of patients without (n = 397) and with (n = 213) PCa with PSA in the grey zone. Results Key obesity-related factors associated with PCa risk (BMI, diabetes, glucose and insulin levels) were strongly correlated to In1-ghrelin levels. Importantly, In1-ghrelin levels were higher in PCa patients compared to control patients with suspect of PCa but negative biopsy). Moreover, high In1-ghrelin levels were associated with increased PCa risk and linked to PCa aggressiveness (eg, tumor stage, lymphovascular invasion). In1-ghrelin levels added significant diagnostic value to a clinical model consisting of age, suspicious digital rectal exam, previous biopsy, and PSA levels. Furthermore, a multivariate model consisting of clinical and metabolic variables, including In1-ghrelin levels, showed high specificity and sensitivity to diagnose PCa (area under the receiver operating characteristic curve = 0.740). Conclusions Urine In1-ghrelin levels are associated with obesity-related factors and PCa risk and aggressiveness and could represent a novel and valuable noninvasive PCa biomarker, as well as a potential link in the pathophysiological relationship between obesity and PCa.

Introduction. Our aim was to assess the value of adding standard biopsy to targeted biopsy in cases of suspicious multiparametric magnetic resonance imaging (mp-MRI) and also to evaluate when a biopsy of a PI-RADS 3 lesion could be avoided. Methods: A retrospective study of patients who underwent targeted biopsy plus standard systematic biopsy between 2016–2019 was performed. All the 1.5 T magnetic resonance images were evaluated according to PI-RADSv.2. An analysis focusing on the clinical scenario, lesion location, and PI-RADS score was performed. Results. A total of 483 biopsies were evaluated. The mean age was 65 years, with a PSA density of 0.12 ng/mL/cc. One-hundred and two mp-MRIs were categorized as PI-RADS-3. Standard biopsy was most helpful in detecting clinically significant prostate cancer (csPCa) in patients in the active surveillance (AS) cohort (increasing the detection rate 12.2%), and in peripheral lesions (6.5%). Adding standard biopsy showed no increase in the detection rate for csPCa in patients with PI-RADS-5 lesions. Considering targeted biopsy in patients with PI-RADS 3 lesions, a higher detection rate was shown in biopsy-naïve patients versus AS and in patients with a previous negative biopsy (p = 0.002). Furthermore, in these patients, the highest rate of csPCa detection was in anterior lesions [42.9% (p = 0.067)]. Conclusions. Our results suggest that standard biopsy could be safely omitted in patients with anterior lesions and in those with PI-RADS-5 lesions. Targeted biopsy for PI-RADS-3 lesions would be less effective in peripheral lesions with a previous negative biopsy.

Intake of olive oil as the main source of fat in Mediterranean diet is related to positive effects on human health. The olive biophenol hydroxytyrosol (HT) is considered a promising cancer chemopreventive compound against different types of cancer. The aim of the present study was to compare the cytotoxic activity against prostate cancer (PCa) cell lines of HT, obtained from olive mill wastewaters, and five semisynthetic alkyl ether, ester, and nitro-derivatives. HT, hydroxytyrosyl acetate (HT-Ac) and ethyl hydroxytyrosyl ether (HT-Et) exerted higher cytotoxic effect against 22Rv1 and PC-3 PCa cell lines than in non-malignant RWPE-1 cells. These compounds also significantly decreased the migration rate of RWPE-1 and PC-3 cells and the colony and prostatosphere formation of 22Rv1 cells. However, HT-Ac and HT-Et, but not HT, were able to decrease p-AKT levels and colony and prostatosphere formation in PC-3. In sum, HT and its lipophilic derivatives could be considered as potential therapeutic tools in PCa.

Context Prostate cancer (PCa) is one of the leading causes of cancer-related death among the male population worldwide. Unfortunately, current medical treatments fail to prevent PCa progression in a high percentage of cases; therefore, new therapeutic tools to tackle PCa are urgently needed. Biguanides and statins have emerged as antitumor agents for several endocrine-related cancers. Objective To evaluate: (1) the putative in vivo association between metformin and/or statins treatment and key tumor and clinical parameters and (2) the direct effects of different biguanides (metformin/buformin/phenformin), statins (atorvastatin/simvastatin/lovastatin), and their combination, on key functional endpoints and associated signalling mechanisms. Methods An exploratory/observational retrospective cohort of patients with PCa (n = 75) was analyzed. Moreover, normal and tumor prostate cells (normal [RWPE-cells/primary prostate cell cultures]; tumor [LNCaP/22RV1/PC3/DU145 cell lines]) were used to measure proliferation/migration/tumorsphere-formation/signalling pathways. Results The combination of metformin+statins in vivo was associated to lower Gleason score and longer biochemical recurrence-free survival. Moreover, biguanides and statins exerted strong antitumor actions (ie, inhibition of proliferation/migration/tumorsphere formation) on PCa cells, and that their combination further decreased; in addition, these functional parameters compared with the individual treatments. These actions were mediated through modulation of key oncogenic and metabolic signalling pathways (ie, AR/mTOR/AMPK/AKT/ERK) and molecular mediators (MKI67/cMYC/androgen receptor/cell-cycle inhibitors). Conclusions Biguanides and statins significantly reduced tumor aggressiveness in PCa, with this effect being more potent (in vitro and in vivo) when both compounds are combined. Therefore, given the demonstrated clinical safety of biguanides and statins, our results suggest a potential therapeutic role of these compounds, especially their combination, for the treatment of PCa.

ContextObesity is a major health problem associated with severe comorbidities, including type 2 diabetes and cancer, wherein microRNAs (miRNAs) might be useful as diagnostic/prognostic tools or therapeutic targets.ObjectiveTo explore the differential expression pattern of miRNAs in obesity and their putative role in obesity-related comorbidities such as insulin resistance.MethodsAn Affymetrix-miRNA array was performed in plasma samples from normoweight (n = 4/body mass index < 25) and obese subjects (n = 4/body mass index > 30). The main changes were validated in 2 independent cohorts (n = 221/n = 18). Additionally, in silico approaches were performed and in vitro assays applied in tissue samples and prostate (RWPE-1) and liver (HepG2) cell-lines.ResultsA total of 26 microRNAs were altered (P < 0.01) in plasma of obese subjects compared to controls using the Affymetrix-miRNA array. Validation in ampler cohorts revealed that miR-4454 levels were consistently higher in obesity, associated with insulin-resistance (Homeostatic Model Assessment of Insulin Resistance/insulin) and modulated by medical (metformin/statins) and surgical (bariatric surgery) strategies. miR-4454 was highly expressed in prostate and liver tissues and its expression was increased in prostate and liver cells by insulin. In vitro, overexpression of miR-4454 in prostate cells resulted in decreased expression levels of INSR, GLUT4, and phosphorylation of AMPK/AKT/ERK, as well as in altered expression of key spliceosome components (ESRP1/ESRP2/RBM45/RNU2) and insulin-receptor splicing variants.ConclusionsObesity was associated to an alteration of the plasmatic miRNA landscape, wherein miR-4454 levels were higher, associated with insulin-resistance and modulated by obesity-controlling interventions. Insulin regulated miR-4454, which, in turn may impair the cellular response to insulin, in a cell type-dependent manner (i.e., prostate gland), by modulating the splicing process.

The crisis in the SARSCoV-2 coronavirus causing COVID-19 is putting health systems around the world to the test. In a great effort to standardize the management and treatment guidelines, the different health authorities and scientific associations have tried to issue recommendations on how to act in this new and complex scenario. OBJECTIVE: To synthesize the existing evidence and recommendations about urological emergency surgery during the COVID-19 pandemic situation. Furthermore, we propose a general action protocol for these patients.The document is based ont he scarce evidence on SARS / Cov-2 and the experience of the authors in the management of COVID-19 in their institutions, including specialists from Andalusia, Cantabria, Madrid and the Basque Country. A web and PubMed search was performed using the keywords "SARS-CoV-2", "COVID19", "COVID Urology", "COVID19 surgery" and "emergency care". A narrative review of the literature was carried out until April 30, 2020, including only articles and documents written in Spanish and English. After the nominal group technique modified due to the extraordinary restrictions, a first draft was made to unify criteria. Finally, a definitive version was made, agreed by all the authors on May 12, 2020.General principles of action are set out, as well as specific recommendations for the most frequent urgent urological procedures.Given the exceptional nature of the situation, there is a lack of evidence regarding the optimal management of the patient with urgent urological pathology. The information is changing, as the epidemiological knowledge of the disease advances. The establishment of multidisciplinary surgical committees that develop and implement action protocols appropriate to the different resources and particular situations of each center is recommended. Likewise, these committees must individually assess each possible urological surgical emergency situation and ensure compliance with protective measures for the patient and other healthcare personnel.INTRODUCCIÓN: La crisis del coronavirus SARS-CoV-2 causante del COVID-19 está poniendoa prueba los sistemas sanitarios de todo el mundo. En un gran esfuerzo por estandarizar las pautas de manejo y tratamiento, las distintas autoridades sanitarias y asociaciones científicas han tratado de dictar unas recomendaciones sobre como actuar en este nuevo y complejo escenario.OBJETIVO: Sintetizar la evidencia y recomendaciones existentes acerca de la cirugía de urgencia urológica durante la situación de pandemia COVID-19. Además, proponemos un protocolo de actuación general para estos pacientes. MATERIAL Y MÉTODOS: El documento se basa en la escasa evidencia sobre SARS/Cov-2 y la experiencia de los autores en el manejo de COVID-19 en sus instituciones incluyendo especialistas de Andalucía, Cantabria, Madrid y País Vasco. Se realizó una búsqueda web y en PubMed utilizando las palabras clave “SARSCoV-2”, “COVID19”, “COVID Urology”, “COVID19 surgery” y “emergency care”. Se realizó una revisión narrativa de la literatura hasta el día 30 de Abril de2020 incluyendo solo artículos y documentos escritos en lengua española e inglesa. Tras técnica de grupo nominal modificada debido a las restricciones extraordinarias se realizó un primer borrador para unificar criterios. Finalmente, se realizó una versión definitiva, consensuada por todos los autores el 12 Mayo 2020. RESULTADOS: Se exponen unos principios generales de actuación, así como unas recomendaciones específicas para los procedimientos urológicos urgentes más frecuentes.CONCLUSIONES: Dado el carácter excepcional de la situación, existe un déficit de evidencia respecto al óptimo manejo del paciente con patología urológica urgente. La información es cambiante, según avanza el conocimiento epidemiológico de la enfermedad. Es recomendable el establecimiento de comités multidisciplinares quirúrgicos que desarrollen e implementen protocolos de actuación adecuados a los distintos recursos y situaciones particulares de cada centro. Del mismo modo, estos comités deben evaluar de forma individualizada cada posible situación de urgencia quirúrgica urológica y velar por el cumplimiento de las medidas de protección para el paciente y resto del personal sanitario.

Certain components of the somatostatin-system play relevant roles in Prostate Cancer (PCa), whose most aggressive phenotype (Castration-Resistant-PCa (CRPC)) remains lethal nowadays. However, neuronostatin and the G protein-coupled receptor 107 (GPR107), two novel members of the somatostatin-system, have not been explored yet in PCa. Consequently, we investigated the pathophysiological role of NST/GPR107-system in PCa. GPR107 expression was analyzed in well-characterized PCa patient&prime, s cohorts, and functional/mechanistic assays were performed in response to GPR107-silencing and NST-treatment in PCa cells (androgen-dependent (AD: LNCaP) and androgen-independent (AI: 22Rv1/PC-3), which are cell models of hormone-sensitive and CRPC, respectively), and normal prostate cells (RWPE-1 cell-line). GPR107 was overexpressed in PCa and associated with key clinical parameters (e.g., advance stage of PCa, presence of vascular invasion and metastasis). Furthermore, GPR107-silencing inhibited proliferation/migration rates in AI-PCa-cells and altered key genes and oncogenic signaling-pathways involved in PCa aggressiveness (i.e., KI67/CDKN2D/MMP9/PRPF40A, SST5TMD4/AR-v7/In1-ghrelin/EZH2 splicing-variants and AKT-signaling). Interestingly, NST treatment inhibited proliferation/migration only in AI-PCa cells and evoked an identical molecular response than GPR107-silencing. Finally, NST decreased GPR107 expression exclusively in AI-PCa-cells, suggesting that part of the specific antitumor effects of NST could be mediated through a GPR107-downregulation. Altogether, NST/GPR107-system could represent a valuable diagnostic and prognostic tool and a promising novel therapeutic target for PCa and CRPC.

Background The objective of this study was to explore telomere-associated variables (TAV) as complementary biomarkers in the early diagnosis of prostate cancer (PCa), analyzing their application in risk models for significant PCa (Gleason score > 6). Methods As part of a larger prospective longitudinal study of patients with suspicion of PCa undergoing prostate biopsy according to clinical practice, a subgroup of patients (n = 401) with PSA 3–10 ng/ml and no prior biopsies was used to evaluate the contribution of TAV to discern non-significant PCa from significant PCa. The cohort was randomly split for training (2/3) and validation (1/3) of the models. High-throughput quantitative fluorescence in-situ hybridization was used to evaluate TAV in peripheral blood mononucleated cells. Models were generated following principal component analysis and random forest and their utility as risk predictors was evaluated by analyzing their predictive capacity and accuracy, summarized by ROC curves, and their clinical benefit with decision curves analysis. Results The median age of the patients was 63 years, with a median PSA of 5 ng/ml and a percentage of PCa diagnosis of 40.6% and significant PCa of 19.2%. Two TAV-based risk models were selected (TAV models 1 and 2) with an AUC ≥ 0.83 in the full study cohort, and AUC > 0.76 in the internal validation cohort. Both models showed an improvement in decision capacity when compared to the application of the PCPT-RC in the low-risk probabilities range. In the validation cohort, with TAV models 1 and 2, 33% /48% of biopsies would have been avoided losing 0/10.3% of significant PCa, respectively. The models were also tested and validated on an independent, retrospective, non contemporary cohort. Conclusions Telomere analysis through TAV should be considered as a new risk-score biomarker with potential to increase the prediction capacity of significant PCa in patients with PSA between 3–10 ng/ml.

Early detection of PCa faces severe limitations as PSA displays poor‐specificity/sensitivity. As we recently demonstrated that plasma ghrelin O‐acyltransferase (GOAT)‐enzyme is significantly elevated in PCa‐patients compared with healthy‐controls, using a limited patients‐cohort, we aimed to further explore the potential of GOAT to improve PCa diagnosis using an ample patients‐cohort (n = 312) and defining subgroups (i.e. significant PCa/metastatic patients, etc.) that could benefit from this biomarker. Plasma GOAT‐levels were evaluated by ELISA in patients with (n = 183) and without (n = 129) PCa. Gleason Score ≥ 7 was considered clinically significant PCa. GOAT‐levels were higher in PCa patients vs control patients, and in those with significant PCa vs non‐significant PCa. GOAT‐levels association with the diagnoses of significant PCa was independent from traditional clinical variables (i.e. PSA/age/DRE). Remarkably, GOAT outperformed PSA in patients with PSA‐levels ranging 3‐20 ng/mL for the significant PCa diagnosis [GOAT‐AUC = 0.612 (0.531‐0.693) vs PSA‐AUC = 0.494 (0.407‐0.580)]. A panel of key variables including GOAT/age/DRE/testosterone also outperformed the same panel but with PSA [AUC = 0.720 (0.710‐0.730) vs AUC = 0.705 (0.695‐0.716), respectively]. Notably, GOAT‐levels could also represent a novel predictive biomarker of aggressiveness, as its levels are positively associated with Gleason Score and the presence of metastasis at the time of diagnoses. Altogether, our data reveal that GOAT‐levels can be used as a non‐invasive biomarker for significant PCa diagnosis in patients at risk of PCa (with PSA: 3‐20 ng/mL).

Management of active surveillance (AS) in low-risk prostate cancer (PCa) patients could be improved with new biomarkers, such as the 4Kscore test. We analyze its ability to predict tumor reclassification by upgrading at the confirmatory biopsy at 6 months. Observational, prospective, blinded, and non-randomized study, within the Spanish National Registry on AS (AEU/PIEM/2014/0001; NCT02865330) with 181 patients included after initial Bx and inclusion criteria: PSA ≤10 ng/mL, cT1c-T2a, Grade group 1, ≤2 cores, and ≤5 mm/50% length core involved. Central pathological review of initial and confirmatory Bx was performed on all biopsy specimens. Plasma was collected 6 months after initial Bx and just before confirmatory Bx to determine 4Kscore result. In order to predict reclassification defined as Grade group ≥2, we analyzed 4Kscore, percent free to total (%f/t) PSA ratio, prostate volume, PSA density, family history, body mass index, initial Bx, total cores, initial Bx positive cores, initial Bx % of positive cores, initial Bx maximum cancer core length and initial Bx cancer % involvement. Wilcoxon rank-sum test, non-parametric trend test or Fisher’s exact test, as appropriate established differences between groups of reclassification. A total of 137 patients met inclusion criteria. Eighteen patients (13.1%) were reclassified at confirmatory Bx. The %f/t PSA ratio and 4Kscore showed differences between the groups of reclassification (Yes/No). Using 7.5% as cutoff for the 4Kscore, we found a sensitivity of 89% and a specificity of 29%, with no reclassifications to Grade group 3 for patients with 4Kscore below 7.5% and 2 (6%) missed Grade group 2 reclassified patients. Using this threshold value there is a biopsy reduction of 27%. Additionally, 4Kscore was also associated with changes in tumor volume. Our preliminary findings suggest that the 4Kscore may be a useful tool in the decision-making process to perform a confirmatory Bx in active surveillance management.

IntroductionRisk calculators (RCs) are easy-to-use tools considering available clinical variables that could help to select those patients with risk of prostate cancer (PCa) who should undergo a prostate biopsy.ObjectiveTo perform a comparison for the prediction of significant PCa (SigPCa) between the European Randomised Study of Screening for PCa (ERSPC) and the PCa Prevention Trial (PCPT) RCs in patients with prostate-specific antigen (PSA) between 3 and 10 ng/mL through an evaluation of the accuracy/variability between two consecutive PSA values.SettingAn observational study in a major university hospital in the south of Spain.Methods and participantsAn observational study was performed in patients who underwent a prostate biopsy. SigPCa probabilities were calculated with the two PSA measures using ERSPC3/4+digital rectal examination and PCPT v2+free PSA RCs. The prediction of SigPCa was determined by the area under the receiver operating characteristic curve (AUC). Calibration, discrimination and decision curve analysis were studied. The variability between both RCs’ agreement was compared using Cohen’s kappa coefficient.Results510 patients were analysed (87 diagnosed with SigPCa). The median PSA values were 5.3 and 5 ng/mL for PSA1 and PSA2, respectively. Both RCs overestimated the risk in the case of high-risk probabilities. Discriminative ability for SigPCa was similar between models with an AUC=0.73 (0.68–0.79) for ERSPC-RC versus 0.73 (0.67–0.79) for PCPT-RC. ERSPC-RC showed less variability than PCPT-RC, with a constant agreement (k=0.7–0.8) for usual range of clinical decision-making. Remarkably, a higher number of biopsies would be avoided using the ERSPC-RC, but more SigPCa would be missed along all the risk probabilities.ConclusionsBoth RCs performed similar in the prediction of SigPCa. However, ERSPC-RC seems to be more stable for intraindividual PSA variations.

A high adherence to a Mediterranean diet has been related to numerous beneficial effects in human health, including a lower incidence and mortality of prostate cancer (PCa). Olive oil is an important source of phenolic bioactive compounds, mainly hydroxytyrosol (HT), of this diet. Be-cause of the growing interest of this compound and its derivatives as a cancer chemopreventive agent, we aimed to compare the in vitro effect of HT isolated from olive mill wastewaters and five semisynthetic alkyl ether, ester, and nitro-derivatives against prostate cancer (PCa) cell lines. The effect in cell proliferation was determined in RWPE-1, LNCaP, 22Rv1, and PC-3 cells by resazurin assay, the effect in cell migration by wound healing assay, and tumorsphere and colony formation were evaluated. The changes in key signaling pathways involved in carcinogenesis were assessed by using a phosphorylation pathway profiling array and by Western blotting. Antiproliferative effects of HT and two lipophilic derivatives [hydroxytyrosyl acetate (HT-Ac)/ethyl hydroxytyrosyl ether (HT-Et)] were significantly higher in cancerous PC-3 and 22Rv1 cells than in non-malignant RWPE-1 cells. HT/HT-Ac/HT-Et significantly reduced migration capacity in RWPE-1 and PC-3 and prostatosphere size and colony formation in 22Rv1, whereas only HT-Ac and HT-Et reduced these functional parameters in PC-3. The cytotoxic effect in 22Rv1 cells was correlated with modifications in the phosphorylation pattern of key proteins, including ERK1/2 and AKT. Consistently, HT-Ac and HT-Et decreased p-AKT levels in PC-3. In sum, our results suggest that HT and its lipophilic derivatives could be considered as potential therapeutic tools in PCa. Junta de Andalucía PI-0152-2019, BIO-0139, RH-0084-2020 Ministerio de Economía y Competitividad PID2019-105564RB-I00, PID2019-105201RB-I00, FPU17/00263, FPU16/06190, FPU18/02485

Background Prostate cancer (PCa) is a highly prevalent neoplasia that is strongly influenced by the endocrine system. Somatostatin (SST) and its five receptors (sst1-5 encoded by SSTR1-5 genes) comprise a pleiotropic system present in most endocrine-related cancers, some of which are successfully treated with SST analogs. Interestingly, it has been reported that SSTR1 is overexpressed in PCa, but its regulation, functional role, and clinical implications are still poorly known. Methods PCa specimens (n = 52) from biopsies and control prostates from cystoprostatectomies (n = 12), as well as in silico databases were used to evaluate SSTR1 and miRNAs expression. In vitro studies in 22Rv1 PCa cells were implemented to explore the regulation of SSTR1/sst1 by different miRNAs, and to evaluate the consequences of SSTR1/sst1 overexpression, silencing and/or activation [with the specific BIM-23926 sst1 agonist (IPSEN)] on cell-proliferation, migration, signaling-pathways, and androgen-signaling. Results We found that SSTR1 is overexpressed in multiple cohorts of PCa samples, as compared with normal prostate tissues, wherein it correlates with androgen receptor (AR) expression, and appears to be associated with aggressiveness (metastasis). Furthermore, our data revealed that SSTR1/sst1 expression might be regulated by specific miRNAs in PCa, including miR-24, which is downregulated in PCa samples and correlates inversely with SSTR1 expression. In vitro studies indicated that treatment with the BIM-23926 sst1 agonist, as well as SSTR1 overexpression, decreased, whereas SSTR1 silencing increased, cell-proliferation in 22Rv1 cells, likely through the regulation of PI3K/AKT-CCND3 signaling-pathway. Importantly, sst1 action was also able to modulate androgen/AR activity, and reduced PSA secretion from PCa cell lines. Conclusions Altogether, our results indicate that SSTR1 is overexpressed in PCa, where it can exert a relevant pathophysiological role by decreasing cell-proliferation and PSA secretion. Therefore, sst1, possibly in combination with miR-24, could be used as a novel tool to explore therapeutic targets in PCa.

Objective To externally validate the European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculator (RC) and to evaluate its variability between 2 consecutive prostate-specific antigen (PSA) values. Materials and Methods We prospectively catalogued 1021 consecutive patients before prostate biopsy for suspicion of prostate cancer (PCa). The risk of PCa and significant PCa (Gleason score ≥7) from 749 patients was calculated according to ERSPC-RC (digital rectal examination-based version 3 of 4) for 2 consecutive PSA tests per patient. The calculators' predictions were analyzed using calibration plots and the area under the receiver operating characteristic curve (area under the curve). Cohen kappa coefficient was used to compare the ability and variability. Results Of 749 patients, PCa was detected in 251 (33.5%) and significant PCa was detected in 133 (17.8%). Calibration plots showed an acceptable parallelism and similar discrimination ability for both PSA levels with an area under the curve of 0.69 for PCa and 0.74 for significant PCa. The ERSPC showed 226 (30.2%) unnecessary biopsies with the loss of 10 significant PCa. The variability of the RC was 16% for PCa and 20% for significant PCa, and a higher variability was associated with a reduced risk of significant PCa. Conclusion We can conclude that the performance of the ERSPC-RC in the present cohort shows a high similitude between the 2 PSA levels; however, the RC variability value is associated with a decreased risk of significant PCa. The use of the ERSPC in our cohort detects a high number of unnecessary biopsies. Thus, the incorporation of ERSPC-RC could help the clinical decision to carry out a prostate biopsy.

Introduction Nowadays, the number of patients receiving a second graft is growing, and the management of failed grafts is still controversial. Objective Our objective was to analyze the influence of graft nephrectomy on graft and patient survival. Materials and Methods We retrospectively evaluated the demographic features and graft outcomes of 63 recipients who received second allografts between August 1985 and April 2013. They were divided into two groups: group A, those who underwent nephrectomy of failed graft (n = 21, 33.3%), and group B, those whose failed graft was retained (n = 42, 66.6%). χ2 and Mann-Whitney U tests were used to compare demographic characteristics and graft features in both groups. Kaplan-Meier test was used to analyze graft and patient survival. Finally, univariate and multivariate analysis was done using Cox regression. Results Demographic characteristics of donor and receptors were similar in both groups. Overall panel-reactive antibody (P = .040) showed statistically significant differences between groups (72.0 ± 25.3 in group A and 54.8 ± 30.0 in group B). Hemodialysis duration was longer in group A (P = .023, 112.2 ± 72.8 vs 70.9 ± 66.9 months). The percentage of patients who had delayed graft function was higher in group A (58.8% vs 27.3%, P = .029). Kaplan-Meier test found no differences between groups (P = .344); group A, 107.4 months (95% confidence interval [CI] 74.0 to 140.8) and group B, 82.7 months (95% CI 62.5 to 102.8). We found no differences in terms of patient survival (P = .798) with the Kaplan-Meier test. In group A, patient survival was 164.5 months (CI 137.7 to 191.31) and in group B, 152.0 months (95% CI 125.5 to 178.5). Conclusions Failed graft nephrectomy did not show a negative impact on graft and patient survival.

Resumen Objetivo Analizar la utilidad predictiva de la ecografia doppler color peneana tras la inyeccion de vasoactivos en la recuperacion de la funcion erectil tras prostatectomia radical. Material y metodos Estudio retrospectivo en pacientes con disfuncion erectil tras prostatectomia radical tratados con inyecciones intracavernosas de prostaglandinas E1 entre el 1 de enero de 2006 y el 31 de diciembre de 2012. Se incluyeron enfermos sin antecedente de disfuncion erectil previa a la cirugia, no respondedores a tratamiento medico. En todos se realizo eco doppler color tras la inyeccion intracavernosa. Una velocidad picosistolica ≥ 30 cm/seg y una velocidad diastolica final ≤ 5 cm/seg fueron considerados valores hemodinamicos normales. Se evaluo el resultado del tratamiento durante el seguimiento mediante el uso de IIEF-5. Resultados Se incluyeron 197 pacientes. La edad media fue de 60,8 (± 6,3 DE). El diagnostico anatomopatologico en todos ellos fue de adenocarcinoma, siendo el 74,1% organoconfinados (T1-T2/Nx-N0). El tratamiento con inyecciones tras la cirugia se inicio una vez transcurridos 6,8 meses de media (± 3,5 DE). La ecografia doppler fue normal en 53 pacientes (26,9%). Durante el seguimiento, 113 pacientes (57,4%) mantenian erecciones funcionales, estando 55 de ellos (28%) sin necesidad de inyecciones. La presencia de una ecografia doppler normal se asocio a una respuesta favorable al tratamiento (p Conclusiones El test de prostaglandina E1 nos va a permitir una orientacion diagnostica en la disfuncion erectil de los pacientes prostatectomizados. Permite obtener informacion sobre el estado vascular del pene y aporta informacion pronostica de utilidad en el seguimiento de estos pacientes.