Lower baseline testosterone level is related to earlier development of castration resistance in metastatic prostate cancer: a multi-center cohort study.

Purpose: In the era of concurrent combination therapy in metastatic hormone sensitive prostate cancer, the impact of the testosterone level before initiating androgen deprivation therapy on treatment outcome is still uncertain. We aimed to investigate its effect on time-to-castration-resistance in a metastatic hormone sensitive prostate cancer cohort. Methods: This is a multi-center retrospective study of 5 databases from China, Japan, Austria and Spain including 258 metastatic hormone sensitive prostate cancer patients with androgen deprivation therapy initiated between 2002 and 2021. Baseline testosterone was divided into high and low groups using 12 nmol/L as cutoff level. Primary outcome was time-to-castration-resistance. Secondary outcomes were survival functions. Kaplan-Meier method was employed to evaluate the correlation between baseline testosterone and time-to-castration-resistance. Subgroup analysis was performed to elucidate the effect of upfront combination-therapy and metastatic volume. Results: Median age was 72 years. Median follow-up time was 31 months. Median pre-treatment prostate-specific-antigen level was 161 ng/mL. Majority of case were graded as International-Society-of-Urological-Pathology grade 5 (63.6%). 57.8% patients had high volume disease and 69.0% received upfront combination treatment. 44.6% of the cohort developed castration-resistance. The low testosterone group demonstrated shorter mean-time-to-castration-resistance (19.0 vs 22.4 months, p=0.031). The variance was more significant in patients without combination therapy (13.2 vs 26.3 months, p=0.015). Cancer-specific and overall survival were inferior in the low baseline testosterone level group without receiving combination therapy (p=0.001). Conclusions: Lower pre-treatment testosterone level is correlated to shorter time-to-castration resistance and worse survival in metastatic prostate cancer patients without upfront combination therapy. Those with low baseline testosterone should be encouraged to adopt combination therapy to delay progression.

Dysregulation of RNA-Exosome machinery is directly linked to major cancer hallmarks in prostate cancer: Oncogenic role of PABPN1.

Novel biomarkers and therapeutic strategies for prostate-cancer (PCa) are required to overcome its lethal progression. The dysregulation/implication of the RNA-Exosome-complex (REC; cellular machinery controlling the 3'-5'processing/degradation of most RNAs) in different cancer-types, including PCa, is poorly known. Herein, different cellular/molecular/preclinical approaches with human PCa-samples (tissues and/or plasma of 7 independent cohorts), and in-vitro/in-vivo PCa-models were used to comprehensively characterize the REC-profile and explore its role in PCa. Moreover, isoginkgetin (REC-inhibitor) effects were evaluated on PCa-cells. We demonstrated a specific dysregulation of the REC-components in PCa-tissues, identifying the Poly(A)-Binding-Protein-Nuclear 1 (PABPN1) factor as a critical regulator of major cancer hallmarks. PABPN1 is consistently overexpressed in different human PCa-cohorts and associated with poor-progression, invasion and metastasis. PABPN1 silencing decreased relevant cancer hallmarks in multiple PCa-models (proliferation/migration/tumourspheres/colonies, etc.) through the modulation of key cancer-related lncRNAs (PCA3/FALEC/DLEU2) and mRNAs (CDK2/CDK6/CDKN1A). Plasma PABPN1 levels were altered in patients with metastatic and tumour-relapse. Finally, pharmacological inhibition of REC-activity drastically inhibited PCa-cell aggressiveness. Altogether, the REC is drastically dysregulated in PCa, wherein this novel molecular event/mechanism, especially PABPN1 alteration, may be potentially exploited as a novel prognostic and therapeutic tool for PCa.

Graft survival and delayed graft function with normothermic regional perfusion and rapid recovery after circulatory death in kidney transplantation: a propensity score matching study.

BACKGROUND: A shortage of kidney grafts has led to the implementation of various strategies, including donations after circulatory death. The in situ normothermic regional perfusion technique has been introduced to improve graft quality by reducing warm ischemia times. However, there is limited evidence available on its mid- and long-term outcomes. Therefore, this study aimed to compare the incidence of delayed graft function, graft function, and survival at three years among three groups: brain death donors, rapid recovery, and normothermic regional perfusion. METHODS: A retrospective analysis of a cohort of kidney transplantations was conducted at a single referral center between January 1, 2015, and December 31, 2019. Univariate and multivariate regression models and propensity score matching analysis were performed to compare recipient-related, transplantation procedure-related, donor-related, and kidney function variables. RESULTS: A total of 327 patients were included, with 256 kidneys from brain death donors, 52 kidneys from rapid recovery, and 19 patients from normothermic regional perfusion. After propensity score matching, univariate and multivariate analyses showed a higher incidence of delayed graft function in the rapid recovery group compared to the others (OR: 2.39 CI95%: 1.19, 4.77) with a longer hospital stay (median 11, 15 and 10 days, respectively). However, no differences in 1- and 3-year graft function and survival were found. CONCLUSIONS: Normothermic regional perfusion offers advantages over rapid recovery, with a reduced incidence of delayed graft function and a shorter hospital stay. However, no differences in mid-term graft function and survival were found.

Kidney Survival Impact of Delayed Graft Function Depends on Kidney Donor Risk Index: A Single-Center Cohort Study.

BACKGROUND: Delayed graft function (DGF) is a significant challenge in renal transplantation, particularly with deceased donors, necessitating early postoperative dialysis. The prolonged effects of medium- and long-term DGF remain uncertain, marked by contradictory graft survival outcomes. This incongruity might arise from the inherent graft resilience and regenerative capacity during transplantation. This study investigates DGF's impact on graft survival, focusing on grafts displaying favorable (KDRI < 1) and unfavorable outcomes (KDRI ≥ 1). METHODS: In this retrospective cohort study (January 2015-December 2019), we assessed kidney transplants at our center, excluding multiorgan simultaneous cases, primary non-functioning grafts, and surgical complications causing graft loss. Patients were categorized into DGF presence or absence groups. Univariate and multivariate analyses, alongside propensity score matching (PSM), were performed. RESULTS: The study encompassed 322 deceased donor kidneys, with 83 encountering DGF. Grafts with higher KDRI indices (KDRI ≥ 1) and DGF exhibited a notably increased graft loss risk (HR: 4.17, 95% CI: 1.93-9.01). However, lower-KDRI donor grafts displayed no significant disparities between the DGF and non-DGF groups. CONCLUSIONS: Delayed graft function (DGF) development significantly contributes to graft loss in kidney transplants, particularly in grafts with KDRI ≥ 1.

LRP10, PGK1 and RPLP0: Best Reference Genes in Periprostatic Adipose Tissue under Obesity and Prostate Cancer Conditions.

Obesity (OB) is a metabolic disorder characterized by adipose tissue dysfunction that has emerged as a health problem of epidemic proportions in recent decades. OB is associated with multiple comorbidities, including some types of cancers. Specifically, prostate cancer (PCa) has been postulated as one of the tumors that could have a causal relationship with OB. Particularly, a specialized adipose tissue (AT) depot known as periprostatic adipose tissue (PPAT) has gained increasing attention over the last few years as it could be a key player in the pathophysiological interaction between PCa and OB. However, to date, no studies have defined the most appropriate internal reference genes (IRGs) to be used in gene expression studies in this AT depot. In this work, two independent cohorts of PPAT samples (n = 20/n = 48) were used to assess the validity of a battery of 15 literature-selected IRGs using two widely used techniques (reverse transcription quantitative PCR [RT-qPCR] and microfluidic-based qPCR array). For this purpose, ΔCt method, GeNorm (v3.5), BestKeeper (v1.0), NormFinder (v.20.0), and RefFinder software were employed to assess the overall trends of our analyses. LRP10, PGK1, and RPLP0 were identified as the best IRGs to be used for gene expression studies in human PPATs, specifically when considering PCa and OB conditions.

Prognostic impact of serum testosterone in metastatic hormone-naive prostate cancer: a systematic review and meta-analysis.

PURPOSE OF REVIEW: In daily practice, there is an unmet medical need for biomarkers that facilitate therapeutic decision-making in the metastatic hormone sensitive prostate cancer (mHSPC) scenario. Although recent studies have highlighted the potential of testosterone as a prognostic and predictive marker in prostate cancer, the evidence is controversial. The objective of this review was to summarize and analyze the scientific evidence regarding the prognostic role of basal testosterone levels in patients with mHSPC. METHODS: A systematic review was performed. Three authors selected the articles from Web of Science, PubMed, Scopus, and Cochrane Library electronic databases. Risk of bias was assessed by the Newcastle Ottawa Scale. RECENT FINDINGS: Most of the selected articles suggest that low testosterone levels before starting hormonal blockade imply a worse prognosis for patients with mHSPC. However, the quality of the evidence is poor, the studies are heterogeneous, and it is not possible to meta-analyze most of the published results. SUMMARY: Testosterone is an accessible and affordable biomarker. If it were correctly demonstrated that it harbors a prognostic and/or predictive role in the mHSPC setting, it could represent an advance in decision-making in these patients. Well designed prospective studies are needed to correctly answer this question.

ProsTAV, a novel blood-based test for biopsy decision management in significant prostate cancer.

BACKGROUND: Current pathways in early diagnosis of prostate cancer (PCa) can lead to unnecessary biopsy procedures. Here, we used telomere analysis to develop and evaluate ProsTAV®, a risk model for significant PCa (Gleason score >6), with the objective of improving the PCa diagnosis pathway. METHODS: This retrospective, multicentric study analyzed telomeres from patients with serum PSA 3-10 ng/mL. High-throughput quantitative fluorescence in-situ hybridization was used to evaluate telomere-associated variables (TAVs) in peripheral blood mononucleated cells. ProsTAV® was developed by multivariate logistics regression based on three clinical variables and six TAVs. The predictive capacity and accuracy of ProsTAV® were summarized by receiver operating characteristic (ROC) curves and its clinical benefit with decision curves analysis. RESULTS: Telomeres from 1043 patients were analyzed. The median age of the patients was 63 years, with a median PSA of 5.2 ng/mL and a percentage of significant PCa of 23.9%. A total of 874 patients were selected for model training and 169 patients for model validation. The area under the ROC curve of ProsTAV® was 0.71 (95% confidence interval [CI], 0.62-0.79), with a sensitivity of 0.90 (95% CI, 0.88-1.0) and specificity of 0.33 (95% CI, 0.24-0.40). The positive predictive value was 0.29 (95% CI, 0.21-0.37) and the negative predictive value was 0.91 (95% CI, 0.83-0.99). ProsTAV® would make it possible to avoid 33% of biopsies. CONCLUSIONS: ProsTAV®, a predictive model based on telomere analysis through TAV, could be used to increase the prediction capacity of significant PCa in patients with PSA between 3 and 10 ng/mL.

Midterm Outcomes of Kidney Transplantation from Expanded Criteria Donors After Circulatory Death: A Single-Center Retrospective Cohort Study.

OBJECTIVES: Kidney transplant is the optimal treatment for end-stage renal disease; however, due to the imbalance between demand and supply, several strategies have been implemented to increase the donor pool. To increase the number of donors, expanded criteria donors after circulatory death have been explored as an acceptable graft source. In this study, we compared graft survival, estimated glomerular filtration rate at 3 and 5 years, and the incidence of delayed graft function between standard and expanded criteria donors after brain death and between standard and expanded criteria donors after circulatory death. MATERIALS AND METHODS: A prospective cohort study was conducted between January 1, 2015, and December 31, 2019, at Reina Sofia University Hospital. Variables related to the donor, recipient, and transplant procedure were analyzed, and univariate and multivariate logistic and Cox regression analyses were performed. RESULTS: Our study included 308 deceased donor kidneys. The kidneys from standard criteria brain dead donors had higher estimated glomerular filtration rate than the other groups (P < .03).However, no significant differences in estimated glomerular filtration rate were observed among the suboptimal groups (expanded criteria and standard criteria donors after brain death and expanded criteria donors after circulatory death). The incidence of delayed graft function was significantly higher in expanded criteria donors after circulatory death than in the other groups (odds ratio = 6.9; 95% CI, 2.22-21.71; P < .001). Nevertheless, we found no significant differences in death-censored graft loss among the groups. CONCLUSIONS: Kidney transplants from expanded criteria donors and donors after cardiac death are comparable, even when both criteria are combined. The use of expanded criteria donor kidneys after cardiac death is therefore a suitable approach to expand the donor pool, despite the higher risk of delayed graft function, as there were no significant differences in death-censored graft loss.

Management of Penis Fracture: Clinical Cases Treated in Our Center and Comparison with Literature

Abstract Objective: To expose our clinical experience in the management of the penis fracture and make a literature review about this topic. Methods: We present a case of a 49 years old man diagnosticated penis fracture. We expose the results of our clinical cases diagnosticated and treated from October 2018 to October 2020 and make a literature review. Results: A 49 years old man that presented swallow and sensation of snap during a sexual intercourse. He was diagnosticated of penis fracture with the help of ultrasound and was performed an urgent reparation. The results of our serial of 4 cases were: The 75% (3) presented pain and sensation of snap during the sexual intercourse, 50% (2) detumescence, the 100% (4) ecchymosis and the 25% (1) present an actual lateral deviation. Anyone presents erectile dysfunction nowadays. Conclusions: The penis fracture has a clinical diagnosis but the ultrasound could be useful. The early surgical repair has a good result with low tase of complications (AU)

Clinical utility of checkpoint inhibitors against metastatic bladder cancer: overcoming challenges to find a way forward.

INTRODUCTION: Cisplatin-based chemotherapy is currently considered the gold-standard treatment for metastatic urothelial carcinoma (mUC). Nevertheless, most mUC patients develop resistance to chemotherapy. Immune checkpoint inhibitors (ICI) have emerged as a therapeutic option for mUC. ICI are used as both first- and second-line therapy for patients with mUC but also for maintenance following chemotherapy and durable responses may be expected in these settings. AREAS COVERED: Patients with mUC who experience progression after platinum-based chemotherapy regimens, those who are cisplatin-ineligible and have positive PD-L1 expression, and those who are platinum-ineligible, regardless of PD-L1 status, are the target population. The role of ICI monotherapy or drug combinations and newer proposals for mUC therapy are reviewed. The current status of biomarkers to guide ICI treatments in mUC is also provided, focusing on PD-L1, tumor mutational load, and liquid biopsies using ctDNA. EXPERT OPINION: Current challenges to improve the role of ICI in mUC could be summarized as i) development of better drugs; ii) advances in drug-combinations schemes; iii) development of novel biomarkers and techniques to better select patients for this treatment; iv) providing the drugs in the optimal clinical setting; v) promoting trials covering more demographic and clinical heterogeneity (i.e. wider age range, gender, and diverse clinical representation).

Risk Classification of Bladder Cancer by Gene Expression and Molecular Subtype.

This study evaluated a panel including the molecular taxonomy subtype and the expression of 27 genes as a diagnostic tool to stratify bladder cancer patients at risk of aggressive behavior, using a well-characterized series of non-muscle invasive bladder cancer (NMIBC) as well as muscle-invasive bladder cancer (MIBC). The study was conducted using the novel NanoString nCounter gene expression analysis. This technology allowed us to identify the molecular subtype and to analyze the gene expression of 27 bladder-cancer-related genes selected through a recent literature search. The differential gene expression was correlated with clinicopathological variables, such as the molecular subtypes (luminal, basal, null/double negative), histological subtype (conventional urothelial carcinoma, or carcinoma with variant histology), clinical subtype (NMIBC and MIBC), tumor stage category (Ta, T1, and T2-4), tumor grade, PD-L1 expression (high vs. low expression), and clinical risk categories (low, intermediate, high and very high). The multivariate analysis of the 19 genes significant for cancer-specific survival in our cohort study series identified TP53 (p = 0.0001), CCND1 (p = 0.0001), MKI67 (p < 0.0001), and molecular subtype (p = 0.005) as independent predictors. A scoring system based on the molecular subtype and the gene expression signature of TP53, CCND1, or MKI67 was used for risk assessment. A score ranging from 0 (best prognosis) to 7 (worst prognosis) was obtained and used to stratify our patients into two (low [score 0-2] vs. high [score 3-7], model A) or three (low [score 0-2] vs. intermediate [score 3-4] vs. high [score 5-7], model B) risk categories with different survival characteristics. Mean cancer-specific survival was longer (122 + 2.7 months) in low-risk than intermediate-risk (79.4 + 9.4 months) or high-risk (6.2 + 0.9 months) categories (p < 0.0001; model A); and was longer (122 + 2.7 months) in low-risk than high-risk (58 + 8.3 months) (p < 0.0001; model B). In conclusion, the molecular risk assessment model, as reported here, might be used better to select the appropriate management for patients with bladder cancer.

The role of multiparametric magnetic resonance in active surveillance of a low-risk prostate cancer cohort from clinical practice.

INTRODUCTION: Active surveillance (AS) is considered a suitable management practice for those patients with low-risk prostate cancer (PCa). At present, however, the role of multiparametric magnetic resonance imaging (mpMRI) in AS protocols has not yet been clearly established. OUTCOMES: To determine the role of mpMRI and its ability to detect significant prostate cancer (SigPCa) in PCa patients enrolled in AS protocols. MATERIALS AND METHODS: There were 229 patients enrolled in an AS protocol between 2011 and 2020 at Reina Sofía University Hospital. MRI interpretation was based on PIRADS v.1 or v.2/2.1 classification. Demographics, clinical, and analytical data were collected and analyzed. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for mpMRI in different scenarios. We defined SigPCa and reclassification/progression as a Gleason score (GS) ≥ 3 + 4, a clinical stage ≥T2b, or an increase in PCa volume. Kaplan-Meier and log-rank tests were used to estimate progression-free survival time. RESULTS: Median age was 69.02 (±7.73) at diagnosis, with a 0.15 (±0.08) PSA density (PSAD). Eighty-six patients were reclassified after confirmatory biopsy, with a suspicious mpMRI an indication for a clear reclassification and risk-predictor factor in disease progression (p < 0.05). During follow-up, 46 patients were changed from AS to active treatment mainly due to disease progression. Ninety patients underwent ≥2mpMRI during follow-up, with a median follow-up of 29 (15-49) months. Thirty-four patients had a baseline suspicious mpMRI (at diagnostic or confirmatory biopsy): 14 patients with a PIRADS 3 and 20 patients with ≥PIRADS 4. From 14 patients with a PIRADS 3 baseline mpMRI, 29% progressed radiologically, with a 50% progression rate versus 10% (1/10 patients) for those with similar or decreased mpMRI risk. Of the 56 patients with a non-suspicious baseline mpMRI (PIRADS < 2), 14 patients (25%) had an increased degree of radiological suspicion, with a detection rate of SigPCa of 29%. The mpMRI NPV during follow-up was 0.91. CONCLUSION: A suspicious mpMRI increases the reclassification and disease progression risk during follow-up and plays an important role in monitoring biopsies. In addition, a high NPV at mpMRI follow-up can help to decrease the need to monitor biopsies during AS.

Mass Spectrometry-Based Biomarkers to Detect Prostate Cancer: A Multicentric Study Based on Non-Invasive Urine Collection without Prior Digital Rectal Examination.

(1) Background: Prostate cancer (PCa) is the most frequently diagnosed cancer in men. Wide application of prostate specific antigen test has historically led to over-treatment, starting from excessive biopsies. Risk calculators based on molecular and clinical variables can be of value to determine the risk of PCa and as such, reduce unnecessary and invasive biopsies. Urinary molecular studies have been mostly focusing on sampling after initial intervention (digital rectal examination and/or prostate massage). (2) Methods: Building on previous proteomics studies, in this manuscript, we aimed at developing a biomarker model for PCa detection based on urine sampling without prior intervention. Capillary electrophoresis coupled to mass spectrometry was applied to acquire proteomics profiles from 970 patients from two different clinical centers. (3) Results: A case-control comparison was performed in a training set of 413 patients and 181 significant peptides were subsequently combined by a support vector machine algorithm. Independent validation was initially performed in 272 negative for PCa and 138 biopsy-confirmed PCa, resulting in an AUC of 0.81, outperforming current standards, while a second validation phase included 147 PCa patients. (4) Conclusions: This multi-dimensional biomarker model holds promise to improve the current diagnosis of PCa, by guiding invasive biopsies.

Tumor suppressor role of RBM22 in prostate cancer acting as a dual-factor regulating alternative splicing and transcription of key oncogenic genes.

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.

Alternative splicing in bladder cancer: potential strategies for cancer diagnosis, prognosis, and treatment.

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 Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease.

Somatostatin, Cortistatin and Their Receptors Exert Antitumor Actions in Androgen-Independent Prostate Cancer Cells: Critical Role of Endogenous Cortistatin.

Somatostatin (SST), cortistatin (CORT), and their receptors (SSTR1-5/sst5TMD4-TMD5) comprise a multifactorial hormonal system involved in the regulation of numerous pathophysiological processes. Certain components of this system are dysregulated and play critical roles in the development/progression of different endocrine-related cancers. However, the presence and therapeutic role of this regulatory system in prostate cancer (PCa) remain poorly explored. Accordingly, we performed functional (proliferation/migration/colonies-formation) and mechanistic (Western-blot/qPCR/microfluidic-based qPCR-array) assays in response to SST and CORT treatments and CORT-silencing (using specific siRNA) in different PCa cell models [androgen-dependent (AD): LNCaP; androgen-independent (AI)/castration-resistant PCa (CRPC): 22Rv1 and PC-3], and/or in the normal-like prostate cell-line RWPE-1. Moreover, the expression of SST/CORT system components was analyzed in PCa samples from two different patient cohorts [internal (n = 69); external (Grasso, n = 88)]. SST and CORT treatment inhibited key functional/aggressiveness parameters only in AI-PCa cells. Mechanistically, antitumor capacity of SST/CORT was associated with the modulation of oncogenic signaling pathways (AKT/JNK), and with the significant down-regulation of critical genes involved in proliferation/migration and PCa-aggressiveness (e.g., MKI67/MMP9/EGF). Interestingly, CORT was highly expressed, while SST was not detected, in all prostate cell-lines analyzed. Consistently, endogenous CORT was overexpressed in PCa samples (compared with benign-prostatic-hyperplasia) and correlated with key clinical (i.e., metastasis) and molecular (i.e., SSTR2/SSTR5 expression) parameters. Remarkably, CORT-silencing drastically enhanced proliferation rate and blunted the antitumor activity of SST-analogues (octreotide/pasireotide) in AI-PCa cells. Altogether, we provide evidence that SST/CORT system and SST-analogues could represent a potential therapeutic option for PCa, especially for CRPC, and that endogenous CORT could act as an autocrine/paracrine regulator of PCa progression.

Physiopathology of the Priapism Secondary to Tamsulosin: Clinical Cases of Our Hospital and Literature Review.

OBJECTIVE: To describe two cases of man with the diagnosis of ischemic priapism after the intake of tamsulosin and to revise the scientific literature. METHODS: We present two cases of men that developed an ischemic priapism after the intake of tamsulosin prescribed for STUI and were treated in our hospital. We described the two cases, from the diagnosis until the surgery that was performed. Also, we review the scientific literature about this topic. RESULTS: In one hand, a 67 years old man with the previous diagnosis of diabetes mellitus, hypertension and dyslipidemia that take a one single dosis of tamsulosin and developed a priapism of 9 hours of duration. He was diagnosticated of low-flow priapism that was reverted after the use of intracavernosal phenylephrine. On the other hand, a 61 years old man without any medical condition. He developed a priapism after the intake of also one single dosis of tamsulosin and came to the hospital after 48 hours of the beginning of the erection. In this case, the use of intracavernosal phenylephrine wasn´t effective so we decided to performed a distal shunt between cavernosal and spongy body according to the techniques of Winter, Ebbehoj and Al-Ghorab. All of them without results. At the end, we tried a proximal shunt according Quackles technique, also ineffective. The patient declined another surgery for implantation of a pennis prothesis and went home after four days of hospitalization with the disappearance of the pain. CONCLUSIONS: The tamsulosin is a drug well known by urologist that have a safety profile probed with the years. Nevertheless, it's association with a disease like the priapism forced us to explain to our patients this rare adverse effect.

Validation of diagnostic nomograms based on CE-MS urinary biomarkers to detect clinically significant prostate cancer.

PURPOSE: Prostate cancer (PCa) is one of the most common cancers and one of the leading causes of death worldwide. Thus, one major issue in PCa research is to accurately distinguish between indolent and clinically significant (csPCa) to reduce overdiagnosis and overtreatment. In this study, we aim to validate the usefulness of diagnostic nomograms (DN) to detect csPCa, based on previously published urinary biomarkers. METHODS: Capillary electrophoresis/mass spectrometry was employed to validate a previously published biomarker model based on 19 urinary peptides specific for csPCa. Added value of the 19-biomarker (BM) model was assessed in diagnostic nomograms including prostate-specific antigen (PSA), PSA density and the risk calculator from the European Randomized Study of Screening. For this purpose, urine samples from 147 PCa patients were collected prior to prostate biopsy and before performing digital rectal examination (DRE). The 19-BM score was estimated via a support vector machine-based software based on the pre-defined cutoff criterion of - 0.07. DNs were subsequently developed to assess added value of integrative diagnostics. RESULTS: Independent validation of the 19-BM resulted in an 87% sensitivity and 65% specificity, with an AUC of 0.81, outperforming PSA (AUC PSA: 0.64), PSA density (AUC PSAD: 0.64) and ERSPC-3/4 risk calculator (0.67). Integration of 19-BM with the rest clinical variables into distinct DN, resulted in improved (AUC range: 0.82-0.88) but not significantly better performances over 19-BM alone. CONCLUSION: 19-BM alone or upon integration with clinical variables into DN, might be useful for detecting csPCa by decreasing the number of biopsies.

Dysregulation of the miRNome unveils a crosstalk between obesity and prostate cancer: miR-107 asa personalized diagnostic and therapeutic tool.

Prostate-specific antigen (PSA) is the gold-standard marker to screen prostate cancer (PCa) nowadays. Unfortunately, its lack of specificity and sensitivity makes the identification of novel tools to diagnose PCa an urgent medical need. In this context, microRNAs (miRNAs) have emerged as potential sources of non-invasive diagnostic biomarkers in several pathologies. Therefore, this study was aimed at assessing for the first time the dysregulation of the whole plasma miRNome in PCa patients and its putative implication in PCa from a personalized perspective (i.e., obesity condition). Plasma miRNome from a discovery cohort (18 controls and 19 PCa patients) was determined using an Affymetrix-miRNA array, showing that the expression of 104 miRNAs was significantly altered, wherein six exhibited a significant receiver operating characteristic (ROC) curve to distinguish between control and PCa patients (area under the curve [AUC] = 1). Then, a systematic validation using an independent cohort (135 controls and 160 PCa patients) demonstrated that miR-107 was the most profoundly altered miRNA in PCa (AUC = 0.75). Moreover, miR-107 levels significantly outperformed the ability of PSA to distinguish between control and PCa patients and correlated with relevant clinical parameters (i.e., PSA). These differences were more pronounced when considering only obese patients (BMI > 30). Interestingly, miR-107 levels were reduced in PCa tissues versus non-tumor tissues (n = 84) and in PCa cell lines versus non-tumor cells. In vitro miR-107 overexpression altered key aggressiveness features in PCa cells (i.e., proliferation, migration, and tumorospheres formation) and modulated the expression of important genes involved in PCa pathophysiology (i.e., lipid metabolism [i.e., FASN] and splicing process). Altogether, miR-107 might represent a novel and useful personalized diagnostic and prognostic biomarker and a potential therapeutic tool in PCa, especially in obese patients.

Serum biomarkers for diagnosis and characterization of prostate cancer. / Biomarcadores plasmáticos en el diagnóstico y caracterización del cáncer de próstata.

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.