Clinical association of metabolic syndrome, C-reactive protein and testosterone levels with clinically significant prostate cancer.

Recently, the influence that metabolic syndrome (MetS), hormonal alterations and inflammation might have on prostate cancer (PCa) risk has been a subject of controversial debate. Herein, we aimed to investigate the association between MetS-components, C-reactive protein (CRP) and testosterone levels, and the risk of clinically significant PCa (Sig-PCa) at the time of prostate biopsy. For that, men scheduled for transrectal ultrasound guided biopsy of the prostate were studied. Clinical, laboratory parameters and criteria for MetS characterization just before the biopsy were collected. A total of 524 patients were analysed, being 195 (37.2%) subsequently diagnosed with PCa and 240 (45.8%) meet the diagnostic criteria for MetS. Among patients with PCa, MetS-diagnosis was present in 94 (48.2%). Remarkably, a higher risk of Sig-PCa was associated to MetS, greater number of MetS-components and higher CRP levels (odds-ratio: 1.83, 1.30 and 2.00, respectively; P < 0.05). Moreover, higher circulating CRP levels were also associated with a more aggressive Gleason score in PCa patients. Altogether, our data reveal a clear association between the presence of MetS, a greater number of MetS-components or CRP levels >2.5 mg/L with an increased Sig-PCa diagnosis and/or with aggressive features, suggesting that MetS and/or CRP levels might influence PCa pathophysiology.

CE-MS-based urinary biomarkers to distinguish non-significant from significant prostate cancer.

BACKGROUND: Prostate cancer progresses slowly when present in low risk forms but can be lethal when it progresses to metastatic disease. A non-invasive test that can detect significant prostate cancer is needed to guide patient management. METHODS: Capillary electrophoresis/mass spectrometry has been employed to identify urinary peptides that may accurately detect significant prostate cancer. Urine samples from 823 patients with PSA (<15 ng/ml) were collected prior to biopsy. A case-control comparison was performed in a training set of 543 patients (nSig = 98; nnon-Sig = 445) and a validation set of 280 patients (nSig = 48, nnon-Sig = 232). Totally, 19 significant peptides were subsequently combined by a support vector machine algorithm. RESULTS: Independent validation of the 19-biomarker model in 280 patients resulted in a 90% sensitivity and 59% specificity, with an AUC of 0.81, outperforming PSA (AUC = 0.58) and the ERSPC-3/4 risk calculator (AUC = 0.69) in the validation set. CONCLUSIONS: This multi-parametric model holds promise to improve the current diagnosis of significant prostate cancer. This test as a guide to biopsy could help to decrease the number of biopsies and guide intervention. Nevertheless, further prospective validation in an external clinical cohort is required to assess the exact performance characteristics.

Plasma ghrelin O-acyltransferase (GOAT) enzyme levels: A novel non-invasive diagnosis tool for patients with significant prostate cancer.

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).

The oncogenic role of the spliced somatostatin receptor sst5TMD4 variant in prostate cancer.

sst5TMD4, a splice variant of the sst5 gene, is overexpressed and associated with aggressiveness in various endocrine-related tumors, but its presence, functional role, and mechanisms of actions in prostate cancer (PCa)-the most common cancer type in males-is completely unexplored. In this study, formalin-fixed, paraffin-embedded prostate pieces from patients with localized PCa, which included tumoral and nontumoral adjacent regions (n = 45), fresh biopsies from patients with high-risk PCa (n = 52), and healthy fresh prostates from cystoprostatectomies (n = 14) were examined. In addition, PCa cell lines and xenograft models were used to determine the presence and functional role of sst5TMD4. Results demonstrated that sst5TMD4 is overexpressed (mRNA/protein) in PCa samples, and this is especially drastic in metastatic and/or high Gleason score tumor samples. Remarkably, sst5TMD4 expression was associated with an altered frequency of 2 single-nucleotide polymorphisms: rs197055 and rs12599155. In addition, PCa cell lines and xenograft models were used to demonstrate that sst5TMD4 overexpression increases cell proliferation and migration in PCa cells and induces larger tumors in nude mice, whereas its silencing decreased proliferation and migration. Remarkably, sst5TMD4 overexpression activated multiple intracellular pathways (ERK/JNK, MYC/MAX, WNT, retinoblastoma), altered oncogenes and tumor suppressor gene expression, and disrupted the normal response to somatostatin analogs in PCa cells. Altogether, we demonstrate that sst5TMD4 is overexpressed in PCa, especially in those patients with a worse prognosis, and plays an important pathophysiologic role in PCa, which suggesting its potential as a biomarker and/or therapeutic target.-Hormaechea-Agulla, D., Jiménez-Vacas, J. M., Gómez-Gómez, E., L.-López, F., Carrasco-Valiente, J., Valero-Rosa, J., Moreno, M. M., Sánchez-Sánchez, R., Ortega-Salas, R., Gracia-Navarro, F., Culler, M. D., Ibáñez-Costa, A., Gahete, M. D., Requena, M. J., Castaño, J. P., Luque, R. M. The oncogenic role of the spliced somatostatin receptor sst5TMD4 variant in prostate cancer.

The oncogenic role of the In1-ghrelin splicing variant in prostate cancer aggressiveness.

BACKGROUND: The Ghrelin-system is a complex, pleiotropic family composed of several peptides, including native-ghrelin and its In1-ghrelin splicing variant, and receptors (GHSR 1a/b), which are dysregulated in various endocrine-related tumors, where they associate to pathophysiological features, but the presence, functional role, and mechanisms of actions of In1-ghrelin splicing variant in prostate-cancer (PCa), is completely unexplored. Herein, we aimed to determine the presence of key ghrelin-system components (native-ghrelin, In1-ghrelin, GHSR1a/1b) and their potential pathophysiological role in prostate cancer (PCa). METHODS: In1-ghrelin and native-ghrelin expression was evaluated by qPCR in prostate tissues from patients with high PCa-risk (n = 52; fresh-tumoral biopsies), and healthy-prostates (n = 12; from cystoprostatectomies) and correlated with clinical parameters using Spearman-test. In addition, In1-ghrelin and native-ghrelin was measured in plasma from an additional cohort of PCa-patients with different risk levels (n = 30) and control-healthy patients (n = 20). In vivo functional (proliferation/migration) and mechanistic (gene expression/signaling-pathways) assays were performed in PCa-cell lines in response to In1-ghrelin and native-ghrelin treatment, overexpression and/or silencing. Finally, tumor progression was monitored in nude-mice injected with PCa-cells overexpressing In1-ghrelin, native-ghrelin and empty vector (control). RESULTS: In1-ghrelin, but not native-ghrelin, was overexpressed in high-risk PCa-samples compared to normal-prostate (NP), and this expression correlated with that of PSA. Conversely, GHSR1a/1b expression was virtually absent. Remarkably, plasmatic In1-ghrelin, but not native-ghrelin, levels were also higher in PCa-patients compared to healthy-controls. Furthermore, In1-ghrelin treatment/overexpression, and to a much lesser extent native-ghrelin, increased aggressiveness features (cell-proliferation, migration and PSA secretion) of NP and PCa cells. Consistently, nude-mice injected with PC-3-cells stably-transfected with In1-ghrelin, but not native-ghrelin, presented larger tumors. These effects were likely mediated by ERK1/2-signaling activation and involved altered expression of key oncogenes/tumor suppressor genes. Finally, In1-ghrelin silencing reduced cell-proliferation and PSA secretion from PCa cells. CONCLUSIONS: Altogether, our results indicate that In1-ghrelin levels (in tissue) and circulating levels (in plasma) are increased in PCa where it can regulate key pathophysiological processes, thus suggesting that In1-ghrelin may represent a novel biomarker and a new therapeutic target in PCa.

[Current recommendations about the diagnosis and treatment of testosterone deficit syndrome: Clinical guidelines]. / Recomendaciones actuales sobre el diagnóstico y tratamiento del SDT: Guías de practica clínica.

Testosterone deficit syndrome (TDS) is a clinical and biochemical syndrome associated with advanced age and characterized by some typical symptoms and decrease in serum testosterone levels, which can affect multiple organs and systems, deteriorating the quality of life of the males who suffer it. Due to the low specificity of the clinical picture, as well as that of the commonly used questionnaires, when there is a diagnostic suspicion, serum testosterone determination is necessary, without a current universally accepted determination method. The increased survival of males in the western world and their demand of a better quality of life,including the preservation of sexual activity, up to increasingly more advanced ages: together with the appearance of new ways of testosterone delivery, make this entity, clinical-biochemical, acquirean increasingly greater importance. From a therapeutic point of view, testosterone replacement therapy has precise indications, with individualized evaluation in each patient on the basis of risk/benefit, and with an adequate, well defined follow up, that will allow the control of possible adverse events. TRT is recommended in patients with diminished testosterone associated with muscle mass and strength loss, decrease of bone density of the lumbar spine or diminished libido and quality of erection. Contraindications for therapy would include active or non treated prostate cancer, PSA >4 ng/ml before evaluation, breast cancer, severe sleep apnea, infertility, hematocrit over 50% or severe LUTS due to BPH.

Does Adding Standard Systematic Biopsy to Targeted Prostate Biopsy in PI-RADS 3 to 5 Lesions Enhance the Detection of Clinically Significant Prostate Cancer? Should All Patients with PI-RADS 3 Undergo Targeted Biopsy?

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.

Role of Multiparametric Prostate Magnetic Resonance Imaging before Confirmatory Biopsy in Assessing the Risk of Prostate Cancer Progression during Active Surveillance.

OBJECTIVE: To evaluate the impact of multiparametric magnetic resonance imaging (mpMRI) before confirmatory prostate biopsy in patients under active surveillance (AS). MATERIALS AND METHODS: This retrospective study included 170 patients with Gleason grade 6 prostate cancer initially enrolled in an AS program between 2011 and 2019. Prostate mpMRI was performed using a 1.5 tesla (T) magnetic resonance imaging system with a 16-channel phased-array body coil. The protocol included T1-weighted, T2-weighted, diffusion-weighted, and dynamic contrast-enhanced imaging sequences. Uroradiology reports generated by a specialist were based on prostate imaging-reporting and data system (PI-RADS) version 2. Univariate and multivariate analyses were performed based on regression models. RESULTS: The reclassification rate at confirmatory biopsy was higher in patients with suspicious lesions on mpMRI (PI-RADS score ≥ 3) (n = 47) than in patients with non-suspicious mpMRIs (n = 61) and who did not undergo mpMRIs (n = 62) (66%, 26.2%, and 24.2%, respectively; p < 0.001). On multivariate analysis, presence of a suspicious mpMRI finding (PI-RADS score ≥ 3) was associated (adjusted odds ratio: 4.72) with the risk of reclassification at confirmatory biopsy after adjusting for the main variables (age, prostate-specific antigen density, number of positive cores, number of previous biopsies, and clinical stage). Presence of a suspicious mpMRI finding (adjusted hazard ratio: 2.62) was also associated with the risk of progression to active treatment during the follow-up. CONCLUSION: Inclusion of mpMRI before the confirmatory biopsy is useful to stratify the risk of reclassification during the biopsy as well as to evaluate the risk of progression to active treatment during follow-up.

A Single-Center Experience With Third and Fourth Kidney Transplants and Second Kidney Transplant After Pancreas-Kidney Transplant: Surgical Aspects and Outcomes.

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.

Oncogenic Role of Secreted Engrailed Homeobox 2 (EN2) in Prostate Cancer.

Engrailed variant-2 (EN2) has been suggested as a potential diagnostic biomarker; however, its presence and functional role in prostate cancer (PCa) cells is still controversial or unknown. Here, we analyzed 1) the expression/secretion profile of EN2 in five independent samples cohorts from PCa patients and controls (prostate tissues and/or urine) to determine its utility as a PCa biomarker; and 2) the functional role of EN2 in normal (RWPE1) and tumor (LNCaP/22Rv1/PC3) prostate cells to explore its potential value as therapeutic target. EN2 was overexpressed in our two cohorts of PCa tissues compared to control and in tumor cell lines compared with normal-like prostate cells. This profile was corroborated in silico in three independent data sets [The Cancer Genome Atlas(TCGA)/Memorial Sloan Kettering Cancer Center (MSKCC)/Grasso]. Consistently, urine EN2 levels were elevated and enabled discrimination between PCa and control patients. EN2 treatment increased cell proliferation in LNCaP/22Rv1/PC3 cells, migration in RWPE1/PC3 cells, and PSA secretion in LNCaP cells. These effects were associated, at least in the androgen-sensitive LNCaP cells, with increased AKT and androgen-receptor phosphorylation levels and with modulation of key cancer-associated genes. Consistently, EN2 treatment also regulated androgen-receptor activity (full-length and splicing variants) in androgen-sensitive 22Rv1 cells. Altogether, this study demonstrates the potential utility of EN2 as a non-invasive diagnostic biomarker for PCa and provides novel and valuable information to further investigate its putative utility to develop new therapeutic tools in PCa.

Observational study comparing the accuracy/variability between the ERSPC and the PCPT risk calculators for the prediction of significant prostate cancer in patients with PSA <10 ng/mL.

INTRODUCTION: Risk 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. OBJECTIVE: To 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. SETTING: An observational study in a major university hospital in the south of Spain. METHODS AND PARTICIPANTS: An 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. RESULTS: 510 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. CONCLUSIONS: Both RCs performed similar in the prediction of SigPCa. However, ERSPC-RC seems to be more stable for intraindividual PSA variations.

New Approach to Guide Target Prostate Biopsy: Technique and Initial Experience.

OBJECTIVE: To describe the technique of transrectal biopsy with a new device that fuses multiparametric magnetic resonance (mpMRI) and ultrasound images in real time to guide target biopsies and to evaluate our initial experience. METHODS: Patients with persistent suspicion of prostate cancer despite a previous negative biopsy and who had an mpMRI before the biopsy were selected. All patients underwent target biopsy plus standard systematic biopsy. Significant prostate cancer (sig PCa) was defined according to the Epstein criteria for standard biopsy and Gleason grade of ≥7 and a positive core length of ≥5 mm for target biopsy. RESULTS: The first 40 patients were evaluated. The median age was 65 years old. In a sagittal isotropic sequence, the fusion process was started. The fusion can be improved by using different tools such as concordant points and Global Positioning System corrections tools. In the target biopsy, a median of 4 cores was taken, whereas in the standard biopsy, 12 cores were taken. Twenty-two patients were diagnosed with prostate cancer; of these patients, 17 were diagnosed with sig PCa. The fusion target biopsy diagnosed more sig PCa than the standard biopsy; however, it was not statistically significant (37.5% vs 25%, P=.08). The probability of being diagnosed with cancer increased in correlation with the Prostate Imaging Reporting and Data System score, without reaching statistical significance (k=0.45, P=.08). CONCLUSIONS: This new device is a useful tool to guide biopsy in patients with target lesions in an mpMRI to increase the detection of sig PCa. A larger cohort would be required to show significant differences.

European Randomized Study of Screening for Prostate Cancer Risk Calculator: External Validation, Variability, and Clinical Significance.

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.

Ghrelin O-acyltransferase (GOAT) enzyme is overexpressed in prostate cancer, and its levels are associated with patient's metabolic status: Potential value as a non-invasive biomarker.

Ghrelin-O-acyltransferase (GOAT) is the key enzyme regulating ghrelin activity, and has been proposed as a potential therapeutic target for obesity/diabetes and as a biomarker in some endocrine-related cancers. However, GOAT presence and putative role in prostate-cancer (PCa) is largely unknown. Here, we demonstrate, for the first time, that GOAT is overexpressed (mRNA/protein-level) in prostatic tissues (n = 52) and plasma/urine-samples (n = 85) of PCa-patients, compared with matched controls [healthy prostate tissues (n = 12) and plasma/urine-samples from BMI-matched controls (n = 28), respectively]. Interestingly, GOAT levels in PCa-patients correlated with aggressiveness and metabolic conditions (i.e. diabetes). Actually, GOAT expression was regulated by metabolic inputs (i.e. In1-ghrelin, insulin/IGF-I) in cultured normal prostate cells and PCa-cell lines. Importantly, ROC-curve analysis unveiled a valuable diagnostic potential for GOAT to discriminate PCa at the tissue/plasma/urine-level with high sensitivity/specificity, particularly in non-diabetic individuals. Moreover, we discovered that GOAT is secreted by PCa-cells, and that its levels are higher in urine samples from a stimulated post-massage vs. pre-massage prostate-test. In conclusion, plasmatic GOAT levels exhibit high specificity/sensitivity to predict PCa-presence compared with other PCa-biomarkers, especially in non-diabetic individuals, suggesting that GOAT holds potential as a novel non-invasive PCa-biomarker.

Palliative surgery for rare cases of anterior urethral metastasis in prostate cancer.

Penis metastasis from prostate cancer is very rare, and its management varies from case to case as there are very few cases reported in the literature. We describe a patient with prostate cancer treated with radiotherapy and androgen deprivation therapy who presented with urethral bleeding as a symptom of anterior urethral metastasis during followup. We propose a way to manage this and review the literature.