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.

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.

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.

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).

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.

¿A qué nivel se produce la fragmentación del ADN en pacientes infértiles con varicocele? / Analysis of the site of DNA fragmentation in infertile men with varicocele

Objetivo: Establecer a qué nivel se produce la fragmentación del ácido desoxirribonucleico (FADN), intratesticular o en la vía seminal, en varones infértiles con varicocele. Material y métodos: Análisis preliminar sobre 15 sujetos en estudio por infertilidad de un año de evolución con varicocele como causa más probable de su alteración. Realizamos FADN en semen previo a la varicocelectomía quirúrgica. Durante la intervención, se obtuvo una muestra testicular mediante biopsia (TESE), para la medición de FADN en espermatozoides intratesticulares, con el objetivo de establecer sus valores y si había diferencias respecto al semen. Resultados: Quince pacientes fueron intervenidos de varicocele izquierdo. En el seminograma, la alteración más frecuente fue la oligoastenozoospermia. Presentaron ADN fragmentado en semen 9 pacientes con una media de 47,8% (rango 38,8-59,2%), y en 6 fueron normales (media 27,4%; rango 12,7-35,3%). La FADN en testículo presentó valores más elevados que en el semen, estando alterados en 14 de los 15 pacientes (media 62,3%, rango 39,0-83,3%). Conclusiones: La FADN parece tener un papel importante en la fisiopatología actual del varicocele y aumenta en el semen de varones infértiles con esta alteración. Derivado de nuestros resultados, podríamos deducir que el mecanismo más importante de fragmentación se situaría a nivel intratesticular, en contra de lo que actualmente se postula. Confirmar esta hipótesis con mayor número de casos supondría un avance significativo en el conocimiento y aplicaciones clínicas en cuanto a esta patología (AU)

Objective: To establish the site at which intratesticular or seminal DNA fragmentation (DNAF) occurs in infertile men with varicocele. Material and Methods: A preliminary analysis was performed in a 1-year study of 15 patients in whom the suspected cause of infertility was varicocele. Analysis of DNAF was performed in semen prior to surgical varicocelectomy. To measure DNAF in intratesticular sperm, testicular samples were obtained by biopsy during the intervention. Results: Fifteen patients had left varicocele surgery. The most frequent abnormality observed in the semen was oligoasthenozoospermia. Nine patients had DNAF (average: 47.8%, range: 38.8-59.2%), and six were normal (average; 27.4%, range: 12.7-35.3%). DNAF levels were higher in testicular tissue samples than in semen (average: 62.3%, range: 39.0-83.3%). Only one of these patient samples did not reveal DNAF. Conclusions: DNAF seems to be related to the physiopathology of varicocele and is present at higher levels in the semen of infertile men with this alteration. In view of these results, we deduce that DNA fragmentation will primarily occur in the testes, which is contrary to current understanding. Testing this hypothesis in studies that include more patients would allow important advances to be made in the knowledge and treatment of this alteration (AU)