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Purpose The prognosis of muscle-invasive bladder cancer (MIBC) has not improved for three decades. Transurethral resection of the bladder tumor (TURBT) is the standard procedure for local tumor staging. TURBT has several limitations, including the spread of tumor cells. Therefore, an alternative is needed in patients with suspected MIBC. Recent studies have shown that mpMRI is very accurate in staging bladder tumors. Because the diagnostic efficacy of urethrocystoscopy (UCS) has been reported as good as the efficacy of mpMRI to predict muscle invasion we performed this prospective multicenter study in which we compare UCS with pathology. Methods From July 2020 until March 2022, 321 patients with suspected primary BC in seven participating Dutch hospitals were included in this study. A flexible UCS was performed by urologists, physician assistants, or residents. Predictions of muscle invasion using a 5-point Likert scale alongside the histopathology data were recorded. The sensitivity, specificity, predictive values, and 95% confidence intervals were determined using a standard contingency table. Results Of the 321 included patients, 232 (72.3%) received a histopathological diagnosis of non-muscle-invasive bladder cancer (NMIBC) and 71 (22.1%) were histopathologically diagnosed as MIBC. In 2 patients (0.6%), classification was not possible (Tx). Cystoscopy predicted muscle invasion with a sensitivity of 71.8% (95% CI 59.9–81.9), and a specificity of 89.9% (95% CI 85.4–93.3). This corresponds to a positive predictive value (PPV) of 67.1% and a negative predictive value (NPV) of 91.7%. Conclusion Our study shows a moderate accuracy of cystoscopy to predict muscle invasion. This result does not support the use of cystoscopy only instead of TURBT for local staging.

SamenvattingHet doel van deze studie was de oncologische en functionele uitkomsten van salvage cryochirurgie (sCC) te beoordelen bij lokaal recidief prostaatcarcinoom na radiotherapie (rrPCA). De studie werd uitgevoerd bij 169 patiënten. Er vond retrospectieve analyse plaats van recidiefvrije overleving (BRFS), algehele overleving, metastasevrije overleving, androgeendeprivatietherapie (ADT)-vrije overleving, functionele uitkomsten en complicaties. De mediane follow-up was 36 maanden (IQR = 18–66). BRFS na vijf en acht jaar was 52% (95%-BI = 43–62) en 45% (95%-BI = 35–57), respectievelijk. PSA bij initiële diagnose, de initiële behandeling, het interval tussen de primaire behandeling en SCS, leeftijd bij SCS en post-SCS PSA-nadir waren significante voorspellers van BRFS. De vijf-jaars ADT-vrije overleving was 70% (95%-BI = 62–79). Complicaties van graad III of hoger traden op bij 1,2% van de patiënten. Bij 19% en 92% van de patiënten trad new onset urine-incontinentie respectievelijk erectiele disfunctie op, bij 6,5% persisterende urinaire fistels en bij 12% desobstructie. SCS heeft aanvaardbare oncologische resultaten, maar kan gepaard gaan met ernstige complicaties (urine-incontinentie, stenose en fistels).

Om overdiagnostiek en overbehandeling te verminderen, is er dringend behoefte aan een test voor detectie van klinisch significant prostaatcarcinoom. In deze studie werd een model ontwikkeld (met behulp van geidentificeerde biomarkers HOXC6, DLX1, TDRD1 en HOXC4) voor het voorspellen van hooggradig prostaatcarcinoom in prostaatbiopten. In twee prospectieve, multicenterstudies (cohort A: n = 492; cohort B: n = 371) werd urine verzameld voorafgaand aan prostaatbiopten. De resultaten van cohort A werden gebruikt voor het model en gevalideerd in het onafhankelijke cohort B. De HOXC6-DLX1-score had de hoogste area under the curve (0,76; 95 %-betrouwbaarheidsinterval (BI) = 0,71–0,81), met een specificiteit van 36 % bij een sensitiviteit van 92 %. De score was gecorreleerd met de Gleason-score van de prostaatbiopten; subgroepanalyse bevestigde de potentiele meerwaarde van deze urinetest voor patienten met lage PSA-waarden (

Background : Noninvasive biomarkers to guide personalized treatment for castration‐resistant prostate cancer (CRPC) are needed. In this study, we analyzed hypermethylation patterns of two genes (GSTP1 and APC) in plasma cell‐free DNA (cfDNA) of CRPC patients. The aim of this study was to analyze the cfDNA concentrations and levels of the epigenetic markers and to assess the value of these biomarkers for prognosis. Methods : In this prospective study, patients were included before starting new treatment after developing CRPC. The blood samples were collected prior to start of the treatment and at three time points thereafter. cfDNA was extracted from 1.5 mL of plasma and before performing a methylation‐specific PCR, bisulfate modification was carried out. Results : The median levels of cfDNA, GSTP1, and APC copies in the baseline samples of CRPC patients (n = 47) were higher than in controls (n = 30). In the survival analysis, the group with baseline marker levels below median had significant less PCa‐related deaths (P‐values

Contains fulltext : 177822.pdf (Publisher’s version ) (Closed access) BACKGROUND: Prostate cancer (PCa) diagnostics would greatly benefit from more accurate, non-invasive techniques for the detection of clinically significant disease, leading to a reduction of over-diagnosis and over-treatment. The aim of this study was to determine the association between a novel urinary biomarker-based risk score (SelectMDx), multiparametric MRI (mpMRI) outcomes, and biopsy results for PCa detection. METHODS: This retrospective observational study used data from the validation study of the SelectMDx score, in which urine was collected after digital rectal examination from men undergoing prostate biopsies. A subset of these patients also underwent a mpMRI scan of the prostate. The indications for performing mpMRI were based on persistent clinical suspicion of PCa or local staging after PCa was found upon biopsy. All mpMRI images were centrally reviewed in 2016 by an experienced radiologist blinded for the urine test results and biopsy outcome. The PI-RADS version 2 was used. RESULTS: In total, 172 patients were included for analysis. Hundred (58%) patients had PCa detected upon prostate biopsy, of which 52 (52%) had high-grade disease correlated with a significantly higher SelectMDx score (P < 0.01). The median SelectMDx score was significantly higher in patients with a suspicious significant lesion on mpMRI compared to no suspicion of significant PCa (P < 0.01). For the prediction of mpMRI outcome, the area-under-the-curve of SelectMDx was 0.83 compared to 0.66 for PSA and 0.65 for PCA3. There was a positive association between SelectMDx score and the final PI-RADS grade. There was a statistically significant difference in SelectMDx score between PI-RADS 3 and 4 (P < 0.01) and between PI-RADS 4 and 5 (P < 0.01). CONCLUSIONS: The novel urinary biomarker-based SelectMDx score is a promising tool in PCa detection. This study showed promising results regarding the correlation between the SelectMDx score and mpMRI outcomes, outperforming PCA3. Our results suggest that this risk score could guide clinicians in identifying patients at risk for significant PCa and selecting patients for further radiological diagnostics to reduce unnecessary procedures.

BACKGROUND: To monitor systemic disease activity, the potential of circulating tumor cells (CTCs) bears great promise. As surrogate for CTCs we measured KLK3, PCA3, and TMPRSS2-ERG messenger RNA (mRNA) in the peripheral blood mononuclear cell (PBMC) fraction from a castration-resistant prostate cancer (CRPC) patient cohort and three control groups. Moreover, biomarker response to docetaxel treatment was evaluated in the patient group. METHODS: Blood samples from 20 CRPC patients were analyzed at four different time points (prior to docetaxel treatment, at 9 weeks, 27 weeks, and 2 months after treatment). Blood was drawn once from three control groups (10 age-matched men, 10 men under 35 years of age, 12 women). All samples were analyzed for KLK3, PCA3, and TMPRSS2-ERG mRNA by using a quantitative nucleic acid amplification assay with gene-specific primers in the complementary DNA synthesis. RESULTS: At baseline, mRNA for KLK3 was detected in 17 (89%, 95% CI 76-100%), PCA3 in 10 (53%, 95% CI 30-75%), and TMPRSS2-ERG in seven of 19 evaluable patients (37%, 95% CI 15-59%). In contrast, the blood samples from all 32 healthy volunteers were reproducible negative for all markers. In response to docetaxel treatment, KLK3 levels decreased in 80% (95% CI 60-100%), PCA3 in 89% (95% CI 68-100%), and TMPRSS2-ERG in 86% (95% CI 60-100%) of patients. CONCLUSIONS: The feasibility of a highly sensitive modified nucleic acid amplification assay to assess KLK3, PCA3, and TMPRSS2-ERG mRNA in the PBMC fraction from CRPC patients was demonstrated. Moreover, response of these markers to systemic treatment was shown.

Contains fulltext : 136616.pdf (Publisher’s version ) (Open Access) PURPOSE: Urinary biomarker tests for diagnosing prostate cancer have gained considerable interest. Urine is a complex mixture that can be subfractionated. We evaluated 2 urinary fractions that contain nucleic acids, ie cell pellets and exosomes. The influence of digital rectal examination before urine collection was also studied and the prostate cancer specific biomarkers PCA3 and TMPRSS2-ERG were assayed. MATERIALS AND METHODS: Urine samples were prospectively obtained before and after digital rectal examination from 30 men scheduled for prostate biopsy. Cell pellet and exosomes were isolated and used for biomarker analysis. Analytical and diagnostic performance was tested using the Student t-test and ROC curves. RESULTS: Unlike the exosome fraction, urinary sediment gene expression analysis was compromised by amorphous precipitation in 10% of all specimens. Digital rectal examination resulted in increased mRNA levels in each fraction. This was particularly relevant for the exosomal fraction since after digital rectal examination the number of samples decreased in which cancer specific markers were below the analytical detection limit. Biomarker diagnostic performance was comparable to that in large clinical studies. In exosomes the biomarkers had to be normalized for prostate specific antigen mRNA while cell pellet absolute PCA3 levels had diagnostic value. CONCLUSIONS: Exosomes have characteristics that enable them to serve as a stable substrate for biomarker analysis. Thus, digital rectal examination enhances the analytical performance of biomarker analysis in exosomes and cell pellets. The diagnostic performance of biomarkers in exosomes differs from that of cell pellets. Clinical usefulness must be prospectively assessed in larger clinical cohorts.

Background: PCA3 and ERG are mRNA-based prostate cancer (PCa) specific biomarkers that can be detected in urine. However, urine is a complex substrate that can be separated in several fractions. In this study we compared the levels of PCa-specific biomarkers (PCA3 and ERG) and KLK3 as prostate-specific reference gene in three urine substrates–whole urine, urinary sediment (cell pellet) and exosomes–and evaluated the influence of performing a digital rectal examination (DRE) prior to urine sampling. Methods: First-voided urine samples were prospectively obtained before and after DRE from 29 men undergoing prostate biopsies. The urine was separated in whole urine, cell pellet and exosomes and the biomarker levels were measured with RT-qPCR. Results: PCa was identified in 52% (15/29) of men. In several samples the mRNA levels were below the analytical limit of detection (BDL). The biomarker levels were highest in whole urine and significantly higher after DRE in all substrates. In PCa patients higher levels of PCA3 and ERG were found in all urine substrates after DRE compared to non-PCa patients. Conclusions: This is the first study in which urinary PCa-specific biomarker levels were compared directly in three separate urine fractions. These results suggest that whole urine could be the urine substrate of choice for PCa-diagnostics based on analytical sensitivity, which is reflected directly in the high informative rate. Moreover, the significant positive effect of performing a DRE prior to urine sampling is confirmed. These findings could be of influence in the development of PCa-diagnostic urine tests.

Background To reduce overdiagnosis and overtreatment, a test is urgently needed to detect clinically significant prostate cancer (PCa). Objective To develop a multimodal model, incorporating previously identified messenger RNA (mRNA) biomarkers and traditional risk factors that could be used to identify patients with high-grade PCa (Gleason score ≥7) on prostate biopsy. Design, setting, and participants In two prospective multicenter studies, urine was collected for mRNA profiling after digital rectal examination (DRE) and prior to prostate biopsy. The multimodal risk score was developed on a first cohort ( n =519) and subsequently validated clinically in an independent cohort ( n =386). Outcome measurements and statistical analysis The mRNA levels were measured using reverse transcription quantitative polymerase chain reaction. Logistic regression was used to model patient risk and combine risk factors. Models were compared using the area under the curve (AUC) of the receiver operating characteristic, and clinical utility was evaluated with a decision curve analysis (DCA). Results and limitations HOXC6 and DLX1 mRNA levels were shown to be good predictors for the detection of high-grade PCa. The multimodal approach reached an overall AUC of 0.90 (95% confidence interval [CI], 0.85–0.95) in the validation cohort (AUC 0.86 in the training cohort), with the mRNA signature, prostate-specific antigen (PSA) density, and previous cancer-negative prostate biopsies as the strongest, most significant components, in addition to nonsignificant model contributions of PSA, age, and family history. For another model, which included DRE as an additional risk factor, an AUC of 0.86 (95% CI, 0.80–0.92) was obtained (AUC 0.90 in the training cohort). Both models were successfully validated, with no significant change in AUC in the validation cohort, and DCA indicated a strong net benefit and the best reduction in unnecessary biopsies compared with other clinical decision-making tools, such as the Prostate Cancer Prevention Trial risk calculator and the PCA3 assay. Conclusions The risk score based on the mRNA liquid biopsy assay combined with traditional clinical risk factors identified men at risk of harboring high-grade PCa and resulted in a better patient risk stratification compared with current methods in clinical practice. Therefore, the risk score could reduce the number of unnecessary prostate biopsies. Patient summary This study evaluated a novel urine-based assay that could be used as a noninvasive diagnostic aid for high-grade prostate cancer (PCa). When results of this assay are combined with traditional clinical risk factors, risk stratification for high-grade PCa and biopsy decision making are improved.

Contains fulltext : 137643.pdf (Publisher’s version ) (Closed access) In the era of upcoming techniques for molecular profiling, breakthroughs led to new discoveries in the field of prostate cancer (PCa) biomarkers. Since the early 1990s a tremendous increase in PCa incidence is seen, dedicated to the introduction of prostate specific antigen (PSA) testing. However, due to its lack of specificity many men undergo unnecessary biopsies, resulting in a rising incidence of clinically insignificant PCa. To overcome this drawback, cancer specific biomarkers are needed to identify patients who are at high risk of harbouring PCa and to distinguish patients with aggressive disease from patients with insignificant cancer. The most non-invasive, easy to obtain substrate for biomarker measurement is urine. The most promising markers to date are PCA3 and TMPRSS2-ERG. Both markers demonstrate to have a higher specificity and diagnostic accuracy for PCa outcome compared to serum PSA. This might better predict the presence of PCa and therefore reduce the number of unnecessary biopsies. Combining both markers in a panel might result in an even higher diagnostic accuracy, given the heterogeneity of the disease. In PCa management, circulating tumour cells (CTCs) detected in the blood seem a promising tool to predict treatment response and survival benefit. Although results appear to be encouraging, the biggest challenge about new markers in PCa is to validate them in large clinical trials and subsequently implement these markers into clinical practice. In this review we discuss the clinical usefulness of novel, non-invasive tests in PCa management.

31 Background: The major challenge in prostate cancer (PCa) diagnostics is to improve the early detection of clinically significant or high-grade PCa, especially in the sPSA "grey-zone" (4-10 ng/ml). Ideally, PCa-specific biomarkers would be obtained non-invasively, for example derived from urine. The aim of this study was to evaluate the expression levels and clinical utility of the recently identified urinary HOXC6-DLX1 mRNA biomarker combination in men at risk of having high-grade PCa. Methods: From two prospective, multicenter studies, a total of 863 post-DRE urine samples were collected from men with elevated sPSA levels before undergoing a prostate biopsy procedure. The HOXC6-DLX1 mRNA biomarkers were measured in urine using RT-qPCR and results were quantified using the Delta DeltaCt method (ΔΔCT), normalized and expressed in a score from 1 to 1421. Results: The HOXC6-DLX1 risk score was significantly higher in urine from patients with high-grade PCa upon prostate biopsy compared to no PCa and PCa Gleason score ≤6. In the sPSA "grey-zone", the HOXC6-DLX1 combination had the highest area-under-the-curve (AUC) of 0.67 (95% confidence interval (CI): 0.58-0.75) for prediction of high-grade PCa upon prostate biopsy in cohort A and 0.68 (95% CI: 0.59-0.76) in cohort B; as compared to sPSA with an AUC of 0.60 (95% CI: 0.51-0.70) and 0.62 (95% CI: 0.52-0.73) respectively. Overall, elevated HOXC6-DLX1 risk scores correlated with an increased risk of high-grade PCa detected on biopsy; 47% of men with a score >108 had significant cancer as compared to 6% with a risk score

Contains fulltext : 170222.pdf (Publisher’s version ) (Open Access) PURPOSE: Compare the efficacy and tolerability of dutasteride in combination with bicalutamide to bicalutamide monotherapy in the treatment of locally advanced and metastatic prostate cancer (PCa). METHODS: One-hundred-fifty PCa patients with locally advanced or metastatic disease were prospectively enrolled and randomly assigned to receive either bicalutamide monotherapy 150 mg once daily (79 patients) or bicalutamide 150 mg plus dutasteride 0.5 mg once daily (71 patients). Treatment response was assessed by serum PSA level measurement, and standard procedures for diagnosis of clinical progression were used during follow-up. Patient-reported quality of life (QoL) was assessed using validated questionnaires (EORTC QLQ-C30 and QLQ-PR25). RESULTS: At 3 years follow-up, PSA progression was found in 52 patients [65.8 %; 95 % confidence interval (CI) 55.4-76.3] in the monotherapy group compared to 38 patients (53.5 %; 95 % CI 41.9-65.1) in the combined therapy group (p = 0.134). At the time of analysis 37 men (46.8 %; 95 % CI 35.8-57.8) in the monotherapy group had died versus 30 men (42.3 %; 95 % CI 30.8-53.7) in the combined therapy group. Median survival time was 5.4 and 5.8 years, respectively (p = 0.694). There was no statistically significant difference in the presentation frequency of adverse events between groups (p = 0.683). QoL was good and comparable between the two groups. CONCLUSIONS: Both therapies were well tolerated with a good QoL. However, despite a trend toward higher efficacy of the combined therapy, progression-free survival and overall survival was not significantly different between the groups. Further research on this therapy should be performed.

In men aged 15-34 testicular cancer is the most commonly occurring malignancy. After treatment, the average 5-year survival rate is 85%. Recurring symptoms or raised tumour markers may indicate the presence of a second primary contralateral testicular tumour.A 34-year-old man presented with pain in his left testicle. Eight years previously he had been diagnosed with cancer of his right testicle which was treated successfully by orchidectomy and two cycles of chemotherapy. Further investigations revealed raised tumour markers. The patient proved to have a contralateral testis carcinoma with 2 lung metastases.1-3% of patients with testicular cancer develop metachronous (i.e. not concurrent) contralateral testicular cancer. Follow-up and self-examination are very important for early diagnosis of a metachronous contralateral malignancy.

Het prostaatspecifiek antigeen (PSA) wordt gebruikt als tumormarker voor prostaatkanker, maar heeft als belangrijk nadeel dat het niet specifiek is. PCA3 en TMPRSS2-ERG zijn prostaatkankerspecifieke biomarkers die gedetecteerd kunnen worden in urine. Urine is een complex substraat en bestaat uit meerdere fracties.

Contains fulltext : 109659.pdf (Publisher’s version ) (Open Access) Metastasis to the glans penis is a rare phenomenon and usually occurs in a late stage of disease. A 68-year-old man was referred to our clinic because of two indurated lesions of the glans penis and minor lower urinary tract symptoms. Digital rectal examination revealed a hard nodular prostate, and serum prostate-specific antigen (sPSA) level was 13.3 ng/mL. Biopsies of the penile lesions and transrectal ultrasound-guided prostate biopsies were taken. Immunohistochemical staining of formalin-fixed paraffin-embedded tissue exposed a synchronous penile metastasis from a high-grade adenocarcinoma of the prostate. Except a pathologically enlarged lymph node detected with MRI there was no suspicion on other metastases. Currently this patient is being treated with a Gonadoreline (GnRH) antagonist. Nevertheless, the prognosis will be poor.