A Multivariate Diagnostic Model Based on Urinary EpCAM-CD9-Positive Extracellular Vesicles for Prostate Cancer Diagnosis

IntroductionProstate cancer (PCa) is one of the most frequently diagnosed cancers and the leading cause of cancer death in males worldwide. Although prostate-specific antigen (PSA) screening has considerably improved the detection of PCa, it has also led to a dramatic increase in overdiagnosing indolent disease due to its low specificity. This study aimed to develop and validate a multivariate diagnostic model based on the urinary epithelial cell adhesion molecule (EpCAM)-CD9–positive extracellular vesicles (EVs) (uEVEpCAM-CD9) to improve the diagnosis of PCa.MethodsWe investigated the performance of uEVEpCAM-CD9 from urine samples of 193 participants (112 PCa patients, 55 benign prostatic hyperplasia patients, and 26 healthy donors) to diagnose PCa using our laboratory-developed chemiluminescent immunoassay. We applied machine learning to training sets and subsequently evaluated the multivariate diagnostic model based on uEVEpCAM-CD9 in validation sets.ResultsResults showed that uEVEpCAM-CD9 was able to distinguish PCa from controls, and a significant decrease of uEVEpCAM-CD9 was observed after prostatectomy. We further used a training set (N = 116) and constructed an exclusive multivariate diagnostic model based on uEVEpCAM-CD9, PSA, and other clinical parameters, which showed an enhanced diagnostic sensitivity and specificity and performed excellently to diagnose PCa [area under the curve (AUC) = 0.952, P < 0.0001]. When applied to a validation test (N = 77), the model achieved an AUC of 0.947 (P < 0.0001). Moreover, this diagnostic model also exhibited a superior diagnostic performance (AUC = 0.917, P < 0.0001) over PSA (AUC = 0.712, P = 0.0018) at the PSA gray zone.ConclusionsThe multivariate model based on uEVEpCAM-CD9 achieved a notable diagnostic performance to diagnose PCa. In the future, this model may potentially be used to better select patients for prostate transrectal ultrasound (TRUS) biopsy.

499 A Retrospective Audit on Detection Rate of Clinically Significant Cancer Among MP-MRI Targeted Biopsy – A Single Centre Experience

Men with high serum prostate specific antigen (PSA) typically undergo standard transrectal ultrasound-guided prostate biopsy (TRUS-biopsy) during which 10 to 12 cores are obtained. TRUS-biopsy can cause side-effects including bleeding, pain, and infection. Multi-parametric MRI (MP-MRI) used as a triage test might allow men to avoid unnecessary TRUS-biopsy and improve diagnostic accuracy. According to the renowned PROMIS study, for clinically significant cancer, MP-MRI was more sensitive and less specific than TRUS-biopsy. In this study, we performed a single centre, retrospective audit on the detection rate of clinically significant cancer among MP-MRI targeted biopsy and compare it with the standard TRUS biopsy. Clinically significant cancer is defined as Gleason score ³ 4 +3 or a maximum cancer core length 6mm or longer. Besides, we also compare the rate of clinically significant cancer in MP-MRI targeted biopsy against the PROMIS study. Through this audit, we found that in 2019, there is a 54% (60 out of 112 patients) of clinically significant cancer in MP-MRI biopsy and 41% (26 out of 64 patients) of clinically significant cancer among standard TRUS biopsy. Comparing it with the PROMIS study in which clinically significant cancer was detected in 38% in the MP-MRI targeted biopsy group and 26% in the standard-biopsy group, the adjusted difference in our study (13%) is similar to PROMIS study which is 12%. In conclusion, our study reaffirms that MP-MRI targeted biopsy reduce over-diagnosis of clinically insignificant prostate cancer and improve detection of clinically significant cancer.

MRI and Targeted Biopsy Essential Tools for an Accurate Diagnosis and Treatment Decision Making in Prostate Cancer

Prostate cancer (PCa) is one of the most frequent causes of cancer death worldwide. Historically, diagnosis was based on physical examination, transrectal (TRUS) images, and TRUS biopsy resulting in overdiagnosis and overtreatment. Recently magnetic resonance imaging (MRI) has been identified as an evolving tool in terms of diagnosis, staging, treatment decision, and follow-up. In this review we provide the key studies and concepts of MRI as a promising tool in the diagnosis and management of prostate cancer in the general population and in challenging scenarios, such as anteriorly located lesions, enlarged prostates determining extracapsular extension and seminal vesicle invasion, and prior negative biopsy and the future role of MRI in association with artificial intelligence (AI).

Robotic Transrectal Computed Tomographic Ultrasound with Artificial Neural Network Analysis: First Validation and Comparison with MRI-Guided Biopsies and Radical Prostatectomy

<b><i>Introduction:</i></b> There is still a lack of availability of high-quality multiparametric magnetic resonance imaging (mpMRI) interpreted by experienced uro-radiologists to rule out clinically significant PC (csPC). Consequently, we developed a new imaging method based on computed tomographic ultrasound (US) supported by artificial neural network analysis (ANNA). <b><i>Methods:</i></b> Two hundred and two consecutive patients with visible mpMRI lesions were scanned and recorded by robotic CT-US during mpMRI-TRUS biopsy. Only significant index lesions (ISUP ≥2) verified by whole-mount pathology were retrospectively analyzed. Their visibility was reevaluated by 2 blinded investigators by grayscale US and ANNA. <b><i>Results:</i></b> In the cohort, csPC was detected in 105 cases (52%) by mpMRI-TRUS biopsy. Whole-mount histology was available in 44 cases (36%). In this subgroup, mean PSA level was 8.6 ng/mL, mean prostate volume was 33 cm³, and mean tumor volume was 0.5 cm³. Median PI-RADS and ISUP of index lesions were 4 and 3, respectively. Index lesions were visible in grayscale US and ANNA in 25 cases (57%) and 30 cases (68%), respectively. Combining CT-US-ANNA, we detected index lesions in 35 patients (80%). <b><i>Conclusions:</i></b> The first results of multiparametric CT-US-ANNA imaging showed promising detection rates in patients with csPC. US imaging with ANNA has the potential to complement PC diagnosis.

Clinical Significance of Caseating Granulomas Detected on Transrectal Ultrasound Biopsy of Prostate Gland: The Recommended Management

Introduction: The histopathological examination (HPE) findings of caseating granulomas from the transrectal ultrasound (TRUS) of prostate biopsy are rare. A high index of suspicion is necessary to diagnose a tuberculosis infection. Here, we present the clinical outcomes of patients and the practical management steps when encounter these findings. Methods: We conducted a retrospective analysis of three cases in a tertiary care centre and reviewed the available literature on the topic. Results: All patients were aged less than 55 years and were considered young adults. One patient presented with neurogenic systemic symptoms, and two patients presented with lower urinary tract symptoms. All patients had abnormal digital rectal examination findings that warranted a TRUS biopsy of the prostate. All biopsies reported caseating granuloma with multinucleated giant cells. Additional investigations led to the diagnosis of tuberculosis infections in two patients, and one patient was diagnosed as having non-specific granulomatous prostatitis. All patients were treated according to their specific diagnosis and recovered fully. Conclusion: The detection of caseating granuloma on prostate biopsy may lead to diagnoses of several conditions, either infective or non-infective in origin. Further investigation is mandatory to provide appropriate treatment.

New TRUS Techniques and Imaging Features of PI-RADS 4 or 5: Influence on Tumor Targeting

PurposeTo determine if the new transrectal ultrasound (TRUS) techniques and imaging features contribute to targeting Prostate Imaging and Reporting and Data System (PI-RADS) 4 or 5.Materials and MethodsBetween December 2018 and February 2020, 115 men underwent cognitive biopsy by radiologist A, who was familiar with the new TRUS findings and biopsy techniques. During the same period, 179 men underwent magnetic resonance imaging–TRUS image fusion or cognitive biopsy by radiologist B, who was unfamiliar with the new biopsy techniques. Prior to biopsy, both radiologists knew MRI findings such as the location, size, and shape of PI-RADS 4 or 5. We recorded how many target biopsies were performed without systematic biopsy and how many of these detected higher Gleason score (GS) than those detected by systematic biopsy. The numbers of biopsy cores were also obtained. Fisher Exact or Mann–Whitney test was used for statistical analysis.ResultsFor PI-RADS 4, target biopsy alone was performed in 0% (0/84) by radiologist A and 0.8% (1/127) by radiologist B (p&gt;0.9999). Target biopsy yielded higher GSs in 57.7% (30/52) by radiologist A and 29.5% (23/78) by radiologist B (p = 0.0019). For PI-RADS 5, target biopsy alone was performed in 29.0% (9/31) by radiologist A and 1.9% (1/52) by radiologist B (p = 0.0004). Target biopsy yielded higher GSs in 50.0% (14/28) by radiologist A and 18.2% (8/44) by radiologist B (p = 0.0079). Radiologist A sampled fewer biopsy cores than radiologist B (p = 0.0008 and 0.0023 for PI-RADS 4 and 5), respectively.ConclusionsPI-RADS 4 or 5 can be more precisely targeted if the new TRUS biopsy techniques are applied.

Phase 2b trial results of padeliporfin (WST11 or Tookad) vascular-targeted photodynamic therapy for partial gland ablation in men with intermediate-risk prostate cancer.

e17006 Background: Padeliporfin (WST11) vascular-targeted photodynamic therapy (VTP) has shown significant clinical benefit as a localized partial gland ablation (PGA) therapy when compared to active surveillance for low-risk prostate cancer, by curbing progression and the need for radical treatment, leading to its regulatory approval in Europe. This phase 2b trial prospectively investigated WST11-VTP for intermediate-risk cancers. Methods: Men with unilateral Grade Group 2 (GG2) cancers (Gleason 3+4), evaluated with MRI and ultrasound-guided (TRUS) biopsy, underwent up to two WST11-VTP PGA sessions. Eligibility criteria included <cT2b, PSA < 10, and fusion biopsy for PIRADS 3+ lesions on pretreatment MRI. Contralateral very low–risk disease was observed. The primary endpoint was prevalence of any Gleason Grade 4 or 5 (≥GG2) cancer, determined by MRI and systematic, 14-core TRUS biopsy of the entire gland (+/- fusion) at 3 and 12 months after treatment. Treatment safety and patient-reported quality of life for sexual and urinary function were assessed with validated questionnaires (IIEF-15 and IPSS, respectively). The study was powered using β = 0.2 to reject the null hypothesis (r≤70%), using a one-sided exact binomial test with 5% alpha risk. To be valid, 44 evaluable patients were required for the 12-month primary endpoint assessment. Results: Of the 50 men treated, 46 were evaluable for the 12-month primary endpoint. Before 12 months, 1 man proceeded to prostatectomy (treatment failure), 2 men refused 12-month biopsy, and 1 man died of COVID-19. At 3 months, 12/49 (24%) men underwent per protocol second WST11-VTP PGA session for GG2 tumor: 9 for residual cancer and 4 for newly identified contralateral GG2 tumors (1 bilateral). The 12-month biopsy was performed in 45 men; 38 (83%) had no Gleason grade 4 or 5 cancer, including 11/12 (92%) patients who underwent 2 PGA sessions. By 3 months, median decline in erectile function score (IIEF-5) from baseline was -1.0 (IQR -7,0). Median improvement in urinary function score (IPSS) was -1.0 (IQR -1,5), with pad-free continence observed in all patients. Median change in IIEF score by 12-months was -1.0 (IQR -5,0). Grade 3 treatment-related adverse events occurred in 6 (12%) patients. All procedure-related prostate/pelvic pain resolved by 3 weeks. Conclusions: The positive results from this trial show that WST11-VTP is effective for PGA of intermediate-risk prostate cancer, with minimal toxicity or impact on urinary and sexual function, consistent with the phase 3 trial results in low-risk disease. Based on these data, this therapy bears consideration for approval as a conservative therapeutic option for selected cases of intermediate-risk disease. Clinical trial information: NCT03315754.

678 An Audit of TRUS Biopsy Sepsis Within A District General Hospital Setting

Introduction Transrectal ultrasound (TRUS) biopsy is the standard investigation of suspected prostate cancer within the United Kingdom. TRUS biopsy has significant risks of associated complications, the most serious being sepsis. An audit was designed to evaluate the rate of sepsis following TRUS biopsy within a district general hospital setting. Method All men who underwent TRUS biopsy over a four-month period between October 2019 and January 2020 were retrospectively reviewed. Standard rate of sepsis for benchmarking was identified as 0.8% as quoted in the European Association of Urology (EAU) prostate cancer guidelines. Results 88 men underwent TRUS biopsy between October and January. Three cases of TRUS biopsy sepsis requiring hospital admission were identified. The rate of sepsis determined was 3.4%. The average length of stay for the cases was 4.7 days. Oral co-trimoxazole was used as the empirical antibiotic prophylaxis pre-procedure in all. Conclusions The rate of sepsis was higher than the figure quoted in EAU guidelines. Routine local audit for TRUS sepsis is necessary to maintain standards and efficacy of prophylaxis, as well as the accurate counselling of patients on the expected risks of the procedure. Consideration should be given to targeted antibiotic prophylaxis based on pre-biopsy rectal swabs.

Integration of Urinary EN2 Protein & Cell-Free RNA Data in the Development of a Multivariable Risk Model for the Detection of Prostate Cancer Prior to Biopsy

The objective is to develop a multivariable risk model for the non-invasive detection of prostate cancer prior to biopsy by integrating information from clinically available parameters, Engrailed-2 (EN2) whole-urine protein levels and data from urinary cell-free RNA. Post-digital-rectal examination urine samples collected as part of the Movember Global Action Plan 1 study which has been analysed for both cell-free-RNA and EN2 protein levels were chosen to be integrated with clinical parameters (n = 207). A previously described robust feature selection framework incorporating bootstrap resampling and permutation was applied to the data to generate an optimal feature set for use in Random Forest models for prediction. The fully integrated model was named ExoGrail, and the out-of-bag predictions were used to evaluate the diagnostic potential of the risk model. ExoGrail risk (range 0–1) was able to determine the outcome of an initial trans-rectal ultrasound guided (TRUS) biopsy more accurately than clinical standards of care, predicting the presence of any cancer with an area under the receiver operator curve (AUC) = 0.89 (95% confidence interval(CI): 0.85–0.94), and discriminating more aggressive Gleason ≥ 3 + 4 disease returning an AUC = 0.84 (95% CI: 0.78–0.89). The likelihood of more aggressive disease being detected significantly increased as ExoGrail risk score increased (Odds Ratio (OR) = 2.21 per 0.1 ExoGrail increase, 95% CI: 1.91–2.59). Decision curve analysis of the net benefit of ExoGrail showed the potential to reduce the numbers of unnecessary biopsies by 35% when compared to current standards of care. Integration of information from multiple, non-invasive biomarker sources has the potential to greatly improve how patients with a clinical suspicion of prostate cancer are risk-assessed prior to an invasive biopsy.