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We present the protocol for a study testing the hypothesis that a computer-aided diagnosis (CAD) system for three-dimensional multiparametric ultrasound (3D mpUS) is noninferior to magnetic resonance imaging (MRI) in guiding prostate biopsies for detection of clinically significant prostate cancer (csPCa). The prospective study has a fully paired design for assessment of diagnostic accuracy and is registered on ClinicalTrials.gov as NCT06281769. A total of 438 biopsy-naïve men scheduled for prostate MRI evaluation because of an abnormal digital rectal examination and/or elevated serum prostate-specific antigen will be included. All patients will undergo both MRI (multiparametric or biparametric) and 3D mpUS with CAD (PCaVision). Suspicious lesions will be independently identified using each imaging technique. MRI targeted biopsy (TBx) and/or PCaVision TBx will be performed if suspicious lesions are identified on imaging. When both PCaVision and MRI identify lesions in an individual patient, the TBx order for this patient will be randomized. Three TBx samples per lesion will be taken for a maximum of two lesions per modality. The primary objective is the detection rate for csPCa (International Society of Urological Pathology grade group [GG] ≥2) with the PCaVision versus the MRI TBx pathway. The noninferiority margin for the absolute difference in detection rates is set at a difference of 5%. Secondary outcomes are the proportion of men in whom TBx could have been safely omitted in each pathway. Additional diagnostic accuracy analyses will be performed for different definitions of PCa (GG ≥3; GG ≥2 with cribriform growth and/or intraductal carcinoma; and GG 1). The frequency of insufficient image quality for the two pathways will also be assessed. Lastly, we will determine the diagnostic performance for csPCa detection at various 3D mpUS image quality thresholds for PCaVision., (© 2024 The Author(s).)

In this multicenter, retrospective study, we evaluated the added value of magnetic resonance dispersion imaging (MRDI) to standard multiparametric MRI (mpMRI) for PCa detection. The study included 76 patients, including 51 with clinically significant prostate cancer (csPCa), who underwent radical prostatectomy and had an mpMRI including dynamic contrast-enhanced MRI. Two radiologists performed three separate randomized scorings based on mpMRI, MRDI and mpMRI+MRDI. Radical prostatectomy histopathology was used as the reference standard. Imaging and histopathology were both scored according to the Prostate Imaging-Reporting and Data System V2.0 sector map. Sensitivity and specificity for PCa detection were evaluated for mpMRI, MRDI and mpMRI+MRDI. Inter- and intra-observer variability for both radiologists was evaluated using Cohen's Kappa. On a per-patient level, sensitivity for csPCa for radiologist 1 (R1) for mpMRI, MRDI and mpMRI+MRDI was 0.94, 0.82 and 0.94, respectively. For the second radiologist (R2), these were 0.78, 0.94 and 0.96. R1 detected 4% additional csPCa cases using MRDI compared to mpMRI, and R2 detected 20% extra csPCa cases using MRDI. Inter-observer agreement was significant only for MRDI (Cohen's Kappa = 0.4250, p = 0.004). The results of this study show the potential of MRDI to improve inter-observer variability and the detection of csPCa.

Background and Objective: A combined approach of magnetic resonance imaging (MRI)-targeted biopsy (TBx) and bilateral systematic biopsy (SBx) is advised in patients who have an increased risk of prostate cancer (PCa). The diagnostic gain of SBx in detecting PCa for treatment planning of patients undergoing robot-assisted radical prostatectomy (RARP) is unknown. This study aims to determine the impact of omitting contralateral SBx on the surgical planning of patients undergoing RARP in terms of nerve-sparing surgery (NSS) and extended pelvic lymph node dissection (ePLND)., Methods: Case files from 80 men with biopsy-proven PCa were studied. All men had a unilateral suspicious lesion on MRI, and underwent TBx and bilateral SBx. Case files were presented to five urologists for the surgical planning of RARP. Each case file was presented randomly using two different sets of information: (1) results of TBx + bilateral SBx, and (2) results of TBx + ipsilateral SBx. The urologists assessed whether they would perform NSS and/or ePLND., Key Findings and Limitations: A change in the surgical plan concerning NSS on the contralateral side was observed in 9.0% (95% confidence interval [CI] 6.4-12.2) of cases. Additionally, the indication for ePLND changed in 5.3% (95% CI 3.3-7.9) of cases. Interobserver agreement based on Fleiss' kappa changed from 0.44 to 0.15 for the indication of NSS and from 0.84 to 0.83 for the indication of ePLND., Conclusions and Clinical Implications: In our series, the diagnostic information obtained from contralateral SBx has limited impact on the surgical planning of patients with a unilateral suspicious lesion on MRI scheduled to undergo RARP., Patient Summary: In patients with one-sided prostate cancer on magnetic resonance imaging, omitting biopsies on the other side rarely changed the surgical plan with respect to nerve-sparing surgery and the indication to perform extended lymph node dissection., (© 2024 The Author(s).)

The development of artificial intelligence-based imaging techniques for prostate cancer (PCa) detection and diagnosis requires a reliable ground truth, which is generally based on histopathology from radical prostatectomy specimens. This study proposes a comprehensive protocol for the annotation of prostatectomy pathology slides. To evaluate the reliability of the protocol, interobserver variability was assessed between five pathologists, who annotated ten radical prostatectomy specimens consisting of 74 whole mount pathology slides. Interobserver variability was assessed for both the localization and grading of PCa. The results indicate excellent overall agreement on the localization of PCa (Gleason pattern ≥ 3) and clinically significant PCa (Gleason pattern ≥ 4), with Dice similarity coefficients (DSC) of 0.91 and 0.88, respectively. On a per-slide level, agreement for primary and secondary Gleason pattern was almost perfect and substantial, with Fleiss Kappa of .819 (95% CI .659-.980) and .726 (95% CI .573-.878), respectively. Agreement on International Society of Urological Pathology Grade Group was evaluated for the index lesions and showed agreement in 70% of cases, with a mean DSC of 0.92 for all index lesions. These findings show that a standardized protocol for prostatectomy pathology annotation provides reliable data on PCa localization and grading, with relatively high levels of interobserver agreement. More complicated tissue characterization, such as the presence of cribriform growth and intraductal carcinoma, remains a source of interobserver variability and should be treated with care when used in ground truth datasets., (© 2023. The Author(s).)

Objective: Surgical outcomes are dependent on multiple factors. Besides patient-related or procedure-related factors, several surgeon-related factors contribute to surgical outcomes. The Surgery Task Load Index (SURG-TLX) questionnaire helps to assess the impact of several stressors on the perceived demands of surgeons during surgery. In this study, we evaluate the applicability of the SURG-TLX questionnaire for endourologic procedures and set a first point of reference. Materials and Methods: Between March and August 2022, 15 urologists and urology residents at a tertiary referral center for endourology completed the SURG-TLX questionnaire after endourologic procedures. After data acquisition, all participants were asked to evaluate the applicability of the questionnaire for endourologic procedures. Results: A total of 130 procedures were included between March and August 2022. Situational stress had the lowest median score (3.0/20; interquartile range [IQR] 2.0-7.0) and task complexity the highest (5.0/20; IQR 3.0-8.0). After weighing, the dimensions showed different proportions when compared with the nonweighted scores. Distractions received the highest score (15.0/100; IQR 7.5-32.8), temporal demands (6.0/100; IQR 3.0-12.5), and situational stress the lowest (6.0/100; IQR 2.0-21.0). This was caused by the higher weight that was attributed to distractions (3.4/5), as opposed to task complexity (2.6/5). In the questionnaire regarding applicability of the SURG-TLX, the overall satisfaction (6.0/10; IQR 5.0-7.0) and clarity (6.5/10; IQR 5.0-7.5) were moderate. The user-friendliness and applicability of the questionnaire were rated high (7.0/10; IQR 5.5-8.0 and 7.0/10; IQR 6.0-8.0, respectively) and task load (3.0/10; IQR 2.0-5.0) and time load (2.0/10; IQR 2.0-3.5) low. Conclusion: The SURG-TLX questionnaire is appropriate to assess the different dimensions of workload during endourologic procedures. Furthermore, the perceived workload during endourologic procedures is relatively low.

Introduction and Hypothesis: The tendency toward population-based screening programs for prostate cancer (PCa) is expected to increase demand for prebiopsy imaging. This study hypothesizes that a machine learning image classification algorithm for three-dimensional multiparametric transrectal prostate ultrasound (3D mpUS) can detect PCa accurately., Design: This is a phase 2 prospective multicenter diagnostic accuracy study. A total of 715 patients will be included in a period of approximately 2 yr. Patients are eligible in case of suspected PCa for which prostate biopsy is indicated or in case of biopsy-proven PCa for which radical prostatectomy (RP) will be performed. Exclusion criteria are prior treatment for PCa or contraindications for ultrasound contrast agents (UCAs)., Protocol Overview: Study participants will undergo 3D mpUS, consisting of 3D grayscale, 4D contrast-enhanced ultrasound, and 3D shear wave elastography (SWE). Whole-mount RP histopathology will provide the ground truth to train the image classification algorithm. Patients included prior to prostate biopsy will be used for subsequent preliminary validation. There is a small, anticipated risk for participants associated with the administration of a UCA. Informed consent has to be given prior to study participation, and (serious) adverse events will be reported., Statistical Analysis: The primary outcome will be the diagnostic performance of the algorithm for detecting clinically significant PCa (csPCa) on a per-voxel and a per-microregion level. Diagnostic performance will be reported as the area under the receiver operating characteristic curve. Clinically significant PCa is defined as the International Society of Urological grade group ≥2. Full-mount RP histopathology will be used as the reference standard. Secondary outcomes will be sensitivity, specificity, negative predictive value, and positive predictive value for csPCa on a per-patient level, evaluated in patients included prior to prostate biopsy, using biopsy results as the reference standard. A further analysis will be performed on the ability of the algorithm to differentiate between low-, intermediate-, and high-risk tumors., Discussion and Summary: This study aims to develop an ultrasound-based imaging modality for PCa detection. Subsequent head-to-head validation trials with magnetic resonance imaging have to be performed in order to determine its role in clinical practice for risk stratification in patients suspected for PCa., (© 2023 Amsterdam University Medical Centers.)

Purpose: The introduction of magnetic resonance imaging (MRI)-targeted biopsy (TBx) besides systematic prostate biopsies has resulted in a discussion on what the optimal prostate biopsy strategy is. The ideal template has high sensitivity for clinically significant prostate cancer (csPCa), while reducing the detection rate of clinically insignificant prostate cancer (iPCa). This study evaluates different biopsy strategies in patients with a unilateral prostate MRI lesion., Methods: Retrospective subgroup analysis of a prospectively managed database consisting of patients undergoing prostate biopsy in two academic centres. Patients with a unilateral lesion (PI-RADS ⩾ 3) on MRI were included for analysis. The primary objective was to evaluate the diagnostic performance for different biopsy approaches compared with bilateral systematic prostate biopsy (SBx) and TBx. Detection rates for csPCa (ISUP ⩾ 2), adjusted csPCa (ISUP ⩾ 3) and iPCa (ISUP = 1) were determined for SBx alone, TBx alone, contralateral SBx combined with TBx and ipsilateral SBx combined with TBx. A subgroup analysis was performed for biopsy-naive patients., Results: A total of 228 patients were included from October 2015 to September 2021. Prostate cancer (PCa) detection rate of combined SBx and TBx was 63.5% for csPCa, 35.5% for adjusted csPCa, and 14% for iPCa. The best performing alternative biopsy strategy was TBx and ipsilateral SBx, which reached a sensitivity of 98.6% (95% CI: 95.1-99.6) for csPCa and 98.8% (95% CI: 96.3-99.9) for adjusted csPCa, missing only 1.4% of csPCa, while reducing iPCa detection by 15.6% compared with SBx and TBx. TBx or SBx alone missed a significant amount of csPCa, with sensitivities of 90.3% (95% CI: 84.4-94.2) and 86.8% (95% CI: 80.4-91.4) for csPCa. Subgroup analysis on biopsy-naive patients showed similar results as the overall group., Conclusion: This study shows that performing TBx with ipsilateral SBx and omitting contralateral SBx is the optimal biopsy strategy in patients with a unilateral MRI lesion. With this strategy, a very limited amount of csPCa is missed and iPCa detection is reduced., Competing Interests: Competing interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Purpose: A pre-biopsy decision aid is needed to counsel men with a clinical suspicion for clinically significant prostate cancer (csPCa), despite normal prostate magnetic resonance imaging (MRI)., Methods: A risk calculator (RC) for csPCa (International Society of Urological Pathology grade group (ISUP) ⩾ 2) presence in men with a negative-MRI (Prostate Imaging-Reporting and Data System (PI-RADS) ⩽ 2) was developed, and its performance was compared with RCs of the European Randomized Study of Screening for Prostate Cancer (ERSPC), Prostate Biopsy Collaborative Group (PBCG), and Prospective Loyola University mpMRI (PLUM). All biopsy-naïve and prior negative biopsy men with a negative-MRI followed by systematic prostate biopsy were included from October 2015 to September 2021. The RC was developed using multivariable logistic regression with the following parameters: age (years), family history of PCa (first- or second-degree family member), ancestry (African Caribbean/other), digital rectal exam (benign/malignant), MRI field strength (1.5/3.0 Tesla), prior negative biopsy status, and prostate-specific antigen (PSA) density (ng/ml/cc). Performance of RCs was compared using receiver operating characteristic (ROC) curve analysis., Results: A total of 232 men were included for analysis, of which 18.1% had csPCa. Parameters associated with csPCa were family history of PCa ( p  < 0.0001), African Caribbean ancestry ( p  = 0.005), PSA density ( p  = 0.002), prior negative biopsy ( p  = 0.06), and age at biopsy ( p  = 0.157). The area under the curve (AUC) of the developed RC was 0.76 (95% CI 0.68-0.85). This was significantly better than the RCs of the ERSPC (AUC: 0.59; p  = 0.001) and PBCG (AUC: 0.60; p  = 0.002), yet similar to PLUM (AUC: 0.69; p  = 0.09)., Conclusion: The developed RC (Prostate Biopsy Cohort Amsterdam ('PROBA' RC), integrated predictors for csPCa at prostate biopsy in negative-MRI men and outperformed other widely used RCs. These findings require external validation before introduction in daily practice., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Background: Although recent advances in multiparametric magnetic resonance imaging (MRI) led to an increase in MRI-transrectal ultrasound (TRUS) fusion prostate biopsies, these are time consuming, laborious, and costly. Introduction of deep-learning approach would improve prostate segmentation., Objective: To exploit deep learning to perform automatic, real-time prostate (zone) segmentation on TRUS images from different scanners., Design, Setting, and Participants: Three datasets with TRUS images were collected at different institutions, using an iU22 (Philips Healthcare, Bothell, WA, USA), a Pro Focus 2202a (BK Medical), and an Aixplorer (SuperSonic Imagine, Aix-en-Provence, France) ultrasound scanner. The datasets contained 436 images from 181 men., Outcome Measurements and Statistical Analysis: Manual delineations from an expert panel were used as ground truth. The (zonal) segmentation performance was evaluated in terms of the pixel-wise accuracy, Jaccard index, and Hausdorff distance., Results and Limitations: The developed deep-learning approach was demonstrated to significantly improve prostate segmentation compared with a conventional automated technique, reaching median accuracy of 98% (95% confidence interval 95-99%), a Jaccard index of 0.93 (0.80-0.96), and a Hausdorff distance of 3.0 (1.3-8.7) mm. Zonal segmentation yielded pixel-wise accuracy of 97% (95-99%) and 98% (96-99%) for the peripheral and transition zones, respectively. Supervised domain adaptation resulted in retainment of high performance when applied to images from different ultrasound scanners (p > 0.05). Moreover, the algorithm's assessment of its own segmentation performance showed a strong correlation with the actual segmentation performance (Pearson's correlation 0.72, p < 0.001), indicating that possible incorrect segmentations can be identified swiftly., Conclusions: Fusion-guided prostate biopsies, targeting suspicious lesions on MRI using TRUS are increasingly performed. The requirement for (semi)manual prostate delineation places a substantial burden on clinicians. Deep learning provides a means for fast and accurate (zonal) prostate segmentation of TRUS images that translates to different scanners., Patient Summary: Artificial intelligence for automatic delineation of the prostate on ultrasound was shown to be reliable and applicable to different scanners. This method can, for example, be applied to speed up, and possibly improve, guided prostate biopsies using magnetic resonance imaging-transrectal ultrasound fusion., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: To determine the value of two-dimensional (2D) contrast-enhanced ultrasound (CEUS) imaging and the additional value of contrast ultrasound dispersion imaging (CUDI) for the localization of clinically significant prostate cancer (csPCa)., Methods: In this multicentre study, subjects scheduled for a radical prostatectomy underwent 2D CEUS imaging preoperatively. CUDI maps were generated from the CEUS recordings. Both CEUS recordings and CUDI maps were scored on the likelihood of presenting csPCa (any Gleason ≥ 4 + 3 and Gleason 3 + 4 larger than 0.5 mL) by five observers and compared to radical prostatectomy histopathology. An automated three-dimensional (3D) fusion protocol was used to match imaging with histopathology. Receiver operator curve (ROC) analysis was performed per observer and imaging modality., Results: 133 of 216 (62%) patients were included in the final analysis. Average area under the ROC for all five readers for CEUS, CUDI and the combination was 0.78, 0.79 and 0.78, respectively. This yields a sensitivity and specificity of 81 and 64% for CEUS, 83 and 56% for CUDI and 83 and 55% for the combination. Interobserver agreement for CEUS, CUDI and the combination showed kappa values of 0.20, 0.18 and 0.18 respectively., Conclusion: The sensitivity and specificity of 2D CEUS and CUDI for csPCa localization are moderate. Despite compressing CEUS in one image, CUDI showed a similar performance to 2D CEUS. With a sensitivity of 83% at cutoff point 3, it could become a useful imaging procedure, especially with 4D acquisition, improved quantification and combination with other US imaging techniques such as elastography.

Objectives: To compare and evaluate a multiparametric magnetic resonance imaging (mpMRI)-targeted biopsy (TBx) strategy, contrast-ultrasound-dispersion imaging (CUDI)-TBx strategy and systematic biopsy (SBx) strategy for the detection of clinically significant prostate cancer (csPCa) in biopsy-naïve men., Patients and Methods: A prospective, single-centre paired diagnostic study included 150 biopsy-naïve men, from November 2015 to November 2018. All men underwent pre-biopsy mpMRI and CUDI followed by a 12-core SBx taken by an operator blinded from the imaging results. Men with suspicious lesions on mpMRI and/or CUDI also underwent MRI-TRUS fusion-TBx and/or cognitive CUDI-TBx after SBx by a second operator. A non-inferiority analysis of the mpMRI- and CUDI-TBx strategies in comparison with SBx for International Society of Urological Pathology Grade Group [GG] ≥2 PCa in any core with a non-inferiority margin of 1 percentage point was performed. Additional analyses for GG ≥2 PCa with cribriform growth pattern and/or intraductal carcinoma (CR/IDC), and GG ≥3 PCa were performed. Differences in detection rates were tested using McNemar's test with adjusted Wald confidence intervals., Results: After enrolment of 150 men, an interim analysis was performed. Both the mpMRI- and CUDI-TBx strategies were inferior to SBx for GG ≥2 PCa detection and the study was stopped. SBx found significantly more GG ≥2 PCa: 39% (56/142), as compared with 29% (41/142) and 28% (40/142) for mpMRI-TBx and CUDI-TBx, respectively (P < 0.05). SBx found significantly more GG = 1 PCa: 14% (20/142) compared to 1% (two of 142) and 3% (four of 142) with mpMRI-TBx and CUDI-TBx, respectively (P < 0.05). Detection of GG ≥2 PCa with CR/IDC and GG ≥3 PCa did not differ significantly between the strategies. The mpMRI- and CUDI-TBx strategies were comparable in detection but the mpMRI-TBx strategy had less false-positive findings (18% vs 53%)., Conclusions: In our study in biopsy-naïve men, the mpMRI- and CUDI-TBx strategies had comparable PCa detection rates, but the mpMRI-TBX strategy had the least false-positive findings. Both strategies were inferior to SBx for the detection of GG ≥2 PCa, despite reduced detection of insignificant GG = 1 PCa. Both strategies did not significantly differ from SBx for the detection of GG ≥2 PCa with CR/IDC and GG ≥3 PCa., (© 2020 The Authors BJU International © 2020 BJU International Published by John Wiley & Sons Ltd.)

Purpose: Similar to multiparametric magnetic resonance imaging, multiparametric ultrasound represents a promising approach to prostate cancer imaging. We determined the diagnostic performance of B-mode, shear wave elastography and contrast enhanced ultrasound with quantification software as well as the combination, multiparametric ultrasound, for clinically significant prostate cancer localization using radical prostatectomy histopathology as the reference standard., Materials and Methods: From May 2017 to July 2017, 50 men with biopsy proven prostate cancer underwent multiparametric ultrasound before radical prostatectomy at 1 center. Three readers independently evaluated 12 anatomical regions of interest for the likelihood of clinically significant prostate cancer on a 5-point Likert scale for all separate ultrasound modalities and multiparametric ultrasound. A logistic linear mixed model was used to estimate diagnostic performance for the localization of clinically significant prostate cancer (any tumor with Gleason score 3 + 4 = 7 or greater, tumor volume 0.5 ml or greater, extraprostatic extension or stage pN1) using a Likert score of 3 or greater and 4 or greater as the threshold. To detect the index lesion the readers selected the 2 most suspicious regions of interest., Results: A total of 48 men were included in the final analysis. The region of interest specific sensitivity of multiparametric ultrasound (Likert 3 or greater) for clinically significant prostate cancer was 74% (95% CI 67-80) compared to 55% (95% CI 47-63), 55% (95% CI 47-63) and 59% (95% CI 51-67) for B-mode, shear wave elastography and contrast enhanced ultrasound, respectively. Multiparametric ultrasound sensitivity was significantly higher for Likert thresholds and all different clinically significant prostate cancer definitions (all p <0.05). Multiparametric ultrasound improved the detection of index lesion prostate cancer., Conclusions: Multiparametric ultrasound of the prostate, consisting of B-mode, shear wave elastography and contrast enhanced ultrasound with parametric maps, improved localization and index lesion detection of clinically significant prostate cancer compared to single ultrasound modalities, yielding good sensitivity.

Background: The diagnostic pathway for prostate cancer (PCa) is advancing towards an imaging-driven approach. Multiparametric magnetic resonance imaging, although increasingly used, has not shown sufficient accuracy to replace biopsy for now. The introduction of new ultrasound (US) modalities, such as quantitative contrast-enhanced US (CEUS) and shear wave elastography (SWE), shows promise but is not evidenced by sufficient high quality studies, especially for the combination of different US modalities. The primary objective of this study is to determine the individual and complementary diagnostic performance of greyscale US (GS), SWE, CEUS and their combination, multiparametric ultrasound (mpUS), for the detection and localization of PCa by comparison with corresponding histopathology., Methods/design: In this prospective clinical trial, US imaging consisting of GS, SWE and CEUS with quantitative mapping on 3 prostate imaging planes (base, mid and apex) will be performed in 50 patients with biopsy-proven PCa before planned radical prostatectomy using a clinical ultrasound scanner. All US imaging will be evaluated by US readers, scoring the four quadrants of each imaging plane for the likelihood of significant PCa based on a 1 to 5 Likert Scale. Following resection, PCa tumour foci will be identified, graded and attributed to the imaging-derived quadrants in each prostate plane for all prostatectomy specimens. Primary outcome measure will be the sensitivity, specificity, negative predictive value and positive predictive value of each US modality and mpUS to detect and localize significant PCa evaluated for different Likert Scale thresholds using receiver operating characteristics curve analyses., Discussion: In the evaluation of new PCa imaging modalities, a structured comparison with gold standard radical prostatectomy specimens is essential as first step. This trial is the first to combine the most promising ultrasound modalities into mpUS. It complies with the IDEAL stage 2b recommendations and will be an important step towards the evaluation of mpUS as a possible option for accurate detection and localization of PCa., Trial Registration: The study protocol for multiparametric ultrasound was prospectively registered on Clinicaltrials.gov on 14 March 2017 with the registry name 'Multiparametric Ultrasound-Study for the Detection of Prostate Cancer' and trial registration number NCT03091231.

Diffusion tensor tractography (DTT) enables visualization of fiber trajectories in soft tissue using magnetic resonance imaging. DTT exploits the anisotropic nature of water diffusion in fibrous structures to identify diffusion pathways by generating streamlines based on the principal diffusion vector. Anomalies in these pathways can be linked to neural deficits. In a different field, contrast-enhanced ultrasound is used to assess anomalies in blood flow with the aim of locating cancer-induced angiogenesis. Like water diffusion, blood flow and transport of contrast agents also shows a principal direction; however, this is now determined by the local vasculature. Here we show how the tractographic techniques developed for magnetic resonance imaging DTT can be translated to contrast-enhanced ultrasound, by first estimating contrast flow velocity fields from contrast-enhanced ultrasound acquisitions, and then applying tractography. We performed 4D in-vivo contrast-enhanced ultrasound of three human prostates, proving the feasibility of the proposed approach with clinically acquired datasets. By comparing the results to histopathology after prostate resection, we observed qualitative agreement between the contrast flow tracts and typical markers of cancer angiogenic microvasculature: higher densities and tortuous geometries in tumor areas. The method can be used in-vivo using a standard contrast-enhanced ultrasound protocol, opening up new possibilities in the area of vascular characterization for cancer diagnostics.

As the development of modalities for prostate cancer (PCa) imaging advances, the challenge of accurate registration between images and histopathologic ground truth becomes more pressing. Localization of PCa, rather than detection, requires a pixel-to-pixel validation of imaging based on histopathology after radical prostatectomy. Such a registration procedure is challenging for ultrasound modalities; not only the deformations of the prostate after resection have to be taken into account, but also the deformation due to the employed transrectal probe and the mismatch in orientation between imaging planes and pathology slices. In this work, we review the latest techniques to facilitate accurate validation of PCa localization in ultrasound imaging studies and extrapolate a general strategy for implementation of a registration procedure.

Contrast-enhanced ultrasound (CEUS) is an innovative ultrasound technique capable of visualizing both the macro- and microvasculature of tissues. In this prospective pilot study, we evaluated the feasibility of using CEUS to visualize the microvasculature of uterine fibroids and compared CEUS with conventional ultrasound. Four women with fibroids underwent gray-scale ultrasound, sonoelastography and power/color Doppler scans followed by CEUS examination. Analysis of CEUS images revealed initial perfusion of the peripheral rim, that is, a pseudo-capsule, followed by enhancement of the entire lesion through vessels traveling from the exterior to the interior of the fibroid. The pseudo-capsules exhibited slight hyper-enhancement, making a clear delineation of the fibroids possible. The centers of three fibroids exhibited areas lacking vascularization, information not obtainable with the other imaging techniques. CEUS is a feasible technique for imaging and quantifying the microvasculature of fibroids. In comparison with conventional ultrasound imaging modalities, CEUS can provide additional diagnostic information based on the microvasculature., (Copyright © 2018 World Federation for Ultrasound in Medicine and Biology. Published by Elsevier Inc. All rights reserved.)

Purpose: Imaging plays a crucial role in ablative therapies for prostate cancer (PCa). Irreversible electroporation (IRE) is a new treatment modality used for focal treatment of PCa. We aimed to demonstrate what imaging modalities can be used by descriptively reporting contrast-enhanced ultrasonography (CEUS), multiparametric magnetic resonance imaging (mpMRI), and grey-scale transrectal ultrasound (TRUS) results. Furthermore, we aimed to correlate quantitatively the ablation zone seen on mpMRI and CEUS with treatment planning to provide therapy feedback., Methods: Imaging data was obtained from two prospective multicenter trials on IRE for localized low- to intermediate-risk PCa. The ablation zone volume (AZV) seen on mpMRI and CEUS was 3D reconstructed to correlate with the planned AZV., Results: Descriptive examples are provided using mpMRI, TRUS, and CEUS for treatment planning and follow-up after IRE. The mean AZV on T2-weighted imaging 4 weeks following IRE was 12.9 cm3 (standard deviation [SD]=7.0), 5.3 times larger than the planned AZV. Linear regression showed a positive correlation (r=0.76, P = 0.002). For CEUS the mean AZV was 20.7 cm3 (SD=8.7), 8.5 times larger than the planned AZV with a strong positive correlation (r=0.93, P = 0.001). Prostate volume is reduced over time (mean= -27.5%, SD=11.9%) due to ablation zone fibrosis and deformation, illustrated by 3D reconstruction., Conclusion: The role of imaging in conjunction with IRE is of crucial importance to guide clinicians throughout the treatment protocol. CEUS and mpMRI may provide essential treatment feedback by visualizing the ablation zone dimensions and volume.

Objectives: The aim of this study is to improve the accuracy of dynamic contrast-enhanced ultrasound (DCE-US) for prostate cancer (PCa) localization by means of a multiparametric approach., Materials and Methods: Thirteen different parameters related to either perfusion or dispersion were extracted pixel-by-pixel from 45 DCE-US recordings in 19 patients referred for radical prostatectomy. Multiparametric maps were retrospectively produced using a Gaussian mixture model algorithm. These were subsequently evaluated on their pixel-wise performance in classifying 43 benign and 42 malignant histopathologically confirmed regions of interest, using a prostate-based leave-one-out procedure., Results: The combination of the spatiotemporal correlation (r), mean transit time (μ), curve skewness (κ), and peak time (PT) yielded an accuracy of 81% ± 11%, which was higher than the best performing single parameters: r (73%), μ (72%), and wash-in time (72%). The negative predictive value increased to 83% ± 16% from 70%, 69% and 67%, respectively. Pixel inclusion based on the confidence level boosted these measures to 90% with half of the pixels excluded, but without disregarding any prostate or region., Conclusions: Our results suggest multiparametric DCE-US analysis might be a useful diagnostic tool for PCa, possibly supporting future targeting of biopsies or therapy. Application in other types of cancer can also be foreseen., Key Points: • DCE-US can be used to extract both perfusion and dispersion-related parameters. • Multiparametric DCE-US performs better in detecting PCa than single-parametric DCE-US. • Multiparametric DCE-US might become a useful tool for PCa localization.

Purpose: To codify the use of multiparametric magnetic resonance imaging (mpMRI) for the interrogation of prostate neoplasia (PCa) in clinical practice and focal therapy (FT)., Methods: An international collaborative consensus project was undertaken using the Delphi method among experts in the field of PCa. An online questionnaire was presented in three consecutive rounds and modified each round based on the comments provided by the experts. Subsequently, a face-to-face meeting was held to discuss and finalize the consensus results., Results: mpMRI should be performed in patients with prior negative biopsies if clinical suspicion remains, but not instead of the PSA test, nor as a stand-alone diagnostic tool or mpMRI-targeted biopsies only. It is not recommended to use a 1.5 Tesla MRI scanner without an endorectal or pelvic phased-array coil. mpMRI should be performed following standard biopsy-based PCa diagnosis in both the planning and follow-up of FT. If a lesion is seen, MRI-TRUS fusion biopsies should be performed for FT planning. Systematic biopsies are still required for FT planning in biopsy-naïve patients and for patients with residual PCa after FT. Standard repeat biopsies should be taken during the follow-up of FT. The final decision to perform FT should be based on histopathology. However, these consensus statements may differ for expert centers versus non-expert centers., Conclusions: The mpMRI is an important tool for characterizing and targeting PCa in clinical practice and FT. Standardization of acquisition and reading should be the main priority to guarantee consistent mpMRI quality throughout the urological community.

Background: The current standard for Prostate Cancer (PCa) detection in biopsy-naïve men consists of 10-12 systematic biopsies under ultrasound guidance. This approach leads to underdiagnosis and undergrading of significant PCa while insignificant PCa may be overdiagnosed. The recent developments in MRI and Contrast Enhanced Ultrasound (CEUS) imaging have sparked an increasing interest in PCa imaging with the ultimate goal of replacing these "blind" systematic biopsies with reliable imaging-based targeted biopsies., Methods/design: In this trial, we evaluate and compare the PCa detection rates of multiparametric (mp)MRI-targeted biopsies, CEUS-targeted biopsies and systematic biopsies under ultrasound guidance in the same patients. After informed consent, 299 biopsy-naïve men will undergo mpMRI scanning and CEUS imaging 1 week prior to the prostate biopsy procedure. During the biopsy procedure, a systematic transrectal 12-core biopsy will be performed by one operator blinded for the imaging results and targeted biopsy procedure. Subsequently a maximum of 4 CEUS-targeted biopsies and/or 4 mpMRI-targeted biopsies of predefined locations determined by an expert CEUS reader using quantification techniques and an expert radiologist, respectively, will be taken by a second operator using an MRI-US fusion device. The primary outcome is the detection rate of PCa (all grades) and clinically significant PCa (defined as Gleason score ≥7) compared between the three biopsy protocols., Discussion: This trial compares the detection rate of (clinically significant) PCa, between both traditional systematic biopsies and targeted biopsies based on predefined regions of interest identified by two promising imaging technologies. It follows published recommendations on study design for the evaluation of imaging guided prostate biopsy techniques, minimizing bias and allowing data pooling. It is the first trial to combine mpMRI imaging and advanced CEUS imaging with quantification., Trial Registration: The Dutch Central Committee on Research Involving Human Subjects registration number NL52851.018.15, registered on 3 Nov 2015. Clinicaltrials.gov database registration number NCT02831920 , retrospectively registered on 5 July 2016.

Objective: The role of angiogenesis in cancer growth has stimulated research aimed at noninvasive cancer detection by blood perfusion imaging. Recently, contrast ultrasound dispersion imaging was proposed as an alternative method for angiogenesis imaging. After the intravenous injection of an ultrasound-contrast-agent bolus, dispersion can be indirectly estimated from the local similarity between neighboring time-intensity curves (TICs) measured by ultrasound imaging. Up until now, only linear similarity measures have been investigated. Motivated by the promising results of this approach in prostate cancer (PCa), we developed a novel dispersion estimation method based on mutual information, thus including nonlinear similarity, to further improve its ability to localize PCa., Methods: First, a simulation study was performed to establish the theoretical link between dispersion and mutual information. Next, the method's ability to localize PCa was validated in vivo in 23 patients (58 datasets) referred for radical prostatectomy by comparison with histology., Results: A monotonic relationship between dispersion and mutual information was demonstrated. The in vivo study resulted in a receiver operating characteristic (ROC) curve area equal to 0.77, which was superior (p = 0.21-0.24) to that obtained by linear similarity measures (0.74-0.75) and (p <; 0.05) to that by conventional perfusion parameters (≤0.70)., Conclusion: Mutual information between neighboring time-intensity curves can be used to indirectly estimate contrast dispersion and can lead to more accurate PCa localization., Significance: An improved PCa localization method can possibly lead to better grading and staging of tumors, and support focal-treatment guidance. Moreover, future employment of the method in other types of angiogenic cancer can be considered.

Prostate cancer care can benefit from accurate and cost-efficient imaging modalities that are able to reveal prognostic indicators for cancer. Angiogenesis is known to play a central role in the growth of tumors towards a metastatic or a lethal phenotype. With the aim of localizing angiogenic activity in a non-invasive manner, Dynamic Contrast Enhanced Ultrasound (DCE-US) has been widely used. Usually, the passage of ultrasound contrast agents thought the organ of interest is analyzed for the assessment of tissue perfusion. However, the heterogeneous nature of blood flow in angiogenic vasculature hampers the diagnostic effectiveness of perfusion parameters. In this regard, quantification of the heterogeneity of flow may provide a relevant additional feature for localizing angiogenesis. Statistics based on flow magnitude as well as its orientation can be exploited for this purpose. In this paper, we estimate the microbubble velocity fields from a standard bolus injection and provide a first statistical characterization by performing a spatial entropy analysis. By testing the method on 24 patients with biopsy-proven prostate cancer, we show that the proposed method can be applied effectively to clinically acquired DCE-US data. The method permits estimation of the in-plane flow vector fields and their local intricacy, and yields promising results (receiver-operating-characteristic curve area of 0.85) for the detection of prostate cancer.

Prostate cancer (PCa) is the second-leading cause of cancer death in men; however, reliable tools for detection and localization are still lacking. Dynamic Contrast Enhanced UltraSound (DCE-US) is a diagnostic tool that is suitable for analysis of vascularization, by imaging an intravenously injected microbubble bolus. The localization of angiogenic vascularization associated with the development of tumors is of particular interest. Recently, methods for the analysis of the bolus convective dispersion process have shown promise to localize angiogenesis. However, independent estimation of dispersion was not possible due to the ambiguity between convection and dispersion. Therefore, in this study we propose a new method that considers the vascular network as a dynamic linear system, whose impulse response can be locally identified. To this end, model-based parameter estimation is employed, that permits extraction of the apparent dispersion coefficient (D), velocity (v), and Péclet number (Pe) of the system. Clinical evaluation using data recorded from 25 patients shows that the proposed method can be applied effectively to DCE-US, and is able to locally characterize the hemodynamics, yielding promising results (receiver-operating-characteristic curve area of 0.84) for prostate cancer localization., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The World Federation for Ultrasound in Medicine and Biology (WFUMB) has produced guidelines for the use of elastography techniques, including basic science, breast, liver and thyroid elastography. Here we present elastography in prostate diseases. For each available technique, procedure, reproducibility, results and limitations are analyzed and recommendations are given. Finally, recommendations are given based on the level of evidence of the published literature and on the WFUMB expert group's consensus. This document has a clinical perspective and is aimed at assessing the usefulness of elastography in the management of prostate diseases., (Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Purpose: To reach standardized terminology in focal therapy (FT) for prostate cancer (PCa)., Methods: A four-stage modified Delphi consensus project was undertaken among a panel of international experts in the field of FT for PCa. Data on terminology in FT was collected from the panel by three rounds of online questionnaires. During a face-to-face meeting on June 21, 2015, attended by 38 experts, all data from the online rounds were reviewed and recommendations for definitions were formulated., Results: Consensus was attained on 23 of 27 topics; Targeted FT was defined as a lesion-based treatment strategy, treating all identified significant cancer foci; FT was generically defined as an anatomy-based (zonal) treatment strategy. Treatment failure due to the ablative energy inadequately destroying treated tissue is defined as ablation failure. In targeting failure the energy is not adequately applied to the tumor spatially and selection failure occurs when a patient was wrongfully selected for FT. No definition of biochemical recurrence can be recommended based on the current data. Important definitions for outcome measures are potency (minimum IIEF-5 score of 21), incontinence (new need for pads or leakage) and deterioration in urinary function (increase in IPSS >5 points). No agreement on the best quality of life tool was established, but UCLA-EPIC and EORTC-QLQ-30 were most commonly supported by the experts. A complete overview of statements is presented in the text., Conclusion: Focal therapy is an emerging field of PCa therapeutics. Standardization of definitions helps to create comparable research results and facilitate clear communication in clinical practice., Competing Interests: Compliance with ethical standards This is a report of a Delphi consensus project among experts only. No human or animal subjects were involved; therefore, no informed consent was collected. Conflict of interest O.U reports being a consultant for Sonacare Medical. A.A. reports consulting for Steba Biotech. A.Bl., M.S., R.S. and S.C. report being consultants for EDAP TMS. S.E. reports being a consultant for NxThera and Profound Medical. J.J. reports being consultant for Endocare. C.K. reports being a consultant for Elekta and organizing educational internships sponsored by Elekta, Siemens, Philips, Medicom and Hitachi. T.P. reports performing a clinical trial with Angiodynamics and being a consultant for Healthtronics. The other authors report no conflicts of interest.

Purpose: Irreversible electroporation is a tissue ablation modality that uses high voltage electric energy to induce an increase in cell membrane permeability. This causes destabilization of the existing cellular transmembrane potential leading to cell death, due to the inability to maintain cellular homeostasis. This phase I-II study was designed to evaluate the histopathological outcomes of irreversible electroporation to prostate and surrounding tissue in radical prostatectomy specimens., Materials and Methods: Sixteen patients with prostate cancer underwent an irreversible electroporation ablation without curative intent, followed by radical prostatectomy scheduled 4 weeks later. For histopathological examination of the prostate, whole mounted tissue slices were examined by dedicated genitourinary pathologists. The borders of the ablation zone and residual tumor were outlined on the slides., Results: The irreversible electroporation ablation zones were characterized as areas of fibrosis, necrosis and loss of epithelial tissue in terms of denudation in the glandular structures. The ablation zone was well demarcated, showing trenchant delineations between viable and nonviable tissue. The ablated tissue showed mild to moderate inflammation, with atrophic cells in 1 case. The area was surrounded by hemorrhage at the location of the electrodes. No skip lesions or viable tissue was seen in the ablation zone. Fibrinoid necrosis of the neurovascular bundle was observed in 13 patients and denudation of the urothelium of the prostatic urethra was seen in 9., Conclusions: Histopathological assessment of the prostate 4 weeks after irreversible electroporation ablation showed sharply demarcated fibrotic and necrotic tissue in the ablation zone. No viable tissue was observed in the irreversible electroporation ablation zone., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: Irreversible electroporation (IRE) is an ablative therapy with a low side-effect profile in prostate cancer. The objective was: 1) To compare the volumetric IRE ablation zone on grey-scale transrectal ultrasound (TRUS), contrast-enhanced ultrasound (CEUS) and multiparametric MRI (mpMRI) with histopathology findings; 2) To determine a reliable imaging modality to visualize the IRE ablation effects accurately., Methods: A prospective phase I-II study was performed in 16 patients scheduled for radical prostatectomy (RP). IRE of the prostate was performed 4 weeks before RP. Prior to, and 4 weeks after the IRE treatment, imaging was performed by TRUS, CEUS, and mpMRI. 3D-analysis of the ablation volumes on imaging and on H&E-stained whole-mount sections was performed. The volumes were compared and the correlation was calculated., Results: Evaluation of the imaging demonstrated that with T2-weighted MRI, dynamic contrast enhanced (DCE) MRI, and CEUS, effects of IRE are visible. T2MRI and CEUS closely match the volumes on histopathology (Pearson correlation r = 0.88 resp. 0.80). However, IRE is not visible with TRUS., Conclusions: mpMRI and CEUS are appropriate for assessing IRE effects and are the most feasible imaging modalities to visualize IRE ablation zone. The imaging is concordant with results of histopathological examination., Key Points: • mpMRI and contrast-enhanced ultrasound are appropriate imaging modalities for assessing IRE effects • mpMRI and CEUS are the most feasible imaging modalities to visualize IRE ablation zone • The imaging is concordant with results of histopathological examination after IRE • Grey-scale US is insufficient for assessing IRE ablations.

Objective: Focal therapy (FT) is a tissuesparing treatment paradigm for localized prostate cancer (PCa) with the potential to improve functional outcomes while maintaining oncologic safety. This paper aims to provide an overview of important considerations and practical recommendations relating to the follow-up after FT., Methods: Literature review of papers related to FT in PCa derived from Medline/Pubmed database., Results: The recommended minimum follow-up period after FT is 5 years. Standard history taking should include: signs of disease progression, treatment-related complications and psychological aspects. Oncological outcome is based on serial prostate specific antigen monitoring, follow-up imaging (most commonly with multiparametric magnetic resonance imaging) and repeat biopsies (systematic from entire gland or targeted from treated zone). Significant PCa has been found at biopsy in up to 17% of patients after FT. Functional outcomes are evaluated using standardized questionnaires that relate to urinary function, erectile function and quality of life. A systematic review reports urinary continence in 83-100% of patients, erections sufficient for penetration in 54-100%. Outcomes differ between ablative energies and treatment templates. The most common side effects after FT are urinary retention (0-17%), urinary tract infection (UTI) (0-17%) and urinary stricture (0-5%). Rectal fistula is a rare complication occurring in up to 0.1-2% of patients. Clavien-Dindo Grade 3-4 complications are reported in 0-4% of patients. Type and rate vary with treatment modality. Complications should be reported using standardized reporting systems. Most data on FT outcomes come from small heterogeneous trials. Pooling of standardized data is necessary to advance the field of FT., Conclusion: Stringent follow-up after FT is required to confirm oncologic safety of the individual patient. Standardized data gathering and data pooling is necessary to evaluate whether FT can live up to its promise of improving functional outcomes while maintaining oncological safety.

The extensive use of prostate-specific antigen (PSA) testing and improved imaging technologies have resulted in an increased diagnosis of prostate cancer. Early diagnosis is often accompanied by an increased number of localized (i.e. unifocal or unilateral), small-volume and low-grade prostate cancers. Focal therapy is an emerging treatment option in prostate cancer, targeting individual cancer areas while sparing important functional and anatomical urological structures. Irreversible electroporation is an innovative treatment modality in focal therapy based on the process of cell membrane electroporation limiting damage to adjacent tissue and vital structures. The first phase I-II trials in humans have shown the safety of IRE for focal ablative therapy of prostate cancer and showed encouraging results considering functional preservation. Histological analysis after IRE showed fibrosis without glandular ducts and necrotic tissue with sharp demarcation between unaffected prostatic glandular tissue and the ablation zone. Short-term oncological results are promising; however more data on long-term oncological outcomes are necessary. New studies with IRE and other focal treatment modalities are initiated to explore opportunities for focal therapy in prostate cancer and to optimize current treatment protocols.

Objective: To investigate the value of dynamic contrast-enhanced (DCE)-ultrasonography (US) and software-generated parametric maps in predicting biopsy outcome and their potential to reduce the amount of negative biopsy cores., Materials and Methods: For 651 prostate biopsy locations (82 consecutive patients) we correlated the interpretation of DCE-US recordings with and without parametric maps with biopsy results. The parametric maps were generated by software which extracts perfusion parameters that differentiate benign from malignant tissue from DCE-US recordings. We performed a stringent analysis (all tumours) and a clinical analysis (clinically significant tumours). We calculated the potential reduction in biopsies (benign on imaging) and the resultant missed positive biopsies (false-negatives). Additionally, we evaluated the performance in terms of sensitivity, specificity negative predictive value (NPV) and positive predictive value (PPV) on a per-prostate level., Results: Based on DCE-US, 470/651 (72.2%) of biopsy locations appeared benign, resulting in 40 false-negatives (8.5%), considering clinically significant tumours only. Including parametric maps, 411/651 (63.1%) of the biopsy locations appeared benign, resulting in 23 false-negatives (5.6%). In the per-prostate clinical analysis, DCE-US classified 38/82 prostates as benign, missing eight diagnoses. Including parametric maps, 31/82 prostates appeared benign, missing three diagnoses. Sensitivity, specificity, PPV and NPV were 73, 58, 50 and 79%, respectively, for DCE-US alone and 91, 56, 57 and 90%, respectively, with parametric maps., Conclusion: The interpretation of DCE-US with parametric maps allows good prediction of biopsy outcome. A two-thirds reduction in biopsy cores seems feasible with only a modest decrease in cancer diagnosis., (© 2015 The Authors BJU International © 2015 BJU International Published by John Wiley & Sons Ltd.)

Numerous age-related pathologies affect the prostate gland, the most menacing of which is prostate cancer (PCa). The diagnostic tools for prostate investigation are invasive, requiring biopsies when PCa is suspected. Novel dynamic contrast-enhanced ultrasound (DCE-US) imaging approaches have been proposed recently and appear promising for minimally invasive localization of PCa. Ultrasound imaging of the prostate is traditionally performed with a transrectal probe because the location of the prostate allows for high-resolution images using high-frequency transducers. However, DCE-US imaging requires lower frequencies to induce bubble resonance and, thus, improve contrast-to-tissue ratio. For this reason, in this study we investigate the feasibility of quantitative DCE-US imaging of the prostate via the abdomen. The study included 10 patients (age = 60.7 ± 5.7 y) referred for a needle biopsy study. After having given informed consent, patients underwent DCE-US with both transabdominal and transrectal probes. Time-intensity contrast curves were derived using both approaches and their model-fit quality was compared. Although further improvements are expected by optimization of the transabdominal settings, the results of transabdominal and transrectal DCE-US are closely comparable, confirming the feasibility of transabdominal DCE-US; transabdominal curve fitting revealed an average determination coefficient r(2) = 0.91 (r(2) > 0.75 for 78.6% of all prostate pixels) compared with r(2) = 0.91 (r(2) > 0.75 for 81.6% of all prostate pixels) by the transrectal approach. Replacing the transrectal approach with more acceptable transabdominal scanning for prostate investigation is feasible. This approach would improve patient comfort and represent a useful option for PCa localization and monitoring., (Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)