Image-guided in-Vivo Needle-Based Confocal Laser Endomicroscopy in the Prostate: Safety and Feasibility Study in 2 Patients.

Purpose: To assess the safety and technical feasibility of in-vivo needle-based forward-looking confocal laser endomicroscopy in prostate tissue. Methods: For this feasibility study, 2 patients with a suspicion of prostate cancer underwent transperineal needle-based confocal laser endomicroscopy during ultrasound-guided transperineal template mapping biopsies. After intravenous administration of fluorescein, needle-based confocal laser endomicroscopy imaging was performed with a forward-looking probe (outer diameter 0.9 mm) in 2 trajectories during a manual push-forward and pullback motion. A biopsy was taken in a coregistered parallel adjacent trajectory to the confocal laser endomicroscopy trajectory for histopathologic comparison. Peri- and postprocedural adverse events, confocal laser endomicroscopy device malfunction and procedural failures were recorded. Needle-based confocal laser endomicroscopy image quality assessment, image interpretation, and histology were performed by an experienced confocal laser endomicroscopy rater and uro-pathologist, blinded to any additional information. Results: In both patients, no peri- and post-procedural adverse events were reported following needle-based confocal laser endomicroscopy. No confocal laser endomicroscopy device malfunction nor procedural failures were reported. Within 1.5 min after intravenous administration of fluorescein, needle-based confocal laser endomicroscopy image quality was sufficient for interpretation for at least 14 min, yielding more than 5000 confocal laser endomicroscopy frames per patient. The pullback confocal laser endomicroscopy recordings and most of the push-forward recordings almost only visualized erythrocytes, being classified as non-representative. During the push-forward recordings, prostate tissue was occasionally visualized in single frames, insufficient for histopathologic comparison. Prostate carcinoma was identified by biopsy in one patient (Gleason score 4 + 3 = 7, >50%), while the biopsy from the other patient showed no malignancy. Conclusion: Needle-based confocal laser endomicroscopy imaging of in-vivo prostate tissue with a forward-looking confocal laser endomicroscopy probe is safe without device malfunctions or procedural failures. Needle-based confocal laser endomicroscopy is technically feasible, but the acquired confocal laser endomicroscopy datasets are non-representative. The confocal laser endomicroscopy images' non-representative nature is possibly caused by bleeding artifacts, movement artifacts and a lack of contact time with the tissue of interest. A different confocal laser endomicroscopy probe or procedure might yield representative images of prostatic tissue.

Deep Learning for Real-time, Automatic, and Scanner-adapted Prostate (Zone) Segmentation of Transrectal Ultrasound, for Example, Magnetic Resonance Imaging-transrectal Ultrasound Fusion Prostate Biopsy.

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.

Detection of clinically significant prostate cancer in biopsy-naïve men: direct comparison of systematic biopsy, multiparametric MRI- and contrast-ultrasound-dispersion imaging-targeted biopsy.

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.

Contrast-enhanced ultrasound with dispersion analysis for the localization of prostate cancer: correlation with radical prostatectomy specimens.

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.

Automated multiparametric localization of prostate cancer based on B-mode, shear-wave elastography, and contrast-enhanced ultrasound radiomics.

OBJECTIVES: The aim of this study was to assess the potential of machine learning based on B-mode, shear-wave elastography (SWE), and dynamic contrast-enhanced ultrasound (DCE-US) radiomics for the localization of prostate cancer (PCa) lesions using transrectal ultrasound. METHODS: This study was approved by the institutional review board and comprised 50 men with biopsy-confirmed PCa that were referred for radical prostatectomy. Prior to surgery, patients received transrectal ultrasound (TRUS), SWE, and DCE-US for three imaging planes. The images were automatically segmented and registered. First, model-based features related to contrast perfusion and dispersion were extracted from the DCE-US videos. Subsequently, radiomics were retrieved from all modalities. Machine learning was applied through a random forest classification algorithm, using the co-registered histopathology from the radical prostatectomy specimens as a reference to draw benign and malignant regions of interest. To avoid overfitting, the performance of the multiparametric classifier was assessed through leave-one-patient-out cross-validation. RESULTS: The multiparametric classifier reached a region-wise area under the receiver operating characteristics curve (ROC-AUC) of 0.75 and 0.90 for PCa and Gleason > 3 + 4 significant PCa, respectively, thereby outperforming the best-performing single parameter (i.e., contrast velocity) yielding ROC-AUCs of 0.69 and 0.76, respectively. Machine learning revealed that combinations between perfusion-, dispersion-, and elasticity-related features were favored. CONCLUSIONS: In this paper, technical feasibility of multiparametric machine learning to improve upon single US modalities for the localization of PCa has been demonstrated. Extended datasets for training and testing may establish the clinical value of automatic multiparametric US classification in the early diagnosis of PCa. KEY POINTS: • Combination of B-mode ultrasound, shear-wave elastography, and contrast ultrasound radiomics through machine learning is technically feasible. • Multiparametric ultrasound demonstrated a higher prostate cancer localization ability than single ultrasound modalities. • Computer-aided multiparametric ultrasound could help clinicians in biopsy targeting.

Multiparametric Ultrasound for Prostate Cancer Detection and Localization: Correlation of B-mode, Shear Wave Elastography and Contrast Enhanced Ultrasound with Radical Prostatectomy Specimens.

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.

The First In Vivo Needle-Based Optical Coherence Tomography in Human Prostate: A Safety and Feasibility Study.

OBJECTIVE: To demonstrate the safety and feasibility of clinical in vivo needle-based optical coherence tomography (OCT) imaging of the prostate. MATERIALS AND METHODS: Two patients with prostate cancer underwent each two percutaneous in vivo needle-based OCT measurements before transperineal template mapping biopsy. The OCT probe was introduced via a needle and positioned under ultrasound guidance. To test the safety, adverse events were recorded during and after the procedure. To test the feasibility, OCT and US images were studied during and after the procedure. Corresponding regions for OCT and biopsy were determined. A uropathologist evaluated and annotated the histopathology. Three experts assessed all the corresponding OCT images. The OCT and biopsy conclusions for the corresponding regions were compared. RESULTS: No adverse events during and following the, in total four, in vivo needle-based OCT measurements were reported. The OCT measurements showed images of prostatic tissue with a penetration depth of ~1.5 mm. The histological-proven tissue types, which were also found in the overlapping OCT images, were benign glands, stroma, glandular atrophy, and adenocarcinoma (Gleason pattern 3). CONCLUSIONS: Clinical in vivo needle-based OCT of the prostate is feasible with no adverse events during measurements. OCT images displayed detailed prostatic tissue with a imaging depth up to ~1.5 mm. We could co-register four histological-proven tissue types with OCT images. The feasibility of in vivo OCT in the prostate opens the pathway to the next phase of needle-based OCT studies in the prostate. Lasers Surg. Med. 51:390-398, 2019. © 2019 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

Three-dimensional greyscale transrectal ultrasound-guidance and biopsy core preembedding for detection of prostate cancer: Dutch clinical cohort study.

BACKGROUND: To overcome the limitations regarding two dimensional (2D) greyscale (GS) transrectal ultrasound (TRUS)-guided biopsy in prostate cancer (PCa) detection and tissue packaging in biopsy processing, there is an ongoing focus on new imaging and pathology techniques. A three-dimensional (3D) model of the prostate with biopsy needle guidance can be generate by the Navigo™ workstation (UC-care, Israel). The SmartBX™ system (UC-care, Israel) provides a prostate biopsy core preembedding method. The aim of this study was to compare cancer detection rates between the 3D TRUS-guidance and preembedding method with conventional 2D GS TRUS-guidance among patients undergoing prostate biopsies. METHODS: We retrospectively analyzed the records of all patients who underwent prostate biopsies for PCa detection at our institution from 2007 to 2016. The cohort was divided into a 2D GS TRUS-guidance cohort (from 2007 to 2013, n = 1149) and a 3D GS TRUS-guidance with preembedding cohort (from 2013 to 2016, n = 469). Effect of 3D GS TRUS-guidance with preembedding on detection rate of PCa and clinically significant PCa (Gleason score ≥ 7 or > 2 biopsy cores with a Gleason score 6) was compared to 2D GS TRUS-guidance using regression models. RESULTS: Detection rate of PCa and clinically significant PCa was 39.0 and 24.9% in the 3D GS TRUS cohort compared to 33.5 and 19.0% in the 2D GS TRUS cohort, respectively. On multivariate regression analysis the use of 3D GS TRUS-guidance with preembedding was associated with a significant increase in detection rate of PCa (aOR = 1.33; 95% CI: 1.03-1.72) and clinically significant PCa (aOR = 1.47; 95% CI: 1.09-1.98). CONCLUSION: Our results suggest that 3D GS TRUS-guidance with biopsy core preembedding improves PCa and clinically significant PCa detection compared to 2D GS TRUS-guidance. Additional studies are needed to justify the application of these systems in clinical practice.

The added value of systematic biopsy in men with suspicion of prostate cancer undergoing multiparametric MRI-targeted biopsy.

PURPOSE: Incorporation of multiparametric magnetic resonance imaging (mpMRI) and targeted biopsy (TBx) in the diagnostic pathway for prostate cancer (CaP) is rapidly becoming common practice. In men with a prebiopsy positive mpMRI a TBx only approach, thereby omitting transrectal ultrasound-guided systematic biopsy (SBx), has been postulated. In this study we evaluated the additional clinical relevance of SBx in men with a positive prebiopsy mpMRI (Prostate Imaging Reporting and Data System [PI-RADS] ≥ 3) undergoing TBx for CaP detection, Gleason grading and CaP localization. MATERIAL AND METHODS: Prospective data of 255 consecutive men with a prebiopsy positive mpMRI (PI-RADS ≥ 3) undergoing 12-core SBx and subsequent MRI-transrectal ultrasound fusion TBx in 2 institutions between 2015 and 2018 was obtained. The detection rate for significant CaP (Gleason score [GS] ≥ 3 + 4) for TBx and SBx were compared. The rate of potentially missed significant CaP by a TBx only approach was determined and GS concordance and CaP localization by TBx and SBx was evaluated. RESULTS: TBx yielded significant CaP in 113 men (44%) while SBx yielded significant CaP in 110 men (43%) (P = 0.856). Insignificant CaP was found in 21 men (8%) by TBx, while SBx detected 34 men (13%) with insignificant CaP (P = 0.035). A TBx only approach, omitting SBx, would have missed significant CaP in 13 of the 126 men (10%) with significant CaP on biopsy. Ten of the 118 men (8%), both positive on TBx and SBx, were upgraded in GS by SBx while 11 men (9%) had higher maximum tumor core involvement on SBx. Nineteen of the 97 men (20%) with significant CaP in both TBx and SBx were diagnosed with unilateral significant CaP on mpMRI and TBx while SBx demonstrated bilateral significant CaP. CONCLUSIONS: In men with a prebiopsy positive mpMRI, TBx detects high-GS CaP while reducing insignificant CaP detection as compared to SBx. SBx and TBx as stand-alone missed significant CaP in 13% and 10% of the men with significant CaP on biopsy, respectively. A combination of SBx and TBx remains necessary for the most accurate assessment of detection, grading, tumor core involvement, and localization of CaP.

Prediction of High-grade Prostate Cancer Following Multiparametric Magnetic Resonance Imaging: Improving the Rotterdam European Randomized Study of Screening for Prostate Cancer Risk Calculators.

BACKGROUND: The Rotterdam European Randomized Study of Screening for Prostate Cancer risk calculators (ERSPC-RCs) help to avoid unnecessary transrectal ultrasound-guided systematic biopsies (TRUS-Bx). Multivariable risk stratification could also avoid unnecessary biopsies following multiparametric magnetic resonance imaging (mpMRI). OBJECTIVE: To construct MRI-ERSPC-RCs for the prediction of any- and high-grade (Gleason score ≥3 + 4) prostate cancer (PCa) in 12-core TRUS-Bx±MRI-targeted biopsy (MRI-TBx) by adding Prostate Imaging Reporting and Data System (PI-RADS) and age as parameters to the ERSPC-RC3 (biopsy-naïve men) and ERSPC-RC4 (previously biopsied men). DESIGN, SETTING, AND PARTICIPANTS: A total of 961 men received mpMRI and 12-core TRUS-Bx±MRI-TBx (in case of PI-RADS ≥3) in five institutions. Data of 504 biopsy-naïve and 457 previously biopsied men were used to adjust the ERSPC-RC3 and ERSPC-RC4. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Logistic regression models were constructed. The areas under the curve (AUCs) of the original ERSPC-RCs and MRI-ERSPC-RCs (including PI-RADS and age) for any- and high-grade PCa were compared. Decision curve analysis was performed to assess the clinical utility of the MRI-ERSPC-RCs. RESULTS AND LIMITATIONS: MRI-ERSPC-RC3 had a significantly higher AUC for high-grade PCa compared with the ERSPC-RC3: 0.84 (95% confidence interval [CI] 0.81-0.88) versus 0.76 (95% CI 0.71-0.80, p<0.01). Similarly, MRI-ERSPC-RC4 had a higher AUC for high-grade PCa compared with the ERSPC-RC4: 0.85 (95% CI 0.81-0.89) versus 0.74 (95% CI 0.69-0.79, p<0.01). Unlike for the MRI-ERSPC-RC3, decision curve analysis showed clear net benefit of the MRI-ERSPC-RC4 at a high-grade PCa risk threshold of ≥5%. Using a ≥10% high-grade PCa risk threshold to biopsy for the MRI-ERSPC-RC4, 36% biopsies are saved, missing low- and high-grade PCa, respectively, in 15% and 4% of men who are not biopsied. CONCLUSIONS: We adjusted the ERSPC-RCs for the prediction of any- and high-grade PCa in 12-core TRUS-Bx±MRI-TBx. Although the ability of the MRI-ERSPC-RC3 for biopsy-naïve men to avoid biopsies remains questionable, application of the MRI-ERSPC-RC4 in previously biopsied men in our cohort would have avoided 36% of biopsies, missing high-grade PCa in 4% of men who would not have received a biopsy. PATIENT SUMMARY: We have constructed magnetic resonance imaging-based Rotterdam European Randomized study of Screening for Prostate Cancer (MRI-ERSPC) risk calculators for prostate cancer prediction in transrectal ultrasound-guided biopsy and MRI-targeted biopsy by incorporating age and Prostate Imaging Reporting and Data System score into the original ERSPC risk calculators. The MRI-ERSPC risk calculator for previously biopsied men could be used to avoid one-third of biopsies following MRI.

Multiparametric ultrasound: evaluation of greyscale, shear wave elastography and contrast-enhanced ultrasound for prostate cancer detection and localization in correlation to radical prostatectomy specimens.

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.

Contrast-enhanced ultrasound tractography for 3D vascular imaging of the prostate.

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.

Accurate validation of ultrasound imaging of prostate cancer: a review of challenges in registration of imaging and histopathology.

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.

Confocal Laser Endomicroscopy and Optical Coherence Tomography for the Diagnosis of Prostate Cancer: A Needle-Based, In Vivo Feasibility Study Protocol (IDEAL Phase 2A).

BACKGROUND: Focal therapy for prostate cancer has been proposed as an alternative treatment to whole-gland therapies in selected men to diminish side effects in localized prostate cancer. As nowadays imaging cannot offer complete prostate cancer disease characterization, multicore systematic biopsies are recommended (transrectal or transperineal). Optical imaging techniques such as confocal laser endomicroscopy and optical coherence tomography allow in vivo, high-resolution imaging. Moreover, they can provide real-time visualization and analysis of tissue and have the potential to offer additive diagnostic information. OBJECTIVE: This study has 2 separate primary objectives. The first is to assess the technical feasibility and safety of in vivo focal imaging with confocal laser endomicroscopy and optical coherence tomography. The second is to identify and define characteristics of prostate cancer and normal prostate tissue in confocal laser endomicroscopy and optical coherence tomography imaging by comparing these images with the corresponding histopathology. METHODS: In this prospective, in vivo feasibility study, needle-based confocal laser endomicroscopy and optical coherence tomography imaging will be performed before transperineal template mapping biopsy or radical prostatectomy. First, confocal laser endomicroscopy and optical coherence tomography will be performed in 4 patients (2 for each imaging modality) undergoing transperineal template mapping biopsy to assess the feasibility and safety of confocal laser endomicroscopy and optical coherence tomography. If proven to be safe and feasible, confocal laser endomicroscopy and optical coherence tomography will be performed in 10 patients (5 for each imaging modality) undergoing radical prostatectomy. Confocal laser endomicroscopy and optical coherence tomography images will be analyzed by independent, blinded observers. Confocal laser endomicroscopy- and optical coherence tomography-based qualitative and quantitative characteristics and histopathology will be compared. The study complies with the IDEAL (Idea, Development, Exploration, Assessment, Long-term study) stage 2a recommendations. RESULTS: At present, the study is enrolling patients and results and outcomes are expected in 2019. CONCLUSIONS: Confocal laser endomicroscopy and optical coherence tomography are promising optical imaging techniques that can visualize and analyze tissue structure, possible tumor grade, and architecture in real time. They can potentially provide real-time, high-resolution microscopic imaging and tissue characteristics of prostate cancer in conjunction with magnetic resonance imaging or transrectal ultrasound fusion-guided biopsy procedures. This study will provide insight into the feasibility and tissue-specific characteristics of confocal laser endomicroscopy and optical coherence tomography for real-time optical analysis of prostate cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT03253458; https://clinicaltrials.gov/ct2/show/NCT03253458 (Archived by WebCite at http://www.webcitation.org/6z9owM66B). REGISTERED REPORT IDENTIFIER: RR1-10.2196/9813.

Concordance of Gleason grading with three-dimensional ultrasound systematic biopsy and biopsy core pre-embedding.

PURPOSE: To determine the value of a three-dimensional (3D) greyscale transrectal ultrasound (TRUS)-guided prostate biopsy system and biopsy core pre-embedding method on concordance between Gleason scores of needle biopsies and radical prostatectomy (RP) specimens. METHODS: Retrospective analysis of prostate biopsies and subsequent RP for PCa in the Jeroen Bosch Hospital, the Netherlands, from 2007 to 2016. Two cohorts were analysed: conventional 2D TRUS-guided biopsies and RP (2007-2013, n = 266) versus 3D TRUS-guided biopsies with pre-embedding (2013-2016, n = 129). The impact of 3D TRUS-guidance with pre-embedding on Gleason score (GS) concordance between biopsy and RP was evaluated using the κ-coefficient. Predictors of biopsy GS 6 upgrading were assessed using logistic regression models. RESULTS: Gleason concordance was comparable between the two cohorts with a κ = 0.44 for the 3D cohort, compared to κ = 0.42 for the 2D cohort. 3D TRUS-guidance with pre-embedding, did not significantly affect the risk of biopsy GS 6 upgrading in univariate and multivariate analysis. CONCLUSIONS: 3D TRUS-guidance with biopsy core pre-embedding did not improve Gleason concordance. Improved detection techniques are needed for recognition of low-grade disease upgrading.

Prediction of Prostate Cancer: External Validation of the ERSPC Risk Calculator in a Contemporary Dutch Clinical Cohort.

BACKGROUND: The validity of prediction models needs external validation to assess their value beyond the original development setting. OBJECTIVE: To report the diagnostic accuracy of the European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculator (RC)3 and RC4 in a contemporary Dutch clinical cohort. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively identified all men who underwent prostate biopsy (PBx) in the Jeroen Bosch Hospital, The Netherlands, between 2007 and 2016. Patients were included if they met ERSPC RC requirements of age (50-80 yr), prostate-specific antigen (PSA) (0.4-50 ng/ml), and prostate volume (10-150ml). The probability of a positive biopsy for prostate cancer (PCa) and significant PCa (Gleason score ≥7 and/or higher than T2b) were calculated and compared with PBx pathology results. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Evaluation was performed by calibration, discrimination, and clinical usefulness using calibration plots, area under the receiver operating characteristic curves (AUCs), and decision curve analyses (DCAs), respectively. RESULTS AND LIMITATIONS: A total of 2270 PBx sessions were eligible for final analysis. Discriminative ability of RC3 (AUC) was 0.78 and 0.90 for any PCa and significant PCa, respectively. For RC4 the calculated AUCs were 0.62 (any PCa) and 0.76 (significant PCa). The calibration plots of RC3 showed good results for both any PCa risk and significant PCa risk. In the repeat PBx group, RC4 tended to underestimate outcomes for PCa and showed moderate calibration for significant PCa. DCA showed an overall net benefit compared with PSA and digital rectal examination (DRE) alone. Limitations of this study are its retrospective single-institution design, retrospectively assessed DRE outcomes, no time restrictions between the first and repeat biopsy sessions, and no anterior sampling in the repeat PBx protocol. CONCLUSIONS: The ERSPC RCs performed well in a contemporary clinical setting. Most pronounced in the biopsy-naive group, both RCs should be favoured over a PSA plus DRE-based stratification in the decision whether or not to perform PBx. PATIENT SUMMARY: We looked at the ability of the existing European Randomized Study of Screening for Prostate Cancer risk calculator (RC), using different clinical data to predict the presence of prostate cancer in Dutch men. The RC performed well and should be favoured in the decision of whether or not to perform prostate biopsies over the conventional diagnostic pathway.

Prostate Cancer Risk Assessment in Biopsy-naïve Patients: The Rotterdam Prostate Cancer Risk Calculator in Multiparametric Magnetic Resonance Imaging-Transrectal Ultrasound (TRUS) Fusion Biopsy and Systematic TRUS Biopsy.

BACKGROUND: The value of multiparametric magnetic resonance imaging (mpMRI) and targeted biopsy (TBx) remains controversial for biopsy-naïve men when compared to transrectal ultrasound (TRUS)-guided systematic biopsy (SBx). Risk-based patient selection could help to selectively identify men with significant prostate cancer (PCa) and thus reduce unnecessary mpMRI and biopsies. OBJECTIVES: To compare PCa detection rates for mpMRI TBx with SBx and to determine the rate of potentially avoided mpMRI and biopsies through risk-based selection using the Rotterdam Prostate Cancer Risk Calculator (RPCRC). DESIGN, SETTING, AND PARTICIPANTS: Two-hundred consecutive biopsy-naïve men in two centres underwent mpMRI scanning, 12-core SBx, and subsequent MRI-TRUS TBx in the case of suspicious lesion(s) (Prostate Imaging-Reporting and Data System v.2 score ≥3). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured the detection rate for high-grade (Gleason score ≥ 3+4) PCa for TBx and SBx. We carried out a retrospective stratification according to RPCRC biopsy advice to determine the rate of mpMRI and biopsies that could potentially be avoided by RPCRC-based patient selection in relation to the rate of high-grade PCa missed. RESULTS AND LIMITATIONS: TBx yielded high-grade PCa in 51 men (26%) and low-grade PCa in 14 men (7%), while SBx yielded high-grade PCa in 63 men (32%) and low-grade PCa in 41 men (21%). Four out of 73 men (5%) with negative RPCRC advice and 63 out of 127 men (50%) with positive advice had high-grade PCa. Upfront RPCRC-based patient selection for mpMRI and TBx would have avoided 73 out of 200 (37%) mpMRI scans, missing two out of 51 (4%) high-grade PCas. Limitations include the RPCRC definition of high- and low-grade PCa and different mpMRI techniques. CONCLUSIONS: mpMRI with TBx detected PCa with high Gleason score and avoided biopsy in low-grade PCa, but failed to detect all high-grade PCa when compared to SBx among biopsy-naïve men. Risk-based patient selection using the RPCRC can avoid one-third of mpMRI scans and SBx in biopsy-naïve men. PATIENT SUMMARY: Men with a suspicion of prostate cancer are increasingly undergoing a magnetic resonance imaging (MRI) scan. Although promising, MRI-targeted biopsy is not accurate enough to safely replace systematic prostate biopsy for now. Individualised assessment of prostate cancer risk using the Rotterdam Prostate Cancer Risk Calculator could avoid one-third of MRI scans and systematic prostate biopsies.

First-in-Human Ultrasound Molecular Imaging With a VEGFR2-Specific Ultrasound Molecular Contrast Agent (BR55) in Prostate Cancer: A Safety and Feasibility Pilot Study.

OBJECTIVE: BR55, a vascular endothelial growth factor receptor 2 (VEGFR2)-specific ultrasound molecular contrast agent (MCA), has shown promising results in multiple preclinical models regarding cancer imaging. In this first-in-human, phase 0, exploratory study, we investigated the feasibility and safety of the MCA for the detection of prostate cancer (PCa) in men using clinical standard technology. MATERIALS AND METHODS: Imaging with the MCA was performed in 24 patients with biopsy-proven PCa scheduled for radical prostatectomy using a clinical ultrasound scanner at low acoustic power. Safety monitoring was done by physical examination, blood pressure and heart rate measurements, electrocardiogram, and blood sampling. As first-in-human study, MCA dosing and imaging protocol were necessarily fine-tuned along the enrollment to improve visualization. Imaging data were correlated with radical prostatectomy histopathology to analyze the detection rate of ultrasound molecular imaging with the MCA. RESULTS: Imaging with MCA doses of 0.03 and 0.05 mL/kg was adequate to obtain contrast enhancement images up to 30 minutes after administration. No serious adverse events or clinically meaningful changes in safety monitoring data were identified during or after administration. BR55 dosing and imaging were fine-tuned in the first 12 patients leading to 12 subsequent patients with an improved MCA dosing and imaging protocol. Twenty-three patients underwent radical prostatectomy. A total of 52 lesions were determined to be malignant by histopathology with 26 (50%) of them seen during BR55 imaging. In the 11 patients that were scanned with the improved protocol and underwent radical prostatectomy, a total of 28 malignant lesions were determined: 19 (68%) were seen during BR55 ultrasound molecular imaging, whereas 9 (32%) were not identified. CONCLUSIONS: Ultrasound molecular imaging with BR55 is feasible with clinical standard technology and demonstrated a good safety profile. Detectable levels of the MCA can be reached in patients with PCa opening the way for further clinical trials.