Adaptation of a Clinical High-Frequency Transrectal Ultrasound System for Prostate Photoacoustic Imaging: Implementation and Pre-clinical Demonstration.

OBJECTIVE: High-frequency, high-resolution transrectal micro-ultrasound (micro-US: ≥15 MHz) imaging of the prostate is emerging as a beneficial tool for scoring disease risk and accurately targeting biopsies. Adding photoacoustic (PA) imaging to visualize abnormal vascularization and accumulation of contrast agents in tumors has potential for guiding focal therapies. In this work, we describe a new imaging platform that combines a transrectal micro-US system with transurethral light delivery for PA imaging. METHODS: A clinical transrectal micro-US system was adapted to acquire PA images synchronous to a tunable laser pulse. A transurethral side-firing optical fiber was developed for light delivery. A polyvinyl chloride (PVC)-plastisol phantom was developed and characterized to image PA contrast agents in wall-less channels. After resolution measurement in water, PA imaging was demonstrated in phantom channels with dyes and biodegradable nanoparticle contrast agents called porphysomes. In vivo imaging of a tumor model was performed, with porphysomes administered intravenously. RESULTS: Photoacoustic imaging data were acquired at 5 Hz, and image reconstruction was performed offline. PA image resolution at a 14-mm depth was 74 and 261 µm in the axial and lateral directions, respectively. The speed of sound in PVC-plastisol was 1383 m/s, and the attenuation was 4 dB/mm at 20 MHz. PA signal from porphysomes was spectrally unmixed from blood signals in the tumor, and a signal increase was observed 3 h after porphysome injection. CONCLUSION: A combined transrectal micro-US and PA imaging system was developed and characterized, and in vivo imaging demonstrated. High-resolution PA imaging may provide valuable additional information for diagnostic and therapeutic applications in the prostate.

Development and Characterization of 99mTc-scFvD2B as a Potential Radiopharmaceutical for SPECT Imaging of Prostate Cancer.

Previously, we demonstrated that the 177Lu-labeled single-chain variable fragment of an anti-prostate-specific membrane antigen (PSMA) IgG D2B antibody (scFvD2B) showed higher prostate cancer (PCa) cell uptake and tumor radiation doses compared to 177Lu-labeled Glu-ureide-based PSMA inhibitory peptides. To obtain a 99mTc-/177Lu-scFvD2B theranostic pair, this research aimed to synthesize and biochemically characterize a novel 99mTc-scFvD2B radiotracer. The scFvD2B-Tag and scFvD2B antibody fragments were produced and purified. Then, two HYNIC derivatives, HYNIC-Gly-Gly-Cys-NH2 (HYNIC-GGC) and succinimidyl-HYNIC (S-HYNIC), were used to conjugate the scFvD2B-Tag and scFvD2B isoforms, respectively. Subsequently, chemical characterization, immunoreactivity tests (affinity and specificity), radiochemical purity tests, stability tests in human serum, cellular uptake and internalization in LNCaP(+), PC3-PIP(++) or PC3(-) PCa cells of the resulting unlabeled HYNIC-scFvD2B conjugates (HscFv) and 99mTc-HscFv agents were performed. The results showed that incorporating HYNIC as a chelator did not affect the affinity, specificity or stability of scFvD2B. After purification, the radiochemical purity of 99mTc-HscFv radiotracers was greater than 95%. A two-sample t-test of 99mTc-HscFv1 and 99mTc-HscFv1 uptake in PC3-PIP vs. PC3 showed a p-value < 0.001, indicating that the PSMA receptor interaction of 99mTc-HscFv agents was statistically significantly higher in PSMA-positive cells than in the negative controls. In conclusion, the results of this research warrant further preclinical studies to determine whether the in vivo pharmacokinetics and tumor uptake of 99mTc-HscFv still offer sufficient advantages over HYNIC-conjugated peptides to be considered for SPECT/PSMA imaging.

Characterizing Prostate-Specific Antigen Levels at Death in Patients with Metastatic Castration-Resistant Prostate Cancer: Are We Underutilizing Imaging?

BACKGROUND: Prostate-specific antigen (PSA) is a valuable prognostic and predictive biomarker in prostate cancer; however, the significance of PSA at or near the time of death is not well understood. This study aimed to characterize the significance of PSA at death in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: The Mount Sinai Genitourinary Cancer Biorepository, an institutional review board-approved, single-institution database containing all consented genitourinary cancer patients seen between 2010 and 2018, was used to identify and stratify patients into the following cohorts based on their PSA at or near death: <100 ng/mL, 100-1000 ng/mL, and >1000 ng/mL. Analyses were performed to assess clinical characteristics of disease, treatment response, and outcomes. RESULTS: We identified 1097 patients with prostate cancer, and 101 were confirmed to be deceased following a diagnosis of mCRPC. In patients with mCRPC, cohorts of higher PSA level at death were associated with lower Gleason score at diagnosis and a trend toward longer time to mCRPC and longer time from diagnosis to death, despite a higher burden of disease at death. Conversely, subgroup analysis of PSA < 10 ng/mL at death was associated with lower rates of imaging within 6 months of death, lower treatment rate, and worse clinical outcomes. CONCLUSIONS: Cohorts of different PSA levels at death in mCRPC patients showed distinct patterns of disease characteristics and clinical outcomes, likely due to the underlying molecular phenotype differences. Imaging for the patient population with very low PSA levels may be underutilized and should be considered more routinely.

Distortion-free 3D diffusion imaging of the prostate using a multishot diffusion-prepared phase-cycled acquisition and dictionary matching.

PURPOSE: To achieve three-dimensional (3D) distortion-free apparent diffusion coefficient (ADC) maps for prostate imaging using a multishot diffusion prepared-gradient echo (msDP-GRE) sequence and ADC dictionary matching. METHODS: The msDP-GRE sequence is combined with a 3D Cartesian, centric k-space trajectory with center oversampling. Oversampled k-space center averaging and phase cycling are used to address motion- and eddy current-induced magnitude corruption. Extended-phase-graph (EPG) simulations and ADC dictionary matching are used to compensate for T1 effects. To shorten the acquisition time, each volume is undersampled by a factor of two and reconstructed using iterative sensitivity encoding. The proposed approach is characterized using simulations and validated in a kiwifruit phantom, comparing the msDP-GRE ADC maps obtained using both standard monoexponential fitting and dictionary matching with the clinical standard single-shot diffusion weighted-echo planar imaging (ssDW-EPI) ADC. Initial in vivo feasibility is tested in three healthy subjects, and geometric distortion is compared with anatomical T2 -weighted-turbo spin echo. RESULTS: In the kiwifruit phantom experiment, the signal magnitude could be recovered using k-space center averaging and phase cycling. No statistically significant difference was observed in the ADC values estimated using msDP-GRE with dictionary matching and clinical standard DW-EPI (P < .05). The in vivo prostate msDP-GRE scans were free of geometric distortion caused by off-resonance susceptibility, and the ADC values in the prostate were in agreement with values found in the published literature. CONCLUSION: Nondistorted 3D ADC maps of the prostate can be achieved using a msDP sequence and dictionary matching.

Combined Intravenous Urogram and 68Ga-PSMA PET/ CT for Improved Staging and Restaging of Prostate Cancer.

Staging/restaging of prostate cancer utilizing Gallium-68 (68Ga) prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in combination with an intravenous urogram allows improved discrimination between radiotracer activity in the renal tract and small pelvic nodes or local recurrences. Within this pictorial essay, we describe the imaging protocol utilized at our institution and present cases which demonstrate the utility of this combined imaging approach.

Positron emission tomography (PET) radiotracers for prostate cancer imaging.

Imaging plays an increasing role in prostate cancer diagnosis and staging. Accurate staging of prostate cancer is required for optimal treatment planning. In detecting extraprostatic cancer and sites of early recurrence, traditional imaging methods (computed tomography, magnetic resonance imaging, radionuclide bone scan) have suboptimal performance. This leaves a gap between known disease recurrence as indicated by rising prostate-specific antigen and the ability to localize the recurrence on imaging. Novel positron emission tomography (PET) agents including radiolabeled choline, fluciclovine (18F-FACBC), and agents targeting prostate-specific membrane antigen are being developed and tested to increase diagnostic performance of non-invasive prostate cancer localization. When combined with CT or MRI, these tracers offer a combination of functional information and anatomic localization that is superior to conventional imaging methods. These PET radiotracers have varying mechanisms and excretion patterns affecting their pharmacokinetics and diagnostic performance, which will be reviewed in this article.

[68Ga]Ga-P16-093 as a PSMA-Targeted PET Radiopharmaceutical for Detection of Cancer: Initial Evaluation and Comparison with [68Ga]Ga-PSMA-11 in Prostate Cancer Patients Presenting with Biochemical Recurrence.

PURPOSE: This study was undertaken to evaluate radiation dosimetry for the prostate-specific membrane antigen targeted [68Ga]Ga-P16-093 radiopharmaceutical, and to initially assess agent performance in positron emission tomography (PET) detection of the site of disease in prostate cancer patients presenting with biochemical recurrence. PROCEDURES: Under IND 133,222 and an IRB-approved research protocol, we evaluated the biodistribution and pharmacokinetics of [68Ga]Ga-P16-093 with serial PET imaging following intravenous administration to ten prostate cancer patients with biochemical recurrence. The recruited subjects were all patients in whom a recent [68Ga]Ga-PSMA-11 PET/X-ray computed tomography (CT) exam had been independently performed under IND 131,806 to assist in decision-making with regard to their clinical care. Voided urine was collected from each subject at ~ 60 min and ~ 140 min post-[68Ga]Ga-P16-093 injection and assayed for Ga-68 content. Following image segmentation to extract tissue time-activity curves and corresponding cumulated activity values, radiation dosimetry estimates were calculated using IDAC Dose 2.1. The prior [68Ga]Ga-PSMA-11 PET/CT exam (whole-body PET imaging at 60 min post-injection, performed with contrast-enhanced diagnostic CT) served as a reference scan for comparison to the [68Ga]Ga-P16-093 findings. RESULTS: [68Ga]Ga-P16-093 PET images at 60 min post-injection provided diagnostic information that appeared equivalent to the subject's prior [68Ga]Ga-PSMA-11 scan. With both radiopharmaceuticals, sites of tumor recurrence were found in eight of the ten patients, identifying 16 lesions. The site of recurrence was not detected with either agent for the other two subjects. Bladder activity was consistently lower with [68Ga]Ga-P16-093 than [68Ga]Ga-PSMA-11. The kidneys, spleen, salivary glands, and liver receive the highest radiation exposure from [68Ga]Ga-P16-093, with estimated doses of 1.7 × 10-1, 6.7 × 10-2, 6.5 × 10-2, and 5.6 × 10-2 mGy/MBq, respectively. The corresponding effective dose from [68Ga]Ga-P16-093 is 2.3 × 10-2 mSv/MBq. CONCLUSIONS: [68Ga]Ga-P16-093 provided diagnostic information that appeared equivalent to [68Ga]Ga-PSMA-11 in this limited series of ten prostate cancer patients presenting with biochemical recurrence, with the kidneys found to be the critical organ. Diminished tracer appearance in the urine represents a potential advantage of [68Ga]Ga-P16-093 over [68Ga]Ga-PSMA-11 for detection of lesions in the pelvis.

A cohort of transperineal electromagnetically tracked magnetic resonance imaging/ultrasonography fusion-guided biopsy: assessing the impact of inter-reader variability on cancer detection.

OBJECTIVE: To evaluate the ability to detect clinically significant prostate cancer (PCa) using a novel electromagnetically (EM) tracked transperineal magnetic resonance imaging (MRI)/ultrasonography (US) fusion-guided targeted biopsy (transperineal TBx) platform and the impact of inter-reader variability on cancer detection. MATERIALS AND METHODS: A total of 176 patients with suspicious lesions detected on multiparametric MRI (mpMRI) underwent a systematic modified Barzel template biopsy (12-core) transperineal biopsy (transperineal SBx) and transperineal TBx with EM tracking (UroNav; Philips Healthcare, Best, the Netherlands) in the same setting. Cancer detection rates (CDRs) were stratified by Prostate Imaging Reporting and Data System (PI-RADS) v2 scores and compared with Fisher's exact test. Area under the curve (AUC) was calculated for prostate-specific antigen (PSA), PSA density (PSAD), PI-RADS score, and subgroup analysis of individual readers' PI-RADS scores with respect to overall CDR and clinically significant CDR. RESULTS: The overall CDR was 76.7% (135/176), of which 76.3% (103/135) was clinically significant PCa. Among the 135 patients with PCa, transperineal TBx detected 90.4% of cases (122/135), either alone or in combination with transperineal SBx. The remaining 9.6% of cases (13/135) missed by transperineal TBx were diagnosed by transperineal SBx alone, of which three were clinically significant. Conversely, transperineal SBx missed 14% of cases (19/135), 14 of which were clinically significant PCa. Sensitivities for transperineal TBx and transperineal SBx were 90.4% and 85.9%, respectively. On a per-lesion basis, PI-RADS score (AUC 0.74) outperformed both PSA (AUC 0.59) and PSAD (AUC 0.63) in discriminating clinically significant from non-clinically significant PCa on transperineal TBx. Although not formally statistically tested, AUCs amongst different mpMRI readers appeared to display considerable variability. There were no adverse events, including sepsis. CONCLUSIONS: Electromagnetically tracked transperineal TBx of MRI-visible lesions enhanced the ability of transperineal SBx to detect PCa, with greater sensitivity for clinically significant disease. These findings suggest transperineal TBx is a safe, alternative fusion platform for patients with a suspicious lesion on prostate MRI. The assessment of inter-reader variability, in conjunction with prediction of clinically significant PCa and CDR, is an important first step for quality control in implementing an MRI-based screening programme.

Novel Imaging in Detection of Metastatic Prostate Cancer.

PURPOSE OF REVIEW: This review aims to highlight the limitations of current standard-of-care prostate cancer (PCa) imaging and discuss novel clinical imaging in advanced disease. RECENT FINDINGS: PCa staging through imaging is important for proper selections in clinical treatment. Traditional imaging techniques for metastatic disease (i.e., computed tomography [CT], magnetic resonance imaging [MRI], and radionuclide bone scan) have suboptimal performance in early recurrent or metastatic disease. Novel positron emission tomography agents including radiolabeled prostate specific membrane antigen (PSMA), choline, and anti-18F-fluorocyclobutane-1-carboxylic acid (18F-FACBC) have demonstrated improved sensitivity and specificity in initial staging and early biochemical recurrence (BCR). Conventional imaging modalities for PCa incompletely characterize disease burden. The development of new PET tracers in combination with CT and MRI offers superior anatomic localization and biologic correlation of tumor sites, which enhance providers' abilities to make appropriate decisions regarding treatment.

Impact of sodium 18F-fluoride PET/CT, 18F-fluorocholine PET/CT and whole-body diffusion-weighted MRI on the management of patients with prostate cancer suspicious for metastasis: a prospective multicentre study.

PURPOSE: To compare the impact of 18F-sodium-fluoride (NaF) PET/CT, 18F-fluorocholine (FCH) PET/CT and diffusion-weighted whole-body MRI (DW-MRI) on the management of patients with prostate cancer (PCa) suspicious for distant metastasis. METHODS: Prostate cancer patients were prospectively included between December 2011 and August 2014 and benefited from these three whole-body imaging (WBI) modalities within 1 month in addition to the standard PCa workup. Management was prospectively decided by clinicians during two multidisciplinary meetings, before and after the whole-body imaging workup. Rates of induced changes of whole-body imaging modalities were compared by Cochran's Q test. RESULTS: One-hundred-one patients (27 at staging, 59 at first biochemical recurrence (BCR) and 15 at first episode of rising serum level of prostate-specific antigen during androgen-deprivation therapy) were included. The overall rate of management changes was 52%: 29% as a consequence of WBI, higher for FCH-PET/CT than for NaF-PET/CT or DW-MRI (p < 0.0001) and highest (41%) for FCH-PET/CT at BCR. Actual management was adequate in all patients but two. CONCLUSIONS: Whole-body imaging induced a change in management in approximately a third of PCa patients suspicious for metastasis. The impact rate was determined to be greatest at first BCR using FCH-PET/CT. NaF-PET/CT and DW-MRI seemed less useful in this context.

Accelerated 3D T2 mapping with dictionary-based matching for prostate imaging.

PURPOSE: To develop a fast and accurate method for 3D T2 mapping of prostate cancer using undersampled acquisition and dictionary-based fitting. METHODS: 3D high-resolution T2 -weighted images (0.9 × 0.9 × 3 mm3 ) were obtained with a multishot T2 -prepared balanced steady-state free precession (T2 -prep-bSSFP) acquisition sequence using a 3D variable density undersampled Cartesian trajectory. Each T2 -weighted image was reconstructed using total variation regularized sensitivity encoding. A flexible simulation framework based on extended phase graphs generated a dictionary of magnetization signals, which was customized to the proposed sequence. The dictionary was matched to the acquired T2 -weighted images to retrieve quantitative T2 values, which were then compared to gold-standard spin echo acquisition values using monoexponential fitting. The proposed approach was validated in simulations and a T1 /T2 phantom, and feasibility was tested in 8 healthy subjects. RESULTS: The simulation analysis showed that the proposed T2 mapping approach is robust to noise and typically observed T1 variations. T2 values obtained in the phantom with T2 prep-bSSFP and the acquisition-specific, dictionary-based matching were highly correlated with the gold-standard spin echo method (r = 0.99). Furthermore, no differences were observed with the accelerated acquisition compared to the fully sampled acquisition (r = 0.99). T2 values obtained in prostate peripheral zone, central gland, and muscle in healthy subjects (age, 26 ± 6 years) were 97 ± 14, 76 ± 7, and 36 ± 3 ms, respectively. CONCLUSION: 3D quantitative T2 mapping of the whole prostate can be achieved in 3 minutes.

Synthesis and preclinical evaluation of novel 18F-labeled Glu-urea-Glu-based PSMA inhibitors for prostate cancer imaging: a comparison with 18F-DCFPyl and 18F-PSMA-1007.

BACKGROUND: Due to its high and consistent expression in prostate cancer (PCa), the prostate-specific membrane antigen (PSMA) represents an ideal target for molecular imaging and targeted therapy using highly specific radiolabeled PSMA ligands. To address the continuously growing clinical demand for 18F-labeled PSMA-probes, we developed two novel Glu-urea-Glu-(EuE)-based inhibitors, EuE-k-18F-FBOA (1) and EuE-k-ß-a-18F-FPyl (2), both with optimized linker structure and different 18F-labeled aromatic moieties. The inhibitors were evaluated in a comparative preclinical study with 18F-DCFPyl and 18F-PSMA-1007. RESULTS: Radiolabeling procedures allowed preparation of (1) and (2) with high radiochemical yields (67 ± 7 and 53 ± 7%, d.c.) and purity (> 98%). When compared with 18F-DCFPyl (IC50 = 12.3 ± 1.2 nM) and 18F-PSMA-1007 (IC50 = 4.2 ± 0.5 nM), both metabolically stable EuE-based ligands showed commensurable or higher PSMA affinity (IC50 = 4.2 ± 0.4 nM (1), IC50 = 1.1 ± 0.2 nM (2)). Moreover, 1.4- and 2.7-fold higher internalization rates were observed for (1) and (2), respectively, resulting in markedly enhanced tumor accumulation in LNCaP-tumor-bearing mice ((1) 12.7 ± 2.0% IA/g, (2) 13.0° ± 1.0% IA/g vs. 7.3 ± 1.0% IA/g (18F-DCFPyl), 7.1 ± 1.5% IA/g (18F-PSMA-1007), 1 h p.i.). In contrast to (1), (2) showed higher kidney accumulation and delayed clearance kinetics. Due to the high hydrophilicity of both compounds, almost no unspecific uptake in non-target tissue was observed. In contrast, due to the less hydrophilic character (logP = - 1.6) and high plasma protein binding (98%), 18F-PSMA-1007 showed uptake in non-target tissue and predominantly hepatobiliary excretion, whereas, 18F-DCFPyl exhibited pharmacokinetics quite similar to those obtained with (1) and (2). CONCLUSION: Both 18F-labeled EuE-based PSMA ligands showed excellent in vitro and in vivo PSMA-targeting characteristics. The substantially higher tumor accumulation in mice compared to recently introduced 18F-PSMA-1007 and 18F-DCFPyl suggests their high value for preclinical studies investigating the effects on PSMA-expression. In contrast to (2), (1) seems to be more promising for further investigation, due to the more reliable 18F-labeling procedure, the faster clearance kinetics with comparable high tumor uptake, resulting therefore in better high-contrast microPET imaging as early as 1 h p.i.

3-D Quantitative Dynamic Contrast Ultrasound for Prostate Cancer Localization.

To investigate quantitative 3-D dynamic contrast-enhanced ultrasound (DCE-US) and, in particular 3-D contrast-ultrasound dispersion imaging (CUDI), for prostate cancer detection and localization, 43 patients referred for 10-12-core systematic biopsy underwent 3-D DCE-US. For each 3-D DCE-US recording, parametric maps of CUDI-based and perfusion-based parameters were computed. The parametric maps were divided in regions, each corresponding to a biopsy core. The obtained parameters were validated per biopsy location and after combining two or more adjacent regions. For CUDI by correlation (r) and for the wash-in time (WIT), a significant difference in parameter values between benign and malignant biopsy cores was found (p < 0.001). In a per-prostate analysis, sensitivity and specificity were 94% and 50% for r, and 53% and 81% for WIT. Based on these results, it can be concluded that quantitative 3-D DCE-US could aid in localizing prostate cancer. Therefore, we recommend follow-up studies to investigate its value for targeting biopsies.

Performance of a fast and high-resolution multi-echo spin-echo sequence for prostate T2 mapping across multiple systems.

PURPOSE: To evaluate the performance of a multi-echo spin-echo sequence with k-t undersampling scheme (k-t T2 ) in prostate cancer. METHODS: Phantom experiments were performed at five systems to estimate the bias, short-term repeatability, and reproducibility across all systems expressed with the within-subject coefficient of variation (wCV). Monthly measurements were performed on two systems for long-term repeatability estimation. To evaluate clinical repeatability, two T2 maps (voxel size 0.8 × 0.8 × 3 mm3 ; 5 min) were acquired at separate visits on one system for 13 prostate cancer patients. Repeatability was assessed per patient in relation to spatial resolution. T2 values were compared for tumor, peripheral zone, and transition zone. RESULTS: Phantom measurements showed a small bias (median = -0.9 ms) and good short-term repeatability (median wCV = 0.5%). Long-term repeatability was 0.9 and 1.1% and reproducibility between systems was 1.7%. The median bias observed in patients was -1.1 ms. At voxel level, the median wCV was 15%, dropping to 4% for structures of 0.5 cm3 . The median tumor T2 values (79 ms) were significantly lower (P < 0.001) than in the peripheral zone (149 ms), but overlapped with the transition zone (91 ms). CONCLUSIONS: Reproducible T2 mapping of the prostate is feasible with good spatial resolution in a clinically reasonable scan time, allowing reliable measurement of T2 in structures as small as 0.5 cm3 . Magn Reson Med 79:1586-1594, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

The prostate cancer detection rates of CEUS-targeted versus MRI-targeted versus systematic TRUS-guided biopsies in biopsy-naïve men: a prospective, comparative clinical trial using the same patients.

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.

Clinical translation of a PSMA inhibitor for 99mTc-based SPECT.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is highly over-expressed in advanced prostate cancers. 68Ga-labeled PSMA inhibitors (iPSMA) are currently used for prostate cancer detection by PET imaging. The availability of simple, efficient and reproducible radiolabeling procedures is essential for developing new SPECT radiopharmaceuticals for clinical translation. The aim of this research was to prepare 99mTc-EDDA/HYNIC-Lys(Nal)-Urea-Glu (99mTc-EDDA/HYNIC-iPSMA) obtained from lyophilized kit formulations and evaluate the in vitro and in vivo radiopharmaceutical binding to prostate cancer cells over-expressing PSMA, as well as the 99mTc-EDDA/HYNIC-iPSMA normal biodistribution in humans and the preliminary uptake in patients with prostate cancer. METHODS: 99mTc labeling was performed by adding sodium pertechnetate solution and a 0.2M phosphate buffer (pH 7.0) to a lyophilized formulation containing HYNIC-iPSMA, EDDA, tricine, mannitol and stannous chloride. The radiochemical purity was evaluated by reversed-phase HPLC and ITLC-SG analyses. Stability studies in human serum were performed by size-exclusion HPLC. In vitro cell uptake was tested using prostate cancer cells (LNCaP) with blocked and non-blocked receptors. Biodistribution and tumor uptake were determined in LNCaP tumor-bearing nude mice with blocked and non-blocked receptors, and images were obtained using a micro-SPECT/CT. Whole-body images from three healthy men and two patients with histologically-confirmed prostate cancer (one of them with a previous 68Ga-PSMA-617scan) were acquired at 1h and 3h after 99mTc-EDDA/HYNIC-iPSMA administration with radiochemical purities of >98%. RESULTS: In vitro and in vivo studies showed high radiopharmaceutical stability in human serum, specific recognition for PSMA, high tumor uptake (10.22±2.96% ID/g at 1h) with rapid blood clearance and mainly kidney elimination. Preliminary images in patients demonstrated the ability of 99mTc-EDDA/HYNIC-iPSMA to detect tumors and metastases of prostate cancer as well as 68Ga-PSMA-617 does. CONCLUSIONS: The results obtained in this study warrant further dosimetry and clinical studies to determine the specificity and sensitivity of 99mTc-EDDA/HYNIC-iPSMA.

First-in-Human Imaging with 89Zr-Df-IAB2M Anti-PSMA Minibody in Patients with Metastatic Prostate Cancer: Pharmacokinetics, Biodistribution, Dosimetry, and Lesion Uptake.

We conducted a phase I dose-escalation study with 89Zr-desferrioxamine-IAB2M (89Zr-IAB2M), an anti-prostate-specific membrane antigen minibody, in patients with metastatic prostate cancer. METHODS: Patients received 185 MBq (5 mCi) of 89Zr-IAB2M and Df-IAB2M at total mass doses of 10 (n = 6), 20 (n = 6), and 50 mg (n = 6). Whole-body and serum clearance, normal-organ and lesion uptake, and radiation absorbed dose were estimated, and the effect of mass escalation was analyzed. RESULTS: Eighteen patients were injected and scanned without side effects. Whole-body clearance was monoexponential, with a median biologic half-life of 215 h, whereas serum clearance showed biexponential kinetics, with a median biologic half-life of 3.7 (12.3%/L) and 33.8 h (17.9%/L). The radiation absorbed dose estimates were 1.67, 1.36, and 0.32 mGy/MBq to liver, kidney, and marrow, respectively, with an effective dose of 0.41 mSv/MBq (1.5 rem/mCi). Both skeletal and nodal lesions were detected with 89Zr-IAB2M, most visualized by 48-h imaging. CONCLUSION: 89Zr-IAB2M is safe and demonstrates favorable biodistribution and kinetics for targeting metastatic prostate cancer. Imaging with 10 mg of minibody mass provides optimal biodistribution, and imaging at 48 h after injection provides good lesion visualization. Assessment of lesion targeting is being studied in detail in an expansion cohort.

Co-administration of succinylated gelatine with a (99m)Tc-bombesin analogue, effects on pharmacokinetics and tumor uptake.

The bombesin analogue, [(99m)Tc-GGC]-(Ornithine)3-BN(2-14), (99m)Tc-BN-O, targeting gastrin releasing peptide receptors (GRPrs) on the surface of tumors, was pre-clinically investigated as potential imaging agent for single photon emission computed tomography (SPECT). In addition, the improvement of its pharmacokinetic profile (PK) was investigated through the co-administration of a succinylated gelatin plasma expander (Gelofusine), aiming to reduce its kidney accumulation and enhance its tumor-to-normal tissue contrast ratios. Biodistribution data were collected from normal mice and rats, and PC-3 tumor bearing mice, in reference to its PK, metabolism and tumor uptake. Imaging data were also collected from PC-3 tumor bearing mice. Biodistribution and imaging experiments showed that (99m)Tc-BN-O was able to efficiently localize the tumor (5.23 and 7.00% ID/g at 30 and 60min post injection, respectively), while at the same time it was rapidly cleared from the circulation through the kidneys. HPLC analysis of kidney samples, collected at 60min p.i. from normal mice and rats, showed that the majority of radioactivity detected was due to intact peptide i.e. 56% for mice and 73% for rats. Co-administration of (99m)Tc-BN-O with Gelo resulted in the reduction of kidney uptake in both animal models. The integrated area under the curve (AUC30-60 min) from the concentration-time plots of kidneys was decreased in both mice and rats by 25 and 50%, respectively. In PC-3 tumor bearing mice, an increase of tumor uptake (AUCtumor increased by 69%) was also observed with Gelo. An improvement in tumor-to-blood and tumor-to-normal tissue ratios was noted in all cases with the exception of the pancreas, which normally expresses GRPr. The results of this preclinical study may also be extended to other similar peptides, which are utilized in prostate cancer imaging and present similar PK profile.

Rapid quantitative T2 mapping of the prostate using three-dimensional dual echo steady state MRI at 3T.

PURPOSE: To develop and evaluate a rapid three-dimensional (3D) quantitative T2 mapping method for prostate cancer imaging using dual echo steady state (DESS) MRI at 3T. METHODS: In simulations, DESS-T2 mapping in the presence of T1 and B1+ variations was evaluated. In a phantom and in healthy volunteers (n = 4), 3D DESS-T2 mapping was compared with a two-dimensional turbo spin echo (TSE) approach. In volunteers and a pilot patient study (n = 29), quantitative T2 in normal prostate anatomical zones and in suspected cancerous lesions was evaluated. RESULTS: The simulated bias for DESS-T2 was < 2% (5%) for typically observed T1 ( B1+) variations. In phantoms and in vivo, high correlation of DESS-T2 and TSE-T2 (r2 = 0.98 and 0.88, P < 0.001) was found. DESS-T2 in the normal peripheral zone and transition zone was 115 ± 26 ms and 64 ± 7 ms, respectively, in healthy volunteers and 129 ± 39 ms and 83 ± 12 ms, respectively, in patients. In suspected cancerous lesions, DESS-T2 was 72 ± 14 ms, which was significantly decreased from the normal peripheral zone (P < 0.001) but not from the transition zone. CONCLUSION: Rapid 3D T2 mapping in the entire prostate can be performed in 1 min using DESS MRI. Magn Reson Med 76:1720-1729, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

Dynamic contrast-enhanced ultrasound parametric imaging for the detection of prostate cancer.

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.