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Opinion statement: PSMA-PET has been a practice-changing imaging biomarker for the management of men with PCa. Research suggests improved accuracy over conventional imaging and other PET radiotracers in many contexts. With multiple approved PSMA-targeting radiotracers, PSMA PET will become even more available in clinical practice. Its increased use requires an understanding of the prospective data available and caution when extrapolating from prior trial data that utilized other imaging modalities. Future trials leveraging PSMA PET for treatment optimization and management decision-making will ultimately drive its clinical utility. [ABSTRACT FROM AUTHOR]

Purpose of Review: Multimodality therapy including radical prostatectomy, radiation therapy, and hormone therapy are frequently deployed in the management of localized prostate cancer. We sought to perform a critical appraisal of the most contemporary literature focusing on the multimodality management of localized prostate cancer. Recent Findings: Men who are ideal candidates for multimodality therapy include those with unfavorable intermediate-risk disease, high-risk disease, and very high-risk disease. Enhancements in both systemic agents (including second-generation antiandrogens) as well as localized therapies (such as stereotactic body radiotherapy and brachytherapy) are refining the optimal balance between the use of systemic and local therapies for localized prostate cancer. Genomic predictors are emerging as critical tools for more precisely allocating treatment intensification with multimodality therapies as well as treatment de-intensification. Summary: Close collaboration among medical oncologists, surgeons, and radiation oncologists will be critical for coordinating evidence-based multimodality therapies when clearly indicated and for supporting shared decision-making in areas where the evidence is mixed. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed at developing dictionary learning (DL) based compressed sensing (CS) reconstruction for randomly undersampled five-dimensional (5D) MR Spectroscopic Imaging (3D spatial + 2D spectral) data acquired in prostate cancer patients and healthy controls, and test its feasibility at 8x and 12x undersampling factors. Materials and methods: Prospectively undersampled 5D echo-planar J-resolved spectroscopic imaging (EP-JRESI) data were acquired in nine prostate cancer (PCa) patients and three healthy males. The 5D EP-JRESI data were reconstructed using DL and compared with gradient sparsity-based Total Variation (TV) and Perona-Malik (PM) methods. A hybrid reconstruction technique, Dictionary Learning-Total Variation (DLTV), was also designed to further improve the quality of reconstructed spectra. Results: The CS reconstruction of prospectively undersampled (8x and 12x) 5D EP-JRESI data acquired in prostate cancer and healthy subjects were performed using DL, DLTV, TV and PM. It is evident that the hybrid DLTV method can unambiguously resolve 2D J-resolved peaks including myo-inositol, citrate, creatine, spermine and choline. Conclusion: Improved reconstruction of the accelerated 5D EP-JRESI data was observed using the hybrid DLTV. Accelerated acquisition of in vivo 5D data with as low as 8.33% samples (12x) corresponds to a total scan time of 14 min as opposed to a fully sampled scan that needs a total duration of 2.4 h (TR = 1.2 s, 32 k x ×16 k y ×8 k z , 512 t 2 and 64 t 1 ). [ABSTRACT FROM AUTHOR]

Purpose: We present an overview of the literature regarding the use of MRI in active surveillance of prostate cancer. Methods: Both MEDLINE® and Cochrane Library were queried up to May 2020 for studies of men on active surveillance with MRI and later confirmatory biopsy. The terms studied were 'prostate cancer' as the anchor followed by two of the following: active surveillance, surveillance, active monitoring, MRI, NMR, magnetic resonance imaging, MRI, and multiparametric MRI. Studies were excluded if pathologic reclassification (GG1 → ≥ GG2) and PI-RADS or equivalent was not reported. Results: Within active surveillance, baseline MRI is effective for identifying clinically significant prostate cancer and thus associated with fewer reclassification events. A positive initial MRI (≥ PI-RADS 3) with GG1 identified at biopsy has a positive predictive value (PPV) of 35–40% for reclassification by 3 years. MRI possessed a stronger negative predictive value, with a negative MRI (≤ PI-RADS 2) yielding a negative predictive value of up to 85% at 3 years. Surveillance MRI, obtained after initial biopsy, yielded a PPV of 11–65% and NPV of 85–95% for reclassification. Conclusion: MRI is useful for initial risk stratification of prostate cancer in men on active surveillance, especially if MRI is negative when imaging is obtained during surveillance. While useful, MRI cannot replace biopsy and further research is necessary to fully integrate MRI into active surveillance. [ABSTRACT FROM AUTHOR]

Purpose: Readers need to be informed about potential pitfalls of [68Ga]Ga-PSMA-11 PET interpretation. Methods: Here we report [68Ga]Ga-PSMA-11 PET findings discordant with the histopathology/composite reference standard in a recently published prospective trial on 635 patients with biochemically recurrent prostate cancer. Results: Consensus reads were false positive in 20 regions of 17/217 (8%) patients with lesion validation. Majority of the false positive interpretations (13 of 20, 65%) occurred in the context of suspected prostate (bed) relapse (T) after radiotherapy (n = 11); other false positive findings were noted for prostate bed post prostatectomy (T, n = 2), pelvic nodes (N, n = 2), or extra pelvic lesions (M, n = 5). Major sources of false positive findings were PSMA-expressing residual adenocarcinoma with marked post-radiotherapy treatment effect. False negative interpretation occurred in 8 regions of 6/79 (8%) patients with histopathology validation, including prostate (bed) (n = 5), pelvic nodes (n = 1), and extra pelvic lesions (n = 2). Lesions were missed mostly due to small metastases or adjacent bladder/urine uptake. Conclusion: [68Ga]Ga-PSMA-11 PET at biochemical recurrence resulted in less than 10% false positive interpretations. Post-radiotherapy prostate uptake was a major source of [68Ga]Ga-PSMA-11 PET false positivity. In few cases, PET correctly detects residual PSMA expression post-radiotherapy, originating however from treated, benign tissue or potentially indolent tumor remnants. Trial registration number: ClinicalTrials.gov Identifiers: NCT02940262 and NCT03353740. [ABSTRACT FROM AUTHOR]

Purpose: Radioimmunotherapy uses tumor-specific antibodies to deliver therapeutic radionuclides, but hematological toxicity due to the long serum half-life of intact antibodies remains a challenge. We evaluated a smaller antibody fragment, the minibody, with faster kinetics and a potentially improved therapeutic index. Procedures: The anti-prostate stem cell antigen (PSCA) minibody (A11 Mb) was radiolabeled with iodine-124 ([124I]I-A11 Mb) or conjugated with deferoxamine (DFO) and labeled with zirconium-89 ([89Zr]Zr-DFO-A11 Mb) for surrogate immunoPET to profile pharmacokinetics in a human prostate cancer xenograft model. Subsequently, minibodies labeled with two therapeutic beta emitters, directly iodinated [131I]I-A11 Mb (non-residualizing) and 177Lu chelated using DTPA ([177Lu]Lu-DTPA-A11 Mb) (residualizing), were compared for in vitro antigen-specific cytotoxicity. Full biodistribution studies (in 22Rv1-PSCA tumor bearing and hPSCA knock-in mice) were conducted for dosimetry calculations. Finally, the lead candidate [131I]I-A11 Mb was evaluated in a radioimmunotherapy experiment. Escalating single doses (3.7, 11, or 37 MBq) and saline control were administered to 22Rv1-PSCA tumor bearing mice and anti-tumor effects (tumor volume) and toxicity (body weight) were monitored. Results: Minibodies radiolabeled with therapeutic beta emitters [131I]I-A11 Mb and [177Lu]Lu-DTPA-A11 Mb exhibited comparable tumor cell growth inhibition in vitro. In vivo surrogate immunoPET imaging using [89Zr]Zr-DFO-A11 Mb showed activity retention in liver and kidney up to 72 h, while [124I]I-A11 Mb cleared from liver, kidney, and blood by 48 h. Based on full biodistribution and dosimetry calculations, administering 37 MBq [131I]I-A11 Mb was predicted to deliver a favorable dose to the tumor (35 Gy), with a therapeutic index of 22 (tumor:bone marrow). For [177Lu]Lu-DTPA-A11 Mb, the kidneys would be dose-limiting, and the maximum tolerated activity (7.4 MBq) was not predicted to deliver an effective radiation dose to tumor. Radioimmunotherapy with a single dose of [131I]I-A11 Mb showed dose-dependent tumor inhibition with minimal off-target toxicity and improved median survival (19 and 24 days, P < 0.001) compared with untreated mice (12 days). Conclusions: These findings show the potential of the anti-PSCA minibody for targeted radioimmunotherapy with minimal toxicity, and the application of immunoPET and dosimetry for personalized treatment. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the role of qualitative and quantitative DCE-MRI parameters in prostate cancer (PCa) stratified by whole-mount histopathology (WMHP) Gleason score (GS) and PI-RADSv2. Methods: This retrospective study included 323 PCa tumors in 254 men, who underwent 3T MRI prior to prostatectomy, 7/2009-12/2016. Qualitative DCE curve types included type 1 (progressive), type 2 (plateau) and type 3 (washout). Quantitative DCE-MRI pharmacokinetic (PK) parameters included Ktrans (influx volume transfer coefficient), Kep (efflux reflux rate constant) and iAUC (initial area under the curve). DCE-MRI features of true positive lesions were evaluated for overall, index, transition zone (TZ) and peripheral zone (PZ), based on GS grade (low = 6, high > 6) and PI-RADSv2 score using SPSSv24. Results: There were 57 (17.6%) low-grade and 266 (82.4%) high-grade PCa lesions. PI-RADSv2 3, 4 and 5 included 106, 120 and 97 lesions, respectively. 251 (77.7%) and 72 (22.3%) lesions were located in PZ and TZ, respectively. High-grade lesions had significantly higher proportion of Type 3 curves compared to low-grade lesions in overall (70.3% vs. 54.4%) and TZ (73.5% vs. 43.5%). As PI-RADSv2 increased, the proportion of type 3 curve significantly increased for overall (80.4–51.9%), index (80.4–54.7%) and PZ (78.7–52.1%) lesions. Among PK parameters, Ktrans (0.43 vs 0.32) and iAUC (8.99 vs 6.9) for overall PCa, Ktrans (0.43 vs 0.31) and iAUC (9 vs 6.67) for PZ PCa, and iAUC (8.94 vs 7.42) for index PCa were significantly higher for high-grade versus low-grade lesions. Also, Ktrans (0.51–0.34), Kep (1.75–1.29) and iAUC (9.79–7.6) for overall PCa, Ktrans (0.53–0.32), Kep (1.81–1.26) and iAUC (9.83–7.34) for PZ PCa; and Kep (1.79–1.17) and iAUC (11.3–8.45) for index PCa increased significantly with a higher PI-RADSv2 score. Conclusions: The results of study show the possible utility of qualitative and quantitative DCE-MRI parameters for assessment of PCa GS and PI-RADSv2 categorization. [ABSTRACT FROM AUTHOR]

Purpose: A great challenge in the diagnosis and treatment of prostate cancer is distinguishing between indolent or local disease and aggressive or metastatic disease. Antibody-based positron emission tomography (immuno-PET) as a cancer-specific imaging modality could improve diagnosis of primary disease, aid the detection of metastases to regional lymph nodes as well as to distant sites (e.g., bone), and monitor response to therapy.Procedure: In search for a more physiologically relevant disease model, a human prostate stem cell antigen knock-in (hPSCA KI) mouse model was generated. The use of a syngeneic prostate cancer cell line transduced to express human PSCA (RM-9-hPSCA) enabled the evaluation of anti-PSCA immuno-PET in immunocompetent mice and in the context of normal tissue expression of PSCA. Two PSCA-specific humanized antibody fragments, A11 minibody and A2 cys-diabody, were radiolabeled with positron emitters iodine-124 and zirconium-89, respectively ([124I]A11 Mb and [89Zr]A2cDb), and used for immuno-PET in wild-type, hPSCA KI and tumor-bearing mice.Results: The hPSCA KI mice express PSCA at low levels in the normal prostate, bladder and stomach, reproducing the expression pattern seen in humans. [124I]A11 Mb immuno-PET detected increased levels of PSCA expression in the stomach, and because I-124 is non-residualizing, very little activity was seen in organs of clearance (liver, kidney, spleen). However, due to the longer half-life of the 80 kDa protein, blood activity (and thus urine activity) at 20 h postinjection remains high. The smaller 50 kDa [89Zr]A2cDb cleared faster, resulting in lower blood and background activity, despite the use of a residualizing radiometal. Importantly, [89Zr]A2cDb immuno-PET showed antigen-specific targeting of PSCA-expressing tumors and minimal nonspecific uptake in PSCA-negative controls.Conclusion: Tracer biodistribution was not significantly impacted by normal tissue expression of PSCA. [89Zr]A2cDb immuno-PET yielded high tumor-to-blood ratio at early time points. Rapid renal clearance of the 50 kDa tracer resulted in an unobstructed view of the pelvic region at 20 h postinjection that would allow the detection of cancer in the prostate. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate 3T mpMRI characteristics of transition zone and peripheral zone index prostate cancer lesions stratified by Gleason Score and PI-RADSv2 with whole mount histopathology correlation.Methods: An institution review board-approved, HIPAA-compliant single-arm observational study of 425 consecutive men with 3T mpMRI prior to radical prostatectomy from December 2009 to October 2016 was performed. A genitourinary radiologist and a genitourinary pathologist matched all lesions detected on whole mount histopathology with lesions concordant for size and location on 3T mpMRI. Differences in clinical, MRI parameters, and histopathology between transition zone and peripheral zone were determined and analyzed with χ2 and Mann-Whitney U test. AUC was measured.Results: 3T mpMRI detected 248/323 (76.7%) index lesions in peripheral zone and 75/323 (23.2%) in transition zone. Transition zone prostate cancer had higher median prostate-specific antigen (p = 0.001), larger tumor on 3T mpMRI (p = 0.001), lower proportions of PI-RADSv2 category 4 and 5 (p < 0.001), and lower pathological stage (p = 0.055) compared to peripheral zone prostate cancer. No significant differences were detected in prostate-specific antigen density, preoperative biopsy, and pathology Gleason Scores. After adjusting for significant variables from univariate analysis including prostate volume, tumor volume, prostate-specific antigen, PI-RADSv2 category, AUC for predicting clinically significant tumor in transition zone and peripheral zone were 0.80 and 0.72, respectively (p = 0.36).Conclusions: The diagnostic performance of PI-RADSv2 for clinically significant transition and peripheral zone prostate cancer was similar. However, there was a lower portion of PI-RADSv2 4 and 5 lesions in transition zone compared to peripheral zone. [ABSTRACT FROM AUTHOR]

Purpose: We present a method for generating a T2 MR-based probabilistic model of tumor occurrence in the prostate to guide the selection of anatomical sites for targeted biopsies and serve as a diagnostic tool to aid radiological evaluation of prostate cancer.Materials and methods: In our study, the prostate and any radiological findings within were segmented retrospectively on 3D T2-weighted MR images of 266 subjects who underwent radical prostatectomy. Subsequent histopathological analysis determined both the ground truth and the Gleason grade of the tumors. A randomly chosen subset of 19 subjects was used to generate a multi-subject-derived prostate template. Subsequently, a cascading registration algorithm involving both affine and non-rigid B-spline transforms was used to register the prostate of every subject to the template. Corresponding transformation of radiological findings yielded a population-based probabilistic model of tumor occurrence. The quality of our probabilistic model building approach was statistically evaluated by measuring the proportion of correct placements of tumors in the prostate template, i.e., the number of tumors that maintained their anatomical location within the prostate after their transformation into the prostate template space.Results: Probabilistic model built with tumors deemed clinically significant demonstrated a heterogeneous distribution of tumors, with higher likelihood of tumor occurrence at the mid-gland anterior transition zone and the base-to-mid-gland posterior peripheral zones. Of 250 MR lesions analyzed, 248 maintained their original anatomical location with respect to the prostate zones after transformation to the prostate.Conclusion: We present a robust method for generating a probabilistic model of tumor occurrence in the prostate that could aid clinical decision making, such as selection of anatomical sites for MR-guided prostate biopsies. [ABSTRACT FROM AUTHOR]

The transition from androgen-dependent to castration-resistant prostate cancer (CRPC) is a lethal event of uncertain molecular etiology. Comparing gene expression in isogenic androgen-dependent and CRPC xenografts, we found a reproducible increase in N-cadherin expression, which was also elevated in primary and metastatic tumors of individuals with CRPC. Ectopic expression of N-cadherin in nonmetastatic, androgen-dependent prostate cancer models caused castration resistance, invasion and metastasis. Monoclonal antibodies against the ectodomain of N-cadherin reduced proliferation, adhesion and invasion of prostate cancer cells in vitro. In vivo, these antibodies slowed the growth of multiple established CRPC xenografts, blocked local invasion and metastasis and, at higher doses, led to complete regression. N-cadherin-specific antibodies markedly delayed the time to emergence of castration resistance, markedly affected tumor histology and angiogenesis, and reduced both AKT serine-threonine kinase activity and serum interleukin-8 (IL-8) secretion. These data indicate that N-cadherin is a major cause of both prostate cancer metastasis and castration resistance. Therapeutic targeting of this factor with monoclonal antibodies may have considerable clinical benefit. [ABSTRACT FROM AUTHOR]

Prostate stem cell antigen (PSCA), a cell surface glycoprotein expressed in normal human prostate and bladder, is over-expressed in the majority of localized prostate cancer and most bone metastases. We have previously shown that the hu1G8 minibody, a humanized anti-PSCA antibody fragment (single-chain Fv-CH3 dimer, 80 kDa), can localize specifically and image PSCA-expressing xenografts at 21 h post-injection. However, the humanization and antibody fragment reformatting decreased its apparent affinity. Here, we sought to evaluate PET imaging contrast with affinity matured minibodies. Yeast scFv display, involving four rounds of selection, was used to generate the three affinity matured antibody fragments (A2, A11, and C5) that were reformatted into minibodies. These three affinity matured anti-PSCA minibodies were characterized in vitro, and following radiolabeling with 124I were evaluated in vivo for microPET imaging of PSCA-expressing tumors. The A2, A11, and C5 minibody variants all demonstrated improved affinity compared to the parental (P) minibody and were ranked as follows: A2 > A11 > C5 > P. The 124I-labeled A11 minibody demonstrated higher immunoreactivity than the parental minibody and also achieved the best microPET imaging contrast in two xenograft models, LAPC-9 (prostate cancer) and Capan-1 (pancreatic cancer), when evaluated in vivo. Of the affinity variant minibodies tested, the A11 minibody that ranked second in affinity was selected as the best immunoPET tracer to image PSCA-expressing xenografts. This candidate is currently under development for evaluation in a pilot clinical imaging study. [ABSTRACT FROM AUTHOR]

Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a promising yet not curative approach in castration-resistant (CR) prostate cancer (PC). Rational combination therapies may improve treatment efficacy. Here, we explored the effect of androgen receptor blockade (ARB) on PSMA expression visualized by PET and its potential additive effect when combined with 177Lu-PSMA RLT in a mouse model of prostate cancer.Methods: Mice bearing human CRPC (C4-2 cells) xenografts were treated with 10 mg/kg enzalutamide (ENZ), with 50 mg/kg bicalutamide (BIC), or vehicle (control) for 21 days. PSMA expression was evaluated by 68Ga-PSMA11 PET/CT and quantified by flow cytometry of tumor fine needle aspirations before treatment and on days 23, 29, 34, and 39 post-therapy induction. For the RLT combination approach, mice bearing C4-2 tumors were treated with 10 mg/kg ENZ or vehicle for 21 days before receiving either 15 MBq (84 GBq/μmol) 177Lu-PSMA617 or vehicle. DNA damage was assessed as phospho-γH2A.X foci in tumor biopsies. Reduction of tumor volume on CT and survival were used as study endpoints.Results: Tumor growth was delayed by ARB while 68Ga-PSMA11 uptake increased up to 2.3-fold over time when compared to controls. ABR-induced upregulation of PSMA expression was confirmed by flow cytometry. Phospho-γH2A.X levels increased 1.8- and 3.4-fold at 48 h in response to single treatment ENZ or RLT and ENZ+RLT, respectively. Despite significantly greater DNA damage and persistent increase of PSMA expression at the time of RLT, no additional tumor growth retardation was observed in the ENZ+RLT group (vs. RLT only, p = 0.372 at day 81). Median survival did not improve significantly when ENZ was combined with RLT.Conclusion: ARB-mediated increases in PSMA expression in PC xenografts were evident by 68Ga-PSMA11 PET imaging and flow cytometry. 177Lu-PSMA617 effectively decreased C4-2 tumor size. However, while pre-treatment with ARB increased DNA damage significantly, it did not result in synergistic effects when combined with RLT. [ABSTRACT FROM AUTHOR]