Prostate-specific Membrane Antigen Uptake Research Articles

Prostate-specific membrane antigen (PSMA) expression in patients with metastatic triple negative breast cancer: Initial results of the PRISMA study.

1025 Background: Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) prolongs survival of patients (pts) with prostate cancer. Preliminary immunohistochemistry (IHC)-based studies suggest that PSMA is highly expressed in triple negative breast cancer (TNBC). The PRISMA study aims to assess PSMA expression in pts with metastatic TNBC (mTNBC) via positron-emission tomography/computed tomography (PET/CT) to evaluate the feasibility of PSMA-targeted RLT for TNBC. Methods: PRISMA is a prospective, single-center study that enrolled pts with progressive mTNBC and measurable disease on 18F-FDG PET/CT to undergo 68Ga-PSMA-11 PET/CT. TNBC definition (ASCO/CAP) was based on the IHC of the primary breast cancer (BC) or metastasis. Target lesions (TL) were defined as metastatic lesions ≥1.5 cm with significant uptake in 18FDG-PET/CT. The same TL regions were propagated to the 68Ga-PSMA-PET/CT. 68Ga-PSMA-11 maximum standard uptake value (SUVmax) was measured for each TL. PSMA patterns A and B were defined according to presence of a majority (pattern A) or a minority (pattern B) of positive TL on 68Ga-PSMA (ie. uptake greater than that of normal liver parenchyma). Mann-Whitney U test was used to assess differences in median SUVmax (mSUVmax) between subgroups. Results: Ten pts with progressive mTNBC were enrolled. One pt was excluded due to lack of TL on 18FDG-PET/CT. Median age was 48 years (range 36-68), median number of TL per patient was 8 (5-18). Five pts had a TNBC IHC since the initial BC diagnosis, while 4 had a switch to TNBC (4 with initial estrogen receptor [ER]-positive and 1 with HER2-positive BC). All evaluable pts had inter- and intra-organ heterogeneity in PSMA uptake in TL and 2 pts had some mismatch with FDG-positive and PSMA-negative TL. mSUVmax was 2.99 (range 1.7-6.3) in the overall population and was higher in pts with pattern A (5.1 vs 2.6 in patterns A and B, respectively, p = 0.03). mSUVmax was numerically higher in younger pts (5.0 vs 2.6 in pts <50y and ≥50y, p = 0.28), PD-L1-positive (5.0 vs 2.7 in PD-L1-positive and -negative, p = 0.14), de novo metastatic disease (5.0 vs 2.9 in de novo and recurrent BC, p = 0.38) and those with ER-negative primary breast tumor (3.4 vs 3.0 in ER-negative and ER-positive primary BC, p = 0.9). Conclusions: A significant PSMA uptake was observed in a proportion of pts with mTNBC. Inclusion of additional pts and translational analyses will allow the identification of PSMA expression determinants. PSMA-targeted RLT may be considered as an innovative therapeutic strategy to be explored in selected pts with mTNBC. [Table: see text]

Preclinical Evaluation of a PSMA-Targeting Homodimer with an Optimized Linker for Imaging of Prostate Cancer.

Prostate-specific membrane antigen (PSMA) targeting radiopharmaceuticals have been successfully used for diagnosis and therapy of prostate cancer. Optimization of the available agents is desirable to improve tumor uptake and reduce side effects to non-target organs. This can be achieved, for instance, via linker modifications or multimerization approaches. In this study, we evaluated a small library of PSMA-targeting derivatives with modified linker residues, and selected the best candidate based on its binding affinity to PSMA. The lead compound was coupled to a chelator for radiolabeling, and subject to dimerization. The resulting molecules, 22 and 30, were highly PSMA specific (IC50 = 1.0-1.6 nM) and stable when radiolabeled with indium-111 (>90% stable in PBS and mouse serum up to 24 h). Moreover, [111In]In-30 presented a high uptake in PSMA expressing LS174T cells, with 92.6% internalization compared to 34.1% for PSMA-617. Biodistribution studies in LS174T mice xenograft models showed that [111In]In-30 had a higher tumor and kidney uptake compared to [111In]In-PSMA-617, but increasing T/K and T/M ratios at 24 h p.i. Tumors could be clearly visualized at 1 h p.i. by SPECT/CT after administration of [111In]In-22 and [111In]In-PSMA-617, while [111In]In-30 showed a clear signal at later time-points (e.g., 24 h p.i.).

Tumor Sink Effect with Prostate-Specific Membrane Antigen-Targeted Theranostics in Patients with Metastatic Castration-Resistant Prostate Cancer: Intra-Individual Evaluations.

"Tumor sink effects", decreased physiological uptake of radiopharmaceuticals due to sequestration by a tumor, may impact radioligand therapy (RLT) toxicity and dosing. We investigated these effects with prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals in the healthy organs-at-risk (the parotid glands, kidneys, liver, and spleen) of 33 patients with metastatic castration-resistant prostate cancer (mCRPC). We retrospectively performed three intra-individual comparisons. First, we correlated changes from baseline to post-RLT (after two 177-lutetium (177Lu)-PSMA-617 cycles) in total lesional PSMA (∆TLP) and organ mean standardized uptake values (∆SUVmean). Second, in 25 RLT responders, we compared the organ SUVmean post-RLT versus that at baseline. Lastly, we correlated the baseline TLP and organ SUVmean. Data were acquired via 68-gallium-PSMA-11 positron emission tomography before the first and after the second 177Lu-PSMA-617 cycle. In the parotid glands and spleen, ∆TLP and ∆SUVmean showed a significant inverse correlation (r = -0.40, p = 0.023 and r = -0.36, p = 0.042, respectively). Additionally, in those tissues, the median organ SUVmean rose significantly from baseline after the response to RLT (p ≤ 0.022), and the baseline TLP and SUVmean were significantly negatively correlated (r = -0.44, p = 0.01 and r = -0.42, p = 0.016, respectively). These observations suggest tumor sink effects with PSMA-targeted radiopharmaceuticals in the salivary glands and spleen of patients with mCRPC.

Prostate-Specific Membrane Antigen PET Positivity in a Lung Mass: Diagnosis of Diffuse Large B-Cell Lymphoma.

An 84-year-old man with nonmetastatic castrate-sensitive prostate cancer was referred for a 68Ga-prostate-specific membrane antigen (PSMA) PET/CT scan with a prostate-specific antigen level of 3.6 ng/mL for restaging. He was 22 years post-radical prostatectomy and had salvage radiation being managed with intermittent hormonal therapy. Imaging revealed a right lower lobe mass with increased PSMA uptake (SUVmax 6.2). Biopsy and subsequent immunostaining determined the mass to be diffuse large B-cell lymphoma. We report a case of diffuse large B-cell lymphoma diagnosed in the setting of PSMA positivity, highlighting awareness for oncologists and radiologists to know this possibility.

Heterogeneity of [68Ga]Ga-PSMA-11 PET/CT in metastatic castration-resistant prostate cancer: genomic characteristics and association with abiraterone response.

The aim of this study was to evaluate the impact of the spatial heterogeneity of prostate-specific membrane antigen (PSMA) uptake on circulating tumor DNA (ctDNA) characteristics and the response rate to new hormonal agent (NHA) treatment. This retrospective study included 153 patients with metastatic castration-resistant prostate cancer (mCRPC) who underwent gallium-68 [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) and ctDNA sequencing with a less than 2-week interval. SUVhetero was defined as the variance of SUVmean for each PSMA-positive lesion. SUVmax-mean was obtained by subtracting the SUVmax by the SUVmean. Patients receiving abiraterone treatment after [68Ga]Ga-PSMA-11 PET/CT and ctDNA sequencing and with complete follow-up record were included into prostate-specific antigen (PSA) response rate analysis. PSA response was defined as a reduction of greater than 50% from baseline. The ctDNA detection rate was 65% (100/153). Higher SUVhetero value contributed to higher ctDNA% (Spearman's rho = 0.278, p < 0.002). A total of 60 patients were included in PSA response rate analysis. The median follow-up was 19.3 (IQR 16.2-23.2) months. Compare to patients with higher SUVhetero value, patients with NA SUVhetero had a higher PSA response rate (52% vs. 90%, p = 0.036). A higher SUVmax-mean value was strongly correlated with higher SUVhetero (Spearman's rho = 0.833, p < 0.0001). Patients with higher SUVmax-mean value also had a higher PSA response rate compared to patients with lower SUVmax-mean value (83.3% vs. 53.3%, p = 0.024). An external cohort confirmed baseline SUVmax-mean value was associated with enzalutamide treatment response rate. Patients with alterations in AR, DNA damage repair pathway, TP53, AR-associated pathway, cell cycle pathway, or WNT pathway had higher SUVmax-mean value compared to those without (p < 0.05). Spatial heterogeneity of the PSMA uptake was associated with ctDNA characteristics and response rate to NHA treatment.

Baseline [68Ga]Ga-PSMA-11 PET/CT before [177Lu]Lu-PSMA-617 Radioligand Therapy: Value of PSMA-Uptake Thresholds in Predicting Targetable Lesions.

Baseline uptake on prostate-specific membrane antigen (PSMA)-targeted imaging is a prerequisite for radioligand therapy (RLT) with [177Lu]Lu-PSMA-617. This study aims to quantify lesion-based response to RLT in relation to pretreatment standard molecular imaging metrics derived from [68Ga]Ga-PSMA-11 PET/CT. Sixty-one patients with mCRPC underwent [68Ga]Ga-PSMA-11 PET/CT imaging before and after a median of 4 (IQR 2−6) RLT cycles. Maximum and mean standardized uptake values (SUVmax, SUVmean), as well as tumor-to-liver ratio (TLR), were assessed. A median of 12 (IQR 7−17) lesions was analyzed per patient, resulting in a total of 718 lesions. Lesions with ≥30% SUVmax decline or falling below the blood pool uptake were considered responsive; ≥30% SUVmax increase marked lesion progression. Additionally, 4-point visual scoring was performed according to E-PSMA consensus. In total, 550/718 (76.6%) lesions responded to RLT, including 389/507 (76.7%) bone metastases and 143/181 (79.0%) lymph node metastases. Baseline SUVmax, SUVmean, and TLR values were associated with lesion response by a moderate but significant correlation (rs = 0.33, p < 0.001, rs = 0.32, p < 0.001, and rs = 0.31, p < 0.001, respectively). For the classification of lesion progression based on baseline PSMA uptake, receiver operating characteristics (ROC) found SUVmax, SUVmean, and TLR to have comparable discriminatory value (AUC 0.85, 0.87, and 0.83). Of 42 tumor sites with baseline uptake below the liver (V-score < 2), 19/42 (45.2%) were responsive, 9/42 (21.4%) were stable, and 14/42 (33.3%) showed progression, leaving liver uptake a threshold with low prognostic value for the identification of RLT-refractory lesions (PPV 33%). This was observed accordingly for various liver uptake-based thresholds, including TLR < 1.5, <2.0 with a PPV at 24%, 20%, respectively. Standard uptake parameters quantified by routine baseline [68Ga]Ga-PSMA-11 PET/CT are moderately associated with post-treatment lesion response to [177Lu]Lu-PSMA-617. Commonly applied liver-based uptake thresholds have limited value in predicting refractory lesions at individual tumor sites.

Follicular thyroid carcinoma detected in ⁶⁸Ga-PSMA PET/CT imaging. Case report.

Introduction: Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein located on the cell membrane, initially discovered in prostate cells, and highly expressed in the cells and metastases of prostate carcinoma. 68Ga-PSMA PET/CT is a molecular imaging technique widely used in the algorithm of this pathology. PSMA expression has been observed in several malignancies, usually incidentally. We report a case of follicular thyroid carcinoma detected in ⁶⁸Ga-PSMA PET/CT. To our knowledge, only 3 cases have been reported in the literature to date. Clinical findings: Patient with a history of prostate cancer adenocarcinoma, who after initial treatment, presented biochemical recurrence. A Ga68-PSMA PET/CT was performed, showing uptake of the radiopharmaceutical in the left thyroid lobe. Interventions: The patient was evaluated by the head and neck specialty, taken to total thyroidectomy plus central dissection. The pathology report confirms a follicular thyroid carcinoma. Conclusion: Ga68-PSMA PET/CT is a molecular image with high diagnostic performance in prostate cancer, however, its uptake in other solid tumors is well established, so attention should be paid to these uptakes, since the the vast majority may be related to another type of primary tumor. This is an example of PSMA uptake in follicular carcinoma of the thyroid.

Musculoskeletal pitfalls in 68Ga-PSMA PET/CT.

Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed in normal prostate cells and overexpressed in prostate cancer. Consequently, it is an important tool in the evaluation of prostate cancer, including the staging of high-risk patients and the assessment of biochemical recurrence. Despite the "specific" designation, benign musculoskeletal conditions, such as fractures, osteodegenerative changes, and fibrous dysplasia, can also show PSMA uptake, which can lead to misinterpretation of the imaging findings. Therefore, radiologists must be aware of these potential pitfalls, understand their causes, and fully analyze their morphologic features on unfused computed tomography (CT) and magnetic resonance imaging scans to correctly interpret the examination. In this pictorial essay, we review the basic characteristics of the 68Ga-PSMA positron-emission tomography/CT (PET/CT) radiotracer, discuss potential causes of false-positive findings on 68Ga-PSMA PET/CT in the musculoskeletal system, and illustrate the corresponding imaging findings.

PSMA Expression in Solid Tumors beyond the Prostate Gland: Ready for Theranostic Applications?

In the past decades, the expanding use of prostate-specific membrane antigen (PSMA) imaging for prostate cancer has led to the incidental detection of a lot of extra-prostatic malignancies showing an increased uptake of PSMA. Due to these incidental findings, the increasing amount of immunohistochemistry studies and the deeper knowledge of the mechanisms of expression of this antigen, it is now clear that "PSMA" is a misnomer, since it is not specific to the prostate gland. Nevertheless, this lack of specificity could represent an interesting opportunity to bring new insights on the biology of PSMA and its sites of expression to image and treat new conditions, particularly several cancers. In this review, we will describe the main extra-prostatic cancers that exhibit PSMA expression and that can be studied with PSMA-based positron emission tomography-computed tomography (PET/CT) as an additional or alternative tool to conventional imaging. In particular, we will focus on cancers in which a radioligand therapy with 177lutetium has been attempted, aiming to provide an overview of the possible future theragnostic applications of PSMA.

Combined Biology-Guided Radiotherapy and Lutetium PSMA Treatment in Metastatic Prostate Cancer

<h3>Purpose/Objective(s)</h3> Biology-guided radiotherapy (BgRT) is a new technology that delivers radiation based on positron emission tomography (PET) signal. Lutetium-177 (¹⁷⁷Lu) prostate-specific membrane antigen (PSMA) is a novel theranostic treatment that demonstrated high response and low toxicities in patients with metastatic castrate-resistant prostate cancer. However, patients may be excluded from this theranostic treatment due to discordance between Gallium-68 (⁶⁸Ga)-PSMA-11 and ¹⁸F-fluorodeoxyglucose (FDG) PET uptake at screening. Using the theranostic treatment alone on these excluded patients would result in untreated FDG-only avid tumor deposits. However, FDG-only avid tumor deposits may be treated with BgRT. This study investigates the feasibility of a combined theranostic/BgRT treatment to excluded patients with discordant uptake. <h3>Materials/Methods</h3> Patients excluded from the LuPSMA clinical trial (ID ANZCTR12615000912583) were retrospectively reviewed. A hypothetical hybrid treatment was considered in which BgRT would supplement ¹⁷⁷Lu-PSMA treatment in discordant FDG-avid tumors. In this treatment, FDG-only avid tumors would be treated with BgRT whereas PSMA-avid tumors would be treated with LuPSMA treatment (100% efficacy was assumed). PSMA PET uptake was mapped to the FDG PET frame of reference using deformable registration between the CT-component of the two PET scans. Gross tumor volume (GTV) of FDG-only avid tumors were contoured on the CT-component of the FDG PET/CT scan by a radiation oncologist. Biological tracking zones (BTZ) for BgRT dose delivery were generated from GTV outer margin expansion of 5 mm / 10 mm / 20 mm. Normalized SUV (nSUV) was calculated as the ratio of the maximum SUV inside the GTV to the mean of SUV inside the outer margin expansions. Tumors were considered suitable to BgRT if nSUV was larger than 3 and if the normal tissue surrounding the tumor was free of any PET signal inside the BTZ. <h3>Results</h3> Of 75 patients screened for LuPSMA treatment, 7 patients had discordant PSMA and FDG uptake, 6 of which had FDG-only avid tumors and were included in this study. In these 6 patients, 89 potential BgRT targets were identified. GTV volumes ranged from 0.3 cm³ to 186 cm³ (median GTV volume = 4.3 cm³, IQR = 2.2 cm³ – 7.4 cm³). SUVmax inside GTVs was between 3 and 12 (median SUVmax = 4.8, IQR = 3.9 – 6.2). With nSUV ≥ 3, 67% / 48% / 28% of all GTVs were free of FDG uptake within 5 mm / 10 mm / 20 mm from the tumor and therefore suitable to BgRT. Bone and lung sites were the best candidates for BgRT (27% / 18% of all tumors were bone / lung GTVs with nSUV ≥ 3 and were isolated from PET uptake within 5 mm). <h3>Conclusion</h3> 67% of FDG-only avid tumors were suitable to BgRT treatment inside a BTZ generated from a margin expansion of 5 mm. BgRT treatment to FDG-only avid tumor in combination with Lutetium PSMA theranostic treatment is therefore feasible.

Mild 68Ga PSMA-11 Uptake in Incidental Pituitary Adenoma.

A 76-year-old man with metastatic prostate cancer was referred to 68Ga prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) for restaging. A consecutive 18F-fluorodeoxyglucose (FDG) PET/CT was performed due to the history of lung cancer in the left lung treated with stereotactic radiotherapy. Intense 18F-FDG uptake was detected in the pituitary gland despite the mild uptake of 68Ga PSMA. Contrast-enhanced magnetic resonance imaging confirmed pituitary adenoma.

Flare on [18F]PSMA-1007 PET/CT after short-term androgen deprivation therapy and its correlation to FDG uptake: possible marker of tumor aggressiveness in treatment-naïve metastatic prostate cancer patients

PurposeShort-term androgen deprivation therapy (ADT) is known to increase heterogeneously prostate-specific membrane antigen (PSMA) expression. This phenomenon might indicate the potential of cancer lesions to respond to ADT. In this prospective study, we evaluated the flare on [18F]PSMA-1007 PET/CT after ADT in metastatic prostate cancer (PCa). Given that aggressive PCa tends to display FDG uptake, we particularly investigated whether the changes in PSMA uptake might correlate with glucose metabolism.MethodsTwenty-five men with newly diagnosed treatment-naïve metastatic PCa were enrolled in this prospective registered clinical trial. All the patients underwent [18F]PSMA-1007 PET/CT immediately before and 3–4 weeks after ADT initiation (degarelix). Before ADT, [18F]FDG PET/CT was also performed. Standardized uptake values (SUV)max of primary and metastatic lesions were calculated in all PET scans. Serum PSA and testosterone blood samples were collected before the two PSMA PET scans. The changes in PSMA uptake after ADT were represented as ΔSUVmax.ResultsAll the patients reached castration levels of testosterone at the time of the second [18F]PSMA-1007 PET/CT. Overall, 57 prostate, 314 lymph nodes (LN), and 406 bone lesions were analyzed. After ADT, 104 (26%) bone, 33 (11%) LN, and 6 (11%) prostate lesions showed an increase (≥ 20%) in PSMA uptake, with a median ΔSUVmax of + 50%, + 60%, and + 45%, respectively. Among the lesions detected at the baseline [18F]PSMA-1007 PET/CT, 63% bone and 46% LN were FDG-positive. In these metastases, a negative correlation was observed between the PSMA ΔSUVmax and FDG SUVmax (p < 0.0001). Moreover, a negative correlation between the ΔSUVmax and the decrease in serum PSA after ADT was noted (p < 0.0001).ConclusionsA heterogeneous increase in PSMA uptake after ADT was detected, most evidently in bone metastases. We observed a negative correlation between the PSMA flare and the intensity of glucose uptake as well as the decrease of serum PSA, suggesting that lesions presenting with such flare might potentially be less aggressive.Trial registrationNCT03876912, registered 15 March 2019.

68Ga]Ga-PSMA PET/MRI, histological PSMA expression and preliminary experience with [177Lu]Lu-PSMA therapy in relapsing high-grade glioma.

PurposeHigh-grade gliomas (HGG) are still associated with a dismal prognosis. Prostate specific membrane antigen (PSMA) is discussed as a theranostic target for PSMA-directed radioligand therapy ([177Lu]Lu-PSMA RLT). Here, we report on the correlation of [68Ga]Ga-PSMA uptake with histological PSMA expression and on our preliminary experience with [177Lu]Lu-PSMA RLT in relapsing HGG.MethodsPatients with relapsing HGG underwent [68Ga]Ga-PSMA PET/MRI to evaluate eligibility for an individualized treatment approach with [177Lu]Lu-PSMA. Standard uptake values (SUV) for tumor and liver and respective tumor-to-background ratios (compared to the liver) (TBR) on [68Ga]Ga-PSMA PET/MRI were assessed. Eligibility criteria for [177Lu]Lu-PSMA therapy were exhaustion of all standard treatment options available and TBRmax>1.0. In 11 samples, immunohistochemical PSMA expression was determined, quantified using the H-score and correlated with uptake on [68Ga]Ga-PSMA PET/MRI.ResultsWe included 20 patients with a median age of 53 years (IQR 42-57). The median SUV on [68Ga]Ga-PSMA PET/MRI was 4.5 (3.7-6.2) for SUVmax and 1.4 (1.1-1.7) for SUVmean. The respective TBR was maximum 0.6 (0.4-0.8) and mean 0.3 (0.2-0.4). High TBRmax correlated with increased endothelial PSMA expression [H-score of 65 (62.5-77.5)]. Three patients (15%) presented a TBRmax>1.0 and qualified for [177Lu]Lu-PSMA RLT. No treatment related toxicity was observed.ConclusionOnly a minority of patients with relapsing HGG qualified for [177Lu]Lu-PSMA RLT. Our data demonstrates that PSMA expression in the neo-vasculature corresponds to PSMA uptake on [68Ga]Ga-PSMA PET/MRI and might be used as a screening tool for patient selection. Future prospective studies need to focus the debate on TBRmax thresholds as inclusion criteria for PSMA RLT.

Radiopharmaceutical for detecting PSMA - positive metastatic colon cancer: Matched-pair comparison of 18F-BF3-Cy3-ACUPA and 68Ga-PSMA PET/MRI.

Prostate-specific membrane antigen (PSMA) - based radiopharmaceuticals are promising for the evaluation of PSMA-positive non-prostate cancers. In this case study, 18F-BF3-Cy3-ACUPA and 68Ga-PSMA positron emission tomography/magnetic resonance imaging (PET/MRI) were compared in a patient with metastatic colon cancer. Both 18F-BF3-Cy3-ACUPA and 68Ga-PSMA PET/MRI showed biopsy-proven metastatic left external iliac adenopathy, highlighting the feasibility of PSMA uptake in PET/MRI of metastatic nodal disease from colon cancer. Along with imaging evaluation, PSMA-based radiopharmaceuticals may also be used as a surrogate imaging tracer for potential theranostic applications using alpha or beta emitters in the context of PSMA-directed radiopharmaceutical therapy in advanced and progressive colorectal cancer.

Evaluation of a Radio-IMmunoStimulant (RIMS) in a Syngeneic Model of Murine Prostate Cancer and ImmunoPET Analysis of T-cell Distribution

An immunosuppressive tumor microenvironment and tumor heterogeneity have led to the resilience of metastatic castrate resistant prostate cancer (mCRPC) to current treatments. To address these challenges, we developed and evaluated a new drug paradigm, Radio-IMmunostimulant (RIMS), in a syngeneic model of murine prostate cancer. RIMS-1 was generated using a convergent synthesis employing solid phase peptide and solution chemistries. The prostate-specific membrane antigen (PSMA) inhibitory constant for natLu-RIMS-1 was determined, and radiolabeling with 177Lu generated 177Lu-RIMS-1. The TLR 7/8 agonist payload release from natLu-RIMS-1 was determined using a cathepsin B assay. The biodistribution of 177Lu-RIMS-1 was evaluated in a bilateral xenograft model in NCru nude mice bearing PSMA(+) (PC3-PiP) and PSMA(-) (PC3-Flu) tumors at 2, 24, and 72 h. The therapeutic effect of 177Lu-RIMS-1 was evaluated in C57BL/6J mice bearing RM1-PGLS (PSMA-positive, green fluorescent protein-positive, and luciferase-positive) tumors and compared to that of 177Lu-PSMA-617 at the same total administered radioactivity of 57 MBq and molar activity of 5.18 MBq/nmol. natLu-RIMS-1 and vehicle were evaluated as the controls. Immuno-positron emission tomography (PET) using 89Zr-DFO-anti-CD3 was used to visualize T-cell distribution during treatment. 177Lu-RIMS-1 was quantitatively radiolabeled at >99% radiochemical purity and maintained a high affinity toward PSMA (Ki = 3.77 ± 0.5 nM). Cathepsin B efficiently released the entire immunostimulant payload in 17.6 h. 177Lu-RIMS-1 displayed a sustained uptake in PSMA(+) tumor tissue up to 72 h (2.65 ± 1.03% ID/g) and was not statistically different (P = 0.1936) compared to 177Lu-PSMA-617 (3.65 ± 0.59% ID/g). All animals treated with 177Lu-RIMS-1 displayed tumor growth suppression and provided a median survival of 30 days (P = 0.0007) while 177Lu-PSMA-617 provided a median survival of 15 days, which was not statistically significant (P = 0.3548) compared to the vehicle group (14 days). ImmunoPET analysis revealed 2-fold more tumor infiltrating T-cells in 177Lu-RIMS-1-treated animals compared to 177Lu-PSMA-617-treated animals; 177Lu-RIMS-1 improves therapeutic outcomes in a syngeneic model of mouse prostate cancer and elicits greater T-cell infiltration to the tumor compared to 177Lu-PSMA-617. These results support further investigation of the RIMS paradigm as the first example of a single molecular entity combining radiotherapy and immunostimulation.

PSMA PET Imaging and Therapy in Adenoid Cystic Carcinoma and Other Salivary Gland Cancers: A Systematic Review.

Simple SummaryAdenoid cystic carcinoma (ACC) and other salivary gland cancers (SGC) are rare conditions with limited treatment options when they recur or spread to other parts of the body. There is increasing interest in the interaction of radioactive labeled proteins 68Gallium- Prostate Specific Membrane Antigen (68Ga-PSMA) with their corresponding receptors on tumor cells (PSMA receptor) which can be detected on scans. This innovation has created diagnostic and therapeutic progress in management of metastatic prostate cancer. These interactions are also found in SGCs though studies are currently limited. Our systematic review aims to collate available published scientific information on this technology to better inform its potential use, pitfalls and its future directions as a diagnostic and therapeutic option in SGCs. We concluded that the 68Ga-PSMA scans can be useful in detecting ACC and SGC not detected on standard radioimaging and that small studies have shown the therapeutic potential of this innovation in advanced or metastatic ACC and SGC.Adenoid cystic carcinoma (ACC) and other salivary gland cancers (SGCs) are rare tumors where application of prostate specific membrane antigen (PSMA) positron emission tomography (PET) and PSMA radioligand therapy have yet to be studied extensively. This review explores the role of PSMA PET imaging and therapy as a theranostic tool for ACC and other SGCs based on current literature. A comprehensive literature search on PubMed and Embase was performed. All relevant studies containing information on PSMA PET imaging in ACC and SGC were included. Ten studies (one prospective, three retrospective, five case reports and one review paper) were included. For ACC, the mean maximum standardized uptake value (SUVmax) for local recurrence and distant metastases ranged from 2.41 to 13.8 and 2.04 to 14.9, respectively. In SGC, the meanSUVmax ranged from 1.2–12.50. Most studies observed PSMA expression positivity on immunohistochemistry (IHC) when there was PSMA PET uptake. PSMA PET was able to detect lesions not detected on standard imaging. Despite the small number of studies and wide intra-patient and inter-tumor variation of PSMA uptake in ACC and SGC, 68Gallium (68Ga)-PSMA PET has promising prospects as a diagnostic and radioligand therapeutic option. Further studies to answer the various theranostics considerations are required to guide its use in the real-world setting.

The future of PSMA PET and WB MRI as next-generation imaging tools in prostate cancer

Radiolabelled prostate-specific membrane antigen (PSMA)-based PET-CT has been shown in numerous studies to be superior to conventional imaging in the detection of nodal or distant metastatic lesions. 68Ga-PSMA PET-CT is now recommended by many guidelines for the detection of biochemically relapsed disease after radical local therapy. PSMA radioligands can also function as radiotheranostics, and Lu-PSMA has been shown to be a potential new line of treatment for metastatic castration-resistant prostate cancer. Whole-body (WB) MRI has been shown to have a high diagnostic performance in the detection and monitoring of metastatic bone disease. Prospective, randomized, multicentre studies comparing 68Ga-PSMA PET-CT and WB MRI for pelvic nodal and metastatic disease detection are yet to be performed. Challenges for interpretation of PSMA include tracer trapping in non-target tissues and also urinary excretion of tracers, which confounds image interpretation at the vesicoureteral junction. Additionally, studies have shown how long-term androgen deprivation therapy (ADT) affects PSMA expression and could, therefore, reduce tracer uptake and visibility of PSMA+ lesions. Furthermore, ADT of short duration might increase PSMA expression, leading to the PSMA flare phenomenon, which makes the accurate monitoring of treatment response to ADT with PSMA PET challenging. Scan duration, detection of incidentalomas and presence of metallic implants are some of the major challenges with WB MRI. Emerging data support the wider adoption of PSMA PET and WB MRI for diagnosis, staging, disease burden evaluation and response monitoring, although their relative roles in the standard-of-care management of patients are yet to be fully defined.

Feasibility of biology-guided radiotherapy using PSMA-PET to boost to dominant intraprostatic tumour

BackgroundBiology-guided radiotherapy (BgRT) delivers dose to tumours triggered from positron emission tomography (PET) detection. Prostate specific membrane antigen (PSMA) PET uptake is abundant in the dominant intraprostatic lesion (DIL). This study investigates the feasibility of BgRT to PSMA-avid subvolume in the prostate region. MethodsPatients enrolled in the prospective randomized trial ProPSMA at our institution were included (ID: ANZCTR12617000005358). Gross tumour volumes (GTVs) were delineated on the PET component of a PET/CT scan from a standardized uptake value (SUV) threshold technique. Suitability for BgRT requires a strong signal-to-background ratio with a surrounding tissue free of significant PSMA uptake. The signal-to-background ratio was quantified from the calculation of the normalized SUV (nSUV), defined as the ratio between SUVmax within the GTV and SUVmean inside a 3D margin expansion of the GTV. The PSMA distribution surrounding the tumour was quantified as a function of the distance from the GTV. ResultsIn this cohort of 84 patients, 83 primary tumours were included. Prostate volume ranged from 19 cm3 to 148 cm3 (median = 52 cm3; IQR = 39 cm3 – 63 cm3). SUVmax inside the prostate was between 2 and 125 (median = 19; IQR = 11 – 30). More than 50% of GTVs generated with threshold between 25%SUVmax (median volume = 10.0 cm3; IQR = 4.5 cm3 – 20.0 cm3) and 50%SUVmax (median volume = 1.9 cm3; IQR = 1.1 cm3 – 3.8 cm3) were suitable for BgRT by using nSUV ≥ 3 and a margin expansion of 5 mm. ConclusionsIt is feasible to identify GTVs suitable for BgRT in the prostate. These GTVs are characterized by a strong signal-to-background ratio and a surrounding tissue free of PSMA uptake.

Optimization of ODAP-Urea-based dual-modality PSMA targeting probes for sequential PET-CT and optical imaging

Prostate-specific membrane antigen (PSMA) is emerging as a promising target to specifically image prostate cancer. Dual-modality probe combining radionuclide imaging and near-infrared fluorescence navigation targeting PSMA would enable both the preoperative staging and intraoperative detection of the tumor lesions. To overcome one of the key barriers for achieving high contrast imaging at both early and late time points, we optimized the pharmacokinetics of dual-modality probes based on oxalyldiaminopropionic acid-urea (ODAP-Urea) PSMA inhibitors recently developed. Four dual-modality probes with variable hydrophilicity were synthesized and evaluated. They displayed good optical properties (λem max = 835 nm, QY = 0.67%-1.50%), high affinity to PSMA (Ki = 2.09 ± 1.71–4.15 ± 2.20 nM) and PSMA specific cellular uptake (0.48 ± 0.01% − 0.64 ± 0.04% IA/105 LNCaP cells) upon labeled with 68Ga. In vivo studies showed that [68Ga]Ga-P3 exhibited an optimum pharmacokinetic property with high specific tumor uptake (SUVmax = 1.88 ± 0.36, at 1 h) in medium level PSMA expressing 22Rv1 tumor model and high tumor-to-muscle ratio (12.56 ± 2.63, at 1 h). Specific fluorescence imaging could also be achieved with high contrast for later time points (tumor-to-background ratio = 11.63 ± 4.16 at 24 h). This study demonstrates that ODAP-Urea-based P3 has the potential for PET imaging and intraoperative optical imaging of prostate cancer.

MP09-20 PROSTATE BIOPSY TARGETED TO PROSTATE SPECIFIC MEMBRANE ANTIGEN (PSMA) FOCI

You have accessJournal of UrologyCME1 May 2022MP09-20 PROSTATE BIOPSY TARGETED TO PROSTATE SPECIFIC MEMBRANE ANTIGEN (PSMA) FOCI David Kuppermann, Jeremie Calais, Wayne Brisbane, Elizabeth Tran, Lorna Herbert, Matthias Benz, Johannes Czernin, and Leonard Marks David KuppermannDavid Kuppermann More articles by this author , Jeremie CalaisJeremie Calais More articles by this author , Wayne BrisbaneWayne Brisbane More articles by this author , Elizabeth TranElizabeth Tran More articles by this author , Lorna HerbertLorna Herbert More articles by this author , Matthias BenzMatthias Benz More articles by this author , Johannes CzerninJohannes Czernin More articles by this author , and Leonard MarksLeonard Marks More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002531.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: PSMA PET imaging is the most accurate imaging method known for detection of metastatic PCa. PSMA PET may also reveal intra-prostatic cancer. 68Ga-PSMA scanning was approved by FDA in December 2020 for pre-op staging of PCa and to detect possible recurrence. MRI-guided biopsy (MRGB) is the preferred method for diagnosis of prostate cancer (PCa), but PCa may be MRI-invisible (≈15-20%). Herein we study intra-prostatic PSMA focal uptake as a target for biopsy detection of PCa using PET/CT-US fusion (PSMA-guided biopsy, PSMA-GB). METHODS: In a prospective trial, 13 men underwent PSMA PET/CT imaging prior to fusion biopsy at UCLA. Subjects are men with negative prior biopsy (10 MRGB), but continued clinical suspicion of PCa and focal uptake of PSMA in the prostate. Method of PSMA-GB is identical to MRGB (PMID 26749141) but employs US fusion with PET/CT instead of MRI, as detailed previously (PMID: 28607878). Method of Ga-PSMA image acquisition via PET/CT scanning has been reported (PMID: 30920593). Contouring of intra-prostatic foci of PSMA positivity was via Profuse software by co-author J.C. Image fusion & trans-rectal targeted biopsy was via Artemis device (LSM). Detection rate of csPCa ( >GG2) by PSMA-GB was primary endpoint. RESULTS: To date, 13 men have completed study. Median age=71 yrs.; prostate volume=27.7 cc (IQR 22.1, 38.3); PSA density=0.25 ng/ml/cc (IQR 0.10, 0.45 PSMA-GB was successfully completed in all 13 with no more difficulty than usual MRI-GB. Overall detection rate was 9/13 (70%): GG2 in 1, GG3 in 6, and GG4 in 2. Max Cancer Core Length was 4 mm median (IQR 3, 9). 4 PSMA foci were anterior; all 4 contained csPCa. Median SUVmax (standardized uptake value) was 6 in PSMA lesions returning <GG1 findings vs 8.2 in men with csPCa. Median PSAD (density) was higher in men with csPCa (0.25) than others (0.20). Of 5 men with prior radiation, 4 had csPCa on PSMA-GB. CONCLUSIONS: Prostate biopsy, which targets PSMA “hot spots” via PET/CT-US fusion, may lead to detection of clinically significant cancers missed by MRI-guided biopsy. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e144 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information David Kuppermann More articles by this author Jeremie Calais More articles by this author Wayne Brisbane More articles by this author Elizabeth Tran More articles by this author Lorna Herbert More articles by this author Matthias Benz More articles by this author Johannes Czernin More articles by this author Leonard Marks More articles by this author Expand All Advertisement PDF DownloadLoading ...