Prostate-specific Membrane Antigen Uptake Research Articles

Subacute Cerebral Infarct: An Unusual Cause of Radiotracer Uptake at 18F-PSMA PET/CT.

Prostate-specific membrane antigen (PSMA) PET/CT has become an unparalleled modality in the diagnosis of primary and recurrent prostatic adenocarcinoma, often revealing sites of disease that were previously invisible on conventional imaging. In this 78-year-old man with suspected prostate cancer recurrence, PSMA PET/CT revealed focal radiotracer uptake in the brain, which would ordinarily raise suspicion for metastases, but was a false positive in the setting of a recent stroke. Increased PSMA uptake has been reported in subacute infarcts and primary and secondary brain tumors. Careful history and comparison with prior imaging are vital to avoid false-positive diagnosis in such patients.

Multiparametric MRI and 18F-PSMA-1007 PET/CT for the Detection of Clinically Significant Prostate Cancer.

Background Multiparametric MRI (mpMRI) is effective for detecting prostate cancer (PCa); however, there is a high rate of equivocal Prostate Imaging Reporting and Data System (PI-RADS) 3 lesions and false-positive findings. Purpose To investigate whether fluorine 18 (18F) prostate-specific membrane antigen (PSMA) 1007 PET/CT after mpMRI can help detect localized clinically significant PCa (csPCa), particularly for equivocal PI-RADS 3 lesions. Materials and Methods This prospective study included participants with elevated prostate-specific antigen (PSA) levels referred for prostate mpMRI between September 2020 and February 2022. 18F-PSMA-1007 PET/CT was performed within 30 days of mpMRI and before biopsy. PI-RADS category and level of suspicion (LOS) were assessed. PI-RADS 3 or higher lesions at mpMRI and/or LOS 3 or higher lesions at 18F-PSMA-1007 PET/CT underwent targeted biopsies. PI-RADS 2 or lower and LOS 2 or lower lesions were considered nonsuspicious and were monitored during a 1-year follow-up by means of PSA testing. Diagnostic accuracy was assessed, with histologic examination serving as the reference standard. International Society of Urological Pathology (ISUP) grade 2 or higher was considered csPCa. Results Seventy-five participants (median age, 67 years [range, 52-77 years]) were assessed, with PI-RADS 1 or 2, PI-RADS 3, and PI-RADS 4 or 5 groups each including 25 participants. A total of 102 lesions were identified, of which 80 were PI-RADS 3 or higher and/or LOS 3 or higher and therefore underwent targeted biopsy. The per-participant sensitivity for the detection of csPCa was 95% and 91% for mpMRI and 18F-PSMA-1007 PET/CT, respectively, with respective specificities of 45% and 62%. 18F-PSMA-1007 PET/CT was used to correctly differentiate 17 of 26 PI-RADS 3 lesions (65%), with a negative and positive predictive value of 93% and 27%, respectively, for ruling out or detecting csPCa. One additional significant and one insignificant PCa lesion (PI-RADS 1 or 2) were found at 18F-PSMA-1007 PET/CT that otherwise would have remained undetected. Two participants had ISUP 2 tumors without PSMA uptake that were missed at PET/CT. Conclusion 18F-PSMA-1007 PET/CT showed good sensitivity and moderate specificity for the detection of csPCa and ruled this out in 93% of participants with PI-RADS 3 lesions. Clinical trial registration no. NCT04487847 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Turkbey in this issue.

A Case Series Depicting PSMA Expression in Nonmalignant Lesions

Abstract Prostate-specific membrane antigen (PSMA) is a widely accepted and used tracer in staging and biochemical recurrences of prostate cancer. PSMA is extensively expressed in normal prostatic epithelial cells and prostate cancer cells, with some amount of expression also in nonprostatic cells. False-positive PSMA uptake in nonmalignant lesions creates ambiguity in disease detection. In such cases, histopathological correlation and radiological follow-up assist in clinical decision-making. In this case series, we illustrate a few cases where PSMA uptake was incidentally found in some of the commonly occurring benign conditions.

68Ga Prostate-specific Membrane Antigen Uptake in Metastatic Medullary Thyroid Carcinoma.

We present the case of a 58-year-old man with advanced medullary thyroid carcinoma who had a treatment history with different types of modalities. In the follow-up, the patient had rising calcitonin and CEA levels. Metastatic lymph nodes, liver, and bone metastases with varying degrees of uptake were detected on 18F-fluorodeoxyglucose (FDG) and 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT). 68Ga prostate-specific membrane antigen (PSMA) PET/CT was performed to explore whether the patient might have a chance for PSMA-targeted radionuclide therapy, and increased PSMA expression was noted in most of the metastatic lesions, even some of which have higher PSMA uptake than 18F-FDG and 68Ga-DOTATATE.

Prognostic value of FDG, PSMA, and DOTATATE uptake on PET imaging in metastatic castration-resistant prostate cancer (mCRPC).

31 Background: In mCRPC, fluorodeoxyglucose (FDG) and prostate-specific membrane antigen (PSMA) PET/CT are often used in combination for selecting patients for PSMA-radioligand therapy (PSMA-RLT). Few studies have specifically assessed the prognostic value of FDG+/PSMA- lesions, which exclude patients from PSMA-RLT. Also, little is known about the significance of somatostatin receptor expression, a potential biomarker of neuroendocrine differentiation of mCRPC, which can be assessed with DOTATATE-PET/CT. 3TMPO is a prospective study in progressing mCRPC patients who were imaged with up to 3 PET tracers. Here, we report on patient’s overall survival (OS), with respect to the presence of FDG+/PSMA- and DOTATATE+ lesions. Methods: In 3TMPO (NCT04000776, protocol in PMID 34674367), all patients had 68Ga-PSMA-617 and 18F-FDG PET/CT scans. A 68Ga-DOTATATE scan was ordered if an FDG+/PSMA- lesion was found. For all tracers, positivity was defined as lesion SUVpeak being 1.5x higher than liver SUVmean. Kaplan-Meier with log-rank test was used to assess the difference in OS between groups. Cox regression model was used to quantify the effect of factors predictive of OS. Results: The median [95% CI] OS of the 98 enrolled patients was 10.2 [8.5-11.8] mo. At least one FDG+/PSMA- lesion was found in 45 (45.9%) patients and their OS was shorter than that of the others: 5.6 [4.3-6.9] vs. not reached (p=0.0001). Six (16.2%) of 37 patients who underwent 68Ga-DOTATATE-PET had ≥1 DOTATATE+ lesion and their OS was shorter than that of patients without a DOTATATE+ lesion: 3.0 [2.2-3.7] vs. 6.4 [1.6-11.1] mo. (p=0.0004). Characteristics significantly associated with worse OS were ECOG, ISUP grade, number of metastases, number of lines of therapy, presence of visceral metastases, FDG and PSMA molecular tumor volumes (MTV) (p<0.05). In a multivariate analysis adjusted for the number of metastases and of treatment lines, the presence of an FDG+/PSMA- lesion increased the risk of death (HR [95% CI]=2.4 [1.4-4.3], p=0.002), and this was also significant after adjusting for both PSMA and FDG-MTV (HR [95% CI]=2.9 [1.4-5.8], p=0.003). Conclusions: mCRPC patients harboring FDG+/PSMA- lesion(s) had a shorter OS than those who did not, and their prognosis was even poorer if they also had DOTATATE+ lesion(s). Upfront FDG/PSMA-PET followed by DOTATATE-PET might help clinicians to guide patient towards palliative care vs. further systemic therapy, including PSMA-RLT. Clinical trial information: NCT04000776 .

PSMA Avidity in the Heterotropic Ossification-An Incidental Finding on PSMA PET/CT.

The upregulations of prostate-specific membrane antigen (PSMA) antigen are used for the presence of prostate cancer. However, published literature shows incidentally detected PSMA uptake in various nonprostatic benign and malignant conditions, which led to questioning the specificity of PSMA-targeted PET. In present case, we highlighted the abnormal PSMA expression in the benign bone abnormality.

PSMA-targeted dendrimer as an efficient anticancer drug delivery vehicle for prostate cancer.

Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men in the United States. Although early-stage treatments exhibit promising 5-year survival rates, the treatment options for advanced stage disease are constrained, with short survival benefits due to the challenges associated with effective and selective drug delivery to PCa cells. Even though targeting Prostate Specific Membrane Antigen (PSMA) has been extensively explored and is clinically employed for imaging and radio-ligand therapy, the clinical success of PSMA-based approaches for targeted delivery of chemotherapies remains elusive. In this study, we combine a generation 4 hydroxy polyamidoamine dendrimer (PD) with irreversible PSMA ligand (CTT1298) to develop a PSMA-targeted nanoplatform (PD-CTT1298) for selective intracellular delivery of potent chemotherapeutics to PCa. PD-CTT1298-Cy5 exhibits a PSMA IC50 in the nanomolar range and demonstrates selective uptake in PSMA (+) PCa cells via PSMA mediated internalization. When systemically administered in a prostate tumor xenograft mouse model, PD-CTT1298-Cy5 selectively targets PSMA (+) tumors with significantly less accumulation in PSMA (-) tumors or upon blocking of the PSMA receptors. Moreover, the dendrimer clears rapidly from the off-target organs limiting systemic side-effects. Further, the conjugation of an anti-cancer agent, cabozantinib to the PSMA-targeted dendrimer translates to a significantly enhanced anti-proliferative activity in vitro compared to the free drug. These findings highlight the potential of PD-CTT1298 nanoplatform as a versatile approach for selective delivery of high payloads of potent chemotherapeutics to PCa, where dose related systemic side-effects are a major concern.

Novel Biodistribution of PSMA Radiotracer in the Uvula of Patients Undergoing PSMA PET/CT.

Prostate-specific membrane antigen (PSMA) PET/CT is an imaging technique that detects primary and metastatic prostate cancer and evaluates treatment effectiveness. The radioligands for PSMA PET/CT are known to have physiological off-target uptake in various tissues. These include the well-known off-target major and minor salivary glands. We report that, in addition to this location, radioligand uptake can be seen in the uvula, which we suggest is from salivary tissue in this location. PSMA uptake in the uvula is not reported in the literature and is a rare, but normal location for tracer biodistribution in some patients.

68Ga-PSMA-11 PET/CT Imaging in Brain Gliomas and Its Correlation With Clinicopathological Prognostic Parameters.

Gliomas are the most common primary central nervous system tumors, of which the malignant gliomas account for 60%-75%. The primary and secondary brain malignancies are highly treatment resistant, and their marked angiogenesis attracts interest as a potential therapeutic target. The grade of gliomas, Ki-67 index, and IDH mutation status are among the major prognostic markers in gliomas. Prostate-specific membrane antigen (PSMA) is a zinc-dependent peptidase that is not only expressed in prostate cancer cells but also in the tumor neovasculature. The initial PSMA PET studies in central nervous system tumors using 68Ga-HBED-CC-PSMA (68Ga-PSMA-11) PET tracer confirmed selective target expression in gliomas of different grades, with higher expression in high-grade glioma compared with low-grade glioma. The aim of the present study was to correlate and compare the 68Ga-PSMA-11 and 18F-FDG uptake in brain tumors with their clinicopathological prognostic parameters, so as to study their prognostic implications. In addition, the study also aimed to identify patients who are likely to benefit from potential PSMA-targeted therapies. This ongoing prospective study was approved by the institutional scientific and medical ethics committee. The patients with primary or recurrent glioma lesions on MRI underwent regional brain PET/CT scanning with 68Ga-PSMA-11 and 18F-FDG. The final histopathology of the brain lesions (glioma grade), Ki-67 index, and IDH mutation status were compared with SUVmax values of the 68Ga-PSMA-11 and 18F-FDG PET/CT. A total of 15 patients (13 males and 2 females; age range, 21-73 years; median age, 58 years) were included in this study analysis. Among the 15 patients, 10 were treatment naive and 2 were patients with recurrent glioma. Three patients turned out to be WHO grade I-II, 6 belonged to grade III, and 6 grade IV (glioblastoma multiforme) on final histopathology. The 68Ga-PSMA-11 PET/CT showed tracer uptake in all high-grade gliomas with good tumor-to-background ratio. It was PSMA nonavid in 2/3 low-grade gliomas, and it showed low-grade uptake in 1/3 patients. PSMA expression (as evaluated by SUVmax values) was significantly higher in higher-grade tumors, those with IDH mutation wildtype status, and higher Ki-67 indices. FDG PET SUVmax also showed significant correlation with these prognostic parameters. In these preliminary results, PSMA PET appears to be an important tool in the evaluation and prognosis of gliomas. PSMA-directed theranostics can be explored as a personalized approach in gliomas with high PSMA uptake. However, with the limitation of small sample size, larger clinical trials are warranted to draw conclusive evidence regarding the same.

Tumoral Ki67 and PSMA Expression in Fresh Pre-PSMA-RLT Biopsies and Its Relation With PSMA-PET Imaging and Outcomes of PSMA-RLT in Patients With mCRPC.

Prostate specific membrane antigen (PSMA) directed radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC) patients. However, it is still poorly understood why approximately 40% of the patients does not respond to PSMA-RLT. The aims of this study were to evaluate the pretreatment PSMA expression on immunohistochemistry (IHC) and PSMA uptake on PET/CT imaging in mCRPC patients who underwent PSMA-RLT. We correlated these parameters and a cell proliferation marker (Ki67) to the therapeutic efficacy of PSMA-RLT. In this retrospective study, mCRPC patients who underwent PSMA-RLT were analyzed. Patients biopsies were scored for immunohistochemical Ki67 expression, PSMA staining intensity and percentage of cells with PSMA expression. Moreover, the PSMA tracer uptake of the tumor lesion(s) and healthy organs on PET/CT imaging was assessed. The primary outcome was to evaluate the association between histological PSMA protein expression of tumor in pre-PSMA-RLT biopsies and the PSMA uptake on PSMA PET/CT imaging of the biopsied lesion. Secondary outcomes were to assess the relationship between PSMA expression and Ki67 on IHC and the progression free survival (PFS) and overall survival (OS) following PSMA-RLT. In total, 22 mCRPC patients were included in this study. Nineteen (86%) patients showed a high and homogenous PSMA expression of >80% on IHC. Three (14%) patients had low PSMA expression on IHC. Although there was limited PSMA uptake on PET/CT imaging, these 3 patients had lower PSMA uptake on PET/CT imaging compared to the patients with high PSMA expression on IHC. Yet, no correlation was found between PSMA uptake on PET/CT imaging and PSMA expression on IHC (SUVmax: R2=0.046 and SUVavg: R2=0.036). The 3 patients had a shorter PFS compared to the patients with high PSMA expression on IHC (HR: 4.76, 95% CI: 1.14-19.99; P=.033). Patients with low Ki67 expression had a longer PFS and OS compared to patients with a high Ki67 expression (HR: 0.40, 95% CI: 0.15-1.06; P=.013) CONCLUSION: The PSMA uptake on PSMA-PET/CT generally followed the PSMA expression on IHC. However, heterogeneity may be missed on PSMA-PET/CT. Immunohistochemical PSMA and Ki67 expression in fresh tumor biopsies, may contribute to predict treatment efficacy of PSMA-RLT in mCRPC patients. This needs to be further explored in prospective cohorts.

Analysing the tumor transcriptome of prostate cancer to predict efficacy of Lu-PSMA therapy

Rationale177Lu-PSMA ([177Lu]Lutetium-PSMA-617) therapy is an effective treatment option for patients with prostate specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer, but still shows a non-responder rate of approximately 30%. Combination...

Antihormonal-Treatment Status Affects 68Ga-PSMA-HBED-CC PET Biodistribution in Patients with Prostate Cancer.

Androgen deprivation therapy (ADT) is known to influence the prostate-specific membrane antigen (PSMA) expression of prostate cancer, potentially complicating the interpretation of PSMA ligand PET findings and affecting PSMA radioligand therapy. However, the impact of ADT on PSMA ligand biodistribution in nontumorous organs is not well understood. Methods: Men (n = 112) with histologically proven prostate cancer who underwent 68Ga-PSMA-HBED-CC (68Ga-PSMA-11) PET/CT between November 2015 and July 2021 at the Medical University Vienna with known ADT status were retrospectively recruited. Fifty-six patients were on gonadotropin-releasing hormone-interfering ADT at the time of imaging (ADT group), whereas 56 patients with no history of ADT served as a control group. Physiologically PSMA-expressing organs (salivary glands, kidneys, liver, and spleen) were delineated, and their uptake was compared according to their data distributions. Multivariate regression analysis assessed the relationship between renal, hepatic, splenic, and salivary gland uptake and the explanatory variables metabolic tumor volume, glomerular filtration rate, and ADT status. Results: ADT was associated with lower levels of PSMA uptake in the kidneys (SUVmean: Δ[ADT - control] = -7.89; 95% CI, -10.73 to -5.04; P < 0.001), liver (SUVpeak: Δ[ADT - control] = -2.3; 95% CI, -5.72 to -0.93; P = 0.003), spleen (SUVpeak: Δ[ADT - control] = -1.27; 95% CI, -3.61 to -0.16; P = 0.033), and salivary glands (SUVmean: Δ[ADT - control] = -1.04; 95% CI, -2.48 to -0.13; P = 0.027). In a multivariate analysis, ADT was found to be associated with lower renal (SUVmean: β = -7.95; 95% CI, -11.06 to -4.84; P < 0.0001), hepatic (SUVpeak: β = -7.85; 95% CI, -11.78 to -3.91; P < 0.0001), splenic (SUVpeak: β = -5.83; 95% CI, -9.95 to -1.7; P = 0.006), and salivary gland (SUVmean: β = -1.47; 95% CI, -2.76 to -0.17; P = 0.027) uptake. A higher glomerular filtration rate was associated with a higher renal SUVmean (β = 0.16; 95% CI, 0.05 to 0.26; P = 0.0034). Conclusion: These findings suggest that ADT systemically modulates PSMA expression, which may have implications for treatment-optimizing and side-effect-minimizing strategies for PSMA radioligand therapies, particularly those using more potent 225Ac-labeled PSMA conjugates.

The role of PSMA PET/CT to predict upgrading in patients undergoing radical prostatectomy for ISUP grade group 1 prostate cancer.

To investigate the additive role of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) independent from multiparametric magnetic resonance imaging (mpMRI) and clinical-pathological parameters to predict pathological upgrading in patients with ISUP grade group (GG) 1 prostate cancer (PCa) at prostate biopsy. A total of 41 patients who underwent robotic radical prostatectomy (RP) for GG1 disease at prostate biopsy with preoperative PSMA PET/CT and mpMRI images available for central review were included in the study. Univariate and multivariate logistic regression analyses were performed to determine the independent predictors of pathological upgrading (GG ≥ 2). Final RP pathology revealed upgrading in 26 patients (65.9%); to GG 2 disease in 25 cases and GG 4 disease in one case. International Society of Urological Pathology (ISUP) upgrading rates for prostate imaging-reporting and data system (PIRADS)-5, PIRADS-4, and PIRADS ≤ 3 lesions were 78%, 74%, and 38%, respectively. Fourteen out of 15 (93.3%) patients with an SUVmax ≥ 5.6 and all patients with an SUVmax ≥ 6.5 (n = 10) had pathological upgrading. The upgrading rate in patients with SUV < 5.6 was 46.2% (12/26). Intraprostatic SUVmax ≥ 5.6 was found as the only independent predictor of pathological upgrading in multivariate analysis. High prostatic PSMA uptake was found to be a very reliable predictor of pathological upgrading, but low PSMA uptake cannot exclude pathological upgrading. Intraprostatic PSMA uptake along with previously known mpMRI and biopsy-related parameters should be considered when making a treatment decision in patients with GG1 PCa at prostate biopsy.

Preclinical Evaluation of a New Series of Albumin-Binding 177Lu-Labeled PSMA-Based Low-Molecular-Weight Radiotherapeutics.

Prostate-specific membrane antigen (PSMA)-based low-molecular-weight agents using beta(β)-particle-emitting radiopharmaceuticals is a new treatment paradigm for patients with metastatic castration-resistant prostate cancer. Although results have been encouraging, there is a need to improve the tumor residence time of current PSMA-based radiotherapeutics. Albumin-binding moieties have been used strategically to enhance the tumor uptake and retention of existing PSMA-based investigational agents. Previously, we developed a series of PSMA-based, β-particle-emitting, low-molecular-weight compounds. From this series, 177Lu-L1 was selected as the lead agent because of its reduced off-target radiotoxicity in preclinical studies. The ligand L1 contains a PSMA-targeting Lys-Glu urea moiety with an N-bromobenzyl substituent in the ε-amino group of Lys. Here, we structurally modified 177Lu-L1 to improve tumor targeting using two known albumin-binding moieties, 4-(p-iodophenyl) butyric acid moiety (IPBA) and ibuprofen (IBU), and evaluated the effects of linker length and composition. Six structurally related PSMA-targeting ligands (Alb-L1-Alb-L6) were synthesized based on the structure of 177Lu-L1. The ligands were assessed for in vitro binding affinity and were radiolabeled with 177Lu following standard protocols. All 177Lu-labeled analogs were studied in cell uptake and selected cell efficacy studies. In vivo pharmacokinetics were investigated by conducting tissue biodistribution studies for 177Lu-Alb-L2-177Lu-Alb-L6 (2 h, 24 h, 72 h, and 192 h) in male NSG mice bearing human PSMA+ PC3 PIP and PSMA- PC3 flu xenografts. Preliminary therapeutic ratios of the agents were estimated from the area under the curve (AUC0-192h) of the tumors, blood, and kidney uptake values. Compounds were obtained in >98% radiochemical yields and >99% purity. PSMA inhibition constants (Kis) of the ligands were in the ≤10 nM range. The long-linker-based agents, 177Lu-Alb-L4 and 177Lu-Alb-L5, displayed significantly higher tumor uptake and retention (p < 0.001) than the short-linker-bearing 177Lu-Alb-L2 and 177Lu-Alb-L3 and a long polyethylene glycol (PEG) linker-bearing agent, 177Lu-Alb-L6. The area under the curve (AUC0-192h) of the PSMA+ PC3 PIP tumor uptake of 177Lu-Alb-L4 and 177Lu-Alb-L5 were >4-fold higher than 177Lu-Alb-L2, 177Lu-Alb-L3, and 177Lu-Alb-L6, respectively. Also, the PSMA+ PIP tumor uptake (AUC0-192h) of 177Lu-Alb-L2 and 177Lu-Alb-L3 was ~1.5-fold higher than 177Lu-Alb-L6. However, the lowest blood AUC0-192h and kidney AUC0-192h were associated with 177Lu-Alb-L6 from the series. Consequently, 177Lu-Alb-L6 displayed the highest ratios of AUC(tumor)-to-AUC(blood) and AUC(tumor)-to-AUC(kidney) values from the series. Among the other agents, 177Lu-Alb-L4 demonstrated a nearly similar ratio of AUC(tumor)-to-AUC(blood) as 177Lu-Alb-L6. The tumor-to-blood ratio was the dose-limiting therapeutic ratio for all of the compounds. Conclusions: 177Lu-Alb-L4 and 177Lu-Alb-L6 showed high tumor uptake in PSMA+ tumors and tumor-to-blood ratios. The data suggest that linker length and composition can be modulated to generate an optimized therapeutic agent.

18F]-PSMA-1007-PET for evaluation of kidney function.

Prostate-specific membrane antigen (PSMA) is present in the proximal tubule cells of the kidneys. This results in high renal tracer uptake in PSMA-PET, which may contain useful information on renal function. As part of the evaluation for [177Lu]-PSMA therapies, patients undergo PSMA-PET and additional [99mTc]-mercapto-acetyltriglycine (MAG3) scintigraphy to assess renal function. Aim of this study was to evaluate estimation of renal function with [18F]-PSMA-1007-PET/CT (PSMA-PET) by comparison to timely MAG3-scintigraphies. We retrospectively investigated 73 prostate cancer patients with 93 timely available PSMA-PET/CT, MAG3-scintigraphies and serum creatinine. For determination of split renal function in PSMA-PET/CT, we evaluated the relative unilateral total renal PSMA uptake, i.e. SUVmean multiplied by the renal volume (SRFPSMA-TOTAL) and relative unilateral maximal standardized uptake value (SRFSUV). These were compared to MAG3 split renal function (SRFMAG3) using Pearson correlation and receiver operating characteristics analysis. For determination of global renal function, correlation of bilateral total renal PSMA uptake with MAG3 tubular excretion rate and serum creatinine was assessed. SRFMAG3 was strongly correlated with SRFPSMA-TOTAL (r= 0.872, p<0.001) and with SRFSUV (r=0.815, p<0.001). Relevant abnormalities of SRFMAG3 (unilateral renal function < 25 %) could be detected with sensitivities and specificities of 90% and 92% for SRFPSMA-TOTAL, and 80% and 95% for SRFSUV. Measures of absolute renal function were only weakly correlated with bilateral total renal PSMA uptake. Renal [18F]-PSMA-1007 uptake allowed to quantify renal split function with good accuracy based on SRFPSMA-TOTAL or SRFSUV.

Prostate-Specific Membrane Antigen Uptake Heterogeneity in Mixed Ductal-Acinar Adenocarcinoma of the Prostate.

Prostate-specific membrane antigen (PSMA) PET findings of mixed ductal-acinar adenocarcinoma of the prostate are rarely reported. We describe 18 F-PSMA-1007 PET/CT and delayed pelvic 18 F-PSMA-1007 PET/MRI findings in a case of prostatic mixed ductal-acinar adenocarcinoma with multiple lymph node and bone metastases. The primary tumor showed heterogeneous PSMA uptake. The metastases in the right ilium and acetabulum showed intense PSMA uptake, but the pelvic lymph node and left iliac bone metastases showed no significant PSMA uptake. Knowledge of the intraprimary and intermetastatic heterogeneity of PSMA uptake in mixed ductal-acinar adenocarcinoma of the prostate may be helpful for accurate interpretation.

Distribution of prostate specific membrane antigen (PSMA) on PET-MRI in patients with and without ovarian cancer.

Ovarian cancer is the most lethal cancer and future research needs to focus on the early detection and exploration of new therapeutic agents. The objectives of this proof-of-concept study are to assess the feasibility of PSMA 18F-DCFPyl PET/MR imaging for detecting ovarian cancer and to evaluate the PSMA distribution in patients with and without ovarian cancer. This prospective pilot proof-of-concept study in patients with and without ovarian cancers occurred between October 2017 and January 2020. Patients were recruited from gynecologic oncology or hereditary ovarian cancer clinics, and underwent surgical removal of the uterus and ovaries for gynecologic indications. PSMA 18F-DCFPyl PET/MRI was obtained prior to standard of care surgery. Fourteen patients were scanned: four patients with normal ovaries, six patients with benign ovarian lesions, and four patients with malignant ovarian lesions. Tracer uptake in normal ovaries (SUVmax = 2.8±0.4) was greater than blood pool (SUVmax = 1.8±0.5, p < 0.0001). Tracer uptake in benign ovarian lesions (2.2±1.0) did not differ significantly from blood pool (p=0.331). Tracer uptake in ovarian cancer (SUVmax = 7.8±3.8) was greater than blood pool (p<0.0001), normal ovaries (p=0.0014), and benign ovarian lesions (p=0.005). PET/MR imaging detected PSMA uptake in ovarian cancer, with little to no uptake in benign ovarian findings. These results are encouraging and further studies in a larger patient cohort would be useful to help determine the extent and heterogeneity of PSMA uptake in ovarian cancer patients.

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 &lt;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.