Prostate-specific Membrane Antigen Research Articles

Prostate-Specific Membrane Antigen Positron Emission Tomography Oncological Applications beyond Prostate Cancer in Comparison to Other Radiopharmaceuticals

Background: Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein overexpressed on the surface of tumor cells in most of the patients affected by prostate adenocarcinoma (PCa). However, PSMA expression has also been demonstrated in the endothelial cells of newly formed vessels of various solid tumors, suggesting a role for PSMA in neoangiogenesis. In this scenario, gallium-68 (68Ga) or fluoro-18 (18F)-labeled PSMA positron emission tomography (PET) may play a role in tumors other than PCa, generally evaluated employing other radiopharmaceuticals targeting different pathways. This review aims to investigate the detection rate of PSMA-PET compared to other radiopharmaceuticals (especially [18F]FDG) in non-prostate tumors to identify patients who may benefit from the use of such a theragnostic agent. Methods: We performed a bibliographic search on three different databases until February 2024 using the following terms: “positron emission tomography”, “PET”, “PET/CT”, “Prostate-specific membrane antigen”, “PSMA”, “non-prostate”, “not prostate cancer”, “solid tumor”, “FDG”, “Fluorodeoxyglucose”, “FAPi”, “FET”, “MET”, “DOPA”, “choline”, “FCH”, “FES”, “DOTATOC”, “DOTANOC”, and “DOTATATE”. Only original articles edited in English with at least 10 patients were included. Results: Out of a total of 120 articles, only 25 original articles comparing PSMA with other radiotracers were included in this study. The main evidence was demonstrated in renal cell carcinoma, where PSMA showed a higher detection rate compared to [18F]FDG PET/CT, with implications for patient management. PSMA PET may also improve the assessment of other entities, such as gliomas, in defining regions of early neoangiogenesis. Further data are needed to evaluate the potential role of PSMA-PET in triple-negative breast cancer as a novel therapeutic vascular target. Finally, unclear applications of PSMA-PET include thyroid and gastrointestinal tumors. Conclusions: The present review shows the potential use of PSMA-labeled PET/CT in solid tumors beyond PCa, underlining its value over other radiopharmaceuticals (mainly [18F]FDG). Prospective clinical trials with larger sample sizes are crucial to further investigate these possible clinical applications.

Increased α2,3-sialyl N-glycosylated prostate-specific membrane antigen (PSMA) in post-DRE urine is associated with high grade group prostate cancer.

Aberrant glycosylation of proteins is an important hallmark in multiple cancers. Prostate-specific membrane antigen (PSMA), a highly glycosylated protein with 10 N-linked glycosylation sites, is an Food and Drug Administration approved theranostic for prostate cancer. However, glycosylation changes in PSMA that are associated with prostate cancer disease progression have not been fully characterized. We investigated whether urinary PSMA sialylation correlate with high-grade prostate cancer. Urine samples were collected from men after digital rectal examination (DRE) before prostate biopsy. Lectin-antibody enzyme-linked immunoassay was used to quantify α2,3-sialyl PSMA in post-DRE urine samples from subjects with benign prostate tumors, Grade Group 1 prostate cancer and those with Grade Group ≥2 disease. There are significant increases in α2,3-sialylated PSMA in patients with Grade Group ≥2 disease compared to benign (p = 0.0009) and those with Grade Group 1 disease (p = 0.0063). There were no significant differences in α2,3-sialyl PSMA levels between Grade Group 1 and benign prostate tumors (p = 0.7947). Our study shows that there are significant differences in the abundance of α2,3-sialylated PSMA in post-DRE urines from disease stratified prostate cancer patients, and the increase is correlated with progression and disease severity. The detection of increased PSMA sialyation in post-DRE urines from patients with higher Grade Group ≥2 disease states provides novel untapped potential for the development of prognostic biomarkers for prostate cancer. Specifically, quantitation of α2,3-sialylated PSMA shows potential for discriminating between benign to intermediate grade disease, which is a significant clinical challenge in staging and risk stratification of prostate cancer.

Imaging and therapy in prostate cancer using PSMA radioligands.

Prostate specific membrane antigen (PSMA)-directed PET imaging has rapidly transformed prostate cancer workup over the past decade and paved the way for a theranostic approach using 177Lu-labelled PSMA radioligand therapy. This review gives an overview of the underlying principles behind PSMA as a target; the current use of PSMA PET in prostate cancer imaging and benefits compared to conventional imaging; and therapeutic applications including optimisation of patient selection. It also explores the evidence base of PSMA PET for other indications not in routine clinical use and the future of PSMA-directed radioligand therapy.

PSMA-Targeted Therapy: Advancements in Detection and Treatment Modalities with Dr. Scott T. Tagawa

Prostate cancer is one of the most challenging malignancies due to its high incidence and prevalence, as it is the most frequently diagnosed non-skin cancer in men. The timely identification of prostate cancer and its metastasis is paramount for ensuring favorable outcomes for patients. Prostate-specific membrane antigen (PSMA) emerges as a promising biomarker for its detection, due to its specificity. This makes it an ideal target for the early identification of a metastatic phenotype. Situated on the membrane of tumor cells, PSMA facilitates the attachment of PSMA-targeting particles, enabling their detection through positron emission tomography (PET) scans with relative ease. Utilizing these imaging agents in conjunction with PET scans enhances the accuracy of prostate cancer tumor detection compared to PET scans alone. The advancement in prostate cancer imaging has paved the way for innovative treatment modalities. Prostate-specific membrane antigen-targeted radionuclide therapies (PSMA-TRT) exploit PSMA imaging agents to target identified prostate cancer malignancies with precise radiation, thereby reducing or eliminating the tumor mass. PSMA-TRT exhibits significant promise in prostate cancer therapy, evident from the notable declines in prostate-specific antigen (PSA) levels post treatment. However, PSMA-TRT carries both beneficial and adverse effects. While it represents a substantial leap forward in tumor cell imaging, PSMA-based antigens, being larger particles than ligands, offer prolonged imaging capabilities. Yet, the long-term effects of PSMA-TRT remain unknown, with the short-term adverse ones including fatigue, nausea, pain flares, and potential radiation exposure to others.

A phase 2, single-arm trial evaluating 131I-PSMA-1095 targeted radioligand therapy for metastatic castration-resistant prostate cancer.

Metastatic castration-resistant prostate cancer (mCRPC) remains uniformly lethal. Prostate specific membrane antigen (PSMA) is a transmembrane glycoprotein overexpressed in prostate cancer. 131I-PSMA-1095 (also known as 131I-MIP-1095) is a PSMA-targeted radioligand which selectively delivers therapeutic radiation to cancer cells and the tumor microenvironment. We conducted a single-arm, phase 2 trial to assess efficacy and tolerability of 131I-PSMA-1095 in mCRPC patients who had exhausted all lines of approved therapy. All patients underwent 18F-DCFPyL PET and 18F-FDG PET to determine PSMA-positive tumor volume, and patients with >50% PSMA-positive tumor volume were treated with up to four doses of 131I-PSMA-1095. The primary endpoint was the response rate of prostate specific antigen (PSA). Secondary endpoints included rates of radiographic response and adverse events. Overall and radiographic progression-free survival were also analyzed. Eleven patients were screened for inclusion and nine patients received 131I-PSMA-1095. The median baseline PSA was 162 µg/l, and six patients demonstrated a >50% PSA decrease. One patient demonstrated a confirmed radiographic response. Median overall survival was 10.3 months, and median progression-free survival was 5.4 months. Four patients experienced adverse events of grade 3 or higher, the most frequent being thrombocytopenia and anemia. 131I-PSMA-1095 is highly active against heavily-pretreated PSMA-positive mCRPC, significantly decreasing tumor burden as measured by PSA. Adverse events, mainly hematologic toxicity, were not infrequent, likely related to off-target irradiation. This hematologic toxicity, as well as a higher logistical burden associated with use, could represent relative disadvantages of 131I-PSMA-1095 compared to 177Lu-PSMA-617.

Retrospective analysis of thyroid incidentalomas detected by [68Ga]Ga-PSMA-11 PET/CT.

Prostate cancer patients, undergo imaging procedures, with [68Ga]Ga-PSMA-11 PET/CT (prostate-specific membrane antigen based positron emission tomography/computed tomography) utilized for primary and secondary staging. PSMA thyroid incidentalomas (PTI) are discovered in the thyroid gland while imaging prostate cancer patients with [68Ga]Ga-PSMA-11 PET/CT. The aim of the study was to determine the clinical significance of PTIs detected on [68Ga]Ga-PSMA-11 PET/CT. Another goal was to identify a possible threshold for the maximum standardized uptake value (SUVmax), above which a malignant growth could be suspected. A retrospective cross-sectional study. 769 patients with prostat cancer who underwent [68Ga]Ga-PSMA-11 PET/CT scans in the nuclear medicine department of a tertiary care hospital between January 2020 and December 2022 were retrospectively screened in this study. We analyzed 67 patients in whom PTI was detected. Patients who exceeded the inclusion criteria had their thyroid ultrasonography and ultrasonography -guided fine needle aspiration findings analyzed. PTI was discovered in 67 patients (8%). 42 patients who met the inclusion and exclusion criteria were included in the study. Of the 4 malignant patients (9.5%) in the study population, 2 were classified as TIRADS 3 and 2 were classified as TIRADS 4. The cut-off SUVmax value was found to be 5.6. With 100% sensitivity and 47.37% specificity, a cutoff SUVmax of 5.3 was determined through receiver-operator characteristic analysis in order to predict malignant cytology. PTI is a significant clinical finding; most of diffuse and focal uptakes are frequently related to benign diseases. Each center should establish its own a possible SUVmax cut-off over which a malignant lesion should be suspected.

PSMA-Avid Desmoid Tumor of the Abdominal Wall on 18F-Piflufolastat PET/CT

Abstract Prostate-specific membrane antigen (PSMA) PET/CT is widely used in the evaluation of suspected metastasis for initial definitive therapy and suspected recurrence of prostate cancer. We outline a case report of a 62-year-old man with history of prostate cancer treated with surgery, salvage radiation, and hormonal therapy presenting with rising PSA levels. There was incidental detection of a PSMA-avid subcutaneous abdominal wall mass on PSMA PET/CT study, which was consistent with desmoid fibromatosis on an ultrasound-guided biopsy.

Assessing Response to PSMA Radiopharmaceutical Therapies with Single SPECT Imaging at 24 Hours After Injection.

Understanding the relationship between lesion-absorbed dose and tumor response in 177Lu-PSMA-617 radiopharmaceutical therapies (RPTs) remains complex. We aimed to investigate whether baseline lesion-absorbed dose can predict lesion-based responses and to explore the connection between lesion-absorbed dose and prostate-specific antigen (PSA) response. Methods: In this retrospective study, we evaluated 50 patients with 335 index lesions undergoing 177Lu-PSMA-617 RPT, who had dosimetry analysis performed on SPECT/CT at 24 h after cycles 1 and 2. First, we identified the index lesions for each patient and measured the lesion-based absorbed doses. Lesion-based response was calculated after cycle 2. Additionally, PSA50 response (a decline of 50% from baseline PSA) after cycle 2 was also calculated. The respective responses for mean and maximum absorbed doses and prostate-specific membrane antigen (PSMA) volumetric intensity product (VIP-PSMA) at cycles 1 and 2 were termed SPECTmean, SPECTmaximum, and SPECTVIP-PSMA, respectively. Results: Of the 50 patients reviewed, 46% achieved a PSA50 response after cycle 2. Of the 335 index lesions, 58% were osseous, 32% were lymph nodes, and 10% were soft-tissue metastatic lesions. The SPECT lesion-based responses were higher in PSA responders than in nonresponders (SPECTmean response of 46.8% ± 26.1% vs. 26.2% ± 24.5%, P = 0.007; SPECTmaximum response of 45% ± 25.1% vs. 19% ± 27.0%, P = 0.001; SPECTVIP-PSMA response of 49.2% ± 30.3% vs. 14% ± 34.7%, P = 0.0005). An association was observed between PSA response and SPECTVIP-PSMA response (R 2 = 0.40 and P < 0.0001). A limited relationship was found between baseline absorbed dose measured with a 24-h single time point and SPECT lesion-based response (R 2 = 0.05, P = 0.001, and R 2 = 0.03, P = 0.007, for mean and maximum absorbed doses, respectively). Conclusion: In this retrospective study, quantitative lesion-based response correlated with patient-level PSA response. We observed a limited relationship between baseline absorbed dose and lesion-based responses. Most of the variance in response remains unexplained solely by baseline absorbed dose. Establishment of a dose-response relationship in RPT with a single time point at 24 h presented some limitations.

Discovery of Glutamate Carboxypeptidase III Ligands to Compete the Uptake of [177Lu]Lu-PSMA-617 in Healthy Organs.

Prostate-specific membrane antigen (PSMA)-targeted radio ligand therapeutics (RLTs), such as [177Lu]Lu-PSMA-617 (Pluvicto), have been shown to accumulate in salivary glands and kidneys, potentially leading to undesired side effects. As unwanted accumulation in normal organs may derive from the cross-reactivity of PSMA ligands to glutamate carboxypeptidase III (GCPIII), it may be convenient to block this interaction with GCPIII-selective ligands. Parallel screening of a DNA-encoded chemical library (DEL) against GCPIII and PSMA allowed the identification of GCPIII binders. Structure-activity relationship (SAR) studies resulted in the identification of nanomolar GCPIII ligands with up to 1000-fold selectivity over PSMA. We studied the ability of GCPIII ligands to counteract the binding of [177Lu]Lu-PSMA-617 to human salivary glands by autoradiography and could demonstrate a partial radioprotection.

Predictors of Metastasis in 68GA-Prostate Specific Membrane Antigen Pet-CT in the Primary Staging of Prostate Cancer

Background: The objective of this study was to investigate factors influencing Gallium 68 Prostate Specific Membrane Antigen Positron Emission Tomography (Ga68 PSMA PET-CT) uptake for primary staging in prostate cancer. Methods: Retrospective analysis was conducted on 499 non-metastatic and 243 de novo metastatic prostate cancer cases undergoing Ga68 PSMA PET-CT. Demographic, clinical, and imaging data were collected and analyzed. Multivariate logistic regression determined independent risk factors for metastasis detection on Ga68 PSMA PET-CT. Results: Metastatic cases showed higher levels of total PSA, PSA density (dPSA) and biopsy ISUP grade group compared to non-metastatic cases. Multivariate analysis identified cT2 stage and dPSA as independent predictors of metastasis detection on Ga68 PSMA PET-CT. Conclusions: Ga68 PSMA PET-CT plays a crucial role in prostate cancer staging, with identified factors such as clinical T stage and dPSA significantly impacting its diagnostic accuracy. These findings underscore the importance of Ga68 PSMA PET-CT in refining clinical staging and guiding treatment decisions for prostate cancer patients.

Prostate-Specific Membrane Antigen Targeted StarPEG Nanocarrier for Imaging and Therapy of Prostate Cancer.

The uptake of large (>10nm) non-targeted nanocarriers by bulk tumors is thought to be dominated by passive extravasation through porous tumor vessels and limited lymphatic drainage, the enhanced permeability and retention (EPR) effect. Prior studies demonstrated radiolabeled tumor-targeted and non-targeted 4-arm 40kDa star polyethylene glycol (StarPEG) polymers for cancer imaging. By adding small molecule ligands targeting prostate-specific membrane antigen (PSMA) to the StarPEG polymer, marked increase in tumor uptake, penetration and retention in the tumor core was observed. These prior studies support the application of imaging surrogates for the evaluation of targeted delivery of chemotherapeutic nanomedicines and the potential for therapy using analogous β-emitting radiopharmaceuticals. To evaluate the delivery and therapeutic efficacy of PSMA-targeted StarPEG nanocarriers, StarPEG nanodrugs with or without three copies of PSMA-targeting, ACUPA, ligands were designed and synthesized. One copy of the radiometal chelator, DOTA, was conjugated to each nanocarrier for labelling with b-emitting 177Lu, providing non-targeted [177Lu]PEG-(DOTA)1 and PSMA targeting [177Lu]PEG-(DOTA)1(ACUPA)3, for SPECT imaging and therapy. The radiolabeled nanodrugs were evaluated in vitro and in vivo using PSMA+ PC3-Pip and/or PSMA- PC3-Flu cell lines, subcutaneous xenografts and disseminated metastatic models. The nanocarriers PEG-(DOTA)1 and PEG-(DOTA)1(ACUPA)3 were efficiently radiolabeled with 177Lu with molar activities of 10.8-15.8 MBq/nmol. Along with excellent in vitro PSMA binding affinity (kD = 51.7nM in PC3-Pip cells), the targeted nanocarrier [177Lu]PEG-(DOTA)1(ACUPA)3 demonstrated excellent in vivo single-photon emission computed tomography (SPECT) imaging contrast with 21.3% ID/g uptake in PC3-Pip tumors at 192h post injection. Single doses of 18.5 MBq [177Lu]PEG-(DOTA)1(ACUPA)3 showed complete resolution of the PC3-Pip xenografts, without any regrowth up to 138 days. The StarPEG nanocarriers demonstrated high PSMA-targeted delivery of the therapeutic isotope 177Lu with excellent imaging contrast. The targeted nanocarrier eliminated subcutaneous and metastatic PC3-Pip tumors. Overall, these preclinical results demonstrated high treatment efficacy of the PSMA-targeted nanocarrier [177Lu]PEG-(DOTA)1(ACUPA)3 for prostate cancer, with potential for clinical translation. This article is protected by copyright. All rights reserved.

Abstract PO4-13-05: Spotlight on PSMA as a new theranostic biomarker for breast cancer

Abstract Breast cancer patients are risk-stratified on the basis of the subtype classification. However, this parameter is not completely accurate in discriminating between high- and low-risk disease, creating a need for a reliable marker to determine aggressiveness. Prostate-specific membrane antigen (PSMA) could fulfill this need given that it has been reported to be expressed by breast cancer tumor cells and the endothelial cells of tumor vessels. We analyzed 68 breast cancers (BC) of whom 14 luminal A, 28 Luminal B, 15 HER2 positive and 11 triple negative BC to assess whether PSMA expression by immunohistochemistry was different in the several tumor subtypes and was related to ki67 expression and stromal TILs. PSMA positivity was calculated as the number of positive vessels on 10 fields at 40X magnifications. Kruskal Wallis’s test was used to assess difference in PSMA positivity among BC subgroups and Dunn’s test was performed for post-hoc comparisons; Spearman’s rho coefficient was calculated to analyze the correlation among PSMA, KI67 and TILs. Our results show that median PSMA was higher both considering the number of positive vessels and the staining intensity in TNBC compared to Luminal A and B tumors (p&amp;lt; 0.001). Ki67 was higher in TNBC compared to Luminal A tumors (p&amp;lt; 0.001). We saw a correlation between PSMA and ki67, especially in HER2+ tumors (p=0.002), while a correlation between PSMA and TILs was observed in TNBC (p=0.014). The analysis of PSMA expression on the lymph nodes showed the same trend observed for the primary tumors given that it was higher in TNBC compared to HER2 positive and luminal cancers. Our results suggest that PSMA could be used as theranostic biomarker in BC considering that it is highly expressed in more aggressive tumors and the possibility to treat PSMA-expressing patients for anti-angiogenesis and/or radionuclide treatment. Citation Format: Sara Bravaccini, Stefania Cortecchia, Flavia Foca, Giovanni Martinelli, Sara Ravaioli, Maria Maddalena Tumedei, Federica Matteucci, Roberta Maltoni, Giovanni Paganelli, Francesca Poli, Maurizio Puccetti. Spotlight on PSMA as a new theranostic biomarker for breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-13-05.

Comparison of discovery rates and prognostic utility of [68Ga]Ga-PSMA-11 PET/CT and circulating tumor DNA in prostate cancer-a cross-sectional study.

Circulating-tumor DNA (ctDNA) and prostate-specific membrane antigen (PSMA) ligand positron-emission tomography (PET) enable minimal-invasive prostate cancer (PCa) detection and survival prognostication. The present study aims to compare their tumor discovery abilities and prognostic values. One hundred thirty men with confirmed PCa (70.5 ± 8.0years) who underwent [68Ga]Ga-PSMA-11 PET/CT (184.8 ± 19.7MBq) imaging and plasma sample collection (March 2019-August 2021) were included. Plasma-extracted cell-free DNA was subjected to whole-genome-based ctDNA analysis. PSMA-positive tumor lesions were delineated and their quantitative parameters extracted. ctDNA and PSMA PET/CT discovery rates were compared, and the prognostic value for overall survival (OS) was evaluated. PSMA PET discovery rates according to castration status and PSA ranges did differ significantly (P = 0.013, P < 0.001), while ctDNA discovery rates did not (P = 0.311, P = 0.123). ctDNA discovery rates differed between localized and metastatic disease (P = 0.013). Correlations between ctDNA concentrations and PSMA-positive tumor volume (PSMA-TV) were significant in all (r = 0.42, P < 0.001) and castration-resistant (r = 0.65, P < 0.001), however not in hormone-sensitive patients (r = 0.15, P = 0.249). PSMA-TV and ctDNA levels were associated with survival outcomes in the Logrank (P < 0.0001, P < 0.0001) and multivariate Cox regression analysis (P = 0.0023, P < 0.0001). These findings suggest that PSMA PET imaging outperforms ctDNA analysis in detecting prostate cancer across the whole spectrum of disease, while both modalities are independently highly prognostic for survival outcomes.

Abstract ED02-03: Innovative approaches at the diagnosis and treatment of invasive lobular carcinoma

Abstract Invasive Lobular Carcinoma (ILC) represents a unique subtype of breast cancer characterized by distinctive clinical and molecular features. This presentation aims to delve into innovative approaches in the diagnosis and treatment of ILC, focusing on novel techniques in imaging, unique molecular findings, signaling pathway alterations, targetable biomarkers, and microenvironment profiling that can pave the way for the development of novel therapies. Imaging Techniques in ILC: Accurate diagnosis is the foundation for effective treatment. ILC often presents diagnostic challenges due to the fact that lobular cells tends to infiltrate the affected organs in a diffuse manner instead of forming a discrete tumor mass making diagnostic imaging such as screening mammograms and CT scans less precise. This presentation will explore cutting-edge imaging techniques such as contrast-enhanced mammography, novel radioisotopes for positron emission tomography (PET) such as Fluoroestradiol F18 (FES), Fluciclovine and prostate-specific membrane antigen (PSMA) for improved detection and characterization of ILC lesions. Furthermore, we will discuss emerging modalities like radiomics and artificial intelligence, which hold promise in enhancing early diagnosis and risk assessment. Molecular Insights into ILC: ILC is distinguished by its unique molecular profile, notably the loss of E-cadherin expression. We will delve into recent advancements in understanding the molecular landscape of ILC, including genomic alterations, epigenetic changes, and the role of signaling pathways providing insights into potential therapeutic vulnerabilities. Targetable Biomarkers and Pathways: Identification of targetable biomarkers is essential for the development of precision therapies in ILC. This presentation will highlight promising targets, including ERBB2 (HER2), ROS1, TROP2, AKT1 along with other novel biomarkers. Microenvironment Profiling: The tumor microenvironment plays a pivotal role in cancer progression and therapy response. We will discuss recent advancements in characterizing the ILC microenvironment, including the immune cell infiltrate and stromal components. Understanding the dynamic interplay between the tumor and its microenvironment can inform the development of immunotherapies and combination strategies tailored to ILC. In conclusion, this presentation will provide a comprehensive overview of the latest innovations in ILC diagnosis and treatment. Our exploration of advanced imaging techniques, molecular findings, targetable pathways, biomarkers, and microenvironment profiling will shed light on the exciting potential for personalized therapeutic approaches in the management of ILC. By staying at the forefront of these developments, we can pave the way for improved outcomes and enhanced quality of life for patients with ILC. Citation Format: J. Mouabbi. Innovative approaches at the diagnosis and treatment of invasive lobular carcinoma [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr ED02-03.

Design, synthesis and evaluation of novel prostate-specific membrane antigen-targeted aryl [18F]fluorosulfate PET tracers

The expression of prostate-specific membrane antigen (PSMA) in prostate cancer is 100–1000 times higher than that in normal tissues, and it has shown great advantages in the diagnosis and treatment of prostate cancer. The combination of PSMA and PET imaging technology based on the principle of metabolic imaging can achieve high sensitivity and high specificity for diagnosis. Due to its suitable half-life (109 min) and good positron abundance (97 %), as well as its cyclotron accelerated generation, 18F has the potential to be commercialize, which has attracted much attention. In this article, we synthesized a series of fluorosulfate PET tracers targeting PSMA. All four analogues have shown high affinity to PSMA (IC50 = 1.85–5.15 nM). After the radioisotope exchange labeling, [18F]L9 and [18F]L10 have PSMA specific cellular uptake (0.65 ± 0.04 % AD and 1.19 ± 0.03 % AD) and effectively accumulated in 22Rv1 xenograft mice model. This study demonstrates that PSMA-1007-based PSMA-targeted aryl [18F]fluorosulfate novel tracers have the potential for PET imaging in tumor tissues.

Intramuscular Granular Cell Tumor Detected on 68Ga-PSMA PET/CT.

Finding of the prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer (PC) cells that have made it possible to evaluate the patients with PC with a single imaging method. 68Ga-PSMA PET/CT is now part of the routine in patients with PC. After several years of clinical experience with PSMA tracers, the specificity is satisfactory; however, concerns about the specificity are raising day by day due to the newly laid out nonprostatic malignant and benign lesions with high PSMA expression. Herein, we present an incidental 68Ga-PSMA uptake in an intramuscular granular cell tumor.

Heterogeneous PSMA ligand uptake inside parotid glands

The purpose of this investigation is to quantify the spatial heterogeneity of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) uptake within parotid glands. We aim to quantify patterns in well-defined regions to facilitate further investigations. Furthermore, we investigate whether uptake is correlated with computed tomography (CT) texture features. Methods: Parotid glands from [18F]DCFPyL PSMA PET/CT images of 30 prostate cancer patients were analyzed. Uptake patterns were assessed with various segmentation schemes. Spearman’s rank correlation coefficient was calculated between PSMA PET uptake and feature values of a Grey Level Run Length Matrix using a long and short run length emphasis (GLRLML and GLRLMS) in subregions of the parotid gland. Results: PSMA PET uptake was significantly higher (p < 0.001) in lateral/posterior regions of the glands than anterior/medial regions. Maximum uptake was found in the lateral half of parotid glands in 50 out of 60 glands. The difference in SUVmean between parotid halves is greatest when parotids are divided by a plane separating the anterior/medial and posterior/lateral halves symmetrically (out of 120 bisections tested). PSMA PET uptake was significantly correlated with CT GLRLML (p < 0.001), and anti-correlated with CT GLRLMS (p < 0.001). Conclusion: Uptake of PSMA PET is heterogeneous within parotid glands, with uptake biased towards lateral/posterior regions. Uptake within parotid glands was strongly correlated with CT texture feature maps.

Challenges in the solution phase synthesis of PSMA-11 and PSMA-617: organic ligands for radiopharmaceutical preparations in prostate cancer medication

Abstract Patient specific treatments for different cancers are currently being actively addressed through nuclear medicine. More recently, the identification of biomarker namely; prostate-specific membrane antigen (PSMA) expressed on the prostate cancer cell surface has been considered as a turning point in prostate cancer management using radiopharmaceuticals. In this treatment method, apart from radionuclide, organic ligands that target PSMA constitute an essential component. PSMA-11 and PSMA-617 are two important ligands that form the radiopharmaceuticals, [68Ga]Ga-PSMA-11, [177Lu]Lu-PSMA-617, which are currently powering the prostate cancer management, especially metastatic castration resistant prostate cancer (mCRPC) in most part of the world. Identification of efficient synthetic routes towards these highly expensive ligands is an important prerequisite to make this treatment modality more popular. In this account, the synthetic challenges that we circumvent during the solution phase synthesis of PSMA-11 and PSMA-617, through different chemical synthetic routes are demonstrated. Post-synthesis, both the ligands, PSMA-11 and PSMA-617 were successfully radiolabelled using 68Ga, and 177Lu, respectively, to generate corresponding labelled products [68Ga]Ga-PSMA-11, and [177Lu]Lu-PSMA-617, in good radiochemical purity.

Biochemical Response of

BackgroundIn a subset of patients with oligorecurrent prostate cancer (PCa), salvage surgery with prostate-specific membrane antigen (PSMA) radioguided surgery (PSMA-RGS) seems to be of value. ObjectiveTo evaluate whether a lower level of postoperative prostate-specific antigen (PSA; <0.1 ng/ml) is predictive of therapy-free survival (TFS) following salvage PSMA-RGS. Design, setting, and participantsThis cohort study evaluated patients with biochemical recurrence after radical prostatectomy and oligorecurrent PCa on PSMA positron emission tomography treated with PSMA-RGS in three tertiary care centers (2014–2022). InterventionPSMA-RGS. Outcome measurements and statistical analysisPostsalvage surgery PSA response was categorized as <0.1, 0.1–<0.2, or >0.2 ng/ml. Kaplan-Meier and multivariable Cox regression models evaluated TFS according to PSA response. Results and limitationsAmong 553 patients assessed, 522 (94%) had metastatic soft tissue lesions removed during PSMA-RGS. At 2–16 wk after PSMA-RGS, 192, 62, and 190 patients achieved PSA levels of <0.1, 0.1–<0.2, and >0.2 ng/ml, respectively. At 2 yr of follow-up, TFS rate was 81.1% versus 56.1% versus 43.1% (p < 0.001) for patients with PSA <0.1 versus 0.1–<0.2 versus >0.2 ng/ml. In multivariable analyses, PSA levels of 0.1–0.2 ng/ml (hazard ratio [HR]: 1.9, confidence interval [CI]: 1.1–3.1) and ≥0.2 ng/ml (HR: 3.2, CI: 2.2–4.6, p < 0.001) independently predicted the need for additional therapy after PSMA-RGS. The main limitation is the lack of a control group. ConclusionsFor patients after salvage PSMA-RGS, a lower biochemical response (PSA <0.1 ng/ml) seems to predict longer TFS. This insight may help in counseling patients postoperatively as well as guiding the timely selection of additional therapy. Patient summaryWe studied what happened to prostate cancer patients in three European centers who had salvage surgery using a special method called prostate-specific membrane antigen–targeted radioguidance. We found that patients who had low prostate-specific antigen levels soon after surgery were less likely to need further treatment for a longer time.

A Comparison of Globally Applied Prognostic Risk Groups and the Prevalence of Metastatic Disease on Prostate-specific Membrane Antigen Positron Emission Tomography in Patients with Newly Diagnosed Prostate Cancer

BackgroundVarious risk classification systems (RCSs) are used globally to stratify newly diagnosed patients with prostate cancer (PCa) into prognostic groups. ObjectiveTo compare the predictive value of different prognostic subgroups (low-, intermediate-, and high-risk disease) within the RCSs for detecting metastatic disease on prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) for primary staging, and to assess whether further subdivision of subgroups would be beneficial. Design, setting, and participantsPatients with newly diagnosed PCa, in whom PSMA-PET/CT was performed between 2017 and 2022, were studied retrospectively. Patients were stratified into risk groups based on four RCSs: European Association of Urology, National Comprehensive Cancer Network (NCCN), Cambridge Prognostic Group (CPG), and Cancer of the Prostate Risk Assessment. Outcome measurements and statistical analysisThe prevalence of metastatic disease on PSMA-PET/CT was compared among the subgroups within the four RCSs. Results and limitationsIn total, 2630 men with newly diagnosed PCa were studied. Any metastatic disease was observed in 35% (931/2630) of patients. Among patients classified as having intermediate- and high-risk disease, the prevalence of metastases ranged from approximately 12% to 46%. Two RCSs further subdivided these groups. According to the NCCN, metastatic disease was observed in 5.8%, 13%, 22%, and 62% for favorable intermediate-, unfavorable intermediate-, high-, and very-high-risk PCa, respectively. Regarding the CPG, these values were 6.9%, 13%, 21%, and 60% for the corresponding risk groups. ConclusionsThis study underlines the importance of nuanced risk stratification, recommending the further subdivision of intermediate- and high-risk disease given the notable variation in the prevalence of metastatic disease. PSMA-PET/CT for primary staging should be reserved for patients with unfavorable intermediate- or higher-risk disease. Patient summaryThe use of various risk classification systems in patients with prostate cancer helps identify those at a higher risk of having metastatic disease on prostate-specific membrane antigen positron emission tomography/computed tomography for primary staging.