Diagnostic efficacy of [99mTc]Tc-PSMA SPECT/CT for prostate cancer: a meta-analysis.

BACKGROUND: Prompt and accurate diagnosis of prostate cancer (PCa) is of paramount importance for effective treatment planning. While Gallium-68 labeled prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) has proven efficacy in detecting PCa, limited availability poses challenges. As a potential alternative, [99mTc]Tc-PSMA single photon emission computed tomography (SPECT)/computed tomography (CT) holds promise. This systematic review and meta-analysis aimed to evaluate the diagnostic value of [99mTc]Tc-PSMA SPECT/CT for prostate cancer. METHODS: A comprehensive search of PubMed, Cochrane, EMBASE, Scopus, Ovid, and Web of Science databases was conducted until July 2024. Sensitivity and specificity data were extracted to assess the diagnostic accuracy of [99mTc]Tc-PSMA SPECT/CT, while the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was used to evaluate study quality. Statistical analyses were performed using STATA 18, with MetaDisc 1.4 employed to detect threshold effects. Diagnostic accuracy indicators, including sensitivity, specificity, diagnostic odds ratio (DOR), negative likelihood ratio (LR-), and positive likelihood ratio (LR+), were pooled. The area under the curve (AUC) of the combined model was calculated using summary receiver-operating characteristic (SROC) curves. RESULTS: Seven studies meeting the inclusion criteria were identified from an initial pool of 1467 articles, with no publication bias observed. The pooled sensitivity, specificity, and AUC of [99mTc]Tc-PSMA SPECT/CT were found to be 0.89 (95% CI, 0.84-0.93), 0.92 (95% CI, 0.67-0.99), and 0.93 (95% CI, 0.90-0.95), respectively. Additionally, the comprehensive diagnostic odds ratio, diagnostic score, positive likelihood ratio, and negative likelihood ratio were calculated as 95.24 (95% CI, 17.30-524.41), 4.56 (95% CI, 2.85-6.26), 11.35 (95% CI, 2.31-55.71), and 0.12 (95% CI, 0.08-0.18), respectively. CONCLUSIONS: In conclusion, our findings demonstrate that [99mTc]Tc-PSMA SPECT/CT exhibits favorable diagnostic performance for prostate cancer and can provide valuable supplementary information, particularly in regions and settings where [68Ga]Ga-PSMA PET/CT availability is limited, such as remote areas. These results highlight the potential of [99mTc]Tc-PSMA SPECT/CT as a valuable tool in the diagnosis and management of prostate cancer, warranting further investigation and validation in larger patient cohorts.

PSMA-PET follow-up to assess response in patients not receiving PSMA therapy: Is there value beyond localization of disease?

Introduction: Prostate Specific Membrane Antigen Positron Emission Tomography (PSMA-PET) is routinely used for the staging of patients with prostate cancer, but data on response assessment are sparse and primarily stem from metastatic castration-resistant prostate cancer (mCRPC) patients treated with PSMA radioligand therapy. Still, follow-up PSMA-PET is employed in earlier disease stages in case of clinical suspicion of disease persistence, recurrence or progression to decide if localized or systemic treatment is indicated. Therefore, the prognostic value of PSMA-PET derived tumor volumes in earlier disease stages (i.e., hormone-sensitive prostate cancer (HSPC) and non-[177Lu]Lu-PSMA-617 (LuPSMA) therapy castration resistant prostate cancer (CRPC)) are evaluated in this manuscript. Methods: A total number of 73 patients (6 primary staging, 42 HSPC, 25 CRPC) underwent two (i.e., baseline and follow-up, median interval: 379 days) whole-body [68Ga]Ga-PSMA-11 PET/CT scans between Nov 2014 and Dec 2018. Analysis was restricted to non-LuPSMA therapy patients. PSMA-PETs were retrospectively analyzed and primary tumor, lymph node-, visceral-, and bone metastases were segmented. Body weight-adjusted organ-specific and total tumor volumes (PSMAvol: sum of PET volumes of all lesions) were measured for baseline and follow-up. PSMAvol response was calculated as the absolute difference of whole-body tumor volumes. High metastatic burden (>5 metastases), RECIP 1.0 and PSMA-PET Progression Criteria (PPP) were determined. Survival data were sourced from the cancer registry. Results: The average number of tumor lesions per patient on the initial PET examination was 10.3 (SD 28.4). At baseline, PSMAvol was strongly associated with OS (HR 3.92, p <0.001; n = 73). Likewise, response in PSMAvol was significantly associated with OS (HR 10.48, p < 0.005; n = 73). PPP achieved significance as well (HR 2.19, p <0.05, n = 73). Patients with hormone sensitive disease and poor PSMAvol response (upper quartile of PSMAvol change) in follow-up had shorter outcome (p < 0.05; n = 42). PSMAvol in bones was the most relevant parameter for OS prognostication at baseline and for response assessment (HR 31.11 p < 0.001; HR 32.27, p < 0.001; n = 73). Conclusion: PPP and response in PSMAvol were significantly associated with OS in the present heterogeneous cohort. Bone tumor volume was the relevant miTNM region for OS prognostication. Future prospective evaluation of the performance of organ specific PSMAvol in more homogeneous cohorts seems warranted.

[68Ga]PSMA-11 for positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA)-positive lesions in men with prostate cancer.

INTRODUCTION: Theranostics targeting prostate-specific membrane antigen (PSMA) represent a new targeted approach for prostate cancer care that combines diagnostic and therapeutic radiopharmaceuticals to diagnose and treat the disease. Positron emission tomography (PET) is the imaging method of choice and several diagnostic radiopharmaceuticals for quantifying PSMA have received FDA approval and are in clinical use. [68Ga]Ga-PSMA-11 is one such imaging agent and the focus of this article. One beta-emitting radioligand therapy ([177Lu]Lu-PSMA-617) has also received FDA approval for prostate cancer treatment, and several other alpha- and beta-emitting radioligand therapies are in clinical trials. AREAS COVERED: Theranostics targeting PSMA in men with prostate cancer are discussed with a focus on use of [68Ga]Ga-PSMA-11 for imaging PSMA-positive lesions in men with prostate cancer. The review covers [68Ga]Ga-PSMA-11 manufacture, current regulatory status, comparison of [68Ga]Ga-PSMA-11 to other imaging techniques, clinical updates, and emerging applications of artificial intelligence for [68Ga]Ga-PSMA-11 PET. EXPERT OPINION: [68Ga]Ga-PSMA-11 is used in conjunction with a PET/CT scan to image PSMA positive lesions in men with prostate cancer. It is manufactured by chelating precursor with68Ga, either from a generator or cyclotron, and has regulatory approval around the world. It is widely used clinically in conjunction with radioligand therapies like [177Lu]Lu-PSMA-617.

PSMA-targeted combination brusatol and docetaxel nanotherapeutics for the treatment of prostate cancer.

Active targeting to cancer involves exploiting specific interactions between receptors on the surface of cancer cells and targeting moieties conjugated to the surface of vectors such that site-specific delivery is achieved. Prostate specific membrane antigen (PSMA) has proved to be an excellent target for active targeting to prostate cancer. We report the synthesis and use of a PSMA-specific ligand (Glu-NH-CO-NH-Lys) for the site-specific delivery of brusatol- and docetaxel-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles to prostate cancer. The PSMA targeting ligand covalently linked to PLGA-PEG3400 was blended with methoxyPEG-PLGA to prepare brusatol- and docetaxel-loaded nanoparticles with different surface densities of the targeting ligand. Flow cytometry was used to evaluate the impact of different surface densities of the PSMA targeting ligand in LNCaP prostate cancer cells at 15 min and 2 h. Cytotoxicity evaluations of the targeted nanoparticles reveal differences based on PSMA expression in PC-3 and LNCaP cells. In addition, levels of reactive oxygen species (ROS) were measured using the fluorescent indicator, H2DCFDA, by flow cytometry. PSMA-targeted nanoparticles loaded with docetaxel and brusatol showed increased ROS generation in LNCaP cells compared to PC-3 at different time points. Furthermore, the targeted nanoparticles were evaluated in male athymic BALB/c mice implanted with PSMA-producing LNCaP cell tumors. Evaluation of the percent relative tumor volume show that brusatol-containing nanoparticles show great promise in inhibiting tumor growth. Our data also suggest that the dual drug-loaded targeted nanoparticle platform improves the efficacy of docetaxel in male athymic BALB/c mice implanted with PSMA-producing LNCaP cell tumors.

68Ga/177Lu-Labeled Bivalent Agents for Targeting Hypoxia and PSMA-Binding in Prostate Cancer.

Prostate-specific membrane antigen (PSMA) is an excellent target for cancer detection and therapy. Hypoxia is prevalent in solid tumors, and various nitroimidazole (NI) radioligands can be trapped inside hypoxic cells for diagnosis and therapy. To enhance tumor uptake and retention, we designed bivalent agents (compounds 1-8) incorporating a hypoxia-sensitive NI-moiety and a PSMA-targeting group. Ligands 1-8 were successfully prepared and labeled with 68Ga or 177Lu. Among them, [68Ga]Ga-8 ([68Ga]Ga-AAZTA-NI-PSMA-093) demonstrated significantly higher cellular accumulation under hypoxic conditions than under normoxic conditions, suggesting hypoxia-selective trapping by the introduction of NI group. PET/CT imaging at 60 min postinjection of [68Ga]Ga-8 revealed high tumor uptake (SUVmax: 10.68%ID/mL) in the tumor-bearing mice model. SPECT/CT imaging of [177Lu]Lu-8 at 24 and 48 h postinjection demonstrated excellent accumulation and retention. Preliminary studies indicate that [68Ga]Ga/[177Lu]Lu-8 may be promising bivalent agents targeting hypoxia and PSMA binding for diagnosis and radiotherapy.

GCPII Inhibition Promotes Remyelination after Peripheral Nerve Injury in Aged Mice.

Peripheral nerve injuries (PNIs) represent a significant clinical challenge, particularly in elderly populations where axonal remyelination and regeneration are impaired. Developing therapies to enhance these processes is crucial for improving PNI repair outcomes. Glutamate carboxypeptidase II (GCPII) is a neuropeptidase that plays a pivotal role in modulating glutamate signaling through its enzymatic cleavage of the abundant neuropeptide N-acetyl aspartyl glutamate (NAAG) to liberate glutamate. Within the PNS, GCPII is expressed in Schwann cells and activated macrophages, and its expression is amplified with aging. In this study, we explored the therapeutic potential of inhibiting GCPII activity following PNI. We report significant GCPII protein and activity upregulation following PNI, which was normalized by the potent and selective GCPII inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA). In vitro, 2-PMPA robustly enhanced myelination in dorsal root ganglion (DRG) explants. In vivo, using a sciatic nerve crush injury model in aged mice, 2-PMPA accelerated remyelination, as evidenced by increased myelin sheath thickness and higher numbers of remyelinated axons. These findings suggest that GCPII inhibition may be a promising therapeutic strategy to enhance remyelination and potentially improve functional recovery after PNI, which is especially relevant in elderly PNI patients where this process is compromised.

Fluorine-18 Prostate-Specific Membrane Antigen-1007 PET/CT vs Multiparametric MRI for Locoregional Staging of Prostate Cancer.

Importance: Prostate-specific membrane antigen (PSMA) demonstrates overexpression in prostate cancer and correlates with tumor aggressiveness. PSMA positron emission tomography (PET) is superior to conventional imaging for the metastatic staging of prostate cancer per current research but studies of second-generation PSMA PET radioligands for locoregional staging are limited. Objective: To determine the accuracy of fluorine-18 PSMA-1007 PET/computed tomography (18F-PSMA-1007 PET/CT) compared to multiparametric magnetic resonance imaging (MRI) in the primary locoregional staging of intermediate-risk and high-risk prostate cancers. Design, Setting, and Participants: The Next Generation Trial was a phase 2 prospective validating paired cohort study assessing the accuracy of 18F-PSMA-1007 PET/CT and MRI for locoregional staging of prostate cancer, with results of histopathologic examination as the reference standard comparator. Radiologists, nuclear medicine physicians, and pathologists were blinded to preoperative clinical, pathology, and imaging data. Patients underwent all imaging studies and radical prostatectomies at 2 tertiary care hospitals in Alberta, Canada. Eligible participants included men with intermediate-risk or high-risk prostate cancer who consented to radical prostatectomy. Participants who underwent radical prostatectomy were included in the final analysis. Patients were recruited between March 2022 and June 2023, and data analysis occurred between July 2023 and December 2023. Exposures: All participants underwent both 18F-PSMA-1007 PET/CT and MRI within 2 weeks of one another and before radical prostatectomy. Main Outcomes and Measures: The primary outcome was the correct identification of the prostate cancer tumor stage by each imaging test. The secondary outcomes were correct identification of the dominant nodule, laterality, extracapsular extension, and seminal vesical invasion. Results: Of 150 eligible men with prostate cancer, 134 patients ultimately underwent radical prostatectomy (mean [SD] age at prostatectomy, 62.0 [5.7] years). PSMA PET was superior to MRI for the accurate identification of the final pathological tumor stage (61 [45%] vs 38 [28%]; P = .003). PSMA PET was also superior to MRI for the correct identification of the dominant nodule (126 [94%] vs 112 [83%]; P = .01), laterality (86 [64%] vs 60 [44%]; P = .001), and extracapsular extension (100 [75%] vs 84 [63%]; P = .01), but not for seminal vesicle invasion (122 [91%] vs 115 [85%]; P = .07). Conclusions and Relevance: In this phase 2 prospective validating paired cohort study, 18F-PSMA-1007 PET/CT was superior to MRI for the locoregional staging of prostate cancer. These findings support PSMA PET in the preoperative workflow of intermediate-risk and high-risk tumors.

Simultaneous targeting and monitoring of free antigen and in-situ membrane antigen in prostate cancer cells via an aggregation-induced emission-based bifunctional probe.

The precise clinical diagnosis of prostate cancer still presents inherent challenges, and usually a monitoring of multiple biomarkers is required. In this study, a new aggregation-induced emission (AIE)-based bifunctional strategy was developed for the simultaneous detection of prostate cancer-specific in situ membrane antigens (PSMA) and free antigens (PSA). First, a bifunctional fluorescent probe with double sensing sites (a PSA-specific sensing site and a PSMA-targeted ligand) was constructed. In the presence of PSA, it specifically binds to the PSA-specific sensing site of the probe, resulting in the restoration of the fluorescence signal, enabling linear sensing of PSA. For the detection of PSMA, the PSMA-targeted ligand modified on the probe can specifically recognize PSMA, inducing the aggregation of the AIE material and resulting in an enhanced fluorescence signal. Moreover, a liposome-based artificial cell was developed to simulate the real prostate cancer cell, and it was used to investigate the feasibility of monitoring the two types of antigens. Utilizing this bifunctional fluorescent strategy, a dual-analysis of free serum antigen biomarker of PSA and in-situ membrane antigen of PSMA was achieved. The assay exhibited a wide linearity range for PSA detection from 0.0001 to 0.1 µg/mL, with a low limit of detection (LOD) of 6.18 pg/mL. For PSMA, the obtained LOD is 8.79 pg/mL, with a linearity range from 0.0001 to 0.1 µg/mL. This strategy allows us to simultaneously assess the levels of two types of biomarkers in living human prostatic cancer cells, providing a highly accurate and selective tool for early screening and monitoring of prostatic cancer.

PSMA-based therapeutics for prostate cancer.

INTRODUCTION: The prostate cancer (PCa) consists the most frequently diagnosed malignancy of urogenital system in males. Traditionally, treatment of localized PCa was based on surgery or radiotherapy while hormonotherapy was used in more advanced stages. However, the implementation of radiolabels has revolutionized the landscape of prostate cancer. Specifically, prostate-specific membrane antigen (PSMA) has been investigated in different aspects of PCa therapeutic era. AREAS COVERED: A literature review is presented about the implications of PSMA radiolabels on prostate cancer treatment. PSMA tracers were initially used as an imaging technique. Afterwards, PSMA labeled with isotopes presenting cytotoxic abilities, such as lutetium-117 and actinium-225, while reports exist about the use of radioligand immunotherapy. Meanwhile, ongoing trials examine the development of novel radionuclides as well as the evolution of the PSMA-targeted ligands. EXPERT OPINION: Currently, PSMA radioligand treatment of prostate cancer is approved in the metastatic stage of the disease. Meanwhile, a variety of trials exist about its possible role in less advanced stages. However, plenty of parameters should be addressed before these implementations, such as PSMA dosage, dosimetry issues, and its safety profile. A future well-designed study with proper patient selection is mandatory to further explore PSMA radioligand theranostics perspectives.

Transcriptomic Profiling of Primary Prostate Cancers and Nonlocalized Disease on Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography: A Multicenter Retrospective Study.

PURPOSE: To characterize the relationship between Decipher genomic classifier scores and prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-based metastatic spread. MATERIALS AND METHODS: We identified patients from four institutions who underwent PSMA PET/CT scans pretreatment for primary staging or postradical prostatectomy (RP) for suspected recurrence and had Decipher transcriptomic data available from biopsy or RP specimens. PSMA PET/CT-based patterns of spread were classified as localized (miT + N0M0) or nonlocalized (miN1M0 or miM1a-c). We calculated the association between Decipher scores and the risk of nonlocalized disease on PSMA PET/CT using multivariable logistic regression for pretreatment patients and multivariable Cox regression for post-RP patients. We also compared select transcriptomic signatures between patients with localized and nonlocalized diseases. RESULTS: Five hundred eighty-six patients were included (pretreatment: n = 329; post-RP: n = 257). Higher Decipher scores were associated with nonlocalized disease on PSMA PET/CT both pretreatment (odds ratio, 1.18 [95% CI, 1.03 to 1.36] per 0.1 increase in Decipher score, P = .02) and post-RP (hazard ratio, 1.15 [95% CI, 1.05 to 1.27] per 0.1 increase in Decipher score, P = .003). In the pretreatment setting, nonlocalized disease was associated with higher rates of TP53 mutations and lower rates of PAM50 luminal A subtype compared with localized disease. In the post-RP setting, overexpression of signatures related to metabolism, DNA repair, and androgen receptor signaling were associated with higher rates of nonlocalized disease. CONCLUSION: Higher Decipher scores were associated with nonlocalized disease identified on PSMA PET/CT both pretreatment and post-RP. There were several transcriptomic differences between localized and nonlocalized diseases in both settings.

A Synergistic Strategy Combining Chemotherapy and Photodynamic Therapy to Eradicate Prostate Cancer.

Prostate cancer is the most prevalent cancer among men in the United States and is a leading cause of cancer-related death. Prostate specific membrane antigen (PSMA) has been established as a biomarker for prostate cancer diagnosis and treatment. This study aimed to develop a novel theranostic agent, PSMA-1-MMAE-Pc413, which integrates a PSMA-targeting ligand, the photosensitizer Pc413, and the microtubular inhibitor monomethyl auristatin E (MMAE) for synergistic therapeutic efficacy. In vitro uptake studies revealed that PSMA-1-MMAE-Pc413 demonstrated selective and specific uptake in PSMA-positive PC3pip cells but not in PSMA-negative PC3flu cells, with the uptake in PC3pip cells being approximately three times higher. In vitro cytotoxicity assays showed that, when exposed to light, PSMA-1-MMAE-Pc413 had a synergistic effect, leading to significantly greater cytotoxicity in PSMA-positive cells (IC50 = 2.2 nM) compared to PSMA-1-Pc413 with light irradiation (IC50 = 164.9 nM) or PSMA-1-MMAE-Pc413 without light irradiation (IC50 = 12.6 nM). In vivo imaging studies further demonstrated the selective uptake of PSMA-1-MMAE-Pc413 in PC3pip tumors. In in vivo studies, PSMA-1-MMAE-Pc413 dramatically improves the therapeutic outcome for prostate cancer by providing a synergistic effect that surpasses the efficacy of each treatment modality alone in PC3pip tumors. These findings suggest that PSMA-1-MMAE-Pc413 has strong potential for clinical application in improving prostate cancer treatment.

Prostate-Specific Membrane Antigen Use in Glioma Management: Past, Present, and Future.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a membrane-bound metallopeptidase highly expressed in the neovasculature of many solid tumors including gliomas. It is a particularly enticing therapeutic target due to its ability to internalize, thereby delivering radioligands or pharmaceuticals to the intracellular compartment. Targeting the neovasculature of gliomas using PSMA for diagnosis and management has been a recent area of increased study and promise. The purpose of this review is to synthesize the current state and future directions of PSMA use in the histopathologic study, imaging, and treatment of gliomas. METHODS: PubMed and Scopus databases were used to conduct a literature review on PSMA use in gliomas in June 2023. Terms searched included "PSMA," "Prostate-Specific Membrane Antigen" OR "PSMA" OR "PSMA PET" AND "glioma" OR "high grade glioma" OR "glioblastoma" OR "GBM." RESULTS: Ninety-four publications were screened for relevance with 61 studies, case reports, and reviews being read to provide comprehensive context for the historical, contemporary, and prospective use of PSMA in glioma management. CONCLUSIONS: PSMA PET imaging is currently a promising and accurate radiographic tool for the diagnosis and management of gliomas. PSMA histopathology likely represents a viable tool for helping predict glioma behavior. More studies are needed to investigate the role of PSMA-targeted therapeutics in glioma management, but preliminary reports have indicated its potential usefulness in treatment.

Co-delivery of Siape1 and Melatonin by 125I-loaded PSMA-targeted Nanoparticles for the Treatment of Prostate Cancer.

BACKGROUND: Both apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) inhibition and melatonin suppress prostate cancer (PCa) growth. OBJECTIVE: This study evaluated the therapeutic efficiency of self-assembled and prostate-specific membrane antigen (PSMA)-targeted nanocarrier loading 125I radioactive particles and encapsulating siRNA targeting APE1 (siAPE1) and melatonin for PCa. METHODS: The linear polyarginine R12 polypeptide was prepared using Fmoc-Arg-Pbf-OH. The PSMA-targeted polymer was synthesized by conjugating azide-modified R12 peptide to PSMA monoclonal antibody (mAb). Before experiments, the PSMA-R12 nanocarrier was installed with melatonin and siAPE1, which were subsequently labeled by 125I radioactive particles. In vitro biocompatibility and cytotoxicity of nanocomposites were examined in LNCaP cells and in vivo biodistribution and pharmacokinetics were determined using PCa tumor-bearing mice. RESULTS: PSMA-R12 nanocarrier was ~120 nm in size and was increased to ~150 nm by melatonin encapsulation. PSMA-R12 nanoparticles had efficient loading capacities of siAPE1, melatonin, and 125I particles. The co-delivery of melatonin and siAPE1 by PSMA-R12-125I showed synergistic effects on suppressing LNCaP cell proliferation and Bcl-2 expression and promoting cell apoptosis and caspase-3 expression. Pharmacokinetics analysis showed that Mel@PSMA-R12-125I particles had high uptake activity in the liver, spleen, kidney, intestine, and tumor, and were accumulated in the tumor sites within the first 8 h p.i., but was rapidly cleared from all the tested organs at 24 h p.i. Administration of nanoparticles to PCa tumors in vivo showed that Mel@PSMA-R12- 125I/siAPE1 had high efficiency in suppressing PCa tumor growth. CONCLUSION: The PSMA-targeted nanocarrier encapsulating siAPE1 and melatonin is a promising therapeutic strategy for PCa and can provide a theoretical basis for patent applications.

Pelvic lymph node mapping in prostate cancer: examining the impact of PSMA PET/CT on radiotherapy decision-making in patients with node-positive disease.

INTRODUCTION: Prostate Specific Membrane Antigen (PSMA) imaging with Positron Emission Tomography (PET) plays a crucial role in prostate cancer management. However, there is a lack of comprehensive data on how PSMA PET/CT (Computed Tomography) influences radiotherapeutic decisions, particularly in node-positive prostate cancer cases. This study aims to address this gap by evaluating two primary objectives: (1) Mapping the regional and non-regional lymph nodes (LNs) up to the aortic bifurcation and their distribution using conventional methods with CT compared to PSMA PET/CT, and (2) assessing the impact of PSMA PET/CT findings on radiotherapeutic decisions. METHODS: A retrospective analysis of 95 node-positive prostate cancer patients who underwent both CT and PSMA PET/CT imaging prior to primary radiotherapy and androgen deprivation therapy (ADT) was conducted. The analysis focused on identifying LNs in various regions including the common iliac, external iliac, internal iliac, obturator, presacral, mesorectal, inguinal, and other stations. Treatment plans were reviewed for modifications based on PSMA PET/CT findings, and statistical analysis was performed to identify predictors for exclusive nodal positivity on PSMA PET/CT scans. RESULTS: PSMA PET/CT identified additional positive nodes in 48% of cases, resulting in a staging shift from N0 to N1 in 29% of patients. The most frequent metastatic LNs were located in the external iliac (76 LNs; 34%), internal iliac (43 LNs; 19%), and common iliac (35 LNs; 15%) stations. In patients with nodes only detected on PSMA PET the most common nodes were in the external iliac (27, 40%), internal iliac (13, 19%), obturator (11, 15%) stations. Within the subgroup of 28 patients exclusively demonstrating PSMA PET-detected nodes, changes in radiotherapy treatment fields were implemented in 5 cases (18%), and a dose boost was applied for 23 patients (83%). However, no discernible predictors for exclusive nodal positivity on PSMA PET/CT scans emerged from the analysis. DISCUSSION: The study underscores the pivotal role of PSMA PET/CT compared to CT alone in accurately staging node-positive prostate cancer and guiding personalized radiotherapy strategies. The routine integration of PSMA PET/CT into diagnostic protocols is advocated to optimize treatment precision and improve patient outcomes.

Quantitative PSMA-PET parameters in localized prostate cancer: prognostic and potential predictive value.

BACKGROUND: PSMA-PET is increasingly used for staging prostate cancer (PCA) patients. However, it is not clear if quantitative imaging parameters of positron emission tomography (PET) have an impact on disease progression and are thus important for the prognosis of localized PCA. METHODS: This is a monocenter retrospective analysis of 86 consecutive patients with localized intermediate or high-risk PCA and PSMA-PET before treatment The quantitative PET parameters maximum standardized uptake value (SUVmax), tumor asphericity (ASP), PSMA tumor volume (PSMA-TV), and PSMA total lesion uptake (PSMA-TLU = PSMA-TV × SUVmean) were assessed for their prognostic significance in patients with radiotherapy or surgery. Cox regression analyses were performed for biochemical recurrence-free survival, overall survival (OS), local control, and loco-regional control (LRC). RESULTS: 67% of patients had high-risk disease, 51 patients were treated with radiotherapy, and 35 with surgery. Analysis of metric PET parameters in the whole cohort revealed a significant association of PSMA-TV (p = 0.003), PSMA-TLU (p = 0.004), and ASP (p < 0.001) with OS. Upon binarization of PET parameters, several other parameters showed a significant association with clinical outcome. When analyzing high-risk patients according to the primary treatment approach, a previously published cut-off for SUVmax (8.6) showed a significant association with LRC in surgically treated (p = 0.048), but not in primary irradiated (p = 0.34) patients. In addition, PSMA-TLU (p = 0.016) seemed to be a very promising biomarker to stratify surgical patients. CONCLUSION: Our data confirm one previous publication on the prognostic impact of SUVmax in surgically treated patients with high-risk PCA. Our exploratory analysis indicates that PSMA-TLU might be even better suited. The missing association with primary irradiated patients needs prospective validation with a larger sample size to conclude a predictive potential. Trial registration Due to the retrospective nature of this research, no registration was carried out.

Dosimetry of [177Lu]Lu-PSMA-Targeted Radiopharmaceutical Therapies in Patients with Prostate Cancer: A Comparative Systematic Review and Metaanalysis.

Novel theranostic approaches using radiopharmaceuticals targeting prostate-specific membrane antigen (PSMA) have emerged for treating metastatic castration-resistant prostate cancer. The physical properties and commercial availability of 177Lu make it one of the most used radionuclides for radiopharmaceutical therapy (RPT). In this literature review, we aimed at comparing the dosimetry of the most used [177Lu]Lu-PSMA RPT compounds. Methods: This was a systematic review and metaanalysis of [177Lu]Lu-PSMA RPT (617, I&T, and J591) dosimetry in patients with prostate cancer. Absorbed doses in Gy/GBq for each organ at risk (kidney, parotid and submandibular glands, bone marrow, liver, and lacrimal glands) and for tumor lesions (bone and nonbone lesions) were extracted from included articles. These were used to estimate the pooled average absorbed dose of each agent in Gy/GBq and in Gy/cycle, normalized to the injected activity (per cycle) used in the VISION (7.4 GBq), SPLASH (6.8 GBq), and PROSTACT trials (5.8 GBq). Results: Twenty-nine published articles comprising 535 patients were included in the metaanalysis. The pooled doses (weighted average across studies) of [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T were 4.04 Gy/GBq (17 studies, 297 patients) and 4.70 Gy/GBq (10 studies, 153 patients) for the kidney (P = 0.10), 5.85 Gy/GBq (14 studies, 216 patients) and 2.62 Gy/GBq (5 studies, 86 patients) for the parotids (P < 0.01), 5.15 Gy/GBq (5 studies, 81 patients) and 4.35 Gy/GBq (1 study, 18 patients) for the submandibular glands (P = 0.56), 11.03 Gy/GBq (6 studies, 121 patients) and 19.23 Gy/GBq (3 studies, 53 patients) for the lacrimal glands (P = 0.20), 0.24 Gy/GBq (12 studies, 183 patients) and 0.19 Gy/GBq (4 studies, 68 patients) for the bone marrow (P = 0.31), and 1.11 Gy/GBq (9 studies, 154 patients) and 0.56 Gy/GBq (4 studies, 56 patients) for the liver (P = 0.05), respectively. Average tumor doses tended to be higher for [177Lu]Lu-PSMA-617 than for [177Lu]Lu-PSMA-I&T in soft tissue tumor lesions (4.19 vs. 2.94 Gy/GBq; P = 0.26). Dosimetry data of [177Lu]Lu-J591 were limited to one published study of 35 patients with reported absorbed doses of 1.41, 0.32, and 2.10 Gy/GBq to the kidney, bone marrow, and liver, respectively. Conclusion: In this metaanalysis, there was no significant difference in absorbed dose between [177Lu]Lu-PSMA-I&T and [177Lu]Lu-PSMA-617. There was a possible trend toward a higher kidney dose with [177Lu]Lu-PSMA-I&T and a higher tumor lesion dose with [177Lu]Lu-PSMA-617. It remains unknown whether this finding has any clinical impact. The dosimetry methodologies were strikingly heterogeneous among studies, emphasizing the need for standardization.

Multimodal, PSMA-Targeted, PAMAM Dendrimer-Drug Conjugates for Treatment of Prostate Cancer: Preclinical Evaluation.

Introduction: Prostate cancer (PC) is the second most common cancer and the fifth most frequent cause of cancer death among men. Prostate-specific membrane antigen (PSMA) expression is associated with aggressive PC, with expression in over 90% of patients with metastatic disease. Those characteristics have led to its use for PC diagnosis and therapies with radiopharmaceuticals, antibody-drug conjugates, and nanoparticles. Despite these advancements, none of the current therapeutics are curative and show some degree of toxicity. Here we present the synthesis and preclinical evaluation of a multimodal, PSMA-targeted dendrimer-drug conjugate (PT-DDC), synthesized using poly(amidoamine) (PAMAM) dendrimers. PT-DDC was designed to enable imaging of drug delivery, providing valuable insights to understand and enhance therapeutic response. Methods: The PT-DDC was synthesized through consecutive conjugation of generation-4 PAMAM dendrimers with maytansinoid-1 (DM1) a highly potent antimitotic agent, Cy5 infrared dye for optical imaging, 2,2',2"-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA) chelator for radiolabeling with copper-64 and positron emission tomography tomography/computed tomography (PET/CT), lysine-urea-glutamate (KEU) PSMA-targeting moiety and the remaining terminal primary amines were capped with butane-1,2-diol. Non-targeted control dendrimer-drug conjugate (Ctrl-DDC) was formulated without conjugation of KEU. PT-DDC and Ctrl-DDC were characterized using high-performance liquid chromatography, matrix assisted laser desorption ionization mass spectrometry and dynamic light scattering. In vitro and in vivo evaluation of PT-DDC and Ctrl-DDC were carried out in isogenic human prostate cancer PSMA+ PC3 PIP and PSMA- PC3 flu cell lines, and in mice bearing the corresponding xenografts. Results: PT-DDC was stable in 1×PBS and human blood plasma and required glutathione for DM1 release. Optical, PET/CT and biodistribution studies confirmed the in vivo PSMA-specificity of PT-DDC. PT-DDC demonstrated dose-dependent accumulation and cytotoxicity in PSMA+ PC3 PIP cells, and also showed growth inhibition of the corresponding tumors. PT-DDC did not accumulate in PSMA- PC3 flu tumors and did not inhibit their growth. Ctrl-DDC did not show PSMA specificity. Conclusion: In this study, we synthesized a multimodal theranostic agent capable of delivering DM1 and a radionuclide to PSMA+ tumors. This approach holds promise for enhancing image-guided treatment of aggressive, metastatic subtypes of prostate cancer.

Novel [68Ga/177Lu]Ga/Lu-AZ-093 as PSMA-Targeting Agent for Diagnosis and Radiotherapy.

Prostate-specific membrane antigen (PSMA) overexpressed in prostate cancer cells can serve as a target for imaging and radioligand therapy (RLT). Previously, [68Ga]Ga-P16-093, containing a Ga(III) chelator, N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC), displayed excellent PSMA-targeting properties and showed a high tumor uptake and retention useful for diagnosis in prostate cancer patients. Recently, [177Lu]Lu-PSMA-617 has been approved by the U.S. food and drug administration (FDA) for the treatment of prostate cancer patients. Derivatives of PSMA-093 using AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid), as the chelator, were designed as alternative agents forming complexes with both diagnostic and therapeutic radiometals, such as gallium-68 (log K = 22.18) or lutetium-177 (log K = 21.85). The aim of this study is to evaluate AAZTA-Gly-O-(methylcarboxy)-Tyr-Phe-Lys-NH-CO-NH-Glu (designated as AZ-093, 1) leading to a gallium-68/lutetium-177 theranostic pair as potential PSMA targeting agents. Synthesis of the desired precursor, AZ-093, 1, was effectively accomplished. Labeling with either [68Ga]GaCl3 or [177Lu]LuCl3 in a sodium acetate buffer solution (pH 4-5) at 50 °C in 5 to 15 min produced either [68Ga]Ga-1 or [177Lu]Lu-1 with high yields and excellent radiochemical purities. Results of in vitro binding studies, cell uptake, and retention (using PSMA-positive prostate carcinoma cells line, 22Rv1-FOLH1-oe) were comparable to that of [68Ga]Ga-P16-093 and [177Lu]Lu-PSMA-617, respectively. Specific cellular uptake was determined with or without the competitive blocking agent (2 µM of "cold" PSMA-11). Cellular binding and internalization showed a time-dependent increase over 2 h at 37 °C in the PSMA-positive cells. The cell uptakes were completely blocked by the "cold" PSMA-11 suggesting that they are competing for the same PSMA binding sites. In the mouse model with implanted PSMA-positive tumor cells, both [68Ga]Ga-1 and [177Lu]Lu-1 displayed excellent uptake and retention in the tumor. Results indicate that [68Ga]Ga/[177Lu]Lu-1 (68Ga]Ga/[177Lu]Lu-AZ-093) is potentially useful as PSMA-targeting agent for both diagnosis and radiotherapy of prostate cancer.

PSMA-Avid Liver Metastasis in a Case of Prostate Carcinoma and Poorly Differentiated Thyroid Carcinoma.

ABSTRACT: Although PSMA-targeted PET imaging is predominantly used for prostate carcinoma (PC), it has also been reported for thyroid carcinoma (TC). A 77-year-old man had a liver metastasectomy for poorly differentiated TC, which had elevated 18 F-FDG uptake. Two years later, he was diagnosed with acinar-type modified Gleason score of 7 (3 + 4) PC. Four years later, he had metastatic liver lesions that had no radioactive iodine and 18 F-FDG avidity. These lesions were 68 Ga-PSMA avid, and the biopsy confirmed TC metastasis. This case emphasizes the importance of 68 Ga-PSMA-based imaging in poorly differentiated TC and pathological confirmation for lesions that were 68 Ga-PSMA-positive.