Prostate-specific Membrane Antigen Research Articles

Tubarial salivary glands show a low relative contribution to functional salivary gland tissue mass.

In 2021, the tubarial salivary glands (TSGs) were newly identified on prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) as macroscopic glands in the nasopharyngeal wall. However, the relative contribution of the TSGs to the total salivary gland function, and consequently on the development of xerostomia after external beam radiotherapy (EBRT) or PSMA-targeted radionuclide therapy (RNT) is not known. Therefore, we aimed to determine the presence of the TSGs and to quantify uptake in the TSGs on PSMA PET. Qualitative and quantitative analyses were performed on 68Ga-PSMA-11 PET/CT scans of 100 patients with prostate cancer. The mean and maximum standardized uptake value (SUVmean and SUVmax) in the TSGs were measured and compared to the parotid, submandibular and sublingual salivary glands (PSGs, SMSGs and SLSGs, respectively). Furthermore, proportional function of the TSGs was compared to the PSGs, SMSGs and SLSGs based on the total organ PSMA (TO-PSMA). The TSGs were visible on 95% of the 68Ga-PSMA-11 PET/CT scans. The normalized median SUVmean and SUVmax was significantly higher for the PSGs (p < 0.001) and SMSGs (p < 0.001) compared to the TSGs, but not for the SLSGs (p = 0.242 and p = 0.300, respectively). The normalized median TO-PSMA was significantly higher for the PSGs (p < 0.001) and SMSGs (p < 0.001), and significant lower for the SLSGs (p < 0.001) compared the TSGs. The SUVmean, SUVmax and TO-PSMA of the TSGs were most comparable to the SLSGs. However, the measured PSMA uptake may be disproportional towards the saliva production. Therefore, future studies should focus on the relation between PSMA uptake and salivary function before and after PSMA therapy.

Multivariable models of outcomes with [177Lu]Lu-PSMA-617: analysis of the phase 3 VISION trial

[177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged life in patients with metastatic castration-resistant prostate cancer (mCRPC) in VISION (NCT03511664). However, distinguishing between patients likely and unlikely to respond remains a clinical challenge. We present the first multivariable models of outcomes with 177Lu-PSMA-617 built using data from VISION, a large prospective phase 3 clinical trial powered for overall survival. Adults with progressive post androgen receptor pathway inhibitor and taxane prostate-specific membrane antigen (PSMA)-positive mCRPC received 177Lu-PSMA-617 plus protocol-permitted standard of care (SoC) or SoC alone. In this post hoc analysis, multivariable Cox proportional hazards models of overall survival (OS) and radiographic progression-free survival (rPFS), and a logistic regression model of prostate-specific antigen response (≥50% decline; PSA50) were constructed and evaluated using C-index or receiver operating characteristic (ROC) analyses with bootstrapping validation. Nomograms were constructed for visualisation. Patients were randomised between June 2018 and October 2019. Data from all 551 patients in the 177Lu-PSMA-617 arm were analysed in multivariable modelling. The OS nomogram (C-index, 0.73; 95% confidence interval [CI], 0.70-0.76) included whole-body maximum standardised uptake value (SUVmax), time since diagnosis, opioid analgesic use, aspartate aminotransferase, haemoglobin, lymphocyte count, presence of PSMA-positive lesions in lymph nodes, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and neutrophil count. The rPFS nomogram (C-index, 0.68; 0.65-0.72) included SUVmax, time since diagnosis, opioid analgesic use, lymphocyte count, presence of liver metastases by computed tomography, LDH, and ALP. The PSA50 nomogram (area under ROC curve, 0.72; 95% CI, 0.68-0.77) included SUVmax, lymphocyte count and ALP. Performances of the OS and rPFS models were maintained when they were reconstructed excluding SUVmax. These models of outcomes with 177Lu-PSMA-617 are the first built using prospective phase 3 data. They show that a combination of pretreatment laboratory, clinical, and imaging parameters, reflecting both patient and tumour status, influences outcomes. These models are important for aiding treatment selection, patient management, and clinical trial design. Novartis.

Assessment of the therapeutic efficacy of [177Lu]Lu-PSMA-X compared to taxane chemotherapy in taxane-chemo-naïve patients with metastatic castration-resistant prostate cancer: A systematic review and meta-analysis.

Radioligand therapy (RLT) with 177Lu-labelled prostate specific membrane antigen ([177Lu]Lu-PSMA-X, referring with "PSMA-X" to a generic PSMA chemical compound) inhibitors has emerged as a viable treatment option in metastatic castration resistant prostate cancer patients having previously progressed on taxane and androgen receptor inhibitors. The aim of this study was to perform a systematic review and meta-analysis to assess the therapeutic efficacy of [177Lu]Lu-PSMA-X compared to taxane chemotherapy in taxane-chemo-naïve patients with metastatic castration-resistant prostate cancer. Searches in several bibliographic databases were made using relevant key words, and articles published up to March 2024 were included. The endpoints included prostate specific antigen (PSA) response rate (RR), progression-free survival, and overall survival. Individual patient data were pooled when feasible. PSA50 was defined as the median proportion of patients achieving at least a 50% decline in serum PSA from baseline. A meta-analysis of the PSA50 response rate (proportion meta-analysis) was performed, generating pooled estimates and 95% confidence intervals (95% CI). From the initially selected 8,414 studies published between 2019 and 2023, 24 were included in the [177Lu]Lu-PSMA-X treated group and 17 in the taxane treated group. Our findings show that [177Lu]Lu-PSMA-X RLT yielded comparable PSA50 responses in taxane-naïve patients versus those receiving taxane chemotherapy, despite considerable study heterogeneity. Notably, the taxane-naïve group had more extensive pretreatment. This meta-analysis combines the largest cohorts of taxane-naïve mCRPC patients treated with [177Lu]Lu-PSMA-X RLT and taxane-treated mCRPC. It underscores similar PSA50 response rates in both groups, suggesting a potential role for [177Lu]Lu-PSMA-X RLT in taxane-naïve patients who cannot or choose not to undergo chemotherapy.

Long-Term Outcomes of Prostate-Specific Membrane Antigen–PET Imaging of Recurrent Prostate Cancer

Although prostate-specific membrane antigen positron emission tomography (PSMA-PET) has shown improved sensitivity and specificity compared with conventional imaging for the detection of biochemical recurrent (BCR) prostate cancer, the long-term outcomes of a widespread shift in imaging are unknown. To estimate long-term outcomes of integrating PSMA-PET into the staging pathway for recurrent prostate cancer. This decision analytic modeling study simulated outcomes for patients with BCR following initial definitive local therapy. Inputs used were from the literature and a retrospective cohort study conducted at 2 institutions. The base case analysis assumed modest benefits of earlier detection and treatment, and scenario analyses considered prostate-specific antigen (PSA) level at imaging and different outcomes of earlier vs delayed treatment. The analysis was performed between April 1, 2023, and May 1, 2024. (1) Immediate PSMA-PET imaging, (2) conventional imaging (computed tomography and bone scan [CTBS]) followed by PSMA-PET if CTBS findings were negative or equivocal, and (3) CTBS alone. The main outcomes were detection of metastases, deaths from prostate cancer, and life-years and quality-adjusted life-years (QALYs) gained. The model estimated that per 1000 simulated patients with BCR (assumed median age, 66 years), PSMA-PET is expected to diagnose 611 (95% uncertainty interval [UI], 565-656) patients with metastasis compared with 630 (95% UI, 586-675) patients diagnosed using CTBS followed by PSMA-PET and 297 (95% UI, 202-410) patients diagnosed using CTBS alone. Moreover, the estimated number of prostate cancer deaths was 512 (95% UI, 472-552 deaths) with PSMA-PET, 520 (95% UI, 480-559 deaths) with CTBS followed by PSMA-PET, and 587 (95% UI, 538-632 deaths) with CTBS alone. Imaging with PSMA-PET yielded the highest number of QALYs, which were 824 (95% UI, 698-885) higher than CTBS. These results differed by PSA level at the time of testing, with the highest incremental life-years and QALYs and lowest number of deaths from prostate cancer among patients with PSA levels of at least 5.0 ng/mL. Finally, the estimates were sensitive to the expected benefit of initiating therapy for recurrent prostate cancer earlier in the disease course. The results of this decision-analytic model suggest that upfront PSMA-PET imaging for the evaluation of BCR is expected to be associated with reduced cancer mortality and gains in life-years and QALYs compared with the conventional imaging strategy, assuming modest benefits of earlier detection and treatment.

Characterization of exclusive rib lesions detected by [68Ga]Ga-PSMA-11 PET/CT.

The objective of this study was to characterize exclusive costal lesions detected by 68Gallium-labelled prostate-specific membrane antigen ([68Ga]Ga-PSMA-11) PET/computed tomography (CT) at initial staging or biochemical recurrence (BCR) in prostate cancer (PCa) patients, and to identify clinical and/or PET/CT criteria associated with benign and malignant lesions. We retrospectively identified 54 patients with PCa who underwent [68Ga]Ga-PSMA-11 PET/CT for initial staging (N = 39) or BCR (N = 15) and whose reports described rib lesions, at the exclusion of any other lesions, whether doubtful, suspicious, or established. Posttherapy prostate-specific antigen (PSA) levels were used to determine whether those lesions were benign or malignant. Each patient's prostate-specific membrane antigen PET/CT report was classified as true positive, true negative, false positive, or false negative based on the posttherapy PSA level. We then assessed whether any clinical and/or PET/CT criteria could help differentiate benign from malignant lesions, and if any criteria were misleading. Among the 54 patients, 46 (85.2%) had 64 benign costal lesions, and eight (14.8%) had 10 malignant lesions. PET/CT reports indicated rib lesions as benign/equivocal in 38/54 (55.6%) patients and malignant in 16/54 (29.6%). Benign features on CT were the only parameter significantly associated with the final diagnosis. Factors such as patient age, maximum standardized uptake value of lesions, lesion dispersion, and malignant features described on CT were found to be misleading when deciding the malignant or benign status. Most exclusive costal lesions detected by [68Ga]Ga-PSMA-11 PET/CT are benign. Apart from specific benign CT features, no clinical or PET/CT criteria reliably differentiate benign from malignant costal lesions.

Phase 2 trial of PSMA PET CT versus planar bone scan and CT in prostate cancer patients progressing while on androgen deprivation therapy

For prostate cancer patients who experience biochemical progression during androgen deprivation therapy (ADT), prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) has not been prospectively compared to planar bone scan plus CT. This was a single-arm, head-to-head, prospective phase II trial (NCT04928820) designed to enroll 102 men with prostate cancer who experienced biochemical progression (rising prostate-specific antigen [PSA] ≥ 1 ng/mL) during ADT. All patients received 68Ga-PSMA-11 PET/CT and 99mTc-MDP planar bone scans. Each scan was interpreted by three central independent readers. The primary endpoint was the per-patient bone metastasis detection rate of PSMA PET/CT versus planar bone scan and CT. Secondary endpoints compared the number of bone metastases detected per patient and the inter-reader agreement of each imaging modality. Twenty-two men were enrolled between July 2021 and June 2022. Due to slow accrual following approval of PSMA PET radiotracers in the U.S. and a lack of a statistical signal between the two imaging modalities on interim analysis, this trial was closed early on October 2022. Median PSA was 8.5 ng/mL (interquartile range: 1.6–77.6). There was 100% agreement between the two scans. Six patients (27%) had negative findings and 16 patients (73%) had positive findings on both scans. PSMA PET/CT and bone scan plus CT detected an equal number of bone lesions for 14 patients (64%), PSMA PET/CT detected more bone lesions for six patients (27%), and bone scan plus CT detected more bone lesions for two patients (9.1%) (p = 0.092). The inter-reader agreement rates of PSMA PET/CT and bone scan plus CT were 96% and 82%, respectively (p = 0.25). In men with biochemical progression during ADT, 68Ga-PSMA-11 PET/CT and 99mTc-MDP planar bone scan plus CT had identical bone metastasis detection rates. Bone scan plus CT can continue to serve as a cost-effective and readily accessible restaging modality in patients with biochemical progression. ClinicalTrials.gov NCT04928820. Registered 16/06/2021.

The effect of PSMA PET/CT on clinical decision-making of radical prostatectomy and pelvic lymph node dissection

Objective To evaluate the effect of prostate-specific membrane antigen (PSMA) PET/computed tomography (CT) on clinical decision-making of radical prostatectomy (RP) and pelvic lymph node dissection (PLND) after its utilization in daily clinical practice at an European high-volume cancer center. Materials and methods Patients who had unfavorable intermediate- and high-risk prostate cancer between 2017 and 2021 were included retrospectively and divided into two groups; those who staged using PSMA PET/CT (group 1) and those who staged using conventional modalities (group 2). Clinical decision-making of RP over nonsurgical treatments and f PLND were primary endpoints and evaluated using regression models. Results PSMA PET/CT claimed significantly more N1 (24.2% vs. 11.3%; P = 0.01; OR, 1.97; 95% CI, 1.18–3.28) but insignificantly more M1 disease (9.9% vs. 5.7%; P = 0.42; OR, 1.91; 95% CI, 0.39–9.23), compared with the conventional imaging modalities. miN0 stage was related to more RP decisions compared with cN0 stage (P &lt; 0.001; OR, 1.91; 95% CI, 1.48–2.46). PLND decision-making was significantly driven by positive c\miN stage findings, which were more reliable when it was reported after a PSMA PET/CT examination (P &lt; 0.001; OR, 35.55; 95% CI, 6.74–187.45 for conventional imaging modalities vs. P &lt; 0.001; OR, 91.72; 95% CI, 11.25–747.56 for PSMA PET/CT). Conclusions Patients with no suspicion of lymph node invasion on molecular imaging (PSMA PET/CT) tended to be referred to RP more compared to radiological imaging. Also, the PLND decision was strongly driven by staging findings. Compared with conventional imaging, PSMA PET/CT findings were more reliable during PLND decision-making.

Assessment of Different Castration Resistance Definitions and Staging Modalities in Metastatic Castration-Resistant Prostate Cancer.

Background/Objectives: Progression to metastatic castration-resistant prostate cancer (mCRPC) is defined either biochemically, radiographically or both. Moreover, staging for mCRPC can be performed either conventionally or with molecular imaging such as prostate-specific membrane antigen computer tomography (PSMA-PET/CT). Methods: We relied on the Frankfurt Metastatic Cancer Database of the Prostate (FRAMCAP) database to compare progression-free (PFS) and overall survival (OS) outcomes regarding the cause of castration resistance and the staging modality used. Results: Overall, 35% progressed to mCRPC biochemically vs. 23% radiographically vs. 42% biochemically + radiographically. The PSA nadir in mHSPC (1.4 vs. 0.4 vs. 0.8 ng/mL) and PSA level at mCRPC progression (15 vs. 2 vs. 21 ng/mL, both p ≤ 0.01) were significantly higher for biochemical vs. radiographic vs. both progressed patients. In PFS and OS analyses, no significant differences were observed among all three compared groups. In the comparison of the staging used for progression to mCRPC, 67% received conventional vs. 33% PSMA-PET/CT, with higher metastatic burden in mHSPC and osseous lesions in mCRPC for conventionally staged patients (both p < 0.01). In PFS (15.3 vs. 10.1 months, hazard ratio [HR]: 0.75) and OS analyses (52.6 vs. 34.3 months, HR: 0.61, both p < 0.05), PSMA-PET/CT harbored better prognosis; however, this did not hold after multivariable adjustment. Similar results were observed for further analyses in second- and third-line mCRPC or patients with a PSA level of ≥2 ng/mL. Conclusions: The cause of progression to mCRPC seems not to influence cancer-control outcomes, despite important baseline tumor characteristic differences. The PSMA-PET/CT staging modality might be associated with better PFS and OS outcomes, possibly due to its more sensitive detection of progression or new metastatic lesions.

Prognostic Role of PSMA-Targeted Imaging in Metastatic Castration-Resistant Prostate Cancer: An Overview.

Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has gained a primary role in prostate cancer (PCa) imaging, overcoming conventional imaging and prostate-specific antigen (PSA) serum levels, and has recently emerged as a promising technique for monitoring therapy response in metastatic castration-resistant prostate cancer (mCRPC) patients treated with novel hormonal therapy, taxanes, and radioligand therapy (RLT). In this review, we aim to provide an overview of the most relevant aspects under study and future prospects related to the prognostic role of PSMA PET/CT in mCRPC. A systematic literature search was performed in the following databases: MEDLINE, PubMed, and EMBASE databases. The study focused exclusively on English-language studies, excluding papers not pertinent to the topic. PSMA PET imaging offers a higher sensitivity and specificity than conventional imaging and provides accurate staging and efficient diagnosis of distant metastases. The data presented herein highlight the usefulness of PET in risk stratification, with a prognostic potential that can have a significant impact on clinical practice. Several prospective trials are ongoing and will shortly provide more evidence supporting the prognostic potential of PET PSMA data in this clinical scenario. Current evidence proves the prognostic role of PSMA PET/CT in different settings, with raising relevance also in the context of mCRPC.

Advanced Imaging for Localized Prostate Cancer

Background/Objectives: Prostate cancer is a prevalent malignancy often presenting without early symptoms. Advanced imaging technologies have revolutionized its diagnosis and management. This review discusses the principles, benefits, and clinical applications of multiparametric magnetic resonance imaging (mpMRI), micro-ultrasound (microUS), and prostate-specific membrane antigen positron emission tomography–computed tomography (PSMA PET/CT) in localized prostate cancer. Methods: We conducted a comprehensive literature review of recent studies and guidelines on mpMRI, microUS, and PSMA PET/CT in prostate cancer diagnosis, focusing on their applications in biopsy-naïve patients, those with previous negative biopsies, and patients under active surveillance. Results: MpMRI has demonstrated high sensitivity and negative predictive value in detecting clinically significant prostate cancer (csPCa). MicroUS, a newer technology, has shown promising results in early studies, with sensitivity and specificity comparable to mpMRI. PSMA PET/CT has emerged as a highly sensitive and specific imaging modality, particularly valuable for staging and detecting metastatic disease. All three technologies have been incorporated into urologic practice for prostate cancer diagnosis and management, with each offering unique advantages in different clinical scenarios. Conclusions: Advanced imaging techniques, including mpMRI, microUS, and PSMA PET/CT, have significantly improved the accuracy of prostate cancer diagnosis, staging, and management. These technologies enable more precise targeting of suspicious lesions during biopsy and therapy planning. However, further research, especially randomized controlled trials, is needed to fully establish the optimal use and inclusion of these imaging modalities in various stages of prostate cancer care.

Using a novel PSMA-PET and PSA-based model to enhance the diagnostic accuracy for clinically significant prostate cancer and avoid unnecessary biopsy in men with PI-RADS ≤ 3 MRI.

The diagnostic evaluation of men with suspected prostate cancer (PCa) yet inconclusive MRI (PI-RADS ≤ 3) presents a common clinical challenge. [68Ga]Ga-labelled prostate-specific membrane antigen ([68Ga]Ga-PSMA) positron emission tomography/computed tomography (PET/CT) has shown promise in identifying clinically significant PCa (csPCa). We aim to establish a diagnostic model incorporating PSMA-PET to enhance the diagnostic process of csPCa in PI-RADS ≤ 3 men. This study retrospective included 151 men with clinical suspicion of PCa and PI-RADS ≤ 3 MRI. All men underwent [68Ga]Ga-PSMA PET/CT scans and ultrasound/MRI/PET fusion-guided biopsies. csPCa was defined as Grade Group ≥ 2. PRIMARY-scores from PSMA-PET scans were evaluated. A diagnostic model incorporating PSMA-PET and prostate-specific antigen (PSA)-derived parameters was developed. The discriminative performance and clinical utility were compared with conventional methods. Internal validation was conducted using a fivefold cross-validation with 1000 iterations. In this PI-RADS ≤ 3 cohort, areas-under-the-curve (AUCs) for detecting csPCa were 0.796 (95%CI, 0.738-0.853), 0.851 (95%CI, 0.783-0.918) and 0.806 (95%CI, 0.742-0.870) for PRIMARY-score, SUVmax and routine clinical PSMA-PET assessment, respectively. The diagnostic model comprising PRIMARY-score, SUVmax and serum free PSA/total PSA (fPSA/tPSA) achieved a significantly higher AUC of 0.906 (95%CI, 0.851-0.961) compared to strategies based on PRIMARY-score or SUVmax (P < 0.05) and markedly superior to conventional strategies typically based on PSA density (P < 0.001). The average fivefold cross-validated AUC with 1000 iterations was 0.878 (95%CI, 0.820-0.954). Theoretically, using a threshold of 21.6%, the model could have prevented 78% of unnecessary biopsies while missing only 7.8% of csPCa cases in this cohort. A novel diagnostic model incorporating PSMA-PET derived metrics-PRIMARY-score and SUVmax-along with serum fPSA/tPSA, has been developed and validated. The integrated model may assist clinical decision-making with enhanced diagnostic accuracy over the individual conventional metrics. It has great potential to reduce unnecessary biopsies for men with PI-RADS ≤ 3 MRI results and warrants further prospective and external evaluations.

Diagnostic Accuracy of PSMA PET-Guided Prostate Biopsy in Prostate Cancer—A Systematic Review and Meta-analysis

Purpose Early diagnosis and treatment of prostate cancer (PC) are crucial for effective management and improved patient outcomes. Newer imaging modalities like prostate-specific membrane antigen PET have shown superior diagnostic performance in detecting PC and clinically significant PC (csPC). This systematic review and meta-analysis aims to synthesize evidence on the diagnostic performance of PSMA PET-guided prostate biopsy in detecting PC and csPC. Patients and Methods The study followed the PRISMA-DTA guidelines. Using a predefined search strategy, 3 databases (PubMed, Embase, and Web of Science) were systematically searched using appropriate keywords. A meta-analysis was conducted using diagnostic accuracy parameters of the included studies. Risk of bias assessment was done using the QUADAS-2 tool. Results Out of 378 articles, 20 were assessed for full-text screening and 10 articles with 874 patients were finally included. Eight studies reported a pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio of 0.90 (95%confidence interval [CI], 0.82–0.95), 0.93 (95% CI, 0.57–0.99), 12.3 (95% CI, 1.5–98.9), 0.10 (95% CI, 0.05–0.20), and 117 (95% CI, 12–1178), respectively, for detecting PC using PSMA PET-guided prostate biopsy with an area under the summary receiver operating characteristics curve of 0.94 (95% CI, 0.92–0.96). Similarly, 6 studies reported a pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio of 0.89 (95% CI, 0.82–0.94), 0.65 (95% CI, 0.49–0.79), 2.6 (95% CI, 1.6–4.1), 0.17 (95% CI, 0.09–0.31), and 15 (95% CI, 6–41), respectively, for detecting csPC using PSMA PET-guided prostate biopsy with area under summary receiver operating characteristics curve of 0.86 (95% CI, 0.82–0.88). Conclusions PSMA PET-guided prostate biopsy has a high diagnostic accuracy in detecting PC and csPC in patients with clinical suspicion of PC, and provides a 1-stop solution for early diagnosis and staging of PC.

Novel astatine (211At)-labelled prostate-specific membrane antigen ligand with a neopentyl-glycol structure: evaluation of stability, efficacy, and safety using a prostate cancer xenograft model.

Prostate-specific membrane antigen (PSMA)-targeted alpha therapy is considered a promising alternative treatment for metastatic castration-resistant prostate cancer (mCRPC). Though astatine-211 (211At) is potentially useful alpha-emitter producible by cyclotrons, its clinical application has been limited by instability and a tendency to deastatination in vivo. To overcome these challenges, we developed [211At]At-NpG-PSMA, a novel PSMA ligand with a neopentyl-glycol structure that enhances in vivo stability against deastatination. This study aimed to evaluate the stability, anti-tumour effect, and safety of [211At]At-NpG-PSMA in mice. Xenograft models were prepared by subcutaneous transplantation of PSMA-positive PC-3 PIP cells into BALB/c nu/nu mice. [211At]At-NpG-PSMA was administered to assess biodistribution, and the anti-tumour effect was evaluated at doses of 0.32, 1.00 and 1.93 MBq in comparison with saline. Histopathological examinations were performed to evaluate damage to normal organs. [211At]At-NpG-PSMA demonstrated high tumour uptake (42.0 ± 13.1%ID/g at 3h) with minimal uptake in non-target tissues, including thyroid, stomach and salivary grands (0.28 ± 0.20%ID, 0.71 ± 0.12%ID/g and 0.88 ± 0.10%ID/g at 3h, respectively). A dose-dependent anti-tumour effect was observed, with tumour volumes increasing by 796.0 ± 437.6% in the control versus 161.0 ± 213.4%, -76.4 ± 19.2% and - 59.5 ± 41.6% in the 0.32, 1.00 and 1.93 MBq groups, respectively, by day 15. Mild renal tubule regeneration was noted in the 1.00 MBq group. [211At]At-NpG-PSMA demonstrated significant stability in vivo and anti-tumour effects with minimal side effects, indicating its potential as a new therapeutic drug for PSMA-targeted alpha therapy in mCRPC.

Comparison of the predictive value of multiparametric MRI and prostate-specific membrane antigen PET/CT for pelvic lymph node metastasis in prostate cancer

Objective: To compare the diagnostic performance of multiparametric magnetic resonance imaging (mpMRI) and prostate-specific membrane antigen (PSMA) PET/CT in detecting pelvic lymph node metastasis in prostate cancer. Methods: This is a retrospective case series study. A retrospective analysis was conducted on the data of 115 prostate cancer patients who underwent both mpMRI and PSMA PET/CT before undergoing radical prostatectomy and extended pelvic lymph node dissection at the Department of Urology, Xiangya Hospital, Central South University, between March 2020 and September 2023. The age (M(IQR)) was 67(10) years (range: 45 to 84 years), and the body mass index was 24(4) kg/m2 (range: 18 to 30 kg/m2). Pathological and imaging data were obtained from the patients. Lymph node pathology results were used as the gold standard to evaluate the diagnostic performance of mpMRI and PSMA PET/CT for detecting pelvic lymph node metastasis in PCa through diagnostic evaluation tests. Comparisons between groups were performed using independent samples t-test, Mann-Whitney U test, or χ2 test. Results: The positive rate for detecting pelvic lymph node metastasis was 18.3% (21/115) with mpMRI and 25.2% (29/115) with PSMA PET/CT. The pathological positive rate for lymph nodes was 28.7% (33/115). In patient-based analysis, the diagnostic sensitivity of PSMA PET/CT was significantly higher than that of mpMRI (63.6% vs. 30.3%, χ2=7.36, P=0.007). In lesion-based analysis, both the sensitivity and positive predictive value of PSMA PET/CT were significantly higher than those of mpMRI (sensitivity: 68.0% vs. 21.6%, χ2=42.20, P<0.01; positive predictive value: 50.0% vs. 23.1%, χ2=7.54, P=0.006). Conclusions: PSMA PET/CT and mpMRI both demonstrates good specificity in predicting pelvic lymph node metastasis in prostate cancer. However, PSMA PET/CT is significantly superior to mpMRI in terms of sensitivity and the detection rate of pathologically positive lymph nodes.

Prognostic value of PSMA PET in predicting long-term biochemical control following curative intent treatment for prostate cancer.

The aim of this study is to investigate the prognostic value of 68Ga-labelled prostate-specific membrane antigen (PSMA) positron emission tomography (PET) metrics in predicting long-term biochemical failure-free survival (BFFS) following curative intent treatment for prostate cancer. We completed a prospective study that followed men who had PSMA PET for staging of newly diagnosed prostate cancer between 2015 and 2017 who went on to have curative intent treatment with radiotherapy (RT) or radical prostatectomy (RP). PSMA PET CT imaging was reported and the intraprostatic maximum standardised uptake value (SUVmax) was recorded. The primary outcome was BFFS. Statistical analysis included descriptive statistics, Cox proportional hazards (PH) models, Kaplan-Meier survival analysis and a regression tree structured method. A total of 183 men were included in the analysis with a median age of 66 years and the majority of patients (55.2%) had ISUP grade 1-3 disease. All patients had PSMA PET staging prior to curative intent treatment with RP (66.1%) or external beam radiotherapy (33.9%). PSMA-avid pelvic nodes were present in 26 patients but were not associated with worse biochemical control. A PSMA SUVmax of the prostate primary greater than the median (>5.6) was associated with a lower BFFS (HR: 4.4, 95% CI 1.42-3.72, P = 0.01). A multivariate Cox model incorporating initial biopsy grade, age and PSMA SUVmax showed that PSMA SUVmax was an independent predictor of BFFS. The RT-structured method identified an optimal threshold of 6.8 for PSMA SUVmax, above which patients with ISUP 1-3 disease had a significantly worse BFFS. PSMA SUVmax is a strong predictor of BFFS in patients with non-metastatic prostate cancer who underwent curative intent treatment. Patients with low-risk disease on biopsy (ISUP 1-3) but high PSMA SUVmax may have biochemical failure risk analogous to higher-risk disease (ISUP 4-5). These findings allow for further risk stratification and prognosis of patients with newly diagnosed prostate cancer planned for definitive treatment.

Targeted Delivery of AR-V7 siRNA with Bivalent PSMA Aptamers Effectively Suppresses the Growth of Enzalutamide-Resistant Prostate Cancer.

Androgen deprivation therapy has been the primary treatment strategy for advanced prostate cancer (PCa). But most patients develop castration resistance over time. For FDA-approved second-generation androgen receptor (AR) antagonists, including enzalutamide (ENZ) and abiraterone (AA), patients who initially respond to them eventually develop resistance. The key mechanism for resistance to ENZ/AA involves AR splice variants (AR-Vs) and specifically AR-V7. Current AR antagonists cannot target AR-V7 due to its lack of the C-terminal ligand-binding domain (LBD) but keeping the AR N-terminal domain (NTD) which still can activate androgen-responsive genes. Therefore, targeting the AR NTD and AR-V7 is critically important to overcome ENZ resistance. Unfortunately, AR NTD has been considered an "undruggable" target due to the difficulty in defining its three-dimensional (3D) structure. In this context, siRNA is highly suitable to address this undruggable target. However, siRNA cannot freely diffuse into cells, and a carrier is needed. In this regard, nucleic acid-based aptamers are highly suitable for cell type-specific delivery of siRNA in vivo. In this study, we have developed a serum-stable bivalent prostate-specific membrane antigen (PSMA) aptamer-AR-V7 siRNA chimera (PAP). The results show that PAP can knock down both AR-full length and AR-V7 in PSMA-expressing castration-resistant cells. It can resensitize ENZ in cell lines and PCa xenografts. ENZ combined with PAP can significantly inhibit 22Rv1 xenograft growth in mice without experiencing castration. Owing to the low toxicity, PAP has potential to offer a new antiandrogen treatment for current ENZ-resistant PCa.

The first experience of multi-modal in vivo PET/SPECT/CT and MRI imaging of laboratory mice with melanoma B16F10 (short message)

Background. For in vivo determination of size and metabolic characteristics of model tumors in laboratory animals, it is recommended to use imaging methods: positron emission tomography (PET), single-photon emission computed tomography (SPECT), computed tomography (CT) and magnetic resonance imaging (MRI). Due to the limited availability of hybrid scanners, it is necessary to investigate the feasibility of obtaining tomograms on separate devices with subsequent geometric comparison of images.Aim. To investigate the feasibility of multimodal imaging of mice with subcutaneous melanoma B16F10.Materials and methods. PET, SPECT and CT were performed using a preclinical VECTor 6 tomograph (MILabs, the Netherlands), MRI was performed using a preclinical nanoScan® 3T tomograph (Mediso, Hungary). The following modality combinations were studied: MRI and PET / CT with 18F-fluorodeoxyglucose; MRI and PET / CT with 18F-boronphenylalanine; MRI and PET / SPECT / CT with 18F-fluoroethyltyrosine (18F-FET) and 177lutetium – prostate-specific membrane antigen (177Lu-PSMA). Mice were immobilized in a custom-made device during scanning and during movement between tomographs. PET and MRI, SPECT and MRI images were fused in the program InterView FUSION 3.09.008.0000 through an intermediate stage of fusion with CT.Results. Multimodal PET / CT / MRI and PET / SPECT / CT / MRI images of tumor-bearing mice were obtained for the first time in Russia. PET / MRI data confirmed development of the tumor from 6 × 4 × 4 mm in size. PET / SPECT / CT / MRI enabled to image visceral organs with high accumulation of radionuclide tracers: pancreas with 18F-FET (standardized uptake value 2.6) and kidneys with 177Lu-PSMA (standardized uptake value 4.4), while the obtained images of organs did not merge and did not overlap.Conclusion. Multimodal imaging enables the selection of experimental animals with tumors of specific size and metabolic activity for the study of new radiopharmaceuticals, including those with vector delivery.

Outstanding increase in tumor-to-background ratio over time allows tumor localization by [89Zr]Zr-PSMA-617 PET/CT in early biochemical recurrence of prostate cancer

BackgroundPositron emission tomography/computed tomography (PET/CT) using prostate-specific membrane antigen (PSMA)-targeted radiotracers labeled with zirconium-89 (89Zr; half-life ~ 78.41 h) showed promise in localizing biochemical recurrence of prostate cancer (BCR) in pilot studies.MethodsRetrospective analysis of 38 consecutive men with BCR (median [minimum–maximum] prostate-specific antigen 0.52 (0.12–2.50 ng/mL) undergoing [89Zr]Zr-PSMA-617 PET/CT post-negative [68Ga]Ga-PSMA-11 PET/CT. PET/CT acquisition 1-h, 24-h, and 48-h post-injection of a median (minimum–maximum) [89Zr]Zr-PSMA-617 tracer activity of 123 (84–166) MBq.Results[89Zr]Zr-PSMA-617 PET/CT detected altogether 57 lesions: 18 local recurrences, 33 lymph node metastases, 6 bone metastases in 30/38 men with BCR (78%) and prior negative conventional PSMA PET/CT. Lesion uptake significantly increased from 1-h to 24-h and, in a majority of cases, from 24-h to 48-h. Tumor-to-background ratios significantly increased over time, with absolute increases of 100 or more. No side effects were noted. After [89Zr]Zr-PSMA-617 PET/CT-based treatment, prostate-specific antigen concentration decreased in all patients, becoming undetectable in a third of patients. Limitations: retrospective, single center design; infrequent histopathological and imaging verification.ConclusionThis large series provides further evidence that [89Zr]Zr-PSMA-617 PET/CT is a beneficial imaging modality to localize early BCR. A remarkable increase in tumor-to-background ratio over time allows localization of tumor unidentified on conventional PSMA PET/CT.

Evaluating response to radium-223 using 68Ga-PSMA PET/CT imaging in patients with metastatic castration-resistant prostate cancer.

Conventional imaging techniques and prostate-specific antigen (PSA) values are not useful to follow-up patients during Radium-223 treatment. The study aimed to evaluate the predictive value of prostate-specific membrane antigen PSMA PET/CT-based response in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving Radium-223 dichloride treatment. Patients treated with radium-223, having performed two 68Ga-PSMA-11 PET/CT scans (baseline 1month before treatment initiation and follow-up 2weeks after the third cycle), were retrospectively evaluated. Visual and quantitative PET image analyses were performed, and patients were dichotomized into progressive (PD) and non-PD according to Response Evaluation Criteria in PSMA‑imaging (RECIP1.0) and PSMA-PET Progression criteria (PPP). The primary endpoint was overall survival (OS). Cohen's Kappa (κ) was used to test the agreement between the two criteria. The Cox regression hazard model and Kaplan-Meier method were used for survival analyses. Twenty-eight mCRPC patients were evaluated. Sixteen (43%) and 18 (64%) patients had PD according to RECIP1.0 and PPP, respectively; κ = 0.85 (95% CI 0.65-1.00). After a median follow-up of 16months (interquartile IQR 9-33), 20 (71%) patients died. Patients with PSMA PD showed a higher risk of death than non-PD according to RECIP1.0 (HR = 2.9; 95% CI 1.14-7.46; p = 0.029) and PPP (HR = 2.8; 95% CI 1.04-7.64; p = 0.042). For both criteria, the median OS was shorter for PD than non-PD (37 vs. 12months, Log-rank; p < 0.05). The C-index for RECIP1.0 and PPP were almost equal (0.66 and 0.63; respectively). This study demonstrated that PSMA-PET/CT imaging is valuable for monitoring radium-223 treatment. Both PSMA PET/CT response criteria (RECIP1.0 and PPP) perform similarly predicting OS at follow-up after three cycles of radium-223. These findings urge further validation in prospective trials.

Best Patient Care Practices for Administering PSMA-Targeted Radiopharmaceutical Therapy.

Optimal patient management protocols for metastatic castration-resistant prostate cancer (mCRPC) are poorly defined and even further complexified with new therapy approvals, such as radiopharmaceuticals. The prostate-specific membrane antigen (PSMA)-targeted agent 177Lu vipivotide tetraxetan ([177Lu]Lu-PSMA-617), approved after the phase III VISION study, presents physicians with additional aspects of patient management, including specific adverse event (AE) monitoring and management, as well as radiation safety. Drawing on our experience as VISION study investigators, here we provide guidance on best practices for delivering PSMA-targeted radiopharmaceutical therapy (RPT) to patients with mCRPC. After a comprehensive review of published evidence and guidelines on RPT management in prostate cancer, we identified educational gaps in managing the radiation safety and AEs associated with [177Lu]Lu-PSMA-617. Our results showed that providing sufficient education on AEs (e.g., fatigue and dry mouth) and radiation safety principles is key to effective delivery and management of patient expectations. Patient counseling by health care professionals, across disciplines, is a cornerstone of optimal patient management during PSMA-targeted RPT. Multidisciplinary collaboration is crucial, and physicians must adhere to radiation safety protocols and counsel patients on radiation safety considerations. Treatment with [177Lu]Lu-PSMA-617 is generally well tolerated; however, additional interventions may be required, such as dosing modification, medications, or transfusions. Urinary incontinence can be challenging in the context of radiation safety. Multidisciplinary collaboration between medical oncologists and nuclear medicine teams ensures that patients are monitored and managed safely and efficiently. In clinical practice, the benefit-to-risk ratio should always be evaluated on a case-by-case basis.