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We have previously shown that maternal endotoxin exposure leads to a phenotype of cerebral palsy and pro-inflammatory microglia in the brain in neonatal rabbits. "Activated" microglia overexpress the enzyme glutamate carboxypeptidase II (GCPII) that hydrolyzes N-acetylaspartylglutamate to N-acetylaspartate and glutamate, and we have shown previously that inhibiting microglial GCPII is neuroprotective. Glutamate-induced injury and associated immune signaling can alter microglial responses including microglial process movements for surveillance and phagocytosis. We hypothesize that inhibition of GCPII activity could alter microglial phenotype and normalize microglial process movement/dynamics. Newborn rabbit kits exposed to endotoxin in utero, when treated with dendrimer-conjugated 2-(phosphonomethyl)-pentanedioic acid (D-2PMPA), a potent and selective inhibitor of microglial GCPII, showed profound changes in microglial phenotype within 48 h of treatment. Live imaging of hippocampal microglia in ex vivo brain slice preparations revealed larger cell body and phagocytic cup sizes with less stable microglia processes in CP kits compared to healthy controls. D-2PMPA treatment led to significant reversal of microglial process stability to healthy control levels. Our results emphasize the importance of microglial process dynamics in determining the state of microglial function in the developing brain and demonstrate how GCPII inhibition specifically in microglia can effectively change the microglial process motility to healthy control levels, potentially impacting migration, phagocytosis, and inflammatory functions. [ABSTRACT FROM AUTHOR]

Glutamate carboxypeptidase II (GCPII), localized on the surface of astrocytes and activated microglia, regulates extracellular glutamate concentration in the central nervous system (CNS). We have previously shown that GCPII is upregulated in activated microglia in the presence of inflammation. Inhibition of GCPII activity could reduce glutamate excitotoxicity, which may decrease inflammation and promote a 'normal' microglial phenotype. 2-(3-Mercaptopropyl) pentanedioic acid (2-MPPA) is the first GCPII inhibitor that underwent clinical trials. Unfortunately, immunological toxicities have hindered 2-MPPA clinical translation. Targeted delivery of 2-MPPA specifically to activated microglia and astrocytes that over-express GCPII has the potential to mitigate glutamate excitotoxicity and attenuate neuroinflammation. In this study, we demonstrate that 2-MPPA when conjugated to generation-4, hydroxyl-terminated polyamidoamine (PAMAM) dendrimers (D-2MPPA) localize specifically in activated microglia and astrocytes only in newborn rabbits with cerebral palsy (CP), not in controls. D-2MPPA treatment led to higher 2-MPPA levels in the injured brain regions compared to 2-MPPA treatment, and the extent of D-2MPPA uptake correlated with the injury severity. D-2MPPA was more efficacious than 2-MPPA in decreasing extracellular glutamate level in ex vivo brain slices of CP kits, and in increasing transforming growth factor beta 1 (TGF-β1) level in primary mixed glial cell cultures. A single systemic intravenous dose of D-2MPPA on postnatal day 1 (PND1) decreased microglial activation and resulted in a change in microglial morphology to a more ramified form along with amelioration of motor deficits by PND5. These results indicate that targeted dendrimer-based delivery specifically to activated microglia and astrocytes can improve the efficacy of 2-MPPA by attenuating glutamate excitotoxicity and microglial activation. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background Prostate-specific membrane antigen (PSMA) overexpression has been observed in the endothelial neovasculature of several solid malignancies. This study aimed to identify PSMA expression in the primary tumor of classical papillary thyroid carcinoma (PTC) and assess the correlation between the degree of PSMA expression and recurrence. Methods We reviewed the electronic medical records of patients who underwent total thyroidectomy and central neck dissection, with or without lateral neck dissection, for classical PTC between 2009 and 2014 at our institution. Recurrence was defined as a structural disease based on histological confirmation on follow-up. Fifty-one patients with the recurrent structural disease were matched, using a propensity score matching method, to patients with no disease evidence during follow-up. Clinicopathological and follow-up data were collected for 102 patients. The monoclonal mouse anti-human PSMA/FOLH1/NAALADase I antibody was used for staining the primary tumor. The score of PSMA expression was classified as negative (< 5% positivity), weak (5–10 % positivity), moderate (11–49% positivity), and strong (more than 50% positivity). Clinicopathological factors were compared between patients with low and high PSMA expression. Moreover, whether the degree of PSMA expression and clinicopathological factors could predict recurrence was investigated. Cox proportional hazard regression models were used to evaluate the risk of recurrence. Results There was no significant difference in clinicopathological factors between low (negative or weak) and high (moderate or strong) PSMA expression. Gross extrathyroidal extension (ETE), absence of chronic lymphocytic thyroiditis, and high PSMA expression were all associated with lower recurrence-free survival (RFS) rate in a univariate analysis. In multivariate analysis, gross ETE (hazard ratio [HR], 2.279; 95% confidence interval [CI], 1.257−4.132; p = 0.007) and high PSMA expression (HR, 1.895; 95% CI, 1.073−3.348; p = 0.028) were associated with poor RFS. Conclusions High PSMA expression in the primary tumor was a significant factor in predicting recurrence in classic PTC. PSMA could be a potential biomarker for personalized management for PTC.

Background: Prostate-specific membrane antigen (PSMA) overexpression has been observed in the endothelial neovasculature of several solid malignancies. This study aimed to identify PSMA expression in the primary tumor of classical papillary thyroid carcinoma (PTC) and assess the correlation between the degree of PSMA expression and recurrence. Methods: We reviewed the electronic medical records of patients who underwent total thyroidectomy and central neck dissection, with or without lateral neck dissection, for classical PTC between 2009 and 2014 at our institution. Recurrence was defined as a structural disease based on histological confirmation on follow-up. Fifty-one patients with the recurrent structural disease were matched, using a propensity score matching method, to patients with no disease evidence during follow-up. Clinicopathological and follow-up data were collected for 102 patients. The monoclonal mouse anti-human PSMA/FOLH1/NAALADase I antibody was used for staining the primary tumor. The score of PSMA expression was classified as negative (< 5% positivity), weak (5–10 % positivity), moderate (11–49% positivity), and strong (more than 50% positivity). Clinicopathological factors were compared between patients with low and high PSMA expression. Moreover, whether the degree of PSMA expression and clinicopathological factors could predict recurrence was investigated. Cox proportional hazard regression models were used to evaluate the risk of recurrence. Results: There was no significant difference in clinicopathological factors between low (negative or weak) and high (moderate or strong) PSMA expression. Gross extrathyroidal extension (ETE), absence of chronic lymphocytic thyroiditis, and high PSMA expression were all associated with lower recurrence-free survival (RFS) rate in a univariate analysis. In multivariate analysis, gross ETE (hazard ratio [HR], 2.279; 95% confidence interval [CI], 1.257−4.132; p = 0.007) and high PSMA expression (HR, 1.895; 95% CI, 1.073−3.348; p = 0.028) were associated with poor RFS. Conclusions: High PSMA expression in the primary tumor was a significant factor in predicting recurrence in classic PTC. PSMA could be a potential biomarker for personalized management for PTC. [ABSTRACT FROM AUTHOR]

Glutamate carboxypeptidase-II (GCPII) is a zinc-dependent metalloenzyme implicated in numerous neurological disorders. The pharmacophoric requirements of active-site GCPII inhibitors makes them highly charged, manifesting poor pharmacokinetic (PK) properties. Herein, we describe the discovery and characterization of catechol-based inhibitors including L-DOPA, D-DOPA, and caffeic acid, with sub-micromolar potencies. Of these, D-DOPA emerged as the most promising compound, with good metabolic stability, and excellent PK properties. Orally administered D-DOPA yielded high plasma exposures (AUCplasma = 72.7 nmol·h/mL) and an absolute oral bioavailability of 47.7%. Unfortunately, D-DOPA brain exposures were low with AUCbrain = 2.42 nmol/g and AUCbrain/plasma ratio of 0.03. Given reports of isomeric inversion of D-DOPA to L-DOPA via D-amino acid oxidase (DAAO), we evaluated D-DOPA PK in combination with the DAAO inhibitor sodium benzoate and observed a >200% enhancement in both plasma and brain exposures (AUCplasma = 185 nmol·h/mL; AUCbrain = 5.48 nmol·h/g). Further, we demonstrated GCPII target engagement; orally administered D-DOPA with or without sodium benzoate caused significant inhibition of GCPII activity. Lastly, mode of inhibition studies revealed D-DOPA to be a noncompetitive, allosteric inhibitor of GCPII. To our knowledge, this is the first report of D-DOPA as a distinct scaffold for GCPII inhibition, laying the groundwork for future optimization to obtain clinically viable candidates. [ABSTRACT FROM AUTHOR]

Objectives: To assess artificial intelligence (AI) ability to evaluate intraprostatic prostate cancer (PCa) on prostate-specific membrane antigen positron emission tomography (PSMA PET) scans prior to active treatment (radiotherapy or prostatectomy)., Materials and Methods: This systematic review was registered on the International Prospective Register of Systematic Reviews (PROSPERO identifier: CRD42023438706). A search was performed on Medline, Embase, Web of Science, and Engineering Village with the following terms: 'artificial intelligence', 'prostate cancer', and 'PSMA PET'. All articles published up to February 2024 were considered. Studies were included if patients underwent PSMA PET scan to evaluate intraprostatic lesions prior to active treatment. The two authors independently evaluated titles, abstracts, and full text. The Prediction model Risk Of Bias Assessment Tool (PROBAST) was used., Results: Our search yield 948 articles, of which 14 were eligible for inclusion. Eight studies met the primary endpoint of differentiating high-grade PCa. Differentiating between International Society of Urological Pathology (ISUP) Grade Group (GG) ≥3 PCa had an accuracy between 0.671 to 0.992, sensitivity of 0.91, specificity of 0.35. Differentiating ISUP GG ≥4 PCa had an accuracy between 0.83 and 0.88, sensitivity was 0.89, specificity was 0.87. AI could identify non-PSMA-avid lesions with an accuracy of 0.87, specificity of 0.85, and specificity of 0.89. Three studies demonstrated ability of AI to detect extraprostatic extensions with an area under curve between 0.70 and 0.77. Lastly, AI can automate segmentation of intraprostatic lesion and measurement of gross tumour volume., Conclusion: Although the current state of AI differentiating high-grade PCa is promising, it remains experimental and not ready for routine clinical application. Benefits of using AI to assess intraprostatic lesions on PSMA PET scans include: local staging, identifying otherwise radiologically occult lesions, standardisation and expedite reporting of PSMA PET scans. Larger, prospective, multicentre studies are needed., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

The application of PET/CT with radiopharmaceuticals targeting PSMA is significantly transforming the diagnostic and therapeutic strategies of patients with prostate cancer. In Spain, the availability and access to positron-emitting radiopharmaceuticals targeting Prostate-Specific Membrane Antigen (PSMA) have significantly changed in recent months. These changes are affecting their use in diagnostic procedures. As a result, its use within diagnostic protocols for patients with prostate cancer is undergoing significant modifications. In this collective and cooperative document, the authors have selected the most robust evidence accumulated to date to generate a clinical guide to achieve appropriate use of this technology. A format that presents the most frequent clinical situations and the patient profiles in which PSMA PET/CT plays a significant role or will do so in the immediate future has been chosen. It should be taken into account that regulatory restrictions mediate the current indications for its use in Spain, as well as its current cost and the production capacity of radiopharmaceuticals. The guideline presents a review of the established methodology for optimized imaging with each of the radiopharmaceutical variants targeting PSMA and recommendations for structured and accurate reporting of metabolic findings in combination with CT., (Copyright © 2024 Sociedad Española de Medicina Nuclear e Imagen Molecular. Published by Elsevier España, S.L.U. All rights reserved.)

Purpose: The aim of this study was to determine the agreement between three observers with different levels of experience using the PSMA-RADS 2.0 criteria and the miTNM system for the interpretation of PET-PSMA with [ 18 F]DCFPyL in males with prostate cancer., Materials and Methods: PET-PSMA images from 114 prostate cancer patients were blindly reported twice by three different observers at intervals of 8 weeks. The evaluations were performed according to the molecular imaging TNM (miTNM) and PSMA-RADS 2.0 criteria. We used Fleiss' Kappa to analyse inter and intraobserver agreements., Results: Moderate overall agreement was obtained in the assessment of the PET-PSMA results (Fleiss'k = 0.53; 95% CI 0.45-0.62; p < 0.001), with significant agreement in the miT, miN and miM reports. There was a substantial level of agreement in the reporting of prostatic disease and lymphatic involvement (Fleiss'k = 0.66 and 0.65), being lower than that observed in the reporting of metastatic disease (Fleiss'k = 0.86), especially in the M0 group (Fleiss'k = 0.99). Upon re-evaluation of the images, observer 1 had moderate overall agreement for miT (Fleiss'k = 0.51) and substantial agreement for miN and miM (Fleiss'k 0.75 and 0.63, respectively)., Conclusions: The use of a structured scoring system such as PSMA-RADS 2.0, as well as the miTNM classification system in the interpretation of PET-PSMA images in prostate cancer patients, provides a highly reproducible report format. High levels of interobserver and intraobserver agreement are found, especially when ruling out disease, which supports its use in routine clinical practice., (Copyright © 2024 Sociedad Española de Medicina Nuclear e Imagen Molecular. Published by Elsevier España, S.L.U. All rights reserved.)

Purpose: TMPRSS2:ERG gene fusion negatively regulates PSMA expression in prostate adenocarcinoma (PCa) cell lines. Therefore, immunohistochemical (IHC) ERG expression, a surrogate for an underlying ERG rearrangement, and PSMA expression patterns in radical prostatectomy (RPE) specimens of primary PCa, including corresponding PSMA-PET scans were investigated.Two cohorts of RPE samples (total n=148): In cohort #1 (n=62 patients) with available RPE and preoperative [68Ga]Ga-PSMA-11 PET, WHO/ISUP grade groups, IHC-ERG (positive vs. negative) and IHC-PSMA expression (% PSMA-negative tumour area, PSMA%neg) were correlated with the corresponding SUVmax. In the second cohort #2 (n=86 patients) including RPE only, same histopathological parameters were evaluated.Cohort #1: PCa with IHC-ERG expression (35.5%) showed significantly lower IHC-PSMA expression and lower SUVmax values on the corresponding PET scans. Eight of 9 PCa with negative PSMA-PET scans had IHC-ERG positivity, and confirmed TMPRSS2::ERG rearrangement. In IHC-PSMA positive PCa, IHC-ERG positivity was significantly associated with lower SUVmax values. In cohort #2, findings of higher IHC-PSMA%neg and IHC-ERG expression was confirmed with only 0-10% PSMA%neg tumour areas in IHC-ERG-negative PCa.IHC-ERG expression is significantly associated with more heterogeneous and lower IHC-PSMA tissue expression in two independent RPE cohorts. There is a strong association of ERG positivity in RPE tissue with lower [68Ga]Ga-PSMA-11 uptake on corresponding PET scans. Results may serve as a base for future biomarker development to enable tumour-tailored, individualized imaging approaches.Methods: TMPRSS2:ERG gene fusion negatively regulates PSMA expression in prostate adenocarcinoma (PCa) cell lines. Therefore, immunohistochemical (IHC) ERG expression, a surrogate for an underlying ERG rearrangement, and PSMA expression patterns in radical prostatectomy (RPE) specimens of primary PCa, including corresponding PSMA-PET scans were investigated.Two cohorts of RPE samples (total n=148): In cohort #1 (n=62 patients) with available RPE and preoperative [68Ga]Ga-PSMA-11 PET, WHO/ISUP grade groups, IHC-ERG (positive vs. negative) and IHC-PSMA expression (% PSMA-negative tumour area, PSMA%neg) were correlated with the corresponding SUVmax. In the second cohort #2 (n=86 patients) including RPE only, same histopathological parameters were evaluated.Cohort #1: PCa with IHC-ERG expression (35.5%) showed significantly lower IHC-PSMA expression and lower SUVmax values on the corresponding PET scans. Eight of 9 PCa with negative PSMA-PET scans had IHC-ERG positivity, and confirmed TMPRSS2::ERG rearrangement. In IHC-PSMA positive PCa, IHC-ERG positivity was significantly associated with lower SUVmax values. In cohort #2, findings of higher IHC-PSMA%neg and IHC-ERG expression was confirmed with only 0-10% PSMA%neg tumour areas in IHC-ERG-negative PCa.IHC-ERG expression is significantly associated with more heterogeneous and lower IHC-PSMA tissue expression in two independent RPE cohorts. There is a strong association of ERG positivity in RPE tissue with lower [68Ga]Ga-PSMA-11 uptake on corresponding PET scans. Results may serve as a base for future biomarker development to enable tumour-tailored, individualized imaging approaches.Results: TMPRSS2:ERG gene fusion negatively regulates PSMA expression in prostate adenocarcinoma (PCa) cell lines. Therefore, immunohistochemical (IHC) ERG expression, a surrogate for an underlying ERG rearrangement, and PSMA expression patterns in radical prostatectomy (RPE) specimens of primary PCa, including corresponding PSMA-PET scans were investigated.Two cohorts of RPE samples (total n=148): In cohort #1 (n=62 patients) with available RPE and preoperative [68Ga]Ga-PSMA-11 PET, WHO/ISUP grade groups, IHC-ERG (positive vs. negative) and IHC-PSMA expression (% PSMA-negative tumour area, PSMA%neg) were correlated with the corresponding SUVmax. In the second cohort #2 (n=86 patients) including RPE only, same histopathological parameters were evaluated.Cohort #1: PCa with IHC-ERG expression (35.5%) showed significantly lower IHC-PSMA expression and lower SUVmax values on the corresponding PET scans. Eight of 9 PCa with negative PSMA-PET scans had IHC-ERG positivity, and confirmed TMPRSS2::ERG rearrangement. In IHC-PSMA positive PCa, IHC-ERG positivity was significantly associated with lower SUVmax values. In cohort #2, findings of higher IHC-PSMA%neg and IHC-ERG expression was confirmed with only 0-10% PSMA%neg tumour areas in IHC-ERG-negative PCa.IHC-ERG expression is significantly associated with more heterogeneous and lower IHC-PSMA tissue expression in two independent RPE cohorts. There is a strong association of ERG positivity in RPE tissue with lower [68Ga]Ga-PSMA-11 uptake on corresponding PET scans. Results may serve as a base for future biomarker development to enable tumour-tailored, individualized imaging approaches.Conclusion: TMPRSS2:ERG gene fusion negatively regulates PSMA expression in prostate adenocarcinoma (PCa) cell lines. Therefore, immunohistochemical (IHC) ERG expression, a surrogate for an underlying ERG rearrangement, and PSMA expression patterns in radical prostatectomy (RPE) specimens of primary PCa, including corresponding PSMA-PET scans were investigated.Two cohorts of RPE samples (total n=148): In cohort #1 (n=62 patients) with available RPE and preoperative [68Ga]Ga-PSMA-11 PET, WHO/ISUP grade groups, IHC-ERG (positive vs. negative) and IHC-PSMA expression (% PSMA-negative tumour area, PSMA%neg) were correlated with the corresponding SUVmax. In the second cohort #2 (n=86 patients) including RPE only, same histopathological parameters were evaluated.Cohort #1: PCa with IHC-ERG expression (35.5%) showed significantly lower IHC-PSMA expression and lower SUVmax values on the corresponding PET scans. Eight of 9 PCa with negative PSMA-PET scans had IHC-ERG positivity, and confirmed TMPRSS2::ERG rearrangement. In IHC-PSMA positive PCa, IHC-ERG positivity was significantly associated with lower SUVmax values. In cohort #2, findings of higher IHC-PSMA%neg and IHC-ERG expression was confirmed with only 0-10% PSMA%neg tumour areas in IHC-ERG-negative PCa.IHC-ERG expression is significantly associated with more heterogeneous and lower IHC-PSMA tissue expression in two independent RPE cohorts. There is a strong association of ERG positivity in RPE tissue with lower [68Ga]Ga-PSMA-11 uptake on corresponding PET scans. Results may serve as a base for future biomarker development to enable tumour-tailored, individualized imaging approaches. [ABSTRACT FROM AUTHOR]

There is an urgent need for novel systemic therapies for recurrent/systemic salivary gland cancer, as current treatment options are scarce. [ 68 Ga]Ga-PSMA-11 PET/CT revealed relevant uptake of prostate-specific membrane antigen (PSMA) in adenoid cystic carcinoma (AdCC) and salivary duct carcinoma (SDC). Therefore, we assessed the safety, feasibility, efficacy and radiation dosimetry of [ 177 Lu]Lu-PSMA-I&T treatment in AdCC and SDC patients in a prospective pilot study. Methods: This single-center, single-arm study intended to include 10 recurrent/metastatic AdCC patients and five recurrent/metastatic SDC patients. AdCC patients could only participate in case of progressive and/or symptomatic disease. Patients required ≥ 1 lesion ≥ 1.5 cm with an SUV max on [ 68 Ga]Ga-PSMA-11 PET/CT above liver SUV mean . Patients were planned to receive four cycles ~ 7.4 GBq [ 177 Lu]Lu-PSMA-I&T. In case of progressive disease per RECIST 1.1 at mid-treatment evaluation after two cycles, treatment was discontinued. Safety was the primary endpoint. Secondary endpoints included objective response rate (ORR), tumor- and organ-absorbed radiation doses and progression-free survival. Results: After screening, 10 out of 15 (67%) AdCC and two out of 10 (20%) SDC patients were eligible. Two patients (17%) demonstrated grade 3 treatment-related toxicity: lymphocytopenia (8%) and hyponatremia (8%). No dose-limiting toxicities occurred. In the AdCC cohort, six patients (60%) completed the four treatment cycles. Due to progressive disease, treatment was discontinued after two cycles in three patients (30%) and after one cycle in one patient (10%). No objective responses were observed (ORR: 0%). Three AdCC patients (30%) showed stable disease ≥ 6 months (7, 17 and 23 months). None of the two SDC patients completed the treatment: one patient deteriorated after the first cycle, while the other had progressive disease after two cycles. The high screen failure rate due to insufficient PSMA uptake resulted in premature closure of the SDC cohort. Dosimetry revealed low tumor-absorbed doses (median 0.07 Gy/GBq, range 0.001-0.63 Gy/GBq). Conclusions: [ 177 Lu]Lu-PSMA-I&T in AdCC and SDC patients was safe and generally well-tolerated. However, efficacy was limited, likely due to low tumor-absorbed doses. For SDC, [ 177 Lu]Lu-PSMA-I&T appears unfeasible due to insufficient PSMA uptake., Competing Interests: Competing Interests: NvR, MU, CD, SP, BP, AvEvG, MK, MK: nothing to declare. JN: has received research grants from ABX and Novartis, and has received consulting and teaching fees from ITM, POINT biopharma, CURIUM, Novartis and Bayer. CvH: has been member of advisory boards for Bayer, Bristol-Myers Squibb, Elevar, Ipsen, MSD and Regeneron, and has received research grants from Astra Zeneca, Bristol-Myers Squibb, MSD, Merck, Ipsen, Novartis and Sanofi., (© The author(s).)

Purpose: This study aimed to verify the feasibility and short-term prognosis of prostatectomy without biopsy., Materials and Methods: Patients with a rising PSA level ranging from 4 to 30 ng/mL were scheduled for multiparametric (mp) MRI and 18 F-labeled prostate-specific membrane antigen (PSMA) positron emission tomography (PET). Forty-seven patients (cT2N0M0) with Prostate Imaging Reporting and Data System ≥ 4 and molecular imaging PSMA score ≥ 2 were enrolled. All candidates underwent robot-assisted laparoscopic radical prostatectomy without biopsy. Prostate cancer detection rate, index tumors localization correspondence rate, positive surgical margin, complications, postoperative hospital stay, and PSA level in a 6-week postoperative follow-up visit were collected., Results: All the patients with positive mpMRI and PSMA PET were diagnosed with clinically significant prostate cancer. A total of 80 lesions were verified as cancer by pathology, of which 63 cancer lesions were clinically significant prostate cancer. Fifty-one lesions were simultaneously found by mpMRI and PSMA PET. A total of 23 lesions were invisible on either image, and all lesions were ≤ International Society of Urological Pathology 2 or ≤ 15 mm. Forty-five (95.7%) index tumors found by mpMRI combined with PSMA PET were consistent with pathology. Nine patients reported positive surgical margin., Conclusions: Biopsy-free prostatectomy is safe and feasible for patients with evaluation strictly by mpMRI combined with 18 F-PSMA PET/CT.

Prostate cancer represents a significant public health challenge, with its management requiring precise diagnostic and prognostic tools. Prostate-specific membrane antigen (PSMA), a cell surface enzyme overexpressed in prostate cancer cells, has emerged as a pivotal biomarker. PSMA's ability to increase the sensitivity of PET imaging has revolutionized its application in the clinical management of prostate cancer. The advancements in PET-PSMA imaging technologies and methodologies, including the development of PSMA-targeted radiotracers and optimized imaging protocols, led to diagnostic accuracy and clinical utility across different stages of prostate cancer. This highlights its superiority in staging and its comparative effectiveness against conventional imaging modalities. This paper analyzes the impact of PET-PSMA on prostate cancer management, discussing the existing challenges and suggesting future research directions. The integration of recent studies and reviews underscores the evolving understanding of PET-PSMA imaging, marking its significant but still expanding role in clinical practice. This comprehensive review serves as a crucial resource for clinicians and researchers involved in the multifaceted domains of prostate cancer diagnosis, treatment, and management.

Prostate-specific membrane antigen targeting positron emission tomography (PSMA-PET) is routinely used for the staging and restaging of patients with various stages of prostate cancer. For clear communication with referring physicians and to improve inter-reader agreement, the use of standardized reporting templates is mandatory. Increasingly, tumor volume is used by reporting and response assessment frameworks to prognosticate patient outcome or measure response to therapy. However, the quantification of tumor volume is often too time-consuming in routine clinical practice. Machine learning-based tools can facilitate the quantification of tumor volume for improved outcome prognostication., Competing Interests: Disclosure R. Seifert received research funding from Boehringer Ingelheim Fonds, Germany and Else Kröner-Fresenius-Stiftung, Germany. The authors declare that there is no conflict of interest regarding this article. A. Gafita is supported by the Prostate Cancer Foundation (21YOUN18), United States., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Oral squamous cell carcinoma (OSCC) is a globally prevalent cancer with significant mortality rates. OSCC a predominant subtype of head and neck squamous cell carcinoma (HNSCC), poses a substantial health burden. Despite advancements in diagnosis and therapy, OSCC prognosis remains poor. The 26S proteasome, a cellular protein degradation complex, is associated with cancer, including PSMA1, a proteasomal subunit, which is upregulated in various cancers. We analyzed PSMA1 expression using TCGA data, validated it in OSCC samples using real-time PCR, and explored its role through various databases. Tumor and adjacent normal tissues from OSCC patients were examined, and PSMA1 expression was analyzed. Survival analysis assessed the impact of PSMA1 on patient outcomes, while immune infiltration was examined using the TIMER database. GeneMANIA, STRING, and Metascape were utilized for gene interaction and pathway analysis. PSMA1 was significantly upregulated in OSCC and HNSCC. Its overexpression correlated with advanced clinicopathological features and poorer prognosis in HNSCC patients. PSMA1 expression is also related to immune cell infiltration. Gene interaction analysis revealed PSMA1 involvement in proteolysis regulation, suggesting its potential as a therapeutic target. PSMA1 upregulation in HNSCC association with adverse clinicopathological features and prognosis underscores its potential significance. Further research is warranted to elucidate its molecular mechanisms and therapeutic potential in OSCC management., (© 2024. The Author(s), under exclusive licence to The Society of The Nippon Dental University.)

Novel prostate-specific membrane antigen (PSMA) ligands labeled with α-emitting radionuclides are sparking a growing interest in prostate cancer treatment. These targeted alpha therapies (TATs) have attractive physical properties that deem them effective in progressive metastatic castrate-resistant prostate cancer (mCRPC). Among the PSMA TAT radiopharmaceuticals, [225Ac]Ac-PSMA has been used extensively on a compassionate basis and is currently undergoing phase I trials. Notably, TAT has the potential to improve quality of life and has favorable antitumor activity and outcomes in multiple scenarios other than in mCRPC. In addition, resistance mechanisms to TAT may be amenable to combination therapies., Competing Interests: Disclosure Ethical approval and consent to participate: Although this is a review article, ethics approval and informed consent for the images used are available. Competing interests: The authors declare that they have no competing interests. Consent for publication: Informed patient consent for publication of [(68) Ga] Ga-DOTATATE PET/CT and [(68) Ga]Ga-PSMA-PET/CT images and other relevant information was obtained. Availability of data and materials: The articles quoted and referenced are available online as referenced. The images used for the review are available from the corresponding author on request. Funding: The authors declare that the review was conducted in the absence of any commercial or financial relationships., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Prostate-specific membrane antigen (PSMA)-targeting PET radiotracers reveal physiologic uptake in the urinary system, potentially misrepresenting activity in the prostatic urethra as an intraprostatic lesion. This study examined the correlation between midline 18 F-DCFPyL activity in the prostate and hyperintensity on T2-weighted (T2W) MRI as an indication of retained urine in the prostatic urethra., Patients and Methods: Eighty-five patients who underwent both 18 F-DCFPyL PSMA PET/CT and prostate MRI between July 2017 and September 2023 were retrospectively analyzed for midline radiotracer activity and retained urine on postvoid T2W MRIs. Fisher's exact tests and unpaired t tests were used to compare residual urine presence and prostatic urethra measurements between patients with and without midline radiotracer activity. The influence of anatomical factors including prostate volume and urethral curvature on urinary stagnation was also explored., Results: Midline activity on PSMA PET imaging was seen in 14 patients included in the case group, whereas the remaining 71 with no midline activity constituted the control group. A total of 71.4% (10/14) and 29.6% (21/71) of patients in the case and control groups had urethral hyperintensity on T2W MRI, respectively ( P < 0.01). Patients in the case group had significantly larger mean urethral dimensions, larger prostate volumes, and higher incidence of severe urethral curvature compared with the controls., Conclusions: Stagnated urine within the prostatic urethra is a potential confounding factor on PSMA PET scans. Integrating PET imaging with T2W MRI can mitigate false-positive calls, especially as PSMA PET/CT continues to gain traction in diagnosing localized prostate cancer., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Previously, we demonstrated that prostate-specific membrane antigen positron emission tomography (PSMA-PET) revealed distant metastases in 109/200 patients (39% distant nodes, 24% bone, and 6% visceral organ) with nonmetastatic castration-resistant prostate cancer (nmCRPC) and high-risk features (International Society of Urological Pathology score ≥4 and/or prostate-specific antigen doubling time ≤10 mo) without metastases by conventional imaging. However, the impact of disease extent determined by PSMA-PET on patient outcomes is unknown. We followed these 200 patients for a median of 43 mo after PSMA-PET and retrospectively assessed the association between patient characteristics, PSMA-PET findings, treatment management, and outcomes using a Kaplan-Meier model and Cox multivariable regressions. Among assessed disease characteristics, polymetastatic disease (five or more distant lesions on PET) was independently associated with shorter overall survival (OS; median 61 mo vs not reached; hazard ratio [95% confidence interval], 1.81 [1.00-3.27]; p = 0.050) and time to new metastases (median 38 vs 60 mo; 1.80 [1.10-2.96]; p = 0.019), and initial pN1 status with shorter OS (55 mo vs not reached; 1.94 [1.12-3.37]; p = 0.019). Following PSMA-PET, locoregional salvage therapies were used most commonly in no/local disease (58%), and androgen receptor signaling inhibitors were used in distant metastatic disease (51%). PSMA-PET provides additional risk stratification for patients with nmCRPC. Polymetastatic disease (five or more distant lesions) is associated with worse outcomes. PATIENT SUMMARY: A novel sensitive imaging technology, called prostate-specific membrane antigen positron emission tomography (PSMA-PET), allows doctors to detect the spread of prostate cancer, known as distant metastases, earlier and more accurately than in the past. In our study, PSMA-PET detected none to many metastases in patients who were considered free of distant metastasis by conventional imaging. These findings predicted outcomes and were used to select appropriate treatment., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Targeted radionuclide therapy, in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation, has addressed unmet clinical needs and improved outcomes for patients with cancer 1-4 . A therapeutic radiopharmaceutical must achieve both sustainable tumour targeting and fast clearance from healthy tissue, which remains a major challenge 5,6 . A targeted ligation strategy that selectively fixes the radiopharmaceutical to the target protein in the tumour would be an ideal solution. Here we installed a sulfur (VI) fluoride exchange (SuFEx) chemistry-based linker on radiopharmaceuticals to prevent excessively fast tumour clearance. When the engineered radiopharmaceutical binds to the tumour-specific protein, the system undergoes a binding-to-ligation transition and readily conjugates to the tyrosine residues through the 'click' SuFEx reaction. The application of this strategy to a fibroblast activation protein (FAP) inhibitor (FAPI) triggered more than 80% covalent binding to the protein and almost no dissociation for six days. In mice, SuFEx-engineered FAPI showed 257% greater tumour uptake than did the original FAPI, and increased tumour retention by 13-fold. The uptake in healthy tissues was rapidly cleared. In a pilot imaging study, this strategy identified more tumour lesions in patients with cancer than did other methods. SuFEx-engineered FAPI also successfully achieved targeted β- and α-radionuclide therapy, causing nearly complete tumour regression in mice. Another SuFEx-engineered radioligand that targets prostate-specific membrane antigen (PSMA) also showed enhanced therapeutic efficacy. Considering the broad scope of proteins that can potentially be ligated to SuFEx warheads, it might be possible to adapt this strategy to other cancer targets., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Prostate-specific membrane antigen (PSMA-) PET has become a promising tool in staging and restaging of prostate carcinoma (PCa). However, specific primary tumour features might impact accuracy of PSMA-PET for PCa detection. We investigated histopathological parameters and immunohistochemical PSMA expression patterns on radical prostatectomy (RPE) specimens and correlated them to the corresponding 68Ga-PSMA-11-PET examinations. Methods: RPE specimens of 62 patients with preoperative 68Ga-PSMA-11-PET between 2016 and 2018 were analysed. WHO/ISUP grade groups, growth pattern (expansive vs. infiltrative), tumour area and diameter as well as immunohistochemical PSMA heterogeneity, intensity and negative tumour area (PSMA%neg) were correlated with spatially corresponding SUVmax on 68Ga-PSMA-11-PET in a multidisciplinary analysis. Results: All tumours showed medium to strong membranous (2–3 +) and weak to strong cytoplasmic (1–3 +) PSMA expression. Heterogeneously expressed PSMA was found in 38 cases (61%). Twenty-five cases (40%) showed at least 5% and up to 80% PSMA%neg. PSMA%neg, infiltrative growth pattern, smaller tumour area and diameter and WHO/ISUP grade group 2 significantly correlated with lower SUVmax values. A ROC curve analysis revealed 20% PSMA%neg as an optimal cutoff with the highest sensitivity and specificity (89% and 86%, AUC 0.923) for a negative PSMA-PET scan. A multiple logistic regression model revealed tumoural PSMA%neg (p < 0.01, OR = 9.629) and growth pattern (p = 0.0497, OR = 306.537) as significant predictors for a negative PSMA-PET scan. Conclusions: We describe PSMA%neg, infiltrative growth pattern, smaller tumour size and WHO/ISUP grade group 2 as parameters associated with a lower 68Ga-PSMA-11 uptake in prostate cancer. These findings can serve as fundament for future biopsy-based biomarker development to enable an individualized, tumour-adapted imaging approach. [ABSTRACT FROM AUTHOR]

Glutamate carboxypeptidase-II (GCPII) is a zinc-dependent metalloenzyme implicated in numerous neurological disorders. The pharmacophoric requirements of active-site GCPII inhibitors makes them highly charged, manifesting poor pharmacokinetic (PK) properties. Herein, we describe the discovery and characterization of catechol-based inhibitors including L-DOPA, D-DOPA, and caffeic acid, with sub-micromolar potencies. Of these, D-DOPA emerged as the most promising compound, with good metabolic stability, and excellent PK properties. Orally administered D-DOPA yielded high plasma exposures (AUCplasma = 72.7 nmol·h/mL) and an absolute oral bioavailability of 47.7%. Unfortunately, D-DOPA brain exposures were low with AUCbrain = 2.42 nmol/g and AUCbrain/plasma ratio of 0.03. Given reports of isomeric inversion of D-DOPA to L-DOPA via D-amino acid oxidase (DAAO), we evaluated D-DOPA PK in combination with the DAAO inhibitor sodium benzoate and observed a >200% enhancement in both plasma and brain exposures (AUCplasma = 185 nmol·h/mL; AUCbrain = 5.48 nmol·h/g). Further, we demonstrated GCPII target engagement; orally administered D-DOPA with or without sodium benzoate caused significant inhibition of GCPII activity. Lastly, mode of inhibition studies revealed D-DOPA to be a noncompetitive, allosteric inhibitor of GCPII. To our knowledge, this is the first report of D-DOPA as a distinct scaffold for GCPII inhibition, laying the groundwork for future optimization to obtain clinically viable candidates.

Abstract Background Prostate-specific membrane antigen (PSMA) is overexpressed on the endothelial cells of tumor neo-vessels of several solid malignancies, including differentiated thyroid cancer (DTC). We aimed to test the potential role of PSMA as a biomarker for DTC aggressiveness and outcome prediction. We retrospectively screened all patients who underwent thyroidectomy between 1 January 2010 and 31 December 2017 in our institution. Applying the inclusion (histological diagnosis of thyroid cancer and tissue availability) and exclusion criteria (no clinical or follow-up data or diagnosis of medullary thyroid cancer), a cohort of 59 patients was selected. The monoclonal mouse anti-human PSMA antibody was used to stain tissue sections. A 3-point scale was used to score PSMA positivity: 0–5% expression was considered as negative (score 0), 6–50% as moderately positive (score 1), and 51–100% as highly positive (score 2). A cumulative score (0–10%, 11–79%, and 80–100%) was also explored. Univariate and multivariate logistic regression analyses were performed to predict the presence of distant metastases, chosen as endpoint of aggressiveness. The area under the curve (AUC) was calculated. Cox models were built to predict patient outcome in terms of recurrence, iodine refractoriness, and status at last follow-up, which were calculated using the Kaplan-Meier failure function. Results At immunostaining, 12, 25, and 22 patients had scores of 0, 1, and 2, respectively. According to the cumulative score, PSMA expression was ≤ 10% in 17 cases, 11–79% in 31 cases, and ≥ 80% in 11 cases. At multivariate analysis, age, sex, histotype, vascular invasion, T and N parameters, and PSMA positivity were significant predictors of distant metastases. The AUC was 0.92. Recurrence or progression occurred in 19/59 patients. Twelve patients developed radioiodine (RAI) refractoriness, after a median time of 17 months (range 2–32). One patient died of DTC; 46 of the 58 patients alive at last follow-up were disease free. Median DFS was 23 months (range 3–82). The final multivariate model to predict RAI refractoriness included as covariates the stage, high PSMA expression (≥ 80%), and the interaction between moderate PSMA expression (11–79%) and stage. Conclusions PSMA, a marker of neovasculature formation expressed by DTC, contributes in the prediction of tumor aggressiveness and patient outcome.

Objective: Differentiation of malignant and benign pancreatic lesions on anatomical imaging is difficult in some cases with overlapping features. Prostate-specific membrane antigen (PSMA) is overexpressed during angioneogenesis in many tumors. We aimed to evaluate the PSMA expression in pancreatic lesions to differentiate these lesions and explore the performance of Ga-68 PSMA-PET/CT vis-a-vis F-18 FDG-PET/CT. Methods: Patients with pancreatic lesions on conventional imaging were prospectively recruited. All the patients underwent a whole-body F-18 FDG-PET/CT and a regional abdominal Ga-68 PSMA-PET/CT. Focal tracer uptake (FDG or PSMA) on PET images was considered positive. Histopathology and/or cytopathology were considered the reference standard. Results: A total of forty patients (27 males, mean age 55.3 ± 9.8, range 37–71 years) were enrolled. Of these, 19 were diagnosed as malignant on histopathology/cytology. Patients with benign lesions showed no worsening of symptoms for at least 6 months on follow-up. FDG-PET/CT revealed 17 true-positive (TP), 9 false-positive (FP), 12 true-negative (TN), and 2 false-negative (FN) findings, whereas PSMA-PET/CT had 18 TP, 2 FP, 19 TN, and 1 FN finding. The sensitivity, specificity, PPV, NPV, and accuracy for FDG-PET/CT were 89.5%, 57.1%, 65.4%, 85.7%, and 72.5%, respectively, while for PSMA-PET/CT were 94.7%, 90.5%, 90%, 95%, and 92.5%, respectively. ROC curve analysis showed that the SUVmax value of 4.8 on PSMA-PET/CT could predict the malignant potential of a lesion with a specificity of 90.5% and a sensitivity of 84.2%. Conclusions: Ga-68 PSMA-PET/CT imaging helped in establishing a non-invasive pre-operative diagnosis of primary pancreatic malignancy with a higher degree of specificity and accuracy compared with FDG-PET/CT. Key Points: • Conventional imaging such as CT and MRI are unable to reliably differentiate localized malignant pancreatic lesion from benign lesions mimicking malignancy such as mass-forming pancreatitis. • FDG PET/CT helps in detecting malignant foci in view of their increased glucose metabolism. However, it may be falsely positive in inflammatory lesions which may occasionally hinder its ability to differentiate between benign and malignant lesions. • Apart from prostatic malignancy, PSMA is overexpressed in neovasculature of many non-prostatic malignancies. The present study highlights that Ga68 PSMA PET/CT performed better in diagnosing malignancy non-invasively than FDG-PET/CT with a higher PPV (90.5% vs. 65.4%) and accuracy (92.5% vs. 72.5%). [ABSTRACT FROM AUTHOR]

Prostate-specific membrane antigen (PSMA)-targeted radio ligand therapeutics (RLTs), such as [ 177 Lu]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 [ 177 Lu]Lu-PSMA-617 to human salivary glands by autoradiography and could demonstrate a partial radioprotection.

Background: To investigate the predictable parameters associated with downgrading in patients with a Gleason score (GS) 8 (4+4) in prostate biopsy after radical prostatectomy., Methods: We retrospectively analyzed 62 patients with a GS of 4+4 on prostate biopsy who underwent robotic radical prostatectomy between 2017 and 2022., Results: 38 of 62 (61.2%) were downgraded. In multivariable logistic regression model, Ga-68 prostate-specific membrane antigen (PSMA) positron-emission tomography (PET)/computed tomography (CT) SUV max was independent predictor of downgrading (OR 0.904; p = 0.011) and a Logistic Regression model was constructed using the following formula: Y = 1.465-0.95 (PSMA PET/CT SUV max). The model using this variable correctly predicted the downgrading in 72.6% of patients. The AUC for PSMA PET/CT SUV max was 0.709 the cut off being 8.8. A subgroup analysis was performed in 37 patients who had no other European Association of Urology (EAU) high risk features. 25 out of 37 (67.5%) were downgraded, and 21 of these 25 had organ confined disease. Low PSMA SUV max (<8.1) and percentage of GS 4+4 biopsy cores to cancer bearing cores (45.0%) were independently associated with downgrading to GS 7., Conclusion: PSMA PET/CT can be used to predict downgrading in patients with GS 4+4 PCa. Patients with GS 4+4 disease, but no other EAU high risk features, low percentage of GS 4+4 biopsy cores to cancer bearing cores, and a low PSMA PET/CT SUV max are associated with a high likelihood of the cancer reclassification to intermediate risk group., (© 2024. The Author(s).)

Purpose: Approximately 5% of differentiated thyroid cancers lose the ability to uptake iodine, leading to limited treatment options and poor prognosis due to invasion and distant metastasis. PSMA imaging probes have been proposed as a potential diagnostic and therapeutic tool for iodine-refractory thyroid cancer. However, there are limited reports and significant heterogeneity in patient selection, warranting further exploration of the application value of PSMA in thyroid cancer., Methods: We performed Western Blot, PCR, and [ 68 Ga]Ga-PSMA uptake experiments on cell lines and conducted in vivo small animal imaging. Clinical and radiological results of included differentiated thyroid cancer patients were collected. (Trial registration number: 2021-669, Trial registration date: December 30, 2021)., Results: PSMA expression levels were significantly higher in poorly differentiated thyroid cancer (7.86 ± 1.90 vs. 1.00 ± 0, P < 0.01; 7.86 ± 1.90 vs. 0.03 ± 0.02, P < 0.01), but [ 68 Ga]Ga-PSMA imaging correlated with tumor burden, such as 18F-FDG (8.08 ± 7.74 and 5.67 ± 4.23, P = 0.01) and Tg levels (307.1 ± 183.4 vs. 118.0 ± 116.1, P = 0.002)., Conclusion: Our results showed that PSMA expression increased with the decrease of thyroid cancer differentiation. However, the level of [ 68 Ga]Ga-PSMA uptake in thyroid cancer patients was not significantly associated with the degree of thyroid cancer differentiation, but also with the metabolism and burden of tumors such as 2-[ 18 F]FDG and Tg levels. These findings provide additional clinical significance and application value for PSMA in thyroid cancer., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

For dosimetry of radiopharmaceutical therapies, it is essential to determine the volume of relevant structures exposed to therapeutic radiation. For many radiopharmaceuticals, the kidneys represent an important organ-at-risk. To reduce the time required for kidney segmentation, which is often still performed manually, numerous approaches have been presented in recent years to apply deep learning-based methods for CT-based automated segmentation. While the automatic segmentation methods presented so far have been based solely on CT information, the aim of this work is to examine the added value of incorporating PSMA-PET data in the automatic kidney segmentation., Methods: A total of 108 PET/CT examinations (53 [ 68 Ga]Ga-PSMA-I&T and 55 [ 18 F]F-PSMA-1007 examinations) were grouped to create a reference data set of manual segmentations of the kidney. These segmentations were performed by a human examiner. For each subject, two segmentations were carried out: one CT-based (detailed) segmentation and one PET-based (coarser) segmentation. Five different u-net based approaches were applied to the data set to perform an automated segmentation of the kidney: CT images only, PET images only (coarse segmentation), a combination of CT and PET images, a combination of CT images and a PET-based coarse mask, and a CT image, which had been pre-segmented using a PET-based coarse mask. A quantitative assessment of these approaches was performed based on a test data set of 20 patients, including Dice score, volume deviation and average Hausdorff distance between automated and manual segmentations. Additionally, a visual evaluation of automated segmentations for 100 additional (i.e., exclusively automatically segmented) patients was performed by a nuclear physician., Results: Out of all approaches, the best results were achieved by using CT images which had been pre-segmented using a PET-based coarse mask as input. In addition, this method performed significantly better than the segmentation based solely on CT, which was supported by the visual examination of the additional segmentations. In 80% of the cases, the segmentations created by exploiting the PET-based pre-segmentation were preferred by the nuclear physician., Conclusion: This study shows that deep-learning based kidney segmentation can be significantly improved through the addition of a PET-based pre-segmentation. The presented method was shown to be especially beneficial for kidneys with cysts or kidneys that are closely adjacent to other organs such as the spleen, liver or pancreas. In the future, this could lead to a considerable reduction in the time required for dosimetry calculations as well as an improvement in the results., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Michael Lassmann has received institutional grants by IPSEN Pharma, Nordic Nanovector, and Novartis. No other potential conflicts of interest relevant to this article exist., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Glutamate carboxypeptidase II (GCPII, also known as PSMA or FOLH1) is responsible for the cleavage of N -acetyl-aspartyl-glutamate (NAAG) to N -acetyl-aspartate and glutamate in the central nervous system and facilitates the intestinal absorption of folate by processing dietary folyl-poly-γ-glutamate in the small intestine. The physiological function of GCPII in other organs like kidneys is still not known. GCPII inhibitors are neuroprotective in various conditions (e.g., ischemic brain injury) in vivo ; however, their utilization as potential drug candidates has not been investigated in regard to not yet known GCPII activities. To explore the GCPII role and possible side effects of GCPII inhibitors, we performed parallel metabolomic and lipidomic analysis of the cerebrospinal fluid (CSF), urine, plasma, and brain tissue of mice with varying degrees of GCPII deficiency (fully deficient in Folh1 , -/-; one allele deficient in Folh1 , +/-; and wild type, +/+). Multivariate analysis of metabolites showed no significant differences between wild-type and GCPII-deficient mice (except for NAAG), although changes were observed between the sex and age. NAAG levels were statistically significantly increased in the CSF, urine, and plasma of GCPII-deficient mice. However, no difference in NAAG concentrations was found in the whole brain lysate likely because GCPII, as an extracellular enzyme, can affect only extracellular and not intracellular NAAG concentrations. Regarding the lipidome, the most pronounced genotype-linked changes were found in the brain tissue. In brains of GCPII-deficient mice, we observed statistically significant enrichment in phosphatidylcholine-based lipids and reduction of sphingolipids and phosphatidylethanolamine plasmalogens. We hypothesize that the alteration of the NAA-NAAG axis by absent GCPII activity affected myelin composition. In summary, the absence of GCPII and thus similarly its inhibition do not have detrimental effects on metabolism, with just minor changes in the brain lipidome.

Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men in the United States. Although early-stage treatments exhibit promising 5-year survival rates, the treatment options for advanced stage disease are constrained, with short survival benefits due to the challenges associated with effective and selective drug delivery to PCa cells. Even though targeting Prostate Specific Membrane Antigen (PSMA) has been extensively explored and is clinically employed for imaging and radio-ligand therapy, the clinical success of PSMA-based approaches for targeted delivery of chemotherapies remains elusive. In this study, we combine a generation 4 hydroxy polyamidoamine dendrimer (PD) with irreversible PSMA ligand (CTT1298) to develop a PSMA-targeted nanoplatform ( PD-CTT1298 ) for selective intracellular delivery of potent chemotherapeutics to PCa. PD-CTT1298-Cy5 exhibits a PSMA IC 50 in the nanomolar range and demonstrates selective uptake in PSMA (+) PCa cells via PSMA mediated internalization. When systemically administered in a prostate tumor xenograft mouse model, PD-CTT1298-Cy5 selectively targets PSMA (+) tumors with significantly less accumulation in PSMA (-) tumors or upon blocking of the PSMA receptors. Moreover, the dendrimer clears rapidly from the off-target organs limiting systemic side-effects. Further, the conjugation of an anti-cancer agent, cabozantinib to the PSMA-targeted dendrimer translates to a significantly enhanced anti-proliferative activity in vitro compared to the free drug. These findings highlight the potential of PD-CTT1298 nanoplatform as a versatile approach for selective delivery of high payloads of potent chemotherapeutics to PCa, where dose related systemic side-effects are a major concern.

Cancer radiopharmaceutical therapies (RPTs) have demonstrated great promise in the treatment of neuroendocrine and prostate cancer, giving hope to late-stage metastatic cancer patients with currently very few treatment options. These therapies have sparked a large amount of interest in pre-clinical research due to their ability to target metastatic disease, with many research efforts focused towards developing and evaluating targeted RPTs for different cancer types in in vivo models. Here we describe a method for monitoring real-time in vivo binding kinetics for the pre-clinical evaluation of cancer RPTs. Recognizing the significant heterogeneity in biodistribution of RPTs among even genetically identical animal models, this approach offers long-term monitoring of the same in vivo organism without euthanasia in contrast to ex vivo tissue dosimetry, while providing high temporal resolution with a low-cost, easily assembled platform, that is not present in small-animal SPECT/CTs. The method utilizes the developed optical fiber-based γ-photon biosensor, characterized to have a wide linear dynamic range with Lutetium-177 ( 177 Lu) activity (0.5-500 μCi/mL), a common radioisotope used in cancer RPT. The probe's ability to track in vivo uptake relative to SPECT/CT and ex vivo dosimetry techniques was verified by administering 177 Lu-PSMA-617 to mouse models bearing human prostate cancer tumors (PC3-PIP, PC3-flu). With this method for monitoring RPT uptake, it is possible to evaluate changes in tissue uptake at temporal resolutions <1 min to determine RPT biodistribution in pre-clinical models and better understand dose relationships with tumor ablation, toxicity, and recurrence when attempting to move therapies towards clinical trial validation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

N-acetyl-aspartyl-glutamate (NAAG) is the most abundant dipeptide in the brain, where it acts as a neuromodulator of glutamatergic synapses by activating presynaptic metabotropic glutamate receptor 3 (mGluR3). Recent data suggest that NAAG is selectively localized to postsynaptic dendrites in glutamatergic synapses and that it works as a retrograde neurotransmitter. NAAG is released in response to glutamate and provides the postsynaptic neuron with a feedback mechanisms to inhibit excessive glutamate signaling. A key regulator of synaptically available NAAG is rapid degradation by the extracellular enzyme glutamate carboxypeptidase II (GCPII). Increasing endogenous NAAG—for instance by inhibiting GCPII—is a promising treatment option for many brain disorders where glutamatergic excitotoxicity plays a role. The main effect of NAAG occurs through increased mGluR3 activation and thereby reduced glutamate release. In the present review, we summarize the transmitter role of NAAG and discuss the involvement of NAAG in normal brain physiology. We further present the suggested roles of NAAG in various neurological and psychiatric diseases and discuss the therapeutic potential of strategies aiming to enhance NAAG levels.

Abstract Background Traumatic brain injury (TBI) is a complex condition and remains a prominent public and medical health issue in individuals of all ages. A rapid increase in extracellular glutamate occurs after TBI, leading to glutamate-induced excitotoxicity, which causes neuronal damage and further functional impairments. Although inhibition of glutamate carboxypeptidase II (GCP II) is considered a potential approach for reducing glutamate-induced excitotoxicity after TBI, further detailed evidence regarding its efficacy is required. Therefore, in this study, we examined the differences in the metabolite status between wild-type (WT) and GCP II gene-knockout (KO) mice after TBI using proton magnetic resonance spectroscopy (1H-MRS) and T2-weighted magnetic resonance (MR) imaging with a 7-tesla imaging system, and brain water-content analysis. Results Evaluation of glutamate and N-acetylaspartate concentrations revealed a decrease in both levels in the ipsilateral hippocampus at 24 h post-TBI; however, the reduction in glutamate and N-acetylaspartate levels was less marked in GCP II-KO mice than in WT mice (p

The aim of the investigation. Synthesis of a peptide with a cysteine knot, affinity to glutamate carboxypeptidase II, evaluation of its binding to glutamate carboxypeptidase II on the surface of LNCaP prostate cancer cells. Comparison of peptide binding to a cysteine knot, affinity to glutamate carboxypeptidase II with the parent peptide, affinity to glutamate carboxypeptidase II. Materials and Methods. Peptide with sequense GTIQPYPFSWGY, affinity to glutamate carboxypeptidase II, was inserted into the peptide with the cysteine knot U5-Sth1a (isolated from the spider venom of the family Scytodes thoracica). The peptides were synthesized using a peptide synthesizer (ResPepSL, Intavis), the synthesis result was monitored by high performance liquid chromatography (NGC Quest, Bio-Rad) and mass spectrometry (MALDITOF MS, Bruker Daltonics). As an object of study, we used prostate cancer cell cultures LNCaP (synthesizes glutamate carboxypeptidase II on the surface), PC3 and DU145 (they do not synthesize glutamate carboxypeptidase II). In the course of the study, the initial tropic glutamate carboxypeptidase II peptide and hybrid peptide were labeled with 6-FAM NHS fluorescent dye, then added to the cell culture medium, then fluorescence was evaluated and compared. Results. Greater binding of the peptide to the cysteine knot with glutamate carboxypeptidase II on the surface of LNCaP culture cells was noted, compared with the original peptide, affinity to glutamate carboxypeptidase II. An increase in the binding of the hybrid peptide to glutamate carboxypeptidase II with time, in the range from one hour to one day, was also noted. [ABSTRACT FROM AUTHOR]

Background: 68Ga prostate specific membrane antigen PET/CT (68Ga-PSMA PET/CT) may be superior to multiparametric MRI (mpMRI) for localisation of prostate cancer tumour foci, however the concordance and differences between 68Ga-PSMA PET/CT and mpMRI when applied to all biopsied patients and potential benefit in patients with negative mpMRI is unclear. Methods: Retrospective analysis of patients undergoing mpMRI, prostate biopsy and 68Ga-PSMA PET/CT over a 3-year period. Diagnostic performance of 68Ga-PSMA PET/CT and mpMRI were assessed using biopsy histopathology for the entire cohort and radical prostatectomy specimen in a subset of patients. Lesion concordance and additional detection of each modality were determined, including in a dedicated cohort of patients with mpMRI PIRADS 2 scans. Results: A total of 144 patients were included in the study. Index lesion/foci detection was similar between 68Ga-PSMA PET/CT and mpMRI (sensitivity 83.1% vs 90.1%; p = 0.267), however lesions missed by mpMRI were larger (1.66 cm3 vs 0.72 cm3; p = 0.034). Lesion detection rates were similar across the biopsy histopathology and radical prostatectomy specimen subset, with a high concordance for index (80.1%) and a moderate concordance for total (67%) lesions between the 2 imaging modalities. The additional detection yield favoured 68Ga-PSMA PET/CT over mpMRI for index (13.5% vs 4.3%) and total (18.2% vs 5.4%) lesions; both modalities missed 2.1% and 12.3% of index and total lesions, respectively. 68Ga-PSMA PET/CT identified 9 of 11 patients with PIRADS 2 mpMRI but subsequently diagnosed with Gleason ≥ 3 + 4 disease. Conclusions: Despite high concordance rates, 68Ga-PSMA PET/CT incrementally improved tumour localisation compared with mpMRI. These results suggest that 68Ga-PSMA PET/CT may have an incremental value to that of mpMRI in the diagnostic process for prostate. [ABSTRACT FROM AUTHOR]

Cerebral ischemia-reperfusion (I/R) injury is notably linked with folic acid (FA) deficiency. The aim of our investigation was to explore the effects and underlying mechanisms by which FA mitigates I/R, specifically through regulating the GCPII transcriptional adaptive program. Initially, we discovered that following cerebral I/R, levels of FA, methionine synthase (MTR), and methylenetetrahydrofolate reductase (MTHFR) were decreased, while GCPII expression was elevated. Secondly, administering FA could mitigate cognitive impairment and neuronal damage induced by I/R. Thirdly, the mechanism of FA supplementation involved suppressing the transcriptional factor Sp1, subsequently inhibiting GCPII transcription, reducing Glu content, obstructing cellular ferroptosis, and alleviating cerebral I/R injury. In summary, our data demonstrate that FA affords protection against cerebral I/R injury by inhibiting the GCPII transcriptional adaptive response. These findings unveil that targeting GCPII might be a viable therapeutic strategy for cerebral I/R. [ABSTRACT FROM AUTHOR]

Glutamate carboxypeptidase II (GCPII), also known as prostate‐specific membrane antigen (PSMA) or folate hydrolase, is a metallopeptidase expressed predominantly in the human brain and prostate. GCPII expression is considerably increased in prostate carcinoma, and the enzyme also participates in glutamate excitotoxicity in the brain. Therefore, GCPII represents an important diagnostic marker of prostate cancer progression and a putative target for the treatment of both prostate cancer and neuronal disorders associated with glutamate excitotoxicity. For the development of novel therapeutics, mouse models are widely used. However, although mouse GCPII activity has been characterized, a detailed comparison of the enzymatic activity and tissue distribution of the mouse and human GCPII orthologs remains lacking. In this study, we prepared extracellular mouse GCPII and compared it with human GCPII. We found that mouse GCPII possesses lower catalytic efficiency but similar substrate specificity compared with the human protein. Using a panel of GCPII inhibitors, we discovered that inhibition constants are generally similar for mouse and human GCPII. Furthermore, we observed highest expression of GCPII protein in the mouse kidney, brain, and salivary glands. Importantly, we did not detect GCPII in the mouse prostate. Our data suggest that the differences in enzymatic activity and inhibition profile are rather small; therefore, mouse GCPII can approximate human GCPII in drug development and testing. On the other hand, significant differences in GCPII tissue expression must be taken into account when developing novel GCPII‐based anticancer and therapeutic methods, including targeted anticancer drug delivery systems, and when using mice as a model organism.

Background: Prostate-specific membrane antigen (PSMA) PET imaging represents a valuable source of information reflecting disease stage, response rate, and treatment optimization options, particularly with PSMA radioligand therapy. Quantification of radiopharmaceutical uptake in healthy organs from PSMA images has the potential to minimize toxicity by extrapolation of the radiation dose delivery towards personalization of therapy. However, segmentation and quantification of uptake in organs requires labor-intensive organ delineations that are often not feasible in the clinic nor scalable for large clinical trials., Purpose: In this work we develop and test the PSMA Healthy organ segmentation network (PSMA-Hornet), a fully-automated deep neural net for simultaneous segmentation of 14 healthy organs representing the normal biodistribution of [ 18 F]DCFPyL on PET/CT images. We also propose a modified U-net architecture, a self-supervised pre-training method for PET/CT images, a multi-target Dice loss, and multi-target batch balancing to effectively train PSMA-Hornet and similar networks., Methods: The study used manually-segmented [ 18 F]DCFPyL PET/CT images from 100 subjects, and 526 similar images without segmentations. The unsegmented images were used for self-supervised model pretraining. For supervised training, Monte-Carlo cross-validation was used to evaluate the network performance, with 85 subjects in each trial reserved for model training, 5 for validation, and 10 for testing. Image segmentation and quantification metrics were evaluated on the test folds with respect to manual segmentations by a nuclear medicine physician, and compared to inter-rater agreement. The model's segmentation performance was also evaluated on a separate set of 19 images with high tumor load., Results: With our best model, the lowest mean Dice coefficient on the test set was 0.826 for the sublingual gland, and the highest was 0.964 for liver. The highest mean error in tracer uptake quantification was 13.9% in the sublingual gland. Self-supervised pretraining improved training convergence, train-to-test generalization, and segmentation quality. In addition, we found that a multi-target network produced significantly higher segmentation accuracy than single-organ networks., Conclusions: The developed network can be used to automatically obtain high-quality organ segmentations for PSMA image analysis tasks. It can be used to reproducibly extract imaging data, and holds promise for clinical applications such as personalized radiation dosimetry and improved radioligand therapy., (© 2023 American Association of Physicists in Medicine.)

Background: Prostate-specific membrane antigen (PSMA) is an ideal target for molecular imaging and targeted radionuclide therapy in prostate cancer. Consequently, various PSMA ligands were developed. Some of these molecules are functionalized with a chelator that can host radiometals, such as 68 Ga for PET imaging. The 68 Ga radiolabeling step benefits from process automation, making it more robust and reducing radiation exposure., Objective: To design a single automated radiolabeling protocol for the GMP-compliant preparation of [ 68 Ga]Ga-PSMA-11, transposable to the production of [ 68 Ga]Ga-PSMA-617 and [ 68 Ga]Ga-PSMA-I&T., Methods: A GAIA ® synthesis module and a GALLIAD ® generator were used. Radio-TLC and radio-HPLC methods were validated for radiochemical purity (RCP) determination. Three [ 68 Ga]Ga-PSMA-11 validation batches were produced and thoroughly tested for appearance and pH, radionuclide identity and purity, RCP, stability, residual solvent and sterility. Minimal modifications were made to the reagents and disposables for optimal application to other PSMA ligands., Results: [ 68 Ga]Ga-PSMA-11 for clinical application was produced in 27 min. The 3 validation batches met the quality criteria expected by the European Pharmacopoeia to allow routine production. For optimal transposition to PSMA-617, the solid phase extraction cartridge was changed to improve purification of the radiolabeled product. For application to PSMA-I&T, the buffer solution initially used was replaced by HEPES 2.7 M to achieve good radiochemical yields. Residual HEPES content was checked in the final product and was below the Ph. Eur. threshold., Conclusion: A single automated radiolabeling method on the GAIA ® module was developed and implemented for 68 Ga radiolabeling of 3 PSMA ligands, with slight adjustments for each molecule., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The therapeutic efficacy of a Russian radiopharmaceutical 177 Lu-DOTA-PSMA was studied in vivo using male BALB/c nu/nu (nude) mice with prostate carcinoma 22Rv1 xenografts by tumor growth inhibition criterion. The mean tumor volumes in mice treated with 177 Lu-DOTA-PSMA were significantly lower than in animals of the control group. There were no significant differences in the values of tumor growth inhibition between the groups of animals receiving 3.7 or 7.4 MBq of 177 Lu-DOTA-PSMA., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Radiopharmaceuticals used for diagnosis or therapy induce DNA strand breaks, which may be detectable by single-cell gel electrophoresis (called comet assay). Blood was taken from patients before and at different time points after treatment with radiopharmaceuticals; blood cells were investigated by the comet assay using the percentage of DNA in the tail as the critical parameter. Whereas [225Ac]Ac-prostate-specific membrane antigen (PSMA)-617 alpha therapy showed no difference relative to the blood sample taken before treatment, beta therapy with [177Lu]Lu-PSMA-617 3 h post-injection revealed a small but significant increase in DNA strand breaks. In blood of patients who underwent positron emission tomography (PET) with either [18F]2-fluor-2-deoxy-D-glucose (FDG) or [68Ga]Ga-PSMA-11, an increase of DNA migration determined by the comet assay was not found when analysed at different time points (2–70 min) after intravenous tracer injection. Human whole blood was incubated with the targeted clinically relevant therapeutic radiopharmaceuticals [225Ac]Ac-PSMA-617, [177Lu]Lu-PSMA-617 and [90Y]Y-DOTA(0)-Phe(1)-Tyr(3)-octreotide (DOTA-TOC) at different activity concentrations (kBq/ml) for 5 days and then analysed by the comet assay. DNA damage increased with higher concentrations of all radiolabeled compounds tested. [177Lu]Lu-PSMA-617 caused higher blood cell radiotoxicity than equal activity concentrations of [90Y]Y-DOTA-TOC. Likewise, whole human blood was exposed to the positron emitters [18F]FDG and [68Ga]Ga-PSMA-11 in vitro for 24 h with activity concentrations ranging between 5 and 40 MBq/ml. The same activity concentration dependent elevated DNA migration was observed for both compounds although decay energies are different. This study demonstrated that the amount of DNA damage detected by the comet assay in whole human blood is similar among different positron emitters and divergent by a factor of 200 between alpha particles and beta radiation. [ABSTRACT FROM AUTHOR]

Purpose: The rationale of the current study was to develop 6-mercaptopurine (6-MP)-mediated hematological toxicity prediction model for acute lymphoblastic leukemia (ALL) therapeutic management.Methods: A total of 96 children with ALL undergoing therapy with MCP-841 protocol were screened for all the ten exons of TPMT, exon 2, exon 3 and intron 2 of ITPA using bidirectional sequencing. This dataset was used to construct prediction models of leucopenia grade by constructing classification and regression trees (CART) followed by smart pruning.Results: The developed CART model indicated TPMT*12 and TPMT*3C as the key determinants of toxicity. TPMT int3, int4 and int7 polymorphisms exert toxicity when co-segregated with one mutated allele of TPMT*12 or TPMT*3C or ITPA exon 3. The developed CART model exhibited 93.6% accuracy in predicting the toxicity. The area under the receiver operating characteristic curve was 0.9649.Conclusions: TPMT *3C and TPMT*12 are the key determinants of 6-MP-mediated hematological toxicity while other variants of TPMT (int3, int4 and int7) and ITPA ex2 interact synergistically with TPMT*3C or TPMT*12 variant alleles to enhance the toxicity. TPMT and ITPA variants cumulatively are excellent predictors of 6-MP-mediated toxicity. [ABSTRACT FROM AUTHOR]

Highlight • The peptide transmitter NAAG has procognitive activity. • GCPII inhibitors increase synaptic NAAG and affect cognition in animal models of Alzheimer's disease, inflammatory pain, and ethanol intoxication. • GCPII inhibitors. • The procognitive efficacy of GCPII and NAAG is mediated by mGluR3. • Defining the procognitive role of NAAG at the behavioral and the cellular levels is a promising area for future research. Abstract The peptide transmitter N-acetylaspartylglutamate (NAAG) and its receptor, the type 3 metabotropic glutamate receptor (mGluR3, GRM3), are prevalent and widely distributed in the mammalian nervous system. Drugs that inhibit the inactivation of synaptically released NAAG have procognitive activity in object recognition and other behavioral models. These inhibitors also reverse cognitive deficits in animal models of clinical disorders. Antagonists of mGluR3 block these actions and mice that are null mutant for this receptor are insensitive to the actions of these procognitive drugs. A positive allosteric modulator of this receptor also has procognitive activity. While some data suggest that drugs acting on mGluR3 achieve their procognitive action by increasing arousal during acquisition training, exploration of the procognitive efficacy of NAAG is in its early stages and thus substantial opportunities exist to define the breadth and nature of this activity. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract A series of carbamate-based inhibitors of glutamate carboxypeptidase II (GCPII) were designed and synthesized using ZJ-43 , N -[[[(1S)-1-carboxy-3-methylbutyl]amino]carbonyl]- l -glutamic acid, as a molecular template in order to better understand the impact of replacing one of the two nitrogen atoms in the urea-based GCPII inhibitor with an oxygen atom. Compound 7 containing a C-terminal 2-oxypentanedioic acid was more potent than compound 5 containing a C-terminal glutamic acid (2-aminopentanedioic acid) despite GCPII's preference for peptides containing an N-terminal glutamate as substrates. Subsequent crystallographic analysis revealed that ZJ-43 and its two carbamate analogs 5 and 7 with the same (S , S)-stereochemical configuration adopt a nearly identical binding mode while (R , S)-carbamate analog 8 containing a d -leucine forms a less extensive hydrogen bonding network. QM and QM/MM calculations have identified no specific interactions in the GCPII active site that would distinguish ZJ-43 from compounds 5 and 7 and attributed the higher potency of ZJ-43 and compound 7 to the free energy changes associated with the transfer of the ligand from bulk solvent to the protein active site as a result of the lower ligand strain energy and solvation/desolvation energy. Our findings underscore a broader range of factors that need to be taken into account in predicting ligand-protein binding affinity. These insights should be of particular importance in future efforts to design and develop GCPII inhibitors for optimal inhibitory potency. [ABSTRACT FROM AUTHOR]

Introduction There is an unmet clinical need for early, accurate imaging of recurrent prostate cancer to improve patient outcomes. Staging, by conventional bone scintigraphy and CT have become outdated. 68Ga-PSMA PET/CT imaging in this setting has developed rapidly, with widespread International adoption in line with evidence-based guidelines in this group of patients. Sources of data A PubMed search of English language articles was performed using following keywords: PSMA, PET/CT, biochemical recurrence, prostate cancer. The search revealed 85 articles, of which 75 were original; 70 of these involved use of the most widely available type of PSMA tracer (HBED). The review also relied on the clinical experience of reporting over 1000 PSMA PET/CT studies at a major tertiary referral centre for uro-oncology, with the majority of cases having been performed in the biochemical recurrence setting from 2015 to 2018. Areas of agreement 68Ga-PSMA PET is a game changer and superior to choline PET and other established tracers which have been used in prostate cancer evaluation. Detection of recurrence at the prostate bed remains challenging due to bladder and urethral tracer accumulation. The main strength of PSMA PET/CT is its ability to identify small (<8 mm) pathological lymph nodes, upstaging nodal status in up to two-thirds of cases. Additionally, PSMA PET/CT, detects bone and bone marrow metastases missed by conventional bone and CT imaging. Thus, PSMA PET/CT has major impact on patient management, with studies reporting overall changes in 39–76% of cases. Areas of controversy Controversy exists regarding patient access and NHS affordability of PSMA PET/CT imaging. Currently, no reimbursement is available under the NHS tariff system. The cost outlay for tertiary hospital linked PET centres ranges from £150-170 K. Large referral volumes, and technical advances in manufacturing process will make this tracer cost neutral and similar to the current funded, but less sensitive, choline PET. Current NICE guidelines for prostate cancer management do not include a recommendation on when PSMA PET/CT should be used and this is likely to remain the case in the next revision, due in 2019. Growing points Although PSMA PET/CT imaging results in significant management change, there is a need for high quality economic evaluation and cost analysis for this modality. Lack of this data will result in poor adoption of this technique and thus limit patient access. Furthermore, it is hoped that future tracers will become even more sensitive and identify disease at earlier thresholds. Areas timely for developing research Well-designed clinical trials with consideration of the health economic benefit of using PSMA PET/CT will be essential to provide a basis for entry into guidelines such as NICE and to provide a rationale for reimbursement. [ABSTRACT FROM AUTHOR]