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Background: [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) plus protocol-permitted standard of care (SOC) prolonged overall survival (OS) and radiographic progression-free survival (rPFS) versus SOC in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 VISION study, in addition to beneficial effects on symptomatic skeletal events (SSEs) and health-related quality of life (HRQOL)., Methods: Post hoc analyses used the full analysis set from the VISION study (N = 831) overall and by randomized treatment arm ( 177 Lu-PSMA-617 plus SOC, n = 551; SOC, n = 280). Correlations were determined between OS and rPFS and between rPFS or OS and time to SSE or to worsening HRQOL (Functional Assessment of Cancer Therapy-Prostate [FACT-P] and 5-level EQ-5D [EQ-5D-5L]). Correlation analyses used an iterative multiple imputation copula-based approach (correlation coefficients [rho] of <0.3 were defined as weak, ≥0.3 and <0.5 as mild, ≥0.5 and <0.7 as moderate, and ≥0.7 as strong)., Results: In the overall population, rPFS correlated strongly with OS (rho, ≥0.7). Correlations between rPFS or OS and time to SSE without death were weak or mild. Time to worsening in the FACT-P total score and emotional and physical well-being domains correlated mildly or moderately with rPFS and moderately with OS. Correlation coefficients for time-to-worsening EQ-5D-5L scores were mild to moderate for both rPFS and OS. Correlation coefficients were similar between treatment arms., Conclusions: In this analysis of the VISION study, rPFS correlated strongly with OS but not with time to SSE or worsening HRQOL. These findings require further investigation., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: [ 177 Lu]Lu-PSMA-617 ( 177 Lu-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 177 Lu-PSMA-617 built using data from VISION, a large prospective phase 3 clinical trial powered for overall survival., Methods: Adults with progressive post androgen receptor pathway inhibitor and taxane prostate-specific membrane antigen (PSMA)-positive mCRPC received 177 Lu-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., Findings: Patients were randomised between June 2018 and October 2019. Data from all 551 patients in the 177 Lu-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 (SUV max ), 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 SUV max , 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 SUV max , lymphocyte count and ALP. Performances of the OS and rPFS models were maintained when they were reconstructed excluding SUV max ., Interpretation: These models of outcomes with 177 Lu-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., Funding: Novartis., Competing Interests: KH reports receiving grants or contracts from Boston Scientific, Janssen, and Novartis; consulting fees from Amgen, AstraZeneca, Bain Capital, Bayer, Boston Scientific, Convergent, Curium, Debiopharm, EcoR1, Fusion, GE Healthcare, Immedica, Isotopen Technologien München, Janssen, Merck, Molecular Partners, Novartis, NVision, POINT Biopharma, Pfizer, Radiopharm Theranostics, Rhine Pharma, Siemens Healthineers, Sofie Biosciences, Telix, Theragnostics, and ymabs; and stock or other ownership in AdvanCell, Aktis Oncology, Convergent, NVision, Pharma 15, and Sofie Biosciences. JSdB reports receiving grants or contracts from Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Crescendo, Daiichi-Sankyo, Endocyte, Genentech/Roche, GlaxoSmithKline, ImCheck Therapeutics, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, and Sanofi Aventis; consulting or advisory fees from Astellas, AstraZeneca, Bayer, Daiichi-Sankyo, Genentech/Roche, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Orion, Pfizer, Sanofi Aventis, and Taiho; payment or honorarium from Astellas, AstraZeneca, Bayer, Cellcentric, Crecendo, Daiichi, Genentech, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Mycrix, MSD, Orion, Pfizer, Sanofi Aventis, and Taiho; being an inventor on patent 8,822,438; participating on a data safety monitoring or advisory board for Amgen, AstraZeneca, Bayer, Bioxcel Therapeutics, Crescendo, Daiichi-Sankyo, Endocyte, Genentech/Roche, GlaxoSmithKline, ImCheck Therapeutics, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Oncternal, Pfizer, and Sanofi Aventis; and receiving institutional royalties or licenses related to abiraterone, PARP inhibitor, and PI3K/AKT. OS reports receiving support for the present manuscript from Novartis; institutional grants or contracts from Amgen, AstraZeneca, Bayer, Endocyte, Invitae, Janssen, Lantheus, Merck, Novartis, Progenics, and Tenebio; consulting fees from ARTBIO, AstraZeneca, Bayer, Blue Earth Diagnostics, Clarity Pharmaceuticals, Fusion, Isotopen Technologien Muenchen, Janssen, Merck, Myovant, Myriad, Noria Therapeutics, NorthStar, Novartis, Pfizer, POINT Biopharma, Sanofi, Telix, and Tenebio; travel and accommodation expenses from Lantheus, NorthStar, and Novartis; participation on a data safety monitoring or advisory board for AstraZeneca, Merck, and Pfizer; and stock or stock options in ARTBIO, Clarity Pharmaceuticals, Convergent, Fusion, Lilly, Pfizer, Ratio, and Telix. KNC reports receiving grants or contracts from AstraZeneca, Bayer, Janssen, Merck, Novartis, Pfizer, POINT Biopharma, and Roche; and consulting fees from Astellas, AstraZeneca, Bayer, Janssen, Merck, Novartis, Pfizer, POINT Biopharma, and Roche. BJK reports receiving consultant or advisory fees from Bayer, Isotope Technologies Munich, and Novartis; and research funding from Novartis. KR reports receiving consultant fees from ABX, ABX-CRO, Amgen, Bayer Healthcare, Janssen Cilag, Novartis, and Sirtex; and lecture payments from AstraZeneca, Bayer Healthcare, Novartis, and Siemens Healthcare. STT reports receiving institutional fees from AbbVie, Ambrx, Amgen, Astellas, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Clarity, Clovis, Endocyte, Genentech, Gilead, Inovio, Janssen, Karyopharm, Medivation, Merck, Newlink, Novartis, POINT Biopharma, Rexahn, Sanofi, and Seattle Genetics; and consultant fees from AbbVie, Aikido Pharma, Ambrx, Amgen, Astellas, Bayer, Blue Earth, Clarity Pharma, Clovis, Convergent Therapeutics, Daiichi Sankyo, Eisai, EMD Serono, Genentech, Genomic Health, Janssen, Medivation, Merck, Myovant, Novartis, Pfizer, POINT Biopharma, Regeneron, Sanofi, Seattle Genetics, Telix, Tolmar, and TransThera. JC reports stock or other ownership interest in Sofie Biosciences, Inc., and Trethera; acting as an uncompensated founder for Trethera; and an uncompensated adviser for Amgen, Atkis Oncology, Jubilant Radiopharma, Novartis, POINT Biopharma, and RayzeBio. GEH reports receiving consultant fees from Bayer HealthCare, Boston Scientific Corporation, NorthStar Medical Radioisotopes, Novartis, and Terumo; and stock ownership in Johnson and Johnson. CCW reports employment and stock ownership with Novartis. ZZ reports previous employment and current stock ownership with Novartis. CW reports employment and stock ownership with Novartis. OM reports employment and stock ownership with Novartis. MJM reports receiving consulting or advisory fees from Amgen, AstraZeneca, Blue Earth Diagnostics, Clarity Pharmaceuticals, Convergent Therapeutics, Daiichi, ITM Isotope Technologies Munich, Lantheus Medical Imaging, Pfizer, POINT Biopharma, Progenics, Telix Pharmaceuticals, and Z-Alpha; stock and other ownership in Doximity; travel, accommodations, and expenses from APCCC, AstraZeneca, and Memorial Sloan-Kettering Cancer Center; institutional research funding from Astellas Pharma, Bayer, Celgene, Corcept Therapeutics, Janssen, Novartis, Progenics, and Roche/Genentech; patents pending with Novartis; and royalties from Telix. KF reports receiving institutional honorarium or payments to Gustave Roussy Institute from Astellas, AstraZeneca, Bayer, Janssen, MSD, Novartis, and Sanofi; institutional participation on data safety monitoring or advisory boards for Amgen, Astellas, AstraZeneca, Bayer, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis, Pfizer, and Sanofi; and personal participation on a data safety monitoring or advisory board for Arvinas, CureVac, Macrogenics, Orion. No other potential conflict of interest relevant to this article was reported., (© 2024 The Authors.)

Aim: Prostate-specific membrane antigen-positron emission tomography (PSMA-PET) is a widely used diagnostic tool in patients with prostate cancer (PC). However, due to the limited availability of PET scanners and relevant acquisition costs, it is important to consider the indications and acquisition time. The aim of this investigation was to determine whether a PET scan from the skull base to the proximal thigh is sufficient to detect the presence of bone metastases., Methods: A retrospective analysis was conducted on 1050 consecutive [ 18 F]PSMA-1007-PET-CT scans from the head to the proximal lower leg. The PET scans were categorised according to the presence and amount of bone metastases: (1) 1-5, (2) 6-19 and (3) ≥20. Additionally, the PET scans were evaluated for the presence of bone metastases below the proximal thigh as well as bone metastases above the skull base. Imaging results were compared to patients PSA values., Results: Of the 391 patients with bone metastases, 146 (37.3%) exhibited metastases located below the proximal thigh and 104 (26.6%) above the skull base. The majority of bone metastases located below the proximal thigh (145, 99.3%) and above the skull base (94, 90.4%) were identified in patients with more than five bone metastases. No solitary distal metastasis was detected. The PSA value correlated significantly with number of bone metastases (e. g., 1-5 vs. ≥20 bone metastases, P < 0.001) and was significantly higher in patients with distal bone metastases ( P < 0.001). ROC analysis showed that a PSA value of 11.15 ng/mL is the optimal cut-off for detecting bone metastases located below the proximal thigh, with an AUC of 0.919 (95% CI: 0.892-0.945, sensitivity 87%, specificity 86%). Similarly, the PSA value of 12.86 ng/mL is the optimal cut-off for detecting bone metastases above the skull base with an AUC of 0.904 (95% CI: 0.874-0.935, sensitivity 87%, specificity 83%).  CONCLUSION: PSMA-PET acquisition protocols from the skull base to the proximal femur may be sufficient to accurately detect bone metastatic disease in PC. PSA values can provide decision support for individual PET acquisition protocols., Competing Interests: Kambiz Rahbar reports honoraria from Advanced Accelerator Applications (AAA/Novartis), Bayer, Jahnsen Cielag, Amgen, Astrazeneca and Pharmtrace and a consultancy/advisory role with ABX GmbH, ABX-CRO, Bayer, and AAA/Novartis and UroTrials. Martin Boegemann receives honoraria from and has a consultancy/advisory role with Advanced Accelerator Applications (AAA/Novartis), Bayer, Janssen, Sanofi, Merck, MSD, BMS, Roche, Astellas, Exelixis, Pahrmtrace, Amgen, AstraZeneca, Eisai, Gilead, and EUSApharma., (Thieme. All rights reserved.)

Background: Prostate-specific membrane antigen positron emission tomography (PSMA-PET) is an essential tool for patient selection before radioligand therapy (RLT). Interim-staging with PSMA-PET during RLT allows for therapy monitoring. However, its added value over post-treatment imaging is poorly elucidated. The aim of this study was to compare early treatment response assessed by post-therapeutic whole-body scans (WBS) with interim-staging by PSMA-PET after 2 cycles in order to prognosticate OS., Methods: Men with metastasized castration-resistant PC (mCRPC) who had received at least two cycles of RLT, and interim PSMA-PET were evaluated retrospectively. PROMISE V2 framework was used to categorize PSMA expression and assess response to treatment. Response was defined as either disease control rate (DCR) for responders or progression for non-responders., Results: A total of 188 men with mCRPC who underwent RLT between February 2015 and December 2021 were included. The comparison of different imaging modalities revealed a strong and significant correlation with Cramer V test: e.g. response on WBS during second cycle compared to interim PET after two cycles of RLT (c φ = 0.888, P < 0.001, n = 188). The median follow-up time was 14.7 months (range: 3-63 months; 125 deaths occurred). Median overall survival (OS) time was 14.5 months (95% CI: 11.9-15.9). In terms of OS analysis, early progression during therapy revealed a significantly higher likelihood of death: e.g. second cycle WBS (15 vs. 25 months, P < 0.001) with a HR of 2.81 (P < 0.001) or at PET timepoint after 2 cycles of RLT (11 vs. 24 months, P < 0.001) with a HR of 3.5 (P < 0.001). For early biochemical response, a PSA decline of at least 50% after two cycles of RLT indicates a significantly lower likelihood of death (26 vs. 17 months, P < 0.001) with a HR of 0.5 (P < 0.001)., Conclusion: Response assessment of RLT by WBS and interim PET after two cycles of RLT have high congruence and can identify patients at risk of poor outcome. This indicates that interim PET might be omitted for response assessment, but future trials corroborating these findings are warranted., (© 2024. The Author(s).)

Background and Objective: The prognostic value of declining prostate-specific antigen (PSA) levels is under investigation in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) receiving PSMA-targeted radioligand therapy with [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617). This post hoc analysis of the phase 3 VISION trial aimed to evaluate associations between PSA decline and clinical and patient-reported outcomes in patients receiving 177 Lu-PSMA-617., Methods: Of 831 enrolled patients with PSMA-positive progressive mCRPC treated previously with one or more androgen receptor pathway inhibitors and one to two taxanes, 551 were randomised to 177 Lu-PSMA-617 plus protocol-permitted standard of care (SoC). Radiographic progression-free survival, overall survival, radiographic objective response rate, and patient-reported health-related quality of life (HRQoL) and pain were analysed in subgroups of patients categorised by the magnitude of unconfirmed PSA decline from baseline., Key Findings and Limitations: Patients randomised to 177 Lu-PSMA-617 with the best PSA declines of ≥0-<50% (96/551 [17%]), ≥50-<90% (152/551 [28%]), and ≥90% (83/551 [15%]) up to and including week 12 had 61%, 72%, and 88% reduced risks of radiographic disease progression or death, and 51%, 70%, and 87% reduced risks of death, respectively, versus those with increased PSA levels (160/551 [29%]), based on hazard ratios in a multivariate Cox proportional hazard model. In patients with greater PSA declines, radiographic responses were more frequent and median time to worsening in HRQoL and pain scores were longer., Conclusions and Clinical Implications: The magnitude of PSA decline was associated with improvement in clinical and patient-reported outcomes in patients with mCRPC receiving 177 Lu-PSMA-617 plus SoC in VISION. PSA decline therefore appears to have a prognostic value during 177 Lu-PSMA-617 treatment in this population., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Prostate-specific membrane antigen (PSMA)-PET was introduced into clinical practice in 2012 and has since transformed the staging of prostate cancer. Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria were proposed to standardise PSMA-PET reporting. We aimed to compare the prognostic value of PSMA-PET by PROMISE (PPP) stage with established clinical nomograms in a large prostate cancer dataset with follow-up data for overall survival., Methods: In this multicentre retrospective study, we used data from patients of any age with histologically proven prostate cancer who underwent PSMA-PET at the University Hospitals in Essen, Münster, Freiburg, and Dresden, Germany, between Oct 30, 2014, and Dec 27, 2021. We linked a subset of patient hospital records with patient data, including mortality data, from the Cancer Registry North-Rhine Westphalia, Germany. Patients from Essen University Hospital were randomly assigned to the development or internal validation cohorts (2:1). Patients from Münster, Freiburg, and Dresden University Hospitals were included in an external validation cohort. Using the development cohort, we created quantitative and visual PPP nomograms based on Cox regression models, assessing potential PPP predictors for overall survival, with least absolute shrinkage and selection operator penalty for overall survival as the primary endpoint. Performance was measured using Harrell's C-index in the internal and external validation cohorts and compared with established clinical risk scores (International Staging Collaboration for Cancer of the Prostate [STARCAP], European Association of Urology [EAU], and National Comprehensive Cancer Network [NCCN] risk scores) and a previous nomogram defined by Gafita et al (hereafter referred to as GAFITA) using receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) estimates., Findings: We analysed 2414 male patients (1110 included in the development cohort, 502 in the internal cohort, and 802 in the external validation cohort), among whom 901 (37%) had died as of data cutoff (June 30, 2023; median follow-up of 52·9 months [IQR 33·9-79·0]). Predictors in the quantitative PPP nomogram were locoregional lymph node metastases (molecular imaging N2), distant metastases (extrapelvic nodal metastases, bone metastases [disseminated or diffuse marrow involvement], and organ metastases), tumour volume (in L), and tumour mean standardised uptake value. Predictors in the visual PPP nomogram were distant metastases (extrapelvic nodal metastases, bone metastases [disseminated or diffuse marrow involvement], and organ metastases) and total tumour lesion count. In the internal and external validation cohorts, C-indices were 0·80 (95% CI 0·77-0·84) and 0·77 (0·75-0·78) for the quantitative nomogram, respectively, and 0·78 (0·75-0·82) and 0·77 (0·75-0·78) for the visual nomogram, respectively. In the combined development and internal validation cohort, the quantitative PPP nomogram was superior to STARCAP risk score for patients at initial staging (n=139 with available staging data; AUC 0·73 vs 0·54; p=0·018), EAU risk score at biochemical recurrence (n=412; 0·69 vs 0·52; p<0·0001), and NCCN pan-stage risk score (n=1534; 0·81 vs 0·74; p<0·0001) for the prediction of overall survival, but was similar to GAFITA nomogram for metastatic hormone-sensitive prostate cancer (mHSPC; n=122; 0·76 vs 0·72; p=0·49) and metastatic castration-resistant prostate cancer (mCRPC; n=270; 0·67 vs 0·75; p=0·20). The visual PPP nomogram was superior to EAU at biochemical recurrence (n=414; 0·64 vs 0·52; p=0·0004) and NCCN across all stages (n=1544; 0·79 vs 0·73; p<0·0001), but similar to STARCAP for initial staging (n=140; 0·56 vs 0·53; p=0·74) and GAFITA for mHSPC (n=122; 0·74 vs 0·72; p=0·66) and mCRPC (n=270; 0·71 vs 0·75; p=0·23)., Interpretation: Our PPP nomograms accurately stratify high-risk and low-risk groups for overall survival in early and late stages of prostate cancer and yield equal or superior prediction accuracy compared with established clinical risk tools. Validation and improvement of the nomograms with long-term follow-up is ongoing (NCT06320223)., Funding: Cancer Registry North-Rhine Westphalia., Competing Interests: Declaration of interests MJK reports ownership of stocks in Bayer. JH reports participation on a data safety monitoring board for CARP-Study (carp-studie.de). VG reports grants or contracts from Pfizer, AstraZeneca, Bristol Myers Squibb (BMS), and MSD; consulting fees from BMS, Pfizer, Novartis, MSD Oncology, Ipsen, Janssen-Cilag, Eisai, Debiopharm, PCI Biotech, Gliead, Cureteq, Oncorena, and Synthekine; payment or honoraria from BMS, Pfizer, Ipsen, Eisai, MSD Oncology, Merck Serono, AstraZeneca, Janssen-Cilag, AAA/Novartis, Apogepha, Ono Pharmaceutical, Astellas Pharma, and Amgen; ownership of stocks in MSD, BMS, AstraZeneca, Genmab, and Bicycle Therapeutics; travel support from Pfizer, AstraZeneca, Janssen, Merck Serono, and Ipsen; participation on a data safety monitoring board or advisory board for the European Organisation for Research and Treatment of Cancer; and a leadership role for Arbeitsgemeinschaft Internistische Onkologie of the German Cancer Society. MS reports patents not related to the manuscript as planned, issued, or pending. ME reports grants or contracts from Blue Earth Diagnostics and Bayer; royalties from POSLUMA (an FDA-approved radiohybrid PSMA-targeted agent for PET imaging of prostate cancer in adults); consulting fees for Blue Earth Diagnostics, Novartis/AAA, Bayer, Telix, RayzeBio, Point Biopharma, and Janssen Pharmaceuticals; payment or honoraria from Novartis/AAA, Eckert-Ziegler, ABX, and Janssen Pharmaceuticals; patent application as inventor of radiohybrid PSMA; a leadership role in the European Association of Nuclear Medicine committee meeting; ownership of stocks in Novartis, Telix, Bayer, and Point Biopharma; support for travel from Blue Earth Diagnostics and Terumo; and payment for expert testimony from Paraxel and Bioclinica. TT reports grants from DAAD Researcher Grant and speaker fees from ABX. CK reports ownership of stocks in Telix and Actinium Pharmaceuticals; grants or contracts from Novartis, Mariana Oncology, and Amgen; payment or honoraria from Novartis and Pfizer; and travel support from Bayer, Janssen, and Amgen. KH reports grants or contracts from Novartis and Sofie Biosciences; consulting fees from Advanced Accelerator Applications, a Novartis company, Amgen, AstraZeneca, Bain Capital, Bayer, Boston Scientific, Convergent, Curium, Debiopharm, EcoR1, Fusion, GE Healthcare, Immedica, Isotopen Technologien München, Janssen, Merck, Molecular Partners, NVision, POINT Biopharma, Pfizer, Radiopharm Theranostics, Rhine Pharma, Siemens Healthineers, Sofie Biosciences, Telix, Theragnostics, and ymabs; payment or honoraria for educational events from PeerVoice; support for American Society of Clinical Oncology participation from Janssen; participation on a data safety monitoring board or advisory board for Fusion and GE Healthcare; and ownership of stocks in Sofie Biosciences, Pharma15, NVision, Convergent, Aktis Oncology, and AdvanCell. KR reports consulting fees from AAA/Novartis, Bayer, ABX, ABX-CRO, UroTrials, and Pharmtrace; honoraria or payment from AAA/Novartis, Bayer, and ABX; and travel support from Bayer. PTM reports payment to their institution from Siemens Healthineers. BAH reports consulting fees from Lightpoint medical, Janssen, Bayer, ABX, Astellas, Merck, Amgen, MSD/Pfizer, Novartis, BMS, Onkowissen, POINT Biopharma, Ipsen, AstraZeneca, Lightpoint medical, Telix, and Accord Healthcare; travel support from AstraZeneca, BMS, Janssen, Bayer, and Ipsen; grants or contracts from Janssen, Deutsche Forschungsgesellschaft, Novartis, and BMS; royalties or licenses from Uromed; payment or honoraria from Janssen, Amgen, Astellas, and Monrol; participation on a data safety monitoring board or advisory board for Janssen and ABX; and a leadership role for Deutsche Gesellschaft für Urologie. WPF reports grants from SOFIE Biosciences; consulting fees from Janssen, Calyx, Bayer, Novartis, and Urotrials; payment or Honoraria from Janssen, Calyx, Bayer, Novartis, Urotrials, Amgen, ABX, Eczacıbaşı Monrol, GE Healthcare, and Telix. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: This study aims to evaluate the prognostic significance of various previously reported PSMA-PET parameters in patients undergoing 177 Lu-PSMA radioligand therapy (RLT). While individual studies have investigated the prognostic value of one or few of these factors, comprehensive analyses are rare., Methods: Data of 82 patients undergoing 177 Lu-PSMA-radiologand-therapy (RLT) were analyzed. Total tumor volume (tumor volume), average SUVmean of all tumor lesions (SUVmean) and the quotient of sum of SUVmean of all tumor lesions to SUVmean of the parotid glands (tumor-parotid-ratio; TPR) and of the kidneys (tumor-kidney-ratio; TKR) were included in analysis., Results: This study showed that a tumor volume of <290.6 ml is associated with a better survival in patients undergoing PSMA-RLT (median PFS: 4.2, median OS: 13.2 months) compared to patients with higher tumor volume (median PFS: 3.4,median OS: 6.2 months; p-value = 0.01 for PFS and <0.001 for OS). The average SUVmean correlated inversely with survival. Patients with a SUVmean > 10.7 had a median PFS of 4.2 and OS of 11.4 months while patients with SUVmean <10.7 had a median PFS of 1.6 and OS of 5 months (p-value <0.001 for both). The assessment of TPR showed no significant difference regarding OS and PFS. TKR showed a better PFS in patients with ratio > 0.33 (p-value 0.009) but no significant difference regarding OS., Conclusion: The present study confirms that pretherapeutic PSMA-PET before RLT with 177 Lu-PSMA has a prognostic value., Competing Interests: Kambiz Rahbar reports honoraria from Advanced Accelerator Applications (AAA/Novartis), Bayer Healthcare, and SIRTEX and a consultancy/advisory role with ABX GmbH, ABX-CRO, Bayer, AAA, Pharmtrace, Jahnsen Cielag, Amgen, and Astrazeneca. Martin Boegemann receives honoraria from and has a consultancy/ advisory role with Advanced Accelerator Applications (AAA/ Novartis), Bayer, Janssen, Sanofi, Merck, MSD, BMS, Roche, Astellas, Exelixis, Pahrmtrace, Amgen, AstraZeneca, Eisai, Gilead, and EUSApharma. No other potential conflict of interest relevant to this article was reported., (Thieme. All rights reserved.)

Background Lutetium 177 [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) is a prostate-specific membrane antigen (PSMA)-targeted radioligand therapy for metastatic castration-resistant prostate cancer (mCRPC). Quantitative PSMA PET/CT analysis could provide information on 177 Lu-PSMA-617 treatment benefits. Purpose To explore the association between quantitative baseline gallium 68 [ 68 Ga]Ga-PSMA-11 ( 68 Ga-PSMA-11) PET/CT parameters and treatment response and outcomes in the VISION trial. Materials and Methods This was an exploratory secondary analysis of the VISION trial. Eligible participants were randomized (June 2018 to October 2019) in a 2:1 ratio to 177 Lu-PSMA-617 therapy (7.4 GBq every 6 weeks for up to six cycles) plus standard of care (SOC) or to SOC only. Baseline 68 Ga-PSMA-11 PET parameters, including the mean and maximum standardized uptake value (SUV mean and SUV max ), PSMA-positive tumor volume, and tumor load, were extracted from five anatomic regions and the whole body. Associations of quantitative PET parameters with radiographic progression-free survival (rPFS), overall survival (OS), objective response rate, and prostate-specific antigen response were investigated using univariable and multivariable analyses (with treatment as the only other covariate). Outcomes were assessed in subgroups based on SUV mean quartiles. Results Quantitative PET parameters were well balanced between study arms for the 826 participants included. The median whole-body tumor SUV mean was 7.6 (IQR, 5.8-9.9). Whole-body tumor SUV mean was the best predictor of 177 Lu-PSMA-617 efficacy, with a hazard ratio (HR) range of 0.86-1.43 for all outcomes (all P < .001). A 1-unit whole-body tumor SUV mean increase was associated with a 12% and 10% decrease in risk of an rPFS event and death, respectively. 177 Lu-PSMA-617 plus SOC prolonged rPFS and OS in all SUV mean quartiles versus SOC only, with no identifiable optimum among participants receiving 177 Lu-PSMA-617. Higher baseline PSMA-positive tumor volume and tumor load were associated with worse rPFS (HR range, 1.44-1.53 [ P < .05] and 1.02-1.03 [ P < .001], respectively) and OS (HR range, 1.36-2.12 [ P < .006] and 1.04 [ P < .001], respectively). Conclusion Baseline 68 Ga-PSMA-11 PET/CT whole-body tumor SUV mean was the best predictor of 177 Lu-PSMA-617 efficacy in participants in the VISION trial. Improvements in rPFS and OS with 177 Lu-PSMA-617 plus SOC were greater among participants with higher whole-body tumor SUV mean , with evidence for benefit at all SUV mean levels. ClinicalTrials.gov identifier: NCT03511664 Published under a CC BY 4.0 license. Supplemental material is available for this article.

Dural arteriovenous fistulas (DAVFs) are rare vascular abnormalities that can present with diverse neurological symptoms. We report a case of a woman in her early 60s who presented with pain in the left ear and dizziness. Neurological evaluation and imaging studies revealed a DAVF in the left cerebellopontine angle. This case underscores the importance of considering DAVF as a potential etiology in patients presenting with atypical otological symptoms., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, El Atrache et al.)

This review paper highlights the transformative role of PSMA-targeted diagnostics and therapy in prostate cancer management, particularly focusing on 177 Lu-PSMA-617, approved by the FDA and EMA for metastatic castration-resistant prostate cancer (mCRPC) patients post-chemotherapy and ARPI treatment. Originating from the VISION trial's success, this paper navigates the current radioligand therapy (RLT) indications, emphasizing practical patient selection, planning, and treatment execution. It critically examines Lu-PSMA's comparative effectiveness against cabazitaxel and Ra-223, addressing decision-making dilemmas for mCRPC treatments. Furthermore, the paper discusses Lu-PSMA in chemotherapy-naïve patients and its application in hormone-sensitive prostate cancer, underlined by ongoing global studies. A significant concern is Lu-PSMA's long-term safety profile, particularly nephrotoxicity risks, necessitating further investigation. The possibility of Lu-PSMA rechallenge in responsive patients is explored, stressing the need for comprehensive analyses and real-world data to refine treatment protocols. Conclusively, PSMA-targeted therapy marks a significant advance in prostate cancer therapy, advocating for its integration into a multimodal, patient-centric treatment approach. The review underscores the imperative for additional comparative studies to optimize treatment sequences and outcomes, ultimately enhancing long-term prognosis and disease control in prostate cancer management., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: HA reports receiving honoraria from Advanced Accelerator Applications (AAA/Novartis) and Bayer Healthcare for delivering oral presentations at various conferences. KR reports honoraria from Advanced Accelerator Applications (AAA/Novartis), Bayer Healthcare, and SIRTEX and a consultancy/advisory role with ABX GmbH, ABX-CRO, Bayer, AAA, Pharmtrace, Jahnsen Cielag, Amgen, and AstraZeneca. RS has received research support from Else Kröner-Fresenius-Stiftung and Boehringer Ingelheim Funds. AAO and CK have no disclosures to report. If there are other authors, they 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 © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Prospective results have demonstrated favorable safety and efficacy of [ 177 Lu]Lu-PSMA radiopharmaceutical therapy for up to 6 cycles in men with metastatic castration-resistant prostate cancer. However, no systematic data are available outlining the feasibility of extended therapy beyond 6 cycles. We aim to evaluate the safety and efficacy of extended [ 177 Lu]Lu-PSMA radiopharmaceutical therapy in patients who have received more than 6 cycles. Methods: In total, 111 patients were included in this multicenter retrospective analysis. Based on individual decisions, patients underwent uninterrupted continuation of therapy (continuous treatment) or reexposure after a therapy break (rechallenge treatment) between 2014 and 2023. Overall survival, 50% prostate-specific antigen (PSA) decline (measured 8-12 wk after treatment initiation or rechallenge), PSMA PET response, and grades per Common Terminology Criteria for Adverse Events were assessed. χ 2 tests, multivariable Cox regression analysis, and log-rank tests were applied for statistical analyses. Results: Patients received extended treatment with [ 177 Lu]Lu-PSMA, either as a continuous treatment (43/111, 38.7%) or as a rechallenge (68/111, 61.3%) treatment, with median cumulative doses of 57.4 or 60.8 GBq, respectively. Overall survival from the initiation of [ 177 Lu]Lu-PSMA was 31.3, 23.2, and 40.2 mo for the entire cohort, the continuous treatment group, and the rechallenge treatment group, respectively. The initial 50% PSA decline was significantly higher in the retreated group than in the continuous group (57/63 [90.4%] vs. 26/42 [61.9%]; P = 0.006). A 50% PSA decline was observed in 23 of 62 patients (37.1%) after the first rechallenge. The rate of grades 3-4 toxicity was comparable between continuous and rechallenge treatments (anemia, 7/43 [16.3%] vs. 13/68 [19.1%)], P = 0.6; leukocytopenia, 1/43 [2.3%] vs. 2/67 [3.0%], P = 0.3; thrombocytopenia, 3/43 [7.0%] vs. 3/68 [4.4%], P = 0.3; renal, 2/43 [4.7%] vs. 5/68 [7.4%], P = 0.2). Conclusion: Extended therapy with [ 177 Lu]Lu-PSMA is safe and has not been associated with increased grades 3-4 toxicity. Patient candidates for extended treatment experienced a favorable median survival of 31.3 mo from the first administration. Response under [ 177 Lu]Lu-PSMA rechallenge demonstrated preserved efficacy of [ 177 Lu]Lu-PSMA after a treatment break., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: We describe the development of a molecular assay from publicly available tumor tissue mRNA databases using machine learning and present preliminary evidence of functionality as a diagnostic and monitoring tool for prostate cancer (PCa) in whole blood., Materials and Methods: We assessed 1055 PCas (public microarray data sets) to identify putative mRNA biomarkers. Specificity was confirmed against 32 different solid and hematological cancers from The Cancer Genome Atlas (n = 10,990). This defined a 27-gene panel which was validated by qPCR in 50 histologically confirmed PCa surgical specimens and matched blood. An ensemble classifier (Random Forest, Support Vector Machines, XGBoost) was trained in age-matched PCas (n = 294), and in 72 controls and 64 BPH. Classifier performance was validated in two independent sets (n = 263 PCas; n = 99 controls). We assessed the panel as a postoperative disease monitor in a radical prostatectomy cohort (RPC: n = 47)., Results: A PCa-specific 27-gene panel was identified. Matched blood and tumor gene expression levels were concordant (r = 0.72, p < 0.0001). The ensemble classifier ("PROSTest") was scaled 0%-100% and the industry-standard operating point of ≥50% used to define a PCa. Using this, the PROSTest exhibited an 85% sensitivity and 95% specificity for PCa versus controls. In two independent sets, the metrics were 92%-95% sensitivity and 100% specificity. In the RPCs (n = 47), PROSTest scores decreased from 72% ± 7% to 33% ± 16% (p < 0.0001, Mann-Whitney test). PROSTest was 26% ± 8% in 37 with normal postoperative PSA levels (<0.1 ng/mL). In 10 with elevated postoperative PSA, PROSTest was 60% ± 4%., Conclusion: A 27-gene whole blood signature for PCa is concordant with tissue mRNA levels. Measuring blood expression provides a minimally invasive genomic tool that may facilitate prostate cancer management., (© 2024 The Authors. The Prostate published by Wiley Periodicals LLC.)

To sensitively determine 99 Tc, a new method for internal quantification of its most common and stable species, [ 99 Tc]Tc O 4 - , was developed. Anion-exchange chromatography (IC) was coupled to inductively coupled plasma-mass spectrometry (ICP-MS) and equipped with an aerosol desolvation system to provide enhanced detection power. Due to a lack of commercial Tc standards, an isotope dilution-like approach using a Ru spike and called isobaric dilution analysis (IBDA) was used for internal quantification of 99 Tc. This approach required knowledge of the sensitivities of 99 Ru and 99 Tc in ICP-MS. The latter was determined using an in-house prepared standard manufactured from decayed medical 99m Tc-generator eluates. This standard was cleaned and preconcentrated using extraction chromatography with TEVA resin and quantified via total reflection X-ray fluorescence (TXRF) analysis. IC coupled to ICP-MS enabled to separate, detect and quantify [ 99 Tc]Tc O 4 - as most stable Tc species in complex environments, which was demonstrated in a proof of concept. We quantified this species in untreated and undiluted raw urine collected from a patient, who previously underwent scintigraphy with a 99m Tc-tracer, and determined a concentration of 19.6 ± 0.5 ng L -1 . The developed method has a high utility to characterize a range of Tc-based radiopharmaceuticals, to determine concentrations, purity, and degradation products in complex samples without the need to assess activity parameters of 99(m) Tc., (© 2024. The Author(s).)

Background and Objective: [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) plus the standard of care (SoC) significantly improved overall survival and radiographic progression-free survival versus SoC alone in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer in the VISION trial. We evaluated the safety of additional cycles of 177 Lu-PSMA-617 and the impact of longer observation time for patients receiving 177 Lu-PSMA-617 plus SoC., Methods: VISION was an international, open-label study. Patients were randomised 2:1 to receive 177 Lu-PSMA-617 plus SoC or SoC alone. The incidence of treatment-emergent adverse events (TEAEs) was assessed in prespecified subgroups of patients who received ≤4 cycles versus 5-6 cycles of treatment and during each cycle of treatment. The TEAE incidence was also adjusted for treatment exposure to calculate the incidence per 100 patient-treatment years of observation. This analysis was performed for the first occurrence of TEAEs., Key Findings and Limitations: The any-grade TEAE incidence was similar in cycles 1-4 and cycles 5-6. TEAE frequency was similar across all cycles of 177 Lu-PSMA-617 treatment. No additional safety concerns were reported for patients who received >4 cycles. The exposure-adjusted safety analysis revealed that the overall TEAE incidence was similar between arms, but distinct trends for different TEAE types were noted and the incidence of events associated with 177 Lu-PSMA-617 remained higher in the 177 Lu-PSMA-617 arm., Conclusions and Clinical Implications: Longer exposure to 177 Lu-PSMA-617 plus SoC was not associated with a higher toxicity risk, and the extended time for safety observation could account for the higher TEAE incidence in comparison to SoC alone. The findings support a favourable benefit-risk profile for 6 cycles of 177 Lu-PSMA-617 in this setting and the use of up to 6 cycles of 177 Lu-PSMA-617 in patients who are clinically benefiting from and tolerating this therapy., Patient Summary: For patients with metastatic prostate cancer no longer responding to hormone therapy, an increase in the number of cycles of treatment with a radioactive compound called 177 Lu-PSMA-617 from four to six had no additional adverse side effects., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: The emergence of chimeric antigen receptor (CAR) T-cell therapy fundamentally changed the management of individuals with relapsed and refractory large B-cell lymphoma (LBCL). However, real-world data have shown divergent outcomes for the approved products. The present study therefore set out to evaluate potential risk factors in a larger cohort., Methods: Our analysis set included 88 patients, treated in four German university hospitals and one Italian center, who had undergone 2-[ 18 F]fluoro-2-deoxy-D-glucose positron emission tomography (PET) before CAR T-cell therapy with tisagenlecleucel or axicabtagene ciloleucel. We first determined the predictive value of conventional risk factors, treatment lines, and response to bridging therapy for progression-free survival (PFS) through forward selection based on Cox regression. In a second step, the additive potential of two common PET parameters was assessed. Their optimal dichotomizing thresholds were calculated individually for each CAR T-cell product., Results: Extra-nodal involvement emerged as the most relevant of the conventional tumor and patient characteristics. Moreover, we found that inclusion of metabolic tumor volume (MTV) further improves outcome prediction. The hazard ratio for a PFS event was 1.68 per unit increase of our proposed risk score (95% confidence interval [1.20, 2.35], P = 0.003), which comprised both extra-nodal disease and lymphoma burden. While the most suitable MTV cut-off among patients receiving tisagenlecleucel was 11 mL, a markedly higher threshold of 259 mL showed optimal predictive performance in those undergoing axicabtagene ciloleucel treatment., Conclusion: Our analysis demonstrates that the presence of more than one extra-nodal lesion and higher MTV in LBCL are associated with inferior outcome after CAR T-cell treatment. Based on an assessment tool including these two factors, patients can be assigned to one of three risk groups. Importantly, as shown by our study, metabolic tumor burden might facilitate CAR T-cell product selection and reflect the individual need for bridging therapy., (© 2023. The Author(s).)

Purpose: To evaluate the benefit of a contrast-enhanced computed tomography (CT) radiomics-based model for predicting response and survival in patients with colorectal liver metastases treated with transarterial Yttrium-90 radioembolization (TARE)., Materials and Methods: Fifty-one patients who underwent TARE were included in this single-center retrospective study. Response to treatment was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) at 3-month follow-up. Patients were stratified as responders (complete/partial response and stable disease, n = 24) or non-responders (progressive disease, n = 27). Radiomic features (RF) were extracted from pre-TARE CT after segmentation of the liver tumor volume. A model was built based on a radiomic signature consisting of reliable RFs that allowed classification of response using multivariate logistic regression. Patients were assigned to high- or low-risk groups for disease progression after TARE according to a cutoff defined in the model. Kaplan-Meier analysis was performed to analyze survival between high- and low-risk groups., Results: Two independent RF [Energy, Maximal Correlation Coefficient (MCC)], reflecting tumor heterogeneity, discriminated well between responders and non-responders. In particular, patients with higher magnitude of voxel values in an image (Energy), and texture complexity (MCC), were more likely to fail TARE. For predicting treatment response, the area under the receiver operating characteristic curve of the radiomics-based model was 0.75 (95% CI 0.48-1). The high-risk group had a shorter overall survival than the low-risk group (3.4 vs. 6.4 months, p < 0.001)., Conclusion: Our CT radiomics model may predict the response and survival outcome by quantifying tumor heterogeneity in patients treated with TARE for colorectal liver metastases., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

[ 18 F]tetrafluoroborate ([ 18 F]TFB) is an emerging PET tracer with excellent properties for human sodium iodide symporter (NIS)-based imaging in patients with differentiated thyroid cancer (DTC). The aim of this study was to compare [ 18 F]TFB PET with high-activity posttherapeutic [ 131 I]iodine whole-body scintigraphy and SPECT/CT in recurrent DTC and with [ 18 F]FDG PET/CT in suspected dedifferentiation. Methods: Twenty-six patients treated with high-activity radioactive [ 131 I]iodine therapy (range, 5.00-10.23 GBq) between May 2020 and November 2022 were retrospectively included. Thyroid-stimulating hormone was stimulated by 2 injections of recombinant thyroid-stimulating hormone (0.9 mg) 48 and 24 h before therapy. Before treatment, all patients underwent [ 18 F]TFB PET/CT 40 min after injection of a median of 321 MBq of [ 18 F]TFB. To study tracer kinetics in DTC lesions, 23 patients received an additional scan at 90 min. [ 131 I]iodine therapeutic whole-body scintigraphy and SPECT/CT were performed at a median of 3.8 d after treatment. Twenty-five patients underwent additional [ 18 F]FDG PET. Two experienced nuclear medicine physicians evaluated all imaging modalities in consensus. Results: A total of 62 suspected lesions were identified; of these, 30 lesions were [ 131 I]iodine positive, 32 lesions were [ 18 F]TFB positive, and 52 were [ 18 F]FDG positive. Three of the 30 [ 131 I]iodine-positive lesions were retrospectively rated as false-positive iodide uptake. Tumor-to-background ratio measurements at the 40- and 90-min time points were closely correlated (e.g., for the tumor-to-background ratio for muscle, the Pearson correlation coefficient was 0.91; P < 0.001; n = 49). We found a significant negative correlation between [ 18 F]TFB uptake and [ 18 F]FDG uptake as a potential marker for dedifferentiation (Pearson correlation coefficient, -0.26; P = 0.041; n = 62). Conclusion: Pretherapeutic [ 18 F]TFB PET/CT may help to predict the positivity of recurrent DTC lesions on [ 131 I]iodine scans. Therefore, it may help in the selection of patients for [ 131 I]iodine therapy. Future prospective trials for iodine therapy guidance are warranted. Lesion [ 18 F]TFB uptake seems to be inversely correlated with [ 18 F]FDG uptake and therefore might serve as a dedifferentiation marker in DTC., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

In the VISION trial, [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) plus protocol-permitted standard of care significantly improved overall survival and radiographic progression-free survival compared with standard of care alone in patients with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer. This VISION dosimetry substudy quantified absorbed doses of 177 Lu-PSMA-617 in the kidneys and other organs. Methods: Participants were a separate cohort of 30 nonrandomized patients receiving standard of care plus 177 Lu-PSMA-617 at 7.4 GBq per cycle for up to 6 cycles. Blood samples, whole-body conjugate planar image scintigraphy, and abdominal SPECT/CT images were collected. SPECT/CT images were collected at 2, 24, 48, and 168 h after administration in cycle 1 and at a single time point 48 h after administration in cycles 2-6. Outcomes were absorbed dose per unit activity per cycle and cumulative absorbed dose over all cycles. Cumulative absorbed doses were predicted by extrapolation from cycle 1, and calculation of observed values was based on measurements of cycle 1 and cycles 2-6. Safety was also assessed. Results: Mean (±SD) absorbed doses per cycle in the kidneys were 0.43 ± 0.16 Gy/GBq in cycle 1 and 0.44 ± 0.21 Gy/GBq in cycles 2-6. The observed and predicted 6-cycle cumulative absorbed doses in the kidneys were 15 ± 6 and 19 ± 7 Gy, respectively. Observed and predicted cumulative absorbed doses were similar in other at-risk organs. Safety findings were consistent with those in the VISION study; no patients experienced renal treatment-emergent adverse events of a grade higher than 3. Conclusion: The renal cumulative absorbed 177 Lu-PSMA-617 dose was below the established limit. 177 Lu-PSMA-617 had a good overall safety profile, and low renal radiotoxicity was not a safety concern. Cumulative absorbed doses in at-risk organs over multiple cycles can be predicted by extrapolation from cycle 1 data in patients with metastatic castration-resistant prostate cancer receiving 177 Lu-PSMA-617., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Abstract: A 73-year-old man with metastatic pancreatic neuroendocrine tumor was evaluated with 68 Ga-DOTATATE PET/CT for peptide receptor radionuclide therapy. Both PET-positive and negative lesions were seen in the liver, along with extrahepatic metastases. Histopathology was obtained from one of the PET-negative liver lesions to exclude secondary malignancy. Histology confirmed a well-differentiated (G2) metastasis of pNET with high somatostatin receptor expression. We initiated peptide receptor radionuclide therapy with close monitoring of the PET-negative liver metastases. We present a rare case, where posttherapeutic scintigraphy revealed vigorous uptake of 177 Lu-DOTATATE even in the 68 Ga-DOTATATE PET-negative liver metastases. Follow-up PET/CT showed a partial response to therapy., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

223 Ra-dichloride ( 223 Ra) and 177 Lu-prostate-specific membrane antigen (PSMA) are approved treatments for metastatic castration-resistant prostate cancer (mCRPC). The safety and effectiveness of sequential use of 223 Ra and 177 Lu-PSMA in patients with mCRPC are not well described. This study aimed to evaluate 177 Lu-PSMA safety and efficacy in patients with mCRPC previously treated with 223 Ra. Methods: The radium→lutetium (RALU) study was a multicenter, retrospective, medical chart review. Participants had received at least 1 223 Ra dose and, in any subsequent therapy line, at least 1 177 Lu-PSMA dose. Primary endpoints included the incidence of adverse events (AEs), serious AEs, grade 3-4 hematologic AEs, and abnormal laboratory values. Secondary endpoints included overall survival, time to next treatment/death, and change from baseline in serum prostate-specific antigen and alkaline phosphatase levels. Results: Data were from 133 patients. Before 177 Lu-PSMA therapy, 56% (75/133) of patients received at least 4 life-prolonging therapies; all patients received 223 Ra (73% received 5-6 injections). Overall, 27% (36/133) of patients received at least 5 177 Lu-PSMA infusions. Any-grade treatment-emergent AEs were reported in 79% (105/133) of patients and serious AEs in 30% (40/133). The most frequent grade 3-4 laboratory abnormalities were anemia (30%, 40/133) and thrombocytopenia (13%, 17/133). Median overall survival was 13.2 mo (95% CI, 10.5-15.6 mo) from the start of 177 Lu-PSMA. Conclusion: In this real-world setting, 223 Ra followed by 177 Lu-PSMA therapy in heavily pretreated patients with mCRPC was clinically feasible, with no indication of impairment of 177 Lu-PSMA safety or effectiveness., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Prostate-specific membrane antigen (PSMA) is present in the proximal tubule cells of the kidneys. This results in high renal tracer uptake in PSMA-PET, which may contain useful information on renal function. As part of the evaluation for [ 177 Lu]-PSMA therapies, patients undergo PSMA-PET and additional [ 99m Tc]-mercapto-acetyltriglycine (MAG3) scintigraphy to assess renal function. Aim of this study was to evaluate estimation of renal function with [ 18 F]-PSMA-1007-PET/CT (PSMA-PET) by comparison to timely MAG3-scintigraphies., Materials and Methods: We retrospectively investigated 73 prostate cancer patients with 93 timely available PSMA-PET/CT, MAG3-scintigraphies and serum creatinine. For determination of split renal function in PSMA-PET/CT, we evaluated the relative unilateral total renal PSMA uptake, i.e. SUV mean multiplied by the renal volume (SRF PSMA-TOTAL ) and relative unilateral maximal standardized uptake value (SRF SUV ). These were compared to MAG3 split renal function (SRF MAG3 ) using Pearson correlation and receiver operating characteristics analysis. For determination of global renal function, correlation of bilateral total renal PSMA uptake with MAG3 tubular excretion rate and serum creatinine was assessed., Results: SRF MAG3 was strongly correlated with SRF PSMA-TOTAL (r= 0.872, p<0.001) and with SRF SUV (r=0.815, p<0.001). Relevant abnormalities of SRF MAG3 (unilateral renal function < 25 %) could be detected with sensitivities and specificities of 90% and 92% for SRF PSMA-TOTAL , and 80% and 95% for SRF SUV . Measures of absolute renal function were only weakly correlated with bilateral total renal PSMA uptake., Conclusion: Renal [ 18 F]-PSMA-1007 uptake allowed to quantify renal split function with good accuracy based on SRF PSMA-TOTAL or SRF SUV ., Competing Interests: Kambiz Rahbar reports receiving consultation or lectureship fees from ABX, ABX CRO, AAA, Bayer, SIRTEX and Jansen Cielag., (Thieme. All rights reserved.)

Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can easily be identified by PSMA PET imaging. Promising results with PSMA-targeted radiopharmaceutical therapy have already been obtained in early-phase studies using various combinations of targeting molecules and radiolabels. Definitive evidence of the safety and efficacy of [ 177 Lu]Lu-PSMA-617 in combination with standard-of-care has been demonstrated in patients with metastatic castration-resistant prostate cancer, whose disease had progressed after or during at least one taxane regimen and at least one novel androgen-axis drug. Preliminary data suggest that 177 Lu-PSMA-radioligand therapy (RLT) also has high potential in additional clinical situations. Hence, the radiopharmaceuticals [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T are currently being evaluated in ongoing phase 3 trials. The purpose of this guideline is to assist nuclear medicine personnel, to select patients with highest potential to benefit from 177 Lu-PSMA-RLT, to perform the procedure in accordance with current best practice, and to prepare for possible side effects and their clinical management. We also provide expert advice, to identify those clinical situations which may justify the off-label use of [ 177 Lu]Lu-PSMA-617 or other emerging ligands on an individual patient basis., (© 2023. The Author(s).)

Background Prostate-specific membrane antigen (PSMA) PET has high specificity in localizing primary tumors and metastases in patients with prostate cancer, but the individual overall survival probability is still difficult to estimate. Purpose To develop a prognostic risk score using PSMA PET-derived organ-specific total tumor volumes for predicting overall survival in patients with prostate cancer. Materials and Methods Men with prostate cancer who underwent PSMA PET/CT from January 2014 to December 2018 were evaluated retrospectively. All patients from center A were split into training (80%) and internal validation (20%) cohorts. Randomly selected patients from center B were used for external validation. Organ-specific tumor volumes were automatically quantified from PSMA PET scans by a neural network. A prognostic score was selected using multivariable Cox regression guided by the Akaike information criterion (AIC). The final prognostic risk score fitted on the training set was applied to both validation cohorts. Results A total of 1348 men (mean age, 70 years ± 8 [SD]) were included, with 918 patients in the training cohort, 230 in the internal validation cohort, and 200 in the external validation cohort. The median follow-up time was 55.7 months (IQR, 46.7-65.1 months; >4 years; 429 deaths occurred). A body weight-adjusted prognostic risk score integrating total, bone, and visceral tumor volumes obtained high C index values in the internal (0.82) and external (0.74) validation cohorts, as well as in patients with castration-resistant (0.75) and hormone-sensitive (0.68) disease. The fit of the statistical model for the prognostic score was improved compared with a model containing total tumor volume only (AIC, 3324 vs 3351; likelihood ratio test, P < .001). Calibration plots ascertained good model fit. Conclusion The newly developed risk score that included prostate-specific membrane antigen PET-derived organ-specific tumor volumes had good model fit for predicting overall survival in both internal and external validation cohorts. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Civelek in this issue.

The radium lutetium (RALU) study evaluated the feasibility of sequential α- and β-emitter use in patients with bone-predominant metastatic castration-resistant prostate cancer. Methods: This preplanned interim retrospective analysis investigated safety and survival outcomes with 177 Lu-PSMA in patients treated with prior 223 Ra. Results: Forty-nine patients were evaluated. Patients received a median of 6 223 Ra injections; 59% of patients received at least 4 177 Lu-PSMA cycles. Most (69%) patients received at least 4 life-prolonging therapies before 177 Lu-PSMA. Common Terminology Criteria for Adverse Events grade 3-4 treatment-emergent adverse events during 177 Lu-PSMA therapy and a 30-d follow-up period included anemia (18%) and thrombocytopenia (2%). Median overall survival was 12.6 mo (95% CI, 8.8-16.1 mo) and 31.4 mo (95% CI, 25.7-37.6 mo) from starting 177 Lu-PSMA or 223 Ra, respectively. Conclusion: 177 Lu-PSMA treatment was well tolerated in patients who had received prior 223 Ra. 223 Ra use before 177 Lu-PSMA is feasible and can be considered for future assessment of the optimal treatment sequence., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)