Purpose To qualitatively and quantitatively compare 18 F-flotufolastat-PET and 68 Ga-PSMA-11-PET urinary and lesion activity in a matched cohort of primary prostate cancer patients. Methods Data from patients who underwent 18 F-flotufolastat-PET or 68 Ga-PSMA‑11-PET (n=62 each) were cohort-matched by disease characteristics. An experienced nuclear medicine physician assessed radiopharmaceutical activity retained in the bladder using a three-point qualitative scale (0 [none]/1 [moderate]/2 [severe]), and conducted a semi-quantitative analysis of retention in the bladder (0mean/max ) were performed, and tumor-to-bladder ratios calculated and compared using Mann-Whitney-U-Tests. Results Overall interference from bladder activity was significantly greater with 68 Ga-PSMA-11-PET than 18 F-flotufolastat-PET (scores=0, 1 and 2 were n=47, n=10 and n=5 for 68 Ga-PSMA-11-PET, and n=60, n=2 and n=0 for 18 F-flotufolastat-PET; p =0.0006). Median bladder retention score was 2 for 68 Ga-PSMA-11-PET and 0 for 18 F-flotufolastat-PET. 18% (3/17) and 0% (0/24) of primary tumors located near the bladder could not be differentiated from bladder retention in 68 Ga-PSMA-11-PET and 18 F-flotufolastat-PET, respectively. Ureter retention was present in 21% (13/62) 68 Ga-PSMA-11-PET and 0% (0/62) 18 F-flotufolastat-PET. Twenty-three 68 Ga-PSMA-11-PET showed halo artifacts vs 4 18 F-flotufolastat-PET scans. Median SUV max in the bladder was 7.4 for 68 Ga-PSMA-11-PET and 3.3 for 18 F-flotufolastat-PET ( p <0.0001), and 14.7 and 19.7 in primary tumors, respectively ( p =0.1338). Resulting tumor-to-bladder ratios were significantly lower for 68 Ga-PSMA-11-PET ( p <0.0001). Conclusions 68 Ga-PSMA-11-PET was significantly more impacted by bladder activity than 18 F-flotufolastat-PET.

Physiological prostate-specific membrane antigen (PSMA) expression in renal proximal tubules results in radiopharmaceutical uptake in PSMA-PET, suggesting the potential to assess renal function. To evaluate split renal function derived from [18F]F-flotufolastat ([18F]F-rhPSMA-7.3) PET/CT and to systematically compare its performance with [68Ga]Ga-PSMA-11 PET/CT and the reference standard [99mTc]Tc-MAG3 scintigraphy, we retrospectively analyzed 302 patients with metastatic castration-resistant prostate cancer undergoing PSMA-PET/CT using either [18F]F-flotufolastat (n = 221) or [68Ga]Ga-PSMA-11 (n = 81), along with [99mTc]Tc-MAG3 scintigraphy, prior to PSMA radioligand therapy. SRF was calculated from PSMA-PET/CT using mean standardized uptake values and CT-derived renal volumes. SRF was calculated from [99mTc]Tc-MAG3 using standard integral analysis. SRF derived from PSMA-PET/CT ([18F]F-flotufolastat and [68Ga]Ga-PSMA-11) was correlated with split renal function obtained from [99mTc]Tc-MAG3 scintigraphy on a side-specific basis using Pearson correlation and Bland–Altman analysis. Receiver operating characteristic (ROC) analyses were performed to evaluate diagnostic performance for detecting impaired renal function (SRF ≤ 25

Glypican-3, a cell-surface proteoglycan, is overexpressed in most hepatocellular carcinomas (HCCs). Recently, the glypican-3-targeted PET tracer [68Ga]Ga-RAYZ-8009 was shown to enable noninvasive detection of HCC. This retrospective analysis evaluates the correlation between tumor uptake of [68Ga]Ga-RAYZ-8009 PET/CT and glypican-3 expression, as determined by immunohistochemistry. Methods: [68Ga]Ga-RAYZ-8009 PET/CT scans of 14 patients with histologically confirmed HCC were analyzed. Tracer uptake by HCC lesions was quantified by SUVmax and SUVmean Glypican-3 expression was assessed by immunohistochemistry using the semiquantitative H-score. Correlations between PET/CT uptake and H-score were analyzed using Spearman rank correlation. Results: Of the 14 HCC lesions analyzed, 13 were visually positive on PET, with an SUVmean ranging from 1.9 to 63.7 (median, 7.1) and SUVmax ranging from 3.9 to 147.9 (median, 17.7). One extrahepatic HCC lesion did not demonstrate uptake on PET or glypican-3 expression. A strong positive correlation was observed between tracer uptake and glypican-3 expression (SUVmean: ρ = 0.72, P = 0.0048; SUVmax: ρ = 0.71, P = 0.0058). Conclusion: [68Ga]Ga-RAYZ-8009 uptake in HCC lesions is a promising biomarker for noninvasive in vivo assessment of glypican-3 expression and may support the planning and monitoring of glypican-3-targeted therapies.

Understanding how uncertainties in physiological parameters propagate into the uncertainty of estimated absorbed doses (eADs) is desirable for optimizing individualized radiopharmaceutical therapy (RPT). In this study, we applied global sensitivity analysis (GSA) to a published whole-body physiologically-based pharmacokinetic (PBPK) model, developed using biokinetic data from 13 patients treated with [177Lu]Lu-PSMA-I&T, to identify influential parameters on the individual eAD uncertainty. Model inputs included patient-specific parameters such as receptor densities (R₀), blood flow densities (f), and release rates (λ) across relevant organs, with their uncertainties and correlations incorporated. A GSA method extended for dependent parameters (GSADPK) was employed to compute main effects (Si) and total effects (STi), with kidney and tumor eADs as the outputs of interest. Overall, kidney eADs showed lower uncertainty than tumors. For kidneys, receptor density emerged as the dominant contributor (Si, median [range] = 0.40 [0.10–0.58]), followed by blood flow density (Si = 0.27 [0.12–0.48]). In tumors, receptor density was also found as the primary determinant (Si = 0.42 [0.02–0.80]), with tumor release rate as a secondary contributor (Si = 0.04 [0.00–0.67]). These findings highlight that accurate estimation of receptor density and blood flow density could substantially reduce eAD uncertainty. By identifying the physiological parameters most critical for dose prediction, this work provides a foundation for digital twin–based frameworks.

Background Lutetium 177 (177Lu) prostate-specific membrane antigen (PSMA)-617 SPECT/CT has demonstrated promise as a response biomarker for 177Lu-PSMA-617 therapy. Purpose To predict overall survival (OS) after enzalutamide plus 177Lu-PSMA-617 using quantitative parameters at 177Lu-PSMA-617 SPECT/CT at 6 weeks, as well as prostate-specific antigen (PSA) response, in participants with metastatic castration-resistant prostate cancer. Materials and Methods This secondary analysis of the multisite prospective ENZA-p trial (August 2020-July 2022) included participants who received enzalutamide plus 177Lu-PSMA-617 (7.5 GBq). SPECT/CT was performed 24 hours after each treatment, and total tumor volume (TTV) and mean standardized uptake value were compared between the first (baseline) and second (6-week) doses. TTV complete response (CR) at SPECT/CT was defined as TTV less than 1 mL at dose 2, and deep PSA response was defined as 90% or greater PSA reduction at dose 2. Relationships between TTV CR and deep PSA response at dose 2 and OS were examined. Results This analysis included 74 men (median age, 71 years [IQR, 66-78 years]). Median follow-up was 33 months (95% CI: 28, 37). Median OS was 31 months (95% CI: 25, 33), and the 2-year survival rate was 70% (95% CI: 58, 79). Median TTV was 236 mL (IQR, 81-688 mL) at baseline and 65 mL (IQR, 12-215 mL) at 6 weeks. Median change in TTV was -57% (IQR, -89% to -38%); 4.1% (three of 74) of participants had an increase in TTV, and 16% (12 of 74) had TTV CR. Deep PSA response was seen in 63% (45 of 71) of participants. The 2-year survival rate with TTV CR was 83% (95% CI: 48, 96), versus 67% (95% CI: 54, 77) without TTV CR (hazard ratio, 0.26 [95% CI: 0.08, 0.85]; log-rank P = .02). The 2-year survival rate was 76% (95% CI: 58, 87) with deep PSA response without TTV CR (log-rank P = .05 vs TTV CR) and 54% (95% CI: 33, 71) with neither deep PSA response nor TTV CR (log-rank P = .003 vs TTV CR). Conclusion TTV CR at 177Lu-PSMA-617 SPECT/CT at 6 weeks was associated with improved OS and may be a valuable tool for treatment personalization with 177Lu-PSMA-617. ClinicalTrials.gov Identifier: NCT04419402 © RSNA, 2026 Supplemental material is available for this article. See also the editorial by Galgano and Turner in this issue.

Transarterial radioembolization (TARE) is a well-established treatment for unresectable hepatocellular carcinoma (HCC), though its effects on non-tumorous tissue remain a concern. In particular, the prognostic relevance of splenic volume changes after TARE is not fully understood. This study aimed to assess imaging-derived markers—specifically splenic volume dynamics—as predictors of disease progression. We retrospectively analyzed laboratory and imaging data from 73 patients with histologically or imaging-confirmed HCC who underwent TARE with Yttrium-90 (90Y) at our institution between January 2012 and September 2022. Inclusion criteria were age ≥ 18 years, availability of baseline and 3-month follow-up imaging, and complete clinical documentation. Patients undergoing liver resection, transplantation, or additional therapies during follow-up were excluded. A relative increase in splenic volume at 3 months was the only independent predictor of progression-free survival (PFS), yielding a ROC-AUC of 0.86 (95

311 Background: 18 F-Flotufolastat is a prostate-specific membrane antigen (PSMA)-targeting PET radiopharmaceutical approved in the US for diagnostic use in men with prostate cancer. The Phase 3 LIGHTHOUSE study (NCT04186819) assessed 18 F-flotufolastat in men with newly diagnosed prostate cancer planned for radical prostatectomy (RP) and pelvic lymph node dissection (PLND). This post-hoc descriptive analysis aimed to compare the diagnostic performance of 18 F-flotufolastat with baseline conventional imaging (CT or MRI). Methods: LIGHTHOUSE enrolled patients with newly diagnosed unfavorable intermediate-risk (UIR) to very high-risk prostate cancer. Patients underwent PET/CT 50–70 min after 18 F-flotufolastat (296 MBq ± 20%) administration. 18 F-Flotufolastat scans were evaluated by three blinded independent central readers. Patients had baseline conventional imaging with CT, MRI or bone scan, within 60 days before screening or at least 24 h before 18 F-flotufolastat PET. Baseline conventional imaging was evaluated by local read. Histopathology was used as standard of truth (SoT), with ≥ 1 PET positive lesion and one histopathological confirmed lymph node (LN) classed as true positive (TP). Study endpoints included patient-level sensitivity and specificity for the detection of pelvic LN metastases. This post-hoc descriptive analysis explored the sensitivity and specificity of baseline conventional imaging with CT and/or MRI in LIGHTHOUSE with the sensitivity and specificity reported for 18 F-flotufolastat PET among the efficacy analysis population (EAP). Results: In total, 296 patients (33% with UIR disease) underwent 18 F-flotufolastat PET followed by RP and PLND (EAP). Within the LIGHTHOUSE EAP, the majority read patient-level sensitivity for detecting pelvic LN metastasis with 18 F-flotufolastat was 24% (23–30% across readers) and specificity was 96% (93–97% across readers). Comparatively, among the subset of patients who had baseline CT and/or MRI scans available (N=267), the majority read patient-level sensitivity and specificity for 18 F-flotufolastat were 23% (22–29% across readers) and 96% (93–97% across readers), respectively. Notably lower sensitivity values were observed for baseline conventional imaging – for CT and/or MRI, the patient-level sensitivity was 3% (CT, 4%; MRI, 0%) and specificity was 95% (CT, 95%; MRI, 93%; N=267). Conclusions: This post-hoc analysis demonstrated the superior sensitivity of 18 F-flotufolastat PET compared with baseline conventional CT or MRI for the detection of pelvic LN metastasis. The very low sensitivity of conventional imaging (3%) highlights that detection of pelvic LN metastasis in the population enrolled in the LIGHTHOUSE study is highly challenging. Clinical trial information: NCT04186819 .

We aimed to assess the prognostic value of [18F]flotufolastat PET in patients with metastatic prostate cancer during taxane-based chemotherapy (CTx). Methods: In total, 69 patients who received CTx as well as baseline and follow-up [18F]flotufolastat PET/CT scans were included. Imaging response was assessed by visual RECIP 1.0 dichotomized into progressive disease (PD) and non-PD. Biochemical response was defined as a prostate-specific antigen decrease of greater than 50% (castration-resistant) or a decline to less than 0.2 ng/mL (hormone-sensitive). Kaplan-Meier analysis was performed regarding overall survival, and the Harrell concordance index was calculated. Results: Patients with PD showed a significantly shorter median overall survival of 12 mo (95% CI, 8.3 mo to not reached) compared with non-PD (45 mo; 95% CI, 37 mo to not reached). The Harrell concordance index for RECIP (0.84; 95% CI, 0.72-0.97; P < 0.001) was higher than biochemical response (0.66; 95% CI, 0.49-0.84; P = 0.07). Conclusion: [18F]flotufolastat PET assessed using visual RECIP has high prognostic utility in patients with metastatic prostate cancer undergoing CTx.

5020 Background: In the phase 3 PSMAddition study (NCT04720157), combining [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) with ADT + ARPI significantly improved rPFS in patients with PSMA+ mHSPC vs ADT + ARPI at rPFS interim analysis (data cut off Jan 13, 2025), with a HR of 0.72 (95% CI 0.58, 0.90; p = 0.002). Methods: Patients had treatment-naive/minimally treated mHSPC diagnosed by CT/MRI/bone scan and ≥1 PSMA+ metastatic lesion on [ 68 Ga]Ga-PSMA-11 PET/CT. Patients were randomized 1:1 to 177 Lu-PSMA-617 (7.4 GBq ± 10% q6w, 6 cycles) + ADT + ARPI ( 177 Lu-PSMA-617 arm) or ADT + ARPI (control arm). The primary endpoint of rPFS (centrally assessed rPD per PCWG3/RECIST v1.1 or death) and selected secondary efficacy, safety, and patient-reported outcomes (PROs) were assessed in subgroups of high/low disease volume (DV) per CHAARTED criteria (locally assessed by CT/MRI/bone scan; prespecified) and de novo /recurrent mHSPC (AJCC stage ≥/post hoc ) . Results: Of 572 patients randomized to the 177 Lu-PSMA-617 arm and 572 to the control arm, 68.0% and 68.2% had high DV, and 52.1% and 47.9% had de novo mHSPC. Efficacy and PRO HRs for the 177 Lu-PSMA-617 arm vs control arm were generally similar in the overall population and DV and mHSPC subgroups (rPFS HR 0.72–0.74; time to PSA progression HR 0.29–0.51) (Table). Incidences of AEs, grade ≥3 AEs, serious AEs, and selected safety topics of interest (cytopenias, dry mouth) were similar across subgroups within each treatment arm. Conclusions: In patients with PSMA+ mHSPC, combining 177 Lu-PSMA-617 with ADT + ARPI improved rPFS vs ADT + ARPI across high/low DV and de novo /recurrent mHSPC subgroups. Other efficacy outcomes, PROs, and the safety profile were generally consistent across subgroups. Clinical trial information: NCT04720157 . Efficacy and PROs. HR (95% CI) for 177 Lu-PSMA-617 arm vs control arm OverallN = 1144 High DVn = 779 Low DVn = 365 De novo mHSPCn = 572 Recurrent mHSPCn = 523 rPFS a 0.72 (0.58, 0.90) 0.72 (0.56, 0.92) 0.73 (0.42, 1.27) 0.74 (0.54, 1.01) 0.74 (0.53, 1.04) PFS per investigator b 0.64 (0.51, 0.79) 0.61 (0.48, 0.78) 0.80 (0.46, 1.37) 0.65 (0.48, 0.88) 0.64 (0.46, 0.89) Time to: PSA progression 0.42 (0.30, 0.59) 0.43 (0.31, 0.62) 0.29 (0.08, 1.05) 0.51 (0.32, 0.79) 0.35 (0.21, 0.60) Symptomatic skeletal event 0.89 (0.62, 1.26) 0.93 (0.64, 1.37) 0.67 (0.27, 1.66) 0.97 (0.60, 1.57) 0.82 (0.48, 1.40) mCRPC 0.70 (0.58, 0.84) 0.67 (0.54, 0.82) 0.87 (0.55, 1.37) 0.61 (0.47, 0.80) 0.75 (0.56, 1.00) BPI-SF pain intensity worsening c 1.02 (0.87, 1.18) 0.98 (0.82, 1.18) 1.09 (0.83, 1.44) 1.06 (0.85, 1.31) 0.97 (0.78, 1.22) FACT-P total score worsening c 1.14 (0.98, 1.33) 1.13 (0.94, 1.37) 1.16 (0.88, 1.53) 1.13 (0.90, 1.41) 1.16 (0.92, 1.46) EQ-5D-5L worsening c 1.13 (0.97, 1.31) 1.04 (0.87, 1.25) 1.34 (1.01, 1.77) 1.17 (0.93, 1.45) 1.09 (0.87, 1.37) N may differ across outcomes. a rPD by BIRC or death. b Composite of radiographic, clinical, and PSA progression and death. c Composite with clinical progression and death.

Systematic transrectal ultrasound-guided biopsy lacks accuracy in the primary diagnosis of prostate cancer (PCa) and causes side effects. We investigated prostate-specific membrane antigen (PSMA)-targeted PET/MRI as a less-invasive alternative for biopsy guidance and risk assessment. Methods: The RAPID study was a randomized, controlled, single-center, open-label phase 3 trial comparing the diagnostic efficacy of 68Ga-PSMA-11 PET/MRI with systematic transrectal ultrasound-guided prostate biopsy. In total, 220 men with suspected PCa were randomized to either a standard (random 12-core biopsy; RB) group or an image-guided biopsy (IGB) group. Biopsy, prostatectomy histology, and follow-up visits served as references. Results: PET/MRI prospectively predicted 91 of 113 histologically verified tumors, corresponding to a sensitivity of 80.5% and a positive predictive value of 84.3%. Among tumors characterized as ISUP GG of 3 or greater (n = 60), PSMA PET/MRI prospectively detected 95% (n = 57). The IGB group demonstrated slightly higher sensitivity, specificity, positive predictive value, and negative predictive value compared with the RB group (79.3%, 94.7%, 85.2%, 92.2% vs. 74.2%, 88.0%, 71.9%, 89.2%). Seventy-nine patients were eligible for a direct IGB and RB subanalysis, with IGB detecting 15 additional cases. PET/MRI showed high specificity (94%) and negative prediction (86%) for tumor aggressiveness. In a median follow-up period of 3 y, an aggressive course of disease was detected in 25 of 199 patients. RB correlation identified 24 patients with an ISUP GG of 3 or greater with aggressive disease development during follow-up, compared with 23 patients identified by PET/MRI. Negative prediction of both methods was comparably high at 99%; however, PET/MRI overestimated fewer patients (21) as aggressive compared with RB (34). Conclusion: PSMA-targeted PET/MRI-guided biopsy is a reliable, less invasive method for detecting and characterizing PCa in a cohort with moderately increased PSA values, potentially reducing unnecessary biopsies and provides a reliable prognosis of the course of disease. These results support the integration of modern imaging techniques into clinical practice to improve the treatment of PCa.

To investigate the potential of a second 18F-flotufolastat positron emission tomography (PET) scan in patients with suspected biochemical recurrence (BCR) of prostate cancer (PCa) who had a previous negative 18F-flotufolastat PET, and to identify prostate-specific antigen (PSA) parameters influencing detection efficacy. Our retrospective analysis included data from patients who underwent second 18F-flotufolastat PET between 2019 and 2024, following negative 18F-flotufolastat PET for suspected BCR of PCa (PSA ≥ 0.2 ng/mL) after radical prostatectomy. Two board-certified experts classified 18F-flotufolastat-avid lesions per miTNM categories. Patient-level detection rates were stratified by: pre-PET scan PSA; absolute/relative difference in PSA (ΔPSA) between negative first and second PET; PSA velocity (PSAvel); PSA doubling time (PSAdt). Receiver operating characteristic (ROC) curve analyses were performed. Of 101 patients (median age = 70 years; median PSA = 0.79 ng/mL), 58 (57

This study aimed to estimate the diagnostic accuracy and stage migration of [18F]PSMA-1007 PET/CT and its impact on patient management when compared with [18F]NaF PET/CT for primary staging of prostate cancer (PCa). Methods: In a substudy of the PRISMA-PET trial (EudraCT 2021-000123-12), patients with intermediate- and high-risk primary PCa were clinically staged using [18F]PSMA-1007 PET/CT with contrast-enhanced CT (ceCT). A masked [18F]NaF PET/CT was also performed for research purposes only. A research-focused multidisciplinary team (rMDT) conference was then conducted, beginning with the presentation of patient data. [18F]NaF PET/CT and ceCT results were presented, with masked results from the [18F]PSMA-1007 PET/CT, and stage and treatment decisions were made by consensus. Subsequently, the [18F]PSMA-1007 PET/CT results were reviewed, and the decisions were reconsidered. Final rMDT decisions, incorporating all imaging and available histology results, formed the composite reference standard. Diagnostic accuracy, stage migration, and treatment decision were compared. Treatment decisions made by the rMDT were compared with the clinical treatment decisions made. Results: In total, 128 men (median age, 72 y) were included in this study. Of these, 25 (19.5%) had intermediate-risk PCa and 103 (80.5%) had high-risk PCa. Our results revealed significantly higher accuracy in diagnosing lymph node metastases with [18F]PSMA-1007 PET/ceCT compared with ceCT with [18F]NaF PET/CT (P = 0.021). There was no significant difference for diagnosing bone metastases. Stage migration was observed in 22 patients (17%); 15 (12%) were upstaged and 7 (5%) downstaged. Treatment management changed for 18 patients (14%): 5 had altered curative strategy but the intent remained curative, 8 shifted from curative to life-prolonging treatment, 2 moved from life-prolonging to curative treatment, and 3 had adjustments within life-prolonging strategies. Forty patients received treatment that deviated from the rMDT decision. Conclusion: Staging PCa with [18F]PSMA-1007 PET/CT versus [18F]NaF PET/CT led to stage migration for 17% of patients and treatment management change for 14% of patients. Follow-up results from the PRISMA-PET trial will clarify the impact on patient outcomes.

Although tumor volume and new lesions (NLs) have been investigated previously as measures of response, the clinical impact of changes in tumor uptake on prostate-specific membrane antigen (PSMA) PET remains largely unknown. Methods: This multicenter retrospective study investigated the clinical impact of changes in tumor uptake and volume on PSMA PET during [177Lu]Lu-PSMA in metastatic castration-resistant prostate cancer (mCRPC). The primary outcomes were the associations of changes in SUVmax (ΔSUVmax) and SUVmean (ΔSUVmean), changes in total tumor volume (ΔTTV), and occurrence of NLs with prostate-specific antigen (PSA) progression-free survival (PSA-PFS) and overall survival (OS). The study included patients with mCRPC who received [177Lu]Lu-PSMA between 2014 and 2019. PSMA PET/CT was performed at baseline and after 2 cycles of therapy. Whole-body analyses (SUVmax, SUVmean, TTV, and NLs) were performed and calculated using qPSMA software. Results: In total, 124 patients with mCRPC (median age, 73 y; interquartile range, 67-76 y) were included in the study. Whole-body ΔTTV and the occurrence of NLs were significantly associated with shorter PSA-PFS (hazard ratio [HR], 5.7; 95% CI, 3.59-9.06; and HR, 1.6; 95% CI, 1.4-1.8; P < 0.0001) and with OS (HR, 2.3; 95% CI, 1.61-3.43; and HR, 1.3; 95% CI, 1.1-1.4; P < 0.001). Patient-based analysis showed that ΔSUVmax and ΔSUVmean were not associated with outcome (HR, 1.00; 95% CI, 0.99-1.00; P = 0.30; and HR, 0.90; 95% CI, 0.99-1.00; P = 0.11). Region-based analysis found that only ΔSUVmax in visceral lesions was significantly associated with PSA-PFS (P = 0.007) but not with OS. Conclusion: Only ΔTTV and the occurrence of NLs provided significant prognostic value and should be considered when evaluating treatment response to [177Lu]Lu-PSMA therapy.

In the VISION trial, [177Lu]Lu-PSMA-617 (177Lu-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 177Lu-PSMA-617 in the kidneys and other organs. Methods: Participants were a separate cohort of 30 nonrandomized patients receiving standard of care plus 177Lu-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 177Lu-PSMA-617 dose was below the established limit. 177Lu-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 177Lu-PSMA-617.

Introduction Single-time-point (STP) dosimetry is practical for clinical routine but remains limited by population-based kinetic assumptions and strict late imaging time points. This study introduced a deep learning (DL) method for voxel-wise adjustment of STP dosimetry in 177Lu-PSMA radiopharmaceutical therapy (RPT), aiming to improve accuracy and scan-time flexibility. Methods A total of 317 post-therapeutic SPECT/CT scans from 21 patients with metastatic castration-resistant prostate cancer (mCRPC) receiving multiple cycles of [177Lu]Lu-PSMA-617 RPT were included. A decomposition-based DL model was developed to predict a voxel-wise scaling factor map from single-time-point SPECT/CT. The predicted map was multiplied with the quantified SPECT and a learned polynomial of imaging time to generate the corrected TIA map. Ground-truth TIA maps were generated using voxel-wise integrals of time-activity curves fitted by sums of exponential functions. Patient-wise five-fold cross-validation and comparative experiments were performed. Generalization was evaluated using an external dataset of 23 patients with mCRPC receiving [177Lu]Lu-PSMA-I&T RPT. Results Across all test data (n = 317), the average voxel-wise normalized root-mean-square errors were within 15.0% for all evaluated organs and tumors, with a global structural similarity of 0.9691. Using 24h SPECT/CT (n = 81), the method achieved mean absolute percentage errors of 17.9% ± 16.5% for kidneys, 15.8% ± 13.4% for liver, 21.0% ± 28.8% for spleen, 20.6% ± 18.2% for bone marrow, and 26.5% ± 19.1% for tumors. The MAPEs generally decreased with later imaging, reaching 10.3% ± 9.1% (kidneys), 10.2% ± 7.8% (liver), 21.3% ± 12.9% (spleen), 11.1% ± 8.7% (bone marrow), and 13.3% ± 11.2% (tumors) at 72h (n = 49). On the external dataset, the lowest MAPEs were 18.6% ± 12.0% for liver and 23.7% ± 20.9% for spleen at 24h, and 12.6% ± 14.4% for kidneys and 20.2% ± 12.2% for bone marrow at 48h. Conclusion The decomposition-based DL method enabled voxel-wise correction of STP dosimetry at time points including 24h, 48h, and 72h post injection, improved scan-time flexibility, and demonstrated the technical feasibility of instant STP dosimetry.

This study aimed to estimate the diagnostic accuracy and stage migration of [18F]PSMA-1007 PET/CT and its impact on patient management when compared with [18F]NaF PET/CT for primary staging of prostate cancer (PCa). Methods: In a substudy of the PRISMA-PET trial (EudraCT 2021-000123-12), patients with intermediate-and high-risk primary PCa were clinically staged using [18F]PSMA-1007 PET/CT with contrast-enhanced CT (ceCT). A masked [18F]NaF PET/CT was also performed for research purposes only. A research-focused multidisciplinary team (rMDT) conference was then conducted, beginning with the presentation of patient data. [18F]NaF PET/CT and ceCT results were presented, with masked results from the [18F]PSMA-1007 PET/CT, and stage and treatment decisions were made by consensus. Subsequently, the [18F]PSMA-1007 PET/CT results were reviewed, and the decisions were reconsidered. Final rMDT decisions, incorporating all imaging and available histology results, formed the composite reference standard. Diagnostic accuracy, stage migration, and treatment decision were compared. Treatment decisions made by the rMDT were compared with the clinical treatment decisions made. Results: In total, 128 men (median age, 72 y) were included in this study. Of these, 25 (19.5%) had intermediate-risk PCa and 103 (80.5%) had high-risk PCa. Our results revealed significantly higher accuracy in diagnosing lymph node metastases with [18F]PSMA-1007 PET/ceCT compared with ceCT with [18F]NaF PET/CT (P 5 0.021). There was no significant difference for diagnosing bone metastases. Stage migration was observed in 22 patients (17%); 15 (12%) were upstaged and 7 (5%) downstaged. Treatment management changed for 18 patients (14%): 5 had altered curative strategy but the intent remained curative, 8 shifted from curative to life-prolonging treatment, 2 moved from life-prolonging to curative treatment, and 3 had adjustments within life-prolonging strategies. Forty patients received treatment that deviated from the rMDT decision. Conclusion: Staging PCa with [18F]PSMA-1007 PET/CT versus [18F]NaF PET/CT led to stage migration for 17% of patients and treatment management change for 14% of patients. Follow-up results from the PRISMA-PET trial will clarify the impact on patient outcomes.

This retrospective analysis aimed to evaluate the diagnostic performance of 18F-flotufolastat PET/MRI for the detection of clinically significant prostate cancer (csPCa). The primary objective of the study was to assess the proportion of patients for whom a prostate biopsy could be safely circumvented by combining the Prostate Imaging Reporting and Data System (PI-RADS) from multiparametric MRI and quantitative data from PET. Methods: This study included 79 patients with suspicion of csPCa based on elevated prostate-specific antigen (>4 ng/mL) who underwent 18F-flotufolastat PET/MRI before biopsy or surgical resection of the prostate. Analytic methods included receiver operating characteristic analysis, logistic regression, and threshold-based evaluation of PI-RADS and of SUVmax Imaging findings were compared against histopathology. Results: csPCa (International Society of Urological Pathology grade group ≥ 2) was confirmed in 42 patients, whereas histopathology excluded csPCa in 37 patients. The combination of PI-RADS and SUVmax resulted in an area under the curve (AUC) of 87.1%, outperforming PI-RADS alone (AUC of 75.2%) and SUVmax alone (AUC of 80.7); however, differences were not statistically significant. A PI-RADS score of at least 3 and 18F-flotufolastat PET showed comparable sensitivity (0.90 vs. 0.91) and specificity (0.42 vs. 0.32) in the detection of csPCa, when applying a low SUVmax threshold (>4.5). Using a high SUVmax threshold (>10.0) increased the specificity of 18F-flotufolastat PET to 100%. Furthermore, combined PET/MRI increased the number of patients for whom csPCa can be reliably diagnosed to 28%, as well as increasing to 29% the number of patients for whom csPCa can be ruled out with a very high degree of certainty. Conclusion: This retrospective analysis suggests that prostate-specific membrane antigen PET/MRI can stratify patients with suspected prostate cancer into 3 groups: one with a very high likelihood of csPCa who may undergo definitive therapy without biopsy, one with a very low risk for csPCa who may not require biopsy, and an indeterminate group who still need biopsy. Overall, in our cohort, prostate biopsy would have been avoided in 57% of patients. Therefore, there is an urgent need for prospective studies on prostate-specific membrane antigen PET/MRI to reduce the number of unnecessary biopsies in men with suspected prostate cancer.

This is a dosimetry analysis of the prospective randomized phase 2 trial RESIST-PC which evaluated the efficacy and safety of 2 injected activity regimens of [177Lu]Lu-PSMA-617 in patients with progressive metastatic castration-resistant prostate cancer. Methods: This biinstitutional study randomized patients with metastatic castration-resistant prostate cancer to receive either 6.0 or 7.4 GBq of [177Lu]Lu-PSMA-617 per cycle for up to 4 cycles (1:1 randomization). The γ-images were obtained at the first cycle using a hybrid protocol (planar + SPECT). Whole-body planar scintigraphy images were acquired at 4, 24, 48, and 72 h (optionally at 168 h), and a quantitative SPECT/CT was performed at 24 h postinjection. Absorbed doses (ADs) were calculated for the kidneys, salivary glands, liver, and tumors. Planar time-activity curves were derived on a per-region basis from counts in the serial scans, with exponential curve fit selection based on Akaike information criterion. Quantitative SPECT data per region were scaled by the planar time-activity data and then convolved with a voxel-S value dose kernel to yield AD estimates. No partial volume corrections were applied. Adverse events and efficacy data were correlated to the calculated AD. Results: A total of 48 of 64 patients (16 treated with 6.0 GBq vs. 32 in the 7.4-GBq arm) had complete imaging datasets and were analyzed. The mean kidney, submandibular, parotid, and liver ADs were 0.29 ± 0.11, 0.23 ± 0.18, 0.26 ± 0.15, and 0.11 ± 0.09 Gy/GBq, respectively. There was no significant difference in organ or tumor ADs between arms. In total, 358 lesions were included in the analysis (median, 7/patient [range, 0-18/patient]). The mean AD to bone lesions (n = 304) was 1.90 ± 1.83 and 1.64 ± 1.77 Gy/GBq for the 6.0-GBq (n = 121) and 7.4-GBq (n = 183) groups, respectively. For lymph node lesions (n = 35), mean ADs were 5.61 ± 3.93 Gy/GBq (n = 22) and 1.79 ± 1.96 Gy/GBq (n = 13) for the 6.0- and 7.4-GBq groups, respectively. Only the 7.4-GBq cohort presented liver lesions; mean AD was 1.59 ± 1.45 Gy/GBq (n = 19). A statistically significant inverse correlation was observed between prostate-specific antigen response and tumor AD (ρ = -0.404, P = 0.006). Conclusion: In the RESIST-PC prospective phase 2 trial, dosimetry analyses using a hybrid imaging protocol revealed organ ADs within tolerable ranges, and tumor ADs varied widely on the inter- and intrapatient level regardless of injected activity.

To compare changes in estimated glomerular filtration rate (eGFR) following Lutetium-177 prostate-specific membrane antigen I T radioligand therapy (177Lu-PSMA I T) and docetaxel chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). This retrospective multicenter analysis included 145 patients treated with 177Lu-PSMA I T and 39 patients treated with docetaxel. Inclusion required ≥ 4 cycles of 177Lu-PSMA I T or ≥ 10 docetaxel administrations and ≥ 12 months of eGFR follow-up. Docetaxel patients were excluded if 177Lu-PSMA I T was initiated within 12 months after therapy initiation. Patients were stratified by treatment sequence (docetaxel only, pre-chemo and post-chemo 177Lu-PSMA I T). Linear mixed models (LMM) assessed longitudinal eGFR changes with adjustment and matching for baseline renal risk factors (arterial hypertension, diabetes mellitus, age ≥ 65 years, prior platinum-based chemotherapy). Median age (interquartile range, IQR) was 75.0 (67.0–77.0) years in the docetaxel group, 81.5 (77.5–87.0) years in the pre-chemo 177Lu-PSMA I T subgroup (n = 58), and 75.5 (71.0–78.3) years in the post-chemo 177Lu-PSMA I T subgroup (n = 87). Mean eGFR declined over time in both pre- and post-chemo 177Lu-PSMA I T subgroups compared with docetaxel-treated patients, with significant differences emerging earlier in the pre-chemo subgroup (from 3 months) and later in the post-chemo subgroup (from 12 months), persisting through follow-up. At 12 months, severe eGFR decline (≥ 30