BACKGROUND:For over a decade the Advanced Prostate Cancer Consensus Conference (APCCC) covers a variety of topics that greatly impact daily practice. In 2025, a dedicated event was organised to discuss key questions in clinical management of patients with prostate cancer (PC) related to diagnostic tools (APCCC Diagnostics). Here we present the voting results of the APCCC Diagnostics questions. OBJECTIVE; DESIGN, SETTING, AND PARTECIPANTS: APCCC Diagnostics 2025 is a pilot project. The scientific committee for APCCC Diagnostics 2025 developed 88 multiple-choice consensus questions on six different topics. Prior to the conference, the panel members (''panellists'') voted on these questions via a web-based survey. Consensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS:Consensus was only reached on 17 of 88 questions (19%), of which six (7%) received a strong consensus. Specifically, consensus was reached for two of 17 questions (14%) in "how to diagnose PC"; seven of 16 (44%) in "how to stage PC"; three of 14 (21%) in "Biochemical Recurrence Scenario"; two of 11 (18%) in "metastatic disease: what to do?"; zero of 18 (0%) in "monitoring metastatic PC"; and three of 12 (25%) in "radioligand therapy and imaging." CONCLUSIONS:The voting results and their discussion may assist physicians in navigating controversial areas of clinical management related to diagnosis, staging, and restaging in the different clinical settings for PC, particularly where high-level evidence is scarce or conflicting. The findings can also help funders and policymakers in prioritising areas for future research.

Zusammenfassung Bei Patienten mit metastasiertem Prostatakrebs wird das Ansprechen auf die Behandlung derzeit überwiegend mit Hilfe konventioneller Bildgebung bewertet. Aktuelle Studien belegen den Wert der PSMA-Liganden-PET für die Beurteilung des Ansprechens. In aktuellen Veröffentlichungen wurden die PSMA-PET-Progressionskriterien (PPP) und die Response Evaluation Criteria In PSMA-imaging (RECIP) 1.0 für eine standardisierte Beurteilung des Ansprechens definiert. Während sich PPP auf das Auftreten neuer Läsionen oder einer biochemischen bzw. klinischen Progression stützt, bewertet RECIP neue Läsionen zusammen mit Veränderungen des gesamten PSMA-Tumorvolumens. Beide Systeme sollten zur klinischen Validierung in zukünftigen prospektiven Studien eingebunden werden.

162 Background: Clinical trial conduct in advanced prostate cancer has changed dramatically with the continued development of new imaging approaches, molecular phenotypes and genetic subtypes, prognosis assessments, and effective therapies across a range of disease states. This created a need to redefine terminology and best practices for clinical trials. Methods: We convened PCWG4, an international expert committee of multidisciplinary working groups, between 2016 and 2025 to update and expand PCWG2-3 recommendations based on emerging evidence and clinical trial data in an innovative biomarker and imaging context to provide guidance for clinical trial design, eligibility, and endpoint assessments. Results: PCWG4 redefines terminology around disease states and prior therapies in a patient-centric context, considering imaging modalities, with a particular focus on PET-defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, imaging and non-imaging-based responses. We define delay/prevent endpoints including responses by pathology, ctDNA, circulating tumor cells, and PSA declines, and specify intervals for re-assessments including imaging, biomarker assessments, and patient reported outcomes. We propose new imaging-specific rPFS criteria including guidance with serial PSMA PET/CT imaging (Table). We provide recommendations in a biomarker-based context for the indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. Conclusions: PCWG4 expands guidance on patient and tumor profiling, as well as therapy development, to include both androgen deprivation therapy sensitive and resistant settings, reflecting today’s more heterogeneous and diverse patient population to optimize outcomes. PCWG4-defined radiographic progression by imaging modality for patients with metastatic disease. Pretreatment Scan On-treatment Scan #1(≥week 8) On-treatment Scan #2 All Subsequent Scans Bone scintigraphy Comparator Comparator for subsequent scansPOD never called here POD:PCWG3 criteria (2+2 additional new lesions) POD:≤5 new lesions: PCWG3 criteria 2 new lesions confirmed≥6 new lesions CT/MRI Any measurable disease Comparator PCWG3/RECIST PCWG3/RECIST PCWG3/RECIST PSMA PET Bones, and lymph nodes and lung metastases (non-RECIST qualifying by + on PET only) Comparator POD:≤5 new lesions: 2 new lesions confirmed on a subsequent scan≥6 new lesions Same as prior Same as prior Liver and non-pulmonary viscera Comparator POD:Any single new lesion that represents disease Same as prior Same as prior

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas that can develop either de novo or as a result of malignant transformation of neurofibromas. Diagnostic modalities of choice, such as MRI or 18F-FDG PET/CT, show high sensitivity for the detection of MPNSTs but moderate specificity, as MPNSTs and benign peripheral nerve sheath tumors (BPNSTs) can initially present similar clinical and radiologic pictures. PET/CT with 68Ga-labeled fibroblast activation protein inhibitor (68Ga-FAPI) showed specific uptake in sarcomas and enabled differentiation of benign and malignant lesions in other entities. Here, we analyzed the ability of 68Ga-FAPI PET/CT to differentiate between MPNSTs and BPNSTs. Methods: Twenty-six patients with suspected or histologically confirmed peripheral nerve sheath tumors who were scheduled to have surgical resection/biopsy underwent 68Ga-FAPI-46 PET/CT with static and dynamic acquisition. SUVmax, SUVmean, maximum and mean tumor-to-background ratios, and time-activity curves were evaluated using volume-of-interest-based analysis (isocontour 50%). Time to peak was derived from time-activity curves. Statistical analyses were performed, and receiver-operating-characteristic curves were calculated. Exemplary target validation by fibroblast activation protein immunohistochemistry was performed in 13 cases. Results: Eighteen patients (4 with MPNSTs, 5 with neurofibromas, 9 with schwannomas) were included in the final analysis. MPNSTs showed significantly higher 68Ga-FAPI uptake compared with BPNSTs. Neurofibromas showed higher 68Ga-FAPI uptake compared with schwannomas. In dynamic imaging, time to peak of MPNSTs and neurofibromas was prolonged compared with schwannomas. Analysis of receiver-operating-characteristic curves displayed high sensitivity (100%) and specificity (92.86%) of 68Ga-FAPI PET/CT for discrimination of MPNSTs and BPNSTs, for an exploratory SUVmax cutoff value of 7.53. Fibroblast activation protein expression was strong in MPNSTs and moderate in BPNSTs. Conclusion: 68Ga-FAPI PET/CT may aid in differentiating between MPNSTs and BPNSTs, thereby improving lesion characterization in indeterminate MRI or 18F-FDG PET/CT scenarios.

Somatostatin receptor (SSTR)-targeting radiotracers hold promise for theranostic applications in breast cancer (BC). This retrospective single-center study aimed to assess the proportion of SSTR-positive BC and its relevance for peptide receptor radionuclide therapy. SSTR-agonist- and SSTR-antagonist-based PET tracers are compared. Methods: Patients with BC who underwent PET imaging with SSTR agonist [68Ga]Ga-DOTATOC or SSTR antagonist [68Ga]Ga-SSO120 (February 2023 to February 2025) for initial or follow-up staging were included. All patients underwent [18F]FDG PET, which was used as the reference standard. Mean administered activities and uptake times were 88 MBq for 64 min with [68Ga]Ga-DOTATOC and 131 MBq for 66 min with [68Ga]Ga-SSO120, respectively. PET-positive lesions were reported in 6 anatomic categories. Tumors were segmented; SUVs, tumor-to-liver ratios, and tumor volumes were calculated. Time to progression stratified by SSTR expression was assessed using the log-rank test. Results: In total, 37 patients with BC (26 estrogen-receptor [ER]-positive, 11 triple negative [TN]) were identified; final analysis was limited to 30 patients after excluding 7 with no detectable tumor. Most had metastatic disease (M1) at staging (26/36). On the patient level, SSTR-positive tumor (≥1 lesion) was detected in 80% of ER-positive BC (16/20) and in 50% of patients with TNBC (5/10). In ER-positive disease, positivity was comparable for [68Ga]Ga-DOTATOC (85%) and [68Ga]Ga-SSO120 (71%), whereas in TNBC, positivity was observed with [68Ga]Ga-DOTATOC (83%) only. On the region level, 60% (31/52) of [18F]FDG-positive regions in ER-positive BC and 33% (7/21) in TNBC were SSTR-positive. Region-based mean SUVmax was generally lower with SSTR imaging: 7.2 ± 3.4 versus 9.3 ± 4.3 ([68Ga]Ga-DOTATOC vs. [18F]FDG) and 4.5 ± 1.4 versus 8.1 ± 3.2 ([68Ga]Ga-SSO120 vs. [18F]FDG) in ER-positive BC and 4.1 ± 0.6 versus 19.8 ± 3.3 ([68Ga]Ga-DOTATOC vs. [18F]FDG), with absent [68Ga]Ga-SSO120 uptake in patients with TNBC. One patient reached a Krenning score of 3, indicating technical eligibility for peptide receptor radionuclide therapy. SSTR positivity did not correlate with time to progression. Conclusion: SSTR may serve as a promising radiotheranostic target in a small subset of patients with advanced metastatic ER-positive BC. Tumor uptake was mostly moderate, without substantial difference between [68Ga]Ga-DOTATOC and [68Ga]Ga-SSO120. For imaging, [18F]FDG PET outperformed [68Ga]Ga-SSTR PET in patients with ER-positive BC and TNBC.

3068 Background: The role of adjuvant radioiodine therapy (RIT) in differentiated thyroid carcinoma (DTC) remains controversial due to a lack of long-term data from randomized controlled trials. Consequently, international guidelines diverge; while some advocate broad application, others prioritize a restrictive, risk-adapted approach. The CLERAD-PROBE trial aims to bridge this gap by comparing both strategies regarding blood dose — as an established surrogate for secondary malignancy risk — and oncological outcomes. Methods: CLERAD-PROBE is a prospective, randomized, bicentric study (NCT01704586) in adult DTC patients, excluding those with unifocal papillary microcarcinomas ≤ 10 mm limited to the thyroid. Following thyroidectomy, patients in Arm 1 underwent I-124 PET for staging and dosimetry. Adjuvant RIT was administered if one or multiple of the following risk factors were present: incomplete surgical resection, tumor size >4cm or extrathyroidal extent, lymph node metastases and age ≥ 45 years, distant metastases, and/or iodine-avid lesions on I-124 PET. In Arm 2, adjuvant RIT was generally performed. Follow-up was performed every 4–6 months using thyroglobulin measurements and cervical ultrasound. The primary endpoint was the mean blood dose after complete remission or 18 months. Secondary endpoints included progression- and recurrence-free survival at 3 and 10 years. Results: The primary endpoint was evaluable in 315 patients, enrolled from May 2015 to May 2021 (148 in Arm 1, 167 in Arm 2). Study arms were matched with regards to histology, age, and tumor/nodal stage, though Arm 1 had significantly fewer men (22% vs. 34%, p = 0.02). I-124 PET identified lymph node metastases in 49 patients and distant metastases in 13 patients. RIT was performed in 68 of 148 (46%) patients in Arm 1. Of these, 13 patients with low-risk carcinoma underwent RIT because of new metastases found on I-124 PET. The mean absorbed blood doses (252 mGy vs 447 mGy, range: 4 - 3217 mGy vs. 48 - 2520 mGy; p < 0.001) and administered I-131-activities (2.3 GBq vs. 4.9 GBq; range: 0 – 18.6 GBq vs. 1.0 – 26.2 GBq; p < 0.001) were lower in Arm 1. Conclusions: I-124 PET identifies persistent, iodine-avid disease in patients who would not routinely receive adjuvant RIT pursuant to ATA Guidelines, while enabling individualized selection in the others to minimize secondary malignancy risk. The impact on long term oncological outcomes has yet to be determined. Three years follow-up analyses evaluating recurrence rates and overall oncological safety are currently in progress and will be presented at the congress. Clinical trial information: NCT01704586 .

Abstract This single-center subgroup analysis of a prospective trial (NCT04571086) at University Hospital Essen investigated tumor uptake and detection rates of [ 68 Ga]Ga-FAPI-46- versus [ 18 F]FDG PET in triple-negative breast cancer (TNBC) patients undergoing initial or follow-up staging. Lesions were recorded across anatomical regions, with detection efficacy, uptake values, tumor-to-liver ratios, and tumor volumes assessed. 22 patients were included (initial- n = 10, follow-up staging n = 12). No significant difference in region-based detection rates was observed between [ 18 F]FDG- (93%, 53/57 regions) and [ 68 Ga]Ga-FAPI-46 PET (93%, 53/57 regions) (McNemar p = 1.0). Three patients (25%) at follow-up staging showed an average tumor SUV mean ≥5 on [ 68 Ga]Ga-FAPI-46 PET; 2/3 showed SUV max >10 in most lesions. Mean tumor volume was higher for [ 68 Ga]Ga-FAPI-46, though not statistically significant at initial- (50.1 ± 120.8 mL vs. 11.9 ± 18.5 mL) and follow-up staging (102.2 ± 122.3 mL vs. 79.0 ± 90.4 mL). [⁶⁸Ga]Ga-FAPI-46 PET demonstrated comparable detection in TNBC; high tumor uptake in a subset, supporting its theranostic potential.

Fibroblast activation protein (FAP) is highly expressed in many cancers, especially sarcomas, and represents a promising theranostic target. We present an updated retrospective analysis of 90Y-FAP inhibitor (FAPI)-46 treatment in patients with sarcoma or other solid tumors. Methods: We performed monocentric analysis of patients with progressive sarcoma or metastatic cancer who were eligible for 90Y-FAPI-46 therapy after approved treatments had been exhausted and who showed high FAP expression (SUVmax, ≥10 in over 50% of lesions on 68Ga-FAPI-46 PET). After therapy, 90Y-FAPI-46 scintigraphy confirmed distribution and uptake, and serial 90Y-FAPI-46 PET/CT scans measured absorbed doses. Adverse events were graded by Common Terminology Criteria for Adverse Events version 5.0. Tumor responses were evaluated using RECIST and PERCIST. Results: Thirty patients-23 (77%) with sarcoma, 3 (10%) with pancreatic cancer, 1 (3%) with prostate cancer, 1 (3%) with gastric cancer, 1 (3%) with nonmelanoma skin cancer, and 1 (3%) with cholangiocarcinoma-received a total of 77 cycles of 90Y-FAPI-46 radiopharmaceutical therapy between June 2020 and December 2023 and were followed until death or the last follow-up (April 2024). The median interval between cycles was 5 mo (interquartile range [IQR], 4 mo). Of the 30 patients, 11 (37%) received 4 or more cycles. A median of 3.7 GBq (IQR, 3.7-3.8 GBq) was administered during the first cycle, and a median of 7.4 GBq (IQR, 7.2-7.4 GBq) was administered for subsequent cycles. The mean absorbed dose was 0.48 Gy/GBq (SD, 0.06 Gy/GBq) in the kidneys and 0.04 Gy/GBq (SD, 0.01 Gy/GBq) in the bone marrow. Lesions with the highest uptake absorbed a mean dose of 2.4 Gy/GBq (SD, 1.04 Gy/GBq). After treatment, hematotoxicity of any grade was observed in 20 of 30 (67%) patients. Eight of 30 (27%) patients reached a Common Terminology Criteria for Adverse Events grade of at least 3, experiencing adverse events that included thrombocytopenia in 2 (6%), neutropenia in 2 (6%), anemia in 2 (6%), leukopenia in 1 (3%), and elevated γ-glutamyl transferase in 1 (3%) patient. RECIST (n = 25) and PERCIST (n = 20) responses after treatment were assessed. Disease control according to RECIST was 48% (12/25), including 3 partial responses (12%). Disease control correlated with extended overall survival (median, 14.6 vs. 1.9 mo). Metabolic response per PERCIST was observed in 12 of 20 (60%) patients. Conclusion: With long-term follow-up, the favorable safety profile of 90Y-FAPI-46 therapy is confirmed. Nearly half of the patients demonstrated disease stabilization, almost exclusively in sarcomas. Our findings support the role of FAP-directed radiopharmaceutical therapy in patients with metastatic sarcoma.

BACKGROUND:The 2025 update of the German S3 guideline on prostate cancer introduces major revisions in early detection and diagnostic strategies, marking a paradigm shift in the management of localized prostate cancer. METHODS:This review summarizes the main evidence-based recommendations on early detection derived from the systematic evidence synthesis conducted for the 2025 guideline update. RESULTS:The revised guideline establishes a risk-adapted, prostate-specific antigen (PSA)-based screening strategy starting at age 45, with individualized follow-up intervals (2 or 5 years) and indication-based diagnostic clarification using short-term PSA retesting, multiparametric magnetic resonance imaging (mpMRI), and targeted biopsy where appropriate. Digital rectal examination is no longer recommended for screening purposes. The structured integration of mpMRI increases the detection of clinically significant prostate cancer while reducing unnecessary biopsies and overdiagnosis. Active surveillance (AS) is a key component of the updated early detection and management strategy. For men with low-risk disease (ISUP 1), the guideline issues a strong "should" recommendation for AS, whereas for men with favorable intermediate-risk disease (ISUP 2 without cribriform or intraductal growth and with a limited proportion of Gleason pattern 4), AS carries a weaker "may" recommendation. Recent 15-year long-term results from the international Prostate Cancer Research International: Active Surveillance (PRIAS) cohort confirm the oncological safety of AS and highlight the pivotal role of mpMRI in patient selection and longitudinal monitoring. CONCLUSION:Combining individualized PSA-based early detection with high-quality MRI diagnostics enables precise, risk-adapted, and patient-centered prostate cancer management. This approach minimizes overdiagnosis and overtreatment while ensuring timely intervention for clinically relevant disease.

5112 Background: Previously, we proposed novel risk group definitions for prostate cancer patients based on Prostate-Specific Membrane Antigen (PSMA) targeted positron emission tomography (PET). PSMA-PET pan-stage nomograms (PPP3) were developed using the international, multicentre PROMISE registry (NCT06320223) to prognosticate overall survival (OS). Here, we present an external validation of PPP3. Methods: Eligible patients enrolled into our PROMISE registry database after the PPP3 data cap were included into this external validation study. Included patients had histologically proven prostate cancer and underwent PSMA-PET at hospitals in Turkey, Cyprus, Italy, China, South Africa or Germany between 2015 and 2022. PSMA-PET was standardized by PROMISE version 2 (V2); total lesion count, total tumor volume, PSMA expression score and OS follow-up were obtained as per local site practice. PPP3 nomograms were applied to calculate risk groups and Harrell´s C-indices for the external validation cohort. Calibration curves were measured for 5-year OS. Head-to-head comparison between the visual PPP3 nomogram and the simplified risk stratification table was examined by area under the receiver operating characteristics curve (ROC-AUC). Results: 1855 male patients across all disease stages with 179 (9.6%) reported deaths and median OS follow-up of 4.8 years (IQR 3.7-6.1) were analysed. In the external validation cohort C-indices (95% CI) were 0.71 (0.67-0.76) for the visual nomogram and 0.73 (0.69-0.77) for the quantitative nomogram, respectively. By simplified risk stratification table, 77 of 1855 patients (4.2%) were underestimated and 16 (0.9%) were overestimated, when compared with visual nomograms. Prognostic accuracy was comparable using both methods (AUC Nomogram: 0.64 vs. AUC Table: 0.63, p = 0.02). Conclusions: PPP3 nomograms were validated in an external multi-site patient cohort. Prognostication was accurate (C-indices > 0.70) for both PPP3 nomograms. Clinical trial information: NCT06320223 .

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Although contrast-enhanced CT (ceCT) and 2-[18F]FDG PET/CT remain standard imaging modalities, both exhibit limitations in detecting small peritoneal metastases and tumors with low metabolic activity. 68Ga-labeled fibroblast activation protein inhibitors (FAPIs) have shown promising results in various malignancies; however, comparative data on GISTs are limited. This study aimed to assess the diagnostic performance of [68Ga]Ga-FAPI-46 PET/CT in comparison with 2-[18F]FDG PET/CT and ceCT, including evaluation of interreader reproducibility and clinical impact. Methods: This study retrospectively reviewed 25 patients with histopathologically confirmed GISTs undergoing [68Ga]Ga-FAPI-46 PET/CT as part of a prospective observational study (NCT04571086). All patients (n = 25) underwent additional clinical 2-[18F]FDG PET/CT; ceCT was performed for 23 of 25 patients. Imaging was assessed per patient and per region (primary tumor, lymph nodes, and visceral and bone metastases), and a composite reference standard that included histopathology, follow-up imaging, and clinical data was applied. Interreader agreement, stratified by experience level, was analyzed using Cohen κ (κCohen). Referring physicians completed questionnaires before and after imaging to determine clinical impact. Results: In total, 28 validated regions (n = 20 patients) were included in the diagnostic efficacy analysis. Per region, ceCT and [68Ga]Ga-FAPI-46 PET/CT demonstrated comparable sensitivity (83% vs. 81%), followed by 2-[18F]FDG PET/CT (65%). [68Ga]Ga-FAPI-46 PET/CT demonstrated the highest region-based positive predictive value (100%). The liver tumor-to-background ratio was significantly higher for [68Ga]Ga-FAPI-46 PET/CT than for 2-[18F]FDG PET/CT (median, 7.6 vs. 5.9; P = 0.034), whereas overall tumor uptake showed no significant difference. Changes in clinical management attributable to [68Ga]Ga-FAPI-46 PET/CT were observed for 6 of 24 patients (25%), including 1 major change. Interreader agreement for [68Ga]Ga-FAPI-46 PET/CT varied with reader experience, showing the highest concordance between high- and intermediate-experience readers (κCohen = 0.87 per patient and 0.47-1.00 across regions), whereas comparisons involving less experienced readers yielded lower agreement (κCohen = 0.00-0.60). Conclusion: [68Ga]Ga-FAPI-46 PET/CT demonstrated diagnostic sensitivity comparable to ceCT and superior to 2-[18F]FDG PET/CT for patients with GISTs. High diagnostic performance, especially in hepatic and peritoneal metastases, and relevant clinical impact support a role for [68Ga]Ga-FAPI-46 PET/CT as complementary imaging modality.

Background Prostate cancer remains under-prioritised from a policy and advocacy perspective, despite a growing global disease burden. Objective To identify system-level barriers that prevent patients with prostate cancer from receiving high-quality care and to generate expert consensus on priority areas for health system action. Methods A targeted evidence review was conducted to identify barriers across the prostate cancer care pathway. Consensus was generated using a structured process informed by Delphi methodology. Two advisory panels comprising 37 experts, including multidisciplinary healthcare professionals, health policy experts, and patient advocacy representatives from Europe, the Americas, and Asia, assessed and prioritised the barriers by impact and feasibility of addressing. Following the panels, the experts developed a set of position statements to inform system-level action on prostate cancer. Results The expert consensus highlighted nine priority areas for prostate cancer policy, including elevating prostate cancer on health agendas; recognising broader societal and economic consequences; better-organised, risk-adapted approaches to screening; stronger diagnostic pathways with expanded access to biomarker testing, digital pathology, and standardised data integration; more evidence-based treatment practices, including multidisciplinary decision-making, timely treatment intensification, clearer guidance on treatment sequencing and reduced inequitable treatment access; and more structured, holistic survivorship care. Conclusions Health systems face challenges across the continuum of care in prostate cancer. While tailored approaches are required at the country level, global expert recommendations provide guidance on prioritising shared challenges across geographies to move towards more integrated, data-driven, and patient-centred prostate cancer pathways.

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.

Enantiomeric composition may impact binding and potentially performance of a drug product but is not routinely tested and minimum acceptance criteria are not always established. Some batches of the precursors FAPI-46 and FAPI-74 used clinically contain a mixture of (S)- and (R)-enantiomers. This study investigates the in vitro pharmacodynamic characteristics of different enantiomeric compositions of FAP-targeting radioligands FAPI-46 and FAPI-74 and in vivo pharmacokinetics of FAPI-46 in naïve mice. (S)-, (R)-, and (S/R)-enantiomers of radiolabeled FAPI-46 and FAPI-74 were evaluated for stability in human serum, binding affinity, internalization, retention, and selectivity using HT1080-hFAP cells and HEK293-hCD26 cells. All enantiomeric compositions showed high stability in human serum with minimal serum protein adhesion. (S)- and (S/R)-enantiomers exhibited comparable binding, internalization, and retention characteristics. High selectivity for FAP over CD26/DPP4 was maintained. (R)-enantiomers showed no specific binding to FAP. Additionally, the same enantiomers of 68Ga-labeled FAPI-46 were evaluated by dynamic positron emission tomography (PET) imaging (0–60 min post-injection) and ex vivo organ biodistribution in naïve BALB/c mice (10, 30, and 60 min, or 4 h post-injection) to compare their pharmacokinetic profiles. PET imaging revealed nearly identical time-activity curves for the enantiomers of [68Ga] Ga-FAPI-46, indicating similar whole-body distribution within 1 h post-injection, with rapid renal clearance and minimal muscle uptake. Ex vivo organ biodistribution confirmed comparable pharmacokinetic profiles between enantiomers, with no significant differences in tissue distribution. These findings provide important validation that current clinical (S/R)-mixtures of FAPI-46/-74 exhibit pharmacokinetic and pharmacodynamic behavior comparable to pure (S)-enantiomers, supporting regulatory confidence and cross-trial reproducibility in the global FAPI-46/-74 imaging landscape.

Background Timely detection is crucial to improve outcomes in patients with cardiac amyloidosis (CA) by initiation of life-saving treatments. Although confirmatory bone scintigraphy is highly accurate for CA detection, identifying at-risk patients for referral remains challenging. Objectives This study aimed to develop and validate a machine learning model, Amylo-Detect, using structured multimodal electronic health record (EHR) data to guide referrals for confirmatory scintigraphy and monoclonal protein testing. Methods Consecutive all-comer patients (n=11,616) referred for bone scintigraphy at the Vienna General Hospital (2010-2023) were retrospectively included. Patients referred before August 2020 formed the development cohort. The remaining patients comprised the internal validation cohort. External validation was performed at the University Hospital Essen (n=1,521). Amylo-Detect was trained using 50 routinely available parameters to predict CA-suggestive uptake (Perugini grade >=2) and compared with an existing score and clinical routine. Results High-grade uptake was present in 388 patients (3.0%). Amylo-Detect demonstrated excellent performance in development (AUC 0.93), independent internal validation (AUC 0.91), and external validation cohort (AUC 0.91), outperforming existing scoring systems and clinical routine. Results were consistent across subgroups, even when crucial predictors were missing. Of the 42/388 (10.8%) patients missed in clinical routine, 12/42 (29%) were additionally detected by Amylo-Detect. The model further conveyed significant prognostic value for mortality and heart failure hospitalization. Conclusions We present Amylo-Detect, a validated EHR-based tool for CA risk prediction, available as a web app, allowing application and further evaluation. By improving timely detection and referral, Amylo-Detect promises to address diagnostic delays and improve outcomes. ### Competing Interest Statement CN reports speaker/consulting honoraria from Pfizer, Bayer, Prothena, and Boehringer Ingelheim and research contracts with Pfizer, AstraZeneca, the Austrian Society of Cardiology, the European Association of Cardiovascular Imaging, and the Austrian Science Fund. CPS received consulting and speaker fees from Pfizer. MH has received lecture fees from Siemens Healthineers and GE Healthcare. MH has received consulting fees from Evomics. TR has received honoraria, lecture fees, and grant support from Edwards Lifesciences, AstraZeneca, Bayer, Novartis, Berlin Chemie, Daiicho-Sankyo, Boehringer Ingelheim, Novo Nordisk, Cardiac Dimensions, and Pfizer. TR is co-founder of mycor GmbH, a company focusing on the development of ECG-algorithms for the identification of amyloidosis. The remaining authors have nothing to disclose. ### Funding Statement none ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Medical University of Vienna's institutional review board gave ethical approval for this work (1557/2020). The requirement for informed consent was waived. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data supporting this study cannot be shared due to restrictions imposed by the ethical approvals. Researchers interested in accessing the data may contact the corresponding author to discuss potential options.