This article evaluates whether early same-day posttherapy whole-body SPECT/CT assessed using visual RECIP 1.0 is associated with overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) that is positive for prostate-specific membrane antigen (PSMA) and treated with [177Lu]Lu-PSMA-617, and it assesses concordance among posttherapy SPECT/CT, PSMA PET/CT, and prostate-specific antigen (PSA). Methods: We retrospectively analyzed 158 men with mCRPC who received at least 2 cycles [177Lu]Lu-PSMA-617 between June 2022 and January 2025. Same-day posttherapy SPECT/CT was performed after each cycle. Early SPECT imaging response was assessed after cycle 2 using visual RECIP 1.0. Baseline tumor burden was classified as low or high volume using CHAARTED criteria on baseline SPECT. Early biochemical response was defined as a PSA decline of at least 50% (PSA50) before cycle 3. OS was the primary endpoint. Kaplan-Meier analysis, log-rank testing, and univariable and multivariable Cox regression were performed. Interim imaging response and concordance were evaluated for SPECT/CT and PSMA PET/CT after cycle 3. Results: Median follow-up was 23.9 mo, and median OS was 14.4 mo. Early SPECT response after cycle 2 was associated with longer OS than occurred with no response (21.5 vs. 11.3 mo, P < 0.001). High-volume baseline disease and absence of PSA50 were associated with shorter OS. The combination of imaging response, baseline tumor burden, and PSA50 improved survival stratification. Patients with high-volume disease and without imaging response were associated with the shortest OS compared with those with low-volume disease and imaging response (10.6 vs. 23.7 mo, P < 0.001). Among patients who underwent interim SPECT/CT and PSMA PET/CT (n = 97), progressive disease on either modality was associated with shorter survival. SPECT, PET, and PSA responses were concordant in 59.8% of patients. Discordant findings reflected differences in imaging timing, sensitivity, and biologic heterogeneity, including PSMA-negative disease. Conclusion: Early same-day posttherapy SPECT/CT assessed using visual RECIP 1.0 was associated with OS in patients with mCRPC who received [177Lu]Lu-PSMA-617. Integration of early SPECT response, baseline tumor burden, and PSA50 improved survival stratification. Substantial concordance among SPECT, PSMA PET, and PSA response, together with characteristic discordance patterns, supports a complementary role for SPECT/CT in treatment response assessment.

BACKGROUND: Molecular imaging, particularly PET, has advanced the diagnosis and management of disease by visualizing biologic processes at a cellular and molecular level. PET imaging of the brain, spine, and head/neck, summarized under the umbrella term neuro-PET, enables noninvasive diagnosis and monitoring of diseases such as dementia, epilepsy, cancer, movement, or autoimmune disorders. The increasing prevalence of these conditions, as well as new treatment options necessitating response assessment, are expected to escalate neuro-PET imaging volumes, with projections for an increase in the need for specialized imaging services. This increasing clinical need highlights existing workforce shortages and underscores the need for neuroradiologists to acquire proficiency in molecular imaging. This expanded role seeks to address the growing demand. To this end, we propose a rigorous, structured, patient-centered, and collaborative framework for expanding neuroradiologists? training and practice to include neuro-PET interpretation. METHODS: This American Society of Neuroradiology consensus statement outlines competency recommendations, training pathways, and implementation strategies to incorporate neuro-PET into neuroradiology practice. This approach is based on existing guidelines and was informed by survey data from neuroradiologists and molecular imaging subspecialists revealing current practice patterns and training needs. For neuroradiology fellows, structured training encompasses hands-on neuro-PET imaging experience, understanding the biologic and molecular basis of radiopharmaceuticals used in neuro-PET, and integrating molecular insights with anatomic data. Neuroradiologists beyond fellowship can undertake practice-based curriculum involving supervised case interpretation, standardized reader training courses, continuing medical education (CME), and peer review. KEY MESSAGE: Neuroradiologists, with their in-depth expertise of central nervous system structure and function, are well positioned to meld molecular imaging data with traditional anatomic findings. They can achieve competency and should be granted practice privileges in interpreting neuro-PET studies through a comprehensive combination of structured training, hands-on clinical experience, and documented CME hours.

Fluorodeoxyglucose (FDG) PET to evaluate patients with epilepsy is one of the most common applications for simultaneous PET/MRI, given the need to image both brain structure and metabolism but is suboptimal due to the radiation dose in this young population. Little work has been done synthesizing diagnostic quality PET images from MRI data or MRI data with ultralow-dose PET using advanced generative AI methods, such as diffusion models, with attention to clinical evaluations tailored for the epilepsy population. We compared the performance of diffusion- and non-diffusion-based deep learning models for the MRI-to-PET image translation task for epilepsy imaging using simultaneous PET/MRI in 52 subjects (40 train/2 validate/10 hold-out test). We tested three different models: 2 score-based generative diffusion models (SGM-Karras Diffusion [SGM-KD] and SGM-variance preserving [SGM-VP]) and a Transformer-U-net. We report results on standard image processing metrics as well as clinically relevant metrics, including congruency measures (Congruence Index and Congruency Mean Absolute Error) that assess hemispheric metabolic asymmetry, which is a key part of the clinical analysis of these images. We compared the model performance using different inputs such as T1-weighted (T1w), T2 FLAIR (T2F), and 1% ultralow-dose PET images to evaluate the effect and necessity of each imaging contrast. The SGM-KD produced the best qualitative and quantitative results when synthesizing PET purely from T1w and T2 FLAIR images with the least mean absolute error in whole-brain specific uptake value ratio (SUVR) and highest intraclass correlation coefficient. When 1% low-dose PET images are included in the inputs, all models improve significantly and are interchangeable for quantitative performance and visual quality. SGMs hold great potential for pure MRI-to-PET translation, while all 3 model types can synthesize full-dose FDG-PET accurately using MRI and ultralow-dose PET. This suggests that deep learning diffusion models could reduce or eliminate radiation dose for patients being evaluated for epilepsy.

Fibroblast activation protein (FAP) is a type II integral membrane glycoprotein, highly expressed on the cell surface of cancer-associated fibroblasts (CAFs) present in the tumor microenvironment of most epithelial cancers and showing limited expression in normal tissues. Given this expression profile, FAP appears to be a promising target for radioligand therapy that has pan-cancer potential. [177Lu]Lu-NNS309 is a FAP-targeted radiopharmaceutical that shows improved tumor retention and demonstrates promising anti-tumor activity in translationally relevant preclinical models (e.g., PDAC, NSCLC) where FAP is expressed on CAFs. CFXX489A12101 (NCT06562192) is a first-in-human phase I, open-label, multi-center study of [177Lu]Lu-NNS309 in patients with pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), breast cancer (BC), and colorectal cancer (CRC). The study includes a dose escalation part followed by a dose expansion part. Key eligibility criteria include prior treatment for locally advanced unresectable or metastatic disease and having all measurable lesions (per RECIST 1.1) showing [68Ga]Ga-NNS309 uptake on positron emission tomography/computed tomography (PET/CT). Patients who are eligible for treatment receive one dose of [177Lu]Lu-NNS309 on day 1 of each cycle. A 6-week and a 4-week dosing schedule will be explored. Dosimetry data will be obtained from patients in the dose escalation part after the first dose and will be used to calculate the cumulative radiation exposure. Dose escalation will be guided by a Bayesian hierarchical logistic regression model with overdose control (EWOC) principle, and assessment of all relevant data available from all dose levels including safety, tolerability, clinical dosimetry, pharmacodynamics, and preliminary efficacy. Once the recommended dose(s) (RD) and schedule(s) of [177Lu]Lu-NNS309 are determined, the expansion part may open and will include patients with locally advanced or metastatic PDAC (n∼20), locally advanced or metastatic NSCLC (n∼20), HR+/HER2- ductal BC (n∼15), HR+/HER2- lobular BC (n∼15), and triple negative BC (; n∼24).The primary objectives of the study are to evaluate the safety and tolerability of [177Lu]Lu-NNS309 and to identify the RD(s) and regimen(s) of [177Lu]Lu-NNS309 for further clinical evaluation. Secondary objectives of the study are to evaluate the preliminary anti-tumor activity of [177Lu]Lu-NNS309, characterize the pharmacokinetics of [177Lu]Lu-NNS309 in blood and urine, the radiation dosimetry for organs and tumor lesions, and to evaluate the safety and imaging properties of [68Ga]Ga-NNS309. The study is currently enrolling in the dose escalation part. Ravit Geva, Daniel Juneau, Shadi Abdar Esfahani, Cristiano Ferrario, Farshad Moradi, Amir Iravani, Jordi Ahnert, Ivan Manuel Victoria Ruiz, Thibaud Koessler, Aitana Calvo Ferrandiz, Bernard Doger de Speville, Patrick Flamen, Albiruni Razak, Desiree Deandreis, Laure Al-Mansour, Niklaus Schaefer, James Nagarajah, Hilde Nienhuis, Marco Maccauro, Angelina Filice, Jonathan Goldman, Ken Herrmann, Matthias Eiber, Alexander Drzezga, Martin Heuschkel, Jonathan McConathy, Johnson Geoffrey, Ephraim Parent, Yasutoshi Kuboki, Shizuka Origuchi, Xuan Mai Couillebault, Elisa Garcia Garayoa, Jayarama Naidu Roopa, Christopher Straub, Dominik Hainzl, Xinyu Chen, Fang Yang, Eirini Pectasides, Brandon Mancini. Phase I open-label, multi-center study to evaluate the safety, tolerability, dosimetry, and preliminary activity of FXX489 ([177Lu]Lu-NNS309) in patients with pancreatic, lung, breast and colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT112.

Background: PSMA PET radiomics is a promising tool for primary prostate cancer (PCa) characterisation. However, small single-centre studies and lack of external validation hinder definitive conclusions on the potential of PSMA PET radiomics in the initial workup of PCa. We aimed to validate a radiomics signature in a larger internal cohort and in an external cohort from a separate centre. Methods: One hundred and twenty-seven PCa patients were retrospectively enrolled across two independent hospitals. The first centre (IRCCS San Raffaele Scientific Institute, Centre 1) contributed 62 [68Ga]Ga-PSMA-11 PET scans, 20 patients classified as low-grade (ISUP grade < 4), and 42 as high-grade (ISUP grade ≥ 4). The second centre (Stanford University Hospital, Centre 2) provided 65 [68Ga]Ga-PSMA-11 PET scans, and 49 low-grade and 16 high-grade patients. A radiomics model previously generated in Centre 1 was tested on the two cohorts separately and afterward on the entire dataset. Then, we evaluated whether the radiomics features selected in the previous investigation could generalise to new data. Several machine learning (ML) models underwent training and testing using 100-fold Monte Carlo cross-validation, independently at both Centre 1 and Centre 2, with a 70–30% train–test split. Additionally, models were trained in one centre and tested in the other, and vice versa. Furthermore, data from both centres were combined for training and testing using Monte Carlo cross-validation. Finally, a new radiomics signature built on this bicentric dataset was proposed. Several performance metrics were computed. Results: The previously generated radiomics signature resulted in an area under the receiver operating characteristic curve (AUC) of 80.4% when tested on Centre 1, while it generalised poorly to Centre 2, where it reached an AUC of 62.7%. When the whole cohort was considered, AUC was 72.5%. Similarly, new ML models trained on the previously selected features yielded, at best, an AUC of 80.9% for Centre 1 and performed at chance for Centre 2 (AUC of 49.3%). A new signature built on this bicentric dataset reached, at best, an average AUC of 91.4% in the test set. Conclusions: The satisfying performance of radiomics models when used in the original development settings, paired with the poor performance otherwise observed, emphasises the need to consider centre-specific factors and dataset characteristics when developing radiomics models. Combining radiomics datasets is a viable strategy to reduce such centre-specific biases, but external validation is still needed.

32 Background: Multi-detector cadmium-zinc-telluride (CZT) based whole-body digital SPECT/CT is a new generation of imaging system. We aim to assess the clinical utility of rapid post-therapy whole-body SPECT/CT scan in evaluating early treatment response of 177Lu-PSMA-617 treatment. Methods: We retrospectively reviewed patients with progressive metastatic castration resistant prostate cancer (mCRPC) who were treated with at least two cycles of 177Lu-PSMA-617 at our institution from June 2022 to June 2023. Post-therapy whole-body digital SPECT/CT (GE StarGuide) was performed from vertex to mid-thigh at 1-2 hours after 177Lu-PSMA-617 infusion. Post-therapy SPECT/CT images were quantified with MIM software. Lu177-PSMA positive lesions were delineated with liver parenchyma uptake as cut-off. Lu-PSMA positive total tumor volume (Lu-TTV), tumor SUVmax and SUVmean were obtained. Post-therapy SPECT/CT image after cycle 1 was used as baseline for comparison with SPECT/CT after cycle 2 and 3. Overall survival, PSA progression free survival (PSA-PFS) as defined by PCWG3 and PSA decline > 50% from baseline (PSA50) at any time after treatment were measured. Changes in post-therapy SPECT/CT were correlated with clinical outcomes to assess quantitative SPECT/CT as a tool for early treatment response. Analyses were performed with SPSS. Results: A total of 56 patients (76±8, mean ± SD, range 60-93 years old) who were imaged with at least 2 post-therapy SPECT/CT were included in the analysis. Post-therapy whole body SPECT/CT was acquired in ~12 mins. All scanned patients tolerated the rapid whole-body SPECT/CT very well. With median follow up of 10 months, median PSA-PFS was 5.0 months (range 1.0-15 months), 33 of 56 patients (58.9%) achieved PSA50 at any time after treatment, and 42 of 56 patients (75%) were alive at data cutoff. Quantitative analysis of SPECT/CT images showed that 36 of 56 patients (64%) had a >30% decrease in Lu-TTV on early follow-up post-therapy SPECT/CT after cycle 2 or 3. Kaplan-Meier survival analysis showed that a >30% decrease in Lu-TTV was associated with longer overall survival (median not reached vs 6 months, P = 0.008) and longer PSA-PFS (6 months vs 1 months, P < 0.001). Decrease in SUVmax or SUVmean, however, was not associated with PSA-PFS or overall survival. Conclusions: Rapid post-therapy whole-body digital SPECT/CT was well tolerated in post-therapy SPECT/CT imaging following 177Lu-PSMA-617 treatment. Quantitation of post-therapy SPECT/CT may be useful in evaluating early treatment response of 177Lu-PSMA-617. Prospective validation and larger patient cohorts are needed to further elucidate the role of post-therapy SPECT/CT imaging in guiding patient management in 177Lu-PSMA-617 therapy.

Lutetium-177 [177Lu]Lu-PSMA-617 radioligand therapy (RLT) represents a significant advancement for metastatic castration-resistant prostate cancer (mCRPC), demonstrating improvements in radiographic progression free survival (rPFS) and overall survival (OS) with a low rate of associated side effects. Currently, most post-therapy SPECT/CT is conducted at 24 h after infusion. This study examines the clinical utility of a next-generation multi-detector Cadmium-Zinc-Telluride (CZT) SPECT/CT system (StarGuide) in same-day post-infusion assessment and early treatment response to [177Lu]Lu-PSMA-617. In this retrospective study, 68 men with progressive mCRPC treated with [177Lu]Lu-PSMA-617 at our center from June 2022 to June 2023 were evaluated. Digital whole-body SPECT/CT imaging was performed after [177Lu]Lu-PSMA-617infusion (mean ± SD: 1.8 ± 0.6 h, range 1.1–4.9 h). Quantitative analysis of [177Lu]Lu-PSMA-617 positive lesions was performed in patients who underwent at least 2 post-therapy SPECT/CT, using liver parenchyma uptake as reference. Metrics including [177Lu]Lu-PSMA-617 positive total tumor volume (Lu-TTV), SUVmax and SUVmean were calculated. These quantitative metrics on post-infusion SPECT/CT images after cycles 1, 2 and 3 were correlated with overall survival (OS), prostate specific antigen-progression free survival (PSA-PFS) as defined by prostate cancer working group 3 (PCWG3), and PSA decrease over 50

Prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptors are both overexpressed in prostate cancer (PC) but may provide complementary information.68Ga-PSMA-R2 and 68Ga-NeoB (DOTA-p-aminomethylaniline-diglycolic acid-DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH[CH2-CH(CH3)2]2) are novel PET radiopharmaceuticals that were developed for theranostic use. In this phase II imaging study, we assessed the feasibility, safety, and diagnostic performance of 68Ga-NeoB and 68Ga-PSMA-R2 PET/MRI for detection of biochemically recurrent PC. Methods: We prospectively enrolled 27 men with suspected biochemically recurrent PC after initial treatment but noncontributory conventional imaging results (negative or equivocal findings on MRI, CT, and/or bone scan). Participants underwent 68Ga-NeoB and 68Ga-PSMA-R2 PET/MRI within 2 wk in noncontrolled order. The SUVmax of putative PC lesions was measured and compared with a composite reference standard (histopathology, follow-up imaging, prostate-specific antigen change). The SUVmax and SUVmean of background organs were measured. Vital signs were recorded before injection of the radiopharmaceuticals and after the scans. Adverse events were recorded up to 72 h after each scan. Results: The prostate-specific antigen level at enrollment was 3.5 ± 3.9 ng/mL (range, 0.3-13.5 ng/mL). 68Ga-NeoB PET/MRI detected 31 lesions in 18 patients (66.7%), whereas 68Ga-PSMA-R2 identified 20 lesions in 15 participants (55.6%). 68Ga-NeoB PET/MRI showed higher sensitivity (85.7% vs. 71.4%), accuracy (88.9% vs. 77.8%), and negative predictive value (66.7% vs. 50.0%) than 68Ga-PSMA-R2, whereas specificity and positive predictive value were equally high (100.0% for both). In 6 patients, 68Ga-NeoB PET/MRI identified 14 lesions that were false-negative on 68Ga-PSMA-R2 PET/MRI. The mean lesion SUVmax was 6.6 ± 3.2 (range, 2.9-13.2) for 68Ga-NeoB and 4.4 ± 1.5 (range, 2.6-8.8) for 68Ga-PSMA-R2 (P = 0.019). Overall lower uptake was noted in tumors and background organs for 68Ga-PSMA-R2. There were no significant changes in vital signs before and after the scans. No adverse events were reported in the 72-h period after scans. Conclusion: 68Ga-NeoB and 68Ga-PSMA-R2 are safe for diagnostic imaging. 68Ga-NeoB PET/MRI showed better diagnostic performance than 68Ga-PSMA-R2. 68Ga-PSMA-R2 showed overall lower uptake, equally in background organs and tumors, and might therefore not be an ideal theranostic compound. Further evaluation in larger cohorts is needed to confirm our preliminary data.

BackgroundNational Comprehensive Cancer Network guidelines include prostate-specific membrane antigen (PSMA)-targeted PET for detection of biochemical recurrence of prostate cancer. However, targeting a single tumour characteristic might not be sufficient to reflect the full extent of disease. Gastrin releasing peptide receptors (GRPR) have been shown to be overexpressed in prostate cancer. In this study, we aimed to evaluate the diagnostic performance of the GRPR-targeting radiopharmaceutical 68Ga-RM2 in patients with biochemical recurrence of prostate cancer.MethodsThis single-centre, single-arm, phase 2/3 trial was done at Stanford University (USA). Adult patients (aged ≥18 years) with biochemical recurrence of prostate cancer, a Karnofsky performance status of 50 or higher, increasing prostate-specific antigen concentration 0·2 ng/mL or more after prostatectomy or 2 ng/mL or more above nadir after radiotherapy, and non-contributory conventional imaging (negative CT or MRI, and bone scan) were eligible. All participants underwent 68Ga-RM2 PET–MRI. The primary outcome was the proportion of patients with PET-positive findings on 68Ga-RM2 PET–MRI compared with MRI alone after initial therapy, at a per-patient and per-lesion level. The primary outcome would be considered met if at least 30% of patients had one or more lesions detected by 68Ga-RM2 PET–MRI and the detection by 68Ga-RM2 PET–MRI was significantly greater than for MRI. Each PET scan was interpreted by three independent masked readers using a standardised evaluation criteria. This study is registered with ClinicalTrials.gov, NCT02624518, and is complete.FindingsBetween Dec 12, 2015, and July 27, 2021, 209 men were screened for eligibility, of whom 100 were included in analyses. Median follow-up was 49·3 months (IQR 36·7–59·2). The primary endpoint was met; 68Ga-RM2 PET–MRI was positive in 69 (69%) patients and MRI alone was positive in 40 (40%) patients (p<0·0001). In the per-lesion analysis 68Ga-RM2 PET–MRI showed significantly higher detection rates than MRI alone (143 vs 96 lesions; p<0·0001). No grade 1 or worse events were reported.Interpretation68Ga-RM2 PET–MRI showed better diagnostic performance than MRI alone in patients with biochemical recurrence of prostate cancer. Further prospective comparative studies with PSMA-targeted PET are needed to gain a better understanding of GRPR and PSMA expression patterns in these patients.FundingThe US Department of Defense.

Prostate cancer (PC) is a prevalent malignancy in men worldwide. Early and accurate detection of metastatic disease is critical for treatment planning and outcome in both initial presentation and after biochemical recurrence. Molecular imaging with PET using radiopharmaceuticals that target prostate-specific membrane antigen (PSMA) or gastrin-releasing peptide receptor (GRPR) have shown high sensitivity and specificity for recurrent disease. Due to the high tumor heterogeneity in PC, a single radiopharmaceutical might not be sufficient to show the true extent of the disease. Although performing multiple PET scans with different radiotracers can achieve better disease characterization, it is quite impractical and is thus rarely done. In this study, we employed a conditional generative adversarial network (cGAN) to generate synthetic PET images of a second tracer based on data acquired from a first tracer. A retrospective study was conducted in twenty patients with biochemical recurrence (BCR) of PC after primary treatment, who underwent GRPR and PSMA PET utilizing 68Ga-RM2, and either 68Ga-PSMA11 or 18F-DCFPyL, respectively. The synthetic generation of 68Ga-PSMA11/18F-DCFPyL from 68Ga-RM2 and 68Ga-RM2 from 68Ga-PSMA11/ 18F-DCFPyL yielded PSNR of 26.32 ± 3.24 and 27.53 ± 2.86, mean SSIM of 0.88 ± 0.06 and 0.92 ± 0.042, and MSE of 0.011 ± 0.006 and 0.008 ± 0.005, respectively. These initial results show the feasibility of utilizing cGAN to produce synthetic PET images of just one tracer for the assessment of multiple cancer biomarkers in PC. Additional investigations are examining lesion detectability within the synthetic PET images and how they are affected by biomarker heterogeneity in PC. If successful, this method could revolutionize PC imaging by providing physicians with comprehensive biomarker information from a single-tracer PET study.