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.
OPTIMAL-PSMA aims to determine the safety and efficacy of a dose-intensified (intense induction followed by a maintenance period) regimen of [177Lu]Lu-PSMA-597 compared with the standard-of-care regimen (every 6 wk for up to 6 doses) in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: OPTIMAL-PSMA is a phase 2, open-label, 2-arm, multicenter, randomized controlled trial of [177Lu]Lu-PSMA-597, a novel prostate-specific membrane antigen (PSMA) peptide with low nontarget organ dosimetry. A total of 120 patients with mCRPC will be enrolled and randomized 2:1 to receive either a dose-intensified regimen (arm 1) or the standard-of-care regimen (arm 2) of [177Lu]Lu-PSMA-597. Eligible participants must have mCRPC with disease progression after androgen receptor pathway inhibitor therapy, have received or are not considered medically fit for docetaxel chemotherapy, and demonstrate PSMA-avid disease on PET/CT. Participants assigned to arm 1 will receive early intensified [177Lu]Lu-PSMA-597 dosing (7.5 or 8.5 GBq on the basis of an interim safety assessment) on days 1, 3, and 15 and during weeks 10, 20, and 30 (6 doses). All participants in arm 2 will receive the standard dose of 7.5 GBq of [177Lu]Lu-PSMA-597 administered every 6 wk until they are no longer clinically benefiting, for a maximum of 6 doses. Clinical and laboratory safety assessments will be conducted 3 times weekly, with diagnostic CT and bone scans performed at 8 wk and then every 12 wk until radiographic progression. Translational studies incorporate serial multiple-time-point circulating tumor DNA matched with SPECT/CT dosimetry at each time point and PSMA PET at baseline and 8 wk for correlation with clinical outcomes. The primary endpoint is a 90% or greater decline in prostate-specific antigen (PSA) level. Key secondary endpoints include the safety of intensified dosing, a 50% or greater decline in PSA level, radiographic and PSA progression-free survival, and overall survival. Translational endpoints include evaluation of serial circulating tumor DNA, biologic effective dose with intensified versus standard dosing of [177Lu]Lu-PSMA-597, and evaluation of serial SPECT/CT and PSMA PET/CT for treatment response. Conclusion: OPTIMAL-PSMA will determine whether a dose-intensified regimen of [177Lu]Lu-PSMA-597 is safe and improves depth of response and survival outcomes compared with the standard dosing regimen. The results of this study may redefine the optimal treatment scheduling for PSMA-targeted radiopharmaceutical therapy for patients with mCRPC.
The value of [18F]FDG PET/CT imaging in the management of SMARCB1-deficient renal medullary carcinoma (RMC), a rare and aggressive type of kidney cancer, has not been established. We sought to determine the utility of [18F]FDG PET/CT findings for the evaluation of disease burden and treatment planning in patients with RMC. Methods: Using an institutional database, we identified patients with RMC who underwent [18F]FDG PET/CT scans as part of clinical care between 2016 and 2025. When available, baseline [18F]FDG PET/CT images were used; otherwise, the earliest available follow-up scan performed because of concern of recurrence or progression was included. For all scans, sites of abnormal [18F]FDG uptake were assessed, the SUVmax of the most avid site was quantified, and tumor-to-normal tissue ratios (TNRs) were calculated. PET/CT findings were compared with anatomic imaging (CT/MRI-based) performed within 30 d. Instances in which PET/CT findings altered treatment were recorded. Results: On PET, 48 of 49 patients had clearly [18F]FDG-avid disease. The single patient without [18F]FDG-avid lesions also lacked evidence of disease on anatomic imaging. Of the 23 patients who received a baseline PET/CT scan for staging purposes, 15 had intact renal primary tumors, and all tumors were [18F]FDG-avid (median SUVmax, 13.4; range, 9.5-23.5; median TNR blood, 10.7; range, 4.2-16.6). Ten patients were imaged during therapy, and 16 underwent imaging after progression or before the start of a new treatment. Forty-three patients had [18F]FDG-avid nodal metastatic disease (median SUVmax, 8.9; range, 1.8-27.0). Extranodal disease was observed in 36 patients, most commonly in the lungs (n = 24; median SUVmax, 5.8; range, 1.7-17.5) and bones (n = 19; median SUVmax,10.7; range, 3.7-24.8). In 31 patients, [18F]FDG PET/CT identified additional lesions not detected on anatomic imaging, predominantly involving bones (n = 18), lymph nodes (n = 13), and soft tissues (n = 11). These additional findings led to a change in clinical management for 10 (21%) of 48 patients with active disease. In contrast, no lesions were identified on anatomic imaging that were not apparent on PET/CT scans. Conclusion: RMC is a highly [18F]FDG-avid malignancy. [18F]FDG PET frequently detects additional metastatic sites missed by conventional anatomic imaging, facilitating disease extent assessment and optimizing treatment strategy in patients with RMC.
Accurate estimation of organ and effective doses in CT imaging is essential for risk assessment, protocol optimization, and personalized care in diagnostic radiology and nuclear medicine. We systematically benchmarked MIRDct, a freely available mesh phantom-based CT dose calculation software, against established reference software (National Cancer Institute Dosimetry System for Computed Tomography [NCICT] and VirtualDose [Virtual Phantoms]) by evaluating agreement between organ-absorbed doses and effective doses across representative scanners, phantoms, and protocols. Methods: Organ absorbed and effective doses were calculated for adult and pediatric phantoms for whole-body (WB) and regional (head, chest, abdomen-pelvis [AP]) CT examinations. MIRDct uses mesh-based International Commission on Radiologic Protection (ICRP) reference phantoms with anatomically realistic organ surfaces, whereas NCICT and VirtualDose use voxel-based ICRP 110 and hybrid Rensselaer Polytechnic Institute/University of Florida phantom models, respectively. For each software, volumetric CT dose index (CTDIvol) values were obtained from the software interface using matched acquisition parameters; in MIRDct, these values were derived from scanner console-reported outputs for the corresponding protocol settings. Organ absorbed doses, dose coefficients, and effective doses were computed across 44 matched scanner-phantom-protocol configurations. Inter-software differences were summarized using medians and interquartile ranges. For regional protocols, organ-absorbed doses were stratified by irradiation category (in-field, partial-in-field, out-of-field), to assess field-dependent variability. Results: CTDIvol​ values reported by the 3 software tools showed close agreement across matched protocol configurations, with median inter-software differences not exceeding 7%. For in-field organs, dose coefficients from NCICT and VirtualDose generally agreed with MIRDct values within ±25% across adult and pediatric head, chest, AP, and WB protocols, indicating good agreement in the primary beam region. Larger relative deviations occurred for partial-in-field and out-of-field organs, where doses were scatter-dominated; however, absolute organ doses were less than 2 mGy, limiting clinical relevance. Effective dose estimates showed similar concordance: differences were below 25% for all VirtualDose comparisons except head scans and for WB protocols, whereas adult chest and AP protocols differed by up to 40% relative to NCICT. These differences were associated with variations in phantom anatomy and fixed, pre-tabulated CTDIvol reference values in NCICT and VirtualDose, compared with protocol-specific, console-reported CTDIvol inputs in MIRDct. Conclusion: MIRDct provides organ- and effective-dose estimates that are broadly consistent with established CT dosimetry tools, with agreement typically within ±25% for in-field organs and within a few milligray for absolute doses across adult and pediatric protocols. The use of mesh-based ICRP reference phantoms with anatomically realistic organ surfaces, protocol-specific CTDIvol inputs from the scanner console, and uncertainty propagation supports its application as a research tool for CT dose benchmarking, protocol optimization, and quality assurance in diagnostic CT and nuclear medicine.
Staphylococcus aureus is a leading cause of life-threatening infections worldwide. The diagnosis and treatment of S. aureus infections are further complicated by the global rise of antimicrobial resistance. Therefore, rapid detection of active S. aureus remains a critical unmet need to provide effective infection management. In this study, we identified 2-deoxy-2-[18F]-fluorosakebiose ([18F]FSK) as an optimal radiotracer to detect active S. aureus and established its efficient chemoenzymatic radiosynthesis to facilitate clinical translation. Methods: Several [18F]FDG-derived disaccharides were obtained via reverse phosphorolysis: [18F]FSK (α-1,3-linked), 2-deoxy-[18F]-fluoromaltose (α-1,4-linked), 2-deoxy-2-[18F]-fluorolaminaribiose (β-1,3-linked), and 2-deoxy-2-[18F]-fluorocellobiose (β-1,4-linked). These tracers were screened in vitro in multiple S. aureus isolates to identify bacterial incorporation. The lead candidate, [18F]FSK, was further characterized via biodistribution and dosimetry analyses and evaluated in a S. aureus myositis model to assess antimicrobial treatment response. Finally, to promote the clinical translation of [18F]FSK, 2 different radiosynthetic strategies were investigated: reverse phosphorolysis of [18F]FDG using maltose phosphorylase and using newly identified nigerose (also called sakebiose) phosphorylases. Results: Nigerose phosphorylase-derived [18F]FSK was selected as the optimal radiotracer for detecting S. aureus because of its consistent and robust uptake in multiple S. aureus isolates. [18F]FSK demonstrated favorable distribution and elimination over time, with minimal nonspecific signals in uninfected organs. The estimated human effective doses indicated an effective dose comparable to that of [18F]FDG. The radiosynthesis of [18F]FSK, initially obtained as an accidental byproduct of maltose phosphorylase catalysis, was further improved using a nigerose phosphorylase originating from thermostable Spirochaeta thermophila, enabling nearly quantitative conversion of [18F]FDG to [18F]FSK (up to 97%). Conclusion: We demonstrated that [18F]FSK is a potent and robust PET radiotracer for the detection of active S. aureus in vivo and aids in the selection of an appropriate antimicrobial treatment. These findings highlight the potential use of [18F]FSK in promoting the effective management of S. aureus infections in clinical settings.
We investigated the prognostic value of baseline [18F]FDG and [68Ga]Ga-PSMA-11 PET/CT in patients with metastatic castration-resistant prostate cancer treated with [177Lu]Lu-PSMA-617. Methods: In this multicenter retrospective study, the associations between several clinical, biologic, and radiologic parameters and overall survival (OS) were tested in a development cohort using univariable analyses, followed by the construction of a multivariable Cox model. The PROFILE prognostic score was subsequently derived from this model, internally validated, and externally validated in an independent cohort. Results: Data from 174 patients from 3 centers were used to construct the multivariable Cox model. Five independent adverse prognostic factors were identified and incorporated into the PROFILE score: an SUVmax exceeding 300% of the PERCIST threshold on [18F]FDG PET/CT, a "nonhigh" classification on [68Ga]Ga-PSMA-11 PET/CT using the visual PSMA tumor-to-salivary gland ratio, a baseline hemoglobin level of 11 g/dL or less, a baseline alkaline phosphatase level of greater than 220 IU/L, and a disease duration not exceeding 100 mo. The PROFILE score stratified patients into 3 risk groups and achieved a Harrell C-index of 0.67 (95% CI, 0.62-0.72). The median OS in the low-, intermediate-, and high-risk groups was 17.2, 13.0, and 8.6 mo, respectively (P < 0.0001). These results were confirmed in 114 patients in an independent, single-center validation cohort, with median OS of 20.4, 14.3, and 8.8 mo (P < 0.0001), respectively, and a C-index of 0.73 (95% CI, 0.68-0.78). Conclusion: The PROFILE score offers valuable prognostic information for patients with metastatic castration-resistant prostate cancer when considering the use of [177Lu]Lu-PSMA-617 therapy.
Off-line PET imaging after proton therapy is limited by transport delay and by the sensitivity and short axial field of view of conventional scanners, which hinder imaging at ultralow activity and characterization of whole-body biologic washout. We evaluated whether a near-room total-body PET/CT system could enable clinically practical imaging of proton-induced activity after treatment and its whole-body biologic washout. Methods: We conducted a series of phantom studies to evaluate the performance of total-body PET at ultralow activity with Monte Carlo (MC)-simulated activity distributions as references. Nineteen patients with solid tumors underwent off-line total-body dynamic PET/CT imaging shortly after proton therapy. Spatial correlation between PET and MC results was quantified using the Dice similarity coefficient (DSC) and normalized cross-correlation (NCC). Dynamic images were reconstructed, and time-activity curves were extracted from volumes of interest to analyze the dynamic behavior of proton-induced activity. Results: In phantom experiments, PET images showed close spatial correspondence to MC reference distributions under ultralow activity. In patients, the agreement between PET and MC was higher for relatively stationary targets, with a mean DSC/NCC of 0.81 ± 0.09/0.81 ± 0.09 for the brain and 0.81 ± 0.05/0.83 ± 0.08 for the breast. Dynamic total-body PET images revealed biologic washout and whole-body redistribution of isotope activity within and beyond the gross tumor volumes, showing enrichment within the cardiac blood pool, major blood vessels, and blood-rich organs, such as the spleen and liver. Conclusion: Near-room total-body PET/CT enabled interpretable imaging under ultralow activity after treatment. Dynamic total-body imaging additionally captured whole-body biologic washout of proton-induced activity through blood circulation, providing a foundation for future washout modeling and methodologic development for in vivo treatment assessment.
The prevalence, clinical impact, and clonal dynamics of clonal hematopoiesis (CH) in patients receiving 177Lu-PSMA-617 (LuPSMA) for metastatic castration-resistant prostate cancer (mCRPC) are unknown. Methods: Targeted next-generation sequencing of 21 genes recurrently mutated in CH was performed on DNA extracted from the peripheral blood of patients who received at least 4 cycles of LuPSMA for mCRPC at our institution between 2022 and 2023. Pathogenic somatic mutations with a variant allele fraction of at least 1% were identified using a standardized pipeline. Clinical outcomes pertaining to efficacy (overall survival [OS], measured from date of planned cycle 5) and hematologic toxicity of LuPSMA were collected from the electronic medical record. Results: Fifty patients treated with LuPSMA were eligible, with a median follow-up of 23 mo. At least 1 CH variant was detected in 33 patients (66%). The most common mutations were TET2 (n = 16), PPM1D (n = 15), and DNMT3A (n = 6). OS was similar in patients with or without CH (12-mo OS, 92% vs. 80%; hazard ratio, 0.89; 95% CI, 0.3-2.68). There was a trend toward greater hematologic toxicity in patients with CH, with a greater need for growth factor support (12% vs. 0%). In patients with serial samples available, the emergence of new clones or expansion of preexisting CH variants was detected in most patients, particularly with PPM1D and TP53-mutant clones. The key limitation was the small sample size and short follow-up. Conclusion: CH was highly prevalent and tended to lead to greater hematologic toxicity in patients with mCRPC receiving LuPSMA. Expansion or emergence of DNA damage repair CH clones was very common during and after LuPSMA therapy. Further study of the impact of CH on radiopharmaceutical therapy, particularly when used in earlier prostate cancer disease settings, is warranted.
The aim of this study was to investigate the dynamic biodistribution of [68Ga]Ga-TEoS-DAZA, a functional liver PET tracer, in 2 preclinical models (ostrich embryos and mice) and in a healthy human liver donor to identify similarities and differences among the 3 species, which are relevant in translational nuclear medicine. Furthermore, the molecular pathway and metabolism of [68Ga]Ga-TEoS-DAZA was investigated. Methods: The dynamic biodistribution of [68Ga]Ga-TEoS-DAZA was determined via PET/CT in ostrich embryos, in healthy mice (C57BL/6), and in a healthy human liver donor. Hepatocyte transporter binding studies were performed in transfected HEK293t cells. Metabolite analysis was performed in samples from ostrich embryos and a healthy liver donor. Blocking studies against cyclosporine A were performed in ostrich embryos. Results: The biodistribution of [68Ga]Ga-TEoS-DAZA was comparable in ostrich embryos, healthy mice (C57BL/6), and the healthy donor. In all 3 species, the tracer showed specific uptake in liver tissue (30-40 %IA at time of peak) and subsequent biliary excretion, whereas less than 5 %IA activity was excreted renally. The hepatic transit time in mice was significantly faster than in ostrich embryos and human, with mice exhibiting a much shorter time-to-peak (1.7 min) than the other 2 species (15-21 min) and rapid clearance of the tracer from the liver into the intestines. [68Ga]Ga-TEoS-DAZA is a substrate for OATP1B3, with tracer uptake into the liver being hampered in the presence of cyclosporine A. Tissue samples revealed an as yet unknown radiometabolite of [68Ga]Ga-TEoS-DAZA, indicating hepatic metabolism. Conclusion: [68Ga]Ga-TEoS-DAZA was shown to be a suitable hepatobiliary tracer using both mice and ostrich embryos as preclinical models; however, there were limits in translatability in both models because of a distinctly faster hepatic uptake and biliary excretion (mice) or a slower biliary excretion (ostrich embryo) compared with that in the human.
The effectiveness and safety of Auger electron (AE)-emitting epidermal growth factor receptor (EGFR)-targeted panitumumab-197gHg-gold nanoparticles (AuNPs) or nontargeted 197gHg-AuNPs for treating glioblastoma multiforme (GBM) were studied after convection-enhanced delivery (CED) in NOD-Rag1nullIL2rgnull (NRG) mice with orthotopic GBM tumors. We hypothesized that EGFR binding, internalization, and nuclear importation of panitumumab-197gHg-AuNPs would make these radiation nanomedicines more effective than nontargeted 197gHg-AuNPs because of the subcellular range of AEs, but that both would be safe because of their confined localization at the infusion site in the brain after CED. Methods: Localization of 197gHg in NRG mice after CED was assessed by SPECT/CT imaging. Toxicity was evaluated after CED of 1.8 × 1011 to 2.3 × 1011 panitumumab-197gHg-AuNPs (0.9 ± 0.5 MBq) or nontargeted 197gHg-AuNPs (2.6 ± 0.8 MBq) by hematology, blood biochemistry, and body weight monitoring. Mice with U251-Luc tumors were treated with panitumumab-197gHg-AuNPs (1.3 ± 0.3 MBq) or 197gHg-AuNPs (1.1 ± 0.4 MBq), panitumumab-AuNPs or AuNPs, or 0.9% NaCl. Tumor response was assessed by MRI and Kaplan-Meier median survival. Self-absorbed doses in the nucleus of tumor cells from AEs were estimated. Toxicity to the brain was assessed by MRI and ex vivo histologic examination. Results: Both panitumumab-197gHg-AuNPs and 197gHg-AuNPs were confined to the infusion site with no redistribution to healthy brain or other organs. There was no hematologic, liver, or kidney toxicity and no decrease in body weight. MRI at 21 d and 34 d revealed that tumors in mice treated with panitumumab-197gHg-AuNPs or 197gHg-AuNPs were significantly smaller than tumors in mice treated with panitumumab-AuNPs, AuNPs, or 0.9% NaCl. Median survival in mice treated with panitumumab-197gHg-AuNPs (59 d) was significantly longer than that in mice treated with nontargeted 197gHg-AuNPs (43 d) or control treatments (31-33 d). The self-radiation absorbed dose in the nucleus of GBM tumor cells from AEs was 3.2-fold higher for panitumumab-197gHg-AuNPs (40.2 Gy) than for 197gHg-AuNPs (12.2 Gy). Conclusion: EGFR-targeted panitumumab-197gHg-AuNPs were more effective than nontargeted 197gHg-AuNPs for treating U251-Luc human GBM tumors in NRG mice. This approach may offer a safe and effective treatment for GBM that could improve patient survival.
Lesions with a Prostate Imaging-Reporting and Data System (PI-RADS) score of 4 or greater on multiparametric MRI (mpMRI) indicate a high likelihood of prostate cancer (PCa), and guidelines recommend a targeted biopsy. We aimed to compare the diagnostic performance of robotic arm-assisted [68Ga]Ga-PSMA-11 PET/CT-guided prostate biopsy (PGPB) with mpMRI-directed cognitive-fusion transrectal ultrasound-guided biopsy (MCFB) in biopsy-naïve men with clinical findings suggestive of PCa. Methods: This prospective, single-center, randomized clinical trial (NCT05137561) enrolled biopsy-naïve men age 50-90 y with elevated levels of prostate-specific antigen (≥4 ng/mL) and abnormal digital rectal examination findings. All participants underwent mpMRI, and those with a PI-RADS score of 4 or greater were randomized into 2 arms. In arm 1, participants underwent PGPB for a [68Ga]Ga-PSMA-avid lesion, and participants in arm 2 underwent MCFB. Participants in arm 1 with PET-negative findings subsequently underwent MCFB, and participants with negative biopsy results underwent PET and PGPB. The primary outcome was the detection of PCa. Secondary outcomes included complication rates and participant-reported pain. Result: Of the 267 participants enrolled, 81.3% (217) had lesions with a PI-RADS score of 4 or greater and were randomized to either PGPB (n = 112) or MCFB (n = 105). PCa was detected in 97.1% of participants (101/104) in arm 1 and 81.0% (85/105) in arm 2 (P < 0.05). PGPB showed higher diagnostic accuracy for PI-RADS 5 lesions (100% vs. 95.1%, P = 0.09). Major complications were observed in arm 2 only (n = 5). Arm 1 had significantly fewer complications (10.8% vs. 51.4%, P < 0.01), a lower median visual analog scale score for pain (3 vs. 5), and shorter procedure times. The core positivity rate was higher in arm 1 (60% ± 20%), despite obtaining fewer cores. Conclusion: [68Ga]Ga-PSMA-11 PCPB demonstrated higher diagnostic performance, fewer complications, and better tolerability compared with MCFB. This approach enables integrated diagnosis and staging, offering a promising alternative for efficient, safe, and accurate evaluation of prostate cancer.
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Radiopharmaceutical therapy (RPT) has re-emerged as a potent approach for targeting tumors, particularly for the treatment of neuroendocrine tumors and prostate cancer expressing the somatostatin and prostate-specific membrane antigen receptors, respectively. In addition to endogenously expressed proteins specific for these cancers, RPT has been explored using synthetic, engineered expression of proteins in tumor tissues. An early example of this was the use of sodium iodide symporter delivered to tumors using viral vectors, which were subsequently treated with [131I]NaI. This approach is complicated by the natural uptake in human tissues that express sodium iodide symporter (e.g., the thyroid). However, given the rapid acceleration of gene and cell therapies, expansion and re-exploration of the synthetic, genetically engineered RPT paradigm is warranted. This is especially true for RPT, which can be coupled with PET companion imaging agents. Methods: Here, we developed a β-emitter radiotherapeutic probe, radioiodinated trimethoprim ([131I]I-TMP), and evaluated its therapeutic potential. In addition, we developed [124/125I]I-TMP radiotracers for uptake and imaging studies. The selective cytotoxicity of [131I]I-TMP toward E. coli dihydrofolate reductase (eDHFR)-expressing cells was evaluated using time- and dose-dependent responses. Biodistribution was characterized in healthy mice followed by small-animal PET/CT studies using a tumor xenograft model and [124I]I-TMP. Finally, the eDHFR synthetic RPT approach was applied in murine cancer models to evaluate its cytotoxicity in tumors. Results: Radioiodinated trimethoprim radiotracers ([131/125/124I]I-TMP) exhibited selective uptake in eDHFR-positive tumors both in vitro and in vivo. Small-animal imaging with [124I]I-TMP demonstrated specific retention in I45-eDHFR tumors with negligible background signals. A dose-dependent and time-dependent cytotoxic effect was observed selectively in eDHFR cell lines. Furthermore, targeted treatment with [131I]I-TMP led to a significant reduction in tumor volume expressing eDHFR compared with wild-type tumors or untreated controls. Conclusion: This synthetic RPT approach shows promise for future applications in targeted cancer therapies and genetic medicine, particularly in the realm of theranostic strategies that integrate trimethoprim-based companion imaging and radiotherapy for the treatment of cancer.
Tau PET imaging with [18F]flortaucipir allows for the visualization and mapping of aggregated tau deposits, a key neuropathologic feature of Alzheimer disease (AD). A visual interpretation method for [18F]flortaucipir was approved by the Food and Drug Administration and European Medicines Agency and has been implemented for a standardized, clinically usable definition of tau PET positivity. The CenTauRz method, on the other hand, offers the possibility to harmonize the definition of tau PET positivity across different radiotracers using quantitative metrics, but its concordance with clinically relevant [18F]flortaucipir visual reads remains unclear. Methods: A convenience sample of 3991 participants, including cognitively unimpaired (CU) and cognitively impaired (CI) individuals (i.e., those with mild cognitive impairment or AD dementia), underwent [18F]flortaucipir PET imaging. Each [18F]flortaucipir scan was assessed by 3 trained readers using the approved visual interpretation method and quantified using the CenTauRz quantification pipeline in different regions of interest (ROIs). Concordance between positive visual reads and CenTauRz-defined positivity (i.e., >2 on the CenTauRz scale) was assessed using Cohen κ. Receiver-operating-characteristic (ROC) analysis evaluated the discriminative power of continuous CenTauRz values in distinguishing between negative and positive visual reads. Generalized additive models examined clinical progression on the basis of visual and CenTauRz-based assessments of tau PET positivity. Results: Concordance between visual reads and CenTauRz-based assessments of tau PET positivity was moderate, particularly in CU individuals (κ = 0.23-0.55 for CU participants, κ = 0.57-0.82 for CI participants, depending on the ROI). ROC analysis revealed that the agreement remained moderate, independent of the CenTauRz cut point used (area under the ROC curve, 0.72-0.87 vs. 0.87-0.97 for CU and CI individuals, respectively). Among discordant cases, participants with visually positive/CenTauRz-negative tau PET scans were more frequently amyloid-positive and exhibited faster clinical progression compared with visually negative/CenTauRz-positive individuals. Conclusion: Our findings highlight the relatively limited agreement between the visual assessment of [18F]flortaucipir PET images and CenTauRz-based quantification, particularly in CU individuals. Participants with visually positive/CenTauRz-negative tau PET scans showed a high frequency of amyloid positivity and faster clinical progression, suggesting that visual reads are more sensitive to heterogeneous, clinically relevant tau accumulation patterns not captured by ROI-based methods. These findings underscore the need for new quantification approaches to better capture the complex patterns of tau deposition, important for early AD detection and monitoring.
Metastatic castration-resistant prostate cancer (mCRPC) remains challenging to treat, especially after failure of standard therapies, such as androgen receptor pathway inhibitors and taxane-based chemotherapy. Radiopharmaceutical therapy with [177Lu]Lu-PSMA-617 targets prostate-specific membrane antigen (PSMA)-positive tumor cells. In the VISION trial, [177Lu]Lu-PSMA-617 has demonstrated significant benefits in terms of median overall survival and a significant improvement of median radiographic progression-free survival (PFS) versus standard of care. Recent guidelines support its use in PSMA-positive mCRPC. In France, [177Lu]Lu-PSMA-617 was available via an early-access program from December 1, 2021, to April 29, 2025. This analysis reports the largest real-world cohort of patients with mCRPC treated with [177Lu]Lu-PSMA-617, evaluating its use, safety, and effectiveness in routine clinical practice. Methods: This multicenter descriptive cohort included adult patients with mCRPC who had progressive disease after at least 1 androgen receptor pathway inhibitor and 1 taxane-based treatment, and 1 positive PSMA PET scan. Patients received up to 6 cycles of intravenous [177Lu]Lu-PSMA-617 every 6 wk. Clinical evaluation, prostate-specific antigen (PSA) status, imaging assessments, and treatment-related adverse events were prospectively collected during regular follow-up. PFS was analyzed using Kaplan-Meier methods. Outcomes were compared descriptively to the VISION trial. Results: From December 2021 to April 2025, 3709 patients from 46 centers received at least 1 dose and 2476 had more than 8 mo of follow-up for efficacy analysis. Compared with VISION, patients were older, more heavily pretreated, and had more lymph node metastases but lower baseline PSA. Median imaging PFS was 7.6 mo versus 8.7 mo in VISION. Disease control was achieved in 82% according to PSA criteria. Some patients with early PSA progression after the first cycle subsequently showed a response, suggesting a flare-up effect. The safety profile was manageable, with treatment discontinuations mainly due to progression. No new safety signals were identified. Subgroup analyses confirmed efficacy in elderly patients (aged >75 y) and more favorable outcomes in patients less heavily pretreated with taxane-based chemotherapy. Conclusion: The French early-access program confirms a favorable benefit-risk profile for [177Lu]Lu-PSMA-617 in a real-world mCRPC population. Use trends suggest earlier use of the treatment after 1 taxane-based treatment, with patients being less pretreated and characterized by fewer metastases.
Prostate-specific membrane antigen (PSMA) PET/CT has become a common staging modality for newly diagnosed high-risk and unfavorable intermediate-risk prostate cancer after showing improved sensitivity and specificity compared with conventional imaging in clinical trials. We aimed to assess the causal impact of PSMA PET staging on initial treatment selection in real-world practice. Methods: We used observational data from the U.S. Veterans Health Administration to emulate a randomized controlled trial in which patients with newly diagnosed, unfavorable intermediate-, high-, and very-high-risk prostate cancer from January 2022 to December 2023 would have been randomized to undergo either upfront 18F- or 68Ga-PSMA PET staging or conventional imaging (99mTc bone scan and pelvic CT or MRI). Outcomes of interest included use of frontline androgen deprivation therapy (ADT), second-generation androgen receptor pathway inhibitors (ARPIs), radiotherapy, and radical prostatectomy. Weighted univariable Cox regression was performed to assess the effect of treatment group on each outcome, and 95% CIs were generated from 1,000 bootstrap replicates. Results: In total, 9,049 patients met the criteria for inclusion. PSMA PET staging was associated with higher rates of any ADT use relative to conventional staging (adjusted hazard ratio [aHR], 1.26; 95% CI, 1.19-1.44), higher rates of ARPI use (aHR, 1.52; 95% CI, 1.33-1.78), lower rates of prostatectomy (aHR, 0.69; 95% CI, 0.56-0.83), and no significant effect on the use of radiotherapy (aHR, 1.10; 95% CI, 0.99-1.25). Compared with patients with PSMA stage N0M0, ARPI use was more common in patients with PSMA stage N1M0 (aHR, 6.87; 95% CI, 5.41-8.73) and PSMA stage M1 (aHR, 10.13; 95% CI, 8.16-1.2.58). Patients with PSMA N1M0 disease were much less likely to undergo prostatectomy compared with PSMA N0M0. Conclusion: PSMA PET staging may be leading to fewer prostatectomies and higher use rates of ADT and ARPIs in the Veterans Health Administration.
177Lu-prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical therapy is an established treatment for metastatic castration-resistant prostate cancer, though responses vary. A prognostic model using [68Ga]Ga-PSMA-11 PET-derived parameters was developed to predict therapy outcomes. This retrospective analysis validates the model in an independent cohort imaged with [18F]F-flotufolastat ([18F]rhPSMA-7.3 PET) before [177Lu]Lu-PSMA I&T. Methods: In total, 174 consecutive patients treated with [177Lu]Lu-PSMA I&T at a single center were included in this analysis. The Cox proportional hazards models for overall survival (OS) and prostate-specific antigen (PSA) progression-free survival (PFS) and the logistic regression model for PSA response, as proposed in the prognostic model, were applied to our validation data. Model performance was evaluated using the Harrell concordance index (C-index) and calibration plots. OS, PSA-PFS, and PSA response were reported with median values and 95% CI, as well as stratified by published cutoff values into low- and high-risk groups. Results: The estimated OS probabilities were 60% (95% CI, 53%-68%) at 12 mo and 40% (95% CI, 33%-49%) at 18 mo. Our validation yielded a C-index of 0.71 (95% CI, 0.67-0.76) for OS prediction compared with a C-index of 0.72 (95% CI, 0.68-0.76) in the validation cohort. For PSA-PFS, the estimated probabilities were 56% (95% CI, 49%-65%) at 3 mo and 34% (95% CI, 27%-42%) at 6 mo, with a C-index of 0.62 (95% CI, 0.57-0.67) compared with a C-index of 0.71 (95% CI, 0.68-0.74) in the validation data. Low-risk patients had significantly longer OS (21.8 vs. 11.6 mo, P < 0.0001) and PSA-PFS (6.9 vs. 2.9 mo, P = 0.003) than did high-risk patients. The prognostic PSA response model showed slightly worse discrimination in our cohort (area under the receiver operating characteristic curve, 0.71; 95% CI, 0.63-0.79) than with the validation data (area under the receiver operating characteristic curve; 95% CI, 0.78, 0.68-0.88). Conclusion: Our results indicate accuracy similar to that of the prognostic model for prediction of OS and PSA-PFS and for PSA response in an independent patient population undergoing [177Lu]Lu-PSMA I&T radiopharmaceutical therapy with [18F]F-flotufolastat instead of [68Ga]Ga-PSMA-11.
Macrophage depletion before myocardial infarction (MI) in mice disrupts the inflammatory healing response and leads to left ventricular thrombus formation and tissue calcification. Here, we aimed to determine the effect of clodronate-loaded liposome-mediated macrophage depletion on C-C chemokine receptor 2 (CCR2)-expressing immune cells after MI in male and female mice. Further, we sought to discern the relationship of clodronate liposomes with thrombus calcification and functional outcome using multitracer imaging. Methods: Male and female C57BL/6N mice underwent 60-min ischemia/reperfusion MI or sham surgery after a single or repeated injection of clodronate liposomes for macrophage depletion or injection with liposomes containing phosphate-buffered saline. Macrophage depletion was verified in peripheral blood. PET imaging was performed to assess infarct CCR2 signal at 2 or 4 d after MI and fibroblast activation protein expression at 7 d after MI. Microcalcification was assessed by 18F-NaF PET/CT over 4 wk. Cardiac function was assessed at 6 wk by MRI. Histopathology validated inflammation and calcification in the heart. Results: Macrophage depletion significantly increased susceptibility to early death after MI, especially in male mice. Molecular imaging revealed an early increase in cardiac CCR2 content after MI compared with sham, which persisted despite macrophage depletion. Histology verified reduced CD68 cell content but sustained CCR2 signal that partially overlapped CD11c, a marker of dendritic cells among other cell types. Ly6G-positive cell content increased in the myocardium of macrophage-depleted mice after MI but did not overlap with CCR2. All macrophage-depleted male mice and 64% of macrophage-depleted female mice developed a dense intracavity thrombus overlying endocardial damage, with gradual microcalcification starting from 2 wk and reaching a maximum at 4 wk after MI. Macrophage depletion did not impact infarct size or contractile function at 6 wk after MI in surviving mice. Conclusion: Macrophage depletion before MI elevated the risk of acute death, particularly in male mice. A persistent CCR2 PET signal suggested that non-CD68-positive immune cells contribute to tracer substrate and altered proportions of other immune cell subtypes during healing. These findings suggest that extreme antiinflammatory interventions after MI may have unintended consequences for scar formation and remodeling, which may be monitored by molecular imaging.
18F-PSMA PET/CT and pelvic MRI are useful for assessing biochemical recurrence of prostate cancer after prostatectomy. We evaluated the role of 18F-PSMA PET/MRI in a 1-stop-shop protocol combining a single injection of 18F-PSMA, followed by pelvic PET/multiparametric MRI (mpMRI) and whole-body PET/CT acquisitions for the detection of recurrent disease. Methods: We evaluated 106 consecutive patients referred to our institute for biochemical recurrence after prostatectomy using a 1-stop-shop protocol comprising whole-body 18F-PSMA PET/CT and pelvic 18F-PSMA PET/mpMRI. Each imaging modality was reviewed in a blinded manner by 2 independent, experienced readers. 18F-PSMA PET/MRI, with positivity on either MRI or PSMA PET, served as the reference standard. Results: 18F-PSMA PET/MRI detected more local recurrences (n = 52, 49.06%) compared with 18F-PSMA PET/CT (n = 42, 39.62%) and mpMRI (n = 46, 43.00%). Discordant cases accounted for 18 patients (17%): 10% were positive only on MRI and 7% only on PSMA PET. Compared with 18F-PSMA PET/MRI, both mpMRI and 18F-PSMA PET demonstrated similar performance, with sensitivities of 88.5% and 78.8% and specificities of 100% and 98.1%, respectively. Conclusion: 18F-PSMA PET/MRI outperformed PET/CT and mpMRI in the detection of local recurrences of prostate cancer.
Determination of glomerular filtration rate (GFR) with 99mTc-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA) is a validated method to assess renal function, but there are no well-established pediatric reference ranges for GFR. The aim of this study was to establish reference GFRs in children and young adults. Methods: GFR was calculated for 235 reference subjects (median age, 4.86 y; range, 20 d to 24.8 y) using 99mTc-DTPA at Boston Children's Hospital between 2000 and 2020. This included 220 patients for prechemotherapy evaluation and 15 potential kidney donors. GFR was determined using a single-compartment model after a single intravenous injection technique and serial blood sampling at 2, 3, and 4 h. Data were analyzed by age, corrected for body surface area, and normalized to a body surface area of 1.73 m2 The 95% reference ranges were calculated as mean ± 1.96 SD. Results: GFR increased with age, likely reflecting increased functional renal mass. Lower normalized GFR in children younger than 1 y may reflect renal immaturity. Conclusion: The use of a single injection of 99mTc-DTPA revealed that GFR increases with age, likely reflecting increased renal mass. Further, in patients younger than 1 y, GFR rapidly increases initially, with a subsequent more gradual increase, reaching the adult level by approximately 2 y of age. Between 2 and 10 y of age, the GFR slightly exceeds the adult level, stabilizing at a slightly lower adult level by 10 y of age.