Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME). The abundance and distribution of TAMs significantly affect the immune responses of TME to determine the tumor progression and treatment response of solid tumors such as head and neck squamous cell carcinoma (HNSCC). Molecular characterization of human HNSCC specimens and mouse models has identified CD163 as a unique biomarker for TAMs in HNSCC. The goal of this study was to determine the dynamic changes of CD163-positive TAMs in HNSCC progression and treatment response to assess the potential of a CD163 targeted radiotracer, 64Cu-ICT-01, in detecting CD163-positive TAMs for translation in HNSCC. Methods: We assessed the capability of 64Cu-ICT-01 for noninvasive imaging of CD163-positive TAMs using PET. We determined its targeting specificity in multiple mouse HNSCC models to track the progression of tumors. We assessed its sensitivity in tracking variations of CD163-positive TAMs and correlation with tumor volumes after clinical treatment. We also measured its binding to CD163-positive TAMs upregulated on human HNSCC tissues. Results: 64Cu-ICT-01 PET specifically determined the spatiotemporal distribution of CD163-positive TAMs in a MOC1 cell line model and patient-derived xenograft HNSCC models. CD163 PET sensitively tracked the dynamics of CD163-positive TAMs after clinical treatment. Its tumor binding correlated with CD163 expression levels and the volumes of tumors. In human HNSCC specimens, 64Cu-ICT-01 showed strong and specific binding to human CD163. Conclusion: 64Cu-ICT-01 demonstrated accurate targeting of CD163 in both mouse tumor models and human HNSCC tissues. CD163 PET has great potential to be a noninvasive biomarker to measure TAM activities within TME, monitor treatment response, and optimize treatment strategy.
Rapid radiopharmaceutical clearance limits the efficacy of peptide receptor radionuclide therapy (PRRT) for the treatment of advanced neuroendocrine tumors (NETs). In this prospective, single-center, single-arm, investigator-initiated trial, we evaluated the safety and efficacy of 177Lu-LNC1010-an optimized, long-acting somatostatin analog-in patients with progressive metastatic NETs. Methods: Twenty-two patients with unresectable, metastatic NETs and disease progression despite treatment with somatostatin analogs or tyrosine kinase inhibitors were enrolled in the study. Participants received up to 4 cycles of PRRT with 177Lu-LNC1010 (3.3 GBq/cycle) at 8-wk intervals. Adverse events were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0. The treatment response was evaluated using RECIST 1.1. Kaplan-Meier analysis was used to estimate progression-free survival (PFS) and overall survival (OS). Results: The patients (13 men, 9 women; median age, 50.5 y) received 69 PRRT cycles in total. Treatment-related grade 3 or 4 hematologic toxicities were observed in 6 patients (27%). No grade 3 or higher nephrotoxicity or hepatotoxicity was recorded. The median absorbed tumor dose was 2.12 (interquartile range: 1.68-2.96) Gy/GBq. Response after PRRT was assessed in 18 patients. A partial response was achieved in 8 patients (44.0%), stable disease in 9 (50.0%), and progressive disease in 1 (5.6%). The objective response rate was 44.4%, and the disease control rate was 94.4%. After a median follow-up of 21.0 mo, the median PFS was 15.0 mo, and the median OS was not reached. Conclusion: PRRT with 3.3 GBq/cycle of 177Lu-LNC1010 was well-tolerated and exhibited an acceptable safety profile. The objective response rate and disease control rate were high and positively correlated with improved PFS and OS. Appropriate patient selection and earlier intervention may further optimize the therapeutic benefit.
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.
Real-world disparities in access to PSMA-targeted theranostics are poorly characterized. We compared waiting times for PSMA PET/CT and 177Lu-PSMA therapy between centers in Brazil and Europe. Methods: This retrospective multicenter study included 91 patients (50 from Brazil, 41 from Europe) treated with 177Lu-PSMA. Outcomes were days from request to PSMA PET/CT completion (diagnostic access) and days from request to first therapy dose (therapeutic access). Groups were compared using the Mann-Whitney U test. Results: Diagnostic access was similar between Brazil (median, 17.5 d; interquartile range [IQR], 9-34 d) and Europe (median, 19 d; IQR, 14-23 d; P = 0.39). Therapeutic access was significantly delayed in Brazil (median, 59 d; IQR, 54.5-91) compared with Europe (median, 21 d; IQR, 17-31 d; P < 0.01), representing a 2.8-fold longer wait. Conclusion: Despite comparable access to PSMA PET/CT, initiation of 177Lu-PSMA therapy is nearly 3 times slower in Brazil than in Europe. Closing the therapeutic access gap requires targeted investments in radiopharmaceutical supply chains and regulatory efficiency.
Fibroblast activation protein (FAP) and integrin αvβ3 are attractive theranostic targets. We developed a dual-targeting radiotheranostic agent, 177Lu-DOTA-FAPI-RGD (177Lu-LNC1009), and conducted a first-in-human study to evaluate its safety, biodistribution, dosimetry, and preliminary efficacy in patients with advanced adenocarcinomas. Methods: LNC1009 was synthesized by conjugating an FAP inhibitor, an RGDfK peptide, and DOTA. Preclinical biodistribution was assessed in HT1080-FAP and U87MG xenografts. Nine patients with advanced solid tumors and positive 68Ga-FAPI-RGD PET/CT received 2.0 ± 0.3 GBq (range, 1.6-2.4 GBq) of 177Lu-LNC1009. Primary endpoints included biodistribution, dosimetry, and safety; efficacy was the secondary endpoint. Results: 177Lu-LNC1009 showed high radiochemical purity and stability, strong dual-target binding, and sustained tumor uptake with favorable tumor-to-background ratios. In patients, treatment was well-tolerated, with no grade 4 adverse events. The whole-body effective dose was 0.08 ± 0.02 mSv/MBq. Mean absorbed doses were 0.04 ± 0.01 Gy/GBq (red marrow), 0.50 ± 0.31 Gy/GBq (liver), and 0.31 ± 0.11 Gy/GBq (kidneys). Tumor-absorbed doses reached 6.10 ± 1.42 Gy/GBq (lung metastases) and 4.20 ± 0.84 Gy/GBq (lymph nodes). Grade 3 adverse events included thrombocytopenia (n = 3), leukopenia (n = 2), and anemia (n = 1). Partial responses occurred in 2 patients (22.2%), stable disease in 6 (66.7%), and progressive disease in 1 (11.1%), yielding an objective response rate of 22.2% and disease control rate of 88.9%. Conclusion: This first-in-human, dual-targeting radiopharmaceutical therapy agent 177Lu-LNC1009 demonstrated favorable dosimetry, high tumor radiation delivery, and encouraging preliminary efficacy across a variety of advanced solid tumors. Future ligand structural optimization and refined screening protocols are warranted to improve safety and further efficacy in multicycle, tumor-specific dose-escalation trials.
Prostate-specific membrane antigen (PSMA)-targeted PET/CT (PSMA PET/CT) has become the first-line imaging modality used for staging and restaging prostate cancer. Its utility after minimally invasive focal therapy (high-intensity focused ultrasound, laser ablation, cryoablation) remains unclear. This study evaluated PSMA PET/CT for detecting and localizing recurrence after focal therapy. Methods: This retrospective single-center study included patients with prior focal therapy for prostate cancer who underwent 68Ga-PSMA-11 PET/CT for suspected recurrence between 2016 and 2023 without intervening treatment. Three masked readers analyzed whole-body PET/CT images using a per-region (prostate, pelvic nodes, distant metastases) majority rule for per-patient positivity. Interreader agreement was determined using Fleiss κ. In a subcohort of 39 patients with both MRI and biopsy results available within 3 mo of PSMA PET/CT, per-patient and per-segment (12 prostate segments) accuracy was assessed. One masked reader evaluated PET/CT at 60 min (whole-body) and 90 min (pelvic) postinjection, and one prostate MRI expert independently read the MRI scans. Biopsy pathology-confirmed clinically significant prostate cancer, defined as International Society of Urological Pathology grade 2 or greater, served as the reference standard. Results: In total, 112 patients were included. PSMA PET/CT showed 82% positivity for intraprostatic recurrence, 15% for pelvic nodes, and 9% for distant metastases. Interreader agreement was moderate (κ = 0.4; 95% CI, 0.32-0.54). In the subcohort, per-patient sensitivity was 85% for PET vs. 82% for MRI. All cases with an SUVmax of 10 or greater had an ISUP grade group of 3 or greater. Conclusion: PSMA PET/CT effectively localizes prostate cancer recurrence after focal therapy, outperforming MRI on sensitivity.
The Highlights Lecture, presented at the closing session of each SNMMI Annual Meeting, was originated and presented for more than 30 years by Henry N. Wagner, Jr., MD. Beginning in 2010, the duties of summarizing selected significant presentations at the meeting were divided annually among 4 distinguished nuclear and molecular medicine subject matter experts. The 2026 Highlights Lectures were delivered on June 2 at the SNMMI Annual Meeting in Los Angeles, California. Presented here is the lecture by René R. Sevag Packard, MD, PhD, Associate Professor-in-Residence, David Geffen School of Medicine, University of California Los Angeles, California, who spoke on cardiovascular topics presented at the meeting. Note that in the following presentation summary, numerals in brackets represent abstract numbers as published in The Journal of Nuclear Medicine (2026;67[suppl 1]).
C-X-C motif chemokine receptor 4 (CXCR4) has emerged as a powerful imaging target in nuclear oncology. In this regard, the PET agent [68Ga]Ga-pentixafor is promising but still evolving. In this article, we provide an overview of potentially useful imaging applications for CXCR4-targeted imaging in hemato-oncology and guidance on scan interpretation by discussing diagnostic pitfalls. We also report on theranostic efforts and how the field has been expanded toward the imaging of solid tumors. As such, this review focuses on potential clinical integration of CXCR4-targeted molecular imaging across multiple disease entities, particularly in the field of hemato-oncology.
