The Journal of Nuclear Medicine最新文献

Gastric cancer remains a major global health challenge with few durable treatments, and claudin-18.2 (CLDN18.2) has emerged as an attractive therapeutic target, highlighted by the modest activity of zolbetuximab in clinical trials. To further leverage CLDN18.2 as a therapeutic target, we developed a radiotheranostic strategy using [⁸⁹Zr]Zr-zolbetuximab and [¹⁷⁷Lu]Lu-zolbetuximab for molecular imaging and targeted radiotherapy, respectively. Methods: We performed [⁸⁹Zr]Zr-zolbetuximab immuno-PET imaging to quantify and localized CLDN18.2 expression in vivo, comparing uptake with [⁸⁹Zr]Zr-trastuzumab in matched human epidermal growth factor receptor 2–positive patient-derived xenograft models. We then evaluated the therapeutic efficacy and safety of [¹⁷⁷Lu]Lu-zolbetuximab versus [¹⁷⁷Lu]Lu-trastuzumab, assessing tumor inhibition, tolerability, hematologic profiles, and histopathology. Results: PET imaging confirmed selective accumulation in tumor tissue, which correlated with immunohistochemistry results, validating a biomarker-driven approach for patient stratification. Therapeutic dosing resulted in sustained tumor control with an acceptable safety profile characterized by transient weight loss and hematologic suppression that largely recovered over time. Unlike prior studies using engineered cell line–derived xenografts that overexpress CLDN18.2 and display high hepatic uptake with limited tumor localization, we used patient-derived xenograft models that preserved endogenous antigen levels, stromal complexity, and vascular heterogeneity, achieving superior tumor targeting and lower nonspecific liver uptake. Conclusion: These findings outline a clinically relevant roadmap for CLDN18.2 radiotheranostics in which imaging enables patient selection and dosimetry, therapy delivers targeted tumor control, and rational combinations with chemotherapy or immunotherapy may further extend efficacy. Ultimately, this approach could make antibody-based radiopharmaceuticals a transformative modality in gastric cancer.

Coronary artery calcium (CAC) scoring has been incorporated into preventive guidelines and is increasingly studied as a gatekeeper to further testing. A CAC score of 0 is traditionally associated with low cardiovascular risk. However, the CAC score primarily quantifies calcified plaque, potentially overlooking noncalcified atherosclerosis and microvascular dysfunction, which also contribute to adverse outcomes. This study aimed to assess the prevalence, predictors, and prognostic value of impaired PET-derived myocardial flow reserve (MFR) in patients with a CAC score of 0. Methods: We analyzed 2,270 symptomatic patients across 2 centers who had a CAC score of 0 and underwent a clinically indicated PET. Multivariate logistic regression was used to identify predictors of impaired MFR. Nested Cox models were used to assess the incremental prognostic value of MFR for a composite of all-cause death, myocardial infarction/late revascularization, and heart failure admission. The C-index and net reclassification improvement (NRI) were also calculated. Results: The prevalence of impaired MFR was 30.5%. Significant predictors included age, morbid obesity (BMI ≥ 40 kg/m²), diabetes, hypertension, and chronic kidney disease. Over a median follow-up of 1.63 y, impaired MFR was associated with higher event rates (hazard ratio, 4.69; 95% CI, 2.69–8.2). Adding MFR improved risk prediction (C-index, 0.784–0.815; P < 0.001; categoric NRI, 0.163; continuous NRI, 0.899). The impact of MFR was most pronounced in the intermediate risk category, upgrading 16.8% of patients (4% annual event rate) and downgrading 53.9% (0.9% annual event rate). Conclusion: One in 3 symptomatic patients with a CAC score of 0 had impaired MFR, which was independently associated with adverse outcomes. MFR enhanced risk stratification, highlighting its utility in identifying high-risk individuals with a CAC score of 0 who may benefit from intensive therapy.

In transthyretin cardiac amyloidosis (ATTR-CA), static ¹⁸F-flutemetamol PET–derived SUVs do not adequately capture intricate tracer kinetics, limiting the accurate quantification of amyloid burden. We developed dynamic parametric PET imaging methods to improve the quantification of myocardial amyloid burden in ATTR-CA. Methods: Twelve treatment-naïve ATTR-CA patients underwent 60-min dynamic cardiac ¹⁸F-flutemetamol PET/CT at baseline and after 6 mo of treatment with tafamidis. Image-derived input functions were corrected for blood-to-plasma ratios and metabolites. Myocardium blood volume fraction was estimated using a 1-tissue compartment model (0–10 min), and volume-of-distribution (V_T) images were generated using the multilinear analysis 1 method (2–20 min). V_T was correlated with echocardiography, ⁸²Rb myocardial blood flow, and biomarkers. Results: The mean myocardial blood volume fraction was 22% ± 6%. A 2-tissue reversible model with metabolite- and plasma-corrected input functions provided optimal kinetic fits. Multilinear analysis 1 using 2- to 20-min PET data produced V_T images with the lowest variance. V_T decreased significantly after 6 mo of treatment with tafamidis (from 2.11 ± 0.33 to 1.96 ± 0.20, P = 0.046). Conclusion: Dynamic ¹⁸F-flutemetamol PET enabled robust quantification of myocardial amyloid burden using metabolite-corrected 2-compartment modeling. V_T imaging demonstrated sensitivity to treatment-related changes in ATTR-CA.

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 (SUV_max, ≥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.

Genomic alterations are common in metastatic castration-resistant prostate cancer (mCRPC), but limited data exist on the response to ¹⁷⁷Lu-PSMA-617 (LuPSMA) in patients with these aberrations. We aimed to characterize oncologic outcomes of patients with mCRPC and germline or somatic aberrations after treatment with LuPSMA. Methods: The medical record was surveyed for all patients with mCRPC treated with LuPSMA between October 2022 and October 2024. All patients who had received at least 1 cycle of LuPSMA and underwent either germline or somatic testing were included. Results: Seventy-two patients were included. Patients with TP53/PTEN/RB1 mutations demonstrated inferior overall survival, even after adjustment for age and race. TP53/PTEN/RB1, BRCA1/2, and CHEK2/PALB2/ATM were not associated with inferior progression-free survival. No individual mutation was significantly associated with changes in the percentage decline in prostate-specific antigen levels from baseline. Conclusion: TP53, PTEN, and RB1 mutations were linked to inferior overall survival in LuPSMA-treated patients and may serve as prognostic biomarkers. Prospective validation is required to establish their predictive value.

Treatment-refractory and relapsed disease remain leading causes of death for patients with lymphoma. Virtually all lymphomas are exquisitely sensitive to radiation, and α-particle radiation therapies are notably suited to targeting microcluster disease common in the setting of early relapse. Refractory or relapsed lymphoma may also involve the loss of therapeutic targets, but radiation may stimulate antitumor immune effects against disease with incomplete target expression. Such effects make immune checkpoint inhibition a compelling candidate for combination treatment. Methods: We evaluated the therapeutic efficacy of ²¹¹At-labeled antihuman CD20 monoclonal antibodies combined with immune checkpoint inhibition in human CD20 transgenic mice bearing murine lymphomas on opposing flanks that were either positive or negative for human CD20 expression (hCD20⁽⁺⁾ and hCD20^(–), respectively). Results: In the absence of ²¹¹At-hCD20, the antimurine checkpoint inhibitors PD1, CTLA4, CD47, and TIM3 had no efficacy given alone or in doublets. ²¹¹At-hCD20 given alone suppressed growth of both hCD20⁽⁺⁾ and hCD20^(–) tumors in a dose-dependent fashion, with predictably stronger suppression of hCD20⁽⁺⁾ tumors. Strikingly, the addition of PD1 alone or the PD1 plus CTLA4 doublet to low-dose ²¹¹At-hCD20 significantly strengthened suppression of both tumors and increased mouse survival. Conclusion: Future translation of this synergistic combination of α-radiotherapy and immune checkpoint inhibition holds promise for the treatment of high-risk aggressive lymphomas, including cases with postinduction minimal residual disease or antigen loss after targeted therapies.