Chinese journal of cancer research = Chung-kuo yen cheng yen chiu · 2026
Early prediction of synergistic cardiotoxicity induced by PD-1 inhibitors and doxorubicin using cardiac 18F-FDG PET/MRI.
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Cai Yuqi, Yuan Tingting, Xu Xiaoxia, Sun Yang, Chen Xuetao, Wei Maomao, Wu Yichen, Zhu Hua, Yang Zhi, Wang Xuejuan
Аннотация
OBJECTIVE: Early detection of synergistic cardiotoxicity induced by sequential anthracycline and programmed cell death protein 1 (PD-1) inhibitor therapy remains challenging because conventional assessments identify late-stage functional impairment. This study aimed to determine the sensitive imaging probe for early therapy-associated cardiotoxicity and validate findings using integrated positron emission tomography/magnetic resonance imaging (PET/MRI).
METHODS: Cardiotoxicity was assessed in mouse models treated with PD-1 inhibitor or sequential doxorubicin (DOX) and PD-1 inhibitor therapy. Serial biodistribution analyses of 18F-fluorodeoxyglucose (18F-FDG), 18F-fibroblast activation protein inhibitor (18F-FAPI), 99mTc-methoxyisobutylisonitrile (99mTc-MIBI), and 11C-acetate were performed. Histopathological evaluation assessed inflammation, mitochondrial injury, and fibrosis. Findings were validated in a prospective lymphoma cohort receiving sequential anthracycline and PD-1 inhibitor therapy using integrated 18F-FDG PET/MRI. Myocardial maximum standardized uptake value (SUVmax), strain parameters, tissue mapping indices, and electrocardiographic (ECG) changes were analyzed.
RESULTS: Sequential DOX and PD-1 inhibitor therapy induced an early increase in myocardial 18F-FDG uptake in mice before preceding systolic dysfunction. Histopathological examination confirmed inflammatory cell infiltration and mitochondrial swelling without extracellular matrix remodeling. In contrast, uptake of 18F-FAPI, 99mTc-MIBI, and 11C-acetate remained unchanged. In patients with lymphoma, myocardial SUVmax was significantly higher in patients with ECG abnormalities [ECG(+)] than in those without ECG abnormalities [ECG(-)], whereas global longitudinal strain, global radial strain, and global circumferential strain were significantly reduced (all P<0.05). After the third PD-1 cycle, myocardial SUVmax remained elevated in ECG(+) patients, whereas strain parameters declined after 5-6 cycles, suggesting that metabolic alterations precede functional impairment. SUVmax_heart demonstrated the highest diagnostic accuracy for cardiotoxicity [cutoff=3.0; area under the curve (AUC)=0.873; sensitivity=93.3%; specificity=80.0%].
CONCLUSIONS: Cardiac 18F-FDG PET/MRI enables early detection of synergistic cardiotoxicity induced by DOX and PD-1 inhibitors before structural or functional deterioration occurs. SUVmax_heart may serve as an imaging biomarker for risk stratification and timely cardioprotective intervention.
METHODS: Cardiotoxicity was assessed in mouse models treated with PD-1 inhibitor or sequential doxorubicin (DOX) and PD-1 inhibitor therapy. Serial biodistribution analyses of 18F-fluorodeoxyglucose (18F-FDG), 18F-fibroblast activation protein inhibitor (18F-FAPI), 99mTc-methoxyisobutylisonitrile (99mTc-MIBI), and 11C-acetate were performed. Histopathological evaluation assessed inflammation, mitochondrial injury, and fibrosis. Findings were validated in a prospective lymphoma cohort receiving sequential anthracycline and PD-1 inhibitor therapy using integrated 18F-FDG PET/MRI. Myocardial maximum standardized uptake value (SUVmax), strain parameters, tissue mapping indices, and electrocardiographic (ECG) changes were analyzed.
RESULTS: Sequential DOX and PD-1 inhibitor therapy induced an early increase in myocardial 18F-FDG uptake in mice before preceding systolic dysfunction. Histopathological examination confirmed inflammatory cell infiltration and mitochondrial swelling without extracellular matrix remodeling. In contrast, uptake of 18F-FAPI, 99mTc-MIBI, and 11C-acetate remained unchanged. In patients with lymphoma, myocardial SUVmax was significantly higher in patients with ECG abnormalities [ECG(+)] than in those without ECG abnormalities [ECG(-)], whereas global longitudinal strain, global radial strain, and global circumferential strain were significantly reduced (all P<0.05). After the third PD-1 cycle, myocardial SUVmax remained elevated in ECG(+) patients, whereas strain parameters declined after 5-6 cycles, suggesting that metabolic alterations precede functional impairment. SUVmax_heart demonstrated the highest diagnostic accuracy for cardiotoxicity [cutoff=3.0; area under the curve (AUC)=0.873; sensitivity=93.3%; specificity=80.0%].
CONCLUSIONS: Cardiac 18F-FDG PET/MRI enables early detection of synergistic cardiotoxicity induced by DOX and PD-1 inhibitors before structural or functional deterioration occurs. SUVmax_heart may serve as an imaging biomarker for risk stratification and timely cardioprotective intervention.