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PurposeThis study aimed to evaluate the potential utility of [68Ga]Ga-FAPI-04 PET/CT for diagnosing primary and metastatic lesions in patients with liver cancer, as well as to compare it with contrast-enhanced CT (CE-CT), liver MRI, and [18F]-FDG PET/CT.MethodsWe performed a single-center post hoc retrospective analysis of data obtained from a prospective parent study (NCT04416165). This study included 34 patients diagnosed with or suspected hepatic lesions who underwent concomitant [68Ga]Ga-FAPI-04 and [18F]-FDG/CT scans. Moreover, these patients underwent liver MRI (n = 34) and CE-CT (n = 25). Histopathologic (n = 62) or radiographic follow-up (n = 128) served as the reference standard for the final diagnosis.ResultsAmong the 34 patients, 20, 12, and 2 patients presented with hepatocellular carcinomas, intrahepatic cholangiocarcinomas, and benign hepatic nodules, respectively. The sensitivities of CE-CT, MRI, [68Ga]Ga-FAPI-04, and [18F]-FDG/CT for detecting primary liver tumors were 96%, 100%, 96%, and 65%, respectively. Regarding the diagnosis of all intrahepatic lesions, the per-lesion detection rate of [68Ga]Ga-FAPI-04 PET/CT was slightly lower than that of MRI (85% vs. 100%, P = 0.34) and significantly higher than that of [18F]-FDG PET/CT (85% vs. 52%, P < 0.001). Regarding the diagnosis of all malignant lesions (including extrahepatic disease), the tumor detection rate of [68Ga]Ga-FAPI-04 PET/CT was 87.4%, which was significantly higher than that of [18F]-FDG PET/CT (65.0%, P < 0.001).ConclusionsOur findings indicate that the sensitivity of [68Ga]Ga-FAPI-04 PET/CT to correctly identify primary liver tumors and metastatic lesions is equivalent to that of CE-CT and liver MRI. Moreover, [68Ga]Ga-FAPI-04 PET/CT is better at identifying liver lesions than [18F]-FDG PET/CT, and its use may improve tumor staging, recurrence detection, and implementation of necessary treatment modifications.

Purpose The aim of this study was to explore the correlation of 18 F-labeled fibroblast activation protein inhibitor (FAPI) and cardiovascular magnetic resonance (CMR) parameters in ST-elevation myocardial infarction (STEMI) patients with successful primary percutaneous coronary intervention (PPCI) and to investigate the value of FAPI imaging in predicting cardiac functional recovery, as well as the correlation between FAPI activity and circulating fibroblast activation protein (FAP) and inflammatory biomarkers. Methods Fourteen first-time STEMI patients (11 men, mean age: 62 ± 11 years) after PPCI and 14 gender-matched healthy volunteers (10 men, mean age: 50 ± 14 years) who had completed FAPI imaging and blood sample collection were prospectively recruited. All patients underwent baseline FAPI imaging (6 ± 2 days post-MI) and CMR (8 ± 2 days post-MI). Ten patients had follow-up CMR (84 ± 4 days post-MI). Myocardial FAPI activity was analyzed for extent (the percentage of FAPI uptake volume over the left ventricular volume, FAPI%), intensity (target-to-background uptake ratio, TBRmax), and amount (FAPI% × TBRmax). Late gadolinium enhancement (LGE), T2-weighted imaging (T2WI), extracellular volume (ECV), microvascular obstruction (MVO), and cardiac function from CMR imaging were analyzed. Blood samples obtained on the day of FAPI imaging were used to assess circulating FAP, TGF-β1, TNF-α, IL-6, and hsCRP in STEMI patients and controls. Results Localized but inhomogeneous FAPI uptake was observed in STEMI patients, which was larger than the edematous and infarcted myocardium, whereas no uptake was detected in controls. The MVO area showed lower FAPI uptake compared with the surrounding myocardium. FAPI activity was associated with the myocardial injury biomarkers T2WI, LGE, and ECV at both per-patient and per-segment levels (all p  < 0.05), but was not associated with circulating FAP, TGF-β1, TNF-α, IL-6, or hsCRP. Among the CMR parameters, T2WI had the greatest correlation coefficient with both FAPI% and FAPI% × TBRmax. Baseline TBRmax was inversely correlated with the follow-up left ventricular ejection fraction (LVEF) ( r  =  − 0.73, p  = 0.02). Conclusion FAPI imaging detects more involved myocardium than CMR in reperfused STEMI, and is associated with myocardial damage and follow-up LVEF.

PurposeThis study aimed to explore the clinical utility of [68Ga]Ga-labeled fibroblast activation protein inhibitor ([68Ga]Ga-FAPI) positron emission tomography/computed tomography (PET/CT) relative to [18F]-fluorodeoxyglucose ([18F]FDG) PET/CT and magnetic resonance imaging (MRI) for primary staging and recurrence detection in nasopharyngeal carcinoma (NPC).MethodsThis retrospective analysis utilized a sub-cohort of patients from a previously acquired database. Patients with NPC who underwent [18F]FDG and [68Ga]Ga-FAPI PET/CT between October 2019 and November 2020 were included. The radiotracer uptake and clinical staging/restaging performances of [18F]FDG and [68Ga]Ga-FAPI PET/CT were compared.ResultsForty-five participants (39 for initial assessment, 6 for recurrence detection) were included. In treatment-naïve participants, [68Ga]Ga-FAPI PET/CT showed higher radiotracer uptake than [18F]FDG PET/CT in primary tumors (16.18 vs. 10.11, P < 0.001), regional lymph nodes (11.42 vs. 7.37, P < 0.001), and bone and visceral metastases (6.94 vs. 3.11, P < 0.001). Compared with the [18F]FDG-based TNM stage, the [68Ga]Ga-FAPI-based TNM stage was upgraded in ten patients (26%), resulting in management changes in seven patients (18%). Compared with MRI, [68Ga]Ga-FAPI PET/CT upgraded and underestimated the T stage in four and two patients, respectively. In post-treatment patients, [68Ga]Ga-FAPI PET/CT yielded more true-positive findings than [18F]FDG PET/CT in detecting local recurrence.Conclusion[68Ga]Ga-FAPI PET/CT is a promising imaging modality for the diagnosis of primary and metastatic NPC. The exact tumor geographic imaging obtained through [68Ga]Ga-FAPI PET/CT may be a supplement to MRI for T staging and radiotherapy planning.

PurposeTo assess predictive value of 68Ga-labeled fibroblast activation protein inhibitor-04 ([68Ga]Ga-DOTA-FAPI-04) PET/MR for late left ventricular (LV) remodeling in patients with ST-segment elevated myocardial infarction (STEMI).MethodsTwenty-six patients with STEMI were included in the study. [68Ga]Ga-DOTA-FAPI-04 PET/MR was performed at baseline and at average 12 months after STEMI. LV remodeling was defined as >10% increase in LV end-systolic volume (LVESV) from baseline to 12 months.ResultsThe LV remodeling group demonstrated higher [68Ga]Ga-DOTA-FAPI-04 uptake volume (UV) at baseline than the non-LV remodeling group (p < 0.001). [68Ga]Ga-DOTA-FAPI-04 UV at baseline was a significant predictor (OR = 1.048, p = 0.011) for LV remodeling at 12 months after STEMI. Compared to clinical information, MR imaging and cardiac function parameters at baseline, [68Ga]Ga-DOTA-FAPI-04 UV demonstrated better predictive ability (AUC = 0.938, p < 0.001) for late LV remodeling, with sensitivity of 100.0% and specificity of 81.3%.Conclusions[68Ga]Ga-DOTA-FAPI-04 PET/MR is an effective tool to non-invasively quantify myocardial fibroblasts activation, and baseline [68Ga]Ga-DOTA-FAPI-04 UV may have potential predictive value for late LV remodeling.

Purpose The upregulation of fibroblast activation protein (FAP) expression has been observed in various cancers, including metastatic breast carcinoma, prompting research into small molecule inhibitors for both diagnostic and therapeutic purposes. While the diagnostic value of PET/CT imaging using 68  Ga- or 18 F-labelled FAPi-monomers in breast cancer diagnosis is well-established, there is a significant need for therapeutic analogs. This retrospective study aimed to assess the safety and effectiveness of [ 177 Lu]Lu-DOTAGA.FAPi dimer radionuclide therapy in patients with advanced-stage breast cancer who had previously undergone [ 68  Ga]Ga-DOTA.SA.FAPi PET/CT scans to confirm the expression of FAP. Materials and methods Between November 2020 and March 2023, a compassionate treatment approach was utilized to administer [ 177 Lu]Lu-DOTAGA.FAPi dimer radionuclide therapy to heavily pretreated patients with advanced breast cancer. Nineteen patients (18 females, 1 male) with metastatic breast cancer participated in the study, with an average age of 44.6 ± 10.7 years. The therapy was administered at intervals of 8 to 12 weeks, and the median follow-up duration was 14 months. The primary objective of the study was to assess molecular response using [ 68  Ga]Ga-DOTA.SA.FAPi PET/CT scans, with response evaluation based on the PERCIST criteria. Secondary endpoints included overall survival (OS), progression-free survival (PFS), clinical response assessment, and safety evaluation using CTCAE v5.0 guidelines. Results A total of 65 cycles were administered, with a mean cumulative activity of 19 ± 5.7 GBq (510 ± 154 mCi) ranging from 11 to 33.3 GBq (300 to 900 mCi) of [ 177 Lu]Lu-DOTAGA.FAPi dimer. The number of cycles ranged from 2 to 6, with a median of 3 cycles. The treatment protocol consisted of different numbers of cycles administered to the patients: specifically, two cycles were given to five patients, three cycles to nine patients, four cycles to one patient, and six cycles to four patients. Most patients had invasive/infiltrative ductal carcinoma (94.7%), while a small percentage had invasive lobular carcinoma (5.3%). All patients had bone metastases, and five of them also had liver involvement, while seven had brain metastases. Response assessment using [ 68  Ga]Ga-DOTA.SA.FAPi PET/CT scans showed that 25% of the 16 patients evaluated had partial remission, while 37.5% exhibited disease progression. According to the VAS response criteria, 26.3% achieved complete response, 15.7% had partial response, 42% showed minimal response, 11% had stable disease, and 5% had no response. The clinical disease control rate was promising, with 95% of patients achieving disease control. The clinical objective response rate was 84%. The median follow-up period was 14 months. At the time of analysis, the median overall survival was 12 months, and the median progression-free survival was 8.5 months. Notably, no severe hematological, renal, or hepatic toxicities, electrolyte imbalances, or adverse events of grade 3 or 4 were observed during the study. Conclusion The findings suggest that [ 177 Lu]Lu-DOTAGA.FAPi dimer therapy is well-tolerated, safe, and effective for treating end-stage metastatic breast cancer patients. [ 177 Lu]Lu-DOTAGA.FAPi dimer treatment demonstrated promising efficacy in patients with advanced breast cancer, as indicated by high disease control rates, favorable response outcomes, and acceptable safety profile. Further research and longer follow-up are warranted to assess long-term outcomes and validate these findings.

Purpose Gallium-68-labeled fibroblast activation protein inhibitor ( 68 Ga-FAPI) is an emerging promising tumor tracer. This study aims to evaluate the diagnostic efficiency of 68 Ga-FAPI PET in gastrointestinal cancer, and to determine its potential impact on clinical management. Methods Patients with malignancies were prospectively enrolled in a clinical trial to evaluate the diagnostic value of 68 Ga-FAPI PET. One hundred twenty patients with gastrointestinal malignancies (121 68 Ga-FAPI PET scans) between June 2020 and May 2021 were retrospectively analyzed. Initial staging of untreated patients and restaging of treated patients were evaluated. The treatment scheme promoted by imaging was determined according to NCCN guidelines. Final diagnosis and treatment reference standards were determined by a dedicated multidisciplinary team. The diagnostic performance and treatment guidance of 68 Ga-FAPI PET were compared with those of conventional imaging (CI) and 18 F-FDG PET. Results The diagnostic accuracy of 68 Ga-FAPI PET was much higher than that of CI and 18 F-FDG PET (95.0% vs. 65.1% and 69.0%, respectively, both p  < 0.001). 68 Ga-FAPI PET revised diagnosis in 30.3% and 26.2% of patients compared with CI and 18 F-FDG PET. The accordance rate of 68 Ga-FAPI PET-guided treatment in comparison with the reference standard was significantly higher than that of CI and 18 F-FDG PET (96.7% vs. 75.2% and 76.2%, respectively, both p  < 0.001). 68 Ga-FAPI PET changed treatment in 22.9% and 23.8% of patients compared with CI and 18 F-FDG PET. Conclusions 68 Ga-FAPI PET showed remarkable diagnostic performance in gastrointestinal cancer, resulting in more accurate staging and guidance for timely treatment revision, thereby having a critical impact on clinical management. Trial registration NCT04554719. Registered September 8, 2020—retrospectively registered, http://clinicaltrails.gov/show/NCT04554719

Purpose The role of fibroblast activation protein (FAP)-targeted imaging in systemic vasculitis is currently unclear. We aimed to evaluate the clinical value of fluorine-18-labeled FAP inhibitor 42 ([ 18 F]FAPI-42) in patients with systemic vasculitis and to compare with [ 18 F]fluorodeoxyglucose (FDG) imaging. Methods Patients with systemic vasculitis who underwent dual-tracer PET/CT([ 18 F]FDG and [ 18 F]FAPI) imaging from September 2020 to March 2022 were retrospectively analyzed. Positive lesions are defined as vascular/extravascular lesions with increased tracer uptake above surrounding background, which cannot be attributed to the physiologic biodistribution of the radiotracer. The vascular/extravascular lesion detection rate and semiquantitative values (SUVmax, TBR blood and TBR liver ) of [ 18 F]FAPI and [ 18 F]FDG were compared, and the correlation between the extent and range of tracer uptake and levels of inflammatory markers was investigated. Results Thirty patients (13 males and 17 females; mean age, 52.5 ± 17.2 years) with systemic vasculitis were included (17 large vessel vasculitis, 10 anti-neutrophil cytoplasmic antibody-associated vasculitis, 2 Behcet’s disease and 1 polyarteritis nodosa). [ 18 F]FDG PET/CT had positive findings in 93.3% (28/30) of patients, while [ 18 F]FAPI PET/CT had positive findings in all patients (100%, P  = 0.500). Compared with [ 18 F]FDG PET/CT, [ 18 F]FAPI PET/CT detected more lesions (161/168 vs. 145/168, P  = 0.005), and more extensive vascular involvement in 60% (18/30) of patients. Although SUVmax did not differ significantly between [ 18 F]FAPI and [ 18 F]FDG (median, 5.94 vs. 5.46, P  = 0.517), [ 18 F]FAPI had higher TBR liver (median, 9.59 vs. 3.15, P  < 0.001) and TBR blood (median, 5.45 vs. 4.20, P  = 0.006). The total number of positive lesions in FAPI PET/CT show a moderate correlation with erythrocyte sedimentation rate ( r s =0.478, P  = 0.008) and C-reactive protein ( r s =0.486, P  = 0.006). After treatment, follow-up FAPI PET/CT of 6 patients showed decreased SUVmax, TBR and number of detected lesions, paralleling the clinical remission. Conclusion [ 18 F]FAPI PET/CT imaging is a promising imaging modality for the diagnosis and therapeutic monitoring of systemic vasculitis.

Over the past decade, the tumor microenvironment (TME) has become a new paradigm of cancer diagnosis and therapy due to its unique biological features, mainly the interconnection between cancer and stromal cells. Within the TME, cancer-associated fibroblasts (CAFs) demonstrate as one of the most critical stromal cells that regulate tumor cell growth, progression, immunosuppression, and metastasis. CAFs are identified by various biomarkers that are expressed on their surfaces, such as fibroblast activation protein (FAP), which could be utilized as a useful target for diagnostic imaging and treatment. One of the advantages of targeting FAP-expressing CAFs is the absence of FAP expression in quiescent fibroblasts, leading to a controlled targetability of diagnostic and therapeutic compounds to the malignant tumor stromal area using radiolabeled FAP-based ligands. FAP-based radiopharmaceuticals have been investigated strenuously for the visualization of malignancies and delivery of theranostic radiopharmaceuticals to the TME. This review provides an overview of the state of the art in TME compositions, particularly CAFs and FAP, and their roles in cancer biology. Moreover, relevant reports on radiolabeled FAP inhibitors until the year 2021 are highlighted—as well as the current limitations, challenges, and requirements for those radiolabeled FAP inhibitors in clinical translation.

Purpose The reversibility of early liver fibrosis highlights the need for improved early detection and monitoring techniques. Fibroblast activation protein (FAP) is a promising theranostics target significantly upregulated during fibrosis. This preclinical and preliminary clinical study investigated a FAP-targeted probe, gallium-68-labeled FAP inhibitor 04 ([ 68 Ga]Ga-DOTA-FAPI-04), for its capability to visualize liver fibrosis. Methods The preclinical study employed [ 68 Ga]Ga-DOTA-FAPI-04 micro-positron emission tomography (PET)/computed tomography (CT) on carbon tetrachloride-induced mice model (n = 34) and olive oil-treated control group (n = 26), followed by validation of the probe's biodistribution. Hepatic uptake was correlated with fibrosis and inflammation levels, quantified through histology and serum assays. FAP and α-smooth muscle actin expression were determined by immunohistochemistry, as well as immunofluorescence. The subsequent clinical trial enrolled 26 patients with suspected or confirmed liver fibrosis to undergo [ 68 Ga]Ga-DOTA-FAPI-04 PET/magnetic resonance imaging or PET/CT. Key endpoints included correlating [ 68 Ga]Ga-DOTA-FAPI-04 uptake with histological inflammation grades and fibrosis stages, and evaluating its diagnostic and differential efficacy compared to established serum markers and liver stiffness measurement (LSM). Results [ 68 Ga]Ga-DOTA-FAPI-04 mean uptake in mice livers was notably higher than in control mice, increasing from week 6 [0.70 ± 0.11 percentage injected dose per cubic centimeter (%ID/cc)], peaking at week 10 (0.97 ± 0.15%ID/cc) and slightly reducing at week 12 (0.89 ± 0.28%ID/cc). The hepatic biodistribution and FAP expression showed a consistent trend. In the patient cohort, hepatic [ 68 Ga]Ga-DOTA-FAPI-04 uptake presented moderate correlations with inflammation grades (r = 0.517 to 0.584, all P  < 0.05) and fibrosis stages (r = 0.653 to 0.698, all P  < 0.01). The average SUVmax to background ratio in the liver showed superior discriminative ability, especially between stage 0 and stage 1, outperforming LSM (area under curve 0.984 vs. 0.865). Conclusion [ 68 Ga]Ga-DOTA-FAPI-04 PET shows significant potential for non-invasive visualization and dynamic monitoring of liver fibrosis in both preclinical experiment and preliminary clinical trial, especially outperforming other common clinical indicators in the early stage. Trial registration NCT04605939. Registered October 25, 2020, https://clinicaltrials.gov/study/NCT04605939

Background [ 68 Ga]Ga-labeled fibroblast activation protein inhibitor ([ 68 Ga]Ga-FAPI) PET/CT has shown promising potential in predicting pathological complete response (pCR) in patients with breast cancer (BC). However, current literature lacks comprehensive data addressing molecular subtype-specific variations. This study aims to evaluate the predictive value of [ 68 Ga]Ga-FAPI-04 PET/CT across different BC molecular subtypes. Methods This preliminary study enrolled 66 patients with clinical stage II-III BC scheduled for neoadjuvant chemotherapy (NAC). Patients underwent [ 68 Ga]Ga-FAPI-04 PET/CT at baseline (PET1), after two NAC cycles (PET2), and presurgery (PET3). The maximum standardized uptake value (SUVmax) and its percentage change from baseline (ΔSUVmax) were calculated for the primary tumors. Pathological response was assessed postsurgery. Patients were stratified into three molecular subtypes: hormone receptor-positive/HER2-negative (HR+/HER2−), HER2-positive (HER2+), and triple-negative breast cancer (TNBC). Receiver operating characteristic (ROC) curve analysis was utilized to evaluate the predictive performance of FAPI parameters for pCR. Results Among the 66 patients, 21 (31.8%) achieved pCR, with rates varying significantly across molecular subtypes ( P  = 0.002). Baseline [ 68 Ga]Ga-FAPI-04 uptake (SUVmax1) was significantly higher in HER2+ tumors (17.98 ± 6.34) compared to HR+/HER2− (14.37 ± 4.11) and TNBC tumors (15.00 ± 5.25) ( P  = 0.043). The predictive value of [ 68 Ga]Ga-FAPI-04 parameters for pCR was highly dependent on molecular subtype. In HER2+ tumors, early response assessment was most effective, with ΔSUVmax1 (change after two cycles) being the strongest predictor (area under the curve [AUC] = 0.799). A cutoff of − 69.49% yielded 85.7% sensitivity and 72.7% specificity. For TNBC, late-phase parameters demonstrated exceptional accuracy, with SUVmax3 (presurgery) achieving near-perfect discrimination (AUC = 0.967). A cutoff of ≤ 2.19 provided 100% sensitivity and 95.5% specificity. In HR+/HER2− tumors, late-phase parameters were most predictive, with SUVmax3 showing excellent performance (AUC = 0.948). A cutoff of ≤ 1.58 yielded 75.0% sensitivity and 91.7% specificity. Conclusion The predictive efficacy of [ 68 Ga]Ga-FAPI-04 PET/CT for pCR demonstrates substantial variability across BC molecular subtypes. These findings underscore the potential of [ 68 Ga]Ga-FAPI-04 PET/CT to inform subtype-specific, personalized treatment approaches.