Pancreatic ductal carcinoma (PDAC) is a highly lethal cancer, and early detection and accurate staging are critical to prolonging survival. PDAC typically has a prominent stroma including cancer-associated fibroblasts that express fibroblast activation protein (FAP). FAP is a new target molecule for PET imaging of various tumors. In this retrospective study, we describe the clinical impact of PET/CT imaging using ⁶⁸Ga-labeled FAP-inhibitors (⁶⁸Ga-FAPI PET/CT) in 19 patients with PDAC (7 primary, 12 progressive/recurrent). Methods: All patients underwent contrast-enhanced CT (ceCT) for TNM staging before ⁶⁸Ga-FAPI PET/CT imaging. PET scans were acquired 60 min after administration of 150–250 MBq of ⁶⁸Ga-labeled FAP-specific tracers. To characterize ⁶⁸Ga-FAPI uptake over time, additional scans after 10 or 180 min were acquired in 6 patients. SUV_max and SUV_mean values of PDAC manifestations and healthy organs were analyzed. The tumor burden according to ⁶⁸Ga-FAPI PET/CT was compared with TNM staging based on ceCT and changes in oncologic management were recorded. Results: Compared with ceCT, ⁶⁸Ga-FAPI PET/CT results led to changes in TNM staging in 10 of 19 patients. Eight of 12 patients with recurrent/progressive disease were upstaged, 1 was downstaged, and 3 had no change. In newly diagnosed PDAC, 1 of 7 patients was upstaged, and the staging of 6 patients did not change. Changes in oncologic management occurred in 7 patients. Markedly elevated uptake of ⁶⁸Ga-FAPI in PDAC manifestations after 1 h was seen in most cases. Differentiation from pancreatitis based on static imaging 1 h after injection was challenging. With respect to imaging after multiple time points, PDAC and pancreatitis showed a trend for differential uptake kinetics. Conclusion:⁶⁸Ga-FAPI PET/CT led to restaging in half of the patients with PDAC and most patients with recurrent disease compared with standard of care imaging. The clinical value of ⁶⁸Ga-FAPI PET/CT should be further investigated. Visual Abstract

Purpose: Interstitial lung diseases (ILD) comprise over 200 parenchymal lung disorders. Among them, fibrosing ILDs, especially idiopathic pulmonary fibrosis (IPF) in particular are associated with a poor prognosis, while some others ILDs like sarcoidosis have a much better prognosis. A high proportion of ILD manifests as fibrotic ILD (fILD). Lung cancer (LC) is a frequent complication of fILD. Activated fibroblasts are crucial for fibrotic processes in fILD. The aim of this exploratory study was to evaluate the imaging properties of static and dynamic FAPI-PET/CT in various types of fILD and to confirm FAP expression of fILD lesions by FAP immunohistochemistry of human fILD biopsy samples and of lung sections of genetically engineered (Nedd4-2 -/- ) mice with an idiopathic pulmonary fibrosis (IPF) -like lung disease. Patients and Methods: PET-Scans of 15 patients with fILD and suspected LC were acquired 10, 60 and 180 minutes after the administration of 150-250 MBq of a ⁶⁸Ga labelled FAPI tracer (FAPI-46). In three patients, dynamic scans over 40 mins were performed instead of imaging after 10 minutes. Standardized uptake values (SUV_max and SUVmean) of fibrotic lesions and LC were measured and CT-density-corrected. Target-to-background ratios (TBR) were calculated. PET imaging was correlated with CT-based fibrosis scores. Time-activity curves derived from dynamic imaging were analyzed. FAP immunohistochemistry of 4 human fILD biopsy samples and of fibrotic lungs of Nedd4-2-/- mice was carried out. Results: FILD lesions as well as LC showed markedly elevated FAPI-uptake (density corrected SUV_max / mean values 60 minutes post injection: 11,12 +/- 6,71 and 4,29 +/- 1,61 for fILD lesions and 16,69 +/- 9,35 and 6,44 +/- 3,29 for LC) and high TBR (TBR of density corrected SUV_max/SUVmean values 60 minutes post injection: 2,30 +/- 1,47 and 1,67 +/- 0,79 for fILD and 3,90 +/- 2,36 and 2,37 +/- 1,14 for LC). SUV_max and SUVmean values decreased over time with stable TBR of fILD and increasing TBR in LC on trend. Dynamic imaging showed differing time activity curves of fILD and LC. FAPI uptake showed a positive correlation with the CT-based fibrosis index (FIBI). Immunohistochemistry of human biopsy samples and lungs of Nedd4-2-/- mice showed a patchy expression of FAP in fibrotic lesions, preferentially in the transition zone to healthy lung parenchyma. Conclusion: FAPI-PET/CT imaging is a promising new imaging modality for fILD and LC. Its potential clinical value for monitoring and therapy evaluation of fILD should be investigated in future studies.

⁶⁸Ga-labeled fibroblast activation protein (FAP) inhibitor (⁶⁸Ga-FAPI) PET targets ⁶⁸Ga-FAPI–positive activated fibroblasts and is a promising imaging technique for various types of cancer and nonmalignant pathologies. However, discrimination between malignant and nonmalignant ⁶⁸Ga-FAPI–positive lesions based on static PET with a single acquisition time point can be challenging. Additionally, the optimal imaging time point for ⁶⁸Ga-FAPI PET has not been identified yet, and different ⁶⁸Ga-FAPI tracer variants are currently used. In this retrospective analysis, we evaluate the diagnostic value of repetitive early ⁶⁸Ga-FAPI PET with ⁶⁸Ga-FAPI-02, ⁶⁸Ga-FAPI-46, and ⁶⁸Ga-FAPI-74 for malignant, inflammatory/reactive, and degenerative lesions and describe the implications for future ⁶⁸Ga-FAPI imaging protocols. Methods: Whole-body PET scans of 24 cancer patients were acquired at 10, 22, 34, 46, and 58 min after the administration of 150–250 MBq of ⁶⁸Ga-FAPI tracer molecules (8 patients each for ⁶⁸Ga-FAPI-02, ⁶⁸Ga-FAPI-46, and ⁶⁸Ga-FAPI-74). Detection rates and SUVs (SUV_max and SUV_mean) for healthy tissues, cancer manifestations, and nonmalignant lesions were measured, and target-to-background ratios (TBR) versus blood and fat were calculated for all acquisition time points. Results: For most healthy tissues except fat and spinal canal, biodistribution analysis showed decreasing uptake over time. We analyzed 134 malignant, inflammatory/reactive, and degenerative lesions. Detection rates were minimally reduced for the first 2 acquisition time points and remained at a constant high level from 34 to 58 min after injection. The uptake of all 3 variants was higher in malignant and inflammatory/reactive lesions than in degenerative lesions. ⁶⁸Ga-FAPI-46 showed the highest uptake and TBRs in all pathologies. For all variants, TBRs versus blood constantly increased over time for all pathologies, and TBRs versus fat were constant or decreased slightly. Conclusion:⁶⁸Ga-FAPI PET/CT is a promising imaging modality for malignancies and benign lesions. Repetitive early PET acquisition added diagnostic value for the discrimination of malignant from nonmalignant ⁶⁸Ga-FAPI–positive lesions. High detection rates and TBRs over time confirmed that PET acquisition earlier than 60 min after injection delivers high-contrast images. Additionally, considering clinical feasibility, acquisition at 30–40 min after injection might be a reasonable compromise. Different ⁶⁸Ga-FAPI variants show significant differences in time-dependent biodistributional behavior and should be selected carefully depending on the clinical setting. Visual Abstract