Efficacy of FAPI-PET as a non-invasive evaluation method of liver fibrosis

Efficacy of FAPI-PET as a non-invasive evaluation method of liver fibrosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy of FAPI-PET as a non-invasive evaluation method of liver fibrosis Yuriko Mori, Katharina Tamburini, Emil Novruzov, Dominik Schmitt, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5341784/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Mar, 2025 Read the published version in Annals of Nuclear Medicine → Version 1 posted 4 You are reading this latest preprint version Abstract Liver fibrosis is a chronic fibrosing hepatic disorder following recurrent injury, characterized by the excessive accumulation of extracellular matrix. Early detection has great clinical impact because 80–90% of hepatocellular carcinomas are known to develop in fibrotic or cirrhotic (end-stage fibrotic) livers. PET imaging with FAP ligands exhibited highly promising results in recent years to visualize fibrosis in various organs due to the crucial role of activated fibroblasts in fibrosing processes. However, still little is known about the efficacy of FAP imaging in liver fibrosis. Thus, we sought to investigate the potential of FAPI-PET in a cohort of oncological and non-oncological patients. Methods : 360 patients who underwent FAPI-PET/CT at the University Hospital of Heidelberg between July 2017 and October 2020 were retrospectively analyzed. The tracer uptake of the liver was analyzed and correlated with radiological and clinical parameters. Results : We observed a strong negative correlation between the hepatic FAPI uptake and CT density (r=-0.264, P < 0.001***). A positive correlation was observed between hepatic FAPI uptake and the aspartate aminotransferase (AST)-to-platelet ratio index (APRI) (r = 0.178, P = 0.006**), an established surrogate for liver fibrosis. The liver SUV (standardized uptake value) mean and SUVmax of FAPI showed significant differences between groups of patients with low ( 1.5) APRI (P = 0.002* and P < 0.001***). Conclusion : These preliminary observational results suggest that FAPI-PET may be a viable non-invasive method to asses liver fibrosis. Fibroblast activation protein FAPI PET Liver Fibrosis Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Liver fibrosis is a regenerative tissue process following liver injury and is characterized by an increased extracellular matrix (ECM) deposition 1 . Chronic liver injury such as alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD) or viral hepatitis (chronic hepatitis B or C), can lead to recurrent scarring and subsequent progressive fibrogenic processes, resulting in an abnormal proliferative tissue response 1 . The end-stage disease is known as cirrhosis, which, together with other chronic liver diseases, is the 14th leading cause of death worldwide 2 , 3 . Early detection of liver fibrosis and/or cirrhosis has a significant clinical impact, as 80–90% of hepatocellular carcinomas (HCCs) are known to develop in fibrotic or cirrhotic livers 4 . At the cellular level, hepatic stellate cells (HSCs), a vitamin A-storing cell located in the perisinusoidal space (space of Disse), play a predominant role in the liver fibrogenesis 5 . Quiescent HSCs can be activated after injury and differentiate into myofibroblasts, which then migrate to the repair site and begin to proliferate, facilitating further fibrogenic processes through active secretion of growth factors and cytokines 6 . Activated HSCs can be distinguished from the inactive quiescent phenotype by the expression of surface markers such as alpha-smooth muscle actin (α-SMA) and fibroblast activation protein (FAP) 7 , 8 . The recent introduction of FAP ligands as fibroblast-targeting agents 9 – 11 offers a potentially effective method of non-invasively detecting fibrosis in various organs at an early stage of disease 12 , 13 . Several studies have demonstrated the efficacy of FAP ligands in fibrotic organ processes, such as lung 14 or kidney 15 , suggesting the promising potential of FAP imaging to detect the clinical course of fibrosis. The evaluation of liver fibrosis with FAP in a large cohort of patients has not yet been performed. Therefore, we aimed to provide the first preliminary evaluation of hepatic FAP expression in a cohort of oncological and non-oncological patients. Material and Methods Patient cohort The cohort consists of 360 patients, who underwent FAPI-PET/CT at the University Hospital of Heidelberg between July 2017 and October 2020. All patients were referred by their treating oncologists for suspected malignancies, which was confirmed in the majority of cases. Thus, the cohort consists of oncological patients (n = 334) with small number of non-oncological patients (n = 26) (Table 1 ) . Written informed consent was obtained from all patients on an individual basis. The retrospective data analysis was approved by the local ethics committee (approval S358/2022). Table 1 Patient Characteristics Patient characteristics Number of patients Total number of patients 360 Sex Male 213 Female 147 Disease entitiy PDAC 71 Lung cancer 38 Colorectal cancer 45 Head and neck cancer 45 Gynecological cancer 28 Prostate cancer 14 Sarcoma 13 CUP 13 Esophageal cancer 13 Thyroid cancer 10 Cholangiocarcinoma 8 Gastric cancer 7 Urothelcarcinoma 5 Liver cancer 3 Melanoma 2 Other malignancies 19 Benign 26 PDAC: Pancreatic ductal adenocarcinoma, CUP: Carcinoma of unknown primary Image Acquisition All PET scans were performed 1 h after intravenous tracer administration using a Biograph mCT Flow scanner (Siemens, Erlangen, Germany). Imaging data were acquired in 3-dimensional mode (matrix, 220 x 220) with an acquisition time of 3 minutes per bed position. Attenuation correction was performed using CT data (170 mAs, 100 kV, 2 mm slice thickness). The following FAP ligands were used for FAP imaging: FAPI-02, n = 20; FAPI-04, n = 193; FAPI-46, n = 82; FAPI-74, n = 65. The median injected activity was 185 MBq (range 52–325 MBq). Radiosynthesis and labeling of the FAP tracer was performed at the University of Heidelberg as described previously (Lindner, Giesel, Meyer). Image Evaluation Tracer uptake in the liver was quantified using the mean and maximum standardized uptake value (SUVmean and SUVmax). For SUV calculation, circular regions of interest (ROI) of 2 cm diameter were drawn in the liver parenchyma on transaxial slices and automatically fitted to a 3-dimensional volume of interest using Syngovia (Siemens) with a 60% isocontour. The ROI was defined in the region of the liver parenchyma with the most homogeneous appearance. Tracer uptake in the blood pool was measured by placing the ROI of 1 cm diameter in the descending aorta. Calculation of fibrosis index The aspartate aminotransferase (AST) to platelet ratio index (APRI) and the fibrosis index based on 4 factors (FIB-4) were calculated based on the laboratory test results, available for a subgroup of patients (n = 236). The maximum time interval of laboratory data and FAP scan was 6 weeks. These values were calculated using the following formulae: APRI = AST level (/upper limit of normal)*100/ platelet count (10 9 /L). FIB-4 = (age*AST)/(platelet count*√ALT) (ALT: alanine transaminase). Statistical Analysis Statistical analysis was performed using SigmaPlot version 11.0 (Systat Software, Inc., San Jose, CA, USA). Comparison of tracer uptake between groups was determined using two-sided t-test. A p-value of less than 0.05 was considered as statistically significant. The correlation between tracer uptake and clinical parameters was determined using Pearson correlation analysis. Regression analysis was performed for parameters which correlated significantly to each other. Analysis of variance (ANOVA) using Kruskal-Wallis-Test was performed to evaluate the differences of FAPI uptake in liver between the groups of patients with low ( 1.5) levels of APRI. Results Baseline characteristics The cohort included 213 male and 147 female patients with a median age of 64 years (range 16–92 years). 93% of the cohort were oncological patients with different cancer entities (Table 1 ). Correlation between hepatic FAPI uptake liver CT density FAP ligand uptake in the liver was assessed as SUVmean and SUVmax (n = 360). The SUVmean was 0.970 ± 0.343 and the SUVmax 1.553 ± 0.555, respectively. The mean CT density (Hounsfield scale, HUmean) was 50.99 ± 12.89 HU. We observed a significant correlation between the SUVmean and the HUmean (r=-0.264, P < 0.001***, Fig. 1 ). Correlation between hepatic FAPI uptake and markers of liver fibrosis We next analyzed a potential correlation between the hepatic SUVmax, SUVmean and the two liver fibrosis indices APRI und FIB-4 in a subgroup of patients (n = 236). The median values of APRI and FIB-4 were 0.296 (range 0.080–4.481) and 1.503 (range 0.115–20.101), respectively. There was a significant correlation between both, the SUVmean as well as the SUVmax and the APRI score (r = 0.178, P = 0.006** and r = 0.140, P = 0.032*, Fig. 2 a-b). Linear regression analysis revealed a regression coefficient of R = 0.176 (P = 0.007**) and R = 0.178 (P = 0.006**). There was no significant correlation between hepatic FAPI uptake and the FIB-4 index. We then compared SUVmax and SUV mean values between three subgroups of patients based on their respective APRI score ( 1.0). Here, we observed a significant and stepwise increase of SUVmean (P = 0.002**) as well as the SUVmax (P < 0.001***), respectively (Fig. 3 – 4 ) . Discussion Recent reports on fibrosis imaging using FAP ligands suggest a great potential for imaging and monitoring fibrotic changes in various organs with a simple, repeatable whole-body scan 14 – 16 . As biopsies are associated with risk of morbidity, high patient burden and a lack of cost-effectiveness, fibrosis imaging with FAP holds a great promise in this regard. There are still insufficient data to assess liver fibrosis, but in a preclinical porcine model, Pirasteh et al. have previously shown that hepatic 68 Ga-FAPI-46 uptake strongly correlates with the degree of fibrosis, as indicated by collagen proportionate area (CPA) (r = 0.89, P < 0.001) 17 . 68 Ga-FAPI-46 uptake in this study was significantly and progressively higher with increasing stage of liver fibrosis (P < 0.001) 17 , which is corroborated in another study using a preclinical mouse model and subsequent human translation, evaluating 26 patients with confirmed liver fibrosis 18 . This translational study showed a correlation between 68 Ga-DOTA-FAPI-04 uptake and fibrosis stage (r = 0.653 to 0.698, all P < 0.01) 18 . The strong correlation between liver 68 Ga-FAPI-46 uptake and histological stage of liver fibrosis suggests that FAPI-PET may play an important role in the non-invasive staging of liver fibrosis, which may be pathophysiologically explained by the fact that activated hepatic stellate cells (HSCs) express FAP and are thought to play an essential role in promoting fibrosis in the liver. HSCs, which in the quiescent state represent 5–10% of the total number of liver cells, begin to proliferate and differentiate into myofibroblasts upon paracrine stimulation by neighbouring cells, including Kupffer cells, hepatocytes or sinusoidal endothelial cells 19 . To date, several methods have been proposed to non-invasively assess the severity of liver fibrosis 20 . These include radiographic assessment, stiffness measurement (liver elastography), and several scoring systems based on laboratory tests, although all these mentioned methods remain still controversial. In radiology, the iodine density of the liver parenchyma in relation to that of the aorta, obtained from the equilibrium phase on dynamic contrast-enhanced CT, is reported to be useful for the staging of liver fibrosis 21 , while other authors demonstrated the significant predictive value of the iodine washout rate (IWR), calculated from the hepatic iodine uptake during the portal venous phase (PVP) and the 3-minute delayed phase (DP) using multiphasic dual-energy CT 22 . Liver elastography offers the possibility of a rapid, non-invasive, and painless assessment of the liver with several options available, e.g. transient elastography, point shear wave elastography, 2D shear wave elastography, or magnetic resonance elastography 23 , 24 . However, patient, operator and examination characteristics have all been shown to influence the result of liver stiffness measurements, e.g. food intake increases liver stiffness, whereas alcohol withdrawal is associated with a decrease in elastography results. The inter-observer reproducibility of the measurement seems suboptimal, and the influence of the operator experience is still being debated 23 . Regarding scoring systems, several scores have been proposed and are widely used in clinical routine for the non-invasive assessment of fibrosis due to their easy availability 25 , 26 . Aspartate aminotransferase (AST)-to-platelet ratio index (APRI) and the fibrosis index based on 4 factors (FIB-4) are the two commonly used indices in chronic liver disease 27 , but the performance of these indices remain controversial 28 – 31 . It has been suggested that they may overestimate the fibrosis stage due to the effect of necroinflammatory activity on transaminases in chronic hepatitis 27 , 32 . Another limitation appears to be the limited sensitivity especially for fibrosis in advanced stage 33 , 34 . In a meta-analysis comparing the performance of APRI and FIB-4 in patients with hepatitis B, revealed for APRI the sensitivity and specificity of 70% and 60%, 50% and 83%, and 36.9% and 92.5% for mild fibrosis, advanced fibrosis, and cirrhosis, respectively (APRI thresholds: 0.5, 1, and 1.5) and for FIB-4 the sensitivity and specificity of 65.4% and 73.6%, 16.2% and 95.2% for mild and advanced fibrosis (FIB-4 thresholds 1.45 and 3.25, respectively) 33 . In another study evaluating patients with hepatitis C, APRI showed similar performance to FIB-4 with positive predictive value (PPV) of 77% (for APRI > 1.5) and negative predictive value (NPV) of 83% (for APRI < 0.5) 34 . A cutoff of 0.5 (APRI) showed 81% of sensitivity and 50% of specificity, while a cutoff of 1.5 was more specific (94%) and less sensitive (42%) in this study 34 . This suggests that at least APRI is not sensitive enough to detect advanced fibrosis, but probably suitable to exclude healthy patients in the early stage. For FIB-4, a large cross-sectional study enhancing 5129 patients revealed that almost one-third (28%) of elevated FIB-4 was false-positive 35 . In view of this insufficient situation, we hypothesized that FAP imaging might be useful as a non-invasive imaging method for the assessment of liver fibrosis. The basic characteristic of our present study to be considered in the interpretation of our results is that our cohort consists of patients who were originally referred for FAPI-PET/CT due to suspected malignancy of any etiologies. Thus, the basic character of the cohort is somewhat similar to that of a general population in the respect that no previous selection of patients was performed due to the known liver pathologies. This matches to the resulting overall low to moderate hepatic FAPI uptake and majorably normal liver enzymes levels in our results. In the current study, we found a strong negative correlation between hepatic FAPI uptake and CT density (Hounsfield scale). This may be possibly due to the fact that lipogenic alteration of liver parenchyma is one of the most frequent phenomenon in the initial phase of fibrotic liver processes, the most common causes being the alcoholic and non-alcoholic fatty liver diseases. Further, we found that hepatic FAPI uptake correlates weak but significantly with APRI. Based on this result, we split in the next step the patients in three groups according to the level of APRI. This resulted in the significant difference in SUV value between the groups with a weak positive correlation. Interestingly, FIB-4 showed no correlation with the uptake value of FAP ligand in liver. The possible interpretation of these results is that APRI may possibly show better performance in detecting early fibrotic changes compared to FIB-4, although both scoring systems do not seem to be sensitive enough to detect advanced fibrosis, as mentioned above. For the conclusive analysis of the performance of FAPI-PET though, a histological validation is essential, which is not available in this retrospective study. There are several essential limitations in the present study. The most significant limitation is the lack of histology as already mentioned, for the ultimate validation of the accuracy of each method. Another main limitation is the character of the cohort with non-selective benign and malignant diseases. Although this might partly provide an advantage to mimic a general population cohort for screening, it seems yet to limit the validity of our results essentially because the majority of patients have no pathologic elevation of liver enzymes or platelet counts. Other limitations include varying FAP tracers and time interval between FAP imaging and laboratory tests. Conclusion FAP imaging is possibly an effective method for non-invasive detection of liver fibrosis especially in the early phase, which is frequently accompanied with lipogenic changes and slightly altered serum parameters. Although the currently presented data are promising, further evaluation in a selected patient cohort with histological validation and a well-designed preclinical study with various liver pathologies are necessary to determine the accuracy of the best surrogate marker for liver fibrosis. Declarations Ethics approval and consent to participate All procedures performed in studies involving human participants were approved by regional ethics committee board (approval S358/2022) and carried out in accordance with the ethical standards of the institutional and/or national research committees and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. Conflict of interest FLG has a patent application for quinolone based FAP-targeting agents for imaging and therapy in nuclear medicine and shares of a consultancy group for iTheranostics. FLG is also advisor at ABX, Telix, Alpha Fusion and SOFIE Biosciences. C.K. Royalties from SOFIE Biosciences and iTheranostics; patents for FAP inhibitors; participates on advisory board on neuroendocrine tumors for Advanced Accelerator Applications Germany, a Novartis company; stock or stock options in FAPi-Holding. U.H. Royalties from iTheranostics and SOFIE Biosciences; patent for FAPI tracers licensed to SOFIE Biosciences. The other authors declare no conflict of interest regarding this manuscript. Author Contributions: Study design and conceptualization: U.H., F.L.G., C.K.; patient recruitment, data collection, evaluation and analysis: E.M., C.K., M.R., formal analysis, data interpretation: K.T., Y.M., E.M., D.S., T.W.; original manuscript preparation: Y.M., S.H.L., C.R.; supervision: F.L.G., A.A., U.H.; review and editing: all. All authors have read and agreed to the published version of the manuscript. Acknowledgements This work is supported by Abass Alavi Fund. The authors gratefully acknowledge all participating patients. Data availability The data used and/or analyzed during the current study are available from the corresponding author on reasonable request. References Roehlen N, Crouchet E, Baumert TF. Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives. Cells. 2020;9(4):875. 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Cite Share Download PDF Status: Published Journal Publication published 06 Mar, 2025 Read the published version in Annals of Nuclear Medicine → Version 1 posted Reviewers agreed at journal 31 Oct, 2024 Reviewers invited by journal 31 Oct, 2024 Editor assigned by journal 28 Oct, 2024 First submitted to journal 27 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5341784","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":372530424,"identity":"3fddc540-622c-426e-ae6f-44fd621068df","order_by":0,"name":"Yuriko Mori","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-5666-0559","institution":"University Hospital Dusseldorf: Universitatsklinikum Dusseldorf","correspondingAuthor":true,"prefix":"","firstName":"Yuriko","middleName":"","lastName":"Mori","suffix":""},{"id":372530425,"identity":"c555e85c-409a-49c7-abdd-2398b9feeff3","order_by":1,"name":"Katharina Tamburini","email":"","orcid":"","institution":"University Hospital Heidelberg","correspondingAuthor":false,"prefix":"","firstName":"Katharina","middleName":"","lastName":"Tamburini","suffix":""},{"id":372530426,"identity":"e8c89d8f-ad50-4c0c-bf98-b0ca4ffbab33","order_by":2,"name":"Emil Novruzov","email":"","orcid":"","institution":"University Hospital Düsseldorf","correspondingAuthor":false,"prefix":"","firstName":"Emil","middleName":"","lastName":"Novruzov","suffix":""},{"id":372530427,"identity":"cfdbf677-be48-4904-b8cd-6863e3288a52","order_by":3,"name":"Dominik Schmitt","email":"","orcid":"","institution":"University Hospital Düsseldorf","correspondingAuthor":false,"prefix":"","firstName":"Dominik","middleName":"","lastName":"Schmitt","suffix":""},{"id":372530428,"identity":"2414e19e-b9c1-45d8-9610-19178640b408","order_by":4,"name":"Eleni Mavriopoulou","email":"","orcid":"","institution":"University Hospital Heidelberg","correspondingAuthor":false,"prefix":"","firstName":"Eleni","middleName":"","lastName":"Mavriopoulou","suffix":""},{"id":372530429,"identity":"b247e3ee-97c2-4638-ac77-b710c6dbecc8","order_by":5,"name":"Sven H. Loosen","email":"","orcid":"","institution":"University Hospital Düsseldorf","correspondingAuthor":false,"prefix":"","firstName":"Sven","middleName":"H.","lastName":"Loosen","suffix":""},{"id":372530430,"identity":"96658e4e-3bc2-4c48-8397-0d6cadec897c","order_by":6,"name":"Christoph Roderburg","email":"","orcid":"","institution":"University Hospital Düsseldorf","correspondingAuthor":false,"prefix":"","firstName":"Christoph","middleName":"","lastName":"Roderburg","suffix":""},{"id":372530431,"identity":"13e4241e-fc1d-4606-ae30-4f0d229fda61","order_by":7,"name":"Tadashi Watabe","email":"","orcid":"","institution":"Institute for Radiation Sciences, Osaka University","correspondingAuthor":false,"prefix":"","firstName":"Tadashi","middleName":"","lastName":"Watabe","suffix":""},{"id":372530432,"identity":"92cdf42e-9c1d-455e-9f25-1fcc86113d70","order_by":8,"name":"Clemens Kratochwil","email":"","orcid":"","institution":"University Hospital Heidelberg","correspondingAuthor":false,"prefix":"","firstName":"Clemens","middleName":"","lastName":"Kratochwil","suffix":""},{"id":372530433,"identity":"23d4ec74-0b71-4b66-bc99-1c5d44fb28bf","order_by":9,"name":"Manuel Röhrich","email":"","orcid":"","institution":"University Hospital Mainz","correspondingAuthor":false,"prefix":"","firstName":"Manuel","middleName":"","lastName":"Röhrich","suffix":""},{"id":372530434,"identity":"582b1c2c-4ba7-4f2f-891c-5bccedc8b6bb","order_by":10,"name":"Abass Alavi","email":"","orcid":"","institution":"Hospital of University of Pennsylvania Philadelphia","correspondingAuthor":false,"prefix":"","firstName":"Abass","middleName":"","lastName":"Alavi","suffix":""},{"id":372530435,"identity":"5bac00a5-614c-4152-a738-97b5c58b47a2","order_by":11,"name":"Uwe Haberkorn","email":"","orcid":"","institution":"University Hospital Heidelberg","correspondingAuthor":false,"prefix":"","firstName":"Uwe","middleName":"","lastName":"Haberkorn","suffix":""},{"id":372530436,"identity":"bfd52514-391e-4bed-bf04-98a1df40e80f","order_by":12,"name":"Frederik L. Giesel","email":"","orcid":"","institution":"University Hospital Düsseldorf","correspondingAuthor":false,"prefix":"","firstName":"Frederik","middleName":"L.","lastName":"Giesel","suffix":""}],"badges":[],"createdAt":"2024-10-27 14:45:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5341784/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5341784/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12149-025-02027-6","type":"published","date":"2025-03-06T15:57:05+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69445815,"identity":"11310a3e-7d4e-4bc8-998d-b167f02e8d71","added_by":"auto","created_at":"2024-11-20 11:59:26","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":145032,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation between liver FAPI uptake and CT density (Hounsfield scale)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5341784/v1/9aa87a2198d663ba2b849e7d.jpeg"},{"id":69446553,"identity":"f589d2c1-7df4-4832-86e2-cc1dfd901218","added_by":"auto","created_at":"2024-11-20 12:07:26","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":201014,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation between liver FAPI uptake and APRI score\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) Correlation between SUVmean and APRI\u003c/p\u003e\n\u003cp\u003e(b) Correlation between SUVmax and APRI\u003c/p\u003e","description":"","filename":"floatimage222.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5341784/v1/349c387f6566aeeabaddfd19.jpeg"},{"id":69445813,"identity":"3d71d47d-4d2d-46e7-9870-429bfe6f1d82","added_by":"auto","created_at":"2024-11-20 11:59:26","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":33938,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFAP ligand uptake in liver\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) Difference of SUVmean between groups of patients with low, middle or higher APRI\u003c/p\u003e\n\u003cp\u003e(b) Difference of SUVmax between groups of patients with low, middle or higher APRI\u003c/p\u003e","description":"","filename":"floatimage432.png","url":"https://assets-eu.researchsquare.com/files/rs-5341784/v1/a6063d4a102ee1277e6119d1.png"},{"id":69445817,"identity":"bef7b217-61b8-4b62-899a-5567b5575fcf","added_by":"auto","created_at":"2024-11-20 11:59:26","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":449666,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFAP ligand uptake in liver\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRepresentative images of FAPI-PET/CT scan for elevated APRI (a), moderately elevated APRI (b) and low APRI (c).\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-5341784/v1/0030bc036ce72c8f707dd4e6.png"},{"id":78191255,"identity":"09593183-380b-4367-8ecd-6f81fe6297c0","added_by":"auto","created_at":"2025-03-10 19:54:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1910094,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5341784/v1/b000534c-bee8-4a5d-a90c-3c19b790ab03.pdf"}],"financialInterests":"","formattedTitle":"Efficacy of FAPI-PET as a non-invasive evaluation method of liver fibrosis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLiver fibrosis is a regenerative tissue process following liver injury and is characterized by an increased extracellular matrix (ECM) deposition\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Chronic liver injury such as alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD) or viral hepatitis (chronic hepatitis B or C), can lead to recurrent scarring and subsequent progressive fibrogenic processes, resulting in an abnormal proliferative tissue response\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. The end-stage disease is known as cirrhosis, which, together with other chronic liver diseases, is the 14th leading cause of death worldwide\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Early detection of liver fibrosis and/or cirrhosis has a significant clinical impact, as 80\u0026ndash;90% of hepatocellular carcinomas (HCCs) are known to develop in fibrotic or cirrhotic livers\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAt the cellular level, hepatic stellate cells (HSCs), a vitamin A-storing cell located in the perisinusoidal space (space of Disse), play a predominant role in the liver fibrogenesis\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Quiescent HSCs can be activated after injury and differentiate into myofibroblasts, which then migrate to the repair site and begin to proliferate, facilitating further fibrogenic processes through active secretion of growth factors and cytokines\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Activated HSCs can be distinguished from the inactive quiescent phenotype by the expression of surface markers such as alpha-smooth muscle actin (α-SMA) and fibroblast activation protein (FAP)\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe recent introduction of FAP ligands as fibroblast-targeting agents\u003csup\u003e\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e offers a potentially effective method of non-invasively detecting fibrosis in various organs at an early stage of disease\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Several studies have demonstrated the efficacy of FAP ligands in fibrotic organ processes, such as lung\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e or kidney\u003csup\u003e15\u003c/sup\u003e, suggesting the promising potential of FAP imaging to detect the clinical course of fibrosis. The evaluation of liver fibrosis with FAP in a large cohort of patients has not yet been performed. Therefore, we aimed to provide the first preliminary evaluation of hepatic FAP expression in a cohort of oncological and non-oncological patients.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient cohort\u003c/h2\u003e \u003cp\u003eThe cohort consists of 360 patients, who underwent FAPI-PET/CT at the University Hospital of Heidelberg between July 2017 and October 2020. All patients were referred by their treating oncologists for suspected malignancies, which was confirmed in the majority of cases. Thus, the cohort consists of oncological patients (n\u0026thinsp;=\u0026thinsp;334) with small number of non-oncological patients (n\u0026thinsp;=\u0026thinsp;26) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. Written informed consent was obtained from all patients on an individual basis. The retrospective data analysis was approved by the local ethics committee (approval S358/2022).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient Characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of patients\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal number of patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e360\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e213\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e147\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease entitiy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePDAC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eColorectal cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHead and neck cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGynecological cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProstate cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSarcoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCUP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEsophageal cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThyroid cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCholangiocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastric cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrothelcarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMelanoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther malignancies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBenign\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003ePDAC: Pancreatic ductal adenocarcinoma, CUP: Carcinoma of unknown primary\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eImage Acquisition\u003c/h3\u003e\n\u003cp\u003eAll PET scans were performed 1 h after intravenous tracer administration using a Biograph mCT Flow scanner (Siemens, Erlangen, Germany). Imaging data were acquired in 3-dimensional mode (matrix, 220 x 220) with an acquisition time of 3 minutes per bed position. Attenuation correction was performed using CT data (170 mAs, 100 kV, 2 mm slice thickness). The following FAP ligands were used for FAP imaging: FAPI-02, n\u0026thinsp;=\u0026thinsp;20; FAPI-04, n\u0026thinsp;=\u0026thinsp;193; FAPI-46, n\u0026thinsp;=\u0026thinsp;82; FAPI-74, n\u0026thinsp;=\u0026thinsp;65. The median injected activity was 185 MBq (range 52\u0026ndash;325 MBq). Radiosynthesis and labeling of the FAP tracer was performed at the University of Heidelberg as described previously (Lindner, Giesel, Meyer).\u003c/p\u003e\n\u003ch3\u003eImage Evaluation\u003c/h3\u003e\n\u003cp\u003eTracer uptake in the liver was quantified using the mean and maximum standardized uptake value (SUVmean and SUVmax). For SUV calculation, circular regions of interest (ROI) of 2 cm diameter were drawn in the liver parenchyma on transaxial slices and automatically fitted to a 3-dimensional volume of interest using Syngovia (Siemens) with a 60% isocontour. The ROI was defined in the region of the liver parenchyma with the most homogeneous appearance. Tracer uptake in the blood pool was measured by placing the ROI of 1 cm diameter in the descending aorta.\u003c/p\u003e\n\u003ch3\u003eCalculation of fibrosis index\u003c/h3\u003e\n\u003cp\u003eThe aspartate aminotransferase (AST) to platelet ratio index (APRI) and the fibrosis index based on 4 factors (FIB-4) were calculated based on the laboratory test results, available for a subgroup of patients (n\u0026thinsp;=\u0026thinsp;236). The maximum time interval of laboratory data and FAP scan was 6 weeks. These values were calculated using the following formulae: APRI\u0026thinsp;=\u0026thinsp;AST level (/upper limit of normal)*100/ platelet count (10\u003csup\u003e9\u003c/sup\u003e/L). FIB-4 = (age*AST)/(platelet count*\u0026radic;ALT) (ALT: alanine transaminase).\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using SigmaPlot version 11.0 (Systat Software, Inc., San Jose, CA, USA). Comparison of tracer uptake between groups was determined using two-sided t-test. A p-value of less than 0.05 was considered as statistically significant. The correlation between tracer uptake and clinical parameters was determined using Pearson correlation analysis. Regression analysis was performed for parameters which correlated significantly to each other. Analysis of variance (ANOVA) using Kruskal-Wallis-Test was performed to evaluate the differences of FAPI uptake in liver between the groups of patients with low (\u0026lt;\u0026thinsp;0.5), middle (0.5-1.0) and high (\u0026gt;\u0026thinsp;1.5) levels of APRI.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eBaseline characteristics\u003c/h2\u003e \u003cp\u003eThe cohort included 213 male and 147 female patients with a median age of 64 years (range 16\u0026ndash;92 years). 93% of the cohort were oncological patients with different cancer entities (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCorrelation between hepatic FAPI uptake liver CT density\u003c/h3\u003e\n\u003cp\u003eFAP ligand uptake in the liver was assessed as SUVmean and SUVmax (n\u0026thinsp;=\u0026thinsp;360). The SUVmean was 0.970\u0026thinsp;\u0026plusmn;\u0026thinsp;0.343 and the SUVmax 1.553\u0026thinsp;\u0026plusmn;\u0026thinsp;0.555, respectively. The mean CT density (Hounsfield scale, HUmean) was 50.99\u0026thinsp;\u0026plusmn;\u0026thinsp;12.89 HU. We observed a significant correlation between the SUVmean and the HUmean (r=-0.264, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001***, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation between hepatic FAPI uptake and markers of liver fibrosis\u003c/h2\u003e \u003cp\u003eWe next analyzed a potential correlation between the hepatic SUVmax, SUVmean and the two liver fibrosis indices APRI und FIB-4 in a subgroup of patients (n\u0026thinsp;=\u0026thinsp;236). The median values of APRI and FIB-4 were 0.296 (range 0.080\u0026ndash;4.481) and 1.503 (range 0.115\u0026ndash;20.101), respectively. There was a significant correlation between both, the SUVmean as well as the SUVmax and the APRI score (r\u0026thinsp;=\u0026thinsp;0.178, P\u0026thinsp;=\u0026thinsp;0.006** and r\u0026thinsp;=\u0026thinsp;0.140, P\u0026thinsp;=\u0026thinsp;0.032*, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea-b). Linear regression analysis revealed a regression coefficient of R\u0026thinsp;=\u0026thinsp;0.176 (P\u0026thinsp;=\u0026thinsp;0.007**) and R\u0026thinsp;=\u0026thinsp;0.178 (P\u0026thinsp;=\u0026thinsp;0.006**). There was no significant correlation between hepatic FAPI uptake and the FIB-4 index. We then compared SUVmax and SUV mean values between three subgroups of patients based on their respective APRI score (\u0026lt;\u0026thinsp;0.5, 0.5-1.0 and \u0026gt;\u0026thinsp;1.0). Here, we observed a significant and stepwise increase of SUVmean (P\u0026thinsp;=\u0026thinsp;0.002**) as well as the SUVmax (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001***), respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eRecent reports on fibrosis imaging using FAP ligands suggest a great potential for imaging and monitoring fibrotic changes in various organs with a simple, repeatable whole-body scan\u003csup\u003e\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. As biopsies are associated with risk of morbidity, high patient burden and a lack of cost-effectiveness, fibrosis imaging with FAP holds a great promise in this regard. There are still insufficient data to assess liver fibrosis, but in a preclinical porcine model, Pirasteh et al. have previously shown that hepatic \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46 uptake strongly correlates with the degree of fibrosis, as indicated by collagen proportionate area (CPA) (r\u0026thinsp;=\u0026thinsp;0.89, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001)\u003csup\u003e17\u003c/sup\u003e. \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46 uptake in this study was significantly and progressively higher with increasing stage of liver fibrosis (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001)\u003csup\u003e17\u003c/sup\u003e, which is corroborated in another study using a preclinical mouse model and subsequent human translation, evaluating 26 patients with confirmed liver fibrosis\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. This translational study showed a correlation between \u003csup\u003e68\u003c/sup\u003eGa-DOTA-FAPI-04 uptake and fibrosis stage (r\u0026thinsp;=\u0026thinsp;0.653 to 0.698, all P\u0026thinsp;\u0026lt;\u0026thinsp;0.01)\u003csup\u003e18\u003c/sup\u003e. The strong correlation between liver \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46 uptake and histological stage of liver fibrosis suggests that FAPI-PET may play an important role in the non-invasive staging of liver fibrosis, which may be pathophysiologically explained by the fact that activated hepatic stellate cells (HSCs) express FAP and are thought to play an essential role in promoting fibrosis in the liver. HSCs, which in the quiescent state represent 5\u0026ndash;10% of the total number of liver cells, begin to proliferate and differentiate into myofibroblasts upon paracrine stimulation by neighbouring cells, including Kupffer cells, hepatocytes or sinusoidal endothelial cells\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo date, several methods have been proposed to non-invasively assess the severity of liver fibrosis\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. These include radiographic assessment, stiffness measurement (liver elastography), and several scoring systems based on laboratory tests, although all these mentioned methods remain still controversial. In radiology, the iodine density of the liver parenchyma in relation to that of the aorta, obtained from the equilibrium phase on dynamic contrast-enhanced CT, is reported to be useful for the staging of liver fibrosis\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, while other authors demonstrated the significant predictive value of the iodine washout rate (IWR), calculated from the hepatic iodine uptake during the portal venous phase (PVP) and the 3-minute delayed phase (DP) using multiphasic dual-energy CT\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Liver elastography offers the possibility of a rapid, non-invasive, and painless assessment of the liver with several options available, e.g. transient elastography, point shear wave elastography, 2D shear wave elastography, or magnetic resonance elastography\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. However, patient, operator and examination characteristics have all been shown to influence the result of liver stiffness measurements, e.g. food intake increases liver stiffness, whereas alcohol withdrawal is associated with a decrease in elastography results. The inter-observer reproducibility of the measurement seems suboptimal, and the influence of the operator experience is still being debated\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Regarding scoring systems, several scores have been proposed and are widely used in clinical routine for the non-invasive assessment of fibrosis due to their easy availability\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Aspartate aminotransferase (AST)-to-platelet ratio index (APRI) and the fibrosis index based on 4 factors (FIB-4) are the two commonly used indices in chronic liver disease\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e, but the performance of these indices remain controversial\u003csup\u003e\u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR27\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. It has been suggested that they may overestimate the fibrosis stage due to the effect of necroinflammatory activity on transaminases in chronic hepatitis\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Another limitation appears to be the limited sensitivity especially for fibrosis in advanced stage\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. In a meta-analysis comparing the performance of APRI and FIB-4 in patients with hepatitis B, revealed for APRI the sensitivity and specificity of 70% and 60%, 50% and 83%, and 36.9% and 92.5% for mild fibrosis, advanced fibrosis, and cirrhosis, respectively (APRI thresholds: 0.5, 1, and 1.5) and for FIB-4 the sensitivity and specificity of 65.4% and 73.6%, 16.2% and 95.2% for mild and advanced fibrosis (FIB-4 thresholds 1.45 and 3.25, respectively)\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. In another study evaluating patients with hepatitis C, APRI showed similar performance to FIB-4 with positive predictive value (PPV) of 77% (for APRI\u0026thinsp;\u0026gt;\u0026thinsp;1.5) and negative predictive value (NPV) of 83% (for APRI\u0026thinsp;\u0026lt;\u0026thinsp;0.5)\u003csup\u003e34\u003c/sup\u003e. A cutoff of 0.5 (APRI) showed 81% of sensitivity and 50% of specificity, while a cutoff of 1.5 was more specific (94%) and less sensitive (42%) in this study\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. This suggests that at least APRI is not sensitive enough to detect advanced fibrosis, but probably suitable to exclude healthy patients in the early stage. For FIB-4, a large cross-sectional study enhancing 5129 patients revealed that almost one-third (28%) of elevated FIB-4 was false-positive\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn view of this insufficient situation, we hypothesized that FAP imaging might be useful as a non-invasive imaging method for the assessment of liver fibrosis. The basic characteristic of our present study to be considered in the interpretation of our results is that our cohort consists of patients who were originally referred for FAPI-PET/CT due to suspected malignancy of any etiologies. Thus, the basic character of the cohort is somewhat similar to that of a general population in the respect that no previous selection of patients was performed due to the known liver pathologies. This matches to the resulting overall low to moderate hepatic FAPI uptake and majorably normal liver enzymes levels in our results.\u003c/p\u003e \u003cp\u003eIn the current study, we found a strong negative correlation between hepatic FAPI uptake and CT density (Hounsfield scale). This may be possibly due to the fact that lipogenic alteration of liver parenchyma is one of the most frequent phenomenon in the initial phase of fibrotic liver processes, the most common causes being the alcoholic and non-alcoholic fatty liver diseases. Further, we found that hepatic FAPI uptake correlates weak but significantly with APRI. Based on this result, we split in the next step the patients in three groups according to the level of APRI. This resulted in the significant difference in SUV value between the groups with a weak positive correlation. Interestingly, FIB-4 showed no correlation with the uptake value of FAP ligand in liver. The possible interpretation of these results is that APRI may possibly show better performance in detecting early fibrotic changes compared to FIB-4, although both scoring systems do not seem to be sensitive enough to detect advanced fibrosis, as mentioned above. For the conclusive analysis of the performance of FAPI-PET though, a histological validation is essential, which is not available in this retrospective study.\u003c/p\u003e \u003cp\u003eThere are several essential limitations in the present study. The most significant limitation is the lack of histology as already mentioned, for the ultimate validation of the accuracy of each method. Another main limitation is the character of the cohort with non-selective benign and malignant diseases. Although this might partly provide an advantage to mimic a general population cohort for screening, it seems yet to limit the validity of our results essentially because the majority of patients have no pathologic elevation of liver enzymes or platelet counts. Other limitations include varying FAP tracers and time interval between FAP imaging and laboratory tests.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eFAP imaging is possibly an effective method for non-invasive detection of liver fibrosis especially in the early phase, which is frequently accompanied with lipogenic changes and slightly altered serum parameters. Although the currently presented data are promising, further evaluation in a selected patient cohort with histological validation and a well-designed preclinical study with various liver pathologies are necessary to determine the accuracy of the best surrogate marker for liver fibrosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e \u003cp\u003e All procedures performed in studies involving human participants were approved by regional ethics committee board (approval S358/2022) and carried out in accordance with the ethical standards of the institutional and/or national research committees and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\u003ch2\u003eConflict of interest\u003c/strong\u003e \u003cp\u003eFLG has a patent application for quinolone based FAP-targeting agents for imaging and therapy in nuclear medicine and shares of a consultancy group for iTheranostics. FLG is also advisor at ABX, Telix, Alpha Fusion and SOFIE Biosciences. C.K. Royalties from SOFIE Biosciences and iTheranostics; patents for FAP inhibitors; participates on advisory board on neuroendocrine tumors for Advanced Accelerator Applications Germany, a Novartis company; stock or stock options in FAPi-Holding. U.H. Royalties from iTheranostics and SOFIE Biosciences; patent for FAPI tracers licensed to SOFIE Biosciences. The other authors declare no conflict of interest regarding this manuscript.\u003c/p\u003e \u003ch2\u003eAuthor Contributions:\u003c/h2\u003e \u003cp\u003eStudy design and conceptualization: U.H., F.L.G., C.K.; patient recruitment, data collection, evaluation and analysis: E.M., C.K., M.R., formal analysis, data interpretation: K.T., Y.M., E.M., D.S., T.W.; original manuscript preparation: Y.M., S.H.L., C.R.; supervision: F.L.G., A.A., U.H.; review and editing: all. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThis work is supported by Abass Alavi Fund. The authors gratefully acknowledge all participating patients.\u003c/p\u003e\u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eThe data used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRoehlen N, Crouchet E, Baumert TF. Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives. Cells. 2020;9(4):875.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet. 2014;383:1749\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu XN, Xue F, Zhang N et al. Global burden of liver cirrhosis and other chronic liver diseases caused by specific etiologies from 1990 to 2019. BMC Public Health volume 24, Article number: 363 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEl-Serag HB. Hepatocellular carcinoma. 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Clin Gastroenterol Hepatol. 2022;20(11):2567\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-nuclear-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anme","sideBox":"Learn more about [Annals of Nuclear Medicine](http://link.springer.com/journal/12149)","snPcode":"12149","submissionUrl":"https://www.editorialmanager.com/anme/default2.aspx","title":"Annals of Nuclear Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Fibroblast activation protein, FAPI, PET, Liver, Fibrosis","lastPublishedDoi":"10.21203/rs.3.rs-5341784/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5341784/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eLiver fibrosis is a chronic fibrosing hepatic disorder following recurrent injury, characterized by the excessive accumulation of extracellular matrix. Early detection has great clinical impact because 80\u0026ndash;90% of hepatocellular carcinomas are known to develop in fibrotic or cirrhotic (end-stage fibrotic) livers. PET imaging with FAP ligands exhibited highly promising results in recent years to visualize fibrosis in various organs due to the crucial role of activated fibroblasts in fibrosing processes. However, still little is known about the efficacy of FAP imaging in liver fibrosis. Thus, we sought to investigate the potential of FAPI-PET in a cohort of oncological and non-oncological patients.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMethods\u003c/b\u003e: 360 patients who underwent FAPI-PET/CT at the University Hospital of Heidelberg between July 2017 and October 2020 were retrospectively analyzed. The tracer uptake of the liver was analyzed and correlated with radiological and clinical parameters.\u003c/p\u003e \u003cp\u003e \u003cb\u003eResults\u003c/b\u003e: We observed a strong negative correlation between the hepatic FAPI uptake and CT density (r=-0.264, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001***). A positive correlation was observed between hepatic FAPI uptake and the aspartate aminotransferase (AST)-to-platelet ratio index (APRI) (r\u0026thinsp;=\u0026thinsp;0.178, P\u0026thinsp;=\u0026thinsp;0.006**), an established surrogate for liver fibrosis. The liver SUV (standardized uptake value) mean and SUVmax of FAPI showed significant differences between groups of patients with low (\u0026lt;\u0026thinsp;0.5), middle (0.5-1.0) and high (\u0026gt;\u0026thinsp;1.5) APRI (P\u0026thinsp;=\u0026thinsp;0.002* and P\u0026thinsp;\u0026lt;\u0026thinsp;0.001***).\u003c/p\u003e \u003cp\u003e \u003cb\u003eConclusion\u003c/b\u003e: These preliminary observational results suggest that FAPI-PET may be a viable non-invasive method to asses liver fibrosis.\u003c/p\u003e","manuscriptTitle":"Efficacy of FAPI-PET as a non-invasive evaluation method of liver fibrosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-20 11:59:21","doi":"10.21203/rs.3.rs-5341784/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-10-31T12:04:40+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-31T07:55:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-28T04:42:16+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Nuclear Medicine","date":"2024-10-27T10:43:54+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-nuclear-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anme","sideBox":"Learn more about [Annals of Nuclear Medicine](http://link.springer.com/journal/12149)","snPcode":"12149","submissionUrl":"https://www.editorialmanager.com/anme/default2.aspx","title":"Annals of Nuclear Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c23a4a92-2da6-4877-ac6e-4d555af9967a","owner":[],"postedDate":"November 20th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-03-10T19:54:26+00:00","versionOfRecord":{"articleIdentity":"rs-5341784","link":"https://doi.org/10.1007/s12149-025-02027-6","journal":{"identity":"annals-of-nuclear-medicine","isVorOnly":false,"title":"Annals of Nuclear Medicine"},"publishedOn":"2025-03-06 15:57:05","publishedOnDateReadable":"March 6th, 2025"},"versionCreatedAt":"2024-11-20 11:59:21","video":"","vorDoi":"10.1007/s12149-025-02027-6","vorDoiUrl":"https://doi.org/10.1007/s12149-025-02027-6","workflowStages":[]},"version":"v1","identity":"rs-5341784","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5341784","identity":"rs-5341784","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}