68Gallium-FAPI-positron emission tomography for dignity assessment of mass-forming chronic pancreatitis and pancreatic ductal adenocarcinomas compared to laboratory parameters, ultrasound and computed tomography

68Gallium-FAPI-positron emission tomography for dignity assessment of mass-forming chronic pancreatitis and pancreatic ductal adenocarcinomas compared to laboratory parameters, ultrasound and computed tomography | 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 68 Gallium-FAPI-positron emission tomography for dignity assessment of mass-forming chronic pancreatitis and pancreatic ductal adenocarcinomas compared to laboratory parameters, ultrasound and computed tomography Matthias Lang, Markus Preussig, Anna-Maria Spektor, Isabelle von Goetze, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5640954/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: The differentiation of mass-forming chronic pancreatitis (MFCP) and pancreatic ductal adenocarcinomas (PDAC) based on conventional imaging methods like ultrasound, CT and MRI is frequently not possible. Here, we applied static (60 minutes post injection) and dynamic PET/CT with 68 Gallium-labelled Fibroblast Activated Protein Inhibitors ( 68 Ga-FAPI-PET/CT) in 26 preoperative, treatment-naive patients with unclear pancreatic masses to evaluate its potential diagnostic value for MFCP and PDAC. Methods: 26 Patients underwent static and dynamic 68 Ga-FAPI-PET/CT as well as dedicated fundamental (US) and contrast-enhanced ultrasonography (CEUS) before surgical resection or biopsy of pancreatic masses and subsequent histological analyses. Static parameters (SUVmax and SUVmean and target to background ratios) were generated from VOIs of pancreatic masses. Time activity curves and dynamic parameters were extracted from dynamic PET data. Results: Histology revealed 12 PDAC, 2 high-grade IPMN and 12 MFCP. We observed higher 68 Ga-FAPI-uptake in PDACs (average SUVmax/mean 18.09 +/- 5.5 / 10.55 +/- 2.97) than in MFCP (average SUVmax/mean 11.55 +/- 3.88 / 6.83 +/- 2.20). In dynamic PET-imaging, PDAC and MFCP showed differential time activity curves and the average time to peak was markedly longer for PDAC (1094 +/- 945 seconds ) than for MFCP (449 seconds +/- 203). In ROC curves, static and dynamic imaging parameters showed higher sensitivity and specificity than laboratory parameters, CT- and US-size. Conclusion: 68 Ga-FAPI-PET/CT displays the fibrotic activity of MFCP. Static and dynamic 68 Ga-FAPI-PET/CT should be considered, when clinical parameters and other imaging methods are not able to distinguish between PDAC and MFCP. FAPI mass forming chronic pancreatitis PDAC contrast-enhanced ultrasonography Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide [ 1 ]. Chronic pancreatitis (CP) is a disease triggered by tobacco and alcohol consumption, hereditary risk factors and autoimmune mechanisms [ 2 ]. CP bears an increased risk for transition into PDAC as well as for benign inflammatory tumors, like mass forming chronic pancreatitis (MFCP), localized autoimmune pancreatitis (AIP), paraduodenal pancreatitis (“groove pancreatitis”), or other inflammatory pseudotumors [ 2 – 5 ]. Among these, MFCP is of particular diagnostic interest as MFCP frequently mimics clinical and imaging features of PDAC [ 6 ]. Accurate and timely diagnosis of PDAC is crucial, as only early stages allow a surgical approach as potentially curative therapy. Pancreatic surgery is a highly operator dependent procedure with significant morbidity and mortality, so that a careful indication is required [ 7 , 8 ]. Therefore, the distinction between benign and malignant pancreatic lesions is indispensable for accurate patient management. Magnetic resonance imaging (MRI), computed tomography (CT), abdominal ultrasonography with (CEUS) and without contrast-enhancing agents (US), and endoscopic ultrasound (EUS) are the most frequently used imaging methods for CP, its complications and PDAC. However, their informative value is still limited – or even unknown for ultrasound - especially regarding the distinction between MFCP and PDAC [ 6 , 9 ]. 18 F-Fluorodesoxyglucose ( 18 F-FDG) positron emission tomography (PET) has been used to characterize suspicious pancreatic lesions, but has been proved to be of limited efficacy for the differentiation of MFCP and PDAC [ 10 ]. PET with 68 Gallium ( 68 Ga)-labelled Inhibitors of Fibroblast Activation Protein (FAPIs) has been used for various malignant and non-malignant diseases with tissue remodeling, in particular for pancreatic masses [ 11 – 15 ]. 68 Ga-FAPI-PET canonically visualizes the stromal tumor compartment in terms of FAP-positive fibroblasts [ 16 – 18 ]. Due to the vast stromal portion and minor portion of neoplastic cells in pancreatic cancers, FAPIs have a high tumor accumulation in PDAC [ 12 ]. Despite the high interest in 68 Ga-FAPI-PET for tumor staging of PDAC, no evaluation of a 68 Ga-FAPI-PET-based characterization of primary solid pancreatic lesions, that can display PDAC as well as MFCP in chronic pancreatitis, exists to date. Here, we applied static and dynamic 68 Ga-FAPI-46-PET imaging in 26 treatment-naïve patients with unclear pancreatic masses. The entire study cohort underwent bioptic or surgical histological confirmation of their lesions after imaging. The purpose of this analysis is to demonstrate the diagnostic potential of supplemental 68 Ga-FAPI-46-PET for the primary assessment of patients with suspicious pancreatic lesions in chronic pancreatitis. PATIENTS AND METHODS Patients Between September 2018 and October 2023, 26 patients with chronic pancreatitis and suspicious solid lesions or with a pancreatic mass and signs of chronic pancreatitis (as assessed by clinical examination, lab test s (carbohydrate-antigen19-9 (CA19-9), carcinoembryonic antigen (CEA) and C-reactive protein (CRP)), ultrasound (US) and computed tomography (CT) and/or magnetic resonance imaging (MRI)) underwent supplemental static and dynamic 68 Ga-FAPI-46-PET at the University Hospital Heidelberg. Patients were individually referred to 68 Ga-FAPI-46-PET by their treating physicians for characterization of their pancreatic masses. Written informed consent was obtained from all patients on an individual-patient basis following the regulations of the German Pharmaceuticals Act §13(2b). After 68 Ga-FAPI-46-PET, all patients underwent resection or biopsy and subsequent histopathological diagnosis of their pancreatic masses. Retrospective analysis of imaging, clinical and pathological data was approved by the local institutional review board (study number S-115/2020). Ultrasound and contrast-enhanced ultrasound, computed tomography and magnetic resonance imaging Ultrasound examinations started in supine position with transsplenic visualization of pancreatic tail, epigastric visualization of pancreatic tail and body followed by evaluation of pancreatic head. Ultrasound systems were a Siemens S3000 (Siemens Healthcare, Germany, built 2013) with an Acuson 6C1 HD curved transducer and Acuson 9L4 linear array transducer, and a General Electric GE Logiq E10s (GE Medical System, Milwaukee, USA, built 2021) with C1-6VN curved and L2-9VN linear transducers. For contrast-enhanced ultrasound imaging (CEUS) 1.5 - 2.4 ml of reconstituted SonoVue® (Bracco Imaging SpA, Milan, Italy) were applied by antecubital i.v. line. The suspicious lesion was continuously scanned and cine loops were recorded. Multiphase contrast-enhanced CT imaging of the abdomen and multimodal MRI were applied according to established in-house protocols as previously described [19]. Ultrasound and CT image analysis Ultrasound and CT images were used for size measurement of pancreatic masses. The following sonographic aspects were regarded as signs of malignancy: solid hypoechogenic mass with displaced or missing calcifications, non-calcification related abrupt interruption of the bile or pancreatic duct, solid encasement of adjacent vessels (especially pancreatic arteries)[20], and in CEUS a pancreatic mass with reduced contrast enhancement [21, 22]. Chronic pancreatitis was considered in the following conditions: criteria of Cambridge classification [23], duct penetrating sign and side branch dilatation [24] and iso- or hyperenhancing intrapancreatic lesion in CEUS [25]. 68 Ga-FAPI-46-PET/CT Synthesis and labeling of 68 Ga-FAPI-46 were conducted as previously described [18]. Static and dynamic 68 Ga-FAPI-46-PET/CT was carried out using a Biograph mCT Flow scanner (Siemens) as previously described [26]. In short, after injection of 187–329 MBq of 68 Ga-labeled FAPI-46 a low-dose CT without contrast was performed followed by dynamic PET scans (28 frames over 60 minutes) followed by whole body PET/CT scans 60 minutes after tracer injection. Reconstructions were performed with corrections for scatter, decay and attenuation. The average time spans between 68 Ga-FAPI-46-PET/CT and other modalities were 15,8 (US) and 9,7 (CT) days. PET imaging analysis Pancreatic masses as well as background organs (bloodpool and liver) were contoured manually on static 68 Ga-FAPI-PET/CT-PET images based on their CT appearance. For all pancreatic masses and background tissues, maximum and mean standardized uptake values (SUVmax / SUVmean) were extracted. Target-to-background ratios (TBR) against blood pool and liver tissue were calculated by dividing lesional SUVmax by SUVmean values of background tissues. Differences in these parameters between PDACs and MFCPs were analyzed. For dynamic 68 Ga-FAPI-PET data, time activity curves and quantitative dynamic parameters (time to peak (TTP), (time span between start of the dynamic image acquisition and the frame with the highest activity) and slope (calculated as relative gradient of the TAC between 180 seconds and 1 hour as previously published [27]) and their differences between PDACs and MFCPs were analyzed. Image analysis was performed using Pmod software (version 4.1). Statistical analysis We performed descriptive analyses of clinical patient characteristics and lesional imaging properties, whereby median and range were utilized. For determination of significances, after identification of outliers, a normality testing, followed by either 2-sided t-test or Wilcoxon test was used and p-values of less than 0.05 were considered statistically significant. Receiver operating characteristic (ROC) curves and corresponding area under the curve (AUC) estimates were computed for static and dynamic PET parameters. GraphPadPRISM, version 10, was used for statistical analyses. RESULTS Patient characteristics, surgical management and histological diagnoses 23/26 patients underwent surgery and 3/26 were diagnosed by endoscopic ultrasound-guided fine needle biopsy. Histological diagnoses were 12 PDACs (2 G1, 6 G2, 2 G3, 1 G4, 1 without grading) and 2 high grade intraductal papillary mucinous neoplasms (IPMN), classified together with PDAC since the biological aggressiveness and increased risk of malignization into PDAC require the same surgical management of high-grade IPMN as for PDAC. 12 patients were diagnosed with MFCP (3 based on auto-immune pancreatitis, 1 based eosinophilic pancreatitis, 8 based on chronic pancreatitis without further specification). Table 1 provides a patientwise overview of clinical patient features and detailed pathological diagnoses. Table 1: Clinical parameters and histological diagnoses of 26 patients with suspicious pancreatic masses No Age (years) Sex Localization Surgery / Intervention Diagnosis Classification 1 78 m Head Whipple High grade IPMN PDAC 2 73 m Head Whipple High grade IPNM 3 75 m Tail DP PDAC 4 69 f Head Whipple PDAC 5 67 m Tail EUS-FNB PDAC 6 69 m Head Whipple PDAC 7 68 m Tail DP PDAC 8 68 f Corpus DP PDAC 9 56 f Tail DP PDAC 10 73 f Head, Corpus Whipple PDAC 11 72 m Head Whipple PDAC 12 67 f Head Whipple PDAC 13 37 m Head Complete pancreatectomy PDAC 14 54 f Head SE PDAC 15 55 m Head EUS-FNB Autoimmune pancreatitis MFCP 16 57 m Head Duodenum preserving pancreatic head resection Autoimmune pancreatitis 17 50 m Head Whipple Chronic pancreatitis 18 30 m Head Whipple Chronic pancreatitis 19 60 m Corpus Whipple Chronic pancreatitis 20 59 f Head Whipple Chronic pancreatitis 21 61 m Head Whipple Chronic pancreatitis 22 32 m Tail EUS-FNB Eosinophile pancreatitis 23 71 m Head SE Pancreatitis 24 43 m Head Whipple Autoimmune pancreatitis 25 51 m Tail DP Chronic pancreatitis 26 41 m Head Whipple Chronic pancreatitis Abbreviations: m = male, f = female, DP = distal pancreatectomy, EUS-FNB = endoscopic ultrasound-guided fine needle biopsy, SE = surgical exploration, PDAC = pancreatic ductal adenocarcinoma, MFCP = mass forming chronic pancreatitis Laboratory parameters, ultrasound and CT findings in PDAC and MFCP In these 26 patients, neither pre-operative tumor marker levels (CA19-9 or CEA) nor inflammation marker CRP levels were significantly different between patients with PDAC and MFCP (figure 1a, supplemental table 1).Though, one data outlier with extremely elevated CA19-9 in a metastasized PDAC was omitted from statistical analysis. Similarly, lesion sizes of PDAC and MFCP did not differ significantly as assessed either by US or diagnostic CT (figure 1b). Hereby, US size of MFCP was slightly higher than that of than PDAC. According to pre-defined criteria for ultrasound examination, in 11/26 cases a mixture of PDAC-suggesting and MFCP-suggesting features was observed. Similarly, no marked differences occurred between PDAC and MFCP with regard to arterial or late contrast enhancement (supplemental table 1). 68 Ga-FAPI-46-uptake in PDAC and MFCP PDAC showed significantly increased 68 Ga-FAPI-46-uptake compared to MFCP in terms of SUVmax and SUVmean (figure 2a). With regard to TBR versus blood and versus liver tissue, the differences between PDAC and MFCP were less pronounced, but still significant (figure 2b). Nevertheless, a certain overlap between PDAC and MFCP was found for all uptake parameters. With regard to PDAC grading and MFCP subentities, no significant differences or trends could be detected, especially the high-grade IPMN did not show reduced 68 Ga-FAPI-46-uptake compared to PDAC (data not shown). PDAC and MFCP in dynamic 68 Ga-FAPI-46-PET Dynamic 68 Ga-FAPI-46-PET imaging was acquired in 25/26 patients (all except patient 14). Time activity curves of PDAC showed a delayed peak (average time to peak 1094 +/- 945 seconds) and only slightly decreasing uptake up to 60 minutes p.i. MFCP showed an earlier peak (average time to peak 449 +/- 203 seconds) and afterwards, a more clearly decreasing time activity curve compared to PDAC (figure 3a). Quantitative analysis of dynamic parameters revealed a significantly prolonged TTP in PDAC compared to MFCP and a trend towards a more pronounced negative slope in MFCP compared to PDAC (figure 3b). Figures 4 and 5 show exemplary cases of one patient with PDAC and one patient with MFCP, where clinical, ultrasound, CT and MRI findings did not allow a clear dignity assessment of the pancreatic lesions, but static as well as dynamic 68 Ga-FAPI-46-PET findings showed pronounced differential findings in PDAC and MFCP. Sensitivity and specificity of clinical and 68 Ga-FAPI-46-PET parameters ROC curves for the differentiation between PDAC and MFCP were calculated for CA19-9, CEA, CRP, ultrasound and CT size as well as static and dynamic 68 Ga-FAPI-46-PET parameters. Laboratory parameters and CT size all had low AUC values (< 0.60). US size showed an AUC of 0.70, however the average US size of MFCP was higher than that of PDAC (figure 6a). The highest AUC values were calculated for SUVmax and SUVmean (0.84 each) (figure 6b). TBR values and dynamic parameters showed slightly lower AUC (TBR versus blood 0.74, TBR versus liver 0.74, TTP 0.73 and slope 0.62) (figure 6c, d). Exemplary sensitivities / specificities were 92.31% (95% CI interval 66.69% to 99.61%) / 57.14% (95% CI interval 32.59% to 78.62%) for a cut-off value of 16.58 for SUVmax and 92.31% (95% CI interval 66.69% to 99.61%) / 57.14% (95% CI interval 32.59% to 78.62%) for a cutoff-value of 9.316 for SUVmean. DISCUSSION Summary of the results Despite the rapidly emerging evidence in favor of the great potential of FAPI-PET with respect to staging of primary and recurrent PDAC [ 11 , 28 ], data on FAPI-PET for the differentiation of PDAC and its differential diagnoses are very limited [ 11 , 29 ]. To our best knowledge, no data on the signal behavior of PDAC and MFCP in FAPI-PET have been published to date. Here, we have demonstrated that not only PDAC as a malignancy with strong desmoplastic reaction, but also MFCP, a chronic inflammatory disease with fibrotic tissue remodeling, are both FAPI-positive. The signal intensity of PDACs was markedly higher than that of MFCP and dynamic 68 Ga-FAPI-imaging revealed differential kinetic behavior of FAPI-46 in both entities. These marked differences in static and dynamic 68 GA-FAPI-46 imaging are reflected by higher diagnostic accuracy for the differentiation of PDAC and MFCP compared to laboratory, ultrasound- and CT size, which did not significantly differ between the two diseases in our dataset. Similarly, morphological features assessed by ultrasound could not rule out malignancy with the necessary certainty. PDAC grading in our dataset (G1 18%, G2 55%, G3 18%, G4 9%) tended towards more favorable grades than reported elsewhere [ 30 ]. Relatively favorable grading suggests lower FAPI-uptake than in PDACs with higher grading according to our recently published work [ 12 ]. Nevertheless, differences between PDAC and MFCP in static and dynamic 68 GA-FAPI-46-PET/CT were pronounced. In conclusion, our results suggest that 68 Ga-FAPI-PET could be a reasonable supplemental imaging tool for the differentiation of PDAC and MFCP in clinically and morphologically unclear cases. Possible clinical applications of 68 Ga-FAPI-PET for MFCP The pronounced FAPI-positivity of MFCP reflects marked fibrotic activity of MFCP. According to this, FAPI-PET appears to be a valuable new tool for the assessment of MFCP that displays fibrotic activity and may serve as prognostic tool for risk stratification with regard to clinical course and malignant progression. Malignant transformation of chronic fibro-inflammatory lesions is a canonic factor of carcinogenesis and can generally occur in various fibrotic lesions and especially in PDAC developed from MFP [ 31 ]. Given the differential signal behavior of PDAC and MFCP, 68 Ga-FAPI-PET/CT may be a helpful future monitoring tool for MFCP that could lead to timely detection of malignant transformation. Another possible clinical application of 68 Ga-FAPI-PET for MFCP is therapy evaluation of anti-fibrotic MFCP treatments which have shown promising results for the treatment of MFCP [ 32 ]. Based on our results, a systematic evaluation of 68 Ga-FAPI-PET for MFCP with regard to prognostic value and therapy response assessment appears a promising future project. 68 Ga-FAPI-PET for the differentiation of PDAC, MFCP and other differential diagnoses of pancreatic lesions Our results on static 68 Ga-FAPI-PET imaging are in line with our previous publications, where we have compared 68 Ga-FAPI-uptake of PDAC and its differential diagnoses. In an earlier publication, we drew a comparison between 68 Ga-FAPI-uptake of PDAC and pancreatitis of the remaining pancreas parenchyma related to obstruction of the main pancreatic duct and found higher FAPI-avidity in PDAC than in pancreatitis, but a certain overlap between both pathologies [ 11 ]. Similarly, we have found increased 68 Ga-FAPI-uptake of PDAC compared to benign intraductal papillary mucinous neoplasms of the pancreas (IPMN) [ 13 ], which was concordantly reflected by immunohistochemical FAP expression of both entities [ 12 ]. For the differentiation between PDAC and high-grade IPMN versus low-grade IPMN, we have also found very distinct differences in their time-dependent signal behavior in dynamic PET-imaging, in particular in terms of prolonged TTP of PDAC and high grade IPMN compared to low-grade IPMN [ 13 ]. Here, we found similar results, but the additional value of FAPI-46-uptake and tracer kinetics for the differentiation of PDAC and MFCP appears less pronounced than for PDAC and IPMN. This could be explained by the fact that low-grade IPMN show – in contrast to PDAC – little desmoplastic reaction involving activated fibroblasts, but MFCP leads not only to inflammatory, but also to significant fibrotic reactions of the pancreatic tissue [ 33 ]. Thus, one would assume a high prevalence of FAP-positive activated fibroblasts in MFCP. However, a systematic evaluation of FAP-expression and fibroblast subgroups in MFCP that could further explain our imaging findings does not exist to date. Limitations Major limitation of this work are the limited number of patients and retrospective data analysis. Additionally, this work is limited by our patient collective containing only patients with unclear pancreatic masses, so our findings are limited to that certain subpopulation of PDAC/MFCP patients and cannot be generalized, as patients with more suggestive clinical findings were not analyzed. Further clinical studies with prospective design and higher numbers of clearly characterized patients are necessary to validate our findings. Conclusion MFCP is a FAPI-positive pancreatic lesion, but FAPI-positivity in MFCP is less pronounced than in PDAC and both entities showed differential kinetic behavior in dynamic imaging. In our dataset, static and dynamic 68 Ga-FAPI-PET parameters exceeded laboratory parameters, CT size, US size and US morphology in diagnostic accuracy for the differentiation of PDAC and MFCP. 68 Ga-FAPI-PET is a promising tool for the assessment of MFCP and PDAC, which may help to detect malignant transformation and to improve patient stratification with respect to pancreatectomy. Declarations Funding: This work was funded by the Federal Ministry of Education and Research, grant number 13N 13341. Competing interests : UH has filed a patent application for quinoline based FAP targeting agents for imaging and therapy in nuclear medicine. UH has shares of a consultancy group for iTheranostics. No other potential conflicts of interest relevant to this article exist. Author contributions : All authors contributed to the study conception and design. Data collection and analysis were performed by Matthias Lang, Markus Preussig, Anna-Maria Spektor, Isabelle von Goetze, Ewgenija Gutjahr, Frederik Glatting and Manuel Röhrich. The first draft of the manuscript was written by Matthias Lang and Manuel Röhrich and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Data availability: The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request. Ethics approval: All procedures performed in studies involving human participants confirmed to the ethical standards of the institutional and/or national research committee and to the Helsinki declaration (1964) and its later amendments or comparable ethical standards. This retrospective study was approved by the local advisory ethic committee (study number S-115/2020). Clinical trial number: not applicable. Consent to participate: Informed consent was obtained from all individual participants included in the study. Consent to publish: The authors affirm that human research participants provided informed consent for publication of the images in Figures 4 and 5. References Park, W., A. Chawla, and E.M. O'Reilly, Pancreatic Cancer: A Review. JAMA, 2021. 326 (9): p. 851-862. Beyer, G., et al., Chronic pancreatitis. Lancet, 2020. 396 (10249): p. 499-512. Gandhi, S., et al., Chronic Pancreatitis Is a Risk Factor for Pancreatic Cancer, and Incidence Increases With Duration of Disease: A Systematic Review and Meta-analysis. Clin Transl Gastroenterol, 2022. 13 (3): p. e00463. Kirkegard, J., F.V. Mortensen, and D. Cronin-Fenton, Chronic Pancreatitis and Pancreatic Cancer Risk: A Systematic Review and Meta-analysis. Am J Gastroenterol, 2017. 112 (9): p. 1366-1372. Lowenfels, A.B., et al., Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. 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BMJ, 2024. 384 : p. e070920. Li, B.Q., et al., The research progress of anti-inflammatory and anti-fibrosis treatment of chronic pancreatitis. Front Oncol, 2022. 12 : p. 1050274. Apte, M., R. Pirola, and J. Wilson, The fibrosis of chronic pancreatitis: new insights into the role of pancreatic stellate cells. Antioxid Redox Signal, 2011. 15 (10): p. 2711-22. Additional Declarations No competing interests reported. Supplementary Files FAPIMFCPPDACsupplementalfileML161224.docx Cite Share Download PDF Status: Posted Version 1 posted 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. 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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-5640954","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":391439548,"identity":"783d5771-4a90-4f7b-b9a4-0d3c2cef8505","order_by":0,"name":"Matthias Lang","email":"","orcid":"","institution":"Heidelberg University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Matthias","middleName":"","lastName":"Lang","suffix":""},{"id":391439552,"identity":"0283a62b-8f4c-4304-b55c-251790484ad3","order_by":1,"name":"Markus Preussig","email":"","orcid":"","institution":"University Hospital Heidelberg","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Markus","middleName":"","lastName":"Preussig","suffix":""},{"id":391439553,"identity":"2bf7090f-fcde-4066-8215-8f4c0fc062bc","order_by":2,"name":"Anna-Maria Spektor","email":"","orcid":"","institution":"University Hospital Mainz","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Anna-Maria","middleName":"","lastName":"Spektor","suffix":""},{"id":391439554,"identity":"553abb6a-7b75-43d6-9045-75572638880b","order_by":3,"name":"Isabelle von Goetze","email":"","orcid":"","institution":"University Hospital Mainz","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Isabelle","middleName":"","lastName":"von Goetze","suffix":""},{"id":391439555,"identity":"0a1c5802-9193-4de7-84e7-ef3fc287b4ea","order_by":4,"name":"Joel Wessendorf","email":"","orcid":"","institution":"University Hospital Mainz","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Joel","middleName":"","lastName":"Wessendorf","suffix":""},{"id":391439556,"identity":"08a16a93-aa60-4cc4-a3b9-8b64851d0c80","order_by":5,"name":"Frederik M. Glatting","email":"","orcid":"","institution":"University Hospital Heidelberg","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Frederik","middleName":"M.","lastName":"Glatting","suffix":""},{"id":391439557,"identity":"1fef625f-5b72-4735-9516-365ec0142ec0","order_by":6,"name":"Ewgenija Gutjahr","email":"","orcid":"","institution":"University Hospital Heidelberg","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ewgenija","middleName":"","lastName":"Gutjahr","suffix":""},{"id":391439558,"identity":"48c0bb36-3f89-44c9-844b-ba466096d277","order_by":7,"name":"Thomas M. Pausch","email":"","orcid":"","institution":"Heidelberg University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"M.","lastName":"Pausch","suffix":""},{"id":391439559,"identity":"f7c9d43a-5b4e-4e76-aa0b-bcb18120b87e","order_by":8,"name":"Ulrike Heger","email":"","orcid":"","institution":"Heidelberg University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ulrike","middleName":"","lastName":"Heger","suffix":""},{"id":391439560,"identity":"5dda360a-11ab-45ed-aa5e-a3c8210b70aa","order_by":9,"name":"Philipp Mayer","email":"","orcid":"","institution":"University Hospital Heidelberg","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Philipp","middleName":"","lastName":"Mayer","suffix":""},{"id":391439561,"identity":"b7111e9b-51b3-4e1f-a50d-f1a6084f5b69","order_by":10,"name":"Hans-Georg Buchholz","email":"","orcid":"","institution":"University Hospital Mainz","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hans-Georg","middleName":"","lastName":"Buchholz","suffix":""},{"id":391439562,"identity":"0594f674-e0ea-46cf-a381-fe019489af38","order_by":11,"name":"Mathias Schreckenberger","email":"","orcid":"","institution":"University Hospital Mainz","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mathias","middleName":"","lastName":"Schreckenberger","suffix":""},{"id":391439563,"identity":"353748d2-f33d-4457-9b3a-e5e8d3a2c4bf","order_by":12,"name":"Hans-Ulrich Kauczor","email":"","orcid":"","institution":"University Hospital Heidelberg","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hans-Ulrich","middleName":"","lastName":"Kauczor","suffix":""},{"id":391439564,"identity":"4b103957-6454-46ed-83c6-260e6e629a93","order_by":13,"name":"Christin Tjaden","email":"","orcid":"","institution":"University Hospital Munich, Klinikum rechts der Isar (TU)","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Christin","middleName":"","lastName":"Tjaden","suffix":""},{"id":391439565,"identity":"4bff40bf-8206-43d0-a238-1d4fd7f9a019","order_by":14,"name":"Thilo Hackert","email":"","orcid":"","institution":"University Hospital Hamburg","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Thilo","middleName":"","lastName":"Hackert","suffix":""},{"id":391439566,"identity":"27718319-6bf6-4cee-a1ee-ee48af3a7745","order_by":15,"name":"Christoph Michalski","email":"","orcid":"","institution":"University Hospital Heidelberg","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Christoph","middleName":"","lastName":"Michalski","suffix":""},{"id":391439567,"identity":"f04e5c5f-10c2-4e6a-a3a9-76f77eb3c540","order_by":16,"name":"Uwe Haberkorn","email":"","orcid":"","institution":"University Hospital Heidelberg","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Uwe","middleName":"","lastName":"Haberkorn","suffix":""},{"id":391439568,"identity":"f230362d-9c54-48f5-b599-43b56474525d","order_by":17,"name":"Manuel Röhrich","email":"data:image/png;base64,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","orcid":"","institution":"University Hospital Mainz","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Manuel","middleName":"","lastName":"Röhrich","suffix":""}],"badges":[],"createdAt":"2024-12-14 01:23:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5640954/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5640954/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":72287198,"identity":"5702da29-a36b-4fd5-aa63-b2b06ea2b6e9","added_by":"auto","created_at":"2024-12-24 17:08:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":39817,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eQuantitative analysis Carboanhydrate Antigen 19-9 (CA 19-9), carcinoembryonal antigen (CEA), C-reactive protein (CRP) and size measured by ultrasound (US) and diagnostic CT of PDAC and MFCP in 27 patients. A, B, C: \u003c/strong\u003eBox plots with single values depicted of CA-19-9, CEA and CRP (\u003cstrong\u003eA\u003c/strong\u003e) and US/CT size (\u003cstrong\u003eB\u003c/strong\u003e) of PDAC and MFCP. Boxes represent interquartile range. Whiskers represent interquartile range of 1.5. The horizontal line within boxes indicates median. Individual values are shown as black dots or squares within graphs. Ns = not significant.\u003c/p\u003e","description":"","filename":"fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-5640954/v1/ee9769f204f8b5e14a3c2598.png"},{"id":72287199,"identity":"1506815a-0c88-4017-a222-03854fd74d2e","added_by":"auto","created_at":"2024-12-24 17:08:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":34829,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eQuantitative analysis of \u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e68\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eGa-FAPI-46 uptake of PDAC and MFCP in 27 patients. A,B \u003c/strong\u003eBox plots with single values depicted of SUVmax and SUVmean (A) of PDAC and MFCP and corresponding target-to-background ratios (TBR) against blood pool and liver tissue (B). Boxes represent interquartile range. Whiskers represent interquartile range of 1.5. The horizontal line within boxes indicates median. Individual values are shown as black dots or squares within graphs. Stars indicate significant differences: *= p \u0026lt; 0.05, **= p \u0026lt; 0.01.\u003c/p\u003e","description":"","filename":"fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-5640954/v1/6527b8cf8d9ee936cf72a73f.png"},{"id":72288509,"identity":"f44a4171-1b84-41fc-b03c-87759da912ac","added_by":"auto","created_at":"2024-12-24 17:16:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":42007,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSignal behavior of PDAC and MFCP in dynamic \u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e68\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eGa-FAPI-46-PET imaging. A \u003c/strong\u003eAveraged time activity curves (relative to peak) of PDAC and MFCP Red (for PDAC) and green (for MFCP) arrows indicate the peaks of the curves. \u003cstrong\u003eB\u003c/strong\u003e Box plots of time to peak (TTP) and slope of PDAC and MFCP. Boxes represent interquartile range, whiskers represent interquartile range of 1.5 and horizontal line within box indicates median. Individual values are shown as black dots or squares within graphs. Star indicates significant difference: *= p \u0026lt; 0.05. Ns = not significant.\u003c/p\u003e","description":"","filename":"fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-5640954/v1/0cf5606a34ea23788efa2a64.png"},{"id":72287204,"identity":"53ac77c0-001e-4183-80ff-86df4fe3afe9","added_by":"auto","created_at":"2024-12-24 17:08:58","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1051422,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExemplary MRI, ultrasound and \u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e68\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eGa-FAPI-46-PET/CT images of a PDAC.\u003c/strong\u003e A 27 year-old male patient presented with elevated CA 19-9 (251.4 U/ml) and a suspicious mass in the pancreatic head, which was diagnosed as PDAC after whipple resection. \u003cstrong\u003eA\u003c/strong\u003e Axial contrast enhanced (ce) T1w images. Right: Overview of the abdomen at the level of the pancreatic body: Marked smooth dilatationof the main pancreatic duct with concomitant parenchymal atrophy in the pancreatic body with abrupt duct cutoff due to the PDAC in the pancreatic head. Middle: Overview of the abdomen at the level of the PDAC in the pancreatic head. Left: Detail view of the PDAC, which shows diffuse contrast enhancement. \u003cstrong\u003eB\u003c/strong\u003e Contrast-enhanced ultrasound confirms marked dilatation of the main pancreatic duct and the PDAC of the pancreatic head appears inhomogenously hyperechogenic. \u003cstrong\u003eC\u003c/strong\u003e \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46 PET of the same patient. Left: Maximum Intensity Projection (MIP), right: Axial CT (left upper image), \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46 PET (right upper image) and fused (left lower image) images at the level of the green line. Green arrows indicate the PDAC in CT, PET and fused images. Left lower image: time activity curve of the PDAC, which has its peak after 2250 seconds and shows a slightly increasing slope.\u003c/p\u003e","description":"","filename":"fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-5640954/v1/10f092c5841c2df0ecdbbeaf.png"},{"id":72287209,"identity":"2048855f-18d5-4fc7-b209-e2fd37203ed6","added_by":"auto","created_at":"2024-12-24 17:08:58","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1241555,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExemplary MRI, ultrasound and \u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e68\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eGa-FAPI-46-PET/CT images of a MFCP.\u003c/strong\u003e A 43- year-old male patient with CA19-9 of 26.2 U/ml had a mass in the pancreatic head and Whipple pancreatoduodenectomy led to the diagnosis of MFCP.\u003cstrong\u003e A \u003c/strong\u003eAxial late (10 minutes p.i.) contrast-enhanced (ce) T1w images: \u0026nbsp;Right: Overview of the Abdomen at the level of the pancreatic body: Dilated main pancreatic duct due to MFCP in the pancreatic head. Middle: Overview of the abdomen at the level of the pancreatic head, left: detailed view of the MFCP, which shows focal contrast enhancement (green arrow).\u003cstrong\u003e B \u003c/strong\u003eContrast enhanced ultrasound of the pancreas: Right: Dilatation of the main pancreatic duct up to 57 mm in the pancreatic body. Left: The MFCP in the pancreatic head appears hypoechogenic.\u003cstrong\u003e C \u003c/strong\u003e\u003csup\u003e68\u003c/sup\u003eGa-FAPI-46 PET images:\u003cstrong\u003e Left: \u003c/strong\u003eMaximum Intensity Projection (MIP), Axial CT (left upper image), \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46 PET (right upper image) and fused (left lower image) images at the level of the green line. Green arrows indicate the MFCP in CT, PET and fused images. Left lower image: time activity curve of the MFCP, which has its peak after 450 seconds and shows a decreasing slope.\u003c/p\u003e","description":"","filename":"fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-5640954/v1/6392e73fa151446393485a08.png"},{"id":72290942,"identity":"e9c1121f-8a65-4f9b-b262-42ff0a0681e6","added_by":"auto","created_at":"2024-12-24 17:24:58","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":72459,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eReceiver-operating-characteristic (ROC) curves of clinical parameters (CA 19-9, ultrasound size, CT size) and static and dynamic \u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e68\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eGa-FAPI-PET-parameters with the highest discriminatory power depicted as areas under the ROC curve: A \u003c/strong\u003eCA 19-9, ultrasound size and CT size, \u003cstrong\u003eB \u003c/strong\u003eSUVmax and SUVmean \u003cstrong\u003eB\u003c/strong\u003e TBR versus bloodpool and liver, \u003cstrong\u003eD \u003c/strong\u003eTTP and slope.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e","description":"","filename":"fig6.png","url":"https://assets-eu.researchsquare.com/files/rs-5640954/v1/26817744055e7d27c011d719.png"},{"id":81807398,"identity":"b76fa496-98fe-4610-94ff-2f40b7331cd7","added_by":"auto","created_at":"2025-05-02 07:47:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4067931,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5640954/v1/dfa4f65f-c273-4d41-b470-588232a3badc.pdf"},{"id":72290941,"identity":"77d073c8-cb49-4310-9a35-b9d4bfc96781","added_by":"auto","created_at":"2024-12-24 17:24:58","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19605,"visible":true,"origin":"","legend":"","description":"","filename":"FAPIMFCPPDACsupplementalfileML161224.docx","url":"https://assets-eu.researchsquare.com/files/rs-5640954/v1/f5777576a214f25fd0ffa0f5.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003csup\u003e\u003cstrong\u003e68\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eGallium-FAPI-positron emission tomography for dignity assessment of mass-forming chronic pancreatitis and pancreatic ductal adenocarcinomas compared to laboratory parameters, ultrasound and computed tomography\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003ePancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Chronic pancreatitis (CP) is a disease triggered by tobacco and alcohol consumption, hereditary risk factors and autoimmune mechanisms [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. CP bears an increased risk for transition into PDAC as well as for benign inflammatory tumors, like mass forming chronic pancreatitis (MFCP), localized autoimmune pancreatitis (AIP), paraduodenal pancreatitis (\u0026ldquo;groove pancreatitis\u0026rdquo;), or other inflammatory pseudotumors [\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Among these, MFCP is of particular diagnostic interest as MFCP frequently mimics clinical and imaging features of PDAC [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Accurate and timely diagnosis of PDAC is crucial, as only early stages allow a surgical approach as potentially curative therapy. Pancreatic surgery is a highly operator dependent procedure with significant morbidity and mortality, so that a careful indication is required [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Therefore, the distinction between benign and malignant pancreatic lesions is indispensable for accurate patient management. Magnetic resonance imaging (MRI), computed tomography (CT), abdominal ultrasonography with (CEUS) and without contrast-enhancing agents (US), and endoscopic ultrasound (EUS) are the most frequently used imaging methods for CP, its complications and PDAC. However, their informative value is still limited \u0026ndash; or even unknown for ultrasound - especially regarding the distinction between MFCP and PDAC [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. \u003csup\u003e18\u003c/sup\u003eF-Fluorodesoxyglucose (\u003csup\u003e\u003cem\u003e18\u003c/em\u003e\u003c/sup\u003eF-FDG) positron emission tomography (PET) has been used to characterize suspicious pancreatic lesions, but has been proved to be of limited efficacy for the differentiation of MFCP and PDAC [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePET with \u003csup\u003e68\u003c/sup\u003eGallium (\u003csup\u003e68\u003c/sup\u003eGa)-labelled Inhibitors of Fibroblast Activation Protein (FAPIs) has been used for various malignant and non-malignant diseases with tissue remodeling, in particular for pancreatic masses [\u003cspan additionalcitationids=\"CR12 CR13 CR14\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. \u003csup\u003e68\u003c/sup\u003eGa-FAPI-PET canonically visualizes the stromal tumor compartment in terms of FAP-positive fibroblasts [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Due to the vast stromal portion and minor portion of neoplastic cells in pancreatic cancers, FAPIs have a high tumor accumulation in PDAC [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Despite the high interest in \u003csup\u003e68\u003c/sup\u003eGa-FAPI-PET for tumor staging of PDAC, no evaluation of a \u003csup\u003e68\u003c/sup\u003eGa-FAPI-PET-based characterization of primary solid pancreatic lesions, that can display PDAC as well as MFCP in chronic pancreatitis, exists to date. Here, we applied static and dynamic \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46-PET imaging in 26 treatment-na\u0026iuml;ve patients with unclear pancreatic masses. The entire study cohort underwent bioptic or surgical histological confirmation of their lesions after imaging. The purpose of this analysis is to demonstrate the diagnostic potential of supplemental \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46-PET for the primary assessment of patients with suspicious pancreatic lesions in chronic pancreatitis.\u003c/p\u003e"},{"header":"PATIENTS AND METHODS","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatients\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween September 2018 and October 2023, 26 patients with chronic pancreatitis and suspicious solid lesions or with a pancreatic mass and signs of chronic pancreatitis (as assessed by clinical examination, lab test\u003cs\u003es\u003c/s\u003e (carbohydrate-antigen19-9 (CA19-9), carcinoembryonic antigen (CEA) and C-reactive protein (CRP)), ultrasound (US) and computed tomography (CT) and/or magnetic resonance imaging (MRI)) underwent supplemental static and dynamic \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46-PET at the University Hospital Heidelberg. Patients were individually referred to \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46-PET by their treating physicians for characterization of their pancreatic masses. Written informed consent was obtained from all patients on an individual-patient basis following the regulations of the German Pharmaceuticals Act \u0026sect;13(2b). After \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46-PET, all patients underwent resection or biopsy and subsequent histopathological diagnosis of their pancreatic masses. Retrospective analysis of imaging, clinical and pathological data was approved by the local institutional review board (study number S-115/2020). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eUltrasound and contrast-enhanced ultrasound, computed tomography and magnetic resonance imaging\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUltrasound examinations started in supine position with transsplenic visualization of pancreatic tail, epigastric visualization of pancreatic tail and body followed by evaluation of pancreatic head. Ultrasound systems were a Siemens S3000 (Siemens Healthcare, Germany, built 2013) with an Acuson 6C1 HD curved transducer and Acuson 9L4 linear array transducer, and a General Electric GE Logiq E10s (GE Medical System, Milwaukee, USA, built 2021) with C1-6VN curved and L2-9VN linear transducers. For contrast-enhanced ultrasound imaging (CEUS) 1.5 - 2.4 ml of reconstituted SonoVue\u0026reg; (Bracco Imaging SpA, Milan, Italy) were applied by antecubital i.v. line. The suspicious lesion was continuously scanned and cine loops were recorded. Multiphase contrast-enhanced CT imaging of the abdomen and multimodal MRI were applied according to established in-house protocols as previously described [19].\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eUltrasound and CT image analysis\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUltrasound and CT images were used for size measurement of pancreatic masses. The following sonographic aspects were regarded as signs of malignancy: solid hypoechogenic mass with displaced or missing calcifications, non-calcification related abrupt interruption of the bile or pancreatic duct, solid encasement of adjacent vessels (especially pancreatic arteries)[20], and in CEUS a pancreatic mass with reduced contrast enhancement [21, 22]. Chronic pancreatitis was considered in the following conditions: criteria of Cambridge classification [23], duct penetrating sign and side branch dilatation [24] and iso- or hyperenhancing intrapancreatic lesion in CEUS [25].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u003csup\u003e68\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eGa-FAPI-46-PET/CT\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSynthesis and labeling of \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46 were conducted as previously described [18]. Static and dynamic \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46-PET/CT was carried out using a Biograph mCT Flow scanner (Siemens) as previously described [26]. In short, after injection of 187\u0026ndash;329 MBq of \u003csup\u003e68\u003c/sup\u003eGa-labeled FAPI-46 a low-dose CT without contrast was performed followed by dynamic PET scans (28 frames over 60 minutes) followed by whole body PET/CT scans 60 minutes after tracer injection. Reconstructions were performed with corrections for scatter, decay and attenuation. The average time spans between \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46-PET/CT and other modalities were 15,8 (US) and 9,7 (CT) days.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePET imaging analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePancreatic masses as well as background organs (bloodpool and liver) were contoured manually on static \u003csup\u003e68\u003c/sup\u003eGa-FAPI-PET/CT-PET images based on their CT appearance. For all pancreatic masses and background tissues, maximum and mean standardized uptake values (SUVmax / SUVmean) were extracted. Target-to-background ratios (TBR) against blood pool and liver tissue were calculated by dividing lesional SUVmax by SUVmean values of \u0026nbsp;background tissues. Differences in these parameters between PDACs and MFCPs were analyzed. For dynamic \u003csup\u003e68\u003c/sup\u003eGa-FAPI-PET data, time activity curves and quantitative dynamic parameters (time to peak (TTP), (time span between start of the dynamic image acquisition and the frame with the highest activity) and slope (calculated as relative gradient of the TAC between 180 seconds and 1 hour as previously published [27]) and their differences between PDACs and MFCPs were analyzed. Image analysis was performed using Pmod software (version 4.1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe performed descriptive analyses of clinical patient characteristics and lesional imaging properties, whereby median and range were utilized. For determination of significances, after identification of outliers, a normality testing, followed by either 2-sided t-test or Wilcoxon test was used and p-values of less than 0.05 were considered statistically significant. Receiver operating characteristic (ROC) curves and corresponding area under the curve (AUC) estimates were computed for static and dynamic PET parameters. GraphPadPRISM, version 10, was used for statistical analyses.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatient characteristics, surgical management and histological diagnoses\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e23/26 patients underwent surgery and 3/26 were diagnosed by endoscopic ultrasound-guided fine needle biopsy. Histological diagnoses were 12 PDACs (2 G1, 6 G2, 2 G3, 1 G4, 1 without grading) and 2 high grade intraductal papillary mucinous neoplasms (IPMN), classified together with PDAC since the biological aggressiveness and increased risk of malignization into PDAC require the same surgical management of high-grade IPMN as for PDAC. 12 patients were diagnosed with MFCP (3 based on auto-immune pancreatitis, 1 based eosinophilic pancreatitis, 8 based on chronic pancreatitis without further specification). Table 1 provides a patientwise overview of clinical patient features and detailed pathological diagnoses. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1:\u003c/strong\u003e Clinical parameters and histological diagnoses of 26 patients with suspicious pancreatic masses\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"96%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocalization\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSurgery / Intervention\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClassification\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"33\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd height=\"31\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eWhipple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003eHigh grade IPMN\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"14\" style=\"width: 17px;\"\u003e\n \u003cp\u003ePDAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eWhipple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003eHigh grade IPNM\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eTail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eDP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003ePDAC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"3\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003ef\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eWhipple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003ePDAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"8\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eTail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eEUS-FNB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003ePDAC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eWhipple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003ePDAC \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"5\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eTail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eDP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003ePDAC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003ef\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eCorpus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eDP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003ePDAC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"2\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003ef\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eTail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eDP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003ePDAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"16\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003ef\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead, Corpus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eWhipple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003ePDAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"2\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eWhipple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003ePDAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003ef\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eWhipple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003ePDAC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e13\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eComplete pancreatectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003ePDAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e14\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003ef\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eSE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003ePDAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eEUS-FNB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003eAutoimmune pancreatitis\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"12\" style=\"width: 17px;\"\u003e\n \u003cp\u003eMFCP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e16\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eDuodenum preserving pancreatic head resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003eAutoimmune pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e17\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eWhipple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003eChronic pancreatitis\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"2\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eWhipple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003eChronic pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e19\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eCorpus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eWhipple\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003eChronic pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e20\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003ef\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eWhipple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003eChronic pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e21\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eWhipple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003eChronic pancreatitis\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e22\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eTail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eEUS-FNB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003eEosinophile pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e23\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eSE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003ePancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e24\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eWhipple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003eAutoimmune pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"11\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e25\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eTail\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eDP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003eChronic pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"2\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e26\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003em\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eHead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eWhipple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003eChronic pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e m = male, f = female, DP = distal pancreatectomy, EUS-FNB = endoscopic ultrasound-guided fine needle biopsy, SE = surgical exploration, PDAC =\u0026nbsp;pancreatic ductal adenocarcinoma, MFCP = mass forming chronic pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"20\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eLaboratory parameters, ultrasound and CT findings in PDAC and MFCP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn these 26 patients, neither pre-operative tumor marker levels (CA19-9 or CEA) nor inflammation marker CRP levels were significantly different between patients with PDAC and MFCP (figure 1a, supplemental table 1).Though, one data outlier with extremely elevated CA19-9 in a metastasized PDAC was omitted from statistical analysis. Similarly, lesion sizes of PDAC and MFCP did not differ significantly as assessed either by US or diagnostic CT (figure 1b). Hereby, US size of MFCP was slightly higher than that of than PDAC. According to pre-defined criteria for ultrasound examination, in 11/26 cases a mixture of PDAC-suggesting and MFCP-suggesting features was observed. Similarly, no marked differences occurred between PDAC and MFCP with regard to arterial or late contrast enhancement (supplemental table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u003csup\u003e68\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eGa-FAPI-46-uptake in PDAC and MFCP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePDAC showed significantly increased \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46-uptake compared to MFCP in terms of SUVmax and SUVmean (figure 2a). With regard to TBR versus blood and versus liver tissue, the differences between PDAC and MFCP were less pronounced, but still significant (figure 2b). Nevertheless, a certain overlap between PDAC and MFCP was found for all uptake parameters. With regard to PDAC grading and MFCP subentities, no significant differences or trends could be detected, especially the high-grade IPMN did not show reduced \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46-uptake compared to PDAC (data not shown).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePDAC and MFCP in dynamic \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46-PET\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDynamic \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46-PET imaging was acquired in 25/26 patients (all except patient 14). Time activity curves of PDAC showed a delayed peak (average time to peak 1094 +/- 945 seconds) and only slightly decreasing uptake up to 60 minutes p.i. MFCP showed an earlier peak (average time to peak 449 +/- 203 seconds) and afterwards, a more clearly decreasing time activity curve compared to PDAC (figure 3a). Quantitative analysis of dynamic parameters revealed a significantly prolonged TTP in PDAC compared to MFCP and a trend towards a more pronounced negative slope in MFCP compared to PDAC (figure 3b). Figures 4 and 5 show exemplary cases of one patient with PDAC and one patient with MFCP, where clinical, ultrasound, CT and MRI findings did not allow a clear dignity assessment of the pancreatic lesions, but static as well as dynamic \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46-PET findings showed pronounced differential findings in PDAC and MFCP.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSensitivity and specificity of clinical and \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46-PET parameters\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eROC curves for the differentiation between PDAC and MFCP were calculated for CA19-9, CEA, CRP, ultrasound and CT size as well as static and dynamic \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46-PET\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eparameters. Laboratory parameters and CT size all had low AUC values (\u0026lt; 0.60). US size showed an AUC of 0.70, however the average US size of MFCP was higher than that of PDAC (figure 6a). The highest AUC values were calculated for SUVmax and SUVmean (0.84 each) (figure 6b). TBR values and dynamic parameters showed slightly lower AUC (TBR versus blood 0.74, TBR versus liver 0.74, TTP 0.73 and slope 0.62) (figure 6c, d). Exemplary sensitivities / specificities were 92.31% (95% CI interval 66.69% to 99.61%) / 57.14% (95% CI interval 32.59% to 78.62%) for a cut-off value of 16.58 for SUVmax and 92.31% (95% CI interval 66.69% to 99.61%) / 57.14% (95% CI interval 32.59% to 78.62%) for a cutoff-value of 9.316 for SUVmean.\u0026nbsp;\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSummary of the results\u003c/h2\u003e \u003cp\u003eDespite the rapidly emerging evidence in favor of the great potential of FAPI-PET with respect to staging of primary and recurrent PDAC [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], data on FAPI-PET for the differentiation of PDAC and its differential diagnoses are very limited [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. To our best knowledge, no data on the signal behavior of PDAC and MFCP in FAPI-PET have been published to date. Here, we have demonstrated that not only PDAC as a malignancy with strong desmoplastic reaction, but also MFCP, a chronic inflammatory disease with fibrotic tissue remodeling, are both FAPI-positive. The signal intensity of PDACs was markedly higher than that of MFCP and dynamic \u003csup\u003e68\u003c/sup\u003eGa-FAPI-imaging revealed differential kinetic behavior of FAPI-46 in both entities. These marked differences in static and dynamic \u003csup\u003e68\u003c/sup\u003eGA-FAPI-46 imaging are reflected by higher diagnostic accuracy for the differentiation of PDAC and MFCP compared to laboratory, ultrasound- and CT size, which did not significantly differ between the two diseases in our dataset. Similarly, morphological features assessed by ultrasound could not rule out malignancy with the necessary certainty. PDAC grading in our dataset (G1 18%, G2 55%, G3 18%, G4 9%) tended towards more favorable grades than reported elsewhere [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Relatively favorable grading suggests lower FAPI-uptake than in PDACs with higher grading according to our recently published work [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Nevertheless, differences between PDAC and MFCP in static and dynamic \u003csup\u003e68\u003c/sup\u003eGA-FAPI-46-PET/CT were pronounced. In conclusion, our results suggest that \u003csup\u003e68\u003c/sup\u003eGa-FAPI-PET could be a reasonable supplemental imaging tool for the differentiation of PDAC and MFCP in clinically and morphologically unclear cases.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003ePossible clinical applications of \u003csup\u003e68\u003c/sup\u003eGa-FAPI-PET for MFCP\u003c/h2\u003e \u003cp\u003eThe pronounced FAPI-positivity of MFCP reflects marked fibrotic activity of MFCP. According to this, FAPI-PET appears to be a valuable new tool for the assessment of MFCP that displays fibrotic activity and may serve as prognostic tool for risk stratification with regard to clinical course and malignant progression. Malignant transformation of chronic fibro-inflammatory lesions is a canonic factor of carcinogenesis and can generally occur in various fibrotic lesions and especially in PDAC developed from MFP [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Given the differential signal behavior of PDAC and MFCP, \u003csup\u003e68\u003c/sup\u003eGa-FAPI-PET/CT may be a helpful future monitoring tool for MFCP that could lead to timely detection of malignant transformation. Another possible clinical application of \u003csup\u003e68\u003c/sup\u003eGa-FAPI-PET for MFCP is therapy evaluation of anti-fibrotic MFCP treatments which have shown promising results for the treatment of MFCP [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Based on our results, a systematic evaluation of \u003csup\u003e68\u003c/sup\u003eGa-FAPI-PET for MFCP with regard to prognostic value and therapy response assessment appears a promising future project.\u003c/p\u003e \u003cp\u003e \u003csup\u003e \u003cb\u003e68\u003c/b\u003e \u003c/sup\u003e \u003cb\u003eGa-FAPI-PET for the differentiation of PDAC, MFCP and other differential diagnoses of pancreatic lesions\u003c/b\u003e \u003c/p\u003e \u003cp\u003eOur results on static \u003csup\u003e68\u003c/sup\u003eGa-FAPI-PET imaging are in line with our previous publications, where we have compared \u003csup\u003e68\u003c/sup\u003eGa-FAPI-uptake of PDAC and its differential diagnoses. In an earlier publication, we drew a comparison between \u003csup\u003e68\u003c/sup\u003eGa-FAPI-uptake of PDAC and pancreatitis of the remaining pancreas parenchyma related to obstruction of the main pancreatic duct and found higher FAPI-avidity in PDAC than in pancreatitis, but a certain overlap between both pathologies [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Similarly, we have found increased \u003csup\u003e68\u003c/sup\u003eGa-FAPI-uptake of PDAC compared to benign intraductal papillary mucinous neoplasms of the pancreas (IPMN) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], which was concordantly reflected by immunohistochemical FAP expression of both entities [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. For the differentiation between PDAC and high-grade IPMN versus low-grade IPMN, we have also found very distinct differences in their time-dependent signal behavior in dynamic PET-imaging, in particular in terms of prolonged TTP of PDAC and high grade IPMN compared to low-grade IPMN [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Here, we found similar results, but the additional value of FAPI-46-uptake and tracer kinetics for the differentiation of PDAC and MFCP appears less pronounced than for PDAC and IPMN. This could be explained by the fact that low-grade IPMN show \u0026ndash; in contrast to PDAC \u0026ndash; little desmoplastic reaction involving activated fibroblasts, but MFCP leads not only to inflammatory, but also to significant fibrotic reactions of the pancreatic tissue [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Thus, one would assume a high prevalence of FAP-positive activated fibroblasts in MFCP. However, a systematic evaluation of FAP-expression and fibroblast subgroups in MFCP that could further explain our imaging findings does not exist to date.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eMajor limitation of this work are the limited number of patients and retrospective data analysis. Additionally, this work is limited by our patient collective containing only patients with unclear pancreatic masses, so our findings are limited to that certain subpopulation of PDAC/MFCP patients and cannot be generalized, as patients with more suggestive clinical findings were not analyzed. Further clinical studies with prospective design and higher numbers of clearly characterized patients are necessary to validate our findings.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eMFCP is a FAPI-positive pancreatic lesion, but FAPI-positivity in MFCP is less pronounced than in PDAC and both entities showed differential kinetic behavior in dynamic imaging. In our dataset, static and dynamic \u003csup\u003e68\u003c/sup\u003eGa-FAPI-PET parameters exceeded laboratory parameters, CT size, US size and US morphology in diagnostic accuracy for the differentiation of PDAC and MFCP. \u003csup\u003e68\u003c/sup\u003eGa-FAPI-PET is a promising tool for the assessment of MFCP and PDAC, which may help to detect malignant transformation and to improve patient stratification with respect to pancreatectomy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis work was funded by the Federal Ministry of Education and Research, grant number 13N 13341.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: UH has filed a patent application for quinoline based FAP targeting agents for imaging and therapy in nuclear medicine. UH has shares of a consultancy group for iTheranostics. No other potential conflicts of interest relevant to this article exist.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e: All authors contributed to the study conception and design. Data collection and analysis were performed by Matthias Lang, Markus Preussig, Anna-Maria Spektor, Isabelle von Goetze, Ewgenija Gutjahr, Frederik Glatting and Manuel R\u0026ouml;hrich. The first draft of the manuscript was written by Matthias Lang and Manuel R\u0026ouml;hrich and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u0026nbsp;\u003c/strong\u003eAll procedures performed in studies involving human participants confirmed to the ethical standards of the institutional and/or national research committee and to the Helsinki declaration (1964) and its later amendments or comparable ethical standards. This retrospective study was approved by the local advisory ethic committee (study number S-115/2020).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u003c/strong\u003e not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish:\u003c/strong\u003e The authors affirm that human research participants provided informed consent for publication of the images in Figures 4 and 5.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePark, W., A. Chawla, and E.M. 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Siveke, \u003cem\u003eThe Latest Developments in Imaging of Fibroblast Activation Protein.\u003c/em\u003e J Nucl Med, 2021. \u003cstrong\u003e62\u003c/strong\u003e(2): p. 160-167.\u003c/li\u003e\n\u003cli\u003eLindner, T., et al., \u003cem\u003eDevelopment of Quinoline-Based Theranostic Ligands for the Targeting of Fibroblast Activation Protein.\u003c/em\u003e J Nucl Med, 2018. \u003cstrong\u003e59\u003c/strong\u003e(9): p. 1415-1422.\u003c/li\u003e\n\u003cli\u003eLoktev, A., et al., \u003cem\u003eA Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts.\u003c/em\u003e J Nucl Med, 2018. \u003cstrong\u003e59\u003c/strong\u003e(9): p. 1423-1429.\u003c/li\u003e\n\u003cli\u003eKhristenko, E., et al., \u003cem\u003eImaging features of intraductal tubulopapillary neoplasm of the pancreas and its differentiation from conventional pancreatic ductal adenocarcinoma.\u003c/em\u003e Sci Rep, 2022. \u003cstrong\u003e12\u003c/strong\u003e(1): p. 15557.\u003c/li\u003e\n\u003cli\u003eSchima, W., et al., \u003cem\u003eMass-forming pancreatitis versus pancreatic ductal adenocarcinoma: CT and MR imaging for differentiation.\u003c/em\u003e Cancer Imaging, 2020. \u003cstrong\u003e20\u003c/strong\u003e(1): p. 52.\u003c/li\u003e\n\u003cli\u003eLang, M., T. Hackert, and C. Tjaden, \u003cem\u003eNative Sonografie \u0026ndash; Mittel der Wahl zur Fr\u0026uuml;herkennung des Pankreaskarzinoms.\u003c/em\u003e European Journal of Ultrasound, 2019. \u003cstrong\u003e40\u003c/strong\u003e: p. 68-69.\u003c/li\u003e\n\u003cli\u003eRickes, S., et al., \u003cem\u003eDifferentiation of pancreatic tumours by conventional ultrasound, unenhanced and echo-enhanced power Doppler sonography.\u003c/em\u003e Scand J Gastroenterol, 2002. \u003cstrong\u003e37\u003c/strong\u003e(11): p. 1313-20.\u003c/li\u003e\n\u003cli\u003eSarner, M. and P.B. Cotton, \u003cem\u003eClassification of pancreatitis.\u003c/em\u003e Gut, 1984. \u003cstrong\u003e25\u003c/strong\u003e(7): p. 756-9.\u003c/li\u003e\n\u003cli\u003eWolske, K.M., et al., \u003cem\u003eChronic Pancreatitis or Pancreatic Tumor? A Problem-solving Approach.\u003c/em\u003e Radiographics, 2019. \u003cstrong\u003e39\u003c/strong\u003e(7): p. 1965-1982.\u003c/li\u003e\n\u003cli\u003eKersting, S., et al., \u003cem\u003eQuantitative perfusion analysis of transabdominal contrast-enhanced ultrasonography of pancreatic masses and carcinomas.\u003c/em\u003e Gastroenterology, 2009. \u003cstrong\u003e137\u003c/strong\u003e(6): p. 1903-11.\u003c/li\u003e\n\u003cli\u003eRohrich, M., et al., \u003cem\u003eFibroblast Activation Protein-Specific PET/CT Imaging in Fibrotic Interstitial Lung Diseases and Lung Cancer: A Translational Exploratory Study.\u003c/em\u003e J Nucl Med, 2022. \u003cstrong\u003e63\u003c/strong\u003e(1): p. 127-133.\u003c/li\u003e\n\u003cli\u003eMaurer, G.D., et al., \u003cem\u003e(18)F-FET PET Imaging in Differentiating Glioma Progression from Treatment-Related Changes: A Single-Center Experience.\u003c/em\u003e J Nucl Med, 2020. \u003cstrong\u003e61\u003c/strong\u003e(4): p. 505-511.\u003c/li\u003e\n\u003cli\u003eKoerber, S.A., et al., \u003cem\u003eImpact of (68)Ga-FAPI PET/CT on Staging and Oncologic Management in a Cohort of 226 Patients with Various Cancers.\u003c/em\u003e J Nucl Med, 2023. \u003cstrong\u003e64\u003c/strong\u003e(11): p. 1712-1720.\u003c/li\u003e\n\u003cli\u003eHoppner, J., et al., \u003cem\u003eComparison of early and late (68)Ga-FAPI-46-PET in 33 patients with possible recurrence of pancreatic ductal adenocarcinomas.\u003c/em\u003e Sci Rep, 2023. \u003cstrong\u003e13\u003c/strong\u003e(1): p. 17848.\u003c/li\u003e\n\u003cli\u003eKonig, A.K., et al., \u003cem\u003eRefined prognostic staging for resected pancreatic cancer by modified stage grouping and addition of tumour grade.\u003c/em\u003e Eur J Surg Oncol, 2022. \u003cstrong\u003e48\u003c/strong\u003e(1): p. 113-120.\u003c/li\u003e\n\u003cli\u003eHines, O.J. and S.J. Pandol, \u003cem\u003eManagement of chronic pancreatitis.\u003c/em\u003e BMJ, 2024. \u003cstrong\u003e384\u003c/strong\u003e: p. e070920.\u003c/li\u003e\n\u003cli\u003eLi, B.Q., et al., \u003cem\u003eThe research progress of anti-inflammatory and anti-fibrosis treatment of chronic pancreatitis.\u003c/em\u003e Front Oncol, 2022. \u003cstrong\u003e12\u003c/strong\u003e: p. 1050274.\u003c/li\u003e\n\u003cli\u003eApte, M., R. Pirola, and J. Wilson, \u003cem\u003eThe fibrosis of chronic pancreatitis: new insights into the role of pancreatic stellate cells.\u003c/em\u003e Antioxid Redox Signal, 2011. \u003cstrong\u003e15\u003c/strong\u003e(10): p. 2711-22.\u003cstrong\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"FAPI, mass forming chronic pancreatitis, PDAC, contrast-enhanced ultrasonography","lastPublishedDoi":"10.21203/rs.3.rs-5640954/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5640954/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose:\u003c/h2\u003e \u003cp\u003eThe differentiation of mass-forming chronic pancreatitis (MFCP) and pancreatic ductal adenocarcinomas (PDAC) based on conventional imaging methods like ultrasound, CT and MRI is frequently not possible. Here, we applied static (60 minutes post injection) and dynamic PET/CT with \u003csup\u003e68\u003c/sup\u003eGallium-labelled Fibroblast Activated Protein Inhibitors (\u003csup\u003e68\u003c/sup\u003eGa-FAPI-PET/CT) in 26 preoperative, treatment-naive patients with unclear pancreatic masses to evaluate its potential diagnostic value for MFCP and PDAC.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003e26 Patients underwent static and dynamic \u003csup\u003e68\u003c/sup\u003e Ga-FAPI-PET/CT as well as dedicated fundamental (US) and contrast-enhanced ultrasonography (CEUS) before surgical resection or biopsy of pancreatic masses and subsequent histological analyses. Static parameters (SUVmax and SUVmean and target to background ratios) were generated from VOIs of pancreatic masses. Time activity curves and dynamic parameters were extracted from dynamic PET data.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eHistology revealed 12 PDAC, 2 high-grade IPMN and 12 MFCP. We observed higher \u003csup\u003e68\u003c/sup\u003eGa-FAPI-uptake in PDACs (average SUVmax/mean 18.09 +/- 5.5 / 10.55 +/- 2.97) than in MFCP (average SUVmax/mean 11.55 +/- 3.88 / 6.83 +/- 2.20). In dynamic PET-imaging, PDAC and MFCP showed differential time activity curves and the average time to peak was markedly longer for PDAC (1094 +/- 945 seconds ) than for MFCP (449 seconds +/- 203). In ROC curves, static and dynamic imaging parameters showed higher sensitivity and specificity than laboratory parameters, CT- and US-size.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003e \u003csup\u003e68\u003c/sup\u003eGa-FAPI-PET/CT displays the fibrotic activity of MFCP. Static and dynamic \u003csup\u003e68\u003c/sup\u003eGa-FAPI-PET/CT should be considered, when clinical parameters and other imaging methods are not able to distinguish between PDAC and MFCP.\u003c/p\u003e","manuscriptTitle":"68Gallium-FAPI-positron emission tomography for dignity assessment of mass-forming chronic pancreatitis and pancreatic ductal adenocarcinomas compared to laboratory parameters, ultrasound and computed tomography","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-24 17:08:53","doi":"10.21203/rs.3.rs-5640954/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b8a45d55-6b20-4e04-8742-0195da858a5e","owner":[],"postedDate":"December 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-02T07:38:45+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-24 17:08:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5640954","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5640954","identity":"rs-5640954","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}