[68Ga]Ga-FAPI-2286 PET Imaging in Pediatric Midline Gliomas: Preliminary Findings and Clinical Implications

[68Ga]Ga-FAPI-2286 PET Imaging in Pediatric Midline Gliomas: Preliminary Findings and Clinical Implications | 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 [68Ga]Ga-FAPI-2286 PET Imaging in Pediatric Midline Gliomas: Preliminary Findings and Clinical Implications Soheila Mirabedian, azade kiumarsi, saeed farzanefar, Mehrshad Abbasi, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6259698/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 Background Regarding the poor prognosis, limited efficacy of standard therapies, and scarce data on FAPI imaging in pediatric midline gliomas, we conducted this pilot study to investigate the potential role of [68Ga]Ga-FAPI-2286 PET/CT for improved diagnosis and possible theranostic applications in these high-risk tumors. Objective The study aims to evaluate the diagnostic efficacy and potential theranostic implications of [68Ga]Ga-FAPI-2286 PET/CT imaging in pediatric patients with midline gliomas. Methods This prospective small cohort study involved six pediatric patients aged 5–13 years diagnosed with midline gliomas (three diffuse intrinsic pontine gliomas [DIPGs], two midbrain astrocytomas, one thalamic astrocytoma). Intravenous administration of [68Ga]Ga-FAPI-2286 (1.8–2.2 MBq/kg) was followed by PET/CT scan 45 minutes later. Lesion uptake (SUVmax) and tumor-to-background ratios (TBR) were measured. Comparison analyses were done between DIPG vs non-DIPG and high-grade vs low-grade tumors. Results SUVmax varied widely (0.06–2.24), as did TBR (6–224). Non-DIPG tumors demonstrated higher uptake (mean SUVmax: 1.84, TBR: 184) compared to DIPG tumors (mean SUVmax: 0.34, TBR: 9), though differences were not statistically significant (SUVmax, p = 0.057; TBR, p = 0.091). Similarly, no significant differences were observed between high-grade and low-grade tumors. Tumors in the thalamus and midbrain showed generally higher uptake compared to pontine locations. Conclusion [68Ga]Ga-FAPI-2286 PET imaging showed limited utility in pediatric midline gliomas, particularly DIPGs, due to inherently low fibroblast activation protein (FAP) expression and possibly intact blood-brain barriers. Larger, more controlled studies are necessary to clarify the theranostic potential of FAPI PET in pediatric neuro-oncology. DIPG Midline glioma brainstem glioma pediatric glioma ^68Ga-FAPI-2286 PET/CT cancer-associated fibroblasts Figures Figure 1 Figure 2 Introduction Pediatric gliomas are the most common brain tumors in children, with a broad spectrum of histological subtypes ranging from low-grade astrocytomas to highly aggressive glioblastomas. Diffuse midline gliomas often involve subsets such as the brainstem glioma e.g. diffuse intrinsic pontine glioma (DIPG), midbrain glioma and others involving thalamus, or spinal cord. These deep-seated gliomas carry a worse prognosis. Midline pediatric gliomas, regardless of their categorization as high- or low-grade gliomas, can be viewed independently due to their specific nature, molecular characteristics, and management strategy, particularly when they are inoperable due to critical locations. Despite advancements in chemotherapeutic, and radiotherapeutic interventions, prognosis remains very poor for diffuse midline gliomas with a 5-year survival rate of less than 1%. Most children die from the disease within 1–2 years of diagnosis[ 1 ] Palliative care is of utmost importance in midline gliomas where standard options (surgery, chemotherapy, radiotherapy) have limited efficacy or are not feasible (e.g., DIPG is considered inoperable and managed through chemoradiotherapy, but with poor results (11-months median overall survival) [ 2 ]. As many positron emission tomography (PET) tracers provide theranostics options, an investigational imaging approach using [68Ga]Ga-FAPI-2286 PET/CT seems rationale to find those candidate for personalized radioligand therapy (RLT) (i.e. 177Lu-FAPI) to slow tumor progression and relieve symptoms. Radiolabeled FAP inhibitors, such as [68Ga] Ga-FAPI, bind specifically to FAP, allowing noninvasive tracing of CAFs in the tumor stroma. Recent advances in molecular imaging have explored fibroblast activation protein (FAP), a protease highly expressed in the tumor microenvironment (TME) of various cancers, as a potential theranostic target in gliomas. Clinical studies in various gliomas have shown that 68Ga-FAPI PET can yield high contrast images and provide potentially specific information about the tumor microenvironment and invasive behavior of glioma to differentiate high-grade from low-grade glioma[ 3 , 4 ]. In addition, it has also been explored for use in radiotherapy or biopsy planning in glioblastoma[ 5 ]. [68Ga]Ga-FAPI PET/CT proves promising for brain tumors, often outperforming [18F]F-FDG PET/CT due to negligible physiologic [68Ga]Ga-FAPI uptake in normal brain tissue and high target to background (TBR) values, suggesting targeted therapy potentials[ 6 ]. Additionally, a case of promising [68Ga]Ga-FAPI PET results was previously detected in brainstem glioma (WHO grade IV)[ 7 ]. While adult studies have demonstrated promising uptake of FAPI-based PET tracers in high-grade gliomas, data on pediatric gliomas remain scarce. Furthermore, the role of FAPI imaging in midline gliomas remains largely unexplored. This pilot study aims to assess FAPI uptake in pediatric midline gliomas. This prospective small cohort study applied [68Ga]Ga-FAPI-2286 imaging to patients with end-stage resistant midline glioma to investigate the spectrum and volume of FAP expression as a possible theranostic opportunity. Methodology Study Design This was a prospective diagnostic accuracy study assessing the efficacy of [68Ga]Ga-FAPI-2286 PET imaging in pediatric patients diagnosed with midline gliomas. Approval for this study was obtained from the Institutional Ethics Committee (No. IR.TUMS.IKHC.REC.1403.144), and informed consent was obtained from parents of all participants. All procedures followed ethical standards set by the Declaration of Helsinki. Study Population We prospectively enrolled six pediatric patients diagnosed with midline gliomas, including four with diffuse intrinsic pontine gliomas (DIPGs), one with midbrain astrocytomas, and one with a thalamic astrocytoma. The inclusion criteria were patients aged 1 to 18 years with confirmed midline gliomas (DIPG, midbrain astrocytoma, or thalamic astrocytoma) who were unsuitable for further surgical resection due to tumor location. Exclusion criteria included poor clinical status to participate in imaging, allergy or hypersensitivity to radiopharmaceuticals and those who were not willing to participate and fill the informed consent. Tumor Grading and Diagnostic Criteria Tumor grading and diagnosis were confirmed through biopsy and histopathological evaluation in three patients. For the remaining, diagnosis was based on MRI imaging characteristics and clinical progression, reviewed by experienced pediatric neuro-radiologists. Surgical resection was not feasible due to the critical anatomical location of these tumors. PET Imaging and Analysis PET imaging was performed using [68Ga]Ga-FAPI-2286. The radiopharmaceutical was prepared according to established clinical radiopharmacy guidelines. Patients received intravenous injections of [68Ga]Ga-FAPI-2286, with doses adjusted according to body weight based on pediatric standards (1.8–2.2 MBq/kg). After administration, patients rested quietly for approximately 45–60 minutes to allow optimal tracer uptake and clearance from non-target tissues. Whole-body PET/CT scanning commenced precisely 45 minutes post-injection. Scanning was conducted on a GE PET/CT scanner, acquiring PET images in three-dimensional mode, with typical acquisition times of 3–5 minutes per bed position to ensure an adequate signal-to-noise ratio. Low-dose CT scans were performed simultaneously for attenuation correction and anatomical localization to minimize radiation exposure. Images were reconstructed using iterative reconstruction algorithms such as ordered-subset expectation maximization (OSEM), employing standardized post-processing techniques. For each PET image, the maximum standardized uptake value (SUVmax) within the lesion was determined. Background uptake was calculated using SUV measurements from white matter of centrum semiovale. The tumor-to-background ratio (TBR) was then derived by dividing the lesion SUVmax by the background SUV. Data Analysis and Comparisons We performed comparative analyses among patient subgroups to assess potential differences in PET imaging findings. Specifically, we evaluated differences in SUVmax and TBR between patients with DIPG and non-DIPG tumors, high-grade and low-grade tumors, and enhancing versus non-enhancing tumors based on MRI findings. Additionally, tumor locations (e.g., pontine/brainstem versus non-pontine regions) were analyzed to investigate any relationship with PET imaging outcomes. Results The study involved six pediatric patients, comprising four males and two females. The patients ranged in age from 5 to 13 years, with an average age of approximately 9 years(Table 1 ). Tumor locations varied among the participants, predominantly involving critical midline brain regions, including the pons, midbrain, and thalamus. All tumors demonstrated notable size and anatomical complexity, with dimensions ranging from approximately 25×12 mm to 55×45×45 mm. Enhancement on MRI was a common feature observed in five of the six cases. One case, notably patient 5, exhibited no enhancement throughout the imaging evaluations, suggesting a lower-grade or less active tumor (Table 2 ). The PET imaging results demonstrated considerable variability in lesion metabolic activity, with SUVmax values ranging from as low as 0.06 to as high as 2.24. Tumor-to-background ratios (TBR) ranged widely from 6 to 224, with higher values notably present in patients with tumor located in thalamus and midbrain. In contrast, lower values were generally associated with tumor located in pons (Table 3 ). Table 1 Demographic Information Participants Age (years) Sex Grade Patient 1 6 Male Low based on histopathology Patient 2 7 Female High based on histopathology Patient 3 13 Male Low based on histopathology Patient 4 5 Female High based on MRI features Patient 5 13 Male Low based on MRI features Patient 6 11 Male High based on MRI features Table 2 Tumor Locations and MRI Findings. Participants Tumor Location on MRI Patient 1 Left thalamus, posterior pons, midbrain, paraventricular region Patient 2 Pons, midbrain, medulla Patient 3 Midbrain, extending to floor of the 3rd and 4th ventricles Patient 4 Pons, midbrain, medulla Patient 5 Pons extending to medulla Patient 6 Posterior of pons Table 3 PET Imaging Results (SUV and TBR). Participants SUVmax TBR Patient 1 2.24 224 Patient 2 0.82 16 Patient 3 1.45 145 Patient 4 0.33 8 Patient 5 0.06 6 Patient 6 0.16 6 The comparative analyses indicated a trend toward lower SUVmax and TBR values in patients with DIPG compared to those with non-DIPG tumors (thalamus and midbrain involvements) (Figs. 1 , 2 ), although these differences did not reach statistical significance due to the small sample size (SUVmax, p = 0.057; TBR, p = 0.091). Similarly, comparisons between high-grade and low-grade tumors showed no significant differences in SUVmax or TBR (SUVmax, p = 0.680; TBR, p = 0.751) (Table 4 ). Table 4 PET imaging parameters (SUVmax and TBR) across patient subgroup Parameters Mean ± Std SUVmax DIPG 0.34 ± 0.33 non-DIPG 1.84 ± 0.55 High-Grade 0.43 ± 0.34 Low-Grade 1.25 ± 1.1 TBR DIPG 9 ± 4.7 non-DIPG 184 ± 55 High-Grade 10 ± 5.2 Low-Grade 125 ± 110 Discussion This study highlights a crucial limitation of [68Ga]Ga-FAPI-2286 PET in pediatric midline gliomas. Many adult solid tumors and also gliomas, reported to have pronounced desmoplastic or mesenchymal stroma and consequently higher FAP expression and supported the utility of FAPI tracers. High TBR values are observed in some midline gliomas of our small cohort, aligning with previous reports of [68Ga]Ga-FAPI detectability in the brain and minimal background accumulation[ 8 ] However, low overall tracer uptake in the tumor lesions were disappointing for future RLT programs in these devastating midline glioma patients. This observation was at least once published as a false-negative [68Ga]Ga-FAPI scan in a brainstem tumor[ 9 ]. Delving into possible underlying molecular characteristics, there are some evidences confirming our cohort findings. Diffuse midline gliomas (including DIPGs) typically exhibit high cellularity but minimal stromal reaction. Pediatric brainstem gliomas, particularly DIPGs, also tend to be more “immunologically cold.” For instance, they frequently lack key drivers of fibrogenesis—such as TGF-β1—resulting in limited CAF recruitment and a paucity of extracellular matrix remodeling[ 10 ]. Autopsy data consistently reveal little to no desmoplastic response in brainstem lesions, unlike in certain cortical high-grade gliomas (e.g., desmoplastic infantile astrocytomas or pleomorphic xanthoastrocytomas), which do demonstrate robust fibroblastic infiltration[ 11 , 12 ]. This distinction helps explain why ^68Ga-FAPI uptake remains minimal in midline gliomas of our cohort study despite their aggressive biological behavior. Adult glioblastomas classified as mesenchymal subtype often overexpress YKL-40/CHI3L1, TGF-β, VEGF, and matrix metalloproteinases, creating a stromal microenvironment conducive to strong FAP expression[ 13 , 14 ]. However, such features appear less prevalent in pediatric diffuse midline gliomas, which frequently adopt an oligodendroglia or progenitor-like phenotype rather than a desmoplastic one; potentially explaining limited diagnostic and therapeutic benefit of DIPGs and pediatric midline lesions in this study. Another important factor is the integrity of the blood–brain barrier (BBB). Non-enhancing tumors—which often have an intact BBB—typically can demonstrate minimal radiotracer accumulation. In our cohort, the only completely non-enhancing tumor indeed showed the lowest [68Ga]Ga-FAPI uptake, consistent with literature reports of BBB disruption enhancing tracer delivery[ 3 , 4 ]. Ultimately, the pilot data indicate that [68Ga]Ga-FAPI PET imaging may have limited utility in pediatric midline gliomas, particularly DIPGs, given their intrinsically low CAF density and possibly intact BBB. Future research in larger, more uniform cohorts, including direct correlation with histopathological FAP expression, is warranted to clarify the potentials of FAPI-based imaging or therapies in pediatric neuro-oncology. This study has some limitations; first meanwhile this study was stopped in pediatric cohort according to negligible FAPI avidity and disappointing theranostic results. This small cohort remains a main point warranting caution in drawing robust conclusions; larger studies are required to confirm whether pediatric gliomas, especially diffuse midline gliomas, commonly lack FAP expression or if these cases are an atypical subset. Other limitations is that only one FAPI tracer [68Ga]Ga-FAPI-2286) was evaluated; other FAPI tracers may have different affinity, retention characteristics, and pharmacokinetics, although 68Ga-FAPI-2286 has shown promising results in many studies [ 15 ]. Histopathological FAP expression was not assessed in this study; however, FAPI uptake was previously reported to be concordant with IHC FAP expression in another research[ 16 ]. Additionally, prior treatments (chemotherapy and radiotherapy) were not controlled, potentially affecting tracer uptake. Chemotherapeutic agents and radiotherapy may alter the tumor microenvironment and fibroblast activity. Conclusion FAPI PET may not be broadly suitable for imaging and subsequent therapy in pediatric midline gliomas. While [68Ga]Ga-FAPI PET holds promise in the imaging of adult solid tumors with prominent desmoplastic reactions, its role in pediatric midline gliomas remains uncertain and should be interpreted with caution based on these limited data. Further histopathological investigations particularly in larger controlled cohorts may determine the role of FAPI PET in certain pediatric gliomas of heavier desmoplastic stroma. Declarations Author Contribution All authors contributed to the study conception and design. All authors commented on previous versions of the manuscript and approved the final manuscript.Conceptualization: Azade Kiumarsi, Zeinab Paymani; Data Collection: Soheila Mirabedian; Formal analysis and investigation: Soheila Mirabedian, Saeed Farzanefar, Mehrshad Abbasi, Neda Pak, Marzie Ebrahimi, Mostafa Nazari, Zeinab paymani; Writing - original draft preparation: Zeinab Paymani, Soheila Mirabedian, Mostafa Nazari, Azade kiumarsi; Writing - review and editing: Zeinab Paymani, Mostafa Nazari; Preparing figures: Marzie Ebrahimi, Mostafa Nazari, Soheila MirabedianSupervision: Azade Kiumarsi, Saeed Farzanefar, Mehrshad Abbasi, Zeinab Paymani. Data Availability Data is provided within the manuscript References Vanan MI, Eisenstat DD. DIPG in Children – What Can We Learn from the Past? Frontiers in Oncology. 2015;5. Baugh JN, Veldhuijzen van Zanten S, Fiocco M, Colditz N, Hoffmann M, Janssens GO, et al. Treatment-related survival patterns in diffuse intrinsic pontine glioma using a historical cohort: A report from the European Society for Pediatric Oncology DIPG/DMG Registry. Neuro Oncol Adv. 2024;6(1):vdae155. Röhrich M, Loktev A, Wefers AK, Altmann A, Paech D, Adeberg S, et al. IDH-wildtype glioblastomas and grade III/IV IDH-mutant gliomas show elevated tracer uptake in fibroblast activation protein-specific PET/CT. Eur J Nucl Med Mol Imaging. 2019;46(12):2569-80. Liu Y, Ding H, Cao J, Liu G, Chen Y. [68Ga]Ga-FAPI PET/CT in brain tumors: comparison with [18F]F-FDG PET/CT. Frontiers in Oncology. 2024;14. Windisch P, Röhrich M, Regnery S, Tonndorf-Martini E, Held T, Lang K, et al. Fibroblast Activation Protein (FAP) specific PET for advanced target volume delineation in glioblastoma. Radiother Oncol. 2020;150:159-63. Liu Y, Ding H, Cao J, Liu G, Chen Y, Huang Z. [(68)Ga]Ga-FAPI PET/CT in brain tumors: comparison with [(18)F]F-FDG PET/CT. Front Oncol. 2024;14:1436009. Ruan D, Sun J, Han C, Cai J, Yu L, Zhao L, et al. (68)Ga-FAPI-46 PET/CT in the evaluation of gliomas: comparison with (18)F-FDG PET/CT and contrast-enhanced MRI. Theranostics. 2024;14(18):6935-46. Djekidel M, Alsadi R, Abi Akl M, Bouhali O, O’Doherty J. Tumor microenvironment and fibroblast activation protein inhibitor (FAPI) PET: developments toward brain imaging. Frontiers in Nuclear Medicine. 2023;3. Ruan D, Sun J, Han C, Cai J, Yu L, Zhao L, et al. 68Ga-FAPI-46 PET/CT in the evaluation of gliomas: comparison with 18F-FDG PET/CT and contrast-enhanced MRI. Theranostics. 2024;14(18):6935-46. Lieberman NAP, DeGolier K, Kovar HM, Davis A, Hoglund V, Stevens J, et al. Characterization of the immune microenvironment of diffuse intrinsic pontine glioma: implications for development of immunotherapy. Neuro Oncol. 2019;21(1):83-94. Koelsche C, Sahm F, Wöhrer A, Jeibmann A, Schittenhelm J, Kohlhof P, et al. BRAF-mutated pleomorphic xanthoastrocytoma is associated with temporal location, reticulin fiber deposition and CD34 expression. Brain Pathol. 2014;24(3):221-9. Ballester LY, Wang Z, Shandilya S, Miettinen M, Burger PC, Eberhart CG, et al. Morphologic characteristics and immunohistochemical profile of diffuse intrinsic pontine gliomas. Am J Surg Pathol. 2013;37(9):1357-64. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98-110. Busek P, Balaziova E, Matrasova I, Hilser M, Tomas R, Syrucek M, et al. Fibroblast activation protein alpha is expressed by transformed and stromal cells and is associated with mesenchymal features in glioblastoma. Tumor Biology. 2016;37(10):13961-71. Pang Y, Zhao L, Meng T, Xu W, Lin Q, Wu H, et al. PET imaging of fibroblast activation protein in various types of cancers by using 68Ga-FAP-2286: Comparison with 18F-FDG and 68Ga-FAPI-46 in a single-center, prospective study. Journal of Nuclear Medicine. 2022:jnumed.122.264544. Oster C, Kessler L, Blau T, Keyvani K, Pabst KM, Fendler WP, et al. The Role of Fibroblast Activation Protein in Glioblastoma and Gliosarcoma: A Comparison of Tissue, 68 Ga-FAPI-46 PET Data, and Survival Data. J Nucl Med. 2024 Aug;65(8):1217–23. doi:10.2967/jnumed.123.267151. Additional Declarations No competing interests reported. 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. 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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-6259698","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":434495672,"identity":"6515b095-dc6e-4cb7-a2e9-8692ed75bfa0","order_by":0,"name":"Soheila Mirabedian","email":"","orcid":"","institution":"Tehran University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Soheila","middleName":"","lastName":"Mirabedian","suffix":""},{"id":434495673,"identity":"380c8020-afcc-4092-929e-c683fc3ac6b5","order_by":1,"name":"azade kiumarsi","email":"","orcid":"","institution":"Tehran University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"azade","middleName":"","lastName":"kiumarsi","suffix":""},{"id":434495674,"identity":"d80c49e3-642c-44ee-9201-b1ab43594470","order_by":2,"name":"saeed farzanefar","email":"","orcid":"","institution":"Tehran University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"saeed","middleName":"","lastName":"farzanefar","suffix":""},{"id":434495675,"identity":"63b12cd4-0cb8-4525-a0c9-6b8b421384be","order_by":3,"name":"Mehrshad Abbasi","email":"","orcid":"","institution":"Tehran University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Mehrshad","middleName":"","lastName":"Abbasi","suffix":""},{"id":434495676,"identity":"1b7260f4-f623-428d-9efd-079c542c0a2a","order_by":4,"name":"neda pak","email":"","orcid":"","institution":"Tehran University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"neda","middleName":"","lastName":"pak","suffix":""},{"id":434495677,"identity":"049e496b-0086-42c9-ac95-5b19453a8a34","order_by":5,"name":"mostafa nazari","email":"","orcid":"","institution":"Tehran University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"mostafa","middleName":"","lastName":"nazari","suffix":""},{"id":434495678,"identity":"1d0ce11b-847e-48e3-b174-5d248f151ab0","order_by":6,"name":"marzieh ebrahimi","email":"","orcid":"","institution":"Iran University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"marzieh","middleName":"","lastName":"ebrahimi","suffix":""},{"id":434495679,"identity":"b5cb3a17-dabd-4ce9-bd0d-b46d67fd50d3","order_by":7,"name":"Zeinab Paymani","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzUlEQVRIiWNgGAWjYBAC+wYwJcHAz8DARpwWgwNQLZINJGoBM4jVcvyM6YafOyzsjW8kP3vwoYJBnl/sAH4t9j05Zjd7z0gwm91IMzeccYbBcObsBAK2MOSY3eBtk2Azu5FgJs3bxpBgcJuQFv43Zjf/tknwGM9I/0akFokcs9tAWyRADGK1PCu7LdsG1HHmTZnkjDMSRPiFP3nbzbdtdfb87enbJD5U2MjzSxPQwsDAYQChBcAqJQgpBwH2BxCa/wAxqkfBKBgFo2AkAgDgV0CHJJ0ssQAAAABJRU5ErkJggg==","orcid":"","institution":"Tehran University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Zeinab","middleName":"","lastName":"Paymani","suffix":""}],"badges":[],"createdAt":"2025-03-19 08:53:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6259698/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6259698/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":79586350,"identity":"434c75df-4a7d-4aee-bffe-518fca6db4ad","added_by":"auto","created_at":"2025-03-31 12:31:52","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":130974,"visible":true,"origin":"","legend":"\u003cp\u003eA) An 11-year-old boy with a high-grade glioma. MRI shows a hyperintense mass lesion centered in the pons, extending to the right cerebellar peduncle and midbrain with punctate enhancement, but no ^68Ga-FAPI uptake. B) A 5-year-old female with a high-grade glioma. MRI shows a large intrinsic mass lesion in the pons and midbrain encasing the basilar artery, with evidence of central necrosis and hemorrhage showing rim-like enhancement and no \u0026nbsp;^68Ga-FAPI uptake\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6259698/v1/5e010392f2f4725acad4d56a.jpeg"},{"id":79587484,"identity":"35a18e40-9332-48f2-b68f-c51612c3e545","added_by":"auto","created_at":"2025-03-31 12:39:53","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":137554,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e) A 6-year-old boy with a low-grade glioma. CT scan reveals a large hypervascular soft tissue density mass centered in the left thalamus and pedunculated to the 4th ventricle, with moderate ^68Ga-FAPI uptake. \u003cstrong\u003eB\u003c/strong\u003e) A 13-year-old boy with a low-grade glioma. MRI shows a hyperintense mass lesion arising from the tectal plate with extension to the 4th ventricle, presenting rim-like thick enhancement and a central non-enhancing area without restriction on DWI, demonstrating mild to moderate ^68Ga-FAPI uptake.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6259698/v1/f7b9b23452aa9f9e58084e2d.jpeg"},{"id":80485643,"identity":"aa70912b-340f-41d9-a59d-54ddf330ca48","added_by":"auto","created_at":"2025-04-13 15:31:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":804091,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6259698/v1/9b6a242a-4612-4042-9ff3-991fd08f33b5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"[68Ga]Ga-FAPI-2286 PET Imaging in Pediatric Midline Gliomas: Preliminary Findings and Clinical Implications","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePediatric gliomas are the most common brain tumors in children, with a broad spectrum of histological subtypes ranging from low-grade astrocytomas to highly aggressive glioblastomas. Diffuse midline gliomas often involve subsets such as the brainstem glioma e.g. diffuse intrinsic pontine glioma (DIPG), midbrain glioma and others involving thalamus, or spinal cord. These deep-seated gliomas carry a worse prognosis. Midline pediatric gliomas, regardless of their categorization as high- or low-grade gliomas, can be viewed independently due to their specific nature, molecular characteristics, and management strategy, particularly when they are inoperable due to critical locations. Despite advancements in chemotherapeutic, and radiotherapeutic interventions, prognosis remains very poor for diffuse midline gliomas with a 5-year survival rate of less than 1%. Most children die from the disease within 1\u0026ndash;2 years of diagnosis[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e \u003cp\u003ePalliative care is of utmost importance in midline gliomas where standard options (surgery, chemotherapy, radiotherapy) have limited efficacy or are not feasible (e.g., DIPG is considered inoperable and managed through chemoradiotherapy, but with poor results (11-months median overall survival) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. As many positron emission tomography (PET) tracers provide theranostics options, an investigational imaging approach using [68Ga]Ga-FAPI-2286 PET/CT seems rationale to find those candidate for personalized radioligand therapy (RLT) (i.e. 177Lu-FAPI) to slow tumor progression and relieve symptoms.\u003c/p\u003e \u003cp\u003eRadiolabeled FAP inhibitors, such as [68Ga] Ga-FAPI, bind specifically to FAP, allowing noninvasive tracing of CAFs in the tumor stroma. Recent advances in molecular imaging have explored fibroblast activation protein (FAP), a protease highly expressed in the tumor microenvironment (TME) of various cancers, as a potential theranostic target in gliomas. Clinical studies in various gliomas have shown that 68Ga-FAPI PET can yield high contrast images and provide potentially specific information about the tumor microenvironment and invasive behavior of glioma to differentiate high-grade from low-grade glioma[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In addition, it has also been explored for use in radiotherapy or biopsy planning in glioblastoma[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. [68Ga]Ga-FAPI PET/CT proves promising for brain tumors, often outperforming [18F]F-FDG PET/CT due to negligible physiologic [68Ga]Ga-FAPI uptake in normal brain tissue and high target to background (TBR) values, suggesting targeted therapy potentials[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Additionally, a case of promising [68Ga]Ga-FAPI PET results was previously detected in brainstem glioma (WHO grade IV)[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile adult studies have demonstrated promising uptake of FAPI-based PET tracers in high-grade gliomas, data on pediatric gliomas remain scarce. Furthermore, the role of FAPI imaging in midline gliomas remains largely unexplored. This pilot study aims to assess FAPI uptake in pediatric midline gliomas. This prospective small cohort study applied [68Ga]Ga-FAPI-2286 imaging to patients with end-stage resistant midline glioma to investigate the spectrum and volume of FAP expression as a possible theranostic opportunity.\u003c/p\u003e"},{"header":"Methodology","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThis was a prospective diagnostic accuracy study assessing the efficacy of [68Ga]Ga-FAPI-2286 PET imaging in pediatric patients diagnosed with midline gliomas. Approval for this study was obtained from the Institutional Ethics Committee (No. IR.TUMS.IKHC.REC.1403.144), and informed consent was obtained from parents of all participants. All procedures followed ethical standards set by the Declaration of Helsinki.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Population\u003c/h3\u003e\n\u003cp\u003eWe prospectively enrolled six pediatric patients diagnosed with midline gliomas, including four with diffuse intrinsic pontine gliomas (DIPGs), one with midbrain astrocytomas, and one with a thalamic astrocytoma. The inclusion criteria were patients aged 1 to 18 years with confirmed midline gliomas (DIPG, midbrain astrocytoma, or thalamic astrocytoma) who were unsuitable for further surgical resection due to tumor location. Exclusion criteria included poor clinical status to participate in imaging, allergy or hypersensitivity to radiopharmaceuticals and those who were not willing to participate and fill the informed consent.\u003c/p\u003e\n\u003ch3\u003eTumor Grading and Diagnostic Criteria\u003c/h3\u003e\n\u003cp\u003eTumor grading and diagnosis were confirmed through biopsy and histopathological evaluation in three patients. For the remaining, diagnosis was based on MRI imaging characteristics and clinical progression, reviewed by experienced pediatric neuro-radiologists. Surgical resection was not feasible due to the critical anatomical location of these tumors.\u003c/p\u003e\n\u003ch3\u003ePET Imaging and Analysis\u003c/h3\u003e\n\u003cp\u003ePET imaging was performed using [68Ga]Ga-FAPI-2286. The radiopharmaceutical was prepared according to established clinical radiopharmacy guidelines. Patients received intravenous injections of [68Ga]Ga-FAPI-2286, with doses adjusted according to body weight based on pediatric standards (1.8\u0026ndash;2.2 MBq/kg). After administration, patients rested quietly for approximately 45\u0026ndash;60 minutes to allow optimal tracer uptake and clearance from non-target tissues. Whole-body PET/CT scanning commenced precisely 45 minutes post-injection. Scanning was conducted on a GE PET/CT scanner, acquiring PET images in three-dimensional mode, with typical acquisition times of 3\u0026ndash;5 minutes per bed position to ensure an adequate signal-to-noise ratio. Low-dose CT scans were performed simultaneously for attenuation correction and anatomical localization to minimize radiation exposure. Images were reconstructed using iterative reconstruction algorithms such as ordered-subset expectation maximization (OSEM), employing standardized post-processing techniques.\u003c/p\u003e \u003cp\u003eFor each PET image, the maximum standardized uptake value (SUVmax) within the lesion was determined. Background uptake was calculated using SUV measurements from white matter of centrum semiovale. The tumor-to-background ratio (TBR) was then derived by dividing the lesion SUVmax by the background SUV.\u003c/p\u003e\n\u003ch3\u003eData Analysis and Comparisons\u003c/h3\u003e\n\u003cp\u003eWe performed comparative analyses among patient subgroups to assess potential differences in PET imaging findings. Specifically, we evaluated differences in SUVmax and TBR between patients with DIPG and non-DIPG tumors, high-grade and low-grade tumors, and enhancing versus non-enhancing tumors based on MRI findings. Additionally, tumor locations (e.g., pontine/brainstem versus non-pontine regions) were analyzed to investigate any relationship with PET imaging outcomes.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe study involved six pediatric patients, comprising four males and two females. The patients ranged in age from 5 to 13 years, with an average age of approximately 9 years(Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTumor locations varied among the participants, predominantly involving critical midline brain regions, including the pons, midbrain, and thalamus. All tumors demonstrated notable size and anatomical complexity, with dimensions ranging from approximately 25\u0026times;12 mm to 55\u0026times;45\u0026times;45 mm. Enhancement on MRI was a common feature observed in five of the six cases. One case, notably patient 5, exhibited no enhancement throughout the imaging evaluations, suggesting a lower-grade or less active tumor (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe PET imaging results demonstrated considerable variability in lesion metabolic activity, with SUVmax values ranging from as low as 0.06 to as high as 2.24. Tumor-to-background ratios (TBR) ranged widely from 6 to 224, with higher values notably present in patients with tumor located in thalamus and midbrain. In contrast, lower values were generally associated with tumor located in pons (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic Information\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParticipants\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGrade\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow based on histopathology\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHigh based on histopathology\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow based on histopathology\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHigh based on MRI features\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow based on MRI features\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHigh based on MRI features\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTumor Locations and MRI Findings.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParticipants\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTumor Location on MRI\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePatient 1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeft thalamus, posterior pons, midbrain, paraventricular region\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePatient 2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePons, midbrain, medulla\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePatient 3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMidbrain, extending to floor of the 3rd and 4th ventricles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePatient 4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePons, midbrain, medulla\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePatient 5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePons extending to medulla\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePatient 6\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePosterior of pons\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePET Imaging Results (SUV and TBR).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParticipants\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSUVmax\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTBR\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e224\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e145\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe comparative analyses indicated a trend toward lower SUVmax and TBR values in patients with DIPG compared to those with non-DIPG tumors (thalamus and midbrain involvements) (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e,\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), although these differences did not reach statistical significance due to the small sample size (SUVmax, p\u0026thinsp;=\u0026thinsp;0.057; TBR, p\u0026thinsp;=\u0026thinsp;0.091). Similarly, comparisons between high-grade and low-grade tumors showed no significant differences in SUVmax or TBR (SUVmax, p\u0026thinsp;=\u0026thinsp;0.680; TBR, p\u0026thinsp;=\u0026thinsp;0.751) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePET imaging parameters (SUVmax and TBR) across patient subgroup\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;Std\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSUVmax\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDIPG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.34\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enon-DIPG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.84\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh-Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.43\u0026thinsp;\u0026plusmn;\u0026thinsp;0.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow-Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.25\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTBR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDIPG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enon-DIPG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e184\u0026thinsp;\u0026plusmn;\u0026thinsp;55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh-Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e10\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow-Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e125\u0026thinsp;\u0026plusmn;\u0026thinsp;110\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study highlights a crucial limitation of [68Ga]Ga-FAPI-2286 PET in pediatric midline gliomas. Many adult solid tumors and also gliomas, reported to have pronounced desmoplastic or mesenchymal stroma and consequently higher FAP expression and supported the utility of FAPI tracers. High TBR values are observed in some midline gliomas of our small cohort, aligning with previous reports of [68Ga]Ga-FAPI detectability in the brain and minimal background accumulation[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] However, low overall tracer uptake in the tumor lesions were disappointing for future RLT programs in these devastating midline glioma patients. This observation was at least once published as a false-negative [68Ga]Ga-FAPI scan in a brainstem tumor[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDelving into possible underlying molecular characteristics, there are some evidences confirming our cohort findings. Diffuse midline gliomas (including DIPGs) typically exhibit high cellularity but minimal stromal reaction. Pediatric brainstem gliomas, particularly DIPGs, also tend to be more \u0026ldquo;immunologically cold.\u0026rdquo; For instance, they frequently lack key drivers of fibrogenesis\u0026mdash;such as TGF-β1\u0026mdash;resulting in limited CAF recruitment and a paucity of extracellular matrix remodeling[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Autopsy data consistently reveal little to no desmoplastic response in brainstem lesions, unlike in certain cortical high-grade gliomas (e.g., desmoplastic infantile astrocytomas or pleomorphic xanthoastrocytomas), which do demonstrate robust fibroblastic infiltration[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. This distinction helps explain why ^68Ga-FAPI uptake remains minimal in midline gliomas of our cohort study despite their aggressive biological behavior.\u003c/p\u003e \u003cp\u003eAdult glioblastomas classified as mesenchymal subtype often overexpress YKL-40/CHI3L1, TGF-β, VEGF, and matrix metalloproteinases, creating a stromal microenvironment conducive to strong FAP expression[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, such features appear less prevalent in pediatric diffuse midline gliomas, which frequently adopt an oligodendroglia or progenitor-like phenotype rather than a desmoplastic one; potentially explaining limited diagnostic and therapeutic benefit of DIPGs and pediatric midline lesions in this study.\u003c/p\u003e \u003cp\u003eAnother important factor is the integrity of the blood\u0026ndash;brain barrier (BBB). Non-enhancing tumors\u0026mdash;which often have an intact BBB\u0026mdash;typically can demonstrate minimal radiotracer accumulation. In our cohort, the only completely non-enhancing tumor indeed showed the lowest [68Ga]Ga-FAPI uptake, consistent with literature reports of BBB disruption enhancing tracer delivery[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eUltimately, the pilot data indicate that [68Ga]Ga-FAPI PET imaging may have limited utility in pediatric midline gliomas, particularly DIPGs, given their intrinsically low CAF density and possibly intact BBB. Future research in larger, more uniform cohorts, including direct correlation with histopathological FAP expression, is warranted to clarify the potentials of FAPI-based imaging or therapies in pediatric neuro-oncology.\u003c/p\u003e \u003cp\u003eThis study has some limitations; first meanwhile this study was stopped in pediatric cohort according to negligible FAPI avidity and disappointing theranostic results. This small cohort remains a main point warranting caution in drawing robust conclusions; larger studies are required to confirm whether pediatric gliomas, especially diffuse midline gliomas, commonly lack FAP expression or if these cases are an atypical subset.\u003c/p\u003e \u003cp\u003eOther limitations is that only one FAPI tracer [68Ga]Ga-FAPI-2286) was evaluated; other FAPI tracers may have different affinity, retention characteristics, and pharmacokinetics, although 68Ga-FAPI-2286 has shown promising results in many studies [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Histopathological FAP expression was not assessed in this study; however, FAPI uptake was previously reported to be concordant with IHC FAP expression in another research[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAdditionally, prior treatments (chemotherapy and radiotherapy) were not controlled, potentially affecting tracer uptake. Chemotherapeutic agents and radiotherapy may alter the tumor microenvironment and fibroblast activity.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eFAPI PET may not be broadly suitable for imaging and subsequent therapy in pediatric midline gliomas. While [68Ga]Ga-FAPI PET holds promise in the imaging of adult solid tumors with prominent desmoplastic reactions, its role in pediatric midline gliomas remains uncertain and should be interpreted with caution based on these limited data. Further histopathological investigations particularly in larger controlled cohorts may determine the role of FAPI PET in certain pediatric gliomas of heavier desmoplastic stroma.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors contributed to the study conception and design. All authors commented on previous versions of the manuscript and approved the final manuscript.Conceptualization: Azade Kiumarsi, Zeinab Paymani; Data Collection: Soheila Mirabedian; Formal analysis and investigation: Soheila Mirabedian, Saeed Farzanefar, Mehrshad Abbasi, Neda Pak, Marzie Ebrahimi, Mostafa Nazari, Zeinab paymani; Writing - original draft preparation: Zeinab Paymani, Soheila Mirabedian, Mostafa Nazari, Azade kiumarsi; Writing - review and editing: Zeinab Paymani, Mostafa Nazari; Preparing figures: Marzie Ebrahimi, Mostafa Nazari, Soheila MirabedianSupervision: Azade Kiumarsi, Saeed Farzanefar, Mehrshad Abbasi, Zeinab Paymani.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData is provided within the manuscript\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eVanan MI, Eisenstat DD. DIPG in Children \u0026ndash; What Can We Learn from the Past? Frontiers in Oncology. 2015;5.\u003c/li\u003e\n\u003cli\u003eBaugh JN, Veldhuijzen van Zanten S, Fiocco M, Colditz N, Hoffmann M, Janssens GO, et al. Treatment-related survival patterns in diffuse intrinsic pontine glioma using a historical cohort: A report from the European Society for Pediatric Oncology DIPG/DMG Registry. Neuro Oncol Adv. 2024;6(1):vdae155.\u003c/li\u003e\n\u003cli\u003eR\u0026ouml;hrich M, Loktev A, Wefers AK, Altmann A, Paech D, Adeberg S, et al. IDH-wildtype glioblastomas and grade III/IV IDH-mutant gliomas show elevated tracer uptake in fibroblast activation protein-specific PET/CT. Eur J Nucl Med Mol Imaging. 2019;46(12):2569-80.\u003c/li\u003e\n\u003cli\u003eLiu Y, Ding H, Cao J, Liu G, Chen Y. [68Ga]Ga-FAPI PET/CT in brain tumors: comparison with [18F]F-FDG PET/CT. Frontiers in Oncology. 2024;14.\u003c/li\u003e\n\u003cli\u003eWindisch P, R\u0026ouml;hrich M, Regnery S, Tonndorf-Martini E, Held T, Lang K, et al. Fibroblast Activation Protein (FAP) specific PET for advanced target volume delineation in glioblastoma. Radiother Oncol. 2020;150:159-63.\u003c/li\u003e\n\u003cli\u003eLiu Y, Ding H, Cao J, Liu G, Chen Y, Huang Z. [(68)Ga]Ga-FAPI PET/CT in brain tumors: comparison with [(18)F]F-FDG PET/CT. Front Oncol. 2024;14:1436009.\u003c/li\u003e\n\u003cli\u003eRuan D, Sun J, Han C, Cai J, Yu L, Zhao L, et al. (68)Ga-FAPI-46 PET/CT in the evaluation of gliomas: comparison with (18)F-FDG PET/CT and contrast-enhanced MRI. Theranostics. 2024;14(18):6935-46.\u003c/li\u003e\n\u003cli\u003eDjekidel M, Alsadi R, Abi Akl M, Bouhali O, O\u0026rsquo;Doherty J. Tumor microenvironment and fibroblast activation protein inhibitor (FAPI) PET: developments toward brain imaging. Frontiers in Nuclear Medicine. 2023;3.\u003c/li\u003e\n\u003cli\u003eRuan D, Sun J, Han C, Cai J, Yu L, Zhao L, et al. \u0026lt;sup\u0026gt;68\u0026lt;/sup\u0026gt;Ga-FAPI-46 PET/CT in the evaluation of gliomas: comparison with \u0026lt;sup\u0026gt;18\u0026lt;/sup\u0026gt;F-FDG PET/CT and contrast-enhanced MRI. Theranostics. 2024;14(18):6935-46.\u003c/li\u003e\n\u003cli\u003eLieberman NAP, DeGolier K, Kovar HM, Davis A, Hoglund V, Stevens J, et al. Characterization of the immune microenvironment of diffuse intrinsic pontine glioma: implications for development of immunotherapy. Neuro Oncol. 2019;21(1):83-94.\u003c/li\u003e\n\u003cli\u003eKoelsche C, Sahm F, W\u0026ouml;hrer A, Jeibmann A, Schittenhelm J, Kohlhof P, et al. BRAF-mutated pleomorphic xanthoastrocytoma is associated with temporal location, reticulin fiber deposition and CD34 expression. Brain Pathol. 2014;24(3):221-9.\u003c/li\u003e\n\u003cli\u003eBallester LY, Wang Z, Shandilya S, Miettinen M, Burger PC, Eberhart CG, et al. Morphologic characteristics and immunohistochemical profile of diffuse intrinsic pontine gliomas. Am J Surg Pathol. 2013;37(9):1357-64.\u003c/li\u003e\n\u003cli\u003eVerhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98-110.\u003c/li\u003e\n\u003cli\u003eBusek P, Balaziova E, Matrasova I, Hilser M, Tomas R, Syrucek M, et al. Fibroblast activation protein alpha is expressed by transformed and stromal cells and is associated with mesenchymal features in glioblastoma. Tumor Biology. 2016;37(10):13961-71.\u003c/li\u003e\n\u003cli\u003ePang Y, Zhao L, Meng T, Xu W, Lin Q, Wu H, et al. PET imaging of fibroblast activation protein in various types of cancers by using \u0026amp;lt;sup\u0026amp;gt;68\u0026amp;lt;/sup\u0026amp;gt;Ga-FAP-2286: Comparison with \u0026amp;lt;sup\u0026amp;gt;18\u0026amp;lt;/sup\u0026amp;gt;F-FDG and \u0026amp;lt;sup\u0026amp;gt;68\u0026amp;lt;/sup\u0026amp;gt;Ga-FAPI-46 in a single-center, prospective study. Journal of Nuclear Medicine. 2022:jnumed.122.264544.\u003c/li\u003e\n\u003cli\u003eOster C, Kessler L, Blau T, Keyvani K, Pabst KM, Fendler WP, et al. The Role of Fibroblast Activation Protein in Glioblastoma and Gliosarcoma: A Comparison of Tissue, \u003csup\u003e68\u003c/sup\u003eGa-FAPI-46 PET Data, and Survival Data. J Nucl Med. 2024 Aug;65(8):1217\u0026ndash;23. doi:10.2967/jnumed.123.267151.\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":"DIPG, Midline glioma, brainstem glioma, pediatric glioma, ^68Ga-FAPI-2286 PET/CT, cancer-associated fibroblasts","lastPublishedDoi":"10.21203/rs.3.rs-6259698/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6259698/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eRegarding the poor prognosis, limited efficacy of standard therapies, and scarce data on FAPI imaging in pediatric midline gliomas, we conducted this pilot study to investigate the potential role of [68Ga]Ga-FAPI-2286 PET/CT for improved diagnosis and possible theranostic applications in these high-risk tumors.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThe study aims to evaluate the diagnostic efficacy and potential theranostic implications of [68Ga]Ga-FAPI-2286 PET/CT imaging in pediatric patients with midline gliomas.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis prospective small cohort study involved six pediatric patients aged 5\u0026ndash;13 years diagnosed with midline gliomas (three diffuse intrinsic pontine gliomas [DIPGs], two midbrain astrocytomas, one thalamic astrocytoma). Intravenous administration of [68Ga]Ga-FAPI-2286 (1.8\u0026ndash;2.2 MBq/kg) was followed by PET/CT scan 45 minutes later. Lesion uptake (SUVmax) and tumor-to-background ratios (TBR) were measured. Comparison analyses were done between DIPG vs non-DIPG and high-grade vs low-grade tumors.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSUVmax varied widely (0.06\u0026ndash;2.24), as did TBR (6\u0026ndash;224). Non-DIPG tumors demonstrated higher uptake (mean SUVmax: 1.84, TBR: 184) compared to DIPG tumors (mean SUVmax: 0.34, TBR: 9), though differences were not statistically significant (SUVmax, p\u0026thinsp;=\u0026thinsp;0.057; TBR, p\u0026thinsp;=\u0026thinsp;0.091). Similarly, no significant differences were observed between high-grade and low-grade tumors. Tumors in the thalamus and midbrain showed generally higher uptake compared to pontine locations.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003e[68Ga]Ga-FAPI-2286 PET imaging showed limited utility in pediatric midline gliomas, particularly DIPGs, due to inherently low fibroblast activation protein (FAP) expression and possibly intact blood-brain barriers. Larger, more controlled studies are necessary to clarify the theranostic potential of FAPI PET in pediatric neuro-oncology.\u003c/p\u003e","manuscriptTitle":"[68Ga]Ga-FAPI-2286 PET Imaging in Pediatric Midline Gliomas: Preliminary Findings and Clinical Implications","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-31 12:31:48","doi":"10.21203/rs.3.rs-6259698/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":"30db31ce-61df-48a3-a3da-ffae812d9542","owner":[],"postedDate":"March 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-04-13T15:23:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-31 12:31:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6259698","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6259698","identity":"rs-6259698","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}