Angiogenesis PET/MRI predicts initial growth of sporadic vestibular schwannomas: a prospective study with follow-up in 29 patients using [68Ga]Ga-NODAGA-E[c(RGDyK)]2

Angiogenesis PET/MRI predicts initial growth of sporadic vestibular schwannomas: a prospective study with follow-up in 29 patients using [68Ga]Ga-NODAGA-E[c(RGDyK)]2 | 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 Angiogenesis PET/MRI predicts initial growth of sporadic vestibular schwannomas: a prospective study with follow-up in 29 patients using [ 68 Ga]Ga-NODAGA-E[c(RGDyK)] 2 Hjalte CR Sass, Ramon G Jensen, Helle H Johannesen, Johan O Löfgren, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7415784/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Jan, 2026 Read the published version in EJNMMI Research → Version 1 posted 5 You are reading this latest preprint version Abstract Background Vestibular schwannomas (VS) are benign tumors located at the cerebellopontine angle. Although benign, the growth of VS can result in significant morbidity and ultimately incarceration if left untreated. An MRI of the cerebellopontine angle is the standard-of-care examination when diagnosing a VS. 75% of newly diagnosed VS undergo conservative management with follow-up scans every 6-12th months. No robust clinical prognostic marker of initial sVS tumor growth exists. We performed a phase 2 clinical trial evaluating whether our PET tracer [ 68 Ga]Ga-NODAGA-E[c(RGDyK)] 2 could be used to predict initial sVS growth rate. The study was a non-randomized prospective clinical phase II study. 43 patients were included, either with a newly MRI-verified sporadic VS (sVS) or in a watchful waiting regime, with only a diagnostic MRI scan. All patients were injected intravenously with approximately 200 MBq of [ 68 Ga]Ga-NODAGA-E[c(RGDyK)] 2 followed by a sequential whole-body dynamic PET/MR scan of 60 minutes. All volume measurements were performed on T1 w sequences after intravenous gadolinium contrast injection in the Mirada DBx software version 1.2.0. A volume of interest (VOI) was drawn to encompass the lesion on PET images and a maximal standardized uptake value (SUVmax) for the sVS was registered. Growth over time was expressed as relative growth rate. Results Of the 37 patients initially scanned, results for the first 6 months of follow-up MRI scans are available for 29 of the included patients. The tracer demonstrated stable tumor retention and a high tumor-to-background uptake. SUVmax correlates to the initial growth rate of sVS with a correlation of 0.477 (P = 0.009). A receiver operating characteristic was performed with an area under the curve of 0.7. For the detection of growing tumors (> 20% relative growth annually), a cut-off at 0.555 could be established with a sensitivity of 100% and a specificity of 73% for detecting growing tumors Conclusions This study presents the largest PET-MRI study performed in patients with sporadic vestibular schwannomas. Using the PET tracer [ 68 Ga]Ga-NODAGA-E[c(RGDyK)] 2 , targeting α v β 3 integrins, we found a significant correlation between uptake of the PET tracer at an initial scan and the relative growth rate as measured volumetric on consecutive MRI scans. Trial registration NCT, NCT03393689. Registered 02 january 2018, https//clinicaltrials.gov/study/NCT03393689 Vestibular Schwannoma RGD PET-MRI αvβ3 Figures Figure 1 Figure 2 Figure 3 Introduction Vestibular schwannomas (VS) are benign tumors located at the cerebellopontine angle, originating from the Schwann cells, sheathing the 8th cranial nerve 1 . Sporadic VS (sVS) are the most common variant, while approximately 5% of the tumors are associated with Neurofibromatosis type 2 (NF2), giving rise to bilateral VS 2,3 . Symptoms of a VS include unilateral hearing loss, unilateral tinnitus, dizziness, and less frequent trigeminal affection 4 . Although benign, the growth of VS can result in significant morbidity and ultimately, incarceration if left untreated 4 . An MRI of the cerebellopontine angle is the standard-of-care examination when diagnosing a VS. Primary treatment of sVS is debated and differentiated worldwide 5 . In North America and several European countries, tumors with an extrameatal size below 15 mm often enter a watchful waiting regime, and thus conservative management 6 . The most common cause for active treatment when in a watchful waiting regime is tumor growth identified on follow-up MRI scans 7 . Identifying tumor growth is, therefore, one of the most important aspects of sVS treatment. Growth rates of sVS in watchful waiting regimes depend on the location of the tumor, with data from an unselected national cohort showing 21% of intrameatal tumors and 37% of extrameatal tumors showing growth after 5 years increasing to 25% and 42% after 10 years respectively 7 . Previous studies have shown that pro-angiogenetic markers correlate with the growth rate of sVS 8–10 . Integrins are important in angiogenesis and tumor growth, and the tripeptide Arginine-Glycine-Aspartate (RGD) binds to integrins, in particular the α v β 3 integrin. Recent research has illuminated the role of the α v β 3 integrin in the processes of angiogenesis and tumor growth 11 . Our group has evaluated different PET tracers, including tracers specifically targeting the α v β 3 integrin 12,13 . [ 68 Ga]Ga-NODAGA-E[c(RGDyK)] 2 emerged as particularly promising, as it is fast and reliable in radiochemical production, has stable tumor retention and a favourable tumor-to-background ratio. Most importantly, it correlates with integrin gene expression 13–16 . In 2022, we published a first-in-human phase 1 clinical trial, which found that the novel PET-tracer, [ 68 Ga]Ga-NODAGA-E[c(RGDyK)] 2 , was safe and showed promising tumor uptake 17 . We have also published the results from a prospective phase 2 clinical trial regarding neuroendocrine tumors, where a high uptake of [ 68 Ga]Ga-NODAGA-E[c(RGDyK)] 2 was associated with a poorer prognosis 18 . Currently, no robust clinical prognostic marker of sVS initial tumor growth exists. We performed a phase 2 clinical trial evaluating whether our PET tracer [ 68 Ga]Ga-NODAGA-E[c(RGDyK)] 2 could be used to predict the sVS initial growth rate. Materials and Methods Study design The study was a non-randomized prospective clinical phase II study. 43 patients were included, either with a newly MRI-verified sVS or in a watchful waiting regime, with only a diagnostic MRI scan. They were enrolled between January 2018 and March 2020. All patients fulfilled inclusion criteria and did not meet any exclusion criteria. All patients gave written informed consent prior to inclusion. The study was approved by the Danish Health and Medicine Authority (EudraCT no. 2017-002604-27) and the Regional Scientific Ethical Committee (H-17024682) and registered at ClinicalTrials.gov (NCT03393689). The study was performed in accordance with the Declaration of Helsinki as well as Good Clinical Practice (GCP) and independently monitored by the GCP unit of the Capital Region of Denmark. All patients were injected intravenously with approximately 200 MBq of [ 68 Ga]Ga-NODAGA-E[c(RGDyK)] 2 followed by a sequential whole-body dynamic PET/MR scan of 60 minutes. Synthesis of [Ga]Ga-NODAGA-E[c(RGDyK)] NODAGA-E[c(RGDyK)] 2 acetate was obtained from ABX GmbH. All reagents and cassettes were purchased from Eckert & Ziegler. Gallium-68 (T 1/2 = 68 min; E max, β+ = 1.90 MeV (89%)) labelling of NODAGA-E[c(RGDyK)] 2 acetate was performed using a Modular-Lab Pharmtracer module (Eckert & Ziegler) using a 68 Ge/ 68 Ga generator (Galliapharm, 50 mCi, Eckert & Ziegler). The generator was eluted with 6 ml 0.1M HCl. The eluate was concentrated on a Bond Elut SCX cartridge and eluted with 700 µl 5M NaCl/5.5M HCl (41:1). NODAGA-E[c(RGDyK)] 2 (50 µg, 30 nmol) was labelled in 1,000 µl 1.4M NaOAc buffer pH 4.5 and 400 µl 50% EtOH at 60°C for 300 s. The resulting mixture was transferred to a Sep-pak C2 light cartridge and washed with saline. [ 68 Ga]Ga-NODAGA-E[c(RGDyK)] 2 was eluted with 1 ml 50% EtOH through a sterile filter and formulated with saline. The synthesis time was 20 minutes and 533 ± 167 MBq [ 68 Ga]Ga-NODAGA-E[c(RGDyK)] 2 was obtained. See Supplemental Data (section 1) for a description of the quality control. PET/MR acquisition and image analysis Subjects have no need of fasting before injection of [ 68 Ga]Ga-NODAGA-E[c(RGDyK)] 2 . One peripheral intravenous catheter was placed for tracer injection. PET/MRI ໿examinations were carried out on a whole-body hybrid PET/MRI system (Biograph mMR, Siemens, Germany). ໿PET data was acquired dynamically for 60 minutes after injection of 200 MBq tracer as a single bed centered on the head/neck region. Images were reconstructed with 3D-OP-OSEM (4 iterations and 21 subsets, a Gaussian filter with 4 mm FWHM) on a 344×344 image matrix ໿with pixel size 0.8×0.8 mm 2 , slice thickness of 2 mm. The data from 50–60 minutes after tracer injection was employed. Images were corrected for attenuation using an MRI ultrashort echo time sequence 19 . Simultaneously with PET, T2 and T1 weighted turbo spin echo were acquired for tumor delineation. All volume measurements were performed on T1 weighted sequences after intravenous gadolinium contrast injection in the Mirada DBx software version 1.2.0. A manual contouring tool was used guided by the setting of a lover threshold that excluded non-contrast enhancing surroundings of the tumor. The apparent diffusion coefficient (ADC) was also noted, except for patients whose tumors were too small. Tumor uptake by visual image analysis and activity quantification Image analysis was performed by two experienced certified specialists in nuclear medicine and radiology, respectively. A volume of interest (VOI) was drawn to encompass the lesion on PET images, with care taken to avoid spill from the sigmoid sinus, and a maximal standardized uptake value (SUVmax) for the sporadic vestibular schwannoma was registered. Tumor size was determined by direct volume measurement on the MRI images. Growth over time was expressed as relative growth rate. Histology Histology was confirmed for patients undergoing surgery. No other tissue analysis was performed. Statistics All statistical analyses were performed using IBM SPSS Statistics (Version 29.0.1.0 (171)). A correlational value between SUVmax and the relative growth rate on MRI of sVS was evaluated using the Pearsons correlations coefficient, while the Kruskal-Wallies test was used to determine the difference in SUVmax when grouping sVS in shrinking, static and growing tumors. If not stated otherwise, values are mean +/- SD. Results Patients characteristics A total of 43 patients with a newly diagnosed sporadic vestibular schwannoma were included. For inclusion and exclusion criteria see Table 1. Six were excluded. Three due to claustrophobia and three due to withdrawal of consent. Inclusion criteria Exclusion criteria Patients > 18 years with an MRI-verified, newly diagnosed sporadic Vestibular Schwannoma Pregnancy or lactation Patients > 18 years under watchful waiting for a maximum of 12 months, or with only one follow-up MRI Non-MRI-compatible implants Patients who can understand the study information and provide informed consent Claustrophobia Current hormone treatment, including birth control pills Ongoing steroid treatment Age > 85 years Obesity with a body weight > 140 kilograms Known allergy to the tracer 68Ga-NODAGA-E[c(RGDyK)]₂ Tabel 1 - Inclusion & Exclusions criteria Of the included patients, 51.4% were women with a mean age of 63 (range, 30–81) while 48.6% were men with a mean age of 56 (range, 41–78). See Table 2 for patient characteristics. The tumor location was intrameatal in 16 patients and extrameatal in 21 patients. Of the 37 patients initially scanned, results for the first 6 months of follow-up MRI scans are available for 29 of the included patients. Table 2 -Patient characteristics for the 29 patients receiving a follow-up MR scan approximately 6 months after the PET-RGD MRI scan. L - Left. R - Right. Tumor side and location Patient nr SUVmax SUVmean Initial volume in ccm FollowUp volume in ccm Growth rate in ccm/year Relative growth rate in % L/Extrameatal 1 4.2 2.3 3.0 2.6 -0.80 -26.6 R/Extrameatal 3 3.2 1.8 2.5 3.3 1.35 54.0 L/Intrameatal 5 1.5 0.9 0.4 0.5 0.17 43.5 L/Extrameatal 8 3.1 1.7 2.0 1.9 -0.20 -10.1 R/Extrameatal 9 4.3 2.3 3.1 4.5 4.30 138.5 L/Extrameatal 10 3.4 1.6 1.3 1.2 -0.20 -15.3 R/Extrameatal 11 0.8 0.4 0.5 0.5 0 0 R/Intrameatal 12 1.5 0.8 0.3 0.4 0.21 69.9 L/Extrameatal 13 2.5 1.3 0.9 0.7 -0.40 -43.8 L/Intrameatal 14 0.3 0.2 0.0 0 0 0 L/Extrameatal 16 1.7 0.9 0.2 0.2 0 0 L/Extrameatal 17 3.4 1.7 1.3 1 -0.54 -41.3 L/Extrameatal 19 3.6 1.9 1.6 1.5 -0.20 -12.3 L/Intrameatal 21 0.5 0.4 0.1 0 -0.19 -192.1 R/Extrameatal 23 4.1 1.7 3.1 2.5 -1.20 -38.8 R/Intrameatal 26 0.4 0.3 0.1 0 -0.19 -185.3 L/Extrameatal 27 1.4 0.6 0.4 0.3 -0.20 -48.8 L/Intrameatal 29 0.6 0.4 0.2 0.1 -0.19 -95.6 R/Extrameatal 30 3.2 1.6 3.7 3.1 -1.09 -29.5 R/Intrameatal 31 0.2 0.2 0.3 0.1 -0.53 -175.1 R/Extrameatal 33 8.3 4.6 2.3 2.6 0.71 30.9 R/Intrameatal 34 0 0 0.1 0 -0.20 -201.7 R/Extrameatal 35 2.4 1.2 7.4 7.5 0.52 7.0 L/Extrameatal 36 4 2.5 2.9 2.3 -1.40 -48.4 R/Extrameatal 37 2.4 1.1 2.0 2.6 1.29 64.4 L/Extrameatal 39 3.1 1.8 1.6 1.6 0 0 R/Extrameatal 40 1.7 1.2 0.9 0.6 -0.43 -47.9 R/Extrameatal 41 2.2 1.3 1.0 1.1 0.21 21.0 L/Intrameatal 43 0.3 0.2 0.1 0.1 0 0 Patient Safety and dosimetry The mean and standard deviation of the administered activity was 194 ± 33 MBq (range: 124–233 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the 28 patients, where the administered dose was available. One patient, patient 10, did not have a registered dose, and we were not able to identify the exact number. However, also this patient did not experience any side effects. T umor uptake of [ 68 Ga]Ga-NODAGA-E[c(RGDyK)] 2 The tracer demonstrated stable tumor retention and a high tumor-to-background uptake. See Fig. 1 . We also found that the SUVmax correlates to the initial growth rate of sVS with a correlation of 0.477 (P = 0.009) as seen in Fig. 2 . The mean follow-up was 182 ± 36 days (range, 70–258 days). A receiver operating characteristic (ROC) curve analysis was performed to evaluate and visualize the trade-off between sensitivity (true positive rate) and specificity (false positive rate) at various threshold settings. See Fig. 3 . The area under the curve was 0.7. For the detection of growing tumors (> 20% relative growth annually), a cut-off at 0.555 could be established with a sensitivity of 100% and a specificity of 73% for detecting growing tumors. Our cut-off value is based, not on patients terminating or dropping out of follow-up regimes, but rather on patients increasing the interval between follow-up scans. With such a cut-off, 6 of 29 (21%) patients could safely be identified as non-growing without overlooking any growing tumors. Discussion Here we present the results of our phase II study, evaluating [ 68 Ga]Ga-NODAGA-E[c(RGDyK)] 2 PET imaging as a predictor of tumor growth. The major finding was a significant correlation between the PET tracer uptake at an initial scan and the relative growth rate as measured volumetric on consecutive MRI scans in newly diagnosed sVS. This is the largest PET-MRI study in patients with sVS, and the second study to demonstrate a significant positive correlation between PET-tracer uptake and growth rate 20 . Our study demonstrates that tumor uptake of [ 68 Ga]Ga-NODAGA-E[c(RGDyK)] 2 was consistent and specific for sVS, and patients reported no changes in well-being and no adverse reactions or events. Secondly, we demonstrated a significant positive correlation between maximum tracer uptake and relative growth rate. Over the past two decades, the molecular biology of sVS has been studied extensively, especially as treatment has shifted towards conservative, watchful waiting regimes 21,22 . As tumor growth is the most common cause of active treatment for patients in watchful waiting regimes 23 , understanding the underlying causes is therefore of great interest. Several studies have found that both angiogenesis as well as inflammation take part in driving the sVS growth rate 8–10,20,24–35 . Our group has previously found pro-angiogenetic factors such as vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 1 (VEGF-R1), Matrix metalloproteinase 9 (MMP-9) and Platelet-derived growth factor C (PDGF-C) correlate positively with the growth rate of sVS 8–10,25,26 . Angiogenesis is required for the growth of solid tumors, as growth above 2–3 mm 3 requires new vessels to support nutrient and oxygen requirements 36 . During angiogenesis, migration, growth, and differentiation of endothelial cells take place. Endothelial cells must adhere to one another to form new microvessels. Recent research has illuminated the role of the subfamily of Arginine-Glycine-Aspartate (RGD)-recognizing integrins, due to the involvement of their targets in several hallmarks of cancer development 11 . Especially the α v β 3 integrin, a heterodimeric cell surface receptor, which is involved in cell adhesion and signal transduction, influencing various cellular behaviours essential for tumor progression 37 . α v β 3 integrin is highly expressed in activated endothelial cells and has been identified as a critical modulator of angiogenesis 38–40 . It has been found upregulated in different central nervous tumors including VS but has not previously been correlated with tumor growth rate 41 . α v β 3 integrin is a receptor for fibronectin and vitronectin, ECM components critical in angiogenesis. The binding of α v β 3 integrin to these ligands initiates intracellular signalling cascades that promote key steps in new blood vessel formation. Specifically, α v β 3 integrin modulates the activity of focal adhesion kinase (FAK) and Src family kinases, leading to the activation of the PI3K/Akt and MAPK/ERK pathways, which are essential for angiogenic processes, and upregulated in fast-growing sVS 8 . In our study, we did find a significant correlation between sVS relative tumor growth and SUVmax. We could establish a cut-off where sensitivity and specificity for the detection of growing tumors were 100% and 73%, respectively. However, it may be discussed if this diagnostic performance is sufficient to warrant use in a clinical setting. Perhaps a prolonged interval between follow-up MRI scans could be justified. Angiogenesis is correlated to sVS tumor growth, but most likely not as a sole driving mechanism. In recent years, the tumor microenvironment has been gaining attention, with a special focus on tumor-associated macrophages (TAMs), driving inflammatory processes and through this, tumor growth 30,33,34,42–45 . In the first prospective, non-randomized PET/MRI study looking at the tracer maximum binding potential (BPmax) correlated to tumor growth rates 20 , the PET-tracer, 11C-(R)-PK11195, was targeting the 18kDa translocator protein (TSPO), which is expressed by inflammatory cells and can thus be viewed as a marker of inflammation. The PET-tracer demonstrated a significantly higher BPmax in growing versus static and shrinking sVS. They performed tissue analysis and found that macrophage count predominated over tumor cells in growing sVS, underlining the importance of inflammation as well as the tumor microenvironment in sVS tumor growth. Limitations Several limitations of this study should be acknowledged. To ensure broad applicability to all patients with vestibular schwannoma, all newly diagnosed cases were included, regardless of tumor size. This approach may lead to an overestimation of changes in tumor size, as the risk of measurement error increases with smaller lesions. Initial tumor growth generally guides subsequent treatment decisions, and reducing the number of follow-up scans offers both socioeconomic and patient centered advantages. Although a follow-up period of about six months may be considered short, we believe it is adequate to assess early tumor growth. Conclusion This study presents the largest PET-MRI study performed in patients with sporadic vestibular schwannomas. Using the PET tracer [ 68 Ga]Ga-NODAGA-E[c(RGDyK)] 2 , targeting α v β 3 integrins, we found a significant correlation between uptake of the PET tracer at an initial scan and the relative growth rate as measured volumetric on consecutive MRI scans in newly diagnosed sVS. The tracer was safe and we found no adverse events. The significant although, moderate correlation underlines the partial role of angiogenesis in the growth of sporadic vestibular schwannomas. Non-invasive prognostic markers are pivotal in the future management of sVS. Recent research has focused on the inflammatory processes most likely also driving tumor growth of sVS. Perhaps a combination of PET tracers reflecting both inflammation and angiogenesis may be stronger in predicting tumor growth of sVS. However, further studies and longer follow-up times are needed. Declarations Ethics approval and consent to participate The study was approved by the Danish Health and Medicine Authority (EudraCT no. 2017-002604-27) and the Regional Scientific Ethical Committee (H-17024682) and registered at ClinicalTrials.gov ( NCT03393689 ). The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP) and independently monitored by the GCP unit of the Capital Region of Denmark. All participants signed informed consent before participation. Consent for publication Consent to participate and publication of results were obtained from all individuals included in the study. Availability of data and material The datasets generated and/or analysed during the current study are not publicly available as data are still undergoing analysis. The data are available from the corresponding author on reasonable request. Competing interests Andreas Kjær MD, PhD, DMSc, holds a patent for the PET-MRI tracer [ 68 Ga]Ga-NODAGA-E[c(RGDyK)] 2 with publication number 20200282084. No other potential conflicts of interest relevant to this article exist. Funding This work has been performed with the help of Copenhagen university hospital, RIgshospitalets internal funding, Aase og Ejner Danielsens Fond and Fabrikant Einar Willumsens Mindelegat. Author contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by HCRS, RGJ, PCT obtained the material for analysis. Radiological data was analyzed and obtained by HCRS, HHJ, JOL, AL while nuclear medicine data was obtained and analyzed by JOL, TLA, AEH and AK. The first draft of the manuscript was written by Hjalte CR Sass and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Acknowledgements We would like to acknowledge all funding parties, including all collaborating parties, who contributed to handling the samples. References Khrais T, Romano G, Sanna M. Nerve origin of vestibular schwannoma: a prospective study. J Laryngol Otol . 2008;122(2):128-131. doi:10.1017/S0022215107001028 Gareth Evans DR, Moran A, King A, Saeed S, Gurusinghe N, Ramsden R. Incidence of Vestibular Schwannoma and Neurofibromatosis 2 in the North West of England over a 10-Year Period: Higher Incidence than Previously Thought .; 2005. Reznitsky M, Petersen MMBS, West N, Stangerup SE, Cayé-Thomasen P. 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Otol Neurotol . 2004;25(5):791-796. http://www.ncbi.nlm.nih.gov/pubmed/15354013 Koutsimpelas D, Stripf T, Heinrich UR, Mann WJ, Brieger J. Expression of vascular endothelial growth factor and basic fibroblast growth factor in sporadic vestibular schwannomas correlates to growth characteristics. Otol Neurotol . 2007;28(8):1094-1099. doi:10.1097/MAO.0b013e31814b2787 Cayé-Thomasen P, Baandrup L, Jacobsen GK, Thomsen J, Stangerup SE. Immunohistochemical demonstration of vascular endothelial growth factor in vestibular schwannomas correlates to tumor growth rate. Laryngoscope . 2003;113(December):2129-2134. doi:10.1097/00005537-200312000-00014 De Vries M, Briaire-De Bruijn I, Malessy MJA, De Bruïne SFT, Van Der Mey AGL, Hogendoorn PCW. Tumor-associated macrophages are related to volumetric growth of vestibular schwannomas. Otology and Neurotology . 2013;34(2):347-352. doi:10.1097/MAO.0b013e31827c9fbf Seol HJ, Jung HW, Park SH, et al. Aggressive vestibular schwannomas showing postoperative rapid growth - their association with decreased p27 expression. J Neurooncol . 2005;75(2):203-207. doi:10.1007/s11060-005-2886-0 Saydam O, Senol O, Würdinger T, et al. miRNA-7 attenuation in Schwannoma tumors stimulates growth by upregulating three oncogenic signaling pathways. Cancer Res . 2011;71(3):852-861. doi:10.1158/0008-5472.CAN-10-1219 de Vries WM, Briaire-de Bruijn IH, van Benthem PPG, van der Mey AGL, Hogendoorn PCW. M-CSF and IL-34 expression as indicators for growth in sporadic vestibular schwannoma. Virchows Archiv . 2019;474(3):375-381. doi:10.1007/s00428-018-2503-1 Taurone S, Bianchi E, Attanasio G, et al. Immunohistochemical profile of cytokines and growth factors expressed in vestibular schwannoma and in normal vestibular nerve tissue. Mol Med Rep . 2015;12(1):737-745. doi:10.3892/mmr.2015.3415 Gonçalves VM, Suhm EM, Ries V, et al. Macrophage and lymphocyte infiltration is associated with volumetric tumor size but not with volumetric growth in the tübingen schwannoma cohort. Cancers (Basel) . 2021;13(3):1-15. doi:10.3390/cancers13030466 Arnold F. Tumour angiogenesis. Ann R Coll Surg Engl . 1985;67(5):295-298. doi:10.1201/B23252-48/TUMOUR-ANGIOGENESIS-JUDAH-FOLKMAN Mezu-Ndubuisi OJ, Maheshwari A. The role of integrins in inflammation and angiogenesis. Pediatr Res . 2021;89(7):1619-1626. doi:10.1038/s41390-020-01177-9 Ludwig BS, Kessler H, Kossatz S, Reuning U. RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field. Cancers 2021, Vol 13, Page 1711 . 2021;13(7):1711. doi:10.3390/CANCERS13071711 Nieberler M, Reuning U, Reichart F, et al. Exploring the Role of RGD-Recognizing Integrins in Cancer. Cancers 2017, Vol 9, Page 116 . 2017;9(9):116. doi:10.3390/CANCERS9090116 Brooks PC, Clark RAF, Cheresh DA. Requirement of Vascular Integrin αvβ3 for Angiogenesis. Science (1979) . 1994;264(5158):569-571. doi:10.1126/SCIENCE.7512751 Lim M, Guccione S, Haddix T, et al. αvβ3 Integrin in central nervous system tumors. Hum Pathol . 2005;36(6):665-669. doi:10.1016/J.HUMPATH.2005.03.014 De Vries M, Hogendoorn PCW, De Bruyn IB, Malessy MJA, Van Der Mey AGL. Intratumoral hemorrhage, vessel density, and the inflammatory reaction contribute to volume increase of sporadic vestibular schwannomas. Virchows Archiv . 2012;460(6):629-636. doi:10.1007/s00428-012-1236-9 Perry A, Graffeo CS, Carlstrom LP, et al. Predominance of M1 subtype among tumor-associated macrophages in phenotypically aggressive sporadic vestibular schwannoma. J Neurosurg . Published online October 4, 2019:1-9. doi:10.3171/2019.7.JNS19879 Hannan C, Lewis D, O’leary C, et al. The Inflammatory Microenvironment in Vestibular Schwannoma. doi:10.1093/noajnl/vdaa023/5760813 Lewis D, Donofrio CA, O’Leary C, et al. The microenvironment in sporadic and neurofibromatosis type II–related vestibular schwannoma: the same tumor or different? A comparative imaging and neuropathology study. J Neurosurg . Published online May 2020:1-11. doi:10.3171/2020.3.JNS193230 Supplementary Data The Supplementary Data file is not available with this version. Cite Share Download PDF Status: Published Journal Publication published 13 Jan, 2026 Read the published version in EJNMMI Research → Version 1 posted Editorial decision: Major Revision 24 Oct, 2025 Reviewers agreed at journal 25 Sep, 2025 Reviewers invited by journal 19 Sep, 2025 Editor assigned by journal 09 Sep, 2025 First submitted to journal 08 Sep, 2025 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. 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11:29:55","extension":"html","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":85066,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7415784/v1/faa5de80a3e33f6f0633300d.html"},{"id":92801118,"identity":"e65bce2b-c8df-4620-b776-b1734d5d8cf7","added_by":"auto","created_at":"2025-10-05 11:37:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":58678,"visible":true,"origin":"","legend":"\u003cp\u003ePrimary PET-MRI scan and follow-up scan for patient 1, 3 and 9 respectively. Frem left to right; Primary MRI,Primary PET-MRI, Folllow-up MRI. From top to bottom; patient 1, patient 3 and patient 9. Tumor size, SUVmax and relative growth rate are shown in table 1.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7415784/v1/8215cbb48b572fe995c70264.png"},{"id":92802847,"identity":"3748bf8a-8d95-4049-b2b5-eff06ac0d32b","added_by":"auto","created_at":"2025-10-05 11:45:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":57550,"visible":true,"origin":"","legend":"\u003cp\u003eRGD/PET-MRI SUVmax correlated to the relative growth rate of sVS with 95% confidence interval of mean. The correlation coefficient is 0.477 with a p-value of 0.009.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7415784/v1/548b86826f0a6d0a61a93094.png"},{"id":92801119,"identity":"30e1a350-faf1-47b3-8239-6af8b417483b","added_by":"auto","created_at":"2025-10-05 11:37:55","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":371838,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eA ROC curve demonstrating the sensitivity and specificity at various SUVmax values, and the corresponding coordinates of the ROC curve.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7415784/v1/fb6011ad387ef7b51dbdc49f.png"},{"id":100616162,"identity":"1c6b3ab1-20d5-45c8-875e-d0372e58ddda","added_by":"auto","created_at":"2026-01-19 17:40:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1328700,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7415784/v1/814d4457-436a-4c6b-85a2-450e806ba927.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eAngiogenesis PET/MRI predicts initial growth of sporadic vestibular schwannomas: a prospective study with follow-up in 29 patients using [\u003csup\u003e68\u003c/sup\u003eGa]Ga-NODAGA-E[c(RGDyK)]\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eVestibular schwannomas (VS) are benign tumors located at the cerebellopontine angle, originating from the Schwann cells, sheathing the 8th cranial nerve\u003csup\u003e1\u003c/sup\u003e. Sporadic VS (sVS) are the most common variant, while approximately 5% of the tumors are associated with Neurofibromatosis type 2 (NF2), giving rise to bilateral VS\u003csup\u003e2,3\u003c/sup\u003e. Symptoms of a VS include unilateral hearing loss, unilateral tinnitus, dizziness, and less frequent trigeminal affection\u003csup\u003e4\u003c/sup\u003e. Although benign, the growth of VS can result in significant morbidity and ultimately, incarceration if left untreated\u003csup\u003e4\u003c/sup\u003e. An MRI of the cerebellopontine angle is the standard-of-care examination when diagnosing a VS. Primary treatment of sVS is debated and differentiated worldwide\u003csup\u003e5\u003c/sup\u003e. In North America and several European countries, tumors with an extrameatal size below 15 mm often enter a watchful waiting regime, and thus conservative management\u003csup\u003e6\u003c/sup\u003e. The most common cause for active treatment when in a watchful waiting regime is tumor growth identified on follow-up MRI scans\u003csup\u003e7\u003c/sup\u003e. Identifying tumor growth is, therefore, one of the most important aspects of sVS treatment. Growth rates of sVS in watchful waiting regimes depend on the location of the tumor, with data from an unselected national cohort showing 21% of intrameatal tumors and 37% of extrameatal tumors showing growth after 5 years increasing to 25% and 42% after 10 years respectively\u003csup\u003e7\u003c/sup\u003e. Previous studies have shown that pro-angiogenetic markers correlate with the growth rate of sVS \u003csup\u003e8\u0026ndash;10\u003c/sup\u003e. Integrins are important in angiogenesis and tumor growth, and the tripeptide Arginine-Glycine-Aspartate (RGD) binds to integrins, in particular the α\u003csub\u003ev\u003c/sub\u003eβ\u003csub\u003e3\u003c/sub\u003e integrin. Recent research has illuminated the role of the α\u003csub\u003ev\u003c/sub\u003eβ\u003csub\u003e3\u003c/sub\u003e integrin in the processes of angiogenesis and tumor growth\u003csup\u003e11\u003c/sup\u003e. Our group has evaluated different PET tracers, including tracers specifically targeting the α\u003csub\u003ev\u003c/sub\u003eβ\u003csub\u003e3\u003c/sub\u003e integrin\u003csup\u003e12,13\u003c/sup\u003e. [\u003csup\u003e68\u003c/sup\u003eGa]Ga-NODAGA-E[c(RGDyK)]\u003csub\u003e2\u003c/sub\u003e emerged as particularly promising, as it is fast and reliable in radiochemical production, has stable tumor retention and a favourable tumor-to-background ratio. Most importantly, it correlates with integrin gene expression\u003csup\u003e13\u0026ndash;16\u003c/sup\u003e. In 2022, we published a first-in-human phase 1 clinical trial, which found that the novel PET-tracer, [\u003csup\u003e68\u003c/sup\u003eGa]Ga-NODAGA-E[c(RGDyK)]\u003csub\u003e2\u003c/sub\u003e, was safe and showed promising tumor uptake\u003csup\u003e17\u003c/sup\u003e. We have also published the results from a prospective phase 2 clinical trial regarding neuroendocrine tumors, where a high uptake of [\u003csup\u003e68\u003c/sup\u003eGa]Ga-NODAGA-E[c(RGDyK)]\u003csub\u003e2\u003c/sub\u003e was associated with a poorer prognosis\u003csup\u003e18\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eCurrently, no robust clinical prognostic marker of sVS initial tumor growth exists. We performed a phase 2 clinical trial evaluating whether our PET tracer [\u003csup\u003e68\u003c/sup\u003eGa]Ga-NODAGA-E[c(RGDyK)]\u003csub\u003e2\u003c/sub\u003e could be used to predict the sVS initial growth rate.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design\u003c/h2\u003e\u003cp\u003eThe study was a non-randomized prospective clinical phase II study. 43 patients were included, either with a newly MRI-verified sVS or in a watchful waiting regime, with only a diagnostic MRI scan. They were enrolled between January 2018 and March 2020. All patients fulfilled inclusion criteria and did not meet any exclusion criteria. All patients gave written informed consent prior to inclusion. The study was approved by the Danish Health and Medicine Authority (EudraCT no. 2017-002604-27) and the Regional Scientific Ethical Committee (H-17024682) and registered at ClinicalTrials.gov (NCT03393689). The study was performed in accordance with the Declaration of Helsinki as well as Good Clinical Practice (GCP) and independently monitored by the GCP unit of the Capital Region of Denmark.\u003c/p\u003e\u003cp\u003eAll patients were injected intravenously with approximately 200 MBq of [\u003csup\u003e68\u003c/sup\u003eGa]Ga-NODAGA-E[c(RGDyK)]\u003csub\u003e2\u003c/sub\u003e followed by a sequential whole-body dynamic PET/MR scan of 60 minutes.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSynthesis of [Ga]Ga-NODAGA-E[c(RGDyK)]\u003c/h3\u003e\n\u003cp\u003eNODAGA-E[c(RGDyK)]\u003csub\u003e2\u003c/sub\u003e acetate was obtained from ABX GmbH. All reagents and cassettes were purchased from Eckert \u0026amp; Ziegler. Gallium-68 (T\u003csub\u003e1/2\u003c/sub\u003e = 68 min; E\u003csub\u003emax, β+\u003c/sub\u003e = 1.90 MeV (89%)) labelling of NODAGA-E[c(RGDyK)]\u003csub\u003e2\u003c/sub\u003e acetate was performed using a Modular-Lab Pharmtracer module (Eckert \u0026amp; Ziegler) using a \u003csup\u003e68\u003c/sup\u003eGe/\u003csup\u003e68\u003c/sup\u003eGa generator (Galliapharm, 50 mCi, Eckert \u0026amp; Ziegler). The generator was eluted with 6 ml 0.1M HCl. The eluate was concentrated on a Bond Elut SCX cartridge and eluted with 700 \u0026micro;l 5M NaCl/5.5M HCl (41:1). NODAGA-E[c(RGDyK)]\u003csub\u003e2\u003c/sub\u003e (50 \u0026micro;g, 30 nmol) was labelled in 1,000 \u0026micro;l 1.4M NaOAc buffer pH 4.5 and 400 \u0026micro;l 50% EtOH at 60\u0026deg;C for 300 s. The resulting mixture was transferred to a Sep-pak C2 light cartridge and washed with saline. [\u003csup\u003e68\u003c/sup\u003eGa]Ga-NODAGA-E[c(RGDyK)]\u003csub\u003e2\u003c/sub\u003e was eluted with 1 ml 50% EtOH through a sterile filter and formulated with saline. The synthesis time was 20 minutes and 533\u0026thinsp;\u0026plusmn;\u0026thinsp;167 MBq [\u003csup\u003e68\u003c/sup\u003eGa]Ga-NODAGA-E[c(RGDyK)]\u003csub\u003e2\u003c/sub\u003e was obtained. See Supplemental Data (section 1) for a description of the quality control.\u003c/p\u003e\n\u003ch3\u003ePET/MR acquisition and image analysis\u003c/h3\u003e\n\u003cp\u003eSubjects have no need of fasting before injection of [\u003csup\u003e68\u003c/sup\u003eGa]Ga-NODAGA-E[c(RGDyK)]\u003csub\u003e2\u003c/sub\u003e. One peripheral intravenous catheter was placed for tracer injection. PET/MRI ໿examinations were carried out on a whole-body hybrid PET/MRI system (Biograph mMR, Siemens, Germany). ໿PET data was acquired dynamically for 60 minutes after injection of 200 MBq tracer as a single bed centered on the head/neck region. Images were reconstructed with 3D-OP-OSEM (4 iterations and 21 subsets, a Gaussian filter with 4 mm FWHM) on a 344\u0026times;344 image matrix ໿with pixel size 0.8\u0026times;0.8 mm\u003csup\u003e2\u003c/sup\u003e, slice thickness of 2 mm. The data from 50\u0026ndash;60 minutes after tracer injection was employed. Images were corrected for attenuation using an MRI ultrashort echo time sequence\u003csup\u003e19\u003c/sup\u003e. Simultaneously with PET, T2 and T1 weighted turbo spin echo were acquired for tumor delineation.\u003c/p\u003e\u003cp\u003eAll volume measurements were performed on T1 weighted sequences after intravenous gadolinium contrast injection in the Mirada DBx software version 1.2.0. A manual contouring tool was used guided by the setting of a lover threshold that excluded non-contrast enhancing surroundings of the tumor. The apparent diffusion coefficient (ADC) was also noted, except for patients whose tumors were too small.\u003c/p\u003e\n\u003ch3\u003eTumor uptake by visual image analysis and activity quantification\u003c/h3\u003e\n\u003cp\u003eImage analysis was performed by two experienced certified specialists in nuclear medicine and radiology, respectively. A volume of interest (VOI) was drawn to encompass the lesion on PET images, with care taken to avoid spill from the sigmoid sinus, and a maximal standardized uptake value (SUVmax) for the sporadic vestibular schwannoma was registered. Tumor size was determined by direct volume measurement on the MRI images. Growth over time was expressed as relative growth rate.\u003c/p\u003e\n\u003ch3\u003eHistology\u003c/h3\u003e\n\u003cp\u003eHistology was confirmed for patients undergoing surgery. No other tissue analysis was performed.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStatistics\u003c/h2\u003e\u003cp\u003eAll statistical analyses were performed using IBM SPSS Statistics (Version 29.0.1.0 (171)). A correlational value between SUVmax and the relative growth rate on MRI of sVS was evaluated using the Pearsons correlations coefficient, while the Kruskal-Wallies test was used to determine the difference in SUVmax when grouping sVS in shrinking, static and growing tumors. If not stated otherwise, values are mean +/- SD.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003ePatients characteristics\u003c/h2\u003e\u003cp\u003eA total of 43 patients with a newly diagnosed sporadic vestibular schwannoma were included. For inclusion and exclusion criteria see Table\u0026nbsp;1. Six were excluded. Three due to claustrophobia and three due to withdrawal of consent.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\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\u003e\u003cem\u003eInclusion criteria\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eExclusion criteria\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatients\u0026thinsp;\u0026gt;\u0026thinsp;18 years with an MRI-verified, newly diagnosed sporadic Vestibular Schwannoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePregnancy or lactation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatients\u0026thinsp;\u0026gt;\u0026thinsp;18 years under watchful waiting for a maximum of 12 months, or with only one follow-up MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNon-MRI-compatible implants\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatients who can understand the study information and provide informed consent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClaustrophobia\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCurrent hormone treatment, including birth control pills\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOngoing steroid treatment\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAge\u0026thinsp;\u0026gt;\u0026thinsp;85 years\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eObesity with a body weight\u0026thinsp;\u0026gt;\u0026thinsp;140 kilograms\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eKnown allergy to the tracer 68Ga-NODAGA-E[c(RGDyK)]₂\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eTabel 1 - Inclusion \u0026amp; Exclusions criteria\u003c/h2\u003e\u003cp\u003eOf the included patients, 51.4% were women with a mean age of 63 (range, 30\u0026ndash;81) while 48.6% were men with a mean age of 56 (range, 41\u0026ndash;78). See Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e for patient characteristics. The tumor location was intrameatal in 16 patients and extrameatal in 21 patients. Of the 37 patients initially scanned, results for the first 6 months of follow-up MRI scans are available for 29 of the included patients.\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 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e-Patient characteristics for the 29 patients receiving a follow-up MR scan approximately 6 months after the PET-RGD MRI scan. L - Left. R - Right.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\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\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eTumor side and location\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ePatient nr\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eSUVmax\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eSUVmean\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eInitial volume in ccm\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eFollowUp volume in ccm\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cem\u003eGrowth rate in ccm/year\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eRelative growth rate in %\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-26.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e54.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL/Intrameatal\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\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e43.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-10.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e4.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e138.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-15.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR/Extrameatal\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\u003e0.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR/Intrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e69.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL/Extrameatal\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\u003e2.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-43.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL/Intrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-41.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-12.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL/Intrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-192.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-1.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-38.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR/Intrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-185.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-48.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL/Intrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-95.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-1.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-29.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR/Intrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-175.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e30.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR/Intrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-201.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e7.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e7.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-1.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-48.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e64.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-47.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR/Extrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e21.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL/Intrameatal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003ePatient Safety and dosimetry\u003c/h2\u003e\u003cp\u003eThe mean and standard deviation of the administered activity was 194\u0026thinsp;\u0026plusmn;\u0026thinsp;33 MBq (range: 124\u0026ndash;233 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the 28 patients, where the administered dose was available. One patient, patient 10, did not have a registered dose, and we were not able to identify the exact number. However, also this patient did not experience any side effects.\u003c/p\u003e\u003cp\u003eT\u003cem\u003eumor uptake of [\u003c/em\u003e\u003csup\u003e\u003cem\u003e68\u003c/em\u003e\u003c/sup\u003e\u003cem\u003eGa]Ga-NODAGA-E[c(RGDyK)]\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e\u003c/p\u003e\u003cp\u003eThe tracer demonstrated stable tumor retention and a high tumor-to-background uptake. See Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eWe also found that the SUVmax correlates to the initial growth rate of sVS with a correlation of 0.477 (P\u0026thinsp;=\u0026thinsp;0.009) as seen in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The mean follow-up was 182\u0026thinsp;\u0026plusmn;\u0026thinsp;36 days (range, 70\u0026ndash;258 days).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eA receiver operating characteristic (ROC) curve analysis was performed to evaluate and visualize the trade-off between sensitivity (true positive rate) and specificity (false positive rate) at various threshold settings. See Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The area under the curve was 0.7. For the detection of growing tumors (\u0026gt;\u0026thinsp;20% relative growth annually), a cut-off at 0.555 could be established with a sensitivity of 100% and a specificity of 73% for detecting growing tumors. Our cut-off value is based, not on patients terminating or dropping out of follow-up regimes, but rather on patients increasing the interval between follow-up scans. With such a cut-off, 6 of 29 (21%) patients could safely be identified as non-growing without overlooking any growing tumors.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eHere we present the results of our phase II study, evaluating [\u003csup\u003e68\u003c/sup\u003eGa]Ga-NODAGA-E[c(RGDyK)]\u003csup\u003e2\u003c/sup\u003e PET imaging as a predictor of tumor growth. The major finding was a significant correlation between the PET tracer uptake at an initial scan and the relative growth rate as measured volumetric on consecutive MRI scans in newly diagnosed sVS. This is the largest PET-MRI study in patients with sVS, and the second study to demonstrate a significant positive correlation between PET-tracer uptake and growth rate\u003csup\u003e20\u003c/sup\u003e. Our study demonstrates that tumor uptake of [\u003csup\u003e68\u003c/sup\u003eGa]Ga-NODAGA-E[c(RGDyK)]\u003csup\u003e2\u003c/sup\u003e was consistent and specific for sVS, and patients reported no changes in well-being and no adverse reactions or events. Secondly, we demonstrated a significant positive correlation between maximum tracer uptake and relative growth rate.\u003c/p\u003e\u003cp\u003eOver the past two decades, the molecular biology of sVS has been studied extensively, especially as treatment has shifted towards conservative, watchful waiting regimes\u003csup\u003e21,22\u003c/sup\u003e. As tumor growth is the most common cause of active treatment for patients in watchful waiting regimes\u003csup\u003e23\u003c/sup\u003e, understanding the underlying causes is therefore of great interest. Several studies have found that both angiogenesis as well as inflammation take part in driving the sVS growth rate\u003csup\u003e8\u0026ndash;10,20,24\u0026ndash;35\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eOur group has previously found pro-angiogenetic factors such as vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 1 (VEGF-R1), Matrix metalloproteinase 9 (MMP-9) and Platelet-derived growth factor C (PDGF-C) correlate positively with the growth rate of sVS\u003csup\u003e8\u0026ndash;10,25,26\u003c/sup\u003e. Angiogenesis is required for the growth of solid tumors, as growth above 2\u0026ndash;3 mm\u003csup\u003e3\u003c/sup\u003e requires new vessels to support nutrient and oxygen requirements\u003csup\u003e36\u003c/sup\u003e. During angiogenesis, migration, growth, and differentiation of endothelial cells take place. Endothelial cells must adhere to one another to form new microvessels. Recent research has illuminated the role of the subfamily of Arginine-Glycine-Aspartate (RGD)-recognizing integrins, due to the involvement of their targets in several hallmarks of cancer development\u003csup\u003e11\u003c/sup\u003e. Especially the α\u003csub\u003ev\u003c/sub\u003eβ\u003csub\u003e3\u003c/sub\u003e integrin, a heterodimeric cell surface receptor, which is involved in cell adhesion and signal transduction, influencing various cellular behaviours essential for tumor progression\u003csup\u003e37\u003c/sup\u003e. α\u003csub\u003ev\u003c/sub\u003eβ\u003csub\u003e3\u003c/sub\u003e integrin is highly expressed in activated endothelial cells and has been identified as a critical modulator of angiogenesis\u003csup\u003e38\u0026ndash;40\u003c/sup\u003e. It has been found upregulated in different central nervous tumors including VS but has not previously been correlated with tumor growth rate\u003csup\u003e41\u003c/sup\u003e. α\u003csub\u003ev\u003c/sub\u003eβ\u003csub\u003e3\u003c/sub\u003e integrin is a receptor for fibronectin and vitronectin, ECM components critical in angiogenesis. The binding of α\u003csub\u003ev\u003c/sub\u003eβ\u003csub\u003e3\u003c/sub\u003e integrin to these ligands initiates intracellular signalling cascades that promote key steps in new blood vessel formation. Specifically, α\u003csub\u003ev\u003c/sub\u003eβ\u003csub\u003e3\u003c/sub\u003e integrin modulates the activity of focal adhesion kinase (FAK) and Src family kinases, leading to the activation of the PI3K/Akt and MAPK/ERK pathways, which are essential for angiogenic processes, and upregulated in fast-growing sVS\u003csup\u003e8\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn our study, we did find a significant correlation between sVS relative tumor growth and SUVmax. We could establish a cut-off where sensitivity and specificity for the detection of growing tumors were 100% and 73%, respectively. However, it may be discussed if this diagnostic performance is sufficient to warrant use in a clinical setting. Perhaps a prolonged interval between follow-up MRI scans could be justified. Angiogenesis is correlated to sVS tumor growth, but most likely not as a sole driving mechanism. In recent years, the tumor microenvironment has been gaining attention, with a special focus on tumor-associated macrophages (TAMs), driving inflammatory processes and through this, tumor growth\u003csup\u003e30,33,34,42\u0026ndash;45\u003c/sup\u003e. In the first prospective, non-randomized PET/MRI study looking at the tracer maximum binding potential (BPmax) correlated to tumor growth rates\u003csup\u003e20\u003c/sup\u003e, the PET-tracer, 11C-(R)-PK11195, was targeting the 18kDa translocator protein (TSPO), which is expressed by inflammatory cells and can thus be viewed as a marker of inflammation. The PET-tracer demonstrated a significantly higher BPmax in growing versus static and shrinking sVS. They performed tissue analysis and found that macrophage count predominated over tumor cells in growing sVS, underlining the importance of inflammation as well as the tumor microenvironment in sVS tumor growth.\u003c/p\u003e\u003cp\u003eLimitations\u003c/p\u003e\u003cp\u003eSeveral limitations of this study should be acknowledged. To ensure broad applicability to all patients with vestibular schwannoma, all newly diagnosed cases were included, regardless of tumor size. This approach may lead to an overestimation of changes in tumor size, as the risk of measurement error increases with smaller lesions. Initial tumor growth generally guides subsequent treatment decisions, and reducing the number of follow-up scans offers both socioeconomic and patient centered advantages. Although a follow-up period of about six months may be considered short, we believe it is adequate to assess early tumor growth.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study presents the largest PET-MRI study performed in patients with sporadic vestibular schwannomas. Using the PET tracer [\u003csup\u003e68\u003c/sup\u003eGa]Ga-NODAGA-E[c(RGDyK)]\u003csub\u003e2\u003c/sub\u003e, targeting α\u003csub\u003ev\u003c/sub\u003eβ\u003csub\u003e3\u003c/sub\u003e integrins, we found a significant correlation between uptake of the PET tracer at an initial scan and the relative growth rate as measured volumetric on consecutive MRI scans in newly diagnosed sVS. The tracer was safe and we found no adverse events. The significant although, moderate correlation underlines the partial role of angiogenesis in the growth of sporadic vestibular schwannomas. Non-invasive prognostic markers are pivotal in the future management of sVS. Recent research has focused on the inflammatory processes most likely also driving tumor growth of sVS. Perhaps a combination of PET tracers reflecting both inflammation and angiogenesis may be stronger in predicting tumor growth of sVS. However, further studies and longer follow-up times are needed.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Danish Health and Medicine Authority (EudraCT no.\u0026nbsp;2017-002604-27) and the Regional Scientific Ethical Committee (H-17024682) and registered at ClinicalTrials.gov (\u003cstrong\u003eNCT03393689\u003c/strong\u003e). The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP) and independently monitored by the GCP unit of the Capital Region of Denmark. All participants signed informed consent before participation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Consent for publication\u003c/p\u003e\n\u003cp\u003eConsent to participate and publication of results were obtained from all individuals included in the study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Availability of data and material\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The datasets generated and/or analysed during the current study are not publicly available as data are still undergoing analysis. The data are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Competing interests\u003c/p\u003e\n\u003cp\u003eAndreas Kj\u0026aelig;r MD, PhD, DMSc, holds a patent for the PET-MRI tracer [\u003csup\u003e68\u003c/sup\u003eGa]Ga-NODAGA-E[c(RGDyK)]\u003csub\u003e2\u003c/sub\u003e\u0026nbsp; with publication number 20200282084. No other potential conflicts of interest relevant to this article exist.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Funding\u003c/p\u003e\n\u003cp\u003eThis work has been performed with the help of Copenhagen university hospital, RIgshospitalets internal funding, Aase og Ejner Danielsens Fond and Fabrikant Einar Willumsens Mindelegat.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Author contributions\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by\u0026nbsp;\u003c/em\u003eHCRS, RGJ, PCT obtained the material for analysis. Radiological data was analyzed and obtained by HCRS, HHJ, JOL, AL \u0026nbsp;while nuclear medicine data was obtained and analyzed by JOL, TLA, AEH\u003csup\u003e\u0026nbsp;\u003c/sup\u003eand AK. \u003cem\u003eThe first draft of the manuscript was written by Hjalte CR Sass and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Acknowledgements\u003c/p\u003e\n\u003cp\u003eWe would like to acknowledge all funding parties, including all collaborating parties, who contributed to handling the samples.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKhrais T, Romano G, Sanna M. Nerve origin of vestibular schwannoma: a prospective study. \u003cem\u003eJ Laryngol Otol\u003c/em\u003e. 2008;122(2):128-131. doi:10.1017/S0022215107001028\u003c/li\u003e\n\u003cli\u003eGareth Evans DR, Moran A, King A, Saeed S, Gurusinghe N, Ramsden R. \u003cem\u003eIncidence of Vestibular Schwannoma and Neurofibromatosis 2 in the North West of England over a 10-Year Period: Higher Incidence than Previously Thought\u003c/em\u003e.; 2005.\u003c/li\u003e\n\u003cli\u003eReznitsky M, Petersen MMBS, West N, Stangerup SE, Cay\u0026eacute;-Thomasen P. 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The role of integrins in inflammation and angiogenesis. \u003cem\u003ePediatr Res\u003c/em\u003e. 2021;89(7):1619-1626. doi:10.1038/s41390-020-01177-9\u003c/li\u003e\n\u003cli\u003eLudwig BS, Kessler H, Kossatz S, Reuning U. RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field. \u003cem\u003eCancers 2021, Vol 13, Page 1711\u003c/em\u003e. 2021;13(7):1711. doi:10.3390/CANCERS13071711\u003c/li\u003e\n\u003cli\u003eNieberler M, Reuning U, Reichart F, et al. Exploring the Role of RGD-Recognizing Integrins in Cancer. \u003cem\u003eCancers 2017, Vol 9, Page 116\u003c/em\u003e. 2017;9(9):116. doi:10.3390/CANCERS9090116\u003c/li\u003e\n\u003cli\u003eBrooks PC, Clark RAF, Cheresh DA. Requirement of Vascular Integrin \u0026alpha;v\u0026beta;3 for Angiogenesis. \u003cem\u003eScience (1979)\u003c/em\u003e. 1994;264(5158):569-571. doi:10.1126/SCIENCE.7512751\u003c/li\u003e\n\u003cli\u003eLim M, Guccione S, Haddix T, et al. \u0026alpha;v\u0026beta;3 Integrin in central nervous system tumors. \u003cem\u003eHum Pathol\u003c/em\u003e. 2005;36(6):665-669. doi:10.1016/J.HUMPATH.2005.03.014\u003c/li\u003e\n\u003cli\u003eDe Vries M, Hogendoorn PCW, De Bruyn IB, Malessy MJA, Van Der Mey AGL. Intratumoral hemorrhage, vessel density, and the inflammatory reaction contribute to volume increase of sporadic vestibular schwannomas. \u003cem\u003eVirchows Archiv\u003c/em\u003e. 2012;460(6):629-636. doi:10.1007/s00428-012-1236-9\u003c/li\u003e\n\u003cli\u003ePerry A, Graffeo CS, Carlstrom LP, et al. Predominance of M1 subtype among tumor-associated macrophages in phenotypically aggressive sporadic vestibular schwannoma. \u003cem\u003eJ Neurosurg\u003c/em\u003e. Published online October 4, 2019:1-9. doi:10.3171/2019.7.JNS19879\u003c/li\u003e\n\u003cli\u003eHannan C, Lewis D, O\u0026rsquo;leary C, et al. The Inflammatory Microenvironment in Vestibular Schwannoma. doi:10.1093/noajnl/vdaa023/5760813\u003c/li\u003e\n\u003cli\u003eLewis D, Donofrio CA, O\u0026rsquo;Leary C, et al. The microenvironment in sporadic and neurofibromatosis type II\u0026ndash;related vestibular schwannoma: the same tumor or different? A comparative imaging and neuropathology study. \u003cem\u003eJ Neurosurg\u003c/em\u003e. Published online May 2020:1-11. doi:10.3171/2020.3.JNS193230\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Supplementary Data","content":"\u003cp\u003eThe Supplementary Data file is not available with this version.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejre","sideBox":"Learn more about [EJNMMI Research](http://ejnmmires.springeropen.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ejre/default.aspx","title":"EJNMMI Research","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Vestibular Schwannoma, RGD, PET-MRI, αvβ3","lastPublishedDoi":"10.21203/rs.3.rs-7415784/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7415784/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eVestibular schwannomas (VS) are benign tumors located at the cerebellopontine angle. Although benign, the growth of VS can result in significant morbidity and ultimately incarceration if left untreated. An MRI of the cerebellopontine angle is the standard-of-care examination when diagnosing a VS. 75% of newly diagnosed VS undergo conservative management with follow-up scans every 6-12th months. No robust clinical prognostic marker of initial sVS tumor growth exists. We performed a phase 2 clinical trial evaluating whether our PET tracer [\u003csup\u003e68\u003c/sup\u003eGa]Ga-NODAGA-E[c(RGDyK)]\u003csub\u003e2\u003c/sub\u003e could be used to predict initial sVS growth rate. The study was a non-randomized prospective clinical phase II study. 43 patients were included, either with a newly MRI-verified sporadic VS (sVS) or in a watchful waiting regime, with only a diagnostic MRI scan. All patients were injected intravenously with approximately 200 MBq of [\u003csup\u003e68\u003c/sup\u003eGa]Ga-NODAGA-E[c(RGDyK)]\u003csub\u003e2\u003c/sub\u003e followed by a sequential whole-body dynamic PET/MR scan of 60 minutes. All volume measurements were performed on T1 w sequences after intravenous gadolinium contrast injection in the Mirada DBx software version 1.2.0. A volume of interest (VOI) was drawn to encompass the lesion on PET images and a maximal standardized uptake value (SUVmax) for the sVS was registered. Growth over time was expressed as relative growth rate.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eOf the 37 patients initially scanned, results for the first 6 months of follow-up MRI scans are available for 29 of the included patients. The tracer demonstrated stable tumor retention and a high tumor-to-background uptake. SUVmax correlates to the initial growth rate of sVS with a correlation of 0.477 (P\u0026thinsp;=\u0026thinsp;0.009). A receiver operating characteristic was performed with an area under the curve of 0.7. For the detection of growing tumors (\u0026gt;\u0026thinsp;20% relative growth annually), a cut-off at 0.555 could be established with a sensitivity of 100% and a specificity of 73% for detecting growing tumors\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eThis study presents the largest PET-MRI study performed in patients with sporadic vestibular schwannomas. Using the PET tracer [\u003csup\u003e68\u003c/sup\u003eGa]Ga-NODAGA-E[c(RGDyK)]\u003csub\u003e2\u003c/sub\u003e, targeting α\u003csub\u003ev\u003c/sub\u003eβ\u003csub\u003e3\u003c/sub\u003e integrins, we found a significant correlation between uptake of the PET tracer at an initial scan and the relative growth rate as measured volumetric on consecutive MRI scans.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e\u003cp\u003eNCT, NCT03393689. Registered 02 january 2018, https//clinicaltrials.gov/study/NCT03393689\u003c/p\u003e","manuscriptTitle":"Angiogenesis PET/MRI predicts initial growth of sporadic vestibular schwannomas: a prospective study with follow-up in 29 patients using [68Ga]Ga-NODAGA-E[c(RGDyK)]2","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-05 11:29:50","doi":"10.21203/rs.3.rs-7415784/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revision","date":"2025-10-25T02:51:14+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-09-25T06:33:07+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-19T10:00:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-09T05:31:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"EJNMMI Research","date":"2025-09-08T14:21:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejre","sideBox":"Learn more about [EJNMMI Research](http://ejnmmires.springeropen.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ejre/default.aspx","title":"EJNMMI Research","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9c06f458-6e1d-444c-8ead-a466d9cedee8","owner":[],"postedDate":"October 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-19T17:06:01+00:00","versionOfRecord":{"articleIdentity":"rs-7415784","link":"https://doi.org/10.1186/s13550-025-01362-z","journal":{"identity":"ejnmmi-research","isVorOnly":false,"title":"EJNMMI Research"},"publishedOn":"2026-01-13 16:30:09","publishedOnDateReadable":"January 13th, 2026"},"versionCreatedAt":"2025-10-05 11:29:50","video":"","vorDoi":"10.1186/s13550-025-01362-z","vorDoiUrl":"https://doi.org/10.1186/s13550-025-01362-z","workflowStages":[]},"version":"v1","identity":"rs-7415784","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7415784","identity":"rs-7415784","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}