Imaging MRI Biomarkers for Diagnosing Brain Radionecrosis: Focus on Incomplete Ring Enhancement Sign

Imaging MRI Biomarkers for Diagnosing Brain Radionecrosis: Focus on Incomplete Ring Enhancement Sign | 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 Imaging MRI Biomarkers for Diagnosing Brain Radionecrosis: Focus on Incomplete Ring Enhancement Sign Ana Ortiz de Mendivil, Ernesto Santana-Suarez, Julian Perez-Beteta, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8090402/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract PURPOSE Differentiating brain radionecrosis from recurrent metastases after radiotherapy remains challenging due to the lack of definitive imaging tool modality. This study evaluated the diagnostic accuracy of the “incomplete ring enhancement sign” on contrast-enhanced 3D T1-weighted gradient-echo sequence (CE 3D T1 GRE) as a biomarker of radionecrosis and analyzed additional associated features. METHODS In this retrospective case-control study, 45 cases of radionecrosis were identified from an institutional database of 1,179 brain metastases consecutively treated with stereotactic radiotherapy (2015–2022). Ninety CE 3D T1 GRE (45 radionecrosis and 45 matched metastases controls from the same patients obtained before radiotherapy) were randomly reviewed under blinded conditions, as observers were unaware of whether each case corresponded to metastases or to radionecrosis. The presence of an incomplete ring enhancement sign was assessed, and diagnostic performance was calculated. Interobserver agreement was evaluated using Fleiss’s kappa. Fragmentation, satellite lesions, and lesion distribution were compared using χ². RESULTS Sensitivity was 97% (95% CI, 87–99) and specificity 76% (95% CI, 61–88). Interobserver agreement was good (k = 0.75). Incomplete ring enhancement appeared in 50% of the MRIs where radionecrosis was initially suspected. Fragmentation occurred in 89% of radionecrosis cases compared to 2% of metastases ( p < 0.001), and satellite lesions in 29% vs. 2%, respectively ( p < 0.001). Watershed localization was found in 67% of radionecrosis cases. CONCLUSION The incomplete ring enhancement sign is an early and reliable imaging biomarker of brain radionecrosis supported by associated features such as fragmentation, satellite foci, and watershed localization. Brain Radionecrosis Metastases Incomplete ring enhancement sign Treatment-related inflammatory changes Magnetic resonance imaging (MRI) Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Brain metastases (BM) are the most common intracranial tumors in adults, affecting 20% of cancer patients [ 1 ]. Conventional therapeutic options include surgery and stereotactic radiosurgery or hypofractionated stereotactic radiotherapy (SRS/fSRT) while chemotherapy has traditionally shown limited efficacy. However, antibody-drug conjugate, immune checkpoints, and tyrosine kinase inhibitors can cross the blood-brain barrier, expanding systemic therapy's role in specific patient subgroups. Whole-brain RT is primarily used for palliative care in patients with multiple metastases. In contrast, stereotactic radiosurgery has emerged as a mainstay treatment option for BM, providing superior local control rates compared to whole-brain RT and allowing the treatment of up to 10 metastases [ 2 – 4 ]. Approximately one-third of BM treated with SRS/fSRT exhibits an increase in size, making it challenging to distinguish between true tumor progression and treatment-related effects [ 5 ] Two-thirds of these enlargements are due to either pseudoprogression or radiation necrosis (RN) [ 5 , 6 ]. Pseudoprogression involves transient growth due to inflammatory changes induced by SRS/fSRT or systemic treatment [ 7 , 8 ], occurring in up to 10% of irradiated BM typically within the first 3 months post-SRS/fSRT [ 6 , 8 ]. It has been associated with the “inflammatory cloud sign”, manifesting as blurred and intense enhancement around the metastases [ 9 ] RN is a delayed complication of SRS/fSRT, potentially emerging from months to years after treatment, usually later than 6 months [ 10 ]. Its reported incidence ranges from 3% to 26% [ 10 , 11 ]. Suspicion should arise with exponential growth of a treated lesion, unusual for tumor recurrence [ 12 – 14 ]often with associated edema. Progressive growth can last for up to 15 months before stabilizing or decreasing [ 14 ]. MRI is crucial in diagnosing radionecrosis, appearing as a heterogeneous lesion with peripheral enhancement resembling cut green pepper or Swiss cheese [ 15 , 16 ]. Previous studies have attempted to distinguish between RN and tumor, but no definitive technique is available. Perfusion is a method commonly used in clinical practice. However, relying on qualitative analysis, time variation in dynamic methods, and disparity in the software packages can also lead to poor reproducibility [ 17 , 18 ]​. Derived from routine practice, a radiological sign observed in radionecrosis (RN), the 'incomplete ring enhancement sign' (IRES), has been described [ 9 ]. Our study aims to evaluate the diagnostic accuracy of IRES in identifying RN and to assess its subsequent fragmentation. To our knowledge, its diagnostic performance has not been established in the literature. Additionally, we analyzed other RN features, including satellite lesions, transgression of anatomical boundaries, and localization in watershed areas [ 19 ]. MATERIALS AND METHODS Cases selection The Institutional Review Board approved this study and waived the requirement for written informed consent, as this was a retrospective study using fully anonymized imaging and clinical data. This case-control study included 1179 brain metastases treated with radiosurgery or fractionated stereotactic radiotherapy (SRS/fSRT) between January 2015 and December 2022. The study team consisted of three neuroradiologists (x,xx,xxx), a radiation neuro-oncologist (y) with over a decade of experience, a radiology resident (z), and a research staff member (zz) (Fig. 1). Research design MRI follow-up was used as the primary reference standard. Radionecrosis (RN) cases were included based on the following criteria: prior SRS/fSRT for brain metastases, localization within the radiation field, irregular annular enhancement, central necrosis, vasogenic edema, and a relative cerebral blood volume lesser than 1,85 in dynamic susceptibility contrast MR perfusion [20] Additionally, one of three criteria had to be met: histopathological confirmation of radionecrosis, regression after initial growth, or stability for at least 9 months. Although systemic treatment can influence the development of radionecrosis, it was not the focus of this study. To ensure the inclusion of true cases of radionecrosis and avoid mistaking a shrinking metastases for radionecrosis, patients receiving active brain treatment (chemotherapy or immunotherapy) were excluded. Suspected tumor recurrence on PET imaging, hemorrhagic metastases, and lesions with an uncertain diagnosis based on neuro-oncology board review were excluded. Additionally, lesions showing early post-treatment pseudoprogression (within the first 3 months) were excluded to avoid confusing transient treatment effects with true radionecrosis. Based on these criteria, a total of 45 cases of radionecrosis were incorporated in the study. Incomplete ring enhancement analysis The incomplete ring enhancement sign (IRES) was defined as a discontinuous ring of enhancement across at least two axial slices. IRES was classified based on the number of discontinuities into isolated, multifocal (2-3 discontinuities), or fragmented forms (> 3 discontinuities). The opening of the IRES was analyzed: pial, ventricular, or oriented toward a surgical cavity. Additional imaging markers were also evaluated, such as fragmentation, satellite lesions (peripheral foci of enhancement within 2 cm stable for > 6 months), anatomical boundaries transgression (such as the falx cerebri or tentorium cerebelli), and anatomical distribution, including watershed regions, periventricular, subcortical, and juxtacortical zones). A total of 90 contrast-enhanced 3D T1-weighted gradient echo MRI scans were randomly evaluated in a single-blinded analysis. The dataset included 45 cases of confirmed radionecrosis and 45 matched control scans obtained from the same patients prior to radiotherapy. Three independent investigators (y, xx, and zz) assessed the presence or absence of the incomplete ring enhancement sign, blinded to the clinical and pathological status of the lesions, meaning that the readers were unaware whether the presented lesion represented radionecrosis or metastases. Interobserver agreement was measured. For each case, both the pre-treatment MRI used for radiotherapy planning (pre-RT MRI) and a follow-up contrast-enhanced 3D T1-weighted gradient-echo sequence (CE 3D T1 GRE) showing the radionecrosis were reviewed. They assigned a confidence index ranging from 0 to 10, based on visual examples. All MRIs were obtained using 1.5T and 3T MRI scanners. The contrast-enhanced 3D T1-weighted gradient-echo sequences were acquired with a slice thickness of 0.8 to 1 mm. Gradient echo sequences, specifically 3D-T1-fast-spoiled gradient recalled and 3D-T1-turbo field echo, were acquired five minutes after intravenous administration of gadobutrol (0.1 ml/kg, Gadovist®) (supplementary files). Subsequently, two investigators, (X and z) independently reviewed all follow-up MRI sequences from the 45 patients. By consensus, they determined the date of the first appearance of the incomplete ring enhancement sign (IRES) when present. The following time intervals were recorded: (1) between the end date of SRS/fSRT and the first MRI suggestive of radionecrosis, (2) between the end date of SRS/fSRT and the first detection of IRES, and (3) between the first MRI suggestive of radionecrosis and the initial identification of IRES. In addition, volumetric measurements (based on three orthogonal axes) were performed for both metastases and radionecrosis lesions. Statistical analysis A descriptive analysis was first performed to summarize the main clinical and demographic characteristics of the study population. Continuous variables were expressed as mean ± standard deviation or median as appropriate, and categorical variables as counts and percentages. All lesion-based analyses were conducted to evaluate the diagnostic performance of the IRES for identifying radionecrosis. Three blinded readers independently assessed the presence of IRES and rated their diagnostic confidence on a 0–10 scale (0 = not confident, 10 = fully confident). For each reader, sensitivity, specificity, and positive and negative likelihood ratios were calculated using the RN diagnosis defined in the Methods section as the reference standard. The mean values across the three readers were reported as summary estimates of diagnostic performance. Interobserver agreement was measured using Fleiss's kappa coefficient, which assessed agreement among multiple reviewers in the blinded reading. The percentage of agreement among three observers for IRES detection in RN and for IRES detection in metastases was also calculated. Confidence scores assigned by blinded readers were compared between cases of radionecrosis and metastases using analysis of variance. Comparisons between radionecrosis lesions and their corresponding native metastases were performed using the chi-square test or Fisher’s exact test for categorical variables and the Mann–Whitney U test for continuous variables. Statistical testing was applied only to imaging features that could differ between RN and native metastases, such as fragmentation or satellite lesions. For features inherently shared by both lesions in the same patient, such as anatomic location or vascular territory, only descriptive statistics were reported, as inferential testing would not be meaningful in this paired design. All analyses were performed using SPSS Statistics software (version 27; IBM Corp., Armonk, NY), and a p -value below 0.05 was considered statistically significant. RESULTS Patient and Lesion Characteristics Out of the 76 potential cases of radionecrosis initially screened, 45 lesions met the strict inclusion criteria. Relevant clinical and oncologic variables are summarized in Table 1. Table 1. Basal demographic, clinical, and oncological characteristics of the cases. Variable n=45 Age (years) a 53 (13) Sex b Female 36 (80) Male 9 (20) Primary Tumor b Lung 27(60) Ovarian 8 (18) Breast 6 (13) Others 4 (9) Radiation course b First course SRS/fSRT 43 (96) Reirradiation 2 (4) Radiation Dose (Gy) Single fraction dose 21 (1) Fractionated fSRT dose 30 (3.7) Surgery b Previous surgery 7 (16) Intact brain metastases 38 (84) Histological confirmation of radionecrosis b 7 (16) Follow-up time from RT to death (months) b 60 (59) a Data are medians, with IQR in parentheses b Categorical variables are presented as the numbers of participants, with percentages in parentheses. SRS, stereotactic radiosurgery; fSRT, fractionated stereotactic radiotherapy. Diagnostic Performance and Interobserver Agreement The IRE sign reached a mean sensitivity of 43/45, 97% (95% CI, 87–99) and a mean specificity of 34/45, 76% (95% CI, 61–88). The breakdown of the readings, the respective confidence intervals, positive and negative likelihood ratios, and the inter-observer agreement analysis are shown in Table 2. Table 2 . Diagnostic values of the incomplete ring enhancement sign Reader Sensitivity a Specificity a LR+ b LR- b k c y. 44/45 (98; 88 -99) 36/45 (80; 67 - 92) 5,3 (2,8 - 9,8) 0,03 (0 - 0,19) xx. 43/45 (96; 85 - 99) 35/45 (78; 61 - 88) 4,1 (2,3 - 7,1) 0,06 (0,01 - 0,23) 0,75 (0,75 – 0,76) zz 44/45 (98; 88 - 99) 32/45 (71; 54 - 85) 3,2 (2,1 - 5,1) 0,03 (0 - 0,22) a Data are raw values and diagnostic performance parameters, with 95% CIs in parentheses. b Data are likelihood ratios, with 95% confidence intervals in parentheses. c Data are interobserver agreement with 95% confidence intervals in parentheses. y, radiation oncologist; xx, neuroradiologist, zz, research staff; LR+, likelihood positive ratio; LR-, likelihood negative ratio. Interobserver agreement on the presence of IRE sign in cases of radionecrosis was 93%, whereas agreement on its absence in treatment-naïve metastases was only 62%. This difference was statistically significant ( p < 0.001), indicating that the IRE sign is a highly reproducible finding in RN, while its absence in naïve metastases is less consistently identified. No statistically significant differences in confidence scores were found between RN and naïve metastases for any of the three observers ( p = 0.09, p = 0.1, and p = 0.52 for y, xx, and zz, respectively). Morphological and Topographic Features The incomplete ring enhancement sign was initially observed as isolated or multifocal (Fig. 2), ultimately resulting in a fragmented ring in 89% of cases (Fig. 3) (vs BM, p < 0.001). The ring's opening was oriented toward the ventricular surface in 26,6% of cases, toward a surgical cavity in 13.6%, and was either pial or directed toward the white matter in the remaining 59,8% (Fig. 4). Additionally, satellite lesions were also identified as a significant imaging feature associated with radionecrosis (p < 0.001). A comprehensive analysis of the remaining imaging characteristics is presented in Table 3. Table 3. Characteristics of the cases of radionecrosis and metastatic controls. Variable n=90 Cases (n=45) Controls (n=45) p value Radiological features Fragmentation a 40 (89) 1 (2) <.001 Satellite lesions a 13 (29) 1 (2) <.001 Anatomical boundary transgression a 3 (7) 0 (0) 0.08 Time from RN suspicion to IRES appearance b (m) 0 (2) Locations of the lesion a Frontal 15 (33) Cerebellar 9 (20) Temporal 7 (16) Occipital 6 (13) Others 8 (17) Topographies of the lesion a Juxtacortical 24 (53) Periventricular 13 (29) Subcortical 8 (18) Watershed supratentorial radionecrosis a 30 (67) Volume of the lesion (cc) b 6.6 (14) 4.5 (27) 0.53 a Categorical variables are presented as the numbers of cases, with percentages in parentheses. b Data are medians, with IQR in parentheses RN, radionecrosis; IRES, incomplete ring enhancement sign; m; months; cc, cubic centimeter. The median interval between the end date of SRS/fSRT and the first MRI suggestive of radionecrosis and the first MRI suggestive of radionecrosis was 12 months (IQR, 17 months), and the interval between the end date of SRS/fSRT and the first detection of IRES was 16 months (IQR, 21.5 months). The median interval between the first MRI suggesting radionecrosis and the first appearance of the IRE sign was 0 months (IQR, 2 months), indicating that at least 50% of radionecrosis lesions already showed the IRE sign on the first MRI in which radionecrosis was suspected. DISCUSSION The incomplete ring enhancement sign (IRES) refers to an interruption in the ring enhancement of radionecrosis [ 9 ]. In the present study, we evaluated the IRES diagnostic accuracy in diagnosing RN, showing high mean sensitivity (97% [95% (CI): 87%, 99%]) and specificity (76% [95% CI: 61%, 88%]) with a concordance between observers of 0.75 in a blinded reading. The IRES can be identified on contrast-enhanced 3D T1-weighted gradient-echo sequence (CE 3D T1 GRE), making it accessible to most centers. IRES visualization in RN exhibited a high agreement of 93%, indicating it is a readily recognizable sign. Additionally, IRES was present at the time of radionecrosis suspicion in more than half of cases, supporting its potential role as an early biomarker for radionecrosis. The IRES has not been histopathologically evaluated but may correspond to the open ring pattern observed in multiple sclerosis. Brück et al. reported early active demyelination with myelin protein-positive degradation products in macrophages, correlating with a T2 low rim and contrast enhancement [ 21 ]. Ring enhancement was also linked with neovascularization [ 22 ]. Similarly, RN shows areas of coagulative necrosis surrounded by an inflammatory infiltrate, including lymphocytes and macrophages [ 23 , 24 ] with marginal contrast enhancement bordered by gliosis and demyelination [ 5 ]. IRES may represent the polarization phenomenon described in RN, characterized by an active rim of inflammatory cells and neovascularization, in contrast to interrupted enhancement [ 24 ]. These findings support the hypothesis that IRES in radionecrosis may be associated with demyelination; moreover, the open-ring sign aids in distinguishing demyelinating lesions from tumors and infections, thereby favoring a demyelinating nature [ 25 ]. Comparable to our use of IRES for the detection of radionecrosis, previous studies have reported variable sensitivity (27%–71%) but consistently high specificity (98%–100%) for the diagnosis of tumefactive demyelination using open-ring enhancement [ 26 , 27 ]. In contrast, our findings demonstrated a high sensitivity, suggesting a high prevalence of IRES in RN. Additionally, ring fragmentation in radionecrosis was identified in 89% of cases, characterized by a progressive increase in discontinuities within the ring enhancement ( p < 0.001). Over time, the morphology of RN evolves, with some regions enlarging and others regressing, highlighting its active nature [ 19 ]. This variability can be attributed to differences in radiation dose and the timing of the radiation necrosis onset. Husain et al.[ 28 ] reported that early-onset RN was characterized by demyelination plaques resembling acute multiple sclerosis, whereas late-onset RN was associated with vascular proliferation and coagulative necrosis. In animal models, vascular proliferation was also identified after lower radiation doses (75 Gy), whereas higher doses (150 Gy) resulted in coagulative necrosis and hemorrhage [ 29 , 30 ]. This dynamic behavior, along with the presence of satellite lesions, anatomic boundary transgression [ 30 ], and the patchy distribution of IRES may reflect heterogeneous radiation dose distribution across subregions within the same irradiated field, as well as differences in intrinsic tissue radiosensitivity. These findings may also support our observation of a significant association between satellite lesions and RN, with rare occurrence in BM ( p < 0.001). The pathobiology of radionecrosis remains unclear but is believed to originate from vascular and glial injury, along with an abnormal inflammatory response [ 31 ]. We observed that 67% of RN appeared in border zones between two main arterial territories and 29% precisely in the periventricular white matter. Reduced perfusion in the distal regions of the vascular territories increases susceptibility to ischemia, making these areas particularly vulnerable to post-irradiation vasculopathy [ 32 ]. Moreover, RN has been described to progress earlier and more frequently in the subventricular zone, likely given the presence of neural stem cells in this region [ 30 ]. Conversely, we also found that RN commonly appears in juxtacortical regions (53%), which may be explained by the predominant localization of BM in these areas. These regions, characterized by abrupt changes in vascular caliber, are prone to metastatic emboli deposition [ 33 ]. On the other hand, the abundant cortical blood supply may provide a protective effect against RN [ 19 ]. Our study had limitations. First, the inherent limitations of the reference standard (follow-up MRI) may have introduced verification bias. Classification did not rely on histology because surgery was replaced by a conservative approach whenever feasible. To mitigate misclassification, we applied predefined strict criteria however, this also reduced the final sample size despite an extensive initial metastases database. Interobserver variability was assessed with an inexperienced rater and yielded substantial agreement (κ = 0.75), supporting the reproducibility of IRES. Additionally, we analyzed volume differences between cases and controls to ensure that IRE discrimination was not biased towards larger lesions. The single-center design was a limitation, but it was partially addressed by applying standardized institutional criteria for radiosurgery prescription and evaluation. However, external validation in multicenter cohorts is required to confirm generalizability. Finally, the lack of pathological correlation limits our understanding of the IRES etiopathogenesis. Future prospective studies with histopathological validation are necessary to confirm these findings. The incomplete ring enhancement sign is a reliable early imaging biomarker of brain radionecrosis supported by associated features such as fragmentation, satellite foci, and watershed localization. Abbreviations BM, Brain metastases; IRES, incomplete ring enhancement sign; RN, radionecrosis; SRS/fSRT, stereotactic radiosurgery or hypofractionated stereotactic radiotherapy; CE 3D T1 GRE, contrast-enhanced 3D T1-weighted gradient-echo sequence; preRT MRI, MRI-based treatment planning Declarations Funding The authors acknowledge the support of the Spanish Society of Neuroradiology (SENR), which awarded this work the 2024 Research Grant. Competing Interest All authors declare no conflicts of interest related to this manuscript. Author Contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [Ortiz de Mendivil A.], [Santana-Suarez E] and [Perez-Beteta J.]. The first draft of the manuscript was written by [Ortiz de Mendivil A.] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Data Availability The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Ethics approval and Consent to participate This retrospective case-control study was approved by the Institutional Review Board (IRB), which waived the requirement for informed consent due to the use of fully anonymized imaging and clinical data. Consent to publish The manuscript contains no personal data of any individual. Confirmation of Sole Submission We confirm that this manuscript is being submitted solely to Journal of Neuro-Oncology and is not under consideration elsewhere. Subject Overlap Statement We confirm that there is no substantial overlap between this manuscript and any previously published work. Acknowledgments We would like to express our gratitude to Mateo Rosillo for his collaboration on one of the readings conducted in this study. References Nayak L, Lee EQ, Wen PY (2012) Epidemiology of brain metastases. Curr Oncol Rep 14:48–54. https://doi.org/10.1007/S11912-011-0203-Y Rades D, Pluemer A, Veninga T, et al (2007) Whole-brain radiotherapy versus stereotactic radiosurgery for patients in recursive partitioning analysis classes 1 and 2 with 1 to 3 brain metastases. Cancer 110:2285–92. https://doi.org/10.1002/cncr.23037 Sneed PK, Suh JH, Goetsch SJ, et al (2002) A multi-institutional review of radiosurgery alone vs. radiosurgery with whole brain radiotherapy as the initial management of brain metastases. Int J Radiat Oncol Biol Phys 53:519–26 Ciérvide R, Martí J, López M, et al (2025) Single and multitarget stereotactic radiosurgery (SRS) with single isocenter in the treatment of multiple brain metastases (BM): institutional experience. Clinical and Translational Oncology 2025 1–15. https://doi.org/10.1007/S12094-024-03844-3 Patel TR, McHugh BJ, Bi WL, et al (2011) A comprehensive review of MR imaging changes following radiosurgery to 500 brain metastases. American Journal of Neuroradiology 32:1885–1892. https://doi.org/10.3174/ajnr.A2668 Huber PE, Hawighorst H, Fuss M, et al (2001) Transient enlargement of contrast uptake on MRI after linear accelerator (linac) stereotactic radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys 49:1339–1349. https://doi.org/10.1016/S0360-3016(00)01511-X Lin NU, Lee EQ, Aoyama H, et al (2015) Response assessment criteria for brain metastases: Proposal from the RANO group. Lancet Oncol 16:270–278. https://doi.org/10.1016/S1470-2045(15)70057-4 Ruzevick J, Kleinberg L, Rigamonti D (2014) Imaging changes following stereotactic radiosurgery for metastatic intracranial tumors: Differentiating pseudoprogression from tumor progression and its effect on clinical practice. Neurosurg Rev 37:193–201. https://doi.org/10.1007/s10143-013-0504-8 Ortiz de Mendivil A, Martín-Medina P, García-Cañamaque L, et al (2024) Challenges in radiological evaluation of brain metastases, beyond progression. Radiología (English Edition) 66:166–180. https://doi.org/10.1016/j.rxeng.2024.03.003 Kohutek ZA, Yamada Y, Chan TA, et al (2015) Long-term risk of radionecrosis and imaging changes after stereotactic radiosurgery for brain metastases. J Neurooncol 125:149–56. https://doi.org/10.1007/s11060-015-1881-3 Barajas RF, Chang JS, Sneed PK, et al (2009) Distinguishing recurrent intra-axial metastatic tumor from radiation necrosis following gamma knife radiosurgery using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging. AJNR Am J Neuroradiol 30:367–372. https://doi.org/10.3174/ajnr.A1362 Ocaña-Tienda B, Pérez-Beteta J, Jiménez-Sánchez J, et al (2023) Growth exponents reflect evolutionary processes and treatment response in brain metastases. NPJ Syst Biol Appl 9:. https://doi.org/10.1038/S41540-023-00298-1 Pérez-García VM, Calvo GF, Bosque JJ, et al (2020) Universal scaling laws rule explosive growth in human cancers. Nat Phys 16:1232–1237. https://doi.org/10.1038/S41567-020-0978-6 Ocaña-Tienda B, Perez-Beteta J, Molina-García D, et al (2023) Growth dynamics of brain metastases differentiate radiation necrosis from recurrence. Neurooncol Adv 5:. https://doi.org/10.1093/noajnl/vdac179 Shah R, Vattoth S, Jacob R, et al (2012) Radiation necrosis in the brain: Imaging features and differentiation from tumor recurrence. Radiographics 32:1343–1359. https://doi.org/10.1148/rg.325125002 Vellayappan B, Tan CL, Yong C, et al (2018) Diagnosis and Management of Radiation Necrosis in Patients With Brain Metastases. Front Oncol 8:395. https://doi.org/10.3389/FONC.2018.00395/BIBTEX Van Den Bent MJ, Dhermain FG, Hau P, et al (2010) Advanced MRI and PET imaging for assessment of treatment response in patients with gliomas. Lancet Neurol 9:906–926. https://doi.org/10.1016/S1474 Armitage PA, Schwindack C, Bastin ME, Whittle IR (2007) Quantitative assessment of intracranial tumor response to dexamethasone using diffusion, perfusion and permeability magnetic resonance imaging. Magn Reson Imaging 25:303–310. https://doi.org/10.1016/J.MRI.2006.09.002 Lasocki A, Sia J, Stuckey SL (2022) Improving the diagnosis of radiation necrosis after stereotactic radiosurgery to intracranial metastases with conventional MRI features: a case series. Cancer Imaging 22:. https://doi.org/10.1186/s40644-022-00470-6 Hoefnagels FW a, Lagerwaard FJ, Sanchez E, et al (2009) Radiological progression of cerebral metastases after radiosurgery: Assessment of perfusion MRI for differentiating between necrosis and recurrence. J Neurol 256:878–887. https://doi.org/10.1007/s00415-009-5034-5 Brück W, Bitsch A, Kolenda H, et al (1997) Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann Neurol 42:783–793. https://doi.org/10.1002/ANA.410420515 Kobayashi M, Shimizu Y, Shibata N, Uchiyama S (2014) Gadolinium enhancement patterns of tumefactive demyelinating lesions: Correlations with brain biopsy findings and pathophysiology. J Neurol 261:1902–1910. https://doi.org/10.1007/s00415-014-7437-1 Jagannathan J, Bourne TD, Schlesinger D, et al (2010) Clinical and pathological characteristics of brain metastasis resected after failed radiosurgery. Neurosurgery 66:208–217. https://doi.org/10.1227/01.NEU.0000359318.90478.69 Yoshii Y (2008) Pathological review of late cerebral radionecrosis. Brain Tumor Pathol 25:51–58. https://doi.org/10.1007/S10014-008-0233-9/METRICS Masdeu JC, Quinto ; C, Olivera ; C, et al (1427) Open-ring imaging sign Highly specific for atypical brain demyelination Mabray MC, Cohen BA, Villanueva-Meyer JE, et al (2015) Performance of apparent diffusion coefficient values and conventional MRI features in differentiating tumefactive demyelinating lesions from primary brain neoplasms. American Journal of Roentgenology 205:1075–1085. https://doi.org/10.2214/AJR.14.13970 Nakayama M, Naganawa S, Ouyang M, et al (2021) A review of clinical and imaging findings in tumefactive demyelination. American Journal of Roentgenology 217:186–197. https://doi.org/10.2214/AJR.20.23226 Husain MM, Garcia JH (1976) Cerebral “Radiation Necrosis”: Vascular and Glial Features Spiegelmann R, Friedman WA, Bova FJ, et al (1993) LINAC radiosurgery: an animal model Al-Rubaiey S, Senger C, Bukatz J, et al (2024) Determinants of cerebral radionecrosis in animal models: A systematic review. Radiotherapy and Oncology 199 Rahmathulla G, Marko NF, Weil RJ (2013) Cerebral radiation necrosis: A review of the pathobiology, diagnosis and management considerations. Journal of Clinical Neuroscience 20:485–502 Valk PE, Dillon WP Radiation Injury of the Brain Hwang TL, Close TP, Grego JM, et al (1996) Predilection of brain metastasis in gray and white matter junction and vascular border zones. Cancer 77:1551–1555. https://doi.org/10.1002/(SICI)1097-0142(19960415)77:83.0.CO;2-Z Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterial.docx graphicalabstractEJNO.pptx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8090402","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":549376181,"identity":"a31140bf-7023-42c0-8339-7c231419e625","order_by":0,"name":"Ana Ortiz de Mendivil","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYNACNgkGNnbmAwyMDSRpYWZLIEkLEDPzGBCnhb+9O/FxQZlFYh8zzzeJnzts5BjY2x/g1SJx5uxm4xnnJBLbmHm3SfaeSTNm4DljgN+aG7nbpHnbJIzZgFokeNsOJzZI5ODXIX8jd/tviBaeZ5J/QVrkn+N3mAHQFmagFjmgFjZpiC0M+B1mCPSLNM85kBY2Y2vZtjRjNp4c/Frkjvdu/MxTVscj39788ObbNhs5fvbj+B2GDFgkQCQb0eqBgPkDKapHwSgYBaNg5AAAj909KKWL8lcAAAAASUVORK5CYII=","orcid":"","institution":"University Hospital HM Sanchinarro","correspondingAuthor":true,"prefix":"","firstName":"Ana","middleName":"Ortiz","lastName":"de Mendivil","suffix":""},{"id":549376182,"identity":"305a454a-ba38-4070-8107-f196f7f2cc2b","order_by":1,"name":"Ernesto Santana-Suarez","email":"","orcid":"","institution":"Hospital Universitario Insular de Gran Canaria","correspondingAuthor":false,"prefix":"","firstName":"Ernesto","middleName":"","lastName":"Santana-Suarez","suffix":""},{"id":549376183,"identity":"d899c2e6-7d3b-4fdb-aa57-aca09aee50bb","order_by":2,"name":"Julian Perez-Beteta","email":"","orcid":"","institution":"University of Castilla-La Mancha","correspondingAuthor":false,"prefix":"","firstName":"Julian","middleName":"","lastName":"Perez-Beteta","suffix":""},{"id":549376184,"identity":"f1457d26-bd04-4903-94f6-c7c7d0032d7d","order_by":3,"name":"Raquel Ciervide","email":"","orcid":"","institution":"University Hospital HM Sanchinarro","correspondingAuthor":false,"prefix":"","firstName":"Raquel","middleName":"","lastName":"Ciervide","suffix":""},{"id":549376185,"identity":"6e2a26e7-a515-48a1-a36e-32bd1ce66bcc","order_by":4,"name":"Jorge Diamantopoulos","email":"","orcid":"","institution":"University Hospital HM Sanchinarro","correspondingAuthor":false,"prefix":"","firstName":"Jorge","middleName":"","lastName":"Diamantopoulos","suffix":""},{"id":549376186,"identity":"283e1a9c-e796-429e-a3bc-eff75058ca28","order_by":5,"name":"Patricia Martin-Medina","email":"","orcid":"","institution":"University Hospital HM Sanchinarro","correspondingAuthor":false,"prefix":"","firstName":"Patricia","middleName":"","lastName":"Martin-Medina","suffix":""},{"id":549376187,"identity":"f7e9d616-806e-419e-85fd-890ee0f4728e","order_by":6,"name":"Juan Sepulveda-Sanchez","email":"","orcid":"","institution":"University Hospital HM Sanchinarro","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Sepulveda-Sanchez","suffix":""},{"id":549376188,"identity":"efc7bf58-c799-4e2a-bd5f-00c89bb3f41c","order_by":7,"name":"Sara Garcia-Duque","email":"","orcid":"","institution":"University Hospital HM Sanchinarro","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Garcia-Duque","suffix":""},{"id":549376189,"identity":"0d3e5c35-01c7-4c44-bb08-a67f1431c5a9","order_by":8,"name":"Ovidio Hernando","email":"","orcid":"","institution":"University Hospital HM Sanchinarro","correspondingAuthor":false,"prefix":"","firstName":"Ovidio","middleName":"","lastName":"Hernando","suffix":""},{"id":549376190,"identity":"2e6a6f1b-24d0-4a7c-aa2d-1f8deb26e435","order_by":9,"name":"Aurelio Hernandez-Lain","email":"","orcid":"","institution":"Research Institute Hospital 12 de Octubre","correspondingAuthor":false,"prefix":"","firstName":"Aurelio","middleName":"","lastName":"Hernandez-Lain","suffix":""},{"id":549376191,"identity":"56641e6a-91ef-4152-9115-cc2b2272811c","order_by":10,"name":"Mercedes Lopez","email":"","orcid":"","institution":"University Hospital HM Sanchinarro","correspondingAuthor":false,"prefix":"","firstName":"Mercedes","middleName":"","lastName":"Lopez","suffix":""},{"id":549376192,"identity":"2e5cbb5d-423d-45f5-bd31-5b150540dd53","order_by":11,"name":"Laura Koren","email":"","orcid":"","institution":"Hospital Universitario Fundación Jiménez Díaz","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Koren","suffix":""},{"id":549376193,"identity":"d128f7ae-1a12-4fb6-9d5d-4495aa36b294","order_by":12,"name":"Carmen Rubio","email":"","orcid":"","institution":"University Hospital HM Sanchinarro","correspondingAuthor":false,"prefix":"","firstName":"Carmen","middleName":"","lastName":"Rubio","suffix":""}],"badges":[],"createdAt":"2025-11-11 22:08:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8090402/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8090402/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":96788289,"identity":"fddc044e-d70b-48c3-8fad-6ea876e77ebf","added_by":"auto","created_at":"2025-11-26 06:33:53","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1676742,"visible":true,"origin":"","legend":"","description":"","filename":"MANUSCRIPTEJNOdef.docx","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/f5df625246a5cbbbf2ead503.docx"},{"id":96788282,"identity":"6acd4ef9-7304-4ae9-97e1-21d042de24df","added_by":"auto","created_at":"2025-11-26 06:33:53","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":13175,"visible":true,"origin":"","legend":"","description":"","filename":"3bff4d5cf9a84667b68b91f272668834.json","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/7d82bf5b0fcb638e19d024b0.json"},{"id":96788287,"identity":"72f6fa78-926d-44a6-8ad3-d8ac559ba758","added_by":"auto","created_at":"2025-11-26 06:33:53","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":158114,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/76f4ea8cb57f306c06f54628.docx"},{"id":96916717,"identity":"3f52d9ac-4bcf-46fd-b931-945f5f6d27f9","added_by":"auto","created_at":"2025-11-27 14:08:51","extension":"pptx","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":11893699,"visible":true,"origin":"","legend":"","description":"","filename":"graphicalabstractEJNO.pptx","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/4866c0590c79bb07bd78601a.pptx"},{"id":96788291,"identity":"89f800e9-9e1d-45d6-9585-a889fcab0307","added_by":"auto","created_at":"2025-11-26 06:33:53","extension":"xml","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":109821,"visible":true,"origin":"","legend":"","description":"","filename":"3bff4d5cf9a84667b68b91f2726688341enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/51408ef639597529ef579bd5.xml"},{"id":96788292,"identity":"42081ea5-5ae7-42e5-848b-14cd4177571f","added_by":"auto","created_at":"2025-11-26 06:33:53","extension":"jpeg","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":602337,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/ba5c452127de4bc04e4cc4da.jpeg"},{"id":96915376,"identity":"0d3abb41-8274-4e9e-b77f-137626430b66","added_by":"auto","created_at":"2025-11-27 14:07:11","extension":"jpeg","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":494407,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/796910e5a57e5fe5c98fcf70.jpeg"},{"id":96788296,"identity":"45c612ed-fe24-4282-a639-23b1da7c244e","added_by":"auto","created_at":"2025-11-26 06:33:53","extension":"jpeg","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":377657,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/ac78169581ee37e6e9320005.jpeg"},{"id":96788297,"identity":"5396c5be-4438-41a2-a50e-4972f108e796","added_by":"auto","created_at":"2025-11-26 06:33:53","extension":"jpeg","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":572853,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/cabb67f9207011221f1429ea.jpeg"},{"id":96788299,"identity":"08b618ac-3948-4ba8-99f3-b6e79b5642a5","added_by":"auto","created_at":"2025-11-26 06:33:53","extension":"png","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":140628,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/b5afbc0c6533eb59010e0714.png"},{"id":96916173,"identity":"c5627564-2688-4bce-b94b-44b0d76add06","added_by":"auto","created_at":"2025-11-27 14:08:08","extension":"png","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":176096,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/00ffdffe438181c6091cefe3.png"},{"id":96788294,"identity":"4c3ab085-0fd4-48a3-9d37-945f4d4c0ad5","added_by":"auto","created_at":"2025-11-26 06:33:53","extension":"png","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":99069,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/44813c77ff1c9ed8b223a4f4.png"},{"id":96916849,"identity":"c10f6c84-0449-4f0c-b45a-15457051ef7d","added_by":"auto","created_at":"2025-11-27 14:08:58","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":178990,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/cec9125b430fa37f5be65c90.png"},{"id":96915353,"identity":"60d5b1c6-1701-474b-b952-732b508cf68a","added_by":"auto","created_at":"2025-11-27 14:07:09","extension":"xml","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":107558,"visible":true,"origin":"","legend":"","description":"","filename":"3bff4d5cf9a84667b68b91f2726688341structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/87835e26b42aef1d811e7403.xml"},{"id":96915995,"identity":"eac6fb56-bf15-458c-8016-5aa72f104e0c","added_by":"auto","created_at":"2025-11-27 14:07:52","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":123228,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/00bee0c35861a79455876fd0.html"},{"id":96788283,"identity":"290be231-4f65-403e-a90e-9453ce053ea4","added_by":"auto","created_at":"2025-11-26 06:33:53","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":235828,"visible":true,"origin":"","legend":"\u003cp\u003eThe flowchart illustrates the case selection process and criteria used to define the control and radionecrosis groups. Ninety contrast-enhanced 3D-T1 MRIs (45 MRI-based treatment planning brain metastases and 45 radionecrosis scans) were randomly analyzed by three blinded readers to identify the incomplete ring enhancement sign and assess its diagnostic performance.\u003c/p\u003e\n\u003cp\u003eDSC, Dynamic Susceptibility Contrast; rCBV, relative Cerebral Blood Volume; RN, Radionecrosis; PreRT, MRI-based treatment planning; CE 3D T1 GRE, contrast-enhanced 3D T1-weighted gradient-echo sequence; IRE, incomplete ring enhancement.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/5d0b13c7105277eecd5ee906.png"},{"id":96788284,"identity":"7ee290d7-5e5f-4068-beaa-9c87c0bab8cb","added_by":"auto","created_at":"2025-11-26 06:33:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":272012,"visible":true,"origin":"","legend":"\u003cp\u003eDifferent patterns of incomplete ring enhancement: isolated and multifocal, in a 45-year-old woman with two radionecrosis. She was previously treated with 21 Gy single-fraction stereotactic radiosurgery (SRS) for ovarian brain metastases. (A) Axial post-contrast T1-weighted MRI, obtained 22-month post-SRS, shows a narrow discontinuity in the ring (arrow). Satellite lesions are also visible (arrowhead) and stayed stable (not shown). (B) Representative image of the incomplete ring enhancement open to the pial surface. (C) Axial T1-weighted contrast-enhanced MRI in the same patient reveals another radionecrosis with two distinct foci of incomplete ring enhancement (arrows). (D) Representative image of the multifocal incomplete ring enhancement pattern of the radiation necrosis.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/c652f49c021c616d4db632f4.png"},{"id":96788285,"identity":"2fe98138-89e3-476c-bcb9-85caf15f680e","added_by":"auto","created_at":"2025-11-26 06:33:53","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":167395,"visible":true,"origin":"","legend":"\u003cp\u003eProgressive radionecrosis fragmentation in a 40-year-old woman with lung cancer. The patient underwent whole-brain radiotherapy, followed by 21 Gy single-fraction stereotactic radiosurgery (SRS) for nine brain metastases (BM) one year later. (A) Pretreatment axial contrast-enhanced T1-weighted MRI shows the absence of incomplete ring enhancement in two BM. (B) Follow-up MRI at 12 months post-SRS reveals a significant enlargement of both lesions. (C,D) MRI scans at 15 months and 3,5 years after SRS show a progressive size reduction with increasing fragmentation, characterized by multiple foci of incomplete ring enhancement in both radionecrosis (arrows). (D) A satellite lesion is located adjacent to the radiation necrosis (arrowhead).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/e403b0e96b6543afa9a53293.png"},{"id":96915323,"identity":"815e6ebe-5c5f-4c99-87d8-a4da566bb64e","added_by":"auto","created_at":"2025-11-27 14:07:07","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":313016,"visible":true,"origin":"","legend":"\u003cp\u003eDifferent anatomical locations of the incomplete ring enhancement opening. (A) Axial contrast-enhanced T1-weighted MRI of a 50-year-old woman with lung cancer, obtained 22 months after gross total resection of a brain metastases followed by bed tumor radiation (30 Gy in 5 fractions). The image shows a ring-enhancing necrotic lesion with a wide communication (double-headed arrow) between the collapsed surgical cavity (*) and the central necrosis of the radionecrosis. (B) Representative image of the incomplete ring enhancement opening to the surgical bed. (C) Axial T1-weighted contrast-enhanced image acquired 6 months after a complete response (not shown) to stereotactic radiosurgery (21 Gy) for a brain metastases in a 55-year-old man with lung cancer. The image demonstrates a radionecrosis with incomplete ring enhancement opening (double-headed arrow) to the ventricular atrium (**). (D) Representative image of the incomplete ring enhancement of the radiation necrosis open to the atrium\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/3df2190041b7192727eac650.png"},{"id":97249793,"identity":"aee7cfa2-8e52-4644-a655-92a986b64f9f","added_by":"auto","created_at":"2025-12-02 13:13:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1867749,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/0d42c812-2eaa-48bd-a5c4-dbbef875b7ce.pdf"},{"id":96788293,"identity":"de7af2b0-d880-40e4-805e-9684d239bac8","added_by":"auto","created_at":"2025-11-26 06:33:53","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":158114,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/f992a63f3db2bfa2e6f94650.docx"},{"id":96788303,"identity":"b0a70861-38cc-41da-ba0d-7b4e9499fad0","added_by":"auto","created_at":"2025-11-26 06:33:54","extension":"pptx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":11893699,"visible":true,"origin":"","legend":"","description":"","filename":"graphicalabstractEJNO.pptx","url":"https://assets-eu.researchsquare.com/files/rs-8090402/v1/5aaae364f6a41e808c727d2d.pptx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Imaging MRI Biomarkers for Diagnosing Brain Radionecrosis: Focus on Incomplete Ring Enhancement Sign","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eBrain metastases (BM) are the most common intracranial tumors in adults, affecting 20% of cancer patients [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Conventional therapeutic options include surgery and stereotactic radiosurgery or hypofractionated stereotactic radiotherapy (SRS/fSRT) while chemotherapy has traditionally shown limited efficacy. However, antibody-drug conjugate, immune checkpoints, and tyrosine kinase inhibitors can cross the blood-brain barrier, expanding systemic therapy's role in specific patient subgroups. Whole-brain RT is primarily used for palliative care in patients with multiple metastases. In contrast, stereotactic radiosurgery has emerged as a mainstay treatment option for BM, providing superior local control rates compared to whole-brain RT and allowing the treatment of up to 10 metastases [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eApproximately one-third of BM treated with SRS/fSRT exhibits an increase in size, making it challenging to distinguish between true tumor progression and treatment-related effects [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] Two-thirds of these enlargements are due to either pseudoprogression or radiation necrosis (RN) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Pseudoprogression involves transient growth due to inflammatory changes induced by SRS/fSRT or systemic treatment [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], occurring in up to 10% of irradiated BM typically within the first 3 months post-SRS/fSRT [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. It has been associated with the \u0026ldquo;inflammatory cloud sign\u0026rdquo;, manifesting as blurred and intense enhancement around the metastases [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] RN is a delayed complication of SRS/fSRT, potentially emerging from months to years after treatment, usually later than 6 months [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Its reported incidence ranges from 3% to 26% [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Suspicion should arise with exponential growth of a treated lesion, unusual for tumor recurrence [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]often with associated edema. Progressive growth can last for up to 15 months before stabilizing or decreasing [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMRI is crucial in diagnosing radionecrosis, appearing as a heterogeneous lesion with peripheral enhancement resembling cut green pepper or Swiss cheese [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Previous studies have attempted to distinguish between RN and tumor, but no definitive technique is available. Perfusion is a method commonly used in clinical practice. However, relying on qualitative analysis, time variation in dynamic methods, and disparity in the software packages can also lead to poor reproducibility [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]​.\u003c/p\u003e\u003cp\u003eDerived from routine practice, a radiological sign observed in radionecrosis (RN), the 'incomplete ring enhancement sign' (IRES), has been described [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Our study aims to evaluate the diagnostic accuracy of IRES in identifying RN and to assess its subsequent fragmentation. To our knowledge, its diagnostic performance has not been established in the literature. Additionally, we analyzed other RN features, including satellite lesions, transgression of anatomical boundaries, and localization in watershed areas [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCases selection\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Institutional Review Board approved this study and waived the requirement for written informed consent, as this was a retrospective study using fully anonymized imaging and clinical data. This case-control study included 1179 brain metastases treated with radiosurgery or fractionated stereotactic radiotherapy (SRS/fSRT) between January 2015 and December 2022. The study team consisted of three neuroradiologists (x,xx,xxx), a radiation neuro-oncologist (y) with over a decade of experience, a radiology resident (z), and a research staff member (zz) (Fig. 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eResearch design\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMRI follow-up was used as the primary reference standard. Radionecrosis (RN) cases were included based on the following criteria: prior SRS/fSRT for brain metastases, localization within the radiation field, irregular annular enhancement, central necrosis, vasogenic edema, and a relative cerebral blood volume lesser than 1,85 in dynamic susceptibility contrast MR perfusion [20]\u003c/p\u003e\n\u003cp\u003eAdditionally, one of three criteria had to be met: histopathological confirmation of radionecrosis, regression after initial growth, or stability for at least 9 months.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough systemic treatment can influence the development of radionecrosis, it was not the focus of this study. To ensure the inclusion of true cases of radionecrosis and avoid mistaking a shrinking metastases for radionecrosis, patients receiving active brain treatment (chemotherapy or immunotherapy) were excluded. Suspected tumor recurrence on PET imaging, hemorrhagic metastases, and lesions with an uncertain diagnosis based on neuro-oncology board review were excluded. Additionally, lesions showing early post-treatment pseudoprogression (within the first 3 months) were excluded to avoid confusing transient treatment effects with true radionecrosis. Based on these criteria, a total of 45 cases of radionecrosis were incorporated in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eIncomplete ring enhancement analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe incomplete ring enhancement sign (IRES) was defined as a discontinuous ring of enhancement across at least two axial slices. IRES was classified based on the number of discontinuities into isolated, multifocal (2-3 discontinuities), or fragmented forms (\u0026gt; 3 discontinuities). The opening of the IRES was analyzed: pial, ventricular, or oriented toward a surgical cavity. Additional imaging markers were also evaluated, such as fragmentation, satellite lesions (peripheral foci of enhancement within 2 cm stable for \u0026gt; 6 months), anatomical boundaries transgression (such as the falx cerebri or tentorium cerebelli), and anatomical distribution, including watershed regions, periventricular, subcortical, and juxtacortical zones).\u003c/p\u003e\n\u003cp\u003eA total of 90 contrast-enhanced 3D T1-weighted gradient echo MRI scans were randomly evaluated in a single-blinded analysis. The dataset included 45 cases of confirmed radionecrosis and 45 matched control scans obtained from the same patients prior to radiotherapy. Three independent investigators (y, xx, and zz) assessed the presence or absence of the incomplete ring enhancement sign, blinded to the clinical and pathological status of the lesions, meaning that the readers were unaware whether the presented lesion represented radionecrosis or metastases. Interobserver agreement was measured. For each case, both the pre-treatment MRI used for radiotherapy planning (pre-RT MRI) and a follow-up contrast-enhanced 3D T1-weighted gradient-echo sequence (CE 3D T1 GRE) showing the radionecrosis were reviewed. They assigned a confidence index ranging from 0 to 10, based on visual examples.\u003c/p\u003e\n\u003cp\u003eAll MRIs were obtained using 1.5T and 3T MRI scanners. The contrast-enhanced 3D T1-weighted gradient-echo sequences were acquired with a slice thickness of 0.8 to 1 mm. Gradient echo sequences, specifically 3D-T1-fast-spoiled gradient recalled and 3D-T1-turbo field echo, were acquired five minutes after intravenous administration of gadobutrol (0.1 ml/kg, Gadovist\u0026reg;) (supplementary files).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSubsequently, two investigators, (X and z) independently reviewed all follow-up MRI sequences from the 45 patients. By consensus, they determined the date of the first appearance of the incomplete ring enhancement sign (IRES) when present. The following time intervals were recorded: (1) between the end date of SRS/fSRT and the first MRI suggestive of radionecrosis, (2) between the end date of SRS/fSRT and the first detection of IRES, and (3) between the first MRI suggestive of radionecrosis and the initial identification of IRES. In addition, volumetric measurements (based on three orthogonal axes) were performed for both metastases and radionecrosis lesions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA descriptive analysis was first performed to summarize the main clinical and demographic characteristics of the study population. Continuous variables were expressed as mean \u0026plusmn; standard deviation or median as appropriate, and categorical variables as counts and percentages. All lesion-based analyses were conducted to evaluate the diagnostic performance of the IRES for identifying radionecrosis. Three blinded readers independently assessed the presence of IRES and rated their diagnostic confidence on a 0\u0026ndash;10 scale (0 = not confident, 10 = fully confident).\u003c/p\u003e\n\u003cp\u003eFor each reader, sensitivity, specificity, and positive and negative likelihood ratios were calculated using the RN diagnosis defined in the Methods section as the reference standard. The mean values across the three readers were reported as summary estimates of diagnostic performance. Interobserver agreement was measured using Fleiss\u0026apos;s kappa coefficient, which assessed agreement among multiple reviewers in the blinded reading. The percentage of agreement among three observers for IRES detection in RN and for IRES detection in metastases was also calculated. Confidence scores assigned by blinded readers were compared between cases of radionecrosis and metastases using analysis of variance. Comparisons between radionecrosis lesions and their corresponding native metastases were performed using the chi-square test or Fisher\u0026rsquo;s exact test for categorical variables and the Mann\u0026ndash;Whitney U test for continuous variables. Statistical testing was applied only to imaging features that could differ between RN and native metastases, such as fragmentation or satellite lesions. For features inherently shared by both lesions in the same patient, such as anatomic location or vascular territory, only descriptive statistics were reported, as inferential testing would not be meaningful in this paired design. All analyses were performed using SPSS Statistics software (version 27; IBM Corp., Armonk, NY), and a \u003cem\u003ep\u003c/em\u003e-value below 0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatient and Lesion Characteristics\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOut of the 76 potential cases of radionecrosis initially screened, 45 lesions met the strict inclusion criteria. Relevant clinical and oncologic variables are summarized in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 360px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Basal demographic, clinical, and oncological characteristics of the cases.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 285px;\"\u003e\n \u003cp\u003eVariable\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003en=45\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003eAge (years)\u003csup\u003ea\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e53 (13)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003eSex\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Female\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e36 (80)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Male\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e9 (20)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003ePrimary Tumor\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Lung\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e27(60)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Ovarian\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e8 (18)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Breast\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e6 (13)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Others\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e4 (9)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003eRadiation course \u003csup\u003eb\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;First course SRS/fSRT\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e43 (96)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Reirradiation\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e2 (4)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003eRadiation Dose (Gy)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Single fraction dose\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e21 (1)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Fractionated fSRT dose\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e30 (3.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003eSurgery\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Previous surgery \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e7 (16)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Intact brain metastases\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e38 (84)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 285px;\"\u003e\n \u003cp\u003eHistological confirmation of radionecrosis\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e7 (16)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 285px;\"\u003e\n \u003cp\u003eFollow-up time from RT to death (months)\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e60 (59)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 360px;\"\u003e\n \u003cp\u003e\u003csup\u003ea \u0026nbsp;\u0026nbsp;\u003c/sup\u003eData are medians, with IQR in parentheses \u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003csup\u003eb\u0026nbsp;\u003c/sup\u003eCategorical variables are presented as the numbers of participants, with percentages in parentheses.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eSRS, stereotactic radiosurgery; fSRT, fractionated stereotactic radiotherapy.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDiagnostic Performance and Interobserver Agreement\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe IRE sign reached a mean sensitivity of 43/45, 97% (95% CI, 87\u0026ndash;99) and a mean specificity of 34/45, 76% (95% CI, 61\u0026ndash;88). The breakdown of the readings, the respective confidence intervals, positive and negative likelihood ratios, and the inter-observer agreement analysis are shown in Table 2.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" style=\"width: 566px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e. Diagnostic values of the incomplete ring enhancement sign \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11.2676%;\"\u003e\n \u003cp\u003eReader\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eSensitivity\u003csup\u003ea\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eSpecificity\u003csup\u003ea\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eLR+\u003csup\u003eb\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2535%;\"\u003e\n \u003cp\u003eLR-\u003csup\u003eb\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u0026nbsp;k\u003csup\u003ec\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11.2676%;\"\u003e\n \u003cp\u003ey.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e44/45 (98; 88 -99)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e36/45 (80; 67 - 92)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e5,3 (2,8 - 9,8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2535%;\"\u003e\n \u003cp\u003e0,03 (0 - 0,19)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11.2676%;\"\u003e\n \u003cp\u003exx.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e43/45 (96; 85 - 99)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e35/45 (78; 61 - 88)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4,1 (2,3 - 7,1)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2535%;\"\u003e\n \u003cp\u003e0,06 (0,01 - 0,23)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e0,75 (0,75 \u0026ndash; 0,76)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11.2676%;\"\u003e\n \u003cp\u003ezz\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e44/45 (98; 88 - 99)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e32/45 (71; 54 - 85)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3,2 (2,1 - 5,1)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2535%;\"\u003e\n \u003cp\u003e0,03 (0 - 0,22)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" style=\"width: 566px;\"\u003e\n \u003cp\u003e\u003csup\u003ea\u0026nbsp;\u003c/sup\u003eData are raw values and diagnostic performance parameters, with 95% CIs in parentheses.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003csup\u003eb\u0026nbsp;\u003c/sup\u003eData are likelihood ratios, with 95% confidence intervals in parentheses.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ec\u0026nbsp;\u003c/sup\u003eData are interobserver agreement with 95% confidence intervals in parentheses.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ey, radiation oncologist; xx, neuroradiologist, zz, research staff; LR+, likelihood positive ratio; LR-, likelihood negative ratio.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eInterobserver agreement on the presence of IRE sign in cases of radionecrosis was 93%, whereas agreement on its absence in treatment-na\u0026iuml;ve metastases was only 62%. This difference was statistically significant (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), indicating that the IRE sign is a highly reproducible finding in RN, while its absence in na\u0026iuml;ve metastases is less consistently identified. No statistically significant differences in confidence scores were found between RN and na\u0026iuml;ve metastases for any of the three observers (\u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.09, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.1, and\u003cem\u003e\u0026nbsp;p\u0026nbsp;\u003c/em\u003e= 0.52 for y, xx, and zz, respectively).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMorphological and Topographic Features\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe incomplete ring enhancement sign was initially observed as isolated or multifocal (Fig. 2), ultimately resulting in a fragmented ring in 89% of cases (Fig. 3) (vs BM, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). The ring\u0026apos;s opening was oriented toward the ventricular surface in 26,6% of cases, toward a surgical cavity in 13.6%, and was either pial or directed toward the white matter in the remaining 59,8% (Fig. 4). Additionally, satellite lesions were also identified as a significant imaging feature associated with radionecrosis (p \u0026lt; 0.001). A comprehensive analysis of the remaining imaging characteristics is presented in Table 3.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width: 566px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Characteristics of the cases of radionecrosis and metastatic controls.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 330px;\"\u003e\n \u003cp\u003eVariable n=90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eCases \u0026nbsp;(n=45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003eControls\u003c/p\u003e\n \u003cp\u003e(n=45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 330px;\"\u003e\n \u003cp\u003eRadiological features\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Fragmentation\u003csup\u003ea\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e40 (89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e1 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Satellite lesions\u003csup\u003ea\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e13 (29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e1 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Anatomical boundary transgression\u003csup\u003ea\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e3 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003eTime from RN suspicion to IRES appearance\u003csup\u003eb\u003c/sup\u003e (m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 330px;\"\u003e\n \u003cp\u003eLocations of the lesion\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 330px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Frontal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e15 (33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 330px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Cerebellar\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e9 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 330px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Temporal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e7 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 330px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Occipital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e6 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 330px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Others\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e8 (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 330px;\"\u003e\n \u003cp\u003eTopographies of the lesion\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Juxtacortical\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e24 (53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Periventricular\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e13 (29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Subcortical\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e8 (18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 330px;\"\u003e\n \u003cp\u003eWatershed supratentorial radionecrosis\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e30 (67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 330px;\"\u003e\n \u003cp\u003eVolume of the lesion (cc)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e6.6 (14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e4.5 (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e0.53\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 566px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ea\u0026nbsp;\u003c/sup\u003eCategorical variables are presented as the numbers of cases, with percentages in parentheses.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003eb\u0026nbsp;\u003c/sup\u003eData are medians, with IQR in parentheses\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRN, radionecrosis; IRES, incomplete ring enhancement sign; m; months; cc, cubic centimeter.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe median interval between the end date of SRS/fSRT and the first MRI suggestive of radionecrosis and the first MRI suggestive of radionecrosis was 12 months (IQR, 17 months), and the interval between the end date of SRS/fSRT and the first detection of IRES was 16 months (IQR, 21.5 months). The median interval between the first MRI suggesting radionecrosis and the first appearance of the IRE sign was 0 months (IQR, 2 months), indicating that at least 50% of radionecrosis lesions already showed the IRE sign on the first MRI in which radionecrosis was suspected.\u0026nbsp;\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe incomplete ring enhancement sign (IRES) refers to an interruption in the ring enhancement of radionecrosis [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In the present study, we evaluated the IRES diagnostic accuracy in diagnosing RN, showing high mean sensitivity (97% [95% (CI): 87%, 99%]) and specificity (76% [95% CI: 61%, 88%]) with a concordance between observers of 0.75 in a blinded reading. The IRES can be identified on contrast-enhanced 3D T1-weighted gradient-echo sequence (CE 3D T1 GRE), making it accessible to most centers. IRES visualization in RN exhibited a high agreement of 93%, indicating it is a readily recognizable sign. Additionally, IRES was present at the time of radionecrosis suspicion in more than half of cases, supporting its potential role as an early biomarker for radionecrosis.\u003c/p\u003e\u003cp\u003eThe IRES has not been histopathologically evaluated but may correspond to the open ring pattern observed in multiple sclerosis. Br\u0026uuml;ck et al. reported early active demyelination with myelin protein-positive degradation products in macrophages, correlating with a T2 low rim and contrast enhancement [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Ring enhancement was also linked with neovascularization [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Similarly, RN shows areas of coagulative necrosis surrounded by an inflammatory infiltrate, including lymphocytes and macrophages [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] with marginal contrast enhancement bordered by gliosis and demyelination [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. IRES may represent the polarization phenomenon described in RN, characterized by an active rim of inflammatory cells and neovascularization, in contrast to interrupted enhancement [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. These findings support the hypothesis that IRES in radionecrosis may be associated with demyelination; moreover, the open-ring sign aids in distinguishing demyelinating lesions from tumors and infections, thereby favoring a demyelinating nature [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Comparable to our use of IRES for the detection of radionecrosis, previous studies have reported variable sensitivity (27%\u0026ndash;71%) but consistently high specificity (98%\u0026ndash;100%) for the diagnosis of tumefactive demyelination using open-ring enhancement [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In contrast, our findings demonstrated a high sensitivity, suggesting a high prevalence of IRES in RN.\u003c/p\u003e\u003cp\u003eAdditionally, ring fragmentation in radionecrosis was identified in 89% of cases, characterized by a progressive increase in discontinuities within the ring enhancement (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Over time, the morphology of RN evolves, with some regions enlarging and others regressing, highlighting its active nature [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This variability can be attributed to differences in radiation dose and the timing of the radiation necrosis onset. Husain et al.[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] reported that early-onset RN was characterized by demyelination plaques resembling acute multiple sclerosis, whereas late-onset RN was associated with vascular proliferation and coagulative necrosis. In animal models, vascular proliferation was also identified after lower radiation doses (75 Gy), whereas higher doses (150 Gy) resulted in coagulative necrosis and hemorrhage [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. This dynamic behavior, along with the presence of satellite lesions, anatomic boundary transgression [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], and the patchy distribution of IRES may reflect heterogeneous radiation dose distribution across subregions within the same irradiated field, as well as differences in intrinsic tissue radiosensitivity. These findings may also support our observation of a significant association between satellite lesions and RN, with rare occurrence in BM (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003cp\u003eThe pathobiology of radionecrosis remains unclear but is believed to originate from vascular and glial injury, along with an abnormal inflammatory response [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. We observed that 67% of RN appeared in border zones between two main arterial territories and 29% precisely in the periventricular white matter. Reduced perfusion in the distal regions of the vascular territories increases susceptibility to ischemia, making these areas particularly vulnerable to post-irradiation vasculopathy [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Moreover, RN has been described to progress earlier and more frequently in the subventricular zone, likely given the presence of neural stem cells in this region [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Conversely, we also found that RN commonly appears in juxtacortical regions (53%), which may be explained by the predominant localization of BM in these areas. These regions, characterized by abrupt changes in vascular caliber, are prone to metastatic emboli deposition [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. On the other hand, the abundant cortical blood supply may provide a protective effect against RN [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOur study had limitations. First, the inherent limitations of the reference standard (follow-up MRI) may have introduced verification bias. Classification did not rely on histology because surgery was replaced by a conservative approach whenever feasible. To mitigate misclassification, we applied predefined strict criteria however, this also reduced the final sample size despite an extensive initial metastases database. Interobserver variability was assessed with an inexperienced rater and yielded substantial agreement (κ\u0026thinsp;=\u0026thinsp;0.75), supporting the reproducibility of IRES. Additionally, we analyzed volume differences between cases and controls to ensure that IRE discrimination was not biased towards larger lesions. The single-center design was a limitation, but it was partially addressed by applying standardized institutional criteria for radiosurgery prescription and evaluation. However, external validation in multicenter cohorts is required to confirm generalizability. Finally, the lack of pathological correlation limits our understanding of the IRES etiopathogenesis. Future prospective studies with histopathological validation are necessary to confirm these findings.\u003c/p\u003e\u003cp\u003eThe incomplete ring enhancement sign is a reliable early imaging biomarker of brain radionecrosis supported by associated features such as fragmentation, satellite foci, and watershed localization.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBM, Brain metastases; IRES, incomplete ring enhancement sign; RN, radionecrosis; SRS/fSRT, stereotactic radiosurgery or hypofractionated stereotactic radiotherapy; CE 3D T1 GRE, contrast-enhanced 3D T1-weighted gradient-echo sequence; preRT MRI, MRI-based treatment planning\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors acknowledge the support of the Spanish Society of Neuroradiology (SENR), which awarded this work the 2024 Research Grant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no conflicts of interest related to this manuscript. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [Ortiz de Mendivil A.], [Santana-Suarez E] and [Perez-Beteta J.]. The first draft of the manuscript was written by [Ortiz de Mendivil A.] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and Consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective case-control study was approved by the Institutional Review Board (IRB), which waived the requirement for informed consent due to the use of fully anonymized imaging and clinical data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe manuscript contains no personal data of any individual.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfirmation of Sole Submission\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe confirm that this manuscript is being\u0026nbsp;submitted\u0026nbsp;solely to\u0026nbsp;Journal of Neuro-Oncology and is not under consideration elsewhere.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubject Overlap Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe confirm that there is no substantial overlap between this manuscript and any previously published work. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to express our gratitude to Mateo Rosillo for his collaboration on one of the readings conducted in this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eNayak L, Lee EQ, Wen PY (2012) Epidemiology of brain metastases. Curr Oncol Rep 14:48\u0026ndash;54. https://doi.org/10.1007/S11912-011-0203-Y\u003c/li\u003e\n\u003cli\u003eRades D, Pluemer A, Veninga T, et al (2007) Whole-brain radiotherapy versus stereotactic radiosurgery for patients in recursive partitioning analysis classes 1 and 2 with 1 to 3 brain metastases. Cancer 110:2285\u0026ndash;92. https://doi.org/10.1002/cncr.23037\u003c/li\u003e\n\u003cli\u003eSneed PK, Suh JH, Goetsch SJ, et al (2002) A multi-institutional review of radiosurgery alone vs. radiosurgery with whole brain radiotherapy as the initial management of brain metastases. Int J Radiat Oncol Biol Phys 53:519\u0026ndash;26\u003c/li\u003e\n\u003cli\u003eCi\u0026eacute;rvide R, Mart\u0026iacute; J, L\u0026oacute;pez M, et al (2025) Single and multitarget stereotactic radiosurgery (SRS) with single isocenter in the treatment of multiple brain metastases (BM): institutional experience. Clinical and Translational Oncology 2025 1\u0026ndash;15. https://doi.org/10.1007/S12094-024-03844-3\u003c/li\u003e\n\u003cli\u003ePatel TR, McHugh BJ, Bi WL, et al (2011) A comprehensive review of MR imaging changes following radiosurgery to 500 brain metastases. American Journal of Neuroradiology 32:1885\u0026ndash;1892. https://doi.org/10.3174/ajnr.A2668\u003c/li\u003e\n\u003cli\u003eHuber PE, Hawighorst H, Fuss M, et al (2001) Transient enlargement of contrast uptake on MRI after linear accelerator (linac) stereotactic radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys 49:1339\u0026ndash;1349. https://doi.org/10.1016/S0360-3016(00)01511-X\u003c/li\u003e\n\u003cli\u003eLin NU, Lee EQ, Aoyama H, et al (2015) Response assessment criteria for brain metastases: Proposal from the RANO group. Lancet Oncol 16:270\u0026ndash;278. https://doi.org/10.1016/S1470-2045(15)70057-4\u003c/li\u003e\n\u003cli\u003eRuzevick J, Kleinberg L, Rigamonti D (2014) Imaging changes following stereotactic radiosurgery for metastatic intracranial tumors: Differentiating pseudoprogression from tumor progression and its effect on clinical practice. Neurosurg Rev 37:193\u0026ndash;201. https://doi.org/10.1007/s10143-013-0504-8\u003c/li\u003e\n\u003cli\u003eOrtiz de Mendivil A, Mart\u0026iacute;n-Medina P, Garc\u0026iacute;a-Ca\u0026ntilde;amaque L, et al (2024) Challenges in radiological evaluation of brain metastases, beyond progression. Radiolog\u0026iacute;a (English Edition) 66:166\u0026ndash;180. https://doi.org/10.1016/j.rxeng.2024.03.003\u003c/li\u003e\n\u003cli\u003eKohutek ZA, Yamada Y, Chan TA, et al (2015) Long-term risk of radionecrosis and imaging changes after stereotactic radiosurgery for brain metastases. J Neurooncol 125:149\u0026ndash;56. https://doi.org/10.1007/s11060-015-1881-3\u003c/li\u003e\n\u003cli\u003eBarajas RF, Chang JS, Sneed PK, et al (2009) Distinguishing recurrent intra-axial metastatic tumor from radiation necrosis following gamma knife radiosurgery using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging. AJNR Am J Neuroradiol 30:367\u0026ndash;372. https://doi.org/10.3174/ajnr.A1362\u003c/li\u003e\n\u003cli\u003eOca\u0026ntilde;a-Tienda B, P\u0026eacute;rez-Beteta J, Jim\u0026eacute;nez-S\u0026aacute;nchez J, et al (2023) Growth exponents reflect evolutionary processes and treatment response in brain metastases. NPJ Syst Biol Appl 9:. https://doi.org/10.1038/S41540-023-00298-1\u003c/li\u003e\n\u003cli\u003eP\u0026eacute;rez-Garc\u0026iacute;a VM, Calvo GF, Bosque JJ, et al (2020) Universal scaling laws rule explosive growth in human cancers. Nat Phys 16:1232\u0026ndash;1237. https://doi.org/10.1038/S41567-020-0978-6\u003c/li\u003e\n\u003cli\u003eOca\u0026ntilde;a-Tienda B, Perez-Beteta J, Molina-Garc\u0026iacute;a D, et al (2023) Growth dynamics of brain metastases differentiate radiation necrosis from recurrence. Neurooncol Adv 5:. https://doi.org/10.1093/noajnl/vdac179\u003c/li\u003e\n\u003cli\u003eShah R, Vattoth S, Jacob R, et al (2012) Radiation necrosis in the brain: Imaging features and differentiation from tumor recurrence. Radiographics 32:1343\u0026ndash;1359. https://doi.org/10.1148/rg.325125002\u003c/li\u003e\n\u003cli\u003eVellayappan B, Tan CL, Yong C, et al (2018) Diagnosis and Management of Radiation Necrosis in Patients With Brain Metastases. Front Oncol 8:395. https://doi.org/10.3389/FONC.2018.00395/BIBTEX\u003c/li\u003e\n\u003cli\u003eVan Den Bent MJ, Dhermain FG, Hau P, et al (2010) Advanced MRI and PET imaging for assessment of treatment response in patients with gliomas. Lancet Neurol 9:906\u0026ndash;926. https://doi.org/10.1016/S1474\u003c/li\u003e\n\u003cli\u003eArmitage PA, Schwindack C, Bastin ME, Whittle IR (2007) Quantitative assessment of intracranial tumor response to dexamethasone using diffusion, perfusion and permeability magnetic resonance imaging. Magn Reson Imaging 25:303\u0026ndash;310. https://doi.org/10.1016/J.MRI.2006.09.002\u003c/li\u003e\n\u003cli\u003eLasocki A, Sia J, Stuckey SL (2022) Improving the diagnosis of radiation necrosis after stereotactic radiosurgery to intracranial metastases with conventional MRI features: a case series. Cancer Imaging 22:. https://doi.org/10.1186/s40644-022-00470-6\u003c/li\u003e\n\u003cli\u003eHoefnagels FW a, Lagerwaard FJ, Sanchez E, et al (2009) Radiological progression of cerebral metastases after radiosurgery: Assessment of perfusion MRI for differentiating between necrosis and recurrence. J Neurol 256:878\u0026ndash;887. https://doi.org/10.1007/s00415-009-5034-5\u003c/li\u003e\n\u003cli\u003eBr\u0026uuml;ck W, Bitsch A, Kolenda H, et al (1997) Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann Neurol 42:783\u0026ndash;793. https://doi.org/10.1002/ANA.410420515\u003c/li\u003e\n\u003cli\u003eKobayashi M, Shimizu Y, Shibata N, Uchiyama S (2014) Gadolinium enhancement patterns of tumefactive demyelinating lesions: Correlations with brain biopsy findings and pathophysiology. J Neurol 261:1902\u0026ndash;1910. https://doi.org/10.1007/s00415-014-7437-1\u003c/li\u003e\n\u003cli\u003eJagannathan J, Bourne TD, Schlesinger D, et al (2010) Clinical and pathological characteristics of brain metastasis resected after failed radiosurgery. Neurosurgery 66:208\u0026ndash;217. https://doi.org/10.1227/01.NEU.0000359318.90478.69\u003c/li\u003e\n\u003cli\u003eYoshii Y (2008) Pathological review of late cerebral radionecrosis. Brain Tumor Pathol 25:51\u0026ndash;58. https://doi.org/10.1007/S10014-008-0233-9/METRICS\u003c/li\u003e\n\u003cli\u003eMasdeu JC, Quinto ; C, Olivera ; C, et al (1427) Open-ring imaging sign Highly specific for atypical brain demyelination\u003c/li\u003e\n\u003cli\u003eMabray MC, Cohen BA, Villanueva-Meyer JE, et al (2015) Performance of apparent diffusion coefficient values and conventional MRI features in differentiating tumefactive demyelinating lesions from primary brain neoplasms. American Journal of Roentgenology 205:1075\u0026ndash;1085. https://doi.org/10.2214/AJR.14.13970\u003c/li\u003e\n\u003cli\u003eNakayama M, Naganawa S, Ouyang M, et al (2021) A review of clinical and imaging findings in tumefactive demyelination. American Journal of Roentgenology 217:186\u0026ndash;197. https://doi.org/10.2214/AJR.20.23226\u003c/li\u003e\n\u003cli\u003eHusain MM, Garcia JH (1976) Cerebral \u0026ldquo;Radiation Necrosis\u0026rdquo;: Vascular and Glial Features\u003c/li\u003e\n\u003cli\u003eSpiegelmann R, Friedman WA, Bova FJ, et al (1993) LINAC radiosurgery: an animal model\u003c/li\u003e\n\u003cli\u003eAl-Rubaiey S, Senger C, Bukatz J, et al (2024) Determinants of cerebral radionecrosis in animal models: A systematic review. Radiotherapy and Oncology 199\u003c/li\u003e\n\u003cli\u003eRahmathulla G, Marko NF, Weil RJ (2013) Cerebral radiation necrosis: A review of the pathobiology, diagnosis and management considerations. Journal of Clinical Neuroscience 20:485\u0026ndash;502\u003c/li\u003e\n\u003cli\u003eValk PE, Dillon WP Radiation Injury of the Brain\u003c/li\u003e\n\u003cli\u003eHwang TL, Close TP, Grego JM, et al (1996) Predilection of brain metastasis in gray and white matter junction and vascular border zones. Cancer 77:1551\u0026ndash;1555. https://doi.org/10.1002/(SICI)1097-0142(19960415)77:8\u0026lt;1551::AID-CNCR19\u0026gt;3.0.CO;2-Z\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Brain, Radionecrosis, Metastases, Incomplete ring enhancement sign, Treatment-related inflammatory changes, Magnetic resonance imaging (MRI)","lastPublishedDoi":"10.21203/rs.3.rs-8090402/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8090402/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003ePURPOSE\u003c/b\u003e\u003c/p\u003e\u003cp\u003eDifferentiating brain radionecrosis from recurrent metastases after radiotherapy remains challenging due to the lack of definitive imaging tool modality. This study evaluated the diagnostic accuracy of the \u0026ldquo;incomplete ring enhancement sign\u0026rdquo; on contrast-enhanced 3D T1-weighted gradient-echo sequence (CE 3D T1 GRE) as a biomarker of radionecrosis and analyzed additional associated features.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMETHODS\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIn this retrospective case-control study, 45 cases of radionecrosis were identified from an institutional database of 1,179 brain metastases consecutively treated with stereotactic radiotherapy (2015\u0026ndash;2022). Ninety CE 3D T1 GRE (45 radionecrosis and 45 matched metastases controls from the same patients obtained before radiotherapy) were randomly reviewed under blinded conditions, as observers were unaware of whether each case corresponded to metastases or to radionecrosis. The presence of an incomplete ring enhancement sign was assessed, and diagnostic performance was calculated. Interobserver agreement was evaluated using Fleiss\u0026rsquo;s kappa. Fragmentation, satellite lesions, and lesion distribution were compared using χ\u0026sup2;.\u003c/p\u003e\u003cp\u003e\u003cb\u003eRESULTS\u003c/b\u003e\u003c/p\u003e\u003cp\u003eSensitivity was 97% (95% CI, 87\u0026ndash;99) and specificity 76% (95% CI, 61\u0026ndash;88). Interobserver agreement was good (k\u0026thinsp;=\u0026thinsp;0.75). Incomplete ring enhancement appeared in 50% of the MRIs where radionecrosis was initially suspected. Fragmentation occurred in 89% of radionecrosis cases compared to 2% of metastases (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and satellite lesions in 29% vs. 2%, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Watershed localization was found in 67% of radionecrosis cases.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCONCLUSION\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe incomplete ring enhancement sign is an early and reliable imaging biomarker of brain radionecrosis supported by associated features such as fragmentation, satellite foci, and watershed localization.\u003c/p\u003e","manuscriptTitle":"Imaging MRI Biomarkers for Diagnosing Brain Radionecrosis: Focus on Incomplete Ring Enhancement Sign","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-26 06:33:48","doi":"10.21203/rs.3.rs-8090402/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"90fa63b5-f5c7-4654-90bf-047acf7aa051","owner":[],"postedDate":"November 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-02T01:38:45+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-26 06:33:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8090402","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8090402","identity":"rs-8090402","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}