Prognostic value of pretreatment metabolic tumor volume on [S-methyl-11C]-L-methionine PET/CT in patients with local non-small cell lung carcinoma treated with single-fraction carbon-ion radiotherapy

Prognostic value of pretreatment metabolic tumor volume on [S-methyl-11C]-L-methionine PET/CT in patients with local non-small cell lung carcinoma treated with single-fraction carbon-ion radiotherapy | 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 Prognostic value of pretreatment metabolic tumor volume on [S-methyl- 11 C]-L-methionine PET/CT in patients with local non-small cell lung carcinoma treated with single-fraction carbon-ion radiotherapy Kentaro Tamura, Ryuichi Nishii, Atsushi B Tsuji, Jitsuro Tsukada, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6310988/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Jun, 2025 Read the published version in Annals of Nuclear Medicine → Version 1 posted 4 You are reading this latest preprint version Abstract Purpose: This study aimed to evaluate the prognostic predictive ability of MET-PET/CT-derived imaging biomarkers in patients with localized non-small cell lung cancer (NSCLC) undergoing single-fraction carbon-ion radiotherapy (CIRT) and to clarify the additional prognostic information these biomarkers can provide beyond the standard UICC staging protocol. Methods: With institutional review board approval, 67 localized NSCLC patients eligible for CIRT between 2007 and 2012 were included. Single-fraction doses of 40-50 Gy were irradiated. MET-PET imaging using the Toshiba Aquiduo or Siemens Biograph 16 commenced 20 minutes post 740MBq MET injection before CIRT. Experienced radiologists analyzed the images, defining metabolic tumor volume (MTV) as areas with SUV >1.5. Statistical analysis was performed using SPSS 29, including Cox proportional hazard models for disease-free and overall survival. Results: Seven cases with Tis of T stage were excluded because of low MET radiotracer uptake. A total of 60 patients were analyzed: 36 males and 24 females with a mean age of 73 years; 35 cases of T1, 24 cases of T2, and one T3 case. The average follow-up period was 74.3 months. The univariate Cox proportional hazard analyses showed that SUVmax, MTV, and total lesion retention (TLR) correlated with disease-free survival (DFS), while no significant difference was noted in treatment dose. For overall survival (OS), solid tumor diameter, SUVmax, MTV, TLR, and sex showed significant correlations in the univariate analysis. The multivariate analysis identified MTV as the only significant prognostic factor for both DFS and OS. Kaplan-Meier survival curves further supported these findings, with log-rank tests indicating a significant difference in survival duration related to MTV in both DFS and OS. Conclusion: MTV in pretreatment MET-PET/CT would be a valuable predictor of DFS and OS of localized NSCLC treated with single-fraction CIRT. Metabolic tumor volume Methionine PET/CT Amino Acid PET/CT Non-Small Cell Lung Cancer Figures Figure 1 Figure 2 Figure 3 Introduction Lung cancer remains the most common cancer diagnosis worldwide and continues to be the leading cause of cancer deaths[ 1 ]. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancer cases[ 2 ]. The prognosis worsens significantly as the disease advances, with 5-year survival rates dropping from 74.9% in Stage I to 55.3% in Stage II, 32.0% in Stage IIIA, 20.4% in Stage IIIB, and a mere 5.8% in Stage IV[ 3 ]. While surgery remains the standard of care for resectable tumors, recent advances in radiation therapy, including combined chemoradiation approaches, have emerged as valuable alternatives, particularly for elderly patients and those with compromised lung function who cannot undergo surgery. These therapeutic advances have enhanced our ability to control local disease, providing effective options when surgery isn't feasible. Carbon-ion radiotherapy (CIRT), an innovative form of particle therapy, shows particular promise in this context, offering both precise dose delivery and enhanced biological effectiveness while sparing surrounding healthy tissues [ 4 ]. The advent of PET/CT imaging has revolutionized our ability to assess tumor metabolism through quantitative measurements of radiotracer uptake. Given that cancer cells typically show increased glucose consumption, 18 F-fluorodeoxyglucose (FDG) PET/CT has become crucial in lung cancer management, enabling comprehensive evaluation of primary tumors, lymph node involvement, and distant spread[ 5 ]. Several quantitative markers derived from FDG-PET/CT, including standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), have demonstrated prognostic value in lung cancer[ 6 – 9 ]. While FDG remains the cornerstone of PET imaging in lung cancer staging[ 10 ], emerging evidence points to the potential value of amino acid PET[ 11 ]. [S-methyl- 11 C]-L-methionine (MET) is a key amino acid tracer. Kubota et al. demonstrated that MET-PET can clearly delineate lung cancer lesions with high contrast[ 12 ]. MET-PET is more specific than FDG-PET for neoplastic lesions and is useful in differentiating between benign and malignant nodules[ 13 , 14 ]. MET-PET/CT has also been shown to be useful for staging lung cancer because MET-PET/CT shows higher specificity than FDG-PET/CT, whereas inflammatory accumulation in hilar lymph nodes interferes with the diagnosis of metastatic disease in East Asian populations[ 15 , 16 ]. Despite the accumulating clinical experience with MET and substantial evidence supporting its diagnostic value in lung cancer, its prognostic implications haven't been fully explored. Some studies suggest that MET-PET might be as effective as FDG-PET in monitoring radiation therapy response[ 17 ], highlighting its potential dual role in diagnosis and prognosis. Miyazawa reported that tracer uptake of MET-PET in NSCLC reflects the proliferative activity of tumor cells[ 18 ]. MET is predominantly internalized into cells via the Na⁺-independent transporter known as L-type amino acid transporter 1 (LAT1)[ 19 ]. LAT1 is highly expressed in malignant neoplasms, and elevated LAT1 expression has been demonstrated to correlate with poor prognosis in lung cancer and various other malignancies[ 20 – 26 ]. The cellular mechanisms linking MET uptake with tumor proliferation and the correlation between LAT1 expression and prognosis have been well established. However, the direct relationship between MET PET uptake parameters and clinical outcomes in NSCLC patients remains unexplored, particularly in the context of CIRT. In this retrospective analysis, we examined MET-PET/CT scans obtained before CIRT in patients with localized NSCLC. We sought to understand how imaging biomarkers derived from MET-PET/CT relate to patient outcomes, aiming to shed light on MET-PET's potential role in guiding NSCLC treatment decisions. Materials and Methods Patient Selection The study was conducted with approval from the institutional review board. Patients who were eligible for CIRT with a single fraction were selected from our institutional database between August 2007 and February 2012. At the time of treatment, patients were staged according to the Japan Lung Cancer Society criteria 6th edition (valid until 2009) and AJCC/UICC 6th edition, where tumors up to 7 cm were classified as T2, potentially qualifying for single-fraction CIRT. For this retrospective analysis, we reclassified all patients according to the current UICC 8th edition criteria, resulting in a cohort that includes some cases now classified as Stage IIB. Therefore, while all patients were initially considered appropriate candidates for single-fraction CIRT based on contemporary staging criteria, the retrospective reclassification revealed a broader range of disease stages than would be classified as 'early-stage' by current standards. Among these, 67 consecutive patients underwent MET-PET/CT scans using either Aquiduo (Toshiba Medical Systems, Tochigi, Japan) or Biograph 16 (Siemens Medical Systems, Nashville, TN, USA). The average age of the participants was 73.2 years, with an age range of 51–89 years; the cohort included 43 males and 24 females. All patients who were eligible for CIRT treatment during this period underwent MET-PET/CT scans. Seven cases at the clinical T-stage of Tis were excluded due to extremely low radiotracer accumulation, which prevented reliable quantitative analysis. CIRT CIRT was performed at QST hospital. A single irradiation protocol of CIRT for stage I lung cancer was originally designed as a dose-escalation trial, as previously reported[ 27 ]. The dose-escalation trial, which began in 2003, initially started treatments at a irradiation dose of 28 Gy. The included patients in the present study are those treated after August 2007 in the trial, receiving dosage levels ranging from 40 to 50 Gy (described as the relative biological effect [RBE]-weighted dose based on the modified microdosimetric kinetic model). As described above, when reclassified according to current UICC-8 criteria, some patients now fall into the Stage IIB category. Follow-up and Assessment As part of the follow-up, almost all patients underwent regular blood tests, CT scans, and PET/CT scans at our facility. The initial follow-up examination was conducted 4 weeks after treatment, followed by repeat examinations every 3 months for at least two years. Subsequently, check-ups were carried out every 6 months over a period of 5 years. For patients unable to visit our facility, we also conducted postal surveys. Local recurrence and metastases were defined based on findings from CT and PET/CT scans, as well as increases in tumor marker levels in blood tests. Radiotracer Preparation and PET Imaging Protocol The study used two whole-body PET/CT scanners: the Biograph 16 (Siemens Healthcare, Nashville, TN, USA) and the Aquiduo PET/CT (Toshiba Medical Systems, Tochigi, Japan). The choice of which PET/CT scanner to use was determined randomly in accordance with our clinical practice. MET administered for the imaging was synthesized in our facility's cyclotron. Patients were given an intravenous injection of 740 MBq of MET, and imaging commenced 20 minutes post-injection. Emission data were acquired for 3 minutes per bed position. PET images were reconstructed using iterative algorithms (4 iterations, 24 subsets) with an 8-mm Gaussian filter, a 256 × 256 matrix (2mm/pixel), and a 2 mm slice thickness. Whole-body spiral CT scanning was performed under the following parameters: 120 kV; automatic exposure control; 512 × 512 matrix; beam pitch of 0.94; and a 2 mm × 16-row mode. The CT data were used for attenuation correction. Measurement of PET/CT Parameters All images were analyzed by a board-certified diagnostic radiologist with over ten years of experience using AW Server 3.2 (GE Healthcare, MI, USA). Tumor size was measured on transaxial slices, defined as the longest diameter of the solid component. To delineate the metabolic tumor volume (MTV), we applied a fixed threshold SUV of 1.5 in the volume of interest (VOI). Although this cutoff is not yet standardized for MET-PET, we selected 1.5 based on the commonly used threshold of 2.5 for FDG-PET and the generally lower uptake of MET compared with FDG. We also considered the potential prognostic utility of a fixed-threshold approach. MTV was then semi-automatically generated within the VOI, and SUVmax was calculated automatically. Total lesion retention (TLR) was calculated by multiplying MTV by the mean SUV (SUVmean) within the delineated volume, providing a parameter that incorporates both volumetric and metabolic information. This calculation is analogous to total lesion glycolysis (TLG) in FDG-PET studies but reflects methionine retention rather than glucose metabolism. All measurements were corroborated by PET/CT fusion images to ensure accurate localization and quantification. Statistical Analysis All values were calculated as means ± standard deviations. Statistical analyses were performed using SPSS 29 (SPSS, Chicago, IL, USA), with p -values of less than 0.05 considered statistically significant. Univariate Cox proportional hazard analysis was conducted for both disease-free survival (DFS) and overall survival (OS), considering factors such as age, sex, treatment dose, tumor diameter, SUVmax, MTV, and TLR. Both disease-free survival (DFS) and overall survival (OS) were calculated from the date of CIRT to the date of the event or last follow-up. DFS events were defined as local recurrence, regional or distant metastasis, or death from any cause, while OS events were defined as death from any cause. The cutoff value was determined using the Youden Index, selecting the threshold that maximized the sum of sensitivity and specificity. We used Pearson's correlation coefficient to examine the correlation between variables to prevent multicollinearity. Variables with a Pearson correlation coefficient exceeding 0.8 were considered to have multicollinearity. While most variables showed a coefficient below 0.8, MTV and TLR exceeded this threshold, indicating multicollinearity between them. Therefore, TLR was excluded from the subsequent multivariate Cox proportional hazard analysis. In addition to these analyses, Kaplan-Meier survival curves were plotted to visually assess and compare DFS and OS across different groups or variables with the log-rank test. Results The clinical and pathological characteristics of the patients are summarized in Table 1. Figure 1 shows representative MET-PET/CT images demonstrating the typical uptake pattern in NSCLC lesions before CIRT. Out of 60 cases, 36 were male and 24 were female. The mean age of the patients was 73.3 ± 9.3 years, ranging from 51 to 89 years old. All individuals were pathologically confirmed to have cancer, with 45 cases being adenocarcinoma, 14 cases being squamous cell carcinoma, and one other case included. The T factor included 35 cases of T1, 24 cases of T2, and 1 case of T3 with UICC-8 criteria. No lymph node metastases or distant metastases were confirmed prior to treatment. The treatment dose ranged from 40Gy to 44Gy in 25 cases and from 46Gy to 50Gy in 35 cases. Imaging was performed on 31 cases using the Toshiba Aquiduo and 29 using the Siemens Biograph 16. The follow-up period was 74.3 ± 37.4 months. During the follow-up period, 7 patients developed local recurrence, 8 experienced nodal recurrence (with overlap in 2 patients who also had local recurrence), and 10 had distant metastases. In addition, 1 patient showed both nodal and distant metastases. Overall, 14 patients died of lung cancer and 11 died from other causes. The average tumor diameter was 2.74 ± 1.00 cm, with a mean SUVmax value of 3.53 ± 1.92. The mean metabolic tumor volume (MTV) was 12.4 ± 15.22 ml. To determine the optimal cutoff values for predicting disease recurrence, receiver operating characteristic (ROC) curve analysis was performed (Fig. 2). The cutoff values were selected to optimize the balance between sensitivity and specificity. In the disease-free survival (DFS) analysis, the most discriminative cutoff values were a solid tumor diameter of 2.9 cm (sensitivity 61.5%, specificity 64.7%), an SUVmax value of 2.5 (sensitivity 80.8%, specificity 50.0%), and an MTV of 6.0 ml (sensitivity 76.9%, specificity 64.7%). Among these parameters, MTV provided the most balanced combination of sensitivity and specificity for predicting disease recurrence. The results of the univariate and multivariate Cox proportional hazard analysis for DFS and OS are shown in Table 2. In the univariate analysis for DFS, SUVmax (hazard ratio (HR) 3.2, p < 0.05), MTV (HR 4.5, p < 0.005), and Total lesion retention (TLR) (HR 4.0, p < 0.005) were found to be significantly correlated with disease recurrence. No significant difference was observed in terms of treatment dose. For overall survival, the univariate analysis revealed significant correlations with solid tumor diameter (HR 2.4, p < 0.05), SUVmax (HR 2.9, p < 0.05), MTV (HR 4.7, p < 0.001), TLR (HR 4.8, p < 0.001), and sex (HR 0.6, p < 0.05). Both MTV and TLR demonstrated particularly strong prognostic values with HRs above 4.5 and high statistical significance (p < 0.001). A high correlation was observed between MTV and TLR. Considering multicollinearity, TLR was excluded from the multivariate analysis. Upon performing multivariate Cox Hazard analysis (forced entry method) with tumor longest diameter, SUVmax, MTV, age, and sex, only MTV remained as a significant independent prognostic factor for both DFS (HR 3.9, p < 0.05) and OS (HR 4.3, p < 0.05). These results demonstrate that patients with MTV ≥ 6ml had approximately four times higher risk of both disease recurrence and death compared to those with MTV < 6ml, even after adjusting for other clinicopathological factors. For visual assessment, Kaplan-Meier survival curves were analyzed for both DFS and OS (Fig. 3A, 3B). Log-rank tests revealed a significant difference in survival duration related to MTV in DFS and OS. Discussion Our study reveals a strong correlation between the MTV captured by MET-PET and the prognosis of localized lung cancer patients treated with single-fractionated CIRT. Volumetric parameters like MTV can comprehensively capture tumor characteristics and biological behavior, offering a more complete evaluation than non-volumetric measures like SUVmax. Although MET is more conventionally used for brain tumor imaging, our study emphasizes its value in lung cancer assessment. In our multivariate analysis, MTV in MET-PET emerged as the sole independent prognostic factor, while SUVmax, tumor diameter, and treatment dose did not retain statistical significance. The superiority of MTV over SUVmax can be explained by their inherent measurement differences. While SUVmax captures only the single most metabolically active point within the tumor, MTV represents the entire volume of metabolically active tissue, providing a more comprehensive assessment of tumor burden and total LAT1-expressing cells. Im et al. showed in their meta-analysis of FDG-PET in NSCLC that this volumetric approach better reflects the overall tumor metabolism and is less susceptible to sampling bias than single-voxel measurements[ 28 ]. However, previous FDG-PET studies in patients treated by stereotactic body radiotherapy with stage I NSCLC have primarily relied on SUVmax, and investigations into volumetric parameters have yielded conflicting results[ 29 , 30 ]. In contrast, our present study showed that MET-PET provided a robust volumetric parameter, MTV, that may offer more accurate prognostic information and potentially guide CIRT more effectively than SUVmax alone. Moreover, MET-PET’s volumetric assessment may prove useful beyond CIRT by aiding pre-treatment evaluation for other local therapies such as stereotactic body radiation therapy or radiofrequency ablation. In this study, tumor diameter (T stage) did not show a significant association with DFS, but it did reach significance for OS. In our previous report with a larger cohort[ 27 ], tumor diameter was significantly correlated with both DFS and OS. Specifically, we found that tumors classified as T1a or T1b, measuring 2 cm or less according to the UICC 8th edition, showed favorable outcomes, whereas tumors exceeding 5 cm (T3) presented difficulties in achieving local control. The discrepancy between the present findings and our earlier research may be explained by the smaller sample size in this study, which lowered statistical power, and by the exclusion of Tis cases, leading to a more homogeneous T-stage distribution. Meanwhile, MTV reflects both the anatomical size of tumors and their metabolic activity. In relatively small tumors, biological aggressiveness and metastatic potential do not always align with their diameter. Thus, MTV can provide a more comprehensive assessment than size alone, highlighting its potential utility in clinical practice. The current study provided no significant association between treatment dose and prognosis. In our previous analysis, we likewise found no statistically significant difference in local control between patients receiving 36 to 42 Gy [RBE] and those treated with 44 Gy [RBE] or more, suggesting that once the dose surpasses approximately 40 Gy [RBE], CIRT exerts sufficiently potent tumoricidal activity. The present findings are thus consistent with our earlier observations. Nevertheless, local control may be further improved at doses of 48 Gy [RBE] or above, indicating the potential benefits of higher dose escalation in selected cases. While MET is a natural amino acid and can be taken up by various amino acid transporters, its primary cellular entry route is through the LAT1 transporter[ 19 , 31 ]. This is especially relevant as malignant tumors often overexpress the LAT1 transporter[ 20 , 32 ], enhancing MET's specificity and potential utility. LAT1 expression strongly correlates with prognosis in resectable NSCLC[ 21 ]. This prognostic stratification is particularly valuable in radiation therapy settings where lymph node dissection (a key advantage of surgical approaches) is not performed. Kumasaka et al. demonstrated that FAMT-PET, which specifically targets LAT1, provides superior prognostic discrimination compared to FDG-PET[ 21 , 33 , 34 ], with an MTV > 7.0 ml (SUV > 1.2) associated with poorer survival (HR 3.14). Our findings using MET-PET with a threshold of SUV > 1.5 and a cutoff of 6.0 ml yielded comparable results, confirming the prognostic significance of LAT1-mediated transport across different tracers and treatment modalities. Importantly, our study validates this prognostic value specifically in localized disease, offering a non-invasive approach to risk stratification that can guide clinical decision-making for early-stage NSCLC patients. This study has several limitations that should be acknowledged. First, this is a retrospective single-institution study with a relatively small sample size (n = 60), which may limit the generalizability of our findings. The statistical power might be insufficient to detect smaller effects, potentially explaining why some variables did not reach statistical significance in multivariate analysis. Second, the SUV threshold of 1.5 used for MTV delineation was selected based on empirical considerations rather than standardized criteria, as no established cutoff exists for MET-PET in lung cancer. Finally, external validation in a larger, multi-institutional prospective cohort would be necessary to confirm the prognostic value of MET-PET-derived MTV. Despite these limitations, our findings provide valuable insights into the potential utility of MET-PET as a prognostic biomarker in early-stage NSCLC treated with single-fractionated carbon-ion radiotherapy. Conclusion MTV in pretreatment MET-PET/CT would be a valuable predictor of DFS and OS of localized NSCLC treated with CIRT. This finding suggests that MET-PET/CT could be integrated into risk stratification to guide personalized treatment decisions for patients with localized NSCLC. Abbreviations MET, [S‑methyl‑ 11 C]‑L‑methionine; PET, Positron Emission Tomography; NSCLC, Non-Small Cell Lung Cancer; MTV, Metabolic Tumor Volume; 18 F-FDG, 18 F-Fluorodeoxyglucose; 18 F-FAMT, L- [3- 18 F]-α-methyltyrosine Declarations Funding information: none Conflicts of interest: There are no conflicts of interest to declare. Authors contribution KT and RN were responsible for the research, wrote the main manuscript text as the first author (KT) and the corresponding author (TH) responsible for this study, and coordinated and supervised the entire study. TM is a radiological technologist responsible for PET/CT scans and image reconstruction for this study. 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Tables Tables 1 to 3 are available in the Supplementary Files section Supplementary Files METTables.pptx Cite Share Download PDF Status: Published Journal Publication published 30 Jun, 2025 Read the published version in Annals of Nuclear Medicine → Version 1 posted Reviewers agreed at journal 30 Mar, 2025 Reviewers invited by journal 27 Mar, 2025 Editor assigned by journal 26 Mar, 2025 First submitted to journal 26 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6310988","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":435066178,"identity":"e208c14b-1115-4e64-b882-21a3d0a4a70a","order_by":0,"name":"Kentaro Tamura","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-9176-7140","institution":"Fujita Health University","correspondingAuthor":true,"prefix":"","firstName":"Kentaro","middleName":"","lastName":"Tamura","suffix":""},{"id":435066179,"identity":"73d0815c-7b9c-4f8e-80e4-e6dc079cc10b","order_by":1,"name":"Ryuichi Nishii","email":"","orcid":"","institution":"Department of Integrated Health Sciences, Graduate School of Medicine, Nagoya University","correspondingAuthor":false,"prefix":"","firstName":"Ryuichi","middleName":"","lastName":"Nishii","suffix":""},{"id":435066180,"identity":"484e33ec-fc0d-45cb-8022-a22c30928235","order_by":2,"name":"Atsushi B Tsuji","email":"","orcid":"","institution":"Institute for Quantum Medical Science","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"B","lastName":"Tsuji","suffix":""},{"id":435066181,"identity":"1e7c87ac-2a79-4360-a531-71bdc0e7be7f","order_by":3,"name":"Jitsuro Tsukada","email":"","orcid":"","institution":"Keio University, Schoold of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jitsuro","middleName":"","lastName":"Tsukada","suffix":""},{"id":435066182,"identity":"ad5fa083-563a-4c18-afaf-7d790abe161d","order_by":4,"name":"Takamasa Maeda","email":"","orcid":"","institution":"National Institutes for Quantum Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Takamasa","middleName":"","lastName":"Maeda","suffix":""},{"id":435066183,"identity":"8a4929cc-9c36-4983-9304-64079f850920","order_by":5,"name":"Mio Nakajima","email":"","orcid":"","institution":"National Institutes for Quantum Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Mio","middleName":"","lastName":"Nakajima","suffix":""},{"id":435066184,"identity":"b5a7757a-38cf-44d6-96fe-68311d2bd13f","order_by":6,"name":"Shigeru Yamada","email":"","orcid":"","institution":"National Institutes for Quantum Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Shigeru","middleName":"","lastName":"Yamada","suffix":""},{"id":435066185,"identity":"f12968dc-33ac-40cf-b84c-6f1ebc95cab7","order_by":7,"name":"Hitoshi Ishikawa","email":"","orcid":"","institution":"National Institutes for Quantum Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Hitoshi","middleName":"","lastName":"Ishikawa","suffix":""},{"id":435066186,"identity":"54faa5ad-6436-46d7-972d-53457a9d77a1","order_by":8,"name":"Kana Yamazaki","email":"","orcid":"","institution":"National Institutes for Quantum Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Kana","middleName":"","lastName":"Yamazaki","suffix":""},{"id":435066187,"identity":"b132f504-4a36-40e0-977c-1513355ee94d","order_by":9,"name":"Tatsuya Higashi","email":"","orcid":"https://orcid.org/0000-0002-8338-4737","institution":"National Institutes for Quantum Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Tatsuya","middleName":"","lastName":"Higashi","suffix":""},{"id":435066188,"identity":"209b2bb6-c977-42d2-b90e-14d522c167c6","order_by":10,"name":"Masahiro Jinzaki","email":"","orcid":"","institution":"Keio University, School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Masahiro","middleName":"","lastName":"Jinzaki","suffix":""}],"badges":[],"createdAt":"2025-03-26 09:52:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6310988/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6310988/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12149-025-02067-y","type":"published","date":"2025-06-30T15:57:15+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":80812385,"identity":"3e425e30-a20e-405b-9b04-e880f4b307ab","added_by":"auto","created_at":"2025-04-17 10:37:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":113262,"visible":true,"origin":"","legend":"\u003cp\u003eMET-PET/CT images. A. Thoracic Maximum Intensity Projection (MIP) image. A strong tumoral uptake of MET is observed in the right lung. Physiological uptake is also seen in the salivary glands, bone marrow, liver, and pancreas. B. Axial PET image. Clear uptake is noted in the tumor located in the upper lobe of the right lung. C. CT image. An irregularly marginated tumor is visible in the upper lobe of the right lung.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6310988/v1/e01bfedf8a4cd165f7f6f85b.png"},{"id":80814055,"identity":"ed4768df-0b11-49ab-81fa-d8530c0c3c94","added_by":"auto","created_at":"2025-04-17 10:45:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":104130,"visible":true,"origin":"","legend":"\u003cp\u003eReceiver operating characteristic (ROC) curves for Diameter, MTV, and SUVmax in predicting tumor recurrence. The x-axis represents the false positive rate (FPR), and the y-axis represents the true positive rate (TPR). The area under the curve (AUC) was 0.68 for Diameter, 0.69 for MTV, and 0.64 for SUVmax, indicating that MTV provided the highest discriminative performance among the three parameters.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6310988/v1/d44345960601fb88cd025a3a.png"},{"id":80812386,"identity":"6f97cff9-cb77-4e76-90c7-2c36e9ee7400","added_by":"auto","created_at":"2025-04-17 10:37:43","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":87489,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival rates of patients following carbon ion radiotherapy. A. In Disease-Free Survival (DFS), patients with a metabolic tumor volume (MTV) greater than 6 ml exhibited a significantly poorer survival rate compared to those with less than 6 ml (Log Rank \u0026lt; 0.001). B. For Overall Survival (OS), patients with an MTV over 6 ml also showed a significantly lower survival rate compared to those with an MTV under 6 ml.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6310988/v1/bc15113c2209607141230f9d.png"},{"id":86178943,"identity":"219a52bc-bb2c-47fc-bdc7-8c49a4cf23a3","added_by":"auto","created_at":"2025-07-07 16:12:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":855206,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6310988/v1/be31f5e2-ac39-495c-8665-39e53c6be819.pdf"},{"id":80814054,"identity":"6d5aa25d-ba7f-487f-bda6-98a7abb3bbb1","added_by":"auto","created_at":"2025-04-17 10:45:43","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":54336,"visible":true,"origin":"","legend":"","description":"","filename":"METTables.pptx","url":"https://assets-eu.researchsquare.com/files/rs-6310988/v1/aa99f77f1edd06222d0bee1c.pptx"}],"financialInterests":"","formattedTitle":"\u003cp\u003ePrognostic value of pretreatment metabolic tumor volume on [S-methyl-\u003csup\u003e11\u003c/sup\u003eC]-L-methionine PET/CT in patients with local non-small cell lung carcinoma treated with single-fraction carbon-ion radiotherapy\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLung cancer remains the most common cancer diagnosis worldwide and continues to be the leading cause of cancer deaths[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancer cases[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The prognosis worsens significantly as the disease advances, with 5-year survival rates dropping from 74.9% in Stage I to 55.3% in Stage II, 32.0% in Stage IIIA, 20.4% in Stage IIIB, and a mere 5.8% in Stage IV[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. While surgery remains the standard of care for resectable tumors, recent advances in radiation therapy, including combined chemoradiation approaches, have emerged as valuable alternatives, particularly for elderly patients and those with compromised lung function who cannot undergo surgery. These therapeutic advances have enhanced our ability to control local disease, providing effective options when surgery isn't feasible. Carbon-ion radiotherapy (CIRT), an innovative form of particle therapy, shows particular promise in this context, offering both precise dose delivery and enhanced biological effectiveness while sparing surrounding healthy tissues [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe advent of PET/CT imaging has revolutionized our ability to assess tumor metabolism through quantitative measurements of radiotracer uptake. Given that cancer cells typically show increased glucose consumption, \u003csup\u003e18\u003c/sup\u003eF-fluorodeoxyglucose (FDG) PET/CT has become crucial in lung cancer management, enabling comprehensive evaluation of primary tumors, lymph node involvement, and distant spread[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Several quantitative markers derived from FDG-PET/CT, including standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), have demonstrated prognostic value in lung cancer[\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile FDG remains the cornerstone of PET imaging in lung cancer staging[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], emerging evidence points to the potential value of amino acid PET[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. [S-methyl-\u003csup\u003e11\u003c/sup\u003eC]-L-methionine (MET) is a key amino acid tracer. Kubota et al. demonstrated that MET-PET can clearly delineate lung cancer lesions with high contrast[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. MET-PET is more specific than FDG-PET for neoplastic lesions and is useful in differentiating between benign and malignant nodules[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. MET-PET/CT has also been shown to be useful for staging lung cancer because MET-PET/CT shows higher specificity than FDG-PET/CT, whereas inflammatory accumulation in hilar lymph nodes interferes with the diagnosis of metastatic disease in East Asian populations[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite the accumulating clinical experience with MET and substantial evidence supporting its diagnostic value in lung cancer, its prognostic implications haven't been fully explored. Some studies suggest that MET-PET might be as effective as FDG-PET in monitoring radiation therapy response[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], highlighting its potential dual role in diagnosis and prognosis. Miyazawa reported that tracer uptake of MET-PET in NSCLC reflects the proliferative activity of tumor cells[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. MET is predominantly internalized into cells via the Na⁺-independent transporter known as L-type amino acid transporter 1 (LAT1)[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. LAT1 is highly expressed in malignant neoplasms, and elevated LAT1 expression has been demonstrated to correlate with poor prognosis in lung cancer and various other malignancies[\u003cspan additionalcitationids=\"CR21 CR22 CR23 CR24 CR25\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe cellular mechanisms linking MET uptake with tumor proliferation and the correlation between LAT1 expression and prognosis have been well established. However, the direct relationship between MET PET uptake parameters and clinical outcomes in NSCLC patients remains unexplored, particularly in the context of CIRT.\u003c/p\u003e \u003cp\u003eIn this retrospective analysis, we examined MET-PET/CT scans obtained before CIRT in patients with localized NSCLC. We sought to understand how imaging biomarkers derived from MET-PET/CT relate to patient outcomes, aiming to shed light on MET-PET's potential role in guiding NSCLC treatment decisions.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient Selection\u003c/h2\u003e \u003cp\u003e The study was conducted with approval from the institutional review board. Patients who were eligible for CIRT with a single fraction were selected from our institutional database between August 2007 and February 2012. At the time of treatment, patients were staged according to the Japan Lung Cancer Society criteria 6th edition (valid until 2009) and AJCC/UICC 6th edition, where tumors up to 7 cm were classified as T2, potentially qualifying for single-fraction CIRT. For this retrospective analysis, we reclassified all patients according to the current UICC 8th edition criteria, resulting in a cohort that includes some cases now classified as Stage IIB. Therefore, while all patients were initially considered appropriate candidates for single-fraction CIRT based on contemporary staging criteria, the retrospective reclassification revealed a broader range of disease stages than would be classified as 'early-stage' by current standards.\u003c/p\u003e \u003cp\u003eAmong these, 67 consecutive patients underwent MET-PET/CT scans using either Aquiduo (Toshiba Medical Systems, Tochigi, Japan) or Biograph 16 (Siemens Medical Systems, Nashville, TN, USA). The average age of the participants was 73.2 years, with an age range of 51\u0026ndash;89 years; the cohort included 43 males and 24 females. All patients who were eligible for CIRT treatment during this period underwent MET-PET/CT scans. Seven cases at the clinical T-stage of Tis were excluded due to extremely low radiotracer accumulation, which prevented reliable quantitative analysis.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCIRT\u003c/h3\u003e\n\u003cp\u003eCIRT was performed at QST hospital. A single irradiation protocol of CIRT for stage I lung cancer was originally designed as a dose-escalation trial, as previously reported[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The dose-escalation trial, which began in 2003, initially started treatments at a irradiation dose of 28 Gy. The included patients in the present study are those treated after August 2007 in the trial, receiving dosage levels ranging from 40 to 50 Gy (described as the relative biological effect [RBE]-weighted dose based on the modified microdosimetric kinetic model). As described above, when reclassified according to current UICC-8 criteria, some patients now fall into the Stage IIB category.\u003c/p\u003e\n\u003ch3\u003eFollow-up and Assessment\u003c/h3\u003e\n\u003cp\u003eAs part of the follow-up, almost all patients underwent regular blood tests, CT scans, and PET/CT scans at our facility. The initial follow-up examination was conducted 4 weeks after treatment, followed by repeat examinations every 3 months for at least two years. Subsequently, check-ups were carried out every 6 months over a period of 5 years. For patients unable to visit our facility, we also conducted postal surveys. Local recurrence and metastases were defined based on findings from CT and PET/CT scans, as well as increases in tumor marker levels in blood tests.\u003c/p\u003e\n\u003ch3\u003eRadiotracer Preparation and PET Imaging Protocol\u003c/h3\u003e\n\u003cp\u003eThe study used two whole-body PET/CT scanners: the Biograph 16 (Siemens Healthcare, Nashville, TN, USA) and the Aquiduo PET/CT (Toshiba Medical Systems, Tochigi, Japan). The choice of which PET/CT scanner to use was determined randomly in accordance with our clinical practice. MET administered for the imaging was synthesized in our facility's cyclotron. Patients were given an intravenous injection of 740 MBq of MET, and imaging commenced 20 minutes post-injection. Emission data were acquired for 3 minutes per bed position. PET images were reconstructed using iterative algorithms (4 iterations, 24 subsets) with an 8-mm Gaussian filter, a 256 \u0026times; 256 matrix (2mm/pixel), and a 2 mm slice thickness. Whole-body spiral CT scanning was performed under the following parameters: 120 kV; automatic exposure control; 512 \u0026times; 512 matrix; beam pitch of 0.94; and a 2 mm \u0026times; 16-row mode. The CT data were used for attenuation correction.\u003c/p\u003e\n\u003ch3\u003eMeasurement of PET/CT Parameters\u003c/h3\u003e\n\u003cp\u003eAll images were analyzed by a board-certified diagnostic radiologist with over ten years of experience using AW Server 3.2 (GE Healthcare, MI, USA). Tumor size was measured on transaxial slices, defined as the longest diameter of the solid component. To delineate the metabolic tumor volume (MTV), we applied a fixed threshold SUV of 1.5 in the volume of interest (VOI). Although this cutoff is not yet standardized for MET-PET, we selected 1.5 based on the commonly used threshold of 2.5 for FDG-PET and the generally lower uptake of MET compared with FDG. We also considered the potential prognostic utility of a fixed-threshold approach. MTV was then semi-automatically generated within the VOI, and SUVmax was calculated automatically. Total lesion retention (TLR) was calculated by multiplying MTV by the mean SUV (SUVmean) within the delineated volume, providing a parameter that incorporates both volumetric and metabolic information. This calculation is analogous to total lesion glycolysis (TLG) in FDG-PET studies but reflects methionine retention rather than glucose metabolism. All measurements were corroborated by PET/CT fusion images to ensure accurate localization and quantification.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eAll values were calculated as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations. Statistical analyses were performed using SPSS 29 (SPSS, Chicago, IL, USA), with \u003cem\u003ep\u003c/em\u003e-values of less than 0.05 considered statistically significant. Univariate Cox proportional hazard analysis was conducted for both disease-free survival (DFS) and overall survival (OS), considering factors such as age, sex, treatment dose, tumor diameter, SUVmax, MTV, and TLR. Both disease-free survival (DFS) and overall survival (OS) were calculated from the date of CIRT to the date of the event or last follow-up. DFS events were defined as local recurrence, regional or distant metastasis, or death from any cause, while OS events were defined as death from any cause. The cutoff value was determined using the Youden Index, selecting the threshold that maximized the sum of sensitivity and specificity. We used Pearson's correlation coefficient to examine the correlation between variables to prevent multicollinearity. Variables with a Pearson correlation coefficient exceeding 0.8 were considered to have multicollinearity. While most variables showed a coefficient below 0.8, MTV and TLR exceeded this threshold, indicating multicollinearity between them. Therefore, TLR was excluded from the subsequent multivariate Cox proportional hazard analysis. In addition to these analyses, Kaplan-Meier survival curves were plotted to visually assess and compare DFS and OS across different groups or variables with the log-rank test.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe clinical and pathological characteristics of the patients are summarized in Table\u0026nbsp;1. Figure\u0026nbsp;1 shows representative MET-PET/CT images demonstrating the typical uptake pattern in NSCLC lesions before CIRT.\u003c/p\u003e \u003cp\u003eOut of 60 cases, 36 were male and 24 were female. The mean age of the patients was 73.3\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3 years, ranging from 51 to 89 years old. All individuals were pathologically confirmed to have cancer, with 45 cases being adenocarcinoma, 14 cases being squamous cell carcinoma, and one other case included. The T factor included 35 cases of T1, 24 cases of T2, and 1 case of T3 with UICC-8 criteria. No lymph node metastases or distant metastases were confirmed prior to treatment. The treatment dose ranged from 40Gy to 44Gy in 25 cases and from 46Gy to 50Gy in 35 cases. Imaging was performed on 31 cases using the Toshiba Aquiduo and 29 using the Siemens Biograph 16.\u003c/p\u003e \u003cp\u003eThe follow-up period was 74.3\u0026thinsp;\u0026plusmn;\u0026thinsp;37.4 months. During the follow-up period, 7 patients developed local recurrence, 8 experienced nodal recurrence (with overlap in 2 patients who also had local recurrence), and 10 had distant metastases. In addition, 1 patient showed both nodal and distant metastases. Overall, 14 patients died of lung cancer and 11 died from other causes.\u003c/p\u003e \u003cp\u003eThe average tumor diameter was 2.74\u0026thinsp;\u0026plusmn;\u0026thinsp;1.00 cm, with a mean SUVmax value of 3.53\u0026thinsp;\u0026plusmn;\u0026thinsp;1.92. The mean metabolic tumor volume (MTV) was 12.4\u0026thinsp;\u0026plusmn;\u0026thinsp;15.22 ml. To determine the optimal cutoff values for predicting disease recurrence, receiver operating characteristic (ROC) curve analysis was performed (Fig.\u0026nbsp;2). The cutoff values were selected to optimize the balance between sensitivity and specificity. In the disease-free survival (DFS) analysis, the most discriminative cutoff values were a solid tumor diameter of 2.9 cm (sensitivity 61.5%, specificity 64.7%), an SUVmax value of 2.5 (sensitivity 80.8%, specificity 50.0%), and an MTV of 6.0 ml (sensitivity 76.9%, specificity 64.7%). Among these parameters, MTV provided the most balanced combination of sensitivity and specificity for predicting disease recurrence.\u003c/p\u003e \u003cp\u003eThe results of the univariate and multivariate Cox proportional hazard analysis for DFS and OS are shown in Table\u0026nbsp;2. In the univariate analysis for DFS, SUVmax (hazard ratio (HR) 3.2, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), MTV (HR 4.5, p\u0026thinsp;\u0026lt;\u0026thinsp;0.005), and Total lesion retention (TLR) (HR 4.0, p\u0026thinsp;\u0026lt;\u0026thinsp;0.005) were found to be significantly correlated with disease recurrence. No significant difference was observed in terms of treatment dose. For overall survival, the univariate analysis revealed significant correlations with solid tumor diameter (HR 2.4, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), SUVmax (HR 2.9, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), MTV (HR 4.7, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), TLR (HR 4.8, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and sex (HR 0.6, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Both MTV and TLR demonstrated particularly strong prognostic values with HRs above 4.5 and high statistical significance (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eA high correlation was observed between MTV and TLR. Considering multicollinearity, TLR was excluded from the multivariate analysis. Upon performing multivariate Cox Hazard analysis (forced entry method) with tumor longest diameter, SUVmax, MTV, age, and sex, only MTV remained as a significant independent prognostic factor for both DFS (HR 3.9, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and OS (HR 4.3, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). These results demonstrate that patients with MTV\u0026thinsp;\u0026ge;\u0026thinsp;6ml had approximately four times higher risk of both disease recurrence and death compared to those with MTV\u0026thinsp;\u0026lt;\u0026thinsp;6ml, even after adjusting for other clinicopathological factors.\u003c/p\u003e \u003cp\u003eFor visual assessment, Kaplan-Meier survival curves were analyzed for both DFS and OS (Fig.\u0026nbsp;3A, 3B). Log-rank tests revealed a significant difference in survival duration related to MTV in DFS and OS.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study reveals a strong correlation between the MTV captured by MET-PET and the prognosis of localized lung cancer patients treated with single-fractionated CIRT. Volumetric parameters like MTV can comprehensively capture tumor characteristics and biological behavior, offering a more complete evaluation than non-volumetric measures like SUVmax. Although MET is more conventionally used for brain tumor imaging, our study emphasizes its value in lung cancer assessment.\u003c/p\u003e \u003cp\u003eIn our multivariate analysis, MTV in MET-PET emerged as the sole independent prognostic factor, while SUVmax, tumor diameter, and treatment dose did not retain statistical significance. The superiority of MTV over SUVmax can be explained by their inherent measurement differences. While SUVmax captures only the single most metabolically active point within the tumor, MTV represents the entire volume of metabolically active tissue, providing a more comprehensive assessment of tumor burden and total LAT1-expressing cells. Im et al. showed in their meta-analysis of FDG-PET in NSCLC that this volumetric approach better reflects the overall tumor metabolism and is less susceptible to sampling bias than single-voxel measurements[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. However, previous FDG-PET studies in patients treated by stereotactic body radiotherapy with stage I NSCLC have primarily relied on SUVmax, and investigations into volumetric parameters have yielded conflicting results[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In contrast, our present study showed that MET-PET provided a robust volumetric parameter, MTV, that may offer more accurate prognostic information and potentially guide CIRT more effectively than SUVmax alone. Moreover, MET-PET\u0026rsquo;s volumetric assessment may prove useful beyond CIRT by aiding pre-treatment evaluation for other local therapies such as stereotactic body radiation therapy or radiofrequency ablation.\u003c/p\u003e \u003cp\u003eIn this study, tumor diameter (T stage) did not show a significant association with DFS, but it did reach significance for OS. In our previous report with a larger cohort[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], tumor diameter was significantly correlated with both DFS and OS. Specifically, we found that tumors classified as T1a or T1b, measuring 2 cm or less according to the UICC 8th edition, showed favorable outcomes, whereas tumors exceeding 5 cm (T3) presented difficulties in achieving local control. The discrepancy between the present findings and our earlier research may be explained by the smaller sample size in this study, which lowered statistical power, and by the exclusion of Tis cases, leading to a more homogeneous T-stage distribution. Meanwhile, MTV reflects both the anatomical size of tumors and their metabolic activity. In relatively small tumors, biological aggressiveness and metastatic potential do not always align with their diameter. Thus, MTV can provide a more comprehensive assessment than size alone, highlighting its potential utility in clinical practice.\u003c/p\u003e \u003cp\u003eThe current study provided no significant association between treatment dose and prognosis. In our previous analysis, we likewise found no statistically significant difference in local control between patients receiving 36 to 42 Gy [RBE] and those treated with 44 Gy [RBE] or more, suggesting that once the dose surpasses approximately 40 Gy [RBE], CIRT exerts sufficiently potent tumoricidal activity. The present findings are thus consistent with our earlier observations. Nevertheless, local control may be further improved at doses of 48 Gy [RBE] or above, indicating the potential benefits of higher dose escalation in selected cases.\u003c/p\u003e \u003cp\u003eWhile MET is a natural amino acid and can be taken up by various amino acid transporters, its primary cellular entry route is through the LAT1 transporter[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. This is especially relevant as malignant tumors often overexpress the LAT1 transporter[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], enhancing MET's specificity and potential utility. LAT1 expression strongly correlates with prognosis in resectable NSCLC[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This prognostic stratification is particularly valuable in radiation therapy settings where lymph node dissection (a key advantage of surgical approaches) is not performed. Kumasaka et al. demonstrated that FAMT-PET, which specifically targets LAT1, provides superior prognostic discrimination compared to FDG-PET[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], with an MTV\u0026thinsp;\u0026gt;\u0026thinsp;7.0 ml (SUV\u0026thinsp;\u0026gt;\u0026thinsp;1.2) associated with poorer survival (HR 3.14). Our findings using MET-PET with a threshold of SUV\u0026thinsp;\u0026gt;\u0026thinsp;1.5 and a cutoff of 6.0 ml yielded comparable results, confirming the prognostic significance of LAT1-mediated transport across different tracers and treatment modalities. Importantly, our study validates this prognostic value specifically in localized disease, offering a non-invasive approach to risk stratification that can guide clinical decision-making for early-stage NSCLC patients.\u003c/p\u003e \u003cp\u003eThis study has several limitations that should be acknowledged. First, this is a retrospective single-institution study with a relatively small sample size (n\u0026thinsp;=\u0026thinsp;60), which may limit the generalizability of our findings. The statistical power might be insufficient to detect smaller effects, potentially explaining why some variables did not reach statistical significance in multivariate analysis. Second, the SUV threshold of 1.5 used for MTV delineation was selected based on empirical considerations rather than standardized criteria, as no established cutoff exists for MET-PET in lung cancer. Finally, external validation in a larger, multi-institutional prospective cohort would be necessary to confirm the prognostic value of MET-PET-derived MTV. Despite these limitations, our findings provide valuable insights into the potential utility of MET-PET as a prognostic biomarker in early-stage NSCLC treated with single-fractionated carbon-ion radiotherapy.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eMTV in pretreatment MET-PET/CT would be a valuable predictor of DFS and OS of localized NSCLC treated with CIRT. This finding suggests that MET-PET/CT could be integrated into risk stratification to guide personalized treatment decisions for patients with localized NSCLC.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eMET, [S‑methyl‑\u003csup\u003e11\u003c/sup\u003eC]‑L‑methionine; PET, Positron Emission Tomography; NSCLC, Non-Small Cell Lung Cancer; MTV, Metabolic Tumor Volume; \u003csup\u003e18\u003c/sup\u003eF-FDG, \u003csup\u003e18\u003c/sup\u003eF-Fluorodeoxyglucose; \u003csup\u003e18\u003c/sup\u003eF-FAMT, L- [3-\u003csup\u003e18\u003c/sup\u003eF]-α-methyltyrosine\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding information:\u003c/strong\u003e none\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u0026nbsp;\u003c/strong\u003eThere are no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKT and RN were responsible for the research, wrote the main manuscript text as the first author (KT) and the corresponding author (TH) responsible for this study, and coordinated and supervised the entire study. TM is a radiological technologist responsible for PET/CT scans and image reconstruction for this study. JT, ABT, and KY contributed to the statistical analysis and helped in drafting the manuscript. RN, MN, HI and SY contributed to the manuscript\u0026apos;s data collection and drafting.\u003c/p\u003e\n\u003cp\u003eAs the principal investigator, MJ provided oversight and guidance for the project and was accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003eAll authors conducted this study and read and approved the final version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394\u0026ndash;424.\u003c/li\u003e\n\u003cli\u003eNavada S, Lai P, Schwartz AG, Kalemkerian GP. Temporal trends in small cell lung cancer: Analysis of the national Surveillance, Epidemiology, and End-Results (SEER) database. J Clin Orthod. 2006;24:7082\u0026ndash;7082.\u003c/li\u003e\n\u003cli\u003eGanti AK, Klein AB, Cotarla I, Seal B, Chou E. Update of Incidence, Prevalence, Survival, and Initial Treatment in Patients With Non-Small Cell Lung Cancer in the US. JAMA Oncol. 2021;7:1824\u0026ndash;32.\u003c/li\u003e\n\u003cli\u003eKamada T, Tsujii H, Blakely EA, Debus J, De Neve W, Durante M, et al. Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience. Lancet Oncol. 2015;16:e93\u0026ndash;100.\u003c/li\u003e\n\u003cli\u003eLi J, Xu W, Kong F, Sun X, Zuo X. Meta-analysis: accuracy of 18FDG PET-CT for distant metastasis staging in lung cancer patients. Surg Oncol. 2013;22:151\u0026ndash;5.\u003c/li\u003e\n\u003cli\u003eObara P, Pu Y. Prognostic value of metabolic tumor burden in lung cancer. 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The Value of FDG PET/CT in Treatment Response Assessment, Follow-Up, and Surveillance of Lung Cancer. AJR Am J Roentgenol. 2017;208:420\u0026ndash;33.\u003c/li\u003e\n\u003cli\u003eKrarup MMK, Fischer BM, Christensen TN. New PET Tracers: Current Knowledge and Perspectives in Lung Cancer. Semin Nucl Med. 2022;52:781\u0026ndash;96.\u003c/li\u003e\n\u003cli\u003eKubota K, Matsuzawa T, Ito M, Ito K, Fujiwara T, Abe Y, et al. Lung tumor imaging by positron emission tomography using C-11 L-methionine. J Nucl Med. 1985;26:37\u0026ndash;42.\u003c/li\u003e\n\u003cli\u003eKanegae K, Nakano I, Kimura K, Kaji H, Kuge Y, Shiga T, et al. Comparison of MET-PET and FDG-PET for differentiation between benign lesions and lung cancer in pneumoconiosis. Ann Nucl Med [Internet]. 2007;21. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17705012\u003c/li\u003e\n\u003cli\u003eHsieh HJ, Lin SH, Lin KH, Lee CY, Chang CP, Wang SJ. The feasibility of 11C-methionine-PET in diagnosis of solitary lung nodules/masses when compared with 18F-FDG-PET. Ann Nucl Med. 2008;22:533\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eSchmidt-Hansen M, Baldwin DR, Hasler E, Zamora J, Abraira V, Roqu\u0026eacute; I Figuls M. PET-CT for assessing mediastinal lymph node involvement in patients with suspected resectable non-small cell lung cancer. Cochrane Database Syst Rev. 2014;2016:CD009519.\u003c/li\u003e\n\u003cli\u003eYasukawa T, Yoshikawa K, Aoyagi H, Yamamoto N, Tamura K, Suzuki K, et al. Usefulness of PET with 11C-methionine for the detection of hilar and mediastinal lymph node metastasis in lung cancer. J Nucl Med. 2000;41:283\u0026ndash;90.\u003c/li\u003e\n\u003cli\u003eIshimori T, Saga T, Nagata Y, Nakamoto Y, Higashi T, Mamede M, et al. 18F-FDG and 11C-methionine PET for evaluation of treatment response of lung cancer after stereotactic radiotherapy. Ann Nucl Med. 2004;18:669\u0026ndash;74.\u003c/li\u003e\n\u003cli\u003eMiyazawa H, Arai T, Iio M, Hara T. PET imaging of non-small-cell lung carcinoma with carbon-11-methionine: relationship between radioactivity uptake and flow-cytometric parameters. J Nucl Med. 1993;34:1886\u0026ndash;91.\u003c/li\u003e\n\u003cli\u003eChristensen HN. Role of amino acid transport and countertransport in nutrition and metabolism. Physiol Rev. 1990;70:43\u0026ndash;77.\u003c/li\u003e\n\u003cli\u003eZhang J, Xu Y, Li D, Fu L, Zhang X, Bao Y, et al. Review of the Correlation of LAT1 With Diseases: Mechanism and Treatment. Front Chem. 2020;8:564809.\u003c/li\u003e\n\u003cli\u003eKaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, et al. Prognostic significance of L-type amino acid transporter 1 expression in resectable stage I-III nonsmall cell lung cancer. Br J Cancer. 2008;98:742\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eKaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, et al. Prognostic significance of L-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (CD98) expression in early stage squamous cell carcinoma of the lung. Cancer Sci. 2009;100:248\u0026ndash;54.\u003c/li\u003e\n\u003cli\u003eKaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, et al. Prognostic significance of L-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (CD98) expression in stage I pulmonary adenocarcinoma. Lung Cancer. 2009;66:120\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eImai H, Kaira K, Oriuchi N, Yanagitani N, Sunaga N, Ishizuka T, et al. L-type amino acid transporter 1 expression is a prognostic marker in patients with surgically resected stage I non-small cell lung cancer. Histopathology. 2009;54:804\u0026ndash;13.\u003c/li\u003e\n\u003cli\u003eLu J-J, Li P, Yang Y, Wang L, Zhang Y, Zhu J-Y, et al. Prognostic value of LAT-1 status in solid cancer: A systematic review and meta-analysis. PLoS One. 2020;15:e0233629.\u003c/li\u003e\n\u003cli\u003eYazawa T, Shimizu K, Kaira K, Nagashima T, Ohtaki Y, Atsumi J, et al. Clinical significance of coexpression of L-type amino acid transporter 1 (LAT1) and ASC amino acid transporter 2 (ASCT2) in lung adenocarcinoma. Am J Transl Res. 2015;7:1126\u0026ndash;39.\u003c/li\u003e\n\u003cli\u003eYamamoto N, Miyamoto T, Nakajima M, Karube M, Hayashi K, Tsuji H, et al. A Dose Escalation Clinical Trial of Single-Fraction Carbon Ion Radiotherapy for Peripheral Stage I Non-Small Cell Lung Cancer. J Thorac Oncol. 2017;12:673\u0026ndash;80.\u003c/li\u003e\n\u003cli\u003eIm HJ, Pak K, Cheon GJ, Kang KW, Kim SJ, Kim IJ, et al. Prognostic value of volumetric parameters of (18)F-FDG PET in non-small-cell lung cancer: a meta-analysis. Eur J Nucl Med Mol Imaging [Internet]. 2015;42. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25193652\u003c/li\u003e\n\u003cli\u003eVu CC, Matthews R, Kim B, Franceschi D, Bilfinger TV, Moore WH. Prognostic value of metabolic tumor volume and total lesion glycolysis from \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT in patients undergoing stereotactic body radiation therapy for stage I non-small-cell lung cancer. Nucl Med Commun. 2013;34:959\u0026ndash;63.\u003c/li\u003e\n\u003cli\u003eSatoh Y, Onishi H, Nambu A, Araki T. Volume-based parameters measured by using FDG PET/CT in patients with stage I NSCLC treated with stereotactic body radiation therapy: prognostic value. Radiology. 2014;270:275\u0026ndash;81.\u003c/li\u003e\n\u003cli\u003eKandasamy P, Gyimesi G, Kanai Y, Hediger MA. Amino acid transporters revisited: New views in health and disease. Trends Biochem Sci. 2018;43:752\u0026ndash;89.\u003c/li\u003e\n\u003cli\u003eLeskinen-Kallio S, Ruotsalainen U, N\u0026aring;gren K, Ter\u0026auml;s M, Joensuu H. Uptake of carbon-11-methionine and fluorodeoxyglucose in non-Hodgkin\u0026rsquo;s lymphoma: a PET study. J Nucl Med. 1991;32:1211\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eKumasaka S, Nakajima T, Arisaka Y, Tokue A, Achmad A, Fukushima Y, et al. Prognostic value of metabolic tumor volume of pretreatment 18F-FAMT PET/CT in non-small cell lung Cancer. BMC Med Imaging. 2018;18:46.\u003c/li\u003e\n\u003cli\u003eKaira K, Oriuchi N, Shimizu K, Tominaga H, Yanagitani N, Sunaga N, et al. 18F-FMT uptake seen within primary cancer on PET helps predict outcome of non-small cell lung cancer. J Nucl Med. 2009;50:1770\u0026ndash;6.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-nuclear-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anme","sideBox":"Learn more about [Annals of Nuclear Medicine](http://link.springer.com/journal/12149)","snPcode":"12149","submissionUrl":"https://www.editorialmanager.com/anme/default2.aspx","title":"Annals of Nuclear Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Metabolic tumor volume, Methionine PET/CT, Amino Acid PET/CT, Non-Small Cell Lung Cancer","lastPublishedDoi":"10.21203/rs.3.rs-6310988/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6310988/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study aimed to evaluate the prognostic predictive ability of MET-PET/CT-derived imaging biomarkers in patients with localized non-small cell lung cancer (NSCLC) undergoing single-fraction carbon-ion radiotherapy (CIRT) and to clarify the additional prognostic information these biomarkers can provide beyond the standard UICC staging protocol.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWith institutional review board approval, 67 localized NSCLC patients eligible for CIRT between 2007 and 2012 were included. Single-fraction doses of 40-50 Gy were irradiated. MET-PET imaging using the Toshiba Aquiduo or Siemens Biograph 16 commenced 20 minutes post 740MBq MET injection before CIRT. Experienced radiologists analyzed the images, defining metabolic tumor volume (MTV) as areas with SUV \u0026gt;1.5. Statistical analysis was performed using SPSS 29, including Cox proportional hazard models for disease-free and overall survival.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSeven cases with Tis of T stage were excluded because of low MET radiotracer uptake. A total of 60 patients were analyzed: 36 males and 24 females with a mean age of 73 years; 35 cases of T1, 24 cases of T2, and one T3 case. The average follow-up period was 74.3 months. The univariate Cox proportional hazard analyses showed that SUVmax, MTV, and total lesion retention (TLR) correlated with disease-free survival (DFS), while no significant difference was noted in treatment dose. For overall survival (OS), solid tumor diameter, SUVmax, MTV, TLR, and sex showed significant correlations in the univariate analysis. The multivariate analysis identified MTV as the only significant prognostic factor for both DFS and OS. Kaplan-Meier survival curves further supported these findings, with log-rank tests indicating a significant difference in survival duration related to MTV in both DFS and OS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMTV in pretreatment MET-PET/CT would be a valuable predictor of DFS and OS of localized NSCLC treated with single-fraction CIRT.\u003c/p\u003e","manuscriptTitle":"Prognostic value of pretreatment metabolic tumor volume on [S-methyl-11C]-L-methionine PET/CT in patients with local non-small cell lung carcinoma treated with single-fraction carbon-ion radiotherapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-17 10:37:39","doi":"10.21203/rs.3.rs-6310988/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-03-31T02:47:10+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-28T00:28:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-27T00:01:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Nuclear Medicine","date":"2025-03-26T05:51:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-nuclear-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anme","sideBox":"Learn more about [Annals of Nuclear Medicine](http://link.springer.com/journal/12149)","snPcode":"12149","submissionUrl":"https://www.editorialmanager.com/anme/default2.aspx","title":"Annals of Nuclear Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"18009058-8366-4098-a2af-50f95cd23e88","owner":[],"postedDate":"April 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-07T16:00:53+00:00","versionOfRecord":{"articleIdentity":"rs-6310988","link":"https://doi.org/10.1007/s12149-025-02067-y","journal":{"identity":"annals-of-nuclear-medicine","isVorOnly":false,"title":"Annals of Nuclear Medicine"},"publishedOn":"2025-06-30 15:57:15","publishedOnDateReadable":"June 30th, 2025"},"versionCreatedAt":"2025-04-17 10:37:39","video":"","vorDoi":"10.1007/s12149-025-02067-y","vorDoiUrl":"https://doi.org/10.1007/s12149-025-02067-y","workflowStages":[]},"version":"v1","identity":"rs-6310988","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6310988","identity":"rs-6310988","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}