Prognostic Value of FDG-PET/CT Findings in Mucosal Melanoma of the Head and Neck Treated with Carbon Ion Radiotherapy

Prognostic Value of FDG-PET/CT Findings in Mucosal Melanoma of the Head and Neck Treated with 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 FDG-PET/CT Findings in Mucosal Melanoma of the Head and Neck Treated with Carbon Ion Radiotherapy Ayako Hino, Nobutaka Mizoguchi, Hiroaki Koge, Ryohei Yaguchi, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5887618/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Jul, 2025 Read the published version in Annals of Nuclear Medicine → Version 1 posted 4 You are reading this latest preprint version Abstract Objective To investigate the prognostic value of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) in patients with mucosal melanoma of the head and neck (MMHN) treated with carbon ion radiotherapy (CIRT). Methods This single-center retrospective study included patients with MMHN who underwent CIRT and FDG-PET/CT. Correlations of pre-treatment FDG-PET/CT-derived parameters, including the maximum standardized uptake variable (SUVmax), metabolic tumor volume (MTV) with a 50% threshold, total lesion glycolysis (TLG), bone marrow-to-liver ratio (BLR), and spleen-to-liver ratio (SLR), with clinical parameters and prognosis were statistically analyzed. Results A total of 32 patients with MMHN were enrolled (median age, 72.5 years). The tumor stages were distributed as follows: T3, 17 patients; T4a, 14 patients; and T4b, one patient. The median total observation period was 22.6 months, the median overall survival (OS) was 21.6 months, and the median progression-free survival (PFS) was 11.5 months. Thirteen patients (40.6%) died, 10 (31.3%) experienced local recurrence, and 19 (59.4%) had distant metastases during the observation period. The 1-year survival rate was 78.1% and the 3-year survival rate was 62.5%. FDG-PET/CT show pronounced positive uptake for all tumors (median SUVmax 13.80, range 2.74–32.99). SLR was high in patients with negative programmed death-ligand 1 (PD-L1) expression in the tumor ( p = 0.05). PFS was shorter in patients with a high MTV ( p = 0.018). In multivariate analysis, MTV was an independent prognostic factor for PFS (hazard ratio (HR), 2.60; 95% confidence interval (CI), 1.065–6.345; p = 0.036). MTV and TLG were not predictive of OS in the univariate analysis. Conclusion FDG-PET/CT showed a strong positive uptake for MMHN. FDG-PET/CT-derived imaging parameters may be significant prognostic biomarkers for predicting tumor progression in patients with MMHN. Mucosal melanoma of the head and neck (MMHN) pre-treatment FDG-PET/CT prognosis carbon ion radiotherapy (CIRT) metabolic tumor volume (MTV) spleen-to-liver ratio (SLR) programmed death-ligand 1 (PD-L1) Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Mucosal melanoma of the head and neck (MMHN) is a rare and highly aggressive disease associated with a poor prognosis, with a 5-year overall survival (OS) rate of approximately 30% [ 1 – 3 ]. The standard treatment for local control of MMHN typically involves surgical resection with elective neck dissection, followed by postoperative radiotherapy and chemotherapy [ 4 ]. Immune checkpoint inhibitors (ICIs), particularly those targeting cytotoxic T-lymphocyte (associated) antigen 4 (CTLA4) and programmed cell death 1 (PD-1)/ programmed death-ligand 1 (PD-L1), are used in adjuvant settings for both resected and unresectable/metastatic melanoma [ 5 ]. Previous studies have also demonstrated the efficacy of carbon ion radiotherapy (CIRT) combined with chemotherapy and ICIs, yielding excellent local control in advanced MMHN [ 6 – 8 ]. Given the rapid progression and poor prognosis of MMHN, validating prognostic predictors before treatment is crucial. High phosphohistone-H3 (PHH3) expression, the absence of pigmentation, NRAS or KRAS mutations, and larger tumor volumes have been associated with poor prognosis; however, to date, no correlation between radiological findings and prognosis has been established [ 9 – 11 ]. 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) is a useful imaging tool for detecting malignant tumors, and recent studies have highlighted its effectiveness for prognostic prediction in various cancers, including cutaneous malignant melanoma [ 12 – 18 ]. This retrospective study aimed to investigate the imaging findings of FDG-PET/CT and correlate them with the clinical characteristics and prognosis of patients with MMHN. Materials and methods Patients This single-center retrospective study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and all subsequent revisions, and was approved by the Institutional Ethics Committee (approval number 2024-eki7). The requirement for written informed consent was waived by the Institutional Review Board due to the its retrospective nature. Participants were given the opportunity to refuse by an opt-out method. We retrospectively reviewed our radiology reporting database to identify patients with pathologically confirmed MMHN who underwent FDG-PET/CT between January 2015 and August 2023. The exclusion criteria were as follows: patients who did not undergo CIRT, patients whose pre-treatment FDG-PET/CT data were unavailable, patients without residual tumors at the time of FDG-PET/CT due to surgical resection, and patients without available clinical follow-up records after CIRT. Clinical information Patient clinical information, including age, sex, lactate dehydrogenase (LDH) levels, Eastern Cooperative Oncology Group (ECOG) performance status, sinusitis complications, and timing of initiation of ICI treatment, was collected from clinical records. Tumor characteristics, including primary site of the tumor, TNM stage (8th edition of the Union for International Cancer Control TNM staging system), lymph node metastasis, size of the tumor, PD-L1 status, and BRAF mutation, was also collected. FDG-PET/CT protocol and imaging analysis FDG-PET/CT images from the head to the mid-thigh were acquired using PET/CT scanners. The detailed PET/CT image acquisition protocols are summarized in Online Resource 1. The PET and CT images were transferred to an Advantage Workstation (version AW 4.7; GE Healthcare, WI, USA), where the fusion PET/CT images were constructed and analyzed. Regions of interest (ROIs) were manually delineated on the PET/CT images by a board-certified nuclear medicine physician (A.H.) and a radiologist (Y.Y.) for each lesion to assess maximum standardized uptake variable (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), bone marrow/liver SUVmax ratio (BLR) and spleen/liver SUVmax ratio (SLR). MTV was measured by setting a 50% SUVmax threshold for the tumor, and TLG was calculated by multiplying the MTV by the mean SUV of the tumor. The BLR and SLR were calculated by dividing the SUVmax of the bone marrow and spleen by the SUVmax of the liver. The tumor diameter was also measured using the simultaneous CT images. Evaluation of prognosis To assess the response to treatment, local recurrence, and distant metastasis, imaging analysis using either CT or MRI was performed every 2 or 3 months after CIRT. Tumor size regression after treatment was evaluated and categorized according to the Revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). Progression-free survival (PFS) and OS were assessed to evaluate prognosis. PFS was defined as the time from the start of CIRT to the occurrence of local progression or the detection of new metastases. OS was defined as the time from the initiation of therapy to death or the date of the last confirmation of survival. Patients alive at the cut-off date of August 31, 2024, were censored. Statistical analysis Patients were categorized into two groups based on pre-treatment parameters and tumor response, according to whether the values were higher or lower than the mean for continuous variables, T3 or T4 for the TNM stage, 0 or any other values for ECOG performance status, within the normal range or higher for LDH, and progressive disease (PD) or stable disease (SD) and partial response (PR) or complete response (CR) for response to CIRT, as defined by the RECIST guidelines. Differences in FDG-PET/CT parameters between the two groups were analyzed using the Mann–Whitney U test. To evaluate prognosis, patients were divided into two groups with higher- and lower-than-mean values of FDG-PET/CT parameters, and differences in OS and PFS between the two groups were evaluated using the Kaplan–Meier method and the log-rank test. The prognostic value of the FDG-PET/CT parameters was assessed using univariate and multivariate Cox regression analyses, and hazard ratios (HRs) were calculated. All statistical analyses were performed using SPSS Statistics for Windows version 29 (BM Corp., Armonk, NY, USA). Statistical significance was set at p < 0.05. Results Patient characteristics and pre-treatment clinical parameters Radiological images of 60 patients with MMHN were obtained from our radiological database. Subsequently, 28 patients (Nineteen patients who did not undergo CIRT, four patients whose pre-treatment FDG-PET/CT was not available, one patient without residual tumor at the time of FDG-PET/CT because of surgical resection, and four patients whose clinical records of follow-up after CIRT were insufficient) were excluded, with 32 patients finally enrolled (Fig. 1 ). CIRT was administered at a total dose of 64.0 Gy, divided into 16 fractions over four weeks. The inclusion criteria for pathologically proven MMHN for CIRT were the same as in our previously reported study, except for choroidal melanoma, N0 or N1 and M0 status, inoperable cases or patients who refused surgical resection, and an ECOG PS of 0–2 [ 6 ]. The interval between FDG-PET/CT and CIRT initiation was 2–68 days (mean: 27.67 ± 15.36, median: 27). ICIs were administered to 24 patients (75%). Eight patients (25%) were treated with an adjuvant single-agent administration of anti-PD1, and eight patients were administered single-agent administration of anti-PD1 preceded to CIRT (25%). Eight patients (25%) were treated with anti-PD1 plus anti- CTLA4 after progression to distant metastasis. The other detailed patient characteristics are shown in Table 1. Pre-treatment FDG-PET/CT imaging findings and volumetric parameters The pre-treatment FDG-PET/CT imaging findings are shown in Fig. 2 . FDG accumulation in the primary tumor was enhanced, and the surrounding sinusitis also showed enhanced accumulation of FDG. Physiological accumulation in the brain and external eye muscles was also pronounced, in some cases overlapping with accumulation in the tumor. The FDG-PET/CT parameters (SUVmax, MTV, TLG, BLR, and SLR) are summarized in Table 2, and the histograms for each parameter are presented in Online Resource 2. The correlations between each FDG-PET/CT parameter are shown in Online Resource 3. Positive correlations were observed between SUVmax and TLG (r = 0.447, p = 0.01), TLG and MTV (r = 0.803, p < 0.001), and BLR and SLR (r = 0.543, p = 0.001). Correlations between pre-treatment FDG-PET/CT parameters and clinical characteristics Differences in FDG-PET/CT parameters between clinical characteristics were evaluated using the Mann–Whitney U test and are summarized in Fig. 3 . MTV and TLG were high in patients with T4a and T4b stage disease ( p = 0.005, p < 0.001) (Fig. 3 a), large tumor size ( p = 0.004, p = 0.001) (Fig. 3 b), and presence of sinusitis ( p = 0.003, p = 0.03) (Fig. 3 c). SLR was significantly lower in PD-L1-positive cases ( p = 0.05) and higher in patients with sinusitis ( p = 0.048) (Fig. 3 d). The BLR was also low in PD-L1-positive patients, but the difference was not statistically significant ( p = 0.234) (Fig. 3 d). Correlation of pre-treatment FDG-PET/CT parameters with response to CIRT The responses to the CIRT assessed using the Revised RECIST (version 1.1) are summarized in Table 3. CR was achieved in seven patients (21.9%), PR in 18 patients (56.3%), SD in six patients (18.8%), and PD in one patient (3.1%). FDG-PET/CT-derived parameters showed no difference between the two groups of patients who showed a response to treatment (PR and CR) and those who did not show a response to treatment (PD and SD). Prognostics The prognostic data of the patients are summarized in Table 3. The median total observation period was 22.6 months (range, 7–58; mean, 25.9; standard deviation (SD), 14.8). During follow-up, 13 patients died (40.6%) and 10 patients (31.3%) died from disease-related causes. Three patients died of pneumonia. Seven (21.9%) patients died within 1 year of treatment initiation, and 12 (37.5%) patients died within 3 years. The 1-year and 3-year survival rates were 78.1% and 62.5%, respectively. Three patients (9.3%) were censored because they changed hospitals, and 16 patients (50%) were alive. Disease progression, including distant metastasis or local recurrence, was observed in 16 patients (50%) within 1 year of treatment initiation and in 22 patients (68.8%) within 3 years after treatment initiation. Local recurrence was observed in 8 cases (25.0%) within 1 year after treatment initiation and in 9 patients (28.1%) within 3 years after treatment initiation. Distant metastasis was observed in 16 cases (50.0%) within 1 year after treatment initiation and in 19 cases (59.4%) within 3 years. The median OS was 21.6 months (range, 6–57 months; mean, 24.8; SD, 14.7). The median PFS was 11.5 months (range, 1–51 months; mean, 14.8 months; SD, 12.9). Correlation of clinical parameters and FDG-PET/CT-derived parameters with prognosis No clinical parameters or FDG-PET/CT-derived parameters were independently associated with shorter OS by Kaplan–Meier analysis or the log-rank test. Patients with poor ECOG performance status had a relatively shorter OS, but this was not statistically significant. Patients with high TNM tumor stage (T4a and T4b) (Fig. 4 a) and high MTV (Fig. 4 b) had shorter PFS according to the Kaplan–Meier analysis and log-rank test ( p = 0.009 and 0.012, respectively). The results of univariate and multivariate Cox regression analysis for OS and PFS are summarized in Table 4. MTV was the only FDG-PET/CT-derived prognostic factor for predicting short PFS ( p = 0.018; HR = 2.851; 95% confidence interval (CI) = 1.195–6.803). A higher TNM tumor stage (T4a and T4b) was also independently associated with shorter PFS ( p = 0.014; HR = 2.946; 95%CI = 1.224–6.989). The final multivariate model included MTV, sex, and ECOG performance status as potential confounders. We did not include TNM stage and MTV in the same multivariate model because elevated MTV and high TNM stage showed a significant correlation. MTV remained an independent prognostic factor for PFS in the multivariate model ( p = 0.036; HR ratio, 2.60; 95%CI, 1.065–6.345). Discussion The results of our study revealed a correlation between the MTV of pre-treatment FDG-PET/CT and PFS, as determined by the Kaplan–Meier method and the log-rank test. MTV was also identified as an independent prognostic factor for PFS based on a robust multivariate Cox regression analysis. Due to the rarity of MMHN, few clinical trials with small sample sizes have investigated optimal treatment strategies and prognostic indicators. Several studies have assessed the prognostic value of FDG-PET/CT in cutaneous malignant melanoma; however, only one study, conducted by Seban et al., has explored the utility of FDG-PET/CT in mucosal malignant melanoma, and it was limited to a small cohort that included cases from the esophagus and vagina, rather than exclusively focusing on MMHN [ 17 ]. To date, our study is the first clinical report indicating that FDG-PET/CT-derived volumetric parameters may serve as optimal biomarkers for predicting prognosis in patients with MMHN treated with CIRT. MMHN is associated with a poor prognosis and frequently recurs locally or metastasizes, even after achieving local control, suggesting that FDG-PET/CT could be an effective tool for predicting the risk of recurrence before treatment initiation. In contrast to previous studies that reported shorter OS in patients with high FDG-PET/CT accumulation in the primary tumor, our study found no correlation between FDG-PET/CT-derived parameters and OS. One potential explanation for this discrepancy is the influence of surrounding tissue, such as the sinus, brain, and exophthalmic muscles, due to the tumor’s location in MMHN. Previous reports have indicated that inflammatory complications can cause false-positive results when assessing head and neck malignancies [ 18 ], and the surrounding conditions of MMHN may have impacted the FDG-PET/CT parameters. Additionally, although CIRT has been reported to be particularly effective in achieving local control in the treatment of MMHN, its contribution to improving OS has been shown to be limited due to the high frequency of distant metastases [ 7 ]. This study also demonstrated a high frequency of distant metastases, and local treatment options for metastatic sites were restricted to palliative irradiation, which may explain why FDG-PET/CT did not prove useful in predicting OS in MMHN patients after CIRT. As a single-center retrospective study with a small sample size, the present study has several limitations. First, data on PD-L1 expression status were missing for some patients. Recently, PD-L1 expression on tumor cells has emerged as a potential prognostic marker for predicting sensitivity to ICIs [ 19 , 20 ]. Although previous studies have reported a correlation between PD-L1 expression and FDG-PET/CT accumulation [ 21 – 23 ], only PD-L1 expression and SLR showed a statistically significant negative correlation in the present study. Additionally, pronounced FDG uptake in hematopoietic organs such as the bone marrow and spleen has been identified as a negative prognostic marker for various malignancies, including melanoma [ 20 , 24 , 25 ]. Since statistical significance could not be established between OS and SLR due to the small sample size in this study, further verification in a larger cohort is necessary. Second, uniformity in the administration of ICIs should be ensured. ICIs are a crucial treatment for advanced MMHN, as they can improve prognosis. As noted earlier, MMHN frequently metastasizes, even when localized; therefore, the addition of adjuvant ICI therapy to CIRT is recommended. Third, all patients were treated with CIRT, which could have introduced selection bias, as patients were given CIRT instead of surgical resection or ICI treatment. To address these limitations, it would be beneficial to conduct a comparative study of different treatment modalities, including ICI treatment, CIRT alone, CIRT with adjuvant ICI, and conventional surgery with adjuvant radiation therapy, using a larger patient cohort. Conclusion Correlations between FDG-PET/CT-derived parameters, clinical parameters, and prognosis were evaluated in patients with MMHN treated with CIRT. A higher SLR correlated with negative PD-L1 expression in tumors. MTV was the sole prognostic factor for PFS. Therefore, FDG-PET-derived parameters may serve as significant prognostic markers for predicting tumor progression in patients with MMHN. Declarations Acknowledgments No potential conflicts of interest were disclosed. Sources of funding : The Authors received no funds for this study. References Lombardi D, Bottazzoli M, Turri-Zanoni M, Raffetti E, Villaret AB, Morassi ML, et al. Sinonasal mucosal melanoma: A 12-year experience of 58 cases. 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The prognostic value of bone marrow retention index and bone marrow-to-liver ratio of baseline 18F-FDG PET/CT in diffuse large B-cell lymphoma. Eur Radiol. 2024;34:2500-11. doi: 10.1007/s00330-023-10150-z. Wong A, Callahan J, Keyaerts M, Neyns B, Mangana J, Aberle S, et al. (18)F-FDG PET/CT based spleen to liver ratio associates with clinical outcome to ipilimumab in patients with metastatic melanoma. Cancer Imaging. 2020;20:36. doi: 10.1186/s40644-020-00313-2. Tables Tables are available in the Supplementary Files section. Supplementary Files OnlineResource1.pdf OnlineResource2.pdf OnlineResource3.pdf Table1.xlsx Table2.xlsx Table3.xlsx table4.xlsx Cite Share Download PDF Status: Published Journal Publication published 25 Jul, 2025 Read the published version in Annals of Nuclear Medicine → Version 1 posted Reviewers agreed at journal 01 Feb, 2025 Reviewers invited by journal 31 Jan, 2025 Editor assigned by journal 30 Jan, 2025 First submitted to journal 30 Jan, 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-5887618","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":409511729,"identity":"cd7a7cd3-7208-4965-af90-ea2097da5de6","order_by":0,"name":"Ayako Hino","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-3430-7567","institution":"Kanagawa Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"Ayako","middleName":"","lastName":"Hino","suffix":""},{"id":409511730,"identity":"946ea59d-ce5a-4031-a1e1-4027435630a2","order_by":1,"name":"Nobutaka Mizoguchi","email":"","orcid":"","institution":"Kanagawa Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Nobutaka","middleName":"","lastName":"Mizoguchi","suffix":""},{"id":409511731,"identity":"ebbf509f-d78e-4dff-afde-58ec4e797b48","order_by":2,"name":"Hiroaki Koge","email":"","orcid":"","institution":"Kanagawa Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Hiroaki","middleName":"","lastName":"Koge","suffix":""},{"id":409511732,"identity":"9df72dfb-2a7f-4056-9d14-dfe6757bea68","order_by":3,"name":"Ryohei Yaguchi","email":"","orcid":"","institution":"Kanagawa Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Ryohei","middleName":"","lastName":"Yaguchi","suffix":""},{"id":409511733,"identity":"f93f4914-724e-40c5-aa6b-86cc49abeb96","order_by":4,"name":"Manatsu Yoshida","email":"","orcid":"","institution":"Kanagawa Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Manatsu","middleName":"","lastName":"Yoshida","suffix":""},{"id":409511734,"identity":"e717ef1d-01f5-4015-ac8e-8a0be170599e","order_by":5,"name":"Takashi Matsuki","email":"","orcid":"","institution":"Kanagawa Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Matsuki","suffix":""},{"id":409511735,"identity":"e2122bf3-158b-4f1c-89b2-de98050d6fde","order_by":6,"name":"Madoka Furukawa","email":"","orcid":"","institution":"Kanagawa Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Madoka","middleName":"","lastName":"Furukawa","suffix":""},{"id":409511736,"identity":"b0a45673-605d-4d84-9b1a-2a01e3c48a59","order_by":7,"name":"Tomoaki Nagase","email":"","orcid":"","institution":"Kanagawa Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Tomoaki","middleName":"","lastName":"Nagase","suffix":""},{"id":409511737,"identity":"3aaf431d-3187-4ec1-8902-1f5a141febc1","order_by":8,"name":"Harumi Mochizuki","email":"","orcid":"","institution":"Kanagawa Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Harumi","middleName":"","lastName":"Mochizuki","suffix":""},{"id":409511738,"identity":"6ae47f4e-70d7-466c-a3c8-2bb1d51100ae","order_by":9,"name":"Akira Kakiuchi","email":"","orcid":"","institution":"Kanagawa Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Akira","middleName":"","lastName":"Kakiuchi","suffix":""},{"id":409511739,"identity":"f8cb0864-d277-47b9-a071-f7c680e2f803","order_by":10,"name":"Shihyao Cheng","email":"","orcid":"","institution":"Kanagawa Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Shihyao","middleName":"","lastName":"Cheng","suffix":""},{"id":409511740,"identity":"b799548c-9f27-4511-a5a5-39eb1d99d2dd","order_by":11,"name":"Yayoi Yamamoto","email":"","orcid":"","institution":"Kanagawa Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Yayoi","middleName":"","lastName":"Yamamoto","suffix":""},{"id":409511741,"identity":"fefa5993-9b01-4faa-b8ab-6c15aee3f968","order_by":12,"name":"Tsunehiro Doiuchi","email":"","orcid":"","institution":"Kanagawa Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Tsunehiro","middleName":"","lastName":"Doiuchi","suffix":""},{"id":409511742,"identity":"29b70fb6-c70e-4965-9d0e-2ed98bf760ba","order_by":13,"name":"Hiroaki Kurihara","email":"","orcid":"","institution":"Kanagawa Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Hiroaki","middleName":"","lastName":"Kurihara","suffix":""}],"badges":[],"createdAt":"2025-01-23 10:47:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5887618/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5887618/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12149-025-02069-w","type":"published","date":"2025-07-25T15:58:27+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":75408280,"identity":"a987e8cc-aa42-4fc8-a319-a98f9b4970ce","added_by":"auto","created_at":"2025-02-04 08:58:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2951549,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patient inclusion and exclusion.\u003c/p\u003e\n\u003cp\u003eMMHN, malignant melanoma of the head and neck; CIRT, carbon ion radiotherapy; FDG-PET/CT, 18F-fluorodeoxyglucose positron emission tomography-computed tomography;\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-5887618/v1/54e81e744df9912710fff228.png"},{"id":75410059,"identity":"9a97496f-5be0-43a2-8b25-a740d1a6374b","added_by":"auto","created_at":"2025-02-04 09:06:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":12317550,"visible":true,"origin":"","legend":"\u003cp\u003eFDG-PET/CT images of a 61-year-old male with MMHN.\u003c/p\u003e\n\u003cp\u003ea. FDG-PET/CT accumulation was pronounced for MMHN on the MIP image (*).\u003c/p\u003e\n\u003cp\u003eb. Strong FDG-PET/CT accumulation was also observed for MMHN on axial images (*). In addition, physiological uptake in the brain (white star) was also notable.\u003c/p\u003e\n\u003cp\u003ec. Pronounced uptake was observed for MMHN on coronal images (*). Physiological uptake in the brain (white star) and orbital muscles (white arrowheads) was also notable.\u003c/p\u003e\n\u003cp\u003eFDG-PET/CT, 18F-fluorodeoxyglucose positron emission tomography-computed tomography; MMHN, malignant melanoma of the head and neck; MIP, Maximum Intensity Projection.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-5887618/v1/cae3dc3c2adc9d86d36ff024.png"},{"id":75411692,"identity":"cdfc2bb8-fc55-474c-b8c1-6e1c8b1360d4","added_by":"auto","created_at":"2025-02-04 09:14:22","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2751764,"visible":true,"origin":"","legend":"\u003cp\u003eDifferences in FDG-PET/CT-derived biomarkers according to patient clinical parameters.\u003c/p\u003e\n\u003cp\u003ea. Box plots for SUVmax, MTV and TLG according to TNM stage using the Mann–Whitney U test are presented. TNM stage was dichotomized as follows: T3 vs. T4a and T4b. MTV and TLG were significantly high in T4a and T4b patients (\u003cem\u003ep\u003c/em\u003e = 0.005, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). SUVmax was also relatively high in T4a and T4b patients, but not statistically significant.\u003c/p\u003e\n\u003cp\u003eb. Box plots for SUVmax, MTV and TLG according to tumor size using the Mann–Whitney U test are presented. MTV and TLG were significantly high in patients with large tumor size (\u003cem\u003ep\u003c/em\u003e = 0.004, \u003cem\u003ep\u003c/em\u003e = 0.001).\u003c/p\u003e\n\u003cp\u003ec. Box plots for SUVmax, MTV and TLG according presence of sinusitis using the Mann–Whitney U test are presented. MTV and TLG were high in patient with presence of sinusitis (\u003cem\u003ep\u003c/em\u003e = 0.003, \u003cem\u003ep\u003c/em\u003e= 0.030).\u003c/p\u003e\n\u003cp\u003ed. Box plots for BLR and SLR according expression of PD-L1 using the Mann–Whitney U test are presented. SLR was high in PD-L1-negative patients (\u003cem\u003ep\u003c/em\u003e = 0.05). BLR was also high in PD-L1-negative patients, but the difference was not statistically significant (p = 0.234).\u003c/p\u003e\n\u003cp\u003eFDG-PET/CT, 18F-fluorodeoxyglucose positron emission tomography-computed tomography; SUVmax, maximum standardized uptake variable; MTV, metabolic tumor volume; TLG, total lesion glycolysis; BLR, bone marrow-to-liver ratio; SLR, spleen-to-liver ratio; PD-L1, programmed death-ligand 1.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-5887618/v1/8810b542d0bfbe425c2eb7d5.png"},{"id":75408284,"identity":"66b8cfaf-89b0-46a5-87c0-217215c4875e","added_by":"auto","created_at":"2025-02-04 08:58:22","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1737302,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation of clinical parameters and FDG-PET/CT-derived parameters with prognosis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea.\u003c/strong\u003e TNM tumor stage (T4) was associated with shorter PFS, as determined by Kaplan–Meier analysis and the log-rank test (p = 0.009).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eb.\u003c/strong\u003e High MTV was associated with shorter PFS, as determined by Kaplan–Meier analysis and the log-rank test (p = 0.012).\u003cbr\u003e\nPFS, progression-free survival; MTV, metabolic tumor volume; HR, hazard ratio; CI, confidence interval.\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-5887618/v1/694480bbf599f5c463181626.png"},{"id":88506179,"identity":"d7d69633-683f-4357-83cf-3ed214618d83","added_by":"auto","created_at":"2025-08-07 07:32:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":19968275,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5887618/v1/acc88805-ef9c-4358-aa36-262260f8be4a.pdf"},{"id":75410058,"identity":"6c0b762d-62d3-4d5a-b2c8-b1d1ac6efcfa","added_by":"auto","created_at":"2025-02-04 09:06:22","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":108092,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineResource1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5887618/v1/8ced42149281003580fb778d.pdf"},{"id":75408283,"identity":"8e2e0d97-aed1-4028-b1ac-c38c9e83a864","added_by":"auto","created_at":"2025-02-04 08:58:22","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":139036,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineResource2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5887618/v1/a56f30fd502a14de711b9728.pdf"},{"id":75410061,"identity":"95f3ee9b-89ce-4735-a41a-966142a6f012","added_by":"auto","created_at":"2025-02-04 09:06:22","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":174177,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineResource3.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5887618/v1/41157570cb4fa393471bf2db.pdf"},{"id":75408291,"identity":"2d56a165-69dc-4253-ae5f-d51394d0b891","added_by":"auto","created_at":"2025-02-04 08:58:22","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":13528,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5887618/v1/9e40c9e5cb8e249221498ae1.xlsx"},{"id":75410066,"identity":"5a250e22-6a89-443e-9594-a8dc94bbc63a","added_by":"auto","created_at":"2025-02-04 09:06:23","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":11993,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5887618/v1/4bfe9bab20c46a533a0ff6d1.xlsx"},{"id":75408292,"identity":"2c98725e-bb05-475a-9efa-8015687311a0","added_by":"auto","created_at":"2025-02-04 08:58:22","extension":"xlsx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":13126,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5887618/v1/ac64acfcab083771c463cfe6.xlsx"},{"id":75408300,"identity":"97e72dfd-1b5c-4f61-81ed-222349edfd69","added_by":"auto","created_at":"2025-02-04 08:58:23","extension":"xlsx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":14305,"visible":true,"origin":"","legend":"","description":"","filename":"table4.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5887618/v1/e34f7e1befa4ea424dc2f467.xlsx"}],"financialInterests":"","formattedTitle":"Prognostic Value of FDG-PET/CT Findings in Mucosal Melanoma of the Head and Neck Treated with Carbon Ion Radiotherapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMucosal melanoma of the head and neck (MMHN) is a rare and highly aggressive disease associated with a poor prognosis, with a 5-year overall survival (OS) rate of approximately 30% [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The standard treatment for local control of MMHN typically involves surgical resection with elective neck dissection, followed by postoperative radiotherapy and chemotherapy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Immune checkpoint inhibitors (ICIs), particularly those targeting cytotoxic T-lymphocyte (associated) antigen 4 (CTLA4) and programmed cell death 1 (PD-1)/ programmed death-ligand 1 (PD-L1), are used in adjuvant settings for both resected and unresectable/metastatic melanoma [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Previous studies have also demonstrated the efficacy of carbon ion radiotherapy (CIRT) combined with chemotherapy and ICIs, yielding excellent local control in advanced MMHN [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Given the rapid progression and poor prognosis of MMHN, validating prognostic predictors before treatment is crucial. High phosphohistone-H3 (PHH3) expression, the absence of pigmentation, NRAS or KRAS mutations, and larger tumor volumes have been associated with poor prognosis; however, to date, no correlation between radiological findings and prognosis has been established [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) is a useful imaging tool for detecting malignant tumors, and recent studies have highlighted its effectiveness for prognostic prediction in various cancers, including cutaneous malignant melanoma [\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16 CR17\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This retrospective study aimed to investigate the imaging findings of FDG-PET/CT and correlate them with the clinical characteristics and prognosis of patients with MMHN.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003ePatients\u003c/h2\u003e\n \u003cp\u003eThis single-center retrospective study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and all subsequent revisions, and was approved by the Institutional Ethics Committee (approval number 2024-eki7). The requirement for written informed consent was waived by the Institutional Review Board due to the its retrospective nature. Participants were given the opportunity to refuse by an opt-out method. We retrospectively reviewed our radiology reporting database to identify patients with pathologically confirmed MMHN who underwent FDG-PET/CT between January 2015 and August 2023. The exclusion criteria were as follows: patients who did not undergo CIRT, patients whose pre-treatment FDG-PET/CT data were unavailable, patients without residual tumors at the time of FDG-PET/CT due to surgical resection, and patients without available clinical follow-up records after CIRT.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eClinical information\u003c/h3\u003e\n\u003cp\u003ePatient clinical information, including age, sex, lactate dehydrogenase (LDH) levels, Eastern Cooperative Oncology Group (ECOG) performance status, sinusitis complications, and timing of initiation of ICI treatment, was collected from clinical records. Tumor characteristics, including primary site of the tumor, TNM stage (8th edition of the Union for International Cancer Control TNM staging system), lymph node metastasis, size of the tumor, PD-L1 status, and BRAF mutation, was also collected.\u003c/p\u003e\n\u003ch3\u003eFDG-PET/CT protocol and imaging analysis\u003c/h3\u003e\n\u003cp\u003eFDG-PET/CT images from the head to the mid-thigh were acquired using PET/CT scanners. The detailed PET/CT image acquisition protocols are summarized in Online Resource 1. The PET and CT images were transferred to an Advantage Workstation (version AW 4.7; GE Healthcare, WI, USA), where the fusion PET/CT images were constructed and analyzed. Regions of interest (ROIs) were manually delineated on the PET/CT images by a board-certified nuclear medicine physician (A.H.) and a radiologist (Y.Y.) for each lesion to assess maximum standardized uptake variable (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), bone marrow/liver SUVmax ratio (BLR) and spleen/liver SUVmax ratio (SLR). MTV was measured by setting a 50% SUVmax threshold for the tumor, and TLG was calculated by multiplying the MTV by the mean SUV of the tumor. The BLR and SLR were calculated by dividing the SUVmax of the bone marrow and spleen by the SUVmax of the liver. The tumor diameter was also measured using the simultaneous CT images.\u003c/p\u003e\n\u003ch3\u003eEvaluation of prognosis\u003c/h3\u003e\n\u003cp\u003eTo assess the response to treatment, local recurrence, and distant metastasis, imaging analysis using either CT or MRI was performed every 2 or 3 months after CIRT. Tumor size regression after treatment was evaluated and categorized according to the Revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). Progression-free survival (PFS) and OS were assessed to evaluate prognosis. PFS was defined as the time from the start of CIRT to the occurrence of local progression or the detection of new metastases. OS was defined as the time from the initiation of therapy to death or the date of the last confirmation of survival. Patients alive at the cut-off date of August 31, 2024, were censored.\u003c/p\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003ePatients were categorized into two groups based on pre-treatment parameters and tumor response, according to whether the values were higher or lower than the mean for continuous variables, T3 or T4 for the TNM stage, 0 or any other values for ECOG performance status, within the normal range or higher for LDH, and progressive disease (PD) or stable disease (SD) and partial response (PR) or complete response (CR) for response to CIRT, as defined by the RECIST guidelines. Differences in FDG-PET/CT parameters between the two groups were analyzed using the Mann\u0026ndash;Whitney U test. To evaluate prognosis, patients were divided into two groups with higher- and lower-than-mean values of FDG-PET/CT parameters, and differences in OS and PFS between the two groups were evaluated using the Kaplan\u0026ndash;Meier method and the log-rank test. The prognostic value of the FDG-PET/CT parameters was assessed using univariate and multivariate Cox regression analyses, and hazard ratios (HRs) were calculated. All statistical analyses were performed using SPSS Statistics for Windows version 29 (BM Corp., Armonk, NY, USA). Statistical significance was set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics and pre-treatment clinical parameters\u003c/h2\u003e \u003cp\u003eRadiological images of 60 patients with MMHN were obtained from our radiological database. Subsequently, 28 patients (Nineteen patients who did not undergo CIRT, four patients whose pre-treatment FDG-PET/CT was not available, one patient without residual tumor at the time of FDG-PET/CT because of surgical resection, and four patients whose clinical records of follow-up after CIRT were insufficient) were excluded, with 32 patients finally enrolled (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). CIRT was administered at a total dose of 64.0 Gy, divided into 16 fractions over four weeks. The inclusion criteria for pathologically proven MMHN for CIRT were the same as in our previously reported study, except for choroidal melanoma, N0 or N1 and M0 status, inoperable cases or patients who refused surgical resection, and an ECOG PS of 0\u0026ndash;2 [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The interval between FDG-PET/CT and CIRT initiation was 2\u0026ndash;68 days (mean: 27.67\u0026thinsp;\u0026plusmn;\u0026thinsp;15.36, median: 27). ICIs were administered to 24 patients (75%). Eight patients (25%) were treated with an adjuvant single-agent administration of anti-PD1, and eight patients were administered single-agent administration of anti-PD1 preceded to CIRT (25%). Eight patients (25%) were treated with anti-PD1 plus anti- CTLA4 after progression to distant metastasis. The other detailed patient characteristics are shown in Table\u0026nbsp;1.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePre-treatment FDG-PET/CT imaging findings and volumetric parameters\u003c/h3\u003e\n\u003cp\u003eThe pre-treatment FDG-PET/CT imaging findings are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. FDG accumulation in the primary tumor was enhanced, and the surrounding sinusitis also showed enhanced accumulation of FDG. Physiological accumulation in the brain and external eye muscles was also pronounced, in some cases overlapping with accumulation in the tumor. The FDG-PET/CT parameters (SUVmax, MTV, TLG, BLR, and SLR) are summarized in Table\u0026nbsp;2, and the histograms for each parameter are presented in Online Resource 2. The correlations between each FDG-PET/CT parameter are shown in Online Resource 3. Positive correlations were observed between SUVmax and TLG (r\u0026thinsp;=\u0026thinsp;0.447, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01), TLG and MTV (r\u0026thinsp;=\u0026thinsp;0.803, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and BLR and SLR (r\u0026thinsp;=\u0026thinsp;0.543, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCorrelations between pre-treatment FDG-PET/CT parameters and clinical characteristics\u003c/h2\u003e \u003cp\u003eDifferences in FDG-PET/CT parameters between clinical characteristics were evaluated using the Mann\u0026ndash;Whitney U test and are summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. MTV and TLG were high in patients with T4a and T4b stage disease (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea), large tumor size (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb), and presence of sinusitis (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec). SLR was significantly lower in PD-L1-positive cases (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.05) and higher in patients with sinusitis (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.048) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed). The BLR was also low in PD-L1-positive patients, but the difference was not statistically significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.234) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation of pre-treatment FDG-PET/CT parameters with response to CIRT\u003c/h2\u003e \u003cp\u003eThe responses to the CIRT assessed using the Revised RECIST (version 1.1) are summarized in Table\u0026nbsp;3. CR was achieved in seven patients (21.9%), PR in 18 patients (56.3%), SD in six patients (18.8%), and PD in one patient (3.1%). FDG-PET/CT-derived parameters showed no difference between the two groups of patients who showed a response to treatment (PR and CR) and those who did not show a response to treatment (PD and SD).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePrognostics\u003c/h2\u003e \u003cp\u003eThe prognostic data of the patients are summarized in Table\u0026nbsp;3. The median total observation period was 22.6 months (range, 7\u0026ndash;58; mean, 25.9; standard deviation (SD), 14.8). During follow-up, 13 patients died (40.6%) and 10 patients (31.3%) died from disease-related causes. Three patients died of pneumonia. Seven (21.9%) patients died within 1 year of treatment initiation, and 12 (37.5%) patients died within 3 years. The 1-year and 3-year survival rates were 78.1% and 62.5%, respectively. Three patients (9.3%) were censored because they changed hospitals, and 16 patients (50%) were alive. Disease progression, including distant metastasis or local recurrence, was observed in 16 patients (50%) within 1 year of treatment initiation and in 22 patients (68.8%) within 3 years after treatment initiation. Local recurrence was observed in 8 cases (25.0%) within 1 year after treatment initiation and in 9 patients (28.1%) within 3 years after treatment initiation. Distant metastasis was observed in 16 cases (50.0%) within 1 year after treatment initiation and in 19 cases (59.4%) within 3 years. The median OS was 21.6 months (range, 6\u0026ndash;57 months; mean, 24.8; SD, 14.7). The median PFS was 11.5 months (range, 1\u0026ndash;51 months; mean, 14.8 months; SD, 12.9).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation of clinical parameters and FDG-PET/CT-derived parameters with prognosis\u003c/h2\u003e \u003cp\u003eNo clinical parameters or FDG-PET/CT-derived parameters were independently associated with shorter OS by Kaplan\u0026ndash;Meier analysis or the log-rank test. Patients with poor ECOG performance status had a relatively shorter OS, but this was not statistically significant. Patients with high TNM tumor stage (T4a and T4b) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea) and high MTV (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb) had shorter PFS according to the Kaplan\u0026ndash;Meier analysis and log-rank test (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009 and 0.012, respectively). The results of univariate and multivariate Cox regression analysis for OS and PFS are summarized in Table\u0026nbsp;4. MTV was the only FDG-PET/CT-derived prognostic factor for predicting short PFS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.018; HR\u0026thinsp;=\u0026thinsp;2.851; 95% confidence interval (CI)\u0026thinsp;=\u0026thinsp;1.195\u0026ndash;6.803). A higher TNM tumor stage (T4a and T4b) was also independently associated with shorter PFS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014; HR\u0026thinsp;=\u0026thinsp;2.946; 95%CI\u0026thinsp;=\u0026thinsp;1.224\u0026ndash;6.989). The final multivariate model included MTV, sex, and ECOG performance status as potential confounders. We did not include TNM stage and MTV in the same multivariate model because elevated MTV and high TNM stage showed a significant correlation. MTV remained an independent prognostic factor for PFS in the multivariate model (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036; HR ratio, 2.60; 95%CI, 1.065\u0026ndash;6.345).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe results of our study revealed a correlation between the MTV of pre-treatment FDG-PET/CT and PFS, as determined by the Kaplan\u0026ndash;Meier method and the log-rank test. MTV was also identified as an independent prognostic factor for PFS based on a robust multivariate Cox regression analysis. Due to the rarity of MMHN, few clinical trials with small sample sizes have investigated optimal treatment strategies and prognostic indicators. Several studies have assessed the prognostic value of FDG-PET/CT in cutaneous malignant melanoma; however, only one study, conducted by Seban et al., has explored the utility of FDG-PET/CT in mucosal malignant melanoma, and it was limited to a small cohort that included cases from the esophagus and vagina, rather than exclusively focusing on MMHN [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. To date, our study is the first clinical report indicating that FDG-PET/CT-derived volumetric parameters may serve as optimal biomarkers for predicting prognosis in patients with MMHN treated with CIRT. MMHN is associated with a poor prognosis and frequently recurs locally or metastasizes, even after achieving local control, suggesting that FDG-PET/CT could be an effective tool for predicting the risk of recurrence before treatment initiation.\u003c/p\u003e \u003cp\u003eIn contrast to previous studies that reported shorter OS in patients with high FDG-PET/CT accumulation in the primary tumor, our study found no correlation between FDG-PET/CT-derived parameters and OS. One potential explanation for this discrepancy is the influence of surrounding tissue, such as the sinus, brain, and exophthalmic muscles, due to the tumor\u0026rsquo;s location in MMHN. Previous reports have indicated that inflammatory complications can cause false-positive results when assessing head and neck malignancies [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], and the surrounding conditions of MMHN may have impacted the FDG-PET/CT parameters. Additionally, although CIRT has been reported to be particularly effective in achieving local control in the treatment of MMHN, its contribution to improving OS has been shown to be limited due to the high frequency of distant metastases [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This study also demonstrated a high frequency of distant metastases, and local treatment options for metastatic sites were restricted to palliative irradiation, which may explain why FDG-PET/CT did not prove useful in predicting OS in MMHN patients after CIRT.\u003c/p\u003e \u003cp\u003eAs a single-center retrospective study with a small sample size, the present study has several limitations. First, data on PD-L1 expression status were missing for some patients. Recently, PD-L1 expression on tumor cells has emerged as a potential prognostic marker for predicting sensitivity to ICIs [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Although previous studies have reported a correlation between PD-L1 expression and FDG-PET/CT accumulation [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], only PD-L1 expression and SLR showed a statistically significant negative correlation in the present study. Additionally, pronounced FDG uptake in hematopoietic organs such as the bone marrow and spleen has been identified as a negative prognostic marker for various malignancies, including melanoma [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Since statistical significance could not be established between OS and SLR due to the small sample size in this study, further verification in a larger cohort is necessary. Second, uniformity in the administration of ICIs should be ensured. ICIs are a crucial treatment for advanced MMHN, as they can improve prognosis. As noted earlier, MMHN frequently metastasizes, even when localized; therefore, the addition of adjuvant ICI therapy to CIRT is recommended. Third, all patients were treated with CIRT, which could have introduced selection bias, as patients were given CIRT instead of surgical resection or ICI treatment. To address these limitations, it would be beneficial to conduct a comparative study of different treatment modalities, including ICI treatment, CIRT alone, CIRT with adjuvant ICI, and conventional surgery with adjuvant radiation therapy, using a larger patient cohort.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCorrelations between FDG-PET/CT-derived parameters, clinical parameters, and prognosis were evaluated in patients with MMHN treated with CIRT. A higher SLR correlated with negative PD-L1 expression in tumors. MTV was the sole prognostic factor for PFS. Therefore, FDG-PET-derived parameters may serve as significant prognostic markers for predicting tumor progression in patients with MMHN.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo potential conflicts of interest were disclosed.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eSources of funding\u003c/strong\u003e: The Authors received no funds for this study.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLombardi D, Bottazzoli M, Turri-Zanoni M, Raffetti E, Villaret AB, Morassi ML, et al. Sinonasal mucosal melanoma: A 12-year experience of 58 cases. Head Neck. 2016;38 Suppl 1:E1737-45. doi: 10.1002/hed.24309.\u003c/li\u003e\n\u003cli\u003eMoreno MA, Roberts DB, Kupferman ME, DeMonte F, El-Naggar AK, Williams M, et al. Mucosal melanoma of the nose and paranasal sinuses, a contemporary experience from the M. D. Anderson Cancer Center. Cancer. 2010;116:2215-23. doi: 10.1002/cncr.24976.\u003c/li\u003e\n\u003cli\u003eTajudeen BA, Vorasubin N, Sanaiha Y, Palma-Diaz MF, Suh JD, Wang MB. Sinonasal mucosal melanoma: 20-year experience at a tertiary referral center. Int Forum Allergy Rhinol. 2014;4:592-7. doi: 10.1002/alr.21324.\u003c/li\u003e\n\u003cli\u003eNenclares P, Ap Dafydd D, Bagwan I, Begg D, Kerawala C, King E, et al. Head and neck mucosal melanoma: The United Kingdom national guidelines. Eur J Cancer. 2020;138:11-8. doi: 10.1016/j.ejca.2020.07.017.\u003c/li\u003e\n\u003cli\u003eSeth R, Messersmith H, Kaur V, Kirkwood JM, Kudchadkar R, McQuade JL, et al. Systemic Therapy for Melanoma: ASCO Guideline. J Clin Oncol. 2020;38:3947-70. doi: 10.1200/JCO.20.00198.\u003c/li\u003e\n\u003cli\u003eMizoguchi N, Kano K, Okuda T, Koge H, Shima S, Tsuchida K, et al. Adjuvant Therapy with Immune Checkpoint Inhibitors after Carbon Ion Radiotherapy for Mucosal Melanoma of the Head and Neck: A Case-Control Study. Cancers (Basel). 2024;16. doi: 10.3390/cancers16152625.\u003c/li\u003e\n\u003cli\u003eTakayasu Y, Kubo N, Shino M, Nikkuni O, Ida S, Musha A, et al. Carbon-ion radiotherapy combined with chemotherapy for head and neck mucosal melanoma: Prospective observational study. Cancer Med. 2019;8:7227-35. doi: 10.1002/cam4.2614.\u003c/li\u003e\n\u003cli\u003eKoto M, Demizu Y, Saitoh JI, Suefuji H, Tsuji H, Okimoto T, et al. Multicenter Study of Carbon-Ion Radiation Therapy for Mucosal Melanoma of the Head and Neck: Subanalysis of the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS) Study (1402 HN). Int J Radiat Oncol Biol Phys. 2017;97:1054-60. doi: 10.1016/j.ijrobp.2016.12.028.\u003c/li\u003e\n\u003cli\u003eComoglu S, Polat B, Celik M, Sahin B, Enver N, Keles MN, et al. Prognostic factors in head and neck mucosal malignant melanoma. Auris Nasus Larynx. 2018;45:135-42. doi: 10.1016/j.anl.2017.03.016.\u003c/li\u003e\n\u003cli\u003eThierauf JC, Kaluziak ST, Codd E, Dybel SN, Jobbagy S, Purohit R, et al. Prognostic biomarkers for survival in mucosal melanoma. Pigment Cell Melanoma Res. 2023;36:378-87. doi: 10.1111/pcmr.13104.\u003c/li\u003e\n\u003cli\u003eFlukes S, Lohia S, Barker CA, Cracchiolo JR, Ganly I, Patel SG, et al. Primary tumor volume as a predictor of distant metastases and survival in patients with sinonasal mucosal melanoma. Head Neck. 2020;42:3316-25. doi: 10.1002/hed.26380.\u003c/li\u003e\n\u003cli\u003eEl-Adem D, Yang N, Gudis DA. The Role of Positron Emission Tomography for the Management of Sinonasal Malignancies: A Systematic Review. Am J Rhinol Allergy. 2023;37:593-610. doi: 10.1177/19458924231177854.\u003c/li\u003e\n\u003cli\u003eShirai K, Abe T, Saitoh JI, Mizukami T, Irie D, Takakusagi Y, et al. Maximum standardized uptake value on FDG-PET predicts survival in stage I non-small cell lung cancer following carbon ion radiotherapy. Oncol Lett. 2017;13:4420-6. doi: 10.3892/ol.2017.5952.\u003c/li\u003e\n\u003cli\u003eShrestha S, Higuchi T, Shirai K, Tokue A, Shrestha S, Saitoh JI, et al. Prognostic significance of semi-quantitative FDG-PET parameters in stage I non-small cell lung cancer treated with carbon-ion radiotherapy. Eur J Nucl Med Mol Imaging. 2020;47:1220-7. doi: 10.1007/s00259-019-04585-0.\u003c/li\u003e\n\u003cli\u003eNakamoto R, Zaba LC, Liang T, Reddy SA, Davidzon G, Aparici CM, et al. Prognostic Value of Bone Marrow Metabolism on Pre-treatment (18)F-FDG PET/CT in Patients with Metastatic Melanoma Treated with Anti-PD-1 Therapy. J Nucl Med. 2021;62:1380-3. doi: 10.2967/jnumed.120.254482.\u003c/li\u003e\n\u003cli\u003ePerng P, Marcus C, Subramaniam RM. (18)F-FDG PET/CT and Melanoma: Staging, Immune Modulation and Mutation-Targeted Therapy Assessment, and Prognosis. AJR Am J Roentgenol. 2015;205:259-70. doi: 10.2214/AJR.14.13575.\u003c/li\u003e\n\u003cli\u003eSeban RD, Moya-Plana A, Antonios L, Yeh R, Marabelle A, Deutsch E, et al. Prognostic 18F-FDG PET biomarkers in metastatic mucosal and cutaneous melanoma treated with immune checkpoint inhibitors targeting PD-1 and CTLA-4. Eur J Nucl Med Mol Imaging. 2020;47:2301-12. doi: 10.1007/s00259-020-04757-3.\u003c/li\u003e\n\u003cli\u003eReinert CP, Gatidis S, Sekler J, Dittmann H, Pfannenberg C, la Fougere C, et al. Clinical and prognostic value of tumor volumetric parameters in melanoma patients undergoing (18)F-FDG-PET/CT: a comparison with serologic markers of tumor burden and inflammation. Cancer Imaging. 2020;20:44. doi: 10.1186/s40644-020-00322-1.\u003c/li\u003e\n\u003cli\u003ePlacke JM, Kimmig M, Griewank K, Herbst R, Terheyden P, Utikal J, et al. Correlation of tumor PD-L1 expression in different tissue types and outcome of PD-1-based immunotherapy in metastatic melanoma - analysis of the DeCOG prospective multicenter cohort study ADOREG/TRIM. EBioMedicine. 2023;96:104774. doi: 10.1016/j.ebiom.2023.104774.\u003c/li\u003e\n\u003cli\u003eShimura K, Mabuchi S, Komura N, Yokoi E, Kozasa K, Sasano T, et al. Prognostic significance of bone marrow FDG uptake in patients with gynecological cancer. Sci Rep. 2021;11:2257. doi: 10.1038/s41598-021-81298-1.\u003c/li\u003e\n\u003cli\u003eJiang H, Zhang R, Jiang H, Zhang M, Guo W, Zhang J, et al. Retrospective analysis of the prognostic value of PD-L1 expression and (18)F-FDG PET/CT metabolic parameters in colorectal cancer. J Cancer. 2020;11:2864-73. doi: 10.7150/jca.38689.\u003c/li\u003e\n\u003cli\u003eHu B, Xiao J, Xiu Y, Fu Z, Shi H, Cheng D. Correlation of PD-L1 expression on tumor cell and tumor infiltrating immune cell with 18F-fluorodeoxyglucose uptake on PET/computed tomography in surgically resected pulmonary adenocarcinoma. Nucl Med Commun. 2020;41:252-9. doi: 10.1097/MNM.0000000000001136.\u003c/li\u003e\n\u003cli\u003eWu X, Huang Y, Zhao Q, Wang L, Song X, Li Y, et al. PD-L1 expression correlation with metabolic parameters of FDG PET/CT and clinicopathological characteristics in non-small cell lung cancer. EJNMMI Res. 2020;10:51. doi: 10.1186/s13550-020-00639-9.\u003c/li\u003e\n\u003cli\u003eEl-Azony A, Basha MAA, Almalki YE, Abdelmaksoud B, Hefzi N, Alnagar AA, et al. The prognostic value of bone marrow retention index and bone marrow-to-liver ratio of baseline 18F-FDG PET/CT in diffuse large B-cell lymphoma. Eur Radiol. 2024;34:2500-11. doi: 10.1007/s00330-023-10150-z.\u003c/li\u003e\n\u003cli\u003eWong A, Callahan J, Keyaerts M, Neyns B, Mangana J, Aberle S, et al. (18)F-FDG PET/CT based spleen to liver ratio associates with clinical outcome to ipilimumab in patients with metastatic melanoma. Cancer Imaging. 2020;20:36. doi: 10.1186/s40644-020-00313-2.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e\n"}],"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":"Mucosal melanoma of the head and neck (MMHN), pre-treatment FDG-PET/CT, prognosis, carbon ion radiotherapy (CIRT), metabolic tumor volume (MTV), spleen-to-liver ratio (SLR), programmed death-ligand 1 (PD-L1)","lastPublishedDoi":"10.21203/rs.3.rs-5887618/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5887618/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo investigate the prognostic value of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) in patients with mucosal melanoma of the head and neck (MMHN) treated with carbon ion radiotherapy (CIRT).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis single-center retrospective study included patients with MMHN who underwent CIRT and FDG-PET/CT. Correlations of pre-treatment FDG-PET/CT-derived parameters, including the maximum standardized uptake variable (SUVmax), metabolic tumor volume (MTV) with a 50% threshold, total lesion glycolysis (TLG), bone marrow-to-liver ratio (BLR), and spleen-to-liver ratio (SLR), with clinical parameters and prognosis were statistically analyzed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 32 patients with MMHN were enrolled (median age, 72.5 years). The tumor stages were distributed as follows: T3, 17 patients; T4a, 14 patients; and T4b, one patient. The median total observation period was 22.6 months, the median overall survival (OS) was 21.6 months, and the median progression-free survival (PFS) was 11.5 months. Thirteen patients (40.6%) died, 10 (31.3%) experienced local recurrence, and 19 (59.4%) had distant metastases during the observation period. The 1-year survival rate was 78.1% and the 3-year survival rate was 62.5%. FDG-PET/CT show pronounced positive uptake for all tumors (median SUVmax 13.80, range 2.74\u0026ndash;32.99). SLR was high in patients with negative programmed death-ligand 1 (PD-L1) expression in the tumor (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.05). PFS was shorter in patients with a high MTV (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.018). In multivariate analysis, MTV was an independent prognostic factor for PFS (hazard ratio (HR), 2.60; 95% confidence interval (CI), 1.065\u0026ndash;6.345; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036). MTV and TLG were not predictive of OS in the univariate analysis.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eFDG-PET/CT showed a strong positive uptake for MMHN. FDG-PET/CT-derived imaging parameters may be significant prognostic biomarkers for predicting tumor progression in patients with MMHN.\u003c/p\u003e","manuscriptTitle":"Prognostic Value of FDG-PET/CT Findings in Mucosal Melanoma of the Head and Neck Treated with Carbon Ion Radiotherapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-04 08:58:17","doi":"10.21203/rs.3.rs-5887618/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-02-01T08:12:49+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-01-31T11:11:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-01-31T00:10:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Nuclear Medicine","date":"2025-01-30T05:22:14+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":"e1f60851-7c28-452d-a863-ff08c05f3e27","owner":[],"postedDate":"February 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-07T07:20:00+00:00","versionOfRecord":{"articleIdentity":"rs-5887618","link":"https://doi.org/10.1007/s12149-025-02069-w","journal":{"identity":"annals-of-nuclear-medicine","isVorOnly":false,"title":"Annals of Nuclear Medicine"},"publishedOn":"2025-07-25 15:58:27","publishedOnDateReadable":"July 25th, 2025"},"versionCreatedAt":"2025-02-04 08:58:17","video":"","vorDoi":"10.1007/s12149-025-02069-w","vorDoiUrl":"https://doi.org/10.1007/s12149-025-02069-w","workflowStages":[]},"version":"v1","identity":"rs-5887618","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5887618","identity":"rs-5887618","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}