Radiolabeled anti-PD-L1 peptide PET/CT in predicting the efficacy of neoadjuvant immunotherapy combined with chemotherapy in resectable non-small cell lung cancer

Radiolabeled anti-PD-L1 peptide PET/CT in predicting the efficacy of neoadjuvant immunotherapy combined with chemotherapy in resectable non-small cell lung cancer | 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 Radiolabeled anti-PD-L1 peptide PET/CT in predicting the efficacy of neoadjuvant immunotherapy combined with chemotherapy in resectable non-small cell lung cancer Xin Zhou, Shi Yan, Dan Li, Hua Zhu, Bing Liu, Shiwei Liu, Wei Zhao, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4645551/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Dec, 2024 Read the published version in Annals of Nuclear Medicine → Version 1 posted 4 You are reading this latest preprint version Abstract Background: This study aimed to evaluate the predictive value of baseline PD-L1 targeted peptide 68 Ga-NOTA-WL12 PET/CT in neoadjuvant immunotherapy combined with chemotherapy of resectable NSCLC. Methods: Patients with resectable NSCLC (n = 20) enrolled­­­­­­­ in this prospective study received baseline paired 68 Ga-NOTA-WL12 PET/CT and 18 F-FDG PET/CT. After 2–4 cycles of toripalimab plus nab-paclitaxel and cisplatin, surgery was performed if R0 resection was available. The major pathologic response (MPR) state of the post-operative specimen was recorded. The imaging parameters of the 68 Ga-NOTA-WL12 PET/CT, 18 F-FDG PET/CT and CT between the MPR and non-MPR groups and their predictive efficacy of MPR were compared. Results: Among 20 patients, 17patients underwent surgery, 10 achieved an MPR and 7 did not. The SUV max and tumour-to-blood pool (TBR) of baseline 68 Ga-NOTA-WL12 in the MPR group were higher than those in the non-MPR group, and the difference of TBR was statistically significant. The DSUL peak % of 18 F-FDG exhibited differences between the MPR and non-MPR groups with no significance. Baseline 18 F-FDG PET/CT parameters and DD% failed to differentiate the two groups. The areas under the ROC curves of SUV max , TBR in 68 Ga-NOTA-WL12 PET/CT, DD% and DSUL peak % in 18 F-FDG PET/CT were 0.76, 0.79, 0.71 and 0.80, respectively, in predicting MPR. Conclusion: Baseline 68 Ga-NOTA-WL12 PET/CT has a potential to predict the pathological response of neoadjuvant immunotherapy combined with chemotherapy in patients with resectable NSCLC, whose efficacy is comparable to that of therapy evaluations employing baseline and follow-up CT and 18 F-FDG PET/CT examinations. Trial registration: NCT04304066, registered 13 November 2020, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000AEI9&selectaction=Edit&uid=U000503E&ts=2&cx=-awajet 68Ga-NOTA-WL12 PET/CT resectable NSCLC toripalimab neoadjuvant immunotherapy. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Background Non-small cell lung cancer (NSCLC) accounts for 80% of newly diagnosed cases of lung cancer, which ranks in the top two in morbidity and mortality among malignant tumours worldwide [ 1 ] . Approximately 50% of patients with NSCLC present with localized disease or localized advanced disease (I-III) [ 2 ] . The traditional treatment strategy of resectable patients combines neoadjuvant therapy, complete surgery and adjuvant therapy, the prognosis is poor and overall survival (OS) substantially decreases with the increasing stage [ 3 , 4 ] . Immunotherapy employing therapeutics targeting the programmed cell death (ligand)-1 (PD-[L]1) is recognized as first-line therapy for patients with advanced NSCLC without genetic aberrations because of its excellent efficacy [ 5 , 6 ] . For resectable patients with NSCLC, the clinical application of neoadjuvant immunotherapy is in the exploratory stage. At the beginning of the exploration, a series of clinical trials concerning neoadjuvant immunotherapy [ 7 , 8 ] employed the major pathological response (MPR) as an important surrogate for predicting prognosis. Furthermore, the MPR serves as the endpoint of most neoadjuvant clinical trials [ 7 ] ; and the prognosis of the MPR group is significantly better than that of the non-MPR group [ 9 , 10 ] . The results of several clinical trials indicate that a compelling MPR rate higher than 55% was achieved by neoadjuvant immunotherapy combined with chemotherapy [ 7 , 8 , 11 ] . Therefore, predicting MPR to screen patients who benefit from neoadjuvant immunotherapy combined with chemotherapy is an important research topic. PD-L1 expression detected using immunohistochemistry (IHC) in tumour tissue serves as the traditional indicator of predicting MPR [ 12 , 13 ] . However, the above-cited clinical trials do not indicate PD-L1 expression predicts MPR status after neoadjuvant immunotherapy combined with chemotherapy, neither does tumour mutation burden (TMB) [ 7 , 8 , 11 ] . Positron emission tomography (PET) enables whole-body, quantitative, real-time non-invasive assessment of expression levels of targeted receptors detected using suitable radiotracers [ 14 , 15 ] . Previous studies concerning the clinical translation of several radiolabelled PD-L1-targeted antibodies and adnectins in patients with NSCLC, show that PET/CT imaging reflects the efficacy of immunotherapy [ 16 , 17 ] . However, these probes have imitations of relatively large molecular weight with slow metabolism and poor penetration ability. The small peptide WL12 binds PD-L1 with high-affinity [ 18 , 19 ] , and when labelled with 68 Ga, serves as a specific radiotracer for PD-L1. Our previous research indicates the potential of 68 Ga-NOTA-WL12 PET/CT to monitor the efficacy of immunotherapy [ 20 ] . To extend these findings, here we evaluated the predictive value of baseline 68 Ga-NOTA-WL12 PET/CT in neoadjuvant immunotherapy combined with chemotherapy of patients with resectable NSCLC. Methods Patients The Medical Ethics Committee of Peking University Cancer Hospital approved this prospective study (2019 KT62), and informed consent was acquired from patients. The trial was registered at www.clinicaltrialsregister.eu (Trial Identifier: NCT04304066). Consecutive patients with resectable NSCLC were recruited from January 2021 to October 2021. The inclusion criteria were as follows: (1) Patients with NSCLC with clinical stages IIb–IIIa/b; (2) consented to neoadjuvant immunotherapy plus chemotherapy; (3) underwent baseline-paired 68 Ga-NOTA-WL12 PET/CT and 18 F-FDG PET/CT within 2 weeks; (4) with acceptable kidney and liver function, together with sound hemopoietic function of the bone marrow and (5) ECOG scores 0–1. The exclusion criteria were as follows: (1) prior chemotherapy or radiotherapy and (2) unable to complete 2 cycles of neoadjuvant immunotherapy combined with chemotherapy. Patients’ clinical characteristics, pathology and follow-up information were recorded. The neoadjuvant therapy regimen comprised toripalimab plus nab-paclitaxel and cisplatin. After the second cycle of neoadjuvant therapy, if R0 resection was available, radical resection and mediastinal lymph node dissection were performed within 6–8 weeks. R0 resection means that both the primary lesion and metastatic lymph nodes can be completely removed. For clinical N0-1 patients and N2 patients with single-station and non-bulky lymph node, R0 resection is achievable. For clinical multi-station N2 patients, multi-disciplinary team (MDT) will be conducted to evaluate whether R0 resection can be achieved. If R0 resection was not available, the former regimen was continued until a response state occurred, enabling surgery. If remission was not achieved after 4 cycles of the regimen, no surgery would be performed, and treatment was determined according to the specific condition. A post-operative MPR or a non-MPR was regarded as an endpoint of the study. Production of 68 Ga-NOTA-WL12 NOTA-WL12 was synthesized and provided by Chinapeptides (Shanghai, China). As described previously [20] , to radiolabel NOTA-WL12, 925~1110 Mbq 68 GaCl 3 was mixed with 195 μL 1 M (pH 8.5) sodium acetate buffer and reacted with NOTA-WL12 (30 μg) at 60℃ for 15 min. The final product was sep-pak purified and obtained in > 99% radiochemical purity by HPLC, as described previously [20] . Pathology IHC analysis of PD-L1 expression levels in pre-therapy biopsies employed an anti-PD-L1 monoclonal designated clone 22C3 (Dako Denmark A/S). High positive, low-positive and negative PD-L1 expression was defined as a tumor proportion score (TPS) ≥ 50%, 49 ≥ TPS > 1% and TPS < 1%. The MPR was defined as ≤ 10% of residual viable tumour upon surgery. PET/CT Patients were intravenously injected with 68 Ga-NOTA-WL12 (1.9-3.7 MBq/kg) and co-administered 120 μg of WL12. Patients drank 800-1500 mL of water, and PET/CT was performed 1 h after injection. Patients urinated before the examination. Imaging was performed using a Biograph mCT Flow 64 scanner (Siemens, Erlangen, Germany) (120 kV; 146 mA; slice; 3 mm; matrix 200 × 200; iterations, 2; subsets, 11; filter, 5-mm Gaussian). The patient’s bed continuously moved at 1.5 mm/s to cover the body from the top of the skull to the middle of the femur. Images were reconstructed using ordered subset expectation maximization. CT reconstruction used a standard method with a 512 × 512 matrix and a layer thickness of 3–5 mm. CT data were used to correct the PET images for attenuation. Vital signs, laboratory studies and electrocardiograms were obtained before injection, during the screening period and 2 h after PET/CT. The patients were instructed to fast for ≥ 6 h before undergoing the 18 F-FDG PET/CT scans to ensure normal blood glucose levels (4.4-9.3 mmol/L). The intravenously injected dose was calculated according to body weight (3.7 MBq/kg), and patients rested for 1 h before the examination. The remaining acquisition conditions were consistent with 68 Ga-NOTA-WL12 PET/CT. And all the patients were recommended to undergo follow-up 18 F-FDG PET/CT within 3 weeks after 2–4 cycles of the therapy regimen. Image Analysis A Siemens workstation (Syngo.via VB20, MM Oncology) was used for post-processing images. Two physicians specializing in nuclear medicine with 5–10 years of diagnostic experience blinded to the prior imaging findings and pathological results reviewed all images independently, and any discordant results were resolved by a third physician with 15–20 years of diagnostic experience. The volume of interest of the primary pulmonary tumour on 18 F-FDG PET/CT and 68 Ga-NOTA-WL12 PET/CT was automatically delineated to completely cover the extent of the target lesion while avoiding surrounding tissues and organs. The values of SUV max of the lesions and SUV mean of the blood pool (BP) based on the uptake of the left atrium, which served as background uptake, were recorded, and the ratio of tumour-to-BP (TBR) was calculated as tumour SUV max /BP SUV mean . SUV lean (SUL) was obtained by standardizing SUV to the body mass, and the average uptake of the 15-mm-diameter circle centered over the highest-uptake part of the tumor was SUL peak , which serves as the standard parameter for therapy evaluation using 18 F-FDG PET/CT [21] . DSUL peak % was calculated as ([baseline SUL peak – follow-up SUL peak ]/baseline SUL peak )*100%. The longest diameter (D) of the tumour was determined, and DD% was calculated as follows: ([baseline D – follow-up D]/baseline D) * 100%. Statistical analysis IBM SPSS Statistics (version 25.0) and GraphPad Prism (version 8.0) were used to perform statistical analyses of patients’ data. SUV max and TBR were expressed as the median (inter-quartile range). The values and change rates of uptake in 18 F-FDG PET/CT and 68 Ga-NOTA-WL12 PET/CT were compared among MPR and non-MPR groups (Mann–Whitney test). Data distribution was displayed using a violin plot. The area under the receiver operating characteristic (ROC) curve was used to analyse the predictive value of the uptake parameters of the response to therapy, and the cut-off value was obtained from the Youden index. Diagnostic performance, including sensitivity, specificity and accuracy were calculated. Differences with P <0.05 were considered statistically significant. Results Patients’ Characteristics The clinicopathological characteristics of 20 patients with resectable NSCLC (2 women, 18 men; median age, 62 years; range, 51–75 years) enrolled in the study are presented in Table 1 . All patients underwent paired baseline 18 F-FDG PET/CT and 68 Ga-NOTA-WL12 PET/CT before neoadjuvant therapy and follow-up enhanced CT after that. Fourteen patients underwent follow-up 18 F-FDG PET/CT. Seventeen patients underwent surgery after neoadjuvant immunotherapy combined with chemotherapy, among which 10 achieved MPR and 7 did not. A flow diagram of the study is depicted in Fig. 1 . Table 1 Patients’ clinicopathological characteristics Information Patients n (%) Age (y) Median (range) 62 (51–75) Gender Female 2 (10.0) Male 18 (90.0) Smoking No 3 (15.0) Yes 17 (85.0) Family history of malignancy No 18 (90.0) Yes 2 (10.0) Clinical staging Staging II 8 (40.0) Staging III 12 (60.0) Pathology Adenocarcinoma 1 (5.0) Squamous carcinoma 19 (95.0) PD-L1 expression NA 3 (15.0) TPS TPS ≥ 1% 4 (20.0) TPS ≥ 50% 8 (40.0) Note. NA, not available. 68 Ga-NOTA-WL12 PET/CT and PD-L1 expression Among 17 patients with pre-therapy PD-L1 IHC expression, the IHC scores of 5, 4 and 8 patients were negative, low-positive and high-positive, respectively. The uptake values of baseline 68 Ga-NOTA-WL12 (SUV max and TBR) were not significantly different among the groups (Fig. 2 ). Among patients with negative, low-positive and high-positive PD-L1 expression, there was no significant difference in the incidence of MPR ( P = 0.34). PET/CT and pathological responses There were 10 patients in MPR and 7 patients in non-MPR groups, respectively. In baseline 68 Ga-NOTA-WL12 PET/CT, SUV max (median: 3.1 [2.8, 3.4] vs 2.7 [2.6, 2.8]; P = 0.073) and TBR (median: 3.1 [2.6, 4.1] vs 2.4 [2.3, 2.7]; P = 0.046) in the MPR group were higher compared with the non-MPR group, and the difference of TBR was statistically significant (Fig. 3 , A and B ). Figure 4 shows that the SUV max values of the non-MPR and MPR patients were 2.6 and 3.9, respectively. SUV max (median: 15.8 [10.3, 19.3] vs 15.9 [8.6, 17.6]; P = 0.887], TBR (median: 8.6 [6.9, 12.9] vs 9.9 [7.1, 16.0]; P = 0.813) in baseline 18 F-FDG PET/CT and ΔD% (median: 57.3% [41.5%, 71.8%] vs 43.2% [7.9%, 58.3%]; P = 0.161) were not significantly different between the MPR and non-MPR groups (Fig. 3 , C, D and E ). Among 14 patients underwent follow-up 18 F-FDG PET/CT, 9 achieved MPR and 5 did not, the 18 F-FDG ΔSUL peak % differed between MPR and non-MPR groups (median: 83.5% [63.8%, 87.2%] vs 28.4% [-27.4%, 77.5%]; P = 0.083) (Fig. 3 , F), but the difference was not statistically significant either. The predictive value of PET/CT parameters in the pathological response The areas under the ROC curve of SUV max , TBR in 68 Ga-NOTA-WL12 PET/CT, ΔD% and ΔSUL peak % in 18 F-FDG PET/CT were 0.76 (95%CI: 0.52–1.00), 0.79 (0.56–1.00), 0.71 (0.46–0.96) and 0.80 (0.51-1.00) respectively, indicating the good predictive value of the above parameters except for ΔD% ( P = 0.143) in identifying MPR (Fig. 5 ). Furthermore, the cut-off values obtained from the Youden index were 2.9, 2.7, 60% and 30% respectively. The detailed diagnostic values are depicted in Table 2 . The TBR in 68 Ga-NOTA-WL12 PET/CT and ΔD% of patients were ordered as shown in the waterfall chart (Fig. 6 ), and the waterfall chart of SUV max was shown in Supplementary Fig. 1 . Which indicates that the 68 Ga-NOTA-WL12 TBR values of nearly all non-MPR patients were < 2.7, while nearly all patients with TBR ≥ 2.7 achieved an MPR. Patients with ΔD% ≥60% achieved an MPR, while the ΔD% values of all non-MPR patients were < 60%. Table 2 The diagnostic efficacy of the imaging parameters that predict MPR Parameters Cut-off AUC 95%CI P value SEN (%) SPEC (%) WL12 SUV max ≥ 2.9 0.76 0.52-1.00 0.071 70.0 85.7 WL12 TBR ≥ 2.7 0.79 0.56-1.00 0.045 80.0 85.7 ΔD% ≥ 60% 0.71 0.46–0.96 0.143 100 50 FDG ΔSUL peak % ≥ 30% 0.80 0.51-1.00 0.070 100 60 Note. AUC, area under the curve; SEN, sensitivity; SPEC, specificity; TBR, tumour-to-blood pool; D, the longest diameter. Discussion Recent clinical studies of neoadjuvant immunotherapy combined with chemotherapy administered to patients with resectable NSCLC show excellent efficacy as indicated by a high MPR rate [ 7 , 8 , 11 ] . However, these studies indicated the common criteria including PD-L1 IHC data and TMB failed to identify patients who may benefit from currently available neoadjuvant immunotherapy combined with chemotherapy. In the present study, we therefore evaluated the predictive value of the specific PD-L1-binding radiotracer, 68 Ga-NOTA-WL12, in neoadjuvant immunotherapy combined with chemotherapy of resectable patients with NSCLC [ 18 , 19 ] . 68 Ga-NOTA-WL12 is a specific radiotracer that binds to PD-L1. The preliminary clinical translation of 68 Ga-NOTA-WL12 PET/CT achieved here indicates its feasibility for non-invasive in vivo detection of PD-L1 expression levels and its potential value for predicting the outcomes of immunotherapy [ 20 ] . The results of present study show that there was no significant relationship between the uptake value of 68 Ga-NOTA-WL12 in primary lesions and PD-L1 IHC expression. Furthermore, previous studies of PD-(L)1-targeted radiotracers report inconsistent and controversial correlations with PD-L1 expression [ 17 , 20 , 22 , 23 ] . For example, two studies found the uptake of PD-(L)1-targeted radiotracers correlate with PD-(L)1 expression [ 17 , 20 ] , although others arrived at the opposite conclusion [ 22 , 23 ] . A possible explanation of these discordant findings is the inherent limitation of IHC to detect intra-tumour heterogeneity [ 24 ] . Moreover, the subjects in the above cited studies included advanced NSCLC, but the biopsy specimens used for PD-L1 expression analysis were obtained from a single site, which may lead to inconsistent findings. Furthermore, the relationship between PD-L1 expression and the response to immunotherapy was not determined. Some studies indicate that PD-L1 expression is not related to the efficacy of therapy [ 25 – 28 ] , while some studies conclude that PD-L1 expression is a sound predictor of efficacy [ 29 ] . The uptake of 68 Ga-NOTA-WL12 enables the assessment of PD-L1 expression in the whole lesion, thus, it may outperform PD-L1 detected using IHC analysis to predict the efficacy of immunotherapy. The present analysis detected differences between uptake of baseline 68 Ga-NOTA-WL12 PET/CT (SUV max and TBR) and change rate of baseline and follow-up 18 F-FDG PET/CT (ΔSUL peak %) in MPR and non-MPR groups, and the difference of 68 Ga-NOTA-WL12 TBR was statistically significant. Whereas there were no significant differences in the D% and baseline 18 F-FDG PET/CT data. The excellent ability of morphological change rate of CT and metabolic change rate of 18 F-FDG PET/CT to predict MPR in neoadjuvant immunotherapy has long been recognized [ 30 , 31 ] . However, these parameters require follow-up CT and 18 F-FDG PET/CT examinations, which fail to identify patients who may benefit from neoadjuvant therapy prior to main therapy. Previous studies concerning the clinical translation of other PD-L1-targeted probes in NSCLC confirmed the predictive value of probes that reflect the efficacy of immunotherapy [ 16 , 17 ] . For example, Bensch et al. [ 16 ] . detected tumour heterogeneity using the PD-L1-targeted agent 89 Zr-atezolizumab and a higher uptake of the radiotracer leads to higher response rate, which is strongly related to progression-free survival and OS at the same time [ 16 ] . Furthermore, Niemeijer et al. [ 17 ] detected a relationship between tracer uptake and response state. The probes used in these studies included anti-PD-L1 antibodies or adnectin with high molecular weight, which failed to reflect PD-L1 expression and its change state over time because of their slow metabolism and long circulation time in vivo [ 16 , 17 ] . Moreover, these agents failed to detect PD-L1 expression inside the tumour because of their poor ability to penetrate tumour tissue [ 16 , 17 ] . In contrast, these studies indicate the importance of future investigations to evaluate the efficacies of PD-L1-targeted probes in immunotherapy. The small-molecule peptide radiotracer 68 Ga-NOTA-WL12 used here is rapidly metabolised in vivo and easily penetrated target tissues, which may simplify the imaging techniques and monitor the real-time changes in PD-L1 expression. Here we calculated thresholds of uptake parameters through analysis of the predictive value of MPR, which is of great significance for identifying patients who may benefit from immunotherapy. Compared with the previous studies of the clinical translation of PD-L1-targeted probes that employ CT imaging as the therapeutic evaluation criterion [ 16 , 23 ] , here we used MPR of the primary tumour as the study’s endpoint to represent the response to therapy. The study’s endpoint based on pathological evaluation are more convincing than those acquired through image analysis. This strategy shortened the follow-up time comparing with studies employing PFS and OS as endpoints, and avoided the problem of evaluating the effects of therapy on multiple lesions in patients with multiple metastases, thus achieving more accurate evaluation of the efficacy of therapy. There are several limitations to the present study. First, though there were significant differences in 68 Ga-NOTA-WL12 uptake between the MPR and non-MPR groups, the overall extent of uptake was relatively low, which reflected the limited affinity of 68 Ga-NOTA-WL12 for PD-L1. Further improvements in structural design are required to increase affinity in vivo. Furthermore, the sample size of the present study was larger compared with those of other similar studies. Nevertheless, further studies with more subjects are required to confirm the clinical validity of our findings. Conclusion For patients with resectable NSCLC, baseline 68 Ga-NOTA-WL12 uptake has a potential to predict the pathological response, whose efficacy is comparable to that of the traditional evaluations employing baseline and follow-up CT and 18 F-FDG PET/CT examinations, which will help to identify patients who may benefit from the neoadjuvant immunotherapy combined with chemotherapy in clinical practice. Declarations Ethical Approval and Consent to participate ： This study was approved by the Medical Ethics Committee of Peking University Cancer Hospital (2019 KT62), oral and written informed consent was obtained from all participants. This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Consent for publication ： Not applicable. Availability of data and materials ： All data relevant to the study are included in the article. Competing interests: The authors have declared that no competing interests exist. Funding: The current research was financially supported by the Natural Science Foundation of Beijing project No. 7202027, National Natural Science Foundation of China No. 81871387, National Key R&D Program of China No. 2022YFC2406804, Science Foundation of Peking University Cancer Hospital PY202311 and the Capital’s Funds for Health Improvement and Research (No. 2022-2Z-2155). Acknowledgements: Not applicable. References Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin 2021; 71: 7-33. Asamura H, Chansky K, Crowley J et al. 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Supplementary Files SupplementaryInformation.docx Cite Share Download PDF Status: Published Journal Publication published 14 Dec, 2024 Read the published version in Annals of Nuclear Medicine → Version 1 posted Reviewers agreed at journal 26 Jul, 2024 Reviewers invited by journal 02 Jul, 2024 Editor assigned by journal 26 Jun, 2024 First submitted to journal 26 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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hospital","correspondingAuthor":false,"prefix":"","firstName":"Shi","middleName":"","lastName":"Yan","suffix":""},{"id":321737665,"identity":"581d241f-79c9-459d-8597-c906d3c037f1","order_by":2,"name":"Dan Li","email":"","orcid":"","institution":"Peking university cancer hospital","correspondingAuthor":false,"prefix":"","firstName":"Dan","middleName":"","lastName":"Li","suffix":""},{"id":321737666,"identity":"22030055-cc42-4eb7-9923-e404411b3574","order_by":3,"name":"Hua Zhu","email":"","orcid":"","institution":"Peking university cancer hospital","correspondingAuthor":false,"prefix":"","firstName":"Hua","middleName":"","lastName":"Zhu","suffix":""},{"id":321737667,"identity":"1f658632-3dc3-4d18-aa27-4b656d55fa04","order_by":4,"name":"Bing Liu","email":"","orcid":"","institution":"Peking university cancer hospital","correspondingAuthor":false,"prefix":"","firstName":"Bing","middleName":"","lastName":"Liu","suffix":""},{"id":321737668,"identity":"86992e6b-b021-49eb-8ea3-d6efba4ebbcf","order_by":5,"name":"Shiwei Liu","email":"","orcid":"","institution":"Peking university cancer hospital","correspondingAuthor":false,"prefix":"","firstName":"Shiwei","middleName":"","lastName":"Liu","suffix":""},{"id":321737669,"identity":"2053731e-3d59-40c5-bc05-f8bc278f8a50","order_by":6,"name":"Wei Zhao","email":"","orcid":"","institution":"Peking university cancer hospital","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Zhao","suffix":""},{"id":321737670,"identity":"508a5ba5-ad0f-4a8d-9ec9-968c200d4620","order_by":7,"name":"Zhi Yang","email":"","orcid":"","institution":"Peking university cancer hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhi","middleName":"","lastName":"Yang","suffix":""},{"id":321737671,"identity":"97c71705-d35e-4fb7-bcd2-62f3f19b4931","order_by":8,"name":"Nan Wu","email":"","orcid":"","institution":"Peking university cancer hospital","correspondingAuthor":false,"prefix":"","firstName":"Nan","middleName":"","lastName":"Wu","suffix":""},{"id":321737672,"identity":"cdb721c5-3311-4022-b6ad-0e7aae0876ab","order_by":9,"name":"Nan Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2klEQVRIiWNgGAWjYFACxgZmICnHz95+8AGDAQlajCV7ziQbEKmFgQGkJdHgRoKZBFHKzdsPtz0uqDicwHDmQFrlj4I78gzsh49uwKdF5kxiu/GMM4fzGNsbj93mMXhm2MCTlnYDnxYJhsQ2ad6228XMPAfSbjMYHGZskOAxw6+F/yFYS2KbRIJZ4Q+Dw/aEtUhAbEnsAWph4DE4nEiEFqAtM878N5bgOZMsDdSS3EbQL/zpz6QLKtLk7I+3H/z4489h2372w8fwasEEbKQpHwWjYBSMglGADQAAKs1MTXOxHc4AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-8619-7550","institution":"Peking University Cancer Hospital: Beijing Cancer Hospital","correspondingAuthor":true,"prefix":"","firstName":"Nan","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2024-06-27 02:46:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4645551/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4645551/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12149-024-02009-0","type":"published","date":"2024-12-14T15:57:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":61181891,"identity":"d5aefbb0-a483-4192-99cf-efa9b5ac0499","added_by":"auto","created_at":"2024-07-26 16:52:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":362425,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the study protocol.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4645551/v1/37de4ce4bce747bd0a3826f6.png"},{"id":61181888,"identity":"bcc2e591-380b-48b3-9791-c3a679bc8318","added_by":"auto","created_at":"2024-07-26 16:52:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":45478,"visible":true,"origin":"","legend":"\u003cp\u003eThe relationship between the uptake value of \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 and PD-L1 expression.\u003c/p\u003e\n\u003cp\u003eA, Differences of SUV\u003csub\u003emax\u003c/sub\u003e in negative (PD-L1–), low-positive (PD-L1+L) and high-positive (PD-L1+H) PD-L1 expression groups; B, Differences of TBR in negative, low-positive and high-positive PD-L1 expression groups.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4645551/v1/12c976a7ccdd03a154e5c359.png"},{"id":61181895,"identity":"a205638b-7bd4-45c7-9ad4-89389a79f4c9","added_by":"auto","created_at":"2024-07-26 16:52:33","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":141330,"visible":true,"origin":"","legend":"\u003cp\u003eThe relationship between the uptake value in baseline PET/CT and pathological response.\u003c/p\u003e\n\u003cp\u003eA, SUV\u003csub\u003emax \u003c/sub\u003eof \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 in the MPR and non-MPR groups; B, TBR\u003csub\u003e \u003c/sub\u003eof \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 in the MPR and non-MPR groups; C, SUV\u003csub\u003emax \u003c/sub\u003eof \u003csup\u003e18\u003c/sup\u003eF-FDG in the MPR and non-MPR groups; D, TBR\u003csub\u003e \u003c/sub\u003eof \u003csup\u003e18\u003c/sup\u003eF-FDG in the MPR and non-MPR groups; E, DD% in the MPR and non-MPR groups; F, DSUL\u003csub\u003epeak\u003c/sub\u003e% of \u003csup\u003e18\u003c/sup\u003eF-FDG in the MPR and non-MPR groups.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-4645551/v1/39a12bb3d8d04d2adb77a6d4.png"},{"id":61181893,"identity":"75af13e5-bdea-46c2-bff8-cffa958bdcf0","added_by":"auto","created_at":"2024-07-26 16:52:33","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1384374,"visible":true,"origin":"","legend":"\u003cp\u003eThe uptake value of baseline \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 correlated with the pathological response of a 70-year-old male with squamous carcinoma. The SUV\u003csub\u003emax\u003c/sub\u003e of the tumour in \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT was 2.6 and the TBR was 2.6 (A and B). The post-surgery biopsy confirmed MPR was not achieved. (C); A 59-year-old male with squamous carcinoma. The SUV\u003csub\u003emax\u003c/sub\u003e of the tumour in \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT was 3.9 and the TBR was 4.9 (D and E); The post-surgery biopsy confirmed an MPR (F).\u003c/p\u003e\n\u003cp\u003eThe uptake value of baseline \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 in patients with or without MPR.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4645551/v1/5346ae8454a1d9ba9aa7a6cd.png"},{"id":61181889,"identity":"94209fe3-84a5-4b91-8ff3-69c909ec685f","added_by":"auto","created_at":"2024-07-26 16:52:33","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":56566,"visible":true,"origin":"","legend":"\u003cp\u003eReceiver operating characteristic curve of the imaging parameters that predict MPR.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-4645551/v1/9effd18025b847bc961075f8.png"},{"id":61182938,"identity":"513fa38b-dced-4c00-a8cb-8834509d8595","added_by":"auto","created_at":"2024-07-26 17:00:33","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":42676,"visible":true,"origin":"","legend":"\u003cp\u003eWaterfall chart of imaging parameters.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-4645551/v1/f97af1c25229c7e1fc193d08.png"},{"id":71552887,"identity":"7b304d3e-f179-4e57-8a2f-3da40fefbd16","added_by":"auto","created_at":"2024-12-16 16:07:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3039547,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4645551/v1/71b8602c-99b7-41e5-96fb-6deb47b521f1.pdf"},{"id":61181890,"identity":"dc0162e0-c26d-4f23-990c-e845303435b4","added_by":"auto","created_at":"2024-07-26 16:52:33","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":54886,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-4645551/v1/17f9842c9a0e19c776bcd3e7.docx"}],"financialInterests":"","formattedTitle":"Radiolabeled anti-PD-L1 peptide PET/CT in predicting the efficacy of neoadjuvant immunotherapy combined with chemotherapy in resectable non-small cell lung cancer","fulltext":[{"header":"Background","content":"\u003cp\u003eNon-small cell lung cancer (NSCLC) accounts for 80% of newly diagnosed cases of lung cancer, which ranks in the top two in morbidity and mortality among malignant tumours worldwide\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Approximately 50% of patients with NSCLC present with localized disease or localized advanced disease (I-III)\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. The traditional treatment strategy of resectable patients combines neoadjuvant therapy, complete surgery and adjuvant therapy, the prognosis is poor and overall survival (OS) substantially decreases with the increasing stage\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eImmunotherapy employing therapeutics targeting the programmed cell death (ligand)-1 (PD-[L]1) is recognized as first-line therapy for patients with advanced NSCLC without genetic aberrations because of its excellent efficacy\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. For resectable patients with NSCLC, the clinical application of neoadjuvant immunotherapy is in the exploratory stage. At the beginning of the exploration, a series of clinical trials concerning neoadjuvant immunotherapy \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e employed the major pathological response (MPR) as an important surrogate for predicting prognosis. Furthermore, the MPR serves as the endpoint of most neoadjuvant clinical trials\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e; and the prognosis of the MPR group is significantly better than that of the non-MPR group\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. The results of several clinical trials indicate that a compelling MPR rate higher than 55% was achieved by neoadjuvant immunotherapy combined with chemotherapy \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Therefore, predicting MPR to screen patients who benefit from neoadjuvant immunotherapy combined with chemotherapy is an important research topic.\u003c/p\u003e \u003cp\u003ePD-L1 expression detected using immunohistochemistry (IHC) in tumour tissue serves as the traditional indicator of predicting MPR\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. However, the above-cited clinical trials do not indicate PD-L1 expression predicts MPR status after neoadjuvant immunotherapy combined with chemotherapy, neither does tumour mutation burden (TMB)\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Positron emission tomography (PET) enables whole-body, quantitative, real-time non-invasive assessment of expression levels of targeted receptors detected using suitable radiotracers\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Previous studies concerning the clinical translation of several radiolabelled PD-L1-targeted antibodies and adnectins in patients with NSCLC, show that PET/CT imaging reflects the efficacy of immunotherapy\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. However, these probes have imitations of relatively large molecular weight with slow metabolism and poor penetration ability.\u003c/p\u003e \u003cp\u003eThe small peptide WL12 binds PD-L1 with high-affinity \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e, and when labelled with \u003csup\u003e68\u003c/sup\u003eGa, serves as a specific radiotracer for PD-L1. Our previous research indicates the potential of \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT to monitor the efficacy of immunotherapy\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. To extend these findings, here we evaluated the predictive value of baseline \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT in neoadjuvant immunotherapy combined with chemotherapy of patients with resectable NSCLC.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003ePatients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Medical Ethics Committee of Peking University Cancer Hospital approved this prospective study (2019 KT62), and informed consent was acquired from patients. The trial was registered at www.clinicaltrialsregister.eu (Trial Identifier: NCT04304066).\u003c/p\u003e\n\u003cp\u003eConsecutive patients with resectable NSCLC were recruited from January 2021 to October 2021. The inclusion criteria were as follows: (1) Patients with NSCLC with clinical stages\u0026nbsp;IIb–IIIa/b; (2) consented to neoadjuvant immunotherapy plus chemotherapy; (3) underwent baseline-paired \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT and \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT within 2 weeks; (4) with acceptable kidney and liver function, together with sound hemopoietic function of the bone marrow and (5) ECOG scores 0–1. The exclusion criteria were as follows: (1) prior chemotherapy or\u0026nbsp;radiotherapy and (2) unable to complete 2 cycles of\u0026nbsp;neoadjuvant immunotherapy combined\u0026nbsp;with\u0026nbsp;chemotherapy. Patients’ clinical characteristics, pathology and follow-up information were recorded.\u003c/p\u003e\n\u003cp\u003eThe neoadjuvant therapy regimen comprised toripalimab plus nab-paclitaxel and cisplatin. After the second cycle of neoadjuvant therapy, if R0 resection was available, radical resection and mediastinal lymph node dissection were performed within 6–8 weeks.\u0026nbsp;R0 resection means that both the primary lesion and metastatic lymph nodes can be completely removed. For clinical N0-1 patients and N2 patients with single-station and non-bulky lymph node, R0 resection is achievable. For clinical multi-station N2 patients,\u0026nbsp;multi-disciplinary team\u0026nbsp;(MDT) will be conducted to evaluate whether R0 resection can be achieved.\u0026nbsp;If R0 resection was not available, the former regimen was continued until a response state occurred, enabling surgery. If remission was not achieved after 4 cycles of the regimen, no surgery would be performed, and treatment was determined according to the specific condition. A post-operative MPR or a non-MPR was regarded as an endpoint of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProduction of \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNOTA-WL12 was synthesized and provided by Chinapeptides\u0026nbsp;(Shanghai, China).\u0026nbsp;As described previously\u003csup\u003e[20]\u003c/sup\u003e, to radiolabel NOTA-WL12, 925~1110 Mbq \u003csup\u003e68\u003c/sup\u003eGaCl\u003csub\u003e3\u003c/sub\u003e was mixed with 195 μL 1 \u003cem\u003eM\u0026nbsp;\u003c/em\u003e(pH 8.5) sodium acetate buffer and reacted with NOTA-WL12 (30 μg) at 60℃ for 15 min.\u0026nbsp;The final product was sep-pak purified and obtained in \u0026gt; 99% radiochemical purity by HPLC, as described previously\u003csup\u003e[20]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePathology\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIHC analysis of PD-L1 expression levels in pre-therapy biopsies employed an anti-PD-L1 monoclonal designated clone 22C3 (Dako Denmark A/S). High\u0026nbsp;positive, low-positive and negative PD-L1 expression was defined as a tumor proportion score (TPS) ≥ 50%, 49 ≥\u0026nbsp;TPS \u0026gt; 1% and\u0026nbsp;TPS \u0026lt; 1%. The MPR was defined as ≤ 10% of residual viable tumour upon surgery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePET/CT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were\u0026nbsp;intravenously\u0026nbsp;injected with \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 (1.9-3.7 MBq/kg) and\u0026nbsp;co-administered 120 μg of WL12. Patients drank 800-1500 mL of water, and PET/CT was performed 1 h after injection. Patients urinated before the examination. Imaging was performed using a Biograph mCT Flow 64 scanner (Siemens, Erlangen, Germany) (120 kV; 146 mA; slice; 3 mm; matrix 200 × 200; iterations, 2; subsets, 11; filter, 5-mm Gaussian). The patient’s bed continuously moved at 1.5 mm/s to cover the body from the top of the skull to the middle of the femur. Images were reconstructed using ordered subset expectation maximization. CT reconstruction used a standard method with a 512 × 512 matrix and a layer thickness of 3–5 mm. CT data were used to correct the PET images for attenuation. Vital signs, laboratory studies and electrocardiograms were obtained before injection, during the screening period and 2 h after PET/CT.\u003c/p\u003e\n\u003cp\u003eThe patients were instructed to fast for\u0026nbsp;≥\u0026nbsp;6 h before undergoing the\u0026nbsp;\u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT\u0026nbsp;scans to ensure normal blood glucose levels (4.4-9.3\u0026nbsp;mmol/L). The intravenously injected dose was calculated according to body weight (3.7 MBq/kg), and patients rested for 1 h before the examination. The remaining acquisition conditions were consistent with \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT.\u0026nbsp;And all the patients were recommended to undergo follow-up \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT within\u0026nbsp;3 weeks after 2–4 cycles of the therapy regimen.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImage Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA Siemens workstation (Syngo.via VB20, MM Oncology) was used for post-processing images. Two physicians specializing in nuclear medicine with 5–10 years of diagnostic experience blinded to the prior imaging findings and pathological results reviewed all images independently, and any discordant results were resolved by a third physician with 15–20 years of diagnostic experience.\u003c/p\u003e\n\u003cp\u003eThe volume of interest of the primary pulmonary tumour on \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT and \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT was automatically delineated to completely cover the extent of the target lesion while avoiding surrounding tissues and organs. The values of SUV\u003csub\u003emax\u003c/sub\u003e of the lesions and SUV\u003csub\u003emean\u003c/sub\u003e of the blood pool (BP) based on the uptake of the left atrium, which served as background uptake, were recorded, and the ratio of tumour-to-BP (TBR) was calculated as tumour SUV\u003csub\u003emax\u003c/sub\u003e/BP SUV\u003csub\u003emean\u003c/sub\u003e.\u0026nbsp;SUV lean\u0026nbsp;(SUL) was obtained by standardizing SUV to the body mass, and the average uptake of the 15-mm-diameter circle centered over the highest-uptake part of the tumor was\u0026nbsp;SUL\u003csub\u003epeak\u003c/sub\u003e, which serves as the standard parameter for therapy evaluation using\u0026nbsp;\u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT\u003csup\u003e[21]\u003c/sup\u003e.\u0026nbsp;DSUL\u003csub\u003epeak\u003c/sub\u003e% was calculated as ([baseline SUL\u003csub\u003epeak\u0026nbsp;\u003c/sub\u003e– follow-up SUL\u003csub\u003epeak\u003c/sub\u003e]/baseline SUL\u003csub\u003epeak\u003c/sub\u003e)*100%.\u0026nbsp;The longest diameter (D) of the tumour was determined, and\u0026nbsp;DD% was calculated as follows: ([baseline D – follow-up D]/baseline D)\u0026nbsp;*\u0026nbsp;100%.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIBM SPSS Statistics (version 25.0) and GraphPad Prism (version 8.0) were used to perform statistical analyses of patients’ data. SUV\u003csub\u003emax\u003c/sub\u003e and TBR were expressed as the\u0026nbsp;median (inter-quartile range). The values and change rates of uptake in\u0026nbsp;\u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT and \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT\u0026nbsp;were compared among MPR and non-MPR groups (Mann–Whitney test). Data distribution was displayed using a violin plot.\u0026nbsp;The area under the receiver operating characteristic (ROC) curve was used to analyse the predictive value of the uptake parameters of the response to therapy, and the cut-off value was obtained from the Youden index. Diagnostic performance, including sensitivity, specificity and accuracy were calculated. Differences with \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05 were considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u0026rsquo; Characteristics\u003c/h2\u003e \u003cp\u003eThe clinicopathological characteristics of 20 patients with resectable NSCLC (2 women, 18 men; median age, 62 years; range, 51\u0026ndash;75 years) enrolled in the study are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. All patients underwent paired baseline \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT and \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT before neoadjuvant therapy and follow-up enhanced CT after that. Fourteen patients underwent follow-up \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT. Seventeen patients underwent surgery after neoadjuvant immunotherapy combined with chemotherapy, among which 10 achieved MPR and 7 did not. A flow diagram of the study is depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatients\u0026rsquo; clinicopathological characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInformation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients n (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62 (51\u0026ndash;75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (10.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (90.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (15.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (85.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily history of malignancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (90.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (10.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical staging\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStaging II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (40.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStaging III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (60.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSquamous carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (95.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePD-L1 expression\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (15.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTPS\u0026thinsp;\u0026lt;\u0026thinsp;1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (25.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50% \u0026gt; TPS\u0026thinsp;\u0026ge;\u0026thinsp;1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (20.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTPS\u0026thinsp;\u0026ge;\u0026thinsp;50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (40.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eNote. NA, not available.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003e \u003cb\u003e68\u003c/b\u003e \u003c/sup\u003e \u003cb\u003eGa-NOTA-WL12 PET/CT and PD-L1 expression\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAmong 17 patients with pre-therapy PD-L1 IHC expression, the IHC scores of 5, 4 and 8 patients were negative, low-positive and high-positive, respectively. The uptake values of baseline \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 (SUV\u003csub\u003emax\u003c/sub\u003e and TBR) were not significantly different among the groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Among patients with negative, low-positive and high-positive PD-L1 expression, there was no significant difference in the incidence of MPR (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.34).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePET/CT and pathological responses\u003c/h2\u003e \u003cp\u003eThere were 10 patients in MPR and 7 patients in non-MPR groups, respectively. In baseline \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT, SUV\u003csub\u003emax\u003c/sub\u003e (median: 3.1 [2.8, 3.4] vs 2.7 [2.6, 2.8]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.073) and TBR (median: 3.1 [2.6, 4.1] vs 2.4 [2.3, 2.7]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.046) in the MPR group were higher compared with the non-MPR group, and the difference of TBR was statistically significant (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, A \u003cb\u003eand B\u003c/b\u003e). Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows that the SUV\u003csub\u003emax\u003c/sub\u003e values of the non-MPR and MPR patients were 2.6 and 3.9, respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSUV\u003csub\u003emax\u003c/sub\u003e (median: 15.8 [10.3, 19.3] vs 15.9 [8.6, 17.6]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.887], TBR (median: 8.6 [6.9, 12.9] vs 9.9 [7.1, 16.0]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.813) in baseline \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT and ΔD% (median: 57.3% [41.5%, 71.8%] vs 43.2% [7.9%, 58.3%]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.161) were not significantly different between the MPR and non-MPR groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, C, D \u003cb\u003eand E\u003c/b\u003e). Among 14 patients underwent follow-up \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT, 9 achieved MPR and 5 did not, the \u003csup\u003e18\u003c/sup\u003eF-FDG ΔSUL\u003csub\u003epeak\u003c/sub\u003e% differed between MPR and non-MPR groups (median: 83.5% [63.8%, 87.2%] vs 28.4% [-27.4%, 77.5%]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.083) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, F), but the difference was not statistically significant either.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eThe predictive value of PET/CT parameters in the pathological response\u003c/h2\u003e \u003cp\u003eThe areas under the ROC curve of SUV\u003csub\u003emax\u003c/sub\u003e, TBR in \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT, ΔD% and ΔSUL\u003csub\u003epeak\u003c/sub\u003e% in \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT were 0.76 (95%CI: 0.52\u0026ndash;1.00), 0.79 (0.56\u0026ndash;1.00), 0.71 (0.46\u0026ndash;0.96) and 0.80 (0.51-1.00) respectively, indicating the good predictive value of the above parameters except for ΔD% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.143) in identifying MPR (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Furthermore, the cut-off values obtained from the Youden index were 2.9, 2.7, 60% and 30% respectively. The detailed diagnostic values are depicted in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The TBR in \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT and ΔD% of patients were ordered as shown in the waterfall chart (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e), and the waterfall chart of SUV\u003csub\u003emax\u003c/sub\u003e was shown in \u003cb\u003eSupplementary Fig.\u0026nbsp;1\u003c/b\u003e. Which indicates that the \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 TBR values of nearly all non-MPR patients were \u0026lt;\u0026thinsp;2.7, while nearly all patients with TBR\u0026thinsp;\u0026ge;\u0026thinsp;2.7 achieved an MPR. Patients with ΔD% \u0026ge;60% achieved an MPR, while the ΔD% values of all non-MPR patients were \u0026lt;\u0026thinsp;60%.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe diagnostic efficacy of the imaging parameters that predict MPR\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCut-off\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAUC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95%CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSEN (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSPEC (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWL12 SUV\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.52-1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.071\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e70.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e85.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWL12 TBR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;2.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.56-1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.045\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e80.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e85.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔD%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;60%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.46\u0026ndash;0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.143\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFDG ΔSUL\u003csub\u003epeak\u003c/sub\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.51-1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.070\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eNote. AUC, area under the curve; SEN, sensitivity; SPEC, specificity; TBR, tumour-to-blood pool; D, the longest diameter.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eRecent clinical studies of neoadjuvant immunotherapy combined with chemotherapy administered to patients with resectable NSCLC show excellent efficacy as indicated by a high MPR rate\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. However, these studies indicated the common criteria including PD-L1 IHC data and TMB failed to identify patients who may benefit from currently available neoadjuvant immunotherapy combined with chemotherapy. In the present study, we therefore evaluated the predictive value of the specific PD-L1-binding radiotracer, \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12, in neoadjuvant immunotherapy combined with chemotherapy of resectable patients with NSCLC\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e\u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 is a specific radiotracer that binds to PD-L1. The preliminary clinical translation of \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT achieved here indicates its feasibility for non-invasive in vivo detection of PD-L1 expression levels and its potential value for predicting the outcomes of immunotherapy\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. The results of present study show that there was no significant relationship between the uptake value of \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 in primary lesions and PD-L1 IHC expression. Furthermore, previous studies of PD-(L)1-targeted radiotracers report inconsistent and controversial correlations with PD-L1 expression\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. For example, two studies found the uptake of PD-(L)1-targeted radiotracers correlate with PD-(L)1 expression \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e, although others arrived at the opposite conclusion\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. A possible explanation of these discordant findings is the inherent limitation of IHC to detect intra-tumour heterogeneity\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. Moreover, the subjects in the above cited studies included advanced NSCLC, but the biopsy specimens used for PD-L1 expression analysis were obtained from a single site, which may lead to inconsistent findings. Furthermore, the relationship between PD-L1 expression and the response to immunotherapy was not determined. Some studies indicate that PD-L1 expression is not related to the efficacy of therapy\u003csup\u003e[\u003cspan additionalcitationids=\"CR26 CR27\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e, while some studies conclude that PD-L1 expression is a sound predictor of efficacy \u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e. The uptake of \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 enables the assessment of PD-L1 expression in the whole lesion, thus, it may outperform PD-L1 detected using IHC analysis to predict the efficacy of immunotherapy.\u003c/p\u003e \u003cp\u003eThe present analysis detected differences between uptake of baseline \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT (SUV\u003csub\u003emax\u003c/sub\u003e and TBR) and change rate of baseline and follow-up \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT (ΔSUL\u003csub\u003epeak\u003c/sub\u003e%) in MPR and non-MPR groups, and the difference of \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 TBR was statistically significant. Whereas there were no significant differences in the D% and baseline \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT data. The excellent ability of morphological change rate of CT and metabolic change rate of \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT to predict MPR in neoadjuvant immunotherapy has long been recognized\u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. However, these parameters require follow-up CT and \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT examinations, which fail to identify patients who may benefit from neoadjuvant therapy prior to main therapy.\u003c/p\u003e \u003cp\u003ePrevious studies concerning the clinical translation of other PD-L1-targeted probes in NSCLC confirmed the predictive value of probes that reflect the efficacy of immunotherapy\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. For example, Bensch et al.\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. detected tumour heterogeneity using the PD-L1-targeted agent \u003csup\u003e89\u003c/sup\u003eZr-atezolizumab and a higher uptake of the radiotracer leads to higher response rate, which is strongly related to progression-free survival and OS at the same time \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Furthermore, Niemeijer et al.\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e detected a relationship between tracer uptake and response state. The probes used in these studies included anti-PD-L1 antibodies or adnectin with high molecular weight, which failed to reflect PD-L1 expression and its change state over time because of their slow metabolism and long circulation time in vivo\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Moreover, these agents failed to detect PD-L1 expression inside the tumour because of their poor ability to penetrate tumour tissue\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. In contrast, these studies indicate the importance of future investigations to evaluate the efficacies of PD-L1-targeted probes in immunotherapy. The small-molecule peptide radiotracer \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 used here is rapidly metabolised in vivo and easily penetrated target tissues, which may simplify the imaging techniques and monitor the real-time changes in PD-L1 expression.\u003c/p\u003e \u003cp\u003eHere we calculated thresholds of uptake parameters through analysis of the predictive value of MPR, which is of great significance for identifying patients who may benefit from immunotherapy. Compared with the previous studies of the clinical translation of PD-L1-targeted probes that employ CT imaging as the therapeutic evaluation criterion\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e, here we used MPR of the primary tumour as the study\u0026rsquo;s endpoint to represent the response to therapy. The study\u0026rsquo;s endpoint based on pathological evaluation are more convincing than those acquired through image analysis. This strategy shortened the follow-up time comparing with studies employing PFS and OS as endpoints, and avoided the problem of evaluating the effects of therapy on multiple lesions in patients with multiple metastases, thus achieving more accurate evaluation of the efficacy of therapy.\u003c/p\u003e \u003cp\u003eThere are several limitations to the present study. First, though there were significant differences in \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 uptake between the MPR and non-MPR groups, the overall extent of uptake was relatively low, which reflected the limited affinity of \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 for PD-L1. Further improvements in structural design are required to increase affinity in vivo. Furthermore, the sample size of the present study was larger compared with those of other similar studies. Nevertheless, further studies with more subjects are required to confirm the clinical validity of our findings.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eFor patients with resectable NSCLC, baseline \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 uptake has a potential to predict the pathological response, whose efficacy is comparable to that of the traditional evaluations employing baseline and follow-up CT and \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT examinations, which will help to identify patients who may benefit from the neoadjuvant immunotherapy combined with chemotherapy in clinical practice.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval and Consent to participate\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eThis study was approved by the Medical Ethics Committee of Peking University Cancer Hospital (2019 KT62), oral and written informed consent was obtained from all participants. This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eAll data relevant to the study are included in the article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors have declared that no competing interests exist.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThe current research was financially supported by the Natural Science Foundation of Beijing project No. 7202027, National Natural Science Foundation of China No. 81871387, National Key R\u0026amp;D Program of China No. 2022YFC2406804, Science Foundation of Peking University Cancer Hospital PY202311 and the Capital\u0026rsquo;s Funds for Health Improvement and Research (No. 2022-2Z-2155).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel RL, Miller KD, Fuchs HE, Jemal A. 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J Thorac Oncol 2017; 12: 458-466.\u003c/li\u003e\n\u003cli\u003eMunari E, Zamboni G, Lunardi G et al. PD-L1 Expression Heterogeneity in Non-Small Cell Lung Cancer: Defining Criteria for Harmonization between Biopsy Specimens and Whole Sections. J Thorac Oncol 2018; 13: 1113-1120.\u003c/li\u003e\n\u003cli\u003eTang H, Liang Y, Anders RA et al. PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression. J Clin Invest 2018; 128: 580-588.\u003c/li\u003e\n\u003cli\u003eWu SP, Liao RQ, Tu HY et al. Stromal PD-L1-Positive Regulatory T cells and PD-1-Positive CD8-Positive T cells Define the Response of Different Subsets of Non-Small Cell Lung Cancer to PD-1/PD-L1 Blockade Immunotherapy. J Thorac Oncol 2018; 13: 521-532.\u003c/li\u003e\n\u003cli\u003eYu H, Chen Z, Ballman KV et al. Correlation of PD-L1 Expression with Tumor Mutation Burden and Gene Signatures for Prognosis in Early-Stage Squamous Cell Lung Carcinoma. J Thorac Oncol 2019; 14: 25-36.\u003c/li\u003e\n\u003cli\u003eMidha A, Sharpe A, Scott M et al. PD-L1 expression in advanced NSCLC: Primary lesions versus metastatic sites and impact of sample age. Journal of Clinical Oncology 2016; 34: 3025-3025.\u003c/li\u003e\n\u003cli\u003eHodi FS, Ballinger M, Lyons B et al. Immune-Modified Response Evaluation Criteria In Solid Tumors (imRECIST): Refining Guidelines to Assess the Clinical Benefit of Cancer Immunotherapy. J Clin Oncol 2018; 36: 850-858.\u003c/li\u003e\n\u003cli\u003eTao X, Li N, Wu N et al. The efficiency of 18F-FDG PET-CT for predicting the major pathologic response to the neoadjuvant PD-1 blockade in resectable non-small cell lung cancer. European Journal of Nuclear Medicine and Molecular Imaging 2020; 47: 1209-1219.\u003c/li\u003e\n\u003c/ol\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":"68Ga-NOTA-WL12, PET/CT, resectable NSCLC, toripalimab, neoadjuvant immunotherapy.","lastPublishedDoi":"10.21203/rs.3.rs-4645551/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4645551/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study aimed to evaluate the predictive value of baseline PD-L1 targeted peptide \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT in neoadjuvant immunotherapy combined with chemotherapy of resectable NSCLC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients with resectable NSCLC (n = 20) enrolled­­­­­­­ in this prospective study received baseline paired \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT and \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT. After 2–4 cycles of toripalimab plus nab-paclitaxel and cisplatin, surgery was performed if R0 resection was available. The major pathologic response (MPR) state of the post-operative specimen was recorded. The imaging parameters of the \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT, \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT and CT between the MPR and non-MPR groups and their predictive efficacy of MPR were compared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong 20 patients, 17patients underwent surgery, 10 achieved an MPR and 7 did not. The SUV\u003csub\u003emax\u003c/sub\u003e and tumour-to-blood pool (TBR) of baseline \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 in the MPR group were higher than those in the non-MPR group, and the difference of TBR was statistically significant. The DSUL\u003csub\u003epeak\u003c/sub\u003e% of \u003csup\u003e18\u003c/sup\u003eF-FDG exhibited differences between the MPR and non-MPR groups with no significance. Baseline \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT parameters and DD% failed to differentiate the two groups. The areas under the ROC curves of SUV\u003csub\u003emax\u003c/sub\u003e, TBR in\u003csup\u003e 68\u003c/sup\u003eGa-NOTA-WL12 PET/CT, DD% and DSUL\u003csub\u003epeak\u003c/sub\u003e% in \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT were 0.76, 0.79, 0.71 and 0.80, respectively, in predicting MPR.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBaseline \u003csup\u003e68\u003c/sup\u003eGa-NOTA-WL12 PET/CT has a potential to predict the pathological response of neoadjuvant immunotherapy combined with chemotherapy in patients with resectable NSCLC, whose efficacy is comparable to that of therapy evaluations employing baseline and follow-up CT and \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT examinations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration: \u003c/strong\u003eNCT04304066, registered 13 November 2020, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000AEI9\u0026amp;selectaction=Edit\u0026amp;uid=U000503E\u0026amp;ts=2\u0026amp;cx=-awajet\u003c/p\u003e","manuscriptTitle":"Radiolabeled anti-PD-L1 peptide PET/CT in predicting the efficacy of neoadjuvant immunotherapy combined with chemotherapy in resectable non-small cell lung cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-26 16:52:28","doi":"10.21203/rs.3.rs-4645551/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-07-26T12:43:42+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-02T13:09:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-27T03:25:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Nuclear Medicine","date":"2024-06-26T22:45:58+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":"10642d42-90b8-4782-88e0-32d767550a1a","owner":[],"postedDate":"July 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-16T16:07:05+00:00","versionOfRecord":{"articleIdentity":"rs-4645551","link":"https://doi.org/10.1007/s12149-024-02009-0","journal":{"identity":"annals-of-nuclear-medicine","isVorOnly":false,"title":"Annals of Nuclear Medicine"},"publishedOn":"2024-12-14 15:57:06","publishedOnDateReadable":"December 14th, 2024"},"versionCreatedAt":"2024-07-26 16:52:28","video":"","vorDoi":"10.1007/s12149-024-02009-0","vorDoiUrl":"https://doi.org/10.1007/s12149-024-02009-0","workflowStages":[]},"version":"v1","identity":"rs-4645551","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4645551","identity":"rs-4645551","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}