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Purpose: Somatostatin Receptor 2 (SSTR2)-targeted radiopharmaceutical [ 68 Ga]Ga-DOTATATE has potential advantages in the diagnosis of nasopharyngeal carcinoma (NPC). This study introduces a novel long-lasting SSTR2 analogue, LNC1010, based on DOTATATE, a truncated Evans blue-binding moiety, and a polyethylene-glycol linker. We hypothesised that peptide receptor radionuclide therapy (PRRT) is more effective with [ 177 Lu]Lu-LNC1010 than with [ 177 Lu]Lu-DOTATATE in treating metastatic NPC., Methods: We assessed binding characteristics of LNC1010 in vitro using C666-1 NPC cells and in-vivo pharmacokinetics of [ 68 Ga]Ga/[ 177 Lu]Lu-LNC1010 in C666-1 NPC xenografts via PET and SPECT imaging, biodistribution studies, and PRRT, and compared them with [ 68 Ga]Ga/[ 177 Lu] Lu-labelled DOTATATE. Furthermore, a proof-of-concept approach for imaging and therapy was conducted in a patient with metastatic NPC., Results: LNC1010 exhibited strong uptake and specific affinity for SSTR2 in C666-1 NPC cells. PET and SPECT imaging demonstrated higher uptake and longer tumour retention of [ 68 Ga]Ga/[ 177 Lu]Lu-LNC1010 than [ 68 Ga]Ga/[ 177 Lu]Lu-DOTATATE in C666-1 NPC xenografts, indicating its suitability for PRRT applications in NPCs. Biodistribution studies confirmed the higher uptake and prolonged retention of [ 177 Lu]Lu-LNC1010 than [ 177 Lu]Lu-DOTATATE. In preclinical PRRT studies, [ 177 Lu]Lu-LNC1010 showed greater inhibition of tumour growth in C666-1 NPC xenografts than [ 177 Lu]Lu-DOTATATE. In a subsequent pilot clinical study, PRRT with [ 177 Lu]Lu-LNC1010 achieved favourable therapeutic and negligible side effects in a patient with metastatic NPC., Conclusion: [ 177 Lu]Lu-LNC1010 demonstrated increased tumour uptake and prolonged retention in SSTR2-positive NPCs, with superior anti-tumour efficacy to that of [ 177 Lu]Lu-DOTATATE in preclinical studies. These findings suggest that PRRT with [ 177 Lu]Lu-LNC1010 is a promising treatment for advanced NPC, extending the clinical scope of PRRT beyond neuroendocrine tumours., Competing Interests: Declarations. Ethical approval: All procedures involving human participants were carried out in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any experiments with animals. Consent to participate: Informed consent was obtained from all individual participants included in the study. Conflict of interest: X Chen is co-founder of the Yantai LNC Biotechnology. The other authors declare that they have no potential conflicts of interest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: We aimed to compare the staging efficiency of [ 68 Ga]Ga-DOTATATE and [ 68 Ga]Ga-FAPI PET/CT in nasopharyngeal carcinoma (NPC) patients., Methods: Thirty-nine patients with pathologically confirmed NPC were enrolled in this prospective study. Each patient underwent paired [ 68 Ga]Ga-DOTATATE and [ 68 Ga]Ga-FAPI PET/CT on 2 successive days. The accuracy of two PET/CT for assessing T, N, and M stages was compared by using head-and-neck MRI, histopathologic diagnosis and follow-up results as reference standards. The radiotracer uptake derived from two PETs was also compared., Results: For treatment-naïve patients, [ 68 Ga]Ga-DOTATATE PET/CT showed identical sensitivity for the primary tumours but clearer tumor delineation induced by higher tumour-to-background (TBR) ratio (19.1 ± 8.7 vs. 12.4 ± 7.7, P = 0.003), compared with [ 68 Ga]Ga-FAPI PET/CT. Regarding cervical lymph node (CLN) metastases, [ 68 Ga]Ga-DOTATATE PET had significantly better sensitivity and accuracy based on neck sides (98% vs. 82%, P < 0.001; 99% vs. 88% P = 0.008), neck levels (98% vs. 78%, 99% vs. 97%; both P < 0.001) and individual nodes (89% vs. 56%, 91% vs. 76%; both P < 0.001), and higher TBR (8.1 ± 4.1 vs. 6.3 ± 3.7, P < 0.001). Additionally, [ 68 Ga]Ga-DOTATATE PET/CT revealed higher sensitivity and accuracy for distant metastases (96% vs. 53%, 95% vs. 52%; both P < 0.001), particularly in bone metastases (99% vs. 49%, 97% vs. 49%; both P < 0.001). For post-treatment patients, [ 68 Ga]Ga-DOTATATE PET/CT identified one more true-negative case than [ 68 Ga]Ga-FAPI PET/CT., Conclusion: [ 68 Ga]Ga-DOTATATE PET/CT performed better than [ 68 Ga]Ga-FAPI PET/CT in visualizing the primary tumours, detecting the metastatic lesions and identifying the local recurrence, suggesting [ 68 Ga]Ga-DOTATATE PET/CT may be superior to [ 68 Ga]Ga-FAPI PET/CT for NPC staging., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Prognostic prediction is crucial to guide individual treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) patients. Recently, multi-task deep learning was explored for joint prognostic prediction and tumor segmentation in various cancers, resulting in promising performance. This study aims to evaluate the clinical value of multi-task deep learning for prognostic prediction in LA-NPC patients., Methods: A total of 886 LA-NPC patients acquired from two medical centers were enrolled including clinical data, [ 18 F]FDG PET/CT images, and follow-up of progression-free survival (PFS). We adopted a deep multi-task survival model (DeepMTS) to jointly perform prognostic prediction (DeepMTS-Score) and tumor segmentation from FDG-PET/CT images. The DeepMTS-derived segmentation masks were leveraged to extract handcrafted radiomics features, which were also used for prognostic prediction (AutoRadio-Score). Finally, we developed a multi-task deep learning-based radiomic (MTDLR) nomogram by integrating DeepMTS-Score, AutoRadio-Score, and clinical data. Harrell's concordance indices (C-index) and time-independent receiver operating characteristic (ROC) analysis were used to evaluate the discriminative ability of the proposed MTDLR nomogram. For patient stratification, the PFS rates of high- and low-risk patients were calculated using Kaplan-Meier method and compared with the observed PFS probability., Results: Our MTDLR nomogram achieved C-index of 0.818 (95% confidence interval (CI): 0.785-0.851), 0.752 (95% CI: 0.638-0.865), and 0.717 (95% CI: 0.641-0.793) and area under curve (AUC) of 0.859 (95% CI: 0.822-0.895), 0.769 (95% CI: 0.642-0.896), and 0.730 (95% CI: 0.634-0.826) in the training, internal validation, and external validation cohorts, which showed a statistically significant improvement over conventional radiomic nomograms. Our nomogram also divided patients into significantly different high- and low-risk groups., Conclusion: Our study demonstrated that MTDLR nomogram can perform reliable and accurate prognostic prediction in LA-NPC patients, and also enabled better patient stratification, which could facilitate personalized treatment planning., (© 2023. The Author(s).)

Purpose: To compare PET/CT, MRI and ultrasonography in detecting recurrence of nasopharyngeal carcinoma and identify their benefit in staging, contouring and overall survival (OS)., Methods: Cohort A included 1453 patients with or without histopathology-confirmed local recurrence, while cohort B consisted of 316 patients with 606 histopathology-confirmed lymph nodes to compare the sensitivities and specificities of PET/CT, MRI and ultrasonography using McNemar test. Cohorts C and D consisted of 273 patients from cohort A and 267 patients from cohort B, respectively, to compare the distribution of PET/CT-based and MRI-based rT-stage and rN-stage and the accuracy of rN-stage using McNemar test. Cohort E included 30 random patients from cohort A to evaluate the changes in contouring with or without PET/CT by related-samples T test or Wilcoxon rank test. The OS of 61 rT3-4N0M0 patients staged by PET/CT plus MRI (cohort F) and 67 MRI-staged rT3-4N0M0 patients (cohort G) who underwent similar salvage treatment were compared by log-rank test and Cox regression., Results: PET/CT had similar specificity to MRI but higher sensitivity (93.9% vs. 79.3%, P < 0.001) in detecting local recurrence. PET/CT, MRI and ultrasonography had comparable specificities, but PET/CT had greater sensitivity than MRI (90.9% vs. 67.6%, P < 0.001) and similar sensitivity to ultrasonography in diagnosing lymph nodes. According to PET/CT, more patients were staged rT3-4 (82.8% vs. 68.1%, P < 0.001) or rN + (89.9% vs. 69.3%, P < 0.001), and the rN-stage was more accurate (90.6% vs. 73.8%, P < 0.001). Accordingly, the contours of local recurrence were more precise (median Dice similarity coefficient 0.41 vs. 0.62, P < 0.001) when aided by PET/CT plus MRI. Patients staged by PET/CT plus MRI had a higher 3-year OS than patients staged by MRI alone (85.5% vs. 60.4%, P = 0.006; adjusted HR = 0.34, P = 0.005)., Conclusion: PET/CT more accurately detected and staged recurrence of nasopharyngeal carcinoma and accordingly complemented MRI, providing benefit in contouring and OS., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Accurate identification of nodal status enables adequate neck irradiation for nasopharyngeal carcinoma (NPC). However, most conventional techniques are unable to pick up occult metastases, leading to underestimation of tumor extensions. Here we investigate the clinical significance of carbonic anhydrase IX (CAIX) in human NPC samples, and develop a CAIX-targeted imaging strategy to identify occult lymph node metastases (LNMs) and extranodal extension (ENE) in animal studies., Methods: A total of 211 NPC samples are performed CAIX staining, and clinical outcomes are analyzed. The metastatic murine models are generated by foot pad injection of NPC cells, and a CAIX-targeted imaging agent (CAIX-800) is intravenously administered. We adopt fluorescence molecular tomography and ultrasonography (US)-guided spectroscopic photoacoustic (sPA) imaging to perform in vivo studies. Histological and immunohistochemical characterization are carried out via node-by-node analysis., Results: For clinical samples, 90.1% (91/101) primary tumors, 73.3% (66/90) metastases, and 100% (20/20) local recurrences are CAIX positive. In metastases group, 84.7% (61/72) nodal metastases and 22.2% (4/18) organ metastases are CAIX positive. CAIX expression in primary tumors is significantly associated with NPC stage and prognosis. For animal studies, CAIX-800-based fluorescence imaging achieves 81.3% sensitivity and 93.8% specificity in detecting occult LNMs in vivo, with a minimum detectable diameter of 1.7 mm. Coupled with CAIX-800, US-guided sPA imaging could not only detect subcapsular deposits of metastatic cancer cells 2 weeks earlier than conventional techniques, but also successfully track pathological ENE., Conclusion: CAIX remarkably expresses in human NPCs and stratifies patient prognosis. In preclinical studies, CAIX-800-based imaging successfully identifies occult LNMs and tracks early stage of pathological ENE. This attractive method shows potential in clinic, allowing medical workers to longitudinally monitor nodal status and helping to reduce unnecessary nodal biopsy for patients with NPC. The schematic diagram for the study. CAIX, carbonic anhydrase IX; NPC, nasopharyngeal carcinoma; US, ultrasonography; sPA, spectroscopic photoacoustic., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: How to discriminate different risks of recurrent nasopharyngeal carcinoma (rNPC) patients and guide individual treatment has become of great importance. This study aimed to explore the associations between deep learning signatures and biological functions as well as survival in (rNPC) patients., Methods: A total of 420 rNPC patients with PET/CT imaging and follow-up of overall survival (OS) were retrospectively enrolled. All patients were randomly divided into a training set (n = 269) and test set (n = 151) with a 6:4 ratio. We constructed multi-modality deep learning signatures from PET and CT images with a light-weighted deep convolutional neural network EfficienetNet-lite0 and survival loss DeepSurvLoss. An integrated nomogram was constructed incorporating clinical factors and deep learning signatures from PET/CT. Clinical nomogram and single-modality deep learning nomograms were also built for comparison. Furthermore, the association between biological functions and survival risks generated from an integrated nomogram was analyzed by RNA sequencing (RNA-seq)., Results: The C-index of the integrated nomogram incorporating age, rT-stage, and deep learning PET/CT signature was 0.741 (95% CI: 0.688-0.794) in the training set and 0.732 (95% CI: 0.679-0.785) in the test set. The nomogram stratified patients into two groups with high risk and low risk in both the training set and test set with hazard ratios (HR) of 4.56 (95% CI: 2.80-7.42, p < 0.001) and 4.05 (95% CI: 2.21-7.43, p < 0.001), respectively. The C-index of the integrated nomogram was significantly higher than the clinical nomogram and single-modality nomograms. When stratified by sex, N-stage, or EBV DNA, risk prediction of our integrated nomogram was valid in all patient subgroups. Further subgroup analysis showed that patients with a low-risk could benefit from surgery and re-irradiation, while there was no difference in survival rates between patients treated by chemotherapy in the high-risk and low-risk groups. RNA sequencing (RNA-seq) of data further explored the mechanism of high- and low-risk patients from the genetic and molecular level., Conclusion: Our study demonstrated that PET/CT-based deep learning signatures showed satisfactory prognostic predictive performance in rNPC patients. The nomogram incorporating deep learning signatures successfully divided patients into different risks and had great potential to guide individual treatment: patients with a low-risk were supposed to be treated with surgery and re-irradiation, while for high-risk patients, the application of palliative chemotherapy may be sufficient., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: We longitudinally evaluated the tumour growth and metabolic activity of three nasopharyngeal carcinoma (NPC) cell line models (C666-1, C17 and NPC43) and two xenograft models (Xeno76 and Xeno23) using a micropositron emission tomography and magnetic resonance (microPET/MR). With a better understanding of the interplay between tumour growth and metabolic characteristics of these NPC models, we aim to provide insights for the selection of appropriate NPC cell line/xenograft models to assist novel drug discovery and evaluation., Methods: Mice were imaged by 18 F-deoxyglucose ([ 18 F]FDG) microPET/MR twice a week for consecutive 3-7 weeks. [ 18 F]FDG uptake was quantified by standardized uptake value (SUV) and presented as SUVmean tumour-to-liver ratio (SUVRmean). Longitudinal tumour growth patterns and metabolic patterns were recorded. SUVRmean and histological characteristics were compared across the five NPC models. Cisplatin was administrated to one selected optimal tumour model, C17, to evaluate our imaging platform., Results: We found variable tumour growth and metabolic patterns across different NPC tumour types. C17 has an optimal growth rate and higher tumour metabolic activity compared with C666-1. C666-1 has a fast growth rate but is low in SUVRmean at endpoint due to necrosis as confirmed by H&E. NPC43 and Xeno76 have relatively slow growth rates and are low in SUVRmean, due to severe necrosis. Xeno23 has the slowest growth rate, and a relative high SUVRmean. Cisplatin showed the expected therapeutic effect in the C17 model in marked reduction of tumour size and metabolism., Conclusion: Our study establishes an imaging platform that characterizes the growth and metabolic patterns of different NPC models, and the platform is well able to demonstrate drug treatment outcome supporting its use in novel drug discovery and evaluation for NPC., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To explore the feasibility of [ 68 Ga]Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) in patients with non-keratinizing nasopharyngeal carcinoma (NPC) and to evaluate whether [ 68 Ga]Ga-DOTATATE PET/CT could be used for non-invasive determination of somatostatin receptor 2 (SSTR2) expression in NPC., Methods: This prospective study included patients with NPC who underwent [ 68 Ga]Ga-DOTATATE PET/CT between February and May 2021. The [ 68 Ga]Ga-DOTATATE and [ 18 F]FDG uptakes in primary and metastatic NPC lesions were calculated and compared, and the [ 68 Ga]Ga-DOTATATE uptake between SSTR2 score groups was analysed., Results: A total of 36 participants (25 patients, initial staging; 11 patients, recurrence detection) were included; 33 patients also underwent [ 18 F]FDG PET/CT for staging/restaging as a part of their routine diagnostic workup. [ 68 Ga]Ga-DOTATATE PET/CT showed an intense tracer uptake in primary and metastatic NPC lesions. The radiotracer uptake was higher with [ 68 Ga]Ga-DOTATATE than with [ 18 F]FDG PET in primary NPC lesions (SUVmax: 12.03 vs. 10.07, P = 0.048; tumour-to-brain ratio: 36.16 vs. 0.86, P < 0.001) and regional lymph node metastases (median SUVmax: 9.11 vs. 6.12, P < 0.001) and comparable in bone and visceral metastases. Importantly, most NPC lesions showed intense SSTR2 expression (85.7%), which was strongly correlated with the [ 68 Ga]Ga-DOTATATE uptake. The SUVmax of SSTR2-negative lesions was significantly lower than that of SSTR2-positive lesions (SUVmax: 4.95 vs. 12.61, P = 0.013)., Conclusion: [ 68 Ga]Ga-DOTATATE PET/CT is a promising imaging modality for detecting primary and metastatic NPC, with favourable image contrast and comparable diagnostic efficacy when compared to [ 18 F]FDG PET/CT. An intense SSTR2 expression was observed in most NPCs, and this expression was significantly correlated with the [ 68 Ga]Ga-DOTATATE uptake., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: To test the advantages of positron emission tomography and computed tomography (PET/CT) for diagnosing lymph nodes and staging nasopharyngeal carcinoma and to investigate its benefits for survival and treatment decisions., Methods: The performance of PET/CT and magnetic resonance imaging (MRI) in diagnosis was compared based on 460 biopsied lymph nodes. Using the propensity matching method, survival differences of T3N1M0 patients with (n = 1093) and without (n = 1377) PET/CT were compared in diverse manners. A radiologic score model was developed and tested in a subset of T3N1M0 patients., Results: PET/CT performed better than MRI with higher sensitivity, accuracy, and area under the receiver operating characteristic curve (96.7% vs. 88.5%, p < 0.001; 88.0% vs. 81.1%, p < 0.001; 0.863 vs. 0.796, p < 0.05) in diagnosing lymph nodes. Accordingly, MRI-staged T3N0-3M0 patients showed nondifferent survival rates, as they were the same T3N1M0 if staged by PET/CT. In addition, patients staged by PET/CT and MRI showed higher survival rates than those staged by MRI alone (p < 0.05), regardless of the Epstein-Barr virus DNA load. Interestingly, SUVmax-N, nodal necrosis, and extranodal extension were highly predictive of survival. The radiologic score model based on these factors performed well in risk stratification with a C-index of 0.72. Finally, induction chemotherapy showed an added benefit (p = 0.006) for the high-risk patients selected by the model but not for those without risk stratification (p = 0.78)., Conclusion: PET/CT showed advantages in staging nasopharyngeal carcinoma due to a more accurate diagnosis of lymph nodes and this contributed to a survival benefit. PET/CT combined with MRI provided prognostic factors that could identify high-risk patients and guide individualized treatment., (© 2021. The Author(s).)

Purpose: This study aimed to explore the clinical utility of [ 68 Ga]Ga-labeled fibroblast activation protein inhibitor ([ 68 Ga]Ga-FAPI) positron emission tomography/computed tomography (PET/CT) relative to [ 18 F]-fluorodeoxyglucose ([ 18 F]FDG) PET/CT and magnetic resonance imaging (MRI) for primary staging and recurrence detection in nasopharyngeal carcinoma (NPC)., Methods: This retrospective analysis utilized a sub-cohort of patients from a previously acquired database. Patients with NPC who underwent [ 18 F]FDG and [ 68 Ga]Ga-FAPI PET/CT between October 2019 and November 2020 were included. The radiotracer uptake and clinical staging/restaging performances of [ 18 F]FDG and [ 68 Ga]Ga-FAPI PET/CT were compared., Results: Forty-five participants (39 for initial assessment, 6 for recurrence detection) were included. In treatment-naïve participants, [ 68 Ga]Ga-FAPI PET/CT showed higher radiotracer uptake than [ 18 F]FDG PET/CT in primary tumors (16.18 vs. 10.11, P < 0.001), regional lymph nodes (11.42 vs. 7.37, P < 0.001), and bone and visceral metastases (6.94 vs. 3.11, P < 0.001). Compared with the [ 18 F]FDG-based TNM stage, the [ 68 Ga]Ga-FAPI-based TNM stage was upgraded in ten patients (26%), resulting in management changes in seven patients (18%). Compared with MRI, [ 68 Ga]Ga-FAPI PET/CT upgraded and underestimated the T stage in four and two patients, respectively. In post-treatment patients, [ 68 Ga]Ga-FAPI PET/CT yielded more true-positive findings than [ 18 F]FDG PET/CT in detecting local recurrence., Conclusion: [ 68 Ga]Ga-FAPI PET/CT is a promising imaging modality for the diagnosis of primary and metastatic NPC. The exact tumor geographic imaging obtained through [ 68 Ga]Ga-FAPI PET/CT may be a supplement to MRI for T staging and radiotherapy planning., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To conduct a head-to-head comparison of the diagnostic ability of 68 Ga-DOTA-FAPI-04 ( 68 Ga-FAPI) and 18 F-FDG PET/MR in nasopharyngeal carcinoma (NPC) patients., Methods: Patients diagnosed with NPC were prospectively enrolled. All patients underwent head-and-neck 68 Ga-FAPI PET/MR and 18 F-FDG PET/MR within 1 week. Primary tumor, lymph node numbers, and tracer uptake were compared by SUVmax and visual evaluation. The primary tumor volumes derived from 68 Ga-FAPI, 18 F-FDG PET, and MRI were also compared., Results: Fifteen patients were enrolled from June to August 2020. Both 68 Ga-FAPI and 18 F-FDG PET had 100% detection rate of the primary tumor. The 68 Ga-FAPI SUVmax of primary tumors (13.87 ± 5.13) was lower than that of 18 F-FDG (17.73 ± 6.84), but the difference was not significant (p = 0.078). Compared with 18 F-FDG, 68 Ga-FAPI PET improved the delineation of skull-base invasion in eight out of eight patients and intracranial invasion in four out of four patients. When 25%SUVmax of 68 Ga-FAPI or 20%SUVmax of 18 F-FDG was utilized as a threshold for determining tumor volume, it was highly consistent with MRI. 18 F-FDG PET detected much more positive lymph nodes than 68 Ga-FAPI (100 vs 48). The SUVmax of 48 paired lymph nodes was significantly lower on 68 Ga-FAPI than 18 F-FDG (8.67 ± 3.88 vs 11.79 ± 6.17, p < 0.001). Additionally, 68 Ga-FAPI further detected four highly suspected small, distant metastases in three patients. Compared with 18 F-FDG, 68 Ga-FAPI changed overall staging in six of fifteen patients, with three patients being up-staged, and three down-staged., Conclusion: 68 Ga-FAPI outperforms 18 F-FDG in delineating the primary tumor and detecting suspected distant metastases, particularly in the evaluation of skull-base and intracranial invasion, suggesting 68 Ga-FAPI hybrid PET/MR has the potential to serve as a single-step staging modality for patients with NPC. However, its value regarding lymph node and distant metastases evaluation needs further study., Trial Registration: NCT04554719. Registered September 8, 2020 - retrospectively registered, http://clinicaltrails.gov/show/NCT04554719., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Purpose: This study aimed to establish an effective nomogram to predict primary distant metastasis (DM) in patients with nasopharyngeal carcinoma (NPC) to guide the application of PET/CT., Methods: In total, 3591 patients with pathologically confirmed NPC were consecutively enrolled. The nomogram was constructed based on 1922 patients treated between 2007 and 2014. Multivariate logistical regression was applied to identify the independent risk factors of DM. The predictive value of the nomogram was evaluated using the concordance index (C-index), calibration curve, probability density functions (PDFs), and clinical utility curve (CUC). The results were validated in 1669 patients enrolled from 2015 to 2016. Net reclassification improvement (NRI) was applied to compare performances of the nomogram with other clinical factors. The best cut-off value of the nomogram chosen for clinical application was analyzed., Results: A total of 355 patients showed primary DM among 3591 patients, yielding an incidence rate of 9.9%. Sex, N stage, EBV DNA level, lactate dehydrogenase level, and hemoglobin level were independent predictive factors for primary DM. C-indices in the training and validation cohort were 0.796 (95% CI, 0.76-0.83) and 0.779 (95% CI, 0.74-0.81), respectively. The NRI indices demonstrated that this model had better predictive performance than plasma EBV DNA level and N stage. We advocate for a threshold probability of 3.5% for guiding the application of PET/CT depending on the clinical utility analyses., Conclusion: This nomogram is a useful tool to predict primary DM of NPC and guide the clinical application of PET/CT individually at the initial staging.

Purpose: Accurate evaluation of hypoxia is particularly important in patients with nasopharyngeal carcinoma (NPC) undergoing radiotherapy. The aim of this study was to propose a novel imaging strategy for quantitative three-dimensional (3D) evaluation of hypoxia in a small animal model of NPC., Methods: A carbonic anhydrase IX (CAIX)-specific molecular probe (CAIX-800) was developed for imaging of hypoxia. Mouse models of subcutaneous, orthotopic, and spontaneous lymph node metastasis from NPC (5 mice per group) were established to assess the imaging strategy. A multi-modality imaging method that consisted of a hybrid combination of fluorescence molecular tomography-computed tomography (FMT-CT) and multispectral optoacoustic tomography (MSOT) was used for 3D quantitative evaluation of tumour hypoxia. Magnetic resonance imaging, histological examination, and immunohistochemical analysis were used as references for comparison and validation., Results: In the early stage of NPC (2 weeks after implantation), FMT-CT enabled precise 3D localisation of the hypoxia biomarker with high sensitivity. At the advanced stage (6 weeks after implantation), MSOT allowed multispectral analysis of the biomarker and haemoglobin molecules with high resolution. The combination of high sensitivity and high resolution from FMT-CT and MSOT could not only detect hypoxia in small-sized NPCs but also visualise the heterogeneity of hypoxia in 3D., Conclusions: Integration of FMT-CT and MSOT could allow comprehensive and quantifiable evaluation of hypoxia in NPC. These findings may potentially benefit patients with NPC undergoing radiotherapy in the future. Graphical abstract A novel multimodality imaging strategy for three-dimensional evaluation of tumour hypoxia in an orthotopic model of nasopharyngeal carcinoma.

Purpose: To explore the relationship between [ 18 F]fluorodeoxyglucose ( 18 F-FDG uptake) and PD-L1 expression and determine the usefulness of 18 F-FDG PET/CT for evaluating the PD-L1 status in tumour cells (TCs) and tumour-infiltrating immune cells (TIICs) in patients with nasopharyngeal carcinoma (NPC)., Methods: We retrospectively evaluated the records of 84 eligible patients who received an initial histopathological diagnosis of NPC between December 2016 and March 2019. All tissue specimens and PET/CT images were collected prior to treatment. High PD-L1 expression in TCs and TIICs was defined as ≥ 50% of stained cells., Results: There was a significant difference in 18 F-FDG uptake according to the PD-L1 status in TCs and TIICs. Univariate analysis showed that PD-L1 expression in TCs was associated with tumour maximum standardized uptake value (SUVmax) (P < 0.001), primary tumour total lesion glycolysis (TLG; P < 0.001), and T stage (P = 0.044), but not with plasma Epstein-Barr virus (EBV) load (P = 0.816), whereas PD-L1 expression in TIICs was related to SUVmax (P = 0.011), TLG (P = 0.001), T stage (P = 0.028), and plasma EBV load (P = 0.003). In multivariate logistic regression, PD-L1 expression in TCs was positively associated with SUVmax (P = 0.003) and TLG (P = 0.001), and in TIICs, negatively associated with SUVmax (P = 0.038) and plasma EBV load (P = 0.025)., Conclusions: 18 F-FDG uptake in NPC lesions was positively correlated with PD-L1 expression in TCs and negatively correlated with PD-L1 expression in TIICs. Thus, 18 F-FDG PET/CT may be useful for evaluating the PD-L1 status in patients with NPC.

Purpose: To determine the value of early evaluation of response to concurrent chemoradiotherapy (CCRT) using 18 F-FDG PET-derived parameters and the Epstein-Barr virus (EBV) DNA titre in outcome prediction in patients with primary nasopharyngeal carcinoma (NPC)., Methods: Sixty patients with primary NPC were prospectively enrolled. All patients underwent 18 F-FDG PET/CT before and during CCRT. The plasma EBV DNA titre was measured along with the PET/CT-derived parameters. Changes in EBV DNA titre and PET/CT-derived parameters during CCRT were analysed in relation to response to treatment, recurrence-free survival (RFS) and overall survival (OS)., Results: A total lesion glycolysis (TLG) reduction ratio of ≤0.6 and a detectable EBV DNA titre during CCRT were predictors of an unfavourable response to treatment, RFS and OS. In multivariate analysis, a TLG reduction ratio of ≤0.6 predicted incomplete remission (p = 0.002) and decreased RFS (p = 0.003). The proportion of patients with a TLG reduction ratio of >0.6 who achieved a complete response was more than twice that of patients with a TLG reduction ratio of ≤0.6. A detectable EBV DNA titre, a TLG reduction ratio of ≤0.6 and older age were independently associated with a poorer OS (p = 0.037, 0.009 and 0.016, respectively). A scoring system was developed based on these independent predictors of OS. Patients with a score of 1 and 2/3 had poorer survival outcomes than those with a score of 0 (hazard ratio 4.756, p = 0.074, and hazard ratio 18.973, p = 0.001, respectively). This scoring system appeared to be superior to the traditional TNM staging system (p < 0.001 versus p = 0.175)., Conclusion: Early evaluation of response to CCRT using 18 F-FDG PET-derived parameters and the EBV DNA titre can predict outcome in patients with primary NPC. A combination of interim PET parameters and the EBV DNA titre enables better stratification of patients into subgroups with different survival rates.

Purpose: Both head and neck magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) play a crucial role in the staging of primary nasopharyngeal carcinoma (NPC). In this study, we sought to prospectively investigate the clinical utility of simultaneous whole-body 18F-FDG PET/MRI for primary staging of NPC patients., Methods: We examined 113 patients with histologically confirmed NPC who underwent pretreatment, simultaneous whole-body PET/MRI and PET/CT for primary tumor staging. The images obtained with the different imaging modalities were interpreted independently and compared with each other., Results: PET/MRI increased the accuracy of head and neck MRI for assessment of primary tumor extent in four patients via addition of FDG uptake information to increase the conspicuity of morphologically subtle lesions. PET/MR images were more discernible than PET/CT images for mapping tumor extension, especially intracranial invasion. Regarding the N staging assessment, the sensitivity of PET/MRI (99.5%) was higher than that of head and neck MRI (94.2%) and PET/CT (90.9%). PET/MRI was particularly useful for distinguishing retropharyngeal nodal metastasis from adjacent nasopharyngeal tumors. For distant metastasis evaluation, PET/MRI exhibited a similar sensitivity (90% vs. 86.7% vs. 83.3%), but higher positive predictive value (93.1% vs. 78.8% vs. 83.3%) than whole-body MRI and PET/CT, respectively., Conclusions: For tumor staging of NPC, simultaneous whole-body PET/MRI was more accurate than head and neck MRI and PET/CT, and may serve as a single-step staging modality.