Overexpression of CENPU promotes cancer growth and metastasis and is associated with poor survival in patients with nasopharyngeal carcinoma.

Background: Centromere protein U (CENPU) is key for mitosis in the carcinogenesis of cancers. However, the roles of CENPU have not been inspected in nasopharyngeal carcinoma (NPC). Thus, we aimed to explore the functions and mechanisms of CENPU in NPC. Methods: Expression of CENPU was evaluated by real-time quantitative polymerase chain reaction, western blotting and immunohistochemistry. The biological functions of CENPU were evaluated in vitro and in vivo. Gene chip analysis, ingenuity pathway analysis, and coimmunoprecipitation experiments were used to explore the mechanisms of CENPU. Results: CENPU was highly expressed in NPC. High expression of CENPU was associated with advanced tumor, node and metastasis (TNM) stage and poor overall survival. Cox regression analysis demonstrated that CENPU expression was an independent prognostic factor in NPC. Knockdown of CENPU inhibited proliferation and migration in vitro and in vivo. Knockdown of CENPU upregulated dual specificity phosphatase 6 (DUSP6) expression. The expression of CNEPU was inversely correlated with the expression of DUSP6 in NPC tissues. Mechanistic studies confirmed that CENPU increased the activation of the ERK1/2 and p38 signaling pathways by suppressing the expression of DUSP6. Conclusions: CENPU acts as an oncogene in NPC by interacting with DUSP6, and may represent a promising prognostic biomarker for patients with NPC.

A positive feedback loop between PLD1 and NF-κB signaling promotes tumorigenesis of nasopharyngeal carcinoma.

Phospholipase D (PLD) lipid-signaling enzyme superfamily has been widely implicated in various human malignancies, but its role and underlying mechanism remain unclear in nasopharyngeal carcinoma (NPC). Here, we analyze the expressions of 6 PLD family members between 87 NPC and 10 control samples through transcriptome analysis. Our findings reveal a notable upregulation of PLD1 in both NPC tumors and cell lines, correlating with worse disease-free and overall survival in NPC patients. Functional assays further elucidate PLD1's oncogenic role, demonstrating its pivotal promotion of critical tumorigenic processes such as cell proliferation and migration in vitro, as well as tumor growth in vivo. Notably, our study uncovers a positive feedback loop between PLD1 and the NF-κB signaling pathway to render NPC progression. Specifically, PLD1 enhances NF-κB activity by facilitating the phosphorylation and nuclear translocation of RELA (p65), which in turn binds to the promoter of PLD1, augmenting its expression. Moreover, RELA overexpression significantly rescues the inhibitory effects in PLD1-depleted NPC cells. Importantly, the application of the PLD1 inhibitor, VU0155069, significantly inhibits NPC tumorigenesis in a patient-derived xenograft model. Together, our findings identify PLD1/NF-κB signaling as a positive feedback loop with promising therapeutic and prognostic potential in NPC.

Characterization of unique pattern of immune cell profile in patients with nasopharyngeal carcinoma through flow cytometry and machine learning.

In patients with nasopharyngeal carcinoma (NPC), the alteration of immune responses in peripheral blood remains unclear. In this study, we established an immune cell profile for patients with NPC and used flow cytometry and machine learning (ML) to identify the characteristics of this profile. After isolation of circulating leukocytes, the proportions of 104 immune cell subsets were compared between NPC group and the healthy control group (HC). Data obtained from the immune cell profile were subjected to ML training to differentiate between the immune cell profiles of the NPC and HC groups. We observed that subjects in the NPC group presented higher proportions of T cells, memory B cells, short-lived plasma cells, IgG-positive B cells, regulatory T cells, MHC II+ T cells, CTLA4+ T cells and PD-1+ T cells than subjects in the HC group, indicating weaker and compromised cellular and humoral immune responses. ML revealed that monocytes, PD-1+ CD4 T cells, memory B cells, CTLA4+ CD4 Treg cells and PD-1+ CD8 T cells were strongly contributed to the difference in immune cell profiles between the NPC and HC groups. This alteration can be fundamental in developing novel immunotherapies for NPC.

Pixelwise Gradient Model for Image Fusion (PGMIF): a multi-sequence magnetic resonance imaging (MRI) fusion model for tumor contrast enhancement of nasopharyngeal carcinoma.

Background: Different image modalities capture different aspects of a patient. It is desirable to produce images that capture all such features in a single image. This research investigates the potential of multi-modal image fusion method to enhance magnetic resonance imaging (MRI) tumor contrast and its consistency across different patients, which can capture both the anatomical structures and tumor contrast clearly in one image, making MRI-based target delineation more accurate and efficient. Methods: T1-weighted (T1-w) and T2-weighted (T2-w) magnetic resonance (MR) images from 80 nasopharyngeal carcinoma (NPC) patients were used. A novel image fusion method, Pixelwise Gradient Model for Image Fusion (PGMIF), which is based on the pixelwise gradient to capture the shape and a generative adversarial network (GAN) term to capture the image contrast, was introduced. PGMIF is compared with several popular fusion methods. The performance of fusion methods was quantified using two metrics: the tumor contrast-to-noise ratio (CNR), which aims to measure the contrast of the edges, and a Generalized Sobel Operator Analysis, which aims to measure the sharpness of edge. Results: The PGMIF method yielded the highest CNR [median (mdn) =1.208, interquartile range (IQR) =1.175-1.381]. It was a statistically significant enhancement compared to both T1-w (mdn =1.044, IQR =0.957-1.042, P<5.60×10-4) and T2-w MR images (mdn =1.111, IQR =1.023-1.182, P<2.40×10-3), and outperformed other fusion models: Gradient Model with Maximum Comparison among Images (GMMCI) (mdn =0.967, IQR =0.795-0.982, P<5.60×10-4), Deep Learning Model with Weighted Loss (DLMWL) (mdn =0.883, IQR =0.832-0.943, P<5.60×10-4), Pixelwise Weighted Average (PWA) (mdn =0.875, IQR =0.806-0.972, P<5.60×10-4) and Maximum of Images (MoI) (mdn =0.863, IQR =0.823-0.991, P<5.60×10-4). In terms of the Generalized Sobel Operator Analysis, a measure based on Sobel operator to measure contrast enhancement, PGMIF again exhibited the highest Generalized Sobel Operator (mdn =0.594, IQR =0.579-0.607; mdn =0.692, IQR =0.651-0.718 for comparison with T1-w and T2-w images), compared to: GMMCI (mdn =0.491, IQR =0.458-0.507, P<5.60×10-4; mdn =0.495, IQR =0.487-0.533, P<5.60×10-4), DLMWL (mdn =0.292, IQR =0.248-0.317, P<5.60×10-4; mdn =0.191, IQR =0.179-0.243, P<5.60×10-4), PWA (mdn =0.423, IQR =0.383-0.455, P<5.60×10-4; mdn =0.448, IQR =0.414-0.463, P<5.60×10-4) and MoI (mdn =0.437, IQR =0.406-0.479, P<5.60×10-4; mdn =0.540, IQR =0.521-0.636, P<5.60×10-4), demonstrating superior contrast enhancement and sharpness compared to other methods. Conclusions: Based on the tumor CNR and Generalized Sobel Operator Analysis, the proposed PGMIF method demonstrated its capability of enhancing MRI tumor contrast while keeping the anatomical structures of the input images. It holds promises for NPC tumor delineation in radiotherapy.

TMEM52B Isoforms P18 and P20 Differentially Promote the Oncogenesis and Metastasis of Nasopharyngeal Carcinoma.

Transmembrane protein 52B (TMEM52B), a newly identified tumor-related gene, has been reported to regulate various tumors, yet its role in nasopharyngeal carcinoma (NPC) remains unclear. Transcriptomic analysis of NPC cell lines reveals frequent overexpression of TMEM52B, and immunohistochemical results show that TMEM52B is associated with advanced tumor stage, recurrence, and decreased survival time. Depleting TMEM52B inhibits the proliferation, migration, invasion, and oncogenesis of NPC cells in vivo. TMEM52B encodes two isoforms, TMEM52B-P18 and TMEM52B-P20, differing in their N-terminals. While both isoforms exhibit similar pro-oncogenic roles and contribute to drug resistance in NPC, TMEM52B-P20 differentially promotes metastasis. This functional discrepancy may be attributed to their distinct subcellular localization; TMEM52B-P18 is confined to the cytoplasm, while TMEM52B-P20 is found both at the cell membrane and in the cytoplasm. Mechanistically, cytoplasmic TMEM52B enhances AKT phosphorylation by interacting with phosphoglycerate kinase 1 (PGK1), fostering NPC growth and metastasis. Meanwhile, membrane-localized TMEM52B-P20 promotes E-cadherin ubiquitination and degradation by facilitating its interaction with the E3 ubiquitin ligase NEDD4, further driving NPC metastasis. In conclusion, the TMEM52B-P18 and TMEM52B-P20 isoforms promote the metastasis of NPC cells through different mechanisms. Drugs targeting these TMEM52B isoforms may offer therapeutic benefits to cancer patients with varying degrees of metastasis.

The potential advantages of 18F sodium fluoride positron emission tomography-computed tomography for clinical staging and management planning in patients with nasopharyngeal carcinoma.

Background: The staging and treatment planning of nasopharyngeal carcinoma (NPC) face challenges due to limited sensitivity of conventional imaging. 18F-sodium fluoride (18F-NaF) positron emission tomography-computed tomography (PET/CT) offers potential advantages in detecting early bone involvement. This retrospective cohort study aimed to assess the potential advantage of 18F-NaF PET/CT for clinical staging and management planning in patients with NPC and to compare 18F-NaF PET/CT findings with those of conventional imaging modalities. Methods: We enrolled a cohort of patients with NPC who underwent 18F-NaF PET/CT at our PET/CT center between July 1, 2017, and June 30, 2021, and analyzed the findings of 18F-NaF PET/CT and conventional imaging modalities. Data from multidisciplinary team discussions on clinical staging and management planning both before and after 18F-NaF PET/CT were recorded. Additionally, any changes in clinical staging and management planning following 18F-NaF PET/CT were documented. Results: A total of 58 patients were included in this study. After 18F-NaF PET/CT imaging, clinical tumor-node-metastasis (TNM) staging was observed to have changed in seven cases (12.1%). Among these, four cases had changes in T stage and three cases in the M stage. Additionally, changes in clinical management plans were observed in eight patients (13.8%). Changes due the results of 18F-NaF PET/CT included three cases with major modification (two cases switched from curative treatment to palliative treatment, and one case switched from palliative treatment to curative treatment) and five cases with minor changes. The minor changes involved alteration to the radiotherapy target volume (three cases with an increased target volume and one case with a reduced target area). Furthermore, one case required an alteration to the radiotherapy strategy for local bone involvement. Conclusions: The use of 18F-NaF PET/CT in patients newly diagnosed with NPC may offer potential advantages for clinical staging and treatment planning, enabling physicians to select a more individualized treatment approach.

In-silico evaluation of Oroxylum indicum vent compounds in the plausible treatment and prevention of nasopharyngeal cancer.

BACKGROUND: Shyonaka (Oroxylum indicum Vent) is widely used in Ayurveda and in ethnomedical practice for the treatment of inflammation, pain, diarrhea, non-healing ulcers, and cancer. Owing to the high prevalence of Epstein-Barr virus (EBV) infection in Nasopharyngeal carcinoma (NPC) patients, simultaneous targeting of proteins involved in both EBV replication and NPC proliferation might help to manage the disease effectively. OBJECTIVES: This study is designed to identify potential dual targeting inhibitors from Oroxylum indicum having the potential to inhibit both EBV and NPC. This study also attempted quantitative analysis of Shyonaka Bark Decoction (SBD) to confirm the presence of Baicalein and Chrysin which are predominant marker compounds of Shyonaka. METHODOLOGY: The HPLC analysis of stem bark and root bark of Oroxylum indicum was done to estimate the presence of marker compounds Baicalein and Chrysalin. The in-silico analysis included ADMET analysis followed by molecular docking of known compounds from Oroxylum indicum (retrieved from IMPPAT database) onto the target proteins of EBV (BHRF1, NEC1, dUTPase, Uracil DNA glycosylase) and NPC (COX-2, EGFR, and MDM2) using DOCK6 tool. Further validations were done using the molecular dynamics simulations of top screened molecules onto the selected target proteins using AMBER20 package and their corresponding MMGBSA binding free-energy values were calculated. RESULTS: The molecular docking revealed that the key molecules from the plant, scutellarein 7-rutinoside (S7R), scutellarin (SCU) and 6-hydroxyluteolin, Baicalein and 5,7-Dihydroxy-2-phenyl-6-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxychromen-4-one (57D) are effectively intervening with the target proteins of EBV, one of the key causative factors of NPC and the NPC specific targets which have the potential to reduce tumor size and other consequences of NPC. The molecular dynamics simulations of S7R, Baicalein and 57D, Baicalein with MDM-2 protein and dUTPase protein, respectively, showed stable interactions between them which were further assessed by the binding energy calculations. CONCLUSION: Overall, the in-silico evaluation of these phytochemicals with target proteins indicates their potential to inhibit both EBV and NPC which needs further in-vitro and in-vivo validations.

Deep Learning for Nasopharyngeal Carcinoma Segmentation in Magnetic Resonance Imaging: A Systematic Review and Meta-Analysis.

Nasopharyngeal carcinoma is a significant health challenge that is particularly prevalent in Southeast Asia and North Africa. MRI is the preferred diagnostic tool for NPC due to its superior soft tissue contrast. The accurate segmentation of NPC in MRI is crucial for effective treatment planning and prognosis. We conducted a search across PubMed, Embase, and Web of Science from inception up to 20 March 2024, adhering to the PRISMA 2020 guidelines. Eligibility criteria focused on studies utilizing DL for NPC segmentation in adults via MRI. Data extraction and meta-analysis were conducted to evaluate the performance of DL models, primarily measured by Dice scores. We assessed methodological quality using the CLAIM and QUADAS-2 tools, and statistical analysis was performed using random effects models. The analysis incorporated 17 studies, demonstrating a pooled Dice score of 78% for DL models (95% confidence interval: 74% to 83%), indicating a moderate to high segmentation accuracy by DL models. Significant heterogeneity and publication bias were observed among the included studies. Our findings reveal that DL models, particularly convolutional neural networks, offer moderately accurate NPC segmentation in MRI. This advancement holds the potential for enhancing NPC management, necessitating further research toward integration into clinical practice.

Long-term follow-up of protective effects on salivary and swallowing structures and improvement of late xerostomia and dysphagia by level IIb optimisation in clinical target volume of nasopharyngeal carcinoma.

BACKGROUND: This study aimed to assess the long-term effect of level IIb clinical target volume (CTV) optimisation on survival, xerostomia, and dysphagia in patients with nasopharyngeal carcinoma (NPC). METHODS: Clinical data of 415 patients with NPC treated with intensity-modulated radiotherapy between December 2014 and October 2018 were retrospectively analysed. The patients were categorised into modified and comparison groups. Late xerostomia and dysphagia were evaluated using Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer scoring. Survival analysis was performed using the Kaplan-Meier method. Differences in late toxicity and dose parameters between both groups were compared. Prognostic factors for survival and late toxicity were assessed using regression analyses. RESULTS: Patients in the modified group developed late xerostomia and dysphagia less frequently than those in the comparison group did (P < 0.001). The mean dose (Dmean) and V26 of parotid glands; Dmean and V39 of submandibular glands; and Dmean of sublingual glands, oral cavity, larynx, and superior, middle, and lower pharyngeal constrictor muscles were lower in the modified group than those in the comparison group (all P < 0.001). Both groups had no significant differences in overall, local recurrence-free, distant metastasis-free, or progression-free survival. The Dmean of the parotid and sublingual glands was a risk factor for xerostomia. The Dmean of the parotid and sublingual glands and middle pharyngeal constrictor muscle was a risk factor for dysphagia. CONCLUSIONS: Level IIb optimisation in NPC patients who meet certain criteria specially the exclusion of positive retropharyngeal nodes treated with intensity-modulated radiotherapy has the potential to better protect the salivary and swallowing structures, decreasing the development of late radiation-induced xerostomia and dysphagia while maintaining long-term survival.

Dynamic monitoring of radiation-induced white matter microstructure injury in nasopharyngeal carcinoma via high-angular resolution diffusion imaging.

PURPOSE: To investigate white matter microstructural abnormalities caused by radiotherapy in nasopharyngeal carcinoma (NPC) patients using MRI high-angular resolution diffusion imaging (HARDI). METHODS: We included 127 patients with pathologically confirmed NPC: 36 in the pre-radiotherapy group, 29 in the acute response period (post-RT-AP), 23 in the early delayed period (post-RT-ED) group, and 39 in the late-delayed period (post-RT-LD) group. HARDI data were acquired for each patient, and dispersion parameters were calculated to compare the differences in specific fibre bundles among the groups. The Montreal Neurocognitive Assessment (MoCA) was used to evaluate neurocognitive function, and the correlations between dispersion parameters and MoCA were analysed. RESULTS: In the right cingulum frontal parietal bundles, the fractional anisotropy value decreased to the lowest level post-RT-AP and then reversed and increased post-RT-ED and post-RT-LD. The mean, axial, and radial diffusivity were significantly increased in the post-RT-AP (p < 0.05) and decreased in the post-RT-ED and post-RT-LD groups to varying degrees. MoCA scores were decreased post-radiotherapy than those before radiotherapy (p = 0.005). MoCA and mean diffusivity exhibited a mild correlation in the left cingulum frontal parahippocampal bundle. CONCLUSIONS: White matter tract changes detected by HARDI are potential biomarkers for monitoring radiotherapy-related brain damage in NPC patients.

Significance of saline nasalirrigation for COVID-19 infection: observations and reflections from nursing care of nasopharyngeal carcinoma.

Background: Coronavirus disease 2019 (COVID-19) has placed a tremendous burden on the world's healthcare systems, prompting medical professionals worldwide to diligently research and experiment with treatment methods to prevent infection and alleviate symptoms. Previous studies have shown the potential of nasal irrigation in reducing viral clearance time and alleviating local symptoms of COVID-19. However, views differ regarding its efficacy in improving systemic symptoms. Thus, we sought to examine whether saline nasal irrigation might play a role in treatment and self-care after COVID-19 infection, but further validation is still necessary. Methods: We conducted a retrospective analysis of 468 patients and 51 healthcare personnel concurrently. The participants were grouped based on whether they received saline nasal irrigation. We used χ2 tests and Fisher's exact tests to assess the differences in the rates of COVID-19 infection and the rates of developing a fever after COVID-19 infection among different groups. Additionally, we used independent samples t-tests and Mann-Whitney U tests to evaluate differences in the maximum fever temperature and fever duration among participants with fever in different groups. Results: The rate of developing a fever after COVID-19 infection was lower (37.7%) in the patients who underwent saline nasal irrigation. Among all febrile patients, there was no difference in the highest fever temperature, but patients who underwent saline nasal irrigation had a shorter fever duration (1.72±1.05 days). Additionally, the rate of COVID-19 infection and the rate of developing a fever were higher, and fever symptoms were more severe in the healthcare worker group than in the patient group. Conclusions: Saline nasal irrigation can alleviate symptoms caused by COVID-19 infection.

A real-world evaluation of tislelizumab in patients with head and neck cancer.

Background: Various studies support the use of programmed cell death protein 1 (PD-1) blockades, also known as immune checkpoint inhibitors (ICIs), to treat head and neck cancer (HNC). Tislelizumab is a humanised immunoglobulin G4 (IgG4) monoclonal antibody with a high affinity and specificity for PD-1. However, the "real-world" clinical evidence of tislelizumab for HNC is limited. Methods: In this study, the medical records of 39 patients with head and neck squamous cell carcinoma (HNSCC) or nasopharyngeal carcinoma (NPC) who received tislelizumab between January 2021 and March 2022 were reviewed retrospectively. Tislelizumab was administered to 15 patients during neoadjuvant therapy (Group 1), five patients during adjuvant therapy (Group 2), 14 patients during consolidation therapy (Group 3), and five patients during salvage therapy (Group 4). The Kaplan-Meier method was used to calculate progression-free survival (PFS) and overall survival (OS). Results: The median age of enrolled patients was 55 (range, 28-83) years. The median follow-up time was 27.1, 26.1, 28.6, and 20.9 months for Groups 1, 2, 3, and 4, respectively. The mean PFS and OS of Groups 1, 2, 3, and 4 were 21.5 and 22.8; 24.1 and 24.2; 26.9 and 28.1; and 13.9 and 17.1 months, respectively. In Groups 1 and 4, the objective response rate (ORR) was 86.7% and 60%, respectively. Meanwhile, except for one (2.6%) patient with grade 4 enteritis, the other observed non-haematological adverse events (AEs) were ≤ grade 2. Conclusions: Tislelizumab demonstrated promising efficacy and tolerability in patients with HNSCC or NPC in a real-world setting, consistent with previous reports.

ThermomiR-377-3p-induced suppression of Cirbp expression is required for effective elimination of cancer cells and cancer stem-like cells by hyperthermia.

BACKGROUND: In recent years, the development of adjunctive therapeutic hyperthermia for cancer therapy has received considerable attention. However, the mechanisms underlying hyperthermia resistance are still poorly understood. In this study, we investigated the roles of cold­inducible RNA binding protein (Cirbp) in regulating hyperthermia resistance and underlying mechanisms in nasopharyngeal carcinoma (NPC). METHODS: CCK-8 assay, colony formation assay, tumor sphere formation assay, qRT-PCR, Western blot were employed to examine the effects of hyperthermia (HT), HT + oridonin(Ori) or HT + radiotherapy (RT) on the proliferation and stemness of NPC cells. RNA sequencing was applied to gain differentially expressed genes upon hyperthermia. Gain-of-function and loss-of-function experiments were used to evaluate the effects of RNAi-mediated Cirbp silencing or Cirbp overexpression on the sensitivity or resistance of NPC cells and cancer stem-like cells to hyperthermia by CCK-8 assay, colony formation assay, tumorsphere formation assay and apoptosis assay, and in subcutaneous xenograft animal model. miRNA transient transfection and luciferase reporter assay were used to demonstrate that Cirbp is a direct target of miR-377-3p. The phosphorylation levels of key members in ATM-Chk2 and ATR-Chk1 pathways were detected by Western blot. RESULTS: Our results firstly revealed that hyperthermia significantly attenuated the stemness of NPC cells, while combination treatment of hyperthermia and oridonin dramatically increased the killing effect on NPC cells and cancer stem cell (CSC)­like population. Moreover, hyperthermia substantially improved the sensitivity of radiation­resistant NPC cells and CSC­like cells to radiotherapy. Hyperthermia noticeably suppressed Cirbp expression in NPC cells and xenograft tumor tissues. Furthermore, Cirbp inhibition remarkably boosted anti­tumor­killing activity of hyperthermia against NPC cells and CSC­like cells, whereas ectopic expression of Cirbp compromised tumor­killing effect of hyperthermia on these cells, indicating that Cirbp overexpression induces hyperthermia resistance. ThermomiR-377-3p improved the sensitivity of NPC cells and CSC­like cells to hyperthermia in vitro by directly suppressing Cirbp expression. More importantly, our results displayed the significantly boosted sensitization of tumor xenografts to hyperthermia by Cirbp silencing in vivo, but ectopic expression of Cirbp almost completely counteracted hyperthermia-mediated tumor cell-killing effect against tumor xenografts in vivo. Mechanistically, Cirbp silencing-induced inhibition of DNA damage repair by inactivating ATM-Chk2 and ATR-Chk1 pathways, decrease in stemness and increase in cell death contributed to hyperthermic sensitization; conversely, Cirbp overexpression-induced promotion of DNA damage repair, increase in stemness and decrease in cell apoptosis contributed to hyperthermia resistance. CONCLUSION: Taken together, these findings reveal a previously unrecognized role for Cirbp in positively regulating hyperthermia resistance and suggest that thermomiR-377-3p and its target gene Cirbp represent promising targets for therapeutic hyperthermia.

[Epstein-Barr virus (Herpesviridae: Lymphocryptovirus) types 1 and 2 and other viral markers in patients with nasopharyngeal carcinoma in two geographically and ethnically distinct regions of Russia].

INTRODUCTION: The discovery of two types of Epstein-Barr virus (EBV) (EBV-1 and EBV-2) that have different biological properties stimulated the search for neoplasms associated with each type of the virus. The aim of the work is to study the nature of the association of nasopharyngeal cancer (NPC) with EBV-1 and EBV-2, serological activity for each viral type and the concentration of EBV DNA in the blood plasma of two gender, age and ethnic groups of NPC patients that represent geographically and climatically different regions of Russia,. MATERIALS AND METHODS: In the blood plasma of patients with NPC and other non- EBV associated tumors of oral cavity (OTOCEBV-) from the North Caucasian (NCFD) and Central (CFD) Federal Districts of Russia, the types of EBV and the concentration of viral DNA were determined using respectively «nested¼ and real time PCR; titers of IgG and IgA antibodies to viral capsid antigen (VCA) were measured in indirect immunofluorescence assay. RESULTS: The blood plasma samples testing showed that NPC and OTOCEBV- patients were infected with both types of EBV in approximately equal proportions. In two groups of NPC patients infected with one of the virus types only, EBV-1 or EBV-2, respectively, no statistically significant differences were found between the geometric mean values of IgG and IgA anti-EBV antibody titers and viral DNA concentrations in blood plasma. The distribution of virus types was not affected by either patient gender or ethnogeographic origin. The difference was found only between age groups: EBV-2 dominated in NPC patients up to 60 years, and EBV-1 was prevalent in patients over 60 years. CONCLUSION: The lack of the predominance of one of EBV types in NPC patients that are the representatives of different ethnic groups from geographically and climatically different regions, suggests that none of these factors play an important role in the NPC carcinogenesis. Evidently, each type of EBV, EBV-1 or EBV-2, if the necessary conditions arise, are able to exhibit its oncogenic potential to initiate tumor development.

Failure patterns of locoregional recurrence after reducing target volumes in patients with nasopharyngeal carcinoma receiving adaptive replanning during intensity-modulated radiotherapy: a single-center experience in China.

BACKGROUND: Previous researches have demonstrated that adaptive replanning during intensity-modulated radiation therapy (IMRT) could enhance the prognosis of patients with nasopharyngeal carcinoma (NPC). However, the delineation of replanning target volumes remains unclear. This study aimed to evaluate the feasibility of reducing target volumes through adaptive replanning during IMRT by analyzing long-term survival outcomes and failure patterns of locoregional recurrence in NPC. METHODS: This study enrolled consecutive NPC patients who received IMRT at our hospital between August 2011 and April 2018. Patients with initially diagnosed, histologically verified, non-metastatic nasopharyngeal cancer were eligible for participation in this study. The location and extent of locoregional recurrences were transferred to pretreatment planning computed tomography for dosimetry analysis. RESULTS: Among 274 patients, 100 (36.5%) received IMRT without replanning and 174 (63.5%) received IMRT with replanning. Five-year rates of locoregional recurrence-free survival (LRFS) were 90.1% (95%CI, 84.8% to 95.4%) and 80.8% (95%CI, 72.0% to 89.6%) for patients with and without replanning, P = 0.045. There were 17 locoregional recurrences in 15 patients among patients with replanning, of which 1 (5.9%) was out-field and 16 (94.1%) were in-field. Among patients without replanning, 19 patients developed locoregional recurrences, of which 1 (5.3%) was out-field, 2 (10.5%) were marginal, and 16 (84.2%) were in-field. CONCLUSIONS: In-field failure inside the high dose area was the most common locoregional recurrent pattern for non-metastatic NPC. Adapting the target volumes and modifying the radiation dose prescribed to the area of tumor reduction during IMRT was feasible and would not cause additional recurrence in the shrunken area.

Predictive accuracy of machine learning for radiation-induced temporal lobe injury in nasopharyngeal carcinoma patients: a systematic review and meta-analysis.

Background: Radiotherapy is a common treatment for nasopharyngeal carcinoma (NPC) but can cause radiation-induced temporal lobe injury (RTLI), resulting in irreversible damage. Predicting RTLI at the early stage may help with that issue by personalized adjustment of radiation dose based on the predicted risk. Machine learning (ML) models have recently been used to predict RTLI but their predictive accuracy remains unclear because the reported concordance index (C-index) varied widely from around 0.31 to 0.97. Therefore, a meta-analysis was needed. Methods: The PubMed, Web of Science, Embase, and Cochrane Library databases were searched from inception to November 2022. Studies that fully develop one or more ML risk models of RTLI after radiotherapy for NPC were included. The Prediction model Risk Of Bias Assessment Tool (PROBAST) was used to assess the risk of bias in the included research. The primary outcome of this review was the C-index, specificity (Spe), and sensitivity (Sen). Results: The meta-analysis included 14 studies with 15,573 NPC patients reporting a total of 72 prediction models. Overall, 94.44% of models were found to have a high risk of bias. Radiomics was included in 57 models, dosimetric predictors in 28, and clinical data in 27. The pooled C-index for ML models predicting RTLI was 0.77 [95% confidence interval (CI): 0.75-0.79] in the training set and 0.78 (95% CI: 0.75-0.81) in the validation set. The pooled Sen was 0.75 (95% CI: 0.69-0.80) in the training set and 0.70 (95% CI: 0.66-0.73) in the validation set and the pooled Spe was 0.78 (95% CI: 0.73-0.82) in the training set and 0.79 (95% CI: 0.75-0.82) in the validation set. Models with radiomics and clinical data achieved the most excellent discriminative performance, with a pooled C-index of 0.895. Conclusions: ML models can accurately predict RTLI at an early stage, allowing for timely interventions to prevent further damage. The kind of ML methods and the selection of predictors may influence the predictive accuracy.

E3 ubiquitin ligases in nasopharyngeal carcinoma and implications for therapies.

Nasopharyngeal carcinoma (NPC) is one of the most common squamous cell carcinomas of the head and neck, and Epstein-Barr virus (EBV) infection is one of the pathogenic factors involved in the oncogenetic development and progression of NPC. E3 ligases, which are key members of the ubiquitin proteasome system (UPS), specifically recognize various oncogenic factors and tumor suppressors and contribute to determining their fate through ubiquitination. Several studies have demonstrated that E3 ligases are aberrantly expressed and mutated in NPC and that these changes are closely associated with the occurrence and progression of NPC. Herein, we aim to thoroughly review the specific action mechanisms by which E3 ligases participate in NPC signaling pathways and discuss their functional relationship with EBV. Moreover, we describe the current progress in and limitations for targeted therapies against E3 ligases in NPC. KEY MESSAGES: • E3 ubiquitin ligases, as members of the UPS system, determine the fate of their substrates and may act either as oncogenic or anti-tumorigenic factors in NPC. • Mutations or dysregulated expression of E3 ubiquitin ligases is closely related to the occurrence, development, and therapeutic sensitivity of NPC, as they play important roles in several signaling pathways affected by EBV infection. • As promising therapeutic targets, E3 ligases may open new avenues for treatment and for improving the prognosis of NPC patients.

mRNA-based Vaccines Targeting the T-cell Epitope-rich Domain of Epstein Barr Virus Latent Proteins Elicit Robust Anti-Tumor Immunity in Mice.

Epstein-Barr virus (EBV) is associated with various malignancies and infects >90% of the global population. EBV latent proteins are expressed in numerous EBV-associated cancers and contribute to carcinogenesis, making them critical therapeutic targets for these cancers. Thus, this study aims to develop mRNA-based therapeutic vaccines that express the T-cell-epitope-rich domain of truncated latent proteins of EBV, including truncatedlatent membrane protein 2A (Trunc-LMP2A), truncated EBV nuclear antigen 1 (Trunc-EBNA1), and Trunc-EBNA3A. The vaccines effectively activate both cellular and humoral immunity in mice and show promising results in suppressing tumor progression and improving survival time in tumor-bearing mice. Furthermore, it is observed that the truncated forms of the antigens, Trunc-LMP2A, Trunc-EBNA1, and Trunc-EBNA3A, are more effective than full-length antigens in activating antigen-specific immune responses. In summary, the findings demonstrate the effectiveness of mRNA-based therapeutic vaccines targeting the T-cell-epitope-rich domain of EBV latent proteins and providing new treatment options for EBV-associated cancers.

Scheduling radiotherapy for patients with nasopharyngeal carcinoma in the corresponding time window can reduce radiation-induced oral mucositis: A randomized, prospective study.

BACKGROUND: To explore a new method to reduce radiation-induced oral mucositis by scheduling radiotherapy for patients with nasopharyngeal carcinoma (NPC) in the corresponding time window of the cycle of oral mucosal cells. METHODS: Eighty-two NPC patients were randomly divided into a day group (n = 41) and a night group (n = 41). The radiotherapy was scheduled at noon (11:30-15:30) for the day group, while at night (19:00-23:00) for the night group. Oral mucositis and oral pain were recorded in both groups after each radiotherapy fraction. The short-term efficacy of primary tumor regression, weight loss, and bone marrow suppression was recorded. RESULTS: The incidence of Grade 2 oral mucositis was 87.8% (36/41) and 63.4% (26/41) in the night group and day group, respectively (p = 0.010). The incidence of Grade 3 oral mucositis was 65.9% (27/41) and 22.0% (9/41) in the night group and day group, respectively (p < 0.001). The mean number of radiotherapy for patients to develop Grade 2 oral mucositis was 15.67 ± 5.05 and 20.92 ± 6.21 in the night group and day group, respectively. The incidence of Grade 2 oral pain was 48.8% (20/41) and 22.0% (9/41) in the night group and day group, respectively (p = 0.011). There were no significant differences in tumor regression, weight loss, and bone marrow suppression between the two groups. CONCLUSION: By scheduling radiotherapy based on the corresponding time window of the cycle of oral mucosal cells, the severity of oral mucositis in NPC patients was reduced.