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Background: To compare the differences in long-term quality of life (QoL) between survivors of paediatric and adult patients with nasopharyngeal carcinoma (NPC) and assess the clinical factors that predict long-term QoL. Methods: We enrolled 420 long-term NPC survivors who were alive for at least 8 years after treatment, including 195 paediatric and 225 adult patients diagnosed and treated with intensity-modulated radiotherapy (IMRT) at Sun Yat-sen University Cancer Centre (SYSUCC) between 2011 and 2015. Data on clinical factors and EORTC QLQ-C30 were collected from all participants. The QoL of paediatric and adult NPC survivors was compared. Results: The paediatric group had significantly better outcomes in global health status (paediatric: 80.2 ± 12.7; adult: 77.2 ± 11.5; P = 0.027), physical function (paediatric: 98.5 ± 4.6; adult: 95.1 ± 7.0; P < 0.001), role function (paediatric: 97.0 ± 9.2; adult: 90.5 ± 15.2; P < 0.001), social function (paediatric: 96.0 ± 8.9; adult: 93.5 ± 11.8; P = 0.038), insomnia (paediatric: 1.9 ± 7.8; adult: 13.1 ± 22.3; P < 0.001), constipation (paediatric: 1.3 ± 7.5; adult: 8.0 ± 17.4; P < 0.001), diarrhea (paediatric: 0.7 ± 4.6; adult: 2.8 ± 9.3; P = 0.010), and financial difficulties (paediatric: 1.9 ± 7.8; adult: 11.0 ± 19.8; P < 0.001), but poorer cognitive function (paediatric: 88.3 ± 9.9; adult: 93.8 ± 12.6; P < 0.001) than the adult group. Pretreatment clinical factors, including T stage, N stage, and pre-treatment EBV (Epstein-Barr Virus) DNA, showed a strong association with QoL. However, the factors that affected the QoL outcomes differed between the two groups. In survivors of paediatric cancer, global health status/QoL was strongly correlated with T stage (P < 0.001) and clinical stage (P = 0.018), whereas it was strongly correlated with pre-treatment EBV DNA (P = 0.008) in adults. Conclusion: Paediatric survivors of NPC have a significantly better QoL than adult NPC survivors. Moreover, pre-treatment T stage, N stage, and EBV DNA significantly influenced the overall health status of the survivors. These results highlight the need to tailor care to both age groups to promote better long-term health outcomes. [ABSTRACT FROM AUTHOR]

Abstract Background To compare the differences in long-term quality of life (QoL) between survivors of paediatric and adult patients with nasopharyngeal carcinoma (NPC) and assess the clinical factors that predict long-term QoL. Methods We enrolled 420 long-term NPC survivors who were alive for at least 8 years after treatment, including 195 paediatric and 225 adult patients diagnosed and treated with intensity-modulated radiotherapy (IMRT) at Sun Yat-sen University Cancer Centre (SYSUCC) between 2011 and 2015. Data on clinical factors and EORTC QLQ-C30 were collected from all participants. The QoL of paediatric and adult NPC survivors was compared. Results The paediatric group had significantly better outcomes in global health status (paediatric: 80.2 ± 12.7; adult: 77.2 ± 11.5; P = 0.027), physical function (paediatric: 98.5 ± 4.6; adult: 95.1 ± 7.0; P

Abstract Nasopharyngeal carcinoma (NPC) is often diagnosed at a very advanced stage due to its location and non-specific initial symptoms. Moreover, no clinically useful serological marker has been established so far for early detection of NPC. In this study, we have investigated the clinical significance of plasma Epstein–Barr virus DNA load along with interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) levels to evaluate if these three all together can be useful as a strong serological marker for early detection and prediction of treatment response in patients with NPC. Plasma EBV DNA load, IL-6 level, VEGF expressions were measured in 24 patients with NPC at presentation and various time points during and after treatment. There was a positive correlation between high plasma EBV DNA load with higher IL-6 and VEGF expression, which was closely associated with therapeutic response as well. Persistent or recurrent plasma EBV load with higher IL-6 and VEGF levels can potentially predict disease progression and may be useful to select patients for additional therapy and longer follow-up.

Nasopharyngeal carcinoma (NPC) is often diagnosed at a very advanced stage due to its location and non-specific initial symptoms. Moreover, no clinically useful serological marker has been established so far for early detection of NPC. In this study, we have investigated the clinical significance of plasma Epstein–Barr virus DNA load along with interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) levels to evaluate if these three all together can be useful as a strong serological marker for early detection and prediction of treatment response in patients with NPC. Plasma EBV DNA load, IL-6 level, VEGF expressions were measured in 24 patients with NPC at presentation and various time points during and after treatment. There was a positive correlation between high plasma EBV DNA load with higher IL-6 and VEGF expression, which was closely associated with therapeutic response as well. Persistent or recurrent plasma EBV load with higher IL-6 and VEGF levels can potentially predict disease progression and may be useful to select patients for additional therapy and longer follow-up. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Distant metastasis is the primary cause of unsuccessful treatment in nasopharyngeal carcinoma (NPC), suggesting the crucial need to comprehend this process. A tumor related to NPC does not have flat surfaces, but consists of confined microenvironments, proteins, and surface topography. To mimic the complex microenvironment, three-dimensional platforms with microwells and connecting channels were designed and developed with a fibronectin (FN) coating or nanohole topography. The potential of the transforming growth factor-β (TGF-β) inhibitor (galunisertib) for treating NPC was also investigated using the proposed platform. Our results demonstrated an increased traversing probability of NPC43 cells through channels with an FN coating, which correlated with enhanced cell motility and dispersion. Conversely, the presence of nanohole topography patterned on the platform bottom and the TGF-β inhibitor led to a reduced cell traversing probability and decreased cell motility, likely due to the decrease in the F-actin concentration in NPC43 cells. This study highlights the significant impact of confinement levels, surface proteins, nanotopography, and the TGF-β inhibitor on the metastatic probability of cancer cells, providing valuable insights for the development of novel treatment therapies for NPC. The developed platforms proved to be useful tools for evaluating the metastatic potential of cells and are applicable for drug screening. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is a distinct type of cancer that affects the head and neck region, and it is notably linked to infection with the Epstein-Barr Virus (EBV), particularly in endemic regions such as Southeast Asia and Southern China. Despite advances in the conventional care for NPC, including radiation and chemotherapy, the prognosis remains poor for individuals with relapsed or metastatic stages of the disease. Immune checkpoint inhibitors (ICIs), particularly those targeting the PD-1/PD-L1 axis, have emerged as an optimistic therapeutic option. PD-L1 overexpression in NPC contributes to immune avoidance and correlates in relation to these immunotherapies. This review comprehensively explores PD-L1 expression in NPC and its role in tumor immune escape, along with a detailed analysis of clinical trials investigating PD-1/PD-L1 blockade. While PD-L1 overexpression is associated with better responses to ICIs, resistance mechanisms and the complex tumor microenvironment (TME) limit their overall efficacy. We will address these barriers and highlight future directions for improving outcomes, including combination therapies, novel biomarkers, and personalized approaches to treatment. With ongoing research and clinical trials, immune checkpoint inhibition holds great potential to revolutionize NPC therapy, offering hope for improved sustained survival rates and overall well-being for individuals.

Nasopharyngeal carcinoma (NPC) is a distinct malignancy in head and neck cancer, notably linked to Epstein-Barr virus (EBV) infections in regions with high prevalence. NPC's tumor microenvironment fosters immune escape mechanisms that support tumor cell survival, with programmed death-ligand 1 (PD-L1) as a key player. PD-L1 expression on NPC cells binds to the programmed death-1 (PD-1) receptor on T cells, thereby creating an immunosuppressive environment that impairs immune surveillance. Two significant modulators of PD-L1 expression in NPC include the EBV-encoded latent membrane protein 1 (LMP1) and the immune cytokine interferon-gamma (IFN-γ). Together, they contribute to the intricate regulation of PD-L1, enhancing immune evasion and complicating the landscape for effective treatment approaches. This review explores the molecular mechanisms underlying PD-L1 upregulation, focusing on LMP1's activation of the NF-κB and JAK/STAT pathways and IFN-γ′s paradoxical role in facilitating immune escape. Clinical evidence indicates that PD-L1 expression correlates with poor prognosis and resistance to standard therapies in NPC patients. Understanding these regulatory pathways may inform potential therapeutic strategies, including immune checkpoint inhibitors, combination therapies, and novel immune-based approaches tailored to NPC's unique etiology. By providing a comprehensive synthesis of existing studies, this review highlights the interplay between PD-L1, LMP1, and IFN-γ, offering a framework for innovative therapeutic strategies targeting immune escape mechanisms. Identifying patients most likely to benefit from immune-targeted approaches and leveraging combination treatments could improve outcomes for NPC patients facing advanced or resistant disease.

Abstract 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

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is a unique malignancy with a distinct epidemiological pattern, primarily affecting populations in Southeast Asia and Southern China. The identification and utilization of biomarkers in NPC have significantly advanced over recent years, offering promising avenues for improving clinical outcomes. Epstein-Barr virus (EBV) DNA remains the most widely recognized biomarker, playing a pivotal role in early detection, prognostic evaluation, and monitoring treatment responses. However, ongoing research has identified additional biomarkers, such as circulating tumor cells (CTCs), microRNAs, and immune-related molecules that provide further prognostic insights. These biomarkers not only enhance our understanding of NPC pathogenesis but also support personalized treatment approaches by stratifying patients based on risk and expected treatment outcomes. Clinically, the application of these biomarkers has the potential to transform NPC management, enabling more precise interventions and improving survival rates while minimizing treatment-related toxicity. The integration of these biomarkers into routine clinical practice could facilitate early diagnosis, predict therapeutic responses, and identify patients at higher risk of recurrence. Despite these advancements, further validation in large-scale clinical trials is required to fully realize their potential. This review discusses the clinical relevance and prognostic potential of established and emerging biomarkers in NPC, emphasizing their role in refining patient management and enhancing personalized therapeutic strategies. The continued exploration of these biomarkers holds promise for the development of novel diagnostic tools and treatment paradigms, ultimately improving outcomes for patients with NPC.

Abstract 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.

Abstract 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 cold‑inducible 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 radiation‑resistant NPC cells and CSC‑like cells to radiotherapy. Hyperthermia noticeably suppressed Cirbp expression in NPC cells and xenograft tumor tissues. Furthermore, Cirbp inhibition remarkably boosted anti‑tumor‑killing activity of hyperthermia against NPC cells and CSC‑like cells, whereas ectopic expression of Cirbp compromised tumor‑killing effect of hyperthermia on these cells, indicating that Cirbp overexpression induces hyperthermia resistance. ThermomiR-377-3p improved the sensitivity of NPC cells and CSC‑like 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.

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.

Abstract 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.

Distant metastasis is the primary cause of unsuccessful treatment in nasopharyngeal carcinoma (NPC), suggesting the crucial need to comprehend this process. A tumor related to NPC does not have flat surfaces, but consists of confined microenvironments, proteins, and surface topography. To mimic the complex microenvironment, three-dimensional platforms with microwells and connecting channels were designed and developed with a fibronectin (FN) coating or nanohole topography. The potential of the transforming growth factor-β (TGF-β) inhibitor (galunisertib) for treating NPC was also investigated using the proposed platform. Our results demonstrated an increased traversing probability of NPC43 cells through channels with an FN coating, which correlated with enhanced cell motility and dispersion. Conversely, the presence of nanohole topography patterned on the platform bottom and the TGF-β inhibitor led to a reduced cell traversing probability and decreased cell motility, likely due to the decrease in the F-actin concentration in NPC43 cells. This study highlights the significant impact of confinement levels, surface proteins, nanotopography, and the TGF-β inhibitor on the metastatic probability of cancer cells, providing valuable insights for the development of novel treatment therapies for NPC. The developed platforms proved to be useful tools for evaluating the metastatic potential of cells and are applicable for drug screening.

Introduction. The discovery of two types of EpsteinBarr 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 nested 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.

Abstract 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

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Key points 1. SyMRI showed excellent performance in predicting disease progression in NPC. 2. T1_Kurtosis and ADC were independent predictors of progression-free survival. 3. T1_Kurtosis was lower in the non-disease progression group than the disease progression group. 4. Combination of SyMRI, DWI, and clinical factors could improve the predictive performance.

Background: Uncontrolled cellular proliferation may result in the progression of diseases such as cancer that promote organism death. Programmed cell death (PCD) is an important mechanism that ensures the quality and quantity of cells, which could be developed as a potential biomarker for disease diagnosis and treatment. Methods: RNA-seq data and clinical information of nasopharyngeal carcinoma (NPC) patients were downloaded from the Gene Expression Omnibus (GEO), and 1548 PCD-related genes were collected. We used the “limma” package to analyze differentially expressed genes (DEGs). The STRING database was used for protein interaction analysis, and the least absolute shrinkage and selection operator (Lasso) and support vector machines (SVMs) regression analyses were used to identify biomarkers. Then, the timeROC package was used for classifier efficiency assessment, and the “CIBERSORT” package was used for immune infiltration analysis. Wound healing and transwell migration assay were performed to evaluate migration and invasion. Results: We identified 800 DEGs between our control and NPC patient groups, in which 59 genes appeared to be PCD-related DEGs, with their function closely associated with NPC progression, including activation of the PI3K–Akt, TGF-β, and IL-17 signaling pathways. Furthermore, based on the STRING database, Cytoscape and six algorithms were employed to screen 16 important genes (GAPDH, FN1, IFNG, PTGS2, CXCL1, MYC, MUC1, LTF, S100A8, CAV1, CDK4, EZH2, AURKA, IL33, S100A9, and MIF). Subsequently, two reliably characterized biomarkers, FN1 and MUC1, were obtained from the Lasso and SVM analyses. The Receiver operating characteristic (ROC) curves showed that both biomarkers had area under the curve (AUC) values higher than 0.9. Meanwhile, the enrichment analysis showed that in NPC patients, the FN1 and MUC1 expression levels correlated with programmed cell death-related pathways. The enrichment analysis and cellular experimental results indicated that FN1 and MUC1 were overexpressed in NPC cells and associated with programmed cell death-related pathways. Importantly, FN1 and MUC1 severely affected the ability of NPC cells to migrate, invade, and undergo apoptosis. Finally, medroxyprogesterone acetate and 8-Bromo-cAMP acted as drug molecules for the docking of FN1 and MUC1 molecules, respectively, and had binding capacities of –9.17 and –7.27 kcal/mol, respectively. Conclusion: We examined the PCD-related phenotypes and screened FN1 and MUC1 as reliable biomarkers of NPC; our findings may promote the development of NPC treatment strategy.

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.

Abstract 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.

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. [ABSTRACT FROM AUTHOR]

Abstract Background Radiotherapy resistance is the main cause of treatment failure in nasopharyngeal carcinoma (NPC), which leads to poor prognosis. It is urgent to elucidate the molecular mechanisms underlying radiotherapy resistance. Methods RNA-seq analysis was applied to five paired progressive disease (PD) and complete response (CR) NPC tissues. Loss-and gain-of-function assays were used for oncogenic function of FLI1 both in vitro and in vivo. RNA-seq analysis, ChIP assays and dual luciferase reporter assays were performed to explore the interaction between FLI1 and TIE1. Gene expression with clinical information from tissue microarray of NPC were analyzed for associations between FLI1/TIE1 expression and NPC prognosis. Results FLI1 is a potential radiosensitivity regulator which was dramatically overexpressed in the patients with PD to radiotherapy compared to those with CR. FLI1 induced radiotherapy resistance and enhanced the ability of DNA damage repair in vitro, and promoted radiotherapy resistance in vivo. Mechanistic investigations showed that FLI1 upregulated the transcription of TIE1 by binding to its promoter, thus activated the PI3K/AKT signaling pathway. A decrease in TIE1 expression restored radiosensitivity of NPC cells. Furthermore, NPC patients with high levels of FLI1 and TIE1 were correlated with poor prognosis. Conclusion Our study has revealed that FLI1 regulates radiotherapy resistance of NPC through TIE1-mediated PI3K/AKT signaling pathway, suggesting that targeting the FLI1/TIE1 signaling pathway could be a potential therapeutic strategy to enhance the efficacy of radiotherapy in NPC.

Abstract Nasopharyngeal carcinoma (NPC) has insidious onset, late clinical diagnosis and high recurrence rate, which leads to poor quality of patient life. Therefore, it is necessary to further explore the pathogenesis and therapy targets of NPC. BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) was found to be up-regulated in a variety of cancers, but only two previous study showed that BUB1B was overexpressed in NPC and the sample size was small. The clinical role of BUB1B expression and its underlying mechanism in NPC require more in-depth research. Immunohistochemical samples and public RNA-seq data indicated that BUB1B protein and mRNA expression levels were up-regulated in NPC, and summary receiver operating characteristic curve indicated that BUB1B expression level had a strong ability to distinguish NPC tissues from non-NPC tissues. Gene ontology and Kyoto Encyclopedia of genes and genomes were performed and revealed that BUB1B and its related genes were mainly involved in cell cycle and DNA replication. Protein- Protein Interaction were built to interpret the BUB1B molecular mechanism. Histone deacetylase 2 (HDAC2) could be the upstream regulation factor of BUB1B, which was verified by Chromatin Immunoprecipitation Sequencing samples. In summary, BUB1B was highly expressed in NPC, and HDAC2 may affect cell cycle by regulating BUB1B to promote cancer progression.

Background: Because the vast majority of nasopharyngeal carcinoma (NPC) in Chinese patients is a direct result of Epstein–Barr virus (EBV) infection, there is a dearth of data for EBV-negative patients in this population. This multicenter study sought to examine the clinical characteristics of EBV-negative patients and compare long-term outcomes with a propensity-matched (1:1.5) EBV-positive cohort. Methods: NPC patients with known EBV status from four hospitals were collated (2013–2021). A logistic regression model was conducted to evaluate the relationship between patient characteristics and EBV status. The Kaplan–Meier method and Cox regression analysis were used to analyze survival data. Results: This study analyzed 48 (40%) EBV-negative and 72 (60%) EBV-positive patients. The median follow-up time was 63.5 months. Most EBV-negative NPC patients (77.1%) were diagnosed in advanced stages with a higher rate (87.5%) of positive lymph node disease, and no significant prognostic factors were discerned in this subpopulation. The EBV-negative disease was more associated with the keratinizing subtype (18.8% vs. 1.4%, p < 0.05). Compared to EBV-negative NPC patients, EBV-positive NPC patients were more likely to develop a local recurrence (9.7% vs. 0%, p = 0.026). There was no statistical difference in mortality (EBV-negative vs. EBV- positive, 8.3% vs. 4.2%, p = 0.34) during the follow-up period. Although the median PFS and median OS were not reached, the 3-year PFS rate was 68.8% vs. 70.8% (EBV-negative vs. EBV-positive, p = 0.06), the 3-year OS rate was 70.8% vs. 76.4% (EBV-negative vs. EBV-positive, p = 0.464), the 5-year PFS rate was 56.3% vs. 50% (EBV-negative vs. EBV-positive, p = 0.451), and the 5-year OS rate was 56.3% vs. 58.3% (EBV-negative vs. EBV-positive, p = 0.051), respectively. These data show that EBV-positive NPC patients seem to have a tendency to gain better survival compared with EBV-negative NPC patients. Conclusions: Most of the EBV-negative patients were in the middle and late stages at the time of diagnosis and were more associated with the keratinizing subtype. EBV status may be associated with prognosis in NPC. EBV positivity seems to be associated with better survival in NPC patients. Still, due to the small cohort of patients and the short observation period for a number of patients, further work is required to corroborate these conclusions. [ABSTRACT FROM AUTHOR]

Background: To investigate the potential of synthetic MRI (SyMRI) in the prognostic assessment of patients with nonmetastatic nasopharyngeal carcinoma (NPC), and the predictive value when combined with diffusion-weighted imaging (DWI) as well as clinical factors. Methods: Fifty-three NPC patients who underwent SyMRI were prospectively included. 10th Percentile, Mean, Kurtosis, and Skewness of T1, T2, and PD maps and ADC value were obtained from the primary tumor. Cox regression analysis was used for analyzing the association between SyMRI and DWI parameters and progression-free survival (PFS), and then age, sex, staging, and treatment as confounding factors were also included. C-index was obtained by bootstrap. Moreover, significant parameters were used to construct models in predicting 3-year disease progression. ROC curves and leave-one-out cross-validation were used to evaluate the performance and stability. Results: Disease progression occurred in 16 (30.2%) patients at a follow-up of 39.6 (3.5, 48.2) months. T1_Kurtosis, T1_Skewness, T2_10th, PD_Mean, and ADC were correlated with PFS, and T1_Kurtosis (HR: 1.093) and ADC (HR: 1.009) were independent predictors of PFS. The C-index of SyMRI and SyMRI + DWI + Clinic models was 0.687 and 0.779. Moreover, the SyMRI + DWI + Clinic model predicted 3-year disease progression better than DWI or Clinic model (p ≤ 0.008). Interestingly, there was no significant difference between the SyMRI model (AUC: 0.748) and SyMRI + DWI + Clinic model (AUC: 0.846, p = 0.092). Conclusion: SyMRI combined with histogram analysis could predict disease progression in NPC patients, and SyMRI + DWI + Clinic model further improved the predictive performance. Key points: SyMRI showed excellent performance in predicting disease progression in NPC. T1_Kurtosis and ADC were independent predictors of progression-free survival. T1_Kurtosis was lower in the non-disease progression group than the disease progression group. Combination of SyMRI, DWI, and clinical factors could improve the predictive performance. [ABSTRACT FROM AUTHOR]

BackgroundAssociations between trace elements and nasopharyngeal carcinoma (NPC) have been speculated but not thoroughly examined.MethodsThis study registered a total of 225 newly diagnosed patients with NPC and 225 healthy controls matched by sex and age from three municipal hospitals in Guangdong Province, southern China between 2011 and 2015. Information was collected by questionnaire on the demographic characteristics and other possibly confounding lifestyle factors. Eight trace elements and the level of Epstein–Barr virus (EBV) antibody were measured in casual (spot) serum specimens by inductively coupled plasma–mass spectrometry (ICP-MS) and enzyme-linked immunosorbent assay (ELISA), respectively. Restricted cubic splines and conditional logistic regression were applied to assess the relationship between trace elements and NPC risk through single-and multiple-elements models.ResultsSerum levels of chromium (Cr), cobalt (Co), nickel (Ni), arsenic (As), strontium (Sr) and molybdenum (Mo) were not associated with NPC risk. Manganese (Mn) and cadmium (Cd) were positively associated with NPC risk in both single-and multiple-element models, with ORs of the highest tertile compared with the reference categories 3.90 (95% CI, 1.27 to 7.34) for Mn and 2.30 (95% CI, 1.26 to 3.38) for Cd. Restricted cubic splines showed that there was a linear increasing trend between Mn and NPC risk, while for Cd there was a J-type correlation.ConclusionSerum levels of Cd and Mn was positively related with NPC risk. Prospective researches on the associations of the two trace elements with NPC ought to be taken into account within the future.

Background: Radiotherapy resistance is the main cause of treatment failure in nasopharyngeal carcinoma (NPC), which leads to poor prognosis. It is urgent to elucidate the molecular mechanisms underlying radiotherapy resistance. Methods: RNA-seq analysis was applied to five paired progressive disease (PD) and complete response (CR) NPC tissues. Loss-and gain-of-function assays were used for oncogenic function of FLI1 both in vitro and in vivo. RNA-seq analysis, ChIP assays and dual luciferase reporter assays were performed to explore the interaction between FLI1 and TIE1. Gene expression with clinical information from tissue microarray of NPC were analyzed for associations between FLI1/TIE1 expression and NPC prognosis. Results: FLI1 is a potential radiosensitivity regulator which was dramatically overexpressed in the patients with PD to radiotherapy compared to those with CR. FLI1 induced radiotherapy resistance and enhanced the ability of DNA damage repair in vitro, and promoted radiotherapy resistance in vivo. Mechanistic investigations showed that FLI1 upregulated the transcription of TIE1 by binding to its promoter, thus activated the PI3K/AKT signaling pathway. A decrease in TIE1 expression restored radiosensitivity of NPC cells. Furthermore, NPC patients with high levels of FLI1 and TIE1 were correlated with poor prognosis. Conclusion: Our study has revealed that FLI1 regulates radiotherapy resistance of NPC through TIE1-mediated PI3K/AKT signaling pathway, suggesting that targeting the FLI1/TIE1 signaling pathway could be a potential therapeutic strategy to enhance the efficacy of radiotherapy in NPC. [ABSTRACT FROM AUTHOR]

Background: Afatinib, a second-generation tyrosine kinase inhibitor (TKI), exerts its radiosensitive effects in nasopharyngeal carcinoma (NPC). However, the detailed mechanism of afatinib-mediated sensitivity to radiation is still obscure in NPC. Methods: Quantitative phosphorylated proteomics and bioinformatics analysis were performed to illustrate the global phosphoprotein changes. The activity of the CD44-Stat3 axis and Epithelial-Mesenchymal Transition (EMT)-linked markers were evaluated by Western blotting. Wound healing and transwell assays were used to determine the levels of cell migration upon afatinib combined IR treatment. Cell proliferation was tested by CCK-8 assay. A pharmacological agonist by IL-6 was applied to activate Stat3. The xenograft mouse model was treated with afatinib, radiation or a combination of afatinib and radiation to detect the radiosensitivity of afatinib in vivo. Results: In the present study, we discovered that afatinib triggered global protein phosphorylation alterations in NPC cells. Further, bioinformatics analysis indicated that afatinib inhibited the CD44-Stat3 signaling and subsequent EMT process. Moreover, functional assays demonstrated that afatinib combined radiation treatment remarkably impeded cell viability, migration, EMT process and CD44-Stat3 activity in vitro and in vivo. In addition, pharmacological stimulation of Stat3 rescued radiosensitivity and biological functions induced by afatinib in NPC cells. This suggested that afatinib reversed the EMT process by blocking the activity of the CD44-Stat3 axis. Conclusion: Collectively, this work identifies the molecular mechanism of afatinib as a radiation sensitizer, thus providing a potentially useful combination treatment and drug target for NPC radiosensitization. Our findings describe a new function of afatinib in radiosensitivity and cancer treatment. [ABSTRACT FROM AUTHOR]

Hehe Wang,1 Junge Zhang2 1Department of Otolaryngology, Head and Neck Surgery, Ningbo First Hospital, Ningbo, Zhejiang, People’s Republic of China; 2Department of Anesthesiology, Ningbo First Hospital, Ningbo, Zhejiang, People’s Republic of ChinaCorrespondence: Hehe Wang, Department of Otolaryngology Head and Neck Surgery, Ningbo First Hospital, Ningbo, Zhejiang, 315010, People’s Republic of China, Email entwhh@hotmail.comPurpose: Although considerable progress has been made in basic and clinical research on nasopharyngeal carcinoma (NPC), the biomarkers of the progression of NPC have not been fully studied and described. This study was designed to identify potential novel biomarkers for NPC using integrated analyses and explore the immune cell infiltration in this pathological process.Methods: Five GEO data sets were downloaded from gene expression omnibus database (GEO) and analysed to identify differentially expressed genes (DEGs), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The four algorithms were adopted for screening of novel and key biomarkers for NPC, including random forest (RF) machine learning algorithm, least absolute shrinkage and selection operator (LASSO) logistic regression, support vector machine-recursive feature elimination (SVM-RFE), and weighted gene co-expression network analysis (WGCNA). Lastly, CIBERSORT was used to assess the infiltration of immune cells in NPC, and the correlation between diagnostic markers and infiltrating immune cells was analyzed.Results: Herein, we identified 46 DEGs, and enrichment analysis results showed that DEGs and several kinds of signaling pathways might be closely associated with the occurrence and progression of NPC. DTL was recognized as NPC-related biomarker. DTL, also known as retinoic acid-regulated nuclear matrix-associated protein (RAMP), or DNA replication factor 2 (CDT2), is reported to be correlated with the cell proliferation, cell cycle arrest and cell invasion in hepatocellular carcinoma, breast cancer and gastric cancer. Immune infiltration analysis demonstrated that macrophages M0, macrophages M1 and T cells CD4 memory activated were linked to pathogenesis of NPC.Conclusion: In summary, we adopted a comprehensive strategy to screen DTL as biomarkers related to NPC and explore the critical role of immune cell infiltration in NPC.Graphical Abstract: Keywords: nasopharyngeal carcinoma, NPC, biomarkers, machine learning algorithm, DTL

Nasopharyngeal carcinoma (NPC) has insidious onset, late clinical diagnosis and high recurrence rate, which leads to poor quality of patient life. Therefore, it is necessary to further explore the pathogenesis and therapy targets of NPC. BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) was found to be up-regulated in a variety of cancers, but only two previous study showed that BUB1B was overexpressed in NPC and the sample size was small. The clinical role of BUB1B expression and its underlying mechanism in NPC require more in-depth research. Immunohistochemical samples and public RNA-seq data indicated that BUB1B protein and mRNA expression levels were up-regulated in NPC, and summary receiver operating characteristic curve indicated that BUB1B expression level had a strong ability to distinguish NPC tissues from non-NPC tissues. Gene ontology and Kyoto Encyclopedia of genes and genomes were performed and revealed that BUB1B and its related genes were mainly involved in cell cycle and DNA replication. Protein- Protein Interaction were built to interpret the BUB1B molecular mechanism. Histone deacetylase 2 (HDAC2) could be the upstream regulation factor of BUB1B, which was verified by Chromatin Immunoprecipitation Sequencing samples. In summary, BUB1B was highly expressed in NPC, and HDAC2 may affect cell cycle by regulating BUB1B to promote cancer progression. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to investigate the prognostic value of composition and spatial architecture of tumor-infiltrating lymphocytes (TILs) as well as PDL1 expression on TILs subpopulations in nasopharyngeal carcinoma (NPC). Methods: A total of 121 patients with NPC were included and divided into two groups: favorable (n = 68) and unfavorable (n = 53). The archived tumor tissues of the included patients were retrieved, and a tissue microarray was constructed. The density and spatial distribution of TILs infiltration were analyzed using the multiplex fluorescent immunohistochemistry staining for CD3, CD4, CD8, Foxp3, cytokeratin (CK), PDL1, and 4',6-diamidino-2-phenylindole (DAPI). The infiltration density of TILs subpopulations and PDL1 expression were compared between the two groups. The Gcross function was calculated to quantify the relative proximity of any two types of cells. The Cox proportional hazards regression model was used to identify factors associated with overall survival (OS) and disease-free survival (DFS). Results: The densities of regulatory T-cells (Tregs), effector T-cells (Teffs), PDL1 + Tregs, and PDL1+ Teffs were significantly higher in patients with unfavorable outcomes. PDL1 expression on tumor cells (TCs) or overall TILs was not associated with survival. Multivariate analysis revealed that higher PDL1+ Tregs infiltration density was independently associated with inferior OS and DFS, whereas Tregs infiltration density was only a prognostic marker for DFS. Spatial analysis revealed that unfavorable group had significantly stronger Tregs and PDL1+ Tregs engagement in the proximity of TCs and cytotoxic T lymphocyte (CTLs). Gcross analysis further revealed that Tregs and PDL1+ Tregs were more likely to colocalize with CTLs. Moreover, increased GTC:Treg (Tregs engagement surrounding TCs) and GCTL:PDL1+ Treg were identified as independent factors correlated with poor outcomes. Conclusion: TILs have a diverse infiltrating pattern and spatial distribution in NPC. Increased infiltration of Tregs, particularly PDL1+ Tregs, as well as their proximity to TCs and CTLs, correlates with unfavorable outcomes, implying the significance of intercellular immune regulation in mediating disease progression. [ABSTRACT FROM AUTHOR]

Background: Nasopharyngeal carcinoma (NPC) originates in the nasopharyngeal mucosa, the lateral wall of the nasopharynx. A significant challenge in NPC management is skull-base bone invasion (SBBI), which affects prognosis and treatment planning. Magnetic resonance imaging (MRI) is the primary diagnostic tool for SBBI in NPC patients; however, the detection of SBBI can be challenging due to skull-base complexity and overlapping MRI signals. 18 fluorine-sodium fluoride ( 18 F-NaF) positron emission tomography/computed tomography (PET/CT) is an emerging imaging technique that has shown promise in detecting osseous lesions. This cohort study aimed to assess the supplementary diagnostic value of 18 F-NaF PET/CT in detecting SBBI in NPC patients compared to that of MRI alone., Methods: Imaging data were retrospectively collected from 18 F-NaF PET/CT and head-and-neck MRI examinations conducted within a 7-day period. The sensitivity, specificity, and accuracy of 18 F-NaF PET/CT, MRI, and the combination of both modalities in detecting SBBI were individually assessed. Both lesion- and patient-based analyses were employed for the comparison. Cochran's Q test was used to compare the accuracy of these methods, while the Bonferroni-corrected McNemar test was used for the pairwise comparisons. The data analysis was performed using the R software package, and a significance level of P < 0.05 was considered statistically significant., Results: A total of 164 patients were enrolled in the study. Using 18 F-NaF PET/CT, MRI, and the combined modality of 18 F-NaF PET/CT with MRI, 97, 84, and 94 cases of SBBI were diagnosed, respectively. At the patient level, the diagnostic efficacy (sensitivity, specificity, and accuracy) was as follows: 18 F-NaF PET/CT had 100% sensitivity, 93.1% specificity, and 97.0% accuracy; MRI had 90.2% sensitivity, 98.6% specificity, and 93.9% accuracy; and the combination of 18 F-NaF PET/CT and MRI had 100% sensitivity, 97.2% specificity, and 98.8% accuracy. The accuracy rate of 18 F-NaF PET/CT combined with MRI were significantly higher than that of MRI alone (P = 0.034). A total of 284, 243, and 276 SBBI lesions were diagnosed using 18 F-NaF PET/CT, MRI, and 18 F-NaF PET/CT combined with MRI, respectively. The diagnostic efficacy (sensitivity, specificity, and accuracy) at the lesion level was as follows: 18 F-NaF PET/CT had 99.6% sensitivity, 75.9% specificity, and 95.4% accuracy; MRI had 88.2% sensitivity, 93.1% specificity, and 89.1% accuracy; and the combination of 18 F-NaF PET/CT with MRI had 100% sensitivity, 91.4% specificity, and 98.5% accuracy. The combination of 18 F-NaF PET/CT with MRI significantly improved the accuracy rate compared to that of MRI alone, and the difference was statistically significant (P<0.001)., Conclusions: The combined use of 18 F-NaF PET/CT and MRI significantly enhanced the diagnosis of SBBI in NPC patients, and the combined method had improved diagnostic sensitivity and accuracy than MRI alone., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-265/coif). The authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Background: Early detection of nasopharyngeal carcinoma (NPC) patients who are not sensitive to neoadjuvant chemotherapy (NAC) can guard against overtreatment. This study aimed to evaluate the effectiveness of amide proton transfer (APT) imaging and diffusion-weighted imaging (DWI) in predicting the early response to NAC in patients with NPC., Methods: This prospective study enrolled fifty patients with biopsy-confirmed NPC from September 2021 to May 2023. Magnetic resonance imaging (MRI) including APT and DWI, was performed before NAC. After NAC, patients were divided into complete response (CR), partial response (PR), and stable disease (SD) and progressive disease (PD) groups based on the Response Evaluation Criteria in Solid Tumours Version 1.1. The Kruskal-Wallis H test was used for statistical analysis. The differences in APT and apparent diffusion coefficient (ADC) values among the different efficacy groups were compared, the receiver operating characteristic (ROC) curve was drawn for statistically significant parameters, and the area under the curve (AUC) was calculated., Results: Fifty patients (mean age: 47±14 years; 42 males and 8 females) were included in the final analysis (11 were in the CR group, 30 in the PR group, 9 in the SD group, and 0 in the PD group). The ADC values showed no significant differences among the different treatment response groups. The SD group showed significantly lower APT max (P=0.025), APT skewness (P=0.025) and APT 90% (P=0.001) values than the CR and PR groups. Setting APT 90% =3.10% as the cut-off value, optimal diagnostic performance (AUC: 0.831; sensitivity: 0.778; specificity: 0.878) was obtained in predicting the SD group., Conclusions: APT imaging can predict the early tumour response to NAC in patients with NPC. APT imaging may be superior to DWI in predicting tumour response., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-188/coif). Y.G. is from Central Research Institute, United Imaging Healthcare. The other authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Despite extensive use of radiotherapy in nasopharyngeal carcinoma (NPC) treatment because of its high radiosensitivity, there have been huge challenges in further improving therapeutic effect, meanwhile obviously reducing radiation damage. To this end, synergistic chemoradiotherapy has emerged as a potential strategy for highly effective NPC therapy. Here, we developed RGD-targeted platinum-based nanoparticles (RGD-PtNPs, denoted as RPNs) to achieve targeted chemoradiotherapy for NPC. Such nanoparticles consist of an RGD-conjugated shell and a cis-platinum (CDDP) crosslinking core. Taking advantage of RGD, the RPNs may effectively accumulate in tumor, penetrate into tumor tissues and be taken by cancer cells, giving rise to a high delivery efficiency of CDDP. When they are fully enriched in tumor sites, the CDDP loaded RPNs can act as radiotherapy sensitizer and chemotherapy agents. By means of X-ray-promoted tumor cell uptake of nanoparticle and CDDP-induced cell cycle arrest in radiation-sensitive G2/M phases, RPNs may offer remarkable therapeutic outcome in the synergistic chemoradiotherapy for NPC.

The incidence rate of nasopharyngeal carcinoma (NPC) is the highest among the malignant tumors of otorhinolaryngology, posing a huge burden to public health. Long noncoding RNAs (lncRNAs) exert an important role in tumorigenesis and the progression of various cancers. The present study found that HOXC-AS1 was highly expressed in NPC and in NPC cell lines, suggesting a critical role of HOXC-AS1 in NPC progression. In addition, the abundance of HOXC-AS1 was negatively correlated with the prognosis of NPC. To molecularly dissect the mechanism of HOXC-AS1 in NPC progression, we knocked down the expression of HOXC-AS1 in HNE1 and C666-1 cells. Then, we employed CCK8, colony-formation experiment and Transwell to investigate how the cell performed when HOXC-AS1 was knocked down. It could be observed that HOXC-AS1 knockdown decreases cell proliferation, migration and invasion, but induces cell apoptosis in NPC. We found that HOXC-AS1 could sponge miR-4651 subsequently binding FOXO6 and inhibiting its expression. Therefore, HOXC-AS1/miR-4651/FOXO6 may form a competing endogenous RNA (ceRNA) network that promotes NPC progression. In conclusion, our study demonstrates that HOXC-AS1 promotes NPC progression by sponging miR-4651 and regulating FOXO6 expression, thus providing potential pharmaceutical targets for developing new NPC treatments.

Cancer cell separation is highly desirable for cancer diagnosis and therapy. Besides biochemical methods, engineered platforms are effective alternatives for sorting carcinoma cells from normal cells based on their unique properties in responding to the physical changes of the surrounding microenvironment. In this work, three-dimensional (3D) biomimetic scaffold platforms were developed to separate nasopharyngeal carcinoma 43 (NPC43) cells from immortalized nasopharyngeal epithelial 460 (NP460) cells based on precisely controlled design parameters including stiffness, number of layers, and structural layout. The migration characteristics of NPC43 and NP460 cells on the scaffold platforms revealed that NPC43 cells could squeeze into 10 μm wide, 15 μm deep trenches while NP460 cells could not. The different migration behavior was mainly due to cells having different interactions with the surrounding microenvironment. NPC43 cells had filopodia-like protrusions, while NP460 cells exhibited a sheet-like morphology. Using these 3D biomimetic platforms, 89% separation efficiency of NPC43 cells from NP460 cells was achieved on stiffer two-layer scaffold platforms with a 40/10 μm ridge/trench (R/T) grating on the top layer and a 20/10 μm R/T grid on the bottom layer. Moreover, the separation efficiency was further increased to 93% by adding an active conditioned medium (ACM) that caused the cells to have higher motility and deformability. These results demonstrate the capability to apply biomimetic engineered platforms with appropriate designs to separate cancer cells from normal cells for potential cancer diagnosis and treatment.

This study aimed to understand the prognosis of patients with head and neck squamous cell carcinoma (HNSCC) and to develop and validate a prognostic model for HNSCC based on pyroptosis-associated genes (PAGs) in nasopharyngeal carcinoma. The Cancer Genome Atlas database was used to identify differentially expressed PAGs. These genes were analyzed using the Kyoto Encyclopedia of Genes and Genomes functional annotation analyses and Gene Ontology analyses. The NLR family pyrin domain containing 1 (NLRP1) gene, charged multivesicular body protein 7 (CHMP7) gene, and cytochrome C (CYCS) gene were used to create a prognostic model for HNSCC. The results of the Kaplan-Meier (K-M) and Cox regression analyses indicated that the developed model served as an independent risk factor for HNSCC. According to the K-M analysis, the overall survival of high-risk patients was lower than that of low-risk patients. The hazard ratios corresponding to the risk scores determined using the multivariate and univariate Cox regression analyses were 1.646 (95% confidence interval (CI): 1.189-2.278) and 1.724 (95% CI: 1.294-2.298), respectively, and the area under the receiver operator characteristic curve was 0.621. The potential mechanisms associated with the functions of the identified genes were then identified, and the tumor microenvironment and levels of immune cell infiltration achieved were analyzed. The immune infiltration analysis revealed differences in the distribution of Th cells, tumor-infiltrating lymphocytes, regulatory T cells, follicular helper T cells, adipose-derived cells, interdigitating dendritic cells, CD8+ T cells, and B cells. However, validating bioinformatics analyses through biological experiments is still recommended. This study developed a prognostic model for HNSCC that included NLRP1, CHMP7, and CYCS. [ABSTRACT FROM AUTHOR]

The phenome of E-cadherin gene methylation and the expression of latent membrane protein 1 (LMP-1) gene are associated with nasopharyngeal carcinoma (NPC). In order to determine whether cooperative LMP-1 expression or methylation of E-cadherin could serve as the potential molecule biomarker target for diagnosis and therapy of NPC, a case-control study including 93 NPC biopsy samples and 100 non cancerous nasopharyngeal swab samples were examined, as well as the strength of association among them by the quantitative polymerase chain reaction (qPCR) and nested-methylation-specific PCR methods. The significantly higher frequency of LMP-1 expression and E-cadherin methylation in NPC biopsy samples, accounting for 76.34 and 73.12%, respectively, compared to non cancerous samples, accounting for 0.00 and 30.00%, respectively, were observed. The significant correlation between the LMP-1 expression and E-cadherin methylation in NPC samples was reported. In detail, in the stage IV of NPC, in case of LMP-1-positive samples, 35 of 37 samples (accounting for 94.60%) were positive for methylation of E-cadherin. It was demonstrated that cooperative LMP-1 expression and E-cadherin gene methylation could serve as a molecular biomarker in NPC.

Several studies showed that the index of nasopharyngeal carcinoma (NPC) cell growth could be used to assess the carcinogenesis interaction factor, development and prognosis of NPC. Cell proliferation index could always be assessed with Ki-67 protein expression test. This research was conducted to study the correlation between cell proliferation index with cervical lymphoid node status in NPC in clinical manifestation to asses the progressivity and prognosis on NPC patients. This study used cross sectional design. Biopsy tissue specimen were acquired from 35 NPC patients clinically divided into four criteria of cervical lymphoid node status (N0, N1, N2 and N3). Expression of Ki-67 protein was acquired by immunohistochemistry test using monoclonal rabbit antibody anti-human Ki-67 clone 901-325-091911 (Biocare Medical, LCC. 4040 Pike Line, CA 94520 USA). The measurement of Ki-67 protein was conducted by pathology consultant. Spearman statistic test was performed to asses the correlation between Ki-67 protein expression and cervical lymphoid node status. The statistical significance was defined as p

Suberoylanilide hydroxamic acid (SAHA), a famous histone deacetylase (HDAC) inhibitor, has been utilized in clinical treatment for cutaneous T-cell lymphoma. Previously, the mechanisms underlying SAHA anti-tumor activity mainly focused on acetylome. However, the characteristics of SAHA in terms of other protein posttranslational modifications (PTMs) and the crosstalk between various modifications are poorly understood. Our previous work revealed that SAHA had anti-tumor activity in nasopharyngeal carcinoma (NPC) cells as well. Here, we reported the profiles of global proteome, acetylome, and phosphoproteome of 5–8 F cells upon SAHA induction and the crosstalk between these data sets. Overall, we detected and quantified 6,491 proteins, 2,456 phosphorylated proteins, and 228 acetylated proteins in response to SAHA treatment in 5–8 F cells. In addition, we identified 46 proteins exhibiting both acetylation and phosphorylation, such as WSTF and LMNA. With the aid of intensive bioinformatics analyses, multiple cellular processes and signaling pathways involved in tumorigenesis were clustered, including glycolysis, EGFR signaling, and Myc signaling pathways. Taken together, this study highlighted the interconnectivity of acetylation and phosphorylation signaling networks and suggested that SAHA-mediated HDAC inhibition may alter both acetylation and phosphorylation of viral proteins. Subsequently, cellular signaling pathways were reprogrammed and contributed to anti-tumor effects of SAHA in NPC cells. [ABSTRACT FROM AUTHOR]

Abstract Background Early diagnosis of nasopharyngeal carcinoma (NPC) is vital to improve the prognosis of these patients. However, early diagnosis of NPC is typically challenging. Therefore, we explored the pathogenetic roles and associated mechanisms of exosomes in plasma of patients with early-stage NPC. Methods Exosomes in plasma were extracted by ultra-high-speed centrifugation. Western blot and transmission electron microscopy (TEM) were used to verify the purity of exosomes. The sequencing data (6 plasma samples from healthy volunteers vs. 6 NPC plasma samples) were analyzed by principal component analysis (PCA), DESeq2, gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and TargetScan. The differentially expressed miRNAs (DEmiRNAs) were obtained from the dataset (GSE118720) downloaded from the Gene Expression Omnibus (GEO) repository. Additionally, the datasets downloaded from the GEO database (GSE12452, GSE13597, GSE53819, GSE64634) were used to predict the target genes and functions of hsa-miR-1301-3p. qPCR was applied to verify the differences in the expressions of hsa-miR-1301-3p between 10 normal plasma and 10 NPC plasma samples. Results Western blot, TEM, and Nanoparticle Tracking Analysis showed adequate purity of the extracted exosomes. RNA-seq analysis revealed 21 upregulated miRNAs, and 10 downregulated miRNAs in plasma exosomes of early-stage NPC patients. GO analysis showed that the target genes of DEmiRNAs were mainly enriched in DNA synthesis and transcription regulation. KEGG analysis revealed that DEmiRNAs were mainly enriched in PI3K-Akt and MAPK signaling pathways. Moreover, the expression of hsa-mir-1301-3p was verified to be significantly upregulated in enlarged samples of plasma exosomes. Conclusions We identified several DEmiRNAs extracted from tumor-derived exosomes between normal plasma and early-stage NPC plasma. Bioinformatics analyses indicated that these DEmiRNAs may be related to NPC development. Our study may provide novel insights into underlying biomarkers and mechanisms of plasma exosomes in early-stage NPC.

Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic disease occurring in the nasopharynx. For early diagnosis or treatment, it is helpful to separate invasive nasopharyngeal carcinoma (NPC43) cells from epithelial (NP460) cells. However, the lack of proper in vivo models significantly hinders the systematic study of NPC. In this study, an in vitro two-layer scaffold platform was developed to mimic the extracellular matrix of the tissue that allows the investigation of carcinoma and epithelial cell migration behaviors. Three precisely controlled factors were designed to investigate how topographic cues affected migration of NP460 and NPC43 cells: overlay angles between the top and bottom layers, top layer thicknesses, and surface topography of the bottom layer ridges. These designs offered different surface contact areas for cells to probe and form focal adhesions as they migrated on the platforms. As NP460 and NPC43 cells respond differently to the surrounding microenvironments, when the top layers were perpendicular to the bottom layers, 66.3% NPC43 cells could move into the $10~\mu \text{m}$ wide trenches compared to 5.5% for NP460 cells. However, NP460 and NPC43 cells migrating into top layer trenches were hindered when the top layer was too shallow or too thick. Moreover, the gratings added on the bottom layer ridges promoted cells to squeeze into the trenches. These results yielded over 92.3% separation efficiency on platforms with a 15- $\mu \text{m}$ thick top layer being perpendicular to the bottom layer and gratings on the bottom layer ridges.