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Nasopharyngeal carcinoma (NPC) is a highly prevalent head and neck malignancy in southern China frequently diagnosed at advanced stages owing to subtle early symptoms and associated metastasis. Angiogenesis emerges as a pivotal factor in NPC progression, with numerous angiogenesis-related factors showing aberrant expression and contributing to increased neovascularization within NPC tumors. These abnormal vessels not only nourish tumor growth but also facilitate metastasis, culminating in unfavorable patient outcomes. Multiple studies have demonstrated the applicability of various imaging techniques for assessing angiogenesis in NPC tumors, thus serving as a foundation for personalized treatment strategies and prognostic assessments. Anti-angiogenic therapies have exhibited significant potential for inhibiting NPC angiogenesis and exerting anti-tumor effects. To enhance efficacy, anti-angiogenic drugs are frequently combined with other treatment modalities to synergistically enhance anti-tumor effects while mitigating the side effects associated with single-agent therapies, consequently improving patient prognosis. Identifying the potential mechanisms and key targets underlying NPC angiogenesis and exploring more effective detection and treatment approaches holds promise for shaping the future of NPC diagnosis, treatment, and prognosis, thereby offering new avenues and perspectives for research and clinical practice. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming induced by Epstein‐Barr virus (EBV) often mirrors metabolic changes observed in cancer cells. Accumulating evidence suggests that lytic reactivation is crucial in EBV‐associated oncogenesis. The aim of this study was to explore the role of metabolite changes in EBV‐associated malignancies and viral life cycle control. We first revealed that EBV (LMP1) accelerates the secretion of the oncometabolite D‐2HG, and serum D‐2HG level is a potential diagnostic biomarker for NPC. EBV (LMP1)‐driven metabolite changes disrupts the homeostasis of global DNA methylation and demethylation, which have a significantly inhibitory effect on active DNA demethylation and 5hmC content. We found that loss of 5hmC indicates a poor prognosis for NPC patients, and that 5hmC modification is a restriction factor of EBV reactivation. We confirmed a novel EBV reactivation inhibitor, α‐KG, which inhibits the expression of EBV lytic genes with CpG‐containing ZREs and the latent‐lytic switch by enhancing 5hmC modification. Our results demonstrate a novel mechanism of which metabolite abnormality driven by EBV controls the viral lytic reactivation through epigenetic modification. This study presents a potential strategy for blocking EBV reactivation, and provides potential targets for the diagnosis and therapy of NPC. [ABSTRACT FROM AUTHOR]

Simple Summary: Nasopharyngeal carcinoma (NPC) is an epithelial cancer associated with Epstein–Barr virus (EBV) infection. EBV infection contributes to not only the tumorigenesis of NPC but also the formation of a complicated tumor immune microenvironment (TIME) in NPC. Natural killer (NK) cells are lymphoid members of the innate immune system exhibiting both anti-tumor and anti-virus abilities. The cytokine and cellular interaction features of NK cells are distinct from those of CD8+ cytotoxic T cells. This unique characteristic has not been fully described in EBV+ NPC. This review provides an overview of the complicated crosstalk between NK cells and the TIME of EBV+ NPC and potential therapeutic strategies. A new perspective is proposed to direct future exploration. Endemic nasopharyngeal carcinoma (NPC) is closely associated with the Epstein–Barr virus (EBV), which contributes to tumor development and influences the tumor immune microenvironment (TIME) in NPC. Natural killer (NK) cells, as part of the innate immune system, play a crucial role in responding to viral infections and malignant cell transformations. Notably, NK cells possess a unique ability to target tumor cells independent of major histocompatibility complex class I (MHC I) expression. This means that MHC I-deficient tumor cells, which can escape from effective T cell attack, are susceptible to NK-cell-mediated killing. The activation of NK cells is determined by the signals generated through inhibitory and activating receptors expressed on their surface. Understanding the role of NK cells in the complex TIME of EBV+ NPC is of utmost importance. In this review, we provide a comprehensive summary of the current understanding of NK cells in NPC, focusing on their subpopulations, interactions, and cytotoxicity within the TIME. Moreover, we discuss the potential translational therapeutic applications of NK cells in NPC. This review aims to enhance our knowledge of the role of NK cells in NPC and provide valuable insights for future investigations. [ABSTRACT FROM AUTHOR]

Epstein‐Barr virus (EBV)‐associated nasopharyngeal carcinoma (NPC) cells have high metastatic potential. Recent research has revealed that the interaction of between tumor cells and the surrounding stroma plays an important role in tumor invasion and metastasis. In this study, we showed the prognostic value of expression of SPARC, an extracellular matrix protein with multiple cellular functions, in normal adjacent tissues (NAT) surrounding NPC. In the immunohistochemical analysis of 51 NPC biopsy specimens, SPARC expression levels were significantly elevated in the NAT of EBER (EBV‐encoded small RNA)‐positive NPC compared to that in the NAT of EBER‐negative NPC. Moreover, increased SPARC expression in NAT was associated with a worsening of overall survival. The enrichment analysis of RNA‐seq of publicly available NPC and NAT surrounding NPC data showed that high SPARC expression in NPC was associated with epithelial mesenchymal transition promotion, and there was a dynamic change in the gene expression profile associated with interference of cellular proliferation in NAT, including SPARC expression. Furthermore, EBV‐positive NPC cells induce SPARC expression in normal nasopharyngeal cells via exosomes. Induction of SPARC in cancer‐surrounding NAT cells reduced intercellular adhesion in normal nasopharyngeal structures and promoted cell competition between cancer cells and normal epithelial cells. These results suggest that epithelial cells loosen their own binding with the extracellular matrix as well as stromal cells, facilitating the invasion of tumor cells into the adjacent stroma by activating cell competition. Our findings reveal a new mechanism by which EBV creates a pro‐metastatic microenvironment by upregulating SPARC expression in NPC. [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]

Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with high propensity for lymphatic spread and distant metastasis. It is prominent as an endemic malignancy in Southern China and Southeast Asia regions. Studies on NPC pathogenesis mechanism in the past decades such as through Epstein Barr Virus (EBV) infection and oncogenic molecular aberrations have explored several potential targets for therapy and diagnosis. The EBV infection introduces oncoviral proteins that consequently hyperactivate many promitotic pathways and block cell-death inducers. EBV infection is so prevalent in NPC patients such that EBV serological tests were used to diagnose and screen NPC patients. On the other hand, as the downstream effectors of oncogenic mechanisms, the promitotic pathways can potentially be exploited therapeutically. With the apparent heterogeneity and distinct molecular aberrations of NPC tumor, the focus has turned into a more personalized treatment in NPC. Herein in this comprehensive review, we depict the current status of screening, diagnosis, treatment, and prevention in NPC. Subsequently, based on the limitations on those aspects, we look at their potential improvements in moving towards the path of precision medicine. The importance of recent advances on the key molecular aberration involved in pathogenesis of NPC for precision medicine progression has also been reported in the present review. Besides, the challenge and future outlook of NPC management will also be highlighted. [ABSTRACT FROM AUTHOR]

Saliva sampling is a non‐invasive method, and could be performed by donors themselves. However, there are few studies reporting biomarkers in saliva in the diagnosis of NPC. A total of 987 salivary samples were used in this study. First, EBV DNA methylation was profiled by capture sequencing in the discovery cohort (n = 36). Second, a q‐PCR based method was developed and five representative EBV DNA CpG sites (11 029 bp, 45 849 bp, 57 945 bp, 66 226 bp and 128 102 bp) were selected and quantified to obtain the methylated density in the validation cohort1 (n = 801). Third, a validation cohort2 (n = 108) was used to further verify the differences of EBV methylation in saliva. A significant increase of EBV methylation was found in NPC patients compared with controls. The methylated score of EBV genome obtained by capture sequencing could distinguish NPC from controls (sensitivity 90%, specificity 100%). Further, the methylated density of EBV DNA CpG sites revealed by q‐PCR showed a good diagnostic performance. The sensitivity and specificity of detecting a single CpG site (11 029 bp) could reach 75.4% and 99.7% in the validation cohort1, and 78.2% and 100% in the validation cohort2. Besides, the methylated density of the CpG site was found to decrease below the COV in NPC patients after therapy, and increase above the COV after recurrence. Our study provides an appealing alternative for the non‐invasive detection of NPC without clinical setting. It paves the way for conducting a home‐based large‐scale screening in the future. [ABSTRACT FROM AUTHOR]

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Background: Refractory or metastatic nasopharyngeal carcinoma (NPC) patients have a poor prognosis due to the lack of effective salvage treatments and prolonged survival by means of combination chemotherapy being described only for a minority of younger patients with oligometastatic disease. Targeting the Epstein - Barr virus (EBV) proteins expressed in NPC cells has been shown to be a feasible strategy that could help control systemic disease. Patients and Methods: Between 2011 and 2014, 16 patients with recurrent/metastatic EBV-NPC received first-line chemotherapy (CT) followed by 2 doses of autologous cytotoxic EBV specific T-lymphocytes (15-25 x 107 total cells/dose, 2 weeks apart), based on our previous studies showing the feasibility and efficacy of this infusion regimen. Cumulative overall survival (OS) and median OS were analysed in the whole population and according to specific clinical and biological parameters. Results: All patients received the planned T-cell therapy schedule, 9 after reaching partial (n=5) or complete (n=4) disease remission with CT, and 7 after failing to obtain benefit from chemotherapy. No severe adverse events were recorded. Patients who received cytotoxic T-lymphocytes (CTLs) had a cumulative 10-year OS of 44%, with a median OS of 60 months (95% CI 42-62). Patients responding to CT, with oligometastatic disease (<3 disease sites), and plasma EBV-DNA <1000 copies/mL had a better outcome. Conclusions: Autologous EBV-specific CTLs transplanted following conventional first-line CT demonstrated promising efficacy with several patients obtaining long-lasting disease control. The rationale provided by this study, with the crucial role likely played by the timing of CTL administration when trying to induce synergy with conventional treatment needs to be confirmed in a prospective controlled trial. [ABSTRACT FROM AUTHOR]

Purposes: To evaluate the diagnostic value of tumor-educated platelets (TEP) lncRNA ROR for nasopharyngeal carcinoma (NPC). Methods: Quantitative real-time PCR was used to determine the expression level of TEP lncRNA ROR in NPC patients (n = 50) as compared to normal subjects (n = 33). The ROC curve analysis was performed to assess the diagnostic value of TEP lncRNA ROR for NPC. Correlations between TEP lncRNA ROR and clinical parameters were further analyzed. Results: The median of TEP lncRNA ROR was significantly lower in NPC patients than that in normal subjects (0.0209 vs 0.0610, p = 0.0019), while no significant difference was found in plasma lncRNA ROR. ROC analysis showed that TEP lncRNA ROR had a sensitivity of 60%, specificity of 70%, and accuracy of 63.9% in diagnosing NPC, and the area under ROC curve (AUC) was 0.70. The expression level of TEP lncRNA ROR in NPC showed no significant difference among different TNM stages. However, low level of TEP lncRNA ROR correlated well with positive Epstein–Barr virus (EBV) DNA (kappa value = 0.314, p = 0.06), TEP lncRNA ROR and EBV DNA had similar diagnostic positive rate (58.3%) for NPC, and the combination of TEP lncRNA ROR and EBV DNA increased the positive rate to 74%. Conclusion: The expression level of TEP lncRNA ROR was down-regulated in NPC and the diagnostic value of TEP lncRNA ROR was similar to EBV DNA. Our study indicated that TEP lncRNA ROR might serve as a novel type of liquid biopsy biomarker in diagnosis of NPC patients. [ABSTRACT FROM AUTHOR]

Detecting EBV DNA load in nasopharyngeal (NP) brushing samples for the diagnosis of nasopharyngeal carcinoma (NPC) has attracted widespread attentions. Currently, NP brush sampling mostly relies on endoscopic guidance, and there are few reports on diagnostic markers suitable for nonguided conditions (blind brush sampling), which is of great significance for extending its application. One hundred seventy nasopharyngeal brushing samples were taken from 98 NPC patients and 72 non‐NPC controls under the guidance of endoscope, and 305 blind brushing samples were taken without endoscopic guidance from 164 NPC patients and 141 non‐NPC controls (divided into discovery and validation sets). Among these, 38 cases of NPC underwent both endoscopy‐guided NP brushing and blind brushing. EBV DNA load targeting BamHI‐W region and EBV DNA methylation targeting 11029 bp CpG site located at Cp‐promoter region were detected by quantitative polymerase chain reaction (q‐PCR). EBV DNA load showed good classification accuracy for NPC in endoscopy‐guided brushing samples (AUC = 0.984). However, in blind bushing samples, the diagnostic performance was greatly reduced (AUC = 0.865). Unlike EBV DNA load, the accuracy of EBV DNA methylation was less affected by brush sampling methods, whether in endoscopy‐guided brushing (AUC = 0.923) or blind brushing (AUC = 0.928 in discovery set and AUC = 0.902 in validation set). Importantly, EBV DNA methylation achieved a better diagnostic accuracy than EBV DNA load in blind brushing samples. Overall, detection of EBV DNA methylation with blind brush sampling shows great potential in the diagnosis of NPC and may facilitate its use in nonclinical screening of NPC. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is rare in most parts of the world but endemic in southern Asia. Here, we describe the molecular abnormalities in NPC and point out potential molecular mechanisms for future therapy. This article provides a brief up-to-date review focusing on the molecular pathways of NPC, which may improve our knowledge of this disease, and we also highlight some issues for further research. In brief, some heritable genes are related to NPC; therefore, people with a family history of NPC have an increased risk of this disease. Carcinogenic substances and Epstein–Barr virus (EBV) exposure both contribute to tumorigenesis through the accumulation of multiple genomic changes. In recent years, salted fish intake has decreased the impact on NPC, which implies that changing exposure to carcinogens can modify the risk of NPC. Eradication of cancer-associated viruses potentially eradicates cancer, and EBV vaccines might also prevent this disease in the future. Screening patients by using an EBV antibody is feasible in the high-risk group; plasma EBV DNA measurement could also be conducted for screening, prognosis, and monitoring of this disease. Understanding the molecular mechanisms of NPC can further provide novel information for health promotion, disease screening, and precision cancer treatment. [ABSTRACT FROM AUTHOR]

Background: To develop and validate a predictive nomogram for tumor residue 3–6 months after treatment based on postradiotherapy plasma Epstein–Barr virus (EBV) deoxyribonucleic acid (DNA), clinical stage, and radiotherapy (RT) dose in patients with stage II–IVA nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). Methods: In this retrospective study, 1050 eligible patients with stage II–IVA NPC, who completed curative IMRT and underwent pretreatment and postradiotherapy (-7 to +28 days after IMRT) EBV DNA testing, were enrolled from 2012 to 2017. The prognostic value of the residue was explored using Cox regression analysis in patients (n=1050). A nomogram for predicting tumor residues after 3–6 months was developed using logistic regression analyses in the development cohort (n=736) and validated in an internal cohort (n=314). Results: Tumor residue was an independent inferior prognostic factor for 5-year overall survival, progression-free survival, locoregional recurrence-free survival and distant metastasis-free survival (all P<0.001). A prediction nomogram based on postradiotherapy plasma EBV DNA level (0 vs. 1–499 vs. ≥500 copies/ml), clinical stage (II vs. III vs. IVA), and RT dose (68.00–69.96 vs. 70.00–74.00 Gy) estimated the probability of residue development. The nomogram showed better discrimination (area under the curve (AUC): 0.752) than either the clinical stage (0.659) or postradiotherapy EBV DNA level (0.627) alone in the development and validation cohorts (AUC: 0.728). Conclusions: We developed and validated a nomogram model integrating clinical characteristics at the end of IMRT for predicting whether tumor will residue or not after 3–6 months. Thus, high-risk NPC patients who might benefit from immediate additional intervention could be identified by the model, and the probability of residue can be reduced in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: IgA and IgG antibodies against Epstein-Barr virus (EBV) proteins in human serum are well-known markers for EBV-positive nasopharyngeal carcinoma (NPC). Bead-based multiplex serology assays can characterize antibodies against several antigens simultaneously; however, these assays were, so far, specific for single antibody isotypes. Here, we describe the development of a duplex serological multiplex assay for the simultaneous detection of EBV IgA and IgG antibodies in a combined assay. The novel duplex assay decreases costs and effort for future epidemiological studies in EBV and NPC research and could serve as a model for other duplex multiplex applications. Epstein-Barr virus (EBV) IgA and IgG antibodies in serum from nasopharyngeal carcinoma (NPC) patients are well-established markers for EBV-positive NPC. Luminex-based multiplex serology can analyze antibodies to multiple antigens simultaneously; however, the detection of both IgA and IgG antibodies requires separate measurements. Here we describe the development and validation of a novel duplex multiplex serology assay, which can analyze IgA and IgG antibodies against several antigens simultaneously. Secondary antibody/dye combinations, as well as serum dilution factors, were optimized, and 98 NPC cases matched to 142 controls from the Head and Neck 5000 study (HN5000) were assessed and compared to data previously generated in separate IgA and IgG multiplex assays. EBER in situ hybridization (EBER-ISH) data available for 41 tumors was used to calibrate antigen-specific cut-offs using receiver operating characteristic (ROC) analysis with a prespecified specificity of ≥90%. A directly R-Phycoerythrin-labeled IgG antibody in combination with a biotinylated IgA antibody and streptavidin-BV421 reporter conjugate was able to quantify both IgA and IgG antibodies in a duplex reaction in a 1:1000 serum dilution. The combined assessment of IgA and IgG antibodies in NPC cases and controls from the HN5000 study yielded similar sensitivities as the separate IgA and IgG multiplex assays (all > 90%), and the duplex serological multiplex assay was able to unequivocally define the EBV-positive NPC cases (AUC = 1). In conclusion, the simultaneous detection of IgA and IgG antibodies provides an alternative for the separate IgA/IgG antibody quantification and may present a promising approach for larger NPC screening studies in NPC endemic areas. [ABSTRACT FROM AUTHOR]

Purpose: There is still uncertainty regarding the prognosis of nasopharyngeal carcinoma (NPC) based on hemoglobin, albumin, lymphocytes, and platelets (HALP) score. The aim of this study was to build and verify a nomogram using HALP score to investigate the prognostic value of NPC and identify low-risk patients in T3-4N0-1 NPC to guide treatment options. Patients and methods: A total of 568 NPC patients with stage T3-4N0-1M0 were recruited in the study, who were given either concurrent chemoradiotherapy (CCRT) or induction chemotherapy (IC) plus CCRT. The prognostic factors of overall survival (OS) were picked by Cox proportional hazards regression analysis to generate a nomogram, which appraised by discrimination, calibration and clinical utility. Patients were stratified according to risk scores calculated by the nomogram, and compared to the 8th TNM staging system using the Kaplan–Meier methods. Results: Multivariate analysis showed that TNM stage, Epstein–Barr virus DNA (EBV DNA), HALP score, lactate dehydrogenase-to-albumin ratio (LAR) and systemic inflammatory response index (SIRI) were independent prognostic indicators for OS, and these factors contained in the nomogram. The nomogram demonstrated a significant enhancement over the 8th TNM staging system in terms of assessing OS (C-index, 0.744 vs 0.615 in the training cohort, P < 0.001; 0.757 vs 0.646 in the validation cohort, P = 0.002). Calibration curves displayed good agreement and the stratification in high-risk and low-risk groups resulted in a significant divergence of Kaplan–Meier curves for OS (P < 0.001). In addition, the decision analysis (DCA) curves confirmed satisfactory discriminability and clinical utility. Conclusion: The HALP score was an independent prognostic factor for NPC. The prognostic function of the nomogram for T3-4N0-1 NPC patients was more accurate compared to the 8th TNM system, facilitating personalized treatment planning. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma is a malignancy from epithelial cells predominantly associated with the Epstein–Barr virus (EBV) infection, and it is responsible for 140,000 deaths annually. There is a current need to develop new strategies to increase the efficacy of antineoplastic treatment and reduce side effects. Thus, the present study aimed to perform a systematic review and meta-analysis of the ability of photodynamic therapy (PDT) to modulate the tumor microenvironment and PDT efficacy in nasopharyngeal carcinoma treatment. The reviewers conducted all steps in the systematic review. PubMed, Science Direct, Scopus, Scielo, Lilacs, EMBASE, and the Cochrane library databases were searched. The OHAT was used to assess the risk of bias. Meta-analysis was performed with a random-effects model (α = 0.05). Nasopharyngeal carcinoma cells treated with PDT showed that IL-8, IL-1α, IL-1β, LC3BI, LC3BII, MMP2, and MMP9 levels were significantly higher than in groups that did not receive PDT. NF-ĸB, miR BART 1-5p, BART 16, and BART 17-5p levels were significantly lower in the PDT group than in the control group. Apoptosis levels and the viability of nasopharyngeal carcinoma cells (>70%) infected with EBV were effective after PDT. This treatment also increased LMP1 levels (0.28–0.50/p < 0.05) compared to the control group. PDT showed promising results for efficacy in killing nasopharyngeal carcinoma cells infected with EBV and modulating the tumor microenvironment. Further preclinical studies should be performed to validate these results. [ABSTRACT FROM AUTHOR]

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]

Epstein‐Barr virus (EBV)‐encoded BamHI A rightward transcript (BART) microRNAs (miRNAs) play important roles in viral infection and tumorigenesis. The association of sequence variations in the BART miRNA cluster 1 region with diseases remains unclear. Herein, 6 types and 11 subtypes of BART cluster 1 were identified in 354 tumors and healthy donors (HDs) from nasopharyngeal carcinoma (NPC)‐endemic and nonendemic China (genotyped data), and 905 EBV genomes retrieved from GenBank from diseased and normal people from around the world (archived data). The distributions of BART cluster 1 types/subtypes between NPC‐endemic and nonendemic China; between Asian regions and Africa/Europe & Australia & United States; and among Asian regions (NPC‐endemic China, NPC‐nonendemic East Asia and Southeast Asia) were significantly different (p < 0.001). The subtype BART‐D2 was not found outside Asia and was only common in NPC‐endemic China. More importantly, BART‐D2 had a higher frequency in NPCs than in HDs in NPC‐endemic China (genotyped data, 78.0% vs. 44.1%, p < 0.001; achieved data, 89.3% vs. 43.7%, p < 0.001), and was also more frequent in NPCs than in HDs, gastric carcinomas, and lymphomas in NPC‐nonendemic China (genotyped data, 27.9% vs. 1.9%, 2.4%, and 0.0%, p < 0.001). BART‐D2 was preferentially linked with the high‐risk subtypes for NPC previously reported, 162476C or 163364T, in the BALF2 gene, and was associated with NPC risk (p < 0.01). In vitro experiments showed that BART‐D2 affected the expression of some mature BART miRNAs. These findings demonstrate geographically restricted variations of BART cluster 1 and identify distinct subtype that is confined to NPC‐endemic China and is associated with NPC. [ABSTRACT FROM AUTHOR]

Background: Nasopharyngeal carcinoma (NPC), especially the nonkeratinizing type, is a malignant tumor primarily occurring in southern China and Southeast Asia. Chemotherapy (CT) and combined radiotherapy (RT) is used to treat NPC. However, the mortality rate is high in recurrent and metastatic NPC. We developed a molecular marker, analyzed its correlation with clinical characteristics, and assessed the prognostic value among NPC patients with or without chemoradiotherapy. Methods: A total of 157 NPC patients were included in this study, with 120 undergoing treatment and 37 without treatment. EBER1/2 expression was investigated using in situ hybridization (ISH). Expression of PABPC1, Ki-67, and p53 was detected with immunohistochemistry. The correlations of EBER1/2 and the expression of the three proteins having clinical features and prognosis were evaluated. Results: The expression of PABPC1 was associated with age, recurrence, and treatment but not with gender, TNM classification, or the expression of Ki-67, p53, or EBER. High expression of PABPC1 was associated with poor overall survival (OS) and disease-free survival (DFS) and was an independent predictor depending on multivariate analysis. Comparatively, no significant correlation was observed between the expression of p53, Ki-67, and EBER and survival. In this study, 120 patients received treatments and revealed significantly better OS and DFS than the untreated 37 patients. PABPC1 high expression was an independent predictor of shorter OS in the treated (HR = 4.012 (1.238–13.522), 95% CI, p = 0.021) and the untreated groups (HR = 5.473 (1.051–28.508), 95% CI, p = 0.044). However, it was not an independent predictor of shorter DFS in either the treated or the untreated groups. No significant survival difference was observed between patients with docetaxel-based induction chemotherapy (IC) + concurrent chemoradiotherapy (CCRT) and those with paclitaxel-based IC + CCRT. However, when combined with treatment and PABPC1 expression, patients with paclitaxel-added chemoradiotherapy plus PABPC1 low expression had significantly better OS than those who underwent chemoradiotherapy (p = 0.036). Conclusions: High expression of PABPC1 is associated with poorer OS and DFS among NPC patients. Patients with PABPC1 having low expression revealed good survival irrespective of the treatment received, indicating that PABPC1 could be a potential biomarker for triaging NPC patients. [ABSTRACT FROM AUTHOR]

• Distant metastasis is the main failure pattern for NPC after treatment. • Prognosticators for distant metastasis, including EBV DNA and lymph node-to-primary tumor ratio (NTR) of PET SUV, were proposed. • We showed the integration of EBV DNA and SUV NTR further improves the prognosis prediction in AJCC stages. • The inclusion of these two prognosticators may guide adjuvant treatment and follow-up protocols. To determine the clinical impact of integrating Epstein–Barr virus (EBV) DNA and lymph node-to-primary tumor ratio (NTR) of positron emission tomography (PET) standardized uptake value (SUV) in predicting distant metastasis, such as distant metastasis-free survival (DMFS), in patients with nasopharyngeal carcinoma (NPC). We retrospectively reviewed patients diagnosed with non-disseminated NPC between 2010 and 2017. The optimal cut-off values of EBV DNA and SUV NTR were determined using receiver operating characteristic analysis. The prognostic values of SUV NTR and EBV DNA on DMFS and overall survival were evaluated using the Kaplan–Meier method. Univariate and multivariable analyses were performed using the Wald Chi-squared test and Cox proportional hazards regression, respectively. A total of 488 patients were included in the analysis. The median follow-up period was 61.6 months. The optimal cut-off values of EBV DNA and SUV NTR were 3377.5 copies per mL and 0.64, respectively. The five-year DMFS for patients with high vs low EBV DNA and SUV NTR levels were 64.9% vs 86.6% (p < 0.001) and 78.7% vs 87.4% (p = 0.021), respectively. In subgroup analysis, the high-risk group with high levels of pretreatment EBV DNA and SUV NTR had worse DMFS in either American Joint Committee on Cancer (AJCC) stage I–III or IVA–B (p = 0.001 and <0.001, respectively). Univariate and multivariable analyses showed the statistical significance of EBV DNA, SUV NTR, and their composite in DMFS (p < 0.001 for EBV DNA; p = 0.022 for SUV NTR; p < 0.001 for their composite). This study showed that EBV DNA and SUV NTR have independent and additive values as prognosticators for distant metastasis in patients with NPC, suggesting that these two individual factors, except the AJCC staging system, should be included in future studies. [ABSTRACT FROM AUTHOR]

Background: We aim to investigate the prognostic value of weight loss during radiotherapy (RT) among patients with nasopharyngeal carcinoma (NPC).Methods: A total of 1149 NPC patients who received radical RT were retrospectively analyzed. Patients' weight were measured at initiation of RT (WPre-RT) and every week during RT (WRT1,2,3,4,5,6,7). Percentage of weight loss (PWL) at 1st, 2nd, 3rd, 4th, 5th, 6th, and 7th week of RT (RT-PWL1,2,3,4,5,6,7) were calculated using the following equation: (WPre-RT -WRT1,2,3,4,5,6,7)/WPre-RT × 100%. The optimal threshold of RT-PWL7 was determined by recursive partitioning analyses (RPAs). Our endpoints included disease-free survival (DFS), overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS).Results: The median RT-PWLs were 0, 0, 1.5, 2.9, 4.1, 5.5, 6.6% at 1st, 2nd, 3rd, 4th, 5th, 6th, and 7th week of RT, respectively. RT-PWL7 optimal threshold with respect to DFS was 5.3% based on RPAs. Therefore, a consistent threshold of 5% (<5% vs > ≥5%) was selected to classify NPC patients into low RT-PWL7 and high RT-PWL7 groups for survival analysis. Compared to high RT-PWL7 (≥5%), patients with low RT-PWL7 (< 5%) had significantly better ten-year DFS (61.2% vs 78.8%; P < 0.001), OS (70.1% vs 86.6%; P < 0.001), and DMFS (80.2% vs 88.5%; P = 0.007). However, no difference was observed between LRRFS groups (91.7% vs 94.3%; P = 0.173). In multivariate analysis, high RT-PWL7 was an independent risk factor for DFS (HR, 1.56; 95%CI, 1.19-2.03; P = 0.001), OS (HR, 1.54; 95%CI, 1.11-2.15; P = 0.011), and DMFS (HR, 1.47; 95%CI, 1.03-2.10; P = 0.033) in patients with NPC. In addition, treatment strategy, plasma Epstein-Barr virus DNA, and N stage were associated with weight loss.Conclusions: High RT-PWL7 was significantly associated with decreased DFS, OS, and DMFS for NPC patients. Clinicians should continuously inform patients on the health impact of minimizing RT-PWL7 under 5% during radiotherapy. [ABSTRACT FROM AUTHOR]

Importance: Concurrent chemoradiotherapy has been the standard treatment for stage II nasopharyngeal carcinoma (NPC) based on data using 2-dimensional conventional radiotherapy. There is limited evidence for the role of chemotherapy with use of intensity-modulated radiation therapy (IMRT).Objective: To assess whether concurrent chemotherapy can be safely omitted for patients with low-risk stage II/T3N0 NPC treated with IMRT.Design, Setting, and Participants: This multicenter, open-label, randomized, phase 3, noninferiority clinical trial was conducted at 5 Chinese hospitals, including 341 adult patients with low-risk NPC, defined as stage II/T3N0M0 without adverse features (all nodes <3 cm, no level IV/Vb nodes; no extranodal extension; Epstein-Barr virus DNA <4000 copies/mL), with enrollment between November 2015 and August 2020. The final date of follow-up was March 15, 2022.Interventions: Patients were randomly assigned to receive IMRT alone (n = 172) or concurrent chemoradiotherapy (IMRT with cisplatin, 100 mg/m2 every 3 weeks for 3 cycles [n = 169]).Main Outcomes and Measures: The primary end point was 3-year failure-free survival (time from randomization to any disease relapse or death), with a noninferiority margin of 10%. Secondary end points comprised overall survival, locoregional relapse-free survival, distant metastasis-free survival, adverse events, and health-related quality of life (QOL) measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30; range, 0-100 points; minimum clinically important difference ≥10 for physical function, symptom control, or health-related QOL; higher score indicates better functioning and global health status or worse symptoms).Results: Among 341 randomized patients (mean [SD] age, 48 [10] years; 30% women), 334 (98.0%) completed the trial. Median follow-up was 46 months (IQR, 34-58). Three-year failure-free survival was 90.5% for the IMRT-alone group vs 91.9% for the concurrent chemoradiotherapy group (difference, -1.4%; 1-sided 95% CI, -7.4% to ∞; P value for noninferiority, <.001). No significant differences were observed between groups in overall survival, locoregional relapse, or distant metastasis. The IMRT-alone group experienced a significantly lower incidence of grade 3 to 4 adverse events (17% vs 46%; difference, -29% [95% CI, -39% to -20%]), including hematologic toxicities (leukopenia, neutropenia) and nonhematologic toxicities (nausea, vomiting, anorexia, weight loss, mucositis). The IMRT-alone group had significantly better QOL scores during radiotherapy including the domains of global health status, social functioning, fatigue, nausea and vomiting, pain, insomnia, appetite loss, and constipation.Conclusions and Relevance: Among patients with low-risk NPC, treatment with IMRT alone resulted in 3-year failure-free survival that was not inferior to concurrent chemoradiotherapy.Trial Registration: ClinicalTrials.gov Identifier: NCT02633202. [ABSTRACT FROM AUTHOR]

Background: Inflammatory parameters and Epstein-Barr virus (EBV) DNA status have been confirmed to be associated with prognosis in nasopharyngeal carcinoma (NPC) patients. However, there are few in-depth studies on the prognosis of NPC patients with negative EBV DNA. Our study aimed to look for inflammatory biomarkers that can identify disease progression in NPC patients with negative EBV DNA.Methods: A total of 795 NPC patients were recruited, and ultimately 325 NPC patients with negative EBV DNA were included in this study (170 in training cohort and 155 in validation cohort). Kaplan-Meier method and log-rank test were used to analyze progression-free survival (PFS) and overall survival (OS). The multivariate analysis of Cox proportional hazards regression model was used to determine the independent prognostic factors. Receiver operating characteristic (ROC) curves were used to assess prognostic value. The logistic regression was used to evaluate the relationship between EBV DNA status and inflammatory parameters. The correlation between clinical characteristics was analyzed by the chi-squared test or the Fisher's exact test.Results: The optimal cutoff point for the SIRI was 1.12. The EBV DNA-negative NPC patients with high SIRI level had worse PFS and OS (all p < 0.001). In multivariate Cox proportional hazard models analysis, SIRI was an independent prognostic factor for PFS and OS (all p < 0.05), and had higher prognostic value than other indicators. Above results were found in the training cohort and confirmed in the validation cohort. In addition, EBV DNA status was not associated with any inflammatory parameters.Conclusions: The SIRI can provide more accurate risk stratification and better prognostic prediction for NPC patients with negative EBV DNA. [ABSTRACT FROM AUTHOR]

Simple Summary: Novel insights into the basic and translational findings on Epstein–Barr virus-related diseases were presented at the "19th International Symposium on Epstein–Barr Virus and Associated Diseases" in Asahikawa, Japan. Novel insights into Epstein–Barr virus (EBV) pathogenicity were presented at the "19th International Symposium on Epstein-Barr Virus and Associated Diseases" in Asahikawa, Japan. In addition, basic and translational findings on EBV-associated tumors, including natural killer (NK)/T-cell lymphoma, gastric cancer, and nasopharyngeal cancer, were presented by an international group of scientists and clinicians. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck cancer is the sixth most common type of solid tumor and harbors a poor prognosis since most patients are diagnosed at an advanced stage. The study of different tumor components in the blood, saliva or other body fluids is called liquid biopsy. The introduction of novel diagnostic tools such as liquid biopsy could aid in achieving earlier diagnoses and more accurate disease monitoring during treatment. In this manuscript, the reader will find an in-depth review of the current evidence and a future perspective on the role of liquid biopsy in head and neck cancer. Head and neck cancer (HNC) is currently the sixth most common solid malignancy, accounting for a 50% five-year mortality rate. In the past decade, substantial improvements in understanding its molecular biology have allowed for a growing development of new biomarkers. Among these, the field of liquid biopsy has seen a sustained growth in HNC, demonstrating the feasibility to detect different liquid biomarkers such as circulating tumor DNA (ctDNA), circulating tumor cells (CTC), extracellular vesicles and microRNAs. Liquid biopsy has been studied in HPV-negative squamous cell carcinoma of the head and neck (SCCHN) but also in other subentities such as HPV-related SCCHN, EBV-positive nasopharyngeal cancer and oncogene-driven salivary gland cancers. However, future studies should be internally and externally validated, and ideally, clinical trials should incorporate the use of liquid biomarkers as endpoints in order to prospectively demonstrate their role in HNC. A thorough review of the current evidence on liquid biopsy in HNC as well as its prospects will be conducted. [ABSTRACT FROM AUTHOR]

Purpose: We hypothesized that diffusion-weighted magnetic resonance imaging (DWI)-guided dose-painting intensity modulated radiation therapy (DP-IMRT) is associated with improved local tumor control and survival in locoregionally advanced nasopharyngeal carcinoma (NPC). The purpose of this randomized study was to compare the efficacy and toxicity of DWI-guided DP-IMRT to conventional magnetic resonance imaging (MRI)-based IMRT in locoregional advanced NPC.Methods and Materials: A total of 260 patients with stage III-IVa NPC disease were randomly assigned in a 1:1 ratio to receive induction chemotherapy followed by chemoradiotherapy by DWI-guided DP-IMRT (group A, n = 130) or conventional MRI-based IMRT (group B, n = 130) in this prospective clinical trial. In group A, subvolume GTVnx-DWI (gross tumor volume of nasopharynx in DWI) was defined as the areas within the GTVnx (gross tumor volume of nasopharynx) with an apparent diffusion coefficient (ADC) below the mean ADC (ADC < mean) according to MRI before induction chemotherapy. The dose to GTVnx-DWI was escalated to 75.2 Gy/32 fx in patients with T1-2 disease and to 77.55 Gy/33 fx in those with T3-4 disease in 2.35 Gy per fraction. In group B, planning gross tumor volume of nasopharynx was irradiated at 70.4 to 72.6 Gy/32 to 33 fx in 2.2 Gy per fraction. This trial is registered with chictr.org.cn (ChiCTR1800015779).Results: A total of 260 patients were included in the trial (130 patients in group A and 130 in group B). Complete response rates after chemoradiotherapy were 99.2% (129 of 130) and 93.8% (122 of 130) in groups A and B, respectively (P = .042). At a median follow-up of 25 months, DWI-guided DP-IMRT was associated with improved 2-year disease-free survival (DFS; 93.6% [95% confidence interval {CI}, 88.1%-99.1%] vs 87.5% [95% CI, 81.4%-93.6%], P = .015), local recurrence-free survival (100% [95% CI, not applicable {NA}] vs 91.3% [95% CI, 85.4%-97.2%]), locoregional recurrence-free survival (LRRFS; 95.8% [95% CI, NA] vs 91.3% [95% CI, 85.4%-97.2%]), distant metastasis-free survival (DMFS; 97.8% [95% CI, NA] vs 90.9% [95% CI, 85.8%-96.0%]), and overall survival (100% [95% CI, NA] vs 94.5% [95% CI, 89.2%-99.8%]). Zero and 3 patients had local-only recurrences in group A and B, respectively. The most common site of first failure in each arm was distant organ failure. No statistically significant differences in acute and late toxic effects were observed. Multivariate analyses showed that DP (DWI-guided DP-IMRT vs conventional MRI-based IMRT without DP) was associated with DFS, local recurrence-free survival, LRRFS, and distant metastasis-free survival. Epstein-Barr virus DNA level was associated with DFS and LRRFS.Conclusions: DWI-guided DP-IMRT plus chemotherapy is associated with a disease-free survival benefit compared with conventional MRI-based IMRT among patients with locoregionally advanced NPC without increasing acute toxic effects. [ABSTRACT FROM AUTHOR]

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Background: Nasopharyngeal carcinoma (NPC) is a rare malignancy with multiple risk factors (Epstein–Barr virus, etc.) that seriously threatens the health of people. CircRNAs are known to regulate the tumorigenesis of malignant tumours, including NPC. Moreover, circCRIM1 expression is reported to be upregulated in NPC. Nevertheless, the impact of circCRIM1 on NPC progression is not clear. Methods: An MTT assay was performed to assess cell viability. In addition, cell invasion and migration were assessed by the transwell assay. Dual luciferase assays were performed to assess the association among circCRIM1, miR-34c-5p and FOSL1. Moreover, RT-qPCR was applied to assess mRNA levels, and protein levels were determined by Western blot. Results: CircCRIM1 and FOSL1 were upregulated in NPC cells, while miR-34c-5p was downregulated. Knockdown of circCRIM1 significantly decreased the invasion, viability and migration of NPC cells. The miR-34c-5p inhibitor notably promoted the malignant behaviour of NPC cells, while miR-34c-5p mimics exerted the opposite effect. Moreover, circCRIM1 could bind with miR-34c-5p, and FOSL1 was identified to be downstream of miR-34c-5p. Furthermore, circCRIM1 downregulation notably inhibited the proliferation and invasion of NPC cells, while this phenomenon was significantly reversed by FOSL1 overexpression. Conclusion: Silencing circCRIM1 inhibited the tumorigenesis of NPC. Thus, circCRIM1 might be a novel target for NPC. [ABSTRACT FROM AUTHOR]

Background: The molecular mechanisms underlying chemoresistance are still poorly understood in nasopharyngeal cancer. The protein expression of ERCC1 in DNA repair genes has been reported related to resistance platinum and predicting treatment outcomes in various malignant carcinomas, but the benefit for predicting outcomes with optimal cutoff value of ERCC1mRNA is controversial. The level of plasma Epstein-Barr virus (EBV) DNA is positively correlated with clinical stages of nasopharyngeal carcinoma (NPC). The predictive value of ERCC1mRNA from receiver-operator characteristic (ROC) and EBV-DNA level for stratified treatment with stage II NPC is exactly unclear. This study aims to assess the predictive value of combined EBV-DNA and ERCC1 in stage II nasopharyngeal cancer (NPC) patients treated with intensity-modulated radiotherapy (IMRT) with concurrent cisplatin, and provide guidance for future stratified treatment. Methods: A total of 86 stage II NPC patients who received IMRT and concurrent cisplatin-based chemotherapy with or without cisplatin-based adjuvant chemotherapy had measurements of ERCC1 mRNA, and pretreatment EBV-DNA levels were analyzed by real-time PCR (RT-PCR). Associations of ERCC1 mRNA and pretreatment EBV-DNA levels with clinical characteristics and survivals were evaluated. Results: Cutoff value of ERCC1 mRNA obtained from ROC curve was used, and there were significant differences in progression-free survival (PFS) and overall survival (OS) and overall response rate (ORR) between high expression group and low expression group (p = 0.021 and 0.030 and 0.000, respectively). Patients with pretreatment EBV-DNA <2000 copies/mL had significantly better PFS and ORR (p = 0.024 and 0.043, respectively) and a marginally significant impact on OS (p = 0.062) than those with pretreatment EBV-DNA ≥2000 copies/mL. Patients were divided into three groups by combination of ERCC1 mRNA and EBV-DNA level: ERCC1 mRNA low expression/pre-EBV-DNA <2000 copies/mL, ERCC1 mRNA low expression/pre-EBV-DNA ≥2000 copies/mL, and ERCC1 mRNA high expression/pre-EBV-DNA ≥2000 copies/mL. There were significant differences in ORR among the three groups (p = 0.005). The median follow-up was 62 months (range 22-84) with a follow-up rate of 90.70%. In these groups by combination of ERCC1 mRNA and EBV-DNA level, 1, 3, 5-year OS were 100%, 100%, 100%; 100%, 94.1%, 90.9%; and 100%, 85%, 72.9%, respectively (p = 0.038); 1, 3, 5-year PFS were 100%, 100%, 100%; 97.1%, 91.2%, 84.8%; and 95%, 85%, 71.4%, respectively (p = 0.028). Multivariate analysis showed that combination of ERCC1 mRNA and EBV-DNA levels remained independent prognostic factor but not ERCC1 mRNA and EBV-DNA alone. Conclusions: Combined ERCC1 mRNA and pre-EBV-DNA is a better prognostic biomarker in stage II NPC patients treated with concurrent chemoradiation. Patients with ERCC1 mRNA high expression/pre-EBV-DNA ≥2000 copies/mL may benefit from more aggressive treatment. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is the most common malignant tumor of the nasopharynx. Although NPC is not endemic in India, higher incidences were observed in its North‐Eastern regions particularly Sikkim, Nagaland, Manipur, and Mizoram. Early detection of NPC is difficult because the nasopharynx is not readily amenable to clinical examination and symptoms of NPC are nonspecific. The development of suitable biomarkers for early diagnosis of NPC as well as accurate monitoring of treatment response is needed urgently. In this exploratory pilot study, we have investigated the clinical significance of assessing plasma Epstein–Barr virus (EBV) DNA load at diagnosis and during treatment. We found that EBV DNA is detectable at diagnosis in the majority of patients with nonendemic NPC and the absolute copy number of circulating EBV DNA per milliliter increases progressively with the stage of the disease. The viral load declined significantly with induction chemotherapy and definitive chemoradiation but showed a sharp rise at relapse. Patients with EBV DNA levels ≥1500 copies/ml had a higher risk of disease progression or relapse when compared with patients who had EBV DNA <1500 copies/ml at baseline. Estimation of plasma EBV DNA may serve as an excellent noninvasive tool to monitor disease extent, response to therapy, and for better prediction of future relapse or progression‐free survival in a nonendemic NPC patient population. [ABSTRACT FROM AUTHOR]

The present meta-analysis was conducted to evaluate the prognostic value of pre and post-Epstein Barr Virus (EBV) DNA load testing and to assess the clinical benefit of using this molecular approach in the prognosis for a better nasopharyngeal carcinoma (NPC) management. Relevant studies were searched in different database until May 2020. Patient's outcomes overall survival (OS), disease free survival (DFS), progression-free survival (PFS), distant-metastasis-free survival (DMFS), and local-regional-failure-free survival (LRFS), hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted from selected studies. The association of pre and post-EBV DNA load and survival outcomes was assessed using review manager and the pooled HRs with 95% CIs were calculated. Twenty-six eligible studies were included in this meta-analysis, with a total of 9966 patients. Pooled HRs showed that EBV DNA levels before and after treatment are significantly associated with survival outcomes, with HR (95% CI) of 2.09 [1.74, 2.51]for OS, 1.77 [1.19, 2.62]for DFS, 2.53 [2.18, 2.92] for DMFS, 1.78 [1.45, 2.19]for LRFS and 2.17 [1.91, 2.47] for PFS in pre-EBV DNA, and an HR (95%) of 4.52 [2.44, 8.36], 4.08 [2.38, 6.99], 5.59 [3.58, 8.71] and 8.88 [5.29, 14.90] for OS, DFS and PFS and DMFS in post-EBV DNA, respectively. High pre and post-EBV DNA levels were significantly associated with poor NPC patient's survival outcomes; which clearly confirm the high interest to introduce viral EBV DNA load as a prognostic biomarker for NPC management. [ABSTRACT FROM AUTHOR]

Objective: Circulating cell-free Epstein-Barr virus (EBV) DNA has been shown to be a valuable biomarker for population screening and prognostic surveillance for nasopharyngeal carcinoma (NPC). Despite important insights into the biology of persistence, few studies have addressed the clinical significance of cell-based EBV-DNA loads in peripheral blood cells (PBCs). Methods: A prospective observational cohort study was conducted involving 1,063 newly diagnosed, locoregionally-advanced NPC patients at Sun Yat-sen University Cancer Center from 2005 to 2007. Cox regression analysis was conducted to identify the association of PBC EBV DNA loads to overall survival (OS) and other prognostic outcomes. Prognostic nomograms were developed based on PBC EBV DNA loads to predict survival outcomes for NPC patients. Results: After a median follow-up of 108 months, patients with higher PBC EBV-DNA loads had significantly worse OS [hazard ratio (HR) of medium, medium-high, and high vs. low were 1.50, 1.52, and 1.85 respectively; Ptrend < 0.001]. Similar results were found for progression-free survival and distant metastasis-free survival. The concordance index of the prognostic nomogram for predicting OS in the training set and validation set were 0.70 and 0.66, respectively. Our data showed that the PBC EBV DNA load was an independent and robust survival biomarker, which remained significant even after adjusting for plasma EBV DNA loads in a subset of 205 patients of the cohort (HR: 1.88; P = 0.025). Importantly, a combination of PBC EBV DNA load and plasma EBV DNA load improved the predicted OS. Conclusions: The EBV-DNA load in PBCs may be an independent prognosis marker for NPC patients. [ABSTRACT FROM AUTHOR]

Background: The incidence of endemic Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) varies considerably worldwide. In high-incidence regions, screening trials have been conducted. We estimated the mortality reduction and cost-effectiveness of EBV-based NPC screening in populations worldwide.Methods: We identified 380 populations in 132 countries with incident NPC and developed a decision-analytic model to compare 10 unique onetime screening strategies with no screening for men and women aged 50 years. Screening performance and the stage distribution of undiagnosed NPC were derived from a systematic review of prospective screening trials.Results: Screening was cost-effective in up to 14.5% of populations, depending on the screening strategy. These populations were limited to East Asia, Southeast Asia, and North Africa or were Asian, Pacific Islander, or Inuit populations in North America. A combination of serology and nasopharyngeal polymerase chain reaction was most cost-effective, but other combinations of serologic and/or plasma polymerase chain reaction screening were also cost-effective. The estimated reduction in NPC mortality was similar across screening strategies. For a hypothetical cohort of patients in China, the 10-year survival improved from 71.0% (95% confidence interval = 68.8% to 73.0%) without screening to a median of 86.3% (range = 83.5%-88.2%) with screening. This corresponded to a median 10-year reduction in NPC mortality of 52.9% (range = 43.1%-59.3%). Screening interval affected absolute mortality reduction and cost-effectiveness.Conclusions: We observed decreased NPC mortality with EBV-based screening. Screening was cost-effective in many high-incidence populations and could be extended to men and women as early as age 40 years in select regions. These findings may be useful when choosing among local public health initiatives. [ABSTRACT FROM AUTHOR]

Objectives: To establish and validate an effective nomogram to predict clinical outcomes for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Materials and Methods: The clinicopathological parameters and follow-up information of 402 locoregionally advanced NPC patients (training cohort, n = 302; validation cohort, n = 100) were retrospectively enrolled. The nomogram was built with the important prognostic variables identified by Cox regression analysis. Overall survival (OS) and progression-free survival (PFS) were the primary and secondary endpoints, respectively. The predictive power and clinical utility of the nomogram were assessed using the Harrell concordance index (C-index), calibration curve, and decision curve analysis. We compared the eighth staging system model with the nomogram to analyze whether the model could improve the accuracy of prognosis Results: Epstein–Barr virus (EBV) DNA load, the gross tumor volume (GTVnx), and cervical lymph node tumor volume (GTVnd) after induction chemotherapy were the independent predictors of OS and PFS. The calibration curves indicated superb agreement between the nomogram-predicted probabilities and observed actual probabilities of survival. The C-index and area under the receiver operator characteristic curve (AUC) of the nomogram integrating these significant factors and N stage, and TNM stage were higher than those of the eighth TNM system alone. In addition, the decision curve analyses demonstrated the clinical value and higher overall net benefit of the nomogram. High-risk groups identified by the nomogram had significantly poorer OS and PFS than the low-risk group (p < 0.05). Conclusions: The multidimensional nomogram incorporating TNM stage, EBV DNA load, and tumor volume after induction chemotherapy led to a more precise prognostic prediction and could be helpful for stratifying risk and guiding treatment decisions in locoregionally advanced NPC patients who have undergone induction chemotherapy and concurrent chemoradiation. [ABSTRACT FROM AUTHOR]

Nasopharyngeal cancer (NPC) is a deadly disease where over 50% of people are diagnosed at advanced stage, of whom a third dies from cancer recurring after radiotherapy. It is endemic to Southeast Asia, Southern China and North Africa, with an age-standardized global incidence rate of over 2 per 100,000 in 2019. Over the last two decades, the treatment paradigm of advanced NPC has changed substantially. These advances include the use of concurrent chemotherapy during radiotherapy, the use of immunotherapy in combination with chemotherapy, and also the clinical application of 'liquid biopsy' with plasma Epstein-Barr virus DNA blood test in monitoring response to treatment. The mutational and immune landscape of NPC has also been extensively elucidated since 2014, leading to the discovery of new biomarkers and potential therapeutic targets. This lecture will outline the practice-changing in the treatment of advanced NPC over the last two decades and their impact on patient's survival. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to investigate whether Epstein–Barr virus (EBV) could produce differences on MRI by examining the histogram and texture imaging features. We also sought to determine the predictive value of pretreatment MRI texture analyses incorporating with EBV status for disease progression (PD) in patients with primary nasopharyngeal carcinoma (NPC). Materials and Methods: Eighty-one patients with primary T2-T4 NPC and known EBV status who underwent contrast-enhanced MRI were included in this retrospective study. Whole-tumor-based histogram and texture features were extracted from pretreatment T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and contrast-enhanced (CE)-T1WI images. Mann–Whitney U -tests were performed to identify the differences in histogram and texture parameters between EBV DNA-positive and EBV DNA-negative NPC images. The effects of clinical variables as well as histogram and texture features were estimated by using univariate and multivariate logistic regression analyses. Receiver operating characteristic (ROC) curve analysis was used to predict the EBV status and PD. Finally, an integrated model with the best performance was built. Results: Of the 81 patients included, 54 had EBV DNA-positive NPC, and 27 had EBV DNA-negative NPC. Patients who were tested EBV DNA-positive had higher overall stage (P = 0.016), more lymphatic metastases (p < 0.0001), and easier distant metastases (P = 0.026) than the patients who were tested EBV DNA-negative. Tumor volume, T1WI Skewness and T2WI Kurtosis showed significant differences between the two groups. The combination of the three features achieved an AUC of 0.783 [95% confidence interval (CI) 0.678–0.888] with a sensitivity and specificity of 70.4 and 74.1%, respectively, in differentiating EBV DNA-positive tumors from EBV DNA-negative tumors. The combination of overall stage and tumor volume of T2WI Kurtosis and EBV status was the most effective model for predicting PD in patients with primary NPC. The overall accuracy was 84.6%, with a sensitivity and specificity of 93.8 and 66.2%, respectively (AUC, 0.800; 95% CI 0.700–0.900). Conclusion: This study demonstrates that MRI-based radiological features and EBV status can be used as an aid tool for the evaluation of PD, in order to develop tailored treatment targeting specific characteristics of individual patients. [ABSTRACT FROM AUTHOR]

Background: Nasopharyngeal carcinoma (NPC) is a rare epithelial carcinoma arising from the nasopharyngeal region. The pathogenesis of NPC is linked to Epstein–Barr virus (EBV) infection, although genetics and lifestyle factors appears to be also implicated. NKG2D is an immunoreceptor expressed by NK and T-cell subsets that recognizes MICA protein and other ligands on tumor cells. NKG2D interaction with MICA plays a role in the immunosurveillance to viruses and cancer. Methods: We investigated potential associations between functional polymorphisms in NKG2D and MICA genes with NPC susceptibility. We conducted a case–control study including 255 Vietnamese patients with EBV + non-differentiated NPC and 220 healthy controls. Results: We observed a significant association between the LNK/LNK genotype of rs1049174 (a variant associated with lower NKG2D receptor expression and reduced NK cell cytotoxicity) and increased susceptibility to NPC (adjusted OR = 1.66, 95% CI 1.07–2.59; p = 0.024). Similarly, the AA genotype of MICA rs2596542 was significantly associated with NPC (adjusted OR = 2.12; 95% CI 1.22–3.81; p = 0.009). In addition, tumor specimens of NPC patients with the AA genotype displayed a higher expression level of MICA proteins and showed higher EBV titers compared with tumor tissues from patients with the GG or GA genotypes. Higher EBV copy numbers were also observed in tumors with the A allele of MICA rs1051792 (also known as MICA-129 Met/Val) compared with those with the G allele; however, MICA rs1051792 variants were not associated with NPC susceptibility. These results suggest that genetic variants in components of the NKG2D axis may influence the individual susceptibility to EBV-induced NPC. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) occurring in children and adolescence is extremely rare and till present there is a lack of understanding on their clinicopathological and prognostic features of this rare entity. For our study, data of 196 cases children and adolescents with NPC from the past 18 years at a high‐volume cancer center from South China were retrospectively analyzed. Half of the evaluated NPC patients (83/166, 50.0%) were staged as Stage IVa disease, whereas 1.2% (2/166), 27.7% (46/166), 16.9% (28/166) and 4.2% (7/166) had Stage II, III, IVb and IVc disease, respectively. Serum EBV EA‐IgA ≥1:10 and VCA‐IgA ≥1:40 were found in 67.7% (113/167) and 76.6% (128/167) of the evaluated patients, respectively, whereas 56.8% (84/148) of the patients had plasma EBV DNA ≥1000 copies/mL. Histologically, all tumors were classified as nonkeratinizing squamous cell carcinoma (NK‐SCC). Immunohistochemistrically, the expression of CK (AE1/AE3), P63, CK5/6 and P40 were observed in 100% (88/88), 93.2% (68/73), 84.1% (58/69) and 63.2% (12/19) of the detected cases, respectively. All cases show similar immunophenotype compared to that occurring in adult patients. All evaluated cases (71/71 100%) harbored EBER. Patients with plasma EBV DNA ≥1000 copies/mL and positive serum EBV antibodies had significantly inferior 3‐year OS (88% vs 100%, P =.007) compared to other corresponding groups. The combination of EBV serology and plasma EBV DNA are useful to predict the outcome of patients with NPC in children and adolescents. What's new Nasopharyngeal carcinoma (NPC) is extremely rare in children and adolescents, and the clinicopathological characteristics and prognostic features of pediatric NPC remain largely unknown. In this retrospective study, the authors describe the largest series of NPC in children and adolescents in southern China, the most endemic area of NPC, and reveal that all cases histologically belonged to nonkeratinizing squamous cell carcinoma. Moreover, they provide evidence that the combination of Epstein‐Barr virus (EBV) serology and plasma EBV DNA is useful for predicting patient outcome, with potential clinical applications for risk group stratification and prognostic prediction for pediatric NPC patients. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is caused by Epstein-Barr virus (EBV) and is more likely to occur in susceptible families. Whether genetic susceptibility operates through altered EBV control is incompletely understood. We used a NPC risk prediction model based on 14 EBV markers to compare risk score distribution in unaffected members from multiplex families with that in population-based controls. Despite the absence of NPC at the time of antibody measurement, we observed an upward shift in risk score among multiplex family members compared to the general population, consistent with the possibility that genetic factors affect NPC risk through alterations in EBV control. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC), the most common head and neck cancer, is characterized by distinct geographic distribution and familial aggregation. Multiple risk factors, including host genetics, environmental factor, and EBV infection, have been linked to the development of NPC, particularly in the familial clustering cases. However, the cause of NPC endemicity remains enigmatic due possibly to the complicated interplay between these risk factors. Recently, positive Epstein‐Barr virus (EBV) DNA loads at nasopharyngeal (NP) cavity has been found to reflect NPC development and applied in NPC screening. To examine whether the increased NP EBV loads could aggregate in the families and be affected by host genetics and environmental factor, EBV loads were obtained by 510 NP brushing samples from eligible unaffected individuals, who have two or more relatives affected with NPC, in 116 high‐risk NPC families. The correlation of relative pairs was estimated using S.A.G.E. (version 6.4, 2016), and host heritability of NP EBV loads was calculated with variance component models using SOLAR (version 8.4.2, 2019). In result, significant correlations of EBV loads were observed between parent‐offspring pairs and sibling‐sibling pairs (P <.001), but not in distant kin relationship pairs. Interestingly, after excluding the shared environmental factor within families, host genetics contributes significantly to NP EBV loads with a heritability of 56.41% (P = 1.00 × 10−7), and its effect was slightly elevated (68.86%, P = 3.40 × 10−6) in families with more NPC cases (≥3). These findings indicate that additional host‐genetic variants involved in the EBV local NP mucosal behavior may be especially important for the development of NPC. [ABSTRACT FROM AUTHOR]

Purpose: Cervical lymph-node (CLN) metastasis commonly occurs in patients with nasopharyngeal carcinoma (NPC) metastasis. The presence of Epstein–Barr virus (EBV) genomes in neck lymph nodes may diagnose CLN. This research was designed to appraise the diagnostic value of EBV concentration for cervical lymph nodes in NPC. Methods: Two hundred and fifty-three NPC patients with 276 CLNs were enrolled. MRI was performed to detect CLN metastasis, and plasma EBV concentration was measured by quantitative PCR before treatment. Ultrasonography (US) and US-FNA were subsequently performed in the suspicious lymph nodes. Fifteen patients (22 lymph nodes) underwent fine-needle aspiration cytology (FNAC), and the remaining 242 patients (254 lymph nodes) underwent core needle biopsy (CNB) for CLNs at the clinician's demand. The aspiration needle was rinsed with 1 ml of normal saline for EBV detection. The method of lymph-node EBV measurement was consistent with that for plasma. The MRI results and EBV concentrations in plasma and lymph nodes were recorded and analyzed. Plasma EBV concentrations ≥ 4000 copies/ml were regarded as positive. Results: CLN-EBV concentrations ≥ 787.5 copies/ml were regarded as positive according to receiver-operating characteristic curve analysis. The AUC of the EBV (0.925) concentration in CLN metastasis was significantly larger than the AUC of MRI (0.714) (P < 0.001). The sensitivity and specificity were 94.09% and 48.72% for MRI in lymph-node metastasis and 95.36% (P > 0.05) and 84.62% (P < 0.01) for EBV DNA in CLN metastasis, respectively. The sensitivity and specificity of EBV in plasma were 77.2% and 71.8%, respectively. The diagnostic specificity and AUC of EBV in CLNs were higher than those of MRI and plasma EBV (P < 0.005). Conclusions: Ultrasound-guided CLN FNA to obtain EBV concentrations may provide a new method to diagnose CLN metastasis with high sensitivity and specificity. [ABSTRACT FROM AUTHOR]

The authors of this editorial evaluate the current data examining the benefit of neoadjuvant chemotherapy versus adjuvant chemotherapy in the management of advanced nasopharynx cancer. [ABSTRACT FROM AUTHOR]

Epstein‐Barr virus (EBV) causes nasopharyngeal carcinoma (NPC) in endemic regions, where almost every tumor is EBV‐positive. In Western populations, NPC is rare, and human papillomavirus infection (HPV) has been suggested as another viral cause. We validated multiplex serology with molecular tumor markers, to define EBV‐positive, HPV‐positive and EBV‐/HPV‐negative NPCs in the United Kingdom, and analyzed survival differences between those groups. Sera from NPC cases (n = 98) and age‐ and sex‐matched controls (n = 142) from the Head and Neck 5000 clinical cohort study were analyzed. IgA and IgG serum antibodies against 13 EBV antigens were measured and compared with EBER in situ hybridization (EBER‐ISH) data of 41 NPC tumors (29 EBER‐ISH positive, 12 negative). IgG antibodies to EBV LF2 correctly diagnosed EBV‐positive NPCs in 28 of 29 cases, while all EBER‐ISH negative NPCs were seronegative to LF2 IgG (specificity = 100%, sensitivity = 97%). HPV early antigen serology was compared to HPV molecular markers (p16 expression, HPV DNA and RNA) available for 41 NPCs (13 positive, 28 negative). Serology matched molecular HPV markers in all but one case (specificity = 100%, sensitivity = 92%). EBV and HPV infections were mutually exclusive. Overall, 67% of the analyzed NPCs were defined as EBV‐positive, 18% as HPV‐positive and 14% as EBV/HPV‐negative. There was no statistical evidence of a difference in survival between the three groups. These data provide evidence that both, EBV‐positive and HPV‐positive NPCs are present in a low incidence country, and that EBV and HPV serum antibodies correlate with the viral status of the tumor. What's new? While Epstein‐Barr virus (EBV) causes almost all nasopharyngeal carcinoma (NPC) in endemic regions, human papillomavirus (HPV) may also cause NPCs in low‐incidence, Western populations. Here, the authors used molecular tumor markers to validate EBV and HPV multiplex serology to define the viral status of NPCs in the United Kingdom. IgG antibodies to the EBV antigen LF2 and HPV early antigen serology were highly specific and sensitive to identify EBV‐ and HPV‐positive NPCs, respectively. The results show that both EBV‐positive and HPV‐positive NPCs are present in a low‐incidence country, and that EBV and HPV serum antibodies correlate with the viral status of the tumor. [ABSTRACT FROM AUTHOR]

Purpose: Nasopharyngeal cancer is a type of malignancy originating from the epithelial cells lining the nasopharynx. In genetic and environmental factors, infection with Epstein–Barr virus is one of the particular factors held accountable for the etiopathogenesis. Human papillomavirus has been associated with cervical, anogenital, and oropharyngeal cancers. The aim of the present study is to demonstrate the presence and incidence of Epstein–Barr virus and human papillomavirus in patients with nasopharyngeal cancer. Methods: The information collected for these patients included age at the time of biopsy, gender, alcohol consumption and smoking, and histopathological type of nasopharyngeal cancer. Only patients for whom nasopharyngeal biopsy was performed as punch biopsy were included in the study. In situ hybridization was performed with formalin-fixed, paraffin-embedded tissue sections for Human Papillomavirus and Epstein–Barr virus nucleic acids obtained by means of automated Ventana BenchMark Medical system Results: Utilizing in situ hybridization with samples obtained from 56 patients diagnosed with nasopharyngeal cancer. Epstein–Barr virus was positive in 41 out of the 56 (73.2%) patients, while human papillomavirus was positive in 3 (5.4%), and 1 patient (1.8%) had co-infection. Thirty seven (90.2%) of the 41 patients positive for Epstein–Barr virus were Type-2 according to WHO, while 4 (9.8%) were Type-1. All three patients (100%) with Human Papillomavirus positivity were Type-2 according to WHO. Conclusions: This study shows the close association between nasopharyngeal cancer and Epstein–Barr virus whereas such an association is not shown for Human Papillomavirus. [ABSTRACT FROM AUTHOR]

Distant metastasis is among the main reasons for treatment failure in nasopharyngeal carcinoma (NPC) patients. To identify patients with a high risk of distant metastasis is important to guide posttreatment surveillance, appropriate time treatments, and prolonging their long-term survival. In this study, we systematically examined the associations between a series of nodal-related characteristics and distant metastasis-free survival (DMFS) by detailed MRI reading and established a nomogram for DMFS in NPC patients. T-stage, age group, Epstein–Barr virus (EBV) level, central nodal necrosis, and nodal number were identified as independent risk factors for distant metastasis and were included into the final nomogram. The calibration plot showed a high agreement between the prediction by the nomogram and actual observations. Our established nomogram achieved a high C-index in predicting distant metastasis in both of the training cohort (0.737) and the validation cohort (0.718). This nomogram incorporated several readily available nodal features from the MR images, and it might be useful for guiding clinical decision and NPC patients' posttreatment surveillance. It also provides cues for how to redefine N-stage. Additional research is needed to confirm our conclusions. [ABSTRACT FROM AUTHOR]