BACKGROUND:The long-term impact of magnetic resonance imaging (MRI) on nasopharyngeal carcinoma (NPC) detection in screening remains unclear as a result of limited follow-up. METHODS:A prospective population-based screening study was conducted in Southern China from October 2014 to November 2018 among Epstein-Barr virus (EBV)-seropositive individuals aged 30-69 years. EBV-seropositive participants underwent both endoscopy and MRI. Suspicious findings from either modality triggered a second endoscopy with biopsy. Followup for cancer diagnoses was completed via multiple methods in October 2023. Primary end points included the 5-year NPC detection rate (overall and by stage) and the false-negative rate. Secondary end points were sensitivity, specificity, positive predictive value (PPV), and referral rate. RESULTS:The analysis included 814 individuals (455 females; 56%) with a median age of 53 years (interquartile range, 46-60 years). Thirty-two NPC cases were detected (30 via MRI; 21 via endoscopy) over 5 years. MRI showed a significantly higher overall NPC detection rate (36.9 [95% CI, 25.9-52.1] vs. 25.8 [95% CI, 16.9-39.1] per 1000; p = .007) and early-stage tumor detection (20.9 [95% CI, 13.1-27.1] vs. 12.3 [95% CI, 6.7-22.5] per 1000; p = .020) than endoscopy. MRI also demonstrated a lower false-negative rate (3.0 [95% CI, 0.8-11.0] vs. 14.9 [95% CI, 8.4-26.5] per 1000; p = .024) and higher sensitivity (93.8% vs. 65.6%; p = .007) but lower specificity (84.0% vs. 92.8%; p < .001) and PPV (19.6% vs. 27.6%; p = .019). CONCLUSIONS:Single MRI demonstrated superior NPC detection versus endoscopy, particularly for early-stage tumors, in high-risk populations during a 5-year period, which suggests the potential for extending the rescreening interval to 5 years for MRI-negative individuals.

Nasopharyngeal carcinoma screening in southern China relies on Epstein-Barr virus serology, but its limited positive predictive value leads to excessive referrals. Here we evaluate a triage approach based on nasopharyngeal swab Epstein-Barr virus C promoter methylation quantification (E-CpMQ) among serology high-risk individuals in two population-based screening cohorts (N = 55,682). In the initial screening round (≤18 months) of a single-center cohort (N = 313), E-CpMQ identifies 91.7% of nasopharyngeal carcinoma cases (22/24) with 91.7% specificity (265/289), reducing referrals by 85.3%. Findings are replicated in an independent six-center cohort (N = 345), where E-CpMQ achieves 100% sensitivity (15/15) and 96.1% specificity (317/330), reducing referrals by 91.9%. Compared with nasopharyngeal swab Epstein-Barr virus DNA load triage, E-CpMQ shows equivalent sensitivity but higher specificity, lowering referrals needed to detect one case from 10-14 to approximately 2. Modeling further indicates improved specificity and positive predictive value when integrated into serology-based screening.

PURPOSE Screening for nasopharyngeal carcinoma (NPC) has shown an improvement in early detection and survival rates of NPC in endemic regions. It is critical to evaluate whether NPC screening can reduce NPC-specific mortality in the population. METHODS Sixteen towns in Sihui and Zhongshan cities, China, were selected; eight were randomly allocated to the screening group and eight to the control group. Residents age 30-69 years with no history of NPC were included from January 1, 2008, to December 31, 2015. Residents in the screening towns were invited to undergo serum Epstein-Barr virus (EBV) viral capsid antigen/nuclear antigen 1-immunoglobulin A antibody tests; others received no intervention. The population was followed until December 31, 2019. Nonparametric tests and Poisson regression models were used to estimate the screening effect on NPC mortality, accounting for the cluster-randomized design. The trial is registered with ClinicalTrials.gov (identifier: NCT00941538 ). RESULTS A total of 174,943 residents in the screening group and 186,263 residents in the control group were included. NPC incidence and overall mortality were similar between the two groups. A total of 52,498 (30.0% of 174,943) residents participated in the serum EBV antibody test. The overall compliance rate for endoscopic examination and/or biopsies among baseline and ever-classified high-risk participants was 65.9% (1,110 of 1,685) and 67.6% (1,703 of 2,518), respectively. A significant 30% reduction in NPC mortality was observed in the screening group compared with the control group (standardized NPC-specific mortality rate of 8.2 NPC deaths per 1,000 person-years versus 12.5; adjusted rate ratio [RR], 0.70 [95% CI, 0.49 to 0.997]; P = .048). This benefit was most evident among individuals age 50 years and older (RR, 0.56 [95% CI, 0.37 to 0.85]; P = .007) compared with those younger than 50 years (RR, 0.96 [95% CI, 0.64 to 1.46]; P = .856). CONCLUSION In this 12-year trial, EBV antibody testing resulted in a significant reduction in NPC mortality.

Purpose To estimate the effectiveness of an Epstein–Barr virus (EBV) serology-based screening program to reduce nasopharyngeal carcinoma (NPC) mortality in a cluster randomized controlled trial in an NPC high-risk population.Methods Sixteen towns in Sihui and Zhongshan Cities, China were selected; eight were randomly allocated to the screening group and eight to the control group. Cantonese residents aged 30-69 years with no history of NPC were included January 1, 2008 to December 31, 2015. Residents in the screening towns were invited to undergo serum EBV VCA/EBNA1 IgA antibody tests; others received no intervention. Screening lasted through December 31, 2015; the population was followed through December 31, 2017.Results A total of 175,037 residents in the screening group and 184,526 residents in the control group were included. NPC incidence was similar in screening and control groups. A 28% reduction in NPC mortality was observed in the screening versus control arms in the overall study population (8.0 NPC deaths per 1000 person years versus 11.1; adjusted rate ratio [aRR]=0.72; 95% confidence interval=0.48-1.09; p=0.12). A stronger benefit was observed among individuals aged >50 (aRR=0.63; p=0.048) compared to those <50 (aRR 0.93; p=0.75). The reduction was increased among individuals from towns randomized to screening who participated in the screening program (aRR=0.38, p=0.001).Conclusion In this near 10-year trial, serology EBV VCA and EBNA1 IgA antibody testing led to a reduction in NPC mortality, particularly among individuals aged ⩾50. EBV antibody-based screening for NPC is effective at reducing NPC mortality in high-risk populations.Trial registration number NCT00941538### Competing Interest StatementThe authors have declared no competing interest.### Clinical TrialNCT00941538### Funding StatementThis work was supported by National Key R&D Program of China (2020YFC1316905); National Natural Science Foundation of China (81872700, 82073625); Eleventh National Science and Technology Support Program of China, National Key Research and Development Program of China (2017YFC0907100, 2016YFC0902000); Sun Yat-Sen University Clinical Research 5010 Program (2013012); Intramural Research Program of National Cancer Institute (NCI), USA.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethics committee/IRB of Sun Yat-sen University Cancer Center gave ethical approval for this work.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the present work are contained in the manuscript.

BACKGROUND:Epstein-Barr virus (EBV) DNA detection in the nasopharynx is considered a biomarker for nasopharyngeal carcinoma (NPC). We evaluated its performance as a reflex test to triage EBV seropositives within an NPC screening program in China.METHODS:The study population was embedded within an ongoing NPC screening trial and included 1111 participants who screened positive for anti-EBV VCA (antibodies against EBV capsid antigens)/EBNA1 (EBV nuclear antigen1)-IgA antibodies (of 18 237 screened). Nasopharynx swabs were collected/tested for EBNA1 gene EBV DNA load. We evaluated performance of EBV DNA in the nasopharynx swab as a reflex test to triage EBV serological high-risk (those referred to endoscopy/MRI) and medium-risk (those referred to accelerated screening) individuals.RESULTS:By the end of 2019, we detected 20 NPC cases from 317 serological high-risk individuals and 4 NPC cases from 794 medium-risk individuals. When used to triage serological high-risk individuals, nasopharynx swab EBV DNA was detected in 19/20 cases (positivity rate among cases: 95.0%; 95% CI, 75.1%-99.9%), with a referral rate of 63.4% (201/317, 95% CI, 57.8%-68.7%) and NPC detection rate among positives of 9.5% (19/201, 95% CI, 5.8%-14.4%). The performance of an algorithm that combined serology with triage of serology high-risk individuals using EBV DNA testing yielded a sensitivity of 72.4% (95% CI, 3.0%-81.4%) and specificity of 97.6% (95% CI, 97.2%-97.9%). When used to triage EBV serological medium-risk individuals, the positivity rate among cases was 75.0% (95% CI, 19.4%-99.4%), with a referral rate of 61.8% (95% CI, 58.4%-65.2%) and NPC detection rate among positives of 0.6% (95% CI, 0.1%-1.8%).CONCLUSIONS:Nasopharynx swab EBV DNA showed promise as a reflex test to triage serology high-risk individuals, reducing referral by ca. 40% with little reduction in sensitivity compared to a serology-only screening program.

Epstein-Barr virus (EBV) is one of the risk factors of nasopharyngeal carcinoma (NPC), and understanding the modifiable risk factors of EBV activation is crucial in the prevention of NPC. In this study, we aimed to investigate the association between solid fuel use and EBV seropositivity in a high-risk area of NPC. Our study was based on the baseline findings from an ongoing population-based prospective cohort in Sihui county in Southern China. We explored the association between current use of solid fuel in cooking and EBV seropositivity, and NPC-related EBV activation, using logistic regression models. Stratification analyses were further conducted to assess potential effect modifiers. We also examined the impact of frequency and duration of solid fuel use, and switch in fuel types, on EBV seropositivity among ever users. Of the 12,579 participants included in our analysis, 4088 (32.5%) were EBV seropositive and 421 (3.3%) were high risk for NPC-related EBV activation. Solid fuel use was associated with a higher risk of EBV seropositivity and NPC-related EBV activation, with odds ratios (ORs) of 1.33 (95%CI: 1.01, 1.76) and 1.81 (95%CI: 1.03, 3.18), respectively. Higher risk of EBV seropositivity was observed for those who did not use ventilation apparatus and those who consumed salted food. Among ever users, OR was highest for participants with more than 40 years of solid fuel exposure (1.17, 95%CI: 1.00-1.37) and who have been constantly using solid fuel (1.30, 95%CI: 0.96-1.75). We did not find a statistically significant impact of cooking frequency on EBV seropositivity. The identification of solid fuel as a risk factor for EBV activation is of great value for understanding the etiology of NPC. Our findings also have important public health implications given the fact that a third of the global population still lack access to clean cooking, especially in low resource settings.

BACKGROUND Although stratifying individuals with respect to nasopharyngeal carcinoma (NPC) risk with Epstein-Barr virus-based markers is possible, the performance of diagnostic methods for detecting lesions among screen-positive individuals is poorly understood. METHODS The authors prospectively evaluated 882 participants aged 30 to 70 years who were enrolled between October 2014 and November 2018 in an ongoing, population-based NPC screening program and had an elevated NPC risk. Participants were offered endoscopy and magnetic resonance imaging (MRI), and lesions were identified either by biopsy at a follow-up endoscopy or further contact and linkage to the local cancer registry through December 31, 2019. The diagnostic performance characteristics of endoscopy and MRI for NPC detection were investigated. RESULTS Eighteen of 28 identified NPC cases were detected by both methods, 1 was detected by endoscopy alone, and 9 were detected by MRI alone. MRI had significantly higher sensitivity than endoscopy for NPC detection overall (96.4% vs 67.9%; P-difference = .021) and for early-stage NPC (95.2% vs 57.1%; P = .021). The sensitivity of endoscopy was suggestively lower among participants who had previously been screened in comparison with those undergoing an initial screening (50.0% vs 81.2%; P = .11). The authors observed a higher overall referral rate by MRI versus endoscopy (17.3% vs 9.1%; P < .001). Cases missed by endoscopy had early-stage disease and were more commonly observed for tumors originating from the pharyngeal recess. CONCLUSIONS MRI was more sensitive than endoscopy for NPC detection in the context of population screening but required the referral of a higher proportion of screen-positive individuals. The sensitivity of endoscopy was particularly low for individuals who had previously been screened.

IntroductionProspective evidence for herbal diet and nasopharyngeal carcinoma (NPC) development is absent. We therefore evaluated the associations of herbal soup and herbal tea with NPC in a prospective cohort study in southern China.MethodsBased on an NPC screening cohort established in 2008–2015, information on herbal diet consumption, potential confounding factors, and Epstein-Barr virus (EBV) antibody levels were collected from 10,179 individuals aged 30–69 years in Sihui city, southern China. Cox regression models were performed to examine herbal diet with NPC risk, and logistic regression models were used to examine herbal diet with EBV reactivation.ResultsDuring a median of 7.54 years of follow-up, 69 participants developed NPC. Herbal soup consumption was associated with decreased NPC risk, with HRs of 0.31 (95% confidence interval (CI): 0.15–0.62) for the highest intake frequency and 0.29 (95% CI: 0.16–0.51) for a longer duration. However, herbal tea was not significantly associated. Moreover, we identified herbal soup was inversely associated with EBV seropositivity among all the participants at baseline, with the adjusted ORs being 0.78 (95% CI: 0.65–0.93) for immunoglobulin A antibodies against EBV capsid antigens (VCA-IgA) and 0.76 (95% CI: 0.64–0.91) for nuclear antigen 1 (EBNA1-IgA) in those with the highest frequency and 0.70 (95% CI: 0.59–0.84) for VCA-IgA and 0.64 (95% CI: 0.54–0.77) for EBNA1-IgA in those with the longer duration. Inverse associations were also observed in non-NPC individuals.ConclusionsWith inhibition of EBV reactivation by plants, herbal soup could significantly decrease the risk of NPC in endemic areas.

Despite evidence suggesting the utility of Epstein‐Barr virus (EBV) markers to stratify individuals with respect to nasopharyngeal carcinoma (NPC) risk in NPC high‐risk regions, no validated NPC risk prediction model exists. We aimed to validate an EBV‐based NPC risk score in an endemic population undergoing screening for NPC. This prospective study was embedded within an ongoing NPC screening trial in southern China initiated in 2008, with 51 235 adult participants. We assessed the score's discriminatory ability (area under the receiver‐operator‐characteristics curve, AUC). A new model incorporating the EBV score, sex and family history was developed using logistic regression and internally validated using cross‐validation. AUCs were compared. We also calculated absolute NPC risk combining the risk score with population incidence and competing mortality data. A total of 151 NPC cases were detected in 2008 to 2016. The EBV‐based score was highly discriminating, with AUC = 0.95 (95% CI = 0.93‐0.97). For 90% specificity, the score had 87.4% sensitivity (95% CI = 81.0‐92.3%). As specificity increased from 90% to 99%, the positive predictive value increased from 2.4% (95% CI = 1.9‐3.0%) to 12.5% (9.9‐15.5%). Correspondingly, the number of positive tests per detected NPC case decreased from 272 (95% CI = 255‐290) to 50 (41‐59). Combining the score with other risk factors (sex, first‐degree family history of NPC) did not improve AUC. Men aged 55 to 59 years with the highest risk profile had the highest 5‐year absolute NPC risk of 6.5%. We externally validated the discriminatory accuracy of a previously developed EBV score in a high‐risk population. Adding nonviral risk factors did not improve NPC prediction.

Abstract Background The association between smoking and nasopharyngeal carcinoma (NPC) is still uncertain. The aim of this study was to validate smoking effect on NPC and explore if smoking can induce NPC by persistently reactivating EBV in long‐term based on a prospective cohort design. Methods A NPC screening cohort with 10 181 eligible residents in Sihui city, southern China was conducted from 2008 to 2015. The smoking habit was investigated through the trained interviewers and EBV antibodies (VCA‐IgA, EBNA1‐IgA) as screening markers were tested periodically. New NPC cases were identified through local cancer registry. Cox's regression model was used to estimate the adjusted hazard ratios (aHRs) of smoking on NPC incidence. In the non‐NPC participants, the associations between smoking and EBV seropositivity in different periods were assessed by logistic regression and generalized estimating equations (GEE). Results With a median of 7.54 years, 71 NPCs were diagnosed ≥1 year after recruitment. Compared with never smokers, the aHRs of developing NPC among ever smokers were 3.00 (95%CI: 1.46‐6.16). Stratified by sex, the HRs of ever smoking were 2.59 (95%CI: 1.07‐6.23) for male and 3.75 (95%CI: 1.25‐11.20) for female, respectively. Among the non‐NPC individuals, ever smoking was not only associated with EBV seropositivity at baseline, but also in the 3‐5 years of follow up, with adjusted odds ratios (aORs) of 1.68 (95%CI: 1.29‐2.18) for VCA‐IgA and 1.92 (95%CI: 1.42‐2.59) for EBNA1‐IgA. Among the smokers who were tested EBV antibodies at least twice, the similar results were obtained using GEE. Conclusion Smoking could significantly increase the long‐term risk of NPC in southern China, partly by persistently reactivating EBV.

[目的]评价以VCA-IgA联合EBNA1-IgA为筛查指标开展鼻咽癌筛查,能否有效提高筛查检出患者的生存率.[方法] 2008～2015年期间,在广东省四会市7个镇中招募30～69岁的当地居民参加鼻咽癌筛查,收集筛查人群与非筛查人群的鼻咽癌发病信息,用卡方检验比较筛查组与非筛查组的基本信息差异,通过Kaplan-Meier法和Cox比例风险模型比较筛查组与非筛查组鼻咽癌患者的长期生存情况.[结果]无论在筛查组还是非筛查组中,男性鼻咽癌发病率均高于女性.筛查组鼻咽癌早诊率为53.57％(30/56),显著高于非筛查组(17.40％,43/247) (P＜0.001).Kaplan-Meier法及Log-rank检验显示筛查组检出患者5年生存率为74.36％,非筛查组鼻咽癌患者5年生存率为63.90％,差异有统计学意义(P=0.044).[结论]以VCA-IgA联合EBNA1-IgA为筛查指标的鼻咽癌筛查方案可提高鼻咽癌患者长期生存状况.该筛查方案值得在鼻咽癌高发区推广.

Introduction:In the past several decades,declining incidences of nasopharyngeal carcinoma(NPC) have been observed in Chinese populations in Hong Kong,Taiwan,Los Angeles,and Singapore.A previous study indicated that the incidence of NPC in Sihui County,South China remained stable until 2002,but whether age,diagnosis period,and birth cohort affect the incidence of NPC remains unknown.Methods:Age-standardized rates(ASRs) of NPC incidence based on the world standard population were examined in both males and females in Sihui County from 1987 to 2011.Joinpoint regression analysis was conducted to quantify the changes in incidence trends.A Poisson regression age-period-cohort model was used to assess the effects of age,diagnosis period,and birth cohort on the risk of NPC.Results:The ASRs of NPC incidence during the study period were 30.29/100,000 for males and 13.09/100,000 for females.The incidence of NPC remained stable at a non-significant average annual percent change of 0.2%for males and-1.6%for females throughout the entire period.A significantly increased estimated annual percent change of 6.8%(95%confidence interval,0.1%-14.0%) was observed from 2003 to 2009 for males.The relative risk of NPC increased with advancing age up to 50-59 and decreased at ages >60 years.The period effect curves on NPC were nearly flat for males and females.The birth cohort effect curve for males showed an increase from the1922 cohort to the 1957 cohort and a decrease thereafter.In females,there was an undulating increase in the relative risk from the 1922 cohort to the 1972 cohort.Conclusions:The incidence trends for NPC remained generally stable in Sihui from 1987 to 2011,with an increase from 2003 to 2009.The relative risks of NPC increased in younger females.

A nasopharyngeal carcinoma (NPC) mass screening trial using a combination of immunoglobulin A antibodies to Epstein-Barr virus capsid antigen and nuclear antigen-1 by enzyme-linked immunosorbent assay in addition to indirect mirror examination in the nasopharynx and/or lymphatic palpation (IMLP) was conducted in southern China. Cantonese aged 30-59 years residing in 2 cities randomly selected by cluster sampling, Sihui and Zhongshan, were invited to participate in this screening from May 2008 through May 2010. Participants were offered fiberoptic endoscopy examination and/or pathologic biopsy if their serologic tests reached our predefined level of high risk or if results from the physical examination indicated possible cancer (i.e., were IMLP positive). A total of 28,688 individuals were voluntarily screened in the initial round. The overall NPC detection rate was 0.14% (41/28,688) with an early diagnosis rate of 68.3% (28/41) during the first year of follow-up. Thirty-eight of 41 cases (92.7%) were detected among the high-risk group, and 7 of 41 cases (17.1%) were detected among the IMLP-positive group. The 2 Epstein-Barr virus serologic tests by enzyme-linked immunosorbent assay could be a feasible alternative for NPC screening in endemic areas. Further follow-up is needed to examine whether screening has an effect on decreasing mortality from NPC in these areas.

BACKGROUND AND OBJECTIVECurrently, the serum immunoglobulin A against Epstein-Barr virus capsid antigen (EBV-VCA/IgA) is one of the most commonly used markers for diagnosis of nasopharyngeal carcinoma (NPC). However, its value for prognostic implication in NPC patients is unclear. This study was to evaluate the relationship between pretreatment titers of EBV-VCA/IgA and NPC patients' survival.METHODSThe clinicopathologic data of 317 NPC patients treated in Sun Yat-sen University Cancer Center between 1990 and 2003 were retrieved from the registration system of cancer incidence and mortality of Sihui city, Guangdong province. The correlation of pretreatment EBV-VCA/IgA titers to the survival of these patients was analyzed.RESULTSPretreatment VCA/IgA titer was significantly higher in stage III-IV NPC patients than in stage I-II patients (p = 0.01). The survival time was significantly shorter in the 170 patients with higher EBV-VCA/IgA titers (>or= 1:160) than in the 147 patients with lower EBV-VCA/IgA titers ( < 1:160). The 5-year survival rate was 65% in low EBV-VCA/IgA titer group and 43% in high titer group (p = 0.01). Multivariate analyses showed that clinical stage, sex, the year of treatment, and pretreatment serum EBV-VCA/IgA titer were all independent prognostic factors of NPC.CONCLUSIONPretreatment serum EBV-VCA/IgA titer may be used as an independent prognostic marker of NPC.