Utility of Epstein-Barr Virus DNA in Nasopharynx Swabs as a Reflex Test to Triage Seropositive Individuals in Nasopharyngeal Carcinoma Screening Programs.

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.

Prospective assessment of a nasopharyngeal carcinoma risk score in a population undergoing screening.

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.

Occupational exposures and risk of nasopharyngeal carcinoma in a high-risk area: A population-based case-control study.

BACKGROUND: The potential role of occupational exposures in the development of nasopharyngeal carcinoma (NPC) remains unclear, particularly in high-incidence areas. METHODS: The authors conducted a population-based case-control study, consisting of 2514 incident NPC cases and 2586 randomly selected population controls, in southern China from 2010 to 2014. Occupational history and other covariates were self-reported using a questionnaire. Multivariate logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for the risk of NPC associated with occupational exposures. Restricted cubic splines were used to evaluate potentially nonlinear duration-response relations. RESULTS: Individuals who had exposure to occupational dusts (OR, 1.45; 95% CI, 1.26-1.68), chemical vapors (OR, 1.37; 95% CI, 1.17-1.61), exhausts/smokes (OR, 1.42; 95% CI, 1.25-1.60), or acids/alkalis (OR, 1.56; 95% CI, 1.30-1.89) in the workplace had an increased NPC risk compared with those who were unexposed. Risk estimates for all 4 categories of occupational exposures appeared to linearly increase with increasing duration. Within these categories, occupational exposure to 14 subtypes of agents conferred significantly higher risks of NPC, with ORs ranging from 1.30 to 2.29, including dust from metals, textiles, cement, or coal; vapor from formaldehyde, organic solvents, or dyes; exhaust or smoke from diesel, firewood, asphalt/tar, vehicles, or welding; and sulfuric acid, hydrochloric acid, nitric acid, and concentrated alkali/ammonia. CONCLUSIONS: Occupational exposures to dusts, chemical vapors, exhausts/smokes, or acids/alkalis are associated with an excess risk of NPC. If the current results are causal, then the amelioration of workplace conditions might alleviate the burden of NPC in endemic areas. LAY SUMMARY: The role of occupational exposures in the development of nasopharyngeal carcinoma (NPC) remains unclear, particularly in high-incidence areas. The authors conducted a population-based study with 2514 incident NPC cases and 2586 population controls in southern China and observed that occupational exposures were associated with an increased risk of NPC. Duration-response trends were observed with increasing duration of exposure. These findings provide new evidence supporting an etiologic role of occupational exposures for NPC in a high-incidence region.

Comparison of new magnetic resonance imaging grading system with conventional endoscopy for the early detection of nasopharyngeal carcinoma.

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%; Pdifference = .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.

Plasma Epstein-Barr virus DNA and risk of nasopharyngeal carcinoma in a prospective seropositive population.

OBJECTIVE: Plasma Epstein-Barr virus (EBV) DNA is considered a biomarker for nasopharyngeal carcinoma (NPC). However, its long-term role in NPC development is unclear. MATERIALS AND METHODS: A total of 1363 participants seropositive for EBV VCA-IgA and EBNA1-IgA in a community-based NPC screening program in southern China were tested for plasma EBV DNA levels by real-time qPCR between 2008 and 2015. New NPC cases were confirmed by active follow-up approach and linkage to local cancer registry through the end of 2016. Cox proportional hazards regression analysis was performed to calculate the hazard ratios (HRs) for NPC risk with plasma EBV DNA. RESULTS: Thirty patients were newly diagnosed during a median 7.5 years follow-up. NPC incidence increased with the plasma EBV DNA load ranging from 281.46 to 10,074.47 per 100,000 person-years in participants with undetectable and ≥ 1000 copies/ml levels; the corresponding cumulative incidence rates were 1.73 and 50%. Furthermore, plasma EBV DNA loads conferred an independent risk for NPC development after adjustment for other risk factors, with HRs of 7.63 for > 3-999 copies/ml and 39.79 for ≥1000 copies/ml. However, the HRs decreased gradually after excluding NPC cases detected in the first 2 to 3 years and became statistically nonsignificant by excluding cases detected during the first 4 years. CONCLUSION: Elevated plasma EBV DNA can predict NPC risk over 3 years. Monitoring plasma EBV DNA can be used as a complementary approach to EBV serological antibody-based screening for NPC.

Development and validation of a flexible DNA extraction (PAN) method for liquid biopsy of multiple sample types.

BACKGROUND: Liquid biopsy is gaining increasing popularity in cancer screening and diagnosis. However, there is no relatively mature DNA isolation method or commercial kit available that is compatible with different LB sample types. This study developed a PAN-sample DNA isolation method (PAN method) for liquid biopsy samples. METHODS: The PAN method has two key steps, including biosample-specific pretreatments for various LB sample types and high concentration guanidine thiocyanate buffer for lysis and denaturation procedure. Subsequently, the performance of PAN method was validated by a series of molecular analyses. RESULTS: The PAN method was used to isolate DNA from multiple sample types related to LB, including plasma, serum, saliva, nasopharyngeal swab, and stool. All purified DNA products showed good quality and high quantity. Comparison of KRAS mutation analysis using DNA purified using PAN method versus QIAamp methods showed similar efficiency. Epstein-Barr virus DNA was detected via Q-PCR using DNA purified from serum, plasma, nasopharyngeal swab, and saliva samples collected from nasopharyngeal carcinoma patients. Similarly, methylation sequencing of swab and saliva samples revealed good coverage of target region and high methylation of HLA-DPB1 gene. Finally, 16S rDNA gene sequencing of saliva, swab, and stool samples successfully defines the relative abundance of microbial communities. CONCLUSIONS: This study developed and validated a PAN-sample DNA isolation method that can be used for different LB samples, which can be applied to molecular epidemiological research and other areas.

Chinese nonmedicinal herbal diet and risk of nasopharyngeal carcinoma: A population-based case-control study.

BACKGROUND: An association between a nonmedicinal herbal diet and nasopharyngeal carcinoma (NPC) has often been hypothesized but never thoroughly investigated. METHODS: This study enrolled a total of 2469 patients with incident NPC and 2559 population controls from parts of Guangdong and Guangxi Provinces in southern China between 2010 and 2014. Questionnaire information was collected on the intake of traditional herbal tea and herbal soup as well as the specific herbal plants used in soups and other potentially confounding lifestyle factors. Multivariate logistic regression models were used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for the NPC risk in association with herbal tea and soup intake. RESULTS: Ever consumption of herbal tea was not associated with NPC risk (OR, 1.03; 95% CI, 0.91-1.17). An inverse association was observed for NPC among ever drinkers of herbal soup (OR, 0.78; 95% CI, 0.67-0.90) but without any monotonic trend with an increasing frequency or duration of herbal soup consumption. Inverse associations with NPC risk were detected with 9 herbal plants used in herbal soup, including Ziziphus jujuba, Fructus lycii, Codonopsis pilosula, Astragalus membranaceus, Semen coicis, Smilax glabra, Phaseolus calcaratus, Morinda officinalis, and Atractylodes macrocephala (OR range, 0.31-0.79). CONCLUSIONS: Consuming herbal soups including specific plants, but not herbal tea, was inversely associated with NPC. If replicated, these results might provide potential for NPC prevention in endemic areas.

Multilaboratory Assessment of Epstein-Barr Virus Serologic Assays: the Case for Standardization.

IgA antibodies targeting Epstein-Barr virus (EBV) have been proposed for screening for nasopharyngeal carcinoma (NPC). However, methods differ, and the antigens used in these assays differ considerably between laboratories. To enable formal comparisons across a range of established EBV serology assays, we created a panel of 66 pooled serum samples and 66 pooled plasma samples generated from individuals with a broad range of IgA antibody levels. Aliquots from these panels were distributed to six laboratories and were tested by 26 assays measuring antibodies against VCA, EBNA1, EA-EBNA1, Zta, or EAd antigens. We estimated the correlation between assay pairs using Spearman coefficients (continuous measures) and percentages of agreement (positive versus negative, using predefined positivity cutoffs by each assay developer/manufacturer). While strong correlations were observed between some assays, considerable differences were also noted, even for assays that targeted the same protein. For VCA-IgA assays in serum, two distinct clusters were identified, with a median Spearman coefficient of 0.41 (range, 0.20 to 0.66) across these two clusters. EBNA1-IgA assays in serum grouped into a single cluster with a median Spearman coefficient of 0.79 (range, 0.71 to 0.89). Percentages of agreement differed broadly for both VCA-IgA (12% to 98%) and EBNA1-IgA (29% to 95%) assays in serum. Moderate-to-strong correlations were observed across assays in serum that targeted other proteins (correlations ranged from 0.44 to 0.76). Similar results were noted for plasma. We conclude that standardization of EBV serology assays is needed to allow for comparability of results obtained in different translational research studies across laboratories and populations.

Past and Recent Salted Fish and Preserved Food Intakes Are Weakly Associated with Nasopharyngeal Carcinoma Risk in Adults in Southern China.

BACKGROUND: Chinese-style salted fish intake in early life is considered an established risk factor for nasopharyngeal carcinoma (NPC). However, results for adult intakes of salted fish and preserved foods are inconsistent. OBJECTIVE: The aim of this study was to ascertain the relations of Chinese-style hard and soft salted fish and preserved food intakes with NPC risk. METHODS: We conducted a population-based case-control study in southern China with 2554 NPC cases identified through a rapid case ascertainment system and 2648 healthy controls, frequency-matched on age, sex, and area. Subjects (aged 20-74 y) were interviewed via a food-frequency questionnaire, including information on portion size. Data were also collected on alcohol consumption and potential confounders. Food intake was grouped into 3-5 energy-adjusted intake levels during adulthood (10 y prior) and adolescence (16-18 y). For childhood (at age 10 y), intake frequency of selected food items was collected. Multivariate-adjusted ORs with 95% CIs were estimated via logistic regression. RESULTS: We found no association between NPC and intake of hard Chinese-style salted fish during adulthood, and an increased risk at the highest level of intake during adolescence (OR: 1.19; 95% CI: 1.03, 1.39). In contrast, we found a decreased risk for the middle intake level of soft salted fish during adulthood (OR: 0.68; 95% CI: 0.57, 0.81) and adolescence (OR: 0.71; 95% CI: 0.59, 0.85). Preserved foods showed contrasting risk profiles, e.g., the highest adult intake level of salted egg (OR: 1.51; 95% CI: 1.22, 1.87) and fermented black beans (OR: 0.67; 95% CI: 0.56, 0.80). Associations with NPC were weaker than previously reported, e.g., for weekly childhood intake of salted fish (OR: 1.56; 95% CI: 1.24, 1.97). CONCLUSIONS: Hard and soft salted fish have different risk profiles. Salted fish and other preserved foods were at most weak risk factors for NPC in all periods and may play a smaller role in NPC occurrence than previously thought.

Medical History, Medication Use, and Risk of Nasopharyngeal Carcinoma.

Because persistent inflammation may render the nasopharyngeal mucosa susceptible to carcinogenesis, chronic ear-nose-throat (ENT) disease and its treatment might influence the risk of nasopharyngeal carcinoma (NPC). Existing evidence is, however, inconclusive and often based on methodologically suboptimal epidemiologic studies. In a population-based case-control study in southern China, we enrolled 2,532 persons with NPC and 2,597 controls, aged 20-74 years, from 2010 to 2014. Odds ratios were estimated for associations between NPC risk and history of ENT and related medications. Any history of chronic ENT disease was associated with a 34% increased risk of NPC. Similarly, use of nasal drops or aspirin was associated with approximately doubled risk of NPC. However, in secondary analyses restricted to chronic ENT diseases and related medication use at least 5 years prior to diagnosis/interview, most results were statistically nonsignificant, except a history of uncured ENT diseases, untreated nasal polyps, and earlier age at first diagnosis of ENT disease and first or most recent aspirin use. Overall, these findings suggest that ENT disease and related medication use are most likely early indications rather than causes of NPC, although the possibility of a modestly increased NPC risk associated with these diseases and related medications cannot be excluded.

Active and Passive Smoking and Risk of Nasopharyngeal Carcinoma: A Population-Based Case-Control Study in Southern China.

The magnitude and patterns of associations between smoking and risk of nasopharyngeal carcinoma (NPC) in high-incidence regions remain uncertain. Associations with active and passive tobacco smoking were estimated using multivariate logistic regression in a population-based case-control study of 2,530 NPC cases and 2,595 controls in Guangdong and Guangxi, southern China, in 2010-2014. Among men, risk of NPC was significantly higher in current smokers compared with never smokers (odds ratio (OR) = 1.32, 95% confidence interval (CI): 1.14, 1.53) but not in former smokers (OR = 0.92, 95% CI: 0.73, 1.17). Risk increased with smoking intensity (per 10 cigarettes/day, OR = 1.09, 95% CI: 1.03, 1.16), smoking duration (per 10 years, OR = 1.11, 95% CI: 1.06, 1.16), and cumulative smoking (per 10 pack-years, OR = 1.08, 95% CI: 1.04, 1.12). Risk decreased with later age at smoking initiation (per year, OR = 0.97, 95% CI: 0.96, 0.98) but not greater time since smoking cessation. Exposures to passive smoking during childhood (OR = 1.24, 95% CI: 1.03, 1.48) and from a spouse during adulthood (OR = 1.30, 95% CI: 1.03, 1.63) were independently associated with increased NPC risk in never-smoking men and women, but exposure-response trends were not observed. In conclusion, active and passive tobacco smoking are associated with modestly increased risk of NPC in southern China; risk is highest among long-term smokers.

Quantification of familial risk of nasopharyngeal carcinoma in a high-incidence area.

BACKGROUND: To the authors' knowledge, no studies to date have explored familial risks of nasopharyngeal carcinoma (NPC) in detail and quantified its lifetime risk in high-incidence populations. METHODS: The authors conducted a population-based case-control study of 2499 NPC cases and 2576 controls randomly selected in southern China from 2010 through 2014. Unconditional logistic regression was used to estimate multivariable-adjusted odds ratios (ORs) with 95% confidence intervals (95% CIs) associated with a family history of NPC. In addition, the authors compiled a reconstructed cohort comprising 40,781 first-degree relatives of cases and controls to calculate the lifetime cumulative risk of NPC. RESULTS: Individuals with a first-degree family history of NPC were found to be at a >4-fold risk of NPC (OR, 4.6; 95% CI, 3.5-6.1) compared with those without such a history, but had no excess risk of other malignancies. The excess risk was higher for a maternal than a paternal history and was slightly stronger for a sibling compared with a parental history, and for a sororal than a fraternal history. Among relatives of cases, the cumulative risk of NPC up to age 74 years was 3.7% (95% CI, 3.3%-4.2%), whereas that among relatives of controls was 0.9% (95% CI, 0.7%-1.2%). Cumulative risk was higher in siblings than in parents among relatives of cases, whereas no such difference was noted among relatives of controls. CONCLUSIONS: Individuals with a family history of NPC have a substantially higher risk of NPC. These relative and cumulative risk estimates can guide the development of strategies for early detection and clinical consultation in populations with a high incidence of NPC. Cancer 2017;123:2716-25. © 2017 American Cancer Society.

Estimation of cancer burden in Guangdong Province, China in 2009.

BACKGROUND: Surveying regional cancer incidence and mortality provides significant data that can assist in making health policy for local areas; however, the province- and region-based cancer burden in China is seldom reported. In this study, we estimated cancer incidence and mortality in Guangdong Province, China and presented basic information for making policies related to health resource allocation and disease control. METHODS: A log-linear model was used to calculate the sex-, age-, and registry-specific ratios of incidence to mortality (I/M) based on cancer registry data from Guangzhou, Zhongshan, and Sihui between 2004 and 2008. The cancer incidences in 2009 were then estimated according to representative I/M ratios and the mortality records from eight death surveillance sites in Guangdong Province. The cancer incidences in each city were estimated by the corresponding sex- and age-specific incidences from cancer registries or death surveillance sites in each area. Finally, the total and region-based cancer incidences and mortalities for the entire population of Guangdong Province were summarized. RESULTS: The estimated I/M ratios in Guangzhou (3.658), Zhongshan (2.153), and Sihui (1.527) were significantly different (P < 0.001), with an average I/M ratio of 2.446. Significant differences in the estimated I/M ratios were observed between distinct age groups and the three cancer registries. The estimated I/M ratio in females was significantly higher than that in males (2.864 vs. 2.027, P < 0.001). It was estimated that there were 163,376 new cancer cases (99,689 males and 63,687 females) in 2009; it was further estimated that 115,049 people (75,054 males and 39,995 females) died from cancer in Guangdong Province in 2009. The estimated crude and age-standardized rate of incidences (ASRI) in Guangdong Province were 231.34 and 246.87 per 100,000 males, respectively, and 156.98 and 163.57 per 100,000 females, respectively. The estimated crude and age-standardized rate of mortalities (ASRM) in Guangdong Province were 174.17 and 187.46 per 100,000 males, respectively, and 98.59 and 102.00 per 100,000 females, respectively. In comparison with the western area and the northern mountain area, higher ASRI and ASRM were recorded in the Pearl River Delta area and the eastern area in both males and females. CONCLUSIONS: Cancer imposes a heavy disease burden, and cancer patterns are unevenly distributed throughout Guangdong Province. More health resources should be allocated to cancer control, especially in the western and northern mountain areas.

Incidence trend of nasopharyngeal carcinoma from 1987 to 2011 in Sihui County, Guangdong Province, South China: an age-period-cohort analysis.

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 the 1922 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.

Secular trend analysis of lung cancer incidence in Sihui city, China between 1987 and 2011.

BACKGROUND: With industrial and econom ic development in recent decades in South China, cancer incidence may have changed due to the changing lifestyle and environment. However, the trends of lung cancer and the roles of smoking and other environmental risk factors in the development of lung cancer in rural areas of South China remain unclear. The purpose of this study was to explore the lung cancer incidence trends and the possible causes of these trends. METHODS: Joinpoint regression analysis and the age-period-cohort (APC) model were used to analyze the lung cancer incidence trends in Sihui, Guangdong province, China between 1987 and 2011, and explore the possible causes of these trends. RESULTS: A total of 2,397 lung cancer patients were involved in this study. A 3-fold increase in the incidence of lung cancer in both sexes was observed over the 25-year period. Joinpoint regression analysis showed that while the incidence continued to increase steadily in females during the entire period, a sharp acceleration was observed in males starting in 2005. The full APC model was selected to describe age, period, and birth cohort effects on lung cancer incidence trends in Sihui. The age cohorts in both sexes showed a continuously significant increase in the relative risk (RR) of lung cancer, with a peak in the eldest age group (80-84 years). The RR of lung cancer showed a fluctuating curve in both sexes. The birth cohorts identified an increased trend in both males and females; however, males had a plateau in the youngest cohorts who were born during 1955-1969. CONCLUSIONS: Increasing trends of the incidence of lung cancer in Sihui were dominated by the effects of age and birth cohorts. Social aging, smoking, and environmental changes may play important roles in such trends.

Evaluation of plasma Epstein-Barr virus DNA load to distinguish nasopharyngeal carcinoma patients from healthy high-risk populations in Southern China.

BACKGROUND: The utility of circulating Epstein-Barr Virus (EBV) DNA as a tumor marker for nasopharyngeal carcinoma (NPC) detection suggests that it might improve the diagnostic performance of anti-EBV antibody markers in NPC screening. In this study, the authors evaluated whether circulating EBV DNA load is capable of distinguishing NPC patients from high-risk individuals who have positive anti-EBV antibodies. METHODS: In a population-based NPC screening trial in Sihui City and Zhongshan City, Guangdong Province, China, the authors previously identified 862 high-risk participants with 2 screening markers, immunoglobulin A (IgA) antibodies to EBV capsid antigen (VCA/IgA) and nuclear antigen-1 (EBNA1/IgA). In the current study, real-time polymerase chain reaction was used to measure the baseline plasma EBV DNA load among 825 participants (97%). Follow-up was extended to the end of 2011 to evaluate the diagnostic and predictive values of plasma EBV DNA load. RESULTS: By using 0 copies/mL as the cutoff value, plasma EBV DNA had a sensitivity of 86.8% (33 of 38 patients) for NPC detected within the first year of follow-up, yielding a positive predictive value of 30% (33 of 110 participants) and a negative predictive value of 99.3% (696 of 701 participants). The patients who had early stage NPC had lower sensitivity (81.5%; 22 of 27 patients) than those who had advanced NPC (100%; 11 of 11 patients). For the 14 patients who had NPC detected after 1 year of follow-up, only 50% (7 of 14 patients) tested positive for EBV DNA at baseline. CONCLUSIONS: The plasma EBV DNA load may improve the accuracy of diagnosing NPC in high-risk individuals, but it appears to have limited value in screening patients who have early stage NPC and predicting NPC development.

Host genetic variants, Epstein-Barr virus subtypes, and the risk of nasopharyngeal carcinoma: Assessment of interaction and mediation.

Epstein-Barr virus (EBV) and human leukocyte antigen (HLA) polymorphisms are well-known risk factors for nasopharyngeal carcinoma (NPC). However, the combined effects between HLA and EBV on the risk of NPC are unknown. We applied a causal inference framework to disentangle interaction and mediation effects between two host HLA SNPs, rs2860580 and rs2894207, and EBV variant 163364 with a population-based case-control study in NPC-endemic southern China. We discovered the strong interaction effects between the high-risk EBV subtype and both HLA SNPs on NPC risk (rs2860580, relative excess risk due to interaction [RERI] = 4.08, 95% confidence interval [CI] = 2.03-6.14; rs2894207, RERI = 3.37, 95% CI = 1.59-5.15), accounting for the majority of genetic risk effects. These results indicate that HLA genes and the high-risk EBV have joint effects on NPC risk. Prevention strategies targeting the high-risk EBV subtype would largely reduce NPC risk associated with EBV and host genetic susceptibility.

Two Epstein-Barr virus-related serologic antibody tests in nasopharyngeal carcinoma screening: results from the initial phase of a cluster randomized controlled trial in Southern China.

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.

Associations between serum trace elements and the risk of nasopharyngeal carcinoma: a multi-center case-control study in Guangdong Province, southern China.

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

Association between solid fuel use and seropositivity against Epstein-Barr virus in a high-risk area for nasopharyngeal carcinoma.

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.