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.

Autocrine INSL5 promotes tumor progression and glycolysis via activation of STAT5 signaling.

Metabolic reprogramming plays important roles in development and progression of nasopharyngeal carcinoma (NPC), but the underlying mechanism has not been completely defined. In this work, we found INSL5 was elevated in NPC tumor tissue and the plasma of NPC patients. Plasma INSL5 could serve as a novel diagnostic marker for NPC, especially for serum VCA-IgA-negative patients. Moreover, higher plasma INSL5 level was associated with poor disease outcome. Functionally, INSL5 overexpression increased, whereas knockdown of its receptor GPCR142 or inhibition of INSL5 reduced cell proliferation, colony formation, and cell invasion in vitro and tumorigenicity in vivo. Mechanistically, INSL5 enhanced phosphorylation and nuclear translocation of STAT5 and promoted glycolytic gene expression, leading to induced glycolysis in cancer cells. Pharmaceutical inhibition of glycolysis by 2-DG or blockade of INSL5 by a neutralizing antibody reversed INSL5-induced proliferation and invasion, indicating that INSL5 can be a potential therapeutic target in NPC. In conclusion, INSL5 enhances NPC progression by regulating cancer cell metabolic reprogramming and is a potential diagnostic and prognostic marker as well as a therapeutic target for NPC.

Incidence and mortality of liver cancer in China, 2010.

Liver cancer is a common malignant tumor in China and a major health concern. We aimed to estimate the liver cancer incidence and mortality in China in 2010 using liver cancer data from some Chinese cancer registries and provide reference for liver cancer prevention and treatment. We collected and evaluated the incidence and mortality data of liver cancer in 2010 from 145 cancer registries, which were included in the 2013 Chinese Cancer Registry Annual Report, calculated crude, standardized, and truncated incidences and mortalities, and estimated new liver cancer cases and deaths from liver cancer throughout China and in different regions in 2010 from Chinese practical population. The estimates of new liver cancer cases and deaths were 358,840 and 312,432, respectively, in China in 2010. The crude incidence, age-standardized rate by Chinese standard population (ASR China), and age-standardized rate by world standard population (ASR world) were 27.29/100,000, 21.35/100,000, and 20.87/100,000, respectively; the crude, ASR China, and ASR world mortalities were 23.76/100,000, 18.43/100,000, and 18.04/100,000, respectively. The incidence and mortality were the highest in western regions, higher in rural areas than in urban areas, and higher in males than in females. The age-specific incidence and mortality of liver cancer showed a rapid increase from age 30 and peaked at age 80-84 or 85+. Our results indicated that the 2010 incidence and mortality of liver cancer in China, especially in undeveloped rural areas and western regions, were among high levels worldwide. The strategy for liver cancer prevention and treatment should be strengthened.

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.

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.

[Expressions of p53 pathway genes and EZH2 in undifferentiated nasopharyngeal carcinoma].

OBJECTIVE: To investigate the relationship between the expressions of p53 pathway genes and EZH2 in nasopharyngeal carcinoma (NPC). METHODS: The expression levels of p53, mdm2, p63 and EZH2 proteins were detected by immunohistochemistry in 47 cases of undifferentiated NPC and 12 cases of chronic nasopharyngitis, and their correlation to the clinical parameters and prognosis were analyzed. RESULTS: The protein expressions of p53, mdm2, p63 and EZH2 in NPC were 31.9%, 85.1%, and 95.7%, respectively. mdm2 and EZH2 was not correlated to p53 protein expression (P>0.05); positive correlations was found between EZH2 and p63 expressions and between p53 and p63. The high expression of EZH2 and p63 proteins was correlated to advanced T stage and clinical stage of NPC (P<0.05). The five-year disease-free survival rate in patients with high EZH2 protein expression was significantly lower than that in patients with low EZH2 expression. CONCLUSION: mdm2 does not show an obvious correlation to p53 protein inactivation in NPC. p63 protein overexpression may be associated with p53 protein inactivation. The overexpression of EZH2 is correlated to NPC progression and poor prognosis.

Detection of Stage I nasopharyngeal carcinoma by serologic screening and clinical examination.

In a prospective study, 42 048 adults residing in Zhongshan City, Guangdong, China, were followed for 16 years, and 171 of them developed nasopharyngeal carcinoma (NPC). Although Epstein-Barr virus (EBV) antibody levels of the cohort fluctuated, the antibody levels of 93% of the patients with NPC were raised and maintained at high levels for up to 10 years prior to diagnosis. This suggests that the serologic window affords an opportunity to monitor tumor progression during the preclinical stage of NPC development, facilitating early NPC detection. We reviewed the clinical records of the 171 patients with NPC in the prospective study to assess the efficacy of early NPC detection by serologic screening and clinical examination. Of the 171 patients, 51 had Stage I tumor (44 were among the 73 patients detected by clinical examination and 7 were among the 98 patients presented to outpatient department). Initial serologic screening predicted 58 (95.1%) of the 61 patients detected within 2 years. The risk of the screened population (58/3093) raised 13 times relative to cohort (61/42 048) during this period. Clinical examination detected all the 58 predicted cases, and 35 (60.3%) of which were diagnosed with Stage I tumor. The serologic prediction rate fell to 33.6% (37/110) 2 to 16 years after screening. The proportion of cases detected by clinical examination fell to 40.5% (15/37). The proportion of Stage I tumors among the cases detected by clinical examination during both periods remained at about 60%. We concluded that early detection of NPC can be accomplished by repeated serologic screening to maintain high prediction rates and by promptly examining screened subjects to detect tumors before the symptoms develop.

Epidemiological trends of nasopharyngeal carcinoma in China.

Research papers and data concerning NPC epidemiology in China available worldwide were reviewed. It was found that although the results of three national all death-causes sampling surveys in China showed mortality rates in most sampling areas and all as overall to be declining continuously and remarkably, figures for 1987-2000 in some selected areas of China released by the World Health Organization were relatively stable, and the NPC incidence and mortality rates reported by Zhongshan and Sihui cities of Guangdong Province in China had shown ascending or stable trends, respectively. Differences with regard to change in NPC incidence and mortality rates over time may be caused by variation in the data quality from divergent sources, but the exact reasons clearly warrant further analysis.

[Six anti-Epstein-Barr virus antibodies in healthy adults in a high risk area of nasopharyngeal carcinoma].

BACKGROUND AND OBJECTIVE: Nasopharyngeal carcinoma (NPC), with a remarkable geographic distribution, is consistently associated with Epstein-Barr virus (EBV) infection, and almost all NPC patients have sustained high levels of serum antibodies against EBV. This study was to compare the levels of six anti-EBV antibodies in healthy natives of Zhongshan (a high-incidence area of NPC) with those in provisional migrants from foreign provinces (low-incidence areas of NPC), and to illustrate the relationship between EBV infection and the geographic distribution of NPC. METHODS: The serum levels of EBNA1-IgA, EBNA1-IgG, VCA-p18-IgA, VCA-p18-IgG, Zta-IgA and Zta-IgG in 303 healthy Zhongshan natives and 92 provisional migrants were tested using ELISA, and presented by values of adjusted relative absorbance (ArA). The serum levels and positive rates of the six antibodies were compared between the two groups. RESULTS: The mean ArA values of both Zta-IgA and VCA-p18-IgA were significantly higher in Zhongshan natives than in provisional migrants (0.84+/-0.03 vs. 0.42+/-0.04, P <0.05; 0.96+/-0.05 vs. 0.40+/-0.05, P<0.05). In addition, the positive rates of Zta-IgA and VCA-p18-IgA in subjects aged of 30-49, or of 50 and above were significantly higher in Zhongshan natives than in provisional migrants (29.27% vs. 3.03% and 48.28% vs. 6.67% for Zta-IgA, P<0.05; 28.46% vs. 9.09% and 43.10% vs. 13.33% for VCA-p18-igA, P<0.05). CONCLUSION: Zhongshan natives are likely to have an elevation of serum IgA antibodies against EBV lytic antigens (Zta and VCA-p18), which represents reactivation of EBV latency infection and implies that Zhongshan natives may have higher risk to develop NPC than provisional migrants.

[Effects of paclitaxel and 5-fluorouracil on growth inhibition and apoptosis of hepatoma cells: a comparative study].

OBJECTIVE: To investigate the effect of paclitaxel and 5-flurouracil (5-Fu) on growth inhibition and apoptosis of human hepatoma BEL-7402 cells. METHODS: Growth inhibition of BEL-7402 cells treated with paclitaxel and 5-Fu, respectively, was measured by ATP-tumor chemosensitivity assay (ATP-TCA), and the cell cycle kinetics and apoptosis were analyzed by flow cytometry and microscopic examination. RESULTS: BEL-7402 cells were highly sensitive to paclitaxel with growth inhibition observed in both dose- and time-dependent manners (IC(50)=5.58 x 10(-7) mol/L). Paclitaxel induced significantly higher rate of cell apoptosis than the control group (P<0.05) but significantly lower rate than that induced by 5-Fu (P<0.01). Necrosis was observed predominantly in paclitaxel-treated cells whereas 5-Fu caused mainly cell apoptosis (P<0.05). Levels of apoptosis increased in proportion to the decrement of paclitaxel concentration but directly proportional to increment of 5-Fu concentration. CONCLUSIONS: Paclitaxel and 5-Fu are effective in inducing growth inhibition and apoptosis of BEL-7402 cells. While 5-Fu causes mainly apoptosis in hepatoma cells, the anticancer mechanism of paclitaxel is predominantly through induction of necrosis.

[A dynamic study on titer of EB virus VCA/IgA and EA/IgA in nasopharygeal carcinoma patients].

OBJECTIVE: To analyze the change of EB virus VCA/IgA and EA/IgA titer during the development of nasopharyngeal carcinoma (NPC), and the role in screening for NPC. METHODS: VCA/IgA and EA/IgA were monitored in a period of 12 years by immunoenzymatic titration from the sera of 54 NPC patients after primary serological screening. RESULTS: VCA/IgA and EA/IgA titer had shown gradual increment 1 - 7 years before NPC was pathologically diagnosed. The mean titer of VCA/IgA was 1:21.04, 7 - 4 years before diagnosis. VCA/IgA titer ascended quickly within 3 years before diagnosis. The geometric mean titer (GMT) of VCA/IgA and EA/IgA were 1:76.86 and 1:6.49 when NPC was diagnosed, which descended quickly after radiotherapy and, in 4 years, approached the average titer of VCA/IgA positive population. CONCLUSION: VCA/IgA titer rises uninterruptedly 3 years before NPC is diagnosed pathologically in most patients but their EA/IgA titer rises slowly. The detection of VCA/IgA titer can be used to find early NPC, whereas EA/IgA can not. The pre-clinical phase of NPC is 3 years according to this dynamic study.

[Clinical analysis and long-term follow up study of asymptomatic nasopharyngeal carcinoma patients].

OBJECTIVE: To observe the character of Epstein-Barr(EB) virus serology, fibroscopy appearance and prognosis of asymptomatic nasopharyngeal carcinoma(NPC). METHODS: Viral capsid antigen's IgA (VCA/IgA) of EB virus and early antigen's IgA(EA/IgA) of EB virus were detected by immunoenzymatic method. The clinical examination was carried out, including indirect mirror examination and fibroscopy of the nasopharynx and multiple biopsies. All patients of NPC were followed up to the end of 1999. RESULTS: 1. The geometric mean titer of VCA/IgA and EA/IgA are 1:100.79 and 1:10.76 respectively when asymptomatic NPC was diagnosed. There were no significant difference between VCA/IgA and EA/IgA antibody titres of asymptomatic patients and symptomatic cases (P > 0.05). The survival rates in these asymptomatic cases were higher than symptomatic patients (P < 0.05). 2. There was no correlation with the VCA/IgA or EA/IgA titer and the prognosis (P > 0.05) and the cervical lymph node metastasis (P > 0.05) when NPC was diagnosed. CONCLUSION: This is helpful to detect asymptomatic NPCs by EB serological screening periodically and nasopharyngeal fibroscopy and multiple biopsies.

[Detection of serum Epstein-Barr virus antibody level by ELISA in normal populations and nasopharyngeal carcinoma patients in Zhongshan City of China].

OBJECTIVE: To understand the distribution of Epstein-Barr virus (EBV) antibodies, namely EBNA 1/IgA, ZEBRA/IgA, EBNA 1/IgG in the populations of different ages or genders in Zhongshan City of Guangdong Province, China. METHOD: A total of 484 serum samples were obtained from the population of Zhongshan City including 16 patients with nasopharyngeal carcinoma (NPC) and were assayed with enzyme-linked immunosorbent assay (ELISA) for EBV antibodies. RESULTS: The serum antibody level of EBNA1/IgA, represented by its relative optical density value abbreviated as D(lambda), was 0.726 +/- 0.541 in male and 0.563 +/- 0.340 in female subjects, showing significant difference (P<0.001). The level of ZEBRA/IgG in the male subjects was significantly lower than that of the female subjects (0.709 +/- 0.480 vs 0.829 +/- 0.480, P<0.01). EBNA1/IgG levels differed little between the male and the female subjects, being 0.781 +/- 0.285 and 0.784 +/- 0.302 respectively (P<0.05). The positivity rate of ZEBRA/IgG was obviously related to the subjects' ages with a correlation factor of 0.766 (P<0.05), and NPC patients had significantly higher levels of the 3 antibodies than did the healthy subjects (P<0.01). CONCLUSIONS: The serum levels of these 3 antibodies fluctuate within a limited range in different age groups or between genders, significant increasing in NPC group and therefore may help the diagnosis of NPC. It can be imperative to set differently critical values of EBV antibody for different population groups to facilitate nasopharyngeal carcinoma (NPC) diagnosis and high-risk screening.

Assessing the risk of nasopharyngeal carcinoma on the basis of EBV antibody spectrum.

We have evaluated the performance of 3 new EBV ELISA for the diagnosis of nasopharyngeal carcinoma (NPC). The tests were specific for EBNA 1 IgA, EBNA 1 IgG and zta IgG, respectively. Their distinct antigenic specificity permits these assays to be used in concert in an approach that differentiates patients and apparently healthy subjects on the basis of their antibody spectrum. By so exploiting a distinguishing feature of NPC first described by Lloyd Olds and his group (Olds et al., Proc Nat Acad Sci 1966;56:1699-1704) [corrected] that the patients sustain high levels of a broad spectrum of serum EBV antibodies, this approach achieved a sensitivity of 92% and a specificity of 93%, surpassing the performance of each of these assays individually. The enhanced performance is especially useful in population screening. It was shown that relative risk of NPC sustained by apparently healthy subjects residing in a high incidence area for NPC in the Pearl River estuary in Southern China may vary according to EBV antibody spectrum. The risk of the cancer was markedly reduced with odds ratios of 0.009 for 59% of those who had low level of all 3 antibodies. The risk was increased as antibody spectrum broadens and the risk was the highest with an odds ratio of 138 for 0.4% of those who had high levels of all 3 antibodies. Thus, EBV antibody spectrum may serve to guide follow-up measures for early detection of the cancer and/or risk counseling according to level of the risk of the cancer sustained by the screened individuals.