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1.  Burden of Total and Cause-Specific Mortality Related to Tobacco Smoking among Adults Aged ≥45 Years in Asia: A Pooled Analysis of 21 Cohorts 
PLoS Medicine  2014;11(4):e1001631.
Wei Zheng and colleagues quantify the burden of tobacco-smoking-related deaths for adults in Asia.
Please see later in the article for the Editors' Summary
Background
Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men's smoking prevalence is among the world's highest.
Methods and Findings
We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged ≥45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan—accounting for ∼71% of Asia's total population. An approximately 1.44-fold (95% CI = 1.37–1.51) and 1.48-fold (1.38–1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CI = 14.3%–17.2%) and 3.3% (2.6%–4.0%) of deaths, respectively, in men and women aged ≥45 y in the seven countries/regions combined, with a total number of estimated deaths of ∼1,575,500 (95% CI = 1,398,000–1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: a 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged ≥45 y.
Conclusions
Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged ≥45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, more than 5 million smokers die from tobacco-related diseases. Tobacco smoking is a major risk factor for cardiovascular disease (conditions that affect the heart and the circulation), respiratory disease (conditions that affect breathing), lung cancer, and several other types of cancer. All told, tobacco smoking kills up to half its users. The ongoing global “epidemic” of tobacco smoking and tobacco-related diseases initially affected people living in the US and other Western countries, where the prevalence of smoking (the proportion of the population that smokes) in men began to rise in the early 1900s, peaking in the 1960s. A similar epidemic occurred in women about 40 years later. Smoking-related deaths began to increase in the second half of the 20th century, and by the 1990s, tobacco smoking accounted for a third of all deaths and about half of cancer deaths among men in the US and other Western countries. More recently, increased awareness of the risks of smoking and the introduction of various tobacco control measures has led to a steady decline in tobacco use and in smoking-related diseases in many developed countries.
Why Was This Study Done?
Unfortunately, less well-developed tobacco control programs, inadequate public awareness of smoking risks, and tobacco company marketing have recently led to sharp increases in the prevalence of smoking in many low- and middle-income countries, particularly in Asia. More than 50% of men in many Asian countries are now smokers, about twice the prevalence in many Western countries, and more women in some Asian countries are smoking than previously. More than half of the world's billion smokers now live in Asia. However, little is known about the burden of tobacco-related mortality (deaths) in this region. In this study, the researchers quantify the risk of total and cause-specific mortality associated with tobacco use among adults aged 45 years or older by undertaking a pooled statistical analysis of data collected from 21 Asian cohorts (groups) about their smoking history and health.
What Did the Researchers Do and Find?
For their study, the researchers used data from more than 1 million participants enrolled in studies undertaken in Bangladesh, India, mainland China, Japan, the Republic of Korea, Singapore, and Taiwan (which together account for 71% of Asia's total population). Smoking prevalences among male and female participants were 65.1% and 7.1%, respectively. Compared with never-smokers, ever-smokers had a higher risk of death from any cause in pooled analyses of all the cohorts (adjusted hazard ratios [HRs] of 1.44 and 1.48 for men and women, respectively; an adjusted HR indicates how often an event occurs in one group compared to another group after adjustment for other characteristics that affect an individual's risk of the event). Compared with never smoking, ever smoking was associated with a higher risk of death due to cardiovascular disease, cancer (particularly lung cancer), and respiratory disease among Asian men and among East Asian women. Moreover, the researchers estimate that, in the countries included in this study, tobacco smoking accounted for 15.8% of all deaths among men and 3.3% of deaths among women in 2004—a total of about 1.5 million deaths, which scales up to 2 million deaths for the population of the whole of Asia. Notably, in 2004, tobacco smoking accounted for 60.5% of lung-cancer deaths among Asian men and 16.7% of lung-cancer deaths among East Asian women.
What Do These Findings Mean?
These findings provide strong evidence that tobacco smoking is associated with a substantially raised risk of death among adults aged 45 years or older throughout Asia. The association between smoking and mortality risk in Asia reported here is weaker than that previously reported for Western countries, possibly because widespread tobacco smoking started several decades later in most Asian countries than in Europe and North America and the deleterious effects of smoking take some years to become evident. The researchers note that certain limitations of their analysis are likely to affect the accuracy of its findings. For example, because no data were available to estimate the impact of secondhand smoke, the estimate of deaths attributable to smoking is likely to be an underestimate. However, the finding that nearly 45% of the global deaths from active tobacco smoking occur in Asia highlights the urgent need to implement comprehensive tobacco control programs in Asia to reduce the burden of tobacco-related disease.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001631.
The World Health Organization provides information about the dangers of tobacco (in several languages) and about the WHO Framework Convention on Tobacco Control, an international instrument for tobacco control that came into force in February 2005 and requires parties to implement a set of core tobacco control provisions including legislation to ban tobacco advertising and to increase tobacco taxes; its 2013 report on the global tobacco epidemic is available
The US Centers for Disease Control and Prevention provides detailed information about all aspects of smoking and tobacco use
The UK National Health Services Choices website provides information about the health risks associated with smoking
MedlinePlus has links to further information about the dangers of smoking (in English and Spanish)
SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
doi:10.1371/journal.pmed.1001631
PMCID: PMC3995657  PMID: 24756146
2.  Optimal Positive Cutoff Points for careHPV Testing of Clinician- and Self-Collected Specimens in Primary Cervical Cancer Screening: an Analysis from Rural China 
Journal of Clinical Microbiology  2014;52(6):1954-1961.
careHPV, a lower-cost DNA test for human papillomavirus (HPV), is being considered for cervical cancer screening in low- and middle-income countries. However, not a single large-scaled study exists to investigate the optimal positive cutoff point of careHPV test. We pooled data for 9,785 women participating in two individual studies conducted from 2007 to 2011 in rural China. Woman underwent multiple screening tests, including careHPV on clinician-collected specimens (careHPV-C) and self-collected specimens (careHPV-S), and Hybrid Capture 2 on clinician-collected specimens (HC2-C) as a reference standard. The primary endpoint was cervical intraepithelial neoplasia grade 3 or more severe (CIN3+) (n = 127), and secondary endpoint was CIN2+ (n = 213). The area under the curves (AUCs) for HC2-C and careHPV-C were similar (0.954 versus 0.948, P = 0.166), and better than careHPV-S (0.878; P < 0.001 versus both). The optimal positive cutoff points for HC2-C, careHPV-C, and careHPV-S were 1.40, 1.74, and 0.85, respectively. At the same cutoff point, careHPV-C was not significantly less sensitive and more specific for CIN3+ than HC2-C, and careHPV-S was significantly less sensitive for CIN3+ than careHPV-C and HC2-C. Raising the cutoff point of careHPV-C from 1.0 to 2.0 could result in nonsignificantly lower sensitivity but significantly higher specificity. Similar results were observed using CIN2+ endpoint. careHPV using either clinician- or self-collected specimens performed well in detecting cervical precancer and cancer. We found that the optimal cutoff points of careHPV were 2.0 on clinician-collected specimens and 1.0 on self-collected specimens.
doi:10.1128/JCM.03432-13
PMCID: PMC4042749  PMID: 24671789
3.  Pooled Analysis of Performance of Liquid Based Cytology in Population-Based Cervical Cancer Screening Studies in China 
Cancer cytopathology  2013;121(9):473-482.
Background
Liquid based cytology (LBC) has been widely used for cervical cancer screening. Despite numerous studies and systematic reviews, few large studies have focused on biopsy-confirmed cervical lesions and controversy remains about its diagnostic accuracy. The aim of our study was to assess LBC for detecting biopsy-confirmed cervical intraepithelial neoplasia (CIN) and cancer.
Methods
We performed a pooled analysis of LBC using data from 13 population-based, cross-sectional, cervical-cancer screening studies performed in China from 1999 to 2008. Participants (n = 26782) received LBC and HPV testing. Screen-positive women were referred for colposcopy and biopsy. We analyzed the accuracy of LBC for detecting biopsy-confirmed CIN2 or worse lesion (CIN2+) as well as CIN3 or worse lesion (CIN3+).
Results
Of 25830 women included in the analysis, CIN2+ was found in 107/2612(4.1%) with ASC, 142/923 (15.4%) with LSIL, 512/784 (65.3%) with HSIL, 29/30 (96.7%) with SCC, 4/27(14.8%) with AGC, and 0.4% (85/21454) with normal cytology results. No invasive cancers had ASC, AGC or cytological normal slides. The overall sensitivity, specificity, PPV, NPV and accuracy of LBC for detecting CIN2+ were 81.0%, 95.4%, 38.3%, 99.3 % and 94.9% respectively. Although HC2 was more sensitive than LBC, the specificity, PPV and overall accuracy of LBC were higher than those of HC2, at 85.2%, 18.6% and 85.5%, respectively.
Conclusions
The results indicate that performance of LBC can effectively predict a risk of existing CIN2+ and may be a good screening tool for cervical cancer prevention in a developing country.
doi:10.1002/cncy.21297
PMCID: PMC3775994  PMID: 23907807
Pool analysis; liquid-based cytology; Population-based; cervical cancer; screening
6.  Evaluation of routine biopsies in endoscopic screening for esophagogastric junction cancer 
AIM: To explore whether routine biopsies at the high incidence spot of esophagogastric junction (EGJ) cancer are justified in endoscopic screening.
METHODS: This was a multicenter population-based study conducted in eight high-risk areas in China. A total of 37396 participants underwent endoscopic examination. Biopsies were obtained from visible mucosal abnormalities or from normal-appearing mucosa at the high incidence spot of esophagogastric junction cancer when no abnormality was detected. Specimens showing high-grade intraepithelial neoplasia (HIN) or higher grade lesions were deemed as pathologically “positive”. The ratios of positive pathologic diagnosis between participants with abnormal and normal-appearing mucosa were compared using the Pearson χ2 test. Odds ratios and 95% confidence intervals, adjusted for potential confounders, were calculated using logistic regression.
RESULTS: A total of 37520 individuals participated in this study and 37396 (99.7%) participants had full information and were suitable for analysis. During endoscopic examinations, 9.11% (3405/37396) participants were found to have visible mucosal lesions. Of the participants who had normal-appearing mucosa at the EGJ, only 0.28% (94/33991) were diagnosed with HIN or higher grade lesions, whereas 6.05% (206/3405) of participants with abnormalities at the EGJ had a positive pathologic result. After controlling for other variables, visible abnormal mucosa detected under endoscopy strongly predicted a positive pathologic result (OR = 32.51, 95%CI: 23.96-44.09). The proportion of participants with “positive” pathologic diagnoses increased as the total number of endoscopic examinations performed by the doctors increased (< 5000 cases vs 5000-10000 cases vs > 10000 cases, Z = -2.7207, P = 0.0065, Cochran Armiger trend test). The same trend was found between the proportion of participants with positive pathologic diagnoses and the total number of years the doctors performed endoscopy (< 5 years vs 5-10 years vs > 10 years, Z = -10.3222, P < 0.001, Cochran Armiger trend test).
CONCLUSION: Additional routine biopsies from the high incidence spot of EGJ cancer are of limited value and are unjustified.
doi:10.3748/wjg.v20.i17.5074
PMCID: PMC4009543  PMID: 24803821
Esophagogastric junction cancer; High incidence spot; Screening; Endoscopy; Biopsy
7.  SIX-YEAR REGRESSION AND PROGRESSION OF CERVICAL LESIONS OF DIFFERENT HPV VIRAL LOADS IN VARIED HISTOLOGICAL DIAGNOSES 
Objective
This study aims to evaluate HPV viral load as a biomarker for triage into colposcopy and CIN2 therapy, in order to reduce the colposcopy referral rate and CIN2 over treatment in low resource settings.
Methods
In 1999, 1997 women aged 35–45 in Shanxi, China, received six cervical screenings with pathological confirmation. In 2005, 1461 histologically normal women, 99 with cervical intraepithelial neoplasia (CIN) grade 1 (CIN1), and 30 with CIN grade 2 or worse (CIN2+) were rescreened in a follow-up study. HPV was detected by Hybrid Capture 2. Viral load, estimated by the ratio of relative light units to standard positive control, was categorized into four groups: negative (<1.0), low (≥1.0, <10.0), moderate (≥10.0, <100.0) and high (≥100.0). We estimated cumulative incidence of CIN2+ by viral load subgroups and calculated adjusted hazard ratios (aHR) for CIN2+ using Cox proportional hazards regression.
Results
Cumulative incidence of CIN2+ increased with baseline HPV viral load among normal women and women with CIN1 at baseline (P-trend<0.001). Repeat moderate-high viral load was associated with the highest risk for CIN2+ (aHR=188.8, 95% confidence interval: 41.2–864.1). Raising the RLU/PC cutoff from 1.0 to 10.0 for colposcopy greatly reduced the referral rate from 18.1% to 12.9%. It also increased the specificity (84.8% vs. 90.4%), the positive predictive value (22.5% vs. 28.9%), and the positive likelihood ratio (6.4 vs. 8.9), yet with loss of the sensitivity by 12% (97.6% vs. 85.7%). Among women with CIN2 at baseline, 56% regressed to normal, 24% regressed to CIN1, 4% remained CIN2, and 16% progressed to CIN3+.
Conclusions
Locales using HPV testing as the primary screening method, and lacking high-quality cytology-based screening, should consider viral load as an alternative to colposcopy triage for women over age 35. Viral load may also predict CIN2 progression until additional biomarkers become available.
doi:10.1097/IGC.0b013e318286a95d
PMCID: PMC3636161  PMID: 23455757
Cervical Intraepithelial Neoplasia (CIN); Hazard Ratios (HR); Human Papillomavirus (HPV) viral load; Regression; Progression
8.  Genetic variants in Fas signaling pathway genes and risk of gastric cancer 
Populations in north central China are at high risk for gastric cancers (GC), and altered FAS-mediated cell signaling and/or apoptosis may contribute to this risk. We examined the association of 554 single nucleotide polymorphisms (SNPs) in 53 Fas signaling-related genes using a pathway-based approach in 1758 GC cases (1126 gastric cardia adenocarcinomas (GCA) and 632 gastric noncardia adenocarcinomas (GNCA)), and 2111 controls from a genome-wide association study (GWAS) of GC in ethnic Chinese. SNP associations with risk of overall GC, GCA and GNCA were evaluated using unconditional logistic regressions controlling for age, sex and study. Gene- and pathway-based associations were tested using the adaptive rank-truncated product (ARTP) method. Statistical significance was evaluated empirically by permutation. Significant pathway-based associations were observed for Fas signaling with risk of overall GC (P = 5.5E-04) and GCA (P = 6.3E-03), but not GNCA (P = 8.1E-02). Among examined genes in the Fas signaling pathway, MAP2K4, FAF1, MAPK8, CASP10, CASP8, CFLAR, MAP2K1, CAP8AP2, PAK2 and IKBKB were associated with risk of GC (nominal P < 0.05), and FAF1 and MAPK8 were significantly associated with risk of both GCA and GNCA (nominal P < 0.05). Our examination of genetic variation in the Fas signaling pathway is consistent with an association of altered Fas signaling and/or apoptosis with risk of GC. As one of the first attempts to investigate a pathway-level association, our results suggest that these genes and the Fas signaling pathway warrant further evaluation in relation to GC risk in other populations.
doi:10.1002/ijc.28415
PMCID: PMC3858487  PMID: 23921907
Gastric cancer; gastric cardia; gastric noncardia; Fas signaling; genetic variants; GWAS; single nucleotide polymorphisms; pathway genes
9.  Prevalence of Human Papillomavirus and Cervical Intraepithelial Neoplasia in China: A pooled analysis of 17 Population-based Studies 
High-risk (HR) human papillomavirus (HPV) prevalence has been shown to correlate well with cervical cancer incidence rates. Our study aimed to estimate the prevalence of HR-HPV and cervical intraepithelial neoplasia (CIN) in China and indirectly inform on the cervical cancer burden in the country. 30,207 women from 17 population-based studies throughout China were included. All women received HPV DNA testing (HC2, Qiagen), visual inspection with acetic acid, and liquid-based cytology. Women positive for any test received colposcopy-directed or 4-quadrant biopsies. 29,579 women had HR-HPV testing results, of whom 28,761 had biopsy-confirmed (9019, 31.4%) or assumed (19,742, 68.6%) final diagnosis. Overall crude HR-HPV prevalence was 17.7%. HR-HPV prevalence was similar in rural and urban areas but showed dips in different age groups: at age 25–29 years (11.3%) in rural and at age 35–39 (11.3%) in urban women. In rural and urban women, age-standardized CIN2 prevalence was 1.5% (95%CI: 1.4%–1.6%) and 0.7% (95%CI: 0.7%–0.8%), and CIN3+ prevalence was 1.2% (95%CI: 1.2%–1.3%) and 0.6% (95%CI: 0.5%–0.7%), respectively. Prevalence of CIN3+ as a percentage of either all women or HR-HPV positive women steadily increased with age, peaking in 45–49 year-old women. High prevalence of HR-HPV and CIN3+ was detected in both rural and urban China. The steady rise of CIN3+ up to the age group 45–49 is attributable to lack of lesion removal through screening. Our findings document the inadequacy of current screening in China while indirectly raising the possibility that the cervical cancer burden in China is under-reported.
doi:10.1002/ijc.27571
PMCID: PMC3435460  PMID: 22488743
Cervical Cancer; Human Papillomavirus; Cervical Intraepithelial Neoplasia; Prevalence; China
10.  Population-based study of DNA image cytometry as screening method for esophageal cancer 
AIM: To explore the DNA image cytometry (DNA-ICM) technique as a primary screening method for esophageal squamous precancerous lesions.
METHODS: This study was designed as a population-based screening study. A total of 582 local residents aged 40 years-69 years were recruited from Linzhou in Henan and Feicheng in Shandong. However, only 452 subjects had results of liquid-based cytology, DNA-ICM and pathology. The sensitivity and specificity of DNA-ICM were calculated and compared with liquid-based cytology in moderate dysplasia or worse.
RESULTS: Sensitivities of DNA-ICM ranging from at least 1 to 4 aneuploid cells were 90.91%, 86.36%, 79.55% and 77.27%, respectively, which were better than that of liquid-based cytology (75%). Specificities of DNA-ICM were 70.83%, 84.07%, 92.65% and 96.81%, but the specificity of liquid-based cytology was 91.91%. The sensitivity and specificity of a combination of liquid-based cytology and DNA-ICM were 84.09% and 85.78%, respectively.
CONCLUSION: It is possible to use DNA-ICM technique as a primary screening method for esophageal squamous precancerous lesions.
doi:10.3748/wjg.v18.i4.375
PMCID: PMC3261533  PMID: 22294844
DNA image cytometry; Aneuploidy; Screening; Esophageal cancer; Precancerous lesions
11.  The diversity of human papillomavirus infection among human immunodeficiency virus-infected women in Yunnan, China 
Virology Journal  2014;11(1):202.
Background
Yunnan has one of the oldest and the most severe human immunodeficiency virus (HIV) epidemics in China. We conducted an observational study to evaluate the human papillomavirus (HPV) genotype distribution in relation to cervical neoplastic disease risk among HIV-infected women in Yunnan.
Methods
We screened 301 HIV-infected non-pregnant women in Mangshi prefecture in Yunnan province. All consenting participants underwent simultaneous and independent assessment by cervical cytology, colposcopy-histopathology, and HPV genotyping. Unadjusted and multivariable-adjusted multinomial logistic regression analysis was conducted to evaluate factors associated with single or multiple carcinogenic HPV genotypes.
Results
HPV genotypes were present in 43.5% (131/301) overall, and carcinogenic HPV genotypes were present in 37.5% (113/301) women. Among women with carcinogenic HPV genotypes, 80 (70.8% of 113) had a single carcinogenic HPV type, while 33 (29.2%) women had multiple (2 or more) carcinogenic HPV types. Overall, the most common carcinogenic HPV types were HPV52 (7.3%), HPV58 (6.6%), HPV18 (6.3%), HPV16 (6.0%), and HPV33 (5.3%). In women with cervical precancerous lesions (i.e., high-grade squamous intraepithelial lesions [HSIL] on cytology or cervical intraepithelial neoplasia grade 2 or worse [CIN2+] detected on colposcopy-histology), the most commonly detected genotypes were HPV16 (28.6%), HPV52 (25.0%), HPV58 (17.9%), HPV18 (10.7%) and HPV31 (10.7%). Increasing age was an independent risk factor associated with presence of single carcinogenic HPV types (adjusted odds ratio: 1.04, 95%CI: 1.01-1.07, p = 0.012) but not with the presence of multiple carcinogenic types in the multivariable-adjusted models.
Conclusions
As HIV-infected women continue to live longer on antiretroviral therapy in China, it will be increasingly important to screen for, and prevent, HPV-associated cervical cancer in this population, especially given the wide diversity and multiplicity of HPV genotypes.
doi:10.1186/s12985-014-0202-3
PMCID: PMC4279793  PMID: 25481842
HPV; Genotypes; HIV; Cervix; China
12.  Lower cost strategies for triage of human papillomavirus DNA-positive women 
Using human papillomavirus (HPV) testing for cervical cancer screening in lower-resource settings (LRS) will result in a significant number of screen-positive women. This analysis compares different triage strategies for detecting cervical precancer and cancer among HPV-positive women in LRS. This was a population-based study of women aged 25–65 years living in China (n = 7,541). Each woman provided a self-collected and two clinician-collected specimens. The self-collected and one clinician-collected specimen were tested by two HPV DNA tests—careHPV™ and Hybrid Capture 2; the other clinician-collected specimen was tested for HPV16/18/45 E6 protein. CareHPV™-positive specimens were tested for HPV16/18/45 DNA. HPV DNA-positive women underwent visual inspection with acetic acid (VIA) and then colposcopic evaluation with biopsies. The performance for detection of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) among HPV DNA-positive women was assessed for different triage strategies: HPV16/18/45 E6 or DNA detection, VIA, colposcopic impression, or higher signal strength (≥10 relative light units/positive control [rlu/pc]). The percent triage positive ranges were 14.8–17.4% for VIA, 17.8–20.9% for an abnormal colposcopic impression; 7.9–10.5% for HPV16/18/45 E6; 23.4–28.4% for HPV16/18/45 DNA; and 48.0–62.6% for higher signal strength (≥10 rlu/pc), depending on the HPV test/specimen combination. The positivity for all triage tests increased with severity of diagnosis. HPV16/18/45 DNA detection was approximately 70% sensitive and had positive predictive values (PPV) of approximately 25% for CIN3+. HPV16/18/45 E6 detection was approximately 50% sensitive with a PPV of nearly 50% for CIN3+. Different triage strategies for HPV DNA-positive women provide important tradeoffs in colposcopy or treatment referral percentages and sensitivity for prevalent CIN3+.
What's new?
The careHPV™ test is a novel technology for primary cervical cancer screening of women from lower-resource settings. However, triage strategies are needed to identify which HPV-positive women are at highest risk of cervical precancer and cancer. Here, multiple viable and affordable strategies to manage HPV-positive women depending on local requirements and resources are identified, based on evaluation of the performance of different triage strategies for developing countries. The different strategies for women who test positive for HPV DNA provide important tradeoffs in colposcopy or treatment referral percentages and sensitivity for cervical intraepithelial neoplasia grade 3 or cancer (CIN3+).
doi:10.1002/ijc.28616
PMCID: PMC4232922  PMID: 24248915
HPV; triage; cervical cancer; careHPV; developing countries; E6
13.  The association between the upper digestive tract microbiota by HOMIM and oral health in a population-based study in Linxian, China 
BMC Public Health  2014;14(1):1110.
Background
Bacteria affect oral health, but few studies have systematically examined the role of bacterial communities in oral diseases. We examined this relationship in a large population-based Chinese cancer screening cohort.
Methods
Human Oral Microbe Identification Microarrays were used to test for the presence of 272 human oral bacterial species (97 genera) in upper digestive tract (UDT) samples collected from 659 participants. Oral health was assessed using US NHANES (National Health and Nutrition Examination Survey) protocols. We assessed both dental health (total teeth missing; tooth decay; and the decayed, missing, and filled teeth (DMFT) score) and periodontal health (bleeding on probing (BoP) extent score, loss of attachment extent score, and a periodontitis summary estimate).
Results
Microbial richness, estimated by number of genera per sample, was positively correlated with BoP score (P = 0.015), but negatively correlated with tooth decay and DMFT score (P = 0.008 and 0.022 respectively). Regarding β-diversity, as estimated by the UniFrac distance matrix for pairwise differences among samples, at least one of the first three principal components of the UniFrac distance matrix was correlated with the number of missing teeth, tooth decay, DMFT, BoP, or periodontitis. Of the examined genera, Parvimonas was positively associated with BoP and periodontitis. Veillonellacease [G-1] was associated with a high DMFT score, and Filifactor and Peptostreptococcus were associated with a low DMFT score.
Conclusions
Our results suggest distinct relationships between UDT microbiota and dental and periodontal health. Poor dental health was associated with a less microbial diversity, whereas poor periodontal health was associated with more diversity and the presence of potentially pathogenic species.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-1110) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2458-14-1110
PMCID: PMC4223728  PMID: 25348940
Microbiota; Oral health; Dental caries; Periodontitis; Bleeding on probe; Attachment loss
14.  Prospective Study of Serum Cysteine Levels and Oesophageal and Gastric Cancers in China 
Gut  2011;60(5):618-623.
Background
Cancers of the upper gastrointestinal tract remain a significant cause of morbidity and mortality. Cysteine, known to be involved in a myriad of immuno-modulatory, anti-oxidant, and anti-carcinogenic pathways, has not been investigated in the aetiology of oesophageal or gastric cancers. To examine the relationship between serum cysteine concentration and risk of these cancers we conducted a nested case-cohort study within the General Population Nutrition Intervention Trial in Linxian, China.
Methods
498 oesophageal squamous cell carcinomas (OSCC) and 255 gastric cardia adenocarcinomas (GCA) were matched by age and sex to 947 individuals from the wider cohort. We calculated hazard ratios (HR) and 95% confidence intervals (95% CI) using the case-cohort estimator for the Cox proportional hazards models, stratified on age and sex, with adjustment for potential confounders.
Results
Higher concentrations of serum cysteine were significantly associated with a lower risk of both OSCC and GCA. For those in the highest quartile of serum cysteine, compared to those in the lowest, the multivariate HRs were 0.70 for OSCC (95% CI: 0.51, 0.98) and 0.59 for GCA (95% CI: 0.38, 0.91). These associations were dose dependent (P for trend = 0.006 and 0.008, respectively). These inverse associations were not significantly modified by other risk factors, with the exception of age, where a stronger association was noted among persons in the older age strata.
Conclusion
Higher serum concentrations of cysteine were associated with a significantly reduced risk of OSCC and GCA. Cysteine should be further investigated for its potential as a chemopreventive agent for upper gastrointestinal cancers.
doi:10.1136/gut.2010.225854
PMCID: PMC3428021  PMID: 21242262
oesophageal squamous cell carcinoma; gastric cardia cancer; hazard ratio; cysteine
15.  Long-term Survival After Esophagectomy for Early Esophageal Squamous Cell Carcinoma in Linxian, China 
Journal of surgical oncology  2011;104(2):176-180.
Background and Objectives
Linxian in Henan Province, China, has among the highest rates of esophageal cancer worldwide. Little is known about long-term survival after esophagectomy for early neoplastic lesions found during early detection screening. A long-term survival analysis was performed for 315 patients from Linxian who received esophagectomy for early esophageal squamous cell carcinoma.
Methods
Cases that received esophagectomy for early esophageal squamous cell carcinoma were age- and gender-matched with two healthy controls, and Kaplan-Meier survival analyses were performed for both groups.
Results
10-year survival was 77% for cases and 64% for controls, and this difference was not statistically significant (p = 0.33). There were no significant differences in survival based on age or gender (p>0.05). Cases with esophageal squamous cell carcinoma-in-situ had significantly better survival than cases with invasive esophageal squamous cell carcinoma (p=0.035).
Conclusions
Survival of cases who received esophagectomy for early esophageal squamous cell carcinoma was not significantly different from survival of age- and gender-matched controls. Early intervention probably improved survival rates for these patients who otherwise would most likely have developed advanced esophageal carcinoma. Early screening and intervention are highly relevant in areas with a high risk of esophageal cancer such as Linxian, China.
doi:10.1002/jso.21953
PMCID: PMC3129477  PMID: 21538356
Esophageal Cancer; Esophageal Surgery; Statistics; survival analysis
16.  Cost-benefit analysis of esophageal cancer endoscopic screening in high-risk areas of China 
AIM: To estimate the cost-benefit of endoscopic screening strategies of esophageal cancer (EC) in high-risk areas of China.
METHODS: Markov model-based analyses were conducted to compare the net present values (NPVs) and the benefit-cost ratios (BCRs) of 12 EC endoscopic screening strategies. Strategies varied according to the targeted screening age, screening frequencies, and follow-up intervals. Model parameters were collected from population-based studies in China, published literatures, and surveillance data.
RESULTS: Compared with non-screening outcomes, all strategies with hypothetical 100 000 subjects saved life years. Among five dominant strategies determined by the incremental cost-effectiveness analysis, screening once at age 50 years incurred the lowest NPV (international dollar-I$55 million) and BCR (2.52). Screening six times between 40-70 years at a 5-year interval [i.e., six times(40)f-strategy] yielded the highest NPV (I$99 million) and BCR (3.06). Compared with six times(40)f-strategy, screening thrice between 40-70 years at a 10-year interval resulted in relatively lower NPV, but the same BCR.
CONCLUSION: EC endoscopic screening is cost-beneficial in high-risk areas of China. Policy-makers should consider the cost-benefit, population acceptance, and local economic status when choosing suitable screening strategies.
doi:10.3748/wjg.v18.i20.2493
PMCID: PMC3360447  PMID: 22654446
Cost-benefit analysis; Esophageal cancer; Endoscopy; Screening; High-risk area
17.  Attributable Causes of Breast Cancer and Ovarian Cancer in China: Reproductive Factors, Oral Contraceptives and Hormone Replacement Therapy 
Objective
To provide an evidence-based, consistent assessment of the burden of breast cancer attributable to reproductive factors (RFs, including nulliparity, mean number of children, age at first birth and breastfeeding), use of oral contraceptives (OCs, restricted to the age group of 15-49 years), and hormone replacement therapy (HRT), as well as of the burden of ovarian cancer attributable to the mean number of children in China in 2005.
Methods
We derived the prevalence of these risk factors and the relative risk of breast and ovarian cancer from national surveys or large-scale studies conducted in China. In the case of RFs, we compared the exposure distributions in 2001 and counterfactual exposure.
Results
Exposure of RFs in 2001 was found to account for 6.74% of breast cancer, corresponding to 9,617 cases and 2,769 deaths, and for 2.78% of ovarian cancer (711 cases, 294 deaths). The decrease in mean number of children alone was responsible for 1.47% of breast cancer and 2.78% of ovarian cancer. The prevalence of OC use was 1.74% and the population attributable fraction (PAF) of breast cancer was 0.71%, corresponding to 310 cases and 90 deaths. The PAF of breast cancer due to HRT was 0.31%, resulting in 297 cases and 85 deaths.
Conclusion
RFs changes in China contributed to a sizable fraction of breast and ovarian cancer incidence and mortality, whereas HRT and OCs accounted for relatively low incidence of breast cancer in China.
doi:10.1007/s11670-012-0009-y
PMCID: PMC3555252  PMID: 23359757
Reproductive factors; Oral contraceptives; Hormone replacement therapy; Cancer; Population attributable fraction
18.  Pooled Analysis of a Self-Sampling HPV DNA Test as a Cervical Cancer Primary Screening Method 
Background
Worldwide, one-seventh of cervical cancers occur in China, which lacks a national screening program. By evaluating the diagnostic accuracy of self-collected cervicovaginal specimens tested for human papillomavirus (HPV) DNA (Self-HPV testing) in China, we sought to determine whether Self-HPV testing may serve as a primary cervical cancer screening method in low-resource settings.
Methods
We compiled individual patient data from five population-based cervical cancer–screening studies in China. Participants (n = 13 140) received Self-HPV testing, physician-collected cervical specimens for HPV testing (Physician-HPV testing), liquid-based cytology (LBC), and visual inspection with acetic acid (VIA). Screen-positive women underwent colposcopy and confirmatory biopsy. We analyzed the accuracies of pooled Self-HPV testing, Physician-HPV testing, VIA, and LBC to detect biopsy-confirmed cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) and CIN3+. All statistical tests were two-sided.
Results
Of 13 004 women included in the analysis, 507 (3.9%) were diagnosed as CIN2+, 273 (2.1%) as CIN3+, and 37 (0.3%) with cervical cancer. Self-HPV testing had 86.2% sensitivity and 80.7% specificity for detecting CIN2+ and 86.1% sensitivity and 79.5% specificity for detecting CIN3+. VIA had statistically significantly lower sensitivity for detecting CIN2+ (50.3%) and CIN3+ (55.7%) and higher specificity for detecting CIN2+ (87.4%) and CIN3+ (86.9%) (all P values < .001) than Self-HPV testing, LBC had lower sensitivity for detecting CIN2+ (80.7%, P = .015), similar sensitivity for detecting CIN3+ (89.0%, P = .341), and higher specificity for detecting CIN2+ (94.0%, P < .001) and CIN3+ (92.8%, P < .001) than Self-HPV testing. Physician-HPV testing was more sensitive for detecting CIN2+ (97.0%) and CIN3+ (97.8%) but similarly specific for detecting CIN2+ (82.7%) and CIN3+ (81.3%) (all P values <.001) than Self-HPV testing.
Conclusions
The sensitivity of Self-HPV testing compared favorably with that of LBC and was superior to the sensitivity of VIA. Self-HPV testing may complement current screening programs by increasing population coverage in settings that do not have easy access to comprehensive cytology-based screening.
doi:10.1093/jnci/djr532
PMCID: PMC3274511  PMID: 22271765
19.  Comparative epidemiology of gastric cancer between Japan and China 
AIM: To clarify the similarities and differences in gastric cancer epidemiology between Japan and China.
METHODS: A comprehensive literature search of the PubMed database was performed. The relevant literature published in China was also been cited. Data on incidence and mortality rates in 2008 were obtained from the Cancer Mondial database, published by International Agency for Research on Cancer at http://www-dep.iarc.fr/.
RESULTS: Gastric cancer remains a significant public health burden in both Japan and China. The prevalence of Helicobacter pylori (H. pylori) colonization is high in the adult populations of both countries. Accumulating evidence from intervention studies in both countries has shown the effectiveness of H. pylori eradication in reducing gastric cancer incidence. There are differences, however, in many aspects of gastric cancer, including patterns of incidence and mortality, trends in the prevalence of H. pylori infection, H. pylori strains, the magnitude of risk of gastric cancer related to H. pylori infection, and associations with dietary habits. Compared with China, Japan has seen a more rapid decline in H. pylori infection among adolescents. While Japanese cohort studies have dominated the literature concerning the associations between gastric cancer and dietary habits, numerous case-control studies in China suggest a positive association between a high intake of preserved fish and vegetables and gastric cancer risk. There is a need for a multidisciplinary research approach to understand the interactions between various strains of H. pylori, host factors, and other lifestyle and environmental factors in gastric carcinogenesis in both countries.
CONCLUSION: The shared high incidence of gastric cancer and high prevalence of H. pylori, as well as differences in many aspects of gastric cancer, provide an excellent opportunity to establish Sino-Japanese collaborations.
doi:10.3748/wjg.v17.i39.4421
PMCID: PMC3218157  PMID: 22110269
Gastric cancer; Risk factor; Helicobacter pylori; Epidemiology
20.  Human papillomavirus-related psychosocial impact of patients with genital warts in China: a hospital-based cross-sectional study 
BMC Public Health  2014;14:739.
Background
Genital warts (GW) are the most common sexually transmitted infections. To date, few studies using a human papillomavirus (HPV)-specific questionnaire have focused on the impact of quality of life (QoL) among patients with GW in developing countries. The origins of GW related psychosocial burdens and variations between genders were poorly characterized as well.
Methods
A hospital-based survey was conducted in Beijing and Nanjing of China in 2008. Eligible patients aged 18–65 who had a diagnosis of GW within 3 months were recruited. Demographic information, HPV knowledge, and assessment of psychosocial burden were collected by the HPV Impact Profile (HIP). The HIP examined 7 specific psychosocial domains by 29 items: (1) worries and concerns, (2) emotional impact, (3) sexual impact, (4) self-image, (5) partner and transmission, (6) interactions with physicians, and (7) control/life impact. HIP scores are reversely relates to the subjects’ QoL, by which a higher score indicating a heavier psychosocial burden.
Results
Patients with GW experienced heavier psychosocial burdens than those of the general population, and females experienced heavier burdens than males (male vs. female: 49.20 vs.51.38, P < 0.001). “Self Image” and “Sexual Impact” were the two domains that affected patients the most, with mean HIP scores of 63.09 and 61.64, respectively. Women suffered heavier psychosocial burdens than men in the domain of “Worries and Concerns” (female vs. male: 54.57 vs. 42.62, P < 0.001), but lower psychosocial burdens in the domains of “Sexual Impact” (female vs. male: 59.16 vs. 65.26, P < 0.001) and “Interactions with Doctors” (female vs. male: 34.40 vs. 41.97, P < 0.001). Patients from Nanjing suffered a higher psychosocial burden than those of Beijing, especially in domains of “Emotional Impact”, “Sexual Impact”, “Partner and Transmission”, and “Interactions with Doctors”.
Conclusions
Patients with GW suffered heavy psychological burden, and self-image and sexual-related concern were the primary cause of burdens. It’s important to change the current biomedical model to bio-psycho-social model, and establish psychosocial support systems. The distinctions of origins of psychosocial burden between genders identified will be informative for prevention of GW and control efforts in China and other similar settings.
doi:10.1186/1471-2458-14-739
PMCID: PMC4223584  PMID: 25048000
Genital warts (GW); Psychosocial burden; Quality of Life (QoL); Human papillomavirus Impact Profile (HIP)
21.  A Nation-Wide Multicenter 10-Year (1999-2008) Retrospective Clinical Study of Endocrine Therapy for Chinese Females with Breast Cancer 
PLoS ONE  2014;9(7):e100159.
Endocrine therapy (ET) is one of the main systemic treatments for patients with breast cancer. To our knowledge, few studies have addressed the performance of ET or relevant influencing factors in cancer treatment in China. By retrospectively analyzing the clinicopathological data on breast cancer collected from representative hospitals of 7 traditional areas in China in one random month from each year between year 1999 and 2008, we found that: 1) The rate of the use of hormone receptor (HR) testing was 83.8% (3529/4211), with the estrogen receptor-positive (ER+) rate and/or the progesterone receptor-positive (PR+) rate being 67.9% (2395/3529), and the ER-PR rate being 32.1% (1134/3529). 2) Of the 1599 patients who had received ET, 999 patients (58.3%) were premenopausal while 600 (41.7%) were postmenopausal; 1598 patients received adjuvant hormonal therapy (AHT), whereas only 1 patient received palliative therapy. The medications mainly administered to patients were anti-estrogen agents (80.3% [1283/1598]), followed by AIs (15.5% [248/1598]). Of the 1598 patients receiving AHT, 1416 patients (88.6%) were positive for ER and/or PR, while 75 (4.7%) were negative for both and 108 patients (6.7%) had unknown HR status. The ratio of the use of endocrine therapy for breast cancer patients with ER+ and/or PR+ status was 60.0% (1416/2395). 3) Results from the logistic regression analysis revealed that geography, occupations, and history of chemotherapy and surgery were dependent factors affecting the application of ET in breast cancer treatment in China (P<0.001). In conclusion, the use of ET on Chinese women with breast cancer is increasingly and gradually accounted into the standardized process. Economic status, occupations, and history of chemotherapy and surgery were key factors affecting the application of ET. People residing in developed areas, engaging in mental labour, having history of chemotherapy and surgery are susceptible to accept ET.
doi:10.1371/journal.pone.0100159
PMCID: PMC4103779  PMID: 25036532
22.  Application of intraoperative frozen section examination in the management of female breast cancer in China: a nationwide, multicenter 10-year epidemiological study 
Background
Intraoperative frozen section examination (IFSE) during breast cancer surgery can partly reflect the status of surgical treatment since the surgical method used directly determines the purpose of IFSE use in disease management. This study aims to investigate the application of, changing trends in, and factors influencing IFSE in the management of female breast cancer in China.
Methods
We collected the sociodemographic and clinical data of 4,211 breast cancer patients between 1999 and 2008 and statistically analyzed these data using χ2 or Fisher’s exact tests.
Results
A total of 2,283 (54.22%) patients with breast cancer underwent IFSE. During the 10-year study period, IFSE use was associated with an increase in the number of sentinel lymph node biopsies (SLNB) and breast-conserving surgeries (BS) performed, with significant regional differences noted in this trend (P <0.05). Patients’ education, occupation, age, tumor size estimated by preoperative palpation, and the use of imaging examinations affected the purpose of IFSE use (P <0.05).
Conclusions
Our results show that the purpose of IFSE in the surgical treatment of breast cancer in China is gradually approaching that in developed countries. We believe that policymakers must address the differences in breast cancer treatment based on the socioeconomic status of patients. Lastly, the use of IFSE for determining tumor characteristics should be avoided as far as possible, and patient education and breast cancer screening programs tailored to the Chinese population should be established. Our findings may guide the formulation of breast cancer control strategies in China and other low-income countries.
doi:10.1186/1477-7819-12-225
PMCID: PMC4105393  PMID: 25034137
Application mode; Female breast cancer; Intraoperative frozen section examination; Sociodemographic factor
23.  No role for human papillomavirus in esophageal squamous cell carcinoma in China 
Certain regions of China have high rates of esophageal squamous cell carcinoma (ESCC). Previous studies of human papillomavirus (HPV), a proposed causal factor, have produced highly variable results. We attempted to evaluate HPV and ESCC more definitively using extreme care to prevent DNA contamination. We collected tissue and serum in China from 272 histopathologically-confirmed ESCC cases with rigorous attention to good molecular biology technique. We tested for HPV DNA in fresh-frozen tumor tissue using PCR with PGMY L1 consensus primers and HPV16 and 18 type-specific E6 and E7 primers, and in formalin-fixed paraffin-embedded tumor tissue using SPF10 L1 primers. In HPV-positive cases, we evaluated p16INK4a overexpression and HPV E6/E7 seropositivity as evidence of carcinogenic HPV activity. β-globin, and thus DNA, was adequate in 98.2% of the frozen tumor tissues (267/272). Of these, 99.6% (95% confidence interval (CI) = 97.9–100.0%) were negative for HPV DNA by PGMY, and 100% (95% CI = 98.6–100%) were negative by HPV16/18 E6/E7 PCR. In the corresponding formalin-fixed paraffin-embedded tumor specimens, 99.3% (95% CI = 97.3–99.9%) were HPV negative by SPF10. By PGMY, 1 case tested weakly positive for HPV89, a noncancer causing HPV type. By SPF10, 2 cases tested weakly positive: 1 for HPV16 and 1 for HPV31. No HPV DNA-positive case had evidence of HPV oncogene activity as measured by p16INK4a overexpression or E6/E7 seropositivity. This study provides the most definitive evidence to date that HPV is not involved in ESCC carcinogenesis in China. HPV DNA contamination cannot be ruled out as an explanation for high HPV prevalence in ESCC tissue studies with less stringent tissue procurement and processing protocols.
doi:10.1002/ijc.25023
PMCID: PMC3069961  PMID: 19918949
human papillomavirus; esophageal squamous cell carcinoma
24.  Genetic variants in DNA repair pathway genes and risk of esophageal squamous cell carcinoma and gastric adenocarcinoma in a Chinese population 
Carcinogenesis  2013;34(7):1536-1542.
The DNA repair pathways help to maintain genomic integrity and therefore genetic variation in the pathways could affect the propensity to develop cancer. Selected germline single nucleotide polymorphisms (SNPs) in the pathways have been associated with esophageal cancer and gastric cancer (GC) but few studies have comprehensively examined the pathway genes. We aimed to investigate associations between DNA repair pathway genes and risk of esophageal squamous cell carcinoma (ESCC) and GC, using data from a genome-wide association study in a Han Chinese population where ESCC and GC are the predominant cancers. In sum, 1942 ESCC cases, 1758 GC cases and 2111 controls from the Shanxi Upper Gastrointestinal Cancer Genetics Project (discovery set) and the Linxian Nutrition Intervention Trials (replication set) were genotyped for 1675 SNPs in 170 DNA repair-related genes. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-level associations were determined using the resampling-based adaptive rank-truncated product approach. The DNA repair pathways overall were significantly associated with risk of ESCC (P = 6.37 × 10− 4), but not with GC (P = 0.20). The most significant gene in ESCC was CHEK2 (P = 2.00 × 10− 6) and in GC was CLK2 (P = 3.02 × 10− 4). We observed several other genes significantly associated with either ESCC (SMUG1, TDG, TP53, GTF2H3, FEN1, POLQ, HEL308, RAD54B, MPG, FANCE and BRCA1) or GC risk (MRE11A, RAD54L and POLE) (P < 0.05). We provide evidence for an association between specific genes in the DNA repair pathways and the risk of ESCC and GC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.
doi:10.1093/carcin/bgt094
PMCID: PMC3697889  PMID: 23504502
25.  Quality of life in women with cervical precursor lesions and cancer: a prospective, 6-month, hospital-based study in China 
Chinese Journal of Cancer  2014;33(7):339-345.
The overall survival of patients with cervical cancer has improved due to detection at an early stage and availability of comprehensive treatments in China. As patients' lives prolonged, it is important to understand their health-related quality of life (QoL) during and after treatment. We used the EQ-5D questionnaire to assess QoL of 194 patients with cervical lesions at Sichuan University West China Second Hospital between May 2010 and January 2011. Patients were surveyed before primary treatment and at 1, 3, and 6 months after primary treatment. Results showed a consistent decline in EQ-5D scores in the spectrum of cervical lesions at each time point after treatment (all P < 0.05). For patients with precursor lesions, there was an increasing trend along the timeline of treatment (P < 0.01). For patients with early-stage cervical cancer, EQ-5D scores declined in the first month (P = 0.01) and gradually increased to higher levels at 6 months post-treatment than those before treatment (P < 0.01). EQ-5D scores followed a similar trend in patients with advanced cervical cancer (P = 0.04), though they did not statistically rebound after 6 months (0.84 ± 0.19 vs. 0.86 ± 0.11, P = 0.62). Regarding advanced cervical cancer, EQ-5D scores for women above 40 years of age appeared to recover more rapidly and reached higher levels than those for women below 40 years (P = 0.03). Caution and extra care are recommended in the early period of cervical cancer treatment given the slight deterioration in the QoL, and in particular, for younger cervical cancer patients. Our study implies that health care providers may need to improve the health-related QoL of cervical cancer patients.
doi:10.5732/cjc.013.10139
PMCID: PMC4110466  PMID: 24698497
Cervical cancer; cervical precursor lesion; quality of life; EQ-5D; prospective study; Chinese women

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