Absence of NOTCH1 mutation and presence of CDKN2A deletion predict progression of esophageal lesions.

Currently, surveillance for esophageal squamous cell carcinoma (ESCC) runs a risk of underestimation of early lesions which show absence of iodine staining, with no or only mild histologic changes. The development of molecular markers that indicate risk of progression is thus warranted. We performed whole-exome sequencing on biopsies from two sequential endoscopies of a single esophageal lesion and matching blood samples. There were 27 pairs of age-, gender-, pathologic stage-, and sampling interval-matched progressors and non-progressors identified in a prospective community-based ESCC screening trial. Putative molecular progression markers for ESCC were first evaluated by comparing somatic mutation, copy number alteration (CNA), and mutational signature information among progressors and non-progressors. These markers were then validated with another 24 pairs of matched progressors and non-progressors from the same population using gene alteration status identified by target sequencing and quantitative PCR. Progressors had more somatic mutation and CNA burden, as well as apolipoprotein B mRNA editing catalytic polypeptide-like and age-related signature weights compared with non-progressors. A gene score consisting of somatic NOTCH1 mutation and CDKN2A deletion is predictive of risk of progression in lesions which show absence of iodine staining under endoscopy but have no or only mild dysplasia. This gene score was also validated in an external cohort of matched progressors and non-progressors. Absence of NOTCH1 mutation and presence of CDKN2A deletion are markers of progression in squamous lesions of the esophagus. This gene score would be an ideal indicator for assisting the pathologist in the identification of high-risk individuals who could be potentially 'missed' or subject to a risk underestimation by histologic analysis, and might improve the performance of ESCC surveillance. © 2022 The Pathological Society of Great Britain and Ireland.

Multiple Lugol-unstained lesions predict higher cumulative risk of malignance in the esophagus.

BACKGROUND AND AIM: The impact of the presence of multiple Lugol-unstained lesions (LULs) in the esophagus on the risk of having severe dysplasia and above (SDA) lesions among asymptomatic individuals is unknown. METHODS: We collected demographic factors, behavioral variables, and features of LULs from 1073 participants who were biopsied at baseline endoscopic screening in a population-based screening trial, and these individuals were followed over a median time of 7 years. Outcome events were defined as SDA identified at screening, at reexamination, or during follow-up. "Multiple LULs" were defined as ≥ 2 LULs found in the entirety of the esophagus. Multivariable logistic regression models were fitted to assess the effect of "multiple LULs" on the cumulative risk of SDA. RESULTS: There were 147 SDA cases in the current study. After adjustment for potential risk factors and endoscopic features of LULs, the presence of "multiple LULs" slightly increased the cumulative risk of having SDA with no statistical significance (adjusted odds ratio [OR] = 1.26; 95% confidence interval [CI] [0.85, 1.88]). Further stratified analysis showed that this association was strong among subjects with small LULs (≤ 5 mm) (adjusted OR = 3.29; 95% CI [1.39, 7.79]). However, no such association was observed in subjects with larger LULs (adjusted OR = 0.99; 95% CI [0.63, 1.55], P interaction  = 0.022). CONCLUSIONS: The presence of "multiple small LULs (≤ 5 mm)" in chromoendoscopy indicates a higher cumulative risk of having SDA in the esophagus. We recommend biopsies be taken and surveillance be maintained at a more active level in individuals with relatively small but multiple LULs.

Lugol-unstained lesions location in the esophagus affects the detection rate of malignancy: a population-based study.

INTRODUCTION: This study aimed to evaluate the impact of Lugol-unstained lesion (LUL) location on the detection yield, which may help the endoscopist select targets for biopsy. METHODS: We enrolled 1064 subjects who had LULs at the baseline screening of a population-based randomized controlled trial. There were 1166 LULs with recorded location and pathologic diagnosis, and these were used for analysis. The detection rate of severe dysplasia and above (SDA) was calculated as the number of LULs identified as SDA divided by the number of LULs biopsied. Logistic regression with a generalized estimating equation was applied to evaluate the association between the location of a given LUL and the risk of the LUL being SDA. RESULTS: The detection rate of SDA for LULs located in the lower, middle, and upper esophagus increased from 5.9% and 10.9% to 16.7%. LUL location was significantly associated with having SDA (adjusted odds ratio (OR)upper vs. lower  = 2.88, 95% confidential interval (CI) = 1.48-5.60; adjusted ORmiddle vs. lower  = 1.63, 95% CI = 0.96-2.76), and the association was stronger in subgroups with a family history of esophageal squamous cell carcinoma (ESCC) (adjusted ORupper vs. lower  = 9.72, 95% CI = 2.57-36.69; adjusted ORmiddle vs. lower  = 3.76, 95% CI = 0.93-15.21). CONCLUSIONS: Our results suggest that more attention should be paid by endoscopists to LULs in the upper and middle esophagus, particularly for individuals with a family history of ESCC.

PPI-Miner: A Structure and Sequence Motif Co-Driven Protein-Protein Interaction Mining and Modeling Computational Method.

Protein-protein interactions (PPIs) play important roles in biological processes of life, and predicting PPIs becomes a critical scientific issue of concern. Most PPIs occur through small domains or motifs (fragments), which are challenging and laborious to map by standard biochemical approaches because they generally require the cloning of several truncation mutants. Here, we present a computational method, named as PPI-Miner, to fish potential protein interacting partners utilizing protein motifs as queries. In brief, this work first developed a motif-matching algorithm designed to identify the proteins that contain sequential or structural similar motifs with the given query motif. Being aligned to the query motif, the binding mode of the discovered motif and its receptor protein will be initially determined to be used to build PPI complexes accordingly. Eventually, a PPI complex structure could be built and optimized with a designed automatic protocol. Besides discovering PPIs, PPI-Miner can also be applied to other areas, i.e., the rational design of molecular glues and protein vaccines. In this work, PPI-Miner was employed to mine the potential cereblon (CRBN) substrates from human proteome. As a result, 1,739 candidates were predicted, and 16 of them have been experimentally validated in previous studies. The source code of PPI-Miner can be obtained from the GitHub repository (https://github.com/Wang-Lin-boop/PPI-Miner), the webserver is freely available for users (https://bailab.siais.shanghaitech.edu.cn/services/ppi-miner), and the database of predicted CRBN substrates is accessible at https://bailab.siais.shanghaitech.edu.cn/services/crbn-subslib.

Size of Lugol-unstained lesions as a predictor for risk of progression in premalignant lesions of the esophagus.

BACKGROUND AND AIMS: At present, the surveillance strategy for premalignant esophageal lesions in China is based solely on the pathologic diagnosis in Lugol's chromoendoscopy (LCE). In this study, we sought to determine the degree to which various unstained features under LCE may lead to improved ability to predict the risk of progression in esophageal lesions. METHODS: We re-examined and followed up on 1058 subjects who had Lugol-unstained lesions (LULs) together with a pathologic diagnosis that was lower than severe dysplasia at baseline screening based on a population-based randomized controlled trial over a median time of 5.8 years. We established a logistic regression model and calculated the adjusted cumulative incidence of severe dysplasia or malignancy. RESULTS: LUL size was predictive of progression to malignant lesions in individuals with a nondysplastic diagnosis (adjusted odd ratio6-10 mm vs ≤5 mm, 6.7; 95% confidence interval, 1.7-25.7; adjusted odds ratio>10 mm vs ≤5 mm, 27.9; 95% confidence interval, 7.3-105.7), and the corresponding adjusted cumulative incidence of malignant lesions was 3.6 and 13.2 per 100 persons. This is higher than that of small (≤5 mm) lesions, which showed mild dysplasia (2.7 per 100 persons), a condition for which surveillance every 3 years is recommended. Under the current approach, 65.3% of interval cancers missed at surveillance would be detected if individuals with medium (6-10 mm) and large (>10 mm) nondysplastic LULs were additionally monitored. CONCLUSIONS: We propose a modified surveillance strategy that combines findings under LCE examination and the pathologic analysis, where follow-up endoscopy is recommended for individuals with relatively large nondysplastic lesions.

Pulmonary Daoyin as a traditional Chinese medicine rehabilitation programme for patients with IPF: A randomized controlled trial.

BACKGROUND AND OBJECTIVE: IPF is a chronic progressive lung disease in which PR provides benefit for patients. PD, a TCM PR programme, has known effectiveness in COPD, but its utility in IPF is unknown. We investigated its effectiveness and safety in patients with IPF. METHODS: A 6-month randomized controlled trial (RCT) was conducted in three Chinese clinics. Ninety-six participants diagnosed with IPF were randomly assigned to one of the three groups: the PD group received a PD programme two times a day, 5 days/week for 2 months, and the exercise group exercised via a stationary cycle ergometer, 30 min/day, 5 days/week for 2 months. Volunteers in the control group were advised to maintain their usual activities. Primary outcomes were changes from baseline in the 6MWD and HRQoL score on the SGRQ-I at 1 and 2 months (at the end of the intervention) and at 6 months (4 months after the intervention). Secondary outcomes measures included FVC, DLCO (% predicted) and the changes in mMRC. RESULTS: The 6MWD was increased in the PD group compared to exercise and control groups. 6MWD increased by 60.44 m in the PD group, 32.16 m in the exercise group and 12.42 m in controls after the 2 months of rehabilitation programme. The between-group differences in the change from baseline were 28.78 m (95% CI: 0.54 to 56.01; P = 0.044) and 48.02 m (95% CI: 23.04 to 73.00; P < 0.001) at 2 months, and 25.61 m (95% CI: -0.67 to 51.89; P = 0.058) and 50.93 m (95% CI: 25.47 to 76.40; P < 0.001) at 6 months, respectively, including a difference exceeding the MCID. There was no significant change in the SGRQ-I score, the mMRC dyspnoea score, FVC and DLCO (% predicted) in either the PD or exercise groups. CONCLUSION: Two months after the intervention, a clinically meaningful difference in 6MWD was observed favouring the PD programme. The PD programme is safe and effective as a rehabilitation intervention designed to increase exercise tolerance and is an appropriate substitute for PR.

Association of early-life undernutrition and risk of dyslipidemia in adulthood: a population-based cohort study.

BACKGROUND: The association of early-life undernutrition and dyslipidemia found in previous studies may be confounded by the uncontrolled age difference between exposed and unexposed participants. The study aimed to investigate the association of early-life undernutrition and the risk of dyslipidemia in adulthood with good control of the age variable. METHODS: We took the Great Chinese Famine (1959-1961) as a natural experiment of severe undernutrition. This study was based on the baseline investigation of a population-based cohort in rural China. Undernutrition in early life was defined as being exposed to famine at younger than 3 years of age. Three approaches including Adjustment, Restriction, and Matching were applied to control the confounding effect of age. Logistic regression models were applied to evaluate the association between early-life famine and the presence of dyslipidemia. Stratified analysis by gender was also performed, and potential effect modification was tested by adding the interaction term of the famine exposure variable and gender into the model. RESULTS: Undernutrition in early life was associated with increased risk of borderline high and above (BHA) levels of total cholesterol (TC, ORAdjustment = 1.61; ORRestriction = 1.56; ORMatching = 1.87), triglycerides (TG, ORAdjustment = 1.33; ORRestriction = 1.30; ORMatching = 1.34), low-density lipoprotein cholesterol (LDL-C, ORAdjustment = 1.75; ORRestriction = 1.53; ORMatching = 1.77) and dyslipidemia (ORAdjustment = 1.52; ORRestriction = 1.45; ORMatching = 1.60), as well as high levels of TC, TG, LDL-C and dyslipidemia. An inverse association of undernutrition and risk of low high-density lipoprotein cholesterol (HDL-C) was found. Female participants with undernutrition experience had an increased risk of BHA TG and LDL-C (TG: ORAdjustment, female = 1.45; ORRestriction, female = 1.39; ORMatching, female = 1.51; LDL-C: ORAdjustment, female = 2.11; ORRestriction, female = 1.80; ORMatching, female = 2.15), but this association was not found in males. CONCLUSION: Early-life undernutrition increased the risk of TC, TG, LDL-C, and dyslipidemia. Gender would significantly modify this effect for TG and LDL-C. These results emphasize the importance of nutritional conditions in the early stages of life to long-term health consequences.

Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease.

BACKGROUND: Patients with mild or moderate chronic obstructive pulmonary disease (COPD) rarely receive medications, because they have few symptoms. We hypothesized that long-term use of tiotropium would improve lung function and ameliorate the decline in lung function in patients with mild or moderate COPD. METHODS: In a multicenter, randomized, double-blind, placebo-controlled trial that was conducted in China, we randomly assigned 841 patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (mild) or 2 (moderate) severity to receive a once-daily inhaled dose (18 µg) of tiotropium (419 patients) or matching placebo (422) for 2 years. The primary end point was the between-group difference in the change from baseline to 24 months in the forced expiratory volume in 1 second (FEV1) before bronchodilator use. Secondary end points included the between-group difference in the change from baseline to 24 months in the FEV1 after bronchodilator use and the between-group difference in the annual decline in the FEV1 before and after bronchodilator use from day 30 to month 24. RESULTS: Of 841 patients who underwent randomization, 388 patients in the tiotropium group and 383 in the placebo group were included in the full analysis set. The FEV1 in patients who received tiotropium was higher than in those who received placebo throughout the trial (ranges of mean differences, 127 to 169 ml before bronchodilator use and 71 to 133 ml after bronchodilator use; P<0.001 for all comparisons). There was no significant amelioration of the mean (±SE) annual decline in the FEV1 before bronchodilator use: the decline was 38±6 ml per year in the tiotropium group and 53±6 ml per year in the placebo group (difference, 15 ml per year; 95% confidence interval [CI], -1 to 31; P=0.06). In contrast, the annual decline in the FEV1 after bronchodilator use was significantly less in the tiotropium group than in the placebo group (29±5 ml per year vs. 51±6 ml per year; difference, 22 ml per year [95% CI, 6 to 37]; P=0.006). The incidence of adverse events was generally similar in the two groups. CONCLUSIONS: Tiotropium resulted in a higher FEV1 than placebo at 24 months and ameliorated the annual decline in the FEV1 after bronchodilator use in patients with COPD of GOLD stage 1 or 2. (Funded by Boehringer Ingelheim and others; Tie-COPD ClinicalTrials.gov number, NCT01455129 .).

Absence of Iodine Staining Associates With Progression of Esophageal Lesions in a Prospective Endoscopic Surveillance Study in China.

BACKGROUND & AIMS: Chromoendoscopy with iodine staining is used to identify esophageal squamous dysplasia and esophageal squamous cell carcinomas (ESCCs)-absence of staining indicates suspicious regions of dysplasia. However, screening detects precancerous lesions (mild and moderate dysplasia) that do not require immediate treatment; it is a challenge to which lesions are at risk for progression. We investigated the association between absence of iodine staining at chromoendoscopy screening and lesion progression using 6 years of follow-up data from a population-based randomized controlled trial in China. We then constructed and validated a model to calculate risk of progression to severe dysplasia, carcinoma in situ, or ESCC. METHODS: We collected data from 1468 participants (45-69 years old) who were either negative for iodine staining at a baseline chromoendoscopy or found to have mild or moderate dysplasia in histologic analysis of biopsies in the Endoscopic Screening for Esophageal Cancer study in China, from January 2012 through September 2016; 788 of these participants were re-examined by endoscopy after a median interval of 4.2 years (development cohort). We investigated the association between absence of iodine staining and progression of esophageal lesions using Cox prediction models, considering corresponding baseline pathology findings and patient answers to a comprehensive questionnaire. Patients who did not receive a follow-up examination (n = 680) was used as the validation cohort; outcome events in these patients were identified by annual door to door active interviews or linkage with local electronic registry data. The primary outcome was incident esophageal severe dysplasia, carcinoma in situ, or ESCC. RESULTS: In the development cohort, 11 lesions that did not stain with iodine but were classified as not dysplastic in the histology analysis were found to be severe dysplasia, carcinoma in situ, or ESCC at the follow-up evaluation. These lesions accounted for 39.3% of all progressed lesions (n = 28). In the validation cohort, 6 patients with lesions did not stain with iodine but were classified as not dysplastic by histology had a later diagnosis of ESCC, determined from medical records; these patients accounted for 50.0% of all patients with lesion progression (n = 12) until the closing date of this study. We developed a model based on patient age, body mass index, pathology findings, and baseline iodine staining to calculate risk for severe dysplasia, carcinoma in situ, or ESCC. It identified patients for severe dysplasia, carcinoma in situ, or ESCC in the development set with an area under the curve of 0.868 (95% CI, 0.817-0.920) and in the validation set with an area under the curve of 0.850 (95% CI, 0.748-0.952). Almost no cases would be missed if subjects determined to be high or intermediate-high risk subjects by the model were included in surveillance. CONCLUSIONS: Absence of iodine staining at baseline chromoendoscopy identifies esophageal lesions at risk of progression with a high level of sensitivity. A model that combines results of iodine chromoendoscopy with other patient features identifies patients at risk of lesion progression with greater accuracy than histologic analysis of baseline biopsies.

A clinical model predicting the risk of esophageal high-grade lesions in opportunistic screening: a multicenter real-world study in China.

BACKGROUND AND AIMS: Prediction models for esophageal squamous cell carcinoma are not common, and no model targeting a clinical population has previously been developed and validated. We aimed to develop a prediction model for estimating the risk of high-grade esophageal lesions for application in clinical settings and to validate the performance of this model in an external population. METHODS: The model was developed based on the results of endoscopic evaluation of 5624 outpatients in one hospital in a high-risk region in northern China and was validated using 5765 outpatients who had undergone endoscopy in another hospital in a non-high-risk region in southern China. Predictors were selected with unconditional logistic regression analysis. The Akaike information criterion was used to determine the final structure of the model. Discrimination was estimated using the area under the receiver operating characteristic curve (AUC). Calibration was assessed using a calibration plot with an intercept and slope. RESULTS: The final prediction model contained 5 variables, including age, smoking, body mass index, dysphagia, and retrosternal pain. This model generated an AUC of 0.871 (95% confidence interval, 0.842-0.946) in the development set, with an AUC of 0.862 after bootstrapping. The 5-variable model was superior to a single age model. In the validation population, the AUC was 0.843 (95% confidence interval, 0.793-0.894). This model successfully stratified the clinical population into 3 risk groups and showed high ability for identifying concentrated groups of cases. CONCLUSIONS: Our model for esophageal high-grade lesions has a high predictive value. It has the potential for application in clinical opportunistic screening to aid decision making for both health care professionals and individuals.

An evaluation of EQ-5D-3L health utility scores using five country-specific tariffs in a rural population aged 45-69 years in Hua county, Henan province, China.

BACKGROUND: This study aims to compare the performance of the recently developed Chinese (city) tariff of the EQ-5D-3L against the UK, US, Japanese and Korean tariffs in a general rural population in China. METHODS: From November 2015 to September 2016, 12,085 permanent residents aged 45-69 from 257 villages randomly selected from Hua County, Henan Province, China, were interviewed using EQ-5D-3L, and a one-on-one questionnaire investigation was used to collect data on factors associated with HRQOL. The health utility scores were calculated using the UK, US, Japanese, Korean and Chinese (city) tariffs. The agreement, known-groups validity and sensitivity of these five tariffs were evaluated. Transition scores for pairs of observed EQ-5D-3L health states were calculated and compared. RESULTS: The Korean tariff yielded the highest mean health utility score (0.963), followed by the Chinese (city) (0.948), US (0.943), UK (0.930) and Japanese (0.921) tariffs, but the differences in the scores of any two tariffs did not exceed the MCID. The Chinese (city) tariff showed higher ICC values (ICCs> 0.89, 95% CI:0.755-0.964) and narrower limits of agreement (0.099-0.167) than the Korean tariff [(ICCs> 0.71, 95% CI:0.451-0.955); (0.146-0.253)]. The Chinese (city) tariff had a higher relative efficiency and effect size statistics in 10 out of 11 variables as compared to the UK, US and Japanese tariffs. The Chinese (city) tariff (0.215) was associated with moderate mean absolute transition scores compared with the UK (0.342), US (0.230), Japanese (0.149) and Korean (0.189) tariffs for 1485 observed pairs of the EQ-5D-3L health states. CONCLUSIONS: Health utility scores derived from the five tariffs differed. The Chinese (city) tariff was the most suitable of these tariffs and was without obvious weakness. We recommend adopting the Chinese (city) tariff when applying EQ-5D-3L to assess quality of life among the elderly in China's agricultural region with socio-economic status similar to Hua County. Results of this study had provided a crucial basis for health surveys, health promotion projects, health intervention trials, and health economic evaluation taking HRQOL as a target in rural areas of China.

Gender heterogeneity in dyslipidemia prevalence, trends with age and associated factors in middle age rural Chinese.

BACKGROUND: Heterogeneity should be carefully addressed to facilitate establishment of effective population-level blood lipid management. The primary aim of the study was to investigate gender heterogeneity in prevalence of dyslipidemia, including trends with age and associated factors in middle age rural Chinese. METHODS: This is a cross-sectional study based on a baseline investigation of a population-based randomized controlled trial in rural China, involving 26,378 permanent residents of age 45-69. The age-specific prevalence of dyslipidemia was estimated for men and women, and the trends of prevalence with age were compared. Logistic regression was used to explore the factors associated with prevalent risk of dyslipidemia. RESULTS: The overall prevalence of dyslipidemia was significantly higher in females than in males for borderline high and above (BHA) total cholesterol (TC ≥ 200 mg/dL), BHA triglycerides (TG ≥ 150 mg/dL) and BHA low-density lipoprotein cholesterol (LDL-C ≥ 130 mg/dL), but was lower for low high-density lipoprotein cholesterol (HDL-C < 40 mg/dL) in females than the corresponding prevalence in males. The prevalence of borderline high and above TC, TG and LDL-C all rose with age in females, but was stable or even decreased with age in males. In contrast, graphic representation of the prevalence of low HDL-C showed no striking age related trend in both genders. Risk of dyslipidemia was associated predominantly with obesity in males, but was more predominantly associated with hypertension in females. CONCLUSION: Heterogeneity was found in comparing the prevalence of dyslipidemia in men and women, and gender heterogeneity was found in its trend with age and associated factors in middle aged rural Chinese. The effectiveness of population-level blood lipid management and CVD primary prevention programs in China is expected to be improved if gender heterogeneity is considered.

Oral microbiome and risk of malignant esophageal lesions in a high-risk area of China: A nested case-control study.

OBJECTIVE: We aimed to prospectively evaluate the association of oral microbiome with malignant esophageal lesions and its predictive potential as a biomarker of risk. METHODS: We conducted a case-control study nested within a population-based cohort with up to 8 visits of oral swab collection for each subject over an 11-year period in a high-risk area for esophageal cancer in China. The oral microbiome was evaluated with 16S ribosomal RNA (rRNA) gene sequencing in 428 pre-diagnostic oral specimens from 84 cases with esophageal lesions of severe squamous dysplasia and above (SDA) and 168 matched healthy controls. DESeq analysis was performed to identify taxa of differential abundance. Differential oral species together with subject characteristics were evaluated for their potential in predicting SDA risk by constructing conditional logistic regression models. RESULTS: A total of 125 taxa including 37 named species showed significantly different abundance between SDA cases and controls (all P<0.05 & false discovery rate-adjusted Q<0.10). A multivariate logistic model including 11 SDA lesion-related species and family history of esophageal cancer provided an area under the receiver operating characteristic curve (AUC) of 0.89 (95% CI, 0.84-0.93). Cross-validation and sensitivity analysis, excluding cases diagnosed within 1 year of collection of the baseline specimen and their matched controls, or restriction to screen-endoscopic-detected or clinically diagnosed case-control triads, or using only bacterial data measured at the baseline, yielded AUCs>0.84. CONCLUSIONS: The oral microbiome may play an etiological and predictive role in esophageal cancer, and it holds promise as a non-invasive early warning biomarker for risk stratification for esophageal cancer screening programs.

Efficacy of endoscopic screening for esophageal cancer in China (ESECC): design and preliminary results of a population-based randomised controlled trial.

OBJECTIVE: Description of the design and preliminary results of baseline recruitment and screening in the endoscopic screening for esophageal cancer in China (ESECC), the first randomised controlled trial (RCT) assessing efficacy and cost-effectiveness of endoscopic screening for esophageal squamous cell carcinoma (ESCC). DESIGN: ESECC trial is a cluster RCT, and 668 villages in rural Hua County, Henan Province, a high-incidence area of ESCC in China, were randomised into two arms at a ratio of 1:1. Screening arm participants were screened by Lugol chromoendoscopy; no screening was performed in the control arm. ESCC-specific and all-cause mortality, incidence of advanced ESCC and cost-effectiveness of screening will be evaluated in the next 10-year follow-up. Here, we report the performance of baseline recruitment and randomisation, prevalence of upper GI lesions and risk factors for ESCC. RESULTS: A total of 17 151 and 16 797 participants were enrolled in screening and control arms from January 2012 to September 2016. The truncated prevalence (aged 45-69 years) of oesophageal and overall upper GI high-grade lesions was 744.0/100 000 and 902.0/100 000. 69.9% of the 113 patients with high-grade oesophageal lesions were of early stage. Risk factors for severe oesophageal dysplasia and more severe lesions in this population included higher age, family history of ESCC, lower body mass index, eating rapidly and frequent ingestion of leftovers. CONCLUSION: This ESECC trial met the predesigned recruitment and randomisation requirements. Age, family history, undernutrition and unhealthy dietary habits increased the risk for high-grade oesophageal lesions in this high-risk population. TRAIL REGISTRATION NUMBER: NCT01688908; Pre-results.

Effectiveness of Intensive Endoscopic Screening for Esophageal Cancer in China: A Community-Based Study.

Evidence is required to evaluate the effectiveness of population-level endoscopic screening for esophageal cancer (EC). In this study, 5,632 permanent residents aged 25-65 years from 6 villages in Hua County, Henan Province, China, were defined as the screening cohort and were offered intensive endoscopic screening. Residents of all 914 remaining villages in Hua County were included as the control cohort, and age-sex standardization was used to calculate the expected numbers of EC and upper gastrointestinal (GI) tract cancer cases and deaths in the screening cohort. The effectiveness of screening was assessed by comparing observed numbers of cases and deaths with expected numbers after 9-year follow-up of these screened subjects (2007-2016). In the screening cohort, 23 upper GI cancers (including 16 ECs) and 10 upper GI cancer deaths (including 5 EC deaths) were identified, and 47% (standardized incidence ratio = 0.53, 95% confidence interval (CI): 0.33, 0.87) and 66% (standardized mortality ratio = 0.34, 95% CI: 0.14, 0.81) reductions in cumulative EC incidence and mortality were found. For upper GI cancers, incidence and mortality were lowered by 43% (standardized incidence ratio = 0.57, 95% CI: 0.38, 0.86) and 53% (standardized mortality ratio = 0.47, 95% CI: 0.25, 0.88), respectively. This study showed that upper GI tract endoscopy is an effective population-level screening test for EC in high-risk regions.

Generating Supercharged Protein Ions for Breath Analysis by Extractive Electrospray Ionization Mass Spectrometry.

Supercharged protein ions produced by electrospray ionization are extremely efficient proton donors for secondary ionization. Here, by electrospraying the protein solutions containing 5% 1,2-butylene carbonate, the supercharged protein ions with unusually high proton density were produced as the primary ions for the ionization of exhaled breath samples in the extractive electrospray ionization mass spectrometry (EESI-MS), which resulted in the enhanced ionization efficiency for the breath analytes even with relatively low gas phase basicity. Moreover, the total number of metabolites detected in breath increased by about 260% in the mass range of 200-500 Da, owing to the substantial signal enhancement for breath metabolites, providing complementary and additional information to conventional SESI.

Identification of cancer patients using claims data from health insurance systems: A real-world comparative study.

OBJECTIVE: To evaluate the accuracy of identifying cancer patients by use of medical claims data in a health insurance system in China, and provide the basis for establishing the claims-based cancer surveillance system in China. METHODS: We chose Hua County, Henan Province as the study site, and randomly selected 300 and 1,200 qualified inpatient electronic medical records (EMRs) as well as the New Rural Cooperative Medical Scheme (NCMS) claims records for cancer patients in Hua County People's Hospital (HCPH) and Anyang Cancer Hospital (ACH) in 2017. Diagnostic information for NCMS claims was evaluated on an individual level, and sensitivity and positive predictive value (PPV) were calculated taking the EMRs as the gold standard. RESULTS: The sensitivity of NCMS was 95.2% (93.8%-96.3%) and 92.0% (88.3%-94.8%) in ACH and HCPH, respectively. The PPV of the NCMS was 97.8% (96.7%-98.5%) in ACH and 89.0% (84.9%-92.3%) in HCPH. Overall, the weighted and combined sensitivity and PPV of NCMS in Hua County was 93.1% and 92.1%, respectively. Significantly higher sensitivity and PPV in identifying patients with common cancers than non-common cancers were detected in HCPH and ACH separately (P<0.01). CONCLUSIONS: Identification of cancer patients by use of the NCMS is accurate on individual level, and it is therefore feasible to conduct claims-based cancer surveillance in areas not covered by cancer registries in China.

Lugol Chromoendoscopy Detects Esophageal Dysplasia With Low Levels of Sensitivity in a High-Risk Region of China.

BACKGROUND & AIMS: Chromoendoscopy with Lugol dye is used to screen for early-stage esophageal squamous dysplasia (ESD) and esophageal cancer. However, the sensitivity with which Lugol chromoendoscopy detects ESD or esophageal cancer has not been fully assessed in large populations in China. METHODS: From 2012 to 2016, a total of 15,264 residents in rural Hua County, Henan Province, which is a high-incidence area of esophageal cancer in China, were screened by Lugol chromoendoscopy. Biopsies were collected from endoscopically visualized lesions, identified before and after Lugol chromoendoscopy, and analyzed histologically. Biopsies were also collected from standard sites in the esophagus (28 and 33 cm distal to the incisors) if no abnormalities were found. We calculated the sensitivity with which Lugol chromoendoscopy detects esophageal dysplasia and carcinoma, using findings from biopsy analysis as the reference standard. RESULTS: A total 586 participants were found by biopsy analysis to have ESD or more severe lesions. After endoscopy images were reviewed twice, Lugol chromoendoscopy sensitivity values for the detection of mild, moderate, and severe dysplasia, and esophageal cancer, were 45.9%, 55.3%, 87.0%, and 97.7%, respectively. ESDs were most frequently missed by Lugol chromoendoscopy in younger patients and men with moderate levels of dysplasia. CONCLUSION: In a screening analysis of a general population in China, we found Lugol chromoendoscopy to identify individuals with ESD with lower levels of sensitivity (46%-87%) than previously believed, although it identified patients with esophageal cancer with almost 98% sensitivity. Prospective studies are needed to evaluate the clinical significance of esophageal lesions that are not detected by endoscopy.

Health-related quality of life among rural residents aged 45-69 years in Hua County, Henan Province, China: Results of ESECC Trial for esophageal cancer screening with endoscopy.

OBJECTIVE: There have been few population-based studies evaluating health related quality of life (HRQOL) in rural populations in China, and this study aimed to assess the current status of and risk factors for HRQOL in a general rural population in high risk region of esophageal cancer in China. METHODS: From November 2015 to September 2016, 12,085 permanent residents aged 45-69 years from 257 villages in the Endoscopic Screening for Esophageal Cancer in China (ESECC) trial (ClinicalTrials.gov: NCT01688908) randomly selected from Hua County, Henan Province, China were interviewed. The EQ-5D-3L, a generic measure of HRQOL, and a questionnaire were used to assess their HRQOL and potential risk factors. RESULTS: Among all the participants, 30.62% of the participants reported problems in at least one EQ-5D dimension. Pain/discomfort (25.52%) was the most frequently reported problem followed by anxiety/depression (7.97%), mobility (5.82%), usual activities (2.61%) and self-care (1%). These rural residents had a mean EQ-5D index score of 0.948, and lower EQ-5D index scores were associated with older age, female gender, lower levels of household annual per capita income, living alone, using shallow wells as main source of drinking water, exposure to family members smoking, testiness, unhealthy dietary habits, overweight or obesity, upper gastrointestinal cancer related symptoms and chronic diseases. CONCLUSIONS: Rural residents in China have a relatively low quality of life. Health promotion programs in this population should focus on the elderly, especially elderly women and the elderly living alone. Improving basic living circumstances and primary medical care services should be priorities. Results of this study will also serve as the basis for the cost-utility evaluation in our ESECC screening trial.

IL-12-based vaccination therapy reverses liver-induced systemic tolerance in a mouse model of hepatitis B virus carrier.

Liver-induced systemic immune tolerance that occurs during chronic hepadnavirus infection is the biggest obstacle for effective viral clearance. Immunotherapeutic reversal of this tolerance is a promising strategy in the clinic but remains to be explored. In this study, using a hepatitis B virus (HBV)-carrier mouse model, we report that IL-12-based vaccination therapy can efficiently reverse systemic tolerance toward HBV. HBV-carrier mice lost responsiveness to hepatitis B surface Ag (HBsAg) vaccination, and IL-12 alone could not reverse this liver-induced immune tolerance. However, after IL-12-based vaccination therapy, the majority of treated mice became HBsAg(-) in serum; hepatitis B core Ag was also undetectable in hepatocytes. HBV clearance was dependent on HBsAg vaccine-induced anti-HBV immunity. Further results showed that IL-12-based vaccination therapy strongly enhanced hepatic HBV-specific CD8(+) T cell responses, including proliferation and IFN-γ secretion. Systemic HBV-specific CD4(+) T cell responses were also restored in HBV-carrier mice, leading to the arousal of HBsAg-specific follicular Th-germinal center B cell responses and anti-hepatitis B surface Ag Ab production. Recovery of HBsAg-specific responses also correlated with both reduced CD4(+)Foxp3(+) regulatory T cell frequency and an enhanced capacity of effector T cells to overcome inhibition by regulatory T cells. In conclusion, IL-12-based vaccination therapy may reverse liver-induced immune tolerance toward HBV by restoring systemic HBV-specific CD4(+) T cell responses, eliciting robust hepatic HBV-specific CD8(+) T cell responses, and facilitating the generation of HBsAg-specific humoral immunity; thus, this therapy may become a viable approach to treating patients with chronic hepatitis B.