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1.  Association between upper digestive tract microbiota and cancer predisposing states in the esophagus and stomach 
Background
The human upper digestive tract microbial community (microbiota) is not well characterized and few studies have explored how it relates to human health. We examined the relationship between upper digestive tract microbiota and two cancer predisposing states, serum pepsinogen I/pepsinogen II ratio (PGI/II) (predictor of gastric cancer risk), and esophageal squamous dysplasia (ESD) (the precursor lesion of esophageal squamous cell carcinoma (ESCC)) in a cross-sectional design.
Methods
The Human Oral Microbe Identification Microarray was used to test for the presence of 272 bacterial species in 333 upper digestive tract samples from a Chinese cancer screening cohort. Serum PGI and PGII were determined by enzyme-linked immunosorbent assays. ESD was determined by chromoendoscopy with biopsy.
Results
Lower microbial richness (number of bacterial genera per sample) was significantly associated with lower PGI/II ratio (P=0.034) and the presence of ESD (P=0.018). We conducted principal component (PC) analysis on a β-diversity matrix (pairwise difference in microbiota), and observed significant correlations between PC1, PC3 and PGI/II (P=0.004, 0.009 respectively), and between PC1 and ESD (P=0.003).
Conclusions
lower microbial richness in upper digestive tract was independently associated with both cancer predisposing states in the esophagus and stomach (presence of ESD and lower PGI/II).
doi:10.1158/1055-9965.EPI-13-0855
PMCID: PMC4011942  PMID: 24700175
microbiota; gastric cancer; esophageal squamous cell carcinoma; esophageal squamous dysplasia; serum pepsinogen I/pepsinogen II ratio
2.  Serum pepsinogens and risk of gastric and esophageal cancers in the General Population Nutrition Intervention Trial cohort 
Gut  2009;58(5):636-642.
Objective
Low serum pepsinogen I (PGI) and low pepsinogen I/pepsinogen II ratio (PGI/II ratio) are markers of gastric fundic atrophy. We aimed to prospectively test the association between serum PGI/II ratio and risks of gastric noncardia adenocarcinoma, gastric cardia adenocarcinoma, and esophageal squamous cell carcinoma.
Design
Case-cohort study nested in a prospective cohort with over 15 years of follow-up.
Setting
Rural region of the People’s Republic of China.
Subjects
Men and women aged 40-69 at study baseline.
Main outcome measures
Adjusted hazard ratios and 95% confidence intervals for the association between serum PGI/II ratio and caner risk
Results
Compared to subjects with PGI/II ratio of > 4, those with ≤4 had HRs (95%CIs) of 2.72 (1.77-4.20) and 2.12 (1.42-3.16) for noncardia and cardia gastric cancers, respectively. Risk of both cancers were also increased when other cut points ranging from 3 to 6, or when we used quartile models, or nonlinear continuous models. Risk of ESCC was marginally increased in those with PGI/II ratio ≤4, with HR (95% CI) of 1.56 (0.99-2.47), but quartile models and continuous models showed no increased risk. The nonlinear continuous models suggested that any single cut point collapsed subjects with dissimilar gastric cancer risks, and that using cut points was not an efficient use of data in evaluating these associations.
Conclusion
In this prospective study, we found similar and significantly increased risks of noncardia and cardia gastric adenocarcinomas in subjects with low PGI/II ratio, but little evidence for an association with ESCC risk.
doi:10.1136/gut.2008.168641
PMCID: PMC2792746  PMID: 19136509
Gastric cancer; Esophageal cancer; Pepsinogen; Case-cohort
3.  Accuracy and Cut-Off Values of Pepsinogens I, II and Gastrin 17 for Diagnosis of Gastric Fundic Atrophy: Influence of Gastritis 
PLoS ONE  2011;6(10):e26957.
Background
To establish optimal cutoff values for serologic diagnosis of fundic atrophy in a high-risk area for oesophageal squamous cell carcinoma and gastric cancer with high prevalence of Helicobacter pylori (H. pylori) in Northern Iran, we performed an endoscopy-room-based validation study.
Methods
We measured serum pepsinogens I (PGI) and II (PGII), gastrin 17 (G-17), and antibodies against whole H. pylori, or cytotoxin-associated gene A (CagA) antigen among 309 consecutive patients in two major endoscopy clinics in northeastern Iran. Updated Sydney System was used as histology gold standard. Areas under curves (AUCs), optimal cutoff and predictive values were calculated for serum biomarkers against the histology.
Results
309 persons were recruited (mean age: 63.5 years old, 59.5% female). 84.5% were H. pylori positive and 77.5% were CagA positive. 21 fundic atrophy and 101 nonatrophic pangastritis were diagnosed. The best cutoff values in fundic atrophy assessment were calculated at PGI<56 µg/l (sensitivity: 61.9%, specificity: 94.8%) and PGI/PGII ratio<5 (sensitivity: 75.0%, specificity: 91.0%). A serum G-17<2.6 pmol/l or G-17>40 pmol/l was 81% sensitive and 73.3% specific for diagnosing fundic atrophy. At cutoff concentration of 11.8 µg/l, PGII showed 84.2% sensitivity and 45.4% specificity to distinguish nonatrophic pangastritis. Exclusion of nonatrophic pangastritis enhanced diagnostic ability of PGI/PGII ratio (from AUC = 0.66 to 0.90) but did not affect AUC of PGI. After restricting study samples to those with PGII<11.8, the sensitivity of using PGI<56 to define fundic atrophy increased to 83.3% (95%CI 51.6–97.9) and its specificity decreased to 88.8% (95%CI 80.8–94.3).
Conclusions
Among endoscopy clinic patients, PGII is a sensitive marker for extension of nonatrophic gastritis toward the corpus. PGI is a stable biomarker in assessment of fundic atrophy and has similar accuracy to PGI/PGII ratio among populations with prevalent nonatrophic pangastritis.
doi:10.1371/journal.pone.0026957
PMCID: PMC3204997  PMID: 22066020
4.  Serum pepsinogens and Helicobacter pylori in relation to the risk of esophageal squamous cell carcinoma in the ATBC Study 
Background
Helicobacter pylori (H. pylori) can induce gastric atrophy in humans, which in turn increases gastric cancer risk. Whether H. pylori and gastric atrophy also affect the risk of esophageal squamous cell carcinoma (ESCC), however, remains unresolved.
Methods
We performed a nested case-control study within the prospective ATBC Study to assess these relationships. The ATBC Study is composed of 29,133 Finnish male smokers, aged 50–69, who were recruited during 1985–1988. Using baseline sera, we assessed H. pylori status (via IgG antibodies against whole-cell and CagA antigens) and gastric atrophy status (via the biomarkers pepsinogen I (PGI) and II (PGII)) in 79 ESCC cases and 94 controls. Logistic regression with adjustment for age, date of blood draw, education, cigarette smoking, alcohol, body mass index, and fruit and vegetable intake was used to estimate odds ratios (OR) and 95% confidence intervals (95%CI).
Results
Gastric atrophy (PGI:PGII <4) was associated with ESCC (OR=4.58, 95%CI:2.00–10.48). There was no evidence for an association between H. pylori and ESCC (OR=0.94, 95%CI:0.40–2.24).
Conclusions
These results could be explained by misclassification of H. pylori status due to serologic amnesia, ESCC risk being dependent upon the functional consequences or interactions of H. pylori, rather than the infection per se, gastric atrophy having a different histogenesis in ESCC without being primarily dependent upon H. pylori acquisition, or a lack of statistical power to detect an effect.
Impact
Validation of these results may warrant mechanistic studies to determine the route of association between gastric atrophy and ESCC.
doi:10.1158/1055-9965.EPI-10-0270
PMCID: PMC2919643  PMID: 20647397
Atrophy; Esophageal Neoplasms; Helicobacter pylori; Nested Case-Control Studies; Pepsinogens; Prospective Studies
5.  Serum Ghrelin; A New Surrogate Marker of Gastric Mucosal Alterations in Upper Gastrointestinal Carcinogenesis 
PLoS ONE  2013;8(9):e74440.
Background
A few studies have indicated inverse relationships between serum ghrelin and gastric and esophageal cancers but those associations have been restricted to specific populations, including smokers and overweight individuals. We examined the association between ghrelin and gastroesophageal cancers and atrophic gastritis in a population-based setting.
Methods
In total 220 gastroesophageal cancers, comprising non-cardia and cardia gastric cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma (SCC) and age and gender-matched controls were recruited. Serum ghrelin, pepsinogen I/II ratio (PGI/II) and anti-H.pylori IgG antibodies were measured. Relationships between ghrelin and gastroesophageal cancers, after adjustment for PGI/II ratio, H.pylori status and smoking, were tested using logistic regression. Furthermore, in 125 endoscopically normal volunteers, with and without histological atrophic gastritis, the relationship with ghrelin was compared.
Results
Serum ghrelin (lowest vs. highest quintile) was inversely associated with gastric cancer: OR (95% CI) 8.71 (1.70–44.59) for cardia and 6.58 (1.26–34.46) for non-cardia cancer. Lower serum ghrelin was also associated with esophageal SCC: OR (95% CI) 5.69 (1.36–23.78), but not with esophageal adenocarcinoma. A similar association was observed between gastric cancer (cardia and non-cardia) and esophageal SCC when serum ghrelin was analysed as a continuous scaled variable. In endoscopically-normal volunteers, extensive atrophic gastritis was associated with low serum ghrelin [OR (95% CI) 0.25 (0.10–0.64)].
Conclusion
Inverse associations between ghrelin and some gastroesophageal cancers suggest a potential role for serum ghrelin as a biomarker of upper gastrointestinal cancers and atrophic gastritis. In areas with a high incidence of gastric and/or esophageal cancer, screening might be more effectively targeted to individuals with low serum ghrelin in addition to the PGI/II ratio.
doi:10.1371/journal.pone.0074440
PMCID: PMC3787044  PMID: 24098650
6.  Gastric atrophy and oesophageal squamous cell carcinoma: possible interaction with dental health and oral hygiene habit 
British Journal of Cancer  2012;107(5):888-894.
Background:
Gastric fundal atrophy has been hypothesised to increase the risk of oesophageal squamous cell carcinoma (OSCC), but studies have shown inconsistent results.
Methods:
We measured serum pepsinogen I (PGI) and pepsinogen II (PGII) among 293 incident cases and 524 matched neighbourhood controls in a high-risk area of Northern Iran. Conditional logistic regression model was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs).
Results:
After controlling for age, sex, residence area and other potential confounders, gastric atrophy (defined by a validated criterion, PGI <55 μg dl−1) was associated with a two-fold increased risk (OR=2.01, 95% CI: 1.18, 3.45) of OSCC in the absence of nonatrophic pangastritis (defined as PGII <11.8 μg dl−1). Stratification by PGII decreased the misclassification errors due to cancer-induced gastritis. Presence of both poor dental health, indicated by higher than median sum of decayed, missing, and filled teeth (DMFT score), and gastric atrophy further increased the risk of OSCC (OR=4.15, 95% CI: 2.04, 8.42) with relative excess risk due to interaction (RERI) of 1.47 (95% CI: −1.15, 4.1). Coexistence of poor oral hygiene habit with gastric atrophy elevated OSCC risk eight times (OR=8.65, 95% CI: 3.65, 20.46) and the additive interaction index was marginally statistically significant (RERI=4.34, 95% CI: −1.07, 9.76).
Conclusion:
Gastric atrophy is a risk factor for OSCC, and poor dental health and oral hygiene habit may act synergistically in increasing the risk.
doi:10.1038/bjc.2012.332
PMCID: PMC3425966  PMID: 22814581
atrophic gastritis; oesophageal neoplasm; relative risk; dental health; oral hygiene; pepsinogen
7.  Serum ghrelin is inversely associated with risk of subsequent oesophageal squamous cell carcinoma 
Gut  2011;61(11):1533-1537.
Background
Oesophageal cancers rank as the eighth most common cancer and the sixth most common cause of cancer death, worldwide. Gastric atrophy, as determined by a low serum pepsinogen I/II ratio, may be associated with an increased risk of oesophageal squamous cell carcinoma (OSCC). Ghrelin, a hormone which, like pepsinogen, is produced in the fundic glands of the stomach, may be a sensitive and specific marker of gastric atrophy, but its association with OSCC is not known.
Methods
To examine the relationship between baseline serum ghrelin concentration and subsequent risk of OSCC, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. 82 cases of OSCC were matched (1:1) by age and date of blood draw to controls from the ATBC study. Serum ghrelin was measured by radioimmunoassay. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression with adjustment for potential confounders.
Results
For those individuals in the lowest quartile of serum ghrelin, compared to those in the highest, the multivariate odds ratio of subsequent OSCC was 6.83 (95% CI: 1.46, 31.84). These associations were dose dependent (P for trend = 0.005 for both), and independent of the effects of low pepsinogen I/II ratio (a marker of gastric fundic atrophy) and Helicobacter pylori infection. The significance of these associations remained even for individuals developing OSCC up to 10 years after baseline ghrelin measurement, though they become attenuated after 10 years.
Conclusion
Lower baseline concentrations of serum ghrelin were associated with an increase in risk of OSCC. Further studies are needed to confirm this finding in other populations and to explore the role of ghrelin in the aetiology of OSCC.
doi:10.1136/gutjnl-2011-300653
PMCID: PMC3462270  PMID: 22180062
ghrelin; oesophageal squamous cell carcinoma; atrophy
8.  Pepsinogen I and II expressions in situ and their correlations with serum pesignogen levels in gastric cancer and its precancerous disease 
Background
Serum pepsinogen (PG) I/II ratio has been widely used as “serological biopsy” for the screening of gastric cancer (GC) and atrophic gastritis (GA). However, study concerning in situ expression of PGs is currently insufficient, particularly for their relationship with serum PGs levels. This study was designed to investigate in situ expression of PGI and PGII in subjects with normal mucosa (NOR), superficial gastritis (GS), GA and GC, and to evaluate the correlations between PGs expressions in situ and in serum.
Methods
185 subjects were enrolled for the study, including 30 NOR, 70 GS, 54 GA and 31 GC. PGI and PGII expressions in situ and in serum were detected by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) respectively. H. pylori immunoglobulin (Ig) G was also determined by ELISA.
Results
In situ expressions of PGI, PGII and PGI/II ratio consistently decreased in sequence of NOR/GS- > GA- > GC. The expressions of PGI, PGII and PGI/II ratio in situ were statistically higher in youngers than in olders (P < 0.05). In the NOR subjects, PGI staining was statistically higher in males than that in females (p = 0.02). For the correlations between in situ and serum expressions of PGI, PGII and PGI/II ratio, a borderline correlation in the total study sample (r = 0.131, P = 0.076) and a statistical correlation in GA cases (r = 0.307, P = 0.027) were observed for the PGI/II ratio. The PGI expression correlated well with that of PGII in situ and in serum.
Conclusions
The in situ levels of PGI, PGII and PGI/II ratio sharply decreased in the GA and GC cases. The youngers exhibited higher levels of PGI, PGII and PGI/II ratios than the olders. The in situ PGI/II ratio rather than PGI and PGII alone showed certain correlation with that in serum, and the PGI expression correlated well with PGII expression. Further studies with large-scale samples are still required to validate our findings.
doi:10.1186/1472-6890-13-22
PMCID: PMC3846408  PMID: 24004680
Pepsinogen; Gastric disease; Correlation
9.  Serum thyroglobulin, a biomarker for iodine deficiency, is not associated with increased risk of upper gastrointestinal cancers in a large Chinese cohort 
Iodine concentrates in gastric tissue and may act as an antioxidant for the stomach. We previously showed that self-reported goiter was associated with significantly increased risk of gastric noncardia adenocarcinoma (GNCA) and non-significantly increased risks of gastric cardia adenocarcinoma (GCA) and esophageal squamous cell carcinoma (ESCC) in a prospective case-cohort study in a high-risk population in China. Negatively correlated with iodine levels, serum thyroglobulin (Tg) is a more sensitive biomarker of iodine deficiency than goiter. This study aimed to determine whether baseline serum Tg was also associated with development of GNCA, GCA, and ESCC in the same cohort, the Linxian General Population Nutrition Intervention Trial. Sera from approximately 200 subjects of each case type and 400 non-cases were tested for serum Tg concentration using appropriate assays. Tg was modeled as sex- and assay-specific quartiles in Cox regression models adjusted for age, smoking, alcohol, Helicobacter pylori status, pepsinogens I/II ratio, family history, and commune of residence. In the final combined analysis, participants in the highest quartile of serum Tg, compared to those in the lowest quartile, had adjusted Hazard Ratios of 0.88 (95% confidence interval 0.50–1.52), 1.14 (0.63–2.05), and 0.78 (0.47–1.31) for GNCA, GCA, and ESCC, respectively. Using serum Tg, a sensitive biomarker of iodine deficiency, we found no association between serum Tg concentrations and risk of these upper gastrointestinal (UGI) cancers in the study population. Our results do not support the hypothesis that iodine deficiency, as assessed by serum Tg, is associated with an increased risk of UGI cancers.
doi:10.1002/ijc.25789
PMCID: PMC3075342  PMID: 21105043
iodine deficiency; esophageal cancer; gastric cancer; thyroglobulin; China
10.  Measuring telomere length for the early detection of precursor lesions of esophageal squamous cell carcinoma 
BMC Cancer  2013;13:578.
Background
Esophageal cancer is the sixth leading cause of cancer death worldwide; current early detection screening tests are inadequate. Esophageal balloon cytology successfully retrieves exfoliated and scraped superficial esophageal epithelial cells, but cytologic reading of these cells has poor sensitivity and specificity for detecting esophageal squamous dysplasia (ESD), the precursor lesion of esophageal squamous cell carcinoma (ESCC). Measuring telomere length, a marker for chromosomal instability, may improve the utility of balloon cytology for detecting ESD and early ESCC.
Methods
We examined balloon cytology specimens from 89 asymptomatic cases of ESD (37 low-grade and 52 high-grade) and 92 age- and sex-matched normal controls from an esophageal cancer early detection screening study. All subjects also underwent endoscopy and biopsy, and ESD was diagnosed histopathologically. DNA was extracted from the balloon cytology cells, and telomere length was measured by quantitative PCR. A receiver operating characteristic (ROC) curve was plotted for telomere length as a diagnostic marker for high-grade dysplasia.
Results
Telomere lengths were comparable among the low- and high-grade dysplasia cases and controls, with means of 0.96, 0.96, and 0.92, respectively. The area under the ROC curve was 0.55 for telomere length as a diagnostic marker for high-grade dysplasia. Further adjustment for subject characteristics, including sex, age, smoking, drinking, hypertension, and body mass index did not improve the use of telomere length as a marker for ESD.
Conclusions
Telomere length of esophageal balloon cytology cells was not associated with ESCC precursor lesions. Therefore, telomere length shows little promise as an early detection marker for ESCC in esophageal balloon samples.
doi:10.1186/1471-2407-13-578
PMCID: PMC3882883  PMID: 24308314
Esophageal squamous cell carcinoma; Esophageal squamous dysplasia; Early detection; Screening; Balloon cytology; Telomeres
11.  Serum pepsinogen II is a better diagnostic marker in gastric cancer 
AIM: To investigate screening makers for gastric cancer, we assessed the association between gastric cancer and serum pepsinogens (PGs).
METHODS: The subjects comprised 450 patients with gastric cancer, 111 individuals with gastric atrophy, and 961 healthy controls. Serum anti-Helicobacter pylori (H. pylori) immunoglobulin G (IgG), PGIand PG II were detected by enzyme-linked immunosorbent assay. Gastric atrophy and gastric cancer were diagnosed by endoscopy and histopathological examinations. Odds ratios and 95%CIs were calculated using multivariate logistic regression.
RESULTS: Rates of H. pylori infection remained high in Northeastern China. Rates of H. pylori IgG positivity were greater in the gastric cancer and gastric atrophy groups compared to the control group (69.1% and 75.7% vs 49.7%, P < 0.001). Higher levels of PG II (15.9 μg/L and 13.9 μg/L vs 11.5 μg/L, P < 0.001) and lower PGI/PG II ratio (5.4 and 4.6 vs 8.4, P < 0.001) were found in patients with gastric cancer or gastric atrophy compared to healthy controls, whereas no correlation was found between the plasma PGIconcentration and risk of gastric cancer (P = 0.537). In addition, multivariate logistic analysis indicated that H. pylori infection and atrophic gastritis were independent risk factors for gastric cancer. Lower plasma PGI/PG II ratio was associated with higher risks of atrophy and gastric cancer. Furthermore, plasma PG II level significantly correlated with H. pylori-infected gastric cancer.
CONCLUSION: Serum PG II concentration and PGI/PG II ratio are potential biomarkers for H. pylori-infected gastric disease. PG II is independently associated with risk of gastric cancer.
doi:10.3748/wjg.v18.i48.7357
PMCID: PMC3544042  PMID: 23326145
Gastric cancer; Pepsinogens; Helicobacter pylori; Gastric atrophy; Screening
12.  Low Levels of Pepsinogen I and Pepsinogen I/II Ratio are Valuable Serologic Markers for Predicting Extensive Gastric Corpus Atrophy in Patients Undergoing Endoscopic Mucosectomy 
Gut and Liver  2010;4(4):475-480.
Background/Aims
The levels of pepsinogen (PG) I and the PGI/II ratio are useful serologic markers for chronic atrophic gastritis. This study evaluated the performance and clinical implications of these markers in patients undergoing endoscopic mucosectomy.
Methods
We enrolled 142 consecutive patients with early gastric tumors and Helicobacter pylori infection who were eligible for mucosectomy. Chronic gastritis and atrophy were assessed using four defined biopsy procedures. Serum PGs were measured by an enzyme immunoassay. Optimal diagnostic cut-offs and performance were determined using receiver operating characteristic curves.
Results
The PGI level and the PGI/II ratio decreased with corpus-dominant gastritis and as atrophy advanced toward the corpus greater curvature (GC). For the presence of corpus GC atrophy, the areas under the PGI and PGI/II-ratio curves were 0.82 and 0.77, respectively. The optimal cut-off levels were 59.3µg/L for PGI (sensitivity, 83.3%; specificity, 78.4%) and 3.6µg/L for PGI/II ratio (sensitivity, 70.0%; specificity, 78.4%). Using these serologic cut-off levels, we found that the frequency of corpus tumor location differed significantly (32.9% vs 11.1% for PGI <59.3 and ≥59.3µg/L, respectively; and 31.1% vs 14.8% for PGI/II ratio <3.5 and ≥3.5, respectively; p<0.05).
Conclusions
A low PGI level and PGI/II ratio are valuable serologic markers for predicting corpus GC atrophy, and have clinical implications with respect to the corpus location of tumors in mucosectomy patients.
doi:10.5009/gnl.2010.4.4.475
PMCID: PMC3021602  PMID: 21253295
Pepsinogens; Atrophic gastritis; Stomach neoplasia; Helicobacter pylori; Endoscopy
13.  Validity of Serum Pepsinogen I/II Ratio for the Diagnosis of Gastric Epithelial Dysplasia and Intestinal Metaplasia during the Follow-Up of Patients at Risk for Intestinal-Type Gastric Adenocarcinoma1 
Neoplasia (New York, N.Y.)  2004;6(5):449-456.
Abstract
A cohort of individuals (n = 136) with lesions as severe as atrophic chronic gastritis (ACG) was cross-sectionally evaluated for the validity assessment of pepsinogen I (PGI) and pepsinogen II (PGII) serum levels for the diagnosis of intestinal metaplasia (IM) and gastric dysplasia. PGI/PGII ratio [median (range)] was 4 (0.5–7.5) in patients with ACG (n = 35); 4.6 (1.9–6.8) in type I IM (n = 18); 4.2 (1.4–5.9) in type II or type III IM limited to the antrum and incisura (n = 20); 2.4 (0.4–5.6) in extensive incomplete IM (n = 38); and 1.3 (0.4–6.4) in low-grade dysplasia (n = 23) (P = .002). Using histopathologic data as a reference test, the area under the receiver operating characteristic curves (CI 95%) was 0.73 (0.64–0.82) for extensive IM, 0.72 (0.58–0.85) for the diagnosis of dysplasia, and 0.81 (0.66–0.95) for the diagnosis of high-grade dysplasia. Using a PGI/PGII ratio of ≤3 as the cutoff for dysplasia diagnosis, the sensitivity was 70% (62–78%), the specificity was 65% (57–73%), and the negative predictive value estimates were over 90%. No differences in PG levels according to age or gender were observed. Helicobacter pylori did not significantly influence validity measurement estimates. PGI/PGII serum level ratio can be used even in the management of patients with a high a priori probability for a positive test. It may be useful for the exclusion of more advanced lesions (extensive IM and neoplastic lesions).
PMCID: PMC1531649  PMID: 15548353
Pepsinogens; stomach neoplasms; receiver operating characteristic curve; disease management; precancerous conditions
14.  Relation of atrophic gastritis with Helicobacter pylori-CagA+ and interleukin-1 gene polymorphisms 
AIM: To determine the association of Helicobacter pylori (H pylori) CagA+ infection and pro-inflammatory polymorphisms of the genes interleukin (IL)-1RN and IL-1B with the risk of gastric atrophy and peptic ulcers in a dyspeptic population in Costa Rica, a country with high incidence and mortality of gastric cancer.
METHODS: Seven biopsy specimens, a fasting blood sample and a questionnaire concerning nutritional and sociodemographic factors were obtained from 501 consecutive patients who had undergone endoscopy for dyspeptic symptoms. A histopathological diagnosis was made. Pepsinogen concentrations were analyzed by enzyme linked immunosorbent assay (ELISA). Infection with H pylori CagA+ was determined by serology and polymerase chain reaction (PCR). IL-1B and IL-1RN polymorphisms genotyping was performed by PCR-restriction fragment length polymorphism (PCR-RFLP) and PCR respectively.
RESULTS: In this dyspeptic population, 86% were H pylori positive and of these, 67.8% were positive for CagA. Atrophic antral gastritis (AAG) was associated with CagA+ status [odd ratio (OR) = 4.1; P < 0.000] and fruit consumption (OR = 0.3; P < 0.00). Atrophic body gastritis (ABG) was associated with pepsinogen PGI/PGII < 3.4 (OR = 4.9; P < 0.04) and alcohol consumption (OR = 7.3; P < 0.02). Duodenal ulcer was associated with CagA+ (OR = 2.9; P < 0.04) and smoking (OR = 2.4; P < 0.04). PGI < 60 μg/L as well as PGI/PGII < 3.4 were associated with CagA+.
CONCLUSION: In a dyspeptic population in Costa Rica, H pylori CagA+ is not associated with ABG, but it is a risk factor for AAG. The pro-inflammatory cytokine polymorphisms IL-1B + 3945 and IL-1RN are not associated with the atrophic lesions of this dyspeptic population.
doi:10.3748/wjg.14.6481
PMCID: PMC2773333  PMID: 19030199
Atrophic gastritis; Pepsinogen; Peptic ulcers; Helicobacter pylori-CagA; Interleukins
15.  Accuracy of pepsinogens for early diagnosis of atrophic gastritis and gastric cancer in Iranian population 
Background: Currently, non-invasive methods for screening atrophic gastritis and gastric cancer are lacking. The purpose of this study was to evaluate the value of serological parameters including serum pepsinogen I (PGI), pepsinogen II (PGII) and pepsinogen I: II ratio for the screening atrophic gastritis and gastric cancer.
Methods: The study population consisted of 132 dyspeptic patients who had undergone upper endoscopy with biopsy. Blood samples for ELISA assays of serum PGI, PGII and IgG antibodies against Helicobacter pylori were drawn. Comparison between the two groups was done by Student’s t- test, and Mann Whitney test. Cut-off points were calculated using receiver operating curves (ROC).
Results: Mean (±SD) age of the study population was 51.4 (±15.5) years. Values of PGI and PG ratio decreased significantly in the atrophic gastritis as compared with the control group (p<0.05). Values of PG and PG ratio didn’t show any significant difference between the gastric cancer and control group (p>0.05). For patients with atrophic gastritis, the area under the ROC for PGI was 0.639 (95% CI:0.538-0.741, p=0.008) in which the best cut-off value was 40μg/L (sensitivity 90%, specificity 67%, accuracy 69%, negative predictive value 92%, YI : 0.429). The area under the ROC for PG ratio was 0.711 (95% CI: 0.617–0.806, p=0.0001) and the best cut-off value was 8 (sensitivity 71%, specificity 71%, accuracy 71%, negative predictive value 86%,YI : 0.431).
Conclusion: It seems that PGI, PGI: PGII ratio is potential biomarkers for screening atrophic gastritis with high sensitivity, specificity, accuracy and negative predictive value. Serology could be used as a screening method for the detection of precancerous states due to its convenience, relative low cost and safety.
PMCID: PMC4322333  PMID: 25695008
Pepsinogens; Atrophic gastritis; Gastric cancer; Biomarkers
16.  Variations of gastric corpus microbiota are associated with early esophageal squamous cell carcinoma and squamous dysplasia 
Scientific Reports  2015;5:8820.
Observational studies revealed a relationship between changes in gastric mucosa and risk of esophageal squamous cell carcinoma (ESCC) which suggested a possible role for gastric microbiota in ESCC carcinogenesis. In this study we aimed to compare pattern of gastric corpus microbiota in ESCC with normal esophagus. Cases were included subjects with early ESCC (stage I–II) and esophageal squamous dysplasia (ESD) as the cancer precursor. Control groups included age and sex-matched subjects with mid-esophagus esophagitis (diseased-control), and histologically normal esophagus (healthy-control). DNA was extracted from snap-frozen gastric corpus tissues and 16S rRNA was sequenced on GS-FLX Titanium. After noise removal, an average of 3004 reads per sample was obtained from 93 subjects. We applied principal coordinate analysis to ordinate distances from beta diversity data. Pattern of gastric microbiota using Unifrac (p = 0.004) and weighted Unifrac distances (p = 0.018) statistically varied between cases and healthy controls. Sequences were aligned to SILVA database and Clostridiales and Erysipelotrichales orders were more abundant among cases after controling for multiple testing (p = 0.011). No such difference was observed between mid-esophagitis and healthy controls. This study is the first to show that composition of gastric corpus mucosal microbiota differs in early ESCC and ESD from healthy esophagus.
doi:10.1038/srep08820
PMCID: PMC4351546  PMID: 25743945
17.  Seroepidemiology of gastritis in Japanese and Dutch working populations: evidence for the development of atrophic gastritis that is not related to Helicobacter pylori. 
Gut  1995;37(2):199-204.
Serological markers of gastritis, like pepsinogen A, pepsinogen C, gastrin, and Helicobacter pylori antibodies, can be used to explore the state of the gastric mucosa in populations with contrasting cancer risks. A decreasing pepsinogen A:C ratio and an increasing serum gastrin are known to reflect an increasing severity of atrophic corpus gastritis, which is a precursor of gastric cancer. In 723 subjects (without gastroduodenal surgery) from Japanese (n = 225) and Dutch (n = 498) working populations, which had a similar composition of age (mean 48 years), sex (male to female ratio 6:1), and type of occupation, fasting serum samples were analysed for IgG antibodies to H pylori, pepsinogen A, pepsinogen C, and gastrin in the same laboratory. H pylori infection was significantly more prevalent in the Japanese than in the Dutch (74.7% and 31.3%); as was a very low pepsinogen A, indicative of severe mucosal atrophy (4.4% and 1.6%). Among subjects with and without severe mucosal atrophy the H pylori seropositivity rate was similar. Between the Japanese and the Dutch there were significant differences in mean gastrin (31.8 and 13.4 pmol/l) and pepsinogen A:C ratio (1.7 and 2.9). These intercountry differences were as great for H pylori negative subjects (gastrin: 23.7 and 10.3 pmol/l, pepsinogen A:C ratio: 2.4 and 3.2) as for H pylori positive subjects (gastrin: 34.6 and 20.1 pmol/l, pepsinogen A:C ratio: 1.5 and 2.5). The intercountry difference in gastrin nearly disappeared after stratification into categories of pepsinogen A:C ratio. In conclusion, the intercountry differences in pepsinogen A:C ratio and gastrin reflect a higher prevalence of mild and severe mucosal atrophy of the corpus in the Japanese than in the Dutch, both among H pylori positive and negative subjects. Thus, these findings suggest that in the Japanese the development of atrophic gastritis is in part unrelated to H pylori.
PMCID: PMC1382718  PMID: 7557568
18.  None-endoscopic Screening for Esophageal Squamous Cell Carcinoma- A Review 
Esophageal cancer (EC) is the eighth most common cancer and sixth most frequent cause of cancer mortality worldwide. Esophageal squamous cell carcinoma (ESCC) is the most common type of EC. ESCC develops by progression from premalignant lesions, which are called esophageal squamous dysplasia (ESD). Prevention is the most effective strategy for controlling this disease. Generally, two methods may be defined for ESCC prevention. The aim of the first preventive method is to prevent the initiation of ESD by avoiding the known risk factors, or primary prevention. Secondary prevention focuses on detection of the disease in its early curable stage, thus preventing its progression into advanced stages. Endoscopy with iodine staining and biopsy is the diagnostic choice for ESD. However it is invasive and expensive, and not accepted by asymptomatic ESD cases. Therefore, it is necessary to find a non-endoscopic screening method. Despite the large number of studies conducted worldwide, no approved method has been developed for ESCC screening. Regarding the multi-factorial nature of ESCC, it is proposed that the use of a combination of various criteria, such as cytological examination, risk factors, genetic alteration, and molecular markers may result in the development of a comprehensive and effective ESCC screening program.
PMCID: PMC4017690  PMID: 24829644
Esophageal squamous cell carcinoma; Screening; Non-endoscopic; Review
19.  The Role of Serum Pepsinogen in the Detection of Gastric Cancer 
Gut and Liver  2010;4(3):307-319.
The incidence of gastric cancer is very high in Japan, Korea, and China. Reducing the morbidity and mortality associated with gastric cancer requires early diagnosis, which can be facilitated by applying gastroscopy more frequently in high-risk groups. A strategy of population screening for gastric cancer is currently being adopted in Korea, Japan, and the Matsu region of Taiwan, but using different screening methods. In addition, the history of pepsinogen (PG) in research as a gastric cancer biomarker has varied, in that the use of serum levels of PGI and PGII and the PGI/PGII ratio as gastric cancer screening tools was introduced in Japan before 1990, but in Korea the first research results were only reported in 2008. This review first evaluates the physiology of PG, followed by the usefulness or limitations of serum PG testing with regard to the detection of gastric cancer. Finally, the factors affecting the efficacy of PG tests as a gastric cancer biomarker (i.e., Helicobacter pylori infection status, gender, histopathologic features, and cancer location and depth) are evaluated. It was found that the strategies used to increase the efficacy of PG tests should be individualized in each country according to the seroprevalence of H. pylori.
doi:10.5009/gnl.2010.4.3.307
PMCID: PMC2956341  PMID: 20981206
Pepsinogen; Gastric cancer; Atrophic gastritis; Helicobacter pylori
20.  Serum 25(OH)-Vitamin D concentration and risk of esophageal squamous dysplasia 
Background
Squamous dysplasia is the precursor lesion for esophageal squamous cell carcinoma (ESCC), and nutritional factors play an important role in the etiology of this cancer. Previous studies using a variety of measures of vitamin D exposure have reached different conclusions about the association between vitamin D and risk of developing esophageal cancer.
Methods
We measured serum 25-hydroxyvitamin D (25(OH)D) concentrations in a cross-sectional analysis of 720 subjects from Linxian, China, a population at high risk for developing ESCC. All subjects underwent endoscopy and biopsy and were categorized by presence or absence of histologic squamous dysplasia. We used crude and multivariate adjusted generalized linear models to estimate the relative risk (RR) and 95% confidence intervals (CI) for the association between squamous dysplasia and sex-specific quartiles of serum 25(OH)D concentration.
Results
Two hundred and thirty (32%) of 720 subjects had squamous dysplasia. Subjects with dysplasia had significantly higher median serum 25(OH)D concentrations then subjects without dysplasia, 36.5 and 31.5 nmol/L respectively (Wilcoxon two-sample test p = 0.0004). In multivariate adjusted models, subjects in the highest compared to the lowest quartile were at significantly increased risk of squamous dysplasia, RR (95% CI) = 1.86 (1.35–2.62). Increased risks were similar when examined in men and women separately: Men RR (95% CI) = 1.74 (1.08–2.93); Women RR (95% CI) = 1.96 (1.28–3.18).
Conclusions
Higher serum 25(OH)D concentration was associated with significantly increased risk of squamous dysplasia. No obvious source of measured or unmeasured confounding explains this finding.
doi:10.1158/1055-9965.EPI-07-0461
PMCID: PMC2812415  PMID: 17855710
Esophageal cancer; Squamous dysplasia; Vitamin D; Serum 25(OH)D; China
21.  Serum pepsinogens I and II and gastric mucosal histology after partial gastrectomy. 
Gut  1985;26(11):1179-1182.
We determined the effect of postgastrectomy gastritis on serum pepsinogen I and pepsinogen II concentrations in 108 subjects with subtotal gastric resection. Eleven had normal remnant mucosa, 22 had superficial gastritis, and 75 had atrophic gastritis. In the subjects with superficial gastritis, serum pepsinogen I and II concentrations were significantly higher than in those with normal remnant mucosa, but the ratio of pepsinogen I to II did not differ from normal. In atrophic gastritis, serum pepsinogen I concentrations fell with increasing severity of mucosal damage, but pepsinogen II was persistently raised. Consequently, the ratio of pepsinogen I to II in subjects with atrophic gastritis was significantly lower than in those with superficial gastritis or normal remnant mucosa. Discriminant function analysis revealed that the ratio of pepsinogen I to II, in combination with the absolute level of pepsinogen II, had a sensitivity of 80%, a specificity of 73%, and a positive predictive value of 87% for atrophic gastritis in this population. We propose that the parallel increase in serum pepsinogen I and II concentrations in postgastrectomy superficial gastritis is because of an increased rate of endocrine release of both zymogens from the fundic glands, and that the dichotomy in pepsinogen I and II concentrations in postgastrectomy atrophic gastritis results from the loss of fundic glands, which produce both zymogens, and the appearance of metaplastic pyloric glands, which produce only pepsinogen II.
PMCID: PMC1432904  PMID: 4065694
22.  Pepsinogen II Can Be a Potential Surrogate Marker of Morphological Changes in Corpus before and after H. pylori Eradication 
BioMed Research International  2014;2014:481607.
Background. The aim of this investigation is to study the relationship between gastric morphology and serum biomarkers before and after Helicobacter pylori eradication. Methods. First-degree relatives of gastric cancer patients underwent gastroscopy before and 2.5 years after H. pylori eradication. The morphological changes in two categories (normal to mild and moderate to severe) were compared with level of pepsinogens I and II before eradication (n = 369), after eradication (n = 115), and in those with persistent infection (n = 250). Results: After eradication, pepsinogen I decreased to 70% and pepsinogen II to 45% of the previous values. Unlike pepsinogen II and pepsinogen I to II ratio that were affected by the severity of inflammation and atrophy in corpus in all groups, pepsinogen I generally did not change. After eradication, subjects with high mononuclear infiltration in corpus had lower pepsinogen I (54 versus 77.1 μ/mL), higher pepsinogen II (9.4 versus 6.9 μ/mL), and lower ratio (7.9 versus 11.6) than those without (P < 0.05). Conclusion. Pepsinogen II is a good marker of corpus morphological changes before and after H. pylori eradication.
doi:10.1155/2014/481607
PMCID: PMC4083213  PMID: 25028655
23.  Helicobacter pylori infection and markers of gastric cancer risk in Alaska Native persons: A retrospective case-control study 
The high prevalence of Helicobacter pylori infection in Alaska Native people is believed to be a major contributor to the increased incidence of gastric cancer and mortality in this population. Due to several factors, however, general screening of this population for H pylori infection is highly impractical. Identifying associations between specific serological markers and gastric cancer, therefore, has been an emerging area of investigation. Prompted by the lack of data from this population, this retrospective study examined potential serological cancer markers from samples obtained years before cancer diagnoses.
BACKGROUND:
Alaska Native persons experience gastric cancer incidence and mortality rates that are three to four times higher than in the general United States population.
OBJECTIVE:
To evaluate pepsinogen I, pepsinogen I/II ratio, anti-Helicobacter pylori and cytotoxin-associated gene A (CagA) antibody levels, and blood group for their associations with gastric cancer development in Alaska Native people.
METHODS:
The present analysis was a retrospective case-control study that matched gastric cancers reported to the Alaska Native Tumor Registry from 1969 to 2008 to three controls on known demographic risk factors for H pylori infection, using sera from the Alaska Area Specimen Bank. Conditional logistic regression evaluated associations between serum markers and gastric cancer.
RESULTS:
A total of 122 gastric cancer cases were included, with sera predating cancer diagnosis (mean = 13 years) and 346 matched controls. One hundred twelve cases (91.8%) and 285 controls (82.4%) had evidence of previous or ongoing H pylori infection as measured by anti-H pylori antibody levels. Gastric cancer cases had a 2.63-fold increased odds of having positive anti-H pylori antibodies compared with their matched controls (P=0.01). In a multivariate model, non-cardia gastric cancer (n=94) was associated with anti-H pylori antibodies (adjusted OR 3.92; P=0.004) and low pepsinogen I level (adjusted OR 6.04; P=0.04). No association between gastric cancer and blood group, anti-CagA antibodies or pepsinogen I/II ratio was found.
CONCLUSION:
Alaska Native people with gastric cancer had increased odds of previous H pylori infection. Low pepsinogen I level may function as a precancer marker for noncardia cancer.
PMCID: PMC4072235  PMID: 24945184
Alaska Native; cagA+; Gastric cancer; Helicobacter pylori; Pepsinogen I
24.  Predominant mucosal IL-8 mRNA expression in non-cagA Thais is risk for gastric cancer 
AIM: To study gastric mucosal interleukine-8 (IL-8) mRNA expression, the cytotoxin-associated gene A (cagA) mutation, and serum pepsinogen (PG) I/II ratio related risk in Thai gastric cancer.
METHODS: There were consent 134 Thai non-cancer volunteers who underwent endoscopic narrow band imaging examination, and 86 Thais advance gastric cancer patients who underwent endoscopic mucosal biopsies and gastric surgery. Tissue samples were taken by endoscopy with 3 points biopsies. The serum PG I, II, and Helicobacter pylori (H. pylori) immunoglobulin G (IgG) antibody for H. pylori were tested by enzyme-linked immunosorbent assay technique. The histopathology description of gastric cancer and non-cancer with H. pylori detection was defined with modified Sydney Score System. Gastric mucosal tissue H. pylori DNA was extracted and genotyped for cagA mutation. Tissue IL-8 and cyclooxygenase-2 (COX-2) mRNA expression were conducted by real time relative quantitation polymerase chain reaction. From 17 Japanese advance gastric cancer and 12 benign gastric tissue samples, all were tested for genetic expression with same methods as well as Thai gastric mucosal tissue samples. The multivariate analysis was used for the risk study. Correlation and standardized t-test were done for quantitative data, P value < 0.05 was considered as a statistically significant.
RESULTS: There is a high non cagA gene of 86.8 per cent in Thai gastric cancer although there are high yields of the East Asian type in the positive cagA. The H. pylori infection prevalence in this study is reported by combined histopathology and H. pylori IgG antibody test with 77.1% and 97.4% of sensitivity and specificity, respectively. The serum PG I/II ratio in gastric cancer is significantly lower than in the non-cancer group, P = 0.045. The serum PG I/II ratio of less than 3.0 and IL-8 mRNA expression ≥ 100 or log10 ≥ 2 are significant cut off risk differences between Thai cancer and non-cancer, P = 0.03 and P < 0.001, respectively. There is a significantly lower PGI/II ratio in Japanese than that in Thai gastric cancer, P = 0.026. Serum PG I/II ratio at cut off less than 3.0 and IL-8 mRNA expression Raw RQ > 100 or log10 > 2 are significantly difference between Thai cancer group when compared to non-cancer group, P = 0.013 and P < 0.001, respectively. In the correlation study, low PG I/II ratio does not associate with chronic atrophic gastritis severity score in Thais non-cancer cases. However, there is a trend, but not significant convert correlation between IL-8 mRNA expression level and low PG I/II ratio in Thai positive H. pylori infection. The high expression of IL-8 gene demonstrates a poorer prognosis by stage and histology.
CONCLUSION:Predominant gastric mucosal IL-8 mRNA expression level, H. pylori infection, and low PG I/II ratio are relative risks for Thai gastric cancer without correlation with cagA mutation.
doi:10.3748/wjg.v19.i19.2941
PMCID: PMC3660819  PMID: 23704827
Gastric cancer; CagA mutation; Interleukine-8 mRNA expression; Helicobacter pylori; Pepsinogen I/II ratio
25.  Squamous dysplasia – the precursor lesion for esophageal squamous cell carcinoma 
Esophageal squamous cell carcinoma (ESCC) accounts for 80% of all esophageal cancers worldwide, and esophageal squamous dysplasia (ESD) is the only histopathology that predicts the development of ESCC. The prevalence of ESD parallels rates of invasive ESCC, and is typically found in 25% or more of adults above the age of 35 years in populations in north central China, where risk for ESCC is among the highest in the world. Results of chemoprevention and early detection studies to prevent progression of ESD suggest that these approaches, coupled with emerging endoscopic therapies, offer promise for the prevention of esophageal cancer mortality in high-risk populations. Future research on ESD and ESCC should focus on finding additional modifiable risk factors and on identifying biomarkers to incorporate into early detection strategies.
doi:10.1158/1055-9965.EPI-12-1347
PMCID: PMC3681095  PMID: 23549398

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