Intake of Proton-Pump Inhibitors and Gastric Cancer within the Stomach Cancer Pooling (StoP) Project.

BACKGROUND: A potential association between proton-pump inhibitors (PPI) and gastric cancer remains undefined. Thus, we aimed to evaluate such association within the Stomach cancer Pooling (StoP) Project. METHODS: Data from five case-control studies of the StoP Project were included (1,889 cases and 6,517 controls). We assessed the impact of different exposure definitions, specifically any reported use of PPIs and exposure definitions based on the duration of PPI intake. Additionally, we modeled the dose-response relationship between the cumulative duration of PPI intake and gastric cancer. RESULTS: Significant associations between PPI intake and gastric cancer, both overall and in the stratified analyses, were limited to exposure definitions based on short durations of intake. The overall odds ratio (OR) for any reported PPI intake was 1.78 [95% confidence interval (CI): 0.76-4.14]. In the dose-response analysis, the ORs of gastric cancer were found to be higher for short durations of PPI intake (6 months: OR 3.26; 95% CI: 2.40-4.42; one year: OR 2.14; 95% CI: 1.69-2.70; 2 years: OR 1.50; 95% CI: 1.22-1.85; 3 years: OR 1.27; 95% CI: 1.03-1.56), with the association becoming not significant for durations longer than 3 years. CONCLUSIONS: Our findings suggest that the observed association between PPIs and gastric cancer might be mainly due to reverse causality. IMPACT: The results of this study suggest that PPIs are a safe therapeutic choice regarding their effect on the occurrence of gastric cancer. See related commentary by Richman and Leiman, p. 1127.

Breath Volatile Organic Compounds in Surveillance of Gastric Cancer Patients following Radical Surgical Management.

As of today, there is a lack of a perfect non-invasive test for the surveillance of patients for potential relapse following curative treatment. Breath volatile organic compounds (VOCs) have been demonstrated to be an accurate diagnostic tool for gastric cancer (GC) detection; here, we aimed to prove the yield of the markers in surveillance, i.e., following curative surgical management. Patients were sampled in regular intervals before and within 3 years following curative surgery for GC; gas chromatography-mass spectrometry (GC-MS) and nanosensor technologies were used for the VOC assessment. GC-MS measurements revealed a single VOC (14b-Pregnane) that significantly decreased at 12 months, and three VOCs (Isochiapin B, Dotriacontane, Threitol, 2-O-octyl-) that decreased at 18 months following surgery. The nanomaterial-based sensors S9 and S14 revealed changes in the breath VOC content 9 months after surgery. Our study results confirm the cancer origin of the particular VOCs, as well as suggest the value of breath VOC testing for cancer patient surveillance, either during the treatment phase or thereafter, for potential relapse.

Assessing the utility of pepsinogens and gastrin-17 in gastric cancer detection.

OBJECTIVES: The aim of the study was to determine the proportion of gastric cancer patients with decreased levels of pepsinogen and gastrin-17 in plasma, with the goal of providing indirect evidence of the sensitivity of these biomarkers when applied in a cancer screening setting. METHODS: The levels of pepsinogens I and II, gastrin-17, and Helicobacter pylori immunoglobulin antibodies in plasma samples of gastric cancer patients were evaluated using the GastroPanel test system (Biohit Oyj, Helsinki, Finland). A decreased level of the pepsinogen I/II ratio was defined as less than three, while a decrease in gastrin-17 was defined as less than 1 pmol/L. Univariate analysis using non-parametric tests was used to investigate differences between normal and low concentrations of biomarkers. RESULTS: In total, 481 plasma samples from patients (59.9% male) with a median age of 64 years (ranging from 27 to 88 years) were analyzed. Out of the 400 cases of gastric cancer (83.2% of the total), 182 were categorized as the intestinal type, 141 as the diffuse type, 60 as the mixed type, and 17 as indeterminate according to the Lauren classification system. The H. pylori immunoglobulin test was positive in 74.0% of the patients. Pepsinogen I/II ratio was decreased in 32.4% (36.8% of the intestinal type); gastrin-17 in 12.3% (10.1% of the antral region) of all cases. CONCLUSION: The majority of gastric cancer patients had normal levels of pepsinogen and gastrin-17, suggesting that these biomarkers have limited application as screening tools in the Caucasian population.

"True" Helicobacter pylori infection and non-cardia gastric cancer: A pooled analysis within the Stomach Cancer Pooling (StoP) Project.

BACKGROUND: Helicobacter pylori is the most important risk factor for non-cardia gastric cancer (NCGC); however, the magnitude of the association varies across epidemiological studies. This study aimed to quantify the association between H. pylori infection and NCGC, using different criteria to define infection status. METHODS: A pooled analysis of individual-level H. pylori serology data from eight international studies (1325 NCGC and 3121 controls) from the Stomach Cancer Pooling (StoP) Consortium was performed. Cases and controls with a negative H. pylori infection status were reclassified as positive considering the presence of anti-Cag A antibodies, gastric atrophy, or advanced stage at diagnosis, as available and applicable. A two-stage approach was used to pool study-specific adjusted odds ratios (OR), and 95% confidence intervals (95% CI). A meta-analysis of published prospective studies assessing H. pylori seropositivity in NCGCs was conducted. RESULTS: The OR for the association between serology-defined H. pylori and NCGC was 1.45 (95% CI: 0.87-2.42), which increased to 4.79 (95% CI: 2.39-9.60) following the reclassification of negative H. pylori infection. The results were consistent across strata of sociodemographic characteristics, clinical features and lifestyle factors, though significant differences were observed according to geographic region-a stronger association in Asian studies. The pooled risk estimates from the literature were 3.01 (95% CI: 2.22-4.07) for ELISA or EIA and 9.22 (95% CI: 3.12-27.21) for immunoblot or multiplex serology. CONCLUSION: The NCGC risk estimate from StoP based on the reclassification of H. pylori seronegative individuals is consistent with the risk estimates obtained from the literature. Our classification algorithm may be useful for future studies.

Identifying the Profile of Helicobacter pylori-Negative Gastric Cancers: A Case-Only Analysis within the Stomach Cancer Pooling (StoP) Project.

BACKGROUND: The prevalence of Helicobacter pylori-negative gastric cancer (HpNGC) can be as low as 1%, when infection is assessed using more sensitive tests or considering the presence of gastric atrophy. HpNGC may share a high-risk profile contributing to the occurrence of cancer in the absence of infection. We estimated the proportion of HpNGC, using different criteria to define infection status, and compared HpNGC and positive cases regarding gastric cancer risk factors. METHODS: Cases from 12 studies from the Stomach cancer Pooling (StoP) Project providing data on H. pylori infection status determined by serologic test were included. HpNGC was reclassified as positive (eight studies) when cases presented CagA markers (four studies), gastric atrophy (six studies), or advanced stage at diagnosis (three studies), and were compared with positive cases. A two-stage approach (random-effects models) was used to pool study-specific prevalence and adjusted odds ratios (OR). RESULTS: Among non-cardia cases, the pooled prevalence of HpNGC was 22.4% (n = 166/853) and decreased to 7.0% (n = 55) when considering CagA status; estimates for all criteria were 21.8% (n = 276/1,325) and 6.6% (n = 97), respectively. HpNGC had a family history of gastric cancer more often [OR = 2.18; 95% confidence interval (CI), 1.03-4.61] and were current smokers (OR = 2.16; 95% CI, 0.52-9.02). CONCLUSION: This study found a low prevalence of HpNGC, who are more likely to have a family history of gastric cancer in first-degree relatives. IMPACT: Our results support that H. pylori infection is present in most non-cardia gastric cancers, and suggest that HpNGC may have distinct patterns of exposure to other risk factors.

How do international gastric cancer prevention guidelines influence clinical practice globally?

Clinical guidelines recommend particular approaches, including 'screen-and-treat' strategy for Helicobacter pylori, to prevent gastric cancer. However, little of this is implemented in clinical practice. The aim of the study was to identify barriers to implementation of international guidelines. A web-based questionnaire distributed globally to specialists in the field. Altogether 886 responses from 75 countries were received. Of the responders, 570 (64%) were men of mean age 47 years. There were 606 gastroenterologists and 65 epidemiologists among the responders. Altogether, 79.8% of the responders disagreed that the burden of gastric cancer is a diminishing problem. 'Screen-and-treat' strategy for H. pylori in the responder's country was considered appropriate by 44.4%, inappropriate by 24.3%, with 31.3% being uncertain. Population-based screening for gastric cancer was considered appropriate in the respective home-country by 62.2%, in other areas - but not the home country - by 27.6%, and inappropriate by 10.2%. As a screening tool, upper endoscopy was acceptable by 35.6%, upper X-ray series by 55.3%, pepsinogens by 26.2% and breath-tests by 23.4%; accuracy, cost-effectiveness and feasibility among the tests varied widely. The attitude towards H. pylori vaccination was that 4.6% of the responders were eager to start vaccination immediately, 55.9% were supporting vaccination but considered that more data are required 12% were negative, and 27.6% did not have an opinion. In general, the attitude of the specialists was in line with guidelines, but was not always translated into clinical practice, particularly in the case of 'screen-and-treat' strategy.

Clinicopathological characteristics of Epstein-Barr virus-positive gastric cancer in Latvia.

OBJECTIVE: Epstein-Barr virus (EBV)-associated gastric cancer has been proposed to be a distinct gastric cancer molecular subtype. The prognostic significance of EBV infection in gastric cancer remains unclear and needs further investigation. Our study aimed to analyze EBV-positive and EBV-negative gastric cancer patients regarding their personal and tumor-related characteristics, and compare their overall survival. METHODS: Gastric cancer patients consecutively treated at the Riga East University Hospital during 2009-2016 were identified retrospectively. Tumor EBV status was determined by in-situ hybridization for EBV-encoded RNA (EBER). Information about clinicopathological characteristics was obtained from patient questionnaires, hospital records. Overall survival was ascertained through 30 July 2017. Cox proportional hazard regression models adjusted for personal and tumor-related covariates compared survival between EBV-positive and EBV-negative patients. RESULTS: There were a total of 302 gastric cancer patients (61% males) with mean and SD age 63.6 ± 11.5 years. EBER positivity was present in 8.6% of tumors. EBV-positive gastric cancer patients had better survival at 80 months [adjusted hazard ratio = 0.37, 95% confidence interval (CI) = 0.19-0.72] compared to EBV-negative patients. Worse survival was observed for patients with stage III (hazard ratio = 2.76, 95% CI = 1.67-4.56) and stage IV (hazard ratio = 10.02, 95% CI = 5.72-17.57) compared to stage I gastric cancer, and overlapping and unspecified subsite (hazard ratio = 1.85; 95% CI = 1.14; 3.00) compared to distal tumors. CONCLUSION: Tumor EBV positivity is a favorable prognostic factor in gastric cancer.

Sex differences in the prevalence of Helicobacter pylori infection: an individual participant data pooled analysis (StoP Project).

BACKGROUND: Helicobacter pylori (H. pylori) infection is more frequent among men, though the magnitude of the association might be inaccurate due to potential misclassification of lifetime infection and publication bias. Moreover, infection is common, and most studies are cross-sectional. Thus, prevalence ratios (PRs) may be easier to interpret than odds ratios (ORs). AIM: The aim of this study was to quantify the association between sex and H. pylori infection using controls from 14 studies from the Stomach Cancer Pooling (StoP) Project. PARTICIPANTS AND METHODS: H. pylori infection was defined based on IgG serum antibody titers or multiplex serology. Participants were also classified as infected if gastric atrophy was present, based on histological examination or serum pepsinogen (PG) levels (PG I≤70 and PG I/II ratio≤3). Summary ORs and PRs, adjusted for age, social class and smoking, and corresponding 95% confidence intervals (CIs), were estimated through random-effects meta-analysis. RESULTS: Men had significantly higher OR (OR: 1.33, 95% CI: 1.04-1.70) and PR (PR: 1.05, 95% CI: 1.00-1.10) of infection, with stronger associations among hospital-based or older controls. Results were similar when considering the presence of gastric atrophy to define infection status, particularly among participants older than 65 years. CONCLUSION: This collaborative pooled-analysis supports an independent effect of sex on the prevalence of H. pylori infection, while minimizing misclassification of lifetime infection status and publication bias.

Non-contact breath sampling for sensor-based breath analysis.

Breath analysis holds great promise for real-time and non-invasive medical diagnosis. Thus, there is a considerable need for simple-in-use and portable analyzers for rapid detection of breath indicators for different diseases in their early stages. Sensor technology meets all of these demands. However, miniaturized breath analyzers require adequate breath sampling methods. In this context, we propose non-contact sampling; namely the collection of breath samples by exhalation from a distance into a miniaturized collector without bringing the mouth into direct contact with the analyzing device. To evaluate this approach different breathing maneuvers have been tested in a real-time regime on a cohort of 23 volunteers using proton transfer reaction mass spectrometry. The breathing maneuvers embraced distinct depths of respiration, exhalation manners, size of the mouth opening and different sampling distances. Two inhalation modes (normal, relaxed breathing and deep breathing) and two exhalation manners (via smaller and wider lips opening) forming four sampling scenarios were selected. A sampling distance of approximately 2 cm was found to be a reasonable trade-off between sample dilution and requirement of no physical contact of the subject with the analyzer. All four scenarios exhibited comparable measurement reproducibility spread of around 10%. For normal, relaxed inspiration both dead-space and end-tidal phases of exhalation lasted approximately 1.5 s for both expiration protocols. Deep inhalation prolongs the end-tidal phase to about 3 s in the case of blowing via a small lips opening, and by 50% when the air is exhaled via a wide one. In conclusion, non-contact breath sampling can be considered as a promising alternative to the existing breath sampling methods, being relatively close to natural spontaneous breathing.

Smoking and Helicobacter pylori infection: an individual participant pooled analysis (Stomach Cancer Pooling- StoP Project).

Smoking has been associated with acquisition and increased persistence of Helicobacter pylori infection, as well as with lower effectiveness of its eradication. A greater prevalence of infection among smokers could contribute to the increased risk for gastric cancer. We aimed to estimate the association between smoking and seropositivity to H. pylori through an individual participant data pooled analysis using controls from 14 case-control studies participating in the Stomach Cancer Pooling Project. Summary odds ratios and prevalence ratios (PRs), adjusted for age, sex and social class, and the corresponding 95% confidence intervals (CIs) were estimated through random-effects meta-analysis. Heterogeneity was quantified using the I statistic and publication bias with Egger's test. There was no significant association between smoking (ever vs. never) and H. pylori seropositivity (adjusted odds ratio = 1.08; 95% CI: 0.89-1.32; adjusted PR = 1.01; 95% CI: 0.98-1.05). The strength of the association did not increase with the intensity or duration of smoking; stratified analyses according to sex, age, region or type of sample did not yield a consistent pattern of variation or statistically significant results, except for participants younger than 55 years and who had been smoking for more than 30 years (adjusted PR = 1.08; 95% CI: 1.02-1.15). This is the first collaborative analysis providing pooled estimates for the association between smoking and H. pylori seropositivity, based on detailed and uniform information and adjusting for major covariates. The results do not support an association between smoking and H. pylori infection.

Evidence for PTGER4, PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level.

Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 × 10-04 ) and on chromosome 8q24 at rs2585176 (P = 1.09 × 10-09 ). On chromosome 5p13 we found cis-eQTL effects with an upregulation of PTGER4 expression in GC risk allele carrier (P = 9.27 × 10-11 ). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 × 10-47 ). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 × 10-09 ). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms.

Ex vivo emission of volatile organic compounds from gastric cancer and non-cancerous tissue.

The presence of certain volatile organic compounds (VOCs) in the breath of patients with gastric cancer has been reported by a number of research groups; however, the source of these compounds remains controversial. Comparison of VOCs emitted from gastric cancer tissue to those emitted from non-cancerous tissue would help in understanding which of the VOCs are associated with gastric cancer and provide a deeper knowledge on their generation. Gas chromatography with mass spectrometric detection (GC-MS) coupled with head-space needle trap extraction (HS-NTE) as the pre-concentration technique, was used to identify and quantify VOCs released by gastric cancer and non-cancerous tissue samples collected from 41 patients during surgery. Excluding contaminants, a total of 32 VOCs were liberated by the tissue samples. The emission of four of them (carbon disulfide, pyridine, 3-methyl-2-butanone and 2-pentanone) was significantly higher from cancer tissue, whereas three compounds (isoprene, γ-butyrolactone and dimethyl sulfide) were in greater concentration from the non-cancerous tissues (Wilcoxon signed-rank test, p < 0.05). Furthermore, the levels of three VOCs (2-methyl-1-propene, 2-propenenitrile and pyrrole) were correlated with the occurrence of H. pylori; and four compounds (acetonitrile, pyridine, toluene and 3-methylpyridine) were associated with tobacco smoking. Ex vivo analysis of VOCs emitted by human tissue samples provides a unique opportunity to identify chemical patterns associated with a cancerous state and can be considered as a complementary source of information on volatile biomarkers found in breath, blood or urine.