The Association of Circulating L-Carnitine, γ-Butyrobetaine and Trimethylamine N-Oxide Levels with Gastric Cancer.

Our study aimed to evaluate the association between gastric cancer (GC) and higher concentrations of the metabolites L-carnitine, γ-butyrobetaine (GBB) and gut microbiota-mediated trimethylamine N-oxide (TMAO) in the circulation. There is evidence suggesting that higher levels of TMAO and its precursors in blood can be indicative of either a higher risk of malignancy or indeed its presence; however, GC has not been studied in this regard until now. Our study included 83 controls without high-risk stomach lesions and 105 GC cases. Blood serum L-carnitine, GBB and TMAO levels were measured by ultra-high-performance liquid chromatography-mass spectrometry (UPLC/MS/MS). Although there were no significant differences between female control and GC groups, we found a significant difference in circulating levels of metabolites between the male control group and the male GC group, with median levels of L-carnitine reaching 30.22 (25.78-37.57) nmol/mL vs. 37.38 (32.73-42.61) nmol/mL (p < 0.001), GBB-0.79 (0.73-0.97) nmol/mL vs. 0.97 (0.78-1.16) nmol/mL (p < 0.05) and TMAO-2.49 (2.00-2.97) nmol/mL vs. 3.12 (2.08-5.83) nmol/mL (p < 0.05). Thus, our study demonstrated the association between higher blood levels of L-carnitine, GBB, TMAO and GC in males, but not in females. Furthermore, correlations of any two investigated metabolites were stronger in the GC groups of both genders in comparison to the control groups. Our findings reveal the potential role of L-carnitine, GBB and TMAO in GC and suggest metabolic differences between genders. In addition, the logistic regression analysis revealed that the only significant factor in terms of predicting whether the patient belonged to the control or to the GC group was the blood level of L-carnitine in males only. Hence, carnitine might be important as a biomarker or a risk factor for GC, especially in males.

The Diagnostic Value of Anti-Parietal Cell and Intrinsic Factor Antibodies, Pepsinogens, and Gastrin-17 in Corpus-Restricted Atrophic Gastritis.

We aimed to determine the diagnostic value of anti-parietal cell antibodies (anti-PCA), anti-intrinsic factor antibodies (anti-IFA), pepsinogen ratio (PGI/II), and gastrin-17 (G-17) in corpus-restricted atrophic gastritis (CRAG) detected by ELISA (Inova, Biohit). Our study compared 29 CRAG cases against 58 age- and sex-matched controls with mild or no atrophy. Anti-PCA and anti-IFA positive cutoff values were ≥25 units for both. PGI/II value <3 was considered characteristic for atrophy; positive cutoff values for G-17 and anti-H. pylori IgG were >5 pg/L and >30 EIU. Anti-PCA was positive in 65.5% For CRAG cases and 13.8% of the controls (p < 0.0001), anti-IFA was positive in 13.8% and 0% (p = 0.01), respectively. Decreased pepsinogen levels were present in 79.3% of CRAG cases and 10.3% of the controls (p < 0.0001). PGI/II ratio was the best single biomarker, with sensitivity = 79%, specificity = 90%, and AUC 0.90. The combined use of PGI/II and anti-PCA resulted in AUC 0.93 for detecting CRAG. Our study suggests that the best combination of non-invasive biomarkers for detecting CRAG is PGI/II with anti-PCA. The addition of G-17 and anti-IFA is of little utility in clinical application.

Factors Associated with False Negative Results in Serum Pepsinogen Testing for Precancerous Gastric Lesions in a European Population in the GISTAR Study.

The accuracy of plasma pepsinogen (Pg) as a marker for precancerous gastric lesions (PGL) has shown variable results. We aimed to identify factors associated with false negative (FN) cases in Pg testing and to adjust cut-off values for these factors in order to improve Pg yield. Plasma Pg was measured and upper endoscopy with biopsy was performed within the "Multicentric randomized study of Helicobacter pylori eradication and pepsinogen testing for prevention of gastric cancer mortality: the GISTAR study". A multivariable logistic model was built for FN and multiple factors. Values of Pg were compared and sensitivity and specificity were calculated using pre-existing Pg cut-offs for factors showing strong associations with FN. New cut-offs were calculated for factors that showed substantially lower sensitivity. Of 1210 participants, 364 (30.1%) had histologically confirmed PGL, of which 160 (44.0%) were FN. Current smokers, men, and H. pylori positives were more likely FN. Smoking in H. pylori negatives was associated with a higher Pg I/II ratio and substantially lower sensitivity of Pg testing than in other groups. Adjusting Pg cut-offs for current smokers by H. pylori presence improved sensitivity for detecting PGL in this group. Our study suggests that adjusting Pg cut-offs for current smokers by H. pylori status could improve Pg test performance.

Lifestyle and dietary factors associated with serologically detected gastric atrophy in a Caucasian population in the GISTAR study.

OBJECTIVE: To identify dietary and lifestyle factors associated with decreased pepsinogen levels indicative of gastric atrophy. METHODS: Participants aged 40 to 64 from the "Multicentric randomized study of H. pylori eradication and pepsinogen testing for prevention of gastric cancer mortality (GISTAR study)" in Latvia tested for serum pepsinogen, as well as for Helicobacter pylori infection by 13 C-urea breath test or serology were included. Data on sex, age, education, employment, diet, smoking, alcohol and proton pump inhibitor use were obtained by survey and compared for participants with and without serologically detected gastric atrophy defined as pepsinogen I/pepsinogen II ≤ 2 and pepsinogen I ≤ 30 ng/mL. RESULTS: Of 3001 participants (median age 53, interquartile range, 11.0, 36.9% male) 52.8% had H. pylori and 7.7% had serologically detected gastric atrophy. In multivariate analysis, increasing age, consumption of alcohol, coffee, and onions were positively, while H. pylori , former smoking, pickled product and proton pump inhibitor use were inversely associated with gastric atrophy. Pepsinogen values were higher in smokers and those with H. pylori . Pepsinogen ratio was lower in those with H. pylori . When stratifying by H. pylori presence, significantly higher pepsinogen levels remained for smokers without H. pylori . CONCLUSION: Several dietary factors and smoking were associated with serologically detected gastric atrophy. Pepsinogen levels differed by smoking and H. pylori status, which may affect the serologic detection of gastric atrophy. There seems to be a complicated interaction between multiple factors. A prospective study including atrophy determined by both serology and histology is necessary.

Who Could Be Blamed in the Case of Discrepant Histology and Serology Results for Helicobacter pylori Detection?

BACKGROUND: Discrepancies between histology and serology results for Helicobacter pylori detection could be caused by a variety of factors, including a biopsy sampling error, expertise of the pathologist, natural loss of infection due to advanced atrophy, or a false-positive serology in the case of a previous infection, since antibodies may be present in blood following recovery from the infection. AIMS: To identify true H. pylori-positive individuals in discrepant cases by serology and histology using real time polymerase chain reaction (RT-PCR) as a gold standard. METHODS: Study subjects with discrepant histology and serology results were selected from the GISTAR pilot study data base in Latvia. Subjects having received previous H. pylori eradication therapy or reporting use of proton pump inhibitors, antibacterial medications, or bismuth containing drugs one month prior to upper endoscopy were excluded. We compared the discrepant cases to the corresponding results of RT-PCR performed on gastric biopsies. RESULTS: In total, 97 individuals with discrepant results were identified: 81 subjects were serology-positive/histology-negative, while 16 were serology-negative/histology-positive. Among the serology-positive/histology-negative cases, 64/81 (79.0%) were false-positives by serology and, for the majority, inflammation was absent in all biopsies, while, in the serology-negative/histology-positive group, only 6.2% were proven false-positives by histology. CONCLUSIONS: Among this high H. pylori prevalent, middle-aged population, the majority of discrepant cases between serology and histology were due to false positive-serology, rather than false-negative histology. This confirms the available evidence that the choice of treatment should not be based solely on the serological results, but also after excluding previous, self-reported eradication therapy.

Factors influencing participation in preventive interventions for gastric cancer: the results from the GISTAR study.

OBJECTIVES: Search-and-treat strategy for Helicobacter pylori and surveillance of patients with precancerous lesions are recommended to decrease the burden of gastric cancer in high-risk areas. We aimed to evaluate the acceptance of the target population to these strategies. METHODS: We applied a search-and-treat strategy combined with biomarker screening (pepsinogens I and II, gastrin-17) for atrophic gastritis to healthy individuals aged 40-64 years within the GISTAR Pilot study. Different means of invitation were evaluated - direct telephone calls, letters of invitation via the general practitioners. Participants with altered biomarker results were invited to undergo upper gastrointestinal endoscopy. H.pylori positive individuals were offered eradication therapy. Data on the compliance to the treatment and reasons for noncompliance were collected via telephone. RESULTS: Altogether 3453 participants were enrolled. The attendance of women participants was 1.9 times higher although active invitation strategies were mainly targeting men. The yield for the telephone invitations was higher than for mail-delivered invitations (2.1 calls vs. 7.7 letters required to recruit one study subject). Out of 661 individuals reached with the invitation to undergo upper endoscopy, 520 (78.7%) attended the procedure. Out of 1185 study subjects eligible for eradication, 810 (68.4%) accepted it. Of those having received the medication, 765(94.4%) completed it. The reasons for nonparticipation were the overall misconception of the importance of screening, busy schedule and others. CONCLUSIONS: While only the minority of the target population participated in the gastric cancer prevention strategy, relatively high compliance was seen among the participants. The acceptance rate and the identified reasons for refusing to participate in our study indicate that there is a need to raise gastric cancer awareness and its existent preventive strategies within the general population for their successful implementation in the community.

Post-reproductive aged women: a lost generation in the cervical cancer screening programme.

OBJECTIVES: The aims of the study were to find out why some post-reproductive aged women did not participate in the organised cervical cancer screening programme in Latvia and to clarify factors that would motivate them to take part. METHODS: A cross-sectional study was carried out between January and July 2017 among female patients in three general practitioner (GP) practices. GP practice nurses used the Latvian national health service database to identify women aged 25-70 who had not participated in the organised programme for the last 3 years. Participants were asked to complete a specially developed questionnaire. The results were then compared between three age groups: 25-34, 35-49 and 50-70 years. RESULTS: Included in the study were 523 out of 992 women who had not attended screening; 41% were in the age group 50-70 years. Post-reproductive aged women statistically significantly more often did not take part in the programme because of lack of time (26.4%), too great a distance to the gynaecology screening clinic (10.4%), lengthy appointment waiting time (8.5%) and a belief that a smear test was unnecessary for them (8.5%); 32.1% of women in this age group indicated that if the cervical screen could be carried out by their GP it would facilitate their participation in the programme. CONCLUSION: Post-reproductive aged women in Latvia often do not attend cervical cancer screening. Analysis of personal and organisational barriers confirmed that the involvement of GPs would encourage older women to participate in the organised screening programme.

Does Family History of Cancer Influence Undergoing Screening and Gastrointestinal Investigations?

BACKGROUND AND AIMS: Although a family history of cancer (FHC) can modify the lifestyle and attitudes towards participation in cancer screening programs, studies on this relationship show mixed results and vary across populations. The objectives of the study were to compare sociodemographic characteristics, history of gastrointestinal (GI) investigations and Helicobacter pylori eradication, and modifiable cancer risk factors between those with FHC and those with no FHC (NFHC), and to investigate the association between FHC and a history of GI investigations. METHODS: A total of 3,455 questionnaires from the pilot study of the "Helicobacter pylori eradication and pepsinogen testing for prevention of gastric cancer mortality (GISTAR study)" in Latvia were analysed. We compared sociodemographic characteristics and history of GI investigations between participants with self- reported FHC and NFHC. Binary logistic regression models adjusted for socio-demographic characteristics and modifiable cancer risk factors were built for a FHC and each GI investigation. RESULTS: Participants with a FHC were more likely to be women, have a higher education and less likely to have harmful habits (smoking, alcohol consumption) than those with NFHC. Participants with a FHC were approximately twice as likely to report recent colorectal investigations specifically for screening, than those with NFHC. In fully adjusted logistic regression models, FHC was significantly associated with a recent history of faecal occult blood tests (FOBTs), colonoscopies, and colorectal investigations (FOBT or colonoscopy) specifically for screening as part of the national organized screening programme. CONCLUSION: Our results indicate that those with a FHC have different patterns of health-related behaviour than those with NFHC.

Sociodemographic, Lifestyle and Medical Factors Associated with Helicobacter Pylori Infection.

BACKGROUND AND AIMS: The prevalence of Helicobacter pylori (H. pylori) infection is higher in developing countries and is often linked to lower socioeconomic status. Few studies have investigated the association between H. pylori and individual level characteristics in Europe, where several countries have a high prevalence of H. pylori infection. The study aimed to identify risk factors for H. pylori infection among adults in a large clinical trial in Latvia. METHODS: 1,855 participants (40-64 years) of the "Multicenter randomized study of H. pylori eradication and pepsinogen testing for prevention of gastric cancer mortality" (GISTAR study) in Latvia tested for H. pylori IgG antibodies were included in a cross-sectional analysis. Sociodemographic, lifestyle and medical factors were compared for participants seropositive (H. pylori+) and seronegative. Mutually adjusted odds ratios (OR) were calculated for H. pylori+ and factors significant in univariate analysis (education, smoking, binge drinking, several dietary habits, history of H. pylori eradication and disease), adjusting for age, gender and income. RESULTS: Of the participants 1,044 (55.4%) were H. pylori seropositive. The infection was associated with current (OR: 1.34, 95%CI: 1.01-1.78) and former (OR: 1.38; 95%CI: 1.03-1.85) smoking, binge drinking (OR: 1.35; 95%CI: 1.03-1.78), having ≥200g dairy daily (OR: 1.37; 95%CI: 1.11-1.69), and very hot food/drinks (OR: 1.32; 95%CI: 1.03-1.69) and inversely with ≥400g vegetables/fruit daily (OR: 0.76; 95%CI: 0.60-0.96), history of H. pylori eradication (OR: 0.57; 95%CI: 0.39-0.84), peptic ulcer (OR: 0.55; 95%CI: 0.38-0.80) and cardiovascular disease (OR: 0.78; 95%CI: 0.61-0.99). CONCLUSIONS: After mutual adjustment, H. pylori seropositivity was associated with lifestyle and in particular dietary factors rather than socioeconomic indicators in contrast to the majority of other studies.

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.

Accuracy of two plasma antibody tests and faecal antigen test for non-invasive detection of H. pylori in middle-aged Caucasian general population sample.

OBJECTIVE: The aim of the study was to assess the accuracy of two plasma Helicobacter pylori (H. pylori) antibody test-systems and a stool antigen test (SAT) system in a general population sample in Latvia. MATERIALS AND METHODS: Blood and faecal samples were analysed in healthy individuals (40-64 years), referred for upper gastrointestinal endoscopy according to pilot study protocol within a population-based study investigating gastric cancer prevention strategies (GISTAR pilot study). Antibodies to H. pylori were assessed in plasma by latex-agglutination test and enzyme-linked immunosorbent assay (ELISA). H. pylori antigen in faecal samples was detected by a monoclonal enzyme immunoassay-based SAT. Histological assessment of H. pylori based on a modified Giemsa staining method was used as the gold standard. Individuals having received H. pylori eradication within one year prior to enrolment were excluded. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and overall accuracy were calculated. Receiver-operating characteristic curves were designed to estimate the optimal diagnostic cut-off value of tests. RESULTS: The analysis included 779 participants for latex-agglutination test, 1002 for ELISA and 672 individual samples for SAT. The sensitivity, specificity, PPV, NPV and overall accuracy were as follows: latex-agglutination test (86;81;87;80;84%), ELISA (97;72;83;94;86%) and SAT (87;81;87;81;85%), respectively. The optimal diagnostic cut-off value for ELISA test was ≥50.26 g/L. CONCLUSIONS: Although the performance of the three tests was comparable to each other, the three test systems showed suboptimal accuracy, with important implications for public health programs based on 'test-and-treat' strategy.

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.

Generation of a novel next-generation sequencing-based method for the isolation of new human papillomavirus types.

With the advent of new molecular tools, the discovery of new papillomaviruses (PVs) has accelerated during the past decade, enabling the expansion of knowledge about the viral populations that inhabit the human body. Human PVs (HPVs) are etiologically linked to benign or malignant lesions of the skin and mucosa. The detection of HPV types can vary widely, depending mainly on the methodology and the quality of the biological sample. Next-generation sequencing is one of the most powerful tools, enabling the discovery of novel viruses in a wide range of biological material. Here, we report a novel protocol for the detection of known and unknown HPV types in human skin and oral gargle samples using improved PCR protocols combined with next-generation sequencing. We identified 105 putative new PV types in addition to 296 known types, thus providing important information about the viral distribution in the oral cavity and skin.

Pepsinogen test for the evaluation of precancerous changes in gastric mucosa: a population-based study.

AIMS: The aim of the study was to evaluate the rationale of blood pepsinogen (PG) testing in population based screening settings. METHODS: Participants from a cross-sectional population-based study of cardiovascular risk factors in Latvia were invited to participate in the current study. Pepsinogen I and II were measured in blood samples taken during the initial study and at follow-up; upper gastrointestinal endoscopy was performed. There were three groups of patients: with moderately decreased (PG I< 70 ng/ml and PG I/PG II ratio < 3), with strongly decreased (PG I< 30 ng/ml and PG I/PG II ratio < 2), and with normal PG level. Biopsy with H. pylori detection was performed (updated Sydney system). RESULTS: Results from 259 patients were analyzed. Pepsinogens were decreased in 133 (51.4%), H. pylori was positive in 177 (66.0%) cases. Mean age was significantly lower in patients with normal compared to strongly decreased PG level group (52.8 vs. 64.1 years, p<0.001). Prevalence of severe corpus atrophy was higher in the strongly decreased compared to the normal PG test group: 7.0% vs. 0%; the same tendency was noted in the distribution of OLGA stages III-IV - 10.5% and 0.0%, OLGIM stages III-IV - 3.5% and 0%, and low-grade dysplasia - 15.8% and 2.4% (p<0.05). Two cases of gastric cancer were found; both presented decreased PG levels. A strong association between H. pylori eradication and PG ratio dynamics was found (p<0.05). CONCLUSIONS: All high-risk lesions were found in the decreased PG test groups; two cancer cases were revealed. However, PG demonstrated low specificity and low value of repeated testing. The value of PG as a sole test for gastric cancer risk is limited.

Detection of circulating miRNAs: comparative analysis of extracellular vesicle-incorporated miRNAs and cell-free miRNAs in whole plasma of prostate cancer patients.

BACKGROUND: Circulating cell-free miRNAs have emerged as promising minimally-invasive biomarkers for early detection, prognosis and monitoring of cancer. They can exist in the bloodstream incorporated into extracellular vesicles (EVs) and ribonucleoprotein complexes. However, it is still debated if EVs contain biologically meaningful amounts of miRNAs and may provide a better source of miRNA biomarkers than whole plasma. The aim of this study was to systematically compare the diagnostic potential of prostate cancer-associated miRNAs in whole plasma and in plasma EVs. METHODS: RNA was isolated from whole plasma and plasma EV samples from a well characterised cohort of 50 patient with prostate cancer (PC) and 22 patients with benign prostatic hyperplasia (BPH). Nine miRNAs known to have a diagnostic potential for PC in cell-free blood were quantified by RT-qPCR and the relative quantities were compared between patients with PC and BPH and between PC patients with Gleason score ≥ 8 and ≤6. RESULTS: Only a small fraction of the total cell-free miRNA was recovered from the plasma EVs, however the EV-incorporated and whole plasma cell-free miRNA profiles were clearly different. Four of the miRNAs analysed showed a diagnostic potential in our patient cohort. MiR-375 could differentiate between PC and BPH patients when analysed in the whole plasma, while miR-200c-3p and miR-21-5p performed better when analysed in plasma EVs. EV-incorporated but not whole plasma Let-7a-5p level could distinguish PC patients with Gleason score ≥ 8 vs ≤6. CONCLUSIONS: This study demonstrates that for some miRNA biomarkers EVs provide a more consistent source of RNA than whole plasma, while other miRNAs show better diagnostic performance when tested in the whole plasma.

Multicentric randomised study of Helicobacter pylori eradication and pepsinogen testing for prevention of gastric cancer mortality: the GISTAR study.

INTRODUCTION: Population-based eradication of Helicobacter pylori has been suggested to be cost-effective and is recommended by international guidelines. However, the potential adverse effects of widespread antibiotic use that this would entail have not been sufficiently studied. An alternative way to decrease gastric cancer mortality is by non-invasive search for precancerous lesions, in particular gastric atrophy; pepsinogen tests are the best currently available alternative. The primary objective of GISTAR is to determine whether H pylori eradication combined with pepsinogen testing reduces mortality from gastric cancer among 40-64-year-old individuals. The secondary objectives include evaluation of H pylori eradication effectiveness in gastric cancer prevention in patients with precancerous lesions and evaluation of the potential adverse events, including effects on microbiome. METHODS AND ANALYSIS: Individuals are recruited from general population (50% men) in areas with high gastric cancer risk in Europe and undergo detailed lifestyle and medical history questionnaire before being randomly allocated to intervention or control groups. The intervention group undergoes H pylori testing and is offered eradication therapy if positive; in addition, pepsinogen levels are detected in plasma and those with decreased levels are referred for upper endoscopy. All participants are offered faecal occult blood testing as an incentive for study participation. Effectiveness of eradication and the spectrum of adverse events are evaluated in study subpopulations. A 35% difference in gastric cancer mortality between the groups is expected to be detectable at 90% power after 15 years if 30 000 individuals are recruited. Biological materials are biobanked for the main and ancillary studies. The study procedure and assumptions will be tested during the pilot phase. ETHICS AND DISSEMINATION: The study was approved by the respective ethics committees. An independent Data Safety and Monitoring Board has been established. The findings will be published in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: NCT02047994.

The Prevalence of Cancer-Associated Autoantibodies in Patients with Gastric Cancer and Progressive Grades of Premalignant Lesions.

Background: Serum autoantibodies against tumor-associated antigens (TAAs) are detectable in early-stage gastric cancer patients; however, the time point during cancerogenesis when they appear in circulation is still obscure.Methods: In this study, we developed a recombinant antigen microarray and analyzed the prevalence of autoantibodies against 102 TAAs in 829 gastric cancer patients and 929 healthy controls from Caucasian and Asian populations, as well as 100 patients with chronic atrophic gastritis and 775 individuals staged according to different grades of intestinal metaplasia.Results: Six antigens, including CTAG1B/CTAG2, DDX53, IGF2BP2, TP53, and MAGEA3, were predominantly reacting with sera from gastric cancer patients when compared with healthy controls, and the seroreactivity was associated with intestinal-type gastric cancer, but not with patients' Helicobacter pylori status, grade, age, gender, or stage of gastric cancer. We detected gastric cancer-associated seroreactivity in 13% of patients with advanced/severe intestinal metaplasia, which was increased in comparison with mild/moderate intestinal metaplasia (5.3%) and was comparable with that seen in early-stage gastric cancer patients (12%). Moreover, by testing serum samples taken 1 to 9 years before the clinical diagnosis of 18 incident gastric cancer cases, we detected autoantibody responses against several TAAs-SOX2, MYC, BIRC5, IGF2BP1, and MUC1.Conclusions: Our results suggest that humoral immune response against TAAs is generated already during premalignant stages.Impact: Based on the obtained results, cancer-associated autoantibodies might make a valuable contribution to the stratification of high-risk patients with premalignant lesions in the stomach through enhancing the positive predictive power of existing risk models. Cancer Epidemiol Biomarkers Prev; 26(10); 1564-74. ©2017 AACR.

Comparison of the yield from two faecal immunochemical tests at identical cutoff concentrations - a randomized trial in Latvia.

OBJECTIVE: We have compared the performance of two faecal immunochemical tests (FIT) in an average-risk population. MATERIALS AND METHODS: Altogether, 10 000 individuals aged 50-74 were selected randomly from the population of Latvia in 2011 and assigned randomly either to OC-Sensor or to FOB Gold single-time testing. Positivity of the test, frequency of colonic lesions, number needed to screen (NNscreen) and scope for the detection of an advanced neoplasm (cancer and advanced adenoma) were compared between the tests using the same cutoff concentrations in µg/g faeces. Confidence intervals (CIs) at 95% were calculated. RESULTS: Positivity with the cutoff set at 10 µg/g faeces was 12.8% (95% CI: 11.4-14.2) for FOB Gold and 8.3% (95% CI: 7.2-9.4) for OC-Sensor (P<0.001). Positivity was higher in men and the older age groups. Colonoscopy compliance was 55.5%. There was no significant difference between the two tests at comparable cutoff concentrations in µg/g, colonoscopy attendance rate or colonoscopy results. For advanced neoplasm detection, there was no significant difference in number needed to scope and NNscreen at a cutoff of 10 µg/g faeces; however, lower NNscreen was required to detect advanced neoplasms with the FOB Gold test at increased cutoff concentrations. CONCLUSION: Different quantitative FIT systems may report different positivity rate at identical cutoff concentrations, which has to be considered when implementing the use of FIT in national screening programmes.

Different Pattern of Inflammatory and Atrophic Changes in the Gastric Mucosa of the Greater and Lesser Curvature.

BACKGROUND AND AIMS: Appropriate biopsy sampling is important for the classification of gastritis, yet the extent of inflammation and atrophy of different regions of the stomach with chronic gastritis have been addressed only in a few studies. The aim of our study was to analyze the inflammatory, atrophic and metaplastic changes in the greater and lesser curvature of the antrum and corpus mucosa. METHODS: 420 patients undergoing upper endoscopy were enrolled in the study. Four expert gastrointestinal pathologists graded biopsy specimens according to the updated Sydney classification. RESULTS: The obtained results showed that the mononuclear and granulocyte inflammatory cells were more prominent in the corpus lesser curvature compared to the corpus greater curvature (p=0.01 and p=0.0001, respectively). In addition, the extent and degree of atrophy and intestinal metaplasia were more prominent in the corpus lesser compared to the greater curvature (p=0.002 and p=0.0065, respectively). The frequency of distribution of H. pylori did not differ throughout both the corpus and antrum greater and lesser curvature. However, the degree of H. pylori colonization in the corpus was higher in the lesser than in the greater curvature. The interobserver agreement was significantly higher for corpus atrophy compared to antrum atrophy. CONCLUSIONS: These findings demonstrated that the more severe atrophic, metaplastic and inflammatory changes were observed in the lesser compared to the greater curvature of the stomach. In routine clinical settings, corpus and antral biopsies should be obtained from both lesser and greater curvature. Analysis of the incisura biopsy is also important.

Helicobacter pylori and allergy: Update of research.

Recently a lot of literature has been published about the possible preventive action of Helicobacter pylori (H. pylori) against allergy. The present review summarizes research data about the association between H. pylori and allergic diseases, as well as discusses possible hypotheses about the preventive action of H. pylori against atopy. There is evidence from observational studies to support a weak inverse association between prevalence of H. pylori infection and allergy. However, confounders like some unidentified socioeconomic factors, antibiotic use and others could bias the association. Although data from cohort studies point to a possible association of H. pylori with some of the allergic diseases, no definite proof for causal relationship has been clearly demonstrated yet. A biological mechanism proposed to explain the preventive action of H. pylori to allergy is reduced exposure to a major stimulus for the generation of Treg cells in individuals without H. pylori infection. In addition, H. pylori could be an indicator for changes in gut microbiome, reflecting the complex interaction between microbes and immune system.