Ilze Kikuste

Gastric cancer: Prevention, screening and early diagnosis

Gastric cancer continues to be an important healthcare problem from a global perspective. Most of the cases in the Western world are diagnosed at late stages when the treatment is largely ineffective. Helicobacter pylori (H. pylori) infection is a well-established carcinogen for gastric cancer. While lifestyle factors are important, the efficacy of interventions in their modification, as in the use of antioxidant supplements, is unconvincing. No organized screening programs can be found outside Asia (Japan and South Korea). Although several screening approaches have been proposed, including indirect atrophy detection by measuring pepsinogen in the circulation, none of them have so far been implemented, and more study data is required to justify any implementation. Mass eradication of H. pylori in high-risk areas tends to be cost-effective, but its adverse effects and resistance remain a concern. Searches for new screening biomarkers, including microRNA and cancer-autoantibody panels, as well as detection of volatile organic compounds in the breath, are in progress. Endoscopy with a proper biopsy follow-up remains the standard for early detection of cancer and related premalignant lesions. At the same time, new advanced high-resolution endoscopic technologies are showing promising results with respect to diagnosing mucosal lesions visually and targeting each biopsy. New histological risk stratifications (classifications), including OLGA and OLGIM, have recently been developed. This review addresses the current means for gastric cancer primary and secondary prevention, the available and emerging methods for screening, and new developments in endoscopic detection of early lesions of the stomach.

Diagnosis and Classification of 17 Diseases from 1404 Subjects via Pattern Analysis of Exhaled Molecules

We report on an artificially intelligent nanoarray based on molecularly modified gold nanoparticles and a random network of single-walled carbon nanotubes for noninvasive diagnosis and classification of a number of diseases from exhaled breath. The performance of this artificially intelligent nanoarray was clinically assessed on breath samples collected from 1404 subjects having one of 17 different disease conditions included in the study or having no evidence of any disease (healthy controls). Blind experiments showed that 86% accuracy could be achieved with the artificially intelligent nanoarray, allowing both detection and discrimination between the different disease conditions examined. Analysis of the artificially intelligent nanoarray also showed that each disease has its own unique breathprint, and that the presence of one disease would not screen out others. Cluster analysis showed a reasonable classification power of diseases from the same categories. The effect of confounding clinical and environmental factors on the performance of the nanoarray did not significantly alter the obtained results. The diagnosis and classification power of the nanoarray was also validated by an independent analytical technique, i.e., gas chromatography linked with mass spectrometry. This analysis found that 13 exhaled chemical species, called volatile organic compounds, are associated with certain diseases, and the composition of this assembly of volatile organic compounds differs from one disease to another. Overall, these findings could contribute to one of the most important criteria for successful health intervention in the modern era, viz. easy-to-use, inexpensive (affordable), and miniaturized tools that could also be used for personalized screening, diagnosis, and follow-up of a number of diseases, which can clearly be extended by further development.

Detection of precancerous gastric lesions and gastric cancer through exhaled breath

Objectives Timely detection of gastric cancer (GC) and the related precancerous lesions could provide a tool for decreasing both cancer mortality and incidence. Design 968 breath samples were collected from 484 patients (including 99 with GC) for two different analyses. The first sample was analysed by gas chromatography linked to mass spectrometry (GCMS) while applying t test with multiple corrections (p value<0.017); the second by cross-reactive nanoarrays combined with pattern recognition. For the latter, 70% of the samples were randomly selected and used in the training set while the remaining 30% constituted the validation set. The operative link on gastric intestinal metaplasia (OLGIM) assessment staging system was used to stratify the presence/absence and risk level of precancerous lesions. Patients with OLGIM stages III–IV were considered to be at high risk. Results According to the GCMS results, patients with cancer as well as those at high risk had distinctive breath-print compositions. Eight significant volatile organic compounds (p value<0.017) were detected in exhaled breath in the different comparisons. The nanoarray analysis made it possible to discriminate between the patients with GC and the control group (OLGIM 0–IV) with 73% sensitivity, 98% specificity and 92% accuracy. The classification sensitivity, specificity, and accuracy between the subgroups was as follows: GC versus OLGIM 0–II—97%, 84% and 87%; GC versus OLGIM III–IV—93%, 80% and 90%; but OLGIM I–II versus OLGIM III–IV and dysplasia combined—83%, 60% and 61%, respectively. Conclusions Nanoarray analysis could provide the missing non-invasive screening tool for GC and related precancerous lesions as well as for surveillance of the latter. Trial registration number Clinical Trials.gov number, NCT01420588 (3/11/2013).

Breath testing as potential colorectal cancer screening tool

Although colorectal cancer (CRC) screening is included in organized programs of many countries worldwide, there is still a place for better screening tools. In this study, 418 breath samples were collected from 65 patients with CRC, 22 with advanced or nonadvanced adenomas, and 122 control cases. All patients, including the controls, had undergone colonoscopy. The samples were analysed with two different techniques. The first technique relied on gas chromatography coupled with mass spectrometry (GC‐MS) for identification and quantification of volatile organic compounds (VOCs). The T‐test was used to identify significant VOCs (p values < 0.017). The second technique relied on sensor analysis with a pattern recognition method for building a breath pattern to identify different groups. Blind analysis or leave‐one‐out cross validation was conducted for validation. The GC‐MS analysis revealed four significant VOCs that identified the tested groups; these were acetone and ethyl acetate (higher in CRC), ethanol and 4‐methyl octane (lower in CRC). The sensor‐analysis distinguished CRC from the control group with 85% sensitivity, 94% specificity and 91% accuracy. The performance of the sensors in identifying the advanced adenoma group from the non‐advanced adenomas was 88% sensitivity, 100% specificity, and 94% accuracy. The performance of the sensors in identifying the advanced adenoma group was distinguished from the control group was 100% sensitivity, 88% specificity, and 94% accuracy. For summary, volatile marker testing by using sensor analysis is a promising noninvasive approach for CRC screening.

Breath Testing as Potential Colorectal Cancer Screening Tool

Although colorectal cancer (CRC) screening is included in organized programs of many countries worldwide, there is still a place for better screening tools. In this study, 418 breath samples were collected from 65 patients with CRC, 22 with advanced or nonadvanced adenomas, and 122 control cases. All patients, including the controls, had undergone colonoscopy. The samples were analysed with two different techniques. The first technique relied on gas chromatography coupled with mass spectrometry (GC‐MS) for identification and quantification of volatile organic compounds (VOCs). The T‐test was used to identify significant VOCs (p values < 0.017). The second technique relied on sensor analysis with a pattern recognition method for building a breath pattern to identify different groups. Blind analysis or leave‐one‐out cross validation was conducted for validation. The GC‐MS analysis revealed four significant VOCs that identified the tested groups; these were acetone and ethyl acetate (higher in CRC), ethanol and 4‐methyl octane (lower in CRC). The sensor‐analysis distinguished CRC from the control group with 85% sensitivity, 94% specificity and 91% accuracy. The performance of the sensors in identifying the advanced adenoma group from the non‐advanced adenomas was 88% sensitivity, 100% specificity, and 94% accuracy. The performance of the sensors in identifying the advanced adenoma group was distinguished from the control group was 100% sensitivity, 88% specificity, and 94% accuracy. For summary, volatile marker testing by using sensor analysis is a promising noninvasive approach for CRC screening.

Systematic review of the diagnosis of gastric premalignant conditions and neoplasia with high-resolution endoscopic technologies

Abstract Aim. The aim of the article is to systematically review the current evidence on the diagnostic use of narrow band imaging (NBI), flexible spectral imaging color enhancement (FICE) and endoscopic image enhancement technology i-scan endoscopies for gastric precancerous and cancerous lesions. Materials and methods. Original manuscripts were searched in PubMed until October 2012. Pertinent data were collected and pooled diagnostic accuracy measures were estimated when possible. Results. In total, 38 studies were evaluated. Thirty-one studies were included for NBI and 7 studies for FICE assessment in this systematic review. No article was found meeting inclusion criteria for i-scan endoscopy. The most defined and evaluated outcomes were cancer-related (n = 26). Quality Assessment of Diagnostic Accuracy Studies score varied from 9 to 12 (out of 14). Only few studies assessed the interobserver reliability. On a patient level analysis, NBIs pooled sensitivity, specificity and diagnostic odds ratio were 0.67 (95% CI: 0.61–0.73), 0.81 (95% CI: 0.76–0.85) and 22.71 (95% CI: 12.53–41.1), respectively for diagnosing normal mucosa; 0.86 (95% CI: 0.82–0.90), 0.77 (95% CI: 0.73–0.80) and 17.01 (95% CI: 1.4–207.2) for intestinal metaplasia and 0.90 (95% CI: 0.84–0.94), 0.83 (95% CI: 0.80–0.86) and 47.61 (95% CI: 4.61–491.34) for dysplasia. Owing to the insufficient data and different definitions, we could not aggregate the results for FICE. Conclusion. Gastric pattern descriptions have been proposed for NBI and FICE studies by gathering all descriptions in one single description. The classification systems varied between studies, a single description of gastric mucosal features with HR – scopes or at least per technology – will have to be agreed on.

Emerging blood-based biomarkers for detection of gastric cancer

Early detection and efficient monitoring of tumor dynamics are prerequisites for reducing disease burden and mortality, and for improving the management of patients with gastric cancer (GC). Blood-based biomarker assays for the detection of early-stage GC could be of great relevance both for population-wide or risk group-based screening programs, while circulating biomarkers that reflect the genetic make-up and dynamics of the tumor would allow monitoring of treatment efficacy, predict recurrences and assess the genetic heterogeneity of the tumor. Recent research to identify blood-based biomarkers of GC has resulted in the identification of a wide variety of cancer-associated molecules, including various proteins, autoantibodies against tumor associated antigens, cell-free DNA fragments, mRNAs and various non-coding RNAs, circulating tumor cells and cancer-derived extracellular vesicles. Each type of these biomarkers provides different information on the disease status, has different advantages and disadvantages, and distinct clinical usefulness. In the current review, we summarize the recent developments in blood-based GC biomarker discovery, discuss the origin of various types of biomarkers and their clinical usefulness and the technological challenges in the development of biomarker assays for clinical use.

The accuracy of flexible spectral imaging colour enhancement for the diagnosis of gastric intestinal metaplasia: do we still need histology to select individuals at risk for adenocarcinoma?

Background Targeting biopsies on the basis of visual recognition of mucosal changes in the stomach instead of the currently accepted random biopsy sampling may be attractive. Aim The aim of this study was to evaluate the accuracy of endoscopic findings using flexible spectral imaging colour enhancement (FICE) for intestinal metaplasia (IM) in the gastric mucosa. Methods A consecutive cohort of 126 individuals aged over 50 years (27% men) was subjected to upper endoscopy using FICE. Histological assessment (per patient and per biopsy) was considered the gold standard to accuracy estimates. Results Histological assessment revealed IM in 50% of the individuals [OLGIM (operative link on gastric intestinal metaplasia assessment) stages I–IV]. Overall, endoscopy presented sensitivities, specificities, positive likelihood ratio, negative likelihood ratio and accuracies per patient of 60% [95% confidence interval (95% CI) 48–72], 87% (95% CI 79–95), 4.7 (95% CI 2.4–93), 0.45 (95% CI 0.33–0.62) and 74% (95% CI 0.66–0.82), respectively, for IM diagnosis and 71% (95% CI 37–100), 87% (95% CI 79–95), 5.6 (95% CI 2.5–12.5), 0.32 (95% CI 0.10–1.0) and 86% (95% CI 77–94), respectively, for selecting individuals with OLGIM (III–IV). The proportions of agreement (and &kgr; values) for IM in the antrum and the corpus were 75% (0.37) and 81% (0.19), respectively. Conclusion FICE endoscopy yielded favourable results in the endoscopic diagnosis of IM of the gastric mucosa, and this is a very practical and easy method to use in daily clinical practice for unselected patients. Our study demonstrated a good specificity for FICE endoscopy to detect IM in the stomach. Further improvement in disseminating and training of this assessment is required to improve the reliability.

The effect of incisura angularis biopsy sampling on the assessment of gastritis stage.

Objectives It is important to stratify patients according to the magnitude of risk for gastric cancer development; the OLGA (Operative Link for Gastritis Assessment) and OLGIM (Operative Link on Gastric Intestinal Metaplasia) staging systems of lesions in the stomach mucosa have been proposed for this purpose. There are some discrepancies in the current guidelines regarding the value of incisura angularis biopsies. The aim of our study was to assess the value of incisura angularis biopsy in staging gastritis according to the OLGA and OLGIM systems by examining the atrophic, metaplastic and inflammatory changes in the antrum, incisura angularis and corpus. Patients and methods We enrolled 835 patients undergoing upper endoscopy. Three expert gastrointestinal pathologists graded biopsy specimens according to the Sydney classification and the stage of gastritis was assessed by the OLGA and OLGIM systems. Results The results demonstrated that severe atrophic, metaplastic and chronic inflammatory changes were more frequently observed in the incisura angularis mucosa than in the antrum or corpus mucosae (P<0.05). There was a general downgrading of stage by 18.0% for OLGA and by 4.0% for OLGIM when the incisura angularis was excluded from the staging. Furthermore, there was a 30–35% downgrading for high-risk OLGA/OLGIM stages. Conclusion The incisura angularis undergoes more severe atrophic, metaplastic and chronic inflammatory changes than the antrum and corpus. Incisura angularis biopsies should be routinely included in the biopsy sampling protocol.

Interobserver variation in assessment of gastric premalignant lesions: higher agreement for intestinal metaplasia than for atrophy.

Background Either atrophy or intestinal metaplasia of the gastric mucosa are considered premalignant lesions. The new operative link for gastritis assessment staging system is based on the detection of atrophy, and the operative link for assessment of intestinal metaplasia staging system is based on the detection of intestinal metaplasia. Good interobserver agreement is necessary for identification of any premalignant condition. Aims The aim of this study was to compare the agreement between findings of gastric atrophy and intestinal metaplasia by expert and general pathologists and to analyze the possible reasons behind any possible disagreement. Methods Patients with dyspeptic symptoms, aged 55 years and above, without previous Helicobacter pylori eradication were enrolled and analyzed according to the updated Sydney Classification by two expert pathologists and an experienced general pathologist; the results were compared with the consensus driven by the two experts. Results Gastric biopsy specimens from 121 patients (91 women) were included in the analysis; the mean age of the patients was 67.4 years. H. pylori infection was present in 61.2% of patients. The level of agreement between the general pathologist and the two experts (&kgr;-value) was 0.12, 0.46, and 0.87, respectively, for detecting atrophy in the corpus; 0.77, 0.77, and 0.65, respectively, for detecting intestinal metaplasia in the corpus; 0.06, 0.51, and 0.54, respectively, for detecting atrophy in the antrum; and 0.69, 0.85, and 0.79, respectively, for detecting metaplasia in the antrum. Conclusion The agreement was substantially higher for intestinal metaplasia than for atrophy. This could result in discrepancies when the operative link for gastritis assessment and operative link for assessment of intestinal metaplasia staging systems are applied and can be caused by differences in the criteria used to define atrophy.