Special Issue "Advances in the Detection and Screening of Gastric Cancer"

A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: 28 February 2023 | Viewed by 7653

Special Issue Editor

Prof. Dr. Mārcis Leja
E-Mail Website1 Website2
Guest Editor
Institute of Clinical and Preventive Medicine, Faculty of Medicine, University of Latvia, Riga, Latvia
Interests: cancer prevention and early detection; gastric cancer; precancerous lesions; H. pylori; microbiota; new technologies; volatile marker testing; breath analysis

Special Issue Information

Dear Colleagues,

The absolute number of new gastric cancer cases is expected to grow to 1.77 million in 2040 despite the decreasing overall incidence, therefore demonstrating the importance of this healthcare problem. The burden of the disease could be decreased either by spotting cancer at an early, ideally precancerous stage or by timely eradication of H. pylori infection, the major cause of gastric cancer. Screening for cancer via endoscopy or photophluoroscopy is included in nationwide programs in Japan and Korea, and a number of other countries are in the process of implementing preventive programs. This Special Issue is planned to summarize recent developments in the field.

Furthermore, non-invasive testing for gastric cancer or precancerous lesions has been at the focus of researchers for decades. In addition to traditional biomarkers, such as pepsinogens and gastrin-17, as well as markers for autoimmunity, the role of potential new approaches, including volatile organic compounds in breath, has shown promise. We intend to also address these issues in this issue by presenting the status of the ongoing studies.

Finally, large data and artificial intelligence are expected to change the mentality in medicine, including also in gastric-cancer-related aspects. We intend to identify the areas where data collaborations could facilitate efforts aimed at gastric cancer mortality reduction.

Therefore, with the current issue, we aim to present the current status in various aspects of gastric cancer screening and prevention and provide an update on screening programs, summary of the currently ongoing major studies globally, as well as give an opportunity to present original research results from groups active in the field.

Prof. Dr. Mārcis Leja
Guest Editor

Manuscript Submission Information

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Keywords

  • Gastric cancer
  • Precancerous lesions
  • Autoimmune gastritis
  • Screening
  • Early detection
  • Helicobacter pylori
  • Biomarkers
  • Pepsinogens
  • ABC method
  • Volatile markers
  • Microbiome
  • Large data
  • Artificial intelligence

Published Papers (11 papers)

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Research

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Article
Assessment of Serum Pepsinogens with and without Co-Testing with Gastrin-17 in Gastric Cancer Risk Assessment—Results from the GISTAR Pilot Study
Diagnostics 2022, 12(7), 1746; https://doi.org/10.3390/diagnostics12071746 - 19 Jul 2022
Viewed by 519
Abstract
Introduction––Serum pepsinogen tests for gastric cancer screening have been debated for decades. We assessed the performance of two pepsinogen assays with or without gastrin-17 for the detection of different precancerous lesions alone or as a composite endpoint in a Latvian cohort. Methods––Within the [...] Read more.
Introduction––Serum pepsinogen tests for gastric cancer screening have been debated for decades. We assessed the performance of two pepsinogen assays with or without gastrin-17 for the detection of different precancerous lesions alone or as a composite endpoint in a Latvian cohort. Methods––Within the intervention arm of the GISTAR population-based study, participants with abnormal pepsinogen values by ELISA or latex-agglutination tests, or abnormal gastrin-17 by ELISA and a subset of subjects with all normal biomarker values were referred for upper endoscopy with biopsies. Performance of biomarkers, corrected by verification bias, to detect five composite outcomes based on atrophy, intestinal metaplasia, dysplasia or cancer was explored. Results––Data from 1045 subjects were analysed, of those 273 with normal biomarker results. Both pepsinogen assays showed high specificity (>93%) but poor sensitivity (range: 18.4–31.1%) that slightly improved when lesions were restricted to corpus location (40.5%) but decreased when dysplasia and prevalent cancer cases were included (23.8%). Adding gastrin-17 detection, sensitivity reached 33–45% while specificity decreased (range: 61.1–62%) and referral rate for upper endoscopy increased to 38.6%. Conclusions––Low sensitivity of pepsinogen assays is a limiting factor for their use in population-based primary gastric cancer screening, however their high specificity could be useful for triage. Full article
(This article belongs to the Special Issue Advances in the Detection and Screening of Gastric Cancer)
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Article
MCRS1 Expression Regulates Tumor Activity and Affects Survival Probability of Patients with Gastric Cancer
Diagnostics 2022, 12(6), 1502; https://doi.org/10.3390/diagnostics12061502 - 20 Jun 2022
Viewed by 535
Abstract
Gastric cancer is the fifth most common cancer worldwide and the third most common cause of cancer-related deaths. Surgery remains the first-choice treatment. Chemotherapy is considered in the middle and advanced stages, but has limited success. Microspherule protein 1 (MCRS1, also known as [...] Read more.
Gastric cancer is the fifth most common cancer worldwide and the third most common cause of cancer-related deaths. Surgery remains the first-choice treatment. Chemotherapy is considered in the middle and advanced stages, but has limited success. Microspherule protein 1 (MCRS1, also known as MSP58) is a protein originally identified in the nucleus and cytoplasm that is involved in the cell cycle. High expression of MCRS1 increases tumor growth, invasiveness, and metastasis. The mechanistic relationships between MCSR1 and proliferation, apoptosis, angiogenesis, and epithelial–mesenchymal transition (EMT) remain to be elucidated. We clarified these relationships using immunostaining of tumor tissues and normal tissues from patients with gastric cancer. High MCRS1 expression in gastric cancer positively correlated with Ki-67, Caspase3, CD31, Fibronectin, pAKT, and pAMPK. The hazard ratio of high MCRS1 expression was 2.44 times that of low MCRS1 expression, negatively impacting patient survival. Full article
(This article belongs to the Special Issue Advances in the Detection and Screening of Gastric Cancer)
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Article
Dynamics of Oxidative Stress in Helicobacter pylori-Positive Patients with Atrophic Body Gastritis and Various Stages of Gastric Cancer
Diagnostics 2022, 12(5), 1203; https://doi.org/10.3390/diagnostics12051203 - 11 May 2022
Viewed by 507
Abstract
Gastric cancer is a global health problem. The pathogenesis of this disease remains unclear. This study included 198 H. pylori (+) men aged 45 to 60 years old. Group A included 63 practically healthy men, group B included 45 men with severe atrophic [...] Read more.
Gastric cancer is a global health problem. The pathogenesis of this disease remains unclear. This study included 198 H. pylori (+) men aged 45 to 60 years old. Group A included 63 practically healthy men, group B included 45 men with severe atrophic body gastritis, group C included 37 men with epithelial gastric cancer stages I–II according to TNM, and group D included 54 men with epithelial gastric cancer stages III–IV according to the TNM scale. The content of malondialdehyde (MDA), diene conjugates (DCs), superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), and glutathione peroxidase (GPO) was detected using an enzyme immunoassay (ELISA) or spectrophotometric methods in the blood plasma. The concentrations of MDA and DC were increased in the patients of group B compared with group A, and in patients of groups C and D compared with groups A and B. The ratio of MDA/SOD and MDA/CAT was decreased in the patients in group D compared with the patients in group C, and was significantly higher compared with group A. The ratios of MDA/GPO and MDA/GST increased linearly and were at a maximum in groups C and D. Our work determined that indicators of oxidative stress may be the biochemical substrate, which brings together the various stages of the Correa cascade, and may explain disease progression. The dynamics of changes in the content of SOD and CAT in the plasma in patients with gastric cancer may be a target of future investigations. Full article
(This article belongs to the Special Issue Advances in the Detection and Screening of Gastric Cancer)
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Article
Factors Associated with False Negative Results in Serum Pepsinogen Testing for Precancerous Gastric Lesions in a European Population in the GISTAR Study
Diagnostics 2022, 12(5), 1166; https://doi.org/10.3390/diagnostics12051166 - 07 May 2022
Viewed by 406
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Advances in the Detection and Screening of Gastric Cancer)
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Article
Impact of Selected Serum Factors on Metastatic Potential of Gastric Cancer Cells
Diagnostics 2022, 12(3), 700; https://doi.org/10.3390/diagnostics12030700 - 12 Mar 2022
Cited by 2 | Viewed by 788
Abstract
(1) Background: stromal-derived factor-1 (SDF-1/CXCL12), hepatocyte and vascular-endothelial growth factors (HGF and VEGF) have been shown to facilitate cell motility, proliferation and promote local tumor progression and metastatic spread. Recent research shows the important role of these cytokines in gastric cancer (GC) progression. [...] Read more.
(1) Background: stromal-derived factor-1 (SDF-1/CXCL12), hepatocyte and vascular-endothelial growth factors (HGF and VEGF) have been shown to facilitate cell motility, proliferation and promote local tumor progression and metastatic spread. Recent research shows the important role of these cytokines in gastric cancer (GC) progression. (2) Methods: 21 gastric cancer patients and 19 healthy controls were included in the study. SDF-1, HGF and VEGF levels were evaluated in sera by ELISA. Patients and control sera were used to stimulate CRL-1739 GC cell line, and chemotaxis, adhesion and proliferation potential were assessed. (3) Results: Concentrations of SDF-1, HGF and VEGF were significantly higher in patients than in controls. Chemotaxis and adhesion assays revealed a significant response of GC cells to patients’ serum. Furthermore, significant relationships were seen between chemotactic/adhesion response and tumor stage. Serum from intestinal early GC patients produced significantly stronger chemotactic response when compared to patients with metastatic spread. In turn, serum from patients with distal metastases significantly increased the adhesion of GC cells when compared to sera from the patients with no distal metastases. We also observed that HGF strongly stimulated the proliferation of CRL-1739 cells. (4) Conclusions: We observed that the sera from GC patients, but also SDF-1, HGF and VEGF used alone, have a strong pro-metastatic effect on CRL-1739 cells. We also demonstrated that the concentration of these cytokines is specifically elevated in the sera of patients in an early stage of malignancy. Our results indicate that SDF-1, HGF and VEGF are very important molecules involved in gastric cancer progression. Full article
(This article belongs to the Special Issue Advances in the Detection and Screening of Gastric Cancer)
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Article
Serum Pepsinogens Combined with New Biomarkers Testing Using Chemiluminescent Enzyme Immunoassay for Non-Invasive Diagnosis of Atrophic Gastritis: A Prospective, Multicenter Study
Diagnostics 2022, 12(3), 695; https://doi.org/10.3390/diagnostics12030695 - 12 Mar 2022
Viewed by 781
Abstract
Background: Analysis of serum biomarkers for the assessment of atrophic gastritis (AG), a gastric precancerous lesion, is of growing interest for identification of patients at increased risk of gastric cancer. The aim was to analyze the diagnostic performance of serum pepsinogen testing using [...] Read more.
Background: Analysis of serum biomarkers for the assessment of atrophic gastritis (AG), a gastric precancerous lesion, is of growing interest for identification of patients at increased risk of gastric cancer. The aim was to analyze the diagnostic performance of serum pepsinogen testing using another method, chemiluminescent enzyme immunoassay (CLEIA), as well as of other new potential biomarkers. Material and Methods: The sera of patients considered at increased risk of gastric cancer and undergoing upper endoscopy collected in our previous prospective, multicenter study were tested for pepsinogen I (PGI) and II (PGII), interleukin-6 (IL-6), human epididymal protein 4 (HE-4), adiponectin, ferritin and Krebs von den Lungen (KL-6) using the CLEIA. The diagnostic performance for the detection of AG was calculated by taking histology as the reference. Results: In total, 356 patients (162 men (46%); mean age 58.6 (±14.2) years), including 152 with AG, were included. For the detection of moderate to severe corpus AG, sensitivity and specificity of the pepsinogen I/II ratio were of 75.0% (95%CI 57.8–87.9) and 92.6% (88.2–95.8), respectively. For the detection of moderate to severe antrum AG, sensitivity of IL-6 was of 72.2% (95%CI 46.5–90.3). Combination of pepsinogen I/II ratio or HE-4 showed a sensitivity of 85.2% (95%CI 72.9–93.4) for the detection of moderate to severe AG at any location. Conclusion: This study shows that PG testing by CLEIA represents an accurate assay for the detection of corpus AG. Additionally, IL-6 and HE-4 may be of interest for the detection of antrum AG. Mini-abstract: Pepsinogens testing by chemiluminescent enzyme immunoassay is accurate for the detection of corpus atrophic gastritis. IL-6 and HE-4 maybe of interest for the detection of antrum atrophic gastritis. Full article
(This article belongs to the Special Issue Advances in the Detection and Screening of Gastric Cancer)
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Article
Modular Point-of-Care Breath Analyzer and Shape Taxonomy-Based Machine Learning for Gastric Cancer Detection
Diagnostics 2022, 12(2), 491; https://doi.org/10.3390/diagnostics12020491 - 14 Feb 2022
Cited by 1 | Viewed by 803
Abstract
Background: Gastric cancer is one of the deadliest malignant diseases, and the non-invasive screening and diagnostics options for it are limited. In this article, we present a multi-modular device for breath analysis coupled with a machine learning approach for the detection of cancer-specific [...] Read more.
Background: Gastric cancer is one of the deadliest malignant diseases, and the non-invasive screening and diagnostics options for it are limited. In this article, we present a multi-modular device for breath analysis coupled with a machine learning approach for the detection of cancer-specific breath from the shapes of sensor response curves (taxonomies of clusters). Methods: We analyzed the breaths of 54 gastric cancer patients and 85 control group participants. The analysis was carried out using a breath analyzer with gold nanoparticle and metal oxide sensors. The response of the sensors was analyzed on the basis of the curve shapes and other features commonly used for comparison. These features were then used to train machine learning models using Naïve Bayes classifiers, Support Vector Machines and Random Forests. Results: The accuracy of the trained models reached 77.8% (sensitivity: up to 66.54%; specificity: up to 92.39%). The use of the proposed shape-based features improved the accuracy in most cases, especially the overall accuracy and sensitivity. Conclusions: The results show that this point-of-care breath analyzer and data analysis approach constitute a promising combination for the detection of gastric cancer-specific breath. The cluster taxonomy-based sensor reaction curve representation improved the results, and could be used in other similar applications. Full article
(This article belongs to the Special Issue Advances in the Detection and Screening of Gastric Cancer)
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Article
Who Could Be Blamed in the Case of Discrepant Histology and Serology Results for Helicobacter pylori Detection?
Diagnostics 2022, 12(1), 133; https://doi.org/10.3390/diagnostics12010133 - 06 Jan 2022
Cited by 3 | Viewed by 594
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Advances in the Detection and Screening of Gastric Cancer)
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Review

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Review
Artificial Intelligence for Upper Gastrointestinal Endoscopy: A Roadmap from Technology Development to Clinical Practice
Diagnostics 2022, 12(5), 1278; https://doi.org/10.3390/diagnostics12051278 - 21 May 2022
Viewed by 687
Abstract
Stomach cancer is the third deadliest type of cancer in the world (0.86 million deaths in 2017). In 2035, a 20% increase will be observed both in incidence and mortality due to demographic effects if no interventions are foreseen. Upper GI endoscopy (UGIE) [...] Read more.
Stomach cancer is the third deadliest type of cancer in the world (0.86 million deaths in 2017). In 2035, a 20% increase will be observed both in incidence and mortality due to demographic effects if no interventions are foreseen. Upper GI endoscopy (UGIE) plays a paramount role in early diagnosis and, therefore, improved survival rates. On the other hand, human and technical factors can contribute to misdiagnosis while performing UGIE. In this scenario, artificial intelligence (AI) has recently shown its potential in compensating for the pitfalls of UGIE, by leveraging deep learning architectures able to efficiently recognize endoscopic patterns from UGIE video data. This work presents a review of the current state-of-the-art algorithms in the application of AI to gastroscopy. It focuses specifically on the threefold tasks of assuring exam completeness (i.e., detecting the presence of blind spots) and assisting in the detection and characterization of clinical findings, both gastric precancerous conditions and neoplastic lesion changes. Early and promising results have already been obtained using well-known deep learning architectures for computer vision, but many algorithmic challenges remain in achieving the vision of AI-assisted UGIE. Future challenges in the roadmap for the effective integration of AI tools within the UGIE clinical practice are discussed, namely the adoption of more robust deep learning architectures and methods able to embed domain knowledge into image/video classifiers as well as the availability of large, annotated datasets. Full article
(This article belongs to the Special Issue Advances in the Detection and Screening of Gastric Cancer)
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Other

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Comment
Comment on Skrebinska et al. Who Could Be Blamed in the Case of Discrepant Histology and Serology Results for Helicobacter pylori Detection? Diagnostics 2022, 12, 133
Diagnostics 2022, 12(6), 1424; https://doi.org/10.3390/diagnostics12061424 - 09 Jun 2022
Viewed by 398
Abstract
In their article, Skebrinska and colleagues analysed the potential pitfalls of detecting Helicobacter pylori (H. pylori) by serology, histological (Giemsa) and immunohistochemical (IHC) staining. However, in the Introduction, the authors state: “…IHC is recommended only in individuals with active gastritis without [...] Read more.
In their article, Skebrinska and colleagues analysed the potential pitfalls of detecting Helicobacter pylori (H. pylori) by serology, histological (Giemsa) and immunohistochemical (IHC) staining. However, in the Introduction, the authors state: “…IHC is recommended only in individuals with active gastritis without H. pylori identification by histochemistry”. Although this is a widely-held view, it does not seem to hold up in view of the results of the study by Kocsmár et al., which showed that the diagnostic sensitivity of Giemsa in the absence of activity is only 33.6%, but it is 92.6% in the presence of active gastritis, which is close to the 99.4% sensitivity of IHC. Considering that chronic active gastritis with the features of H. pylori gastritis is also common in other entities, if active inflammation is present in the sample, there is a very small chance that a Giemsa-negative case will be confirmed as H. pylori-positive by IHC. Based on this, the use of IHC is more reasonable in Giemsa-negative cases with no activity in which the etiological role of H. pylori is suggested by clinical, anamnestic or other data. However, it may also be reasonable to routinely use IHC as the primary staining method instead of Giemsa. Full article
(This article belongs to the Special Issue Advances in the Detection and Screening of Gastric Cancer)
Protocol
Introducing the Sanguis-Filum for Detection of Gastric Mucosal Lesions Prior to Endoscopy: A Study Protocol
Diagnostics 2022, 12(5), 1160; https://doi.org/10.3390/diagnostics12051160 - 07 May 2022
Viewed by 420
Abstract
Early diagnosis of gastric cancer (GC) is compromised by a lack of specific signs to enable identification of affected individuals. We designed the Sanguis-filum (S-filum) as a simple bedside tool that could be used to detect the presence of gastric mucosal lesions prior [...] Read more.
Early diagnosis of gastric cancer (GC) is compromised by a lack of specific signs to enable identification of affected individuals. We designed the Sanguis-filum (S-filum) as a simple bedside tool that could be used to detect the presence of gastric mucosal lesions prior to endoscopy. We previously published evidence that at a sensitivity of 91%, the presence of free blood in the stomach was associated with mucosal lesions. The S-filum is made of an inert but absorbent string coiled up in a gelatin capsule (Capsuline, FL, USA), which can be swallowed and the string retrieved to test for free blood. Preliminary testing of the S-filum was successfully conducted on healthy volunteers. We now intend to test it on actual patients, comparing the results to oesophagogastroduodenoscopy (OGD) findings. This will enable us to determine the diagnostic accuracy of the S-filum at detecting GC and other mucosal lesions. The S-filum as a bedside tool has the potential to assist healthcare providers to identify individuals likely to have early gastric mucosal lesions and requiring OGD examination. The S-filum could, in the long run, facilitate population-wide screening for early GC prior to endoscopy. Full article
(This article belongs to the Special Issue Advances in the Detection and Screening of Gastric Cancer)
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