Intestinal-type Cancer Research Articles

Mutations in Helicobacter pylori infected patients with chronic gastritis, intestinal type of gastric cancer and familial gastric cancer

BackgroundDevelopment of sequential changes of mucous leading to gastric cancer and familial cases of gastric cancer of intestinal type is widely connected with Helicobacter pylori infections. In this study we analysed variants of genes involved in cancerogenesis and inflammatory processes of intestines in patients infected with H.pylori. Our goal was to test whether mutations in these genes predestinate to development of gastric cancer, and whether there is a genetic factor that makes it more likely for infections with H.pylori to cause gastric cancer. As infections with H. pylori are relatively common, discovering such genetic predispositions could be used for establishing risk-groups and for planning treatments.MethodsOur studies cover analysis of variants in genes involved in cancerogenesis: TP53 (rs11540652, rs587782329, COSM10771), MSH2 (rs193922376), MLH1 (rs63750217), and inflammatory processes of intestine: NOD2 (rs2066847, rs2066842), IL1A (rs1800587) and IL1B (rs1143634) from H.pylori-infected patients.ResultsMutations were more common in the group of patients with gastric cancer of intestinal type and familial cases of gastric cancer in comparison with patients with chronic gastritis, chronic atrophic gastritis, intestinal metaplasia, dysplasia or gastric cancer (p-value = 0.00824), with the prevalence of p53 mutations in patients with familial gastric cancer vs. patients with other changes of mucosa (p-value = 0.000049). Additionally, gastric cancer patients have mainly genotype TT or CT of the rs2066842 variant of the NOD2 gene.ConclusionsThe lack of statistically significant changes of other interleukin genes involved in inflammatory processes may suggest the presence of H.pylori infection as a potential trigger for the development of the inflammatory process of the mucosa, leading through microbiota dysbiosis to the development of enteric gastric cancer. Mutations in analysed genes correlated with more severe mucosal changes, with a much more frequent presence of TP53 gene mutations, with a limited presence of other mutations in the familial history of gastric cancer.

Goblet cells segmentation from confocal laser endomicroscopy with an improved U-Net

Gastric intestinal metaplasia (GIM) is regarded as a remarkable precursor for the development of intestinal-type stomach cancer. Goblet cell (GC) segmentation is the crucial step for assessing the degree of GIM by confocal laser endomicroscopy (CLE). However, GC segmentation by hand is difficult, unreliable, and time-consuming. Meanwhile, due to the high resolution and noise interference of CLE images, existing segmentation approaches perform poorly on this task. To tackle those issues, we collected 343 confocal laser endomicroscopy images of 62 patients from a Grade-A tertiary hospital. Each CLE image is manually annotated and then verified three times by skilled medical specialists. Then, U-Net is improved by incorporating the pixel gradient attention mechanism, which focuses on color gradient information around GC and captures color gradient features to direct feature maps in the skip connection layer. At last, the model output vector is used to calculate the possibility map and generate the final segmentation area. Compared with mainstream models, our proposed GC segmentation method from CLE with an improved U-Net (GCSCLE) performs the better segmentation result when tested on our CLE dataset and achieved an IOU of 87.95% and a DICE of 86.64%. Our result shows, the performance of the GCSCLE can be compared with the manual CLE image processing in clinical settings, and it can improve segmentation accuracy and save time and costs.

Intertumor heterogeneity of locally advanced gastric cancer.

435 Background: The aim of the present study was to determine to the effect of HER2, dMMR, PD-L1 status in the primary tumor and in metastasis to the regional lymph node of GC patients. Methods: A total of 44 patients with primary loco-regional (N+) gastric adenocarcinoma were recruited, and two formalin-fixed paraffin-embedded (FFPE) tumor-containing blocks of each patient (one block with primary tumor and one block with metastasis to the regional lymph node)were selected for HER2, dMMR, PD-L1 (CPS) immunohistochemical (IHC) assay. Clinicopathological characteristics were recorded, and intertumoral heterogeneity of HER2, dMMR, PD-L1 IHC expression was determined. Results: The study included 19 women and 25 men, 30 patients had Laurén’s intestinal type of cancer, 14 had a Laurén’s diffuse type. In 5 patients (11.4%) overexpression of Her-2 neu was detected, and heterogeneity was detected in all five cases: in three patients with HER2 overexpression in the primary tumor, no overexpression was detected in the metastasis to the regional lymph node, in two cases overexpression was detected in the metastasis, while no overexpression was observed in the primary tumor. 2 patients showed signs of dMMR (4.5%), in one case, heterogeneity in dMMR status was also revealed: signs of dMMR in the primary tumor and its absence in regional metastasis (pMMR). Assessment of PD-L1 status was carried out using the CPS formula. Ten patients (22.7%) had a negative PD-L1 status (CPS=0) both in the primary tumor and in regional metastasis. Positive PD-L1 status in the primary tumor: in 24 patients CPS= 0-5 (54.5%), in 5 patients CPS= 5-10 (11.4%) and 5 patients CPS= 10 or more (11.4% ). Positive PD-L1 status in regional lymph node metastasis: in 24 patients CPS= 0-5 (54.5%), in 5 patients CPS= 5-10 (11.4%) and in 5 patients CPS= 10 or more ( 11.4%). In 5 cases (11.4%) marked heterogeneity in PD-L1 status between the primary tumor and its regional metastasis (1 case with dMMR heterogeneity). Conclusions: The research findings in this paper indicate that the intertumoral heterogeneity of HER2 overexpression is common in GC patients, We highly recommend multi-block HER2 assessment for accurate diagnosis of GC. Given the rarity of status detection dMMR, a study in a larger number of patients is required, however, our data also confirm the presence of heterogeneity in dMMR status, and probably the possibility of metastasis of a more aggressive pMMR clone. Heterogeneity in PD-L1 status is quite rare and amounted to only 11.4%, which also has important practical significance.

Single-cell analysis of gastric pre-cancerous and cancer lesions reveals cell lineage diversity and intratumoral heterogeneity

Single-cell transcriptomic profiles analysis has proposed new insights for understanding the behavior of human gastric cancer (GC). GC offers a unique model of intratumoral heterogeneity. However, the specific classes of cells involved in carcinogenetic passage, and the tumor microenvironment of stromal cells was poorly understood. We characterized the heterogeneous cell population of precancerous lesions and gastric cancer at the single-cell resolution by RNA sequencing. We identified 10 gastric cell subtypes and showed the intestinal and diffuse-type cancer were characterized by different cell population. We found that the intestinal and diffuse-type cancer cells have the differential metaplastic cell lineages: intestinal-type cancer cells differentiated along the intestinal metaplasia lineage while diffuse-type cancer cells resemble de novo pathway. We observed an enriched CCND1 mutation in premalignant disease state and discovered cancer-associated fibroblast cells harboring pro-stemness properties. In particular, tumor cells could be categorized into previously proposed molecular subtypes and harbored specific subtype of malignant cell with high expression level of epithelial-myofibroblast transition which was correlated with poor clinical prognosis. In addition to intratumoral heterogeneity, the analysis revealed different cellular lineages were responsible for potential carcinogenetic pathways. Single-cell transcriptomes analysis of gastric pre-cancerous lesions and cancer may provide insights for understanding GC cell behavior, suggesting potential targets for the diagnosis and treatment of GC.

Which gastric cancer patients could benefit from staging laparoscopy? A GIRCG multicenter cohort study

BackgroundThis study aimed to investigate which gastric cancer patients could benefit the most from staging laparoscopy. MethodsA retrospective cohort study was carried out, including 316 (216 cM- and 100 cM+) gastric cancer patients who had undergone staging laparoscopy between 2010 and 2020 in seven GIRCG centers. A model including easily-accessible clinical, biochemical and pathological markers was constructed to predict the risk of carcinomatosis. ROC curve and decision curve analyses were used to verify its accuracy and net benefit. ResultsIn the cM-population staging laparoscopy could detect 67 cases who had peritoneal carcinomatosis or positive cytology, for a yield of 30.5%. In cM-patients, intestinal type tumors (0.25, 0.12–0.51; p = 0.002), cT4 tumors (2.18, 1.11–4.28; p = 0.023) and cancers of the lower third (0.31, 0.14–0.70; p = 0.004) were associated with the presence of peritoneal carcinomatosis and/or positive cytology. The ROC curve analysis of the model including the three variables showed an AUC of 0.75 (0.68–0.81, p < 0.001). The decision curve analyses showed that the model had a higher net benefit than the treating all strategy between threshold probabilities of 15 and 50%. ConclusionsStaging laparoscopy is a useful tool to address the patient with gastric cancer to the most adequate treatment. In cM-patients the assessment of the location of the tumor, the Lauren's histotype and the cT status may help in providing additional elements in indicating or not the use of staging laparoscopy.

Time to Classify Tumours of the Stomach and the Kidneys According to Cell of Origin.

Malignant tumours are traditionally classified according to their organ of origin and whether they are of epithelial (carcinomas) or mesenchymal (sarcomas) origin. By histological appearance the site of origin may often be confirmed. Using same treatment for tumours from the same organ is rational only when there is no principal heterogeneity between the tumours of that organ. Organ tumour heterogeneity is typical for the lungs with small cell and non-small cell tumours, for the kidneys where clear cell renal carcinoma (CCRCC) is the dominating type among other subgroups, and in the stomach with adenocarcinomas of intestinal and diffuse types. In addition, a separate type of neuroendocrine tumours (NETs) is found in most organs. Every cell type able to divide may develop into a tumour, and the different subtypes most often reflect different cell origin. In this article the focus is on the cells of origin in tumours arising in the stomach and kidneys and the close relationship between normal neuroendocrine cells and NETs. Furthermore, that the erythropoietin producing cell may be the cell of origin of CCRCC (a cancer with many similarities to NETs), and that gastric carcinomas of diffuse type may originate from the ECL cell, whereas the endodermal stem cell most probably gives rise to cancers of intestinal type.

Methylation silencing of ULK2 via epithelial-mesenchymal transition causes transformation to poorly differentiated gastric cancers.

Diffuse-type gastric cancers (DGC) typically have a poor prognosis related to their invasion and metastasis, in which the epithelial-mesenchymal transition (EMT) is the initiation step. ULK2 plays a role in the autophagy initiation, which might provide a survival advantage in cancer cells. Although knock-down of ULK2 reportedly induces autophagy and EMT in a lung cancer cell line, the mechanism of EMT via the down-regulation of ULK2, as well as its clinical significance, remains yet unclear. The present study, therefore, aims at clarifying this mechanism and its clinical significance in gastric cancers. We examined ULK2 mRNA expression in gastric cancer tissues and normal gastric tissues of healthy people. The effects of knock-downed ULK2 were examined in two gastric cancer cells, which were investigated in terms of their gene expression changes by the mRNA microarray. ULK2 was strongly expressed in intestinal-type cancers but was scarcely expressed in DGC by immunohistochemical staining. Furthermore, we found that ULK2 was methylated in DGC and was unmethylated in corresponding adjacent normal tissues. Then, we validated whether knock-down of ULK2 could induce autophagy, cell migration, and EMT in NUGC3 and MKN45 cells. Using mRNA microarray analysis, we confirmed that knock-down of ULK2 changed expressions of oncogenic genes associated with cell migration and EMT. Autophagy inhibitor suppressed cell migration and EMT induced by knock-down of ULK2 in NUGC3 and MKN45. Methylation silencing of ULK2 could induce cell migration and EMT by means of autophagy induction, causing transformation to poorly differentiated cancers.

783Lifetime alcohol intake and stomach cancer risk: a pooled analysis of two prospective cohort studies

Abstract Background Alcohol consumption is causally linked to several cancer sites but the evidence for stomach cancer is still inconclusive. We aimed to quantify the association between alcohol intake and risk of stomach cancer, including subtypes. Methods We pooled data from two cohort studies including 452,958 individuals enrolled in the European Prospective Investigation into Cancer in 1992-98 and 38,756 Australians enrolled in the Melbourne Collaborative Cohort Study in 1990-94. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) for incident stomach cancer were estimated using Cox regression. Results 1,225 incident stomach cancers were diagnosed over 7,094,637 person-years. Alcohol intake was not associated with overall stomach cancer risk. We observed a weak positive dose-response association for lifetime intake with non-cardia stomach cancer (HR = 1.03, 95% CI: 1.00-1.06/per 10 g/day increment), which is the more common type (77.6% of cases), and a weak inverse association with cardia cancer (HR = 0.93, 95% CI: 0.87-1.00) (phomogeneity=0.006). These associations did not differ appreciably by smoking or Helicobacter pylori infection status. Differences in HRs between diffuse-type and intestinal-type cancer were minimal (phomogeneity=0.97). HRs of 1.50 (95% CI: 1.12-2.01) for non-cardia and 0.53 (95% CI: 0.27-1.02) for cardia cancer were observed for a life course trajectory characterised by sustained heavy drinking compared with light drinking (phomogeneity=0.01). Conclusions Lifetime alcohol intake was associated with increased risk of non-cardia stomach cancer. The inverse association for cardia cancer indicates aetiologic differences between subsites. Key messages Limiting long-term alcohol consumption, and avoiding heavy use in particular, might be beneficial in preventing non-cardia stomach cancer.

Evaluation of miR-21 Expression in the Gastric Mucosa of Patients with Chronic Gastritis as the Predictive Factor of Gastric Cancer

The aim of the study was to evaluate the potential of miR-21 expression in the gastric mucosa as the marker of early stage gastric adenocarcinoma and cancer development. Material and methods . The study included the following materials: the first group consisted of surgical material of 60 stomachs (gastric cancer of intestinal type), in each case, 1 fragment of tumor tissue and 4 specimens of the gastric mucosa of the distant zone (2 – antrum mucosa and 2 – fundal mucosa) were taken; the second group consisted of biopsy material of 62 cases in patients with chronic gastritis (5 specimens according to the OLGA-system protocol). The level of miR-21 expression in tissues was determined by reverse transcription polymerase chain reaction. Results. miR-21 expression in samples with gastric cancer was significantly higher (median – 158, p=0.0006) compared with the group of endoscopic biopsies of the gastric mucosa (median – 42). The highest level of expression was observed in adenocarcinoma tissues (median – 270), while there were no significant differences when comparing it with the level of miR-21 expression in samples of the distant zone mucosa (p=0.2).тIncreased miR-21 expression may indicate the high risk group of developing gastric adenocarcinoma, probablyтbefore the appearance of histological signs of neoplasia. Conclusion. Regression analysis performed to confirm the predictive potential of miR-21 expression demonstrated 13-fold increased risk of adenocarcinoma development associated with an increase in miR-21 levels for every 50 units of relative expression normalized to small U6 RNA. The constructed statistical model, which includes morphological criteria for evaluating the gastric mucosa and miR-21 expression, may reflect the degree of violation of cellular epigenetic molecular pathways and allows increasing the prognostic value of a biopsy investigation and the accuracy of a stratified assessment of the gastric adenocarcinoma risk development

Survival of Stomach Cancer Patients in Western Kazakhstan: a Registry-Based Study

Introduction: Stomach cancer is the fourth most common cancer worldwide. Although there is a lot of international evidence on survival of stomach cancer patients, the data from Central Asia is still scarce. Aims: To study one- and five-years survival of stomach cancer patients and its correlates in Western Kazakhstan. Methods: All histologically confirmed cases of stomach cancer (ICD10 code: C16) registered from 2015 to 2019 in the Aktobe region, Western Kazakhstan, were included in a registry-based historical cohort study. One- and five-years survival with 95 % confidence intervals (CI) was calculated by life tables method. Independent associations between survival and its correlates were studied using Cox regression and presented as crude and adjusted hazard ratios (HR). Results: Altogether, there were 793 new cases of and 587 deaths from stomach cancer in the Aktobe region over the study period. Sixty-five percent of cases were diagnosed at stage III or IV. The overall one- and five-year survival was 33.1 % and 8.4 %, respectively. Significant differences in survival functions across categories were observed for cancer stage (p &lt; 0.001), morphological type (p &lt; 0.001) and ethnic background (p = 0.017). After adjustment, only stage and morphological type of tumor remained significantly associated with the out come. Stage III (HR = 2.3, 95 % CI: 1.5-3.6) and stage IV (HR = 4.4, 95 % CI: 2.8-6.9) were associated with shorter survival compared to the reference category. Patients with intestinal type of cancer were more likely to survive longer (HR = 0.7, 95 % CI: 0.6-0.8). Conclusions: High proportion of cases diagnosed at advance stage and low survival warrant urgent measures on both population and institutional levels. Preventive activities, increased awareness of the population and implementation of routine screening should be among the priority actions to improve survival of stomach cancer patients and decrease cancer mortality in Western Kazakhstan.

Circulating CEA-positive and EpCAM-negative tumor cells might be a predictive biomarker for recurrence in patients with gastric cancer.

It has been reported that circulating tumor cells (CTCs) are beneficial for predicting tumor stage or treatment response. Although epithelial cell adhesion molecules (EpCAMs) and cytokeratin (CK) have been often used for the identification of CTCs, other tumor markers have not been fully investigated as detecting tools for CTCs. Thus, this study aims to clarify the significance of carcinoembryonic antigen (CEA, CD66e)‐positive CTCs in patients with gastric cancer. A total of 150 patients with gastric cancer were enrolled in this study. The mononuclear fraction of peripheral blood was enriched by Ficoll. The number of cells was enumerated depending on the positivity of EpCAM and CEA or CK by flow cytometry. The association of these cells with clinicopathologic characteristics was investigated. The mean age was 70 (range 28–92). The macroscopic type of gastric cancer was classified as 0/1/2/3/4/5 in 59/11/22/38/16/4 patients, respectively. Seventy‐one patients (47.3%) were diagnosed with intestinal‐type cancer, while 76 patients (50.7%) were diagnosed with the diffuse type. The mean numbers of cells with EpCAM−CK+, EpCAM+CK−, EpCAM+CK+, EpCAM−CEA+, EpCAM+CEA−, and EpCAM+CEA+ were 618, 237, 19.9, 1147, 291, and 7.41, respectively. The number of EpCAM−CEA+cells was significantly higher in patients with stage II–III and IV than in patients with stage I. The 3‐year RFS rate in patients with a high number of EpCAM−CEA+cells (>=622) was 57.5%, while it was 79.3% in patients with a low number of EpCAM−CEA+cells (<622) (log‐rank p = 0.0079). Thus, we conclude that CEA‐positive CTCs will be a clinically beneficial biomarker in patients with gastric cancer.

White-Light Endoscopy Versus Magnifying Narrow-Band Imaging for Diagnosis of the Histological Subtype of Gastric Cancer

Background: Distinguishing gastric cancer from non-cancer using endoscopy has already been validated. However, distinguishing undifferentiated-type (diffuse-type) from differentiated-type (intestinal-type) cancer is also crucial for determining the indication of endoscopic resection for gastric cancer. This study aimed to evaluate on-site diagnostic performance of conventional white-light endoscopy (WLE) and magnifying narrow-band imaging (M-NBI) in determining the subtype of gastric cancer. Methods: We conducted a multicenter prospective single-arm trial. This study was registered with UMIN Clinical Trials Registry, number UMI32151. Patients who planned to undergo treatment for histologically proven cT1 gastric cancer were recruited from six tertiary care institutions. The primary and key secondary endpoints were diagnostic accuracy and specificity, respectively. The diagnostic algorithm of WLE was based on lesion color. The M-NBI algorithm was based on the microsurface and microvascular patterns. Findings: A total of 208 patients were enrolled. After protocol endoscopy, 167 gastric cancers were included in the analysis. The accuracy, sensitivity, specificity, and positive likelihood ratio of WLE for undifferentiated-type cancer were 80% (95% CI 73%–86%), 69% (53%–82%), 84% (77%–90%), and 4·4 (2·8–7·0), respectively. Those of M-NBI were 82% (75%–88%), 53% (38%–68%), 93% (87%–97%), and 7·2 (3·6–14·4), respectively. There was no significant difference in accuracy between WLE and M-NBI (p = 0·755), but specificity was significantly higher with M-NBI than with WLE (p = 0·041). Those of M-NBI combined with WLE were 81% (74%–87%), 38% (24%–54%), 97% (92%–99%), and 11·5 (4·1–32·4), respectively. Interpretation: M-NBI is more specific than WLE in distinguishing undifferentiated-type from differentiated-type gastric cancer. M-NBI combined with WLE is highly reliable (positive likelihood ratio >10) for diagnosing the subtype of gastric cancer, and optical biopsy may be introduced to determine the indication for endoscopic resection of gastric cancer. Trial Registration: UMIN Clinical Trials Registry, number UMI32151 Funding: The Yasuda Medical Foundation. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This multicenter, prospective, single-arm, phase II trial was conducted in accordance with the Declaration of Helsinki and Ethical Guidelines for Medical and Health Research Involving Human Subjects. The study protocol was approved by the Institutional Review Board of Osaka International Cancer Institute on December 22, 2017 (approval number: 1712226191) and each participating institution. All participants provided written informed consent.

S3305 Surgical Outcomes of Gastric Cancer Patients Seen at a Safety Net Hospital in an Urban Academic Setting

INTRODUCTION: Gastric cancer remains a significant public health concern, and it is the third leading cause of cancer related deaths worldwide. We evaluated surgical outcomes in gastric cancer patients seen at a safety-net hospital with a high immigrant patient population. METHODS: A retrospective study was conducted to identify patients diagnosed with gastric cancer between 2010 and 2019 (N = 111) at our institution. All cases were histologically confirmed. Data on demographics, pathology, type of gastric cancer, surgery, and chemotherapy were obtained. Kaplan Meier and Cox regression analyses were used to evaluate factors associated with survival. Hazard ratios (HR) and confidence intervals (CI) are reported. RESULTS: Of the 111 patients with gastric cancer included in this study, 41.2% of patients underwent surgery; of which 26.2% were proximal, 52.4% were distal, and 21.4% were total gastrectomies (Table 1). Also, 61.9% of the surgeries were radical, and 38.1% palliative. Likewise, 68.4% had chemotherapy, of which 27.3% was neoadjuvant, 9.1% was adjuvant, and 63.6% was palliative. Gastric adenocarcinoma types were diffuse-type (61%), intestinal-type (33%), and mixed-type (6%). Diffuse-type cancer was more common in the younger population (≤40 years) compared to the older population, >40 years (P = 0.01). Mortality was significantly lower in those who had surgery (HR 0.36 CI 0.18–0.78), chemotherapy (HR 0.43 CI 0.23–0.80) compared to those who did not (P < 0.001). furthermore, patients who had neoadjuvant chemotherapy had a lower mortality compared to those who received palliative chemotherapy (HR 0.37 CI 0.15–0.89). Although survival appeared to be higher in patients with intestinal-type cancer compared to those with diffuse-type cancer who underwent surgery, this difference was not statistically significant (P = 0.136) See Figure 1. CONCLUSION: Gastric cancer surgery was associated with a lower mortality in our patient population. Also, multimodal therapy including surgery, chemotherapy, and neoadjuvant chemotherapy all improved survival outcomes. There was no difference in survival between patients with intestinal-type cancer compared to those with diffuse-type cancer who underwent surgery. In addition, the fact that diffuse-type cancer was more common in the younger population suggest that genetics may play a major role in these gastric cancer subtype. Further research is needed to identify pertinent prognostic indicators in gastric cancer patients.Figure 1Table 1.: Gastric cancer percentages for surgery and chemotherapy

Application of artificial intelligence using a convolutional neural network for diagnosis of early gastric cancer based on magnifying endoscopy with narrow-band imaging.

Background and AimMagnifying endoscopy with narrow‐band imaging (ME‐NBI) has made a huge contribution to clinical practice. However, acquiring skill at ME‐NBI diagnosis of early gastric cancer (EGC) requires considerable expertise and experience. Recently, artificial intelligence (AI), using deep learning and a convolutional neural network (CNN), has made remarkable progress in various medical fields. Here, we constructed an AI‐assisted CNN computer‐aided diagnosis (CAD) system, based on ME‐NBI images, to diagnose EGC and evaluated the diagnostic accuracy of the AI‐assisted CNN‐CAD system.MethodsThe AI‐assisted CNN‐CAD system (ResNet50) was trained and validated on a dataset of 5574 ME‐NBI images (3797 EGCs, 1777 non‐cancerous mucosa and lesions). To evaluate the diagnostic accuracy, a separate test dataset of 2300 ME‐NBI images (1430 EGCs, 870 non‐cancerous mucosa and lesions) was assessed using the AI‐assisted CNN‐CAD system.ResultsThe AI‐assisted CNN‐CAD system required 60 s to analyze 2300 test images. The overall accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the CNN were 98.7%, 98%, 100%, 100%, and 96.8%, respectively. All misdiagnosed images of EGCs were of low‐quality or of superficially depressed and intestinal‐type intramucosal cancers that were difficult to distinguish from gastritis, even by experienced endoscopists.ConclusionsThe AI‐assisted CNN‐CAD system for ME‐NBI diagnosis of EGC could process many stored ME‐NBI images in a short period of time and had a high diagnostic ability. This system may have great potential for future application to real clinical settings, which could facilitate ME‐NBI diagnosis of EGC in practice.

Biomass Smoke Exposure Is Associated With Gastric Cancer and Probably Mediated Via Oxidative Stress and DNA Damage: A Case-Control Study.

PURPOSEWe investigated the association between gastric cancer and environmental and dietary exposures. In addition, we explored probable mechanistic pathways for the influence of biomass smoke on gastric carcinogenesis.PATIENTS AND METHODSThe study was conducted in Lusaka, Zambia. Questionnaires were used to collect data on risk factors, whereas enzyme-linked immunosorbent assays and high-performance liquid chromatography were used to measure biologic exposures. Study data were analyzed using contingency tables and logistic regression.RESULTSWe enrolled 72 patients with gastric adenocarcinoma and 244 controls. Gastric cancer was positively associated with rural residence (odds ratio [OR], 2.9; 95% CI, 1.5 to 5.3), poverty (OR, 4.2; 95% CI, 1.9 to 9.1), and daily consumption of processed meat (OR, 6.4; 95% CI, 1.3 to 32) and negatively associated with consumption of green vegetables (OR, 0.2; 95% CI, 0.1 to 0.5). Gastric cancer was also associated with biomass smoke exposure (OR, 3.5; 95% CI, 1.9 to 6.2; P < .0001), an association that was stronger for intestinal-type cancers (OR, 3.6; 95% CI, 1.5 to 9.1; P = .003). Exposure to biomass smoke in controls was associated with higher urinary levels of 8-isoprostane (P < .0001), 8-hydroxydeoxyguanosine (P = .029), and 1-hydroxypyrene (P = .041). Gastric cancer was not associated with biochemical measures of current exposure to aflatoxins or ochratoxins.CONCLUSIONIn Zambia, exposure to biomass smoke, daily consumption of processed meat, and poverty are risk factors for gastric cancer, whereas daily consumption of green vegetables is protective against gastric cancer. Exposure to biomass smoke was associated with evidence of oxidative stress and DNA damage, suggesting mechanistic plausibility for the observed association, and the association was restricted to intestinal-type gastric cancer.

Risk of gastric cancer in the second decade of follow-up after Helicobacter pylori eradication

Background and aimsEradication of Helicobacter pylori reduces the risk of gastric cancer. In this study, we investigated the risk beyond 10 years after eradication of H. pylori.MethodsWe conducted a retrospective cohort study of 2737 patients who had yearly endoscopic follow-up after cure of H. pylori infection. For comparison of gastric cancer risk in the second decade of follow-up with that in the first decade, we calculated standardized incidence ratios (SIRs) by dividing the number of observed cases of gastric cancer in the second decade of follow-up by that of expected cases which was estimated using the incidence rate ratio of age in the first decade.ResultsDuring the follow-up for as long as 21.4 years (mean 7.1 years), gastric cancer developed in 68 patients (0.35% per year). The SIRs for diffuse-type gastric cancer was infinity (0 expected case and 4 observed cases) in patients with mild gastric mucosal atrophy and 10.9 (95% confidence interval 4.53–26.1) with moderate atrophy, whereas no significant increase of SIRs was observed in intestinal-type cancer regardless of the grade of baseline gastric atrophy or in diffuse-type cancer in patients with severe atrophy even though who had the highest risk.ConclusionsThe longer the follow-up, the greater the risk of developing diffuse-type gastric cancer becomes in patients with mild-to-moderate gastric atrophy at baseline. Endoscopic surveillance should be continued beyond 10 years after cure of H. pylori irrespective of the severity of gastric atrophy.

Evaluation of toll-like receptors as prognostic biomarkers in gastric cancer: high tissue TLR5 predicts a better outcome

Toll-like receptors (TLRs), key proteins in innate immunity, appear to contribute to the inflammatory environment in carcinogenesis. Thus, we aimed to evaluate the tissue expressions of TLR1, TLR2, TLR4, TLR5, TLR7, and TLR9 as potential prognostic biomarkers in gastric cancer. We applied immunohistochemistry to study tissue samples from 313 patients operated on for gastric adenocarcinoma between 2000 and 2009 at the Department of Surgery, Helsinki University Hospital, Finland. A high expression of each TLR studied associated with the high expression of each other and with the intestinal-type histology (p < 0.001 for all). Five-year disease-specific survival among patients with a high TLR5 was 53.4% (95% confidence interval [CI] 43.4–63.4), whereas among patients with a low TLR5 it was 37.6% (95% CI 30.0–45.2; p = 0.014). A high TLR5 expression functioned as a marker of a better prognosis, particularly among those with a stage II disease (hazard ratio [HR] 0.33; 0.13–0.83; p = 0.019) or an intestinal-type cancer (HR 0.58; 95% CI 0.34–0.98; p = 0.043). In this study we show, for the first time, that a high TLR5 tissue expression may identify gastric cancer patients with a better prognosis, particularly among those with a stage II disease or an intestinal-type cancer.

Helicobacter pylori and cytokine gene variants as predictors of premalignant gastric lesions.

Gastric cancer remains the third leading cause of mortality from cancer worldwide and carries a poor prognosis, due largely to late diagnosis. The importance of the interaction between Helicobacter pylori (H. pylori) infection, the main risk factor, and host-related genetic factors has been studied intensively in recent years. The genetic predisposition for non-hereditary gastric cancer is difficult to assess, as neither the real prevalence of premalignant gastric lesions in various populations nor the environmental risk factors for cancer progression are clearly defined. For non-cardiac intestinal-type cancer, identifying the factors that modulate the progression from inflammation toward cancer is crucial in order to develop preventive strategies. The role of cytokines and their gene variants has been questioned in regard to non-self-limiting H. pylori gastritis and its evolution to gastric atrophy and intestinal metaplasia; the literature now includes various and non-conclusive results on this topic. The influence of the majority of cytokine single nucleotide polymorphisms has been investigated for gastric cancer but not for preneoplastic gastric lesions. Among the investigated gene variants onlyIL10T-819C, IL-8-251, IL-18RAP917997, IL-22 rs1179251, IL1-B-511, IL1-B-3954, IL4R-398 and IL1RN were identified as predictors for premalignant gastric lesions risk. One of the most important limiting factors is the inhomogeneity of the studies (e.g., the lack of data on concomitant H. pylori infection, methods used to assess preneoplastic lesions, and source population). Testing the modifying effect of H. pylori infection upon the relationship between cytokine gene variants and premalignant gastric lesions, or even testing the interaction between H. pylori and cytokine gene variants in multivariable models adjusted for potential covariates, could increase generalizability of results.

Immunistochemical Analysis of the Expression of TGFβ, Galectin-1, Vimentin, and Thrombospondin in Gastric Cancer Associated with Systemic Undifferentiated Connective Tissue Dysplasia.

We performed immunohistochemical analysis of the expression of TGFβ, galectin-1, vimentin, and thrombospondin in the mucosa in gastric cancer of diffuse and intestinal type associated with systemic undifferentiated connective tissue dysplasia. In diffuse gastric cancer, both with and without association with connective tissue dysplasia, a higher level of expression of TGFβ, galectin-1, vimentin, and thrombospondin in the tumor was detected in comparison with the perifocal and tumor zones in intestinal gastric cancer, which may reflect the pathogenetic peculiarities of the two histotypes of gastric cancer. Intestinal type of gastric cancer associated with connective tissue dysplasia is characterized by a high level of expression of galectin-1 and vimentin in the perifocal zone and TGFβ in the tumor zone. The pattern of expression of the studied markers can reflect both the pathogenetic peculiarities of the two histotypes of gastric cancer and peculiar expression of some growth factors, cytoskeleton proteins, and matrix-cell proteins associated with undifferentiated connective tissue dysplasia which may contribute to epithelial-mesenchymal transition.

High serum MMP-14 predicts worse survival in gastric cancer.

Matrix metalloproteinases (MMPs), endopeptidases with diverse biochemical functions, can promote cancer cell invasion and metastasis by degrading the extracellular matrix. A high matrix metalloproteinase-14 (MMP-14) expression in gastric cancer tissue has been associated with metastasis and poor prognosis. To further understand this association, we investigated serum MMP-14 as a biomarker in gastric cancer patients. The patient cohort consisted of 240 gastric adenocarcinoma patients who underwent surgery at Helsinki University Hospital, Finland, between 2000 and 2009. We determined the soluble MMP-14 serum levels using an enzyme-linked immunosorbent assay. We then calculated the associations between serum levels and clinicopathologic variables using the Mann-Whitney U-test or the Kruskal-Wallis test. We constructed survival curves using the Kaplan-Meier method and calculating the hazard ratios using the Cox proportional hazard model. We revealed a positive association between a high serum MMP-14 level and stages III–IV (p = 0.029), and between a high serum MMP-14 and distant metastasis (p = 0.022). Patients with a low serum MMP-14 had a 5-year disease-specific survival of 49.2% (95% confidence interval [CI] 45.5–52.9), whereas patients with a high serum MMP-14 had a 5-year survival of 22.1% (95% CI 15.2–29.0; p = 0.001). High serum MMP-14 was a statistically significant prognostic factor among patients with an intestinal type of cancer (hazard ratio [HR] 3.54; 95% CI 1.51–8.33; p = 0.004), but not among patients with a diffuse type. The serum MMP-14 level remained an independent prognostic factor in our multivariate survival analysis (HR 1.55; 95% CI 1.02–2.35; p = 0.040). This study indicates for the first time that high serum soluble MMP-14 levels in gastric cancer serves as a marker for a poor prognosis, possibly indicating the presence of distant metastases.