Inverse association between age and risk of lymph node metastasis in patients with early gastric cancer: a surveillance, epidemiology, and end results analysis.

Background: Recent studies have shown that young patients with gastric cancer are at a more advanced stage and have poor survival, but the cause is still unclear. The prognosis of gastric cancer is closely related to LNM, but the relationship between age and LNM in early gastric cancer (EGC) is currently unclear. Therefore, we aimed to study the relationship between age and the risk of LNM in EGC. Materials and Methods: We screened out patients with EGC who underwent surgery from the SEER research database from 1975 to 2016, and retrospectively analyzed the proportion of LNM in different age groups. We grouped age into 18-39, 40-49, 50-59, 60-69, 70-79, and ≥ 80 years old, and used univariate analysis and multivariate logistic regression to analyze the correlation between age and LNM. Results: We included 9231 patients with EGC, with LNM rates of 20.3%, 23.3%, 21.0%, 19.8%, 18.1%, and 13.2% in the age groups of 18-39 years old (2.3%), 40-49 (6.1%), 50-59 years old (15.7%), 60-69 years old (24.8%), 70-79 years old (27.2%) and ≥80 years old (23.9%), respectively. We found that when older than 39 years old, the risk of LNM and postoperative survival time of EGC patients decrease (p<0.001). Multivariate analysis results showed that age, tumor size, the number of retrieved lymph nodes (rN), tumor grade, and tumor location were related to LNM. Conclusions: This study found that age in patients with EGC was inversely related to the risk of LNM, and positively correlated with postoperative survival. For older patients with EGC, endoscopic treatment is more appropriate. For young patients with EGC, LNM should be considered when choosing endoscopic treatment.

Microvesicles from bone marrow-derived mesenchymal stem cells promote Helicobacter pylori-associated gastric cancer progression by transferring thrombospondin-2.

BACKGROUND: Our previous study found that bone marrow-derived mesenchymal stem cells (BMSCs) promote Helicobacter pylori (H pylori)-associated gastric cancer (GC) progression by secreting thrombospondin-2 (THBS2). Extracellular vesicles (EVs) are important carriers for intercellular communication, and EVs secreted by BMSCs have been shown to be closely related to tumor development. The aim of this study was to investigate whether BMSC-derived microvesicles (MVs, a main type of EV) play a role in H. pylori-associated GC by transferring THBS2. METHODS: BMSCs and THBS2-deficient BMSCs were treated with or without the supernatant of H. pylori for 12 h at a multiplicity of infection of 50, and their EVs were collected. Then, the effects of BMSC-derived MVs and THBS2-deficient BMSC-derived MVs on the GC cell line MGC-803 were assessed by in vitro proliferation, migration, and invasion assays. In addition, a subcutaneous xenograft tumor model, a nude mouse intraperitoneal metastasis model, and a tail vein injection metastasis model were constructed to evaluate the effects of BMSC-derived MVs and THBS2-deficient BMSC-derived MVs on GC development and metastasis in vivo. RESULTS: BMSC-derived MVs could be readily internalized by MGC-803 cells. BMSC-derived MVs after H. pylori treatment significantly promoted their proliferation, migration and invasion in vitro (all P < 0.05) and promoted tumor development and metastasis in a subcutaneous xenograft tumor model, a nude mouse intraperitoneal metastasis model, and a tail vein injection metastasis model in vivo (all P < 0.05). The protein expression of THBS2 was significantly upregulated after H. pylori treatment in BMSC-derived MVs (P < 0.05). Depletion of the THBS2 gene reduces the tumor-promoting ability of BMSC-MVs in an H. pylori infection microenvironment both in vitro and in vivo. CONCLUSION: Overall, these findings indicate that MVs derived from BMSCs can promote H. pylori-associated GC development and metastasis by delivering the THBS2 protein. Video Abstract.

Glucocorticoid receptor-mediated Nr1d1 chromatin circadian misalignment in stress-induced irritable bowel syndrome.

Stress-elevated glucocorticoids cause circadian disturbances and gut-brain axis (GBA) disorders, including irritable bowel syndrome (IBS). We hypothesized that the glucocorticoid receptor (GR/NR3C1) might cause chromatin circadian misalignment in the colon epithelium. We observed significantly decreased core circadian gene Nr1d1 in water avoidance stressed (WAS) BALB/c colon epithelium, like in IBS patients. WAS decreased GR binding at the Nr1d1 promoter E-box (enhancer box), and GR could suppress Nr1d1 via this site. Stress also altered GR binding at the E-box sites along the Ikzf3-Nr1d1 chromatin and remodeled circadian chromatin 3D structures, including Ikzf3-Nr1d1 super-enhancer, Dbp, and Npas2. Intestinal deletion of Nr3c1 specifically abolished these stress-induced transcriptional alternations relevant to IBS phenotypes in BALB/c mice. GR mediated Ikzf3-Nr1d1 chromatin disease related circadian misalignment in stress-induced IBS animal model. This animal model dataset suggests that regulatory SNPs of human IKZF3-NR1D1 transcription through conserved chromatin looping have translational potential based on the GR-mediated circadian-stress crosstalk.

A novel intelligent chromo capsule endoscope for the diagnosis of neoplastic lesions in the gastrointestinal tract.

Background: Chromoendoscopy has not been fully integrated into capsule endoscopy. This study aimded to develop and validate a novel intelligent chromo capsule endoscope (ICCE). Methods: The ICCE has two modes: a white-light imaging (WLI) mode and an intelligent chromo imaging (ICI) mode. The performance of the ICCE in observing colors, animal tissues, and early gastrointestinal (GI) neoplastic lesions in humans was evaluated. Images captured by the ICCE were analysed using variance of Laplacian (VoL) values or image contrast evaluation. Results: For color observation, conventional narrow-band imaging endoscopes and the ICI mode of the ICCE have similar spectral distributions. Compared with the WLI mode, the ICI mode had significantly higher VoL values for animal tissues (2.154 ± 1.044 vs 3.800 ± 1.491, P = 0.003), gastric precancerous lesions and early gastric cancers (2.242 ± 0.162 vs 6.642 ± 0.919, P < 0.001), and colon tumors (3.896 ± 1.430 vs 11.882 ± 7.663, P < 0.001), and significantly higher contrast for differentiating tumor and non-tumor areas (0.069 ± 0.046 vs 0.144 ± 0.076, P = 0.005). More importantly, the sensitivity, specificity, and accuracy of the ICI mode for early GI tumors were 95.83%, 91.67%, and 94.64%, respectively, which were significantly higher than the values of the WLI mode (78.33% [P < 0.001], 77.08% [P = 0.01], and 77.98% [P < 0.001], respectively). Conclusions: We successfully integrated ICI into the capsule endoscope. The ICCE is an innovative and useful tool for differential diagnosis based on contrast-enhanced images and thus has great potential as a superior diagnostic tool for early GI tumor detection.

Tumor size as a significant prognostic factor in T1 gastric cancer: a Surveillance, Epidemiology, and End Results (SEER) database analysis.

BACKGROUND: It has previously been observed that the prognostic value of tumor size varied according to different stages patients enrolled in gastric cancer. We aimed to investigate the influence of T stage on the prognostic and predicting value of tumor size. MATERIAL AND METHODS: A total of 13,585 patients with stage I-III gastric cancer were selected from the Surveillance, Epidemiology, and End Results Program (SEER) database. Univariate and multivariate cox regression analysis stratified by T stage were performed. C-index and time-dependent receiver operating characteristic curve (ROC) curve were applied to assess discrimination ability of tumor size and other factors. Nomograms were constructed to further assess the performance of tumor size in a specific model. Calibration ability, discrimination ability, reclassification ability and clinical benefits were executed to judge the performance of models. RESULTS: Stratified analyses according to T stage illustrated that with the increase of T stage, the effect of tumor size on overall survival (OS) and cancer-specific survival (CSS) significantly decreased. Moreover, tumor size showed superior discrimination ability in T1 gastric cancer, outperformed other prognostic factors in predicting both CSS (C-index: 0.666, AUC: 0.687) and OS (C-index: 0.635, AUC: 0.660). The cox regression model included tumor size showed better performance than the model excluded tumor size in every aspect. CONCLUSION: T stage had a negative impact on the predicting value of tumor size. Tumor size showed significant prognostic value in T1 gastric cancer, which may be effective in clinical practice.

Gamma-glutamyltransferase of Helicobacter pylori alters the proliferation, migration, and pluripotency of mesenchymal stem cells by affecting metabolism and methylation status.

Virulence factor gamma-glutamyltransferase (GGT) of H. pylori consumes glutamine (Gln) in the stomach to decrease the tricarboxylic acid metabolite alpha-ketoglutarate (α-kg) and alter the downstream regulation of α-kg as well as cellular biological characteristics. Our previous research indicated that under H. pylori infection, mesenchymal stem cells (MSCs) migrated to the stomach and participated in gastric cancer (GC) development either by differentiating into epithelial cells or promoting angiogenesis. However, how MSCs themselves participate in H. pylori-indicated GC remains unclear. Therefore, a GGT knockout H. pylori strain (Hp-KS-1) was constructed, and downstream histone H3K9 and H3K27 methylation and the PI3K/AKT signaling pathway of α-kg were detected using Western blotting. The biological characteristics of MSCs were also examined. An additive α-kg supplement was also added to H. pylori-treated MSCs to investigate alterations in these aspects. Compared to the control and Hp-KS-1 groups, H. pylori-treated MSCs reduced Gln and α-kg, increased H3K9me3 and H3K27me3, activated the PI3K-AKT signaling pathway, and promoted the proliferation, migration, self-renewal, and pluripotency of MSCs. The addition of α-kg rescued the H. pylori-induced alterations. Injection of MSCs to nude mice resulted in the largest tumors in the H. pylori group and significantly reduced tumor sizes in the Hp-KS-1 and α-kg groups. In summary, GGT of H. pylori affected MSCs by interfering with the metabolite α-kg to increase trimethylation of histone H3K9 and H3K27, activating the PI3K/AKT signaling pathway, and promoting proliferation, migration, self-renewal, and pluripotency in tumorigenesis, elucidating the mechanisms of MSCs in GC development.

Confocal Laser Endomicroscopy Can Improve the Diagnosis Rate and Range Assessment of Patients With Conflicting Chronic Atrophic Gastritis Results of White Light Endoscopic and Pathological Diagnosis.

Background and Aims: Chronic atrophic gastritis (CAG) is closely related to the development of gastric cancer. However, the diagnostic accuracy of white light endoscopy (WLE) biopsy for CAG is poor. The diagnostic role and efficacy of confocal laser endomicroscopy (CLE) in CAG missed under WLE biopsy remain unclear. Methods: This study is a single-center prospective study that included 21 patients from 1,349 patients who underwent WLE and biopsy and whose WLE results confirmed CAG, but pathological results did not. Then, all these patients received CLE examination and underwent targeted biopsies and five-point standard biopsies. The sensitivity, specificity, and accuracy of CLE diagnosis and targeted biopsy were analyzed. Results: The pathological results of five-point standard biopsies in 21 patients confirmed CAG, and 17 patients (81.0%) were confirmed to have intestinal metaplasia (IM). According to the image diagnosis of CLE, there were 19 cases (90.5%) of CAG and 14 cases (66.7%) of IM among these 21 patients. According to the targeted biopsy of CLE, 17 cases (81.0%) of CAG and 14 cases (66.7%) of IM were diagnosed. There was no significant difference between CLE image diagnosis and five-point standard biopsies in terms of atrophy severity score (p = 0.927), IM severity score (p = 0.250), atrophy scope score (p = 0.781), and IM scope score (p = 0.195). For CAG, the sensitivity and accuracy of CLE image diagnosis were higher than those of CLE targeted biopsies (90.5% vs. 81.0%, p = 0.331), but for IM, the diagnosis was the same. Conclusions: CLE can improve the diagnosis rate of CAG and can increase the comprehensive assessment of the scope and severity of CAG.

The Gamma-glutamyltransferase gene of Helicobacter pylori can promote gastric carcinogenesis by activating Wnt signal pathway through up-regulating TET1.

AIMS: Helicobacter pylori (Hp) infection plays an important role in the development of gastric cancer. Hp can secrete gamma-glutamyltransferase (GGT), however, the impact of GGT of Hp on the human gastric cells is not clear. Although it has been demonstrated that ten-eleven translocation 1 (TET1) is overexpressed in gastric cancer, the relationship between the GGT of Hp and TET1 has not been studied. The aim of this study was to explore the relationship between GGT and TET1, and the role of TET1 in the development of gastric cancer induced by Hp was also explored. MATERIALS AND METHODS: The correlation between TET1 and prognosis of gastric adenoma cancer was analyzed by bioinformatics. The GGT gene of Hp26695 was knocked out by electroporation with plasmid to construct the GGT knockout strain of Hp (Hp-KS-1). The shTET1 lentivirus transfected GES-1, MGC-803 and SGC-7901 cell lines were constructed. The biological characteristics of the three kind of cells were detected. KEY FINDINGS: TET1 was overexpressed in gastric tissues of Hp infected patients and mice. Bioinformatics analysis showed that in patients with gastric cancer, higher TET1 expression would result in poorer prognosis. The GGT gene of Hp can lead to overexpression of TET1 in GES-1, MGC-803 and SGC-7901 cells, along with the activation of Wnt/ß-catenin signaling pathway, and then promoting tumorigenesis. After silencing TET1, the Wnt/ß-catenin signaling pathway which was activated by GGT of Hp was inhibited. SIGNIFICANCE: GGT of Helicobacter pylori can promote gastric carcinogenesis by activating Wnt/ß-catenin signaling pathway trough up-regulating TET1.

Molecular Imaging of Ulex Europaeus Agglutinin in Colorectal Cancer Using Confocal Laser Endomicroscopy (With Video).

BACKGROUND AND STUDY AIMS: Previous studies have identified that colorectal cancer has different fucosylation levels compared to the normal colon. Ulex europaeus agglutinin-I (UEA-I), which specifically combines with α1-2 fucose glycan, is usually used to detect fucosylation levels. Therefore, we used confocal laser endomicroscopy (CLE) to investigate fluorescently labeled UEA-Fluorescein isothiocyanate (FITC) for detecting colonic cancer. PATIENTS AND METHODS: We stained frozen mouse colon tissue sections of normal, adenoma, and adenocarcinoma species with UEA-FITC to detect fucosylation levels in different groups. White light endoscopy and endocytoscopy were first used to detect the lesions. The UEA-FITC was then stained in the mice and human colon tissues in vitro. The CLE was used to detect the UEA-FITC levels of the corresponding lesions, and videos were recorded for quantitation analysis. The diagnostic accuracy of UEA-FITC using CLE was evaluated in terms of sensitivity and specificity. RESULTS: The UEA expression level in colorectal cancer was lower than that in normal intestinal epithelium. The fluorescence intensity ratio of UEA-FITC in colorectal cancer was significantly lower than that in normal tissue detected by CLE in both mice and humans. The combination of UEA-FITC and CLE presented a good diagnostic accuracy with a sensitivity of 95.6% and a specificity of 97.7% for detecting colorectal cancer. The positive and negative predictive values were 91.6% and 95.6%, respectively. Overall, 95.6% of the sites were correctly classified by CLE. CONCLUSIONS: We developed a new imaging strategy to improve the diagnostic efficacy of CLE by using UEA-FITC.

Do neuroendocrine carcinomas and mixed neuroendocrine-non-neuroendocrine neoplasm of the gastrointestinal tract have the same prognosis? A SEER database analysis of 12,878 cases.

BACKGROUND: Neuroendocrine carcinomas (NECs) and mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) in the gastrointestinal (GI) tract are both rare and malignant; however, it is unclear whether their prognosis is the same. METHODS: In this cross-sectional study, a total of 12,878 patients with NEC or MiNEN in the GI tract were reviewed retrospectively by searching the Surveillance, Epidemiology, and End Results (SEER) program database. Next, we compared the characteristics and survival between patients with NEC or MiNEN and further analyzed the prognostic factors for the patients. RESULTS: The data showed that patients with MiNEN had a worse prognosis as compared with patients with pure NEC in the small intestine (SI) and appendix, whereas there was no significant survival difference between NEC and MiNEN in the other parts of the GI system. On the whole, age ⩾55 years (p < 0.0001), male (p = 0.002), being diagnosed at TNM Stage II-IV (p < 0.0001) or not receiving surgical treatment (p < 0.0001) were the independent negative prognostic factors for NEC patients, whereas age ⩾55 years (p = 0.003), being diagnosed at TNM Stage III-IV (p < 0.001) or not receiving surgical treatment (p < 0.001) were identified as the independent negative prognostic factors for the MiNEN patients. Furthermore, when NECs or MiNENs were classified based on the primary tumor site, the results showed that the prognostic factors for NEC and MiNEN varied between the tumor sites. CONCLUSION: The prognostic differences between NECs and MiNENs in the GI tract are heterogeneous and site-related. Patients with appendiceal or SI MiNEN have a poorer prognosis than patients with pure appendiceal or SI NEC. Therefore, we should pay more attention to patients with MiNEN in the SI and appendix and monitor them more closely.

Advanced endoscopic methods in gastrointestinal diseases: a systematic review.

Endoscopic imaging is the main method for detecting gastrointestinal diseases, which adversely affect human health. White light endoscopy (WLE) was the first method used for endoscopic examination and is still the preliminary step in the detection of gastrointestinal diseases during clinical examination. However, it cannot accurately diagnose gastrointestinal diseases owing to its poor correlation with histopathological diagnosis. In recent years, many advanced endoscopic methods have emerged to improve the detection accuracy by endoscopy. Chromoendoscopy (CE) enhances the contrast between normal and diseased tissues using biocompatible dye agents. Narrow band imaging (NBI) can improve the contrast between capillaries and submucosal vessels by changing the light source acting on the tissue using special filters to realize the visualization of the vascular structure. Flexible spectral imaging color enhancement (FICE) technique uses the reflectance spectrum estimation technique to obtain individual spectral images and reconstructs an enhanced image of the mucosal surface using three selected spectral images. The i-Scan technology takes advantage of the different reflective properties of normal and diseased tissues to obtain images, and enhances image contrast through post-processing algorithms. These abovementioned methods can be used to detect gastrointestinal diseases by observing the macroscopic structure of the digestive tract mucosa, but the ability of early cancer detection is limited with low resolution. However, based on the principle of confocal imaging, probe-based confocal laser endomicroscopy (pCLE) can enable cellular visualization with high-performance probes, which can present cellular morphology that is highly consistent with that shown by biopsy to provide the possibility of early detection of cancer. Other endoscopic imaging techniques including endoscopic optical coherence tomography (EOCT) and photoacoustic endoscopy (PAE), are also promising for diagnosing gastrointestinal diseases. This review focuses on these technologies and aims to provide an overview of different technologies and their clinical applicability.